Adrenal Fatigue: Faux Diagnosis?

Posted on November 30, 2021 by MaryO

This article is based on reporting that features expert sources.

U.S. News & World Report

Adrenal Fatigue: Is It Real?

You may have heard of so-called ‘adrenal fatigue,’ supposedly caused by ongoing emotional stress. Or you might have come across adrenal support supplements sold online to treat it. But if someone suggests you have the controversial, unproven condition, seek a second opinion, experts say. And if someone tries to sell you dietary supplements or other treatments for adrenal fatigue, be safe and save your money.

Tired man sitting at desk in modern office

(GETTY IMAGES)

Physicians tend to talk about ‘reaching’ or ‘making’ a medical diagnosis. However, when it comes to adrenal fatigue, endocrinologists – doctors who specialize in diseases involving hormone-secreting glands like the adrenals – sometimes use language such as ‘perpetrating a diagnosis,’ ‘misdiagnosis,’ ‘made-up diagnosis,’ ‘a fallacy’ and ‘nonsense.’

About 20 years ago, the term “adrenal fatigue” was coined by Dr. James Wilson, a chiropractor. Since then, certain practitioners and marketers have promoted the notion that chronic stress somehow slows or shuts down the adrenal glands, causing excessive fatigue.

“The phenomenon emerged from the world of integrative medicine and naturopathic medicine,” says Dr. James Findling, a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin. “It has no scientific basis, and there’s no merit to it as a clinical diagnosis.”

An online search of medical billing code sets in the latest version of the International Classification of Diseases, or the ICD-10, does not yield a diagnostic code for ‘adrenal fatigue’ among the 331 diagnoses related either to fatigue or adrenal conditions or procedures.

In a March 2020 position statement, the American Association of Clinical Endocrinologists and American College of Endocrinology addressed the use of adrenal supplements “to treat common nonspecific symptoms due to ‘adrenal fatigue,’ an entity that has not been recognized as a legitimate diagnosis.”

The position statement warned of known and unknown health risks of off-label use and misuse of hormones and supplements in patients without an established endocrine diagnosis, as well as unnecessary costs to patients and the overall health care system.

Study after study has refuted the legitimacy of adrenal fatigue as a medical diagnosis. An August 2016 systematic review combined and analyzed data from 58 studies on adrenal fatigue including more than 10,000 participants. The conclusion in a nutshell: “Adrenal fatigue does not exist,” according to review authors in the journal BMC Endocrine Disorders.

Adrenal Action

You have two adrenal glands in your body. These small triangular glands, one on top of each kidney, produce essential hormones such as aldosterone, cortisol and male sex hormones such as DHEA and testosterone.

Cortisol helps regulate metabolism: How your body uses fat, protein and carbohydrates from food, and cortisol increases blood sugar as needed. It also plays a role in controlling blood pressure, preventing inflammation and regulating your sleep/wake cycle.

As your body responds to stress, cortisol increases. This response starts with signals between two sections in the brain: The hypothalamus and the pituitary gland, which act together to release a hormone that stimulates the adrenal glands to make cortisol. This interactive unit is called the hypothalamic pituitary adrenal axis.

While some health conditions really do affect the body’s cortisol-making ability, adrenal fatigue isn’t among them.

“There’s no evidence to support that adrenal fatigue is an actual medical condition,” says Dr. Mary Vouyiouklis Kellis, a staff endocrinologist at Cleveland Clinic. “There’s no stress connection in the sense that someone’s adrenal glands will all of a sudden just stop producing cortisol because they’re so inundated with emotional stress.”

If anything, adrenal glands are workhorses that rise to the occasion when chronic stress occurs. “The last thing in the body that’s going to fatigue are your adrenal glands,” says Dr. William F. Young Jr., an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota. “Adrenal glands are built for stress – that’s what they do. Adrenal glands don’t fatigue. This is made up – it’s a fallacy.”

The idea of adrenal glands crumbling under stress is “ridiculous,” Findling agrees. “In reality, if you take a person and subject them to chronic stress, the adrenal glands don’t shut down at all,” Findling says. “They keep making cortisol – it’s a stress hormone. In fact, the adrenal glands are just like the Energizer Bunny – they just keep going. They don’t stop.”

Home cortisol tests that allow consumers to check their own levels can be misleading, Findling says. “Some providers who make this (adrenal fatigue) diagnosis, provide patients with testing equipment for doing saliva cortisol levels throughout the day,” he says. “And then, regardless of what the results are, they perpetrate this diagnosis of adrenal fatigue.”

Saliva cortisol is a legitimate test that’s frequently used in diagnosing Cushing’s syndrome, or overactive adrenal glands, Findling notes. However, he says, a practitioner pursuing an adrenal fatigue diagnosis could game the system. “What they do is: They shape a very narrow normal range, so narrow, in fact, that no normal human subject could have all their saliva cortisol (levels) within that range throughout the course of the day,” he says. “Then they convince the poor patients that they have adrenal fatigue phenomena and put them on some kind of adrenal support.”

Loaded Supplements

How do you know what you’re actually getting if you buy a dietary supplement marketed for adrenal fatigue or ‘adrenal support’ use? To find out, researchers purchased 12 such supplements over the counter in the U.S.

