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Highlights The most common cause of ectopic ACTH syndrome is pulmonary carcinoid tumors and squamous cell lung cancer; however it is a relatively uncommon complication of pulmonary neoplasms. The most common cause of Cushing syndrome is iatrogenic corticosteroid use and it should be considered in all patients regardless of clinical background. Low urine cortisol levels may be associated with exogenous glucocorticoid exposure. Occult glucocorticoid exposure is rare but can be evaluated with liquid chromatography. Consumers should be aware of the potential risks of taking supplements, especially those advertised as joint pain relief products. Abstract Background Well differentiated bronchial neuroendocrine neoplasms often follow a clinically indolent course and rarely cause Ectopic ACTH syndrome. Iatrogenic corticosteroid use is the most common cause of Cushing syndrome and should be considered in all patients regardless of clinical background. Case report A 59 year old woman with an 11 year history of a 1.5 cm well differentiated bronchial carcinoid, presented with Cushingoid features. Laboratory results were not consistent with an ACTH dependent Cushing Syndrome and exogenous steroids were suspected. The patient received an FDA alert regarding a glucosamine supplement she had started 4 months prior for joint pain. Discussion Ectopic ACTH production is reported in less than 5% of patients with squamous cell lung cancer and 3% of patients with lung or pancreatic (non-MEN1) neuroendocrine tumors. Factitious corticoid exposure is rare and can be evaluated with synthetic corticosteroid serum testing. Conclusion Cushing syndrome due to supplements containing unreported corticosteroid doses should be considered in patients with typical Cushingoid features and contradictory hormonal testing. 1. Introduction Well differentiated bronchial neuroendocrine neoplasms often follow a clinically indolent course and can rarely exhibit Cushing syndrome due to ectopic production of adrenocorticotropic hormone (ACTH). However the most common cause of Cushing syndrome is iatrogenic corticosteroid use and should be considered in all patients regardless of clinical background (see Fig. 1, Fig. 2, Fig. 3, Fig. 4). Download : Download high-res image (243KB) Download : Download full-size image Fig. 1. DOTATATE PET/CT demonstrates a right upper lobe pulmonary nodule with intense uptake. Download : Download high-res image (201KB) Download : Download full-size image Fig. 2. DOTATATE PET/CT demonstrates intense uptake within a right upper lobe pulmonary nodule, consistent with biopsy-proven carcinoid tumor. There are no distant sites of abnormal uptake to suggest metastatic disease. Download : Download high-res image (399KB) Download : Download full-size image Fig. 3. Artri Ajo King Supplement (Source: FDA). The label claims that the product contains glucosamine, chondroitin, collagen, vitamin C, curcumin, nettle, omega 3, and methylsulfonylmethane. Download : Download high-res image (288KB) Download : Download full-size image Fig. 4. Artri King Supplement (Source: FDA). 2. Case report A 59–year old woman with an 11 year history of a 1.5 cm well-differentiated bronchial carcinoid, presented with 20 lb. weight gain, facial swelling, flushing, lower extremity edema and shortness of breath over 3 months. On exam, the patient was normotensive, centrally obese with mild hirsutism, facial fullness and ruddiness with evidence of a dorsocervical fat pad. Initially there was concern for hormonal activation of her known bronchial carcinoid. Testing resulted in a normal 24-hour urine 5-HIAA (6 mg/d, n < 15 mg/dL), elevated chromogranin A (201 ng/mL, n < 103 ng/mL), normal histamine (<1.5 ng/mL, n < 1.7 ng mL), low-normal 7 AM serum cortisol (5.1 μg/dL, n 3.6–19.3 μg/dL), normal 7 AM ACTH (17 pg/mL, n < 46 pg/mL) and a surprisingly low 24-hr urinary free cortisol (1.8 mcg/hr, n 4.0–50.0 mcg/hr). A late night saliva cortisol was 0.03 mcg/dL (n 3.4–16.8 mcg/dL). Testosterone, IGF-1, glucose and electrolytes were appropriate. An echocardiogram showed an ejection fraction of 60% with no evidence of carcinoid heart disease. A Dotatate PET-CT was obtained to evaluate for progression of the neuro-endocrine tumor and revealed a stable right upper lobe pulmonary nodule with no evidence of metastatic disease. Given low cortisol levels, ectopic Cushing syndrome was excluded and exogenous steroids were suspected, however