Iatrogenic Cushing's Syndrome Research Articles

Iatrogenic cushings syndrome precipitated by fluticasone nasal drops in HIV infected patient

Iatrogenic cushings syndrome precipitated by fluticasone nasal drops in HIV infected patient

Adulteration of proprietary Chinese medicines and health products with undeclared drugs: experience of a tertiary toxicology laboratory in Hong Kong.

Proprietary Chinese medicines (pCMs) and health products, generally believed to be natural and safe, are gaining popularity worldwide. However, the safety of pCMs and health products has been severely compromised by the practice of adulteration. The current study aimed to examine the problem of adulteration of pCMs and health products in Hong Kong. The present study was conducted in a tertiary referral clinical toxicology laboratory in Hong Kong. All cases involving the use of pCMs or health products, which were subsequently confirmed to contain undeclared adulterants, from 2005 to 2015 were reviewed retrospectively. A total of 404 cases involving the use of 487 adulterated pCMs or health products with a total of 1234 adulterants were identified. The adulterants consisted of approved drugs, banned drugs, drug analogues and animal thyroid tissue. The six most common categories of adulterants detected were nonsteroidal anti-inflammatory drugs (17.7%), anorectics (15.3%), corticosteroids (13.8%), diuretics and laxatives (11.4%), oral antidiabetic agents (10.0%) and erectile dysfunction drugs (6.0%). Sibutramine was the most common adulterant (n = 155). The reported sources of these illicit products included over-the-counter drug stores, the internet and Chinese medicine practitioners. A significant proportion of patients (65.1%) had adverse effects attributable to these illicit products, including 14 severe and two fatal cases. Psychosis, iatrogenic Cushing syndrome and hypoglycaemia were the three most frequently encountered adverse effects. Adulteration of pCMs and health products with undeclared drugs poses severe health hazards. Public education and effective regulatory measures are essential to address the problem.

Administering steroids with HIV treatment‐boosting agents

Co‐administration of a steroid with an HIV treatment‐boosting agent such as ritonavir or cobicistat increases the risk of iatrogenic Cushing syndrome and subsequent secondary adrenal suppression. This article discusses the strategies to help prevent this and describes how to identify and manage such interactions.

Preventing Cushing: Iatrogenic Cushing Syndrome due to Ritonavir-Fluticasone Interaction

Ritonavir is commonly used in low doses to boost plasma levels of protease inhibitors in patients with human immunodeficiency virus (HIV) infections. It is also a potent inhibitor of cytochrome P450. We present a 50-year-old African American male with past medical history of HIV on highly active antiretroviral therapy (HAART), which also included ritonavir and long standing asthma that has been treated with inhaled fluticasone, who presented with back pain. He had central obesity, prominent abdominal striae and wasted extremities on physical examination. Laboratory tests showed low morning serum cortisol and suboptimal cosyntropin test consistent with adrenal insufficiency. Computed tomography (CT) of the spine showed a fracture of inferior endplate of the lumbar (L3) vertebra. The cause of osteoporosis is believed to be iatrogenic Cushing syndrome caused by enhanced levels of inhaled fluticasone effects secondary to inhibition of cytochrome P450. The patient was managed surgically and fluticasone was discontinued.

Iatrogenic Cushing syndrome and suprarenal secondary insufficiency due to interaction between fluticasone and ritonavir

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Fluticasone furoate induced iatrogenic Cushing syndrome in a pediatric patient receiving anti-retroviral therapy.