Laboratory tests revealed that all supplements contained a small amount of thyroid hormone and most contained at least one steroid hormone, according to the study published in the March 2018 issue of Mayo Clinic Proceedings. “These results may highlight potential risks for hidden ingredients in unregulated supplements,” the authors concluded.

Supplements containing thyroid hormones or steroids can interact with a patient’s prescribed medications or have other side effects.

“Some people just assume they have adrenal fatigue because they looked it up online when they felt tired and they ultimately buy these over-the-counter supplements that can be very dangerous at times,” Vouyiouklis Kellis says. “Some of them contain animal (ingredients), like bovine adrenal extract. That can suppress the pituitary axis. So, as a result, your body stops making its own cortisol or starts making less of it, and as a result, you can actually worsen the condition rather than make it better.”

Any form of steroid from outside the body, whether a prescription drug like prednisone or extract from cows’ adrenal glands, “can shut off the pituitary,” Vouyiouklis Kellis explains. “Because it’s signaling to the pituitary like: Hey, you don’t need to stimulate the adrenals to make cortisol, because this patient is taking it already. So, as a result, the body ultimately doesn’t produce as much. And, so, if you rapidly withdraw that steroid or just all of a sudden decide not to take it anymore, then you can have this acute response of low cortisol.”

Some adrenal support products, such as herbal-only supplements, may be harmless. However, they’re unlikely to relieve chronic fatigue.

Fatigue: No Easy Answers

If you’re suffering from ongoing fatigue, it’s frustrating. And you’re not alone. “I have fatigue,” Young Jr. says. “Go to the lobby any given day and say, ‘Raise your hand if you have fatigue.’ Most of the people are going to raise their hands. It’s a common human symptom and people would like an easy answer for it. Usually there’s not an easy answer. I think ‘adrenal fatigue’ is attractive because it’s like: Aha, here’s the answer.”

There aren’t that many causes of endocrine-related fatigue, Young Jr. notes. “Hypothyroidism – when the thyroid gland is not working – is one.” Addison’s disease, or adrenal insufficiency, can also lead to fatigue among a variety of other symptoms. Established adrenal conditions – like adrenal insufficiency – need to be treated.

“In adrenal insufficiency, there is an intrinsic problem in the adrenal gland’s inability to produce cortisol,” Vouyiouklis Kellis explains. “That can either be a primary problem in the adrenal gland or an issue with the pituitary gland not being able to stimulate the adrenal to make cortisol.”

Issues can arise even with necessary medications. “For example, very commonly, people are put on steroids for various reasons: allergies, ear, nose and throat problems,” Vouyiouklis Kellis says. “And with the withdrawal of the steroids, they can ultimately have adrenal insufficiency, or decrease in cortisol.”

Opioid medications for pain also result in adrenal sufficiency, Vouyiouklis Kellis says, adding that this particular side effect is rarely discussed. People with a history of autoimmune disease can also be at higher risk for adrenal insufficiency.

Common symptoms of adrenal insufficiency include:

  • Fatigue.
  • Weight loss.
  • Decreased appetite.
  • Salt cravings.
  • Low blood pressure.
  • Abdominal pain.
  • Nausea, vomiting or diarrhea.
  • Muscle weakness.
  • Hyperpigmentation (darkening of the skin).
  • Irritability.

Medical tests for adrenal insufficiency start with blood cortisol levels, and tests for the ACTH hormone that stimulates the pituitary gland.

“If the person does not have adrenal insufficiency and they’re still fatigued, it’s important to get to the bottom of it,” Vouyiouklis Kellis says. Untreated sleep apnea often turns out to be the actual cause, she notes.

“It’s very important to tease out what’s going on,” Vouyiouklis Kellis emphasizes. “It can be multifactorial – multiple things contributing to the patient’s feeling of fatigue.” The blood condition anemia – a lack of healthy red blood cells – is another potential cause.

“If you are fatigued, do not treat yourself,” Vouyiouklis Kellis says. “Please seek a physician or a primary care provider for evaluation, because you don’t want to go misdiagnosed or undiagnosed. It’s very important to rule out actual causes that would be contributing to symptoms rather than ordering supplements online or seeking an alternative route like self-treating rather than being evaluated first.”

SOURCES

The U.S. News Health team delivers accurate information about health, nutrition and fitness, as well as in-depth medical condition guides. All of our stories rely on multiple, independent sources and experts in the field, such as medical doctors and licensed nutritionists. To learn more about how we keep our content accurate and trustworthy, read our editorial guidelines.

James Findling, MDFindling is a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin.

Mary Vouyiouklis Kellis, MDVouyiouklis Kellis is a staff endocrinologist at Cleveland Clinic.

William F. Young Jr., MDYoung Jr. is an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota

From https://health.usnews.com/health-care/patient-advice/articles/adrenal-fatigue-is-it-real?

