Alagille syndrome

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Alagille syndrome
Other namesAlagille–Watson syndrome (ALGS), hepatic ductular hypoplasia
Autosomal dominant - en.svg
Alagille syndrome is inherited in an autosomal dominant manner
Specialty Medical genetics, Gastroenterology, Cardiology
Named after Daniel Alagille

Alagille syndrome (ALGS) is a genetic disorder that affects primarily the liver and the heart. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 30,000 [1] [2] to 1 in every 40,000 live births. It is named after the French pediatrician Daniel Alagille, who first described the condition in 1969. [3] [4] Children with Alagille syndrome live to the age of 18 in about 90% of the cases. [5]

Contents

Signs and symptoms

The severity of the disorder can vary within the same family, with symptoms ranging from so mild as to go unnoticed, to severe heart and/or liver disease that requires transplantation. [6] It is uncommon, but Alagille syndrome can be a life-threatening disease with a mortality rate of 10%. [7] The majority of deaths from ALGS are typically due to heart complications or chronic liver failure. [8]

Liver

Signs and symptoms arising from liver damage in Alagille syndrome may include a yellowish tinge in the skin and the whites of the eyes (jaundice), itching (pruritus), pale stools (acholia), an enlarged liver (hepatomegaly), an enlarged spleen (splenomegaly) and deposits of cholesterol in the skin (xanthomas). [9] A liver biopsy may indicate too few bile ducts (bile duct paucity) or, in some cases, the complete absence of bile ducts (biliary atresia). Bile duct paucity results in the reduced absorption of fat and fat-soluble vitamins (A, D, E and K), which may lead to rickets or a failure to thrive. Cirrhosis and eventual liver failure is fairly common among ALGS patients, and 15% of those with severe hepatic manifestations require a liver transplant. [10] Hepatocellular cancer has been reported in a small number of cases, but it is extremely rare. [11]

Heart

Tetralogy of Fallot is a common heart defect experienced in Alagille syndrome patients. Tetralogy of Fallot.svg
Tetralogy of Fallot is a common heart defect experienced in Alagille syndrome patients.

Other

Other presentations of Alagille's syndrome include butterfly vertebrae, ophthalmic defects, and distinct facial structures. The butterfly vertebrae can be detected with an x-ray, but there typically are no symptoms from this abnormality. Other skeletal defects common in ALGS patients are spina bifida and the fusion of vertebrae. [10] Most of the ophthalmological defects affect the anterior chamber of the eyeball, including Axenfeld's anomaly and Rieger anomaly, but retina pigment changes are also common. [10] These anomalies can be beneficial in diagnosing Alagille syndrome. Many people with ALGS have similar facial features, including a broad, prominent forehead, deep-set eyes, and a small pointed chin. While these distinct facial features are often presented in ALGS patients, the features are presumably not due to Alagille syndrome, but they are characteristic of patients with intrahepatic cholestatic liver disease. [12] So while these facial characteristics are extremely common in ALGS patients, it is because many patients experience extreme liver complications or liver failure, but it is not caused by the disease itself. The kidneys may also be affected because the mutations in JAG1 and NOTCH2 often lead to renal dysplasia, deformed proximal tubules, or lipidosis caused by the hindrance of lipid metabolism. [13]

Genetics

ALGS is caused by loss of function mutations in either JAG1 (Jagged1) or NOTCH2 (Notch homolog 2). [14] [15] In the majority of people with ALGS, the gene mutation occurs in the JAG1 gene. The JAG1 mutation is either intragenic and found on chromosome 20p12, or it is a deletion of the entire JAG1 gene. [16] Mutations in NOTCH2 are much less likely to cause Alagille syndrome, but the primary type of ALGS-causing mutation in NOTCH2 is a missense mutation. [17] A missense mutation is a point mutation that changes one nucleotide, which results in a codon that codes for the wrong amino acid. Alagille syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene is sufficient to cause the disorder. The "autosomal" aspect of the disease means that the gene mutation occurs in an autosome, which is one of the 44 chromosomes in the human body that is not a sex chromosome (chromosome X or Y). Although the majority of cases are due to the autosomal dominant gene, there have been reports of a rare, autosomal recessive version of the disease. [16] In the autosomal recessive case, the ALGS patient must inherit two mutated genes: one from each parent. Although about 40% of the mutations are inherited from affected parents, most cases result from new, acquired mutations. These are caused by environmental factors that mutate one copy of the gene. [17] Environmental factors that can result in gene mutations may include radiation such as ultraviolet rays from the sun, or chemicals such as benzene, which is found in cigarette smoke. [18]

