Hypoadrenalism

Key facts:

Authors: Khaled Ashawesh and Andrew Stein
Top Tip: If you think of it, treat it. Don't forget fludrocortisone

Key Differential Diagnoses

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

Key Investigations

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

Key Treatment

• 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

Background

The initial management should be based on the history, clinical suspicion and blood pressure. Symptoms and signs are often vague, hence diagnosis easy to miss

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

Definition (Addisonian Crisis)

• Potentially fatal condition associated with acute deficiency of the glucocorticoid, cortisol; and to a lesser extent, the mineralocorticoid aldosterone

Causes

Acute hypoadrenalism (adrenal crisis)

• 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 
• Pituitary apoplexy; Acute severe headache and/visual field defects
• 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

• Primary hypoadrenalism; caused by adrenal destruction (no pituitary disease)
  Note: the phrase 'Addison’s Disease' only refers to primary hypoadrenalism
  • 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)
• 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)
  
  • 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

• Depression, psychosis
• Signs of chronic disease (eg hyperpigmentation) or associated autoimmune disorders - eg
• Vitiligo

Note 1: 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

Note 2: In chronic secondary (pituitary failure), hyperpigmentation also does not occur

Investigation

The name Addison's Disease refers only to primary hypoadrenalism

Blood

• 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)

Other

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

Key Investigations

• 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

Specialist Investigations

• MRI head (pituitary tumour?)
• CT abdomen (renal TB?)
• Pituitary hormonal profile

Differential Diagnoses

• Septic shock (can have both); for eg, sepsis can cause hypoadrenalism
• Other causes hyponatraemia/hyperkalaemia
• Other causes hypotension/hypoglycaemia
• Other causes hyperpigmentation: bronchogenic carcinoma, ingestion of heavy metals (eg, iron, silver), chronic skin conditions, or haemochromatosis. Peutz-Jeghers syndrome is characterised by pigmentation of the buccal and rectal mucosa
  Note: frequently, hyperpigmentation occurs with vitiligo, which may indicate Addison's Disease, although other diseases can cause this association

Vitiligo

Vitiligo (associated with hypoadrenalism)

Treatment

Treatment - first line

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
• 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 + 5 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)

Prescribing issues

• 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

Treatment - second line

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

Treatment of panhypopituitarism

• Hypoadrenal crisis is likely if a patient is treated for a single endocrine problem, especially thyroxine, without hydrocortisone replacement

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)

The Rest

Maxim

• "No one should die with low BP, without having had 100 mg IV HYDROCORTISONE"

Complications

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

Follow-up

• Endocrine
• ± Specialist (who prescribes steroids for another condition)

Risk stratification

• Mild cases can be managed as an out-patient

Prognosis

• Depends on cause. Primary hypoadrenalism can be good; with a 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

• Low threshold for broad-spectrum IV antibiotics (can have septic shock as well)
• In acute (and secondary) hypoadrenalism, characteristic signs (eg hyperpigmentation) may not occur
• Hypotension may be only clue
• Treat with fludrocortisone, not just hydrocortisone (in primary hypoadrenalism)
• Send home with information on risks of severe hypoadrenalism (and prevention)
• Medic-Alert bracelet

Red flags

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

References