Alternative titles; symbols
ORPHA: 65682, 99960; DO: 0070231;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18q21.31 | Cholestasis, benign recurrent intrahepatic | 243300 | Autosomal recessive | 3 | ATP8B1 | 602397 |
A number sign (#) is used with this entry because benign recurrent intrahepatic cholestasis-1 (BRIC1) is caused by homozygous or compound heterozygous mutation in the ATP8B1 gene (602397) on chromosome 18q. Some patients may have a heterozygous mutation.
Progressive familial intrahepatic cholestasis-1 (PFIC1; 211600) and intrahepatic cholestasis of pregnancy-1 (ICP1; 147480) are allelic disorders.
Benign recurrent intrahepatic cholestasis is characterized by intermittent episodes of cholestasis without extrahepatic bile duct obstruction. There is initial elevation of serum bile acids, followed by cholestatic jaundice which generally spontaneously resolves after periods of weeks to months (Summerskill and Walshe, 1959; Schapiro and Isselbacher, 1963; Brenard et al., 1989).
Tygstrup et al. (1999) stated that referring to this disorder as 'benign' is a misnomer, because the disease has an impact on the quality of life in some patients. They preferred the term 'recurrent familial intrahepatic cholestasis.'
Genetic Heterogeneity of Benign Recurrent Intrahepatic Cholestasis
See also BRIC2 (605479), caused by mutation in the ABCB11 gene (603201) on chromosome 2q24.
Summerskill and Walshe (1959) reported 2 unrelated patients with recurrent intrahepatic cholestasis. Kuhn (1963) described 2 teenaged brothers who had repeated attacks of jaundice accompanied by itching and hepatomegaly. Progression to biliary cirrhosis was suspected in one.
Tygstrup (1960) described the condition in 2 distantly related 15-year-old boys living in a small village in the Faroe Islands. Onset in these patients was in the first 2 years of life. Cholestasis was demonstrated by liver biopsy and direct cholangiography. Tygstrup and Jensen (1969) described intermittent intrahepatic cholestasis in 5 young males from the Faroe Islands. The disorder was characterized by recurrent attacks of pruritus and jaundice. During disease-free intervals, which lasted for months or years, no clinical or biochemical indication of cholestasis was found. Tygstrup et al. (1999) reported a follow-up 30 years later on the 5 patients in the original report and described 5 additional patients from the Faroe Islands. Progression to chronic liver disease had not occurred. The episodes of cholestasis tended to reduce in frequency with age. The youngest patient, aged 25 years, who had had 16 episodes lasting about 6 months each, had a liver transplant after which no further episodes were recorded 1 year after surgery.
Minuk and Shaffer (1987) studied a man who developed severe pruritus followed by jaundice and thereafter had 5 episodes, each of 3 or 4 months' duration, during the next 8 years. A brother and sister also had episodes of pruritus followed by jaundice.
De Koning et al. (1995) provided full pedigree and clinical information on a large kindred with BRIC reported by Houwen et al. (1994). Four patients in 3 distantly related sibships, all with consanguineous parents, were described. Affected children first developed pruritus and icterus at ages ranging from 2 to 8 months. Cholestatic jaundice disappeared clinically and biochemically after 6 to 9 months, but subsequent episodes occurred. None of the obligatory carriers of the BRIC gene experienced signs of the disease. Four patients observed were from a population estimated to number 10,000 descended from the inhabitants of a small village founded in the middle ages, indicating a high carrier frequency.
Nagasaka et al. (2004) reported 2 unrelated patients with PFIC1 and BRIC1 confirmed by the finding of mutations in the ATP8B1 gene. Both patients had short stature, decreased bone mineral density, and episodic hypocalcemia as a result of resistance to parathyroid hormone (PTH; 168450). Detailed biochemical analysis of both patients showed that calcium and phosphorus levels were decreased and increased, respectively, with increasing serum total bilirubin levels. The findings corresponded clinically to pseudohypoparathyroidism type II, in which cAMP response to PTH infusion is normal.
In 3 distantly related patients with BRIC, Houwen et al. (1994) used linkage disequilibrium (LD) mapping (Lander and Botstein, 1986) to assign the BRIC gene to chromosome 18. Identification of an extended haplotype conserved between patients confirmed the results. Houwen et al. (1994) suggested that this was the first example of the use of LD mapping for assignment of a locus that had not previously been mapped. The authors made a distinction between linkage disequilibrium and other methods, notably homozygosity mapping (HM). HM had been used to map autosomal recessive loci in selected candidate regions, but its efficiency for full genome screening was unknown. In contrast, the search for shared segments treats each chromosome separately and thus is feasible for dominant as well as recessive disorders.
In 14 affected families, Sinke et al. (1997) narrowed the candidate BRIC disease region to a 7-cM interval between markers D18S69 and D18S64 on chromosome 18q21.
