• Primary Adrenocortical insufficiency: Laboratory Findings and Diagnostic Testing.
    •  Laboratory findings:
      • initially:steroid output normal; but adrenal reserve reduced
        • ACTH-adrenal stimulation: produces some normal cortisol increase or no increase
      • more advanced disease: (more adrenal destruction)
        •  serum sodium, bicarbonate, chloride: reduced
          1. decreased serum sodium: due to excessive urinary loss (secondary to aldosterone deficiency) and movement into intracellular compartments
          2. extravascular sodium loss -- depleting extracellular fluid; promotes hypotension; elevated plasma angiotensin II and vasopressin promote hyponatremia by reducing free water clearance
        •  serum potassium: elevated
          • Hyperkalemia due to:
            1. aldosterone deficiency
            2. acidosis
            3. impaired glomerular filtration

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    •  Diagnosis:
      • Based on ACTH stimulation testing: evaluation of adrenal steroid production reserve capacity
      • Severe adrenal insufficiency: rate of cortisol secretion significantly reduced; low to absent 24 urine cortisol levelto
      • Mild adrenal insufficiency (decreased adrenal reserve)
      • Aldosterone secretion: low-- causing:
        • salt wasting
        • increased plasma renin

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Glucocorticoid Reserve Test
  • Shortly after ACTH administration (minutes), cortisol increases in adrenal venous blood.
    • Responsiveness: an indication of functional adrenal gland cortisol production reserve
    • Maximal ACTH stimulation: cortisolsecretion may increase tenfold -- with prolonged ACTH infusion;
      • with 24 hour infusion of cosyntropin, patients with secondary or primary adrenal insufficiency will have diminished maximal plasma cortisol values
  • Screening Test-- rapid ACTH stimulation test
    • administer 0.25mg of cosyntropin by intravenous or intramuscular injection
    • measure plasma cortisol levels before and 30 and 60 minutes after:
      • minimal stimulated normal cortisol increment: > 7 ug/dL; normal response > 18 ug/dL

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  • Acute Adrenocortical Insufficiency:
    • May occur are due to:
      1.  rapid intensification of chronic adrenal insufficiency
        • precipitated by sepsis or surgical stress
      2.  acute hemorrhagic adrenal gland destruction in a previously healthy individual
        •  in children: associated with Pseudomonas septicemia or meningiococcemia
        •  in adults: associated with anticoagulant treatment/coagulation disorder
      3. Most frequent cause of acute adrenal insufficiency:
        • rapid withdrawal of steroids from patients who have adrenal atrophy following prolonged chronic steroid administration
      4. Other causes:
        • patients with congenital adrenal hyperplasia or with decreased adrenocortical reserve when:
          • they are given drugs that inhibit steroid synthesis, e.g. mitotane (Lysodren), ketoconazole (Nizoral) or
          • their given drugs that increase steroid metabolism, e.g. phenytoin (Dilantin), rifampin (Rimactane)

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    • Prognosis:
      • Long-term survival: dependent on prevention and proper treatment of adrenal crisis:
      • Prevention of crisis: infection, trauma, gastrointestinal upsets, other stresses: require immediate increase in administered hormone. Otherwise, symptoms may intensify --
        • nausea
        • vomiting
        • abdominal pain
        • lethargy, somnolence
        • hypovolemic vascular collapse
      • Treatment: based on replacing glucocorticoids and sodium/water deficits
        • intravenous 5% glucose infusion (in normal saline)
        • initiated with IV bolus of 100 mg hydrocortisone, followed by continuous hydrocortisone (Cortef, Solu-Cortef) infusion (10 mg/h)
        • Management of hypotension requires glucocorticoid replacement and correction of sodium and water deficit
        • Vasoconstrictive agents (dopamine) may be required in some extreme cases
        • Mineralocorticoid supplementation may be required (full mineralocorticoid effect will accompany the 100 mg hydrocortisone infusion)

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Adrenocortical hyperfunction

  • Congenital adrenal hyperplasia
    • Caused by cortisol synthetic defects
      • autosomal recessive mutations
    • Most common adrenal disorder of childhood and infancy
    • Late-onset adrenal hyperplasia cause:
      • 5%-25% of hirsuitism and oligomenorrhea cases in women
      • Pregnancy at risk for congenital adrenal hyperplasia:
        • dexamethasone administration to the mother protects

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    • Most common deficiency:
      •  decrease or lack of cytochrome P450c21 (21ß hydroxylase) activity {95% frequency) which results in:
        • cortisol synthesis reduction
        • compensatory increase of ACTH release
      • Other deficiencies:
        • P450c18, P450c17a , P450c11ß, 3ß- hydroxysteroid dehydrogenase
      • Increased compensatory ACTH can result in normal cortisol levels if sufficient P450c21 activity is present; however the gland will:
        • become hyperplastic
        • produce excessive precursors such as 17-hydroxyprogesterone -- diverted to androgen pathways-- leading to virilization.
        • Diagnosis:
          • Excessive 17-hydroxyprogesterone is metabolized in the liver to pregnanetriol, detected in large amounts in the urine.
          • Most reliable detection: increased plasma 17-hydroxyprogesterone to ACTH stimulation

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      • Physiological consequences:
        • Female:
          • adrenal virilization associated with:
            1. ambiguous external genitalia (female pseudohermaphroditism)
            2. enlargement of the clitoris
            3. partial/complete labial fusion
            4. urogenital sinus (possible)
        • Male: enlarged genitalia
        • Postnatal period:
          • female virilization
          • isosexual prococity in the male
          • excessive androgen levels:
            • accelerated growth
            • early epiphyseal closure; growth stops --truncal development continues-- (short child with well-developed trunk.
        • 11-hydroxylation defects:
          •  excessive desoxycorticosterone production: hypertension
        • 17-hydroxylation defects:
          •  adrenal and gonadal defects increased 11-desoxycorticosterone levels-- mineralocorticoid excess signs/symptoms:
            1.  hypertension
            2.  hypokalemia

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      • Infant with congenital adrenal hyperplasia:Presenting Symptoms --
        • Treatment
        •  If acute adrenal crisis:
          1. IV cortisol
          2. mineralocorticoid
          3. electrolyte solutions
        • After stabilization:
          •  hydrocortisone (Cortef, Solu-Cortef)-- adjusted as required
          • alternative: prednisone (Deltasone)
          • mineralocorticoids may be required (fludrocortisone (Florinef))

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Goldfien, A.,Adrenocorticosteroids and Adrenocortical Antagonists, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 635-650.
Williams, G. H and Dluhy, R. G. , Diseases of the Adrenal Cortex, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2035-2056.