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Adrenal cortical hypofunction may be primary (Addison's
disease) or secondary.
An insidious, usually progressive disease resulting from
About 70% of cases of Addison's disease in the USA are due
to idiopathic atrophy of the adrenal cortex, probably caused by autoimmune
processes. The remainder result from destruction of the adrenal gland by
granuloma (eg, TB, which has become increasingly common recently, especially
in developing countries), tumor, amyloidosis, or inflammatory necrosis.
Hypoadrenocorticism can also be caused by administration, for nonendocrine
reasons, of drugs that block steroid synthesis, such as ketoconazole (an
antifungal drug). The incidence of hypoadrenocorticism in the general
population is about 4/100,000. Addison's disease occurs in all age groups,
about equally in each sex, and tends to become clinically apparent during
metabolic stress or trauma.
The principal hormones produced by the adrenal cortex are
cortisol (hydrocortisone), aldosterone, and dehydroepiandrosterone (DHEA).
Adults secrete about 20 mg of cortisol, 2 mg of corticosterone (which has
similar activity), and 0.2 mg of aldosterone daily. Although considerable
quantities of androgens (primarily DHEA and androstenedione) are normally
produced by the adrenal cortex, their chief physiologic activity occurs
after conversion to testosterone and dihydrotestosterone.
In Addison's disease, there is increased excretion of Na and
decreased excretion of K, chiefly in the urine, which is isotonic, and also
in the sweat, saliva, and GI tract. Low blood concentrations of Na and Cl
and a high concentration of serum K result. Inability to concentrate the
urine, combined with changes in electrolyte balance, produces severe
dehydration, plasma hypertonicity, acidosis, decreased circulatory volume,
hypotension, and circulatory collapse.
Cortisol deficiency contributes to
hypotension and produces disturbances in carbohydrate, fat, and protein
metabolism and severe insulin sensitivity. In the absence of cortisol,
insufficient carbohydrate is formed from protein; hypoglycemia and
diminished liver glycogen result. Weakness follows, due in part to deficient
neuromuscular function. Resistance to infection, trauma, and other stress is
diminished because of reduced adrenal output. Myocardial weakness and
dehydration cause reduced cardiac output, and circulatory failure can occur.
Decreased cortisol blood levels result in increased pituitary ACTH
production and increased blood levels of -lipotropin,
which has melanocyte-stimulating activity and produces the hyperpigmentation
of skin and mucous membranes characteristic of Addison's disease.
Weakness, fatigue, and orthostatic hypotension are early
symptoms. Pigmentation is usually increased except in adrenal insufficiency
secondary to pituitary failure. Increased pigmentation (hyperpigmentation)
is characterized by diffuse tanning of both exposed and unexposed portions
of the body, especially on pressure points (bony prominences), skinfolds,
scars, and extensor surfaces. Common are black freckles over the forehead,
face, neck, and shoulders; areas of vitiligo; and bluish black
discolorations of the areolae and of the mucous membranes of the lips,
mouth, rectum, and vagina. Anorexia, nausea, vomiting, and diarrhea often
occur. A decreased tolerance to cold, with hypometabolism, may be noted.
Dizziness and syncope may occur. ECG may show decreased voltage and
prolonged PR and QT intervals. The EEG shows a generalized slowing of the
rhythm. The gradual onset and nonspecific nature of early symptoms often
lead to an incorrect initial diagnosis of neurosis. Weight loss,
dehydration, hypotension, and small heart size are characteristic of the
later stages of Addison's disease.
An adrenal crisis is characterized by
profound asthenia; severe pains in the abdomen, lower back, or legs;
peripheral vascular collapse; and, finally, renal shutdown with azotemia.
Body temperature may be subnormal, although severe hyperthermia due to
infection often occurs. Crisis is precipitated most often by acute infection
(especially with septicemia), trauma, operative procedures, and Na loss due
to excessive sweating during hot weather.
