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Addison's disease and hyperthyroidism
Addison’s
Disease and Hyperthyroidism*
Report of a Case and Demonstration of Circulating Adrenal and Thyroid Antibodies GERALD
BURKE,
M.D. and JEROME
M.
FELDMAN, M.D.
Chicago, Illinois cal impression of thyrotoxicosis. The patient was given 5 mc. of radioactive iodine and when seen again on June 28, 1963, she had regained the weight lost previously and was clinically euthyroid. The plasma protein-bound iodine at that time was 3.1 pg. per cent. The patient continued to do well until three weeks prior to admission when she had what she described as “stomach flu” which was manifested by anorexia, nausea, vague abdominal discomfort unrelieved by the ingestion of antacids, occasional vomiting and marked asthenia. Further questioning disclosed that in the three months prior to admission she had lost 15 pounds and had had recurrent episodes of hiccoughs almost daily. She had no symptoms suggestive of hypoglycemia but in the week prior to admission she had noted “dizziness and light-headedness” on assuming the upright position. Menses were normal and no salt craving could be elicited. With the exception of a sister treated surgically for Graves’ disease, the family history was noncontributory. Her past medical history was negative for tuberculosis or exposure to the disease. Both the patient and her husband stated that although she had always tanned readily and deeply, her present tan was unusually intense and had persisted even though she had not been exposed to the sun or ultraviolet light for approximately four months. On physical examination the patient was a thin, profoundly weak, deeply tanned, white woman. The tan was limited to the extremities and those areas of the trunk normally exposed to the sun. However, numerous deeply brown pigmented “freckles” were present over both exposed and unexposed areas of the trunk. Pressure points such as the beltline, back, axillas and groin were not unduly pigmented. The areolas and knuckles were normal in color. The flexural creases of the fingers and palms were excessively pigmented. No surgical scars were present. Minute areas of brownish black pigmentation were observed at the junction of the buccal mucosa and vermillion border at the angles of the mouth and on the gingivae. There was a normal female escutcheon
T
HE simultaneous orsequential occurrence of Addison’s disease and thyrotoxicosis has been reported with sufficient frequency to indicate more than a chance association of these endocrinopathies [ 1,2]. Individually these disease entities are characterized by a number of similar symptoms including weight loss, asthenia, gastrointestinal disturbances and increased pigmentation. The presence of the latter as the initial manifestation of Addison’s disease has been reviewed recently [3]. Increased pigmentation in thyrotoxicosis, although not as extensive or as frequent as in Addison’s disease, is also a recognized phenomenon [4]. This report presents the twenty-seventh case in which the occurrence of both diseases has been documented adequately and serves as the basis for consideration of a possible relationship between Addison’s disease and hyperthyroidism. CASE REPORT
A forty year old white woman entered Michael Reese Hospital on December 15, 1963, with the chief complaints of anorexia, nausea, vomiting and vague abdominal discomfort of three weeks’ duration. The patient had enjoyed excellent health until January 1963 when heat intolerance, nervousness, metrorrhagia and muscle weakness developed. Over the next three months she noted a 12 pound weight loss despite a good appetite. On referral to the Radioisotope Laboratory in March 1963 a “stare,” with no other abnormal eye signs, and slight symmetrical enlargement of the thyroid gland were observed. The examiner noted that the patient was deeply tanned. The blood pressure was 11 O/70 mm. Hg and the pulse rate was 110 per minute and regular. Laboratory studies revealed the basal metabolic rate to be +27 per cent, the plasma protein-bound iodine 8.1 pg. per cent and the 24 hour thyroidal uptakeof radioiodine 63 per cent, substantiating theclini-
* From the Department of Metabolism and Endocrinology, Division of Medicine, Michael Reese Hospital and Medical Center, Chicago, Illinois. Manuscript received May 25, 1964. 470
AMERICAN
JOURN.4L
or
MEDICINE
Addison’s
Ikzase
and Hyperthyroidim-l,‘wXe,
'I“4eLE I URIVAKY
Time
STEROID
Urinary Steroids (mg./24 hr.)
of
I)etrrmination
Day
DErERMINATIONS
17 Ketosteroids*
17 Hydroxycorticoidst
1
~chttd j Day 2 (ACTH)$ Day 3 (ACTI)
:
* Normal female values: 7 to 15 mg. per 24 hours. t Normal female values: 3 to 7 mg. per 24 hours. $ Fifty units in 1,000 cc. 5 per cent dextrose in normal saline solution infused intravenously from 8:00 A.M. to 4:oo P.M. with sparse (unshaven) axillary hair. Skin turgor was poor. The radial pulse was not palpable and the brachial pulse was weak with a regular rate of 108 per minute. ‘The blood pressure by auscultation was 64/46 mm. Hg (in the right arm, with the patient recumbent), falling to 50/O mm. Hg when the patient was in a sitting position at which point she was forced to lie down because of marked light-headedness and a feeling of impending syncope. The remainder of the physical examination was within normal limits. Laboratory studies revealed a hemoglobin of 15.9 gm. per cent with a hematocrit of 49 per cent, white blood cell count 10,600 per cu. mm. with 29 per cent segmented polymorphonuclear leukocytes, 13 per cent nonsegmcnted polymorphonuclear leukocytes, 3 per cent eosinophils, 50 per cent lymphocytes and 5 per cent monocytes. The serum sodium was 135, potassium 4.6, chloride 90 and carbon dioxide 23 mEq. per L.; the pH was 7.34. The fasting blood sugar was 97 mg. per cent, the blood urea nitrogen 50 mg. per cent and the serum creatinine 1.9 mg. per cent. Urinalysis revealed 50 hyaline casts per low power field. with occasional coarse and degenerated casts, 3 to 12 white blood cells per low power’field, and moderate proteinuria with a specific gravity of 1.014. The serum calcium was 10.1 and serum phosphorus 2.8 mg. per cent. The plasma protein-bound iodine was 5.4 hg. per cent. Antithyroglobulin antibodies were detected in a titer greater than 1 :4,000 by a modification of the Boyden tanned red cell hemagglutination technic [5]. The patient’s serum was shown to possess complement-fixing antibodies to both thyroid and adrenal tissue by the technic of Blizzard et al. [fi.7];* a 4f result was obtained in * Wt. are indebted to Dr. Robert M. Blizzard, Johns Hopkins Hospital. Baltimore, Maryland, for formins
these studies.
