Mark Goodarzi, M.D.
 | 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% of cortisol is bound to cortisol-binding globulin, which protects circulating cortisol from hepatic clearance. CBG is elevated 2-3 fold by estrogen and decreased in cirrhosis, severe illness, nephrotic syndrome and hyperthyroidism. CBG is saturated at a cortisol concentration of 25 µg/dL. A small amount of cortisol is bound to albumin (low affinity). |
Causes of Primary Adrenal Insufficiency
| Adrenal destruction |
Autoimmune Addison’s disease (isolated or APS)
Infection (tuberculosis, systemic mycoses, opportunistic infections)
Metastatic disease
Infiltration (amyloidosis)
Adrenoleukodystrophy
Adrenal hemorrhage
Wolman disease
Mitotane
| Adrenal dysgenesis/hypoplasia |
Congenital adrenal hypoplasia (mutation of DAX-1)
Mutation of steroidogenic factor-1 (SF-1)
Corticotropin resistance syndrome
Familial glucocorticoid deficiency
FGD Type-1: mutation of ACTH receptor
Triple A syndrome (Allgrove’s syndrome)
| Impaired steroidogenesis |
Congenital adrenal hyperplasia
Mitochondrial disorders
Kearns-Sayre syndrome
Defective cholesterol metabolism
Smith-Lemli-Opitz syndrome
Abetalipoproteinemia (not clinically significant)
Drug-induced (aminoglutethimide, etomidate, ketoconazole, metyrapone, suramin)
| Accelerated cortisol metabolism |
Thyrotoxicosis
Drug-induced (phenytoin, barbiturates, rifampin, mitotane)
I. Primary adrenal insufficiency (Addison’s disease, affects 1 in 8500 people): Destruction of the adrenal cortex itself, resulting in deficiency of cortisol and aldosterone. Need over 90% destruction before symptoms occur.
A. Adrenal destruction:
| 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. Genetic risk for autoimmune Addison’s is associated with HLA-DR3-DQ2 and with the allele 5.1 of the MHC class I chain-related A (MIC-A) gene. CTLA-4 (cytotoxic T lymphocyte antigen-4) polymorphisms have been associated with Addison’s disease. The predictive value of genetic markers for Addison’s is very low. |
-Isolated autoimmune Addison’s is thought to result from a T-cell mediated destructive process, with autoantibodies serving as a marker of the autoimmune process. Autoantibodies: adrenal cortex antibodies (ACA, by indirect immunofluorescence using cortical tissue) and 21-hydroxylase (21-OH) antibodies, rarely others. Anti 21-OH ab (the major target of ACA) are found in 80-90% of patients with clinically idiopathic Addison’s disease and in almost all subjects with disease duration < 15 years. This natural history has been proposed: 21-OH ab become positive, then ACA, then aldosterone is normal/low with elevated renin. At this point up to 50% of patients may have spontaneous remission and disappearance of antibodies. With progression the process becomes irreversible; ACTH-stimulated cortisol becomes low, then ACTH becomes elevated, and finally basal cortisol and aldosterone are low. Antibodies tend to disappear after many years, with 21-OH ab persisting longer (even to 40 years) than ACA.
