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Lecture 8 Adrenocortical insufficiency. Adrenocortical insufficiency (Addison disease) is a syndrome that is caused by lack of secretion of adrenal cortex hormones (glucocorticoids). Etiology and pathogenesis of adrenocortical insufficiency Glucocorticoids secretion is controlled by hypothalamic-pituitary-adrenal axis. Different levels of the axis may be injured (see fig.1).

TERTIARY ADRENOCORTICAL INSUFFICIENCY

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CRH

C O R T I S O L

SECONDARY ADRENOCORTICAL INSUFFICIENCY

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ACTH PRIMARY ADRENOCORTICAL INSUFFICIENCY

Fig.1. Adrenocortical insufficiency may be classified according to etiology and level of injury.

Classification of adrenocortical insufficiency. 1. Primary adrenal insufficiency that is caused by:  autoimmune destruction (isolated and within autoimmune polyglandular syndromes);  tuberculosis;  adrenoleukodystrophy (It is congenital pathology that causes derangement of oxidation of long-chain fatty acids. The acids are mainly deposited in adrenal cortex and neuronal tissue. It causes spinal and cerebral demyelinization and adrenal insufficiency. Gen of adrenoleukodystrophy is placed at X-chromosome. Therefore only male patients are suffered of adrenoleukodystrophy. Heterozygotes are asymptomatic.);  iatrogenic;  metastatic neoplasia;  adrenal hemorrhage;  others cause rarely (amyloidosis, mycosis, sarcoidosis etc.). 2. Central adrenal insufficiency A. Secondary one that is caused by  exogenous glucocorticoids (long-time immunosuppressive therapy of corticosteroids);  management of ACTH-independent Cushing syndrome (surgical eradication of corticosteroma). B. Tertiary (damage of hypothalamus).

Adrenocortical insufficiency mainly results from autoimmune destruction and TBinfection (more than 90% of cases). Other reasons are rare. Clinical picture of adrenocortical insufficiency Addison disease is characterized by several clinical syndromes. 1. Syndrome of asthenia. It is common fatigability, weakness, low work capacity. But severe somatogenic asthenia has some peculiarities. Patient’s state is improving in the early morning after night rest. But it is rapidly worsening in several hours. Severe fatigue is developed in the afternoon. Fatigue may be very intensive. Sometimes patients can not stand up from the chair. Severe somatogenic asthenia is differentiated of neurasthenia. Neurasthenia cases have no improving in the morning after night rest. But patient state is slightly improved after beginning of habitual daily activity. 2. Dyspeptic syndrome. It is commonly loss of appetite, weight loss, nausea, vomiting, retching, stomachache, diarrhea, salt craving. Ulcer disease is common. It is characterized by relapsed clinical course and resistance to conventional therapy.

3. ACTH-hypersecretion syndrome. It is characterized by hyperpigmentation of skin and mucous membranes. Skin affection can be accompanied by vitiligo in autoimmune cases. Hyperpigmentation is not presented in acute cases of primary adrenal insufficiency (there is not enough time for development of hyperpigmentation). Initially, pigmentation is more expressed at areolas, genitals, scars and zones of friction (knee, elbow, neck, palmary skin folds, and axillaries). Skin pigmentation may be very intensive in severe cases. It is unimportant symptom of black race cases. Inspection of oral cavity gives value information (pigment spots on the mucous membranes). Hyperpigmentation is explained this way. ACTH is derivate of proopiomelanocortin (POMC). It is cleaved from POMC. But some other derivates are cleaved from POMC too. They are melanocyte-stimulating hormones (MSHs) and β-endorphins. ACTH hyperproduction is associated with increased secretion of MSHs. It causes melanocytes hyperactivity and hyperpigmentation.

POMC ACTH

MSHs β-endorphins

Fig.2. 4. Arterial hypotension syndrome. Systolic arterial pressure is usually lower than 80-90 mm Hg, diastolic pressure is lower than 60 mm Hg. Postural events are common. 5. Syndrome of androgen deficiency. The syndrome is more expressed in female cases. Male patients have alternative source of androgen. Syndrome of androgen deficiency is characterized by decreased libido, scanty pubic and axillaries hair. 6. Syndrome of electrolytes abnormalities. It is commonly hyponatriemia, hyperkalemia, and hyperchloremia. Diagnosis of adrenocortical insufficiency Addison disease is usually proved by rapid ACTH stimulation test. It is the “gold standard” of diagnosis of adrenocortical insufficiency. The test is performed with synthetic ACTH-analogues (cortrosyn, synacten, syncorpine etc.). Injection of synthetic ACTH-analogue stimulates adrenal cortex. It allows estimating of adrenal cortex reserves. The test is made this way: 1. Basal plasma cortisol level is measured.

