Yuejing WU*， Jiong CHEN Yongchun MA Zhenxin CHEN

·Case report·

Case report of Cushing's syndrome with an acute psychotic presentation

Yuejing WU1，2，*， Jiong CHEN1， Yongchun MA1， Zhenxin CHEN1

Cushing’s syndrome； psychosis； differential diagnosis； case report； China

1. Case report

A 36-year-old Chinese woman was brought to the emergency department of a large general hospital with a 3-day history of acute irritability， mania， aggressive behavior， persecutory delusions， and suicidal ideation.Over the prior 6 months she had had disrupted sleep，hypervigilance， and somatic complaints for which she had irregularly taken over-the-counter benzodiazepines.Three years previously she had had diabetes during a pregnancy. More recently she reported hypertension and menstrual irregularity for which she had been treated with felodipine and ethinylestradiol. She had no history of smoking or drinking and no family history of serious physical or psychiatric illness.

She was initially admitted to the psychosomatic ward where her physical examination revealed a moon face， exophthalmos （abnormally protruding eyeballs）， central adiposity， and purple striae on her legs. Her blood pressure was 140/106 mm Hg and her blood sugar was 6.88 nmol/L （normal range， 3.89-6.11 nmol/L）. An acute episode of Cushing’s syndrome with psychiatric manifestations was the provisional diagnosis. Her plasma cortisol levels were grossly elevated： the early a.m. （8：00） and midnight （24：00）values were ＞46.7 μg/dl and ＞50 μg/dl， respectively（normal range， 2.5-12.57 μg/dl）. However， her adrenocorticotropic hormone （ACTH） levels were low：the early a.m. and midnight values were both ＜5 pg/ml（normal range， 5-46 pg/ml）. In addition， her cortisol levels were not suppressed after the administration of dexamethasone （DST） 1 mg （the cortisol level remained at ＞50 μg/dl）. Computerized tomography （CT） scan of her abdomen revealed a 2.5 cm × 2.8 cm tumor on her left adrenal gland.

The adrenal tumor was the presumptive cause of the physical and psychiatric symptoms， so on consultation with an endocrinologist and surgeon an elective surgery was scheduled one week later， at which point she was transferred to a surgical ward. In the intervening week she was started on low-dose quetiapine （75-125 mg/d）and alprazolam （0.4 mg/qn）， which partially reduced the severity of her psychotic symptoms and improved her sleep. The resected tumor was a benign ACTH-independent adrenal adenoma. One week after surgical removal of the adrenal tumor， her plasma cortisol and ACTH levels in the early morning （8：00） were ＜1 μg/dl and 8.93 pg/ml， respectively， and at midnight （24：00）they were 1.01 μg/dl and 5.81 pg/ml， respectively.She remained hospitalized for one month after the surgery； during this time her physical symptoms were treated with prednisolone， felodipine， metoprolol， and omeprazole， and her psychiatric symptoms and sleep disorder were treated with quetiapine and alprazolam.On discharge her physical symptoms had resolved and her persecutory delusions， mood dysregulation， and insomnia， had disappeared， though she continued to have some non-specific somatic complaints such as fatigue and backache. After discharge she continued to take quetiapine 75 mg/qn but discontinued the alprazolam. After two months of outpatient follow-up her psychiatric symptoms had completely resolved， so the quetiapine was stopped. On telephone follow-up several months later she reported no recurrence of any symptoms.

