1. Dr. Atallah Al-Ruhaily Consultant Endocrinologist
ADRENAL DISORDERS
Dr. Atallah Al-Ruhaily
Consultant Endocrinologist

2. Adrenal Insufficiency
Adrenocortical insufficiency (hypofunction of the adrenal cortex) includes all conditions in which there is deficient production of:
Adrenal glucocorticoids
Mineralocorticoids hormones.

3. Types of adrenal insufficiency
These conditions are divided into 2 general groups according to the level of hypofunction:
Primary adrenal insufficiency (Addison’s disease)
due to primary hypofunction of the adrenal cortex.
Secondary adrenal insufficiency
adrenocortical failure secondary to a primary deficient secretion of ACTH from the pituitary gland.

4. Etiology of Primary Adrenal Insufficiency
Anatomic destruction of gland (chronic & acute)
“Idiopathic” atrophy (autoimmune)
Surgical removal
Infection (Tb., fungal, viral-esp. AIDS)
Adrenal Hemorrhage
Invasion: metastases, amyloidosis, sarcoidosis
Metabolic failure in hormone production
Congenital adrenal hyperplasia (CAH)
Enzyme inhibitors:
(Metyrapone, Ketoconazole, Aminoglutethemide)
3. Cytotoxic agents: (Mitotane)
ACTH-blocking Antibodies

5. Etiology of Secondary Adrenal Insufficiency
Hypopituitarism due to hypothalamic-pituitary disease.
Suppression of hypothalamic-pituitary axis.
Exogenous steroids (Iatrogenic)
Endogenous steroids (from tumors)

6. Incidence Primary Adrenal Insufficiency: Relatively rare.
Occurs at any age.
affects both sexes equally.
Secondary Adrenal Insufficiency:
Relatively common (because of common therapeutic use of steroids).

7. Etiology and Pathogenesis
Addison’s Disease:
Etiology and Pathogenesis
Addison’s disease results from progressive destruction of adrenal cortex.
At least 90% of gland is destroyed before signs of insufficiency appear.

9. Etiology and Pathogenesis
Addison’s Disease:
Etiology and Pathogenesis
50% of patients have +ve circulating adrenal Abs.
Some Abs destroy the adrenal glands, others block the binding of ACTH to its receptors. 
In addition, some patients have +ve Abs to thyroid, parathyroid and/or gonadal tissues.
Polyglandular Autoimmune (PGA) syndromes

10. Associated Autoimmune Disorders
Endocrine Disorders:
Chronic lymphocytic thyroiditis
Premature ovarian failure
DM type 1
Primary hypothyroidism
Hyperthyroidism
Nonendocrine Disorders:
Pernicious anemia
Vitiligo
Alopecia
Chronic active hepatitis
Nontropical sprue
Myasthenia gravis

11. in chronic primary adrenal insufficiency
Common Symptoms
in chronic primary adrenal insufficiency
Symptoms
Frequency
Asthenia (weakness, tiredness, fatigue)
Anorexia
Gastrointestinal symptoms
Nausea
Vomiting
Constipation
Abdominal pain
Diarrhea
Salt craving
Postural dizziness
Muscular or joint pains
100 90 85 75 30 15 10

12. in chronic primary adrenal insufficiency
Common Signs
in chronic primary adrenal insufficiency
Signs
Frequency
Weight loss
Hyperpigmentation of skin
Pigmentation of mucous membrane
Decreased axillary and pubic hair (in women only)
Hypotension (systolic BP <110 mm Hg) with postural accentuation
Vitiligo (with autoimmune)
100 95 80 60 15 10

13. Hyperpigmentation
Generalized hyperpigmentation of skin & mucous membrane (the classical physical finding).
Along with other features, suggests primary adrenocortical insufficiency.
One of earliest manifestations of Addison’s disease.

14. Hyperpigmentation
Increased at exposed areas and accentuated at pressure areas (knuckles, toes, elbows, knees)
Associated with black or dark brown freckles.
Hperpigmentation of buccal mucosa & gum is preceded by generalized hyperpigmentation of skin.
Other areas: palmar creases, nail beds, nipples, areolae, perivaginal, perianal mucosa & scars that formed after onset of ACTH excess (but not older scars).

