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Abstract Here, we present the case of a 40-year-old man in whom the diagnosis of ectopic adrenocorticotropin (ACTH) syndrome went unrecognized despite evaluation by multiple providers until it was ultimately suspected by a nephrologist evaluating the patient for edema and weight gain. On urgent referral to endocrinology, screening for hypercortisolism was positive by both low-dose overnight dexamethasone suppression testing and 24-hour urinary free cortisol measurement. Plasma ACTH values confirmed ACTH-dependent Cushing syndrome. High-dose dexamethasone suppression testing was suggestive of ectopic ACTH syndrome. Inferior petrosal sinus sampling demonstrated no central-to-peripheral gradient, and 68Ga-DOTATATE scanning revealed an avid 1.2-cm left lung lesion. The suspected source of ectopic ACTH was resected and confirmed by histopathology, resulting in surgical cure. While many patients with Cushing syndrome have a delayed diagnosis, this case highlights the critical need to increase awareness of the signs and symptoms of hypercortisolism and to improve the understanding of appropriate screening tests among nonendocrine providers. ACTH-dependent Cushing syndrome, ectopic ACTH, ectopic Cushing syndrome, glucocorticoid excess Issue Section: Case Report Introduction Even in the face of overt clinical signs and symptoms of hypercortisolism, diagnosing Cushing syndrome requires a high index of suspicion, and people with hypercortisolism experience a long road to diagnosis. In a recent meta-analysis including more than 5000 patients with Cushing syndrome, the mean time to diagnosis in all Cushing syndrome, including Cushing disease and ectopic adrenocorticotropin (ACTH) syndrome, was 34 months (1). Reasons for delayed diagnosis are multifactorial, including the nonspecific nature of subjective symptoms and objective clinical signs, as well as notorious challenges in the interpretation of diagnostic testing. Furthermore, the health care system's increasingly organ-specific referral patterns obfuscate multisystem disorders. Improving the recognition of and decreasing time to diagnosis in Cushing syndrome are critical factors in reducing morbidity and mortality. Here, we present the case of a patient who, despite classic signs of Cushing syndrome as well as progressive physical and mental decline, remained undiagnosed for more than 3 years while undergoing repeated evaluation by primary care and subspecialty providers. The case (1) highlights the lack of awareness of Cushing syndrome as a potential unifying diagnosis for multiorgan system problems; (2) underscores the necessity of continued education on the signs and symptoms of hypercortisolism, appropriate screening for hypercortisolism, and early referral to endocrinology; and (3) provides an opportunity for systemic change in clinical laboratory practice that could help improve recognition of pathologic hypercortisolism. Case Presentation In August 2018, a previously healthy 40-year-old man with ongoing tobacco use established care with a primary care provider complaining that he had been ill since the birth of his son 13 months prior. He described insomnia, headaches, submandibular swelling, soreness in his axillary and inguinal regions, and right-sided chest discomfort (Fig. 1). Previously, he had been diagnosed with sinusitis, tonsillitis, and allergies, which had been treated with a combination of antibiotics, antihistamines, and intranasal glucocorticoids. He was referred to otolaryngology where, in the absence of cervical lymphadenopathy, he was diagnosed with sternocleidomastoid pain with recommendations to manage conservatively with stretching and massage. A chest x-ray demonstrated a left apical lung nodule. Symptoms continued unabated throughout 2019, now with a cough. Repeat chest x-ray demonstrated opacities lateral to the left hilum that were attributed to vascular structures. Figure 1. Open in new tabDownload slide Timeline of development of subjective symptoms and objective clinical findings preceding diagnosis and surgical cure of ectopic Cushing syndrome. In May 2020, increasingly frustrated with escalating symptoms, the patient transitioned care to a second primary care provider and was diagnosed with hypertension. He complained of chronic daily headaches that prompted brain imaging with magnetic resonance imaging (MRI), which noted findings consistent with left maxillary silent sinus syndrome. He was sent back to otolaryngology, which elected to proceed with sinus surgery. During this time, he suffered a fibular fracture for which he was evaluated by orthopedic surgery. In the second half of 2020, he was seen by neurology to evaluate his chronic headaches and paresthesias with electromyography demonstrating a left ulnar mononeuropathy consistent with cubital tunnel syndrome. His primary care provider diagnosed him with fibromyalgia for which he started physical therapy, and he was referred to a pain clinic for cognitive behavioral