2. Discussion

Cushing’s syndrome （CS） is a clinical condition that results from chronic secretion of excessive levels of glucocorticoids by the adrenal glands which then directly influences the functioning of the hypothalamus and pituitary glands—the other components of the hypothalamic-pituitary-adrenal （HPA） axis.The hypercortisolism directly or indirectly results in the common clinical presentation of obesity，hypertension， diabetes， osteoporosis， amenorrhea， and hirsutism.［1］In 80-85% of cases CS is adrenocorticotropic hormone （ACTH） dependent， the result of a pituitary corticotrophic adenoma or an extra-pituitary corticotrophic adenoma （i.e.， ectopic ACTH syndrome）.In the remaining 10-20% of cases the disease is ACTH-independent （as was the case with this patient），usually the result of an adrenal gland tumor or adrenal hyperplasis， which can be unilateral or bilateral and benign or malignant.［2］

The insidious onset of prodromal fatigue and increased vigilance in CS are usually ignored by the individual and overlooked by clinicians.［2］The subsequent emergence of more troubling symptoms（hypertension， diabetes， osteoporosis， fractures， easy bruising， peripheral edema， back pain， menstrual irregularity， muscle weakness， and acne） results in greater clinical attention， and the presence of specific physical signs of CS （purple striae， facial plethora，exophthalmos， proximal myopathy， hirsutism， truncal obesity， and buffalo hump） often leads to the diagnosis.The median delay from onset of first symptoms to treatment is two years.［3］Clinical complications negatively impact the quality of life of individuals with CS and associated cardiovascular and infectious diseases substantially increase their morbidity and mortality（Hazard Ratio， 2.8-16）.［4］

Premorbid， concurrent， and consecutive psychiatric symptoms occur in 40-86% of individuals with CS.［3］A wide range of specific and non-specific psychiatric symptoms have been reported：［1，5，6］hypervigilance，fatigue， irritability， somatic complaints， sleep disturbance， decreased libido， depression， mood dysregulation， anxiety， cognitive abnormalities， suicide intent， personality changes， psychotic episodes， and anorexia nervosa. The reported prevalence of these neuropsychiatric signs and symptoms in CS varies across studies. One review［7］reported major depressive syndrome in 50-81% of individuals with CS， anxiety in 12-79%， cognitive impairment in 66%， and mania in 3%. The occurrence of depression in CS is significantly associated with female gender， older age， higher urinary cortisol levels， and more severe physical symptoms.［8］These neuropsychiatric symptoms significantly impair the health-related quality of life （HRQOL）［7］of individuals with CS.

The presumed cause of these neuropsychiatric symptoms in CS is chronic glucocorticoid-induced damage to the brain and the hippocampus. Research about depression in CS suggests that atrophy of the prefrontal cortex and/or suppression of neurogenesis in the dentate gyrus is a proximal cause of the depressive symptoms.［7］

When CS is suspected， the first step is to exclude hypercortisolemia attributed to exogenous glucocorticoid exposure or a pseudo-Cushing’s state［4］（such as alcohol abuse）. Then one of three biochemical screening tests is recommended： （a） the 24-hour Urinary Free Cortisol （UFC） test， （b） the latenight salivary cortisol test， or （c） the 1 mg overnight dexamethasone suppression test （DST）. After a diagnosis of CS is made， the primary cause should be determined， typically by abdominal or pituitary imaging to identify tumors or adrenal hyperplasia. Recent clinical practice guidelines for CS［4］recommend that all patients with comorbid psychiatric disorders receive immediate and long-term monitoring and adjunctive treatment for the psychiatric condition. After effective treatment of the hypercortisolemia， the psychiatric symptoms usually resolve gradually，［5］but these individuals are subsequently at increased risk of developing anxiety，depression， maladaptive personality traits， and cognitive impairment.［4］

Acute psychotic episodes associated with CS， though relatively uncommon，［5］require urgent treatment because they may be associated with a life-threatening acute infection， pulmonary thromboembolism， or other cardiovascular events.［9］Acute psychosis with a high suicide risk can occur in CS with even modest hypercortisolism （which may have less prominent physical symptoms），［10］so psychiatric clinicians must always consider CS as a potential differential diagnosis for any unexplained psychosis.

Funding

No funding support was obtained for preparing this case report.

Conflict of interest statement

The authors declare that they have no conflict of interest related to this manuscript.

Informed consent

The patient signed an informed consent form and agreed to the publication of this case report.

