Progressive Familial Intrahepatic Cholestasis

Progressive familial intrahepatic cholestasis (PFIC) is a class of chronic cholestasis disorders that comprises a variety of genetic diseases.[1, 2] These conditions begin in infancy and usually progress to cirrhosis within the first decade of life. The average age at onset is 3 months, although some patients do not develop jaundice until later, even as late as adolescence. PFIC 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.[3, 4]

Initially described in Amish descendants of Jacob Byler, PFIC was originally named Byler disease. The condition was inherited in an autosomal recessive manner and was characterized by hepatocellular cholestasis. 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 These terms now have been superseded by the term progressive familial intrahepatic cholestasis.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 three subtypes of PFIC (see Table 1 under Pathophysiology). PFIC1 (the former Byler disease) and PFIC2 are characterized by low gamma-glutamyl peptidase (GGT) levels. Despite their genetic distinctiveness, PFIC1 and PFIC2 have few clinical differences, and both are caused by the absence of a gene product required for canalicular export and bile formation.

In PFIC3, patients have a similar clinical presentation, but laboratory results reveal an elevated serum GGT. Rather than defective bile acid export, patients with PFIC3 have deficient hepatocellular phospholipid export. The lack of phospholipids produces unstable micelles that have a toxic effect on the bile ducts, leading to bile duct plugs and biliary obstruction.

For patient education resources, see the Cholesterol Center, as well as Cirrhosis, High Cholesterol, and Cholesterol FAQs.

Progressive familial intrahepatic cholestasis is a genetically determined autosomal recessive disorder, predominantly from mutations in ATP8B1, ABCB11 and ABCB4,[5, 6]  but the range of genetic etiologies continues to grow and include mutations in TJP2, NR1H4), and MYO5B), among others.[7]  Consanguinity is a major risk factor,[8]  

The primary mechanism of disease in patients with PFIC1-2 is a defect in canalicular bile acid transport with primary retention of hydrophobic bile salts. 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 (i.e., usually >200 mmol/L compared to normal concentrations of < 10 mmol/L). Total biliary bile acid concentrations are low (i.e., 0.1-0.3 mmol/L, compared with normal concentrations of >20 mmol/L) and have a predominance of cholic acid conjugates. These findings suggest a defect in biliary excretion, particularly of chenodeoxycholic acid conjugates.

PFIC1 is caused by a genetic mutation in the ATP8B1 gene on chromosome 18q21-22. This gene encodes the protein FIC1, also known as ATP8B1. FIC1 is a P-type ATPase responsible for maintaining a high concentration of phospholipids in the inner hepatocyte membrane. The mechanism whereby the loss of FIC1 activity results in defective bile salts excretion is unknown, but it has been hypothesized that a mutation in this protein causes phospholipid membrane instability leading to reduced function of bile acid transporters.[9]

PFIC2 is caused by a mutation in the ABCB11 gene on chromosome 2q24 that encodes the bile salt export pump (BSEP). BSEP is the major canalicular bile acid pump, and thus the loss of BSEP function results in severe hepatocellular cholestasis.[10]  In a immunohistochemical study, BSEP was not detected in the canalicular membrane in PFIC patients having ABCB11 mutation, in contrast to patients with PFIC1 or PFIC3. 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.[3]

While the PFIC1 and PFIC2 involve a defect in bile acid secretion, PFIC3 involves a defect in phospholipid secretion. In PFIC3, a mutation in the gene ABCB4 on chromosome 7q21 encodes the protein MDR3, which functions in the translocation of phosphatidylcholine across the canalicular membrane.[11, 12, 13] Bile from patients with PFIC3 has very low concentrations of phospholipid. In an animal model of PFIC3, Abcb4 (Mdr2) knockout mice cannot excrete phospholipid into bile and develop progressive liver disease characterized by portal inflammation, proliferation of bile ducts, and fibrosis. This phenotype is rescued by transgenic expression of the human ABCB4 gene, confirming that phospholipid excretion is dependent on ABCB4. Functional loss of this gene results in cholestatic liver disease.