the patient denied use of oral,inhaled, or injected steroids. A cosyntropin stimulation study yielded a pre-stimulation cortisol 6.2 μg/dL with an adequate post-stimulation cortisol 23.5 μg/dL. At this stage of evaluation, the patient received an FDA alert regarding a glucosamine supplement she had started 4 months prior for joint pain. The notification advised of hidden drug ingredients including dexamethasone, diclofenac, and methocarbamol contained within Artri King Glucosamine supplements not listed on the product label but verified by FDA lab analysis. The FDA had received several adverse event reports including liver toxicity and even death associated with such products. The patient's symptoms gradually improved after discontinuation of the supplement. 3. Discussion 3.1. Ectopic ACTH syndrome This patient's Cushingoid features were initially suspected to be secondary to the known bronchial neuroendocrine tumor. Ectopic ACTH production accounts for about 5–10% of all Cushing Syndrome cases [1]. The most common location of ectopic ACTH is the lungs with pulmonary carcinoid tumors being the most common cause, followed by squamous cell lung cancer [2]. Despite this patient's history of bronchial carcinoid tumor and positive chromogranin histopathological marker, her laboratory results were not consistent with an ACTH dependent Cushing Syndrome. In fact, Cushing syndrome is a relatively uncommon neuroendocrine neoplasm complication. The prevalence of ectopic ACTH production in patients with lung tumors is rare, at less than 5% in squamous cell lung cancer and about 3% in patients with lung or pancreatic (non-MEN1) neuroendocrine tumors1. Patients with ACTH dependent Cushing syndrome not suspected to originate from the pituitary, undergo further testing to evaluate for an ectopic ACTH secreting tumor. These tests include conventional imaging of the chest, abdomen and pelvis, as well as functional imaging such as octreotide scans, fluoride 18-fluorodeoxyglucose-positron emission tomography [18F-FDG PET], and gallium-68 DOTATATE positron emission tomography-computed tomography [Dotatate PET-CT] scan [3]. In our literature review, we found that there was insufficient evidence to determine the sensitivity and specificity of nuclear medicine imaging techniques [4,5]. In this case, the patient had no laboratory evidence for ACTH dependent Cushing Syndrome, but given the known bronchial carcinoid tumor, a repeat Dotatate PET-CT scan was obtained which demonstrated no indication of growth or spread of the known bronchial tumor. 3.2. Supplement induced Cushing Syndrome One of the most remarkable findings in this case was the patient's low urine cortisol level in the setting of her overt Cushingoid features. In our survey of the literature, we found that low urine cortisol levels were associated with exogenous glucocorticoid use [6,7]. The low urine cortisol levels may be reflective of intermittent glucocorticoid exposure. Indeed, this patient's Cushingoid features were determined to be secondary to prolonged use of Artri King supplement. Occult glucocorticoid use is difficult to diagnose even after performing a thorough medication reconciliation as patients may unknowingly consume unregulated doses of glucocorticoids in seemingly harmless supplements and medications. The incidence of supplement induced Cushing Syndrome is currently unknown as supplements are not regularly tested to detect hidden glucocorticoid doses. Additionally, the likelihood of developing supplement induced Cushing syndrome is dependent on dosage and duration of use. In our literature review we found nine published articles describing supplement induced Cushing Syndrome [[7], [8], [9], [10], [11], [12], [13], [14], [15]], one case report of tainted counterfeit medication causing Cushing Syndrome [16], and two cases of substances with probable glucocorticoid-like activity [17,18]. Of the nine published articles of supplement induced Cushing Syndrome, six were associated with supplements marketed as arthritic joint pain relief products including ArtriKing, Maajun, and AtriVid [[7], [8], [9], [10], [11], [12]]. These products later received government issued warnings in Mexico, Malaysia, and Colombia respectively [[19], [20], [21]]. To our knowledge there have been four published reports of ArtiKing supplement induced Cushing Syndrome [[7], [8], [9], [10]]. The first documented cases were reported in 2021 in Vera Cruz, Mexico; since then the