Adults with a severe form of alpha-1 antitrypsin deficiency (AATD) caused by the Pi*Z mutation, and mice with the same genetic alteration, can have liver steatosis and impaired lipid secretion, researchers report in the September issue of Gastroenterology. The research team found factors associated with significant liver fibrosis in patients that might facilitate assessment and counseling of people with this inherited disease.
AATD is a common autosomal recessive disorder caused by a mutation in the SERPINA1 gene, which encodes the serine protease inhibitor AAT. Targets of AAT include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. AAT is produced in the liver, released into the blood, and protects the lungs.
AATD is most often caused by homozygosity for the PiZ allele, which encodes the Glu342Lys substitution in SERPINA1. The most common manifestation of AATD is emphysema, which becomes evident by the time patients are in their 30s or 40s.
A less common manifestation of AATD is liver disease, which occurs in children and adults, and can result in cirrhosis and liver failure. Progression and prevalence of PiZ-related liver disease in adults have been poorly characterized. Furthermore, adults homozygous the PiZ variant (Pi*ZZ) are managed based on serum levels of liver enzymes, although these have been reported to fail to reliably predict the course of disease.
Karim Hamesch et al performed a systematic study of liver disease burden and laboratory parameters in 554 PiZZ adults in 9 European countries, comparing them with 234 adults without the genetic variant (controls). They also performed histologic analyses of livers from transgenic mice that overexpress the PiZ variant of AAT.
Serum levels of liver enzymes were significantly higher in PiZZ patients than controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%–36% of PiZZ carriers. Signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers than non-carriers.
Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase (AST), or gamma-glutamyltransferase (GGT); and low numbers of platelets were associated with higher liver fibrosis burden. Hamesch et al did not find evidence for a relationship between lung function and liver fibrosis.
Based on controlled attenuation parameter (CAP) values of 280 dB/m or more, severe steatosis was detected in 39% of PiZZ carriers vs 31% of controls. PiZZ carriers had had higher mean CAP values than non-carriers (267±57 dB/m vs 246±56 dB/m). A significantly higher proportion of Pi*ZZ carriers had mild steatosis (CAP values of 248 dB/m, 61.1%) than non-carriers (48.2%).
Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very low-density lipoprotein cholesterol than controls, indicating impaired hepatic secretion of lipid.
Livers from PiZ-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. Oil Red O staining and assessment of hepatic triglyceride content revealed higher levels of lipid accumulation in PiZ-overexpressing mice compared with their non-transgenic littermates. In contrast, there were no significant differences between groups of mice in serum cholesterol or serum triglyceride levels.
Hamesch et al state that demographic parameters as well as laboratory values can help clinicians calculate patients’ risk for significant liver fibrosis and can be used in patient counseling (see figure).
The authors conclude that 20%–36% of PiZZ carriers have significant liver fibrosis and 5%–26% have advanced liver fibrosis. PiZZ carriers had 9–20-fold higher odds than non-carriers of having results from liver fibrosis test that indicate advanced liver fibrosis. These findings reveal the vulnerability of Pi*ZZ carriers to liver disease, at frequencies lower than former reports.
One limitation to the study was that the extent of liver fibrosis was evaluated by only non-invasive methods. However, combined analysis of results from 3 non-invasive fibrosis tests revealed the usefulness of measurement of AST, GGT, and platelets in initial assessments of liver damage in Pi*ZZ carriers.
How does the PiZ variant cause liver diseases? The simultaneous decrease in triglyceride and very low-density lipoprotein cholesterol levels indicate that PiZ accumulation in the endoplasmic reticulum affects lipid metabolism in this cellular compartment. Impaired hepatocyte nuclear factor 4 alpha (HNF4A) signaling in PiZ-overexpressing mice impairs lipoprotein assembly and lipid secretion. An alternative explanation is that hepatic steatosis arises from proteo-toxic stress, due to the accumulation of PiZ in hepatocytes. The need to degrade the excess mutant protein might overwhelm lipid autophagy in liver cells; Pi*Z also interacts with lipoprotein particles.
Further studies are needed to determine the mechanisms that contribute to hepatic steatosis in PiZ-overexpressing mice and human carriers of the PiZZ variant.