CHAPTER 34 ANEMIA OF ENDOCRINE DISORDERS
CHAPTER 34 ANEMIA OF ENDOCRINE DISORDERS
ALLAN J. ERSLEV
Anemia of Pituitary Deficiency
Anemia of Thyroid Dysfunction
Anemia of Adrenal Dysfunction
Anemia of Gonadal Dysfunction
Anemia of Pregnancy
Anemia of Parathyroid Dysfunction
Anemia of Pancreatic Dysfunction
The hormones released by specific endocrine organs all play a role in modulating the rate of red cell production. The mechanisms involved vary greatly, and current interest in unraveling single actions have been replaced by attempts to integrate the actions of multiple hormonal-like growth factors and cytokines on the sequential proliferation and differentiation of red cell precursors. Consequently, the discussion in this chapter of anemias caused by a deficiency of a single traditional hormone is by necessity more historic than current.
Acronyms and abbreviations that appear in this chapter include: ACTH, adrenocorticotrophic hormone; 2,3-BPG, 2,3-bisphosphoglycerate; TSH, thyroid-stimulating hormone.
Numerous growth factors and cytokines are involved in the regulation and function of the erythropoietic tissue (see Chap. 14). Some are autocrine and released by the same cells on which they are acting, some are paracrine and released by neighboring cells, and some are endocrine and released from distant tissue and carried by blood to their target cells. The latter are traditionally designated hormones, and the effect on red cell production of altered hormone levels in blood due to endocrine tissue dysfunction is described here.1,2 The effect of the renal hormone erythropoietin is covered in Chap. 33.
ANEMIA OF PITUITARY DEFICIENCY
Hypophysectomy in the experimental animal is regularly followed by the development of moderately severe erythroid hypoplasia and anemia.3,4 In rats, the selective removal of the posterior or intermediate lobe does not cause anemia,5 and it is generally assumed that the pathogenesis of the anemia is related to the absence of anterior lobe hormones, which in turn modulate renal erythropoietin production.6 Of these, TSH is probably of most importance, since the anemia of hypophysectomy is very similar to the anemia of thyroidectomy.7 Nevertheless, it is claimed that the rate of red cell production in hypophysectomized animals is restored to normal only if the administration of TSH is supplemented by ACTH8 or if the administration of thyroid hormone is supplemented by both glucocorticoids and androgens.3 It has been proposed repeatedly that the pituitary gland produces a specific erythropoietic hormone,9,10 but the therapeutic effectiveness of target organ hormones alone is not in accord with such a possibility. Growth hormone has been shown to be capable of stimulating red cell production in vitro,11 an effect possibly mediated by insulin-like growth factor,12 but whether this effect is of physiologic significance remains unclear.13 The same holds true for the hypothetical effect of the hypothalamus on red cell production. It has been claimed that hypothalamic injury may affect erythropoietin release,14 the rate of red cell production,15 or both,16 and it has been proposed that these effects are mediated via the hypophysis. However, the experimental data provided in support of this hypothesis are unimpressive.15,16
In human subjects, hypophyseal dysfunction or hypophyseal ablation is often associated with leukopenia and is regularly accompanied by a normochromic and normocytic anemia. The red cell life span is normal, but marrow examination and ferrokinetic studies disclose moderate hypoplasia and relative marrow failure.17,18 Replacement therapy with a combination of thyroid, adrenal, and gonadal hormones usually corrects the anemia.19,20 It is probable that treatment with recombinant human erythropoietin would also do so.
