Addison's Disease
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Dr. Mohd Ashraf Ganie is a renowned endocrinologist who has specialized in adrenal insufficiency (Addison's disease). He provides a detailed overview of Addison's disease, including its history, physiology, causes, clinical features, laboratory findings, diagnosis, and treatment. Some key points include: - Addison's disease was first described in 1855 and is characterized by destruction of the adrenal glands and a deficiency of cortisol and aldosterone. - The most common cause is an autoimmune process that destroys the adrenal cortex. Other causes include infections, hemorrhage, infiltrative diseases, and metastatic tumors. - Clinical features include fatigue, weight loss, low
![PHYSIOLOGY [contd.]
Mineralocorticoid
Modulates renal handling of Na+,
K+, and H+ ions
Retains Na+ at expense of K+ & H+
Deficiency
Hyponatremia,hyperkalemia, and acidosis
In primary AI combined glucocorticoid and mineralocorticoid deficiency causes
orthostatic hypotension,hyponatremia, hyperkalemia,and mild metabolic acidosis.](https://image.slidesharecdn.com/yenpoaaddison-200426161200/85/Addison-s-Disease-7-320.jpg)
![Endocrine testing [contd.]
5. Low dose (1mcg) ACTH test recommended by
some; may diagnose subtle abnormalities of
HPA axis; difficult to organize
6. Insulin tolerance test ; tests entire HPA axis
– Intrepetation same as ACTH test
7. Prolonged ACTH stimulation test
– Used as alternative to plasma ACTH to tell between
primary and secondary AI.](https://image.slidesharecdn.com/yenpoaaddison-200426161200/85/Addison-s-Disease-44-320.jpg)
![Summary [contd.]
However, large trials of dehydroepiandosterone for adrenal
insufficiency are still lacking and it has not yet been approved
for the treatment of this disease.
Patients with adrenal insufficiency are at risk of adrenal crisis,
usually precipitated by major stress, such as severe infection
or surgery.
Early dose adjustments are required to cover the increased
glucocorticoid demand in stress.
Careful & repeated education of patients & their partners is
the best strategy to avoid this life-threatening emergency.](https://image.slidesharecdn.com/yenpoaaddison-200426161200/85/Addison-s-Disease-52-320.jpg)
Addison's Disease
- 1. Dr. MOHD ASHRAF GANIE MBBS,MD,FRCP,DM Professor Endocrinology & Metabolism SKIMS Srinagar Former Associate Professor AIIMS,New Delhi • President Metabolic syndrome- Prediabetes-PCOS Society (M P PCOS), Chief Coordinator ICMR- PCOS Task Force, Editor Diabetes Obesity International J. • T C Anand Kumar Gold Medal, 3 Best paper Awards • Best DM Scholar AIIMS 2003, Rashtriya Gaurav Award, DSL Award, Best Researcher Award at SKIMS 2017 • 104 publications including journals like NEJM, Frontiers in Endocrinology, JCEM, Fertility Sterility, Diabetic Medicine, Gynecol Endocrinol, J of Obesity, Diabetes, Am J Clin Nutr etc. • REVIWER OF 20 HIGH IMPACT JOURNALS Primary Adrenal Insufficiency (Addison’s Disease)
- 2. Adrenal Insufficiency First clinical disorder linked to pathology in an endocrine gland Clinical syndrome –Thomas Addison in 1855 Named Addison’s disease by Trousseau in 1856 Acute Adrenal crisis in 1962 – surgical patient in chronic steroid user.
- 3. … the pioneer in clinical research who had the ability to observe, the genius to create, and the courage to publish his conclusions… Dr. Kendal (1956), on Dr. Sorkin’s paper, A Centaury of Addison's Disease, presented to New York Academy of Sciences
- 4. Patient with typical hyperpigmentation and vitiligo, as presented by Thomas Addison in his monograph
- 5. PHYSIOLOGY Glucocorticoids Modulates ACTH secretion Modulates vascular response to catecholamnines Maintains cardiac contractility Required for glycogenesis
- 6. PHYSIOLOGY Glucocorticoid Deficiency ACTH mediated hyperpigmentation ↓BP (tachycardia, ↓stroke volume, ↓peripheral vascular resistance) Hypoglycemia (occasionally)
- 7. PHYSIOLOGY [contd.] Mineralocorticoid Modulates renal handling of Na+, K+, and H+ ions Retains Na+ at expense of K+ & H+ Deficiency Hyponatremia,hyperkalemia, and acidosis In primary AI combined glucocorticoid and mineralocorticoid deficiency causes orthostatic hypotension,hyponatremia, hyperkalemia,and mild metabolic acidosis.
