February 2025
Evaluation of C-reactive protein in patients with schizophrenia: A study of 126 cases hospitalized at Ar-Razi psychiatric university hospital in Salé, Morocco
Fouad Laboudı 1, 4, Soukaina Statı 1, 4, El Hassan Ouanouche 3, 5, Zineb Bencharfa 1, 4, Oumaima Seyar 1, 4, Lamia Azızı 1, 4, Soukaina Belafqıh 1, 4, Majdouline Obtel 2, Ryad Tamuza 6, Abderrazak Ouanass 1, 4
1 Department of Psychiatric Emergency, Arrazi Psychiatric University Hospital, Sale, Morocco, 2 Department of Biostatistics, Faculty of Medicine and Pharmacy, Clinical Research and Epidemiology Laboratory, Rabat, Morocco, 3 Higher Institute of Nursing and Health Technology of Tanger, Tanger, Morocco, 4 Department of Psychiatry, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco, 5 Department of Biology, Faculty of Science, Ibn Tofail University, Kenitra, Morocco, 6 Department of Immunology, Hôpital Saint-Louis, Paris, France
DOI: 10.4328/ACAM.22187 Received: 2024-03-20 Accepted: 2024-08-07 Published Online:2024-10-25 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):77-81
Corresponding Author: El Hassan Ouanouche, Department of Biology, Faculty of Science, Ibn Tofail University, Kenitra, Morocco. E-mail: elhassanouanouche@gmail.com P: +212 06 06 14 66 16 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1219-619X
Other Authors ORCID ID: Fouad Laboudı, https://orcid.org/0000-0002-4024-2528 . Soukaina Statı, https://orcid.org/0000-0002-0064-4768 . Zineb Bencharfa, https://orcid.org/0009-0007-1563-8508 . Oumaima Seyar, https://orcid.org/0009-0008-2654-6235 . Lamia Azızı, https://orcid.org/0000-0001-9894-2618 . Soukaina Belafqıh, https://orcid.org/0009-0002-5151-6309 . Majdouline Obtel, https://orcid.org/0000-0002-3357-0603 . Ryad Tamuza, https://orcid.org/0000-0003-3992-9565 . Abderrazak Ouanass, https://orcid.org/0000-0002-2552-1772
This study was approved by the Ethics Committee of Biomedical Research at the Faculty of Medicine (Date: 2022-09-24, No: 60/22)
Aim: In dis study in Morocco, we aimed to explore the inflammatory profile of schizophrenia patients, with a particular focus on the relationship between inflammation, as assessed by CRP levels, and schizophrenia in the active phase.
Material and Methods: A cross-sectional study, analytical study of patients with schizophrenia hospitalised during the study period. Data collection included socio-demographic information, medical history, and clinical assessment, with biological analysis including CRP assay.
Results: The study included 124 participants with schizophrenia and revealed a predominance of males (92.7%) with a median age of 32 years. At admission, 58% had a CRP>6, but this proportion decreased to 23.3% at D15. Clinical assessments, such as PANSS, BPRS, and GAF, showed an improvement in scores at D15. Statistical analyses identified significant differences between the groups in terms of family situation, medical history, and interpretation of the BPRS scale, highlighting the importance of these factors in the variation in CRP levels. The fact of having a medical history and presenting a score of 2 (Moderately ill) on the BPRS scale is a risk factor that multiplies the risk of having a CRP >6 by 3.
Discussion: The hypothesis that immune factors are linked to schizophrenia has been revived, and the role of immune dysfunction and inflammatory processes are validated as contributing elements to the development and relapse of the disease.
Keywords: Schizophrenia, Inflammation, Inflammatory Biomarkers, Morocco
Introduction
Schizophrenia is a psychiatric disorder with a prolonged and disabling course. Its prevalence is estimated at 1% [3]. It is a national and international public health problem and is currently ranked by the World Health Organisation as one of the ten most disabling diseases, especially in young people [3]. The National Survey on the Prevalence of Mental Disorders in the general population aged 15 and over carried out in Morocco revealed that 5.6% suffer from a psychotic disorder [4].
There is no single recognised aetiology for schizophrenia; it is underpinned by an interplay of genetic, environmental and immuno-inflammatory mechanisms [5], so significant evidence is accumulating to suggest that schizophrenia is a heterogeneous syndrome with overlapping symptoms and aetiologies. The high social and personal costs of schizophrenia justify the search for better treatment, diagnosis and prevention strategies [3].
In recent years, there has been a return to the hypothesis that immune factors are associated with schizophrenia [5]. Thus, the role of immune dysfunction and inflammatory processes have been described as factors in the development of schizophrenia and relapse during the course of the illness [6].
A growing number of clinical, epidemiological and experimental studies have shown links between schizophrenia and inflammatory diseases [7]. Studies have shown that the immune system plays an important role in neurodevelopment through the regulation of various neuronal processes, including brain plasticity and the regulation of neurotransmitters [8].
Observational studies have reported positive associations between inflammatory biomarkers and the risk of psychiatric disorders, including schizophrenia [7, 8]. These biomarkers may be direct pathophysiological mechanisms and may therefore serve as true intermediate or surrogate endpoints and may validate new therapeutic targets and pathways, predict response, facilitate patient treatment selection, guide therapeutic regimens and provide the rationale for personalised treatment [1].
C-reactive protein (CRP) is a protein produced by hepatocytes following an acute or chronic inflammatory state. It is a non-specific marker of inflammation that is associated with a number of pathologies, including coronary heart disease, stroke and peripheral vascular disease. Some studies have also suggested that CRP may play a role in the pathogenesis of schizophrenia, while others have suggested that it may be a consequence of the disease or linked to co-morbid conditions such as obesity and smoking [9].
CRP has the advantage of being easily measured by blood sampling and is part of the usual work-up carried out in a hospital [10]. However, few publications have dealt with the association of schizophrenia in the active phase and a biological marker such as CRP in Morocco.
The aim of our study is to investigate the inflammatory profile of Moroccan patients with schizophrenia and to explore the relationship between inflammation assessed by CRP levels in patients with schizophrenia.
Material and Methods
Study Type and Population: This is a cross-sectional, descriptive, and analytical study.
Study Duration: January 1 ,2023 to May 31, 2023.
Inclusion Criteria
• Patients diagnosed with schizophrenia according to DSM-5 criteria.
• Men or women aged 18 and older.
• Hospitalized at Ar-razi Hospital in Salé during the study period.
Exclusion Criteria
• Records with missing data.
• Other psychiatric disorders than schizophrenia.
• Refusal to participate.
Sample Size Calculation: This is a conducted study targeting all patients during the study period.
Data Collection: Data collection was through a questionnaire covering sociodemographic elements, personal and family history, toxic substance consumption, clinical, evolutionary, and therapeutic data of the disease. It focused on the patient and their socio-economic environment, including age, family and socio-professional situation. Clinical and therapeutic characteristics of the disease were assessed using scales: PANSS (Positive and Negative Syndrome Scale), CGI (Clinical Global Impression), GAF (Global Assessment of Functioning Scale), BPRS (Brief Psychiatric Rating Scale), and CDSS (The Calgary Depression Scale for Schizophrenia).
Biological Analysis: Hematological assessment is part of the routine examination in the service, including white blood cell counts, neutrophil counts, lymphocyte counts, liver function tests, kidney function tests, and CRP. For blood sampling and CRP measurement: blood sampling is systematically performed for each admitted patient, ideally within 24 hours of admission, in the morning while fasting. CRP levels are categorized as follows: levels < 6 mg/l (the laboratory’s normal reference value) or > 6 mg/l considered elevated. If it is higher than 6 mg/l, a second CRP measurement for patient monitoring is performed after three weeks of antipsychotic treatment.
Data Management and Statistical Analysis: Data management and statistical analysis were conducted using the JAMOVI software for Windows 2016. Qualitative variables were presented as frequencies and percentages, while quantitative variables were presented as mean standard deviation (SD) or median interquartile range (IQR). The Chi-square test (χ2) or Fisher’s exact test was performed based on specific application conditions to identify differences in proportions of categorical variables between the two groups. Additionally, multivariate logistic regression analyses were used to identify risk factors. All independent variables with a statistically significant value of P < 0.05 between the two groups were considered in the multivariate logistic regression.
Respect for Confidentiality and Anonymity:
Preparation of a dossier to be submitted to the Rabat Ethics Committee (CER): Informed consent form (Consent should be obtained for each participant).
Financial Aspect of the Study: Participants in this study will not be remunerated for their questionnaire responses.
Ethical approval
This study was approved by the Ethics Committee of Ethics Committee for Biomedical Research at the Faculty of Medicine, Rabat (Date: 2022-09-24, No: 60/22).
Results
Descriptive Statistics
Socio-demographic Characteristics
A total of 124 participants meeting the study criteria were included. 92.7% were male, with a median age of 32 [26,38]. More than half (60.7%) had a secondary level of education, 79.0% were unmarried, 90.3% had no profession, and the majority had no prior medical history (81.5%). (table 1)
CRP Characteristics
At admission, 65 (58%) had a CRP level > 6. At Day 15, there was a decrease, with only 21 (23.3%) maintaining levels above 6.
Scale Interpretations
• PANSS: At admission, 35 (28.7%) had a PANSS score > 86 (notoriously ill). At Day 15, only 8 (7.8%) maintained this score.
• BPRS: At admission, 44 (37%) had a BPRS score between 42 and 53 (very ill). At Day 15, only
Analytical Statistics
Comparing the two groups (G1 CRP at admission <6 and G2 CRP at admission >6) using the Chi-square test (x2) or Fisher’s exact test reveals a statistically significant difference with P <0.05 in terms of family situation and medical history (table 2).
Furthermore, comparing the two groups (G’1 CRP at 15 days <6 and G’2 CRP at 15 days >6) shows a statistically significant difference with P <0.05 in the interpretation of the BPRS scale (table 2).
Multinomial Logistic Regression: Utilizing multivariate logistic regression and adjusting for confounding factors, it is concluded that having a medical history and presenting a score of 2 (Moderately ill) on the BPRS scale is a risk factor that triples the risk of having a CRP >6 (table 4).
Discussion
According to our results, 92.7% of the participants were men. This contradicts the literature, which shows that the incidence of schizophrenia is higher in men than in women, with a ratio of almost (1.4 /1), although several studies have found no difference between the sexes in the lifetime prevalence of the disease[3], our results can be explained by the earlier onset of symptoms in men than in women [11], better compliance with treatment [12] and social skills better preserved by women [13], and as the presentation of schizophrenia in women may be less typical than in men, women run the risk of delayed diagnosis [14], potentially reducing their chances of seeking appropriate care and obtaining good results [15].
According to our results, having a score of 2 (moderately ill) on the BPRS scale is a risk factor that multiplies by 3 the risk of having a CRP >6. In parallel with our results, a study by FAWZI et al [16] on Egyptian patients diagnosed with schizophrenia showed that higher CRP levels were positively correlated with the severity of psychopathology as measured by the PANSS, bearing in mind that the PANSS and BPRS scores explore the same dimensions of psychotic illness, another study by Steiner et al [17] showed that activation of the innate immune system correlated with PANSS score, and concluded that neutrophil and monocyte counts and CRP levels may be useful markers of disease acuity, severity and response to treatment.
Several studies have reported elevated levels of CRP at different stages of schizophrenia, indicating its potential to be used as a viable biomarker in the diagnosis and monitoring of schizophrenia as well as in the assessment of treatment response to conventional and non-conventional therapeutic regimens [18], several theories can explain the relationship between inflammation and schizophrenia such as the vulnerability-stress-inflammation model which suggests that stress can contribute to increased inflammation and exacerbate symptoms, it can also increase pro-inflammatory cytokines and contribute to chronic pro-inflammatory states [19].
General population evidence of an association between elevated inflammatory markers in childhood and adolescence and risk of schizophrenia and associated psychosis later in adulthood suggests that inflammation may be a causal risk factor for psychosis rather than simply a consequence of the illness [20], which explains the favourable effects of anti-inflammatory and immunomodulatory therapy in schizophrenia, particularly at an early stage of the disease to prevent cognitive and social dysfunction in patients [21].
According to our results, medical history is a risk factor for an increase in CRP, which is logical given that C-reactive protein is highly expressed in inflammatory conditions such as rheumatoid arthritis, certain cardiovascular diseases and infections[9]. As an acute-phase protein, the plasma concentration of CRP deviates by at least 25% during inflammatory disorders [10]. The highest concentrations of CRP are found in serum, with certain bacterial infections increasing levels by up to 1,000 times [10].
Medical history is common in patients with schizophrenia and this has been demonstrated in several studies which confirm that patients suffering from schizophrenia have a higher prevalence of somatic diseases and early mortality than the general population [22]. Furthermore, there are several causes of the increased frequency of somatic co-morbidities in patients with schizophrenia, including factors related to the illness itself, factors secondary to treatment, factors inherent in the perception of the illness, including the stigma attached to mental illness, and finally physical factors [22].
Schizophrenia appears to be caused by complex interactions between multiple risk factors, with the role of immune dysfunction and inflammatory processes strongly present according to the results of the literature [5], anti-inflammatory targeted therapy shows promise as predictors of treatment response and as therapeutic targets [23, 1].
Limitations of the Study
Low Participation of Women
The study faces a limitation in terms of gender participation, with a relatively low percentage of women compared to men. This gender imbalance may impact the generalizability of the findings and should be considered when interpreting the results.
Lack of Investigation into Cytokine Levels in Prodromal Psychosis
The study did not investigate cytokine levels in subjects with prodromal psychosis. It could be hypothesized that these subjects might exhibit abnormal markers compared to controls. Exploring cytokine levels in individuals with prodromal psychosis could provide valuable insights into the early stages of the disease.
Need for Replication of Results
Replicating the current results in different populations, both among patients and controls, would be beneficial. This would contribute to the robustness and generalizability of the findings, ensuring that the observed associations are consistent across diverse samples.
Exploration of Inflammatory Profiles in Treatment-Resistant Schizophrenia
It would be valuable to test the hypothesis that patients with treatment-resistant schizophrenia have a distinct inflammatory profile compared to other schizophrenia patients. Understanding the inflammatory patterns in different subgroups of schizophrenia patients could guide tailored therapeutic interventions.
Longitudinal Studies with Serial Inflammatory Parameter Measurements
The study’s cross-sectional design provides a snapshot of inflammatory markers at a specific point in time. To enhance understanding, more longitudinal studies with serial measurements of inflammatory parameters throughout the clinical course of the disease are necessary. This would allow for tracking changes in inflammation over time and exploring potential correlations with the progression of schizophrenia.
Addressing these limitations in future research endeavors could contribute to a more comprehensive understanding of the relationship between inflammation and schizophrenia, potentially leading to more targeted and effective interventions.
Conclusion
Schizophrenia emerges as a complex disorder resulting from intricate interactions among various risk factors. Literature findings confirm the role of immune system dysfunction and inflammatory processes in this context. However, the relationship between C-reactive protein (CRP) and schizophrenia is a complex dynamic, requiring in-depth investigations to better understand its nature. These additional research efforts are crucial to open new avenues for therapeutic and preventive interventions. These interventions should be informed by a comprehensive understanding of the underlying pathogenesis of this complex psychiatric disorder. The complexity of this relationship underscores the importance of continuing studies to further elucidate the underlying mechanisms and guide the development of more targeted and effective clinical strategies.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Aleman A, Kahn RS, Selten JP. Sex differences in the risk of schizophrenia: Evidence from meta-analysis. Arch Gen Psychiatry. 2003;60(6):565-71
2. Kadri N, Agoub M, Assouab F, Tazi MA, Didouh A, Stewart R et al. Moroccan national study on prevalence of mental disorders: A community-based epidemiological study. Acta Psychiatr Scand. 2010;121(1):71-4.
3. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):7510.
4. Sun HL, Bai W, Li XH, Huang H, Cui XL, Cheung T et al. Schizophrenia and inflammation research: A bibliometric analysis. Front Immunol. 2022;13:907851.
5. Feigenson KA, Kusnecov AW, Silverstein SM. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci Biobehav Rev. 2014;38:72-93.
6. Campeau A, Mills RH, Stevens T, et al. Multi-omics of human plasma reveals molecular features of dysregulated inflammation and accelerated aging in schizophrenia. Mol Psychiatry. 2022;27(2):1217-1225.
7. Miller BJ, Goldsmith DR. Inflammatory biomarkers in schizophrenia: Implications for heterogeneity and neurobiology. Biomarkers in Neuropsychiatry. 2019;1(100006):1-8.
8. Kraguljac NV, McDonald WM, Widge AS, Rodriguez CI, Tohen M, Nemeroff CB. Neuroimaging biomarkers in schizophrenia. Am J Psychiatry. 2021;178(6):509-521.
9. Du Clos TW, Mold C. C-reactive protein: an activator of innate immunity and a modulator of adaptive immunity. Immunol Res. 2004;30(3):261-277.
10. Sproston NR, Ashworth JJ. Role of C-Reactive Protein at Sites of Inflammation and Infection. Front Immunol. 2018;9:754.
11. Li R, Ma X, Wang G, Yang J, Wang C. Why sex differences in schizophrenia?. J Transl Neurosci (Beijing). 2016;1(1):37-42.
12. Morken G, Widen JH, Grawe RW. Non-adherence to antipsychotic medication, relapse and rehospitalisation in recent-onset schizophrenia. BMC Psychiatry. 2008;8:32.
13. Brabban A, Tai S, Turkington D. Predictors of outcome in brief cognitive behavior therapy for schizophrenia. Schizophr Bull. 2009;35(5):859-64.
14. Chen JH, Sun Y, Ju PJ, Wei JB, Li QJ, Winston JH. Estrogen augmented visceral pain and colonic neuron modulation in a double-hit model of prenatal and adult stress. World J Gastroenterol. 2021;27(30):5060-5075.
15. Sommer IE, Tiihonen J, van Mourik A, Tanskanen A, Taipale H. The clinical course of schizophrenia in women and men-a nation-wide cohort study. NPJ Schizophr. 2020;6(1):12
16. Fawzi MH, Fawzi MM, Fawzi MM, Said NS. C-reactive protein serum level in drug-free male Egyptian patients with schizophrenia. Psychiatry Res. 2011;190(1):91-97.
17. Steiner J, Frodl T, Schiltz K, et al. Innate immune cells and C-reactive protein in acute first-episode psychosis and schizophrenia: Relationship to psychopathology and treatment. Schizophr Bull. 2020;46(2):363-373.
18. Awan HA, Aamir A, et al. Role and perspectives of inflammation and C-reactive protein (CRP) in psychosis: An economic and widespread tool for assessing the disease. Int J Mol Sci. 2021;22(23):13032.
19. Müller N. Inflammation in schizophrenia: Pathogenetic aspects and therapeutic considerations. Schizophr Bull. 2018;44(5):973-982.
20. Upthegrove R, Khandaker GM. Cytokines, oxidative stress and cellular markers of inflammation in schizophrenia. Curr Top Behav Neurosci. 2020;44:49-66.
21. Mongan D, Ramesar M, Föcking M, Cannon M, Cotter D. Role of inflammation in the pathogenesis of schizophrenia: A review of the evidence, proposed mechanisms and implications for treatment. Early Interv Psychiatry. 2020;14(4):385‑397.
22. Khlif H, Gressier F, Vacheron M-N, Corruble E. Somatic pathologies associated with schizophrenia. In: Pathologies schizophréniques in Psychiatrie. Cachan: Lavoisier; 2012:191-198.
23. Halaris A, Cantos A, Johnson K, Hakimi M, Sinacore J. Modulation of the inflammatory response benefits treatment-resistant bipolar depression: A randomized clinical trial. J Affect Disord. 2020;261:145-152.
Download attachments: 10.4328.ACAM.22187
Fouad Laboudı, Soukaina Statı, El Hassan Ouanouche, Zineb Bencharfa, Oumaima Seyar, Lamia Azızı, Soukaina Belafqıh, Majdouline Obtel, Ryad Tamuza, Abderrazak Ouanass. Evaluation of C-reactive protein in patients with schizophrenia: A study of 126 cases hospitalized at Ar-Razi Psychiatric University Hospital in Salé, Morocco. Ann Clin Anal Med 2025;16(2):77-81
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Resection arthroplasty in diabetic foot patients: A paradigm shift in finger amputations and its clinical implications
İsmail Sezikli 1, Kaan Canal 1, Taner Alic 2, Murat Kendirci 1
1 Department of Surgery, 2 Department of Orthopedics and Traumatology, Faculty of Medicine, Hitit University, Çorum, Turkiye
DOI: 10.4328/ACAM.22260 Received: 2024-05-13 Accepted: 2024-10-21 Published Online: 2024-11-06 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):82-85
Corresponding Author: İsmail Sezikli, Department of Surgery, Faculty of Medicine, Hitit University, Çorum, Turkiye. E-mail: ismailsezikli@yahoo.com P: +90 555 686 30 83 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6801-1465
Other Authors ORCID ID: Kaan Canal, https://orcid.org/0000-0001-9168-4652 . Taner Alic, https://orcid.org/0000-0003-3848-8577 . Murat Kendirci, https://orcid.org/0000-0002-6594-3777
This study was approved by the Ethics Committee of Hitit University (Date: 2024-04-03, No: 2024-0116)
Aim: This study aims to investigate the clinical implications of resection arthroplasty in diabetic foot patients and assess its potential advantages over conventional methods.
Material and Methods: A thorough literature review was conducted, encompassing clinical studies, case reports, and expert opinions on resection arthroplasty in diabetic finger amputations. Data were extracted and analyzed to determine key clinical implications and outcomes associated with this innovative surgical approach.
Results:Resection arthroplasty offers several benefits in managing diabetic finger amputations. It preserves functional digit length, enhances aesthetic outcomes, and reduces wound healing complications compared to traditional methods. Additionally, precise bone resection and joint preservation may maintain joint function and overall foot functionality, leading to improved psychological well-being and postoperative quality of life.
Discussion:The clinical implications of resection arthroplasty extend beyond immediate surgical outcomes. Preserving finger length and function can enhance overall foot functionality, aiding patients in daily activities and preserving independence. Moreover, the psychological impact of improved foot aesthetics and function is significant. Furthermore, by reducing wound complications and hospital stays, resection arthroplasty may generate healthcare cost savings. It represents a promising shift in managing diabetic finger amputations, offering clinical advantages over traditional approaches.
Keywords: Diabetic Foot Complications, Finger Amputations, Resection Arthroplasty, Surgical Techniques, Diabetes-Related Complications, Clinical Implications, Paradigm Shift, Foot Syndrome, Neuropathy, Vascular Complications
Introduction
Diabetes mellitus, a chronic metabolic disorder characterized by hyperglycemia, has become a global epidemic. Its long-term complications span from cardiovascular diseases to neuropathy and nephropathy, with diabetic foot syndrome posing a significant challenge. Among its consequences are digital ischemia and necrosis, often leading to necessary surgical interventions like finger amputations.
Historically, traditional surgical approaches focused on infection control but often resulted in significant tissue loss and functional limitations for patients [2, 9]. However, a paradigm shift has occurred with the emergence of resection arthroplasty, a technique aiming to preserve both digit length and function by meticulously removing affected bone and joint structures and reconstructing the finger.
This innovative approach offers potential advantages over conventional methods, including improved functional and aesthetic outcomes [17]. Through a systematic literature review, this study aims to explore the multifaceted implications of resection arthroplasty, addressing questions about its effectiveness, impact on quality of life, and economic implications [13].
By delving into the clinical, functional, psychological, and economic dimensions of resection arthroplasty, this research seeks to contribute to a deeper understanding of its benefits and empower healthcare providers and patients in decision-making regarding diabetic finger amputations.
Material and Methods
This study employed a retrospective analysis of clinical cases and a comprehensive literature review to investigate the clinical implications of resection arthroplasty in the context of diabetic finger amputations. Patient data from the Diabetic Foot Surgery Clinic at Hitit University Research Hospital underwent retrospective scrutiny, focusing on demographic characteristics, diabetic status, preoperative evaluations, surgical particulars, and postoperative follow-up details. Inclusion criteria encompassed diabetic patients who underwent finger amputation with resection arthroplasty as the primary intervention, provided their medical records were complete and follow-up information was sufficient. Conversely, exclusion criteria entailed cases with incomplete data, alternative surgical methods, or contraindications for resection arthroplasty.
A systematic review of literature from 2020 to 2023 was conducted to identify pertinent articles from electronic databases and academic journals. The surgical procedure was characterized by meticulous bone resection, joint preservation, and tendon realignment, aimed at optimizing postoperative outcomes. Short-term metrics, including wound healing and pain management, as well as long-term indicators such as preservation of finger length and functional recovery, were scrutinized. Furthermore, specific complications relevant to diabetic patients were examined, along with strategies for their mitigation. Through this integrative approach, the study sought to furnish comprehensive insights into the efficacy and challenges associated with resection arthroplasty in managing diabetic finger amputations.
Ethical Approval
This study was approved by the Ethics Committee of Hitit University (Date: 2024-04-03, No: 2024-0116).
Results
Resection arthroplasty, heralded as a transformative surgical intervention, marks a departure from conventional techniques in the realm of finger amputations, particularly pertinent in the context of diabetic foot patients [5]. This innovative procedure intricately involves the precise excision of diseased bone and joint structures while concurrently safeguarding finger length and functionality to an exceptional extent [9]. Its emergence has captured considerable attention for its potential to redefine the treatment landscape for finger amputations, presenting a paradigmatic shift in addressing the complexities inherent in managing diabetic foot complications. This exposition undertakes a comprehensive exploration of resection arthroplasty, elucidating its procedural intricacies and the profound transformative impact it imparts upon the lives of patients [4].
Resection arthroplasty, positioned as a cornerstone in the surgical armamentarium for diabetic finger amputations, is distinguished by its methodical approach encompassing precise bone resection, joint preservation, and tendon realignment. These meticulous maneuvers are aimed at excising pathological tissue while preserving essential anatomical structures and optimizing functional outcomes [3].The preservation of finger length constitutes a pivotal aspect. Notably, resection arthroplasty confers advantages over conventional techniques, notably in mitigating wound healing complications and neuroma formation, thereby facilitating a smoother postoperative course.
Psychologically, the preservation of finger length and aesthetics engenders a sense of contentment and self-assurance among patients, augmenting their overall well-being and psychological resilience. Furthermore, the economic ramifications of resection arthroplasty cannot be understated, with its potential to curtail healthcare costs stemming from complications and protracted hospital stays. Thus, resection arthroplasty emerges as a holistic therapeutic modality, addressing multifaceted dimensions encompassing functional rehabilitation, aesthetic restoration, psychological well-being, and healthcare resource optimization.
Assessment of clinical outcomes and long-term follow-up serves as a linchpin in evaluating the efficacy and durability of resection arthroplasty in the context of diabetic finger amputations [7]. Short-term outcomes, including wound healing, pain management, and early functional recovery, underscore the immediate benefits conferred by this technique, underscored by minimized tissue trauma and optimized wound healing [12]. Furthermore, the perpetuation of finger length and aesthetics bears tangible psychological dividends, fostering a positive outlook and reinforcing patient satisfaction.
In the continuum of care, sustained success hinges upon meticulous long-term follow-up, encompassing vigilant surveillance for complications, ongoing functional assessments, and psychosocial support. Key determinants of enduring success encompass patient compliance, rehabilitation initiatives, and judicious diabetes management strategies, epitomizing the imperative for comprehensive care extending beyond the immediate perioperative period. Thus, amidst the evolving landscape of diabetic finger amputations, resection arthroplasty emerges as a beacon of hope, embodying a paradigmatic shift towards patient-centered, evidence-based therapeutic approaches.
Discussion
The discussion section critically evaluates the study’s findings on resection arthroplasty for diabetic finger amputations. It underscores the significance of this novel surgical approach in addressing the complex needs of diabetic patients with finger complications. Methodological limitations, such as sample size and follow-up duration, are acknowledged, providing transparency and context to the study’s scope. Comparative analyses with existing literature illuminate how resection arthroplasty aligns with or diverges from established practices, contributing to the broader understanding of surgical interventions for diabetic foot care. The clinical implications of the study’s findings are emphasized, particularly in terms of patient satisfaction, quality of life improvements, and healthcare resource utilization. Lastly, avenues for future research are outlined, including prospective studies with larger cohorts and investigations into economic impact and cost-effectiveness. Overall, the discussion section serves to interpret the study’s findings, contextualize them within the existing body of knowledge, and delineate directions for further research, thus advancing the field of diabetic foot care and surgical management.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Armstrong D, Lavery L, Vazquez J, Short B, Kimbriel H, Nixon B, et al. Clinical efficacy of the first metatarsophalangeal joint arthroplasty as a curative procedure for hallux interphalangeal joint wounds in patients with diabetes. Diabetes Care. 2003;26(12):3284-7.
2. Boileau P, Raynier J, Chelli M, Gonzalez J. Reverse shoulder–allograft prosthesis composite, with or without tendon transfer, for the treatment of severe proximal humeral bone loss. J. Shoulder Elbow Surg. 2020;29(11):e401-e415.
3. Brooks F, Hariharan K. The rheumatoid forefoot. Curr Rev Musculoskelet Med. 2013;6(4):320-7.
4. Chaudhary M, Walker P. Analysis of an early intervention tibial component for medial osteoarthritis. J. Biomech. Eng. 2014;136(6).136(6):061008.
5. Cooney W, Manuel J, Froelich J, Rizzo M.Total wrist replacement: a retrospective comparative study. J. Wrist Surg. 2012;01(02):165-72.
6. Horita M, Nishida K, Hashizume K, Nasu Y, Saiga K, Nakahara R, et al. Outcomes of resection and joint-preserving arthroplasty for forefoot deformities for rheumatoid arthritis. Foot Ankle Int. 2018;39(3):292-9.
7. Kang H, Chung S. Resection arthroplasty in radiation-induced osteonecrosis of the hip. J Clin Orthop Trauma. 2019;10(2):364-7.
8. Lee J, Balso C, Gupta S , Tay S , Daniels T. A two-stage diabetic foot salvage using synthetic bone void filler and lesser toe fillet flap. JBJS Case Connect. 2022;12(1).12(1):e21.
9. Malhotra V, Singh V, Rao J, Yadav S, Gupta P, Shyam R, et al. Lateral arthroplasty along with buccal fat pad inter-positioning in the management of sawhney type iii temporomandibular joint ankylosis. J Korean Assoc Oral Maxillofac Surg. 2019;45(3):129.
10. Mavrogenis A, Galanopoulos J, Vottis C, Megaloikonomos P, Palmerini E. Osteoarticular allograft reconstruction for an angiosarcoma of the distal radius. J. Long Term Eff. Med. Implants. 2016;26(1):79-87.
11. Muh S, Streit J, Lenarz C, McCrum C , Wanner J, Shishani Y, et al. Resection arthroplasty for failed shoulder arthroplasty. J. Shoulder Elbow Surg. 2013;22(2):247-52.
12. Periasamy M, Muthukumar V, Reddy R, Asokan K. Outcomes of keller gap arthroplasty for plantar hallux interphalangeal joint ulcers in patients with diabetes mellitus. Foot Ankle Int. 2023;44(3):192-9.
13. Pontes J, Ferreira-Pinto P, Martha B, Silva W, Senior M. Resection arthroplasty for isolated costotransverse joint osteoarthritis: a case report and literature review. Surg. Neurol. Int. 2022;13:62.
14. Rasmussen J, Polk A, Olsen B. Outcome, revision rate and indication for revision following resurfacing hemiarthroplasty for osteoarthritis of the shoulder. Bone Joint J. 2014;96-B(4):519-25.
15. Sawachika F, Uemura H, Katsuura-Kamano S, Yamaguchi M, Bahari T, Miki K , et al. Changes in foot function, disease activity, and disability after forefoot resection arthroplasty in patients with rheumatoid arthritis. J Med Invest. 2016; 63(1.2):38-44.
16. Schenk S, Meizer R, Kramer R, Aigner N, Landsiedl F. Resection arthroplasty with and without capsular interposition for treatment of severe hallux rigidus. Int Orthop. 2007;33(1):145-50.
17. Scimeca C, Bharara M, Fisher T, Kimbriel H. Novel use of platelet-rich plasma to augment curative diabetic foot surgery. J Diabetes Sci Technol. 2010;4(5):1121-6.
18. Sharma H, Leeuw J, Rowley D. Girdlestone resection arthroplasty following failed surgical procedures. Int Orthop. 2005;29(2):92-5.
19. Shimomura K, Yasui T, Teramoto A, Ozasa Y, Yamashita T. Time course of quality of life improvement between resection arthroplasty and metatarsophalangeal joint-preserving forefoot arthroplasty for rheumatoid arthritis. Foot Ankle Int. 2020;42(2):166-75.
20. Tamir E, Tamir J, Beer Y, Kosashvili Y, Finestone A. Resection arthroplasty for resistant ulcers underlying the hallux in insensate diabetics. Foot Ankle Int. 2015;36(8):969-75.
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İsmail Sezikli, Kaan Canal, Taner Alic, Murat Kendirci. Resection arthroplasty in diabetic foot patients: a paradigm shift in finger amputations and its clinical implications. Ann Clin Anal Med 2025;16(2):82-85
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Overlapping sphincteroplasty in anal incontinence: Our clinical experience
Uğur Topal 1, İsa Armağan Çıklar 1, Burak Yavuz 1, İshak Aydın 1, Ahmet Gökhan Sarıtaş 1, Kubilay Dalcı 1, Orçun Yalav 2, İsmail Cem Eray 1
1 Department of General Surgery, Faculty of Medicine, Çukurova University, 2 Department of General Surgery, Acibadem Adana Hospital, Adana, Turkey
DOI: 10.4328/ACAM.22261 Received: 2024-05-13 Accepted: 2024-07-02 Published Online: 2024-08-18 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):86-89
Corresponding Author: Uğur Topal, Department of General Surgery, Faculty of Medicine, Cukurova University, Adana, Turkey. E-mail: sutopal2005@hotmail.com P: +90 532 113 91 12 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1305-2056
Other Authors ORCID ID: İsa Armağan Çıklar, https://orcid.org/0009-0004-5456-4095 . Burak Yavuz, https://orcid.org/0000-0002-5262-0346 . İshak Aydın, https://orcid.org/0000-0002-6366-2461 . Ahmet Gökhan Sarıtaş, https://orcid.org/0000-0003-2715-6390 . Kubilay Dalcı, https://orcid.org/0000-0002-3156-4269 . Orçun Yalav, https://orcid.org/0000-0001-9239-4163 . İsmail Cem Eray, https://orcid.org/0000-0002-1560-7740
This study was approved by the Ethics Committee of Çukurova University, Faculty of Medicine (Date: 2023-11-3, No: 138/29)
Aim: Primary sphincter repair remains the first-choice surgical treatment for patients diagnosed with anal sphincter defect incontinence. This study aims to present the outcomes of patients who underwent overlapping sphincteroplasty for anal incontinence treatment at our clinic over the past five years.
