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Cholestasis, progressive familial intrahepatic, 12(PFIC12)

MedGen UID:
1824084
•Concept ID:
C5774311
•
Disease or Syndrome
Synonyms: CHOLESTASIS, ISOLATED LOW-GGT; PFIC12
 
Gene (location): VPS33B (15q26.1)
 
Monarch Initiative: MONDO:0031040
OMIM®: 620010

Definition

Progressive familial intrahepatic cholestasis-12 (PFIC12) is characterized by neonatal-onset jaundice and conjugated hyperbilirubinemia, associated with intense pruritus. Transaminases are mildly elevated but GGT (see 612346) is normal. Hepatosplenomegaly and mildly prolonged activated partial thromboplastin time (APTT) have been observed in some patients (Qiu et al., 2019). [from OMIM]

Clinical features

From HPO
Proteinuria
MedGen UID:
10976
•Concept ID:
C0033687
•
Finding
Increased levels of protein in the urine.
See: Feature record | Search on this feature
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).
See: Feature record | Search on this feature
Cholestasis
MedGen UID:
925
•Concept ID:
C0008370
•
Disease or Syndrome
Impairment of bile flow due to obstruction in bile ducts.
See: Feature record | Search on this feature
Hepatomegaly
MedGen UID:
42428
•Concept ID:
C0019209
•
Finding
Abnormally increased size of the liver.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
Prolonged partial thromboplastin time
MedGen UID:
66815
•Concept ID:
C0240671
•
Finding
Increased time to coagulation in the partial thromboplastin time (PTT) test, a measure of the intrinsic and common coagulation pathways. Phospholipid, and activator, and calcium are mixed into an anticoagulated plasma sample, and the time is measured until a thrombus forms.
See: Feature record | Search on this feature
Splenomegaly
MedGen UID:
52469
•Concept ID:
C0038002
•
Finding
Abnormal increased size of the spleen.
See: Feature record | Search on this feature
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
•Concept ID:
C0151904
•
Finding
The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal.
See: Feature record | Search on this feature
Elevated circulating alanine aminotransferase concentration
MedGen UID:
57740
•Concept ID:
C0151905
•
Finding
An abnormally high concentration in the circulation of alanine aminotransferase (ALT).
See: Feature record | Search on this feature
Conjugated hyperbilirubinemia
MedGen UID:
82787
•Concept ID:
C0268307
•
Disease or Syndrome
Abnormally high level of conjugated bilirubin in the blood.
See: Feature record | Search on this feature
Hyperbilirubinemia
MedGen UID:
86321
•Concept ID:
C0311468
•
Finding
An increased amount of bilirubin in the blood.
See: Feature record | Search on this feature
Increased serum bile acid concentration
MedGen UID:
868605
•Concept ID:
C4023004
•
Finding
An increase in the concentration of bile acid in the blood.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
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Professional guidelines

PubMed

Diagnosis and management of Alagille and progressive familial intrahepatic cholestasis.
Cheng K, Rosenthal P
Hepatol Commun 2023 Dec 1;7(12) Epub 2023 Dec 7 doi: 10.1097/HC9.0000000000000314. PMID: 38055640Free PMC Article
Single-center experience in management of progressive familial intrahepatic cholestasis.
Varol Fİ, Selimoğlu MA, Güngör Ş, Yılmaz S, Tekedereli İ
Arab J Gastroenterol 2021 Dec;22(4):310-315. Epub 2021 Nov 25 doi: 10.1016/j.ajg.2021.05.021. PMID: 34840097
ABCB11 deficiency presenting as transient neonatal cholestasis: Correlation with genotypes and BSEP expression.
Li LT, Li ZD, Yang Y, Lu Y, Xie XB, Chen L, Feng JY, Knisely AS, Wang JS
Liver Int 2020 Nov;40(11):2788-2796. Epub 2020 Oct 13 doi: 10.1111/liv.14642. PMID: 32808743

