For US Health Care Professionals
Meet Teddy

Teddy has a chronic pediatric cholestatic liver 
disease—and it’s unbearable. That’s why there’s 
ongoing research to address challenges and, 
ultimately, help patients like Teddy.

Teddy’s fur is scratched, scarred, and yellowing. He has deep-set eyes and a prominent chin. He has poor weight gain and growth. Teddy has Alagille syndrome (ALGS).

Like with every pediatric patient with chronic cholestatic liver disease, ALGS has impaired Teddy’s quality of life and robbed him of his childhood.1 Teddy shouldn't have to bear it any longer.

That’s why Mirum is focusing on ALGS. We’re dedicated to raising awareness and addressing the impact cholestatic liver diseases can have on patients like Teddy. In support of this commitment, we are doing our part to conduct research and help patients reclaim their childhoods.

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What Is 
ALGS?

ALGS is a rare, life-threatening multisystem disease that often presents in childhood.2 With ALGS, bile ducts are abnormally narrow, malformed, and reduced in number, which leads to bile accumulation in the liver and, ultimately, progressive liver disease.1,3

For more information about cholestatic liver disease, visit these Resources.

ALGS is an autosomal dominant disorder caused by mutations/deletions in the1,2,4:

PREVALENCE
PREVALENCE
Disruptions in these genes cause defective bile duct morphogenesis and impaired angiogenesis, and abnormalities in skeletal, ocular, cardiovascular, and kidney development.5 In some cases, the mutation occurs de novo in the individual.6

ALGS affects 
males and 
females equally
6

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The estimated incidence 
of ALGS is 1 in every 
30,000 births
6

There are currently an estimated 2500 children living with ALGS in the United States.
There are currently 
an estimated 
2500 children 
living with ALGS in 
the United States7

In patients with ALGS, multiple 
organs/areas may be affected, including6:

In patients with ALGS, multiple organs/areas may be affected. In patients with ALGS, multiple organs/areas may be affected.

Importantly, the bile duct paucity associated with ALGS leads to impaired bile flow, accumulation of bile acids, and cholestatic liver injury.1,8 Increased bile acids lead to debilitating pruritus. This, in turn, can cause severe sleep deprivation, resulting in fatigue, a failure to thrive, and a dramatic reduction in quality of life.9,10 In approximately 15% of patients, progressive liver disease results in cirrhosis of the liver and liver failure. Phenotype is not a clear predictor for risk of progressive liver disease in ALGS.6

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Symptoms of Alagille syndrome usually appear in the first 2 years of life.11 Driven by the increase in serum bile acids, cholestatic pruritus is described as a severe, unrelenting itch, and has been identified as the most bothersome symptom of ALGS.1 This unrelenting pruritus negatively impacts patients’ quality of life, and is a leading cause of liver transplantation.1,12

pruritus
DESKTOP_pruritus (1)

In a study of 44 patients with ALGS, indications for liver transplantation were refractory pruritus (n=36), disfiguring xanthomas (n=32), bone fractures (n=15), and/or signs of end-stage liver disease (ESLD) (n=5), all resulting in a very poor quality of life.13

Although liver transplantation can effectively address severe pruritus, many patients with ALGS do not undergo surgery until the age of 18. In turn, most spend the majority of their childhoods suffering from unrelenting itch. Even more, in patients who do not receive a liver transplant, 75% continue to experience insufferable scratching.7

Additional signs and symptoms arising from chronic cholestasis in ALGS may include1,2,14:

JAUNDICE
JAUNDICE
XANTHOMAS
XANTHOMAS
FAILURE TO THRIVE AND GROWTH DEFICIENCIES
FAILURE TO THRIVE AND GROWTH DEFICIENCIES
DIMINISHED QUALITY OF LIFE
DIMINISHED QUALITY OF LIFE(eg, fatigue, sleep problems, and mood disturbances)

Extrahepatic manifestations include6,14,15:

