Hypoadrenalism

Key Differential Diagnoses

Septic shock (can have both)
Other causes hyponatraemia/hyperkalaemia
Other causes hypotension/hypoglycaemia
Other causes hyperpigmentation

FBC, ESR, CRP
U+E, LFT, Bone, Glucose, Cortisol, ACTH
Blood cultures
ECG, CXR

IV HYDROCORTISONE 100 mg stat then 100 mg qds for first 24h, then halve doses
IV (or PO) FLUDROCORTISONE 50-200 mcg od (not necessary acutely)
IV fluids (N saline)
± GLUCOSE, 20 mls 50%, if necessary

Key Management Decision

ITU

Introduction

• Hypoadrenalism results from inadequate corticosteroid production from the adrenal glands. Patients may be deficient of salt, fluids, steroids and glucose
• The two main types, acute and chronic, present quite differently
• Acute hypoadrenalism =  an acute medical emergency, whether a complication of chronic disease, or a de novo problem. Acute hypoadrenal crises tend to become clinically apparent during physiological stress (eg sepsis, see below), which may also need treating. Hypotension may be the only sign initially
• Patients may not initially have the characteristic biochemical abnormalities
• So, do not wait for them. Ie if you think of it, treat it (it is life-threatening)
• Commonest cause of acute hypoadrenalism is abrupt withdrawal of steroids. But don't forget abrupt onset of hypotension in a patient with metastatic disease (lung, breast, kidney, lymphoma, leukaemia)
• Chronic hypoadrenalism = an insidious, usually progressive hypofunctioning of the adrenal cortex. It produces various symptoms, including hypotension and hyperpigmentation. The gradual onset and nonspecific nature of early symptoms often lead to an incorrect initial diagnosis of a neurotic disease
• Diagnosis is clinical; and by finding elevated low plasma cortisol with high (or low) ACTH. Hyperkalaemia, hyponatraemia (mineralocorticoid deficiency) and hypoglycaemia (glucocorticoid deficiency) are characteristic of some causes of chronic secondary hypoadrenalism
• It can be complicated by an acute hypoadrenal ('Addisonian') crisis with cardiovascular collapse
• With treatment, chronic hypoadrenalism should not typically reduce life expectancy
• Treatment of both types depends on the cause but includes hydrocortisone, fludrocortisone; and glucose, N saline, and potassium-lowering drugs, if necessary
• Thomas Addison first described adrenal insufficiency in 1855. JFK had Addison's Disease

[Ref]

Epidemiology

Incidence 4/100,000 annually. It occurs in all age groups, about equally in each sex

Causes

Acute hypoadrenalism (adrenal crisis). Consider diagnosis in patients with:
• Steroid withdrawal (especially if too abrupt) in any patient on steroids (oral or inhaled) for > 3 wks; this is commonest cause (deliberately or inadvertently)
• Stress (physiological eg surgery, burns, trauma, infection, dehydration, alcohol, MI, CVA, asthma, hypothermia) in patient with known hypoadrenalism
• Abdominal pain and hyponatraemia
• Acute severe headache and/visual field defects (pituitary apoplexy)
• Postpartum haemorrhage and hypotension, not responding to blood transfusion (Sheehan’s syndrome)
Note: it should also be considered in any patient with unexplained hypotension, with and with out associated hyperkalemia, hyponatremia and/or hypoglycaemia. Hyperpigmentation does not occur, unless it is part of acute-on-chronic primary hypoadrenalism

