Adrenal insufficiency

Presenting problem
A 27-year-old woman is referred by her GP to an
endocrine clinic with gradual onset of fatigue, anorexia,
weight loss and hyperpigmentation dating back to her
second and last pregnancy 5 years ago. She also
complains of amenorrhoea of 4 months’ duration, intermittent
diarrhoea and orthostatic dizziness.
What would your differential diagnosis include
before examining the patient?
Fatigue is a frequent complaint in an endocrine clinic.
Hypothyroidism is unlikely since the patient lost weight and
she also complains of amenorrhoea and not menorrhagia.
Rheumatoid arthritis and multiple sclerosis are examples of
autoimmune conditions associated with fatigue and could
easily be excluded on further enquiry. Chronic fatigue syndrome
may follow after a viral infection such as infectious
mononucleosis, influenza or hepatitis. Anorexia nervosa
should also be considered in the differential diagnosis of
weight loss and amenorrhoea. The absence of similar complaints
during adolescence would argue against this condition.
None of the above conditions is, however, characterised
by hyperpigmentation. Primary adrenocortical failure, pellagra
and malabsorption may also present with
hyperpigmentation, weight loss and diarrhoea.

Causes of diffuse
Hyperpigmentation

Endocrinopathies
1.• Addison’s disease
2.• Nelson’s syndrome
3.• Ectopic ACTH secretion
Metabolic
4.• Porphyria cutanea tarda
5.• Haemochromatosis
6.• Vitamin B12 and folate deficiency
7.• Pellagra
8.• Malabsorption
Autoimmune
9.• Hepatic cirrhosis
10.• Systemic sclerosis
Drug-induced
11.• Amiodarone
12.• Busulfan
13.• Chloroquine
14.• Minocycline
15.• Phenothiazines
16.• Psoralens
Acute adrenal (addisonian) crisis is an emergency caused by
insufficient cortisol.Crisis may occur in the course of treatment of
chronic adrenal insufficiency, or it may be the presenting
manifestation of adrenal insufficiency. Acute adrenal crisis is more
commonly seen in primary adrenal insufficiency than in secondary
adrenal insufficiency.
Adrenal crisis may occur in the following situations: (1) during
stress (eg, infection, trauma, surgery, hyperthyroidism, or
prolonged fasting) in a patient with latent or treated
adrenal insufficiency; (2) following sudden withdrawal of
adrenocortical hormone in a patient with chronic insufficiency or
in a patient with temporary insufficiency due to suppression by
exogenous corticosteroids or megestrol; (3) following bilateral
adrenalectomy or removal of a functioning adrenal tumor that
had suppressed the other adrenal gland; (4) following sudden
destruction of the pituitary gland (pituitary necrosis), or when
thyroid hormone is given to a patient with adrenal insufficiency;
(5) following injury to both adrenals (by trauma, hemorrhage,
anticoagulant therapy, thrombosis, infection or, rarely, metastatic
carcinoma); and (6) following administration of intravenous
etomidate (used for rapid anesthesia induction or intubation).
Examination
This young woman’s height is 1.69 m and she
weighs 52 kg (BMI: 18.2). Generalised hyperpigmentation
is present but is more pronounced on the sun-exposed areas .
Her hair is dark, and dark freckles are also present over the
anterior chest wall. Pressure areas, such as the elbows, the skin
over spinous processes and underneath the brassiere straps, are
also darker than surrounding skin. The patient’s pulse rate is
88/min and blood pressure is 100/70 mmHg lying down
and 60/40 mmHg in the erect position. Vitiligo is absent and no
abnormal

abnormal pigmentation is present on the oral mucous

membranes. Initial blood test
results are .