  • Hypovitaminosis leading to rickets, brittle bones, and blood clotting problems
  • Cardiovascular issues, including peripheral pulmonic stenosis (PPS)
  • Facial structural changes, including prominent forehead, deep-set eyes, pointed chin, and prominent nose
  • Skeletal abnormalities, including butterfly vertebrae
  • Ocular, including posterior embryotoxon
  • Renal and vascular abnormalities

Diagnosing ALGS early is critical.2 However, diagnosis of ALGS can be challenging due to variable presentation of the clinical manifestations.8 There is no strong correlation between mutation type, clinical manifestation, and severity.2,16

When diagnosing ALGS, 3 of the following 5 major clinical features must be present: cholestasis with bile duct paucity on liver biopsy, congenital cardiac defects (with particular involvement of the pulmonary arteries), posterior embryotoxon in the eye, characteristic facial features, and butterfly vertebrae.8,15

From there, diagnostic workup includes17:

diagnosis chart diagnosis chart

For more information about early identification of cholestatic liver disease, visit the Children’s Liver Disease Foundation’s Yellow Alert.

Pathophysiology

The main pathophysiologic characteristics underlying cholestasis in nearly every individual with ALGS are abnormal development of intrahepatic bile ducts and bile duct paucity.1 Because of this, infants can develop jaundice and cholestasis during the first 4 months of life.6

Cholestasis is defined as the impaired formation or flow of bile in the hepatobiliary system. With cholestasis, the reabsorption of bile acids from the intestine back to the liver via the portal vein can lead to the toxic accumulation of bile acids. This toxic buildup of bile acids can present with features of jaundice and unbearable pruritus, as well as damage to liver cells and, ultimately, liver injury.1

In ALGS, complications of profound cholestasis—most commonly intractable pruritus and poor quality of life—result as the main indication or driver for liver transplantation.12

Living With ALGS

The symptoms and severity of ALGS can vary greatly from one person to another. For most families with ALGS, life can feel uncertain.

Pruritus affects up to 88% of children with ALGS, and it is among the most severe in any chronic liver disease, negatively impacting quality of life, physical health, and psychosocial health.1,2

Poor Quality of Life

ALGS is more than an insufferable itch. Parents and caregivers of children with ALGS describe pruritus as the most challenging symptom, citing the anxiety, fatigue, and emotional distress associated with unrelenting itching and scratching.2,18,19

In addition to unrelenting itching and scratching, cholestatic pruritus leads to skin damage, bleeding, scarring, cutaneous mutilation, sleep disturbances, disrupted school activities, and more.1,2,18 Furthermore, many children with ALGS encounter significant growth deficits and a failure to thrive.2,19,20


We end up with bloody bed sheets, wounds on his face, and him wanting to tear his skin off. –Robigaile B.

Lack of Effective Treatments

There are currently no approved drugs to treat the underlying disease or provide symptomatic relief of ALGS. Several medications are often utilized to treat symptoms, including rifampin, ursodiol, cholestyramine, naltrexone, and antihistamines. However, these approaches are often ineffective.1,15 With a lack of response to pharmacologic agents, surgery becomes the only viable option to treat the signs and symptoms of cholestatic pruritus. Therefore, there is a high unmet need in ALGS for novel pharmacologic strategies to serve as an alternative to surgical interventions, including liver transplantation.1


We run 14 syringes of medication through his G-tube every morning, night and midnight. Still, he itches and scratches all the time. –Chad H.

Surgical Options + Transplantation

In the absence of effective pharmacotherapy, cholestatic pruritus in ALGS is often managed by surgery, including surgical biliary diversion and more commonly, liver transplantation.1,5,21 While liver transplantation addresses cholestatic liver disease and its manifestations, there are transplant-related considerations, including lifelong immunosuppressive therapy.1

…Knowing our son might one day need a liver transplant, we worried and had many questions. –Maribel V.
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Patients like Teddy 
shouldn't have to 
bear ALGS
any longer

divider Patients like Teddy shouldn't have to bear ALGS any longer

Long-Term Outlook

Current Therapies

Symptom management of ALGS only scratches the surface and does not target the source of patients’ suffering. Surgical biliary diversion and liver transplantation are viable treatment options, but they present several issues, such as the need for lifelong immunosuppressive therapy, permanent stoma, or surgical complications. These are practical limitations to treatment.1


