PRACTICE For the full versions of these articles see bmj.

com

Easily Missed?
Addison’s disease
Bijay Vaidya,1 2 Ali J Chakera,1 Catherine Dick3

Practice, p 106 What is Addison’s disease?

Addison’s disease (also known as primary adrenal insuf- How common is Addison’s disease?
1
Department of Endocrinology, ficiency) is a chronic disorder of the adrenal cortex Addison’s disease has a prevalence of 93-140 per
Royal Devon and Exeter Hospital, resulting in inadequate secretion of glucocorticoid and million people and an annual incidence of 4.7-6.2
Exeter EX2 5DW per million people in Western populations.1 2 A recent
2
Peninsula Medical School, Exeter mineralocorticoid. The commonest cause of Addison’s
epidemiological study suggests that the incidence of
3
Devon Primary Care Trust, disease in developed countries is autoimmune disorder
Addison’s disease is rising2
Topsham Surgery, Exeter EX3 0EN and in developing countries is tuberculosis.1
Correspondence to: B Vaidya, A survey of patients with Addison’s disease found that
[Link]@[Link] 60% had seen two or more clinicians before the diagnosis
Why is it missed? of Addison’s disease was ever considered3
Cite this as: BMJ 2009;339:b2385
doi: 10.1136/bmj.b2385
The onset of Addison’s disease is often insidious. Its
An observational study of children with Addison’s disease
usual symptoms (such as fatigue, lethargy, weakness, found that a delay in diagnosis occurred in about a third of
and low mood) are non-specific, are highly prevalent the cases, in whom the median duration between the onset
in the general population, and overlap with many other of first symptoms and the correct diagnosis was two years4
common conditions.

Why does this matter? c­ ommon symptoms, although non-specific in them-

A patient with untreated Addison’s disease becomes selves, may point to Addison’s disease. A cohort study
progressively unwell with a markedly reduced quality of 108 patients with Addison’s disease found that they
of life.5 If Addison’s disease is not suspected, such a had all experienced fatigue, weakness, anorexia, and
patient is often misdiagnosed as having other condi- unintentional weight loss.7 Other symptoms included
tions such as depression, chronic fatigue syndrome, gastrointestinal complaints such as nausea and vague
anorexia nervosa, or gastrointestinal disorders, leading abdominal pain (56%), postural dizziness (12%), and
to unnecessary investigations and inappropriate treat- musculoskeletal pains (6%).7 Hyperpigmentation of
ments. Moreover, the patient is at risk of developing skin and mucous membranes is a characteristic fea-
serious acute adrenal crisis during an intercurrent ill- ture of Addison’s disease; however, it is absent in about
ness or stress. Acute adrenal crisis, if not recognised and 10% of cases, which may delay diagnosis.7 8 Postural
treated urgently, could be fatal.6 hypotension is common in Addison’s disease; however,
low blood pressure without a postural drop can also
How is it diagnosed? occur.
Clinical features Autoimmune Addison’s disease is associated with
A high index of suspicion is required for the diag- other autoimmune conditions. For example, vitiligo
nosis of Addison’s disease. Doctors need to be alert often coexists with Addison’s disease.7 It is important
to the possibility of Addison’s disease. A cluster of to consider Addison’s disease if a patient with type
1 diabetes starts developing unexplained recurrent
Case scenario hypoglycaemia or the patient’s insulin requirement
falls as this may signal adrenal insufficiency.9 Likewise,
A 34 year old woman presented with a 12 month history
of increasing tiredness, anorexia, weight loss, and
worsening of symptoms in a patient with autoimmune
This is a series of occasional
articles highlighting conditions depression. During that period, she had tried two different hypothyroidism after the start of thyroxine treatment
that may be commoner than antidepressant tablets without benefit. She saw her general should also raise the suspicion of Addison’s disease
many doctors realise or may be as thyroxine replacement in a patient with untreated
missed at first presentation.
practitioner’s locum, who thought she looked tanned.
The series advisers are Anthony Her blood pressure was 90/60 mm Hg, although it had Addison’s disease can precipitate an adrenal crisis.10
Harnden, university lecturer in always tended to be low. Her serum sodium concentration About half of patients with Addison’s disease are
general practice, Department of was 130 (normal range 135-145) mmol/l and potassium diagnosed only after an acute adrenal crisis.1 It is a
Primary Health Care, University concentration was 5.7 (normal range 3.5-5.5) mmol/l.
of Oxford, and Richard Lehman, medical emergency often precipitated by an infection
general practitioner, Banbury. If
A short Synacthen (tetracosactide) test showed an or other forms of stress in an undiagnosed or inad-
you would like to suggest a topic inadequate serum cortisol response, which together with
equately treated patient with Addison’s disease. In this
for this series please email us raised plasma adrenocorticotrophic hormone confirmed
([Link]@bmjgroup. the diagnosis of Addison’s disease. condition, patients present acutely unwell with severe
com) dehydration, hypotension, or circulatory shock.