- 8. ADRENAL INSUFFICIENCY Inadequate Adrenocortical Function PRIMARY TERTIARYSECONDARY ADRENAL PITUITARY HYPOTHALAMUS ADDISON’S DISEASE
- 9. PRIMARYADRENAL INSUFFICIENCY (ADDISON’S DISEASE) First described by Thomas Addison in 1855 in patient of Adrenal tuberculosis In West incidence of TB decreased, presently Autoimmune Adrenalitis commonest cause of Addison’s disease Incidence 40-60 / million adults
- 10. PRIMARY ADRENAL INSUFFICIENCY Destruction of Adrenals Adrenal Dysplasia or Hypoplasia Impaired Steroidogenesis >90 % Gland destroyed before manifestation Reduction in all adrenal hormones Cortisol Minerellocorticoid Androgens Defect in genes for normal Adrenal Gland development Presents in early life
- 11. PRIMARY ADRENAL INSUFFICIENCY Destruction of Adrenals Adrenal Dysplasia or Hypoplasia Impaired Steroidogenesis 1. Autoimmune 2. Infections 3. Hemmorhage 4. Infiltration 5. Metastasis 1. SF-1 2. DAX-1 3. AHC 4. Corticotropin resistance Syn 5. Continous gene deletion defect CHOLESTEROL 1. Smith-lemli-Opitz 2. Abetalipoproteinemia STEROIDOGENESIS 1. StAR 2. Mitochondrial Dna del 3. CAH
- 12. Destruction of Adrenal Glands Autoimmune Infections Hemorrhage Infiltration Metastasis 70 % of cases in the West Usually associated with APS-1 and APS-2 In APS symptoms appear over many years, hence important to screen for “Adrenal Autoantibody” APS-1 1. Candidiasis 2. Addison’s (60%) 3. Hypoparathyroidism APS-2 1. Addison’s (100%) 2. Thyroid Disease 3. Diabetes
- 13. Destruction of Adrenal Glands InfectionsAutoimmune Hemorrhage Infiltration Metastasis 1. Tuberculosis 2. AIDS 3. Fungal Tuberculosis of Adrenal glands
- 14. Destruction of Adrenal Glands Autoimmune Infiltration 1. Amyloidosis 2. Sarcoidosis 3. Hemochrom atosis 4. Lymphoma MetastasisInfections Hemorrhage 1. Septic Shock (esp. meningococ cal) 2. Antiphosph olipid Syx 3. Anticoagula nts
- 15. Dysplasia/ Hypoplasia of Adrenal Glands SF-1 DAX-1 CRSAHC Cont gene DelA H C Adrenal Hypoplasia Hypogonadism Hypothalamic Hypoplasia Adrenal Hypoplasia Hypogonadism
- 16. Dysplasia/ Hypoplasia of Adrenal Glands SF-1 DAX-1 CRSAHC Cont gene DelA H C 4 Clinical forms I. Sporadic adrenal insufficiency + Pit Hypoplasia II. AR- distinct miniature Adrenal morphology III. X-L hypogonadotropic hypogonadism IV. X-L With glycerol Kinase deficiency I. Familial glucocorticoid deficiency Inactivating mutations of ACTH Receptor Deficient Cortisol and Androgens II. Allgrove Syx (Triple A) ACTH resistance Achalasia Alacrimia
- 17. Dysplasia/ Hypoplasia of Adrenal Glands SF-1 DAX-1 CRSAHC Cont gene DelA H C
- 18. CLINICAL FEATURES Adrenal insufficiency Chronic InsufficiencyAdrenal Crisis Fever Vomiting / nausea Abd Pain Diarrhoea Hypotension/Shock Confusion / coma + Features of Ppt. Event
- 19. CLINICAL FEATURES Adrenal insufficiency Chronic InsufficiencyAdrenal Crisis General Anorexia Wt. Loss Fatiguiblity Gen. Weakness Salt craving CVS Postural dizziness Hypotension GIT Abd Pain Vomiting Diarhhoea CNS Headache Depression Behavioural Changes Dermatologic Pigmentation Darkened Skin Creases Sexual Characters Loss of Axillary and Pubic Hair in Females with Loss of Libido
- 20. Lab Abnormalities High (supine) Plasma Renin Activity (Earliest Abnormality) Increased Nightime ACTH levels Low ACTH stimulated Cortisol responses At Crises Hyponatremia Hypoglycemia Hyperkalemia Misc Eosinophillia Lymphocytosis
- 21. Antibodies in Autoimmune Adrenalitis I. Adrenal Autoantibody (Adrenal Cortex) II. 21- hydroxylase III. Steroid Producing Cell Antibody IV. Steroidgenic Enzyme Antibodies (P450scc, P450c17) 17-alpha hydroxylase Ab in autoimmune Addison’s strong predictor for developing P.O.F.
