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Anemia: A Cause of Intolerance to Thyroxine Sodium

      Usual causes of intolerance to thyroxine sodium include coronary artery disease, advanced age, untreated adrenal insufficiency, and severe hypothyroidism. We describe 4 patients with iron deficiency anemia and primary hypothyroidism. After treatment with thyroxine sodium, these patients developed palpitations and feelings of restlessness, which necessitated discontinuation of the thyroid hormone. After the anemia was treated with ferrous sulfate for 4 to 7 weeks, they were able to tolerate thyroxine sodium therapy. Iron deficiency anemia coexisting with primary hypothyroidism results in a hyperadrenergic state. In such patients, we postulate that thyroid hormone administration causes palpitations, nervousness, and feelings of restlessness. Correction of any existing pronounced anemia in hypothyroid patients who are intolerant to thyroxine sodium therapy may result in tolerance to this agent.
      TSH (thyroid-stimulating hormone)
      Thyroxine sodium, a commonly prescribed medication, is well tolerated by most patients. However, a small percentage of patients may manifest intolerance to this agent. Usual causes of intolerance include coronary artery disease, advanced age, untreated adrenal insufficiency, and severe hypothyroidism. Rarely, patients may develop allergic reactions, most commonly due to other ingredients contained in the tablet.
      The cardiovascular manifestations of anemia include dyspnea on exertion, fatigue, and tachycardia. The anemic state is often associated with increased cardiac output, typically when the hematocrit level is less than 27%. There is also decreased peripheral vascular resistance with anemia.
      • Varat MA
      • Adolph RJ
      • Fowler NO
      Cardiovascular effeels of anemia.
      We recently treated 4 patients with anemia and primary hypothyroidism who could not tolerate thyroxine sodium (Synthroid) until the anemia was corrected.

      Report Of Cases

      Case 1

      A 28-year-old woman was evaluated for primary hypothyroidism (thyroid-stimulating hormone [TSH], 70 mIU/L; free thyroxine, 0.3 ng/dL). She also had iron deficiency anemia (hematocrit, 23%) secondary to menorrhagia (Figure 1). Physical examination revealed a heart rate of 78/min and a blood pressure of 100/60 mm Hg. Thyroxine sodium was initiated at 50 μg daily. Three days later, the patient complained of severe palpitations and feelings of restlessness. Physical examination at that time revealed a heart rate of 120/min, blood pressure of 110/70 mm Hg, normal deep tendon reflexes, and no evidence of tremor of her outstretched fingers. Findings on cardiac examination were normal. Echocardiography showed no evidence of any valvular abnormalities. Although the dosage of thyroxine sodium was reduced to 25 μg/d, the patient refused to take the drug because her symptoms persisted. Thyroxine sodium was discontinued, and the patient was treated with ferrous sulfate for 6 weeks. The hematocrit level improved to 33%. Subsequently, 25 μg/d of thyroxine sodium was initiated, and the dose was gradually increased to 112 μg/d; no symptoms occurred. Three months later, the patient had normal thyroid function (serum total thyroxine, 7.4 μg/dL; TSH, 2.4 mIU/L).
      Figure thumbnail gr1
      Figure 1Alterations in hematocrit (upper left), plasma norepinephrine (upper right), urine norepinephrine (lower left), and thyroidstimulating hormone (TSH) (lower right) levels in patients with iron deficiency anemia and primary hypothyroidism before treatment, after treatment of anemia for 6 to 8 weeks, and after treatment of hypothyroidism for 4 months (following correction of anemia). Initial values were obtained while patients had severe palpitations, restlessness, and nervousness. Patients were asymptomatic when values were obtained 6 to 8 weeks and 4 months after treatment.

