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Iatrogenic Cushing's Disease

Iatrogenic Cushing's Syndrome

Iatrogenic Cushing's disease (iatrogenic Cushing's syndrome) is the most common cause of cushingoid symptoms. Glucocorticoids, not only those given by oral and parenteral routes, but also those administered topically, or as drops or inhalants, can lead to the development of the condition. The progress of the disease may sometimes be facilitated by interactions with other drugs that prolong glucocorticoid action. Taking steroids suppresses endogenous glucocorticoid production, putting patients at risk of developing an adrenal crisis if the medication is discontinued suddenly.


Presentation

The set of symptoms accompanying abnormally high levels of plasma glucocorticoids – whether of endogenous or exogenous origin - is called Cushing’s syndrome. Endogenous Cushing’s syndrome can be adrenocorticotropic hormone (ACTH) dependent or independent. In ACTH-dependent condition, ACTH levels are high, whereas, in ACTH-independent cases, which often derive from adrenal neoplasms, ACTH levels are low because of the feedback effect of the glucocorticoids on the pituitary gland. Cushing’s syndrome caused by exogenously administered glucocorticoids is called iatrogenic Cushing's disease or iatrogenic Cushing's syndrome. It occurs more frequently than the endogenous condition due to the extensive use of glucocorticoids for their anti-inflammatory and immunosuppressive effects.

The severity of the Cushing’s syndrome symptoms in patients on glucocorticoids will depend on the dosage, the length of treatment, and the variant of glucocorticoid compound used. Many different versions of glucocorticoids have been synthesized with the aim of optimizing their effects, and these compounds may differ in many respects; for example, by their rate of absorption, metabolism, water solubility, and affinity for glucocorticoid and mineralocorticoid receptors. Drug interactions also have an important role in the development of the condition. Prominent examples are drugs that inactivate cytochrome P450 enzymes, interfering with the breakdown of glucocorticoids, and thereby enhancing their activities. Ritonavir, a protease inhibitor and a component of combination antiretroviral therapy, is a powerful inhibitor of cytochrome P450. Its use, together with fluticasone has led to exogenous Cushing’s disease, with complications of osteoporosis and diabetes [1]. Together with oral budesonide, it resulted in weakness, muscle wasting, and other characteristic symptoms in a hepatitis sufferer [2]. Inhaled fluticasone propionate taken together with antidepressants was reported to result in the rapid development of symptoms of Cushing’s syndrome [3].

The increased prevalence of obesity can make it difficult to identify a patient with true Cushing’s syndrome [4], but there are several characteristic features of the condition that together allow it to be diagnosed (apart from laboratory tests that verify the condition). These effects include redistribution of fat resulting in moon face and centripetal obesity, glucocorticoid acne, buffalo hump, thinning of the skin, and purple striae. Patients also notice a weakening of muscles, diabetes, hypertension, increased infections, problems with wound healing, osteopenia, osteoporosis [5], and psychological problems. Women may experience hormonal problems leading to amenorrhea and infertility. Men may also be affected with infertility and loss of libido. Diabetes and peptic ulceration may also cause symptoms. Children’s growth is retarded, but otherwise, their symptoms are somewhat different and less striking than those of adults [6].

