Progressive familial intrahepatic cholestasis type 3 (PFIC3)

PFIC3 is an autosomal recessive childhood disorder of bile formation in hepatocytes caused by mutations in the ABCB4 gene coding for the phospholipid transporter MDR3, which is expressed in the canalicular membrane of hepatocytes.32,58

PFIC3 results from a mutation in the ABCB4 gene, which codes for a canalicular transporter protein responsible for the bile secretion of phosphatidylcholine. In the absence of phosphatidylcholine, bile becomes excessively detergent. Cholestasis occurs in infants, children, and adults, and may progress to portal hypertension, cholelithiasis and liver failure.4

PFIC3 is generally associated with more moderate pruritus than PFIC1 and PFIC2, and is characterised by a high serum GGT activity.4

Diagnosis32
  • Liver tissue analysis may show cholestasis, portal inflammatory infiltrate, and periportal ductular proliferation accompanied by various stages of fibrosis
  • Bile plugs within bile ducts and fibro-obliterative bile duct lesions can be seen
  • Age at presentation is variable62,63

Diagnosis is confirmed by genetic sequencing of the ABCB4 gene.32,58

Clinical, biochemical and histological features of PFIC1, PFIC2 and PFIC331
FeaturePFIC type 1PFIC type 2PFIC type 3
Age at onsetInfancyNeonatal period-early infancyLate infancy (30%) to early adulthood
End stage liver diseaseFirst decadeRapid, first few years1st to 2nd decade of life
Course of diseaseModerately severeSevereInsidious
PruritusSevereVery severeModerate
Extrahepatic manifestations (watery diarrhoea, pancreatitis, sensorineural deafness, short stature, abnormalities in sweat chloride)PresentAbsentAbsent
Risk of development of liver tumoursLowHighMild increase
Risk of cholesterol stone formationAbsentIncreasedIncreased
Serum ALTMild elevationModerate elevationMild elevation
Serum AFPNormalElevatedNormal
Serum GGTNormalNormalElevated
Serum bile acidsElevated ++Elevated +++Elevated +
Primary bile acidsLow (3–8 mM)Very low ( ‹ 1 mM)Normal
PhospholipidsNormalNormalLow
Liver histologyCholestasis, mild lobular fibrosisCholestasis, giant cell hepatitis, hepatocellular necrosis, lobular fibrosisBile ductular proliferation, cholestasis, portal fibrosis
Electron microscopyGranular bileAmorphous bile -
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4. Protocole national de diagnostic et de soins : Déficits de synthèse des acides biliaires primaires. Centre de Référence Coordonnateur de l’Atrésie des Voies Biliaires et des Cholestases Génétiques; 2019.

31. Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol 2014;4:25-36.

32. Sticova E, Jirsa M, Pawłowska J. New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications. Can J Gastroenterol Hepatol 2018;2018:2313675.

58. Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis 2009;4:1.

62. Davit-Spraul, Anne et al. “The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects.” Seminars in liver disease vol. 30,2 (2010): 134-46.

63. Stättermayer, Albert Friedrich et al. “Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults.” Journal of hepatology vol. 73,3 (2020): 651-663.