The goals of treatment are clear, but an unmet need still remains in cholestatic liver diseases (ChLD)
Goals of treatment
The treatment and care of ChLD focuses on 3 main areas
Provide relief from cholestatic pruritus (itch)1,2
Improve nutrition1,2
Manage disease complications and help delay liver transplantation2-5
All images are actor portrayals.
Palliative care and nutrition
Palliative options and supplemental nutrition are often the first steps for treating pruritus
Palliative treatment of cholestatic pruritus3,4
- Cold, short baths
- Moisturizers
- Local, topical steroids (corticosteroid creams)
- Antihistamines and sedatives
The key areas of focus for supplemental nutrition are1,3,4,6
- Caloric intake
- Dietary fat
- Water-soluble vitamins
- FSVs
- Sunlight and dietary calcium
The use of these palliative approaches may help keep skin healthy, but they may not sufficiently address pruritus in all patients7
Pharmacologic treatments
While the use of several drugs aim to treat cholestasis and pruritus in ChLD, they are not approved for PFIC or ALGS
Drugs frequently used to treat pruritus in PFIC and ALGS are listed below
Proposed mechanism or intended use
Approved for pruritus in PFIC or ALGS?
Hydrophilic bile acid used to treat primary biliary cirrhosis and gallstones is frequently used as initial pharmacologic treatment in PFIC and ALGS1,2,8,9
An antibiotic used to treat bacterial infections, such as tuberculosis10
A resin used to lower cholesterol levels in the blood12
*Hydrophilic bile acid is approved for PFIC 3 in France.14
Untreated ChLD may result in surgery, and these treatments may not provide relief from cholestatic pruritus3,15-17
Surgical intervention in PFIC and ALGS is associated with serious risks
The goal of surgical intervention in ChLD is to reduce unbearable pruritus and delay disease progression3,18
The first main type of surgery used in ChLD is surgical biliary diversion (SBD).
SBD aims to interrupt enterohepatic circulation to reduce the size of the bile acid pool. Common types of SBD include partial biliary diversion (PBD) and ileal bypass.1,19
Partial biliary diversion
- Although PBD may delay liver transplantation, in addition to complications, many patients still go on to require transplantation3,19
Ileal bypass
- Although ileal bypass avoids the external stoma of partial external biliary diversion and its associated complications, ileal adaptation occurs over time and symptoms return in about half of PFIC patients within a year1
- In ALGS, ileal bypass may not fully resolve xanthomas or severe pruritus in all patients19
A liver transplantation is the second main type of surgery used in PFIC and ALGS.
Even when liver function is satisfactory, the debilitating nature of cholestatic pruritus may necessitate transplantation. Other indications for liver transplantation include end-stage liver disease and hepatocellular carcinoma.1,18-20
In patients with PFIC from a large, worldwide, natural history cohort21,22
- At age 10, 33%-59% of patients with PFIC 1 and 53% of patients with PFIC 2 had a liver transplantation21,22
- The mortality rate following liver transplantation in PFIC 1 and PFIC 2 patients was 16%, according to one study23*
In patients with ALGS from a large, worldwide, natural history cohort24
- At age 10, 37.8% of patients with ALGS had a liver transplantation24
- The mortality rate following liver transplantation in ALGS patients was 13% after 1 year and 14% after 5 years, according to one study25
Liver transplantation has considerable risks, including graft rejection, vascular and CNS complications, disease recurrence, and the need for lifelong immunosuppression3,25
*Based on a retrospective analysis of 62 children who were admitted to the hospital between 1978 and 2007. Liver transplantation was performed in 25 patients, directly before the routine administration of UDCA in 1990 and use of biliary diversion in 1995, or after failure of UDCA treatment with or without biliary diversion.23
Connect with a representative to learn more about the challenges of treating ChLD
ChLD=cholestatic liver diseases; CNS=central nervous system; UDCA=ursodeoxycholic acid.
References: 1. Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol. 2014;4(1):25-36. 2. Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics (Basel). 2020;10(11):1-18. 3. Gunaydin M, Bozkurter Cil AT. Progressive familial intrahepatic cholestasis: diagnosis, management, and treatment. Hepat Med. 2018;10:95-104. 4. Kamath BM, Loomes KM, Piccoli DA. Medical management of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2010;50(6):580-586. 5. Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis, and management. Eur J Hum Genet. 2012;20(3):251-257. 6. Children’s Hospital of Philadelphia. Alagille syndrome. Accessed March 4, 2020. https://www.chop.edu/conditions-diseases/alagille-syndrome# 7. Hegade VS, Kendrick SFW, Rehman J, Jones DEJ. Itch and liver: management in primary care. Br J Gen Pract. 2015;65(635):e418-e420. 8. URSO Forte Prescribing Information. Aptalis Pharma US, Inc. 9. Actigall Prescribing Information. Allergan, Inc. 10. MedlinePlus. Rifampin. Accessed February 22, 2023. https://medlineplus.gov/druginfo/meds/a682403.html 11. Rifadin Prescribing Information. Sanofi-Aventis U.S. LLC. 12. MedlinePlus. Cholestyramine resin. Accessed February 22, 2023. https://medlineplus.gov/druginfo/meds/a682672.html 13. Drugs.com. Cholestyramine Prescribing Information. Accessed April 20, 2023. https://www.drugs.com/pro/cholestyramine.html 14. European Medicines Agency. Orphan Maintenance Assessment report. Published July 16, 2021. 15. Mehl A, Bohorquex H, Serrano M-S, Galliano G, Reichman TW. Liver transplantation and the management of progressive familial intrahepatic cholestasis in children. World J Transplant. 2016;6(2):278-290. 16. Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N. Systematic review: the epidemiology, natural history, and burden of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2018;67(2):148-156. 17. National Organization for Rare Disorders. Alagille syndrome. Updated May 13, 2020. Accessed February 22, 2023. https://rarediseases.org/rare-diseases/alagille-syndrome/?filter=ovr-ds-resources 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. 19. Wang KS, Tiao G, Bass LM, et al. Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis. Hepatology. 2017;65(5):1645-1654. 20. Bjornland K, Hukkinen M, Gatzinsky V, et al. Partial biliary diversion may promote long-term relief of pruritus and native liver survival in children with cholestatic liver diseases. Eur J Pediatr Surg. 2021;31(4):341-346. 21. 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(2):892-906. 22. van Wessel D, Thompson R, Grammatikopoulos T, et al. The natural course of FIC1 deficiency and BSEP deficiency: initial results from the NAPPED-consortium (NAtural course and Prognosis of PFIC and Effect of biliary Diversion). J Hepatol. 2018;68:S626-S627. 23. 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(5):1645-1655. 24. Vandriel SM, Li L-T, She H, et al. Natural history of liver disease in a large international cohort of children with Alagille syndrome: results from the GALA study. Hepatology. 2023;77(2):512-529. 25. Kamath BM, Yin W, Miller H, et al. Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience. Liver Transpl. 2012;18(8):940-948.
