Daniel Alagille, MD
Dr. Alagille is professor emeritus at the Université Paris-Sud in Bicêtre, France.
Clin Invest Med 1996; 19 (5): 325-30.
[résumé]
A genetic syndrome causing paucity of interlobular bile ducts (Alagille syndrome) is characterized by five main characteristics: typical, peculiar facies; chronic cholestasis; posterior embryotoxon; butterfly-like vertebral-arch defects; and cardiovascular malformations. In the complete form of the syndrome, all five features are observed. Four or less of these characteristics are present in the incomplete or partial forms of this syndrome. Other, less frequent characteristics (growth retardation, mental retardation, renal and bone abnormalities as well as a high-pitched voice) have also been observed. An autosomal dominant mode of genetic transmission with variable penetrance seems likely. Therapy consists of nutritional supplementation of medium-chain triglycerides, essential fatty acids and fat-soluble vitamins. Liver transplantation has been used successfully to treat patients with liver failure, portal hypertension or severe pruritus and xanthomatosis.
Le syndrome d'Alagille est une maladie génétique associée à un faible nombre de canaux biliaires inter-lobulaires et associée a cinq anomalies caractéristiques : visage particulier, cholestase chronique, embryotoxon postérieur, anomalie des arcs vertébraux en forme de papillon, et malformation cardiovasculaire. La forme complète du syndrome est caractérisée par la présence de ces cinq anomalies. La forme partielle du syndrome est associée à moins de cinq anomalies. D'autres anomalies moins fréquentes ont été observées, tels que retard de croissance, retard mental, anomalies rénales et osseuses et voix aigüe. Le mode de transmission génétique le plus probable est autosomal dominant avec pénétrance variable. Le traitement consiste en un supplément nutritionnel en triglycérides à chaîne moyenne, acides gras essentiels et vitamines liposolubles. La transplantation hépatique a été employée avec succès chez les sujets avec insuffisance hépatique, hypertension portale ou prurit sévère et xanthomatose.
This syndrome, characterized by the association of five major groups of features, was gradually identified over 15 years. In 1965 Smith, Optiz and Inhorn1 described intrahepatic biliary dysgenesis associated with polycystic kidneys and cardiac anomalies. In 1969 I and my colleagues Habib and Thomasin[2] reported 25 cases of intrahepatic biliary hypoplasia and cardiac and vertebral malformations associated with a peculiar facies. The syndrome was better defined in 1975,[3] and the view that it is a specific entity was further strengthened by the description of posterior embryotoxon in 1979 by Riely and associates.[4]
The five major clinical features of this syndrome are chronic intrahepatic cholestasis, characteristic facies, cardiovascular abnormalities, vertebral-arch defects and posterior embryotoxon.
Cholestasis develops during the first 3 months of life in 45% to 75% of patients and before the age of 3 in the remainder. Episodes of jaundice, with hyperbilirubinemia in the range of 70 to 120 mmol/L, are interspersed with periods of anicteric remission. Pruritus is present by the 4th month of life in 85% of patients affected and is generally persistent thereafter. In all patients, the liver, and predominantly the left lobe, is enlarged. Its consistency is normal or somewhat firm. Splenomegaly is likely to be found in 40% of cases of this syndrome, but in our experience portal hypertension proven by angiography, direct measurement of portal pressure and visualization of esophageal varices is present in only half of the patients with splenomegaly. Xanthomas are usually noted on the extensor surface of the fingers, palmar creases, nape of the neck, anal folds, popliteal fossa or inguinal area among 30% of the patients with prolonged and severe cholestasis and severe hypercholesterolemia (serum cholesterol level of more than 15 to 20 mmol/L). Xanthomas usually progress from age 4 on, but are attenuated or disappear by the age of 10, paralleling the decrease observed in the serum cholesterol level. For some children, the xanthomatosis can be extensive and disfiguring and can cause social difficulties. Early liver transplantation may be warranted in these extreme cases if drug therapy has failed to control the hypercholesterolemia and xanthomas.
