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 or hypertrichosis was observed. Althoughplasma adrenocorticotropin and serum levels were within normal ranges, the has completely disappeared. Free thyroxine and triiodothyronine levels were decreased. Adrenocorticotropin did not respond to corticotropin- releasing , 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 . The resected left adrenal mass was pathologically diagnosed as the rare condition of adrenocortical nodular hyperplasia. (Internal Medicine 37: 385-390, 1998) Key words: , adrenalectomy, dexamethasone suppression test,

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 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 , 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 , 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 concentration, DHEAS: dehydroepiandrosterone sulfate, AVP: arginine , 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. 4). Three months after the surgery, ACTH and TSHresponses to CRHand TRH, respectively, became normal, while prolactin (PRL) response to TRHwas augmented compared with the preoperative one. Serum F response to CRH was impaired, reflecting the right adrenal suppression (Table 2b). Oneyear after the surgery, she has been maintained with 5 mg/dayof hydrocortisone, and her clinical symptomsdue to hypercortisolemia have completely disappeared. Discussion

The present case is a rare pathologic variety of Cushing's syndrome, which has been diagnosed as a unilateral adrenal adenoma before the surgery. In this case, the basal endocrinological data was not adequate for the diagnosis of Figure 2. 131I-Adosterol scintigraphy. 131I-Adosterol Cushing' s syndrome, because both serum F and plasma ACTH scintigraphy showedthe marked accumulation in accor- have been within the normal ranges. Taking the periodic hyper- dance with the left adrenal mass, while the uptake in the secretion of F into consideration (6, 7), it is quite difficult to right adrenal gland was not detectable. prove the clinical hypercortisolemia. The diagnosis for Cush- ing's syndromehence requires repeated endocrinological ob-

Internal Medicine Vol. 37, No. 4 (April 1998) 387 Otsuka et al

Figure 3. The resected adrenal gland. The resected left adrenal gland included a macronodule measuring 3.0x2.4x2.0 cm (large arrow, A) and micronodules (small arrow, A). The nodules were not encapsulated, and no atrophic findings were observed in the perinodular region (B). The adrenal was diagnosed as nodular adrenocortical hyperplasia, consisting of macro- (C) and micronodules (D) clustering compact cells [HE stain, xl.5 (B), x50 (C, D)]. servations including stimulation or suppression tests. In the not been completely clarified, it was suggested that the cause of present case, the symptoms due to hypercortisolemia seemed to this phenomenon might be an upward slope in periodic manifest at the age of 47, whenthe patient's menopauseand hormogenesis, an upsetting of negative feedback effect to weight gain appeared gradually. Furthermore, the lack ofACTH glucocorticoid or paradoxical positive feedback to ACTH(8, elevation induced by CRHand the disappearance of circadian 9). The radiological findings including adrenal CTand adosterol rhythm in serum F disclosed the autonomoussecretion of F. scintigraphy demonstrated the existence of unilateral function- This phenomenonwas also confirmed by the dexamethasone (2 ing adrenal mass, which usually should be expected as an or 8 mg/day) suppression test showing a paradoxical increase in adrenocortical adenoma. In the present case, however, the left urinary 17-OHCS excretion. Although this paradoxical re- adrenal mass was pathologically diagnosed as a unilateral sponse to dexamethasone, which is occasionally reported in adrenocortical nodular hyperplasia, because of the lack of Cushing' s disease and more rarely in Cushing's syndrome, has capsule, the formation of macro- or micro-nodules chiefly

388 Internal Medicine Vol. 37, No. 4 (April 1998) Gushing' s Syndrome and Hyperplasia

T-^T T^T 4 3 Hydrocortisone (i. v.)

