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Addison disease
The document discusses Addison's disease, characterized by adrenal insufficiency and the failure of the adrenal cortex to secrete adequate glucocorticoids and mineralocorticoids. It includes case studies, details on the disease's epidemiology, presentations, and diagnostic procedures for primary and secondary adrenal insufficiency, along with treatment protocols such as glucocorticoid and mineralocorticoid replacement. The document also mentions the associations with autoimmune diseases and highlights the importance of monitoring and management of acute adrenal crises.
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Addison disease
- 1. Addison Disease Usama RagabYoussif, MD Lecturer of Medicine Zagazig University Email: usamaragab@medicine.zu.edu.eg Slideshare: https://www.slideshare.net/dr4spring/ Mobile: 00201000035863
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- 6. ACTH manner of secretion •ACTH secretion is pulsatile • Amplitude of each pulse varies in circadian fashion Highest at time of awakening Lowest in late evening
- 8. The secreted steroids are 1.From ZG (under control of RAAS ± ACTH): • Aldosterone • Deoxycorticosterone (DOCA) 2. From ZF (under control of ACTH): • Cortisol (GC) 3. From ZR (under control of ACTH): • Dehydroepiandrosteron (DHEA) • Dehydroepiandrosterons(DHEAS) • +/- glucocorticoids
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- 10. Steroidogenesis ACTH Only source infemales Cortisone G G: 11 B-hydroxysteroid dehydrogenase 2
- 12. Cortisol action Metabolic= anti-insulin+ lipogenesis Water= Inhibit vasopressin + K loss +/- Na retention Blood= ↓ eosinophil & lymphocytes
- 13. Aldosterone action Act onDCT and CD Na reabsorption & K loss
- 14. DHEA Action In males=very little effect, responsible of first appearance of axillary & pubic hair In females= it is the only androgen, adrenarche & pubarche + sense of well being + libido
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- 17. 3 arteries &1 vein
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- 19. Case Vignette A 26-year-old manwas admitted to the medical assessment unit with progressive lethargy and malaise for the previous 6 weeks. He was previously well and played football for a local club. For the last few weeks he had felt exhausted after playing for 10–15 minutes. He had a family history of Type 1 DM and autoimmune hypothyroidism.
- 20. Case Vignette (cont.) •On examination, he had pigmentation of the palmer surface of the hand and buccal mucosa, with the rest of his general physical and systemic examination being unremarkable. • Investigations: Na 130 mmol/L (135–145) K 5.9 mg/dL (3.5–5.5) urea 10.5 mg/dL (5–9) creatinine 95 µmol/L (60–115) calcium 2.65 mmol/L (2.2–2.6) phosphate 0.94 mmol/L (0.8–1.5)
- 21. Adrenal insufficiency • The term‘adrenal insufficiency’ (AI) refers to failure of the adrenal cortex to secrete enough glucocorticoids, mineralocorticoids, or both. AI can be divided into two general categories: 1) lack of adequate hormone secretion by the adrenals (primary AI) 2) inadequate ACTH or CRH secretion (secondary AI).
- 22. Primary adrenal insufficiency • Anatomic destructionof gland (acute or chronic) Autoimmune: isolated or APS Infections: TB, fungi, CMV Infiltration: amyloidosis, sarcoidosis, hemochromatosis Hemorrhage/infarction • Metabolic failure in hormone production Congenital adrenal hyperplasia Medications: ketoconazole & other adrenolytic drugs. • Others Adrenoleukodystrophy/ adrenomyeloneuronopathy Congenital adrenal hypoplasia ACTH-resistant syndromes
- 23. Secondary adrenal insufficiency • Secondary AIis most often due to sudden cessation of glucocorticoid (exogenous = therapy) or (endogenous = removal of adrenal). • Deficiency of ACTH or CRH in association with deficiency of other hormones. • Lesions of the hypothalamus and/or pituitary gland.
- 24. Epidemiology Incidence: 0.8 casesper 100,000 Prevalence: 4–11 cases per 100,000 Autoimmune destruction of adrenals (Addison’s disease) ~ 70% of all cases of primary AI (in isolation or in association with other autoimmune disorders) TB, fungi, HIV, and CMV (in context of AIDS) are among the most common infections associated with adrenal insufficiency.
- 25. Rationale Of 1ry AIOf 2ry AI Damage to adrenal gland All 3 hormones are affected Increase compensation due to lack of feed back High ACTH levels High Renin levels Damage to pituitary/hypothalamus ACTH levels are low Only cortisol & androgens are affected
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- 27. Presentation Primary AI haveboth glucocorticoid and mineralocorticoid deficiency. Secondary AI have an intact RAAS Almost all patients with primary adrenal insufficiency complain of fatigue, anorexia, and weight loss.
