Malin Fromme, MD: Lung, Liver Risk Stratification in Alpha-1 Antitrypsin Deficiency

Noninvasive surrogates of liver fibrosis can be used to accurately stratify hepatic decompensation risk in adults with Pi*ZZ alpha-1 antitrypsin deficiency (AATD), according to findings from a recent study.

The research was presented at The Liver Meeting 2024 from the American Association for the Study of Liver Diseases (AASLD) in San Diego, California, by Malin Fromme, MD, a physician-scientist at the University Hospital RWTH Aachen in Germany, and suggests liver stiffness measurement (LSM)-based intermediate liver fibrosis and mild-moderately impaired pulmonary function are associated with greater liver-related risks than lung-related risks.

“At the moment, in some countries, we have augmentation therapy for the treatment of lung disease, but we only have liver transplantation for really advanced liver disease… we don't have a disease-specific therapy to treat the AATD-related liver disease,” Fromme explained in an interview with HCPLive.

She and colleagues sought to evaluate the disease course and noninvasive surrogates for the development of hepatic and pulmonary endpoints in an international, multicenter, longitudinal cohort of patients with Pi*ZZ AATD.

A pair of cohorts were examined, the first of which included 737 Pi*ZZ subjects from 25 centers who received a standardized assessment at baseline and an additional interview 6 months later to review liver- and lung-related endpoints, including first hepatic decompensation/liver transplantation; liver-related death; lung transplantation; and lung-related death. The second cohort consisted of 135 Pi*ZZ subjects without significant liver fibrosis, who received a baseline and follow-up examination ≥ 2 years later.

During 2634 patient-years of follow-up, 39 patients died, with 46% and 36% of deaths attributed to hepatic and pulmonary causes, respectively. Analysis of 41 Pi*ZZ subjects who developed a hepatic endpoint revealed they were most accurately predicted by LSM (AUC, 0.95) followed by AST to Platelet Ratio Index (APRI) (AUC, 0.92) and FIB-4 (AUC, 0.90). Of note, baseline lung parameters displayed only a moderate predictive utility for pulmonary endpoints (FEV1 AUC, 0.76).

Among 540 Pi*ZZ subjects with LSM <7.1 kPa, none developed a hepatic endpoint despite having > 1900 follow-up years. Investigators pointed out an increase in all noninvasive liver fibrosis scores coincided with an increased occurrence of hepatic endpoints. Similarly, there was an increased incidence of lung endpoints in subgroups with lower FEV1 values.

Pi*ZZ subjects with mild-to-moderate pulmonary function impairment and intermediate liver fibrosis (i.e., FEV1 50-70% vs. LSM 7.1-10 kPa) had a 3 times greater risk of liver- versus lung-related endpoints. In the second cohort, 8.9% of patients showed a fibrosis progression based on LSM (P = .004), baseline LSM (6.1 vs 4.6 kPa; P = .002), and APRI (0.44 vs 0.28; P <.001).

“In AATD, with all the new drug approaches, it's important to choose the right patients for the different clinical trials. For this, lung and liver need to be assessed and balanced at the same time,” Fromme said. “With this, we can do a pretty good risk assessment of the liver disease as well as the lung disease and decide which patient needs to get therapy.”

Editors’ note: Fromme has relevant disclosures with Takeda, CSL Behring, and Grifols.

Reference

^{Fromme M, Payancé A, Mandorfer M, et al. 4462 - Prediction of hepatic and pulmonary endpoints in a longitudinal cohort of individuals with homozygous alpha-1 antitrypsin deficiency (Pi*ZZ genotype). Paper presented at: AASLD’s The Liver Meeting 2024. San Diego, California. November 15-19, 2024.}