Alagille syndrome: A nutritional niche for Notch

Abstract

See related article, p. 172.In 1975 Daniel Alagille, a prominent pediatric hepatologist in France, first described in the English literature a group of children with chronic cholestatic liver disease that also exhibited a unique cluster of extrahepatic features.1Alagille D Odievre M Gautier M Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur.J Pediatr. 1975; 86: 63-71Abstract Full Text PDF PubMed Scopus (512) Google Scholar This disorder has since been labeled Alagille syndrome . The liver histology in these children uniformly showed a reduced number of portal tract bile ducts, now commonly referred to as paucity of interlobular bile ducts, usually associated with a hypoplastic extrahepatic biliary tree. The other major features of AGS include pulmonary artery and valve abnormalities (including tetralogy of Fallot), vertebral arch defects, posterior embryotoxon, and characteristic facies.1Alagille D Odievre M Gautier M Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur.J Pediatr. 1975; 86: 63-71Abstract Full Text PDF PubMed Scopus (512) Google Scholar, 2Alagille D Estrada A Hadouchel M Gautier M Odievre M Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases.J Pediatr. 1987; 110: 195-200Abstract Full Text PDF PubMed Scopus (531) Google Scholar AGS is inherited in an autosomal dominant manner with incomplete penetrance. Subsequent reports have extended the clinical phenotype to include growth and developmental delays, renal abnormalities, pancreatic insufficiency, and a relatively high frequency of intracranial hemorrhage.3Chong SKF Lindridge J Moniz C Mowat AP. Exocrine pancreatic insufficiency in syndromic paucity of interlobular bile ducts.J Pediatr Gastroenterol Nutr. 1989; 9: 445-449Crossref PubMed Scopus (29) Google Scholar, 4Hoffenberg EJ Narkewicz MR Sondheimer JM Smith DJ Silverman A Sokol RJ. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy.J Pediatr. 1995; 127: 220-224Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar AGS is estimated to occur in 1 of 70,000 live births among all ethnic groups, putting it among the 5 most common causes of chronic childhood cholestasis. The clinical criteria for diagnosis set forth by Alagille et al2Alagille D Estrada A Hadouchel M Gautier M Odievre M Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases.J Pediatr. 1987; 110: 195-200Abstract Full Text PDF PubMed Scopus (531) Google Scholar include paucity of interlobular bile ducts plus 3 of the 5 other major criteria (cardiac and pulmonary artery abnormalities, vertebral arch defects, posterior embryotoxon, characteristic facies, and chronic cholestasis). Clearly, many family members of known patients demonstrate several of these features (eg, isolated congenital heart or pulmonary artery anomalies), and some patients do not fulfill all criteria, yet are suspected of having AGS. Furthermore, there is considerable concern for recurrence in future pregnancies for families with a severely affected infant. Thus the need for improved diagnostic testing and a better understanding of the pathogenesis of AGS led several groups to search for the AGS gene.The chromosomal location of the AGS gene was first suggested by reports of deletions of 20p12 associated with a clinical phenotype resembling that of AGS5Krantz ID Colliton RP Genin A Rand EB Li L Piccoli DA et al.Deletions of 20p12 in Alagille syndrome: frequency and molecular characterization.Am J Med Genet. 1997; 70: 80-86Crossref PubMed Scopus (71) Google Scholar; however, deletions were detected in less that 7% of patients. As several research groups were focusing in on a region of 20p, Li et al6Li L Milner LA Deng Y Iwata M Banta A Graf L et al.The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1.Immunity. 1998; 8: 43-55Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar cloned the human homolog (JAG1 ) of a rat gene called Jagged1 and found that it mapped to the region in which AGS was believed to be found.7Li L Drantz ID Deng Y Gennin A Banta AB Collins CC et al.Alagille syndrome is caused by mutations in human Jagged1 , which encodes a ligand for Notch1.Nat Genet. 1997; 16: 243-251Crossref PubMed Scopus (997) Google Scholar A coordinated effort among investigators from multiple centers soon showed that patients with AGS had mutations in the JAG1 gene.7Li L Drantz ID Deng Y Gennin A Banta AB Collins CC et al.Alagille syndrome is caused by mutations in human Jagged1 , which encodes a ligand for Notch1.Nat Genet. 