-Autoimmune polyglandular syndrome, type I: autosomal recessive, develops in childhood (peak incidence age 10). Also known as APECED (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, affects 1/9,000 Iranian Jews, 1/25,000 Finnish, 1/14,500 Sardinian); dx requires 2 of following (or 1 if a relative has APS-I): adrenal insufficiency [mean age onset 12, M=F, seen in 90%], hypoparathyroidism [usually before age 10, the hypocalcemia can be masked by untreated Addison’s], mucocutaneous candidiasis [e.g. monilia of the nails & mouth, usually before age 2; due to a T cell defect]. Also see hypogonadism, T1 DM (18%), chronic active hepatitis, alopecia universalis, vitiligo, malabsorption syndromes, juvenile-onset pernicious anemia, myositis, enamel hypoplasia, nail dystrophy, keratoconjunctivitis, thyroiditis, hypophysitis. A case report suggests that the fat malabsorption seen in 20% of patients may be due to deficiency of cholecystokinin-producing enteroendocrine cells. Recessive mutation in AIRE gene (autoimmune regulator), a transcription factor. AIRE is expressed in the medulla of the thymus and may be involved in deletion of self-reactive T cells. Autoantibodies: ACA, 21-OH, 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. Autoantibodies are thought to reflect autoimmune gland destruction (normal antibody response). Pathology involves the T cells (cutaneous anergy is seen) with biased self-reactive Th2 and defective protective Th1 responses. Severe cases can thus be treated with cyclosporine to suppress T cell activity.
-APS-II is defined by Addison’s disease plus autoimmune thyroid disease (Schmidt syndrome) and/or T1DM (Carpenter’s) and is the most common syndrome associated with Addison’s [mean age onset 30]; most cases are women aged 20-40. May also see hypogonadism, celiac disease, myasthenia gravis, chronic active hepatitis, vitiligo, pernicious anemia, alopecia, stiff-man syndrome, and serositis. Interitance seems to be polygenic & associated with HLA-B8, HLA-DR3. Autoantibodies (pathogenic role uncertain): ACA, 21-hydroxylase, occasionally others. When gonadal insufficiency is present, autoantibodies to 17a -hydroxylase, P450scc are often also detected.
| Tuberculosis (10-15% of Addison’s, increasingly rare, formerly most common cause; more common worldwide). Adrenals often enlarged and calcified. If suspected, must give antiTB meds. Giving corticosteroids alone can encourage spread of TB. |
| Metastatic disease (lung, breast, kidney, pancreas, melanoma, gastric); lymphoma. Adrenal metastases are seen in up to 60% of disseminated breast or lung cancer, but many do not result in adrenal insufficiency. |
| Infiltration: amyloidosis, hemochromatosis, sarcoid, syphilitic gumma, scleroderma |
| Systemic fungal infections (all fungi except candida; histoplasmosis [most common], cryptococcosis, coccidiomycosis, blastomycosis) |
| Adrenoleukodystrophy (ALD): X-linked (thus, affects more men, seen in 1 in 20,000 males) peroxisomal disorder (mutation in gene for peroxisomal membrane-transport protein, the adrenoleukodystrophy protein, an ATP-binding cassette protein) resulting in defective b -oxidation and excess of very-long-chain fatty (> 23 carbons) acids, which accumulate in blood, lipid-rich glands (adrenal, testes), and neural tissues. See adrenal insufficiency and central nervous system demyelination. Diagnosis by measuring hexacosanoic acid, MRI (measure VLCFA in all males with Addison’s disease and no autoantibodies). Manage with diet change (restrict saturated fats). Dietary therapy with glycerol trioleate and glycerol trierucate (4:1 mixture) has had limited efficacy. Bone marrow transplantation done early may arrest disease progression in patients with mild nervous system involvement. Experimental therapies include a. lovastatin plus fenofibrate or b. butyric acid analogs to increase adrenoleukodystrophy-related protein or c. gene therapy. Four phenotypes, which can coexist in the same family (no correlation between genotype and phenotype): |
-Asymptomatic
-Adrenal insufficiency only (15% of cases)
-Cerebral adrenoleukodystrophy (brown Schilder's disease, 40% of ALD): onset age 5-12 of adrenal insufficiency and central demyelination leading to seizures, cortical blindness, dementia, coma, death, usually before puberty.
-Adrenomyeloneuropathy (sudanophilic leukodystrophy, 30% of ALD): 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 than 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; not observed with itraconazole or fluconazole); rifampin, phenytoin, opiates ( steroid catabolism)
-Cytokines (IL-1, TNF, IFN) released by macrophages in patients with AIDS may inhibit the hypothalamic-pituitary-adrenal (HPA) axis.
| 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. Asplenia is associated with increased risk of adrenal hemorrhage in sepsis.
