Alagille syndrome (ALGS) is a
genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
that affects primarily the
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
and the
heart
The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
. 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
to 1 in every 40,000 live births. It is named after the French pediatrician
Daniel Alagille, who first described the condition in 1969.
Children with Alagille syndrome live to the age of 18 in about 90% of the cases.
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.
It is uncommon, but Alagille syndrome can be a life-threatening disease with a mortality rate of 10%. The majority of deaths from ALGS are typically due to heart complications or chronic liver failure.
Liver
Signs and symptoms arising from liver damage in Alagille syndrome may include a yellowish tinge in the
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different ...
and the whites of the eyes (
jaundice
Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving ...
), itching (
pruritus
An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...
), pale stools (
acholia
Acholia is pale feces, due to lack of bile which results in the normal brown colour.Dorland's Medical Dictionary for Health Consumers. Saunders; 2007. It is a sign of reduced conjugated bilirubin into the bowel, as a result of a problem in the ...
), an enlarged liver (hepatomegaly), an enlarged spleen (splenomegaly) and deposits of
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
in the skin (
xanthomas). A
liver biopsy
Liver biopsy is the biopsy (removal of a small sample of tissue) from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.
Medica ...
may indicate too few
bile duct
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).
Bile is requ ...
s (bile duct paucity) or, in some cases, the complete absence of bile ducts (
biliary atresia
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. ...
). 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
Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...
.
Cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...
and eventual
liver failure
Liver failure is the inability of the liver to perform its normal synthetic and metabolic functions as part of normal physiology. Two forms are recognised, acute and chronic (cirrhosis). Recently, a third form of liver failure known as acute- ...
is fairly common among ALGS patients, and 15% of those with severe
hepatic
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
manifestations require a liver transplant.
Hepatocellular cancer has been reported in a small number of cases, but it is extremely rare.
Heart
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.
Most of the ophthalmological defects affect the
anterior chamber of the eyeball, including
Axenfeld's anomaly and Rieger anomaly, but
retina
The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...
pigment changes are also common.
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. 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
kidney
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
s may also be affected because the mutations in ''
JAG1
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 ...
'' and ''
NOTCH2
Neurogenic locus notch homolog protein 2 (Notch 2) is a protein that in humans is encoded by the ''NOTCH2'' gene.
NOTCH2 is associated with Alagille syndrome and Hajdu–Cheney syndrome.
Function
Notch 2 is a member of the notch family. Me ...
'' often lead to
renal dysplasia
Multicystic dysplastic kidney (MCDK) is a condition that results from the malformation of the kidney during fetal development. The kidney consists of irregular cysts of varying sizes. Multicystic dysplastic kidney is a common type of renal cyst ...
, deformed
proximal tubule
The proximal tubule is the segment of the nephron in kidneys which begins from the renal (tubular) pole of the Bowman's capsule to the beginning of loop of Henle. At this location, the glomerular parietal epithelial cells (PECs) lining bowman’s ...
s, or
lipidosis caused by the hindrance of
lipid metabolism
Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In ani ...
.
Genetics
ALGS is caused by loss of function mutations in either ''
JAG1
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 ...
'' (Jagged1) or ''
NOTCH2
Neurogenic locus notch homolog protein 2 (Notch 2) is a protein that in humans is encoded by the ''NOTCH2'' gene.
NOTCH2 is associated with Alagille syndrome and Hajdu–Cheney syndrome.
Function
Notch 2 is a member of the notch family. Me ...
'' (Notch homolog 2).
In the majority of people with ALGS, the gene mutation occurs in the ''
JAG1
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 ...
'' gene. The ''
JAG1
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 ...
'' mutation is either intragenic and found on
chromosome
A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...
20p12, or it is a deletion of the entire ''
JAG1
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 ...
'' gene.
Mutations in ''
NOTCH2
Neurogenic locus notch homolog protein 2 (Notch 2) is a protein that in humans is encoded by the ''NOTCH2'' gene.
NOTCH2 is associated with Alagille syndrome and Hajdu–Cheney syndrome.
Function
Notch 2 is a member of the notch family. Me ...
'' are much less likely to cause Alagille syndrome, but the primary type of ALGS-causing mutation in ''
NOTCH2
Neurogenic locus notch homolog protein 2 (Notch 2) is a protein that in humans is encoded by the ''NOTCH2'' gene.
NOTCH2 is associated with Alagille syndrome and Hajdu–Cheney syndrome.
Function
Notch 2 is a member of the notch family. Me ...
'' is a
missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...
.
A
missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...
is a
point mutation
A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
that changes one
nucleotide
Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...
, which results in a
codon
Genetic code is a set of rules used by living cells to translate information encoded within genetic material (DNA or RNA sequences of nucleotide triplets or codons) into proteins. Translation is accomplished by the ribosome, which links prote ...
that codes for the wrong
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
. Alagille syndrome is inherited in an
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
pattern, which means one copy of the altered gene is sufficient to cause the disorder. The "
autosomal
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosome ...
" aspect of the disease means that the gene mutation occurs in an
autosome
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosomes ...
, which is one of the 44 chromosomes in the human body that is not a
sex chromosome
Sex chromosomes (also referred to as allosomes, heterotypical chromosome, gonosomes, heterochromosomes, or idiochromosomes) are chromosomes that
carry the genes that determine the sex of an individual. The human sex chromosomes are a typical pair ...
(chromosome X or Y). Although the majority of cases are due to the
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
gene, there have been reports of a rare, autosomal recessive version of the disease.
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.
Environmental factors that can result in gene mutations may include radiation such as ultraviolet rays from the sun, or chemicals such as
benzene
Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...
, which is found in cigarette smoke.