1997; 16: 243-251Crossref PubMed Scopus (997) Google Scholar, 8Oda T Elkahloun AG Pike BL Okajima K Krantz ID Gennin A et al.Mutations in the human Jagged1 gene are responsible for Alagille syndrome.Nat Genet. 1997; 16: 235-242Crossref PubMed Scopus (915) Google Scholar JAG1 encodes a ligand for the Notch receptor , initiating a signaling pathway that controls the ability of nonterminally differentiated cells to respond to differentiation and proliferation signals. In fact, Notch seems to control the ability of almost all precursor cells to progress to a more differentiated state. In Drosophila , loss of Notch function leads to embryonic lethality; female flies that carry only one copy of the gene have notched wings, hence, the name Notch . Most likely in AGS, mutations of one copy of JAG1 reduce Notch activation and disrupt normal morphogenesis in the varied organ systems involved in AGS. Indeed, JAG1 is normally expressed in human heart, lungs, and kidneys; and in the liver JAG1 is highly expressed in fetal ductal plate epithelia that are destined to develop into the mature interlobular bile ducts.9Loomes KKM Spinner NB Piccoli DA Oakey RJ. Jagged1 expression in the developing liver: correlation with histologic features in Alagille syndrome.Hepatology. 1998; 28 ([abstract]): 317AGoogle Scholar Of interest is the marked heterogeneity in clinical expression even within the same family, implicating other genetic modifiers, such as other genes involved in the Notch or in other similar pathways. Unraveling the role of JAG1 and the Notch signaling pathway will assuredly improve our understanding of the morphogenesis of the fetal heart and great vessels, the liver and bile ducts, and other structures. Unfortunately, almost each mutation identified in over 40 patients with AGS to date has been unique, making rapid genetic evaluation for a common mutation in patients suspected of having AGS impossible.9Loomes KKM Spinner NB Piccoli DA Oakey RJ. Jagged1 expression in the developing liver: correlation with histologic features in Alagille syndrome.Hepatology. 1998; 28 ([abstract]): 317AGoogle Scholar Nevertheless, identification of a specific mutation in a proband can be used to determine whether parents are carriers and whether there is any risk for future pregnancies. In this regard, it has been pointed out that perhaps 50% of mutations arise de novo (are not inherited from parents) and that no JAG1 mutation can be identified in 30% of patients.10Krantz ID Colliton RP Gennin A Rand EB Linheng L Piccoli DA et al.Spectrum and frequency of Jagged1 (JAG1 ) mutations in Alagille syndrome patients and their families.Am J Hum Genet. 1998; 62: 1361-1369Abstract Full Text Full Text PDF PubMed Scopus (176) Google ScholarAGS, being a disease of chronic cholestasis, is associated with many consequences of impaired bile flow, including pruritus, hyperlipidemia and xanthoma formation, malabsorption of dietary fat, and growth failure. Because most patients do not have significant portal fibrosis and portal hypertension, the nutritional consequences of AGS frequently eclipse the other manifestations of chronic liver disease. The severe cholestasis characteristic of AGS causes low intraluminal concentrations of secreted bile acids in the intestine, impaired solubilization of fat and significant steatorrhea, and malabsorption of fat-soluble vitamins.11Sokol RJ. Fat-soluble vitamins and their importance in patients who have cholestatic liver disease.Gastroenterol Clin North Am. 1994; 23: 673-705PubMed Google Scholar An unknown proportion of patients also have pancreatic insufficiency, which compounds the steatorrhea.3Chong SKF Lindridge J Moniz C Mowat AP. Exocrine pancreatic insufficiency in syndromic paucity of interlobular bile ducts.J Pediatr Gastroenterol Nutr. 1989; 9: 445-449Crossref PubMed Scopus (29) Google Scholar The resulting energy deficit leads to growth failure, malnutrition, and delay in onset of puberty. Sokol and Stall12Sokol RJ Stall C. Anthropometric evaluation of children with chronic liver disease.Am J Clin Nutr. 1990; 52: 203-208PubMed Google Scholar evaluated a large cohort of children with chronic liver disease without signs of liver failure and reported that various parameters of malnutrition (z scores for weight for height, triceps skinfold thickness, midarm circumference, and midarm muscle area) were all significantly lower in 5 patients with AGS compared with 51 other children with chronic liver disease, including 32 with biliary atresia. In this issue of The Journal, Wasserman et al13Wasserman D Zemel BS Mulberg AE John HA Emerick KM Barden EM et al.Growth, nutritional status, body composition, and energy expenditure in prepubertal children with Alagille syndrome.J Pediatr. 