Authors' contributions

YJW wrote the first draft of the case report that was subsequently revised by JC and YCM. YCM and ZXC both treated the patient.

1. Hatakeyama M， Nakagami T， Yasui-Furukori N. Adrenal Cushing’s syndrome may resemble eating disorders. Gen Hosp Psychiatry. 2014； 36（6）： 760.e9-760.e10. doi： http：//dx.doi.org/10.1016/j.genhosppsych.2014.06.006

2. Guaraldi F， Salvatori R. Cushing syndrome： maybe not so uncommon of an endocrine disease. J Am Board Fam Med.2012； 25（2）： 199-208. doi： http：//dx.doi.org/10.3122/jabfm.2012.02.110227

3. Kelly W. Psychiatric aspects of Cushing’s syndrome. QJM.1996； 89（7）： 543-552. doi： http：//dx.doi.org/10.1093/qjmed/89.7.543

4. Nieman LK， Biller BM， Findling JW， Murad MH， Newell-Price J， Savage MO， et al. Treatment of Cushing’s syndrome： an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015； 100（8）： 2807-2831. doi： http：//dx.doi.org/10.1210/jc.2015-1818

5. Tang A， O’Sullivan AJ， Diamond T， Gerard A， Campbell P.Psychiatric symptoms as a clinical presentation of Cushing’s syndrome. Ann Gen Psychiatry. 2013； 12（1）： 23. doi： http：//dx.doi.org/10.1186/1744-859X-12-23

6. Starkman MN， Schteingart DE， Schork AM. Depressed mood and other psychiatric manifestations of Cushing’s syndrome：relationship to hormone levels. Psychosom Med. 1981；43（1）： 3-18

7. Pivonello R， Simeoli C， De Martino MC， Cozzolino A， De Leo M， Iacuaniello D， et al. Neuropsychiatric disorders in Cushing’s syndrome. Front Neuro. 2015； 9： 129. doi： http：//dx.doi.org/10.3389/fnins.2015.00129

8. Sonino N， Fava GA， RaffiAR， Boscaro M， Fallo F. Clinical correlates of major depression in Cushing’s disease.Psychopathology. 1998； 31（6）： 302-306 9. Drake WM， Perry LA， Hinds CJ， Lowe DG， Reznek RH，Besser GM. Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing’s syndrome and peritonitis. J Clin Endocrinol Metab.1998； 83（10）： 3542-3544. doi： http：//dx.doi.org/10.1210/jcem.83.10.5156

10. Feelders RA， Pulgar SJ， Kempel A， Pereira AM. Management of endocrine disease： the burden of Cushing’s disease：clinical and health-related quality of life aspects. Eur J Endocrinol. 2012； 167（3）： 311-326. doi： http：//dx.doi.org/10.1530/EJE-11-1095

（received， 2015-11-30； accepted， 2016-01-15）

Dr. Yuejing Wu obtained a bachelor's degree in June 2006 from Southern Medical University（formerly the First Military Medical University） in Guangzhou， China. In May 2012 she obtained a master's degree in psychiatry and mental health from Sichuan University， Huaxi Medical College in Chengdu. She is currently working as a physician in the psychiatry department of Zhejiang Hospital.Her research interests are psychosomatic medicine and consultation liaison psychiatry in general hospitals and the study of senile dementia and cognitive impairment. Presently she is participating in the compilation of a text.

