InternalMed_Harrison

InternalMed_Harrison. When moderate anemia is present (hemoglobin 10–13 g/dL), the bone marrow remains hypoproliferative. With more severe anemia (hemoglobin 7–8 g/dL), hypochromia and microcytosis become more prominent, target cells and misshapen red cells (poikilocytes) appear on the blood smear as cigaror pencil-shaped forms, and the erythroid marrow becomes increasingly ineffective. Consequently, with severe prolonged iron-deficiency anemia, erythroid hyperplasia of the marrow develops, rather than hypoproliferation. Conditions that increase demand for iron, increase iron loss, or decrease iron intake or absorption can produce iron deficiency (Table 126-2). Chronic blood loss Menses Acute blood loss Blood donation Phlebotomy as treatment for polycythemia vera Malabsorption from disease (sprue, Crohn’s disease) Malabsorption from surgery (gastrectomy and some forms of bariatric surgery)


InternalMed_Harrison

InternalMed_Harrison. Malabsorption from disease (sprue, Crohn’s disease) Malabsorption from surgery (gastrectomy and some forms of bariatric surgery) LABORATORY IRON STUDIES Serum Iron and Total Iron-Binding Capacity The serum iron level represents the amount of circulating iron bound to transferrin. The TIBC is an indirect measure of the circulating transferrin. The normal range for the serum iron is 50–150 μg/dL; the normal range for TIBC is 300–360 μg/dL. Transferrin saturation, which is normally 25–50%, is obtained by the following formula: serum iron × 100 ÷ TIBC. Iron-deficiency states are associated with saturation levels below 20%. There is a diurnal variation in the serum iron. A transferrin saturation % >50% indicates that a disproportionate amount of the iron bound to transferrin is being delivered to nonerythroid tissues. If this persists for an extended time, tissue iron overload may occur.


InternalMed_Harrison

InternalMed_Harrison. Serum Ferritin Free iron is toxic to cells, and the body has established an elaborate set of protective mechanisms to bind iron in various tissue compartments. Within cells, iron is stored complexed to protein as ferritin or hemosiderin. Apoferritin binds to free ferrous iron and stores it in the ferric state. As ferritin accumulates within cells of the RE system, protein aggregates are formed as hemosiderin. Iron in ferritin or hemosiderin can be extracted for release by the RE cells, although hemosiderin is less readily available. Under steady-state conditions, the serum ferritin level correlates with total body iron stores; thus, the serum ferritin level is the most convenient laboratory test to estimate iron stores. The normal value for ferritin varies according to the age and gender of the individual (Fig. 126-3). Adult males have serum Serum ferritin, ˜g/L


InternalMed_Harrison

InternalMed_Harrison. Serum ferritin, ˜g/L Certain clinical conditions carry an increased likelihood of iron deficiency. Pregnancy, adolescence, periods of rapid growth, and an intermittent history of blood loss of any kind should alert the clini-0 cian to possible iron deficiency. A cardinal rule is that the appearance of iron deficiency in an adult male means gastrointestinal blood loss until proven otherwise. Signs related to iron deficiency depend on the severity and chronicity of the anemia in addition to the usual signs of anemia—fatigue, pallor, and reduced exercise capacity. Cheilosis (fissures at the corners of the mouth) and koilonychia (spooning of the fingernails) are signs of advanced tissue iron deficiency. The diagnosis of iron deficiency is typically based on laboratory results. 0 1020304050607080 Age, years FIGURE 126-3 Serum ferritin levels as a function of sex and age.


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InternalMed_Harrison. 0 1020304050607080 Age, years FIGURE 126-3 Serum ferritin levels as a function of sex and age. Iron store depletion and iron deficiency are accompanied by a decrease in serum ferritin level below 20 μg/L. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2011, with permission.) Iron Stores Marrow Iron Stain, 0–4+ Serum Ferritin, μg/L 1–300 mg Trace to 1+ 15–30 ferritin values averaging 100 μg/L, while adult females have levels averaging 30 μg/L. As iron stores are depleted, the serum ferritin falls to <15 μg/L. Such levels are diagnostic of absent body iron stores.


InternalMed_Harrison

InternalMed_Harrison. Evaluation of Bone Marrow Iron Stores Although RE iron stores can be estimated from the iron stain of a bone marrow aspirate or biopsy, the measurement of serum ferritin has largely supplanted these procedures for determination of storage iron (Table 126-3). The serum ferritin level is a better indicator of iron overload than the marrow iron stain. However, in addition to storage iron, the marrow iron stain provides information about the effective delivery of iron to developing erythroblasts. Normally, when the marrow smear is stained for iron, 20–40% of developing erythroblasts—called sideroblasts—will have visible ferritin granules in their cytoplasm. This represents iron in excess of that needed for hemoglobin synthesis. In states in which release of iron from storage sites is blocked, RE iron will be detectable, and there will be few or no sideroblasts. In the myelodysplastic syndromes, mitochondrial dysfunction can occur, and accumulation of iron in mitochondria appears in a


InternalMed_Harrison

InternalMed_Harrison. RE iron will be detectable, and there will be few or no sideroblasts. In the myelodysplastic syndromes, mitochondrial dysfunction can occur, and accumulation of iron in mitochondria appears in a necklace fashion around the nucleus of the erythroblast. Such cells are referred to as ringed sideroblasts.


InternalMed_Harrison

InternalMed_Harrison. Red Cell Protoporphyrin Levels Protoporphyrin is an intermediate in the pathway to heme synthesis. Under conditions in which heme synthesis is impaired, protoporphyrin accumulates within the red cell. This reflects an inadequate iron supply to erythroid precursors to support hemoglobin synthesis. Normal values are <30 μg/dL of red cells. In iron deficiency, values in excess of 100 μg/dL are seen. The most common causes of increased red cell protoporphyrin levels are absolute or relative iron deficiency and lead poisoning.


InternalMed_Harrison

InternalMed_Harrison. Serum Levels of Transferrin Receptor Protein Because erythroid cells have the highest numbers of transferrin receptors of any cell in the body, and because transferrin receptor protein (TRP) is released by cells into the circulation, serum levels of TRP reflect the total erythroid marrow mass. Another condition in which TRP levels are elevated is absolute iron deficiency. Normal values are 4–9 μg/L determined by immunoassay. This laboratory test is becoming increasingly available and, along with the serum ferritin, has been proposed to distinguish between iron deficiency and the anemia of inflammation (see below).


InternalMed_Harrison

InternalMed_Harrison. Other than iron deficiency, only three conditions need to be considered in the differential diagnosis of a hypochromic microcytic anemia (Table 126-4). The first is an inherited defect in globin chain synthesis: the thalassemias. These are differentiated from iron deficiency most readily by serum iron values; normal or increased serum iron levels and transferrin saturation are characteristic of the thalassemias. In addition, the red blood cell distribution width (RDW) index is generally normal in thalassemia and elevated in iron deficiency.


InternalMed_Harrison

InternalMed_Harrison. The second condition is the anemia of inflammation (AI; also referred to as the anemia of chronic disease) with inadequate iron supply to the erythroid marrow. The distinction between true iron-deficiency anemia and AI is among the most common diagnostic problems encountered by clinicians (see below). Usually, AI is normocytic and normochromic. The iron values usually make the differential diagnosis clear, as the ferritin level is normal or increased and the percent transferrin saturation and TIBC are typically below normal. Finally, the myelodysplastic syndromes represent the third and least common condition. Occasionally, patients with myelodysplasia have impaired hemoglobin synthesis with mitochondrial dysfunction, resulting in impaired iron incorporation into heme. The iron values again reveal normal stores and more than an adequate supply to the marrow, despite the microcytosis and hypochromia.


InternalMed_Harrison

InternalMed_Harrison. The severity and cause of iron-deficiency anemia will determine the appropriate approach to treatment. As an example, symptomatic elderly patients with severe iron-deficiency anemia and cardiovascular instability may require red cell transfusions. Younger individuals who have compensated for their anemia can be treated more conservatively with iron replacement. The foremost issue for the latter patient is the precise identification of the cause of the iron deficiency. For the majority of cases of iron deficiency (pregnant women, growing children and adolescents, patients with infrequent episodes of bleeding, and those with inadequate dietary intake of iron), oral iron therapy will suffice. For patients with unusual blood loss or malabsorption, specific diagnostic tests and appropriate therapy take priority. Once the diagnosis of iron-deficiency anemia and its cause is made, there are three major therapeutic approaches.


InternalMed_Harrison

InternalMed_Harrison. Transfusion therapy is reserved for individuals who have symptoms of anemia, cardiovascular instability, and continued and excessive blood loss from whatever source and who require immediate intervention. The management of these patients is less related to the iron deficiency than it is to the consequences of the severe anemia. Not only do transfusions correct the anemia acutely, but the transfused red cells provide a source of iron for reutilization, assuming they are not lost through continued bleeding. Transfusion therapy will stabilize the patient while other options are reviewed. In the asymptomatic patient with established iron-deficiency anemia, treatment with oral iron is usually adequate. Multiple preparations are available, ranging from simple iron salts to complex iron compounds designed for sustained release throughout the small intestine (Table 126-5). Although the various preparations


InternalMed_Harrison

InternalMed_Harrison. Tablet (Iron Elixir (Iron Content), Generic Name Content), mg mg in 5 mL contain different amounts of iron, they are generally all absorbed well and are effective in treatment. Some come with other compounds designed to enhance iron absorption, such as ascorbic acid. It is not clear whether the benefits of such compounds justify their costs. Typically, for iron replacement therapy, up to 200 mg of elemental iron per day is given, usually as three or four iron tablets (each containing 50–65 mg elemental iron) given over the course of the day. Ideally, oral iron preparations should be taken on an empty stomach, since food may inhibit iron absorption. Some patients with gastric disease or prior gastric surgery require special treatment with iron solutions, because the retention capacity of the stomach may be reduced. The retention capacity is necessary for dissolving the shell of the iron tablet before the release of iron. A dose of 200 mg of elemental iron per day should result in the


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InternalMed_Harrison. the stomach may be reduced. The retention capacity is necessary for dissolving the shell of the iron tablet before the release of iron. A dose of 200 mg of elemental iron per day should result in the absorption of iron up to 50 mg/d. This supports a red cell production level of two to three times normal in an individual with a normally functioning marrow and appropriate erythropoietin stimulus. However, as the hemoglobin level rises, erythropoietin stimulation decreases, and the amount of iron absorbed is reduced. The goal of therapy in individuals with iron-deficiency anemia is not only to repair the anemia, but also to provide stores of at least 0.5–1 g of iron. Sustained treatment for a period of 6–12 months after correction of the anemia will be necessary to achieve this.


InternalMed_Harrison

InternalMed_Harrison. Of the complications of oral iron therapy, gastrointestinal distress is the most prominent and is seen in 15–20% of patients. Abdominal pain, nausea, vomiting, or constipation may lead to noncompliance. Although small doses of iron or iron preparations with delayed release may help somewhat, the gastrointestinal side effects are a major impediment to the effective treatment of a number of patients.