Mexican medical community reported seeing a disproportionate increase in cases of iatrogenic Cushing Syndrome due to these supplements [7]. There have also been three American published articles describing a total of 4 cases of ArtriKing supplement induced Cushing syndrome [[8], [9], [10]]. In January 2022 the FDA issued a warning about Atri Ajo King containing diclofenac, which was not listed in the product label [22]. In April 2022 the FDA expanded its warning, advising consumers to avoid all Artri and Ortiga products after the FDA found these products contained dexamethasone and diclofenac [23]. In October 2022 the FDA issued warning letters to Amazon, Walmart, and Latin Foods market for distributing Artri and Ortiga products [24]. Many supplements are not regulated by the government and may contain hidden ingredients such as glucocorticoids. In these cases further evaluation of suspected products [25], medications [16], and patient serum [26] and urine [6] utilizing techniques such as liquid chromatography may be used to confirm occult glucocorticoid exposure. This case highlights the importance of educating patients to exercise caution when purchasing health products both online and abroad. Consumers should be aware of the potential risks of taking supplements, especially those advertised as joint pain relief products. 4. Conclusion Although the most common cause of ectopic ACTH syndrome is pulmonary carcinoid tumors and squamous cell lung cancer, it is a relatively uncommon complication of pulmonary neoplasms. Exogenous Cushing syndrome due to supplements containing unreported corticosteroid doses should be considered in patients with typical Cushingoid features and contradictory hormonal testing. Occult glucocorticoid exposure is rare but can be evaluated with liquid chromatography. This case report emphasizes the importance of teaching patients to be vigilant and appropriately research their health supplements. Patient consent Formal informed consent was obtained from the patient for publication of this case report. Declaration of competing interest The authors (Tomas Morales and Shanika Samarasinghe) of this case report declare that they have no financial conflicts of interest. Shanika Samrasinghe is an editorial member of the Journal of Clinical and Translational Endocrinology: Case Reports, and declares that she was not involved in the peer review and editorial decision making process for the publishing of this article. References [1] A.R. Hayes, A.B. Grossman The ectopic adrenocorticotropic hormone syndrome: rarely easy, always challenging Endocrinol Metab Clin N Am, 47 (2) (2018 Jun), pp. 409-425, 10.1016/j.ecl.2018.01.005 PMID: 29754641 View PDFView articleView in ScopusGoogle Scholar [2] A.M. Isidori, A. Lenzi Ectopic ACTH syndrome Arq Bras Endocrinol Metabol, 51 (8) (2007 Nov), pp. 1217-1225, 10.1590/s0004-27302007000800007 PMID: 18209859 View article View in ScopusGoogle Scholar [3] J. Young, M. Haissaguerre, O. Viera-Pinto, O. Chabre, E. Baudin, A. Tabarin Management of endocrine disease: cushing's syndrome due to ectopic ACTH secretion: an expert operational opinion Eur J Endocrinol, 182 (4) (2020 Apr), pp. R29-R58, 10.1530/EJE-19-0877 PMID: 31999619 View article View in ScopusGoogle Scholar [4] E. Varlamov, J.M. Hinojosa-Amaya, M. Stack, M. Fleseriu Diagnostic utility of Gallium-68-somatostatin receptor PET/CT in ectopic ACTH-secreting tumors: a systematic literature review and single-center clinical experience Pituitary, 22 (5) (2019 Oct), pp. 445-455, 10.1007/s11102-019-00972-w PMID: 31236798 View article View in ScopusGoogle Scholar [5] A.M. Isidori, E. Sbardella, M.C. Zatelli, M. Boschetti, G. Vitale, A. Colao, R. Pivonello, ABC Study Group Conventional and nuclear medicine imaging in ectopic cushing's syndrome: a systematic review J Clin Endocrinol Metab, 100 (9) (2015 Sep), pp. 3231-3244, 10.1210/JC.2015-1589 PMID: 26158607; PMCID: PMC4570166 View article View in ScopusGoogle Scholar [6] G. Cizza, L.K. Nieman, J.L. Doppman, M.D. Passaro, F.S. Czerwiec, G.P. Chrousos, G.B. Cutler Jr. Factitious cushing syndrome J Clin Endocrinol Metab, 81 (10) (1996 Oct), pp. 3573-3577, 10.1210/jcem.81.10.8855803 PMID: 8855803 View article View in ScopusGoogle Scholar [7] R. Patel, S. Sherf, N.B. Lai, R. Yu Exogenous cushing syndrome caused by a "herbal" supplement AACE Clin Case Rep, 8 (6) (2022 Aug 5), pp. 239-242, 10.1016/j.aace.2022.08.001 PMID: 36447831; PMCID: PMC9701910 View PDFView articleView in