Cushing syndrome and addison disease

The adrenal cortex produces three major classes of steroids:
glucocorticoids,
(2) mineralocorticoids, and
(3) adrenal androgens.
Consequently, normal adrenal function is important for
-modulating intermediary metabolism and immune responses through glucocorticoids;
blood pressure, vascular volume, and electrolytes through mineralocorticoids;
secondary sexual characteristics (in females) through androgens.
The adrenal axis plays an important role in the stress response by rapidly increasing cortisol levels.
Adrenal disorders include hyperfunction (Cushing's syndrome) and hypofunction (adrenal insufficiency) as well as a variety of genetic abnormalities of steroidogenesis.

1. CUSHING SYNDROME AND ADDISON DISEASE Presented by Dr. PANKAJ YADAV [email protected] [email protected]

2. The adrenal cortex produces three major classes of steroids: glucocorticoids, (2) mineralocorticoids, and (3) adrenal androgens. Consequently, normal adrenal function is important for -modulating intermediary metabolism and immune responses through glucocorticoids; blood pressure, vascular volume, and electrolytes through mineralocorticoids; secondary sexual characteristics (in females) through androgens. The adrenal axis plays an important role in the stress response by rapidly increasing cortisol levels. Adrenal disorders include hyperfunction (Cushing's syndrome) and hypofunction (adrenal insufficiency) as well as a variety of genetic abnormalities of steroidogenesis. [email protected]

3. When stimulated by ACTH, the adrenal gland secretes cortisol and other steroid hormones. ACTH is produced by the pituitary gland and released into the petrosal venous sinuses in response to stimulation by corticotropin-releasing hormone (CRH) from the hypothalamus [email protected]

4. A constellation of clinical abnormalities due to chronic exposure to excess of cortisol or related corticosteroid described by Harvey Cushing in 1932 Definition [email protected]

5. CAUSES OF CUSHING’ S SYNDROME ACTH-dependent causes ACTH-secreting pituitary tumor ( Cushing’ s disease ) Pituitary CRH-secreting neoplasm ( ectopic CRP syndrome ) Nonpituitary ACTH-secreting neoplasm ( ectopic ACTH syndrome ) ACTH-independent causes Adrenal adenoma Adrenal carcinoma Micronodular adrenal disease McCune-Albright syndrome Massive macronodular adrenal diease Pseudo- cushing Syndrome Factitious or surreptitious glucocorticoid administration (IATROGENIC) Etiology and Pathophysiology [email protected]

6. COMMON CAUSES OF ECTOPIC ACTH SECRETION Small cell carcinoma of the lung 50% Endocrine tumors of foregut origin 35 % Thymic carcinoid Islet cell tumor Medullary carcinoma thyroid Bronchial carcinoid Pheochromocytoma 5 % Ovarian tumors 2 % [email protected]

7. Clinical Feature Hypercotisolism Lipid mobilization  Lipid catabolism  Lipid redistribution Moon-face buffalo hump truncal obesity Violaceous striae Hepatic glucose production Insulin resistance Glucose intolerance protein metabolism negative nitrogen balance disruption of water and electrocytes metabolism Proximal muscle weakness Dependent edema Hypertension Hypokalemic metabolic alkalosis [email protected]

8. Frequency(%) Weight gain 90 “Moon facies ” 75 Hypertension 75 Violaceous striae 65 Hirsutism 65 Glucose intolerance 65 Proximal muscle weakness 60 Plethora 60 Menstrual dysfunction 60 Acne 40 Easy bruising 40 Osteopenia 40 Dependent edema 40 Hyperpigmentation 20 Hypokalemic metabolic alkalosis 15 CLINICAL FEATURES OF GLUCOCORTICOID EXCESS [email protected]

9. Clinical manifestations Cortisol levels in blood are normally elevated at 8 a . m . and decrease to less than 50% by midnight except in infants and young children in whom a diurnal rhythm is not always established. In patients with Cushing syndrome this circadian rhythm is lost, and cortisol levels at midnight and 8 a . m . are usually comparable. Urinary excretion of free cortisol is increased. This is best measured in a 24-hr urine sample and is expressed as a ratio of micrograms of cortisol excreted per gram of creatinine . Diagnosis [email protected]

