METABOLIC LIVER DISEASE IN THE PEDIATRIC PATIENT

METABOLIC LIVER DISEASE

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METABOLIC LIVER DISEASE IN THE PEDIATRIC PATIENT Deirdre A. Kelly, MD, and Patrick J. McKiernan, BSc, MD

Metabolic liver disease in the pediatric patient has a varied clinical presentation: Neonate FefallNeonafalAscites Salla disease (sialidosis type 11) Niemann Pick C GMI Gangliosidosis Mucopolysaccharidosis VII Tyrosinaemia type I Carbohydrate deficient glycoprotein syndrome Wolman’s Cholesfasis a,-Antitrypsin deficiency Bile salt disorders Biliary hypoplasia Niemann Pick C Cystic fibrosis Acute Liver Failure Mitochondria1 disorders Neonatal hemochromatosis Galactosemia Tyrosinemia type I Hypoglycemia and Metabolic Acidosis Glycogen storage disease

From the Liver Unit, Birmingham Children’s Hospital, Birmingham, United Kingdom

CLINICS IN LIVER DISEASE VOLUME 2 NUMBER 1 FEBRUARY 1998

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KELLY & McKIERNAN

The majority of patients present in infancy with either cholestatic liver disease, acute liver failure, or multisystem disease. Recent advances in biochemical techniques and molecular genetics have dramatically improved the diagnosis of these conditions, although significant developments in therapy have altered the management and outcome. METABOLIC LIVER DISEASE IN THE CHOLESTATIC INFANT Almost two-thirds of children with liver disease present in infancy with prolonged jaundice and cholestasis. Because the signs and symptoms of liver disease at this age are similar, it is important to carry out a detailed investigation of the infant to differentiate between extrahepatic biliary atresia and choledochal cyst, neonatal hepatitis secondary to intrauterine infection, or metabolic liver disease. Signs and Symptoms of Liver Disease in Infancy Cholestatic liver disease Persistent jaundice (greater than 14 days after birth) Pale stools Dark urine Bleeding tendency Poor growth Acute Liver Failure Jaundice Coagulopathy Encephalopathy Hypotonia Multisystem involvement Investigation of Metabolic Liver Disease in the Neonate Conjugated hyperbilirubinemia Toxoplasniosis Other virus Rubella Cytomegalovirus Herpes simplex (TOUCH) a,-antitrypsin level and phenotype RBC Galactose-&phosphate uridyl transferase Fasting glucose, lactate, 3 hydroxy butyrate, free fatty acids Serum iron and ferritin Plasma amino acids (tyrosine and methionine) Urinary amino acids (succinylacetone) Organic acids Reducing sugars (for galactosemia, fructosemia) Immnoreactive trypsin/sweat test Abdominal ultrasound Trimethyl-bromo Iminodiacetic Acid (TBIDA) scan (to exclude biliary atresia, choledocal cyst) Liver biopsy Neonatal hepatitis Paucity of bile ducts

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Microvesicular steatosis Hemosiderosis Cirrhosis In general, children with neonatal hepatitis secondary to intrauterine infection or metabolic liver disease will either have intrauterine growth retardation or be small for gestational dates. In contrast, children with biliary atresia or choledochal cysts are usually born with a normal birth weight. All children with significant liver disease fail to grow adequately after birth without nutritional support. Alpha,-Antitrypsin Deficiency

Clinical Presentation Alpha,-Antitrypsin (a,-AT) deficiency is the most common inherited liver disease to present with neonatal cholesta~is.~~ (see article by Rosen) It is an autosomal recessive disorder with an incidence of approximately 1:4000 live births worldwide. Infants usually present with intrauterine growth retardation, cholestasis, hepatomegaly, and failure to thrive. Splenomegaly is unusual until significant hepatic fibrosis develops. About 2% of infants present with a vitamin-K-responsive coagulopathy that is more likely in those infants not given prophylactic vitamin K at birth or who are breastfed. The coagulopathy may be obvious, with bruising and bleeding from the umbilicus, but in many babies the initial symptom is an intraventricular hemorrhage that may result in long-term neurologic di~ability.2~ Cholestasis may be extreme with acholic stools and difficult to differentiate from extrahepatic biliary atresia. Diagnosis Biochemical evaluation demonstrates a mixed hepatocellular/obstructive pattern with raised aminotransferases, alkaline phosphatase, and y glutamyl transpeptidase (GGT). Radiologic investigation may demonstrate severe intrahepatic cholestasis with a contracted gallbladder on abdominal ultrasound and delayed or absent excretion of radioisotope following a T-BIDA scan. In homozygotes the diagnosis is confirmed by demonstrating low-serum a-l-antitrypsin (normal >1.0 g/L) and determining the phenotype by isoelectric focus. Liver disease is usually associated with protein inhibitor ZZ (Pi ZZ). Liver histology typically demonstrates a giant-cell hepatitis with the characteristic Periodic Acid Schiff, diastase-resistant positive granules in hepatocytes that may be detected as early as 6 to 8 weeks of age. Liver Disease with Other Alpha, -antitrypsin Phenotypes Liver disease has been reported in both infants and adults with phenotypes SZ, SS, FZ, and MZ.8,l5 As the carrier state (Pi MZ) is common, it is possible that the development of liver disease may be

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coincidental or that heterozygotes have an increased risk of developing liver disease. In the authors' experience in Birmingham (unpublished observation), progression of liver disease to cirrhosis has developed in two infants with Pi MZ-associated liver disease. Management, Outcome, and Liver Transplantation Management consists of nutritional support, fat-soluble vitamin supplementation, treatment of pruritus and cholestasis as required with phenobarbitone 5 to 15 mg/k/d, ursodeoxycholic acid 75 mg b.i.d., or cholestyramine 1 to 2 g daily. Nutritional Support For Infants with Prolonged Cholestasis Modular Feed-Energy intake 150-200 cal/ kg Carbohydrate-Glucose polymer (8-l0g/kg/d) Protein-Whe y protein (2.5-3.5g / kg / d) Fat-50/50 medium chain triglyceride (MCT)/long chain triglyceride (LCT) (Sg/kg/d) Fat-soluble vitamins-A, 5-10,000 units/d B, 50-100 mg/d K, 1-2 mg/d D, 50 ng/kg/d The prognosis is varied. Jaundice diminishes in most infants, and 30% appear to regain normal liver function. One third develop an inactive fibrosis with cirrhosis, and the remaining two thirds develop chronic liver failure requiring transplantation later in childhood.lO,57 A small number of children (i.e.,
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INTRAHEPATIC BlLlARY HYPOPLASIA The term intruheputic biliury hypoplusiu refers to an absence or reduction in the number of bile ductules seen in portal tracts in association with normal-sized branches of the portal vein and hepatic artery. A reduction in bile ducts or biliary hypoplasia may occur in other liver diseases, such as a,-antitrypsin deficiency, chromosomal abnormalities, such as Down’s syndrome, and intrauterine infection; however, the term intrahepatic biliary hypoplasia is usually only associated with syndromic biliary hypoplasia or Alagille’s syndrome, or nonsyndromic biliary hypoplasia.