the per-
Fddrrwri
each instance. In addition, a 4+ rcsl~lt \~a> obtained the presence of using fixed thyroid tissue, indicating agglutinating (antithyroglobulin) antibodies and confirming the findings with the tanned rrd cell technic. An electrocardiogram revealed a regular ratr of 100 per minute, a P-R interval of 0.16 scci)nd and a Q-T segment that was prolonged to +O. 10 second; the latter was thought to be compatible with hypokalemia and/or hypocalcemia. In addition, low voltage was present throughout all leads. Chest roentgenograms revealed no abnormalities but abdominal x-ray films showed calcification in the projection field of the right adrenal gland. Sephrotomograms established later that this calcification was anterior to the area of the right adrcsnal gland and probably represented a calcified abdominal lymph node. l’he results of tuberculin skin testing with purified protein derivative up to and including purified protein derivative no. 2 were negative, and several specimens of sputum revealed no organisms on smear or culture. On the second hospital day an infusion of 5 per cent dextrose in normal saline solution was started; the patient’s condition improved markedly over the next 24 hours when her blood pressure rose to 78150 mm. Hg with no evidence of postural hypotension and with a stronger and slower pulse. Corticoid determinations on blood samples obtained in the early morning (7: 00 A.M.) and the afternoon (4: 30 P.M.) of that day gave values of 4.3 and 1.8 pg. per cent, respectively (normal values 4 to 28 pg. per cent). That evening, therapy with 9-alpha-fluorohydrocortisone (Florinef@), 1 mg. twice daily, was startrd preparatory to performance of an ACTH stimulation test (50 units ACTH in 1 I,. normal saline solution infused over an 8 hour period). The AC’I‘H stimulation study was performed on two consecutive days and the results of these studies and of the baseline 24 hour urinary steroid determinations are shown in Table I. The data obtained confirmed the clinical impression of Addison’s disease. Following the ACTH stimulation tt’st. therapy with cortisone acetate, 37.5 mg. daily, was instituted and the Florinef dosage was reduced to C.1 mg. per day. By the fifth hospital day, the blood urea nitrogen had fallen to 8 mg. per cent, the serum creatinine was 0.9 mg. per cent, and the urinalysis was normal. A complete blood count on December 26 r(bvcaled a hemoglobin value of 10.5 gtn. per cent, a red blood cell count of 3.2 million per cu. mm. and a hematocrit of 30 per cent with a white blood cell count of 6,400 per cu. mm. The differential count again showed a marked lymphocytosis. The decrease in hemoglobin and hematocrit following therapy confirmed the clinical impression of initial hemoconcentration and relative hypovolemia. A repeat electrocardiogram was still abnormal, with a tendency to low voltage, but the Q-T interval was within normal limits. Since the institution of cortisone replacement
472
Addison’s
Disease
and Hyperthyroidism-Burke,
the patient has been asymptomatic and has had no more hiccoughs. Her weight has remained stable at 100 pounds and her blood pressure at 100/60 mm. Hg with no orthostatic hypotension. therapy,
COMMENTS
The statistical association of Addison’s disease and hyperthyroidism seems to be significant. In 1951 Frederickson [ 71 reviewed 180 cases of Addison’s disease and found a 4.4 per cent incidence of thyrotoxicosis, which is ten times that found in the general population. McConahey reviewed the records of 538 Addisonian patients seen at the Mayo Clinic from 1913 to 1958 and found sixteen with thyrotoxicosis, giving a similar incidence of 3 per cent [2]. However, it should be noted that in this series many patients were studied before specific diagnostic procedures were available and no mention of laboratory data was made in McConahey’s report. If a pathogenic mechanism is to be established, the sequence of the appearance of these two entities must be accounted for. In a review of the world literature in 1957 Rupp [S] noted eight documented cases in which Addison’s disease preceded or occurred simultaneously with hyperthyroidism to which he added a case of his own. Rupp found five adequately documented cases in which hyperthyroidism preceded Addison’s disease. In reviewing the world literature since 1957 we have found ten additional cases in the first category [g-76] and three, including our own, in the second [ 16-781. Thus there are now nineteen well documented cases in which Addison’s disease preceded or occurred simultaneously with hyperthyroidism and eight in which hyperthyroidism preceded Addison’s disease. The sequence in which hypoadrenocorticism follows hyperthyroidism is more easily explicable. The accelerated degradation of corticosteroids with normal plasma hydrocortisone levels and increased excretion of 17-OH corticoids in the urine over 24 hours has been well documented in hyperthyroidism [ 19,201. In addition, ACTH-like activity has been observed in the plasma of patients with thyrotoxicosis [27]. D’Angelo and Grodin [22] showed recently that continued administration of triiodothyronine to rats in large daily doses induced hyperactivity of the adrenal cortex, as indicated by markedly increased concentrations of corticoids in plasma and the adrenal gland and by hypertrophy of the gland. There was an inverse relationship between ascorbic acid and
Feldman
