Metabolic Liver Disease: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

Abstract

I. SUMMARY OF THE PROBLEM A considerable number of metabolic diseases cause liver injury in infants and children. In many cases, the liver is the sole organ clinically affected by the metabolic disease. In other metabolic diseases, other organs/tissues are affected but liver disease still constitutes a major cause of morbidity and mortality. Some of the diseases are relatively common. For instance, α1-antitrypsin (α1-AT) deficiency affects approximately 1 in 1,800 live births, and the incidence of cystic fibrosis is as high as 1 in 1,700 in some populations. Moreover, taken together, the genetic/metabolic liver diseases account for approximately 30% of children who undergo liver transplantation. Improved methods for diagnosis and treatment of metabolic liver diseases are likely to have a major impact on the outcome of affected children and the cost of their care. The cost for care of patients with the more common metabolic liver diseases (glycogen storage disease, alpha-1-antitrypsin deficiency, and Wilson's disease) is more than $150,000,000 per year. Moreover, liver transplantation, when a child is fortunate enough to undergo the procedure, costs almost $300,000 for the first year of care. Lifelong immunosuppression adds to the burden of health care costs, particularly with prolonged survival of pediatric transplant patients. Some of the affected patients will also have severe neurologic impairment, chronic pulmonary disease, and, in the fatty acid oxidation defects, be susceptible to acute life-threatening episodes/sudden infant death syndrome. A chronic disease prevented or successfully cured in a child will also restore a healthy, productive citizen to the work force for many decades. Our understanding of the inborn errors of metabolism has been greatly advanced in recent years by the availability of recombinant DNA technology, development of transgenic and knockout animal models, and also by the incorporation of sophisticated concepts derived from basic cell biology and biochemistry research. Identification of the copper transporter that is mutated in Wilson's disease and of several other cellular copper transporters and chaperones has provided information that could revolutionize our understanding of Wilson's disease and other inherited hepatic copper storage/toxicity states. An animal model and a novel therapeutic agent for hereditary tyrosinemia have been developed. Cell biologic principles have been used to develop a therapeutic agent that ameliorates Gaucher disease. The mechanism by which a subgroup of individuals with α1-AT deficiency develops liver injury, a co-inherited defect in intracellular degradation of the mutant α1-AT molecule, has been, at least in part, elucidated. The identification of the gene that is mutated in cystic fibrosis has permitted an analysis of the genotypes responsible for liver disease in cystic fibrosis and focused our attention on the role of the biliary epithelial cell in liver disease associated with cystic fibrosis. Cloning and characterization of the genes involved in mitochondrial fatty acid oxidation has led to the recognition of genetic defects that cause acute fatty liver of pregnancy, Reyes-like syndromes, and liver failure in infants. The genes for glycogen storage disease types Ia, Ib, Ic, III and VI have been characterized. Studies of the role of peroxisomes and mitochondria in liver cellular metabolism have led to the identification of a large number of defects that cause liver injury in children. Positional cloning techniques has permitted the elucidation of a gene that causes Niemann-Pick type C disease, and recent studies have suggested that the gene product plays a role in retrograde transport of endocytosed cargo, including sterols, out of the lysosome. Recent observations from basic research have suggested that application of novel treatment/prevention strategies for metabolic liver disease may be possible in the near future, including chemical chaperones that can reverse misfolding/mislocalization of mutant polypeptides in vivo, chimeric oligonucleotides which can emend mutations in vivo, and hepatocyte transplantation. SUMMARY OF EACH METABOLIC LIVER DISEASE Alpha-1-Antitrypsin Deficiency This is the most common metabolic liver disease affecting children (1). It also predisposes adults to hepatocellular carcinoma and causes emphysema, particularly in adults who smoke cigarettes. Recent studies have provided further information about the biochemical basis of the deficiency, about the cellular mechanisms that account for the wide variation in phenotypic expression of liver disease and have shown that this disease is prototypic for many genetic diseases associated with misfolded proteins and disturbances in the fundamental cellular pathways for responding to misfolded proteins, or stressors (2). Recent studies have also provided evidence for the feasibility of chemoprophylaxis with a novel class of compounds called “chemical chaperones” that may have broad applicability to metabolic liver disease. Cystic Fibrosis It had been thought that only 2% to 8% of CF patients develop liver disease with portal hypertension and its complications. However, with increasing survival of patients with this diagnosis, liver disease may have a higher prevalence than previously appreciated: up to 15% of patients. The characterization of the CFTR gene, the use of gene-based techniques for population studies, the use of molecular genetic techniques to create animal models, and the study of the cell biologic basis of cystic fibrosis have revolutionized our understanding of this disease (3). There have also been major advances in understanding the susceptibility to pulmonary infection and in clinical care of pulmonary involvement (4,5). There are recent developments in the use of ursodeoxycholic acid for amelioration of liver disease and in the use of chemical chaperones for chemoprophylaxis. Hereditary Tyrosinemia This is a relatively rare disease in which mutations in fumaryl acetoacetotate hydrolase, an enzyme in the tyrosine degradation pathway, lead to progressive liver failure, renal tubular dysfunction, and hypophosphatemic rickets. Patients with this disorder are predisposed to hepatocellular carcinoma. Characterization of the gene and the development of animal models of this disease have resulted in major advances in understanding its molecular genetics, its treatment with a new drug, NTBC, and its possible prevention with cell transplantation therapy (6). Several recent observations have provided new information about metabolic intermediates responsible for liver injury, for the profound nodular regenerative activity and for the remarkable propensity for genetic reversion of the primary defect within regions of the liver that are associated with this disease (7,8). Mitochondrial Defects In recent years, several different types of mitochondrial defects have been recognized to cause liver disease in children. Mitochondrial respiratory chain defects, mitochondrial genomic deletion and depletion syndromes and Alpers disease all affect the liver and may cause liver failure, but almost always in association with severe, progressive neurodegeneration. There is reason to believe that inherited defects in fatty acid oxidation in the mitochondria are a cause of many cases of liver disease in children previously categorized as idiopathic. Defects in 12 different enzymes/transporters have been recognized. A specific mutation in the long chain 3-hydroxy acyl coA dehydrogenase (LCHAD) activity of the mitochondrial trifunctional protein has been shown to cause acute fatty liver of pregnancy, acute liver failure in infants, and Reyes-like syndrome (9). Studies of the genotype–phenotype relationships and studies in newly developed animal (genetically altered mouse) models of LCHAD deficiency could now be used to make further major advances in this area. Peroxisomal Disorders Zellweger (cerebrohepatorenal) syndrome, Refsum disease, rhizomelic chondrodysplasia punctata, adrenoleukodystrophy, and several other inherited diseases are associated with liver disease, impairment of the nervous system, and mental development and multiple congenital anomalies. Although neurologic involvement is usually the major clinical issue in these diseases, liver failure may develop in some cases and become an important part of the overall clinical care. There have been major advances in recent years in understanding the genetic basis of and genotype–phenotype relationships for these disorders, as well as development of new animal models (10). Gaucher Disease This is a group of disorders in which autosomal recessive deficiency in the lysosomal enzyme glucocerebrosidase leads to bone deformities, neurologic impairment, hepatosplenomegaly, and sometimes portal hypertension (11). The molecular basis of these disorders has been studied extensively, and new animal models have recently been developed. Specific enzyme replacement therapy has become possible by modifying the carbohydrate side chain of glucocerebrosidase so that it can be delivered to the lysosome of tissue macrophages via the mannose receptor (12). Niemann-Pick Disease This is a group of lysosomal storage disorders associated with neurologic symptoms, psychomotor retardation, and liver dysfunction. Although liver involvement is usually only a trivial problem in the other forms of Niemann-Pick, the type C form usually presents with neonatal liver dysfunction. Positional cloning studies have permitted molecular characterization of the defective gene in Niemann-Pick disease type C (13), and recent studies have suggested that the accumulation of LDL cholesterol in lysosomes in this disease is due to alteration