Alagille’s Syndrome Alagille’s syndrome is an autosomal dominant condition with an incidence of 1:100,000 live births worldwide, which is associated with cardiac, facial, renal, ocular, and skeletal abnormalities.’ Some patients have an interstitial deletion on chromosome 2 0 ~ . * ~ Clinical Presentation

Infants usually present with persistent cholestasis, severe pruritis, hepatomegaly, and striking failure to thrive. The characteristic facial features, which include a triangular face with a high forehead and frontal bossing, deep-set, widely-spaced eyes, saddle-shaped nasal bridge, and pointed chin, are often difficult to distinguish in infancy, but become more prominent later in childhood. The most common cardiac abnormality is peripheral pulmonary stenosis, although pulmonary and aortic valve stenosis and Fallot’s tetralogy have been reported. The most common skeletal abnormalities include abnormal thoracic vertebrae (butterfly vertbrae) and curving of the proximal digit of the third and fourth fingers. Posterior embryotoxin, which is detected on the inner aspects of the cornea near the junction of the iris, is usually only demonstrated by slitlamp examination, but is present in 90% of patients with Alagille’s syndrome compared to 10% in the normal population. There may also be retinal pigmentation on fundoscopy and calcific deposits in the optic nerve head.42A variety of different renal abnormalities may also occur, varying from renal tubular acidosis to glomerulonephritis. Alagille’s syndrome is characterised by severe failure to thrive, which may be associated with severe vomiting secondary to gastrointestinal reflux complicated by recurrent aspiration pneumonia, as well as severe steatorrhoea secondary to fat malabsorption or pancreatic insufficienc

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Investigations and Diagnosis As Alagille’s syndrome affects many organs, a multidisciplinary approach is required. Many infants will have complete cholestasis; therefore, differentiation from extrahepatic biliary atresia may be difficult. Liver biochemistry indicates severe cholestasis with conjugated bilirubin of more than 5 mg/dL (normal <2 mg/dL), raised alkaline phosphatase (>600 U/L), GGT (>200 U/L), raised aminotransferases, or plasma cholesterol (>6 mmol/L) with normal triglycerides. Hepatic synthetic function tests, such as albumin and coagulation, are usually normal. Liver histology may be nonspecific, and careful examination is required to identify the reduction in interlobular bile ducts. In the first 6 to 8 weeks of life, the paucity of interlobular bile ducts may be masked by the features of cholestasis and giant-cell hepatitis. The biopsy may be differentiated from extrahepatic biliary atresia by the absence of portal fibrosis and extrahepatic biliary ductule proliferation.’ Renal dysfunction may be suspected by an increased urinary protein/creatinine ratio (>20 mg/L) and the presence of aminoaciduria, even though serum urea and creatinine may be normal. Radiologic examination of the chest and the hands may reveal the characteristic skeletal abnormalities. In children with peripheral pulmonary stenosis, electrocardiography may demonstrate right bundle branch block or right ventricular hypertrophy. Echocardiography may be normal, but if the diagnosis is suspected clinically, it should be confirmed by angiography. Management Intensive nutritional support is essential. Pruritus may be intractable, and is managed with cholestyramine 1 to 2 g/day, phenobarbitone 5 to 15 mg/kg/d, rifampicin 50 mg/kg/d, or ursodeoxycholic acid 20 mg/kg/d. Pancreatic supplements may be required if there is significant exocrine pancreatic dysfunction. Prognosis The prognosis is variable, and depends on the severity of liver, cardiac, or renal disease.20,50 Up to 50% of children may regain normal liver function by adolescence whereas others may develop liver or renal 50 Liver failure or manifest significant cardiologic or neurologic disease.20, transplantation is indicated for the development of cirrhosis and decompensated portal hypertension or intractable pruritis. Pulmonary stenosis or peripheral pulmonary stenosis may require balloon dilatation or pulmonary valvotomy. Liver transplantation may be contraindicated because of severe inoperable cardiac disease. Nonsyndromic Biliary Hypoplasia

Nonsyndromic biliary hypoplasia is a rare disorder with a similar clinical presentation to Alagille’s syndrome, but without the extrahepatic

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manifestations. It is thought that the disease is an autosomal recessive condition. Biochemical and histologic features may be identified, although hepatic fibrosis is often more with a rapid progression to cirrhosis and the necessity for liver transplantation.

Progressive lntrahepatic Cholestasis (Progressive Fibrosing lntrahepatic Cholestasis)

Progressive intrahepatic cholestasis is the term given to a number of poorly defined conditions in which there is persistent jaundice, cholestasis, hepatomegaly, pruritis, and failure to thrive. A number of different variants have been identified, and they are assumed to be autosomal recessive disorders in which the underlying metabolic defect is unknown.

Byler’s Disease

This severe form of familial idiopathic cholestasis was first described in an Amish family7 Since then, a number of other variants have been identified. Maggiore et a P described a group of children with familial cholestasis and normal GGT who had rapid progression to cirrhosis whereas S t r u m et a156demonstrated impaired synthesis of apolipoprotein A1 in hepatocytes in 18 patients with Byler’s disease. Diagnosis, Prognosis, and Management

Biochemical liver function includes elevated aminotransferases, and a raised alkaline phosphatase with or without an elevated GGT. Liver histology demonstrates severe cholestasis and progressive hepatic fibrosis. Nutritional support and relief of pruritus are required. Biliary diversion may be effective for pruritus. Most children have progressive fibrosis with the development of cirrhosis and portal hypertension, and will require liver transplantation in childhood.