15. Hyperpigmentation in Addison’s disease

16. Hyperpigmentation in Addison’s disease

17. in chronic primary adrenal insufficiency
Common Laboratory findings
in chronic primary adrenal insufficiency
Laboratory Findings
Frequency
Electrolytes disturbances
Hyponatremia
Hyperkalemia
Hypercalcemia
Azotemia
Anemia
Eosinophilia 90 65 5 55 40 15

18. Adrenal Imaging CT Scan Abdominal x-rays
Adrenal calcification
in 50% tuberculous cases & some other invasive or hemorrhagic causes.
CT Scan
more sensitive for adrenal calcification & enlargement
Causes of bilateral adrenal enlargement: Tb
Fungal infection
CMV infection
Infiltrative diseases (malignant or nonmalignant)
Adrenal hemorrhage

19. Rt Adrenal mass

20. Acute Adrenal Crisis
A state of acute adrenal insufficiency occurring in patients with Addison’s disease who are exposed to any form of stress.
Precipitating stress factors:
Infection
Trauma
Surgery
Dehydration (Salt deprivation, vomiting, diarrhea)
Discontinuation of steroids replacement therapy

21. Acute Adrenal Crisis: Clinical Features Common Clinical Features
Hypotension & shock
Fever (due to infection or hypoadrenalism per se)
Dehydration, volume depletion
Nausea, vomiting, anorexia
Abdominal pain (may mimic acute abdomen)
Weakness, apathy, depressed mentation
Hypoglycemia (more in children)
Shock and coma may rapidly lead to death in untreated patients.

22. Laboratory Findings Suggestive of Diagnosis
Acute Adrenal Crisis
Laboratory Findings Suggestive of Diagnosis
Hyponatremia & Hyperkalemia
(In a small number of acute cases).
Azotemia (usual)
Lymphocytosis
Eosinophilia
Hypoglycemia

23. Acute Adrenal Hemorrhage
A progressively deteriorating condition resulting from bilateral adrenal hemorrhage and acute adrenal destruction in an already compromised patient with major illness.

24. Acute Adrenal Hemorrhage Manifestations
Abdominal, flank or back pain & abdominal tenderness (Less frequently, abdominal distention, rigidity & rebound tenderness).
Hypotension & shock
Fever
Nausea & Vomiting
Confusion & disorientation
Tachycardia

25. Acute Adrenal Hemorrhage
With progression, the following manifestations may ensue:
Severe hypotension
Volume depletion
Dehydration
Hyperpyrexia
Cyanosis
Hypoglycemia
Coma
Death

26. Secondary Adrenal Insufficiency Causes
ACTH deficiency most commonly due to exogenous glucocorticoid therapy.
Pituitary & Hypothalamus tumors the most common causes of naturally occurring pituitary ACTH hyposecretion.

27. Secondary Adrenal Insufficiency Pathophysiology
ACTH deficiency is the primary event.
This leads to:
Decreased Cortisol & Androgen secretion.
But Aldosterone secretion remains normal except in few cases.

28. Secondary Adrenal Insufficiency Pathophysiology
In early stages,
Basal ACTH & cortisol levels may be normal.
ACTH reserve is impaired. Response of ACTH & cortisol to stress is subnormal.
With further loss of basal ACTH secretion,
There is atrophy of Z. Fasciculata & Z. Reticularis.
Basal cortisol secretion is decreased.
The entire pituitary adrenal axis is impaired (i.e. Decreased ACTH responsiveness to stress & decreased adrenal responsiveness to stimulation with exogenous ACTH).

29. Secondary Adrenal Insufficiency Clinical Features
Usually chronic nonspecific manifestations.
Acute crisis occurs in:
Undiagnosed patients
Patients who do not receive increased steroid dosage during periods of stress.

30. Secondary Adrenal Insufficiency Clinical Features
Clinical features differ from primary in that:
Hyperpigmentation does not occur (Because of ACTH deficiency).
Manifestations of mineralocorticoid deficiency are usually absent (Because Aldosterone secretion by Z. G. is usually preserved). Therefore:
Volume depletion, dehydration & hyperkalemia usually absent.
Hypotention is usually absent except in acute presentations.
Hyponatremia may occur as a result of water retention.

31. Secondary Adrenal Insufficiency Clinical Features
Prominent features (due to glucocorticoid deficiency) are nonspecific & include:
Weakness, lethargy & easy fatigability
anorexia, nausea & occasionally vomiting
Arthralgias & myalgias
Hypoglycemia
Acute decompensation with severe hypotension or shock unresponsive to vasopressors.

32. Secondary Adrenal Insufficiency Associated Features
The following additional features may be present:
History of glucocorticoid therapy or Cushingoid features.
Features of loss of other pituitary hormones (hypogonadism & hypothyroidism).
Features of hypersecretion of GH or PRL from pituitary adenoma.
Pressure symptoms from pituitary tumors.