InternalMed_Harrison

InternalMed_Harrison. The response to iron therapy varies, depending on the erythropoietin stimulus and the rate of absorption. Typically, the reticulocyte count should begin to increase within 4–7 days after initiation of therapy and peak at 1–1½ weeks. The absence of a response may be due to poor absorption, noncompliance (which is common), or a confounding diagnosis. A useful test in the clinic to determine the patient’s ability to absorb iron is the iron tolerance test. Two iron tablets are given to the patient on an empty stomach, and the serum iron is measured serially over the subsequent 2 h. Normal absorption will result in an increase in the serum iron of at least 100 μg/ dL. If iron deficiency persists despite adequate treatment, it may be necessary to switch to parenteral iron therapy.


InternalMed_Harrison

InternalMed_Harrison. Intravenous iron can be given to patients who are unable to tolerate oral iron; whose needs are relatively acute; or who need iron on an ongoing basis, usually due to persistent gastrointestinal blood loss. Parenteral iron use has been increasing rapidly in the last several years with the recognition that recombinant erythropoietin (EPO) therapy induces a large demand for iron—a demand that frequently cannot be met through the physiologic release of iron from RE sources or oral iron absorption. The safety of parenteral iron— particularly iron dextran—has been a concern. The serious adverse reaction rate to intravenous high-molecular-weight iron dextran is 0.7%. Fortunately, newer iron complexes are available in the United States, such as ferumoxytol (Feraheme), sodium ferric gluconate (Ferrlecit), iron sucrose (Venofer), and ferric carboxy-629 maltose (Injectafer), that have much lower rates of adverse effects. Ferumoxytol delivers 510 mg of iron per injection; ferric gluconate 125 mg


InternalMed_Harrison

InternalMed_Harrison. iron sucrose (Venofer), and ferric carboxy-629 maltose (Injectafer), that have much lower rates of adverse effects. Ferumoxytol delivers 510 mg of iron per injection; ferric gluconate 125 mg per injection, ferric carboxymaltose 750 mg per injection, and iron sucrose 200 mg per injection.


InternalMed_Harrison

InternalMed_Harrison. Parenteral iron is used in two ways: one is to administer the total dose of iron required to correct the hemoglobin deficit and provide the patient with at least 500 mg of iron stores; the second is to give repeated small doses of parenteral iron over a protracted period. The latter approach is common in dialysis centers, where it is not unusual for 100 mg of elemental iron to be given weekly for 10 weeks to augment the response to recombinant EPO therapy. The amount of iron needed by an individual patient is calculated by the following formula: Body weight (kg) × 2.3 × (15 – patient’s hemoglobin, g/dL) + 500 or 1000 mg (for stores).


InternalMed_Harrison

InternalMed_Harrison. Body weight (kg) × 2.3 × (15 – patient’s hemoglobin, g/dL) + 500 or 1000 mg (for stores). In administering intravenous iron dextran, anaphylaxis is a con cern. Anaphylaxis is much rarer with the newer preparations. The factors that have correlated with an anaphylactic-like reaction include a history of multiple allergies or a prior allergic reaction to dextran (in the case of iron dextran). Generalized symptoms appearing several days after the infusion of a large dose of iron can include arthralgias, skin rash, and low-grade fever. These may be dose-related, but they do not preclude the further use of parenteral iron in the patient. To date, patients with sensitivity to iron dextran have been safely treated with other parenteral iron preparations.


InternalMed_Harrison

InternalMed_Harrison. If a large dose of iron dextran is to be given (>100 mg), the iron preparation should be diluted in 5% dextrose in water or 0.9% NaCl solution. The iron solution can then be infused over a 60to 90-min period (for larger doses) or at a rate convenient for the attending nurse or physician. Although a test dose (25 mg) of parenteral iron dextran is recommended, in reality a slow infusion of a larger dose of parenteral iron solution will afford the same kind of early warning as a separately injected test dose. Early in the infusion of iron, if chest pain, wheezing, a fall in blood pressure, or other systemic symptoms occur, the infusion of iron should be stopped immediately.


InternalMed_Harrison

InternalMed_Harrison. In addition to mild to moderate iron-deficiency anemia, the hypo-proliferative anemias can be divided into four categories: (1) chronic inflammation, (2) renal disease, (3) endocrine and nutritional deficiencies (hypometabolic states), and (4) marrow damage (Chap. 130). With chronic inflammation, renal disease, or hypometabolism, endogenous EPO production is inadequate for the degree of anemia observed. For the anemia of chronic inflammation, the erythroid marrow also responds inadequately to stimulation, due in part to defective iron reutilization. As a result of the lack of adequate EPO stimulation, an examination of the peripheral blood smear will disclose only an occasional polychromatophilic (“shift”) reticulocyte. In cases of iron deficiency or marrow damage, appropriate elevations in endogenous EPO levels are typically found, and shift reticulocytes will be present on the blood smear.


InternalMed_Harrison

InternalMed_Harrison. AI—which encompasses inflammation, infection, tissue injury, and conditions (such as cancer) associated with the release of proinflammatory cytokines—is one of the most common forms of anemia seen clinically. It is the most important anemia in the differential diagnosis of iron deficiency, because many of the features of the anemia are brought about by inadequate iron delivery to the marrow, despite the presence of normal or increased iron stores. This is reflected by a low serum iron, increased red cell protoporphyrin, a hypoproliferative marrow, transferrin saturation in the range of 15–20%, and a normal or increased serum ferritin. The serum ferritin values are often the most distinguishing features between true iron-deficiency anemia and the iron-restricted erythropoiesis associated with inflammation. Typically, serum ferritin values increase threefold over basal levels 630 Neoplasms with angina, exercise intolerance, and shortness of breath. The eryth-Bacterial infections


InternalMed_Harrison

InternalMed_Harrison. with inflammation. Typically, serum ferritin values increase threefold over basal levels 630 Neoplasms with angina, exercise intolerance, and shortness of breath. The eryth-Bacterial infections ropoietic profile that distinguishes the anemia of inflammation from the other causes of hypoproliferative anemias is shown in Table 126-6.


InternalMed_Harrison

InternalMed_Harrison. Progressive CKD is usually associated with a moderate to severe hypoproliferative anemia; the level of the anemia corre-EPO Marrow lates with the stage of CKD. Red cells are typically normocytic and normochromic, and reticulocytes are decreased. The anemiaIron is primarily due to a failure of EPO production by the diseased kidney and a reduction in red cell survival. In certain forms of acuteInterferon ° renal failure, the correlation between the anemia and renal function is weaker. Patients with the hemolytic-uremic syndrome increase erythropoiesis in response to the hemolysis, despite renal failure requiring Rheumatoid arthritis dialysis. Polycystic kidney disease also shows a smaller degree of EPO FIGURE 126-4 Suppression of erythropoiesis by inflammatory deficiency for a given level of renal failure. By contrast, patients with cytokines. Through the release of tumor necrosis factor (TNF) and diabetes or myeloma have more severe EPO deficiency for a given level interferon γ


InternalMed_Harrison

InternalMed_Harrison. level of renal failure. By contrast, patients with cytokines. Through the release of tumor necrosis factor (TNF) and diabetes or myeloma have more severe EPO deficiency for a given level interferon γ (IFN-γ), neoplasms and bacterial infections suppress of renal failure. erythropoietin (EPO) production and the proliferation of erythroid Assessment of iron status provides information to distinguish the progenitors (erythroid burst-forming units and erythroid colony-anemia of CKD from the other forms of hypoproliferative anemia forming units [BFU/CFU-E]). The mediators in patients with vasculitis (Table 126-6) and to guide management. Patients with the anemia of and rheumatoid arthritis include interleukin 1 (IL-1) and IFN-γ. The red CKD usually present with normal serum iron, TIBC, and ferritin levarrows indicate sites of inflammatory cytokine inhibitory effects. RBC, els. However, those maintained on chronic hemodialysis may develop red blood cell. iron deficiency from blood loss


InternalMed_Harrison

InternalMed_Harrison. ferritin levarrows indicate sites of inflammatory cytokine inhibitory effects. RBC, els. However, those maintained on chronic hemodialysis may develop red blood cell. iron deficiency from blood loss through the dialysis procedure. Iron must be replenished in these patients to ensure an adequate response to EPO therapy (see below).


InternalMed_Harrison

InternalMed_Harrison. in the face of inflammation. These changes are due to the effects of inflammatory cytokines and hepcidin, the key iron regulatory hor-ANEMIA IN HYPOMETABOLIC STATES mone, acting at several levels of erythropoiesis (Fig. 126-4). Patients who are starving, particularly for protein, and those with a


InternalMed_Harrison

InternalMed_Harrison. Interleukin 1 (IL-1) directly decreases EPO production in response variety of endocrine disorders that produce lower metabolic rates, may to anemia. IL-1, acting through accessory cell release of interferon γ develop a mild to moderate hypoproliferative anemia. The release of (IFN-γ), suppresses the response of the erythroid marrow to EPO—an EPO from the kidney is sensitive to the need for O2, not just O2 levels. effect that can be overcome by EPO administration in vitro and in vivo. Thus, EPO production is triggered at lower levels of blood O2 content In addition, tumor necrosis factor (TNF), acting through the release in disease states (such as hypothyroidism and starvation) where meta-of IFN-γ by marrow stromal cells, also suppresses the response to bolic activity, and thus O2 demand, is decreased. EPO. Hepcidin, made by the liver, is increased in inflammation via an


InternalMed_Harrison

InternalMed_Harrison. Endocrine Deficiency States The difference in the levels of hemoglobinIL-6 mediated pathway, and acts to suppress iron absorption and iron between men and women is related to the effects of androgen andrelease from storage sites. The overall result is a chronic hypoproliferaestrogen on erythropoiesis. Testosterone and anabolic steroids augtive anemia with classic changes in iron metabolism. The anemia is furment erythropoiesis; castration and estrogen administration to malesther compounded by a mild to moderate shortening in red cell survival.


InternalMed_Harrison

InternalMed_Harrison. decrease erythropoiesis. Patients who are hypothyroid or have deficitsWith chronic inflammation, the primary disease will determine in pituitary hormones also may develop a mild anemia. Pathogenesisthe severity and characteristics of the anemia. For example, many may be complicated by other nutritional deficiencies because iron andpatients with cancer also have anemia that is typically normocytic and folic acid absorption can be affected by these disorders. Usually, cornormochromic. In contrast, patients with long-standing active rheurection of the hormone deficiency reverses the anemia.


InternalMed_Harrison

InternalMed_Harrison. matoid arthritis or chronic infections such as tuberculosis will have a Anemia may be more severe in Addison’s disease, depending on themicrocytic, hypochromic anemia. In both cases, the bone marrow is level of thyroid and androgen hormone dysfunction; however, anemiahypoproliferative, but the differences in red cell indices reflect differ-may be masked by decreases in plasma volume. Once such patients areences in the availability of iron for hemoglobin synthesis. Occasionally, given cortisol and volume replacement, the hemoglobin level may fallconditions associated with chronic inflammation are also associated rapidly. Mild anemia complicating hyperparathyroidism may be duewith chronic blood loss. Under these circumstances, a bone marrow to decreased EPO production as a consequence of the renal effects ofaspirate stained for iron may be necessary to rule out absolute iron hypercalcemia or to impaired proliferation of erythroid progenitors.