The biliary damage in PFIC3 is due to the absence of phospholipid in the ductular lumen. 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 destabilizes micelles and promotes lithogenic bile with crystallized cholesterol, which could produce small bile duct obstruction.

The absence of bile salts in the bile ducts in PFIC1 and PFIC2 and their presence in the bile ducts in PFIC3 accounts for the difference in biochemical tests. In PFIC3, as in most cholestatic diseases, prolonged exposure of the duct cell membranes to bile salts results in solubilization of GGT, absorption of the enzyme into the circulation, and elevated GGT levels on serum tests. In contrast, in PFIC1 and PFIC2 there are low levels of biliary bile salts, the GGT is never solubilized, and the serum GGT is normal.

Several clinical differences have been reported between patients with PFIC1-3. Clinically, patients with PFIC1 and PFIC2 present with jaundice and severe pruritus in the first few months of life. Patients with PFIC1 may experience a relapsing and remitting course of symptoms, but permanent cholestasis, fibrosis, and liver failure are inevitable without treatment. PFIC1 is also associated with watery diarrhea. This secretory diarrhea may persist after liver transplantation and may reflect an important role for FIC1 in the intestine, where it is highly expressed. Other extrahepatic manifestations associated with PFIC1 include short stature, sensorineural deafness, pancreatitis, and hepatic steatosis.

Mutations in the ATP8B1 gene also cause a less severe form of cholestasis, known as benign recurrent intrahepatic cholestasis type 1 (BRIC1). BRIC1 is characterized by episodic jaundice and pruritus that resolve with no progression to liver failure. Genotype-phenotype correlation between PFIC1 and BRIC1 is imperfect, although mutations predicted to have a more severe effect on protein function (eg, nonsense, frameshifts, deletions) are more common in PFIC1. This suggests that other modifier genes may also play a role.

In a manner similar to PFIC1/BRIC1, BRIC2 is a benign cholestatic disease associated with ABCB11 mutations. In this case, the genotype-phenotype correlation is more clear, with mutations in patients with BRIC2 resulting in more mild loss of protein function that those found in patients with PFIC2. In practice, there is likely to be a spectrum of disease for both PFIC1/BRIC1 and PFIC2/BRIC2, with patients having intermediate levels of cholestasis and long-term complications.

PFIC2 is associated with a continuous course of symptoms, in contrast to the episodic pattern seen in PFIC1. Once cholestasis develops, patients rapidly progress to liver failure within several years. Consistent with the restricted expression of ABCB11 to the liver, there are no extrahepatic manifestations of PFIC2. However, PFIC2 is associated with hepatocellular carcinoma in children. One case series identified 11 children with clinically diagnosed PFIC and hepatocellular carcinoma. Retrospective immunohistochemical analysis with anti-BSEP antibody showed that 10 of these children had little or no BSEP in the canalicular membrane and genetic analysis in these 10 children revealed ABCB11 mutations. The exact mechanism of carcinogenesis is unknown; however, this risk stresses the importance of determining the type of PFIC on diagnosis.

Only one third of patients with PFIC3 present with cholestasis during infancy; the rest become symptomatic in childhood and adolescence. The pruritus tends to be less severe than in PFIC1 and PFIC2, but progression to biliary cirrhosis and liver failure is still rapid.

Table 1. (Open Table in a new window)

United States data

PFIC types 1 and 2 are rare, but the exact frequency is unknown. Incidence is estimated at 1:50,000 to 1:100,000 births.[3]  Fewer than 200 patients with PFIC1 or PFIC2 are reported in the medical literature or are otherwise known to the authors. PFIC3 is even rarer, with fewer than 20 reported patients. Both have a greater frequency in some cultures in which consanguineous marriage is common.

