Hereditary Hemochromatosis

Common, Yet Underdetected

Nancy Henderson Staible, PA-C

Hereditary hemochromatosis (HHC), an autosomal recessive disorder, is the most common genetically transmitted disease in the white population. Yet, because of the nonspecific nature of early symptoms (and the tendency for complications to be treated as primary disorders), it remains underrecognized.^1,2

Research has shown that among white persons in the United States with central, western, and northern European ancestry, 4.8 per 1,000 women and 6.6 per 1,000 men are homozygous for the disease; another 10% are heterozygous.³ Similar white populations in Canada and Austral ia also have a high prevalence for genetic expression of hemochromatosis.1, ^4,5 The estimated frequency of the hemochromatosis gene mutation in Mexican-Americans and American blacks is 0.22% and 0.06%, respectively.⁴

Normally, small bowel iron absorption from food is selectively blocked to prevent iron intoxication. In HHC patients, the intestinal barrier malfunctions, resulting in excessive iron storage and diminished cell viability in parenchymal organs, such as the heart, liver, pancreas, and pituitary gland.⁴

The etiology of hemochromatosis was the subject of debate until 1975, when the genetic origin of the disease was confirmed⁶ and the gene later known as HFE was subsequently identified on the short arm of chromosome 6.⁷ In 1996, the C282Y and H63D mutations were identified.⁸ Most patients with HHC are homozygous for C282Y.¹

Iron Metabolism and Toxicity

Iron absorption occurs in the deep crypts of the small gut and is regulated by a multigene system of beta₂ receptors. ⁵ Transferrin, a glycoprotein, binds to iron absorbed in the gut and is the sole carrier of iron between tissues.

When the body is overloaded with iron, homeostatic mechanisms to prevent iron absorption occur, including the production of less transferrin. In addition, excess serum iron impedes transferrin's access to the cell by blocking the transport sites.⁴

The protein apoferritin binds excess iron in cells and forms ferritin. When apoferritin is saturated, some excess iron is stored intracellularly as hemosiderin, which is nontoxic. The remaining unbound iron accumulates in hepatocytes, b cells of the islets of Langerhans, and in the myocardium, causing oxidant damage of proteins, nucleic acids, lysosomes, mitochondria, and organelle membranes.³

Persons without iron overload usually absorb 1 to 2 mg/d of iron from di­ etary intake. In HHC patients, iron absorption in the gut is continuous and in excess of the body's needs. An estimated 10 to 30 mg/d of iron is absorbed, accumulating to as much as 15 to 20 g or more of stored iron by age 50.⁹

The results of clinical and epidemiologic studies suggest that excessive iron stores may contribute to the occurrence and complications of diabetes mellitus.¹⁰ The cofactor effect of excess iron and alcohol consumption (both of which cause oxidative stress, hepatic stellate cell activation, and hepatic fibrogenesis) increases ninefold the risk of cirrhosis in those with HHC.¹¹

Zoller et al¹² found duodenal iron accumulation in HFE (hereditary) and non-HFE (secondary) hemochromatosis to be pathophysiologically different. Potential causes of non- HFE hemochromatosis include iron-loading anemias (eg, chronic hemolytic, sideroblastic, thalassemia major), transfusions, chronic liver disease, and high intake of bioavailable iron (eg, iron supplements, red meat) and iron uptake enhancers (alcohol, vitamin C).¹³

Diagnosis

HHC is often asymptomatic until target organ damage has occurred. When symptoms do occur, they usually appear between the ages of 40 and 60. Symptom onset typically begins at younger ages in men than in women, possibly because of the iron-depleting processes of menstruation, childbirth, and breast-feeding.^14,15 It is rare to see iron overload in homozygous persons younger than 20.¹⁶

Nonspecific symptoms, experienced by 55% of males and 43% of females with HHC, include fatigue and lethargy.¹⁷ The liver is most susceptible to iron overload, and a frequent finding at clinical presentation is abdominal pain with hepato­megaly.¹⁸ Other specific symptoms reflect the disease of the affected target organ and include the following:

• Liver disease (cirrhosis, portal hypertension with esophageal varices, hepatocellular carcinoma).¹⁹

• Increased pigmentation/bronzing of the skin. ²⁰

• Cardiac arrhythmias, congestive cardiomyopathy. ²⁰

• Arthropathy (typically the second and third metacarpophalangeal joints).^14,21

• Decreased libido, impotence, amenorrhea. ¹

• Testicular atrophy, loss of midline body hair. ²²

• Diabetes mellitus.¹⁹

There is a strong association between heavy alcohol intake and the clinical expression of hemochromatosis.¹¹

Distinct radiologic evidence of arthropathy typically shows subchondral cyst formation, sclerosis, and thinning of cartilage. Chondrocalcinosis involving both fibrous and hyaline cartilage is seen in the large joints.¹⁴

If HHC is part of the differential diagnosis after the history and physical examination, fasting liver function and iron studies, including serum iron, ferritin, transferrin, and transferrin saturation (TS [serum iron divided by the total iron-binding capacity]), should be ordered (see Table 1^23,24). If the results of iron studies are abnormal, particularly the ferritin and the TS, the patient should be considered for a liver biopsy and genotyping.⁹ The spouses of patients found to be C282Y homozygotes should also be checked for HHC to determine if genotyping is necessary for their children.