1999; 134: 172-177Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar confirm these findings in 13 patients with AGS. More thorough body compositional analysis by dual-energy x-ray absorptiometry showed a reduction in fat and fat-free mass but not in percent body fat. In addition, resting energy expenditure (expressed per kilogram of body weight or per kilogram of fat-free mass) did not differ from that of control children. Thus there does not appear to be any significant increase in energy requirement to account for the poor growth and undernutrition in children with AGS. We do not know the contribution of appetite and intake on nutritional status in patients with AGS because a detailed analysis of food intake has not been performed. Nevertheless, it seems reasonable to recommend supplementation with high-calorie, readily absorbed nutrients (such as medium-chain triglyceride-containing formulas) to maximize growth potential and fat-soluble vitamin supplements in order to prevent deficiencies.11Sokol RJ. Fat-soluble vitamins and their importance in patients who have cholestatic liver disease.Gastroenterol Clin North Am. 1994; 23: 673-705PubMed Google ScholarOther factors may affect growth in patients with AGS. Growth failure may be part of the spectrum of bone involvement in AGS, although Hoffenberg et al14Hoffenberg EJ Smith D Sauaia A Narkewicz MR Sokol RJ. Growth is not related to the presence of vertebral anomalies in Alagille syndrome.J Pediatr Gastroenterol Nutr. 1998; 27 ([abstract]): 469Crossref Scopus (6) Google Scholar were unable to show any relationship between the presence of vertebral abnormalities and growth in AGS. It is also not yet clear whether chronic cholestasis itself may impair growth by virtue of interference with peripheral effects of growth-promoting factors or the hepatic insulin-like growth factor-I response to growth hormone, as suggested by Bucuvalas et al.15Bucuvalas JC Horn JA Carlsson L Balistreri WF Chernausek SD. Growth hormone insensitivity associated with elevated circulating growth hormone-binding protein in children with Alagille syndrome and short stature.J Clin Endocrinol Metab. 1993; 76: 1477-1482Crossref PubMed Scopus (44) Google Scholar Holt et al16Holt RI Crossey PA Hones JS Baker AJ Portmann B Miell JP. Hepatic growth hormone receptor, insulin-like growth factor I, and insulin-like growth factor-binding protein messenger RNA expression in pediatric liver disease.Hepatology. 1997; 26: 1600-1606Crossref PubMed Scopus (20) Google Scholar recently reported that growth hormone receptor and insulin-like growth factor-I messenger RNA levels were reduced significantly in liver specimens from patients with biliary atresia and end-stage liver disease, which could account for reduced responsiveness to growth hormone. The catch-up growth in patients with AGS after liver transplantation17Holt RI Droide E Buchanan CR Miell JP Baker AJ Mowat AP et al.Orthotopic liver transplantation reverses the adverse nutritional changes of end-stage liver disease in children.Am J Clin Nutr. 1997; 65: 534-542PubMed Google Scholar and the increased insulin-like growth factor-I levels after liver transplantation for other pediatric liver diseases18Holt RI Jones JS Stone NM Baker AJ Miell JP. Sequential changes in insulin-like growth factor I (IGF-I) and IGF-binding proteins in children with end-stage liver disease before and after successful orthotopic liver transplantation.J Clin Endocrinol Metab. 1996; 81: 160-168Crossref PubMed Google Scholar support this notion that the liver plays a role in determining linear growth in AGS. Clearly, further study of the metabolic consequences of cholestasis is needed to determine whether the abnormal expression of JAG1 in AGS contributes directly or indirectly to these perturbations.The relatively favorable course and outcome of AGS have recently been called into question. In prior series1Alagille D Odievre M Gautier M Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur.J Pediatr. 1975; 86: 63-71Abstract Full Text PDF PubMed Scopus (512) Google Scholar, 2Alagille D Estrada A Hadouchel M Gautier M Odievre M Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases.J Pediatr. 