ANEMIA OF THYROID DYSFUNCTION
In 1881, Charcot21 first recognized that cretins and patients with myxedema were anemic. At about the same time, the great Swiss surgeon Kocher22 reported that thyroidectomy also is followed by a reduction in the red cell count. The character of this type of anemia has been a source of debate ever since, and it has been variously described as normocytic, microcytic, or macrocytic.23 Studies have clarified the pathogenesis by separating the component caused by a lack of thyroid hormone from the components caused by complicating deficiencies of iron, vitamin B12, or folic acid.24,25,26 The rate of red cell production in experimental animals increases after the administration of thyroxin, triiodothyronine, or desiccated thyroid27,28 and decreases after thyroidectomy.29,30 These erythropoietic responses appear to be quite appropriate, since the need for circulating red cells depends on the cellular requirements for oxygen, which in turn are influenced by thyroid hormones.23,31,32 Nevertheless, it has also been proposed that the thyroid hormones have a noncalorigenic effect on red cell production.33 Studies of the influence of thyroid hormones on in vitro erythropoiesis have shown that both calorigenic T3 and T4 and noncalorigenic rT3 potentiate the effect of erythropoietin on the formation of erythroid colonies34,35 or increasing hypoxia-induced production of erythropoietin.36 This effect appears to be mediated by burst-promoting factors released by activated lymphocytes37 and/or by receptors with b2-adrenergic properties.37 Anemia observed in thyroidectomized animals conforms to both mechanisms by being normochromic and normocytic and associated with reticulocytopenia and hypoplasia of the erythropoietic tissue in the marrow. The red cell life span is normal, and ferrokinetic studies indicate the existence of a hypofunctioning but effective marrow.38
Anemia observed in human subjects with myxedema or other hypothyroid conditions is not always this clear-cut, since the condition may be complicated by nutritional deficiencies. However, many hypothyroid patients have a hypoplastic anemia that is unresponsive to therapy with iron, vitamin B12, or folic acid and is very similar to the form of anemia observed in thyroidectomized animals.23,24,39 The degree of anemia is mild to moderate, with a hemoglobin concentration rarely less than 8 to 9 g/dl. The corresponding decrease in erythroid marrow activity is frequently too small to be morphologically demonstrable.40 Ferrokinetic studies show a decrease in the turnover of plasma and red cell iron, a decrease that also may be so small that it is first recognized when compared with values obtained after thyroid replacement therapy.41,42 As in hypothyroid animals, the red cell life span and the rate of red cell utilization of iron are normal. The degree of anemia does not always reflect the reduction in marrow activity and the size of the red cell volume, since the plasma volume is decreased in hypothyroid patients.43 This may result in a temporary aggravation of apparent anemia after thyroid replacement therapy, since the plasma volume will be restored to normal before the red cell volume. Although normochromic and normocytic anemia must be considered the characteristic form of anemia of hypothyroidism, the most frequent type of anemia observed is a microcytic, hypochromic anemia caused by iron deficiency.23,44 In hypothyroid women, menorrhagia is a frequent complication and may explain adequately the lack of iron. However, even in men, iron is in short supply either because of the histamine-refractory achlorhydria, which is present in about 50 percent of anemic patients,45 or possibly because of intestinal malabsorption of iron.46,47 Macrocytosis is frequently identified with anemia of hypothyroidism.23,39 However, when a substantial increase in the mean corpuscular volume occurs, it is usually caused by a megaloblastic erythropoiesis owing to vitamin B12 or folic acid deficiency.24 In hypothyroid patients, the incidence of true pernicious anemia with gastric atrophy and intrinsic factor deficiency appears to be unusually high.48,49,50 This has led to interesting but still inconclusive speculations on the effect of cross-reacting autoantibodies against thyroglobulins and intrinsic factor or gastric parietal cells.51,52,53 This may be of special etiologic importance for Graves’ disease and Hashimoto’s thyroiditis, both autoimmune disorders. However, in a study of eight patients with coexisting megaloblastic anemia and hypothyroidism, it was concluded that all eight, rather than having vitamin B12 deficiency, had folic acid deficiency from either poor dietary intake of folic acid or intestinal malabsorption.26
