Endocrinol . Japon. 1990, 37(2), 255-260 Hyperparathyroidism Associated with Cushing's Syndrome Due to an Adrenal Cortical Adenoma SHINJI SAWANO, YOSHIMASA SHISHIBA, TAEKO SHIMIZU, YASUNORI OZAWA, EIZO MIYATA, HIDEKI NAKAZAWA*, NORIYUKI SUZUKI* AND HIROSHI AKIYAMA* From Division of Endocrinology and Metabolism, and Division of Endocrine Surgery*, Toranomon Hospital; and Okinaka Memorial Institute for Medical Research, Tokyo 105, Japan Abstract Two patients with the rare association of Cushing's syndrome and primary hyperparathyroidism are reported. Initially, both patients suffered from Cushing's syndrome due to adrenal cortical adenomas with typical features and laboratory findings. Five years after treatment of the Cushing's syndrome by removal of the tumor, asymptomatic mild hypercalcemia was incidentally noticed in both patients, which suggested the occurrence of primary hyper- parathyroidism. An enlarged parathyroid gland was removed surgically in both cases and was histologically shown to be a parathyroid adenoma. The levels of serum calcium returned to normal after parathyroidectomy. Papillary adenocarcinoma of the thyroid in one patient and adenomatous goiter in the other were also incidentally detected at operation. These findings suggest that Cushing's syndrome resulting from an adrenal cortical adenoma may be another presentation of multiple endocrine neoplasia type I. Multiple endocrine neoplasia type I Griin, 1981; Boey et al., 1975). Such (MEN I) is characterized by benign tumors adenomas are usually non-functioning, and of the parathyroid and pituitary, and benign the occurrence of Cushing's syndrome re- or malignant tumors of the islet cells of sulting from an autonomous adrenocortical the pancreas (Ballard et al., 1964; Eberle tumor is extremely rare (Coughs et al., 1972; and Gran, 1981). The typical pathological Tajima et al., 1977 ; Igarashi et al., 1981). change in the parathyroid gland in MEN I We describe here two patients with Cushing's has been described as primary chief cell syndrome due to an adrenal cortical adenoma hyperplasaia. In addition to these, MEN I who also developed hyperparathyroidism is occasionally associated with adrenocortical resulting from a parathyroid adenoma. adenomas (Ballard et al., 1964; Eberle and Received December 19, 1989 Case Reports Mailing address for reprints: SHINJI SAWANO, MD. Division of Endocrinology and Metabolism, Case 1 Toranomon Hospital, 2-2-2 Minato-ku, Tokyo 105, Japan. A 42-year-old married woman was ad- Endocrinol. Japon. 256 SAWANO et al. April 1990 mitted to our hospital on September 30, graphy and abdominal angiography were 1971, with obesity, hypertension, and low performed, but no positive ndings were back pain. She had a history of a weight obtained. On October 29, 1971, the right gain of 15 kg and mild hypertension since adrenal gland was explored surgically. A the age of 40. There was no history to tumor measuring 3•~2.5•~2cm was found, suggest endocrine disease in any other and the pathological diagnosis was adrenal member of the family. On admission, her cortical adenoma. Substitution therapy with weight was 65 kg and her height was 160 hydrocortisone was initiated soon after the cm. The blood pressure was 150/90mmHg. operation. Postoperative levels of plasma Features compatible with Cushing's syndrome cortisol at 8 a.m., 11 a.m., 4 p.m. and 11 were present, including central obesity, buf- p.m. were 1.7, 1.7, 1.7 and 1.4ƒÊg/dl, res- falo hump, and moon-face. Purple striae pectively, indicating that the tumor had were seen all over the lower abdomen. No been removed completely. masses were palpable in the neck. The physical changes of Cushing's synd- Laboratory investigations gave the fol- rome gradually disappeared, and she was lowing results: serum sodium, 147mEq/l; discharged on 20mg of hydrocortisone daily potassium, 3.3mEq/l; chloride, 105mEq/l; on December 13, 1971. One year later, calcium, 9.4mg/dl (normal range, 8.1-10.0 both the basal urinary excretion of 17-OHCS mg/dl); and serum phosphate, 2.6mg/dl and the plasma cortisol level were normal, (normal range, 2.5-4.3mg/di). The fasting so the daily administration of hydrocortisone blood glucose level was 74 mg/dl; following was terminated in December, 1972. Since a 100g oral glucose load a diabetic type mild hypertension persisted, she was follow- response was seen. Skeletal X-ray lms ed up in the outpatient clinic. revealed a moderate degree of osteoporosis. In December 1976, a relatively high The plasma cortisol level was 25ƒÊg/dl at level of serum calcium (11.0 mg/dl) was 8 a.m., 29ƒÊg/di at 11 a.m., 28ƒÊg/dl at 4 incidentally noticed, with the serum phos- p.m. and 24ƒÊg/dl at 11 p.m.. Base line phorus level remaining normal (2.8mg/dl). urinary 17-hydroxycorticosteroid (OHCS) and