therapy. Unfortunately his wife, dealing with her husband's increasing cognitive and personality changes including irritability and aggression, filed for divorce. At the end of 2020, the patient developed bilateral lower extremity edema and was prescribed hydrochlorothiazide, subsequently developing hypokalemia attributed to diuretic use. With worsening bilateral lower extremity edema and new dyspnea on exertion, he was evaluated for heart failure with an echocardiogram, which was unremarkable. Over the next several months, he gained approximately 35 pounds (∼16 kg). It was in the setting of weight gain that he was first evaluated for hypercortisolism with random serum cortisol of 22.8 mcg/dL (629 nmol/L) and 45.6 mcg/dL (1258 nmol/L) in the late morning and mid-day, respectively. No reference range was provided for the times of day at which these laboratory values were drawn. Although these serum cortisol values were above provided reference ranges for other times of day, they were not flagged as abnormal by in-house laboratory convention, and they were overlooked. The search for other etiologies of his symptoms continued. In early 2021, diuretic therapy and potassium supplementation were escalated for anasarca. He developed lower extremity cellulitis and received multiple courses of antibiotics. Skin biopsy performed by dermatology demonstrated disseminated Mycobacterium and later Serratia (2), prompting referral to infectious disease for management. Additional subspecialty referrals included rheumatology (polyarthralgia) and gastroenterology (mildly elevated alanine transaminase with planned liver biopsy). In July 2021, he was evaluated for edema by nephrology, where the constellation of subjective symptoms and objective data including hypertension, central weight gain, abdominal striae, fracture, edema, easy bruising, medication-induced hypokalemia, atypical infections, and high afternoon serum cortisol were noted, and the diagnosis of Cushing syndrome was strongly suspected. Emergent referral to endocrinology was placed. Diagnostic Assessment At his first clinic visit with endocrinology in June 2021, the patient’s blood pressure was well-controlled on benazepril. Following weight gain of 61 pounds (∼28 kg) in the preceding 2 years, body mass index was 33. Physical examination demonstrated an ill-appearing gentleman with dramatic changes when compared to prior pictures (Fig. 2), including moon facies, dorsocervical fat pad, violaceous abdominal striae, weeping lower extremity skin infections, an inability to stand without assistance from upper extremities, and depressed mood with tangential thought processes. Figure 2. Open in new tabDownload slide Photographic representation of physical changes during the years leading up to diagnosis of ectopic Cushing syndrome in June 2021 and after surgical resection of culprit lesion. Diagnostic workup for hypercortisolism included a morning cortisol of 33.4 mcg/dL (922 nmol/L) (normal reference range, 4.5-22.7 mcg/dL) and ACTH of 156 pg/mL (34 pmol/L) (normal reference range, 7.2-63 pg/mL) following bedtime administration of 1-mg dexamethasone, and 24-hour urine free cortisol of 267 mcg/24 hours (737 nmol/24 hours) (normal reference range, 3.5-45 mcg/24 hours). Morning serum cortisol and plasma ACTH following bedtime administration of 8-mg dexamethasone were 27.9 mcg/dL (770 nmol/L) and 98 pg/mL (22 pmol/L), respectively. Given concern for potential decompensation, he was hospitalized for expedited work-up. Brain MRI did not demonstrate a pituitary lesion (Fig. 3), and inferior petrosal sinus sampling under desmopressin stimulation showed no central-to-peripheral gradient (Table 1). He underwent a positron emission tomography–computed tomography 68Ga-DOTATATE scan that demonstrated a 1.2-cm left pulmonary nodule with radiotracer uptake (Fig. 4). Figure 3. Open in new tabDownload slide A, Precontrast and B, postcontrast T1-weighted sagittal magnetic resonance imaging of the sella. Images were affected by significant motion degradation, precluding clear visualization of the pituitary gland on coronal imaging. Figure 4. Open in new tabDownload slide 68Ga-DOTATATE imaging. A, Coronal and B, axial views of the chest after administration of radiopharmaceutical. Arrow in both panels indicates DOTATATE-avid 1.2-cm left lung lesion. Table 1. Bilateral petrosal sinus and peripheral adrenocorticotropin levels preintravenous and postintravenous injection of desmopressin acetate 10 mcg Time post DDAVP, min Left petrosal ACTH Left petrosal:peripheral ACTH Right petrosal ACTH Right petrosal:peripheral ACTH Peripheral ACTH Left:right petrosal ACTH 0 172 pg/mL (37.9 pmol/L) 1.1 173 pg/mL (38.1 pmol/L) 1.2 150 pg/mL (33.0 pmol/L) 1.0 3 288 pg/mL (63.4 pmol/L) 1.8 292 pg/mL (64.3 pmol/L) 1.8 162 pg/mL (35.7 pmol/L) 1.0 5 348 pg/mL (76.6 pmol/L) 1.8 341 pg/mL (75.1 pmol/L) 1.8 191 pg/mL (42.1 pmol/L) 1.0 10 367 pg/mL (80.8 pmol/L) 1.3 375 pg/mL (82.6 pmol/L) 1.3 278 pg/mL (61.2 pmol/L) 1.0 Abbreviations: ACTH, adrenocorticotropin; DDAVP, desmopressin