Metabolomic Biomarkers in Urine of Cushing’s Syndrome Patients

Posted on January 29, 2026 by MaryO
Int. J. Mol. Sci. 2017, 18(2), 294; doi:10.3390/ijms18020294 (registering DOI)

Alicja Kotłowska 1,* , Tomasz Puzyn 2, Krzysztof Sworczak 3, Piotr Stepnowski 4 and Piotr Szefer 1

1 Department of Food Sciences, Faculty of Pharmacy, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland
2 Laboratory of Environmental Chemometrics, Faculty of Chemistry, University of Gdańsk, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland
3 Department of Endocrinology and Internal Medicine, Medical University of Gdańsk, ul. Dębinki 7, 80-211 Gdańsk, Poland
4 Department ofEnvironmental Analytics, Institute for Environmental and Human Health Protection, Faculty of Chemistry, University of Gdańsk, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland
* Author to whom correspondence should be addressed.
Academic Editor: Ting-Li (Morgan) Han
Received: 5 December 2016 / Revised: 9 January 2017 / Accepted: 19 January 2017 / Published: 29 January 2017
(This article belongs to the Section Molecular Diagnostics)
Download PDF [1853 KB, uploaded 29 January 2017]

Abstract

Cushing’s syndrome (CS) is a disease which results from excessive levels of cortisol in the human body. The disorder is associated with various signs and symptoms which are also common for the general population not suffering from compound hypersecretion. Thus, more sensitive and selective methods are required for the diagnosis of CS.

This follow-up study was conducted to determine which steroid metabolites could serve as potential indicators of CS and possible subclinical hypercortisolism in patients diagnosed with so called non-functioning adrenal incidentalomas (AIs).

Urine samples from negative controls (n = 37), patients with CS characterized by hypercortisolism and excluding iatrogenic CS (n = 16), and patients with non-functioning AIs with possible subclinical Cushing’s syndrome (n = 25) were analyzed using gas chromatography-mass spectrometry (GC/MS) and gas chromatograph equipped with flame ionization detector (GC/FID). Statistical and multivariate methods were applied to investigate the profile differences between examined individuals. The analyses revealed hormonal differences between patients with CS and the rest of examined individuals.

The concentrations of selected metabolites of cortisol, androgens, and pregnenetriol were elevated whereas the levels of tetrahydrocortisone were decreased for CS when opposed to the rest of the study population. Moreover, after analysis of potential confounding factors, it was also possible to distinguish six steroid hormones which discriminated CS patients from other study subjects.

The obtained discriminant functions enabled classification of CS patients and AI group characterized by mild hypersecretion of cortisol metabolites. It can be concluded that steroid hormones selected by applying urinary profiling may serve the role of potential biomarkers of CS and can aid in its early diagnosis.

 

Keywords: Cushing’s syndrome; metabolomics; multivariate analysis; biomarkers; steroid hormones; urinary profiling; gas chromatography; linear discriminant analysis
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. (CC BY 4.0).

Supplementary material

From http://www.mdpi.com/1422-0067/18/2/294

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Think Like a Doctor: Red Herrings Solved!

Posted on January 11, 2026 by MaryO

By LISA SANDERS, M.D.

On Thursday we challenged Well readers to take the case of a 29-year-old woman with an injured groin, a swollen foot and other abnormalities. Many of you found it as challenging as the doctors who saw her. I asked for the right test as well as the right diagnosis. More than 200 answers were posted.

The right test was…

The dexamethasone suppression test,though I counted those of you who suggested measuring the cortisol in the urine.

The right diagnosis was…

Cushing’s disease

More than a dozen of you got the right answer or the right test, but Dr. Davin Quinn, a consultant psychiatrist at the University of New Mexico Hospital, was the first to be right on both counts. As soon as he saw that the patient’s cortisol level was increased, he thought of Cushing’s. And he had treated a young patient like this one some years ago as a second year resident.

The Diagnosis:

Cushing’s disease is caused by having too much of the stress hormone cortisol in the body. Cortisol is made in the adrenal glands, little pyramid shaped organs that sit atop the kidneys. It is normally a very tightly regulated hormone that helps the body respond to physical stress.