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Novel Predictive Model for Adrenal Insufficiency in Dermatological Patients with Topical Corticosteroids Use: A Cross-Sectional Study

Posted on November 16, 2021 by MaryO

Purpose: This study aimed to identify predictive factors and to develop a predictive model for adrenal insufficiency (AI) related to topical corticosteroids use.
Methods: The research was conducted using a cross-sectional design. Adult patients with dermatological conditions who had been prescribed topical steroids for at least 12 months by the dermatology outpatient departments of the Faculty of Medicine, Chiang Mai University from June through October 2020 were included. Data on potential predictors, including baseline characteristics and laboratory investigations, were collected. The diagnoses of AI were based on serum 8AM cortisol and low-dose ACTH stimulation tests. Multivariable logistic regression was used for the derivation of the diagnostic score.
Results: Of the 42 patients, 17 (40.5%) had AI. The statistically significant predictive factors for AI were greater body surface area of corticosteroids use, age < 60 years, and basal serum cortisol < 7 μg/dL. In the final predictive model, duration of treatment was added as a factor based on its clinical significance for AI. The four predictive factors with their assigned scores were: body surface area involvement 10– 30% (20), > 30% (25); age < 60 years old (15); basal serum cortisol of < 7 μg/dL (30); and duration of treatment in years. Risk of AI was categorized into three groups, low, intermediate and high risk, with total scores of < 25, 25– 49 and ≥ 50, respectively. The predictive performance for the model was 0.92 based on area under the curve.
Conclusion: The predictive model for AI in patients using topical corticosteroids provides guidance on the risk of AI to determine which patients should have dynamic ACTH stimulation tests (high risk) and which need only close follow-up (intermediate and low risk). Future validation of the model is warranted.

Keywords: adrenal insufficiency, topical corticosteroids, predictive model, skin diseases

Introduction

Topical corticosteroids are frequently used for inflammatory skin diseases owing to their anti-inflammatory and immunosuppressive effects. Common indications for use include diseases such as psoriasis, eczema, atopic dermatitis, and vitiligo.1 In clinical practice, a variety of delivery vehicles and potencies of topical corticosteroids are used.1 Prolonged and/or inappropriate use of topical corticosteroids can lead to adverse side effects.2 These adverse side effects can be categorized as cutaneous and systemic side effects. The most common cutaneous side effect is skin atrophy. Systemic side effects include hypothalamic-pituitary-adrenal (HPA) axis suppression, glaucoma, hyperglycemia and hypertension.3

One of the most worrisome adverse side effects from the use of topical corticosteroids is adrenal insufficiency (AI) resulting from HPA axis suppression. Topically applied corticosteroids can be absorbed systemically through the skin and can suppress the HPA axis.4–8 This adverse outcome, the inability to increase cortisol production after stress, can lead to adrenal crisis, which is potentially life-threatening. Tests that are normally used to diagnose or exclude AI include serum morning cortisol and the dynamic ACTH stimulation test.9

Secondary AI from percutaneous absorption of topical corticosteroids is less common than with parenteral or oral administration. The cumulative doses and the durations of oral corticosteroid therapy associated with HPA axis suppression have been well documented.10 Data regarding the dose and duration of oral corticosteroids and HPA axis suppression have similarly been well established. A study by Curtis et al reported that the use of oral prednisolone >7.5 mg/day for an extended period (>3 weeks) was linked to this adverse event, and that the incidence increased with duration.10 However, corresponding data for topical corticosteroids has been limited. The degree of risk of HPA axis suppression from topical corticosteroids use is associated with the level of percutaneous absorption which, in turn, depends on numerous factors including the age of the patient (younger patients are more susceptible), body surface area treated, quantity of topical corticosteroids used, potency of the drug, duration of therapy, body region of application, the associated compounds used, eg, urea or salicylic acid, the characteristics of the diseased skin, the degree of impairment of skin integrity, and the coexistence of hepatic and/or renal disease.11–13 One study reported that HPA axis suppression occurs when high potency steroids are administered at a cumulative dose per week of >50 g.2

Presently, there is a lack of data on predictive factors for AI and no predicative model of the relationship between secondary AI resulting from HPA axis suppression and topical corticosteroids use. A simple predictive model which could help preclude and predict the risk of AI which incorporates both demographic and biochemical data could potentially reduce the number of dynamic ACTH stimulation tests performed. This study aimed to identify potential predictive factors and to design an easy-to-use model for predicting the risk of AI following topical corticosteroids use in dermatological patients.

Materials and Methods

This cross-sectional study was conducted with 42 patients who were seen at the dermatology outpatient departments at the Faculty of Medicine, Chiang Mai University Hospital over a 5-month period (June – October 2020). The study protocol was approved by the Faculty of Medicine, Chiang Mai University, Ethical Committee (Ethical number: MED-2563-07037). Recruited participants were adult dermatological patients (≥18 years) who had used topical corticosteroids for at least 12 months. Patients with pituitary or adrenal diseases, pregnant women and patients who had been treated with either systemic corticosteroids or other local corticosteroids were excluded. Those who meet all the inclusion criteria gave their informed consent prior to the study. This study was conducted in accordance with the Declaration of Helsinki.

Adrenal Function Evaluation

Adrenal function was evaluated by serum morning (8 AM) cortisol and the low-dose ACTH stimulation test. Patients were instructed to suspend use of topical corticosteroids for at least 24 hours before serum morning cortisol measurement and ACTH stimulation tests. In those with serum morning cortisol between 3 and 17.9 µg/dL, ACTH stimulation tests were performed on the same day between 9–11AM to either exclude or diagnose AI. Serum cortisol concentrations were measured at 8 AM 0 (basal cortisol) as well as 20 and 40 minutes after 5 µg ACTH was administered intravenously.

