For US Health Care Professionals
understand ALGS understand PFIC
For patients with cholestatic liver disease,

Life can feel UNBEARABLE

These Teddys have chronic pediatric cholestatic
liver disease—and it’s unbearable.

Learn more about their individual journeys with
Alagille syndrome (ALGS) and progressive familial
intrahepatic cholestasis (PFIC).

What Is Cholestatic Liver Disease?

Cholestasis results from an impairment in bile formation or flow at some point between the liver cells, which produce bile, and the duodenum. When bile flow is stopped, bile acids build up in the liver. This can lead to a range of clinical presentations, from debilitating symptoms such as pruritus to liver injury to progressive liver disease, and, if left untreated, can result in fibrosis, cirrhosis, liver failure, and death. In addition, there is spillover of bile into the bloodstream, resulting in increased serum bile acids (sBA).1,2

digestive system digestive system
symptoms

Although the symptoms of cholestatic liver disease may vary based on the etiology, many patients with cholestasis present with intense itchiness, jaundice, dark urine, and pale stools. The impairment of bile flow into the intestine also means that calcium, lipids, and fat-soluble vitamins are poorly absorbed. If cholestasis persists, a deficiency of these nutrients can cause loss of bone tissue.3,4

pediatric cld

Chronic cholestatic liver diseases are a significant cause of morbidity and mortality within the pediatric population. The primary cholestatic diseases of infancy and childhood are frequently symptomatic and often rapidly progressive. These chronic cholestatic diseases that present in childhood include biliary atresia, Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), bile acid synthesis defects, cystic fibrosis-related liver disease, ductal plate abnormalities, primary sclerosing cholangitis (PSC), and certain metabolic diseases.5 This website focuses on ALGS and PFIC, specifically.

genetic testing

There are several genetic disorders that cause cholestasis, including ALGS and PFIC. Genetic testing can confirm if a patient is carrying the respective gene and aid in diagnosing patients with these cholestatic syndromes.6 However, there are various investigations that aid in diagnosing cholestatic liver disease.

In ALGS, variability of clinical presentation and disease severity can result in underdiagnosis, misdiagnosis, or delayed diagnosis. Molecular genetic testing, therefore, provides valuable confirmation, particularly in milder cases or in diagnosis of extended family.7,8

With PFIC, there are several investigations that help to identify its classification into types 1, 2, or 3, and differentiate it from other causes of cholestasis.9 However, no phenotypic features can distinguish PFIC1 from PFIC2. As a result, genetic testing is the only reliable way to distinguish among PFIC subtypes, making it the gold standard in diagnostic tools.9-11

The field of inherited cholestatic liver diseases is evolving rapidly as a result of advances in diagnosis based on genetic mutation associations.12

Alagille Syndrome

Alagille syndrome (ALGS) is a rare, autosomal dominant, multisystem disorder typically caused by mutations/deletions in the JAG1 gene and/or the NOTCH2 gene.7 Although 30% to 50% of individuals have an inherited pathogenic variant, the mutation occurs de novo in 50% to 70% of cases.13 ALGS often presents in childhood with a range of clinical manifestations.7

For patients with ALGS, cholestatic pruritus—an intense, unrelenting itch—is among the most severe in any chronic liver disease, negatively impacting physical health and psychosocial health.7,14

As a result, living with ALGS can be challenging for patients and their families.

Progressive Familial Intrahepatic Cholestasis

Progressive familial intrahepatic cholestasis (PFIC) is a group of rare, life-threatening autosomal recessive diseases related to functional deficiencies in the hepatocyte transporters.9,11,15 PFIC predominantly affects children, and it has been classified into 3 types—Types 1, 2, and 3—though recent scientific advancements have uncovered a growing list of subtypes that continue to expand our understanding of PFIC. PFIC2, also known as bile salt export pump (BSEP) deficiency, is the most common type.9,10,12,15,16

Cholestatic pruritus has been identified as the most debilitating symptom of PFIC.9 This bothersome pruritus often leads to cutaneous mutilation, loss of sleep, irritability, poor attention, and impaired school performance in children with PFIC.9

With a significant reduction in quality of life, patients and their families face a difficult prognostic journey.

ALGS=Alagille syndrome; BSEP=bile salt export pump; PFIC=progressive familial intrahepatic cholestasis; PSC=primary sclerosing cholangitis; sBA=serum bile acid.
References: 1. Chiang JYL, Ferrell JM. Bile acid metabolism in liver pathobiology. Gene Expr. 2018;18(2):71-87. doi:10.3727/105221618X15156018385515 2. Jones EA, Bergasa NV. The pruritus of cholestasis: from bile acids to opiate agonists. Hepatology. 1990;11(5):884-887. doi:10.1002/hep.1840110526 3. Tholey D. Cholestasis. In: Porter RS. Merck Manual Consumer Version. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Updated February 2021. Accessed March 19, 2021. https://www.merckmanuals.com/home/liver-and-gallbladder-disorders/manifestations-of-liver-disease/cholestasis# 4. 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 5. Kriegermeier A, Green R. Pediatric cholestatic liver disease: review of bile acid metabolism and discussion of current and emerging therapies. Front Med (Lausanne). 2020;7:149. doi:10.3389/fmed.2020.00149 6. Müllenbach R, Lammert F. An update on genetic analysis of cholestatic liver diseases: digging deeper. Dig Dis. 2011;29(1):72-77. doi:10.1159/000324137 7. 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 8. Leonard LD, Chao G, Baker A, Loomes K, Spinner NB. Clinical utility gene card for: Alagille syndrome (ALGS). Eur J Hum Genet. 2014;22(3). doi:10.1038/ejhg.2013.140 9. Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol. 2014;4(1):25-36. doi:10.1016/j.jceh.2013.10.005 10. 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 11. Amer S, Hajira A. A comprehensive review of progressive familial intrahepatic cholestasis (PFIC): genetic disorders of hepatocanalicular transporters. Gastroenterol Res. 2014;7(2):39-43. doi:10.14740/gr609e 12. Goldberg A, Mack CL. Inherited cholestatic diseases in the era of personalized medicine. Clin Liver Dis (Hoboken). 2020;15(3):105-109. doi:10.1002/cld.872 13. Spinner NB, Gilbert MA, Loomes KM, Krantz ID. Alagille syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. Seattle (WA): University of Washington, Seattle. Published online: May 19, 2000. Updated: December 12, 2019. https://www.ncbi.nlm.nih.gov/books/NBK1273/pdf/Bookshelf_NBK1273.pdf 14. 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 15. Jacquemin E. Progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol. 2012;36(suppl 1):S26-S35. doi:10.1016/S2210-7401(12)70018-9 16. Henkel SAF, Squires JH, Ayers M, Ganoza A, Mckiernan P, Squires JE. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol. 2019;11(5):450-463. doi:10.4254/wjh.v11.i5.450