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Steroids in pediatrics : a double edged sword ? Javier Aisenberg M.D overview ACTH Aldosterone Cortisol feedback Sex steroids Adrenal Insufficiency Cortisol secretion by the adrenal cortex is 5-7 mg/m2/day ( 10-12 mg/m2/day oral dose ) Cortisol secretion increase 2-4 folds during stress Adrenal insufficiency occurs when the adrenal cortex fails to produce enough glucocorticoid and mineralocorticoid in response of stress Adrenal Insufficiency - Diagnosis Glucocorticoids are essential for withstanding stress Suspect adrenal insufficiency if there is inappropriately rapid decompensation in the face of metabolic stress Glucocorticoid Deficiency Hypotension permissive effect of glucocorticoids on cardiovascular function Hyponatremia increase ADH secretion water retention hemodilution Hypoglycemia permissive effects on gluconeogenesis Mineralocorticoid Deficiency Hyponatremia sodium loss from kidneys Hypotension: decrease effective blood volume Hyperkalemia & acidosis inability to excrete potassium and acid Primary adrenal insufficiency -Signs & Symptoms Weakness - fatigue Anorexia Nausea - diarrhea Weight loss & poor growth Hyperpigmentation ( primary ) Hypotension 100% 100% 56% 100% 90% 88% Primary adrenal insufficiency: Associated with both, glucocorticoid and mineralocorticoid deficiency. – Hyperkalemia, hyperpigmentation due to elevated ACTH level, high renin level Secondary adrenal insufficiency: Associated with glucocorticoid deficiency only. – NO Hyperkalemia (normal renin level), NO hyperpigmentation (low ACTH level) – Presenting symptoms similar to primary Adrenal insufficiency • Iatrogenic central secondary adrenal insufficiency is the more frequent cause of adrenal insufficiency Frequency of signs and symptoms in Cushing’s syndrome Sign or symptom Occurrence % Sign or symptom Occurrence % Central obesity 94 Easy bruisability 60 Hypertension 82 Osteoporosis 60 Glucose intolerance 80 Personality changes 55 Hirsutism 75 Acne 50 Amenorrhea or impotency 75 Edema 50 Purple striae 65 Headache 40 Plethoric faces 60 Poor wound healing 40 Prior to the availability of synthetic cortisone,it was almost impossible to effect a cure of Cushing’s Syndrome due to adrenal tumor because of the likelihood that the patient would die of adrenal insufficiency if the tumor was completely excised Alan L.Graber j clin Endocr 25:11,1965 Cortisone was the First Steroid Drug • In 1935, E. Kendal and T.Reichstein isolated the hormone cortisone from adrenal secretions. • In 1948, P. Hench et al cortisone used to treat severe rheumatoid arthritis. • 1950 Nobel Prize to Kendal , Reichstein and Hench Cortisone proved to have a remarkable ability to relieve inflamed, swollen joints after just a few days of use. People who couldn't rise from a chair, shave, open a door or lift a cup, now could. After dramatically improving arthritis symptoms in the 1940s, cortisone was hailed as a "miracle drug.“ But problems emerged. People taking cortisone for months in doses high enough to relieve inflammation routinely experienced harmful side effects. Mechanism of action • Glucocorticoids bind to intracellular receptors • The macromolecular complex formed is then transported into the nucleus • In the nucleus by altering gene expression, glucocorticoids alter the regulation of many cellular processes. Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis • Depending on administration form, the percentage of patients with adrenal insufficiency varied from 4.2% for nasal corticosteroids to 52.2% for intra-articular corticosteroids • Stratified by disease, percentages ranged from 6.8% for asthma patients with inhalation corticosteroids only to 60.0% for patients with hematological malignancies • According to dose, the percentage of adrenal insufficiency varied from 2.4% (low dose) to 21.5% (high dose), • And according to treatment duration from 1.4% (28 d) to27.4% (1 y) in asthma patients. • In conclusion, this study demonstrates that all patients