Hpofunction of adrenal cortex
- 1. Disorders of adrenal cortex Hari sharan makaju M.Sc. Clinical biochemistry PG Resident
- 3. Cholesterol (C27) Prognenolone (C21) Progesterone (C21) 17-α-Hydroxyprogesterone C21) Testosterone (C19) Estradiol (C18) 11- Deoxycorticosterone 11- Deoxycortisol Aldosterone Cortisol Congenital Adrenal Hyperplasia Desmolase NADPH O2 3-β-Hydroxysteroid dehydrogenase 17-α-Hydroxylase 11-β-Hydroxylase 21 α hydroxylase Defect in either the steroidogenic acute regulatory protein (StAR) Congenital lipoid adrenal hyperplasia
- 4. Adrenal Cortex Disorder It’s condition that interfere with the normal function of the adrenal glands Diseases of Adrenal cortex are classified as resulting from hypofunction or hyperfunction of the adrenal cortex. Nonfunctional adrenal tumors are diagnosed histologically
- 5. Disorders of Adrenocortical Insufficiency Deficient adrenal production of glucocorticoids or mineralocorticoids results in adrenocortical insufficiency, which is either the consequence of destruction or dysfunction of the cortex (primary adrenocortical insufficiency, or Addison disease) Or secondary to deficient pituitary ACTH secretion (secondary adrenocortical insufficiency). Adrenal insufficiency causing combined mineralocorticoid and glucocorticoid deficiency is a rare disorder with a prevalence of only 4 to 11 cases per 100,000 Thomas Addison fist reported hypofunction of the adrenal cortex in 1855.
- 6. PRIMARY ADRENOCORTICAL INSUFFICIENCY ( “ Addison’s disease “ ) Destruction of adrenal cortex The etiology of primary adrenocortical insufficiency has changed over time. Prior to 1920, tuberculosis was the major cause of adrenocortical insufficiency. Since 1950, autoimmune adrenalitis with adrenal atrophy has accounted for about 80% of cases. Associated with a high incidence of other immunologic and autoimmune endocrine disorders Characterized by loss of both glucocorticoid and mineralocorticoid secretion
- 7. SECONDARY ADRENOCORTICAL INSUFFICIENCY Dysfunction of Hypothalamic pituitary component ACTH deficiency is the primary event and leads to decreased cortisol and adrenal androgen secretion. Aldosterone secretion remains normal except in a few cases. Characterized by loss of glucocorticoid secretion only
- 8. Types of Adrenal Hypofunctions
- 9. Autoimmune Isolated autoimmune adrenalitis Autoimmune polyendocrine syndrome ( APS) Infections Tuberculosis , Fungal infections Cytomegalovirus, HIV , Infiltrations Metastases , lymphomas Amyloidosis , Hemochromatosis Haemorrhage WaterhouseFriderichsen syndrome ( after meningococcal septicemia) Adrenoleukodystrophy Congenital adrenal hyperplasia Bilateral adrenalectomy Drug induced – mitotane, ketoconazole Exogenous glucocorticoid therapy Pituitary tumours Pituitary irradiation and surgery Hypopituitarism Mass lesions affecting HP region like craniopharyngioma , meningioma Pituitary apoplexy Haemorrhage , infarction consequent to major blood loss , Sheehan syndrome Pituitary infiltration (tuberculosis, sarcoid, eosinophilic granuloma, metastases) Isolated ACTH deficiency POMC deficiency PRIMARY ADRENOCORTICAL INSUFFICIENCY SECONDARY ADRENOCORTICAL INSUFFICIENCY Causes Causes
- 10. Pathophysiology of Primary Adrenal Insufficiency In primary adrenal insufficiency, although the above mentioned causes lead to gradual destruction of the adrenal cortex, the symptoms and signs of the disease appear when the loss of adrenocortical tissue is higher than 90% . At the molecular and cellular level, a viral infection, even subclinical, or an excessive tissue response to inflammatory signals may potentially lead to apoptosis or necrosis of adrenocortical cells. Cellular components, such as 21OH-derived peptides, trigger the activation of local dendritic cells, which then transport and present these antigens to CD4+ Th1 cells. Upon activation, CD4+ Th1 cells help the committed clonal expansion of cytotoxic lymphocytes and autoreactive B cells releasing antibodies against 21-hydroxylase and possibly other antibodies.
