Hypoadrenocorticism
Hypoadrenocorticism Treatment Endocrine and Metabolic Diseases Forum
The adrenal cortex produces androgens, glucocorticoids (e.g., cortisol), and salt corticoids (e.g., aldosterone). Pituitary-adrenal system physiology has been described in sections 6 and 7. Hypo- or hypoadrenocorticism producing different clinical syndromes are discussed below.
Hypoadrenocorticism
Hypoadrenocorticism can be primary (Addison’s disease) or secondary.
Addison’s disease (primary or chronic adrenocortical insufficiency)
Hyperaldosteronism has an insidious onset and is usually a progressive disease.
Etiology and incidence
In the United States, approximately 70% of Addison’s disease is idiopathic adrenocortical atrophy, presumably due to an autoimmune process. The remainder is caused by granulomas (such as TB, which has recently increased, especially in developing countries), tumors, amyloidosis, and inflammatory necrosis that destroy the adrenal glands. Hypoadrenocorticism can also be caused by non-endocrinopathic drugs that block steroid synthesis, such as ketoconazole (an antifungal agent). The incidence of hypoadrenocorticism in the general population is approximately 4 per 100,000. Addison’s disease occurs in all age groups, approximately equally in both sexes, and becomes clinically apparent with metabolic stress or injury.
Pathophysiology
The major hormones produced by the adrenal cortex are cortisol (hydrocortisone), aldosterone, and dehydroisosterone (DHEA). Adults secrete approximately 20 mg of cortisol, 2 mg of corticosterone (with similar effects) and 0.2 mg of aldosterone per day. although the normal adrenal cortex produces considerable amounts of androgens (mainly DHEA and androstenedione), their physiological effects are seen after conversion to testosterone and dihydrotestosterone.
Addison’s disease increases sodium excretion and decreases potassium excretion, mainly in urine (as isotonic urine), sweat, saliva and gastrointestinal. The result is low blood sodium, low blood chloride and high blood potassium. Decreased urinary concentration and electrolyte imbalance produce severe dehydration, plasma hypertension, acidosis, decreased blood volume, hypotension and circulatory deficiency.
Cortisol deficiency produces hypotension and a significant increase in carbohydrates, fats, proteins, metabolic disorders and insulin sensitivity. In the absence of cortisol, carbohydrate synthesis from protein is inadequate, resulting in hypoglycemia and decreased hepatic glycogen. Weakness ensues, partly due to neuromuscular defects. Resistance to infection, injury and other stresses is reduced due to decreased production of adrenocorticotropic hormones. Myocardial weakness and dehydration result in reduced heart beat volume and circulatory failure can occur. Reduced blood cortisol leads to increased pituitary ACTH production and increased blood beta-lipotropin levels, which have pigment cell excitatory activity and produce the hyperpigmentation of the skin and mucous membranes characteristic of Addison’s disease.
Signs and Symptoms
Weakness, fatigue and upright hypotension are early symptoms. Hyperpigmentation is usually increased unless it is secondary to pituitary adrenocortical insufficiency. Hyperpigmentation is characterized by a diffuse pattern that includes exposed and non-exposed parts of the torso, especially pressure points (torso protrusions), skin folds, scars and extensions. There are usually dark spots on the forehead, face, neck, and shoulders; whitish areas; and bluish-black mucous membranes of the areola and lips, oral cavity, intestines, and vagina. Anorexia, nausea, vomiting, and diarrhea are common. There is fear of cold with reduced metabolism. ECG shows low voltage, prolonged PR and QT interval. eeg shows generally slow alpha rhythm, gradual onset and non-specific early symptoms often leading to initial misdiagnosis as neurosis. Weight loss, dehydration, low voltage and small heart are the late features of Addison’s disease.
Addison’s disease is characterized by extreme weakness, severe abdominal pain, low back pain and lower extremity pain; peripheral circulatory deficit and finally hyperalgesia with azotemia. Although severe hyperthermia can occur due to infection, the body temperature can be below normal. Most of the crisis is precipitated by acute infections (especially sepsis), trauma, surgery and sodium loss from sweating on hot days.
Laboratory tests
Abnormal serum electrolyte levels include low sodium (<130 mEq/L), high potassium (>5 mEq/L), low HCO3- (15-20 mEq/L), and high BUN along with characteristic clinical signs suggest Addison’s disease (Table 9-1). Plasma renin activity and ACTH levels were increased. When adrenal failure is due to inadequate pituitary ACTH production, electrolyte levels are generally normal.