Material and Methods: In this study, we retrospectively examined the data of 23 patients who underwent surgical treatment for anal incontinence complaints and were subsequently followed up. Our parameters included age, comorbidities, muscle defect duration, muscle defect degree, surgery duration, wound dehiscence, need for stoma, current complaints, Kegel exercises, postoperative smoking, and Cleveland Clinic Fecal Incontinence Score (CCFIS) values before and after surgery.
Results: All patients were female, with a mean age of 40.1 ± 12.81 years. The mean surgery duration was 80 minutes. The CCFIS means was 15.61 preoperatively and 7.65 postoperatively, with a mean CCFIS difference of 7.95 ± 6.87. The median muscle defect duration was 48 months (range 1-360 months). The etiology was incontinence due to obstetric anal sphincter trauma. Wound dehiscence occurred in 60.9% (n=14) of patients. Compliance with Kegel exercises was observed in 52.2% (n=12) of patients. The need for stoma was found in 17.4% (n=4) of all patients, and its clinical significance in remission was not significant. Postoperative complaints were statistically significantly less in patients who performed Kegel exercises after surgery (p<0.05).
Discussion: Our study found that postoperative Kegel exercises led to improvements in symptoms. While there was a weak to moderate correlation between age, defect duration, and CCFIS, this relationship was not statistically significant. Therefore, postoperative Kegel exercises are recommended for symptom improvement.
Keywords: Anal Incontinence, Sphincteroplasty, Kegel Exercises, Obstetric Injury
Introduction
Fecal incontinence, defined as the involuntary discharge of stool, is a condition that causes physical, social, and psychological disorders, significantly impairing the quality of life. This condition affects between 2% to 17% of the general population and nearly half of the elderly population in nursing homes. Fecal incontinence is multifactorial, with the most common causes being sphincter injuries or vaginal injuries, anorectal surgical procedures, and neuronal damage associated with neurological conditions [1, 2].
In recent years, numerous new methods for the treatment of anal incontinence have been introduced. These methods vary in effectiveness, and some are still in the clinical research stage. Despite this, primary sphincter repair continues to be the first-choice surgical treatment for patients diagnosed with an anal sphincter defect incontinence [1, 3, 4]. However, in the past few decades, although short-term high success rates have been reported for overlapping sphincteroplasty, long-term evaluations have revealed a gradual decrease in function. This has led to questioning whether this operation truly represents the gold standard. The method, while relatively inexpensive and straightforward, has sparked various debates. These include the optimal timing from injury to repair; the best way to perform the repair; the benefits of medical or surgical fecal diversion; whether pudendal neuropathy predicts the outcome; and finally, if the age of the patient at the time of repair affects the outcome, what should be the appropriate age range [5, 7].
In our study, we aimed to retrospectively analyze cases undergoing late-stage overlapping sphincteroplasty for fecal incontinence at our clinic and present them in light of the literature.
Material and Methods
After obtaining approval from the ethics committee, our study included patients who underwent overlapping sphincteroplasty for Obstetric Anal Sphincter Injury Incontinence (OASIS) at our clinic between the years 2017 and 2022. Male patients and those who had previously undergone surgery for anal incontinence were excluded from the study. A dataset was created using hospital records, postoperative follow-up forms, and telephone interviews with the patients. Analyses were conducted based on this dataset.
The study included patient data on age, etiological cause, muscle defect duration, muscle defect degree, surgery duration, preoperative and postoperative Cleveland Clinic Incontinence Score (CCFIS), development of wound dehiscence, need for stoma, current complaints, Kegel exercise adherence, and postoperative smoking status.
Preoperative radiological evaluation in our clinic routinely involves the use of a 360° probe (BK Medical, Flexfocus 400, Denmark) for endoanal ultrasound. MRI (3 Tesla, Philips, Netherlands) was performed on patients suspected of complex injury or additional pathology. Follow-up data were obtained from hospital records and telephone conversations.
All procedures were performed in the lithotomy position under spinal anesthesia. We did not routinely use bowel preparation. A mechanical enema was applied on the morning of the procedure. Patients were catheterized prior to surgery. An arcuate incision was made between the anus and vagina, and the vaginal mucosal flap was elevated. The ends of the sphincter on both sides of the defect were identified, and dissection was continued until sufficient length for overlapping was achieved. The dissection was extended deep into the pelvic floor. The sphincter ends were sutured in an overlapping fashion using 3-0 delayed absorbable sutures, along with scar tissue. In some cases, a diverting stoma was applied according to the surgeon’s preference. All patients were advised to abstain from sexual activity for at least three months.
Throughout the duration of the study, all sphincteroplasty operations were attended by at least one senior colorectal surgeon with extensive experience in the surgical technique.
Statistical Analysis
Statistical analyses were conducted using the SPSS 25 software. The Kruskal-Wallis and Shapiro-Wilk tests were employed to assess the normal distribution of numerical data. Results for parameters following a normal distribution were presented as mean and standard deviation (SD), while results for parameters not following a normal distribution were presented as median and interquartile range (IQR). The chi-square test was used for the analysis of categorical variables. Regression analysis was applied to evaluate the relationship between pre-operative and post-operative incontinence scores and other parameters. In all analyses, a p-value of <0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Çukurova University, Faculty of Medicine (Date: 2023-11-3, No: 138/29).
Results
Our study included 23 female patients. The mean age was 40.1 years. Two patients had a history of birth trauma as the etiological cause. The median degree of muscle defect detected by endoanal ultrasound was 91 degrees (range 60-180 degrees). The median duration of the defect was 48 months. Clinical data are presented in Table 1.
The mean duration of the operation was 80.4 minutes. Wound dehiscence developed in 14 patients, and 4 patients underwent stoma surgery. The change in the Cleveland Clinic Incontinence Score (CCFIS) was calculated to be a mean of 7.95 ± 6.87. Perioperative data are shown in Table 2.
It was observed that patients who performed post-operative Kegel exercises had fewer post-operative complaints (p<0.05). However, when comparing CCFIS results between patients who did and did not perform Kegel exercises, although there was a numerical decrease in scores in patients who performed exercises, the difference was not statistically significant (9.4 vs 6.3, p:0.29), as shown in Table 3.
A moderate negative correlation of -0.577 was found between age at presentation and the difference in CCFIS score, and a moderate negative correlation of -0.561 was found between muscle defect duration and the difference in CCFIS score. However, these variables did not have a statistically significant impact on the CCFIS score.
Discussion
In this study, where we presented our results of overlapping sphincteroplasty in patients with anal incontinence due to sphincter damage, we found a wound dehiscence rate of 60%. We observed significant improvements in symptoms due to postoperative Kegel exercises. Although age and defect duration were weakly to moderately correlated with the Cleveland Clinic Fecal Incontinence Score (CCFIS), this relationship was not statistically significant.
Successful treatment of anal incontinence requires the identification of one or multiple causes leading to the disruption of continence and the correct application of medical, psychological, and surgical treatment options. A significant factor in treatment failure includes the inability to fully identify the problem, and it should be kept in mind that incontinence can develop through multiple mechanisms [7].
When sphincter defects are identified in patients presenting with incontinence symptoms, surgery should be the first treatment method considered. The literature has previously presented that the success rates of overlapping sphincteroplasty decrease over long-term follow-up. It has been reported that sphincteroplasty provides short-term improvement in anal incontinence (68-74%), but later the success rate can drop to 0-50%. Pudendal nerve damage, variations in surgical technique, suture breakage, and muscle denervation with age are some of the known possible reasons for this long-term deterioration [8, 12]. In our series, when evaluating the current clinical status of patients, 61% continued to have various complaints to varying degrees. We associated this with a high rate of wound dehiscence during the perioperative period and non-compliance with Kegel exercises.
An important parameter affecting the success rates after sphincteroplasty is the presence of a large sphincter defect (>90°) and the emergence of postoperative wound infection. The benefit of protective colostomy to prevent wound contamination has been investigated, but no definitive conclusion has been reached [13, 14]. Furthermore, it’s crucial to remember that the morbidity associated with stoma formation and closure are significant issues. In our series, the mean muscle defect degree was 91 degrees, which was higher than that reported in the literature, and we believe this influenced our results. We did not find a relationship between the need for a stoma and wound dehiscence, but our study was not sufficiently robust to provide conclusive evidence on this matter.
Several studies in the literature have established a direct association between advanced age during sphincter repair and poorer clinical outcomes [5]. Bravo-Gutierrez et al. found that those with poor outcomes were older than those with successful repairs (49 vs. 43) [15]. Similarly, the Cleveland Clinic group found a positive correlation between the Female Sexual Function Index scores and the age at surgery [16]. Differently, Hull T et al., using the Fecal Incontinence Quality of Life Scale in their study, suggested that age is not a determinant of the outcome for overlapping sphincter repair and that this procedure can be safely applied in both younger and older populations [4]. In our series, the mean age was relatively young, but 20% of the patients had chronic diseases like diabetes, which we believe affected the outcomes by impairing wound healing.
In the literature, the impact of the duration of incontinence symptoms prior to surgical repair on outcomes is a matter of debate. While there are studies claiming that patients who have experienced symptoms for over 10 years have higher Wexner Incontinence scores and poorer outcomes, there are also studies that have not found a significant relationship [17, 18]. In our study, the median symptom duration was 48 months, a lengthy period, and we believe that these delays could affect the long-term outcomes.
The increase in squeezing pressure after sphincter repair is significant. The literature has reported that the contraction of the external anal sphincter and pelvic floor muscle exercises are associated with positive changes in fecal incontinence scores in women [19]. A study comparing sphincter repair alone with sphincter repair combined with biofeedback found no general difference in continence rates, but significant improvements in quality of life scores were observed with the repair and biofeedback combination [20]. The results of our study supported the improvement of symptoms in patients who performed postoperative Kegel exercises.
Limitation
The limitations of our study include its retrospective nature and the limited number of patients. Due to the small sample size, the results were not compared in detail across etiological subgroups.
Conclusion
In this study conducted with a limited number of patients, we believe that there could be multiple factors affecting the success of sphincteroplasty and its long-term efficacy. Postoperative Kegel exercises reduce postoperative symptoms and should be recommended for all patients. However, to determine the predictors of surgical success, there is a need for prospective, multicenter studies with larger patient populations.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Lakmal K, Basnayake O, Jayarajah U, Samarasekera DN. Short-and long-term outcomes of overlap anal sphincter repair for fecal incontinence following sphincter injury. J Coloproctol (Rio Janeiro). 2021;41(01):30-6.
2. Nelson RL. Epidemiology of fecal incontinence. Gastroenterology. 2004;126(1 Suppl 1):3-7.
3. Goetz LH, Lowry AC. Overlapping sphincteroplasty: Is it the standard of care?. Clin Colon Rectal Surg. 2005;18(1):22-31.
4. El-Gazzaz G, Zutshi M, Hannaway C, Gurland B, Hull T. Overlapping sphincter repair: Does age matter?. Dis Colon Rectum. 2012;55(3):256-61.
5. Glasgow SC, Lowry AC. Long-term outcomes of anal sphincter repair for fecal incontinence: A systematic review. Dis Colon Rectum. 2012;55(4):482-90.
6. Haug HM, Carlsen E, Johannessen HO, Johnson E. Short-, long-, and very long-term results of secondary anterior sphincteroplasty in 20 patients with obstetric injury. Int J Colorectal Dis. 2021;36(12):2775-8.
7. Mongardini FM, Cozzolino G, Karpathiotakis M, Cacciatore C, Docimo L. Short-and long-term outcomes of sphincteroplasty for anal incontinence related to obstetric injury: A systematic review. Updates Surg. 2023;75(6):1-8.
8. Berkesoglu M, Colak T, Turkmenoglu MO, Han I, Kirmizi I, Akgul GG, et al. Long-term results from modified sphincteroplasty in patients with traumatic sphincter injury: A retrospective study. Sao Paulo Med J. 2021;139(1):58-64.
9. Ruiz NS, Kaiser AM. Fecal incontinence: Challenges and solutions. World J Gastroenterol. 2017;23(1):11-24.
10. Bleier JI, Kann BR. Surgical management of fecal incontinence. Gastroenterol Clin North Am. 2013;42(4):815-36.
11. Barisic GI, Krivokapic ZV, Markovic VA, Popovic MA. Outcome of overlapping anal sphincter repair after 3 months and after a mean of 80 months. Int J Colorectal Dis. 2006;21(1):52-6.
12. Altomare DF, De Fazio M, Giuliani RT, Catalano G, Cuccia F. Sphincteroplasty for fecal incontinence in the era of sacral nerve modulation. World J Gastroenterol. 2010;16(42):5267-71.
13. Altomare DF, Picciariello A, De Fazio M, Rinaldi M. When everything fails: Prevention and therapy of treatment failures. In: Anal incontinence: Clinical management and surgical techniques. Cham: Springer International Publishing; 2022.p.131-8.
14. Kropshofer S, Aigmüller T, Beilecke K, Frudinger A, Krögler-Halpern K, Hanzal E, et al. Management of third and fourth-degree perineal tears after vaginal birth. Guideline of the DGGG, OEGGG and SGGG (S2k-level, AWMF registry no. 015/079, December 2020). Geburtshilfe Frauenheilkd. 2023;83(2):165-83.
15. Bravo Gutierrez A, Madoff RD, Lowry AC, Parker SC, Buie WD, Baxter NN. Long-term results of anterior sphincteroplasty. Dis Colon Rectum. 2004;47(5):727-31.
16. Zutshi M, Tracey TH, Bast J, Halverson A, Na J. Ten-year outcome after anal sphincter repair for fecal incontinence. Dis Colon Rectum. 2009;52(6):1089-94.
17. Johnson E, Carlsen E, Steen TB, Backer Hjorthaug JO, Eriksen MT, Johannessen HO. Short-and long-term results of secondary anterior sphincteroplasty in 33 patients with obstetric injury. Acta Obstet Gynecol Scand. 2010;89(11):1466-71.
18. Grey BR, Sheldon RR, Telford KJ, Kiff ES. Anterior anal sphincter repair can be of long term benefit: A 12-year case cohort from a single surgeon. BMC Surg. 2007;7:1-6.
19. Markland AD, Richter HE, Burgio KL, Wheeler TL, Redden DT, Goode PS. Outcomes of combination treatment of fecal incontinence in women. Am J Obstet Gynecol. 2008;199(6):699e1-7.
20. Davis KJ, Kumar D, Poloniecki J. Adjuvant biofeedback following anal sphincter repair: A randomized study. Aliment Pharmacol Ther. 2004;20(5):539-49.
Download attachments: 10.4328.ACAM.22261
Uğur Topal, İsa Armağan Çıklar, Burak Yavuz, İshak Aydın, Ahmet Gökhan Sarıtaş, Kubilay Dalcı, Orçun Yalav, İsmail Cem Eray. Overlapping sphincteroplasty in anal incontinence: Our clinical experience. Ann Clin Anal Med 2025;16(2):86-89
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Histology-based survival outcomes in breast cancer patients treated with CDK4/6 inhibitor
Bediz Kurt İnci 1, Pınar Kubilay Tolunay 1, Berkan Karabuğa 1, Ali Topkaç 1, İrem Öner 1, Çiğdem Irkkan 2, Öztürk Ateş 1, Cengiz Karaçin 1, Ülkü Yalçıntaş Arslan 1
1 Department of Medical Oncology, 2 Department of Pathology, Dr. Abdurrahman Yurtaslan Ankara Onkology Training and Research Hospital, Ankara, Turkiye
DOI: 10.4328/ACAM.22317 Received: 2024-07-08 Accepted: 2024-12-24 Published Online: 2024-12-31 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):90-93
Corresponding Author: Bediz Kurt İnci, Department of Medical Oncology, Dr. Abdurrahman Yurtaslan Ankara Onkology Training and Research Hospital, Ankara, Turkiye. E-mail: bedizkurt@gmail.com P: +90 312 336 09 09 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6238-0534
Other Authors ORCID ID: Pınar Kubilay Tolunay, https://orcid.org/0000-0003-2636-5326 . Berkan Karabuğa, https://orcid.org/0000-0001-5357-7610 . Ali Topkaç, https://orcid.org/0000-0003-0608-1641 . İrem Öner, https://orcid.org/0000-0001-9486-6187 . Çiğdem Irkkan, https://orcid.org/0000-0001-6442-7415 . Öztürk Ateş, https://orcid.org/0000-0003-0182-3933 . Cengiz Karaçin, https://orcid.org/0000-0002-7310-9328 . Ülkü Yalçıntaş Arslan, https://orcid.org/0000-0001-5279-0903
This study was approved by the Ethics Committee of Dr. Abdurrahman Yurtaslan Ankara Oncology Hospital (Date: 2024-02-22, No: 2024-02/08)
Aim: Metastatic breast cancer that is hormone receptor-positive and HER2-negative has shown significant advancements in the past decade with the introduction of CDK4/6 inhibitor therapies in the first-line treatment. The aim of our study is to compare the prognosis of CDK4/6 inhibitors combined with endocrine therapy in lobular breast cancer (LBC) and invasive breast carcinoma of no special type (IBC/NST) histologic subtypes.
Material and Methods: We included hormone receptor-positive HER2-negative metastatic breast cancer patients with known histological subtypes and survival times who were initiated on CDK4/6 inhibitor combined with endocrine therapy as first-line treatment.
Results: Out of the 248 patients included in the study, 13.3% (33) had the histologic subtype of lobular breast cancer. The median progression-free survival (mPFS) was 28 months (95% CI: 21.4-34.6) in IBC/NST patients and 31 months (95% CI: 21.2-40.8) in LBC patients (p = 0.861). The median overall survival was 81 months (95% CI: 43.3-118.8) in IBC/NST patients and 66 months (95% CI: 25.3-106.7) in LBC patients (p = 0.112). There were no significant differences in median progression-free survival and median overall survival times between the IBC/NST and LBC groups in both univariate and multivariate analyses.
Discussion: While IBC/NST and LBC have been recognized in the literature as distinct sub-histologic breast cancer groups with varying responses to specific drugs and disease progression, our study revealed that they exhibited similar survival outcomes with the use of CDK4/6 inhibitor therapies.
Keywords: CDK4/6 Inhibitor, Lobular Breast Carcinoma, Invasive Breast Carcinoma/No Special Type (IBC/NST), Histologic Subtypes
Introduction
The treatment of hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2-mBC) has evolved over the past decade from using hormonal therapies alone to the combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) [1]. The most important reason for this change is the discovery of new targets from studies on the mechanisms that cause hormone resistance [2]. Although treatment for these patients is now conducted according to guidelines with standard approaches and CDK4/6i and ET are used as the first-line standard treatment for HR+/HER2-mBC, numerous studies continue to explore which patients derive the greatest benefit from this treatment modality [3]. The basic molecular and histopathologic features associated with the disease gain particular importance.
Invasive breast cancer is a disease that is characterized by more than 20 histological subtypes. The most common subtype, accounting for approximately 80% of cases, is invasive ductal carcinoma (IDC), also classified as invasive carcinoma of no special type (IBC/NST) [4]. Invasive lobular carcinoma (ILC) constitutes approximately 10-15% of breast cancers and differs from IBC/NST in clinical, pathological, and molecular features [5]. One of the critical characteristics of ILC is the loss of the cell adhesion protein E-cadherin in approximately 90% of cases. ILC is typically associated with low grade, low proliferation index, and strong ER positivity [6]. However, compared to IBC/NST, ILC has been observed to have a higher risk of distant recurrence after ten years and exhibits distinct metastatic patterns [7]. ILC is also thought to show a weaker response to systemic chemotherapy than IBC/NST, and there is evidence from cell line studies suggesting a higher likelihood of resistance to tamoxifen in ILC [8].
The phase studies leading to the approval of CDK4/6i and ET combination therapy included patients with predominantly IBC/NST as a histologic subtype. Although the LBC histological subtype is available in phase studies, there is no data regarding the benefit of CDK4/6 combinations as a subgroup. Our study aimed to compare the real-life survival outcomes of CDK4/6i combinations in LBC and IBC/NST patients.
Material and Methods
Between January 2019 and January 2023, 248 HR+/HER2- mBC patients with known histological subtypes and survival times who were started on CDK4/6i treatment in a first-line setting at Dr. Abdurrahman Yurtaslan Ankara Oncology Hospital were included in the study.
The histologic subtyping of BC was performed by experienced pathologists who reviewed hematoxylin and eosin-stained sections of the tumor samples obtained from biopsy or surgical resection specimens. Invasive ductal carcinoma (IDC), commonly classified as invasive carcinoma of no special type (IBC/NST), is considered the subtype of breast cancer in this study, and patients with invasive lobular carcinoma (ILC) were also included. Less common histological subtypes were excluded from the study.
Our study included female patients between the ages of 18 and 80. Patients without histological subtype information and those who received CDK4/6i treatment after the first line were excluded from the study.
Statistical analyses were performed using SPSS version 22.0, and p < 0.05 was considered statistically significant. Descriptive analyses were performed for the demographic and clinical characteristics of the patients. Wilcoxon test was used to analyze repeated nonparametric measurements. The difference in continuous numerical variables between the two groups was evaluated with the Student’s t-test. The Chi-square test describes the relationship between two separate categorical groups. Kaplan-Meier survival analysis method was used. Independent samples t-test was used for ordinal variables, and Cox regression analysis was used for categorical variables in univariate analysis. Cox regression analysis was also used for multivariate analysis.
Ethical Approval
This study was approved by the Ethics Committee of Dr. Abdurrahman Yurtaslan Ankara Oncology Hospital (Date: 2024-02-22, No: 2024-02/08).
Results
Of the 248 patients included in the study, 13.3% (n = 33) had LBC histologic subtype. The median follow-up period of the patients was 30(CI 95%:25-32) months. Patient-related variables according to histologic subtypes are given in Table 1.
The mean age in the whole group was 56.6 ± 12.6 years. The mean age of LBC patients was 56.8 ± 10.3 years, while that of IBC/NST patients was 56.6 ± 12.9 years (p = 0.921). ECOG performance score, presence of comorbidities, menopausal status, disease status at diagnosis, site of metastasis, CDK4/6i type, and hormonal therapy type were similar between LBC and IBC/NST patients(p = 0.315, p = 0.949, p = 0.690, p = 0.301, p = 0.769, p = 0.348, p = 0.449, respectively).
When the factors that may affect survival were evaluated by univariate analysis, age, presence of comorbidities, menopausal status, disease status at diagnosis, site of metastasis, CDK4/6i type and hormonal therapy type and histological subtype did not affect PFS(p=0.395, p = 961,p = 287, p = 0.055, p = 0,204, p = 0.730, p = 0.078, p = 0.863, respectively) (Table 2). However, ECOG performance status affected PFS (p < 0.001) (Table 2).
When all variables in the univariate analysis were included in the multivariate analysis, the ECOG performance score remained significant, and disease status at diagnosis became significant. However, the histological subtype did not affect PFS (p < 0.001, p = 0.050, p = 0.856, respectively).
Median PFS was 28 months (95% Cl: 21.4-34.6) in IBC/ NST patients and 31 months (95% Cl 21.2-40.8) in LBC patients (p = 0.861) (Figure-1). Median OS was 81 months (95% Cl: 43.3-118.8) in IBC/ NST patients and 66 months (95% Cl: 25.3-106.7) in LBC patients (p = 0.112) (Figure-1).
Discussion
In the context of ILC, the benefit of CDK4/6is has been studied less than that of IDC. However, a pooled analysis of phase studies reported by the U.S. Food and Drug Administration (FDA) indicated that both IDC and ILC patients benefited from the addition of a CDK4/6i to aromatase inhibitor (AI) therapy in terms of PFS [9]. This suggests that CDK4/6i may also be beneficial for ILC patients. Similarly, an updated analysis showed that both IDC and ILC patients experienced a longer OS duration by adding a CDK4/6i to AI [10]. These findings suggest that CDK4/6is may positively impact the outcomes of ILC patients, similar to their effects in IDC patients. Although these pooled analyses shed light on the potential impact of CDK4/6i in ILC, real-life data, and further research specifically focusing on ILC are needed to understand better these agents’ efficacy and safety profile in this patient population.
In the study conducted in 2022 from MD Anderson BC databases, they did not find a statistically significant difference in PFS and OS duration between IDC and ILC patients receiving CDK4/6i and ET without or with stratification according to first-line or second-line treatment and above [11]. This analysis was the first known retrospective real-life data with a large number of patients, and the results were similar to our study. However, unlike our study, there were very few ribociclib patients (5/336) and predominantly palbociclib (310/336) patients in this study. In our study, predominantly patients receiving ribociclib, there was no significant difference in the number of patients receiving ribociclib and palbociclib between the ILC and IBC/NST groups, and in univariate analyses, PFS and OS were similar in both subgroups regardless of the treatment option. Therefore, our study emphasizes the real-life efficacy of ribociclib in the ILC subgroup.
In the MD Anderson BC database study [11], mPFS duration was 16.0 months for IDC compared to 18.8 months for ILC (HR, 1.04; 95% CI, 0.84-1.30; P = 0.675) even in patients receiving CDK4/6i and ET in the first line, which was found to be shorter compared to the analyses of the PALOMA-2, MONALEESA-2, and MONALEESA-7 trials [12]. In our study, mPFS was 28 months (95% CI: 21.4-34.6) in IBC/NST patients and 31 months (95% CI: 21.2-40.8) in LBC patients, consistent with the literature data. Since it increases the reliability of the data used in the analysis, it significantly determines survival times similar to those in the literature.
In 2022, a study presented at the 13th European Breast Cancer Conference evaluated 33 patients with LBC or mixed histology. Among these, 18 received CDK4/6 inhibitors as first-line treatment. The median follow-up time was 12.5 months, and the median mPFS was reported as 13.2 months, with the median value not reached. The study was published as single-center data from Portuguese [13]. Also provides insight into a heterogeneous group of LBC patients in which 13/30 (43%) patients received Palbociclib, 14/30 (47%) Ribociclib, and 3/30 (10%) Abemaciclib, published as an abstract in Annals of Oncology in 2023 [14]. Our study stands out from these studies by being conducted on a more homogeneous group, including a larger patient cohort, and showing survival outcomes that align with existing literature. Furthermore, it contributes to the literature by comparing IBC/NST and LBC.
The limitation of our study is the low number of LBCs since they constitute only 10-15% of all breast cancers. Other significant limitations include the lack of knowledge of the treatments received after the first line and the retrospective design. In our study, the primary reason for the discordance between OS and PFS durations has been considered to be the small number of ILC patients and the lack of knowledge regarding the management of second-line treatments.
In conclusion, although studies have shown that IBC/NST and LBC differ in treatment responses with some drugs and clinical progression patterns, mPFS and mOS times are similar with first-line CDK4/6i and ET treatment. The number and scope of studies comparing the response of breast cancer sub-histological types to CDK4/6i are limited. Thus, our study contributes to the literature.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Gennari A, André F, Barrios C, Cortes J, de Azambuja E, DeMichele A, et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021;32(12):1475-95.
2. Watt AC, Goel S. Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer. Breast Cancer Res. 2022;24(1):17.
3. Goyal RK, Chen H, Abughosh SM, Holmes HM, Candrilli SD, Johnson ML. Overall survival associated with CDK4/6 inhibitors in patients with HR+/HER2–metastatic breast cancer in the United States: A SEER‐Medicare population‐based study. Cancer. 2023;129(7):1051-63.
4. Cserni G. Histological type and typing of breast carcinomas and the WHO classification changes over time. Pathologica. 2020;112(1):25.
5. McCart Reed AE, Kalinowski L, Simpson PT, Lakhani SR. Invasive lobular carcinoma of the breast: the increasing importance of this special subtype. Breast Cancer Res. 2021;23:1-16.
6. Mouabbi JA, Hassan A, Lim B, Hortobagyi GN, Tripathy D, Layman RM. Invasive lobular carcinoma: an understudied emergent subtype of breast cancer. Breast Cancer Res Treat. 2022;193(2):253-64.
7. Alexander J, Schipper K, Nash S, Brough R, Kemp H, Iacovacci J, et al. Pathway-based signatures predict patient outcome, chemotherapy benefit and synthetic lethal dependencies in invasive lobular breast cancer. Br J Cancer. 2024;130(11):1828-1840.
8. Pramod N, Nigam A, Basree M, Mawalkar R, Mehra S, Shinde N, et al. Comprehensive review of molecular mechanisms and clinical features of invasive lobular cancer. Oncologist. 2021;26(6):e943-53.
9. Gao JJ, Cheng J, Bloomquist E, Sanchez J, Wedam SB, Singh H, et al. CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis. Lancet Oncol. 2020;21(2):250-60.
10. Gao JJ, Cheng J, Prowell TM, Bloomquist E, Tang S, Wedam SB, et al. Overall survival in patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer treated with a cyclin-dependent kinase 4/6 inhibitor plus fulvestrant: a US Food and Drug Administration pooled analysis. Lancet Oncol. 2021;22(11):1573-81.
11. Mouabbi JA, Raghavendra AS, Bassett Jr RL, Hassan A, Tripathy D, Layman RM. Histology-based survival outcomes in hormone receptor-positive metastatic breast cancer treated with targeted therapies. NPJ Breast Cancer. 2022;8(1):131.
12. Hortobagyi GN, Stemmer SM, Burris HA, Yap Y-S, Sonke GS, Paluch-Shimon S, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541-47.
13. Freitas P, Pina A, Carola S, Cardoso C, Gouveia E, Vaz F, et al. Lobular carcinoma of the breast and response to targeted therapy with CDK4/6 inhibitors–a single Portuguese center experience. Eur J Cancer. 2022;175:S73.
14. von Arx C, Calabrese A, Martinelli C, Di Lauro V, Grimaldi V, Pensabene M, et al. 449P Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) treatment in metastatic lobular breast cancer (mLBC): A retrospective cohort study. Ann Oncol. 2023;34:S370.
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Ovarian endometrioma disrupts cumulus cell vitamin D receptor mRNA expression
Ramazan Ozyurt 1, Aret Kamar 2
1 Department of Obstetrics and Gynecology, Bakırköy Dr. Sadi Konuk Research and Training Hospital, 2 Department of Obstetrics and Gynecology, Private Istanbul IVF-Unit, Istanbul, Turkey
DOI: 10.4328/ACAM.22355 Received: 2024-08-04 Accepted: 2024-09-24 Published Online: 2024-11-11 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):94-98
Corresponding Author: Ramazan Ozyurt, Department of Obstetrics and Gynecology, Bakırköy Dr. Sadi Konuk Research and Training Hospital, Istanbul, Turkey. E-mail: atasagun02@hotmail.com P: +90 532 748 34 90 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6822-2222
Other Authors ORCID ID: Aret Kamar, https://orcid.org/0000-0002-4737-6895
This study was approved by the Ethics Committee of Bakirkoy Dr. Sadi Konuk Education and Research Hospital Clinical Research (Date: 2024-06-24, No: 2024-04-35/161)
Aim: To determine the vitamin D receptor (VDR) mRNA expression pattern in cumulus cells (CCs) isolated from metaphase II (MII) oocytes retrieved from patients with unilateral endometrioma during controlled ovarian stimulation (COS).
Material and Methods: Twelve unilateral unoperated endometrioma patients selected for in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) were included in the study. For the control group, the left ovaries of 12 women undergoing IVF/ICCI treatment due to male factor infertility were chosen. Flexible GnRH antagonist protocol for controlled ovarian stimulation was applied to both groups. A total of 99 CC samples, 28 in the endometrioma group, 34 in the contralateral ovary group, and 37 in the control group, were subjected to qRT-PCR analysis was conducted to assess mRNA expression of VDR transcript 2 (VDR-X2).
Results: CC-VDR-X2 expression of the disease-free contralateral ovary appeared to be equivalent to the control group. mRNA expression levels of CC-VDR-X2 in patients diagnosed with endometrioma were significantly lower than the mRNA expression of the disease-free contralateral ovary and control group. A significant 2.31-fold downregulation was observed in the CC-VDR-X2 mRNA expression of the endometrioma group when compared to the CC-VDR mRNA expression of the contralateral ovary. The expression of CC-VDR-X2 mRNA in MII oocytes of the endometrioma-affected ovary was down-regulated 2.63-fold compared to the CC-VDR-X2 mRNA expression of the control group. 2PN zygote rates of endometrioma patients with low VDR-X2 levels were found to be similar to MII oocytes with normal VDR-X2 expression in the contralateral and control groups.
Discussion: Unilateral endometrioma may cause subfertility by blocking CC-VDR mRNA expression.
Keywords: Endometrioma, Cumulus Cell, Vitamin D Receptor, RT-PCR
Introduction
Endometrioma is a disease characterized by the presence of one or multiple cysts in one ovary or both, which histologically and functionally mimic eutopic endometrium, appearing in approximately one-third of women with endometriosis [1]. Infertility due to endometriomas has been attributed mainly to the adverse effects of cysts on oocytes’ developmental capacity and, less commonly, to endometrial dysfunction [2-5] Mechanical stress caused by endometriomas, depending on their number, size, and location, can harm the both quantity and quality of oocytes by disrupting the blood supply and innervation of developing follicles [1, 3]. If endometrioma disrupts the normal anatomy of the fallopian tubes, it may negatively affect sperm-oocyte interaction and embryo transport [6]. In addition to the mechanical effect, free iron within the cyst may cause inflammation and embryotoxicity, leading to a decrease in the count number and quality of oocytes along with impaired embryo development [7, 8]. Despite all these data, the available data are not clear on how endometriomas affect oocyte developmental capacity. Early follicular atresia due to local inflammation and mechanical compression has been suggested as a possible mechanism [9]. However, the fact that cysts are removed via surgery did not significantly change the reproductive outcome bringing us to the question that endometrioma might be a developmental defect of the oocyte pool [10].
Ovarian steroidogenesis and follicular development are regulated by numerous systemic hormones and local paracrine factors, which act through the two-cell, two-gonadotropin pathway [11]. Vitamin D is a secosteroid that plays a role in the balance of intra-follicular inflammation required for ovarian steroid synthesis and cumulus expansion via its nuclear receptor. There is a broad expression of the Vitamin D Receptor (VDR) not only in calcium metabolism tissues but also in cumulus cells (CCs) [11-13]. The VD-VDR complex, with its anti-inflammatory and immunomodulatory properties, might help regulate the intra-follicle inflammatory balance and steroidogenesis necessary for the development of a competent oocyte [13]. The lower risk of developing endometriosis in women with high serum 25(OH)VitD [14, 15] and lower VD levels in severe endometriosis compared to women with mild endometriosis [16] are clues to the relationship between VD and endometriosis. If the insufficiency of oocyte developmental capacity in endometrioma is due to steroid synthesis defect, VDR expression, which is key to ovarian steroidogenesis, must likewise be negatively affected. The way to test this hypothesis is to analyze VDR-mRNA expression in CC cells obtained from diseased and healthy ovaries in unilateral endometrioma. This study was planned to determine the VDR mRNA expression pattern in CCs isolated from metaphase II (MII) oocytes of patients with unilateral endometrioma during controlled ovarian stimulation (COS).