SummaryWe present a case of iatrogenic Cushing’s syndrome, induced by treatment with fluticasone furoate (1–2 dd, 27.5 µg in each nostril) in a pediatric patient treated for congenital HIV. The pediatric patient described in this case report is a young girl of African descent, treated for congenital HIV with a combination therapy of Lopinavir/Ritonavir (1 dd 320/80 mg), Lamivudine (1 dd 160 mg) and Abacavir (1 dd 320 mg). Our pediatric patient presented with typical Cushingoid features (i.e. striae of the upper legs, full moon face, increased body and facial hair) within weeks after starting fluticasone furoate therapy, which was exacerbated after increasing the dose to 2 dd because of complaints of unresolved rhinitis. Biochemical analysis fitted iatrogenic Cushing’s syndrome, with a repeatedly low cortisol (<0.03 µM, ref 0.14–0.60 µM) and low ACTH (9 pg/mL, ref 9–52 pg/mL) without signs of adrenal insufficiency. No other biochemical abnormalities that could point to adrenal or pituitary dysfunction were detected; electrolytes, thyroid and gonadal function, and IGF-1 were within the normal range. Pharmacogenetic analysis revealed that the pediatric patient carried the CYP3A4 *1B/*1G and CYP3A5 *3/*3 genotype (associated with a partial and complete loss of enzyme activity, respectively) which is associated with the development of iatrogenic Cushing’s syndrome in patients treated for HIV due to the strong inhibition of CYP3 enzymes by Ritonavir. Upon discontinuation of fluticasone treatment, the pediatric patient improved both clinically and biochemically with normalisation of cortisol and ACTH within a couple of weeks.Learning points:Fluticasone therapy may induce iatrogenic Cushing’s syndrome in a patient treated with anti-retroviral therapy.Pharmacogenetic analysis, in particular CYP3A genotyping, provides useful information in patients treated for HIV with respect to possible future steroid treatment.Fluticasone furoate is not detected in the Siemens Immulite cortisol binding assay.

Unexpected transesophageal echocardiography tee finding: mediastinal lipomatosis fakes an aortic intramural haematoma.

Mediastinal lipomatosis (ML) is a benign condition characterized by accumulation of fatty tissue. This condition is usually related to spontaneous or iatrogenic corticosteroid-induced Cushing syndrome or to obesity (1). Although it is an asymptomatic disorder, it can rarely result in compression of adjacent organs with thoracic pain, dyspnea, cough, dysphonia, and dysphagia. In this report we describe a case of fatty infiltration around descending aortic wall in a patient with autoimmune disorders, dilated cardiomyopathy and mitral insufficiency, simulating an intramural hematoma (IMH).

Metabolomic Biomarkers in Urine of Cushing's Syndrome Patients.

Cushing’s syndrome (CS) is a disease which results from excessive levels of cortisol in the human body. The disorder is associated with various signs and symptoms which are also common for the general population not suffering from compound hypersecretion. Thus, more sensitive and selective methods are required for the diagnosis of CS. This follow-up study was conducted to determine which steroid metabolites could serve as potential indicators of CS and possible subclinical hypercortisolism in patients diagnosed with so called non-functioning adrenal incidentalomas (AIs). Urine samples from negative controls (n = 37), patients with CS characterized by hypercortisolism and excluding iatrogenic CS (n = 16), and patients with non-functioning AIs with possible subclinical Cushing’s syndrome (n = 25) were analyzed using gas chromatography-mass spectrometry (GC/MS) and gas chromatograph equipped with flame ionization detector (GC/FID). Statistical and multivariate methods were applied to investigate the profile differences between examined individuals. The analyses revealed hormonal differences between patients with CS and the rest of examined individuals. The concentrations of selected metabolites of cortisol, androgens, and pregnenetriol were elevated whereas the levels of tetrahydrocortisone were decreased for CS when opposed to the rest of the study population. Moreover, after analysis of potential confounding factors, it was also possible to distinguish six steroid hormones which discriminated CS patients from other study subjects. The obtained discriminant functions enabled classification of CS patients and AI group characterized by mild hypersecretion of cortisol metabolites. It can be concluded that steroid hormones selected by applying urinary profiling may serve the role of potential biomarkers of CS and can aid in its early diagnosis.