10. Dexamethasone is an exogenous steroid that provides negative feedback to the pituitary to suppress the secretion of ACTH. This steroid is unable to pass the blood brain barrier which allows this test to assess a specific part of the hypothalamic-pituitary-adrenal axis. Specifically, dexamethasone binds to glucocorticoid receptors in the pituitary gland , which lies outside the blood brain barrier, resulting in regulatory modulation A single-dose dexamethasone suppression test is often helpful; a dose of 25–30 μg /kg (maximum of 2 mg) given at 11 p . m . results in a plasma cortisol level of less than 5 μg / dL at 8 a . m . the next morning in normal individuals but not in patients with Cushing syndrome. A low dose dexamethasone suppresses cortisol in individuals with no pathology in endogenous cortisol production. A high dose dexamethasone exerts negative feedback on pituitary ACTH producing cells but not on ectopic ACTH producing cells or adrenal adenoma. Dexamethasone suppression test [email protected]

11. Low-dose A normal result is decrease in cortisol levels upon administration of low-dose dexamethasone . Cushing's disease involve no change in cortisol on low-dose dexamethasone , but inhibition of cortisol on high-dose dexamethasone [email protected]

12. Large dose DX suppression test D.X 2mg q6h P.O 2 days Urinary free cortisol reduced 50%: Cushing’s disease (Pituitary adenoma) Urinary free cortisol NOT reduced 50%:Adrenal tumor, carcinoma, ectopic ACTH Syndrome Suppression tests [email protected]

13. ACTH 25u intravenously 8h 2-5 fold increase in urinary free cortisol in Cushing’ s disease Plasma cortisol and urinary free cortisol increase in half of adrenal adenoma patients No response in adrenal carcinoma ACTH Stimulation test [email protected]

14. Etiology diagnose (especially for pituitary ACTH-dependent or ectopic ACTH syndrome) A newer approach is to combine a CRH stimulation test with a dexamethasone suppression test(4mg ). method : 1 µg / kg of CRH is administered intravenously. ACTH and cortisol levels are measured before CRH injection and 15, 30, 45, 60, 90 and 120 minutes after injection. A rise in the cortisol value of 20 percent or more above basal level or a rise in the ACTH value of at least 50 percent above basal level is considered evidence for an ACTH-dependent lesion CRH stimulation test [email protected]

15. Etiology diagnose (especially for pituitary or adrenal) Metyrapone (30mg/kg) P.O at midnight Urinary 17-OHCS, Plasma ACTH,11- deoxycortisol more above basal level : Cushing’s disease (Pituitary adenoma) No response in adrenal carcinoma , tumor, ectopic ACTH Syndrome Metyrapone Test [email protected]

16. Pituitary CT has a sensitivity of about 50% for identifying microadenomas MRI has increased sensitivity but is not 100% predictive If diagnostic doubt need bilateral inferior petrosal sinus sampling for ACTH Adrenal ultrasonography- --first choice Abdominal CT will allow identification of adrenal pathology Somatostatin scintigraphy to identify sites of ectopic hormone production Imaging diagnosis [email protected]

17. Cushing’ s disease: Adrenal adenoma: Adrenal carcinoma: Ectopic ACTH Syndrome: Chronic, moderate clinical features can be suppressed by large dose test Shorter course , mild features can NOT be suppressed by large dose test Acute onset, progressive course, hyperandrogenic effect predominate, palpable mass, low ACTH Appear suddenly, progress rapidly, not typical manifestation of Cushing’s syndrome, hyperpigmentation, hypokalemia, high ACTH Etiological diagnosis [email protected]

18. Cushing’s disease Transsphenoidal microadenomectomy Pituitary radiation Bilateral total adrenolectomy Drugs Adrenal adenoma and carcinoma Surgical removal Drugs ( mitotane, metyrapone, ketoconazole ) for nonresectable or metastatic carcinoma Ectopic ACTH Syndrome Surgical removal of the ectopic tumor Chemotherapy, radiotherapy Drugs ( mitotane, metyrapone, ketoconazloe ) Treatment [email protected]

19. Purpose Correct metabolic abnormalities before attempted surgical cure Palliate surgically noncurable disease Achieve remission in patients for whom surgery is unlikely to achieve satisfactory long term results Medical therapy of Cushing’ s Disease [email protected]

20. Steroidogenic inhibition Mitotane Metyrapone Aminoglutethimide Ketoconazole Neuromodulatory treatment Bromocriptine Cyproheptadin Valproic acid Octreotide Glucocorticoid receptor antagonist RU486 [email protected]

