Addisons Disease

AETIOLOGY & PATHOGENESIS
 Addison's disease results

from progressive destruction of the adrenals, which must involve >90% of the glands before adrenal insufficiency appears.  The adrenal is a frequent site for chronic granulomatous diseases, predominantly tuberculosis but also histoplasmosis, coccidioidomycosis, and cryptococcosis.

AETIOLOGY & PATHOGENESIS
In early series, tuberculosis was responsible for 70–90% of cases, The most frequent cause now is idiopathic atrophy, and an autoimmune mechanism is probably responsible.

AETIOLOGY & PATHOGENESIS
Rarely, other lesions are encountered, such as

adrenoleukodystrophy, bilateral hemorrhage, tumor metastases,  HIV, cytomegalovirus (CMV),  amyloidosis,  adrenomyeloneuropathy,  familial adrenal insufficiency, or sarcoidosis

AETIOLOGY & PATHOGENESIS
Although half of patients with idiopathic atrophy have circulating adrenal antibodies, autoimmune destruction is probably secondary to cytotoxic T lymphocytes. Specific adrenal antigens to which autoantibodies may be directed include • 21-hydroxylase (CYP21A2) • and side chain cleavage enzyme.

AETIOLOGY & PATHOGENESIS

circulating adrenal antibodies
significance of these antibodies in the pathogenesis of adrenal insufficiency is unknown. Some antibodies cause adrenal insufficiency by blocking the binding of ACTH to its receptors.

Clinical features
• Adrenocortical insufficiency caused by

gradual adrenal destruction is characterized by an insidious onset of fatigability, weakness, anorexia, nausea and vomiting, weight loss, cutaneous and mucosal pigmentation, hypotension, and occasionally hypoglycemia

Clinical features
DEPENDING ON DURATION & DEGREE OF ADRENAL HYPOFUNCTTION The manifestations vary from mild chronic fatigue TO • fulminating shock associated with acute destruction of the glands, as described by Waterhouse and Friderichsen.

Clinical features
Asthenia is the cardinal symptom. Early it may be sporadic, usually most evident at times of stress; as adrenal function becomes more impaired, the patient is continuously fatigued, and bed rest is necessary.

Clinical features
Hyperpigmentation may be striking • or absent. • It commonly appears as a diffuse brown tan, or bronze darkening of parts such as the elbows or creases of the hand and of areas that normally are pigmented such as the areolae about the nipples.

Clinical features
Bluish-black patches may appear on the mucous membranes. • Some patients develop dark freckles, some times irregular areas of vitiligo may paradoxically be present. As an early sign, tanning following sun exposure may be persistent.

Clinical features
Arterial hypotension with postural accentuation is frequent, and blood pressure may be in the range of 80/50 or less. Axillary and pubic hair may be decreased in women due to loss of adrenal androgens.

Clinical features
Abnormalities of gastrointestinal function are often the presenting complaint. Symptoms vary from mild anorexia with weight loss to fulminating nausea, vomiting, diarrhea, and ill-defined abdominal pain, which may be so severe as to be confused with an acute abdomen.

Clinical features
Patients may have personality changes, usually consisting of excessive irritability and restlessness. Enhancement of the sensory modalities of taste, olfaction, and hearing ( reversible with therapy. )

• • • •

FREQUENCY OF SYMPTOMS & SIGNS
Sign or Symptom of Patients Weakness 99 Pigmentation of skin 98 Weight loss 97 Anorexia, nausea, and vomiting 90 Hypotension (<110/70) 87 Pigmentation of mucous membranes Abdominal pain 34 craving Diarrhea Percent

82 Salt 22

LABORATORY DIAGNOSIS
• Laboratory Findings • The WBC count usually shows moderate

neutropenia, lymphocytosis, and a total eosinophil count over 300/mcL. • Among patients with chronic Addison's disease, the serum sodium is usually low (90%) • while the potassium is elevated (65%). Patients with diarrhea may not be hyperkalemic.