Homozygotes older than 40 and those with an elevated serum alanine transaminase level, hepatomegaly, or other indications of hepatic injury should undergo liver biopsy, as should heterozygotes or non- HFE mutated patients with abnormal liver enzymes or clinical evidence of liver disease. Biopsy may not be necessary for patients who are unlikely to have significant hepatic injury (eg, those younger than 40, those with no clinical evidence of liver disease).⁹

The hepatic iron index--which is the hepatic iron concentration of the liver (determined by biopsy) divided by the patient's age--will distinguish homozygous patients with HHC from heterozygotes and other iron overload patients (see Table 2^23,24). Liver biopsy will also identify iron concentration level in the liver and the presence or absence of fibrosis and cirrhosis.^5,9

Screening

HHC is one of the few genetic disorders in which organ damage is delayed in the majority of cases until adulthood. Screening will be required to identify homozygotes in the asymptomatic phase before target organ destruction occurs. Early identification with treatment can significantly reduce the morbidity and mortality of the disease and prevent end organ accumulation in iron-overloaded patients.

At present, universally accepted guidelines have not been established.^25,26 However, clinicians may wish to conduct screening for selected patients as identified in Table 3²⁷ until a well-publicized screening program is in place.

A practical approach would be to include mea surement of TS and serum ferritin in automated multiple serum-chemistry analyses. If the fasting TS is greater than 60% in a male or 50% in a female on two occasions, with a ferritin value more than twice the normal value, a complete work-up for hemochromatosis should be undertaken.¹⁶

Treatment

The goal of therapeutic phlebotomy--the mainstay of treatment²⁸--is to remove excess iron from the tissues before damage occurs. This should be initiated in men with serum ferritin levels of 300 ng/mL or more and in women with levels of 200 ng/mL or more--whether or not they exhibit HHC symptoms.²⁹ (See "Therapeutic Phlebotomy and the Blood Supply"^27,30.) The amount of overload is determined by the hepatic iron concentration and the hepatic iron index reported from the liver biopsy.

At the onset of treatment, one unit of blood (which yields approximately 250 mg of iron) should be removed once or twice per week as tolerated. The desired end point of initial treatment is to leave the patient just short of iron deficiency (serum ferritin < 25 ng/mL). A hematocrit should be drawn before each phlebotomy and be within 10 points of baseline so as to prevent true anemia.^4,29

TS and ferritin should be checked every six to eight weeks (or after 10 to 12 phlebotomies) during the initial phase of treatment. TS will remain elevated until the patient is iron depleted. Ferritin will fluctuate until it reaches 50 ng/mL; this fluctuation indicates that excess iron stores have been mobilized.^4,29

Caution should be exercised due to the risk of cardiac arrhythmias and complications from cardiomyopathies during rapid mobilization of iron in the body. Similarly, decompensated liver disease may develop during aggressive phlebotomy treatment in HHC patients with cirrhosis. ^3,5

Clinicians must emphasize to patients that phlebotomy treatments are a lifelong necessity. Maintenance therapy will vary with the rate of iron reaccumulation, but in most cases, removal of one unit of blood every two to four months is sufficient. The frequency of phlebotomy is dependent upon the serum ferritin level remaining below 50 ng/mL and TS below 50%.^4,29

As is the case in the treatment of most chronic diseases, patient compliance with therapy is difficult. A recent study demonstrated that in the first year of maintenance therapy, 84% of HHC patients (particularly C282Y homozygotes) were compliant; however, the average rate of compliance declined thereafter by 6.8% annually.³¹

Other Treatment Considerations

The patient's diet should be varied and rich in bread, cereals, fruit, and vegetables. Consumption of red meat and alcohol should be limited, and liver should not be permitted. Vitamin C supplements and foods rich in ascorbic acid should be avoided, as these substances are iron-uptake enhancers. Dietary restriction alone is not considered appropriate treatment for HHC.³²

Although iron-chelating agents have been used in treating some patients with HHC, they have not been found to be effective--either clinically or economically--in most cases.⁵

Prognosis

Overall, morbidity and mortality for HHC pa­ tients receiving proper treatment prior to the on­ set of fibrosis of the liver is essentially identical to that of the general population. However, HHC patients with cirrhosis have a significant increase in mortality; this risk remains unchanged for patients undergoing regular iron overload–depletion therapy. Fibrosis of the liver is the single greatest predictor of risk of hepatocellular carcinoma, which accounts for 75% of HHC-related deaths.^3,5

Nonspecific symptoms of malaise and fatigue may improve with phlebotomies, and patients with diabetes may have reduced insulin requirements. The symptoms of arthropathy and hypogonadism, however, do not improve with iron overload treatment.¹⁹

Conclusion

Hemochromatosis, a common genetic disease in white populations, is underdiagnosed. Yet, if the disease is identified prior to the onset of target organ damage and appropriate treatment is undertaken, the morbidity and mortality can be reduced significantly. A comprehensive history and physical examination, with special attention to the family history, is key to an appropriate diagnosis.  

References

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