Data Collection

Epidemiological data collected included gender, age, blood pressure, underlying dermatologic diseases, other underlying diseases, body surface area involvement, sensitive area involvement, topical corticosteroid potency, amount and duration of topical corticosteroids use, symptoms of AI and the presence of Cushingoid features. Biochemical data included serum cortisol at 8 AM, 0 (basal cortisol) and at 20 and 40 minutes after ACTH intravenous injection, serum creatinine, electrolytes and albumin. Serum cortisol levels were measured by electrochemiluminescence assay (ECLIA) (Elecsys® Cortisol II assay, Roche Diagnostics GmbH, Mannheim, Germany).

Definitions

An 8AM cortisol level of ❤ µg/dL or a peak serum cortisol level of <18 µg/dL at 20 or 40 minutes after an ACTH stimulation test was defined as having AI.14 Sensitive area involvement included the axilla, groin, face and genitalia. Topical corticosteroids are classified by potency based on a skin vasoconstriction assay, and range from ultra-high potency (class I) to low potency (class VII).15 Since some patients had concurrently used more than one class of corticosteroids in one treatment period, the new variable potency·dose·time (summary of corticosteroids potency (I–VII)16 multiplied by total doses (mg) of corticosteroids use and multiplied by duration (months) of corticosteroids use) was created. Symptoms of AI included lethargy, nausea and vomiting, orthostatic hypotension and significant weight loss. Significant weight loss was defined as a loss of 5% of body weight in one month or a loss of 10% over a period of six months.17 Having Cushingoid features was defined as at least one of the excess glucocorticoid features, eg, easy bruising, facial plethora, proximal myopathy, striae, dorsocervical fat pad, facial fullness, obesity, supraclavicular fullness, hirsutism, decreased libido and menstrual abnormalities.

Statistical Analysis

All statistical analyses were performed using Stata 16 (StataCorp, College Station, Texas, USA). Categorical variables are reported as frequency and percentage, while continuous variables are reported as mean ± standard deviation or median and interquartile range (IQR), according to their distribution. For univariable comparison, Fisher’s exact probability test was used for categorical variables, and the independent t-test or the Mann–Whitney U-test was used for continuous variables. p-values less than 0.05 were considered statistically significant.

Multivariable logistic regression was used in the derivation of the prediction model for AI. Predictors with significant p-values in the univariable analysis were included in the multivariable model. We also included age and treatment duration in the model due to the clinical significance of those factors.4,18 The clinical collinearity among the predictors was also evaluated before the selection of the predictors. We generated a weighted score for each predictor by dividing the logit coefficient of the predictor by the lowest coefficient in the model. The discriminative ability of the final multivariable model was assessed using the area under the receiver operating characteristics (ROC) curve. The calibration of the scores was evaluated using the Hosmer-Lemeshow goodness-of-fit test, where a p-value >0.01 was considered a good fit. For clinical applicability, the appropriate cut-off points for the scores were identified based on sensitivity and specificity. We identified one cut-off point with high sensitivity for ruling out AI and another cut-off point with high specificity for ruling in AI. The positive predictive value for each score category with its corresponding confidence interval were presented. A sample size of at least 25 patients with at least 5 patients with AI was estimated to give 80% power at the 5% significance level.4 There was no missing data in this study.

Results

Baseline characteristics and biochemical investigations are shown in Table 1. Forty-two patients with dermatological diseases were included in this study. Of these, 17 patients (40.5%) had AI of whom 5 (29.4%) were female. The mean age of the group was 56.5 ±15.4 years, the mean duration of treatment was 10.1 ± 6 years, and the majority of patients had psoriasis (n = 14, 82.4%). There was no significant difference in sex, age, duration of treatment, potency dose-time, comorbidities, or underlying skin disease between the AI and non-AI groups. The average body surface area of corticosteroids use was significantly higher in patients with AI than in the non-AI group (27.5 ±18.7 m2 and 10.7 ±11.7 m2, p < 0.001, respectively). Basal serum cortisol levels were significantly lower in the AI group (6.52 ± 4.04 µg/dL) than in the non-AI group (10.48 ± 3.45 µg/dL, p 0.003). Although lower serum morning cortisol levels were observed in the AI group, the difference was not statistically significant (5.24 ± 4.65 µg/dL vs 13.39 ± 15.68 µg/dL, p = 0.069). Three patients were identified as having Cushingoid features. All patients with Cushingoid features had AI.

Table 1 Comparison of Clinical Characteristics Between Patients with a History of Topical Corticosteroids Use for at Least 12 Months Who Were Diagnosed with Adrenal Insufficiency and Those without Adrenal Insufficiency (n = 42)

 

Based on the multivariate logistic regression analysis (shown in Table 2), the significant predictive factors for AI in patients who used topical corticosteroids for more than 12 months were body surface area of corticosteroids use of 10–30% and >30% (POR 18.9, p =0.042, and POR 59.2, p = 0.035, respectively), age less than 60 years (POR 13.8, p = 0.04), and basal serum cortisol of <7 µg/dL (POR 131.5, p = 0.003). Only serum basal cortisol was included in the final multivariable model as there was clinical collinearity among serum morning cortisol and basal cortisol as well as 20- and 40-minute cortisol measurements.

