Atypical Presentation of Cushing’s Disease With Weight Loss and Hypokalemia

Posted on October 29, 2024 by MaryO

Abstract

Summary

ACTH-secreting pituitary adenomas causing Cushing’s disease (CD) typically present with weight gain, whereas weight loss and hypokalemia in endogenous Cushing’s patients are suggestive of ectopic ACTH production. We report a case of CD presenting with atypical features of marked weight loss and hypokalemia. A 75-year-old female was admitted to the hospital with a history of profound weight loss, associated with uncontrolled hypertension, hyperglycemia, severe proximal muscle weakness, and hypokalemia. Subsequent investigations, including 24-h urinary free cortisol, 48-h low-dose dexamethasone suppression test, MRI of the sella, and bilateral inferior petrosal sinus sampling, confirmed CD without any evidence of ectopic ACTH production. She became eucortisolemic with medical therapy of ketoconazole and cabergoline, subsequently regained her weight, and became normokalemic. This case illustrates that patients with CD may present with symptoms and biochemical findings that would otherwise suggest ectopic ACTH production.

Learning points

  • Patients with CD do not always present with classical clinical features and may present with symptoms and biochemical findings that would otherwise suggest ectopic ACTH production.
  • While most patients with CD typically lose weight after biochemical remission, some patients gain weight after the normalization of cortisol levels.
  • This case highlights the need to entertain a broad differential in patients presenting with hypokalemia and weight loss and the need to exclude hypercortisolemia.

Background

Pituitary corticotropin (ACTH)-induced Cushing’s disease (CD) accounts for approximately 70% of patients presenting with Cushing’s syndrome (1). ACTH-producing pituitary adenomas are typically microadenomas and, in over a third of CD patients, there is no demonstrable lesion on MRI (2). Clinical and biochemical diagnosis of CD may be challenging, as patients can present with varied symptoms that overlap with other comorbidities. Progressive weight gain associated with central adiposity is a common manifestation of CD occurring during the early stage of the disease. While nonspecific features such as hypertension, diabetes, cardiac hypertrophy, arterial and venous thrombosis, electrolyte abnormalities, and psychiatric disturbances also occur frequently, the more discriminatory signs of hypercortisolemia include proximal myopathy, facial plethora, easy bruising, and wide striae (2). Weight loss with associated hypokalemia typically suggests an underlying ectopic ACTH production. Here we report an unusual case of pituitary ACTH-induced CD who presented with significant hypokalemia and marked weight loss which resolved with medical control of CD.

Case presentation

A 75-year-old female with a history of type 2 diabetes, hypertension, osteoporosis, and coronary artery disease presented to the emergency department (ED) with profound proximal muscle weakness associated with a serum potassium of 2.4 mmol/L (normal = 3.6–5.2 mmol/L). She also reported a weight loss of 90 lbs over the previous 2 years. In addition, she had uncontrolled hypertension despite taking three anti-hypertensive agents and worsening glycemic control requiring increasing anti-hyperglycemic therapy; her hemoglobin A1c at presentation was 9.3%.

Investigation

During hospitalization, she underwent further investigation for hypokalaemia and resistant hypertension, which showed an elevated 24-h urine free cortisol (24-h UFC) of 1904.4 nmol/d (upper limit of normal: 485.4 nmol/d) and consequently was referred to Endocrinology for further assessment. Repeat outpatient-based investigations after discharge from the hospital confirmed an elevated 24-h UFC of 1578.4 nmol/d, elevated AM serum cortisol of 1749.2 nmol/L (normal: 80–477.3 nmol/L), non-suppressed serum cortisol of 1238.8 nmol/L (normal response: < 50 nmol/L) after a 48-h low dose dexamethasone suppression test, and an elevated serum ACTH at 8.2 pmol/L (normal: 0.5–2.2 pmol/L). MRI of the sella as well as gallium DOTATATE PET-CT did not show any demonstrable lesion (Figs 1A, B and 2A, B). Subsequently, she underwent bilateral inferior petrosal sinus sampling (BIPSS) using 100 µg ovine CRH, which showed a post-CRH central to peripheral ACTH ratio of 3, lateralizing to the right with a ratio of 2.1. Based on these findings, a diagnosis of MRI-negative CD was made.

Figure 1View Full Size
Figure 1
(A and B) MRI Sella post-GAD coronal and sagittal sections showing no pituitary lesion.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 3; 10.1530/EDM-24-0011

Figure 2View Full Size
Figure 2
(A and B) Ga68 DOTATATE scan. PET-CT showing non-specific uptake through the distal esophagus and proximal stomach, but otherwise within normal physiological limits.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 3; 10.1530/EDM-24-0011

Treatment

While awaiting surgical opinion, the patient was started on Ketoconazole 200 mg po TID. She was unable to tolerate a larger dose; therefore, cabergoline 1 mg twice a week was added. The options of trans-sphenoidal pituitary surgery and bilateral adrenalectomy were discussed with the patient, which she declined, and decided to continue with medical therapy.

Outcome and follow-up

Medical therapy was adjusted over the next several weeks until 24-h UFC normalized and remained normal during 24 months of follow-up with the most recent being 85 nmol/d. With biochemical remission of CD, her blood pressure normalized, and she required a reduction in the dose of anti-hypertensive and anti-hyperglycaemic therapy. Her serum potassium levels also normalized. She initially regained 15 lbs but called the clinic when, despite taking medical therapy, she once again began losing weight and her serum potassium dropped to 2.7 mmol/L. Repeat serum AM cortisol was significantly elevated at 935.3 nmol/L, as was 24h UFC at 1457.3 nmol/d. Further inquiry revealed that she had been prescribed omeprazole therapy by her family physician for symptoms of reflux. Omeprazole was discontinued due to its potential effect on decreasing the efficacy of ketoconazole therapy, and her cortisol and potassium levels rapidly normalized. Since then, she has regained 50 lbs, being almost back to her baseline weight, and her mobility and strength have improved from being initially bed-bound to now mobilizing independently using a walker. Pre and post therapy values are summarized in Table 1.

Table 1Key investigations at presentation and recent follow-up visit.

Test Reference range At presentation Recent follow-up
24-h urine cortisol (nmol/TV) ULN=486 1908  85
AM cortisol (nmol/L) 133-537 2371 796
Cortisol post-48h low DMS dose (nmol/L) <1.8 44.9 NA
ACTH (pmol/L) 2.3-10.1 37.5 14
Potassium (mmol/L) 3.6-5.2  2.4 4.5

DMS= dexamethasone suppression; NA = Not Applicable; ULN = upper limit of normal.

Discussion

Here we report an unusual case of CD presenting with features that were initially highly suggestive of ectopic ACTH production with weight loss rather than the usual weight gain. All of the initial symptoms resolved following biochemical control of hypercortisolemia. In our review of the literature, CD associated with weight loss has previously only been reported in association with severe depression, psychosis, eating disorders, or malignancy (3, 4). For instance, a case of familial CD was reported in a child who also had an intercurrent eating disorder (anorexia), which led to weight loss despite CD (3). Weight loss due to ectopic ACTH-induced CD has also been previously reported, where weight loss was thought to be due to the underlying malignancy (4). However, our patient had well-documented pituitary ACTH-induced CD.

Chronic hypercortisolemia is associated with increased abdominal adiposity that is thought to be caused by the downregulation of adenosine monophosphate-activated protein kinase (AMPK), which is responsible for regulating lipid metabolism (5). Furthermore, glucocorticoids also induce a direct orexigenic effect, which leads to weight gain (6). Weight loss in association with hypercortisolemia, on the contrary, can be a presenting feature of ectopic ACTH-producing tumors such as small cell lung cancer. While the underlying mechanism of weight loss is not fully understood, it is thought to be partly due to cAMP/Protein kinase A (PKA) pathway activation, with an increase in PKA activity resulting in altered downstream regulation of cAMP-related lipogenic and lipolytic proteins (6). In addition, high ACTH secretion and the malignant characteristics of the neoplastic process are also thought to play roles in weight loss (7). Our patient had no evidence of ectopic ACTH production.

A previous study (8) comparing the clinical features of CD in older vs younger patients reported that weight gain was more common in younger individuals, whereas older patients typically presented with catabolic changes, likely due to age-related variability in tissue sensitivity to glucocorticoid receptors and intracellular cortisol signaling. The overall rates of central adiposity were 71.1% in older patients compared with 80.0% in younger patients (8).

Another unusual feature was hypokalemia, which is generally associated with ectopic ACTH production. However, up to 10% of CD patients present with low potassium. Hypokalemia is caused by the mineralocorticoid effect of excess cortisol. Supraphysiologic production of cortisol tends to saturate 11β-hydroxysteroid dehydrogenase type II (11β-HSD2) activity in the renal tubule, which is primarily responsible for converting active cortisol into inactive cortisone. This could lead to excess binding of cortisol to mineralocorticoid receptors, resulting in an increase in potassium excretion and thus hypokalemia. While some studies have suggested that ACTH can also lead to lowering 11β-HSD2 activity causing hypokalemia, others have not found any such correlation (9, 10). In our patient, serum potassium normalized after she achieved eucortisolemia with medical therapy.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient/parent/guardian/relative of the patient.