acetate. Open in new tab Treatment The patient was started on ketoconazole 200 mg daily for medical management of ectopic ACTH-induced hypercortisolism while awaiting definitive surgical treatment. Within a month of initial endocrinology evaluation, he underwent thoracoscopic left upper lobe wedge resection with intraoperative frozen histopathology section consistent with a well-differentiated neuroendocrine tumor and final pathology consistent with a well-differentiated neuroendocrine tumor. Staining for ACTH was positive (Fig. 5). Postoperative day 1 morning cortisol was 1.4 mcg/dL (39 nmol/L) (normal reference range, 4.5-22.7 mcg/dL). He was started on glucocorticoid replacement with hydrocortisone and was discharged from his surgical admission on hydrocortisone 40 mg in the morning and 20 mg in the afternoon. Figure 5. Open in new tabDownload slide Lung tumor histopathology. A, The tumor was epicentered around a large airway (asterisk) and showed usual architecture for carcinoid tumor. B, The tumor cells had monomorphic nuclei with a neuroendocrine chromatin pattern, variably granulated cytoplasm, and a delicate background vascular network. By immunohistochemistry, the tumor cells were strongly positive for C, synaptophysin; D, CAM5.2; and E, adrenocorticotropin. F, Ki-67 proliferative index was extremely low (<1%). Outcome and Follow-up Approximately 12 days after discharge, the patient was briefly readmitted from the skilled nursing facility where he was receiving rehabilitation due to a syncopal event attributed to hypovolemia. This was felt to be secondary to poor oral intake in the setting of both antihypertensive and diuretic medications as well as an episode of emesis earlier in the morning precluding absorption of his morning hydrocortisone dose. Shortly after this overnight admission, he was discharged from his skilled nursing facility to home. In the first month after surgery, he lost approximately 30 pounds (∼14 kg) and had improvements in sleep and mood. Eight months after surgery, hydrocortisone was weaned to 10 mg daily. Cosyntropin stimulation testing holding the morning dose showed 1 hour cortisol 21.5 mcg/dL (593 nmol/L). Hydrocortisone was subsequently discontinued. In June 2022, 1 year following surgery, 3 sequential midnight salivary cortisol tests were undetectable. At his last visit with endocrinology in June 2023, he felt well apart from ongoing neuropathic pain in his feet and continued but improved mood disturbance. Though his health has improved dramatically, he continues to attribute his divorce and substantial life disruption to his undiagnosed hypercortisolism. Discussion Endogenous neoplastic hypercortisolism encompasses a clinical spectrum from subclinical disease, as is common in benign adrenal cortical adenomas, to overt Cushing syndrome of adrenal, pituitary, and ectopic origin presenting with dramatic clinical manifestations (3) and long-term implications for morbidity and mortality (4). Even in severe cases, a substantial delay in diagnosis is common. In this case, despite marked hypercortisolism secondary to ectopic ACTH syndrome, the patient's time from first symptoms to diagnosis was more than 3 years, far in excess of the typical time to diagnosis in this subtype, noted to be 14 months in 1 study (1). He initially described a constellation of somatic symptoms including subjective neck swelling, axillary and inguinal soreness, chest discomfort, and paresthesias, and during the year preceding diagnosis, he developed hypertension, fibular fracture, mood changes, weight gain, peripheral edema, hypokalemia, unusual infections, and abdominal striae. Each of these symptoms in isolation is a common presentation in the primary care setting, therefore the challenge arises in distinguishing common, singular causes from rare, unifying etiologies, especially given the present epidemics of diabetes, obesity, and associated cardiometabolic abnormalities. By Endocrine Society guidelines, the best discriminatory features of Cushing syndrome in the adult population are facial plethora, proximal muscle weakness, abdominal striae, and easy bruising (5). Furthermore, Endocrine Society guidelines suggest evaluating for Cushing disease when consistent clinical features are present at a younger-than-expected age or when these features accumulate and progress, as was the case with our patient (5). However, even when the diagnosis is considered, the complexities of the hypothalamic-pituitary-adrenal axis make selection and interpretation of screening tests challenging outside the endocrinology clinic. We suspect that in most such situations, a random serum cortisol measurement is far more likely to be ordered than a validated screening test, such as dexamethasone suppression testing, urine free cortisol, and late-night salivary cortisol per Endocrine Society guidelines (5). Although random serum cortisol values are not considered a screening test for Cushing syndrome, elevated values can provide a clue to the diagnosis