Download Steroids in pediatrics : a double edged sword ?

Steroids in pediatrics : a double
edged sword ?
Javier Aisenberg M.D
overview
ACTH
Aldosterone
Cortisol feedback
Sex steroids
Adrenal Insufficiency
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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
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Glucocorticoids are essential for
withstanding stress
Suspect adrenal insufficiency if there is
inappropriately rapid decompensation
in the face of metabolic stress
Glucocorticoid Deficiency
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Hypotension permissive effect of
glucocorticoids on cardiovascular
function
Hyponatremia increase ADH secretion
water retention  hemodilution
Hypoglycemia permissive effects on
gluconeogenesis
Mineralocorticoid Deficiency
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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