21. The original description of Addison's disease"general languor and debility, feebleness of the heart's action, irritability of the stomach, and a peculiar change of the color of the skin"summarizes the dominant clinical features. Addison's disease results from progressive destruction of the adrenals, which must involve >90% of the glands before adrenal insufficiency appears ADDISON’S DISEASE [email protected]

22. PRIMARY ADRENAL INSUFFICIENCY Congenital adrenal hyperplasia Anatomic destruction of gland (chronic or acute ) " Idiopathic" atrophy (autoimmune, adrenoleukodystrophy ) Surgical removal Infection ( tuberculous , fungal, viralæ especially in AIDS patients) Hemorrhage Invasion: metastatic Metabolic failure in hormone production Enzyme inhibitors ( metyrapone , ketoconazole , aminoglutethimide ) Cytotoxic agents ( mitotane ) ACTH-blocking antibodies Mutation in ACTH receptor gene Adrenal hypoplasia congenita SECONDARY ADRENAL INSUFFICIENCY Hypopituitarism due to hypothalamic-pituitary disease Suppression of hypothalamic-pituitary axis By exogenous steroid By endogenous steroid from tumor Classification of Adrenal Insufficiency [email protected]

23. [email protected]

24. Frequency of Symptoms and Signs in Adrenal Insufficiency Sign or Symptom Percent of Patients   Weakness 99   Pigmentation of skin 98   Weight loss 97   Anorexia, nausea, and vomiting 90   Hypotension ( < 110/70) 87   Pigmentation of mucous membranes 82   Abdominal pain 34   Salt craving 22   Diarrhea 20   Constipation 19   Syncope 16   Vitiligo 9   [email protected]

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28. General: K+ ↑ Na+ ↓ glucose ↓ uraemia, mild acidosis, Ca2+ ↑ eosinophilia , neutropenia . lymphocytosis . anaemia, abnormal LFTs, INVESTIGATIONS [email protected]

29. The short test compares blood cortisol levels before and after 250 micrograms of tetracosactide (intramuscular or intravenous) is given. If, one hour later, plasma cortisol exceeds 170 nmol /l and has risen by at least 330 nmol /l to at least 690 nmol /l, adrenal failure is excluded. If the short test is abnormal, the long test is used to differentiate between primary adrenal insufficiency and secondary adrenocortical insufficiency. ACTH stimulation test [email protected]

30. The long test uses 1 mg tetracosactide (intramuscular). Blood is taken 1, 4, 8, and 24 hr later. Normal plasma cortisol level should reach 1000 nmol /l by 4 hr . In primary Addison's disease, the cortisol level is reduced at all stages, whereas in secondary corticoadrenal insufficiency, a delayed but normal response is seen. [email protected]

31. In Addison’s disease ACTH is iniappropriately high Low in secondary causes. ACTH: [email protected]

32. To assess mineralocortocoid status, Adrenal antibodies Plasma reninactivity and aldosterone: [email protected]

33. Look for signs of previous TB, eg calcification. Have a low threshold far further investigations for TB , especially if autoantibodies are negative, eg CT adrenal glands. AXR (plain abdominal films) and CXR: [email protected]

34. All patients with adrenal insufficiency should receive specific hormone replacement. Replacement therapy should correct both glucocorticoid and mineralocorticoid deficiencies. Hydrocortisone ( cortisol ) is the mainstay of treatment. The dose for physiologic replacement (~10 mg/M 2 /24 hr of hydrocortisone) . Patients are advised to take glucocorticoids with meals or, if that is impractical, with milk or an antacid, because the drugs may increase gastric acidity and exert direct toxic effects on the gastric mucosa. To simulate the normal diurnal adrenal rhythm, two-thirds of the dose is taken in the morning, and the remaining one-third is taken in the late afternoon. TREATMENT [email protected]

35. Since the replacement dosage of hydrocortisone does not replace the mineralocorticoid component of the adrenal hormones, mineralocorticoid supplementation is usually needed. This is accomplished by the administration of 0.05 to 0.1 mg fludrocortisone per day by mouth. Patients should also be instructed to maintain an ample intake of sodium (3 to 4 g/d). TREATMENT [email protected]

36. In female patients with adrenal insufficiency, androgen levels are also low. Thus, some physicians believe that daily replacement with 25 to 50 mg of DHEA orally may improve quality of life and skeletal density. TREATMENT [email protected]