1987; 110: 195-200Abstract Full Text PDF PubMed Scopus (531) Google Scholar less severely affected patients, identified because of a family member with AGS, have biased the results toward a good outcome. In our series of 26 children with AGS who presented with neonatal cholestatic liver disease, only 15 (58%) were alive without liver transplantation at a median age of 12.1 years.14Hoffenberg EJ Smith D Sauaia A Narkewicz MR Sokol RJ. Growth is not related to the presence of vertebral anomalies in Alagille syndrome.J Pediatr Gastroenterol Nutr. 1998; 27 ([abstract]): 469Crossref Scopus (6) Google Scholar Thirty-one percent required liver transplantation (successful in all) at a median of 6.5 years of age for recurrent bone fractures caused by metabolic bone disease, severe pruritus with xanthomas, and less commonly, liver synthetic failure. Remarkably, 4 (15%) patients had severe central nervous system abnormalities, including 2 epidural hematomas, 1 ruptured venous malformation, and 1 suprasellar arachnoid cyst; 2 of these hemorrhages were fatal. Recent reports from 2 other centers19McBride KE. Clinical features of the Alagille syndrome: frequency and relation to prognosis.J Pediatr Gastroenterol Nutr. 1998; 26 ([abstract]): 580Crossref Google Scholar, 20Quiros RE Ament ME Heyman MB Hall TR McDiarmid SV Vargas JH. Alagille’s syndrome: outcome of 41 cases.J Pediatr Gastroenterol Nutr. 1998; 26 ([abstract]): 582Google Scholar confirm this high incidence of intracranial hemorrhage. It is not clear whether this indicates another location where vascular structures have developed abnormally or whether the thin cranial bones fail to provide adequate protection from minor trauma. Consequently, anticipatory guidance for patients with AGS should include education of families regarding head trauma prevention and early signs of elevated intracranial pressure. The other major cause of death is severe pulmonary artery hypoplasia or complex congenital heart disease.19McBride KE. Clinical features of the Alagille syndrome: frequency and relation to prognosis.J Pediatr Gastroenterol Nutr. 1998; 26 ([abstract]): 580Crossref Google Scholar, 20Quiros RE Ament ME Heyman MB Hall TR McDiarmid SV Vargas JH. Alagille’s syndrome: outcome of 41 cases.J Pediatr Gastroenterol Nutr. 1998; 26 ([abstract]): 582Google ScholarThe exciting new developments in the genetics of AGS will certainly add substantially to our understanding of liver and bile duct morphogenesis, improve our ability to diagnosis more subtle cases of AGS (eg, isolated right-sided congenital heart disease), and, hopefully, provide the basis for new interventional strategies for children with AGS and other cholestatic disorders. See related article, p. 172. In 1975 Daniel Alagille, a prominent pediatric hepatologist in France, first described in the English literature a group of children with chronic cholestatic liver disease that also exhibited a unique cluster of extrahepatic features.1Alagille D Odievre M Gautier M Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur.J Pediatr. 1975; 86: 63-71Abstract Full Text PDF PubMed Scopus (512) Google Scholar This disorder has since been labeled Alagille syndrome . The liver histology in these children uniformly showed a reduced number of portal tract bile ducts, now commonly referred to as paucity of interlobular bile ducts, usually associated with a hypoplastic extrahepatic biliary tree. The other major features of AGS include pulmonary artery and valve abnormalities (including tetralogy of Fallot), vertebral arch defects, posterior embryotoxon, and characteristic facies.1Alagille D Odievre M Gautier M Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur.J Pediatr. 1975; 86: 63-71Abstract Full Text PDF PubMed Scopus (512) Google Scholar, 2Alagille D Estrada A Hadouchel M Gautier M Odievre M Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases.J Pediatr. 1987; 110: 195-200Abstract Full Text PDF PubMed Scopus (531) Google Scholar AGS is inherited in an autosomal dominant manner with incomplete penetrance. Subsequent reports have extended the clinical phenotype to include growth and developmental delays, renal abnormalities, pancreatic insufficiency, and a relatively high frequency of intracranial hemorrhage.3Chong SKF Lindridge J Moniz C Mowat AP. Exocrine pancreatic insufficiency in syndromic paucity of interlobular bile ducts.J Pediatr Gastroenterol Nutr. 1989; 9: 445-449Crossref PubMed Scopus (29) Google Scholar, 4Hoffenberg EJ Narkewicz MR Sondheimer JM Smith DJ Silverman A Sokol RJ. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy.J Pediatr. 1995; 127: 220-224Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar AGS is estimated to occur in 1 of 70,000 live births among all ethnic groups, putting it among the 5 most common causes of chronic childhood cholestasis. The clinical criteria for diagnosis set forth by Alagille et al2Alagille D Estrada A Hadouchel M Gautier M Odievre M Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases.J Pediatr. 