- 11. Pathophysiology of Primary Adrenal Insufficiency The gradual destruction of adrenocortical tissue seems to be mediated by four distinct and complementary molecular mechanisms: direct cytotoxicity by lymphocytes that induce apoptosis; direct cytotoxic actions by IFN-γ and lymphotoxin-α released by activated CD4+ Th1 cells; cellular cytotoxicity by autoantibodies or by autoantibody- mediated activation of the complement system; and cytotoxic effects of inflammatory cytokines (IL-1β, TNF-α) and free radicals (superoxide, NO) secreted by monocytes/macrophages or by the adrenal cells
- 12. Cortisol deficiency causes weak ness, fatigue, anorexia, nausea and vomiting, hypotension, hyponatremia, and hypoglycemia. Mineralocorticoid deficiency produces renal sodium wasting and potassium retention and can lead to severe dehydration, hypotension, hyponatremia, hyperkalemia, and acidosis. Hyperpigmentation is the classic physical finding Prominent features are weakness, lethargy, easy fatigability, anorexia, nausea, and occasionally vomiting. Hyperpigmentation not present. Volume depletion, dehydration, and hyperkalemia are usually absent PRIMARY ADRENOCORTICAL INSUFFICIENCY SECONDARY ADRENOCORTICAL INSUFFICIENCY Clinical Features Clinical Features
- 13. Hyperpigmentation in areas of increased friction – palmar creases , dorsal foot oral mucosa and sun exposed areas– Seen in Primary adrenal insufficiency ; due to excess of ACTH ( and POMC derivatives )
- 14. Adrenal crisis Adrenal crisis is a potentially life-threatening medical condition requiring immediate emergency treatment Acute adrenal crisis represents a state of acute adrenocortical insufficiency and occurs in patients with Addison disease who are exposed to the stress of infection, trauma, surgery, or dehydration due to salt deprivation, vomiting, or diarrhea Clinical features; Hypotension and shock Fever Dehydration, volume depletion Nausea, vomiting, anorexia Weakness, apathy, depressed mentation Hypoglycemia
- 15. Adrenal crisis Adrenal crisis may be the result of : either previously undiagnosed or untreated Addison's disease a disease process suddenly affecting adrenal function (such as bleeding from the adrenal glands in Waterhouse-Friderichsen syndrome), suddenly stopping intake of glucocorticoids an intercurrent problem (e.g. infection, trauma, in fact any form of physical or mental stress) in someone known to have Addison's disease, congenital adrenal hyperplasia(CAH), or other form of primary adrenal insufficiency. Diagnosis : hyponatremia Hyperkalemia Lymphocytosis Eosinophilia hypoglycemia
- 19. Addison’s Disease: Diagnosis Decrease cortisol Increase ACTH Decrease Sodium Increase Potassium Hypoglycemia Hypotension Hyperpigmentation Confirmatory: ACTH Stimulation Test (Cosyntropin)
- 20. Laboratory Diagnosis of PRIMARY ADRENOCORTICAL INSUFFICIENCY Hyponatremia and hyperkalemia Hypoglycemia Aldosterone ,DHEA ,DHEAS and Androsterone - Low Testosterone – Normal in Man but low in female Increased plasma renin concentration Increased Angiotensin II Basal plasma ACTH concentrations greater than 150 pg/mL, along with serum cortisol concentrations less than 5 µg/dL, are diagnostic of adrenal insufficiency A subnormal cortisol response in the ACTH (Cosyntropin) stimulation test supports thediagnosis of primary adrenal insufficiency Hematologic manifestations Normocytic, Normochromic anemia, Neutropenia, Eosinophilia, and a relative lymphocytosis.
- 21. Laboratory Diagnosis of Secondary ADRENOCORTICAL INSUFFICIENCY Same as Primary Adrenal Insufficiency Excepts: ACTH- Not elevated Hyperkalemia does not occurs Plasma renin level are usually normal but chronic secondary adrenal insufficiency both plasma rennin activity and aldosterone concentration may be low.
