1. Addison’s Disease
Nasimeh Rakhshani CC3

2. Adrenal Insufficiency
Addison’s Disease

3. Addison’s Disease First described by Thomas Addison in 1855
His description referred to primary adrenal insufficiency
At that time, the most common etiology was tuberculosis infiltration
TB infiltration continues to be the leading cause worldwide

4. Adrenal Insufficiency (AI)
Impairment in synthesis and/or release of adrenocortical hormones
Classified as:
Primary AI  results from disease intrinsic to the adrenal cortex
Secondary AI  results from impaired release or effect of adrenocorticotropic hormone (ACTH) from the pituitary gland
Tertiary AI  results from the impaired release or effect of corticotropin releasing hormone (CRH) from the hypothalamus

5. The HPA Axis (-) Hypothalamus CRH (-) ACTH Glucocorticoids
Adrenal Gland

6. Clinical Manifestations
In general, symptoms of AI include fatigue and GI complaints (nausea and vomiting)
Clinical suspicion is important because the presentation of AI may be insidious and subtle
Resultantly, clinical diagnosis is frequently delayed or missed early  if unrecognized, may present in a life-threatening crisis with acute cardiovascular collapse (adrenal crisis)
Simm PJ et al (2004), of found in children diagnosed with primary adrenal insufficiency that there was a median of 2 years delay between the onset of the first symptoms and the diagnosis

7. Clinical Manifestations
Signs and symptoms of primary adrenal insufficiency vary depending on which hormones are deficient and the severity of the defects

8. Clinical Manifestations cont’d
Glucocorticoid Deficiency
Mineralocorticoid Deficiency
Adrenal Androgen Deficiency
Fasting hypoglycemia
Hypotension
Decreased axillary hair (females)
Increased insulin sensitivity
Dizziness
Decreased pubic hair (females)
Muscle weakness
Salt craving
Loss of libido (females)
Morning headache
Weight loss
If prepubescent: assymptomatic
↑ production of POMC  ↑ melanin
Anorexia
↑pigmentation: palmer creases, gingival border,axilla
Electrolyte anomalies (hypoNa, hyperK, metabolic acidosis)
Mineralocorticiod = aldosterone and symptoms mostly b/c of sodium loss
Only females because in males androgen production is mostly by testes

10. Clinical Manifestations
Adrenal Crisis
Hypotension or shock
Particularly if disproportionate to apparent underlying illness
Serum electrolyte and metabolic abnormalities:
Hyponatremia
Hyperkalemia
Metabolic Acidosis
Hypoglycemia
Vomiting and diarrhea, sometimes with severe abdominal pain
Unexplained fever, weight loss and anorexia

11. Clinical Manifestations
Adrenal Crisis: When to be suspicious???
In neonates, presents within 1st few days-weeks of life with vomiting, diarrhea, ↓BP, ↓Na, ↑K and ↓BG
CAH (21-hydroxylase deficiency) most common cause
In females with CAH is suggested by ambiguous genitalia
In infants and older children with previously diagnosed AI
Weight loss, serum electrolyte abnormalities +/- hyperpigmentation
Often a history of an antecedent precipitating stress (eg, surgery or infection)
Bilateral adrenal hemorrhage or infarction
Children with hypotension and shock that fail to respond to vigorous fluid resuscitation and inotropic medications
Especially if have severe hyponatremia and hyperkalemia

12. Etiology
Steroidogenesis disorders: Defects within the biosynthetic pathways of glucocorticoids +/- mineralocorticoids  lead to impaired synthesis of cortisol and/or aldosterone
There are also drugs that inhibit cortisol synthesis (aminoglutethimide, ketoconazole, and etomidate)
Adrenal damage: Injury from factors extrinsic to the adrenal gland may impair adrenal function
Abnormal adrenal development: A lack of normal adrenocortical cell differentiation may result in adrenal hypoplasia
Adrenal unresponsiveness to ACTH: Defects in adrenal responsiveness to ACTH results in cortisol deficiency
Peroxisomal disorders: Accumulation of abnormal very long chain fatty acids within peroxisomes which may lead to adrenal impairment
Adrenal damage; (eg, infection, drugs, antibodies, and hemorrhage)
Congenital adrenal hyperplasia: 73 percent. Almost all of these cases were because of CYP21A2 (21-hydroxylase) deficiency
Autoimmune adrenal failure: 13 percent
Peroxisomal disorders: 5 percent
Wolman disease (lysosomal acid lipase deficiency): 3 percent
Adrenal hypoplasia congenita: 1 percent
Triple A syndrome (Unresponsiveness to ACTH): 1 percent
No diagnosis identified: 6 percent