Inherited Disorders of Bile Salt Metabolism

The development of fast atom bombardment ionization mass spectrometry (FAB-MS) has made it possible to define and detect many defects in primary bile acid synthesis. A number of disorders of bile salt metabolism have been identified, which include 3 P-hydroxy, 6 C 27steroid dehydrogenase isomerase deficiency? 3-0x0- 6 4 steroid 5 p reductase deficiency?*and 24,25-dihydroxy cholanoic cleavage enzymedeficiency5

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Clinical Presentation and Diagnosis

Infants present with prolonged cholestasis, pruritis, hepatomegaly, and failure to thrive with biochemical abnormalities of aminotransferases, elevated alkaline phosphatase, and GGT. Liver histology indicates giant-cell hepatitis or neonatal hepatitis with cholestasis, although development of fibrosis and cirrhosis is rapid if untreated. The diagnosis is made by identifying the abnormal metabolites in urine by FAB-MS. Management and Outcome

These diseases are fatal without liver transplantation. Treatment with a combination of cholic acid and ursodeoxycholic acid may prevent progression to cirrhosis and portal hypertension if started prior to significant fibrosis?

Zellweger's Syndrome

Zellweger 's syndrome (cerebrohepatorenal syndrome) is an autosoma1 recessive syndrome with multiple congenital anomalies. This rare disorder is associated with absent or dysfunctional peroxisome biogenesis leading to secondary defects of bile acid synthesis and abnormal @oxidation of fatty acids; the incidence is 1:100,000 live births. Both sexes are affected equally, with multiorgan failure involving the brain, heart, liver, and kidneys1* Clinical Presentation and Diagnosis

Infants present with severe hypotonia and feeding difficulties with failure to thrive. Only 50% of babies are jaundiced at presentation, but dysmorphic features, which include epicanthic folds, Brushfield spots, and a high forehead, are common in association with psychomotor retardation. The diagnosis is confirmed by demonstrating abnormal urinary bile salt metabolites using FAB-MS or the detection of very-longchain fatty acids in serum. Hepatic pathology may appear almost normal, although there is usually excessive hepatic iron in the first 3 months with the development of fibrosis and micronodular cirrhosis. Ultrastructural studies may indicate abnormal mitochondria and the absence of peroxisomes. Management and Outcome

Treatment is supportive, as death is inevitable. Liver transplantation is contraindicated because of the multisystem disease. Attempts to induce peroxisomes with hypolipemic drugs have been unsuccessful?0 whereas primary bile acid therapy with cholic and chenodeoxycholic

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acid may produce some histologic improvement, but does not prolong life.51

Cystic Fibrosis Cystic fibrosis is a rare cause of neonatal cholestasis, accounting for less than 1% of children with prolonged jaundice33(see article by Flora and Benner). It is an autosomal recessive disorder with an incidence of 1:2000 live births. The genetic defect has been localized to the long arm of chromosome 7. More than 300 mutations have been identified in the gene in coding for the cystic fibrosis transmembrane conductance regulator (CFTR).&,48 Clinical Presentation and Diagnosis

Infants present with cholestasis, meconium ileus, hepatomegaly, failure to thrive, and respiratory symptoms. If cholestasis is complete with acholic stools, differentiation from biliary atresia may be extremely difficult. Biochemical liver function tests reveal elevated aminotransferase, alkaline phosphatase, and GGT. Immunoreactive trypsin concentration may be higher than normal for age (>130 ng/mL), serum cholesterol is usually normal (<4 mmol/L). In children older than 4 weeks of age it is worth performing a sweat test. Sweat sodium and chloride concentration increase with age, but should be less than 50 mmol/L in children under the age of 5 years. Liver histology is varied, but in infancy usually demonstrates diffuse cholestasis with bile duct proliferation, focal biliary cirrhosis, and portal fibrosis. Management and Outcome

Although the efficacy of ursodeoxycholic acid (20-50 mg/kg/d) in the treatment of neonatal cholestasis secondary to cystic fibrosis is unknown, it is empirically used. Nutritional management and fat-soluble vitamin supplementation are essential. The jaundice resolves in 80% of children with neonatal cystic fibrosis liver disease.33Persistent jaundice is associated with the development of cirrhosis, portal hypertension, and liver failure. Malnutrition and respiratory disease may contribute to liver failure, leading to death in infancy.

Niemann Pick Disease Type C Niemann Pick Disease Type C is an autosomal recessive disorder characterized by a defect in cholesterol esterification that results in a neurovisceral lipid storage disorder with an extremely varied spectrum of clinical findings."

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Clinical Presentation and Diagnosis

Sixty-five percent of children will present with prolonged cholestasis and hepatosplenomegaly in infancy, some of whom may present with fetal as cite^.^^ The remainder present with isolated splenomegaly with or without neurologic symptoms. Liver histology may indicate a neonatal hepatitis or giant-cell hepatitis, and the detection of the periodic acidSchiff, diastase-resistant storage cells may be difficult to detect in Kupffer cells and hepatocytes. It may be easier to detect the foamy storage cells in bone marrow aspirate. Neuronal storage is usually present at birth, and may be demonstrated in the ganglion cells of a suction rectal biopsyz7 Management and Prognosis

Jaundice subsides in most children, although hepatosplenomegaly may persist with elevated aminotransferases. Hepatic fibrosis with progression to cirrhosis and portal hypertension is unusual. All children will develop neurologic complications, which include ataxia, convulsions, developmental delay, dementia and supranuclear ophthalmoplegia, with a mean age of onset at 5 years. Most children die in early adolescence from bronchopneumonia rather than liver failure. There is no specific treatment, although a low cholesterol diet has been suggested. Liver and bone marrow transplantation are ineffective. Genetic counseling is essential and antenatal diagnosis is now available by chorionic villus biopsy.65 ACUTE LIVER FAILURE IN INFANCY

Acute liver failure in infancy usually presents with multisystem involvement. The diagnosis may initially be difficult, as jaundice may be a late feature. Infants are usually small for gestational dates, with hypotonia, severe coagulopathy, and encephalopathy. Neurologic problems, such as nystagmus and convulsions, may be secondary to cerebral disease or encephalopathy. Renal tubular acidosis is common. Investigations include a search for pathology throughout the body.

Investigation and Management of Acute Liver Failure in Infancy Inues tigat ions Plasma ammonia, triglycerides and cholesterol Immunoglobulins and autoantibodies (LKM) Urinary succinylacetone and RBC porphobilinogen synthase If either abnormal, measure Fumarylactoacetase activity directly in skin fibroblasts or lymphocytes Plasma lactate, ketone bodies and glucose pre and post glucose load. Plasma lactate/pyruvate ratio (if lactate increased) If L/P ratio high or significant increase in lactate or ketone

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bodies postglucose load look for evidence of extrahepatic mitochondria1 disorder with: Muscle biopsy, CSF lactate, Echocardiography, Visual evoked potentials. Plasma Iron, transferrin and ferritin. If elevated ferritin with high transferrin saturation proceed to lip mucosal biopsy and/or hepatic MRI.

