Endocrine Journal 2004, 51 (1), 105–113 NOTE A Case of Cushing Syndrome with Both Secondary Hypothyroidism and Hypercalcemia Due to Postoperative Adrenal Insufficiency MASAHITO KATAHIRA, TSUTOMU YAMADA* AND MASAHIKO KAWAI* Department of Internal Medicine, Kyoritsu General Hospital, Nagoya 456-8611, Japan *Division of Endocrinology, Department of Internal Medicine, Okazaki City Hospital, Okazaki 444-8553, Japan Abstract. A 48-year-old woman was referred to our hospital because of secondary hypothyroidism. Upon admission a left adrenal tumor was also detected using computed tomography. Laboratory data and adrenal scintigraphy were compatible with Cushing syndrome due to the left adrenocortical adenoma, although she showed no response to the TRH stimulation test. Hypercortisolism resulting in secondary hypothyroidism was diagnosed. After a left adrenalectomy, hydrocortisone administration was begun and the dose was reduced gradually. After discharge on the 23rd postoperative day, she began to suffer from anorexia. ACTH level remained low, and serum cortisol, free thyroxine and TSH levels were within the normal range. Since her condition became worse, she was re-admitted on the 107th postoperative day at which time serum calcium level was high (15.6 mg/dl). Both ACTH response to the CRH stimulation test and TSH response to the TRH stimulation test were restored to almost normal levels, but there was no response of cortisol to CRH stimulation test. We diagnosed that the hypercalcemia was due to adrenal insufficiency. Although the serum calcium level decreased to normal after hydrocortisone was increased (35 mg/day), secondary hypothyroidism recurred. It was suggested that sufficient glucocorticoids suppressed TSH secretion mainly at the pituitary level, which resulted in secondary (corticogenic) hypothyroidism. However, both postoperative glucocorticoid deficiency and adequate amounts of thyroxine due to the elimination of inhibition of TSH secretion by glucocorticoids might cause hypercalcemia possibly through increased bone reabsorption of calcium. Key words: Cushing syndrome, Corticogenic hypothyroidism, Hypercalcemia, Hydrocortisone withdrawal, Thyroxine (Endocrine Journal 51: 105–113, 2004) CUSHING syndrome has been known to occur in with a prevalence of 6% in primary adrenal insuffi- association with secondary hypothyroidism [1, 2]. It is ciency. Some investigators reported a case of hyper- known that both natural and synthetic glucocorticoids calcemia after surgical treatment of Cushing syndrome inhibit thyroid function by suppressing TSH secretion [13, 14]. However, to our knowledge, a case of both at the suprahypophysial level [3–7] and/or at the pitui- Cushing syndrome with secondary hypothyroidism tary level [6–9]. Such secondary hypothyroidism is and hypercalcemia due to adrenal insufficiency after called “corticogenic hypothyroidism” [10]. On the surgical treatment of Cushing syndrome has not been other hand, hypercalcemia in association with hypo- reported to date. We report here the first case of Cush- adrenalism was first described in 1932 [11]. Nerup ing syndrome resulting in secondary hypothyroidism, [12] reported that hypercalcemia was demonstrated which was complicated by hypercalcemia in hydro- cortisone withdrawal. Received: January 15, 2003 Accepted: October 17, 2003 Correspondence to: Masahito KATAHIRA, M.D., Department of Case Report Internal Medicine, Kyoritsu General Hospital, 4-33 Goban-cho, Atsuta-ku, Nagoya 456-8611, Japan A 48-year-old woman had suffered from irritation 106 KATAHIRA et al. and anxiety since 1998, when her menstrual cycle be- hypertension. Her mother had diabetes mellitus and came irregular. After 1995 her weight increased from arrhythmia. 68 kg to 73 kg in 2000 and began to decrease there- Physical examination showed the following findings: after. She also began to suffer from tremors, resulting height 154.6 cm, weight 64.2 kg, body mass index in her admission to a psychiatric hospital on July 25, 26.9 kg/m2, blood pressure 147/97 mmHg, pulse rate 2001. She had a small goiter and decreased levels of 70 beats/min and temperature 37.0ºC. Conjunctivae free thyroxine (FT4) and TSH (0.67 ng/dl and 0.13 were not anemic. Pulmonary, cardiac, abdominal and U/ml, respectively). Hypokalemia (3.13 mmol/l) neurological examinations were unremarkable. The was also detected and potassium was administered. goiter was small, and the tremors had already dimin- She was referred and admitted to our hospital on ished. She had normal hircus and pubic hair, but had September 21, 2001 because of secondary hypothy- moon face and buffalo hump as well as striae cutis roidism and hypokalemia. She has been administered distensae and peripheral edema. hypotensors and diuretics