Progressive Intrahepatic Cholestasis

Byler’s disease, first described in the Amish people by Jacob Byler, is an autosomal recessive disorder of childhood, most often characterised by neonatal onset of cholestasis. The recent demonstration of three different molecular defects-related to progressive familiar intrahepatic cholestasis &, allowed to differentiate three forms of the disease, accounting for the heterogeneity of the clinical, biochemical, and histological pictures, previously reported &.
Progressive familial intrahepatic cholestasis - type 1 (Byler’s disease), is characterized by early onset and severe itching, high bile acid concentration in the serum and low concentration or absence of bile acids in the bile, normal levels of gamma-glutamyl transpeptidase (GGT) and cholesterol. The defective gene is located on chromosome 18, in the same region as the gene for recurrent benign intrahepatic cholestasis. The gene encodes for a P-type ATP-ase expressed in liver and gut. This may explain some of the extrahepatic features of the disease, such as chronic diarrhea. Different mutations of this gene could cause partial or complete defects in bile acid secretion, leading to the development of benign chronic intrahepatic cholestasis or to progressive familial intrahepatic cholestatsis, respectively.
Progressive familial intrahepatic cholestasis - type 2  (Byler-like disease) is phenotypically similar to type 1 disease. This form is caused by defects in a different gene (SPGP gene), encoding for the human sister P-glycoprotein, located on chromosome 2. The SPGP gene encodes for a protein involved in bile acids transport. In this form GGT levels are normal.
Progressive familial intrahepatic cholestasis - type 3 affects older patients compared to the other two types of the disease, and itching is a less constant feature. Bile acids concentration is high in the serum, but normal in the bile fluid, and GGT levels are increased. Signs of portal hypertension occur more rarely than in the other types. The genetic defect is due to an altered expression of the Multi Drug Resistence 3 gene (MDR3) on chromosome 7, resulting in decreased concentration of bile phospholipids, with subsequent bile epithelium damage.
Byler’s disease evolves with progressive and persistent cholestasis, manifestations of vitamin deficiency, development of end-stage liver disease. Hepatocellular carcinoma may also develop &. The liver histologic picture $ includes early giant cell transformation, proliferation or paucity of bile ducts, fibrosis or biliary cirrhosis. Medical treatment is based on nutritional and vitamin support, symptomatic treatment of pruritus. External biliary diversion has been proposed to control cholestasis &. Ursodeoxycholic acid administration can result in significant improvement in up to 40% of patients, mostly PFIC I and PFIC II patients. Liver transplantation is indicated when external biliary diversion is not effective or for end stage liver disease, and has been performed at several centers with low mortality, improved growth and quality of life.
Another rare form of familial intrahepatic cholestasis for which liver transplantation has been reported is the heriditary cholestasis with lymphedema &.