J. Inher. Metab. Dis. 14 (1991) 526-530 © SSIEM and KluwerAcademicPublishers. Printed in the Netherlands
Clinical Presentation of Metabolic Liver Disease M. ODIEVRE Service de Pddiatrie, HOpital Antoine Beclere, 157 rue de la Porte de Trivaux, 92 141 Clamart Cedex, France
Summary:Some clinical clues should alert paediatricians to the possibility of metabolic liver diseases. They can be classified into three categories: (i) Manifestations due to hepatocellular necrosis, acute or subacute, which can reveal galactosaemia, hereditary fructose intolerance, tyrosinaemia type I, Wilson disease and ~l-antitrypsin deficiency. Symptoms and signs suggestive of Reye syndrome should lead to a study of fatty acid oxidation and urea cycle enzymes. All these manifestations may necessitate a rapid diagnosis and treatment when liver dysfunction is severe. (ii) Cholestatic jaundice can reveal el-antitrypsin deficiency, Byler's disease, cystic fibrosis, Niemann-Pick disease and some disorders of peroxisome biogenesis. (iii) Hepatomegaty can reveal disorders with liver damage but also storage diseases such as glycogen storage diseases, cholesteryl ester storage disease and, when associated with sptenomegaly, lysosomal storage diseases. Appropriate investigations for recognizing all these entities are proposed.
The purpose of this paper is to present a clinical approach to the treatment of patients with metabolic liver diseases. The first step in the evaluation is a thorough clinical assessment including history; as many of the metabolic disorders are recessively inherited, the familial history (consanguinity, previous death of one sibling of undetermined cause) is critical. Clinical manifestations of liver involvement which should lead to suspicion of inborn errors of metabolism can be separated into three categories: manifestations due to hepatocellular necrosis, cholestatic conditions and hepatomegaly.
MANIFESTATIONS DUE TO H E P A T O C E L L U L A R NECROSIS The situation, acute or subacute, is characterized by some degree of jaundice and/or oedema, ascites, bleeding tendency and sometimes hepatic encephalopathy. The clinical picture can be similar to septicaemia and it is not uncommon for an intercurrent sepsis to unmask an inborn error of metabolism (Burton, 1987). 526
Clinical Presentation of Metabolic Liver Disease
527
Laboratory studies can show elevated serum transaminases, hypoprothrombinaemia, hypofibrinogenaemia, hypoglycaemia and elevated blood ammonia concentration indistinguishable from the results of liver function tests seen in severe viral hepatitis. The liver size should help to distinguish between the two conditions: in metabolic diseases, the liver remains enlarged while a rapid atrophy is seen in acute liver failure of viral origin (Alagille and Odievre, 1979). A rapid diagnosis of these diseases is essential since many of the patients have a potentially treatable liver dysfunction. The age at which hepatic failure becomes apparent provides an important clue to the aetiology. Onset in infancy."
Three disorders have to be discussed:
(i) Galactosaemia is an early cause of metabolic liver dysfunction. Manifestations, essentially jaundice and bleeding tendency, typically appear at the end of the first or during the second week of life. Other circumstances suggesting galactosaemia are sepsis due to Escherichia coli (Levy et al., 1977) and exceptionally pseudotumour cerebri. Suspicion of this diagnosis requires examination of the lens, immediate suppression of galactose-containing foods and appropriate enzyme assays in erythrocytes, galactosuria being unspecific in an infant with liver failure. (ii) Hereditary fructose intolerance should be considered when symptoms appear as soon as fructose is introduced into the diet. Vomiting is a constant finding while other postprandial symptoms due to hypoglycaemia are in our experience less frequent (Odievre et aI., t978). A distaste for sweet foods represents a good index of suspicion but it occurs later. Any suspicion of fructose intolerance must lead to the immediate withdrawal of sucrose and fructose from the diet. As seen also in galactosaemia, the beneficial effect of withdrawal of the toxic substrates is seen within 2 or 3 days and can be considered as the first positive element of diagnosis before specific investigation can be made. (iii) The acute form of tyrosinaemia type I should be considered in all infants presenting with liver failure in whom galactosaemia and hereditary fructose intolerance have been excluded by specific investigations or when a galactose or fructose-free diet remains ineffective. A boiled cabbage odour of the urine is an index of suspicion. The chronic form is usually diagnosed when vitamin D-resistant rickets associated with liver disease by the age of 6 months to 1 year is discovered. Onset in the older child: Two disorders can be responsible for severe hepatocetlular necrosis: Wilson disease and el-antitrypsin deficiency.