- 22. ALGORITHM FOR THE MANAGEMENT OF PATIENTS WITH SUSPECTED ADRENOCORTICAL DEFICIENCY Clinical suspicion of ADRENOCORTICAL insufficiency Weight loss, fatigue , postural hypotension , hyperpigmentation , hyponatremia Confirmatory test – Cosyntropin/ synacthen test Serum cortisol measured 30-60 mins after 250ug of short acting ACTH Adrenal insufficiency Normal adrenal function Cortisol < 18-20µg/dl Cortisol > 18-20µg/dl Primary adrenal inefficiency Secondary Adrenal insufficiency Plasma ACTH Normal / undetectable Increased( >100pg/dL)
- 23. Primary Adrenocortical inefficiency High ACTH , low aldosterone , low renin Adrenal glands enlarged Secondary Adrenocortical inefficiency Low ACTH , normal aldosterone , normal renin CT Adrenals Normal or atrophic Hypothalamo- Pituitary Mass lesion Mass lesion MRI pituitary No mass History of exogenous glucocorticoids History of headache ? Trauma ? ( for pituitary apoplexy ) Consider isolated ACTH deficiency
- 25. Hypofunction of the adrenal cortex Hypoaldosteronism Deficient aldosterone production occurs in conditions other than Addison disease Isolated aldosterone deficiency accompanied by normal cortisol production is seen in patients with (1) inadequate production of renin by the kidney, which leads to secondary aldosterone deficiency (hyporeninemic hypoaldosteronism); (2) inherited enzyme defects in aldosterone biosynthesis (e.g., CYP11B2 defiiency; CYP11B2 = P450 aldo); (3) acquired forms of primary aldosterone deficiency (heparin therapy and post surgery)
- 26. Hypoaldosteronism Resulting metabolic changes are hyperkalemia and hyponatremia, often with hypochloremia acidosis. Mild or moderate volume depletion, often with postural or unprovoked hypotension, may also occur. Hyporeninemic hypoaldosteronism can be established by demonstrating failure of both plasma renin and aldosterone to increase in response to furosemide stimulation
- 27. Hypoaldosteronism Hyperreninemia hypoaldosteronism (synthetic deficiency) Primary adrenal insufficiency Selective aldosterone deficiency Inborn errors (e.g., CYP11B2 mutations) Drug-induced aldosterone suppression Heparin (direct inhibition of aldosterone secretion) Angiotensin-converting enzyme (ACE) inhibitors Hypoaldosteronism in critical illness/hypotension (e.g., selective zona glomerulosa injury)
- 28. DYNAMIC TESTS OF ADRENAL FUNCTION Dynamic tests are often considered as the backbone of endocrinology. Involve the use of an exogenous agent to manipulate the body's hormonal milieu for the diagnosis and characterization of an endocrine disorder. In general, if a deficiency is suspected a stimulation test should be used If excess is considered likely, a suppression test is required. These tests are typically designed to differentiate between primary and secondary causes of disease, to detect abnormalities that may not be apparent in the results of static, baseline laboratory measurements
- 29. ACTH Stimulation (Cosyntropin) Test Indication: Suspect adrenal insufficiency (Addison’s disease) or congenital adrenal hyperplasia Designed to document the functional capacity of the adrenal glands to synthesize cortisol 1 Hour (Rapid) Cosyntropin Stimulation Test Principle: Administration of ACTH to normal subjects results in a rapid rise in the serum cortisol concentration Patients with adrenal destruction (e.g., Addison disease) show no change or an inadequate change in serum cortisol concentration after ACTH injection. Patients with atrophy of the adrenal cortex caused by exogenous glucocorticoid treatment or dysfunction of the pituitary gland or hypothalamus may show a slight rise in serum cortisol concentration, but not one of normal magnitude.