-Coagulation disorders or warfarin therapy
-Antiphospholipid syndrome.
| Wolman disease (absent lysosomal esterase resulting in a lipid storage disease resulting in hepatomegaly, malabsorption, and adrenal calcification) can lead to Addison’s disease in children. |
B. Adrenal dysplasia/hypoplasia
| Congenital adrenal hypoplasia (AHC): rare disorder characterized by failure of development of adrenal gland, surviving patients often develop hypogonadotropic hypogonadism. Inherited as X-linked disease (DAX-1, dosage-sensitive sex reversal adrenal hypoplasia gene 1, Xp21, a transcription factor involved in adrenal cortex development and gonadotropin secretion), closely linked to Duchenne’s muscular dystrophy locus; occasionally the two disorders occur together, along with glycerol kinase deficiency, leading to elevated serum & urine glycerol, psychomotor retardation, ocular hypertelorism, strabismus, drooping mouth, with or without testicular abnormalities when a single deletion encompasses the three genes. Contiguous gene deletion syndrome can involve ornithine transcarbamylase deficiency, agenesis of the corpus callosum, and high frequency hearing loss with larger deletions. There is also an autosomal recessive (gene unknown) form of AHC and a sporadic form. |
| Adrenal and testicular dysplasia can result from mutations in the transcription factor SF-1 (product of the fushi tarazu factor-1 gene, 9q33). |
| Familial glucocorticoid deficiency (FGD): autosomal recessive; adrenal unresponsiveness to ACTH (responsiveness to AII is normal); present as child with hyperpigmentation, hypoglycemia, failure to thrive, frequent, severe infections. In FGD type-1 (40% of FGD), the ACTH-receptor (melanocortin-2 receptor, a G-protein coupled receptor) is mutated, resulting in agenesis of the zona fasciculata and zona reticularis. FGD type-1 is associated with tall stature, advanced bone age. In FGD type-2 the ACTH receptor is not mutated. There is also an isolated glucocorticoid deficiency syndrome. |
| Triple A syndrome (Allgrove syndrome): adrenal insufficiency (100% have cortisol deficiency (ACTH resistance), only 15-20% have mineralocorticoid deficiency), alacrima (95%), achalasia (75%), an autosomal recessive (12q13) condition also complicated by progressive neurologic symptoms (60%, affecting CNS (nasal speech, deafness, mental retardation), PNS (muscle wasting), autonomic), dermatologic and morphologic abnormalities (caries, periodontitis, palmoplantar hyperkeratosis, short stature, cleft palate, microcephaly). The zona fasciculata and reticularis are replaced by abnormal cells; glomerulosa preserved. |
C. Impaired steroidogenesis
| Severe forms of congenital adrenal hyperplasia (deficiency of 21-hydroxylase, 3b -hydroxysteroid dehydrogenase, 17a -hydroxylase, 11b -hydroxylase (CYP11B1), or steroidogenic acute regulatory protein (StAR)) 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. Lipoid congenital adrenal hyperplasia is the most severe form due to mutation of StAR, characterized by absence of glucocorticoid, mineralocorticoid, or sex steroid production, all patients phenotypically female. CYP11B2 mutation leads to aldosterone deficiency only. |
| Mitochondrial disorders can result in Addison’s disease as well as chronic lactic acidosis, myopathy, cataracts, nerve deafness, and short stature. The Kearns-Sayre form, with large deletions of mitochondrial DNA, is characterized by myopathy, deafness, short stature, hypogonadism, diabetes mellitus, hypoparathyroidism, hypothyroidism, and adrenal insufficiency. |
