Myocardial Metabolism in a Patient with

Hashimoto’s Thyroiditis and Hypothyroidism*

Case &@rt, with Metabolic Studies

P. B. DEN BAKKER, M.D., J. F. SUNDERMEYER, M.D., V. E. WENDT, M.D., M. SALHANEY, M.D.,

S. GUDBJARNASON, PH.D. and R. J. BING, M.D.

Detroit, Michigan

T HYROIDECTOMY in various laboratory ani- mals has been shown to depress oxygen

consumption in striated muscle t/,2]. However, studies in vitro, as reported by Barker and Klit- gaard [3] and Barker and Schwartz [#I, suggest that many tissues are not under the influence of the thyroid gland. In vivo studies in patients with myxedema and hyperthyroidism have shown that the thyroid hormone has no effect on the oxygen consumption of the brain [5,6]; this is in contrast to studies by Scheinberg [7] who found that the oxygen consumption of the brain was reduced in patients with myxedema.

Hypoth~oidism may be complicated by cardiac enlargement and rareIy by congestive heart failure. The enlargement is due to peri- cardial effusion and/or cardiac dilatation f8]. The histologic changes in the heart, if present, are non-specific. They are described as de- generation of the sarcoplasm, with the appear- ance of vacuoles which may contain basophilic granular material [9,70]. Associated coronary artery disease is a frequent finding, possibly due to the altered lipid metabolism in hypothy- roidism. Clinically, the administration of thyroid hormone can reduce the cardiac silhouette to normal. Altered cardiac metabolism, due to insufficient circulating thyroid hormone, may be the underlying cause of the impairment of the cardiac muscle.

Electrocardiographic changes include low voltage of all complexes and flattening or inver- sion of the T waves. Administration of thyroid hormone restores upright T waves and increases the voltage of the ventricular complexes [II].

Experimental studies by Ambrus [72] in 1929 showed decreased glucose consumption by perfused hearts of thyroidectomized cats. Scott and co-workers [ 731 recentIy observed a reduc- tion in coronary blood flow and left ventricular oxygen consumption in experimentally induced hypothyroidism in dogs. Studies by Ellis and co-workers [74] in three patients with myxedema showed a reduced cardiac output which was proportional to the over-all reduction in basal metabolism.

Cardiac metabolism in human subjects with hypothyroidism has not been studied. This report presents the results of such a study in a case of Hashimoto’s ~hyroiditis associated with hypo- thyroidism; the findings in this patient are of interest, since this patient showed a normal cardiac output and a normal left ventricular oxygen consumption, and also evidence of glycolysis in the myocardium.

CASE REPORT

A twenty-one year old white woman (C. E.), was admitted to the Detroit Receiving Hospital in April 1961 for evaluation of abdominal pain of one day’s duration. The abdominal symptoms subsided spon- taneously. During this admission the stigmas of hypo- thyroidism were found. Her symptoms consisted of sensitivity to cold, poor appetite, easy fatiguabiiity, constipation and menorrhagia. She had given birth to two children, the last one three months prior to admission. In April 1960 a thyroglossal cyst was removed.

On physical examination, she appeared lethargic. Speech was delayed, with a low pitched voice; her skin was rough and dry. The hair was coarse. The

* From the Department of Medicine, Wayne State University College of Medicine, Detroit, Michigan. This study was supported by U. S. Public Health Service Grant No. H-5043, The American Heart Association, The Michigan Heart Association, Life Insurance Medical Research Fund, Tobacco Industry Research Committee, The Bumoughs Weilcome Fund, and the John A. Hartford Foundation. Manuscript received August 21,1961.

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Myocardial Metabolism in Hypothyroidism--den Bakker et al. 823

thyroid gland was diffusely enlarged and lobulated, with an estimated weight of 40 gm. The tongue was furrowed. The deep tendon reflexes exhibited a delayed relaxation phase. The cardiovascular system was essentially normal. The blood pressure was 95/60 mm. Hg. The electrocardiogram showed T wave flattening in the limb leads and inversion of the T waves in all precordial leads. X-ray films of the chest were within normal limits.

