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Abstract Objective To evaluate whether age-related differences exist in clinical characteristics, diagnostic approach and management strategies in patients with Cushing’s syndrome included in the European Registry on Cushing’s Syndrome (ERCUSYN). Design Cohort study. Methods We analyzed 1791 patients with CS, of whom 1234 (69%) had pituitary-dependent CS (PIT-CS), 450 (25%) adrenal-dependent CS (ADR-CS) and 107 (6%) had an ectopic source (ECT-CS). According to the WHO criteria, 1616 patients (90.2%) were classified as younger (<65 years) and 175 (9.8%) as older (>65 years). Results Older patients were more frequently males and had a lower BMI and waist circumference as compared with the younger. Older patients also had a lower prevalence of skin alterations, depression, hair loss, hirsutism and reduced libido, but a higher prevalence of muscle weakness, diabetes, hypertension, cardiovascular disease, venous thromboembolism and bone fractures than younger patients, regardless of sex (p<0.01 for all comparisons). Measurement of UFC supported the diagnosis of CS less frequently in older patients as compared with the younger (p<0.05). An extra-sellar macroadenoma (macrocorticotropinoma with extrasellar extension) was more common in older PIT-CS patients than in the younger (p<0.01). Older PIT-CS patients more frequently received cortisol-lowering medications and radiotherapy as a first-line treatment, whereas surgery was the preferred approach in the younger (p<0.01 for all comparisons). When transsphenoidal surgery was performed, the remission rate was lower in the elderly as compared with their younger counterpart (p<0.05). Conclusions Older CS patients lack several typical symptoms of hypercortisolism, present with more comorbidities regardless of sex, and are more often conservatively treated. From https://academic.oup.com/ejendo/advance-article-abstract/doi/10.1093/ejendo/lvad008/7030701?redirectedFrom=fulltext&login=false
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Abstract N-of-1 trials can serve as useful tools in managing rare disease. We describe a patient presenting with a typical clinical picture of Cushing’s Syndrome (CS). Further testing was diagnostic of ectopic Adrenocorticotropic Hormone (ACTH) secretion, but its origin remained occult. The patient was offered treatment with daily pasireotide at very low doses (300 mg bid), which resulted in clinical and biochemical control for a period of 5 years, when a pulmonary typical carcinoid was diagnosed and dissected. During the pharmacological treatment period, pasireotide was tentatively discontinued twice, with immediate flare of symptoms and biochemical markers, followed by remission after drug reinitiation. This is the first report of clinical and biochemical remission of an ectopic CS (ECS) with pasireotide used as first line treatment, in a low-grade lung carcinoid, for a prolonged period of 5 years. In conclusion, the burden of high morbidity caused by hypercortisolism can be effectively mitigated with appropriate pharmacological treatment, in patients with occult tumors. Pasireotide may lead to complete and sustained remission of hypercortisolism, until surgical therapy is feasible. The expression of SSTR2 from typical carcinoids may be critical in allowing the use of very low drug doses for achieving disease control, while minimizing the risk of adverse events. Download PDF (2083K)
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Abstract Neuroendocrine carcinomas (NEC) of the cervix are a rare disease entity and account for only 1-2% of cervical carcinomas. The small-cell variant is the most common, with a worse prognosis and a higher rate of lymphatic and hematogenous metastases when compared with other subtypes of NEC. The diagnosis is usually made when the extra-pelvic disease is already apparent. Cushing’s syndrome due to adrenocorticotropic hormone (ACTH)-secreting tumors of the cervix is exceedingly rare. To date, there have been no reported cases in the literature of Cushing’s syndrome induced by the recurrence of metastases years after the initial diagnosis. This is a case of recurrent small-cell neuroendocrine carcinoma of the cervix presenting with Cushing’s syndrome five years after her original diagnosis. We present here the workup, management, and follow-up of this patient, including multisystemic, coordinated medical care. Introduction Neuroendocrine carcinomas (NECs) are heterogenous groups of tumors derived from neuroendocrine cells. NECs of the cervix are rare and account for 1-2% of all cervical carcinomas, with the small-cell variant being the most common [1,2]. Small-cell NECs have a high rate of lymphatic and hematogenous metastasis even when the carcinoma is limited to the cervix. Patients usually present at a late stage, with the extra-pelvic disease being apparent at the time of diagnosis [2]. Among the different histologic variants of NEC of the cervix, the small-cell variant has the highest rate of recurrence [3]. Adrenocorticotropic hormone (ACTH)-secreting tumors of the cervix are rare [4]. We present a case of recurrent metastatic NEC of the cervix five years after the original diagnosis of NEC of the cervix, now presenting with Cushing’s syndrome [1,2]. Case Presentation A 39-year-old female with a history of recurrent small-cell cervical cancer presented to the emergency department (ED) of our hospital with complaints of weight gain, generalized facial edema, lightheadedness, tingling sensation of her entire face, bilateral leg edema, and abdominal distention. Her problems started a month prior to her ED visit, when she started to complain of abdominal distention. She had a computed tomography (CT) abdomen with contrast, which revealed evidence of metastatic disease, including multiple large liver lesions (Figure 1). Subsequently, she had a positron emission tomography (PET) scan, which confirmed the presence of hypermetabolic lesions in the right peritonsillar tissue, liver, right lower quadrant of the abdomen, and bilateral pulmonary nodules with lymphadenopathy in the left hilum (Figure 2). A liver biopsy was done, with the final pathology consistent with recurrent NEC of the cervix. She was started on cisplatin, etoposide, and atezolizumab by gynecologic oncology but started to develop facial swelling and progressive abdominal distention, prompting this ED consult and subsequent admission. Figure 1: Abdomial CT with contrast done one month prior showed evidence of metastatic disease including multiple large liver lesions. Figure 2: PET/CT demonstrated the presence of hypermetabolic lesions in the liver and right lower quadrant of the abdomen. She had a significant medical history of being diagnosed with cervical cancer (FIGO stage 1B2 NEC) five years prior by gynecologic oncology, at which time she underwent concurrent chemo-radiation followed by surgical assessment of her pelvic lymph nodes with robotic pelvic lymph node dissection and bilateral ovarian transposition to avoid premature menopause. She was subsequently treated with cisplatin and pelvic radiation. She had a follow-up cervical biopsy several months after chemotherapy, which showed persistent NEC, but her PET scan showed no evidence of metastatic disease. After undergoing a robotic total laparoscopic hysterectomy, the final pathology showed a persistent microscopic focus of NEC of the cervix with negative margins. She received adjuvant chemotherapy with cisplatin and etoposide for six cycles with regular follow-up pap smears and annual PET scans, with no evidence of recurrence for five years. On admission, her vital signs were: blood pressure = 129/79 mm Hg, pulse rate = 85/min, respiratory rate = 18/min, and temperature = 98.5 °F (36.9 °C). Her physical examination was notable for moon facies (a noticeable change from her pictures as recent as two months prior), supraclavicular and dorsocervical fat pads, multiple bruises on her arms, edema of her face and legs, acne of her face and neck, and hair growth of her chin area. No purple striae were seen on the abdomen. Laboratory tests revealed leukopenia and thrombocytopenia (which were attributed to her chemotherapy), recently diagnosed diabetes (occasional hyperglycemia and HbA1c 7.7%), and electrolyte imbalances (hypokalemia and hypophosphatemia) (Table 1). Sodium 142 mEq/L (135–145 mEq/L) Potassium 2.0 mEq/L (3.5–5.0 mEq/L) Chloride 98 mEq/L (98–108 mEq/L) CO2 35 mEq/L (21–32 mEq/L) Anion gap 9 mEq/L (8–16 mEq/L) BUN 14 mg/dL (7–13 mEq/L) Creatinine 1.13 mg/dL (0.6–1.1 mg/dL) Glucose 460 mg/dL (74–100 mg/dL) Calcium 7.8 mg/dL (8.5–10.1 mg/dL) Phosphorous 1.0 mg/dL (2.5–4.5 mg/dL) Albumin 2.5 mg/dL (3.1–4.5 mg/dL) AST 43 U/L (15–27 U/L) ALT 76 U/L (12–78 U/L) White blood cell count 0.6 k/cmm (4.5–10.0 k/cmm) Red blood cell count 3.55 million cells/μL (3.7–5 × 2) Hemoglobin 11.9 g/dL (12.0–16.0) Hematocrit 34.3% (35.0–47.0) Platelet 45 k/cmm (150–440 k/cmm) Table 1: Initial laboratory work showed leukopenia, thrombocytopenia, hyperglycemia, hypokalemia, and