33. Laboratory Workup for Adrenal Insufficiency

34. Cortisol Circadian Rhythm

35. Overnight single-dose Metyrapone Test - Procedure
 Metayrapone : 30 mg/kg oral administration of Metyrapone at midnight with milk or snack.
Serum 11-Deoxycortisol & Cortisol measurement (and ACTH level) 7:30 -9:30 AM next morning.

36. Overnight single-dose Metyrapone Test - Interpretation
A normal response to the overnight single-dose test consists of:
An 8 AM serum 11-deoxycortisol concentration of 7 to 22 mcg/dL (200 to 660 nmol/L).
A serum cortisol concentration at 8 AM of less than 5 mcg/dL (138 nmol/L) confirms adequate.

37. Diagnosis of Adrenal Insufficiency
3 Stages of diagnosis confirmation:
Inappropriately low cortisol secretion? ..
Is cortisol deficiency dependent on or independent of corticotropin (ACTH) deficiency
Evaluating mineralocorticoid secretion in patients without ACTH deficiency.
Is there a treatable cause of the primary disorder?

38. Diagnosis of Adrenal Insufficiency
Measuring non-specific anti-adrenal antibodies in serum by indirect immunofluorescence is not useful for establishing the diagnosis.
Antibodies directed to 21-hydroxylase (P450c21) identify nearly all patients with autoimmune adrenal insufficiency and is not positive in any patient with adrenoleukodystrophy-associated adrenal insufficiency.

39. Diagnosis of Adrenal Insufficiency
Basal levels of adrenocortical steroids in plasma or urine may be normal in partial adrenal insufficiency.
Tests for adrenocortical reserve are necessary to establish the diagnosis.
Rapid ACTH Stimulation Test
Plasma ACTH Levels
Metyrapone Test
Insulin-induced Hypoglycemia
CRH Stimulation

40. Diagnosis of Adrenal Insufficiency
Other indirect clues:
Features of hypersecretion of GH or PRL from pituitary adenoma.
Pressure symptoms from pituitary tumors.

41. Evaluation of Suspected Adrenal Insufficiency
Rapid ACTH Stimulation Test
Abormal ACTH Stimulation Test:
Adrenocortical insufficiency +ve.
Which type?
Plasma ACTH level:
Elevated: Primary Adrenal Insufficiency +ve
Normal or Low: Secondary Adrenal Insufficiency +ve

42. Evaluation of Suspected Adrenal Insufficiency
Rapid ACTH Stimulation Test
Normal ACTH Stimulation Test:
This excludes Primary Adrenal Insufficiency & Adrenal atrophy.
But does not exclude “Decreased ACTH Reserve”
Metyrapone Test
or Insulin-hypoglycemia Test
or CRH stimulation Test:
Normal: Exclude Adrenal Insufficiency
Abnormal: Secondary Adrenal Insufficiency +ve

43. Treatment of Adrenal Insufficiency Acute Addisonian Crisis
Glucocorticoid Replacement
Cortisol (Hyrdocortisone succinate or phosphate) 100 mg every 6 hrs. for 24 hrs.
When stable, reduce to 50 mg 6 hrs.
Taper to maintenance therapy by day 4 or 5 & add mineralocorticoid as required.
If complications persist or occur, maintain or increase the dose to mg/d.
General or Supportive Measures
Correct volume depletion, dehydration, & hypoglycemia with I.V. saline and glucose.
Evaluate and treat infection or other precipitating factors.

44. Treatment of Adrenal Insufficiency Maintenance Therapy
Life-long replacement therapy with glucocorticoid and mineralocorticoid.
Preparations:
Cortisol (hydrocortisone) tablets
First choice
Maintenance dose: mg/d.
Usually, divided into 2 doses
(2/3 AM & 1/3 PM)
Cortisone acetate (37.5mg/d)
Absorbed rapidly from GIT
converted in the liver to cortisol.

45. Treatment of Adrenal Insufficiency Maintenance Therapy
Synthetic Steroids:
- Prednisone or Prednisolone
5 mg of prednisone tab is equivalent to 20 mg of hydrocortisone.
- Fludrocortisone (9-alpha fludrocortisol)
Used for mineralocorticoid therapy
Usual dose: mg/d PO AM

46. Treatment of Primary Adrenal Insufficiency Regimen Therapy
Cortisol mg AM & 10 mg at 4-5 pm
Or prednisone mg AM
Fludrocortisone (Fluranif) mg PO AM.
Clinical Follow up:
Maintenance of normal body weight, BP & electrolytes
Regression of clinical features
Patient education & identification card or bracelet
Increased cortisol dosage during stress.