ScopusGoogle Scholar [8] C. Dunn, J. Amaya, P. Green A case of iatrogenic cushing's syndrome following use of an over-the-counter arthritis supplement 2023 Case Rep Endocrinol (2023 Mar 11), Article 4769258, 10.1155/2023/4769258 PMID: 36941974; PMCID: PMC10024620 View article View in ScopusGoogle Scholar [9] N. Mikhail, K. Kurator, E. Martey, A. Gaitonde, C. Cabrera, P. Balingit Iatrogenic cushing's syndrome caused by adulteration of a health product with dexamethasone Int J Endovascul Treatment Innovat Techn, 3 (1) (2022 Nov 23), pp. 6-9 Google Scholar [10] L. Del Carpio-Orantes, A.Q. Barrat-Hernández, A. Salas-González Iatrogenic Cushing syndrome due to fallacious herbal supplements. The case of ortiga ajo rey and Artri king Colegio de Medicina Interna de México, 37 (4) (2021), pp. 599-602 https://doi:10.24245/mim.v37i4.3912 Google Scholar [11] F. Wahab, R.A. Rahman, L.H. Yaacob, N.M. Noor, N. Draman A case report of steroid withdrawal syndrome Korean J Fam Med, 41 (5) (2020 Sep), pp. 359-362, 10.4082/kjfm.18.0181 Epub 2020 Sep 18. PMID: 32961047; PMCID: PMC7509117 View article View in ScopusGoogle Scholar [12] M. Zuluaga Quintero, A. Ramírez, A. Palacio, J.F. Botero, A. Clavijo Síndrome de Cushing exógeno e insuficiencia adrenal relacionada con consumo de producto natural Acta Méd Colomb, 42 (4) (2017), pp. 243-246, 10.36104/amc.2017.1006 View article Google Scholar [13] R. Patell, R. Dosi, S. Sheth, P. Jariwala Averting a crisis by 'add'ing up the clues 2014:bcr2014204685 BMJ Case Rep (2014 Jun 2), 10.1136/bcr-2014-204685 PMID: 24891489; PMCID: PMC4054156 View article Google Scholar [14] H. Hendarto Iatrogenic Cushing's syndrome caused by treatment with traditional herbal medicine, a case report 1st International Integrative Conference on Health, Life and Social Sciences (ICHLaS 2017) (2017 Dec), 10.2991/ichlas-17.2017.9 Atlantis Press View article Google Scholar [15] P.C. Oldenburg-Ligtenberg, M.M. van der Westerlaken A woman with Cushing's syndrome after use of an Indonesian herb: a case report Neth J Med, 65 (4) (2007 Apr), pp. 150-152 PMID: 17452765 View in ScopusGoogle Scholar [16] F. Azizi, A. Jahed, M. Hedayati, M. Lankarani, H.S. Bejestani, F. Esfahanian, N. Beyraghi, A. Noroozi, F. Kobarfard Outbreak of exogenous Cushing's syndrome due to unlicensed medications Clin Endocrinol, 69 (6) (2008 Dec), pp. 921-925, 10.1111/j.1365-2265.2008.03290.x Epub 2008 May 6. PMID: 18462262 View article View in ScopusGoogle Scholar [17] C. Martini, E. Zanchetta, M. Di Ruvo, A. Nalesso, M. Battocchio, E. Gentilin, E. Degli Uberti, R. Vettor, M.C. Zatelli Cushing in a leaf: endocrine disruption from a natural remedy J Clin Endocrinol Metab, 101 (8) (2016 Aug), pp. 3054-3060, 10.1210/jc.2016-1490 Epub 2016 May 24. PMID: 27218272 View article View in ScopusGoogle Scholar [18] A.J. Razenberg, J.W. Elte, A.P. Rietveld, H.C. van Zaanen, M.C. Cabezas A 'smart' type of Cushing's syndrome Eur J Endocrinol, 157 (6) (2007 Dec), pp. 779-781, 10.1530/EJE-07-0538 PMID: 18057386 View article View in ScopusGoogle Scholar [19] COFEPRIS (Federal Committee for Protection from Sanitary Risks) Public notification: COFEPRIS alerts about the illegal marketing of the product "ARTRI AJO KING", Which does not have a sanitary registration https://www.gob.mx/cofepris/articulos/cofepris-alerta-sobre-comercializacion-ilegal-del-producto-artri-ajo-king-el-cual-no-cuenta-con-registro-sanitario?idiom=es Google Scholar [20] Ministry of Health Malaysia Public notification: the truth about Maahun/Jamu http://www.myhealth.gov.my/en/the-truth-about-maajunjamu/ (2023) Google Scholar [21] INVIMA (National Food and Drug Surveillance Institute of Colombia) Health Alert: safety information about the product "ARTRIVID PLUS" promoted in different media of the country https://app.invima.gov.co/alertas/ckfinder/userfiles/files/ALERTAS%20SANITARIAS/medicamentos_pbiologicos/2015/Abril/ARTRIVID%20PLUS.pdf Google Scholar [22] FDA Public notification: Artri ajo king contains hidden drug ingredient https://www.fda.gov/drugs/medication-health-fraud/public-notification-artri-ajo-king-contains-hidden-drug-ingredient (2022) Google Scholar [23] FDA Public Notification: Artri King contains hidden drug ingredients https://www.fda.gov/drugs/medication-health-fraud/public-notification-artri-king-contains-hidden-drug-ingredients (2022) Google Scholar [24] FDA warns consumers not to purchase or use Artri and Ortiga products, which may contain hidden drug ingredients