The hemoglobin was 11.7 gm. per cent, the white blood count 6,900 per cu. mm. with a normal differen- tial and platelet count. The blood serum lipids were 515 mg. per cent, the blood cholesterol 236 mg. per cent. The protein-bound iodine was 1.6 pg. per 100 ml. (normal value 3.5 to 8 pg. per 100 ml.). The radioiodine 1131 uptake by the thyroid gland in two hours was 7 per cent, a twenty-four hour uptake was 3 per cent. Stimulation with 10 units thyroid stimu- lating hormone resulted in a two hour uptake of 4 per cent and a twenty-four hour uptake of 2 per cent (normal value twenty-four hour uptake 15 to 45 per cent). Thyroid stimulating hormone therefore failed to elicit an increased radioiodine uptake by the gland. The erythrocyte triiodothyronine uptake was 9.6 per cent, which is slightly below normal [75,7/J. One month later radioiodine 1131 was given after stimula- tion with 10 units thyroid stimulating hormone for three days. The count resulted in a radioiodine 1131 uptake by the gland of 6 per cent in two, 9 per cent in six, 10 per cent in twenty-four and 9 per cent in forty- eight hours. Scanning of the thyroid gland five hours after the administration of 1131 revealed markedly diminished concentration in the right lobe in compari- son with the left. Six hours after the tracer dose was administered an open biopsy of the right and left lobe of the thyroid gland was performed. Microscopic examination revealed infiltration of thyroidial paren- chyma by mature lymphocytes, which were aggre- gated focally in lymphoid nests. In certain areas these aggregates were organized into well developed follicles. A minimal number of thyroid acini, con- taining small amounts of colloid, were present as well as a minimal degree of interacinar fibrosis.

Autoradiography performed according to the tech- nic described by Boyd [77] showed definite uptake of the radioiodine by the remaining follicles, although the concentration within the follicles varied widely.

SPECIAL STUDIES

Coronary sinus catheterization was performed in the usual fashion [78]. A Cournand needle was placed into the brachial artery. The cardiac output was measured by the Stewart-Hamilton method, injecting cardiogreen dye in the right atrium and sampling through a Gilford densi- tometer from the brachial artery [ 79,201. The coronary blood flow was measured by the nitrous oxide desaturation method [27,22].

VOL. 32, MAY 1962

Simultaneous blood samples from the coronary sinus and the brachial artery were drawn for determination of oxygen, glucose, pyruvate and lactate. The data were obtained at rest and repeated during exercise which extended over fifteen minutes. The exercise, performed on an ergometer, amounted to 250 kg. per minute.

Oxygen was determined by the manometric method of Van Slyke and Neil1 [23], glucose by the method of Hugget and Nixon [24]. Pyruvate was also measured enzymatically [25]. Lactate was determined by a method modified from Hohorst [26]. The oxidation-reduction potential (Eh or redox potential), determined by the ratio of the molar concentration of DPNH to DPN, is reflected by the ratio of the molar concentration of lactate to pyruvate [27]. Thus, the redox potential of arterial and venous blood can be calculated from the lactate and pyruvate blood concentrations. The redox potential is calcu- lated from the formula [25]:

Eh = E” ’ g ’ In

oxygenated substrate

reduced substrate

Experiments in dogs in this laboratory have shown that the changes in redox potential in the heart muscle are reflected by those in coronary vein blood [28]. A relative increase of the ratio of lactate to pyruvate between arterial and coronary vein blood results in a positive differ- ence in redox potential across the heart, sug- gesting the presence of glycolysis in addition to the normal respiration.

The per cent glucose:oxygen extraction ratio was determined from the myocardial extraction of glucose and oxygen.

Glucose : oxygen extraction ratio (per cent)

= 02 equivalent of extracted glucose x loo myocardial oxygen extraction

The oxygen equivalent of glucose is 0.75 X mg. per cent of glucose extracted [29]. A glucose : oxygen extraction ratio of less than 100 per cent indicates that oxygen is available for the breakdown of substrates other than glucose. A ratio of more than 100 per cent suggests that part of the extracted glucose follows metabolic pathways other than oxidative breakdown or is stored as glycogen.

The oxygen consumption per 100 gm. left ventricle per minute was calculated as the product of the coronary blood flow (expressed in cc per 100 gm. left ventricle per minute)

Myocardial Metabolism in Hypothyroidism-&n Bukker et al.

TABLE I

Before Exercise

I-

Brachial Artery

Brachial Artery,

COPXWy Sinus

Difference

Glucose(ma. %I.../ 71.4 Lactate (kg. %). . . 4.69 Pyruvate (mg. %) . . 0.539 Oxygen(vol.%).... 14.9 Oxidation reduction

potential (mv.). . . . . .

+24 +2.?3 +0.337 +9.5

+1.4

-

I -_

-_

-

During Exercise

Brachial Artery

Brachiai Artery,

Coronary Sinus

Difference

----I 83 +21 lb.75 -0.90

0.740 -0.018 14.8 +8.8

. . . +0.4

times the oxygen extraction (expressed in volumes per cent).

