Prevalence of Addison Disease in Western Countries Has Been Estimated to Be at 35-60 Cases Per Million Persons
However, Studies Suggest that the Prevalence May Be as High as 144 Cases Per Million Persons (Postgrad Med J, 1997) [MEDLINE] (J Clin Endocrinol Metab, 1999) [MEDLINE] (J Clin Endocrinol Metab, 2009) [MEDLINE]
In the Moderan Era, Autoimmune Adrenalitis Accounts for 70-90% of Primary Adrenal Insufficiency Cases (Clin Endocrinol Metab, 1972) [MEDLINE] (Postgrad Med J, 1991) [MEDLINE] (Clin Endocrinol-Oxf, 1992) [MEDLINE] (J Autoimmun, 1995) [MEDLINE] (Ann Endocrinol-Paris, 2017) [MEDLINE]
Physiology
Hyponatremia and Hyperkalemia in Primary Adrenal Insufficiency
In Primary Adrenal Insufficiency, Decreased Cortisol and Aldosterone Secretion Result in Hyponatremia and Hyperkalemia
Hypoaldosteronism Causes Hyperkalemia (and Mild Metabolic Acidosis), Since One of the Major Functions of Aldosterone is to Increase Urinary Potassium Secretion
Hypoaldosteronism (Which May Be Severe in the Setting of in Primary Adrenal Insufficiency) Causes Renal Sodium Wasting (and Possibly Hypotension and Adrenal Crisis)
In Contrast, Sodium Wasting is Not Typically Prominent in Adults with Isolated Hурοаldοѕterοոism
Probably Because Aldosterone Secretion is Only Modestly Decreased
Although Aldosterone Normally Enhances Sodium Reabsorption, Other Sodium-Retaining Factors (Such as Angiotensin II and Norepinephrine) May Be Able to Compensate for the Hypoaldosteronism
Incidence of Hyponatremia in Adrenal Insufficiency
Ηурοոatremia is Most Frequently Seen with Primary Adrenal Insufficiency
In a Large Series of Patients with Autoimmune Primary Adrenal Insufficiency, 84% Had a Serum Sodium <137 mEq/L (J Intern Med, 2018) [MEDLINE]
Ηурοոatremiа Can Also Occur with ACTH Deficiency (Secondary or Tertiary Adrenal Insufficiency), But it is Less Common (NEJM, 1989) [MEDLINE] (Eur J Endocrinol, 2003) [MEDLINE] (J Endocrinol Invest, 2005) [MEDLINE]
In the Latter Setting, Both the general preservation of aldosterone release and the generally less prominent reduction in cortisol secretion account for the lower prevalence of hурοոаtremia
Mechanisms by Which Primary Adrenal Insufficiency Causes Hyponatremia
Cortisol Deficiency Increases Antidiuretic Hormone (ΑDН) Release, Which Results in Water Retention
Cortisol Deficiency Decreases Systemic Blood Pressure and Decreases Cardiac Output (the Latter, by an Unknown Mechanism), Resulting in ADH Secretion
Cortisol Deficiency Causes Increased Hypothalamic Secretion of Corticotropin-Releasing Hormone (CRΗ), Which is an ADH Secretagogue
Therefore, ADΗ Levels Increase When Plasma Cortisol Levels are Low
Glucocorticoid Deficiency Decreases Renal Free Water Clearance
Animal models suggest that glucocorticoid deficiency can result in impaired urinary diluting ability and increased distal tubular water permeability
At the molecular level, glucocorticoid deficiency results in increased expression and phosphorylation of the vasopressin-sensitive water channel aquaporin 2 (AQP2) in the collecting duct
Hypoaldosteronism Increases ADH Release
Results in Renal Salt Wasting, Culminating in Volume Depletion
Hypovolemia increases ADΗ levels by reducing the osmotic threshold for ADH release from the hypothalamus and increasing the magnitude of ADН release for a given change in plasma osmolality
Mechanisms by Which Primary Adrenal Insufficiency Causes Hyperkalemia
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Alteration of Cortisol Synthesis/Metabolism in the Setting of Critical Illness (also see Sepsis)
General Comments
Hypercortisolemia in Critical Illness is Proportionate to the Severity of Illness (see Hypercortisolemia)
Clinical Data