InternalMed_Harrison

InternalMed_Harrison. deficiency. However, the administration of iron in this case will correct the iron deficiency component of the anemia and leave the inflamma-Protein Starvation Decreased dietary intake of protein may lead to tory component unaffected. mild to moderate hypoproliferative anemia; this form of anemia may


InternalMed_Harrison

InternalMed_Harrison. The anemia associated with acute infection or inflammation is typi-be prevalent in the elderly. The anemia can be more severe in patients cally mild but becomes more pronounced over time. Acute infection with a greater degree of starvation. In marasmus, where patients are can produce a decrease in hemoglobin span. The fever and cytokines released Anemia Mild to severe Mild Mild to severe Mild exert a selective pressure against cells MCV (fL) 60–90 80–90 90 90 with more limited capacity to maintain Morphology Normo-microcytic Normocytic Normocytic Normocytic the red cell membrane. In most individu- als, the mild anemia is reasonably well tolerated, and symptoms, if present, are associated with the underlying disease. Occasionally, in patients with preexisting cardiac disease, moderate anemia (hemo-Iron stores 0 2–4+ 1–4+ Normal globin 10–11 g/dL) may be associated Abbreviations: MCV, mean corpuscular volume; SI, serum iron; TIBC, total iron-binding capacity.


InternalMed_Harrison

InternalMed_Harrison. both protein and calorie deficient, the release of EPO is impaired in proportion to the reduction in metabolic rate; however, the degree of Disorders of Hemoglobin anemia may be masked by volume depletion and becomes apparent Edward J. Benz, Jr. after refeeding. Deficiencies in other nutrients (iron, folate) may also complicate the clinical picture but may not be apparent at diagnosis. Changes in the erythrocyte indices on refeeding should prompt evaluation of iron, folate, and B12 status.


InternalMed_Harrison

InternalMed_Harrison. Anemia in Liver Disease A mild hypoproliferative anemia may develop in patients with chronic liver disease from nearly any cause. The peripheral blood smear may show spur cells and stomatocytes from the accumulation of excess cholesterol in the membrane from a deficiency of lecithin-cholesterol acyltransferase. Red cell survival is shortened, and the production of EPO is inadequate to compensate. In alcoholic liver disease, nutritional deficiencies are common and complicate the management. Folate deficiency from inadequate intake, as well as iron deficiency from blood loss and inadequate intake, can alter the red cell indices.


InternalMed_Harrison

InternalMed_Harrison. Many patients with hypoproliferative anemias experience recovery of normal hemoglobin levels when the underlying disease is appropriately treated. For those in whom such reversals are not possible— such as patients with end-stage kidney disease, cancer, and chronic inflammatory diseases—symptomatic anemia requires treatment. The two major forms of treatment are transfusions and EPO.


InternalMed_Harrison

InternalMed_Harrison. Thresholds for transfusion should be determined based on the patient’s symptoms. In general, patients without serious underlying cardiovascular or pulmonary disease can tolerate hemoglobin levels above 7–8 g/dL and do not require intervention until the hemoglobin falls below that level. Patients with more physiologic compromise may need to have their hemoglobin levels kept above 11 g/dL. Usually, a unit of packed red cells increases the hemoglobin level by 1 g/dL. Transfusions are associated with certain infectious risks (Chap. 138e), and chronic transfusions can produce iron overload. Importantly, the liberal use of blood has been associated with increased morbidity and mortality, particularly in the intensive care setting. Therefore, in the absence of documented tissue hypoxia, a conservative approach to the use of red cell transfusions is preferable.


InternalMed_Harrison

InternalMed_Harrison. EPO is particularly useful in anemias in which endogenous EPO levels are inappropriately low, such as CKD or AI. Iron status must be evaluated and iron replaced to obtain optimal effects from EPO. In patients with CKD, the usual dose of EPO is 50–150 U/kg three times a week intravenously. Hemoglobin levels of 10–12 g/dL are usually reached within 4–6 weeks if iron levels are adequate; 90% of these patients respond. Once a target hemoglobin level is achieved, the EPO dose can be decreased. A decrease in hemoglobin level occurring in the face of EPO therapy usually signifies the development of an infection or iron depletion. Aluminum toxicity and hyperparathyroidism can also compromise the response to EPO. When an infection intervenes, it is best to interrupt the EPO therapy and rely on transfusions to correct the anemia until the infection is adequately treated. The dose of EPO needed to correct chemotherapy-induced anemia in patients with cancer is higher, up to 300 U/kg three times a


InternalMed_Harrison

InternalMed_Harrison. to correct the anemia until the infection is adequately treated. The dose of EPO needed to correct chemotherapy-induced anemia in patients with cancer is higher, up to 300 U/kg three times a week, and only approximately 60% of patients respond. Because of evidence that there is an increased risk of thromboembolic complications and tumor progression with EPO administration, the risks and benefits of using EPO in such patients must be weighed carefully, and the target hemoglobin should be that necessary to avoid transfusions.


InternalMed_Harrison

InternalMed_Harrison. Longer-acting preparations of EPO can reduce the frequency of injections. Darbepoetin alfa, a molecularly modified EPO with additional carbohydrate, has a half-life in the circulation that is three to four times longer than recombinant human EPO, permitting weekly or every other week dosing. Hemoglobin is critical for normal oxygen delivery to tissues; it is also present in erythrocytes in such high concentrations that it can alter red cell shape, deformability, and viscosity. Hemoglobinopathies are disorders affecting the structure, function, or production of hemoglobin. These conditions are usually inherited and range in severity from asymptomatic laboratory abnormalities to death in utero. Different forms may present as hemolytic anemia, erythrocytosis, cyanosis, or vasoocclusive stigmata.


InternalMed_Harrison

InternalMed_Harrison. Different hemoglobins are produced during embryonic, fetal, and adult life (Fig. 127-1). Each consists of a tetramer of globin polypeptide chains: a pair of α-like chains 141 amino acids long and a pair of β-like chains 146 amino acids long. The major adult hemoglobin, HbA, has the structure α2β2. HbF (α2γ2) predominates during most of gestation, and HbA2 (α2δ2) is minor adult hemoglobin. Embryonic hemoglobins need not be considered here. Each globin chain enfolds a single heme moiety, consisting of a protoporphyrin IX ring complexed with a single iron atom in the ferrous state (Fe2+). Each heme moiety can bind a single oxygen molecule; a molecule of hemoglobin can transport up to four oxygen molecules.


InternalMed_Harrison

InternalMed_Harrison. The amino acid sequences of the various globins are highly homologous to one another. Each has a highly helical secondary structure. Their globular tertiary structures cause the exterior surfaces to be rich in polar (hydrophilic) amino acids that enhance solubility, and the interior to be lined with nonpolar groups, forming a hydrophobic pocket into which heme is inserted. The tetrameric quaternary structure of HbA contains two αβ dimers. Numerous tight interactions (i.e., α1β1 contacts) hold the α and β chains together. The complete tetramer is held together by interfaces (i.e., α1β2 contacts) between the α-like chain of one dimer and the non-α chain of the other dimer.


InternalMed_Harrison

InternalMed_Harrison. The hemoglobin tetramer is highly soluble, but individual globin chains are insoluble. Unpaired globin precipitates, forming inclusions that damage the cell and can trigger apoptosis. Normal globin chain synthesis is balanced so that each newly synthesized α or non-α globin chain will have an available partner with which to pair. Solubility and reversible oxygen binding are the key properties deranged in hemoglobinopathies. Both depend most on the hydrophilic surface amino acids, the hydrophobic amino acids lining the heme pocket, a key histidine in the F helix, and the amino acids forming the α1β1 and α1β2 contact points. Mutations in these strategic regions tend to be the ones that alter oxygen affinity or solubility. FIGURE 127-1 The globin genes. The α-like genes (α, ζ) are encoded on chromosome 16; the β-like genes (β, γ, δ, ε) are encoded on chromosome 11. The ζ and ε genes encode embryonic globins.


InternalMed_Harrison

InternalMed_Harrison. Disorders of Hemoglobin 632 FUNCTION OF HEMOGLOBIN To support oxygen transport, hemoglobin must bind O2 efficiently at the partial pressure of oxygen (Po2) of the alveolus, retain it in the circulation, and release it to tissues at the Po2 of tissue capillary beds. Oxygen acquisition and delivery over a relatively narrow range of oxygen tensions depend on a property inherent in the tetrameric arrangement of heme and globin subunits within the hemoglobin molecule called cooperativity or heme-heme interaction. At low oxygen tensions, the hemoglobin tetramer is fully deoxygenated (Fig. 127-2). Oxygen binding begins slowly as O2 tension rises. However, as soon as some oxygen has been bound by the tetramer, an abrupt increase occurs in the slope of the curve. Thus, hemoglobin molecules that have bound some oxygen develop a higher oxygen affinity, greatly accelerating their ability to combine with more oxygen. This S-shaped oxygen equilibrium curve (Fig. 127-2), along which substantial


InternalMed_Harrison

InternalMed_Harrison. have bound some oxygen develop a higher oxygen affinity, greatly accelerating their ability to combine with more oxygen. This S-shaped oxygen equilibrium curve (Fig. 127-2), along which substantial amounts of oxygen loading and unloading can occur over a narrow range of oxygen tensions, is physiologically more useful than the high-affinity hyperbolic curve of individual monomers. Oxygen affinity is modulated by several factors. The Bohr effect is the ability of hemoglobin to deliver more oxygen to tissues at low pH. It arises from the stabilizing action of protons on deoxyhemoglobin, which binds protons more readily than oxyhemoglobin because the latter is a weaker acid (Fig. 127-2). Thus, hemoglobin has a lower oxygen affinity at low pH. The major small molecule that alters oxygen affinity in humans is 2,3-bisphosphoglycerate (2,3-BPG; formerly 2,3DPG), which lowers oxygen affinity when bound to hemoglobin. HbA has a reasonably high affinity for 2,3-BPG. HbF does not bind 2,3BPG, so


InternalMed_Harrison

InternalMed_Harrison. in humans is 2,3-bisphosphoglycerate (2,3-BPG; formerly 2,3DPG), which lowers oxygen affinity when bound to hemoglobin. HbA has a reasonably high affinity for 2,3-BPG. HbF does not bind 2,3BPG, so it tends to have a higher oxygen affinity in vivo. Hemoglobin also binds nitric oxide reversibly; this interaction influences vascular tone, but its clinical relevance remains incompletely understood. Proper oxygen transport depends on the tetrameric structure of the proteins, the proper arrangement of hydrophilic and hydrophobic amino acids, and interaction with protons or 2,3-BPG.


InternalMed_Harrison

InternalMed_Harrison. Red cells first appearing at about 6 weeks after conception contain the embryonic hemoglobins Hb Portland (ζ2γ2), Hb Gower I (ζ2ε2), and Hb Gower II (α2ε2). At 10–11 weeks, fetal hemoglobin (HbF; α2γ2) becomes predominant. The switch to nearly exclusive synthesis of adult hemoglobin (HbA; α2β2) occurs at about 38 weeks (Fig. 127-1).