Chronic hypoadrenalism
A. Primary hypoadrenalism:
Caused by adrenal destruction (no pituitary disease)
Note: the phrase 'Addison’s Disease' only refers to primary hypoadrenalism
Because it is usually associated with both glucocorticoid and mineralcorticoid deficiency, it tends to cause:
  - Severe hypotension
  - Electrolyte disturbances (hyperkalaemia, hyponatraemia)
  - And is associated with high ACTH and hence high melanocyte-stimulating hormone (the latter may cause hyperpigmentation)
Consider diagnosis in patients with:
• Other autoimmune diseases (eg hypothyroidism, coeliac disease, vitiligo, polyglandular syndrome; autoimmune adrenal atrophy is the most common cause)
• Tuberculosis (adrenal TB is still a major cause of Addison’s Disease in developing countries)
• Metastatic disease (can be associated with bilateral adrenal metastases)
• Opportunistic infection, involving adrenals (eg primary hypoadrenalism occurs in upto 5% of AIDS patients)
• Coagulopathies; eg meningococcal septicaemia, warfarin overcoagulation (can cause bilateral adrenal haemorrhage)
• Drugs that block corticosteroid synthesis (eg, ketoconazole, etomidate, phenytoin, rifampicin, metapyrone or other cytotoxic agents)
• Ambiguous genitalia at birth (congenital adrenal hyperplasia is commonest cause of hypoadrenalism in children)
B. Secondary hypoadrenalism:
  - Adrenal hypofunction secondary to pituitary disease
  - Hyperpigmentation does not occur (low ACTH)
  - Associated with less severe hypotension and electrolyte disturbances (mineralocorticoids are NOT affected)
Consider the diagnosis in patients with:
• Previous pituitary surgery or radiotherapy
• Evidence of hypopituitarism
• Headache and visual field defects
• Long-term steroid therapy (prednisolone > 7.5 mg, or equivalent, for >3 weeks)

Risk factors (associations)

Other organ-specific endocrine disease (DM, thyroid, vitiligo, pernicious anaemia, hypoparathyroidism and ovarian failure)

Symptoms

Acute
• It can present with severe pain in the abdomen, lower back, or legs; severe hypotension; and, finally, ARF
• Body temperature may be low, although fever often occurs particularly when crisis is precipitated by acute infection
• A significant number of patients with partial loss of adrenal function (limited adrenocortical reserve) appear well but experience adrenal crisis when under physiologic stress (eg, surgery, infection, burns, critical illness)
Chronic
• May be non-specific: weakness, fatigue, dizziness and collapse (orthostatic hypotension)
• Anorexia, abdominal pain, nausea, vomiting, and diarrhoea. Decreased tolerance to cold, with hypometabolism
Note: weight loss, dehydration, and hypotension are characteristic of the later stages of chronic disease

Key questions

"When did the symptoms start?"
"Are you on steroid tablets?"

Signs

Acute
• Frequently normal, or just hypotension (ie no pigmentation) OR signs of complications (eg ARF)
• In severe acute hypoadrenalism, shock, fever and confusion/drowsiness (may be due to hypoglycaemia) may be the only signs; often with no pigmentation
• Temperature may be low, although severe fever often occurs, particularly when crisis is precipitated by acute infection
Chronic
• Signs of chronic disease (eg hyperpigmentation) or associated autoimmune disorders - eg vitiligo:
• Vitiligo
Note: in chronic primary hypoadrenalism, hypergmentation is characterised by diffuse tanning of exposed and, to a lesser extent, unexposed portions of the body, especially on pressure points (bony prominences), skin folds, scars, and extensor surfaces. Black freckles are common on the forehead, face, neck, and shoulders
• In chronic secondary (pituitary failure), hyperpigmentation also does not occur
• Depression, psychosis

FBC (eosinophilia, relative polycythaemia = dry), ESR, CRP
U+E (potassium high, sodium low, urea/creatinine raised if dry), LFTs, Bone (mild hypercalcaemia), Glucose (low)
Cortisol (low), ACTH (high in primary hypoadrenalism, low in secondary), Renin
Blood cultures
Adrenal auto-antibodies
OXYGEN saturation ± ABG (acidosis, low bicarbonate)

ECG (prolonged QT interval, which may induce ventricular arrhythmias; inverted T waves), CXR (TB?)

9 am Cortisol, ACTH
Undetectable  serum cortisol confirms the diagnosis
     ↓ cortisol + ↑ ACTH = primary hypoadrenalism
     ↓ cortisol + ↑ ACTH = secondary hypoadrenalism
Note: 9 am serum cortisol > 550 nmol/L excludes the diagnosis
If cortisol detectable but <550 nmol/L, perform short synacthen (ACTH stimulation) test:
0 min. Measure serum cortisol + ACTH followed by IM/IV 250 μg synacthen
30 min. Serum cortisol
60 min. Serum cortisol
Serum cortisol > 550 nmol/L at 30 or 60 min, hypoadrenalism excluded; whilst levels < 550 suggests the diagnosis
Note: short synacthen test can be normal in acute secondary hypoadrenalism

