Progressive familial intrahepatic cholestasis type 3 (PFIC3) infant

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

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

Clinical, biochemical and histological features of PFIC1, PFIC2 and PFIC3³¹

Feature	PFIC type 1	PFIC type 2	PFIC type 3
Age at onset	Infancy	Neonatal period-early infancy	Late infancy (30%) to early adulthood
End stage liver disease	First decade	Rapid, first few years	1^st to 2^nd decade of life
Course of disease	Moderately severe	Severe	Insidious
Pruritus	Severe	Very severe	Moderate
Extrahepatic manifestations (watery diarrhoea, pancreatitis, sensorineural deafness, short stature, abnormalities in sweat chloride)	Present	Absent	Absent
Risk of development of liver tumours	Low	High	Mild increase
Risk of cholesterol stone formation	Absent	Increased	Increased
Serum ALT	Mild elevation	Moderate elevation	Mild elevation
Serum AFP	Normal	Elevated	Normal
Serum GGT	Normal	Normal	Elevated
Serum bile acids	Elevated ++	Elevated +++	Elevated +
Primary bile acids	Low (3–8 mM)	Very low ( ‹ 1 mM)	Normal
Phospholipids	Normal	Normal	Low
Liver histology	Cholestasis, mild lobular fibrosis	Cholestasis, giant cell hepatitis, hepatocellular necrosis, lobular fibrosis	Bile ductular proliferation, cholestasis, portal fibrosis
Electron microscopy	Granular bile	Amorphous bile	-

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.