- 28. Presentation (cont.) • Skinhyperpigmentation, initially on the extensor surfaces, palmar creases, and buccal mucosa • It results from the increased ACTH and other pro- opiomelanocortin (POMC)- related peptide production by the pituitary gland.
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- 32. Presentation (cont.) • Sometimes,hypopigmentation may be present as vitiligo, before skin pigmentation pursue
- 33. Presentation (cont.) It isone of the diseases listed as medical causes of acute abdomen (+ low grade fever + diarrhea). Medical causes of acute abdomen Diabetic ketoacidosis, Addisonian crisis. Gastroenteritis. Henoch Schonlein puroura. Herpes zoster. Myocardial infarction. Sickle cell disease. Pleurisy Vasculitis. FMF.
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- 35. What about other hormones •Androgen deficiency presents in ♀ with reduced axillary and pubic hair and reduced libido. (Testicular production of androgens is more important in ♂.)
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- 37. Intact RAAS system in2ry AI Primary Central Na Low Low K High or high normal Normal or low normal Urea High Normal or high Creatinine Normal or high Low normal Calcium Normal or high Normal or high
- 38. What about 2ry AI •Fatigue, hyponatremia, and hypoglycemia are the predominant • Absence of pigmentation—skin is pale. • Absence of mineralocorticoid deficiency. • Associated features of underlying cause, e.g. visual field defects if pituitary tumour. • Other endocrine deficiencies may manifest due to pituitary failure • Acute onset may occur due to pituitary apoplexy.
- 39. Workup • What isthe lesion? Establishing the presence of adrenal insufficiency. • Where is the lesion? Determining the status of ACTH secretion to differentiate primary and secondary causes. • What is the cause? Investigating the underlying etiology.
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- 41. Cosyntropin stimulation test (CST) • Standarddose CST (250 µg) IV or IM → Measure cortisol 0-30-60 minutes thereafter. A normal response is plasma cortisol concentration >500 nmol/L (18 μg/dL) at 30 minutes.
- 42. Other test of HPAaxis • Not commonly used 1. Insulin tolerance test (ITT) 2. Metyrapone test
- 43. • Increased plasmarenin activity (assessment of mineralocorticoid sufficiency). • Reduced thyroid hormone levels and elevated TSH. Associations
- 44. 2- Differentiation between primaryand secondary AI • An elevated ACTH level (usually >22 pmol/L or 100 pg/mL) in a patient with a low serum cortisol level is consistent with primary AI. • A low or normal range ACTH in the same setting confirms the diagnosis of secondary AI.
- 45. ACTH stimulation examples Baseline30 min 60 min Comment 25 ug/dL 27 32 No AI 7 30 33 Low at baseline Improved on ACTH ++ Denote recent glucocorticoid suppression 5 8 7 AI ACTH 100 = Primary AI ACTH 5 = central lesion
- 46. 3- Diagnosis ofthe cause of AI • 1ry: Addison’s: Dx of exclusion + other autoimmune disease + other autoimmune features + autoantibodies Plain abdomen X-ray CT/MRI adrenals Exclude sepsis Search for TB, HIV… • 2ry: Other causes of pituitary insufficiency • Other causes: X-linked adrenoleukodystrophy: VLCFA
- 47. Plain X-ray ofabdomen
- 48. Diagnostic pearl • Diagnosisof autoimmune AI, should be followed by looking for other autoimmune diseases in isolation or as part of APS.
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- 52. Management of AI •Consider glucocorticoids and mineralocorticoids. • As regard glucocorticoids Hydrocortisone: 20 – 30 mg daily (divided). Prednisone: 3 –5 mg daily • Patients require fludrocortisone 0.05–0.2 mg for mineralocorticoid replacement. Not needed in 2ry AI • Androgen replacement in the form of 25– 50 mg/day of DHEA may improve sexual function and psychological well-being in women with AI.
- 53. Monitoring Clinical response = symptomrelief Lab response = electrolytes Monitor for glucocorticoid excess
- 54. Addisonian Crisis: acuteAI Previous adrenal insufficiency • Acute adrenal injury • Acute pituitary injury • Drug related effect • Functional adrenal insufficiency Previous normal adrenal function Beware of previous corticosteroid use
- 55. Acute AI precipitatingfactors Omission of corticosteroids • Infection • Physical stress • Drugs Increased requirements
- 56. Investigations of acuteAI • As chronic. • In the acute situation if the diagnosis is suspected, an inappropriately low cortisol (i.e. <600nmol/L; 21 μg/dL) is often sufficient to make the diagnosis.
