Publication: Hepatik Ensefalopatili Hastalarda Serum Zonulin Düzeylerinin Değerlendirilmesi
Abstract
Giriş ve Amaç: Hepatik ensefalopati etyopatogenezinde bakteriyel translokasyon, intestinal permeabilitedeki değişimler ve porto-sistemik şantların oluşumu önemli bir yer tutmaktadır. İntestinal permeabilitedeki artış hepatik ensefalopati patogenezinden sorumlu amonyak, bakteri yıkım ürünleri ve diğer toksinlerin sistemik dolaşıma geçip santral sinir sistemine ulaşmasına, klinik semptomların ortaya çıkmasına neden olmaktadır. İntestinal permeabilite paraselüler ve intraselüler olmak üzere iki farklı yolla gerçekleşir. Güncel çalışmalar sonucu keşfedilen zonulin molekülü paraselüler yolda önemli bir yer tutmaktadır. Zonulin paraselüler yolda intestinal epitel hücreleri arasında bulunan tight junction komplekslerinin geri dönüşümlü olarak ayrışmasına yol açarak intestinal permeabiliteyi artırır. Bu bilgiler baz alınarak çalışmamızda karaciğer sirozlu hastalarda hepatik ensefalopati tanı ve takibinde değişen bağırsak geçirgenliğinin bir biyobelirteci olan zonulin molekülünün serum düzeylerinin değişimi, bunun hepatik ensefalopati ile ilgili diğer faktörlerle ilişkisinin değerlendirilmesi amaçlanmıştır. Materyal ve Metot: Çalışmaya Ondokuz Mayıs Üniversitesi Tıp Fakültesi Gastroenteroloji Bilim Dalı'na Ekim 2024 - Mart 2025 tarihleri arasında başvuran hastalar arasından dahil edilme kriterlerini karşılayan 50 karaciğer sirozlu hepatik ensefalopati tanısı alan, 47 siroz tanısı olmayan, toplamda 97 kişi dahil edildi. Çalışma popülasyonunun tamamında serum zonulin düzeyi çalışıldı. Serum zonulin düzeyleri Human zonulin ELISA kit ile double- antibody sandwich method enzim immunosorbent assay yöntemi ile çalışıldı. Veriler R programlama dilinin 4.4.1 versiyonu ile analiz edildi. Bulgular: Hepatik ensefalopati grubunda ortanca serum zonulin düzeyi 10,32 (0,96 - 63) ng/ml kontrol grubunda 7,86 (2,5 – 15,1) ng/ml olarak bulundu. Hepatik ensefalopati grubunda kontrol grubuna göre istatistiksel açıdan sınırda daha yüksek değerler izlendi (p=0,050). Siroz komplikasyonları açısından bakıldığında özofagus varis kanaması öyküsü olanlarda olmayanlara göre istatistiksel açıdan anlamlı olarak daha yüksek değerler bulundu (p=0,027). Porto-sistemik şant gelişmiş hepatik ensefalopatili hastalarda istatistiksel açıdan anlamlı daha yüksek değerler saptandı (p=0,012). Hepatik ensefalopati tanısında kullanılan serum amonyak düzeyleri ile zonulin düzeyi arasında istatistiksel olarak anlamlı pozitif yönlü orta şiddette bir ilişki bulundu (r=0,486; p<0,001). Tartışma ve Sonuç: Hepatik ensefalopati karaciğer sirozunun dekompansasyon bulgularındandır. Aşikâr döneme gelmemiş hepatik ensefalopati semptom ve bulguları silik olan hastalarda tanı ve takip için biyobelirteçlere ihtiyaç vardır. Artan bağırsak geçirgenliğinin hepatik ensefalopati patogenezindeki etkileri göz önüne alındığında serum zonulin düzeylerinin değerlendirilmesi önemli bir biyobelirteç olabilir. Çalışmamızda serum zonulin değerinin hepatik ensefalopati tanısında klinik açıdan anlamlı olabileceğini düşündüren değerler saptandı. Sonuçlarda porto-sistemik şant gelişen ve özofagus varis kanamaları olan hastalarda serum zonulin düzeylerinin istatistiksel olarak anlamlı derecede yüksek olduğu saptanmıştır. Çalışmamız sadece hepatik ensefalopatili hastaların değerlendirilmeye alındığı ve serum zonulin düzeyi ilişkisinin değerlendirilidiği literatürdeki ilk çalışma olması nedeniyle önemlidir.