104 BMJ | 11 july 2009 | Volume 339

 PRACTICE

Plasma renin activity is raised in Addison’s disease, and

Key points
its measurement is also sometimes useful in differentiat-
Common symptoms of Addison’s disease such as fatigue, nausea, anorexia, weight ing between Addison’s disease and secondary adrenal
loss, and depression are non-specific, and a high index of suspicion is required for the
insufficiency. Once the diagnosis of Addison’s disease
diagnosis
is made, further investigations are needed to determine
Addison’s disease should be considered in all patients with persistent non-specific
symptoms plus hyperpigmentation, unexplained hypotension (sitting or postural),
the underlying cause.
electrolyte disturbance (hyponatraemia and/or hyperkalaemia), or a history of other
autoimmune disorders How is it managed?
A short Synacthen (tetracosactide) test is the key investigation to diagnose or exclude Addison’s disease requires lifelong replacement of glu-
Addison’s disease cocorticoid (usually hydrocortisone) and mineralocor-
If acute adrenal crisis is suspected in an undiagnosed patient, the glucocorticoid ticoid (fludrocortisone). The usual replacement dose of
replacement must not be delayed to carry out diagnostic tests hydrocortisone is 15-25 mg a day, given in two or three
divided doses.1 Fludrocortisone is given in a single dose
Investigations of 50-200 μg a day. During intercurrent illnesses and
On routine blood tests, unexplained electrolyte distur- other forms of stress, patients should double or triple
bances such as hyponatraemia and hyperkalaemia may the replacement dose of hydrocortisone; this should
provide a clue to the diagnosis of Addison’s disease. be given parenterally if a patient cannot tolerate the
Other biochemical abnormalities, including raised urea drug orally (for example, during repeated vomiting). A
concentration, hypoglycaemia, hypercalcaemia, and patient with an acute adrenal crisis needs urgent hospi-
raised concentrations of serum thyroid stimulating hor- tal admission for intravenous fluid, parenteral hydro-
mone, may be present. cortisone, and treatment of the precipitating cause (for
A clinical suspicion of Addison’s disease must be con- example, antibiotics for infection). If acute adrenal crisis
firmed biochemically by demonstrating inadequate corti- is suspected in an undiagnosed patient, the treatment
sol production. Owing to the pulsatile nature and diurnal must not be delayed to carry out investigations.
variation of cortisol secretion, random measurement of Contributors: BV wrote the first draft of the manuscript; all authors helped
serum cortisol concentration is inadequate to assess to revise the manuscript and approved the final version. BV is the guarantor.
adrenal function in most cases. A short Synacthen test is Competing interests: None declared.
Provenance and peer review: Commissioned; externally peer reviewed.
the investigation of choice to confirm or exclude Addi-
Patient consent: Patient consent not required
son’s disease; it is a safe test, which can be done either in (patient anonymised, dead, or hypothetical).
primary care by a general practitioner or in secondary 1 Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003;361:1881-93.
care via referral. In the test, 250 μg of tetracosactide (an 2 Lovas K, Husebye ES. High prevalence and increasing incidence
analogue of corticotropin) is injected intramuscularly or of Addison’s disease in western Norway. Clin Endocrinol (Oxf)
2002;56:787-91.
intravenously, and blood samples for serum cortisol are 3 Ten S, New M, Maclaren N. Clinical review 130: Addison’s disease
taken immediately, at 30 minutes, and at 60 minutes. 2001. J Clin Endocrinol Metab 2001;86:2909-22.
A rise in serum cortisol level to above 500 nmol/l 30 4 Simm PJ, McDonnell CM, Zacharin MR. Primary adrenal insufficiency
in childhood and adolescence: advances in diagnosis and
minutes or 60 minutes after the tetracosactide injection management. J Paediatr Child Health 2004;40:596-9.
is considered a normal response,1 although this threshold 5 Hilditch K. My Addison’s disease. BMJ 2000;321:645.
6 Brosnan CM, Gowing NF. Addison’s disease. BMJ 1996;312:1085-7.
cortisol concentration indicating a normal response may 7 Nerup J. Addison’s disease—clinical studies. A report of 108 cases.
vary according to the reference ranges of local labora- Acta Endocrinol (Copenh) 1974;76:127-41.
tory assays. If the cortisol response to tetracosactide is 8 Kendereski A, Micic D, Sumarac M, Zoric S, Macut D, Colic M, et al.
White Addison’s disease: what is the possible cause? J Endocrinol
inadequate, patients should be referred to secondary Invest 1999;22:395-400.
care for further evaluation and management. A plasma 9 Likhari T, Magzoub S, Griffiths MJ, Buch HN, Gama R. Screening for
adrenocorticotrophic hormone concentration should Addison’s disease in patients with type 1 diabetes mellitus and
recurrent hypoglycaemia. Postgrad Med J 2007;83:420-1.
be measured as a raised concentration will distinguish 10 Murray JS, Jayarajasingh R, Perros P. Deterioration of symptoms after
Addison’s disease from secondary adrenal insufficiency. start of thyroid hormone replacement. BMJ 2001;323:332-3.

