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Current Medical Diagnosis & Treatment 2024

28­22: Primary Adrenal Insufficiency (Addison Disease)

Paul A. Fitzgerald

ESSENTIALS OF DIAGNOSIS

ESSENTIALS OF DIAGNOSIS

Deficiency of cortisol and mineralocorticoid from destruction of the adrenal cortex.

Weakness, vomiting, diarrhea; abdominal pain, arthralgias; amenorrhea.

Increased skin pigmentation, especially of creases, pressure areas, and nipples.

Hypovolemic hypotension.

Hyponatremia; hyperkalemia; hypoglycemia; eosinophilia.

Elevated plasma ACTH level; cosyntropin unable to stimulate serum cortisol to ≥ 20 mcg/dL (550 nmol/L).

Acute adrenal crisis: above manifestations become critical, with fever, shock, confusion, coma, death.

GENERAL CONSIDERATIONS
Primary adrenal insufficiency (Addison disease) is caused by dysfunction or absence of the adrenal cortices. Secondary adrenal insufficiency is caused
by deficient secretion of ACTH. (See Anterior Hypopituitarism.) Addison disease refers to a chronic deficiency of cortisol caused by adrenocortical
insufficiency; plasma ACTH and alpha­MSH levels are consequently elevated, causing pigmentation that ranges from none to strikingly dark.

Addison disease is an uncommon disorder. In the United States, the prevalence is about 90–140 cases per million and the annual incidence is about 5–
6 cases per million. Patients with destruction of the adrenal cortices or with classic 21­hydroxylase deficiency also have mineralocorticoid deficiency,
typically with hyponatremia, volume depletion, and hyperkalemia. In contrast, mineralocorticoid deficiency is not present in patients with familial
corticosteroid deficiency, Allgrove syndrome, or secondary adrenal insufficiency.

Acute adrenal (Addisonian) crisis is an emergency caused by insufficient cortisol. Crisis may occur in the course of treatment of chronic adrenal
insufficiency, or it may be the presenting manifestation of adrenal insufficiency. Acute adrenal crisis is more commonly seen in primary adrenal
insufficiency than in secondary adrenal insufficiency. It is usually precipitated by one of the following: (1) severe stress (eg, infection, trauma, surgery,
hyperthyroidism, or prolonged fasting), or minor stress (vaccinations) in patients with latent or treated adrenal insufficiency; (2) hyperthyroidism or
prescription of thyroid hormone to patients with untreated adrenal insufficiency; (3) nonadherence to glucocorticoid replacement or sudden
withdrawal of adrenocortical hormone in patients with chronic primary or secondary adrenal insufficiency; (4) bilateral adrenalectomy or removal of a
functioning adrenal tumor that had suppressed the other adrenal gland; (5) sudden destruction of the pituitary gland (pituitary necrosis) or damage to
both adrenals (by trauma, hemorrhage, anticoagulant therapy, thrombosis, infection or, rarely, metastatic carcinoma); or (6) administration of
intravenous etomidate (used for rapid anesthesia induction or intubation).

ETIOLOGY
Autoimmunity is the most common cause of Addison disease in industrialized countries, accounting for about 90% of spontaneous cases; adrenal
function decreases
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YourasIPitisprogresses to overt adrenal insufficiency. Over half the cases of autoimmune Addison disease occur as part
52.36.32.128
28­22:
of an autoimmune polyendocrine syndrome (APS­1, APS­2).Paul
Primary Adrenal Insufficiency (Addison Disease), Addison disease can also occur following treatment for malignancies with PD­1 Page
A. Fitzgerald 1/8
immune
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checkpoint inhibitors.

APS­1 is caused by a defect in T cell–mediated immunity that is caused by mutations in the autoimmune regulator gene (AIRE). It is inherited as an
both adrenals (by trauma, hemorrhage, anticoagulant therapy, thrombosis, infection or, rarely, metastatic carcinoma); or (6) administration of
intravenous etomidate (used for rapid anesthesia induction or intubation). Universidad Peruana de Ciencias Aplicadas
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ETIOLOGY
Autoimmunity is the most common cause of Addison disease in industrialized countries, accounting for about 90% of spontaneous cases; adrenal
function decreases over several years as it progresses to overt adrenal insufficiency. Over half the cases of autoimmune Addison disease occur as part
of an autoimmune polyendocrine syndrome (APS­1, APS­2). Addison disease can also occur following treatment for malignancies with PD­1 immune
checkpoint inhibitors.

