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The liver plays a central role in the biosynthesis, degradation, and regulation of carbohydrates, lipids, amino acids, trace elements, and vitamins (see Chapter 413). Thus, the liver is involved primarily or secondarily in many inborn errors of metabolism. In certain inborn errors of metabolism (such as hereditary tyrosinemia), the absence of a critical enzyme may cause an accumulation of toxic metabolites. In other disorders (such as inborn error of bile acid metabolism), progressive liver injury may occur because of failure to produce essential compounds such as bile acids. 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.
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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 (HFI). Clinical presentations of metabolic liver disease can vary; some children present with acute liver failure in the neonatal period, while others do not present until adolescence or early adulthood with chronic liver disease. 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 416-1).
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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.
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DISORDERS OF BILIRUBIN METABOLISM AND EXCRETION
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Jaundice is a common presenting feature of a wide range of pediatric disorders. In most circumstances the jaundice results from increased bilirubin load and/or toxic effects on the relatively immature bilirubin conjugation/excretory system that is found in the newborn liver. Neonatal hyperbilirubinemia is discussed in Chapters 56 and 419. Occasionally jaundice is the result of a primary abnormality in the liver’s capacity ...