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Article Excerpt
Hemochromatosis is a disorder of iron metabolism that may lead to abnormalities in multiple organ systems. It is characterized by excessive body iron stores and deposition of hemosiderin, which can cause tissue damage and organ dysfunction. The diagnosis is often delayed, sometimes for decades, because a period of silent iron deposition occurs before symptoms are manifest. Diagnosis is difficult even in symptomatic patients, because the signs and symptoms are nonspecific and overlap with those of many other conditions.
Joint abnormalities are common and often lead to morbidity and loss of quality of life. Joint disease often is an early manifestation of hemochromatosis and may be the symptom complex that leads to hemochromatosis diagnosis; however, a high index of suspicion must be maintained because the joint findings mimic those seen in other common rheumatologic conditions.
In this article, we briefly describe the diagnosis and management of hemochromatosis. Then we focus on the findings in hemochromatosis arthropathy and those of several conditions with similar symptoms involved in the differential diagnosis, including rheumatoid arthritis (RA), osteoarthritis (OA), and calcium pyrophosphate dihydrate (CPPD) crystal deposition disease.
HEMOCHROMATOSIS
Genetics and classification
After elucidation of the genetics of hemochromatosis, the disorder is now best defined as the presence of 2 mutations of the hemochromatosis (HFE) gene. (1) Subsequent development of iron overload, which is variable among persons with the mutations, can cause complications in multiple organ systems.
Several mutations of the HFE gene have been defined. In the United States, homozygosity for the C282Y mutation accounts for most clinical cases of iron overload. (2,3) This mutation may have arisen from a single progenitor in northwestern Europe. (2) H63D is the next most common mutation, followed by S65C. Compound heterozygosity of C282Y and H63D accounts for a very few additional cases. (1,2) The C282Y mutation results in abnormal binding of the HFE protein to [[beta].sub.2]-microglobulin, leading to excessive iron absorption.
Hemochromatosis type 1 is the common adult type of hemochromatosis (mutations of HFE). Hemochromatosis type 2 (juvenile hemochromatosis) is divided into type 2A (mutations of the hemojuvelin gene, HJV) and type 2B (mutations of the hepcidin antimicrobial peptide gene, HAMP). Hemochromatosis types 3 through 5 are associated with mutations that inactivate transferrin receptor 2 (TfR2), mutations of the ferroportin gene (SLC11A3), and mutations of the H ferritin gene, respectively. Intensive investigation is under way to determine the role of each of these genes and their mutations and also of the iron-regulated gene 1, the duodenal cytochrome b (DCYTB, CYBYRD1), and others in iron accumulation.
Symptoms and clinical findings
Symptoms of hemochromatosis result from damage to various organs caused by iron overloading. Symptoms tend to appear earlier in affected men than in women. (2,4) Patients whose hemochromatosis is diagnosed on the basis of symptoms have evidence of iron overload and end-organ damage; those with hemochromatosis diagnosed by screening manifest fewer symptoms, if any (Table 1). (4,5) Because of a trend of earlier diagnosis, the classic symptoms of cirrhosis, diabetes mellitus (DM), and bronze skin are seen infrequently; the most common presenting symptoms are fatigue, malaise, and joint symptoms. (2)
Many organs may be affected by iron overload. Eventually, overload in the liver may lead to cirrhosis and hepatocellular carcinoma. Cardiac iron deposition may lead to cardiomyopathy, with arrhythmia and congestive heart failure. Deposition of iron in the pituitary gland can lead to hypogonadrotropic hypogonadism, hypothyroidism or, rarely, panhypopituitarism. Deposition of iron in the islet cells of the pancreas may lead to DM. The skin may take on a bronze hue (Figure 1). Joint manifestations are common.
Laboratory findings
The most common laboratory abnormalities in hemochromatosis are elevations of serum iron concentration, percent saturation of transferrin, and serum ferritin concentration. (4) Often, transferrin saturation is the first laboratory abnormality observed; it may be detected in some children and teenagers with the disease. (2,4,6) Values for ferritin concentration and transferrin saturation in patients...
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