2. 250μg of synthetic ACTH-analogue is injected intravenously. 3. Plasma cortisol level is measured in 30 and in 60 minutes. Addison disease may be excluded if one and more plasma cortisol level exceeds 20 µg/dL. Addison disease may be verified by insulin tolerance test too. The test directly analyzes integrity of different parts of hypothalamic-pituitary-adrenal axis. The insulin tolerance test is based on inducing of artificial hypoglycemia that is caused by insulin injection. Hypoglycemia leads to hypersecretion of counterregulatory hormones including ACTH. ACTH stimulates adrenal cortex as much as possible and adrenal cortex resources can be estimated. The insulin tolerance test is performed this way: 1. Basal plasma cortisol level is measured. 2. Insulin is injected intravenously. Conventional insulin dose is 0.1 U/kg of body weight. 3. Glycemia and plasma cortisol level are measured in 30 and in 60 minutes again. The insulin tolerance test can not be interpreted if hypoglycemia is not developed. At least one sample should have glycemia lower than 40 µg/dL [2.2 mmol/L]. If hypoglycemia is not achieved, test should be repeated with larger insulin dose (0.15 U/kg of body weight). Successful achievement of hypoglycemia allows interpreting of plasma cortisol level. Addison disease may be excluded if one and more plasma cortisol level exceeds 18 µg/dL. The insulin tolerance test is potentially dangerous! Like any stress, hypoglycemia may induce relapse of adrenal insufficiency and acute adrenal failure. More over, hypoglycemia causes catecholamine hypersecretion. It can lead to hypertonic crisis, cerebral stroke, myocardial infarction etc. The insulin tolerance test is contraindicated to elderly patients with coexisting cardiovascular pathology, epilepsy, etc. Hydrocortisone makes cross-reaction with cortisol. How can we prove Addison disease in hydrocortisone treated cases? Hydrocortisone is temporally replaced by small dexamethasone doses (0.25-0.5 mg daily). Dexamethasone has other chemical structure and does not make cross-reaction with cortisol. Rapid ACTH stimulation test can be made in 24 hours after withdrawal of cortisol. Differential diagnosis of primary and central adrenocortical insufficiency. It is based on several measures: 1. Estimation of plasma ACTH level. High plasma ACTH level confirms primary character of adrenal insufficiency. Normal or low plasma ACTH is typical for central hypocorticism. Plasma ACTH level should be measured before corticosteroids administration. They normalize ACTH in several hours after ingestion.

2. “Long” ACTH stimulation test. Basal free cortisol excretion is measured. Then 1 mg of long-acting ACTH-analogue (synacten-depo etc.) is intramuscularly injected. Free cortisol excretion is measured on 1 st, 3rd and 5th days. There are several possible results:  Healthy. Free cortisol excretion on 5th day is 300-700% of basal one.  Complete primary adrenal insufficiency. Basal free cortisol excretion is low; it is not elevated during carrying out of the test.  Partial primary adrenal insufficiency. Basal free cortisol excretion is normal or slightly lowered. There is normal elevation on 1 st day, but no subsequent elevation or decreasing of cortisol excretion on 3rd and 5th days.  Central (secondary or tertiary) adrenal insufficiency. Basal free cortisol excretion is normal or lowered. No elevation on 1 st day, but normal elevation of cortisol excretion on 3rd and 5th days. 3. Magnetic resonance imaging (MRI) and CT-scanning. They are more useful for diagnosis of central adrenal insufficiency. But some value information can be obtained in primary cases that are caused by adrenal TB-infection or adrenal neoplasia. Etiologic diagnosis of adrenocortical insufficiency. Algorithm of etiologic diagnosis of primary adrenal insufficiency is presented at fig.3. The etiologic diagnosis is based on estimation of C 21-hydroxilaze antibodies, level of long-chain fatty acids, and visualization of adrenals (MRI or CT-scanning). Etiology of central adrenocortical insufficiency may be verified by visualization of pituitary gland or hypothalamus. MRI or CT-scanning allows excluding of spaceoccupying cerebral lesions. Management of adrenocortical insufficiency Addison disease management includes two main approaches: 1. Life-long replacement therapy of corticosteroid and mineralocorticoid deficiency. 2. Eradication of etiology of adrenocortical insufficiency (if it is possible). There are two main goals of treatment: 1. Restoring of water and electrolyte balance. It is achieved by mineralocorticoids ingestion. Uncontrolled mineralocorticoids deficiency causes lethal exits that result from dehydration and derangement of electrolyte balance (hyperkalemia and hyponatremia). 2. Adaptation to the stress. It is achieved by corticosteroids ingestion. If patient has no stresses, mild or moderate cortisol deficiency may by asymptomatic. But stress may exacerbate chronic adrenal insufficiency.

