Primary and secondary adrenal insufficiency

Question 8 from the second paper of 2004 and Question 17 from the second paper of 2022 were the only questions to ask directly about adrenal insufficiency. Beyond that, it pops up now and then among a list of differentials. Oh's Manual divides adrenal insufficiency into primary, secondary, or relative.

Primary adrenal insufficiency is the state of adrenal malfunction due to genuinely disorderly adrenal glands. Taken to its furthest extent, it leads to an "Addisonian crisis", characterised by circulatory collapse hyperkalemia and hypoglycaemia.

Secondary hypoadrenalism is the state of being adreno-suppressed, for whatever reason (be it drugs, critical illness or hypothalamic-pituitary malfunction)- but in the presence of normal adrenal glands. Lastly, one might have completely normal hypothalamic-pituitary-adrenal axis, and it might be secreting normally, but one might have a "relative adrenal insufficiency" if this volume of secretions happens to be inadequate to sustain the magnitude of the stress response which is required.

Apart from Oh's Manual,  another resource worth reading in the lead-up to the exams is an article by Marik and Zaloga (2002).

The following table is an adaptation of an entry in Oh's Manual - Box 61.1 on page 661 is a comprehensive source for causes of primary hypoadrenalism. It is an answer to the question, which aetiologies are responsible for the destruction of adrenal glands?

Causes of adrenal insufficiency

Marik and Zaloga (2002) offer a table of causes, which I have reorganised and adapted here:

Vascular aetiologies

  • Infarction due to arterial embolism
  • Infarction due to AAA
  • Postpartum pituitary necrosis


  • Sepsis
  • Tuberculosis
  • Histoplasmosis
  • Cytomegalovirus
  • Coccidioidomycosis
  • Menigococcal sepsis, purpura fulminans
  • HIV

Neoplastic invasion

  • Renal cell carcinoma
  • Adrenal carcinoma
  • Breast carcinoma
  • Lung (NSCLC)
  • Malignant melanoma
  • Pituitary tumour


  • Corticosteroid withdrawal
  • Etomidate (causes primary adrenal insufficiency)
  • Azole antifungals - Fluconazole, ketoconazole
  • Rifampicin (increases steroid metabolism)
  • Phenytoin (increases steroid metabolism)

Infiltrative systemic disease

  • Amyloid
  • Sarcoidosis
  • Haemochromatosis

Congenital causes

  • Adrenal dysgenesis
  • Adrenoleukodystrophy
  • Impaired steroidogenesis
  • Empty sella syndrome

Autoimmune destruction

  • Addison's disease

Traumatic destruction

  • Trauma is a major cause of adrenal insufficiency

Environmental factors

  • Hypothermia

This can be further separated into primary, secondary and tertiary causes.

Primary causes include anything which attacks the adrenal gland directly. The vascular, autoimmune and neoplastic causes fit here.

Secondary causes feature a structurally and functionally normal adrenal gland, but in the absence of an appropriate stimulus. Such situations arise when the adrenal gland function is suppressed by drugs, or dysregulated by a damaged pituitary. An interesting case of traumatic pituitary injury is presented in Question 12.1 from the second paper of 2014.

Tertiary causes are those which result in hypoadrenalism with an intact hypothalamic-pituitary-adrenal axis, such as the cessation of corticosteroids, or the "relative adrenal insufficiency" of septic shock.

Causes of Addisonian crisis

The examiner comments for Question 17 from the second paper of 2022 complained that few of the exam candidates were able to distinguish between causes of Addisonian crisis as distinct from the causes of Addison's disease. An adrenal crisis typically affects people with an already known adrenal insufficiency, and results from either insufficient corticosteroid supplementation, or an increased demand for it, or both. 

  • Insufficient supplementation
    • Poor medication compliance for chronic steroid replacement
    • Abrupt weaning of long term steroids
    • Decreased oral steroid absorption (eg. bowel obstruction)
  • Increased demand
    • Acute infection
    • Surgery or trauma
    • Pregnancy

Additionally, if one pays attention to the table above, a lot of the etiologies (eg. infarction of the adrenal glands) can bring about an unexpected adrenal crisis more rapidly

Consequences of adrenal insufficiency in critical illness

The stereotypical adrenally suppressed patient in the ICU will have a tanned appearance of their skin, be hypoglycaemic, and will likely be suffering from shock of some sort, with high vasopressor requirements. Hyperkalemia and hyponatremia with a normal anion gap metabolic acidosis will be a feature of mineralocorticoid deficiency, and will resemble the wanton use of spironolactone.

