There are a number of disorders of the liver that fit within the categories of genetic, metabolic, and infiltrative disorders. Inherited disorders include hemochromatosis, Wilson's disease, α1 antitrypsin (α1AT) deficiency, and cystic fibrosis (CF). Hemochromatosis is the most common inherited disorder affecting Caucasian populations, with the genetic susceptibility for the disease being identified in 1 in 250 individuals. Over the past 15 years, it has become increasingly apparent that nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes found in the U.S. population. With the obesity epidemic in the United States, it is estimated that 20% of the population may have abnormal liver enzymes on the basis of NAFLD and 3% may have nonalcoholic steatohepatitis (NASH). Infiltrative disorders of the liver are relatively rare.
Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism (Chap. 357). Our knowledge of the disease and its phenotypic expression has changed since 1996, when the gene for HH, called HFE, was identified, allowing for genetic testing for the two major mutations (C282Y and H63D) that are responsible for HFE-related HH. Subsequently, several additional genes/proteins involved in the regulation of iron homeostasis have been identified, contributing to a better understanding of cellular iron uptake and release and the characterization of additional causes of inherited iron overload (Table 309-1).
Table 309-1 Classification of Iron Overload Syndromes |Favorite Table|Download (.pdf)
Table 309-1 Classification of Iron Overload Syndromes
Hereditary Hemochromatosis (HH)
HFE-related (type 1)
Other HFE mutations
HJV—hemojuvelin (type 2a)
HAMP—hepcidin (type 2b)
TfR2-related HH (type 3)
Ferroportin-related HH (type 4)
African iron overload
Secondary Iron Overload
Parenteral iron overload
Chronic liver disease
Most patients with HH are asymptomatic; however, when patients present with symptoms, they are frequently nonspecific and include weakness, fatigue, lethargy, and weight loss. Specific, organ-related symptoms include abdominal pain, arthralgias, and symptoms and signs of chronic liver disease. Increasingly, most patients are now identified before they have symptoms, either through family studies or from the performance of screening iron studies. Several prospective population studies have shown that C282Y homozygosity is found in about 1 in 250 individuals of Northern European descent, with the heterozygote frequency seen in approximately 1 in 10 individuals. It is important to consider HH in patients who present with the symptoms and signs known to occur in established HH. When confronted with abnormal serum iron studies, clinicians should not wait for typical symptoms or findings of HH to appear before considering the diagnosis. However, once the diagnosis of HH is considered, either by an evaluation of abnormal screening iron studies, in the ...