Cholestasis, or impaired bile flow, is an important but poorly understood manifestation of liver disease. Two clinically distinct forms of inherited cholestasis, benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis type 1 (PFIC1), were previously mapped to 18q21. Haplotype analysis narrowed the candidate region for both diseases to the same interval of less than 1 cM, in which we identified a gene mutated in BRIC and PFIC1 patients. This gene (called FIC1) is the first identified human member of a recently described subfamily of P-type ATPases; ATP-dependent aminophospholipid transport is the previously described function of members of this subfamily. FIC1 is expressed in several epithelial tissues and, surprisingly, more strongly in small intestine than in liver. Its protein product is likely to play an essential role in enterohepatic circulation of bile acids; further characterization of FIC1 will facilitate understanding of normal bile formation and cholestasis.

A patient with t_ype I congenital nonhemolytic jaundice (type I Crigler-Najjar syndrome (CNJ)), who first developed overt neurologic sig& at age 18, is reported.Studies with isotopic bilirubin, performed both when she was well and after the onset of brain damage, demonstrated normal hepatic bilirubin uptake and storage capacity, and normal bilirubin turnover (3.0 mg/kg/24 hr). As a result of a virtual absence of conjugation, net bilirubin clearance was reduced to 0.0075 ml/min/kg, which is approximately 1 % of normal (0.G5 =t 0.18 ml/min/kg) . Therapy with glutethimide, phenobarbital, blue light, and oral agar were all ineffective in reducing the concentration of unconjugated bilirubin in plasma or accelerating radiobilirubin disappearance.The acute onset of neurologic disease occurred at age 18, and may possibly have related to a transient increase in the molar bilirubin to albumin ratio to a value greater than 1.0. Exchange plasmapheresis, performed with a continuous flow centrifuge, rapidly reduced the bilirubin concentration in plasma from 41 to 6 mg/100 ml, and was associated with apparent clinical improvement. A total of 1,900 mg bilirubin was removed by this procedure.Although in vivo phototherapy was ineffective, in vitro illumination of the patient's plasma with special blue lamps produced a rapid fall in the bilirubin concentration in plasma. Bilirubin was converted to polar, diazo-negative derivatives by a process in which several steps could be distinguished. The initial photodegradation products were colored, tightly albumin bound and nondialyzable, which explained their tendency to be excreted in the bile in preference to the urine. Continued illumination for up to 24 hr resulted in the production of colorless, nonalbumin-bound compounds which, when injected into rats, were excreted principally in the urine.