RESULTS AND COMMENTS

Table I lists the data obtained at rest and during exercise. The cardiac index increased from 3.9 L. per minute per sq. M. at rest to 6 L. per minute per sq. M. during exercise. The coronary blood flow at rest was 85 cc. per 100 gm. left ventricle per minute. The determination of the coronary blood flow during exercise was unsatisfactory. Glucose was extracted by the heart at rest and during exercise. Pyruvate and lactate were extracted by the heart (positive myocardial balance) during the basal state; however, these balances became negative during exercise. The myocardial oxygen extraction decreased from 9.5 volumes per cent at rest to 8.8 volumes per cent during exercise. The left ventricular oxygen consumption at rest was 8.1 cc. per 100 gm. left ventricle per minute. The coronary arteriovenous redox potential difference at rest was plus 1.4 mv.; during exer- cise it remained positive and was plus 0.4 mv.

Hashimoto’s thyroiditis, first described in 1912 [N], occurs predominantly in female sub- jects. Its histologic picture shows varying degrees of interfollicular infiltration with lymphoid tissue, together with fibrosis and epithelial changes [37,32]. In a series of 589 patients with Hashimoto thyroiditis reported by Woolner and co-workers [31] in 1959, the incidence of hypo- thyroidism was 8 per cent and of hyperthy- roidism 2 per cent. Lindsay and co-workers [32] in 1952, presented a series of 170 patients with Hashimoto thyroiditis; 2 per cent had hypo- thyroidism and 12 per cent had hyperthyroidism.

It has been postulated that there is a partial defect in the organic binding of iodine by the thyroid gland, as shown by the potassium per-

chlorate discharge test [33]. Attention recently has been focused also on the presence of circu- lating thyroid autoantibodies in thyroiditis [34,35]. In a series of 106 patients with Hashi- moto’s thyroiditis, thyroid autoantibodies were demonstrated by means of a precipitin reaction, tanned red cell agglutination or complement fixation test in 98 per cent of the patients [36]. A control group of 195 serums tested by the complement fixation test against thyrotoxic thyroid gave negative results. However, the tanned red cell agglutination test was positive in eight patients in a control group of 148 serums tested [.%I.

The patient presented in this communication has Hashimoto’s thyroiditis, as confirmed by biopsy. In addition, she had hypothyroidism as indicated by the diminished radioiodine Ii31 uptake by the thyroid gland, the low protein- bound iodine in the circulating blood, and the low erythrocyte triiodothyronine uptake.

Despite the presence of hypothyroidism the cardiac index was not reduced; also the coronary blood flow and the left ventricular oxygen con- sumption were within the normal range. This is in contrast to results obtained by Ellis and co-workers [74] who found a reduced cardiac output in three patients with myxedema, and by Scott and co-workers [73] who observed a reduction in coronary blood flow and left ventricular oxygen consumption in experi- mentally induced hypothyroidism in dogs. The normal cardiac output, coronary blood flow and left ventricular oxygen consumption are difficult to explain. However, it has been shown previously that the oxidative metabolism of many tissues such as the spleen and the brain may be independent of the amount of circulating thyroid hormone [4,5].

It has been shown in this laboratory that the glucose : oxygen extraction ratio in control sub- jects is approximately 35 per cent [37]. A ratio of 191 per cent at rest and 180 per cent at exercise was found in this patient. The extrac- tion of glucose was greater than can be accounted for by the myocardial oxygen extraction. This could be the result of glycolysis; this possibility is supported by the finding of a positive differ- ence of the coronary arteriovenous redox potential at rest.

During exercise, pyruvate and lactate were released by the heart muscle as a result of glycolysis. The coronary arteriovenous redox potential difference remained positive.

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Myocardial Metabolism in Hypothyroidkxn-den Bakker et al. 825

This patient, therefore, showed contradictory spectra uE clinical, dynamic and biochemical finding. Despite the presence of hypothyroidism, the cardiac output, the coronaq bIood A QW, and the IefT ventricular oxygen constirnption were normal. ‘The metabolic studies revealed gly- colysis in cardiac muscle.

SVmfARY

A case of Hashimota’s thyroiditis with clinical and patholagic evidence of hypothyroidism is presented. Cardiac output, coronary blood flaw and myocardial oxygen consumption wcsc. within the normal range. Pyruvate and lactate were extracted by the heart during the basal state and released by the heat-r on exercise. A marked increase in mptocardial glucose : oxygen extraction ratio was found and the differences in oxidation reduction potential between arterial and coronary vein blood were positive at revt and exercise. The results suggest glycoty& in the cardiac rmlscle of this individua1 in the presence of nurrnal myocardial oxygen usage.

~~~~Q~~e$g~~~~: We gmtefully- acknowledge the assistance of Dr. P, Wolf oE the Depwtmcnt of Pathology, Wayne State University and Dr. M. R. Sikov &the Department ot’Radiolagy, Wayne State Universitp,

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