Author contribution statement

All authors reviewed the results and approved the final version of the manuscript.

Acknowledgements

We thank Dr Brian Moses (Yarmouth Regional Hospital, NS, Canada) and Dr Scott Lee (Valley Regional Hospital, NS, Canada) for their contributions in managing the patient.

References

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“The Healthcare System Did Fail Me Repeatedly”: a Qualitative Study On Experiences Of Healthcare Among Canadian Women With Cushing’s Syndrome

Posted on October 4, 2024 by MaryO

Abstract

Background

As a rare endocrine disorder, Cushing’s Syndrome (Cushing’s) is characterized by numerous symptoms and a non-specific presentation, leading to a delay to diagnosis for patients with this disease. To date, research examining the lived experiences of patients with Cushing’s in healthcare is absent in the literature. This preliminary inquiry into the healthcare experiences of women with Cushing’s aimed to examine the utility of this line of inquiry to support the patient centered care of individuals with Cushing’s.

Methods

Seven women from across Canada with endogenous Cushing’s participated in the study. Semi-structured interviews were conducted examining participants’ healthcare and body-related experiences with Cushing’s. Results pertaining to healthcare experiences were analyzed for the current study using reflexive thematic analysis.

Results

Four themes emerged whereby women with Cushing’s experienced (1) a lack of patient centered care, characterized by provider miscommunication and medical gaslighting; (2) a misunderstanding of their symptoms as related to weight gain; (3) weight stigma in healthcare encounters; and (4) a shift in their quality of care following diagnosis.

Conclusions

The results highlight the importance of patient centered care as well as the negative impact of commonly reported barriers to patient centered care. Cushing’s specific barriers to patient centered care may include weight stigma as well as the rare incidence of Cushing’s. Further research is needed to better understand the healthcare experiences of people with Cushing’s in Canada.

Peer Review reports

Cushing Syndrome (Cushing’s) is a rare disorder caused by an increase in circulating free cortisol [1]. As receptors for glucocorticoids are widespread throughout the body, the effect of this increase in circulating cortisol is prolific [2]. Symptoms include uncontrollable weight gain, dorsocervical fat pad, facial plethora, purple striae, easy bruising, fatigue, proximal myopathy, hypertension, as well as menstrual irregularities and hirsutism among women [1, 3]. While Cushing’s is most often caused by corticosteroids (i.e., exogenous Cushing’s) with a more easily identifiable cause, this research is focused on endogenous Cushing’s, which occurs at an approximate rate of 3.2 cases per million per year globally [4]. Endogenous Cushing’s is divided into two types: adrenocorticotropic hormone (ACTH) dependent and ACTH independent [2]. ACTH dependent Cushing’s comprise approximately 80% of endogenous Cushing’s cases and is caused by ACTH secreting tumours most often on the pituitary (i.e., Cushing’s disease), or an ectopic ACTH secreting tumour found elsewhere in the body [2]. ACTH Independent Cushing’s cases account for the remaining 20% and are most often caused by adrenal cortical adenomas or hyperplasia [5].

The rare rate of occurrence, coupled with the broad symptomology contributes to the challenges with diagnosing Cushing’s, with a delay to diagnosis of two to six years [6, 7]. Although individuals may experience few symptoms its early stages, disease progression that occurs with delayed diagnosis can lead to significant impairment in daily life as well as hypertension, metabolic diseases, and other complications [8]. Given that the incidence of Cushing’s is higher among women compared to men, [9]. as well as the gendered nature of weight and appearance expectations for women in society (i.e., thinness), [10] understanding the impact of this disease on women is an important, but unexplored, direction for women’s health research.

The non-specific presentation and rare occurrence of endogenous Cushing’s is also important to consider in the context of patient centered care, defined as relationship-based care that meets the needs, priorities, and values of patients [11, 12]. Patient centered care focuses on the creation of a positive therapeutic alliance between patient and provider, with shared power and responsibility in decision making [11, 12]. A recent systematic literature review identified that most barriers to patient centered care occur at the provider level, including lack of training, physician burnout, and poor-quality communication [12]. One potential barrier to patient centered care for individuals with Cushing’s is weight stigma (i.e., stereotypes and negative attitudes about people with higher weights), which is prevalent in healthcare, [13, 14] and is associated with consequences for healthcare utilization [15, 16].

Although researchers have documented the clinical presentation of Cushing’s, [7] approaches to working with patients with a possible diagnosis, [1] as well as treatment approaches and outcomes, [17, 18] there is an absence of research on the lived experience of patients with Cushing’s in healthcare. Given the established delay to diagnosis of Cushing’s [6, 7] and the possible impact of weight stigma on patient centered care, we sought to conduct a preliminary inquiry into the patient experience in primary care. Thus, the aim of this study was to examine the healthcare experiences of women with Cushing’s in Canada, as women experience greater incidence of Cushing’s [9] as well as greater appearance-based sociocultural pressures [10].

Methods

Research team background and epistemological underpinnings

We recognize that our identities and positionalities as researchers have a significant impact on the research we conduct [19]. All authors identify as White cisgender women with lived experiences with weight-related issues, and SCJ has lived experience of Cushing’s Disease. SCJ led this research project as part of her degree requirements in a double-major biology and psychology undergraduate program. SN is a weight stigma researcher with a background in qualitative research. JFS conducts research on body image and eating disorder recovery, with a background in qualitative methods. Further, this research was undertaken from a social constructionist epistemological position, recognizing the power of sociocultural discourses related to appearance, weight, and health on the experiences of higher-weight people in society broadly as well as healthcare specifically [20,21,22]. These sociocultural discourses position weight as an accurate indicator of health that is within individual control, with lower body weights considered healthiest (i.e., “normal” weight body mass index) [20,21,22].

Participants

Participants were seven women from across Canada (see Table 1 for demographics). The mean age of the sample was 44.14 (SD = 13.32) and mean self-reported time to Cushing’s diagnosis after first seeking medical care was 2.14 years (SD = 0.58). Six participants experienced Adrenocorticotropic hormone (ACTH) dependent Cushing’s, while one patient experienced ACTH independent adrenal adenoma. Of the six participants with ACTH dependent Cushing’s, five had an ACTH secreting pituitary adenoma and one participant had an ectopic ACTH producing lung carcinoma. All participants self-declared that they exhibited clinically significant 24-hour urine free cortisol levels, which contributed to their diagnosis.

Table 1 Participant demographics and pseudonyms

Procedure

This study received research ethics approval from the first and second authors’ institution (#21–0507). Convenience sampling occurred in February 2022 via a shareable recruitment post on five Facebook support groups for Cushing’s Syndrome. Potential participants were directed to reach out to the first author to indicate their interest in the study. Participation was limited to cisgender women over the age of 18 who had been diagnosed with endogenous Cushing’s and received care in the Canadian healthcare system. Nine individuals from one Facebook support group contacted the researcher, two of whom did not receive treatment in Canada. The remaining seven participants were provided with a consent form and demographics survey, which they completed prior to scheduling a semi-structured interview.

Following the completion of informed consent, interviews took place over zoom, in a private location of the participant’s choosing. To obtain a rich understanding of experiences with Cushing’s, we asked a series of questions about participants’: (1) journey to diagnosis, (2) healthcare experience pre- and post-diagnosis, and (3) perception of body and weight pre- and post-diagnosis. Interview questions were open-ended and provided opportunity for participants to describe positive and/or negative experiences. Please see the Appendix for full interview protocol. Interviews lasted approximately one hour with $30 compensation, were recorded, and were transcribed verbatim by the first author. Following transcription, participants had the opportunity to review their transcript and remove any data they were uncomfortable including in the analysis (i.e., member checking). One participant removed a small portion of her transcript, which did not impact the analysis.

Analysis

Following transcription, anonymization, and member checking, the first and second author used a qualitative descriptive approach [23] in the preliminary data analysis stages to become familiar with the data and the experiences of the seven women interviewed. Two main content areas predominated: (1) negative experiences in healthcare and (2) women’s body image as connected to Cushing’s-related changes. Given these divergent content areas, the research team engaged in a two-pronged approach to qualitative data analysis, one for the negative healthcare experiences (reported here) and one for women’s body image.

The data pertaining to negative experiences in healthcare were analysed using reflexive thematic analysis [24, 25]. This method allowed for a rich and flexible understanding of similarities in individual experiences. To generate themes, the first and second authors read the transcripts line-by-line and assigned descriptive codes, which were then reviewed and re-coded at a more interpretive level to create themes in the data, both latent (i.e., underlying) and semantic (i.e., explicitly stated) [24, 25]. Themes were reviewed and approved by all authors. Throughout data collection and analysis, effort was made to discuss reactions to the data and potential biases.

