What is Addison's disease (Adrenal insufficiency)?

From the Guidelines

Addison's disease should be treated with hormone replacement therapy, typically with oral hydrocortisone (15-25 mg daily, divided into 2-3 doses) to replace cortisol, and sometimes fludrocortisone (50-200 µg daily) to replace aldosterone, as recommended by the consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency 1. The diagnosis of primary adrenal insufficiency (PAI) should be considered in all patients presenting with unexplained collapse, hypotension, vomiting or diarrhoea, and the diagnostic test for primary PAI should be paired measurement of serum cortisol and plasma ACTH 1. The aetiology of PAI should be ascertained starting with the measurement of serum 21-hydroxylase (anti-adrenal) autoantibodies, and if antibodies are negative, CT imaging is recommended 1. Patients with PAI should wear Medic Alert identification jewellery and carry a steroid/alert card, and receive sufficient education to manage daily medications and situations of minor to moderate concurrent illnesses 1. The lowest dose of hydrocortisone compatible with health and a sense of well-being should be used, and most patients with primary adrenal insufficiency should take 15–25 mg of HC daily in split doses, with the first dose immediately after waking, and the last dose not <6 h before bedtime 1. Adrenal crisis should be treated immediately with iv or im HC, 100 mg followed by 100 mg 6–8 hourly until recovered, and isotonic (0.9%) sodium chloride solution should usually be administered, at an initial rate of 1 L h1 until haemodynamic improvement 1. Regular monitoring with blood tests and clinical evaluations is essential to adjust medication doses, and patients should be reviewed at least annually, with assessment of health and well-being, measurement of weight, blood pressure and serum electrolytes 1. In addition to patient weight, fine-tuning of the daily HC dosage may be achieved by detailed questioning about the daily intake of tablets, general feelings of energy and ‘get up and go’, mental concentration, daytime somnolence and changes in pigmentation, as well as information about low points or dips in energy during the day and knowledge of the time a patient goes to bed and ease in getting to sleep 1. The preferred choice of glucocorticoid treatment is HC or cortisone acetate (CA), and both HC and CA are taken in two or three divided doses, with the first dose upon awakening and the last dose approximately 4–6 h before bedtime 1. CYP3A4 is the key drug metabolizing enzyme affecting HC clearance, and concomitant administration of several drugs can affect HC efficacy, as shown in Table 4 1. Plasma ACTH and serum cortisol are not useful parameters for glucocorticoid dose adjustment, and monitoring of glucocorticoid replacement predominantly relies on clinical assessment 1. Symptoms and signs of over-replacement are weight gain, insomnia and peripheral oedema, whilst under-replacement is characterized by lethargy, nausea, poor appetite, weight loss and increased pigmentation that often has an uneven distribution 1. In cases in which malabsorption is suspected, serum or salivary cortisol day curve monitoring may be useful to guide dosing, and a morning, postdose peak level and trough predose levels for subsequent dosages are the most useful in adjusting dose timings and quantities 1.

From the FDA Drug Label

In Addison’s disease, the combination of fludrocortisone acetate tablets with a glucocorticoid such as hydrocortisone or cortisone provides substitution therapy approximating normal adrenal activity with minimal risks of unwanted effects. The usual dose is 0.1 mg of fludrocortisone acetate tablets daily, although dosage ranging from 0.1 mg three times a week to 0. 2 mg daily has been employed. Fludrocortisone acetate tablets are preferably administered in conjunction with cortisone (10 mg to 37. 5 mg daily in divided doses) or hydrocortisone (10 mg to 30 mg daily in divided doses). Fludrocortisone acetate tablets, 0.1 mg are indicated as partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison’s disease

Addison's Disease Treatment:

• The recommended treatment for Addison's disease is a combination of fludrocortisone acetate tablets and a glucocorticoid, such as hydrocortisone or cortisone.
• The usual dose of fludrocortisone acetate tablets is 0.1 mg daily, with a range of 0.1 mg three times a week to 0.2 mg daily.
• Fludrocortisone acetate tablets should be administered in conjunction with cortisone (10 mg to 37.5 mg daily) or hydrocortisone (10 mg to 30 mg daily) 2, 2.

From the Research

Definition and Symptoms of Addison's Disease

• Addison's disease, also known as primary adrenal insufficiency, is a condition where the adrenal glands do not produce enough glucocorticoid and mineralocorticoid hormones 3.
• Symptoms of Addison's disease include orthostatic hypotension, fever, and hypoglycemia in acute cases, and malaise, anorexia, diarrhea, weight loss, joint and back pain in chronic cases 3.
• Cutaneous manifestations of Addison's disease include darkening of the skin, especially in sun-exposed areas, and hyperpigmentation of the palmar creases, frictional surfaces, and oral mucosa 3.

Diagnosis of Addison's Disease

• Measurement of basal plasma cortisol is an insensitive screening test for Addison's disease 3.
• Synthetic adrenocorticotropin 1-24 can be used as a dynamic test to diagnose Addison's disease 3.
• Elevated plasma levels of adrenocorticotropin and renin confirm the diagnosis of Addison's disease 3.

Treatment of Addison's Disease

• Treatment of Addison's disease involves replacement of the deficient hormones, including glucocorticoids and mineralocorticoids 4, 5, 3.
• Patients with Addison's disease require mineralocorticoid replacement, typically with fludrocortisone 0.05-0.20 mg once daily 4.
• Starting doses of glucocorticoids should be 15-20 mg for hydrocortisone or 20-30 mg for cortisone acetate, divided into two or three doses, and preferentially weight-adjusted 4.
• New treatment modalities, such as timed-release hydrocortisone tablets and continuous subcutaneous hydrocortisone infusion, offer the potential for closer simulation of the physiological serum cortisol rhythm 4, 5.

Management and Quality of Life

• Optimum steroid replacement and patient education are vital for good quality of life and to prevent acute adrenal crisis in Addison's disease 6.
• Patients with Addison's disease may require adjustments to their treatment regimen to achieve adequate sodium and water balance, and to prevent undertreatment with fludrocortisone 7.
• Some patients with Addison's disease may benefit from replacement with the adrenal androgen dehydroepiandrosterone (DHEA) or testosterone, although this remains to be shown 4.