APS­1 is caused by a defect in T cell–mediated immunity that is caused by mutations in the autoimmune regulator gene (AIRE). It is inherited as an
autosomal recessive trait with a prevalence of 1:100,000 in most countries. APS­1, also known as autoimmune­polyendocrine­candidiasis­ectodermal
dystrophy syndrome (APECED), usually presents in early childhood with mucocutaneous candidiasis, followed by hypoparathyroidism and dystrophy
of the teeth and nails; Addison disease occurs in over 94% of affected patients, usually appearing by age 15 years. Partial or late expression of the
syndrome is common. A varied spectrum of associated diseases may be seen in adulthood, including hypogonadism, hypothyroidism, pernicious
anemia, alopecia, vitiligo, hepatitis, malabsorption, and Sjögren syndrome.

APS­2 is more common than APS­1 with a prevalence of 1:1000. It is characterized by two of the following: Addison disease, type 1 diabetes mellitus,
autoimmune thyroid disease. APS­2 has a polygenetic inheritance pattern and typically presents in young adulthood and more commonly affects
women. Other autoimmune conditions occur frequently, particularly in patients with Addison disease, including celiac disease, vitiligo, alopecia,
pernicious anemia, and premature autoimmune ovarian failure.

Treating malignancy with immune checkpoint inhibitors can cause acquired autoimmune endocrine syndromes. Addison disease and type 1 diabetes
have occurred following treatment with PD­1 blockers such as pembrolizumab or nivolumab.

Bilateral adrenal infiltrative diseases cause primary adrenal insufficiency. Causative neoplasms include lymphomas, breast cancer, and lung
cancer. Causative infections include tuberculosis, coccidiomycosis, histoplasmosis, cytomegalovirus, cryptococcus, and syphilis.

Infections of the adrenal glands, particularly with cytomegalovirus, are found in nearly half of patients with untreated HIV at autopsy. However, a
much lower percentage have clinical Addison disease. The diagnosis of adrenal insufficiency in patients with HIV is often problematic. A cortisol
resistance syndrome has been described in patients with HIV, and a revision of normal range for the cosyntropin test for these patients has been
advocated (normal peak cortisol over 22 mcg/dL). Also, isolated hyperkalemia occurs commonly in patients positive for HIV, particularly during therapy
with pentamidine; this is usually due to isolated hypoaldosteronism and responds to mineralocorticoid (fludrocortisone) therapy alone.

Bilateral adrenal hemorrhage may occur with sepsis, heparin­associated thrombocytopenia, anticoagulation, or the antiphospholipid antibody
syndrome. It may occur in association with major surgery or trauma, presenting about 1 week later with pain, fever, and shock. It may also occur
spontaneously and present with flank pain. Meningococcemia may be associated with purpura and adrenal insufficiency secondary to adrenal
infarction (Waterhouse­Friderichsen syndrome).

Adrenoleukodystrophy is an X­linked peroxisomal disorder causing accumulation of very long­chain fatty acids in the adrenal cortex, testes, brain,
and spinal cord. Adrenal insufficiency ultimately occurs in 80% of affected patients and accounts for one­third of cases of Addison disease in boys. It
presents most commonly in childhood or adolescence but can manifest at any age. Aldosterone deficiency occurs in 9%. Hypogonadism is common.
Psychiatric symptoms often include mania, psychosis, or cognitive impairment. Neurologic deterioration may be severe or mild (particularly in
heterozygote women), mimics symptoms of multiple sclerosis, and can occur years after the onset of adrenal insufficiency.

Congenital adrenal insufficiency occurs in several conditions. Familial corticosteroid deficiency is an autosomal recessive disease that is caused
by germline mutations in the adrenal ACTH receptor (melanocortin 2 receptor, MC2R). It is characterized by isolated cortisol deficiency and ACTH
resistance and may present with neonatal hypoglycemia, frequent infections, and dark skin pigmentation. Triple A (Allgrove) syndrome is caused by a
mutation in the AAAS gene that encodes a protein known as ALADIN (alachrima, a chalasia, ad renal i nsufficiency, n eurologic disorder). It is
characterized by variable expression of the following: adrenal ACTH resistance with cortisol deficiency, achalasia, alacrima, nasal voice, autonomic
dysfunction, and neuromuscular disease of varying severity (hyperreflexia to spastic paraplegia). Cortisol deficiency usually presents in infancy but
may not occur until the third decade of life.

