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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.

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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. 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).

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Table 421-1. Clinical Features Associated with Metabolic Liver Disease
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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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Galactosemia

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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 ...

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