Replacement in Isolated Adrenocorticotropin Deficiency

Transcription

1 CASE REPORT Improvement of Hypothyroidism after Glucocorticoid Replacement in Isolated Adrenocorticotropin Deficiency Misa Tamura, Naokata Yokoyama, Tomoko Nishikawa, Akira Takeshita, Hironori Kimura, Kiyoto Ashizawa, Takeshi Kiriyama and Shigenobu Nagataki Wereport a 50-year-old female who suffered from reversible hypothyroidism accompanied by isolated ACTHdeficiency. There were no findings indicating a complication of autoimmune thyroiditis. Replacement of maintenance dose of glucocorticoid not only led to improvement of thyroid function, but also caused a transient decrease in T3 and an increase in reverse T3, suggesting that chronic cortisol deficiency may impair thyroid function, and that the maintenance dose, as well as pharmacological doses ofglucocorticoids may influence T4 deiodination. The findings of this case suggest that thyroid function should be re-evaluated to avoid unnecessary replacement of thyroid hormone, a few months after glucocorticoid replacement. (Internal Medicine 34: , 1995) Key words: autoimmune thyroiditis, T4 deiodination, reverse T3, physiological dose Introduction Isolated adrenocorticotropin (ACTH) deficiency is a rare cause of secondary adrenocortical insufficiency. Although the pathogenesis of isolated ACTHdeficiency is uncertain in most cases, an autoimmunemechanism may in part, be involved as suggested by the histological evidence of lymphocytic hypophysitis, frequent observation of anti-pituitary antibodies and occasional association with other autoimmune disorders (1). In isolated ACTHdeficiency, there have been clinical associations with autoimmune thyroiditis characterized by the presence ofautoimmune mechanisms, which is a major etiology of primary hypothyroidism (1-4). Some cases have been reported with reversible hypothyroidism in isolated ACTHdeficiency (3-5). On the other hand, there is another possibility that cortisol deficiency could directly affect thyroid function; the mechanisms have been discussed in a few reports (5-7). The actual mechanism, however, remains unresolved. Another effect of glucocorticoid on thyroid function is to suppress conversion of thyroxine (T4) to triiodothyronine (T3). It is well known that peripheral T4 deiodination is affected by pharmacological doses of glucocorticoids (prednisolone or dexamethasone) (8-1 1). There have, however, been few reports on the effect of the physiological dose of glucocorticoid. In this report, we show a case of isolated ACTHdeficiency accompanied by reversible hypothyroidism without autoimmune thyroiditis and a transient decrease in T3 and an increase in reverse T3 (rt3) after replacement of glucocorticoid. The function and presence of autoimmunity in the thyroid gland of this patient were examined in great detail. It is also the purpose of this report to investigate the evidence concerningthe role of maintenance dose of glucocorticoid in the regulation of thyroid func tion. Case Report A 50-year-old womanwas admitted because of loss of consciousness induced by hypoglycemia (blood glucose 2.3 mmol/1). There was no significant family history or past history including excess iodine intake. On admission, she was cm tall and weighed 46.6 kg. Blood pressure was 124/70 mmhg, pulse was 76/min, chest and abdomenwere not remarkable. Face color was pale and slightly anemic. There was no abnormal pigmentation. The thyroid gland was mildly enlarged in size, elastically firm in consistency. Axillary and pubic hair were absent. There was no edema. Musclestrength and tonus werenormal. Tendonreflexes relaxed slowly. There wereno pathological reflexes or sensory disturbance. Blood chemistries revealed slightly increased activity of muscle-derived enzymes [creatine kinase 5.3 nkat/l ( ), lactate dehydrogenase 9.7 jakat/1 ( )], but serum electrolytes were within the normal range. Hematological tests From the First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki Received for publication October 3, 1994; Accepted for publication February 6, Reprint requests should be addressed to Dr. Shigenobu Nagataki, the First Department of Internal Medicine, Nagasaki University School of Medicine, Sakamoto, Nagasaki

