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Progressive familial intrahepatic cholestasis type 1(PFIC1)

MedGen UID:
1645830
Concept ID:
C4551898
Disease or Syndrome
Synonyms: ATP8B1-Related Intrahepatic Cholestasis; Byler disease; Byler's disease
SNOMED CT: Byler syndrome (1155913007); PFIC1 - progressive familial intrahepatic cholestasis type 1 (1155913007); Progressive familial intrahepatic cholestasis type 1 (1155913007)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: 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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): ATP8B1 (18q21.31)
 
Monarch Initiative: MONDO:0008892
OMIM®: 211600
Orphanet: ORPHA79306

Definition

The phenotypic spectrum of ATP8B1 deficiency ranges from severe through moderate to mild. Severe ATP8B1 deficiency is characterized by infantile-onset cholestasis that progresses to cirrhosis, hepatic failure, and early death. Although mild-to-moderate ATP8B1 deficiency initially was thought to involve intermittent symptomatic cholestasis with a lack of hepatic fibrosis, it is now known that hepatic fibrosis may be present early in the disease course. Furthermore, in some persons with ATP8B1 deficiency the clinical findings can span the phenotypic spectrum, shifting over time from the mild end of the spectrum (episodic cholestasis) to the severe end of the spectrum (persistent cholestasis). Sensorineural hearing loss (SNHL) is common across the phenotypic spectrum. [from GeneReviews]

Additional description

From OMIM
Progressive familial intrahepatic cholestasis is a heterogeneous group of autosomal recessive liver disorders characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood (Alonso et al., 1994; Whitington et al., 1994; Klomp et al., 2004). Genetic Heterogeneity of Progressive Familial Intrahepatic Cholestasis PFIC is a genetically heterogeneous disorder caused by defects in the transport of bile acids. See also PFIC2 (601847), caused by mutation in a liver-specific ATP-binding cassette transporter gene (ABCB11; 603201) on chromosome 2q24; PFIC3 (602347), caused by mutation in the class III multidrug resistance P-glycoprotein gene (ABCB4; 171060) on chromosome 7q21; PFIC4 (615878), caused by mutation in the TJP2 gene (607709) on chromosome 9q12; PFIC5 (617049), caused by mutation in the NR1H4 gene (603826) on chromosome 12q23; PFIC6 (619484), caused by mutation in the SLC51A gene (612084) on chromosome 3q29; PFIC7 (619658), caused by mutation in the USP53 gene (617431) on chromosome 4q26; PFIC8 (619662), caused by mutation in the KIF12 gene (611278) on chromosome 9q32; PFIC9 (619849), caused by mutation in the ZFYVE19 gene (619635) on chromosome 15q15; PFIC10 (619868), caused by mutation in the MYO5B gene (606540) on chromosome 18q21; PFIC11 (619874), caused by mutation in the SEMA7A gene (607961) on chromosome 15q24; and PFIC12 (620010), caused by mutation in the VPS33B gene (608552) on chromosome 15q26. PFIC1 and PFIC2 are associated with mildly elevated or normal serum levels of gamma-glutamyltransferase (GGT; see 612346), whereas PFIC3 is associated with high serum GGT levels and liver histology that shows portal inflammation and ductular proliferation in an early stage (Maggiore et al., 1987, 1991). PFIC4 is associated with normal or mildly increased GGT levels (Sambrotta et al., 2014). PFIC5 is associated with low to normal GGT levels. PFIC8 and PFIC9 are associated with high GGT levels. There are also several phenotypically similar liver disorders that result from congenital defects in bile acid synthesis. See CBAS1 (607765).  http://www.omim.org/entry/211600

Clinical features

From HPO
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Cholelithiasis
MedGen UID:
3039
Concept ID:
C0008350
Disease or Syndrome
Hard, pebble-like deposits that form within the gallbladder.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream.
Cirrhosis of liver
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Fat malabsorption
MedGen UID:
108215
Concept ID:
C0554103
Pathologic Function
Abnormality of the absorption of fat from the gastrointestinal tract.
Intrahepatic cholestasis with episodic jaundice
MedGen UID:
870571
Concept ID:
C4025019
Disease or Syndrome
Epistaxis
MedGen UID:
4996
Concept ID:
C0014591
Pathologic Function
Epistaxis, or nosebleed, refers to a hemorrhage localized in the nose.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Rickets
MedGen UID:
48470
Concept ID:
C0035579
Disease or Syndrome
Rickets is divided into two major categories including calcipenic and phosphopenic. Hypophosphatemia is described as a common manifestation of both categories. Hypophosphatemic rickets is the most common type of rickets that is characterized by low levels of serum phosphate, resistance to ultraviolet radiation or vitamin D intake. There are several issues involved in hypophosphatemic rickets such as calcium, vitamin D, phosphorus deficiencies. Moreover, other disorder can be associated with its occurrence such as absorption defects due to pancreatic, intestinal, gastric, and renal disorders and hepatobiliary disease. Symptoms are usually seen in childhood and can be varied in severity. Severe forms may be linked to bowing of the legs, poor bone growth, and short stature as well as joint and bone pain. Hypophosphatemic rickets are associated with renal excretion of phosphate, hypophosphatemia, and mineral defects in bones. The familial type of the disease is the most common type of rickets.
Wheezing
MedGen UID:
21917
Concept ID:
C0043144
Sign or Symptom
A high-pitched whistling sound associated with labored breathing.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Conjugated hyperbilirubinemia
MedGen UID:
82787
Concept ID:
C0268307
Disease or Syndrome
Abnormally high level of conjugated bilirubin in the blood.
Pruritus
MedGen UID:
19534
Concept ID:
C0033774
Sign or Symptom
Pruritus is an itch or a sensation that makes a person want to scratch. This term refers to an abnormally increased disposition to experience pruritus.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

