P&C 41-What is Addison’s Disease?
Addison’s disease, also known as primary adrenal insufficiency or hypocortisolism, is
a rare disorder characterized by the inadequate production of hormones by the
adrenal glands.
Epidemiology
It is estimated to affect 39-60 individuals per million population per year in Western
countries. The condition can occur at any age but is most commonly diagnosed in
individuals aged 30-50 years.
Risk Factors and Etiology
Genetic Factors: Addison’s disease has a genetic component, with certain gene
mutations increasing the risk of developing the condition. Mutations in genes such
as NR0B1 (DAX-1), MC2R (melanocortin 2 receptor), and STAR (steroidogenic acute
regulatory protein) have been linked to familial forms of the disease. Individuals
with a family history of autoimmune disorders or adrenal insufficiency are at a
higher risk of developing Addison’s disease.
Autoimmune Factors: The most common cause of Addison’s disease is autoimmune
adrenalitis, where the body’s immune system mistakenly attacks and destroys the
adrenal cortex. Autoimmune diseases such as type 1 diabetes, thyroid disorders
(Hashimoto’s thyroiditis), and vitiligo are often associated with an increased risk of
developing autoimmune Addison’s disease.
Infectious Factors: Certain infections can trigger or contribute to the development of
Addison’s disease. Tuberculosis is one of the most well-known infectious causes of
adrenal insufficiency, as the bacteria Mycobacterium tuberculosis can infect the
adrenal glands and impair their function. Other infections such as HIV/AIDS and
fungal (i.e. histoplasmosis) infections may also increase the risk of developing
adrenal insufficiency.
Other Risk Factors: Other factors that may increase the risk of Addison’s disease
include previous surgery involving the adrenal glands, certain medications like
corticosteroids and prolonged use of exogenous glucocorticoids for conditions like
asthma or rheumatoid arthritis can suppress adrenal function (via the HPA Axis)
resulting in secondary adrenal insufficiency. Rare conditions such as
adrenoleukodystrophy or amyloidosis that affect the adrenal glands. Metastatic
cancer spreading to the adrenal glands, haemorrhage into the adrenal glands (e.g.,
Waterhouse-Friderichsen syndrome).
Hormonal Imbalance: Hormonal imbalances in conditions such as congenital adrenal
hyperplasia or pituitary disorders can also predispose individuals to developing
Addison’s disease due to disruptions in the normal functioning of the hypothalamic-
pituitary-adrenal axis.
Pathophysiology
Mineralocorticoid deficiency leads to increased excretion of sodium and decreased
excretion of potassium, resulting in hyponatremia (low serum sodium levels) and
hyperkalemia (high serum potassium levels). This imbalance causes severe
dehydration, plasma hypertonicity, acidosis, decreased circulatory volume,
hypotension, and eventually circulatory collapse. However, when adrenal
insufficiency is due to inadequate adrenocorticotropic hormone (ACTH) production
(secondary adrenal insufficiency), electrolyte levels are often normal or only mildly
affected.
Glucocorticoid deficiency contributes to hypotension and causes severe insulin
sensitivity along with disturbances in carbohydrate, fat, and protein metabolism.
Without sufficient cortisol, there is a lack of carbohydrate formation from protein
leading to hypoglycaemia and reduced liver glycogen stores. This can result in
weakness due to deficient neuromuscular function. Furthermore, resistance to
infection, trauma, and stress decreases. Myocardial weakness and dehydration can
reduce cardiac output potentially leading to circulatory failure.
A decrease in blood cortisol levels triggers increased pituitary ACTH production and
elevated blood beta-lipotropin levels. Beta-lipotropin has melanocyte-stimulating
activity which stimulates melanocytes to produce more melanin; contributing to the
hyperpigmentation of the skin and mucous membranes characteristic of Addison’s
disease.