Results

The results of the inductive thematic analysis indicated four overarching themes in the data: (1) lack of patient centered care prior to diagnosis; (2) patient misunderstanding of symptoms; (3) experienced weight stigma; and (4) diagnosis as a golden ticket to treatment and stigma-reduced care. Each of these themes is reviewed below.

Lack of patient-centered care

Lack of patient-centered care prior to diagnosis often took two forms: (1) provider miscommunication, and (2) medical gaslighting. These sub-themes are described below.

Provider miscommunication. In the beginning stages of their investigations, participants reported difficulties in communication with their primary care providers. Honey stated that she was “going back and forth continually, feeling like I wasn’t being heard, feeling like I had to fight for every… For every feeling. I had to try to justify everything I was saying.” Similarly, Abby noted: “I’d started to wake up in the morning with little bruises on my body like almost like a fingerprint. And I thought that was weird and I brought it up to her … And she was like oh that, there’s nothing wrong with that, it’s fine.” Participants described confusion and worry when they perceived that something was wrong but did not perceive they were being taken seriously by their primary care provider.

Sometimes, miscommunication made the diagnostic process even more challenging, as was the case when Bethany was asked about stretch marks by her family doctor:

I remember my family doctor asking me at one point, do you have stretch marks? And I said, ‘no, I don’t have stretch marks. Last time I had them was when I was pregnant. And that was many years ago.’ But he didn’t describe the stretch marks. I was thinking of the pregnancy stretch marks with the fine white lines. And he must have thought about Cushing’s with the striae that are wide and purple. But there was no description of them. If I had [a description], I would have shown them immediately!

Christy noted how phone appointments may have negatively impacted her diagnostic process:

All of this went down in the [COVID-19] pandemic, so I actually never met a doctor in person about this ever. … I explain the weight gain I’m like kay I was 110. Now I’m 230 and these are the bursts. These are when it happened. Um, but they actually never saw me, not once, not even over zoom it was all over the phone … When I explained how much I gained they were just like, no.

In general, participants felt like they were not receiving the care they hoped for from their primary care provider. For example, Abby said that “Cushing’s patients have a lot of things going on and most regular doctors when they see you…they think you’re a hypochondriac because there’s always something wrong with [you].” Participants perceived their primary care providers as missing the big picture. Darby recognized that “I think each time I went into the doctor for the different things, … I would go in for specific things, but we never sort of put them all together as to what it was.” In describing her frustration with this process, Emily said: “And I’m just like how many other people are struggling with stuff like this, and they just get [dismissed].” Together, this miscommunication contributed, in part, to the delayed diagnosis, as it took time for providers to recognize the possible diagnosis of Cushing’s.

Medical gaslighting. Medical gaslighting is the process by which medical professionals will downplay, dismiss, or silence a patients’ view of their illness [26]. Abby described her experience with the first primary care provider she consulted: “he basically told me that I had mental baggage, and it was that I was a head case and that was my problem.” After moving to a different city, she described the next provider she met with as having a similarly dismissing response: “I also explained to her what was going on. I said I think there’s something wrong, I exercise and the harder the exercise more I gain weight. She basically said you’re not trying hard enough and suggested the South Beach diet to me.” Besides their weight, other symptoms were also dismissed. Emily said:

It was always passed off as oh, your high-stress job, high-stress family life, you’re depressed; those were always the comments to me. You’re just depressed, you’re just anxious because of this stuff and blah blah, blah. … As time went on the symptoms started multiplying. So, I’m like it’s not just not sleeping and depressed and anxious I’m like… my resting heart rate is in the 160’s without moving um, my vision’s starting to get impaired, I feel like I’m crazy, um and then the weight gain started. And once again they just said oh you know take up, take up cycling. That’s what the doctor told me.

In describing her experiences with feeling downplayed or dismissed, Honey stated:

I had swollen hands and feet, too, so he said, Well, you’re gonna have to get your diet under control, and I said well my diet is really good actually and I’ve been going to weight watchers for a year, haven’t dropped a pound, so there’s an issue there. And again, he would just chalk it up to PMS.

Honey also experienced skin sensitivities and was told she simply needed to use sunscreen more frequently. During the diagnostic process, Christy experienced medical gaslighting when completing her 24-hour urine free cortisol test:

I did the test and waited months again for my results. And then it came back super high. And so, he accused me of doing the test wrong. He said there’s no way um this makes sense. You need to do the test again. So, then I did the test again. And it was high again. And he accused me of doing it wrong again. And I was like, I’m telling you like I don’t know what you, I’ve got the instructions in front of me. … And so I did it again, and it came back like again in the thousands. … I did feel like I was going nuts, the same way when he kept telling me I was doing the test wrong.

Patient misunderstanding of symptoms

Participants also described misunderstanding their symptoms, which highlights a further breakdown in patient-provider communication about their disease, as these misperceptions were not clarified for them upon diagnosis and treatment. Participants appeared to hyper-fixate on, and misunderstand, their weight gain. They also misunderstood other symptoms as related to weight. Emily noted this fixation on weight directly when she said: “In the very beginning I noticed the weight gain first to be honest.” Abby shared that she decided to approach a health professional because of her weight gain:

I was a happy, healthy active athletic person, and all of a sudden something in my life happened where I just kept gaining weight and gaining weight. No matter how much like exercising or eating properly that I had done… The catalyst for me going to the doctor was, um, I noticed a bunch of stretch marks on my stomach and to me that was a sign of like rapid weight gain in such a small amount of time.

Like Abby, other participants misunderstood their weight gain and attempted to engage in behavioural changes to reverse this process. Bethany said:

Thankfully I did not have a doctor that told me to go and exercise and eat less. But when you did that, you still gained weight. The more I exercised, the more walking I did, the less I ate, the more I gained and the rounder the face got. And the more hair I lost.

Similarly, Christy described her weight gain as the catalyst behind her decision to hire a personal trainer:

I kind of decided based on super significant weight gain that I was going to invest in a personal trainer… So, I was with the personal trainer for about three months, and was only gaining weight, like I was cutting calories and working out I think it was like 12 times a week. … But everything was just getting worse. Like I was weaker, I couldn’t do things the same way that I used to, like the stretch marks were nuts I kept gaining weight I didn’t know why, despite still I was still walking every day and doing what I could.

When describing their experience of symptom onset prior to receiving their diagnosis, participants understood many of their physical changes as connected to their weight gain. This was especially true for those experiences that surrounded muscle weakening and movement, despite these being Cushing’s symptoms that are independent from weight. Bethany recalls how, when called for her appointment in her primary care provider’s waiting room, she “staggered to stand up and was almost immobile to a point, I was so big,” an experience she attributed to her weight gain. As symptoms worsened, participants felt disconnected from their bodies. Emily said: “I can’t trust [my] own body,” and Christy felt “so exhausted” because “of course that’s exhausting. Like, carrying all that [weight] around is tiring. Like, if you’re not exhausted, that would be weird.”

Participants also noted a misunderstanding of other Cushing’s symptoms, both alongside and independent of their weight gain. In recognizing the impact of stress on her symptoms, Honey said:

I opened a business, and the stress came back because of that, and then everything came to a head. Then I got the bruising, then I got the buffalo shoulders, then I got the big moon face. … People were starting to say, like is your whole life okay? It was kind of insulting. And then I got the big belly, and it just got bigger and bigger, and within 3 weeks I had gained 25lbs.

Darby noted that, in the fullness of her busy life, it was easy to explain away her symptoms:

I didn’t acknowledge what was going on it, I just didn’t push to find out why. I was always able to find a reason in my own brain or my own thinking as to all, you know. You know, I’m just I’m working too much and this will pass, and then it’ll get better. Or, you know, when I was falling down for no reason, it was like oh man you just got to pay more attention. All right, you know, I need to eat better because I’m not, you know, exercising. When I was gaining the weight and went to weight watchers and some reason the weight wasn’t coming off. … And I’m thinking, I’m doing all the right stuff.

Similarly, Franny described how she perceived her symptoms to be related to anxiety:

Oh, it’s just anxiety you’re always… It’s like the palpitations Oh, it’s just you’re nervous about something. … I guess I just… in my case, like I haven’t… maybe they caught it so soon enough that, like I haven’t really got to the point where like I’m I’m feeling a lot of symptoms?

Experienced weight stigma

Participants described numerous experiences of weight stigma in healthcare while seeking a diagnosis. Invalidation occurred when patients’ personal accounts of their illness were dismissed or not taken seriously, as described in the Lack of Patient Centered Care sub-themes. While many participant experiences of medical gaslighting can also be regarded as experiences of weight stigma, these themes were differentiated by whether or not participants reported they were dismissed or silenced, consistent with the definition of gaslighting [21].

