Study Suggests Tolerability of Moderate Alcohol Consumption in Pi*MZ, Pi*ZZ AATD

Malin Fromme, MD

Credit: RWTH Aachen

Findings from a recent study are providing clinicians with an overview of the association between alcohol intake and liver-related parameters in individuals with the heterozygous/homozygous Pi*Z alpha-1 antitrypsin variant of alpha-1 antitrypsin deficiency (AATD).¹

Leveraging data from the United Kingdom Biobank and the European Alpha 1 liver consortium, the study found moderate alcohol intake resulted in a minor increase in elevated transaminases in Pi*MZ individuals and non-carriers, and in Pi*ZZ participants, moderate alcohol consumption had no impact on liver enzymes.¹

“While the liver phenotype in AATD subjects is highly variable and the disease modifiers are incompletely understood, known metabolic/nutritional co-factors such as the presence of obesity, metabolic syndrome, or diabetes as well as alcohol consumption have been proposed,” Malin Fromme, MD, a resident physician at University Hospital RWTH Aachen, and colleagues wrote.¹ “With regard to the latest, subjects with Pi*MZ genotype and chronic alcohol misuse display a 2–6 times elevated risk of liver cirrhosis compared to drinkers without AAT mutation. In contrast, the impact of moderate alcohol consumption as well as the impact of alcohol in Pi*ZZ individuals remains to be systematically examined.”

A genetically inherited disorder resulting in impaired production of alpha-1 antitrypsin protein, AATD results in reduced activity of AAT in the blood and lungs and can lead to the accumulation of AAT in the liver, causing liver disease.² Alcohol abstinence is generally recommended among individuals with liver disease, but little is known about differences in its impact among individuals with different AATD genotypes.¹

To explore the association between alcohol intake and liver-related parameters in individuals with the Pi*MZ/Pi*ZZ genotype, investigators examined reported alcohol consumption in 2 cohorts: the United Kingdom Biobank and the European Alpha1 liver consortium. Investigators excluded those with missing data on alcohol consumption, presence of Pi*S allele of SERPINA1, and viral hepatitis in the UK Biobank cohort and those of non-European descent, with invalid liver stiffness measurement by transient elastography or the presence of confounders of valid transient elastography measurement, and the presence of known liver disease or a liver co-morbidity from the European Alpha 1 liver consortium.¹

In total, investigators examined 17,145 individuals with Pi*MZ, 141 individuals with Pi*ZZ, and 425 002 non-carriers (Pi*MM) from the UK Biobank and 561 individuals with Pi*ZZ from the European Alpha1 liver consortium.¹

UK Biobank

Investigators divided participants into subgroups with no/low (n = 14,304), moderate (women 12–39 g/d, men 24–59 g/d; n = 2688), and harmful (women ≥40 g/d, men ≥60 g/d; n = 153) alcohol consumption. In all examined genotypes, >80% of participants reported no/low alcohol intake, while harmful consumption was rare (<1% in Pi*MM/Pi*MZ, 2% in Pi*ZZ).¹

Comparison of liver enzymes among Pi*MM and Pi*MZ individuals with moderate versus no/low consumption revealed Pi*MZ individuals more often displayed elevated liver enzymes than those with Pi*MM (P <.001). Investigators noted in both genotypes, moderate alcohol consumption resulted in a minor increase in the rate of individuals with transaminases above the upper limit of normal (ULN), although the effect on gamma-glutamyl transferase (GGT) was more pronounced (Pi*MM 23.0 vs 15.0%, P <.001; Pi*MZ 22.5 vs 15.7%, P <.001), suggesting moderate alcohol consumption is well tolerated across both genotypes.¹

However, in both Pi*MM and Pi*MZ, harmful alcohol consumption resulted in a marked increase in the proportion of individuals with elevated transaminases as well as elevated GGT, suggesting harmful consumption promotes liver injury to a similar extent in both genotypes. However, investigators pointed out the number of Pi*ZZ individuals was too low to reach a definitive conclusion for both moderate and harmful consumption.¹

European Alpha1 Liver Consortium

Among 561 individuals with the Pi*ZZ genotype, 91% and 8% of participants reported no/low and moderate alcohol consumption, respectively. The differences in liver enzymes with moderate alcohol consumption did not reach statistical significance, indicating tolerability of this level of alcohol consumption. Subjects with harmful alcohol intake had the greatest levels of most liver enzymes, but investigators noted the numbers were too low to reach statistical significance.¹

Among the cohort, 86% of Pi*ZZ participants displayed normal (<1.7%) carbohydrate-deficient transferrin (CDT) values and reported significantly lower alcohol consumption than individuals with elevated CDT levels. In univariable but not multivariable analysis, Pi*ZZ individuals with elevated CDT levels displayed higher GGT serum levels as well as greater APRI scores.¹

Investigators combined both parameters and divided participants with elevated CDT values into subgroups with no/low (n = 60) and at least moderate reported alcohol consumption (n = 19). Upon analysis, those with at least moderate reported alcohol consumption and CDT ≥1.7% presented with greater GGT serum levels (72.5 vs 60.0; P = .020) and higher APRI (.36 vs .30; P = .008) compared to those who did not consume alcohol, and had a greater proportion of subjects with APRI ≥1.00 (8.9% vs 3.2%; P = .038) indicative of advanced liver fibrosis. Based on these results, investigators suggested the utility of CDT assessment in patients with signs of significant liver disease but no/minimal reported alcohol intake.¹

Investigators outlined multiple limitations to these findings, including their reliance on publicly available data that were only partially validated in an additional, original cohort; the lack of participants with higher reported alcohol intake; and the lack of evaluation of additional biomarkers of alcohol consumption such as phosphatidylethanol quantification.¹

“The AATD Pi*MZ/Pi*ZZ genotype does not seem to significantly aggravate the hepatic toxicity of moderate alcohol consumption. CDT values might be helpful to detect alcohol consumption in those with advanced fibrosis,” investigators concluded.¹

References

1. ^{Fromme M, Schneider CV, Guldiken N, et al. Alcohol consumption and liver phenotype of individuals with alpha-1 antitrypsin deficiency. Liver Int. doi:10.1111/liv.16044}
2. ^{Meseeha M, Sankari A, Attia M. Alpha-1 Antitrypsin Deficiency. StatPearls. February 12, 2024. https://www.ncbi.nlm.nih.gov/books/NBK442030/}