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J. St. Marianna Univ. Case Report Vol. 9, pp. 15–21, 2018

Identification of Adrenal Insufficiency Leading to a Diagnosis of POEMS Syndrome

Tomoya Tsuchida1, Hisashi Nishisako1, Masahiro Hirose1, Kana Igarashi2, Chiaki Okuse1, and Takahide Matsuda1

(Received for Publication: February 22, 2018)

Abstract A 57-year-old Japanese man with abdominal distention was referred to gastroenterologists at our hospital, where abdominal computed tomography revealed ascites and swollen lymph nodes. He was admitted for testing and treatment. Suffering from unremitting hyponatremia, hyperkalemia, hypotension, and hypoglycemia, he was transferred to our division for electrolyte correction and further diagnosis. Hormone stimulation testing revealed adrenal insufficiency. Upon electrophysiology, immunoelectrophoresis, and measurement of vascular endothe‐ lial growth factor, POEMS syndrome was diagnosed. POEMS syndrome may underlie adrenal insufficiency and should be considered when polyneuropathy, ascites, and swollen lymph nodes occur along with adrenal insuffi‐ ciency.

Key words Electrolyte abnormalities, Adrenal insufficiency, POEMS syndrome

Introduction Case POEMS (acronym for polyneuropathy, organo‐ The patient was a 57-year-old Japanese man megaly, endocrinopathy, monoclonal gammopathy, who, for 2 months, had suffered numbness in both and skin changes) syndrome is a multisystemic dis‐ lower limbs. He had also noticed darkened skin, pre‐ ease characterized by such symptoms as numbness, dominantly on his legs. He had visited his local tingling, and weakness of the legs; edema, pleural ef‐ physician, complaining of abdominal bloating, and a fusion, ascites, and an enlarged spleen; adrenal insuf‐ few weeks later, he was referred to the Department of ficiency; and hyperpigmentation and angiomas. Al‐ Gastrointestinal Surgery at our hospital for further though endocrine abnormalities are noted in about examination and treatment. It was noted that he was 80% of patients with POEMS syndrome1), there are taking aspirin and losartan because of a previous cer‐ not many reports of adrenal insufficiency in patients ebral infarction, but his family history was unremark‐ with the syndrome. Moreover, in none of the reported able. Abdominal plain computed tomography (CT) cases has POEMS syndrome been diagnosed upon was performed, and edematous change and fluid ac‐ detection of adrenal insufficiency. We encountered a cumulation in the intestines, ascites, and swollen patient who was diagnosed with adrenal insuffi‐ lymph nodes throughout the peritoneal cavity were ciency, and this led to a diagnosis of POEMS syn‐ revealed, so the patient was admitted. There was no drome. obvious sign of gastrointestinal obstruction. He was treated by fasting, intravenous extracellular fluid transfusion, and paracentesis. The abdominal disten‐

1 Kawasaki Municipal Tama Hospital, Division of General Internal Medicine, St. Marianna University School of Medicine 2 Division of Metabolism and Endocrinology, St. Marianna University School of Medicine