InternalMed_Harrison

InternalMed_Harrison. Fetuses and newborns therefore require α-globin but not β-globin for normal gestation. A major advance in understanding the HbF to HbA transition has been the demonstration that the transcription factor Bcl11a plays a pivotal role in its regulation. Small amounts of HbF are produced during postnatal life. A few red cell clones called F cells are progeny of a small pool of immature committed erythroid precursors (BFU-e) that retain the ability to produce HbF. Profound erythroid stresses, such as severe hemolytic anemias, bone marrow transplantation, or cancer chemotherapy, cause more of the F-potent BFU-e to be recruited. HbF levels thus tend to rise in some patients with sickle cell anemia or thalassemia. This phenomenon probably explains the ability of hydroxyurea to increase levels of HbF in adults. Agents such as butyrate and histone deacetylase inhibitors can also activate fetal globin genes partially after birth.


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InternalMed_Harrison. The human hemoglobins are encoded in two tightly linked gene clusters; the α-like globin genes are clustered on chromosome 16 and the β-like genes on chromosome 11 (Fig. 127-1). The α-like cluster consists of two α-globin genes and a single copy of the ζ gene. The non-α gene cluster consists of a single ε gene, the Gγ and Aγ fetal globin genes, and the adult δ and β genes.


InternalMed_Harrison

InternalMed_Harrison. Important regulatory sequences flank each gene. Immediately upstream are typical promoter elements needed for the assembly of the transcription initiation complex. Sequences in the 5′ flanking region of the γ and the β genes appear to be crucial for the correct developmental regulation of these genes, whereas elements that function like classic enhancers and silencers are in the 3′ flanking regions. The locus control region (LCR) elements located far upstream appear to control the overall level of expression of each cluster. These elements achieve their regulatory effects by interacting with transacting transcription factors. Some of these factors are ubiquitous (e.g., Sp1 and YY1), while others are more or less limited to erythroid cells or hematopoietic cells (e.g., GATA-1, NFE-2, and EKLF). The LCR controlling the α-globin gene cluster is modulated by a SWI/SNF-like protein called ATRX; this protein appears to influence chromatin remodeling and DNA methylation. The association of α


InternalMed_Harrison

InternalMed_Harrison. The LCR controlling the α-globin gene cluster is modulated by a SWI/SNF-like protein called ATRX; this protein appears to influence chromatin remodeling and DNA methylation. The association of α thalassemia with mental retardation and myelodysplasia in some families appears to be related to mutations in the ATRX pathway. This pathway also modulates genes specifically expressed during erythropoiesis, such


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InternalMed_Harrison. Percent Saturation of Hemoglobin Tissue PO (mmHg) 0 25 50 75 100 Oxyhemoglobin Oxyhemoglobin Deoxyhemoglobin Deoxyhemoglobin Salt bridges Oxygen HEME P50 pH 2,3-BPG less O2 delivered ˜˜˜˜°°°°2,3-BPG T° pH more O2 delivered 2,3-BPG T°°


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InternalMed_Harrison. FIGURE 127-2 Hemoglobin-oxygen dissociation curve. The hemoglobin tetramer can bind up to four molecules of oxygen in the iron-containing sites of the heme molecules. As oxygen is bound, 2,3-bisphosphoglycerate (2,3-BPG) and carbon dioxide (CO2) are expelled. Salt bridges are broken, and each of the globin molecules changes its conformation to facilitate oxygen binding. Oxygen release to the tissues is the reverse process, with salt bridges being formed and 2,3-BPG and CO2 bound. Deoxyhemoglobin does not bind oxygen efficiently until the cell returns to conditions of higher pH, the most important modulator of O2 affinity (Bohr effect). When acid is produced in the tissues, the dissociation curve shifts to the right, facilitating oxygen release and CO2 binding. Alkalosis has the opposite effect, reducing oxygen delivery.


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InternalMed_Harrison. as those that encode the enzymes for heme biosynthesis. Normal red blood cell (RBC) differentiation requires the coordinated expression of the globin genes with the genes responsible for heme and iron metabolism. RBC precursors contain a protein, α-hemoglobinstabilizing protein (AHSP), that enhances the folding and solubility of α globin, which is otherwise easily denatured, leading to insoluble precipitates. These precipitates play an important role in the thalassemia syndromes and certain unstable hemoglobin disorders. Polymorphic variation in the amounts and/or functional capacity of AHSP might explain some of the clinical variability seen in patients inheriting identical thalassemia mutations.


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InternalMed_Harrison. There are five major classes of hemoglobinopathies (Table 127-1). Structural hemoglobinopathies occur when mutations alter the amino acid sequence of a globin chain, altering the physiologic properties of the variant hemoglobins and producing the characteristic clinical abnormalities. The most clinically relevant variant hemoglobins polymerize abnormally, as in sickle cell anemia, or exhibit altered solubility or oxygen-binding affinity. Thalassemia syndromes arise from mutations that impair production or translation of globin mRNA, leading to deficient globin chain biosynthesis. Clinical abnormalities are attributable to the inadequate supply of hemoglobin and the imbalances in the production of individual globin chains, leading to premature destruction of erythroblasts and RBC. Thalassemic hemoglobin variants combine features of thalassemia (e.g., abnormal globin biosynthesis) and of structural hemoglobinopathies (e.g., an abnormal amino acid sequence). Hereditary persistence of


InternalMed_Harrison

InternalMed_Harrison. hemoglobin variants combine features of thalassemia (e.g., abnormal globin biosynthesis) and of structural hemoglobinopathies (e.g., an abnormal amino acid sequence). Hereditary persistence of fetal hemoglobin (HPFH) is characterized by synthesis of high levels of fetal hemoglobin in adult life. Acquired hemoglobinopathies include modifications of the hemoglobin molecule by toxins (e.g., acquired methemoglobinemia) and clonal abnormalities of hemoglobin synthesis (e.g., high levels of HbF production in preleukemia and α thalassemia in myeloproliferative disorders).


InternalMed_Harrison

InternalMed_Harrison. I. Structural hemoglobinopathies—hemoglobins with altered amino acid sequences that result in deranged function or altered physical or chemical properties A. Abnormal hemoglobin polymerization—HbS, hemoglobin sickling B. Altered O2 affinity 1. 2. Low affinity—cyanosis, pseudoanemia C. Hemoglobins that oxidize readily 1. Unstable hemoglobins—hemolytic anemia, jaundice 2. M hemoglobins—methemoglobinemia, cyanosis II. Thalassemias—defective biosynthesis of globin chains A. B. C. δβ, γδβ, αβ Thalassemias III. Thalassemic hemoglobin variants—structurally abnormal Hb associated with coinherited thalassemic phenotype A. B. C. IV. Hereditary persistence of fetal hemoglobin—persistence of high levels of HbF into adult life V. A. Methemoglobin due to toxic exposures B. Sulfhemoglobin due to toxic exposures C. D. E. Elevated HbF in states of erythroid stress and bone marrow dysplasia


InternalMed_Harrison

InternalMed_Harrison. V. A. Methemoglobin due to toxic exposures B. Sulfhemoglobin due to toxic exposures C. D. E. Elevated HbF in states of erythroid stress and bone marrow dysplasia Hemoglobinopathies are especially common in areas in which malaria is endemic. This clustering of hemoglobinopathies is assumed to reflect a selective survival advantage for the abnormal RBC, which presumably provides a less hospitable environment during the obligate RBC stages of the parasitic life cycle. Very young children with α thalassemia are more susceptible to infection with the nonlethal Plasmodium vivax. Thalassemia might then favor a natural protection against infection with the more lethal Plasmodium falciparum.


InternalMed_Harrison

InternalMed_Harrison. Thalassemias are the most common genetic disorders in the world, affecting nearly 200 million people worldwide. About 15% of African Americans are silent carriers for α thalassemia; α thalassemia trait (minor) occurs in 3% of African American and in 1–15% of persons of Mediterranean origin. β Thalassemia has a 10–15% incidence in individuals from the Mediterranean and Southeast Asia and 0.8% in African Americans. The number of severe cases of thalassemia in the United States is about 1000. Sickle cell disease is the most common structural hemoglobinopathy, occurring in heterozygous form in ~8% of African Americans and in homozygous form in 1 in 400. Between 2 and 3% of African Americans carry a hemoglobin C allele.


InternalMed_Harrison

InternalMed_Harrison. Hemoglobinopathies are autosomal codominant traits—thus, compound heterozygotes who inherit a different abnormal mutant allele from each parent exhibit composite features of each. For example, patients inheriting sickle β thalassemia exhibit features of β thalassemia and sickle cell anemia. The α chain is present in HbA, HbA2, and HbF; α-chain mutations thus cause abnormalities in all three. The α-globin hemoglobinopathies are symptomatic in utero and after birth because normal function of the α-globin gene is required throughout gestation and adult life. In contrast, infants with β-globin hemoglobinopathies tend to be asymptomatic until 3–9 months of age, when HbA has largely replaced HbF. Prevention or partial reversion of the switch should thus be an effective therapeutic strategy for β-chain hemoglobinopathies.


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InternalMed_Harrison. Electrophoretic techniques are still widely used for hemoglobin analysis. Electrophoresis at pH 8.6 on cellulose acetate membranes is especially simple, inexpensive, and reliable for initial screening. Agar gel electrophoresis at pH 6.1 in citrate buffer is often used as a complementary method because each method detects different variants. Some important variants are electrophoretically silent. These mutant hemoglobins can usually be characterized by more specialized techniques such as mass spectroscopy, which is rapidly replacing electrophoresis for initial analysis.


InternalMed_Harrison

InternalMed_Harrison. Quantitation of the hemoglobin profile is often desirable. HbA2 is frequently elevated in β thalassemia trait and depressed in iron deficiency. HbF is elevated in HPFH, some β thalassemia syndromes, and occasional periods of erythroid stress or marrow dysplasia. For characterization of sickle cell trait, sickle thalassemia syndromes, or HbSC disease, and for monitoring the progress of exchange transfusion therapy to lower the percentage of circulating HbS, quantitation of individual hemoglobins is also required. In most laboratories, quantitation is performed only if the test is specifically ordered. Complete characterization, including amino acid sequencing or gene cloning and sequencing, is readily available from several reference laboratories.


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InternalMed_Harrison. Because some variants can comigrate with HbA or HbS (sickle hemoglobin), electrophoretic assessment should always be regarded as incomplete unless functional assays for hemoglobin sickling, solubility, or oxygen affinity are also performed, as dictated by the clinical presentation. The best sickling assays involve measurement of the degree to which the hemoglobin sample becomes insoluble, or gelated, as it is deoxygenated (i.e., sickle solubility test). Unstable hemoglobins are detected by their precipitation in isopropanol or after heating to 50°C. High-O2 affinity and low-O2 affinity variants are detected Disorders of Hemoglobin ing blood viscosity. However, natural history and drug therapy trials suggest that an increase in the hematocrit and feedback inhibition of reticulocytosis might be beneficial, even at the expense of increased blood viscosity. The role of adhesive reticulocytes in vasoocclusion might account for these paradoxical effects.