Material and Methods
A group of twelve patients who applied to the Istanbul IVF unit for in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) with the diagnosis of unilateral unoperated ovarian endometrioma were included in the study. Participants were selected among patients applying to the Istanbul IVF unit.
After obtaining consent to collect cumulus samples from the same center, patient-informed consent was also obtained. A comparison was made between the affected and the intact contralateral gonads in terms of cumulus cell VDR mRNA expression. The control group consisted of the left ovaries of 12 women who were set to undergo IVF/ICSI for male factor infertility. The twelve participants in the control group were identified from infertile patients who were age-matched with the endometrioma group and had both ovaries intact (endometrioma-free). The criteria for inclusion specified women under 35, undergoing IVF-ICSI, having no infertility cause besides endometrioma, possessing one or more ultrasound-diagnosed unilateral endometriomas, confirmed over two cycles, and no prior endometrioma surgeries. The criteria for exclusion were: a history of surgical intervention for either unilateral or bilateral endometrioma, surgery for a non-endometriotic benign ovarian cyst, diagnosis of bilateral endometrioma, and patients over 35 years of age.
Endometrioma diagnosis was established using transvaginal ultrasonography conducted between days 2 and 3 of the cycle, as previously stated [17] the numbers of antral follicles in the diseased and intact ovaries were also recorded. Endometrioma diameter was calculated by taking the average of the lengths of three perpendicular diameters4,5. Flexible GnRH antagonist protocol for controlled ovarian stimulation was applied to both groups. rFSH (Gonal-f, Merck Group, Darmstadt, Germany) was started on days 2 and 3 of the spontaneous menstrual cycle. The initial dose of rFSH was determined according to the patient’s age, AFC, and AMH values. Pituitary suppression was achieved using the GnRH antagonist Cetrotide (Merck Group, Darmstadt, Germany) which was started when the dominant follicle was ≥ 14 mm. Ovulation was triggered with recombinant hCG (Ovitrelle, Merck Group, Darmstadt, Germany) when two or more follicles were ≥ 18 mm. Oocytes were collected 36 hours after the ovulation trigger. COCs, gathered under ultrasound guidance, were then subjected to cumulus cell processing.
CCs were separated from COCs by both enzymatic and mechanical methods. COCs were subjected to COC classification after being placed in new Petri dishes: COC grade 1 refers to mature oocytes that possess the first polar body (MII stage), COC grade 2 indicates the absence of the first polar body (MI stage), and COC grade 3 indicates GV stage oocytes. Mature oocytes (MII) were the sole source of CCs used for qRT-PCR. After two hours of incubation, each COC was denudated first enzymatically with Hyase and then mechanically with pipettes. The collected CCs were transferred to RNA-later-containing tubes and stored until total RNA extraction. CC samples of the ovary containing endometrioma were labeled CCMII-end (+) and CC samples of the contralateral ovary were labeled CCMII-end (-). The vials containing the left ovarian CC samples of the women in the control group were labeled as CCMII-con (Table 1). A total of 99 CC samples, 28 in the endometrioma group, 34 in the contralateral ovary group, and 37 in the control group, were subjected to qRT-PCR.
Quantitative RT-PCR analysis of VDR-X2
The mRNA expression of the VDR transcript 2 (VDR-X2) gene was analyzed using qRT-PCR. Total RNA isolation was performed with PureLink Total RNA Mini Kit (Invitrogen). Total RNA concentration was measured with a Qubit Fluorometer. cDNAs were amplified by qRT-PCR with sequence-specific primers. Glyceraldehyde-3-phosphate dehydrogenase was preferred as a reference gene. Primers used for qRT-PCR had the following sequences: VDR-X2: Forward 5’-ACATTGCTTTGCTTGCCTCC-3’, Reverse 5’-ACGTTCCGGTCAAAGTCTCC-3’,
GAPDH: Forward 5’-GAAGATGGTGATGGGATTTC-3’,
Reverse 5’-GAAGGTGAAGGTCGGAGTC-3’.
Statistical Analysis
The analysis of the data was carried out with IBM SPSS Statistics Version 22.0 for Windows (IBM Corp., Armonk, NY, USA). Independent samples t-test was employed for variables that displayed a normal distribution, whereas the Kruskall-Wallis test was used for those with non-normal distribution. Mean ± standard deviation is used to present continuous variables. p<0.05 was considered significant. Relative gene expression was measured following the 2-ΔΔCt formula. The presence of a statistical difference in VDR-X2 mRNA expression was evaluated using one-way ANOVA, followed by Tukey’s multiple comparison test. CC-VDR-X2 mRNA expressions of endometrioma and contralateral disease-free ovaries were normalized by taking the CC-VDR-X2 mRNA expression of the control group as 1.
Ethical Approval
This study was approved by the Ethics Committee of Bakirkoy Dr. Sadi Konuk Education and Research Hospital Clinical Research Ethics Committee (Date: 2024-06-24, No: 2024-04-35/161).
Results
Table 2 displays the demographic characteristics of the participants. It was highlighted that the mean age (28.4±3.21 years vs. 27.5±3.81, p=0.233) infertility duration, AFC, and serum levels of AMH were similar in both groups. A significant reduction in serum VD levels was observed in the endometrioma group when compared to the control group. There was no significant difference between groups in terms of total gonadotropin dose used and total number of oocytes collected. The average uni-lateral endometrioma diameter was measured as 31.97±1.29 mm. CC-VDR-X2 expression levels of the disease-free contralateral ovary were found to show similarity to the control group (1.01 ± 0.22 vs. 0.88± 0.23, p = 0.556). In patients with endometrioma showed CC-VDR-X2 mRNA expression levels that were significantly lower than the mRNA expression of the disease-free contralateral ovary (0.38± 0.06 vs. 0.88 ± 0.23, p<0.002) and control group (0.38± 0.06 vs. 1.01 ± 0.22, p<0.001). A significant 2.31-fold downregulation was observed in the CC-VDR-X2 mRNA expression of the endometrioma group when compared to the CC-VDR mRNA expression of the contralateral ovary (Figure 1). CC-VDR-X2 mRNA expression of the MII oocytes of endometrioma ovary was down-regulated 2.63-fold compared to the CC-VDR-X2 mRNA expression of the control group. The COC morphologies of the endometrioma group with low VDR mRNA expression and the control and contralateral ovary groups with normal VDR expression were similar. Low VDR-X2 expression did not cause CC loss, darkening, or compaction. Fertilization rates after ICSI were similar in endometrioma and control groups. 2PN zygote rates of endometrioma patients with low VDR-X2 levels were similar to normal VDR-X2-expressing MII oocytes of the contralateral and control groups. In the endometrioma group, the 2 PN zygote rate was 71.4%, while it was 76.4% in the contralateral ovary group, and 78.3% in the control group.
Discussion
Studies on how endometriomas affect oocyte quality and development have been mostly done using granulosa cells [18, 19]. It is thought that endometriomas exert their adverse effects on oocyte developmental capacity through more than one mechanism. One possible cause is that the malfunctioning of the two-cell, two-gonadotropin pathway due to the inflammatory follicular microenvironment negatively affects ovarian steroidogenesis [20, 21]. Cumulus granulosa cells effectively use vitamin D and nuclear vitamin D receptors during estrogen and progesterone synthesis [12]. Our analysis in this study is the first to examine the CC-VDR mRNA expression patterns of patients who underwent IVF/ICSI due to unilateral endometrioma. CC-VDR levels of endometrioma ovaries showed a 2.3-fold downregulation compared to the contralateral ovary. Similarly, CC-VDR levels of the endometrioma group showed a 2.6-fold downregulation compared to healthy controls without endometrioma. Our findings are of clinical importance as they provide the first evidence that CC-VDR expression, which is involved in ovarian steroid synthesis, is defective in the presence of endometrioma. Consistent with our findings, endometriomas are known to disrupt estradiol synthesis by reducing P450 aromatase expression in GCs [3]. For the follicle to reach metaphase II and gain competence, estradiol, a steroid, is necessary. [19]. The reduced estradiol levels in the follicular fluid, as compared to the control group are important evidence that endometrioma causes ovarian steroidogenesis defects [22]. Many studies have suggested that endometriomas disrupt ovarian steroidogenesis through mechanical action and the toxic effect of the ferrous content of the cyst [1-3]. In addition to the mechanical and ferroptotic effects of cysts, the decrease in CC-VDR expression in the presence of endometrioma may also contribute to the steroid synthesis defect.
How endometriomas lead to VDR expression defects is still unclear. In a physiological follicular cycle, CC-VDR expression increases in the presence of active VD. VD-VDR complex activation increases progesterone and estradiol synthesis by stimulating the production of 3β-hydroxysteroid dehydrogenase and insulin-like growth factor binding protein-1 [23]. The reduced serum VD levels in the unilateral endometrioma group, relative to the control group, might cause defects in CC-VDR expression. To clarify the influence of VD deficiency on CC-VDR, cumulus cell VDR expressions of patients with and without VD replacement before endometrioma cystectomy should be analyzed.
Since we found the AFC and total oocyte numbers collected in the endometrioma group to be similar to the contralateral ovary, we thought that unilateral endometrioma did not negatively affect the ovarian reserve. The effects of endometriomas on ovarian reserve may vary depending on whether the cyst is unilateral or bilateral. Although bilateral endometrioma causes a decrease in the total number of oocytes and poor embryo quality, the implantation, clinical pregnancy, or live birth rates are similar to healthy controls. In good agreement with this, a recent meta-analysis reported that endometriomas reduce the total number of oocytes retrieved, the yield of MII oocytes, and the embryo count [24]. Despite this, comparisons between unilateral endometrioma and contralateral normal ovaries in various studies revealed no differences regarding the total oocytes collected, MII oocytes, and embryo numbers [25].
We did not detect a significant difference between the COC morphology of the endometrioma group showing VDR expression defect and the COC morphology of the contralateral ovary and control groups. This finding suggests that VDR expression defect does not cause significant changes in cumulus expansion and corona radiata polarization. If VDR was directly involved in cumulus expansion, the COC morphology of endometrioma patients would be defective. In light of this information, we should not expect to obtain a different image from healthy controls when evaluating the COCs of endometrioma patients exhibiting VDR expression defects. However, normal COC morphology does not exclude the fact that steroid synthesis may be defective in patients with endometriomas with low VDR expression. The fact that fertilization rates after ICSI were similar in the endometrioma and control groups suggests that VDR expression defect is a pathology that can be treated with ICSI. Low VDR expression may contribute to endometrioma-associated infertility by disrupting the intra-follicle anti-inflammatory and immunomodulatory balance.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Sanchez AM, Vigano P, Somigliana E, Panina-Bordignon P, Vercellini P, Candiani M. The Distinguishing Cellular and Molecular Features of the Endometriotic Ovarian Cyst: From Pathophysiology to the Potential Endometrioma-Mediated Damage to the Ovary. Hum Reprod Update. 2014;20(2):217-30.
2. Sanchez AM, Papaleo E, Corti L, Santambrogio P, Levi S, Viganò P, et al. Iron availability is increased in individual human ovarian follicles in close proximity to an endometrioma compared with distal ones. Hum Reprod. 2014;29(3):577-83.
3. Sanchez AM, Somigliana E, Vercellini P, Pagliardini L, Candiani M, Vigano P. Endometriosis as a detrimental condition for granulosa cell steroidogenesis and development: from molecular alterations to clinical impact. J Steroid Biochem Mol Biol. 2016;155(Pt A):35-46.
4. Celik O, Acet M, Kucuk T, Haberal ET, Acet T, Bozkurt M, et al. Surgery for Benign Gynecological Disorders Improve Endometrium Receptivity. Reprod Sci. 2017;24(2): 174-92.
5. Celik O, Celik E, Turkcuoglu I, Yilmaz E, Ulas M, Simsek Y, et al. C. Surgical removal of endometrioma decreases the NF-kB1 (p50/105) and NF-kB p65 (Rel A) expression in the eutopic endometrium during the implantation window. Reprod Sci. 2013;20(7):762-70.
6. Wu Y, Yang R, Lan J, Lin H, Jiao X, Zhang Q. Ovarian Endometrioma Negatively Impacts Oocyte Quality and Quantity But Not Pregnancy Outcomes in Women Undergoing IVF/ICSI Treatment: A Retrospective Cohort Study. Front Endocrinol (Lausanne). 2021;12:739228.
7. Li A, Ni Z, Zhang J, Cai Z, Kuang Y, Yu C. Transferrin Insufficiency and Iron Overload in Follicular Fluid Contribute to Oocyte Dysmaturity in Infertile Women With Advanced Endometriosis. Front Endocrinol. 2020;11:391.
8. Eisenberg VH, Weil C, Chodick G, Shalev V. Epidemiology of Endometriosis: A Large Population-Based Database Study From a Healthcare Provider With 2 Million Members. BJOG. 2018;125(1):55-62.
9. Kitajima M, Dolmans MM, Donnez O, Masuzaki H, Soares M, Donnez J. Enhanced follicular recruitment and atresia in cortex derived from ovaries with endometriomas. Fertil Steril. 2014;101(4):1031-37.
10. Collinet P, Fritel X, Revel-Delhom C, Ballester M, Bolze PA, Borghese B, et al. Management of endometriosis: CNGOF-HAS practice guidelines (short version)]. Gynecol Obstet Fertil Senol. 2018;46(3):144-55.
11. Ciepiela P, Dulęba AJ, Kowaleczko E, Chełstowski K, Kurzawa R. Vitamin D as a follicular marker of human oocyte quality and a serum marker of in vitro fertilization outcome. J Assist Reprod Genet. 2018;35(7):1265-76.
12. Irani M, Merhi Z. Role of vitamin D in ovarian physiology and its implication in reproduction: a systematic review. Fertil Steril. 2014;102(2):460-468.e3.
13. Shahbazi M, Jeddi-Tehrani M, Zareie M, Salek-Moghaddam A, Akhondi MM, Bahmanpoor M, et al. Expression profiling of vitamin D receptor in placenta, decidua and ovary of pregnant mice. Placenta. 2011;32(9):657-64.
14. Harris HR, Chavarro JE, Malspeis S, Willett WC, Missmer SA. Dairy-food, calcium, magnesium, and vitamin D intake and endometriosis: a prospective cohort study. Am J Epidemiol. 2013;177(5):420-30.
15. Kalaitzopoulos DR, Lempesis IG, Athanasaki F, Schizas D, Samartzis EP, Kolibianakis EM, et al. Association between vitamin D and endometriosis: a systematic review. Hormones (Athens). 2020;19(2):109-21.
16. Miyashita M, Koga K, Izumi G, Sue F, Makabe T, Taguchi A, et al. Effects of 1,25-Dihydroxy Vitamin D3 on Endometriosis. J Clin Endocrinol Metab. 2016;101(6):2371-79.
17. Nezhat FR, Cathcart AM, Nezhat CH, Nezhat CR. Pathophysiology and Clinical Implications of Ovarian Endometriomas. Obstet Gynecol. 2024;143(6):759-66.
18. Ouandaogo ZG, Frydman N, Hesters L, Assou S, Haouzi D, Dechaud H, et al.Differences in transcriptomic profiles of human cumulus cells isolated from oocytes at GV, MI and MII stages after in vivo and in vitro oocyte maturation. Hum Reprod. 2012;27(8): 2438-47.
19. Dumesic DA, Meldrum DR, Katz-Jaffe MG, Krisher RL, Schoolcraft WB. Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health. Fertil Steril. 2015;103(2):303-16.
20. Singh AK, Dutta M, Chattopadhyay R, Chakravarty B, Chaudhury K. Intrafollicular interleukin-8, interleukin-12, and adrenomedullin are the promising prognostic markers of oocyte and embryo quality in women with endometriosis. J Assist Reprod Genet. 2016;33(10):1363-72.
21. Sanchez AM, Vanni VS, Bartiromo L, Papaleo E, Zilberberg E, Candiani M, et al. Is the oocyte quality affected by endometriosis? A review of the literature. J Ovarian Res. 2017;10(1):43.
22. Ni Z, Li Y, Song D, Ding J, Mei S, Sun S, et al. Iron-overloaded follicular fluid increases the risk of endometriosis-related infertility by triggering granulosa cell ferroptosis and oocyte dysmaturity. Cell Death Dis. 2022;13(7):579.
23. Yland J, Carvalho LFP, Beste M, Bailey A, Thomas C, Abrão MS, et al. Endometrioma, the follicular fluid inflammatory network, and its association with oocyte and embryo characteristics. Reprod Biomed Online. 2020;40(3):399-408.
24. Yang C, Geng Y, Li Y, Chen C, Gao Y. Impact of ovarian endometrioma on ovarian responsiveness and IVF: A systematic review and meta-analysis. Reprod Biomed Online. 2015;31(1):9-19.
25. Sanchez AM, Vanni VS, Bartiromo L, Papaleo E, Zilberberg E, Candiani M, et al. Is the oocyte quality affected by endometriosis? A review of the literature. J Ovarian Res. 2017;10(1):43.
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Ramazan Ozyurt, Aret Kamar. Ovarian endometrioma disrupts cumulus cell vitamin D receptor mRNA expression. Ann Clin Anal Med 2025;16(2):94-98
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Is there a relationship between temporomandibular disorder and sacroiliac joint dysfunction?
Sultan İğrek 1,2, Tuğba Kuru Çolak 3, İlker Çolak 4, Erdinç Çekiç 5
1 Department of Physiotherapy and Rehabilitation, Institute of Health Sciences, Marmara University, 2 Department of Therapy and Rehabilitation, Vocational School, Istanbul Beykent University, 3 Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Marmara University, 4 Department of Orthopaedics and Traumatology, VM Medical Park Maltepe Hospital, 5 Otorhinolaryngology Private Clinic, Istanbul, Turkey
DOI: 10.4328/ACAM.22373 Received: 2024-08-19 Accepted: 2024-10-21 Published Online: 2024-11-09 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):99-104
Corresponding Author: Sultan İğrek, Department of Therapy and Rehabilitation, Vocational School, Istanbul Beykent University, Istanbul, Turkiye. E-mail: sultanigrek@gmail.com P: +90 537 210 06 54 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6983-0470
Other Authors ORCID ID: Tuğba Kuru Çolak, https://orcid.org/0000-0002-3263-2278 . İlker Çolak, https://orcid.org/0000-0003-2960-2825 . Erdinç Çekiç, https://orcid.org/0000-0001-8784-174X
This study was approved by the Ethics Committee of Marmara University, Faculty of Medicine Clinical Researches (Date: 2023-05-05, No: 09.2023.675)
Aim: The aim of this prospective clinical study was to evaluate the possible association between temporomandibular disorders (TMD) and sacroiliac joint dysfunction (SIJD) and to determine the immediate effect of a single session of orofacial manual therapy (OMT) on SIJD.
Material and Methods: Twenty-four patients, aged 18 to 60, diagnosed with both TMD and SIJD, underwent a single-session OMT treatment. Orofacial pain, pressure pain thresholds (PPT) in the masseter, temporalis, and spina iliaca posterior superior (SIPS), temporomandibular joint (TMJ) range of motion (ROM), hipomobility in the SIPS, and functionality were evaluated before and after the treatment.
Results: A statistically significant improve was observed in the Orofacial pain scores, all TMJ ROM values, PPT in masseter, temporalis, and SIPS, Patrick’s Faber test score, and Oswestry Disability Index score after treatment in all participants (p = .000).
Discussion: Assessing and managing the joints together can lead to a more comprehensive evaluation of patients with Sacroiliac and Temporomandibular joint dysfunction symptoms, enhancing the overall effectiveness of the treatment.
Keywords: Temporomandibular Disorder, Sacroiliac Joint, Facial Pain, Manual Therapies
Introduction
Temporomandibular disorder (TMD) is a specific category of orofacial disorders that encompasses issues such as temporomandibular joint (TMJ) pain, fatigue in the craniocervical muscles—particularly the masticatory muscles—restricted movement of the jaw, and clicking or deviation during jaw movements [1]. TMD is a prevalent issue in clinical settings, affecting approximately 33% of the general population [2]. The most frequently reported symptom is facial pain, which can present as either acute or chronic [1]. The causes of TMD are diverse and include factors such as anxiety, stress, bruxism, alterations in occlusion and posture, dysfunction of the masticatory muscles and other bodily structures, or a combination of these elements [3].
Sacroiliac joint dysfunction (SIJD) is one of the most common causes of non-discogenic low back pain. With a reported incidence of 10-27%, it is also responsible for mechanical and chronic hip or leg pain [4]. The relationship between occlusal disorders of the TMJ, cervical spine and sacroiliac joint (SIJ) has been evaluated and coexisting dysfunction in these regions has been obtained [5]. Cases of TMD have been reported in which lumbosacral pain and malocclusion were successfully treated together [6- 7]. These results suggest a functional connection between these regions. This connection is based on diaphragms, neural connections, and the presence of myofascial chains [8, 9]. Based on these findings, this study focused on the possible relationship between TMD and SIJD.
The aim of this prospective clinical study was to evaluate the possible association between TMD and SIJD, and to determine the immediate effect of a single session of orofacial manual therapy (OMT) on SIJD. The hypothesis was that a single session of manual therapy applied to the temporomandibular joint can reduce complaints related to the sacroiliac joint.
Material and Methods
Study design and participants
This study was conducted on patients aged 18–60 years diagnosed with TMD – reduction disc displacement between September 2023 and March 2024. This study was approved by Ethical Committee (Decision no: 09.2023.675). All the study procedures conformed to the provisions of the World Medical Association Declaration of Helsinki. Patients who agreed to participate in the study were included in the study if they gave verbal and written informed consent. This study was registered in the WHO International Clinical Trials Registry Platform (NCT06035341).
Patients with orofacial pain who presented to the Department of Otorhinolaryngology at Outpatient Clinic and were diagnosed with Temporomandibular Disorder with reduction disc displacement, based on physical and radiological examinations conducted by a specialist physician, were subsequently referred to the Orthopedics and Traumatology Department. In this department, the patients were evaluated for sacroiliac joint dysfunction (SIJD) by an Orthopedics and Traumatology specialist. Those patients who were diagnosed with SIJD in addition to Temporomandibular Disorder with reduction disc displacement and who agreed to participate in the study were included in the research.
Patients were excluded from the study if they had a history of malignant condition, trauma or surgery in the cranial or cervical region, are uncooperative, use regular analgesic or anti-inflammatory drugs, have dentofacial anomalies, active inflammatory arthritis, metabolic diseases (Gout, osteoporosis, Cushing’s disease, and hyper/hypo parathyroidism), connective tissue, rheumatological (Systemic lupus erythematosus and scleroderma) and hematological disorders (Anemia and leukemia), diagnosed psychiatric diseases, and received TMD-related physical therapy less than 6 months ago.
Assessment Methods
Demographic and clinical characteristics of patients were recorded. As evaluation parameters orofacial pain, pressure pain threshold (PPT) in masseter, temporalis, and spina iliaca posterior superior (SIPS), TMJ range of motion (ROM), functionality and mobility in SIJ were evaluated. Orofacial pain, PPT, TMJ ROM and mobility in SIJ were evaluated before treatment and 5 minutes after treatment. Functionality was evaluated before treatment and 1 week after treatment.
Orofacial pain was evaluated using the Visual Analog Scale (VAS). This scale consists of numbers from 0 to 10. Accordingly, “0” describes no pain, and “10” describes unbearable pain. The patient was asked to mark the intensity of the pain he/she felt and it was explained that the intensity of pain increased from 0 to 10 [10].
Mandibular movements depression, right and left lateral excursion, protrusion, and retrusion) using a 15 cm ruler. Individuals were asked to perform these movements as much as possible without causing pain. The distance between the maxillary and mandibular central incisors were measured using a ruler. Measurements were recorded three times and the average of the recorded measurements were noted [11].
A digital algometer (Jtech Medical Commander Algometer) was used to objectively measure the PPT. The algometer was checked by pressing the pulp of the thumb of the hand before starting the measurement. Then, pressure was applied 1 cm below the SIPS and on the central TP of the masseter and temporalis muscles by increasing the pressure by 1 kg/cm² every three seconds until the individual feels pain. The physiotherapist passively supported the individual’s head with the other hand. The individual was instructed to report when they felt pain while applying force with the device (kg/cm²). Three pressure pain threshold measurements were made with a 2-min rest interval between trials. The mean of the 3 trials was calculated and used for analysis [12].
The Patrick-Faber test was used to assess the mobility of the sacroiliac joint. For the measurement of the test, one examiner stabilized the patient while another measured the vertical distance in centimeters between the mark on the lateral edge of the patella and the base. A greater distance indicated higher tension in the adductor muscles and less sacroiliac joint mobility [5].
Functionality was assessed using the Oswestry Disability Index (ODI). The ODI is a valid and reliable questionnaire that evaluates daily living activities across 10 different areas, including pain intensity, personal care, lifting, walking, sitting, standing, sleep, changes in pain, social life, and travel [13]. Scores range from a minimum of 0 to a maximum of 50. The questionnaire was filled out in person prior to treatment and was administered via telephone one week post-treatment.
Treatment Protocol
Participants underwent a single session of OMT (Figure 1). Immediately after the treatment, the participants were asked to walk for 5 minutes and then orofacial pain, pressure pain threshold, TMJ ROM and SIJ mobility were assessed as a second evaluation. Functionality was assessed 1 week later as the third evaluation. The OMT treatment program included trigger point therapy, myofascial release, TMJ traction, joint mobilization with traction, muscle energy technique, mandibular fascia release, occipital release, and ligament therapy [14, 15].
Statistical analysis
G*Power V3.1.9.2 was used to calculate the sample size of the study. The effect size calculated based on the study of Fink et al. (Faber test pre-intervention=16.3±3.8, post-intervention=18.4±3.8) was determined as f=0.55 [5]. Accordingly, the minimum sample size to was reached with a power of 0.80 for α=0.05 type 1 error probability was calculated as 23 people.
IBM Statistical Package for Social Sciences 24 (SPSS, Chicago, USA) statistical program was used for data analysis. Continuous variables were given as mean ± standard deviation, and qualitative variables were given as numbers and percentages (%). It was determined that the data showed normal distribution with the Shapiro–Wilk test, and the relationship between the variables was evaluated with Pearson correlation analysis. Paired Samples test was used to compare the evaluation results obtained before and after treatment. Statistical significance was taken as p < 0.05 in all measurements.
Ethical Approval
This study was approved by the Ethics Committee of Marmara University, Faculty of Medicine Clinical Researches (Date: 2023-05-05, No: 09.2023.675).
Results
Out of the 53 who volunteered to participate in the study, 29 did not meet the inclusion criteria (Figure 2). Twenty-one of the participants were women (87.5%). The median age was 34.8 years and the median BMI was 26.2 kg/m2. 41.7% of the participants had a history of trauma, 8.3% had a history of surgery, 45.8% had allergies, 79.2% had gastrointestinal diseases, 91.7% chewed unilaterally, 70% had missing teeth, 100% had parafunctional habit and 75% had bruxism (Table 1).
Statistically significant improvement were observed in the Orofacial VAS scores, all mandibular joint ROM values, PPT in masseter, temporalis after treatment in all participants (p = .000). Also, statistically significant improvement were observed in the PPT in SIPS, Patrick’s Faber test score, and ODI score after treatment in all participants (p = .000), (Table 2). Positive significant relationship were found between the PPT in masseter, temporalis, and SIPS (r: 0.408, 0.411; p: 0.48, 0.46).
Discussion
The relationship between the craniomandibular system and the SIJ and the mechanisms connecting the two remain unclear. To the best of our knowledge, this study is the first clinical research investigating the effects of OMT applied to the TMJ not only on TMD symptoms but also on SIJ symptoms.
After a single-session treatment, participants showed significant improvements in pain levels, pressure pain thresholds of the masseter and temporalis muscles, and all ranges of motion ROM of the TMJ. Furthermore, enhancements in orofacial pain, all TMJ ROM values, and the pressure pain thresholds of the masseter and temporalis—resulting from orofacial manual therapy—also contributed to better mobility and pressure pain thresholds of the SIPS, along with improved overall functionality.
Although the relationship between TMD and SJD is difficult to explain, a study conducted on healthy individuals [5] showed that hypomobility functional abnormalities of the SIE emerged after artificial occlusal intervention and suggested that there was a correlation between functional abnormalities of the TMJ and SIJ, which were thought to result from ventrodorsal muscle imbalances. In a study comparing the three-dimensional motion SIEs of patients with TMJ disorders and healthy individuals, it was found that especially joint disc disorders (the most common anterior disc displacement with reduction) may alter the kinematics of the sacroiliac joint [16]. This result indicates that there are statistically significant differences in SIJ kinematics between patients with TMD and healthy individuals. However, it remains unclear whether TMD is the cause or the consequence of these changes. In another study, the function of SIEs was evaluated using functional tests before and after stabilizing the abnormal position of the mandibular condyle in patients with TMD with the use of a temporary silicone occlusal splint [17]. Significant improvements in test results were observed following the stabilization of the mandibular condyle. Several case studies have also suggested a correlation between TMD and SIJD [6, 7]. Chinappi et al. observed that simultaneous chiropractic and orthodontic treatment in a patient presenting with SIJD complaints resulted in an improvement in SIJD symptoms and indicated a potential connection between these two areas [6]. In a study where neural therapy was applied to the TMJ, masseter muscle, and C4 level of a patient with both TMD and SIJD, a reduction in the patient’s SIJD symptoms was observed [7]. In this study, improvements in SIJ hypomobility and pressure pain threshold were obtained after OMT was applied to patients with both TMD and SIJD. This results demonstrate a coexistence of these two dysfunctions. However, further research is needed to determine their causative relationships and outcomes.
In the study by Oliveira et al., the effects of occlusal splint and physiotherapy treatment on postural balance were investigated in patients with TMD using a stabilometric platform [18]. A statistically significant increase in antero-posterior velocity was observed in all patients, indicating that this result impacted postural balance. Chung et al., who examined changes in the gait of patients with lower extremity disorders using exercise equipment for TMJ, concluded that the pelvic center point swayed less during the one-legged stance test due to increased stability after treatment [19]. They also reported statistically significant differences in hip, knee, and ankle angles during walking, with these angles returning to the normal range. Tecco et al. found that TMJ disorders were associated with statistically significant changes in walking function based on gait analysis [20]. Although gait analysis was not used in this study, a questionnaire addressing daily life functions—such as walking, sitting, and carrying loads—was utilized. Significant improvements were noted in patients’ daily life functionality following treatment. These results can reflect the relationship between TMD and SIJD and its impact on functionality.
Manual therapy approaches have an important role in TMJ function, ROM and pain [9, 21]. In this study, after the treatment of orofacial pain, pressure pain threshold in masseter, and temporalis muscles, and ROM values improved in participants. These results may occur due to pain modulation via activating low-threshold Aβ fibers pathway. This inhibits nociceptive stimuli from Aδ and C supply fibers. MT can also elicit affective responses activating opioid, oxytocin, and dopaminergic pathways [22]. Due to these effects, several theories exist regarding how improvements in TMD achieved through OMT may impact the SIJ. The relationship between TMJ and SIJ is based on diaphragms, neural connections, and the presence of myofascial chains. The trigeminal nerve is significant due to its role in maintaining postural control, while fascia is of potential importance because it can transmit tension and, through its proprioceptive and nociceptive functions, contribute to referred pain and functional impairments in distant anatomical structures [9]. Additionally, there are five anatomical diaphragms in the body. These are: the diaphragm muscle, the pelvic floor, the floor of the mouth, the thoracic outlet, and the tentorium of the cerebellum. Previous work has shown the connections between all these diaphragms, with links to fascial and neurological continuity (23). The function of these diaphragms is to regulate and respond to any changes in intra-abdominal pressure. For instance, if the main inspiratory muscle descends during inhalation, there will be a corresponding lowering of the pelvic floor. With all these connections, symptoms may also manifest in areas far from the source of the problem [8]. The sacroiliac joint is a gliding joint formed by the iliac and sacral bones, reinforced by the interosseous sacroiliac ligaments, the anterior sacroiliac ligaments, and the dorsal sacroiliac ligaments. The range of motion at the sacroiliac joint is minimal. Therefore, any disorder of this joint and its connections with the structures mentioned above leads to dysfunction [24].
Our study has several limitations. It should be recognized that we assessed immediate effects of OMT on orofacial pain, pressure pain threshold, TMJ range of motion, hipomobility in SIJ, and functionality. Immediate changes occurred after OMT treatment provides impetus for future research in this area. Future studies should investigate the long-term effects of this intervention using larger sample sizes in randomized controlled designs. Another limitation is that we cannot rule out the placebo effect due to the absence of a control group. The wide age range of the participants and the lack of a comparison between genders are additional limitations. Future studies should include participants within a specific age range and investigate the effects of gender.
In summary, comprehensive evaluation of patients diagnosed with TMD and considering the patient and their body as a whole is important in the treatment of TMD. Since the body is interconnected kinematically, specific regions shown to have intimate, yet distal, involvement such as the TMJ and pelvis, warrant close clinical attention. With a specific group of patients evaluation and treatment of the TMJ may be essential for a successful clinical outcome in treatment of the sacroiliac joint. Conversely with a subset of some patients, evaluation and treatment of the sacroiliac joint may be essential for a successful clinical outcome in treatment of the stomatognathic dysfunction.
Conclussion
Therefore, when faced with a patient with TMD symptoms, it would be reasonable to question SIJD complaints and include an examination of the TMJ followed by investigations of these anatomical areas where it is deemed appropriate. As the symptoms of TMJ improved, the pressure pain threshold and the mobility of the SIJ also improved.
Clinical Implication
• One session of orofacial manual therapy can improve symptoms of temporomandibular disorder (TMD).
• As pressure pain threshold (PPT) values in the temporomandibular joint (TMJ) improved, PPT values in the sacroiliac posterior superior (SIPS) also improved.
• In patients admitted to the hospital with sacroiliac joint dysfunction (SIJD), it is recommended to evaluate the temporomandibular joint (TMJ) to achieve more effective treatment results.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Kohler AA, Hugoson A, Magnusson T. Prevalence of symptoms indicative of temporomandibular disorders in adults: Cross-sectional epidemiological investigations covering two decades. Acta Odontol Scand. 2012;70(3):213-23.
2. De Leeuw R, Klasser GD, editors. Orofacial Pain: Guidelines For Assessment, Diagnosis, and Management, American Academy of Orofacial Pain. Chicago: Quintessence Publishing; 2018.p.122-128.
3. Ergezen G, Şahin M, Algun ZC. Investigation of the relationship between temporomandibular disorder and postural analysis. Kocaeli Med J. 2021;10(2):27-32.
4. Kiapour A, Joukar A, Elgafy H, Erbulut DU, Agarwal AK, Goel VK. Biomechanics of the sacroiliac joint: Anatomy, function, biomechanics, sexual dimorphism, and causes of pain. Int J Spine Surg. 2020;14(1):3–13.
