Metabolic and Genetic Disorders of the Liver
Frederick J. Suchy
The liver plays a central role in the biosynthesis and degradation of carbohydrates, lipids, and amino acids (see Chapter 418). Thus, the liver is involved primarily or secondarily in many inborn errors of metabolism. In inborn errors of metabolism such as hereditary tyrosinemia, the absence of a critical enzyme may cause an accumulation of toxic metabolites. In other disorders, progressive liver injury may occur because of failure to produce essential compounds. An example of this process is an inborn error of bile acid metabolism, which leads to progressive cholestasis because of a lack of bile acid synthesis. Severe liver injury may also result from a third mechanism, sequestration of an abnormally synthesized product within the liver, as observed in α1-antitrypsin deficiency. In this section, the focus is on those disorders that lead to acute or chronic damage to the liver. Many of these metabolic disorders are discussed further in Section 11.
Family history, including unexplained infantile deaths or the patterns of observed symptoms, may suggest metabolic liver disease. For example, liver disease occurring after the initial ingestion of fructose should suggest a diagnosis of hereditary fructose intolerance. Clinical features of metabolic liver disease may be nonspecific and can overlap with other hepatic disorders, including viral hepatitis or drug-induced liver injury. These may include jaundice, vomiting, hepatosplenomegaly, failure to thrive, developmental delay, hypotonia, seizures, and progressive neuromuscular dysfunction (Table 421-1).
Coma with hyperammonemia
Failure to thrive
Coagulopathy, particularly out of proportion to liver test abnormalities
Dysmorphic facial features
Initial laboratory studies are often nonspecific and include hypoglycemia, hyperammonemia, increased aminotransferase levels, acidosis, and hypoprothrombinemia. In some disorders such as Wilson disease, hepatocyte injury and loss of hepatic mass occur largely through the process of apoptosis rather than liver cell necrosis. In this setting, liver function can be markedly deranged, but serum aminotransferase levels may be only modestly increased. Percutaneous or open liver biopsy, if possible, allows histologic examination and measurement of enzymatic pathways or substrate accumulation. A specific diagnosis is critically important in that it may allow effective therapy, including liver transplantation and genetic counseling. The natural history of several disorders such as galactosemia and tyrosinemia is changing with presymptomatic diagnosis and early treatment made possible by newborn screening.
DISORDERS OF CARBOHYDRATE METABOLISM
Galactosemia is discussed in detail in Chapter 155. Early manifestations following ingestion of galactose (contained in breast milk and cow’s milk formula) include jaundice, lethargy, vomiting, acidosis, cataracts, failure to thrive, and bleeding. Indirect hyperbilirubinemia is commonly seen and can be accompanied by coagulopathy. Urinary tract infection and/or sepsis, typically with gram-negative species, are also a common presenting problem. Untreated disease causes death within the first several weeks of life in up to 75% of infants, and late recognition of disease is likely to result in severe neurologic injury.1
DIAGNOSIS AND TREATMENT
State programs screen newborns for galactosemia in most of the United States, but clinicians should not rely on these programs for diagnosis in patients with suggestive symptoms. Urine-reducing substances are detected in infants fed galactose-containing formulas, although urine glucose dipsticks are negative. Secondary galactosemia can be seen in severe liver disease because of a lack of hepatic galactose clearance, and urinary screening may be inaccurate in this circumstance. Therefore, enzymatic assays for galactose-1-phosphate uridyl transferase should ultimately be performed using red blood cells in all cases. Mutation analysis is also feasible. Treatment consists of strict elimination of galactose from the diet.2 Treated infants can lead normal lives, although speech defects, learning disabilities and behavioral problems are common.
HEREDITARY FRUCTOSE INTOLERANCE
Hereditary fructose intolerance is also discussed in detail in Chapter 155. It results from an autosomal-recessive disorder caused by a genetic deficiency in the enzyme fructose-1,6-biphosphate aldolase (aldolase B).3
The accumulation of fructose-1-phosphate in affected individuals leads to the sequestration of inorganic phosphate as fructose-1-phosphate with resulting activation of adenosine monophosphate deaminase (AMP), which catalyzes the irreversible deamination of AMP to IMP (inosine monophosphate), a precursor of uric acid. Depletion of tissue ATP occurs through massive degradation to uric acid and impairment of regeneration by oxidative phosphorylation in the mitochondria because of inorganic phosphate depletion. Thus, serum uric acid may be increased and phosphate decreased with acute disease. The depletion of tissue ATP causes symptoms. Sorbitol is converted to fructose and thus can lead to a similar pathologic process in these patients.