Synthetic corticosteroids (prednisolon, dexamethasone etc.) have weak mineralocorticoid action because they were developed for immune suppression. Their mineralocorticoid action was considered as side effect. More over, synthetic corticosteroids have long-time action that easily causes overdosing and exogenous Cushing syndrome. Primary chronic adrenal insufficiency

Elevated (70%)

Titer of antibodies to C21-hydroxilaze

Primary autoimmune chronic adrenal insufficiency Excluding of other autoimmune disorders

Absent (30%)

Long-chain fatty acids Elevated (6%)

Adrenoleukodystrophy 1. Cerebral MRI for demyelinization revealing 2. Family genetic screening

Normal (24%)

Visualization of adrenals

Infiltration of the adrenals (22%)

Other rare cases (2%)

Fig.3. Both aldosteron and cortisol deficiency should be replaced in primary Addison cases. Paying no attention to mineralocorticoids is a typical mistake (see fig.4): Monotherapy of corticosteroids is effective in 6% of primary cases. Central adrenocortical insufficiency should not be treated by mineralocorticoids because ACTH is not involved in control of aldosteron synthesis. There is no aldosteron deficiency in central cases. Replacement of aldosteron deficiency. Nowadays only one mineralocorticoid is applied for management of primary Addison disease. It is cortisol derivate that is called fludrocortisone. Fludrocortisone is prescribed orally. Its common dose is 50-200 μg daily. Daily dose is completely ingested in the morning. Estimation of adequacy of the mineralocorticoid replacing is based on several criteria: Primary autoimmune chronic adrenal insufficiency Elevated (70%)

Titer of autoantibodies Long-chain Long-chain to C fatty acids acids (30%) 21-hydroxilaze Elevated Elevated (6%)(6%) fatty Absent

1. Normal or suitable arterial pressure. 2. Normal serum potassium level. 3. Absence of edemas or water retaining. 4. Normal or slightly increased plasma renin activity.

Corticosteroid monotherapy Uncompensated mineralocorticoids deficiency Insufficient treatment efficacy Increasing of corticosteroid dose Exogenous Cushing syndrome development Fig.3. Pregnant women need to be treated bigger fludrocortisone doses (300-600 μg daily). It is explained of elevation of progesterone level in pregnancy. Progesterone reduces aldosteron action and exacerbates mineralocorticoid deficiency. Therapy efficacy of adrenal insufficiency in pregnant cases must be assessed on 1 st and 2nd criteria only. Others (3rd and 4th ones) are not applied for pregnant cases. Replacement of cortisol deficiency. There are several commonly applied schemes of replacing therapy: 1. Schemes with hydrocortisone that is chemically identical to natural cortisol. A. Hydrocortisone (20 mg in the morning + 10 mg after lunch). B. Hydrocortisone (15-20 mg in the morning + 5-10 mg after lunch + 5 mg in the evening). 2. Schemes with synthetic corticosteroids. A. Prednisolon (5 mg in the morning + 2.5 mg after lunch) B. Dexamethasone (0.5 mg in the morning) C. Dexamethasone (0.5 mg late in the evening, for example at 11 p.m.)

Synthetic corticosteroids can not be administered without mineralocorticoid preparations. Sometimes commonly applied schemes are modified according to peculiarities of the case. Estimation of adequacy of the corticosteroid replacing is based on several criteria: 1. Elimination of fatigue or weakness, improving of patient’s general state of health. 2. Normal or suitable arterial pressure. 3. Good appetite. 4. Absence of signs of exogenous hypercortisolism (weight gain, facial rounding, plethora, supraclavicular puffiness, osteopenia or osteoporosis, etc.). There are no laboratory tests that reliably characterize adequacy of cortisol replacing. It is based on clinical symptoms. Stress increases cortisol requirement. Daily dose of corticosteroids must be increased in stress cases. Stress can be caused by fever, surgical procedure or injuries, gastroenteritis with vomiting or diarrhea, etc. As soon as stress is gone, daily dose of corticosteroids may be reduced till previously applied. This is the most important information about diagnose and management of adrenocortical insufficiency. Thank you for your attention!