(i) The clinical manifestations of Wilson disease are highly variable, but in children are predominantly hepatic (Odievre et al., 1974). Most often the liver disease is subacute or chronic, ranging from a persistent increase in serum transaminases to chronic active hepatitis and/or cirrhosis with progressive development of liver failure. However, some patients present with fulminant liver failure associated with intravascular haemolysis and renal failure. This association is highly suggestive of the disease and has a very high mortality rate. In fact, any type of liver disease of J. Inher. Metab. Dis. 14 (1991)
528
Odievre
unknown aetiology in children above the age of 6 years must be considered to be Wilson disease until proven otherwise. Evidence of renal tubular abnormalities, haemolysis and, from 10 years of age, neurological abnormalities are helpful for diagnosis. Suspicion of Witson's disease must immediately lead to a search for corneal Kayser-Fleisher rings, even in those patients with overwhelming symptoms. Establishing the diagnosis on the basis of a study of copper metabolism poses a problem in fulminant liver failure, since blood ceruloplasmin level can be nonspecifically decreased; in this case, an elevated serum copper level has been shown to be useful in separating patients with Wilson disease from others (Rakela et al., 1986). Patients with fulminant liver failure have to be transferred to the transplantation centre as soon as possible (Sternlieb, 1984). (ii) cq-Antitrypsin deficiency: this disorder is among the most common of all inherited metabolic diseases. Some children develop cirrhosis which can be revealed by unpredictable and unexplained fulminant liver failure (Odievre, 1989). Because a history of prolonged neonatal cholestasis suggesting the aetiology may be absent, the search for absence of an ~l-globulin peak on the serum protein electrophoresis is mandatory in all patients with unexplained overwhelming liver disease.
Onset in infancy or childhood: At any age, any infant or child presenting with findings suggestive of Reye syndrome or with atypical or recurrent Reye-like episodes should be evaluated for the possibility of disorders of fatty acid oxidation and urea cycle defects (Burton, 1987).
DISEASES REVEALED BY CHOLESTATIC JAUNDICE Affected patients have jaundice, dark urine, light or acholic stools and hepatomegaly. c~l-Antitrypsin deficiency is one of the most frequent causes of neonatal cholestasis, 10 to 20% of infants with the phenotype PIZZ developing this type of manifestation. Cholestasis is sometimes so complete that extrahepatic biliary atresia is considered (Odievre et al., 1976). The absence of an ~:-globulin peak permits a rapid diagnosis. Cholestasis usually disappears before the 6th month of age; when it persists, an associated hypoplasia of interlobular bile ducts must be considered. About half of the patients having neonatal cholestasis will develop cirrhosis within the first two or three years of life. Byler disease is considered by some authors to be metabolic in origin. Cholestasis, including pruritus, appears during the first year of life and initially occurs intermittently, often being provoked by infection. Between attacks lasting a few days to several months, remission is never complete and this severe familial intrahepatic cholestasis progresses to cirrhosis and death before 15 years of age. The underlying biochemical abnormality remains to be defined. Other inborn errors of metabolism are rarely associated with neonatal cholestasis. However, some infants with galactosaemia, hereditary fructose intolerance, tyrosinaemia type I or cystic fibrosis can also present with cholestasis. Neonatal cholestasis is a possible presenting manifestation of Niemann-Pick
J. lnher. Metab. Dis. 14 (1991)
529
Clinical Presentation of Metabolic Liver Disease
