corticosteroid insufficiency in acutely ill patients

1. Corticosteroid Insufficiency in Acutely Ill Patients Mark S.Cooper etc. NEJM 2003;348:727-34 Wiebke Arlt etc. Lancet 2003; 361: 1881-93 ?????

3. History of adrenal insufficiency 1855 Thomas Addison-clinical syndrome characterised by wasting and hyperpigmentation Cause as destruction of the adrenal gland 1994 life-saving glucocorticoid-replacement therapy developed�Kendall, Sarett, and Reichstein 1st synthesised cortisone

4. Epidemiology Two types�primary, secondary Chronic primary adrenal insufficiency�prevalence 93-140/million, incidence 4.7-6.2/million in white population-age at diagnosis 4th decade, women more frequently Secondary adrenal insufficiency�prevalence 150-280/million-age peaks in 6th decade, women more frequently Therapeutic glucocorticoid administration--the most common cause

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22. Causes of primary adrenal insufficiency Diagnosis Clinical features in addition to Pathogenesis or genetics adrenal insufficiency Autoimmune adrenalitis Isolated autoimmune adrenalitis No other features Associations with HLA-DR3, CTLA-4 Autoimmune adrenalitis as part Of APS APS type 1 (APECED) Hypoparathyroidism, chronic mucocutaneous AIRE gene mutations (21q22.3 Candidiasis, other autoimmune disorders APS type 2 Thyroid disease, type 1 diabetes mellitus Associations with HLA-DR3, CTLA-4 Other autoimmune diseases APS type 4 Other autoimmune disease, excluding thyroid Associations with HLA-DR3, CTLA-4 Disease or diabetes Infectious adrenalitis Tuberculosis adrenalitis Other organ manifestations of tuberculosis Tuberculosis AIDS Other AIDS associated diseases HIV-1, cytomegalovirus Fungal adrenalitis Mostly in immunosuppressed patients Cryptococcosis, histoplasmosis, coccidoidomycosis Genetic disorders leading to adrenal insufficiency Adrenoleukodystrophy, Demyelination of CNS (cerebral Mutation of the ABCD 1 gene encoding for Adrenomyeloneuropathy adrenoleukodystrophy), spinal cord, or the peroxisomal adrenoleukodsytrophy Peripheral nerves (adrenomyeloneuropathy) protein Congenital adrenal hyperplasia 21-hydroxylase deficiency Ambiguous genitalia in girls CYP21 mutation 11b-hydroxylase deficiency Ambiguous genitalia in girls and hypertension CYP11b1 mutation 3b-HSD type 2 deficiency Ambiguous genitalia in boys, postnatal virilisation HSD3B2 mutation in girls 17a-hydroxylase deficiency Ambiguous genitalia in boys, lack of puberty in both CYP17 mutation Ambiguous genitalia in girls sexes, hypertension

23. Congenital lipoid adrenal XY sex reversal Mutations in the steroidogenic acute hypoplasia regulatory protein (SIAR) gene; mutations in CYP11A (encoding P450SCC) Smith-Lemil-Opitz syndrome Mental retardation, craniofacial malformations, 7-dehydrocholesterol reductase mutations in Growth failure gene DHCR7 Adrenal hypoplasia congenita X-linked Hypogonadotropic hypogonadism Mutation in NROB1 Xp21 contiguous gene syndrome Duchenne muscular dystrophy and glycerol kinase Deletion of the Duchenne muscular deficiency (psychomotor retardation) dystrophy, glycerol kinase, and NROB1 genes SF-1 linked XY sex reversal Mutation in NR5A1 IMAGe syndrome Intrauterine growth retardation, metaphyseal Unknown dysplasia, adrenal, insufficiency, and genital abnormalities (IMAGe) Kearns-Sayre syndrome External ophthalmoplegia, retinal degeneration, Mitochondrial DNA deletions and cardiac conduction defects; other endocrinopathies ACTH insensitivity syndromes Glucocorticoid deficiency, but no impairment (familial glucocorticoid deficiency of mineralocorticoid synthesis Type 1 Tall stature ACTH receptor (MC2R) mutations Type 2 No other features Unknown Triple A syndrome Alacrimia, achalasia; additional symptoms�eg, Mutations in triple A gene (AAAS) (Allgrove�s syndrome) nuerological impairment, deafness, encoding for a WD-repeat protein mental retardation, hyperkeratosis Bilateral adrenal hemorrhage Symptoms of underlying disease Septic shock, specifically meningococcal sepsis (Waterhouse-Friderichsen syndrome); primary antiphospholipis syndrome Adrenal infiltration Symptoms of underlying disease Adrenal metastases primary adrenal lymphoma sarcoidosis, amyloidosis Hemochromatosis Bilateral adrenalectomy Symptoms of underlying disease Unresolved Cushing�s syndrome Drug-induced adrenal No other symptoms Treatment with mitotane, Insufficiency aminoglutethimide, etomidate Ketoconazole, suramin, mifepristone