Congenital adrenal hyperplasia is caused by various genetic defects in the enzymes responsible for steroid synthesis. Due to defective cortisol
synthesis, patients have variable degrees of adrenal insufficiency and increased levels of ACTH that causes hyperplasia of the adrenal cortex. The most
common enzyme defect is P450c21 (21­hydroxylase deficiency). Patients with severely defective P450c21 (classic congenital adrenal hyperplasia)
manifest a deficiency of mineralocorticoids (salt wasting) in addition to deficient cortisol and excessive androgens. Hypertension commonly develops
in older adult patients. Testicular adrenal rests can be found in 44% of men with the condition. Women with milder enzyme defects have adequate
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in adolescence or adulthood and are said to have "late­onset" congenital adrenal hyperplasia. (See Hirsutism.)
28­22: Primary Adrenal Insufficiency (Addison Disease), Paul A. Fitzgerald Page 2 / 8
Congenital adrenal hypoplasia causes adrenal
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Congenital adrenal hyperplasia is caused by various genetic defects in the enzymes responsible for steroid Peruana
synthesis. Due tode Ciencias
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cortisol
synthesis, patients have variable degrees of adrenal insufficiency and increased levels of ACTH that causes hyperplasia
Access Provided by: of the adrenal cortex. The most

common enzyme defect is P450c21 (21­hydroxylase deficiency). Patients with severely defective P450c21 (classic congenital adrenal hyperplasia)
manifest a deficiency of mineralocorticoids (salt wasting) in addition to deficient cortisol and excessive androgens. Hypertension commonly develops
in older adult patients. Testicular adrenal rests can be found in 44% of men with the condition. Women with milder enzyme defects have adequate
cortisol but develop hirsutism in adolescence or adulthood and are said to have "late­onset" congenital adrenal hyperplasia. (See Hirsutism.)
Congenital adrenal hypoplasia causes adrenal insufficiency due to absence of the adrenal cortex; patients may also have hypogonadotropic
hypogonadism, myopathy, and high­frequency hearing loss.

Patients with deficient P450c17 (17­hydroxylase deficiency) have varying degrees of cortisol deficiency with associated hypertension, hypokalemia, and
primary hypogonadism. Severely affected genetic 46 XY males may present with female genitalia at birth (pseudohermaphroditism). The diagnosis is
confirmed with high serum levels of 11­deoxycorticosterone and corticosterone. The absence of sex hormones results in primary amenorrhea.

Patients with deficient P450c11 (11­hydroxylase deficiency) present at birth with partial virilization and ambiguous genitalia in genetically female
infants, childhood virilization in both sexes, and virilization and reduced fertility in adult women. Most patients have hypertension and variable
degrees of cortisol deficiency. The diagnosis is established with elevated serum levels of 11­deoxycorticosterone and 11­deoxycortisol.

Drugs that cause primary adrenal insufficiency include mitotane, abiraterone acetate, and the tyrosine kinase inhibitors lenvatinib and vandetanib.
Rare causes of adrenal insufficiency include lymphoma, metastatic carcinoma, scleroderma, amyloidosis, and hemochromatosis.

CLINICAL FINDINGS
A. Symptoms and Signs

The onset of symptoms can occur suddenly but usually develops gradually over months or years. The diagnosis is often delayed, since many early
symptoms are nonspecific. Over 90% of patients describe fatigue, reduced stamina, weakness, anorexia, and weight loss. Over 80% of affected patients
present with symptoms of orthostatic hypotension (aggravated by dehydration caused by nausea or vomiting), lightheadedness with standing, salt
craving, and eventually hyperpigmentation of skin and gums. Abdominal pain, nausea, and vomiting eventually develop in most patients; diarrhea can
occur, aggravating dehydration and hypotension. Fevers and lymphoid tissue hyperplasia may also occur. Patients often have significant pain:
arthralgias, myalgias, chest pain, abdominal pain, back pain, leg pain, or headache. Psychiatric symptoms include anxiety, irritability, and depression;
by the time of diagnosis, over 40% of patients have been told that their symptoms were psychological. Cerebral edema can cause headache, vomiting,
gait disturbance, and intellectual dysfunction that may progress to coma. Hypoglycemia can occur and worsen the patient’s weakness and mental
functioning. Patients treated long­term for adrenal insufficiency appear to be more prone to pneumonia and GI and UTIs.

Skin hyperpigmentation due to increased pituitary secretion of alpha­MSH varies among affected patients (eg, from none to increased freckling to
diffuse darkening that resembles a suntan or a bronze appearance). Sun­exposed areas darken the most, but nonexposed areas darken as well.
Hyperpigmentation is often especially prominent over the knuckles, elbows, knees, posterior neck, palmar creases, gingival mucosa, and vermilion
border of the lips. Nail beds may develop longitudinal pigmented bands. Nipples and areolas tend to darken. The skin also darkens in pressure areas,
such as the belt or brassiere lines and the buttocks. Skin folds and new scars may also become pigmented. Conversely, patches of autoimmune vitiligo
can be found in about 10% of patients. Scant axillary and pubic hair typically develops in women.

