AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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• Clinical
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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. PFIC can progress rapidly and cause cirrhosis during infancy, or it may progress relatively slowly with minimal scarring well into adolescence. Few patients have survived into the third decade of life without treatment.

The condition clinically characterized by hepatocellular cholestasis, low serum levels of gamma-glutamyl transferase (GGT) activity, and autosomal recessive inheritance is termed low-GGT PFIC. 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 These terms now have been superseded by the term PFIC.

At present, specific gene defects have been identified for 2 subtypes of low-GGT PFIC: 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 PFIC. 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 PFIC. 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 to 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, though 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 exist in PFIC because several families with clinical and biochemical features consistent with PFIC 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 PFIC phenotype, while 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 PFIC 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. 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 PFIC 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 PFIC is even rarer, with fewer than 20 reported patients. Both have a greater frequency in some cultures in which consanguineous marriage is common.

Mortality/Morbidity

All forms of PFIC are lethal in childhood unless treated. Low-GGT PFIC 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 PFIC manifest severe progressive intrahepatic cholestasis in the first year and progress toward hepatic failure in the first few years of life.

PFIC 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 often is 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 PFIC. 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, while significant splenomegaly implies advanced fibrosis or cirrhosis. These patients do not have xanthomas.

Race

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

Sex

Males and females are affected equally.

Age

PFIC affects only infants and children.

CLINICAL

Section 3 of 11  

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History

• 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

PFIC is a genetically determined autosomal recessive disorder. Consanguinity is a major risk factor.

DIFFERENTIALS

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Other Problems to be Considered

Hepatocellular cholestasis from other causes
Inborn errors of bile acid synthesis
Neonatal hepatitis

WORKUP

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Lab Studies

• Serum bilirubin levels are elevated in virtually all patients.
• Serum direct or conjugated bilirubin levels are elevated in virtually all patients.
• Total serum bile salt concentration is elevated 10- to 20-fold in virtually all patients.
• Qualitative serum and urine bile acids by mass spectroscopy are used to exclude genetically determined errors in bile acid synthesis.
• Total serum cholesterol level is within reference ranges; high-density lipoprotein (HDL) level is normal or low.
• Serum alkaline phosphatase is elevated in virtually all patients.
• Serum 5'-nucleotidase is elevated in virtually all patients.
• Serum GGT levels are within reference ranges or low in low-GGT PFIC; patients may have GGT levels of more than 100 IU/L while receiving microsomal inducers (eg, phenobarbital). These levels are elevated (ie, usually 3- to 10-fold) in patients with high-GGT PFIC.
• Fecal fat is elevated in virtually all patients.

Imaging Studies

• No imaging study helps in the diagnosis of PFIC.

Other Tests

• Sampling bile from the duodenum or directly from the biliary tract for analysis of phospholipid content can be useful in making the diagnosis of high-GGT PFIC.

Procedures

• Liver biopsy

Histologic Findings

In patients with low-GGT PFIC, hepatocellular and canalicular cholestasis with pseudoacinar transformation are the most uniform histologic findings. Hepatocellular injury manifests as giant cell formation and ballooned hepatocytes (see Images 1-2). Giant cells are prominent during infancy in 57% of patients and may regress with increasing age. Bile duct damage leads to their loss and ductal paucity in 70% of older patients. The degenerating biliary epithelium shows apoptotic changes, consisting of small hyperchromatic nuclei, attenuated cytoplasm, and loss of duct lumina. Inflammation is absent.

The typical progression of fibrosis starts early (ie, 76% of patients have some fibrosis by age 2 y) and may appear initially as pericentral sclerosis, portal fibrosis, or sometimes both. Portal-to-central bridging then develops in association with lacy lobular fibrosis and eventually leads to cirrhosis. Proliferating bile ductules develop at the edge of the portal tracts in patients with significant fibrosis. The progression rate of the fibrosis is highly variable but loosely correlates to clinical disease severity. Mallory hyaline and hepatocellular carcinoma may occur with very advanced disease.

Examination with electron microscopy shows subtle differences between PFIC-1 and PFIC-2. Samples from patients with PFIC-1 show the retention of coarsely granular bile (so-called Byler bile) in canalicular spaces. Liver biopsies from patients with high-GGT PFIC reveal expanded portal areas with proliferation of interlobular bile ducts plugged with bile.

TREATMENT

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Medical Care

The general treatment of cholestasis applies to PFIC; please see the eMedicine article Cholestasis for treatment information. The disease typically does not respond to any form of medical therapy. Some have reported success in treating patients with low-GGT PFIC with ursodeoxycholic acid (20-30 mg/kg/d), which may be tried as an initial treatment.

Surgical Care

Surgical therapy that diverts bile salts from the enterohepatic recirculation arrests the progression of disease and relieves pruritus in most patients with low-GGT PFIC. The most common procedure, partial cutaneous biliary diversion, diverts gallbladder bile to a cutaneous ostomy. Patients typically drain 30-120 mL of bile per day, which is discarded.

A variation on this procedure is the limited ileal diversion, in which the distal 20-25% of the ileum is removed from the intestinal mainstream and made into a self-emptying blind loop. This diverts the bile salts pool similarly to a partial biliary diversion. Ileal diversion usually is reserved for patients who have had a cholecystectomy but has been used with some success in lieu of biliary diversion. After diversion, the bile salt pool converts to predominantly cholic acid conjugates, which can be transported normally, and the liver disease resolves in most patients.

Liver transplantation is indicated in patients with decompensated cirrhosis or with a failed diversion with debilitating pruritus. Survival rates after transplantation are excellent. Liver transplantation is the only effective treatment of high-GGT PFIC.