From our archive Campylobacter enteritis (1977)

By selective culture campylobacters (C jejuni and C coli) Spread of infection was observed within 12 out of 29
were isolated from the faeces of 57 (7.1%) out of 803 households, and in these cases children were usually
unselected patients with diarrhoea; none were isolated implicated. Several patients were apparently infected
from 194 people who had not got diarrhoea. Specific from chickens, both live and dressed, and poultry may
agglutinins were found in the sera of 31 out of 38 patients be the primary source of the organism. In two cases dogs
with campylobacter enteritis and 10 of them had a rising with diarrhoea were found to be infected with strains
titre. Half the patients were aged 15 to 44 years, but the indistinguishable from their human contacts. Ten patients
incidence was highest in young children. All the patients acquired their infections while travelling abroad.
with campylobacters had a distinctive clinical illness with Skirrow MB. Campylobacter enteritis: a “new” disease.
BMJ 1977;2:9-11, doi:10.1136/bmj.2.6078.9
severe abdominal pain. Campylobacters are a relatively
The entire archive of the BMJ, going back to 1840, is now available at
unrecognised cause of acute enteritis, but these findings [Link]/archive.
suggest that they may be a common cause. Cite this as: BMJ 2009;339:b1269

BMJ | 11 july 2009 | Volume 339 105

 PRACTICE

A Patient’s Journey
Addison’s disease
Sarah J K Baker,1 John A H Wass2

Practice, p 104 I (SJKB) was diagnosed with Addison’s disease in different, non-specific symptoms: the dizziness, low
March 1994. I was 33 years old, living in Princeton, blood pressure, weight loss of about 4 kg. My periods
1
London New Jersey. Two months earlier I had succumbed had stopped. I had developed a bald patch on the
2
University of Oxford, Churchill
Hospital, Oxford OX2 7LJ
to flu, which included copious vomiting. Taken to back of my head. My underarm hair was practically
Correspondence to: J A H Wass hospital for rehydration, I quickly collapsed and non-existent. So was my libido (for which I had been
[Link]@[Link] began hyperventilating. However, the real, under- referred to a psychotherapist). I had strong salt crav-
lying problem remained undetected, as I rallied in ings, pigeon-holed as a bad habit best kept under
Cite this as: BMJ 2009;339:b2384
doi: 10.1136/bmj.b2384 response to a saline drip and was later discharged. wraps; and constant tiredness was easily attributed
In the following weeks, I seemed to recover, but to the demands of two preschool children. Pigmenta-
exercise left me breathless and faint. Nausea and tion, in my case, looked more like a lingering tan.
dizzy spells had become daily occurrences. I called Such vague and disparate symptoms make early
the doctor when, one day, the dizziness didn’t go intervention in the case of Addison’s unlikely. My
away and it became increasingly difficult to breathe. own various accounts during the course of several
By the time I reached the surgery I could no longer visits to the doctor, were selective, based on what
stand or sit. The doctor did an electrocardiogram I thought was relevant and what was not (such as
(ECG), took my blood pressure, and deliberated not mentioning the salt cravings). It is perhaps not
about what the problem might be. His clinical diag- surprising that many patients are referred to several
nosis was Addison’s disease (I had never heard of different specialists for, say, suspected depression,
it; he had never seen a case), and I was admitted to so that the eventual accurate diagnosis is delayed,
hospital for tests. or even too late as an untreated addisonian crisis
can be fatal.
Difficulties in reaching the diagnosis In my case, I was fortunate to have avoided a full
The whole picture became clearer in retrospect. blown crisis before the penny dropped. In hospital,
Interviews with the medical team began to link many steroid replacement therapy began immediately,

