Gastroenterol Res

Gastroenterology Research, ISSN 1918-2805 print, 1918-2813 online, Open Access

Article copyright, the authors; Journal compilation copyright, Gastroenterol Res and Elmer Press Inc

Journal website http://www.gastrores.org

Review

Volume 7, Number 2, April 2014, pages 39-43

A Comprehensive Review of Progressive Familial Intrahepatic Cholestasis (PFIC): Genetic Disorders of Hepatocanalicular Transporters

**Table 1.** Characteristic Features of the Three Types of Progressive Familial Intrahepatic Cholestasis
	PFIC 1	PFIC 2	PFIC 3
BSEP: bile salt export protein; MDR3: multidrug resistance protein; GGTL: gamma glutamyl transpeptidase; ALT: alkaline tranferase; AFP: alpha fetoprotein.
Inheritance	Autosomal recessive	Autosomal recessive	Autosomal recessive
Age of onset	Neonates	Neonates	1 month - 20 years
Gene	ATP8B1/F1C1	ABCB11/BSEP	ABCB4/MDR3
Chromosome	18q21-q22	2q24	7q21
Function of hereditary defect	Aminophospholipid translocase	Bile acid secretion	Phosphatidylcholine secretion
Cholestasis	Chronic	Chronic	Chronic
Pruritus	Severe	Severe	Moderate
Serum GGT	Normal	Normal	High
Serum ALT	Mildly elevated	> 5 × normal	> 5 × normal
Serum AFP	Normal	elevated	Normal
Serum primary bile acid (PBA) concentration	Very high	Very high	High
Lipoprotein X	Present	Present	Absent
Albumin	Low	Usually normal	Normal
Hepatocyte location	Canalicular membrane	Canalicular membrane	Canalicular membrane
Other sites of expression	CholangiocytesPancreasIntestines	None	None
Functional defect	ATP dependent aminophospholipid transport	ATP dependent bile acid transport in bile	ATP dependent phosphatidylcholine translocation in bile
Liver biopsy
Histology	Minimal giant cell transformation, intracanalicular cholestasis, no ductal proliferation, minimal inflammation Late fibrosis	Giant cell transformation, intracanalicular cholestasis, no ductular proliferation, moderate inflammation, fibrosis	Giant cell transformation, intracanalicular cholestatis, ductular proliferation, moderate inflammation, marked fibrosis
Electron microscopy	Coarsely granular bile Loss of microvilli, swollen microvilli	Amorphous filamentous bile Loss of microvilli	Presence of cholesterol crystals Loss of microvilli
Immunohistochemistry	BSEP positive	BSEP negative	BSEP positive
	MDR3 positive	MDR3 positive	MDR3 negative
	GGT negative	GGT negative to weakly positive	GGT positive

Table 1. Characteristic Features of the Three Types of Progressive Familial Intrahepatic Cholestasis

PFIC 1

PFIC 2

PFIC 3

BSEP: bile salt export protein; MDR3: multidrug resistance protein; GGTL: gamma glutamyl transpeptidase; ALT: alkaline tranferase; AFP: alpha fetoprotein.

Inheritance

Autosomal recessive

Age of onset

Neonates

1 month - 20 years

Gene

ATP8B1/F1C1

ABCB11/BSEP

ABCB4/MDR3

Chromosome

18q21-q22

2q24

7q21

Function of hereditary defect

Aminophospholipid translocase

Bile acid secretion

Phosphatidylcholine secretion

Cholestasis

Chronic

Pruritus

Severe

Moderate

Serum GGT

Normal

High

Serum ALT

Mildly elevated

> 5 × normal

Serum AFP

Normal

elevated

Normal

Serum primary bile acid (PBA) concentration

Very high

High

Lipoprotein X

Present

Absent

Albumin

Low

Usually normal

Normal

Hepatocyte location

Canalicular membrane

Other sites of expression

CholangiocytesPancreasIntestines

None

Functional defect

ATP dependent aminophospholipid transport

ATP dependent bile acid transport in bile

ATP dependent phosphatidylcholine translocation in bile

Liver biopsy

Histology

Minimal giant cell transformation, intracanalicular cholestasis, no ductal proliferation, minimal inflammation Late fibrosis

Giant cell transformation, intracanalicular cholestasis, no ductular proliferation, moderate inflammation, fibrosis

Giant cell transformation, intracanalicular cholestatis, ductular proliferation, moderate inflammation, marked fibrosis

Electron microscopy

Coarsely granular bile Loss of microvilli, swollen microvilli

Amorphous filamentous bile Loss of microvilli

Presence of cholesterol crystals Loss of microvilli

Immunohistochemistry

BSEP positive

BSEP negative

BSEP positive

MDR3 positive

MDR3 negative

GGT negative

GGT negative to weakly positive

GGT positive

**Table 2.** Differential Diagnosis of PFIC
A) Disorders of bile acid synthesis biosynthesis and conjugation
i) 3-oxo-4-steroid 5-reductase deficiency
ii) 3 -hydroxy-5-C27-steroid dehydrogenase/isomerase deficiency
iii) Oxysterol 7-hydroxylase deficiency
iv) Bile acid-CoA: amino-acid N-acyltransferase deficiency (familial hypercholanemia)
B) Disorders of embryogenesis
i) Alagille syndrome (jagged 1 defect, syndromic bile duct paucity)
ii) Ductal plate malformation (autosomal recessive polycystic kidney disease, autosomal dominant polycystic liver disease, Caroli’s disease)
C) Trafficking and canalicular targeting defects
i) Arthrogryposis, renal dysfunction, cholestasis
D) Tight, junction defects
i) Neonatal ichthyosis sclerosing cholangitis
ii) Familial Amish hypercholanemia
E) Miscellaneous
i) Aagenaes syndrome ( hereditary cholestasis with lymphedema)
ii) North American Indian Childhood Cirrhosis

Table 2. Differential Diagnosis of PFIC

A) Disorders of bile acid synthesis biosynthesis and conjugation

i) 3-oxo-4-steroid 5-reductase deficiency

ii) 3 -hydroxy-5-C27-steroid dehydrogenase/isomerase deficiency

iii) Oxysterol 7-hydroxylase deficiency

iv) Bile acid-CoA: amino-acid N-acyltransferase deficiency (familial hypercholanemia)

B) Disorders of embryogenesis

i) Alagille syndrome (jagged 1 defect, syndromic bile duct paucity)

ii) Ductal plate malformation (autosomal recessive polycystic kidney disease, autosomal dominant polycystic liver disease, Caroli’s disease)

C) Trafficking and canalicular targeting defects

i) Arthrogryposis, renal dysfunction, cholestasis

D) Tight, junction defects

i) Neonatal ichthyosis sclerosing cholangitis

ii) Familial Amish hypercholanemia

E) Miscellaneous

i) Aagenaes syndrome ( hereditary cholestasis with lymphedema)

ii) North American Indian Childhood Cirrhosis