Alagille syndrome, the most common cause of chronic cholestasis with phenotypic features, is a dominantly inherited disorder involving multiple systems. The syndrome was first reported by Alagille et al. in 1969 and further elaborated in 1975. the organs involved in Alagille syndrome include the liver, heart, bones, eyes and face, and the incidence of the disease has been reported abroad to be about 1 in 70,000. in China, attention has been paid to the disease in recent years, and although there is still no information on the incidence, studies have found that it is equally Chronic biliary depression is one of the most important causes.
1. Naming of Alagille syndrome
Since Alagille syndrome can involve several organs of the body and the severity of each organ manifestation can vary greatly in different individuals, it has been called by different names in the past, including arteriolar hepatic dysplasia (AHD), syndromic ductular dysplasia (hepatic ductular hypoplasia, syndromatic), syndromic paucity of interlobular bile duct, cholestasis with peripheral pulmonary stenosis), ALAGILLE-WATSON syndrome (AWS), intrahepatic biliary atresia, and intrahepatic biliary dysgenesis, among which syndromic interlobular bile duct deficiency was once the most commonly used. Since the above names do not reflect the whole picture of Alagille syndrome, especially some cases may not even have interlobular bile duct deficiency, the name Alagille syndrome is now becoming a consensus name in the literature of liver disease, cardiology and genetics.
2. Clinical manifestations of Alagille syndrome
Alagille syndrome can involve multiple organs, and liver, heart, bone, eye abnormalities and specific facial features are the most common clinical manifestations of the disease.
(1) Liver manifestations
The liver is often characterized by varying degrees of biliary depression, resulting in biliary depressive chronic liver disease. The vast majority of patients are seen for clinical manifestations of biliary depression. Jaundice is one of the most important manifestations of the disease, and most of them present in early infancy, especially in the neonatal period, with hyperconjugated bilirubinemia and obstructive jaundice. Jaundice persists throughout infancy in approximately half of patients, and may gradually resolve in some children. Pruritus is a prominent manifestation of Alagille syndrome and is the most severe of all biliary liver diseases, often more pronounced than jaundice and biliary depression. However, itching is rarely seen in children before 3-5 months of age, probably due to immature sensory nerve development, and is more common after early childhood.
Hepatomegaly is seen in the majority of patients with Alagille syndrome, including in infancy. Splenomegaly is rare at the beginning, but is seen in about 70% of patients as the disease progresses. Because of bile accumulation, patients with Alagille syndrome may have severe hyperlipidemia, especially with elevated blood cholesterol. In severe cases, multiple xanthomas are seen, usually increasing gradually over the first few years of life and disappearing as biliary depression improves. Liver function tests can increase bilirubin up to 30 times the upper limit of normal and bile acids up to 100 times or more. Blood transaminase levels are also elevated to varying degrees, but hepatic synthetic function is often unaffected. Coagulation disorders are common, but are often corrected with vitamin K injections, suggesting that they are secondary to vitamin K deficiency. The severity of liver disease is a major factor in the prognosis of patients with Alagille syndrome.
(2) Cardiac manifestations
A heart murmur is the second most common sign of alagille syndrome. The murmur is mainly caused by stenosis of the pulmonary outflow tract or peripheral pulmonary arteries. Peripheral pulmonary artery stenosis can occur alone or in combination with intracardiac abnormalities, including tetralogy of Fallot, ventricular septal defect, and atrial septal defect. Cardiovascular abnormalities have been reported in 85-95% of patients in the literature. 13 of the 15 patients diagnosed early by Alagille et al. had a coarse systolic murmur. Subsequent large group studies also found cardiac murmurs in 85% of patients, asymptomatic, nonprogressive stenosis of the pulmonary aorta or peripheral pulmonary arteries in 70%, pulmonary vascular dysplasia in 12.5%, and severe tetralogy of Fallot in 8.8%. Cardiovascular malformations are another major cause of prognosis in patients with Alagille syndrome.