In pregnancy, undiagnosed adrenal insufficiency is rare, since the condition tends to cause anovulation and reduced fertility. In the first trimester,
symptoms such as fatigue, nausea, vomiting, abdominal pain, and orthostasis are typically attributed to the pregnancy, thus delaying the diagnosis.
Worse, the increased skin pigmentation of adrenal insufficiency may be mistaken for chloasma (melasma). Undiagnosed adrenal insufficiency can
cause intrauterine growth retardation and fetal loss. Pregnant women with undiagnosed adrenal insufficiency can experience shock from adrenal
crisis, particularly during the first trimester, concurrent illness, labor, or postpartum.

Patients with preexistent type 1 diabetes experience more frequent hypoglycemia with the onset of adrenal insufficiency, such that their insulin dosage
must be reduced.

Acute adrenal crisis is an immediate threat to life. Affected patients have magnified symptoms of chronic adrenal insufficiency and experience an
acute deterioration in their health, typically with acute GI symptoms and fever that can mimic an abdominal emergency. Infections (lower respiratory,
urinary, or GI) are common triggers for acute adrenal crisis. Patients also frequently experience back pain, arthralgias, and profound fatigue. They may
have delirium or coma, sometimes aggravated by hypoglycemia. Adrenal crisis is marked by orthostatic dizziness and hypotension (blood pressure
below 100 mm Hg systolic or 20 mm Hg lower than their baseline). Reversible cardiomyopathy and HF can also occur, causing hypotension that can
progress to life­threatening shock that does not respond to intravenous fluids and vasopressors.
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B. Laboratory
28­22: Findings
Primary Adrenal Insufficiency (Addison Disease), Paul A. Fitzgerald Page 3 / 8
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Typically, there is mild anemia, moderate neutropenia, lymphocytosis, and eosinophilia (total eosinophil count over 300/mcL). Among patients with
chronic adrenal insufficiency, the serum sodium is usually low (88%) and the potassium elevated (64%). However, patients with vomiting or diarrhea
acute deterioration in their health, typically with acute GI symptoms and fever that can mimic an abdominal emergency. Infections (lower respiratory,
urinary, or GI) are common triggers for acute adrenal crisis. Patients also frequently experience back pain,Universidad
arthralgias, Peruana de Ciencias
and profound fatigue. Aplicadas
They may
have delirium or coma, sometimes aggravated by hypoglycemia. Adrenal crisis is marked by orthostatic dizziness andby:hypotension (blood pressure
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below 100 mm Hg systolic or 20 mm Hg lower than their baseline). Reversible cardiomyopathy and HF can also occur, causing hypotension that can
progress to life­threatening shock that does not respond to intravenous fluids and vasopressors.

B. Laboratory Findings

Typically, there is mild anemia, moderate neutropenia, lymphocytosis, and eosinophilia (total eosinophil count over 300/mcL). Among patients with
chronic adrenal insufficiency, the serum sodium is usually low (88%) and the potassium elevated (64%). However, patients with vomiting or diarrhea
may not be hyperkalemic. Fasting hypoglycemia is common. Hypercalcemia may be present.

A plasma cortisol less than 3 mcg/dL (83 nmol/L) at 8 AM is diagnostic, especially if accompanied by simultaneous elevation of the plasma ACTH level
greater than 200 pg/mL (44 pmol/L). The diagnosis is confirmed by a simplified cosyntropin stimulation test: (1) Synthetic ACTH1–24 (cosyntropin), 0.25
mg, is given intramuscularly. (2) Serum cortisol is obtained 45 minutes after cosyntropin is administered. Normally, serum cortisol rises to at least 20
mcg/dL (550 pmol/L), whereas patients with adrenal insufficiency have stimulated serum cortisol levels less than 20 mcg/dL (550 pmol/L). For patients
receiving corticosteroid treatment, hydrocortisone must not be given for at least 8 hours before the test. Other corticosteroids (eg, prednisone,
dexamethasone) do not interfere with specific assays for cortisol. Cosyntropin is usually well tolerated, but infrequent (less than 5%) side effects have
included hypersensitivity reactions with nausea, headache, dizziness, dyspnea, palpitations, flushing, edema, and local injection site reactions.
Cosyntropin may be administered during pregnancy; however, the test may lack sensitivity, since adrenal ACTH­responsiveness increases during
pregnancy.

Serum DHEA levels are less than 1000 ng/mL (350 nmol/L) in 100% of patients with adrenal insufficiency but also in about 15% of the population, so the
test is very sensitive but not specific.

