Adrenal insufficiency

Introduction

• Adrenal insufficiency refers to deficiency of cortical adrenal hormones
• Adrenal crisis refers to life-threatening exacerbation of insufficiency due to increased physiologic demand e.g. infection or decreased supply e.g. discontinuation of steroid therapy
  • Usually due to major stress e.g. CVA, MI, sepsis, surgery, major injury, trauma
• 20% of patients with AIDS suffer adrenal insufficiency ultimately
• Major head trauma patients suffer pituitary insufficiency far more frequently than previously realised with resultant ACTH deficiency and reduced adrenal cortisol release

Pathophysiology

• Primary adrenal insufficiency (Addison disease)
  • Intrinsic adrenal gland dysfunction with reduced cortisol and aldosterone synthesis
  • 90% of gland must be destroyed before symptoms arise
  • TB most common infectious cause worldwide. HIV most common in developed countries
  • Consider if hyperpigmented, vitiligo
• Secondary adrenal insufficiency
  • HPA dysfunction with inadequate ACTH production
  • Cortisol deficiency only

Physiology

• Hypothalamic CRH released in diurnal rhythm with peaks in morning
• Stimulates pituitary ACTH release
• Stimulates adrenal cortex cortisol release
• Aldosterone release is controlled by RAS

Primary adrenal insufficiency – Addison disease

• Autoimmune: Isolated or polyglandular autoimmune syndromes
• Adrenal haemorrhage or trauma: Meningococcal sepsis necrosis (Waterhouse-Friederichsen syndrome), coagulation disorders, warfarin
• Drugs: Adrenolytic agents, ketoconazole
• Infections of adrenal gland: TB, fungal/bacterial sepsis, AIDS
• Infiltrative: Sarcoidosis, haemochromatosis, amyloidosis, lymphoma, metastatic cancer (esp. pulmonary)
• Surgical: Bilateral adrenalectomy
• Hereditary: Adrenal hypoplasia, congenital adrenal hyperplasia, adrenoleukodystrophy, familial glucocorticoid deficiency
• Idiopathic

Secondary adrenal insufficiency

• Iatrogenic
• Postpartum pituitary necrosis (Sheehan syndrome)
• Pituitary tumor
• Hypothalamic tumor
• Local invasion (craniopharyngioma)
• Pituitary irradiation/surgery
• Infiltrative: Sarcoidosis, haemosiderosis, haemochromatosis, histiocytosis X, metastatic cancer, lymphoma
• Infectious: TB, meningitis, fungal sepsis, HIV

HIV and Addison disease

• May be due to CMV infection, use of ketoconazole or inhibition of HPA axis by cytokines released from macrophages

Clinical features

• High index of suspicion required
• Consider in hypotension not responding to therapy, especially if AIDS, prior glucocorticoid therapy, known autoimmune diseases, history of chronic fatigue or hyperpigmentation or previous head trauma
• Primary adrenal insufficiency
  • Symptoms of diminished cortisol AND aldosterone AND increased ACTH (hyperpigmentation)
• Secondary adrenal insufficiency
  • Symptoms of diminished cortisol +- symptoms of pituitary lesions (headache, visual change, galactorrhoea)
  • Lacks mineralocorticoid deficiency – hence no hyperkalaemia

Symptoms

• Cortisol deficiency symptoms
  • Weight loss, lethargy, weakness, ALOC, GI (anorexia, nausea, vomiting, abdominal pain, diarrhoea)
• Aldosterone deficiency symptoms
  • Dehydration, syncope, hypotension, orthostatic hypotension
• Hypoglycaemia is often present due to cortisol deficiency

Labs

• CXR helpful to rule out pneumonia as precipitant +- lung cancer
• CT abdo/pelvis can help rule out adrenal haemorrhage/infarction/tumor
• Baseline cortisol and ACTH
  • Normal cortisol 200-650nmol/L
  • ACTH high in primary adrenal disease and low in secondary disease
  • Synacthen stimulation test is diagnostic
    • 250mcg Synacthen IM and cortisol levels at baseline, 30 minutes and 60 minutes
    • If no rise in cortisol = primary disease

