Endocrine Journal 2007, 54 (4), 543–551

Preclinical Cushing’s Syndrome Resulting from Adrenal Black Diagnosed with Diabetic Ketoacidosis

TOSHIO KAHARA, CHIKASHI SETO*, AKIO UCHIYAMA**, DAISUKE USUDA, HIROSHI AKAHORI, EIJI TAJIKA*, ATSUO MIWA**, RIKA USUDA, TAKASHI SUZUKI*** AND HIRONOBU SASANO***

Department of Internal Medicine, Toyama Prefectural Central Hospital, 2-2-78 Nishinagae, Toyama 930-8550, Japan *Department of Urology, Toyama Prefectural Central Hospital, 2-2-78 Nishinagae, Toyama 930-8550, Japan **Department of Pathology, Toyama Prefectural Central Hospital, 2-2-78 Nishinagae, Toyama 930-8550, Japan ***Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan

Abstract. A right was incidentally discovered on abdominal computed tomography performed on a 53- year-old Japanese man, who had been hospitalized with diabetic ketoacidosis. Normal values were obtained for adrenal in the morning after an overnight fast and urinary cortisol excretion after treatment of diabetic ketoacidosis with . However, overnight dexamethasone administration with 1 mg or 8 mg did not completely suppress serum cortisol levels. There were no remarkable physical findings related to Cushing’s syndrome. The patient was diagnosed as having preclinical Cushing’s syndrome (PCS). Histological examination of the adrenalectomy specimen demonstrated adrenal black adenoma. Blood glucose levels subsequently improved after adrenalectomy, and the patient never developed adrenal insufficiency after hydrocortisone withdrawal. The patient was treated with diet therapy alone, and maintained good glycemic control. However, the patient still showed a diabetic pattern in an oral glucose tolerance test. It seems that the existence of PCS in addition to the underlying type 2 mellitus contributed to aggravation of blood glucose levels. Although there are many aspects of the natural course of PCS that have not been thoroughly elucidated, it is necessary to remain aware that a PCS patient with abnormal glucose metabolism may develop diabetic ketoacidosis by environmental agents.

Key words: Diabetic ketoacidosis, Preclinical Cushing’s syndrome, Adrenal black adenoma, (Endocrine Journal 54: 543–551, 2007)

CORTISOL excess impairs insulin action and increases adrenal incidentaloma associated with PCS have liver gluconeogenesis [1]. Eighty percent of patients demonstrated a wide spectrum in the degree of hyper- with Cushing’s syndrome have impaired glucose toler- cortisolism and autonomy [6]. The degree of glucose ance or diabetes, but these patients improve dramati- intolerance in PCS also varies greatly. cally after adrenalectomy [2]. Based on the criteria of Type 2 diabetes mellitus and other two or more abnormal results on classical tests of the can lead to the development of diabetic ketoacidosis in hypothalamic-pituitary-adrenal (HPA) axis, preclinical the presence of an aggravating factor, such as infection Cushing’s syndrome (PCS), is found in approximately and drinking excessive amounts of sugar-containing 6% of patients with adrenocortical incidentaloma [3], soft drinks, as well as type 1 diabetes without insulin despite the absence of typical physical findings of treatment [7, 8]. Although a patient with PCS who de- Cushing’s syndrome such as truncal , moon veloped diabetic ketoacidosis has not previously been face and striae cutis [4, 5]. Studies of patients with reported in the English literature, their blood glucose levels may be exacerbated by environmental agents in addition to underlying insulin resistance due to PCS. Received: April 14, 2006 Accepted: March 8, 2007 We report a rare case of PCS resulting from adrenal Correspondence to: Toshio KAHARA, M.D., Ph.D., Department black adenoma which was diagnosed with diabetic of Internal Medicine, Toyama Prefectural Central Hospital, 2-2- ketoacidosis. 78 Nishinagae, Toyama 930-8550, Japan 544 KAHARA et al.