Easy Bruising
  • Memory loss was due to job stress and thin skin and easy bruising were due to sun exposure. After foot and back fractures at age 47, I was finally diagnosed.[csrf.net]
  • He had plethoric face, prominent neck hump, pink striae, easy bruising, and vellous hypertrichosis [Figure 1] . There was erythroderma studded with small pustules.[e-ijd.org]
  • Presence of moon face, marked obesity on the body, hirsutism, buffalo hump, purple striae, hypertension, muscle weakness, easy bruising on the skin and acne are classic signs [ 1 ].[academic.oup.com]
  • In 2013 she started gaining weight, noticed easy bruising of her forearms, and developed muscle cramps, lightheadedness, and fatigue.[acgcasereports.gi.org]
  • ICS patients may present with purple striae, central obesity, hypertension, buffalo hump, muscle weakness, moon face, hirsutism, and easy bruising of skin like in our patient [ 1 , 4 – 6 ].[ncbi.nlm.nih.gov]
Weight Gain
  • gain and energy level.[pediatrics.aappublications.org]
  • After 12 months of posaconazole treatment, she progressively presented at first a skin fragility and then a venous stasis dermatitis with weight gain (6 kg) and a moon face.[aac.asm.org]
  • He also complained of progressive weight gain, body ache, and generalized weakness.[e-ijd.org]
  • During infancy, the anthropome tric pattern characterized by weight gain associated with slower growth rates should lead to suspicion of Cushing’s syndrome within the differential diagnosis.[scielo.conicyt.cl]
  • One of the main signs is weight gain and more body fat, such as: increased fat on your chest and tummy, but slim arms and legs a build-up of fat on the back of your neck and shoulders – known as a "buffalo hump" a red, puffy, rounded face Other symptoms[nhs.uk]
Buffalo Hump
  • View of buffalo hump, on the patient’s neck. F ig . 2. View of buffalo hump, on the patient’s neck.[academic.oup.com]
  • These effects include redistribution of fat resulting in moon face and centripetal obesity, glucocorticoid acne, buffalo hump, thinning of the skin, and purple striae.[symptoma.com]
  • The authors note that the patient was referred to the pediatric department with stunted growth, truncal obesity, purple skin striate, buffalo hump, and moon face six months after initiation of topical ocular GC treatment.[medicalxpress.com]
  • He had a moon face appearance with truncal obesity, buffalo hump, hypertrichosis in trunk, and purple striae in the axilla, periumbilical, and inguinal region.[ncbi.nlm.nih.gov]
Cushingoid Facies
  • facies and poor growth.[pediatrics.aappublications.org]
  • At the time of the physical examination, the patient had a cushingoid facies with small eyes, mouth in carp, vultuous cheeks, bitemporal fat, hypertrichosis and chin ( Figure 1 ).[scielo.conicyt.cl]
Supraclavicular Fat Pads
  • Common: centripetal obesity with dorsocervical and supraclavicular fat pads, facial plethora and "moon face," fatigue, hyperglycemia, hypertension, mood lability, easy bruisability and skin atrophy, oligo/amenorrhea, hirsutism/acne (ACTH-dependent) More[hopkinsguides.com]
  • Individuals with Cushing syndrome can develop moon facies, facial plethora, supraclavicular fat pads, buffalo hump, truncal obesity, and purple striae, as shown in the image below. Physical findings in Cushing syndrome.[emedicine.medscape.com]
Hypertension
  • In our case, mild hypertension to the local steroid treatment was recorded and the blood pressure turned into normal limits after the cessation of application.[e-ijd.org]
  • Patients also notice a weakening of muscles, diabetes, hypertension, increased infections, problems with wound healing, osteopenia, osteoporosis, and psychological problems.[symptoma.com]