13. Etiology Steroido-genesis disdorders Adrenal damage
Abnormal adrenal develop’t
Unresponsive to ACTH
Peroxisomal defects
CAH
Adrenal hemorrage
X-linked AHC
Familial GC deficiency
X-linked ALD/AMN
Defect in aldosterone production
Infection
(TB, HIV, fungal)
Adrenal hypoplasia SF-1 defect
- Allgrove syndrome (triple A syn)
Neonatal ALD
Defects in cholesterol biochemistry
Autoimmune (polyglandular AIS)
Refsum disease
-Wolman dz
Zellweger syndrome
AIS autoimmune syndrome
ALD adrenoleukodystrophy AMN adrenomyeloneuropathy
adrenal hypoplasia congenita (AHC)
Steroidogenic factor-1 (SF-1)

14. Etiology Continued Perry et al (2005):
20 years of data, 103 patients <18 y/o  Primary AI
73% congenital adrenal hyperplasia (CAH)
13% autoimmune adrenal insufficiency
5% Peroxisomal disorders
3% Wolman disease (lysosomal acid lipase deficiency)
1% Adrenal hypoplasia congenita
1% Triple A syndrome (Unresponsiveness to ACTH)
6% No diagnosis identified
1 in to
recently reported their experience with primary adrenal
insufficiency in children 18 years old in Montreal,
Canada, over the past 20 years. Of the 103 patients
The high false-positive rate, particularly in premature infants, has prevented universal adoption of biochemical screening for CAH.

15. Diagnosis 3 Step Process:
Confirm adrenal insufficiency  demonstrating inappropriately low cortisol secretion
Determine whether the cortisol deficiency is primary or central AI
Determine the cause of the underlying disorder

16. Diagnostic Tests Static Tests Dynamic Tests
Cortisol, ACTH, Adrenal Androgens
Mineralocorticoid status
Serum electrolytes
Plasma renin activity (PRA), direct [renin]
Dynamic Tests
Short ACTH stimulation test:
Serum cortisol levels are measured before and 60 minutes after the rapid IV infusion of synthetic ACTH (cosyntropin)
Tests of ACTH secretory ability
Insulin-induced hypoglycemia
Glucagon
Metyrapone test
CRH stimulation test: helps determine if 2o or 3o AI
PRA is a measure of the rate of conversion of angiotensinogen to angiotensin I [7], and direct renin measures the concentration of renin in the blood
Cortisol secretion is deficient in patients with primary adrenal insufficiency despite the fact that their ability to secrete ACTH is intact. Conversely, patients with secondary or tertiary adrenal insufficiency have intrinsically normal but atrophic adrenal glands that are capable of producing cortisol but fail to do so because ACTH secretion is deficient.
PLASMA RENIN ACTIVITY
- Secondary adrenal insufficiency (ACTH deficiency) is diagnosed if there is a poor cortisol response to tests of ACTH secretory ability (in addition to low 8 a.m. cortisol and low ACTH).
      - Tertiary adrenal insufficiency (deficient secretion of CRH) is diagnosed if the tests of ACTH secretory ability are low (in addition to low 8 a.m. cortisol and low ACTH), and if ACTH levels rise in response to CRH. In the rare circumstance of a defective CRH receptor, there will be no CRH-stimulated rise in ACTH secretion.
nsulin-induced hypoglycemia — This is the most sensitive standard test of ACTH release. Serial measurements of blood glucose and cortisol are made before and at 15, 30, 45, and 60 minutes after an infusion of insulin (0.05 units/kg). The peak cortisol level should be at least double the baseline level or greater than 20 mcg/dL [8]. If desired, samples for growth hormone can be obtained at the same time. A normal GH response is usually defined as ≥10 mcg/L. (See "Diagnosis of growth hormone deficiency in children", section on GH stimulation tests). Symptomatic hypoglycemia is desirable during the test, but marked changes in levels of consciousness or blood glucose <30 mg/dL must be treated with prompt administration of intravenous dextrose. The test is not recommended for children younger than 3 years old because of the risk of damage to the central nervous system resulting from hypoglycemia.
Glucagon stimulation test — This test is more appropriate in children younger than 3 years. After an intramuscular injection of glucagon, the blood glucose level initially rises then drops rapidly because of the release of endogenous insulin. Serum cortisol and growth hormone levels should increase in response to this fall in blood glucose [9].
Metyrapone test — This test also is used in the assessment of ACTH secretory ability, but is rarely used clinically. Metyrapone blocks the activity of the enzyme 11-beta-hydroxylase, which is needed to convert 11-deoxycortisol to cortisol, causing a decrease in serum cortisol levels (show figure 2). In a normal patient, the decrease in cortisol levels will stimulate ACTH secretion and increase the production of cortisol precursors. This can be measured by a rise in serum levels of ACTH and 11-deoxycortisol and/or in urinary 17-hydroxycorticosteroids and free cortisol. The ACTH-stimulated gland eventually overrides the enzymatic block, allowing cortisol production to occur. However, patients must be observed closely during this test because acute adrenal insufficiency may be precipitated if the patient has marked ACTH deficiency. (See "Metyrapone stimulation tests")

