Alpha-1 antitrypsin deficiency: even MZ carriers were at higher risk of serious liver outcomes

Design

Retrospective national cohort, Fine–Gray competing-risk models

Population

22,537 US veterans with AATD genotyping (1,656 MZ, 281 SZ, 935 ZZ)

Primary outcome

Major adverse liver outcomes

Effect

vs Pi*MM: MZ aHR 1.25 (1.11 to 1.40); SZ 1.51 (1.17 to 1.94); ZZ 1.80 (1.57 to 2.07)

A retrospective cohort in the US Veterans Affairs system identified 22,537 people with alpha-1 antitrypsin genotyping, followed for a median of 15.9 years.

Major adverse liver outcomes (decompensation, liver cancer, transplantation or liver death) rose with Z-allele burden against Pi*MM: Pi*MZ HR 1.25, Pi*SZ 1.51, Pi*ZZ 1.80. Five-year probabilities were 3.5%, 5.5%, 5.3% and 8.1%. Pi*ZZ was associated with every component including liver cancer; MZ and SZ were associated with decompensation, transplantation and liver death but not liver cancer. Results held in people with MASLD.

Heterozygous MZ carriage is common and often dismissed as a trait without consequence. This suggests it acts as a disease modifier, particularly alongside other liver injury such as MASLD or alcohol.

• Consider alpha-1 antitrypsin level and phenotype in unexplained or disproportionately severe liver disease
• Do not dismiss MZ carriage as clinically irrelevant
• Counsel carriers strongly on alcohol and weight
• Assess fibrosis in genotype-positive patients
• Offer family testing when a Z allele is found

Why it matters

It challenges the assumption that a single Z allele carries no liver risk.

Don't overread it

The cohort was veterans who were tested for a reason, mostly men, so it may overstate risk in unselected carriers.

The statistics, in plain English

A hazard ratio of 1.25 for MZ is modest, but MZ carriage is common, so the population impact can be meaningful. Fine–Gray models account for dying of other causes before a liver event. Testing was not universal, so people with suspected liver or lung disease were more likely to be tested, which can inflate risk estimates.

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