Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD).
Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD).
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DOI：
10.1371/journal.pone.0153358
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Häberle J
中科院分区：
文献类型：
--
作者：
Laemmle A;Gallagher RC;Keogh A;Stricker T;Gautschi M;Nuoffer JM;Baumgartner MR;Häberle J
急性肝衰竭（ALF）已报道在鸟氨酸转氨基甲酰基酶缺乏症（OTCD）和其他尿素循环障碍（UCD）。ALF在OTCD中的发生率不明确，发病机制也不清楚。为了评估ALF在OTCD中的患病率，我们分析了瑞士患者队列。对1991年12月至2015年3月诊断的37例患者（27例女性和10例男性）的实验室数据进行了回顾，以寻找ALF的证据。同时，我们用氯化铵处理的单个患者的人原代肝细胞进行细胞培养研究，以研究氨对肝蛋白合成的抑制潜力。超过50%的瑞士OTCD患者在病程中至少有一次ALF累及肝脏。氨水平升高通常与（实验室）凝血病相关，反映在国际标准化比率（INR）升高和低水平的肝凝血因子（对维生素k没有反应）上。相反，在一些病例中，肝转氨酶保持正常，尽管病理INR值评估了大量高氨血症和肝脏受累。在我们的体外研究中，用氯化铵处理人原代肝细胞48小时导致白蛋白合成和分泌减少约40%。总之，ALF是OTCD的常见并发症，可能并不总是导致严重的症状，因此可能未得到充分诊断。细胞培养实验提示氨诱导的肝蛋白合成抑制，从而为高氨相关的ALF提供了可能的病理生理解释。
Acute liver failure (ALF) has been reported in ornithine transcarbamylase deficiency (OTCD) and other urea cycle disorders (UCD). The frequency of ALF in OTCD is not well-defined and the pathogenesis is not known. To evaluate the prevalence of ALF in OTCD, we analyzed the Swiss patient cohort. Laboratory data from 37 individuals, 27 females and 10 males, diagnosed between 12/1991 and 03/2015, were reviewed for evidence of ALF. In parallel, we performed cell culture studies using human primary hepatocytes from a single patient treated with ammonium chloride in order to investigate the inhibitory potential of ammonia on hepatic protein synthesis. More than 50% of Swiss patients with OTCD had liver involvement with ALF at least once in the course of disease. Elevated levels of ammonia often correlated with (laboratory) coagulopathy as reflected by increased values for international normalized ratio (INR) and low levels of hepatic coagulation factors which did not respond to vitamin K. In contrast, liver transaminases remained normal in several cases despite massive hyperammonemia and liver involvement as assessed by pathological INR values. In our in vitro studies, treatment of human primary hepatocytes with ammonium chloride for 48 hours resulted in a reduction of albumin synthesis and secretion by approximately 40%. In conclusion, ALF is a common complication of OTCD, which may not always lead to severe symptoms and may therefore be underdiagnosed. Cell culture experiments suggest an ammonia-induced inhibition of hepatic protein synthesis, thus providing a possible pathophysiological explanation for hyperammonemia-associated ALF.