since 1991 because of hyper- Laboratory data on first admission are shown in tension and edema. Her father and sister also had Table 1. White blood count was normal, but eosinocyte Table 1. Laboratory findings on first admission Urinalysis Endocrinology Protein (–) Free triiodothyronine 1.98 pg/ml Glucose (–) Free thyroxine 0.53 ng/dl Occult blood (–) TSH 0.02 U/ml TGPA (–) Blood cell count MCPA (–) White blood cell 4400/ l Eosinocyte 0% ACTH <5 pg/ml Red blood cell 341×104/ l DHEA-S 306 ng/ml Hemoglobin 10.1 g/dl Cortisol (serum) 23.2 g/dl Hematocrit 31.4% (urine) 153–255 g/day Platelet 21.6×104/ l Urinary 17-KS 3.4–3.7 mg/day Urinary 17-OHCS 9.9–12.6 mg/day Blood chemistry GH 0.26 ng/ml Total protein 5.9 g/dl Somatomedin-C 140 ng/ml Albumin 60.7% PRL 35 ng/ml 1-globulin 2.8% LH 1.3 mIU/ml 2-globulin 8.6% FSH 5.0 mIU/ml -globulin 12.2% Serum estradiol 44.7 pg/ml -globulin 15.7% Serum adrenaline <5 pg/ml Aspartate aminotransferase 26 IU/l Serum noradrenaline 106 pg/ml Alanine aminotransferase 58 IU/l Serum dopamine <5 pg/ml Lactate dehydrogenase 378 IU/l Plasma renin concentration 6.5 pg/ml Alkaline phosphatase 189 IU/l Serum aldosterone 16 pg/ml Sodium 144 mmol/l Potassium 3.2 mmol/l Anti-pituitary cell antibody (–) Chloride 106 mmol/l (indirect fluorescent antibody technique) Calcium 9.4 mg/dl Phosphate 3.6 mg/dl Daily variation Blood urea nitrogen 13 mg/dl Time ACTH (pg/ml) Serum cortisol ( g/dl) Creatinine 0.50 mg/dl 0600 h <5 17.7 Total cholesterol 204 mg/dl 1200 h <5 24.7 Fasting plasma glucose 79 mg/dl 1800 h <5 21.3 Hemoglobin A 5.1% 1c 2400 h <5 22.9 TGPA: anti-thyrogloblin particle agglutination, MCPA: anti-thyroid microsomal particle agglutination, DHEA-S: dehydroepiandrosterone sulfate, 17-KS: 17-ketosteroid, 17-OHCS: 17-hydroxycorticosteroid GLUCOCORTICOID REGULATION OF TSH AND CALCIUM 107 was not detected. Total protein level (normal range: Table 2. Results from the endocrinological examination on 6.2–7.8 g/dl) was slightly low, and plasma protein first admission fraction was normal. Alanine aminotransferase and CRH stimulation test (CRH 100 g iv) lactate dehydrogenase levels were high. Serum potas- Time (min) 0 30 60 90 120 sium level was low. Free triiodothyronine (FT3), FT4 ACTH (pg/ml) 5 <5 <5 <5 <5 and TSH levels (normal range: 3.14–4.93 pg/ml, 0.82– Serum cortisol ( g/dl) 18.8 17.4 17.1 16.0 16.7 1.59 ng/dl, and 0.43–3.94 U/ml, respectively) were TRH stimulation test (TRH 500 g iv) low. PRL level was high. Plasma ACTH level was Time (min) 0 30 60 90 120 suppressed, while serum cortisol, urinary cortisol and TSH ( U/ml) 0.020.030.040.020.02 urinary 17-hydroxycorticosteroid (17-OHCS) levels PRL (ng/ml) 32 55 49 45 39 were high. Daily variations in plasma ACTH and cor- GRH stimulation test (GRH 100 g iv) tisol levels were not observed. Results from the endo- Time (min) 0 30 60 90 120 crinological examination on first admission are shown GH (ng/ml) 0.20 1.21 0.04 0.73 0.49 in Table 2. ACTH did not respond to 100 g CRH LH-RH stimulation test (LH-RH 100 g iv) stimulation, whereas the serum cortisol level remained Time (min) 0 30 60 90 120 high. In addition, TSH did not respond to 500 g TRH LH (mIU/ml) 2.5 9.6 14 16 20 stimulation. Basal PRL had increased, while PRL FSH (mIU/ml) 5.9 9.9 12 15 19 Fig. 1. Clinical imaging on first admission. (A) Abdominal computed tomography. Arrows indicate an adrenal tumor in the left adrenal gland. (B) 131I-adosterol scintigram demonstrated a greater uptake in the left adrenal gland. (C) Magnetic resonance image of the head revealed no mass. 108 KATAHIRA et al. response to TRH had slightly decreased. GH response immediately after the surgical treatment and the dose to GRH had also decreased. Responses of LH and was reduced gradually from 200 mg/day. Potassium FSH to LH-RH were delayed. Computed tomography was discontinued on November 6, 2001. The patient (CT) of the abdomen revealed a distinct solitary mass was discharged with replacement of hydrocortisone (3.5 cm in diameter) on the left adrenal gland (Fig. 1A). 131I-adosterol scintigraphy revealed a hot uptake around the left adrenal gland (Fig. 1B). In contrast, magnetic resonance image (MRI) of the head revealed no mass (Fig. 1C). Based on these findings, the dis- ease was diagnosed as Cushing syndrome due to left adrenal tumor. Administration of levothyroxine (50 g/day) was begun and potassium was increased from 3.6 mEq/day to 16 mEq/day. Although there had been no menstrual bleeding since August 2001, it started on October 13, 2001. After FT4 and serum potassium levels reached the normal ranges, the left adrenal tumor was removed on October 17, 2001. Fine granular cells proliferated and atypical nuclei were not found, histologically suggesting that the adrenal tumor was an adenoma Fig.