1987; 110: 195-200Abstract Full Text PDF PubMed Scopus (531) Google Scholar include paucity of interlobular bile ducts plus 3 of the 5 other major criteria (cardiac and pulmonary artery abnormalities, vertebral arch defects, posterior embryotoxon, characteristic facies, and chronic cholestasis). Clearly, many family members of known patients demonstrate several of these features (eg, isolated congenital heart or pulmonary artery anomalies), and some patients do not fulfill all criteria, yet are suspected of having AGS. Furthermore, there is considerable concern for recurrence in future pregnancies for families with a severely affected infant. Thus the need for improved diagnostic testing and a better understanding of the pathogenesis of AGS led several groups to search for the AGS gene. The chromosomal location of the AGS gene was first suggested by reports of deletions of 20p12 associated with a clinical phenotype resembling that of AGS5Krantz ID Colliton RP Genin A Rand EB Li L Piccoli DA et al.Deletions of 20p12 in Alagille syndrome: frequency and molecular characterization.Am J Med Genet. 1997; 70: 80-86Crossref PubMed Scopus (71) Google Scholar; however, deletions were detected in less that 7% of patients. As several research groups were focusing in on a region of 20p, Li et al6Li L Milner LA Deng Y Iwata M Banta A Graf L et al.The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1.Immunity. 1998; 8: 43-55Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar cloned the human homolog (JAG1 ) of a rat gene called Jagged1 and found that it mapped to the region in which AGS was believed to be found.7Li L Drantz ID Deng Y Gennin A Banta AB Collins CC et al.Alagille syndrome is caused by mutations in human Jagged1 , which encodes a ligand for Notch1.Nat Genet. 1997; 16: 243-251Crossref PubMed Scopus (997) Google Scholar A coordinated effort among investigators from multiple centers soon showed that patients with AGS had mutations in the JAG1 gene.7Li L Drantz ID Deng Y Gennin A Banta AB Collins CC et al.Alagille syndrome is caused by mutations in human Jagged1 , which encodes a ligand for Notch1.Nat Genet. 1997; 16: 243-251Crossref PubMed Scopus (997) Google Scholar, 8Oda T Elkahloun AG Pike BL Okajima K Krantz ID Gennin A et al.Mutations in the human Jagged1 gene are responsible for Alagille syndrome.Nat Genet. 1997; 16: 235-242Crossref PubMed Scopus (915) Google Scholar JAG1 encodes a ligand for the Notch receptor , initiating a signaling pathway that controls the ability of nonterminally differentiated cells to respond to differentiation and proliferation signals. In fact, Notch seems to control the ability of almost all precursor cells to progress to a more differentiated state. In Drosophila , loss of Notch function leads to embryonic lethality; female flies that carry only one copy of the gene have notched wings, hence, the name Notch . Most likely in AGS, mutations of one copy of JAG1 reduce Notch activation and disrupt normal morphogenesis in the varied organ systems involved in AGS. Indeed, JAG1 is normally expressed in human heart, lungs, and kidneys; and in the liver JAG1 is highly expressed in fetal ductal plate epithelia that are destined to develop into the mature interlobular bile ducts.9Loomes KKM Spinner NB Piccoli DA Oakey RJ. Jagged1 expression in the developing liver: correlation with histologic features in Alagille syndrome.Hepatology. 1998; 28 ([abstract]): 317AGoogle Scholar Of interest is the marked heterogeneity in clinical expression even within the same family, implicating other genetic modifiers, such as other genes involved in the Notch or in other similar pathways. Unraveling the role of JAG1 and the Notch signaling pathway will assuredly improve our understanding of the morphogenesis of the fetal heart and great vessels, the liver and bile ducts, and other structures. Unfortunately, almost each mutation identified in over 40 patients with AGS to date has been unique, making rapid genetic evaluation for a common mutation in patients suspected of having AGS impossible.9Loomes KKM Spinner NB Piccoli DA Oakey RJ. Jagged1 expression in the developing liver: correlation with histologic features in Alagille syndrome.Hepatology. 1998; 28 ([abstract]): 317AGoogle Scholar Nevertheless, identification of a specific mutation in a proband can be used to determine whether parents are carriers and whether there is any risk for future pregnancies. In this regard, it has been pointed out that perhaps 50% of mutations arise de novo (are not inherited from parents) and that no JAG1 mutation can be identified in 30% of patients.10Krantz ID Colliton RP Gennin A Rand EB Linheng L Piccoli DA et al.Spectrum and frequency of Jagged1 (JAG1 ) mutations in Alagille syndrome patients and their families.Am J Hum Genet. 