- 22. Etiology of Adrenal insufficiency Idiopathic (autoimmune Adrenalitis) Fungal infections Adrenal hemorrhage Metastasis Sarcoidosis Amyloidosis Adrenoleukodystrophy Adrenomyeloneuropathy AIDS CA hyperplasia CA hypoplasia ACTH hypo responsiveness Toxins/drugs Tuberculosis Others Primary AI (Addison’s Dis.) 1. HPA –Axis suppression • Exogenous-Glucocorticoids, ACTH • Endogenous-Cushing’s syndrome – treated 2. Hypothalamic – pituitary disease • Neoplasm-metastasis, pituitary • Craniopharyngioma • Infections –TB, Nocardia, actinomyces • Sarcoidosis • Head trauma • Isolated ACTH deficiencySecondary AI
- 23. Etiology of Addison’s disease in developing countries Addison’s disease in Africa — a teaching hospital experience Steven Soule. Clinical Endocrinology (1999) 50, 115–120 Idiopathic Active TB Previous TB Autoimmune Malignancy Sarcoidosis Iron overload Ad.leukodystrophy (42%) (18%) (16%) (12%) (6%) Soule et al. Clinical Endocrinology (1999) 50, 115–120
- 24. Changing Pattern of Addison’s Disease
- 25. Autoimmune adrenal insufficiency Most common cause of 10AI Serum Adrenal antibodies (AA) that react with all 3 zones of the adrenal cortex present in 60-75 %. AA are more common in women, particularly those with the polyglandular autoimmune syndrome (APS). Patients with antibodies develop AI @~19% per yr. In APS -1, the presence of AA has a 92 % predictive value for the development of AI Ahonen, P, et al. J Clin Endocrinol Metab 1987; 64:494. Gylling, M, et al. J Clin Endocrinol Metab 2000; 85:4434.
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- 30. Causes of acute Adrenal Insufficiency Stress: – Acute AI precipitated by infection, trauma, surgery, emotional turmoil, etc Failure to increase steroids Bilateral adrenal hemorrhage Bilateral adrenal artery emboli and bilateral vein thrombosis It also may occur as a complication of radiographic contrast studies involving the adrenal glands. Bilateral adrenalectomy for any reason
- 31. Acute hemorrhage in bilateral adrenals - caused acute adrenal insufficiency (Waterhouse-Friderichsen syndrome)
- 33. Twenty nine years old South Asian Generalized hyper pigmentation of one year duration Mild asthenia, appetite normal Ht 170 cm, wt 73 mg, BMI 24.8 BP 110/70 no significant postural fall Gen. Hyper pigmentation of skin including nails Mucosal hyper pigmentation which was patch
- 35. Addison’s Disease and tuberculosis Chung et al Clinical endocrinology 2001:54;633-39 Autopsies- 1376 Active TB 871 Extrapulmonary 261 Adrenal TB 52 Addison's Disease- 7
- 36. Effect of Rifampicin on cortisol metabolism Pharmacokinetics of Prednisolone in 8 patients on rifampicin Clearence increased by 50% Tissue availibility reduced by 50% Doubling of prednisolone dose when given in combination with prednisolone Allister et al Thorax 1982;37:792-93
- 37. Natural history Some case reports of reversal of adrenal function Lack of normalization of adrenal function in 5 cases after one year of ATT Long-term data not available Bhatia E Clin endocrinol 1995;2007:20-23
- 38. CLINICAL AND LABORATORY FEATURES OF ADRENAL CRISIS Dehydration, hypotension, or shock out of proportion to severity of current illness Nausea and vomiting with a history of weight loss Unexplained hypoglycemia Unexplained fever Hyperpigmentation or vitiligo Hyponatremia, hyperkalemia, azotemia, hypercalcemia, eosinophilia Other autoimmune endocrine diseases like hypothyroidism or hypogonadism
- 39. Clinical Features of Primary Adrenal Insufficiency 100 92 86 75 33 31 16 16 12 10 100 94 91 15 5 Weakness, tiredness, fatigue Anorexia Gastrointestinal symptoms Nausea Vomiting Constipation Abdominal pain Diarrhea Salt craving Postural dizziness Muscle or joint pains Weight loss Hyperpigmentation Hypotension (<110 mm Hg systolic) Vitiligo Auricular calcification Percent 0 20 40 60 80 100 120
- 40. Hyperpigmentation of Addison's dis.