Despite the direct and indirect erythropoietic effect of thyroid hormones, patients with hyperthyroidism or thyrotoxicosis rarely have elevated hemoglobin concentrations or hematocrit percentages43,54 and may even be moderately anemic.55,56 This absence of an expected secondary polycythemia has been explained by assuming that an increased cardiac output and rate of tissue perfusion meet the increased tissue requirements for oxygen. Conflicting data have been presented as to the effect of thyroid hormone in vitro on the intracellular concentration of 2,3-BPG and, in turn, the oxygen affinity of hemoglobin.57 So far, however, direct studies of hyperthyroid patients do not suggest the presence of enhanced oxygen transport to the tissues.58 It actually seems more likely that the absence of an overt secondary polycythemia is due to hemodilution. Direct measurements of the size of the red cell volume,43 the erythroid activity of the marrow,40 and the turnover of plasma and red cell iron54 show them to be above normal. If it were not for the concomitant increase in plasma volume, these patients would have elevated hemoglobin and hematocrit levels. Studies of the red cell life span in patients with thyrotoxicosis suggest a moderate shortening in red cell survival,59 possibly reflecting an autoimmune etiology with the production of anti–red-cell antibodies.60 In a few cases, severe hyperthyroidism has been found to be associated with anemia and abnormal iron utilization, apparently reflecting ineffective red cell production,44 or the production of erythropoietin-directed antibodies.61 The institution of radioiodine therapy results in a reduction in the size of the red cell volume to normal but only a slight change in the hematocrit.
ANEMIA OF ADRENAL DYSFUNCTION
Adrenalectomy in experimental animals causes a mild anemia responsive to therapy with adrenal glucocorticoids or erythropoietin.17,29,62 A similar type of normochromic, normocytic anemia has been observed in Addison’s disease,17,63 but because of the concomitant reduction in plasma volume, the hemoglobin concentration and the hematocrit percentage do not reflect the true decrease in red cell volume. The character of this type of anemia and the erythropoietic effect of physiologic amounts of ACTH or adrenal cortical hormones are still unclear, possibly because the changes involved are too small for adequate study. When administered in pharmacologic amounts, these hormones appear to cause mild erythrocytosis64 of about the same magnitude as that observed in Cushing’s disease65,66 and occasionally in Bartter’s syndrome67 and pheochromocytoma.68 However, whether this is mediated via release of renal erythropoietin or by direct action on the erythropoietic cells in the marrow is unknown.69
ANEMIA OF GONADAL DYSFUNCTION
The erythropoietic effect of androgens in both physiologic and pharmacologic dosages is well recognized and extensively utilized in the treatment of patients with various types of refractory anemia. Castration of the male experimental animal causes a decrease in the rate of red cell production until the hemoglobin concentration and the red cell volume become stabilized at levels approximately the same as those of the normal female.70,71 In sexually mature human males, the hemoglobin level is 1 to 2 g/dl higher than the level observed in males during childhood, advanced age, orchiectomy, or gonadal hypofunction. Under those circumstances, the hemoglobin level is similar to that of the normal human female.72,73,74
In pharmacologic doses androgens have been shown to stimulate red cell production75,76 by increasing the production of erythropoietin77 and by enhancing the effect of erythropoietin on the marrow.78 These actions have been attributed to two isomeric metabolites formed by the reduction of a 4-5 double bond. The 5a-H isomer is androgenic and believed to cause a release of erythropoietin from the kidney.79 The 5b-H isomer is not androgenic or erythropoietinogenic but is believed to cause inactive marrow stem cells to enter an erythropoietin-responsive phase.80
Before being replaced by recombinant human erythropoietin in the treatment of anemia of renal failure, androgens were used extensively.81,82 Even now, androgens may enhance the effect of erythropoietin and reduce the cost of such therapy.83
Studies on the effect of physiologic doses of estrogens suggest that these hormones cause a slight suppression of red cell production.83 In large doses, estrogens have been shown to cause the development of moderately severe anemia,84,85 but it has not been resolved whether this is caused by suppressed erythropoietin production85 or by inhibition of the progenitor cell action of erythropoietin.86 Inhibin and activin, two glycoprotein hormones released by gonadal cells in both male and female, have been shown in vitro to have an effect on human erythroid progenitor cells.87,88,89 The physiologic significance of these observations is still unknown.