37. Complications of glucocorticoid therapy, with the exception of gastritis, are rare at the dosages recommended for treatment of adrenal insufficiency. Complications of mineralocorticoid therapy include hypokalemia , hypertension, cardiac enlargement, and even congestive heart failure due to sodium retention. Periodic measurements of body weight, serum potassium level, and blood pressure are useful. ADVERSE EFFECTS [email protected]

38. During periods of intercurrent illness, especially in the setting of fever, the dose of hydrocortisone should be doubled. With severe illness it should be increased to 75 to 150 mg/d. When oral administration is not possible, parenteral routes should be employed Likewise, before surgery or dental extractions, supplemental glucocorticoids should be administered. Special Therapeutic Problems [email protected]

39. Table 331-9. Glucocorticoid Preparations Estimated Potency b   Commonly Used Name a Glucocorticoid Mineralocorticoid   SHORT-ACTING Hydrocortisone 1 1   Cortisone 0.8 0.8   INTERMEDIATE-ACTING Prednisone 4 0.25   Prednisolone 4 0.25   Methylprednisolone 5 < 0.01   Triamcinolone 5 < 0.01   LONG-ACTING Paramethasone 10 < 0.01   Betamethasone 25 < 0.01   Dexamethasone 30-40 < 0.01   a The steroids are divided into three groups according to the duration of biologic activity. Short-acting preparations have a biologic half-life < 12 h; long-acting, > 48 h; and intermediate, between 12 and 36 h. Triamcinolone has the longest half-life of the intermediate-acting preparations. b Relative milligram comparisons with hydrocortisone, setting the glucocorticoid and mineralocorticoid properties of hydrocortisone as 1. Sodium retention is insignificant for commonly employed doses of methylprednisolone, triamcinolone, paramethasone, betamethasone, and dexamethasone. [email protected]

40. A Checklist for Use Prior to the Administration of Glucocorticoids in Pharmacologic Doses -Presence of tuberculosis or other chronic infection (chest x-ray, tuberculin test) -Evidence of glucose intolerance or history of gestational diabetes mellitus -Evidence of preexisting osteoporosis (bone density assessment in organ transplant recipients or postmenopausal patients) -History of peptic ulcer, gastritis, or esophagitis (stool guaiac test) Evidence of hypertension or cardiovascular disease -History of psychological disorders [email protected]

41. Supplementary Measures to Minimize Undesirable Metabolic Effects of Glucocorticoids -Monitor caloric intake to prevent weight gain. -Restrict sodium intake to prevent edema and minimize hypertension and potassium loss. -Provide supplementary potassium if necessary. -Provide antacid, H2 receptor antagonist, and/or H+,K+- ATPase inhibitor therapy. -Institute alternate-day steroid schedule if possible. Patients receiving steroid therapy over a prolonged period should be protected by an appropriate increase in hormone level during periods of acute stress. A rule of thumb is to double the maintenance dose. -Minimize osteopenia by Administering gonadal hormone replacement therapy: 0.625-1.25 mg conjugated estrogens given cyclically with progesterone, unless the uterus is absent; testosterone replacement for hypogonadal men -Ensuring high calcium intake (should be approximately 1200 mg/d) -Administering supplemental vitamin D if blood levels of calciferol or 1,25(OH)2 vitamin D are reduced -Administering bisphosphonate prophylactically , orally or parenterally , in high-risk patients [email protected]

42. 1. Adrenal crisis may be a rapid and overwhelming intensification of chronic adrenal insufficiency, usually precipitated by sepsis or surgical stress. 2. Alternatively , acute hemorrhagic destruction of both adrenal glands can occur in previously well subjects. 3. In children, this event is usually associated with septicemia with Pseudomonas or meningococcemia (Waterhouse- Friderichsen syndrome). 4. In adults, anticoagulant therapy or a coagulation disorder may result in bilateral adrenal hemorrhage . ACUTE ADRENOCORTICAL INSUFFICIENCY [email protected]

43. Treatment is directed primarily toward repletion of circulating glucocorticoids and replacement of the sodium and water deficits. intravenous infusion of 5% glucose in normal saline solution should be started with a bolus intravenous infusion of 100 mg hydrocortisone followed by a continuous infusion of hydrocortisone at a rate of 10 mg/h. TREATMENT [email protected]

44. thanks [email protected]