| Smith-Lemli-Opitz syndrome is caused by mutations in sterol-D -7-reductase (DHCR7) which catalyzes the final step in cholesterol synthesis and features Addison’s disease, abnormal facies, mental retardation, microcephaly, proximally placed thumbs, syndactyly of the second and third toes, congenital cardiac abnormalities, incomplete male genital development and photosensitivity. The 7-dehydrocholesterol to cholesterol ratio is elevated. |
D. Drug-induced
| Drugs such as phenytoin, barbiturates, and rifampin can accelerate hepatic metabolism of cortisol and precipitate adrenal insufficiency. Ketoconazole, aminoglutethimide, etomidate, metyrapone, and suramin inhibit cortisol synthesis. Patients with limited pituitary or adrenal reserve are those most likely to develop drug-induced adrenal insufficiency. Mitotane is toxic to the adrenal cortex and also accelerates metabolism of halogenated steroids (dexamethasone and fludrocortisone). |
II. 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; Rathke's pouch cyst |
| Pituitary surgery or irradiation |
| Lymphocytic hypophysitis |
| Sarcoidosis; histiocytosis X; amyloid |
| Empty sella syndrome: extension of subarachnoid space into sella via a defect in the sellar diaphragm (1/3 of these patients have endocrine dysfunction). |
| Infectious: tuberculosis, fungi (Nocardia, actinomycosis) |
| 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 can be suppressed for ~ 8-12 months. Divided daily dosing is more suppressive than once daily dosing. In inflammatory disorders, 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. A clue to adrenal HPA axis suppression is small joint aches (hands, feet) when the glucocorticoid is withdrawn. Patients vary significantly in their sensitivity to suppression by exogenous glucocorticoids; dose and duration of treatment are not predictive of axis suppression. In one study, 34 of 75 patients treated with 25-250 (median 95) mg/d of prednisone for 5-30 (median 10) days failed 30 minute 1 µg corticotropin stimulation after cessation of prednisone and showed a steady recovery of the adrenal response to normal by 14 days, except 2 patients who remained suppressed at 6 months. Large doses of progesterone or megace can also suppress the adrenal axis. |
| 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) |
| Drugs which have been associated with decreased ACTH secretion include megestrol acetate, valproate, ciproheptadine, and intrathecal opioids. |
III. 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 |
Primary adrenal insuff. and associated disorders |
Secondary adrenal insuff. and associated disorders |
|
Tiredness, weakness, mental depression, headache Anorexia, weight loss Dizziness, orthostatic hypotension1 Abdominal cramps, N/V, diarrhea Hyponatremia2 Hypoglycemia Mild normocytic anemia, lymphocytosis, eosinophilia4 Hypercalcemia (rare) Loss of body hair in women |
Hyperpigmentation3 Hyperkalemia Vitiligo Autoimmune thyroid disease CNS symptoms in adrenomyeloneuropathy Salt craving (e.g. pickle juice) Acidosis (Type IV RTA) Increased taste sensitivity (to salt) Hyperacusis Thorn’s sign: auricular calcification (males only) |
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 elevated MSH and 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. Spots of buccal hyperpigmentation may be normal in a dark-skinned patient, but tongue hyperpigmentation is not. Very rarely, a defect of melanocyte response can result in absence of hyperpigmentation.
4. One study of 40 ICU patients with eosinophils ≥ 3% found that 10 (25%) of them had adrenal insufficiency by 1 µg Synacthen stimulation test, and treatment with hydrocortisone resulted in hemodynamic improvement in 7/10. Thus, relative eosinophilia may be an important warning sign of adrenal insufficiency.