Initial investigations

Sodium 131 mmol/L (mEq/L)

Potassium 5.4 mmol/L (mEq/L)
Urea (19.9 mg/dL)
Creatinine (1.20 mg/dL)
Glucose (66.65 mg/dL)

Have examination and initial investigations narrowed down your

differential diagnosis?
Although the hyperpigmentation in this patient is highly
suggestive of primary adrenocortical failure (Addison’s disease), it
is by no means diagnostic. The absence of vitiligo does not
exclude Addison’s disease since it is seen in only 10–20% of
patients with the autoimmune variety. The orthostatic decrease in
blood pressure and the raised plasma urea and creatinine are
suggestive of primary adrenal insufficiency, but may also be due
to hypovolaemia secondary to chronic diarrhoea and
malabsorption.Hyponatraemia and hyperkalaemia in the presence
of hypovolaemia, however, argue strongly in favour of primary
adrenal insufficiency.

Further investigations
The patient’s morning (08.00 hours) plasma cortisol concentration
is 47.1 nmol/L (1.71 μg/dL) and the corresponding plasma
corticotrophin (ACTH) concentration is 53.5 pmol/L (243 pg/mL).
This woman’s thyroid function test results are normal but her
thyroid microsomal antibody titre is positive to a titre
of 1 : 6400. A computed tomogram (CT) of the adrenal glands
reveals atrophy of both glands, and the serum ferritin
concentration is within the normal range.
Does this narrow down your differential diagnosis?
The clinical picture and the finding of low serum cortisol and
elevated ACTH concentrations all but clinch the diagnosis of
primary adrenocortical failure. In less clear-cut cases, a short
Synacthen test should be performed, as the identification of a low
stimulated cortisol concentration is a more robust marker
of glucocorticoid deficiency than a random or early morning
cortisol. In this case, this might be considered superfluous.
Common causes of chronic primary adrenocortical failure include
autoimmune adrenalitis (Addison’s disease) and infections such as
tuberculosis and human immunodeficiency virus-acquired
immunodeficiency syndrome (HIV/ AIDS). Measurement of
antibodies directed against the adrenal cortex is helpful
to diagnose autoimmune adrenalitis, but unfortunately this assay
is not widely available. The presence of thyroid microsomal
antibodies in this patient argues in favour of an underlying
autoimmune process. The absence of calcification or
evidence of metastatic disease in the adrenal glands rules out
tuberculosis and underlying malignancy respectively as
aetiological factors.
Symptoms and Signs
Chronic Adrenal Insuf ciency
• Symptoms onset is usually gradual and the dia gnosis is often
delayed since many early symptoms are nonspecific
• Muscle weakness and fatigue
• Fever
• anorexia , nausea and vomiting, weight loss
• Anxiety, mental irritability, and emotiona changes
• Patients usually have significant pain
Arthralgias
Mya lgias
Chest pain
Abdom inal pain
Back pain
Leg pain
Headache
• Skin
— Diffuse tanning over nonexposed nd exposed skin or multiple
reckles
— Hyperpigmentation, especially knuckles, elbows, knees,
posterior neck, palm creases,nail beds, pressure areas, and new
scars
— Vitiligo (10%)
• Hypoglycemia , when present, may worsen wea kness and
mental functioning, rarely leading to coma.
• In diabetics, increased insulin sensitivity and hypoglycem ic
reactions
• Other utoimmune disease mani festations
• Hypotension and orthostasis is typical
— Ninety percent have systolic blood pressure (SBP) < 110 Hg
— SBP > 130 Hg is rare
• Small heart
• Scant axillary and pubic hair (especially in wom en, if
hypogonadism also present)
• Neuropsychiatric symptoms, sometimes without drenal
insufficiency, in adult-onset adrenoleukodystrophy.
.
Acute Adrenal Insufficiency
• Headache, alssitude, nausea and vomiting, abdom inal pain,
and diarrhea
• Confusion or coma
• Fever, as high as 40.6°C or more
• Dehydra tion, hypotension, and shock
• Recurrent hypoglycemia and reduced insulin requirements in
patients with preexisting
type 1 dia betes mellitus
• Meningococcemia is associated with purpura and adrenal
insufficiency secondary to
adrenal infarction (Waterhouse–Friderichsen syndrome)
Q. What diseases are associated with Addison’s disease?
A. It is an autoimmune disease, so may be associated with other
autoimmune diseases, such as—
Graves’ disease, Hashimoto’s thyroiditis, pernicious anemia,
primary ovarian failure, myasthenia gravis, type I DM etc.