https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-purchase-or-use-artri-and-ortiga-products-which-may-contain-hidden-drug Google Scholar [25] P. Kempegowda, L. Quinn, L. Shepherd, S. Kauser, B. Johnson, A. Lawson, A. Bates Adrenal insufficiency from steroid-containing complementary therapy: importance of detailed history Endocrinol Diabetes Metab Case Rep, 2019 (1) (2019 Jul 26), pp. 1-4, 10.1530/EDM-19-0047 PMID: 31352697; PMCID: PMC6685090 View article Google Scholar [26] M.M. Pineyro, L. Redes, S. De Mattos, L. Sanchez, E. Brignardello, V. Bianchi, V. Ems, D. Centurión, M. Viola Factitious cushing's syndrome: a diagnosis to consider when evaluating hypercortisolism Front Endocrinol, 10 (2019 Mar 4), p. 129, 10.3389/fendo.2019.00129 PMID: 30886602; PMCID: PMC6409302 View article View in ScopusGoogle Scholar From https://www.sciencedirect.com/science/article/pii/S2214624523000199 -
Urine Tests: These involve collecting urine, usually for periods of twenty-four hours at a time. Twenty-four Hour Urine: The doctor will give you a gallon collection jug, usually with boric acid in it. The instructions are usually printed on the side. Generally, you urinate first thing in the morning, as usual. after that, you collect the rest of the urine for the next 24 hours in the jug. The directions usually tell you to refrigerate the jug. Directions for the Twenty-four Hour Urine Test Physicians have always relied upon analysis of urine specimens in order to diagnosis and treat many disease processes. Twenty-four hour urine collections are often employed to estimate the production rates of various hormones. The accuracy of test results depends entirely on the accuracy of the urine collection technique. These instructions are provided as a guide to ensure that your 24-hour urine collection is obtained in a manner that will permit reliance upon the test results. Urine samples should be collected in a large cup, urine collection hat or other container and then poured into the large bottle. Do not try to urinate directly into the bottle. Void urine prior to bowel movements in order to avoid losing urine that might normally be passed during a bowel movement. Urine collection hats can usually be purchased at medical supply stores if not provided by your physician or lab. If you should have a bowel movement while urinating the urine collection hat should keep the urine clean if used correctly. Urine samples should be collected in a large cup or other container and then poured into the large bottle. Do not try to urinate directly into the bottle. Void urine prior to bowel movements in order to avoid losing urine that might normally be passed during a bowel movement. Some patients are asked to collect more than one consecutive 24-hour urine sample. If that is the case, you should complete the first collection as instructed. Then, begin the second collection by adding any urine made in the next 24-hours to the second bottle. You should not discard any urine when starting the second or any subsequent collections. Simply change bottles at the stop and start times after adding that last sample required to complete the previous collection. The bottles for some tests contain a weak acid as a preservative. Do not discard the acid. If you accidentally get acid or urine from the bottle on your skin or clothing, rinse the effected area immediately with plenty of cold water. Collection bottles must be refrigerated. This is best accomplished by using an ice chest, cooler, or if so inclined, your refrigerator. If you forget to collect all of the urine or perform the test improperly, discard the specimen and start again on another day. If the bottle contained an acid preservative, you will need to obtain a new bottle from the laboratory or your physician's office. Otherwise, you may reuse the bottle after rinsing it with distilled water. Finally, please remember to call your physician, medical provider or nurse if you have any questions about the proper collection of a 24-hour urine sample. This Topic on the Message Boards.
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Abnormally high levels of cortisol in the urine — one of the hallmarks of Cushing’s syndrome — seem to be associated with alterations in blood sugar metabolism in obese patients, a study found. The study, “Hypercortisolism and altered glucose homeostasis in obese patients in the pre-bariatric surgery assessment,” was published in the journal Diabetes/Metabolism Research and Reviews.
