Cushing syndrome and addison disease

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The adrenal cortex produces three major classes of steroids: …

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.

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  • 1. Presented byDr. PANKAJ YADAVdrpankajyadav05@gmail.comdrpankajyadav05@gmail.com
  • 2.  The adrenal cortex produces three major classesof steroids:(1) glucocorticoids,(2) mineralocorticoids, and(3) adrenal androgens.Consequently, normal adrenal function is important for-modulating intermediary metabolism and immuneresponses through glucocorticoids;- blood pressure, vascular volume, and electrolytesthrough mineralocorticoids;- secondary sexual characteristics (in females) throughandrogens.- The adrenal axis plays an important role in the stressresponse by rapidly increasing cortisol levels.- Adrenal disorders include hyperfunction (Cushingssyndrome) and hypofunction (adrenal insufficiency) aswell as a variety of genetic abnormalities ofsteroidogenesis.drpankajyadav05@gmail.com
  • 3. When stimulated by ACTH, the adrenal gland secretes cortisol and other steroidhormones. ACTH is produced by the pituitary gland and released into thepetrosal venous sinuses in response to stimulation by corticotropin-releasingdrpankajyadav05@gmail.com
  • 4.  A constellation of clinical abnormalities dueto chronic exposure to excess of cortisol orrelated corticosteroid described by Harvey Cushing in 1932drpankajyadav05@gmail.com
  • 5. CAUSES OF CUSHING’ S SYNDROMEACTH-dependent causesACTH-secreting pituitary tumor ( Cushing’ s disease )Pituitary CRH-secreting neoplasm ( ectopic CRP syndrome )Nonpituitary ACTH-secreting neoplasm ( ectopic ACTH syndrome )ACTH-independent causesAdrenal adenomaAdrenal carcinomaMicronodular adrenal diseaseMcCune-Albright syndromeMassive macronodular adrenal dieasePseudo-cushing SyndromeFactitious or surreptitious glucocorticoid administration(IATROGENIC)drpankajyadav05@gmail.com
  • 6. COMMON CAUSES OF ECTOPIC ACTH SECRETIONSmall cell carcinoma of the lung50%Endocrine tumors of foregut origin35%Thymic carcinoidIslet cell tumorMedullary carcinoma thyroidBronchial carcinoidPheochromocytoma 5%Ovarian tumors2%drpankajyadav05@gmail.com
  • 7. HypercotisolismLipid mobilization Lipid catabolism Lipid redistributionMoon-facebuffalo humptruncal obesityViolaceous striaeHepatic glucoseproductionInsulin resistanceGlucose intoleranceprotein metabolism negativenitrogen balancedisruption of water andelectrocytes metabolismProximal muscleweakness Dependent edemaHypertensionHypokalemic metabolicalkalosisdrpankajyadav05@gmail.com
  • 8. Frequency(%)Weight gain 90“Moon facies” 75Hypertension 75Violaceous striae65Hirsutism 65Glucose intolerance 65Proximal muscle weakness60Plethora60Menstrual dysfunction 60Acne 40Easy bruising 40Osteopenia 40Dependent edema40Hyperpigmentation 20Hypokalemic metabolic alkalosis15drpankajyadav05@gmail.com
  • 9.  Clinical manifestations Cortisol levels in blood are normally elevated at 8 A.M.and decrease to less than 50% by midnight except ininfants and young children in whom a diurnal rhythm isnot always established. In patients with Cushing syndrome this circadianrhythm is lost, and cortisol levels at midnight and 8A.M. are usually comparable. Urinary excretion of free cortisol is increased. This isbest measured in a 24-hr urine sample and isexpressed as a ratio of micrograms of cortisol excretedper gram of creatinine.drpankajyadav05@gmail.com