- 57. Acute AI presentations Non-specific • Postural •Recumbent Hypotension Abdominal pain Electrolyte disturbances Hypoglycemia
- 58. Treatment of acuteAI Fluids Resuscitate 2 – 3 L of 0.9% NaCl Glucose Glucocorticoids Treat underlying cause Precipitation event Etiology
- 59. Steroids therapy in AI •IV Hydrocortisone drug of choice • Natural compound & mineralocorticoid activity • 50 - 100 mg 6-8 hourly • Taper dose early • No need for mineralocorticoids right now Acute crisis • Maintenance glucocorticoid ± mineralocorticoid Chronic Stress dose adjustment
- 60. Sick day guidance •All patients should carry some form of medical alert. • Don’t stop it • Moderate elective procedures or investigations, e.g. endoscopy or angiography → single dose of 100mg hydrocortisone before the procedure. • Major surgery: 100mg IV/IM premedication 50-100 mg IV/IM 6-8h for 3 days Rapid taper: in 4th day 100-150 mg in IV D5W, then revert to previous dose. Severe illness e.g. pneumonia = 50-100 mg IV/IM 6-8h till resolution
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- 62. Autoimmune polyglandular syndrome(APS) type 1 Mutations in the AIRE (autoimmune regulator), also known as autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED). Autosomal recessive with childhood onset. Chronic mucocutaneous candidiasis. Hypoparathyroidism (90%), 1ry adrenal insufficiency (60%)
- 63. APS type 2 Polygenicinheritance, association with HLA-DR3 and CTLA-4 regions, mixed penetrance. Adult onset. Adrenal insufficiency (100%). 1ry autoimmune thyroid disease (70%), mostly hypothyroidism but also hyperthyroidism. Type 1 DM Other: hypogonadism, myasthenia gravis, celiac disease
- 64. Eponymous syndromes Schmidt’s syndrome: •Addison’s disease, and • Autoimmune hypothyroidism. Carpenter syndrome: • Addison’s disease, and • Autoimmune hypothyroidism, and/or • Type 1 diabetes mellitus.
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Editor's Notes
- #6 We put here an example for increased ACTH and cortisol We are not discussing resistance syndromes
- #7 Pulsatile manner = random samples are not OK with measurement Variation makes measuring ACTH to diagnose Cushing’s syndrome or disease inaccurate
- #9 The zona glomerulosa is deficient in 17α-hydroxylase and, as a result, it cannot produce cortisol or androgens.
- #10 The secretion of mineralocorticoids from zona glomerulosa is regulated primarily by angiotensin 2, serum potassium levels and ACTH. Atrial natriureitc peptide and dopamine can also influence the secretion of mineralocorticoids. ACTH plays a key part in regulation of glucocorticoids secretion from zona fasciculata.
- #11 First step in steroids synthesis is primed with ACTH Plasma lipoproteins are the major source of cholesterol to the adrenal glands. The conversion of cholesterol to pregnenolone is the major site of action of ACTH. The zona glomerulosa is deficient in 17α-hydroxylase and, as a result, it cannot produce cortisol or androgens
- #18 3 arteries and 1 vien 3 taps and 1 pipe
- #22 The most frequent cause is hypothalamic–pituitary damage, which is the cause of AI in 60% of affected patients.
- #23 Tuberculosis, fungal infections, HIV, and cytomegalovirus infection are among the most common infections associated with adrenal insufficiency. The adrenals may be involved in patients with AIDS. About 8–14% of AIDS patients demonstrate a subnormal cortisol response following a short ACTH stimulation test. Metastases from primary cancer (commonly lung and breast) usually do not cause adrenal insufficiency unless more than 90% of the adrenal glands are destroyed. Adrenal hemorrhage and adrenoleukodystrophy syndromes are other rare causes of adrenal insufficiency. ----- Pathophysiology of autoimmune adrenalitis The pathologic changes in autoimmune adrenal insufficiency vary with the stage of the disease. In the initial stage, the adrenal glands may be enlarged, with extensive lymphocytic infiltration. In patients with long-standing disease, the adrenal glands are small and sometimes difficult to locate. The capsule is thickened and fibrotic and the cortex is completely destroyed, although there may be a few small clusters of adrenocortical cells surrounded by lymphocytes. Serum antibodies against all the three zones of the adrenal cortex are present in 60–75% of patients with autoimmune adrenalitis. The medulla is relatively spared.
