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Anemias Associated with Endocrine Disorders

Anemia commonly accompanies disorders affecting the thyroid gland, adrenal glands, parathyroid glands, gonads, or pituitary gland. In general, the anemia associated with all of these conditions is mild to moderate and produces no symptoms. In fact, the amount of circulating hemoglobin may be entirely appropriate to the needs of the organism, because the metabolic disturbance often results in reduced oxygen requirements. In most patients, these endocrine disorders begin insidiously. The early symptoms are nonspecific and include fatigue. Consequently, when the blood hemoglobin level is subnormal, the symptoms may be ascribed to the anemia, and the diagnostic studies may be directed toward the hematopoietic system. Few morphologic abnormalities are observed, and none is specific. Unless the clinician suspects and searches for endocrine disease, the diagnosis may be overlooked.

Hypothyroidism

In various reported series, anemia was observed in 21 to 60% of patients with hypothyroidism ⁽¹⁸⁶⁾ ⁽¹⁸⁷⁾ . Although hypothyroidism is more common in women than in men, anemia is more common in hypothyroid men than in hypothyroid

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women (Fig. 57.5) (Figure Not Available) ⁽¹⁸⁷⁾ . Three morphologic types of anemia have been described in adult patients ⁽¹⁸⁶⁾ ⁽¹⁸⁸⁾ ⁽¹⁸⁹⁾ ⁽¹⁹⁰⁾ ⁽¹⁹¹⁾ . The relative incidence of the three types differs considerably in three large series reported since 1960 (Table 57.3) . The reasons for the differences are not clear, but they may have been related to factors not directly concerned with the thyroid disease as well as to its degree and duration.

When hypochromic, microcytic anemia is found in association with myxedema, it almost always is attributable to iron deficiency ⁽¹⁸⁷⁾ ⁽¹⁸⁸⁾ ⁽¹⁹¹⁾ ⁽¹⁹²⁾ . Serum iron values are subnormal ⁽¹⁸⁷⁾ , and the anemia responds to iron therapy, even if thyroid hormone is not administered; it is not relieved by hormone therapy if iron is withheld. Often, iron deficiency in myxedema produces normocytic anemia. Therefore, an important step is to determine the serum iron concentration, regardless of the morphologic picture. Iron deficiency occurs in association with myxedema in part because menorrhagia is a common manifestation of the illness ⁽¹⁹³⁾ , in part because the achlorhydria found in myxedema subjects ⁽¹⁹¹⁾ may lead to impaired absorption of food iron, and in part because

Figure 57-5 (Figure Not Available) Blood hemoglobin levels in 202 patients with untreated hypothyroidism. If 13.0 g/dl and 12.0 g/dl are taken to be the lower limits of normal in men and women, respectively, then 43% of men and 23% of women were anemic. (From Horton L, et al: The haematology of hypothyroidism. Q J Med 45:101, 1976. Courtesy Oxford University Press.)

**TABLE 57-3** -- Incidence of Various Types of Anemia in Patients with Myxedema from Three Different Studies
Type of Anemia	Sheffield, England ⁽¹⁹¹⁾ (%)	University of Virginia ⁽¹⁸⁶⁾ (%)	Middlesex, England ⁽¹⁸⁷⁾ (%)
Normocytic, normochromic	4	26	13.5
Hypochromic, microcytic	14	3	4.5
Macrocytic	13	14	8
All anemias	31	43	26

thyroid hormone itself may be essential for normal iron absorption ⁽187) ⁽¹⁹⁴⁾ .

Distinctly, macrocytic anemia usually results from complicating deficiency of vitamin B₁₂ ⁽¹⁹¹⁾ or folate ⁽¹⁹⁰⁾ . The increased incidence of pernicious anemia in thyroid disease possibly is the result of an autoimmune mechanism, as discussed in Chapter 31 . Folate deficiency may develop because of an inadequate diet, but this correlation has not been established with certainty ⁽¹⁹⁰⁾ .

