Adrenal Insufficiency

Basics

Description

  • Inadequate glucocorticoid (cortisol) and/or mineralocorticoid (aldosterone) secretion to meet the body’s stress requirement
  • Primary adrenal insufficiency is a primarily adrenal disorder associated with impaired glucocorticoid and mineralocorticoid production
  • Secondary adrenal insufficiency is a problem with the pituitary gland and tertiary adrenal insufficiency is associated with the hypothalamus
  • Adrenal deficiency:
    • Inadequate cortisol/aldosterone
    • Unresponsive to stimulation with adrenocorticotropic hormone (ACTH)
  • Adrenal crisis (Addisonian crisis):
    • Life-threatening emergency
    • Precipitated by:
      • Steroid-dependent patient under stress (pregnancy, surgery, trauma, infection, or dehydration)
      • Rapid steroid withdrawal
      • Acute adrenal hemorrhage
      • Recent pituitary/craniopharyngioma resection
      • Congenital adrenal hyperplasia
      • Postpartum pituitary gland necrosis (Sheehan syndrome)

Etiology

Primary Adrenal Failure: Adrenal Gland Dysfunction

  • Adrenal dysgenesis/impaired steroidogenesis:
    • Congenital hypoplasia
    • Allgrove syndrome:
      • ACTH resistance
      • Achalasia
      • Alacrima
    • Glycerol kinase deficiency:
      • Psychomotor retardation
      • Hypogonadism
      • Muscular dystrophy
  • Congenital adrenal hyperplasia:
    • 21-hydroxylase deficiency accounts for 95% of cases
    • Aldosterone synthetase deficiency
  • Mitochondrial disease
  • Adrenal destruction:
    • Autoimmune:
      • Autoimmune polyglandular syndrome types 1 and 2 (alopecia universalis, chronic mucocutaneous candidiasis, hypoparathyroid, thyroid autoimmunity, diabetes, celiac disease, pernicious anemia)
      • Adrenoleukodystrophy
    • Infectious:
      • Septic shock
      • Tuberculosis
      • Protozoal and fungal: Histoplasmosis, coccidioidomycosis, and candidiasis
      • Viral: Cytomegalovirus, herpes simplex virus, and HIV
      • Syphilis
    • Metastatic tumors
      • Lung, breast, colon
    • Infiltration:
      • Metastatic cancers
      • Sarcoid
      • Hemochromatosis
      • Amyloidosis
  • Bilateral adrenalectomy
  • Adrenal hemorrhage
    • Sepsis: Particularly meningococcemia (Waterhouse–Friderichsen syndrome), Pseudomonas infection, H. Infuenza, E. Coli, Streptococcus pneumoniae
    • Birth trauma/anoxia
    • Pregnancy
    • Seizures
    • Anticoagulants
    • Rhabdomyolysis
  • Pharmacologic inhibition:
    • Etomidate
    • Phenobarbital
    • Ketoconazole/fluconazole
    • Phenytoin
    • Rifampicin

Secondary Adrenal Failure: Pituitary Dysfunction (Corticotropin Deficiency)

  • Steroid withdrawal
  • Pituitary insufficiency
  • Sepsis
  • Head trauma: pituitary damage
  • Hemorrhage
  • Sheehan syndrome: Blood loss, shock
  • Cancer infiltration: Neoplasm, amyloid, sarcoid, and hemochromatosis
  • Prader–Willi syndrome

Tertiary Adrenal Failure: Hypothalamus Dysfunction (Corticotropin-Releasing Hormone Deficiency)

  • Pharmacologic inhibition:
    • Glucocorticoid therapy
    • Mifepristone
    • Chlorpromazine
    • Imipramine
  • Sepsis
  • Infiltrative: Neoplasm, amyloid, sarcoid, and hemochromatosis
  • Head trauma (skull-base fractures most common)

Diagnosis

Signs And Symptoms

  • Symptoms:
    • Depression
    • Weakness, tiredness, fatigue
    • Myalgias
    • Anorexia
    • Abdominal pain, nausea, vomiting
    • Salt craving
    • Dizziness
    • Muscle or joint pains
    • Dehydration
    • Dry/itchy skin (women)
    • Loss of libido (women)
  • Signs:
    • Fever or hypothermia
    • Mental status changes
    • Hypotension, tachycardia
    • Weight loss
    • Goiter
    • Hypogonadism
    • Hyperkalemia (primary)
    • Hypercalcemia (primary)
    • Sodium depletion
    • Azotemia
    • Eosinophilia
    • Hyperpigmentation (primary only)
    • Vitiligo
  • Addisonian crisis:
    • Hypotension and shock
    • Hyponatremia
    • Hyperkalemia
    • Hypoglycemia

Essential Workup

  • Lab confirmation of diagnosis may not be possible in ED
  • Adrenal crisis: Life-threatening condition:
    • High degree of suspicion should prompt initiation of therapy before definitive diagnosis
  • Plasma cortisol level
  • Thyroid levels
  • Chemistry panel
  • CBC with differential
  • Core temperature