corticosterone concentration in the adrenals of severely hyperthyroid animals. Thus a patient with subclinical adrenal insufficiency and/or low adrenal reserve may have frank adrenal insufficiency if the adrenal remnant is unable to increase its steroid output. This explanation does not account for the manifestation of adrenal insufficiency in many of these patients months to years after they have been rendered euthyroid. It is more difficult to establish a pathogenic mechanism for the more frequent sequence in which Addison’s disease precedes hyperthyroidism. In a recent review [16], it was pointed out that a lesion must be postulated in which the increase in corticotrophin in Addison’s disease leads to a secondary increase in the secretion of thyroid stimulating hormones. However, evidence to date indicates that secretion of thyroid stimulating hormones is either moderately depressed or normal in this condition [23]. Pituitary cellular mechanisms have also been proposed as the mechanism [16]. The delta cells are said to elaborate and store gonadotrophins and corticotrophins, whereas the beta cells are believed to elaborate and store thyroid stimulating hormones. The question has been raised as to whether the delta cell can be transformed into a gamma cell and then into a beta cell and elaborate thyroid stimulating hormones, but evidence supporting this hypothesis is meager [76]. There is evidence that other pituitary hormones may affect thyroid function directly. In a recent study of the effects of various peptides on the thyroid in mice given injections of 1131 after they had been treated with thyroxine Bowers et al. [24] found that the greatest effects of 1131 on blood levels were elicited with corticotrophin A and natural or synthetic alpha-melanocyte stimulating and beta-melanocyte stimulating hormones. The latter were active in hypophysectomized mice, implying a direct effect on the thyroid gland. These data suggest that the elevated circulating levels of ACTH and melanocyte stimulating hormones in clinical adrenal insufficiency may in like manner stimulate the thyroid gland directly. A recent report [25] of the occurrence of thyrotoxicosis in two patients given large doses of steroids for long periods of time makes the physiological relationship between these two endocrines even more complex. The possibility of an immunologic basis for the coexistence of adrenal insufficiency and hyperthyroidism merits consideration. Blizzard AMERICAN
JOURNAL
OF
MEDICINE
:1ddison’s
Disease
and
Hyperthyroidisrn
and Kvlr j7J recently reported the demonstration of circulating adrenal antibodies by the indirect Coombs’ test in thirty-six of seventy-one serums from Addisonian patients. Complement fixing antibodies were found in twenty-four of thcsta thirty-six serums. Twenty-two of the Addisonian patients had circulating antithyroid antibodies as measured by the indirect Coombs’ technic with unfixed thyroid tissue, but there was no correlation between the presence of circulating thyroid and adrenal antibodies and these patients did not manifest any evidence of thyroid disease. Although it has been shown [7] that idiopathic Addison’s disease meets all the criteria for an autoimmune process, the role of the circulating antiadrenal (cellular) antibodies has not been determined. These antibodies may reflect only the disease process rather than involvement in the pathogenesis of the adrenal insufliciency. Since the lymphocytic infiltration of the thyroid in autoimmune thyroiditis has been shown to be due to cellular antibodies [26,_37], and the frequent association of lymphocytic thyroiditis with ,4ddison’s disease has long been known [28], further support is lent, in fact, to the concept that Addison’s disease may also result from an autoimmune process. The high incidence of antithyroid antibodies reported bv Blizzard and Kyle [7] in the serums of Addisonian patients and the coincident occurrence of lymphocytic thyroiditis and Addison’s disease alluded to previously suggest the possibility that an autoimmune process may in some instances result in multiple endocrine deficiencies. To our knowledge, the case presented herein is the first reported instance of Addison’s disease and hyperthyroidism in which both antiadrenal and antithyroid antibodies have been demonstrated. Stewart et al. [ 151 described a forty year old man in whom hyperthyroidism developed two years after the diagnosis of Addison’s disease was established. In this case a positive thyroglobulin precipitin test and tanned red cell titers of up to 1 :25,000 were obtained. However, there was no evidence of adrenal antibodies despite repeated testing with the complement-fixing technic. Although our patient was treated with radioactive iodine, the treatment in itself does not result in the increase of thyroglobulin antibodies demonstrated in this case [29]. The usual antithyroglobulin tanned red cell titer in hyperthy-
---11urhc. Feldtnnrr
373
roidism is low, ranging from 1 : 10 to 1 : iI?0 [29]. Patients with hyperthyroidisrrr and high titers of antithyrobulin antibodies ‘ire prone to the development of hypothyroidisul after therapy whether treated with 1’“’ or by subtotal thyroidcctomy [_?,,W]. On this t)asis our patient: although presently euthyroid, may beIn this regard the marked, come hypothyroid. although transient, decrease in plasma proteinbound iodine observed after 1’“’ therapy was instituted is of some interest. As reported in the review of Becker and Randall [,?I, sk’m p’g 1 mentation may precede the other signs and symptoms of Addison’s disease by as much as fifteen years 1.311. The marked increase in melanin pigmentation observed in our patient at the time of diagnosis of thyrotosicosis may therefore have been the first indication of impairment of adrenocortical function. If this were the case, it is indeed surprising that overt adrenal insufficiency did not develop under the stress of the hypermetabolic state but appeared only after the patient had been rendered euthyroid. This difficulty in documenting the sequential onset of these endocrinopathies may well have been present in many of the other reported cases and renders suspect any mechanism(s) of pathogenesis based on the order of appearance of the two disease states. SUMMAR\
A forty year old woman treated for hyperthyroidism with Ii31 and in whom Addison’s disease developed later is described. 0f particular interest is the demonstration of both antithyroid and antiadrenal antibodies in the patient’s serum. The implications of these findings are discussed and related to a postulated pathogenic mechanism for the coexistence of these endocrinopathies. REFERENCES 1. FREDERICKSON,D. S. Effect of massive cortisone therapy on thyroid function. J. Clin. Endocrinol., 11: 760 1951. 2. MCCONAHEY, W. M., MEYERS, W. R. and GASTJNEAU, C. F. Grave’s disease in patients with Addison’s disease. Acta endocrinnl., 51 (supp.): 355, 1960. 3. BECKER, K. L. and RANDALL, R. V. Pigmentation as the presenting feature of Addison’s disease. Metabolism, 12: 1057, 1963. 4. WEGELIUS, 0. In: The Thyroid, p. 523. Edited by Werner, S. New York, 1962. Paul B. Hoeber, Inc. 5. BOYDEN, S. V. Adsorption of proteins on erythrocytes treated with tannic acid and subsequent hemag-
474
6.