Introduction and Aim: Bacterial translocation, changes in intestinal permeability and formation of porto-systemic shunts play an important role in the etiopathogenesis of hepatic encephalopathy. Increased intestinal permeability causes ammonia, bacterial breakdown products and other toxins responsible for hepatic encephalopathy pathogenesis to pass into the systemic circulation and reach the central nervous system, resulting in clinical symptoms. Intestinal permeability occurs in two different ways: paracellular and intracellular. The zonulin molecule discovered as a result of recent studies has an important place in the paracellular pathway. Zonulin increases intestinal permeability by causing reversible dissociation of tight junction complexes found between intestinal epithelial cells in the paracellular pathway. Based on this information, our study aimed to evaluate the changes in serum levels of the zonulin molecule, a biomarker of altered intestinal permeability, in the diagnosis and follow-up of hepatic encephalopathy in patients with liver cirrhosis and its relationship with other factors related to hepatic encephalopathy. Material and Method: A total of 97 patients, 50 of whom were diagnosed with hepatic encephalopathy with liver cirrhosis and 47 of whom were not diagnosed with cirrhosis, were included in the study among the patients who applied to the Department of Gastroenterology, Faculty of Medicine, Ondokuz Mayıs University between November 2024 and February 2025 and met the inclusion criteria. Serum zonulin levels were studied in the entire study population. Serum zonulin levels were studied using the Human zonulin ELISA kit and the double-antibody sandwich method enzyme immunosorbent assay method. Data were analyzed with the R programming language version 4.4.1. Results: Median serum zonulin level was found as 10.32 (0.96 - 63) ng/ml in the hepatic encephalopathy group and 7.86 (2.5 - 15.1) ng/ml in the control group. Borderline statistically higher values were observed in the hepatic encephalopathy group compared to the control group (p=0.050). In terms of cirrhosis complications, statistically significantly higher values were found in patients with a history of esophageal variceal bleeding compared to those without (p=0.027). Statistically significantly higher values were found in patients with hepatic encephalopathy who developed porto-systemic shunt (p=0.012). A statistically significant positive moderate correlation was found between serum ammonia levels used in the diagnosis of hepatic encephalopathy and zonulin levels (r=0.486; p<0.001). Discussion and Conclusion: Hepatic encephalopathy is one of the decompensation findings of liver cirrhosis. In patients with vague symptoms and findings of hepatic encephalopathy that have not reached the overt stage, biomarkers are needed for diagnosis and follow-up. Considering the effects of increased intestinal permeability on the pathogenesis of hepatic encephalopathy, evaluation of serum zonulin levels may be an important biomarker. In our study, values suggesting that serum zonulin values may be clinically significant in the diagnosis of hepatic encephalopathy were detected. The results showed that serum zonulin levels were statistically significantly high in patients with porto-systemic shunts and esophageal variceal bleeding. Our study is important because it is the first study in the literature in which only patients with hepatic encephalopathy were evaluated and the relationship between serum zonulin levels was evaluated.
Introduction and Aim: Bacterial translocation, changes in intestinal permeability and formation of porto-systemic shunts play an important role in the etiopathogenesis of hepatic encephalopathy. Increased intestinal permeability causes ammonia, bacterial breakdown products and other toxins responsible for hepatic encephalopathy pathogenesis to pass into the systemic circulation and reach the central nervous system, resulting in clinical symptoms. Intestinal permeability occurs in two different ways: paracellular and intracellular. The zonulin molecule discovered as a result of recent studies has an important place in the paracellular pathway. Zonulin increases intestinal permeability by causing reversible dissociation of tight junction complexes found between intestinal epithelial cells in the paracellular pathway. Based on this information, our study aimed to evaluate the changes in serum levels of the zonulin molecule, a biomarker of altered intestinal permeability, in the diagnosis and follow-up of hepatic encephalopathy in patients with liver cirrhosis and its relationship with other factors related to hepatic encephalopathy. Material and Method: A total of 97 patients, 50 of whom were diagnosed with hepatic encephalopathy with liver cirrhosis and 47 of whom were not diagnosed with cirrhosis, were included in the study among the patients who applied to the Department of Gastroenterology, Faculty of Medicine, Ondokuz Mayıs University between November 2024 and February 2025 and met the inclusion criteria. Serum zonulin levels were studied in the entire study population. Serum zonulin levels were studied using the Human zonulin ELISA kit and the double-antibody sandwich method enzyme immunosorbent assay method. Data were analyzed with the R programming language version 4.4.1. Results: Median serum zonulin level was found as 10.32 (0.96 - 63) ng/ml in the hepatic encephalopathy group and 7.86 (2.5 - 15.1) ng/ml in the control group. Borderline statistically higher values were observed in the hepatic encephalopathy group compared to the control group (p=0.050). In terms of cirrhosis complications, statistically significantly higher values were found in patients with a history of esophageal variceal bleeding compared to those without (p=0.027). Statistically significantly higher values were found in patients with hepatic encephalopathy who developed porto-systemic shunt (p=0.012). A statistically significant positive moderate correlation was found between serum ammonia levels used in the diagnosis of hepatic encephalopathy and zonulin levels (r=0.486; p<0.001). Discussion and Conclusion: Hepatic encephalopathy is one of the decompensation findings of liver cirrhosis. In patients with vague symptoms and findings of hepatic encephalopathy that have not reached the overt stage, biomarkers are needed for diagnosis and follow-up. Considering the effects of increased intestinal permeability on the pathogenesis of hepatic encephalopathy, evaluation of serum zonulin levels may be an important biomarker. In our study, values suggesting that serum zonulin values may be clinically significant in the diagnosis of hepatic encephalopathy were detected. The results showed that serum zonulin levels were statistically significantly high in patients with porto-systemic shunts and esophageal variceal bleeding. Our study is important because it is the first study in the literature in which only patients with hepatic encephalopathy were evaluated and the relationship between serum zonulin levels was evaluated.
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