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Progressive familial intrahepatic cholestasis type 2(PFIC2)

MedGen UID:
483742
Concept ID:
C3489789
Disease or Syndrome
Synonyms: Cholestasis, progressive familial intrahepatic 2; PFIC2 Progressive familial intrahepatic cholestasis type 2; Progressive familial intrahepatic cholestasis 2
SNOMED CT: Progressive familial intrahepatic cholestasis type 2 (1155841005); PFIC2 - progressive familial intrahepatic cholestasis type 2 (1155841005); BSEP (bile salt export pump) deficiency (1155841005)
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): ABCB11 (2q31.1)
 
Monarch Initiative: MONDO:0011156
OMIM®: 601847
Orphanet: ORPHA79304

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 descriptions

From OMIM
Progressive familial intrahepatic cholestasis-2 (PFIC2) is an autosomal recessive disorder characterized by progressive liver disease with impairment of bile flow, but without hepatobiliary structural abnormality. Patients have amorphous or finely filamentous bile and nonspecific giant cell hepatitis on presentation (summary by Strautnieks et al., 1998). For a phenotypic description and a discussion of genetic heterogeneity of progressive familial intrahepatic cholestasis, see PFIC1 (211600).  http://www.omim.org/entry/601847
From MedlinePlus Genetics
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.

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).

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.

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.

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.

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.  https://medlineplus.gov/genetics/condition/progressive-familial-intrahepatic-cholestasis

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.
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.
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.
Hepatocellular carcinoma
MedGen UID:
389187
Concept ID:
C2239176
Neoplastic Process
Hepatocellular carcinoma is the major histologic type of malignant primary liver neoplasm. It is the fifth most common cancer and the third most common cause of death from cancer worldwide. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Hepatoblastomas comprise 1 to 2% of all malignant neoplasms of childhood, most often occurring in children under 3 years of age. Hepatoblastomas are thought to be derived from undifferentiated hepatocytes (Taniguchi et al., 2002).
Intermittent jaundice
MedGen UID:
871317
Concept ID:
C4025805
Pathologic Function
Jaundice that is sometimes present, sometimes not.
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.
Elevated circulating alkaline phosphatase concentration
MedGen UID:
727252
Concept ID:
C1314665
Finding
Abnormally increased serum levels of alkaline phosphatase activity.
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

Sohail MI, Dönmez-Cakil Y, Szöllősi D, Stockner T, Chiba P
Int J Mol Sci 2021 Jan 14;22(2) doi: 10.3390/ijms22020784. PMID: 33466755Free PMC Article
Mitra S, Das A, Thapa B, Kumar Vasishta R
Fetal Pediatr Pathol 2020 Apr;39(2):107-123. Epub 2019 Jul 23 doi: 10.1080/15513815.2019.1641860. PMID: 31335238
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

Recent clinical studies

Etiology

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Orphanet J Rare Dis 2024 Feb 10;19(1):57. doi: 10.1186/s13023-024-03080-6. PMID: 38341604Free PMC Article
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Hepatology 2015 Aug;62(2):558-66. Epub 2015 Apr 8 doi: 10.1002/hep.27767. PMID: 25716872
Finsterer J, Frank M
Curr Top Med Chem 2013;13(18):2386-94. doi: 10.2174/15680266113136660166. PMID: 24059459

Diagnosis

Kondou H, Nakano S, Mizuno T, Bessho K, Hasegawa Y, Nakazawa A, Tanikawa K, Azuma Y, Okamoto T, Inui A, Imagawa K, Kasahara M, Zen Y, Suzuki M, Hayashi H
Orphanet J Rare Dis 2024 Feb 10;19(1):57. doi: 10.1186/s13023-024-03080-6. PMID: 38341604Free PMC Article
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Transplant Proc 2022 Jun;54(5):1370-1375. Epub 2022 Jun 17 doi: 10.1016/j.transproceed.2022.04.007. PMID: 35718560
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Fetal Pediatr Pathol 2022 Apr;41(2):293-298. Epub 2020 Jun 29 doi: 10.1080/15513815.2020.1783405. PMID: 32597698
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J Gastroenterol Hepatol 2008 Sep;23(9):1390-3. doi: 10.1111/j.1440-1746.2008.05432.x. PMID: 18853996