in the right clinical setting. In this case, 2 mid-day serum cortisols were, by in-house laboratory convention, not flagged as abnormal despite the fact that they were above the upper limit of provided reference ranges. We suspect that the lack of electronic medical record flagging of serum cortisol values contributed to these values being incorrectly interpreted as ruling out the diagnosis. Cushing syndrome remains among the most evasive and difficult diagnoses in medicine due to the doubly difficult task of considering the disorder in the face of often protean signs and symptoms and subsequently conducting and interpreting screening tests. The challenges this presents for the nonendocrinologist have recently been recognized by a group in the United Kingdom after a similarly overlooked case (6). We believe that our case serves as a vivid illustration of the diagnostic hurdles the clinician faces and as a cautionary tale with regard to the potential downstream effects of a delay in diagnosis. Standardization of clinical laboratory practices in flagging abnormal cortisol values is one such intervention that may aid the busy clinician in more efficiently recognizing laboratory results suggestive of this diagnosis. While false-positive case detection is a significant downside to this approach, given the potential harm in delayed or missed diagnosis, the potential benefits may outweigh the risks. Learning Points People with Cushing syndrome frequently experience a prolonged time to diagnosis, in part due to lack of recognition in the primary care and nonendocrine subspecialty settings of the constellation of clinical findings consistent with hypercortisolism. Endocrine Society guidelines recommend against random serum cortisol as initial testing for Cushing syndrome in favor of dexamethasone suppression testing, urine free cortisol, and late-night salivary cortisol. Increased awareness of Cushing syndrome by primary care providers and specialists in other fields could be an important and impactful mechanism to shorten the duration of symptom duration in the absence of diagnosis and hasten cure where cure is achievable. We suggest clinical laboratories consider standardizing flagging abnormal cortisol values to draw attention to ordering providers and perhaps lower the threshold for endocrinology referral if there is any uncertainty in interpretation, especially in the context of patients with persistent symptoms and elusive diagnoses. Acknowledgments We are grateful to the patient for allowing us to present his difficult case to the community with the hopes of improving time to diagnosis for patients with hypercortisolism. Contributors All authors made individual contributions to authorship. J.M.E., E.M.Z., and K.R.K. were involved in the diagnosis and management of this patient. B.C.M., J.M.E., E.M.Z., and K.R.K. were involved in manuscript submission. S.M.J. performed and analyzed histopathology and prepared the figure for submission. All authors reviewed and approved the final draft. Funding No public or commercial funding. Disclosures J.M.E. was on the editorial board of JCEM Case Reports at the time of initial submission. Informed Patient Consent for Publication Signed informed consent obtained directly from the patient. Data Availability Statement Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study. References 1 Rubinstein G , Osswald A , Hoster E , et al. Time to diagnosis in Cushing's syndrome: a meta-analysis based on 5367 patients . J Clin Endocrinol Metab . 2020 ; 105 ( 3 😞 dgz136 . Google Scholar Crossref PubMed WorldCat 2 Park MA , Gaghan LJ , Googe PB , Klein KR , Mervak JE . Disseminated cutaneous Mycobacterium chelonae infection as a presenting sign of ectopic adrenocorticotropic hormone syndrome . JAAD Case Rep . 2021 ; 18 : 79 ‐ 81 . Google Scholar Crossref PubMed WorldCat 3 Reincke M , Fleseriu M . Cushing syndrome: a review . JAMA . 2023 ; 330 ( 2 😞 170 ‐ 181 . Google Scholar Crossref PubMed WorldCat 4 Puglisi S , Perini AME , Botto C , Oliva F , Terzolo M . Long-term consequences of Cushing's syndrome: a systematic literature review . J Clin Endocrinol Metab . 2024; 109 ( 3 😞 e901 ‐ e909 . Crossref PubMed WorldCat 5 Nieman LK , Biller BMK , Findling JW , et al. The diagnosis of Cushing's syndrome: an Endocrine Society clinical practice guideline . J Clin Endocrinol Metab . 2008 ; 93 ( 5 😞 1526 ‐ 1540 . Google Scholar Crossref PubMed WorldCat 6 Scoffings K , Morris D , Pullen A , Temple S , Trigell A , Gurnell M . Recognising and diagnosing Cushing's syndrome in primary care: challenging but not impossible . Br J Gen Pract . 2022 ; 72 ( 721 😞 399 ‐ 401 . Google Scholar Crossref PubMed WorldCat Abbreviations ACTH adrenocorticotropin MRI magnetic resonance imaging © The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com From https://academic.oup.com/jcemcr/article/2/3/luae034/7618559?login=false