hypophosphatemia. AST: aspartate aminotransferase, CO2: carbon dioxide, BUN: blood urea nitrogen, ALT: alanine aminotransferase. Her chest X-ray showed bilateral pleural effusions. Magnetic resonance imaging (MRI) of the brain showed no evidence of pituitary masses, abnormalities, or metastatic disease in the brain. A CT of the chest showed new bilateral non-calcified lung nodules when compared to the previous PET scan, pathologic-sized left hilar adenopathy, and multiple peripherally enhancing hepatic nodules and masses (Figure 3). The adrenal glands were unremarkable. Workup for facial swelling and bilateral leg edema showed no evidence of superior vena cava (SVC) syndrome on both her chest CT and transthoracic echocardiogram. Figure 3: Contrast-enhanced chest CT showing bilateral noncalcified lung nodules. She was admitted to the intensive care unit (ICU) and started on empiric antibiotics and filgrastim for neutropenia. Replacement therapy for both hypokalemia and hypophosphatemia was given. After both electrolytes were normalized, the patient was started on basal-bolus insulin therapy. Based on her clinic presentation of excessive weight gain, new-onset hyperglycemia, hypertension with hypokalemia, and a history of NEC, suspicion of Cushing’s syndrome was high. Further workup showed elevated serum cortisol after 1 mg overnight dexamethasone suppression, elevated 24-hour urine cortisol, and elevated midnight salivary cortisol, which confirmed Cushing’s syndrome (Table 2). ACTH was also elevated, but dehydroepiandrosterone sulfate (DHEAS) was normal. Thyroid function tests showed a slightly low free thyroxine, but this was attributed to an acute illness. HgbA1C 7.7% (4.0-6.0%) ACTH 1207 pg/mL (7.2–63.3 pg/mL) 24-hour urine cortisol 7070 μg/24 hr (6–42 μg/24 hr) Salivary cortisol >1.000 μg /dL (0.025–0.600 μg/dL) Serum cortisol after 1 mg overnight dexamethasone suppression 143.0 μg/dL (3.1–16.7 μg/dL) Total testosterone 77 ng/dL (14–76 ng/dL) DHEAS 250.0 μg/dL (57.3–279.2 μg/dL) Chromogranin A 970.9 ng/mL (0.0–101.8 ng/mL) TSH 0.572 mIU/L (0.358–3.74mIU/L) Free T4 0.70 ng/dl (0.76–1.46) ng/dl Table 2: Work up showed elevated ACTH, elevated 24-hour urine cortisol, elevated salivary cortisol, and elevated serum cortisol after 1 mg overnight dexamethasone suppression test. HgbA1C: hemoglobin A1C; ACTH: adrenocorticotropic hormone; DHEAS: dehydroepiandrosterone sulfate; TSH: thyroid stimulating hormone; free T4: free thyroxine. A diagnosis of Cushing's syndrome due to metastatic small-cell neuroendocrine carcinoma of the cervix was assumed. A bilateral adrenalectomy, which is the definitive treatment of hypercortisolism when surgical removal of the source of excess ACTH is done, was not done because gynecologic oncology wanted to treat her with chemotherapy urgently due to her metastases and the nature of the disease and felt that surgery and recovery would delay the start of chemotherapy. Ketoconazole was felt to be a poor choice in the setting of liver metastases with worsening liver function tests. The patient was thus started on mifepristone 300 mg daily, as it is indicated for hypercortisolism secondary to endogenous Cushing’s syndrome with diabetes. Nephrology was consulted, and potassium supplementation was transitioned to oral potassium chloride 40 meq tablets four times a day; spironolactone 50 mg twice daily was added for the hypokalemia and hypertension, which occurred after the patient started bevacizumab. Hypokalemia is a common side effect of mifepristone therapy due to the glucocorticoid receptor blockade, which leads to cortisol's spillover effect on unopposed mineralocorticoid receptors. She was discharged home with a basal-bolus insulin regimen. Her posthospitalization course was complicated by compression fractures of her lumbar spine one week after discharge with no history of falls. An MRI of the spine showed chronic compression fractures of the T11-L3 vertebral bodies with no evidence of osseous metastatic disease. Dual-energy X-ray absorptiometry (DXA) scan interpretation demonstrated osteoporosis. Vertebral fracture assessment showed morphometric fractures in the lower thoracic and upper lumbar vertebrae. She was subsequently treated with IV administration of 5 mg of zoledronic acid. She was also readmitted multiple times after her initial admission due to the patient's developing neutropenic fever, which was treated with filgrastim and antibiotics. After starting mifepristone, her glycemic control improved to the point that insulin therapy could be subsequently discontinued. Her liver enzymes normalized, and ketoconazole was subsequently added for adjunct therapy to treat hypercortisolism, but the dose could not be optimized due to persistently elevated liver function tests. Hypokalemia management and resistant hypertension were additional challenges encountered by this patient. At her follow-up visits, she had notably lost weight with the improvement of her leg edema. She continued to follow up with a nephrologist on an outpatient basis, and her normal potassium levels were normal on 40 meq of oral potassium chloride tablets four times a day and spironolactone 150 mg twice a day. She was followed up closely by her gynecologic oncologist and was on bevacizumab, topotecan, and paclitaxel before her unfortunate demise a few months later. Discussion Cushing’s syndrome due to ectopic ACTH secretion only represents 9-18% of cases. Most primary endocrine tumors responsible for ectopic ACTH secretion are located in the chest [5]. Abdominal and retroperitoneal neuroendocrine tumors are the second- and third-most reported sites [5]. Neuroendocrine tumors of the cervix are incredibly rare [6-9]. A unique feature of this case is that the patient presented with Cushing’s syndrome due to neuroendocrine tumor metastases found five years after the primary site of the tumor was resected. For this patient, a biopsy of the liver confirmed a metastatic neuroendocrine tumor, but it is unknown if the other sites of metastases are implicated in the production of excess ACTH. The management of this disease focuses on controlling hypercortisolism, consequent hyperglycemia, and hypokalemia. Surgical excision of ACTH-secreting neuroendocrine tumors is the most effective, but in cases where that is not possible, bilateral adrenalectomy and medical treatment are the next best treatments for this disease entity [10]. For this patient, bilateral adrenalectomy was not done as gynecologic oncology wanted to treat her with chemotherapy urgently due to the metastases and nature of the disease and felt that surgery and recovery would delay the start of chemotherapy. We provided medical management for the patient’s hypercortisolism. Pharmacological therapy for hypercortisolism can be categorized into immediate-acting steroidogenesis inhibitors (metyrapone, ketoconazole, and etomidate), slow-acting cortisol-lowering drugs (mitotane), and glucocorticoid receptor antagonists (mifepristone) [5]. We initially chose mifepristone because it is indicated in patients with type 2 diabetes mellitus and could be given safely despite the patient’s worsening liver function levels [11]. As demonstrated, the management of recurrent hypokalemia proved challenging in this patient. The phenomenon is well known to be induced by ectopic ACTH. Several mechanisms contribute to this. Activation of renal tubular type 1 (mineralocorticoid) receptors by cortisol is thought to be the mechanism that applies mainly to patients with severe hypercortisolism due to ectopic ACTH secretion. Additionally, there may also be an increase in the production of renin substrate from the liver. The high serum cortisol concentrations may not be completely inactivated by 11β-hydroxysteroid dehydrogenase type 2 in the kidney and overwhelm its ability to convert cortisol to cortisone, resulting in activation of mineralocorticoid receptors resulting in potassium loss in the distal tubules [12]. Hypokalemia may also result from adrenal hypersecretion of mineralocorticoids, such as deoxycorticosterone and corticosterone. This can also be amplified by mifepristone, as it is a glucocorticoid receptor antagonist that increases circulating cortisol levels [12]. Complications such as hypokalemia, hyperglycemia, acute respiratory distress syndrome, infections, muscle wasting, hypertension, and bone fractures can occur and can arise at any time throughout the course of the disease when urine-free cortisol is fivefold or more above the upper limit of normal [5]. Ketoconazole was initially considered for medical treatment, but due to mildly elevated liver enzymes during the initial presentation, we decided to use mifepristone instead. A small cohort study showed that severe hypercortisolism and increased baseline transaminase levels could be due to cortisol-induced hepatic steatosis [13]. Later in her course, ketoconazole was added to her mifepristone therapy to decrease adrenal cortisol production. Unfortunately, her dose could not be increased due to the patient's persistently elevated liver enzymes. Recurrent pancytopenia due to chemotherapy contributed to the protracted nature of this patient’s clinical course. Due to cortisol's immunosuppressive and anti-inflammatory effects, opportunistic infections can arise [14]. Since her initial hospitalization, she has been readmitted several times due to neutropenic fever, which was treated with filgrastim and antibiotics. Conclusions Ectopic Cushing’s syndrome due to metastatic neuroendocrine small-cell carcinoma is a rare condition with a poor prognosis. The options for treatment are few and not necessarily curative. There needs to be increased awareness of this serious and rare complication. Managing the condition can be a challenge and requires a multidisciplinary team approach to improve outcomes. References Cohen JG, Kapp DS, Shin JY, et al.: Small cell carcinoma of the cervix: treatment and survival outcomes of 188 patients. Am J Obstet Gynecol. 