- 41. Lab Features of Primary Adrenal Insufficiency 92 88 64 6 55 40 17 Electrolyte disturbances Hyponatremia Hyperkalemia Hypercalcemia Azotemia Anemia Eosinophilia Percent 0 20 40 60 80 100 120
- 42. Endocrine testing 1. Urinary excretion of adrenal steroids and their metabolites cumbersome -- rarely used (and needed) 2. Random serum cortisol measurements useless (secretion pulsatile) 3. Plasma ACTH (N up to 50 pg/ml) elevated usually>200pg/ml)in primary AI and low or Inappropriately normal in secondary AI 4. ACTH stimulation test: Standard test for AI 0.25 mg synacthen,cosyntropin (synthetic ACTH 1-24) given I/V or I/M any time of day. Blood drawn for cortical 30 & 60 minutes later – Normal response defined as peak cortisol of 18 to 20 mcg/dl or more
- 43. Logarithmic Plot of plasma Cortisol as a function of plasma ACTH in pts with 10 AI, either untreated or 24h after a dose of hydrocortisone (O), Normal subjects (), & pts with Pituitary disease with or without AI ().
- 44. Endocrine testing [contd.] 5. Low dose (1mcg) ACTH test recommended by some; may diagnose subtle abnormalities of HPA axis; difficult to organize 6. Insulin tolerance test ; tests entire HPA axis – Intrepetation same as ACTH test 7. Prolonged ACTH stimulation test – Used as alternative to plasma ACTH to tell between primary and secondary AI.
- 45. Treatment of Acute Adrenal insufficiency Adrenal Crisis) Emergency Measures 1. Establish intravenous line with large –gauge needle 2. Draw blood for electrolytes, glucose, cortisol, and ACTH. DO NOT wait for results 3. Infuse 2 to 3 L of isotonic saline or 5% glucose in isotonic saline. Monitor for signs of volume overload. Reduce infusion rate, if indicated. 4. Supportive measures as needed.
- 46. TREATMENT OF AI DURING STRESS Intercurrent febrile illness, accident,or mental stress-double daily glucocortocoid dose Parenteral steroids if vomiting precludes oral intake Minor surgery-50-100 mg hydrocortisone with premedication Major operations-follow above with regimen for acute AI In pregnancy,5-10 mg additional hydrocortisone needed per day In labor give saline drip & 50 mg hydrocortisone q 6 hrs
- 47. Addisonian crisis-Therapy 1. Hydrocortisone Na succinate /phosphate – infusion @10-15 mg / hr ideal – pump. 2. Hydrocortisone Na succinate /phosphate – boluses, 100 mg stat followed by 50 mg 4 hrly for 24 hours 3. Step down gradually over 72 hrs & overlap with orals. 4. Replace salt and fluid losses according to grade of dehydration. 5. Primary cases – mineralocorticoids 6. Dx and addressing precipitating illness. 7. Antibiotics
- 48. Addisonian crisis - Treatment (Subacute Measures After Stabilization of the Patient) Search and treat the precipitating cause of the crisis Short ACTH test to confirm AI (if not previously known) Determine type and cause of AI (if not previously known) Taper glucocorticoids to maintenance doses over 1-3 days, if precipitating illness permits. Begin mineralocorticoid replacement with fludrocortisone(0.1 mg PO daily)
- 49. TREATMENT OF CHRONIC INSUFFICIENCY Replace missing hormones – – Glucocorticoids & mineralocorticoids in primary AI – Glucorticoids in secondary AI Hydrocortisone most appropriate glucocorticoid preparation; usual daily dose 12-15 mg/sq m BSA; 50% on rising & 25% each at lunchtime & early evening (Over treatment hazardous especially in children) Fludrocortisone-only mineralocorticoid available;dose 0.05-0.2 mg daily Females with 10 & 20 AI may benefit from adrenal androgen replacement with DHEA at 25-50 mg/day (improves sexual function & well-being) EDUCATION OF CRITICAL IMPORTANCE TO AVOID MORBIDITY AND DEATH
- 50. Summary Clinical presentation of Addison’s disease can be very bizarre ; we need high index of suspicion to diagnose it Addison’s disease is not that rare in the subcontinent in view of wide spread presence of tuberculosis Hypocortisol state because of postpartum pituitary disease is likely to be a significant problem particularly in rural areas
- 51. Summary Chronic glucocorticoid replacement consists of hydrocortisone 15-25 mg/day in divided doses and dose monitoring is largely based on clinical judgement. Fludrocortisone 0.05-0.2 mg/day is given for substitution in mineralocorticoid deficiency aiming at normotension, normokalaemia and a plasma renin activity in the upper normal range It has recently been shown that, despite adequate glucocorticoid and mineralocorticoid replacement well being in patients with adrenal insufficiency is still impaired. Several studies have demonstrated that dehydroepiandosterone 25- 50 mg/day p.o. may improve mood, fatigue, well-being and, in women, also sexuality, suggesting that dehydroepiandosterone should become part of the standard treatment regime.