If the patients with iron, folate, or vitamin B₁₂ deficiency are excluded, a significant population of hypothyroid patients with anemia remains. This type of anemia constitutes the so-called uncomplicated anemia of hypothyroidism ⁽¹⁸⁶⁾ ⁽¹⁹⁰⁾ ⁽¹⁹¹⁾ , and is a manifestation of the hormone deficiency itself. All or nearly all children with anemia and hypothyroidism have the uncomplicated form of the disease ⁽¹⁹⁵⁾ . The anemia usually affects children whose height is below the third percentile.

The anemia usually is mild, the VPRC rarely falling below 0.35 L/L. The plasma volume often is decreased, however ⁽¹⁹¹⁾ ⁽¹⁹⁶⁾ ⁽¹⁹⁷⁾ , a change that tends to make the reduction in VPRC less than might be expected for a given decrease in red cell mass. The degree of anemia is related to both the severity and the duration of the hypothyroidism ⁽¹⁹⁸⁾ . The VPRC continues to fall for as long as 6 months after thyroidectomy in previously euthyroid subjects, even though the basal metabolic rate remains at a stable, reduced level.

In man, the uncomplicated anemia is either normocytic or slightly macrocytic (Fig. 57.6) (Figure Not Available) ⁽¹⁸⁶⁾ ⁽¹⁸⁷⁾ ⁽¹⁹⁰⁾ ⁽¹⁹¹⁾ . It is macrocytic in rabbits ⁽¹⁹⁹⁾ and rats ⁽²⁰⁰⁾ ⁽²⁰¹⁾ and normocytic in dogs ⁽²⁰²⁾ . The MCV may be increased in hypothyroid patients, even in the absence of anemia (Fig. 57.6) (Figure Not Available) ⁽¹⁸⁷⁾ . Anisocytosis, poikilocytosis, or other red cell morphologic abnormalities are not impressive, but acanthocytes are apparent in about 20% of patients ⁽¹⁸⁷⁾ . Usually the leukocyte and platelet counts are within the normal range, although both may be slightly reduced ⁽¹⁹⁸⁾ . The bone marrow may be mildly hypoplastic, but the M:E ratio is not significantly altered ⁽²⁰³⁾ ⁽²⁰⁴⁾ . Hemoglobin A₂ levels are reduced slightly ⁽²⁰⁵⁾ .

From a kinetic point of view, the anemia of myxedema seems to be explained entirely by reduced red cell production. Erythrocyte survival is normal or even slightly prolonged in man ⁽²⁰⁶⁾ ⁽²⁰⁷⁾ ⁽¹⁹¹⁾ and in dogs ⁽²⁰⁸⁾ , but plasma

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Figure 57-6 (Figure Not Available) Mean corpuscular volume (MCV) in 53 patients with hypothyroidism who had normal values for serum iron, folate, and vitamin B12 concentrations. Anemic subjects are shown in black. Normal value for MCV was 80 to 90 fl, and 29 patients (55%) had values greater than 90 fl. (From Horton L, et al: The haematology of hypothyroidism. Q J Med 45:101, 1976. Courtesy Oxford University Press.)

iron transport and erythrocyte iron turnover rates are reduced, indicating subnormal red cell production ⁽²⁸⁾ ⁽²⁰²⁾ ⁽²⁰⁶⁾ .

Bomford was the first to suggest that the anemia of myxedema is adaptive, that is, a physiologic adjustment to the reduced needs of the organism for oxygen ⁽¹⁸⁸⁾ . This hypothesis has since become even more tenable because of what is now known about the erythropoietin-secreting mechanism and its relation to tissue oxygen tension (see Chapter 9 ). Also, experimental efforts have produced evidence consistent with it. For example, the marrow of the isolated, hind limb of the dog exhibits an erythropoietic response to perfusion with erythropoietin, but not to L-triiodothyronine (T3) ⁽²⁰⁹⁾ , an observation that logically leads to the suggestion that the role of the latter hormone is indirect. Furthermore, administration of 2,4-dinitrophenol, a drug that increases oxygen consumption without improving thyroid function, causes an increase in red cell mass in hypothyroid patients ⁽¹⁹⁷⁾ and in thyroidectomized rats ⁽²¹⁰⁾ . Hyperoxia can inhibit the erythropoietic response to T3 ⁽²¹¹⁾ . Finally, erythropoietin secretion is apparently reduced in hypothyroid patients ⁽²¹²⁾ and in thyroidectomized animals ⁽¹⁹⁴⁾ , and 2,3-DPG levels are not increased ⁽²¹³⁾ as occurs in most anemias and hypoxic states (see Chapter 10 ).

