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What is Addison’s disease?Addison’s disease (also known as primary adrenal insuf-ficiency) is a chronic disorder of the adrenal cortex resulting in inadequate secretion of glucocorticoid and mineralocorticoid. The commonest cause of Addison’s disease in developed countries is autoimmune disorder and in developing countries is tuberculosis.1

Why is it missed?The onset of Addison’s disease is often insidious. Its usual symptoms (such as fatigue, lethargy, weakness, and low mood) are non-specific, are highly prevalent in the general population, and overlap with many other common conditions.

Why does this matter?A patient with untreated Addison’s disease becomes progressively unwell with a markedly reduced quality of life.5 If Addison’s disease is not suspected, such a patient is often misdiagnosed as having other condi-tions such as depression, chronic fatigue syndrome, anorexia nervosa, or gastrointestinal disorders, leading to unnecessary investigations and inappropriate treat-ments. Moreover, the patient is at risk of developing serious acute adrenal crisis during an intercurrent ill-ness or stress. Acute adrenal crisis, if not recognised and treated urgently, could be fatal.6

How is it diagnosed?Clinical featuresA high index of suspicion is required for the diag-nosis of Addison’s disease. Doctors need to be alert to the possibility of Addison’s disease. A cluster of

common symptoms, although non-specific in them-selves, may point to Addison’s disease. A cohort study of 108 patients with Addison’s disease found that they had all experienced fatigue, weakness, anorexia, and unintentional weight loss.7 Other symptoms included gastrointestinal complaints such as nausea and vague abdominal pain (56%), postural dizziness (12%), and musculoskeletal pains (6%).7 Hyperpigmentation of skin and mucous membranes is a characteristic fea-ture of Addison’s disease; however, it is absent in about 10% of cases, which may delay diagnosis.7 8 Postural hypotension is common in Addison’s disease; however, low blood pressure without a postural drop can also occur.

Autoimmune Addison’s disease is associated with other autoimmune conditions. For example, vitiligo often coexists with Addison’s disease.7 It is important to consider Addison’s disease if a patient with type 1 diabetes starts developing unexplained recurrent hypoglycaemia or the patient’s insulin requirement falls as this may signal adrenal insufficiency.9 Likewise, worsening of symptoms in a patient with autoimmune hypothyroidism after the start of thyroxine treatment should also raise the suspicion of Addison’s disease as thyroxine replacement in a patient with untreated Addison’s disease can precipitate an adrenal crisis.10

About half of patients with Addison’s disease are diagnosed only after an acute adrenal crisis.1 It is a medical emergency often precipitated by an infection or other forms of stress in an undiagnosed or inad-equately treated patient with Addison’s disease. In this condition, patients present acutely unwell with severe dehydration, hypotension, or circulatory shock.

EAsIly MIssEd?

Addison’s diseaseBijay Vaidya,1 2 Ali J Chakera,1 Catherine Dick3

This is a series of occasional articles highlighting conditions that may be commoner than many doctors realise or may be missed at first presentation. The series advisers are Anthony Harnden, university lecturer in general practice, Department of Primary Health Care, University of Oxford, and Richard Lehman, general practitioner, Banbury. If you would like to suggest a topic for this series please email us (easilymissed.bmj@bmjgroup.com)

For the full versions of these articles see bmj.com

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1Department of Endocrinology, Royal Devon and Exeter Hospital, Exeter EX2 5DW2Peninsula Medical School, Exeter 3Devon Primary Care Trust, Topsham Surgery, Exeter EX3 0ENCorrespondence to: B Vaidya, bijay.vaidya@pms.ac.uk

Cite this as: BMJ 2009;339:b2385doi: 10.1136/bmj.b2385

CAse sCenARIO

A 34 year old woman presented with a 12 month history of increasing tiredness, anorexia, weight loss, and depression. During that period, she had tried two different antidepressant tablets without benefit. She saw her general practitioner’s locum, who thought she looked tanned. Her blood pressure was 90/60 mm Hg, although it had always tended to be low. Her serum sodium concentration was 130 (normal range 135-145) mmol/l and potassium concentration was 5.7 (normal range 3.5-5.5) mmol/l. A short Synacthen (tetracosactide) test showed an inadequate serum cortisol response, which together with raised plasma adrenocorticotrophic hormone confirmed the diagnosis of Addison’s disease.