5. Fink M, Wähling K, Stiesch-Scholz M, Tschernitschek H. The functional relationship between the craniomandibular system, cervical spine, and the sacroiliac joint: A preliminary investigation. Cranio. 2003;21(3):202–8.
6. Chinappi AS Jr, Getzoff H. Chiropractic/dental cotreatment of lumbosacral pain with temporomandibular joint involvement. J Manipulative Physiol Ther. 1996;19(9):607–12.
7. Senlikci HB, Ozen S. Sacroiliac joint dysfunction treated using neural therapy to the temporomandibular joint: A case report. Complement Med Res. 2021;28(4):379-381.
8. Bordoni B, Zanier E. The continuity of the body: Hypothesis of treatment of the five diaphragms. J Altern Complement Med. 2015;21(4):237-42.
9. La Touche R, García SM, García BS, Acosta AP, Juárez DA, Fernández Pérez JJ, et al. Effect of manual therapy and therapeutic exercise applied to the cervical region on pain and pressure pain sensitivity in patients with temporomandibular disorders: A systematic review and meta-analysis. Pain Med. 2020;21(10):2373–2384.
10. Bijur PE, Silver W, Gallagher EJ. Reliability of the visual analog scale for measurement of acute pain. Acad Emerg Med. 2001;8(12):1153–1157.
11. Walker N, Bohannon RW, Cameron D. Discriminant Validity of Temporomandibular Joint Range of Motion Measurements Obtained with a Ruler. J Orthop Sports Phys Ther. 2000;30(8):484-492.
12. Stuginski-Barbosa J, Silva RS, Cunha CO, Bonjardim LR, Ferreira Conti ACC, Conti PCR, et al. Pressure Pain Threshold and Pain Perception in Temporomandibular Disorder Patients: Is There Any Correlation? Rev Dor. São Paulo. 2015;16(1):22-6.
13. Yakut E, Duger T, Öksüz Ç, Yörükan S, Üreten K, Turan D, et al. Validation of the Turkish Version of the Oswestry Disability Index for Patients with Low Back Pain. Spine. 2004;29(5):581-585.
14. Tuncer A, Ergun N, Karahan S. Temporomandibular Disorders Treatment: Comparison of Home Exercise and Manual Therapy. Fizyoter Rehabil. 2013;24(1):09-16.
15. Kalamir A, Pollard H, Vitiello A, Bonello R. Intra-oral Myofascial Therapy for Chronic Myogenous Temporomandibular Disorders: A Randomized, Controlled Pilot Study. J Man Manip Ther. 2010;18(3):139-46.
16. Parchekouhi AB, Karimi N, Barzegar A Rahnama L. The Association Between Temporomandibular Disorders and Kinematics of The Sacroiliac Joint: A 3D motion Analysis Study. Elsevier BV. 2023.
17. Darstka AA, Brzózka M, Bitenc-Jasiejko A, Ardan R, Gronwald H, Skomro P, et al. Cause-Effect Relationships between Painful TMD and Postural and Functional Changes in the Musculoskeletal System: A Preliminary Report. Pain Res Manag. 2022;2022:1-14.
18. Oliveira SS, Pannuti CM, Paranhos KS, Tanganeli JPC, Lagana DC, Sesma N, et al. Effect of occlusal splint and therapeutic exercises on postural balance of patients with signs and symptoms of temporomandibular disorder. Clin Exp Dent Res. 2019;5(2):109-115.
19. Chung GY, Choi GS, Shin GY, Park JS. Gait changes after using a temporomandibular joint exerciser in patients who underwent lower limb joint surgery. J Phys Ther Sci. 2016;28(5):1584–1587.
20. Tecco S, Tetè S, D’Attilio SM, Festa F. The analysis of walking in subjects with and without temporomandibular joint disorders. A cross-sectional analysis. Minerva Stomatol. 2008;57(9):399-411.
21. Asquini G, Pitance L, Michelotti A, Falla D. Effectiveness of manual therapy applied to craniomandibular structures in temporomandibular disorders: A systematic review. J Oral Rehabil. 2022;49(4):442-455.
22. Armijo-Olivo S, Pitance L, Singh V, Neto F, Thie N, Michelotti A. Effectiveness of manual therapy and therapeutic exercise for temporomandibular disorders: Systematic review and meta-analysis. Phys Ther. 2016;96(1):9-25.
23. Bordoni B, Zanier E. The anatomical connections of the diaphragm: The influence of respiration ın the body system. J Multidiscip Healthc. 2013;6:281–291.
24. Vleeming A, Schuenke A, Masi T, Carreiro E, Danneels L, Willard FH. The sacroiliac joint: An overview of its anatomy, function and potential clinical implications. J Anat. 2012;221(6):537–567.
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Sultan İğrek, Tuğba Kuru Çolak, İlker Çolak, Erdinç Çekiç. Is there a relationship between temporomandibular disorder and sacroiliac joint dysfunction? Ann Clin Anal Med 2025;16(2):99-104
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Correlation between endoscopic activity ındices and meteorological parameters in ulcerative colitis
Muhammed Fuad Uslu 1, Esra Suay Timurkaan 1, Mustafa Timurkaan 1, Mustafa Yılmaz 2, Emrullah Dengeşik 3
1 Department of Internal Medicine, Elazig Fethi Sekin City Hospital, 2 Department of Emergency Medicine, Faculty of Medicine, Firat University, 3 Department of Gastroenterology, Elazig Fethi Sekin City Hospital, Elazig, Turkiye
DOI: 10.4328/ACAM.22377 Received: 2024-08-21 Accepted: 2024-10-21 Published Online: 2024-11-05 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):105-108
Corresponding Author: Mustafa Timurkaan, Department of Internal Medicine, Elazig Fethi Sekin City Hospital, Elazığ, Turkiye. E-mail: mustafatimurkan@gmail.com P: +90 505 889 31 50 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1950-0489
Other Authors ORCID ID: Muhammed Fuad Uslu, https://orcid.org/0000-0001-6300-5130 . Esra Timurkaan, https://orcid.org/0000-0001-5654-7070 . Mustafa Yilmaz, https://orcid.org/0000-0002-4457-428X . Emrullah Dengeşik, https://orcid.org/0000-0002-8744-344X
This study was approved by the Ethics Committee of Fırat University (Date: 2024-04-25, No: 2024/06-05)
Aim: The present study aimed to determine the correlation between the Mayo Endoscopic Score (MES), the validated Ulcerative Colitis Endoscopic Severity Index (UCEIS) and seasonal parameters in ulcerative colitis (UC), the prognosis of which is characterized by attacks.
Material And Methods: In the single-center and retrospective study, demographics of the patients who underwent colonoscopy between 2019 and 2023, MES and UCEIS figures, daily and fifteen-day average temperatures (in degrees Celsius), daily average atmospheric pressure (in millibars), daily average humidity (in percentages), and maximum wind speed (in meters per second) were analyzed.
Result: The study was conducted with 103 18-92 years old patients whose average age was 48.25 ± 17.09. 59.2% (n=61) of the participants were male (Female/Male= 42/61) and there was no difference between the participants based on gender (p=0.076). The maximum number of participants (12.9%; n = 13) presented in October, and the minimum presented in July (3.9%; n = 4). It was determined that there was no correlation between MES and UCEIS, and daily and fifteen-day average temperatures, humidity, and pressure. There was no difference between the UCEIS based on the season (p = 0.110); however, there was a significant difference between MES (p = 0.037) in autumn and summer (p = 0.04).
Discussion: It was determined that MES differed based on the season, the difference was between autumn and summer. However, UCEIS did not differ based on the season.
Keywords: Ulcerative Colitis, Colonoscopy, Mes, Uceis, Meteorological Parameters
Introduction
Ulcerative colitis (UC) is a chronic inflammatory disease characterized by mucosal inflammation attacks in the rectum that extend to the proximal sections of the colon [1]. UC is a multifactorial disease induced by the interaction of genetic, immune, microbial and environmental factors in its progress and pathogenesis, and the disease incidence has increased globally [2, 3]. It was suggested that pathogenesis is mostly induced by an inadequate immune response against luminal antigens in the intestine [4].
It is critical to evaluate the extent and activity of the disease to follow the clinical prognosis of UC to regulate the treatment [5]. Disease activity should be analyzed with a holistic approach based on clinical, laboratory, imaging, and colonoscopy findings [2].
Various scoring systems have been developed to objectively measure disease activity and mucosal healing. The easy to determine Mayo Endoscopic Score (MES) and the validated Ulcerative Colitis Endoscopic Severity Index (UCEIS) are the most common indices used to determine the vascular pattern, presence of erythema, fragility, erosions, ulcerations, and bleeding [6, 7].
The incidence and prevalence of inflammatory bowel disease (IBD) were determined to be higher in Northern Europe, North America, Northern Australia and New Zealand when compared to Asia [8, 9]. Furthermore, although the IBD incidence in the Indian subcontinent is low, the fact that Indian individuals who migrated to developed countries in the northern hemisphere exhibited a higher risk demonstrated that geographical location could be effective in the incidence and activation of the disease. Previous studies reported contradictory findings about seasonal changes in IBD activation [10, 11]. The correlation between IBD exacerbation and seasonal variation was reported to be either insignificant or high [12- 14].
Thus, we aimed to determine the correlation between MES, UCEIS, and seasonal parameters, which indicate UC disease activity, an inflammatory bowel disease.
Material and Methods
Demographic and endoscopic data for the adult ulcerative colitis patients who underwent colonoscopy at …hospital between 01 January 2019 and 31 December 2023 were collected from the digital patient records system. Those younger than 18 were excluded from the study. Endoscopic reports, gender, day, month, year and season of application, daily and fifteen-day mean temperature (in degrees Celsius), daily average atmospheric pressure (in millibars), daily average relative humidity (in percentages), and maximum wind speed (in meters per second) during the study period were included in the study data. The weather data were procured from the Environment, Urbanization and Climate Change Ministry, General Directorate of Meteorology internet site.
Statistical Analysis
The study data were analyzed with the SPSS 21.0 (IBM Corporation, Armonk, NY, USA) and Microsoft Excel software. The normal distribution of the data was determined with Kormogrow Smirnov analysis. The data with normal distribution are presented in Mean ± SD and qualitative data are presented in percentages. The independent samples t test was conducted for pairwise group comparison, and Pearson correlation was employed to determine the correlations between the variables. p<0.05 was accepted as statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Fırat University (Date: 2024-04-25, No: 2024/06-05).
Results
The mean age of the 103 18-92 years old patients who underwent colonoscopy due to UC diagnosis in our hospital between 2019 and 2023 was 48.25 ± 17.09. The number of male patients was 61 (59.2%) and female to male ratio was 42/61, and there was no significant difference between the patients based on gender (p = 0.076).
The maximum number of participants (12.9%; n = 13) presented in October, and the minimum number of patients presented in July (3.9%; n = 4) (Table 1, Figure 1).
In the study, it was determined that there were no correlations between MES and UCEIS scores and daily average temperature, humidity, pressure and the 15-day average temperature, humidity, and pressure data. (Table 2).
The comparison of the seasonal patient activation scores revealed that the mean MAYO score differed between all seasons (p = 0.037) and the difference was significant between autumn and summer (p = 0.04) (Table 3). However, the mean UCEIS score did not differ based on the season (p = 0.110).
Discussion
In the study, it was determined that there was no difference between the colonoscopy activation scores of the patients based on the month of the year. The comparison of the activation scores based on the season revealed that the mean MES score differed between the seasons and the difference between autumn and summer was significant (p = 0.04). It was determined that the mean UCEIS score did not differ based on the season.
A systematic review and meta-analysis conducted by Moon SJ et al. reviewed 20 studies on the effects of weather, seasons, and atmosphere on IBD exacerbation, and a meta-analysis was conducted on the correlation between seasonal variations and IBD exacerbation on seven studies. The findings revealed a weak correlation. In the UC subgroup (six studies), seasonal variation also exhibited a weak correlation. Furthermore, studies on temperate climates (five studies) demonstrated a non-negligible, weak but significant positive correlation [15]. Similarly, in the present study, the comparison of the activation scores and seasons demonstrated that the mean MES scores differed between autumn and summer, while there were no differences between the other seasons.
In a survey conducted with more than 1000 IBD outpatients, half of the IBD patients stated that the exacerbation of the disease was seasonal and occurred mostly in winter [16]. However, although the intestinal microbiota in healthy individuals is generally stable throughout the year, the composition of the fecal microbiota could vary based on race and country of residence [17]. Since the present study was regional and conducted with a small sample size, the findings were not consistent with the previous studies. Thus, further studies should be conducted with more participants, further sociodemographic data and analyses.
Country of residence and the time period are important factors in ulcerative colitis. There are differences in the incidence of ulcerative colitis within Europe, with higher incidences in countries in the western and northern regions than in eastern countries [18]. Due to the multitude of measurable and unknown variables associated with latitudinal differences, it is difficult to evidence specific factors. However, numerous hypotheses are known to explain differences between incidences based on latitudinal gradient, including differences between geographic environments, socioeconomic factors, temperature variations, and sunlight exposure. Despite the obvious differences between the incidence rates and latitudes, few studies focused on the factors that could explain the differences. Some suggested that sun or ultraviolet exposure and vitamin D levels could be potential factors. However, these hypotheses were not thoroughly tested [19]. A study reported that the vitamin D levels in a healthy control group were significantly associated with the season (P <0.05), while the same finding was not observed in IBD patients [20]. All these findings could suggest that there was no correlation between colonoscopy scores that indicated disease activation and daily, 15-day average, and monthly meteorological data; however, the present study findings did not demonstrate a significant correlation. The only seasonal correlation was determined for the mean MES score. Thus, future studies should be conducted based on several factors, and it could be suggested that meteorological data could help understand the correlation between the disease and weather.
Conclusion
In conclusion, although the present study was not a preliminary study that demonstrated a significant correlation between UC and seasons, the scoring system revealed that there could be a correlation. However, it could be suggested that this hypothesis would lead to better clinical, laboratory and imaging findings in future more comprehensive and multi-center studies on latitudinal and meteorological factors, namely the unknown aspects of the disease.
Limitation
The main limitation of our study was the fact that it was conducted in a single center, and it was retrospective. Furthermore, since the endoscopies are generally conducted during daytime and on weekdays, this could have further reduced the possibility of UC activation due to daily meteorological parameters. Thus, the 15-day data were employed to reduce the above-mentioned impact in the current study. These limitations of the present study would assist future studies on similar topics.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Jiao N, Ke X, Zhu L, Zhu R. Evidence challenging the causal role of gut microbiota in inflammatory bowel diseases. Gastroenterol Rep (Oxf). 2023;11(11):64.
2. Magro F, Gionchetti P, Eliakim R, Ardizzone S, Armuzzi A, Barreiro-de Acosta M, et al. Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 1: Definitions diagnosis extra-intestinal manifestations pregnancy cancer surveillance surgery and ileo-anal pouch disorders J Crohns Colitis. 2017;11(6):649-670.
3. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet. 2017;389(10080):1756-1770.
4. Ardizzone S, Cassinotti A, Trabattoni D, Manzionna G, Rainone V, Bevilacqua M, et al. Immunomodulatory effects of 1,25-dihydroxyvitamin D3 on TH1/TH2 cytokines in inflammatory bowel disease: An in vitro study. Int J Immunopathol Pharmacol. 2009;22(1):63-71.
5. Maaser C, Sturm A, Vavricka SR, Kucharzik T, Fiorino G, Annese V, et al. ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications. J Crohns Colitis. 2019;13(2):144-164.
6. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterol. 2012;142(1):46-54.
7. Travis SP, Schnell D, Krzeski P, Abreu MT, Altman DG, Colombel JF, et al. Reliability and initial validation of the ulcerative colitis endoscopic index of severity. Gastroenterol. 2013;145(5):987-995.
8. Wilson J, Hair C, Knight R, Catto-Smith A, Bell S, Kamm M, et al. High incidence of inflammatory bowel disease in Australia: A prospective population-based Australian incidence study. Inflamm Bowel Dis. 2010;16(9):1550-1556.
9. Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterol. 2011;140(6):1785-1794.
10. D’Haens G, Sandborn WJ, Feagan BG, Geboes K, Hanauer SB, Irvine EJ, et al. A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterol. 2007;132(2):763-786.
11. Henderson P, Wilson DC. The Role of Seasonality in the Exacerbation of Inflammatory Bowel Disease: A Systematic Review. Gastroenterol. 2010;138(5):207.
12. Lewis JD, Aberra FN, Lichtenstein GR, Bilker WB, Brensinger C, Strom BL. Seasonal variation in flares of inflammatory bowel disease. Gastroenterol. 2004;126:665–673.
13. Auslander JN, Lieberman DA, Sonnenberg A. Lack of seasonal variation in the endoscopic diagnoses of Crohn’s disease and ulcerative colitis. Am J Gastroenterol. 2005;100:2233–2238.
14. Dumitrescu G, Mihai C, Dranga M, Prelipcean CC. Serum 25-hydroxyvitamin D concentration and inflammatory bowel disease characteristics in Romania. World J Gastroenterol. 2014;20(9):2392-2396.
15. Moon SJ, Lee YC, Kim TJ, Kim K, Son HJ. Effects of temperature, weather, seasons, atmosphere, and climate on the exacerbation of inflammatory bowel diseases: A systematic review and meta-analysis. PLoS One. 2022;17(12):277-279.
16. Araki M, Shinzaki S, Yamada T, Arimitsu S, Komori M, Shibukawa N, et al. Age at onset is associated with the seasonal pattern of onset and exacerbation in inflammatory bowel disease. J Gastroenterol. 2017;52(11):1149-1157.
17. Nishijima S, Suda W, Oshima K, Kim SW, Hirose Y, Morita H, et al. The gut microbiome of healthy Japanese and its microbial and functional uniqueness. DNA Res. 2016;23(2):125-133.
18. Burisch J, Pedersen N, Čuković-Čavka S, Brinar M, Kaimakliotis I, Duricova D, et al. EpiCom-group. East-West gradient in the incidence of inflammatory bowel disease in Europe: The ECCO-EpiCom inception cohort Gut. 2014;63(4):588-597.
19. Haderslev KV, Jeppesen PB, Sorensen HA, Mortensen PB, Staun M. Vitamin D status and measurements of markers of bone metabolism in patients with small intestinal resection. Gut. 2003;52(5):653-658.
20. Dumitrescu G, Mihai C, Dranga M, Prelipcean CC. Serum 25-hydroxyvitamin D concentration and inflammatory bowel disease characteristics in Romania. World J Gastroenterol. 2014;20(9):2392-2396.
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Muhammed Fuad Uslu, Esra Suay Timurkaan, Mustafa Timurkaan, Mustafa Yılmaz, Emrullah Dengeşik. Correlation between endoscopic activity ındices and meteorological parameters in ulcerative colitis. Ann Clin Anal Med 2025;16(2):105-108
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Comparison of risk factors for systemic inflammation in patients using different vascular access routes for hemodialysis treatment
Kemal Mağden
Department of Nephrology, Gebze Fatih State Hospital, Kocaeli, Turkiye
DOI: 10.4328/ACAM.22382 Received: 2024-08-27 Accepted: 2024-10-21 Published Online: 2024-11- 05 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):109-112
Corresponding Author: Kemal Mağden, Department of Nephrology, Gebze Fatih State Hospital, Kocaeli, Turkiye. E-mail: kemalmg1967@gmail.com P: +90 505 708 67 57 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6199-5417
This study was approved by the Ethics Committee of Kocaeli City Hospital (Date: 2024-08-15, No: No:2024-65)
Aim: Chronic renal failure is a disease with increased inflammation. In this study, we aimed to evaluate the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII), which have recently been considered as predictive factors for systemic inflammation in patients receiving hemodialysis treatment for chronic renal failure, and also to investigate whether there is a difference between the inflammation markers when the use of hemodialysis catheter as vascular access is compared with the use of arteriovenous fistula.
Material and Methods: A total of 42 patients (15 females, 27 males) receiving hemodialysis treatment for chronic renal failure were included in the study. The ratios of absolute neutrophil, lymphocyte, and platelet count to CRP and hemogram values were analyzed among patients who used hemodialysis catheters or arteriovenous fistula as vascular access routes for hemodialysis treatment.
Results: An NLR threshold of 2.30 was accepted as an indicator of systemic inflammation. The mean NLR value of all patients was 3.87, which was much higher than the accepted value. A moderate positive correlation was found between CRP and SII. Additionally, a strong positive correlation was observed between SII and NLR, as well as SII and PLR. No difference was found between patients with hemodialysis catheter or arteriovenous fistula.
Discussion: NLR, PLR, and SII have been evaluated as indicators of systemic inflammation in recent years. With these indicators, it is possible to say that systemic inflammation is significantly higher in chronic renal failure patients receiving hemodialysis treatment compared to the normal population.
Keywords: Systemic Inflammation, Hemodialysis Treatment, Systemic Immune-Inflammation Index, Neutrophil-Lymphocyte Ratio
Introduction
Chronic renal failure (CRF), like many other chronic diseases, is a disease in which inflammation and atherosclerosis develop with high morbidity and mortality. CRF develops for various reasons, and when it progresses to the end stage, hemodialysis is frequently preferred as a treatment option. In hemodialysis patients, arteriovenous fistulas and peripheral venous catheters are often used as vascular access routes. Catheters are of vital importance as therapeutic support in hemodialysis. The first thought is that peripheral venous catheters may increase inflammation because they are a foreign body. The association of catheters with inflammation is mostly related to local infection but not to systemic inflammation.
In addition to etiologic factors, including diabetes mellitus and hypertension, factors including anemia, inflammation, and endothelial dysfunction have been reported as cardiovascular risk factors in end-stage renal failure (ESRD) patients receiving hemodialysis treatment [1]. It has been emphasized that there is an increase in inflammatory mediators in ESRD patients due to oxidative stress and increased extracellular fluid volume [2]. Chronic inflammation is also a part of malnutrition inflammation atherosclerosis (MIA) syndrome in ESRD patients [3].
Neutrophils are involved in both innate and acquired immune regulation [4]. It is also mentioned that dendritic cells, B cells, NK cells, CD4, CD8, T cells, and mesenchymal stromal cells are also involved in immune regulation by interacting with neutrophils [5]. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune/inflammation ratio (SII) have gained more importance in recent years as markers used to predict inflammation and atherosclerosis. NLR is a test used to evaluate systemic inflammation in diabetes mellitus, hypertension, cirrhosis, malignancies, and cardiovascular diseases, as well as in ESRD, because it is cost-effective and easily calculable [6, 9]. NLR is also emphasized as one of the biomarkers that may indicate that CRF may progress [10].
PLR measurement shows both inflammatory and thrombotic pathways because it is both affordable and easily measurable. It has more significant meaning than platelet or lymphocyte counts alone [11]. PLR can, therefore, be used to assess cardiovascular risk and mortality [12]
The systemic immune/inflammation index has also been shown to have prognostic significance in cardiovascular diseases, cancers, and chronic renal failure [13, 14]. The presence of high levels of albuminuria has been shown to be associated with high systemic immune inflammation index (SII) values [15]. NLR, PLR, and SII are calculated by proportioning the absolute values of neutrophils, lymphocytes, and platelets in the hemogram obtained by the venous route [16]. These three ratios calculated with hemogram values have facilitated approaches to inflammation.
Material and Methods
Patients
Forty-two patients (15 females and 27 males) who were receiving hemodialysis treatment two or three times a week for at least three months due to ESRD and who were being treated at Gebze Fatih State Hospital Nephrology Clinic Hemodialysis Center were retrospectively included in the study. The age range was 27-81 years. Patients with active infection, hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), acute renal failure, and chronic liver disease were excluded. The ratios of absolute neutrophil, lymphocyte, and platelet counts in CRP and hemogram values obtained in the absence of active infection were analyzed.
Statistical Method
GraphPadPrism 9.5.0 and IBM SPSS Statistics for Windows. Version 25.0 (Statistical Package for the Social Sciences, IBM Corp., Armonk, NY, USA) statistical package programs were used. Descriptive statistics of the variables belonging to the patient group participating in the study are presented as frequency and % for categorical variables and as Mean ± SD and median (IQR) for continuous variables. The data of the study were examined in terms of normality assumptions: One-Sample t-test was used to test whether the N/L ratio was different from 2.30, Spearman Correlation analysis was used for the relationships between two continuous variables, Independent Sample t test or Mann Whitney U test was used for two independent group comparisons, One-Way Analysis of Variance (ANOVA) was used for three independent group comparisons. A value of p<0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Kocaeli City Hospital (Date: 2024-08-15, No:2024-65).
Results
A total of 42 patients, 15 females (35.7%) and 27 males (64.3%) were included in the study. The age range was 27 to 81 years, with a mean age of 62.26 years. Patients had been receiving hemodialysis treatment for 1 to 11 years, with a mean of 3.64 years. The mean CRP was 15.95, mean hemoglobin 10.81 g/dL, mean NLR 3.87, mean PLR 168.4, and mean SII 793.11 (Table 1). In all patients, NLR was found to be statistically significantly different from the value of 2.30, which is considered normal in the community (p=0.000) (Figure 1). The mean NLR in patients with a hemoglobin value ≤10 (5.40) was higher than the mean NLR in patients with a Hb value>10 (3.26) (p=0.001). The NLR was not statistically different between the group of patients who used a hemodialysis catheter as the vascular Access route for hemodialysis treatment and the group who used an arteriovenous fistula (p=0.174). There was no statistically significant relationship between gender, duration of dialysis, vascular Access route used, etiology of CRF, and mean NLR (p>0.05) (Table 2). There was a moderate positive correlation between SII and CRP variables (r=0.544, p=0.000), a high positive correlation between SII and NLR (r=0.825, p=0.000), and a high positive correlation between SII and PLR (r=0.820, p=0.000). Furthermore, positive correlations were found between CRP and NLR (r=0.501, p=0.000), CRP and PLR (r=0.407, p=0.007), and NLR and PLR (r=0.789, p=0.000), respectively (Table 3).
Discussion
In this study, systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), which are considered predictive factors of systemic inflammation, were evaluated in end-stage renal failure patients receiving hemodialysis treatment. SII=platelet count x neutrophil count/lymphocyte count ratio, NLR=neutrophil count/lymphocyte count ratio, and PLR=platelet count/lymphocyte count ratio were calculated with the formulas. The results indicated that SII, NLR, and PLR were strong indicators of inflammation in correlation with CRP in ESRD patients receiving hemodialysis treatment. Yesilaltay A. mentioned that the mean NLR was accepted as 2.30 in the normal population [17]. It is possible to say that the mean NLR in the patients we included in the study was considerably higher than 2.30 (3.87±1.92) (Figure 1). In many studies, it has been emphasized that NLR is increased in CRF [18]. Akbaş et al. mentioned in their study that elevated NLR accelerated the progression to dialysis [19]. It was also emphasized by Türkmen et al. that NLR is an important marker of inflammation in CRF patients [20].
In our study, patients undergoing hemodialysis treatment were found to have a significantly elevated NLR. Ercan et al. showed in their study that immune/inflammation and SII were associated with all-cause mortality [2]. According to the results of our study, SII was found to be significantly higher in ESRD patients receiving dialysis treatment. Similarly, it can be said that the depth of anemia (Hb<10) is also associated with higher inflammation in this study. The high rate of erythropoietin-stimulating agent use is associated with the presence of anemia. In addition, in our study, whatever the etiologic factor in the development of CRF, there was no difference in terms of the development of inflammation. In other words, inflammation indices were found to be high in dialysis patients regardless of etiology. The phlebitis, infection, and inflammatory effects of peripheral venous catheters have been emphasized in many studies [21, 22]. In their study, Tudurachi et al. Associated high inflammatory hematologic ratios, including PLR and NLR, with major cardiovascular events, especially in young myocardial infarction patients [11]. Kaya B. et al. mentioned that PLR may be helpful in predicting mortality in hemodialysis patients [23]. In our study, PLR was found to be significantly higher in ESRD patients receiving hemodialysis treatment. Aygün et al. mentioned that catheters were mostly associated with local inflammation in their examination of peripheral venous catheters in terms of inflammation/infection in the intensive care unit [24]. In our study, there was no statistical data showing that the use of hemodialysis catheters as vascular Access increased systemic inflammation. There was no significant difference in inflammatory indicators between the use of arteriovenous fistula as a vascular Access route and catheter use.
Conclusion
Inflammation is associated with all-cause mortality in patients receiving hemodialysis treatment for ESRD. Elevated SII, NLR, and PLR in patients undergoing hemodialysis for ESRD may be used to indicate a more severe increase in inflammation. SII, NLR, and PLR values, which are calculated by the ratio of hemoglobin, neutrophil, lymphocyte, and platelet counts in hemogram values routinely measured in venous blood, are statistically significantly higher. It is seen that inflammation is significantly higher in ESRD patients receiving hemodialysis treatment compared to the normal population. The depth of anemia is also associated with inflammation. There is no statistical evidence that the use of hemodialysis catheters as vascular Access increases systemic inflammation.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Stenvinkel P, Carrero JJ, Axelsson J, Lindholm B, Heimburger O, Massy Z. Emerging biomarkers for evaluating cardiovascular risk in the chronic kidney disease patient: How do new pieces fit into the uremic puzzle? Clin J Am Soc Nephrol. 2008;3(2):505-21.
2. Ercan Z, Ayli MD. Systemic immune inflammation index may predict mortality in dialysis patients. Turk J Clin Lab. 2023;14(2):392-98.
3. Stenvinkel P, Chung SH, Heimburger O, Lindholm B. Malnutrition, inflammation, and atherosclerosis in peritoneal dialysis patients. Perit Dial Int. 2001;21(3):157-62.
4. Leliefeld PH, Koenderman L, Pillay J. How neutrophils shape adaptive immune responses. Front Immunol. 2015;6:471.
5. Li Y, Wang W, Yang F, Xu Y, Feng C, Zhao Y. The regulatory roles of neutrophils in adaptive immunity. Cell Commun Signal. 2019;17(1):147.
6. Sahan E, Polat S. Neutrophil to lymphocyte ratio is associated with more extensive, severe, and complex coronary artery disease and impaired myocardial perfusion. Turk Kardiyol Dern Ars. 2014;42(4):415.
7. Uslu AU, Deveci K, Korkmaz S, Aydin B, Senel S, Sancaktar E, et al. Is neutrophil/lymphocyte ratio associated with subclinical inflammation and amyloidosis in patients with familial Mediterranean fever? Biomed Res Int. 2013;2013:185317.
8. Biyik M, Ucar R, Solak Y, Gungor G, Polat I, Gaipov A. et al. Blood neutrophil-to-lymphocyte ratio independently predicts survival in patients with liver cirrhosis. Eur J Gastroenterol Hepatol. 2013;25(4):435–41.
9. Imtiaz F, Shafique K, Mirza SS, Ayoob Z, Vart P, Rao S. Neutrophil lymphocyte ratio as a measure of systemic inflammation in prevalent chronic diseases in Asian population. Int Arch Med. 2012;5(1):2.
10. Kim J, Song SH, Oh TR, Suh SH, Choi HS, Kim CS, et al. Prognostic role of the neutrophil-to-lymphocyte ratio in patients with chronic kidney disease. Korean J Intern Med. 2023;38:725–33.
11. BS Tudurachi, L Anghel, A Tudurach. Assessment of inflammatory hematological ratios (NLR, PLR, MLR, LMR, and Monocyte/HDL–Cholesterol Ratio) in acute myocardial infarction and … Int J Mol Sci. 2023;24:18.
12. Delcea C, Buzea CA, Vîjan AE, Bădilă E, Dan GA. The platelet to lymphocyte ratio in heart failure: a comprehensive review. Rom J Intern Med. 2023;61(2):84-97.
13. Dziedzic EA, Gąsior JS, Tuzimek A, Paleczny J, Junka A, Dabrowski M, et al. Investigation of the associations of novel inflammatory biomarkers-Systemic Inflammatory Index (SII) and Systemic Inflammatory Response Index (SIRI) with the severity of coronary artery disease and acute coronary syndrome occurrence. Int J Mol Sci. 2022;23(17):9553.
14. Huang P, Mai Y, Zhao J, Yi Y, Wen Y. Association of systemic immune-inflammation index and systemic inflammation response index with chronic kidney disease: Observational study of 40,937 adults. Inflamm Res. 2024;73(4):655-67.
15. Qin Z, Li H, Wang L, Geng J, Yang Q, Su B, et al. Systemic immune-inflammation index is associated with increased urinary albumin excretion: a population-based study. Front Immunol. 2022;13:1-9.
16. Song M, Graubard BI, Rabkin CS, Engels EA. Neutrophil-to-lymphocyte ratio and mortality in the United States general population. Sci Rep. 2021;11(11):464.
17. Yesilaltay A. Evaluation of neutrophil-lymphocyte ratio as a venous risk factor in patients with primary-familial erythrocytosis. Ann Clin Anal Med. 2024;15(1):17-21
18. Ahbap E, Sakaci T, Kara E, Sahutoglu T, Koc Y, Basturk T, et al. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in evaluation of inflammation in end-stage renal disease. Clin Nephrol. 2016;85(4):199-208.
19. Akbas EM, Demirtas L, Ozcicek A, Timuroglu A, Bakirci EM, Hamur H, et al. Association of epicardial adipose tissue, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio with diabetic nephropathy. Int J Clin Exp Med. 2014;7(7):1794–801.
20. Turkmen K, Guney I, Yerlikaya FH, Tonbul HZ. The relationship between neutrophil-to lymphocyte ratio and inflammation in end-stage renal disease patients. Ren Fail. 2012;34(2):155-59.
21. Cimała I, Grosicki S , Barchnicka A , Kotara KK. Evaluation on inflammatory states of peripheral veins connected with cannulation. Przegl Epidemiol. 2018;72(2):205-13.
22. Sicilia AG, Gómez MBS, Peraza MEC, Gómez JAR, Salgado JG, Clíments GD. Prevention and treatment of phlebitis secondary to the insertion of a peripheral venous catheter: A scoping review from a nursing perspective. Healthcare (Basel). 2021;9(5):611
23. Kaya B, Paydas S, Kara E. Relationship between mortality and baseline platelet to lymphocyte ratio in hemodialysis patients. Cukurova Med J. 2019;44(1):400-11.
24. Aygun G, Karasahin K, Dikmen Y, Yasar H, Sıdan A. Yoğun bakım ünitesinde periferik venöz kateterlerin infeksiyon yönünden değerlendirilmesi (Evaluation of peripheral venous catheters for infection in the intensive care unit). Flora. 2004;9(1):43-46.
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Kemal Mağden. Comparison of risk factors for systemic inflammation in patients using different vascular access routes for hemodialysis treatment. Ann Clin Anal Med 2025;16(2):109-112
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Can laparoscopic repair of inguinal hernia approach open repair that is the gold standard?