The classical presentation occurs in infants on the initial presentation of fructose-containing foods with the acute onset of vomiting, hypoglycemia, and hypophosphatemia preceding the development of hepatomegaly with steatosis, jaundice, and ascites. The Fanconi syndrome and renal tubular acidosis may occur. Prolonged exposure to fructose may lead to death from severe liver and kidney failure.
A more chronic presentation is now recognized with presenting signs and symptoms of hepatomegaly, abnormal liver enzymes, and fatty liver. Chronic exposure to fructose causes poor feeding, failure to thrive, vomiting, irritability, and poor growth. Many affected individuals evolve an eating behavior with avoidance of fructose, thus minimizing the acute manifestations of the disease. Some individuals have not been diagnosed until challenged with fructose as adults. Therefore, this disease needs to be considered in children with unexplained hepatomegaly and steatosis.
DIAGNOSIS AND TREATMENT
Several methods are available to make the diagnosis of hereditary fructose intolerance. DNA diagnostic assays (including allele-specific oligo-nucleotide hybridization) utilizing peripheral leukocytes have identified over 15 different mutations in the aldolase gene, but 3 account for the disease in the majority of affected individuals; therefore, genetic testing is usually the initial least invasive and safest test. An intravenous fructose challenge test has been described but is associated with potentially significant complications and should be avoided given current alternative diagnostic approaches. Aldolase B activity can be readily measured from liver tissue.
Treatment involves strict avoidance of fructose, sorbitol, and sucrose. Partial adherence to this difficult diet can ameliorate many of the acute manifestations of this disease but not the chronic problems, such as growth failure. It is imperative to remember that certain intravenous solutions and oral medications can contain fructose and/or sorbitol.
GLYCOGEN STORAGE DISEASES
The glycogen storage diseases include a wide range of clinical phenotypes that are the result of abnormalities in glycogen metabolism and these are discussed in detail in Chapter 154.4
The inability to utilize glycogen stores, accumulation of glycogen within the liver and/or other tissues, and the toxic effects of certain abnormal types of glycogen lead to the clinical manifestations of these disorders. Fasting hypoglycemia is the hallmark of forms of glycogen storage disease in which there is an inability to utilize glycogen stores to produce glucose including the various forms of type I glycogen storage disease and types III (debranching deficiency or Cori disease) and VI (liver phosphor-ylase deficiency or Andersen disease).
The inability to utilize glycogen normally leads to its accumulation in hepatocytes. Significant hepatomegaly is a common feature of glycogen storage disease type I but can also be seen in types III, IV (branching deficiency), and VI, where normal glycogen breakdown is impaired. Long-term glycogen deposition can increase the risk of hepatic adenomas, which are a significant risk in young adults with glycogen storage disease type I.
A very different clinical presentation can be observed in those disorders that lead to hepatic accumulation of toxic forms of glycogen. The best example of this is glycogen storage disease type IV, in which there is a deficiency of the glycogen-branching enzyme. Glycogen that accumulates in this disease has long chains of glucose in a 1 to 4 linkage and resembles plant starch or amylopectin. This form of glycogen is relatively insoluble and presumed to be toxic, leading to hepatocellular injury. Progressive liver disease thus becomes a major distinguishing feature of glycogen storage disease type IV. Portal hypertension and hepatic failure can develop in early childhood. The toxic amylopectin-like glycogen also appears to predispose to the development of hepato-cellular adenomas.
Glycogen storage disease type IX (GSD type IX) is caused by a deficiency of hepatic phosphorylase kinase activity. Clinical symptoms are characterized by hypoglycemia, hepatosplenomegaly, short stature, hepatopathy, weakness, fatigue, and motor delay. Biochemical findings include elevated lactate, urate, and lipids.
DIAGNOSIS AND TREATMENT
Diagnosis of the specific type of glycogen storage disease is critical for proper treatment and for prediction of prognosis and potential complications. Specific enzymatic assays and DNA diagnostic tests are available in specialty laboratories for each of the disorders. Diagnostic assays can be performed on a number of tissues including liver, muscle, leukocytes, and fibroblasts.