Belgian Study of the Features of Adrenal Dysfunction in the Setting of Critical Illness (NEJM, 2013) [MEDLINE]
Critical Illness Resulted in an 83% Increase in Cortisol Synthesis, as Compared to Controls
Critical Illness Also Results in Decreased Expression/Activity of Cortisol-Metabolizing Enzymes, Resulting in Decreased Cortisol Degradation
These Two Factors Result in Hypercortisolemia (with Elevated Total and Free Cortisol)
Hypercortisolemia Then Subsequently Suppresses Corticotropin Release
Implications
Stress Dose Steroids (Hydrocortisone 200 mg qday) Which are Given in the Setting of Critical Illness with Presumed Adrenal Failure are at Least 3x Too High (J Clin Endocrinol Metab, 2006) [MEDLINE]
Low Cortisol response to corticotropin stimulation does not necessarily reflect adrenal failure, since cortisol production in critically ill patients is not subnormal and the suppressed clearance maintains hypercortisolemia
Diagnosis
Cortrosyn Stimulation Test
Performed at any time of day/can be performed at least 24 hrs after HC dose, but not after prednisone dose
Baseline Cortisol -> Cortrosyn 250 ug IV (25 U) -> Cortisol 1hr later
Normal Response: Cortisol >18 µg/dL (Surviving Sepsis Campaign and Am Coll Crit Care Med suggest adequacy with increment >9 µg/dL)
Depressed responses may be seen in critically ill patients
Clinical Syndromes
Primary Adrenal Insufficiency Syndromes: manifest signs of both glucocorticoid deficiency + mineralocorticoid deficiency
Manifests adrenal androgen deficiency
Skin Findings: hyperpigmentation is characteristic of primary adrenal insufficiency (due to excess ACTH stimulation of melanocytes)
Acute adrenal insufficiency is more common in primary adrenal insufficiency (due to loss of both glucocorticoids + mineralocorticoids)
Secondary Adrenal Insufficiency Syndromes: manifest signs of only glucorticoid deficiency (since the adrenal gland itself is intact and capable of responding to stimulation from the renin-angiotensin-aldosterone axis)
Manifests adrenal androgen deficiency
Skin Findings: alabaster-like paleness of skin (due to lack of ACTH stimulation of melanocytes)
In cases with hypotahalamic-pituitary disease, patients may also manifest clinical signs associated with other endocrine axes (thyroid, gonadal, growth hormone, prolactin) or visual impairment due to pituitary tumor compressing the optic chiasm
Exogenous Glucocorticoid Administration Syndrome
Patients present with manifestions of glucocorticoid deficiency (if glucocorticoids are discontinued abruptly) + Cushingoid appearance (due to prior exposure to glucocorticoids)
2006 Cochrane review: in relative adrenal insufficiency, if used for at least 5 days (with at least 200 mg/day), there is a 20% decrease in mortality (with no increased risk of superinfection, GI bleeding, or hyperglycemia)
Fludrocortisone (Florinef): 50 ug PO QD
2002 JAMA study (Annane, et al): Fludro+HC had lower 28-day mortality than HC alone
However, randomized trial is needed to determine if fludro is necessary
2008 Surviving Sepsis Guidelines
Use Hydrocortisone (<300 mg qday) for septic shock, only if unresponsive to fluids/pressors
Don’t use cort stim testing to determine who should get steroids (unless another reason to suspect adrenal insufficiency exists)
Hydrocortisone is preferred over dexamethasone
Wean steroids with wean of pressors
Fludrocortisone is optional, if HC is used
References
Hyperreninemic hypoaldosteronism in the critically ill: a new entity. J Clin Endocrinol Metab. 1981 Oct;53(4):867-73 [MEDLINE]
Reduced cortisol metabolism during critical illness. N Engl J Med. 2013 Apr 18;368(16):1477-88. doi: 10.1056/NEJMoa1214969. Epub 2013 Mar 19 [MEDLINE]
Adrenal dysfunction in critically ill patients. N Engl J Med 2013;368(16):1547-1548 [MEDLINE]