7.
8.
9.
10. 11. 12.
13.
14.
15.
16.
17.
18.
19.
Addison’s
Disease and Hyperthyroidism-Burke,
&tin&ion by antiprotein sera. J. Exper. Med. 93: 107, 1951. BLIZZARD, R. M., CHANDLER, R. W., LANDING, B. H., PETTIT, M. D. and WEST, C. D. Maternal autoimmunization to thyroid as a probable cause of athyreotic cretinism. New England J. Med., 263: 327, 1960. BLIZZARD, R. M. and KYLE, M. Studies of the adrenal antigens and antibodies in Addison’s disease. J. Clin. Invest., 42: 1653, 1963. RUPP, J. J. and PASCHKIS, K. E. Coexistence of Addison’s disease and thyrotoxicosis. J. Clin. Endocrinol., 17: 143, 1957. DECOURT, J., DOUMIC, J. M. and MICHARD, J. P. Un cas de maladie d’Addison associte a une hyperthyroidie. Ann. endocrinol., 18: 423, 1957. FREY, H. M. Addison’s disease complicated by Grave’s disease. J. Clin. Endocrinol., 19 : 1497,1959. GREENBERG, W. V. Addison’s disease and hyperthyroidism. Ann. Int. Med., 55: 663, 1961. GABRILOVE, J. L. and WEINER, H. E. Effect of thyroid function on adrenocortical steroid metabolism in a patient with Addison’s disease and thyrotoxicosis. J. Clin. Endocrinol., 22: 795, 1962. PLAMONDON,C. and BRUNET, J. Maladie d’Addison associee a une hyperthyroidie chez une adolescente. Lava1 mid.. 27: 46, 1959. BOSHELL,B. R., WILSON, R. K. and MAXWELL, M. E. Addison’s disease complicated by thyrotoxicosis. M. Times, 91: 107, 1963. STEWART, W. K. GREEN, D. M. and LOWE, K. G. Addison’s disease and hyperthyroidism. Acto endocrinol., 40: 613, 1962. BRUNO, M. S., OBER, W. B., KUPPERMAN,H. S. and EPSTEIN, J. A. Coexistent Addison’s disease and thyrotoxicosis. Arch. Znt. Med., 110: 155, 1962. JENKINS,J. S., PILKINGTON,T. R. E. and ROSENOER, V. M. Thyrotoxicosis and Addison’s disease in the same patient. Brit. M. J., 1: 1025, 1960. FRIIS, T. Thyrotoxic crisis: two cases of which one subsequently developed Addison’s disease. U,esk. Laeger., 124: 278, 1962. PETERSON, R. E. The influence of the thyroid on
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
Feldman
adrenal cortical function. J. Clin. Inrlest.,37: 736, 1958. MELBY, J. C. Regulatory effect of thyroid hormone on cortisol metabolism. J. Lab. M Clin. Med., 54: 924, 1959. HILTON, J. G., BLOCK, W. C., ATIIOS, W., MCHUGH, B. and WESTERMANN,C. D. Increased ACTH-like activity in plasma of patients with thyrotoxicosis. J. Clin. Endocrinol., 22: 900, 1962. D’ANGELO, S. A. and GRODIN, J. M. Experimental hyperthyroidism and adrenocortical function in the rat. Endocrinology, 74: 509, 1964. INGBAR, S. H. and FREINKEL,N. ACTH, cortisone, and the metabolism of iodine. M&bolism, 5: 652, 1956. BOWERS,C. Y., REDDING,T. W. and SCHALLY, A. V. Effects of OL-and fl-melanocyte stimulating hormones and other peptides on the thyroid in mice. Endocrinology, 74: 559, 1964. BROWN, D. M. and LOWMAN, J. T. Thyrotoxicosis occurring in two patients on prolonged high doses of steroids. New England J. Med., 270: 278, 1964. FELIX-DAVIES,D. and WAKSMAN,B. H. Passive transfer of experimental immune thyroiditis in the guinea-pig. Arthritis @ Rheumat., 4: 416, 1961. MCMASTER, P. R. B., LERNER, E. M., II and EXUM, E. D. The relationship of delayed hypersensitivity and circulating antibody to experimental allergic thyroiditis in inbred guinea pigs. J. Exfer. Med., 113: 611, 1961. WELLS, H. G. Addison’s disease with selective destruction of the suprarenal cortex (“supra-renal cortex atrophy”). Arch. Path., 10: 499, 1930. BLAGG, C. R. Antibodies to thyroglobulin in patients with thyrotoxicosis treated with radioactive iodine. Lancet, 2: 1364, 1960. ,IRVINE, W. J., MCGREGOR, A. G. and STUART, A. E. The prognostic significance of thyroid antibodies in the management of thyrotoxicosis. Lancet, 2: 843, 1962. SIMPSON,S. L. Clinical and pathological aspects of the adrenal glands. Proc. Roy. Sot. Med., 27: 383, 1933-34.