InternalMed_Harrison

InternalMed_Harrison. Granulocytosis is common. The white count can fluctuate substantially and unpredictably during and between painful crises, infectious episodes, and other intercurrent illnesses. Vasoocclusion causes protean manifestations. Intermittent episodes of vasoocclusion in connective and musculoskeletal structures produce ischemia manifested by acute pain and tenderness, fever, tachycardia, and anxiety. These recurrent episodes, called painful crises, are the most common clinical manifestation. Their frequency and severity vary greatly. Pain can develop almost anywhere in the body and may last from a few hours to 2 weeks. Repeated crises requiring hospitalization (>3 episodes per year) correlate with reduced survival in adult life, suggesting that these episodes are associated with accumulation of chronic end-organ damage. Provocative factors include infection, fever, excessive exercise, anxiety, abrupt changes in temperature, hypoxia, or hypertonic dyes.


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InternalMed_Harrison. FIGURE 127-3 Pathophysiology of sickle cell crisis. Repeated microinfarction can destroy tissues having microvascular beds prone to sickling. Thus, splenic function is frequently lost within the first 18–36 months of life, causing susceptibility to infection,by quantitating the P50, the partial pressure of oxygen at which the particularly by pneumococci. Acute venous obstruction of the spleenhemoglobin sample becomes 50% saturated with oxygen. Direct tests (splenic sequestration crisis), a rare occurrence in early childhood, mayfor the percent carboxyhemoglobin and methemoglobin, using spec-require emergency transfusion and/or splenectomy to prevent traptrophotometric techniques, can readily be obtained from most clinical ping of the entire arterial output in the obstructed spleen. Occlusionlaboratories on an urgent basis.


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InternalMed_Harrison. of retinal vessels can produce hemorrhage, neovascularization, andLaboratory evaluation remains an adjunct, rather than the sole eventual detachments. Renal papillary necrosis invariably producesdiagnostic aid. Diagnosis is best established by recognition of a characisosthenuria. More widespread renal necrosis leads to renal failure in teristic history, physical findings, peripheral blood smear morphology, adults, a common late cause of death. Bone and joint ischemia can leadand abnormalities of the complete blood cell count (e.g., profound to aseptic necrosis, especially of the femoral or humeral heads; chronic microcytosis with minimal anemia in thalassemia trait).


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InternalMed_Harrison. arthropathy; and unusual susceptibility to osteomyelitis, which may be caused by organisms, such as Salmonella, rarely encountered in other settings. The hand-foot syndrome is caused by painful infarcts of the SICKLE CELL SYNDROMES digits and dactylitis. Stroke is especially common in children; a small The sickle cell syndromes are caused by a mutation in the β-globin subset tends to suffer repeated episodes. Stroke is less common in gene that changes the sixth amino acid from glutamic acid to adults and is often hemorrhagic. A particularly painful complication valine. HbS (α2β26 Glu→Val) polymerizes reversibly when deoxygenated in males is priapism, due to infarction of the penile venous outflow to form a gelatinous network of fibrous polymers that stiffen the RBC tracts; permanent impotence is a frequent consequence. Chronic lower membrane, increase viscosity, and cause dehydration due to potas-leg ulcers probably arise from ischemia and superinfection in the distal sium leakage and


InternalMed_Harrison

InternalMed_Harrison. is a frequent consequence. Chronic lower membrane, increase viscosity, and cause dehydration due to potas-leg ulcers probably arise from ischemia and superinfection in the distal sium leakage and calcium influx (Fig. 127-3). These changes also circulation. produce the sickle shape. Sickled cells lose the pliability needed to Acute chest syndrome is a distinctive manifestation character-traverse small capillaries. They possess altered “sticky” membranes ized by chest pain, tachypnea, fever, cough, and arterial oxygen that are abnormally adherent to the endothelium of small venules. desaturation. It can mimic pneumonia, pulmonary emboli, bone These abnormalities provoke unpredictable episodes of microvascular marrow infarction and embolism, myocardial ischemia, or in situ vasoocclusion and premature RBC destruction (hemolytic anemia). lung infarction. Acute chest syndrome is thought to reflect in situ Hemolysis occurs because the spleen destroys the abnormal RBC. The sickling within the


InternalMed_Harrison

InternalMed_Harrison. RBC destruction (hemolytic anemia). lung infarction. Acute chest syndrome is thought to reflect in situ Hemolysis occurs because the spleen destroys the abnormal RBC. The sickling within the lung, producing pain and temporary pulmonary rigid adherent cells clog small capillaries and venules, causing tissue dysfunction. Often it is difficult or impossible to distinguish among ischemia, acute pain, and gradual end-organ damage. This venooc-other possibilities. Pulmonary infarction and pneumonia are the clusive component usually dominates the clinical course. Prominent most frequent underlying or concomitant conditions in patients manifestations include episodes of ischemic pain (i.e., painful crises) with this syndrome. Repeated episodes of acute chest pain correlate and ischemic malfunction or frank infarction in the spleen, central with reduced survival. Acutely, reduction in arterial oxygen saturanervous system, bones, joints, liver, kidneys, and lungs (Fig. 127-3). tion is


InternalMed_Harrison

InternalMed_Harrison. or frank infarction in the spleen, central with reduced survival. Acutely, reduction in arterial oxygen saturanervous system, bones, joints, liver, kidneys, and lungs (Fig. 127-3). tion is especially ominous because it promotes sickling on a massive scale. Chronic acute or subacute pulmonary crises lead to pulmonary


InternalMed_Harrison

InternalMed_Harrison. Arterial PO2 oxy Hbs (soluble) Capillary venous PO2 deoxy Hbs (polymerized) Stiff, viscous sickle cell Membrane changes Ca2+ influx, K leakage Capillary venule occlusion Shortened red cell survival (hemolytic anemia) Microinfarction Ischemic tissue pain Ischemic organ malfunction Autoinfarction of spleen Anemia, Jaundice, Gallstones, Leg ulcers hypertension and cor pulmonale, an increasingly common cause of death as patients survive longer. Considerable controversy exists about the possible role played by free plasma HbS in scavenging nitrogen dioxide (NO2), thus raising pulmonary vascular tone. Trials of sildenafil to restore NO2 levels were terminated because of adverse effects.


InternalMed_Harrison

InternalMed_Harrison. Chronic subacute central nervous system damage in the absence of an overt stroke is a distressingly common phenomenon beginning in early childhood. Modern functional imaging techniques have pinpointed circulatory dysfunction due to a likely CNS sickle vasculopathy; these changes correlate with an array of cognitive and behavioral abnormalities in children and young adults. It is important to be aware of these often subtle changes because they can complicate clinical management or be misinterpreted as “difficult patient” behaviors.


InternalMed_Harrison

InternalMed_Harrison. Sickle cell syndromes are remarkable for their clinical heterogeneity. Some patients remain virtually asymptomatic into or even through adult life, while others suffer repeated crises requiring hospitalization from early childhood. Patients with sickle thalassemia and sickle-HbE tend to have similar, slightly milder symptoms, perhaps because of the ameliorating effects of production of other hemoglobins within the RBC. Hemoglobin SC disease, one of the more common variants of sickle cell anemia, is frequently marked by lesser degrees of hemolytic anemia and a greater propensity for the development of retinopathy and aseptic necrosis of bones. In most respects, however, the clinical manifestations resemble sickle cell anemia. Some rare hemoglobin variants actually aggravate the sickling phenomenon.


InternalMed_Harrison

InternalMed_Harrison. The clinical variability in different patients inheriting the same disease-causing mutation (sickle hemoglobin) has made sickle cell disease the focus of efforts to identify modifying genetic polymorphisms in other genes that might account for the heterogeneity. The complexity of the data obtained thus far has dampened the expectation that genome-wide analysis will yield individualized profiles that predict a patient's clinical course. Nevertheless, a number of interesting patterns have emerged from these modifying gene analyses. For example, genes affecting the inflammatory response or cytokine expression appear to be modifying candidates. Genes that affect transcriptional regulation of lymphocytes may also be involved.


InternalMed_Harrison

InternalMed_Harrison. Clinical Manifestations of Sickle Cell Trait Sickle cell trait is often asymptomatic. Anemia and painful crises are rare. An uncommon but highly distinctive symptom is painless hematuria often occurring in adolescent males, probably due to papillary necrosis. Isosthenuria is a more common manifestation of the same process. Sloughing of papillae with urethral obstruction has been reported, as have isolated cases of massive sickling or sudden death due to exposure to high altitudes or extremes of exercise and dehydration. Avoidance of dehydration or extreme physical stress should be advised.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis Sickle cell syndromes are suspected on the basis of hemolytic anemia, RBC morphology (Fig. 127-4), and intermittent episodes of ischemic pain. Diagnosis is confirmed by hemoglobin electrophoresis, mass spectroscopy, and the sickling tests already discussed. Thorough characterization of the exact hemoglobin profile of the patient is important, because sickle thalassemia and hemoglobin SC disease have distinct prognoses or clinical features. Diagnosis is usually established in childhood, but occasional patients, often with compound heterozygous states, do not develop symptoms until the onset of puberty, pregnancy, or early adult life. Genotyping of family members and potential parental partners is critical for genetic counseling. Details of the childhood history establish prognosis and need for aggressive or experimental therapies. Factors associated with increased morbidity and reduced survival include more than three crises requiring hospitalization per year, chronic


InternalMed_Harrison

InternalMed_Harrison. and need for aggressive or experimental therapies. Factors associated with increased morbidity and reduced survival include more than three crises requiring hospitalization per year, chronic neutrophilia, a history of splenic sequestration or hand-foot syndrome, and second episodes of acute chest syndrome. Patients with a history of cerebrovascular accidents are at higher risk for repeated episodes and require partial exchange transfusion and especially close monitoring using Doppler carotid flow measurements. Patients with severe or repeated episodes of acute chest syndrome may need lifelong transfusion support, using partial exchange transfusion, if possible.


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InternalMed_Harrison. FIGURE 127-4 Sickle cell anemia. The elongated and crescent-shaped red blood cells seen on this smear represent circulating irreversibly sickled cells. Target cells and a nucleated red blood cell are also seen. Patients with sickle cell syndromes require ongoing continuity of care. Familiarity with the pattern of symptoms provides the best safeguard against excessive use of the emergency room, hospitalization, and habituation to addictive narcotics. Additional preventive measures include regular slit-lamp examinations to monitor development of retinopathy; antibiotic prophylaxis appropriate for splenectomized patients during dental or other invasive procedures; and vigorous oral hydration during or in anticipation of periods of extreme exercise, exposure to heat or cold, emotional stress, or infection. Pneumococcal and Haemophilus influenzae vaccines are less effective in splenectomized individuals. Thus, patients with sickle cell anemia should be vaccinated early in life.


