Management of Common Anemias

Anemia is prevalent throughout the population and occurs in all age groups, but it is especially common in the elderly (11% in noninstitutionalized persons greater than the age of 65 years), in whom it is both a risk factor for reduced survival and independently associated with impaired cognition and reduced functional status (1).

Most of the anemias encountered in the outpatient setting are sufficiently mild or chronic to allow time for the careful design of a cost-effective treatment program. The ease with which a number of anemias (e.g., deficiencies of iron, folate, and vitamin B₁₂) can be corrected sometimes leads to empiric therapy or selftreatment without adequate workup for the underlying cause. The skillful application of appropriate treatment is based on a thorough etiologic evaluation (see Chapter 79). Once the cause is understood, attention can be turned to treatment modalities. Increasingly prominent among treatment options is erythropoietin therapy, with an expanding list of indications but also with emerging concerns that necessitate caution in prescribing. Those caring for patients with sickle cell anemia (who are subject to painful crises) also need to be familiar with the first line of treatment so as to prevent such disabling episodes.

IRON-DEFICIENCY ANEMIA (2, 3, 4, 5 and 6)

Iron-deficiency anemia is extremely common, occurring in about 10% to 15% of premenopausal women and frequently seen in persons with chronic gastrointestinal blood loss or poor iron absorption. Proper management necessitates identifying the underlying cause (see Chapter 79). Ascribing the anemia to a trivial cause (e.g., menstruation, hemorrhoids) and treating it empirically without a thorough workup for more serious disease (e.g., bowel malignancy) can seriously compromise outcome. A response to iron replacement should not be taken as a sign of a benign cause. The physician must determine whether inadequate intake, poor absorption, increased loss, or a combination of factors is responsible for the anemia. Knowing the most economical, effective, and best-tolerated forms of supplemental iron facilitates the design of an optimal replacement therapy program.

Clinical Presentation and Course

In menstruating women, the balance between dietary iron intake (1 mg/d) and loss (15 mg/mo) is precarious. Low-grade anemia, especially when losses from pregnancy (˜500 mg) are not made up, is common. However, the many vague symptoms in otherwise healthy menstruating women that are attributed to “low iron” have not been found to correlate with the degree of anemia or respond to the correction of anemia in controlled studies (see Chapter 79).

Iron-deficiency anemia is usually slow in onset, so that compensatory changes, such as increases in 2,3-diphosphoglycerate and cardiac output, minimize symptoms. When blood loss has been rapid or the anemia is severe (hemoglobin level <7g/dL), patients are likely to become symptomatic, especially if cardiopulmonary reserve is limited. Replacement therapy is required in such cases, regardless of the underlying cause. The degree of anemia does not correlate with the seriousness of the cause.

Pica (defined as a craving for ice, starch, clay, or any other substance) is particularly common in patients with severe iron deficiency but often goes unreported. Up to 50% of iron-deficient patients may exhibit pica, with pagophagia (the craving for ice) accounting for the vast majority of cases. No correlation has been found between the presence of pica and the cause of iron deficiency. Symptoms resolve with treatment.

The occasional patient with severe iron deficiency who presents with glossitis, angular stomatitis, koilonychia, or esophageal web improves after correction of the deficiency. Whether the menorrhagia sometimes seen with iron deficiency is corrected by iron is a subject of debate. Patients who have undergone subtotal gastrectomy and gastrojejunostomy have up to a 60% chance of incurring iron deficit because of a loss of acid-secreting capacity, rapid gastric emptying, and bypass of the duodenum. Pregnancy is almost certain to produce iron deficiency because a net loss of more than 500 mg of iron occurs. Iron deficiency from chronic gastrointestinal blood loss has been documented in long-distance runners.

Unless the cause of the iron deficiency is removed, recurrence rates are high, even when treatment is prescribed. In a series of 100 cases, 29 relapses were noted: In 24 instances, inadequate iron was being taken; in 12, blood loss continued in excess of iron therapy; and in 4 patients, malabsorption was documented.

Principles of Management

As noted, the importance of identifying and treating the underlying cause cannot be overemphasized, especially when the anemia is found in male patients or the elderly. Even in menstruating women, the probability of finding silent but important gastrointestinal disease is substantial. Correcting iron deficiency without attending to the underlying cause can mask an important clue to treatable disease and compromise timely treatment.

Indications

Symptoms are often minimal, and the morbidity from a mild anemia is low, so that treatment in such situations is less important than the discovery of the underlying cause. Moreover, as noted previously, correction of the iron deficit is not certain to alleviate the host of vague symptoms often attributed to it. Nevertheless, replacement therapy makes sense when (a) the patient is symptomatic and has a limited cardiopulmonary reserve, (b) the anemia has become moderately severe (hemoglobin level of 8 to 9 g/dL), (c) the patient is pregnant, (d) the patient has undergone a subtotal gastrectomy and gastrojejunostomy, (e) continued heavy blood loss is anticipated, or (f) the patient is recovering from megaloblastic anemia.