One or more serum anti­adrenal antibodies are found in about 50% of cases of autoimmune Addison disease. The sensitivity of four serum anti­
adrenal antibodies is as follows: cytoplasmic antibodies (26%), 21­hydroxylase antibodies (21%), 17­hydroxylase antibodies (21%), and side­chain
cleavage antibodies (16%). Antibodies to thyroid (45%) and other tissues may also be present.

Elevated plasma renin activity (PRA) indicates the presence of depleted intravascular volume and the need for fludrocortisone administration. Serum
epinephrine levels are low in untreated patients with adrenal insufficiency. These patients do not have the high local concentrations of cortisol that are
required to induce the adrenal medullary enzyme PNMT that converts norepinephrine to epinephrine.

Salt­wasting congenital adrenal hyperplasia due to 21­hydroxylase deficiency is usually diagnosed at birth in females due to ambiguous
genitalia. Males and patients with milder enzyme defects may present later. The diagnosis of adrenal insufficiency is made as above. The specific
diagnosis requires elevated serum levels of 17­OH progesterone.

Young men with idiopathic Addison disease are screened for X­linked adrenoleukodystrophy by determining plasma very long­chain fatty acid levels;
affected patients have high levels.

In acute adrenal crisis, blood, sputum, or urine cultures may be positive if bacterial infection is the precipitating cause.

C. Imaging

When adrenal insufficiency is not clearly autoimmune, a CT scan of the adrenal glands should be obtained. The adrenals are enlarged in about 85% of
cases related to metastatic or granulomatous disease. Adrenal calcifications occur in 50% of tuberculous Addison cases but are also seen with
hemorrhage, fungal infection, pheochromocytoma, and melanoma. Small, noncalcified adrenals are seen in autoimmune Addison disease.

DIFFERENTIAL DIAGNOSIS
Patients with secondary adrenal insufficiency due to ACTH deficiency have normal mineralocorticoid production and do not develop hyperkalemia
(see Hypopituitarism). In contrast to Addison disease, patients with secondary adrenal insufficiency have normal to decreased skin pigmentation that
has been described as “alabaster skin.” The hyperpigmentation may be confused with that due to ethnic or racial factors. Hemochromatosis also
causes bronze skin hyperpigmentation, and hemochromatosis may in fact be the cause of Addison disease. Acute adrenal crisis must be distinguished
from other causes of shock (eg, septic, hemorrhagic, cardiogenic).

The constitutional symptoms may be mistaken for cancer, anorexia nervosa, or emotional stress. Nausea, vomiting, diarrhea, and abdominal pain may
be misdiagnosed as intrinsic GI disease. Acute adrenal insufficiency must be distinguished from an acute abdomen in which neutrophilia is the rule,
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is lymphocytosis and eosinophilia. The neurologic manifestations of Allgrove syndrome and
28­22: Primary Adrenal Insufficiency (Addison
adrenoleukodystrophy (especially in women) may Disease), Paul A. sclerosis.
mimic multiple
Page 4 / 8
FitzgeraldHyperkalemia can be caused by hyporeninemic hypoaldosteronism from
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type IV renal tubular acidosis (see Chapter 23). This is commonly seen with diabetic nephropathy, hypertensive nephrosclerosis, tubulointerstitial
diseases, AIDS, myotonic dystrophy, aldosterone synthase deficiency, and congenital adrenal hyperplasia. Hyperkalemia is also seen with
has been described as “alabaster skin.” The hyperpigmentation may be confused with that due to ethnic or racial factors. Hemochromatosis also
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causes bronze skin hyperpigmentation, and hemochromatosis may in fact be the cause of Addison disease. Acute adrenal crisis must be distinguished
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from other causes of shock (eg, septic, hemorrhagic, cardiogenic).

The constitutional symptoms may be mistaken for cancer, anorexia nervosa, or emotional stress. Nausea, vomiting, diarrhea, and abdominal pain may
be misdiagnosed as intrinsic GI disease. Acute adrenal insufficiency must be distinguished from an acute abdomen in which neutrophilia is the rule,
whereas in adrenal insufficiency there is lymphocytosis and eosinophilia. The neurologic manifestations of Allgrove syndrome and
adrenoleukodystrophy (especially in women) may mimic multiple sclerosis. Hyperkalemia can be caused by hyporeninemic hypoaldosteronism from
type IV renal tubular acidosis (see Chapter 23). This is commonly seen with diabetic nephropathy, hypertensive nephrosclerosis, tubulointerstitial
diseases, AIDS, myotonic dystrophy, aldosterone synthase deficiency, and congenital adrenal hyperplasia. Hyperkalemia is also seen with
rhabdomyolysis, hyperkalemic paralysis, and some drugs (eg, ACE inhibitors, spironolactone, and drospirenone) (see Chapter 23).