Abnormal serum electrolyte levels, including low Na (<
130 mEq/L), high K (> 5 mEq/L), low HCO3 (15 to 20 mEq/L) and
high BUN, together with a characteristic clinical picture, suggest Addison's
disease. The plasma renin and ACTH levels are increased. When adrenal
failure is caused by inadequate ACTH production by the pituitary gland,
electrolyte levels are usually normal.
Adrenal insufficiency can be diagnosed by demonstrating
failure to increase plasma cortisol levels, or urinary free-cortisol
excretion, upon administration of ACTH. Urinary-free cortisol excretion in
the absence of exogenous ACTH stimulation is unreliable as an index of
adrenocortical functional capacity, since baseline excretion does not
adequately separate the low-normal from the abnormally low value. A single
determination of plasma cortisol or 24-h urinary-free cortisol excretion is
not useful and may be misleading in diagnosing adrenal insufficiency.
However, if the patient is severely stressed or in shock, a single depressed
plasma cortisol determination is highly suggestive. An elevated plasma ACTH
level in association with a low plasma cortisol level is diagnostic.
for adrenal insufficiency: Testing
is performed by injecting cosyntropin 5 to 250 µg IV. Normal preinjection
plasma cortisol ranges from 5 to 25 µg/dL (138 to 690 nmol/L) and doubles
at 30 to 90 min, with a minimum of 20 µg/dL (552 nmol/L). Patients with
Addison's disease have low or normal values that do not rise.
between primary and secondary adrenal insufficiency: Most
instances of secondary hypoadrenocorticism are caused by destruction of the
pituitary. CT or MRI of the sella may, therefore, be useful in ruling out
tumor or atrophy. The empty sella syndrome (see also Ch.
7) is not, however, invariably associated with pituitary insufficiency,
so even when changes occur in the pituitary image, function tests must be
performed. In patients with primary disease of the adrenal, the plasma ACTH
level is high (>= 50 pg/mL). Patients with pituitary failure or with
isolated ACTH deficiency have a low ACTH level. If ACTH determination is
unavailable, a metyrapone test should be performed. Plasma
cortisol levels are reduced by blocking the 11-hydroxylation of the cortisol
precursors with metyrapone. In normal persons, the decreased cortisol
stimulates increased secretion of ACTH and leads to increased production of
cortisol precursors, particularly 11-deoxycortisol ("compound S"),
which is secreted in the urine as its metabolite, tetrahydro-S. The best and
simplest method is to administer metyrapone 30 mg/kg po at midnight with a
little food to avoid gastric irritation. The plasma cortisol at 8 am the
next morning should be < 10 µg/dL (< 276 nmol/L), and the plasma
11-deoxycortisol should be 7 to 22 µg/dL (0.2 to 0.6 µmol/L). For patients
who do not respond to metyrapone, a cosyntropin test must be performed.
Patients with primary adrenal failure will have low levels of both steroids
and will not respond to cosyntropin; those with hypopituitarism will respond
to cosyntropin but not to metyrapone. It may be necessary to prime the
patient with long-acting ACTH 20 U IM bid for 3 days before performing the
cosyntropin test to prevent failure of adrenal response because of atrophy
in patients with pituitary failure. Priming is advisable if an inadequate
but definite response to metyrapone occurs.
Response to corticotropin-releasing hormone (CRH) can be
used to distinguish between hypothalamic and pituitary failure. After
administering CRH 100 µg (or 1 µg/kg) IV, the normal response is a rise of
plasma ACTH of 30 to 40 pg/mL; patients with pituitary failure do not
respond, whereas those with hypothalamic disease usually do respond.
Plasma and urinary cortisol levels are usually determined by
The diagnosis is suspected on the basis of symptoms and
signs and confirmed by laboratory tests as described above. Note that many
patients with some adrenal function but limited reserves appear well until
stress precipitates acute adrenal insufficiency.