  • Keywords: 40 y.o woman Has diabetes & hypertension for 6 months On oral hypoglycemia & antihypertensive medication Height: 165cm Weight: 85kg BMI: overweight/obese Moon shaped facies Truncal obesity Abdominal striae Diminished motor strength of proximal[medatrio.com]
  • The adverse metabolic features associated with glucocorticoid use include obesity, skeletal muscle myopathy, hypertension, insulin resistance and diabetes and are collectively termed 'iatrogenic Cushing's syndrome'.[centerwatch.com]
Muscle Weakness
  • Potty belly due to muscle weakness, fat redistribution and water retention. Muscle weakness leads to instability in standing and walking. Significant coat problems and hair loss. Hair is unable to grow back until the dose is lowered.[secondchanceaihadogs.com]
  • ICS patients may present with purple striae, central obesity, hypertension, buffalo hump, muscle weakness, moon face, hirsutism, and easy bruising of skin like in our patient [ 1 , 4 – 6 ].[ncbi.nlm.nih.gov]
Muscular Atrophy
  • Prevalence rate of the other clinical features such as polyphagia, abdominal enlargement, panting, muscular atrophy, prominent vasculature, calcinosis cutis and thin skin were characteristically high in spontaneous Cushing's syndrome as compared to iatrogenic[ci.nii.ac.jp]
  • atrophy Spinal stenosis Spinocerebellar ataxia Spleen Splenic rupture Splenomegaly Spondylolisthesis Sports injuries Staphylococcal diseases Staphylococcal scalded skin syndrome Statins Statistical analysis of data Stevens-Johnson syndrome Stiff person[amboss.com]
Thin Skin
  • Dry, flaking, and thinning skin, risk of staph infections, difficulty with wound healing, darkening and blackening of skin. Risk of developing iatrogenic diabetes. Increased susceptibility to infections.[secondchanceaihadogs.com]
  • He had Cushingoid image, truncal obesity, drumstick limbs, and paper-thin skin with striae, and crops of dense, inflamed pustules on his chest and back [Figure 1] .[e-ijd.org]
  • Memory loss was due to job stress and thin skin and easy bruising were due to sun exposure. After foot and back fractures at age 47, I was finally diagnosed.[csrf.net]
  • Prevalence rate of the other clinical features such as polyphagia, abdominal enlargement, panting, muscular atrophy, prominent vasculature, calcinosis cutis and thin skin were characteristically high in spontaneous Cushing's syndrome as compared to iatrogenic[ci.nii.ac.jp]
  • Signs and symptoms include a round face, upper body obesity, fragile and thin skin, purple stretch marks in the skin, fatigue, muscle weakness, hypertension, diabetes mellitus, hypertrichosis and amenorrhea in women, impotence in men, and osteoporosis[fpnotebook.com]
Purpura
  • Discussion Local adverse effects of topical steroids are acne, purpura, atrophy, striae, and telangiectasia. ICS and hypothalamic-pituitary-adrenal (HPA) axis suppression are rare but unignorable complications of topical steroids [ 1 , 4 – 6 ].[ncbi.nlm.nih.gov]
Delayed Wound Healing
  • In addition, the systemic side effects of excess cortisol can delay wound healing and result in immune suppression [ 1 , 2 , 6 ].[academic.oup.com]
  • Other possible signs include poor skin and hair condition, muscle atrophy, increased abdominal fat, enlarged liver, chronic or recurrent infections (especially skin or urinary), delayed wound healing, excessive panting, sodium retention (which can cause[hallettvet.com]
  • Decreased IL-2 levels prevent the proliferation of T-lymphocytes. [9] History and Physical Patients may have a history of weight gain, fatigue, weakness, delayed wound healing, easy bruising, back pain, bone pain, loss of height, depression, mood swings[statpearls.com]
