eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Progressive Familial Intrahepatic Cholestasis

Author: Karan M Emerick, MD, Consulting Staff, Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Connecticut Children's Medical Center
Contributor Information and Disclosures

Updated: May 8, 2009

Introduction

Background

Progressive familial intrahepatic cholestasis (PFIC) is a chronic cholestasis syndrome that begins in infancy and usually progresses to cirrhosis within the first decade of life. The average age at onset is 3 months, although some patients do not develop apparent cholestasis until later, even as late as adolescence. Progressive familial intrahepatic cholestasis can progress rapidly and cause cirrhosis during infancy or may progress relatively slowly with minimal scarring well into adolescence. Few patients have survived into the third decade of life without treatment.^1,2

The condition clinically characterized by hepatocellular cholestasis, low serum levels of gamma-glutamyl transferase (GGT) activity, and autosomal recessive inheritance is termed low-GGT progressive familial intrahepatic cholestasis. Initially described in Amish descendants of Jacob Byler, the condition was originally named Byler disease. Subsequently, numerous phenotypically similar non-Amish patients were reported, and the term Byler syndrome was used to describe these patients' condition. These terms now have been superseded by the term progressive familial intrahepatic cholestasis.

At present, specific gene defects have been identified for 2 subtypes of low-GGT progressive familial intrahepatic cholestasis: PFIC-1 (the former Byler disease) and PFIC-2. Despite their genetic distinctiveness, PFIC-1 and PFIC-2 have few clinical differences, and both are caused by the absence of a gene product function for canalicular export and bile formation.

Patients with familial intrahepatic cholestasis but with high serum GGT have a condition termed high-GGT progressive familial intrahepatic cholestasis. These patients manifest severe progressive intrahepatic cholestasis in the first year and progress toward hepatic failure in the first few years of life. Liver biopsy results reveal expanded portal areas with proliferation of interlobular bile ducts plugged with bile, suggesting an obstructive disorder rather than a primary defect in bile formation.

Pathophysiology

Several lines of evidence point to a defect in canalicular bile acid transport with primary retention of hydrophobic bile salts as the mechanism of disease in patients with low-GGT progressive familial intrahepatic cholestasis. This conclusion is supported by the differences in the quantitative and qualitative distribution of bile acids in serum and bile. Total serum bile acid concentrations are markedly elevated (ie, usually >200 mmol/L compared to normal concentrations of <10 mmol/L); the ratio of chenodeoxycholic acid to cholic acid conjugates is elevated, usually more than 10:1. Total biliary bile acid concentrations are low (ie, 0.1-0.3 mmol/L, compared with normal concentrations of >20 mmol/L) and with a predominance of cholic acid conjugates. These findings suggest a defect in biliary excretion, particularly of chenodeoxycholic acid conjugates.

The gene for PFIC-1 has been mapped to a 19 cM region at band 18q21-22 by the detection of a preserved haplotype in affected members of the Byler pedigree. In the process of closely examining the region, a gene named FIC-1 that contains an ATP-binding cassette (ABC) was identified and is being investigated as a transporter of phospholipids and/or bile salts.

Patients from 6 consanguineous families of Middle Eastern origin were found to have a defect in the gene FIC-2, located at band 2q24; this defect has been designated PFIC-2. The FIC-2 gene is analogous to the rat sister gene of p-glycoprotein (S-PGP), an ABC bile salt transporter also called the bile salt export pump (BSEP). In rats, S-PGP is important in bile salt transport, and this discovery provides evidence that FIC-2 is an important human bile salt export pump.

In a recent study using immunohistochemistry, liver tissue from cholestatic patients with defects in FIC-2 did not express BSEP in the canalicular domain, while tissue for other familial cholestasis patients did. This suggests that in most patients with PFIC-2, the gene defect is sufficiently severe to produce no product or a protein that cannot be inserted into the canalicular membrane. This technique may provide a means of diagnosing PFIC-2 in the clinical setting.

Several clinical differences have been reported between patients with PFIC-2 and patients with PFIC-1, although the distinction remains in question. Clinically, patients with PFIC-2 seem to lack the relapsing course seen in the early stages of PFIC-1 and, instead, have a more rapidly progressive course to fibrosis. Light microscopy and transmission electron microscopy demonstrate that liver tissue from patients with PFIC-1 has coarse granular bile and bland canalicular cholestasis, whereas patients with PFIC-2 have amorphous or finely filamentous bile and neonatal hepatitis.

Patients with PFIC-1 are more likely to have associated watery diarrhea, some of which is severe. This secretory diarrhea may persist after liver transplantation and may reflect an important role for FIC-1 in the intestine, where it is expressed in quantity. Work continues to resolve issues related to phenotype and response to therapy, and conclusions must await the identification of the gene defects involved in a large number of patients.