disease type C (several cases of this entity have been published as giant cell hepatitis) and of disorders of peroxisome biogenesis such as Zellweger syndrome and infantile Refsum disease (Lazarow and Moser, 1989). In this last condition, dysmorphic features, hypotonia and sensorineuraI dysfunction should orient the diagnosis. DISEASES R E V E A L E D BY H E P A T O M E G A L Y
Metabolic diseases revealed by hepatomegaly fall into two general categories: disorders with liver damage and storage diseases. An important clue to the diagnosis is the consistency of the liver and characteristic of its surface. The differential diagnosis of a firm or rock-hard liver must include the difference causes of cirrhosis, whether associated with liver dysfunction or not. Galactosaemia, hereditary fructose intolerance and tyrosinaemia type I below 1 year of age, ~l-antitrypsin deficiency above this age, and Wilson disease and cystic fibrosis in school age children are instances of metabolic cirrhosis. In a few patients, intestinal haemorrhage due to portal hypertension is the presenting manifestation. Wilson disease must be recognized in order to avoid surgical portosystemic shunt which is invariably followed by severe encephalopathy (Alagille and Odievre, 1979). Glycogen storage disease type IV (brancher deficiency) is another exceptional cause of cirrhosis during the first years of life. Glycogen storage disease type III (debrancher deficiency) can be complicated by the progressive development of portal fibrosis, sometimes responsible for portal hypertension in late childhood. In other metabolic diseases the consistency of the enlarged liver is normal or soft. Documenting the presence or absence of splenomegaly allows one to distinguish between two categories of patients: (i) In those with isolated hepatomegaly, some additional findings can suggest a diagnosis (Table 1). Sometimes a mild hepatomegaly is the only finding, as seen in some cases of cholesteryl ester storage disease and glycogen storage diseases due to phosphorytase or phosphorylase kinase deficiency. If erythrocyte and leukocyte assays show normal enzyme activity of the phosphorylase system, a liver biopsy is often the only way to progress to aetiology. Table 1 Clinical diagnostic aids in evaluating a patient with isolated hepatomegaly Findings
Metabolic disorder
Liver extending to the iliac crest Doll-like appearance and short stature Enlarged kidneys at X-ray and/or ultrasonography Cardiomegaty Muscular involvement Fasting intolerance
GSD types IA, IB GSD of any type GSD type IA
Chronic diarrhoea and malnutrition Repeated infections
GSD type II GSD types II, III GSD types IA, IB, III Fructose- 1,6-diphosphatase deficiency Cystic fibrosis GSD type IB (with granulopenia)
GSD: Glycogen storage disease
J. Inher. Metab. Dis. 14 (1991)
530
Odievre
(ii) Hepatomegaly and splenomegaly can reflect storage of substances in endothelial and/or parenchymal cells (Sharp, 1978). This is characteristic of lysosomal metabolic defects in which massive enlargement of the spleen is more often seen in storage diseases than in portal hypertension. Many of these diseases are accompanied by a history of slow development or of regression, coarse facial appearance and ocular and skeletal abnormalities. A detailed discussion of each entity is beyond the scope of this paper. Examination of peripheral blood for vacuolated white cells and bone marrow for storage cells and pertinent Xrays are mandatory. When the diagnosis still remains obscure, a liver biopsy should be performed for light and electron microscopy, and additional tissue should be frozen for future biochemical determinations. In rare cases, diagnosis has to be discussed when the history reveals a hydrops fetalis (Gillan, 1984). In summary, we have attempted to present some clinical clues which should alert paediatricians to the possibility of metabolic liver diseases. Some of the diseases are complicated by a severe liver dysfunction which necessitates a rapid diagnosis and treatment while others, not currently amenable to effective treatment, permit time for correct diagnosis and genetic counselling.
