Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation

BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation- associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. METHODS: We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. RESULTS: Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%–36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or g-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter 280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-lowdensity lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Zoverexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. CONCLUSIONS: In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosisinfo:eu-repo/semantics/publishedVersio

The importance of inherited and acquired keratin alterations in liver disease

Keratins (Ks) 8 and 18 are the intermediate filaments of digestive epithelia displaying an important cytoprotective function. Accordingly, K8/K18 variants predispose humans to acute acetaminophen toxicity and chronic liver disease development/progression. Ks are also upregulated in multiple animal stress models and dysregulated keratin production is thought to precipitate in formation of Mallory-Denk bodies (MDBs) that are K-containing aggregates characteristic of chronic liver disorders such as alcoholic and non-alcoholic fatty liver disease (ALD/NAFLD). I analysed the biological importance of K8 variants using the newly generated transgenic mice overexpressing K8 G62C or K8 R341H/C. Furthermore, I studied the expression and the regulation of Ks in context of human liver diseases and the role of K8 overproduction in high-fat (HF) diet-induced liver damage. Under basal conditions, K8 G62C/K8 R341C/H mice did show obvious liver phenotype. 18 h after i.p. administration of 600mg/kg APAP, they exhibited increased liver enzymes, JNK activation and elevated levels of APAP adducts. 21 days after bile duct ligation, a model of cholestatic liver disease, all mouse strains showed a comparable extent of liver injury and fibrosis. HF diet induced development of liver injury, further keratin accumulation as well as MDB formation in K8 overexpressing mice. Hepatic K7/K8/K18 was overexpressed in patients with ALD and chronic HCV infection but not in subjects with NAFLD/chronic HBV while K19 was significantly elevated in all analysed disorders. Ks were overexpressed in subjects with moderate versus minimal inflammation and in patients with advanced liver fibrosis. In HepG2/Hep3B cells, IL-6 treatment significantly increased K8/K18 expression. Consequently, our data suggest that Ks represent type II acute-phase responsive genes in specific human liver disorders. K8 G62C/R341C/H variants predispose to acetaminophen liver toxicity, but not to development of cholestatic liver disease