15 16 Tsuchida T Nishisako H et al tion did not worsen, and the fasting was discontinued Table 1. Blood Test Results Before The Patient was on hospital day 3. Peritoneal fluid was examined cy‐ Transferred to Our Division. tologically, and there was no evidence of malignancy. Hospital day The patient had no difficulty eating and was able to 1 3 6 8 12 ingest full meals, but on admission, blood chemistry Na (mEq/L) 139 134 131 122 121 tests had shown a sodium (Na) concentration of 139 Cl (mEq/L) 105 100 99 93 95 mEq/L and potassium (K) concentration of 5.6 K (mEq/L) 5.6 4.7 5.3 6.6 7.7 mEq/L. On hospital day 3, the Na concentration was Na/K 24.8 28.5 24.7 18.5 15.7 134 mEq/L, and the K concentration was 4.7 mEq/L. BUN (mg/dL) 25.4 17.7 13.0 27.4 41.6 By hospital day 12, the Na concentration had de‐ Cre (mg/dL) 1.31 1.14 1.17 1.07 1.33 creased markedly to 121 mEq/L, and the K concen‐ WBC (μ/L) 8100 6900 4600 5300 5000 tration had increased markedly to 7.7 mEq/L. At this Eosinophils (%) 1 1.3 - - 1.5 point, the patient was referred to our Division of Glu (mg/dL) - - 85 - 70 Na: sodium, Cl: chloride, K: potassium, BUN: blood urea nitrogen, Cre: creatinine, General Internal Medicine for urgent correction of WBC: white blood cell count, Glu: glucose, - not tested the electrolyte levels and for a determination of the cause of the fluctuations. At the time of admission to guinal, periaortic, and mediastinal lymph nodes. The our division, the patient was alert, his blood pressure adrenal glands appeared morphologically normal was 95/57 mmHg, his pulse was regular at 56 beats/ (Fig. 1 A-C). Calcium gluconate was administered to min, and his thyroid was not enlarged. No cervical or treat the hyperkalemia, and glucose-insulin therapy were palpable, but approxi‐ was started. The losartan was discontinued, and by mately 3 cm was palpated in his right groin. His ab‐ hospital day 19, the patient’s K concentration de‐ domen was distended and soft but not tender. Hyper‐ creased to 4.0 mEq/L. The course of the illness sug‐ pigmentation on his lower limbs was noted, and the gested adrenal insufficiency, and hormone stimula‐ hair on his legs was bristly. Pitting edema of both tion tests were performed. In the blood collected at lower limbs was noted. The patient reported that the rest in the morning, the cortisol concentration was numbness he had noticed in both legs before admis‐ 12.8 μg/dL (a concentration below 4 μg/dL suggests sion had worsened progressively. A manual muscle adrenal insufficiency, and, whereas a concentration of test was performed, revealing that muscle strength of 18 μg/dL or above precludes adrenal insufficiency, a the upper and lower limbs was only somewhat de‐ concentration of 4 to 18 μg/dL does not preclude the creased (score 4/5) on both sides. There were no disorder), and the adrenocorticotropic hormone pathologic reflexes. The lower limbs were more sen‐ (ACTH) concentration was 84 pg/mL (7.2–63.3 sitive to touch and pain than were the upper limbs. pg/mL). An adrenocorticotropic hormone (250 μg) There was no autonomic impairment and no obvious stimulation test revealed a cortisol concentration of cerebellar abnormality. Results of cognitive and neu‐ 14.5 μg/dL (i.e., no increase) (Fig. 2), and a cortico‐ rological function tests were normal. Blood chemis‐ tropin-releasing hormone (CRH) stimulation test re‐ try tests revealed a blood urea nitrogen (BUN) con‐ vealed a cortisol level of 12.9 μg/dL (no change, al‐ centration of 41.8 mg/dL, creatinine (Cre) though the ACTH concentration had increased to 170 concentration of 1.33 mg/dL, Na concentration of ng/mL) (Fig. 3). Thus, primary adrenal insufficiency 121 mEq/L, K concentration of 7.7 mEq/L, chloride was diagnosed. Thyroid function tests revealed a free (Cl) concentration of 95 mEq/L, and glucose (Glu) triiodothyronine (FT3) concentration of 0.92 ng/dL, a concentration of 70 mg/dL. In other words, the BUN free thyroxine (FT4) concentration of 2.09 ng/dL, and Cre concentrations were elevated, and hyponatre‐ and a thyroid-stimulating hormone (TSH) concentra‐ mia, hyperkalemia were present (Table 1). The blood tion of 11.412 μIU/mL, subclinical hypothyroidism . cell counts and hepatobiliary enzyme concentrations The anti-thyroid peroxidase and anti-thyroglobulin were normal; the total protein concentration was 7.1 antibody titers were not elevated (<5 and <10, respec‐ g/dL, and the albumin concentration was normal at tively), ruling out Hashimoto’s disease. Assessment 4.1 g/dL. The HbA1c level was 5.0%. On hospital of gonad function, parathyroid function, and pituitary day 5 (before the patient had been admitted to our di‐ function revealed a testosterone concentration of 5.58 vision), contrast-enhanced CT from the chest to the ng/mL (2.0–7.6), an intact parathyroid hormone con‐ lower revealed an increase in the peritoneal centration of 54 pg/mL (10–60), a prolactin (PRL) fluid volume; hepatosplenomegaly; and swollen in‐ concentration of 16.15 ng/mL (3.6–12.8), growth