REFERENCES
Alagille, D. and Odievre, M. Liver and Biliary Tract Disease in Children, Wiley Flammarion, New York and Paris, 1979 Burton, B. K. Inborn errors of metabolism: the clinical diagnosis in early infancy. Pediatrics 79 (1987) 359-369 Gillan, J. E., Lowden, J. A., Gaskin, K. and Cutz, E. Congenital ascites as a presenting sign of lysosomal storage disease. J. Pediatr. 104 (1984) 225-231 Lazarow, P. B. and Moser, H. W. Disorders of peroxisome biogenesis. In Scriver, C. R., Beaudet, A. L., Sly, W. S. and Valle, D. (eds.) The Metabolic Basis of Inherited Disease, McGraw-Hill, New York, 1989, pp. 1479-1509 Levy, H. L., Sepe, S. J., Shih, V. E., Vawter, G. F. and Klein, J. O. Sepsis due to Escherichia coli in neonates with galactosemia. N. Engl. J. Med. 297 (t977) 823-825 Odievre, M. Liver transplantation for inborn errors of metabolism. In Vis, H., Van Hoof, F. and Schaub, J. (eds.) Inborn Errors of Metabolism. Nestl6 Nutrition Workshop Series Vol. 24. New York, Raven Press, 1991 Odievre, M., Vedrenne, J., Landrieu, P. and Alagitle, D. Les formes hbpatiques 'pures' de la maladie de Wilson chez l'enfant. A propos de 10 observations. Arch. Fr. Pediatr. 31 (1974) 215 222 Odievre, M., Martin, J. P., Hadchouel, M. and Alagille, D. Alpha-l-antitrypsin deficiency and liver diseases in children: phenotypes, manifestations and prognosis. Pediatrics 57 (1976) 226 231 Odievre, M., Gentil, C., Gautier, M. and Alagille, D. Hereditary fructose intolerance in childhood: diagnosis, management and course in 55 patients. Am. J. Dis. Child. 132 (1978) 605-608 Rakela, J., Kurtz, S. B., McCarthy, J. T., Ludwig, J., Ascher, N. L., Bloomer, J. R. and Claus, P. L. Fulminant Wilson's disease treated with postdilution hemofiltration and orthotopic liver transplantation. Gastroenterology 90 (1986) 2004-2007 Sharp, N. L. Metabolic liver disease. In Lebenthal, E. (ed.), Digestive Diseases in Children, Grune and Stratton, New York, 1978, pp. 589-610 Sternlieb, I. Witson°s disease. Indications for liver transplants. Hepatology 4 (t984) 15s-17s J. lnher. Metab. Dis. 14 (1991)
Clinical Presentation of Metabolic Liver Disease M. ODIEVRE Service de Pddiatrie, HOpital Antoine Beclere, 157 rue de la Porte de Trivaux, 92 141 Clamart Cedex, France
Summary:Some clinical clues should alert paediatricians to the possibility of metabolic liver diseases. They can be classified into three categories: (i) Manifestations due to hepatocellular necrosis, acute or subacute, which can reveal galactosaemia, hereditary fructose intolerance, tyrosinaemia type I, Wilson disease and ~l-antitrypsin deficiency. Symptoms and signs suggestive of Reye syndrome should lead to a study of fatty acid oxidation and urea cycle enzymes. All these manifestations may necessitate a rapid diagnosis and treatment when liver dysfunction is severe. (ii) Cholestatic jaundice can reveal el-antitrypsin deficiency, Byler's disease, cystic fibrosis, Niemann-Pick disease and some disorders of peroxisome biogenesis. (iii) Hepatomegaty can reveal disorders with liver damage but also storage diseases such as glycogen storage diseases, cholesteryl ester storage disease and, when associated with sptenomegaly, lysosomal storage diseases. Appropriate investigations for recognizing all these entities are proposed.
The purpose of this paper is to present a clinical approach to the treatment of patients with metabolic liver diseases. The first step in the evaluation is a thorough clinical assessment including history; as many of the metabolic disorders are recessively inherited, the familial history (consanguinity, previous death of one sibling of undetermined cause) is critical. Clinical manifestations of liver involvement which should lead to suspicion of inborn errors of metabolism can be separated into three categories: manifestations due to hepatocellular necrosis, cholestatic conditions and hepatomegaly.