in the role that the affected gene product plays in retrograde transport of endocytosed cargo, not restricted to sterols, from the lysosome (14,15). Galactosemia Galactosemia is a syndrome of liver disease, failure to thrive, and developmental delay in infants that is caused by a deficiency of galactose-1-phosphate uridyltransferase (GALT) and the resulting block in the metabolism of galactose, one of the monosaccharide constituents of the milk sugar, lactose. Recent studies have provided confirmation that current dietary restriction therapy is not adequate to prevent neurologic impairment (16). Hereditary Fructose Intolerance This disorder is caused by deficiency of fructose-1, 6-bisphosphate aldolase (17) and is associated with gastrointestinal symptoms, hypoglycemia, hepatic steatosis, and failure to thrive when fructose is introduced into the diet. The molecular basis of this deficiency has recently been characterized but very little is known about its population biology. Glycogen Storage Disease These disorders are associated with glycogen accumulation in the liver and other tissues due to specific defects in glycogenolysis. In GSD type Ia, there is developmental delay, hypoglycemia, metabolic acidosis, elevated triglycerides and uric acid levels in the blood, hepatomegaly, hepatic adenomas, and hepatocellular carcinoma due to defects in glucose-6-phosphatase, catalytic subunit. In GSD type Ib, the patients also have neutrophil dysfunction and recurrent infections due to a primary defect in a microsomal glucose-6-phosphate transporter. In GSD type III, a defect in the glycogen debrancher enzyme, hepatomegaly occurs but liver dysfunction is rare. In GSD type IV, deficiency in the glycogen branching enzyme, there is progressive liver dysfunction and liver failure. GSD type VI is due to defects in liver phosphorylase kinase. There has been major recent progress in characterizing the molecular basis of GSD types Ia (18), Ib (19), III (20) and VI and in developing animal models. Nutritional therapy and the use of dietary cornstarch have had a major impact on GSD type Ia. Cytokine therapy has recently provided marked improvement in the lives of patients with GSD type Ib. Carbohydrate-Deficient Glycoprotein Syndrome This is a group of newly recognized autosomal recessive disorders resulting in incomplete glycosylation of plasma proteins (21). Severe neurologic impairment occurs in most patients but protein-losing enteropathy, hypoglycemia, and hepatic dysfunction may also occur. There have been major recent advances in understanding the molecular basis of this disease and in applying dietary therapy in some cases. Wilson Disease Wilson disease is a progressive disorder characterized by abnormalities of the motor system, psychiatric symptoms, and hepatic disease resulting in cirrhosis. A specific defect in copper transport results in progressive accumulation of copper in target tissues. The Wilson disease ATPase that transports copper from the cytoplasm into the secretory and canalicular excretory pathway has been identified and mutations that cause Wilson disease have been characterized (22). Recent studies have also led to the identification of other cellular copper transporters and chaperones resulting in major advances in our understanding of how copper is handled in the liver. There have also been advances in our knowledge of how copper is toxic to liver cells (23). Neonatal Hemochromatosis (NNH) Neonatal hemochromatosis, which is also called perinatal hemochromatosis or neonatal iron storage disease, is a rare disorder of unknown cause leading to liver failure within days to weeks of birth with liver fibrosis and extrahepatic siderosis (24). Although NNH is genetically distinct from hereditary hemochromatosis, the pattern of hemosiderin deposition in NNH is similar to that in hereditary hemochromatosis. Recent advances in understanding the molecular basis of hereditary hemochromatosis may, therefore, provide a foundation for elucidating the cause of NNH. The major advances for hereditary hemochromatosis include the identification of affected gene product, HFE (25), initial studies indicating that HFE regulates iron transport mediated by the transferrin receptor and initial studies of how population screening can be done (26). II. MAJOR ISSUES IN NEED OF INVESTIGATION OR IMPLEMENTATION Understand the Mechanism of Liver Injury in Each of the Metabolic Liver Diseases For a number of these diseases, we already know the basis of the metabolic defect but not know how the metabolic defect causes liver disease. In a of the metabolic defects only a of the affected children develop clinically liver disease. A understanding of the role of genetic and in the development of liver disease is important to which patients will be affected and will treatment as well as to developing novel therapeutic strategies that are and For only approximately of