A doctor’s perspective
Untreated or undiagnosed Addison’s disease can be fatal levels of libido and lean muscle, and relief from dry skin. As in
because of hypotension and so called adrenal crisis. The this patient, with the right balance of daily medication, most
disease is a rare chronic condition brought about by failure people with Addison’s disease are able to continue life much
of the adrenal glands. As in this patient, the disease is often as it was before their illness. Taking reasonable precautions
not diagnosed on first presentation to a doctor. Symptoms against the possibility of infection, including an annual flu
are often vague, which is one of the reasons why it might vaccination, is also recommended. With autoimmune causes,
be missed. The most important symptoms are weight loss, regular surveillance is important to pick up other associated
headaches, dizziness, and vomiting, and all of these should autoimmune endocrine conditions that may subsequently
make doctors suspect the condition. As in this patient, develop, such as hypothyroidism, early ovarian failure, or
increased pigmentation of the skin and salt cravings can also diabetes mellitus.
occur. In terms of primary adrenal insufficiency, autoimmune Crisis management
adrenalitis accounts for about 70% of all cases in the Western An Addisonian crisis can result in death caused by
world and affects more women than men. Secondary adrenal hypotension, so steroids need to be given rapidly. All patients
insufficiency—sometimes also informally described as with Addison’s disease should have an emergency injection
“Addison’s”—is even rarer and mostly occurs when a pituitary kit of hydrocortisone at home, for use in the case of a crisis. It is
tumour forms. In developing countries today tuberculosis and also prudent to prescribe antinausea tablets or suppositories
increasingly HIV/AIDS are important causes. for home use, if required. A crisis is usually preceded by the
Treatment symptoms of steroid insufficiency: headache, dizziness,
Lifelong, continuous steroid replacement therapy is required. nausea, and vomiting. The most common reason for hospital
This aims to replicate the necessary amounts of the missing admission is because patients do not take sufficient extra
hormones (cortisol and aldosterone) that the patient can no hydrocortisone early enough when they become seriously
longer produce. Most patients are prescribed a combination ill. The second most common reason is reducing their
of hydrocortisone (usually taken in three or two small doses dose again too soon, while still in the middle of a serious
over the course of the day) and fludrocortisone (either as a infectious illness, such as influenza. As a general rule, taking
This is one of a series of single or twice daily dose). DHEA, which is usually lacking supraphysiological amounts of steroid over 24-48 hours is
occasional articles by patients
about their experiences that
in patients with Addison’s disease, is not available in the not harmful. Too little in the event of a crisis may be fatal, and
offer lessons to doctors. The UK at present, although several clinical trials in the UK and so prompt medical attention is essential, together with the
BMJ welcomes contributions to internationally concluded that small quantities of DHEA are administration of 100 mg hydrocortisone by injection every six
the series. Please contact Peter moderately beneficial, improving quality of life by providing to eight hours and intravenous fluids.
Lapsley (plapsley@[Link]) for some protection against osteoporosis, greater energy, higher John A H Wass professor of endocrinology, Oxford
guidance.

106 BMJ | 11 july 2009 | Volume 339

 PRACTICE

resulting in an unforgettable energy surge: I felt Resources

that suddenly I had been plugged in and switched
on. The relief was tremendous. I was told I would Addison’s Disease Self Help Group ([Link].
uk)—UK based support group for patients and their carers
need lifelong, continuous treatment with steroids and
that in the event of extreme physical stress (such as Australian Addison’s Disease Association ([Link].
[Link])—Australian based support group for patients and
trauma, illness, or injury) urgent, extra cover would
their carers
be essential to prevent a potentially life threatening
New Zealand Addison’s Network ([Link].
addisonian crisis, in which without hydrocortisone
nz)—New Zealand based support group for patients
the blood pressure falls very severely.
National Adrenal Diseases Foundation ([Link])—
I was reassured that my children were unlikely
North American support group for patients
directly to inherit the disease, although they would
MedicAlert Foundation ([Link])—Charity
be more prone to developing some kind of metabolic
providing identification system for people with hidden
disorder. I too would be regularly monitored for any medical conditions and allergies
signs of other autoimmune conditions.