Clinical Features of Adrenal Insufficiency

Specific features

  • Hypotension refractory to fluids (and vasopressors)
  • Eosinophilia
  • Hypoglycaemia
  • Hyponatremia
  • Hyperkalemia
  • Hyperpigmentation

Non-specific features

  • Decreased level of consciousness
  • Defects of other hormone systems (eg thyroid)
  • Normocytic anaemia
  • Hyperdynamic circulation
  • Metabolic acidosis (NAGMA)
  • Diarrhoea
  • Nausea
  • Vomiting

Investigation of adrenal insufficiency

  • Serum cortisol level
    • In normal subjects, a good morning cortisol level is 275 to 555 nmol/L
  • High dose ACTH test:
    • 250 μg of synacthen is administered
    • Cortisol levels are taken 30-60 minutes later
    • A normal cortisol level 60 minutes after the synacthen should be >500 nmol/L
    • An abnormal response establishes the diagnosis of hypoadrenalism
    • A normal response rules out primary hypoadrenalism
    • An abnormal response  does not exclude the diagnosis of secondary hypoadrenalism
  • Metyrapone test:
    • Metyrapone blocks the final step in cortisol biosynthesis
    • This should decrease the serum cortisol level and stimulate ACTH secretion
    • Serum 11-deoxycortisol and cortisol are measured on the next morning
    • A normal response consists of a high 11-deoxycortisol level and a low cortisol level
    • ACTH can also be measured: a normal response is 10 to 200 pg/mL.
  • Insulin-hypoglycaemia test
    • Hypoglycaemia is a more potent stimulus for ACTH secretion than metyrapone
    • 0.15 units/kg of insulin is given
    • A hypoglycaemia of ~ 1.9mmol/L is aimed for (under supervision)
    • Cortisol levels are taken at 0, 30 and 45 minutes
    • A normal response is a cortisol level around 500 to 600 nmol/L
  • ACTH level
  • MRI of the adrenal glands

Management of adrenal crisis

  • Immediate priorities:
    • Steroid replacement: hydrocortisone 100mg IV immediately, followed by 50mg four times a day
      • In patients with suspected adrenal insufficiency who do not yet have a diagnosis, giving emergency dexamethasone may be an option, because it will not interfere with cortisol measurements (or, one may simply send a cortisol level and then immediately start hydrocortisone)
    • Volume replacement: isotonic saline, titrated to clinical response
    • Glucose replacement: dextrose, to aim for normal BSL
  • Supportive management:
    • Correct hypotension with vasopressors (noradrenaline) 
    • Correct hyperkalemia with standard measures (cation exchange resin, insulin, salbutamol, etc)
      • Add fludcorotisone if using dexamethasone instead of hydrocortisone
    • Cease any medications that may be precipitating the crisis, eg. any CYP 3A4 inducers, azoles, etomidate, rifampicin, carbamazepine


Oh's Intensive Care manual: Chapter   61   (pp. 660) Adrenocortical  insufficiency  in  critical  illness by Balasubramanian  Venkatesh  and  Jeremy  Cohen

Oelkers, Wolfgang. "Adrenal insufficiency." New England Journal of Medicine335.16 (1996): 1206-1212.

Marik, Paul E. "Mechanisms and clinical consequences of critical illness associated adrenal insufficiency." Current opinion in critical care 13.4 (2007): 363-369.

Cooper, Mark Stuart, and Paul Michael Stewart. "Adrenal insufficiency in critical illness." Journal of intensive care medicine 22.6 (2007): 348-362.

Marik, Paul E., and Gary P. Zaloga. "Adrenal insufficiency in the critically ill: a new look at an old problem." CHEST Journal 122.5 (2002): 1784-1796.

Dorin, Richard I., Clifford R. Qualls, and Lawrence M. Crapo. "Diagnosis of adrenal insufficiency." Annals of Internal Medicine 139.3 (2003): 194-204.

Feeney, C., et al. "Addisonian crisis: assessment and management." British Journal of Hospital Medicine 79.3 (2018): C34-C37.