Could it be progressive familial intrahepatic cholestasis (PFIC)?

Do you have any patients with cholestatic pruritus who have the following?

≈28%

52%

of patients with idiopathic adult-onset cholestasis had an underlying genetic cause, according to several recent studies.^12-15

What is PFIC?

PFIC is a group of rare, genetic liver diseases caused by mutations in hepatocellular transport genes.¹⁷ PFIC is characterized by impaired bile acid secretion or transport, leading to progressive cholestatic liver disease.^17,18

To date, 13 genetically distinct subtypes have been identified,
with more subtypes expected as research advances.¹⁹

Table listing timing of disease onset varies across PFIC subtypes, with some types appearing into adulthood.

PFIC can be easy to miss

Symptoms may mimic other diseases, such as²⁰:

Intrahepatic cholestasis of pregnancy
Drug-induced cholestasis or liver injury

Cholesterol gallstone disease
Adult idiopathic/cryptogenic cirrhosis

Cholestatic pruritus symptoms may be minimized.²³

Genetic testing can support a clinical PFIC diagnosis

Genetic testing can be of diagnostic benefit in patients for whom there is^2,12:

Genetic testing can support a clinical diagnosis; it cannot be used to exclude one¹⁹

A positive result can support diagnosis and guide treatment decisions
A negative result—or a result showing a variant of unknown significance—does not rule out PFIC. Continue to evaluate based on clinical presentation

Genetic testing is a helpful tool for diagnosing PFIC, but it’s not the only one.

Keep these key points in mind:

Look for atypical presentations. In adults, PFIC can mimic other cholestatic liver conditions and may not follow classic patterns.²⁰
Dig deeper. Whether a patient lacks a specific diagnosis or their current diagnosis doesn’t fully explain all their symptoms, ask open-ended questions—especially about symptoms like cholestatic pruritus that may be downplayed or overlooked.²³
Let clinical features lead the way. Diagnosis may be based on clinical findings, especially in patients with persistent cholestatic pruritus. Treatment may be warranted, even in the absence of a confirmed genetic diagnosis.¹⁹

References:

1. Tamburro C, Mentzinger A, Jain D, Vilarinho S. Idiopathic cholestasis in adults: genetics as another lens for liver pathologists. Hum Pathol. 2025;165:105916. doi: 10.1016/j.humpath.2025.105916. 2. European Association for the Study of the Liver: Verkade HJ, Felzen A, Keitel V, et al. EASL Clinical Practice Guidelines on genetic cholestatic liver diseases. J Hepatol. 2024;81(2):303-325. doi:10.1016/j.jhep.2024.04.006 3. Hilscher MB, Kamath PS, Eaton JE. Cholestatic liver diseases: a primer for generalists and subspecialists. Mayo Clin Proc. 2020;95(10):2263-2279. doi:10.1016/j.mayocp.2020.01.015 4. Nayagam JS, Miquel R, Thompson RJ, Joshi D. Genetic cholestasis in children and adults. J Hepatol. 2024;80(4):670-672. doi:10.1016/j.jhep.2023.11.028 5. Goubault P, Brunel T, Rode A, Bancel B, Mohkam K, Mabrut J-Y. Low-phospholipid associated cholelithiasis (LPAC) syndrome: a synthetic review. J Visc Surg. 2019;156(4):319-328. doi:10.1016/j.viscsurg.2019.02.006 6. Hsing AW, Bai Y, Andreotti G, et al. Family history of gallstones and the risk of biliary tract cancer and gallstones: a population-based study. Int J Cancer. 2007;121(4):832-838. doi:10.1002/ijc.22756 7. Chascsa DM, Lindor KD. Antimitochondrial antibody-negative primary biliary cholangitis: is it really the same disease? Clin Liver Dis. 2018;22(3):589-601. doi:10.1016/j.cld.2018.03.009 8. Boehlig A, Gerhardt F, Petroff D, et al. Prevalence of pruritus and association with anxiety and depression in patients with nonalcoholic fatty liver disease. Biomedicines. 2022;10(2):1-10. doi:10.3390/biomedicines.10020451 9. New MASLD Nomenclature. AASLD. Accessed October 30, 2025. https://www.aasld.org/new-masld-nomenclature 10. Geladari EV, Vallianou NG, Margellou E, Kounatidis D, Sevastianos V, Alexopoulou A. Benign recurrent intrahepatic cholestasis: where are we now? Gastroenterol Insights. 2024;15(1):156-167. doi:10.3390/gastroent15010011 11. Zu Y, Yang J, Zhang C, Liu D. The pathological mechanisms of estrogen-induced cholestasis: current perspectives. Front Pharmacol. 2021;12:1-9. doi:10.3389/fphar.2021.761255 12. Nayagam JS, Foskett P, Strautnieks S, et al. Clinical phenotype of adult-onset liver disease in patients with variants in ABCB4, ABCB11, and ATP8B1. Hepatol Commun. 2022;6(10):2654-2664. doi:10.1002/hep4.2051 13. Dröge C, Bonus M, Baumann U, et al. Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants. J Hepatol. 2017;67(6):1253-1264. doi:10.1016/j.jhep.2017.07.004 14. Zheng M, Hakim A, Konkwo C, et al. Advancing diagnosis and management of liver disease in adults through exome sequencing. eBioMedicine. 2023;95:104747. doi:10.1016/j.ebiom.2023.104747 15. Bittencourt P, Codes L, Andrade A, et al. Frequency of ATP8B1, ABCB11 and ABCB4 gene mutations in adult patients with idiopathic chronic cholestasis. Poster presented at: EASL Congress 2024; June 5-8, 2024; Milan, Italy. 16. Jacquemin E. Progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol. 2012;36(suppl 1):S26-S35. doi:10.1016/S2210-7401(12)70018-9 17. Felzen A, Verkade HJ. The spectrum of progressive familial intrahepatic cholestasis diseases: update on pathophysiology and emerging treatments. Eur J Med Genet. 2021;64(11):1-8. doi:10.1016/j.ejmg.2021.104317 18. Kamath BM, Stein P, Houwen RHJ, Verkade HJ. Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis. Liver Int. 2020;40(8):1812-1822. doi:10.1111/liv.14553 19. Vitale G, Sciveres M, Mandato C, Pio d’Adamo A, Di Giorgio A. Genotypes and different clinical variants between children and adults in progressive familial intrahepatic cholestasis: a state-of-the-art review. Orphanet J Rare Dis. 2025;20(1):1-21. doi:10.1186/s13023-025-03599-2 20. Stättermayer AF, Halilbasic E, Wrba F, Ferenci P, Trauner M. Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults. J Hepatol. 2020;73(3):651-663. doi:10.1016/j.jhep.2020.04.036 21. GeneCards®. The Human Gene Database. PSKH1 gene - protein serine kinase H1. Updated July 17, 2025. Accessed October 31, 2025. https://www.genecards.org/cgi-bin/carddisp.pl?gene=PSKH1 22. Online Mendelian Inheritance in Man (OMIM). Cholestasis, progressive familial intrahepatic, 13; PFIC13. Johns Hopkins University School of Medicine. Updated October 14, 2024. Accessed October 31, 2025. https://www.omim.org/entry/620962 23. Data on file. REF-01343. Mirum Pharmaceuticals, Inc.