Case Report Table 1. Laboratory data on admission

[Urinalysis] A 53-year-old Japanese man had experienced thirst, pH 5 general malaise, nausea and poor appetite since the specific gravity 1.040 middle of March 2005, and had been drinking approx- Protein (2+) imately 1.5 liters of sugar-containing soft drinks per Sugar (3+) day. His symptoms gradually worsened, and body Urobilinogen (±) weight decreased 5 kg over a three-week period. Con- Bilirubin (–) sequently, he was referred to our hospital on March 29, Ketone body (3+) 2005. There was no family history of diabetes. His Occult blood (–) maximal body weight was 92 kg at 40 years old. On an [Cell blood count] oral glucose tolerance test in 1998, plasma glucose White blood cells 9900/µl levels after a 75 g oral glucose administration was Neutrophils 52.0% 102 mg/dl at fasting, 193 mg/dl at 60 minutes and 138 Eosinophils 1.0% mg/dl at 120 minutes, indicating a normal glucose tol- Lymphocytes 39.0% erance according to the diagnostic criteria of diabetes Monocytes 8.0% Red blood cells 5.61 × 106/µl mellitus by the Japan Diabetes Society (1999). He de- Hemoglobin 17.7 g/dl veloped gonarthrosis at 49 years old. Hematocrit 49.7% The patient was 180 cm tall and weighed 83 kg on Platelets 266 × 103/µl March 29, 2005. Vital signs were as follows: body temperature, 37.5 degrees; blood pressure, 134/82 [Blood chemistry] C-reactive protein 6.1 mg/dl mmHg; and regular pulse, 120/min. Other physical Total protein 8.4 g/dl examinations did not yield any remarkable findings, Alkaline phosphatase 354 IU/L including signs of Cushing’s syndrome. Laboratory Aspartate aminotransferase 14 IU/L data are summarized in Table 1, and showed a fasting Alanine aminotransferase 16 IU/L plasma glucose level of 504 mg/dl, glycosylated hemo- Lactate dehydrogenase 131 IU/L globin (HbA1c) level of 14.1%, a positive result for Total bilirubin 0.5 mg/dl urinary ketone bodies, and pH 7.169 on arterial blood γ-glutamyl transpeptidase 42 IU/L gas analysis. The patient was diagnosed with diabetic Amylase 57 IU/L ketoacidosis and was hospitalized on the same day. Creatine kinase 71 IU/L Blood urea nitrogen 15 mg/dl Initial treatment consisted of intravenous infusion of Creatinine 0.8 mg/dl regular insulin and large volumes of saline. After these Uric acid 5.7 mg/dl treatments, the patient was prescribed a 1,600 kcal/day Chloride 93 mEq/L diet in addition to subcutaneous multiple insulin injec- Sodium 133 mEq/L tion therapy. Potassium 4.6 mEq/L Anti-glutamic acid decarboxylase (GAD) antibody Total cholesterol 354 mg/dl level was less than 1.3 U/ml (Cosmic, Tokyo, Japan; Triglyceride 322 mg/dl reference range: less than 1.5 U/ml), and urinary excre- Fasting plasma glucose 504 mg/dl tion of C- was 32.5 µg/day (reference range: Glycosylated hemoglobin 14.1% 32–127 µg/day). There were no diabetic complications Anti-glutamic acid decarboxylase antibody <1.3 U/ml such as neuropathy, retinopathy and nephropathy. He [Arterial blood gas analysis (room air)] underwent abdominal enhanced computed tomography pH 7.169 (CT) scan to exclude the possibility of pancreatic ma- PaCO2 11.5 mmHg lignancy. Abdominal CT scan showed a 23 mm round PaO2 124.0 mmHg mass in the right adrenal , but there were no ab- HCO3– 4.0 mmol/L Base excess –24.6 mmol/L normal findings in the (Fig. 1). SaO2 97.8% As shown in Table 2, the early morning levels of Anion gap 36 mEq/L serum cortisol, plasma adrenocorticotrophic (ACTH), plasma and plasma renin activity PRECLINICAL CUSHING’S SYNDROME, DIABETES 545