Pathophysiology

JAG1 and NOTCH2 encode for proteins that are crucial to the notch gene–signaling cascade. Specifically, JAG1 encodes for a surface-binding ligand that regulates the notch signaling pathway. It plays a crucial role in cell signaling during embryonic development. If the pathway is disrupted due to mutations, an infant will not develop properly. [6] Alagille syndrome causes bile duct paucity, which is characterized by narrow and malformed bile ducts. Bile duct paucity causes bile to build up in the liver, resulting in scarring of the liver which hinders the liver's normal functions, like blood filtration and drug metabolism. [6]

Diagnosis

Alagille syndrome can be extremely difficult to diagnose. While people are born with ALGS, it is almost always diagnosed later during childhood. The diagnosis can be difficult because the severity of the disease varies widely among patients. [19] Some common clinical tests that are run in order to diagnose the disease include vertebral x-rays, heart exams to detect any defects such as a heart murmur, and a liver biopsy to detect liver disease or any precursors. If a patient presents with multiple symptoms such as jaundice, heart murmur, and the characteristic facial features discussed above (deep set eyes, broad brow, etc.), they are likely to be diagnosed with Alagille syndrome. [19] A more calculated and specific diagnosis can be done with genetic testing. Next-generation sequencing can be utilized to detect single nucleotide polymorphisms (SNPs) in the affected gene(s). Multiplex ligation-dependent probe amplification (MLPA) can detect large deletions and/or insertions and microarray comparative genomic hybridization is used to improve the accuracy of MLPA. [20]

It is important to distinguish Alagille syndrome from biliary atresia because the latter benefits from a Kasai procedure in the early postnatal period, whereas this operation would make Alagille syndrome worse. Indirect features on ultrasound of biliary atresia include abnormal and diminutive gallbladder shape, the triangular cord sign, and hepatic artery enlargement, though these can overlap with Alagille syndrome. [21]

Treatment

Early treatment is possible once the disease is diagnosed. Treatments of Alagille syndrome typically involve medications, therapies, and/or surgical procedures. All treatments aim to improve bile excretion from the liver, reduce pain caused by the disease, and help improve nutritional deficiencies. [22] Diet can also be a crucial factor in improving quality of life when living with ALGS. [23]

Medication

Several medications are used to improve bile flow, including ursodiol (Actigall or Urso). [22] These medications differ in their rates of success. Certain drugs may be used to reduce itching (pruritus), such as cholestyramine and rifampin. While these medications can reduce pruritus, the itching often is reduced when bile flow is improved via ursodiol or liver transplant. [22]

Many patients with Alagille syndrome have nutritional and/or malabsorption issues which often hinders normal growth. Patients benefit from vitamin A, D, E, and K supplements because the reduced bile flow makes it difficult to absorb and utilize these vitamins. A high-calorie diet is very important, and often requires a gastrostomy tube to maintain the high caloric intake. [2]

Maralixibat (Livmarli) was approved for medical use in the United States in September 2021. [24] [25]

Surgery

Surgery is common in more severe cases on Alagille syndrome, especially for patients with liver disease or end-stage liver failure. Liver transplants can either be a complete liver transplant from a deceased organ donor, or a partial transplant from a living donor. [26] [27]

Partial biliary diversion has been used to significantly reduce pruritus, jaundice, and xanthoma caused by poor bile flow in patients with bile duct paucity. A portion of the bile produced by the liver is directed through a surgically created stoma into a plastic pouch on the patient's lower right abdomen. The pouch is periodically drained as it fills with bile. Patients with biliary atresia may require a Kasai procedure to improve bile drainage; however, later liver transplantation is still often necessary. [28]

See also

Related Research Articles

<span class="mw-page-title-main">Bile duct</span> Type of organ

A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates. The bile duct is separated into three main parts: the fundus (superior), the body (middle), and the neck (inferior).

<span class="mw-page-title-main">Caroli disease</span> Medical condition

Caroli disease is a rare inherited disorder characterized by cystic dilatation of the bile ducts within the liver. There are two patterns of Caroli disease: focal or simple Caroli disease consists of abnormally widened bile ducts affecting an isolated portion of liver. The second form is more diffuse, and when associated with portal hypertension and congenital hepatic fibrosis, is often referred to as "Caroli syndrome". The underlying differences between the two types are not well understood. Caroli disease is also associated with liver failure and polycystic kidney disease. The disease affects about one in 1,000,000 people, with more reported cases of Caroli syndrome than of Caroli disease.