Absorption

Oral iron absorption occurs best under conditions of low pH in the proximal small bowel, such as 1 to 2 hours before a meal or at bedtime. Antacid use reduces absorption, as does food intake; the phytates and phosphates in food bind iron. When iron tablets are taken with meals, absorption drops by more than 50%. Absorption also varies according to the severity of the deficit. About 20% of an oral dose is taken up initially, but absorption falls to 5% after 1 month of replacement therapy, even though the anemia remains incompletely corrected. Ascorbic acid improves absorption in achlorhydric patients.

Side Effects

Upper and lower gastrointestinal symptoms are the principal side effects of oral iron therapy; they can be severe enough to interfere with treatment. The upper gastrointestinal effects are especially troublesome and include nausea, vomiting, epigastric cramping, and acid reflux. Onset is usually within 1 hour of iron intake. Upper gastrointestinal symptoms are proportional to the amount of ionized iron delivered to the stomach and the proximal small bowel, and they decrease with a reduction in dose. Many patients mistakenly attribute their symptoms to the type of iron preparation used and switch to another; however, most often, it is the amount of iron released in the upper digestive tract that accounts for symptoms. Dose reduction is all that is required and frequently suffices. In the very elderly (age >80 years), low-dose therapy can be as effective as normal dosing, minimizing adverse gastrointestinal side effects and improving compliance. The lower gastrointestinal side effects of constipation and diarrhea are reported by about 25% of users, but these are less a function of the amount of iron available for absorption than are upper gastrointestinal side effects. Constipation usually responds to dietary fiber or a stool softener. The intramuscular administration of iron has been associated with the development of sarcomas at injection sites and should be avoided. Fatal anaphylactic reactions and asthma have been associated with all parenteral forms of iron administration. If parenteral iron must be given, it should be administered by the intravenous route—first a very small test dose and then a slow drip; a syringe with epinephrine should be drawn up at the same time and kept on hand.

Preparations

Ferrous iron is required for oral use; ferric iron is poorly absorbed. The most cost-effective approach to oral iron replacement is use of generic ferrous sulfate. It is the least expensive (as little as 10% of the cost of other preparations) and provides the most elemental iron. Its absorption does not require gastric acid, making the preparation useful even in the setting of Helicobacter pylori infection, atrophic gastritis, and achlorhydria. All commonly used ferrous salts (i.e., sulfate, gluconate, citrate) have equivalent rates of absorption, differing principally in the amount of elemental iron released. Choice is a matter of cost and side effects. The severity of gastrointestinal upset is predominantly a function of the amount of iron released rather than the type of ferrous salt used. This is the reason for the increased frequency of gastrointestinal upset associated with the use of ferrous sulfate, which releases the most elemental iron. Some preparations contain ascorbic acid to facilitate absorption, but ferrous sulfate provides sufficient iron to make absorption-enhancing measures unnecessary in most instances. Slow-release and enteric-coated preparations have been touted as producing fewer side effects and requiring only once-daily administration. However, they dissolve slowly and can bypass the proximal small bowel (where most absorption takes place) before dissolving to a significant degree. There is no evidence that they are worth the extra cost, which can be several times that of unadulterated ferrous sulfate. An ingenious but expensive ferrous sulfate formulation uses a gastric delivery system that is activated by stomach secretions; as a result, the capsule floats and remains within the stomach for a few hours after food has passed. The capsule slowly releases iron during this period, so that iron absorption is enhanced by two to three times, gastrointestinal upset is minimized, and the necessary frequency of dosing is reduced.

Parenteral iron has a very limited role. It should be used only in patients who have had an adequate trial of oral iron and have shown a genuine intolerance to all available preparations. Patients with inflammatory bowel disease may require parenteral iron because of the irritant effect of oral iron and the need to take large doses to keep up with blood loss. Parenteral iron has also been suggested for patients with malabsorption, but most patients are able to absorb a sufficient amount of oral iron. Parenteral iron is best given by the intravenous route (see prior discussion).

Dosing

The recommended oral dose for iron deficiency is 300 mg of ferrous sulfate three times daily. As noted, absorption is maximized by dosing 1 to 2 hours before a meal or at bedtime. Although taking iron with a meal reduces absorption, it also lessens disagreeable gastrointestinal symptoms, such as nausea and epigastric discomfort. For the alleviation of gastrointestinal side effects, reducing frequency of dosing is less effective than reducing the dose taken. As noted, low-dose therapy may be as effective in the very elderly as full doses by reducing gastrointestinal upset and enhancing compliance.

