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Benign recurrent intrahepatic cholestasis 2(BRIC2)

MedGen UID:
435857
Concept ID:
C2608083
Disease or Syndrome
Synonyms: BRIC2; Recurrent familial intrahepatic cholestasis 2
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): ABCB11 (2q31.1)
OMIM®: 605479
Orphanet: ORPHA99961

Definition

ATP8B1 deficiency encompasses a phenotypic spectrum ranging from severe to intermediate to mild, based on an individual’s clinical findings and laboratory test results, including liver biopsy. Severe ATP8B1 deficiency is characterized by onset of symptoms of cholestasis (pruritus and attacks of jaundice) within the first few months of life. Secondary manifestations such as coagulopathy (due to vitamin K deficiency), malabsorption, and poor weight gain may present earlier than age three months. Without surgical intervention, cirrhosis and evolution to end-stage hepatic failure and death usually ensue before the third decade. Mild ATP8B1 deficiency is characterized by intermittent episodes of cholestasis manifest as severe pruritus and jaundice; chronic liver damage does not typically develop. In contrast to patients in whom bouts of cholestasis are induced only by particular triggers known to increase risk of cholestasis (drug exposure, shifts in hormonal milieu [including those resulting from ingestion of contraceptive drugs or from pregnancy], coexistent malignancy), some or all bouts of cholestasis in individuals with mild ATP8B1 deficiency have different or unknown triggers. [from GTR]

Additional descriptions

From GeneReviews
ATP8B1 deficiency encompasses a phenotypic spectrum ranging from severe to intermediate to mild, based on an individual’s clinical findings and laboratory test results, including liver biopsy. Severe ATP8B1 deficiency is characterized by onset of symptoms of cholestasis (pruritus and attacks of jaundice) within the first few months of life. Secondary manifestations such as coagulopathy (due to vitamin K deficiency), malabsorption, and poor weight gain may present earlier than age three months. Without surgical intervention, cirrhosis and evolution to end-stage hepatic failure and death usually ensue before the third decade. Mild ATP8B1 deficiency is characterized by intermittent episodes of cholestasis manifest as severe pruritus and jaundice; chronic liver damage does not typically develop. In contrast to patients in whom bouts of cholestasis are induced only by particular triggers known to increase risk of cholestasis (drug exposure, shifts in hormonal milieu [including those resulting from ingestion of contraceptive drugs or from pregnancy], coexistent malignancy), some or all bouts of cholestasis in individuals with mild ATP8B1 deficiency have different or unknown triggers.  https://www.ncbi.nlm.nih.gov/books/NBK1297
From OMIM
Benign recurrent intrahepatic cholestasis is characterized by intermittent episodes of cholestasis without progression to liver failure. The cholestatic attacks vary in severity and duration and patients are asymptomatic between episodes, both clinically and biochemically (van Mil et al., 2004).  http://www.omim.org/entry/605479
From GHR
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.  https://ghr.nlm.nih.gov/condition/benign-recurrent-intrahepatic-cholestasis

Clinical features

Cholelithiasis
MedGen UID:
3039
Concept ID:
C0008350
Disease or Syndrome
Hard, pebble-like deposits that form within the gallbladder.
Intrahepatic cholestasis
MedGen UID:
3042
Concept ID:
C0008372
Disease or Syndrome
Impairment of bile flow due to injury to the HEPATOCYTES; BILE CANALICULI; or the intrahepatic bile ducts (BILE DUCTS, INTRAHEPATIC).
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormal enlargement of the liver.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
A clinical manifestation of HYPERBILIRUBINEMIA, characterized by the yellowish staining of the SKIN; MUCOUS MEMBRANE; and SCLERA. Clinical jaundice usually is a sign of LIVER dysfunction.
Conjugated hyperbilirubinemia
MedGen UID:
82787
Concept ID:
C0268307
Disease or Syndrome
Abnormally high level of conjugated bilirubin in the blood.(NICHD)
Elevated alkaline phosphatase
MedGen UID:
155461
Concept ID:
C0750857
Finding
Abnormally increased serum levels of alkaline phosphatase activity.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
A clinical manifestation of HYPERBILIRUBINEMIA, characterized by the yellowish staining of the SKIN; MUCOUS MEMBRANE; and SCLERA. Clinical jaundice usually is a sign of LIVER dysfunction.
Pruritus
MedGen UID:
19534
Concept ID:
C0033774
Sign or Symptom
A skin disorder characterized by an intense itching sensation.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVBenign recurrent intrahepatic cholestasis 2
Follow this link to review classifications for Benign recurrent intrahepatic cholestasis 2 in Orphanet.

Recent clinical studies

Etiology

Squires JE, Celik N, Morris A, Soltys K, Mazariegos G, Shneider B, Squires RH
J Pediatr Gastroenterol Nutr 2017 Mar;64(3):425-430. doi: 10.1097/MPG.0000000000001493. PMID: 28045770
Togawa T, Sugiura T, Ito K, Endo T, Aoyama K, Ohashi K, Negishi Y, Kudo T, Ito R, Kikuchi A, Arai-Ichinoi N, Kure S, Saitoh S
J Pediatr 2016 Apr;171:171-7.e1-4. Epub 2016 Feb 5 doi: 10.1016/j.jpeds.2016.01.006. PMID: 26858187
Giovannoni I, Callea F, Bellacchio E, Torre G, De Ville De Goyet J, Francalanci P
PLoS One 2015;10(12):e0145021. Epub 2015 Dec 17 doi: 10.1371/journal.pone.0145021. PMID: 26678486Free PMC Article
Beauséjour Y, Alvarez F, Beaulieu M, Bilodeau M
Can J Gastroenterol 2011 Jun;25(6):311-4. PMID: 21766090Free PMC Article
Cavestro GM, Frulloni L, Cerati E, Ribeiro LA, Corrente V, Sianesi M, Franzè A, Di Mario F
Acta Biomed 2002;73(3-4):53-6. PMID: 12596388

