Liver disease with unknown etiology – have you ruled out alpha-1 antitrypsin deficiency?

Abstract

Although a less well-known consequence of alpha-1 antitrypsin deficiency (AATD) liver disease is the second leading cause of death among patients with the condition. The alpha-1 antitrypsin (AAT) protein is produced by hepatocytes within the liver, which retain pathological variants of AAT instead of secreting the proteinase inhibitor into the systemic circulation. This intracellular retention is caused by inefficient folding and polymerization of mutant AAT and the accumulation of these AAT aggregates leads to diverse manifestations of liver disease, which can present differently in both children and adults. The progression from hepatocyte apoptosis to liver inflammation, fibrosis and cirrhosis, and liver failure is still not fully understood, but in older patients, liver disease can surpass lung disease as the principal cause of death. Liver function tests (LFTs) can measure plasma levels of liver enzymes to assess liver function but require careful interpretation. Non-invasive tests are being developed that can detect early liver disease, but liver biopsy is still the gold standard for assessing liver fibrosis once abnormal LFTs have been detected in a patient. Currently, there is no licensed treatment for AATD-related liver disease (intravenous AAT therapy is not indicated for this purpose), but liver transplantation is associated with positive outcomes and may even slow emphysema progression. Therefore, new strategies are being developed to address treatment of AATD-related liver disease, such as accelerating degradation of mutant AAT and assisting hepatocytes in the folding and secretion of mutant AAT, but these approaches remain at early stages of development.

Non-alcoholic Fatty Liver Disease (NAFLD): A Systematic Review and Meta-analysis from an Omics Perspective

“…6 Various physiological changes affect the pathogenesis of liver diseases and may lead to conditions such as acute and chronic liver diseases, Hepatitis A, B, C, D, and E, autoimmune liver diseases including autoimmune hepatitis and primary biliary cirrhosis, alcoholic liver disease, non-alcoholic liver disease, metabolic associated fatty liver diseases, drug-induced liver diseases, and genetic conditions such as hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, hepatocellular carcinoma, and liver transplant condition. 7,8 Liver functions are insulted due to either acute or chronic liver failure. Acute liver failure (ALF) is defined by sudden hepatocellular necrosis that leads to the drastic deterioration of hepatic function, which begins within an hour and lasts up to six months after being jaundiced or a pre-existing liver disease.…”

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“…This study offers another piece to the puzzle underlying genetic causes of liver disease and potential therapeutic options. 33…”

Disease progression in patients with PI*ZZ alpha-1 antitrypsin deficiency

“…The current diagnostic gold standard for AATD is measuring AAT serum level and genotyping [5,6]. Despite guidelines that endorse testing for AATD in all patients with COPD or unexplained liver disease, AATD remains severely underrecognized, with fewer than 15% of those estimated to have AATD diagnosed [7,8]. The delay period between initial symptoms and diagnosis is consistently estimated to be 6–8 years [1].…”