Q. Why vitiligo occurs in Addison’s disease?

A. It is due to autoimmunity. Vitiligo is present in 10 to 20%
cases.

How will you treat this patient?

Both glucocorticoid and mineralocorticoid replacement therapy
should be provided. Hydrocortisone (cortisol) 15 mg orally on
waking and 5 mg orally at approximately 18.00 hours constitute
the glucocorticoid regimen of choice. This dosage regimen is
usually sufficient but may need to be increased to 20 mg and
10 mg,respectively, in some patients.Unfortunately, measurement
of ‘trough and peak’ cortisol concentrations is not very helpful for
determining the optimum dosage of hydrocortisone. Furthermore,
the pharmacokinetics of hydrocortisone makes it very hard to
mimic circadian cortisol secretion. Therefore, some patients
may still experience daily episodes of lassitude and fatigue in
spite of an adequate total daily dose of hydrocortisone. In some
individuals it may be prudent to advise a small dose after lunch
and to postpone the evening dose till bedtime. Cortisol
is a powerful appetite stimulant and excessive weight gain usually
indicates overtreatment.
Hyperpigmentation should improve within several weeks to a few
months. Persistent hyperpigmentation indicates insufficient
chronic suppression of ACTH secretion.
Fludrocortisone (9α-fluorohydrocortisone) is the mineralocorticoid
of choice and can be initiated with 0.05 mg orally on waking. The
objective of fludrocortisones treatment is to prevent further
sodium loss, to restore intravascular volume and to prevent
hyperkalaemia. Adequacy of fludrocortisone replacement can be
monitored by routinely measuring blood pressure in the supine as
well as the upright position, in addition to the serum sodium and
potassium concentrations.
Over-treatment with fludrocortisone should be suspected when
the blood pressure becomes elevated and oedema and
hypokalaemia develop.
Patient education is of the utmost importance in the long-term
successful management of primary adrenal insufficiency. Patients
should be advised to increase their salt intake during summer in
regions known for hot, dry summers.
The dose of hydrocortisone must be doubled during periods of
emotional and physical stress, e.g. febrile periods, and the GP
should be notified if this exceeds 3 days. Parenteral
hydrocortisone and intravenous saline must be administered
during episodes of vomiting. Patients should also be carefully
followed for the development of other autoimmune
endocrinopathies such as hypothyroidism and premature ovarian
failure.
In known patients, as well as in previously undiagnosed ones, an
acute adrenal crisis should be suspected if they present in shock,
especially when this is accompanied by anorexia, nausea,
vomiting, weakness and abdominal pain with deep tenderness on
palpation. Intravenous saline should be infused as required to
normalise haemodynamic indices and care must be taken not to
correct hyponatraemia too rapidly. Hypoglycaemia may be a rare
presentation of acute adrenal insufficiency in adults.
Q. What drug is avoided in acute abdominal pain in Addison’s
disease?
A. Morphine, as the patient is more sensitive to this drug.
Key points and global issues

As the incidence of HIV/AIDS increases, especially in developing

countries, overt adrenal insufficiency may become more
prevalent due to a necrotising adrenalitis secondary to
cytomegalovirus infection or tuberculous involvement; Kaposi’s
sarcoma may also metastasise to the adrenal glands.
• Synacthen (ACTH1–24) is not available in some developing
countries.
• Assays for antibodies directed at the adrenal cortex are also not
widely available in developing countries.
• Patients with chronic adrenal insufficiency must be advised to
increase their salt intake during summer in countries with hot dry
summers.