(3) Skeletal manifestations
Patients with Alagille syndrome may have spinal abnormalities, mainly pterygoid vertebrae. Characteristic pterygoid vertebral manifestations are seen in approximately 33-87% of patients. Skeletal abnormalities usually do not show clinical symptoms, but are detected on x-ray. Other skeletal abnormalities include shortened finger (toe) bones, shortened distal ulna and radius, fusion of contiguous vertebrae, absence of the twelfth rib, and central translucency of the conus. In addition, patients with Alagille syndrome may develop severe metabolic bone disease, osteoporosis, and pathological fractures (especially in the femur).
(4) Ocular manifestations
Ocular abnormalities involve the cornea, iris, retina and optic nerve papillae. The posterior corneal ring is the most characteristic ocular change. The posterior corneal embryonic ring, or Schwalbe’s ring, which projects centrally, is often found at the junction of the corneal endothelium and the trabecular tissue of the pigment layer. The posterior fetal ring is seen in 56C95 % of patients, but can be seen in 8C15 % of normal individuals, so its presence alone is of limited diagnostic value and is only significant when other abnormalities are also present. Other ocular anomalies include glaucoma with corneoscleral hypoplasia (Axenfeld’s anomaly), mesodermal hypoplasia (Rieger’s anomaly), abnormal optic nerve papillae, microcornea, etc. Ocular anomalies in Alagille syndrome rarely present with clinical symptoms.
(5) Facial manifestations
The facial features of Alagille syndrome include prominent forehead, deep sunken eyes with moderate widening of eye spacing, pointed jaw, saddle-shaped nose with anterior hypertrophy. The special facial features may be present as early as infancy. In young infants, forehead protrusion and ear hypoplasia are common, and other features become more prominent with age. In adults, the forehead protrusion is less pronounced, but the jaw protrusion is more pronounced. In lateral view, the head is flattened, but the ears are prominent. Other reported facial features include large ears, recurrent sinusitis, otitis media, and hyperacusis. Many patients have a ghastly facial appearance due to a prominent forehead and deep-set eyes.
(6) Other manifestations
As research progressed, clinical manifestations of many other organs were gradually confirmed to be associated with Alagille syndrome. In addition to the five main manifestations mentioned above, secondary clinical manifestations mainly involve some abnormalities of the kidney, pancreas, trachea or bronchus, jejunum, ileum, and cerebral vessels. Renal abnormalities are seen in 40-50% of patients with Alagille syndrome. Isolated kidney, ectopic kidney, bifurcated renal pelvis, small kidney, unilateral kidney, bilateral polycystic kidney and abnormal renal development are common manifestations, and tracheobronchial stenosis, jejunal stenosis and atresia, and small colon have also been reported.
Alagille syndrome may also include physical and mental developmental disorders, gross motor retardation, abnormal vision, hearing and other somatosensory abnormalities, hypotonia and tremor, but most improve with nutritional enhancement or liver transplantation, suggesting that these changes may be secondary. Intracranial hemorrhage is the most important intracranial comorbidity and can occur in different parts of the skull. Most bleeding occurs in patients without significant coagulation disorders. Trauma to the head, usually minor, is associated with bleeding in some cases. Combined with recent molecular biology studies and autopsy findings, it is speculated that it may be related to inherent intracranial vascular developmental abnormalities, but these minor vascular lesions are also difficult to detect by MRI and therefore cannot be predicted or prevented at this time. Good correction of coagulation mechanisms and careful observation after head trauma may reduce mortality and disability in some cases.
3, Alagille syndrome liver pathology
Pathologic findings of reduced or absent interlobular bile ducts on liver biopsy were once considered the most important and constant feature of Alagille syndrome. However, recent studies have found that some patients with Alagille syndrome may have no interlobular bile duct loss or reduction in early infancy, and that their interlobular bile duct loss occurs gradually after birth. One study found that only about 60% of patients who underwent liver puncture biopsy before 6 months of age had interlobular bile duct deficiency; 95% of patients who underwent liver biopsy after 6 months of age could demonstrate interlobular bile duct deficiency. The fact that some of our cases underwent two liver biopsies may also indicate that the loss of intrahepatic bile ducts occurs gradually.
Some patients with Alagille syndrome may show a reduction in the confluent area. In some cases there may be inflammatory cell infiltration in the confluent area and early fibrosis is often not evident. If early fibrosis is present, it may manifest as paranasal fibrosis rather than fibrosis in the confluent area. A small percentage of patients with Alagille syndrome may have hyperplasia of small bile ducts early in the disease, which is very difficult to differentiate from biliary atresia. Curiously, with age, although the disappearance of interlobular bile ducts develops gradually in most cases, it rarely progresses to cirrhosis.