      Case 2

      A 36-year-old woman presented with iron deficiency anemia (hematocrit, 28%) due to menorrhagia and primary hypothyroidism (TSH, 51 mIU/L; free thyroxine, 0.4 ng/dL; Table 1 and Figure 1). Thyroxine sodium, 25 ug/d, and oral ferrous sulfate, 325 mg 3 times daily, were initiated; the patient was instructed to take these 2 medications at least 6 hours apart. Because of palpitations and restlessness, she discontinued the thyroxine sodium 5 days later. Before she discontinued thyroxine therapy, her heart rate was 116/min, and her blood pressure was 120/78 mm Hg.
      Table 1Laboratory Values in Patients With Anemia and Primary Hypothyroidism
      Values
      Initial values were obtained while patients had anemia and hypothyroidism; 6-to 8-week values were obtained after treatment of anemia; and 4-month values were obtained when patients were euthyroid. Data are presented as mean ± SEM. Differences concerning blood and urine laboratory values were compared by Kruskal-Wallis analysis of variance test.
      VariableInitial6-8 wk4 moReference range
      Blood
       Hematocrit (%)25.0±0.5334.7±1.88
      P=.02.
      41.7+1.45
      P=.02.
      36-40
       Iron μg/dL)13.7511.93120±8.13
      P=.02.
      146±17.3
      P=.02.
      37-170
       Transfer™ (mg/dL)452+29.0298±32.9
      P=.02.
      310±22.4
      P=.02.
      200-347
       Ferritin (μg/L)7.40+1.7032+6.66
      P=.02.
      50+11.76
      P=.02.
      11-120
       Vitamin B12 (ng/L)451+81.5573+126502+74.4225-1000
       Folate μg/L)15.20+2.2116.63+3.7716.0+3.032-20
       Free thyroxine (ng/dL)0.30+0.100.23+0.081.24±0.05
      P=.02.
      0.7-1.85
       Triiodothyronine (ng/dL)58.3+4.8751.0+1.78129±15.2
      P=.02.
      90-170
       Thyroid-stimulating hormone (mlU/L)70+11.089±12.1
      P=.02.
      2.22±0.55
      P=.02.
      0.45-4.0
       Epinephrine, supine (pg/mL)38+9.0131±5.14
      P=.02.
      26±6.44
      P=.02.
      0-110
       Norepinephrine, supine (pg/mL)1118+321623±69
      P=.02.
      212±17
      P=.02.
      112-658
      Urine
       Epinephrine (μg/24 h)14.0+2.017.5+1.5010.0+1.00-25
       Norepinephrine μg/24 h)455+57275+45
      P=.02.
      59.7±9.7
      P=.02.
      0-100
       Metanephrines (mg/24 h)2.53+0.311.82+0.170.81±0.09
      P=.02.
      <1.3
      * Initial values were obtained while patients had anemia and hypothyroidism; 6-to 8-week values were obtained after treatment of anemia; and 4-month values were obtained when patients were euthyroid. Data are presented as mean ± SEM. Differences concerning blood and urine laboratory values were compared by Kruskal-Wallis analysis of variance test.
      P=.02.
      Cardiac examination showed no murmur. An echocardiogram revealed normal findings. After 7 weeks of ferrous sulfate therapy, the patient could tolerate thyroxine sodium at a dose of 25 μg/d. Two months later, the hematocrit level had improved to 36%, at which time she was able to tolerate 125 μg/d of thyroxine and achieve a euthyroid state.

      Case 3

      A 21-year-old woman had iron deficiency anemia (hematocrit, 24%) due to menorrhagia and primary hypothyroidism (Figure 1). The patient was given 25 μg/d of thyroxine sodium and 325 mg of ferrous sulfate 3 times daily with instructions to take these 2 medications at separate times. She discontinued the daily thyroxine therapy 1 week later because of palpitations. Examination before discontinuation of thyroxine sodium revealed a heart rate of 108/min and a blood pressure of 118/84 mm Hg. Findings on cardiac examination were normal. After 4 weeks of ferrous sulfate therapy, the patient could tolerate 25 μg/d of thyroxine. After the thyroxine dose was increased, the patient was euthyroid in 3 months.

      Case 4

      A 33-year-old woman presented with iron deficiency anemia (hematocrit, 20.5%) and primary hypothyroidism (TSH, 98 mIU/L; free thyroxine, 0.1 ng/dL; Figure 1). She was given 50μg/d of thyroxine sodium and 325 mg of ferrous sulfate 3 times daily. The patient complained of nervousness, palpitations, and an uncomfortable feeling after the first dose of thyroxine. No murmurs were detected on a cardiac examination, and an echocardiogram showed no valvular abnormalities. Three days later, her heart rate was 106/min, and her blood pressure was 108/60 mm Hg. The patient continued to have symptoms for the next 2 weeks until thyroxine sodium was discontinued. After 6 weeks of ferrous sulfate, thyroxine therapy was resumed, and the patient experienced no symptoms.

