Endocrine Journal 2007, 54 (4), 543–551 Preclinical Cushing’s Syndrome Resulting from Adrenal Black Adenoma 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 adrenal tumor 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 hormones in the morning after an overnight fast and urinary cortisol excretion after treatment of diabetic ketoacidosis with insulin. 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 diabetes 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, Type 2 diabetes (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 endocrine disease 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 obesity, 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-peptide 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 gland, but there were no ab- HCO3– 4.0 mmol/L Base excess –24.6 mmol/L normal findings in the pancreas (Fig. 1). SaO2 97.8% As shown in Table 2, the early morning levels of Anion gap 36 mEq/L serum cortisol, plasma adrenocorticotrophic hormone (ACTH), plasma aldosterone 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 adrenal gland. 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.