Hyponatremia is seen in many other conditions (eg, hypothyroidism, diuretic use, HF, cirrhosis, vomiting, diarrhea, severe illness, or major surgery)
(see Figure 23–1). Nearly 40% of critically ill patients have low serum cortisol levels due to low serum albumin levels; their total serum cortisol levels
may be low but their serum free cortisol levels are normal.

COMPLICATIONS
Any of the complications of the underlying disease (eg, tuberculosis) are more likely to occur in adrenal insufficiency, and intercurrent infections may
precipitate an acute adrenal crisis. Associated autoimmune diseases are common (see above).

TREATMENT
A. General Measures

Patients and family members must be thoroughly educated about adrenal insufficiency. Patients are advised to wear a medical alert bracelet or medal
reading, “Adrenal insufficiency—takes hydrocortisone.” They need to be provided with a dose escalation schedule for increased corticosteroids for
illness, accidents, or prior to minor surgical procedures and for increased fludrocortisone for hot weather or prolonged strenuous exercise.
Corticosteroids and fludrocortisone must be prescribed in liberal amounts with automatic refills to avoid the patient’s running out of medication. It is
also advisable to prescribe a routine antiemetic such as ondansetron ODT 8­mg tablets to be taken every 8 hours for nausea. Parenteral
hydrocortisone (Solu­Cortef) 100 mg is also prescribed for patient self­injection in the event of vomiting. Patients must receive advance instructions to
seek medical attention at an emergency facility immediately in the event of vomiting or severe illness. All infections should be treated immediately and
vigorously, with hydrocortisone administered at appropriately increased doses.

B. Specific Therapy

Replacement therapy should include corticosteroids with mineralocorticoids for primary adrenal insufficiency. In mild cases, corticosteroids alone
may be adequate.

1. Corticosteroid replacement therapy

Maintenance therapy for most patients with Addison disease is 15–30 mg of hydrocortisone orally daily in two divided doses (10–20 mg in the morning;
5–10 mg in the evening) or three divided doses (eg, 10 mg at 7 AM, 10 mg at 1 PM, and 5 mg at 7 PM). Some patients respond better to prednisone or
methylprednisolone in doses of about 3–6 mg daily in divided doses. Adjustments in dosage are made according to the clinical response. The
corticosteroid dose should be kept at the lowest level at which the patient feels clinically well.

Patients with partial ACTH deficiency (basal morning serum cortisol above 8 mg/dL [220 mmol/L]) require hydrocortisone replacement in lower doses
of about 5 mg orally twice daily or even 10 mg every morning. Some patients feel better with the substitution of prednisone (2–7.5 mg/day orally) or
methylprednisolone (2–6 mg/day orally), given in divided doses. Fludrocortisone is not required. Additional corticosteroid must be given during stress
(eg, infection, trauma, or surgical procedures). For mild illness or mild­moderate surgical stress, corticosteroid doses are doubled or tripled. For
severe illness, trauma, or major surgical stress, hydrocortisone 100 mg is given intravenously, followed by 200 mg daily, given as either a continuous
intravenous infusion or as 50 mg boluses given every 6 hours intravenously or intramuscularly and then reduced to usual doses as the stress subsides.

Patients with secondary adrenal insufficiency due to treatment with corticosteroids require their usual daily dose of corticosteroid during minor
surgery and mild illness; supplemental hydrocortisone is required for major surgeries or illness.

Plenadren MR (5­ or 20­mg modified­release tablets) is a once­daily dual­release oral preparation of hydrocortisone that may be administered in the
morning (usual
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is 52.36.32.128
28­22: Primary Adrenal Insufficiency (Addison Disease),
insufficiency. It is not available in the United States Paul A. in
but is available Fitzgerald
Canada and elsewhere. Page 5 / 8
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Patients must be monitored carefully for clinical signs of over­ or under­replacement of corticosteroid replacement therapy. A proper corticosteroid
dose usually results in clinical improvement. Fatigue may also be an indication of suboptimal dosing of medication, electrolyte imbalance, or
intravenous infusion or as 50 mg boluses given every 6 hours intravenously or intramuscularly and then reduced to usual doses as the stress subsides.
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Patients with secondary adrenal insufficiency due to treatment with corticosteroids require their usual daily dose of corticosteroid during minor
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surgery and mild illness; supplemental hydrocortisone is required for major surgeries or illness.