Diagnostic Tests And Interpretation

Lab

  • CBC with differential:
    • Anemia
    • Eosinophilia
    • Lymphocytosis
  • Arterial blood gases/chemistry:
    • Hypoxemia
    • Acidosis
    • Hyperkalemia (primary insufficiency only)
    • Hyponatremia
    • Elevated creatinine (primary only)
    • Hypoglycemia
    • Hypercalcemia (primary only)
  • Cortisol levels in critically ill patients:
    • Baseline am cortisol <3 mcg/dL diagnostic for adrenal deficiency, but impractical in the ED
    • Standard corticotropin stimulation test with peak cortisol <500 nmol/L
    • Consensus critical care recommendation to diagnose acute adrenal deficiency:
      • Random serum cortisol <10 mcg/dL (while under physiologic stress)
      • Random cortisol <275 nmol/L
  • Cosyntropin stim test also suggestive if cortisol level at 60 min <18 mcg/dL
  • Search for underlying infection

Imaging

CXR:

  • Look for infection or pulmonary edema

Diagnostic Procedures/Surgery

ECG:

  • Evaluate for signs electrolyte disturbances

Differential Diagnosis

  • Sepsis
  • Shock
  • Hypoglycemia
  • Hypothermia
  • Acute abdominal process

Treatment

Initial Stabilization/Therapy

  • Airway, breathing, and circulation management (ABCs)
  • Cardiac monitor
  • BP support for hypotension:
    • Normal saline (0.9%) IV fluids 500 mL–1 L (peds: 20 mL/kg) bolus
  • Supplemental oxygen
  • Correct hyperthermia/hypothermia

Ed Treatment/Procedures

  • Glucocorticoid/mineralocorticoid replacement:
    • IV hydrocortisone or dexamethasone immediately
    • Use IM route if no IV access
    • Hydrocortisone 100 mg × 1 (50 mg/m2), and 200 mg/24 hr
    • Fludrocortisone (oral only) can be given for isolated mineralocorticoid deficiency
  • Volume expansion:
    • In adults, NS (0.9%) or D5NS 1 L/h for 3–4 L, monitor for fluid overload
    • Care should be taken to note patient’s age, volume, and cardiac and renal function
  • For hypoglycemia:
    • D50W
  • Treat life-threatening dysrhythmias secondary to hyperkalemia with calcium, bicarbonate, and insulin/glucose
  • Identification and correction of underlying precipitant
  • Should see BP improvement within 4–6 hr of therapy

Medication

  • Hydrocortisone: 100 mg (peds: 25–100 mg) bolus and 200 mg/d (peds 25–100 mg/d) infusion
  • Fludrocortisone (50–100 mcg) oral formulation only in patients with isolated mineralocorticoid deficiency

Follow-Up

Disposition

Admission Criteria

  • All patients with acute adrenal insufficiency
  • ICU admission for patients with unstable or potentially unstable cases

Discharge Criteria

  • Normal lab evaluation with treated adrenal insufficiency
  • Should speak with endocrinologist before discharge in patients with chronic adrenal insufficiency

Follow-Up Recommendations

  • Should have primary care physician follow-up within a few weeks, depending on symptoms
  • May benefit from endocrinology referral

Pearls And Pitfalls

  • Acute adrenal insufficiency is a life-threatening emergency, and treatment should not be delayed in the ED while waiting for definite lab diagnosis
  • Patients with primary adrenal insufficiency are lacking both glucocorticoids and mineralocorticoids
  • Patients with secondary and tertiary adrenal insufficiency are deficient only in glucocorticoids
  • Morning cortisol levels are not practical in the ED, but a random cortisol <10 mcg/dL in a patient under physiologic stress is suggestive of adrenal insufficiency
  • An increase of cortisol <9 mcg/dL 1 hr after cosyntropin administration or a cortisol level <18 mcg/dL 1 hr after cosyntropin administration is also suggestive of adrenal insufficiency
  • Hydrocortisone doses greater than 50 mg provide adequate mineralocorticoid coverage
  • Patients using chronic steroids may need increased doses during times of critical illness
  • Steroids in septic shock is controversial but still recommended in shock refractory to vasopressors or in patients using chronic corticosteroids
  • The clinical consequence of a single dose of etomidate for rapid sequence intubation is controversial. Studies do show biochemical adrenal suppression, which must be weighed against agents with other undesirable properties while performing a critical, life-saving procedure

Additional Readings

  1. Bancos I, Hahner S, Tomlinson JT, Arlt W. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. 2015;3(3):216–226.  [PMID:25098712]
  2. Bornstein SR, Allolio B, Arit W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364–389.  [PMID:26760044]
  3. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383:2152–2167.  [PMID:24503135]
  4. Chou SH. Adrenal insufficiency. Hosp Med Clin. 2012;1(1):e97–e108.
  5. Gibbison B, López-López JA, Higgins JP, et al. Corticosteroids in septic shock: A systematic review and network meta-analysis. Crit Care. 2017;21:78.  [PMID:28351429]
  6. Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36:1937–1949.  [PMID:18496365]
  7. UCar A, Baş F, Saka N. Diagnosis and management of pediatric adrenal insufficiency. World J Pediatr. 2016;12(3):261–274.  [PMID:27059746]

See Also (Topic, Algorithm, Electronic Media Element)

Cushing Syndrome

The authors gratefully acknowledge Rita K. Cydulka and Joseph P. Tagliaferro for their contribution to the previous edition of this chapter.

Authors

Shayan Ghiaee

Todd A. Taylor