急性精神病性表現(xiàn)的庫(kù)欣綜合征：一例病例報(bào)告

吳月靜 ， 陳炯 ， 馬永春 ， 陳正昕

庫(kù)欣綜合征；精神??；鑒別診斷；病例報(bào)告；中國(guó)

A 36-year-old Chinese woman was brought to the emergency department of a general hospital with a 3-day history of mania， persecutory delusions， and suicidal ideation； she also had a 6-month history of disrupted sleep， hypervigilance， and somatic symptoms. Her physical exam on admission to the psychosomatic ward identified a moon-shaped face， exophthalmos， and purple striae on her legs， so acute psychiatric symptoms secondary to Cushing’s syndrome was suspected. Elevated plasma cortisol and adrenocorticotropic hormone （ACTH） and identification of a mass on her left adrenal gland on the computed tomography （CT） scan of her abdomen confirmed the diagnosis. Low dose quetiapine （75-125 mg/d） and alprazolam （0.4 mg/qn） were prescribed to control the psychotic symptoms and improve her sleep. After surgical removal of a benign ACTH-independent adrenal tumor， her cortisol and ACTH levels returned to normal and her psychiatric symptoms gradually diminished over a one-month period，at which point she was discharged. Low-dose quetiapine was continued for 2 months after discharge and then discontinued； by this time her psychiatric symptoms had completely disappeared. In this case the patient had pathognomonic symptoms of CS， so it was relatively easy to make the diagnosis； but acute psychotic symptoms in CS can be life-threatening and may not be associated with the typical physical symptoms of CS （if there is only modest hypercortisolemia）， so psychiatric clinicians should always consider CS among the possible differential diagnoses for unexplained acute psychosis.

［Shanghai Arch Psychiatry. 2016； 28（3）： 169-172..

http：//dx.doi.org/10.11919/j.issn.1002-0829.215126］

1Psychiatry Department， Zhejiang Provincial Tongde Hospital， Zhejiang， China

2Psychiatry Department， Zhejiang Hospital， Zhejiang， China

*correspondence： Dr. Yuejin Wu， Department of Psychiatry， Zhejiang Hospital. 12 Linyin Road， Xi Hu District， Hangzhou， Zhejiang 310012， China.E-mail： 112977305@qq.com

概述：一位36歲的中國(guó)女性因出現(xiàn)狂躁、被害妄想和自殺意念3 天被送至某綜合醫(yī)院急診。六個(gè)月來(lái)患者易醒、過(guò)度警覺(jué)并出現(xiàn)軀體癥狀。入心身病房后，體檢發(fā)現(xiàn)該患者滿月臉、突眼，且雙腿有紫紋，因此考慮急性精神癥狀繼發(fā)于庫(kù)欣綜合征。血漿皮質(zhì)醇、促腎上腺皮質(zhì)激素 （adrenocorticotropic hormone，ACTH） 水平升高，腹部計(jì)算機(jī)斷層掃描 （computed tomography， CT） 發(fā) 現(xiàn) 左 腎 上 腺 腫 塊， 證 實(shí) 了 該 診斷。使用小劑量喹硫平 （75-125 mg/d） 和阿普唑侖（0.4 mg/qn） 來(lái)控制精神病性癥狀并改善其睡眠。將一個(gè)良性的非ACTH依賴(lài)性腎上腺腫瘤手術(shù)切除后，患者的皮質(zhì)醇和ACTH水平恢復(fù)正常，其精神癥狀也在一個(gè)月內(nèi)逐漸減少，此時(shí)該患者出院?；颊叱鲈汉笠恢遍T(mén)診隨診，維持喹硫平治療（因?yàn)閾?dān)心停藥對(duì)睡眠和情緒穩(wěn)定的影響），總時(shí)間持續(xù)1年左右，劑量從50mg漸減至25mg至減停。這時(shí)她的精神癥狀已經(jīng)完全消失。該病例中，病人具有庫(kù)欣綜合征的特殊癥狀，因此相對(duì)容易診斷；但在庫(kù)欣綜合征中急性精神病性癥狀可能會(huì)危及生命，也可能不出現(xiàn)庫(kù)欣綜合征的典型軀體癥狀（如果皮質(zhì)醇增多癥不嚴(yán)重），所以臨床精神科醫(yī)師在鑒別難以解釋的急性精神病時(shí)，應(yīng)該始終考慮將庫(kù)欣綜合征納入可能的鑒別診斷。