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The definition of hemochromatosis has changed over the years. Previously the definition of hemochromatosis required the presence of iron overload associated with organ injury. This included skin pigmentation, hepatomegaly, arthropathy, diabetes mellitus, heart failure and hypogonadism. Liver biopsy was required to prove or disprove the presence of iron overload. Hemochromatosis can now be appropriately defined as the presence of two hemochromatosis alleles with or without organ injury, and with or without the presence of iron overload.

Patients with hemochromatosis absorb and store more iron than normal individuals and continue to absorb iron even after they have reached the state of iron overload. The majority of this iron is stored in the nontoxic compounds ferritin and hemosiderin. Iron that is released from storage sites can react with hydrogen peroxide to generate highly reactive oxygen species. Oxygen-derived free radicals are known to cause oxidant damage of proteins, nucleic acids, lysosomes, mitochondria, organelle membranes and cells.

Incidence and Epidemiology

The prevalence of hemochromatosis is ten times greater than that of cystic fibrosis, another autosomal recessive disorder that is considered to be common. The prevalence of homozygosity for hemochromatosis is 3 to 5 per thousand among United States Caucasians of European ancestry. The hemochromatosis gene prevalence in the U.S. Caucasian population is about 7% and the prevalence of heterozygosity is ten to thirteen percent. Clinically apparent disease occurs only in homozygotes, and it is five times more frequent in males than in females. Since the disease is transmitted as an autosomal recessive condition, the prevalence should be similar in both sexes, unless there is a sex difference in the expression of hemochromatosis. Multiple theories exist including the fact that women with hemochromatosis possess approximately 40% as much mobilizable iron as men, menstrual blood loss decreases the morbidity as does the loss of iron during pregnancy.


The total body iron of a healthy adult consuming a traditional western diet is three to four grams. Most of this iron is stored in the form of functional compounds, such as hemoglobin, myoglobin and the remainder is stored as ferritin and hemosiderin. Average amounts of iron storage in males and females during their reproductive years are about 1000 milligrams and 300 milligrams, respectively.

Pathologic and clinical problems develop in subjects with HH whose diets have allowed the accumulation of toxic amounts of iron. The total body content is between 15 and 40 grams. The mobilizable iron stores are usually between 20 and 30 grams of iron by the age of 40 to 60.

Although the mechanisms involved in increased iron absorption require further investigation, several possibilities exist. The hemochromatosis gene and its abnormal protein product may stimulate duodenal mucosal cells to continue to absorb iron even after iron overload develops, or it may fail to inhibit duodenal iron absorption. The majority of this storage iron in hemochromatosis homozygotes accumulates within parenchymal cells rather than in reticuloendothelial cells. Additionally some studies have shown that reticuloendothelial cells and monocytes from hemochromatosis homozygotes release more iron and ferritin than cells from normal individuals.

The most common symptoms reported by patients with homozygous hemochromatosis include weakness, fatigue, lethargy, weight loss, abdominal pain,arthralgia,loss of libido and palpitations. Physical findings are vast and include gray or bronzed skin, hepatomegaly, arthropathy of the second and third metacarpophalangeal joints, extrasystoles, splenomegaly, testicular atrophy, loss of midline body hair (hypogonadism), ascites, and signs of congestive heart failure.

Skin manifestations are reported less frequently than before due to earlier diagnosis. Pigmentation when present is particularly prominent in sun exposed areas. The metallic grey or bronze hue is due largely to melanin deposition in the dermis, hemosiderin deposits when present are found most often in the sweat glands.

The liver is the primary site of iron storage in HH and hepatomegaly is present in most subjects with clinical symptoms. On histologic examination, heavy deposits of hemosiderin are present in hepatocytes and in the later stages are also seen in Kuppfer’s cells, macrophages, and bile ducts. There is a fine microlobular or mixed macromicronodular cirrhosis almost universally present with the nodules being separated by large bands of fibrous tissue. Severe portal hypertension is much less common in HH than with alcoholic cirrhosis and ascites is usually seen in association with cardiac failure. Primary hepatocellular carcinoma is an important late complication of HH with a frequency that is about 200 fold that in the general population.

Fibrosis in the pancreas secondary to extensive hemosiderin deposits is almost invariable. Within the islet cells iron is only found in the beta cells, and unlike type 1 diabetes the islets are of normal size. Both insulin resistance and impaired insulin secretion may be present. The insulin resistance is probably due to the excess iron in hepatocytes with cirrhosis as another contributing factor.

The joints that are symptomatic earliest in hemochromatosis are the second and third metacarpophalangeal joints and the knees. The classic presentation resembles degenerative joint disease with bony swelling, deformity and limitation of movement. The radiographic features include narrowing of the joint spaces, loss of cartilage, cysts, and osteogenic metacarpal heads with hooked osteophytes. Chondrocalcinosis is present approximately fifty percent of the time is typically asymptomatic, but in some it causes attacks of acute inflammatory synovitis (pseudogout).

Cardiac manifestations are apparent in approximately one-third of the patients presenting with the clinical manifestations of HH. However, in younger patients cardiac manifestations are often the presenting feature and almost always the cause of early mortality if the underlying problem is not corrected. Clinically, the picture is usually that of a dilated cardiomyopathy with biventricular dilation but restrictive cardiomyopathy has also been described. Arrhythmias are also a feature, with ventricular and supraventricular tachycardias being the most common presentations.