Management General measures Intravenous dextrose, antacids, antibiotics and antifungals Exclude galactose from diet until galactosaemia has been exluded Exchange transfusion Specific measures Tyrosinaemia type 1- NTBC Neonatal Haemachromatosis-”Antioxidant cocktail” Liver transplantation will be indicated for majority of affected infants unless contraindicated by irreversible extrahepatic disease.

Galactosemia Galactosemia is a rare autosomal disorder that is secondary to a deficiency of galactose-1-phosphate uridyl transferase. Acute illness results from the accumulation of the substrate galactose-1-phosphate (gall-l’) following the introduction of milk feeds. Clinical Presentation and Diagnosis Infants may present with collapse with hypoglycemia and encephalopathy in the first few days of life or with progressive jaundice and liver failure. Cataracts are often present even shortly after birth. The disease may be complicated by gram-negative septicemia that stimulates a severe bleeding diathesis. The diagnosis is suggested by the detection of urinary reducing substances in the absence of glycosuria, but should be confirmed by demonstration of reduced enzyme ac.tivity in erythrocytes. Hepatic pathology initially demonstrates fatty change, periportal bile duct proliferation, and iron deposition with extramedullary hematopoeisis. If galactose ingestion persists, hepatic fibrosis and cirrhosis may develop, although in some infants cirrhosis is present at Management and Prognosis Liver function improves following exclusion of galactose from the diet unless liver failure or cirrhosis is already established. Galactose elimination should be life-long, but efficacy may be limited by endogenous synthesis of gal-l-p.2 Learning difficulties and growth disturbance are more common in girls, 75% of whom develop ovarian failureF2

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Detection of galactosemia as part of the neonatal screening program leads to early detection, except in those babies who present with fulminant hepatitis. Antenatal diagnosis is possible by chorionic villus sampling.

Neonatal Hemochromatosis This disorder is the most common cause of acute liver failure in the neonate. It is characterized by the prenatal accumulation of intrahepatic iron, which may be due to a primary disorder of fetoplacental iron handling or a secondary manifestation of fetal liver disease. Clinical Presentation and Diagnosis Intrauterine growth retardation and premature delivery is common. Clinical features, such as hypoglycemia, jaundice, and coagulopathy, present on the first day of life with rapid deterioration and a fatal outcome without treatment within the first month of life. Biochemical liver function tests indicate an elevated bilirubin, usually low aminotransferases, and albumin. Serum iron binding capacity is low and hypersaturated (90%-100%) with a grossly elevated ferritin level (>lo00 ng/L). Diagnostic liver biopsy is not feasible because of the coagulopathy, but extrahepatic siderosis may be demonstrated in minor salivary glands obtained by lip biopsy.29MR imaging may confirm excess hepatic and extrahepatic iron. Postmortem liver histology demonstrates pericellular fibrosis, giant-cell trar,sformation, ductular proliferation, and regenerative nodules. The distribution of siderosis is similar to adult hereditary hemochromatosis with hepatocellular and extrahepatic parenchymal deposition with sparing of the reticuloendothelial system.28 Management and Prognosis Medical management includes supportive therapy for acute liver failure and the use of an "antioxidant cocktail" that combines N-acetylcysteine 150 mg/kg/d, vitamin E 25 mg/kg/d, selenium 2 to 3 kg/kg/ d, prostaglandin E l 0.4 to 0.6 pg/kg/hr, and desferrioxamine 30 mg/ kg/d, and should be started as soon as the diagnosis has been made.53 Liver transplantation is usually required, and if successful, there is resolution of extrahepatic iron.37 Antenatal Diagnosis Currently, early antenatal diagnosis is not possible, but the diagnosis may be suspected by the detection of nonspecific abnormalities, such as hydrops fetalis or intrauterine growth retardation. MR imaging may detect prenatal iron accumulation, but the sensitivity is u n k n ~ w n . ' ~

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Disorders of Mitochondrial Energy Metabolism

Mitochondrial energy metabolism disorders include a wide range of clinical phenotypes with any mode of inheritance: autosomal recessive, autosomal dominant, or transmission through maternal DNA. A number of different defects involving the electron transport chain have been described. The clinical features are secondary to dysfunction of the electron transport chain, which results in cellular ATP deficiency and the generation of toxic-free radicals. Clinical symptoms are variable, depending on the nature of the primary defect, its tissue distribution and abundance, and the importance of aerobic metabolism in the affected tissue. The constituent proteins of the electron transport chain are encoded in two genomes, either by nuclear DNA or mitochondria1 DNA (mDNA) that is maternally inherited.38In the context of liver failure, two entities are relevant: isolated deficiencies of the electron chain enzymes and mDNA depletion syndromes. Deficiencies of the Electron Transport Chain Enzyme

The most common isolated defects are complexes 4 and 1, although multiple deficiencies have been reported. Infants present with multisystem involvement with hypotonia, cardiomyopathy, proximal renal tubulopathy, and a severe metabolic acidosis. Relevant diagnostic investigations include elevated blood lactate; lactate/pyruvate ratio of more than 20; increased 3-OH-butyrate/acetoacetate ratio more than 2, or an increase in lactate (with or without ketone bodies) following a glucose load (2g/kg X 50 g); also suggestive are the detection of specific organic acids, such as urinary 3-methyl-glutaconic acid or other Krebs cycle intermediatesMThe definitive diagnosis is based on demonstrating biochemical dysfunction of electron chain function in liver or muscle by histochemistry or enzyme analysis, but severe coagulopathy is common and may preclude performance of invasive procedures. Demonstration of an elevated cerebrospinal fluid (CSF) lactate compared to plasma lactate indicates neurologic involvement. Management and Prognosis Supportive management may be the only option. Liver transplantation may be. successful if the defect is confined to the liver,’3 but is contraindicated if multisystem involvement is obvious as neurologic deterioration typically progresses post-transplant.60 Antenatal Diagnosis Antenatal diagnosis is rarely possible, as the underlying gene defects are not known and the enzyme measurement in chorionic villi may

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not detect tissue-specific activity. Chorionic villus biopsy is possible in complex 4 defi~iency.~~

Mitochondria1 Depletion Syndrome Mitochondriae normally contain more than one copy of mDNA. Replication of mDNA is regulated by a number of factors encoded by nuclear genes. Mutations in these nuclear genes lead to reduction in copy numbers of mDNA resulting in mitochondria1 depletion. Clinical Presentation and Diagnosis The clinical presentation and biochemical findings are similar to infants presenting with isolated electron transport chain deficiencies. In most patients, tissue measurement of electron chain activities show deficiencies in complexes 1, 3, and 4, although activity may be within the normal range. The diagnosis is confirmed by demonstrating an abnormally low ratio for mDNA/nuclear DNA in affected tissue.62 Management and Prognosis Treatment is supportive as liver transplantation is contraindicated. Antenatal diagnosis is not currently possible.

