Learning Objectives

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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

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Adrenal structure/anatomy

• Fat
• Capsule
• Zona Glomerulosa
• Zona Fasciculata
• Zona Reticularis
• Medulla

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Adrenal structure/anatomy

• Cortex
• Glomerulosa
• Aldosterone synthesis
• Fasiculata
• Glucocorticoid synthesis
• Reticularis
• Sex hormone synthesis

• Medulla
• Catecholamines
• Controlled by ANS

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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.

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Cooper M and Stewart P. N Engl J Med
2003348727-734
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Primary adrenal insufficiency Addisons 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

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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

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Secondary adrenal insufficiency

• Pituitary or hypothalamic dysfunction or
  destruction
• Suppression of gland via exogenous or endogenous
  steroid excess

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Causes of Primary and Secondary Adrenal
Insufficiency
Oelkers W. N Engl J Med 19963351206-1212
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• 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

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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

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Clinical Manifestations of Adrenal Insufficiency
Oelkers W. N Engl J Med 19963351206-1212
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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

Oelkers W. N Engl J Med 19963351206-1212
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• AM plasma cortisol of lt3 µg/dL adrenal
  insufficiency
• AM cortisol gt19 µg/dL no AI
• All other patients need dynamic/functional testing

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• 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

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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 gt18µg
• False positive can occur in mild secondary
  disease
• False negative can occur in severe/prolonged
  secondary disease as a result of adrenal cortical
  atrophy

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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 OP for Entamoeba histolitica

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Insulin provocation testing

• Also performed in the morning
• Hypoglycemia (plasma glucose lt40) 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 gt18µg
  detects ALL types of adrenal insufficiency
• Contraindicated in coronary disease or hx of
  seizures

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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 gt7 µg/dL
• Simultaneous cortisol levels must be lt8 µg/dL to
  show that there was adequate enzyme inhibition

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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

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Hormonal-Function Tests for Adrenal Insufficiency
Oelkers W. N Engl J Med 19963351206-1212
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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

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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

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Treatment (contd)

• 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.

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• 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 hypothalamicpituitarya
  drenal 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
  hypothalamicpituitaryadrenal 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.

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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?

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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