Bilal Turan, Omer Rıdvan Tarhan
Department of General Surgery, Suleyman Demirel University, Isparta, Turkey
DOI: 10.4328/ACAM.22392 Received: 2024-09-03 Accepted: 2024-10-21 Published Online: 2024-11-11 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):113-117
Corresponding Author: Bilal Turan, Department of General Surgery, Suleyman Demirel University, Isparta, Turkey. E-mail: bturan117@gmail.com P: +90 545 478 58 69 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1665-3607
Other Authors ORCID ID: Omer Rıdvan Tarhan, https://orcid.org/0000-0003-1720-3595
This study was approved by the Ethics Committee of Süleyman Demirel University, Faculty of Medicine Clinical Research (Date: 2020-08-12, No: 236)
Aim: The open repair of inguinal hernia is still considered the gold standard. The current status of laparoscopic versus open hernia repair is still under debate. In this study, we compared laparoscopic and open inguinal hernia repairs performed by same surgeon on different patients.
Material and Methods: A total of 129 patients(155 hernias) who underwent inguinal hernia repair at Süleyman Demirel University Research and Application Hospital between January 2010 and January 2020 were evaluated retrospectively, and information about the techniques and their outcomes was collected.
Results: The incidence of Nyhus 3A hernias was higher in patients who underwent open surgery, while Nyhus type 2 hernias were more common in those who had laparoscopic surgery. The mean duration of hospitalization was 1.57 days. A total of, 23 complications (17.83% based on the number of patients) were observed. While the rate of right-sided hernias was higher in patients who underwent open repair, the rates of left-sided and bilateral hernias were higher in those who underwent laparoscopic repair. There was no significant relationship between the type of surgery and the presence or type of complication.
Discussion: The results of our study were generally consistent with the literature and proved that laparoscopic repair can be performed as safely as open repair. However, these techniques should be viewed as complementary. The best approach to an inguinal hernia repair depends on the specific expertise of the surgeon.
Keywords: Hernia, Mesh Repair, Open Inguinal Hernia Repair, Laparoscopic Inguinal Hernia Repair
Introduction
Approximately 75% of hernias occur in the groin, making inguinal hernia repair one of the most common procedures performed by general surgeons. Many hernia repair techniques have been described, and there is no significant difference between the results of these techniques; moreover, the surgeon’s habits and training play the greatest role in the choice of method.
The success of inguinal hernia surgery was evaluated by the recurrence rate. For effective and safe hernia repair:
1. The surgical technique should be suitable for each inguinal hernia.
2. The technique should be chosen with consideration of complications and recurrence rates.
3. The postoperative recovery time and patient comfort should be optimized.
The ultimate goal is to reduce postoperative pain, recovery time and recurrence rates. Understanding the anatomy of the groin can be challenging, and before performing inguinal hernia, surgeons should understand the anatomy of the groin to prevent complications such as reduced chronic pain and recurrence. The laparoscopic approach has been shown to have less postoperative pain and chronic pain and a faster recovery time in the general population. However, the laparoscopic technique has several limitations, including a long learning curve and the patient requiring general anesthesia [1, 2].
Retrospectively, 129 patients (155 hernias) operated on for inguinal hernia at Süleyman Demirel University Research and Application Hospital between January 2010-January 2020, 61 with the open tension-free method and 68 with laparoscopy(TAPP), were evaluated, and information about these techniques and their results was obtained.
Material and Methods
Study objectives
The records of a total of 129 patients who underwent open tension-free (61 patients) or laparoscopic TAPP (68 patients) surgery for inguinal hernia in our hospital between 2010 and 2020 were analyzed retrospectively via our hospital system and general surgery registration system. Patients were contacted by phone call or via hospital records. Comparisons of open and laparoscopic surgical methods were made in terms of age, sex, hernia location, hernia type according to the Nyhus classification, type of operation, length of hospitalization, follow-up period, pain, recurrence and other complications using the SPSS statistical program.
Statistical analysis
All the statistical analyses were performed using the SPSS version 17.0 program. The conformity of the variables to a normal distribution was examined using histogram plots and the Kolmogorov-Smirnov test. The mean, standard deviation, and median were used for descriptive analyses. Categorical variables were compared using the Pearson chi-square test. The Mann-Whitney U test was used to evaluate the differences in non-normally distributed(nonparametric) variables between two groups. P-values less than 0.05 were considered statistically significant.
Ethical Approval
This study is derived from a specialization thesis. This study was approved by the Ethics Committee of Süleyman Demirel University, Faculty of Medicine Clinical Research (Date: 2020-08-12, No: 236). Patients were not required to give their informed consent for inclusion in this retrospective study, as we used anonymous clinical data and because individuals cannot be identified according to the data presented.
Results
Demographic Data
To evaluate the results of laparoscopic (TAPP) and open (tension-free) repair operations, 155 hernia repairs were performed in a total of 129 patients (119 males and 10 females). The male/female ratio was 9:1.
61 patients underwent open repair (tension free) and 68 patients underwent laparoscopic repair(TAPP).
In our study, the mean age was 56,2 ± 16,5 years (15-90). The mean age was 58,7 ± 16,5 years in patients who underwent open surgery, and the mean age was 53,9 ± 16,3 years in patients who underwent TAPP. There was no significant difference between the mean ages of patients who underwent TAPP and those who underwent open surgery (p = 0.124).
Of the 129 patients, 64 had at least one comorbidity, while no comorbidities were detected in 65 patients. Moreover, there was no significant difference between open surgery and laparoscopic surgery in terms of comorbidities.
Hernia Localization (Table-I)
Of the 129 inguinal hernia patients included in the study, 61 had right-sided hernias, 42 had left-sided hernias and 26 had bilateral hernias. However, the rate of bilateral inguinal hernias in laparoscopic surgery was approximately 3 times greater than that in open surgery (27,94% vs. 11,48%). The rate of right inguinal hernia was also greater in the open surgery group (59,02% and 36,76%).
Nyhus Classification (Table-II)
In this study, 155 hernia operations were performed on 129 patients. When all hernias in our study were evaluated, indirect inguinal hernia was the most common, direct inguinal hernia was the second most common hernia, and pants hernia was the third most common hernia (44,52%, 36,77% and 11,61%, respectively). The frequency of femoral hernia was very low (2,58%). The recurrence rates of direct and indirect hernias were 3,23% and 1.29%, respectively. When the Nyhus classification was analyzed according to the type of surgery:
• Among parients who underwent open surgery, direct inguinal hernia was the most common (44,12%), followed by indirect (26,47%) and third by trouser (19,2%) hernias.
• Among those who underwent laparoscopic surgery, indirect inguinal hernia was the most common (58,62%), direct hernia was the second most common (31,03%) and pant hernia was the third most common (5,75%).
Open surgery was performed for all femoral hernias(4 patients).
Length of stay
In our study, the mean duration of hospitalization was 1,50 days in the laparoscopic group (min:1, max:7) and 1,64 days in the open group (min:1, max:6 days). Moreover, there was no significant correlation between the type of surgery and the length of hospitalization.
Complications (Table-III)
The rate of complications according to the type of surgery is given in Table-III.
Discussion
According to the results obtained from our study, both patient groups were generally discharged on postoperative day 1 for open and laparoscopic inguinal hernia repair. There was no difference between the types of surgery in terms of the presence or types of complications. When both surgical techniques were analyzed, the recurrence rates, which are a measure of success of inguinal hernia repair, were similarly low and consistent with the literature.
According to these findings, laparoscopic repair is an effective and safe alternative to open tension-free repair, which is widely accepted as the gold standard for inguinal hernia repair.
In our study, the mean age was 56.2 years in general, 58.7 years in open surgery and 53.9 years in laparoscopic surgery. In the study by Koju et all., the mean age of patients who underwent Lichtenstein repair was 49.2 years and the mean age of patients who underwent TAPP was 44.3 years [3]. According to published studies, most inguinal hernias are observed at the age of 45 years and older [4]. In our study, the general age range and the greater mean age of patients who underwent open surgery were similar to those in the literature.
The main comorbidities found in the patients in our study were hypertension, diabetes mellitus, COPD, coronary disease and prostatism that like previous studies. However, there was no significant correlation between the surgical technique and the presence or types of comorbidities [5, 6]. Additionally, in our study, no intraoperative or postoperative problems related to CO2 insufflation developed in our patients who underwent TAPP.
In our study, 47.3% of the patients had right-sided inguinal hernias, 32.5% had left-sided inguinal hernias and 20.1% had bilateral inguinal hernias. In the literature, the incidence of right inguinal hernia is higher than that of left inguinal hernia.
In our study, the rate of bilaterality in laparoscopic surgery was approximately 3 times greater than that in open surgery (27.94% vs. 11.48%). The reason for this difference is that hernias that were not detected preoperatively were detected during laparoscopic surgery. In other words, some of the patients who underwent unilateral open surgery were bilateral. Evaluation the inner ring bilaterally is an advantage of the TAPP.
There are different incidences of bilateral inguinal hernia in the literature and some studies have found an incidence of approximately 6% based on physical examination. In the same studies, 54% of right inguinal hernias were reported to be inguinal hernias, whereas 40% were left inguinal hernias [6]. Bilateral hernias were detected 20% more often by laparoscopy than by physical examination [5-7]. The advantage of the TAPP is that bilateral inguinal hernias can be diagnosed in patients with unclear clinical examination findings in addition to the diagnosis of contralateral hernias.
When all hernias in our study were evaluated, indirect inguinal hernia was the most common, direct inguinal hernia was the second most common hernia, and pants hernia was the third most common hernia (44.52%, 36,77%, 11.61%, respectively). The frequency of femoral hernia was very low (2.58%). The recurrence rates of direct and indirect hernias were 3.23% and 1.29%, respectively. These rates seem to be compatible with the literature [8].
When the Nyhus classification was analyzed according to the type of surgery, direct inguinal hernia (44.12%) was most common in patients who underwent open surgery, whereas indirect inguinal hernia (58.62%) was most common in patients who underwent laparoscopic surgery. Two possible reasons for this difference may be that direct inguinal hernia was more common in patients with more comorbidities, and open surgery was preferred more in patients with more comorbidities. Indeed, in our study, the rate of comorbidities was greater in those who underwent open surgery (54.10% – 45.59%, respectively).
Open surgery was performed for all femoral hernias (4 patients). Laparoscopic repair of femoral hernias is still in its infancy and although its results have been reported to be superior to those of open repair, open surgical treatment is still the standard of care for femoral hernias [9].
In our study, no significant difference was found in the length of hospitalization. Patients in both groups were generally discharged on postoperative day 1. However, the time to return to normal activity was significantly shorter in the laparoscopic group [10].
In our study, there was no significant relationship between the type of surgery in terms of the presence or type of complication. The overall complication rate was 17,8%. Although laparoscopic repair had a proportionally greater complication rate (19,2%) than open repair (16,4%) and the difference was not significant (p = 0.687). The rates given here are based on the number of patients (129 patients). When the rates are calculated on a case-by-case basis, the complication rates are slightly lower (155 patients).
Many studies have reported that laparoscopic inguinal hernia repair leads to less postoperative pain, lower rates of numbness, shorter recovery times and greater returns to normal activity than does the open technique. However, some studies have reported a greater complication rate with laparoscopic repair than with primary hernia repair. Some studies have reported no difference between the two methods in terms of complications, length of hospital stay or patient satisfaction.
In our study, the overall recurrence rate was 2.33%, while the recurrence rates were similar between open and laparoscopic repair. Several studies have reported high, recurrence rates, several studies have reported equal recurrence rates and several studies have reported low recurrence rates after laparoscopic hernia repair [11-14]. Inguinal hernia repair success is associated with long-term recurrence. In the literature, recurrence rates for inguinal hernia repair vary between 0%-3.4% for mesh repairs and between 2.9%-21% for non-mesh repairs [15]. These rates have been reported to be in the range of 1-2% for the TEP method and 0-3% for the TAPP method [16]. In our study, no significant difference was observed between the recurrence rates of the two methods, which was consistent with the literature.
In our study, the rate of chronic pain was slightly greater in patients who underwent laparoscopic repair, than in those who did not (7.35% vs. 1.64%, respectively). The cause of chronic pain in patients who underwent laparoscopic repair is thought to be due to the tacker placed on the anterior abdominal wall (nerve compression) or shrinkage of the prolene patch (inflammation).
It is accepted that pain may occur in the acute and chronic periods after inguinal hernia repair. However, the underlying causes and prevalence, duration of pain and social consequences of this pain have not been fully elucidated. Nerve compression or injury may be a pathogenic risk factor for both acute and chronic pain. This pain is caused mainly by stimulation of afferent nerves as a result of activation of skin and subcutaneous receptors [17, 18].
Studies chronic pain, affecting daily activities, have been reported to occur in 6–10%. To prevent nerve injuries, staples should not be placed below the iliopubic tract or lateral to the spermatic vessels [19, 20].
In our study, 2 wound infections were observed in patients who underwent open technique repair and these infections did not cause recurrence. No wound infections developed in the laparoscopic repair group. Cosmetically, patients who undergo laparoscopy experience complete disappearance or minimal scarring at the trocar entry sites.
In our study, the overall rate of seroma/hematoma was 4.65%. This rate was 3.28% in those who underwent open repair and 5,88% in those who underwent laparoscopic repair and no significant difference was found. In several large series, the rates were 13.6% and 16.4% for open and laparoscopic repair, respectively, and the rates of seroma and hematoma development in our study were lower than those in the literature [21].
Noninvasive scrotal edema, swelling, numbness, burning and urinary retention were similar in both groups. For each of these complications, the rates are low compared to those in the literature.
The hernia can be repaired with two main surgical treatment options: open surgery or laparoscopy. Hundreds of repair methods have been described in modern inguinal hernia surgery, which classically started with Bassini. The common aspect of these methods is that the herniated defect is reinforced with sutures despite the formation of tension. The high recurrence rates in hernia surgery and the fact that this high recurrence rate was caused by tension are important problems that require a solution. Although inguinal hernias are common enough to occur in 75% of all external hernias and in 4% of the population, the best repair method has not yet been determined. The success of inguinal hernia operation is evaluated by the recurrence rate. With this in mind, Lichtenstein initiated the development of the open-tension-free inguinal hernia operation in 1984. The aim is to reduce postoperative pain, the healing process and recurrence rates [22-24].
The next major change was the introduction of laparoscopic repair. Following the introduction of laparoscopic techniques in general surgery, the first minimally invasive inguinal hernia repair was reported in 1990 [25].
In conclusion, the success of inguinal hernia operation was evaluated by the recurrence rate. Although inguinal hernias are common enough to be seen in 3-8% of the population, the best method of surgery to be preferred has not yet been fully determined. The aim of hernia repair is to minimize postoperative pain, the healing process, the recurrence rate and other complications. The “Lichtenstein” tension-free graft hernia repair operation can be considered a method that reduces the patient’s hospital stay, postoperative discomfort, recovery time and cost of hernia treatment in real terms. Since its introduction this method has been successfully applied by many surgeons worldwide.
In addition, as shown in our study, laparoscopic repair is as effective as open tension-free repair and there was no difference between these two techniques in terms of length of stay, pain, recurrence and other complications. This finding proves that laparoscopic repair can be performed as safely as open repair, although it is accepted that laparoscopic repair has a longer learning curve.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Zhu X, Liu Z, Shen J, Liu J, Tang R. Comparison of open and laparoscopic inguinal-hernia repair in octogenarians. Asian J Surg. 2023;46(2):738–41.
2. Xi S, Chen Z, Lu Q, Liu C, Xu L, Lu C, et al. Comparison of laparoscopic and open inguinal-hernia repair in elderly patients: The experience of two comprehensive medical centers over 10 years. Hernia. 2024;28(4):1195-203.
3. Koju R, Koju RB, Malla B, Dongol Y, Thapa LB. Transabdominal Preperitoneal Mesh Repair versus Lichtenstein’s Hernioplasty. J Nepal Health Res Counc. 2017;15(2):135-40.
4. Glorieux R, Van Aerde M, Vissers S, Fieuws S, De Groof P, Miserez M, et al. Incidence and risk factors of metachronous contralateral inguinal hernia development up to 25 years after unilateral inguinal hernia repair: a single-centre retrospective cohort study. Surg Endosc. 2024;38:1170–9.
5. Xi S, Chen Z, Lu Q, Liu C, Xu L, Lu C, et al. Comparison of laparoscopic and open inguinal–hernia repair in elderly patients: the experience of two comprehensive medical centers over 10 years. Hernia. 2024;28:1195–203.
6. Huerta S, Timmerman C, Argo M, Favela J, Pham T, Kukreja S. et al. Open, Laparoscopic, and Robotic Inguinal Hernia Repair: Outcomes and Predictors of Complications. J Surg Res. 2019;241:119-27.
7. Griffin K, Harris S, Tang T, Skelton N, Reed J, Harris A. Incidence of contralateral occult inguinal hernia found at the time of laparoscopic trans-abdominal preperitoneal (TAPP) repair. Hernia. 2010;14(4):345–9.
8. Köckerling F, Krüger C, Gagarkin, I, Kuthe A, Adolf D, Stechemesser B, et al. What is the outcome of re-recurrent vs recurrent inguinal hernia repairs? An analysis of 16,206 patients from the Herniamed Registry. Hernia. 2020;24:811–19.
9. Yagan P. Laparoscopic repair of an incarcerated femoral hernia. Int J Surg Case Rep. 2015;17:85–8.
10. DA Watters. Better and cheaper by day! Most inguinal herniorrhaphy patients are suitable for day‐stay repair regardless of surgical approach. ANZ J Surg. 2022;92(10):2404-5.
11. Y Celik, C Tiryaki. Tek Taraflı İnguinal Hernilerde Genel Anestezi Altında Laparoskopik Herni TEP Onarımı ile Açık Lichtenstein Herni Onarımının Karşılaştırılması [Totally Extraperitoneal Repair Under General Anesthesia Versus Lichtenstein Repair Under Spinal Anesthesia for Unilateral Inguinal Hernia]. Kocaeli Med J. 2019;8;2:155-9.
12. O’reilly EA, Burke JP, O’connell PR. A meta-analysis of surgical morbidity and recurrence after laparoscopic and open repair of primary unilateral inguinal hernia. Ann Surg. 2012;255(5):846-53.
13. Neumayer L, Giobbie-Hurder A, Jonasson O, Fitzgibbons Jr R, Dunlop D, Gibbs J, et al. Open mesh versus laparoscopic mesh repair of inguinal hernia. N Eng J Med. 2004;350(18):1819-27.
14. Haladu N, Alabi A, Brazzelli M, Imamura M, Ahmed I, Ramsay G, et al. Open versus laparoscopic repair of inguinal hernia: an overview of systematic reviews of randomised controlled trials. Surg Endosc. 2022; 36:4685–700.
15. Douek M, Smith G, Oshowo A, Stoker D, Wellwood J. Prospective randomized controlled trial of laparoscopic versus open inguinal hernia mesh repair: five year follow up. Bmj. 2003;326(7397):1012-3.
16. Y Celik, OA Erbil. Genel Anestezi Altında Laparoskopik Transabdominal Preperitoneal ve Total Ekstraperitoneal Herni Tamirinin Karşılaştırılması [Laparoscopic Transabdominal Preperitoneal versus Total Extraperitoneal Hernia Repair under General Anesthesia]. Anatol Clin. 2020;25(1):7-11.
17. Reinpold W. Risk factors of chronic pain after inguinal hernia repair: A systematic review. Innov Surg Sci. 2017;2(2):61–8
18. Olsson A, Sandblom G, Franneby U, A Sondén A, Gunnarsson U, Dahlstrand U. Do postoperative complications correlate to chronic pain following inguinal hernia repair? A prospective cohort study from the Swedish Hernia Register. Hernia. 2023;27:21–9.
19. Reinpold W. Risk factors of chronic pain after inguinal hernia repair: A systematic review. Innov Surg Sci. 2017;2(2):61–8.
20. Bjurstrom MF, Nicol AL, Amid PK, Chen DC. Pain control following inguinal herniorrhaphy: current perspectives. J Pain Res. 2014;7:277–90
21. McCormack K, Scott NW, Go PM, Ross S, Grant AM. EU Hernia Trialists Collaboration. Laparoscopic techniques versus open techniques for inguinal hernia repair. Cochrane Database Syst Rev. 2003;2003(1):CD001785.
22. Lichtenstein IL. Hernioraphy. Am J Surg. 1987;153:533-59.
23. Lichtenstein IL, Shulman AG, Amid PK. The tension-free hernioplasty. Am J Surg. 1989;157:188-93.
24. Amid PK, Lichtenstein IL. Aktüelle Einschetzung der spannungsfrein Hernienreoperationach Lichtenstein. Chirurg PP. 1997;68:959-64.
25. Schultz L, Craber J, Pietrafitta J. Laser laparoscopic herniorrhappy: A dinicaJ trial. Preliminary results. J Laparoendosc Surg. 1990;1:41-4.
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Bilal Turan, Omer Rıdvan Tarhan. Can laparoscopic repair of inguinal hernia approach open repair that is the gold standard? Ann Clin Anal Med 2025;16(2):113-117
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Could corneal densitometry be a diagnostic criterion for keratoconus?
Cigdem Coskun, Sebile Çomçalı
Department of Ophthalmology, Ankara Bilkent City Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.22400 Received: 2024-09-13 Accepted: 2024-10-21 Published Online: 2024-11-07 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):118-121
Corresponding Author: Cigdem Coskun, Department of Ophthalmology, Ankara Bilkent City Hospital, Ankara, Turkey. E-mail: drcigdem@hotmail.com P: +90 312 552 60 00 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2215-306X
Other Authors ORCID ID: Sebile Çomçalı , https://orcid.org/0000-0003-0596-1452
This study was approved by the Ethics Committee of Ankara Bilkent City Hospital (Date: 2023-06-07, No: E1-23-3673)
Aim: To examine corneal densitometry measurements with the Pentacam Scheimpflug imaging system in keratoconus patients and compare them with a healthy control group.
Material and Methods: The study included 112 eyes of 112 keratoconus patients followed up in the cornea clinic and 246 eyes of age-matched 246 healthy individuals. In all cases, K1, K2, K Max, central corneal thickness, thinnest corneal thickness, anterior elevation, posterior elevation, and corneal densitometry values were measured using the Scheimpflug imaging system. Corneal densitometry was evaluated based on four concentric radial zones (0-2 mm, 2-6 mm, 6-10 mm, and 10-12 mm) and by depth (anterior, central, posterior, and total). Keratoconus patients were divided into four stages. Corneal densitometry values were compared between each stage and the healthy control group. The results were statistically analyzed.
Results: The average age between the groups did not show any statistically significant difference (p>0.05). Corneal densitometry values were found to be statistically significantly higher in kera-toconus patients compared to the healthy control group in all zones and layers, except for the 10-12 mm zone (p<0.01). Nevertheless, no statistically significant differences were observed in cor-neal densitometry values across the various stages of keratoconus (p>0.05).
Discussion: Scheimpflug topography combined with corneal densitometry measurement is a non-invasive examination method that provides information about corneal transparency. Changes in corneal histology in keratoconus patients may influence densitometry values. According to our study, the higher corneal densitometry values observed in keratoconus patients compared to the healthy group may provide supportive evidence for the diagnosis of keratoconus, in addition to other criteria used for diagnosis.
Keywords: Keratoconus, Cornea, Densitometry, Pentacam
Introduction
Keratoconus is an advancing ectatic condition of the cornea, marked by gradual thinning and out-ward bulging, resulting in irregular astigmatism and diminished visual acuity [1, 2]. Despite nu-merous pathological changes observed in the histopathology of keratoconus, the exact pathogene-sis of the disease remains incompletely understood [3]. Several studies have reported ultrastruc-tural alterations in keratoconus, including the loss of stromal collagen lamellae, changes in colla-gen fibril orientation, and a notable decrease in keratocyte density, especially in the anterior cen-tral region [4- 7].
Pentacam® HR Scheimpflug tomography (Oculus, Inc., Wetzlar, Germany) is an objective and non-invasive method that assists in detecting changes in curvature and elevation of both the ante-rior and posterior corneal surfaces. Additionally, it measures corneal transparency by quantifying the intensity of light scattered back from the cornea [8].
This study aims to evaluate corneal densitometry in previously untreated keratoconus patients, compare these results with those of healthy individuals, and assess whether there are differences in densitometry among different stages of keratoconus.
Material and Methods
This retrospective observational study was conducted by the cornea unit of the Ankara Bilkent City Hospital Ophthalmology Clinic. Patients diagnosed with keratoconus who had not received treatment and who presented to our clinic between March 2021 and March 2023 were retrospec-tively screened. The study included 112 eyes of 112 keratoconus patients and 246 eyes of 246 age-matched healthy individuals. The healthy control group was made up of individuals who came to our clinic for soft contact lens fitting and were confirmed to be free of ectasia. Keratoconus pa-tients were categorized into four stages. Corneal densitometry values were compared between each stage and the healthy control group. Patients with a history of ocular trauma and surgery, contact lens use, significant corneal opacity, glaucoma, uveitis, lack of compliance/cooperation, diabetes mellitus, hypertension, or systemic rheumatologic diseases were excluded from the study.
Both groups underwent a comprehensive ophthalmological examination, including an assessment of best-corrected visual acuity using Snellen charts, anterior and posterior segment biomicroscop-ic examination, and measurement of various parameters using the Scheimpflug imaging system (Pentacam HR, Oculus, Germany). The measured parameters included K1, K2, K Max, central corneal thickness, thinnest corneal thickness, anterior elevation, posterior elevation, and corneal densitometry values. Intraocular pressure (IOP) measurements were also taken using a Goldmann application tonometer. Scheimpflug imaging was performed in the morning hours, in the same dark room, and by the same individual (CC).
For corneal densitometry analysis, the Pentacam® Scheimpflug imaging system, equipped with software add-ons, was used to measure the amount of scattered light.
The measurements were conducted three times, and only those with a “quality specification = OK” reading were considered for inclusion in this study. This system is capable of measuring corneal densitometry in a 12 mm diameter area, with the central corneal apex being the reference point in four radial regions and three different depths. The first region consisted of a circular area with a 2 mm diameter at the center of the cornea. The second region was a ring-shaped area around the first region, ranging from 2 to 6 mm in diameter. The third region encompassed an area from 6 to 10 mm in diameter, and the fourth region covered a ring-shaped area from 10 to 12 mm in diame-ter. Based on depth, three different layers were defined: the most anterior 120 µm as the anterior layer, the most posterior 60 µm as the posterior layer, and the region between these two layers as the central layer. Densitometry results were expressed in units of grayscale, with maximum light scattering assigned a value of 100 (indicating minimum transparency, a fully opaque cornea) and minimum light scattering assigned a value of 0 (indicating maximum transparency). The values could vary between 0 and 100. All data were analyzed using the IBM SPSS Statistics 21.0 soft-ware. Continuous variables were summarized as mean ± SD or median (min-max), and categorical variables were reported as frequencies and percentages. Pearson’s correlation test was employed for correlation analysis, and for comparing groups, the Mann-Whitney U test and Wilcoxon W test were used. A p-value of less than 0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Ankara Bilkent City Hospital (Date: 2023-06-07, No: E1-23-3673).
Results
The study included a total of 358 eyes from 358 individuals, comprising 112 eyes of 112 kerato-conus patients who had not received prior treatment and 246 eyes of 246 healthy individuals. The mean age of the keratoconus patients was 27.49±8.21 years, while that of the healthy controls was 26.3±7.22 years. There was no statistically significant difference in mean age between the two groups (p=0.192). According to the Amsler-Krumeich classification, 35 (31.25%) keratoconus patients were classified as stage 1, 36 (32.14%) as stage 2, 32 (28.57%) as stage 3, and 9 (8.03%) as stage 4. Detailed anterior segment parameters for both keratoconus patients and healthy con-trols are presented in Table 1.
Significant differences in corneal densitometry were observed between keratoconus patients and healthy controls in the 0-2 mm, 2-6 mm, and 6-10 mm annular regions (p<0.01). However, there was no significant difference in corneal densitometry values in the peripheral 10-12 mm zone be-tween the two groups (p>0.05). The corneal densitometry measurements for keratoconus patients and healthy controls are presented in Table 2.
There were no statistically significant differences in corneal densitometry values among different stages of keratoconus (p>0.05). The detailed comparison of corneal densitometry measurements between keratoconus stages and healthy controls is shown in Table 3.
Discussion
Corneal densitometry is an objective measurement that evaluates the amount of light reflected from various areas of the cornea.[9]. Even though the cornea may appear transparent during slit-lamp examination, light can still scatter back from the cornea. Therefore, corneal densitometry can serve as an indicator and an objective tool for measuring mild corneal edema. The total corne-al densitometry measured with Scheimpflug corneal topography represents the sum of epithelial, stromal, and endothelial light scattering [10]. For corneal transparency, collagen fibrils should have a small diameter, be arranged perpendicularly, and exhibit regular spacing, while keratocyte distribution should align with this arrangement [11]. The corneal epithelial cell layer and corneal endothelium are the main sources of light scattering. In contrast, the corneal stroma causes less light scattering due to the regular arrangement of collagen fibrils and the precise organization of the extracellular matrix [10].
Studies, both in vivo and in vitro, have demonstrated that structural disruption in the corneal stroma is most pronounced in the anterior and central corneal stroma in keratoconus and that all corneal layers except the endothelium are affected [4, 12- 14].
We believe that structural changes in the cornea may lead to an increase in corneal densitometry, and therefore, densitometric analysis can be utilized in the diagnosis of keratoconus. In our study, we observed that corneal densitometry values were higher in keratoconus patients compared to a healthy control group, except for the 10-12 mm zone, across all zones and layers. In a study evalu-ating the histopathology of the cornea, it has been reported that the anterior cornea is affected in the early stages of keratoconus and that the first changes leading to thinning and disappearance of the epithelial layer, along with breaks in the basal epithelial cell layer, Bowman’s layer, and thick-ening of the sub-basal nerve plexus, are observed [4]. In a study by Koç et al., corneal densitome-try measurements were found to increase in adult subclinical keratoconus patients, suggesting that these measurements could be a useful tool for early diagnosis of corneal densitometry [15].
In two separate studies, it was demonstrated that corneal densitometry values in the central 0-2 mm and 2-6 mm zones increased in keratoconus patients compared to healthy controls, suggesting that corneal densitometry can serve as a prognostic determinant of the disease [16, 17]. In our study, unlike these previous studies, we did not observe any differences in corneal densitometry among different stages of keratoconus. Therefore, we do not believe that corneal densitometry indicates the prognosis of the disease. We suggest that additional research with a larger patient population is required to provide further clarity on this issue.
Statistically significant differences in peripheral cornea were not found between the two groups. This may be attributed to the possibility that the pathology of the peripheral cornea is not affected in keratoconus [18]. Additionally, it should be noted that peripheral corneal densitometry meas-urements are known to have the weakest repeatability and reproducibility, which could explain the lack of differences observed between the two groups [9].
Limitation
Our study has a limitation. Because it was conducted with a relatively small number of patients, the number of patients in each stage is limited, which can potentially affect the densitometric measurements between stages.
Conclusion
Our study demonstrates that corneal densitometry values are significantly higher in all areas of the cornea, except for the anterior 10-12 mm zone, in previously untreated keratoconus patients when compared to healthy controls. We believe that corneal densitometric measurements can be used as an independent method for the diagnosis of keratoconus, irrespective of topographic measurements. The lack of differences in densitometry values among different stages of kerato-conus suggests that corneal densitometry measurements may not serve as a prognostic indicator in keratoconus. Additional research with larger sample sizes is necessary to validate these findings.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Davidson AE, Hayes S, Hardcastle AJ, Tuft SJ. The pathogenesis of keratoconus. Eye. 2014;28:189-95.
2. Vazirani J, Basu S. Keratoconus: Current perspectives. Clin Ophthalmol. 2013;7:2019-30.
3. Meek KM, Tuft SJ, Huang Y, Gil PSI, Hayes S, Newton RH, et al. Changes in collagen orienta-tion and distribution in keratoconus corneas. Invest Ophthalmol Vis Sci 2005;46:1948–56
4. Mathew JH, Goosey JD, Bergmanson JP. Quantified histopathology of the keratoconic cornea. Optom Vis Sci. 2011;88:988-97.
5. Kaldawy RM, Wagner J, Ching S, Seigel GM. Evidence of apoptotic cell death in keratoconus. Cornea. 2002;21(2):206-9.
6. Sherwin T, Brookes NH. Morphological changes in keratoconus: Pathology or pathogenesis. Clin Experiment Ophthalmol. 2004;32:211-7.
7. Sykakis E, Carley F, Irion L, Denton J, Hillarby MC. An in-depth analysis of histopathological characteristics found in keratoconus. Pathology. 2012;44:234-9.
8. Bühren J. Hornhauttopografie und Keratokonusdiagnostik mittels Scheimpflug-Fotografie [Corneal topography and keratoconus diagnostics with Scheimpflug photography].Ophthalmol. 2014;111(4):920–6.
9. Ní Dhubhghaill S, Rozema JJ, Jongenelen S, Hidalgo IR, Zakaria N, Tassignon MJ. Normative values for corneal densitometry analysis by Scheimpflug optical assessment. Invest Ophthalmol Vis Sci. 2014;55:162–8.
10. Otri AM, Fares U, Al-Aqaba MA, Dua HS. Corneal densitometry as an indicator of corneal health. Ophthalmology. 2012;119(3):501-8.
11. Meek KM, Knupp C. Corneal structure and transparency. Prog Retin Eye Res. 2015;49:1-16.
12. Mathew JH, Goosey JD, Söderberg PG, Bergmanson JPG. Lameller changes in the keratoconic cornea. Acta Ophthalmol. 2015;93:767–73.
13. Mercatelli R, Ratto F, Rossi F, Tatini F, Menabuoni L, Malandrini A. Three-dimensional mapping of the orientation of collagen corneal lamellae in healthy and keratoconic human corneas using SHG microscopy. J Biophotonics. 2016;10:75–81.
14. Khaled ML, Helwa I, Drewry M, Seremwe M, Estes A, Liu Y. Molecular and histopathological changes associated with keratoconus. Biomed Res Int. 2017;2017(1):780-3029.
15. Koc M, Tekin K, Tekin MI, Uzel MM, Kosekahya P, Ozulken K. et al. An early finding of kera-toconus: Increase in corneal densitometry. Cornea. 2018;37(5):580–6.
16. Anayol MA, Sekeroglu MA, Ceran BB, Dogan M, Gunaydin S, Yilmazbas P. Quantitative as-sessment of corneal clarity in keratoconus: A case-control study of corneal densitometry. Eur J Ophthalmol. 2016;26(1):18-23.
17. Lopes B, Ramos I, Ambro’sio R. Corneal densitometry in keratoconus. Cornea. 2014;33(12):1282–6.
18. Ucakhan OO KA, Yılmaz N, Ozkan M. In vivo confocal microscopy findings in keratoconus. Eye Contact Lens. 2006;32(4):183-91.