AMERICAN
JOURNAL
OP
MEDICINE
Disease and Hyperthyroidism*
Report of a Case and Demonstration of Circulating Adrenal and Thyroid Antibodies GERALD
BURKE,
M.D. and JEROME
M.
FELDMAN, M.D.
Chicago, Illinois cal impression of thyrotoxicosis. The patient was given 5 mc. of radioactive iodine and when seen again on June 28, 1963, she had regained the weight lost previously and was clinically euthyroid. The plasma protein-bound iodine at that time was 3.1 pg. per cent. The patient continued to do well until three weeks prior to admission when she had what she described as “stomach flu” which was manifested by anorexia, nausea, vague abdominal discomfort unrelieved by the ingestion of antacids, occasional vomiting and marked asthenia. Further questioning disclosed that in the three months prior to admission she had lost 15 pounds and had had recurrent episodes of hiccoughs almost daily. She had no symptoms suggestive of hypoglycemia but in the week prior to admission she had noted “dizziness and light-headedness” on assuming the upright position. Menses were normal and no salt craving could be elicited. With the exception of a sister treated surgically for Graves’ disease, the family history was noncontributory. Her past medical history was negative for tuberculosis or exposure to the disease. Both the patient and her husband stated that although she had always tanned readily and deeply, her present tan was unusually intense and had persisted even though she had not been exposed to the sun or ultraviolet light for approximately four months. On physical examination the patient was a thin, profoundly weak, deeply tanned, white woman. The tan was limited to the extremities and those areas of the trunk normally exposed to the sun. However, numerous deeply brown pigmented “freckles” were present over both exposed and unexposed areas of the trunk. Pressure points such as the beltline, back, axillas and groin were not unduly pigmented. The areolas and knuckles were normal in color. The flexural creases of the fingers and palms were excessively pigmented. No surgical scars were present. Minute areas of brownish black pigmentation were observed at the junction of the buccal mucosa and vermillion border at the angles of the mouth and on the gingivae. There was a normal female escutcheon
T
HE simultaneous orsequential occurrence of Addison’s disease and thyrotoxicosis has been reported with sufficient frequency to indicate more than a chance association of these endocrinopathies [ 1,2]. Individually these disease entities are characterized by a number of similar symptoms including weight loss, asthenia, gastrointestinal disturbances and increased pigmentation. The presence of the latter as the initial manifestation of Addison’s disease has been reviewed recently [3]. Increased pigmentation in thyrotoxicosis, although not as extensive or as frequent as in Addison’s disease, is also a recognized phenomenon [4]. This report presents the twenty-seventh case in which the occurrence of both diseases has been documented adequately and serves as the basis for consideration of a possible relationship between Addison’s disease and hyperthyroidism. CASE REPORT
A forty year old white woman entered Michael Reese Hospital on December 15, 1963, with the chief complaints of anorexia, nausea, vomiting and vague abdominal discomfort of three weeks’ duration. The patient had enjoyed excellent health until January 1963 when heat intolerance, nervousness, metrorrhagia and muscle weakness developed. Over the next three months she noted a 12 pound weight loss despite a good appetite. On referral to the Radioisotope Laboratory in March 1963 a “stare,” with no other abnormal eye signs, and slight symmetrical enlargement of the thyroid gland were observed. The examiner noted that the patient was deeply tanned. The blood pressure was 11 O/70 mm. Hg and the pulse rate was 110 per minute and regular. Laboratory studies revealed the basal metabolic rate to be +27 per cent, the plasma protein-bound iodine 8.1 pg. per cent and the 24 hour thyroidal uptakeof radioiodine 63 per cent, substantiating theclini-
* From the Department of Metabolism and Endocrinology, Division of Medicine, Michael Reese Hospital and Medical Center, Chicago, Illinois. Manuscript received May 25, 1964. 470
AMERICAN
JOURN.4L
or
MEDICINE
Addison’s
Ikzase
and Hyperthyroidim-l,‘wXe,
'I“4eLE I URIVAKY
Time
STEROID
Urinary Steroids (mg./24 hr.)
of
I)etrrmination
Day
DErERMINATIONS
17 Ketosteroids*
17 Hydroxycorticoidst
1
~chttd j Day 2 (ACTH)$ Day 3 (ACTI)
:
* Normal female values: 7 to 15 mg. per 24 hours. t Normal female values: 3 to 7 mg. per 24 hours. $ Fifty units in 1,000 cc. 5 per cent dextrose in normal saline solution infused intravenously from 8:00 A.M. to 4:oo P.M. with sparse (unshaven) axillary hair. Skin turgor was poor. The radial pulse was not palpable and the brachial pulse was weak with a regular rate of 108 per minute. ‘The blood pressure by auscultation was 64/46 mm. Hg (in the right arm, with the patient recumbent), falling to 50/O mm. Hg when the patient was in a sitting position at which point she was forced to lie down because of marked light-headedness and a feeling of impending syncope. The remainder of the physical examination was within normal limits. Laboratory studies revealed a hemoglobin of 15.9 gm. per cent with a hematocrit of 49 per cent, white blood cell count 10,600 per cu. mm. with 29 per cent segmented polymorphonuclear leukocytes, 13 per cent nonsegmcnted polymorphonuclear leukocytes, 3 per cent eosinophils, 50 per cent lymphocytes and 5 per cent monocytes. The serum sodium was 135, potassium 4.6, chloride 90 and carbon dioxide 23 mEq. per L.; the pH was 7.34. The fasting blood sugar was 97 mg. per cent, the blood urea nitrogen 50 mg. per cent and the serum creatinine 1.9 mg. per cent. Urinalysis revealed 50 hyaline casts per low power field. with occasional coarse and degenerated casts, 3 to 12 white blood cells per low power’field, and moderate proteinuria with a specific gravity of 1.014. The serum calcium was 10.1 and serum phosphorus 2.8 mg. per cent. The plasma protein-bound iodine was 5.4 hg. per cent. Antithyroglobulin antibodies were detected in a titer greater than 1 :4,000 by a modification of the Boyden tanned red cell hemagglutination technic [5]. The patient’s serum was shown to possess complement-fixing antibodies to both thyroid and adrenal tissue by the technic of Blizzard et al. [fi.7];* a 4f result was obtained in * Wt. are indebted to Dr. Robert M. Blizzard, Johns Hopkins Hospital. Baltimore, Maryland, for formins
these studies.