<span class="mw-page-title-main">Biliary atresia</span> Absence, blockage, or narrowing of bile ducts in the liver at birth

Biliary atresia, also known as extrahepatic ductopenia and progressive obliterative cholangiopathy, is a childhood disease of the liver in which one or more bile ducts are abnormally narrow, blocked, or absent. It can be congenital or acquired. It has an incidence of one in 10,000–15,000 live births in the United States, and a prevalence of one in 16,700 in the British Isles. Biliary atresia is most common in East Asia, with a frequency of one in 5,000.

<span class="mw-page-title-main">Primary biliary cholangitis</span> Autoimmune disease of the liver

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.

<span class="mw-page-title-main">Alport syndrome</span> Medical condition

Alport syndrome is a genetic disorder affecting around 1 in 5,000–10,000 children, characterized by glomerulonephritis, end-stage kidney disease, and hearing loss. Alport syndrome can also affect the eyes, though the changes do not usually affect vision, except when changes to the lens occur in later life. Blood in urine is universal. Proteinuria is a feature as kidney disease progresses.

<span class="mw-page-title-main">Primary sclerosing cholangitis</span> Hardening of the bile ducts due to scarring and inflammation

Primary sclerosing cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts, which normally allow bile to drain from the gallbladder. Affected individuals may have no symptoms or may experience signs and symptoms of liver disease, such as yellow discoloration of the skin and eyes, itching, and abdominal pain.

Situs ambiguus, or heterotaxy, is a rare congenital defect in which the major visceral organs are distributed abnormally within the chest and abdomen. Clinically, heterotaxy spectrum generally refers to any defect of left-right asymmetry and arrangement of the visceral organs; however, classical heterotaxy requires multiple organs to be affected. This does not include the congenital defect situs inversus, which results when arrangement of all the organs in the abdomen and chest are mirrored, so the positions are opposite the normal placement. Situs inversus is the mirror image of situs solitus, which is normal asymmetric distribution of the abdominothoracic visceral organs. Situs ambiguus can also be subdivided into left-isomerism and right isomerism based on the defects observed in the spleen, lungs and atria of the heart.

<span class="mw-page-title-main">Ursodeoxycholic acid</span> Medication and metabolite of cholesterol

Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in bile of bears of genus Ursus, from which its name derived. In purified form, it has been used to treat or prevent several diseases of the liver or bile ducts.

<span class="mw-page-title-main">Cholestasis</span> Medical condition

Cholestasis is a condition where the flow of bile from the liver to the duodenum is impaired. The two basic distinctions are:

Cholangiocytes are the epithelial cells of the bile duct. They are cuboidal epithelium in the small interlobular bile ducts, but become columnar and carbonate-secreting in larger bile ducts approaching the porta hepatis and the extrahepatic ducts. They contribute to hepatocyte survival by transporting bile acids.

<span class="mw-page-title-main">Dubin–Johnson syndrome</span> Genetic liver disease

Dubin–Johnson syndrome is a rare, autosomal recessive, benign disorder that causes an isolated increase of conjugated bilirubin in the serum. Classically, the condition causes a black liver due to the deposition of a pigment similar to melanin. This condition is associated with a defect in the ability of hepatocytes to secrete conjugated bilirubin into the bile, and is similar to Rotor syndrome. It is usually asymptomatic, but may be diagnosed in early infancy based on laboratory tests. No treatment is usually needed.

<span class="mw-page-title-main">Dyskeratosis congenita</span> Medical condition

Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare progressive congenital disorder with a highly variable phenotype. The entity was classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa, and myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), but these components do not always occur. DKC is characterized by short telomeres. The disease initially can affect the skin, but a major consequence is progressive bone marrow failure which occurs in over 80%, causing early mortality.

<span class="mw-page-title-main">Crigler–Najjar syndrome</span> Rare inherited disorder affecting the metabolism of bilirubin

Crigler–Najjar syndrome is a rare inherited disorder affecting the metabolism of bilirubin, a chemical formed from the breakdown of the heme in red blood cells. The disorder results in a form of nonhemolytic jaundice, which results in high levels of unconjugated bilirubin and often leads to brain damage in infants. The disorder is inherited in an autosomal recessive manner. The annual incidence is estimated at 1 in 1,000,000.