were all normal. Levels of urinary excretion of cortisol and 17-hydroxycorticosteroid (17-OHCS) were also within normal limits. However, the patient’s serum cortisol and ACTH levels after treatment of diabetic ketoacidosis with insulin did not show a diurnal rhythm. After overnight dexamethasone administra- tion with 1 mg and 8 mg, respectively, serum cortisol levels were not completely suppressed. Under magnetic resonance imaging (MRI), the tu- mor was hypointense compared to the liver on T1- weighted image and hyperintense compared to the liver on T2-weighted image (Fig. 2a). On chemical shift MRI, there was no reduction in signal intensity on opposed-phase images compared with that on in-phase images, indicating that the tumor was not rich in a fat component (Fig. 2b). The tumor showed homogenous contrast enhancement on dynamic enhanced study. Fig. 1. Abdominal computed tomography showed a 23 mm Adrenal scintigraphy with 131I-adosterol showed nei- round, well-circumscribed mass in the right . ther marked accumulation on the right adrenal region nor inhibition of the contralateral adrenal region. Clin- ical and laboratory features of the present case fulfilled

Table 2. Endocrinological data (reference range) Serum ACTH 20.5 pg/ml (4.4~48.0) Cortisol 8.8 µg/dl (4.5~21.1) DHEA-S 442 ng/ml (480~2860) Plasma aldosterone concentration 47.4 pg/ml (45.0~105.5) Plasma renin activity 1.3 ng/ml/h (0.2~2.7) Adrenaline 0.062 ng/ml (<0.070) Noradrenaline 0.297 ng/ml (0.06~0.46) Dopamine <0.010 ng/ml (<0.014)

Urine Vanillylmandelic acid 3.85 mg/day (1.5~4.9) Homovanillic acid 4.07 mg/day (2.4~6.0) Cortisol 64.4 µg/day (11.2~80.3) 17-KS 9.01 mg/day (4.6~18.00) 17-OHCS 7.48 mg/day (3.40~12.00)

Diurnal rhythm Clock time 08:00 h 12:00 h 16:00 h 20:00 h 23:00 h ACTH (pg/ml) 20.5 23.1 18.9 20 13.9 Cortisol (µg/dl) 8.8 8.7 10.2 8.8 6.8

Dexamethasone suppression test 1mg 8mg ACTH (pg/ml) 6.9 4.5 Cortisol (µg/dl) 8.3 14.3 546 KAHARA et al.

Fig. 2. Under magnetic resonance imaging (MRI), the tumor was hypointense as compared to the liver on the T1-weighted image and hyperintense compared to the liver on the T2-weighted image (a). Gradient echo methods did not show any reduction in signal intensity on opposed-phase images as compared with in-phase images, indicating that the tumor was not rich in a fat component (b). the diagnostic criteria of PCS by the Japanese Ministry immunoreactivities were detected in the black ade- of Health and Labor [5], and right adrenalectomy was noma, and indicated that the tumor cells could syn- performed on May 18, 2005. thesize cortisol or other biologically active hormones Adrenalectomy specimen weighed 18 g and mea- (Fig. 5a–d). sured 30 × 27 mm (Fig. 3). Histological finding was The patient’s substitutive treatment with hydrocorti- adrenal black adenoma consisting of mainly eosino- sone was started after surgery, and the dosage of hydro- philic compact cells with (Fig. 4a, b). There cortisone was gradually reduced. When the patient had were no histopathological findings suggestive of taken 10 mg hydrocortisone once during breakfast, the adrenocortical malignancy based on the criteria of response of serum cortisol to the intravenous injection Weiss [9]. Non-neoplastic adrenal gland adjacent to of ACTH (tetracosactide acetate with 0.25 mg) at the the adenoma was compressed but not atrophic histo- morning fast was good (basal cortisol level was logically (Fig. 4c). On immunohistochemical studies 12.2 µg/dl, and cortisol level at 60 min was 22.1 µg/ carried out according to a previous report [10], dl). Thereafter, substitutive treatment with oral hydro- 3β-hydroxysteroid dehydrogenase (3β-HSD), 21- cortisone was discontinued 2 weeks after the surgery. hydroxylase (P450c21), 17α-hydroxylase (P450c17) and After overnight dexamethasone administration with dehydroepiandrosterone sulfotransferase (DHEA-ST) 1 mg, serum cortisol level was completely suppressed, PRECLINICAL CUSHING’S SYNDROME, DIABETES 547