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Cigdem Coskun, Sebile Çomçalı. Could corneal densitometry be a diagnostic criterion for keratoconus? Ann Clin Anal Med 2025;16(2):118-121
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Results of combined application of lmwh /alpha lipoic acid in the experimental mesenteric ischemia/reperfusion injury model in rats
Elif Yılmaz 1, Abdulkadir Çelik 2, Arslan Hasan Kocamaz 3, Alper Varman 4, Sıdıka Fındık 5, Tevfik Küçükkartallar 4
1 Department of General Surgery, Kelkit State Hospital, Gümüşhane, 2 Department of General Surgery, Gaziantep Dr. Ersin Arslan Training and Research Hospital, Gaziantep, 3 Department of General Surgery, Kayseri State Hospital, Kayseri, 4 Department of General Surgery, Faculty of Medicine, Necmettin Erbakan University, Konya, 5 Department of Pathology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkiye
DOI: 10.4328/ACAM.22425 Received: 2024-09-27 Accepted: 2024-11-04 Published Online: 2024-11-12 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):122-126
Corresponding Author: Arslan Hasan Kocamaz, Department of General Surgery, Kayseri State Hospital, Kayseri, Turkiye. E-mail: md.ahkocamaz@gmail.com P: +90 530 967 64 11 Corresponding Author ORCID ID: https://orcid.org/0000-0002-5257-9611
Other Authors ORCID ID: Elif Yılmaz, https://orcid.org/0009-0000-6782-8820 . Abdulkadir Çelik, https://orcid.org/0000-0002-5537-7791 . Alper Varman, https://orcid.org/0000-0002-1918-5143 . Sıdıka Fındık, https://orcid.org/0000-0002-3364-7498 . Tevfik Küçükkartallar, https://orcid.org/0000-0002-6326-4623
This study was approved by the Ethics Committee of Necmettin Erbakan University Local Ethics Committee for Animal Experiments (Date: 2022-12-30, No: 076)
Aim: To evaluate the correlation between necrosis levels and parameters by creating an experimental mesenteric ischemia/reperfusion model in rats and assessing the effects of LMWH (Low Molecular Weight Heparin) and ALA (Alpha-Lipoic Acid) administration.
Material and Methods: Twenty-four female rats were randomly divided into three groups of eight. After anesthesia, laparotomy was performed, and the superior mesenteric artery (SMA) was identified and ligated at its origin from the aorta. Following 45 minutes of ischemia, the SMA ligation was released, and 60 minutes of reperfusion was allowed. After reperfusion, a 3 cm segment of the ileum, located 10 cm proximal to the ileocecal valve, was resected. The first group was designated as the control group and underwent only ischemia/reperfusion. In the second group, LMWH was administered subcutaneously 4 hours before laparotomy. In the third group, both LMWH (subcutaneously) and ALA (intraperitoneally) were administered 4 hours before laparotomy. Histopathological examination was conducted based on Chiu scoring to determine necrosis levels. Biochemical analysis was performed using LDH, phosphorus, lactate, complete blood count, TAS (Total Antioxidant Status), TOS (Total Oxidant Status), and OSI (Oxidative Stress Index) parameters.
Results: Our study suggests that ALA may have an inflammation-promoting effect, while LMWH, in addition to its anticoagulant properties, might act as an antioxidant, reducing the oxidative load in the organism. The combined use of LMWH and ALA is expected to reduce potential damage in the ileum.
Discussion: The study indicates that the combined use of LMWH and ALA may have a positive effect on ischemia parameters, oxidation parameters, and necrosis levels.
Keywords: Acute Mesenteric Ischemia, Alpha Lipoic Acid, Low Molecular Weight Heparin
Introduction
Mesenteric ischemia refers to a clinical condition characterized by reduced blood flow to the intestines due to acute arterial occlusion (embolic, thrombotic), venous thrombosis, or decreased perfusion without occlusion [1]. Established risk factors include cardiac arrhythmias, advanced age, low cardiac output states, generalized atherosclerosis, congestive heart failure, severe valvular heart disease, myocardial infarction, and intra-abdominal malignancies. Early diagnosis and effective treatment are crucial to minimize mortality; however, due to vague symptoms, lack of clinically useful diagnostic tests, and a broad spectrum of at-risk patient groups, significant improvement in the prognosis of mesenteric ischemia has not been achieved [2].
Reperfusion refers to the restoration of reduced or interrupted blood flow, and consequently oxygen, to hypoxic tissue. If cells have not irreversibly suffered damage, functions can be regained upon reperfusion; however, the reintroduction of oxygen into ischemic tissue leads to the formation of toxic oxygen radicals through a series of metabolic processes. Following the diagnosis of AMI (acute mesenteric ischemia), treatment should commence promptly. Treatment goals should focus on reducing vasospasm, preventing the spread of intravascular clotting processes, and minimizing reperfusion injury. Based on this premise, our study aimed to investigate the combined use of LMWH, which affects circulation disorders such as vasospasm and thrombosis, along with ALA, an antioxidant, to prevent or minimize post-reperfusion damage in terms of inflammation levels, necrosis/ischemia severity, and oxidation parameters.
ALA is a natural antioxidant synthesized minimally in the liver in humans [3]. It forms stable complexes by binding to transition metals and thereby eliminates heavy metals such as manganese, copper, zinc, and lead [4]. Additionally, ALA plays a role in regulating the synthesis and regeneration of other antioxidants, such as glutathione, and in regulating the activities of cellular transcription factors. It acts both as a coenzyme in metabolic processes and exhibits antioxidant properties [4, 5]. Many studies have been conducted on the antioxidant effects of alpha-lipoic acid in reducing cell damage by combating free radicals [6]. It has been shown to be effective in reducing symptoms of diabetic neuropathy [7]. Based on these observations, ALA is believed to improve inflammatory conditions in the body.
LMWHs exhibit anti-inflammatory effects in addition to their well-known anticoagulant properties. These anti-inflammatory effects are exemplified in chronic disease complications such as diabetes, malignancies, inflammatory diseases like ulcerative colitis, and viral infections [8].
Material and Methods
Groups
The rats were divided into three groups, each consisting of 8 rats. Following surgical area shaving and disinfection, laparotomy was performed via a vertical incision starting from the xiphoid process.
Group 1 (Sham group) (n=8): Intestinal loops were retracted, and the superior mesenteric artery (SMA) was isolated and ligated at its origin from the aorta (Figure 1).
After 45 minutes of ischemia, the ligature on SMA was released to achieve 60 minutes of reperfusion. Following reperfusion, a 3 cm segment of the ileum, starting 10 cm proximal to the ileocecal valve, was resected.
Group 2 (n=8): All rats in this group received subcutaneous administration of LMWH at a dose of 1 mg/kg. Four hours after LMWH administration, the same procedures as in Group 1 were carried out. Following reperfusion, a 3 cm segment of the ileum, starting 10 cm proximal to the ileocecal valve, was resected.
Group 3 (n=8): All rats in this group received subcutaneous administration of LMWH at a dose of 1 mg/kg and intraperitoneal administration of ALA at a dose of 100 mg/kg. Four hours after administration, the procedures identical to those in Groups 1 and 2 were performed. Following reperfusion, a 3 cm segment of the ileum, starting 10 cm proximal to the ileocecal valve, was resected. After intracardiac blood collection, the rats in all three groups were euthanized.
Histopathological changes in the ileum tissues obtained from 24 rats (8 rats per group) were classified according to Chiu’s scoring system (Table 1).
pH and lactate values were determined from blood samples collected from the rats. Data obtained from the study were analyzed using the SPSS (Statistical Package for Social Sciences) 18.0 software. Descriptive analyses presented frequency data as number (n) and percentage (%), while numerical data were expressed as mean ± standard deviation. Categorical data were compared using the Chi-square (ꭕ^2) test and Fisher’s exact test. The normality of numerical data was assessed using the Kolmogorov-Smirnov test. A one-way ANOVA test was used to evaluate numerical data fitting normal distribution among more than two groups. For variables that were significant in ANOVA tests, Tukey or Tamhane post hoc analyses were performed. In cases where numerical data did not fit normal distribution across more than two groups, the Kruskal-Wallis test was applied. Post hoc analysis using the Bonferroni-corrected Mann-Whitney U test was conducted for variables found significant in Kruskal-Wallis tests.
Ethical Approval
This study was approved by the Ethics Committee of Necmettin Erbakan University Local Ethics Committee for Animal Experiments. (Date: 2022-12-30, No: 076).
Results
One rat from Group 1 expired during the study procedures, and therefore, no blood or tissue samples were obtained from this rat, excluding it from statistical analysis. Thus, 23 rats were included in the study: control group (n=7), LMWH group (n=8), and LMWH +ALA group (n=8).
In the LMWH +ALA group, leukocyte levels were significantly higher compared to the control group and LMWH group (p=0.018). Leukocyte levels were similar between the control and LMWH groups. Neutrophil-to-lymphocyte ratio (NLR) levels were found to be similar across all three groups (p>0.05).
LDH levels in the control group rats were significantly higher compared to the LMWH and LMWH +ALA groups (p<0.001). LDH levels were similar between the LMWH and LMWH +ALA groups. Phosphorus and lactate levels were similar across all three groups (p>0.05).
Total antioxidant status (TAS) levels were significantly lower, and oxidative stress index (OSI) levels were significantly higher in the control group rats compared to the LMWH and LMWH +ALA groups (p values: p=0.021 for TAS, p=0.006 for OSI). TAS and OSI levels were similar between the LMWH and LMWH +ALA groups. Total oxidant status (TOS) levels were similar across all three groups (Table 2).
The grade scores of the included rats are compared in Table 3. The proportion of Grade 4 in the control group rats was significantly higher compared to the other groups (p=0.047), while rates were similar between the LMWH and LMWH +ALA groups.
Discussion
Mesenteric ischemia is a challenging diagnosis with a poor prognosis due to delayed diagnosis and the presence of comorbidities that worsen outcomes. The difficulty in diagnosis stems primarily from the wide spectrum of symptoms associated with the condition.
In cases where tissue oxygen delivery is reduced or ineffective, resulting in cellular damage and inflammation, several laboratory parameters such as lactate, leukocytosis, LDH, phosphorus, amylase, and lipase released from intestinal tissues into the plasma have been used as diagnostic aids in AMI. Elevated plasma lactate concentration is a hallmark of acute conditions threatening life. In their study, Lange H. and Jackel observed that lactate levels were elevated in all groups with mesenteric ischemia, exceeding the reference range in those with bacterial peritonitis and intestinal obstruction [9]. In our study, lactate and phosphorus levels were found to be elevated in all three groups, but no significant differences were observed among the groups.
LDH levels can rise in both chronic and acute tissue damage. However, its lack of tissue specificity diminishes its diagnostic contribution. In a study by Lapsekili E., LDH was characterized as a marker for ischemia with 94% sensitivity and 41% specificity [10]. In our study, LDH levels were significantly elevated in the control group compared to the other groups, but no significant difference was found between the LMWH and LMWH +ALA groups.
During acute inflammation, an increase in neutrophil counts and a decrease in lymphocyte counts are expected. Ercan et al. concluded from their retrospective study on patients operated for mesenteric ischemia that high NLR may indicate a poor prognosis [11]. High neutrophil counts are indicative of inflammation, while low lymphocyte counts reflect the overall poor condition and physiological stress. In our study, leukocyte counts were significantly higher in the LMWH +ALA group compared to the other two groups, raising suspicion that ALA may exacerbate inflammation. However, NLR levels were similar across all three groups. Other studies have shown that high NLR correlates not only with increased neutrophil counts but also with decreased lymphocyte counts, which may be attributed to increased steroid exposure due to physiological stress. Considering that the ischemia period was planned as 45 minutes after SMA ligation in our study, the results of our study may suggest that this synthesis pathway may require a longer duration in studies where the ischemia duration is extended.
In mesenteric ischemia, tissue damage occurs due to ischemic injury and subsequent reperfusion of oxygen to the tissue, which triggers a cascade of reactions leading to oxidative stress. When a previously blocked area is suddenly opened, additional cell death occurs compared to the ischemic period alone. This process involves activation of the complement system, activation of leukocytes, increased free oxygen radicals, and dysfunction of endothelial cells, followed by reactions resulting in necrosis and autophagy, ultimately leading to ischemia-reperfusion injury [12].
Several studies have highlighted the role of oxidative metabolism in elucidating the damage mechanism during ischemia. Total antioxidant status (TAS) has been found effective in many studies to illuminate oxidative damage occurring during injury. Similarly, the total oxidant status (TOS) created by free oxygen radicals during damage is assessed under a unified framework. The oxidative stress index (OSI), derived from the ratio of TAS to TOS, serves as an indicator of the effective oxidative burden in the organism. Kartal et al. demonstrated in a skeletal muscle ischemia-reperfusion model using OSI/TAS/TOS indices that ALA exhibits a protective effect against oxidative damage and apoptosis [13]. In our study, alongside the natural antioxidant ALA, we aimed to investigate the antioxidant properties of LMWH. While TAS levels were significantly lower in the control group compared to the other two groups, OSI was significantly higher. Anti-oxidative activity was observed only in the group treated with LMWH alone (Group 2), but no significant differences in oxidation parameters were found between Groups 2 and 3.
In the study by Yaman et al., using a mesenteric ischemia-reperfusion model, they compared intestinal mucosal degeneration and bacterial translocation levels among experimental groups. They found a significantly higher CHIU score in the control group with induced mesenteric ischemia compared to the group treated with ALA and L-carnitine [14]. Conversely, Köksal et al. investigated the efficacy of LMWH on bacterial translocation in a mesenteric ischemia-reperfusion model and did not find a significant difference in CHIU scores in the group treated with LMWH, attributing this to its anticoagulant effects potentially predisposing to hemorrhage and ulceration, thus not exerting a positive effect on ileal damage scoring [15]. However, in our study, contrary to these findings, we observed a significantly higher CHIU grade 4 score in the control group compared to the groups treated with LMWH and LMWH +ALA. Therefore, we hypothesize that both LMWH and the combination of LMWH +ALA may exert a positive effect on ileal damage levels.
Limitation
There are several limitations to consider when evaluating the results of this study. The ischemia and reperfusion durations used in the experimental model may not fully reflect the clinical scenarios encountered in human patients, which could affect the applicability of the results. The effects of LMWH and ALA have been assessed solely in the context of mesenteric ischemia/reperfusion injury; therefore, interactions of these agents with other potential therapeutic agents or underlying health conditions have not been examined. Additionally, while histopathological analyses provide valuable information about tissue damage, long-term outcomes or recovery processes post-treatment have not been evaluated in this study. Lastly, variations in individual responses to LMWH and ALA could not be accounted for, which may influence the overall results. Future studies should investigate the therapeutic effects of these agents in clinical settings using larger sample sizes and diverse experimental designs.
Conclusion
In our study investigating the combined use of LMWH and ALA and their effects on oxidation, inflammation, ischemia, and necrosis levels, significant leukocytosis was observed in the group where both pharmaceutical agents were used, suggesting that ALA may have an inflammatory effect. According to our study’s findings, the group treated with LMWH showed significantly higher TAS levels and lower OSI levels compared to the control group, indicating that in addition to its anticoagulant effect, heparin may also have antioxidant functions. The control group exhibited a higher CHIU grade 4 score compared to the other two groups. Therefore, both LMWH alone and combined use of LMWH+ALA appears effective in preventing damage development in the ileum. However, for a more comprehensive evaluation of the effectiveness of LMWH alone and LMWH +ALA in practice, further animal experiments and subsequent human trials in a larger series are deemed necessary.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Bilge Z, Köksal AŞ. Colonic ischemia. Curr Gastroenterol Rep. 2016;20(4):466-71.
2. Glenister KM, Corke CF. Infarcted intestine: A diagnostic void. ANZ J Surg. 2004;74(4):260-65.
3. Ergene E. A study on alpha-lipoic acid and its metabolic effects. J Adnan Menderes Univ Health Sci. 2018;2(3):159-65.
4. Uygur AG, Şingirik E, Yücel AH. Protective effects of alpha-lipoic acid in methotrexate-induced damage. Arch Res Scan J. 2019;28(3):227-36.
5. Ziegler D, Duenas M, Wiegand W, Schütte K, Tölle T, Lämmermann J, et al. Alpha-lipoic acid improves metabolic control in diabetic patients with symptomatic peripheral neuropathy: A randomized, double-blind, placebo-controlled trial. Diabetes Care. 2004;27(9):2172-78.
6. Huang L, Zhang Y. Protective effects of alpha-lipoic acid against oxidative stress in acute pancreatitis. Clin Sci. 2015;129(10):835-46.
7. Ibrahimpasic K. Alpha-lipoic acid and glycemic control in diabetic neuropathies during type 2 diabetes treatment. Med Arch. 2013;67(1):7-9.
8. Yan Y, Ji Y, Su N, Mei X, Wang Y, Du S, et al. Non-anticoagulant effects of low molecular weight heparins in inflammatory disorders: A review. Carbohydr Polym. 2017;160(1):71-81.
9. Miller AC, Heller M, Kocoshis SA, Goldstein AM, Chinnock B, Parnell R, et al. Lactate as a predictor of outcomes in patients with acute abdomen: A systematic review and meta-analysis. J Trauma Acute Care Surg. 2021;90(2):313-22.
10. Gatta A, De Ceglie A, Viscido A, Manfreda R, De Angelis N, Di Mitri R, et al. Alkaline phosphatase as a potential marker for acute mesenteric ischemia. BMC Gastroenterol. 2018;18(1):32.
11. Ercan KD. The effectiveness of preoperative neutrophil-lymphocyte ratio in determining the prognosis of acute mesenteric ischemia. Selcuk Med J. 2019;35(4):230-34.
12. Collard CD, Gelman S. Pathophysiology, clinical manifestations, and prevention of ischemia-reperfusion injury. Anesthesiology. 2001;94(6):1133-38.
13. Kartal H, Büyük B. Effects of alpha-lipoic acid on skeletal muscle ischemia-reperfusion injury in mice. J Surg Med. 2020;4(7):567-72.
14. Petronilho F, Silva E, Quevedo J, Brizola E, de Almeida J, Ribeiro L, et al. Alpha-lipoic acid attenuates oxidative damage in organs after sepsis. Inflammation. 2016;39:357-365.
15. Yagmurdur MC, Turk E, Moray G, Can F, Demirbilek M, Haberal N, et al. Effects of heparin on bacterial translocation and gut epithelial apoptosis after burn injury in the rat: Dose-dependent inhibition of the complement cascade. Burns. 2005;31(5):603-9.
Download attachments: 10.4328.ACAM.22425
Elif Yılmaz, Abdulkadir Çelik, Arslan Hasan Kocamaz, Alper Varman, Sıdıka Fındık, Tevfik Küçükkartallar. Results of combined application of lmwh /alpha lipoic acid in the experimental mesenteric ischemia/reperfusion injury model in rats. Ann Clin Anal Med 2025;16(2):122-126
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Evaluation of the efficacy of high-dose n-acetylcysteine in preventing contrast-induced nephropathy in the emergency department
Ömerul Faruk Aydın 1, Özlem Güneysel 2
1 Department of Emergency Medicine, Faculty of Medicine, Istanbul Yeni Yüzyıl University, 2 Department of Emergency, Medicana Zincirlikuyu Hospital, Istanbul, Turkiye
DOI: 10.4328/ACAM.22433 Received: 2024-09-30 Accepted: 2024-11-11 Published Online: 2024-11-18 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):127-132
Corresponding Author: Ömerul Faruk Aydın, Department of Emergency Medicine, Faculty of Medicine, Istanbul Yeni Yüzyıl University, Istanbul, Turkiye. E-mail: omerulfaruk.aydin@yeniyuzyil.edu.tr P: +90 507 373 05 20 Corresponding Author ORCID ID: https://orcid.org/0000-0002-4279-297X
Other Authors ORCID ID: Özlem Güneysel, https://orcid.org/0000-0002-1833-2199
This study was approved by the Ethics Committee of Kartal Dr. Lütfi Kırdar City Hospital (Date: 2014-12-09, No: 6)
Aim: The aim of this study is to evaluate the efficacy of high-dose N-Acetylcysteine (NAC) in preventing contrast-induced nephropathy (CIN) in patients with mild renal dysfunction in the emergency department (ED), compared to normal saline (NS).
Material and Methods: This retrospective analysis is based on a previously conducted randomized controlled trial (RCT). The study includes a retrospective analysis of data from an RCT carried out in the ED at a tertiary hospital. A total of 48 patients were deemed eligible for analysis; 23 patients received NAC treatment, while 25 patients received saline treatment. Propensity score matching (PSM) was used to balance the baseline characteristics between the groups.
Results: After propensity score matching, 23 patients remained in each group. In the group treated with NAC in the ED, a significantly greater reduction in serum creatinine (SCr) levels was observed at 24 hours (-0.27 ± 0.15 mg/dL vs. -0.08 ± 0.29 mg/dL, p = 0.022) and 72 hours (-0.46 ± 0.22 mg/dL vs. -0.12 ± 0.34 mg/dL, p = 0.012) compared to the NS group. Although a more pronounced decrease in urea levels was observed in the NAC group, this was not statistically significant. A reduction in creatinine levels of ≥25% was detected in 60.9% of patients in the NAC group, compared to 36% in the saline group (p = 0.027). Contrast-induced nephropathy (CIN) developed in 24% of the saline group patients, while no CIN cases were observed in the NAC group.
Discussion: High-dose NAC treatment in the ED appears to be an effective strategy for preventing CIN in patients with mild renal dysfunction (SCr levels of 1.2-1.8 mg/dL) who are scheduled to receive contrast media.
Keywords: N-Acetylcysteine, Contrast-Induced Nephropathy, Emergency Department, Prevention
Introduction
Acute kidney injury (AKI) that occurs shortly after the administration of intravenous (IV) iodinated contrast for radiological imaging is referred to as contrast-induced AKI (CI-AKI) or, more commonly today, contrast-induced nephropathy (CIN) [1]. Although these two pathophysiological definitions are debated as involving different mechanisms, both describe an iatrogenic clinical condition that results in nephron damage [2, 3]. Although nearly 70 years have passed since the first case of CIN was described, there is still ongoing debate about the best approach to combat this iatrogenic disease [4].
The potential of intravenously administered contrast media to cause CIN, particularly for diagnostic purposes, varies significantly depending on the presence of risk factors, the type of contrast used, the volume of contrast administered, the route of administration, and the patient population being studied. Consequently, while the incidence changes with the presence of risk factors, the incidence of CI-AKI is considered negligible in their absence. However, in patients with risk factors, the incidence of post-contrast AKI has been reported to range from 12% to 50% [5, 6].
Today, emergency departments (EDs) are among the most frequent and rapidly growing settings for the use of contrast media, particularly for diagnosing life-threatening conditions that require urgent and accurate diagnosis. Imaging with contrast is increasingly employed to facilitate timely decision-making in critically ill patients [7]. The rapid advancement of medical imaging technology, the frequent preference for minimally invasive imaging methods in diagnostic tests, and clinicians’ reliance on contrast use in managing patients’ diagnostic processes have contributed to CIN remaining a growing clinical issue. Therefore, developing strategies to combat this iatrogenic condition that arises during the diagnostic process is of great importance. When examining these strategies, efforts have been made to prevent this iatrogenic condition by targeting the pathophysiological mechanisms involved in CIN development. Approaches include the use of agents such as sodium bicarbonate, hydration with 0.9% NaCl solution- normal saline (NS), N-acetylcysteine (NAC), Vitamin C, Statins, Hemofiltration, and Hemodialysis, or Short-term controlled tissue ischemia, as well as medications like Metformin, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin II receptor blockers (ARBs), administered before or after contrast exposure [8]. Although NAC, a potent antioxidant, is believed to have a positive effect on renal hemodynamics by directly reducing renal oxidative damage, it remains a controversial topic due to inconsistencies in research findings [9]. For this reason, in our study, we aimed to evaluate the efficacy of high-dose NAC treatment in preventing CIN in the ED.
Material and Methods
Study Design and Setting
This study is a retrospective analysis of a randomized controlled trial (RCT) conducted as part of a dissertation thesis in the ED at Dr. Lütfi Kırdar Kartal City Hospital. The primary aim of the original RCT was to evaluate the efficacy of high-dose NAC compared to NS in preventing CIN in patients with mild renal impairment (serum creatinine [SCr] levels between 1.2 and 1.8 mg/dL). In this retrospective analysis, propensity score matching (PSM) was employed to balance baseline characteristics between the two treatment groups and to strengthen the comparability of the NAC and Salin groups, thereby improving the accuracy and validity of the estimated treatment effects.
Study Population
Patients aged 16 years and older, with a baseline serum creatinine level of 1.2–1.8 mg/dL, who were included in the original RCT, were eligible for this analysis. Exclusion criteria included: known allergy to NAC or contrast agents, history of contrast-induced nephropathy, chronic heart failure (NYHA class III-IV), end-stage renal disease requiring dialysis, severe hepatic impairment, any active malignancy, inadequate laboratory data, or the need for urgent computed tomography (CT) imaging as determined by the treating physician. Out of the original RCT participants, 48 patients met the inclusion criteria for this retrospective analysis. These patients were randomized into two groups: the NAC group (n=23) and the NS group (n=25).
Randomization and Interventions
In the original RCT, patients were assigned to treatment groups based on the order of hospital admission (odd numbers assigned to NAC, even numbers of toNS). The NAC group received 150 mg/kg of NAC intravenously in 0.9% NaCl-NS over 30-60 minutes before contrast administration (pre-Contrast), followed by a maintenance dose of 50 mg/kg over 2-4 hours post-Contrast [10]. The NS group received IV 0.9% NaCl at 6-8 mL/kg/h for 60-120 minutes before contrast and 3-4 mL/kg/h over 4-6 hours post-contrast. Low-osmolar iohexol (Omnipaque 350 mg/100 ml) was used as the contrast agent.
Data Collection and Variables
For the retrospective analysis, baseline demographic data, including age, gender, and initial serum creatinine and urea levels, were collected. SCr and urea were measured at baseline, 24 hours, and 72 hours post-contrast administration. The primary outcome of this analysis was the change in creatinine and urea levels, defined as an increase or decrease from baseline to 24 or 72 hours. Secondary outcomes included the proportion of patients achieving a ≥25% reduction in SCr and urea levels and the development of CIN, defined as an increase in SCr of ≥0.5 mg/dL.
Propensity Score Matching and Analysis
Propensity score matching (PSM) was performed to ensure balanced baseline characteristics between the NAC and NS groups in the retrospective analysis. Propensity scores were calculated using a logistic regression model based on age, baseline SCr, and baseline urea levels. Nearest neighbor matching without replacement was applied to match each patient in the NAC group with a control from the NS group. Balance was assessed using standardized mean differences (SMD), with an SMD <0.1 indicating good balance.
Analysis
Comparative analyses between groups were conducted using Student’s t-test or Mann-Whitney U test for continuous variables and chi-square or Fisher’s exact test for categorical variables. Changes in creatinine and urea levels were analyzed using linear regression models, adjusting for baseline characteristics. Results were reported as mean differences with 95% confidence intervals (CIs) using the format [mean difference (95% CI)]. Statistical significance was set at p < 0.05. Data analyses were conducted using Python.
Ethical Approval
This study was approved by the Ethics Committee of Kartal Dr. Lütfi Kırdar City Hospital (Date: 2014-12-09, No: 6).
Results
After propensity score matching, 23 patients remained in each group. Baseline characteristics were well-balanced, with no significant differences in age (NAC: 64.4 ± 12.8 vs. NS: 61.8 ± 10.9, p = 0.453), baseline SCr (NAC: 1.48 ± 0.19 mg/dL vs. NS: 1.50 ± 0.18 mg/dL, p = 0.723), and baseline urea (NAC: 79.6 ± 51.2 mg/dL vs. NS: 87.9 ± 30.8 mg/dL, p = 0.523) (Table 1). The gender distribution was also similar, with 60.9% male in the NAC group and 65.2% male in the NS group (p = 0.784).
From baseline to 24 hours, the NAC group demonstrated a significantly greater reduction in SCr levels (-0.27 ± 0.15 mg/dL) compared to the NS group (-0.08 ± 0.29 mg/dL), with a mean difference of -0.19 [95% CI: -0.35, -0.03], p = 0.022 (Table 2).
Similarly, from baseline to 72 hours, the NAC group showed a larger reduction in SCr levels (-0.46 ± 0.22 mg/dL) compared to the NS group (-0.12 ± 0.34 mg/dL), with a mean difference of -0.34 [95% CI: -0.60, -0.09], p = 0.012 (Figure 1).
Urea levels also showed a significant decline in the NAC group. From baseline to 24 hours, the NAC group had a mean urea reduction of -13.13 ± 14.70 mg/dL compared to -11.13 ± 30.08 mg/dL in the NS group. Although this difference was not statistically significant, by 72 hours, the NAC group exhibited a more pronounced reduction in urea levels (-30.96 ± 32.83 mg/dL) compared to the NS group (-17.83 ± 19.80 mg/dL), with a mean difference of -13.13 [95% CI: -27.30, 1.04], p = 0.068 (Figure 2).
The NAC group continued to show a significant reduction in urea levels from 24 to 72 hours, with a mean decrease of -17.83 ± 23.69 mg/dL compared to -6.70 ± 20.11 mg/dL in the NS group, with a mean difference of -11.13 [95% CI: -23.51, 1.24], p = 0.078.
A significantly higher proportion of patients in the NAC group achieved a ≥25% reduction in SCr levels at 72 hours (60.9%) compared to the NS group (36%), with a difference of 24.9% [95% CI: 3.5, 46.3], p = 0.027. In terms of urea levels, 52.2% of patients in the NAC group had a ≥25% reduction at 72 hours compared to 34.8% in the NS group, although this difference was not statistically significant (p = 0.151).
Regression analysis indicated that NAC treatment was associated with a significantly greater reduction in SCr levels compared to NS, with a coefficient of -0.36 [95% CI: -0.64, -0.09], p = 0.014 (Table 3). Similarly, for urea reduction from baseline to 72 hours, NAC treatment showed a significant effect, with a coefficient of -17.57 [95% CI: -28.88, -6.26], p = 0.003. Baseline urea levels were also a significant predictor of the change in urea, with higher baseline levels associated with greater reductions (coefficient: -0.49 [95% CI: -0.64, -0.35], p < 0.001).
In terms of the development of CIN, no patients in the NAC group developed CIN at 24 or 72 hours. In contrast, six patients in the NS group developed CIN at 24 hours (24.0%) and three patients at 72 hours (12.0%). The difference was statistically significant at 24 hours (p = 0.023) but not at 72 hours (p = 0.235).
Discussion
In this study, the efficacy of NAC administered before (pre-contrast) and after (post-contrast) contrast exposure in preventing CIN was investigated in patients with mild renal dysfunction (SCr levels of 1.2-1.8 mg/dL), compared to NS given before and after contrast administration. PSM was used to balance the baseline characteristics between the NAC and NS groups, allowing for a more accurate assessment of treatment effects. More pronounced reductions in SCr and urea levels were observed in the NAC group compared to the NS group. While a significant reduction in SCr levels was detected at 24 and 72 hours in the NAC group, the decrease in the NS group was more limited. Although the NAC group showed more prominent reductions in urea levels, this difference was not statistically significant. The proportion of patients with ≥25% reduction in SCr e levels at 72 hours was significantly higher in the NAC group compared to the NS group. Additionally, no cases of CIN were observed in the NAC group, whereas a certain proportion of CIN development was noted in the NS group. High-dose NAC treatment appears to be effective in reducing the risk of CIN in patients with mild renal dysfunction.
Accurate measurement of kidney function is crucial for the routine care of patients and for determining the status of renal function. Glomerular filtration rate (GFR), considered the gold standard for monitoring kidney function, defines the rate at which fluid is filtered through the kidneys. The gold standard method for measuring GFR involves the injection of inulin, followed by the measurement of its clearance by the kidneys [11]. This method is invasive, time-consuming, and expensive. Therefore, as an alternative, SCr — a biochemical marker found in serum and urine— is the most used point-of-care test for both estimating GFR and monitoring kidney function. It is a rapid, cost-effective biomarker [12, 13]. Therefore, in this study, the definition of the high-risk group was based on SCr levels, with the lower threshold set at 1.2 mg/dL, following international laboratory recommendations, regardless of gender differences [14]. In our study, we observed that NAC administration reduced SCr levels. This observation is consistent with findings from other studies in the literature [15]. Although some studies argue that NAC’s effect may be independent of a change in GFR, potentially increasing SCr tubular secretion or decreasing creatinine production, our study suggests a positive impact of NAC on SCr and, thus, on renal function. This is supported by the observation of lower SCr levels at both 24 and 72 hours compared to the NS group.
The exact mechanism leading to CIN following contrast administration has not yet been fully elucidated through prospective studies. The most likely mechanism remains the combination of contrast media-induced renal vasoconstriction, resulting in hypoxia, along with direct toxicity to the tubular epithelial cells, which together impair kidney function [16]. As a result, reactive oxygen species produced in connection with contrast media administration are considered to play a pivotal role in the development of CIN [17]. Because reactive oxygen species can affect both cortical and medullary microcirculation directly and indirectly, leading to vasoconstriction, antidiuresis, and anti-natriuresis, superoxide dismutase, a scavenger of reactive oxygen species, may inhibit the kidney damage caused by contrast media [18]. Therefore, NAC, which acts on this pathway, remains one of the most frequently studied agents for preventing CIN. The European Renal Best Practice (ERBP) position statement on the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines on Acute Kidney Injury recommends the use of oral NAC only in patients receiving appropriate fluid and salt loading (2D). It also advises against using oral NAC as the sole method for preventing CIN [15]. In this study, all patients were administered serum saline both before and after contrast media administration. While this intervention influenced SCr levels, the difference became more pronounced in patients receiving both NS and NAC at 24 hours, and this effect was even more evident at 72 hours.
In studies conducted in the ED, Turedi et al. reported a high CIN incidence of 23.7% despite the use of at least one prophylactic measure for all ED patients before and after contrast administration [19]. In their study, the prophylactic measures included 3 mL/kg IV NAC + NS (3 g NAC diluted to 1000 mL with NS) or NaHCO3 + NS solution, or at least 1 mL/kg IV NS administered for a minimum of 6 hours after contrast administration. In comparison to our study, this study administered lower amounts of NS and NAC. Overall, significant variations in CIN incidence among ED patients have been reported, which may be attributed to various factors such as underlying patient conditions and the use of different CIN definitions.
In summary, this study divided patients with mild renal dysfunction (SCr levels of 1.2-1.8 mg/dL) into two groups: one receiving only NS before and after contrast administration and the other receiving both NS and high-dose NAC. The NAC group showed significantly greater reductions in SCr and urea levels compared to the NS group. At 72 hours, 60.9% of patients in the NAC group experienced a ≥25% reduction in SCr levels, compared to 36% in the NS group. Furthermore, none of the patients in the NAC group developed CIN, whereas CIN occurred in 24% of the NS group.
