Progressive familial intrahepatic cholestasis type 1 (PFIC1)

PFIC1 is an autosomal recessive childhood bile formation disorder of hepatocellular origin associated with extrahepatic features.31

Initially, PFIC1 was referred to as Byler’s disease.32 It is caused by a mutation in the ATP8B1 gene encoding the FIC-1 protein, the role of which is still unclear, but which directly affects the transport of aminophospholipids and indirectly affects the transport of bile acids into bile4,58 The prevalence of progressive familial intrahepatic cholestasis varies between 1 in 50,000 and 1 in 100,000 births. PFIC1 is less common than PFIC2 and PFIC3.3

The clinical features of PFIC1 appear mostly during infancy. Cholestasis (discoloured stools, dark urine) usually appears in the first months of life with recurrent or permanent jaundice associated with hepatomegaly and severe pruritus. Patients usually develop fibrosis and end-stage liver disease before adulthood. Because the expression of the gene is not limited to the liver, extrahepatic features may be present and include short stature, persistent watery diarrhoea, pancreatitis and sensorineural deafness.4,31,32

PFIC1 should be suspected in children with a clinical history of cholestasis and presenting with normal serum -GGT activity and high serum bile acid concentration after exclusion of the other main causes of cholestasis.32

Diagnosis is confirmed by genetic sequencing of the ATP8B1 gene32,58

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
Liver histologyCholestasis, mild lobular fibrosisCholestasis, giant cell hepatitis, hepatocellular necrosis, lobular fibrosisBile ductular proliferation, cholestasis, portal fibrosis
Electron microscopyGranular bileAmorphous bile -

3. INSERM. Orphanet. European Union: The portal for rare diseases and orphan drugs. 2021 (accessed 09/2021 at

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.