Table 2 Multivariable Model for Prediction of Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38)

 

Predictive risk score was created to determine the probability of patients having AI using the aforementioned three significant predictive factors from the multivariable analysis (Table 2). As previous studies have demonstrated that duration of treatment is a strong predictive factor for AI in corticosteroid users,4,18 this factor was also incorporated in the model. The transformed score for body surface area, age and basal serum cortisol had a range of 0 to 30. For treatment duration, the transformed score was based on cumulative years of treatment. The total score was categorized into three groups: low, intermediate, and high risk (Table 3).

Table 3 Accuracy of the Score to Rule in and Rule Out Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38)

 

The cut-off point of ≥50 suggests high risk for developing AI with a sensitivity of 46.2% and a specificity of 100%, a score of <25 suggests a low risk with a sensitivity of 100% and a specificity of 52%, and a score between 25 and 49 indicates an intermediate risk of having AI. The ROC curve for the model assessing predictive performance which included all significant factors had an AuROC of 0.92 (Figure 1). The Hosmer-Lemeshow goodness-of-fit test revealed non-statistically significant results (p = 0.599), indicating that our newly derived scoring system fits the data well.

Figure 1 Model discrimination via receiver operating characteristic curve in patients with a history of topical corticosteroids use for at least 12 months (n = 42).

 

Discussion

The present study proposes an easy-to-use predictive model for AI following topical corticosteroids use in dermatological patients based on demographic and biochemical factors. The accuracy of the model shows an excellent diagnostic accuracy of 92% based on AuROC. Currently, the diagnosis of AI in dermatological patients with topical corticosteroids use involves multiple steps including screening for serum morning cortisol followed by dynamic ACTH stimulation testing. The proposed simple predictive model, which requires only three demographic data items (age, body surface area of corticosteroids use, duration of use) and one biochemical test (serum basal cortisol), could potentially reduce the number of dynamic ACTH stimulation tests performed, resulting in cost- and time-saving for both patients and health-care facilities.

Based on the proposed cut-off points, we suggest screening of individuals at high risk for having AI, including serum morning cortisol and the ACTH stimulation tests to confirm a diagnosis of AI. If there is evidence of AI, the patient should begin to receive treatment for AI to reduce future complications. For those in the low-risk group, only clinical follow-up should be carried out. In the intermediate-risk group, we recommend regular and close biochemical follow-up including serum morning cortisol and clinical follow-up for signs and symptoms of AI. Signs and symptoms that should raise a high index of suspicion for AI include significant weight loss, nausea and/or vomiting, orthostatic hypotension and lethargy. However, this proposed predictive model was studied in adults and cannot simply be generalized and extrapolated to children or infants.

In our study, 40.5% of the patients were determined to have AI. A previous meta-analysis by Broersen et al reported the percentage of patients with AI secondary to all potencies of topical corticosteroids based on a review of 15 studies was 4.7%, 95% CI (1.1–18.5%).19 The higher prevalence of AI in our study could be a result of differences in patients’ baseline characteristics, eg, duration of treatment, corticosteroids potency and body surface area involvement.

In the predictive model, we incorporated both clinical and biochemical factors which are easy to obtain in actual clinical practice. Some of those predictive factors have been previously reported to be linked to AI. Body surface area of corticosteroids use larger than 10% found to be significantly related to AI, especially in patients with a lesion area of over 30%. This finding is consistent with a study by Kerner et al which suggests the extent of surface area to which the corticosteroids are applied may influence absorption of the drug.20 Regarding the age of the patients, our study found that individuals over 60 years old tended to be at high risk of AI following topical corticosteroids therapy. The underlying explanation is that the stratum corneum acts as a rate-limiting barrier to percutaneous absorption as the stratum corneum in younger individuals is thinner than in older people. Diminished effectiveness of topical corticosteroid treatment in older people was demonstrated in a study by Malzfeldt et al.21 Even though serum basal cortisol is not recommended as a standard test to diagnose AI, a prior study reported that it can be considered as an alternative choice to diagnose AI when serum morning cortisol results are not available. In fact, it has been reported that there is no difference in diagnostic accuracy between serum morning cortisol and basal cortisol22 which supports our finding that serum basal cortisol <7 µg/dL is one of the significant factors related to AI.

The final model found no statistically significant relationship between the incidence of AI and the duration of corticosteroids treatment. However, we decided to include this factor in the final model since previous publications have reported that the duration of treatment is a relevant risk factor for developing AI following continuous topical corticosteroids use. The duration of AI events has been reported to vary between 2 weeks to 18 months.4,18 Additionally, a case report of AI demonstrated that 5 years of topical corticosteroids use can cause AI.6 Together, this suggests that patients with a longer duration of topical corticosteroids use are at increased risk of AI, especially those who also have other risk factors. Although both potency and dosage of topical corticosteroids have been reported to be significantly linked to HPA axis suppression, the present study found only a non-significance link. This could be the result of the small sample size as well as of other factors, eg, body surface area involvement and serum cortisol levels, which could have masked the association between potency and dosage of topical corticosteroids with HPA suppression.