Diagnosis

Squires JE, Celik N, Morris A, Soltys K, Mazariegos G, Shneider B, Squires RH
J Pediatr Gastroenterol Nutr 2017 Mar;64(3):425-430. doi: 10.1097/MPG.0000000000001493. PMID: 28045770
Togawa T, Sugiura T, Ito K, Endo T, Aoyama K, Ohashi K, Negishi Y, Kudo T, Ito R, Kikuchi A, Arai-Ichinoi N, Kure S, Saitoh S
J Pediatr 2016 Apr;171:171-7.e1-4. Epub 2016 Feb 5 doi: 10.1016/j.jpeds.2016.01.006. PMID: 26858187
Giovannoni I, Callea F, Bellacchio E, Torre G, De Ville De Goyet J, Francalanci P
PLoS One 2015;10(12):e0145021. Epub 2015 Dec 17 doi: 10.1371/journal.pone.0145021. PMID: 26678486Free PMC Article
Beauséjour Y, Alvarez F, Beaulieu M, Bilodeau M
Can J Gastroenterol 2011 Jun;25(6):311-4. PMID: 21766090Free PMC Article
van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW, van de Graaf SF, Houwen RH
Best Pract Res Clin Gastroenterol 2010 Oct;24(5):541-53. doi: 10.1016/j.bpg.2010.07.010. PMID: 20955958

Therapy

El Sherrif Y, Potts JR, Howard MR, Barnardo A, Cairns S, Knisely AS, Verma S
Liver Int 2013 Sep;33(8):1266-70. Epub 2013 Jun 10 doi: 10.1111/liv.12216. PMID: 23750872
Mizuochi T, Kimura A, Tanaka A, Muto A, Nittono H, Seki Y, Takahashi T, Kurosawa T, Kage M, Takikawa H, Matsuishi T
Clin Chim Acta 2012 Aug 16;413(15-16):1301-4. Epub 2012 Apr 14 doi: 10.1016/j.cca.2012.04.011. PMID: 22525741
van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW, van de Graaf SF, Houwen RH
Best Pract Res Clin Gastroenterol 2010 Oct;24(5):541-53. doi: 10.1016/j.bpg.2010.07.010. PMID: 20955958
Ermis F, Oncu K, Ozel M, Yazgan Y, Gurbuz AK, Demirturk L, Demirci H, Akyol T, Hahoglu A
Ann Hepatol 2010 Apr-Jun;9(2):207-10. PMID: 20526019
Chen HL, Liu YJ, Su YN, Wang NY, Wu SH, Ni YH, Hsu HY, Wu TC, Chang MH
J Pediatr 2008 Dec;153(6):825-32. Epub 2008 Aug 9 doi: 10.1016/j.jpeds.2008.06.034. PMID: 18692205

Prognosis

Squires JE, Celik N, Morris A, Soltys K, Mazariegos G, Shneider B, Squires RH
J Pediatr Gastroenterol Nutr 2017 Mar;64(3):425-430. doi: 10.1097/MPG.0000000000001493. PMID: 28045770
Beauséjour Y, Alvarez F, Beaulieu M, Bilodeau M
Can J Gastroenterol 2011 Jun;25(6):311-4. PMID: 21766090Free PMC Article
Chen ST, Chen HL, Su YN, Liu YJ, Ni YH, Hsu HY, Chu CS, Wang NY, Chang MH
J Gastroenterol Hepatol 2008 Sep;23(9):1390-3. doi: 10.1111/j.1440-1746.2008.05432.x. PMID: 18853996
Mezey E, Burns C, Burdick JF, Braine HG
Am J Gastroenterol 2002 Feb;97(2):475-7. doi: 10.1111/j.1572-0241.2002.05458.x. PMID: 11866291
al Drees K, al Zaben A, al Amir A, Abdulla A
Ann Trop Paediatr 1999 Jun;19(2):215-7. PMID: 10690264

Clinical prediction guides

Squires JE, Celik N, Morris A, Soltys K, Mazariegos G, Shneider B, Squires RH
J Pediatr Gastroenterol Nutr 2017 Mar;64(3):425-430. doi: 10.1097/MPG.0000000000001493. PMID: 28045770
Beauséjour Y, Alvarez F, Beaulieu M, Bilodeau M
Can J Gastroenterol 2011 Jun;25(6):311-4. PMID: 21766090Free PMC Article
Lam P, Soroka CJ, Boyer JL
Semin Liver Dis 2010 May;30(2):125-33. Epub 2010 Apr 26 doi: 10.1055/s-0030-1253222. PMID: 20422495Free PMC Article
Nagasaka H, Chiba H, Hui SP, Takikawa H, Miida T, Takayanagi M, Yorifuji T, Hasegawa M, Ota A, Hirano K, Kikuchi H, Tsukahara H, Kobayashi K
J Pediatr Gastroenterol Nutr 2007 Jul;45(1):96-105. doi: 10.1097/MPG.0b013e3180331df9. PMID: 17592371
van Mil SW, van der Woerd WL, van der Brugge G, Sturm E, Jansen PL, Bull LN, van den Berg IE, Berger R, Houwen RH, Klomp LW
Gastroenterology 2004 Aug;127(2):379-84. PMID: 15300568

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