Addison's disease is usually suspected after the discovery
of hyperpigmentation, although in some patients this may be minimal. In the
early stages of the disease, weakness, although prominent, is benefited by
rest, unlike neuropsychiatric weaknesses, which are often worse in the
morning than after activity. Most myopathies can be differentiated by their
distribution and the lack of pigmentation and by characteristic laboratory
findings. Patients with hypoglycemia due to oversecretion of insulin may
have attacks at any time, usually have increased appetite with weight gain,
and have normal adrenal function. Patients with adrenal insufficiency
develop hypoglycemia after fasting because of their decreased ability to
carry out gluconeogenesis. The low serum Na must be differentiated from that
of edematous patients with cardiac or liver disease (particularly those
taking diuretics), the dilutional hyponatremia of inappropriate ADH
syndrome, and the rare salt-losing nephritis. These patients are not likely
to show hyperpigmentation, hyperkalemia, and increased BUN, which are
characteristic of adrenal insufficiency. Hyperpigmentation due to
bronchogenic carcinoma, ingestion of heavy metals such as iron or silver,
chronic skin conditions, or hemochromatosis should be considered. The
characteristic pigmentation of the buccal and rectal mucosa seen in
Peutz-Jeghers syndrome should not cause confusion. Frequently, vitiligo is
associated with hyperpigmentation, which may be a helpful indication of
Addison's disease, although other diseases can cause this association.
With continued substitution therapy, the prognosis is
excellent and a patient with Addison's disease should be able to lead a full
In addition to appropriate treatment of complicating
infections (eg, TB), the following conditions should be treated.
adrenal insufficiency: Therapy
should be instituted immediately once a provisional diagnosis of
adrenocortical failure has been made. If the patient is acutely ill,
confirmation by an ACTH response test should be postponed until the patient
has recovered. Hydrocortisone 100 mg as a water-soluble ester (usually the
succinate or phosphate) is injected IV over 30 sec, followed by an infusion
of 1 L of a 5% dextrose in 0.9% sodium chloride solution containing 100 mg
hydrocortisone ester given over 2 h. Additional 0.9% sodium chloride is
given until dehydration and hyponatremia have been corrected. Serum K may
fall during rehydration, requiring careful replacement. Hydrocortisone
therapy is given continuously to a total dosage in 24 h of > 300 mg.
Mineralocorticoids are not required when high-dose hydrocortisone is given.
Restoration of BP and general improvement may be expected
within 1 h after the initial dose of hydrocortisone. Vasopressor drugs may
be needed until the full effect of hydrocortisone is apparent. An IV
infusion of metaraminol bitartrate, 100 mg in 500 mL of sodium chloride
injection, may be given at a rate adjusted to maintain BP. (Caution:
In acute addisonian crisis, a delay in instituting corticosteroid
therapy may result in the patient's death, particularly if hypoglycemia and
hypotension are present.) A total dose of 150 mg hydrocortisone is
usually given over the second 24-h period if the patient has improved
markedly, and 75 mg is given on the third day. Maintenance oral doses of
hydrocortisone (30 mg) and fludrocortisone acetate (0.1 mg) are given daily
thereafter, as described under treatment of chronic adrenal insufficiency,
below. Recovery depends on treatment of the underlying cause (eg, infection,
trauma, metabolic stress) and adequate hydrocortisone therapy.
Recognition of patients with Addison's disease is not
difficult. However, a significant number of patients with "limited
adrenocortical reserve" who appear healthy experience acute
adrenocortical insufficiency when under stress. Shock and fever may be the
only signs observed. Treatment should not be delayed until the diagnosis is
certain; but hydrocortisone should be given as described above. Sodium and
water requirements may be considerably less than in patients with total
of complications: These
complications include hyperpyrexia and psychotic reactions. Fever > 40.6°
C (105° F) orally occasionally accompanies the rehydration process. Except
in the presence of a falling BP, antipyretics (eg, aspirin 600 mg) may be
given orally with caution q 30 min until the temperature begins to fall. If
psychotic reactions occur after the first 12 h of therapy, hydrocortisone
dosage should be reduced to the lowest level consistent with maintenance of
BP and good cardiovascular function.
adrenal insufficiency: Normal
hydration and absence of orthostatic hypotension are criteria for adequate
replacement therapy. Adequacy of mineralocorticoid replacement should be
checked also by restoration of elevated levels of plasma renin activity to
normal. Hydrocortisone 20 mg po is usually given in the morning and 10 mg in
the afternoon. A daily dosage of 40 mg may be required. Night doses should
be avoided, as they may produce insomnia. Normally, hydrocortisone is
secreted maximally in the early morning hours and minimally at night.