Pathophysiology
''
JAG1
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 ...
'' and ''
NOTCH2
Neurogenic locus notch homolog protein 2 (Notch 2) is a protein that in humans is encoded by the ''NOTCH2'' gene.
NOTCH2 is associated with Alagille syndrome and Hajdu–Cheney syndrome.
Function
Notch 2 is a member of the notch family. Me ...
'' encode for proteins that are crucial to the
notch gene–signaling cascade. Specifically, ''
JAG1
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 ...
'' 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.
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.
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.
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
Heart murmurs are unique heart sounds produced when blood flows across a heart valve or blood vessel. This occurs when turbulent blood flow creates a sound loud enough to hear with a stethoscope. The sound differs from normal heart sounds by th ...
, and a
liver biopsy
Liver biopsy is the biopsy (removal of a small sample of tissue) from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.
Medica ...
to detect liver disease or any precursors. If a patient presents with multiple symptoms such as
jaundice
Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving ...
,
heart murmur
Heart murmurs are unique heart sounds produced when blood flows across a heart valve or blood vessel. This occurs when turbulent blood flow creates a sound loud enough to hear with a stethoscope. The sound differs from normal heart sounds by th ...
, and the characteristic facial features discussed above (deep set eyes, broad brow, etc.), they are likely to be diagnosed with Alagille syndrome.
A more calculated and specific diagnosis can be done with
genetic testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
.
Next-generation sequencing
Massive parallel sequencing or massively parallel sequencing is any of several high-throughput approaches to DNA sequencing using the concept of massively parallel processing; it is also called next-generation sequencing (NGS) or second-generation ...
can be utilized to detect
single nucleotide polymorphisms
In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
(SNPs) in the affected gene(s).
Multiplex ligation-dependent probe amplification
Multiplex ligation-dependent probe amplification (MLPA) is a variation of the multiplex polymerase chain reaction that permits amplification of multiple targets with only a single primer (molecular biology), primer pair. It detects copy number cha ...
(MLPA) can detect large deletions and/or insertions and microarray comparative genomic hybridization is used to improve the accuracy of MLPA.
It is important to distinguish Alagille syndrome from
biliary atresia
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. ...
because the latter benefits from a
Kasai procedure
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 smal ...
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
The common hepatic artery is a short blood vessel that supplies oxygenated blood to the liver, pylorus of the stomach, duodenum, pancreas, and gallbladder.
It arises from the celiac artery and has the following branches:
Additional images
...
enlargement, though these can overlap with Alagille syndrome.
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
Bile (from Latin ''bilis''), also known as gall, is a yellow-green/misty green fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is primarily composed of water, is pro ...
excretion from the liver, reduce pain caused by the disease, and help improve nutritional deficiencies.
Diet can also be a crucial factor in improving quality of life when living with ALGS.
Medication
Several medications are used to improve bile flow, including
ursodiol (Actigall or Urso).
These medications differ in their rates of success. Certain drugs may be used to reduce itching (
pruritus
An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...
), such as
cholestyramine
Colestyramine ( INN) or cholestyramine ( USAN) (trade names Questran, Questran Light, Cholybar, Olestyr, Quantalan, Vasosan) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong i ...
and
rifampin
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires' disease. It is almost always used tog ...
. While these medications can reduce
pruritus
An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...
, the itching often is reduced when bile flow is improved via
ursodiol or
liver transplant
Liver transplantation or hepatic transplantation is the replacement of a Liver disease, diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for Cirrhosis, end-stage liver disease and ...
.
Many patients with Alagille syndrome have nutritional and/or
malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a varie ...
issues which often hinders normal growth. Patients benefit from
vitamin A
Vitamin A is a fat-soluble vitamin that is an essential nutrient. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinyl esters, and several provitamin (precursor) carotenoids, most not ...
, 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
A gastrostomy is the creation of an artificial external opening into the stomach for nutritional support or gastric decompression.
Typically this would include an incision in the patient's epigastrium as part of a formal operation. When originall ...
tube to maintain the high caloric intake.
Maralixibat (Livmarli) was approved for medical use in the United States in September 2021.
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.
Partial biliary diversion has been used to significantly reduce
pruritus
An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...
,
jaundice
Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving ...
, and
xanthoma
A xanthoma (pl. xanthomas or xanthomata) (condition: xanthomatosis) is a deposition of yellowish cholesterol-rich material that can appear anywhere in the body in various disease states. They are cutaneous manifestations of lipidosis in which lip ...
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
In botany, a stoma (: stomata, from Greek language, Greek ''στόμα'', "mouth"), also called a stomate (: stomates), is a pore found in the Epidermis (botany), epidermis of leaves, stems, and other organs, that controls the rate of gas exc ...
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
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. ...
may require a
Kasai procedure
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 smal ...
to improve bile drainage; however, later liver transplantation is still often necessary.
See also
*
Progressive familial intrahepatic cholestasis
Progressive familial intrahepatic cholestasis (PFIC) is a group of Genetic disorder, familial cholestasis, cholestatic conditions caused by defects in bile, biliary Epithelium, epithelial transporters. The clinical presentation usually occurs firs ...
References
External links
GeneReviews/NCBI/UW/NIH entry on Alagille syndrome OMIM entries on Alagille syndromeMedlinePlus: Alagille syndrome
{{Other genetic disorders by mechanism
''This article incorporates public domain text fro
The U.S. National Library of Medicine'
Accessory digestive gland disorders
Ciliopathy
Hepatology
Rare syndromes
Syndromes affecting the hepatobiliary system
Congenital disorders of digestive system
Cardiogenetic disorders
Syndromes affecting the heart
Syndromes with tumors
Diseases named after discoverers
Disability