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an-ectopic-cushingrsquos-syndrome-with-severe-psychiatric-presentation-9744.pdf Abstract Ectopic ACTH Secreting (EAS) tumor is relatively rare entity that presents with severe manifestation due to high level of endogenous hypercortisolism and rapidity of its onset. We report a case of severe EAS in a young Tunisian man resulting from a well differentiated Neuroendocrine Tumor (NET) of the lung. Besides catabolic signs and profound hypokalemia orienting towards Cushing’s Syndrome (CS), psychiatric symptoms were particularly severe, dominant and atypical including persecutory delusions, depression and anxiety. After tumor localization, successful resection was performed and the majority of psychiatric symptoms resolved rapidly except for mild depression. -
Bridget Houser felt despairing. In the months before her 2018 wedding, Houser, who had never struggled with her weight, noticed that it inexplicably began to creep up. In response she doubled the length of her runs to eight miles, took back-to-back high intensity workout classes and often consumed only water, coffee and fruit during the day before a spartan, mostly vegetable, dinner. Yet no matter what Houser did, her weight stubbornly increased and her oval face grew round, a transformation that was glaringly obvious in comparison with her identical twin sister. Houser wondered whether the five pounds she gained despite her herculean effort was a corollary of other problems. For the previous two years she had battled a string of maladies: first daily headaches, then crippling anxiety, followed by insomnia, hair loss and acne, something she’d never endured as a teenager. “Stress was the universal explanation,” recalled Houser, a controller for a small business in Chicago. When doctors suggested that her upcoming marriage might be a cause of her problems, Houser considered, then rejected, the theory. It just didn’t jibe with her feelings. In early 2019, about six months after her wedding, Houser insisted that her doctors perform several tests. They ultimately revealed that her symptoms weren’t the result of stress or marital misgivings but of a serious illness that had been smoldering for years. After successful treatment followed by a long recovery Houser, now 34, feels far better than she did during those miserable years in her late 20s. “I wish I’d been nicer to myself and not blamed myself for what was going on,” she said. Getting through the wedding In 2016 Houser began experiencing daily pain in the back of her head, a common spot for tension headaches. When the headaches failed to improve with dietary changes or nonprescription pain relievers, she consulted her primary care doctor, followed by a neurologist who told her she had migraines. Houser, then 27, noticed that the headaches were worse when she wore contact lenses. “It was affecting my daily life and I talked myself into thinking the problem was my contacts,” she said. She decided Lasik surgery might help and in October 2017 underwent the procedure, which uses a laser to reshape the cornea, reducing or eliminating dependence on contacts or glasses. Her vision improved and the pain disappeared — briefly. A week after eye surgery, her headaches returned. “I wasn’t overly concerned,” Houser said. “I know a lot of people have headaches.” A few months later for no apparent reason Houser developed “really bad anxiety. It wasn’t just like I was anxious,” she recalled. “I couldn’t function. I’m Type A so I knew what anxiety is, but not to this degree.” One weekday morning in early 2018 she felt so overwhelmed that she took a sick day, then called her twin, Molly, and their mother and told them she needed help immediately. They managed to schedule a same-day appointment with a psychiatrist whom Houser began seeing regularly, along with a therapist. The psychiatrist zeroed in on her impending wedding and told Houser that the event can cause “huge anxiety.” She began taking an antidepressant along with Ativan, an anti-anxiety drug she used when things got really bad. She also ramped up her yoga practice, hoping it might calm her. Houser vividly remembers riding the escalator to her office one morning “and in my head I kept saying, ‘I’m in trouble, I’m in trouble,’” although she didn’t know what was wrong. Her changing appearance had become a source of great unhappiness. Although her weight remained in the normal range, Houser couldn’t figure out why she was gaining weight after drastically slashing her food intake and dramatically ramping up exercise. Her normally thick hair had thinned so noticeably that her hairdresser gently advised her to consult a doctor. Houser’s psychiatrist thought her hair loss might be caused by her antidepressant and switched medications. That didn’t seem to help. Houser was particularly bothered by her newly chubby face. “It was like a joke in my family,” she said, adding that she was teased about being overly sensitive. Even her wedding day was colored by unhappiness about her appearance and the intense amorphous anxiety that seemed omnipresent. “Rather than think about how excited I was,” Houser