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).
Table 421-1. Clinical
Features Associated with Metabolic Liver Disease ||Download (.pdf)
Table 421-1. Clinical
Features Associated with Metabolic Liver Disease
|Coma with hyperammonemia|
|Failure to thrive|
|Coagulopathy, particularly out of proportion to liver test
|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.
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 ...