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Metyrapone-Responsive Ectopic ACTH-Secreting Pheochromocytoma with a Vicious Cycle Via a Glucocorticoid-Driven Positive-Feedback Mechanism

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Metyrapone-Responsive Ectopic ACTH-Secreting Pheochromocytoma with a Vicious Cycle Via a Glucocorticoid-Driven Positive-Feedback Mechanism 2018, 65 (7), 755-767 Original Metyrapone-responsive ectopic ACTH-secreting pheochromocytoma with a vicious cycle via a glucocorticoid-driven positive-feedback mechanism Minako Inoue1), Ken Okamura1), Chie Kitaoka1), Fumio Kinoshita2), Ryo Namitome3), Udai Nakamura1), Masaki Shiota3), Kenichi Goto1), Toshio Ohtsubo1), Kiyoshi Matsumura4), Yoshinao Oda2), Masatoshi Eto3) and Takanari Kitazono1) 1) Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 2) Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 3) Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 4) Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Abstract. In ectopic ACTH-secreting pheochromocytoma, combined ACTH-driven hypercortisolemia and hyper‐ catecholaminemia are serious conditions, which can be fatal if not diagnosed and managed appropriately, especially when glucocorticoid-driven positive feedback is suggested with a high ACTH/cortisol ratio. A 46-year-old man presented with headache, rapid weight loss, hyperhidrosis, severe hypertension and hyperglycemia without typical Cushingoid appearance. Endocrinological examinations demonstrated elevated plasma and urine catecholamines, serum cortisol and plasma ACTH. Moreover, his ACTH/cortisol ratio and catecholamine levels were extremely high, suggesting catecholamine-dominant ACTH-secreting pheochromocytoma. Computed tomography revealed a large right adrenal tumor. 18F-FDG positron emission tomography showed uptake in the area of the adrenal tumor, while 123I-metaiodobenzylguanidine scintigraphy showed no accumulation. His plasma ACTH level paradoxically became elevated after a dexamethasone suppression test. After metyrapone administration, not only serum cortisol but also plasma ACTH levels were exponentially decreased almost in parallel, suggesting a glucocorticoid-driven positive-feedback regulation in this rapidly exacerbated ectopic ACTH-producing pheochromocytoma. Interestingly enough, plasma catecholamine levels were also decreased by metyrapone, although they remained extremely high. He became severely dehydrated due to hypoadrenalism requiring hydrocortisone supplementation. His clinical signs and symptoms were improved, and right adrenalectomy was performed uneventfully, resulting in complete remission of pheochromocytoma and Cushing’s syndrome. A glucocorticoid-driven positive-feedback regulation in this ectopic ACTH-secreting pheochromocytoma created a vicious cycle with rapid exacerbation of both hypercortisolemia and hypercatecholaminemia with extremely elevated plasma ACTH level. Metyrapone was clinically effective to stop this vicious cycle; nonetheless, great care must be taken to avoid hypoadrenalism especially when hypercatecholaminemia remained. Key words: Pheochromocytoma, Ectopic ACTH syndrome, Metyrapone, Positive feedback PRODUCTION of cortisol in adrenal glands is under the homeostatic regulation and is a management challenge. the control of the pituitary gland and is subject to nega‐ Adrenocorticotrophin (ACTH)-dependent Cushing’s tive feedback, resulting in tight regulation of circulating syndrome is a heterogeneous disorder requiring a multi‐ hormone levels. Ectopic hormone production is not under disciplinary and individualized approach to patient man‐ agement [1]. On the other hand, pheochromocytomas are Submitted Jan. 16, 2018; Accepted Apr. 9, 2018 as EJ18-0025 functional catecholamine-producing tumors originating Released online in J-STAGE as advance publication May 15, 2018 from chromaffin cells in the adrenal medulla. Though Correspondence to: Minako Inoue, MD, PhD, Department of ectopic hormone-secreting pheochromocytomas are rare, Medicine and Clinical Science, Graduate School of Medical Sci‐ ences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka approximately 1% of cases have been associated with 812-8582, Japan. ectopic ACTH production [2-35]. Because of the signifi‐ E-mail: [email protected] cant morbidity of both Cushing’s syndrome and pheo‐ ©The Japan Endocrine Society 756 Inoue et al. Table 1 Clinical data of the present case and reported cases with metyrapone-sensitive ectopic ACTH- secreting pheochromocytoma Author Present case White et al. [16] Sakuma et al. [33] Year 2017 2000 2016 Sex Male Female Female Age 46 44 56 Clinical manifestation Cushingoid appearance (–) (+) (+) Body Mass Index, kg/m2 18.0 32.8 Blood Pressure, mmHg 220/130 220/130 153/93 Fasting blood glucose, mg/dL 350 ↑ NA 341 ↑ Serum potassium, mEq/L 3.0 2.3 NA Liver dysfunction (+) (+) NA Results of dexamethasone suppression test ACTH, pg/mL before 270.5 NA 18.4a 0.5 mg 331.9 NA 1 mg 237.6 18.4a 8 mg 390 241a Cortisol, μg/dL before 32.3 <1.0a 0.5 mg 41.2 NA 