the per-
Fddrrwri
each instance. In addition, a 4+ rcsl~lt \~a> obtained the presence of using fixed thyroid tissue, indicating agglutinating (antithyroglobulin) antibodies and confirming the findings with the tanned rrd cell technic. An electrocardiogram revealed a regular ratr of 100 per minute, a P-R interval of 0.16 scci)nd and a Q-T segment that was prolonged to +O. 10 second; the latter was thought to be compatible with hypokalemia and/or hypocalcemia. In addition, low voltage was present throughout all leads. Chest roentgenograms revealed no abnormalities but abdominal x-ray films showed calcification in the projection field of the right adrenal gland. Sephrotomograms established later that this calcification was anterior to the area of the right adrcsnal gland and probably represented a calcified abdominal lymph node. l’he results of tuberculin skin testing with purified protein derivative up to and including purified protein derivative no. 2 were negative, and several specimens of sputum revealed no organisms on smear or culture. On the second hospital day an infusion of 5 per cent dextrose in normal saline solution was started; the patient’s condition improved markedly over the next 24 hours when her blood pressure rose to 78150 mm. Hg with no evidence of postural hypotension and with a stronger and slower pulse. Corticoid determinations on blood samples obtained in the early morning (7: 00 A.M.) and the afternoon (4: 30 P.M.) of that day gave values of 4.3 and 1.8 pg. per cent, respectively (normal values 4 to 28 pg. per cent). That evening, therapy with 9-alpha-fluorohydrocortisone (Florinef@), 1 mg. twice daily, was startrd preparatory to performance of an ACTH stimulation test (50 units ACTH in 1 I,. normal saline solution infused over an 8 hour period). The AC’I‘H stimulation study was performed on two consecutive days and the results of these studies and of the baseline 24 hour urinary steroid determinations are shown in Table I. The data obtained confirmed the clinical impression of Addison’s disease. Following the ACTH stimulation tt’st. therapy with cortisone acetate, 37.5 mg. daily, was instituted and the Florinef dosage was reduced to C.1 mg. per day. By the fifth hospital day, the blood urea nitrogen had fallen to 8 mg. per cent, the serum creatinine was 0.9 mg. per cent, and the urinalysis was normal. A complete blood count on December 26 r(bvcaled a hemoglobin value of 10.5 gtn. per cent, a red blood cell count of 3.2 million per cu. mm. and a hematocrit of 30 per cent with a white blood cell count of 6,400 per cu. mm. The differential count again showed a marked lymphocytosis. The decrease in hemoglobin and hematocrit following therapy confirmed the clinical impression of initial hemoconcentration and relative hypovolemia. A repeat electrocardiogram was still abnormal, with a tendency to low voltage, but the Q-T interval was within normal limits. Since the institution of cortisone replacement
472
Addison’s
Disease
and Hyperthyroidism-Burke,
the patient has been asymptomatic and has had no more hiccoughs. Her weight has remained stable at 100 pounds and her blood pressure at 100/60 mm. Hg with no orthostatic hypotension. therapy,
COMMENTS
The statistical association of Addison’s disease and hyperthyroidism seems to be significant. In 1951 Frederickson [ 71 reviewed 180 cases of Addison’s disease and found a 4.4 per cent incidence of thyrotoxicosis, which is ten times that found in the general population. McConahey reviewed the records of 538 Addisonian patients seen at the Mayo Clinic from 1913 to 1958 and found sixteen with thyrotoxicosis, giving a similar incidence of 3 per cent [2]. However, it should be noted that in this series many patients were studied before specific diagnostic procedures were available and no mention of laboratory data was made in McConahey’s report. If a pathogenic mechanism is to be established, the sequence of the appearance of these two entities must be accounted for. In a review of the world literature in 1957 Rupp [S] noted eight documented cases in which Addison’s disease preceded or occurred simultaneously with hyperthyroidism to which he added a case of his own. Rupp found five adequately documented cases in which hyperthyroidism preceded Addison’s disease. In reviewing the world literature since 1957 we have found ten additional cases in the first category [g-76] and three, including our own, in the second [ 16-781. Thus there are now nineteen well documented cases in which Addison’s disease preceded or occurred simultaneously with hyperthyroidism and eight in which hyperthyroidism preceded Addison’s disease. The sequence in which hypoadrenocorticism follows hyperthyroidism is more easily explicable. The accelerated degradation of corticosteroids with normal plasma hydrocortisone levels and increased excretion of 17-OH corticoids in the urine over 24 hours has been well documented in hyperthyroidism [ 19,201. In addition, ACTH-like activity has been observed in the plasma of patients with thyrotoxicosis [27]. D’Angelo and Grodin [22] showed recently that continued administration of triiodothyronine to rats in large daily doses induced hyperactivity of the adrenal cortex, as indicated by markedly increased concentrations of corticoids in plasma and the adrenal gland and by hypertrophy of the gland. There was an inverse relationship between ascorbic acid and