Treatment in many of these disorders is directed at maintaining normal blood sugar levels. Frequent feeding of high-carbohydrate-containing foods and nocturnal administration of slow-release glucose polymers, such as uncooked cornstarch, are utilized. This prevents the development of hypoglycemia and also limits incorporation of excess dietary glucose into glycogen. Liver transplantation has been performed for GSD-1, GSD-III, and GSD-IV. As liver pathology is not the major source of morbidity in most cases of GSD-I and GSD-III, liver transplantation should only be performed when there is hepatocellular carcinoma, complicated adenomas at high risk for cancer or evidence of substantial cirrhosis or liver dysfunction.5 Liver transplantation remains the best option for treatment of GSD-IV. It is important to remember that these are systemic diseases that have variable degrees of involvement of both skeletal and cardiac muscle.
OTHER METABOLIC DISORDERS ASSOCIATED WITH LIVER DISEASE
Hereditary tyrosinemia type I is an autosomal-recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme in the tyrosine degradation pathway. It is discussed in more detail in Chapter 136.6 Metabolites of tyrosine that accumulate proximal to the enzymatic block, such as succinyl acetate, succinyl acetone, fumaryl acetoacetate, and maleylacetoacetate, are highly reactive electro-philic toxic compounds that bind to sulfhydryl groups, often leading to tissue injury.
Type 1 hereditary tyrosinemia occurs in acute and chronic forms that may be manifest in the same family. The acute form presents in infancy with severe liver dysfunction including jaundice, hepatosplenomegaly, failure to thrive, anorexia, ascites, coagulopathy, and rickets. The disorder may actually begin in utero as evidenced by the presence of cirrhosis and regenerative nodules at the time of presentation. The chronic form is observed later in childhood with cirrhosis, renal tubular dysfunction, rickets, and hepatocellular carcinoma. Episodes of severe peripheral neuropathy occur in patients surviving infancy, leading to morbidity from severe pain and even mortality from respiratory failure.
DIAGNOSIS AND TREATMENT
Laboratory studies usually indicate that there is more compromise of hepatic synthetic function than would be expected based upon liver biochemical tests. Hypoglycemia is common, particularly in infants. Hypoalbuminemia and a decrease in vitamin K–dependent coagulation factors is common but serum aminotransferase values are only mildly to moderately increased. Total and direct bilirubin concentrations are variably increased. Hemolytic anemia may be present. Renal tubular dysfunction producing a Fanconi syndrome may occur with hyper-phosphaturia, glucosuria, proteinuria, and aminoaciduria. Serum tyrosine and methio-nine concentrations are markedly elevated. Phenolic acid byproducts of tyrosine metabolism are detected in the urine. Succinylacetone and succinylacetoacetate in the urine are typical and diagnostic of this disorder. Serum α-fetoprotein (AFP) concentrations are often significantly elevated in affected infants and in cord blood, suggesting prenatal onset of liver disease.
Histologic examination of the liver reveals fatty infiltration, iron deposition, varying degrees of hepatocyte necrosis, and pseudoacinar formation. Significant fibrosis may be present early in life with gradual evolution to multinodular cirrhosis. Regenerative nodules mimicking neoplasms may be present in some patients. Hepatocellular carcinoma may be found in older patients with cirrhosis.
The acute form of type 1 tyrosinemia is usually fatal in the first year of life without therapy. Treatment with a diet restricted in phenylala-nine, methionine, and tyrosine does not prevent progression of the liver disease or development of hepatocellular carcinoma. Liver transplantation is the only therapy that reverses hepatic, neurologic, and most renal manifestations of the disease. Patients demonstrating cirrhotic nodules on imaging studies should undergo transplantation because of the high risk of developing carcinoma. Early liver transplantation is also indicated in patients with severe neurologic crises. In patients without these sequelae, medical therapy with 2-(nitro-4-trifluromethylbenoy1)-1,3-cyclohexanedione (NTBC) is effective in reversing the metabolic abnormalities in hereditary tyrosinemia type 1.7 NTBC treatment reduces the flux through the tyrosine degradation pathway preventing the formation of metabolites that are toxic to liver and kidney. Toxic metabolites and serum α-fetoprotein levels decrease, and marked improvement in liver synthetic function occurs. NTBC usually provides protection against heptaocellular carcinoma if it is started in infancy, but cases have occurred even when NTBC was started at five months of age. AFP is a marker for both the development of liver cancer and the inadequate control of metabolic derangement of tyrosinemia type I itself. In a group of initially asymptomatic newborns identified by newborn screening in Quebec treated with NTBC within 1 month, none have developed hepatic dysfunction or liver nodules over a follow-up period of up to 9 years. However, the long-term risk of hepatocellular carcinoma even in early-treated patients is unknown.