- #24 It should be anticipated in any patient who has taken more than the equivalent of 30 mg of hydrocortisone per day (7.5 mg prednisone or 0.75 mg dexamethasone) for more than 3 weeks. 2ry adrenal insufficiency due to suppression of pituitary–hypothalamic function by exogenously administered, supraphysiological glucocorticoid doses for treatment of, for example, COPD or rheumatoid arthritis, is much more common (50–200 in 10,000 population). However, adrenal function in these patients can recover, following tapering and cessation of exogenous glucocorticoid administration. ----- Lesions of the hypothalamus and/or pituitary gland Tumours—pituitary tumour, metastases, craniopharyngioma. Infection—tuberculosis. Inflammation—sarcoidosis, histiocytosis X, haemochromatosis, lymphocytic hypophysitis. Iatrogenic—surgery, radiotherapy. Other—isolated ACTH deficiency, trauma. Suppression of the hypothalamo–pituitary–adrenal axis ------------- Isolated ACTH deficiency Rare. Pathogenesis unclear—may be autoimmune (associated with other autoimmune conditions and antipituitary antibodies described in some patients); can be associated with autoimmune hypothyroidism. Absent ACTH response to CRH. POMC mutations and POMC processing abnormalities (e.g. proconvertase PC1)
- #25 Signs & symptoms when >90% of the adrenals structure is destroyed ~ ½ of the patients with Addison's disease have an associated autoimmune disease, also known as autoimmune polyendocrine syndromes (APS) type I and II.
- #26 The manifestations of insufficiency do not usually appear until at least 90% of the gland has been destroyed and are usually gradual in onset, with partial adrenal insufficiency leading to an impaired cortisol response to stress and the features of complete insufficiency occurring later. Acute adrenal insufficiency may occur in the context of acute septicaemia (e.g. meningococcal or haemorrhage).
- #29 Lack of cortisol –ve feedback increases CRH and ACTH secretion. Stimulation of skin melanocortin 1 receptors (MC1R) leads to skin pigmentation and other mucous membranes.
- #31 The excess of ACTH production leads to excess pigmentation (as in Cushings disease and Nelson’s syndrome). 527 shows a patient with Addison’s disease (on the right photographed with her healthy twin sister.
- #37 Hyponatraemia. Hyperkalaemia. Elevated urea. Anaemia (normocytic normochromic). Elevated ESR. Eosinophilia. Mild hypercalcaemia—decreased absorption, d renal absorption of calcium.
- #39 Secondary adrenal insufficiency presents more insidiously and patients do not manifest skin hyperpigmentation, salt-craving, metabolic acidosis, or hyperkalemia. Inadequate ACTH results in deficient cortisol production (and decreased androgens in ♀). Lack of stimulation of skin MC1R due to ACTH deficiency results in pale skin appearance.
- #41 Random cortisol is not useful The standard cosyntropin stimulation test (CST) may be used as the first-line test for evaluation of adrenal function. Due to the diurnal variation of cortisol, random serum cortisol levels are only of value during stress. ----- If CST is not available: Do 9 AM cortisol + ACTH ----- NB Drugs causing i cortisol-binding globulin (e.g. oestrogens) will result in higher total cortisol concentration measurements.
- #42 Patients with recent onset pituitary ACTH or hypothalamic CRH deficiency (e.g. within 2–4 weeks after pituitary surgery) may have a normal response since adrenal glands have not undergone sufficient atrophy and still respond to very high concentrations of ACTH. The sensitivity of CST to diagnose mild adrenal insufficiency may improve with use of the low-dose CST (1 μg cosyntropin given intravenously); however, this may result in a higher false-positive rate. ---------- Low dose CST (1 µg) IV route (this may diagnose mild adrenal insufficiency) A long Synacthen® test may be required to confirm 2° adrenal failure if ACTH is equivocal. Recent onset of s adrenal failure (up to 4 weeks) may produce a normal response to a short Synacthen® test. ------ Long synachten test 1 mg IM Synachten Depot then 0,30, 60, 120 min cortisol + 4, 8, 12, 24 hours A normal response is an elevation in serum cortisol to >1,000nmol/L. Differentiation of 2° from 1° adrenal failure can be made more reliably following 3 days IM ACTH 1mg. There is a progressive rise in cortisol secretion in 2° adrenal insufficiency but little or no response on 1° adrenal insufficiency. This is because the test relies on the ability of the atrophic adrenal glands to respond to ACTH in 2° adrenocortical failure whereas, in 1° adrenal failure, the diseased gland is already maximally stimulated by elevated endogenous levels of ACTH and, therefore, unable to respond to further stimulation. Serum cortisol responses within the first 60min are superimposable with the short Synacthen® test. There is a progressive rise in cortisol secretion in 2° adrenal insufficiency but little or no response on 1° adrenal insufficiency.
