An Unusual Cause of Elevated LFTs: Progressive Familial Intrahepatic Cholestasis

Abstract

Introduction: A 40-year-old otherwise healthy male presented to the GI clinic for follow-up of abnormal LFTs detected on a routine evaluation. The AST was 57 U/L, ALT 88 U/L, and ALP 214 U/L. There was no history of alcohol consumption or blood transfusion. Testing for hepatitis A, B, C, Wilson’s disease, autoimmune hepatitis, hemochromatosis, and alpha-1 antitrypsin deficiency was negative. Ultrasound and CT of the abdomen were unremarkable. MRCP with MR elastography revealed normal liver contour, with mild dilatation of a portion of the right intrahepatic biliary ducts and a mean liver stiffness value of 3.25 kPa. A liver biopsy showed evidence of disrupted hepatic architecture with micronodular cirrhosis. The histology findings were thought to be due to focal liver injury, possibly in or near the location of his prior cholecystectomy. One year later, his AST was 110 U/L, ALT 130 U/L, ALP 374 U/L, and total bilirubin 1.1 mg/dL. The mean stiffness on MR was 5.62 kPa. At that time, the patient revealed that his brother had just been diagnosed with esophageal varices. Given the abrupt change in liver stiffness over 12 months and a family history of esophageal varices, congenital hepatic fibrosis was suspected. Both the patient and his brother then tested positive for a novel heterozygous mutation: c.3531_3533delACG variant that causes in-frame deletion of Glycine at position 1178 of the ABCB4 protein. Thus, the diagnosis of progressive familial intrahepatic cholestasis (PFIC) type 3 was confirmed. The patient was started on ursodeoxycholic acid (UDCA) and his subsequent LFTs gradually normalized. PFIC type 3 is an autosomal recessive disease caused by mutations in ABCB4 gene, which encodes the multidrug resistance - 3 (MDR3) gene, an ATP-binding cassette transporter. It acts as a phospholipid trans-locator involved in biliary phospholipid excretion. ABCB4 defects cause impaired excretion of phosphatidylcholine, an important component in formation of mixed micelles that protect the cell membrane of biliary epithelium from the detergent action of bile salts. Functional deficiency of ABCB4 solubilizes the cell membrane of the biliary epithelium inducing apoptosis. Diagnostic features include elevated serum bile salts, increased GGT, light microscopy findings of ductular proliferation, and inflammatory infiltrate in early stage, progressing to cirrhosis and cholestasis in later stages. Typically, PFIC type 3 is diagnosed in childhood or early adulthood. Rarely, it can also present much later in life, as in this patient. Manifestations are limited to the liver only. UDCA is helpful in about 50% and transplantation is required for hepatic failure.