Laboratory Findings
Fasting blood glucose may be low.

Young men with idiopathic Addison's disease are screened for adrenoleukodystrophy by determining plasma very long-chain fatty acid l

Laboratory Findings
Low plasma cortisol (< 3 mcg/dL) at 8 AM is diagnostic, especially if accompanied by simultaneous elevation of the plasma ACTH level (usually > 200 pg/mL).

Laboratory Findings
The diagnosis is made by a simplified cosyntropin stimulation test, which is performed as follows: (1) Synthetic ACTH1–24 (cosyntropin), 0.25 mg, is given parenterally. (2) Serum is obtained for cortisol between 30 and 60 minutes after cosyntropin is administered. • Normally, serum cortisol rises to at least 20 mcg/dL.

Laboratory Findings
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.

LABORATORY DIAGNOSIS
Serum DHEA levels are under 1000 ng/mL in 100% of patients with Addison's disease and a serum DHEA above 1000 ng/mL excludes the diagnosis. • Antiadrenal antibodies are found in the serum in about 50% of cases of autoimmune Addison's disease. Antibodies to thyroid (45%) and other tissues may be present.

Imaging
When Addison's disease is not clearly autoimmune, a chest radiograph is obtained to look for  tuberculosis,  fungal infection,  or cancer as possible causes. • CT scan of the abdomen will show small noncalcified adrenals in autoimmune Addison's disease.

Imaging
The adrenals are enlarged in about 85% of cases due to metastatic or granulomatous disease. • Calcification is noted in about 50% of cases of tuberculous Addison's disease (but is also seen with hemorrhage, fungal infection, pheochromocytoma, and melanoma.)

D/D
• Differential Diagnosis • Addison's disease should be considered in • • • •

any patient with hypotension or hyperkalemia. Unexplained weight loss, weakness, and anorexia may be mistaken for occult cancer. Nausea, vomiting, diarrhea, and abdominal pain may be misdiagnosed as intrinsic gastrointestinal disease. The hyperpigmentation may be confused with that due to ethnic or racial factors. Weight loss may simulate anorexia nervosa

D/D
The neurologic manifestations of Allgrove's syndrome and adrenoleukodystrophy (especially in women) often mimic multiple sclerosis. Hemochromatosis also enters the differential diagnosis of skin hyperpigmentation, but it may truly be a cause of Addison's disease as well as diabetes mellitus and hypoparathyroidism.

• • • •

D/D
Serum ferritin is increased in most cases of hemochromatosis and is a useful screening test. About 17% of patients with AIDS have symptoms of cortisol resistance. AIDS can also cause frank adrenal insufficiency.

COMPLICATIONS
• Any of the complications of the underlying disease (eg, tuberculosis) are more likely to occur, and the patient is susceptible to intercurrent infections that may precipitate crisis. Associated autoimmune diseases are common

TREATMENT
Hydrocortisone is the drug of choice. Most addisonian patients are well maintained on 15–25 mg of hydrocortisone orally daily in two divided doses, two-thirds in the morning and one-third in the late afternoon or early evening Some patients respond better to prednisone in a dosage of about 2–3 mg in the morning and 1–2 mg in the evening.

TREATMENT
Fludrocortisone acetate has a potent sodium-retaining 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. If edema, hypokalemia, or hypertension ensues, the dose is decreased.

TREATMENT
DHEA is given to some women with adrenal insufficiency. Women taking DHEA 50 mg orally each morning have experienced an improvement in their overall sense of well-being, mood, and sexuality.

TREATMENT
All infections should be treated immediately and vigorously, and the dose of hydrocortisone should be raised appropriately The dose of corticosteroid should also be raised in case of trauma, surgery, stressful diagnostic procedures, or other forms of stress. The dose is reduced back to normal as the stress subsides.