Essential fatty-acid status tends to be marginal in patients with this syndrome. With proper fat-soluble vitamin supplementation, as outlined later, levels of vitamins A, D, E and K can be brought to normal levels, and patients can be free of the clinical manifestations of vitamin deficiencies. There is usually little or no hepatocellular cytolysis, as evidenced by low serum aminotransferase levels. Typically, however, total serum levels of bile acids, gamma-glutamyl transferase and alkaline phosphatase are very high.
A characteristic facies, consisting of a prominent forehead, moderate hypertelorism with deep-set eyes, a small chin pointed in an anterior direction and a saddle or straight nose, is observed in 95% of patients. Although these features are occasionally recognizable in the first few months of life, they are usually fully apparent by 5 to 10 years of age.
Sixty-eight of the 80 patients (85%) seen in our clinic in Bicêtre, France, had cardiac murmurs.[5] In 56 cases, the murmurs were consistent with asymptomatic, isolated and nonprogressive pulmonary stenosis in the peripheral pulmonary vascular tree or the two main pulmonary arteries. In 10 patients, the entire pulmonary vascular tree was hypoplastic, and in some of these patients this feature was combined with other intracardiac defects. Seven patients had a very severe form of Fallot's tetralogy and required surgical intervention.
These are observed in most patients (87%). The anterior arches of one or several dorsal vertebrae are not fused, resulting in a butterfly-like appearance on radiological examination. These abnormalities are present from the first months of life but are more easily recognized in older children. They are unlike those sometimes associated with congenital heart defects and do not interfere with the growth of the spine.
Posterior embryotoxon, an accumulation of pigmentary material on the inner aspects of the cornea near its junction with the iris, are observed, by slit-lamp examination, in more than 80% of patients with this syndrome. This anterior-chamber anomaly is found in only 10% of the normal population, including patients with other types of chronic cholestasis, such as extrahepatic biliary atresia, nonsyndromic paucity of the intralobular biliary ducts, Byler disease, alpha-1-antitrypsin deficiency and primary sclerosing cholangitis. The presence of posterior embryotoxon is unrelated to the level of hyperlipidemia.
Several less frequent manifestations and complications have been described.
This complication affects 50% of patients and is usually related to the degree of cholestasis and resulting malnutrition. It tends to be less severe with age.
Kidney abnormalities were documented in 17 of the 23 children studied at our clinic in Bicêtre.[5] Needle biopsies were performed in patients with renal tubular acidosis while they were receiving cholestyramine therapy. The histologic abnormality observed was limited to glomerular structures and consisted of mesangial lipidosis.[6] In the patients who were not as severely affected, light microscopy showed a fibrillar appearance of the mesangium. Electron microscopy showed lipid vacuoles widely distributed in the mesangial matrix. In the children with more severe histologic changes, light and electron microscopy showed, in addition to mesangial matrix changes, the presence of mesangial foam cells. In all patients with histologic changes, clinical signs of renal involvement were mild (mild isolated proteinuria) or absent. The lesions of mesangial lipidosis were unrelated to serum lipid levels and were not correlated with age. Proximal renal tubular acidosis unrelated to cholestyramine therapy, nephrocalcinosis and small dysplastic kidneys with tubulointerstitial medullary cystic disease have also been reported.[79] Although the relation between these clinical manifestations and the histologic findings has yet to be determined, we can conclude that renal failure will be a major complication for these patients in adulthood.
Contrary to our initial evaluation, an intelligence quotient of less than 80 has been observed in only 16% of patients.
An abnormally narrow interpediculate distance, with lack of the normal progression of interpediculate distance from the thoracic to the lumbar spine, is observed in approximately 50% of patients. Shortness of the ulna and radioulnar synostosis have also been reported, but less frequently.[10]
Thirty percent of patients have a high-pitched, soft voice. However, no vocal-cord or laryngeal abnormality has been found through laryngoscopy.
The major clinical manifestations just discussed have been described in several studies. However, in individual patients, they are expressed to varying degrees. This variable expression affects clinicians' ability to identify specific characteristics of the syndrome and make the correct diagnosis. Differentiating syndromic paucity of the interlobular bile ducts from other forms of cholestasis (mainly extrahepatic biliary atresia) is especially important and should be done in early infancy so that needless surgery may be avoided. Therefore, it is clinically useful to define the minimal number of features needed to recognize this syndrome early in life. The present data support the conclusion that patients with the five main features -- i.e., chronic cholestasis, characteristic facies, cardiovascular abnormalities, vertebral-arch defects and posterior embryotoxon -- have the complete phenotype of the syndrome. Patients with three or four main features have an incomplete or partial form; those with less than three features have a minor form.