children with α1-AT deficiency develop liver disease. The that the liver disease in this deficiency is due to of the in the of liver Recent studies have that there is of the in the of a genetically or deficiency in the cellular mechanism by which proteins are the degradation or the However, we still know very little about the mechanisms by which the degradation pathway is and we know about how the liver cells are by this Wilson disease is disorder in which there have been major advances in knowledge but in which we to know more about the of liver now know that the protein that is mutated is a ATPase that transports copper from the cytoplasm into the secretory and canalicular excretory also know that a number of the mutations associated with Wilson disease prevent this protein from the or it is in the we now know that there are other transporters and chaperones that copper to the Wilson However, we still know very little of the of how copper in the liver cell is and to copper when the Wilson ATPase is There is evidence that some patients with the Wilson not have mutations in the Wilson ATPase and that there are copper storage/toxicity syndromes at least genetic in in which the Wilson ATPase is but the mechanisms of copper we still know very little about how copper the of the liver cell and how the cell Recent advances in understanding the molecular basis of fatty acid oxidation defects make it now possible to the of acute fatty liver of and syndrome. For instance, we now know that a specific mutation that the LCHAD activity of the trifunctional protein leads to and syndromes but of the trifunctional protein These observations make it now possible to develop genetically altered model to the that acute fatty liver is due to accumulation of in predisposed states. also believe that it is very important to how the metabolic liver diseases lead to hepatocellular carcinoma. There is a for the development of hepatocellular carcinoma in hereditary tyrosinemia but patients with α1-AT deficiency and glycogen storage disease also develop metabolic liver diseases, as Wilson's disease, may also to hepatocellular carcinoma but of the incidence of the diseases it has not been possible to the information about the mechanism of and cell survival is important for our understanding of the of these diseases but it is also important for the development and use of novel therapeutic For have a for and in the liver of the model of hereditary and will most of the liver but it is unknown a number of liver cells will become and the for this type of the of Several Metabolic Liver as Neonatal Disease and Some Patients to as Neonatal research studies to the basis of several metabolic liver diseases, as neonatal hemochromatosis and disease, in which is known about The protein that is defective in hereditary hemochromatosis, has recently been several new cellular iron transporters have been and new information about the of iron in cells has recently been In there is some evidence that HFE with the transferrin receptor in This the that HFE or a is defective in neonatal hemochromatosis, a disorder in which iron transport has long been is known about the defect in disease or in cases of neonatal in which there is liver injury and a metabolic is the of the Metabolic Liver of of Liver Injury for Each of to the population biology of the metabolic liver diseases that affect children. For instance, we know very little about the prevalence of disorders, fatty acid oxidation defects, other mitochondrial defects, and syndrome in the population of children neonatal or neonatal Although a screening study done by in has the prevalence of liver disease we know almost about the prevalence of liver disease in other metabolic Moreover, for many of the metabolic liver diseases we have very little information about genotype–phenotype relationships or the of the for Improved and There are still in the diagnosis of some of the metabolic liver diseases, including the glycogen storage diseases, hereditary disorders of fatty acid and Wilson disease, In some cases, liver tissue is and in other cases sophisticated which is not is also to develop that will as for liver involvement in some of the metabolic diseases as cystic mitochondrial defects, and Studies of the of for of Metabolic Liver further studies of hepatocyte transplantation for treatment of metabolic liver disease is Studies by and have shown that can and of the liver but only when the of the the liver by a metabolic hereditary This form of therapy is to liver disease in which the defect is which many of the metabolic liver In have recently shown that hepatocyte transplantation may be in treatment of type syndrome. These studies will to the that in the it is regenerative that cell and how the cells which are to be can be in the use of chemical chaperones for chemoprophylaxis of metabolic liver disease more This class of which and