1. Dr. Atallah Al-Ruhaily Conultant Endocrinolgist
ADRENAL DISORDERS
Dr. Atallah Al-Ruhaily
Conultant Endocrinolgist

2. Adult Adrenal Glands Each gland weighs 4-5 g.
Location: in the retroperitoneum above or medial to the upper poles of the kidneys.
Surrounded by a fibrous capsule.
The yellowish outer cortex comprises 90% of adrenal weight.
The inner medulla 10% of adrenal weight.
Adult Adrenal Glands

3. A normal right adrenal gland is shown here positioned between the liver and the kidney in the retroperitoneum. Note the amount of adipose tissue, some of which has been reflected to reveal the upper pole of the kidney and the adrenal.

4. Each adult adrenal gland weighs from 4 to 6 grams.
Normal Adrenal Glands
Each adult adrenal gland weighs from 4 to 6 grams.

5. Arterial Supply Adrenal cortex is richly vascularised.
Main arterial supply from branches of:
Inferior phrenic artery
Renal arteries
Aorta.
Arterial Supply

6. Rt. adrenal vein drains directly in the posterior aspect of I.V.C.
Lt. adrenal vein into Lt. Renal vein.
Venous Drainage

7. Embryology of Adrenal Cortex
Adrenal Cortex is of mesodermal origin.
Identifiable as a separate organ at the 2 month-old-fetus.
At this stage, composed of:
Fetal zone
additional zone in fetus
makes up the main bulk of weight at this time.
lost in the 1st year (usually within 3 months after birth).
Definitive zone
The origin of the adrenal cortex.

8. Embryology of Adrenal Cortex
Fetal adrenal increases rapidly in size (Larger than the kidney at mid gestation & much larger than adult gland in relation to total body mass).
Fetal adrenal produces mainly DHEA & DHEA-S (precursors of maternal-placental estrogen).
Definitive zone synthesizes many steroids mainly cortisol.

9. Embryology of Adrenal Cortex
The anatomic relationship of fetal and definitive zones is maintained until birth.
Adrenocortical weight decreases gradually until the fetal zone disappears 3 months after delivery.
During the first 3 years, the adult adrenal cortex develops and differentiates into 3 adult zones:
Glomerulosa
Fasciculata
Reticularis

10. Embryology of Adrenal Medulla
Medullary chromaffin cells (the principal cells of adrenal medulla) are from the neural crest.
During development the medullary cells migrate and lie surrounded by the cortex.

11. Adrenal gland is composed of 2 distinct compartments
Adrenal cortex
produces many steroid hormones; the most important of which are:
Cortisol
Aldosterone
Adrenal androgens
Adrenal Medulla
Produces Catecholamines:
Adrenaline (Epinephrine)
Noradrenaline (Norepinephrine)

12. Sectioning across the adrenals reveals:
a golden yellow outer cortex; and
an inner red to grey medulla.

13. Microscopic Anatomy of Adrenal Gland
Remember “GFR”
Periadrenal
Fatt
Fibrous
Capsule
Zona Glomerulsa
Zona Fasciculata
Zona Reticularis
Medulla

14. Zones of Adrenal Cortex Functionally considered as one unit.
Zona Glomerulosa
Zona Fasciculata
Zona Reticularis
The outermost.
the thickest
The innermost
Cells are small & lipid-poor & scattered beneath the adrenal capsule.
Cells are larger, contain more lipid & termed “clear cells”
“Compact” lipid-poor cells but contain lipofuscin granules.
Aldosterone
(Cannot produce cortisol & Androgens)
Cortisol & Androgens
Regulated by Renin-Angiotensin System & K
Both structure and function are regulated by ACTH
Functionally considered as one unit.

15. Classification of Adrenal Steroids
classified into 3 groups based on their predominant functions:
1.      Glucocorticoids
2.      Mineralocorticoids
3.      Androgens

16. (functionally as one unit)
Major Classes of Adrenal Steroids
Steroid Class
Androgens
(C19)
Glucocorticoids
(C21)
Mineralocorticoids
Main Hormones
DHEA, DHEA-S
Androstenidione
Cortisol
Corticosterone
Aldosterone
Predominant action
Androgenic activity
metabolism of:
carbohydrates
and proteins
Na & K
Maintain the ECV
Main Zone of production
Z. Fasciculata
Z. Reticularis
(functionally as one unit)
Z. Glomerulosa

17. Disorders of Adrenal glands
Adrenal Cortex
Cushing’s syndrome
Addison’s disease
Hyperaldoteronism
Syndomes of congenital adrenal hyperplasia (CAH).
Hirsutism
Virilization
Adrenal Medulla
Pheochromocytoma

18. Adrenal Insufficiency
Adrenocortical insufficiency (hypofunction of the adrenal cortex) includes all conditions in which there is deficient production of:
adrenal glucocorticoid, and
mineralocorticoid hormones.

19. Types of adrenal insufficiency
These conditions are divided into 2 general groups according to the level of hypofunction:
Primary adrenal insufficiency (Addison’s diease)
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.

20. Primary Adrenal Insufficiency
Etiology of adrenal insufficiency
Primary Adrenal Insufficiency
A. Anatomic destruction of gland (chronic & acute)
“Idiopathic” atrophy (autoimmune)
Surgical removal
Infection (Tb., fungal, viral-esp. AIDS)
Adrenal Hemorrhage
Invasion: metasteses, amyloidosis, sarcoidosis
B. Metabolic failure in hormone production
Congenital adrenal hyperplasia (CAH)
Enzyme inhibitors:
(metyrapone, ketoconazole, aminoglutethemide)
Cytotoxic agents: (mitotane)
C. ACTH-blocking Antibodies

21. Secondary Adrenal Insufficiency
Etiology of adrenal insufficiency
Secondary Adrenal Insufficiency
A.  Hypopituitarism due to hypothalamic-pituitary disease.
Suppresion of hypothalamic-pituitary axis.
Exogenous steroids (Iatrogenic)
Endogenous steroids (from tumors)

22. 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).

23. 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.

25. 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. 
Some patients have +ve Abs to thyroid, parathyroid and/or gonadal tissues.
Polyglandular Autoimmune (PGA) syndromes

26. 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

27. 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

28. 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)
Hypotention (systolic BP <110 mm Hg) with postural accentuation
Vitiligo (with autoimmune)
100 95 80 60 15 10

29. 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

30. 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.

31. 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).

32. 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

33. Rt Adrenal mass

34. Acute Adrenal Crisis
A state of acute adrenal insufficiency occuring 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

35. Common Clinical Features
Acute Adrenal Crisis
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.

36. 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

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

38. 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

39. Acute Adrenal Hemorrhage
With progression, the following manifestations may ensue:
severe hypotention
volume depletion
Dehydration
Hyperpyrexia
Cynosis
Hypoglycemia
Coma
death

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

41. Secondary Adrenal Insufficiency Pathphysiology
ACTH deficiency is the primary event.
This leads to:
decreased cortisol & androgen secretion.
But aldosterone secretion remains normal except in few cases.

42. Secondary Adrenal Insufficiency Pathphysiology
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).

43. 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.

44. 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.

45. 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 hypotention or shock unresponsive to vasopressors.

46. 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.

47. 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

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

49. 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

50. 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

51. 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.

52. 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.

53. Treatment of Adrenal Insufficiency Maintenance Therapy
Preparations:
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

54. 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.