Facial Redness
  • The most common symptoms and signs of excess levels of cortisol in the body are obesity, facial plethora (facial redness), violaceous abdominal striae (purple or bluish stripes on the abdomen), thinning of the skin that leads to spontaneous bruising,[britannica.com]
Psychiatric Manifestation
Irritability
  • This con dition should be distinguished from irritative diaper dermatitis (90% of cases), as management changes significantly.[scielo.conicyt.cl]
  • Fecal transplant is used to treat gut infections and is now being studied as a treatment for obesity, urinary tract infections, irritable bowel syndrome and more.[nytimes.com]
  • […] face (‘moon face’) Thin skin, easily bruised, slow healing and ulcers Muscular weakness Thirst Frequent urination Headaches High blood pressure High white blood cell count, low serum potassium High blood sugar (in 80 per cent of patients) Mood swings, irritability[betterhealth.vic.gov.au]
  • […] anesthetics Inherited hyperbilirubinemia Innate immune system Insertional tendinopathy Insulin Insulinoma Internal hernia Interstitial lung disease Intestinal ischemia Intracerebral hemorrhage Intravenous anaesthetics Intussusception Iron deficiency anemia Irritable[amboss.com]
Amenorrhea
  • Women may experience hormonal problems leading to amenorrhea and infertility. Men may also be affected with infertility and loss of libido. Diabetes and peptic ulceration may also cause symptoms.[symptoma.com]
  • It is characterized by upper body OBESITY; OSTEOPOROSIS; HYPERTENSION; DIABETES MELLITUS; HIRSUTISM; AMENORRHEA; and excess body fluid.[fpnotebook.com]
  • […] the abdomen), thinning of the skin that leads to spontaneous bruising, muscle weakness and wasting, back pain , osteopenia and osteoporosis , depression and other psychological symptoms, hypertension , and menstrual disturbances ( oligomenorrhea and amenorrhea[britannica.com]
  • Common: centripetal obesity with dorsocervical and supraclavicular fat pads, facial plethora and "moon face," fatigue, hyperglycemia, hypertension, mood lability, easy bruisability and skin atrophy, oligo/amenorrhea, hirsutism/acne (ACTH-dependent) More[hopkinsguides.com]
Polyuria
  • Lab investigation Increased total serum cortisol Increased free cortisol Decreased serum ACTH Hypothesis: Iatrogenic Cushing’s syndrome Additional Learning issues: Pathophysiology of some Cushing’s disease clinical features Polyuria, polydipsia cortisol[medatrio.com]
  • The most common findings were polyuria and polydipsia in 30 dogs (75.0%) consisted of 15 iatrogenic (71.4%) and 15 spontaneous (78.9%) cases, and alopecia in 25 dogs (62.5%) including 13 iatrogenic (61.9%) and 12 spontaneous (63.2%) cases.[ci.nii.ac.jp]
  • […] oligo/amenorrhea, hirsutism/acne (ACTH-dependent) More specific: broad ( 1cm) purple striae, proximal muscle weakness Other: increased risk of infection, increased cardiovascular risk, thromboembolism, bone loss, fractures, kidney stones, polydipsia, polyuria[hopkinsguides.com]
  • 2017: Endocrinology, Diabetes & Metabolism Case Reports # 23 Stefanie Hoffrogge, Lena Fels, Marion Schmicke, Reinhard Mischke In a 12-year-old male Labrador Retriever, presented due to other disease symptoms, clinical signs of hyperadrenocorticism (polyuria[read.qxmd.com]
Oligomenorrhea
  • […] bluish stripes on the abdomen), thinning of the skin that leads to spontaneous bruising, muscle weakness and wasting, back pain , osteopenia and osteoporosis , depression and other psychological symptoms, hypertension , and menstrual disturbances ( oligomenorrhea[britannica.com]