Indications

LIVMARLI (maralixibat) oral solution and tablets are indicated for the treatment of cholestatic pruritus in patients who are 3 months of age and older with Alagille syndrome.

LIVMARLI (maralixibat) oral solution and tablets are indicated for the treatment of cholestatic pruritus in patients who are 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC).

Limitations of Use: LIVMARLI is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in nonfunctional or complete absence of bile salt export pump (BSEP) protein.

Important Safety Information

CONTRAINDICATIONS

LIVMARLI (maralixibat) oral solution and tablets are contraindicated in patients with prior or active hepatic decompensation events (eg, variceal hemorrhage, ascites, or hepatic encephalopathy).

WARNINGS AND PRECAUTIONS

Hepatotoxicity: LIVMARLI treatment is associated with a potential for drug-induced liver injury (DILI). In the PFIC trial, treatment-emergent hepatic decompensation events and elevations of liver tests or worsening of liver tests occurred. Two patients experienced DILI attributable to LIVMARLI. Two additional patients experienced DILI in the open-label extension portion of the trial. Of these 4 patients, 1 patient required liver transplant and another patient died.

In the Alagille syndrome trial, treatment-emergent elevations of liver tests or worsening of liver tests occurred.

Obtain baseline liver tests and monitor during treatment. Liver-related adverse reactions and physical signs of hepatic decompensation should also be monitored. Dose reduction or treatment interruption may be considered if abnormalities occur in the absence of other causes. For persistent or recurrent liver test abnormalities, consider treatment discontinuation. Permanently discontinue LIVMARLI if a patient experiences the following: persistent or recurrent liver test abnormalities, clinical hepatitis, or a hepatic decompensation event.

Gastrointestinal Adverse Reactions: Diarrhea and abdominal pain were reported as the most common adverse reactions. Monitor for dehydration and treat promptly. Consider reducing the dosage or interrupting LIVMARLI treatment if a patient experiences persistent diarrhea or diarrhea with bloody stool, vomiting, dehydration requiring treatment, or fever.

Fat-Soluble Vitamin (FSV) Deficiency: Patients can have FSV deficiency (vitamins A, D, E, and K) at baseline, and LIVMARLI may adversely affect absorption of FSVs. Treatment-emergent bone fracture events have been observed more frequently with patients treated with LIVMARLI compared with patients treated with placebo. If bone fractures or bleeding occurs, consider interrupting LIVMARLI and supplement with FSVs. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels.

Risk of Propylene Glycol Toxicity (Pediatric Patients Less Than 5 Years of Age): LIVMARLI oral solution contains propylene glycol. Total daily intake of propylene glycol should be considered for managing the risk of propylene glycol toxicity. Monitor patients for signs of propylene glycol toxicity. Discontinue LIVMARLI if toxicity is suspected.

ADVERSE REACTIONS

Alagille syndrome: The most common adverse reactions are diarrhea, abdominal pain, vomiting, FSV deficiency, liver test abnormalities, and bone fractures.

PFIC: The most common adverse reactions are diarrhea, FSV deficiency, abdominal pain, liver test abnormalities, hematochezia, and bone fractures.

DRUG INTERACTIONS

Administer LIVMARLI at least 4 hours before or 4 hours after administration of bile acid binding resins.

A decrease in the absorption of OATP2B1 substrates (eg, statins) due to OATP2B1 inhibition by LIVMARLI in the GI tract cannot be ruled out. Consider monitoring the drug effects of OATP2B1 substrates as needed.

DOSING INFORMATION

In patients with Alagille syndrome, LIVMARLI is taken once daily, 30 minutes before a meal in the morning. In patients with PFIC, LIVMARLI is taken twice daily, 30 minutes before a meal. Refer to the dosing by weight guidelines in the full Prescribing Information for complete details on dosing for the oral solution and tablet formulations. The provided oral solution dosing dispenser must be used to accurately measure the dose. Any remaining LIVMARLI oral solution should be discarded 100 days after first opening the bottle. LIVMARLI tablets can be used in patients weighing ≥25 kg who can swallow tablets.

Please see full Prescribing Information for LIVMARLI.