MANIFESTATIONS DUE TO H E P A T O C E L L U L A R NECROSIS The situation, acute or subacute, is characterized by some degree of jaundice and/or oedema, ascites, bleeding tendency and sometimes hepatic encephalopathy. The clinical picture can be similar to septicaemia and it is not uncommon for an intercurrent sepsis to unmask an inborn error of metabolism (Burton, 1987). 526
Clinical Presentation of Metabolic Liver Disease
527
Laboratory studies can show elevated serum transaminases, hypoprothrombinaemia, hypofibrinogenaemia, hypoglycaemia and elevated blood ammonia concentration indistinguishable from the results of liver function tests seen in severe viral hepatitis. The liver size should help to distinguish between the two conditions: in metabolic diseases, the liver remains enlarged while a rapid atrophy is seen in acute liver failure of viral origin (Alagille and Odievre, 1979). A rapid diagnosis of these diseases is essential since many of the patients have a potentially treatable liver dysfunction. The age at which hepatic failure becomes apparent provides an important clue to the aetiology. Onset in infancy."
Three disorders have to be discussed:
(i) Galactosaemia is an early cause of metabolic liver dysfunction. Manifestations, essentially jaundice and bleeding tendency, typically appear at the end of the first or during the second week of life. Other circumstances suggesting galactosaemia are sepsis due to Escherichia coli (Levy et al., 1977) and exceptionally pseudotumour cerebri. Suspicion of this diagnosis requires examination of the lens, immediate suppression of galactose-containing foods and appropriate enzyme assays in erythrocytes, galactosuria being unspecific in an infant with liver failure. (ii) Hereditary fructose intolerance should be considered when symptoms appear as soon as fructose is introduced into the diet. Vomiting is a constant finding while other postprandial symptoms due to hypoglycaemia are in our experience less frequent (Odievre et aI., t978). A distaste for sweet foods represents a good index of suspicion but it occurs later. Any suspicion of fructose intolerance must lead to the immediate withdrawal of sucrose and fructose from the diet. As seen also in galactosaemia, the beneficial effect of withdrawal of the toxic substrates is seen within 2 or 3 days and can be considered as the first positive element of diagnosis before specific investigation can be made. (iii) The acute form of tyrosinaemia type I should be considered in all infants presenting with liver failure in whom galactosaemia and hereditary fructose intolerance have been excluded by specific investigations or when a galactose or fructose-free diet remains ineffective. A boiled cabbage odour of the urine is an index of suspicion. The chronic form is usually diagnosed when vitamin D-resistant rickets associated with liver disease by the age of 6 months to 1 year is discovered. Onset in the older child: Two disorders can be responsible for severe hepatocetlular necrosis: Wilson disease and el-antitrypsin deficiency.
(i) The clinical manifestations of Wilson disease are highly variable, but in children are predominantly hepatic (Odievre et al., 1974). Most often the liver disease is subacute or chronic, ranging from a persistent increase in serum transaminases to chronic active hepatitis and/or cirrhosis with progressive development of liver failure. However, some patients present with fulminant liver failure associated with intravascular haemolysis and renal failure. This association is highly suggestive of the disease and has a very high mortality rate. In fact, any type of liver disease of J. Inher. Metab. Dis. 14 (1991)
528
Odievre
unknown aetiology in children above the age of 6 years must be considered to be Wilson disease until proven otherwise. Evidence of renal tubular abnormalities, haemolysis and, from 10 years of age, neurological abnormalities are helpful for diagnosis. Suspicion of Witson's disease must immediately lead to a search for corneal Kayser-Fleisher rings, even in those patients with overwhelming symptoms. Establishing the diagnosis on the basis of a study of copper metabolism poses a problem in fulminant liver failure, since blood ceruloplasmin level can be nonspecifically decreased; in this case, an elevated serum copper level has been shown to be useful in separating patients with Wilson disease from others (Rakela et al., 1986). Patients with fulminant liver failure have to be transferred to the transplantation centre as soon as possible (Sternlieb, 1984). (ii) cq-Antitrypsin deficiency: this disorder is among the most common of all inherited metabolic diseases. Some children develop cirrhosis which can be revealed by unpredictable and unexplained fulminant liver failure (Odievre, 1989). Because a history of prolonged neonatal cholestasis suggesting the aetiology may be absent, the search for absence of an ~l-globulin peak on the serum protein electrophoresis is mandatory in all patients with unexplained overwhelming liver disease.
