- A 55-year-old male presented with 3 weeks of weakness, fatigue, and weight loss. Physical exam found him to be thin and lean with oral pigmentation. - Labs found leukopenia, a positive PPD test, low cortisol, increased ACTH, and a normal chest x-ray. - The final diagnosis was tuberculosis adrenalitis, which had caused primary adrenal insufficiency.

1. Clinical case
 55 yo male presented with weaknessx3 wks,
insideous onset, progressive, easy fatigability, weight
loss. No cough, SOB, CP, abdominal pain.
 ROS negative
 PE: Thin, lean, oral mucosa black pigmentation.
 Labs: Leukopenia, PPD+, dec cortisol, increase
ACTH, CXR norm
 Final diagnosis: TB adrenalitisPrimary adrenal
insufficiency.

2. Ahad Lodhi, M.D.
07/21/2010

3. The Adrenal Glands

4. Adrenal Cross Section

5. Adrenal Zonation and Vasculature
-blood flow
-steroid gradient

6. Overview: Hypothalamic-Pituitary-Adrenal (HPA)
Axis

7. Activity of the Hypothalamic-Pituitary-Adrenal Axis under Normal Conditions (Panel A), during an
Appropriate Response to Stress (Panel B), and during an Inappropriate Response to Critical Illness (Panel
C)
Cooper M and Stewart P. N Engl J Med 2003;348:727-734

8. Definition
 A disease state caused by insufficient circulating
glucocorticoid and/or mineralocorticoid hormones.
 May be caused by abnormalities at any level of the
hypothalamic-pituitary-adrenal axis.
TYPES
Primary
Secondary
Tertiary

9. EPIDEMIOLOGY
 Prevalence: 12 per 100,000 persons
 Incidence: 0.5 per 100,000 persons
 Age: may occur at any age, with peak incidence in the
fourth decade
 Sex:
Autoimmune causes: female predominance
Non-autoimmune causes: equal sex distribution

10. Risk Factors
1.Genetic:
Isolated autoimmune adrenal insufficiency
Congenital abnormalities of cortisol synthesis
Autoimmune PGS 1:
hypoparathyroidism, adrenal insufficiency, and chronic mucocutaneous candidiasis
PGS 2:
>2 adrenal insufficiency, chronic lymphocytic thyroiditis, premature ovarian failure, type 1
diabetes mellitus, Graves’ disease, hypo-hyperthyroidism
2. Medications:
Rifampin, Phenytoin, Ketoconazole, etomidate, magesterol and opiates .
3. Rapid withdrawal of glucocorticoids after long-term steroid therapy
4. Anticoagulants
5. Hypercoagulable states (adrenal infarction)
6. Severe sepsis (e.g., meningococcus)

11. ETIOLOGY
Destruction of the adrenal glands
 Autoimmune (~80% of cases)
Isolated adrenal insufficiency
Type I or II polyglandular autoimmune syndrome
 Infectious
TB
Fungal (Histoplasmosis, coccidiodomycosis, Cryptococcus)
HIV/AIDS--- HIV, MAI, Cytolomegalovirus( CMV necrotizing adrenalitis)
 Metastatic Invasion
 Bilateral adrenal hemorrhage DIC, APL sepsis(Waterhouse-Friderichsen
syndrome)
 Infiltrative (sarcoidosis, Amyloidosis, Hemochrmotosis )
Rare causes: Adrenoleukodystrophy, Adrenomyeloneuropathy, CAH.
 Bilateral adrenalectomy

12. Histoplasmosis:
Large bilateral
adrenal masses (a
rrows) patchy& per
ipheral enhancem
ent, central hypod
ensities, septation
s.

13. SECONDARY AI
 Hypopituitarism
 Head injury
 Postpartum hemorrhage – Sheehan syndrome
 Craniopharyngiomas, Pituitary radiation
 Pituitary surgery
 Acute interruption of prolonged corticosteroids
 Pituitary infiltrative disease – tuberculosis, sarcoidosis, Wegener's.
 Exogenous glucocorticoid administration
 Lymphocytic hypophysitis

14. Clinical Manifestations
Unexplained hypotension, weight loss, fatigue.
Primary and Sec AI
 Fatigue, weakness, anorexia, weight loss
 N/V/D, dizziness, orthostatic hypotension
 Hyponatremia, hypoglycemia, Eosinophilia
Primary AI and associated conditions.
 Hyperpigmentation, hyperkalemia, salt craving
 Vitiligo, autoimmue thyroid disease
Secondary AI & associated conditions:
 Pale skin, marked anemia
 Amenorrhea, scant pubic and axillary hairs, small testicles.
 Secondary hypothyroidism, delayed puberty
 Headache, visual symptoms, diabetes insipidus

15. Addison’s Disease: effect of MSH activity

16. Hyperpigmentation

17. DIAGNOSTIC APPROACH
The diagnostic approach to adrenal insufficiency has 3
stages.
 Demonstration of an inappropriately low cortisol level
 Determination of the level of adrenal dysfunction
(primary vs secondary)
 Identification of the specific cause of adrenal
insufficiency

18. Screening
1. Morning cortisol level 8am-9am
>18 μg/dl excludes adrenal insufficiency.
< 3 μg/dl is highly suggestive of adrenal insufficiency
Indeterminate value: 3–18 μg/dl
2. ACTH level:
≥ 22 pmol/L (100 pg/mL) primary adrenal insufficiency.

