Addison’s Disease
Julie Adkins, Jill C. Cash, Mellisa A. Hall, Cheryl A. Glass, Angelito Tacderas, and Jenny Nelson Mullen
Definition
A.Primary adrenal insufficiency resulting in glucocorticoid and mineralocorticoid insufficiency.
Incidence
A.Approximately 100 to 140 cases per million, and an incidence of four cases per million annually in Western societies; idiopathic autoimmune disease is more common in women and children. There is no racial predilection.
Pathogenesis
A.Autoimmune dysfunction of the adrenals accounts for up to 80% of cases; 10% to 20% of cases are attributed to tuberculosis. At least 90% of the adrenal gland is destroyed, resulting in chronic cortisol deficiency, reduced aldosterone, and decreased adrenal androgens. As a result, volume and sodium depletions occur with potassium excess. The risk of death in patients with Addison’s disease is two times that of the general population due to higher rates of cardiovascular disease (CVD), cancer, and infectious disease.
Predisposing Factors
A.Other autoimmune disorders:
1.Insulin-dependent diabetes mellitus (IDDM).
2.Pernicious anemia.
3.Thyroid disorders.
B.Disseminated tuberculosis.
C.Gonadal failure.
D.Hypoparathyroidism.
E.Vitiligo.
F.Alopecia areata.
G.Chronic active hepatitis.
H.Metastatic disease (especially lung and breast cancer).
I.AIDS.
J.Certain medications (e.g., ketoconazole, anticoagulant).
K.Fungal disease.
L.Bleeding diathesis (e.g., disseminated intravascular coagulation [DIC]).
M.Sepsis.
N.Metabolic stress.
O.Trauma.
P.Pregnancy.
Common Complaints*
A.Weakness.
B.Fatigue.
C.Anorexia.
D.Nausea.
E.Diarrhea.
F.Abdominal pain.
G.Weight loss.
H.Hyperpigmentation.
I.Fever.
J.Exercise-induced and excess fluid intake hyponatremia.
Other Signs and Symptoms
A.Proximal muscle weakness.
B.Muscle and joint pain.
C.Reduced axillary/pubic hair in women.
D.Amenorrhea.
E.Hypotension.
F.Anemia with:
1.Lymphocytosis.
2.Eosinophilia.
3.Neutropenia.
4.Hyponatremia.
5.Hyperkalemia.
6.Hypoglycemia.
7.Hypercalcemia.
G.Positive antiadrenal antibodies.
H.Low plasma cortisol or failure to rise after corticotropin (adrenocorticotropic hormone [ACTH]) administration
I.ECG changes: Decreased voltage, prolonged PR and QT intervals, and general slowed rhythm.
Missed or delayed diagnosis can lead to acute adrenal crisis, a medical emergency evidenced by sudden low back, abdominal, or leg pain; severe vomiting or diarrhea; hypotension; and loss of consciousness.
Subjective Data
A.Determine extent of fatigue.
B.Elicit degree and location of weakness.
C.Question the patient regarding appetite, nausea, or diarrhea.
D.Evaluate food and fluid intake.
E.Discuss hypopigmentation or hyperpigmentation and whether it occurs on unexposed areas as well as exposed areas of the skin.
F.Note presence of abdominal, muscle, and joint pain.
G.Assess for light-headedness and/or fainting and when it occurs.
H.Inquire about the patient’s history of cancer or fungal infections.
I.Note last date of tuberculosis evaluation (purified protein derivative [PPD]) and results.
J.Determine HIV status or risk.
K.For women, discuss pubic and axillary hair distribution and note menstrual patterns.
L.Inquire about libido.
M.Inquire regarding cold intolerance.
Physical Examination
A.Check pulse, respirations, and blood pressure (BP); pulse and BP seated and standing, weight.
B.Inspect:
1.Observe overall appearance.
2.Note hair distribution and skin pigmentation, especially sun-exposed surfaces.
C.Auscultate:
1.Auscultate the heart, lungs, and abdomen.
D.Palpate:
1.Palpate the abdomen.
E.Musculoskeletal: Perform complete musculoskeletal examination.
Diagnostic Tests
A.Serum chemistry, electrolytes, blood urea nitrogen (BUN), creatinine, glomerular filtration rate (GFR).
B.Complete blood count (CBC).
C.PPD.
D.Rapid ACTH test: Rapid ACTH stimulation test excludes or establishes adrenal insufficiency but does not differentiate between primary and secondary adrenal insufficiency; with abnormal results (plasma cortisol <18 to 20 mcg/dL), proceed to plasma ACTH levels.
E.Determination of serum cortisol and plasma ACTH level, and corticotropin stimulation test as the confirmatory test.
F.Serum creatinine kinase (CK) levels.
Plasma ACTH level differentiates between primary (adrenal) and secondary (pituitary) or tertiary (hypothalamus) etiologies (high plasma ACTH with primary insufficiency, whereas normal or low with secondary insufficiency). The clinician can use ACTH-releasing hormone (CRH) to distinguish between pituitary and hypothalamic etiologies.
G.Antiadrenal antibodies: A negative adrenal antibody test is observed in only 30% to 50% of persons with idiopathic Addison’s disease and does not rule out adrenal insufficiency of autoimmune etiology.*5pt
H.CT scan of adrenal glands.