A variety of rarer presentations have been described in hemochromatosis. Vague abdominal pain has been described in 10-20 percent of cases, this pain is usually described as a chronic ache in the epigastrium or right hypochondrium. Gram negative peritonitis is a rare presenting syndrome. Yersina enterocolitica has been frequently implicated. This is due to not possessing a high-affinity iron chelating system and being unable to obtain sufficient iron from the internal environment of the body. It is able to proliferate in HH where transferrin is saturated and non-transferrin bound iron may be present in extravascular fluids.


There are several ways in which the diagnosis of HH is made. There are the patients who present with clinical symptoms who have obtained toxic concentrations of iron in the body stores and the resultant damage to certain organs. This is irreversible or only partially reversible. Second, there are those subjects that are identified in family studies and thirdly the diagnosis can be made incidentally either on the basis of an increased transferrin saturation or plasma ferritin concentration.

The differential diagnosis of the condition of iron overload includes several other conditions causing diagnostic problems. These include alcoholic liver disease, chronic viral hepatitis, and heterozygosity for the HFE gene.

Patients with alcoholic liver disease can have increased serum ferritin concentrations and increased hepatic iron stores. However the amounts never reach those seen in hereditary hemochromatosis unless the patient also happens to be homozygous for the HFE gene. Clear differentiation between alcoholic liver disease and HH can be obtained by measuring the hepatic iron concentration and calculating the hepatic iron index. The resultant hepatic iron index is less than two in alcoholic liver disease and greater than two in HH.

Small studies have shown that patients with chronic viral hepatitis were found to have increased transferrin saturation and an increased serum ferritin concentration. It is thought that these elevations are secondary to hepatocellular necrosis. This was borne out in a study that showed the majority of subjects studied had a hepatic iron index less than two.

Other iron overload conditions include iron derived from repeated blood transfusions and in a group of sub-Saharan Africans who developed a syndrome of iron overload secondary to large amounts of absorbable iron in their diet derived from the iron drums used for preparation of traditional alcoholic beverages.



One of the earliest manifestations of disordered iron metabolism in subjects homozygous for the HFE gene is an increase in plasma iron and an increase in the transferrin saturation. The transferrin saturation can be calculated as the following:

Transferrin saturation = (serum iron / TIBC) X 100%. A transferrin saturation of 70% or greater on repeated testing is virtually diagnostic and many patients have a saturation of greater than 90% at the time of presentation of clinical manifestations.

A serum ferritin should be evaluated in relation to the transferrin saturation concentration, as the transferrin saturation is first and most sensitive marker of disordered iron metabolism in HH. As iron stores increase there is a progressive increase in the serum ferritin concentration and the value of using both of these tests in the diagnosis of HH is increased. One must remember that the serum ferritin concentration can be elevated in a number of conditions including infection, malignancy, hepatocellular necrosis, and collagen vascular diseases.

Confirmatory diagnostic studies include liver biopsy and now in 1998 the search for the genetic mutation C282Y mutation.

Liver biopsy provides diagnostic information in several ways. It confirms iron overload, provides a degree of fibrosis, and provides a semi-quantitative evaluation of iron index and ability to calculate a hepatic iron index. So liver biopsy can provide both diagnostic information and a degree of prognostic information, such as degree of fibrosis presence of cirrhosis and other histologic abnormalities such as steatosis.

The recent discovery of the candidate gene for hemochromatosis has greatly changed the diagnostic strategy of the disease. The gene, called HFE is located on the short arm of chromosome 6. It is characterized by a major mutation, cysteine replaced by tyrosine (C282Y). This gene has been found to be homozygous in a large proportion of patients presenting a classical phenotypic profile of hemochromatosis.

If there is homozygosity for the C282Y (C282Y +/+) then homozygous hemochromatosis (HH) can be ascertained. The question then becomes how to evaluate the degree of iron excess. If a patient is homozygous for the mutation one can initiate treatment if there are no physical suggestions of chronic liver disease. If there is any suggestion of cirrhosis or chronic liver disease then a liver biopsy can provide prognostic information concerning the degree of fibrosis or even cirrhosis. One must remember to always treat the individual patient and not the results of any one test. In Caucasians there are approximately 15% of patients who phenotypically have the disease of hemochromatosis and are (-/-) for the C282Y gene. These patients need laboratory and liver biopsy information to help ultimately confirm their underlying diagnosis. Heterozygosity for the HFE gene is a more difficult matter. One must evaluate these patients clinically to determine if they fit a phenotypic picture of iron overload. If iron overload is suspected they should undergo liver biopsy for evaluation of iron index and for prognostic information regarding the presence or absence of fibrosis or cirrhosis.


Once the diagnosis of hereditary hemochromatosis is made therapy is directed at removing the excess body iron. Therapeutic phlebotomy should be performed until patients achieve an iron-limited erythropoiesis. This is identified by the failure of the hemoglobin level to recover before the next phlebotomy. It is reasonable to monitor transferrin saturation and or ferritin levels. Some physicians follow these and set a target goal of less than 50% transferrin saturation and a ferritin of less than 20ng/mL. However, following the patient for an iron-limited erythropoiesis with the goal of maintenance therapy with phlebotomy every 1 to 3 months seems to be the most reasonable strategy.

Desferoxamine is a form of chelation therapy that is reserved for individuals that cannot tolerate repeated phlebotomy. It is recommended for patients for whom phlebotomy is contraindicated or in combination with phlebotomy for rapid iron mobilization.



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