Sometimes the excess comes from a tumor in the adrenal gland itself that causes the little organ to go into overdrive, making too much cortisol. More often the excess occurs when a tumor in the pituitary gland in the brain results in too much ACTH, the hormone that controls the adrenal gland.

In the body, cortisol’s most fundamental job is to make sure we have enough glucose around to get the body’s work done. To that end, the hormone drives appetite, so that enough fuel is taken in through the food we eat. When needed, it can break muscle down into glucose. This essential function accounts for the most common symptoms of cortisol excess: hyperglycemia, weight gain and muscle wasting. However, cortisol has many functions in the body, and so an excess of the hormone can manifest itself in many different ways.

Cushing’s was first described by Dr. Harvey Cushing, a surgeon often considered the father of modern neurosurgery. In a case report in 1912, he described a 23-year-old woman with sudden weight gain, mostly in the abdomen; stretch marks from skin too thin and delicate to accommodate the excess girth; easy bruising; high blood pressure and diabetes.

Dr. Cushing’s case was, it turns out, a classic presentation of the illness. It wasn’t until 20 years later that he recognized that the disease had two forms. When it is a primary problem of an adrenal gland gone wild and producing too much cortisol on its own, the disease is known as Cushing’s syndrome. When the problem results from an overgrown part of the pituitary making too much ACTH and causing the completely normal adrenal glands to overproduce the hormone, the illness is called Cushing’s disease.

It was an important distinction, since the treatment often requires a surgical resection of the body part where the problem originates. Cushing’s syndrome can also be caused by steroid-containing medications, which are frequently used to treat certain pulmonary and autoimmune diseases.

How the Diagnosis Was Made:

After the young woman got her lab results from Dr. Becky Miller, the hematologist she had been referred to after seeing several other specialists, the patient started reading up on the abnormalities that had been found. And based on what she found on the Internet, she had an idea of what was going on with her body.

“I think I have Cushing’s disease,” the patient told her endocrinologist when she saw him again a few weeks later.

The patient laid out her argument. In Cushing’s, the body puts out too much cortisol, one of the fight-or-flight stress hormones. That would explain her high blood pressure. Just about everyone with Cushing’s disease has high blood pressure.

She had other symptoms of Cushing’s, too. She bruised easily. And she’d been waking up crazy early in the morning for the past year or so – around 4:30 – and couldn’t get back to sleep. She’d heard that too much cortisol could cause that as well. She was losing muscle mass – she used to have well-defined muscles in her thighs and calves. Not any more. Her belly – it wasn’t huge, but it was a lot bigger than it had been. Cushing’s seemed the obvious diagnosis.

The doctor was skeptical. He had seen Cushing’s before, and this patient didn’t match the typical pattern. She was the right age for Cushing’s and she had high blood pressure, but nothing else seemed to fit. She wasn’t obese. Indeed, she was tall (5- foot-10) and slim (150 pounds) and athletic looking. She didn’t have stretch marks; she didn’t have diabetes. She said she bruised easily, but the endocrinologist saw no bruises on exam. Her ankle was still swollen, and Cushing’s can do that, but so can lots of other diseases.

The blood tests that Dr. Miller ordered measuring the patient’s ACTH and cortisol levels were suggestive of the disease, but many common problems — depression, alcohol use, eating disorders — can cause the same result. Still, it was worth taking the next step: a dexamethasone suppression test.

Testing, Then Treatment:

The dexamethasone suppression test depends on a natural negative feedback loop whereby high levels of cortisol suppress further secretion of the hormone. Dexamethasone is an artificial form of cortisol. Given in high doses, it will cause the level of naturally-occurring cortisol to drop dramatically.

The patient was told to take the dexamethasone pills the night before having her blood tested. The doctor called her the next day.

“Are you sure you took the pills I gave you last night?” the endocrinologist asked her over the phone. The doctor’s voice sounded a little sharp to the young woman, tinged with a hint of accusation.

“Of course I took them,” she responded, trying to keep her voice clear of any irritation.

“Well, the results are crazy,” he told her and proposed she take another test: a 24-hour urine test.

Because cortisol is eliminated through the kidneys, collecting a full day’s urine would show how much cortisol her body was making. So the patient carefully collected a day’s worth of urine.

A few days later, the endocrinologist called again: her cortisol level was shockingly high. She was right, the doctor conceded, she really did have Cushing’s.