Further genetic heterogeneity may be noted in progressive familial intrahepatic cholestasis because several families with clinical and biochemical features consistent with progressive familial intrahepatic cholestasis do not have linkage to either the 18q region (those with PFIC-1) or the 2q region (those with PFIC-2). A defect in the sinusoidal uptake of bile salts recently was described in 4 related Amish children. The proband expressed a progressive familial intrahepatic cholestasis phenotype, whereas 3 siblings expressed only elevated serum bile salt concentrations. Microsatellite markers for the 18q region in these 4 children were inconsistent with linkage to FIC-1. All responded to treatment with ursodeoxycholic acid.

The pathophysiology for high-GGT progressive familial intrahepatic cholestasis is very different. Mutations in MDR-3 were identified as responsible after analysis of bile showed very low concentrations of phospholipid and after the phenotype of the analogous Mdr-2 knockout mouse had been described.

MDR-3 is a primary active export pump that belongs to the family of ABC transporters and is expressed in the canalicular membrane of the hepatocyte.^3,4 It functions in the translocation of phosphatidylcholine across the canalicular membrane. Mdr-2 knockout mice and MDR-3(-) humans cannot excrete this phospholipid into bile. Both develop progressive liver disease characterized by portal inflammation, proliferation of bile ducts, and fibrosis. Mdr-2–deficient mice made transgenic by expression of the human homologue of Mdr-2 (ie, MDR-3) recover function and excrete phospholipid in their bile. This finding confirms the functional homology between the mouse and human genes and further suggests that phospholipid excretion is limited by the amount of MDR-3 or Mdr-2 present.

The mechanism of damage in these patients is unknown but is likely due to the absence of phospholipid. The stability of mixed micelles is determined by a 3-phase system in which a proper proportion of bile salts and phospholipid are necessary to maintain solubility of cholesterol. The absence of phospholipid would be expected to destabilize micelles and promote lithogenic bile with crystallized cholesterol, which could produce small–bile duct obstruction. This mechanism of disease fits well with the histologic findings. The MDR3 gene has been mapped to band 7q21.

Frequency

United States

Low-GGT progressive familial intrahepatic cholestasis is rare, but the exact frequency is unknown. Fewer than 200 patients are reported in the medical literature or are otherwise known to the authors. High-GGT progressive familial intrahepatic cholestasis is even rarer, with less than 20 reported patients. Both have a greater frequency in some cultures in which consanguineous marriage is common.

Mortality/Morbidity

All forms of progressive familial intrahepatic cholestasis are lethal in childhood unless treated. Low-GGT progressive familial intrahepatic cholestasis can be rapidly progressive and result in cirrhosis during infancy, or it may progress relatively slowly well into adolescence and cause minimal scarring. Few patients have survived into the third decade of life without treatment. Patients with high-GGT progressive familial intrahepatic cholestasis manifest severe progressive intrahepatic cholestasis in the first year and progress toward hepatic failure in the first few years of life.

Progressive familial intrahepatic cholestasis morbidity is the result of chronic cholestasis (see Cholestasis). In most patients with cholestasis, the dominant feature is pruritus. Pruritus often occurs out of proportion to the level of jaundice, which is often low grade and can wax and wane. The pruritus is very disabling and usually does not respond to medical therapies. Most patients have debilitating pruritus; most of the remainder have constant itching without treatment.

Growth failure is another major feature of progressive familial intrahepatic cholestasis. More than 95% of patients have short stature. Perennial asthmalike disease and recurrent epistaxis in the absence of thrombocytopenia or coagulopathy are common problems, probably caused by exceedingly high circulating levels of bile salts. Fat-soluble vitamin deficiencies are prevalent in untreated patients. As many as one third have cholelithiasis. Most patients have hepatomegaly, whereas significant splenomegaly implies advanced fibrosis or cirrhosis. These patients do not have xanthomas.

Race

Low-GGT progressive familial intrahepatic cholestasis has been reported in all races. High-GGT progressive familial intrahepatic cholestasis has been found in Western European, white, and North African Arabic populations.

Sex

Males and females are equally affected.

Age

Progressive familial intrahepatic cholestasis affects only infants and children.

Clinical

History

The following may be noted in the history of a patient with progressive familial intrahepatic cholestasis (PFIC)

• Pruritus
  • Scratching
  • Cutaneous mutilation
  • Irritability in infants
  • Attention deficit
• Jaundice
  • Scleral icterus
  • Cutaneous jaundice
• Dark urine
• Malabsorption
  • Fat-soluble vitamin deficiency
  • Steatorrhea
  • Diarrhea
  • Failure to thrive
• Growth failure

Physical

• Pruritus
  • Scratching
  • Cutaneous mutilation
  • Irritability in infants
• Jaundice
  • Scleral icterus
  • Cutaneous jaundice
• Hepatomegaly
• Splenomegaly
• Altered anthropometrics
• Reduced height
• Reduced weight for height

Causes

• Progressive familial intrahepatic cholestasis is a genetically determined autosomal recessive disorder.
• Consanguinity is a major risk factor.⁵

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