recalled, “it was ‘How can I get through this day?’” Normal thyroid After her wedding Houser felt worse. She developed severe insomnia, night sweats and acne. In February 2019 a nurse practitioner in her primary care practice ordered tests of her thyroid, which were normal. When Houser pressed for additional testing, she was referred to an endocrinologist. He told her she was stressed. Dissatisfied, she saw a second endocrinologist who agreed with the first. “She said ‘I don’t think there’s anything wrong with you’” metabolically, Houser recalled. The second endocrinologist’s nurse even revisited the marriage question in the presence of Houser’s husband, Doug, who had accompanied her to the appointment. “She said ‘I knew on my honeymoon I shouldn’t have gotten married,’” Houser remembered her saying. “‘Are you in a happy marriage?’ I couldn’t believe it.” Months earlier, the nurse practitioner who ordered the thyroid tests briefly mentioned measuring levels of cortisol, a hormone involved in the body’s response to stress and other functions. Elevated levels of cortisol can indicate Cushing’s syndrome, an uncommon hormonal disorder that occurs when the body produces too much of the hormone over a prolonged period. “She had thrown cortisol testing out there and I think it was always in the back of my mind,” Houser said. She asked the second endocrinologist to order cortisol tests. The doctor agreed, but not before telling Houser that she didn’t think she had Cushing’s because she lacked the classic symptoms: major weight gain, purple stretch marks and a fatty hump between the shoulders. Houser did have the “moon face” characteristic of Cushing’s that is also seen in people who take high doses of steroids for long periods to treat various illnesses — but Houser wasn’t taking steroids. Insomnia, headaches, acne and anxiety can be symptoms of Cushing’s. There are several forms of Cushing’s syndrome, which typically results from a tumor — usually benign but sometimes cancerous — in the pituitary or adrenal gland that pumps out excess cortisol. Sometimes tumors develop elsewhere in the body such as the lungs or pancreas. Cushing’s affects roughly five times as many women as men and typically occurs between the ages of 30 and 50. If left untreated, it can be fatal. A trio of tests measuring cortisol levels in Houser’s blood, urine and saliva were significantly elevated; the amount in her urine was eight times higher than normal. The formerly skeptical Chicago endocrinologist told Houser she had Cushing’s and referred her to James Findling, a Milwaukee endocrinologist who is internationally recognized for his treatment of the disease. “I was just so happy to have a diagnosis,” Houser recalled. Revealing photos Findling asked Houser to bring photographs taken several years earlier to her October 2018 appointment. It is a request he makes of patients as a way of spotting telltale physical manifestations. In Houser’s case, the facial change was particularly striking because she is an identical twin. Findling noted that delayed diagnosis is typical, because physical changes and other symptoms tend to occur gradually and insidiously. Houser, he added, “didn’t look like the typical Cushing’s patient. She wasn’t obese and she didn’t have diabetes or hypertension. It was more subtle than many cases.” The next step was determining the location of the tiny tumor. Tests found nothing in Houser’s pituitary or adrenal glands, and CT scans of her pelvis, chest and abdomen were clean. Findling ordered a dotatate PET scan, a highly sensitive CT scan that can find tumors that elude conventional imaging. The scan revealed a nodule in Houser’s left lung. Houser sought a second opinion from a thoracic surgeon in Chicago. While Findling and a thoracic surgeon at Milwaukee’s Froedtert Hospital strongly recommended that she undergo surgery to remove the tumor, the Chicago doctor disagreed. He said he didn’t think the lung nodule was causing Cushing’s and recommended that Houser continue therapy and anti-anxiety medication. “Do you know what it’s like to wake up from surgery and to not be better?” she remembers him asking her. After deliberating with her husband and conferring with her Milwaukee doctors, Houser opted for surgery performed Oct. 30, which removed part of her left lung. A pathologist determined that the nodule was a rare, slow-growing neuroendocrine lung cancer known as a bronchial carcinoid, which can cause Cushing’s. The Stage 2 cancer had spread to a nearby lymph node. “Fortunately I think we got it early,” Findling said. “She’s had a sustained remission and a cure of her Cushing’s.” “The cancer didn’t rock my world,” said Houser, who had previously had a melanoma skin cancer removed. (Doctors have told her they don’t think the cancers are related.) “It was about not having Cushing’s anymore, which was more important.” So why didn’t Houser’s doctors, among them endocrinologists, suspect Cushing’s? Findling, who estimates he has treated as many as 2,000 people with the