RBC Function And Disorders Of Iron Metabolism

Patients present to medical attention for evaluation of chemical abnormalities of liver function or hepatomegaly, for evaluation of diabetes or hypogonadism, for arthropathy in the young, or because evaluation for nonspecific fatigue led to measurement of iron levels (usually while looking for iron deficiency anemia). This sort of nonspecific presentation is now more common than the classic tetrad of clinical signs of liver disease, diabetes mellitus, skin pigmentation, and gonadal failure. Although the combination of pancreatic dysfunction and skin pigmentation is referred to as "bronze diabetes," the skin color is more typically a faint bluish gray. Measurement of the serum transferrin saturation is usually recommended as the initial biochemical screening assay. Although individual laboratories may have their own reference ranges, a repeated value greater than 45% in women or 50% in men is usually accepted as the threshold value for further investigation. The serum ferritin concentration is then measured as a biochemical indicator of iron overload, and in the absence of complicating factors, a ferritin concentration greater than 300 µg/L suggests increased iron stores. Some advocate using a ferritin concentration of 1,000 µg/L, arguing that it is a more specific indicator of patients at risk for clinical disease.

It is important to recognize that management of iron defi ciency includes investigation of the etiology of iron loss. In young menstruating or recently postpartum women without clinical evidence of blood loss elsewhere, it is reasonable to attribute iron deficiency to menses or childbirth. For other patients, gastrointestinal investigation (including endoscopy) is usually required. Therapy for iron deficiency anemia should both correct the hemoglobin deficit and replace storage iron.

Traditional red cell indices such as the mean corpuscular volume, mean corpuscular hemoglobin concentration, and red cell distribution width have some utility in the diagnosis of iron deficiency but may be abnormal in other disorders and so are not specific. A low mean corpuscular volume with a normal mean corpuscular hemoglobin concentration and normal red cell distribution width favors a diagnosis of thalassemia rather than iron deficiency anemia. Other red cell indices that can be derived by the newer generations of automated hematology analyzers, such as the proportion of hypochromic red cells and reticulocyte corpuscular hemoglobin, appear to have some utility in the identifi cation of iron deficient erythropoiesis even before iron deficiency anemia develops. Their role in practice is still evolving. Free erythrocyte protoporphyrin, also called zinc protoporphyrin, is elevated in iron deficiency but is rarely used in practice.

Iron removal therapy is always indicated for patients with hereditary hemochromatosis, even when cirrhosis or organ damage is already present, because further progression of the disease can be slowed or arrested, and alleviation of some organ dysfunction is possible. The treatment of choice for hereditary hemochromatosis is phlebotomy to reduce the body iron levels to normal or near-normal and maintain them in that range. The use of iron-chelating agents instead of phlebotomy in patients with hereditary hemochromatosis and severe hemodynamically unstable heart failure in lieu of phlebotomy has been reported. Phlebotomy therapy should be started as soon as the diagnosis of the homozygous state for hereditary hemochromatosis has been established; postponement only increases the risk of organ damage from iron overload. The phlebotomy program should remove 500 mL of blood (containing 200 to 250 mg of iron) once weekly or, for heavily loaded patients, twice weekly until the patient approaches iron deficiency. Before each phlebotomy, the hematocrit or hemoglobin concentration should be measured.