S2869 Cholestasis of Undefined Etiology. Evaluation and the Role of Ileal Bile Acid Transport (iBAT) Inhibitors in Adults

Introduction: Genetic cholestatic disorders (GCD) are considered a rare form of cholestatic liver disease. These disorders are due to defective bile acid (BA) section into bile, intrahepatic accumulation of toxic BA, liver injury, fibrosis, cirrhosis, and liver failure. The most well recognized forms of GCD occur in children and include Progressive Familial Intrahepatic cholestasis (PFIC) and alagille syndrome. These disorders are characterized by high serum BA levels and severe pruritus. iBAT inhibitors lower serum BA and improve/resolve pruritus in these patients (patients). Milder forms of GCD have now been recognized in adults. This has been facilitated by genetic testing for GCD which is now available for clinical use. We hypothesized that adults with cholestasis of undefined etiology with or without pruritus have a GCD. Methods: Pts with an elevation in ALP of undefined etiology based upon serology, MRI/MRCP and/or liver histology, an elevation in serum BA and/or pruritus were screened for genetic mutations associated with cholestasis utilizing the Prevention Genetics Cholestasis panel. This test evaluates for mutations in up to 77 genes which have been associated with cholestatic disorders. Pts were excluded if they had a defined etiology for cholestasis including PBC, PSC, hepatic sarcoidosis, amyloidosis, choledocholithiasis, or a liver transplant. Results: A total of 42 patients underwent genetic testing. The mean age of the cohort was 56 years (16-81), 26% man, 50% White, 36% African American, 12% Hispanic. The mean ALP was 281 (61-1839), GGT 278 (17-1248), aspartate aminotransferase 54 (14-275), alanine aminotransferase 66 (10-488), TBILI 1.2 (0.2-24.0). Mean LS by Fibroscan was 7.2 kPa (3.2-17.3) . 28/42 patients underwent liver biopsy. The most common histologic finding was a mild non-specific portal inflammation with no fibrosis. Seventeen percent had cirrhosis. Twenty-four percent of patients had itching. Genetic mutations associated with cholestasis were identified in 73% of patients. A total of 24 different genes were affected in the 42 patients. Ten patients with moderate-severe pruritus and an affected gene were tread with an iBAT inhibitor. All had a reduction or complete resolution of itching. Conclusion: Mutations in genes associated with cholestasis are common in patients with cholestasis of undefined etiology. About 25% of these patients have pruritus and treatment with an iBAT inhibitor leads to improvement/resolution of itching. Testing for GCD appears to be useful in the evaluation of patients with cholestasis of undefined etiology.