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corticosterone concentration in the adrenals of severely hyperthyroid animals. Thus a patient with subclinical adrenal insufficiency and/or low adrenal reserve may have frank adrenal insufficiency if the adrenal remnant is unable to increase its steroid output. This explanation does not account for the manifestation of adrenal insufficiency in many of these patients months to years after they have been rendered euthyroid. It is more difficult to establish a pathogenic mechanism for the more frequent sequence in which Addison’s disease precedes hyperthyroidism. In a recent review [16], it was pointed out that a lesion must be postulated in which the increase in corticotrophin in Addison’s disease leads to a secondary increase in the secretion of thyroid stimulating hormones. However, evidence to date indicates that secretion of thyroid stimulating hormones is either moderately depressed or normal in this condition [23]. Pituitary cellular mechanisms have also been proposed as the mechanism [16]. The delta cells are said to elaborate and store gonadotrophins and corticotrophins, whereas the beta cells are believed to elaborate and store thyroid stimulating hormones. The question has been raised as to whether the delta cell can be transformed into a gamma cell and then into a beta cell and elaborate thyroid stimulating hormones, but evidence supporting this hypothesis is meager [76]. There is evidence that other pituitary hormones may affect thyroid function directly. In a recent study of the effects of various peptides on the thyroid in mice given injections of 1131 after they had been treated with thyroxine Bowers et al. [24] found that the greatest effects of 1131 on blood levels were elicited with corticotrophin A and natural or synthetic alpha-melanocyte stimulating and beta-melanocyte stimulating hormones. The latter were active in hypophysectomized mice, implying a direct effect on the thyroid gland. These data suggest that the elevated circulating levels of ACTH and melanocyte stimulating hormones in clinical adrenal insufficiency may in like manner stimulate the thyroid gland directly. A recent report [25] of the occurrence of thyrotoxicosis in two patients given large doses of steroids for long periods of time makes the physiological relationship between these two endocrines even more complex. The possibility of an immunologic basis for the coexistence of adrenal insufficiency and hyperthyroidism merits consideration. Blizzard AMERICAN
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:1ddison’s
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and Kvlr j7J recently reported the demonstration of circulating adrenal antibodies by the indirect Coombs’ test in thirty-six of seventy-one serums from Addisonian patients. Complement fixing antibodies were found in twenty-four of thcsta thirty-six serums. Twenty-two of the Addisonian patients had circulating antithyroid antibodies as measured by the indirect Coombs’ technic with unfixed thyroid tissue, but there was no correlation between the presence of circulating thyroid and adrenal antibodies and these patients did not manifest any evidence of thyroid disease. Although it has been shown [7] that idiopathic Addison’s disease meets all the criteria for an autoimmune process, the role of the circulating antiadrenal (cellular) antibodies has not been determined. These antibodies may reflect only the disease process rather than involvement in the pathogenesis of the adrenal insufliciency. Since the lymphocytic infiltration of the thyroid in autoimmune thyroiditis has been shown to be due to cellular antibodies [26,_37], and the frequent association of lymphocytic thyroiditis with ,4ddison’s disease has long been known [28], further support is lent, in fact, to the concept that Addison’s disease may also result from an autoimmune process. The high incidence of antithyroid antibodies reported bv Blizzard and Kyle [7] in the serums of Addisonian patients and the coincident occurrence of lymphocytic thyroiditis and Addison’s disease alluded to previously suggest the possibility that an autoimmune process may in some instances result in multiple endocrine deficiencies. To our knowledge, the case presented herein is the first reported instance of Addison’s disease and hyperthyroidism in which both antiadrenal and antithyroid antibodies have been demonstrated. Stewart et al. [ 151 described a forty year old man in whom hyperthyroidism developed two years after the diagnosis of Addison’s disease was established. In this case a positive thyroglobulin precipitin test and tanned red cell titers of up to 1 :25,000 were obtained. However, there was no evidence of adrenal antibodies despite repeated testing with the complement-fixing technic. Although our patient was treated with radioactive iodine, the treatment in itself does not result in the increase of thyroglobulin antibodies demonstrated in this case [29]. The usual antithyroglobulin tanned red cell titer in hyperthy-
