Health Care Professional Site | Testing + Diagnosis

Clinical Criteria

Alagille syndrome can often be misdiagnosed as other cholestatic liver diseases, such as biliary atresia, due to signiﬁcant overlap of biochemical, histologic, and imaging features.⁴ To help avoid misdiagnosis or a delayed diagnosis, keep the expanded clinical diagnostic criteria top of mind.

Clinical features from 3 of the following 7 clinical criteria must be present when diagnosing Alagille syndrome⁴*^†:

HEPATIC
Cholestasis
Jaundice
Hepatomegaly

CARDIAC
Pulmonary stenosis
Tetralogy of Fallot

FACIAL
Prominent forehead
Pointed chin
Deep-set eyes
Bulbous tipped nose

OCULAR
Posterior embryotoxon
Optic disk drusen

SKELETAL
Butterfly vertebrae
Pathological fractures

RENAL
Renal dysplasia
Renal tubular acidosis

VASCULAR
Intracranial bleeding
Central nervous system (CNS) vascular malformations

Adapted from Ayoub et al. 2020.

*Absent of molecular diagnosis or family history.

^†Does not represent all possible clinical features.

Diagnostic Tools

The diagnosis of Alagille syndrome is established in a patient who meets the clinical diagnostic criteria, and can be further confirmed by identification of a heterozygous pathogenic variant in JAG1 or NOTCH2 on molecular genetic testing.⁵ Learn more about genetic testing.

To establish the extent of disease and needs in an individual diagnosed with Alagille syndrome, the following evaluations are recommended⁵:

Gastrointestinal

Evaluation

Evaluation by gastroenterologist includes liver function tests and clotting studies

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If determined necessary by gastroenterologist, additional studies include serum bile acids (sBA), fat-soluble vitamin levels, hepatic ultrasound, Technetium-99m-DISIDA scintiscan, and liver biopsy

Cardiovascular

Evaluation

Complete cardiology evaluation

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Includes echocardiogram

Eyes

Evaluation

Ophthalmologic evaluation

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Look for anterior chamber anomalies

Skeletal

Evaluation

Anteroposterior (AP) and lateral chest radiographs to evaluate for presence of butterfly vertebrae

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Renal

Evaluation

Evaluate with renal function studies and renal ultrasound

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Growth

Evaluation

Measurement of growth parameters and plotting on age-appropriate growth charts

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Development

Evaluation

Screening developmental evaluation

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More detailed evaluation should be performed if significant delays are identified

Genetics

Evaluation

Genetic testing and consultation with clinical geneticist and/or genetic counselor
Mirum is proud to sponsor free genetic testing through Travere Therapeutics to help with early diagnosis

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Adapted from Spinner et al. 2000.

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

Genetic
Testing

Diagnosis of Alagille syndrome can be challenging due to variable presentation of the clinical manifestations, which may vary even among individuals from the same family sharing the same mutation.² This lack of a genotype-phenotype correlation—or lack of a strong correlation between mutation type, clinical presentation, and severity—also complicates diagnosis.^1,3,5

The clinical diversity and the fact that bile duct paucity and cholestasis can occur in many other diseases may result in the under- or misdiagnosis of Alagille syndrome; molecular genetic testing, therefore, provides valuable confirmation, especially in milder cases or in diagnosis of extended family.^1,6

Molecular genetic testing approaches can include a combination of gene-targeted testing (serial single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing), depending on the phenotype.⁵

Gene-Targeted Testing

When the phenotypic and laboratory findings suggest the diagnosis of Alagille syndrome, individuals are likely to be diagnosed using molecular genetic testing, which can include serial single-gene testing or use of a multigene panel⁵:

Serial single-gene testing is where analysis for pathogenic variants for the JAG1 gene is first performed. If no variants are identified and there is strong clinical suspicion of Alagille syndrome diagnosis, then NOTCH2 molecular genetic testing is performed
A multigene panel covers JAG1, NOTCH2, and other genes of interest at once in order to identify the genetic cause of the condition at a reasonable cost while limiting identification of variants of uncertain significance (VUS) and pathogenic variants in genes that do not explain the underlying phenotype

Comprehensive Genomic Testing

When the diagnosis of Alagille syndrome is suspected, but an individual does not meet the clinical diagnostic criteria, comprehensive genomic testing—which does not require the identification of the gene(s) likely involved—is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. Although fewer patients have been reported to have pathogenic NOTCH2 variants, those who do have a lower prevalence of cardiac, vertebral, and facial abnormalities than those with pathogenic JAG1 variants.⁵

For more information about genetic testing and/or to get started, visit Travere Therapeutics, Inc.

Current Management Strategies

In recent years, a class of medicines called IBAT inhibitors have been approved by the FDA to treat the itch in certain liver disorders.^7,8

Symptom Management
Surgical Options + Transplant

Management of hepatic manifestations of Alagille syndrome focuses on controlling pruritus and supporting nutrition and fat-soluble vitamin deficiencies by nasogastric feeding or gastrostomy.¹

Off-label medications often used to treat symptoms include rifampin, ursodiol, cholestyramine, naltrexone, and antihistamines. However, these approaches may not be entirely effective and many patients either do not respond at all or require combination therapy.^1,7,8 In addition, these treatments are not FDA approved to treat cholestatic pruritus associated with Alagille syndrome.

With a lack of response to off-label pharmacologic agents, surgery, such as surgical biliary diversion or liver transplantation, becomes the only viable option to treat the signs and symptoms of cholestatic pruritus.⁸

If pharmacotherapy is not enough, cholestatic pruritus in Alagille syndrome may be managed by surgery, including surgical biliary diversion and, much more commonly, liver transplant.^7,9,10

Control of pruritus following partial external biliary diversion (PEBD) surgery in patients with Alagille syndrome correlated strongly with substantial reductions in sBA concentrations.¹¹ Liver transplant for Alagille syndrome has an 80% 5-year survival rate.²

It is important to note that a pretransplant evaluation must be conducted and should include an assessment of cardiac function to ensure the heart can handle the demands of transplant. If not, liver transplant may be eliminated from consideration.¹²

For others, while liver transplant addresses cholestatic liver disease and its manifestations, there are transplant-related considerations, including the burden of lifelong immunosuppressive therapy or surgical complications.⁸

AP=anteroposterior; CNS=central nervous system; PEBD=partial external biliary diversion; sBA=serum bile acid; VUS=variants of uncertain significance.

References: 1. 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 2. Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. Appl Clin Genet. 2016;9:75-82. doi:10.2147/TACG.S86420 3. 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 4. Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics (Basel). 2020;10(11):907. doi:10.3390/diagnostics10110907 5. 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 6. 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):1-4. doi:10.1038/ejhg.2013.140 7. Novel Drug Approvals for 2021. U.S. Food and Drug Administration. Accessed August 15, 2022. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2021 8. 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 9. 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

Testing + Diagnosis

In Alagille Syndrome, an Early Diagnosis Is Critical1

Clinical Criteria

HEPATIC

CARDIAC

FACIAL

OCULAR

SKELETAL

RENAL

VASCULAR

Diagnostic Tools

Gastrointestinal

Evaluation

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Cardiovascular

Evaluation

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Eyes

Evaluation

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Skeletal

Evaluation

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Renal

Evaluation

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Growth

Evaluation

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Development

Evaluation

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Genetics

Evaluation

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Genetic Testing

Gene-Targeted Testing

Comprehensive Genomic Testing

Current Management Strategies

In Alagille Syndrome, an
Early Diagnosis
Is Critical¹

Genetic
Testing