Iatrogenic Cushing’s syndrome due to drug interaction between glucocorticoids and the ritonavir or cobicistat containing HIV therapies

Ritonavir and cobicistat, used as pharmacokinetic enhancers in combination with some antiretrovirals (ARVs) for the treatment of HIV, are potent inhibitors of the CYP3A4 isoenzyme. Most glucocorticoids are metabolised via the CYP3A4 pathway and iatrogenic Cushing's syndrome (ICS), with possible secondary adrenal insufficiency (SAI), is a recognised complication following co-administration with ritonavir or cobicistat. A structured approach for identifying and managing potentially affected individuals has not been established.We systematically identified patients with ICS/SAI and found substantial heterogeneity in clinical practice across three large London HIV centres. While this significant drug interaction and its complications are now well-recognised, it is apparent that there is no standardised approach to management or guidance for the general physician. Here we describe the management of ICS/SAI in our current practice, review the available evidence and suggest practice recommendations.

Iatrogenic Cushing's Syndrome in a Small Case Series of HIV Patients on Steroid Inhalation and Antiretroviral Therapies

Cushing's syndrome is uncommon in patients on therapeutic doses of inhaled steroids. We studied 2 cases of human immunodeficiency virus (HIV) infection who had a rapid onset of Cushing's syndrome secondary to fluticasone propionate interacting with their antiretroviral therapy. Case 1 is a 27-year-old woman with a history of drug addiction problems, anxiety disorder, progressive multifocal leukoencephalopathy and asthma. She presented to the emergency room following a 3-week history of frequent fluticasone inhalation for anxiety type symptoms. Her medications included Prezista, Norvir (ritonavir), fluticasone and Bactrim. Clinical findings were abdominal obesity and extensive purple striae. Laboratory results showed normal midnight salivary cortisol, low 24-hour urinary free cortisol and normal overnight dexamethasone suppression of morning cortisol. Case 2 is a 38-year-old woman with history of rapid 50-pound weight gain and painful purple striae associated with fluticasone inhaler abuse for anxiety symptoms. Other medical problems were drug addiction problems, anxiety and asthma. Her medications were Fluoxetine, Olanzapine, Montelukast, Prezista, Norvir, Truvuda, salbutamol inhaler and ranitidine. Laboratory results showed a low 24-hour urinary free cortisol and undetectable plasma adrenocorticotropic hormone (ACTH).

Lessons from iatrogenic Cushing syndrome in children.

Lessons from iatrogenic Cushing syndrome in children.

Iatrogenic Cushing Syndrome from Interaction Between Ritonavir and Oral Budesonide During Direct Acting Antiviral Hepatitis C Therapy

Direct acting antiviral (DAA) regimens containing ritonavir have been developed to treat hepatitis C, with fewer side effects than that by interferon-based regimens. However prescribers must be aware of drug-drug interactions. There are multiple reports of iatrogenic Cushing syndrome (CS) caused by ritonavir, when used to treat human immunodeficiency virus, increasing the bioavailability of exogenous steroids by inhibiting cytochrome p450 enzymes in the liver and gut wall and thus reducing steroid metabolism. We herein report a novel scenario of CS due to interaction between ritonavir for hepatitis C treatment and oral budesonide for autoimmune hepatitis.

Iatrogenic cushing syndrome and acute adrenal insufficiency due to the association of inhaled corticosteroids and ritonavir

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Iatrogenic Cushing's syndrome due to misuse of topical corticosteroids: a case report

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Cushing Syndrome Following Single Steroid Injection: A Case Report and Review of the Literature

Iatrogenic Cushing’s syndrome (ICS) is a well-known adverse effect of glucocorticoids. It usually develops after prolonged exposure to excessive amounts of synthetic glucocorticoids. The manifestations of ICS are generally dose and time dependent. We will report on our own case of ICS followed by a review/highlight of published cases of ICS following single steroid injection. The development of ICS after a single and low dose of synthetic glucocorticoid is an exceptional event and only a few patients have been reported to date in the literature. Here we will report on the case of a twenty-one -year-old female patient who developed ICS with striae rubra which appeared fifteen days after irrational use of a single intramuscular injection of betamethasone (Diprofos). Endocrinological evaluation confirmed hypothalamic-pituitary-adrenal axis suppression. Her striae showed gradual fading over the next two months leaving only thin white striae similar to stretch marks. We performed a review of the literature using a computer search in the Science Direct, Google Scholar, and National Library of Medicine from 1950 to January 2016 for ICS following single injection of synthetic glucocorticoids using the terms ‘single injection’, ‘iatrogenic’, ‘betamethasone’, ‘triamcinolone’, ‘hydrocortisone’ ‘dexamethasone’ ‘adrenal suppression’ ‘Cushing case report’ and ‘Cushing’s syndrome’. Nine case reports of ICS were found in both children and adults following a single steroid injection. There are multiple factors affecting the response to steroids that make one develop Cushing’s syndrome while the others do not. Governments in developing countries must make more serious efforts to enforce the existing laws that prohibit the irrational use of steroids.