Thyroid hormones, however, may have direct effects on erythropoiesis as well ⁽²¹⁴⁾ . The observation that the noncalorigenic d-isomer of triiodothyronine can stimulate erythropoiesis without altering oxygen consumption has been cited as evidence of a hormonal effect that is not oxygen-dependent ⁽¹⁹⁴⁾ ⁽²⁰²⁾ ⁽²¹⁵⁾ . Thyroid hormone may act by modulating the effect of adrenergic agonists on erythropoietic stem cells in the presence of erythropoietin ⁽²¹⁶⁾ .

The response of the anemia of hypothyroidism to thyroid hormone is sluggish. Characteristically, no distinct reticulocytosis occurs, and the VPRC returns to a normal value only gradually over about a 6-month period (range, 3 to 12 months) ⁽¹⁸⁶⁾ ⁽¹⁸⁸⁾ ⁽¹⁹¹⁾ . The MCV almost invariably falls, even if anemia is not present or if the MCV is in the normal range when therapy is instituted (Fig. 57.7) (Figure Not Available) ⁽¹⁸⁷⁾ . The MCV tends to reach stable levels after about 4 months or more.

Hyperthyroidism

An unexplained, mild anemia affects about 10 to 25% of patients with hyperthyroidism ⁽²¹⁷⁾ ⁽²¹⁸⁾ . In patients who are anemic, the hyperthyroidism tends to be of unusual severity or prolonged duration ⁽²¹⁸⁾ . In a larger number of patients, the hemoglobin value falls somewhat but remains within normal limits ⁽²¹⁷⁾ . The MCV is either normal or modestly decreased, even though iron metabolism is not disturbed. Indeed, the MCV may be decreased in patients with hyperthyroidism, even in the absence of anemia ⁽²¹⁷⁾ . Hemoglobin A₂ levels are slightly increased, but not to the same degree as is noted in patients with beta thalassemia minor ⁽²⁰⁵⁾ . Both the anemia and the microcytosis are corrected when the hyperthyroidism is successfully treated; on average, the hemoglobin increases 0.5 g/dl and the MCV increases 6 fl.

The pathogenesis of the anemia and microcytosis of hyperthyroidism is not well understood. One factor may be increased plasma volume ⁽¹⁹⁷⁾ . Erythropoiesis usually is accelerated ⁽²¹⁹⁾ ⁽²²⁰⁾ , but an increase in the ineffective erythropoiesis component has been detected ⁽²¹⁸⁾ . Some investigators report increased levels of erythrocyte 2,3-DPG ⁽²²¹⁾ ⁽²²²⁾ but not all authors concur ⁽²¹³⁾ . Such a change could reduce oxygen affinity and improve oxygen delivery, thereby compensating for the reduced hemoglobin level. Increased plasma erythropoietin levels have been reported ⁽²²³⁾ .

Addison Disease

In 28 patients with untreated Addison disease, the average blood hemoglobin level was 13.2 g/dl and the range was 9.4 to 18 g/dl ⁽²²⁴⁾ . The red cells were normocytic and normochromic.

Figure 57-7 (Figure Not Available) The change in MCV in 10 hypothyroid patients after therapy with L-thyroxine. (From Horton L, et al: The haematology of hypothyroidism. Q J Med 45:101, 1976. Courtesy Oxford University Press.)