Progressive familial intrahepatic cholestasis (PFIC) is a group of familial cholestatic conditions caused by defects in biliary epithelial transporters. The clinical presentation usually occurs first in childhood with progressive cholestasis. This usually leads to failure to thrive, cirrhosis, and the need for liver transplantation.

<span class="mw-page-title-main">Rotor syndrome</span> Medical condition

Rotor syndrome is a rare cause of mixed direct (conjugated) and indirect (unconjugated) hyperbilirubinemia, relatively benign, autosomal recessive bilirubin disorder characterized by non-hemolytic jaundice due to the chronic elevation of predominantly conjugated bilirubin.

Neonatal cholestasis refers to elevated levels of conjugated bilirubin identified in newborn infants within the first few months of life. Conjugated hyperbilirubinemia is clinically defined as >20% of total serum bilirubin or conjugated bilirubin concentration greater than 1.0 mg/dL regardless of total serum bilirubin concentration. The differential diagnosis for neonatal cholestasis can vary extensively. However, the underlying disease pathology is caused by improper transport and/or defects in excretion of bile from hepatocytes leading to an accumulation of conjugated bilirubin in the body. Generally, symptoms associated with neonatal cholestasis can vary based on the underlying cause of the disease. However, most infants affected will present with jaundice, scleral icterus, failure to thrive, acholic or pale stools, and dark urine.

<span class="mw-page-title-main">Hepatoportoenterostomy</span> Type of surgerical treatment

A hepatoportoenterostomy or Kasai portoenterostomy is a surgical treatment performed on infants with Type IVb choledochal cyst and biliary atresia to allow for bile drainage. In these infants, the bile is not able to drain normally from the small bile ducts within the liver into the larger bile ducts that connect to the gall bladder and small intestine.

<span class="mw-page-title-main">JAG1</span> Protein found in humans

Jagged1 (JAG1) is one of five cell surface proteins (ligands) that interact with four receptors in the mammalian Notch signaling pathway. The Notch signaling pathway is a highly conserved pathway that functions to establish and regulate cell fate decisions in many organ systems. Once the JAG1-NOTCH (receptor-ligand) interactions take place, a cascade of proteolytic cleavages is triggered resulting in activation of the transcription for downstream target genes. Located on human chromosome 20, the JAG1 gene is expressed in multiple organ systems in the body and causes the autosomal dominant disorder Alagille syndrome (ALGS) resulting from loss of function mutations within the gene. JAG1 has also been designated as CD339.

<span class="mw-page-title-main">Autosomal recessive polycystic kidney disease</span> Medical condition

Autosomal recessive polycystic kidney disease (ARPKD) is the recessive form of polycystic kidney disease. It is associated with a group of congenital fibrocystic syndromes. Mutations in the PKHD1 cause ARPKD.

Vanishing bile duct syndrome is a loose collection of diseases leading to hepatic bile duct injury and eventual ductopenia.