TREATMENT
Patients are advised to wear a medical alert bracelet or medal reading, "Adrenal insufficiency—takes hydrocortisone.“ • Neurologic manifestations may improve following hematopoietic stem cell transplantation from normal donors.

prognosis
Patients with Addison's disease can expect a

normal life expectancy if their adrenal insufficiency is diagnosed and treated with appropriate replacement doses of corticosteroids and (if required) mineralocorticoids.

prognosis
associated conditions can pose additional health risks. For example, patients with adrenoleukodystrophy or Allgrove syndrome may suffer from neurologic disease. • Patients with adrenal tuberculosis may have a serious systemic infection that requires treatment.

prognosis
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 corticosteroid

Acute Adrenocortical Insufficiency
may result from several processes. • On the one hand, adrenal crisis may be a rapid and overwhelming intensification of chronic adrenal insufficiency, usually precipitated by sepsis or surgical stress. Alternatively, • acute hemorrhagic destruction of both adrenal glands can occur in previously well individuals.

Acute Adrenocortical Insufficiency
In children, this event is usually associated with septicemia with Pseudomonas or meningococcemia (Waterhouse-Friderichsen syndrome) In adults, anticoagulant therapy or a coagulation disorder may result in bilateral adrenal hemorrhage

Acute Adrenocortical Insufficiency
Occasionally, bilateral adrenal hemorrhage in the newborn results from birth trauma. • Hemorrhage has been observed during pregnancy, following idiopathic adrenal vein thrombosis and as a complication of venography (e.g., infarction of an adenoma).

Insufficiency
most frequent cause\ of acute insufficiency is the rapid withdrawal of steroids from patients with adrenal atrophy owing to chronic steroid administration. The third and

Acute Adrenocortical Insufficiency
In patients with congenital adrenal hyperplasia or those with decreased adrenocortical reserve when they are given drugs capable of inhibiting steroid synthesis (mitotane, ketoconazole) or of increasing steroid metabolism (phenytoin, rifampin).

Acute Adrenocortical Insufficiency
• • • •

are intensified. Nausea, vomiting, and abdominal pain may become intractable. Fever may be severe or absent. Lethargy deepens into somnolence, Hypovolemic vascular collapse ensues.

features Preexisting symptoms

Acute Adrenocortical Insufficiency
features patients previously maintained on chronic glucocorticoid therapy In contrast, may not exhibit dehydration or hypotension until they are in a preterminal state, since mineralocorticoid secretion is usually preserved. • In all patients in crisis, • a precipitating cause should be sought

• The long-term survival of patients with adrenocortical insufficiency depends largely on the prevention and treatment of adrenal crisis. • Consequently, the occurrence of infection, trauma (including surgery), gastrointestinal upsets, or other stresses necessitates an immediate increase in hormone.

PREVENTION OF ADRENAL CRISIS

Treatment
Treatment is directed primarily toward repletion of circulating glucocorticoids And replacement of the sodium and water deficits. Hence an IV infusion of 5% glucose in normal saline solution should be started with a bolus IV infusion of 100 mg hydrocortisone followed by a continuous infusion of hydrocortisone at a rate of 10 mg/h.

Treatment
An alternative approach is to administer a 100-mg bolus of hydrocortisone IV every 6 h. only continuous infusion maintains the plasma cortisol constantly at stress levels [>830 nmol/L (30 g/dL)]. Effective treatment of hypotension requires glucocorticoid replacement and repletion of sodium and water deficits

Treatment
If the crisis was preceded by prolonged nausea, vomiting, and dehydration, several liters of saline solution may be required in the first few hours. Vasoconstrictive agents (such as dopamine) may be indicated in extreme conditions as adjuncts to volume replacement.

Treatment
• With large doses of steroid, i.e., 100–200 mg

hydrocortisone, the patient receives a maximal mineralocorticoid effect, and supplementary mineralocorticoid is superfluous. • Following improvement, the steroid dosage is tapered over the next few days to maintenance levels, and mineralocorticoid therapy is reinstituted if needed

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