How common is Addison’s disease?

Addison’s disease has a prevalence of 93-140 per million people and an annual incidence of 4.7-6.2 per million people in Western populations.1 2 A recent epidemiological study suggests that the incidence of Addison’s disease is rising2

A survey of patients with Addison’s disease found that 60% had seen two or more clinicians before the diagnosis of Addison’s disease was ever considered3

An observational study of children with Addison’s disease found that a delay in diagnosis occurred in about a third of the cases, in whom the median duration between the onset of first symptoms and the correct diagnosis was two years4

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InvestigationsOn routine blood tests, unexplained electrolyte distur-bances such as hyponatraemia and hyperkalaemia may provide a clue to the diagnosis of Addison’s disease. Other biochemical abnormalities, including raised urea concentration, hypoglycaemia, hypercalcaemia, and raised concentrations of serum thyroid stimulating hor-mone, may be present.

A clinical suspicion of Addison’s disease must be con-firmed biochemically by demonstrating inadequate corti-sol production. Owing to the pulsatile nature and diurnal variation of cortisol secretion, random measurement of serum cortisol concentration is inadequate to assess adrenal function in most cases. A short Synacthen test is the investigation of choice to confirm or exclude Addi-son’s disease; it is a safe test, which can be done either in primary care by a general practitioner or in secondary care via referral. In the test, 250 μg of tetracosactide (an analogue of corticotropin) is injected intramuscularly or intravenously, and blood samples for serum cortisol are taken immediately, at 30 minutes, and at 60 minutes. A rise in serum cortisol level to above 500 nmol/l 30 minutes or 60 minutes after the tetracosactide injection is considered a normal response,1 although this threshold cortisol concentration indicating a normal response may vary according to the reference ranges of local labora-tory assays. If the cortisol response to tetracosactide is inadequate, patients should be referred to secondary care for further evaluation and management. A plasma adrenocorticotrophic hormone concentration should be measured as a raised concentration will distinguish Addison’s disease from secondary adrenal insufficiency.

Plasma renin activity is raised in Addison’s disease, and its measurement is also sometimes useful in differentiat-ing between Addison’s disease and secondary adrenal insufficiency. Once the diagnosis of Addison’s disease is made, further investigations are needed to determine the underlying cause.

How is it managed?Addison’s disease requires lifelong replacement of glu-cocorticoid (usually hydrocortisone) and mineralocor-ticoid (fludrocortisone). The usual replacement dose of hydrocortisone is 15-25 mg a day, given in two or three divided doses.1 Fludrocortisone is given in a single dose of 50-200 μg a day. During intercurrent illnesses and other forms of stress, patients should double or triple the replacement dose of hydrocortisone; this should be given parenterally if a patient cannot tolerate the drug orally (for example, during repeated vomiting). A patient with an acute adrenal crisis needs urgent hospi-tal admission for intravenous fluid, parenteral hydro-cortisone, and treatment of the precipitating cause (for example, antibiotics for infection). If acute adrenal crisis is suspected in an undiagnosed patient, the treatment must not be delayed to carry out investigations.Contributors: BV wrote the first draft of the manuscript; all authors helped to revise the manuscript and approved the final version. BV is the guarantor.Competing interests: None declared.Provenance and peer review: Commissioned; externally peer reviewed.Patient consent: Patient consent not required (patient anonymised, dead, or hypothetical).

Arlt W, Allolio B. Adrenal insufficiency. 1 Lancet 2003;361:1881-93.Lovas K, Husebye ES. High prevalence and increasing incidence 2 of Addison’s disease in western Norway. Clin Endocrinol (Oxf) 2002;56:787-91.Ten S, New M, Maclaren N. Clinical review 130: Addison’s disease 3 2001. J Clin Endocrinol Metab 2001;86:2909-22.Simm PJ, McDonnell CM, Zacharin MR. Primary adrenal insufficiency 4 in childhood and adolescence: advances in diagnosis and management. J Paediatr Child Health 2004;40:596-9.Hilditch K. My Addison’s disease. 5 BMJ 2000;321:645.Brosnan CM, Gowing NF. Addison’s disease. 6 BMJ 1996;312:1085-7.Nerup J. Addison’s disease—clinical studies. A report of 108 cases. 7 Acta Endocrinol (Copenh) 1974;76:127-41.Kendereski A, Micic D, Sumarac M, Zoric S, Macut D, Colic M, et al. 8 White Addison’s disease: what is the possible cause? J Endocrinol Invest 1999;22:395-400.Likhari T, Magzoub S, Griffiths MJ, Buch HN, Gama R. Screening for 9 Addison’s disease in patients with type 1 diabetes mellitus and recurrent hypoglycaemia. Postgrad Med J 2007;83:420-1.Murray JS, Jayarajasingh R, Perros P. Deterioration of symptoms after 10 start of thyroid hormone replacement. BMJ 2001;323:332-3.