Signs and Symptoms
Chronic fatigue
Muscle weakness
Loss of appetite
Weight loss
Abdominal pain
Nausea
Vomiting
Diarrhoea
Low blood pressure that drops further upon standing, leading to dizziness or
fainting
Irritability and depression
Joint pain
Craving salty foods
Hypoglycaemia (low blood glucose)
Irregular or absent menstrual periods in females
Low libido
Hyperpigmentation, which is most noticeable on scars, skin folds, pressure
points like elbows and knees, areolae and mucous membranes (lips, mouth,
rectum or vagina).
Diagnosis
i. Clinical Evaluation: involves a thorough medical history and physical
examination; where patients may present with symptoms such as fatigue,
weight loss, low blood pressure, salt cravings, hyperpigmentation of the skin,
and gastrointestinal disturbances.
ii. Laboratory Tests: Blood tests are essential for confirming the diagnosis of
Addison’s disease. These tests typically include measurement of serum
cortisol levels, adrenocorticotropic hormone (ACTH) levels, electrolytes (such
as sodium and potassium), and renin levels.
Blood Chemistry
TEST RESULTS
Serum sodium 135 mmol/L
Serum potassium >5 mmol/L
Ratio of serum to 30:1
potassium
Plasma glucose fasting 50 mg/dL (2.8 mmol/L)
Plasma bicarbonate 15-20 mmol/L
BUN >20 mg/dL (>7 mmol/L)
Haematology
TEST RESULTS
Haematocrit Elevated
WBC Low
Lymphocytes Relative lymphocytosis
Eosinophils Increased
Confirmatory Serum Testing
TEST RESULTS
Plasma ACTH High (≥11 pmol/L)
Serum cortisol Low (138 nmol/L)
ACTH stimulation test Subnormal (30 minute
cortisol 414 – 497 nmol/L)
Prolonged 24-hr ACTH Cortisol normal at 1hr and
stimulation test should not rise further at
24hrs
iii. Imaging Studies: CT or MRI of the adrenal glands may be performed to assess
their size and morphology. In some cases, imaging studies can help identify
structural abnormalities in the adrenal glands that may be indicative of
underlying causes of adrenal insufficiency, such as tumors or infections.
- Calcification in adrenal area
- Haemorrhage
- Atrophy
Treatment
a. Hormone Replacement Therapy
o Glucocorticoids (cortisol replacement)
Hydrocortisone
Prednisone
Dexamethasone
o Mineralocorticoids (aldosterone replacement)
Fludrocortisone
b. Dietary Modifications
o Maintain electrolyte balance
Rich-salt diet
c. Other symptom treatment
o Libido improvement
Dehydroepiandrosterone/DHEA
Additional Information: Adrenal Crisis
Adrenal crisis is a life-threatening condition that occurs when there is not enough
cortisol. This condition can be caused by various factors such as damage to the
adrenal glands, pituitary injury, inadequate treatment of adrenal insufficiency,
sudden cessation of glucocorticoid medications, dehydration, infections, or physical
stress. Symptoms of an adrenal crisis may include abdominal pain, confusion,
dehydration, dizziness, fatigue, high fever, low blood pressure, nausea, rapid heart
rate, and unusual sweating.
Tests that may be conducted to diagnose acute adrenal crisis include ACTH
stimulation test, cortisol level test, blood sugar test, potassium level test, sodium
level test, blood pH level test, and thyroid hormone level test. Treatment for adrenal
crisis is considered a medical emergency and involves administering hydrocortisone
immediately through a vein or muscle. Intravenous fluids may also be given if the
individual has low blood pressure.
REFERENCES
Stewart PM, Krone NP. “The Adrenal Cortex.” In: Melmed S, Polonsky KS, Larsen PR,
Kronenberg HM (eds). Williams Textbook of Endocrinology. 13 th ed., Elsevier; 2016.
Ten S, New M., Maclaren N.. “Clinical Review 130: Addison’s Disease 2001.” The
Journal Of Clinical Endocrinology & Metabolism [Internet]. Oxford University Press;
2001.
Addison Disease – Endocrine and Metabolic Disorders [Internet]. MSD Manual
Professional Edition. Available from:
https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/
adrenal-disorders/addison-disease