IV. Laboratory evaluation of adrenal function.
| Cortisol measurement. Drawn before 9 a.m., a value ≤ 3 µg/dl indicates adrenal insufficiency, and concentrations ≥ 19 µg/dl rule it out. Intermediate values necessitate dynamic testing. Remember, estrogen raises corticosteroid binding hormone concentrations, raising [cortisol]; thus, in pregnancy expect morning cortisol of 25-35 m g/dl. Normal range of cortisol is 6-24 µg/dl, in an ICU patient it should be ≥ ~25 µg/dl (with the caveat that severe illness can decrease CBG). |
| 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 µg/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 µg 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 (to ≥ 4 ng/dl or 2X over baseline). Thus, may help distinguish primary from secondary adrenal insufficiency, but has limited utility since affected by volume, posture, and potassium status. |
| Short corticotropin stimulation test: 250 µg of cosyntropin (Cortrosyn, ACTH1-24, normal ACTH has 39 amino acids) 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 µg/dl (using higher cutoff minimizes underdiagnosis, some also consider a rise ≥ 7 µg/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 µg is highly supraphysiologic (5 µg 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. In severe illness (low CBG), a post-ACTH cortisol/CBG > 13 nmol/mg may be used to approximate a normal free cortisol response. |
| Low-dose corticotropin test: 1 µg used instead of 250 µg (IV only). Test used to detect mild secondary (partially atrophied adrenal cortex) adrenal insufficiency (eg. patient taking inhaled glucocorticoids). Normal response is peak cortisol ≥ 18 µg/dl (sampled at 20, 30 min). |
| 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 (or 3 g) 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 µg/dl (simultaneous cortisol < 5-8 µg/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 µg/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. This, however, is not useful in determining therapy. |
| A prolonged cosyntropin stimulation (Rose) test can be used to distinguish primary vs. secondary adrenal insufficiency. [250 µg over 48 hours.] |
| 24-hour urinary free cortisol is not used because it is normal in 20% of patients with adrenal insufficiency. |
| Adrenal autoantibodies: Their use is complicated by issues of assay standardization and transient seropositivity (20-25% spontaneous remission). 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. Adrenal autoantibodies (ACA, 21-OH) are positive in 0.5-3% of patients (T1 DM, Graves’, Hashimoto’s) with other organ-specific autoimmune diseases (2-8.9% in premature ovarian failure). No more than 0.6% of healthy subjects are positive for anti 21-hydroxylase ab. Patients with autoimmune conditions may be tested for adrenal autoantibodies, but only 20-30% of adults who test positive go on to develop Addison’s (compared to 90% of positive children within 4 years). In established Addison’s, use of anti 21-OH is a good tool to distinguish an autoimmune etiology, especially near the time of diagnosis. |
V. Replacement therapy: goal is to find the lowest dose which relieves the patient’s symptoms, to prevent weight gain, osteoporosis, and cataracts while optimizing well-being, weight gain, BP, growth rate (children), and resolve pigmentation (except hyperpigmented scars, which do not fade). Measuring ACTH and renin can be helpful. 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, can also give once in the morning since intermediate half-life). Measuring urinary free cortisol may help dosing (controversial since only reflects excess over CBG); urinary 17OHCS would thus be more useful in this regard. |
| This replacement regimen (12-15 mg/m2/d) may be excessive; recent studies suggest this is double endogenous production but may be needed to allow for losses from absorption, hepatic processing, and bioavailability. |
| Since the natural peak of cortisol occurs with the onset of REM sleep in the early morning hours, the peak from the morning replacement dose typically comes hours late and may explain the occurrence of symptoms in the morning as well as inadequate ACTH suppression. |
| A need for escalating dosing suggests poor compliance, malabsorption (e.g. celiac disease in APS), or increased catabolism (e.g. thyrotoxicosis). |
| If primary adrenal insufficiency, give fludrocortisone, in a single daily dose, 50-200 µg, with adjustments per BP, serum potassium, peripheral edema, and plasma renin activity (upper-normal range, 2-5 ng/ml/hr). Infants may require in addition sodium chloride 1-2 g/d. Extra salt may be needed in the summer since aldosterone deficiency increases the salt content of sweat. |
| 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 (and divide into three daily doses) 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. |
VI. 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. Caution: since glucocorticoid deficiency produces a defect in free water excretion, glucocorticoid replacement and physiologic saline administration to correct volume deficiency may lead to a rapid rise in serum sodium. |
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