- 52. Summary [contd.] However, large trials of dehydroepiandosterone for adrenal insufficiency are still lacking and it has not yet been approved for the treatment of this disease. Patients with adrenal insufficiency are at risk of adrenal crisis, usually precipitated by major stress, such as severe infection or surgery. Early dose adjustments are required to cover the increased glucocorticoid demand in stress. Careful & repeated education of patients & their partners is the best strategy to avoid this life-threatening emergency.
- 53. Central Hypocortisolism Panhypopituitarism Sheehan’s Post surgery-tumours Radiation MPH Deficiency Trauma Developmental anomlies
- 54. Sheehan's syndrome Eponyms & Synonyms: Glinski-Simmonds syndrome Reye-Sheehan syndrome Simmonds-Sheehan syndrome Simmonds cachexia Simmonds syndrome Reye's syndrome
- 55. History of SS Superinvolution of uterus-gynecologists Simpson-cl.course Morris Simmonds-1914-pit destruction German Medical Society 1939-proposed Simmond’s disease to it. 1937 –Sheehan –clinical syndrome (J Pathol Bacteriol)
- 56. Presentation Acute-hemorrhage/shock- death Sub-acute-lactation failure Chronic-trophic hormone deficiency-lag Atypical – Psychogenic,hypoglycemia,Diabetes Insipidus, Hyponatremia, Anemia etc.
- 57. Pathogenesis ISCHEMIA –necrosis physiological enlargement in pregnancy and Spasm/thrombosis SCHWARTZMAN’S REACTION-endotoxin AUTOIMMUNITY ( Engelberth 1965 Lancet) Auto antibodies against 49-Kd cytosolic antigen 19 SS & 28 controls.63.1% and 14.2% had Pit-ab + (R Goswami et al JCEM,2002)
- 58. Pathology Pituitary. Fibrillary scars- Normal- empty sella Lymphocytic infiltration Target organ. Atrophy of varying grades-all target organs
- 59. Endocrine evaluation Basal- T3,T4,TSH,LH,FSH,PRL. Dynamic tests 1, HGH- ITT(Insulin tolerance test) 0.1U/kg I/V-0,30,60,90 &120 mt Arginine () GHRH/GHRP2-6 L-Dopa (10 mg /KG)- 2,Prolactin- CPZ (50 mg I/M) PRL =20,30,60,90 and 120 mts Metaclopramide test(10 mg I/V)=20,40,60 TRH(200 mcg I/V)-0,20,40 Serum TSH
- 60. Evaluation-contd 3, ACTH Synacthene-250 mcg I/V-0,60 mts cortisol (N>20mcg/dl) Glugagon (1mcg I/V) ITT 4, TSH TRH/Triple test 5, Auto-antibodies 49-KDa
- 61. Evaluation-contd Imaging CT/MRI- Empty sella Sellar mass Lympocytic hypophysitis -uniform ,homogenous enlargement - Dural enhancement -sparing PP MRS -p/creatine ratio
- 62. MRI
- 63. Management Acute- Resuscitation-prevent severe hypotension Replacement Steroids-Hydrocortisone/predinisolone- Thyroxine-LT4 100-125 mcg/day E+P = Cyclic HGH= 0.1 U/kg/wk Adult GHD-
- 64. Take home message Secondary Adrenal insufficiency is not un common Autoimmunity is rarest India-Sheehan's commonest Tumours-pit Hypophysistis Granulomatus causes –TB