2010, 203:347.e1-6. 10.1016/j.ajog.2010.04.019 Salvo G, Gonzalez Martin A, Gonzales NR, Frumovitz M: Updates and management algorithm for neuroendocrine tumors of the uterine cervix. Int J Gynecol Cancer. 2019, 29:986-95. 10.1136/ijgc-2019-000504 Stecklein SR, Jhingran A, Burzawa J, Ramalingam P, Klopp AH, Eifel PJ, Frumovitz M: Patterns of recurrence and survival in neuroendocrine cervical cancer. Gynecol Oncol. 2016, 143:552-7. 10.1016/j.ygyno.2016.09.011 Chen J, Macdonald OK, Gaffney DK: Incidence, mortality, and prognostic factors of small cell carcinoma of the cervix. Obstet Gynecol. 2008, 111:1394-402. 10.1097/AOG.0b013e318173570b Young J, Haissaguerre M, Viera-Pinto O, Chabre O, Baudin E, Tabarin A: Management of Endocrine Disease: Cushing's syndrome due to ectopic ACTH secretion: an expert operational opinion. Eur J Endocrinol. 2020, 182:R29-58. 10.1530/EJE-19-0877 Hashi A, Yasumizu T, Yoda I, et al.: A case of small cell carcinoma of the uterine cervix presenting Cushing's syndrome. Gynecol Oncol. 1996, 61:427-31. 10.1006/gyno.1996.0168 Iemura K, Sonoda T, Hayakawa A, et al.: Small cell carcinoma of the uterine cervix showing Cushing's syndrome caused by ectopic adrenocorticotropin hormone production. Jpn J Clin Oncol. 1991, 21:293-8. Barghouthi N, Perini J, Cheng J: Ectopic adrenocorticotropic hormone production: a case of neuroendocrine cervical small cell carcinoma presenting as Cushing syndrome. AACE Clin Case Rep. 2018, 4:e367-e369. 10.4158/ACCR-2018-0080 Di Filippo L, Vitali G, Taccagni G, Pedica F, Guaschino G, Bosi E, Martinenghi S: Cervix neuroendocrine carcinoma presenting with severe hypokalemia and Cushing's syndrome. Endocrine. 2020, 67:318-20. 10.1007/s12020-020-02202-x Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK: Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005, 90:4955-62. 10.1210/jc.2004-2527 Biller BM, Grossman AB, Stewart PM, et al.: Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2008, 93:2454-62. 10.1210/jc.2007-2734 Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross 😄 Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab. 2012, 97:2039-49. 10.1210/jc.2011-3350 Young J, Bertherat J, Vantyghem MC, Chabre O, Senoussi S, Chadarevian R, Castinetti F: Hepatic safety of ketoconazole in Cushing's syndrome: results of a Compassionate Use Programme in France. Eur J Endocrinol. 2018, 178:447-58. 10.1530/EJE-17-0886 Sarlis NJ, Chanock SJ, Nieman LK: Cortisolemic indices predict severe infections in Cushing syndrome due to ectopic production of adrenocorticotropin. J Clin Endocrinol Metab. 2000, 85:42-47. 10.1210/jcem.85.1.6294 From https://www.cureus.com/articles/111698-recurrent-neuroendocrine-tumor-of-the-cervix-presenting-with-ectopic-cushings-syndrome
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Abstract Cushing’s syndrome (CS) secondary to ectopic adrenocorticotrophic hormone (ACTH)-producing prostate cancer is rare with less than 50 cases reported. The diagnosis can be challenging due to atypical and variable clinical presentations of this uncommon source of ectopic ACTH secretion. We report a case of Cushing’s syndrome secondary to prostate adenocarcinoma who presented with symptoms of severe hypercortisolism with recurrent hypokalaemia, limb oedema, limb weakness, and sepsis. He presented with severe hypokalaemia and metabolic alkalosis (potassium 2.5 mmol/L and bicarbonate 36 mmol/L), with elevated 8 am cortisol 1229 nmol/L. ACTH-dependent Cushing’s syndrome was diagnosed with inappropriately normal ACTH 57.4 ng/L, significantly elevated 24-hour urine free cortisol and unsuppressed cortisol after 1 mg low-dose, 2-day low-dose, and 8 mg high-dose dexamethasone suppression tests. 68Ga-DOTANOC PET/CT showed an increase in DOTANOC avidity in the prostate gland, and his prostate biopsy specimen was stained positive for ACTH and markers for neuroendocrine differentiation. He was started on ketoconazole, which was switched to IV octreotide in view of liver dysfunction from hepatic metastases. He eventually succumbed to the disease after 3 months of his diagnosis. It is imperative to recognize prostate carcinoma as a source of ectopic ACTH secretion as it is associated with poor clinical outcomes, and the diagnosis can be missed due to atypical clinical presentations. 1. Introduction Ectopic secretion of adrenocorticotropic hormone (ACTH) is responsible for approximately 10–20% of all causes of Cushing syndrome [1]. The classic sources of ectopic ACTH secretion include bronchial carcinoid tumours, small cell lung carcinoma, thymoma, medullary thyroid carcinoma (MTC), gastroenteropancreatic neuroendocrine tumours (NET), and phaeochromocytomas [2]. Ectopic adrenocorticotropic syndrome (EAS) is diagnostically challenging due to its variable clinical manifestations; however, prompt recognition and treatment is critical. Ectopic ACTH production from prostate carcinoma is rare, and there are less than 50 cases published to date. Here, we report a case of ectopic Cushing’s syndrome secondary to prostate adenocarcinoma who did not present with the typical physical features of Cushing’s syndrome, but instead with features of severe hypercortisolism such as hypokalaemia, oedema, and sepsis. 2. Case Presentation A 61-year-old male presented to our institution with recurrent hypokalaemia, lower limb weakness, and oedema. He had a history of recently diagnosed metastatic prostate adenocarcinoma, for which he was started on leuprolide and finasteride. Other medical history includes poorly controlled diabetes mellitus and hypertension of 1-year duration. He presented with hypokalaemia of 2.7 mmol/L associated with bilateral lower limb oedema and weakness, initially attributed to the intake of complementary medicine, which resolved with potassium supplementation and cessation of the complementary medicine. One month later, he was readmitted for refractory hypokalaemia of 2.5 mmol/L and progression of the lower limb weakness and oedema. On examination, his blood pressure (BP) was 121/78 mmHg, and body mass index (BMI) was 24 kg/m2. He had no Cushingoid features of rounded and plethoric facies, supraclavicular or dorsocervical fat pad, ecchymoses, and no purple striae on the abdominal examination. He had mild bilateral lower limb proximal weakness and oedema. His initial laboratory findings of severe hypokalaemia with metabolic alkalosis (potassium 2.5 mmol/L and bicarbonate 36 mmol/L), raised 24-hour urine potassium (86 mmol/L), suppressed plasma renin activity and aldosterone, central hypothyroidism, and elevated morning serum cortisol (1229 nmol/L) (Table 1) raised the suspicion for endogenous hypercortisolism. Furthermore, hormonal evaluations confirmed ACTH-dependent Cushing’s syndrome with inappropriately normal ACTH (56 ng/L) and failure of cortisol suppression after 1 mg low-dose, 2-day low-dose, and 8 mg high-dose dexamethasone suppression tests (Table 2). His 24-hour urine free cortisol (UFC) was significantly elevated at 20475 (59–413) nmol/day. Table 1 Investigations done during his 2nd admission. Table 2 Diagnostic workup for hypercortisolism. To identify the source of excessive cortisol secretion, magnetic resonance imaging (MRI) of the pituitary fossa and computed tomography (CT) of the thorax, abdomen, and pelvis were performed. Pituitary MRI was unremarkable, and CT scan showed the known prostate lesion with extensive liver, lymph nodes, and bone metastases (Figure 1). To confirm that the prostate cancer was the source of ectopic ACTH production, gallium-68 labelled somatostatin receptor positron emission tomography (PET)/CT (68Ga-DOTANOC) was done, which showed an increased DOTANOC avidity in the inferior aspect of the prostate gland (Figure 2). Immunohistochemical staining of his prostate biopsy specimen was requested, and it stained positive for ACTH and markers of neuroendocrine differentiation (synaptophysin and CD 56) (Figures 3 and 4), establishing the diagnosis of EAS secondary to prostate cancer. Figure 1 CT thorax abdomen and pelvis showing prostate cancer (blue arrow) with liver metastases (red arrow). Figure 2 Ga68-DOTANOC