InternalMed_Harrison

InternalMed_Harrison. The management of an acute painful crisis includes vigorous hydration, thorough evaluation for underlying causes (such as infection), and aggressive analgesia administered by a standing order and/or patient-controlled analgesia (PCA) pump. Morphine (0.1–0.15 mg/kg every 3–4 h) should be used to control severe pain. Bone pain may respond as well to ketorolac (30–60 mg initial dose, then 15–30 mg every 6–8 h). Inhalation of nitrous oxide can provide short-term pain relief, but great care must be exercised to avoid hypoxia and respiratory depression. Nitrous oxide also elevates O2 affinity, reducing O2 delivery to tissues. Its use should be restricted to experts. Many crises can be managed at home with oral hydration and oral analgesia. Use of the emergency room should be reserved for especially severe symptoms or circumstances in which other processes, e.g., infection, are strongly suspected. Nasal oxygen should be used as appropriate to protect arterial saturation. Most crises resolve


InternalMed_Harrison

InternalMed_Harrison. severe symptoms or circumstances in which other processes, e.g., infection, are strongly suspected. Nasal oxygen should be used as appropriate to protect arterial saturation. Most crises resolve in 1–7 days. Use of blood transfusion should be reserved for extreme cases: transfusions do not shorten the duration of the crisis.


InternalMed_Harrison

InternalMed_Harrison. No tests are definitive to diagnose acute painful crisis. Critical to good management is an approach that recognizes that most patients reporting crisis symptoms do indeed have crisis or another significant medical problem. Diligent diagnostic evaluation for underlying causes is imperative, even though these are found infrequently. In adults, the possibility of aseptic necrosis or sickle arthropathy must be considered, especially if pain and immobility become repeated or chronic at a single site. Nonsteroidal anti-inflammatory agents are often effective for sickle cell arthropathy. Acute chest syndrome is a medical emergency that may require management in an intensive care unit. Hydration should be monitored carefully to avoid the development of pulmonary edema, and oxygen therapy should be especially vigorous for protection of


InternalMed_Harrison

InternalMed_Harrison. Disorders of Hemoglobin 636 arterial saturation. Diagnostic evaluation for pneumonia and pulmonary embolism should be especially thorough, since these may occur with atypical symptoms. Critical interventions are transfusion to maintain a hematocrit >30, and emergency exchange transfusion if arterial saturation drops to <90%. As patients with sickle cell syndrome increasingly survive into their fifth and sixth decades, end-stage renal failure and pulmonary hypertension are becoming increasingly prominent causes of end-stage morbidity. A sickle cell cardiomyopathy and/or premature coronary artery disease may compromise cardiac function in later years. Sickle cell patients have received kidney transplants, but they often experience an increase in the frequency and severity of crises, possibly due to increased infection as a consequence of immunosuppression. The most significant advance in the therapy of sickle cell anemia has been the introduction of hydroxyurea as a mainstay of therapy


InternalMed_Harrison

InternalMed_Harrison. due to increased infection as a consequence of immunosuppression. The most significant advance in the therapy of sickle cell anemia has been the introduction of hydroxyurea as a mainstay of therapy for patients with severe symptoms. Hydroxyurea (10–30 mg/kg per day) increases fetal hemoglobin and may also exert beneficial effects on RBC hydration, vascular wall adherence, and suppression of the granulocyte and reticulocyte counts; dosage is titrated to maintain a white cell count between 5000 and 8000/μL. White cells and reticulocytes may play a major role in the pathogenesis of sickle cell crisis, and their suppression may be an important side benefit of hydroxyurea therapy. Hydroxyurea should be considered in patients experiencing repeated episodes of acute chest syndrome or with more than three crises per year requiring hospitalization. The utility of this agent for reducing the incidence of other complications (priapism, retinopathy) is under evaluation, as are the long-term side


InternalMed_Harrison

InternalMed_Harrison. three crises per year requiring hospitalization. The utility of this agent for reducing the incidence of other complications (priapism, retinopathy) is under evaluation, as are the long-term side effects. To date, however, minimal risk of bone marrow dyscrasias or other neoplasms has been documented. Hydroxyurea offers broad benefits to most patients whose disease is severe enough to impair their functional status, and it may improve survival. HbF levels increase in most patients within a few months. The antitumor drug 5-azacytidine was the first agent found to elevate HbF. It never achieved widespread use because of concerns about acute toxicity and carcinogenesis. However, low doses of the related agent 5-deoxyazacytidine (decitabine) can elevate HbF with more acceptable toxicity. Bone marrow transplantation can provide definitive cures but is known to be effective and safe only in children. Clinical trials studying partially myeloablative conditioning regimens (“mini” transplants)


InternalMed_Harrison

InternalMed_Harrison. marrow transplantation can provide definitive cures but is known to be effective and safe only in children. Clinical trials studying partially myeloablative conditioning regimens (“mini” transplants) are likely to support more widespread use of this modality in older patients. Prognostic features justifying bone marrow transplant are the presence of repeated crises early in life, a high neutrophil count, or the development of hand-foot syndrome. Children at risk for stroke can now be identified through the use of Doppler ultrasound techniques. Prophylactic exchange transfusion appears to substantially reduce the risk of stroke in this population. Children who do suffer a cerebrovascular accident should be maintained for at least 3–5 years on a program of vigorous exchange transfusion, as the risk of second strokes is extremely high. Gene therapy for sickle cell anemia is being intensively pursued, but no safe measures are currently available. The development of newer methods of direct


InternalMed_Harrison

InternalMed_Harrison. risk of second strokes is extremely high. Gene therapy for sickle cell anemia is being intensively pursued, but no safe measures are currently available. The development of newer methods of direct gene correction in situ (e.g., zinc finger nucleases, or “CRISPR” [clustered regularly interspaced short palindromic repeats] technology) could well find clinical use in these patients. Experimental methods of derepressing HbF by interfering with Bcl11a are also being explored.


InternalMed_Harrison

InternalMed_Harrison. Amino acid substitutions that reduce solubility or increase susceptibility to oxidation result in unstable hemoglobins that precipitate, forming inclusion bodies injurious to the RBC membrane. Representative mutations are those that interfere with contact points between the α and β subunits (e.g., Hb Philly [β35Tyr→Phe]), alter the helical segments (e.g., Hb Genova [β28Leu→Pro]), or disrupt interactions of the hydrophobic pockets of the globin subunits with heme (e.g., Hb Köln [β98Val→Met]) (Table 127-3). The inclusions, called Heinz bodies, are clinically aSee text for details. detectable by staining with supravital dyes such as crystal violet. Removal of these inclusions by the spleen generates pitted, rigid cells that have shortened life spans, producing hemolytic anemia of variable severity, sometimes requiring chronic transfusion support. Splenectomy may be needed to correct the anemia. Leg ulcers and premature gallbladder disease due to bilirubin loading are frequent stigmata.


InternalMed_Harrison

InternalMed_Harrison. Unstable hemoglobins occur sporadically, often by spontaneous new mutations. Heterozygotes are often symptomatic because a significant Heinz body burden can develop even when the unstable variant accounts for only a portion of the total hemoglobin. Symptomatic unstable hemoglobins tend to be β-globin variants, because sporadic mutations affecting only one of the four α globins alleles would generate only 20–30% abnormal hemoglobin.


InternalMed_Harrison

InternalMed_Harrison. High-affinity hemoglobins (e.g., Hb Yakima [β99Asp→His]) bind oxygen more readily but deliver less O2 to tissues at normal capillary Po2 levels (Fig. 127-2). Mild tissue hypoxia ensues, stimulating RBC production and erythrocytosis (Table 127-3). In extreme cases, the hematocrits can rise to 60–65%, increasing blood viscosity and producing typical symptoms (headache, somnolence, or dizziness). Phlebotomy may be required. Typical mutations alter interactions within the heme pocket or disrupt the Bohr effect or salt-bond site. Mutations that impair the interaction of HbA with 2,3-BPG can increase O2 affinity because 2,3-BPG binding lowers O2 affinity.


InternalMed_Harrison

InternalMed_Harrison. Low-affinity hemoglobins (e.g., Hb Kansas [β102Asn→Lys]) bind sufficient oxygen in the lungs, despite their lower oxygen affinity, to achieve nearly full saturation. At capillary oxygen tensions, they lose sufficient amounts of oxygen to maintain homeostasis at a low hematocrit (Fig. 127-2) (pseudoanemia). Capillary hemoglobin desaturation can also be sufficient to produce clinically apparent cyanosis. Despite these findings, patients usually require no specific treatment. Methemoglobin is generated by oxidation of the heme iron moieties to the ferric state, causing a characteristic bluish-brown muddy color resembling cyanosis. Methemoglobin has such high oxygen affinity that virtually no oxygen is delivered. Levels >50–60% are often fatal.


InternalMed_Harrison

InternalMed_Harrison. Congenital methemoglobinemia arises from globin mutations that stabilize iron in the ferric state (e.g., HbM Iwata [α87His→Tyr], Table 127-3) or from mutations that impair the enzymes that reduce met-hemoglobin to hemoglobin (e.g., methemoglobin reductase, NADP diaphorase). Acquired methemoglobinemia is caused by toxins that oxidize heme iron, notably nitrate and nitrite-containing compounds, including drugs commonly used in cardiology and anesthesiology. DIAGNOSIS AND MANAGEMENT OF PATIENTS WITH UNSTABLE HEMOGLOBINS, HIGH-AFFINITY HEMOGLOBINS, AND METHEMOGLOBINEMIA


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InternalMed_Harrison. DIAGNOSIS AND MANAGEMENT OF PATIENTS WITH UNSTABLE HEMOGLOBINS, HIGH-AFFINITY HEMOGLOBINS, AND METHEMOGLOBINEMIA Unstable hemoglobin variants should be suspected in patients with nonimmune hemolytic anemia, jaundice, splenomegaly, or premature biliary tract disease. Severe hemolysis usually presents during infancy as neonatal jaundice or anemia. Milder cases may present in adult life with anemia or only as unexplained reticulocytosis, hepatosplenomegaly, premature biliary tract disease, or leg ulcers. Because spontaneous mutation is common, family history of anemia may be absent. The peripheral blood smear often shows anisocytosis, abundant cells with punctate inclusions, and irregular shapes (i.e., poikilocytosis).


InternalMed_Harrison

InternalMed_Harrison. The two best tests for diagnosing unstable hemoglobins are the Heinz body preparation and the isopropanol or heat stability test. Many unstable Hb variants are electrophoretically silent. A normal electrophoresis does not rule out the diagnosis. Mass spectroscopy or direct gene analysis will provide a definitive diagnosis. Severely affected patients may require transfusion support for the first 3 years of life, because splenectomy before age 3 is associated with a significantly higher immune deficit. Splenectomy is usually effective thereafter, but occasional patients may require lifelong transfusion support. After splenectomy, patients can develop cholelithiasis and leg ulcers, hypercoagulable states, and susceptibility to overwhelming sepsis. Splenectomy should thus be avoided or delayed unless it is the only alternative. Precipitation of unstable hemoglobins is aggravated by oxidative stress, e.g., infection and antimalarial drugs, which should be avoided where possible.


InternalMed_Harrison

InternalMed_Harrison. High-O2 affinity hemoglobin variants should be suspected in patients with erythrocytosis. The best test for confirmation is measurement of the P50. A high-O2 affinity hemoglobin causes a significant left shift (i.e., lower numeric value of the P50); confounding conditions, e.g., tobacco smoking or carbon monoxide exposure, can also lower the P 50.