Participants contributed their negative experiences, at least in part, to their weight. Participant’s felt like there was a significant difference in how they were treated by practitioners before the onset of their Cushing’s symptoms. Christy contrasted her experiences in healthcare pre- and post- Cushing’s: “When I went to the doctor and I was concerned about something as a kid, nobody ever doubted me like. And yeah, since then … people in general just don’t get [taken] seriously looking the way that I do. And don’t respect me as much it seems.” Although Christy spoke of “people in general,” this sentiment included her primary healthcare provider. Similarly, Honey described a perceived change in her relationship with her primary care provider pre- and post- Cushing’s onset and felt that her weight contributed to this change. She described her once positive relationship as one that is now associated with hurt:

Prior to Cushing’s my doctor was very forthcoming. I would tell him what I needed if I needed, felt I needed blood work, or felt I needed anything, or suggested that I…. maybe he’s not the one to help me that I need to see a specialist he would send me on to that specialist. So, yes, I always felt hurt by him.

Abby summarized participants’ experiences when she said: “Judging books by covers that’s, that’s what the healthcare system seems to do and I do feel that, like some of my treatment was definitely due to my body [size] and what, what they preconceived that I was a fat person, so it was my fault.” Franny described having requested her entire medical file and that seeing herself repeatedly referred to as a “morbidly obese female” in emails and other communication had a negative impact on her body image and self-esteem.

Diagnosis as a golden ticket

Post-diagnosis, participants experienced a profound sense of relief and validation, perceived themselves to be lucky to have received a diagnosis, and were thankful for the subsequent treatment they received. Bethany said: “once you get a diagnosis, it doesn’t matter what the diagnosis is, you’ve got a diagnosis and now we work towards that. Let’s correct it”. Christy felt like “Having that diagnosis under my belt was like a golden ticket … everything was easier.” Abby declared that the doctor who officially diagnosed her saved her life: “She had taken the time to like, say I believe you. Instead of just seeing a fat person and blaming it on me, which is really what the healthcare system does. Really it ruins people.” After waiting three years for a diagnosis, Darby stated that she felt “very lucky” and said:

From when my doctor said to me ‘I think it’s Cushing’s’ to when the actual diagnosis was, it was fast. It was weeks. It was, it was very, very quick. …Once we actually knew what it was to actually being able to have the surgery to have the tumor removed and start reversing the process of what was going on with my body. So. I was very lucky.

In hindsight, participants noticed there was a difference in how they were treated by healthcare professionals pre- and post-diagnosis. Abby said: “I firmly believe that there is a correlation there between how I was treated before, and then how I was treated after.” She elaborated to say that: “people have to believe me now, because a specialist has said, ‘This is what I have, and you may not understand it, but I do’.” Emily noted that “after I got the diagnosis my family doctor was very, very open, and caring with moving forward. And he commended me for pushing and knowing that things were wrong, and he was really good about it, and he apologised that it took long to get figured out.” Honey also noted” “I’d have to say like during the diagnosis, not great, but since I’ve had my pituitary tumor removed great, the aftercare has been fantastic.”

Discussion

Across seven semi-structured interviews with women with endogenous Cushing’s, the results of our preliminary inquiry into the lived experience of patients suggest that both patients and providers struggle to understand the progressive and individualized presentation of Cushing’s. This struggle can come, unintentionally, at the expense of patient centered care in the form of provider miscommunication, medical gaslighting, and weight stigma. Our results also suggest that diagnosis is viewed by patients as an important turning point for both effective treatment as well as reduced stigma.

Overall, the results of our study highlight the importance of patient centered care. Participants reported miscommunication, invalidation, weight stigma, and gaslighting in their healthcare encounters, all of which are contrary to the goals of patient centered communication [11, 12]. These findings are consistent with previous research identifying structural, educational, and resourcing barriers to patient centered communication [11, 27]. These barriers include understaffing, specific healthcare settings (i.e., acute care), limited time, insufficient communication, lack of training in patient centered communication, and inadequate patient education [11, 27]. Given that patient engagement is associated with improved outcomes, a better understanding of their condition, and more awareness of resources, [27] identifying strategies to enhance patient centered communication are of critical importance. Researchers have identified staffing longevity as associated with greater engagement and less burnout [27] and have identified provider training and professional development as significant in the implementation of patient centered communication [12]. Thus, in addition to patient centered communication skills, providers require knowledge of weight stigma and Cushing’s as well as appropriately resourced work environments to enact patient-centered care. However, an important responsibility falls to broader healthcare systems to empower providers by providing comprehensive training, addressing provider burnout, and changing healthcare culture and systems to allow for increased engagement in patient centered communication [12].

The rare occurrence [6, 7] and non-specific presentation [8] of endogenous Cushing’s is a unique barrier to patient centered communication. Participants in this study recognized the impact that the rare occurrence of their disease had on their provider’s misunderstanding of their symptoms. Bethany noted one interaction whereby her primary care provider mentioned being told in medical school that they would never see a case of Cushing’s in their careers. However, knowledge of Cushing’s is a pre-requisite for early detection [6]. Such knowledge is important, as overlooking endogenous Cushing’s is associated with increased mortality rates due to hypertension, metabolic diseases, and bone-related complications, with continued cardiovascular risk persisting after treatment [8].

An additional barrier to patient centered care highlighted in our results is weight stigma. Our findings are consistent with previous qualitative research on experienced weight stigma in healthcare contexts [28,29,30,31]. In previous research, patients have consistently reported the attribution of presenting concerns by healthcare providers to weight without a full exploration of the issue as well as poor verbal and non-verbal communication [28,29,30,31]. Such experiences with poor quality communication and stigmatization from healthcare providers are associated with subsequent patient healthcare delay and avoidance, [15, 17] and may contribute to increased internalization of weight stigma [32]. Our results highlight that, for patients with endogenous Cushing’s, weight stigma may be a contributing factor in the consistently reported delays to diagnosis, [6, 7] due to stereotyped assumptions about weight gain coupled with a lack of knowledge about Cushing’s, among providers as well as patients. Although participants in this study reported symptoms beyond weight gain, they perceived their weight as having an impact on their healthcare encounters.

Our findings related to weight stigma highlight the potential harm of weight- and appearance-focused sociocultural discourses [21, 22] on Cushing’s-related healthcare. For patients, internalization of these discourses may have contributed to the extent to which they understood symptoms such as fatigue and muscle weakening as caused by their weight gain. For providers, this may have contributed to their clinical impressions and decision-making. Researchers have previously identified weight and appearance discourses as contributing to a weight-centric practice paradigm, whereby higher weights are regarded as within individual control as well as the cause of poor health [33]. Within a weight-centric paradigm, recommending weight loss is regarded as an effective health-promoting solution and failure to achieve or sustain weight loss is regarded as the fault of the patient. Criticisms of the unintended consequences of a weight-centric paradigm have prompted researchers to call for a weight-neutral approach to healthcare that recognizes and addresses weight stigma, assesses cardiometabolic and lifestyle health risks in patients across the weight spectrum, and seeks to promote the health of patients independent of changes in weight status [33].

This research was conducted as a preliminary inquiry into the lived experience of patients with Cushing’s, given the lack of such research in the literature. Our findings suggest that patient experiences are an important, but unexplored, line of inquiry and that more research is needed in this area. Given that lived experiences may differ across contexts and may vary by an individual’s culture, race, relationship status, and/or geographical location, further research is needed with larger samples to elucidate the potential impact of provider miscommunication, medical gaslighting, and weight stigma on the experiences of patients with Cushing’s throughout the diagnostic and treatment process. Future research examining Cushing’s-related healthcare experiences access gender and racial identities is also needed to fully understand the broad experiences of patients with this disease.

Limitations

To our knowledge, this is the second study to examine the lived experiences of people with Cushing’s, with only one other qualitative study examining the impact of Cushing’s on quality of life, published in Italian [34]. However, this is the first study to examine patients’ lived experiences in healthcare, as this previously published Italian study examined patients’ perceived quality of life. Despite this novelty and strength, this research is not without its limitations. First, as only seven women with Cushing’s were recruited, this preliminary inquiry is limited by sample size. Thus, the results are not generalizable to all women with Cushing’s, their healthcare providers, or their experiences in healthcare. Second, given that our participants were recruited from an online support group, their reported experiences may be different from those who have not sought such support from the online patient community. Third, our sample was limited in demographics. All participants identified as white women but did represent a broad range in age and socioeconomic status. Finally, as our participants reported a delay to diagnosis of 1.5 to 3 years, their experiences may not represent those of individuals who experienced a longer delay to diagnosis.

Conclusion

The findings of this research indicate that a lack of patient centered care may have an impact on the recognition and referral/diagnosis of Cushing’s in primary healthcare settings. Our results highlight an important area of inquiry that warrants further attention. Given the small sample size, further research is needed to clarify and to expand on these findings. However, these results highlight the importance of patient centered care and curious investigation into the causes of unexpected and uncontrollable weight gain in patient encounters.

Data availability

Data for this study is available on reasonable request to the corresponding author.

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Acknowledgements

Not applicable.

Funding

SCJ was supported by a Jamie Cassels Undergraduate Research Award.