PET/CT demonstrating increased DOTANOC avidity seen in the inferior aspect of the right side of the prostate gland (red arrow). Figure 3 Hematoxylin and eosin staining showing acinar adenocarcinoma of the prostate featuring enlarged, pleomorphic cells infiltrating as solid nests and cords with poorly differentiated glands (Gleason score 5 + 4 = 9). Figure 4 Positive ACTH immunohistochemical staining of prostate tumour (within the circle). The patient was started on potassium chloride 3.6 g 3 times daily and spironolactone 25 mg once daily with normalisation of serum potassium. His BP was controlled with the addition of lisinopril and terazosin to spironolactone and ketoconazole, and his blood glucose was well controlled with metformin and sitagliptin. To manage the hypercortisolism, he was treated with ketoconazole 400 mg twice daily with an initial improvement of serum cortisol from 2048 nmol/L to 849 nmol/L (Figure 5). Systemic platinum and etoposide-based chemotherapy was recommended for the treatment of his prostate cancer after a multidisciplinary discussion, but it was delayed due to severe bacterial and viral infection. With the development of liver dysfunction, ketoconazole was switched to intravenous octreotide 100 mcg three times daily as metyrapone was not readily available in our country. However, the efficacy was suboptimal with marginal reduction of serum cortisol from 3580 nmol/L to 3329 nmol/L (Figure 5). The patient continued to deteriorate and was deemed to be medically unfit for chemotherapy or bilateral adrenalectomy. He was referred to palliative care services, and he eventually demised due to cancer progression within 3 months of his diagnosis. Figure 5 The trend in cortisol levels on pharmacological therapy. 3. Discussion Ectopic ACTH secretion is an uncommon cause of Cushing’s syndrome accounting for approximately 9–18% of the patients with Cushing’s syndrome [3]. Clinical presentation is highly variable depending on the aggressiveness of the underlying malignancy, but patients typically present with symptoms of severe hypercortisolism such as hypokalaemiaa, oedema, and proximal weakness which were the presenting complaints of our patient [4]. The classical symptoms of Cushing’s syndrome are frequently absent due to the rapid clinic onset resulting in diagnostic delay [5]. Prompt diagnosis and localisation of the source of ectopic ACTH secretion are crucial due to the urgent need for treatment initiation. The usual sources include small cell lung carcinoma, bronchial carcinoid, medullary thyroid carcinoma, thymic carcinoid, and pheochromocytoma. CT of the thorax, abdomen, and pelvis should be the first-line imaging modality, and its sensitivity varies with the type of tumour ranging from 77% to 85% [6]. Functional imaging such as 18-fluorodeoxyglucose-PET and gallium-68 labelled somatostatin receptor PET/CT can be useful in localising the source of occult EAS, determining the neuroendocrine nature of the tumour or staging the underlying malignancy [3, 6]. As prostate cancer is an unusual cause of EAS, we proceeded with 68Ga-DOTANOC PET/CT in our patient to localise the source of ectopic ACTH production. The goals of management in EAS include treating the hormonal excess and the underlying neoplasm as well as managing the complications secondary to hypercortisolism [3]. Prompt management of the cortisol excess is paramount as complications such as hyperglycaemia, hypertension, hypokalaemia, pulmonary embolism, sepsis, and psychosis can develop especially when UFC is more than 5 times the upper limit of normal [3]. Ideally, surgical resection is the first-line management, but this may not be feasible in metastatic, advanced, or occult diseases. Pharmacological agents are frequently required with steroidogenesis inhibitors such as ketoconazole and metyrapone, which reduce cortisol production effectively and rapidly [3, 6], the main drawback of ketoconazole being its hepatic toxicity. The efficacy of ketoconazole is reported to be 44%, metyrapone 50–75%, and ketoconazole-metyrapone combination therapy 73% [3, 7]. Mitotane, typically used in adrenocortical carcinoma, is effective in controlling cortisol excess but has a slow onset of action [3, 8]. Etomidate infusion can be used for short-term rapid control of severe symptomatic hypercortisolism and can serve as a bridge to definitive therapy [9]. Mifepristone, a glucocorticoid receptor antagonist, is indicated mainly in difficult to control hyperglycaemia secondary to hypercortisolism [8]. Somatostatin analogue has been proposed as a possible pharmacological therapy due to the expression of somatostatin receptors by ACTH secreting tumours [8, 10]. Bilateral adrenalectomy should be considered in patients with severe symptomatic hypercortisolism and life-threatening complications who cannot be optimally managed with medical therapies, especially in patients with occult EAS or metastatic disease [3, 8]. Bilateral adrenalectomy results in immediate improvement in cortisol levels and symptoms secondary to hypercortisolism [11]. However, surgical complications, morbidity, and mortality are high in patients with uncontrolled hypercortisolism [8], and our patient was deemed by his oncologist and surgeon to have too high a risk for bilateral adrenalectomy. For the treatment of prostate carcinoma, platinum and etoposide-based chemotherapies have been used, but their efficacy is limited with a median survival of 7.5 months [4, 12]. The side effects of chemotherapy can be severe with an enhanced risk of infection due to both cortisol and chemotherapy-mediated immunosuppression. Prompt control of hypercortisolism prior to chemotherapy and surgical procedure is strongly suggested to attenuate life-threatening complications such as infection, thrombosis, and bleeding with chemotherapy or surgery as well as to improve prognosis [3, 13]. There are rare reports of ectopic ACTH secretion from prostate carcinoma. These tumours were predominantly of small cell or mixed cell type, and pure adenocarcinoma with neuroendocrine differentiation are less common [4, 5]. There is a strong correlation between the prognosis and the types of malignancy in patients with EAS, and patients with prostate carcinoma have a poor prognosis [4]. These patients had metastatic disease at presentation, and the median survival was weeks to months despite medical treatment, chemotherapy, and even bilateral adrenalectomy [4], as seen with our patient who passed away within 3 months of his diagnosis. In conclusion, adenocarcinoma of the prostate is a rare cause of EAS. The diagnosis and management are complex and challenging requiring specialised expertise with multidisciplinary involvement. The presentation can be atypical, and it is imperative to suspect and recognise prostate carcinoma as a source of ectopic ACTH secretion. Prompt initiation of treatment is important, as it is a rapidly progressive and aggressive disease associated with intense hypercortisolism resulting in high rates of mortality and morbidity. Data Availability The data used to support the findings of this study are included within the article. Conflicts of Interest The authors declare that there are no conflicts of interest. Acknowledgments The authors would like to thank the Pathology Department of Changi General Hospital for their contribution to this case. References I. Ilias, D. J. Torpy, K. Pacak, N. Mullen, R. A. Wesley, and L. K. Nieman, “Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the national institutes of health,” Journal of Clinical Endocrinology & Metabolism, vol. 90, no. 8, pp. 4955–4962, 2005.View at: Publisher Site | Google Scholar J. Newell-Price, P. Trainer, M. Besser, and A. Grossman, “The diagnosis and differential diagnosis of cushing’s syndrome and pseudo-cushing’s states,” Endocrine Reviews, vol. 19, no. 5, pp. 647–672, 1998.View at: Publisher Site | Google Scholar J. Young, M. Haissaguerre, O. Viera-Pinto, O. Chabre, E. Baudin, and A. 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Herrmann et al., “Continuous etomidate infusion for the management of severe cushing syndrome: validation of a standard protocol,” Journal of the Endocrine Society, vol. 3, no. 1, pp. 1–12, 2019.View at: Publisher Site | Google Scholar K. Von Werder, O. A. Muller, and G. K. Stalla, “Somatostatin analogs in ectopic corticotropin production,” Metabolism, vol. 45, pp. 129–131, 1996.View at: Publisher Site | Google Scholar N. Klomjit, D. J. Rowan, A. G. Kattah, I. Bancos, and S. J. Taler, “New-onset resistant hypertension in a newly diagnosed prostate cancer patient,” American Journal of Hypertension, vol. 32, no. 12, pp. 1214–1217, 2019.View at: Publisher Site | Google Scholar R. Nadal, M. Schweizer, O. N. Kryvenko, J. I. Epstein, and M. A. Eisenberger, “Small cell carcinoma of the prostate,” Nature Reviews Urology, vol. 11, no. 4, pp. 213–219, 2014.View at: Publisher Site | Google Scholar F. A. Collichio, P. D. Woolf, and M. Brower, “Management of patients with small cell carcinoma and the syndrome of ectopic corticotropin secretion,” Cancer, vol. 73, no. 5, pp. 1361–1367, 1994.View at: Google Scholar Copyright Copyright © 2022 Wanling Zeng and Joan Khoo. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. From https://www.hindawi.com/journals/crie/2022/3739957/