KEy PoInTs Common symptoms of Addison’s disease such as fatigue, nausea, anorexia, weight loss, and depression are non-specific, and a high index of suspicion is required for the diagnosisAddison’s disease should be considered in all patients with persistent non-specific symptoms plus hyperpigmentation, unexplained hypotension (sitting or postural), electrolyte disturbance (hyponatraemia and/or hyperkalaemia), or a history of other autoimmune disordersA short Synacthen (tetracosactide) test is the key investigation to diagnose or exclude Addison’s diseaseIf acute adrenal crisis is suspected in an undiagnosed patient, the glucocorticoid replacement must not be delayed to carry out diagnostic tests

By selective culture campylobacters (C jejuni and C coli) were isolated from the faeces of 57 (7.1%) out of 803 unselected patients with diarrhoea; none were isolated from 194 people who had not got diarrhoea. Specific agglutinins were found in the sera of 31 out of 38 patients with campylobacter enteritis and 10 of them had a rising titre. Half the patients were aged 15 to 44 years, but the incidence was highest in young children. All the patients with campylobacters had a distinctive clinical illness with severe abdominal pain. Campylobacters are a relatively unrecognised cause of acute enteritis, but these findings suggest that they may be a common cause.

Spread of infection was observed within 12 out of 29 households, and in these cases children were usually implicated. Several patients were apparently infected from chickens, both live and dressed, and poultry may be the primary source of the organism. In two cases dogs with diarrhoea were found to be infected with strains indistinguishable from their human contacts. Ten patients acquired their infections while travelling abroad.Skirrow MB. Campylobacter enteritis: a “new” disease. BMJ 1977;2:9-11, doi:10.1136/bmj.2.6078.9The entire archive of the BMJ, going back to 1840, is now available at www.bmj.com/archive.Cite this as: BMJ 2009;339:b1269

FRoM ouR ARCHIvE Campylobacter enteritis (1977)

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A PATIEnT’s JouRnEy

Addison’s diseaseSarah J K Baker,1 John A H Wass2

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1London2University of Oxford, Churchill Hospital, Oxford OX2 7LJ Correspondence to: J A H Wass john.wass@noc.anglox.nhs.uk

Cite this as: BMJ 2009;339:b2384doi: 10.1136/bmj.b2384

This is one of a series of occasional articles by patients about their experiences that offer lessons to doctors. The BMJ welcomes contributions to the series. Please contact Peter Lapsley (plapsley@bmj.com) for guidance.

I (SJKB) was diagnosed with Addison’s disease in March 1994. I was 33 years old, living in Princeton, New Jersey. Two months earlier I had succumbed to flu, which included copious vomiting. Taken to hospital for rehydration, I quickly collapsed and began hyperventilating. However, the real, under-lying problem remained undetected, as I rallied in response to a saline drip and was later discharged.

In the following weeks, I seemed to recover, but exercise left me breathless and faint. Nausea and dizzy spells had become daily occurrences. I called the doctor when, one day, the dizziness didn’t go away and it became increasingly difficult to breathe. By the time I reached the surgery I could no longer stand or sit. The doctor did an electrocardiogram (ECG), took my blood pressure, and deliberated about what the problem might be. His clinical diag-nosis was Addison’s disease (I had never heard of it; he had never seen a case), and I was admitted to hospital for tests.

difficulties in reaching the diagnosisThe whole picture became clearer in retrospect. Interviews with the medical team began to link many

different, non-specific symptoms: the dizziness, low blood pressure, weight loss of about 4 kg. My periods had stopped. I had developed a bald patch on the back of my head. My underarm hair was practically non-existent. So was my libido (for which I had been referred to a psychotherapist). I had strong salt crav-ings, pigeon-holed as a bad habit best kept under wraps; and constant tiredness was easily attributed to the demands of two preschool children. Pigmenta-tion, in my case, looked more like a lingering tan.