Author information

Authors and Affiliations

  1. Department of Psychology, University of Victoria, 3800 Finnerty Rd, Victoria, BC, V8P 5C2, Canada

    Sarah C Jones

  2. Educational Psychology and Leadership Studies, University of Victoria, 3800 Finnerty Rd, Victoria, BC, V8P 5C2, Canada

    Sarah Nutter

  3. Institute on Aging and Lifelong Health, University of Victoria, 3800 Finnerty Rd, Victoria, BC, V8P 5C2, Canada

    Sarah Nutter

  4. Brigham and Women’s Hospital, 75 Francis St., Boston, MA, 02115, USA

    Jessica F Saunders

Contributions

SCJ and SN conceptualized the study. All authors contributed to the study design and SCJ conducted all interviews and transcriptions. Data analysis was conducted by SCJ and SN with support from JFS. All authors contributed to manuscript preparation.

Corresponding author

Correspondence to Sarah Nutter.

Ethics declarations

Ethics approval and consent to participate

This study received ethics approval from the Human Research Ethics Board at the University of Victoria (#21–0507). Informed consent was received from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

From https://rdcu.be/dVGRQ

 

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Cancer risk elevated for adults after Cushing’s syndrome diagnosis

Posted on October 1, 2024 by MaryO

I certainly know this to be true :(  I’m an 18 year survivor of yet another disease that I shouldn’t have gotten:  kidney cancer.

 

Key takeaways:

  • Adults with Cushing’s syndrome have a 78% higher risk for any cancer compared with controls.
  • Cushing’s syndrome is tied to a higher risk for genitourinary cancers, thyroid cancer and adrenocortical carcinoma.

Adults diagnosed with endogenous Cushing’s syndrome have a higher risk for developing cancer compared with controls without the condition, according to data published in the European Journal of Endocrinology.

In a retrospective analysis of data from the Clalit Health Services’ electronic health record database in Israel, 19% of adults with endogenous Cushing’s syndrome were diagnosed with cancer during a median follow-up of 14.7 years compared with 11.1% of adults without Cushing’s syndrome (HR = 1.78; 95% CI, 1.44-2.2).

Adults with Cushing's syndrome have an increased risk for any type of cancer vs. controls. Data were derived from Rudman Y, et al. Eur J Endocrinol. 2024;doi:10.1093/ejendo/lvae098.

Adults diagnosed with Cushing’s syndrome also had a greater risk for genitourinary cancers (HR = 1.63; 95% CI, 1.02-2.61), thyroid cancer (HR = 3.68; 95% CI, 1.68-8.01) and adrenocortical carcinoma (HR = 24.72; 95% CI, 2.89-211.56) than controls.

Amit Akirov

“Our study is the first to demonstrate an elevated cancer risk in patients with Cushing’s syndrome, highlighting the importance of raising awareness and the need to establish guideline recommendations for cancer screening in this population, especially for genitourinary, thyroid and gynecological cancers,” Amit Akirov, MD, associate professor in the faculty of medicine at Tel Aviv University and in the Endocrine Institute at Rabin Medical Center in Petach-Tikva, Israel, told Healio.

Akirov and colleagues obtained health record data for 609 adults diagnosed with Cushing’s syndrome from 2000 to June 2023 (mean age at diagnosis, 48.1 years; 65% women; 41.2% with Cushing’s disease, 32.8% with adrenal Cushing’s syndrome; 25.9% with undetermined etiology). Those with Cushing’s syndrome were matched, 1:5, by age, sex, socioeconomic status and BMI with a control group of 3,018 adults who were never tested for hypercortisolism. The outcome of interest was the first diagnosis of any malignant cancer after Cushing’s syndrome diagnosis with the except of nonmelanoma skin cancer.

The increased risk for cancer among those with Cushing’s syndrome was observed both among adults younger than 60 years (HR = 2.15; 95% CI, 1.63-2.84) and those aged 60 years and older (HR = 1.42; 95% CI, 1.02-1.98). Adults with obesity and Cushing’s syndrome had a higher risk for cancer than those with obesity and no hypercortisolism (HR = 2.21; 95% CI, 1.44-3.4). No difference in cancer risk was seen among adults without obesity.

Akirov told Healio that the researchers suspected the presence of Cushing’s syndrome could increase cancer risk prior to conducting the study.

“While some studies suggest that excess growth hormone or prolactin may be linked to an increased cancer risk, this association had not been previously examined in patients with Cushing’s syndrome,” Akirov said in an interview. “However, we hypothesized that elevated cortisol levels could provide a foundation for tumor development.”

Adults with Cushing’s disease had a higher risk for any cancer (HR = 1.65; 95% CI, 1.15-2.36) and gynecological cancers (HR = 3.65; 95% CI, 1.16-11.52) than matched controls. Those with adrenal Cushing’s syndrome had an increased risk for any malignancy (HR = 2.36; 95% CI, 1.7-3.29), lung cancer (HR = 3.06; 95% CI, 1.11-8.42), genitourinary cancers (HR = 2.42; 95% CI, 1.22-4.82), thyroid cancer (HR = 4.97; 95% CI, 1.24-19.87) and adrenocortical carcinoma diagnosed more than 5 years after Cushing’s syndrome diagnosis (HR = 19.73; 95% CI, 2.21-176.5) than controls.

More research is needed to confirm the findings, further assess which cancers adults with Cushing’s syndrome are at the greatest risk for being diagnosed with and whether there are any predictors for cancer in Cushing’s syndrome, according to Akirov.

For more information:

Amit Akirov, MD, can be reached at amit.akirov@gmail.com.

Published by:endocrine today logo
Sources/Disclosures

Disclosures: Akirov reports receiving occasional scientific fees for consulting and serving on advisory board for CTS Pharma, Medison and Neopharm. Please see the study for all other authors’ relevant financial disclosures.

 

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‘Cortisol Face’ Is Real, But It’s Not As Common As You Might Think

Posted on September 6, 2024 by MaryO

Across social media platforms, the hashtag “#cortisolface” has gained traction, with many users claiming that facial swelling and puffiness are due to elevated cortisol levels. Influencers often start their videos with statements like, “You’re not ugly, you just have cortisol face,” and promote various remedies and lifestyle changes as solutions. However, experts warn that although high cortisol can contribute to these symptoms, it is not the sole cause of facial puffiness.

Before blindly believing social media trends, it’s crucial to explore the underlying causes, which might include medications, health conditions or lifestyle factors. Addressing high cortisol levels requires a different approach than what many of these social media influencers suggest.

Dr. Maria Olenick, associate professor at Texas A&M University School of Nursing, offers valuable insights into the concept of “cortisol face,” its effects on the body, and methods for lowering cortisol levels.

What Is ‘Cortisol Face’?

Although high cortisol levels are a factor in some cases of facial swelling and puffiness, the symptom is not as common as social media is making it out to be. In some cases, it’s not cortisol but the foods you eat. For example, eating a meal or snack that’s high in sodium can make you feel bloated because the salt can cause you to retain fluid and look a little puffier than normal.

“Some of the more severe things like moon face and other symptoms are what you might consider a serious issue when a person should really go and see their health care provider, because that would require some medical diagnosis,” Olenick said.

Moon face—or moon facies, in medical terminology—describes an increase of facial swelling due to high cortisol levels. This is a more serious condition that doesn’t just appear or disappear from one day to the next.

How Does Cortisol Affect The Body?

Cortisol is referred to as the body’s “built-in alarm system” because it plays a crucial role in the body’s response to stress, metabolism, immune activity and maintaining homeostasis. The amount of cortisol produced will differ from day to day due to different mental and physical stressors.

“Among healthy individuals, cortisol follows a diurnal pattern in which levels are higher upon waking, increase significantly over about 30 minutes, and steadily decrease from the peak throughout the rest of the day, reaching the nadir in the middle of the night,” said Olenick, whose research focuses on effective stress management techniques and therapies for veterans dealing with post-traumatic stress disorder (PTSD).

Hormones act as chemical messengers working through your bloodstream to regulate various bodily functions. Cortisol, often called the stress hormone, utilizes receptors that receive and use the hormone in different ways by communicating with your brain to control your mood, motivation and fear.

Different ways cortisol reacts and adapts to cope in a stress state include:

  • Regulating blood pressure
  • Regulating metabolism
  • Regulating blood sugar
  • Managing how your body uses carbohydrates, fats and proteins
  • Suppressing inflammation
  • Helping control your sleep/wake cycle
  • Aiding in forming memories

Cortisol secretion is regulated by a hormonal axis through a feedback loop that involves your hypothalamus, pituitary gland, adrenal glands and certain hormones known as the hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus and pituitary gland in your brain monitor your blood’s cortisol levels before signaling the adrenal glands, which sit on top of each kidney. When a change in cortisol levels is detected, your adrenal glands react to these signals by adjusting the amount of cortisol needed to be released.

The feedback system starts when the hypothalamus detects stress and releases corticotrophin-releasing hormone (CRH) accordingly. This hormone travels into the pituitary gland, signaling it to secrete adrenocorticotropic hormone (ACTH). ACTH will then make its way to the adrenal glands, stimulating them to produce cortisol. Once produced, cortisol is released into the bloodstream, where it helps regulate various functions including stress response, metabolism and immune activity. The HPA axis feedback loop is completed when cortisol levels rise and signal the hypothalamus to reduce CRH production, which maintains an effective secretion loop.

