ZZ Genotype Linked to More Severe AATD-Related Liver Disease

New research is shedding light on the burden of liver disease in patients with the ZZ genotype of alpha-1 antitrypsin deficiency (AATD), highlighting high rates of steatosis, fibrosis, and cirrhosis.1

The systematic review and meta-analysis encompassed data from 8638 participants across 45 studies, with results calling attention to high rates of subclinical manifestations of liver disease as well as a heightened risk of severe liver disease progression necessitating liver transplantation.1

“Despite the growing body of research on AATD, there is a critical need to consolidate data on the clinical outcomes associated with this condition,” Adam Syanda, a research assistant at the Imperial BRC Organoid Facility, and colleagues wrote.1

A hereditary disorder characterized by low levels of alpha-1 antitrypsin in the blood, AATD may predispose patients to several illnesses and most commonly manifests as chronic obstructive pulmonary disease or liver disease. Most patients with AATD-related liver disease are homozygous for the Z allele, but underlying mechanisms and subsequent outcomes are not well understood.2

To investigate the risk and extent of liver disease and the prevalence of liver transplantation in ZZ AATD patients, investigators conducted a systematic review and meta-analysis of AATD studies obtained from multiple databases from their inception until May 2024. They excluded animal or cell-based studies, publications solely investigating heterozygous AATD patients or genotypes other than ZZ, non-English language publications, case series studies, and studies with pediatric or mixed-age cohorts.1

Out of an initial 6899 studies identified, 4420 were screened and 45 met the eligibility criteria for inclusion in the meta-analysis. Investigators noted studies were geographically distributed across Europe, North America, and South America, with the majority originating from the US (n = 16), Sweden (n = 8) and the UK (n = 5). Cumulatively, there were 8638 participants in the ZZ cohorts and 685,992 participants in the comparator cohorts.1

Among the included studies, 41 (91.1%) did not pre-select participants based on pre-existing liver pathology (Group 1), while 4 (8.9%) specifically included participants with known liver conditions (Group 2). Investigators analyzed these subsets separately to account for baseline differences in liver disease status.1

In Group 1, the mean participant age was 49.5 (Standard deviation [SD], 8.2) years, with female participants comprising 39.2% of the ZZ cohorts. Conversely, in Group 2, the mean age was 49.5 (SD, 5.8) years, with females representing 31.5% of the study population in the ZZ cohorts.1

The pooled prevalence of steatosis was 29.35% (95% CI, 11.52-47.18), derived from 7 studies encompassing 1291 patients. Further analysis revealed a a pooled crude odds ratio (cOR) of 1.52 (95% CI, 1.21-1.91), indicating a significantly increased incidence of steatosis in the ZZ cohort compared with MM controls.1

The pooled prevalence of fibrosis was 20.06% (95% CI, 10.94-29.18) with a pooled cOR of 9.85 (95% CI, 5.70-17.03), indicating a substantially greater risk of fibrotic progression in the ZZ population. For cirrhosis, the overall pooled prevalence was 8.17% (95% CI, 4.92-11.42) with a cOR of 10.43 (95% CI, 5.51-19.73).1

The pooled prevalence of liver cancers across 5 studies was 5.87% (95% CI, 0.00-11.94), including data from 4 studies not selecting for liver disease, which reported a hepatocellular carcinoma prevalence of 4.53% (95% CI, 0.00-10.86). In contrast, a single study specifically recruiting for liver disease revealed a markedly higher HCC prevalence of 14.00% (95% CI, 4.38-23.62). The cOR for HCC was 14.12 (95% CI, 6.50-30.66), highlighting an increased risk of liver cancer in the ZZ cohort.1

When investigating rates of liver transplantation, investigators called attention to significant variation between the groups, with a prevalence of 0.58% (95% CI, 0.27-0.90) observed in Group 1 compared with 23.13% (95% CI, 10.65-35.60) in Group 2. They estimated the pooled prevalence of liver transplantation to be 4.97% (95% CI, 0.00-12.34) but noted the substantial heterogeneity observed in these rates is likely attributable to variations in sample sizes and recruitment biases between the groups.1

“These data highlight the importance of monitoring liver function in all adults diagnosed with AATD as well as promoting patient education, which emphasises preventative and protective strategies regardless of current liver function,” investigators concluded.1

References

1. Syanda AM, Georgantaki D, Awsaf M, et al. Liver Disease and Prevalence of Liver Transplantation in Adults With ZZ Alpha-1 Antitrypsin Deficiency—A Meta-Analysis. Liver International Communications. https://doi.org/10.1002/lci2.70013

2. Meseeha M, Sankari A, Attia M. Alpha-1 Antitrypsin Deficiency. StatPearls. February 12, 2024. Accessed April 16, 2025. https://www.ncbi.nlm.nih.gov/books/NBK442030/