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Progressive familial intrahepatic cholestasis type 3(PFIC3)

MedGen UID:
356333
Concept ID:
C1865643
Disease or Syndrome
Synonyms: Low Gamma-GT Familial Intrahepatic Cholestasis; MDR3 deficiency; Progressive familial intrahepatic cholestasis with elevated serum gamma-glutamyltransferase
SNOMED CT: Progressive familial intrahepatic cholestasis type 3 (1186865008)
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): ABCB4 (7q21.12)
Related genes: ABCB11, ATP8B1
 
Monarch Initiative: MONDO:0011214
OMIM®: 602347
Orphanet: ORPHA79305

Definition

The signs and symptoms of PFIC2 are typically related to liver disease only; however, these signs and symptoms tend to be more severe than those experienced by people with PFIC1. People with PFIC2 often develop liver failure within the first few years of life. Additionally, affected individuals are at increased risk of developing a type of liver cancer called hepatocellular carcinoma.

In addition to signs and symptoms related to liver disease, people with PFIC1 may have short stature, deafness, diarrhea, inflammation of the pancreas (pancreatitis), and low levels of fat-soluble vitamins (vitamins A, D, E, and K) in the blood. Affected individuals typically develop liver failure before adulthood.

Most people with PFIC3 have signs and symptoms related to liver disease only. Signs and symptoms of PFIC3 usually do not appear until later in infancy or early childhood; rarely, people are diagnosed in early adulthood. Liver failure can occur in childhood or adulthood in people with PFIC3.

There are three known types of PFIC: PFIC1, PFIC2, and PFIC3. The types are also sometimes described as shortages of particular proteins needed for normal liver function. Each type has a different genetic cause.

Signs and symptoms of PFIC typically begin in infancy and are related to bile buildup and liver disease. Specifically, affected individuals experience severe itching, yellowing of the skin and whites of the eyes (jaundice), failure to gain weight and grow at the expected rate (failure to thrive), high blood pressure in the vein that supplies blood to the liver (portal hypertension), and an enlarged liver and spleen (hepatosplenomegaly).

Progressive familial intrahepatic cholestasis (PFIC) is a disorder that causes progressive liver disease, which typically leads to liver failure. In people with PFIC, liver cells are less able to secrete a digestive fluid called bile. The buildup of bile in liver cells causes liver disease in affected individuals. [from MedlinePlus Genetics]

Clinical features

From HPO
Ascites
MedGen UID:
416
Concept ID:
C0003962
Disease or Syndrome
Accumulation of fluid in the peritoneal cavity.
Intrahepatic cholestasis
MedGen UID:
3042
Concept ID:
C0008372
Disease or Syndrome
Impairment of bile flow due to obstruction in the small bile ducts within the liver.
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.
Bile duct proliferation
MedGen UID:
120603
Concept ID:
C0267818
Disease or Syndrome
Proliferative changes of the bile ducts.
Portal inflammation
MedGen UID:
412612
Concept ID:
C2748698
Pathologic Function
Infiltration of portal fields by inflammatory cells.
Malabsorption
MedGen UID:
811453
Concept ID:
C3714745
Finding
Impaired ability to absorb one or more nutrients from the intestine.
Portal fibrosis
MedGen UID:
893107
Concept ID:
C3805083
Disease or Syndrome
Fibroblast proliferation and fiber expansion from the portal areas to the lobule.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Increased serum bile acid concentration
MedGen UID:
868605
Concept ID:
C4023004
Finding
An increase in the concentration of bile acid in the blood.
Elevated gamma-glutamyltransferase level
MedGen UID:
1370086
Concept ID:
C4476869
Finding
Increased level of the enzyme gamma-glutamyltransferase (GGT). GGT is mainly present in kidney, liver, and pancreatic cells, but small amounts are present in other tissues.
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  
Follow this link to review classifications for Progressive familial intrahepatic cholestasis type 3 in Orphanet.

