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Figure 5.6 Dimorphism in the red cells: Two cell populations and different levels of hypochromia.

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Figure 5.7 Pappenheimer bodies.

it is almost always a diagnosis of exclusion. HH is an autosomal recessive disorder carried on chromosome 6 that is closely linked to HLA-A3. It may be inherited homozygously or heterozygously with homozygotes more prone to iron overload. However, 10% of heterozygotes will also show signs of excessive iron load-ing.12 Because of this inheritance, individuals with HH begin to load iron excessively from a young age and continue iron loading with every decade. Most are diagnosed accidentally, as a result of blood screening for a totally unrelated issue. In these individuals, the customary process of iron absorption and storage become unbalanced due to the inheritance of an abnormal gene, HFE, the gene that regulates the amount of iron absorbed from the diet. Two mutations, C282Y and H63D, have been described.12 The complete role of these mutant variations in the HFE gene is not fully understood, yet it is known that the normal product of these genes does not bind to the transferrin receptor in the normal iron delivery process. As a result of this faulty mechanism, iron is constantly loaded into the storage sites and leads to multiorgan damage and symptoms over the decades.13

Symptoms and Laboratory Diagnosis of Hereditary Hemochromatosis

HH is a great impersonator with a myriad of symptoms that usually serve to confuse rather than lead to a direct diagnosis. A few of the more common symptoms are

• Chronic fatigue and weakness

• Cirrhosis of the liver

• Hyperpigmentation

• Cardiac arrhythmias

• Tender swollen joints

• Abdominal symptoms (Table 5.9)

As can be imagined, each of these symptoms alone could point a physician in a direction other than HH, yet when these symptoms are combined with a microcytic process, a screening for iron status will provide relevant information. As has already been indicated, screening for iron status would include

• Serum transferrin level

• Possibly transferrin saturation

In patients with HH, serum iron, serum ferritin, and transferrin saturation will be elevated, while TIBC and transferrin will fall in the normal reference range. It should be noted that symptoms may not be seen and blood values may not be elevated in younger individuals. Serum ferritin levels above 150 pg/L and transferrin saturation levels of greater than 45% are indicative of HH. Genetic testing would be appropriate for these individuals to establish if they possess the G282Y and the H63D mutation present in 80% to 95% of patients with HH, yet this testing is expensive and should be ordered judiciously. The laboratory is critical in the diagnosis of HH and its value cannot be underestimated in providing definitive data for this crucial diagnosis.

Table 5.9 O The Confusing Symptoms of Hereditary Hemochro-matosis

Symptom Possible Other Cause

Chronic fatigue weakness Cirrhosis of the liver

Cardiac arrhythmias

Tender swollen joints Hair loss, hyperpigmentation

Could be seen in IDA

Could be seen in alcoholism

Could be seen in valve problems, congestive heart failure

Could be seen in collagen vascular diseases

Could be seen in endocrine disorders

Treatment for Hereditary Hemochromatosis

Untreated HH can be fatal, and advanced iron overload frequently leads to liver cancer (Fig. 5.8). The treatment of choice for individuals newly diagnosed with HH is aggressive therapeutic phlebotomy, or bloodletting, as it used to be termed. The goal of this procedure is to reduce the serum ferritin level to less than 10 pg/dL and to keep the patient's hematocrit at around 35%. For most patients, there will be one or two phlebotomies performed per week as long as the patient can tolerate the procedure. Once the patient serum ferritin has returned to near normal, phlebotomies will occur three

Pituitary gland

Affects growth, organs thyroid gland, and adrenal glands.

4 Parathyroid glands

May be affected. Control blood calcium level

Heart

Thyroid gland

Not usually affected

Most important organ to be damaged by iron

Liver

May become enlarged cancer possible

Pancreas

Patients may develop diabetes

Pituitary gland

Affects growth, organs thyroid gland, and adrenal glands.

Thyroid gland

Not usually affected

4 Parathyroid glands

May be affected. Control blood calcium level

Heart

Most important organ to be damaged by iron

Liver

May become enlarged cancer possible

Genitals

May have difficulty in development or functioning

Figure 5.8 Organs of the body damaged by iron overload.

Genitals

May have difficulty in development or functioning

Figure 5.8 Organs of the body damaged by iron overload.

74 Part II • Red Cell Disorders or four times a year to keep the serum ferritin in range. Symptoms will lessen and in some cases disappear completely once the iron level is reduced. Excess iron lowers the immune system, and it has been suggested that iron overload causes a significant amount of diabetes. For patients who cannot tolerate phlebotomies or are unwilling to go through the procedure, desferrioxamine (Desferal), an iron-chelating agent, can be used. In this procedure, the dose of Desferal matched to body weight is delivered through a continuous 12- to 16-hour infusion pump. Patients usually use a subcutaneous injection site for infusion and infuse during the nighttime hours. Excess iron is chelated and then excreted in the urine. Infusion sites need to be rotated often to avoid infections and irritation (Fig. 5.9). Patients who are non-compliant in ridding themselves of iron through either phlebotomy or Desferal will significantly shorten their life span. Early diagnosis of HH disorder can easily be accomplished by adding blood tests such as serum ferritin and transferrin saturation to the menu of tests offered during yearly physical examinations. Slowly, the medical community is becoming aware of this "silent killer" as individual consumers become more knowledgeable of this disease and as organizations like the Iron Overload Disease Association (www.ironover-load.org) become more aggressive in outreach and education. HH is preventable, but it will take the efforts of many individuals—nutritionists, physicians, laboratory personnel, and patients—to raise awareness and expand educational outreach.

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