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Justine Herndon, PA-C, and Irina Bancos, MD, on Post-Operative Cushing Syndrome Care – Curative procedures led to widespread resolution or improvement of hyperglycemia by Scott Harris , Contributing Writer, MedPage Today January 18, 2022 In a recent study, two-thirds of people with Cushing syndrome (CS) saw resolved or improved hyperglycemia after a curative procedure, with close post-operative monitoring an important component of the process. Among 174 patients with CS included in the longitudinal cohort study (pituitary in 106, ectopic in 25, adrenal in 43), median baseline HbA1c was 6.9%. Of these, 41 patients were not on any therapy for hyperglycemia, 93 (52%) took oral medications, and 64 (37%) were on insulin. At the end of the period following CS remission (median 10.5 months), 37 (21%) patients had resolution of hyperglycemia, 82 (47%) demonstrated improvement, and 55 (32%) had no change or worsened hyperglycemia. Also at the end of follow-up, HbA1c had fallen 0.84% (P<0.0001), with daily insulin dose decreasing by a mean of 30 units (P<0.0001). Justine Herndon, PA-C, and Irina Bancos, MD, both endocrinology researchers with Mayo Clinic in Minnesota, served as co-authors of the report, which was published in the Journal of the Endocrine Society. Here they discuss the study and its findings with MedPage Today. The exchange has been edited for length and clarity. What was the study's main objective? Herndon: As both a hospital diabetes provider and clinic pituitary/gonadal/adrenal provider, I often hear questions from colleagues about how to manage a patient's diabetes post-operatively after cure from CS. While clinical experience has been helpful in guiding these discussions, the literature offered a paucity of data on diabetes/hyperglycemia specifically after surgery. There was also a lack of data on specific subgroups of CS, whether by sub-type or severity. Therefore, we felt it was important to see what our past patient experiences showed in terms of changes in laboratory data, medications, and which patients were more likely to see improvement in their diabetes/hyperglycemia. The overall goal was to help clinicians provide appropriate patient education and care following a curative procedure. In addition to its primary findings, the study also identified several factors associated with resolution or improvement of hyperglycemia. What were these factors? Bancos: Both clinical and biochemical severity of CS, as well as Cushing subtype, were associated with improvement. We calculated severity based on symptoms and presence of comorbidities, and we calculated biochemical severity based on hormonal measurements. As clinical and biochemical scores were strongly correlated, we chose only one (biochemical) for multivariable analysis. In the multivariable analysis of biochemical severity of Cushing, subtype of Cushing, and subtype of hyperglycemia, we found that patients with a severe biochemical severity score were 2.4 fold more likely to see improved hyperglycemia than people with a moderate or mild severity score (OR 2.4 (95% CI 1.1-4.9). We also found that patients with the nonadrenal CS subtype were 2.9 fold more likely to see improved hyperglycemia when compared to people with adrenal CS (OR of 2.9 (95% CI 1.3-6.4). The type of hyperglycemia (diabetes versus prediabetes) was not found to be significant. Did anything surprise you about the study results? Herndon: I was surprised to see improvement in hyperglycemia in patients who were still on steroids, as you would expect the steroids to still have an impact. This shows how much a CS curative procedure truly leads to changes in the comorbidities that were a result of the underlying disease. Also, I was surprised that the type of hyperglycemia was not a predictor of improvement after cure, although it was quite close. We also had a few patients whose hyperglycemia worsened, and we could not find a specific factor that predicted which patients did not improve. What are the study's implications for clinicians who treat people with CS? Bancos: We think our study shows the clear need for closer follow-up -- more frequently than the typical three-to-six months for diabetes. This can be accomplished through review of more than just HbA1c, such as reviewing blood glucose logbooks, asking about hypoglycemia symptoms, and so forth. Patients with severe CS who are being treated with insulin or hypoglycemic medications are especially likely to decrease their medications to avoid hypoglycemia during postoperative period. Read the study here. Bancos reported advisory board participation and/or consulting with Strongbridge, Sparrow Pharmaceutics, Adrenas Therapeutics, and HRA Pharma outside the submitted work. Herndon did not disclose any relevant financial relationships with industry. Primary Source Journal of the Endocrine Society Source Reference: Herndon J, et al "The effect of curative treatment on hyperglycemia in patients with Cushing syndrome" J Endocrine Soc 2022; 6(1): bvab169. From https://www.medpagetoday.com/reading-room/endocrine-society/adrenal-disorders/96709
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Patient: Female, 74-year-old Final Diagnosis: ACTH-dependent Cushing’s syndrome • ectopic ACTH syndrome Symptoms: Edema • general fatigue • recurrent mechanical fall Medication: — Clinical Procedure: — Specialty: Critical Care Medicine • Endocrinology and Metabolic • Family Medicine • General and Internal Medicine • Nephrology • Oncology Objective: Unusual clinical course Background: Adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (CS) secondary to an ectopic source is an uncommon condition, accounting for 4–5% of all cases of CS. Refractory hypokalemia can be the presenting feature in patients with ectopic ACTH syndrome (EAS), and is seen in up to 80% of cases. EAS can be rapidly progressive and life-threatening without timely diagnosis and intervention. Case Report: We present a case of a 74-year-old White woman who first presented with hypokalemia, refractory to treatment with potassium supplementation and spironolactone. She progressively developed generalized weakness, recurrent falls, bleeding peptic ulcer disease, worsening congestive heart failure, and osteoporotic fracture. A laboratory workup showed hypokalemia, hypernatremia, and primary metabolic alkalosis with respiratory acidosis. Hormonal evaluation showed elevated ACTH, DHEA-S, 24-h urinary free cortisol, and unsuppressed cortisol following an 8 mg dexamethasone suppression test, suggestive of ACTH-dependent CS. CT chest, abdomen, and pelvis, and FDG/PET CT scan showed a 1.4 cm right lung nodule and bilateral adrenal enlargement, confirming the diagnosis of EAS, with a 1.4-cm lung nodule being the likely source of ectopic ACTH secretion. Due to the patient’s advanced age, comorbid conditions, and inability to attend to further evaluation and treatment, her family decided to pursue palliative and hospice care. Conclusions: This case illustrates that EAS is a challenging condition and requires a multidisciplinary approach in diagnosis and management, which can be very difficult in resource-limited areas. In addition, a delay in diagnosis and management often results in rapid deterioration of clinical status. Keywords: Cushing Syndrome, Endocrine System, Hypokalemia Go to: Background Cushing’s syndrome (CS) has a variety of clinical manifestations resulting from excess steroid hormone production from adrenal glands (endogenous) or administration of glucocorticoids (exogenous) [1,2]. Endogenous CS is classified into 2 main categories: ACTH-dependent and ACTH-independent disease. In ACTH-dependent disease, the source of ACTH can further be subdivided into either the pituitary gland or an ectopic source [2]. Ectopic ACTH syndrome (EAS) results from excess production of ACTH from extra-pituitary sources [2] and accounts for approximately 4–5% of cases of CS [3,4]. Common clinical manifestations of CS include weight gain, central obesity, fatigue, plethoric facies, purple striae, hirsutism, irregular menses, hypertension, diabetes/glucose intolerance, anxiety, muscle weakness, bruising, and osteoporosis [2]. Hypokalemia is a less defining feature, seen in roughly 20% of cases with CS. However, it is present in up to 90% of cases with EAS [2,5], which is attributed to the mineralocorticoid action of steroid [6]. Hypercortisolism due to EAS is usually severe and rapid in onset, and excess cortisol levels can lead to severe clinical manifestations, including life-threatening infections [7]. Moreover, in most patients with EAS, the source of excess ACTH is an underlying malignancy that can further result in rapid deterioration of the overall clinical condition. Although numerous malignancies