      Discussion

      The hypothyroid state is known to be associated with increased systemic vascular resistance and elevated levels of serum and urinary noradrenaline.
      • Coulombe P
      • Dussault JH
      • Letarte J
      • Simmard SJ
      Catecholamines metabolism in thyroid diseases, I: epinephrine secretion rate in hyperthyroidism and hypothyroidism.
      • Coulombe P
      • Dussault JH
      • Walker P
      Plasma calccholamine concentrations in hyperthyroidism and hypothyroidism.
      • Manhcm P
      • Bramnert M
      • Hallengren B
      • Lecerof H
      • Werner R
      Increased arterial and venous plasma noradrenaline levels in patients with primary hypothyroidism during hypothyroid as compared to euthyroid state.
      In addition, catecholamine levels are increased in the blood and urine of iron-deficient patients.
      • Dillmann E
      • Johnson DG
      • Martin J
      • Mackler B
      • Finch C
      Catechol-amine elevation in iron deficiency.
      • Voorhess ML
      • Stuan MJ
      • Stockman JA
      • Oski FA
      Iron deficiency anemia and increased urinary norepinephrine excretion.
      • Martinez-Torres C
      • Cubeddu L
      • Dillmann E
      • et al.
      Effect of exposure to low temperature on normal and iron-deficient subjects.
      We postulated that the combination of hypothyroidism and iron deficiency anemia may result in substantially increased levels of catecholamines in the serum and urine. Therefore, we measured serum and urine catecholamine levels in our 4 patients before initiation of treatment, after correction of the anemia, and when the patients were euthyroid. When our patients had both hypothyroidism and anemia, the serum norepinephrine levels were significantly increased (Table 1 and Figure 1). Similarly, urine metanephrine values were also elevated (Table 1). However, epinephrine levels were within normal limits. With the correction of anemia, norepinephrine levels in the serum decreased substantially, although the values in urine were still significantly elevated. When our patients had finally achieved the euthyroid state, the serum and urine levels of norepinephrine were normal.
      After our patients with iron deficiency anemia and hypothyroidism were treated with relatively small doses of thyroxine sodium, they developed symptoms of restlessness, palpitations, nervousness, and tachycardia. These clinical features were not attributable to any other underlying disease. Furthermore, findings on cardiac examination were normal. It is unlikely that any ingredient in the thyroxine sodium preparations other than the hormone caused the symptoms because, in 2 other patients, symptoms continued when treatment with thyroxine sodium was changed to desiccated thyroid extract while the patients were anemic (data not shown). Although we did not use placebo tablets, the symptoms are not likely due to underlying anxiety or other psychiatric illness. First, these patients had unremarkable psychiatric histories. Second, they were able to tolerate thyroxine therapy and achieve a euthyroid state after the anemia had been treated, suggesting that the symptoms were indeed due to thyroxine therapy.
      In patients with anemia, peripheral vascular resistance is decreased. However, myocardial contractility and cardiac output are increased. The anemic state is also associated with increased plasma norepinephrine levels and levels of noncatecholamine inotropic factors, thus increasing sympathetic effects and cardiac excitability. Cardiovascular hemodynamics in hypothyroidism can be the converse of those in anemia. Hypothyroid patients have increased peripheral vascular resistance and decreased cardiac output. However, plasma norepinephrine concentrations are also elevated in such patients because of an increase in the overall production rate of norepinephrine, although the epinephrine secretion rate remains normal.
      • Coulombe P
      • Dussault JH
      • Letarte J
      • Simmard SJ
      Catecholamines metabolism in thyroid diseases, I: epinephrine secretion rate in hyperthyroidism and hypothyroidism.
      • Coulombe P
      • Dussault JH
      • Walker P
      Plasma calccholamine concentrations in hyperthyroidism and hypothyroidism.
      • Manhcm P
      • Bramnert M
      • Hallengren B
      • Lecerof H
      • Werner R
      Increased arterial and venous plasma noradrenaline levels in patients with primary hypothyroidism during hypothyroid as compared to euthyroid state.
      Even though peripheral tissue adrenergic responses are decreased in hypothyroidism, an increase in efferent sympathetic activity affects several tissues. Despite the elevated plasma norepinephrine levels, none of our patients had hypertension. This may be explained by the alterations in peripheral vascular resistance due to the anemia and other reflex homeostatic adjustments.
      There may be several reasons why patients with anemia and hypothyroidism have intolerance to thyroxine sodium. When the anemic state coexists with hypothyroidism, sympathetic activity may be further increased. This theory is supported by the substantial increase in plasma norepinephrine levels in our patients before treatment. Norepinephrine is a potent α-adrenergic receptor agonist, and both norepinephrine and epinephrine are nearly equally potent in stimulating β1-adrenergic receptors. In anemia with hyperstimulated β1-receptors, thyroid hormone administration may further up-regulate β1-receptors, thus causing symptoms.
      • Chapler CK
      • Cain SM
      • Stainsby WN
      Blood flow and oxygen uptake in isolated canine skeletal muscle during acute anemia.
      Some of the symptoms that our patients experienced may not have been entirely due to the effects of excessive norepinephrine levels. The ultimate response of target organs to norepinephrine is dictated not only by the direct effect of this hormone but also by the reflex homeostatic adjustment of patients. Catecholamines may stimulate thyroxine 5′-deiodinase and result in increased conversion of thyroxine to triiodothyronine, thus enhancing thyroid hormone action.
      • Silva JE
      Catecholamines and the sympathoadrcnal system in hypothyroidism.
      • Dluhy RG
      The adrenal cortex in thyrotoxicosis.
      In our patients, measurement of serum triiodothyronine levels when serum norepinephrine levels were elevated did not support this concept. However, increased triiodothyronine generation may occur at the tissue level. Other potential explanations include increased β-receptor density in the cardiac muscle or generation of serum noncatecholamine inotropic factors
      • Varat MA
      • Adolph RJ
      • Fowler NO
      Cardiovascular effeels of anemia.
      • Chapler CK
      • Cain SM
      • Stainsby WN
      Blood flow and oxygen uptake in isolated canine skeletal muscle during acute anemia.
      • Florenzano F
      • Diaz G
      • Regonesi C
      • Escobar E
      Left ventricular function in chronic anemia: evidence of noncatecholamine positive ionotropic factor in the scrum.
      in the anemic state and an increase in the quantity of guanyl nucleotide–binding proteins secondary to hypothyroidism.
      • Silva JE
      Catecholamines and the sympathoadrcnal system in hypothyroidism.
      • Dluhy RG
      The adrenal cortex in thyrotoxicosis.
      Since thyroid hormone can act as a sympathetic neurotransmitter.
      • Dluhy RG
      The adrenal cortex in thyrotoxicosis.
      • Whybraw PC
      • Prange Jr, AJ
      A hypothesis of thyroid-catcchol-aminc-rcccptoT interaction: its relevance to affective illness.
      this could also explain the development of symptoms shortly after administration of thyroxine sodium.