Fig. 3. Adrenalectomy specimen weighed 18 g and measured 30 × 27 mm. The tumor was encapsulated in a film, had clear boundaries, and had a regular border. The cut surface showed dark brown and there was no necrosis. which was 0.6 µg/dl. As shown in Figure 6, blood glu- cose levels after surgery subsequently improved, and insulin treatment was therefore stopped on May 26, 2005. The daily profile of plasma glucose levels was good on 1,600 kcal/day diet therapy alone (128 mg/dl before breakfast, 199 mg/dl 2 h after breakfast, 137 mg/dl before lunch, 157 mg/dl 2 h after lunch, 112 mg/ dl before supper, 188 mg/dl 2 h after supper, 183 mg/dl before going to sleep). Urinary excretion of C-peptide improved at 115 µg/day on June 2, 2005, and he weighed 81 kg and became an outpatient without chronic medication. One month after surgery, plasma glucose levels after a 75 g oral glucose load was 133 mg/dl at fasting (insu- lin level was 6.5 U/ml), 280 mg/dl at 60 min (insulin level was 25.9 U/ml) and 250 mg/dl at 120 min (insulin level was 21.9 U/ml), and the patient still showed a diabetic pattern. The patient continued to be treated with diet therapy alone. He weighed 79 kg, and his blood pressure was 113/ Fig. 4. (a) Light microscopic examination of resected adrenal 65 mmHg in January, 2006. Laboratory data in Janu- tumor demonstrated that the tumor was mainly com- ary 2006 were as follows: HbA1c, 5.8%; total choles- posed of eosinophilic compact cells (HE, ×40). (b) A terol, 257 mg/dl; triglyceride, 216 mg/dl; ACTH, pigment deposition consistent with lipofuscin was 41.7 pg/ml; serum cortisol, 11.3 µg/dl, respectively. markedly observed (HE, ×400). There were no histo- pathological findings suggestive of adrenocortical ma- The patient never developed adrenal insufficiency after lignancy based on the criteria of Weiss. Histological adrenalectomy. His glycemic control has been good findings were consistent with those of adrenal black ad- with diet therapy alone; however, hyperlipidemia has enoma. (c) Non-neoplastic adrenal gland adjacent to the remained present after adrenalectomy. adenoma was compressed but not atrophic (HE, ×40). 548 KAHARA et al.

Fig. 5. Immunohistochemical examination revealed immunoreactivity for 3β-HSD (a), P450c21 (b), P450c17 (c), DHEA-ST (d) in the adrenal tumor (×200). These findings indicated that the tumor cells could synthesize cortisol or other biologically active hormones.

Discussion

Non-functional adrenal black adenoma is seen in approximately 10% of patients at [11], but there have only been approximately 50 reports of func- tional adrenal black adenoma [10, 12–17]. It is known that the fat component is poor and there is accumula- tion of lipofuscin depositions that tend to be associated with aging when examined histologically [12]. For this reason, there tends to be a lack of characteristic MRI findings of typical adrenal adenoma, and it can be dif- ficult to distinguish from malignant tumors on MRI image findings [13]. In our case, there was no reduc- tion in signal intensity on opposed-phase images com- pared with those on in-phase images on abdominal Fig. 6. Treatment course of diabetes mellitus. FBG: fasting MRI, and the tumor did not demonstrate the character- blood glucose at morning. 30R: biphasic human insulin istics of a typical adrenal adenoma because adrenal 30. black adenoma was not rich in a fat component. PRECLINICAL CUSHING’S SYNDROME, DIABETES 549