have been associated with EAS, lung neuroendocrine tumors (NETs) are the most common [2,8]. Since the treatment of choice for EAS is complete resection of the tumor, the correct localization of the source of ectopic ACTH is crucial in managing these patients. Traditional radiological investigations can localize these tumors in up to 50% of cases [9]; however, recent studies utilizing somatostatin receptor (SSTR) analogs have increased the sensitivity and specificity of tumor localization [9–11]. This case report describes a challenging case of an elderly patient with EAS who presented with refractory hypokalemia. Her clinical condition deteriorated rapidly in the absence of surgical intervention. Go to: Case Report A 74-year-old White woman was brought to the Emergency Department from her nephrologist’s office with a chief concern of persistent anasarca and recurrent hypokalemia of 1-month duration. In addition, she reported generalized weakness and recurrent mechanical falls in the preceding 3 months. Before presentation in March 2021, she had a medical history of type 2 diabetes, chronic kidney disease stage 3b, atrial fibrillation on chronic anticoagulation, heart failure with reduced ejection fraction (EF 35–40%), hypothyroidism, hypertension, and hyperlipidemia. Home medications included diltiazem, apixaban, insulin glargine, levothyroxine, simvastatin, carvedilol, glimepiride, sacubitril, valsartan, and furosemide. On presentation, she was hemodynamically stable with temperature 36.5°C, heart rate 67 beats per min, blood pressure 139/57 mmHg, respiratory rate 20 per min, and saturation 98% on 2 L oxygen supplementation. Her height was 162.6 cm, and weight was 80.88 kg, with a body mass index (BMI) of 30.6 kg/m2. A physical exam showed central obesity, bruising in extremities, generalized facial swelling mainly in the periorbital region, severe pitting edema in bilateral lower extremities, and moderate pitting edema in bilateral upper extremities. A laboratory workup revealed serum potassium 2.4 mmol/L (3.6–5.2 mmol/L), serum sodium 148 mmol/L (133–144 mmol/L), and eGFR 31.5 mL/min/1.73 m2. Arterial blood gas analysis showed pH 7.6, PaCO2 48.9 mmHg (35.0–45.0 mmHg), and serum bicarbonate 32 mmol/L (22–29 mmol/L), which was consistent with primary metabolic alkalosis, appropriately compensated by respiratory acidosis. Due to concerns of loop diuretic-induced hypokalemia, she was started on spironolactone and potassium replacement. However, potassium levels persistently remained in the low range of 2–3.5 mmol/L (3.6–5.2 mmol/L) despite confirming compliance to medications and adequate up-titration in the dose of spironolactone and potassium chloride. Hence, the workup for the secondary cause of persistent hypokalemia was pursued. Hormonal evaluation revealed plasma aldosterone concentration (PAC) <1.0 ng/dL, plasma renin activity (PRA) 0.568 ng/mL/h (0.167–5.380 ng/mL/h), 24-h urine free cortisol (UFC) 357 mg/24h (6–42 mg/24h), ACTH 174 pg/mL, and DHEA-S 353 ug/dL (20.4–186.6 ug/dL). ACTH levels on 2 repeat testings were 229 pg/mL and 342 pg/mL. The rest of the laboratory workup is summarized in Table 1. Considering elevated ACTH and 24-h UFC, a preliminary diagnosis of ACTH-dependent Cushing syndrome was made. An 8-mg dexamethasone suppression test revealed non-suppressed cortisol of 62.99 ug/dL along with dexamethasone 4050 ng/dL (1600–2850 ng/dL). A pituitary MRI was unremarkable for any focal lesion suggesting a diagnosis of ACTH-dependent Cushing’s syndrome secondary to an ectopic source. Imaging studies were then performed to determine the source. A CT scan of the chest and abdomen revealed adenomatous thickening with nodularity of bilateral adrenal glands, and a 1.4-cm nodule in the right middle lobe (Figure 1A, 1B). FDG-PET/CT showed severe bilateral enlargement of the adrenal glands with severe hyper-metabolic uptake (mSUV 9.2 and 9.1 for left and right adrenal glands, respectively) (Figure 2A). The uptake of the right lung nodule on PET/CT was 1.4 mSUV (Figure 2B). Figure 1. CT chest, abdomen, and pelvis w/o contrast showed bilateral enlargement of adrenal glands (A, red arrows) and a 1.4-cm nodule in the right middle lobe of the lung (B, blue arrow). Figure 2. Whole-body PET/CT following intravenous injection of 40 mCi FDG showed diffuse enlargement of the bilateral adrenal glands with mSUV of 9.2 on the left and 9.1 on the right adrenal gland, respectively (A, red arrows) and low-grade activity with an MSUV of 1.4 in right lung nodule (B, blue arrow). Table 1. Laboratory on initial presentation. Laboratory test Level Reference range WBCs 7.8 k/uL 3.7–10.3 k/uL RBCs 3.05 M/mL 3.–5.2 M/mL Hemoglobin 9.6 g/dL 11.2–15.7 g/dL Hematocrit 27.3% 34–45% Platelets 98 k/mL 155–369 k/mL MCV 89.7 fl 78.2–101.8 fl MCH 31.5 pg 26.4–33.3 pg MCHC 35.2 g/dL 32.5–35.3 g/dL RDW 15.8% 10.1–16.2% Glucose 73 mg/dL 74–90 mg/dL Sodium 148 mmol/L 136–145 mmol/L Potassium 2.4 mmol/L 3.7–4.8 mmol/L Bicarbonate 32 mmol/L 22–29 mmol/L Chloride 108 mmol/L 97–107 mmol/L Calcium 7.0 mg/dL 8.9–10.2 mg/dL Magnesium 1.7 mg/dL 1.7–2.4 mg/dL Phosphorus 2.3 mg/dL 2.5–4.9 mg/dL Albumin 2.4 g/dL 3.3–4.6 g/dL Blood urea nitrogen 41 mg/dL 0–30 ng/dL Creatinine 1.60 mg/dL 0.60–1.10 mg/dL Estimated GFR 31.5 mL/min/1.73m2 >60 mL/min/1.73 m2 Aspartate transaminase 42 U/L 9–36 U/L Alanine transaminase 67 U/L 8–33 U/L Alkaline phosphatase 90 U/L 46–142 U/L Total protein 4.8 g/dL 6.3–7.9 g/dL Arterial blood gas analysis PaCO2 48.9 mmHg 35.0–45.0 mmHg PaO2 63.1 mmHg 85.0–100.0 mmHg %SAT 92.8% 93.0–97.0 HCO3 47.8 mm/L 20.0–26.0 mm/L Base excess 26.3 mm/L <2.0 mm/L pH 7.599 7.350–7.450 Adrenocorticotropic hormone (ACTH) 174, 229 and 342 pg/mL 15–65 pg/mL Urine free cortisol, 24 h 357 ug/24 hr 6–42 mg/24 hr 8: 00 AM cortisol following 8 mg dexamethasone (4×2 mg doses) previous day 62.99 mg/dL 8: 00 AM dexamethasone following 8 mg dexamethasone (4×2 mg doses) previous day 4050 ng/dL 1600–2850 ng/dL Based on unsuppressed cortisol following an 8-mg dexamethasone suppression test, negative pituitary MRI, and 1.4-cm lung nodule, we diagnosed ACTH-dependent CS secondary to an ectopic source, most likely from the 1.4-cm lung nodule. While awaiting localization studies, within 3 months of initial presentation, she had 2 hospitalizations, one in May 2021 for acute anemia secondary to bleeding peptic ulcer disease (PUD) requiring endoscopic clipping of the bleeding ulcer, and another in June 2021 for acute on chronic congestive heart failure. The patient’s overall condition continued to deteriorate, and she became progressively weak and wheelchair-bound. A 68-Ga-DOTATATE was planned to establish the source of ectopic ACTH definitively; however, she developed a left hip fracture in July 2021 and could not present for follow-up care. Therefore, she was started on Mifepristone until curative surgery. However, considering the patient’s advanced comorbid conditions, the increased burden of the patient’s health care needs on her elderly husband, and the inability of other family members to provide necessary healthcare-related support, palliative care was pursued. In August 2021, she developed a sacral decubitus ulcer and community-acquired pneumonia. However, she was still alive while receiving palliative care in a nursing home until September 2021. Go to: Discussion Ectopic ACTH syndrome (EAS) is defined as secretion of ACTH from an extra-pituitary source and is the cause of Cushing’s syndrome (CS) in approximately 4–5% of cases [3,4]. Clinical features of EAS depend on the rate and amount of ACTH production [12]. Among all forms of Cushing’s (excluding adrenal cortical carcinoma), EAS has the worst outcome, with one of the most extensive combined UK & Athens study demonstrating a 5-year survival rate of 77.6%. Compared to Cushing’s disease (CD), patients with EAS have severe and excessive production of ACTH, resulting in highly elevated cortisol levels. This leads to hypokalemia, metabolic alkalosis, worsening glycemia, hypertension, psychosis, and infections. Metabolic alkalosis and hypokalemia are the 2 most common acid-base and electrolyte abnormalities associated with glucocorticoid excess among these patients. Studies have shown that hypokalemia is seen in up to 90% of patients with EAS. Although hypertension and hypokalemia are often attributed to primary hyperaldosteronism, other causes should be sought. Under normal circumstances, the mineralocorticoid effect of cortisol is insignificant due to local conversion to cortisone by the action of 11 beta-hydroxysteroid dehydrogenase. Excessive cortisol in patients with EAS saturates the action of 11 beta-hydroxysteroid dehydrogenase and leads to the appearance of mineralocorticoid action of cortisol [6]. In our patient, the initial treatment of hypokalemia was unsatisfactory, so additional endocrine workup was pursued. Elevated urinary cortisol excretion, plasma ACTH levels, unsuppressed cortisol following 8 mg dexamethasone, and lung mass on CT scan strongly suggested that the clinical symptoms were due to