The diagnosis is easily made on clinical grounds in cases of the complete form of the syndrome. However, histologic confirmation is always recommended because it has not only a diagnostic but also a prognostic value. The essential histologic feature is paucity of interlobular bile ducts. Examination of at least 10 portal triads is necessary, although these patients tend to have fewer of these structures than usual. The pathologist must note the number and size of portal areas and closely examine the number and shape of the interlobular bile ducts. If at least half of the triads lack identifiable ducts, the diagnosis is confirmed. However, paucity of interlobular bile ducts is also seen in Byler disease (with normal gamma-glutamyl transferase levels) and nonsyndromic forms of intrahepatic cholestasis. In Alagille syndrome, there is invariably a reduced ratio of interlobular bile ducts to portal areas;[11] as well, varying degrees of fibrosis and, ultimately, biliary cirrhosis may be observed.
The clinical course of the syndrome is characterized by persistent or recurrent episodes of cholestasis triggered by common respiratory infections, especially during the first years of life. In 30% of children affected, cholestasis is likely to be severe and permanent during the first 3 or 4 years and may lead to severe malnutrition if it is not carefully monitored.
However, cholestasis may progressively decrease after about 5 years of age, despite the persistence of its biochemical signs. In 17 out of 20 patients observed, portal fibrosis was moderate, mild or absent early in life, even in the presence of severe cholestasis with attendant malnutrition and growth retardation. However, fibrosis becomes more marked with time. Our recent experience suggests that long-standing cholestasis is always associated with biliary cirrhosis; subsequent liver failure may necessitate liver transplantation.[12,13]
The prognosis for growth is closely tied to the duration and severity of malnutrition. Correction of malnutrition leads to resumption of a satisfactory growth pattern. Puberty is frequently delayed but always eventually normal. Three girls with the syndrome later gave birth to normal children.
The long-term prognosis is related to (a) the severity and duration of the early phase of cholestasis and especially of secondary severe malnutrition and infectious complications in the youngest patients; (b) the severity of the complex cardiovascular abnormalities, which may lead to early death (15% of patients seen at Bicêtre died prematurely), before or after cardiac surgery; and (c) liver status, since a poor status may lead to portal hypertension or liver failure in patients with prolonged cholestasis.
Our initial observations suggested autosomal dominance with reduced penetrance; these observations were based on the description of several cases in the same family.[2,3] Intergenerational transmission has been observed among 43 affected children in 33 families. An autosomal dominant mode of transmission is therefore confirmed. In that sample of 43 children, the penetrance was 94% and the proportion of sporadic cases was estimated to be 15%.[5] This study contributed important information for genetic counselling. It is estimated that parents without the characteristic elements of the syndrome who have an affected child run a 55% risk of being carriers of the genetic mutation.
The absence of characteristic signs in the parents, and the existence of minor forms of the syndrome in some patients, indicate that the phenotypic spectrum associated with the mutation can vary, from none of the characteristic features of the syndrome to all five. This variation underlines the importance of the variable intra- and interfamilial expressivity. Therefore, since the estimated prevalence of the syndrome (1 out of 100 000 births) is based on the number of children with hepatic manifestations, and does not take into account those with partial or minor forms, the true prevalence is probably underestimated.
The association of Alagille syndrome with a deletion of the short arm of chromosome 20 was described for the first time in 1986.[14] Among anomalies associated with chromosome 20, only the monosomies of the short arm are associated with the phenotypic abnormalities described in this syndrome.[15,16] Among 22 cases of monosomy involving the short arm of chromosome 20 (22 deletions and 2 unbalanced translocations), 11 have been described in patients with the complete or partial form of the syndrome. The defect has been localized to the interval from 20p11.23 to 20p12.2.[16] The 11 other patients with monosomal deletion of the short arm of chromosome 20 had at least one of the characteristic signs of the syndrome (minor form).