16 Adrenal Insufficiency due to POEMS Syndrome 17

A) Hepatosplenomegaly and ascites are evident. Neither adrenal enlargement nor atrophy is evident on the right or left. Left and right adrenal glands (⇩).

B) Swollen are evident (⇩). C) Swollen are evident (⇩). Figure 1. Abdominal contrast-enhanced computed tomography images obtained on hospital day 5.

Cortisol (µg/dL) ACTH（pg/mL） 20

15

10

5

0 Baseline 30 minutes 60 minutes Figure 3. Results of corticotropin-releasing hormone load‐ Figure 2. Results of rapid adrenocorticotropic hormone ing test performed (Hospital day28). (250 μg) stimulation test performed. (Hospital day24)

17 18 Tsuchida T Nishisako H et al hormone (GH) concentration of 1.98 ng/mL (≤0.42 centration was 6,130 pg/mL (normal: 229 ± 147 ng/mL is normal), luteinizing hormone (LH) concen‐ pg/mL). At this point, POEMS syndrome was diag‐ tration of 5.93 mIU/mL (1.7–8.6), and follicle-stimu‐ nosed definitively, and the patient was transferred to lating hormone (FSH) concentration of 8.00 mIU/mL another hospital for specialized treatment. The pa‐ (1.5–12.4). Quadruple injection test of hypothalamic tient now takes thalidomide regularly and continues peptide revealed no abnormalities except a poor corti‐ to receive dexamethasone pulse therapy. He has been sol response. Hydrocortisone (7.5 mg in the morning, discharged, but he is followed up regularly in a speci‐ 2.5 mg in the evening) was administered for treat‐ alized outpatient services clinic at our hospital and at ment of the adrenal insufficiency; the electrolyte ab‐ another hospital. normalities and hypoglycemia disappeared. Motor Discussion nerve and sensory nerve conduction velocities were measured, and both were found to be decreased; la‐ POEMS syndrome is a multisystemic disease tency was also prolonged, and thus polyneuropathy characterized by monoclonal proliferation of plasma was diagnosed. The increased pigmentation and bris‐ cells and such manifestations as polyneuropathy, tling of the hair spread across the patient’s entire edema, pleural effusion or ascites, organomegaly, en‐ body. Inguinal biopsy was performed, docrinopathy, skin changes (hyperpigmentation but there was no indication of malignancy. Lymphoid and/or angiomas), and monoclonal gammopathy2). On follicles mixed with atrophic germinal centers and the basis of a nationwide survey conducted in 2003, lymphoid follicles with enlarged germinal centers the Research Committee on Autoimmune Neurologi‐ were noted. Hyperplasia with high endothelial ven‐ cal Disorders of the Ministry of Health, Labour, and ules was noted (Fig. 4). Malignancy was judged to be Welfare of Japan estimated the number of patients at unlikely, given the endocrine abnormalities, poly‐ about 3403). Awareness of POEMS syndrome is lim‐ neuropathy, skin changes, and results of peritoneal ited, however, so it is possible that many cases have fluid cytology and lymph node biopsy. POEMS syn‐ gone undiagnosed. Because POEMS syndrome has drome was considered in the differential diagnosis. various clinical manifestations, the departments to Additional testing revealed the presence of monoclo‐ which patients initially present vary. General intern‐ nal IgA (λ) protein in the patient’s urine, and the se‐ ists and the various subspecialists must be aware of rum vascular endothelial growth factor (VEGF) con‐ this condition so that it can be diagnosed and treated early4). An essential diagnostic criterion for POEMS syndrome is polyneuropathy. Two other major criteria are serum VEGF elevation (1000 pg/mL or higher) and the presence of monoclonal proteins, and minor criteria are osteosclerotic lesions, Castleman’s dis‐ ease, organomegaly, edema, pleural effusion, ascites, pericardial effusion, endocrine abnormalities, skin abnormalities, papilledema, and thrombocytosis. A condition that satisfies the 3 major criteria and 1 or more minor criteria is definitively diagnosed as PO‐ EMS syndrome2). About half of the patients present with polyneuropathy, and the remainder present with edema or skin manifestations (increased skin pigmen‐ tation, bristly hair, and/or angiomas); men often present with gynecomastia. During screening or as‐ sessment for various other conditions, pleural effu‐ Figure 4. High-magnification image of a hematoxylin sion/ascites, monoclonal proteins, and high levels of 5) and eosin-stained section of the inguinal Cre are often detected . Multiple symptoms arise as lymph node specimen. Noted are a high en‐ the condition progresses. During the initial examina‐ dothelial venule (proliferation of endothe‐ tion, physicians must take a systematic approach to the differential diagnosis, keeping POEMS syndrome lial cells of the venule) (▽) and lymphoid follicle with an atrophic germinal center in mind so that the condition can be diagnosed early. The patient’s hyperkalemia was noted on the (⇩).