Limitation
This study has several limitations: 1) Although the data were derived from a randomized controlled trial, the retrospective nature of this analysis may introduce inherent biases that could affect the accuracy and reliability of the findings. Despite the use of propensity score matching to balance baseline characteristics, unknown confounding variables may still be present. 2) The study included a relatively small number of patients. This limited sample size may reduce the statistical power of the analysis and restrict the generalizability of the results to broader populations. 3) This study was conducted in a single tertiary hospital’s ED, which may limit the generalizability of the findings to other healthcare settings or populations with different characteristics.4) The study assessed outcomes within 72 hours post-contrast administration, but no long-term follow-up was conducted. Long-term kidney function and the potential for delayed contrast-induced nephropathy were not evaluated. 5)The study focused on patients with mild renal impairment (SCr levels between 1.2 and 1.8 mg/dL). Patients with more severe renal dysfunction, who may be at higher risk of CIN, were excluded, which could limit the applicability of the findings to higher-risk populations. Future studies comparing multiple agents could provide a more comprehensive assessment of CIN prevention strategies.
Conclusion
In the ED setting, for patients undergoing CT with low-osmolar contrast media, high-dose IV NAC treatment (150 mg/kg NAC in 0.9% NaCl administered 30-60 minutes before contrast, followed by a maintenance dose of 50 mg/kg within 2-4 hours after contrast administration) stands out as an effective option for preventing contrast-induced nephropathy in patients with mild renal dysfunction (SCr levels of 1.2-1.8 mg/dL).
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Van der Molen AJ, Reimer P, Dekkers IA, Bongartz G, Bellin MF, Bertolotto M, et al. Post-contrast acute kidney injury – Part 1: Definition, clinical features, incidence, role of contrast medium, and risk factors. Eur Radiol. 2018;28(7):2845-55.
2. Mandurino-Mirizzi A, Munafò A, Crimi G. Contrast-Associated Acute Kidney Injury. J Clin Med. 2022;11(8):2167.
3. Ramachandran P, Jayakumar D. Contrast-induced Acute Kidney Injury. Indian J Crit Care Med. 2020;24(Suppl 3):p.122-5.
4. Novak JE, Handa R. Contrast Nephropathy Associated with Percutaneous Coronary Angiography and Intervention. Cardiol Clin. 2019;37(3):287-96.
5. Rudnick MR, Leonberg-Yoo AK, Litt HI, Cohen RM, Hilton S, Reese PP. The Controversy of Contrast-Induced Nephropathy With Intravenous Contrast: What Is the Risk? Am J Kidney Dis. 2020;75(1):105-13.
6. Davenport MS, Khalatbari S, Cohan RH, Dillman JR, Myles JD, Ellis JH. Contrast material-induced nephrotoxicity and intravenous low-osmolality iodinated contrast material: Risk stratification by using estimated glomerular filtration rate. Radiology. 2013;268(3):719-28.
7. Bellolio MF, Heien HC, Sangaralingham LR, Jeffery MM, Campbell RL, Cabrera D, et al. Increased Computed Tomography Utilization in the Emergency Department and Its Association with Hospital Admission. West J Emerg Med. 2017;18(5):835-45.
8. Biernacka-Fiałkowska B, Szuksztul M, Suślik W, Dzierwa K, Tekieli Ł, Kostkiewicz M, et al. Intravenous N-acetylcysteine for the Prevention of Contrast-induced nephropathy – a prospective, single-center, randomized, placebo-controlled trial. The INPROC trial. Postepy Kardiol Interwencyjnej. 2018;14(1):59-66.
9. Magner K, Ilin JV, Clark EG, Kong JWY, Davis A, Hiremath S. Meta-analytic Techniques to Assess the Association Between N-acetylcysteine and Acute Kidney Injury After Contrast Administration: A Systematic Review and Meta-analysis. JAMA Network Open. 2022;5(7): e2220671.
10. Baker CS, Wragg A, Kumar S, De Palma R, Baker LR, Knight CJ. A rapid protocol for the prevention of contrast-induced renal dysfunction: The RAPPID study. J Am Coll Cardiol. 2003 Jun 18;41(12):2114-8
11. Speeckaert MM, Seegmiller J, Glorieux G, Lameire N, Van Biesen W, Vanholder R, Delanghe JR, et al. Measured Glomerular Filtration Rate: The Query for a Workable Golden Standard Technique. J Pers Med. 2021;11(10):949.
12. Makris K, Spanou L. Acute Kidney Injury: Diagnostic Approaches and Controversies. Clin Biochem Rev. 2016;37(4):153-75.
13. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):p.117-314.
14. Smith E, editor. Biochemistry Laboratory Handbook. Liverpool: D. Powell; 2023.p.385-410.
15. Fliser D, Laville M, Covic A, Fouque D, Vanholder R, Juillard L, et al. A European Renal Best Practice (ERBP) position statement on the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines on Acute Kidney Injury: Part 1: Definitions, conservative management, and contrast-induced nephropathy. Nephrol Dial Transplant. 2012;27(12):4263-72.
16. Lankadeva YR, Okazaki N, Evans RG, Bellomo R, May CN. Renal Medullary Hypoxia: A New Therapeutic Target for Septic Acute Kidney Injury. Semin Nephrol. 2019;39(6):543-53.
17. Mo C, Huang Q, Li L, Long Y, Shi Y, Lu Z, et al. High-mobility group box one and its related receptors: Potential therapeutic targets for contrast-induced acute kidney injury. Int Urol Nephrol. 2024;56(7):2291-99.
18. Cheng AS, Li X. The Potential Biotherapeutic Targets of Contrast-Induced Acute Kidney Injury. Int J Mol Sci. 2023;24(9):8254.
19. Turedi S, Erdem E, Karaca Y, Tatli O, Sahin A, Turkmen S, et al. The High Risk of Contrast-induced Nephropathy in Patients with Suspected Pulmonary Embolism Despite Three Different Prophylaxis: A Randomized Controlled Trial. Acad Emerg Med. 2016;23(10):1136-45.
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Survival outcomes and prognostic factors in stage 2 and 3 colorectal cancer: Comparing elective and emergency surgical approaches
Cem Batuhan Ofluoğlu 1, Fırat Mülküt 2
1 Department of Gastrointestinal Surgery, 2 Department of General Surgery, Faculty of Health Sciences, Sancaktepe Sehit Prof. Dr. İlhan Varank Training and Research Hospital, Istanbul, Turkiye
DOI: 10.4328/ACAM.22496 Received: 2024-11-20 Accepted: 2024-12-24 Published Online: 2025-01-20 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):133-138
Corresponding Author: Cem Batuhan Ofluoğlu, Department of Gastrointestinal Surgery, Faculty of Health Sciences, Sancaktepe Sehit Prof. Dr. İlhan Varank Training and Research Hospital, Istanbul, Turkiye. E-mail: dr.cemofluoglu@gmail.com P: +90 532 366 57 27 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0670-8590
Other Authors ORCID ID: Fırat Mülküt, https://orcid.org/0000-0003-4049-7595
This study was approved by the Ethics Committee of Kartal Dr. Lütfi Kırdar City Hospital (Date: 2023-03-29, No: 2023/514/246/24)
Aim: This study aimed to compare the survival outcomes of Stage 2 and Stage 3 colorectal cancer (CRC) patients undergoing emergency versus elective surgery and to identify critical prognostic factors influencing survival rates.
Material and Methods: We retrospectively analyzed 323 CRC patient records from January 2015 to March 2017, focusing on factors like tumor grade, lymphovascular and perineural invasion, mucinous component, perforation, tumor size, and lymph node count. Exclusions were made for incomplete data, palliative surgeries, and non-standard surgical margins. Survival analysis was performed using Kaplan Meier and logistic regression, with a p-value <0.05 indicating statistical significance.
Results: Of the 181 patients analyzed, 60.2% were stage 2, and 39.8% were stage 3. Emergency surgery correlated with reduced survival in both stages. Notably, stage 2 emergency patients had fewer lymph nodes removed and higher incidences of tumor perforation and perineural invasion (p = 0.01, 0.001, 0.014, respectively). For stage 3, vascular invasion was significantly more common in the emergency group (p = 0.017). Multivariate analysis underscored lymph node count, tumor perforation, and perineural invasion as significant for stage 2 (p = 0.040, 0.012, 0.002, respectively), while vascular invasion was critical for stage 3 (p = 0.023).
Discussion: Emergency CRC surgery is associated with lower survival rates and more aggressive tumor features. These findings suggest that elective surgery may offer a survival advantage in CRC due to less aggressive tumor features, underlining the need for prompt diagnosis and surgical intervention. Future studies should focus on optimizing preoperative care and exploring postoperative strategies to improve outcomes for emergency surgery patients.
Keywords: Colorectal Cancer, Emergency Surgery, Elective Surgery, Prognostic Factors, Stage 2-3
Introduction
In 2022, colorectal cancer (CRC) ranks as the fourth most commonly diagnosed cancer and the second leading cause of cancer-related deaths in the USA [1]. Surgical resection remains the standard of care for non-metastatic CRC. Despite the routine treatment with radical surgery and adjuvant chemotherapy applied today, the survival outcome in CRC is heterogeneous and not satisfactory. The 5-year survival rate for patients diagnosed with local CRC is 90.1%, for those with regional lymph node involvement, it is 69.2%, while for patients with distant metastasis, the rate drops to 11.7% [2]. Currently, the strongest tool for assessing prognosis following potentially curative surgery is the pathological examination of the specimen. Although the depth of tumor invasion, the number of positive lymph nodes, and the presence of metastasis determine the pathological stage and are the strongest predictors of prognosis, other clinical, molecular, and histological features can independently affect the prognosis regardless of the stage.
Approximately 33% of patients with CRC still present in the hospital, requiring urgent intervention due to conditions that necessitate acute care, despite widespread screening programs and endoscopic procedures [3]. Obstruction, haemorrhage, and perforation are the most common indications for emergency CRC surgery, with obstruction being the most frequent at 77% [4]. Emergency colorectal operations are associated with higher mortality and morbidity compared to elective surgery [5]. While some studies suggest that emergency colorectal resection is associated with poor oncological outcomes, others report no difference in prognosis [6-8].
The Clinical Practice Guidelines Committee of the American Society of Colon and Rectal Surgeons has identified three goals that need to be addressed in the treatment of emergent cases of CRC: (1) to eliminate the adverse effects of the condition that necessitates emergency intervention; (2) to achieve the best possible tumor control; and (3) to prepare the patient for adjuvant or systemic therapy as soon as possible [9].
In our study, we aimed to compare the survival of patients with CRC who underwent emergency or elective surgery at the same stage (stage 2 or 3) and to identify other parameters that affect survival independent of the stage.
Material and Methods
Data from 323 patients who underwent surgery for CRC at a tertiary referral hospital between January 2015 and March 2017 were retrospectively analyzed. Factors including grade, lymphovascular invasion, perineural invasion, mucinous component presence, perforation, tumor size, the number of lymph nodes excised, and the number of metastatic lymph nodes (for stage 3 patients) were determined through pathological examination of the specimens. Pieces exhibiting any extracellular mucin were assessed as containing a mucinous component, irrespective of the amount of extracellular mucin secreted. The staging was conducted using the pathological staging criteria from the NCCN’s February 25, 2022, Version 1. 2022 publication for colon cancer. According to the College of American Pathologists Consensus Statement [10], patients were classified into two categories: well-moderately and poorly. Conventional adenocarcinoma is characterized by glandular formation, which forms the basis for histologic tumor grading: well-differentiated adenocarcinoma shows >95% gland formation; moderately differentiated adenocarcinoma has 50%-95% gland formation; and poorly differentiated adenocarcinoma is mostly solid with <50% gland formation. Patients’ survival data were accessed from a national database. Tumor localization was categorized into right colon and left colon, with tumors located in the proximal two-thirds of the transverse colon recorded as right colon and those further distal noted as left colon tumors. Patients excluded from the study were those with missing data, those who underwent palliative surgery, those who received total abdominal colectomy, those with positive surgical margins (1 cm for distal rectal cancer, 5 cm for proximal rectal cancer, 10 cm distal margin for colon cancer, and 10 cm proximal margin for all CRC), those who died perioperatively without discharge, stage I patients (due to insufficient numbers for comparison in emergency surgery), and stage IV metastatic patients.
All statistical analyses were performed using SPSS (Statistical Package for Social Sciences) for Windows version 25.0. Normality was assessed using Skewness and Kurtosis tests and graphical methods. Data were expressed as mean ± standard deviation if normally distributed and median with min-max values if not. Additionally, data were presented as counts (n) and percentages (%). The Chi-square test was utilized for comparing two categorical variables. Fisher’s Exact Test was employed if the Chi-square test did not have a sufficient number of patients for comparison. When comparing a categorical variable with a numerical value, the Independent Sample T-test was used for normally distributed numerical values, while the Mann-Whitney U test was applied for non-normally distributed numerical values. Survival comparisons between patients at the same stage were conducted using Kaplan Meier survival analysis. Logistic regression analysis was used to compare data between emergency and elective patients. Both multivariate and univariate analyses were performed using logistic regression. A p-value of <0.05 within a 95% confidence interval was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Kartal Dr. Lütfi Kırdar City Hospital (Date: 2023-03-29, No: 2023/514/246/24).
Results
Our analysis covered 181 CRC patients, distinguishing 60.2% at stage 2 and 39.8% at stage 3. Notably, the age distribution and lymph node removal followed a normal distribution, contrasting with the non-normal distribution of tumor size and positive lymph node count.
Survival analysis revealed that stage 2 and 3 patients had reduced rates after emergency surgery (as depicted in Figure 1 and Figure 2).
The mean age for stage 2 was 64.72 years, with an average of 21.55 lymph nodes resected. The median tumor size for this group was 5.51 cm. Gender was nearly evenly split with a slight male predominance (51.4%), and tumors were more commonly found in the left colon (67%). Most tumors were well-moderately differentiated (91.7%), with a minority showing vascular invasion (20.2%) and perforation (9.2%). Perineural invasion was present in nearly a third of the cases (29.4%), and a mucinous component was seen in 24.8% of the stage 2 patients (Table 1).
For stage 2 patients, those undergoing emergency surgery had significantly fewer lymph nodes removed (p = 0.01) and higher rates of tumor perforation (p=0.001) and perineural invasion (p = 0.014). Age differences between emergency and elective surgery groups were not statistically significant (p = 0.125). The presence of poorly differentiated tumors, vascular invasion, and mucinous components between the emergency and elective surgery groups showed no statistical significance, with p-values of 0.083, 0.469, and 0.522, respectively (Table 1).
Stage 3 patients had an average age of 63.21 years and an average lymph node harvest of 21.47, with a median tumor size of 4.94 cm. Gender distribution was similar to stage 2, with a slight male predominance. Vascular invasion was seen in a higher proportion (66.7%), particularly in the emergency surgery group, which was a significant finding (p = 0.017). Perineural invasion was present in over half of the stage 3 patients (52.8%). The incidence of poorly differentiated tumors and the presence of a mucinous component showed no statistical difference between the emergency and elective groups (p > 0.05) (Table 1).
When comparing the emergency and elective surgery groups across various clinical and pathological factors in a multivariate framework, stage 2 patients showed significant differences in lymph node count, tumor perforation, and perineural invasion with p-values of 0.040, 0.012, and 0.002, respectively. Stage 3 analysis highlighted vascular invasion as a significant differentiating factor (p = 0.017). Other variables such as age, gender, tumor size, and mucinous component presence did not demonstrate significant differences (Tables 2 and 3).
Discussion
Our study found that in CRC patients undergoing emergency surgery, survival rates were lower at both stages compared to those operated electively. When comparing Stage 2 patients who underwent emergency and elective surgery, we observed fewer dissected lymph nodes in the emergency surgery group, while tumor perforation and perineural invasion were more common. Additionally, in the logistic regression analysis of Stage 2 patients undergoing emergency surgery, the number of dissected lymph nodes, the presence of tumor perforation, and perineural invasion were identified as independent risk factors for mortality, while age was found as a risk factor in univariate analysis.
In the Stage 3 group, vascular invasion was more frequently observed in patients undergoing emergency surgery compared to those with elective surgery. The logistic regression analysis among Stage 3 patients who had emergency surgery revealed that the presence of vascular invasion in the tumor was an independent risk factor for mortality on its own.
Emergency surgery in CRC is associated with higher morbidity, mortality, and poorer prognosis compared to elective surgery. A case-control study conducted in 2003 found that undergoing surgery in an emergency setting was an independent risk factor for both morbidity and mortality [11]. Another study indicated that 2-year disease-free survival was greater in patients who underwent elective surgery [12]. The lower survival rates in emergency surgical interventions are directly related to surgery generally being performed for complications such as obstruction, perforation, or haemorrhage, the biological behavior of the tumor, and the overall condition of the patient [13].
The role of age in the management of CRC is a significant concern in general surgical practice. In univariate analyses, age has emerged as a significant determinant of mortality in CRC patients. In elderly patients, the increase in comorbidities and the decreased capacity of the body to respond to cancer and treatment can affect treatment options and outcomes. Notably, the risk of surgical interventions and the rates of postoperative complications may be higher in older patients [14]. Additionally, age may influence the biological characteristics of CRC; for instance, some studies suggest that tumors may be more aggressive in older patients [15]. This is a critical factor in shaping general surgeons’ approach to elderly CRC patients. Particularly, individualized treatment planning and comprehensive preoperative and postoperative assessments are necessary to achieve optimal outcomes in this population. The pronounced effect of age on mortality necessitates further development of age-specific treatment protocols and clinical decision-making processes.
It is well-known that lymph node dissection has prognostic value in CRC. The removal of a sufficient number of lymph nodes can improve patient survival rates and assist in accurately determining the stage of the disease. The consensus in the field is that at least 12 lymph nodes should be removed during CRC surgery [16]. In light of this information, the threshold has been exceeded for patients operated on both emergently and electively. However, the number is higher in patients who undergo elective surgery. The reasons for this outcome can be attributed to various factors. In emergency surgical operations, the surgeon’s priority may be the hemodynamic stabilization of the patient, which could influence the extent of lymphadenectomy, and the operations are generally more complicated with a higher risk of complications, potentially altering the surgeon’s priorities.
Some studies in the literature suggest that the greater number of lymph nodes removed during elective operations could be due to the surgeon having the opportunity to perform a more meticulous and careful dissection [17]. Additionally, the more planned nature of elective operations allows the surgeon to be better prepared for the surgery, enabling a more comprehensive lymphadenectomy. In our study, while there was a statistically significant difference in the number of lymph nodes removed among stage 2 patients, this difference was not observed in stage 3 patients. We attribute this to the surgeon’s ability to detect palpable lymph nodes during the operation and their diligence in performing a more extensive dissection.
The literature indicates that the need for emergency surgical intervention is often associated with more aggressive biological behavior of the tumor [3]. As a consequence of this aggressive biological behavior, one would expect a higher frequency of tumor perforation, perineural, and vascular invasion. In our study, these adverse prognostic factors were more frequently observed in patients who had undergone emergency surgical intervention.
Vascular invasion is known as a bad prognostic marker of lymph node metastasis in CRC [18]. This invasion is defined as the invasion of tumor cells into blood vessels. A study by Huh et al. has demonstrated that vascular invasion functions as an independent poor prognostic factor in patients with CRC [19]. Emergency surgical procedures are typically applied due to severe complications such as obstruction, perforation, or haemorrhage. This could lead to a more aggressive spread of the tumor to the surrounding vascular structures. As reflected in our study, this may result in increased rates of vascular invasion in patients undergoing emergency surgery. Thus, our findings are consistent with the existing literature. However, when examining the outcomes of the study, perforation and perineural invasion were found as independent risk factors in stage 2 patients, while vascular invasion was not. In contrast, in stage 3 patients, vascular invasion was identified as an independent risk factor, but not perforation and perineural invasion, opposite to stage 2 patients. This result could be due to the small number of patients. As there is no similar study in the literature comparing patients of the same stage who underwent emergency and elective surgery, we cannot comment on this finding. Comparative evaluations of these data with similar studies with larger patient populations to be conducted in the future would be valuable.
Limitation
Our study has some limitations. We didn’t explore disease-free survival or specify the reasons for emergency surgeries like obstruction, haemorrhage, or perforation. The stress response from emergency surgeries, affecting both patients and doctors, can influence the tumor environment and potentially increase metastasis risk. Therefore, elective surgeries are preferable for better outcomes in Stage 2 and 3 CRC patients, when possible.
Conclusion
Our study shows that emergency surgery for stage 2 and 3 colorectal cancer (CRC) patients is associated with significantly bad survival outcomes compared to elective surgery. In stage 2 patients, emergency interventions were linked to a lower number of lymph nodes removed and a higher incidence of tumor perforation and perineural invasion, which are independent risk factors for poor prognosis. In stage 3 patients, vascular invasion was the primary independent risk factor affecting survival. These findings highlight the need for elective surgery whenever possible to achieve better oncological outcomes and suggest that emergency surgeries present additional challenges that affect patient prognosis.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49.
2. Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62(4):220-41.
3. Barnett A, Cedar A, Siddiqui F, Herzig D, Fowlkes E, Thomas CR. Colorectal cancer emergencies. J Gastrointest Cancer. 2013;44(2):132-42.
4. Teixeira F, Akaishi EH, Ushinohama AZ, Dutra TC, Netto SD, Utiyama EM, et al. Can we respect the principles of oncologic resection in an emergency surgery to treat colon cancer? World J Emerg Surg. 2015;10:5.
5. Sjo OH, Larsen S, Lunde OC, Nesbakken A. Short term outcome after emergency and elective surgery for colon cancer. Colorectal Dis. 2009;11(7):733-9.
6. Biondo S, Kreisler E, Millan M, Martí-Ragué J, Fraccalvieri D, Golda T, et al. Long-term results of emergency surgery for colon cancer compared with elective surgery. Cir Esp. 2007;82(2):89-98.
7. McArdle CS, Hole DJ. Emergency presentation of colorectal cancer is associated with poor 5-year survival. Br J Surg. 2004;91(5):605-9.
8. Kim J, Mittal R, Konyalian V, King J, Stamos MJ, Kumar RR. Outcome analysis of patients undergoing colorectal resection for emergent and elective indications. Am Surg. 2007;73(10):991-3.
9. Chang GJ, Kaiser AM, Mills S, Rafferty JF, Buie WD. Practice parameters for the management of colon cancer. Dis Colon Rectum. 2012;55(8):831-43.
10. Compton CC, Fielding LP, Burgart LJ, Conley B, Cooper HS, Hamilton SR, et al. Prognostic factors in colorectal cancer. Arch Pathol Lab Med. 2000;124(7):979-94.
11. Smothers L, Hynan L, Fleming J, Turnage R, Simmang C, Anthony T. Emergency surgery for colon carcinoma. Dis Colon Rectum. 2003;46(1):24-30.
12. Mun JY, Kim JE, Yoo N, Cho HM, Kim H, An HJ, et al. Survival outcomes after elective or emergency surgery for synchronous stage IV colorectal cancer. Biomedicines. 2022;10(12):3114.
13. Biondo S, Gálvez A, Ramírez E, Frago R, Kreisler E. Emergency surgery for obstructing and perforated colon cancer: patterns of recurrence and prognostic factors. Tech Coloproctol. 2019;23(12):1141-61.
14. Sninsky JA, Shore BM, Lupu GV, Crockett SD. Risk factors for colorectal polyps and cancer. Gastrointest Endosc Clin N Am. 2022;32(2):195-213.
15. Baidoun F, Elshiwy K, Elkeraie Y, Merjaneh Z, Khoudari G, Sarmini MT, et al. Colorectal cancer epidemiology: recent trends and impact on outcomes. Curr Drug Targets. 2021;22(9):998-1009.
16. Vather R, Sammour T, Zargar-Shoshtari K, Metcalf P, Connolly A, Hill A. Lymph node examination as a predictor of long-term outcome in Dukes B colon cancer. Int J Colorectal Dis. 2009;24(3):283-8.
17. Sarli L, Bader G, Iusco D, Salvemini C, Mauro DD, Mazzeo A, et al. Number of lymph nodes examined and prognosis of TNM stage II colorectal cancer. Eur J Cancer. 2005;41(2):272-9.
18. Guan Z, Zhang XY, Li XT, Sun RJ, Lu QY, Wu AW, et al. Correlation and prognostic value of CT-detected extramural venous invasion and pathological lymph-vascular invasion in colon cancer. Abdom Radiol. 2022;47(4):1232-43.
19. Huh JW, Lee JH, Kim HR, Kim YJ. Prognostic significance of lymphovascular or perineural invasion in patients with locally advanced colorectal cancer. Am J Surg. 2013;206(5):758-63.
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The prognostic significance of ast/ alt (de ritis) ratio on survival in patients underwent pancreaticoduodenectomy
Saygin Altiner 1, Aydin Yavuz 1, Huseyin Gobut 1, Cagri Buyukkasap 1, Kursat Dikmen 1, Hasan Bostanci 1, Emre Gülçek 2, Ismail Emre Gokce 3, Mustafa Kerem1
1 Department of General Surgery, Faculty of Medical, Gazi University, 2 Department of General Surgery, Polatlı Duatepe State Hospital, 3 Department of General Surgeon, Private Practice, Ankara, Turkiye
DOI: 10.4328/ACAM.22497 Received: 2024-11-22 Accepted: 2024-12-24 Published Online: 2025-01-20 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):139-145
Corresponding Author: Saygın Altıner, Department of General Surgery, Faculty of Medical, Gazi University, Ankara, Turkiye. E-mail: sygn0607@gmail.com P: +90 312 202 57 02 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6118-9984
Other Authors ORCID ID: Yavuz Aydın, https://orcid.org/0000-0003-0091-7997 . Huseyin Gobut, https://orcid.org/0000-0003-0127-7039 . Cagri Buyukkasap, https://orcid.org/0000-0002-9141-4289 . Kursat Dikmen, https://orcid.org/0000-0002-9150-9499 . Hasan Bostanci, https://orcid.org/0000-0002-3160-1488 . Emre Gülçek, https://orcid.org/0000-0003-0189-5312 . Ismail Emre Gokce, https://orcid.org/0000-0002-6362-7543 . Mustafa Kerem, https://orcid.org/0000-0002-1797-6291
This study was approved by the Ethics Committee of Gazi University (Date: 2021-06-09, No: 593)
Aim: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. This study aimed to evaluate the AST/ALT (De Ritis) ratio as a prognostic biomarker in patients undergoing pancreaticoduodenectomy for PDAC.
Material and Methods: Clinical and pathological data of 222 PDAC patients who underwent pancreaticoduodenectomy between November 2010 and December 2018 were retrospectively analyzed. The prognostic value of the De Ritis ratio was assessed using ROC curve analysis. Kaplan–Meier and Cox regression models were used to evaluate their impact on disease-free survival (DFS) and overall survival (OS).
Results: 123 patients were analyzed (mean age: 63.48 ± 10.28 years; 43.1% female). The optimal AST/ALT threshold for survival prediction was 0.66. Patients with a higher De Ritis ratio had significantly shorter median DFS and OS (p < 0.025 and p < 0.048, respectively). Multivariate analysis identified advanced age (p < 0.001), absence of chemotherapy (p < 0.001), recurrence (p = 0.003), prolonged hospital stay (p = 0.016), positive surgical margins (p = 0.012), and high metastatic lymph node count (p = 0.006) as independent risk factors for lower OS. Similar factors also predicted shorter DFS.
Discussion: The De Ritis ratio may serve as a prognostic factor in operable PDAC patients. If validated, it could be a simple, cost-effective tool for guiding surgical and neoadjuvant therapy decisions.
Keywords: Pancreatic Cancer, Pancreaticoduodenectomy, Ast/Alt Ratio, Prognosis
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is the cause of the fourth-highest cancer-related deaths worldwide, and the number of newly diagnosed patients is gradually increasing [1]. Because the disease becomes symptomatic in the advanced stages and therefore delays the diagnosis, only 15–20% of patients have the opportunity to undergo surgery at the time of diagnosis. Most patients have local or distant metastases at the time of diagnosis. Accordingly, the 5-year survival rate is less than 8% [2, 3]. Surgical resection followed by systemic chemotherapy remains the gold standard treatment. Despite advanced surgical and medical treatment methods, overall survival (OS) is quite low due to rapid local recurrence and systemic spread [4, 5]. Detailed preoperative risk assessment may improve treatment outcomes by optimizing patient selection for radical surgery [6]. Therefore, there is a need for prognostic markers before surgery.
Despite recent advances in the identification of genetic, epigenetic, and molecular changes developed for use in preoperative risk assessment, the lack of standardization and expensive and/or time-consuming tests limit their routine use in daily clinical practice. Regularly used blood tests are relatively easy to evaluate without additional effort, making them attractive parameters for risk assessment [7].
The ratio of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) serum activities was first defined by Fernando De Ritis in 1957, and since then, the ratio between AST and ALT activities (AST/ALT) has been known as the De Ritis ratio [8]. Aminotransferases, such as AST and ALT, are expressed by non-cancerous and cancerous cells in different cellular subdivisions and are strongly involved in cellular metabolism and cancer cell turnover [9]. Alanine aminotransferase is involved in the “glucose-alanine cycle,” replacing alanine with pyruvate and strongly contributing to the replenishment of muscle-depleted glucose. Aspartate aminotransferase is required for aerobic glycolysis due to the displacement of nicotinamide adenine dinucleotide (NADH) within mitochondria. These transaminase reactions are especially important in muscle and liver cells but also in other cells with high metabolic activity [10]. Both AST and ALT are easily measurable blood-based biomarkers that are routinely analyzed during preoperative preparation. Many studies conducted with solid tumors have reported that the AST/ALT ratio is a biomarker associated with cancer prognosis. Tan et al. (2013) defined the De Ritis ratio as a suitable prognostic marker for cholangiocarcinoma, and it was associated with poor prognosis [11]. Wu et al. (2019) reported in a meta-analysis involving 9400 patients that a high pretreatment De Ritis ratio is a prognostic factor for overall survival, cancer-related survival, and disease-free survival in solid tumors, such as renal cell cancer, urinary tract urethral carcinoma, bladder cancer, and liver cancer [12]. In a retrospective study by Nishikawa et al. involving 109 patients, the De Ritis ratio in urinary tract urothelial carcinoma was found to be a predictive factor independent of tumour-node-metastasis (TNM) staging [13]. Katzke et al. (2020) conducted a prospective randomized cohort study and showed that a high ratio of De Ritis before treatment increases mortality in all lung, prostate, breast, and colon-rectal cancers [14]. In addition, De Ritis has been proven to be a biomarker with a prognostic role in non-malignant diseases, including cardiovascular-related deaths in diabetic patients [15].
Although there are studies in the literature examining the relationship between AST/ALT ratio, disease-free survival (DFS) time in advanced pancreatic cancer, and chemotherapy response [1, 16], no study examining its possible relationship with the survival time in operable PDAC was found. This study aimed to examine the AST/ALT ratio, which can be a potential biomarker in determining survival time in pancreatic adenocarcinoma, which is one of the most important causes of death and morbidity worldwide.
Material and Methods
After obtaining permission from the Gazi University Clinical Research Ethics Committee, the records of 222 patients who underwent pancreaticoduodenectomy and lymph node dissections for pancreatic adenocarcinoma at the Gazi University Faculty of Medicine General Surgery Clinic between November 2010 and December 2018 were analyzed retrospectively. Patients with metastatic disease at the time of diagnosis, patients who received pre-operative chemotherapy (CT) or radiotherapy (RT), patients who had chronic liver disease or inflammatory disease, and patients whose data could not be accessed were not included in the study.
In addition to demographic characteristics, such as age and gender, comorbidity, tumor diameter, tumor differentiation, TNM stage, T stage, N stage, albumin, carbohydrate antigen 19-9 (CA19-9) value, AST and ALT values, postoperative chemotherapy and/or radiotherapy, surgical margin (R0/R1) status, presence of postoperative complications, and clinicopathological features, such as disease-free and overall survival (OS) times, were recorded. The tumor stage was determined according to the eighth edition of the International Union for Cancer Control (UICC) [17]. Follow-up examinations were performed every 3 months until 2 years after surgery and every 6 months after 2 years. Contrast-enhanced computed tomography sections (CT), biochemistry tests, carcinoembryonic antigen (CEA), and CA 19-9 tumor markers were evaluated in the follow-up examinations. The time between the day of surgery and the date of death was considered the survival time. The serum values of albumin, AST, ALT, and CA-19-9 were measured with a biochemical analyzer (Siemens 5600, Germany) according to the manufacturer’s instructions. The cut-off value was also calculated according to the ROC curve. The patients were divided into two groups according to high and low rates, according to a De Ritis ratio of 0.66 as the cut-off value.
Statistical analysis
The research data were evaluated using the SPSS 22.0 statistical package program. Descriptive statistical methods (mean, standard deviation, median, frequency, percentage, minimum, and maximum) were used to evaluate the study data. The conformity of the variables to the normal distribution was examined by visual (histogram) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk). The DFS time and OS time of the patients were compared with the AST/ALT ratio. The Kaplan-Meier test was used for survival analysis. The Cox regression model was used for univariate and multivariate analyses. The statistical significance value was accepted as p < 0.05.
Ethical Approval
Ethical approval for this study was obtained from the Gazi University Clinical Research Ethics Committee (Date: 2021-06-09, No: 593).
Results
Detailed clinicopathological features of the 123 patients included in the study are shown in Table 1. The mean age of the patients was 63.48 ± 10.28 years; 83 (67.3%) were under the age of 70, and 53 (43.1%) were women. While 50.4% of the patients had concomitant chronic diseases, 23.6% had more than one additional disease. While complications were observed in 39.8% of the patients, the most common complications were intraabdominal abscess, hemorrhage, pancreatic fistula, biliary fistula, and gastric delayed emptying. Eighty-three point seven percent of the patients received adjuvant chemotherapy, and 47.2% received adjuvant radiotherapy. The median value of hospital stay was 17.3 ± 12.5. The mean tumor diameter was 3.1 ± 1.54 cm. While surgical margins were negative in 65% of the patients, the median value of the number of dissected metastatic lymph nodes was 3.2 ± 10.8. While recurrence was observed in 50 patients (40.7%), the median DFS time was 18.4 ± 17.3 months. It was confirmed at the last follow-up that 60.9% of the patients died. The median OS time was 22.2 ± 18.1 months. The mean values of AST, ALT, and AST/ALT ratio before surgery were 75.6 ± 64.9, 93.3 ± 87.4, and 1.0 ± 0.4 U/L, respectively.
The optimal threshold value for the AST/ALT ratio for survival prediction by ROC analysis was 0.66 (Table 2). The patients were divided into two groups according to the AST/ALT ratio: Group 1 < 0.66 (n = 36) and Group 2 ≥ 0.66 (n = 86). The clinicopathological variables of the patients according to the AST/ALT ratio are shown in Table 1. A high AST/ALT ratio was found to be statistically significantly associated with advanced age (p = 0.003), high albumin level (p = 0.007), and prolonged hospital stay (p = 0.010).