CONGENITAL DISORDERS OF GLYCOSYLATION
Congenital disorders of glycosylation (CDG) are inborn errors of metabolism caused by defective N-glycosylation of proteins are discussed in detail in Chapter 163, “Congenital Disorders of Glycosylation.” Depending on the enzymatic defect, the carbohydrate side chains of glycoproteins are either completely absent from the protein core or truncated.20 CDG can affect multiple organs. Common clinical features include dysmorphic facies, mental retardation, failure to thrive, seizures, hypotonia, diarrhea, protein-losing enteropathy, recurrent infection and coagulopathy. Of the 30 known subtypes, at least twelve involve the liver. Hepatomegaly and elevated serum aminotransferases are common. The histopathology is not well defined in most subtypes, but steatosis, fibrosis and even cirrhosis have been described. In CDG-1b congenital hepatic fibrosis occurs. Thus CDG should be considered in any child with cryptogenic liver disease. Detection of abnormally glycosylated transferrin by isoelectric focusing is the commonly used diagnostic screening test, but some forms cannot be detected using this method.21 There is no specific treatment for most of these disorders. Oral mannose supplements appear to be effective for treatment of CDG-1b.
DISORDERS OF FATTY ACID OXIDATION OR METABOLISM
Normal fatty acid oxidation is shown in Figure 150-1 and discussed in Chapter 418. Disorders of fatty acid oxidation or metabolism are discussed further in Chapter 150. Abnormalities in fatty acid metabolism can lead to severe forms of acute liver injury as a result of both energy deprivation and the accumulation of highly toxic intermediary metabolites of fatty acid oxidation. At least 22 different clinical entities have been ascribed to distinct abnormalities in fatty acid oxidation.11
A range of clinical presentations has been described including sudden infant death, cardiomyopathies, skeletal myopathies, hepatopathy, and life-threatening hypoglycemia (Table 421-2). Hepatopathy has been described in two-thirds of these disorders with at least 6 involving relatively severe liver disease (long-chain fatty acid transport defect, carnitine palmitoyltransferase deficiency, long-chain hydroxyacyl-CoA-dehydrogenase deficiency, α- and β-trifunctional protein defects, and short-chain hydroxyacyl-CoA-dehydrogenase deficiency).
The typical case of severe liver disease resulting from an abnormality in fatty acid oxidation presents with acute liver disease characterized by markedly elevated serum aminotransferase levels with variable degrees of cholestasis and coagulopathy. Nonketotic hypoglycemia is a hallmark feature of these disorders. Variable degrees of myopathy (skeletal and/or cardiac) may be an accompanying feature. Some form of stressor that includes fasting typically precedes the onset of the hepatopathy. Manifestations and biochemical abnormalities may be intermittent.
DIAGNOSIS AND TREATMENT
Prompt recognition of defects in fatty acid metabolism is paramount for proper treatment. Diagnostic assays that examine intermediate metabolites of fatty acid oxidation need to be performed during illness, as many of the metabolites will clear with treatment. Testing in suspected fatty acid oxidation defects includes both nonspecific screening assays and more specific enzymatic and DNA diagnostic tests. Initial evaluation should include assays of plasma carnitine, acylcarnitines, free fatty acids, urine organic acids, and acylglycines. Microvesicular steatosis is a common although not universal feature in fatty acid oxidation defects. Analysis of acylcarnitines in bile can be informative. Typically treatment is directed at stopping ongoing fatty acid oxidation by halting fat catabolism. This often can be achieved by intravenous administration of 12 to 15 mg/kg/min of glucose. Subsequent avoidance of fasting is crucial. The benefits of carnitine administration and specific dietary fat restrictions or supplementation are controversial. In many circumstances a diagnosis cannot be made before the development of irreversible hepatic injury. Liver transplantation can be considered, but care must be taken to ensure that there is no evidence of severe systemic or neurologic disease that would not improve following hepatic replacement.