Tyrosinemia Type I Tyrosinemia type I is an autosomal recessive disorder due to a defect of fumaryl acetoacetase (FAA), which is the terminal enzyme in tyrosine degradation. The gene for FAA is on the short arm of chromosome 15. Many mutations have been described, although in some populations a single mutation may be pre~a1ent.l~ Intermediate metabolites, such as maleyl- and fumarylacetoacetate,are highly reactive compounds that are locally toxic within the liver. The secondary metabolite, succinylacetone, has local and systemic effects (Fig. l), including inhibition of porphobilinogen synthase. Clinical Presentation Clinical presentation is heterogenous, even within the same Acute liver failure is a common presentation in infants between 1 to 6 months of age who present with mild jaundice, coagulopathy, encephalopathy, and ascites. Hypoglycemia is common, and may be secondary to liver dysfunction or hyperinsulinism due to pancreatic islet cell hyperplasia. In older infants, failure to thrive, coagulopathy, hepatosplenomegaly, hypotonia, and rickets are common. Older children may present

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'T' Tyrosine

= 4- OH Phenylpyruvate

phenylpyruvate dloxygenase

I

Fumarylacetoacetate

\\

cyclohexenedlome) Porphyrin synthesis pathway 5-aminolaevulinic acid I

Succinylacetone

[Deficient in TT1)

I

Fumarate + Acetoacetate

Synthase

I

Figure 1. Metabolism of tyrosine showing defect in tyrosinaemia type 1 and metabolic effect of NTBC.

with chronic liver disease, cardiomyopathy, renal failure, or a porphyrialike syndrome with self mutilation. Renal tubular dysfunction and hypophosphatemic rickets may occur at any age. Diagnosis Biochemical liver function tests reveal an elevated bilirubin, aminotransferases, alkaline phosphatase, and a reduced albumin. Plasma amino acids indicate increased plasma tyrosine, phenylalanine, and methionine ( X 3 normal) with grossly elevated a-fetoprotein levels. Significant urinary succinyl acetone is a pathognomonic, but not an invariable, finding. The diagnosis is confirmed by measuring FAA activity in fibroblasts or lymphocytes. Proximal tubular dysfunction may be suspected by the demonstration of phosphaturia and aminoaciduria and confirmed by a reduction in renal tubular absorption of phosphate (<80%). Echocardiography may reveal a hypertrophic cardiomyopathy whereas radiologic examination may indicate severe hypophosphatemic rickets. Hepatic histology is nonspecific with steatosis, siderosis, and cirrhosis, which may be present in infancy. Hepatocyte dysplasia is common and is associated with a risk of hepatocellular carcinoma. Antenatal diagnosis is possible either by chorionic villus sampling, which measures FFA directly, from mutation analysis, or by measurement of succinyl acetone in the amniotic fluid. Prospective affected siblings may benefit from early NTBC therapy. Management Initial management is with a phenylalanine- and tyrosine-restricted diet, which may improve overall nutritional status and renal tubular

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function, but has little effect on the progression of liver disease. The recent discovery of NTBC (212 nitro-trifluoromethylbenzoyl]-1,3-cyclohexenedione), which prevents the formation of toxic metabolites (Fig. l), has changed the natural history of this disease in childhood.32In Birmingham the authors have treated 10 children with NTBC, leading to a rapid reduction of toxic metabolites (see Fig. l),normalization of tubular function, prevention of porphyria-like crises, and improvement in both nutritional status and liver function. In 3 of 4 children with acute liver failure there was a complete response to NTBC. The current indications for liver transplantation for this condition include the development of acute or chronic liver failure unresponsive to NTBC or the development of hepatocellular carcinoma. Prognosis

The long-term outcome of children with tyrosinemia type I treated with NTBC is unknown.32These children require long-term monitoring and follow-up with 6 monthly abdominal ultrasounds and a-fetoprotein estimation to detect hepatocellular car~inoma.'~

Familial Hemophagocytic Lymphohistiocytosis This rare disorder appears to be inherited as an autosomal recessive, and is characterized by progressive visceral, neurologic, and bone marrow infiltration with lymphocytes and large erythrophagocytic histiocytes. Clinical Presentation and Diagnosis

Children present with fever, hepatosplenomegaly, jaundice, skin rash, edema, and encephalopathy in the first year of life. There is a pancytopenia, coagulopathy, biochemical features of acute liver failure, hypofibroginemia, and hypertriglyceridemia. Diagnosis is established by identifying the characteristic erythrophagocytic histiocytes in bone marrow, liver, and CSF. Virus-associated hemophagocytic syndrome has a similar clinical presentation. Treatment and Prognosis

The disease is usually fatal, although treatment with antimetabolites and steroids or bone marrow transplantation may be helpful. Liver transplantation is contraindicated if there is extensive bone marrow or neurologic involvement.

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OTHER CLINICAL PRESENTATIONS OF METABOLIC DISEASE IN INFANCY Fetal or Neonatal Ascites Fetal ascites is a rare clinical presentation that may be associated with intrauterine infection or rhesus hemolytic disease. The main metabolic causes include Salla disease, sialadosis type 11, Niemann Pick type C, GMI gangliosidosis, mucopolysaccharidosis VII, Wolman’s disease, Tyrosinemia type I carbohydrate-deficient glycoprotein syndrome, and neonatal hemochromatosis.

Dubin-Johnson Syndrome Dubin-Johnson syndrome is an autosomal recessive disease, and is due to a disorder in bilirubin transport, which leads to prolonged unconjugated bilirubinemia. Clinical Presentation, Diagnosis, and Prognosis Although the syndrome may present in the neonatal period, the onset is usually during puberty. There is persistent prolonged conjugated hyperbilirubinemia without cholestasis or any sign of chronic liver disease. The rise in conjugated bilirubin is intermittent, but is exacerbated by trauma, surgery, pregnancy, or oral contraceptives; liver function tests are typically normal. The diagnosis may be made by demonstrating an abnormal bromosulphathalein sodium retention at 90 to 120 minutes or by estimating coproporphyrin excretion in urine. The ratio of coproporphyrin 3 to coproporphyrin 1 varies from the normal 3:l to 1:4. It is not necessary to perform a liver biopsy, but hepatic histology usually demonstrates a greenish-black appearance of the liver with melanin-like pigmentation in hepatocytes. No treatment is required and prognosis is normal.