Workup

Before any other examination, a suspicion of Cushing’s disease should prompt a thorough review of all medications, including different forms of the administered glucocorticoids, to exclude or verify the possibility of the condition’s iatrogenic origin. Apart from glucocorticoids, other compounds, like megestrol acetate with progesterone activity, also have glucocorticoid-like effects [7]. Herbal products have also been reported to contain glucocorticoids [8].

Laboratory workup shows signs of adrenal suppression (early morning cortisol and ACTH levels being low [1] [2] [3]), owing to low ACTH output caused by the exogenous glucocorticoids. However, it should be remembered that hydrocortisone increases cortisol levels [9]. Dehydroepiandrosterone sulfate levels are also low. ACTH stimulation tests are also below normal [1] [3]. Tests for 24-h urinary cortisol tend to be normal, at the lower values of the normal range [2] [3]. Patients are often hypokalemic, and blood glucose may be high [3]. Bone mineral density measurement will determine the level of osteopenia or osteoporosis.

Nephrolithiasis
  • […] fungoides Myelodysplastic syndromes Myelopathy Myeloproliferative neoplasms Myocarditis Myotonic syndromes Narcolepsy Nasal papilloma Necrotizing enterocolitis Neonatal jaundice Neonatal respiratory distress syndrome Neoplastic meningitis Nephritic syndrome Nephrolithiasis[amboss.com]
  • Typical features include weight gain, central obesity, dorsocervical hump, moon face, facial plethora, thin skin, easy bruising, abdominal striae, hirsutism, proximal myopathy, osteopenia, glucose intolerance, hypertension, nephrolithiasis and psychiatric[springerplus.springeropen.com]
Delayed Bone Age
  • The indica ted treatment was topical with hydrocortisone acetate and delayed bone age (BA) (6 months BA for 1 year 3 months in chronological age).[scielo.conicyt.cl]

Treatment

  • She arrived at the ophthalmology department with a complaint of painful eyes, and was diagnosed with bilateral iridocyclitis and started on betamethasone sodium phosphate eye drop treatment .[medicalxpress.com]
  • In the fourth month of treatment, the basal serum cortisol level was 8.3 g/dl and peak cortisol response to ACTH stimulation test was 24 mg/dl. Therefore, the treatment was terminated by reducing hydrocortisone doses.[academic.oup.com]
  • Topical GC treatment with nasal drops or ointment rarely induces iatrogenic CS. 1 , 2 GC treatment via eye drops is commonly used to treat ocular inflammatory diseases, including juvenile idiopathic uveitis.[pediatrics.aappublications.org]
  • TS is the first choice of treatment for localized and mild PV [ 4 , 5 ].[ncbi.nlm.nih.gov]

Prognosis

  • The prognosis is worsened in the setting of an unresectable hormone-secreting tumor.[statpearls.com]
  • Outlook (Prognosis) Slowly tapering the medicine that is causing the condition can help reverse the effects of adrenal gland shrinkage (atrophy). This may take months to as long as a year.[pennstatehershey.adam.com]
  • Untreated Cushing associated with high risk of mortality, poor prognosis seen in ectopic ACTH syndrome and adrenocortical carcinoma Basis for recommendation Nieman LK et al: The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline[hopkinsguides.com]

Etiology

  • Use Additional Use Additional Help Certain conditions have both an underlying etiology and multiple body system manifestations due to the underlying etiology.[icd10data.com]
  • It has been commonly described with oral and topical steroid use, but scarce reports have documented intranasal steroid usage as the etiology in infancy.[pediatrics.aappublications.org]
  • ACTH-dependent cortisol excess due to a pituitary adenoma is called Cushing disease, and it is responsible for 80% of endogenous Cushing syndrome. [1] [2] [3] Etiology There are two main etiologies of Cushing syndrome: endogenous hypercortisolism and[statpearls.com]
  • May have non-specific manifestations of Cushing and mildly elevated cortisol (1-3 times upper limit of normal) which revert to normal with treatment of underlying etiology.[hopkinsguides.com]

Epidemiology

  • J Clin Endocrinol Metab 85:637, 2000 [PMID:10690869] Etxabe J, Vazquez JA: Morbidity and mortality in Cushing's disease: an epidemiological approach.[hopkinsguides.com]
  • Adrenal hyperplasia, adenoma, and carcinoma are major causes of ACTH-independent Cushing syndrome. [4] [5] [6] Epidemiology Actual incidence and prevalence of Cushing syndrome are not known.[statpearls.com]
  • […] cohort study Research BMJ 2012 ; 345 doi: (Published 30 July 2012) Cite this as: BMJ 2012;345:e4928 Laurence Fardet , associate professor and senior consultant in internal medicine 1 2 3 4 , Irene Petersen , principal research associate in statistics and epidemiology[bmj.com]
  • J Bone Miner Res 15:993–1000 View Article Google Scholar van Staa TP, Leufkens HG et al (2002) The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis.[springerplus.springeropen.com]
Sex distribution
Age distribution

