Addison’s Disease (Primary Adrenal Insufficiency)

Introduction

Addison’s disease is the traditional term for primary adrenal insufficiency. It involves a defective adrenal cortex, which manifests as an impairment in the synthesis and release of glucocorticoids and mineralocorticoids.¹

This can present insidiously or acutely as an Addisonian crisis requiring immediate medical attention. Worldwide, it’s quite rare, with a prevalence of about 100 people per million, with over 90% of patients being female.²

Aetiology

In 75-90% of cases in Europe, Addison’s disease is caused by autoimmunity, often with antibodies against 21-hydroxylase.²

Other less common causes include:^2,3

• Infections like tuberculosis and CMV
• Vascular issues like an adrenal haemorrhage or VTE
• Short-term steroid use
• Trauma
• Adrenal tumours
• Surgery, adrenalectomy
• Congenital Adrenal Hyperplasia (CAH): the most common inherited form of PAI
• Other drugs affecting adrenal steroid synthesis such as ketoconazole, rifampicin, phenytoin

Pathophysiology

In Addison’s disease, there is a lack of adrenal hormones (glucocorticoids, mineralocorticoids, androgens) due to a failure in the adrenal cortex’s three layers – the glomerulosa, fasciculata, and reticularis.³ This is opposed to secondary and tertiary causes of adrenal insufficiency, which would be caused by pituitary or hypothalamic disorders, respectively.

In Addison’s, this decrease in steroid release will provide feedback to the pituitary within the hypothalamus-pituitary-adrenal axis, thus stimulating adrenocorticotrophic hormone (ACTH) release.

As steroids are key managers of both electrolyte homeostasis and the body’s energy balance, Addison’s can be a very severe disease and may result in an acute and potentially life-threatening state of adrenal insufficiency known as an Addisonian crisis.^{4, 5}

Risk factors

Strong risk factors for Addison’s disease include female sex (90% of Addison’s disease patients are female) and other endocrine autoimmune disorders, including autoimmune thyroid disease, type 1 diabetes mellitus, coeliac disease, vitiligo and autoimmune polyglandular syndromes.^{6, 7}

Other significant risk factors include:⁶

• The presence of adrenocortical antibodies
• Thromboembolic or hypercoagulable states like sepsis (causing adrenal haemorrhage)

Clinical features

History

Addison’s disease can present with very vague signs and symptoms, but it is still important to take a thorough and relevant history to avoid misuse of diagnostic investigations.

Symptoms due to hypocortisolism include:^{8, 9}

• Fatigue which increases throughout the day
• Weakness, including muscle weakness, myalgia, arthralgia
• Unintentional weight loss
• Anorexia

Symptoms due to hypoandrogenism include:¹⁰

• Loss of libido
• Loss of sexual function

Symptoms due to hypoaldosteronism include:¹¹

• Nausea and vomiting
• Salt craving
• Dizziness
• Abdominal pain

It is important to also screen for risk factors and causes of Addison’s disease on history, such as known endocrine conditions or recent infectious illnesses like TB. It is also important to take a thorough drug history.

Clinical examination

Due to increased ACTH causing increased melanocortin receptor activation:¹²

• Mucosal and cutaneous hyperpigmentation: more noticeable in sun-exposed areas, skin creases, mucosal membranes, scars.

Due to hypocortisolism:⁹

• Low BMI due to significant unintentional weight loss

Due to hypoaldosteronism:⁹

• Orthostatic hypotension
• Tachycardia

Due to hypoandrogenism in premenopausal women:⁹

• Loss of axillary and pubic hair

Due to other commonly associated endocrine disorders:¹¹

• A goitre and loss of hair: indicative of Hashimoto’s thyroiditis
• Vitiligo
• Dermatitis herpetiformis (indicative of coeliac disease)

Differential diagnoses

Differential diagnoses to consider in the context of suspected Addison’s disease include:⁸

• Secondary/tertiary adrenal insufficiency: would not appear with hyperpigmentation
• Haemochromatosis: due to hyperpigmentation and fatigue, weakness
• Hyperthyroidism: due to weight loss and fatigue
• Anorexia nervosa: due to weight loss

Investigations

Bedside investigations

Relevant bedside investigations include:^{13, 14}

• Blood glucose levels: which may show hypoglycaemia
• ECG: may have signs of hyperkalaemia including peaked T waves and widened QRS complexes
• VBG: may show metabolic acidosis in response to the hyperkalaemia caused by decreased aldosterone secretion

Laboratory investigations

Lab investigations are mostly aimed at evaluating the function of the hypothalamus-pituitary-adrenal axis and adrenal gland by measuring the hormone which stimulates it – ACTH, and the hormones it secretes – cortisol, aldosterone, DHEA, and DHEA-S.