Daley J, Halligan K, Howrie D, Salgado CM, Superdock A, Friehling E, Bailey KM
J Pediatr Hematol Oncol 2023 Jul 1;45(5):e621-e623. Epub 2023 Jan 12 doi: 10.1097/MPH.0000000000002623. PMID: 36728269Free PMC Article
van Wessel DBE, Thompson RJ, Gonzales E, Jankowska I, Shneider BL, Sokal E, Grammatikopoulos T, Kadaristiana A, Jacquemin E, Spraul A, Lipiński P, Czubkowski P, Rock N, Shagrani M, Broering D, Algoufi T, Mazhar N, Nicastro E, Kelly D, Nebbia G, Arnell H, Fischler B, Hulscher JBF, Serranti D, Arikan C, Debray D, Lacaille F, Goncalves C, Hierro L, Muñoz Bartolo G, Mozer-Glassberg Y, Azaz A, Brecelj J, Dezsőfi A, Luigi Calvo P, Krebs-Schmitt D, Hartleif S, van der Woerd WL, Wang JS, Li LT, Durmaz Ö, Kerkar N, Hørby Jørgensen M, Fischer R, Jimenez-Rivera C, Alam S, Cananzi M, Laverdure N, Targa Ferreira C, Ordonez F, Wang H, Sency V, Mo Kim K, Chen HL, Carvalho E, Fabre A, Quintero Bernabeu J, Alonso EM, Sokol RJ, Suchy FJ, Loomes KM, McKiernan PJ, Rosenthal P, Turmelle Y, Rao GS, Horslen S, Kamath BM, Rogalidou M, Karnsakul WW, Hansen B, Verkade HJ; Natural Course and Prognosis of PFIC and Effect of Biliary Diversion Consortium
Hepatology 2021 Aug;74(2):892-906. Epub 2021 Jul 13 doi: 10.1002/hep.31787. PMID: 33666275Free PMC Article
Gonzales E, Spraul A, Jacquemin E
Eur J Hum Genet 2014 Apr;22(4) Epub 2013 Aug 28 doi: 10.1038/ejhg.2013.186. PMID: 23982690Free PMC Article

Recent clinical studies

Etiology

Teker Düztaş D, Sarı S, Eğritaş Gürkan Ö, Sözen MH, Dalgıç B, Dalgıç A
Exp Clin Transplant 2022 May;20(Suppl 3):81-84. doi: 10.6002/ect.PediatricSymp2022.O27. PMID: 35570607
Okamoto T, Sonoda M, Ogawa E, Ito S, Togawa T, Hayashi H, Okajima H, Uemoto S
J Pediatr Gastroenterol Nutr 2021 Mar 1;72(3):425-429. doi: 10.1097/MPG.0000000000002983. PMID: 33264179
Kamath BM, Abetz-Webb L, Kennedy C, Hepburn B, Gauthier M, Johnson N, Medendorp S, Dorenbaum A, Todorova L, Shneider BL
Patient 2018 Feb;11(1):69-82. doi: 10.1007/s40271-017-0266-4. PMID: 28710680Free PMC Article
Miyagawa-Hayashino A, Egawa H, Yorifuji T, Hasegawa M, Haga H, Tsuruyama T, Wen MC, Sumazaki R, Manabe T, Uemoto S
Liver Transpl 2009 Jun;15(6):610-8. doi: 10.1002/lt.21686. PMID: 19479804
van Mil SW, Klomp LW, Bull LN, Houwen RH
Semin Liver Dis 2001 Nov;21(4):535-44. doi: 10.1055/s-2001-19034. PMID: 11745041

Diagnosis

Teker Düztaş D, Sarı S, Eğritaş Gürkan Ö, Sözen MH, Dalgıç B, Dalgıç A
Exp Clin Transplant 2022 May;20(Suppl 3):81-84. doi: 10.6002/ect.PediatricSymp2022.O27. PMID: 35570607
Copeland E, Renault N, Renault M, Dyack S, Bulman DE, Bedard K, Otley A, Magee F, Acott P, Greer WL
J Gastroenterol Hepatol 2013 Mar;28(3):560-4. doi: 10.1111/j.1440-1746.2012.07290.x. PMID: 23033845
Paulusma CC, Elferink RP, Jansen PL
Semin Liver Dis 2010 May;30(2):117-24. Epub 2010 Apr 26 doi: 10.1055/s-0030-1253221. PMID: 20422494
Miyagawa-Hayashino A, Egawa H, Yorifuji T, Hasegawa M, Haga H, Tsuruyama T, Wen MC, Sumazaki R, Manabe T, Uemoto S
Liver Transpl 2009 Jun;15(6):610-8. doi: 10.1002/lt.21686. PMID: 19479804
O'Leary JG, Pratt DS
Curr Opin Gastroenterol 2007 May;23(3):232-6. doi: 10.1097/MOG.0b013e3280d942d8. PMID: 17414837