Consultations

Refer all patients to centers with expertise in pediatric hepatology.

Diet

The treatment of fat malabsorption principally involves dietary substitution. In an older patient, a diet rich in carbohydrates and proteins can be substituted for a diet containing long-chain triglycerides. This may not be possible for infants, for whom substitution of a formula containing medium-chain triglycerides may improve fat absorption and nutrition. However, this substitution has not been proven, and therapeutic formulas containing medium-chain triglycerides may not be worth the expense. Bile salt therapy to replace missing bile salts is not practical. Ursodeoxycholic acid, which is used to treat some cholestatic conditions, does not form mixed micelles and has no effect on fat absorption.

Pay careful attention to preventing fat-soluble vitamin deficiencies, accomplished by administering fat-soluble vitamins and monitoring the response to therapy. Administer vitamin E as tocopherol polyethylene glycol succinate (TPGS) to achieve sufficient absorption in the face of reduced intestinal bile salt concentrations.

Activity

No activity restrictions are needed.

MEDICATION

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For information on most of the medications used to treat PFIC, including fat-soluble vitamins, see the eMedicine article Cholestasis.

Drug Category: Gallstone-solubilizing agents

Ursodeoxycholic acid (ursodiol), a naturally occurring bile acid present in small quantities in human bile, suppresses liver synthesis, suppresses secretion of cholesterol, and inhibits intestinal cholesterol absorption.

Drug Category: Barbiturates

These agents are used to induce activity of hepatic enzymes, thus enhancing bilirubin excretion, which may improve function in some patients with cholestasis. An antipruritic effect is noticed with reduction of serum bilirubin.

Drug Category: Vitamins

Fat-soluble vitamins A, D, E, and K should be administered as individual supplements to ensure proper absorption.

FOLLOW-UP

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Transfer

• Transfer to an appropriate transplant center as the disease progresses to end-stage liver disease (ESLD).

Complications

• Complications are those of chronic cholestasis and include the following:
• • Fat malabsorption
  • Fat-soluble vitamin deficiency
  • Pruritus
  • Hyperlipidemia
  • Progression to ESLD in patients without successful biliary diversions

Prognosis

• PFIC results in ESLD if not diagnosed before the development of cirrhosis. Early diagnosis and biliary diversion may prevent significant morbidity and mortality from ESLD.

Patient Education

• For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center; Hepatitis Center; and Cholesterol Center. Also, see eMedicine's patient education articles Cirrhosis, High Cholesterol, and Cholesterol FAQs.

MISCELLANEOUS

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Medical/Legal Pitfalls

• PFIC presents with a wide spectrum of symptoms, ranging from pruritus and poor growth to overt portal hypertension. Referring patients with unexplained liver disease or elevated bile acids to a hepatologist for further evaluation facilitates early diagnosis and allows possible therapeutic intervention (eg, biliary diversion before ESLD develops).

MULTIMEDIA

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Media file 1:  Progressive familial intrahepatic cholestasis (PFIC), typical findings. Ballooned hepatocytes from cholate injury, scattered giant cells, cholestasis, and lacy fibrosis extending from central veins to portal areas.
	View Full Size Image
Media type:  Photo

Media file 2:  Ballooned hepatocytes with cholestasis and some giant cell transformation. Note the sinusoidal lacy fibrosis.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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• Alonso EM, Snover DC, Montag A, et al. Histologic pathology of the liver in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr. Feb 1994;18(2):128-33. [Medline].
• Bull LN, van Eijk MJ, Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet. Mar 1998;18(3):219-24. [Medline].
• Deleuze JF, Jacquemin E, Dubuisson C, et al. Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis. Hepatology. Apr 1996;23(4):904-8. [Medline].
• Emond JC, Whitington PF. Selective surgical management of progressive familial intrahepatic cholestasis (Byler''s disease). J Pediatr Surg. Dec 1995;30(12):1635-41. [Medline].
• Hollands CM, Rivera-Pedrogo FJ, Gonzalez-Vallina R, et al. Ileal exclusion for Byler''s disease: an alternative surgical approach with promising early results for pruritus. J Pediatr Surg. Feb 1998;33(2):220-4. [Medline].
• Jacquemin E. Progressive familial intrahepatic cholestasis. J Gastroenterol Hepatol. Jun 1999;14(6):594-9. [Medline].
• Jacquemin E, Hermans D, Myara A, et al. Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis. Hepatology. Mar 1997;25(3):519-23. [Medline].
• Jansen PL, Strautnieks SS, Jacquemin E, et al. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology. Dec 1999;117(6):1370-9. [Medline].
• Strautnieks SS, Bull LN, Knisely AS, et al. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet. Nov 1998;20(3):233-8. [Medline].
• Wagner M, Trauner M. Transcriptional regulation of hepatobiliary transport systems in health and disease: implications for a rationale approach to the treatment of intrahepatic cholestasis. Ann Hepatol. Apr-Jun 2005;4(2):77-99. [Medline].
• Whitington PF, Freese DK, Alonso EM, et al. Clinical and biochemical findings in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr. Feb 1994;18(2):134-41. [Medline].
• Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology. Jul 1988;95(1):130-6. [Medline].
• de Vree JM, Jacquemin E, Sturm E, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci U S A. Jan 6 1998;95(1):282-7. [Medline].
• van Mil SW, Houwen RH, Klomp LW. Genetics of familial intrahepatic cholestasis syndromes. J Med Genet. Jun 2005;42(6):449-63. [Medline]. [Full Text].
• van Mil SW, van der Woerd WL, van der Brugge G, et al. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology. Aug 2004;127(2):379-84. [Medline].

Article Last Updated: Jun 19, 2006