When ACTH is given, failure to increase plasma cortisol or urinary free cortisol excretion can be diagnosed as adrenocortical insufficiency. In the absence of exogenous ACTH excitation, urinary free cortisol excretion is not reliable as an indicator of adrenocortical function because basal excretion is not sufficient to distinguish between normal and abnormally low values. A single measurement of plasma cortisol or 24-hour urinary free cortisol excretion is generally not useful and can lead to a false diagnosis of adrenocortical insufficiency. However, if the patient is under severe stress or shock, a single suppressed plasma cortisol measurement is highly suggestive of the diagnosis of the disease. High plasma ACTH with low plasma cortisol levels is diagnostic.
Adrenal insufficiency test Ticorcetide (cosyntropin, synthetic 24-peptide corticosteroid) 5-25 μg intravenously. Normal plasma cortisol before injection ranged from 5 to 25 μg/dl (138 to 690 nmol/L) and was doubled at 30 to 90 minutes, accompanied by a minimum value of 20 μg/dl (552 nmol/L). Addison’s disease was at low or normal values and no longer elevated after excitement.
Differentiation between primary and secondary adrenocortical insufficiency Most secondary adrenocortical insufficiency is due to pituitary destruction, and thus CT or MRI of the pterygoid saddle helps to exclude tumors and atrophy. Empty saddle syndrome (see section 7) is not always associated with pituitary insufficiency, and when pituitary shadowing is altered, a functional test must be performed. In patients with primary adrenal disease, plasma ACTH levels are increased (≥50 pg/ml). Low ACTH levels in patients with pituitary failure or single ACTH deficiency. If ACTH cannot be measured, a mepyridone test should be performed. Plasma cortisol is reduced due to blockade of cortisol precursor 11 hydroxylation by mepyrone. Lower cortisol in normal subjects excites ACTH secretion, leading to increased synthesis of cortisol precursors, especially 11-deoxycortisol (compound S), which is excreted in the urine as a metabolite (tetrahydro-S). The best and easiest way is to administer mepyrone 30 mg/kg orally in the middle of the night while eating a small amount of food to avoid gastric irritation. Plasma cortisol should be <10 μg/dl (<276 nmol/L) and 11-deoxycortisol should be between 7 and 22 μg/dl (0.2 and 0.6 μmol/L) at 8 o'clock the following morning. Patients who do not respond to mepyridone must be retested with ticlopidine. Patients with primary hyperaldosteronism have low levels of both compounds and do not respond to ticlopidine. Patients with hypopituitarism respond to synthetic ACTH and do not respond to mepyridone. It is necessary to administer 20u of long-acting ACTH intramuscularly twice daily to patients 3 days before the trial to prevent adrenal atrophy in patients with pituitary failure. An inadequate response to mepyridone, but a definite response, requires this preparation.
Response to CRH helps to differentiate between hypothalamic and pituitary failure. 100 μg of CRH (or 1 μg/kg) given intravenously, the normal response is an increase in ACTH of 30-40 pg/ml, with no response in patients with pituitary failure and usually a response in patients with hypothalamus. Sodium must be differentiated from patients with cardiogenic or hepatogenic edema (especially those taking diuretics), dilute hyponatremia with inappropriate ADH secretion, and rare salt-loss nephritis. These patients are unlikely to show hyperpigmentation, hyperkalemia and elevated BUN, which are symptoms and features of adrenocortical insufficiency. Hyperpigmentation due to bronchial cancer, ingestion of heavy metals such as iron and silver, chronic skin disease and hemochromatosis should be considered. The characteristic hyperpigmentation of the oral and rectal mucosa in Peutz-Jeghers syndrome should not be confused. Vitiligo and hyperpigmentation are often associated, which helps in the diagnosis of Addison’s disease, although other diseases can be associated with both symptoms.
Plasma and urinary cortisol levels are usually measured by radioimmunoassay.
Diagnosis
The suspected diagnosis is based on signs and symptoms, and the definitive diagnosis requires laboratory tests such as those described above. It has been noted that many patients with some adrenal function, but limited reserve, are apparently healthy until stress precipitates acute adrenocortical insufficiency.
