Jeffrey Teckman, MD: Predicting Severe Liver Disease Risk in ZZ, SZ AATD

A novel risk prediction tool may allow clinicians to determine the likelihood of developing future severe liver disease in patients with homozygous ZZ and SZ alpha-1-antitrypsin deficiency (AATD).

The tool was developed using data from the Childhood Liver Disease Research Network (ChiLDReN), a National Institutes of Health consortium for the study of pediatric liver diseases, and allows for the assignment of a predictive risk with confidence intervals in ZZ and SZ AATD.

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 Jeffrey Teckman, MD, the James and Patrician Monteleone Endowed Chair at Saint Louis University School of Medicine, vice chair of Pediatrics, and a professor of pediatrics and biochemistry and molecular biology.

“[AATD] highly variable. We have some idea why that is – it probably has something to do with protein processing in the hepatocyte, but it's been very frustrating,” Teckman explained in an interview with HCPLive. “There are many new liver drugs for alpha-1 coming into human trials, and we would like to have a better idea of who to enroll in trials. If people are high risk and appear to be on the road to HCC or cirrhosis, then that's who we'd like to be in a trial. That need is the root of this analysis.”

The study included 452 ZZ and SZ patients from the ChiLDReN consortium who were 0-25 years of age and enrolled at 17 tertiary care sites in the US and Canada. Baseline history, physical exam, and standard of care laboratory data were collected, stored in a database, and updated at annual prospective follow-up visits. Outcomes, including the development of clinically evident portal hypertension, liver transplant, and death, were recorded.

Among the cohort, 60% of patients were male, 94% were non-Hispanic white, and 90% had ZZ AATD. During a median of 6.6 years of follow-up totaling 2654 patient-years, 29 subjects underwent liver transplant and 3 deaths were observed during longitudinal follow-up. Investigators noted all patients with liver transplant or death had preceding development of clinically evident portal hypertension documented. An additional 18 participants who entered the study without clinically evident portal hypertension with native liver are alive with clinically evident portal hypertension and native liver.

Investigators identified clinical parameters significantly associated with liver transplant, death, and clinically evident portal hypertension from the data set. Newly designed statistical techniques were then used to construct an algorithm and risk predictive nomogram including age; total bilirubin; AST; GGTP; INR; albumin; and platelet count for liver transplant and death, and including age; a history of neonatal cholestasis; height Z score; total bilirubin; AST; GGTP; and platelet count for the development of clinically evident portal hypertension.

“Our next step is to continue to study this cohort and also study a duplication cohort, because we still have not duplicated it in a separate cohort to validate the outcomes. We're also collecting more data, and we're still following patients in the ChiLDReN network. So we're building our own validation cohort, but we're also looking for other validation cohorts and studying the cohort to try to make this model even stronger,” Teckman explained.

Editors’ note: Teckman has relevant disclosures with Vertex, Arrowhead Inc, Takeda, Alpha-1 Foundation, and others.

Reference

Teckman J, Spino C, Huang S, et al. A first-in-class tool to predict future risk of portal hypertension, liver transplant and death in children with alpha-1-antitrypsin deficiency based on prospective data from the Childhood Liver Disease Research Network. Paper presented at: AASLD’s The Liver Meeting 2024. San Diego, California. November 15-19, 2024.