To the best of our knowledge, this study is the first to use these novel predictive factors to develop a predictive model for AI in patients using topical corticosteroids. This model has multiple potential implications. First, the model uses clinical and biochemical factors which are obtainable in many institutes. Second, the model’s risk score provides good diagnostic accuracy in terms of both sensitivity and specificity. Finally, each of the predictive factors in the model has an underlying pathophysiological explanation and is not due simply to chance.

There are some limitations in this study. First, the sample size is relatively small, although it does offer sufficient statistical power for each of the predictive factors. Second, further external validation is needed to validate the predictive performance of the model. Third, the cut-off level of serum cortisol after ACTH stimulation test was based on the older generation of ECLIA assay. There was a study proposed that the cut-off for serum cortisol in the newer generation of cortisol assay should be lower (~14–15 µg/dL) than the previous one (18 µg/dL).23 However, this proposed cut-off has not yet been established in the current guideline for AI. In the future, if the newer cut-off for serum cortisol will have been employed in the standard guideline, our predictive model may lead to overdiagnosis of AI.

Conclusions

The proposed predictive model uses both demographic and biochemical factors to determine the risk of AI in dermatological patients following topical corticosteroids use with a high level of diagnostic accuracy. This model has advantages in terms of a reduction in the number of dynamic ACTH stimulation tests needed, thus saving time and resources. Additionally, it can provide guidance to clinical practitioners regarding which patients should be closely followed up for development of AI. Future external validation of this predictive model is warranted.

Acknowledgments

The authors are grateful to Lamar G. Robert, PhD and Chongchit S. Robert, PhD for editing the manuscript.

Disclosure

The authors report no conflict of interest in this work.

References

1. Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician. 2009;79(2):135–140.

2. Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol. 2006;54(1):1–15;quiz 16–8. doi:10.1016/j.jaad.2005.01.010

3. Rathi SK, D’Souza P. Rational and ethical use of topical corticosteroids based on safety and efficacy. Indian J Dermatol. 2012;57(4):251–259. doi:10.4103/0019-5154.97655

4. Carruthers JA, August PJ, Staughton RC. Observations on the systemic effect of topical clobetasol propionate (Dermovate). Br Med J. 1975;4(5990):203–204. doi:10.1136/bmj.4.5990.203

5. Staughton RC, August PJ. Cushing’s syndrome and pituitary-adrenal suppression due to clobetasol propionate. Br Med J. 1975;2(5968):419–421. doi:10.1136/bmj.2.5968.419

6. Young CA, Williams IR, MacFarlane IA. Unrecognised Cushing’s syndrome and adrenal suppression due to topical clobetasol propionate. Br J Clin Pract. 1991;45(1):61–62.

7. Abma EM, Blanken R, De Heide LJ. Cushing’s syndrome caused by topical steroid therapy for psoriasis. Neth J Med. 2002;60(3):148–150.

8. Böckle BC, Jara D, Nindl W, Aberer W, Sepp NT. Adrenal insufficiency as a result of long-term misuse of topical corticosteroids. Dermatology. 2014;228(4):289–293. doi:10.1159/000358427

9. Ospina NS, Al Nofal A, Bancos I, et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101(2):427–434. doi:10.1210/jc.2015-1700

10. Curtis JR, Westfall AO, Allison J, et al. Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum. 2006;55(3):420–426. doi:10.1002/art.21984

11. Brazzini B, Pimpinelli N. New and established topical corticosteroids in dermatology: clinical pharmacology and therapeutic use. Am J Clin Dermatol. 2002;3(1):47–58. doi:10.2165/00128071-200203010-00005

12. Dhar S, Seth J, Parikh D. Systemic side-effects of topical corticosteroids. Indian J Dermatol. 2014;59(5):460–464. doi:10.4103/0019-5154.139874

13. Levin C, Maibach HI. Topical corticosteroid-induced adrenocortical insufficiency: clinical implications. Am J Clin Dermatol. 2002;3(3):141–147. doi:10.2165/00128071-200203030-00001

14. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364–389. doi:10.1210/jc.2015-1710

15. Goa KL. Clinical pharmacology and pharmacokinetic properties of topically applied corticosteroids. A review. Drugs. 1988;36(Suppl 5):51–61. doi:10.2165/00003495-198800365-00011

16. Davallow Ghajar L, Wood Heickman LK, Conaway M, Rogol AD. Low risk of adrenal insufficiency after use of low- to moderate-potency topical corticosteroids for children with atopic dermatitis. Clin Pediatr. 2019;58(4):406–412. doi:10.1177/0009922818825154

17. Gaddey HL, Holder K. Unintentional weight loss in older adults. Am Fam Physician. 2014;89(9):718–722.

18. Melian EB, Spencer CM, Jarvis B. Clobetasol propionate foam, 0.05%. Am J Clin Dermatol. 2001;2(2):89–92;discussion 93. doi:10.2165/00128071-200102020-00005

19. Broersen LH, Pereira AM, Jørgensen JO, Dekkers OM. Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100(6):2171–2180. doi:10.1210/jc.2015-1218

20. Kerner M, Ishay A, Ziv M, Rozenman D, Luboshitzky R. Evaluation of the pituitary-adrenal axis function in patients on topical steroid therapy. J Am Acad Dermatol. 2011;65(1):215–216. doi:10.1016/j.jaad.2010.12.033