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roidism is low, ranging from 1 : 10 to 1 : iI?0 [29]. Patients with hyperthyroidisrrr and high titers of antithyrobulin antibodies ‘ire prone to the development of hypothyroidisul after therapy whether treated with 1’“’ or by subtotal thyroidcctomy [_?,,W]. On this t)asis our patient: although presently euthyroid, may beIn this regard the marked, come hypothyroid. although transient, decrease in plasma proteinbound iodine observed after 1’“’ therapy was instituted is of some interest. As reported in the review of Becker and Randall [,?I, sk’m p’g 1 mentation may precede the other signs and symptoms of Addison’s disease by as much as fifteen years 1.311. The marked increase in melanin pigmentation observed in our patient at the time of diagnosis of thyrotosicosis may therefore have been the first indication of impairment of adrenocortical function. If this were the case, it is indeed surprising that overt adrenal insufficiency did not develop under the stress of the hypermetabolic state but appeared only after the patient had been rendered euthyroid. This difficulty in documenting the sequential onset of these endocrinopathies may well have been present in many of the other reported cases and renders suspect any mechanism(s) of pathogenesis based on the order of appearance of the two disease states. SUMMAR\
A forty year old woman treated for hyperthyroidism with Ii31 and in whom Addison’s disease developed later is described. 0f particular interest is the demonstration of both antithyroid and antiadrenal antibodies in the patient’s serum. The implications of these findings are discussed and related to a postulated pathogenic mechanism for the coexistence of these endocrinopathies. REFERENCES 1. FREDERICKSON,D. S. Effect of massive cortisone therapy on thyroid function. J. Clin. Endocrinol., 11: 760 1951. 2. MCCONAHEY, W. M., MEYERS, W. R. and GASTJNEAU, C. F. Grave’s disease in patients with Addison’s disease. Acta endocrinnl., 51 (supp.): 355, 1960. 3. BECKER, K. L. and RANDALL, R. V. Pigmentation as the presenting feature of Addison’s disease. Metabolism, 12: 1057, 1963. 4. WEGELIUS, 0. In: The Thyroid, p. 523. Edited by Werner, S. New York, 1962. Paul B. Hoeber, Inc. 5. BOYDEN, S. V. Adsorption of proteins on erythrocytes treated with tannic acid and subsequent hemag-
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&tin&ion by antiprotein sera. J. Exper. Med. 93: 107, 1951. BLIZZARD, R. M., CHANDLER, R. W., LANDING, B. H., PETTIT, M. D. and WEST, C. D. Maternal autoimmunization to thyroid as a probable cause of athyreotic cretinism. New England J. Med., 263: 327, 1960. BLIZZARD, R. M. and KYLE, M. Studies of the adrenal antigens and antibodies in Addison’s disease. J. Clin. Invest., 42: 1653, 1963. RUPP, J. J. and PASCHKIS, K. E. Coexistence of Addison’s disease and thyrotoxicosis. J. Clin. Endocrinol., 17: 143, 1957. DECOURT, J., DOUMIC, J. M. and MICHARD, J. P. Un cas de maladie d’Addison associte a une hyperthyroidie. Ann. endocrinol., 18: 423, 1957. FREY, H. M. Addison’s disease complicated by Grave’s disease. J. Clin. Endocrinol., 19 : 1497,1959. GREENBERG, W. V. Addison’s disease and hyperthyroidism. Ann. Int. Med., 55: 663, 1961. GABRILOVE, J. L. and WEINER, H. E. Effect of thyroid function on adrenocortical steroid metabolism in a patient with Addison’s disease and thyrotoxicosis. J. Clin. Endocrinol., 22: 795, 1962. PLAMONDON,C. and BRUNET, J. Maladie d’Addison associee a une hyperthyroidie chez une adolescente. Lava1 mid.. 27: 46, 1959. BOSHELL,B. R., WILSON, R. K. and MAXWELL, M. E. Addison’s disease complicated by thyrotoxicosis. M. Times, 91: 107, 1963. STEWART, W. K. GREEN, D. M. and LOWE, K. G. Addison’s disease and hyperthyroidism. Acto endocrinol., 40: 613, 1962. BRUNO, M. S., OBER, W. B., KUPPERMAN,H. S. and EPSTEIN, J. A. Coexistent Addison’s disease and thyrotoxicosis. Arch. Znt. Med., 110: 155, 1962. JENKINS,J. S., PILKINGTON,T. R. E. and ROSENOER, V. M. Thyrotoxicosis and Addison’s disease in the same patient. Brit. M. J., 1: 1025, 1960. FRIIS, T. Thyrotoxic crisis: two cases of which one subsequently developed Addison’s disease. U,esk. Laeger., 124: 278, 1962. PETERSON, R. E. The influence of the thyroid on
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adrenal cortical function. J. Clin. Inrlest.,37: 736, 1958. MELBY, J. C. Regulatory effect of thyroid hormone on cortisol metabolism. J. Lab. M Clin. Med., 54: 924, 1959. HILTON, J. G., BLOCK, W. C., ATIIOS, W., MCHUGH, B. and WESTERMANN,C. D. Increased ACTH-like activity in plasma of patients with thyrotoxicosis. J. Clin. Endocrinol., 22: 900, 1962. D’ANGELO, S. A. and GRODIN, J. M. Experimental hyperthyroidism and adrenocortical function in the rat. Endocrinology, 74: 509, 1964. INGBAR, S. H. and FREINKEL,N. ACTH, cortisone, and the metabolism of iodine. M&bolism, 5: 652, 1956. BOWERS,C. Y., REDDING,T. W. and SCHALLY, A. V. Effects of OL-and fl-melanocyte stimulating hormones and other peptides on the thyroid in mice. Endocrinology, 74: 559, 1964. BROWN, D. M. and LOWMAN, J. T. Thyrotoxicosis occurring in two patients on prolonged high doses of steroids. New England J. Med., 270: 278, 1964. FELIX-DAVIES,D. and WAKSMAN,B. H. Passive transfer of experimental immune thyroiditis in the guinea-pig. Arthritis @ Rheumat., 4: 416, 1961. MCMASTER, P. R. B., LERNER, E. M., II and EXUM, E. D. The relationship of delayed hypersensitivity and circulating antibody to experimental allergic thyroiditis in inbred guinea pigs. J. Exfer. Med., 113: 611, 1961. WELLS, H. G. Addison’s disease with selective destruction of the suprarenal cortex (“supra-renal cortex atrophy”). Arch. Path., 10: 499, 1930. BLAGG, C. R. Antibodies to thyroglobulin in patients with thyrotoxicosis treated with radioactive iodine. Lancet, 2: 1364, 1960. ,IRVINE, W. J., MCGREGOR, A. G. and STUART, A. E. The prognostic significance of thyroid antibodies in the management of thyrotoxicosis. Lancet, 2: 843, 1962. SIMPSON,S. L. Clinical and pathological aspects of the adrenal glands. Proc. Roy. Sot. Med., 27: 383, 1933-34.
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