2 Tamuraet al showed mild anemia [erythrocyte count 3.45xlO12/l, hemoglobin 102 g/l, hematocrit 0.30]. Leukocyte count was 5.0xl09/l and there was no eosinophilia nor lymphocytosis. Tables 1 and 2 show the basal endocrinological data and results of various stimulation tests, respectively, indicating that ACTH, cortisol and growth hormone (GH) were deficient. In addition, hyperprolactinemia and hypothyroidism (increase in TSHand decrease in thyroid hormones) were present. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) increased because the patient was postmenopausal. All of the autoantibodies to the pituitary cells, AtT-20 and GH3, to thyroglobulin (Tg), thyroid peroxidase (TPO), thyrotropin (TSH) receptor, and to the adrenocortical gland were undetectable. Magnetic resonance imaging (MRI) revealed an empty sella. On thyroid echo imaging, the thyroid gland was mildly enlarged and the internal echo level was almost isoechoic and homogeneous. Histological findings of the thyroid gland by needle Hormone Table 1. Endocrinological Findings TSH ( mU/l) 59.6 free T4 ( pmol/l) 4.2 free T3 ( pmol/l) 3.8 T4 ( nmol/l) 33.8 Values T3 ( nmol/l) 1.6 reverse T3 ( nmol/l:) 0.06 Thyroglobulin (<30ng/ml) 1 80 Thyroxine binding globulin (TBG) (15-28 ig/ml) 31.3 GH (<5.0 jug/1) 1.1 LH (3-25IU/1) 27.7 FSH (2-25IU/1) 82.5 Estradiol (70-1, 1 00pmol/l) Progesterone (<6nmol/l) <0.3 PRL (<10 juga) 14.4 Insulin (< 143pmol/l) Low (<0.7) ACTH ( pmol/l) Cortisol ( nmol/l) Low (<34) Dehydroepiandrosterone sulphate ( LimolA) Low (<0.03) 1 7 -hydroxycorticosteroids (17-OHCS) ( jamol/day) ketosteroids (17-KS) ( jimol/day) 3. 1 Autoantibodies Pituitary antibodies AtT-20 cells (-) GH3 cells (-) Thyroid antibodies TSH receptor Ab (<10%) 0.1 thyroglobulin Ab (<0.3U/ml) <0.3 TPO Ab (<0.2U/ml) <0.2 Adrenocortical antibody (-) biopsy revealed thyroid follicles of irregular size, but there was no fibrosis or lymphocyte infiltration (Fig. 1). These findings were not compatible with those of autoimmunethyroiditis. In spite of the increase in TSH, the 123I uptake (%) of the thyroid decreased to 13.3% in 24 hours. Iodide-restricted diets in our hospital were sufficient for evaluating thyroidal 123I uptake, which were supported by results of urinary iodide excretion. There was no obvious iodide organiflcation defect because perchlorate discharge test was negative. After replacement of glucocorticoid (hydrocortisone 15 mg daily; 10 mg in the morning and 5 mgin the evening), basal levels and the response Table 2. Results of Various Stimulation Tests before Glucocorticoid Replacement 1. Insulin tolerance test (regular insulin 0.05 U/kg i.v.) Basal min Bloodglucose * (mmol/1) ACTH (pmol/1) Cortisol(nmol/1) Low Low Low Low Low Low GH**0ig/l) *Hypoglycemiaoccurred during the test. Glucose was administered i.v. **After glucocorticoid replacement, basal levels and response to stimulation tests of GHwere restored. 2. CRF stimulation test (Ovine CRF 100 ig i.v.) Basal min ACTH(pmol/1) Cortisol(nmol/1) Low Low Low Low Low Low 3. Rapid ACTHtest (Tetracosactide acetate 250 jixg i.v.) Basal Cortisol (nmol/1) Low Aldosterone (pmol/1) LH-RH stimulation test (Gonadorelin acetate 100 jag i.v.) Basal min LH (IU/1) FSH (IU/1) TRH stimulation test (Protirelin 500 Jig i.v.) Basal min TSH(mUA) PRL*** (jig/i) ***After glucocorticoid replacement, basal levels and response to stimulation tests of PRLwere restored. 560