disease in his 40-year career, said that while doctors are taught that Cushing’s is rare, it’s not. He cites a 2016 study, which that found that 26 of 353 endocrinology patients were found to have the disease. Textbook descriptions, which include the presence of purple stretch marks and a hump, are “almost a caricature,” Findling observed. “It’s pretty well recognized that Cushing’s is more subtle than that … and can cause neuropsychiatric and neurocognitive problems.” Houser’s normal weight and the fact that she didn’t have high blood pressure or diabetes may have misled doctors. “I think we’ve moved the needle a little bit, especially among endocrinologists,” he continued, adding that “the threshold for screening has got to change. Once you tell a primary care doctor that it’s a rare disorder, it goes in one ear and out the other. They think they’ll never see it.” “When you make this diagnosis it can have fabulous outcomes,” he added, citing Houser’s case. “That’s why I’m still doing this at my age.” Houser considers Findling to be her “literal lifesaver.” She spent the next year seeing him as she was slowly weaned off medications to normalize her hormone levels and recover her strength. She is monitored for Cushing’s annually, remains cancer-free and, other than residual fatigue, feels well. In October 2021 she gave birth to a daughter. Her son was born eight weeks ago. Houser regards the help provided by her family, particularly her husband whom she called “my biggest supporter,” as essential. That seems especially ironic because stress about their marriage had been blamed for symptoms that were actually caused by a cancer. “He was a huge help in calling doctors and making the necessary appointments when I didn’t have the energy to fight anymore.” His unwavering love, she said, was “a testament to our strong marriage.” From https://www.washingtonpost.com/wellness/2023/10/07/weight-anxiety-wedding-medical-mysteries/
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Neuroendocrine pulmonary tumors in people with Cushing syndrome (CS) are associated with increased nodal metastasis, higher recurrence, and lower disease-free survival compared with quiescent bronchopulmonary tumors, according to results from an observational case series published in JAMA Network Open. Researchers said their study shows these tumors are not biologically aggressive and underlying carcinoid biology may not be as important as symptomatic hormonal physiology. Patients (n=68) with CS who underwent curative-intent pulmonary surgery at the National Cancer Institute (NCI) between 1982 and 2020 were retrospectively reviewed for clinical outcomes on the basis of tumor etiology. Outcomes were compared among groups of patients with adrenocorticotropic hormone-secreting carcinoid tumors who were treated at the National Institutes of Health in 2021 (n=68), Hôpital Européen Georges-Pompidou in 2011 (n=14), the Mayo Clinic in 2005 (n=23), and Massachusetts General Hospital in 1997 (n=7). Patients who underwent surgery at the NCI were aged median 41 years (range, 17-80 years), 42.6% were men, 81.8% were White, and mean follow-up after surgery was 16 months (range, 0.1-341 months). Most patients had T status 1a (55.9%). The pathological stages were IA1 (37.3%), IA2 (23.7%), IA3 (1.7%), IIB (16.9%), IIIA (20.3%), or unknown (13.2%). The patients with typical carcinoid tumors (83.8%) underwent lobectomy (70.2%), wedge (22.8%), segmentectomy (5.3%), and pneumonectomy (1.7%) surgical approaches. Patients with atypical carcinoid tumors (16.2%) underwent lobectomy (72.7%) and wedge (27.3%) approaches. Stratified by surgical approach, lobectomy recipients were younger (P =.01) and more had node-positive atypical carcinoid tumors (P =.01). After surgery, morbidity occurred among 19.1% of patients; overall mortality was 1.5%. Disease-free survival at 5 years following surgery was 73.4% (95% CI, 48.7%-87.6%) and 55.1% (95% CI, 26.3%-76.5%) at 10 years. Disease-free survival was 75.4% (95% CI, 49.2%-89.3%) at 5 years and 50.2% (95% CI, 18.3%-75.7%) at 10 years for typical carcinoid tumors and remained stable at 75.0% among those with atypical carcinoid tumors. Median follow-up after surgery was 16 months (range, 0.1-341 months). At the time of last follow-up, 76.4% of the patient population was alive and tumor free. The overall incidence of persistence/recurrence was 16.2%. Recurrent disease occurred in 7 patients and persistent disease in 4 patients. Only one of this group had an atypical carcinoid tumor. Mean time to recurrence in patients with recurrent disease was 76 months with a median of 55 months. The adrenocorticotropic hormone-secreting carcinoid cohort from multiple institutions was aged median 39 years, 46.4% were men, 72.3% underwent lobectomy or pneumonectomy, 18.7% had morbidity, and 0.9% mortality. The majority of these groups had typical carcinoid tumors (83.9%) with a mean size of 1.1 cm (range, 0.1-10 cm) and 39.4% had lymph node positivity. Recurrence occurred among 12.6% of