An M.R.I. scan revealed a tiny tumor on her pituitary. A couple of months later, she had surgery to remove the affected part of the gland.

After recovering from the surgery, the patient’s blood pressure returned to normal, as did her red blood cell count and her persistently swollen ankle. And she was able to once again sleep through the night.

Red Herrings Everywhere:

As many readers noted, there were lots of findings that didn’t really add up in this case. Was this woman’s groin sprain part of the Cushing’s? What about the lower extremity swelling, and the excess red blood cell count?

In the medical literature, there is a single case report of high red blood cell counts as the presenting symptom in a patient with Cushing’s. And with this patient, the problem resolved after her surgery – so maybe they were linked.

And what about the weird bone marrow biopsy? The gastritis? The enlarged spleen? It’s hard to say for certain if any of these problems was a result of the excess cortisol or if she just happened to have other medical problems.

Why the patient didn’t have the typical symptoms of Cushing’s is easier to explain. She was very early in the course of the disease when she got her diagnosis. Most patients are diagnosed once symptoms have become more prominent

By the time this patient had her surgery, a couple of months later, the round face and belly characteristic of cortisol excess were present. Now, two years after her surgery, none of the symptoms remain.

From http://well.blogs.nytimes.com/2014/01/17/think-like-a-doctor-red-herrings-solved/?_php=true&_type=blogs&_r=0

Filed under: adrenal, Cushing's, pituitary | Tagged: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , | Leave a comment »

A Patient With a Bronchial Carcinoid Presents With Cushingoid Symptoms Due To An Atypical and Potentially Dangerous Supplement

Posted on October 11, 2023 by MaryO

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).

Fig. 1

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Fig. 1. DOTATATE PET/CT demonstrates a right upper lobe pulmonary nodule with intense uptake.

Fig. 2

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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.

Fig. 3

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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.

Fig. 4

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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

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High Cortisol Levels in Urine May Be Linked to Changes in Blood Sugar Metabolism

Posted on September 10, 2020 by MaryO

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.

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Rare Nasal Cancer May Have Caused Cushing’s Syndrome

Posted on April 4, 2018 by MaryO

A very rare case of Cushing’s syndrome developing as a result of a large and also rare cancer of the nasal sinuses gives insights into how to screen and treat such an anomaly, of which fewer than 25 cases have been reported in literature.

Paraneoplastic esthesioneuroblastoma (ENB), a very rare type of nasal tumor, may sometimes produce excess adrenocorticotrophic hormone (ACTH), leading to symptoms of Cushing’s syndrome, according to a recent case report that describes a case of ACTH-secreting ENB. The report aims to demonstrate the importance of recognizing its pathophysiology and treatment.

The case report, “A Case of Cushing’s Syndrome due to Ectopic Adrenocorticotropic Hormone Secretion from Esthesioneuroblastoma with Long Term Follow-Up after Resection,” was published in the journal Case Reports in Endocrinology.

It describes a 52-year-old Caucasian male who had a history of high blood pressure, severe weakness, abnormal production of urine, extreme thirstiness, and confusion.

He was scheduled to undergo surgery for a 7-centimeter skull base mass; the surgery was postponed due to severe high serum potassium concentrations and abnormally high pH levels. His plasma ACTH levels also were elevated and Cushing’s syndrome was suspected. Since imaging of the chest, abdomen, and pelvis did not show any ectopic (abnormal) sources of ACTH, the ENB was suspected to be the source.

Surgery was performed to remove the tumor, which was later found to be secreting ACTH. Consequently, following the procedure, his ACTH levels dropped to normal (below detection limit) and he did not need medication to normalize serum potassium levels. He then underwent subsequent chemoradiation and has shown no sign of recurrence 30 months after the operation, which is considered to be one of the longest follow-up periods for such a case.

Researchers declared it “a case of olfactory neuroblastoma with ectopic ACTH secretion that was treated with resection and adjuvant chemoradiation.”

“Given the paucity of this diagnosis, little is known about how best to treat these patients and how best to screen for complications such as adrenal insufficiency and follow-up,” they wrote. “Our case adds more data for better understanding of this disease.”

From https://cushingsdiseasenews.com/2018/04/03/rare-nasal-cancer-caused-cushings-syndrome-case-report-says/

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