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
| Save Table
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 context of family studies, in a patient with an abnormal genetic test, or in the evaluation of a patient with any of the typical symptoms or clinical findings, definitive diagnosis is relatively straightforward. Transferrin saturation [serum iron divided by total iron-binding capacity (TIBC) or transferrin, times 100%] and ferritin levels should be obtained. Both of these will be elevated in a symptomatic patient. It must be remembered that ferritin is an acute-phase reactant and can be elevated in a number of other inflammatory disorders, such as rheumatoid arthritis, or in various neoplastic diseases, such as lymphoma or other cancers. Also, serum ferritin is elevated in a majority of patients with NASH, in the absence of iron overload.
At present, if patients have an elevated transferrin saturation or ferritin level, genetic testing should be performed; if they are a C282Y homozygote or a compound heterozygote (C282Y/H63D), the diagnosis is confirmed. If the ferritin is >1000 μg/L, the patient should be considered for liver biopsy because there is an increased frequency of advanced fibrosis in these individuals. If liver biopsy is performed, iron deposition is found in a periportal distribution with a periportal to pericentral gradient; iron is found predominantly in parenchymal cells, and Kupffer cells are spared.
Treatment: Hereditary Hemochromatosis
Treatment of HH is relatively straightforward with weekly phlebotomy aimed to reduce iron stores, recognizing that each unit of blood contains 200 to 250 mg of iron. If patients are diagnosed and treated before the development of hepatic fibrosis, all complications of the disease can be avoided. Maintenance phlebotomy is required in most patients and usually can be achieved with 1 unit of blood removed every 2–3 months. Family studies should be performed with transferrin saturation, ferritin, and genetic testing offered to all first-degree relatives.
Wilson's disease is an inherited disorder of copper homeostasis first described in 1912 (Chap. 360). The Wilson's disease gene was discovered in 1993, with the identification of ATP7B. This P-type ATPase is involved in copper transport and is necessary for the export of copper from the hepatocyte. Thus, in patients with mutations in ATP7B, copper is retained in the liver, leading to increased copper storage and ultimately liver disease as a result.
The clinical presentation of Wilson's disease is variable and includes chronic hepatitis, hepatic steatosis, and cirrhosis in adolescents and young adults. Neurologic manifestations indicate that liver disease is present and include speech disorders and various movement disorders. Diagnosis includes the demonstration of a reduced ceruloplasmin level, increased urinary excretion of copper, the presence of Kayser-Fleischer rings in the corneas of the eyes, and an elevated hepatic copper level, in the appropriate clinical setting. The genetic diagnosis of Wilson's disease is difficult because >200 mutations in ATP7B have been described with different degrees of frequency and penetration in certain populations.
Treatment: Wilson's Disease