Treatment Landscape

For patients with ALGS, there is a need for disease-modifying treatment options that target the root cause of the disease. These treatment goals should1:

  • Reduce the accumulation of bile acids in the liver
  • Relieve cholestatic pruritus
  • Limit the progression of liver disease
  • Improve long-term prognosis

Promising Research

Preclinical and clinical data support apical sodium-dependent bile acid transporter (ASBT) inhibitors, also known as ileal bile acid transporter (IBAT) inhibitors, as disease-modifying therapeutic treatment options. These may play a crucial role in reducing the symptoms of ALGS by reducing bile acid accumulation in the liver and reducing the potential for hepatobiliary injury.1

Significant scientific discovery for better treatments of ALGS could mean other children won’t have to suffer like my daughter. –Jazmyn R.
Long-Term Outlook

ALGS Resources

  • Children’s Liver Disease Foundation’s Yellow Alert
  • The Alagille Syndrome Alliance
  • National Organization for Rare Disorders
  • Johns Hopkins Medicine

ALGS=Alagille syndrome; ASBT=apical sodium-dependent bile acid transporter; ESLD=end-stage liver disease; IBAT=ileal bile acid transporter.

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;40:1812-1822. doi:10.1111/liv.14553
  2. 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
  3. MedlinePlus. Alagille Syndrome. Accessed December 2, 2020. https://medlineplus.gov/genetics/condition/alagille-syndrome
  4. Goldberg A, Mack CL. Inherited cholestatic diseases in the era of personalized medicine. Clin Liver Dis. 2020;15(3):105-109. doi:10.1002/cld.872
  5. Verkade HJ, Bezerra JA, Davenport M, et al. Biliary atresia and other cholestatic childhood diseases: advances and future challenges. J Hepatol. 2016;65(3):631-642. doi:10.1016/j.jhep.2016.04.032
  6. National Organization for Rare Disorders. Alagille Syndrome. Accessed December 2, 2020. https://rarediseases.org/rare-diseases/alagille-syndrome/
  7. Mirum Pharmaceutical Market Research. 2020.
  8. Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. Appl Clin Genet. 2016;9:75-82. doi:10.2147/TACG.S86420
  9. Gerber L. Sleep deprivation in children: a growing public health concern. Nurs. 2014;44(4):50-54. doi:10.1097/01.NURSE.0000441881.87748.90
  10. 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
  11. Johns Hopkins Medicine. Alagille Syndrome. Accessed December 2, 2020. https://www.hopkinsmedicine.org/health/conditions-and-diseases/alagille-syndrome
  12. Kamath BM, Schwarz KB, Hadzἷć N. Alagille syndrome and liver transplantation. J Pediatr Gastroenterol Nutr. 2010;50(1):11-15. doi:10.1097/MPG.0b013e3181c1601f
  13. 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
  14. Singh SP, Pati GK. Alagille syndrome and the liver: current insights. Euroasian J Hepatogastroenterol. 2018;8(2):140-147. doi: 10.5005/jp-journals-10018-1280
  15. Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2012;20(3):251-257. doi:10.1038/ejhg.2011.181
  16. Fischetto R, Palmieri VV, Tripaldi ME, et al. Alagille syndrome: a novel mutation in JAG1 gene. Front Pediatr. 2019;7:1-5. doi:10.3389/fped.2019.00199
  17. 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
  18. 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
  19. 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
  20. Quiros-Tejeira RE, Ament ME, Heyman MB, et al. Does liver transplantation affect growth pattern in Alagille syndrome? Liver Transpl. 2000;6(5):582-587. doi:10.1053/jlts.2000.9739
  21. Ellinger P, Stindt J, Dröge C, et al. Partial external biliary diversion in bile salt export pump deficiency: association between outcome and mutation. World J Gastroenterol. 2017;23(29):5295-5303. doi:10.3748/wjg.v23.i29.5295