59 Severe Cholestatic Liver Failure in a Young Patient with Hepatocyte Nuclear Factor 1B (HNF1B) Mutation: A Rare Pathologic Presentation

Introduction/Objective Maturity-onset diabetes of the young 5 (MODY5), associated with hepatocyte nuclear factor 1B (HNF1B) gene mutations, is a rare diabetes syndrome affecting young adults. While the hepatic phenotype of HNF1B mutations is poorly characterized, some studies suggest cholestasis or bile duct abnormalities, with ductopenia being rarely reported. Most research focuses on renal and pancreatic pathology. We present a case of a 23-year-old woman with HNF1B-associated MODY, end-stage renal disease (ESRD) due to polycystic kidney disease (PCKD), and long-standing liver enzyme abnormalities who progressed to acute liver failure. Methods/Case Report A 23-year-old woman with MODY due to an HNF1B mutation, ESRD secondary to PCKD, and persistent liver enzyme elevation presented to the emergency department with scleral icterus, elevated blood pressure, headache, nausea, and vomiting, progressively worsening over the past month. On examination, her blood pressure was 161/101 mmHg, heart rate 99 bpm, and respiratory rate 18 breaths/min, with oxygen saturation of 99% on room air. She was afebrile, and scleral icterus was noted. Laboratory tests revealed markedly elevated bilirubin levels [7.30 mg/dl- Ref range 0.15-1.00 mg/dl; Direct bilirubin- 5.18 (range 0.00-0.30 mg/dl)] and signs of coagulopathy, suggesting hepatic synthetic dysfunction. Her MELD score was 35, indicating severe liver disease. Abdominal ultrasound showed increased hepatic echogenicity and coarsened echotexture, consistent with hepatic steatosis and/or chronic liver disease. No biliary ductal dilatation or ascites was noted. CT imaging revealed simple renal cysts without hydronephrosis or urolithiasis, and the pancreas showed hypertrophy of the head and uncinate process, likely due to atrophy of the body and tail. Her liver biopsy from 2021 favored ductopenia, though insufficient portal tracts prevented a definitive diagnosis. Given her clinical deterioration, the patient was listed for and underwent successful combined liver-kidney-pancreas transplantation in 2024. Histopathologic examination of the explanted liver showed severe ductopenia, periportal ductular metaplasia, extensive cholestasis, and feathery degeneration, consistent with advanced cholestatic injury and bile duct loss—features of HNF1B mutation-associated liver disease. Per the last follow-up, she is doing well. Results NA Conclusion HNF1 B mutations are commonly associated with renal cystic disease, MODY5, and genitourinary malformations. While a chronic increase in liver enzymes and cholestasis is common, overt liver failure with ductopenia is rare. Literature reports mild liver abnormalities, but cholestasis and bile duct loss are infrequently described. This case highlights the potential for progressive ductopenic liver disease in HNF1B mutation patients, underscoring the need for careful monitoring for progression of the disease into liver failure or cirrhosis.