EAS. Unfortunately, despite diagnosing the underlying condition contributing to the patient’s symptoms, her clinical condition rapidly deteriorated without surgical treatment. Various factors resulted in delayed diagnosis in our patient. First, the patient sought medical care only 3 months after symptom onset. Second, furosemide, a medication commonly used to treat patients with HFrEF, is a frequent culprit of hypokalemia and often is treated with adequate potassium supplementation. Third, multiple hospitalizations resulted in delays in the proper endocrine workup necessary for establishing hypercortisolism. Fourth, localization of the ectopic source requires advanced imaging studies, which are only available in a few tertiary care centers. Fifth, even after tumor localization with PET/CT scan, there is still a need for a more definitive localization study using Ga-DOTATATE scan, which has a higher specificity. However, it was unavailable in our institution and was only available in a few tertiary care centers, with the nearest center being 2.5 h away. Sixth, the impact of the COVID-19 pandemic also played a critical role in promptly providing critical care necessary to the patient. In addition to those, the social situation of our patient also played an essential role in contributing to delays in diagnosis. It is well recognized that EAS is associated with various malignancies, mostly of neuroendocrine origin. The most common location of these tumors was found to be the lung (55.3%), followed by the pancreas (8.5%), mediastinum-thymus (7.9%), adrenal glands (6.4%), and gastrointestinal tract (5.4%) [9]. Prompt surgical removal of ectopic ACTH-secreting tumors is the mainstay of therapy in patients with EAS [13]. However, localization of such tumors with conventional therapy is often challenging as the sensitivity to localize the tumor is 50–60% for conventional imaging such as CT, MRI, and FDG-PET [9]. In a study by Isidori et al, nuclear imaging improved the sensitivity of conventional radiological imaging [9]. Moreover, newer imaging technologies using somatostatin receptor (SSTR) analogs such as 68Ga-DOTATATE PET/CT further improve the ability to localize the tumor. 68Ga-DOTATATE PET/CT, approved in 2016 by the Federal Drug Administration (FDA) for imaging well-differentiated NETs, has a high sensitivity (88–93%) and specificity (88–95%) to diagnose carcinoid tumor [14]; however, a systematic review reported a significantly lower sensitivity (76.1%) of 68Ga-DOTATATE PET/CT to diagnose EAS [15]. Once localized, the optimal management of EAS is surgical re-section of the causative tumor, which is often curative. However, until curative surgery is done, patients should be medically managed. Drugs used to reduce cortisol levels include ketoconazole, mitotane, and metyrapone [16, 17]. These are oral medications and decrease cortisol synthesis by inhibiting adrenal enzymes [17]. Etomidate is the only intravenous drug that immediately reduces adrenal steroid production and can be used when acute reduction in cortisol production is desired [16]. Medical management requires frequent monitoring of cortisol levels and titration of dose to achieve low serum and urine cortisol levels. Mifepristone, an anti-progesterone at a higher dose, works as a glucocorticoid receptor antagonist and can be used to block the action of cortisol. Its use results in variable levels of ACTH and cortisol levels in patients with EAS. Hence, hormonal measurement cannot be used to judge therapeutic response, and clinical improvement is the goal of treatment [18]. Drugs inhibiting ACTH secretion by NETs such as kinase inhibitors (vandetanib, sorafenib, or sunitinib) are effective in treating EAS secondary to medullary thyroid cancer [19]. Somatostatin analogs such as octreotide and lanreotide have demonstrated short- and medium-term efficacy in a few EAS patients; however, a few patients failed to improve, necessitating the use of more effective treatment options [19,20]. Hence, they are not considered a first-line drug as monotherapy and should be used in combination with other agents, or as anti-tumoral therapy in non-excisable metastatic well-differentiated NETs [19,20]. Cabergoline, a dopamine agonist, has been used with variable therapeutic effects in a few patients [19]. In 1 patient, the use of combination therapy using Mifepristone and a long-acting octreotide significantly improved EAS [21]. In our patient, we initiated Mifepristone to reduce the burden associated with frequent biochemical monitoring and planned 68Ga-DOTATATE PET/CT to localize the tumor; however, further diagnostic and therapeutic approaches could not be further undertaken per family wishes. Go to: Conclusions EAS can present with refractory hypokalemia, especially in patients who are already at risk of developing hypokalemia. Diagnosis of EAS is often challenging and requires a multidisciplinary approach. Localization of source of EAS should be done using nuclear imaging, preferably using SSTR analogs, when available. Urgent surgical evaluation remains the mainstay of treatment following tumor localization and can result in a cure. EAS is a rapidly progressive and life-threatening situation that can be fatal if diagnosis or timely intervention is delayed. Go to: Abbreviations ACTH adrenocorticotropic hormone; CS Cushing’s syndrome; CT computed tomography; EAS ec-topic ACTH syndrome; MRI magnetic resonance imaging; FDG/PET 18-F-fluorodeoxyglucose positron emission tomography; NET neuroendocrine tumors; SSTR somatostatin receptor; EF ejection fraction; PAC plasma aldosterone concentration; PRA plasma renin activity; UFC urine free cortisol; DHEA-S dehydroepiandrosterone sulfate; 68-Ga-DOTATATE Gallium 68 (68Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tet-raacetic acid (DOTA)-octreotate; PUD peptic ulcer disease Go to: Footnotes Financial support: None declared Go to: References: 1. Pluta RM, Burke AE, Golub RM. JAMA patient page. Cushing syndrome and Cushing disease. JAMA. 2011;306:2742. [PubMed] [Google Scholar] 2. Melmed SKR, Rosen C, Auchus R, Goldfine A. Williams textbook of endocrinology. Elsevier; 2020. [Google Scholar] 3. Rubinstein G, Osswald A, Hoster E, et al. 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This article was originally published here Endocrinol Diabetes Metab Case Rep. 2021 May 1;2021:EDM210038. doi: 10.1530/EDM-21-0038. Online ahead of print. ABSTRACT SUMMARY: In this case report, we describe the management of a patient who was admitted with an ectopic ACTH syndrome during the COVID pandemic with new-onset type 2 diabetes, neutrophilia and unexplained hypokalaemia. These three findings when combined should alert physicians to the potential presence of Cushing’s syndrome (CS). On admission, a quick diagnosis of CS was made based on clinical and biochemical features and the patient was treated urgently using high dose oral metyrapone thus allowing delays in surgery and rapidly improving the patient’s clinical condition. This resulted in the treatment of hyperglycaemia, hypokalaemia and hypertension reducing cardiovascular risk and likely risk for infection. Observing COVID-19 pandemic international guidelines to treat patients with CS has shown to be effective and offers endocrinologists an option to manage these patients adequately in difficult times. LEARNING POINTS: This case report highlights the importance of having a low threshold for suspicion and investigation for Cushing’s syndrome in a patient with neutrophilia and hypokalaemia, recently diagnosed with type 2 diabetes especially in someone with catabolic features of the disease irrespective of losing weight. It also supports the use of alternative methods of approaching the diagnosis and treatment of Cushing’s syndrome during a pandemic as indicated by international protocols designed specifically for managing this condition during Covid-19. PMID:34013889 | DOI:10.1530/EDM-21-0038 From https://www.docwirenews.com/abstracts/rapid-control-of-ectopic-cushings-syndrome-during-the-covid-19-pandemic-in-a-patient-with-chronic-hypokalaemia/
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Researchers conducted this retrospective cohort study to investigate acute and life-threatening complications in patients with active Cushing syndrome (CS). Participants in the study were 242 patients with CS, including 213 with benign CS (pituitary n = 101, adrenal n = 99, ectopic n = 13), and 29 with malignant disease. In patients with benign pituitary CS, the prevalence of acute complications was 62%, 40% in patients with benign adrenal CS, and 100% in patients with ectopic CS. Infections, thromboembolic events, hypokalemia, hypertensive crises, cardiac arrhythmias and acute coronary events were complications reported in patients with benign CS. The whole spectrum of acute and life-threatening complications in CS and their high prevalence was illustrated in this study both before disease diagnosis and after successful surgery. Read the full article on Journal of Clinical Endocrinology and Metabolism.