Professional guidelines

PubMed

Wang S, Liu Q, Sun X, Wei W, Ding L, Zhao X
Sci Rep 2024 Nov 9;14(1):27381. doi: 10.1038/s41598-024-79123-6. PMID: 39521930Free PMC Article
Nicastro E, Di Giorgio A, Marchetti D, Barboni C, Cereda A, Iascone M, D'Antiga L
J Pediatr 2019 Aug;211:54-62.e4. Epub 2019 May 31 doi: 10.1016/j.jpeds.2019.04.016. PMID: 31160058
Gonzales E, Spraul A, Jacquemin E
Eur J Hum Genet 2014 Apr;22(4) Epub 2013 Sep 4 doi: 10.1038/ejhg.2013.188. PMID: 24002166Free PMC Article

Recent clinical studies

Etiology

Blázquez-García I, Guerrero L, Cacho-Navas C, Djouder N, Millan J, Paradela A, Carmona-Rodríguez L, Corrales FJ
J Proteome Res 2024 Apr 5;23(4):1433-1442. Epub 2024 Mar 15 doi: 10.1021/acs.jproteome.3c00900. PMID: 38488493Free PMC Article
Guerrero L, Carmona-Rodríguez L, Santos FM, Ciordia S, Stark L, Hierro L, Pérez-Montero P, Vicent D, Corrales FJ
Biofactors 2024 Jul-Aug;50(4):794-809. Epub 2024 Jan 29 doi: 10.1002/biof.2041. PMID: 38284625
Qiao F, Ren F, Lu W, Yang H, Mo G, Wang S, Liu L, Xu X
BMC Med Genomics 2023 Jul 25;16(1):171. doi: 10.1186/s12920-023-01602-y. PMID: 37488596Free PMC Article
Lipiński P, Ciara E, Jurkiewicz D, Płoski R, Wawrzynowicz-Syczewska M, Pawłowska J, Jankowska I
Ann Hepatol 2021 Nov-Dec;25:100342. Epub 2021 Mar 20 doi: 10.1016/j.aohep.2021.100342. PMID: 33757843
Sira MM, Taha M, Sira AM
Eur J Gastroenterol Hepatol 2014 Nov;26(11):1300-5. doi: 10.1097/MEG.0000000000000198. PMID: 25171020

Diagnosis

Wang S, Liu Q, Sun X, Wei W, Ding L, Zhao X
Sci Rep 2024 Nov 9;14(1):27381. doi: 10.1038/s41598-024-79123-6. PMID: 39521930Free PMC Article
Chen R, Yang FX, Tan YF, Deng M, Li H, Xu Y, Ouyang WX, Song YZ
Orphanet J Rare Dis 2022 Dec 22;17(1):445. doi: 10.1186/s13023-022-02597-y. PMID: 36550572Free PMC Article
Stättermayer AF, Halilbasic E, Wrba F, Ferenci P, Trauner M
J Hepatol 2020 Sep;73(3):651-663. Epub 2020 May 4 doi: 10.1016/j.jhep.2020.04.036. PMID: 32376413
Zhang BP, Huang ZH, Dong C
Medicine (Baltimore) 2019 May;98(19):e15593. doi: 10.1097/MD.0000000000015593. PMID: 31083246Free PMC Article
Tan YW, Ji HL, Lu ZH, Ge GH, Sun L, Zhou XB, Sheng JH, Gong YH
World J Gastroenterol 2018 Nov 7;24(41):4716-4720. doi: 10.3748/wjg.v24.i41.4716. PMID: 30416319Free PMC Article