In a 2019 systematic review, PFIC2 was the most common subtype.[1] The investigators found an incidence for intrahepatic cholestasis that included but was not limited to PFIC of 1 in 18,000 live births; the data was from a study that didn't use genetic testing. Another two studies in the review showed 12-13% of their patient population (aged 2-18 years) with cholestasis had genetically diagnosed PFIC.[1] In patients with disease progression, 20=83% required liver transplantation.

Race-, sex-, and age-related demographics

PFIC types 1 and 2 have been reported in all races. PFIC3 has been found in Western European, White, and North African Arabic populations.

Males and females are equally affected.

Progressive familial intrahepatic cholestasis affects only infants and children.

Progressive familial intrahepatic cholestasis results in ESLD if not diagnosed before the development of cirrhosis. Early diagnosis and biliary diversion may prevent significant morbidity and mortality from ESLD. Hepatocellular carcinoma is also a major risk in patients with PFIC2.

Morbidity/mortality

All forms of progressive familial intrahepatic cholestasis are lethal in childhood unless treated. They can be rapidly progressive and result in cirrhosis during infancy, or they may progress relatively slowly well into adolescence and cause minimal scarring. Few patients have survived into the third decade of life without treatment.

Morbidity is the result of chronic cholestasis (see Medscape Reference article Cholestasis). Pruritus is more pronounced in PFIC types 1 and 2 and often occurs out of proportion to the level of jaundice, which is often low grade and can wax and wane. The pruritus may be disabling and usually does not respond to medical therapy.

Growth failure is another major feature of progressive familial intrahepatic cholestasis. More than 95% of patients have short stature. Perennial asthma like 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.

PFIC2 is associated with an increased risk of developing hepatocellular or cholangiocarcinoma carcinoma early in life.[14]  Although a standard frequency of screening for HCC has not been established, it is reasonable to measure the serum alpha-fetoprotein levels and perform a hepatic ultrasound every 6 months.[3]

Complications

Complications are those of chronic cholestasis and include the following:

• Fat malabsorption
• Fat-soluble vitamin deficiency
• Pruritus
• Hyperlipidemia
• Growth failure
• Progression to ESLD in patients without successful biliary diversions
• Hepatocellular carcinoma in PFIC2

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

• Pruritus, including scratching, cutaneous mutilation, irritability in infants, and/or attention deficit

• Jaundice, such as scleral icterus and/or cutaneous jaundice

• Dark urine

• Malabsorption, which may include fat-soluble vitamin deficiency, steatorrhea, diarrhea, and/or failure to thrive

• Growth failure

In addition to the above, physical examination of affected persons may also demonstrate the following findings:

• Hepatomegaly

• Splenomegaly

• Altered anthropometrics

• Reduced height

• Reduced weight for height

Serum bilirubin levels are elevated in virtually all patients with progressive familial intrahepatic cholestasis (PFIC). Serum direct or conjugated bilirubin levels are elevated in virtually all patients.

Total serum bile salt concentration is elevated 10-fold 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 gamma-glutamyl transferase (GGT) levels are within reference ranges or low in PFIC1 and PFIC2; patients may have GGT levels of more than 100 IU/L while receiving microsomal inducers (eg, phenobarbital). These levels are elevated (ie, usually 3-fold to 10-fold) in patients with PFIC3.

Fecal fat is elevated in virtually all patients.

Genetic testing: A DNA resequencing array has been developed that includes the genes associated with PFIC types 1, 2, and 3.[15]

Serum alpha-fetoprotein testing may be performed.

Ultrasonography of the liver and gall bladder is useful in determining biliary tract anatomy and differentiating from extrahepatic causes of cholestasis.

Cholangiography may be necessary to exclude extrahepatic biliary obstruction.

Sampling bile from the duodenum or directly from the biliary tract for analysis of phospholipid content can be useful in making the diagnosis of PFIC3.