21. Malzfeldt E, Lehmann P, Goerz G, Lippold BC. Influence of drug solubility in the vehicle on clinical efficacy of ointments. Arch Dermatol Res. 1989;281(3):193–197. doi:10.1007/bf00456392

22. Manosroi W, Phimphilai M, Khorana J, Atthakomol P. Diagnostic performance of basal cortisol level at 0900-1300h in adrenal insufficiency. PLoS One. 2019;14(11):e0225255. doi:10.1371/journal.pone.0225255

23. Vogeser M, Kratzsch J, Ju Bae Y, et al. Multicenter performance evaluation of a second generation cortisol assay. Clin Chem Lab Med. 2017;55(6):826–835. doi:10.1515/cclm-2016-0400

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Filed under: Addison's disease, adrenal, adrenal crisis, Diagnostic Testing | Tagged: , , , | Leave a comment »

Identified: the gene behind an unusual form of Cushing’s Syndrome

Posted on October 23, 2021 by MaryO

A team of scientists in Montreal and Paris has succeeded in identifying the gene responsible for the development of a food-dependent form of Cushing’s Syndrome, a rare disease affecting both adrenal glands.

In their study published in The Lancet Diabetes & Endocrinology, Dr. Isabelle Bourdeau and Dr. Peter Kamenicky identify in the gene KDM1A the mutations responsible for the development of this unusual form of the disease.

The scientists also show, for the first time, that the disease is genetically transmitted.

Bourdeau is a researcher and a Université de Montréal medical professor practising at the CHUM Research Centre (CRCHUM), while Kamenicky works at the Hôpital de Bicêtre, part of the Assistance publique-hôpitaux de Paris network in France.

Cushing’s Syndrome is caused by the overproduction of cortisol, a steroid hormone, by the two adrenal glands located above the kidneys.

“When the tissues of the human body are exposed to this excess of cortisol, the effects for those with the disease are serious: weight gain, high blood pressure, depression, osteoporosis, and heart complications, for example,” said Bourdeau, co-lead author of the study with Dr. Fanny Chasseloup, a colleague from the French team.

This discovery comes nearly 30 years after food-induced Cushing’s Syndrome was first described in 1992 by a research group led by Dr. André Lacroix at the CRCHUM and his colleagues Drs. Johanne Tremblay and Pavel Hamet.

The form of the disease being studied by Bourdeau and her colleagues is caused specifically by the abnormal expression of the receptors of a hormone named GIP (glucose-dependent insulinotropic peptide), in both adrenal glands of patients. This hormone is produced by the small intestine in response to food intake. For people with the disease, cortisol concentrations increase abnormally every time they ingest food.

The discovery of the genetic mechanism by the French and Quebec teams was made possible through the use of recent cutting-edge genetic techniques on tissues of patients including those investigated by Dr Lacroix at CHUM. Bourdeau was aided by CRCHUM researcher Martine Tétreault during the computer analyses related to the research project.

Earlier diagnosis thanks to genetic analysis

“In general, rare diseases are generally underdiagnosed in clinics,” said Bourdeau, the medical director of the adrenal tumors multidisciplinary team at the CHUM.

“By identifying this new gene, we now have a way of diagnosing our patients and their families earlier and thus offer more personalized medicine. At the CHUM, genetic analysis is already offered in our Genetic Medicine Division.”

In a remarkable demonstration of scientific cooperation, the Quebec and French teams were able to collect and study tissue specimens available in local and international biobanks in Canada, France, Italy, Greece, Belgium and the Netherlands.

Blood and adrenal gland tissue samples of 17 patients—mostly women—diagnosed with GIP-dependent Cushing’s Syndrome were compared genetically with those of 29 others with non-GIP-dependent bilateral adrenal Cushing’s Syndrome.

This was quite an accomplishment, given the rarity of the disease in the general population. It allowed the researchers to identify the genetic mutations of the KDM1A gene and to determine that the disease is genetically transmitted.

Since 2009, the CHUM has been designated as the adrenal tumors quaternary care centre of the Quebec Cancer Program.

About this study

“Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing’s syndrome: a multicenter retrospective cohort study,” by Drs. Fanny Chasseloup, Isabelle Bourdeau and their colleagues, was published Oct. 13, 2021, in The Lancet Diabetes & Endocrinology. Funding was provided by the Agence nationale de la recherche, the Fondation du Grand défi Pierre Lavoie, the Institut national du cancer, the Fonds de recherche du Québec-Santé, INSERM and Assistance publique-hôpitaux de Paris.

About the CRCHUM

The University of Montreal Hospital Research Centre (CRCHUM) is one of North America’s leading hospital research centres. It strives to improve adult health through a research continuum covering such disciplines as the fundamental sciences, clinical research and public health. Over 1,850 people work at the CRCHUM, including more than 550 researchers and more than 460 graduate students

Media contact

  • Jeff HeinrichUniversité de MontréalTel: 514 343-7593
  • Lucie DufresneCentre hospitalier de l’Université de MontréalTel: 514 890-8000 p. 15380

From https://nouvelles.umontreal.ca/en/article/2021/10/15/identified-the-gene-behind-an-unusual-form-of-cushing-s-syndrome/

Filed under: Addison's disease, adrenal, Cushing's, Rare Diseases | Tagged: , , , | Leave a comment »

ACTH-independent Cushing’s syndrome due to bilateral adrenocortical adenoma

Posted on October 2, 2021 by MaryO

https://doi.org/10.1016/j.radcr.2021.07.093

 

Abstract

The chronic excess of glucocorticoids results in Cushing’s syndrome. Cushing’s syndrome presents with a variety of signs and symptoms including: central obesity, proximal muscle weakness, fatigue striae, poor wound healing, amenorrhea, and others.