Pathophysiology

  • Lab investigation Increased total serum cortisol Increased free cortisol Decreased serum ACTH Hypothesis: Iatrogenic Cushing’s syndrome Additional Learning issues: Pathophysiology of some Cushing’s disease clinical features Polyuria, polydipsia cortisol[medatrio.com]
  • The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 1998;128(2):127-37. Endereço para correspondência: Luiz Roberto Salgado Av. Brigadeiro Luiz Antônio 4258 01402-002 São Paulo, SP Fax: (11) 3885-6719 E-mail: [email protected][passeidireto.com]
  • We also discuss the pathophysiology, differential diagnosis and management of the condition in such patients, as well as how it can be distinguished from HIV-associated lipodystrophy.[journals.sagepub.com]
  • […] hypercortisolism outweighs the endogenous causes, of the endogenous causes pituitary mediated ACTH production accounts for up to 80% of cases of hypercortisolism, followed by adrenals, unknown source and ectopic ACTH production secondary to malignancies. [7] [8] Pathophysiology[statpearls.com]
  • Pathophysiology Glucocorticoids’ bioavailability is between 60% and 100%.[emedicine.medscape.com]

Prevention

  • Recommendations of the National Asthma Education and Prevention Program. MMWR Recomm Rep. 2003, 52: 1-8.[mrmjournal.biomedcentral.com]
  • The rational and careful use of topical corticosteroids has multiple therapeutic benefits and may prevent ma jor adverse reactions.[scielo.conicyt.cl]
  • The topical steroid was ceased, and methotrexate (10 mg/week) for psoriatic plaques and hydrocortisone acetate (20 mg/m 2 /d) per oral were initiated in order to prevent adrenal insufficiency in our case.[ncbi.nlm.nih.gov]

References

Article

  1. Epperla N, McKiernan F. Iatrogenic Cushing syndrome and adrenal insufficiency during concomitant therapy with ritonavir and fluticasone. Springerplus. 2015 Aug 27;4:455.
  2. Yeoh SW. Iatrogenic Cushing Syndrome from Interaction Between Ritonavir and Oral Budesonide During Direct Acting Antiviral Hepatitis C Therapy. J Clin Exp Hepatol. 2016 Sep;6(3):246-249.
  3. Celik O, Niyazoglu M, Soylu H, Kadioglu P. Iatrogenic Cushing's syndrome with inhaled steroid plus antidepressant drugs. Multidiscip Respir Med. 2012 Aug 29;7(1):26.
  4. Findling JW, Raff H. Cushing's Syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab. 2006 Oct;91(10):3746-3753
  5. Di Somma C, Pivonello R, Loche S, et al. Severe impairment of bone mass and turnover in Cushing’s disease: comparison between childhood-onset and adulthood-onset disease. Clin Endocrinol (Oxf) 2002; 56:153–158.

  6. Magiakou MA, Mastorakos G, Oldfield EH, et al. Cushing’s syndrome in children and adolescents. Presentation, diagnosis, and therapy. N Engl J Med 1994; 331:629–636.

  7. Mann M, Koller E, Murgo A, Malozowski S, Bacsanyi J, Leinung M. Glucocorticoidlike activity of megestrol. A summary of Food and Drug Administration experience and a review of the literature. Arch Intern Med. 1997 Aug 11-25;157(15):1651-1656.
  8. Abuchaibe C, Akhtar ON. SAT-0776: Exogenous Cushing's Syndrome after Use of OTC Joint Supplement. Adrenal Case Reports 1 - CAH and Adrenal Insufficiency. Endocrine Society's 96th Annual Meeting and Expo, June 21–24, 2014 – Chicago. Available at http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2014.AHPAA.1.SAT-0776. Accessed: 4/2/15.
  9. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing's syndrome. Lancet. 2006 May 13;367(9522):1605-1617.

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Last updated: 2018-06-21 20:16