Benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis (BRIC) is characterized by episodes of liver dysfunction called cholestasis. During these episodes, the liver cells have a reduced ability to release a digestive fluid called bile. Because the problems with bile release occur within the liver (intrahepatic), the condition is described as intrahepatic cholestasis. Episodes of cholestasis can last from weeks to months, and the time between episodes, during which there are usually no symptoms, can vary from weeks to years.

The first episode of cholestasis usually occurs in an affected person's teens or twenties. An attack typically begins with severe itchiness (pruritus), followed by yellowing of the skin and whites of the eyes (jaundice) a few weeks later. Other general signs and symptoms that occur during these episodes include a vague feeling of discomfort (malaise), irritability, nausea, vomiting, and a lack of appetite. A common feature of BRIC is the reduced absorption of fat in the body, which leads to excess fat in the feces (steatorrhea). Because of a lack of fat absorption and loss of appetite, affected individuals often lose weight during episodes of cholestasis.

BRIC is divided into two types, BRIC1 and BRIC2, based on the genetic cause of the condition. The signs and symptoms are the same in both types.

This condition is called benign because it does not cause lasting damage to the liver. However, episodes of liver dysfunction occasionally develop into a more severe, permanent form of liver disease known as progressive familial intrahepatic cholestasis (PFIC). BRIC and PFIC are sometimes considered to be part of a spectrum of intrahepatic cholestasis disorders of varying severity.

BRIC is a rare disorder. Although the prevalence is unknown, this condition is less common than the related disorder PFIC, which affects approximately 1 in 50,000 to 100,000 people worldwide.

Mutations in the ATP8B1 gene cause benign recurrent intrahepatic cholestasis type 1 (BRIC1), and mutations in the ABCB11 gene cause benign recurrent intrahepatic cholestasis type 2 (BRIC2). These two genes are involved in the release (secretion) of bile, a fluid produced by the liver that helps digest fats.

The ATP8B1 gene provides instructions for making a protein that helps to control the distribution of certain fats, called lipids, in the membranes of liver cells. This function likely plays a role in maintaining an appropriate balance of bile acids, a component of bile. This process, known as bile acid homeostasis, is critical for the normal secretion of bile and the proper functioning of liver cells. Although the mechanism is unclear, mutations in the ATP8B1 gene result in the buildup of bile acids in liver cells. The imbalance of bile acids leads to the signs and symptoms of BRIC1.

The ABCB11 gene provides instructions for making a protein called the bile salt export pump (BSEP). This protein is found in the liver, and its main role is to move bile salts (a component of bile) out of liver cells. Mutations in the ABCB11 gene result in a reduction of BSEP function. This reduction leads to a decrease of bile salt secretion, which causes the features of BRIC2.

The factors that trigger episodes of BRIC are unknown.

Some people with BRIC do not have a mutation in the ATP8B1 or ABCB11 gene. In these individuals, the cause of the condition is unknown.

Genetic Testing Information

• Genetic Testing Registry: Benign recurrent intrahepatic cholestasis type 2

Genetic and Rare Diseases Information Center

• Benign recurrent intrahepatic cholestasis type 1
• Benign recurrent intrahepatic cholestasis type 2

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• CHOLESTASIS, BENIGN RECURRENT INTRAHEPATIC, 1; BRIC1
• CHOLESTASIS, BENIGN RECURRENT INTRAHEPATIC, 2; BRIC2

Scientific Articles on PubMed

• PubMed

• Folmer DE, van der Mark VA, Ho-Mok KS, Oude Elferink RP, Paulusma CC. Differential effects of progressive familial intrahepatic cholestasis type 1 and benign recurrent intrahepatic cholestasis type 1 mutations on canalicular localization of ATP8B1. Hepatology. 2009 Nov;50(5):1597-605. doi: 10.1002/hep.23158. Citation on PubMed
• Kagawa T, Watanabe N, Mochizuki K, Numari A, Ikeno Y, Itoh J, Tanaka H, Arias IM, Mine T. Phenotypic differences in PFIC2 and BRIC2 correlate with protein stability of mutant Bsep and impaired taurocholate secretion in MDCK II cells. Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G58-67. doi: 10.1152/ajpgi.00367.2007. Epub 2007 Oct 18. Citation on PubMed
• Klomp LW, Vargas JC, van Mil SW, Pawlikowska L, Strautnieks SS, van Eijk MJ, Juijn JA, Pabon-Pena C, Smith LB, DeYoung JA, Byrne JA, Gombert J, van der Brugge G, Berger R, Jankowska I, Pawlowska J, Villa E, Knisely AS, Thompson RJ, Freimer NB, Houwen RH, Bull LN. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology. 2004 Jul;40(1):27-38. doi: 10.1002/hep.20285. Citation on PubMed
• Lam P, Pearson CL, Soroka CJ, Xu S, Mennone A, Boyer JL. Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases. Am J Physiol Cell Physiol. 2007 Nov;293(5):C1709-16. doi: 10.1152/ajpcell.00327.2007. Epub 2007 Sep 13. Citation on PubMed
• Luketic VA, Shiffman ML. Benign recurrent intrahepatic cholestasis. Clin Liver Dis. 2004 Feb;8(1):133-49, vii. doi: 10.1016/S1089-3261(03)00133-8. Citation on PubMed