General investigations

Initial, general investigations would include: ⁸

• Full blood count: in Addison’s disease, low glucocorticoid and mineralocorticoid can lead to anaemia, eosinophilia and lymphocytosis
• Urea & electrolytes: patients with Addison’s disease will often have hyperkalaemia and hyponatraemia due to low mineralocorticoid levels. Hypercalcaemia can seldom occur in Addison’s disease. Volume depletion in an Addisonian crisis may cause elevated blood urea and creatinine levels.
• Morning serum cortisol: Basal serum cortisol levels should be low in Addison’s disease (in accordance to local reference ranges). This is the most important investigation to order, as it can exclude Addison’s disease or identify patients in which further testing with ACTH stimulation is necessary.¹²
• Random serum cortisol: for acutely ill patients in a suspected Addisonian crisis, it is important to note that the clinician should not wait for a morning serum cortisol.²

Confirming the diagnosis

Investigations to confirm a diagnosis of Addison’s disease:

• Plasma ACTH: A low serum cortisol with an elevated plasma ACTH hormone level indicates Addison’s disease as it suggests a primary insufficiency of the adrenal gland.⁸ On the other hand, if there is a low serum cortisol accompanied by a normal or low ACTH level, this would suggest a secondary cause of adrenal insufficiency.¹⁵
• ACTH stimulation test (Synacthen test): This is used to establish a diagnosis of Addison’s disease in patients who are suspected to have Addison’s disease but may have normal cortisol levels.^{2, 3} In this test, exogenous ACTH is given to a patient before measuring their cortisol levels. If cortisol levels remain low, this indicates that the adrenal cortex is unresponsive to stimulation thus affirming a diagnosis of Addison’s disease. If cortisol levels increase to above the normal range, this can exclude the diagnosis of Addison’s disease.

Other investigations used to confirm Addison’s if still necessary:

• DHEA and DHEA-S: these are androgens which are normally secreted by the adrenal cortex. In Addison’s disease, these levels would be low. These are typically only measured if previous cortisol and ACTH testing were indeterminate.³
• Aldosterone and renin: in a patient with Addison’s disease, there should be lowered aldosterone levels because of deficient mineralocorticoid synthesis.^{3, 16} This should lead to increased renin because of the feedback mechanism within the renin-aldosterone-angiotensin axis. Renin will be increased, but not as significantly, in secondary adrenal insufficiency.¹⁶

Determining the aetiology

Investigations used to determine aetiology after Addison’s is confirmed:

• Autoimmune antibodies: antibodies which destroy the enzyme 21-hydroxylase are often associated with Addison’s disease and can be tested for, although they are not required to make a diagnosis.¹⁷
• Adrenal CT/MRI: these can be useful to help determine the cause of adrenal insufficiency. For example, patients with autoimmune Addison’s disease may have normal or small adrenal glands suggestive of atrophy whereas enlarged adrenal glands may suggest infectious, haemorrhagic, or malignant causes.¹⁸

Management

Addison’s disease is managed through patient education and monitoring, with often lifelong hormone replacement therapy to prevent an Addisonian crisis.

Long term management

Patients with known or suspected adrenal insufficiency should be counselled about the effects of their diagnosis and the importance of hormone replacement. This includes learning to recognise when to come into hospital, and having a ‘sick day’ plan which states when and how to inject extra glucocorticoid for emergencies. Patients should also be provided with a medical bracelet which warns of their condition.¹⁵

First line treatment is oral hydrocortisone and fludrocortisone to replace glucocorticoids and mineralocorticoids respectively.¹² Women who still suffer from low libido and decreased sexual function despite optimised therapy can trial DHEA replacement.⁹

In times of ‘stress’ when a patient with Addison’s disease is suffering from trauma, surgery, or infection, glucocorticoid doses must increase.¹⁹  This compensates for the absence of the body’s usual reaction to physiologically increase cortisol levels in times of stress.

Usually, small stressors such as a minor procedure or flu-like illness require their dose to be doubled until the stressor resolves.¹²

Severe stressors like an acute illness or major trauma require a parenteral dose of hydrocortisone followed by fluid resuscitation and continuous hydrocortisone treatment for 24 hours.¹²

Acute management

An Addisonian crisis is life-threatening and requires an ABCDE approach. If a patient presents with shock, nausea, vomiting and acute abdomen symptoms, they should be immediately treated with IV hydrocortisone.^{1, 12}

To treat the patient’s hypotension and fluid/electrolyte imbalance, 1L of saline should be administered immediately with further fluids in the next 24 hours in conjunction with close electrolyte and glucose monitoring.^{8, 21}

5% dextrose as a supplement to normal saline can be administered for a patient with hypoglycaemia, but it is important to note that this might exacerbate hyponatraemia.⁸

Once the patient is stable enough, investigate and treat the cause. Patients can then return to oral hormone replacement therapy.