Onset in infancy or childhood: At any age, any infant or child presenting with findings suggestive of Reye syndrome or with atypical or recurrent Reye-like episodes should be evaluated for the possibility of disorders of fatty acid oxidation and urea cycle defects (Burton, 1987).
DISEASES REVEALED BY CHOLESTATIC JAUNDICE Affected patients have jaundice, dark urine, light or acholic stools and hepatomegaly. c~l-Antitrypsin deficiency is one of the most frequent causes of neonatal cholestasis, 10 to 20% of infants with the phenotype PIZZ developing this type of manifestation. Cholestasis is sometimes so complete that extrahepatic biliary atresia is considered (Odievre et al., 1976). The absence of an ~:-globulin peak permits a rapid diagnosis. Cholestasis usually disappears before the 6th month of age; when it persists, an associated hypoplasia of interlobular bile ducts must be considered. About half of the patients having neonatal cholestasis will develop cirrhosis within the first two or three years of life. Byler disease is considered by some authors to be metabolic in origin. Cholestasis, including pruritus, appears during the first year of life and initially occurs intermittently, often being provoked by infection. Between attacks lasting a few days to several months, remission is never complete and this severe familial intrahepatic cholestasis progresses to cirrhosis and death before 15 years of age. The underlying biochemical abnormality remains to be defined. Other inborn errors of metabolism are rarely associated with neonatal cholestasis. However, some infants with galactosaemia, hereditary fructose intolerance, tyrosinaemia type I or cystic fibrosis can also present with cholestasis. Neonatal cholestasis is a possible presenting manifestation of Niemann-Pick
J. lnher. Metab. Dis. 14 (1991)
529
Clinical Presentation of Metabolic Liver Disease
disease type C (several cases of this entity have been published as giant cell hepatitis) and of disorders of peroxisome biogenesis such as Zellweger syndrome and infantile Refsum disease (Lazarow and Moser, 1989). In this last condition, dysmorphic features, hypotonia and sensorineuraI dysfunction should orient the diagnosis. DISEASES R E V E A L E D BY H E P A T O M E G A L Y
Metabolic diseases revealed by hepatomegaly fall into two general categories: disorders with liver damage and storage diseases. An important clue to the diagnosis is the consistency of the liver and characteristic of its surface. The differential diagnosis of a firm or rock-hard liver must include the difference causes of cirrhosis, whether associated with liver dysfunction or not. Galactosaemia, hereditary fructose intolerance and tyrosinaemia type I below 1 year of age, ~l-antitrypsin deficiency above this age, and Wilson disease and cystic fibrosis in school age children are instances of metabolic cirrhosis. In a few patients, intestinal haemorrhage due to portal hypertension is the presenting manifestation. Wilson disease must be recognized in order to avoid surgical portosystemic shunt which is invariably followed by severe encephalopathy (Alagille and Odievre, 1979). Glycogen storage disease type IV (brancher deficiency) is another exceptional cause of cirrhosis during the first years of life. Glycogen storage disease type III (debrancher deficiency) can be complicated by the progressive development of portal fibrosis, sometimes responsible for portal hypertension in late childhood. In other metabolic diseases the consistency of the enlarged liver is normal or soft. Documenting the presence or absence of splenomegaly allows one to distinguish between two categories of patients: (i) In those with isolated hepatomegaly, some additional findings can suggest a diagnosis (Table 1). Sometimes a mild hepatomegaly is the only finding, as seen in some cases of cholesteryl ester storage disease and glycogen storage diseases due to phosphorytase or phosphorylase kinase deficiency. If erythrocyte and leukocyte assays show normal enzyme activity of the phosphorylase system, a liver biopsy is often the only way to progress to aetiology. Table 1 Clinical diagnostic aids in evaluating a patient with isolated hepatomegaly Findings