TSH Left adrenalectomy >^ O/ U/ml) ^x^

6" //\

~ KX / Vv

^" FT ' / N^

2_ - !_ TSH

0-1 0-1 0-

1996 Jun Jul Aug Sep

Figure 4. Clinical course. Left adrenalectomy was performed on July 23, 1996. After the surgery, the patient was given hydrocortisone (100 to 50 mg/day) intravenously, followed by the oral administration of 25 mg/day. Both the free triiodothyronine (FT3) and thyroxine (FT4) concentrations normalized on 1 week after the surgery. The serum thyro- tropin (TSH) level showed a gradual increase, and reached a peak on postoperative day 8, and eventually decreased to within the normal limit. consisting of compact cells, and non-atrophic findings in the (TBPA) (19, 20). These phenomena have also been reported in perinodular region (10). The nodular hyperplasia in this case Cushing's syndrome (21-23). Amongthese, the present case was distinguished from ACTH-independent macronodular hy- demonstrated a decreased FT3 and FT4 as well as a blunted perplasia (AIMAH) or primary pigmented nodular adrenocor- response of TSHto TRHpreoperatively. In contrast, rapid tical disease (PPNAD), because of the marked laterality of the increases of FT3 and FT4 have followed the left adrenalectomy adrenal gland in radiographic findings. Although the Cushing' s with replacement therapy, and the serum TSHlevel also even- cases of unilateral adrenal hyperplasia dependent upon ACTH tually normalized. The recovery of thyroid dysfunction after have been occasionally reported in pituitary or ectopic ACTH adrenalectomy suggests that the preoperative hypothyroidism producing tumors (1 1-15), there have been only 5 cases well was affected by the hypercortisolemia which might induce both documented on Cushing' s syndrome due to ACTH-indepen- the inhibition of peripheral conversion of T4 to T3 and the dent unilateral adrenal hyperplasia (1-5). The marked adreno- blunted secretion of TSH( 16-19). Although the interrelation- cortical laterality and the improvement of Cushing' s syndrome ship between the pituitary excretion of PRL and glucocorticoid after hemiadrenalectomy suggest that the adrenocortical hyper- is controversial (16-18), the PRLresponse to TRHwas also plasia in the present case mayhave similar characteristics to augmented under the corrected adrenal state in the present case. adenomas. However,in the cases of hyperplasia, the remained The physiological glucocorticoid level is likely required to adrenal gland should be carefully observed for a long period maintain these pituitary and thyroid functions. after surgery, paying attention to the morphological or hor- In conclusion, we presented a very rare case of Cushing's monal changes. syndrome due to unilateral adrenocortical nodular hyperplasia. Next, the following thyroid abnormalities have proven to be The accumulationof reports concerning the clinical character- associated with excessive glucocorticoid: decreased TSHse- istics of the same pathology may be helpful for resolving the cretion or blunted TSHresponse to TRH(16-19), decreased pathophysiology of this disease. FT3 with or without increased reverse T3 (rT3) (19), and decreased T4-binding protein (TBG) or T4-binding prealbumin