Genetic Heterogeneity
One of the families with BRIC studied by Sinke et al. (1997) showed no linkage to the 18q21 region, consistent with previous reports of genetic heterogeneity in this disorder.
Floreani et al. (2000) studied an Italian family in which 7 of 19 members studied had benign recurrent intrahepatic cholestasis. Both males and females were affected in 2 successive generations and in 4 separate sibships with male-to-male transmission, suggesting autosomal dominant inheritance. Linkage studies excluded 18q and 2q24 where autosomal recessive BRIC1 and BRIC2 have been mapped, indicating genetic heterogeneity.
In patients with BRIC1, Bull et al. (1998) identified mutations in the ATP8B1 gene (602397.0006; 602397.0007). Most had homozygous or compound heterozygous mutations; some only had a heterozygous mutation.
In the patients with BRIC from the Faroe Islands originally reported by Tygstrup (1960), Tygstrup et al. (1999) identified a founder mutation in the ATP8B1 gene (I661T; 602397.0006).
Infusion of BRIC serum into rats and radiotracer studies led Minuk and Shaffer (1987) to conclude that BRIC is not mediated by a circulating cholestatic agent, but rather is secondary to an intrinsic abnormality in hepatocyte bile salt secretion.
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Brenard, R., Geubel, A. P., Benhamou, J. P. Benign recurrent intrahepatic cholestasis: a report of 26 cases. J. Clin. Gastroent. 11: 546-551, 1989. [PubMed: 2794432] [Full Text: https://doi.org/10.1097/00004836-198910000-00011]
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De Koning, T. J., Sandkuijl, L. A., De Schryver, J. E. A. R., Hennekam, E. A. M., Beemer, F. A., Houwen, R. H. J. Autosomal-recessive inheritance of benign recurrent intrahepatic cholestasis. Am. J. Med. Genet. 57: 479-482, 1995. [PubMed: 7677155] [Full Text: https://doi.org/10.1002/ajmg.1320570324]
Floreani, A., Molaro, M., Mottes, M., Sangalli, A., Baragiotta, A., Roda, A., Naccarato, R., Clementi, M. Autosomal dominant benign recurrent intrahepatic cholestasis (BRIC) unlinked to 18q21 and 2q24. Am. J. Med. Genet. 95: 450-453, 2000. [PubMed: 11146465] [Full Text: https://doi.org/10.1002/1096-8628(20001218)95:5<450::aid-ajmg8>3.0.co;2-v]
Houwen, R. H. J., Baharloo, S., Blankenship, K., Raeymaekers, P., Juyn, J., Sandkuijl, L. A., Freimer, N. B. Genome screening by searching for shared segments: mapping a gene for benign recurrent intrahepatic cholestasis. Nature Genet. 8: 380-386, 1994. [PubMed: 7894490] [Full Text: https://doi.org/10.1038/ng1294-380]
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Nagasaka, H., Yorifuji, T., Kosugiyama, K., Egawa, H., Kawai, M., Murayama, K., Hasegawa, M., Sumazaki, R., Tsubaki, J., Kikuta, H., Matsui, A., Tanaka, K., Matsuura, N., Kobayashi, K. Resistance to parathyroid hormone in two patients with familial intrahepatic cholestasis: possible involvement of the ATP8B1 gene in calcium regulation via parathyroid hormone. J. Pediat. Gastroent. Nutr. 39: 404-409, 2004. [PubMed: 15448432] [Full Text: https://doi.org/10.1097/00005176-200410000-00018]
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Sinke, R. J., Carlton, V. E. H., Juijn, J. A., Delhaas, T., Bull, L., van Berge Henegouwen, G. P., van Hattum, J., Keller, K. M., Sinaasappel, M., Bijleveld, C. M. A, Knol, I. E., Ploos van Amstel, H.-K., Pearson, P. L., Berger, R., Freimer, N. B., Houwen, R. H. J. Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64. Hum. Genet. 100: 382-387, 1997. [PubMed: 9272159] [Full Text: https://doi.org/10.1007/s004390050520]
Summerskill, W. H. J., Walshe, J. M. Benign recurrent intrahepatic 'obstructive' jaundice. Lancet 274: 686-690, 1959. Note: Originally Volume 2. [PubMed: 13835689] [Full Text: https://doi.org/10.1016/s0140-6736(59)92128-2]
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Tygstrup, N., Jensen, B. Intermittent intrahepatic cholestasis of unknown etiology in five young males from the Faroe Islands. Acta Med. Scand. 185: 523-530, 1969. [PubMed: 5807632] [Full Text: https://doi.org/10.1111/j.0954-6820.1969.tb07378.x]
Tygstrup, N., Steig, B. A., Juijn, J. A., Bull, L. N., Houwen, R. H. J. Recurrent familial intrahepatic cholestasis in the Faeroe Islands: phenotypic heterogeneity but genetic homogeneity. Hepatology 29: 506-508, 1999. [PubMed: 9918928] [Full Text: https://doi.org/10.1002/hep.510290214]