What Causes High Cortisol Levels?

Cortisol is increased at times of stress for your body, but our bodies aren’t designed to handle long-term stress. When there’s too much cortisol or an excess amount of cortisol produced, it can cause major changes in your body’s everyday functions.

Chronic emotional or physical distress can lead to sustained high levels of cortisol as part of the body’s stress response system. Stress activates signals that prompt the adrenal glands to release hormones like adrenaline and cortisol, leading to an increased heart rate and heightened energy for the fight-or-flight response.

Cortisol temporarily suppresses non-essential functions such as digestion, reproduction and inflammation in the short term to prepare for danger. However, if stress is constant, this response can remain active, which can negatively impact many bodily functions such as sleep, weight management, memory, focus and mental health. Chronic stress can also increase the risk of anxiety, depression, digestive issues, headaches, muscle tension, pain and high blood pressure.

However, stress is not the only culprit for excess cortisol levels. It could indicate serious underlying health issues.

“You need to make sure that if you are having issues with cortisol levels that you don’t really have a tumor or something more serious. If you feel like you are having symptoms and they’re not resolved by implementing lifestyle changes, make sure you see a health care provider, because that could be something very different and it might need significant medical care,” Olenick said.

Cushing Syndrome

Cushing syndrome, also known as hypercortisolism, is characterized by excessive levels of cortisol in the body. Prolonged use of corticosteroid medications can result in exogenous Cushing syndrome, where the excess cortisol originates from external sources rather than the body’s own production. One common cause of high cortisol levels is the use of glucocorticoid medications, such as prednisone, which are prescribed for inflammatory conditions like asthma, rheumatoid arthritis and lupus.

“Sometimes people are on steroids such as prednisone for a different condition. When you’re taking steroids, if you start to show signs of serious cortisol issues, talk to your provider,” Olenick said.

Another significant cause of Cushing syndrome is pituitary tumors that secrete excessive amounts of ACTH, which overstimulates the adrenal glands to produce more cortisol. This form of Cushing syndrome, known as Cushing disease, is attributed to benign pituitary adenomas and accounts for a large proportion of cases in both adults and children. Effective management of Cushing syndrome involves addressing the underlying cause, which may include surgical removal of tumors or adjusting medication regimens to reduce cortisol levels and mitigate associated health challenges.

Adrenal gland tumors can also contribute to high cortisol levels. These tumors may be benign or malignant, leading to similar symptoms as those caused by pituitary tumors. Tumors affecting either the pituitary gland or adrenal glands can lead to elevated cortisol levels, but most of these tumors are noncancerous and may be manageable with proper medical care.

Understanding the underlying causes of high cortisol levels is crucial for appropriate diagnosis and treatment, as the medical implications of these conditions extend beyond the portrayals seen in popular media.

What Are Common Symptoms Of High Cortisol Levels?

Having the right cortisol balance is essential for your health, and producing too much or too little can cause health problems, including:

  • Puffiness or weight gain in the face
  • Weight gain in the midsection or abdomen
  • Excess fat behind the neck, above the back
  • Memory and concentration problems, or brain fog
  • Trouble sleeping, or insomnia
  • Severe fatigue
  • High blood pressure
  • Psychiatric disturbances

Symptoms may vary, so the only real way to validate if your cortisol levels are higher than normal is to get them checked, either with blood, urine or saliva tests. When Olenick evaluates cortisol levels in veterans for PTSD research, her preferred method is to collect samples of saliva. A saliva test can be conducted at home, but it’s most effective when collected at different times throughout the day.

How Can Someone Lower Their Cortisol Levels?

Maintaining a healthy diet, sticking to a regular sleep schedule and incorporating regular, moderate exercise can all help lower cortisol. It’s also important to manage stress effectively; this can involve finding healthy ways to cope with stress, such as talking to someone you trust or allowing yourself time to relax and unwind. Self-care is crucial—taking breaks and engaging in activities that rejuvenate you is not a waste of time but a necessary part of maintaining balance.

Avoid extreme measures like severe caloric restriction or high-intensity workouts, which can increase cortisol levels due to the stress they place on the body. Instead, go for low-intensity exercises like walking. Additionally, Olenick says natural remedies and supplements, such as apple cider vinegar and vitamins, may support cortisol management, but it’s wise to monitor their effects and consult with a health care provider if needed. Ultimately, finding a balance between self-care, stress management and maintaining a healthy lifestyle is key to controlling cortisol levels effectively.

“There are a lot of things you can do to regulate your cortisol, like eating well, sleeping well and lowering our stress. Basically, things to take care of ourselves,” Olenick said.

Olenick says social media platforms are great attention grabbers, but it’s important to take health trends with a grain of salt and pay attention to your body’s needs. If you relate to any of the symptoms and feel concerned about your cortisol levels, notify your health care provider and seek medical attention.

This article by Teresa Saenz originally appeared on Vital Record.

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

Cushing’s Syndrome Masquerading as Fibromyalgia: A Case Series

Posted on September 2, 2024 by MaryO

​Abstract

Three young female patients with a history of generalized body pain were diagnosed with fibromyalgia. They visited several specialities which related patients’ symptoms to their previous diagnosis of fibromyalgia and were treated symptomatically. These patients developed a multitude of clinical features including fractures, hypertension, abnormal weight gain, proximal myopathic pain and bruising. They were seen by rheumatologists whose assessment was that their clinical features were not entirely due to fibromyalgia and suspected that patients have a possible underlying endocrine cause. Patients were referred to an endocrinologist for further tests with suspicion of Cushing’s syndrome. Laboratory tests and imaging confirmed a diagnosis of Cushing’s syndrome. Two of them had adrenal adenoma and one had iatrogenic corticosteroid use. These cases emphasize the need for thorough clinical evaluation for patients who are thought to have fibromyalgia. Fibromyalgia is a diagnosis of exclusion.

Introduction

Fibromyalgia is a chronic functional neurosensory disorder characterized by diffuse musculoskeletal pain, fatigue, and insomnia [1]. The exact cause is yet to be understood and the diagnosis relies solely on the patient’s history as physical examination, imaging, and laboratory tests are usually normal making it a diagnosis of exclusion.

Cushing’s syndrome is an endocrine disorder caused by an increase in cortisol level in the body due to either exogenous glucocorticoid administration or endogenous overproduction of cortisol due to adrenal adenoma, pituitary adenoma, or ectopic paraneoplastic foci [2].

Patients may present with central obesity, easily bruised skin, purple abdominal striae, osteoporosis and pathological fractures, secondary hypertension, hyperglycemia, fatigue, and proximal muscle weakness.

We herein report three cases of patients who had diffuse muscle pain and were misdiagnosed as fibromyalgia without ruling out endocrinological causes such as Cushing’s syndrome which they were found to have.

Case Presentation

Case report 1

A 38-year-old Egyptian female with a history of fibromyalgia presented to the urgent care in November 2020 with right little toe pain and swelling after hitting it against the wall. She had a fracture of the distal phalanx of the fifth toe (Figure 1) and was managed conservatively.

X-ray-of-right-foot-showed-fracture-at-the-distal-phalanx-of-fifth-toe-with-suspected-intra-articular-extension
Figure 1: X-ray of right foot showed fracture at the distal phalanx of fifth toe with suspected intra-articular extension

In January 2022, she presented to her gynaecologist with headache, body swelling and was found to be hypertensive (156/105mmHg). She was referred to cardiology for management of hypertension, who recommended keeping a blood pressure (BP) diary with one-week follow-up as her BP was high on one occasion only.

In May 2022, she visited an internist because of easy bruising for six years in both lower limbs and history of bleeding following dental procedure. She was also complaining of gaining weight (15 kg over seven months). Investigations including coagulation profile, serum electrolyte, blood glucose, liver enzymes, and autoimmune antibodies were ordered, and they were normal. Patient was reassured and was diagnosed as purpura simplex.

In September 2022, she had a visit to the cardiologist after she was diagnosed with hypertension in Egypt and was on ramipril (2.5mg) and torsemide (10mg). The cardiologist continued ramipril and discontinued torsemide. The cardiologist referred her to internal medicine because of her history of fibromyalgia, and review of her prescribed medications from Egypt which included duloxetine, hydroxychloroquine (HCQ), and melatonin.

She had multiple visits to internists between September 2022 and March 2023 with complaints of body swelling, generalized joint stiffness, hip pain, proximal myopathic pain when lifting arms or standing up with oral ulcers and small reddish-purple spots just beneath the skin’s surface most likely purpura simplex. Laboratory tests were ordered, and they showed she had low serum potassium and positive antinuclear antibody (ANA) titer (DFS-70 pattern). Also, she had negative rheumatoid factor (RF), extractable nuclear antigen (ENA) panel, antineutrophil cytoplasmic antibodies (ANCA) and anti-cyclic citrullinated peptide (CCP) with normal C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). She was given potassium supplements and magnesium. During her visits she was prescribed various medications for fibromyalgia including duloxetine, amitriptyline, and tramadol. She also developed back pain and her MRI of sacroiliac joints showed signs of left-sided linear sacrum fracture, crescentic subchondral edema in the right femoral head suggestive of avascular necrosis (AVN) and narrowing of L5/S1 intervertebral disc space with degenerative changes (Figure 2).