- #43 Insulin tolerance test (ITT) and metyrapone test are generally used for the evaluation of patients suspected to have secondary adrenal insufficiency, to evaluate the integrity of the whole hypothalamic–pituitary–adrenal (HPA) axis. ITT is considered the gold standard test for the evaluation of the HPA axis. Metyrapone blocks the final step in cortisol biosynthesis resulting in a reduction in cortisol secretion, which in turn stimulates ACTH secretion leading to a rise in 11-deoxycortisol.
- #44 Reduced thyroid hormone levels and elevated TSH may be due to a direct effect of glucocorticoid deficiency (cortisol inhibits TRH) or due to associated autoimmune hypothyroidism; TSH is usually less than 10U/L in the former and above 10 in the latter. Re-evaluation is, therefore, required after adrenal insufficiency has been appropriately replaced for a few weeks. Initiation of thyroxine replacement prior to glucocorticoid replacement can trigger adrenal crisis, as thyroxine will speed up the inactivation of residual cortisol. -----
- #47 Adrenal autoantibodies: adrenal autoantibodies, which may be present in up to 80–90% of patients and may be detected before the development of overt adrenal dysfunction. The commonly used antibody measurements include nonspecific adrenal cortical antibodies (ACAs) and antisteroid 21-hydroxylase antibodies (21- OHAbs) which are more sensitive indicators of autoimmune adrenal disease.
- #48 Plain X-ray of abdomen demonstrating adrenal calcification on the right side (arrow) in a patient with a history of adrenal insufficiency secondary to tuberculosis.
- #50 Hypotension, a low voltage ECG(520) and a reduced cardiac shadow on the chest radiograph (521) are common. These changes are all reversed by treatment (522 ECG, and 523 radiograph of the same patient as shown in 520 and521 after replacement treatment.
- #51 Before and after
- #52 The pigmentation diminishes after adequate ACTH suppression therapy This image before and after treatment
- #53 Fludrocortisone: Aim to avoid significant postural fall in BP (>10mmHg). Plasma renin should be within the upper third of the normal reference range. 40mg hydrocortisone has the equivalent mineralocorticoid effect of 100 micrograms fludrocortisone. ----- DHEA replacement (25–50mg/day) may improve mood and well-being as well as libido in women with AI.
- #54 Clinical For signs of glucocorticoid excess BP (including postural change). Hypertension and oedema = ↑ mineralocorticoid Postural hypotension and salt craving = ↓ treatment. Biochemical Serum electrolytes. Plasma renin (elevated if insufficient fludrocortisone replacement). Cortisol day curve to assess adequacy.
- #56 Doctor forget tot tell patient about sick day rules ----- At high risk patients for acute AI Head injury Known endocrine disease Previous steroid use Drugs (etomidate, ketoconazole, Medroxyprogesterone, megestrol) HIV Bleeding diathesis
- #59 Cautions should be exercised where there has been chronic hyponatraemia; in this circumstance, rapid correction of the deficit exposes the patient to risk of central pontine myelinolysis. If plasma sodium is <120mmol/L at presentation, aim to correct by no more than 10mmol/L in the first 24h ----- Mineralocorticoid replacement is generally not needed in patients receiving more than 50 – 100 mg hydrocortisone per day. The high-dose glucocorticoid has sufficient mineralocorticoid effects (40mg hydrocortisone equivalent to 100 micrograms fludrocortisone). Once the daily dose of glucocorticoid is reduced to less than 50mg after a couple of days and the patient is taking food and fluids by mouth, fludrocortisone 100 micrograms/day can be commenced. ----- Occasionally required because of risk of hypoglycaemia (low glycogen stores in the liver as a result of glucocorticoid deficiency).
- #60 At doses of hydrocortison 40 – 50 mg, it possess mineralocorticoid effect
- #61 During minor illness (e.g. flu or fever greater than 38°C) the hydrocortisone dose should be doubled for 2–3 days. The inability to ingest hydrocortisone tablets warrants parenteral administration. Most patients can be educated to self-administer hydrocortisone 100 mg intramuscularly and reduce the risk for an emergency room visit. Hydrocortisone 75 mg/day orally (or parenterally if the patient is nil by mouth) provides adequate glucocorticoid coverage for outpatient surgery. Parenteral hydrocortisone 150– 200 mg/day (in 3–4 divided doses) is needed for major surgery with a rapid taper to normal replacement dose during the recovery period.