Endocrinol . Japon. 1990, 37(2), 255-260

Hyperparathyroidism Associated with Cushing's Syndrome Due to an Adrenal Cortical

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 *, 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 are reported. Initially, both patients suffered from Cushing's syndrome due to adrenal cortical 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 was removed surgically in both cases and was histologically shown to be a parathyroid adenoma. The levels of serum calcium returned to normal after . Papillary adenocarcinoma of the 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 (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

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. She has since excretion for the 2 days was 12.2mg/day, remained in good health on 20mg of and it was 21.3 mg/day on day 2). After hydrocortisone for daily maintenance. administration of 3 g of metyrapone the urinary excretion of 17-OHCS was 14.4 mg/day compared with the mean base line Discussion value of 15.5 mg/day. These results were consistent with the diagnosis of Cushing's It is quite interesting that both patients syndrome due to an . Since presented here showed almost identical both retroperitoneal pneumography and ab- clinical courses. They had no family history dominal aortography suggested the existence of endocrine disease. Initially, both patients of a tumor of the left adrenal, this was had Cushing's syndrome due to an adrenal removed on September 18, 1970. However, cortical adenoma. Since the levels of serum the cortex was found to be atrophied, and calcium were normal at that time, the the physical and biochemical features of parathyroid glands appear not to have been Cushing's syndrome did not subside. On affected simultaneously. Asymptomatic mild January 22, 1971, a right total adrenalectomy hypercalcemia was incidentally noticed 5 was performed. A tumor measuring 2.8 •~ years after the removal of the adrenal 2.5•~2.1cm and weighing 10.2g was re- tumor in both patients, and persisted for cognized. Histologically, it was an adrenal more than 10 years in Case 1 until para- cortical adenoma. Hydrocortisone supple- thyroidectomy was performed. Hypercal- ments were commenced soon after the opera- cemia occurring in MEN I is reported to tion. On February 13, 1971, the patient be frequently asymptomatic (Boey et al., was discharged on substitution therapy con- 1975). In addition, the endocrine dis- sisting of 20mg of hydrocortisone daily, turbances that characterize MEN I need and her postoperative course was followed not occur simultaneously, but may develop up in the outpatient clinic. The physical over the course of many years (Synder et al., changes of Cushing's syndrome gradually 1972). If our patients had not been followed disappeared. up postoperatively for Cushing's syndrome, Early in December 1975, high serum the primary hyperparathyroidism would calcium levels ranging from 10.2-12.0mg/dl probably not have been found. It should were noted together with low serum phos- be emphasized, therefore, that careful ex-

