What are the diagnostic criteria for Addison's disease (Adrenal Insufficiency)?

From the Guidelines

Addison's disease is diagnosed through a combination of clinical features, laboratory tests, and imaging studies, with diagnostic criteria including low morning cortisol levels and elevated ACTH levels, confirmed by an ACTH stimulation test, as recommended by the 2014 consensus statement on the diagnosis, treatment, and follow-up of patients with primary adrenal insufficiency 1. The diagnostic process for Addison's disease involves several key steps, including:

• Clinical evaluation for symptoms such as unexplained collapse, hypotension, vomiting, or diarrhea, with hyperpigmentation, hyponatremia, hyperkalemia, acidosis, and hypoglycemia increasing clinical suspicion of primary adrenal insufficiency (PAI) 1
• Laboratory tests, including paired measurement of serum cortisol and plasma ACTH, with a synacthen (tetracosactide) stimulated peak serum cortisol <500 nmol L1 diagnostic of PAI in equivocal cases 1
• Imaging studies, such as CT or MRI of the adrenal glands, to reveal adrenal atrophy or calcifications, and to guide further investigation for underlying causes, including tuberculosis screening, fungal infections, or metastatic disease 1
• Adrenal antibody testing to identify autoimmune etiology, which is the most common cause of Addison's disease 1
• Further investigation for underlying causes, including measurement of very long-chain fatty acids to check for adrenoleukodystrophy in males, and sequencing of the NR0B1 (DAX1) gene for X-linked conditions with PAI associated with delayed or incomplete puberty due to hypogonadotropic hypogonadism 1 The diagnosis of Addison's disease should be considered in all patients presenting with unexplained collapse, hypotension, vomiting, or diarrhea, and treatment should never be delayed by diagnostic procedures, with intravenous hydrocortisone and physiologic saline infusion administered immediately in cases of suspected acute adrenal crisis 1.

From the FDA Drug Label

Severe hypofunction of the pituitary - adrenal axis is usually associated with subnormal plasma cortisol values but a low basal level is not per se evidence of adrenal insufficiency and does not suffice to make the diagnosis. Many patients with proven insufficiency will have normal basal levels and will develop signs of insufficiency only when stressed For this reason a criterion which should be used in establishing the diagnosis is the failure to respond to adequate corticotropin stimulation. Primary adrenal insufficiency (Addison's disease) is the result of an intrinsic disease process, such as tuberculosis within the gland. The production of adrenocortical hormones is deficient despite high ACTH levels (feedback mechanism). The differentiation of both types is based on the premise that a primarily defective gland cannot be stimulated by ACTH whereas a secondarily defective gland is potentially functional and will respond to adequate stimulation with ACTH.

The diagnostic criteria for Addison's disease (Adrenal Insufficiency) include:

• Failure to respond to adequate corticotropin stimulation
• Subnormal plasma cortisol values (although a low basal level is not sufficient to make the diagnosis)
• Intrinsic disease process, such as tuberculosis within the gland
• Deficient production of adrenocortical hormones despite high ACTH levels Key points to consider when diagnosing Addison's disease include:
• A subnormal response to the CORTROSYN test
• No increase in plasma cortisol levels after a 3 or 4 day course of treatment with Repository Corticotropin Injection USP 2

From the Research

Diagnostic Criteria for Addison's Disease

The diagnostic criteria for Addison's disease, also known as primary adrenal insufficiency, involve a combination of clinical manifestations, laboratory tests, and hormone level measurements. The key diagnostic features include:

• Deficiencies in glucocorticoids, mineralocorticoids, and adrenal androgens due to autoimmune destruction of the adrenal cortex 3, 4, 5
• Clinical manifestations such as:
  • Hyperpigmentation 5, 6
  • Fatigue, anorexia, orthostasis, nausea, muscle and joint pain, and salt craving 5
  • Malaise, diarrhea, weight loss, joint, and back pain 6
  • Darkening of the skin, especially in sun-exposed areas, and hyperpigmentation of the palmar creases, frictional surfaces, vermilion border, recent scars, genital skin, and oral mucosa 6
• Laboratory tests:
  • Cosyntropin stimulation test to confirm the diagnosis 5
  • Measurement of basal plasma cortisol, although this is an insensitive screening test 6
  • Synthetic adrenocorticotropin 1-24 as a dynamic test 6
  • Elevated plasma levels of adrenocorticotropin and renin to confirm the diagnosis 6
• Hormone level measurements:
  • Decreased cortisol levels 5, 7
  • Increased adrenocorticotropic hormone levels 5, 7
  • Normal to high basal concentrations of cortisol in the presence of clearly elevated corticotropin, which can be indicative of primary adrenal insufficiency 7

Special Considerations

It is essential to note that approximately 10% of patients with primary adrenal insufficiency may present with normal cortisol concentrations, making diagnosis more challenging 7. In such cases, the presence of elevated corticotropin concentrations and autoantibodies to the adrenal cortex, along with a suggestive case history, can support the diagnosis of Addison's disease 7.