Adrenal Insufficiency and Crisis

Background

Chronic permanent AI is present in about 5 per 10,000 in the general population. Typically this is due to hypothalamic-pituitary disease (3 per 10,000) and primary AI is a little less common (2 per 10,000). Primary AI is 1/2 acquired (autoimmune), and 1/2 genetic (i.e. congenital adrenal hyperplasia). In developed countries, iatrogenic AI due exogenous steroids occurs in 0.5-2% of the general population.

Adrenal crisis, or "acute adrenal insufficiency", "Addisonian crisis", has no single accepted definition. These crises are the most severe manifestation of adrenal insufficiency. Consider the following pragmatic definition per NEJM: "Acute deterioration in health associated with hypotension (absolute or relative) that significantly resolves within 1-2 hours after parenteral glucocorticoids".

Etiology

Primary AI is usually caused by autoimmune adrenalitis (i.e. Addison's disease) which is isolated in 30-40% of patients, but the other 60-70% have autoimmune polyglandular syndrome (AIPS). Other causes of primary AI:

• X-linked adrenoleukodystrophy occurs in 1:20,000 males due to mutations in the X-ALD gene and generally present either in childhood or in early adulthood with neurologic features of myelinopathy and peripheral NS involvement, but can show as isolated primary AI.
• Adrenal gland destruction (infection, hemorrhage, infiltrative disease)
  • Tuberculous adrenalitis
  • Adrenal mets (bilateral and bulky mets)
  • Waterhouse-Friderichsen syndrome, primary APS
  • Lymphoma, sarcoidosis, amyloidosis, hemochromatosis
  • Invasive fungal infections
• Congenital adrenal hyperplasia
• Drug-induced
  • etomidate, abiraterone, ketoconazole, etc.

Secondary AI is due to a dysfunctional hypothalamus-pituitary gland. Generally due to pituitary or hypothalamic tumours or their treatment (radiation, surgery). Can also be due to pituitary apoplexy (infarcted adenoma, perioperative, Sheehan syndrome), more rarely due to autoimmune disease or pituitary infiltration.

Physiology

The HPA axis controls the release of cortisol in response to circadian rhythm and physiologic stressors. However, the mineralocorticoid production in the body is primarily separately controlled by the RAAS (aldosterone release in the adrenal zone glomerulosa).

Manifestations

Absolute/relative cortisol deficiency leads to impaired homeostasis:

Effect	Manifestation
Loss of suppressive effects on endogenous cytokines	Fever, malaise, anorexia, bodily pain
Altered immune-cell populations	Neutropenia, eosinophilia, lymphocytosis, Mild anemia
Loss of synergy with catecholamines on vascular tone	Hypotension, vasodilatation
Hepatic effects on intermediate metabolism	Reduced gluconeogenesis, hypoglycemia, reduced circulating FFA/AAs
Mineralocorticoid deficiency (primary >>> secondary)	Sodium and water loss, potassium retention

Mineralocorticoid deficiency

• occurs in primary AI only
• Hyperkalemia (40%) and non-anion gap metabolic acidosis (NAGMA). These result from mineralocorticoid deficiency that causes a type-4 renal tubular acidosis (RTA).

Glucocorticoid deficiency

• These occur regardless of the type of adrenal insufficiency (either primary or secondary).
  • Hyponatremia which is due to mineralocorticoid deficiency in primary AI (80% of patients) but also decreased ADH inhibition (primary/secondary) leading to mild SIADH.
  • Hypoglycemia.
  • Hypercalcemia (rarely).
• Consider the possibility of adrenal insufficiency in any patient with unexplained hyponatremia or hypoglycemia.

Chronic AI

• Tends to present with relatively nonspecific signs and symptoms (fatigue, loss of energy) which can be misdiagnosed as depression, anorexia, etc. Cardiovascular effects could show as orthostasis, dizziness. Patients may have nonspecific gastrointestinal symptoms (nausea, vomiting, abdominal pain) which can be misdiagnosed as gastroenteritis or gastroparesis.
• Chronic primary AI can lead to hyperpigmentation due to excess melanocortin-induced melanocyte stimulation (from POMC cleavage due to upstream ACTH upregulation). These skin changes are most pronounced in skin areas exposure to friction or shear stress, and are increased by sunlight.
• Chronic secondary AI can lead to pale skin due to lack of ACTH secretion.