Therapy

Chen R, Yang FX, Tan YF, Deng M, Li H, Xu Y, Ouyang WX, Song YZ
Orphanet J Rare Dis 2022 Dec 22;17(1):445. doi: 10.1186/s13023-022-02597-y. PMID: 36550572Free PMC Article
Stättermayer AF, Halilbasic E, Wrba F, Ferenci P, Trauner M
J Hepatol 2020 Sep;73(3):651-663. Epub 2020 May 4 doi: 10.1016/j.jhep.2020.04.036. PMID: 32376413
Sticova E, Jirsa M
Ann Hepatol 2020 Mar-Apr;19(2):126-133. Epub 2019 Oct 31 doi: 10.1016/j.aohep.2019.09.010. PMID: 31759867
Weber ND, Odriozola L, Martínez-García J, Ferrer V, Douar A, Bénichou B, González-Aseguinolaza G, Smerdou C
Nat Commun 2019 Dec 13;10(1):5694. doi: 10.1038/s41467-019-13614-3. PMID: 31836711Free PMC Article
De Masi R, Orlando S, De Donno A
Ann Clin Transl Neurol 2019 Nov;6(11):2347-2350. Epub 2019 Sep 30 doi: 10.1002/acn3.50883. PMID: 31568708Free PMC Article

Prognosis

Guerrero L, Carmona-Rodríguez L, Santos FM, Ciordia S, Stark L, Hierro L, Pérez-Montero P, Vicent D, Corrales FJ
Biofactors 2024 Jul-Aug;50(4):794-809. Epub 2024 Jan 29 doi: 10.1002/biof.2041. PMID: 38284625
Qiao F, Ren F, Lu W, Yang H, Mo G, Wang S, Liu L, Xu X
BMC Med Genomics 2023 Jul 25;16(1):171. doi: 10.1186/s12920-023-01602-y. PMID: 37488596Free PMC Article
Chen R, Yang FX, Tan YF, Deng M, Li H, Xu Y, Ouyang WX, Song YZ
Orphanet J Rare Dis 2022 Dec 22;17(1):445. doi: 10.1186/s13023-022-02597-y. PMID: 36550572Free PMC Article
Lipiński P, Ciara E, Jurkiewicz D, Płoski R, Wawrzynowicz-Syczewska M, Pawłowska J, Jankowska I
Ann Hepatol 2021 Nov-Dec;25:100342. Epub 2021 Mar 20 doi: 10.1016/j.aohep.2021.100342. PMID: 33757843
Colombo C, Vajro P, Degiorgio D, Coviello DA, Costantino L, Tornillo L, Motta V, Consonni D, Maggiore G; SIGENP Study Group for Genetic Cholestasis
J Pediatr Gastroenterol Nutr 2011 Jan;52(1):73-83. doi: 10.1097/MPG.0b013e3181f50363. PMID: 21119540

Clinical prediction guides

Wang S, Liu Q, Sun X, Wei W, Ding L, Zhao X
Sci Rep 2024 Nov 9;14(1):27381. doi: 10.1038/s41598-024-79123-6. PMID: 39521930Free PMC Article
Qiao F, Ren F, Lu W, Yang H, Mo G, Wang S, Liu L, Xu X
BMC Med Genomics 2023 Jul 25;16(1):171. doi: 10.1186/s12920-023-01602-y. PMID: 37488596Free PMC Article
Chen R, Yang FX, Tan YF, Deng M, Li H, Xu Y, Ouyang WX, Song YZ
Orphanet J Rare Dis 2022 Dec 22;17(1):445. doi: 10.1186/s13023-022-02597-y. PMID: 36550572Free PMC Article
Saleem K, Cui Q, Zaib T, Zhu S, Qin Q, Wang Y, Dam J, Ji W, Liu P, Jia X, Wu J, Bai J, Fu S, Sun W
Dis Markers 2020;2020:6292818. Epub 2020 Jun 15 doi: 10.1155/2020/6292818. PMID: 32626542Free PMC Article
Colombo C, Vajro P, Degiorgio D, Coviello DA, Costantino L, Tornillo L, Motta V, Consonni D, Maggiore G; SIGENP Study Group for Genetic Cholestasis
J Pediatr Gastroenterol Nutr 2011 Jan;52(1):73-83. doi: 10.1097/MPG.0b013e3181f50363. PMID: 21119540

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