  • 10.  Dexamethasone is an exogenous steroid that provides negativefeedback to the pituitary to suppress the secretion of ACTH. This steroid is unable to pass the blood brain barrier whichallows this test to assess a specific part of the hypothalamic-pituitary-adrenal axis. Specifically, dexamethasone binds toglucocorticoid receptors in the pituitary gland, which lies outsidethe 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 withCushing syndrome. A low dose dexamethasone suppresses cortisol in individualswith no pathology in endogenous cortisol production. A highdose dexamethasone exerts negative feedback on pituitary ACTHproducing cells but not on ectopic ACTH producing cells oradrenal adenoma.drpankajyadav05@gmail.com
  • 11.  Low-dose A normal result is decrease in cortisol levelsupon administration of low-dosedexamethasone. Cushings disease involve no change incortisol on low-dose dexamethasone, butinhibition of cortisol on high-dosedexamethasonedrpankajyadav05@gmail.com
  • 12.  Large dose DX suppression test◦ D.X 2mg q6h P.O 2 days◦ Urinary free cortisol reduced 50%: Cushing’sdisease (Pituitary adenoma)◦ Urinary free cortisol NOT reduced 50%:Adrenaltumor, carcinoma, ectopic ACTH Syndromedrpankajyadav05@gmail.com
  • 13.  ACTH 25u intravenously 8h 2-5 fold increase in urinary free cortisol inCushing’ s disease Plasma cortisol and urinary free cortisolincrease in half of adrenal adenoma patients No response in adrenal carcinomadrpankajyadav05@gmail.com
  • 14.  Etiology diagnose (especially for pituitaryACTH-dependent or ectopic ACTH syndrome) A newer approach is to combine a CRH stimulationtest with a dexamethasone suppression test(4mg ). method :1 µg / kg of CRH is administered intravenously.ACTH and cortisol levels are measured beforeCRH injection and 15, 30, 45, 60, 90 and 120minutes after injection. A rise in the cortisol value of 20 percent or moreabove basal level or a rise in the ACTH value of atleast 50 percent above basal level is consideredevidence for an ACTH-dependent lesiondrpankajyadav05@gmail.com
  • 15.  Etiology diagnose (especially for pituitary oradrenal)◦ Metyrapone (30mg/kg) P.O at midnight◦ Urinary 17-OHCS, Plasma ACTH,11-deoxycortisolmore above basal level : Cushing’s disease(Pituitary adenoma)◦ No response in adrenalcarcinoma , tumor, ectopic ACTH Syndromedrpankajyadav05@gmail.com
  • 16.  Pituitary CT has a sensitivity of about50% for identifying microadenomas MRI has increased sensitivity but is not100% predictive If diagnostic doubt need bilateral inferiorpetrosal sinus sampling for ACTH Adrenal ultrasonography---first choice Abdominal CT will allow identification ofadrenal pathology Somatostatin scintigraphy to identifysites of ectopic hormone productiondrpankajyadav05@gmail.com
  • 17.  Cushing’ s disease: Adrenal adenoma: Adrenal carcinoma: Ectopic ACTHSyndrome: Chronic, moderate clinicalfeatures can be suppressed bylarge dose test Shorter course , mild featurescan NOT be suppressed by largedose test Acute onset, progressivecourse, hyperandrogenic effectpredominate, palpablemass, low ACTH Appear suddenly, progressrapidly, not typical manifestationof Cushing’ssyndrome, hyperpigmentation, hypokalemia, high ACTHdrpankajyadav05@gmail.com
  • 18.  Cushing’s disease◦ Transsphenoidal microadenomectomy◦ Pituitary radiation◦ Bilateral total adrenolectomy◦ Drugs Adrenal adenoma and carcinoma◦ Surgical removal◦ Drugs ( mitotane, metyrapone, ketoconazole ) fornonresectable or metastatic carcinoma Ectopic ACTH Syndrome◦ Surgical removal of the ectopic tumor◦ Chemotherapy, radiotherapy◦ Drugs ( mitotane, metyrapone, ketoconazloe )drpankajyadav05@gmail.com
  • 19.  Purpose◦ Correct metabolic abnormalities beforeattempted surgical cure◦ Palliate surgically noncurable disease◦ Achieve remission in patients for whom surgeryis unlikely to achieve satisfactory long termresultsdrpankajyadav05@gmail.com
  • 20.  Steroidogenic inhibition◦ Mitotane◦ Metyrapone◦ Aminoglutethimide◦ Ketoconazole Neuromodulatory treatment◦ Bromocriptine◦ Cyproheptadin◦ Valproic acid◦ Octreotide Glucocorticoid receptor antagonist◦ RU486drpankajyadav05@gmail.com