phorus levels of 2.0-2.4mg/dl. She was amination is necessary to detect primary readmitted to our hospital on November hyperparathyroidism without significant me- 29, 1975, with a tentative diagnosis of tabolic disturbances. Both patients were primary hyperparathyroidism. On December physically euthyroid but they had thyroid 23, 1975, exploration of the neck was per- disease, probable papillary adenocarcinoma formed, and an enlarged left lower parathy- of the thyroid in Case 1 and adenomatous Vol. 37, No. 2 CUSHING'S SYNDROME AND HYPERPARATHYROIDISM 259 goiter in Case 2, which was unexpectedly 1972; Friesen et al., 1970) might have suf- found at the time of parathyroid surgery. fered from Cushing's syndrome, but detailed The possibility that these two cases are clinical, laboratory, and histological data the presentation of MEN I is to be dis- sufficient to establish the features of Cushing's cussed. MEN I is inherited as an autosomal syndrome were lacking. On the other hand, dominant trait (Ballard et al., 1964; Eberle there has appeared in the literature 2 ad- and Griin, 1981; Yamaguchi et al., 1980), ditional cases of Cushing's syndrome due yet some patients with MEN I have no to autonomous adrenocortical tumors with family history of endocrine disorders (Ballard the simultaneous occurrence of primary et al., 1964; Eberle and Grun, 1981) like hyperparathyroidism (Tajima and Kawabe, our own cases. It is suggested that such 1977; Igarashi et al., 1981). No other cases are either the first mutant of a line endocrine glands were involved in these 2 or else are familial cases where an inadequate cases. search was conducted for relatives with the A question arises as to the intrinsic disorder (Eberle and Grun, 1981). Kundson nature of the adrenal cortical lesion in (1973) has stated that even when patients MEN I because of its frequent and incidental with MEN I do not have a positive family occurrence (Ballard et al., 1964; Eberle and history, they should be managed as a carrier Grun, 1981; Yamaguchi et al., 1980). How- of the affected gene. ever, as far as functioning adrenocortical Adrenal cortical adenomas in. MEN I tumors are concerned occurrence in MEN I have been occasionally detected as an in- is extremely rare, and only 5 distinct cases cidental finding when laparotomy or autopsy associated with Cushing's syndrome are has been performed (Ballard et al., 1964; known including our own patients. This Eberle and Griin, 1981). The recent develop- sparsity may indicate a genetic difference ment of roentgenographic imaging techniques between functioning adrenocortical tumors such as CT scanning has enabled us to and silent ones, although there exists no detect an increasing number of asymptoma- direct evidence for this hypothesis. Taking tic adrenal masses (Belldegrun et al., 1986). these findings into consideration, it is sug- Most of these adrenal tumors remain sym- gested that Cushing's syndrome resulting ptomless (Ballard et al., 1964; Eberle and from an adrenal adenoma may be another Griin, 1981; Belldegrun et al., 1986), and variant of MEN I. the occurrence of Cushing's syndrome due On the other hand, it is generally ac- to an adrenal cortical adenoma in MEN I cepted that multiple gland involvement of is very rare. Ballard et al., (1964) found the parathyroid is characteristic feature in no patients with Cushing's syndrome due to most MEN I patients (Eberle and Gran, adrenal cortical tumor in their series of 85 1981). However, our own patients as well MEN I cases. According to Eberle and as the other two cases (Croughs et al., Grun (1981), 3 out of 122 MEN I cases 1972; Igarashi et al., 1981) except one had Cushing's syndrome suggested to be (Tajima and Kawabe, 1977) had a solitary due to an adrenal tumor(s). Careful review adenoma of the parathyroid gland. This of these 3 cases showed that a patient re- suggests the existence of another possibility ported by Croughs et al. (1972) had de- that there may be a type of "multiple finite Cushing's syndrome due to an adrenal endocrine neoplasia" syndrome mainly con- cortical adenoma, with MEN I including sisting of a solitary adenoma of the para- primary hyperparathyroidism, , thyroid and functioning adrenal cortical and the amenorrhoea and galactorrhoea adenoma, hitherto unclassified. Three cases syndrome. The remaining two (Craven et al., with the rare occurrence of a solitary Erdocrinol. Japorr. 260 SAWANO et al. April 1990 parathyroid adenoma and primary hyperal- 52, 690-698. dosteronism (Fertig et al., 1980; Ferriss Eberle, F. and R. Griin (1981). Multiple endo- et al., 1983) may also be included in this crine neoplasia, Type I. Ergeb. Inn. Med. category. Further investigation is required Kinderheilkd. 46, 76-149. Ferriss, J. B., J. J. Brown, A. M. M. Cumming, to evaluate the underlying nature of possible R. Fraser, A. F. Lever, M. Peacock and adrenal involvement. The incidence of J. I. S. Robertson (1983). Primary hyper- thyroid diseases in MEN I has been reported parathyroidism associated with primary hy- to be from 18% (Ballard et al., 1964) to peraldosteronism. Acta Endocrinol. (Copenh). 25% (Eberle and Grun, 1981). This high 103, 365-370. frequency makes it difficult to consider such Fertig, A., M. Webley and J. A. Lynn (1980). disorders as an intrinsic part of MEN I. Primary hyperparathyroidism in a patient with Conn's syndrome. Postgrad. Med. J. 56, 45- 47. Friesen, S. F., R. E. Bolinger, A. G. E. Pearse and J. E. McGuigan (1970). Serum gastrin References levels in malignant Zollinger-Ellison syndrome after total gastrectomy and hypophysectomy. Ballard, H. S., B. Frame and R. J. Hartsock Am. J. Surg. 172, 504-519. (1964). Familial multiple endocrine adenoma- Igarashi, M., T. Yamakawa, H. Taniguchi, K. peptic ulcer complex. Medicine. 43, 81-516. Takahashi, K. Yamatani, and H. Sasaki (1981). Belldegrun, A., S. Hussain, S. E. Seltzer, K. R. 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