Additionally, fludrocortisone 0.1 mg to 0.2 mg po once/day is recommended.
This mineralocorticoid replaces aldosterone, which is normally secreted in
healthy persons. It is often necessary to reduce the initial dosage of
fludrocortisone to 0.05 mg every 2nd day because of ankle edema, but the
patient usually adjusts and can then take the larger doses. Fludrocortisone
produces hypertension in some patients. This should be treated by reducing
the dosage or starting a nondiuretic drug for hypertension. However,
restoration of a normal renin level is the best proof of adequate treatment
with fludrocortisone. There is a tendency to give too little fludrocortisone
and to use too few modern hypotensive drugs. Intercurrent illnesses (eg,
infections) should be regarded as potentially serious, and the patient
should double his hydrocortisone dosage until he is well. If nausea and
vomiting preclude oral therapy, medical attention should be sought
immediately and parenteral therapy started. Patients living or traveling
where medical care is not readily available should be instructed in
self-administration of parenteral hydrocortisone.
diabetes mellitus and Addison's disease: In
this common manifestation of polyglandular deficiency syndrome,
hydrocortisone dosage usually should not be > 30 mg/day; otherwise,
insulin requirements are increased. It is often difficult to completely
control hyperglycemia in this syndrome. In coexisting thyrotoxicosis
and Addison's disease, definitive treatment for adrenal failure
should be given early, without waiting for results from treatment of the
thyroid disease. The patient should be maintained on oral hydrocortisone 20
to 30 mg/day after total bilateral adrenalectomy for hyperadrenocorticism,
carcinoma of the breast, or hypertension. In addition, a mineralocorticoid
should be given as described above.
Adrenal hypofunction due to a lack of ACTH.
Adequacy of the hypothalamic-pituitary-adrenal axis during
long-term steroid treatment can be determined by injecting 5 to 250 µg
cosyntropin IV. Thirty minutes thereafter, the plasma cortisol level should
be > 20 µg/dL (> 552 nmol/L). Isolated ACTH deficiency is idiopathic
and extremely rare.
Patients with secondary adrenal insufficiency are not
hyperpigmented, as are those with Addison's disease. They have relatively
normal electrolyte levels. Hyperkalemia and elevated BUN generally are not
present because of the near-normal secretion of aldosterone in these
patients. Hyponatremia may occur on a dilutional basis. Persons with
panhypopituitarism, however, have depressed thyroid and gonadal function and
hypoglycemia, and coma may supervene when symptomatic secondary adrenal
Tests to differentiate primary and secondary adrenal
insufficiency are discussed under Addison's
Disease, above. Evidence of a pituitary mass or of pituitary atrophy
strongly suggests secondary adrenal insufficiency.
Treatment of secondary adrenal insufficiency is similar to
that for Addison's disease. Each case varies regarding the type and degree
of specific adrenocortical hormone deficiencies. Generally, fludrocortisone
is not required, since aldosterone is produced. These patients may do better
on lower doses of hydrocortisone than patients with primary insufficiency.
During acute febrile illness or after trauma, patients receiving
corticosteroids for nonendocrine disorders may require supplemental doses to
augment their endogenous hydrocortisone production.
The Merck Manual of Diagnosis and
Therapy, Edition 17, edited by Mark H. Beers and Robert Berkow.
Copyright 1999 by Merck & Co., Inc., Whitehouse
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