  • 21.  The original description of Addisonsdisease"general languor anddebility, feebleness of the heartsaction, irritability of the stomach, and apeculiar change of the color of theskin"summarizes the dominant clinicalfeatures. Addisons disease results from progressivedestruction of the adrenals, which mustinvolve >90% of the glands before adrenalinsufficiency appearsdrpankajyadav05@gmail.com
  • 22. PRIMARY ADRENAL INSUFFICIENCYCongenital adrenal hyperplasiaAnatomic destruction of gland (chronic or acute)"Idiopathic" atrophy (autoimmune, adrenoleukodystrophy)Surgical removalInfection (tuberculous, fungal, viralæ especially in AIDS patients)HemorrhageInvasion: metastaticMetabolic failure in hormone productionEnzyme inhibitors (metyrapone, ketoconazole, aminoglutethimide)Cytotoxic agents (mitotane)ACTH-blocking antibodiesMutation in ACTH receptor geneAdrenal hypoplasia congenitaSECONDARY ADRENAL INSUFFICIENCYHypopituitarism due to hypothalamic-pituitary diseaseSuppression of hypothalamic-pituitary axisBy exogenous steroidBy endogenous steroid from tumordrpankajyadav05@gmail.com
  • 23. drpankajyadav05@gmail.com
  • 24. Frequency of Symptoms and Signs in AdrenalInsufficiencySign or Symptom Percent of PatientsWeakness 99Pigmentation of skin 98Weight loss 97Anorexia, nausea, and vomiting 90Hypotension (<110/70) 87Pigmentation of mucous membranes 82Abdominal pain 34Salt craving 22Diarrhea 20Constipation 19Syncope 16Vitiligo 9drpankajyadav05@gmail.com
  • 25. drpankajyadav05@gmail.com
  • 26. drpankajyadav05@gmail.com
  • 27. drpankajyadav05@gmail.com
  • 28. General:K+↑ Na+↓ glucose ↓ uraemia,mild acidosis,Ca2+ ↑eosinophilia,neutropenia.lymphocytosis.anaemia,abnormal LFTs,drpankajyadav05@gmail.com
  • 29.  The short test compares blood cortisol levelsbefore and after 250 micrograms oftetracosactide (intramuscular or intravenous) isgiven. If, one hour later, plasma cortisol exceeds 170nmol/l and has risen by at least 330 nmol/l to atleast 690 nmol/l, adrenal failure is excluded. If the short test is abnormal, the long test is usedto differentiate between primary adrenalinsufficiency and secondary adrenocorticalinsufficiency.drpankajyadav05@gmail.com
  • 30.  The long test uses 1 mg tetracosactide(intramuscular). Blood is taken 1, 4, 8, and 24hr later. Normal plasma cortisol level should reach1000 nmol/l by 4 hr. In primary Addisonsdisease, the cortisol level is reduced at allstages, whereas in secondary corticoadrenalinsufficiency, a delayed but normal responseis seen.drpankajyadav05@gmail.com
  • 31. In Addison’s disease ACTH isiniappropriately highLow in secondary causes.drpankajyadav05@gmail.com
  • 32. To assess mineralocortocoid status,Adrenal antibodiesdrpankajyadav05@gmail.com
  • 33. Look for signs of previous TB, eg calcification.Have a low threshold far further investigationsfor TB, especially if autoantibodies arenegative, eg CT adrenal glands.drpankajyadav05@gmail.com
  • 34.  All patients with adrenal insufficiency shouldreceive specific hormone replacement. Replacement therapy should correct bothglucocorticoid and mineralocorticoid deficiencies. Hydrocortisone (cortisol) is the mainstay oftreatment. The dose for physiologic replacement(~10 mg/M2/24 hr of hydrocortisone). Patients are advised to take glucocorticoids withmeals or, if that is impractical, with milk or anantacid, because the drugs may increase gastricacidity and exert direct toxic effects on the gastricmucosa. To simulate the normal diurnal adrenalrhythm, two-thirds of the dose is taken in themorning, and the remaining one-third is taken inthe late afternoon.drpankajyadav05@gmail.com
  • 35.  Since the replacement dosage ofhydrocortisone does not replace themineralocorticoid component of the adrenalhormones, mineralocorticoidsupplementation is usually needed. This isaccomplished by the administration of 0.05to 0.1 mg fludrocortisone per day bymouth. Patients should also be instructed tomaintain an ample intake of sodium (3 to 4g/d).drpankajyadav05@gmail.com
