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Benign recurrent intrahepatic cholestasis
Benign recurrent intrahepatic cholestasis (BRIC) is a hereditary liver disorder characterized by intermittent episodes of intrahepatic cholestasis, generally without progression to chronic liver damage. BRIC is now believed to belong to a clinical spectrum of intrahepatic cholestatic disorders that ranges from the mild intermittent attacks in BRIC to the severe, chronic and progressive cholestasis seen in progressive familial intrahepatic cholestasis (PFIC; see this term).
ORPHA:65682Classification level: Disorder
The prevalence of BRIC is unknown.
The first cholestatic episode can occur at any age but onset within the first two decades of life is most common. Patients present with bouts of intense pruritus and jaundice that may last for several weeks or months before resolving spontaneously. Associated manifestations include fatigue, loss of appetite, dark urine and pale stools. Hepatomegaly is also a common finding. Between episodes patients show no symptoms and the interval between attacks varies from months to years. The factors triggering the onset of the cholestasis remain unclear but viral infections, pregnancy and oral contraceptives have all been implicated. Two forms of BRIC have been described (BRIC1 and BRIC2) (see these terms). Clinically, these forms are very similar; however, patients with BRIC1 can display extrahepatic features such as hearing loss, pancreatitis and diarrhea, whereas cholelithiasis is a common manifestation of BRIC2. Patients with BRIC2 also have an increased risk for hepatobiliary malignancy.
BRIC1 is allelic to PFIC1 (see this term) and is caused by mutations in the ATP8B1 gene (18q21) encoding a P-type ATPase expressed at the canalicular membrane of hepatocytes as well as in other epithelia. BRIC2 is allelic to PFIC2 (see this term) and is caused by mutations in the ABCB11 gene (2q24) encoding the liver-specific bile salt export pump (BSEP). The disease-causing mutations in BRIC are generally missense mutations.
Diagnosis is based on the clinical history (at least 2-3 episodes of cholestasis), serum biochemistry (low to normal serum gamma GT activity and cholesterol, elevated serum total bile acids and high levels of conjugated bilirubin during episodes), cholangiography (showing normal intra- and extrahepatic bile ducts), liver histology (revealing intrahepatic cholestasis with normal liver structure) and immunohistochemical analysis (absent or reduced BSEP staining in majority of BRIC2 patients). Molecular genetic testing confirms the diagnosis and discriminates between subtypes.
Differential diagnoses include drug-induced cholestatic disease as well as intrahepatic cholestasis of pregnancy, primary biliary cirrhosis and primary sclerosing cholangitis (see these terms). BRIC can be differentiated from PFIC on the basis of the disease course and liver histology.
Prenatal testing is available for families in which the disease-causing mutations have already been identified.
Both BRIC1 and BRIC2 are inherited in an autosomal recessive manner, although a BRIC family with seemingly autosomal dominant inheritance has been reported.
Management and treatment
Management is mainly symptomatic: rifampicin and cholestyramine can be used to reduce pruritus and to induce remission of a cholestatic episode in some patients. Plasmapheresis/MARS (Molecular Adsorbents Recirculation System) has also been shown to be of benefit in some cases. For individuals that are unresponsive to medical therapy, endoscopic nasobiliary drainage is generally effective. Partial external biliary diversion is also used to improve quality of life and prevent disease progression. Liver transplantation may eventually be indicated for patients with frequent and severe episodes.
The prognosis is generally good with a tendency for a reduction in the frequency of attacks with age. However, progression from BRIC to PFIC and cirrhosis has been reported in the literature, indicative of a clinical continuum.