The impact of cholestasis

For patients with Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC)
Cholestasis can lead to liver damage and transplant
In cholestatic liver diseases like ALGS and PFIC, the normal formation or flow of bile from the liver is impaired. This leads to a buildup of bile acids within the liver and in the bloodstream, triggering a cascade of damaging effects.1-5
An illustration of normal liver function. An illustration of normal liver function. An illustration of bile acids building up in the liver.
An illustration of normal liver function.
Normal bile acid cycle
In a normal bile acid cycle, a healthy liver contributes to the balanced production and circulation of bile acids.1

An illustration of bile acids building up in the liver.
Cholestasis bile acid cycle
In an ALGS or PFIC bile acid cycle, bile acids build up in the liver (cholestasis).6,7
Over time, cholestasis can lead to progressive liver damage and an increased risk of liver transplant.1,6,8-11
3 key indicators help identify risk of liver transplantation in ALGS and PFIC
1
Cholestatic 
pruritus
A common and relentless 
symptom that's more 
than just an itch
Cholestatic pruritus affects

up to

88%

of patients with ALGS11

up to

100%

of patients with PFIC12 

Uncontrolled cholestatic pruritus causes more than just skin damage. Patients with ALGS or PFIC can also struggle with11,13-18:

  • Fatigue
  • Physical discomfort
  • Decreased physical function
  • Irritability
  • Impaired school performance
  • Negative impact on social activities
Immediate impact on sleep and fatigue:
53%
of patients with ALGS report difficulty falling asleep due to cholestatic pruritus, while 59% report difficulty staying asleep13*
  • *A qualitative, prospective study consisting of interviews with patients and caregivers from 25 families evaluated the symptoms, signs, and impacts of itching in pediatric patients with ALGS.
≈60%
of caregivers of patients with PFIC report that their child needed soothing or help falling asleep due to cholestatic pruritus19†
  • †A qualitative assessment of patient/observer-reported outcome by study participant caregivers (N=62) examined pruritus and sleep disturbance during the
5- to 8-week screening period of a Phase 3 study in patients with PFIC.
A significant driver of liver transplant

Many patients with uncontrolled cholestatic pruritus continue to opt for surgical biliary diversion and/or liver transplant for both ALGS and PFIC.20-23

Refractory cholestatic 
pruritus was an indication in
49%
and
82%
of liver transplants in patients with ALGS20,21‡§
  • ‡A multicenter retrospective study of children with ALGS (N=1433) assessed outcomes in those who presented with neonatal cholestasis (n=1184). Among the 328 patients who underwent liver transplantation and had documented indications, intractable pruritus was cited as an indication in 161 cases (49%). There were 235 cases of ≥1 complication of persistent cholestasis (72%); of these, growth failure was cited in 127 cases (54%); xanthomas in 116 cases (49%); metabolic bone disease in 16 cases (7%); and fat-soluble vitamin deficiency in 3 cases (1%).21,22
  • §A retrospective review of children with ALGS and liver involvement (N=163) investigated between 1960 and 2000 found that among the 44 patients who underwent liver transplantation, refractory pruritus was an indication in 36 patients (82%); disfiguring xanthomas was an indication in 32 patients (73%); bone fractures in 15 patients (34%); and/or patent signs of end-stage liver disease in 5 patients (11%).20
92%
Among 38 pediatric patients with PFIC who underwent SBD, the most common indication was cholestatic pruritus (92%).23∥
End-stage liver disease (80%) was the most common indication for liver transplant in pediatric patients (n=60) with PFIC, followed by refractory cholestatic pruritus (20%).24¶
  • ∥A retrospective evaluation of nontransplant surgical intervention for pediatric cholestasis (N=58) including 38 patients with PFIC. Among these 38 patients, the indications for surgical diversion included pruritus in 92% (35/38 patients) followed by progression of liver disease in 59%.23
  • Based on a single-center, prospective review of 580 consecutive pediatric liver transplants (2011-2022), including 60 performed in children with genetically or clinically confirmed PFIC.24
2
Elevated bile 
acid load
A driver of negative 
impact on the liver
Consequences of elevated bile acid1,6,8,9
A bloated liver illustrating inflammation as a consequence of elevated bile acid.
A blue liver gradually turning darker illustrating injury due to elevated bile acid.
A spotted blue liver illustrating fibrosis due to elevated bile acid.