acid have shown to reverse the cellular or of mutant and secretory proteins including mutant and In has been shown to have biochemical in an animal model of α1-AT deficiency and in with Recent studies have also suggested that may have on mutant in this a of the lysosomal enzyme of the defect in of this enzyme in one type of disease Recent studies have also shown that compounds that side chain of can reverse the of mutant proteins as together, these compounds may have broad applicability to metabolic liver diseases, including α1-AT deficiency, cystic Wilson disease, hemochromatosis, types of Gaucher disease, Niemann-Pick disease, and syndrome. the use of chimeric oligonucleotides for prevention of liver injury in metabolic disease further Studies by and have shown that chimeric oligonucleotides on the of in with so that it could be taken up by delivered to with high and the mutation in of the liver cells in an animal model of to for and of Liver Disease still have very little information about the of as ursodeoxycholic acid and of as and of including and in children with metabolic liver disease. These will of to all types of liver disease in children. Understand the of Liver Injury in Each of the Metabolic Liver Diseases This will the development of animal models knockout and It will be very important to the of genetic in animal model so that genetic of disease can be It will also be important to the of developmental on disease of the genetic for gene expression or gene and of gene expression or gene make this This research will also have to into the of the on disease including the hepatic regenerative the and the of which may be mediated by pathways at the of the at the of the liver as a at the of the hepatocyte as well as its the of developmental stressors will to be It will be important to have a for all of the animal models that have already been developed and are in the of developed. This will also the development of novel to the of liver For instance, several important concepts about the of liver injury in α1-AT deficiency have been derived from a novel cell in which the mutant gene is in cell from individuals previously characterized as to or from liver disease. types of cell studies have provided advances in understanding of the of on further development of techniques for liver epithelial and other cells of the liver will be This include the and of and cells from and from animal models. It will also be to to cell biology and studies of the metabolic liver These types of studies have already provided major advances in the several years but will greatly from and This may from the of of or to research at specific that have and for biologic studies of genetic/metabolic disease. the of Several Metabolic Liver Diseases This will to genes but may also be by some of the newly genomic These will genomic DNA for in The could from the development of gene and sophisticated for It will to of and large the of the Metabolic Liver Diseases This will studies in which clinical for and characterization of patients and genetic is into study mechanisms are likely to be most This type of study include a from the population that not have a in and a from an affected as the population of infants that are to as neonatal or neonatal also believe that this target for population screening specific disorders in which morbidity can be at least as α1-antitrypsin deficiency, and fatty acid oxidation for Improved and This will the development of sophisticated and of screening studies as has been done so for disease and cystic fibrosis. Studies of the of for of Metabolic Liver This will not only cell transplantation gene and but also will basic research on the developmental biology of the biology of how the liver to injury, and the biology of liver the of cell transplantation for treatment of metabolic liver disease will on the of the cells to be the to in gene and the by the of the affected liver to injury and the for the affected liver to Moreover, one that the to injury and in the liver on the developmental of that liver. and large may be particularly to this to for and of Liver Disease This will studies similar to for together, the metabolic liver diseases account for a number of children with and severe liver disease and a number of children who liver transplantation. Our understanding of some of these disorders has been greatly advanced in recent years by the availability of recombinant DNA technology, development of transgenic and knockout animal models, and by the incorporation of sophisticated concepts derived from basic cell biology and molecular biochemistry research. there are still considerable in our knowledge of how liver injury develops in many of these diseases, of the of many of these diseases, and of novel strategies for of the of cell and genetic now it be possible to make more advances in our knowledge of the metabolic liver diseases in the