Therapy

Romeres SGB, Trevizoli NC, Oliveira CAM, Obeid EJ, Arantes Ferreira GS, De Campos PB, Ullmann RFB, Rocha HC, Figueira AVF, Diaz LGG, Jorge FMF, Caja GON, Watanabe ALC, Sobroza de Mello E, Carvalho E
Transplant Proc 2022 Jun;54(5):1370-1375. Epub 2022 Jun 17 doi: 10.1016/j.transproceed.2022.04.007. PMID: 35718560
Zheng Y, Zhou C, Zheng B, Hu G, Wang C, Zhou W, Lu Y, Zhang Z, Lin Q, Guo H, Jin Y, Liu Z, Tang W
Dig Liver Dis 2022 Nov;54(11):1541-1547. Epub 2022 Apr 27 doi: 10.1016/j.dld.2022.04.002. PMID: 35490150
Sohail MI, Dönmez-Cakil Y, Szöllősi D, Stockner T, Chiba P
Int J Mol Sci 2021 Jan 14;22(2) doi: 10.3390/ijms22020784. PMID: 33466755Free PMC Article
Varma S, Revencu N, Stephenne X, Scheers I, Smets F, Beleza-Meireles A, Reding R, Roskams T, Sokal EM
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Prognosis

Kondou H, Nakano S, Mizuno T, Bessho K, Hasegawa Y, Nakazawa A, Tanikawa K, Azuma Y, Okamoto T, Inui A, Imagawa K, Kasahara M, Zen Y, Suzuki M, Hayashi H
Orphanet J Rare Dis 2024 Feb 10;19(1):57. doi: 10.1186/s13023-024-03080-6. PMID: 38341604Free PMC Article
Varma S, Revencu N, Stephenne X, Scheers I, Smets F, Beleza-Meireles A, Reding R, Roskams T, Sokal EM
Hepatology 2015 Jul;62(1):198-206. Epub 2015 May 12 doi: 10.1002/hep.27834. PMID: 25847299
Gonzales E, Grosse B, Schuller B, Davit-Spraul A, Conti F, Guettier C, Cassio D, Jacquemin E
Hepatology 2015 Aug;62(2):558-66. Epub 2015 Apr 8 doi: 10.1002/hep.27767. PMID: 25716872
Kis E, Ioja E, Rajnai Z, Jani M, Méhn D, Herédi-Szabó K, Krajcsi P
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Am J Surg Pathol 2011 May;35(5):687-96. doi: 10.1097/PAS.0b013e318212ec87. PMID: 21490445Free PMC Article

Clinical prediction guides

Dong Y, Wang J, Zhu S, Zheng H, Wang C, Zhao P
Pediatr Res 2021 Jan;89(1):238-245. Epub 2020 Apr 12 doi: 10.1038/s41390-020-0888-4. PMID: 32289814
Gonzales E, Grosse B, Schuller B, Davit-Spraul A, Conti F, Guettier C, Cassio D, Jacquemin E
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Kis E, Ioja E, Rajnai Z, Jani M, Méhn D, Herédi-Szabó K, Krajcsi P
Toxicol In Vitro 2012 Dec;26(8):1294-9. Epub 2011 Nov 18 doi: 10.1016/j.tiv.2011.11.002. PMID: 22120137
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
Dhawan A, Mitry RR, Hughes RD
J Inherit Metab Dis 2006 Apr-Jun;29(2-3):431-5. doi: 10.1007/s10545-006-0245-8. PMID: 16763914

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