A study recently published by JHEP Reports found that patients with alpha-1 antitrypsin deficiency (AATD) and baseline compensated cirrhosis who had the Pi*MZ genotype had an increased rate of hepatic decompensation and risk of liver disease.

Chen et al included 574 patients in a retrospective study of the Michigan Genomics Initiative (MGI) who had no evidence of decompensation until at least 6 months after the cirrhosis diagnosis and had undergone genotyping. Findings revealed that compared to the Pi*MM genotype, the Pi*MZ genotype was associated with increased hepatic decompensation and increased risk of severe liver disease (defined as liver-related death or liver transplant) in patients with baseline cirrhosis.

This effect was robust across several subgroups and for individual outcomes. In contrast, the Pi*MS genotype did not correlate with decompensation or death/liver transplant. The authors defined cirrhosis based on compatible imaging, biopsy, or evidence of portal hypertension without an alternative explanation. The definition of hepatic decompensation corresponded to: (1) ascites severe enough to require treatment (diuretics, paracentesis, or transjugular intrahepatic portosystemic shunt), (2) hepatic encephalopathy, or (3) variceal hemorrhage.


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In survival analyses, the Pi*MZ and Pi*MS genotypes were primary predictors (vs Pi*MM), and the primary outcomes were hepatic decompensation and a combined outcome of liver transplant or liver-related death, used as an indicator of severe liver disease. Overall, 278 patients eventually developed hepatic decompensation, 165 died, and 98 underwent liver transplantation >6 months after enrollment.

Read more about AATD etiology

The decompensating events included ascites in 107 patients, hepatic encephalopathy in 101, variceal bleeding in 23, and a combination of these in the remaining patients. The cause of death was liver-related in 51% of the cases, cardiovascular in 8%, and unknown or other in the rest of the cases. The incidence rate for decompensation was 0.11 per person-year at risk.

“To our knowledge, this is the first study showing that in patients with compensated cirrhosis, Pi*MZ is associated with an increased rate of progression to decompensation or the composite outcome of death/liver transplantation,” the authors wrote.

AATD is a clinically under-recognized inherited disorder affecting the lungs, liver, and, rarely, skin that is estimated to affect around 100,000 people in the United States. It usually presents with chronic obstructive pulmonary disease or chronic liver disease, which ranges from asymptomatic liver enzyme elevations to chronic hepatitis and cirrhosis with portal hypertensive complications. SERPINA1 mutations cause AATD, the most clinically relevant of which are the Pi*Z and Pi*S alleles, while the Pi*M allele corresponds to wild-type AATD.

Reference

Chen VL, Burkholder DA, Moran IJ, et al. Hepatic decompensation is accelerated in patients with cirrhosis and alpha-1 antitrypsin Pi*MZ genotype. JHEP Rep. Published online April 5, 2022. doi:10.1016/j.jhepr.2022.100483