S5616 When Genetics and Alcohol Collide: Twin Cirrhosis and PNPLA3's Role

Introduction: Alcohol-associated liver disease (ALD) causes cirrhosis, yet not all heavy drinkers develop advanced liver damage, highlighting additional factors such as genetic risk. PNPLA3 mutation is strongly linked to hepatic steatosis, inflammation and progression to fibrosis. We report a rare case of dizygotic twins, both PNPLA3 homozygotes, who develop severe decompensated metabolic dysfunction-associated ALD (MetALD) cirrhosis, and present with alcohol associated hepatitis (AH) just days apart. Case Description/Methods: Patients, twins A and B are 41-year-old Hispanic dizygotic twins with a 15-year history of alcohol abuse presenting with AH. Raised together and now neighbors, they share similar diets, environments, socioeconomic status and metabolic risks. Twin A presented with hepatic encephalopathy and ascites without spontaneous bacterial peritonitis. A calculated Maddrey’s Discriminant Function was 70.1 suggesting poor prognosis and steroid benefit. Steroids were initiated but stopped after massive hematemesis requiring intubation and band ligation for variceal bleed. Twin B began drinking at the age of 20, escalating to daily beer, tequila, and vodka over the past 5 years until recent sobriety. She was initially a bilirubin ‘fast faller’ improving without immunosuppression - signaling a favorable prognosis and lower risk of liver failure. Given their young age and severe disease, both twins underwent genetic testing and were homozygous for the PNPLA3 variant. Early AH included psychosocial assessment and sustained alcohol liver transplant (SALT) scoring- a validated tool predicting post-transplant alcohol use based on sobriety duration, rehabilitation history, social support and prior relapse. Both scored SALT 3, indicating lower risk of post-transplant alcohol use. While Twin B has been accepted for transplant, Twin A is still under evaluation. Discussion: The PNPLA3 variant, more common in Hispanic populations, raises risk for MASLD, fibrosis, and hepatocellular carcinoma. Notably, both dizygotic twins independently inherited the variant supporting a multi-hit model, where genetic predisposition synergizes with environment, metabolic risk, and ethnicity to drive rapid cirrhosis progression. The case highlights the complex interplay in liver disease and the potential value of genetic screening in high-risk groups. Disclosure: Portions of this report were edited with the assistance of AI-based tools.