Professor of Endocrinology Simon H Pearce discusses the rarely-seen condition of Addison’s disease
What is it?
Addison’s disease or primary adrenal insufficiency is a high-value diagnosis. Without treatment it is inevitably fatal, but when recognised most people are rapidly restored to a good quality of life with oral steroid medication. It is most commonly caused by autoimmune destruction of the adrenal cortex, but tuberculosis can occasionally be responsible particularly in patients from South Asia or Africa, or those with HIV or other immunocompromise.
Addison’s typically has an insidious onset over months to years, with symptoms that result from lack of both cortisol (glucocorticoid) and aldosterone (mineralocorticoid). Cortisol deficiency leads to fatigue, unexplained weight loss, anorexia, early satiety, nausea, vomiting and occasionally griping abdominal pain. Aldosterone deficiency leads to salt depletion and hyponatraemia, with symptoms of postural light headedness, muscle and back cramps, and cravings for salty or sour foods. Skin pigmentation, visible in the creases and scars, extensor surface of the elbow, knuckles, lips and gingival mucosa is present in 90% of patients. Additionally, women may report loss of axillary or pubic hair due to deficiency of adrenal androgens. Occasionally it may present for the first time as adrenal crisis, with profound circulatory collapse, vomiting, diarrhoea, abdominal pain, shakiness, feeling cold, confusion or reduced level of consciousness.
How rare is it?
New onset Addison’s disease occurs most frequently between the ages of 20 and 50 years, with a slight excess in women. The incidence is 0.6/100,000/year, meaning a GP with an average list size might encounter one undiagnosed case every 75 years of practice. Hence it is frequently overlooked: one study found patients had seen an average of three health care professionals with the relevant symptoms before the correct diagnosis was reached. Unfortunately, there are still fatalities from people whose symptoms go unrecognised.
Often confused with…
Fifteen to 20% of Addison’s disease patients present in their teenage years, and it is imperative to consider this diagnosis in a young woman with unexplained weight loss, poor appetite and/or early satiety, before a presumptive diagnosis of eating disorder/ anorexia nervosa is made.
Where weight loss and GI symptoms predominate the clinical picture, patients are often initially referred to gastroenterology services for endoscopy or other investigations.
In the later stages of disease where fatigue, exhaustion and hypotension become prominent and limit patient activity, the presentation may mimic chronic fatigue syndrome or mood disturbance with apathy.
Red flags to alert the GP
Ninety percent of people with Addison’s disease have an underlying autoimmune aetiology, meaning that there are frequently co-existing autoimmune disorders. Around 50% of patients with Addison’s have autoimmune thyroid disease (either hypothyroidism or Graves’ disease) with 5-10% having pre-existing type 1 diabetes. Therefore, clinicians should have a higher level of suspicion in people with other autoimmune conditions who start to feel unwell. Similarly, a family history of autoimmune conditions is common.
Hyponatraemia is present in 90% of cases at presentation, and even mild hyponatraemia (eg. serum sodium 130-133 mmol/L) may be significant in a previously well young or middle-aged person.
Hyperkalaemia may also be present, and this distinguishes Addison’s from eating disorders with vomiting or purgation, where the serum sodium is normal but there is typically hypokalaemia.
Patients may have profound salt cravings, and may consume several bags of salty snacks daily (commonly salt and vinegar potato crisps). Others may drink ‘neat’ soy sauce or pickle brine from the jar. Some develop a preference for sour fruits, including lemons and cooking apples. These are highly significant symptoms in someone losing weight and should warrant initial investigations or direct referral.
Clues to aid early diagnosis
As with many endocrine conditions, the combination of features should raise suspicion: unexplained weight loss, fatigue, hypotension, postural light-headedness, with pigmentation, hyponatraemia or salt craving are most typical features. Children and teenagers may also have hypoglycaemia.
Serum TSH can be mildly elevated (5–10mU/L), because of a pituitary effect of low cortisol. This can give the false impression that hypothyroidism is responsible for the symptoms. Treatment with levothyroxine is dangerous in this situation and could worsen symptoms or precipitate adrenal crisis.
Early morning serum cortisol (08:00–09:00) and U&E are the initial investigations (see table). A morning cortisol of less than 150nmol/L is highly suggestive of Addison’s and immediate referral or discussion with endocrinology is warranted (noting that exogenous steroids, including steroid inhaler use, may cause a low serum cortisol). Early morning serum cortisol between 150 and 300 nmol/L is a grey area and testing should be repeated once or twice (to take into account the pulsatile release of the hormone) and depending on clinical suspicion refer to endocrinology for gold-standard synacthen testing. An early morning serum cortisol ≥300nmol/L effectively excludes Addison’s disease.
Any degree of hyponatraemia in the context of unexplained weight loss is concerning and should be followed up with additional tests (one or more early morning serum cortisol measurements or synacthen test).
Treatment and prognosis
The usual treatment is a combination of oral hydrocortisone (15-25mg daily in divided doses) and fludrocortisone (typically 100-300mcg once daily). Patient education to up-dose the hydrocortisone (generally to 10mg qds) at times of intercurrent illness, injury or for medical procedures is vital. Because the need to up-dose is unpredictable, patients require additional hydrocortisone tablets in hand. I recommend prescribing 4 month’s supply of hydrocortisone tablets every 3 months.
Patients should be issued with a few vials of parenteral hydrocortisone (100mg) and taught to self-administer by intramuscular injection for use in case of vomiting, when they will be unable to keep down their life-sustaining oral medication.
With good patient education and careful adherence to medication, quality of life is generally good and prognosis excellent. However, there is excess mortality particularly in younger men who may not adjust to their medication dependence or take the condition seriously.
If the patient presents more acutely with hypotension, circulatory collapse, confusion, drowsiness, vomiting, then administer 100mg of hydrocortisone intramuscularly and arrange emergency admission.
Serum cortisol (08:00-09:00 hrs) Interpretation <150 nmol/L Suspicious for adrenal insufficiency (unless there is exogenous steroid use*). Refer immediately to acute secondary care if patient is unwell; take endocrine advice or refer urgently if patient is stable. 151-300 nmol/L Grey area: repeat the test once or twice if the patient is well. If the patient is unwell, discuss with endocrinology- routine referral for synacthen testing is likely to be needed. >300 nmol/L Adrenal insufficiency is very unlikely
*Exogenous steroids including asthma inhalers, topical steroid both on skin and mucous membranes and injections for back or joint pain may all be sufficient to cause low serum cortisol measurements.
Professor Simon H Pearce is professor of endocrinology at Newcastle University, UK
