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Learning Objectives

Adrenal structure/anatomy. FatCapsuleZona GlomerulosaZona FasciculataZona ReticularisMedulla. . . . . . . Adrenal structure/anatomy. CortexGlomerulosaAldosterone synthesisFasiculataGlucocorticoid synthesisReticularisSex hormone synthesis. MedullaCatecholaminesControlled by ANS. Normal physiology.

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Learning Objectives

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    1. Learning Objectives Review normal HPA axis physiology Review primary and secondary adrenal insufficiency What we WILL NOT do: review the role of steroid replacement in critical illness

    3. Adrenal structure/anatomy Fat Capsule Zona Glomerulosa Zona Fasciculata Zona Reticularis Medulla

    4. Adrenal structure/anatomy Cortex Glomerulosa Aldosterone synthesis Fasiculata Glucocorticoid synthesis Reticularis Sex hormone synthesis Medulla Catecholamines Controlled by ANS

    5. Normal physiology Cortisol is the predominant corticosteroid secreted from the adrenal cortex In a healthy, unstressed person, cortisol is secreted in a diurnal pattern under the influence of corticotropin released from the anterior pituitary, ~30mg/d Corticotropin (ACTH) secretion is under the influence of hypothalamic corticotropin-releasing hormone, and both hormones are subject to negative feedback control by cortisol itself. Circulating cortisol is bound to corticosteroid-binding globulin, with less than 10 percent in the free, bioavailable form. With severe infection, trauma, burns, illness, or surgery, there is an increase in cortisol production by as much as a factor of six that is roughly proportional to the severity of the illness Diurnal variation in cortisol secretion is also lost.

    6. Figure 1. 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). A plus sign indicates a stimulatory effect, and a minus sign an inhibitory effect.Figure 1. 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). A plus sign indicates a stimulatory effect, and a minus sign an inhibitory effect.

    7. Primary adrenal insufficiency: Addison’s disease Anatomic destruction Autoimmune Adrenoleukodystrophy Surgery Infections: HIV, TB, fungi Hemorrhage Infarction Metatstatic disease Metabolic failure Congenital adrenal hypoplasia Enzyme inhibitors: ketoconazole, metyrapone, etomidate Cytotoxic agents: mitotane Anti-ACTH receptor antibodies ACTH receptor mutation

    8. Primary adrenal insufficiency Incidence is ~50/million #1 cause ??? Formerly TB Now is autoimmune (often associated with polyendocrine syndromes) Primary adrenal insufficiency results in loss of all 3 cortical products Isolated glucocorticoid deficiency can also occur

    9. Secondary adrenal insufficiency Pituitary or hypothalamic dysfunction or destruction Suppression of gland via exogenous or endogenous steroid excess

    10. Table 1. Causes of Primary and Secondary Adrenal Insufficiency.Table 1. Causes of Primary and Secondary Adrenal Insufficiency.

    11. Most of the symptoms of cortisol deficiency are nonspecific and usually occur insidiously Fatigue Weakness Listlessness Orthostatic dizziness Weight loss Anorexia GI upset/cramps Diarrhea Decreased libido However, some symptoms can help you distinguish primary or secondary causes of adrenal insufficiency

    12. Primary, secondary, or both? Hyperpigmentation of skin/mucosa: Primary Cravings for salt: primary Delayed growth/puberty: secondary Headaches: secondary Hyponatremia: both Primary – salt-wasting from loss of aldosterone activity Secondary – elevated levels of vasopressin/ADH Hyperkalemia: primary Mild eosinophilia: both Orthostasis: both Primary – usually symptoms are much more severe Secondary – RAA axis is preserved, but blood vessels have decreased levels of catecholamine receptors

    13. Table 2. Clinical Manifestations of Adrenal Insufficiency.Table 2. Clinical Manifestations of Adrenal Insufficiency.

    14. Diagnosis Adrenal insufficiency should be suspected in the presence of unexplained catecholamine-resistant hypotension, especially if the patient has hyperpigmentation, vitiligo, pallor, scanty axillary and pubic hair, hyponatremia, or hyperkalemia* A plasma cortisol value in the normal range does not rule out adrenal insufficiency in an acutely ill patient. In one study of plasma cortisol concentrations in patients with sepsis or trauma, a plasma cortisol value of more than 25 µg/dL probably rules out adrenal insufficiency, but a safe cutoff value is unknown

    15. AM plasma cortisol of <3 µg/dL: adrenal insufficiency AM cortisol >19 µg/dL: no AI All other patients need dynamic/functional testing