InternalMed_Harrison

InternalMed_Harrison. High-affinity hemoglobins are often asymptomatic; rubor or plethora may be telltale signs. When the hematocrit approaches 60%, symptoms of high blood viscosity and sluggish flow (headache, lethargy, dizziness, etc.) may be present. These persons may benefit from judicious phlebotomy. Erythrocytosis represents an appropriate attempt to compensate for the impaired oxygen delivery by the abnormal variant. Overzealous phlebotomy may stimulate increased erythropoiesis or aggravate symptoms by thwarting this compensatory mechanism. The guiding principle of phlebotomy should be to improve oxygen delivery by reducing blood viscosity and increasing blood flow rather than restoration of a normal hematocrit. Phlebotomy-induced modest iron deficiency may aid in control.


InternalMed_Harrison

InternalMed_Harrison. Low-affinity hemoglobins should be considered in patients with cyanosis or a low hematocrit with no other reason apparent after thorough evaluation. The P50 test confirms the diagnosis. Counseling and reassurance are the interventions of choice. Methemoglobin should be suspected in patients with hypoxic symptoms who appear cyanotic but have a Pao2 sufficiently high that hemoglobin should be fully saturated with oxygen. A history of nitrite or other oxidant ingestions may not always be available; some exposures may be inapparent to the patient, and others may result from suicide attempts. The characteristic muddy appearance of freshly drawn blood can be a critical clue. The best diagnostic test is methemoglobin assay, which is usually available on an emergency basis.


InternalMed_Harrison

InternalMed_Harrison. Methemoglobinemia often causes symptoms of cerebral ischemia at levels >15%; levels >60% are usually lethal. Intravenous injection of 1 mg/kg of methylene blue is effective emergency therapy. Milder cases and follow-up of severe cases can be treated orally with methylene blue (60 mg three to four times each day) or ascorbic acid (300–600 mg/d). The thalassemia syndromes are inherited disorders of αor β-globin biosynthesis. The reduced supply of globin diminishes production of hemoglobin tetramers, causing hypochromia and microcytosis. Unbalanced accumulation of α and β subunits occurs because the synthesis of the unaffected globins proceeds at a normal rate. Unbalanced chain accumulation dominates the clinical phenotype. Clinical severity varies widely, depending on the degree to which the synthesis of the affected globin is impaired, altered synthesis of other globin chains, and coinheritance of other abnormal globin alleles.


InternalMed_Harrison

InternalMed_Harrison. Mutations causing thalassemia can affect any step in the pathway of globin gene expression: transcription, processing of the mRNA precursor, translation, and posttranslational metabolism of the β-globin polypeptide chain. The most common forms arise from mutations that derange splicing of the mRNA precursor or prematurely terminate translation of the mRNA. FIGURE 127-5 β Thalassemia intermedia. Microcytic and hypochromic red blood cells are seen that resemble the red blood cells of severe iron-deficiency anemia. Many elliptical and teardrop-shaped red blood cells are noted.


InternalMed_Harrison

InternalMed_Harrison. Hypochromia and microcytosis characterize all forms of β thalassemia because of the reduced amounts of hemoglobin tetramers (Fig. 127-5). In heterozygotes (β thalassemia trait), this is the only abnormality seen. Anemia is minimal. In more severe homozygous states, unbalanced αand β-globin accumulation causes accumulation of highly insoluble unpaired α chains. They form toxic inclusion bodies that kill developing erythroblasts in the marrow. Few of the proerythroblasts beginning erythroid maturation survive. The surviving RBCs bear a burden of inclusion bodies that are detected in the spleen, shortening the RBC life span and producing severe hemolytic anemia. The resulting profound anemia stimulates erythropoietin release and compensatory erythroid hyperplasia, but the marrow response is sabotaged by the ineffective erythropoiesis. Anemia persists. Erythroid hyperplasia can become exuberant and produce masses of extramedullary erythropoietic tissue in the liver and spleen.


InternalMed_Harrison

InternalMed_Harrison. Massive bone marrow expansion deranges growth and development. Children develop characteristic “chipmunk” facies due to maxillary marrow hyperplasia and frontal bossing. Thinning and pathologic fracture of long bones and vertebrae may occur due to cortical invasion by erythroid elements and profound growth retardation. Hemolytic anemia causes hepatosplenomegaly, leg ulcers, gallstones, and high-output congestive heart failure. The conscription of caloric resources to support erythropoiesis leads to inanition, susceptibility to infection, endocrine dysfunction, and in the most severe cases, death during the first decade of life. Chronic transfusions with RBCs improve oxygen delivery, suppress the excessive ineffective erythropoiesis, and prolong life, but the inevitable side effects, notably iron overload, often prove fatal by age 30 years.


InternalMed_Harrison

InternalMed_Harrison. Severity is highly variable. Known modulating factors are those that ameliorate the burden of unpaired α-globin inclusions. Alleles associated with milder synthetic defects and coinheritance of α thalassemia trait reduce clinical severity by reducing accumulation of excess α globin. HbF persists to various degrees in β thalassemias. γ-Globin gene chains can substitute for β chains, generating more hemoglobin and reducing the burden of α-globin inclusions. The terms β thalassemia major and β thalassemia intermedia are used to reflect the clinical heterogeneity. Patients with β thalassemia major require intensive transfusion support to survive. Patients with β thalassemia intermedia have a somewhat milder phenotype and can survive without transfusion. The terms β thalassemia minor and β thalassemia trait describe asymptomatic heterozygotes for β thalassemia.


InternalMed_Harrison

InternalMed_Harrison. The four classic α thalassemias, most common in Asians, are α thalassemia-2 trait, in which one of the four α-globin loci is deleted; Disorders of Hemoglobin Hemoglobin Hemoglobin H Hemoglobin Level, vive without chronic hypertransfusion. Condition A, % (β4), % g/L (g/dL) MCV, fL Management is particularly challenging


InternalMed_Harrison

InternalMed_Harrison. Normal Silent thalassemia: −α/αα Thalassemia trait: or −−/αα heterozygous α-thal-1a Hemoglobin H disease: 1/α-thal-2 Hydrops fetalis: −−/−− homozygous α-thal-1 90 because a number of factors can aggra 90 vate the anemia, including infection, 70–80 onset of puberty, and development of splenomegaly and hypersplenism. Some patients may eventually benefit from splenectomy. The expanded erythron 60–70 can cause absorption of excessive dietary iron and hemosiderosis, even without transfusion. Some patients eventually become transfusion dependent. β Thalassemia minor (i.e., thalas aWhen both α alleles on one chromosome are deleted, the locus is called α-thal-1; when only a single α allele on one chromo-semia trait) usually presents as profound some is deleted, the locus is called α-thal-2. b90–95% of the hemoglobin is hemoglobin Barts (tetramers of γ chains). microcytosis and hypochromia with tar α thalassemia-1 trait, with two deleted loci; HbH disease, with three loci deleted; and hydrops


InternalMed_Harrison

InternalMed_Harrison. of the hemoglobin is hemoglobin Barts (tetramers of γ chains). microcytosis and hypochromia with tar α thalassemia-1 trait, with two deleted loci; HbH disease, with three loci deleted; and hydrops fetalis with Hb Barts, with all four loci deleted (Table 127-4). Nondeletion forms of α thalassemia also exist.


InternalMed_Harrison

InternalMed_Harrison. α Thalassemia-2 trait is an asymptomatic, silent carrier state. α Thalassemia-1 trait resembles β thalassemia minor. Offspring doubly heterozygous for α thalassemia-2 and α thalassemia-1 exhibit a more severe phenotype called HbH disease. Heterozygosity for a deletion that removes both genes from the same chromosome (cis deletion) is common in Asians and in those from the Mediterranean region, as is homozygosity for α thalassemia-2 (trans deletion). Both produce asymptomatic hypochromia and microcytosis.


InternalMed_Harrison

InternalMed_Harrison. In HbH disease, HbA production is only 25–30% normal. Fetuses accumulate some unpaired γ chains (Hb Barts; γ-chain tetramers). In adults, unpaired β chains accumulate and are soluble enough to form β4 tetramers called HbH. HbH forms few inclusions in erythroblasts and precipitates in circulating RBC. Patients with HbH disease have thalassemia intermedia characterized by moderately severe hemolytic anemia but milder ineffective erythropoiesis. Survival into midadult life without transfusions is common.


InternalMed_Harrison

InternalMed_Harrison. The homozygous state for the α thalassemia-1 cis deletion (hydrops fetalis) causes total absence of α-globin synthesis. No physiologically useful hemoglobin is produced beyond the embryonic stage. Excess γ globin forms tetramers called Hb Barts (γ4), which has a very high oxygen affinity. It delivers almost no O2 to fetal tissues, causing tissue asphyxia, edema (hydrops fetalis), congestive heart failure, and death in utero. α Thalassemia-2 trait is common (15–20%) among people of African descent. The cis α thalassemia-1 deletion is almost never seen, however. Thus, α thalassemia-2 and the trans form of α thalassemia-1 are very common, but HbH disease and hydrops fetalis are rare. It has been known for some time that some patients with myelodysplasia or erythroleukemia produce RBC clones containing HbH. This phenomenon is due to mutations in the ATRX pathway that affect the LCR of the α-globin gene cluster.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of β-thalassemia major is readily made during childhood on the basis of severe anemia accompanied by the characteristic signs of massive ineffective erythropoiesis: hepatosplenomegaly, profound microcytosis, a characteristic blood smear (Fig. 127-5), and elevated levels of HbF, HbA2, or both. Many patients require chronic hypertransfusion therapy designed to maintain a hematocrit of at least 27–30% so that erythropoiesis is suppressed. Splenectomy is required if the annual transfusion requirement (volume of RBCs per kilogram of body weight per year) increases by >50%. Folic acid supplements may be useful. Vaccination with Pneumovax in anticipation of eventual splenectomy is advised, as is close monitoring for infection, leg ulcers, and biliary tract disease. Many patients develop endocrine deficiencies as a result of iron overload. Early endocrine evaluation is required for glucose intolerance, thyroid dysfunction, and delayed onset of puberty or secondary sexual


InternalMed_Harrison

InternalMed_Harrison. develop endocrine deficiencies as a result of iron overload. Early endocrine evaluation is required for glucose intolerance, thyroid dysfunction, and delayed onset of puberty or secondary sexual characteristics.


InternalMed_Harrison

InternalMed_Harrison. get cells, but only minimal or mild ane mia. The mean corpuscular volume is rarely >75 fL; the hematocrit is rarely <30–33%. Hemoglobin analysis classically reveals an elevated HbA2 (3.5–7.5%), but some forms are associated with normal HbA2 and/or elevated HbF. Genetic counseling and patient education are essential. Patients with β thalassemia trait should be warned that their blood picture resembles iron deficiency and can be misdiagnosed. They should eschew empirical use of iron, yet iron deficiency requiring replacement therapy can develop during pregnancy or from chronic bleeding.