Treatment

• Do not delay for anything
• IV hydrocortisone 250mg stat then 100mg q6h
  • Provides both mineralocorticoid and glucocorticoid effect
  • Unfortunately, this interferes with cortisol assay so dexamethasone is preferred if diagnostic testing is planned
• If in shock, provide fludrocortisone 0.1mg daily also
• Fluid replacement N/S + 5% dextrose
• Supportive measures
  • Hypoglycaemia/sodium changes/K changes
• Find and treat underlying precipitants

Prevention

• For patients on long-term steroids or known adrenal insufficiency
• If not confirmed adrenal insufficiency, Dex 4mg = 100mg hydrocort and does not interfere with serum cortisol levels
• Mild stress
  • Inguinal hernia repair, mild febrile illness, gastro
  • Usual dose (either PO or convert to IV hydrocort) + IV hydrocortisone 25mg per day
• Moderate
  • Open chole, significant febrile illness, pneumonia, severe gastro
  • Usual dose converted to IV hydrocortisone+ IV hydrocortisone 50-75mg per day and taper quickly back to usual dose over 1-2 days
• Severe
  • Major cardiothoracic surgery, pancreatitis
    • Usual dose converted to IV hydrocortisone + IV Hydrocortisone 100-150mg per day with rapid taper
• Critically ill
  • Usual dose converted to IV hydrocortisone + IV hydrocortisone 100mg q6-8h with gradual taper

HPA suppression

• Suppression likely
  • >20mg prednisone daily for >3 weeks
  • Evening dose >5mg prednisone for more than a few weeks
  • Cushingoid appearance
• Suppression uncertain
  • 10-20mg prednisone daily for >3 weeks
  • <10mg daily for more than a few weeks (provided not a single bedtime dose)
• Suppression unlikely
  • Any dose of gluclocorticoid for <3 weeks
  • Alternate day prednisone <10mg

Steroids in critical illness

• Proven role
  • Addisonian crisis
  • Anaphylaxis
  • Asthma
  • Bacterial meningitis (before or with first dose of Ab)
  • COAD
  • Croup
  • Fulminant vasculitis
  • Hypercalcaemia
  • ITP
  • Myaesthenic crisis
  • Myxoedema coma
  • Thyroid storm
  • Organ transplant
  • Pneumocystic jirovecii pneumonia

• Possible role
  • ARDS
    • Early high-dose methylprednisolone no benefit on mortality (Bernard et al.)
    • Prolonged low-dose methylprednisolone in prolonged ARDS (>7 days) no benefit on mortality (Steinberg et al.)
    • Significantly increased mortality if initiated 2 weeks or more after onset
    • Early (before day 14) and prolonged (>7 days) glucocorticoids accelerate resolution and decrease hospital mortality (Meduri et al.)
    • Unclear which steroid or what level of dosing provides benefit
• Septic shock
  • CORTICUS
    • From Schumer et al. short course high-dose steroids became accepted therapy
    • Lower doses have shown earlier reversal of shock and improved survival
    • More benefit suspected in those with relative adrenal insufficiency (poor response to Synacthen)
    • 500 patients, 50mg hydrocortisone q6h for 5 days then BD for days 6-8 then daily for days 9-11
    • No change in mortality
    • More rapid reversal of shock but increased risk of superinfection
  • ADRENAL study
    • Infusion hydrocortisone 200mg/day for 7 days
    • No corticotrophin testing performed
    • No benefit on mortality
    • Improved shock reversal, ventilator free days, ICU LOS
  • Surviving Sepsis Guidelines
    • Currently state to give hydrocort 50mg QID if refractory shock to fluids/vasopressors/inotropes

Side effects of steroid therapy

• Adrenal suppression
• Hypokalaemia
• Myopathy
• Hyperglycaemia
• Leukocytosis
• Poor wound healing
• Immunosuppression
• Pancreatitis
• Peptic ulcer disease
• Glaucoma

Last Updated on October 8, 2021 by Andrew Crofton