18 Adrenal Insufficiency due to POEMS Syndrome 19 day of his initial admission. On hospital day 3, how‐ EMS syndrome. Gandhi et al. examined results of en‐ ever, fluid replacement primarily with extracellular docrine tests performed in 64 patients with POEMS fluid solution alleviated the electrolyte abnormalities, syndrome and found endocrinopathy in 54 (84%) of so adrenal insufficiency could not have been pre‐ these patients1). The most common endocrine abnor‐ dicted on admission. Despite the fluid and electrolyte mality was hypogonadism, followed by hypothyroid‐ replacement therapy, the patient’s Na/K ratio gradu‐ ism and impaired glucose tolerance. Nine patients un‐ ally decreased, and by hospital day 12, prompt cor‐ derwent a rapid ACTH stimulation test, and 6 of rection of the electrolyte levels was necessary these 9 were diagnosed with adrenal insufficiency. (Fig. 5). The patient’s blood pressure on initial ad‐ According to Gandhi et al., endocrine abnormalities mission (and while he was taking losartan) was are not evaluated in many cases of POEMS syn‐ 130/77 mmHg, but it decreased to 95/57 mmHg by drome, and such cases are instead diagnosed on the the time he was treated in our department. Given the basis of other criteria. In fact, endocrine abnormali‐ decreased blood pressure and elevated BUN and Cre ties have, in the past, seldom been assessed in pa‐ levels, adrenal insufficiency was presumed to have tients with POEMS syndrome. The onset of endo‐ developed. Ascites is noted in 7–54% of cases of PO‐ crine abnormalities in POEMS syndrome presumably EMS syndrome6). The patient we describe was admit‐ involves VEGF, but autoantibodies against endocrine ted for further examination of abdominal distention glands have not been detected12), and autopsies have resulting from ascites, and it is likely that the subse‐ revealed no structural endocrine gland abnormalities. quent fasting, fluid replacement therapy, and para‐ Thus, functional abnormalities presumably cause the centesis caused physiological and psychological endocrine abnormalities13). Adrenal insufficiency is a stress. The stress may have been the cause of acute condition that causes a variety of symptoms. When exacerbation of adrenal insufficiency as a manifesta‐ polyneuropathy, ascites, and swollen lymph nodes are tion of the POEMS syndrome. noted along with adrenal insufficiency, POEMS syn‐ Five cases of adrenal insufficiency in association drome must be included in the differential diagnosis, with POEMS syndrome have been reported (Ta‐ even though adrenal insufficiency linked to POEMS ble 2)7–11). In 3 of these cases7–9), adrenal insufficiency syndrome is rare. The case we describe is highly in‐ was originally diagnosed and treated, but other symp‐ structive because the POEMS syndrome was not di‐ toms developed during treatment, leading to a diag‐ agnosed on the basis of the clinical interview, and it nosis of POEMS syndrome 5 months to 2 years after was not considered during the early examinations de‐ the original diagnoses. In 2 of the 5 cases10)11), the spite the presence of hyperpigmentation and foot adrenal insufficiency was diagnosed on the basis of numbness. The adrenal insufficiency was key to the endocrine tests, but with the exception of the case we diagnosis. report, there are no reported cases in which adrenal Acknowledgement insufficiency developed and led to a diagnosis of PO‐ The authors wish to thank Professor Satoshi Ku‐ Na/K wabara of the Department of Neurology, Chiba Uni‐ 35 versity, who treated the patient described herein. Glucose-insulin 30 therapy Authors’ COI disclosure: The authors have no con‐ 25 flict of interest to disclose with regard to this report. 20 References 15 1) Gunjan Y, Gandhi R, Angela D, Ananda B, Vic‐ 10 tor M. Montori, Michael D. Brennan. Endocrin‐ 5 opathy in POEMS syndrome: The Mayo Clinic experience. Mayo Clin Proc 2007; 82: 836–842. 0 2) Kuwabara S, Dispenzieri A, Arimura K, Misawa 1 3 5 7 9 11 13 15 17 19 S. Treatment for POEMS (polyneuropathy, orga‐ Hospital day nomegaly, endocrinopathy, M-protein, and skin Figure 5. Patient’s sodium/potassium ratio during the changes) syndrome. Cochrane Database Syst course of hospitalization. Rev 2008; 8: CD006828. doi: 10.1002/14651858.