Complications

The most important and common complications of Addison’s disease are usually caused by long-term treatment with exogenous glucocorticoids and mineralocorticoids.²⁰

Cushing’s syndrome secondary to exogenous steroids

Glucocorticoid overreplacement can result in high cortisol and Cushing’s syndrome. This would occur over a long period of time and becomes more likely the higher the dose of steroid being given.^20,21

Its presentation can be remembered with the mnemonic CUSHINGOID. If this happens, the dose of glucocorticoid should be tapered off.

• Cataracts
• Ulcers
• Striae/skin thinning
• Hypertension/hirsutism/hyperglycaemia
• Infections
• Necrosis (of the femoral head)
• Glucose elevation
• Osteoporosis/obesity
• Immunosuppression
• Depression/diabetes

Hypertension and hypokalaemia can be caused by exogenous mineralocorticoid overreplacement. The timeframe for this occurring is variable.⁸ Having high mineralocorticoid levels causes the kidneys to retain more sodium (and water) causing hypertension, and lose potassium causing hypokalaemia.

Monitoring should continue for other commonly associated autoimmune conditions. As stated above, autoimmune thyroid disease, type 1 diabetes, especially occur together, which is called autoimmune polyglandular syndrome type 2.⁷

Key points

• Addison’s disease is a primary adrenal insufficiency resulting in deficient glucocorticoid, mineralocorticoid, and androgen secretion
• It is most commonly due to autoimmunity and is rare, with >90% of patients being women
• It has very vague features, including fatigue, weakness, orthostatic hypotension and bradycardia, abdominal pain and weight loss
• A more specific feature is hyperpigmentation, especially in areas of friction like skin folds and creases
• It is screened for with serum cortisol levels and is usually confirmed by also measuring ACTH.
• Patients are generally treated with glucocorticoid/mineralocorticoid replacement which is increased with stressors long-term, and IV hydrocortisone if in an acute Addisonian crisis
• Monitor for overtreatment leading to Cushing’s, or hypertension and hypernatraemia.

Editor

Dr Chris Jefferies

References

1. Barthel A, Benker G, Berens K, et al. An Update on Addison’s Disease. 2019. Available from: [LINK]
2. Betterle C, Presotto F, Furmaniak J. Epidemiology, pathogenesis, and diagnosis of Addison’s disease in adults. Available from: [LINK]
3. Hahner S, Ross RJ, Arlt W, et al. Adrenal insufficiency. Nat Rev Dis Primers. 2021;7(1):19. Published 2021 Mar 11. Available from: [LINK]
4. Elshimy G, Chippa V, Kaur J, Jeong JM. Adrenal Crisis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; September 13, 2023. Available from: [LINK]
5. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. 2014. Available from: [LINK]
6. Shekhda KM, Chua KLA, Rathore A, Ojewuyi T. Bilateral Adrenal Haemorrhages Presenting as Adrenal Insufficiency. Chonnam Med J. 2021;57(2):152-153. 
7. Majeroni BA, Patel P. Autoimmune polyglandular syndrome, type II. 2007. Available from: [LINK]
8. BMJ Best Practice. Primary Adrenal Insufficiency. Available from: [LINK]
9. Husebye ES, Pearce SH, Krone NP, Kämpe O. Adrenal insufficiency. 2021. Available from: [LINK]
10. Erichsen MM, Husebye ES, Michelsen TM, Dahl AA, Løvås K. Sexuality and fertility in women with Addison’s disease. 2010. Available from: [LINK]
11. Munir S, Quintanilla Rodriguez BS, Waseem M. Addison Disease. [Updated 2024 Jan 30]. Available from: [LINK]
12. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. 2016. Available from: [LINK]
13. Lee SC, Baranowski ES, Sakremath R, Saraff V, Mohamed Z. Hypoglycaemia in adrenal insufficiency. 2023. Available from: [LINK]
14. Wrenn KD, Slovis CM, Slovis BS. The ability of physicians to predict hyperkalemia from the ECG. 1991. Available from: [LINK]
15. UpToDate. Diagnosis of Adrenal Insufficiency in Adults. Available from: [LINK]
16. Nieman LK, Chanco Turner ML. Addison’s disease. 2006. Available from: [LINK]
17. Saverino S, Falorni A. Autoimmune Addison’s disease. 2020. Available from: [LINK]
18. Alshahrani MA, Bin Saeedan M, Alkhunaizan T, Aljohani IM, Azzumeea FM. Bilateral adrenal abnormalities: imaging review of different entities. 2019. Available from: [LINK]
19. Arlt W; Society for Endocrinology Clinical Committee. Emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients. 2016. Available from: [LINK]
20. Betterle C, Morlin L. Autoimmune Addison’s disease. 2011. Available from: [LINK]
21. Nowotny H, Ahmed SF, Bensing S, et al. Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis. 2021. Available from: [LINK]