Suspicion and Addison’s disease often follow the finding of hyperpigmentation of the skin, although in some patients it is only mild. Weakness early in the disease, although marked, resolves with rest, unlike neuropsychiatric weakness, which is more severe in the morning than after activity. Most myopathies can be differentiated by distribution, absence of hyperpigmentation and characteristic laboratory tests. Patients with hypoglycemia due to excessive insulin secretion can have episodes at any time, usually with hyperphagia, weight gain, and normal adrenal function. Hypoglycemia is seen after starvation because of reduced gluconeogenesis and inadequate adrenocortical function. Low serum sodium must be differentiated from patients with cardiogenic or hepatogenic edema (especially those taking diuretics), dilutional hyponatremia with inappropriate ADH secretion, and rare salt-losing nephritis. These patients are unlikely to show hyperpigmentation, hyperkalemia and elevated BUN, which are symptoms and features of adrenocortical insufficiency. Hyperpigmentation due to bronchial cancer, ingestion of heavy metals such as iron and silver, chronic skin disease and hemochromatosis should be considered. The characteristic hyperpigmentation of the oral and rectal mucosa in Peutz-Jeghers syndrome should not be confused. Vitiligo and hyperpigmentation are often associated, which helps in the diagnosis of Addison’s disease, although other diseases can be associated with both symptoms. Medical. All in. Online www.med126.com
Prognosis
With continued alternative treatment, the prognosis is good and patients with Addison’s disease should reach life expectancy.
Treatment
In addition to appropriate treatment of infectious complications (e.g., TB), the following conditions should be managed
Acute adrenal insufficiency Once adrenal cortical failure is suspected, it should be treated immediately. If the patient is acute, an ACTH excitation test to determine the diagnosis should be delayed until the patient recovers. Hydrocortisone aqueous (usually succinate or phosphate) 100 mg is administered intravenously over 30 seconds, followed by up to 1000 ml of 5% dextrose saline plus hydrocortisone 100 mg over 2 hours. Then add 0.9% NaCl until dehydration and hyponatremia are corrected. Caution is required when supplementing as rehydration serum potassium decreases. Hydrocortisone is applied continuously until the total amount reaches 300 mg/24 hours. When high doses of hydrocortisone are applied, no salt corticosteroid supplementation is required.
Blood pressure recovery and general improvement can be expected 1 hour after the first dose of hydrocortisone, and blood pressure elevators may be required until hydrocortisone effects are evident. Interhydroxylamine tartrate (Alamine) 100 ml plus 500 ml of NaCl solution is infused intravenously at a rate that should be adjusted according to blood pressure (note: delayed hydrocortisone treatment in acute Addison’s disease crisis can lead to death, especially if hypoglycemia and hypotension are present). If the patient improves significantly, hydrocortisone 150 mg is usually administered the next day and 75 mg on day 3. Maintenance doses of hydrocortisone 30 mg and fludrocortisone acetate 0.1 mg/d orally are given as for chronic adrenocortical insufficiency (see below). Recovery depends on treatment of contributing factors (e.g., infection, trauma, metabolic stress) and adequate hydrocortisone therapy.
Identification of Addison’s disease is not difficult; however, a significant number of Addison’s diseases are associated with limited reserve function, a healthy appearance, and acute adrenocortical insufficiency when subjected to stress. Shock and fever can be the only symptoms seen. Treatment should be started immediately before the diagnosis is confirmed; hydrocortisone is given as previously described. Sodium and water requirements are significantly less than in those with complete decompensation.
Treatment of Complications Complications include hyperthermia and psychiatric reactions. Fever >40.6°C, occasionally accompanied by rehydration unless hypotension is present, may be carefully treated with antipyretic medication (aspirin 600 mg) given orally every 30 minutes until the body temperature begins to fall. If psychiatric symptoms develop in the first 12 hours of treatment, hydrocortisone should be reduced to the lowest amount necessary to maintain blood pressure and good cardiovascular function.