19 20 Tsuchida T Nishisako H et al

Table 2. Reports of Adrenal Insufficiency in Patients with POEMS Syndrome.

Diagnosis of Chief Symptoms of POEMS Treatment and Patient adrenal Reference complaint(s) syndrome outcome insufficiency 44-year-old man Visual Optic nerve edema, Two years prior, The myeloma was Surv Opthalmol impairment polyneuropathy, hypogonadism treated with 59:128–131, osteosclerotic lesions, and adrenal radiation therapy 2014. polycythemia insufficiency were and noted. The patient dexamethasone. was taking hydrocortisone. Impaired vision led to a diagnosis of POEMS syndrome.

32-year-old man Malaise Malaise, thinning One year prior, Symptoms were J Japanese Soc body hair, edema, leg malaise and alleviated with Internal Med pain, increased bristly hair were pulse 100:3038–3040, pigmentation of the noted. Six months corticosteroids, 2011. areolae, erectile prior, treatment treatment with dysfunction with melphalan and hydrocortisone prednisone, and yielded no autologous stem improvement. cell transplantation. Upon admission, POEMS syndrome was diagnosed. 42-year-old woman Fatigue, Increased skin Five months prior, Autologous stem Medscape Med constipation, pigmentation, swollen malaise, cell transplantation 11:21, 2009. amenorrhea axillary lymph nodes, constipation, and was performed. In hepatosplenomegaly, amenorrhea were 4 years, adrenal hypothyroidism, noted. ACTH function improved. polyneuropathy stimulation testing led to a diagnosis of adrenal insufficiency, and hydrocortisone was administered. Further examination of other symptoms led to a diagnosis of POEMS syndrome. 36-year-old man Lower back Polyneuropathy, ACTH stimulation Symptoms were J Med Assoc pain vertebrae with a testing led to a alleviated with Thai 76:585– mixture of diagnosis of radiation therapy 590, 1993. osteosclerosis and adrenal and treatment with osteolysis, increased insufficiency. melphalan and skin pigmentation, prednisone. gynecomastia, hepatosplenomegaly, shrinking of the testes, swollen lymph nodes, ascites 63-year-old man Osteosclerotic Polyneuropathy, Cortisol levels Hormone J Clin Apher myeloma and hepatosplenomegaly, were assessed, replacement 2:253–257, other symptoms optic nerve edema, and a low therapy was 1985. ascites, increased skin morning cortisol started. Treatment pigmentation, level (8.2 g/mL), with melphalan and papilledema led to a diagnosis prednisone was of adrenal ineffective. insufficiency. plasmapheresis was performed, but the patient died subsequently. 57-year-old man Bloating, Polyneuropathy, Electrolyte Symptoms were Case described (our patient) numbness in the hepatosplenomegaly, abnormalities alleviated with herein lower limbs ascites, increased skin were noted on thalidomide and pigmentation, admission. dexamethasone. hypertrichosis, Adrenal swollen lymph nodes insufficiency was suspected, so an ACTH stimulation test was performed. Results led to a diagnosis of adrenal insufficiency. ACTH: adrenocorticotropic hormone