Histologic evaluation of the liver architecture can be helpful as described below. Further immunohistochemical staining of liver specimen for BSEP and MDR3 can be diagnostic and help differentiate between the types of PFIC.

Liver biopsy is an associated procedure for patients with suspected progressive familial intrahepatic cholestasis (PFIC).

In patients with PFIC1 and PFIC2, hepatocellular and canalicular cholestasis with pseudoacinar transformation are the most uniform histologic findings. Hepatocellular injury manifests as giant cell formation and ballooned hepatocytes (see following images).

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 widely varies 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 PFIC1 and PFIC2. Samples from patients with PFIC1 show the retention of coarsely granular bile (so-called Byler bile) in canalicular spaces.

In PFIC3, liver biopsy reveals expanded portal areas with proliferation of interlobular bile ducts plugged with bile. As in PFIC1 and PFIC2, progressive fibrosis, nodularity, and cirrhosis will develop.

In a long-term (>10 years), retrospective study of eight liver biopsies from four patients with PFIC2, all the patients had cholestasis and their biopsies showed the characteristic hepatic lobular rosettes at the time of diagnosis, and the majority had degenerative changes (mild to severe).[16]  Only two patients showed centrrally located bile plugs. Follow-up biopsies revealed complete resolution of cholestatis in three patients (significant reduction in the fourth patient), as well as resolution of liver fibrosis in two of three patients.[16]

The general treatment of cholestasis applies to progressive familial intrahepatic cholestasis (PFIC); please see the 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 progressive familial intrahepatic cholestasis with ursodeoxycholic acid (20-30 mg/kg/d), which may be tried as an initial treatment.[5] Other therapies for the symptomatic relief of pruritus include antihistamines, rifampin, and bile acid-binding agents. 

The FDA approved the ileal bile acid transport (IBAT) inhibitor odevixibat (Bylvay) in July 2021 for treatment of pruritus in patients with progressive familial intrahepatic cholestasis aged 3 months and older.[17] Approval was supported by data from the Demonstrate Efficacy and Safety of A4250 in Children With Progressive Familial Intrahepatic Cholestasis Types 1 and 2 (PEDFIC 1) and PEDFIC 2 phase 3 trials.[17, 18] In PEDFIC 1, a randomized, double-blind, placebo-controlled study, odevixibat showed improvement of pruritus (P = 0.004) and serum bile acid (P = 0.003) compared with placebo. PEDFIC 2, a long-term, open-label phase 3 extension study, showed sustained reductions in serum bile acids as well as improvements in pruritus assessments, growth, and other markers of liver function in patients treated up to 48 weeks.[17, 18]

Transfer

Transfer patients with progressive familial intrahepatic cholestasis (PFIC) to an appropriate transplant center, as the disease will progress to end-stage liver disease (ESLD).

Surgical therapy that diverts bile salts from the enterohepatic recirculation relieves pruritus in most patients, decreases serum bile salt levels, improves growth, and may delay the progression of disease with PFIC1 and PFIC2.[19, 20] 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. 

In a study following children with PFIC, 3 years after diversion procedure, 45% of patients had complete relief of pruritus, 27% had mild pruritus, and 27% experienced no relief. This procedure must be done prior to the development cirrhosis to be effective.[21]  Another study that evaluated outcomes of partial external biliary diversion (PEBD) in 35 patients of whom data for 24 children were available found the procedure to be effective for reducing total biliary acid levels and improving PFIC symptoms.[22]  However, PEBD was less effective in patients with PFIC2. Seven patients were converted to ilial bypass surgery, with no significant changes to their biliary acid levels.[22]

Alternatively, ileal bypass, a procedure in which the proximal ileum is attached to the cecum bypassing the distal 15% of the ileum and therefore avoiding ileal reabsorption of bile acids can be performed in patients that are not candidates for diversion. This procedure provides immediate relief similar the results seen in diversion, but cholestasis eventually returns in most patients.[23]  Partial internal biliary drainage (PIBD) is another technique and involves creating a jejunal conduit from gallbladder to colon to bypass ileal reabsorption of bile acids.[24]  There is no long term data on the efficacy of PIBD.

Liver transplantation is indicated in patients with decompensated cirrhosis or with a failed diversion with debilitating pruritus.[5]  Historically, the clinical courses and outcomes for PFIC1 recipients after living-donor liver transplantation have not been that good when compared with PFIC2 recipients. Hori et al reported 14 PFIC patients who underwent living-donor liver transplantation, comprising 11 PFIC1 and three PFIC2 patients. Three of 11 PFIC1 recipients died, while the three recipients with PFIC2 survived.[25]  A more recent report of seven patients who underwent liver transplantation for PFIC1 showed 100% patient and graft survival.[26] There wasno disease recurrence nor graft loss nor severe extrahepatic manifestations that necessitated hospitalization or surgery, but two patients had persistently high liver parameters albeit with "excellent" liver function.[26]

Liver transplantation is the only effective treatment of PFIC3.

Refer all patients to centers with expertise in pediatric hepatology.

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.

No activity restrictions are needed until late stages of liver disease when precautions should be taken to avoid splenic injury.

For information on most of the medications used to treat progressive familial intrahepatic cholestasis (PFIC), including antipruritic therapy and fat-soluble vitamins, see the Medscape Drugs and Diseases article Cholestasis.

Class Summary

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.

Ursodiol (Actigall, URSO)

Also called ursodeoxycholic acid. Shown to promote bile flow in cholestatic conditions associated with patent extrahepatic biliary system. Decreases cholesterol content of bile and decreases likelihood of sludging and bile stones. Hydrophilic bile acid thought to act by decreasing overall toxicity of bile acid pool.

Class Summary

These agents are FDA approved for pruritus caused by biliary stasis.

Cholestyramine (Prevalite, Questran)

Forms a nonabsorbable complex with bile acids in the intestine, which in turn inhibits enterohepatic reuptake of intestinal bile salts. Take other medications at least 1 h before or 4-6 h after cholestyramine.

Not to be administered in dry powder form. Mix with plenty of water or applesauce.

May use as adjunct in primary hypercholesterolemia.

Class Summary

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.

Phenobarbital (Luminal)

Mainly used as an anticonvulsant that interferes with transmission of impulses from thalamus to cortex of brain, causing an imbalance in central inhibitory and facilitatory mechanisms. Used in cholestasis to induce CYP450 system in treatment of neonatal hyperbilirubinemia and to lower bilirubin in chronic cholestasis.

Rifampin (Rifadin, Rimactane)

Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which in turn blocks RNA transcription.

Class Summary

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

Phytonadione (AquaMEPHYTON)

Vitamin K is a fat-soluble vitamin absorbed by the gut and stored in the liver. Necessary for function of clotting factors in coagulation cascade. Used to replace essential vitamins not obtained in sufficient quantities in diet or to further supplement levels.

Vitamin E (Liqui E)

Protects polyunsaturated fatty acids in membranes from attack by free radicals and protects RBCs against hemolysis.

Vitamin A (Aquasol A)

Needed for bone development, growth, visual adaptation to darkness, and testicular and ovarian function and as a cofactor in many biochemical processes.

Ergocalciferol (Calciferol, Drisdol)

Vitamin D stimulates absorption of calcium and phosphate from small intestine and promotes release of calcium from bone into blood; PO solution is 8000 U/mL (200 mcg/mL, 40 U/mcg).

Class Summary

Inhibitors of ileal bile acid transport (IBAT) act locally in the distal ileum to decrease reuptake of bile acids and increase clearance of bile acids through the colon, thereby reducing bile acid serum concentration.

Odevixibat (Bylvay)

Indicated for pruritus in patients with progressive familial intrahepatic cholestasis (PFIC) aged 3 months and older.