Mild hypercalcemia ranging from 9.6-11.2 17-ketosteroid (KS) levels were 10.0-27.9 mg/dl persisted without any metabolic dis- mg/day and 7.5-12.0mg/day, respectively. turbance until 1988. The serum phosphorus The two-day 8 mg dexamethasone test (2mg ranged from 2.5-3.9 mg/dl during the same every 6 hours, total 8 doses) showed no period. The plasma PTH level was 3.6-3.7 suppression of urinary 17-OHCS levels (mean mIU/ml (C terminal assay, normal range: basal excretion for the 2 days was 12.6 1.6-4.4 mIU/ml) in January 1983, and in- mg/day and it was 14.5mg/day on day 2). creased to 0.70ng/ml (mid-portion assay, After the administration of metyrapone (750 normal range: 0.18-0.56ng/ml) in February mg every 6 hours, total 4 doses), the maxi- 1987. An ultrasonic echogram of the neck mum urinary excretion of 17-OHCS was performed on December 21, 1987, revealed 19.2mg/day compared with a mean basal a hypoechoic mass lesion with a diameter excretion of 26.8mg/day over 2 days. of 6•~3mm in the region of the mid-portion Elevated levels of plasma cortisol with of the right thyroid lobe, suggesting the a loss of the diurnal rhythm and the absence presence of an enlarged parathyroid gland. of any response to dexamethasone or mety- She was readmitted on May 13, 1988, for rapone made it highly likely that the parathyroid surgery. Cushing's syndrome was due to an adrenal Laboratory data on admission are shown tumor. To explore the adrenals, retroperi- in Table 1. The serum Ca, plasma PTH, toneal pneumography, intravenous pyelo- and nephrogenous cAMP levels were high. Vol. 37, No. 2 CUSHING'S SYNDROME AND HYPERPARATHYROIDISM 257 Table 1. Laboratory data of Case 1 when and computed tomography (CT) failed to admitted for operation for primary visualize the mass, but demonstrated another hyperparathyroidism small lesion in the lower region of the left lobe of the thyroid. On June 8, the neck was surgically explored, and an enlarged right upper parathyroid gland weighing 205 mg was removed, which coincided with the mass revealed by ultrasound. The other three parathyroid glands were normal. Pathological examination showed that the lesion was a chief cell adenoma. The mass lesion which had been found by MRI and CT scan was histologically an enlarged lymph node with the characteristics of metastatic papillary adenocacinoma of the thyroid. After surgery, the serum calcium level decreased to 8.0mg/dl. On June 15, 1988, when the patient was discharged, the levels of serum calcium and phosphorus were 8.6 mg/dl and 3.6mg/dl, respectively. Plasma parathyroid hormone was 0.43ng/ml. She required neither calcium nor vitamin D preparations, but was given a daily dose of 50ƒÊg of thyroxin for preoperative treat- ment of papillary adenocarcinoma of the thyroid. Case 2 This 40-year-old married woman was admitted to our hospital on August 4, 1970, because of edema of the lower extremities. She had a history of hypertension for two years, and had gained 3kg in weight. There was no family history of endocrine disease. PTH-M: mid-portion assay of parathyroid hor- mone; ACTH: adreno-corticotropic hormone; On admission her weight was 60 kg and T4: thyroxine; T3: triiodothyronine; TSH: her height was 156cm. The blood pressure thyroid stimulating-hormone. Normal ranges in was 180/110mmHg. She had the charac- parenthesis. teristic facial appearance and fat distribution of Cushing's syndrome. There was 2+ pit- ting edema on the legs. No masses were The other findings were within the normal palpable in the neck. range, indicating that no other endocrine Laboratory investigations revealed the glands were involved. Repeated ultrasound following: serum sodium, 142mEq/l; potas- of the neck revealed the same hypoechoic sium, 3.5mEq/l; chloride, 102mEq/l; mass as detected in December 1987. How- calcium, 9.8mg/ dl; and phosphorus, 3.1 ever, magnetic resonance imaging (MRI) mg/dl. The fasting blood glucose level was Erdocrinol. Japon. 258 SAWANO et al. April 1990 96mg/dl, and after a 100g oral glucose roid gland measuring 0.7•~1.0 cm was re- load a diabetic type response was seen. The moved. Histological examination revealed plasma cortisol level was 13ƒÊg/dl at 8 a.m., a chief cell adenoma. The remaining 3 14ƒÊ/dl at 11 a.m., 13ƒÊg/dl at 4 p.m. and glands were not enlarged. A biopsy taken 12ƒÊg/dl at 11 p.m., indicating loss of the from one of the thyroid nodules at surgery diurnal rhythm. Base line values for urinary showed histologically the characteristics of 17-OHCS and 17-KS were 11.4-32.8mg/day adenomatous goiter. Postoperatively, the and 3.9-4.6mg/day, respectively. The 2-day serum calcium and phosphorus levels re- 8 mg dexamethasone test showed no sup- turned to normal and she was discharged pression of urinary 17-OHCS (mean basal on December 30, 1975.