Iatrogenic Cushing's Syndrome After Topical Steroid Therapy for Psoriasis.

Glucocorticoids are used for the treatment of many diseases, such as inflammatory, allergic, autoimmune, and neoplastic diseases. They can be used in the form of topical, oral, inhalable, rectal, and intra-articular agents. Many topical steroid-related iatrogenic Cushing's syndrome cases affecting especially children have been reported in the literature. Topical steroid-related Cushing's syndrome is rarely seen in adults. In this report, we present the case of a 32-year-old male patient with iatrogenic Cushing's syndrome related to long-term clobetasol propionate treatment for psoriasis. In the context of such treatment, the glucocorticoid withdrawal problem has to be overcome. At present there is no consensus on steroid withdrawal. Patients on long-term glucocorticoid treatment must be evaluated for potential adverse effects and withdrawal symptoms by their physician and their endocrinologist.

Iatrogenic Cushing's syndrome secondary to combined oral contraceptive pill in a patient with congenital adrenal hyperplasia

Iatrogenic Cushing's syndrome secondary to combined oral contraceptive pill in a patient with congenital adrenal hyperplasia

Hormonal circadian rhythms in patients with congenital adrenal hyperplasia: identifying optimal monitoring times and novel disease biomarkers.

The treatment goal in congenital adrenal hyperplasia (CAH) is to replace glucocorticoids while avoiding androgen excess and iatrogenic Cushing's syndrome. However, there is no consensus on how to monitor disease control. Our main objectives were to evaluate hormonal circadian rhythms and use these profiles to identify optimal monitoring times and novel disease biomarkers in CAH adults on intermediate- and long-acting glucocorticoids. This was an observational, cross-sectional study at the National Institutes of Health Clinical Center in 16 patients with classic CAH. Twenty-four-hour serum sampling for ACTH, 17-hydroxyprogesterone (17OHP), androstenedione (A4), androsterone, DHEA, testosterone, progesterone and 24-h urinary pdiol and 5β-pdiol was carried out. Bayesian spectral analysis and cosinor analysis were performed to detect circadian rhythmicity. The number of hours to minimal (TminAC) and maximal (TmaxAC) adrenocortical hormone levels after dose administration was calculated. A significant rhythm was confirmed for ACTH (r(2), 0.95; P<0.001), 17OHP (r(2), 0.70; P=0.003), androstenedione (r(2), 0.47; P=0.043), androsterone (r(2), 0.80; P<0.001), testosterone (r(2), 0.47; P=0.042) and progesterone (r(2), 0.64; P=0.006). The mean (s.d.) TminAC and TmaxAC for 17OHP and A4 were: morning prednisone (4.3 (2.3) and 9.7 (3.5) h), evening prednisone (4.5 (2.0) and 10.3 (2.4) h), and daily dexamethasone (9.2 (3.5) and 16.4 (7.2) h). AUC0-24 h progesterone, androsterone and 24-h urine pdiol were significantly related to 17OHP. In CAH patients, adrenal androgens exhibit circadian rhythms influenced by glucocorticoid replacement. Measurement of adrenocortical hormones and interpretation of results should take into account the type of glucocorticoid and time of dose administration. Progesterone and backdoor metabolites may provide alternative disease biomarkers.

Iatrogenic Cushing syndrome and adrenal insufficiency during concomitant therapy with ritonavir and fluticasone.