      References

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        • Adolph RJ
        • Fowler NO
        Cardiovascular effeels of anemia.
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        • Dussault JH
        • Letarte J
        • Simmard SJ
        Catecholamines metabolism in thyroid diseases, I: epinephrine secretion rate in hyperthyroidism and hypothyroidism.
        J Clin Endoirinol Metab. 1976; 42: 125-131
        • Coulombe P
        • Dussault JH
        • Walker P
        Plasma calccholamine concentrations in hyperthyroidism and hypothyroidism.
        Melabolism. 1976; 25: 973-979
        • Manhcm P
        • Bramnert M
        • Hallengren B
        • Lecerof H
        • Werner R
        Increased arterial and venous plasma noradrenaline levels in patients with primary hypothyroidism during hypothyroid as compared to euthyroid state.
        J Endocrinol Invest. 1992; 15: 763-765
        • Dillmann E
        • Johnson DG
        • Martin J
        • Mackler B
        • Finch C
        Catechol-amine elevation in iron deficiency.
        Am J Physiol. 1979; 237: R297-R300
        • Voorhess ML
        • Stuan MJ
        • Stockman JA
        • Oski FA
        Iron deficiency anemia and increased urinary norepinephrine excretion.
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        • Martinez-Torres C
        • Cubeddu L
        • Dillmann E
        • et al.
        Effect of exposure to low temperature on normal and iron-deficient subjects.
        Am J Physiol. 1984; 246: R380-R383
        • Chapler CK
        • Cain SM
        • Stainsby WN
        Blood flow and oxygen uptake in isolated canine skeletal muscle during acute anemia.
        J Appl Physiol. 1979; 46: 1035-1038
        • Silva JE
        Catecholamines and the sympathoadrcnal system in hypothyroidism.
        in: Bravcrman LE Utiger RD Werner and Ingbar's The Thyroid: A Fundamental and Clinical Text. 7th ed. Lippincott-Raven, Philadelphia, Pa1996: 661-670
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        The adrenal cortex in thyrotoxicosis.
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        • Florenzano F
        • Diaz G
        • Regonesi C
        • Escobar E
        Left ventricular function in chronic anemia: evidence of noncatecholamine positive ionotropic factor in the scrum.
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        • Whybraw PC
        • Prange Jr, AJ
        A hypothesis of thyroid-catcchol-aminc-rcccptoT interaction: its relevance to affective illness.
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