Adrenal Insufficiency can be defined Real, Iatrogenic, and Imagined

1. Real (Primary and Secondary) Adrenal Insufficiency

• Causes:
  • Primary Adrenal Insufficiency (Addisons Disease):
    • destruction of > 90% of adrenal glands
    • loss of mineralocorticoid and glucocorticoid activity
    • causes:
      • autoimmune destruction – anti-adrenal antibodies can only be found in about 50% of cases
      • typically occurs between 30 and 50 years of age
        • Other autoimmune conditions may also be present
          • thyroid disease
          • vitiligo
          • type 1 diabetes
          • primary gonadal failure
          • coeliac disease
          • pernicious anaemia
      • haemorrhage
      • tumour mets (breast and melanoma)
      • infection (Tb, HIV, meningococcaemia, purpura fulminans)
      • inflammatory process
    • Secondary Adrenal Insufficiency:
      • insufficient production of ACTH
      • mineralocorticoid function intact
      • due to destruction or dysfunction of the pituitary
      • (pituitary or hypothalamic dysfunction, leading to decreased ACTH (adrenocorticotropic hormone) secretion, which in turn reduces cortisol production by the adrenal glands.)
      • Common causes include
        • pituitary adenomas
        • surgical removal of pituitary tumors
        • cranial radiation.
• Presentation:
  • Primary: Symptoms include chronic fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, low blood pressure, and hyperpigmentation of the skin.
  • Secondary: Similar to primary but usually lacks hyperpigmentation and has less severe electrolyte disturbances.
• Treatment:
  • Primary: Hormone replacement with glucocorticoids (e.g., hydrocortisone) and mineralocorticoids (e.g., fludrocortisone) to replace deficient hormones.
  • Secondary: Generally requires replacement of only glucocorticoids unless the patient has also undergone bilateral adrenalectomy.

2. Iatrogenic Adrenal Insufficiency

• Causes: Long-term use of exogenous glucocorticoids (like prednisone) suppresses the HPA (hypothalamic-pituitary-adrenal) axis, leading to adrenal atrophy and reduced cortisol production.
• Presentation: symptoms often become evident during periods of stress or after sudden withdrawal of steroids.
• Treatment: Gradual tapering of glucocorticoids to allow the adrenal glands to recover normal function. During periods of stress or illness, temporary increases in glucocorticoid doses may be necessary.

3. Imagined (Functional) Adrenal Insufficiency

• Causes: Not a true adrenal insufficiency but rather a perception of adrenal fatigue without objective evidence of adrenal dysfunction. Often attributed to chronic stress or burnout.
• Presentation: Symptoms are nonspecific and include chronic fatigue, unrefreshing sleep, and generalized malaise. These symptoms are subjective and not linked to measurable adrenal hormone deficiencies.
• Treatment: There’s no specific treatment for imagined adrenal insufficiency since it is not a medically recognized condition. Management focuses on addressing lifestyle factors, stress management, sleep hygiene, and nutrition. Psychological support or counseling may be beneficial.

Symptoms:

• insidious and gradual onset of non-specific symptoms 🡪 often resulting in a delayed diagnosis. 
• In many cases, the diagnosis is made only after the patient presents with an acute adrenal crisis (hypotension, hyponatremia, hyperkalemia, and hypoglycemia), precipitated by a stressful illness or such triggering factors such as infection, trauma, surgery, vomiting, or diarrhea
• Significant stress or illness can unmask cortisol and mineralocorticoid deficiency
• insidious onset – wt loss, GI upset, non-specific malaise 

• ↓ glucocorticoid: cortisol deficiency results in hypoglycaemia & reduced resistance to stress
• ↓ mineralocorticoid: ↓ Na & H2O retention – postural hypotension, hyperkalaemia
• ↓ negative feedback to pituitary to ACTH-MSH increases – ↑ skin pigmentation (sometimes get vitiligo or ↓ pigmentation if Ab also attacking melanocytes) 

Nb: if the cause of adrenal cortex deficiency is due to ACTH deficiency, then will have no pigmentation & will have less postural hypotension/ hyperkalaemia because then aldosterone will be normal & regulated by renin-Ang II

Symptoms of Adrenal Insufficiency:

• Fatigue
• Weight Loss
• Nausea
• Loss of Appetite (Anorexia)
• Depression
• Anxiety
• Postural Hypotension
• Salt Craving
• Hyperpigmentation of the Skin and Mucous Membranes: Due to increased secretion of ACTH and melanocortin

Chronic Adrenal Insufficiency:

General:

• Weight Loss
• Arthralgia (Joint Pain)
• Myalgia (Muscle Pain)

Central Nervous System (CNS):

