CASE REPORT Cushing's Syndrome due to Unilateral Adrenocortical Hyperplasia Fumio Otsuka, Toshio Ogura*, Kazushi Nakao, Nobuhiko Hayakawa, Yukari Mimura, Takayoshi Yamauchi and Hirofumi Makino A 49-year-old womanwith Cushing's syndrome due to unilateral adrenal hyperplasia is presented. She had developed obesity and menopausefor 2 years, but no hypertension or hypertrichosis was observed. Althoughplasma adrenocorticotropin and serum cortisol levels were within normal ranges, the circadian rhythm has completely disappeared. Free thyroxine and triiodothyronine levels were decreased. Adrenocorticotropin did not respond to corticotropin- releasing hormone, and urinary excretion of 17-hydroxycorticosteroids was not suppressed by dexamethasone. Abdominal computed tomography and 131I-Adosterol scintigraphy demonstrated a unilateral functioning mass in the left adrenal gland. The resected left adrenal mass was pathologically diagnosed as the rare condition of adrenocortical nodular hyperplasia. (Internal Medicine 37: 385-390, 1998) Key words: glucocorticoid, adrenalectomy, dexamethasone suppression test, thyroid Introduction The examination findings of lung, heart and nervous system revealed nothing in particular. The laboratory examination Cushing's syndromeis caused by adrenocortical hyperse- revealed the following: white blood cell count, 9,300/|il with cretion of cortisol, most of which results from adrenocortical 15%lymphocytes and 1%eosinophils; red blood cell count, adenoma or pituitary adenoma, i.e. Cushing's disease. The 419x104/jli1; hemoglobin, 13.5 g/dl; hematocrit, 40.6%; plate- present case of Cushing's syndrome is attributable to a unilat- let, 3 10x103/|ll1; total protein, 6. 1 1 g/dl; serum albumin, 3.58 g/ eral adrenocortical hyperplasia. This rare pathology has been dl; serum sodium, 144 mmol//; serum potassium, 3.9 mmol//; documented in only 5 cases ofCushing's syndrome (1-5). This serum chloride, 105 mmol//, serum calcium, 8.6 mg/dl; serum case report not only introduces a clinical variety of Cushing's inorganic phosphate, 3. 1 mg/dl; alkaline phosphatase, 107 IU/ syndrome, but also illustrates the clinical influence of adrenal /; creatinine phosphokinase, 73 IU//; total cholesterol, 227 mg/ function on the thyroid. dl; and triglyceride, 108 mg/dl; liver, renal functions and urinalysis were normal. Fasting blood glucose was 86 mg/dl, Case Report and hemoglobin Alc was 6.4% (normal: 4-6). Oral glucose (75 g) tolerance test revealed an impaired glucose tolerance. The A 49-year-old womaninitially presented a complaint of bone density in her lumbar spine (QDR- 1000) was decreased to pretibial edema in 1989. She has been free of both hypertension 0.609 g/cm2 (mean ± SD in a normal 49-year-old female: 0.993 and diabetes, but she has suffered general fatigue and has gained + 0. 139). The endocrinological data on admission are shown in 5 kg over 2 years. Menopause occurred at the age of47 years Table 1. Free triiodothyronine (FT3) and thyroxine (FT4) con- old. She was admitted to our hospital for evaluation of endo- centrations were decreased, while thyrotropin (TSH) level was crine function in 1996. The physical examination on admission normal. Reverse triiodothyronine (rT3) and thyroxine binding revealed the following: height, 147.9 cm; weight, 55.7 kg, globulin (TBG) were normal. The serum cortisol (F) concentra- featuring mild obesity with a round face; blood pressure, 136/ tion in the morningwasnormal, and the plasma adrenocortico- 80 mmHg;pulse, 75 bpm and regular. No goiter or lymphade- tropin (ACTH)obtained at the sametime was at the lower limit nopathy wasobserved. Nostriae cutis wasfound on abdomen of the normal range. Urinary excretion of both 17-hydroxy- or extremities. Pretibial and pedal pitting edema were noted. corticosteroids (17-OHCS) and 17-ketosteroids (17-KS) were From the Department of Medicine III, Okayama University Medical School and *Health and Medical Center, Okayama University, Okayama Received for publication July 25, 1997; Accepted for publication December 24, 1997 Reprint requests should be addressed to Dr. Fumio Otsuka, the Department of Medicine III, OkayamaUniversity Medical School, 2-5- 1 Shikata-cho, Okayama 700-8558 Internal Medicine Vol. 37, No. 4 (April 1998) 385 Otsuka et al also within normal limits. No thyroid autoantibodies including adrenal mass was discovered on abdominal computed tomo- anti-thyroid peroxidase (TPO) antibody, anti-thyroglobulin graphy (CT; Fig. 1A), while no nodular formation was de- (TG) antibody, or thyrotropin binding inhibitory immunoglobu- tected in right adrenal gland (Fig. IB). The 131I-Adosterol lin (TBII) were detected. The responses of ACTHand F to scintigraphy exhibited a fine accumulation in the left adrenal corticotropin-releasing hormone (CRH)were completely sup- mass, in contrast to no accumulation in the right adrenal gland pressed, and the response of TSHto thyrotropin-releasing (Fig. 2). Because the diagnosis of Cushing's syndrome was hormone (TRH) was also markedly suppressed (Table 2a). confirmed, left adrenalectomy was performed on July 23, 1996. Cranial magnetic resonance imaging (MRI) demonstrated a Histological examination of the resected mass was consistent normal pituitary. The circadian rhythm of ACTHand F was with adrenal macronodular hyperplasia, predominantly con- completely eliminated (Table 3a), and the adrenal response to sisting of compact cells (Fig. 3). Following adrenalectomy, ACTHinjection (0.25 mg) was impaired. Administration of 1 intravenous administration of hydrocortisone (100 to 50 mg/ mg dexamethasone did not suppress serum F level, and the day) was initiated for 3 days, and oral administration with 25 suppression test using 2 or 8 mg dexamethasone revealed a mg/day ofhydrocortisone has been maintained. One weekafter paradoxic increase of urinary 17-OHCS (Table 4). A left the surgery, serum F change in a day has taken the form of a Table 1. Preoperative Endocrinological Data Blood sample: ACTH 4.4 -pg/ml (4.4-48) PRL 26.5 ng/ml (<30) F 16.3 (ig/dl (5-21) GH 1.13 ng/ml (0.28-8.7) FT3 2.30 pg/ml (4-5.8) PAC 53.0 pg/ml (57-150) TSH 2.2 |LiU/ml (0.55-4.8) FT4 0.70 ng/dl (1.03-2.21) DHEAS 26 |ig/dl (33-262) LH 26.57 mlU/ml (>15) rT3 141 pg/ml (140-410) HANP 25.7 pg/ml (<43) FSH 80.43 mIU/ml (>15) TBG 15.4 jig/ml (12-30) AVP 4.4 pg/ml (0.8-6.3) Urine sample: U-AD 6 |Lig/day (3-23) U-NA 80 |ig/day (25-131) U-DA 1,000 jig/day (150-1,000) U-17OHCS 6.0 mg/day (2.6-7.8) U-17KS 3.5 mg/day (1-8) U-CPR 65 Jig/day (20-130) ACTH:adrenocorticotropin, GH: growth hormone, TSH: thyroid stimulating hormone, LH: luteinizing hormone, FSH: follicle stimulating hormone, PRL: prolactin, FT3: free triiodothyronine, FT4: free thyroxine, rT3: reverse triiodothyronine, TBG: thyroxine binding globulin, F: cortisol, PAC: plasma aldosterone concentration, DHEAS: dehydroepiandrosterone sulfate, AVP: arginine vasopressin, HANP: human antinatriuretic hormone, U-AD: urinary adrenaline, NA: noradrenaline, DA: dopamine, 17OHCS: 17-hydroxycorticosteroids, 17KS: 17- ketosteroids, CPR: c-peptide immunoreactivity. Parentheses include the normal ranges. Table 2. Provocative Tests by CRH (100 |jg) and TRH (500 jig) Table 3. Daily Profile ofACTH and F a) Preoperative data a) Preoperative data Time after the injection (min) 0 1 5 30 60 90 1 20 Time 8:00 ll:00 14:00 16:00 20:00 23:00 ACTH (pg/ml) 4.0 4.0 4.0 4.3 4.0 5.1 ACTH (pg/ml) 4.0 4.0 4.0 4.1 4.0 4.0 F (jLig/dl) 17.4 17.2 16.1 17.0 16.6 16.9 F (|ig/dl) 19.5 20.8 18.8 19.1 17.1 18.5 TSH ((lU/ml) 0.06 2.39 3.10 2.46 1.66 1.17 PRL (ng/ml) 28.9 277.3 244.8 156.9 110.8 76.2 Abbreviations and normal values are shownin Table 1. Abbreviations and normal values are shownin Table 1. b) Postoperative data (1 week after the surgery) b) Postoperative data (3 months after the surgery) Time 8:00 ll:00 14:00 16:00 20:00 23:00 Time after the injection (min) 0 15 30 60 90 1 20 ACTH (pg/ml) 18.0 33.3 47.5 47.4 31.5 31.1 I hydrocortisone 25 mg ip.o.) F (]Lig/dl) 0.10 0.10 0.20 0.10 0.10 0.20 ACTH (pg/ml) 4.0 4.1 4.0 4.0 4.0 4.0 TSH QxU/ml) 2.29 14.41 18.48 14.81 10.35 8.08 F (Jig/dl) 0.30 15.3 17.8 6.1 2.0 0.50 PRL (ng/ml) 29.4 368.4 405.9 276.6 175.4 158.6 Abbreviations and normal values are shown in Table 1. Abbreviations and normal values are shown in Table 1. 386 Internal Medicine Vol. 37, No. 4 (April '. Cushing' s Syndrome and Hyperplasia Table 4. DexamethasoneSuppression Test Day 0 1 2 3 4 5 6 7 Dexamethasoneip.o.) - - 2mg 2mg 8mg 8mg Urinary17-OHCS (mg/day) 4.1 7.8 10.8 13.3 12.0 12.8 12.7 16.0 Urinary17-KS (mg/day) 2.9 4.0 3.7 3.7 2.7 2.6 3.2 4.7 Abbreviations and normal values are shown in Table 1. Figure 1. Abdominal computed tomography (CT). Plain abdominal CT revealed a left adrenal mass with 19 HUof CT number (arrow, A), while the right adrenal was presented as a normal shape (arrow, B). circadian rhythm under the replacement therapy (Table 3b), and both FT3 and FT4 concentrations were also normalized. Serum TSH level has gradually increased, and reached the peak on day 8 after surgery, and consequently decreased to within the normal limit (Fig.