Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism (Chap. 428). 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 367e-2).
TABLE 367e-2Classification of Iron Overload Syndromes |Favorite Table|Download (.pdf) TABLE 367e-2 Classification of Iron Overload Syndromes
|Hereditary Hemochromatosis (HH) |
|HFE-related (type 1) |
| C282Y/C282Y |
| C282Y/H63D |
| Other HFE mutations |
| Juvenile HH |
| HJV—hemojuvelin (type 2a) |
| HAMP—hepcidin (type 2b) |
| TfR2-related HH (type 3) |
| Ferroportin-related HH (type 4) |
| African iron overload |
|Secondary Iron Overload |
|Iron-loading anemias |
|Parenteral iron overload |
|Chronic liver disease |
|Neonatal iron overload |
|Congenital atransferrinemia |
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 (Table 367e-3) or clinical findings (Table 367e-4), 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 nonalcoholic steatohepatitis (NASH), hepatitis C, and alcoholic liver disease in the absence of iron overload.
TABLE 367e-3Symptoms of Hereditary Hemochromatosis |Favorite Table|Download (.pdf) TABLE 367e-3 Symptoms of Hereditary Hemochromatosis
|Symptom ||% |
|Weakness, lethargy, fatigue ||40–85 |
|Apathy, lack of interest ||40–85 |
|Abdominal pain ||30–60 |
|Weight loss ||30–60 |
|Arthralgias ||40–60 |
|Loss of libido, impotence ||30–60 |
|Amenorrhea ||20–60 |
|Congestive heart failure symptoms ||0–40 |
TABLE 367e-4Physical Findings in Hereditary Hemochromatosis |Favorite Table|Download (.pdf) TABLE 367e-4 Physical Findings in Hereditary Hemochromatosis
|Finding ||% |
|Hepatomegaly ||60–85 |
|Cirrhosis ||50–95 |
|Skin pigmentation ||40–80 |
|Arthritis (second, third metacarpophalangeal joints) ||40–60 |
|Clinical diabetes ||10–60 |
|Splenomegaly ||10–40 |
|Loss of body hair ||10–30 |
|Testicular atrophy ||10–30 |
|Dilated cardiomyopathy ||0–30 |
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 liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) are elevated or 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 200–250 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. 429). 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 >500 mutations in ATP7B have been described with different degrees of frequency and penetration in certain populations.
TREATMENT Wilson’s Disease
Treatment consists of copper-chelating medications such as D-penicillamine and trientine. A role for zinc acetate has also been established. Medical treatment is lifelong, and severe relapses leading to liver failure and death can occur with cessation of therapy. Liver transplantation is curative with respect to the underlying metabolic defect and restores the normal phenotype with respect to copper homeostasis.
α1 Antitrypsin Deficiency
α1AT deficiency was first described in the late 1960s in patients with severe pulmonary disease. α1AT is a 52-kDa glycoprotein produced in hepatocytes, phagocytes, and epithelial cells in the lungs, which inhibits serine proteases, primarily neutrophil elastase. In α1AT deficiency, increased amounts of neutrophil elastase can result in progressive lung injury from degradation of elastin, leading to premature emphysema. In the 1970s, α1AT deficiency was discovered as a cause of neonatal liver disease, so-called “neonatal hepatitis.” It is now known to be a cause of liver disease in infancy, early childhood, and adolescence, and in adults.
In α1AT deficiency, variants in the proteinase inhibitor (Pi) gene located on chromosome 14 alter α1AT structure, interfering with hepatocellular export. Aggregated, deformed polymers of α1AT accumulate in the hepatocyte endoplasmic reticulum. There are over 75 different α1AT variants. Conventional nomenclature identifies normal variants as PiMM; these individuals have normal blood levels of α1AT. The most common abnormal variants are called S and Z. Individuals homozygous for the Z mutation (PiZZ) have low levels of α1AT (about 15% of normal), and these patients are susceptible to liver and/or lung disease, yet only a proportion (about 25%) of PiZZ patients develop disease manifestations. Null variants have undetectable levels of α1AT and are susceptible to premature lung disease.
α1AT deficiency has been identified in all populations; however, the disorder is most common in patients of northern European and Iberian descent. The disorder affects about 1 in 1500 to 2000 individuals in North America. The natural history of α1AT deficiency is quite variable because many individuals with the PiZZ variant never develop disease, whereas others can develop childhood cirrhosis leading to liver transplantation.
In adults, the diagnosis often comes in the course of evaluation of patients with abnormal liver test abnormalities or in a workup for cirrhosis. A hint to diagnosis may be coexistent lung disease at a relatively young age or a family history of liver and/or lung disease. Patients may have symptoms of pulmonary disease with cough and dyspnea. Liver disease may be asymptomatic other than fatigue, or patients may present with complications of decompensated liver disease.
Diagnosis of α1AT deficiency is confirmed by blood tests showing reduced levels of serum α1AT, accompanied by Pi determinations. Most patients with liver disease have either PiZZ or PiSZ; occasionally, patients with PiMZ have reduced levels of α1AT, but they usually do not have a low enough level to cause disease. Liver biopsy is often performed to determine stage of hepatic fibrosis and shows characteristic PAS-positive, diastase-resistant globules in the periphery of the hepatic lobule.
TREATMENT α1 Antitrypsin Deficiency
Treatment of α1AT deficiency is usually nonspecific and supportive. For patients with liver involvement, other sources of liver injury, such as alcohol, should be avoided. Evidence for other liver diseases (e.g., viral hepatitis B and C, hemochromatosis, NAFLD) should be sought and treated if possible. Smoking can worsen lung disease progression in α1AT deficiency and should be discontinued. Patients with lung disease may be eligible to receive infusions of α1AT, which has been shown to halt further damage to the lungs. If liver disease becomes decompensated, transplantation should be pursued and is curative. Following transplant, patients express the Pi phenotype of the donor. Finally, risk of hepatocellular carcinoma is significantly increased in patients with cirrhosis due to α1AT deficiency.
CF should also be considered as an inherited form of chronic liver disease, although the principal manifestations of CF include chronic lung disease and pancreatic insufficiency (Chap. 313). A small percentage of patients with CF who survive to adulthood have a form of biliary cirrhosis characterized by cholestatic liver enzyme abnormalities and the development of chronic liver disease. Ursodeoxycholic acid is occasionally helpful in improving liver test abnormalities and in reducing symptoms. The disease is slowly progressive.