Hypoadrenal crisis:
• If this diagnosis is suspected, take blood for U/E, cortisol + ACTH (but should not delay treatment) and treatment initiated immediately. Replace corticoid deficiency:
1. IV HYDROCORTISONE 100 mg stat then 100 mg qds (6 hourly) for first 24h then halve doses (later PO HYDROCORTISONE 10 mg 8 am, 5 mg 12 pm & 5 mg 5-6 pm)
Note: hydrocortisone, when given IV in high doses, will have glucocorticoid and mineralocorticoid activities and thus replaces both cortisol and aldosterone deficiencies. If there is a major precipitant illness, continue IV HYDROCORTISONE 100 mg qds until the underlying illness is treated then taper the dose as above
2. IV (or PO) FLUDROCORTISONE 50-200 mcg od (replaces aldosterone). Not necessary acutely because it takes days to work and its action is already covered by IV hydrocortisone
Note: Normal hydration and absence of orthostatic hypotension are evidence of adequate replacement therapy. In some, fludrocortisone produces hypertension, which is treated by reducing the dosage or starting a nondiuretic antihypertensive. Some clinicians tend to give too little fludrocortisone
ll; Correct hypovolaemia: usually 1-3 litres of normal saline/24 hours
• Correct hypoglycaemia: IV dextrose infusion
• Treat intercurrent illnesses (eg infections, broad-spectrum IV antibiotics
Chronic hypoadrenalism:
• PO HYDROCORTISONE 10 mg 8 am, 5 mg 12 pm + mg 5-6 pm
Note: alternative steroid replacement equivalent doses
Hydrocortisone 20 mg = dexamethasone 0.75 mg
Hydrocortisone 20 mg = prednisolone 5 mg
Hydrocortisone 20 mg = cortisone 25 mg
• PO FLUDROCORTISONE 50-200 mg od (not required in secondary hypoadrenalism)
Note: the dosage of both should be doubled during illness. If nausea and vomiting preclude oral therapy, parenteral therapy is necessary. During labour and for severe illness + surgical procedures, IV HYDROCORTISONE 50-100 mg qds hydrocortisone qds is needed (depends on severity of the illness and type of surgery)

• Complications of corticosteroid therapy include psychotic reactions
• If psychotic reactions occur after the first 12 hrs of therapy, the hydrocortisone dose should be reduced to the lowest level consistent with maintaining BP and good cardiovascular function
• Antipsychotics may be temporarily required, but use should not be prolonged
• Fludrocortisone can produce hypertension, treated by reducing dosage or starting a nondiuretic antihypertensive
• Some clinicians give too little fludrocortisone

Drugs
• Of hyperkalaemia
• ARF (dialysis)
• If fever > 40° C; except in the presence of falling BP, antipyretics (eg, aspirin) should be given PO with caution
Procedures
Arterial line, urinary catheter, CVP line

Key management decision

ITU, not

Admit?

Usually

Bed plan

Medical admission or Endocrine/Diabetic ward

Referrals

Medical
Endocrine/diabetic
Patient's specialist (if prescriber of longterm steroids)

Complications

Shock, ARF
Note: if poor response to Rx, suspect another associated autoimmune disease

Follow-up

Endocrine
± Specialist (who prescribes steroids for another condition)

Mild cases can be managed as an out-patient

Prognosis 

Good; normal life expectancy, if diagnosis made early

2° Prevention
+ Health promotion

• Patients should be instructed when to take supplemental prednisolone (eg double doses when infected) and taught to self-administer IM hydrocortisone for urgent situations
• A pre-loaded syringe with IM hydrocortisone 100 mg should be available to the patient
• A Medic-Alert bracelet or wallet card giving the diagnosis and corticosteroid dose may help in case of hypoadrenal crisis that renders the patient unable to communicate. When salt loss severe (eg very hot climates), dose of fludrocortisone may also need to be increased
• Specific advice on pre and post-op supplemental steroid (double doses)

Don't forget

Red flags

• Shock
• Hyperkalaemia (K > 6 mmol/L)
• ARF