Recent clinical studies

Etiology

Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
Miethke AG, Moukarzel A, Porta G, Covarrubias Esquer J, Czubkowski P, Ordonez F, Mosca A, Aqul AA, Squires RH, Sokal E, D'Agostino D, Baumann U, D'Antiga L, Kasi N, Laborde N, Arikan C, Lin CH, Gilmour S, Mittal N, Chiou FK, Horslen SP, Huber WD, Jaecklin T, Nunes T, Lascau A, Longpre L, Mogul DB, Garner W, Vig P, Hupertz VF, Gonzalez-Peralta RP, Ekong U, Hartley J, Laverdure N, Ovchinsky N, Thompson RJ
Lancet Gastroenterol Hepatol 2024 Jul;9(7):620-631. Epub 2024 May 6 doi: 10.1016/S2468-1253(24)00080-3. PMID: 38723644
Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial.
Thompson RJ, Arnell H, Artan R, Baumann U, Calvo PL, Czubkowski P, Dalgic B, D'Antiga L, Durmaz Ö, Fischler B, Gonzalès E, Grammatikopoulos T, Gupte G, Hardikar W, Houwen RHJ, Kamath BM, Karpen SJ, Kjems L, Lacaille F, Lachaux A, Lainka E, Mack CL, Mattsson JP, McKiernan P, Özen H, Rajwal SR, Roquelaure B, Shagrani M, Shteyer E, Soufi N, Sturm E, Tessier ME, Verkade HJ, Horn P
Lancet Gastroenterol Hepatol 2022 Sep;7(9):830-842. Epub 2022 Jul 1 doi: 10.1016/S2468-1253(22)00093-0. PMID: 35780807
Epidemiology and burden of progressive familial intrahepatic cholestasis: a systematic review.
Jones-Hughes T, Campbell J, Crathorne L
Orphanet J Rare Dis 2021 Jun 3;16(1):255. doi: 10.1186/s13023-021-01884-4. PMID: 34082807Free PMC Article
Systematic review of progressive familial intrahepatic cholestasis.
Baker A, Kerkar N, Todorova L, Kamath BM, Houwen RHJ
Clin Res Hepatol Gastroenterol 2019 Feb;43(1):20-36. Epub 2018 Sep 17 doi: 10.1016/j.clinre.2018.07.010. PMID: 30236549
Progressive familial intrahepatic cholestasis (PFIC) type 1, 2, and 3: a review of the liver pathology findings.
Morotti RA, Suchy FJ, Magid MS
Semin Liver Dis 2011 Feb;31(1):3-10. Epub 2011 Feb 22 doi: 10.1055/s-0031-1272831. PMID: 21344347

Diagnosis

Diagnosis and management of Alagille and progressive familial intrahepatic cholestasis.
Cheng K, Rosenthal P
Hepatol Commun 2023 Dec 1;7(12) Epub 2023 Dec 7 doi: 10.1097/HC9.0000000000000314. PMID: 38055640Free PMC Article
Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial.
Thompson RJ, Arnell H, Artan R, Baumann U, Calvo PL, Czubkowski P, Dalgic B, D'Antiga L, Durmaz Ö, Fischler B, Gonzalès E, Grammatikopoulos T, Gupte G, Hardikar W, Houwen RHJ, Kamath BM, Karpen SJ, Kjems L, Lacaille F, Lachaux A, Lainka E, Mack CL, Mattsson JP, McKiernan P, Özen H, Rajwal SR, Roquelaure B, Shagrani M, Shteyer E, Soufi N, Sturm E, Tessier ME, Verkade HJ, Horn P
Lancet Gastroenterol Hepatol 2022 Sep;7(9):830-842. Epub 2022 Jul 1 doi: 10.1016/S2468-1253(22)00093-0. PMID: 35780807
Systematic review of progressive familial intrahepatic cholestasis.
Baker A, Kerkar N, Todorova L, Kamath BM, Houwen RHJ
Clin Res Hepatol Gastroenterol 2019 Feb;43(1):20-36. Epub 2018 Sep 17 doi: 10.1016/j.clinre.2018.07.010. PMID: 30236549
Progressive familial intrahepatic cholestasis and inborn errors of bile acid synthesis.
Jankowska I, Socha P
Clin Res Hepatol Gastroenterol 2012 Jun;36(3):271-4. Epub 2012 May 18 doi: 10.1016/j.clinre.2012.03.020. PMID: 22609295
Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy.
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

Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
Miethke AG, Moukarzel A, Porta G, Covarrubias Esquer J, Czubkowski P, Ordonez F, Mosca A, Aqul AA, Squires RH, Sokal E, D'Agostino D, Baumann U, D'Antiga L, Kasi N, Laborde N, Arikan C, Lin CH, Gilmour S, Mittal N, Chiou FK, Horslen SP, Huber WD, Jaecklin T, Nunes T, Lascau A, Longpre L, Mogul DB, Garner W, Vig P, Hupertz VF, Gonzalez-Peralta RP, Ekong U, Hartley J, Laverdure N, Ovchinsky N, Thompson RJ
Lancet Gastroenterol Hepatol 2024 Jul;9(7):620-631. Epub 2024 May 6 doi: 10.1016/S2468-1253(24)00080-3. PMID: 38723644
Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial.
Thompson RJ, Arnell H, Artan R, Baumann U, Calvo PL, Czubkowski P, Dalgic B, D'Antiga L, Durmaz Ö, Fischler B, Gonzalès E, Grammatikopoulos T, Gupte G, Hardikar W, Houwen RHJ, Kamath BM, Karpen SJ, Kjems L, Lacaille F, Lachaux A, Lainka E, Mack CL, Mattsson JP, McKiernan P, Özen H, Rajwal SR, Roquelaure B, Shagrani M, Shteyer E, Soufi N, Sturm E, Tessier ME, Verkade HJ, Horn P
Lancet Gastroenterol Hepatol 2022 Sep;7(9):830-842. Epub 2022 Jul 1 doi: 10.1016/S2468-1253(22)00093-0. PMID: 35780807
Systematic review of progressive familial intrahepatic cholestasis.
Baker A, Kerkar N, Todorova L, Kamath BM, Houwen RHJ
Clin Res Hepatol Gastroenterol 2019 Feb;43(1):20-36. Epub 2018 Sep 17 doi: 10.1016/j.clinre.2018.07.010. PMID: 30236549
Progressive familial intrahepatic cholestasis and inborn errors of bile acid synthesis.
Jankowska I, Socha P
Clin Res Hepatol Gastroenterol 2012 Jun;36(3):271-4. Epub 2012 May 18 doi: 10.1016/j.clinre.2012.03.020. PMID: 22609295
Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy.
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

Prognosis

Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
Miethke AG, Moukarzel A, Porta G, Covarrubias Esquer J, Czubkowski P, Ordonez F, Mosca A, Aqul AA, Squires RH, Sokal E, D'Agostino D, Baumann U, D'Antiga L, Kasi N, Laborde N, Arikan C, Lin CH, Gilmour S, Mittal N, Chiou FK, Horslen SP, Huber WD, Jaecklin T, Nunes T, Lascau A, Longpre L, Mogul DB, Garner W, Vig P, Hupertz VF, Gonzalez-Peralta RP, Ekong U, Hartley J, Laverdure N, Ovchinsky N, Thompson RJ
Lancet Gastroenterol Hepatol 2024 Jul;9(7):620-631. Epub 2024 May 6 doi: 10.1016/S2468-1253(24)00080-3. PMID: 38723644
Epidemiology and burden of progressive familial intrahepatic cholestasis: a systematic review.
Jones-Hughes T, Campbell J, Crathorne L
Orphanet J Rare Dis 2021 Jun 3;16(1):255. doi: 10.1186/s13023-021-01884-4. PMID: 34082807Free PMC Article
Systematic review of progressive familial intrahepatic cholestasis.
Baker A, Kerkar N, Todorova L, Kamath BM, Houwen RHJ
Clin Res Hepatol Gastroenterol 2019 Feb;43(1):20-36. Epub 2018 Sep 17 doi: 10.1016/j.clinre.2018.07.010. PMID: 30236549
Genetic variants in adult liver diseases.
Dröge C, Häussinger D, Keitel V
Z Gastroenterol 2015 Dec;53(12):1436-46. Epub 2015 Dec 14 doi: 10.1055/s-0035-1566903. PMID: 26666282
Progressive familial intrahepatic cholestasis (PFIC) type 1, 2, and 3: a review of the liver pathology findings.
Morotti RA, Suchy FJ, Magid MS
Semin Liver Dis 2011 Feb;31(1):3-10. Epub 2011 Feb 22 doi: 10.1055/s-0031-1272831. PMID: 21344347