4.Diagnosis and differential diagnosis of Alagille syndrome
The establishment of a clinical diagnosis of Alagille syndrome relies on a comprehensive judgment. The classic diagnostic criteria are a liver tissue biopsy with a reduced number or absence of intrahepatic interlobular bile ducts and at least three of the five major clinical manifestations including chronic biliary depression, cardiac murmur, butterfly vertebrae, posterior corneal embryonic ring and peculiar facial features, and exclusion of other possible causes. Some authors now include renal abnormalities as one of the major abnormalities. If liver biopsy does not show a reduced number or absence of interlobular bile ducts in the liver, or if liver biopsy is not performed in some patients with adult-onset juvenile disorders, the revised diagnostic criteria for Alagille syndrome consider that meeting four or more of the main criteria is also diagnostic. If there is a known Jagged1 mutation or a family history of positivity, 2 of the main criteria are usually sufficient to confirm the diagnosis.
Patients with Alagille syndrome have markedly elevated blood GGT and therefore need to be differentiated from the various forms of infantile biliary depression that are associated with elevated GGT. It is difficult to distinguish Alagille syndrome from other causes of hyperconjugated bilirubinemia. This is because although alagille syndrome is multisystemic, the changes in spine, ophthalmology and renal abnormalities are mostly not clinically significant, and the characteristic facial features are not significant in early infancy, among others. The greatest challenge in early diagnosis is to differentiate it from biliary atresia. We have reported more than 10 cases plus recently diagnosed cases, most of which have had a diagnosis of biliary atresia. Since biliary atresia requires early surgical treatment and the prognosis has been reported to be worse if Alagille syndrome is misdiagnosed and surgery is performed, it is particularly important to effectively differentiate between the two. Liver aspiration biopsy can be very helpful in the differential diagnosis. Biliary atresia is characterized by significant hyperplasia of small bile ducts, whereas in alagille syndrome, although the absence or reduction of intrahepatic bile ducts may not be present in the early stages, significant hyperplasia of small bile ducts is also rare. However, pathologists usually seldom pay attention to and describe the condition of interlobular bile ducts, which may lead to missed diagnosis. Therefore, for patients with clinical suspicion of alagille syndrome, pathologists should be prompted to pay attention to the observation of interlobular bile ducts, and to pay attention to the distinction between small bile ducts and interlobular bile ducts to better identify whether there is absence of interlobular bile ducts.
5. Molecular genetic progress of Alagille syndrome
About 95% of Alagille syndrome is caused by mutations in the Jagged1 gene located on chromosome 20p12. The gene contains 26 exons ranging in size from 28bp to 2284bp, containing 36Kb of genetic information, and encodes a cell surface protein with a large extracellular domain containing a signal peptide, an evolutionarily conserved sequence containing 16 epidermal growth factor-like repeats and a cysteine-rich region. The Jagged1 protein and its receptor (Notch receptor) are both located on the cell surface, and through ligand-receptor interaction, a portion of the Notch protein enters the nucleus, which in turn affects downstream gene expression. This gene has been shown to be expressed in most mammalian tissues and plays an important role in regulating the growth and development of tissues and organs such as the heart, liver, bones, eyes and face. The types of mutations that have been reported include whole gene deletions, protein truncation mutations (including shift and nonsense mutations), splice mutations and missense mutations. A small number of Alagille syndromes may be caused by mutations in Notch receptors.
Although Alagille syndrome is an autosomal dominant disorder with a dominant rate of about 98%, the degree of expression can vary widely among individuals and therefore the phenotype is highly variable. Most children have one or more of the parents with Alagille syndrome, with posterior corneal rings and heart murmurs being the most common, as well as transient biliary depression in infancy and butterfly vertebrae.
In conclusion, Alagille syndrome is an important cause of chronic cholestatic liver disease in infancy. The syndrome is difficult to diagnose early and is highly susceptible to misdiagnosis as biliary atresia, and vigilance must be raised in clinical workup. Early recognition and correct diagnosis can be facilitated by liver puncture pathology, eye examination and spinal radiographs.