ACTH independent Cushing’s syndrome is usually due to unilateral adenoma. A rare cause of it is bilateral adrenal adenomas.

In this paper we report a case of a 43-year-old woman with Cushing’s syndrome due to bilateral adrenal adenoma.

Read the case report at https://www.sciencedirect.com/science/article/pii/S1930043321005690

Filed under: Addison's disease, adrenal, Cushing's, Rare Diseases, symptoms | Tagged: , , , , , , , , , | Leave a comment »

How does COVID-19 impact the adrenal gland?

Posted on April 24, 2021 by MaryO

This month marks a little over one year since the first surge of COVID-19 across the United States. April is also Adrenal Insufficiency Awareness month, a good time to review the data on how COVID-19 infection can impact the adrenal glands.

The adrenal glands make hormones to help regulate blood pressure and the ability to respond to stress. The hormones include steroids such as glucocorticoid (cortisol), mineralocorticoid (aldosterone), and forms of adrenaline known as catecholamines (norepinephrine, epinephrine, and dopamine). The activity of the adrenal gland is controlled through its relationship with the pituitary gland (the master regulator of hormones in the body).

Some common adrenal diseases include the following:

  • Addison’s Disease (where the body attacks the adrenal glands making them dysfunctional)
  • Hyperaldosteronism
  • Cushing’s Syndrome
  • Pheochromocytoma
  • Adrenal Nodules/Masses (termed incidentaloma)
  • Congenital adrenal hyperplasia

COVID-19 was found in the adrenal and pituitary glands of some patients who succumbed to the illness, suggesting that these organs might be among the targets for infection.  One of the first highly effective therapies for COVID-19 infection was the use of IV steroid (dexamethasone) supplementation in hospitalized patients in patients requiring oxygen.

A focused search of COVID-19-related health literature shows 85 peer-reviewed papers that have been published in medical literature specifically on the adrenal gland and COVID-19. This literature focuses on three phases of COVID infection that may impact the adrenal gland: the acute active infection phase, the immediate post-infection phase, and the long-term recovery phase.

Medical research has identified that during the acute active infection, the adrenal system is one of the most heavily affected organ systems in the body in patients who have COVID-19 infection requiring hospitalization. In these cases, supplementation with the steroid dexamethasone serves as one of the most powerful lifesaving treatments.

Concern has also been raised regarding the period of time just after the acute infection phase – particularly, the development of adrenal insufficiency following cases of COVID-19 hospitalizations. Additionally, some professional societies recommend that for patients who have adrenal insufficiency and are on adrenal replacement therapy, they be monitored closely post-COVID-19 vaccine for the development of stress-induced adrenal insufficiency.

In mild-to-moderate COVID-19 cases, there does not seem to be an effect on adrenaline-related hormones (norepinephrine, epinephrine, dopamine). However, in cases of severe COVID-19 infection triggering the development of shock, patients will need supplementation with an infusion of catecholamines and a hormone called vasopressin to maintain their blood pressure.

Finally, some studies have addressed the concern of adrenal insufficiency during the long-term recovery phase. Dr Sara Bedrose, adrenal endocrine specialist at  Baylor College of Medicine, indicates that studies which included adrenal function in COVID survivors showed a large percentage of patients with suboptimal cortisol secretion during what is called ACTH stimulation testing.

Results indicated that most of those cases had central adrenal insufficiency. It was concluded that adrenal insufficiency might be among the long-term consequences of COVID-19 and it seemed to be secondary to pituitary gland inflammation (called hypophysitis) or due to direct hypothalamic damage. Long-term follow-up of COVID 19 survivors will be necessary to exclude a gradual and late-onset adrenal insufficiency.

Some patients who have COVID-19 will experience prolonged symptoms. To understand what is happening to them, patients may question whether or not they have a phenomenon called adrenal fatigue. This is a natural question to ask, especially after having such a severe health condition. A tremendous amount of resources are being developed to investigate the source and treatment of the symptoms, and this work has only just begun.

However, adrenal fatigue is not a real medical diagnosis. It’s a term to describe a group of signs and symptoms that arise due to underactive adrenal glands. Current scientific data indicate that adrenal fatigue is not in and of itself a medical disease – although a variety of over-the-counter supplements and compounded medications may be advocated for in treatment by alternative medicine/naturopathic practitioners.

My takeaway is that we have learned a great deal about the effects COVID-19 infection has on the adrenal glands. Long-term COVID-19 remains an area to be explored –  especially in regards to how it may affect the adrenal glands.

-By Dr. James Suliburk, associate professor of surgery in the Division of Surgical Oncology and section chief of endocrine surgery for the Thyroid and Parathyroid Center at Baylor College of Medicine

From https://blogs.bcm.edu/2021/04/22/how-does-covid-19-impact-the-adrenal-gland/

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

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