MRI-sacroiliac-joints-showed-left-sided-linear-sacrum-fracture
Figure 2: MRI sacroiliac joints showed left-sided linear sacrum fracture

She then visited an orthopedic surgeon in April 2023 with back and right hip pain. The orthopedic doctor thought that her symptoms and signs were not entirely consistent with fibromyalgia, and she was referred to rheumatology for further review.

On rheumatology review she gave a history of whole-body pain, back pain, severe right hip pain, two fractures (left foot and sacrum), hypertension, hypokalaemia, amenorrhea for 18 months, weight gain (of 15 kg over seven months) and skin bruising. Laboratory tests showed negative autoimmune tests, low serum potassium, high alkaline phosphatase (ALP), normal parathyroid hormone (PTH), Mg, vitamin D and calcium. She was referred to internal medicine for low serum potassium, with suspicion of adrenocortical excess.

Her internist suspected Cushing’s syndrome as her physical examination showed that she was obese with florid purple striae on the trunk and arms in addition to proximal muscle weakness . He then ordered investigations that showed low adrenocorticotropic hormone (ACTH) using electrochemiluminescence immunoassay (ECLIA) of <1 pg/mL (normal range 7.2-63.3 pg/mL), and high serum cortisol using chemiluminescence microparticles immunoassay (CMIA) at 5 pm of 604.03 nmol/L (normal range 79.0-478 nmol/L). Her cortisol before 10 am that was collected at 9:02 am was 623.91 nmol/L (normal range 101-536 nmol/L). In view of these values, she was referred to the endocrinologist. Serum aldosterone, renin, and their ratio were all normal. 24-hour urinary cortisol was inconclusive because of low volume of urine. Luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), prolactin, metanephrines and normetanephrines were normal. It was planned to do overnight dexamethasone suppression tests (ODST), but patient travelled to Egypt.

CT abdomen showed a 3.2×2×3 cm well-defined lesion arising from the junction between the arms of the right adrenal gland showing inhomogeneous density with inhomogeneous enhancement after IV contrast administration with delayed washout, the maximum enhancement after the IV contrast administration at the portal phase about 55 Hounsfield units (HU) indicating a right adrenal adenoma (Figure 3). CT sacrum showed fragmented fracture inferior ramus of right pubic bone associated with callus formation and significant fragmented fracture lateral part of superior ramus of right pubic bone associated with callus formation (Figure 4). MRI hips showed avascular necrosis of the right femur head (stage II according to Ficat and Arlet classification) (Figure 5), which was treated with core decompression surgery.

CT-adrenal-showed-a-3.2×2×3-cm-well-defined-inhomogeneous-density-lesion-arising-from-the-junction-between-the-arms-of-the-right-adrenal-gland-consistent-with-adrenal-adenoma
Figure 3: CT adrenal showed a 3.2×2×3 cm well-defined inhomogeneous density lesion arising from the junction between the arms of the right adrenal gland consistent with adrenal adenoma
CT-pelvis-showed-fragmented-fracture-at-the-inferior-and-superior-ramus-of-right-pubic-bone-associated-with-callus-formation.-Subcortical-ill-defined-lytic-area-is-noted-at-the-right-humeral-head-surrounded-with-sclerotic-reaction-could-be-due-to-avascular-necrosis-(AVN)
Figure 4: CT pelvis showed fragmented fracture at the inferior and superior ramus of right pubic bone associated with callus formation. Subcortical ill-defined lytic area is noted at the right humeral head surrounded with sclerotic reaction could be due to avascular necrosis (AVN)
MRI-of-the-pelvis-showed-subcortical-geographic-area-at-the-right-femoral-head-with-inhomogeneous-signal-intensity-(edematous-and-sclerotic-changes)-mostly-due-to-avascular-necrosis-(stage-II-according-to-Ficat-and-Arlet-classification)
Figure 5: MRI of the pelvis showed subcortical geographic area at the right femoral head with inhomogeneous signal intensity (edematous and sclerotic changes) mostly due to avascular necrosis (stage II according to Ficat and Arlet classification)

She had the surgery to remove the adrenal adenoma in Egypt and histopathology confirmed the diagnosis. She was then started on corticosteroids as she had low serum cortisone levels after her surgery. Currently she is also taking duloxetine and calcium/vitamin D. She developed a fracture at the right femoral neck after a fall and had hip replacement in Egypt (Figure 6).

X-ray-of-the-right-hip-joint-showed-signs-of-right-hip-joint-replacement
Figure 6: X-ray of the right hip joint showed signs of right hip joint replacement

Case report 2

A 47-year-old Bangladesh female presented with a complex array of symptoms initially suggestive of fibromyalgia. The patient reported chronic widespread muscle and joint pain, with identification of approximately eight tender points during examination. These symptoms, coupled with fatigue, were initially thought to be fibromyalgia due to their nonspecific nature. Subsequently, the patient started to have multiple bone fractures. In total she had six fractures over one year including fractures of the superior and inferior pubic ramus on the left side, right metatarsal bone fracture, fracture of the left proximal shaft of the fifth metatarsal, fractures of the shafts of the third and fourth left metatarsal. She has been reviewed by multiple physicians. A deeper look at her medical history revealed that despite the absence of overt Cushingoid features, she has several medical problems, including newly diagnosed hypertension and type 2 diabetes mellitus (hemoglobin A1C (HbA1C) 7.3%), raising the possibility of an underlying endocrine disorder. Psychiatric concerns involve a history of anxiety, insomnia, and major depressive disorder, with medication adjustments made independently. In addition, the patient reported irregular menstrual cycles, further complicating the clinical picture. Subtle signs such as unexplained central weight gain and telangiectasia prompted further endocrine evaluation.

Elevated morning cortisol levels and non-suppressed cortisol on an overnight 1 mg dexamethasone suppression test with high am cortisol, low am ACTH, ODST showed non-suppressed cortisol >400, and >500 on two occasions, and 24-hour urine free cortisol is high = 483 nmol (28-138). Adrenal CT without contrast revealed a well-defined heterogeneous isodense-to-hypodense lesion in the left adrenal gland, measuring 3.2 x 2.4 cm with a density of 16 HU, indicative of an adrenal adenoma. Imaging also identified old fractures of the left 10th rib and transverse processes of L1 and L4, which were previously undocumented and suggested underlying bone fragility.

The combination of subtle endocrine symptoms, nonspecific musculoskeletal pain, and psychological components initially led to a misdiagnosis of fibromyalgia. However further endocrine investigation confirmed Cushing’s syndrome due to an adrenal adenoma (Figure 7).

CT-adrenal-showed-a-3.2-x-2.4-cm-well-defined-hypodense-lesion-in-left-adrenal-gland
Figure 7: CT adrenal showed a 3.2 x 2.4 cm well-defined hypodense lesion in left adrenal gland

The patient underwent successful laparoscopic removal of the left adrenal adenoma. Post-operatively, the patient developed adrenal insufficiency, necessitating a carefully managed hydrocortisone tapering regimen. Management of diabetes, hypertension, and psychiatric symptoms continued, with adjustments anticipated in response to changes in endocrine status post-adrenectomy. The patient was started on calcium and vitamin D supplementation to address the secondary osteoporosis.

Case report 3

A 35-year-old Emirati woman with a medical history of hypothyroidism, asthma, obstructive sleep apnea, scoliosis, secondary degenerative lumbosacral changes from a previous accident, and migraines sought consultation at the Department of Rheumatology.

She reported a two-year history of polyarthralgia, proximal muscle weakness, profound fatigue, and peripheral edema. BP was 148/88. Physical examination revealed a round face, dorsocervical fat pad, central obesity, and puffy hands and feet.

Laboratories revealed hemoglobin (Hb) 13 g/l, creatinine kinase (CK) normal, while CRP was high (7 mg/l). Weakly positive anti-NOR 90 antibodies were found and noted to have unclear etiology with no clinical manifestation of scleroderma. Vitamin D deficiency was corrected (level: 47 nmol/L, normal range 50-150 nmol/L), and hypothyroidism medication was adjusted (TSH 7.7 IU/L, T4 9, normal range 12-22).

Despite extensive evaluations, including bilateral hands and feet X-rays, MRI of the hand, PET scan and laboratory assessments, the etiology of her symptoms remained elusive. Following a provisional diagnosis of fibromyalgia, the patient was managed symptomatically with medications, including pregabalin, amitriptyline, and duloxetine for one year. However, her symptoms persisted.