17. 1. Confirming AI
Initial step: measurement of serum ACTH and cortisol in the morning (8 a.m.) and in the fasting state
If serum cortisol is low and serum ACTH is high  likely primary AI and diagnosis can be confirmed with an ACTH stimulation test
If low cortisol and normal lytes the rapid ACTH stimulation test often performed simultaneously
If serum ACTH is also low, serum cortisol is indeterminate or pituitary disease is suspected  likely central AI  tests of ACTH secretory ability
8 am cort <80 nmol/l
Following ACTH stim <500 nmol/l
Normal ACTH 4.50

18. 1. Confirming AI cont’d In patients suspected of adrenal crisis:
Immediate treatment crucial and must not postpone until diagnosis confirmed
Draw required samples and initiate therapy (saline and GC replacement)
Cortisol, ACTH, electrolytes, PRA, renin, etc.
May perform a short ACTH stimulation test following treatment in these patients if:
Treatment has been given for < a few days (no adrenal suppression secondary to treatment)
Dexamethasone used to treat (not detected in cortisol assay unlike hydrocortisone and cortisone)

19. 2. Establish the level of defect
Diagnosis of Primary AI:↓ am cortisol and ↑ am ACTH levels + ↓ or absent cortisol in response to ACTH stimulation test
Often evidence of mineralocorticoid deficiency  hyponatremia, hyperkalemia, ↑ PRA and/or ↑ [renin]
Diagnosis of Central AI: ↓ Basal and ACTH stimulated cortisol secretion and ↓ Basal ACTH  tests of ACTH secretory ability +/- CRF stimulation test
Practically, not always necessary to determine if AI is 2o or 3o treatment is often the same
Plasma levels of renin and aldosterone are usually unaffected in central AI
Plasma levels of renin and aldosterone are usually unaffected in secondary or tertiary adrenal insufficiency, but mineralocorticoid deficiency can sometimes occur after very prolonged deficiency of ACTH.
So whether its primary vs. secondary or tertiary

20. 3. Evaluation of Cause Primary AI Central AI
Evaluate for CAH (most common cause of 1o AI )  adrenal androgens
Measure adrenal antibodies  if +ive screen for autoimmune polyglandular syndromes
Measuring antibodies to other endocrine glands (thyroid, parathyroid, and islet cell antibodies)
If antibodies negative screen for other causes of 1o AI
Imaging (CT) identifying adrenal hemorrhage, calcifications, or infiltrative disease
Central AI
Evaluate for secretion of other pituitary hormones
Very long chain fatty acid panel

21. Diagnostic Approach

22. Treatment of Adrenal Insufficiency
Principles:
Maintenance Therapy (Replacement)
Stressed Conditions

23. Treatment Cont’d Maintenance Therapy Glucocorticoid Therapy
Calculated according to body surface area
Often hydrocortisone is preferred because of its short duration of action and low potency  ease in titration to optimal dose (5-16 mg/m2/d divided into 3 doses)
During follow-up must ensure adequate somatic growth (weight, BA, height and weight velocities) and screen for symptoms of insufficiency
Must also screen for symptoms of GC excess
Mineralocorticoid Therapy
Fludrocortisone (Florinef)  mg/d do not vary by age or surface area because aldosterone secretion rate is nearly constant throughout the lifespan
Monitor for signs of inadequate replacement: dehydration, poor weight gain, salt-craving, and hyponatremia with hyperkalemia
Routine measurement of plasma renin activity (PRA) is not generally useful in monitoring adequacy of treatment because levels of these hormones tend to be variable, based on posture and sodium intake, and are often above the normal range even in patients who are receiving adequate replacement therapy. However, on occasion, measurements of these hormones may be useful in monitoring compliance with therapy, or in response to an unexplained change in clinical status

24. Treatment Cont’d Stress Conditions
Primary goal is to avoid serious consequences of an adrenal crisis  always wear identification
Illness:
Minor stress (e.g. sore throat, rhinorrhea, T < 38ºC)  may not require ∆ dose
Moderate stress (e.g. severe URTI)  double the GC replacement dose
Major stress (e.g. T > 38ºC and/or vomiting), three to four times the GC replacement dose
If child unable to keep down oral dose administer IM GC
Surgery:
During general anesthesia, +/- surgery, the GC requirements increases greatly
Protocols vary depending on nature of surgery, length of surgery, age of patient etc
Stress dosing is generally continued until the patient can tolerate oral intake, is afebrile, and is hemodynamically stable

25. Thank You!!!
Questions???