ERM2 - Adrenal Pathology

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jknell
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184712
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ERM2 - Adrenal Pathology
Updated:
2012-11-20 19:47:10
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Endocrine Reproductive Pathology
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Endocrine and Reproductive Pathology
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  1. Genital and Adrenal Embryology
    • -at 4-5 weeks gonadal ridge develops
    • -gonadal ridge develops into cells of the gonads and the adrenals
    • -4-5 weeks germ cells and neural crest cells migrate to gonadal ridge
    • -9-14 weeks fetus is capable of steroidgenesis

    ***lots of conditions affect both gonads and adrenal glands
  2. Differentiation of Internal Genitalia


    -Male Gonad: AMH dissolves Mullerian Duct, Testosterone stabilizes Wolffian Duct

    -Female Gonad: lack of AMH allows Mullerian Duct to persist, Lack of testosterone allwas Wolffian to dissolve
  3. Differentiation of External Genitalia
    At 8 weeks external genitalia looks the same in male and female. Increased androgen at this stage --> male genitalia by 10 weeks

    • Male
    • -increased male hormone causes development of male external genitalia

    • Female
    • -male hormone is absent, female external genitalia develops
  4. Most Common Causes of Androgen Excess
    • 1. Fetal Adrenal Androgen Overproduction (CAH)
    • 2. Maternal Androgen Overproduction
    • 3. Placental Aromatase Deficiency (androgens normally inactivated by placental aromatases into estrogen)
  5. Hypothalamic-Pituitary-Adrenal Axis
  6. Adrenal Hyperplasia Results from decreased Cortisol Secretion
    • -decreased cortisol --> excess ACTH (due to lack of negative feedback)
    • -excess ACTH causes hyperplastic hypertrophy of the adrenal gland

    • CRH: increased
    • ACTH: increased
    • Cortisol: decreased
  7. Steroidgenesis
  8. Forms of CAH
    • 1. 21-hydroxylase deficiency (most common)
    • 2. 11b-hydroxylase deficiency
    • 3. 3b-hydroxysteroid dehydrogenase II (rare)
  9. 21 Hydroxylase Deficiency: Epidemiology
    • -causes 90% of CAH
    • -autosomal recessive
    • -caucasians 1/15,000
    • -African Americans 1/42,000
    • -Eskimos 1/280
  10. 21 Hydroxylase Deficiency: Pathophysiology
    • -excess production of adrenal androgens
    • -reduction in cortisol and aldosterone

    • Aldosterone pathway: can't progress past progesterone
    • Cortisol pathway: can't progress past 17 OH progesterone

    More precursors are shunted to the androgen pathway
  11. 21 Hydroxylase Deficiency: Genetics
    Chromosome 6 has both a real gene and a non functional pseudogene

    Crossing over can cause mutations that inactivate the real gene

    Compound heterozygotes are common
  12. 21 Hydroxylase Deficiency: Clinical Features
    • -sexual ambiguity
    • -salt wasting
  13. 21 Hydroxylase Deficiency: Diagnostic Tests
    • -chemistry panel
    • -17 OH Progesterone
    • -plasma renin activity (should be elevated)
    • -androgens

    -newborn screening (12hrs - 6 days)
  14. 21 Hydroxylase Deficiency: Subtypes
    • 1. Classic Salt Wasting
    • 2. Classic Simple Virilizing
    • 3. Non-Classic
  15. Classic Salt Wasting
    • -female genitalia: ambiguous
    • -male genitalia: normal
    • -incidence: 1/20000
    • -decreased cortisol
    • -decreased aldosterone

    0% enzyme activity
  16. Classic Simple Virilizing
    • -female genitalia: +/-ambiguous
    • -male genitalia: Normal
    • -Incidence: 1/60000
    • -decreased cortisol
    • -normal aldosterone

    1-2% enzyme activity
  17. Non-Classic
    • * can present at any age from child to adult
    • -female genitalia: +/- clitoromegaly
    • -male genitalia: normal
    • -Incidence: 1/1000
    • -normal cortisol
    • -normal aldosterone

    20-50% enzyme activity
  18. 21 Hydroxylase Deficiency: Treatment
    • 1. Correct glucocorticoid deficiency (late at night)
    • 2. Replace mineralocorticoid (maintain Na balance)
    • 3. Ensure adequate suppression of sex steroids (prevent virilization of females and advancement of skeletal age)
  19. 11 Hydroxylase Deficiency: Epidemiology
    • -second most common form (5-8%)
    • -causes Hypertension
  20. 11 Hydroxylase Deficiency: Pathophysiology
    • Aldosterone Pathway: DOC builds up (has mineralocorticoid activity --> salt and water retention), decreased aldosterone

    Cortisol Pathway: can't progress pass deoxycortisol

    More precursors are shunted to the androgen pathway
  21. 11 Hydroxylase Deficiency: Clinical Features
    -Hypertension (DOC build up has mineralocorticoid activity)

    -decreased aldosterone

    -decreased cortisol

    -increased DHEA
  22. 11 Hydroxylase Deficiency: Treatment
    1. Replace Glucocorticoids (suppresses ACTH, turns off sex steroid production)

    2. Surgery for virilization

    3. HTN therapy
  23. 3b-Hydroxysteroid Dehydrogenase Deficiency: Pathophysiology
    -high Delta5:Delta4???

    -high DHEA, increased peripheral conversion to stronger androgens causes variable clitoromegaly in females