- 30. 1 Hour (Rapid) Cosyntropin Stimulation Test Procedure A baseline blood sample is drawn for determination of serum cortisol concentration Then 250 μg of cosyntropin is given intramuscularly or intravenously. Additional samples for serum cortisol determination are drawn 30 and 60 minutes after injection. Interpretation In normal: serum cortisol concentration peaks to 18 to 20 μg/dL or greater The expected change in cortisol concentration is 7 to 10 μg/dL( the delta cortisol) Normal plasma cortisol response, 30 min after cosyntropin (250 μg); adequately excludes ACTH deficiency,
- 32. Multiple-day ACTH stimulation test Required occasionally to evaluate adrenal cortisol responsiveness Diagnosis of adrenal insufficiency, which is treated with glucocorticosteroids before a cause has been established. Prolonged ACTH stimulation is used to distinguish primary from secondary and/or tertiary causes of adrenal insufficiency. Procedure: A total of 250 μg of cosyntropin is injected daily for 3 days This is followed by an 8 hour infusion of 250 μg of cosyntropin Urinary free cortisol and serum cortisol are measured daily
- 33. Interpretation Serum cortisol values of 18 to 20 μg/dL or greater • exclude primary adrenal insufficiency Little or no increase cortisol secretion • seen in primary adrenal failure even over successive days A progressive staircase rise in cortisol over 2 to 3 days • seen in adrenal insufficiency caused by pituitary or hypothalamic disease or steroid concentration suppression. Little or no response • Seen in congenital adrenal hyperplasia (CAH) caused by 21- and 17-hydroxylase deficiencies.
- 34. Metyrapone Stimulation Test Indirect test of hypothalamic-pituitary-adrenal axis function. Principle: Metyrapone inhibits 11-beta-hydroxylase (CYP11B1), the enzyme that converts 11-desoxycortisol to cortisol. As the blood concentration of cortisol falls, the negative feedback effect is diminished, causing the release of ACTH from the pituitary gland. The stimulatory effect of ACTH on the adrenal cortex leads to a rise in 11-deoxycortisol
- 35. Procedure Metyrapone (30 mg/kg body weight) is given orally at midnight with milk or a snack (to delay absorption). At the following morning at 8am, blood is drawn for determination of 11- deoxycortisol, cortisol, and ACTH concentrations. In normal subjects • 11-desoxycortisol increases from less than μg/dL to greater than 7 μg/dL after metyrapone stimulation, and • ACTH values exceed 150 pg/mL. No response or an impaired response seen in • pituitary or hypothalamic disease combined with inadequate enzyme blockade (plasma cortisol >3 μg/ dL) or Plasma 11-Deoxycorticol <7µg/dl in secondary and tertiary adrenal insufficiency Plasma ACTH <150pg/dl in secondary and tertiary adrenal insufficiency Interpretation
- 36. Mineralocorticoid Stimulation Tests Furosemide Stimulation Test Principle: Administration of furosemide, a potent diuretic, provides a stimulus to increase plasma renin secretion as the Plasma renin activity (PRA) varies with the patient’s state of hydration and sodium intake. Procedure Furosemide 40 to 80 mg is given orally after an overnight fast. The subject is maintained in an upright posture (sitting, standing, or walking) throughout the test. Blood is drawn for determination of PRA before and 4 hours after furosemide administration.
- 37. Interpretation Increased PRA following furosemide seen in: • patients with high-renin essential hypertension, • Pheochromocytoma Patients with hyporeninemic hypoaldosteronism usually have low concentrations of plasma renin and low aldosterone concentrations
- 38. Adrenocortical Insufficiency Normal Primary Secondary Tertiary Screening test Plasma ACTH (0800hours) 10-85pg/ml Increased Normal or decreased Normal or decreased Serum cortisol (0800hour) 5-23µg/dl Decreased Normal or decreased Normal or decreased Challenge Tests Rapid ACTH stimulation Peak cortisol >20µg/dl < 20µg/dl Any Any Overnight Metyrapone test Plasma 11- Deoxycorticol >7µg/dl Not indicated <7µg/dl <7µg/dl Plasma ACTH >150pg/ml Not indicated <150pg/ml <150pg/dl CRH stimulation test Plasma ACTH Not indicated Not indicated Decreased response Increased response Summary of TESTs
Editor's Notes
- #6: Cortisol deficiency is classified as (1) primary, (2) secondary, or (3) tertiary .Glucocorticoid therapy is the most common cause of secondary adrenocortical insufficiency
- #21: Increased Urea and creatinine, Mild to moderate hypercalcemia ,Mild acidosis .Azotemia with increased concentrations of blood urea nitrogen and serum creatinine is due to volume depletion and dehydration. Mild acidosis is frequently present.
- #25: ACTH 10-60pg/ml