Human placental lactogen and sheep prolactin have been shown to have erythropoietic activity in the mouse.90 It has been proposed that human placental lactogen is in part responsible for the stimulation of red cell production in pregnancy.91
ANEMIA OF PREGNANCY
Although pregnancy is not an endocrine disorder, it is associated with a mild anemia, presumably caused by changes in the hormonal environment.92 Studies of pregnant mice have shown that, despite a progressive decrease in the hematocrit, the red cell volume, erythropoietin secretion, and rate of red cell production increase during pregnancy.90 Placental lactogen, which is erythropoietically active in the mouse,92 may in part be responsible for the erythropoietic stimulation, but the hormonal mechanisms underlying both the increase in red cell volume and the even more pronounced increase in plasma volume are not precisely known.
In humans, anemia in pregnancy is most often aggravated by dietary restrictions93 and a concomitant iron deficiency.94,95 In a smaller number of cases, folic acid deficiency may also play a pathogenetic role,96 and it seems appropriate to give every pregnant woman preventive iron and folic acid supplements. However, even in the well-cared-for pregnant woman, anemia becomes manifest at about the eighth week of pregnancy, progresses slowly until the thirty-second to thirty-fourth week, and is then stable until it rather suddenly improves just before delivery.97,98 It is moderate in severity, with hemoglobin concentrations rarely below 10 g/dl, and studies of the red cell volume have shown it to be a dilution anemia.97,98 There has been an obvious reluctance to use radioactive tracers to measure red cell and plasma volume in early pregnancy. However, using a nonradioactive biotin technique,99 it has been shown that there is a gradual increase in red cell volume beginning before the twelfth week of pregnancy. This early increase is not associated with measurable changes in the concentration of serum transferrin receptors, reticulocyte counts, or erythropoietin titers.99,100 However, in the second and third trimester, erythrokinetic studies using both radioactive iron101 and serum transferrin receptor concentrations100 have shown an increased erythropoietic activity. The associated changes in reticulocyte counts, serum ferritin concentrations, and erythropoietin titers are small and difficult to detect102 but in some studies quite significant.103,104 Despite the increase in red cell volume, the hemoglobin concentration falls as a consequence of an even greater increase in plasma volume. The total increase in red cell volume during pregnancy is about 20 percent, while the increase in plasma volume is about 30 percent. The increase in plasma volume can probably be explained on the basis of an increase in the size of the uterine vascular bed, with a shift of fluid from extravascular to vascular space.
The induction of this hypervolemia creates a low-viscosity erythrocytosis, which promotes oxygen transport to the tissues. Although the hemoglobin concentration is decreased, the hypervolemic state ensures the pregnant uterus of an excellent blood perfusion and oxygen supply.
ANEMIA OF PARATHYROID DYSFUNCTION
Primary hyperparathyroidism is occasionally105,106 associated with anemia that disappears after parathyroidectomy.107,108 Similarly, it has been reported that parathyroidectomy in chronic renal disease often results in some improvement in the anemia,109,110 and it has been suggested that the parathyroid hormone may be a toxin that can suppress normal red cell production.111,112 However, other studies have not supported this suggestion.112,113,114,115 These suggest that primary or secondary hyperparathyroidism, when associated with suppressed red cell production, acts by causing either renal calcification with reduction in erythropoietin formation or marrow sclerosis with reduction in erythroid proliferation.116
ANEMIA OF PANCREATIC DYSFUNCTION
Although insulin and the insulin-like growth factors I and II appear to be involved in expanding the red cell mass after treatment with growth hormones, there is little evidence for the notion that insulin is an erythropoietic agent.119,120
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn