About 90% of the adrenal gland tissue consists of the adrenal cortex: glomerulosa (aldosterone); fasciculata (cortisol); reticularis (adrenal androgens).
Cortisol is a vital hormone involved in carbohydrate and protein metabolism and control of the immune system (dampens defense mechanisms, preventing their dangerous overactivity). It exerts negative feedback on CRH and ACTH and vasopressin. ACTH also stimulates secretion of adrenal androgen and, transiently, of aldosterone (mainly regulated by angiotensin II and [K]). 90-95% of cortisol is bound to cortisol-binding globulin. CBG is elevated by estrogen and decreased in cirrhosis, nephrotic syndrome and hyperthyroidism.
Primary adrenal
insufficiency
(Addison's disease)
Destruction of the adrenal cortex itself, resulting in deficiency of
cortisol and aldosterone. Need over 90% destruction before symptoms occur.
Autoimmune adrenalitis: The most common cause of Addison's disease (~70% of cases; prevalence 2-3 per 100,000; female predominance), caused by slow destruction of the cortex by lymphocytes, resulting in cortical atrophy. May occur in isolation, or as part of multiple autoimmune endocrinopathy, often divided into APS-I, II (considerable overlap). Autoimmune adrenalitis usually spares the medulla, but medullary epinephrine synthesis depends on high local cortisol concentrations. - Autoimmune polyglandular syndrome, type I: autosomal recessive, develops in childhood (peak incidence age 10); dx requires 2 of following: adrenal insufficiency, hypoparathyroidism, mucocutaneous candidiasis (e.g. monilia of the nails). Also see hypogonadism, T1DM (18%), chronic active hepatitis, alopecia, vitiligo, malabsorption syndromes, juvenile-onset pernicious anemia, enamel hypoplasia, nail dystrophy, keratopathy. Recessive mutation in AIRE gene (autoimmune regulator), thought to be a transcription factor. Autoantibodies: cytochrome P450 cholesterol side chain cleavage enzyme, aromatic L-amino acid decarboxylase (AADC), 17a-hydroxylase. Some Addisonian patients with anti-AADC antibodies do not meet criteria for APS-I and are clinically more similar to APS-II patients. -APS-II (Schmidt syndrome, more common, most cases are women age 20-40): adrenal insufficiency, thyroiditis (or Graves), T1DM; onset in adulthood. May also see hypogonadism, celiac disease, vitiligo, pernicious anemia, alopecia, stiff-man syndrome, and serositis. Associated with HLA-B8, HLA-DR3. Autoantigen: 21-hydroxylase (role in pathogenesis uncertain).
Tuberculosis: (increasingly rare, formerly most common cause). Adrenals often enlarged and calcified. If suspected, must give antiTB meds. Giving corticosteroids alone can encourage TB spread.
Metastatic disease: (lung, breast, kidney, pancreas, melanoma, gastric); lymphoma
Infiltration: amyloidosis, hemochromatosis, sarcoid, syphilitic gumma, scleroderma
Systemic fungal infections: (all fungi except candida; histoplasmosis (most common), cryptococcosis, coccidiomycosis, blastomycosis)
Adrenoleukodystrophy: X-linked (thus, affects more men, seen in 1 in 20,000 males) peroxisomal disorder (mutation in gene for peroxisomal membrane-transport protein) resulting in excess of very-long-chain fatty acids. See adrenal insufficiency and central nervous system demyelination. Diagnosis by measuring hexacosanoic acid, MRI. Manage with diet change (restrict saturated fats). Dietary therapy with glycerol trioleate and glycerol trierucate has had limited efficacy. Bone marrow transplantation may arrest disease progression in patients with mild nervous system involvement. Two phenotypes: -Cerebral adrenoleukodystrophy (Brown-Schilder disease): onset age 5-12 of adrenal insufficiency and central demyelination leading to seizures, cortical blindness, dementia, coma, death, usually before puberty. -Adrenomyeloneuropathy (sudanophilic leukodystrophy): age 15-30; spinal cord & peripheral neuronal involvement slowly progressing over 5-15 years; develop mixed motor & sensory peripheral neuropathy, bladder dysfunction, adrenal insufficiency, hypogonadism, color blindness. 1/3 develop central demyelination.
AIDS-associated primary adrenal insufficiency. More then 50% of AIDS patients have pathologic evidence of necrotizing adrenalitis, but usually < 50% adrenal destruction. Clinical adrenal insufficiency occurs in less than 5% of patients with AIDS. -Opportunistic infection: CMV infection (accounts for >50% of cases of adrenal insufficiency in AIDS), Mycobacterium avium complex, M.TB, fungi, Toxoplasma, Pneumocystis. -Kaposi's sarcoma -Medications: ketoconazole (inhibits adrenal steroidogenesis); rifampin, phenytoin, opiates (increased steroid catabolism) -Cytokines (IL-1, TNF, IFN) released by macrophages in patients with AIDS may inhibit the hypothalamic-pituitary-adrenal (HPA) axis.
Familial glucocorticoid deficiency: autosomal recessive; adrenal unresponsiveness to ACTH (responsiveness to AII is normal); present as child with hyperpigmentation, hypoglycemia, failure to thrive, frequent, severe infections. Associated with tall stature, advanced bone age. In some, ACTH-receptor mutated. There is also an isolated glucocorticoid deficiency syndrome.
Severe forms of congenital adrenal hyperplasia (deficiency of 21-hydroxylase, 3B-hydroxysteroid dehydrogenase, 17a-hydroxylase, 11B-hydroxylase (CYP11B1), or cholesterol desmolase) result in inability to synthesize cortisol in infants. Except for 17a-hydroxlase and 11B-hydroxylase deficiency, which lead to mineralocorticoid excess and hypertension, these conditions may also lead to severe salt wasting. CYP11B2 mutation leads to aldosterone deficiency only.
Wolman disease (a lipid storage disease resulting in hepatomegaly, malabsorption, and adrenal calcification) can lead to Addison's disease in children.
Congenital adrenal hypoplasia: rare disorder characterized by failure of development of adrenal gland. Inherited as X-linked disease, closely linked to Duchenne's muscular dystrophy locus; occasionally the two disorders occur together, along with glycerol kinase deficiency, when a single deletion encompasses the three genes.
Adrenal hemorrhage, thrombosis, infarction: seen mostly in gravely ill patients, possible etiologies: -Stress ACTH mediated increase in adrenal blood flow exceeding venous drainage -> thrombosis -> hemorrhage. -Meningococcal or other kinds of sepsis (Pseudomonas): Waterhouse-Friderichsen syndrome -Coagulation disorders or warfarin therapy -Antiphospholipid syndrome.
Secondary
adrenal insufficiency
Pituitary
or hypothalamic disease (may see involvement of other hormonal axes,
diabetes insipidus, +/- neurologic, ophthalmologic manifestations if mass
effect). Aldosterone deficiency is not a problem.
Pituitary or metastatic tumor; craniopharyngioma; hypothalamic tumors
Pituitary surgery or irradiation
Lymphocytic hypophysitis
Sarcoidosis; histiocytosis X
Infectious: TB, fungi (Nocardia, actinomycosis)
Empty sella syndrome: extension of subarachnoid space into sella via a defect in the sellar diaphragm (1/3 of these patients have endocrine dysfunction).
Long-term glucocorticoid therapy (suppression of CRH production). If a patient has been on 15 mg qd prednisone (or equivalent) for 3+ weeks, his HPA axis is suppressed for ~ 8-12 months. Divided dosing more suppressive than daily dosing. A clue to adrenal HPA axis suppression is small joint aches (hands, feet). Patients vary significantly in their sensitivity to suppression by exogenous glucocorticoids.
Isolated deficiency of ACTH: isolated deficiency of CRH.
Postpartum pituitary necrosis (Sheehan's syndrome)
Necrosis or bleeding into pituitary macroadenoma (pituitary apoplexy)
Head trauma, lesions of the pituitary stalk
Pituitary or adrenal surgery for Cushing's syndrome (transient)
Clinical
manifestations.
Have low
index of suspicion, patient may present non-specifically. Acute adrenal
insufficiency can be lethal, suspect in setting of unexplained
pressor-resistant hypotension, abdominal pain, vomiting, high fever,
confusion (note: hyponatremia and in particular hyperkalemia is not always
present; up to 40% of Addison's patients are normokalemic).
Primary and secondary adrenal insufficiency Tiredness, weakness, mental depression Anorexia, weight loss Dizziness, orthostatic hypotension1 Abdominal cramps, N/V, diarrhea Hyponatremia2 Hypoglycemia Mild normocytic anemia, lymphocytosis, eosinophilia Hypercalcemia (rare) Loss of body hair in women
Primary adrenal insuff. and associated disorders Hyperpigmentation3 Hyperkalemia Vitiligo Autoimmune thyroid disease CNS symptoms in adrenomyeloneuropathy Salt craving Acidosis (Type IV RTA) Increased taste sensitivity (to salt) Hyperacusis Torn's sign: pinna calcification
Secondary adrenal insuff. and associated disorders Pale skin without marked anemia Amenorrhea, decreased libido and potency Scanty axillary and pubic hair Small testicles Secondary hypothyroidism Prepubertal growth deficit, delayed puberty Headache, visual sx Diabetes insipidus
1. More marked in primary due to aldosterone deficiency and hypovolemia, but present in secondary due to decreased expression of vascular catecholamine receptors. 2. Cortisol deficiency causes hyponatremia because ADH is co-secreted with CRH, leading to water retention. Decreased vascular tone (cortisol sensitizes vessels to catecholamines) leading to relative hypotension also stimulates ADH. Aldosterone deficiency causes sodium wasting. 3. Due to MSH secreted with ACTH: Hyperpigmentation noted usually around the lips, buccal membranes, tongue, posterior neck, nipples, nail beds and in exposed or pressure areas (eg. knuckles, elbows, belt line). New scars (formed during Addison's) are pigmented. May also manifest as freckling. To find pigment changes in dark-skinned patient: look at palate and palmar creases.
**Laboratory evaluation of adrenal function. Cortisol measurement. Drawn 8-9 a.m., a value <= 3 ug/dl indicates adrenal insufficiency, and concentrations >= 19 ug/dl rule it out. Intermediate values necessitate dynamic testing. Remember, estrogen raises corticosteroid binding hormone concentrations, raising [cortisol]. Normal range of cortisol is 6-24 ug/dl, in an ICU patient it should be >= ~25 ug/dl.
Random cortisol: Drawn in an emergency setting (otherwise do a.m. cortisol) before giving stress dose steroids: Normal is >= 18, 14-17 is indeterminate, 5-13 is presumptive (continue treatment), and < 5 ug/dl is definite adrenal insufficiency.
ACTH measurement: helpful in primary adrenal insufficiency where [ACTH] > 100 pg/ml, even if the plasma cortisol is in the normal range. Normal ACTH values rule out primary but not mild secondary adrenal insufficiency. ACTH is the best localizing test for primary adrenal insufficiency.
Aldosterone measurement (pre and post 250 ug cosyntropin): In primary insufficiency, will be low at baseline and not change (or blunted) after stimulation test; in secondary, baseline will be low or normal, and should increase in response to cosyntropin (by >= 4 ng/dl or 2X over baseline).
Short corticotropin stimulation test: 250 ug of cosyntropin (Cortrosyn, ACTH1-24, normal ACTH has 39 a.a) is given IV (give directly IV since it sticks to IV tubing) or IM before 10 am (actually, can do test at any time of the day), and plasma cortisol measured 30-60 minutes later. Adrenal insufficiency ruled out if basal or post-stimulation cortisol is >= 18-20 ug/dl (using higher cutoff minimizes underdiagnosis, some also consider a rise >= 7 ug/dl or doubling of baseline as normal, however, increment does not distinguish normals (1/3 of normals have rise <= 7) and a higher baseline gives a lower increment). This test picks up both primary (adrenals already maximally stimulated) and secondary (adrenal cortex atrophied) insufficiency. However, in recent onset (< 2 weeks) or mild secondary insufficiency, the test may be normal, especially because 250 ug is highly supraphysiologic (5 ug injection and the ITT result in similar ACTH levels). Usually zona fasciculata atrophies by 2 weeks in absence of ACTH, but a normal cosyntropin test with an abnormal ITT has been seen 3 months after pituitary surgery.
Low-dose corticotropin test: 1 ug used instead of 250 ug. Test used to detect mild secondary adrenal insufficiency (eg. patient taking inhaled glucocorticoids). Normal response is cortisol >= 18 ug/dl.
Short metyrapone test: Metyrapone inhibits the conversion of 11-deoxycortisol (compound S) to cortisol (by 11-hydroxylase); the resultant drop in cortisol should stimulate the HPA axis. 30 mg/kg is given at midnight (with a snack, to minimize nausea), cortisol, 11-deoxycortisol, +/- ACTH measured next day 8 a.m. Normally, 11-deoxycortisol rises to >= 7 ug/dl (simultaneous cortisol < 5-8 ug/dl to insure adequate 11-hydroxylase inhibition). An insufficient increase in 11-deoxycortisol reflects the severity of ACTH deficiency. Sensitivity increased by measuring ACTH, which, in normals, should rise > 150 pg/ml. Note: Phenobarbital and phenytoin increase metyrapone metabolic clearance.
Insulin-induced hypoglycemia (insulin tolerance test, ITT), a test for secondary adrenal insufficiency since hypoglycemia stimulates the entire HPA axis. Use 0.1-0.15 U/kg insulin to obtain symptomatic (sympathetic activation) hypoglycemia (< 40 mg/dl. Glucose, cortisol, +/- ACTH are measured before and 15, 30, 45, 60, 75, and 90 minutes after insulin injection. Normal cortisol rises to 18-20 ug/dl. Considered gold standard test, but avoid in elderly, cardiovascular disease, seizure disorders.
Corticotropin-releasing hormone stimulation test may also be used and can be helpful in distinguishing ACTH deficiency from CRH deficiency.
A prolonged cosyntropin stimulation (Rose) test is used to distinguish primary vs. secondary adrenal insufficiency. [250 ug over 48 hours.]
24-hour urinary free cortisol is not used because it is normal in 20% of patients with adrenal insufficiency.
Assays for adrenal autoantibodies are available, but their use is complicated by issues of assay sensitivity and transient seropositivity. However, a high screening titer (>1:16) of adrenal autoantibodies signifies high risk for adrenal failure (6-19% per year) and calls for functional monitoring.
Replacement
therapy.
Goal is to find the lowest dose which relieves the patient's symptoms, to
prevent weight gain, osteoporosis, and cataracts. Replacement
glucocorticoid is given in early morning & afternoon. Initial dosage:
30 mg of hydrocortisone (20 mg, 10 mg) or 37.5 mg cortisone (25 mg, 12.5
mg) or 7.5 mg prednisone (5 mg, 2.5 mg; no mineralocorticoid action, more
difficult to monitor since not picked up on cortisol assay). Measuring
urinary cortisol may help dosing (controversial since only reflects excess
over CBG). This replacement regimen (12-15 mg/m2/d) may be excessive;
recent studies suggest this is double endogenous production. Giving
steroid every other day avoids axis suppression (since the axis is forced
to take over on the off days). QOD dosing helps with all side effects
except the cumulative ones: osteoporosis, cataract.
If primary adrenal insufficiency, give fludrocortisone, in a single daily dose, 50-200 ug, with adjustments per BP, serum potassium, peripheral edema, and plasma renin activity (upper-normal range).
Sex hormone replacement due to associated primary or secondary gonadal insufficiency is required in selected patients.
In women, DHEA replacement (50 mg qd) was found to raise low levels of DHEA, DHEA-S, androstenedione, and testosterone into normal range and improved scores for well-being, depression, anxiety, and sexuality. Such therapy may be considered for patients with subnormal strength and well-being, provided that they are monitored for breast or prostate cancer.
Patients should carry a card or med-alert bracelet, and should be advised to double or triple the dose of hydrocortisone temporarily when they have any febrile illness or injury, and should be given ampules of glucocorticoid for injection or glucocorticoid suppositories to be used if they are vomiting.
Patients traveling at high altitude are predisposed to crisis and should double their glucocorticoid dose.
Emergency
therapy.
Immediate
high dose IV hydrocortisone 100 mg bolus, followed by an infusion of
100-200 mg over the next 24 hours or intermittent IV dosing at 100 mg q
6-8 hours. This is enough to give mineralocorticoid action, so do not need
florinef until taper down to oral glucocorticoids (or once hydrocortisone
is < 100 mg/day).
The classic emergency dosing may be excessive. One study found no benefit (in terms of intra- or postoperative hypotension or tachycardia) of perioperative IV steroid use in patients on chronic oral steroids as long as they received their usual dose on the day of surgery.
Hypovolemia and hyponatremia: IV normal saline, volume needed may be large and should be supplemented by glucose.
References (v1.5.4)
Arlt W, Callies F, et al. Dehydroepiandrosterone replacement in women with
adrenal insufficiency. N Engl J Med 1999;341:1013-20.
Carey RM. The changing clinical spectrum of adrenal insufficiency. Ann Int
Med 1997;127:1103-4. Glowniak JV, Loriaux DL. A double-blind study of
perioperative steroid requirements in secondary adrenal insufficiency.
Surgery 1997;121:123-9. Grinspoon SK, Biller BMK. Laboratory assessment of
adrenal insufficiency. J Clin Endocrinol Metab 1994;79:923-31.
Hasinski S. Assessment of adrenal glucocorticoid function. Postgrad Med
1998;104:61-71.
Loriaux DL. Adrenocortical insufficiency. In: Becker KL, ed. Principles
and Practice of Endocrinology and Metabolism. Philadelphia: J.B.
Lippincott, 1995:682-6.
Oelkers W. Adrenal Insufficiency. N Engl J Med 1996;335:1206-11.
Soderbergh A, Rorsman F, et al. Autoantibodies against aromatic L-amino
acid decarboxylase identifies a subgroup of patients with Addison's
disease. J Clin Endocrinol Metab 2000;85:460-3. Stern N, Tuck M. The
adrenal cortex and mineralocorticoid hypertension. In: Lavin N, ed. Manual
of Endocrinology and Metabolism. Boston: Little, Brown and Co.,
1994:111-29.
White PC. Disorders of aldosterone biosynthesis and action. N Engl J Med
1994;331:250-8.
The above review is a synthesis of the papers listed in the references section. Every effort has been made to ensure accuracy, but I make no warranty regarding errors and omissions and assume no responsibility or liability for loss or damage resulting from the information contained within. For detailed information the reader should refer to the original text of the references. Use of the above information for patient care purposes is done at the discretion of the clinician.
Please email me with any comments or suggestions. Mark Goodarzi, M.D. mgoodarzi@mednet.ucla.edu