Plenadren MR (5­ or 20­mg modified­release tablets) is a once­daily dual­release oral preparation of hydrocortisone that may be administered in the
morning (usual dose range is 20–30 mg daily). Preliminary studies indicate that plenadren may improve quality of life in some patients with adrenal
insufficiency. It is not available in the United States but is available in Canada and elsewhere.

Patients must be monitored carefully for clinical signs of over­ or under­replacement of corticosteroid replacement therapy. A proper corticosteroid
dose usually results in clinical improvement. Fatigue may also be an indication of suboptimal dosing of medication, electrolyte imbalance, or
concurrent hypothyroidism or diabetes mellitus. A WBC count with a differential can be useful, since a relative neutrophilia and lymphopenia can
indicate corticosteroid over replacement, and vice versa. Serum ACTH levels vary substantially and should not be used to determine dosing.

Caution: Increased corticosteroid dosing is required in circumstances of infection, trauma, surgery, stressful diagnostic procedures, or other forms of
stress. For severe stress of major illness, surgery, or delivery, a maximum stress dose of hydrocortisone is given as 50–100 mg intravenously or
intramuscularly, followed by 50 mg every 6 hours (continuous intravenous infusion or boluses), then reduced over several days. However, following
major trauma, increased doses of replacement hydrocortisone may be required for up to several weeks. Lower doses, oral or parenteral, are used for
less severe stress. For immunizations that are given with an adjuvant, such as varicella zoster (Shingrix), there is sufficient local inflammation that
increased doses of hydrocortisone are recommended for 5 days following the immunization. The dose is reduced back to normal as the stress
subsides. Decreased corticosteroid dosing is required when medications are prescribed that inhibit corticosteroid metabolism by blocking the
isoenzyme CYP34A, particularly the antifungals ketoconazole or itraconazole, the antidepressant nefazodone, anti­HIV protease inhibitors, and
cobicistat. Rifampin increases hydrocortisone clearance, necessitating increased corticosteroid dosing. During the third trimester of pregnancy,
corticosteroid requirements are higher, so usual corticosteroid doses are increased by 50%.

2. Mineralocorticoid replacement therapy

Fludrocortisone acetate has a potent sodium­retaining effect. The dosage is 0.05–0.3 mg orally daily or every other day. In the presence of postural
hypotension, hyponatremia, or hyperkalemia, the dosage is increased. Similarly, in patients with fatigue, an elevated PRA indicates the need for a
higher replacement dose of fludrocortisone. If edema, hypokalemia, or hypertension ensues, the dose is decreased. During treatment with
hydrocortisone with maximum doses appropriate for stress, fludrocortisone replacement is not required. Some patients cannot tolerate
fludrocortisone and must substitute NaCl tablets to replace renal sodium loss.

3. DHEA replacement therapy

DHEA is given to some women with adrenal insufficiency. In a double­blind clinical trial, women taking DHEA 50 mg orally each morning experienced
an improved sense of well­being, increased muscle mass, and a reversal in bone loss at the femoral neck. DHEA replacement did not improve fatigue,
cognitive problems, or sexual dysfunction; however, its placebo effect may be significant in that regard. Older women who receive DHEA should be
monitored for androgenic effects. Because over­the­counter preparations have variable potencies, it is best to have the pharmacy formulate this with
pharmaceutical­grade micronized DHEA.

4. Treatment of hyperandrogenism in women with congenital adrenal hyperplasia

See Hirsutism & Virilization.

5. Treatment of acute adrenal crisis

If acute adrenal crisis is suspected but the diagnosis of adrenal insufficiency is not yet established, intravenous access must be established. Blood is
drawn for cultures, plasma ACTH, serum cortisol, serum glucose, BUN, creatinine, and electrolyte levels. A UA is obtained to screen for a UTI. Without
waiting for the results, treatment is initiated immediately with hydrocortisone, 100 mg by intravenous bolus followed by 50 mg intravenously every 6
hours as either intravenous boluses or a continuous intravenous infusion. The hydrocortisone dosage may then be reduced according to the clinical
picture and laboratory test results.

Intravenous fluids are administered as either 0.9% normal saline or 0.9% normal saline/5% dextrose solutions. A volume of 2–3 L is given quickly and
then the intravenous rate is reduced according to clinical parameters and frequent serum electrolytes and glucose determinations. When intravenous
saline is stopped, mineralocorticoid replacement is commenced with fludrocortisone, starting with 0.1 mg orally daily and adjusted according to serum
electrolyte determinations.