Adrenal Crisis

• more common in patients with primary AI who have a background of chronic undertreated AI.
• Can mimic acute abdomen: abdominal pain, N/V, fever.
• Can lead to shock refractory to fluids and vasopressors
• Can lead to acute neurologic disease: stupor and coma

Triggers and Etiologies

1. Chronic AI + physiologic stress trigger
   1. Chronic AI: Addison's, chronic steroid therapy
   2. Trigger:
      1. infection, particularly gastroenteritis or bacterial infections
      2. Surgery or trauma
      3. Steroid nonadherence or dose reductions
      4. Medication interactions (CYP3A4, AEDs, etomidate, azoles, rifampin, thyroid hormone)
      5. Thyrotoxicosis
      6. Psychologic stress and exercise
      7. Volume depletion
      8. Pregnancy
2. Acute AI
   1. Waterhouse-Friderichsen syndrome
   2. Pituitary apoplexy

Diagnosis of AI

Situation 1: You Have Time

1. 8 AM Cortisol
   1. <83 nmol/L --> AI very likely
   2. >500 nmol/L --> AI unlikely
   3. in between --> need to do an ACTH stimulation test
2. ACTH stimulation test
   1. Cortisol should rise to >550 nmol/L at either 30 or 60 minutes (normal response). If not then the diagnosis of AI is made.
   2. 250 mcg cosyntropin is preferred to the 1 mcg low-dose test (the low-dose test has no superior diagnostic value)
   3. can be done if the patient is on dexamethasone, but any other steroid means that these results are impossible to interpret

Situation 2: No Time

1. Random cortisol test
   1. >550 ug/dL excludes adrenal insufficiency
   2. <550 ug/dL is nonspecific and requires an ACTH stim test
   3. <140-200 ug/dL in the setting of physiologic stress suggests AI
2. Empiric treatment (see below)

Primary vs Secondary AI and further workup

• After the diagnosis of AI is confirmed as above, then proceed to measure the plasma ACTH level to determine if the patient has primary or secondary disease
• Increased ACTH --> primary AI. Will also have increased plasma renin
  • Screening for steroid autoantibodies ?autoimmune adrenalitis. If negative, then consider adrenal CT imaging to investigate for possible hemorrhage, infiltration, or masses. In males, consider VLCFA measurements to exclude X-ALD.
• Inappropriately low ACTH --> secondary AI
  • These patients should have HP imaging via MRI

Management of AI

Adrenal Crisis

• Adequate fluid resuscitation, cardiac monitoring
• glucocorticoid boluses as below
• mineralocorticoid replacement can be initiated once the daily hydrocortisone dose <50 mg due to the pleiotropic effect of higher dose hydrocortisone on mineralocorticoid receptors

Suspected AI

1. Dexamethasone 4-6 mg IV x 1 +/- fludrocortisone if hyperkalemic
2. Random cortisol level as above.
3. If the cortisol levels suggest AI then start treatment with hydrocortisone 50 mg IV q6H

Known AI

1. 100 mg hydrocortisone IV STAT as a loading dose then 50 mg IV q6H; OR methylprednisolone 40 mg IV daily
2. Once the patient has recovered then steroid can be tapered over roughly 3 days to the baseline regimen

Chronic AI

• Glucocorticoid replacement should be given at doses that replace the physiologic daily cortisol production:
  • 15-25 mg hydrocortisone in 2-3 divided doses
  • at least 1/2 of the daily dose should be given in the morning
  • long-acting steroids (dexamethasone) are not preferred due to the non-physiologic pharmacokinetics
  • There are no well-established dose equivalencies, but as a guide, equipotency can be assumed for 1 mg hydrocortisone, 1.6 mg cortisone acetate, 0.2 mg prednisolone, 0.25 mg prednisone, and 0.025 mg dexamethasone.
• Mineralocorticoid replacement in primary AI should be given at a dose of 100-150 mcg fludrocortisone (lower dose than in orthostatic hypotension)
  • renin levels should be kept in the high-normal range, and dose titration is by electrolytes and postural hypotension
• consider adrenal androgen replacement in patients (both men and women) who experience a lack of energy despite optimized glucocorticoid and mineralocorticoid replacement
  • once-daily DHEA 25-50 mg
  • monitor DHEAS, androstenedione, testosterone, and SHBG

Adrenal Crisis Prophylaxis

1. Oral stress dosing (2-3x) in situations that lead to bed rest, skipped work, fever
2. Parenteral stress dosing (up to 200 mg q24h), such as 100 mg x 1 in vomiting or diarrhea, or higher in surgery/trauma
3. "steroid card", med alert bracelet

References

1. IBCC - Adrenal Crisis
2. Harrison's Chapter 379 - Disorders of the Adrenal Cortex