    -low androgen production in testes causes undervirilization in males

    • -defect in mineralocorticoid synthesis results in salt wasting
  24. Clinical Sx of Cushing's Syndrome
    • 1. General
    • -central obesity
    • -proximal muscle weakness
    • -HTN
    • -HAs
    • -psychiatric disorders

    • 2. Skin
    • -wide, purpler striae
    • -spontaneous ecchymoses
    • -facial plethora
    • -hyperpigmentation
    • -acne
    • -hirsutism
    • -fungal skin infections

    • 3. Endocrine and Metabolic
    • -hypokalemic alkalosis
    • -osteopenia
    • -delayed bone age in children
    • -menstrual disorders (decreased libido, impotence)
    • -glucose intolerance, DM
    • -kidney stones
    • -polyuria
    • -increase WBC
  25. Cushing's Syndrome: Types
    • 1. ACTH-Dependent (80%)
    • 2. ACTH-Independent (20%)
  26. ACTH-Dependent Cushing's
    1. pituitary corticotroph adenoma (Cushing's Disease: 85%)

    • 2. ectopic ACTH Syndrome (15%)
    •      -small cell lung cancer (50%)
    •      -foregut tumor
    •      -bronchial carcinoid
    •      -MTC
    •      -Pheo
  27. ACTH-Independent Cushing's
    • 1. Adrenal tumors
    •      -adrenal adenoma (>50%)
    •      -adrenal carcinoma (<50%)
    •      -macronodular hyperplasia (rare)

    2. Exogenous Glucocorticoids (common)
  28. Cushing's Syndrome: Diagnosis
    • -24 hour urine collection to measure cortisol
    • -1 mg dexamethasone stim overnight
    • -venous sampling (after stim with CRH)
  29. Cushing's Syndrome: Adrenal Pathology
    • -increased ACTH causes hypertrophy of the adrenal cortex
    • -large cells with pale cytoplasm, lose column structure
    • -expansion of Zona Fasciculata and Reticularis
    • -Zona Glomerulas is normal (aldo under different regulation)
  30. Cushing's Syndrome: Treatment
    • 1. Pituitary Adenoma (resection, radiation, meds, bilateral adrenalectomy)
    • 2. Adrenal adenoma/Macronodular Hyperplasia (resection)
    • 3. Bronchial Carcinoid (resection)
    • 4. SCLCa (chemo)
    • 5. Adrenal carcinoma (poor prognosis)
  31. Conn's Syndrome: Background and Causes
    -primary Aldosteronism (elevated Aldosterone)

    • Causes:
    • 1. Idiopathic Hyperaldosteronism (70%)
    • 2. Aldosterone producing Adenoma (30%)
  32. Conn's Syndrome: Clinical Features
    Aldosterone: increases Na reabsorption, increases K and H secretion

    • 1. HTN (chronic, difficult to control)
    • 2. Hypokalemia
    • 3. Metabolic Alkalosis

    • Labs
    • -suppressed renin activity
    • -elevated aldosterone
    • -PAC:PRA >20
  33. Conn's Syndrome: Diagnosis
    • -confirm increased aldo and decreased renin
    • -CT adrenal gland for tumor
    • -venous sampling of adrenal veins for tumor
  34. Adrenal Insufficiency: Background
    -Addison's disease

    Primary: adrenal gland can be destroyed or absent (elevated ACTH)

    Secondary: hypothalamus or more likley pituitary (decreased ACTH)
  35. Adrenal Insufficiency: Causes of Primary
    • -autoimmune adrenalitis (Addison's)
    • -metastatic cancer (lung, breast, stomach, colon)
    • -infections (TB)
    • -amyloidosis
    • -Menigiococcymal sepsis
  36. Adrenal Insufficiency: Causes of Secondary
    • -hypothalamic disease
    • -pituitary disease
    • -exogenous corticosteroid use and withdrawal (decreased negative feedback to HPA --> decreased CRH and ACTH --> adrenal atrophy, takes time to recover)
  37. Adrenal Insufficiency: Clinical Features
    • -weakness, fatigue
    • -wt loss, anorexia
    • -abdominal pain, N/V
    • -depression
    • -hyperpigmentation
    • -hypotension
    • -hypoglycemia

    ***non-specific
  38. Adrenal Insufficiency: Diagnosis
    • -give synthetic ACTH and watch for cortisol response
    • -should see no change

    -insulin induced hypoglycemia test: stress (ie: hypoglycemia) stimulates CRH and ACTH release, if cortisol doesn't rise have problem with ACTH production

    -Metyrapone test: blocks 11 deoxycortisol conversion to cortisol, decreased cortisol levels should increase ACTH, leading to increased 11 deoxycortisol, if there is no increase there's a problem with ACTH secretion
  39. Incidental Adrenal Tumor: Epidemiology
    • -usually found incidentally on imaging
    • -found on 5% of abdominal CTs
    • -found on 35% of autopsy
    • -increased prevalence with age
  40. Incidental Adrenal Tumor: Types
    • -non-functional benign (76%)
    • -fxnl benign: Cushing's (15%)
    • -primary adrenal cancer (1-4%)
    • -Pheochromocytoma (4%)
    • -Mets (5%)
  41. Incidental Adrenal Tumor: Diagnosis
    • Imaging
    • 1. CT (contrast washes out)
    • 2. MRI
  42. Incidental Adrenal Tumor: Management
    • -Hormonally active: resect tumor
    • -Hormonally inactive: resect > 4cm, tumors >4cm are much more likely to be malignant

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