Rotor Syndrome Rotor syndrome is a rare disorder, and is similar to Dubin Johnson syndrome, but there is no pigment deposition in the hepatocytes. There is mild conjugated hyperbilirubinemia without a rise in the bromsulphaphthalein sodium concentration. Urinary coproporphyrin excretion is increased by 65%, as coproporphyrin 1. Similarly, prognosis is normal and no treatment is required.

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Metabolic Disease in Older Children

Metabolic disease in older children presents with hepatomegaly, often without jaundice, with or without splenomegaly, or neurologic involvement. The main causes of metabolic liver disease in older children include a-1-antitrypsin deficiency, cystic fibrosis, Gaucher’s disease, tyrosinemia type I, glycogen storage diseases, hereditary fructose intolerance, and Wilson’s disease. Metabolic Liver Disease in Older Children Hepatomegaly Glycogen storage disease* Hereditary fructose intolerance* Chronic liver disease ( + / - portal hypertension) el-antitrypsin deficiency Cystic fibrosis Tyrosinemia type I Wilson’s diseaset Gaucher’s disease Acute liver failure Wilson’s disease Alper’s disease Valproate toxicity (See articles by Rosen, Flora and Benner, Ferenci.) Glycogen Storage Disease

The hepatic glycogen storage disorders (GSDs) are a group of inherited disorders affecting the metabolism of glycogen to glucose. Characteristic findings include hepatomegaly, growth failure, and hypoglycemia. The diagnosis is based on demonstrating the respective enzyme deficiency (Table 1).All are autosomal recessive except for phosphorylase kinase deficiency that is X-linked. GSD Type I

Glucose-6-phosphatase(G-6-P) is a microsomal enzyme essential for hepatic glucose export found not only in hepatocytes but also in renal tubular epithelium, pancreatic ductal epithelium, and intestinal mucosa. The gene for glucose-6-phosphatase has been isolated and many mutations described. Antenatal diagnosis by chorionic villus sampling is possible if a known mutation has been identified within the family.31 *GSD I11 and IV and hereditary fructose intolerance (HFI) may progress to cirrhosis. tMay present with any form of liver disease.

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Table 1. HEPATIC GLYCOGEN STORAGE DISEASES

Type

Enzyme Deficiency

Tissue

la Ib lc 3 4 6 9

G-6-P G-6-P translocase Phosphate translocase Amylo-1-6-glucosidase (Debrancher) Brancher Hepatic phosphorylase Phosphorylase kinase

Liver Liver Liver Leucocytes, liver Liver, fibroblasts Leucocytes Leucocytes, liver

Deficiency of the enzyme results in complete dependency on exogenous carbohydrate, and the clinical effects of the disease result from hypoglycemia. Clinical Presentation and Diagnosis

Infants usually present with hypoglycemic seizures, hepatomegaly, and failure to thrive. Biochemical investigations reveal fasting hypoglycemia ( 4 . 5 g/L) with lactic acidosis (>5 mmol/L), hyperlipidemia (cholesterol >6 mmol/L and triglycerides >3 mmol/L), and hyperuricemia. Hepatic aminotransferases are usually normal or mildly elevated. Liver histology reveals steatosis and glycogen storage with no fibrosis. Histochemical stains for (G-6-P) are negative and the enzyme is undectable in the liver. Management and Prognosis

The initial aim of dietary treatment is to provide a continuous supply of exogenous glucose to maintain normal blood sugars and suppression of counterregulatory responses. This is best achieved in infants by frequent daytime feeding, use of oral uncooked corn starch, which is hydrolysed in the gut to release glucose slowly over hours, and continuous nocturnal enteral glucose feeds.68If dietary control is strict in infancy, normal growth and development will be attained despite persistence of hepatomegaly and hyperlipidemia. Long-term complications include osteoporosis, renal dysfunction and calculi, and hepatic adenomata, which have the potential for malignant transformation. The hepatic metabolic defect is corrected by liver transplantation, but it should not be the sole indication for the procedure. GSD Type 1b and l c

In GSD type l b and lc, G-6-P activity is normal but dysfunctional. Type l b is due to a defect in G-6-P transport into the microsome whereas

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type l c is due to abnormalities of phosphate transport out of the microsome. The clinical and biochemical features are similar to GSD type la. In GSD type lb, neutropenia with recurrent infections from oral ulcers and inflammatory bowel disease47have been reported. As the gene defect in GSD l b and l c has not yet been characterized, antenatal diagnosis is not possible.

GSD Type 3 In this disorder there is deficiency in the debrancher enzyme or amylo-1-6-glucosidase activity. The metabolic defect is milder, as other routes of gluconeogenesis are intact and there is no renal involvement. The defect is expressed in muscle in 85% of cases (type 3a). Clinical Presentation and Diagnosis The clinical presentation is similar to GSD 1 without renal involvement. In time a peripheral myopathy and cardiomyopathy may develop. As the abnormally structured residual glycogen is fibrogenic, hepatic fibrosis and cirrhosis are common complicating features. Diagnosis is confirmed by identifying the deficient enzyme in leucocytes or liver tissue. Moreover, antenatal diagnosis is possible by enzyme measurement or mutation analysis on chorionic villi samples.35 Management and Prognosis Dietary treatment is similar to GSD type I, but a higher protein intake is recommended because of the demand of gluconeogenic amino acids. Most metabolic abnormalities diminish by puberty, and long-term outcome is determined by the development of myopathy, cardiomyopathy, or cirrhosis.

GSD Type 4 A rare disease, GSD type 4 is due to a deficiency of the branching enzyme. It usually presents with evidence of severe liver disease in late infancy, but there may be cardiac, muscle, and neurologic involvement. Hepatic histology demonstrates cirrhosis and accumulation of abnormally shaped glycogen, which is diastase resistant.36

Treatment and Prognosis Dietary treatment is as for other forms of glycogen storage disease. There is rapid development of cirrhosis, necessitating liver transplantation within the first 5 years of life. Progression of extrahepatic disease has been reported post-tran~plantation.~~

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GSD Type 6 and 9

GSD type 6 and 9 are due to defects in hepatic phosphorylase and phosphorylase kinase, respectively. The phenotype of both type 6 and type 9 is milder than in other forms of GSD. Children present with hepatomegaly and growth failure but hypoglycaemia is rare. Hyperlipidemia and ketosis may occur. Hepatic aminotransferases are often slightly raised, and progression to cirrhosis is unusual.25Dietary treatment other than nocturnal corn starch is rarely necessary, and spontaneous compensatory growth occurs prior to puberty. Neither cardiomyopathy nor myopathy have been recognized, and the long-term outlook is excellent.