Life with Addison’s ted to hospital overnight for the preparation, intra-
Coming to terms with a chronic condition inevitably venous fluids, and intramuscular steroid cover. The
takes time. At first there was the initial shock at what Addison’s Disease Self Help Group’s guidelines rec-
seemed like the betrayal of my own body and its new ommend 100 mg hydrocortisone by injection every
dependence on prescription drugs. I was grateful for six hours during the preparation and again just before
my treatment, of course, but the loss of a “healthy” the procedure. But the time it can take to respond to
self and the idea of taking tablets on a daily basis took the laxatives (in my case, about six hours) can vary
some getting used to. hugely, and it made little sense to start the extra cover
Gradually I began to feel more in control, and six beforehand. In addition, the timing of the medication
months later we returned to England. The condition had to match the wait between the preparation and
seemed to be stable and I became better able to judge the actual examination: difficult when the colonos-
the effects of over- and under-medication. Two key copy unit runs late and the schedule slips an hour or
turning points stand out here. Firstly, a hydrocortisone two. Options are not necessarily clear cut; flexibility
day curve analysis suggested that taking the hydrocor- and on the spot judgments are needed. Fortunately it
tisone three times a day (on waking, at 12 noon, and at all went smoothly, but it is inevitable that, over the
5 pm) would be better than just twice (on waking and course of several shifts, not all members of the medical
at 5 pm). This made an important difference to my staff are necessarily familiar with Addison’s, or have
energy and concentration levels in the afternoon. experience in treating an adrenal emergency.
Secondly, contrary to the printed instructions, it
proved unnecessary for the hydrocortisone at such Understanding the condition
small doses (10 mg, 5 mg, and 5 mg respectively) to The Addison’s Disease Self Help Group continues to
be taken with meals. Tiny as this piece of knowledge promote further understanding of the disease, both
may seem, it was extremely liberating. Being advised for patients and clinicians. It has successfully lobbied
to “take these tablets three times a day” seems simple for paramedics to administer a steroid injection when
enough. But that means “every day, for the rest of needed. In an emergency, speed is imperative. Anec-
your life, regardless of what you happen to be doing dotal evidence within the self help group suggests just
at the time.” Many practical difficulties can get in the how difficult it can be for patients and their families
way of this (a work meeting, a school event, motorway when encountering doctors who are hesitant in pro-
driving, for example). It’s much easier to make sure viding critical steroid cover. A short term excess of
that water is to hand at the right moment, rather than steroids is much safer than the converse.
food as well. Today, 15 years on, I feel fortunate to have a quality
Both these improvements owe much to the support of life that not all those with Addison’s disease enjoy.
of my endocrinologist in the United Kingdom and Many continue to struggle with fatigue and other
the quality of care he provides. Another considerable debilitating symptoms. I have witnessed—and bene-
source of help and information has come from the fited from—some substantial fine tuning of treatment,
UK Addison’s Disease Self Help Group. The group’s such as adding a small amount of dehydroepiandros-
set of guidelines, not just for managing the disease on terone (DHEA) and splitting the fludrocortisone dose.
a day to day basis but also in terms of crisis manage- Keeping fit helps me significantly. I have a fairly good
ment, provides a key reference when I need it. It is understanding of my body’s limits, and the clues my
difficult to overstate the importance—and authority—of body gives me if I start running a deficit. Above all, I
these guidelines in a hospital setting, not only when am grateful for having had so few real scares to date
admission is Addison’s related, but also when it is not, and, in this respect to have faced few challenges.
such as for a procedure or condition that could easily Competing interests: None declared.
destabilise the Addison’s into a potential crisis. Provenance and peer review: Not commissioned;
A recent colonoscopy brought home the potential not externally peer reviewed.
precariousness of this condition. I had to be admit- Accepted: 24 March 2009

BMJ | 11 july 2009 | Volume 339 107