19. Adrenal autoantibodies test:
for autoimmune adrenalitis
Sensitivity 70%, specificity very high
STIMULATION TESTS:
1. ACTH stimulation test – cortisol response to cosyntropin (250 µg
followed by serial cortisol measures at 30 and 60 minutes)
Cortisol <5 µg/dL – adrenal failure
Cortisol >20 µg/dL – normal
If cortisol ≤20 µg/dL but ≥5 µg/dL – need to evaluate for pituitary
failure
Simultaneous aldosterone: norm in sec AI
2. Pituitary ACTH reserve testing
 Insulin tolerance testing
 Metyrapone overnight testing
 CT/MRI of chest, abdomen, pituitary.

20. Relative adrenal insufficiency
 Critical care and Resuscitation: Journal of the Australian Critical
Care Medicine,2006 Dec;8(4):371-5
- In septic shock
- Increment of < 250 nmol/L(9 µg/dL) in total serum cortisol
level after administration of 250 microg corticotropin
- RAI associated with increased risk of death
- There is strong, but not overwhelming, evidence that
administration of low doses of hydrocortisone to patients with
septic shock, especially those with RAI, improves survival .

21. American Journal of Respiratory and Critical Care Medicine,
2006 Dec 15
 In sepsis, adrenal insufficiency is likely when
- Baseline cortisol levels <10 µg/dL
 Unlikely when
- Cosyntropin-stimulated cortisol level > 44 µg/dL

22. Diagnostic approach

23. Other tests
CBC:
anemia, moderate neutropenia, eosinophilia, relative
lymphocytosis
BMP:
hyponatremia (90%), hyperkalemia(65%), hypoglycemia
TSH, CXR
plasma very long chain fatty acids
S/ DHEA levels
Plasma renin activity

24. D/D
 Occult cancer
 Hemochromatosis
 Anorexia nervosa
 AIDS
 Multiple sclerosis

25. Treatment of chronic AI
Mild cases hydrocortisone alone
Moderate to SevereReplacement of corticosteroids and mineralocorticoid
Hydrocortisone----Drug of choice, 15-25 mg PO BID or
Prednisone: 2-3 mg am, 1-2 mg pm
FU response: normal WBC diff count with proper dose,
Some patients need Florinef 0.05-0.3 qday or QOD---elevated PRA indicates
need for higher dose.
DHEA 50 mg PO qday: to some womenimprove sense of well being, mood
and sexuality
Treat infections immediately and vigorously
Increase dose of steroid in times of stress.
Medical alert bracelet ….adrenal insuffiency ---takes hydrocortisone
.

26. Treatment :Acute Adrenal crisis
Glucocorticoid replacement
1. Hydrocortisone 100 mg iv every 6 hr. for 24 hr.
2. Hydrocortisone 50 mg every 6 hr. when stable
3. Maintenance therapy (10 mg 3 times/days) by day 4 or 5
4. Increase dose to 200-400 mg/day if complication occurs
5. Vasopressors may be needed.
General and supportive measures
1. Correct volume depletion, dehydration, hypoglycemia with iv
saline and glucose
2. Correct infection and other precipitating causes

27. Prognosis & Response to
therapy
Life expectancy is usually normal with good compliance.
It is important to make sure that pt is taking medications
regularly and knowledgeable about his condition.
BP without orthostatic hypotension, normal lytes, PRA
<5ng/ml/h
Cushing syndrome: overtreatment
Persistent fatigue consider epinephrine deficiency, suboptimal
dosing, electrolyte problem.

28. PEARLS
 Mineralocorticoid deficiency is present only in primary adrenal
insufficiency and accounts for hyponatremia, hyperkalemia, and salt
craving.
 In general, a random afternoon or evening serum cortisol level is not useful
for evaluation of adrenal insufficiency.
 A markedly elevated ACTH level in the context of a low cortisol level is
useful to confirm suspected primary adrenal insufficiency.
 ACTH samples must be drawn in EDTA tubes, placed on ice, and
processed immediately for reliable results.

29.  ACTH stimulation testing is not useful in the evaluation of patients who
have recently undergone pituitary surgery.
 Adrenal insufficiency is highly prevalent (~30%) in patients with AIDS
who present with hyponatremia and hypovolemia.
 Pregnant women with adrenal insufficiency generally do not need
increases in glucocorticoid or mineralocorticoid doses until labor and
delivery, when stress doses are required.
 Prior Steroid use: at least 20mg of prednisone or its equivalent for 5 days
in last 12 months. Topical steroids applied over large surface area, using
occlusive dressing, high potency. inhaled steroid >0.8 mg/d for long
duration

30. Thank you
For your attention