Etiology
Primary Adrenal Insufficiency
Adrenal Hemorrhage/Infarction/Loss
- Anti-Phospholipid Antibody Syndrome (see Anti-Phospholipid Antibody Syndrome, [[Anti-Phospholipid Antibody Syndrome]])
- Bilateral Adrenalectomy: after bilateral nephrectomy or in the management of Cushing syndrome
- Heparin-Induced Thrombocytopenia (HIT) (see Heparin, [[Heparin]])
- Waterhouse-Friderichsen Syndrome (Bilateral Adrenal Hemorrhage)
- Abdominal Trauma/Tumors
- Cancer
- Coagulopathy (due to heparin, etc): major risk factor
- Gastrointestinal Perforation
- Hypotension/Sepsis
- Idiopathic Spontaneous Adrenal Hemorrhage: some cases
- Intracranial Trauma/Tumors
- Major Surgery: major risk factor
- Corticosteroids (see Corticosteroids, [[Corticosteroids]])
- Syphilis (see Syphilis, [[Syphilis]])
- Thromboemboli to Adrenals: major risk factor
Autoimmune Disease
Drug
- Aminoglutethimide (Cytadren) (see Aminoglutethimide, [[Aminoglutethimide]])
- Abiraterone (Zytiga) (see Abiraterone, [[Abiraterone]])
- Pharmacology
- Inhibits CYP17A1 enzyme in testicles, adrenal glands, and prostatic cancer -> decreases circulating testosterone levels
- Produces mineralocorticoid excess -> side effects of hypokalemia/hypertension
- Etomidate (see Etomidate, [[Etomidate]]): inhibits adrenal steroidogenesis
- Heparin (see Heparin, [[Heparin]]): the latter three mechanisms below may contribute to the development of hyperkalemia, but heparin does not typically cause adrenal insufficiency (in the absence of adrenal hemorrhage or HIT)
- Potential Pharmacologic Mechanisms of Action on Adrenal Gland/Kidney
- Adrenal hemorrhage (see above under “Adrenal Hemorrhage/Infarction”)
- Decreased aldosterone synthesis
- Atrophy of the adrenocortical zona glomerulosa
- Decreased in number and affinity of aldosterone II receptors
- Ketoconazole (see Ketoconazole, [[Ketoconazole]])
- Mifepristone (RU-486) (see Mifepristone, [[Mifepristone]])
- Mitotane
- Suramin
- Trilostane
Hereditary
- Adrenal Hypoplasia Congenita (AHC)
- Adrenoleukodystrophy (ALD)/Adrenomyeloneuropathy (AMN)
- Autoimmune Polyglandular Syndrome 1 (APS1): involves the AIRE gene
- Autoimmune Polyglandular Syndrome 2 (APS2)
- Congenital Adrenal Hyperplasia (CAH)
- Congenital Lipoid Adrenal Hyperplasia (CLAH)
- Familial Glucocorticoid Deficiency
- IMAGe Syndrome
- Kearns-Sayre Syndrome
- Smith-Lemli-Opitz Syndrome
- Triple A Syndrome
Infection
Infiltration
- Adrenal Malignancy
- Adrenal Metastases
- Amyloidosis (see Amyloidosis, [[Amyloidosis]])
- Hemochromatosis (see Hemochromatosis, [[Hemochromatosis]])
- Sarcoidosis (see Sarcoidosis, [[Sarcoidosis]])
Secondary Adrenal Insufficiency
Drug-Induced Adrenal Insufficiency
- Glucocorticoid Excess (see Corticosteroids, [[Corticosteroids]]): endogenous or exogenous
Pituitary Tumors
Pituitary Metastases
Mass Affecting Hypothalamic-Pituitary Region
- Craniopharyngioma
- Ependymoma
- Meningioma (see Meningioma, [[Meningioma]])
- Metastases
Pituitary Infiltration
Other
- Autoimmune Hypophysitis
- Combined Pituitary Hormone Deficiency (CPHD)
- Congenital Isolated ACTH Deficiency
- Pituitary Apoplexy/Hemorrhage
- Sheehan’s Syndrome (Post-Partum Pituitary Necrosis)
- Pituitary Irradiation
- Proopiomelanocortin Deficiency (POMC)
Isolated Hypoaldosteronism
Isolated Adrenomedullary Insufficiency
- Adrenal Metastases
- Congenital Inherited Dysautonomia
- Surgery
- Tuberculosis (see Tuberculosis, [[Tuberculosis]])
Physiology
Features of Adrenal Dysfunction in Critical Illness [MEDLINE]
- Suppressed Expression/Activity of Cortisol-Metabolizing Enzymes, Resulting in Decreased Cortisol Degradation
- Hypercortisolemia: elevated total and free cortisol
- Corticotropin Suppression
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)
Clinical Manifestations
Symptoms/Signs of Glucocorticoid Deficiency
- Anorexia (see Anorexia, [[Anorexia]])
- Arthralgias (see Arthralgias, [[Arthralgias]])
- Fatigue/Lack of Energy (see Fatigue, [[Fatigue]])
- Fever (see Fever, [[Fever]])
- Hematologic Abnormalities
- Hypoglycemia (see Hypoglycemia, [[Hypoglycemia]]): more common in children
- Hyponatremia (see Hyponatremia, [[Hyponatremia]])
- Epidemiology: found in 80% of primary adrenal insufficiency cases at initial presentation
- Mechanism: loss of cortisol feedback inhibition of AVP release (resulting in mild SIADH)
- Hypotension/Postural Hypotension (see Hypotension, [[Hypotension]])
- Mildly Increased Thyroid Stimulating Hormone (TSH): due to loss of feedback inhibition of TSH release
- Usually normalizes within weeks after glucocorticoid replacement therapy
- Myalgias (see Myalgias, [[Myalgias]])
- Weight Loss (see Weight Loss, [[Weight Loss]])
Symptoms/Signs of Mineralcorticoid Deficiency
- Abdominal Pain (see Abdominal Pain, [[Abdominal Pain]])
- Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]])
- Hyperkalemia (see Hyperkalemia, [[Hyperkalemia]])
- Epidemiology: found in 40% of primary adrenal insufficiency cases at initial presentation
- Hyponatremia (see Hyponatremia, [[Hyponatremia]])
- Epidemiology: found in 80% of primary adrenal insufficiency cases at initial presentation
- Mechanism: primariliy caused by mineralocorticoid deficiency
- Hypotension/Postural Hypotension (see Hypotension, [[Hypotension]])
- Hypovolemia (see Hypovolemic Shock, [[Hypovolemic Shock]])
- Salt-Craving
Treatment
- Hydrocortisone: 100 mg q8 hrs
- 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]