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CD006828.pub2. kai Zasshi 2011; 100: 3038–3040. 3) Osame M, Arimura K, Uehara A. 2004 National 9) Ashawesh K, Fiad TM. Spontaneous recovery of epidemiological survey of Crow-Fukase syn‐ adrenal insufficiency in POEMS syndrome. drome, Research Committee on Autoimmune Medscape J Med 2009; 11: 21. Neurological Disorders of the Ministry of 10) Intragumtornchai T, Phanthumchinda K, Ler‐ Health. Labour and Welfare 2004 Report, To‐ dlum S, Supmpathanikul P, Sakulramrung R. kyo, 2004: 141–144. POEMS syndrome: a case with proliferative vas‐ 4) Kuwabara S. The pathology of and new treat‐ culopathy and a review of cases Thailand. J Med ments for Crow-Fukase syndrome. Nihon Naika Assoc Thai 1993; 76: 585–590. Gakkai Zasshi 2011; 100: 2275–2281. 11) Silberstein LE, Duggan D, Berkman EM. Thera‐ 5) Nakanishi T, Sobue I, Toyokura Y, Nishitani H, peutic trial of plasma exchange in osteosclerotic Kuroiwa Y, Satoyoshi E, Tsubaki T, Igata A, myeloma associated with the POEMS syn‐ Ozaki Y. The Crow-Fukase syndrome. a study drome. J Clin Apher 1985; 2: 253–257. of 102 cases in Japan. Neurology 1984; 34: 12) Bardwick PA, Zvaifler NJ, Gill GN, Newman D, 712–720. Greenway GD, Resnick DL. Plasma cell dyscra‐ 6) Dispenzieri A. POEMS syndrome: 2014 update sia with polyneuropathy, organomegaly, endo‐ on diagnosis, risk stratification, and manage‐ crinopathy, M protein, and skin changes: the ment. Am J Hematol 2014; 89: 214–223. POEMS syndrome. Report on two cases and a 7) Lally DR, Moster ML, Foroozan R. Muscle review of the literature. Medicine (Balti‐ cramping over the diagnosis. Surv Opthalmol more)1980; 59: 311–322. 2014; 59: 128–131. 13) Gherardi R, Baudrimont M, Kujas M, Malapert 8) Itoh Y, Hayakawa N, Okamura T, Tomoko O, D, Lange F, Gray F, Poirier J. Pathological find‐ Takayanagi T, Suzuki A, Oda N, Ueda A, Ina‐ ings in three non-Japanese patients with the PO‐ guma Y, Emi N, Itoh M. A case of POEMS syn‐ EMS syndrome. Virchows Arch A Pathol Anat drome with endocrinopathy. Nihon Naika Gak‐ Histopathol 1998; 413: 357–365.

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