patients and persistence among 5.4% of patients. Among the recurrence cohort, 85.7% had typical carcinoid tumors. Time to recurrence was >6 years. Disease-free survival was 73% at five years and 55% at 10 years. This study was limited by the small group sizes, however, due to the rarity of this cancer it was not possible to include more individuals. “Ectopic adrenocorticotropic hormone secreting carcinoid tumors with Cushing syndrome appear to be associated with increased metastasis to lymph nodes, higher recurrence (mostly local), and lower overall disease-free survival at 5 and 10 years than quiescent bronchial carcinoid tumors, irrespective of histologic subtype,” the researchers wrote. “Nevertheless, we contend these tumors are not biologically aggressive since these patients have distinct, prolonged survival and delayed time to recurrence.” The researchers also noted that “the current staging system applied to these tumors raises questions about prognostic accuracy. Extrapolation may suggest that the underlying carcinoid biology may not be as important as the symptomatic hormonal physiology.” They suggested future studies may test “whether a lung-sparing surgical approach coupled with routine lymphadenectomy is an optimal intervention in this scenario when normal endocrine functioning is restored and CS sequelae resolve.” Reference Seastedt KP, Alyateem GA, Pittala K, et al. Characterization of outcomes by surgical management of lung neuroendocrine tumors associated with Cushing syndrome. JAMA Netw Open. 2021;4(9):e2124739. doi:10.1001/jamanetworkopen.2021.24739 From https://www.endocrinologyadvisor.com/home/topics/general-endocrinology/cushing-syndrome-and-lungs-and-neuoendocrine-tumors/
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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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Tumors located outside the pituitary gland that produce the adrenocorticotropic hormone (ACTH) may cause, on rare occasions, cyclic Cushing’s syndrome — when cortisol levels show substantial fluctuations over time. That finding, based on the case of a patient with ACTH-secreting lung cancer, is found in the study, “Cyclic Cushing’s syndrome caused by neuroendocrine tumor: a case report,” which was published in Endocrine Journal. Cushing’s syndrome is characterized by too much cortisol, either due to adrenal tumors that produce cortisol in excess, or because too much ACTH in circulation — resulting from ACTH-producing tumors — act on the adrenal glands to synthesize cortisol. Cyclic Cushing’s syndrome (CCS) is a rare type of Cushing’s in which cortisol production is not steadily increased. Instead, it cyclically fluctuates, from periods with excessive cortisol production interspersed with periods of normal levels. The fluctuations in cortisol levels over time pose difficulties for a definite diagnosis. Moreover, the precise mechanism underlying the periodic peaks of cortisol peaks are unknown. Investigators now reported the case of a 37-year-old man admitted to the hospital due to repeated attacks of dizziness, weakness, and high cortisol levels for two weeks. Repeated tests measuring the levels of cortisol in the blood and a 24-hour urine free cortisol (24 hUFC) assay confirmed a cyclic fluctuation of cortisol, with levels peaking three times and dropping twice (the standard rule for diagnosing CSC). Upon hospitalization, he further developed high blood pressure and weight gain. The patient underwent computed tomography (CT) scans, which revealed the presence of an ACTH-secreting tumor in the lungs, the likely cause of the patient’s Cushing’s symptoms. These type of tumors are called neuroendocrine tumors because they are able to release hormones into the blood in response to signals from the nervous system. Additional scans detected tumors in the adrenal and pituitary glands, but further analysis revealed they were non-functioning tumors, i.e., as their name indicates, they didn’t release excessive ACTH. The thyroid gland also was positive for a tumor. The patient underwent resection surgery to remove the tumor located in the lungs and nearby lymph nodes. After the surgery, the levels of cortisol in the blood and urine returned to normal, confirming the tumor as the source of the CSC. The patient also received surgery to remove his thyroid tumor. An analysis of the patient’s genomic DNA revealed a novel mutation in the PDE11A gene, which is linked to a rare form of ACTH-independent Cushing’s syndrome called primary pigmented nodular adrenocortical disease (PPNAD) type 2. Whether the patient developed PPNAD, however, and the contribution of a potential PPNAD diagnosis to the CCS, requires further investigation. “To explore pathogenicity of the genetic mutation, we will still plan for a follow-up visit to this patient,” researchers wrote. From https://cushingsdiseasenews.com/2019/01/24/patient-develops-cyclic-cushings-syndrome-due-to-lung-neuroendocrine-tumor/
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