Ritonavir is a potent inhibitor of the cytochrome P450 enzyme CYP3A4 and is subject to multiple drug–drug interactions. This becomes especially important when the patient is also taking medications metabolized through CYP3A pathway as increased and potentially toxic drug levels may ensue. Herein we present one such interaction wherein a 57 year old gentleman with human immunodeficiency virus (HIV) infection on highly active antiretroviral therapy that included ritonavir, had addition of fluticasone inhaler to his medication repertoire for treatment of chronic obstructive pulmonary disease. This resulted in severe osteoporosis, iatrogenic Cushing syndrome and adrenal insufficiency due to the potentiated systemic glucocorticoid effect of inhaled fluticasone by ritonavir. This case emphasizes the need for pharmacovigilance when managing patients on complex drug regimens for physicians treating HIV infected patients.

Adrenal Suppression in EoE Treated With Budesonide?

See “Adrenal Suppression in Children Treated With Oral Viscous Budesonide for Eosinophilic Esophagitis” by Panagiotopoulos et al on page 190. In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Panagiotopoulos et al (1) report on the results of a quality assurance (QA) project conducted in children with eosinophilic esophagitis (EoE) treated with budesonide. They disclose evidence that adrenal suppression may result from administering therapeutic doses of budesonide for relatively short (<3 months and longer) time periods. During the last decade, the number of children being diagnosed as having EoE has greatly increased. A full understanding of the implications of the diagnosis is lacking. Therefore, an appreciation of the risks and benefits of any 1 therapy, such as glucocorticoids (GCs), is also unclear. That the study was undertaken as a QA project raises issues both of its scientific value and its place in a scientific peer-reviewed journal. Readers should take note that this is not a rigorously designed prospective study of the type all editors like to publish. It does however have a place as a “hypothesis generating” or (as described) a “pilot” study. The authors have felt appropriately compelled to bring to our attention the potential risks inherent in a treatment regarded as relatively benign. Budesonide treats the symptoms of EoE effectively. It is a GC, but because it is rapidly metabolized in the liver, it is considered less likely to result in adverse effects associated with the systemic use of other GCs. It has never been suggested that budesonide is completely safe, but it is possible that clinicians have become too comfortable with its safety profile. The introduction of GC as therapy for various clinical conditions started in the 1950s (2). Currently, they are used as physiologic replacement in adrenal insufficiency and pharmacologic treatment in a variety of conditions including rheumatologic diseases, nephrotic syndrome, asthma, inflammatory bowel diseases, and EoE. As a general rule, treatment with GC requires close monitoring for both undertreatment and overtreatment. Undertreatment can result in adrenal insufficiency, and overtreatment may lead to growth suppression, iatrogenic Cushing syndrome, and hypothalamic-pituitary-adrenal (HPA) axis suppression/secondary adrenal insufficiency. HPA axis suppression can occur with the use of GC therapy of >2 weeks duration, which exceeds physiological doses (the normal endogenous cortisol secretory rate is 6–8 mg · m−2 · day−1 in children and adults (3,4)). HPA axis suppression has been reported in prolonged systemic, topical, and intralesional GC therapy (2,5). The low-dose 1-μg adrenocorticotropic hormone test used by the authors is more sensitive than the standard-dose (250 μg) test (2,6–8); thus, if the findings reported are confirmed, then the screening and testing for secondary adrenal insufficiency in patients being treated with budesonide for an extended time period is warranted. Also, stringent guidelines for the use of budesonide might be considered. The authors did not find significant association with the treatment duration, dose, or concomitant use of inhaled/nasal corticosteroids. This should be interpreted with caution because of the small sample size and study design (or perhaps lack of design.) Other risk factors for adrenal suppression may include efficiency of gastrointestinal absorption related to diet, gastric acidity, bowel transit time, and interindividual sensitivity to GC related to genetic factors (9). A prospective study measuring adrenal suppression in EoE patients matched for disease extent and randomized to receive either budesonide or a nonsteroid treatment is warranted to determine the significance of the findings disclosed. The early symptoms of secondary adrenal insufficiency can be too subtle to note, but until the true incidence and extent of adrenal suppression is known, it is worthy of consideration to provide hydrocortisone supplementation in times of stress (such as major surgery) to any patient who has been treated with budesonide for 3 months in the last year.