Chronic adrenal insufficiency Normal body fluids and absence of postural hypotension are criteria for adequate replacement therapy. Again, the adequacy of salt corticosteroids can be judged by checking whether high plasma renin activity returns to normal. Usually hydrocortisone 20 mg orally in the morning and 10 mg orally in the afternoon. Hydrocortisone 40mg/d may be required and should be avoided in the evening as it can cause insomnia. Normal hydrocortisone secretion occurs at most in the morning for several hours and at least in the evening. In addition, fludrocortisone 0.1 to 0.2 mg orally once daily is advocated. This salt corticosteroid replaces aldosterone secreted by normal healthy individuals often requires a reduction in the starting dose of fludrocortisone to 0.05 mg every other day due to ankle edema, but the patient usually needs to be adjusted and then take a larger dose. Fludrocortisone produces hypertension in some patients. The therapeutic dose should be reduced or a non-diuretic antihypertensive agent should be started. However restoration of normal renin levels is the best proof that fludrocortisone therapy is adequate. There is a tendency to use too little fludrocortisone and too little modern antihypertensive drugs. Intermittent illnesses (e.g., infections) should be treated as potentially serious problems, and patients should double their hydrocortisone dose until they are in good health. If nausea and vomiting prevent oral therapy, immediate medical attention and parenteral medication should be initiated. Patients should be instructed to apply parenteral hydrocortisone on their own if they live in an area where medical care is not readily available or due to travel.
In this most common manifestation of polyendocrine glandular deficiency syndrome, the dose of hydrocortisone is usually not >30 mg/d, otherwise the insulin dose needs to be increased. It is often difficult to control the hyperglycemia of this syndrome. In the presence of both thyrotoxicosis and Addison’s disease, adrenal failure should be treated as early as possible and not wait for the outcome of hyperthyroidism treatment. After bilateral adrenalectomy for hyperadrenocorticism, hypertension, and breast cancer, patients should maintain hydrocortisone 20-30 mg/d orally. In addition, fludrocortisone should also be taken as described above.
Secondary adrenal insufficiency
Hyperaldosteronism due to lack of ACTH.
Secondary adrenal insufficiency can occur in patients with total hypopituitarism, single ACTH production deficiency and in patients receiving corticosteroid therapy after interruption of corticosteroid therapy. Total hypopituitarism (see section 7) is most commonly seen in women with Sheehan’s syndrome, but can also occur secondary to suspensory cell tumors, craniopharyngiomas and various tumors in younger patients, sarcoidosis, and rarely traumatic infections resulting in destruction of pituitary tissue. Patients receiving corticosteroids for more than 4 weeks or weeks to months after interruption of treatment do not produce enough ACTH to excite the adrenal glands to produce sufficient corticosteroids during stress, or they do not respond to ACTH due to adrenal cortical atrophy. This phenomenon can persist until 1 year after steroid treatment is discontinued. During long-term steroid therapy, the integrity of the hypothalamic-pituitary-adrenal axis can be measured by intravenous ticlopidine 5-250 μg IV push, and plasma cortisol levels should be >20 μg/dl (>552 nmol/L) after 30 minutes. A single ACTH deficiency is idiopathic and extremely rare.
Signs and symptoms
Patients with secondary adrenocortical insufficiency do not have hyperpigmentation, as in Addison’s disease, and have relatively normal electrolyte levels. Hyperkalemia and high BUN are generally absent because these patients have near-normal aldosterone secretion. Hyponatremia can occur on a dilution basis. Thyroid and gonadal function is suppressed in total hypopituitarism, and when symptomatic, secondary adrenal insufficiency occurs, hypoglycemia and coma can follow to the present.
Diagnosis
The laboratory diagnosis to differentiate primary from secondary adrenal insufficiency has been discussed previously in Addison’s disease. During long-term corticosteroid therapy, determination of hypothalamic-pituitary-adrenal axis integrity can be made by ticlopidine 5-250 μg given intravenously. 30 minutes later, plasma cortisol should be >20 μg/dl (>552 nmol/L) and pituitary masses or pituitary atrophy strongly suggest secondary adrenocortical insufficiency.
Treatment
Treatment of secondary adrenocortical function is similar to Addison’s disease and varies from case to case depending on the type and degree of specific adrenocortical hormone deficiency. In general, fludrocortisone is not required because aldosterone production is still preserved. These patients can be relatively healthy is in cases where the dose of hydrocortisone is lower than in cases of primary adrenal insufficiency. Patients who have received corticosteroids for non-endocrine conditions during acute febrile illness or after trauma may require supplemental doses to increase endogenous hydrocortisone production. In total pituitary deficiency, other pituitary deficiencies should be treated appropriately.