    16. In patients with primary adrenal insufficiency, plasma ACTH concentrations invariably exceed 100 pg per milliliter (22 pmol per liter), even if the plasma cortisol concentration is in the normal range Normal plasma ACTH values rule out primary, but not mild secondary, adrenal insufficiency Basal plasma aldosterone concentrations are low or at the lower end of normal values in primary adrenal insufficiency, whereas the plasma renin activity or concentration is increased because of the sodium wasting

    17. Cosyntropin stimulation testing Primary disease should not respond to exogenous ACTH How is this test performed? 250µg of synthetic ACTH is given IV Should be performed prior to 10am Baseline serum cortisol +/- ACTH measured 30, 60, 90 min serum cortisol obtained Adrenal function is considered normal if any serum cortisol level >18µg False positive can occur in mild secondary disease False negative can occur in severe/prolonged secondary disease as a result of adrenal cortical atrophy

    18. Our patient Random cortisol: 1 µg/dL Cosyntropin stim test: Baseline AM cortisol 1, ACTH 20 30min cortisol: 14 60min cortisol: 16 90min cortisol: 17 Stool O&P + for Entamoeba histolitica

    19. Insulin provocation testing Also performed in the morning Hypoglycemia (plasma glucose <40) activates the entire HPA axis 0.1-0.15 units/kg of regular insulin injected IV Baseline ACTH/cortisol measured Subsequent levels of glucose, cortisol, and sometimes ACTH measured 15, 30, 45, 60, 75, 90min Failure to reach serum cortisol level >18µg detects ALL types of adrenal insufficiency Contraindicated in coronary disease or hx of seizures

    20. Metyrapone testing Metyrapone is an inhibitor of the enzyme 11-hydroxylase, which catalyses 11-deoxycortisol to cortisol 30mg/kg is given at midnight with a snack Plasma cortisol and 11-deoxycortisol concentrations are measured at 8am Normal subjects have elevations in 11-deoxycortisol to >7 µg/dL Simultaneous cortisol levels must be <8 µg/dL to show that there was adequate enzyme inhibition

    21. Corticotropin-releasing hormone Less commonly used is the corticotropin-releasing hormone assay Plasma ACTH and cortisol are measured after injection Offers additional info in secondary disease whether the problem is at the level of hypothalamus or pituitary

    22. Table 3. Hormonal-Function Tests for Adrenal Insufficiency.Table 3. Hormonal-Function Tests for Adrenal Insufficiency.

    23. Imaging Primary disease Not routinely recommended May be helpful if malignancy or acute hemorrhage is suspected Secondary CT or MRI recommended for imaging of the sella or hypothalamus

    24. Treatment Patients with symptomatic adrenal insufficiency, but not those with minimal abnormalities on hormone tests, should be treated with hydrocortisone or cortisone therapy The usual initial dose is 25 mg of hydrocortisone (divided into doses of 15 and 10 mg) or 37.5 mg of cortisone (divided into doses of 25 and 12.5 mg) The daily dose may be decreased to 20 or 15 mg of hydrocortisone as long as the patient remains asymptomatic

    25. Treatment (cont’d) Patients with primary adrenal insufficiency should also receive fludrocortisone, in a single daily dose of 50 to 200 µg, as a substitute for aldosterone. The dose can be guided by measurements of blood pressure, serum potassium, and plasma renin activity, which should be in the upper-normal Patients must be advised to double or triple the dose of hydrocortisone temporarily whenever they have any febrile illness or injury, and should be given ampules of glucocorticoid for self-injection or glucocorticoid suppositories to be used in the case of vomiting.

    26. In practice, it is often unclear whether adrenal insufficiency is functional and transient during acute illness or whether it is due to established structural disease of the hypothalamic–pituitary–adrenal axis. Lifelong corticosteroid-replacement therapy should not be deemed on the basis of equivocal biochemical tests in an acutely ill patient. When there is doubt, testing the hypothalamic–pituitary–adrenal axis with the use of the corticotropin stimulation test or an insulin-tolerance test after resolution of the illness will determine whether long-term corticosteroid replacement will be required.

    27. Where does this leave us? Pt presents with apparent Addisonian crisis, etiology unclear, but may be secondary to infection Technically unresponsive to cosyntropin stim test Cortisol undetectable, with preserved, but not elevated ACTH Isolated, incomplete secondary corticosteroid insufficiency?

    28. In Summary… There are many ways to insult your adrenals Symptomatology may help you distinguish primary from secondary adrenal insufficiency There are a number of tests to help you diagnose adrenal insufficiency, the most common one we use (cosyntropin stim test) is not the most sensitive in diagnosing and distinguishing between causes Recalling normal structure/function can be clinically useful

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