References

  1. ↑ Mitchell E, Gilbert M, Loomes KM (November 2018). "Alagille Syndrome". Clinics in Liver Disease. 22 (4): 625–641. doi:10.1016/j.cld.2018.06.001. PMID   30266153.
  2. 1 2 Ayoub MD, Kamath BM (August 2022). "Alagille Syndrome: Current Understanding of Pathogenesis, and Challenges in Diagnosis and Management". Clinics in Liver Disease. 26 (3): 355–370. doi:10.1016/j.cld.2022.03.002. PMID   35868679.
  3. ↑ synd/729 at Who Named It?
  4. ↑ Alagille D, Odièvre M, Gautier M, Dommergues JP (January 1975). "Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur". The Journal of Pediatrics. 86 (1): 63–71. doi:10.1016/S0022-3476(75)80706-2. PMID   803282.
  5. ↑ Ayoub MD, Bakhsh AA, Vandriel SM, Keitel V, Kamath BM (October 2023). "Management of adults with Alagille syndrome". Hepatology International. 17 (5): 1098–1112. doi:10.1007/s12072-023-10578-x. PMC   10522532 . PMID   37584849.
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  8. ↑ Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N (August 2018). "Systematic Review: The Epidemiology, Natural History, and Burden of Alagille Syndrome". Journal of Pediatric Gastroenterology and Nutrition. 67 (2). J Pediatr Gastroenterol Nutr: 148–156. doi:10.1097/MPG.0000000000001958. PMC   6110620 . PMID   29543694.
  9. ↑ "Symptoms & Causes for Alagille Syndrome". National Institute of Diabetes and Digestive and Kidney Diseases.
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  11. ↑ Sijmons RH (February 2008). "Encyclopaedia of tumour-associated familial disorders. Part I: from AIMAH to CHIME syndrome". Hereditary Cancer in Clinical Practice. 6 (1): 22–57. doi: 10.1186/1897-4287-6-1-22 . PMC   2735164 . PMID   19706204.
  12. ↑ Sokol RJ, Heubi JE, Balistreri WF (August 1983). "Intrahepatic "cholestasis facies": is it specific for Alagille syndrome?". The Journal of Pediatrics. 103 (2): 205–208. doi:10.1016/s0022-3476(83)80345-x. PMID   6875709.
  13. ↑ Bissonnette ML, Lane JC, Chang A (May 2017). "Extreme Renal Pathology in Alagille Syndrome". Kidney International Reports. 2 (3): 493–497. doi:10.1016/j.ekir.2016.11.002. PMC   5720621 . PMID   29318215.
  14. ↑ Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, et al. (July 1997). "Mutations in the human Jagged1 gene are responsible for Alagille syndrome". Nature Genetics. 16 (3): 235–242. doi:10.1038/ng0797-235. PMID   9207787. S2CID   5775213.
  15. ↑ Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, et al. (February 2012). "NOTCH2 mutations in Alagille syndrome". Journal of Medical Genetics. 49 (2): 138–144. doi:10.1136/jmedgenet-2011-100544. PMC   3682659 . PMID   22209762.
  16. 1 2 Vajro P, Ferrante L, Paolella G (June 2012). "Alagille syndrome: an overview". Clinics and Research in Hepatology and Gastroenterology. 36 (3): 275–277. doi:10.1016/j.clinre.2012.03.019. PMID   22521120.
  17. 1 2 Mitchell E, Gilbert M, Loomes KM (November 2018). "Alagille Syndrome". Clinics in Liver Disease. 22 (4). Springer: 625–641. doi:10.1016/j.cld.2018.06.001. PMID   30266153. S2CID   52883591.
  18. ↑ "What is a gene mutation and how do mutations occur?". Genetics Home Reference. U.S. National Library of Medicine.
  19. 1 2 "Alagille Syndrome - Diagnosis & Treatment". Boston Children's Hospital.
  20. ↑ Ohashi K, Togawa T, Sugiura T, Ito K, Endo T, Aoyama K, et al. (November 2017). "Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome". Acta Paediatrica. 106 (11): 1817–1824. doi:10.1111/apa.13981. PMID   28695677. S2CID   24604635.
  21. ↑ Abdel Razek A, Abdalla A, Elfar R, Ashmalla GA, Ali K, Barakat T (December 2020). "Assessment of Diffusion Tensor Imaging Parameters of Hepatic Parenchyma for Differentiation of Biliary Atresia from Alagille Syndrome". Korean journal of radiology. 21 (12): 1367–1373. doi:10.3348/kjr.2019.0824. PMC   7689146 . PMID   32729270.
  22. 1 2 3 "Alagille Syndrome". Department of Surgery. University of California - San Francisco. Retrieved 2019-10-08.
  23. ↑ Jesina D (2017-11-01). "Alagille Syndrome: An Overview". Neonatal Network. 36 (6): 343–347. doi:10.1891/0730-0832.36.6.343. ISSN   1539-2880. PMID   29185945.
  24. ↑ "Highlights of prescribing information: LIVMARLITM (maralixibat) oral solution" (PDF). Mirum Pharmaceuticals, Inc. U.S. Food and Drug Administration.
  25. ↑ "Maralixibat: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 29 September 2021.
  26. ↑ Doria C (2016). Doria C (ed.). Contemporary Liver Transplantation : The Successful Liver Transplant Program. Springer. ISBN   9783319055435. OCLC   1111825084.
  27. ↑ "Donor Requirements & Evaluation - Live Liver Transplant". Lahey Hospital & Medical Center, Burlington & Peabody. Retrieved 2019-10-08.
  28. ↑ Turnpenny PD, Ellard S (March 2012). "Alagille syndrome: pathogenesis, diagnosis and management". European Journal of Human Genetics . 20 (3): 251–257. doi:10.1038/ejhg.2011.181. ISSN   1476-5438. PMC   3283172 . PMID   21934706.

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