Hereditary Fructose Intolerance Hereditary fructose intolerance, an autosomal recessive disorder, is due to the absence or reduction of fructose-l-phosphate aldolase B in liver, kidneys, and small intestine. The incidence has been estimated at 1:20,000 live births. The genetic mutation has been identified on chromosome 9. Clinical Presentation and Diagnosis Clinical presentation is related to the introduction of fructose or sucrose in the diet. Vomiting is a prominent feature that is associated with failure to thrive, hepatomegaly, and coagulopathy. Occasionally, infants may present with acute liver failure with jaundice and encephalopathy and renal failure. Renal tubular acidosis and hypophosphatemic rickets may be present. Older children demonstrate a marked aversion to fructose-containing food. Biochemical liver function tests indicate elevated aminotransferases, hypoalbuminemia, and hyperbilirubinemia. Plasma amino acids tyrosine and methionine may be elevated secondary to liver dysfunction, and there may be hyperuricacidemia, hypoglycemia, and lactic acidosis. Hematologic abnormalities, such as anemia, acanthocytosis, and thrombocytosis are not uncommon. Urinary investigations will indicate fructosuria, proteinuria, amino aciduria, and organic aciduria in association with a raised protein/creatinine ratio and reduction in the tubular reabsorption of phosphate. Diagnosis is suggested by these urinary findings, and is confirmed by demonstration of a reduction or absence of enzymatic activity in liver or intestinal mucosal biopsy or by mutational analysis. Hepatic pathology varies from complete hepatic necrosis to diffuse steatosis and periportal intralobular fibrosis, which may progress to cirrhosis if fructose is continued.

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Management and Prognosis Fructose elimination may have a dramatic effect on hepatic and renal dysfunction. The development of hepatoma has been reported, as has fulminant hepatic failure, upon the reintroduction of fructose.

Gaucher’s Disease

Clinical Presentation and Diagnosis This autosomal recessive disorder is secondary to a deficiency of glucosyl-ceramide-P-glucosidase in leukocytes, bone marrow, hepatocytes, and aminocytes. It may present in infancy with acute liver failure, but is more usual in late childhood with hepatosplenomegaly and respiratory, neurologic, and bone disease. The diagnosis is suggested by the identification of large, multinucleated Gaucher‘s cells in bone marrow aspirate and confirmed by enzyme assay. In liver the cells are also found around central veins, obstructing the sinusoids. Hepatic fibrosis may be severe, leading to cirrhosis. Management and Outcome Recent therapy for Gaucher’s disease includes enzyme replacement, bone marrow, or liver transplantation?

Wilson’s Disease

Wilson’s Disease is an autosomal recessive disorder with an incidence of 1:30,000 live births. The Wilson’s disease gene is on chromosome 13 and encodes a copper binding ATPasel*,l4 (see article by P Ferenci). Clinical Features Clinical features in childhood include hepatic dysfunction (40%), psychiatric symptoms (35%), and renal, hematologic, and endocrinologic symptoms. Children under the age of 10 years old usually present with hepatic symptoms. The earliest reported presentation is 3 years old.66In childhood the hepatic presentation of Wilson’s disease is similar to adults with hepatomegaly, vague gastrointestinal symptoms, subacute or fulminant hepatic failure, chronic hepatitis, or c i r r h ~ s i sNeurologic .~~ symptoms are nonspecific. Children may present with deteriorating school performance, abnormal behavior, lack of coordination, and dysarthria. Renal tubular abnormalities, renal calculi, and acute hemolytic

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anaemia are associated features. The characteristic Kayser-Fleisher rings are not usually detected before the age of 7 and are not invariable. Diagnosis Biochemical liver function tests indicate chronic liver disease with low albumin (<35 g/L), minimal elevations in aminotransferases and a low alkaline phosphatase (<200 units/L). There may be evidence of hemolysis on blood film. The diagnosis is established by detecting a low serum copper (1 pmo1/24 hrs), and an elevated hepatic copper (>250 mg/g dry weight of liver). Approximately 25% of children may have a normal or borderline ceruloplasmin, as it is an acute-phase protein. Urinary copper is elevated, particularly after penicillamine treatment (20 mg / kg /d). Radioactive copper studies are only indicated in children with equivocal copper or ceruloplasmin values in whom liver biopsy is contraindicated. Either Cu" or Cu67is injected intravenously to evaluate the extent of copper incorporation into ceruloplasmin. Copper will not be incorporated into ceruloplasmin in patients with homozygous Wilson's disease; therefore, these tests differentiate between homozygotes and patients with copper deposition secondary to cholestasis. Histologic features of Wilson's disease depend on the clinical presentation. There may be microvesicular fatty infiltration of hepatocytes, chronic hepatitis, hepatocellular necrosis, multinucleated hepatocytes and Mallory's hyaline, hepatic fibrosis, and cirrhosis. In children with fulminant hepatitis, the histologic features are those of severe hepatocellular necrosis, often with an underlying cirrhosis. Management and Prognosis Current management includes a low-copper diet, which is unpopular. Penicillamine (20 mg/kg/d) is effective if started prior to the development of significant hepatic fibrosis or cirrhosis. If penicillamine toxicity is unacceptable, alternative therapies include trientine (triethyline tetra-mine) 25/mg/kg/d in addition to oral zinc. In asymptomatic children or those with minimal hepatic dysfunction, the outlook is excellent, although fulminant hepatic failure with hemolysis may occur if treatment is discontinued. Liver transplantation is essential therapy for children who present with subacute or fulminant hepatitis and in those children with advanced cirrhosis and portal hypertension.40 Family Screening It is essential for the family to be screened in order to treat asymptomatic patients and to detect heterozygotes. Mutation analysis is more reliable than measurement of serum copper and ceruloplasmin.