Therefore, deletion of an area of the short arm of chromosome 20 alone does not permit establishment of the diagnosis. Recognition of this syndrome and its quasi-systematic association with deletions of the short arm of chromosome 20 are now well established. Description of familial cases, as well as of patients with the chromosomal anomaly who have only one or two of the five characteristic features of the syndrome, establishes the existence of partial or minor forms. The great phenotypic variability associated with Alagille syndrome reflects this highly variable clinical expressivity.
All patients should be advised to consume a high-energy diet with an adequate protein intake to prevent malnutrition and growth failure. Formulas containing medium-chain triglycerides should be given to infants. Nasogastric feeding is seldom necessary. Later, medium-chain triglycerides can be given as an extra source of energy (1 to 2 mL/kg each day). Fat intake needs to be monitored, since its tolerance varies with the severity of the cholestasis. To avoid deficiencies, every effort should be made to ensure that patients ingest approximately 5% of their total energy intake in the form of essential fatty acids.[5]
The status of fat-soluble vitamins needs to be closely monitored by periodically checking serum values. Vitamins should be administered in a water-soluble form because of their variable absorption. Regimens should include vitamin A (10 000 to 25 000 IU per day), vitamin D3 (800 to 5000 IU per day as either 25-hydroxycholecalciferol or 1,25 dihydroxy-vitamin D), vitamin K (5 mg twice a week) and vitamin E (50 to 100 IU/kg per day). As an alternative for patients who have a poor response to the oral form of fat-soluble vitamins, studies have suggested that a parenteral form can be safely used in the following dosage schedule: vitamin A (500 000 IU as 30 mg of retinyl palmitate every month), vitamin E (10 mg/kg up to a maximum of 200 mg as alpha-tocopherol every 2 weeks); vitamin D3 (5 mg every 3 months), and vitamin K1 (10 mg every 2 weeks administered intramuscularly).[5] Early vitamin-E supplementation is effective in preventing and improving neurologic manifestations of vitamin-E deficiency associated with prolonged cholestasis. A new oral form of vitamin E, vitamin E-PEG, is well absorbed even in patients with severe cholestasis and can be given at a dosage of 25 mg/kg per day. Furthermore, there is evidence that this type of vitamin E enhances the absorption of vitamin D.[17]
The reason cholestasis causes pruritus is unknown. It has long been postulated that pruritis may result from an interaction between nerve endings in the skin and metabolites retained in plasma. The role of bile acids is conjectural and based largely on the improvement in pruritis observed when patients are receiving cholestyramine therapy. However, cholestyramine binds several substances other than bile acids in the gastrointestinal tract. Recent inquiry into a neurogenic central origin for pruritis has led to the observation that naloxone and nalnifene (a specific opiate-receptor antagonist) are helpful. The side effects of nalnifene are considerable, and this has led to a search for other opiate-receptor antagonists to counter the opiate-agonist ligands presumed to be responsible for the pruritus.[18]
Patients usually receive phenobarbital (3 to 5 mg/kg per day) or cholestyramine (4 to 12 g per day) or both to control pruritus. The clinical response is variable and often disappointing. Although the course of cholestasis is not modified by control of pruritus, the overall well-being of patients is improved. If pruritus is not alleviated by cholestyramine, ursodeoxycholic acid, which alters bile-acid composition, may be helpful. As in other cholestatic diseases affecting children, pruritus tends to be worse in younger patients. It disturbs their sleep and interferes with nutrition and growth because of its energy cost and its anorexic effect. It may also slow development and intellectual performance because it completely absorbs the attention of young patients.
In patients with severe, prolonged cholestasis beyond the age of 1, malnutrition, growth failure, disfiguring xanthomatosis and progressive portal fibrosis and cirrhosis, with its attendant complications, generally ensue. Liver transplantation must be seriously considered in such cases. Guidelines need to be individualized, depending on the severity of the involvement of the liver and on the associated malformations.[12,13]
The publication of this article was supported in part by a grant from the Fonds de la recherche en santé du Québec. The authors would like to thank the Fondation Air France for its sponsorship of the invited speakers' program.