2503 Cholestasis in a Patient With HNF-1B Mutation

Abstract

INTRODUCTION: Maturity Onset Diabetes of the Young, MODY5, is a syndrome characterized primarily by renal cysts, renal dysfunction and early onset diabetes caused by pancreatic atrophy and hepatic insulin resistance. Hepatocyte nuclear factor 1b (HNF1b) plays a key regulatory role in the organogenesis of tubular epithelia within the renal, pancreatic and biliary systems. CASE DESCRIPTION/METHODS: 33-year-old woman presented to hepatology clinic with chronically elevated liver chemistries in a mixed hepatocellular/cholestatic pattern (Table 1). Abnormalities were first noted in her teens with symptoms of fatigue and pruritus. No history of liver-toxic medications. Medical history: pre-diabetes, polycystic ovarian syndrome with associated infertility issues, renal cysts. Surgical history: bladder/ureteral surgery as a child. Unremarkable social history. Father with ulcerative colitis. Work up included negative hepatitis panel, anti-smooth muscle ab, anti-mitochondrial ab, and ANA. Normal ceruloplasmin, copper, and ferritin. Sonogram with a 15.6 cm homogenous liver, cholelithiasis (resolved on repeat study), and bilateral renal cysts. Liver biopsy was essentially normal with minimal focal lobular chronic inflammation and mild sinusoidal congestion. Her medical history prompted genetic testing for HNF1B mutation, positive for heterozygous disease. MRI/MRCP revealed normal appearing bile ducts and pancreatic atrophy, consistent with the diagnosis. DISCUSSION: HNF1b deficiency compromises the functional integrity of human cholangiocytes by altering the structure of primary cilia. Roelandtet al. were the first to demonstrate aberrant cholangiocytes at the structural level in patients with HNF1b heterozygosity (Figures 1 and 2). The defects do not affect the structure of intra and extrahepatic ducts themselves, so patients may present with normal hepatic and biliary architecture. More overt biliary anomalies have been noted in HNF1b associated MODY5, with many carriers of the mutation demonstrating choledochal cysts. HNF-1b mutations should be considered in patients with cholestasis, late onset diabetes and renal cysts, particularly when standard work up does not reveal a cause for abnormal liver chemistries. While morbidity is associated with pancreatic and renal dysfunction, symptomatic management of cholestasis should be addressed. Further studies are needed to determine if surveillance is necessary to assess the development and potential malignant transformation of choledochal cysts.