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Acute Liver Failure

Progressive Neuronal Degeneration of Childhood (Alpers Syndrome) The cause of this familial disorder is unknown, but it is believed to be autosomal recessive, and in some cases, an electron chain transport defect has been identified. Clinical Presentation and Diagnosis Despite a normal neonatal period there may be both physical and developmental delay followed by the sudden onset of intractable seizures between the ages of 1 and 3 years. Although biochemical evidence of liver dysfunction is often present at this stage, clinical liver involvement is a preterminal event. Hepatic disease presents as jaundice, hepatomegaly, and coagulopathy with rapidly progressive liver failure. There are no specific biochemical features. Electroencephalogram demonstrates high-amplitude polyspikes, and CT or MR scans show low-density areas in the occipital and posterior temporal areas. There is gradual extinction of visual-evoked responses. Liver histology characteristically shows microvesicular fatty change, bile duct proliferation, and focal necrosis leading to bridging fibrosis and cirrhosis. Neuropathology reveals cortical involvement with neuronal cell loss and astrocyte replacement.1s Management and Prognosis The condition is uniformally fatal, with most children dying before 3 years of age and within a few months of developing overt liver disease. It is important to avoid the use of valproate, as it is likely to accelerate the development of liver disease. Liver transplantation is contraindicated as neurologic progression continues post-transplant.61Antenatal diagnosis is currently not possible.

Valproate Associated Hepatotoxicity

Sodium valproate is a branched, medium-chain fatty acid with broad-spectrum antiepileptic activity. It has been associated with more than 150 cases of fatal hepatotoxicity worldwide although the mechanism is unclear. Valproate has a complex metabolic fate undergoing partial mitochondrial P oxidation, forming acyl compounds with coenzyme A and carnitine, and inhibiting cellular carnitine ~ p t a k e . 5Hepato~ toxicity has occurred in patients with abnormalities of fatty acid oxidation, mitochondrial energy metabolism, the urea cycle, and those with presumed metabolic disorders, such as Alpers Syndrome, suggesting

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that the normal response to valproate may precipitate hepatotoxicity in those with abnormal intermediary metabolism. Clinical Features and Diagnosis Hepatotoxicity may occur at any age, but is more likely in children less than 2 years old, those on multiple antiseizure medication, and those who had previous neurologic abnormalities or developmental delay. Clinical features include nausea, vomiting, increasing seizure frequency, jaundice, edema, and hypoglycemia leading to drowsiness and coma, usually within the first 6 months of treatment. Biochemical investigations reveal moderate increases in aminotransferases and bilirubin, hypoalbuminemia and severe c~agulopathy.~~ Hepatic histology demonstrates severe microvesicular fatty change with hepatocellular necrosis and occasionally cirrhosis. Treatment and Prognosis Once liver disease is established, the outlook is poor unless valproate has been promptly discontinued at the time symptoms were initially recognized. Carnitine is not effective in preventing or treating hepatotoxi~ity?~ but N-acetylcysteine may have a hepatoprotective role. Liver transplantation is contraindicated, as neurologic disease may progress. LIVER TRANSPLANTATION FOR PEDIATRIC METABOLIC DISEASE Liver transplantation for inherited metabolic disease is indicated in children with inborn errors of metabolism due to a primary hepatic enzyme deficiency that leads to liver failure, hepatic cancer, or severe extrahepatic disease.26Although complete resolution of disease may be anticipated after liver transplantation, some diseases may also require a combination of kidney, heart, or bone marrow transplantation (see article by Goss et al). Inherited Metabolic Disorders Leading to Hepatic Disease

This group of disorders includes those diseases in which the specific hepatic enzyme deficiency leads to acute or chronic liver failure or the potential development of hepatic cancer: Indications for Liver Transplantation for Pediatric Metabolic Disease Liver Failure a,-antitrypsin deficiency

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Tyrosinemia type I Glycogen storage disease type IV Wilson’s Disease Byler’s Disease Neonatal hemochromatosis Severe extrahepatic disease Crigler-Najjar type I Primary oxalosis Familial hypercholesterolemia Urea cycle defects Proprionic acidemia Contraindications for liver transplantation Niemann Pick type C Multisystem mitochondria1 disorders Severe systemic primary oxalosis

In diseases such as a,-AT deficiency and Byler’s disease, liver transplantation provides both phenotypic and functional cure. In tyrosinemia type I the deficiency of the hepatic enzyme, fumaryl acetoacetase, is restored with liver replacement, but production of toxic metabolites (i.e., succinyl acetone) continues, leading to persistent renal dysfunction, which may be exacerbated by immunosuppressant therapy. Inherited Metabolic Disorders Leading to Extrahepatic Disease

In pediatric practice the most common inherited diseases in this category include, Crigler-Najjar type I, primary oxalosis, urea cycle defects, and proprionic acidaemia. Crigler-Najjar type I results from a complete absence of the enzyme bilirubin uridine-diphosphate glucuronyl transferase, and the only effective treatment is phototherapy for 12 to 16 hours per day. Although this may be acceptable in infants, it is inappropriate in older children. Liver transplantation should be performed before the development of neurologic features and significant impairment of quality of life. Children with organic acidurias, such as proprionic acidemia and methylmalonic acidemia, are at risk of severe metabolic acidosis and neurologic deterioration despite medical management with a proteinrestricted diet. Liver transplantation should be performed prior to irreversible mental deterioration in those children who have severe recurrent problems and in whom quality of life is unacceptable. Primary oxalosis is a rare autosomal recessive disorder secondary to a deficiency of the hepatic enzyme, alanine glycoxylate aminotransferase, which leads to over production of oxalate with subsequent deposition in the cornea, brain, cardiac muscle, bones, and kidneys, leading to renal failure and systemic oxalosis. Successful management of this condition requires liver transplantation before the development of renal failure or

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severe systemic oxalosis. In the authors' experience in Birmingham, two infants who presented with acute renal failure secondary to oxalosis in the first year of life received combined liver and kidney transplantation. Despite successful grafts, neither child survived the postoperative period because of hemodynamic problems related to systemic oxalosis. Type of Operation

Until recently, orthotopic liver transplantation was the treatment of choice for metabolic liver disease. The recent development of auxiliary liver transplantation in which only part of the liver is replaced has the advantage that part of the native liver is retained in case of graft failure or for the potential development of gene therapy. Auxiliary liver transplantation has been shown to be effective for Crigler-Najjar syndrome type but is contraindicated in diseases, such as primary oxalosis, as the enzyme defect persists in the native liver and causes an overproduction of oxalate. In the urea cycle defects or the organic acidurias where the enzyme defect is widespread throughout the body, auxiliary liver transplantation may not provide sufficient enzyme replacement to palliate the condition. In Birmingham orthotopic liver replacement in two children with organic aciduria corrected the metabolic defect and reduced the severity of metabolic acidosis, although a protein-restricted diet was required in one of the two children. ACKNOWLEDGMENT The authors are particularly grateful to Mrs. Tracy Ellis for typing the manuscript.

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