There was a report that a case of overt Cushing’s tients with PCS [3, 6] and the lower level of ACTH syndrome due to adrenal black adenoma was not visu- (<10 pg/ml) was 62% in PCS and the absence of diur- alized by radiocholesterol scintigraphy because the nal rhythm was 69% [5]. It seems that autonomous poor lipid content of compact cells of the reticularis cortisol production in PCS is weaker than in overt zone in adrenal black adenoma might be responsible Cushing’s syndrome, and the insufficient suppression for the lower cholesterol uptake [16]. In this case, of plasma ACTH level in the present case may have therefore, adrenal scintigraphy with 131I-adosterol resulted from stress effects due to treatment of diabetic might not have shown any marked accumulation in the ketoacidosis. right adrenal region, although immunohistochemical The normal adrenal gland tissue adjacent to the black studies confirmed that the adrenal black adenoma in adenoma was compressed but not atrophic, based on our case had the ability to produce hormones. histologic examination. DHEA-ST immunoreactivity Komiya et al. reported that the number of compact was noted in a locus in the adjacent adrenal gland. Fur- cells was higher in black adenoma than in yellow ade- thermore, he was able to discontinue hydrocortisone at noma, and this difference may reflect quantitative al- a relatively early stage after surgery. This PCS case is terations in lipid content or qualitative differences in not likely to be full brown Cushing’s syndrome with lipids within the cells [18]. However, there were no complete suppression of the HPA axis, and the influ- significant differences in serum cortisol concentrations ence of autonomous cortisol production in this PCS or dexamethasone suppressibility in patients with ei- may have been somewhat weak for the onset of dia- ther type of adrenal adenoma [18, 19], and the cortisol betic ketoacidosis. composition of black adrenal adenoma was not higher In the present case, the patient showed a diabetic than that of yellow adrenal adenoma. pattern on 75 g oral glucose tolerance test one month We could not evaluate whether the degree of cortisol postoperatively, indicating that he had underlying type composition ability in this adrenal black adenoma was 2 diabetes mellitus. Therefore, it seems that envi- higher than that in the contralateral adrenal gland, be- ronmental factors such as excessive intake of sugar- cause we did not carry out cortisol sampling from each containing soft drinks also contributed to aggravation adrenal vein. However, it is thought that the contralat- of blood glucose levels in this case. However, glucose eral adrenal gland does not have abnormal hormone metabolism rapidly improved postoperatively, as shown production ability from the result of a postoperative in Figure 6, and we could not deny the possibility that dexamethasone suppression test and clinical course. autonomous steroid production from the adrenal black There are many reports that a dexamethasone sup- adenoma also contributed to the exacerbation of glu- pression test is useful in screening for PCS; however, it cose intolerance in this case. It is necessary to examine is known that serum cortisol levels differ with each a larger set of similar cases in order to constructively measurement kit and the correct diagnosis of PCS may discuss whether diabetic ketoacidosis can be caused by depend on the cortisol measurement kit used [20]. Cor- PCS. tisol measurement in our hospital is performed using The transition from PCS to overt Cushing’s syn- ADVIA-Centaur cortisol assay (chemiluminescent im- drome has been reported [4]. However, the average munoassay), and the serum cortisol level may appear patient age at diagnosis of PCS is older than the aver- relatively low compared with that obtained by other age age of those with Cushing’s syndrome, and the measurement kits such as Amerlex cortisol kit (radio- probability of progression from PCS to overt Cushing’s immunoassay). The preoperative serum cortisol levels syndrome seems to be low, especially in older patients on dexamethasone suppression test in the present case [21]. Various degrees of cortisol secretion may influ- did not show marked suppression, and findings in the ence glucose intolerance, and obesity to present case do not contradict the diagnosis of PCS. some extent, but these symptoms may be considered However, this patient’s urinary excretion of cortisol non-specific with respect to PCS. For these reasons, was within normal limits and plasma ACTH sup- uniform guidelines have not yet been established for pression was not sufficient. It is known that the bio- the management of PCS. However, the incidence of chemical findings in PCS cover a wide spectrum [6]. diabetes mellitus is about 25–50% in PCS [22–24], According to previous reports, urinary excretion of and it is known that PCS is present in 3.5% of diabetic cortisol was within normal limits in 39–55% of the pa- patients having both excessive weight and poorly con- 550 KAHARA et al. trolled blood glucose [25], and there may be many man hospitalized with diabetic ketoacidosis, who was more patients similar to the present case. The cases of subsequently diagnosed as having PCS of adrenal PCS complicated by hypertension, diabetes mellitus black adenoma. Since diabetes mellitus retrograded and obesity can be expected to show improvement of postoperatively, the presence of PCS may have been metabolic abnormalities after adrenalectomy [22]. related to the previous deterioration of diabetes melli- Therefore, surgical treatment should be considered as tus. Although there are many aspects of the natural one of the treatment options to prevent the progressive course of PCS that have not been elucidated, it is development of long-term complications of metabolic necessary to remain aware that a PCS patient with abnormality due to subtle corticoid excess [24]. abnormal glucose metabolism may develop diabetic In summary, we reported a 53-year-old Japanese ketoacidosis by environmental agents.

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