Abstract
BackgroundAcute 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.AimTo 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.ResultsMore 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%.ConclusionIn 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.
Highlights
Patients with inherited defects in the urea cycle (Fig 1) are at risk of recurrent acute metabolic crises with life-threatening hyperammonemia, associated with acute or chronic brain damage leading to severe neurological long-term disabilities, impairing quality of life and leading to significant mortality [1,2,3,4]
Liver transaminases remained normal in several cases despite massive hyperammonemia and liver involvement as assessed by pathological international normalized ratio (INR) values
Acute liver failure (ALF) is a common complication of ornithine transcarbamylase deficiency (OTCD), which may not always lead to severe symptoms and may be underdiagnosed
Summary
Patients with inherited defects in the urea cycle (Fig 1) are at risk of recurrent acute metabolic crises with life-threatening hyperammonemia, associated with acute or chronic brain damage leading to severe neurological long-term disabilities, impairing quality of life and leading to significant mortality [1,2,3,4]. In addition to neurological complications, patients with acute hyperammonemia may suffer from recurrent episodes of acute liver failure (recurrent ALF, RALF) with associated coagulopathy [5,6,7,8,9]. ALF may require urgent liver transplantation, which is essentially curative of OTCD, there are several limitations including liver organ shortage, short and longterm morbidity and mortality including lifelong immunosuppressive therapy with major associated complications. The frequency of ALF in OTCD is not welldefined and the pathogenesis is not known.
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