1 mg 25.8 <1.0a 8 mg 34.8 <1.0a Pheochromocytoma Site/Size, cm Right/6.0 Left/4.0 Left/5.3 MIBG scintigraphy (–) (+) (+) Hyperplasia of cortex not apparent contralateral bilateral ACTH, adrenocorticotrophin; NA, Not available a Dexamethasone suppression test was performed taking 6 g/day of metyrapone. chromocytoma, early diagnosis and prompt therapy are Case Description warranted [1, 36, 37]. The survival rate used to be only 43%, with most deaths caused by surgical complications A 46-year-old man presented with headache, rapid [3]. Several case reports have described a paradoxical weight loss (10 kg/year), hyperhidrosis, tachycardia (110 response to the dexamethasone suppression test [3, 11, bpm), severe hypertension (220/130 mmHg) and hyper‐ 19, 22, 23, 29, 33, 35]. In two patients, the effectiveness glycemia (fasting plasma glucose 350 mg/dL, glycated of metyrapone treatment to suppress plasma ACTH level albumin 23.6%, HbA1c 8.3%). There were not typical was reported, suggesting positive-feedback regulation of Cushingoid appearances, such as moon face, buffalo ectopic ACTH secretion [16, 33]. In this report, we hump or central obesity. There was not apparent hyper‐ describe a case of catecholamine-dominant ectopic pigmentation. There was no family history of pheochro‐ ACTH-secreting pheochromocytoma, in whom further mocytoma or correlates except for stroke in his maternal examination confirmed the improvement of not only the grandparents. Height was 170 cm and body weight was plasma ACTH level but also both plasma and urine cate‐ 52 kg (body mass index of 18.0 kg/m2). Initial examina‐ cholamine levels after metyrapone treatment. Appropri‐ tion revealed hypokalemia (3.0 mEq/L), severe dehydra‐ ate treatment in this serious condition is discussed with a tion without diabetic ketoacidosis, and liver dysfunction review of the literature. (Tables 1, 2). He was referred to our hospital for further investigation and treatment. Laboratory studies displayed extremely high levels of ACTH-secreting pheochromocytoma 757 Table 2 Clinical data—before (B) and after (A) metyrapone treatment and post operation (Postop)—of the present case compared with reported cases with metyrapone-sensitive ectopic ACTH-secreting pheochromocytoma Author Present case (Postop) White et al. [16] Sakuma et al. [33] Dose of metyrapone (g/day) 0.5→0.25 none 1.0a 4.0→6.0 Serum or plasma A/B (%) Cortisol, μg/dL B 32.3 1.7 >60.2 85.6 (4.0–18.3) A 5.5 (17.0%) 2.6 <1.0 ACTH, pg/mL B 270.5 5.4 927 995 (7.2–63.3) A 34.8 (12.8%) 50.0 18.4 Adrenaline, pg/mL B 4,448 5 NA 589 (<100) A 1,139 (25.6%) NA Noradrenaline, pg/mL B 8,901 228 NA 1,342 (100–450) A 3,965 (44.5%) NA Dopamine, pg/mL B 203 14 NA 68 (<20) A 21 (10.3%) NA ACTH/Cortisol ratiob B 8.4 × 10–4 3.2 × 10–4 <15.4 × 10–4 11.6 × 10–4 (1–4 × 10–4) A 6.3 × 10–4 19.4 × 10–4 >18.4 × 10–4 Adrenaline/Cortisol ratioc B 137.7 × 10–4 NA 6.9 × 10–4 (<25 × 10–4) A 207.1 × 10–4 POMC, pmol/L B NA 1,625 NA A NA 163 NA ALT/AST, U/L B 119/38 NA NA A 15/12 15/13 Blood Pressure, mmHg B 220/130 200/130 153/93 A 128/80 124/78 110/70 Urine Free cortisol, μg/day B 765 NA NA 1,250 (26–187) A 15.1 (2.0%) NA Adrenaline, μg/day B 2,590 NA 1,181 244.4 (3–30) A 239.4 (9.2%) NA NA Noradrenaline, μg/day B 3,130 NA 1,444 1,175.8 (30–150) A 619.9 (19.8%) NA NA Dopamine, μg/day B 1,536 NA NA 669.8 (350–950) A 188.2 (12.3%) NA Metanephrine, μg/day B 6,660 10 NA 1,120 (40–190) A 1,110 (16.7%) 440 Normetanephrine, μg/day B 2,590 40 NA 1,290 (90–330) A 990 (38.2%) 540 ACTH, adrenocorticotrophin; POMC, proopiomelanocortin; NA, Not available; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; Numbers in parenthesis are reference values. a 0.75 mg dexamethasone was added for replacement b Calculated as plasma ACTH divided by serum cortisol c Calculated as plasma adrenaline divided by serum cortisol plasma and urine catecholamines and their metabolites hemorrhage and necrosis respectively (Fig. 1A). Plain (Table 2). Plain CT revealed a 6.0 cm right adrenal tumor magnetic resonance imaging (MRI) showed mainly a with high- and low-density area, suggesting intratumoral T1-low and T2-high tumor, with mixed-intensity area 758 Inoue et al. Fig. 1 Imaging studies. The right adrenal tumor is indicated by arrows. A. Plain computed tomography, B. Plain magnetic resonance imaging, C. 123I-metaiodobenzylguanidine scintigraphy (C-1; Front view, C-2; Rear view), D. 18F-FDG positron emission tomography suggesting intratumoral hemorrhage and necrosis (Fig. gations suggesting elevated catecholamine levels accom‐ 1B). 123I-metaiodobenzylguanidine (MIBG) scintigraphy panied with ACTH-driven hypercortisolemia, the right showed no accumulation in the tumor (Fig. 1C), while adrenal tumor was diagnosed to be an ACTH-secreting 18F-FDG positron emission tomography (PET) showed pheochromocytoma. The characteristic of this patient uptake in the area of the adrenal tumor, mainly the mar‐ was his extremely elevated levels of catecholamine ginal area (SUVmax 6.25) (Fig.
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