using corticosteroid therapy are at risk for adrenal insufficiency. • This implies that clinicians should: 1) inform patients about the risk and symptoms of adrenal insufficiency; 2) consider testing patients after cessation of high-dose or long-term treatment with corticosteroids; and 3) display a low threshold for testing, especially in those patients with nonspecific symptoms after cessation J Clin Endocrinol Metab, June 2015, 100(6):2171–2180 Endocrine Effects of Inhaled Corticosteroids in Children • Although the long-term use of ICSs has a more favorable safety profile than oral corticosteroids, uncertainty about systemic complications persist 1. In children, the long-term use of oral corticosteroids can lead to compromised linear growth and bone mineralization, diabetes mellitus (DM), Cushing syndrome, obesity, and suppression of the hypothalamic-pituitary-adrenal (HPA) axis. 2. Inhaled corticosteroids have a similar adverse effect profile but with less frequency and severity Adverse Effects of ICSs :Adrenal insufficiency • Patients at Highest Risk :Symptomatic patients And asymptomatic patients with risk factors: high daily dose, taking an ICS and another corticosteroid, or low BMI • Signs and Symptoms :Cushingoid features ,anorexia, weight loss, fatigue, growth failure, or hypoglycemia; typical symptoms of chronic adrenal insufficiency may not occur; hence, also test all high-risk asymptomatic patients • Testing and Action :Symptomatic: if morning cortisol level <3 μg/dL, adrenal insufficiency is likely; if morning cortisol level≥3 μg/dL,do 1-μg ACTH stimulation test (A stimulated cortisol value <18 μg/dL is abnormal ) Asymptomatic but at high risk: if morning cortisol level <3 μg/dL do,1-μg ACTH stimulation test; if morning cortisol level 3-10 μg/dL, refer to a specialist for more testing Adverse Effects of ICSs :Hyperglycemia or diabetes mellitus • Patients at Highest Risk :Patients with risk factors or signs of insulin resistance taking high daily dose ICS • Signs and Symptoms: Polyuria, polydipsia • Testing and Action :Annual hemoglobin A1c levels and fasting glucose ,Refer to a specialist if hemoglobin A1c ≥6.0% or fasting glucose >100 mg/dL Adverse Effects of ICSs :Worsening blood glucose level control in diabetes mellitus (types 1 and 2) • Patients at Highest Risk :Patients with diabetes mellitus after ICS treatment is initiated or if dose is increase • Signs and Symptoms :Worsening blood glucose control • Testing and Action :Adjust diabetes medications Adverse Effects of ICSs :Decrease in bone mineral density • Patients at Highest Risk :Chronic disease, malnutrition, or taking long-term medications that reduce bone mineral density • Signs and Symptoms : usually asymptomatic • Testing and Action :if high risk, consider Bone Density ; • if not at high risk,400- to 800-IU vitamin D supplementation and ensure adequate calcium intake • Test Result Interpretation Higher-dose vitamin D supplementation for levels <30 ng/mL Adverse Effects of ICSs :Growth suppression • Patients at Highest Risk :All patients taking ICSs and additional growth-impairing medications • Signs and Symptoms :Decrease of >2 SDs in height velocity or retarded growth velocity below age and pubertal norms(persisting after 1 year of therapy) • Testing and Action :Refer to a specialist Excess or insufficiency ? • Impaired growth in height is a feature of Cushing’s syndrome secondary to excess exogenous ICS, a recognized systemic effect of conventional doses of ICS1 and also a sign of adrenal insufficiency. • However, the key to differentiation is increased or normal weight gain in the former and poor weight gain/weight loss in adrenal insufficiency. MECHANISMS OF GROWTH SUPPRESSION BY GLUCOCORTICOIDS Complex and multifactorial Multiple catabolic effects of GC GC interfere with the nitrogen and mineral retention required for the growth process Inhibits bone formation directly and indirectly Inhibits chondrocyte mitosis Impairs collagen synthesis and degradation DB Allen M.D