Clinical prediction guides

Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
Miethke AG, Moukarzel A, Porta G, Covarrubias Esquer J, Czubkowski P, Ordonez F, Mosca A, Aqul AA, Squires RH, Sokal E, D'Agostino D, Baumann U, D'Antiga L, Kasi N, Laborde N, Arikan C, Lin CH, Gilmour S, Mittal N, Chiou FK, Horslen SP, Huber WD, Jaecklin T, Nunes T, Lascau A, Longpre L, Mogul DB, Garner W, Vig P, Hupertz VF, Gonzalez-Peralta RP, Ekong U, Hartley J, Laverdure N, Ovchinsky N, Thompson RJ
Lancet Gastroenterol Hepatol 2024 Jul;9(7):620-631. Epub 2024 May 6 doi: 10.1016/S2468-1253(24)00080-3. PMID: 38723644
Outcomes of pediatric liver transplantation for progressive familial intrahepatic cholestasis.
Vasudevan AK, Shanmugam N, Rammohan A, Valamparampil JJ, Rinaldhy K, Menon J, Thambithurai R, Namasivayam S, Kaliamoorthy I, Rela M
Pediatr Transplant 2023 Dec;27(8):e14600. Epub 2023 Sep 7 doi: 10.1111/petr.14600. PMID: 37675889
Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial.
Thompson RJ, Arnell H, Artan R, Baumann U, Calvo PL, Czubkowski P, Dalgic B, D'Antiga L, Durmaz Ö, Fischler B, Gonzalès E, Grammatikopoulos T, Gupte G, Hardikar W, Houwen RHJ, Kamath BM, Karpen SJ, Kjems L, Lacaille F, Lachaux A, Lainka E, Mack CL, Mattsson JP, McKiernan P, Özen H, Rajwal SR, Roquelaure B, Shagrani M, Shteyer E, Soufi N, Sturm E, Tessier ME, Verkade HJ, Horn P
Lancet Gastroenterol Hepatol 2022 Sep;7(9):830-842. Epub 2022 Jul 1 doi: 10.1016/S2468-1253(22)00093-0. PMID: 35780807
Single-center experience in management of progressive familial intrahepatic cholestasis.
Varol Fİ, Selimoğlu MA, Güngör Ş, Yılmaz S, Tekedereli İ
Arab J Gastroenterol 2021 Dec;22(4):310-315. Epub 2021 Nov 25 doi: 10.1016/j.ajg.2021.05.021. PMID: 34840097
Epidemiology and burden of progressive familial intrahepatic cholestasis: a systematic review.
Jones-Hughes T, Campbell J, Crathorne L
Orphanet J Rare Dis 2021 Jun 3;16(1):255. doi: 10.1186/s13023-021-01884-4. PMID: 34082807Free PMC Article

Recent systematic reviews

Epidemiology and burden of progressive familial intrahepatic cholestasis: a systematic review.
Jones-Hughes T, Campbell J, Crathorne L
Orphanet J Rare Dis 2021 Jun 3;16(1):255. doi: 10.1186/s13023-021-01884-4. PMID: 34082807Free PMC Article
Systematic review of progressive familial intrahepatic cholestasis.
Baker A, Kerkar N, Todorova L, Kamath BM, Houwen RHJ
Clin Res Hepatol Gastroenterol 2019 Feb;43(1):20-36. Epub 2018 Sep 17 doi: 10.1016/j.clinre.2018.07.010. PMID: 30236549

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