Abstract

Background: Outcomes of adults with ZZ alpha-1-antitrypsin deficiency (AATD) liver disease is variable and unpredictable. There is a lack of prospective data, including on the utility of liver biopsy. Hypothesis: Prospective clinical and biopsy data will identify factors associated with severe liver disease outcomes in AATD. Objective: Use data from a prospective, multi-center adult cohort of AATD ZZ subjects with protocol enrollment liver biopsies to identify the prognostic value of clinical markers and biopsy for the development of severe liver disease outcomes.

Methods: Homozygous ZZ AATD adults enrolled prospectively at 3 US sites with standardized clinical evaluations, followed annually with standardized data collection and outcomes recorded. Liver biopsy obtained at enrollment, unless previous biopsy confirmed cirrhosis (grouped as Ishak >4). Fibrosis scored using Ishak score (stage 0 – stage 6). Minimal fibrosis defined as Ishak 0-1, increased fibrosis as Ishak ≥ 2. Severe liver disease outcomes defined as death related to liver disease, liver transplantation or listing.

Results: 96 subjects enrolled; 51% had increased fibrosis at enrollment (49% Ishak 0-1, 36% Ishak 2-3, and 15% cirrhotic at enrollment). 62% had normal FEV1 (>80% predicted), 37% on AAT protein replacement. Serum Z polymer levels were associated with increased fibrosis. Mean serum Z polymer levels increased with the degree of fibrosis (9.7 ±6.8 Ishak 0-1, vs 12.1 ± 4.3 Ishak 2-3, vs 16.1± 8.1 for Ishak ≥4 ; p=0.0194). Mean BMI and prevalence of obesity increased with degree of fibrosis (Table 1).Clinical signs of advanced liver disease, and relevant elevations in ALT, AST, and GGT were evident with cirrhosis only. 8 severe liver disease related outcomes were reported in median 3.8 years of follow up; 3 liver disease related deaths, 3 liver transplants and 2 on transplant waiting list. All those with significant events had increased fibrosis on enrollment biopsy (100% with severe outcome, vs 46.9% without severe outcome, p< 0.001). Increased BMI and obesity were associated with increased fibrosis and liver related events. Serum Z polymer levels were higher in those with future adverse events (18.2 ± 9.2 vs 11 ± 6.3; p= 0.011). Low APRI score (<0.5) and FIB –4 score (<1.3) had a NPV of 98% in predicting future severe liver disease related events. Elastography scores, FEV1, smoking and alcohol consumption patterns were not associated with significant fibrosis or adverse liver outcomes.

Conclusion: Significant fibrosis is prevalent in adults with ZZ AATD. Clinical signs of liver disease and elevations of liver enzymes are often delayed until cirrhosis develops. Serum Z polymer levels could be a biomarker to detect fibrosis early and predict outcomes. High BMI and obesity are associated with increased fibrosis and adverse liver disease outcomes. Increased fibrosis at enrollment biopsy is a strong predictor of future severe liver disease outcomes in this cohort.