  • 36.  In female patients with adrenalinsufficiency, androgen levels are also low.Thus, some physicians believe that dailyreplacement with 25 to 50 mg of DHEA orallymay improve quality of life and skeletaldensity.drpankajyadav05@gmail.com
  • 37.  Complications of glucocorticoid therapy, with theexception of gastritis, are rare at the dosagesrecommended for treatment of adrenalinsufficiency. Complications of mineralocorticoid therapyinclude hypokalemia, hypertension, cardiacenlargement, and even congestive heart failure dueto sodium retention. Periodic measurements ofbody weight, serum potassium level, and bloodpressure are useful.drpankajyadav05@gmail.com
  • 38.  During periods of intercurrentillness, especially in the setting of fever, thedose of hydrocortisone should be doubled. With severe illness it should be increasedto 75 to 150 mg/d. When oral administration is notpossible, parenteral routes should beemployed Likewise, before surgery or dentalextractions, supplemental glucocorticoidsshould be administered.drpankajyadav05@gmail.com
  • 39. Table 331-9. Glucocorticoid PreparationsEstimated PotencybCommonly Used Namea Glucocorticoid MineralocorticoidSHORT-ACTINGHydrocortisone 1 1Cortisone 0.8 0.8INTERMEDIATE-ACTINGPrednisone 4 0.25Prednisolone 4 0.25Methylprednisolone 5 <0.01Triamcinolone 5 <0.01LONG-ACTINGParamethasone 10 <0.01Betamethasone 25 <0.01Dexamethasone 30-40 <0.01a The steroids are divided into three groups according to the duration of biologic activity. Short-acting preparations have a biologic half-life <12h; 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. Sodiumretention is insignificant for commonly employed doses of methylprednisolone, triamcinolone, paramethasone, betamethasone, anddexamethasone. drpankajyadav05@gmail.com
  • 40. A Checklist for Use Prior to the Administrationof Glucocorticoids in Pharmacologic Doses-Presence of tuberculosis or other chronic infection (chest x-ray,tuberculin test)-Evidence of glucose intolerance or history of gestational diabetesmellitus-Evidence of preexisting osteoporosis (bone density assessment inorgan transplant recipients or postmenopausal patients)-History of peptic ulcer, gastritis, or esophagitis (stool guaiac test)Evidence of hypertension or cardiovascular disease-History of psychological disordersdrpankajyadav05@gmail.com
  • 41. Supplementary Measures to Minimize Undesirable Metabolic Effects ofGlucocorticoids-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 prolongedperiod should be protected by an appropriate increase in hormone level during periods of acute stress. Arule of thumb is to double the maintenance dose.-Minimize osteopenia byAdministering gonadal hormone replacement therapy: 0.625-1.25 mg conjugated estrogens givencyclically 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 patientsdrpankajyadav05@gmail.com
  • 42. 1. Adrenal crisis may be a rapid andoverwhelming intensification of chronic adrenalinsufficiency, usually precipitated by sepsis orsurgical stress.2. Alternatively, acute hemorrhagic destruction ofboth adrenal glands can occur in previously wellsubjects.3. In children, this event is usually associated withsepticemia with Pseudomonas or meningococcemia(Waterhouse-Friderichsen syndrome).4. In adults, anticoagulant therapy or a coagulationdisorder may result in bilateral adrenalhemorrhage.drpankajyadav05@gmail.com
  • 43.  Treatment is directed primarily towardrepletion of circulating glucocorticoids andreplacement of the sodium and waterdeficits. intravenous infusion of 5% glucose innormal saline solution should be startedwith a bolus intravenous infusion of 100 mghydrocortisone followed by a continuousinfusion of hydrocortisone at a rate of 10mg/h.drpankajyadav05@gmail.com
  • 44. drpankajyadav05@gmail.com