OC27 Rare but treatable cause of cholestasis- primary bile acid synthesis defect

Bile acid synthetic defects are uncommon genetic disorders causing persistent cholestasis in infants. The onset and severity of the liver disease is extremely variable from mild, transient, and delayed in onset, while on the other end of the spectrum, presenting with severe neonatal or infantile cholestasis with progression to early cirrhosis and liver failure necessitating liver transplantation or leading to mortality. Patient was incidentally detected to have jaundice and significantly raised transaminases (> 1000 IU/ml) at the age of 5 months. She was born to non-consanguineous Caucasian parents. At the time of presentation itself metabolic or genetic disorder was considered as a strong possibility as there was massive hepatomegaly, splenomegaly, normal gamma glutamyl peptidase level and diffusely bright liver in ultrasound imaging. Initial assessment for metabolic disorders including tyrosinemia was negative. The serum bile acids were normal. The alpha fetoprotein level was significantly raised and worryingly, showed a rising trend. This prompted further assessment with abdominal magnetic resonance imaging in which showed multiple bilateral T1 hypointense, T2 hyperintense lesions with restricted diffusion with no central enhancement involving both kidneys. Liver biopsy showed features of chronic liver injury with early cirrhosis. Genetic testing identified heterozygous pathogenic variant (HSD3B7 c.45–46del p. (Gly17fs)) in the HSD3B7 gene. Urinary cholanoids by electrospray ionisation tandem mass spectrometry detected sulphated dihydroxy- and trihydroxy-cholenoic acids present as major peaks confirming diagnosis of 3-beta-hydroxy-delta5-C27-steroid dehydrogenase deficiency (3β-HSD), the most common type of bile acid synthetic defect. Patient was started on oral cholic acid therapy. At 2 years of follow-up, cholestasis, hepatomegaly, splenomegaly and renal lesions have resolved, child is growing well with normal developmental milestones. Bile acid synthetic defects are caused by defective enzymes catalyzing key reactions in the formation of the primary bile acids (cholic acid & chenodeoxycholic acid), causing inadequate synthesis of primary bile acids which are critical for bile formation, absence of these leads to the accumulation of atypical and hepatotoxic bile acid intermediates. Absence of pruritus, normal serum gamma glutamyl transferase activity, and normal or low total serum bile acid concentration are diagnostic clues. Care is required when interpreting a serum bile acid level obtained when the patient is receiving ursodeoxycholic acid because elevated serum bile acids may not necessarily exclude a diagnosis of HSD3B7 deficiency in such patients. Renal lesions, most commonly renal cysts, but also renal stones, calcium deposition and renal enlargement are observed in 28% at the time of presentation. The diagnosis is confirmed by mass spectrometry analysis of urinary bile acids showing typical bile acid profiles and genetic analysis. Lifelong oral therapy with bile (cholic) acid is safe, effective with complete normalisation of liver biochemistry, radiological abnormalities and renal lesions. Cholic acid therapy has been shown to reverse the extent of fibrosis. Regular monitoring of urinary bile acid profile is crucial to assess treatment efficacy and compliance