Metabolic disorder
Liver extending to the iliac crest Doll-like appearance and short stature Enlarged kidneys at X-ray and/or ultrasonography Cardiomegaty Muscular involvement Fasting intolerance
GSD types IA, IB GSD of any type GSD type IA
Chronic diarrhoea and malnutrition Repeated infections
GSD type II GSD types II, III GSD types IA, IB, III Fructose- 1,6-diphosphatase deficiency Cystic fibrosis GSD type IB (with granulopenia)
GSD: Glycogen storage disease
J. Inher. Metab. Dis. 14 (1991)
530
Odievre
(ii) Hepatomegaly and splenomegaly can reflect storage of substances in endothelial and/or parenchymal cells (Sharp, 1978). This is characteristic of lysosomal metabolic defects in which massive enlargement of the spleen is more often seen in storage diseases than in portal hypertension. Many of these diseases are accompanied by a history of slow development or of regression, coarse facial appearance and ocular and skeletal abnormalities. A detailed discussion of each entity is beyond the scope of this paper. Examination of peripheral blood for vacuolated white cells and bone marrow for storage cells and pertinent Xrays are mandatory. When the diagnosis still remains obscure, a liver biopsy should be performed for light and electron microscopy, and additional tissue should be frozen for future biochemical determinations. In rare cases, diagnosis has to be discussed when the history reveals a hydrops fetalis (Gillan, 1984). In summary, we have attempted to present some clinical clues which should alert paediatricians to the possibility of metabolic liver diseases. Some of the diseases are complicated by a severe liver dysfunction which necessitates a rapid diagnosis and treatment while others, not currently amenable to effective treatment, permit time for correct diagnosis and genetic counselling.
REFERENCES
Alagille, D. and Odievre, M. Liver and Biliary Tract Disease in Children, Wiley Flammarion, New York and Paris, 1979 Burton, B. K. Inborn errors of metabolism: the clinical diagnosis in early infancy. Pediatrics 79 (1987) 359-369 Gillan, J. E., Lowden, J. A., Gaskin, K. and Cutz, E. Congenital ascites as a presenting sign of lysosomal storage disease. J. Pediatr. 104 (1984) 225-231 Lazarow, P. B. and Moser, H. W. Disorders of peroxisome biogenesis. In Scriver, C. R., Beaudet, A. L., Sly, W. S. and Valle, D. (eds.) The Metabolic Basis of Inherited Disease, McGraw-Hill, New York, 1989, pp. 1479-1509 Levy, H. L., Sepe, S. J., Shih, V. E., Vawter, G. F. and Klein, J. O. Sepsis due to Escherichia coli in neonates with galactosemia. N. Engl. J. Med. 297 (t977) 823-825 Odievre, M. Liver transplantation for inborn errors of metabolism. In Vis, H., Van Hoof, F. and Schaub, J. (eds.) Inborn Errors of Metabolism. Nestl6 Nutrition Workshop Series Vol. 24. New York, Raven Press, 1991 Odievre, M., Vedrenne, J., Landrieu, P. and Alagitle, D. Les formes hbpatiques 'pures' de la maladie de Wilson chez l'enfant. A propos de 10 observations. Arch. Fr. Pediatr. 31 (1974) 215 222 Odievre, M., Martin, J. P., Hadchouel, M. and Alagille, D. Alpha-l-antitrypsin deficiency and liver diseases in children: phenotypes, manifestations and prognosis. Pediatrics 57 (1976) 226 231 Odievre, M., Gentil, C., Gautier, M. and Alagille, D. Hereditary fructose intolerance in childhood: diagnosis, management and course in 55 patients. Am. J. Dis. Child. 132 (1978) 605-608 Rakela, J., Kurtz, S. B., McCarthy, J. T., Ludwig, J., Ascher, N. L., Bloomer, J. R. and Claus, P. L. Fulminant Wilson's disease treated with postdilution hemofiltration and orthotopic liver transplantation. Gastroenterology 90 (1986) 2004-2007 Sharp, N. L. Metabolic liver disease. In Lebenthal, E. (ed.), Digestive Diseases in Children, Grune and Stratton, New York, 1978, pp. 589-610 Sternlieb, I. Witson°s disease. Indications for liver transplants. Hepatology 4 (t984) 15s-17s J. lnher. Metab. Dis. 14 (1991)