Since bacterial infection frequently precipitates acute adrenal crisis, broad­spectrum antibiotics should be administered empirically while waiting for
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the results
28­22: of initial
Primary cultures
Adrenal (see Table(Addison
Insufficiency 32–5). The patient must
Disease), Paul also be treated for electrolyte abnormalities, hypoglycemia, and dehydration,
A. Fitzgerald as 6 / 8
Page
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indicated.

When the patient can take food by mouth, hydrocortisone is administered orally in doses of 10–20 mg every 6 hours, and the dosage is reduced to
Intravenous fluids are administered as either 0.9% normal saline or 0.9% normal saline/5% dextrose solutions. A volume of 2–3 L is given quickly and
Universidad Peruana de Ciencias Aplicadas
then the intravenous rate is reduced according to clinical parameters and frequent serum electrolytes and glucose determinations. When intravenous
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saline is stopped, mineralocorticoid replacement is commenced with fludrocortisone, starting with 0.1 mg orally daily and adjusted according to serum
electrolyte determinations.

Since bacterial infection frequently precipitates acute adrenal crisis, broad­spectrum antibiotics should be administered empirically while waiting for
the results of initial cultures (see Table 32–5). The patient must also be treated for electrolyte abnormalities, hypoglycemia, and dehydration, as
indicated.

When the patient can take food by mouth, hydrocortisone is administered orally in doses of 10–20 mg every 6 hours, and the dosage is reduced to
maintenance levels as needed. Most patients ultimately require hydrocortisone twice daily (10–20 mg in the morning; 5–10 mg in the evening).
Mineralocorticoid replacement is not needed when large amounts of hydrocortisone are given, but as its dose is reduced, it is usually necessary to add
fludrocortisone acetate, 0.05–0.2 mg orally daily. Some patients never require fludrocortisone or become edematous at doses of more than 0.05 mg
once or twice weekly. Once the crisis has passed, the patient must be evaluated to assess the degree of permanent adrenal insufficiency and to
establish the cause, if possible.

PROGNOSIS
The life expectancy of patients with Addison disease is reasonably normal, as long as they are compliant with their medications and knowledgeable
about their condition. However, one retrospective Swedish study of 1675 patients with Addison disease found an unexpected increase in all­cause
mortality, mostly from CVD, malignancy, and infection. Associated conditions can pose additional health risks. For example, patients with
adrenoleukodystrophy or Allgrove syndrome may suffer from neurologic disease. Patients with adrenal tuberculosis have a serious systemic infection
that requires treatment. Adrenal crisis can occur in patients who stop their medication or who experience stress such as infection, trauma, or surgery
without appropriately higher doses of corticosteroids. Cushing syndrome can develop, imposing its own risks, in patients who take excessive doses of
corticosteroid replacement.

Most patients with Addison disease live fully active lives. Some patients feel residual fatigue, despite corticosteroid and mineralocorticoid
replacement. This may be due, in part, to the inadequacy of oral replacement to duplicate cortisol's normal circadian rhythm. Also, patients with
Addison disease are deficient in epinephrine, but replacement epinephrine is not available.

Rapid treatment is usually lifesaving in acute adrenal crisis. However, if adrenal crisis is unrecognized and untreated, shock that is unresponsive to
fluid replacement and vasopressors can result in death.

Esposito D et al. Primary adrenal insufficiency: managing mineralocorticoid replacement therapy. J Clin Endocrinol Metab. 2018;103:376.
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Frommer L et al. Autoimmune polyendocrinopathy. J Clin Endocrinol Metab. 2019;104:4769.

[PubMed: 31127843]

Marguallies SM et al. Addison’s disease in pregnancy: case report, management, and review of the literature. J Neonatal Perinatal Med. 2020;13:275.
[PubMed: 31744021]

Merke DP et al. Congenital adrenal hyperplasia due to 21­hydroxylase deficiency. N Engl J Med. 2020;383:124861.
[PubMed: 32966723]

Prete A et al. Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery. J Clin Endocrinol
Metab. 2020;105:2262.
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Rushworth RL et al. Adrenal crisis. N Engl J Med. 2019;381:852.

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Saverino S et al. Autoimmune Addison's disease. Best Pract Res Clin Endocrinol Metab. 2020;34:101379.
[PubMed: 32063488]

Tresoldi AS et al. Increased infection risk in Addison's disease and congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2020;105:418.
[PubMed: 31532828]
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Saverino S et al. Autoimmune Addison's disease. Best Pract Res Clin Endocrinol Metab. 2020;34:101379. Universidad Peruana de Ciencias Aplicadas
Access Provided by:
[PubMed: 32063488]

Tresoldi AS et al. Increased infection risk in Addison's disease and congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2020;105:418.
[PubMed: 31532828]

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