Design: Retrospective national cohort (US Veterans), Fine-Gray competing-risk models
Population: 22,537 veterans with AAT genotype testing; median follow-up 15.9 years
Primary outcome: Major adverse liver outcomes
Effect: PiMZ aHR 1.25 (1.11–1.40); PiSZ 1.51 (1.17–1.94); PiZZ 1.80 (1.57–2.07)

This US Veterans cohort included 22,537 people with alpha-1 antitrypsin genotype testing, followed for a median 15.9 years. Compared with PiMM, the risk of major adverse liver outcomes (decompensation, HCC, transplant or liver death) rose with Z-allele burden: PiMZ aHR 1.25 (95% CI 1.11 to 1.40), PiSZ 1.51 (1.17 to 1.94), PiZZ 1.80 (1.57 to 2.07).

Five-year probability of an outcome was 3.5% in PiMM, 5.5% in PiMZ and 8.1% in PiZZ. PiZZ raised the risk of every component including HCC; PiMZ and PiSZ raised the risk of decompensation, transplant and liver death but not HCC. Results held in patients with MASLD.

PiMZ carriers are common and often told they are 'just carriers'. This supports treating a Z allele as a liver risk factor, particularly alongside obesity, alcohol or other liver disease.

Consider alpha-1 antitrypsin testing in unexplained chronic liver disease or cirrhosis.
Treat PiMZ as a modest liver risk factor, not a harmless carrier state.
Advise Z-allele carriers to avoid alcohol and manage weight and metabolic risk.
Offer family testing when a Z allele is found.

Why it matters

It turns a common 'carrier' result into a reason to act on other liver risks.

The statistics, in plain English

Hazard ratios of 1.25 to 1.80 are moderate increases. The cohort was of people who had been tested, who may already have been suspected of liver or lung disease, so absolute risks may be higher than in the general population.