Regarding Adrenal Insufficiency....

Regarding Adrenal Insufficiency answer the following questions:
1. What are the general categories of adrenocortical insufficiency?
2. Can you explain why thyroid function tests should be evaluated in a patient with primary adrenal failure?
3. What are the characteristic signs and symptoms of acute and chronic adrenal insufficiency?
4. What criteria are used to make the diagnosis of adrenal insufficiency?
5. What are the considerations in deciding on long-term replacement therapy for Addison's disease?
6. What other metabolic abnormalities may occur in association with adrenal insufficiency?
7. What are the events that take place in the regulation of cortisol secretion by the hypothalamic–pituitary–adrenal axis?
8. What are the specific causes of primary and secondary adrenal failure?

Answers And Discussion

1. What are the general categories of adrenocortical insufficiency?
Adrenocortical insufficiency results primarily from deficient cortisol production and in some cases deficient aldosterone and androgen production by the adrenal gland. Because the adrenal cortex is normally stimulated by pituitary adrenocorticotropic hormone (ACTH; corticotropin), cortisol
deficiency may result from adrenal disease (primary adrenal insufficiency or Addison's disease) or from pituitary or hypothalamic disease with ACTH deficiency (secondary adrenal insufficiency).


2. Can you explain why thyroid function tests should be evaluated in a patient with primary adrenal failure?
The association between autoimmune thyroiditis and autoimmune adrenal disease is well recognized. In general, patients with Addison's disease are afflicted more frequently with Hashimoto's thyroiditis than with Graves' disease. Approximately 50% or more of affected patients have high titers of thyroid antimicrosomal antibodies, although these patients often have no thyroid-related symptoms.
Graves' hyperthyroidism can occur in association with primary adrenal failure.
The association between thyroid failure and adrenal failure can also reflect hypopituitarism, with a consequent deficiency of both ACTH and thyroid-stimulating hormone (TSH). Therefore, abnormal
results from thyroid function tests have been seen in the settings of both primary and secondary hypoadrenalism, making thyroid function tests an important component of the evaluation of a patient with primary or secondary adrenal failure.

3. What are the characteristic signs and symptoms of acute and chronic adrenal insufficiency?
Acute adrenal insufficiency is a potentially fatal medical emergency, and the clinical features include nausea, fever, and shock, progressing to diarrhea, muscular weakness, increased and then decreased body temperature, hypoglycemia, hyponatremia, and hyperkalemia.

The cardinal signs of chronic adrenal insufficiency are weakness, fatigue, and anorexia, along with gastrointestinal complaints of nausea, vomiting, diarrhea, and vague abdominal pain. Other symptoms include salt craving (20% of the patients) and muscle cramps.
Physical findings may comprise weight loss, hyperpigmentation, hypotension, and vitiligo. The ear cartilage may calcify in patients with long-standing adrenal insufficiency.

4. What criteria are used to make the diagnosis of adrenal insufficiency?
The diagnosis of adrenocortical insufficiency is based primarily on the plasma cortisol determinations made during the rapid ACTH stimulation test (Cortrosyn test).
Any screening tests for adrenal insufficiency must include determination of a basal level of cortisol and ACTH, together with a rapid ACTH stimulation test. This test is performed by administering 25 units (0.25 mg) of synthetic ACTH intravenously/intramuscularly (IV or IM) and measuring the response of cortisol and aldosterone. It is performed to assess initially whether the adrenals can respond to exogenous ACTH. A clearly normal response excludes the possibility of primary and chronic, but not acute, secondary adrenal failure. For the cortisol response to be normal, the cortisol level after ACTH administration should be at least 18 ng/dL and increased by at least 9 ng/dL above the basal levels. Normally, the aldosterone levels parallel the cortisol levels, with an increase of at least 14 ng/dL above the basal levels.
Patients with Addison's disease exhibit very low cortisol levels and a clearly elevated ACTH level, whereas the levels of both tend to be low in patients with hypopituitarism.
In the classic situation, the response of aldosterone to ACTH is absent in patients with primary adrenal failure, whereas it is preserved in patients with secondary adrenal failure.

The measurement of aldosterone is not routine but can add diagnostic information for primary adrenal failure.

A low -dose (1 μg cortrosyn) cortrosyn stimulation test is also available and may be more sensitive when appropriate cutoff values are used. How ever, additional technical difficulties in cortrosyn administration and timing of blood tests have prevented this test from becoming routinely accepted.

5. What are the considerations in deciding on long-term replacement therapy for Addison's disease?
Long-term replacement therapy in patients with Addison's disease involves the oral administration of a cortisone preparation in physiologic replacement doses. Usually, two thirds of the total dose is given in the morning and the remainder is given in the evening to mimic the normal circadian secretion of cortisol.
Cortisone acetate can be taken as a dose of 25 mg in the morning and 12.5 mg in the evening. Alternatively, hydrocortisone can be taken in a dosage of 30 to 40 mg per day.
How ever, because cortisone must be converted to hydrocortisone in the body, hydrocortisone is considered the more physiologic agent.
Despite this, prednisone (5–7.5 mg per day) is frequently prescribed for long-term replacement because it costs less than hydrocortisone.
 The side effects from the excessive administration of the
above glucocorticoids include increased appetite, weight gain, insomnia, edema, and hypertension.