3 Hypothyroidism in ACTHDeficiency to stimulation tests (insulin tolerance test and TRHtest, respectively) of GH and prolactin (PRL) improved (data not shown) (1, 12, 13). This case, therefore, was diagnosed as isolated ACTHdeficiency accompanied by hypothyroidism. After replacement therapy of glucocorticoid, basal levels of free T4 and TSH (Fig. 2A), TSH hyperresponse to TRH(Fig. 3) and the difference between T4 values at 0 and 120 minutes (AT4) as an index of thyroidal response to endogenous TSHstimulated by TSH releasing hormone (TRH) (14) (Fig. 4) restored respectively, and 123I uptake (%) of the thyroid increased to 3 1.2% (24 hours) without any replacement of thyroid hormone ^ 200- * ^^"^\^ ^ 100- / Figure 1. Histological findings of thyroid gland obtained by needle biopsy, indicated no autoimmune thyroiditis (HE stain, xloo). A Hydrocortisone (15mg/day) I 1 I 14-1 r 80 OH Figure 3. TRH stimulation test. A single dose of 500 jig of Protirelin i.v. was administered. à"before glucocorticoid replacement, O after glucocorticoid replacement. min 10- m-. 4i^ ^^ ^\^^^-^^^ "20 ^,, 2-0J. å n r-, U day B 3-i r0.5 1 ' / < / 0J.,., å, å day Figure 2. Changes in thyroid function after replacement of maintenance doses of glucocorticoid (hydrocortisone: 15 mg/day). A) ft4 (pmol/1: à") and TSH (mu/1: O), B) T3 (nmol/1: #) and rt3 (nmol/1: O). -ioh 1 1 before glucocorticoid replacement after Figure 4. ThyroidalresponsetoendogenousTSH increased by TRHstimulation before and after glucocorticoid replacement. AT4 (nmol/1): difference between T4 values at 0 and 120 minutes after 500 jag TRH administration. 561

4 Tamuraet al Aside from these, T3 levels decreased and rt3 levels increased contrary to our expectation within a brief period after replacement of glucocorticoid, which seemed to be low T3 syndrome. After a transient interruption (10 days) of replacement of glucocorticoid, T3 and rt3 did, however, return to the levels before replacement. These inverse changes in T3 and rt3 reappeared after resumption of replacement (Fig. 2B). T3 and rt3 levels, finally, were settled into the normal range after longterm replacement of glucocorticoid. Discussion It is well known that the physiological serum level of glucocorticoid is necessary to maintain normal TSHrelease and bioactivity in the pituitary gland. TSH excess before glucocorticoid replacement in adrenal insufficiency may be attributed to direct enhancementof TSHrelease due to chronic cortisol deficiency, and also to a complication of primary hypothyroidism (1, 13). There have been several reports on adrenal insufficiency (isolated ACTHdeficiency and Addison's disease) accompanied by reversible hypothyroidism (1, 3-8, 15-17), in which two theories are proposed as the mechanisms of thyroid dysfunction. The first possibility is autoimmune thyroiditis associated with isolated ACTHdeficiency, which may affect thyroid function (4, 15). The improvement of thyroid function after glucocorticoid replacement may be associated with resolution of intrathyroidal autoimmune processes inhibiting thyroid hormone synthesis. Indeed, it is well known that administration of glucocorticoid can clinically improve thyroid function in autoimmune thyroiditis with not only pharmacologically high doses (dexamethasone) (18), but also physiological doses (hydrocortisone), in several reports (4, 7, 15, 16). There has, however, been no evidence whether the physiological doses are sufficient to improve autoimmune processes. The second possibility is that chronic cortisol deficiency in isolated ACTHdeficiency may directly impair the thyroid response to TSH, synthesis and/or secretion of the thyroid hormone (5, 8, 17, 19, 20). In the present case, autoimmune mechanismswere not detected at all even on measurementof autoantibodies to Tg and TPOby a highly sensitive radioimmune assay (21) and by histological examination by needle biopsy. There has been no report of a detailed investigation of the thyroid gland including functional, immunological and histological analyses. After