Therapy

Teker Düztaş D, Sarı S, Eğritaş Gürkan Ö, Sözen MH, Dalgıç B, Dalgıç A
Exp Clin Transplant 2022 May;20(Suppl 3):81-84. doi: 10.6002/ect.PediatricSymp2022.O27. PMID: 35570607
Oya Y, Sugawara Y, Honda M, Yoshii D, Isono K, Hayashida S, Yamamoto H, Inomata Y
Transplant Proc 2017 Jun;49(5):1123-1125. doi: 10.1016/j.transproceed.2017.03.035. PMID: 28583540
Hasegawa Y, Hayashi H, Naoi S, Kondou H, Bessho K, Igarashi K, Hanada K, Nakao K, Kimura T, Konishi A, Nagasaka H, Miyoshi Y, Ozono K, Kusuhara H
Orphanet J Rare Dis 2014 Jul 15;9:89. doi: 10.1186/1750-1172-9-89. PMID: 25022842Free PMC Article
O'Leary JG, Pratt DS
Curr Opin Gastroenterol 2007 May;23(3):232-6. doi: 10.1097/MOG.0b013e3280d942d8. PMID: 17414837
Lykavieris P, van Mil S, Cresteil D, Fabre M, Hadchouel M, Klomp L, Bernard O, Jacquemin E
J Hepatol 2003 Sep;39(3):447-52. doi: 10.1016/s0168-8278(03)00286-1. PMID: 12927934

Prognosis

Okamoto T, Sonoda M, Ogawa E, Ito S, Togawa T, Hayashi H, Okajima H, Uemoto S
J Pediatr Gastroenterol Nutr 2021 Mar 1;72(3):425-429. doi: 10.1097/MPG.0000000000002983. PMID: 33264179
Deng BC, Lv S, Cui W, Zhao R, Lu X, Wu J, Liu P
World J Gastroenterol 2012 Nov 28;18(44):6504-9. doi: 10.3748/wjg.v18.i44.6504. PMID: 23197899Free PMC Article
Miyagawa-Hayashino A, Egawa H, Yorifuji T, Hasegawa M, Haga H, Tsuruyama T, Wen MC, Sumazaki R, Manabe T, Uemoto S
Liver Transpl 2009 Jun;15(6):610-8. doi: 10.1002/lt.21686. PMID: 19479804
O'Leary JG, Pratt DS
Curr Opin Gastroenterol 2007 May;23(3):232-6. doi: 10.1097/MOG.0b013e3280d942d8. PMID: 17414837
Chen F, Ananthanarayanan M, Emre S, Neimark E, Bull LN, Knisely AS, Strautnieks SS, Thompson RJ, Magid MS, Gordon R, Balasubramanian N, Suchy FJ, Shneider BL
Gastroenterology 2004 Mar;126(3):756-64. doi: 10.1053/j.gastro.2003.12.013. PMID: 14988830

Clinical prediction guides

Uchida H, Sakamoto S, Komine R, Kodama T, Nakao T, Yanagi Y, Shimizu S, Abbas SH, Fukuda A, Kasahara M
Pediatr Transplant 2023 Sep;27(6):e14566. Epub 2023 Jul 7 doi: 10.1111/petr.14566. PMID: 37417206
Henkel SAF, Salgado CM, Reyes-Mugica M, Soltys KA, Strauss K, Mazariegos GV, Squires RH, McKiernan PJ, Zhang X, Squires JE
Pediatr Transplant 2021 Dec;25(8):e14108. Epub 2021 Aug 2 doi: 10.1111/petr.14108. PMID: 34339082
Okamoto T, Sonoda M, Ogawa E, Ito S, Togawa T, Hayashi H, Okajima H, Uemoto S
J Pediatr Gastroenterol Nutr 2021 Mar 1;72(3):425-429. doi: 10.1097/MPG.0000000000002983. PMID: 33264179
Miyagawa-Hayashino A, Egawa H, Yorifuji T, Hasegawa M, Haga H, Tsuruyama T, Wen MC, Sumazaki R, Manabe T, Uemoto S
Liver Transpl 2009 Jun;15(6):610-8. doi: 10.1002/lt.21686. PMID: 19479804
Chen F, Ananthanarayanan M, Emre S, Neimark E, Bull LN, Knisely AS, Strautnieks SS, Thompson RJ, Magid MS, Gordon R, Balasubramanian N, Suchy FJ, Shneider BL
Gastroenterology 2004 Mar;126(3):756-64. doi: 10.1053/j.gastro.2003.12.013. PMID: 14988830

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