389 Internal Medicine Vol. 37, No. 4 (April 1998) Otsuka et al

Borretta G, Terzolo M, CesarioF, Meineri I, PiaA, Angeli A. Coexistence References of unilateral adrenal macronodule and Cushing' s disease. Report of two cases. J Endocrinol Invest 19: 131, 1996. 1) Josse RG, Bear R, Kovacs K, Higgins HP. Cushing's syndrome due to Ishiura Y, Takazakura E, Ojima M. A case of unilateral primary adrenal unilateral nodular adrenal hyperplasia: a new pathophysiological entity? nodular hyperplasia with elevated plasma adrenocorticotropin (ACTH). Acta Endocrinol (Copenh) 93: 495, 1980. Endocrinologia Folia Japonica 70: 1007, 1994 (in Japanese). 2) Catania A, Reschini E, Orsatti A, Motta P, Airaghi L, Cantalamessa L. Abs R, Nobels F, Verhelst J, Chauson P, Mahler C, Corthout B, Blockx Cushing's syndrome due to unilateral adrenal nodular hyperplasia with P, Beckers A. Hyperfunctioning unilateral adrenal macronodule in three incomplete inhibition of the contralateral gland. Horm Res 23: 9, 1986. patients with Cushing's disease: hormonal and imaging characterization. 3) Bronshtein ME, Tsitsiashvili BS, Kolesnikova GS, Rozhinskaia LI, Acta Endocrinol (Copenh) 129: 284, 1993. Kesh'ian RG. Cushing's syndrome in unilateral diffuse-nodular hyper- Watanobe H, Kawagishi T, Hirai Y, Sato T, Tsutsui M, Kamata Y, Takebe plasia of the with a corticosteroma and in combination with K. Cushing's syndrome presenting the coexistence of a pituitary a pheochromocytoma. Probl Endokrinol (Mosk) 35: 46, 1986 (in Rus- corticotropic cell hyperplasia and a unilateral functional adrenal ad- sian). enoma. Acta Endocrinol (Copenh) 110: 302, 1985. 4) Gessler P, Ranke MB, Wollmann H, Aicher KP, Feine U, Kaiserling E, Sigman LM, Wallach L. Unilateral adrenal hypertrophy in ectopic ACTH Leriche C, Steil E. Adrenocortical nodular hyperplasia as a cause of syndrome. Arch Intern Med 144: 1869, 1984. Cushing's syndrome in the neonatal period. Klin Pediatr 203: 462, 1991. Dussault JH. The effect ofdexamethasone on TSHand prolactin secretion 5) Jenkins PJ, Chew SL, Lowe DG, Reznek RH, Wass JA. Adrenocortico- after TRHstimulation. Can Med Assoc J 111: 1 195, 1974. tropin-independent unilateral macronodular adrenal hyperplasia occur- Re RN, Kourides IA, Ridgway EC, Weintraub BD, MaloofF. The effect ring with myelolipoma: an unusual cause of Cushing's syndrome. Clin ofglucocorticoid administration on humanpituitary secretion ofthyrotro- Endocrinol (Oxf) 41: 827, 1994. pin and prolactin. J Clin Endocrinol Metab 43: 338, 1976. 6) Bailey RE. Periodic hormonogenesis - anew phenomenon. Periodicity in Sowers JR, Carlson EH, Brautbar N, Hershhman JM. Effect of dexa- function of a hormone-producing tumor in man. J Clin Endocrinol Metab methasone on prolactin and TSHresponses to TRHand metoclopramide 32:317, 1971. in man. J Clin Endocrinol Metab 44: 237, 1977. 7) Atkinson AB, Kennedy AL, CarsonDJ, HaddenDR, WeaverJA, Sheridan Davies PH, Franklyn JA. The effects of drugs on tests of thyroid function. B. FivecasesofcyclicalCushing's syndrome. BrMedJ291: 1453, 1985. Eur J Clin Pharmacol 40: 439, 1991. 8) French FS, Mac fie JA, Baggett B, Williams TF, Van Wyk JJ. Cushing's Oppenheimer JH, Werner SC. Effect ofprednisone on thyroxine-binding syndrome with a paradoxical response to dexamethasone. AmJ Med47: proteins. J Clin Endocrinol Metab 26: 715, 1966. 619, 1969. Kuku SF, Child DF, Nader S, Fraser TR. Thyrotrophin and prolactin 9) Makino S, Hashimoto K, Sugiyama M, Hirasawa R, Takao T, Ota Z, responsiveness to thyrotrophin releasing hormone in Cushing' s disease. SaegusaM, Ohashi T, Omori H. Cushing's syndrome due to huge nodular Clin Endocrinol (Oxf) 4: 437, 1975. adrenocortical hyperplasia with fluctuation of urinary 17-OHCSexcre- Duick DS, Wahner HW. Thyroid axis in patients with Cushing's syn- tion. Endocrinol Jpn 36: 655, 1989. drome. Arch Intern Med 139: 769, 1979. 10) Neville AM, O'Hare MJ. Histopathology of the human adrenal cortex. Visser TJ, Lambert SW. Regulation of TSHsecretion and thyroid func- Clin Endocrinol Metab 14: 791, 1985. tion in Cushing's disease. Acta Endocrinol (Copenh) 96: 480, 1981.

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