Drug-Drug Interactions

The effect of iron on absorption of other drugs needs to be kept in mind. When iron is ingested simultaneously, the absorption of levodopa, methyldopa, tetracycline, and fluoroquinolone antibiotics is reduced by up to 90%. A similar but more variable effect on l-thyroxine has been noted. Iron intake should be delayed for several hours after the intake of these other medications, and monitoring of their efficacy should be stepped up during iron therapy.

Drugs that neutralize or inhibit acid secretion (e.g., antacids, histamine₂ blockers, proton-pump inhibitors) may reduce iron absorption because a low pH is required in the proximal small bowel for optimal uptake. Taking iron with orange juice (rich in ascorbic acid) or using an ascorbic acid-containing preparation can help in situations in which the suppression of gastric acid is needed.

Duration of Therapy

The response to iron is apparent within 10 days of initiation of therapy; a reticulocytosis is first noted, followed by a rise in the hemoglobin concentration of 0.1 to 0.2 g/dL daily. Therapy for several weeks is required to bring the hemoglobin level back up to normal, and replenishing iron stores may take months.

However, speed is not an issue unless blood loss is rapid, in which case blood transfusion rather than iron therapy is the treatment of choice. The response to parenteral iron therapy is no more rapid than that seen with oral preparations.

Patient Education and Prevention of Iron Deficiency

To maximize compliance, patients need to be instructed about the best means of minimizing gastrointestinal side effects. Starting with a small dose of ferrous sulfate (e.g., 300 mg/d) and building to 900 mg/d avoids initial intolerance. Taking iron just after eating may also help. It needs to be made clear that therapy has to be continued on a regular basis for weeks and often months.

The prevention of iron deficiency is most important in individuals with increased needs (i.e., pregnant women and young children). The average US diet contains 12 mg of iron per 2,000 calories. Twenty percent is absorbed by markedly iron-deficient patients and 5% to 10% by others; thus, about 0.6 to 1.2 mg is taken up under normal circumstances each day. The daily requirement for men and postmenopausal women is 0.5 to 1.0 mg, so that dietary intake should suffice. However, the requirement for menstruating women is 1.5 mg/d and that for pregnant women is 2.5 mg/d. Iron-rich foods can be added to the diet to avoid the need for iron supplements. Liver, oysters, and heavily iron-enriched cereals (containing >45% of the recommended daily iron allowance) are the best dietary sources, providing more than 5mg of iron per serving. Lean beef, veal, moderately iron-fortified cereals (containing >25% of the daily allowance), and beans are good sources, providing 3 to 5 mg of iron per serving. Fish, chicken, egg yolks, raisins, and fortified breads and pasta are fair sources, providing 1 to 3 mg per serving. Green vegetables are rich in iron, but the iron is less readily available for absorption because it is bound to the phosphates and phytates present in these foods.

When diet alone seems to be inadequate and needs are very high, as in pregnancy, a once-daily dose of 150 to 300 mg of ferrous sulfate is recommended to avoid significant iron deficiency. It must be emphasized that most people who eat a balanced diet do not require iron supplements. Taking widely promoted supplements that contain iron, vitamins, and minerals is expensive and unnecessary in most instances. Excessive iron is associated with increased risks for malignancy and atherosclerotic disease. Patients taking expensive vitamin preparations should be advised that much simpler, less costly, yet equally efficacious preparations are available.

VITAMIN B₁₂ DEFICIENCY (7, 8, 9, 10, 11, 12 and 13)

Vitamin B₁₂ deficiency can result from inadequate intake, impaired absorption, increased requirements, or faulty utilization. Poor intake is distinctly rare, occurring mostly in ultrastrict vegetarians who refrain from eating eggs and dairy products as well as meat. Many cases of vitamin B₁₂ deficiency are secondary to pernicious anemia; the lack of intrinsic factor compromises absorption. Absorption can also be impaired by achlorhydria, disease of the terminal ileum, bacterial overgrowth resulting from stasis, and gastrectomy. Faulty utilization is uncommon; it occurs with genetic defects in the synthesis of transcobalamin, the plasma protein that transports vitamin B₁₂.

Clinical Presentation, Course, and Diagnosis

Irrespective of cause, vitamin B₁₂ deficiency may lead to slowly evolving megaloblastic anemia, glossitis, and neuropathy. Macrocytosis is usually the first hematologic manifestation and can precede anemia by as much as 1 to 2 years. Hypersegmentation of neutrophils is another early hematologic finding. Because of the body’s large vitamin B₁₂ storage capacity, the onset of clinical manifestations may take months to years. Although megaloblastic anemia and glossitis also occur with folic acid deficiency, the neuropathy is distinctive. Traditionally, neurologic symptoms were believed to be a late development, associated with a vitamin B₁₂ level of less than 100 pg/mL. However, careful studies have documented vitamin B₁₂-responsive neuropsychiatric deficits in the absence of such marked vitamin B₁₂ deficiency, anemia, or machine-determined macrocytosis (although hypersegmentation and macrocytosis were often noted on examination of the peripheral smear).

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