• Fatigue
• Anorexia (Loss of Appetite)
• Mood Changes (e.g., Depression, Irritability)

Cardiovascular System (CVS):

• Postural Hypotension
• Syncope (Fainting)
• Salt Craving

Skin:

• Hyperpigmentation (Especially in primary adrenal insufficiency)
• Vitiligo (Patchy Loss of Skin Pigmentation, associated with autoimmune Addison’s disease)

Diagnosis

• stimulation with Synacthen^® (ACTH analogue)
  • Stimulation with Synacthen® (ACTH analogue):
    • Procedure:
      • 5 mL blood is collected to check for baseline cortisol and ACTH levels.
      • A dose of 250 µg of aqueous Synacthen® is given intramuscularly (IM).
      • Further blood samples are collected at 30 and 60 minutes after administration.
  • Interpretation:
    • Plasma cortisol levels:
      • Baseline (pre-Synacthen®): The initial blood sample is used to measure the baseline cortisol level.
      • Post-Synacthen®: Blood samples taken at 30 and 60 minutes are used to measure cortisol response.
      • An increment in serum cortisol of > 200 nmol/L at 30 minutes indicates a normal adrenal response.
      • A peak cortisol level of ≥ 500–550 nmol/L (some protocols may use different cut-offs, but generally around this range) is typically considered a normal response, excluding primary adrenal insufficiency.
  • Differentiation:
    • Primary Adrenal Insufficiency (Addison’s Disease):
      • There is little or no increase in cortisol levels after Synacthen® administration due to adrenal cortex damage.
    • Secondary Adrenocortical Failure (Pituitary Insufficiency):
      • The response may be variable; early secondary adrenal insufficiency may still show some response, but with longstanding secondary adrenal insufficiency, the response may be blunted due to adrenal atrophy secondary to chronic lack of ACTH stimulation.
  • Usage:
    • This test is used to assess both primary (adrenal) and secondary (pituitary) adrenocortical insufficiency.
  • Additional Points:
    • For diagnosing secondary adrenocortical insufficiency, especially if it’s early and the pituitary gland is involved, the low-dose Synacthen® test (1 µg) might be more sensitive.
    • A lack of response or suboptimal response in the Synacthen® test warrants further investigation, including possibly an insulin tolerance test (ITT) or CRH stimulation test for more definitive diagnosis of secondary or tertiary causes.
• Biochemistry:
  • low glucose
  • low Na+
  • hypo-osmolar
  • raised K+
  • raised U and Cr
  • raised Ca2+ (primary only)
  • eosinophilia 
  • morning (8.00–9.00 am) cortisol level
    • <140 nmol/L
    • ↓ or ↓/ normal(even in someone who is ill)
  • ↑ ACTH (in primary adrenal disease)
  • Low T4 & high TSH (often also found in Addison’s – may also have Schmidt’s syndrome of Addison’s + Hashimoto’s + diabetes)

Prognosis:

• excellent with replacement (glucocorticoid eg prednisone + mineralocorticoid eg fludrocortisone) 

Treatment of primary adrenal insufficiency 

• glucocorticoid replacement
  • hydrocortisone (15–25 mg per day) or 
  • cortisone acetate (20–35 mg per day) in two or three divided doses
• mineralocorticoid replacement
  • 9α-fludrocortisone (50–200 μg) once daily. 
• Patient education
• carrying an emergency card/bracelet
• increasing glucocorticoid dosage, or seeking specialist/emergency care, in situations of stress such as gastrointestinal disturbance, infections, surgical procedures and emotional stress is crucial for the prevention of adrenal crisis.

Addisonian crisis

• Although insidious in onset, most people present in crisis
• Profoundly ill, hypotension, fever & prostration (exhaustion & ↓↓ strength) 
• Fatal if untreated 
• Crisis can be precipitated by illness
• Rare cause is haemorrhage into the adrenals during meningococcal septicaemia (Waterhouse-Friderichsen syndrome)

Symptoms and signs include:

1. Severe Weakness: Inability to carry out normal activities.
2. Severe Abdominal Pain: Can be sudden and intense.
3. Severe Vomiting and Diarrhea: Leading to dehydration.
4. Confusion or Coma: Severe mental status changes.
5. Hypotension: Shock, which is refractory to fluids and vasopressors.
6. Hypoglycemia: Severe low blood sugar.

• MANAGEMENT
  • fluid resuscitation
  • reversal of electrolyte abnormalities
  • high dose hydrocortisone (100mg IV Q6 hrly)
  • mineralocorticoid replacement (fludrocortisone PO 0.1mg Q6 hrly) – don’t often use this acutely as with > 50mg of hydrocortisone you get a mineralocorticoid effect