Differential Diagnoses
A.Secondary adrenal insufficiency (usually after exogenous glucocorticoid therapy).
B.Hypothalamic/pituitary lesions.
C.Diabetic coma.
D.Salt-losing nephritis.
E.Acute infections.
F.Occult cancer.
G.Anorexia nervosa.
H.Hemochromatosis.
I.Acute poisoning.
J.Myasthenia gravis.
K.Pigmentation due to racial/ethnic variations.
L.Premature primary ovarian failure.
M.Testicular failure.
N.Pernicious anemia.
O.Cancer.
P.Iatrogenic Cushing’s syndrome.
Plan
A.General interventions:
1.If primary adrenal insufficiency is established and the cause is not apparent, order an adrenal CT scan to look for metastatic disease, sarcoidosis, and tuberculosis.
B.Patient teaching:
1. 
See Section III: Patient Teaching Guide Addison’s Disease.
2.Teach the patient regarding adrenal crisis and encourage treatment before symptoms begin.
3.Encourage the patient to avoid contacts that predispose him or her to infections.
C.Pharmaceutical therapy:
1.Hydrocortisone (drug of choice) or prednisone in three doses (every 8 hours), or two-thirds in the morning and the remainder in the afternoon or early evening; 12 to 15 mg cortisol/m² body surface area; most adults need a total of 20 to 30 mg/d.
2.Increase hydrocortisone dose or add prednisone if ill; if accompanied by diarrhea, excessive sweating, or fever, the patient should double the routine dose.
3.Simultaneously decrease fludrocortisone about 50% to avoid salt retention and elevated BP:
a.Total daily stress dose is about 100 to 400 mg hydrocortisone.
4.If serum aldosterone is undetectable, mineralocorticoid replacement is likely necessary in addition to glucocorticoid.
5.Abrupt discontinuation of exogenous glucocorticoid administration after a course as short as 3 weeks may induce temporary secondary adrenal insufficiency, leading to decreased cortisol but normal or near-normal aldosterone production. This may occur up to 12 months after discontinuation of glucocorticoid therapy.
6.In emergency situations: Give hydrocortisone 100 mg intravenous (IV) bolus. If the patient has not been previously diagnosed, then give dexamethasone 4 mg IV bolus.
Follow-Up
A.Plasma renin activity: When less than 10 ng/mL, this is a probable indication of adequate fludrocortisone dose.
B.Serum and urinary cortisol and serum ACTH to monitor hydrocortisone dose. Urinary-free cortisol greater than 70 mcg/24 hour indicates excessive hydrocortisone dose, whereas values less than 20 mcg/24 hour indicate inadequate hydrocortisone dose.
C.Monitor BP and serum electrolytes to determine fludrocortisone dose.
D.Do annual adrenal function studies.
Consultation/Referral
A.If Addison’s disease is suspected, consult with a physician and refer to an endocrinologist.
B.Consider Addison’s disease in any patient with hypotension and hyperkalemia.
Individual Considerations
A.Pregnancy:
1.Because of changes in plasma cortisol, diagnosis is based on lack of rise in plasma cortisol concentration after ACTH administration.
2.If nausea and vomiting are problems, intramuscular glucocorticoid may be necessary.
3.Delivery requires increased glucocorticoid dose similar to surgery.
B.Geriatrics:
1.Urinary excretion rate of cortisol decreases by about 25%; serum level and response to ACTH stimulation are unchanged.
2.Symptoms of depression and elevated levels of cortisol are associated with atrophy of the prefrontal and limbic areas of the brain.
3.Decreased serum sodium and hydration compromise is a frequent electrolyte disorder in geriatrics because of increased antidiuretic hormone and frequent antidiuretic prescriptions. Monitor elderly patients closely to differentiate from an adrenal disorder versus medications and/or natural physiological aging process.
4.Medications prescribed with consideration to the Beers Criteria:
a.Geriatric patients with Addison’s disease/SIADH Syndrome of Inappropriate Antidiuretic Hormone (SIADH) crisis: Check sodium levels when starting Oxcarbazepine (anticonvulsant), Remeron (sleep/appetite enhancer), tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and selective serotonin-norepinephrine reuptake inhibitors (SNRIs; antidepressants). Alternatives for neuropathic pain that are safe for geriatrics with Addison’s disease might include gabapentin, capsaicin, or lidocaine patch depending on associated conditions.
b.Check potassium level at initiation of Spironolactone due to risk of hyperkalemia. It is recommended to not use this medication in the geriatric population if there has been a history of hyperkalemia. An alternative suggestion for heart failure treatment would be a low-dose angiotensin-converting enzyme inhibitor (ACEI) with a thiazide while regularly monitoring the basic metabolic panel (BMP), including electrolytes and renal function.
c.Regarding special concerns for patients with cognitive impairment, history of delirium, dementia, or history/risk for falls: Check sodium level when starting/changing any antipsychotic medications. Non-anticholinergic agents have been acceptable for elderly patients suffering from mental health diseases and/or dementia-related behavioral problems. Use the lowest dose for the shortest time possible.