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Children with Cushing’s syndrome are at risk of developing new autoimmune and related disorders after being cured of the disease, a new study shows. The study, “Incidence of Autoimmune and Related Disorders After Resolution of Endogenous Cushing Syndrome in Children,” was published in Hormone and Metabolic Research. Patients with Cushing’s syndrome have excess levels of the hormone cortisol, a corticosteroid that inhibits the effects of the immune system. As a result, these patients are protected from autoimmune and related diseases. But it is not known if the risk rises after their disease is resolved. To address this, researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) examined 127 children with Cushing’s syndrome at the National Institutes of Health from 1997 until 2017. Among the participants, 77.5 percent had a pituitary tumor causing the disease, 21.7 percent had ACTH-independent disease, and one patient had ectopic Cushing’s syndrome. All patients underwent surgery to treat their symptoms. After a mean follow-up of 31.2 months, 7.8 percent of patients developed a new autoimmune or related disorder. Researchers found no significant differences in age at diagnosis, gender, cortisol levels, and urinary-free cortisol at diagnosis, when comparing those who developed autoimmune disorders with those who didn’t. However, those who developed an immune disorder had a significantly shorter symptom duration of Cushing’s syndrome. This suggests that increased cortisol levels, even for a short period of time, may contribute to more reactivity of the immune system after treatment. The new disorder was diagnosed, on average, 9.8 months after Cushing’s treatment. The disorders reported were celiac disease, psoriasis, Hashimoto thyroiditis, Graves disease, optic nerve inflammation, skin hypopigmentation/vitiligo, allergic rhinitis/asthma, and nerve cell damage of unknown origin responsive to glucocorticoids. “Although the size of our cohort did not allow for comparison of the frequency with the general population, it seems that there was a higher frequency of optic neuritis than expected,” the researchers stated. It is still unclear why autoimmune disorders tend to develop after Cushing’s resolution, but the researchers hypothesized it could be a consequence of the impact of glucocorticoids on the immune system. Overall, the study shows that children with Cushing’s syndrome are at risk for autoimmune and related disorders after their condition is managed. “The presentation of new autoimmune diseases or recurrence of previously known autoimmune conditions should be considered when concerning symptoms arise,” the researchers stated. Additional studies are warranted to further explore this link and improve care of this specific population. From https://cushingsdiseasenews.com/2018/03/06/after-cushings-cured-autoimmune-disease-risk-looms-study/
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Patients with different subtypes of Cushing’s syndrome (CS) have distinct plasma steroid profiles. This could be used as a test for diagnosis and classification, a German study says. The study, “Plasma Steroid Metabolome for Diagnosis and Subtyping Patients with Cushing Syndrome,” appeared in the journal Clinical Chemistry. A quick diagnosis of CS is crucial so that doctors can promptly give therapy. However, diagnosing CS is often complicated by the multiple tests necessary not just to diagnose the disease but also to determine its particular subtype. Cortisol, which leads to CS when produced at high levels, is a steroid hormone. But while earlier studies were conducted to determine whether patients with different subtypes of CS had distinct steroid profiles, the methods researchers used were cumbersome and have been discontinued for routine use. Recently, a technique called LC-MS/MS has emerged for multi-steroid profiling in patients with adrenocortical dysfunction such as congenital adrenal hyperplasia, adrenal insufficiency and primary aldosteronism. Researchers at Germany’s Technische Universität in Dresden used that method to determine whether patients with the three main subtypes of CS (pituitary, ectopic and adrenal) showed differences in plasma steroid profiles. They measured levels of 15 steroids produced by the adrenal glands in single plasma samples collected from 84 patients with confirmed CS and 227 age-matched controls. They found that CS patients saw huge increases in the plasma steroid levels of 11-deoxycortisol (289%), 21-deoxycortisol (150%), 11-deoxycorticosterone (133%), corticosterone (124%) and cortisol (122%), compared to patients without the disease. Patients with the ectopic subtype had the biggest jumps in levels of these steroids. However, plasma 18-oxocortisol levels were particularly low in ectopic disease. Other steroids demonstrated considerable variation. Patients with the adrenal subtype had the lowest concentration of dehydroepiandrosterone (DHEA) and DHEA-SO4, which are androgens. Patients with the ectopic and pituitary subtype had the lowest concentration of aldosterone. Through the use of 10 selected steroids, patients with different subtypes of CS could be identified almost as closely as with other tests, including the salivary and urinary free cortisol test, the dexamethasone-suppressed cortisol test, and plasma adrenocorticotropin levels. The misclassification rate using steroid levels was 9.5 percent, compared to 5.8 percent in other tests. “This study using simultaneous LC-MS/MS measurements of 15 adrenal steroids in plasma establishes distinct steroid metabolome profiles that might be useful as a test for CS,” the team concluded, adding that using LC-MS/MS is advantageous, as specimen preparation is simple and the entire panel takes 12 minutes to run. This means it could be offered as a single test for both identification and subtype classification. From https://cushingsdiseasenews.com/2018/01/02/plasma-steroid-levels-used-screen-diagnosis-subtyping-patients-cushing-syndrome/
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i read an article that was about the many different causes of empty sella one of them being thyroid cancer. it lead me to a link i will post here about an ectopic ACTH source in a vaginal lining malignancy. I have found in my own studies that it is beneficial to be vigilent about rooting out the source of our cushings. some doctors just want to offer multiple band aids. like in my case. doctors suggested removing my pituitary gland or my agrenal glands or trying to sustain me w/tons of insulin & hight blood pressure meds or ketoconazol. they did not get that i had 2 little ones to take care of. i wanted to stop my body from rotting. i knew i had little time left. i did not want agonizing prolongment. i wanted the SOURCE of the cushings hunted down & cut OUT of my body. in my hereditary type of cushings even removing a small portion (debulking) of the tumor, mass, cyst, watever your radiologist wants to call it, can save or add years to your life. it is hard to find such an agressive doctor. in my case it was my sisters who stood up to doctors. demanding they order a full body octreotide scan where they found the source of my cushings, a lung tumor that did not show up on other scans. the tumor can be ANYWHERE in your body. It will produce many different hormones not just ACTH. it can be the size of a spec of dust. Looking for these other tumor markers or hormones in 24hr urine catches besides just cortisol can put us closer to our cure. since i am posting a research link i picked this forum. if it is misplaced i apologize. please see this research link: http://lib.bioinfo.pl/pmid:9190988 our illness is not rare but doctors are not taught how to diagnose it. sometimes they need our help. we need to educate ourselves. my education on this website led to my cure. thank u MaryO for giving us this medium.
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