Further investigations revealed low serum cortisol levels: a morning cortisol level of 20 nmol/l (64-536), ACTH <0.3 pg/ml (1.6-13.9), and a 24-hour urine cortisol level of 11 nmol (28-138 nmol). Dual-energy X-ray absorptiometry (DEXA) scan demonstrated low bone mineral density with highest value at the lumbar sites (L2-L4), with a T-score of -2.4. Upon detailed review, it was noted that the individual had a history of frequent injections in both sacroiliac and lumbar facet joints, as well as trigger point injections ranging from 80-120 mg, administered every two to three months over a period of two years. Given the overall picture, with adequate adrenal response to synacthen test (the synacthen test results were as follows: baseline ACTH level was 1.2 pmol/L, rising to 0.8 pmol/L at 30 minutes and 0.4 pmol/L at 60 minutes; corresponding cortisol levels were 52 nmol/L at baseline, increasing to 433 nmol/L at 30 minutes and 472 nmol/L at 60 minutes), this was correlated with the diagnosis of iatrogenic Cushing’s syndrome.

A summary of the cases is in Table 1, and the timeline of the cases is in Table 2.

Case Age Gender BMI Steroid (Exogenous vs Endogenous) HTN DM Hyperlipidemia Psychiatric symptoms Fracture Abnormal Test Results Treatment
Case 1 38 F 31.4 Endogenous- adrenal adenoma Yes No  No No Four fractures Low potassium, low ACTH (<1pg/mL), high serum cortisol (604.03 nmol/L) Adrenal adenoma surgical resection
Case 2 48 F 26 Endogenous- adrenal adenoma Yes Yes  Yes Depression on Rx Six fractures Low ACTH (<0.3 pmol/L), high serum cortisol (1104 nmol/L), 24-hour urine free cortisol is high = 483 nmol (28-138) Adrenal adenoma surgical resection
Case 3 35 F 38 Exogenous Yes No No Depression and anxiety on Rx – Low serum cortisol 20 nmol/l (64-536), low ACTH <0.3 pg/ml (1.6-13.9), 24-hour urine cortisol 11 nmol (28-138). Refrain from injection
Table 1: Summary of patients with Cushing syndrome who presented with fibromyalgia

F: female, HTN: Hypertension, DM: Diabetes Mellitus, Rx: Treatment, ACTH: Adrenocorticotropic hormone

Case Timeline of clinical features Final diagnosis date
Case 1 Bruises, myalgia, body pain since 2016; headache, body swelling since 2020; hypertension since 2021; hip pain since Jan 2022; fractured toe in Nov 2022; fracture of pubic rami discovered incidentally in April 2023; avascular necrosis of right hip in April 2023 May 2023 she was diagnosed with Cushing syndrome due to adrenal adenoma
Case 2 Widespread muscle and joint pain in 2017; hypertension and type 2 diabetes mellitus in 2019; multiple fractures in 2020-2021; anxiety, insomnia, and major depressive illness in 2020; menstrual irregularities in July 2021 November 2021 she was diagnosed with Cushing syndrome due to adrenal adenoma
Case 3 Polyarthralgia, proximal muscle weakness, profound fatigue, and peripheral oedema in 2021-2023; depression and anxiety in 2022; hypertension in 2023; low bone mineral density in 2023 June 2023 exogenous Cushing syndrome
Table 2: Timeline of the three cases

Discussion

Fibromyalgia is a multifactorial painful body disorder with several hypotheses regarding its etiology and pathophysiology such as increased pain sensitivity, neuroendocrine axis dysregulation, hypermobile joints, poor physical fitness, as well as genetic predisposition and environmental triggers [3].

Fibromyalgia and Cushing’s syndrome are distinct medical conditions, but they can share some common symptoms such as fatigue, muscle weakness, mood changes, sleep disturbances, and memory deficits. Because of the multiple symptoms that are present in both, a patient could be misdiagnosed with fibromyalgia instead of Cushing’s syndrome if proper history-taking, physical examination and relevant investigation are not pursued. Fibromyalgia is a diagnosis of exclusion, so effort should be made to look for any possible cause of the patient’s symptoms before making a diagnosis of fibromyalgia. According to the American College of Rheumatology, a patient must satisfy these three conditions to be diagnosed with fibromyalgia: widespread pain index (WPI) ≥7 and symptom severity (SS) scale score ≥5 or WPI 3-6 and SS scale score ≥9, symptoms have been present at a similar level for at least three months, and the patient does not have a disorder that would otherwise explain the pain [4].

According to the 2008 Endocrine Society guidelines, Cushing syndrome’s diagnosis is made by lab tests that show consistently high production of cortisol using 24-hour urine free cortisol level, low-dose (1mg) dexamethasone suppression test, or late-night salivary or serum cortisol [5].

A literature review was performed using PubMed and Google Scholar databases. Search terms included “fibromyalgia” and “Cushing’s syndrome” to which five results were shown. Out of the five results, only one case report had slight relevance to our two cases which was about a 39-year-old woman previously diagnosed with Cushing’s disease who developed fibromyalgia [1]. Unlike our cases, she was already diagnosed with Cushing’s disease. Several cases of iatrogenic Cushing’s syndrome are widely recognized [6-10]. Although intra-articular corticosteroid injections are uncommon causes, they are becoming increasingly recognized especially in patients who have received multiple or relatively high doses [11-13].

Our patients saw different physicians from various specialties and had multiple hospital visits over two to three years. They were originally diagnosed with fibromyalgia. Despite a multitude of other symptoms and signs such as fractures, weight gain, amenorrhea, easy bruising, and hypertension, the initial diagnosis of fibromyalgia was carried forward by multiple physicians without proper re-evaluation, resulting in only symptomatic treatment. These cases highlight the importance of thorough clinical evaluation and a holistic approach to patients who present with fibromyalgia symptoms even if a previous diagnosis of fibromyalgia has been made.

Conclusions

These cases underscore the challenges in differentiating Cushing’s syndrome from other conditions, particularly when presenting with nonspecific symptoms similar to fibromyalgia. Heightened clinical suspicion, thorough evaluation, and consideration of medication histories are essential. A high index of suspicion, combined with targeted radiological and biochemical testing, is crucial for accurate diagnosis and effective management.

References

  1. Ohara N, Katada S, Yamada T, et al.: Fibromyalgia in a patient with Cushing’s disease accompanied by central hypothyroidism. Intern Med. 2016, 55:3185-90. 10.2169/internalmedicine.55.5926
  2. Sharma ST, Nieman LK, Feelders RA: Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015, 7:281-93. 10.2147/CLEP.S44336
  3. Coles ML, Weissmann R, Uziel Y: Juvenile primary fibromyalgia syndrome: epidemiology, etiology, pathogenesis, clinical manifestations and diagnosis. Pediatr Rheumatol Online J. 2021, 19:22. 10.1186/s12969-021-00493-6
  4. Wolfe F, Clauw DJ, Fitzcharles MA, et al.: The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken). 2010, 62:600-10. 10.1002/acr.20140
  5. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125
  6. Psomadakis C, Tweddell R, Lewis F: Too much of a good thing? Iatrogenic Cushing syndrome secondary to excessive topical steroid use in lichen sclerosus. Clin Exp Dermatol. 2023, 48:429-30. 10.1093/ced/llac097
  7. Jones W, Chastain CA, Wright PW: Iatrogenic cushing syndrome secondary to a probable interaction between voriconazole and budesonide. Pharmacotherapy. 2014, 34:e116-9. 10.1002/phar.1432
  8. Fredman R, Tenenhaus M: Cushing’s syndrome after intralesional triamcinolone acetonide: a systematic review of the literature and multinational survey. Burns. 2013, 39:549-57. 10.1016/j.burns.2012.09.020
  9. Sadarangani S, Berg ML, Mauck W, Rizza S: Iatrogenic cushing syndrome secondary to ritonavir-epidural triamcinolone interaction: an illustrative case and review. Interdiscip Perspect Infect Dis. 2014, 2014:849432. 10.1155/2014/849432
  10. Sukhumthammarat W, Putthapiban P, Sriphrapradang 😄 Local injection of triamcinolone acetonide: a forgotten aetiology of Cushing’s syndrome. J Clin Diagn Res. 2017, 11:OR01-2. 10.7860/JCDR/2017/27238.10091
  11. Tan JW, Majumdar SK: Development and resolution of secondary adrenal insufficiency after an intra-articular steroid injection. Case Rep Endocrinol. 2022, 2022:4798466. 10.1155/2022/4798466
  12. Alidoost M, Conte GA, Agarwal K, Carson MP, Lann D, Marchesani 😧 Iatrogenic Cushing’s syndrome following intra-articular triamcinolone injection in an HIV-infected patient on cobicistat presenting as a pulmonary embolism: case report and literature review. Int Med Case Rep J. 2020, 13:229-35. 10.2147/IMCRJ.S254461
  13. Kumar S, Singh RJ, Reed AM, Lteif AN: Cushing’s syndrome after intra-articular and intradermal administration of triamcinolone acetonide in three pediatric patients. Pediatrics. 2004, 113:1820-4. 10.1542/peds.113.6.1820

 

From https://www.cureus.com/articles/264073-cushings-syndrome-masquerading-as-fibromyalgia-a-case-series#!/

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