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Shortly after hormonal replacement therapy began, various measures of red cell concentration fell about 20%, the average hemoglobin from 13.7 to 10.7 g/dl and the VPRC from 0.42 to 0.33 L/L. The conclusion drawn was that the red cell mass is reduced in Addison disease patients, but that the change is partially obscured by the dehydration that usually accompanies the condition. Treatment corrected the dehydration and restored the plasma volume, thereby clarifying the true degree of anemia. Later in the course of the disease, reticulocytosis and a return to normal hemoglobin levels were observed.

After adrenalectomy, rats maintained on saline solution develop a mild anemia ⁽²²⁵⁾ ⁽²²⁶⁾ ⁽²²⁷⁾ . The blood-hemoglobin concentration drops about 1.5 g/dl in 3 weeks. The anemia is corrected by the administration of adrenal corticoids.

Hypogonadism

After puberty, values for the VPRC, blood-hemoglobin concentration, and red cell count average about 10 to 13% higher in men than in women (Appendix A). In eunuchoid or castrated men, these values fall to within the normal female range ⁽²²⁸⁾ ⁽²²⁹⁾ . Urinary erythropoietin levels in normal men are about three times those found in women ⁽²³⁰⁾ .

The differences between the sexes are accounted for chiefly by the stimulating effect of androgens on erythropoiesis. In addition, some observers suggest that estrogens exert a suppressive effect. Thus, castration of male rats precipitates a decrease in hemoglobin, whereas castration of female rats brings about an increase ⁽²³¹⁾ ⁽²³²⁾ ⁽²³³⁾ . The administration of androgens to castrated males restores male values for hemoglobin concentration. Androgens can also stimulate erythropoiesis in normal subjects. In normal men, testosterone enanthate induced an average increase in the total red cell mass from 1.7 to 2.3 liters ⁽²³⁴⁾ . The increase in VPRC was of smaller magnitude, from 0.456 to 0.494 L/L, probably because the plasma volume also increased. Androgens act by increasing renal synthesis of erythropoietin ⁽²²⁸⁾ ⁽²³⁵⁾ . Estrogens produce anemia when given in large amounts to rats ⁽²³⁶⁾ ⁽²³⁷⁾ , possibly by suppressing hepatic synthesis of erythropoietin (see Chapter 9 ). ⁽²³⁵⁾

Hypopituitarism

Moderately severe, nonprogressive anemia is a well-recognized feature of pituitary insufficiency, regardless of cause. In an extensive review of 595 reported cases of Simmonds disease published in 1942, the average blood hemoglobin concentration was ""67% of normal""(approximately 10 g/dl) ⁽²³⁸⁾ , and the range was ""21 to 103%"" (3 to 16 g/dl). Similar values were found in patients with hypopituitarism that arose from neoplasms ⁽²³⁹⁾ ⁽²⁴⁰⁾ . Anemia is also evident in prepubertal pituitary dwarfs ⁽²⁴¹⁾ ; however, the degree of reduction of circulating red cell volume may be obscured by contraction of the plasma volume ⁽²⁴²⁾ .

The anemia usually is normocytic and normochromic, and the red cells appear normal morphologically. In some patients, slight hypochromia or macrocytosis has been observed ⁽²³⁹⁾ ⁽²⁴³⁾ ; however, complicating deficiencies of iron or folate were not excluded. Results of kinetic studies demonstrate reduced red cell production ⁽²⁴¹⁾ ⁽²⁴⁴⁾ .