1998; 62: 1361-1369Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar AGS, being a disease of chronic cholestasis, is associated with many consequences of impaired bile flow, including pruritus, hyperlipidemia and xanthoma formation, malabsorption of dietary fat, and growth failure. Because most patients do not have significant portal fibrosis and portal hypertension, the nutritional consequences of AGS frequently eclipse the other manifestations of chronic liver disease. The severe cholestasis characteristic of AGS causes low intraluminal concentrations of secreted bile acids in the intestine, impaired solubilization of fat and significant steatorrhea, and malabsorption of fat-soluble vitamins.11Sokol RJ. Fat-soluble vitamins and their importance in patients who have cholestatic liver disease.Gastroenterol Clin North Am. 1994; 23: 673-705PubMed Google Scholar An unknown proportion of patients also have pancreatic insufficiency, which compounds the steatorrhea.3Chong SKF Lindridge J Moniz C Mowat AP. Exocrine pancreatic insufficiency in syndromic paucity of interlobular bile ducts.J Pediatr Gastroenterol Nutr. 1989; 9: 445-449Crossref PubMed Scopus (29) Google Scholar The resulting energy deficit leads to growth failure, malnutrition, and delay in onset of puberty. Sokol and Stall12Sokol RJ Stall C. Anthropometric evaluation of children with chronic liver disease.Am J Clin Nutr. 1990; 52: 203-208PubMed Google Scholar evaluated a large cohort of children with chronic liver disease without signs of liver failure and reported that various parameters of malnutrition (z scores for weight for height, triceps skinfold thickness, midarm circumference, and midarm muscle area) were all significantly lower in 5 patients with AGS compared with 51 other children with chronic liver disease, including 32 with biliary atresia. In this issue of The Journal, Wasserman et al13Wasserman D Zemel BS Mulberg AE John HA Emerick KM Barden EM et al.Growth, nutritional status, body composition, and energy expenditure in prepubertal children with Alagille syndrome.J Pediatr. 1999; 134: 172-177Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar confirm these findings in 13 patients with AGS. More thorough body compositional analysis by dual-energy x-ray absorptiometry showed a reduction in fat and fat-free mass but not in percent body fat. In addition, resting energy expenditure (expressed per kilogram of body weight or per kilogram of fat-free mass) did not differ from that of control children. Thus there does not appear to be any significant increase in energy requirement to account for the poor growth and undernutrition in children with AGS. We do not know the contribution of appetite and intake on nutritional status in patients with AGS because a detailed analysis of food intake has not been performed. Nevertheless, it seems reasonable to recommend supplementation with high-calorie, readily absorbed nutrients (such as medium-chain triglyceride-containing formulas) to maximize growth potential and fat-soluble vitamin supplements in order to prevent deficiencies.11Sokol RJ. Fat-soluble vitamins and their importance in patients who have cholestatic liver disease.Gastroenterol Clin North Am. 1994; 23: 673-705PubMed Google Scholar Other factors may affect growth in patients with AGS. Growth failure may be part of the spectrum of bone involvement in AGS, although Hoffenberg et al14Hoffenberg EJ Smith D Sauaia A Narkewicz MR Sokol RJ. Growth is not related to the presence of vertebral anomalies in Alagille syndrome.J Pediatr Gastroenterol Nutr. 1998; 27 ([abstract]): 469Crossref Scopus (6) Google Scholar were unable to show any relationship between the presence of vertebral abnormalities and growth in AGS. It is also not yet clear whether chronic cholestasis itself may impair growth by virtue of interference with peripheral effects of growth-promoting factors or the hepatic insulin-like growth factor-I response to growth hormone, as suggested by Bucuvalas et al.15Bucuvalas JC Horn JA Carlsson L Balistreri WF Chernausek SD. Growth hormone insensitivity associated with elevated circulating growth hormone-binding protein in children with Alagille syndrome and short stature.J Clin Endocrinol Metab. 1993; 76: 1477-1482Crossref PubMed Scopus (44) Google Scholar Holt et al16Holt RI Crossey PA Hones JS Baker AJ Portmann B Miell JP. Hepatic growth hormone receptor, insulin-like growth factor I, and insulin-like growth factor-binding protein messenger RNA expression in pediatric liver disease.Hepatology. 1997; 26: 1600-1606Crossref PubMed Scopus (20) Google Scholar recently reported that growth hormone receptor and insulin-like growth factor-I messenger RNA levels were reduced significantly in liver specimens from patients with biliary atresia and end-stage liver disease, which could account for reduced responsiveness to growth hormone. The catch-up growth in patients with AGS after liver transplantation17Holt RI Droide E Buchanan CR Miell JP Baker AJ Mowat AP et al.Orthotopic liver transplantation reverses the adverse nutritional changes of end-stage liver disease in children.Am J Clin Nutr. 1997; 65: 534-542PubMed Google Scholar and the increased insulin-like growth factor-I levels after liver transplantation for other pediatric liver diseases18Holt RI Jones JS Stone NM Baker AJ Miell JP. Sequential changes in insulin-like growth factor I (IGF-I) and IGF-binding proteins in children with end-stage liver disease before and after successful orthotopic liver transplantation.J Clin Endocrinol Metab. 1996; 81: 160-168Crossref PubMed Google Scholar support this notion that the liver plays a role in determining linear growth in AGS. Clearly, further study of the metabolic consequences of cholestasis is needed to determine whether the abnormal expression of JAG1 in AGS contributes directly or indirectly to these perturbations. The relatively favorable course and outcome of AGS have recently been called into question. In prior series1Alagille D Odievre M Gautier M Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur.J Pediatr. 1975; 86: 63-71Abstract Full Text PDF PubMed Scopus (512) Google Scholar, 2Alagille D Estrada A Hadouchel M Gautier M Odievre M Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases.J Pediatr. 1987; 110: 195-200Abstract Full Text PDF PubMed Scopus (531) Google Scholar less severely affected patients, identified because of a family member with AGS, have biased the results toward a good outcome. In our series of 26 children with AGS who presented with neonatal cholestatic liver disease, only 15 (58%) were alive without liver transplantation at a median age of 12.1 years.14Hoffenberg EJ Smith D Sauaia A Narkewicz MR Sokol RJ. Growth is not related to the presence of vertebral anomalies in Alagille syndrome.J Pediatr Gastroenterol Nutr. 1998; 27 ([abstract]): 469Crossref Scopus (6) Google Scholar Thirty-one percent required liver transplantation (successful in all) at a median of 6.5 years of age for recurrent bone fractures caused by metabolic bone disease, severe pruritus with xanthomas, and less commonly, liver synthetic failure. Remarkably, 4 (15%) patients had severe central nervous system abnormalities, including 2 epidural hematomas, 1 ruptured venous malformation, and 1 suprasellar arachnoid cyst; 2 of these hemorrhages were fatal. Recent reports from 2 other centers19McBride KE. Clinical features of the Alagille syndrome: frequency and relation to prognosis.J Pediatr Gastroenterol Nutr. 1998; 26 ([abstract]): 580Crossref Google Scholar, 20Quiros RE Ament ME Heyman MB Hall TR McDiarmid SV Vargas JH. Alagille’s syndrome: outcome of 41 cases.J Pediatr Gastroenterol Nutr. 1998; 26 ([abstract]): 582Google Scholar confirm this high incidence of intracranial hemorrhage. It is not clear whether this indicates another location where vascular structures have developed abnormally or whether the thin cranial bones fail to provide adequate protection from minor trauma. Consequently, anticipatory guidance for patients with AGS should include education of families regarding head trauma prevention and early signs of elevated intracranial pressure. The other major cause of death is severe pulmonary artery hypoplasia or complex congenital heart disease.19McBride KE. Clinical features of the Alagille syndrome: frequency and relation to prognosis.J Pediatr Gastroenterol Nutr. 1998; 26 ([abstract]): 580Crossref Google Scholar, 20Quiros RE Ament ME Heyman MB Hall TR McDiarmid SV Vargas JH. Alagille’s syndrome: outcome of 41 cases.J Pediatr Gastroenterol Nutr. 1998; 26 ([abstract]): 582Google Scholar The exciting new developments in the genetics of AGS will certainly add substantially to our understanding of liver and bile duct morphogenesis, improve our ability to diagnosis more subtle cases of AGS (eg, isolated right-sided congenital heart disease), and, hopefully, provide the basis for new interventional strategies for children with AGS and other cholestatic disorders.