For US Health Care Professionals

Mechanism of Disease for Alagille Syndrome

Pathophysiology

The main pathophysiologic characteristics underlying cholestasis in individuals with Alagille syndrome (ALGS) are abnormal development of intrahepatic bile ducts and bile duct paucity.1

pathophysiology

Serum Bile Acids

An important component of bile are bile acids, which help facilitate digestion and absorption of dietary cholesterol, triglycerides, and fat-soluble vitamins.2

Normal Enterohepatic Circulation

NORMAL ENTEROHEPATIC CIRCULATION

Normally, bile acids are synthesized in hepatocytes and secreted in the bile via bile salt export pumps (BSEP) at the apical (canalicular) membrane. Bile acids then move through bile ducts to the gallbladder for storage and, later, for release into the small intestine to aid in digestion and absorption. Per cycle, up to 95% of bile acids are reabsorbed from the ileum via the apical sodium-dependent bile acid transporter (ASBT), also known as the ileal bile acid transporter (IBAT), for return to the liver through the hepatic portal vein.1

CHOLESTATIC LIVER DISEASE MECHANISM OF DISEASE

In cholestatic liver disease, the flow of bile is impaired at some point between the liver cells, which produce bile, and the duodenum. Bile acids, therefore, build up in the liver. This leads to liver injury and/or 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).3,4

Cholestatic Liver Disease Mechanism of Disease
ALGS Mechanism of Disease

ALGS MECHANISM OF DISEASE

In Alagille syndrome (ALGS), specifically, the narrow, malformed, or reduced number of bile ducts results in bile buildup in the liver and subsequent clinical manifestations of the disease.5 In addition, enterohepatic reabsorption of bile acids from the intestine back to the liver may be enhanced or accelerated during cholestasis and can lead to the toxic accumulation of bile acids.1

This toxic buildup of bile acids can damage liver cells, leading to activation of fibrotic and inflammatory pathways that, ultimately, lead to liver injury.1

In ALGS, sBA levels are generally elevated up to several hundred times the typical upper limit of normal.6 Elevated sBA levels have been implicated in pruritus via this hepatocyte toxicity. The detergent bile acids alter hepatocyte membranes, permitting the leakage of hepatocyte contents—some of which are pruritogens—into the bloodstream.7

Reducing sBA levels in patients with cholestasis is predicted to result in decreased liver damage.8

Pruritus

The most debilitating symptom of cholestasis in Alagille syndrome (ALGS) is intense pruritus, which is among the worst in any cholestatic liver disease.9

Driven by the increase in sBA, cholestatic pruritus is described as a severe, unrelenting itch.1 This unrelenting pruritus negatively impacts patients’ quality of life.10

Pruritus is a leading cause of liver transplant in patients with ALGS.
76%
of patients with ALGS have had a liver transplant or died before the age of 18.1,10
82%
of liver transplants in ALGS had refractory pruritus as their indication.11

Therapy-refractory persistent pruritus is an indication for liver transplant, even in the absence of liver failure.12

Because physicians may delay liver transplant to avoid associated complications, pediatric patients can continue to suffer from debilitating pruritus and poor quality of life for years.13

ALGS currently has no cure. The goal of medical management is to relieve pruritus and prevent end-stage liver disease (ESLD), prolong survival, and possibly even prevent the need for liver transplant.14,15

Due to disease management shortcomings, liver transplant is often performed.6 There is a high burden of progressive liver disease in ALGS, with early profound cholestasis, and a second wave of portal hypertension and associated complications later in adolescence. Less than 25% of patients reach young adulthood with their native liver.16

Indications for liver transplant include17:

  • Intractable pruritus or deforming xanthomas
  • Liver failure and complications of portal hypertension
  • Repeated bone fractures due to intractable metabolic bone disease
  • Growth impairment
  • Poor quality of life

In a study of 44 patients with ALGS, indications for liver transplant were refractory pruritus (n=36), disfiguring xanthomas (n=32), bone fractures (n=15), and/or signs of ESLD (n=5), all resulting in a very poor quality of life.11

The pruritus experienced by patients with ALGS is among the most severe in any chronic liver disease, negatively impacting physical and psychosocial health.1,18

Due to a lack of pediatric itch assessments that meet current FDA patient-reported outcome (PRO) guidelines, the Itch Reported Outcome (ItchRO) tool—available as both a patient- and caregiver-reported outcome tool—was developed specifically for, and fully validated in, patients with cholestatic liver disease.19

ItchRO Tool

The ItchRO tool features a 5-point scoring system to assess the intensity of the itching15:

Move the slider to view the itch scale.

point
0=None
point
1=Mild Itch
point
2=Moderate Itch
point
3=Severe Itch
point
4=Very Severe Itch

Move the slider to view the itch scale.

point
point
point
point
point
0=None
1=Mild Itch
2=Moderate Itch
3=Severe Itch
4=Very Severe Itch

In practice, a caregiver is provided with a morning and evening ItchRO electronic diary15:

Morning Diary Example

Morning Diary Example

Based on observations or what your child told you about his/her itching, how severe were your child's itch-related symptoms (rubbing, scratching, skin damage, sleep disturbances, or irritability) from when he/she went to bed last night until he/she woke up this morning?

itch severity
Evening Diary Example

Evening Diary Example

Based on observations or what your child told you about his/her itching, how severe were your child's itch-related symptoms (rubbing, scratching, skin damage, sleep disturbances, or irritability) from the time he/she woke up this morning until he/she went to bed?

itch severity

A patient who is 9 years, on the other hand, is provided with morning and evening diaries that differ slightly19:

ItchRO: Morning Diary Example

ItchRO:
Morning Diary Example

  1. Think about whether itching kept you awake or woke you up last night. Think about whether you felt like rubbing or scratching.

How itchy did you feel last night after you went to bed until you woke up this morning?

ItchRO: Morning Diary Example

(Note: The following two items are exploratory and will not contribute to the ItchRO score. If the subject answered “I didn’t feel itchy”, the following will not be presented on the eDiary)

  1. Did feeling itchy make it hard to fall asleep last night?
    • Yes
    • No
  2. Did feeling itchy wake you up last night?
    • Yes
    • No
ItchRO: Evening Diary Example

ItchRO:
Evening Diary Example

  1. Think about how itchy you were all day. Think about whether you felt like rubbing or scratching.

How itchy were you all day today from the time when you woke up until now?

ItchRO: Morning Diary Example

(Note: The following item is exploratory and will not contribute to the ItchRO score. If the subject answered “I didn’t feel itchy”, the following will not be presented on the eDiary)

  1. Did feeling itchy make you rub or scratch today?
    • No
    • Yes, but it left no marks
    • Yes, and it left marks but my skin wasn’t red
    • Yes, and it left red marks
    • Yes, and my skin bled

Clinician Scratch Scale (CSS)

In addition to the caregiver- and patient-rated ItchRO, pruritus can also be assessed using the physician-rated CSS score.16

The CSS is based on a 5-point scale, where16,20:

  1. none
  2. rubbing or mild scratching when undistracted
  3. active scratching without evident skin abrasions
  4. abrasions evident
  5. cutaneous mutilation, hemorrhage, and scarring evident

These novel tools allow physicians to better assess the severity of itching in children with ALGS and other cholestatic liver diseases.

ALGS=Alagille syndrome; ASBT=apical sodium-dependent bile acid transporter; BSEP=bile salt export pump; CSS=Clinician Scratch Scale; ESLD=end-stage liver disease; IBAT=ileal bile acid transporter; ItchRO=Itch Reported Outcome; PEBD=partial external biliary diversion; PRO=patient-reported outcome; sBA=serum bile acid.
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. Di Ciaula A, Garruti G, Lunardi Baccetto RL, et al. Bile acid physiology. Ann Hepatol. 2017;16(suppl 1):s4-s14. doi:10.5604/01.3001.0010.5493 3. Chiang JYL, Ferrell JM. Bile acid metabolism in liver pathobiology. Gene Expr. 2018;18(2):71-87. doi:10.3727/105221618X15156018385515 4. 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 5. MedlinePlus. Alagille syndrome. Accessed March 9, 2021. https://medlineplus.gov/genetics/condition/alagille-syndrome 6. Gonzales E, Hardikar W, Stormon M, et al. Maralixibat treatment significantly reduces pruritus and serum bile acids in patients with Alagille syndrome: results from a randomized phase II study with 4 years of follow-up. Lancet. In press. 7. Poupon R, Chopra S. Pruritus associated with cholestasis. UpToDate. Published February 16, 2021. Accessed March 9, 2021. https://www.uptodate.com/contents/pruritus-associated-with-cholestasis 8. Perez MJ, Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol. 2009;15(14):1677-1689. doi:10.3748/wjg.15.1677 9. Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics (Basel). 2020;10(11):907. doi:10.3390/diagnostics10110907 10. 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 11. 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 12. 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 13. Mirum Pharmaceutical Market Research. 2020. 14. 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 15. Kamath BM, Spino C, McLain R, et al. Unraveling the relationship between itching, scratch scales, and biomarkers in children with Alagille syndrome. Hepatol Commun. 2020;4(7):1012-1018. doi:10.1002/hep4.1522 16. Kamath BM, Ye W, Goodrich NP, et al. Outcomes of childhood cholestasis in Alagille syndrome: results of a multicenter observational study. Hepatol Commun. 2020;4(3):387-398. doi:10.1002/hep4.1468 17. 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 18. 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 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. Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology. 1988;95(1):130-136. doi:10.1016/0016-5085(88)90301-0