In ALGS, lower serum bile acid (sBA) levels are associated with native liver survival (NLS)

Results from the independent GALA study group (n=570) showed that patients with sBA >102 μmol/L have an increased risk of death, liver transplant, and manifestations of portal hypertension. (NLS HR=3.78, 95% CI, 2.39-5.99; event-free survival HR=3.44, 95% CI, 2.35-5.04).25

GALA=Global ALagille Alliance; HR=hazard ratio; TB=total bilirubin.

In PFIC, sBA levels of

<102 µmol/L (PFIC2)
or
<65 µmol/L (PFIC1)

were associated with improved NLS at 15 years10,26

Study design

A multicenter retrospective cohort study included patients (N=264) with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic bile salt export pump severity (BSEP1, BSEP2, BSEP3). Genotype severity and sBA concentration were strongly associated with NLS.

3
Rising 
bilirubin
A critical indicator of 
transplant risk

A large international study showed that in children with ALGS, total bilirubin (TB) levels between 6 and 12 months of age are a key indicator of future liver transplant risk.21*

4.8x

greater risk of transplant

for patients with median TB levels ≥5.0 and <10.0 mg/dL vs those with bilirubin <5.0 mg/dL22

15.6x

greater risk of transplant

for patients with median TB levels ≥10.0 mg/dL vs those with bilirubin <5.0 mg/dL22

Study design

In a multicenter retrospective study of children (N=1433) with ALGS who presented with neonatal cholestasis (n=1184), serial laboratory measurements were available in 605 patients, with 3777 follow-up visits during the first year of life. Biochemical parameters included sBAs, TB, direct/conjugated bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, total cholesterol, triglyceride, and platelet count.

In PFIC, reduction in bilirubin is a predictor of longer NLS in patients who have had surgical biliary diversion27

Study design

A systematic literature review and meta-analysis evaluated relationships between liver biochemistry parameters (sBA [n=42], bilirubin [n=31], and alanine aminotransferase [n=28]) and early response (pruritus improvement) or long-term outcomes (need for liver transplant) in patients with PFIC who underwent partial external biliary diversion.

