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
Diagnosis
- Serum alpha-fetoprotein levels are usually normal and alanine aminotransferase values are initially within the reference range, but with disease progression, they gradually increase by up to tenfold32
- Liver ultrasound is usually normal but may reveal a massive gallbladder3
- Histopathological changes mainly show hepatocellular cholestasis with various degrees of lobular fibrosis32
- Cholangiography shows a normal biliary tree and allows bile collection; biliary lipid analysis reveals mildly decreased biliary bile salt concentration3
Diagnosis is confirmed by genetic sequencing of the ATP8B1 gene32,58
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 | 1st to 2nd 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 | - |
3. INSERM. Orphanet. European Union: The portal for rare diseases and orphan drugs. 2021 (accessed 09/2021 at https://www.orpha.net/consor/cgi-bin/Disease.php?lng=EN.)
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.
Those requiring urgent treatment:
Biliary atresia