Such vague and disparate symptoms make early intervention in the case of Addison’s unlikely. My own various accounts during the course of several visits to the doctor, were selective, based on what I thought was relevant and what was not (such as not mentioning the salt cravings). It is perhaps not surprising that many patients are referred to several different specialists for, say, suspected depression, so that the eventual accurate diagnosis is delayed, or even too late as an untreated addisonian crisis can be fatal.

In my case, I was fortunate to have avoided a full blown crisis before the penny dropped. In hospital, steroid replacement therapy began immediately,

Untreated or undiagnosed Addison’s disease can be fatal because of hypotension and so called adrenal crisis. The disease is a rare chronic condition brought about by failure of the adrenal glands. As in this patient, the disease is often not diagnosed on first presentation to a doctor. Symptoms are often vague, which is one of the reasons why it might be missed. The most important symptoms are weight loss, headaches, dizziness, and vomiting, and all of these should make doctors suspect the condition. As in this patient, increased pigmentation of the skin and salt cravings can also occur. In terms of primary adrenal insufficiency, autoimmune adrenalitis accounts for about 70% of all cases in the Western world and affects more women than men. Secondary adrenal insufficiency—sometimes also informally described as “Addison’s”—is even rarer and mostly occurs when a pituitary tumour forms. In developing countries today tuberculosis and increasingly HIV/AIDS are important causes.

TreatmentLifelong, continuous steroid replacement therapy is required. This aims to replicate the necessary amounts of the missing hormones (cortisol and aldosterone) that the patient can no longer produce. Most patients are prescribed a combination of hydrocortisone (usually taken in three or two small doses over the course of the day) and fludrocortisone (either as a single or twice daily dose). DHEA, which is usually lacking in patients with Addison’s disease, is not available in the UK at present, although several clinical trials in the UK and internationally concluded that small quantities of DHEA are moderately beneficial, improving quality of life by providing some protection against osteoporosis, greater energy, higher

levels of libido and lean muscle, and relief from dry skin. As in this patient, with the right balance of daily medication, most people with Addison’s disease are able to continue life much as it was before their illness. Taking reasonable precautions against the possibility of infection, including an annual flu vaccination, is also recommended. With autoimmune causes, regular surveillance is important to pick up other associated autoimmune endocrine conditions that may subsequently develop, such as hypothyroidism, early ovarian failure, or diabetes mellitus.

Crisis managementAn Addisonian crisis can result in death caused by hypotension, so steroids need to be given rapidly. All patients with Addison’s disease should have an emergency injection kit of hydrocortisone at home, for use in the case of a crisis. It is also prudent to prescribe antinausea tablets or suppositories for home use, if required. A crisis is usually preceded by the symptoms of steroid insufficiency: headache, dizziness, nausea, and vomiting. The most common reason for hospital admission is because patients do not take sufficient extra hydrocortisone early enough when they become seriously ill. The second most common reason is reducing their dose again too soon, while still in the middle of a serious infectious illness, such as influenza. As a general rule, taking supraphysiological amounts of steroid over 24-48 hours is not harmful. Too little in the event of a crisis may be fatal, and so prompt medical attention is essential, together with the administration of 100 mg hydrocortisone by injection every six to eight hours and intravenous fluids.John A H Wass professor of endocrinology, Oxford

A DOCTOR’s PeRsPeCTIve

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resulting in an unforgettable energy surge: I felt that suddenly I had been plugged in and switched on. The relief was tremendous. I was told I would need lifelong, continuous treatment with steroids and that in the event of extreme physical stress (such as trauma, illness, or injury) urgent, extra cover would be essential to prevent a potentially life threatening addisonian crisis, in which without hydrocortisone the blood pressure falls very severely.