The anemia of hypopituitarism results chiefly from deficiencies of the hormones of target glands controlled by the pituitary, especially the thyroid and adrenal hormones, but also androgens. In addition, lack of other pituitary factors, such as growth hormone ⁽²⁴¹⁾ ⁽²⁴²⁾ ⁽²⁴⁵⁾ , prolactin ⁽²⁴⁶⁾ , or other poorly characterized pituitary principles ⁽²⁴⁷⁾ , may be of importance. The interrelations of these various hormones have been studied experimentally in animals, especially the rat. In this species, hypophysectomy results in a moderately severe, slightly hypochromic and microcytic anemia ⁽²⁴⁵⁾ ⁽²⁴⁸⁾ associated with a pronounced decrease in erythroid elements in the bone marrow ⁽²⁴⁹⁾ . No hemolysis occurs; in fact, red cell survival is prolonged ⁽¹⁹²⁾ . Combined adrenalectomy and thyroidectomy results in an anemia that is similar, but not identical, to that noted after hypophysectomy ⁽²⁴⁵⁾ ⁽²⁵⁰⁾ .

As suggested for the anemia of hypothyroidism, panhypopituitarism probably produces its effects on erythropoiesis chiefly by reducing tissue oxygen consumption ⁽²⁴⁵⁾ . The organism reacts to this decreased need for oxygen by secreting less erythropoietin, and the red cell mass diminishes until a new equilibrium between oxygen supply and demand is established. This hypothesis is supported by the observations that: (1) tissue oxygen consumption is low in the hypophysectomized rat, even if the red cell mass is restored to normal levels ⁽²⁴⁵⁾ ; (2) once equilibrium is established, the marrow of the hypophysectomized animal responds to hypoxia, bleeding, or cobalt administration ⁽²⁴⁵⁾ ⁽²⁵¹⁾ ; (3) correlation between oxygen consumption and rate of erythropoiesis is apparent in hypophysectomized animals given thyroxine or 2,4-dinitrophenol ⁽²⁴⁵⁾ ; and (4) erythrocyte 2,3-DPG levels, which increase when tissue oxygen delivery is compromised, are normal in patients with panhypopituitarism ⁽²⁴²⁾ .

Treatment with a combination of thyroxine, cortisone, and growth hormone corrects both the anemia and the marrow hypoplasia ⁽²⁴⁵⁾ , and is more effective than any single hormone given by itself. In one reported case of panhypopituitarism secondary to craniopharyngioma, anemia persisted and progressed despite replacement hormone therapy. Administration of recombinant human erythropoietin (6000 IU per day) was followed by correction of the anemia, the blood hemoglobin level rising from 6 g/dl to normal over a 3-month period ⁽²⁵²⁾ .

Hyperparathyroidism

Anemia is a rare complication of primary hyperparathyroidism ⁽²⁵³⁾ . At one institution, 17 of 332 patients (5.1%) with primary hyperparathyroidism were anemic, with hematocrit values ranging from 0.23 to 0.37 L/L ⁽²⁵⁴⁾ . None had leukopenia or thrombocytopenia. The anemia was normocytic and normochromic, and no reticulocytosis was evident. Anemic patients appeared to have relatively severe hyperparathyroidism as judged by the presence of bone cysts, subperiosteal bone resorption, and particularly high values for serum calcium, alkaline phosphatase, and parathyroid hormone. In 6 of 7 subjects whose abnormal parathyroid glands were removed, the anemia was corrected.

The cause of the anemia in these patients remains obscure. Although renal failure and gastrointestinal bleeding occur in

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association with hyperparathyroidism, they could not be implicated as an etiologic factor in this group of anemic patients, nor was incidental iron deficiency evident. Some authors conclude that parathyroid hormone decreases proliferation of erythroid precursors in culture ⁽⁵⁵⁾ . Marrow fibrosis may also be a result of excess hormone levels ⁽⁵⁶⁾ ⁽⁵⁸⁾ . Myelofibrosis is a common finding in bone marrow biopsy specimens, but the usual morphologic signs of myelophthisis are lacking ⁽²⁵³⁾ .

When hyperparathyroidism is secondary to renal disease, it is difficult to ascertain the relative importance of the hormone excess versus the erythropoietin deficit characteristic of renal failure. Of note, however, is that medical treatment of hyperparathyroidism with vitamin D3 can bring about improvement in anemia and decreased requirement for erythropoietin in some patients ⁽¹²⁵⁾ .

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