Progressive familial intrahepatic cholestasis (PFIC) is a group of rare genetic diseases that result in reduced bile flow from the liver, also called cholestasis. It commonly presents in infants and early childhood. First identified in 1965, the genetic dysfunction in PFIC causes inadequate bile secretion, a build-up of bile acid in the liver, and can lead to end stage liver disease and death or liver transplantation and ultimately liver failure.[1,2] Patients with the most common forms of PFIC do not generally survive to adulthood, though progress is being made with new and investigational treatment options to treat symptoms of the condition.[1-3] In some types of PFIC, symptoms may not be detected until two to three years of age.[2] This condition is rare with estimates of its prevalence ranging from 1 per 50,000 to 100,000 live births.[1] Unidentified PFIC may be a factor in approximately 12% of young patients with cholestasis, splenomegaly, or acute liver failure.[2,4]
The characteristic pruritus associated with PFIC may result in babies scratching through their skin to ease their discomfort. This constant, severe itching is often the most disturbing symptom. Further, given the progressive course of the disease, it also presents as a burden for caregivers on various aspects of their life.[4,5]
Etiology
There are three main types of PFIC, designated PFIC1, PFIC2, and PFIC3, caused by autosomal recessive mutations in the ATP8B1, ABCB11, and ABCB4 genes, respectively, on different chromosomes.[6] A few new types of PFIC have been identified, with various genotypes and presentations, but the one unifying feature among all forms is cholestasis.[6]
PFIC3 is found least often among the PFIC1, PFIC2, and PFIC3 subtypes.[4] Infants with PFIC1 or PFIC2 have abnormally low bile-acid secretion, and those with PFIC3 have impaired bile phospholipid secretion. Patients with PFIC1 and PFIC2 tend to suffer more severe pruritus symptoms than those with PFIC3.[4]
Each of the mutations encodes for a defect of the bile-acid transport system, leading to cholestasis and the subsequent injury to hepatocytes or cholangiocytes, followed by liver damage.[7,8] Patients with PFIC3 have a more varied rate of progression than those with PFIC1 or PFIC2.[7,8]
Patients with PFIC1 or PFIC2 are usually diagnosed within three months of delivery, though those with PFIC2 usually experience more severe symptoms early on, including progression to severe liver disease.[2]
Patients with PFIC3 who have a heterozygous mutation often experience a less-aggressive natural history. In this form of the disorder, PFIC may not be detected until a patient reaches young adulthood.[3,9] It is more difficult to diagnose in these patients, partly because cholestasis is not always diagnosed early in life.[9] Another factor identified is the period of latency between the onset of symptoms and diagnosis, with patients often showing symptoms of gastrointestinal bleeding, jaundice, or hepatosplenomegaly in addition to pruritus.[9]
Signs and Symptoms
As indicated above, severe pruritus and jaundice are the classic presenting signs. Parents may report that their baby has scratched themselves raw and bloody, in reaction to their constant itching.[10] Severe pruritus was reported in up to 80% of patients.[2] Symptoms may appear by the first month of life in 15% of those with PFIC1 compared with 44% of those with PFIC2.[11]
Other principal symptoms reported at presentation in the 2019 literature review by Baker and colleagues include:[3]
- Hepatomegaly or enlargement of the liver
- Hepatosplenomegaly or simultaneous enlargement of both the liver and spleen
- Portal hypertension, or high blood pressure in the main vein leading to the liver
- Scleral icterus, or yellow pigmentation of the eye’s normally white area
- Pale or discolored stools
- Diarrhea
- Fat malabsorption
- Splenomegaly, or enlargement of the spleen
- Failure to thrive/poor growth
- Fat-soluble vitamin deficiencies[6]
- Pancreatitis
Overall, research shows patients with PFIC may have quite varied clinical presentations.[7]
Diagnosis
PFIC typically presents with cholestasis, which is characterized by jaundice and pruritus.[1] Laboratory testing may reveal any of the following: hyperbilirubinemia, normal serum gamma-glutamyltranspeptidase (GGT) activity, higher serum bile-acid concentrations, and/or elevated transaminase levels.[7]
Liver biopsy may demonstrate various types of findings depending on the PFIC subtype, some of which include canalicular cholestasis, or cholangiolytic changes, and varying degrees of damage to the liver architecture, from inflammation to cirrhosis.[7,10] Targeted gene panels, including those related to PFIC, Alagille syndrome, or Niemann–Pick disease, among others, can now be used to help identify the specific mutational subtype affecting bile-acid synthesis.[7]
Prognosis
In general, patients diagnosed with PFIC will experience progressive liver damage, which may lead to liver failure over time.[3] Patients may require liver transplant, though liver transplant may not cure the disease, as cholestasis is reported to recur with some subtypes[3,10]; the genetic mutation may express itself in tissues other than the liver.[1] Therefore, it is critical for doctors to treat the symptoms of PFIC to address the underlying conditions, possibly even after transplantation.
For patients with PFIC1 or PFIC2, mortality rate can be high, primarily caused by liver failure, complications of liver transplant, hepatocellular carcinoma, complications of cholestasis, infections, and bleeding (not necessarily from hepatic sources).[6]
Treatments and Future Directions
Current treatments focus on alleviating the symptoms of PFIC as no therapy exists to address the underlying genetic causes of the condition.[3,6] Ursodeoxycholic acid (UDCA) may help alleviate the patient’s pruritus, and it is theorized to improve expression of BSEP and MDR3. Rifampin and cholestyramine are two other antipruritics that may be used. Other medications used to treat pruritis symptoms in patients include naltrexone and sertraline, with varied effectiveness.[3] Dietary fat should be supplemented using medium-chain triglycerides, which do not require bile salts for absorption.[1] Fat-soluble vitamin supplementation is part of the standard of care, but in general, medical care for these patients is supportive in nature.[3,12]
When medical therapy inadequately alleviates pruritis symptoms, surgical biliary diversion (internal or external) or ileal exclusion can be effective in decreasing serum bile-salt concentrations and resulting in clinical improvement.[3]
End-stage liver disease may occur in these patients, especially those with PFIC1 or PFIC2. In patients with PFIC1, less than half of patients reach age 18 years of age with their native liver.[13] In patients with PFIC2, hepatocellular carcinoma has been reported. For these patients, liver transplant is the only remaining option and definitively effective treatment (patient survival, 85%).[10] Liver transplant improves cholestasis and its symptoms in 75-100% patients, irrespective of PFIC subtype over a short term follow-up of 3 – 5 years.[1] Although liver transplant is an option for those patients with end-stage liver disease or for those with severe or refractory cholestasis, or hepatocellular carcinoma, PFIC can recur following liver transplantation, especially in those with severe mutations.[13]
Bylvay® (odevixibat) was US FDA-approved in 2021 for the treatment of pruritus in patients 3 months of age and older with PFIC, the first approved treatment in its class.[14,15] Bylvay may not be effective in PFIC type 2 patients with ABCB11 variants resulting in non-functional or complete absence of bile salt export pump protein (BSEP-3). It is an orally available ileal bile-acid transport–inhibiting agent that decreases reuptake of bile salts and results in lower serum bile-acid levels.[14] In essence, it acts as a pharmacologic alternative for biliary diversion.[16]
In a phase 3 double-blind, controlled trial, 62 patients with PFIC1 or PFIC2 (age range, 6 mo to 17 yr) were randomized to receive odevixibat (in one of two doses) or placebo. The primary outcome of the study was reduction in pruritus, assessed by scratching score.[15] Based on assessments of pruritus, the study drug resulted in significant symptomatic improvement over the placebo.[15] Of those taking the placebo, 25% (5/20) discontinued the trial because of no improvement, compared with 19% (8/42) receiving either of the odevixibat doses.[15] Of the 13 discontinuations, 11 rolled over to trial 2 to continue receiving Bylvay at the 120 dose.[15] The most common adverse reactions for Bylvay in the clinical trial were diarrhea, liver test abnormalities, vomiting, abdominal pain, and fat-soluble vitamin deficiency.[15]
Further, pooled analysis from the PEDFIC trials—global, pivotal phase 3 studies conducted in PFIC evaluating the efficacy and tolerability of Bylvay in reducing pruritus and serum bile acids (sBAs), found that the medication was associated with sustained improvements in pruritus scores over time, demonstrating durability of Bylvay across PFIC types.[16] Approximately 60% of 84 patients administered Bylvay achieved a treatment response defined by sBA and/or pruritus criteria (greater than or equal to 70% reduction in serum bile acid levels or serum bile acids ≤70 µmol/L) with a median of 53 weeks of therapy.[16]
Several other nonsurgical therapies to address cholestatic liver diseases are currently being researched, and some may have application to PFIC.[17]
Conclusion
PFIC remains a genetic disorder with a poor prognosis that not only results in severe cholestasis and devastating related complications for the young patients but exacts a considerable toll on parents and caregivers.
Despite the prognosis and impact of PFIC, hope remains among the community with additional research, the science will continue to address the major symptoms caused by the condition.
Bylvay® (odevixibat)
IMPORTANT SAFETY INFORMATION
Warnings and Precautions:
Liver Test Abnormalities
Patients enrolled in a clinical trial had abnormal liver tests at baseline. In a clinical trial, treatment-emergent elevations of liver tests or worsening of liver tests relative to baseline values were observed during the clinical trial. Most abnormalities included elevation in AST, ALT, or total and direct bilirubin. Treatment interruption days ranged from 3 days to 124 days; none of the patients in the pivotal clinical trial permanently discontinued treatment due to liver test abnormalities.
Obtain baseline liver tests and monitor during treatment. Dose reduction or treatment interruption may be required if abnormalities occur. For persistent or recurrent liver test abnormalities, consider treatment discontinuation.
Bylvay was not evaluated in PFIC patients with cirrhosis. Closely monitor for liver test abnormalities; permanently discontinue Bylvay if a patient progresses to portal hypertension or experiences a hepatic decompensation event.
Diarrhea
In a clinical trial, diarrhea was reported in 2 (10%) placebo-treated patients, 9 (39%) Bylvay-treated 40 mcg/kg/day patients and 4 (21%) Bylvay-treated 120 mcg/kg/day patients. Treatment interruption due to diarrhea, occurred in 2 patients with 3 events during treatment with Bylvay 120 mcg/kg/day. Treatment interruption due to diarrhea ranged between 3 to 7 days. One patient treated with Bylvay 120 mcg/kg/day withdrew from the pivotal clinical trial due to persistent diarrhea.
If diarrhea occurs, monitor for dehydration and treat promptly. Interrupt Bylvay dosing if a patient experiences persistent diarrhea. Restart Bylvay at 40 mcg/kg/day when diarrhea resolves, and increase the dose as tolerated if appropriate. If diarrhea persists and no alternate etiology is identified, stop Bylvay treatment.
Fat-Soluble Vitamin (FSV) Deficiency
Fat-soluble vitamins (FSV) include vitamin A, D, E, and K (measured using INR levels). PFIC patients can have FSV deficiency at baseline. Bylvay may affect absorption of fat-soluble vitamins. In a clinical trial, new onset or worsening of existing FSV deficiency was reported in 1 (5%) placebo-treated patient, and 3 (16%) Bylvay-treated 120 mcg/kg/day patients; none of the Bylvay-treated 40 mcg/kg/day patients had new onset or worsening of existing FSV deficiency.
Obtain serum FSV levels at baseline and monitor during treatment, along with any clinical manifestations. If FSV deficiency is diagnosed, supplement with FSV. Discontinue Bylvay if FSV deficiency persists or worsens despite adequate FSV supplementation.
Adverse Reactions
The most common adverse reactions for Bylvay are diarrhea, liver test abnormalities, vomiting, abdominal pain, and fat-soluble vitamin deficiency.
Drug Interactions
For patients taking bile acid binding resins, take Bylvay at least 4 hours before or 4 hours after taking a bile acid binding resin.
Use in Specific Populations
There are no human data on Bylvay use in pregnant persons to establish a drug-associated risk of major birth defects, miscarriage, or adverse developmental outcomes. Based on findings from animal reproduction studies, Bylvay may cause cardiac malformations when a fetus is exposed during pregnancy. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Bylvay during pregnancy. For more information, please call 1-855-252-4736.
INDICATIONS AND USAGE
Bylvay is indicated for the treatment of pruritus in patients 3 months of age and older with progressive familial intrahepatic cholestasis (PFIC).
Limitation of Use
Bylvay may not be effective in PFIC type 2 patients with ABCB11 variants resulting in non-functional or complete absence of bile salt export pump protein (BSEP-3).
Please see full Prescribing Information.
REFERENCES
- Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol 2014;4:25-36.
- Baker A, Kerkar N, Todorova L, et al. Systemic review of progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol 2019;43:20-36.
- Henkel SAF, Squires JH, Ayers M, et al. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol 2019;11:450-463.
- Gunaydin M, Bozkurter Cil AT. Progressive familial intrahepatic cholestasis: Diagnosis, management, and treatment. Hepatic Med Evidence Res 2018;10:95-104.
- Mighlu C, O’Hara S, Ferri Grazzi E, et al. Impact of progressive familial intrahepatic cholestasis on caregivers: Caregiver-reported outcomes from the multinational PICTURE study. Orphanet J Rare Dis 2022;17:32. https://doi.org/10.1186/s13023-022-02177-0
- Amirneni S, Haep N, Gad MA, et al. Molecular overview of progressive familial intrahepatic cholestasis. World J Gastroenterol 2020;26:7470-7484.
- Bull LN, Thompson RJ. Progressive familial intrahepatic cholestasis. Clin Liver Dis 2018;22:657-669.
- Davit-Spraul A, Gonales E, Baussan C, et al. Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis 2009;4:1-12. doi:10.1186/1750-1172-4-1
- Schatz SB, Jungst C, Keitel-Anselmo V, et al. Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset. Hepatol Commun 2018;2:504-514.
- Mehl A, Bohorquez H, Serrano M-S, et al. Liver transplantation and the management of progressive familial intrahepatic cholestasis in children. World J Transplant 2016;6:278-290.
- Davit-Spraul A, Fabre M, Branchereau S, et al. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): Phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology 2010;51:1645-1655.
- Karpen SJ. Pediatric cholestasis: Epidemiology, genetics, diagnosis, and current management. Clin Liver Dis 2020;15:115-119.
- Van Wessel DBE, Thompson RJ, Gonzales E, et al. Impact of genotype, serum bile acids, and surgical biliary diversion on native liver survival in FIC1 deficiency. Hepatology 2021;74:892-906.
- Bylvay prescribing information. Albireo Pharma. February 2023. https://bylvay.com/pdf/Bylvay_PI.pdf.
- Albireo announces FDA approval of Bylvay (odevixibat), the first drug treatment for patients with progressive familial intrahepatic cholestasis (PFIC) (press release). Alberio Pharma. July 2021. https://ir.albireopharma.com/news-releases/news-release-details/multimedia-update-albireo-announces-fda-approval-bylvaytm.
- Loomes KM, Verkade HJ, Thompson RJ, et al. Effects on serum bile acids, pruritus, and safety with up to 72 weeks of odevixibat treatment: pooled data from the PEDFIC 1 and PEDFIC 2 studies in children with progressive familial intrahepatic cholestasis. Poster presented at the 72nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD): The Liver Meeting. November 12–15, 2021; Virtual.
- Kamath BM, Stein P, Houwen RHJ, et al. Potential of ileal bile-acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis. Liver Int 2020;40:18-12-1822.