I was reassured that my children were unlikely directly to inherit the disease, although they would be more prone to developing some kind of metabolic disorder. I too would be regularly monitored for any signs of other autoimmune conditions.

life with Addison’sComing to terms with a chronic condition inevitably takes time. At first there was the initial shock at what seemed like the betrayal of my own body and its new dependence on prescription drugs. I was grateful for my treatment, of course, but the loss of a “healthy” self and the idea of taking tablets on a daily basis took some getting used to.

Gradually I began to feel more in control, and six months later we returned to England. The condition seemed to be stable and I became better able to judge the effects of over- and under-medication. Two key turning points stand out here. Firstly, a hydrocortisone day curve analysis suggested that taking the hydrocor-tisone three times a day (on waking, at 12 noon, and at 5 pm) would be better than just twice (on waking and at 5 pm). This made an important difference to my energy and concentration levels in the afternoon.

Secondly, contrary to the printed instructions, it proved unnecessary for the hydrocortisone at such small doses (10 mg, 5 mg, and 5 mg respectively) to be taken with meals. Tiny as this piece of knowledge may seem, it was extremely liberating. Being advised to “take these tablets three times a day” seems simple enough. But that means “every day, for the rest of your life, regardless of what you happen to be doing at the time.” Many practical difficulties can get in the way of this (a work meeting, a school event, motorway driving, for example). It’s much easier to make sure that water is to hand at the right moment, rather than food as well.

Both these improvements owe much to the support of my endocrinologist in the United Kingdom and the quality of care he provides. Another considerable source of help and information has come from the UK Addison’s Disease Self Help Group. The group’s set of guidelines, not just for managing the disease on a day to day basis but also in terms of crisis manage-ment, provides a key reference when I need it. It is difficult to overstate the importance—and authority—of these guidelines in a hospital setting, not only when admission is Addison’s related, but also when it is not, such as for a procedure or condition that could easily destabilise the Addison’s into a potential crisis.

A recent colonoscopy brought home the potential precariousness of this condition. I had to be admit-

ted to hospital overnight for the preparation, intra-venous fluids, and intramuscular steroid cover. The Addison’s Disease Self Help Group’s guidelines rec-ommend 100 mg hydrocortisone by injection every six hours during the preparation and again just before the procedure. But the time it can take to respond to the laxatives (in my case, about six hours) can vary hugely, and it made little sense to start the extra cover beforehand. In addition, the timing of the medication had to match the wait between the preparation and the actual examination: difficult when the colonos-copy unit runs late and the schedule slips an hour or two. Options are not necessarily clear cut; flexibility and on the spot judgments are needed. Fortunately it all went smoothly, but it is inevitable that, over the course of several shifts, not all members of the medical staff are necessarily familiar with Addison’s, or have experience in treating an adrenal emergency.

understanding the conditionThe Addison’s Disease Self Help Group continues to promote further understanding of the disease, both for patients and clinicians. It has successfully lobbied for paramedics to administer a steroid injection when needed. In an emergency, speed is imperative. Anec-dotal evidence within the self help group suggests just how difficult it can be for patients and their families when encountering doctors who are hesitant in pro-viding critical steroid cover. A short term excess of steroids is much safer than the converse.

Today, 15 years on, I feel fortunate to have a quality of life that not all those with Addison’s disease enjoy. Many continue to struggle with fatigue and other debilitating symptoms. I have witnessed—and bene-fited from—some substantial fine tuning of treatment, such as adding a small amount of dehydroepiandros-terone (DHEA) and splitting the fludrocortisone dose. Keeping fit helps me significantly. I have a fairly good understanding of my body’s limits, and the clues my body gives me if I start running a deficit. Above all, I am grateful for having had so few real scares to date and, in this respect to have faced few challenges.Competing interests: None declared.

Provenance and peer review: Not commissioned; not externally peer reviewed.

Accepted: 24 March 2009

ResOURCes

Addison’s Disease Self Help Group (www.addisons.org.uk)—UK based support group for patients and their carers

Australian Addison’s Disease Association (www.addisons.org.au)—Australian based support group for patients and their carers

New Zealand Addison’s Network (www.addisons.org.nz)—New Zealand based support group for patients

National Adrenal Diseases Foundation (www.nadf.us)—North American support group for patients

MedicAlert Foundation (www.medicalert.org.uk)—Charity providing identification system for people with hidden medical conditions and allergies