maintenance dose of glucocorticoid replacement, the thyroidal 123I uptake and AT4as an index of thyroidal response to endogenous TSH were significantly improved as serum thyroid hormone levels became within the normal range, indicating that maintenance dose of glucocorticoid may improve not only TSH release in the pituitary gland (1), but also the response of the thyroid gland to endogenous TSH. It is also reported that glucocorticoid could induce upregulation of expression of TSHreceptor mrnaby in vitro human thyroid studies (22). In the present case, it is confirmed that reversible primary hypothyroidism in isolated ACTHdeficiency was not due to autoimmunethyroiditis, but was mainly 562 due to chronic cortisol deficiency. Only a mild increase oftsh level after replacement could be due to insufficient doses and/ or periods of glucocorticoid therapy for complete recovery of pituitary-thyroid axis, and also due to any thyroid diseases undetectable even by the detailed examinations. The decrease in TSHand increase in T3 and T4 after admission were observed before replacement therapy, which may be due to the relative amelioration of glucocorticoid deficiency by relieving acute stress (5). At the early period after glucocorticoid replacement, there was transiently shown inverse changes in T3 and rt3 (decreased T3 and increased rt3), which appeared to be, the so-called, low T3 syndrome. LowT3 syndrome was not shownbefore glucocorticoid replacement in this case and these inverse changes in T3 and rt3 were reproducible by the transient interruption and resumption of glucocorticoid replacement. These results suggest that inverse changes in T3 and rt3 appeared as a transiently limited effect of glucocorticoid even with maintenance doses. On the other hand, T4 and TSHlevels were unchanged by a brief interruption of replacement therapy, indicating that such a brief interruption could not directly influence the actual thyroid function which was within nearly normal range after chronic replacement of glucocorticoid. It was previously reported (8) that treatment with physiological levels of adrenal steroids do not cause inverse changes in T3 and rt3, which differs from the present results. However, it is generally thought that these inverse changes are pharmacologically (9-1 1 ) rather than physiological effects of glucocorticoid; the peripheral tissues in this patient with long-term deficiency of glucocorticoid may show an excessive reaction even to maintenancedose transiently. In conclusion, these results indicate that chronic cortisol deficiency may impair thyroid function in several steps : namely, responsiveness to TSH, synthesis and/or secretion of thyroid hormone and also T4 deiodination, even in a patient without obvious autoimmune thyroid diseases. Finally, a follow-up reevaluation of thyroid function is recommended to avoid unnecessary replacement of thyroid hormone a few months after glucocorticoid replacement. Acknowledgments: We are grateful to Miss Ryoko Tamasaki for her excellent assistance in the preparation of this manuscript. References 1) Hashimoto K, Nishioka T, Iyota K, et al. Hyperresponsiveness of TSH and prolactin and impaired responsiveness of GHin Japanese patients with isolated ACTHdeficiency. Nihon Naibunpitsu Gakkai Zasshi (Folia Endocrinol) 68: 1096, 1992 (Abstract in English). 2) Yamamoto T, Fukuyama J, Hasegawa K, Sugiura M. Isolated corticotropin deficiency in adults. Arch Intern Med 152: 1705, ) Horii K, Adachi Y, Aoki N, Yamamoto T. Isolated ACTH deficiency associated with Hashimoto's thyroiditis: report of a case. Jpn J Med23: 53, ) Shigemasa C, Kouchi T, Ueta Y, Mitani Y, Yoshida A, Mashiba H. Evaluation of thyroid function in patients with isolated adrenocorticotropin deficiency. Am J Med Sci 304: 279, ) Murakami T, Wada S, Katayama Y, Nemoto Y, Kugai N, Nagata N. 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