ROC analysis was performed to measure the effectiveness of AST/ALT value in predicting mortality. According to this analysis, the area under the curve (AUC) was found to be 0.633 [AUC-ROC (95% CI): 0.633(0.520–0.747), p = 0.019]. The sensitivity and specificity for the cut-off value of AST/ALT value ≥ 0.66 were 80.2% and 48.6 %, respectively (Graph 1).
The median DFS and OS times were found to be lower in the patient group with a higher De Ritis rate (p < 0.025 and p < 0.048, respectively) (Graphs 2 and 3). The median OS duration of patients with a high AST/ALT ratio was 6 months shorter than patients with a low AST/ALT ratio (19 vs. 25 months). Similarly, the median DFS duration of patients with a high AST/ALT ratio was 7 months shorter (13 vs. 20 months) than patients with a low AST/ALT ratio (Table 3).
According to the univariate analysis results, a high AST/ALT ratio (p = 0.048), advanced age (p < 0.001), presence of complications (p = 0.003), no chemotherapy (p < 0.001), low albumin value (p = 0.004), prolonged hospital stay (p = 0.019), a positive surgical margin (p = 0.003), and a high number of metastatic lymph nodes (p = 0.008) were associated with reduced overall survival times (Table 3). Similarly, a high AST/ALT ratio (p = 0.025), advanced age (p = 0.001), presence of complications (p = 0.001), failure to receive chemotherapy treatment (p < 0.001), low albumin value (p = 0.002), prolonged hospital stay duration (p = 0.018), positive surgical margin (p = 0.002), and high number of metastatic lymph nodes (p = 0.017) were associated with DFS (Table 3).
According to the results of multivariate analysis, advanced age (p < 0.001), not receiving chemotherapy (p < 0.001), presence of recurrence (p = 0.003), prolonged hospital stay (p = 0.016), positive surgical margin (p = 0.012), and high number of metastatic lymph nodes (p = 0.006) were found to be independent risk factors for low OS time (Table 3). Similarly, advanced age (p < 0.001), inability to receive chemotherapy (p = 0.000), prolonged hospital stay (p = 0.028), positive surgical margin (p = 0.031), and high number of metastatic lymph nodes (p = 0.016) were found to be independent prognostic factors for DFS (Table 3).
Discussion
In this study, the prognostic significance of the pretreatment AST/ALT (De Ritis) ratio was evaluated in patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma. In our study, the cut-off value for the De Ritis ratio was 0.66. According to this cut-off value, it was shown that the DFS and OS times of the patients in the group with a high pre-treatment De Ritis ratio were lower than those of the patients in the group with a low De Ritis ratio.
Data on the prognostic role of the AST/ALT ratio in pancreatic adenocarcinoma are limited. To date, only a few studies have examined the prognostic role of the AST/ALT ratio in pancreatic adenocarcinoma. Riedl et al. (2020) showed that a high serum De Ritis ratio before gemcitabine/nab-paclitaxel therapy in 202 patients with advanced PDAC was significantly associated with reduced disease-free survival, overall survival, and time to progression-free survival (PFS). In addition, they showed that a high De Ritis ratio was a strong predictor of a poor response to combination chemotherapy with gemcitabine/nab-paclitaxel. In conclusion, they suggested that the ratio of De Ritis could be an easy and new mediator factor that can be used to predict prognoses for patients with advanced PDAC [16]. Another study evaluating the results of 191 patients with locally advanced and metastatic pancreatic cancer showed that neutrophils, lymphocytes, platelets, CA19-9, total bilirubin, albumin, and alkaline phosphatase, together with the De Ritis ratio, were independent prognostic markers [1]. The results of our study were similar to the results of studies suggesting that the De Ritis ratio is a prognostic factor in patients with PDAC. Contrary to these studies, our study investigated the prognostic significance of the De Ritis ratio in non-advanced patients who underwent pancreaticoduodenectomy, unlike studies investigating the prognostic effect of the De Ritis ratio in advanced pancreatic cancer. The recommendation of the De Ritis ratio as a prognostic marker in operable PDAC increases the clinical importance of our study.
ALT is involved in the “glucose-alanine cycle,” replaces alanine with pyruvate, and strongly contributes to the replenishment of muscle-depleted glucose [10]. Aspartate aminotransferase plays an important role in aerobic glycolysis in mitochondria via the malate-aspartate shuttle and nicotinamide adenine dinucleotide hydrogen (NADH) produced in the cytoplasm [18]. Warburg suggested that aerobic glycolysis, in which AST plays an active role, increases in cancer cells compared to normal cells and that biochemical markers based on this theory can be used to predict prognosis [19]. In our study, the high De Ritis ratio due to increased AST levels in patients with PDAC can be explained by Warburg’s theory.
The mechanisms underlying the relationship between AST and ALT in cancer metabolism are not fully understood. Aspartate aminotransferase is widely expressed in different tissue types, while ALT is thought to be more specific to the liver [10]. Pathological processes associated with higher proliferation, tissue damage, and tumor cell turnover may lead to a stronger increase in AST compared to ALT. In vitro experiments have revealed that ALT levels are decreased in more invasive cells compared to less invasive cancer cells. It is thought that this decrease in serum ALT levels may be due to the result of improved metabolism and increased consumption of ALT in aggressive cancer cells [20]. The serum levels of AST and ALT can be affected by many factors, such as chronic hepatitis, coronary heart disease, impaired kidney function, and certain medications. Therefore, the use of numerical values alone to directly predict cancer prognosis has low sensitivity and specificity. Instead, we think that the combination of AST and ALT is more appropriate as a composite parameter. The highly invasive nature of PDAC can be explained by our results, the high De Ritis ratio, and the effect of ALT levels on cancer metabolism. Considering all these data, our results showed that the De Ritis ratio in patients with PDAC could be an attractive potential biomarker in clinical follow-up. In this study, age, inability of the patient to receive chemotherapy, relapse of the disease, prolonged hospital stay, positive surgical margin, and a high number of metastatic lymph nodes were found to be independent prognostic markers in operable pancreatic cancers. However, the small number of patients and the retrospective analysis of the data can be cited as limitations of our research. To reveal the usefulness of the De Ritis ratio as a biomarker, a longer-term study in a larger population should be conducted with a prospective design.
Limitation
This study has several important limitations. Due to its retrospective design, the collection of data retrospectively may introduce certain biases and missing information. Additionally, the limited sample size restricts the generalizability of the findings. Since our study was conducted at a single center, multicenter studies are needed to validate the results. Finally, comprehensive prospective studies that include other biochemical and genetic markers are necessary to better elucidate the prognostic role of the De Ritis ratio.
Conclusion
The De Ritis ratio can be used as a prognostic factor in patients with PDAC who are considered operable. To reveal the usefulness of the De Ritis ratio as a biomarker, longer-term studies in a larger population should be conducted with a prospective design. If confirmed by additional studies, the De Ritis ratio can be used as a simple and inexpensive marker for prognosis in the decision of surgery or neoadjuvant chemoradiotherapy.
Acknowledgment
We would like to thank the Gazi University Hospital for supplying the data.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Varol U, Kaya E, Oflazoglu U, Salman T, Yildiz Y, Taskaynatan H, et al. Prognostic role of De Ritis and basal neutrophil to lymphocyte ratio in patients with advanced stage pancreatic cancer. J BUON. 2020;25(2):1063-9.
2. Wu W, He X, Yang L, Wang Q, Bian X, Ye J, et al. Rising trends in pancreatic cancer incidence and mortality in 2000-2014. Clin Epidemiol. 2018;10:789-97.
3. Seoane-Mato D, Nuñez O, Fernández-de-Larrea N, Pérez-Gómez B, Pollán M, López-Abente G, et al. Long-term trends in pancreatic cancer mortality in Spain (1952–2012). BMC Cancer. 2018;18(1):625.
4. Hartwig W, Werner J, Jäger D, Debus J, Büchler MW. Improvement of surgical results for pancreatic cancer. Lancet Oncol. 2013;14(11):e476-85.
5. Xu J, Shi KQ, Chen BC, Huang ZP, Lu FY, Zhou MT. A nomogram based on preoperative inflammatory markers predicting the overall survival of pancreatic ductal adenocarcinoma. J Gastroenterol Hepatol. 2017;32(7):1394-402.
6. Stevens L, Pathak S, Nunes QM, Pandanaboyana S, Macutkiewicz C, Smart N, et al. Prognostic significance of pre-operative C-reactive protein and the neutrophil-lymphocyte ratio in resectable pancreatic cancer: A systematic review. HPB (Oxford). 2015;17(4):285-91.
7. Knittelfelder O, Delago D, Jakse G, Reinisch S, Partl R, Stranzl-Lawatsch H, et al. The AST/ALT (De Ritis) ratio predicts survival in patients with oral and oropharyngeal cancer. Diagnostics (Basel). 2020;10(11):1-11.
8. De Ritis F, Coltorti M, Giusti G. An enzymic test for the diagnosis of viral hepatitis; the transaminase serum activities. Clin Chim Acta. 1957;2(1):70-4.
9. Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11(5):325-37.
10. Botros M, Sikaris KA. The de Ritis ratio: the test of time. Clin Biochem Rev. 2013;34(3):117-30.
11. Tan X, Xiao K, Liu W, Chang S, Zhang T, Tang H. Prognostic factors of distal cholangiocarcinoma after curative surgery: A series of 84 cases. Hepatogastroenterology. 2013;60(128):1892-5.
12. Wu J, Chen L, Wang Y, Tan W, Huang Z. Prognostic value of aspartate transaminase to alanine transaminase (De Ritis) ratio in solid tumors: A pooled analysis of 9,400 patients. Onco Targets Ther. 2019;12:5201-13.
13. Nishikawa M, Miyake H, Fujisawa M. De Ritis (aspartate transaminase/alanine transaminase) ratio as a significant predictor of recurrence-free survival in patients with upper urinary tract urothelial carcinoma following nephroureterectomy. Urol Oncol. 2016;34(9):417.e9-.e15.
14. Katzke V, Johnson T, Sookthai D, Hüsing A, Kühn T, Kaaks R. Circulating liver enzymes and risks of chronic diseases and mortality in the prospective EPIC-Heidelberg case-cohort study. BMJ Open. 2020;10(3):e033532.
15. Zoppini G, Cacciatori V, Negri C, Stoico V, Lippi G, Targher G, et al. The aspartate aminotransferase-to-alanine aminotransferase ratio predicts all-cause and cardiovascular mortality in patients with type 2 diabetes. Medicine (Baltimore). 2016;95(43):e4821.
16. Riedl JM, Posch F, Prager G, Eisterer W, Oehler L, Sliwa T, et al. The AST/ALT (De Ritis) ratio predicts clinical outcome in patients with pancreatic cancer treated with first-line nab-paclitaxel and gemcitabine: Post hoc analysis of an Austrian multicenter, noninterventional study. Ther Adv Med Oncol. 2020;12:1758835919900872.
17. Cong L, Liu Q, Zhang R, Cui M, Zhang X, Gao X, et al. The tumor size classification of the 8th edition of the TNM staging system is superior to that of the 7th edition in predicting the survival outcome of pancreatic cancer patients after radical resection and adjuvant chemotherapy. Sci Rep. 2018;8(1):10383.
18. Sookoian S, Pirola CJ. Liver enzymes, metabolomics, and genome-wide association studies: From systems biology to the personalized medicine. World J Gastroenterol. 2015;21(3):711-25.
19. Warburg O. On respiratory impairment in cancer cells. Science. 1956;124(3215):269-70.
20. Conde VR, Oliveira PF, Nunes AR, Rocha CS, Ramalhosa E, Pereira JA, et al. The progression from a lower to a higher invasive stage of bladder cancer is associated with severe alterations in glucose and pyruvate metabolism. Exp Cell Res. 2015;335(1):91-8.
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Saygin Altiner, Aydin Yavuz, Huseyin Gobut, Cagri Buyukkasap, Kursat Dikmen, Hasan Bostanci, Emre Gülçek, Ismail Emre Gokce, Mustafa Kerem. The prognostic significance of ast/ alt (de ritis) ratio on survival in patients underwent pancreaticoduodenectomy. Ann Clin Anal Med 2025;16(2):139-145
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Probing success in congenital nasolacrimal duct obstruction: An evaluation of age-related outcomes and associated sociodemographic, clinical, maternal, and neonatal variables
Ali Hakim Reyhan, Funda Yüksekyayla, Müslüm Toptan, İrfan Uzun, Çağrı Mutaf, Büşra Türk
Department of Ophthalmology, Faculty of Medicine, Harran University, Şanlıurfa, Türkiye
DOI: 10.4328/ACAM.22521 Received: 2024-12-11 Accepted: 2025-01-23 Published Online: 2025-01-30 Printed: 2025-02-01 Ann Clin Anal Med 2025;16(2):146-151
Corresponding Author: Ali Hakim Reyhan, Department of Ophthalmology, Faculty of Medicine, Harran University, Şanlıurfa, Türkiye. E-mail: alihakimreyhan@gmail.com P: +90 505 097 80 70 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8402-0954
Other Authors ORCID ID: Funda Yüksekyayla, https://orcid.org/0009-0005-6991-4120 . Müslüm Toptan, https://orcid.org/0000-0002-9795-8228 . İrfan Uzun, https://orcid.org/0000-0001-6900-6337 . Çağrı Mutaf, https://orcid.org/0000-0001-6612-8160 . Büşra Türk, https://orcid.org/0009-0009-9391-9000
This study was approved by the Ethics Committee of Harran University (Date: 2024-09-23, No: HRÜ/24.14.06)
Aim: Congenital nasolacrimal duct obstruction (CNLDO), which affects 5-20% of newborns, arises from incomplete duct canalization, causing epiphora and mucous discharge. While most cases resolve spontaneously, some require surgical probing. This study examines age-related probing outcomes and their associations with sociodemographic, clinical, maternal, and neonatal factors.
Material and Methods: A retrospective analysis was applied to patients diagnosed with CNLDO who underwent probing. The patients were invited for follow-up examinations, and the parents were administered a questionnaire consisting of 25 items. Patients were divided into three age groups: ≤12, 12-24, and 24-48 months based on surgical timing. Data concernıng age at intervention, sociodemographic factors, maternal characteristics, and neonatal parameters were collected and analyzed to determine their impact on probing success rates.
Results: This study of 63 children (78 eyes) undergoing congenital probing revealed an 83.3% overall success rate, with greater success being achieved in younger age groups (<12 months: 91.7%) (p=0.392). Right-eye involvement was more common (42.9%), with bilateral involvement accounting for 23.8% of cases. No significant differences were found in demographic, socioeconomic, or perinatal variables across the age groups, except for the age of onset of epiphora. Most children were born at term, breastfed, and had normal birth weights. Maternal education was primarily at the elementary level, and family income shifted from low to moderate in the older groups.
Discussion: Early intervention is critical for optimizing probing success in CNLDO. While sociodemographic, maternal, and neonatal variables exhibited no significant impact, further large-scale, multicenter studies are needed to explore their potential subtle effects.
Keywords: Congenital Nasolacrimal Duct Obstruction, Probing, Age-Related Outcomes, Sociodemographic Factors, Neonatal Variables, Maternal Characteristics
Introduction
Congenital nasolacrimal duct obstruction (CNLDO) represents one of the most prevalent ocular conditions in infancy and early childhood, affecting approximately 5-20% of newborns [1]. The condition often leads to excessive tearing and mucous discharge, resulting in considerable discomfort for the child and an increased risk of secondary ocular infections capable of compromising children’s overall health [2]. CNLDO primarily results from the incomplete canalization of the nasolacrimal duct during embryogenesis, most frequently manifesting as an obstruction at the valve of Hasner at the distal end of the nasolacrimal duct [3].
The natural history of CNLDO demonstrates a high rate of spontaneous resolution, with studies indicating that 70-96% of cases resolve within the first year of life without surgical intervention [4]. Although the majority of cases resolve spontaneously within the first year of life, a significant proportion require interventional treatment, such as probing, to alleviate the obstruction and prevent complications [5,6]. Understanding the factors that affect the success of probing procedures is crucial for optimizing the management and outcomes of patients with CNLDO.
However, for cases that persist beyond the scope of conservative management, probing remains the primary surgical intervention, with success rates varying significantly across different age groups. Recent research suggests that probing success rates decline with age, from 90-100% in infants under 12 months to 56-78% in those older than 24 months [7-9]. When considering outcomes related to age, it is also essential to examine a range of social, clinical, maternal, and newborn factors that may affect the success of probing. For instance, socioeconomic status can affect access to healthcare services, potentially leading to delays in diagnosing and treating CNLDO. Older children may then be treated later, which may adversely impact their recovery. Additionally, factors related to the mother, such as age and health during pregnancy, and newborn-associated conditions may also affect the likelihood of CNLDO. Understanding the issues involved in probing success therefore not only guides clinical choices but also points to the necessity for more research to clarify these links and improve treatment methods.
This study addresses the gap in understanding the relationship between sociodemographic factors, clinical presentations, and treatment success rates in CNLDO across different age groups. It investigates the association between probing success rates and various potential risk factors, including sociodemographic characteristics, clinical presentations, maternal health, and neonatal outcomes, stratified by age. The objective of the research was to identify significant predictors of procedural success through an analysis of these variables across different age cohorts.
Material and Methods
The case records of all patients diagnosed with CNLDO who underwent initial probing procedures in our clinic between January 2022 and June 2024 were reviewed retrospectively. The patients were invited to attend follow-up examinations, and the parents were administered a questionnaire consisting of 25 items. They were categorized into three age groups based on the age at which the surgical probing procedure was performed: 12 months and under, 12-24 months, and 24-48 months.
Ethical approval was obtained from the Harran University ethical committee( Date: 2024-09-23, No: HRÜ/24.14.06).
The study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki, and informed consent was obtained from the parents.
The study population consisted of patients who presented with epiphora, underwent fluorescein dye disappearance testing, were diagnosed with CNLDO, and subsequently underwent a first probing procedure. Each child underwent a cycloplegic refraction examination, as well as anterior segment and fundus evaluations. Infants who underwent a second probing procedure, as well as those diagnosed with additional ocular diseases or systemic comorbidities, were excluded from the study.
The probing procedure was performed under general anesthesia in standard operating room conditions. The process began with the dilatation of both puncta using a punctal dilator, followed by an initial irrigation assessment of the nasolacrimal system. A metal probe was introduced perpendicular to the eyelid margin through the punctum, advanced into the ampulla, and then rotated horizontally toward the nasal wall of the lacrimal sac. Upon encountering firm resistance, the probe was rotated 90 degrees and advanced inferiorly through the nasolacrimal duct (figure 1).
The post-procedural treatment regimen included Netilmicin eye drops (four times daily) and Loteprednol eye drops (four times daily) for one week, together with a nasal decongestant spray (used three times daily) for three days. Success in probing was defined as the complete resolution of all clinical signs and symptoms of nasolacrimal duct obstruction observed during follow-up visits conducted three months post-surgery.
The absence of complaints related to tearing, the lack of observed epiphora during examination, and the absence of dye pooling in the fluorescein disappearance test were considered indicators of successful probing. For cases under the age of 2 where obstruction persisted despite the initial probing, a second probing procedure was repeated approximately 2 months later. For cases over the age of 2, silicone tube intubation was performed.
Following the receipt of informed consent from legal guardians, comprehensive data were collected through a systematic review of the patient’s medical records. These data included sociodemographic characteristics, including the child’s gender and age, maternal characteristics (age, education level, and occupation), family income status, and place of residence. Clinical presentation and management variables were documented, consisting of age at epiphora onset in infants, the initial diagnosis provider, ocular characteristics (laterality, severity, and type of epiphora), pre-surgical medical treatment status, lacrimal sac massage protocols employed, and the frequency of hospital visits before surgical intervention. Perinatal and maternal factors were also recorded, including birth characteristics (weight, gestational age, and mode of delivery), infant feeding patterns, history of admission to the neonatal intensive care unit, mode of conception, and birth order. Additional maternal health parameters were documented, including infections, medication use during pregnancy, and lifestyle factors such as alcohol consumption and smoking status during pregnancy. This comprehensive dataset was established to facilitate the analysis of factors potentially affecting congenital nasolacrimal duct probing success rates across different age groups.
Statistical analysis was performed on Statistical Package for the Social Sciences version 22.0 software (IBM Corp., Armonk, NY, USA). The distribution of data was evaluated using the Shapiro-Wilk W test, with mean value and standard deviation being calculated for each data set. The Chi-square test of independence was used to assess statistical relationships between groups.
Ethical Approval
Ethical approval for the study was obtained from the Ethics Committee of Harran University (Date: 2024-09-23, No: HRÜ/24.14.06).
Results
This study involved 78 eyes of 63 children who underwent a congenital probing operation. The gender distribution was nearly equal, with 32 girls (50.79%) and 31 (49.21%) boys. Mean ages were 16.33 ± 7.28 months in the patients and 29 ± 4.17 years in the mothers.
Involvement was predominantly in the right eyes (42.9%, n=27), followed by left eye involvement (33.3%, n=21), with bilateral involvement being observed in 23.8% (n=15) of cases (p=0.385). The median follow-up period for the cases was nine months (5-18 months). The first probing operation achieved an overall success rate of 86.9% across all three age groups, and rates of 90.5% in the <12-month age group, 83.3% in the 12–24-month age group, and 75% in the 24–48-month age group (p=0.392).
In the <12-month age group, 2 patients who did not achieve success with the initial probing procedure underwent a second probing procedure approximately three months later. Following the second probing procedure, these 2 patients experienced complete resolution of their ocular symptoms. In the 12-24-month age group, 3 patients who did not achieve success with the initial probing procedure underwent a second probing procedure approximately three months later. Among these patients, 2 achieved successful outcomes with symptom resolution. However, 1 patient whose symptoms persisted underwent silicone tube intubation three months subsequently. In the 24-48-month age group, 6 patients whose symptoms did not resolve underwent silicone tube intubation. During and after the probing operation for congenital nasolacrimal duct obstruction, no medical complications occurred.
This study analyzed the demographic and socioeconomic characteristics of children and their mothers across three age groups (<12 months, 12-24 months, and 24-48 months), with no significant differences being observed in the variables examined. The mean ages of the children were 10.83, 15.67, and 27 months, respectively (p < 0.05). Gender distribution was balanced, and maternal ages averaged 29.83, 27.67, and 30.25 years, respectively (p=0.88). Mothers were most commonly educated to elementary school level, and no university-level education was reported (p=0.118). Most mothers were housewives (p=0.287), and family income increased from predominantly low in the <12-month group to moderate in the older groups (p=0.378). Urban and rural residency were relatively balanced across all three groups(p=0.455). These findings are presented in Table 1.
The study analyzed clinical, diagnostic, and treatment characteristics of congenital nasolacrimal duct probing across three age groups (< 12 months, 12-24 months, and 24-48 months). The onset age of epiphora showed significant variation (p < 0.05), with most cases in younger infants occurring within the first three months, while older infants had a higher proportion of onset after five months. Other factors, such as primary diagnosis provider, laterality, severity, and pre-surgical treatment, showed no significant differences across age groups (p > 0.05). The frequency of hospital visits and lacrimal sac massage protocols also remained consistent among the groups. The clinical, diagnostic, and treatment characteristics of congenital nasolacrimal duct probing across different age groups are presented in Table 2.
This study evaluated perinatal and maternal characteristics of children across three age groups: <12 months, 12-24 months, and 24-48 months. Statistical analysis revealed no significant differences in any of the variables examined. Birth weight was predominantly normal in all three groups (85.7%, 94.4%, and 91.7%, respectively) (p=0.756). The majority of children were born at term (95.2%, 100%, and 91.7%, respectively) (p=0.771) and were breastfed (85.7%, 88.8%, and 83.3%) (p=0.907). Hospitalization in the neonatal intensive care unit was uncommon (14.3%, 11.1%, and 16.7%, respectively) (p=0.970), and all pregnancies occurred naturally. Pregnancy sequences varied, with first pregnancies accounting for 28.6%, 22.2%, and 41.7% of cases, respectively (p=0.673). Maternal infections were reported in the majority of cases (81.0%, 83.3%, and 91.7%) (p=0.602), while medication use during pregnancy was less frequent (23.8%, 44.4%, and 25.0%) (p=0.297). No alcohol consumption was reported, and smoking was uncommon (14.3%, 11.1%, and 16.7%) (p=0.907). Delivery mechanisms were predominantly natural (66.7%, 66.7%, and 75.0%, respectively) (p=0.987). These findings are presented in Table 3.
Discussion
The study findings show that age at epiphora onset is the primary determinant of successful nasolacrimal duct probing in CNLDO, with early-onset cases showing higher complete recovery rates. Notably, neither sociodemographic factors nor perinatal-maternal variables significantly influenced probing success rates. These findings emphasize that early diagnosis and intervention timing are crucial determinants of treatment success in clinical practice.
Valcheva et al. reported an overall success rate for initial probing of 90%. In terms of age groups, the success rate was 89% for patients aged 2–12 months and 94% for those aged 13–41 months. While these results are similar to the success rate of 90.5% observed in the present study for the < 12-month group, Valcheva et al. achieved a comparable success rate (94%) even in older age groups. In contrast, our findings revealed a decline in success rates to 83.3% in the 12–24 month group and 75% in the 24–48 month group. The results of Valcheva et al’s study suggest that probing can still achieve a high success rate in older age groups [10]. This discrepancy between the two studies may be attributed to methodological differences in case selection, the demographic and clinical characteristics of the patient population, variations in surgical techniques, and differences in follow-up durations.
Świerczyńska et al.’s study demonstrated that the success rate of initial probing procedures for nasolacrimal duct obstruction significantly declines with increasing age [9]. Their research, which included patients aged two weeks to 41 months, reported an overall success rate of 87.2%, with notably higher success rates in infants under six months and a marked increase in failure risk for children over two years. Similarly, the current study corroborates these findings, showing an age-dependent decrease in success rates: 91.7% in the <12-month group, 81.0% in the 12–24-month group, and 78.8% in the 24–48-month group. These results collectively reinforce the widely accepted notion that advancing age adversely impacts the effectiveness of probing as the initial surgical intervention for nasolacrimal duct obstruction.
The existing literature acknowledges probing as a standard treatment option for CNLDO, although there is no consensus regarding the optimal timing [11-17]. Świerczyńska et al. reported the lowest failure rates (8.6%) in patients aged 3–6 months, with success rates declining in older age groups, consistent with the present study [9]. Sathiamoorthi et al. identified 9–15 months as the optimal probing period, noting an 85% likelihood of spontaneous duct opening within the first two months of life, which declines thereafter and plateaus beyond nine months [18]. The research also confirmed that performing probing after 15 months of age is associated with a markedly reduced success rate.
Some researchers advocate delaying nasolacrimal duct probing until later stages [19-21]. A prospective cohort study conducted by the Pediatric Eye Disease Investigator Group (PEDIG) determined no correlation between age at probing and the success rate of the procedure in children up to 36 months of age [14]. Some ophthalmologists contend that probing efficacy is independent of patient age, attributing surgical outcomes primarily to the nature of the underlying obstruction rather than the timing of intervention [19-22]. Retrospective studies, however, indicate that higher failure rates in older age groups may result from self-selection processes. Medghalchi et al. reported a 91% success rate for probing performed after six months in cases of simple obstruction at the valve of Hasner, compared to only 52% in patients with more complex obstructions [23]. Additionally, Kashkouli et al. observed significantly lower success rates in late and very late probing for complex obstructions (33.3%) compared to membranous obstructions (90.2%) [22].
Bilateral nasolacrimal duct obstruction, reported in 9–47.5% of cases, is often associated with more complex underlying causes [10,13,14,19-24]. This condition can pose greater technical challenges during procedures performed under local anesthesia, potentially leading to less favorable outcomes. This observation aligns well with the findings of both the present study and those of other researchers [13-21]. Additionally, Dietze et al. emphasized that factors such as trisomy 21, allergic rhinitis or seasonal allergies, a history of upper respiratory tract infections within the previous month, and obstructive sleep apnea may increase the likelihood of probing failure [25].
The findings of this study confirm that the most influential factor determining probing success in CNLDO is the age at which the procedure is performed, which is closely linked to the onset of epiphora, with earlier procedures yielding higher success rates. Notably, no significant correlations were found between procedural outcomes and various factors, including sociodemographic characteristics, maternal health parameters, and neonatal variables. While these findings suggest these factors may not critically influence therapeutic success, the limited scope of existing research in this area indicates a need for larger-scale, multicenter studies to better understand potential subtle influences on outcomes and develop more personalized treatment approaches.
Limitation
This study has several limitations that may affect the interpretation of its findings. The small sample size and single-center design limit the generalizability of the results to broader populations and sociocultural contexts. The retrospective nature of the study introduces a risk of selection bias due to reliance on previously recorded data. Additionally, variability in surgical techniques and the differing levels of surgeon experience may have influenced the outcomes.
Conclusion
This study demonstrates that early probing of the nasolacrimal duct in cases of CNLDO leads to higher success rates, while delayed intervention is associated with reduced efficacy. The study findings indicate that sociodemographic, maternal, and neonatal characteristics do not significantly affect the success of probing, whereas age at the onset of epiphora emerged as a critical predictive factor. These results underscore the importance of early diagnosis and prompt intervention to optimize patient outcomes and shape future management strategies in cases of CNLDO.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Lin AE, Chang YC, Lin MY, Tam KW, Shen YD. Comparison of treatment for congenital nasolacrimal duct obstruction: a systematic review and meta-analysis. Can J Ophthalmol. 2016;51(1):34-40.
2. Schellini SA, Marques-Fernandez V, Meneghim RLFS, Galindo-Ferreiro A. Current management strategies of congenital nasolacrimal duct obstructions. Expert Rev Ophthalmol. 2021;16(5):377-85.
3. Zhang C, Yu G, Cui Y, Wu Q, Wei W. Anatomical characterization of the nasolacrimal canal based on computed tomography in children with complex congenital nasolacrimal duct obstruction. j pediatr ophthalmol strabismus. 2017;54(4):238-43.
4. Vagge A, Ferro Desideri L, Nucci P. Congenital Nasolacrimal Duct Obstruction (CNLDO): A Review. Diseases. 2018;6(4):96.
5. Kashkouli MB, Karimi N, Khademi B. Surgical management of congenital nasolacrimal duct obstruction; one procedure for all versus all procedures for one. Curr Opin Ophthalmol. 2019;30(5):364-71.
6. Repka MX. Timing of simple probing for congenital nasolacrimal duct obstruction: Not so simple. JAMA Ophthalmol. 2018;136(11):1286-7.
7. Beato J, Mota Á, Gonçalves N, Santos-Silva R, Magalhães A, Breda J, et al. Factors predictive of success in probing for congenital nasolacrimal duct obstruction. J Pediatr Ophthalmol Strabismus. 2017;54(2):123-7.
8. Takahashi Y, Kakizaki H, Chan WO, Selva D. Management of congenital nasolacrimal duct obstruction. Acta Ophthalmol. 2010;88(5):506-13.
9. Świerczyńska M, Tobiczyk E, Rodak P, Barchanowska D, Filipek E. Success rates of probing for congenital nasolacrimal duct obstruction. Eur J Ophthalmol. 2020;30(6):1325-30.
10. Valcheva KP, Murgova SV, Krivoshiiska EK. Success Rate of Probing for Congenital Nasolacrimal Duct Obstruction in Children. Folia Med (Plovdiv). 2019;61(1):97-103.
11. Xiang Q, Gao X, Chen X, Qi J, Fang J. Nasolacrimal Duct Probing for Young Children With Congenital Nasolacrimal Duct Obstructions in China: A 10-Year Systematic Review. J Pediatr Ophthalmol Strabismus. 2019;56(6):365-72.
12. Young JD, MacEwen CJ. Managing congenital lacrimal obstruction in general practice. BMJ. 1997;315(7103):293-6.
13. Repka MX, Chandler DL, Beck RW, Crouch ER, Donahue S, Holmes JM, et al. Primary treatment of nasolacrimal duct obstruction with probing in children younger than 4 years. Ophthalmology. 2008;115(3):577-84.
14. Pediatric Eye Disease Investigator Group. Resolution of congenital nasolacrimal duct obstruction with nonsurgical management. Arch Ophthalmol. 2012;130(6):730-4.
15. Moscato EE, Kelly JP, Weiss A. Developmental anatomy of the nasolacrimal duct: implications for congenital obstruction. Ophthalmology. 2010;117(12):2430-4.
16. Bach A, Vanner EA, Warman R. Efficacy of Office-Based Nasolacrimal Duct Probing. J Pediatr Ophthalmol Strabismus. 2019;56(1):50-4.
17. Paul TO, Shepherd R. Congenital nasolacrimal duct obstruction: natural history and the timing of optimal intervention. J Pediatr Ophthalmol Strabismus. 1994;31(6):362-7.
18. Sathiamoorthi S, Frank RD, Mohney BG. Spontaneous resolution and timing of intervention in congenital nasolacrimal duct obstruction. JAMA Ophthalmol. 2018;136(11):1281-6.
19. Arora S, Koushan K, Harvey JT. Success rates of primary probing for congenital nasolacrimal obstruction in children. J AAPOS. 2012;16(2):173-6.
20. Eshragi B, Fard MA, Masomian B, Akbari M. Probing for congenital nasolacrimal duct obstruction in older children. Middle East Afr J Ophthalmol. 2013;20(4):349-52.
21. Miller AM, Chandler DL, Repka MX, Hoover DL, Lee KA, Melia M. Office probing for treatment of nasolacrimal duct obstruction in infants. J AAPOS. 2014;18(1):26-30.
22. Kashkouli MB, Beigi B, Parvaresh MM, Kassaee A, Tabatabaee Z. Late and very late initial probing for congenital nasolacrimal duct obstruction: what is the cause of failure? Br J Ophthalmol. 2003;87(9):1151-3.
23. Medghalchi A, Mohammadi MJ, Soltani Moghadam R, Dalili H. Results of nasolacrimal duct probing in children between 9-48 months. Acta Med Iran. 2014;52(7):545-51.
24. Perveen S, Sufi AR, Rashid S, Khan A. Success rate of probing for congenital nasolacrimal duct obstruction at various ages. J Ophthalmic Vis Res. 2014;9(1):60-9.
25. Dietze J, Suh D. Risk Factors for Poor Surgical Outcome of Pediatric Nasolacrimal Duct Obstruction. J Pediatr Ophthalmol Strabismus. 2019;56(4):261-64.
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Ali Hakim Reyhan, Funda Yüksekyayla, Müslüm Toptan, İrfan Uzun, Çağrı Mutaf, Büşra Türk. Probing success in congenital nasolacrimal duct obstruction: An evaluation of age-related outcomes and associated sociodemographic, clinical, maternal, and neonatal variables. Ann Clin Anal Med 2025;16(2):146-151
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