Mineralocorticoid replacement (fluorohydrocortisone therapy) is necessary in patients with primary Addison's disease, although the exact replacement dose must be titrated to the patient's response. Dramatic fluid retention may occur with the initial treatment, but this subsides once the dose is adjusted.

6. What other metabolic abnormalities may occur in association with adrenal insufficiency?
Hyperkalemia occurs frequently in patients with primary adrenal failure (approximately 64%). This is largely due to renal tubular absorption of potassium at the expense of sodium stemming from the mineralocorticoid deficiency. In addition, glucocorticoids help in maintaining the function of the sodium pump and the normal gradient between the intracellular and extracellular concentrations of sodium and potassium. Without cortisol, this gradient is not maintained, so that potassium moves out of the cell and sodium moves into the cell, thereby resulting in hyperkalemia.
Of note, in patients  ith secondary (pituitary) adrenal insufficiency, the mineralocorticoid axis is intact and hyperkalemia, arising from the second mechanism only, is mild or absent.

Hypoglycemia occurs infrequently, and primarily in patients with Addison's disease w ho have fasted for any period. It is due to defective gluconeogenesis.

A mild acidosis may eventuate in patients with mineralocorticoid deficiency because of the decreased secretion of ammonia and hydrogen ions.

Hyponatremia: Circulating levels of antidiuretic hormone (ADH) may increase and contribute to the hyponatremia. The excessive loss of sodium by the renal tubules leads to an increased water loss. This is counterbalanced by an increase in the ADH levels, which tends to cause water retention. The low cardiac output and hypovolemia also serve as stimuli for ADH release.
The inability to excrete a water load was once used as a diagnostic test for Addison's disease. This phenomenon is primarily caused by glucocorticoid deficiency, even in the presence of euvolemia. A bolus of cortisol completely reverses the effect and a “water diuresis” ensues, but this also involves the interplay of other factors, such as an improvement in cardiac output, an increase in the effective circulating volume, an increase in the glomerular filtration rate, a reduction in ADH levels, and direct effects on the renal tubule.

Peripheral eosinophilia is a common finding in the setting of primary adrenal insufficiency.

7. What are the events that take place in the regulation of cortisol secretion by the hypothalamic–pituitary–adrenal axis?
Adrenocortical cell growth and steroid secretion are primarily controlled by the pituitary hormone ACTH. The secretory regulation of the hypothalamic– pituitary–adrenal axis involves the release of corticotropin-releasing hormone (CRH) by the hypothalamus into the hypophyseal portal system. This hormone causes the pituitary secretion of ACTH, w hich is transported by the peripheral circulation to the adrenal glands, where it is bound by specific receptors and triggers steroid synthesis and secretion. Cortisol inhibits both CRH and ACTH release, whereas ACTH has a negative feedback effect on CRH release.
Hormonal and neural input from higher brain centers stimulates or inhibits CRH synthesis and secretion in a 24-hour cycle, which causes both ACTH and cortisol secretion to exhibit a circadian rhythm. The circadian rhythm can be overcome by stress, how ever, leading to chronic cortisol synthesis.
Cortisol circulates bound to cortisol-binding globulin (transcortin) and the free cortisol enters a cell and interacts  ith a specific receptor to exert its physiologic effects.

8. What are the specific causes of primary and secondary adrenal failure?
Primary adrenal insufficiency (Addison's disease) is most commonly caused by

• idiopathic adrenal atrophy stemming from autoimmune destruction (68%),
• tuberculosis (17%), or
• some other etiology (15%). 

Ninety percent of the gland must have been destroyed before Addison's disease becomes apparent.

Less common causes of adrenal insufficiency include other granulomatous diseases, such as histoplasmosis and sarcoidosis, or infiltrative diseases, such as amyloidosis, hemochromatosis, metastatic tumor, and adrenal leukodystrophy, as well as chronic anticoagulation and bilateral adrenal hemorrhage. Gram-negative septicemia, bilateral adrenalectomy, abdominal irradiation, adrenal vein thrombosis, adrenal artery embolus, and adrenolytic drugs are also rare causes of adrenal failure.

Adrenal insufficiency is found in some patients with acquired immunodeficiency syndrome (AIDS). The main presentation of adrenal insufficiency in AIDS is fatigue; electrolyte abnormalities are uncommon. Development of adrenal insufficiency in patients with at least one AIDS defining disease is associated with poor prognosis.

Secondary adrenal insufficiency is commonly caused by

• iatrogenic corticosteroid therapy, which suppresses CRH and ACTH secretion and results in adrenal atrophy. 

Other, less common causes include pituitary and hypothalamic tumors, irradiation, trauma, pituitary necrosis, and lymphocytic hypophysitis surgical procedures.