  • * The GALA study was an independent retrospective review, which may introduce variability in how key clinical features were assessed. Liver biopsy findings were extracted from local pathology reports rather than central review. Additionally, individuals with partial or subclinical disease may be underrepresented, as such patients may go undetected.
Efficacy data
See results in patients with ALGS and PFIC.
In ALGS In PFIC
Prescription access and support
Mirum Access Plus supports you and your patients through payer approval and beyond.
More about Mirum Access Plus
References:
1. 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 2. MedlinePlus. Alagille syndrome. Updated December 1, 2023. Accessed October 30, 2025. https://medlineplus.gov/genetics/condition/alagille-syndrome 3. 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):104317. doi:10.1016/j.ejmg.2021.104317 4. Cheng K, Rosenthal P. Diagnosis and management of Alagille and progressive familial intrahepatic cholestasis. Hepatol Commun. 2023;7(12):e0314. doi:10.1097/HC9.0000000000000314 5. Vitale G, Sciveres M, Mandato C, d’Adamo AP, 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 6. Cai S-Y, Li M, Boyer J. The role of bile acid-mediated inflammation in cholestatic liver injury. In: Arias IM, Alter HJ, Boyer JR, et al, eds. The Liver: Biology and Pathobiology. 6th ed. Wiley; 2020:728-736. doi:10.1002/9781119436812.ch56 7. Jesina D. Alagille syndrome: an overview. Neonatal Netw. 2017;36(6):343-347. doi:10.1891/0730-0832.36.6.343 8. Karpen SJ, Kelly D, Mack C, Stein P. Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders. Hepatol Int. 2020;14(5):677-689. doi:10.1007/s12072-020-10070-w 9. Li T, Chiang J. Bile acid-induced liver injury in cholestasis. In: Ding WX, Yin XM, eds. Cellular Injury in Liver Diseases. Springer; 2017:143-172. 10. van Wessel DBE, Thompson RJ, Gonzales E, et al. Genotype correlates with the natural history of severe bile salt export pump deficiency. J Hepatol. 2020;73(1):84-93. doi:10.1016/j.jhep.2020.02.007 11. 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. doi:10.1097/MPG.0000000000001958 12. Baker A, Kerkar N, Todorova L, Kamath BM, Houwen RHJ. Systematic review of progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol. 2019;43(1):20-36. doi:10.1016/j.clinre.2018.07.010 13. Kamath BM, Abetz-Webb L, Kennedy C, et al. Development of a novel tool to assess the impact of itching in pediatric cholestasis. Patient. 2018;11(1):69-82. doi:10.1007/s40271-017-0266-4 14. Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol. 2014;4(1):25-36. doi:10.1016/j.jceh.2013.10.005 15. Kamath BM, Chen Z, Romero R, et al. Quality of life and its determinants in a multicenter cohort of children with Alagille syndrome. J Pediatr. 2015;167(2):390-396. doi:10.1016/j.jpeds.2015.04.077 16. Elisofon SA, Emerick KM, Sinacore JM, Alonso EM. Health status of patients with Alagille syndrome. J Pediatr Gastroenterol Nutr. 2010;51(6):759-765. doi:10.1097/MPG.0b013e3181ef3771 17. Cohran VC, Heubi JE. Treatment of pediatric cholestatic liver disease. Curr Treat Options Gastroenterol. 2003;6(5):403-415. doi:10.1007/s11938-003-0043-4 18. Düll MM, Kremer AE. Newer approaches to the management of pruritus in cholestatic liver disease. Curr Hepatol Rep. 2020;19:86-95. doi:10.1007/s11901-020-00517-x 19. Gwaltney C, Ivanescu C, Karlsson L, Warholic N, Kjems L, Horn P. Validation of the PRUCISION instruments in pediatric patients with progressive familial intrahepatic cholestasis. Adv Ther. 2022;39(11):5105-5125. doi:10.1007/s12325-022-02262-7 20. Lykavieris P, Hadchouel M, Chardot C, Bernard O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut. 2001;49(3):431-435. doi:10.1136/gut.49.3.431 21. Vandriel SM, Li L-T, She H, et al; Global ALagille Alliance (GALA) Study Group. Natural history of liver disease in a large international cohort of children with Alagille syndrome: results from the GALA study (Supplement). Hepatology. 2023;77(2):512-529. doi:10.1002/hep.32761 22. 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. doi:10.1002/hep.32761 23. 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. doi:10.1002/hep.29019 24. Vasudevan AK, Shanmugam N, Rammohan A, et al. Outcomes of pediatric liver transplantation for progressive familial intrahepatic cholestasis. Pediatr Transplant. 2023;(8):e14600. doi:10.1111/petr.14600 25. Murillo Perez CK, Vandriel SM, Wang JS. Serum bile acids are associated with native liver survival in patients with Alagille syndrome: results from the GALA study. Poster presented at: European Association for the Study of the Liver (EASL); June 21-24, 2023. 26. 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. doi:10.1002/hep.31787 27. Verkade HJ, Thompson RJ, Arnell H, et al. Systematic review and meta-analysis: partial external biliary diversion in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr. 2020;71(2):176-183. doi:10.1097/MPG.0000000000002789