8.1 Hemochromatosis

Hemochromatosis is an iron-storage disorder in which there is an inappropriate increase in the absorption of iron from the gut. This leads to iron deposition in various organs with eventual impairment, especially of the liver, pancreas, heart and pituitary gland. The term hemochromatosis is preferred for genetic hemochromatosis, with other diseases associated with iron overload such as thalassemia or a sideroblastic anemia referred to as secondary iron overload. The term hemosiderosis merely describes the appearance histologically of increased stainable tissue iron.

Genetic hemochromatosis is an inherited disease known to be associated with an abnormal gene tightly linked to the A locus of the HLA complex on chromosome 6. A candidate gene has been described (HLA-H) that encodes for a protein with similarities to MHC class-I proteins. It is one of the most common genetic diseases, inherited as an autosomal recessive trait affecting 1 in 300 of the Caucasian population. The heterozygous individual has normal or minor derangements in iron metabolism that have no clinical significance. The homozygote has continued iron accumulation leading to target organ damage. Normally the body iron content of 3-4 g is maintained such that the absorption of iron is equal to iron loss. In hemochromatosis, the absorption of iron is inappropriate to the needs of the body, resulting in the absorption of 4 mg/day or more. In advanced disease, the total body iron accumulation may be 40-60 g.

Most patients are asymptomatic until the fifth or sixth decade, at which time they may present with nonspecific symptoms of arthritis, diabetes, fatigue or hepatomegaly. Other symptoms include pigmentation of the skin, impotence and dyspnea secondary to congestive heart failure. The classic triad of skin pigmentation, diabetes and liver disease ("bronze diabetes") occurs in a minority of patients and is a late stage of the disease. It more commonly affects males than females because of the regular menstrual blood loss in women. The dark skin color in hemochromatosis is attributed to melanin deposition but evolves in tandem with iron deposition in the skin.

A patient with suspected hemochromatosis or unexplained liver disease should be screened for the disease with a serum ferritin and transferrin saturation (serum iron/TIBC). These test abnormalities increase with age and are more abnormal in males than females because of the regular menstrual blood loss in women. The diagnosis is confirmed by a liver biopsy that demonstrates marked parenchymal iron deposition with iron staining of the tissue. The hepatic iron concentration and the hepatic iron index (hepatic iron concentration/age) are the most helpful in distinguishing genetic hemochromatosis from the increased iron overload that is seen in other chronic liver diseases such as alcoholic liver disease and chronic hepatitis C. CT and MRI scanning can detect moderate to marked iron overload in the liver but lack the sensitivity to detect early disease and do not replace the need for liver biopsy.

The treatment of hemochromatosis involves the removal of excess body iron and supportive treatment of the damaged organs. Iron is best removed from the body by weekly or twice-weekly phlebotomy of 500 mL of blood until the body iron stores are within normal limits. The duration of treatment varies with the age and sex of the patient, but older males may require weekly venesections for more than three years. Serum ferritin is measured every three months to assess progress. When the serum ferritin is in the low normal range the frequency of venesections is decreased to three or four per year. The goal of therapy is to prevent any further tissue damage. Unfortunately, many of the symptoms do not improve following iron depletion. The most common cause of death is liver failure and/or hepatocellular carcinoma.

Siblings of the patient with hemochromatosis must be screened with serum ferritin and transferrin saturation, as the siblings have a 1 in 4 chance of being affected. Screening should begin in the teenage years. Screening of the general population for hemochromatosis has been demonstrated to be cost-effective but has not been widely implemented. The development of a low-cost true genetic test for hemochromatosis could lead to more widespread screening. Chelating agents such as deferoxamine (parenteral) or deferiprone (oral) are reserved for the patient with iron overload secondary to an iron-loading anemia such as thalassemia.

Alpha₁-antitrypsin, a glycoprotein produced by the liver, constitutes the majority of the a1 globulin fraction seen on protein electrophoresis. Its deficiency is inherited, resulting in pulmonary emphysema and hepatic disease. Various presentations are possible, including neonatal hepatitis, chronic active hepatitis, cirrhosis and hepatocellular carcinoma.

Alpha₁-antitrypsin is a protease inhibitor. Its production is controlled by multiple alleles in the Pi system. Normal individuals are PiMM. The inheritance is autosomal codominant. Patients with liver disease most frequently have PiZZ and possess only 20% of the normal amount of serum a₁-antitrypsin.

Diagnosis of a₁-antitrypsin deficiency is suggested by the absence of the a₁ peak on protein electrophoresis and is confirmed by a₁-antitrypsin levels and phenotyping. The characteristic changes seen on liver biopsy include the presence of PAS-positive, diastase-resistant granules in the cytoplasm of the hepatocytes; these granules are a₁-antitrypsin collections within the endoplasmic reticulum. There is an inability to transfer synthesized a₁-antitrypsin from the cytoplasm of the hepatocyte to the serum. Cirrhosis will develop in 10-15% of patients with PiZZ. The risk to heterozygotes of developing liver disease is uncertain. Experimental medical therapies including infusion of recombinant a₁-antitrypsin and gene therapy may become a possibility in the future. Patients with advanced forms of liver disease may be candidates for liver transplantation.

Wilson's disease is an inherited disorder characterized by the pathological accumulation of copper in the liver, central nervous system and other organs. The disease has a prevalence of 1:30,000. It is an autosomal recessive disease; the gene responsible has been localized to the long arm of chromosome 13 (ATP7B). The gene product is a copper-transporting ATPase that is highly expressed in the liver. It may present as pediatric liver disease or may have a neuropsychiatric presentation in adults. The hepatic presentation of the disease is variable, and may include fulminant hepatic failure (often with hemolysis), chronic active hepatitis and cirrhosis. Copper deposition in the central nervous system results in extrapyramidal symptoms of rigidity, choreoathetoid movements and ataxia. Biochemical abnormalities include a low serum ceruloplasmin and high urinary copper concentration. Liver biopsy is often not diagnostic, and copper stains are unreliable. It is often necessary to measure the hepatic copper concentration. A Kayser-Fleischer ring - a copper deposition in Descemet's membrane of the cornea - is characteristic of the disease, although it can appear in other chronic cholestatic liver diseases. Visual inspection may identify the Kayser-Fleischer ring, but a detailed slit lamp examination by an ophthalmologist is recommended when the disease is suspected. The chelating agent d-penicillamine is recommended on a lifelong basis. Alternative drug therapies are available for those intolerant of penicillamine. Patients with advanced disease can be successfully cured of the disease by liver transplantation.