InternalMed_Harrison

InternalMed_Harrison. Persons with α thalassemia trait may exhibit mild hypochromia and microcytosis usually without anemia. HbA2 and HbF levels are normal. Affected individuals usually require only genetic counseling. HbH disease resembles β thalassemia intermedia, with the added complication that the HbH molecule behaves like moderately unstable hemoglobin. Patients with HbH disease should undergo splenectomy if excessive anemia or a transfusion requirement develops. Oxidative drugs should be avoided. Iron overload leading to death can occur in more severely affected patients. Antenatal diagnosis of thalassemia syndromes is now widely available. DNA diagnosis is based on polymerase chain reaction (PCR) amplification of fetal DNA, obtained by amniocentesis or chorionic villus biopsy followed by hybridization to allele-specific oligonucleotide probes or direct DNA sequencing. Thalassemic structural variants are characterized by both defective synthesis and abnormal structure.


InternalMed_Harrison

InternalMed_Harrison. Thalassemic structural variants are characterized by both defective synthesis and abnormal structure. Hb Lepore [α2(δβ)2] arises by an unequal crossover and recombination event that fuses the proximal end of the δ-gene with the distal end of the closely linked β-gene. It is common in the Mediterranean basin. The resulting chromosome contains only the fused δβ gene. The Lepore (δβ) globin is synthesized poorly because the fused gene is under the control of the weak δ-globin promoter. Hb Lepore alleles have a phenotype like β thalassemia, except for the added presence of 2–20% Hb Lepore. Compound heterozygotes for Hb Lepore and a classic β thalassemia allele may also have severe thalassemia.


InternalMed_Harrison

InternalMed_Harrison. HbE (i.e., α2β226Glu→Lys) is extremely common in Cambodia, Thailand, and Vietnam. The gene has become far more prevalent in the United States as a result of immigration of Asian persons, especially in California, where HbE is the most common variant detected. HbE is mildly unstable but not enough to affect RBC life span significantly. Heterozygotes resemble individuals with a mild β-thalassemia trait. Homozygotes have somewhat more marked abnormalities but are asymptomatic. Compound heterozygotes for HbE and a β thalassemia gene can have β thalassemia intermedia or β thalassemia major, depending on the severity of the coinherited thalassemic gene.


InternalMed_Harrison

InternalMed_Harrison. HbE and a β thalassemia gene can have β thalassemia intermedia or β thalassemia major, depending on the severity of the coinherited thalassemic gene. The βE allele contains a single base change in codon 26 that causes the amino acid substitution. This mutation also activates a cryptic RNA splice site, generating a structurally abnormal globin mRNA that cannot be translated, from about 50% of the initial pre-mRNA molecules. The remaining 40–50% are normally spliced and generate functional mRNA that is translated into βE-globin because the mature mRNA carries the base change that alters codon 26. Genetic counseling of the persons at risk for HbE should focus especially on the interaction of HbE with β thalassemia, because HbE homozygosity is a condition associated with mildly asymptomatic microcytosis, hypochromia, and hemoglobin levels rarely <100 g/L (<10 g/dL).


InternalMed_Harrison

InternalMed_Harrison. HPFH is characterized by continued synthesis of high levels of HbF in adult life. No deleterious effects are apparent, even when all of the hemoglobin produced is HbF. These rare patients demonstrate convincingly that prevention or reversal of the fetal to adult hemoglobin switch would provide effective therapy for sickle cell anemia and β thalassemia. The two most important acquired hemoglobinopathies are carbon monoxide poisoning and methemoglobinemia (see above). Carbon monoxide has a higher affinity for hemoglobin than does oxygen; it can replace oxygen and diminish O2 delivery. Chronic elevation of carboxyhemoglobin levels to 10 or 15%, as occurs in smokers, can lead to secondary polycythemia. Carboxyhemoglobin is cherry red in color and masks the development of cyanosis usually associated with poor O2 delivery to tissues.


InternalMed_Harrison

InternalMed_Harrison. Abnormalities of hemoglobin biosynthesis have also been described in blood dyscrasias. In some patients with myelodysplasia, erythroleukemia, or myeloproliferative disorders, elevated HbF or a mild form of HbH disease may also be seen. The abnormalities are not severe enough to alter the course of the underlying disease.


InternalMed_Harrison

InternalMed_Harrison. Chronic blood transfusion can lead to bloodborne infection, alloimmunization, febrile reactions, and lethal iron overload (Chap. 138e). A unit of packed RBCs contains 250–300 mg iron (1 mg/mL). The iron assimilated by a single transfusion of 2 units of packed RBCs is thus equal to a 1to 2-year oral intake of iron. Iron accumulates in chronically transfused patients because no mechanisms exist for increasing iron excretion: an expanded erythron causes especially rapid development of iron overload because accelerated erythropoiesis promotes excessive absorption of dietary iron. Vitamin C should not be supplemented because it generates free radicals in iron excess states.


InternalMed_Harrison

InternalMed_Harrison. Patients who receive >100 units of packed RBCs usually develop hemosiderosis. The ferritin level rises, followed by early endocrine dysfunction (glucose intolerance and delayed puberty), cirrhosis, and cardiomyopathy. Liver biopsy shows both parenchymal and reticuloendothelial iron. The superconducting quantum-interference device (SQUID) is accurate at measuring hepatic iron but not widely available. Cardiac toxicity is often insidious. Early development of pericarditis is followed by dysrhythmia and pump failure. The onset of heart failure is ominous, often presaging death within a year (Chap. 428).


InternalMed_Harrison

InternalMed_Harrison. The decision to start long-term transfusion support should also prompt one to institute therapy with iron-chelating agents. Deferoxamine (Desferal) is for parenteral use. Its iron-binding kinetics require chronic slow infusion via a metering pump. The constant presence of the drug improves the efficiency of chelation and pro-639 tects tissues from occasional releases of the most toxic fraction of iron—low-molecular-weight iron—which may not be sequestered by protective proteins.


InternalMed_Harrison

InternalMed_Harrison. Deferoxamine is relatively nontoxic. Occasional cataracts, deafness, and local skin reactions, including urticaria, occur. Skin reactions can usually be managed with antihistamines. Negative iron balance can be achieved, even in the face of a high transfusion requirement, but this alone does not prevent long-term morbidity and mortality in chronically transfused patients. Irreversible end-organ deterioration develops at relatively modest levels of iron overload, even if symptoms do not appear for many years thereafter. To enjoy a significant survival advantage, chelation must begin before 5–8 years of age in β thalassemia major.


InternalMed_Harrison

InternalMed_Harrison. Deferasirox is an oral iron-chelating agent. Single daily doses of 20–30 mg/kg deferasirox produced reductions in liver iron concentration comparable to deferoxamine in long-term transfused adult and pediatric patients. Deferasirox produces some elevations in liver enzymes and slight but persistent increases in serum creatinine, without apparent clinical consequence. Other toxicities are similar to those of deferoxamine. Its toxicity profile is acceptable, although long-term effects are still being evaluated. BONE MARROW TRANSPLANTATION, GENE THERAPY, AND MANIPULATION OF HbF


InternalMed_Harrison

InternalMed_Harrison. BONE MARROW TRANSPLANTATION, GENE THERAPY, AND MANIPULATION OF HbF Bone marrow transplantation provides stem cells able to express normal hemoglobin; it has been used in a large number of patients with β thalassemia and a smaller number of patients with sickle cell anemia. Early in the course of disease, before end-organ damage occurs, transplantation is curative in 80–90% of patients. In highly experienced centers, the treatment-related mortality is <10%. Because survival into adult life is possible with conventional therapy, the decision to transplant is best made in consultation with specialized centers. Gene therapy of thalassemia and sickle cell disease has proved to be an elusive goal, but experimental advances are raising expectations.


InternalMed_Harrison

InternalMed_Harrison. Gene therapy of thalassemia and sickle cell disease has proved to be an elusive goal, but experimental advances are raising expectations. Reestablishing high levels of fetal hemoglobin synthesis should ameliorate the symptoms of β-chain hemoglobinopathies. Cytotoxic agents such as hydroxyurea and cytarabine promote high levels of HbF synthesis, probably by stimulating proliferation of the primitive HbF-producing progenitor cell population (i.e., F cell progenitors). Unfortunately, this regimen has not yet been effective in β thalassemia. Butyrates stimulate HbF production, but only transiently. Pulsed or intermittent administration has been found to sustain HbF induction in the majority of patients with sickle cell disease. It is unclear whether butyrates will have similar activity in patients with β thalassemia.


InternalMed_Harrison

InternalMed_Harrison. Patients with hemolytic anemias sometimes exhibit an alarming decline in hematocrit during and immediately after acute illnesses. Bone marrow suppression occurs in almost everyone during acute and chronic inflammatory illnesses. In patients with short RBC life spans, suppression can affect RBC counts more dramatically. These hypoplastic crises are usually transient and self-correcting before intervention is required.


InternalMed_Harrison

InternalMed_Harrison. Aplastic crisis refers to a profound cessation of erythroid activity in patients with chronic hemolytic anemias. It is associated with a rapidly falling hematocrit. Episodes are usually self-limited. Aplastic crises are caused by infection with a particular strain of parvovirus, B19A. Children infected with this virus usually develop permanent immunity. Aplastic crises do not often recur and are rarely seen in adults. Management requires close monitoring of the hematocrit and reticulocyte count. If anemia becomes symptomatic, transfusion support is indicated. Most crises resolve spontaneously within 1–2 weeks. Disorders of Hemoglobin A. Victor Hoffbrand


InternalMed_Harrison

InternalMed_Harrison. Disorders of Hemoglobin A. Victor Hoffbrand The megaloblastic anemias are a group of disorders characterized by the presence of distinctive morphologic appearances of the developing red cells in the bone marrow. The marrow is usually hypercellular and the anemia is based on ineffective erythropoiesis. The cause is usually a deficiency of either cobalamin (vitamin B12) or folate, but megaloblastic anemia may occur because of genetic or acquired abnormalities that affect the metabolism of these vitamins or because of defects in DNA synthesis not related to cobalamin or folate (Table 128-1). Cobalamin and folate absorption and metabolism are described next, followed by the biochemical basis, clinical and laboratory features, causes, and treatment of megaloblastic anemia.


InternalMed_Harrison

InternalMed_Harrison. Cobalamin (vitamin B12) exists in a number of different chemical forms. All have a cobalt atom at the center of a corrin ring. In nature, the vitamin is mainly in the 2-deoxyadenosyl (ado) form, which is located in mitochondria. It is the cofactor for the enzyme methylmalonyl coenzyme A (CoA) mutase. The other major natural cobalamin is methylcobalamin, the form in human plasma and in cell cytoplasm. It is the cofactor for methionine synthase. There are also minor amounts of hydroxocobalamin to which methyland adocobalamin are converted rapidly by exposure to light.


InternalMed_Harrison

InternalMed_Harrison. Cobalamin is synthesized solely by microorganisms. Ruminants obtain cobalamin from the foregut, but the only source for humans is food of animal origin, e.g., meat, fish, and dairy products. Vegetables, fruits, and other foods of nonanimal origin are free from cobalamin unless they are contaminated by bacteria. A normal Western diet contains 5–30 μg of cobalamin daily. Adult daily losses (mainly in the urine and feces) are 1–3 μg (~0.1% of body stores), and because the body does not have the ability to degrade cobalamin, daily requirements are also about 1–3 μg. Body stores are of the order of 2–3 mg, sufficient for 3–4 years if supplies are completely cut off.