24. Tuberculosis During Thomas Addison times, TB adrenalitis-the most prevalent cause of adrenal insufficiency, in the developing world, it remains a major factor In active TB, incidence of adrenal involvement�5% In developed countries, 80-90% autoimmune adrenalitis, TB 10-20%

25. Autoimmune adrenalitis Isolated 40%-male preponderance Autoimmune polyendocrine syndrome (APS) 60%-female preponderance

26. APS type 1 Also termed APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy)-15% Characterized: adrenal insufficiency, hypoparathyroidism, chronic mucocutaneous candidiasis Onset during childhood Other autoimmune disorders Childhood alopecia (40%), chronic active hepatitis (20%), and malabsorption (15%) Caused by mutations in autoimmune regulator (AIRE) gene, inherited in an autosomal-recessive fashion

27. APS type 2 Most frequently seen Adrenal insufficiency, autoimmune thyroid disease Also primary gonadal failure, type 1 DM Other autoimmune diseases-vitiligo, chronic atrophic gastritis, celiac disease Occurs with autosomal-dominant inheritance with incomplete penetrance Strong association with HLA-DR3 and CTLA-4

28. APS type 3 Involves autoimmune thyroid disease But not adrenal insufficiency

29. APS type 4 Combination of adrenal insufficiency with other autoimmune disorders But without thyroid disease

31. X-linked adrenoleukodystrophy Mutation in ABCD1 gene-encodes a perioxismal membrane protein (adrenoleukodystrophy protein), leading to accumulation of very-long- chain fatty acids (>24 carbon atoms) Comprise adrenal insufficiency and neurological impairment due to white matter demyelination Two forms: cerebral adrenoleukodystrophy-50%, easly childhood manifestations, rapid progression Adrenomyeloneuropathy-35%, onset in early adulthood, slow progression with restriction of demyelination to spinal cord and peripheral nerves 15%-adrenal insufficiency precede the onset of neurological symptoms

32. Causes of secondary adrenal insufficiency Diagnosis Comment Pituitary tumors Secondary adrenal insufficiency mostly as part of panhypopituitarism, additional symptoms (visual-field Impairrnent); generally adenomas, carcinoma is a rarity; consequence of tumor growth, surgical treatment of both Other tumors of the Craniopharyngioma, meningioma, ependymoma, and intrasellar or suprasella metastases hypothalamic-pituitary region Pituitary irradiation Craniospinal irradiation in leukemia, radiaiton for tumors outside the hypothalamic-pituitary axis irradiation of pituitayr tumors Lymphocytic hypophysitis Isolated Autoimmune hypophysitis; most frequently in relaiton to pregnancy (80%); mostly hypopituitarism, but also isolated adrenocorticotropic hormone deficiency As part of APS Associated with autoimmune thyroid disease and, less frequentl, with vitiligo, primary gonadal failure type 1 diabetes, and pernicious anemia Isolated congenital Pro-opiomelanocortin cleavage enzyme defect? ACTH deficiency Pro-opiomelanocortin- Pro-opiomelanocortin gene mutations, clinical triad adrenal insufficiency, and early-onset obsity, red Deficiency syndrome hair pigmentation Combined pituitary- Mutations in the gene encoding the pituitary transcription fractor Prophet of Pit 1 (PROP1), Hormone deficiency progressive development of panhypopituitarism in the older GH, PRL, TSH, LH/FSH, (ACTH) Mutations in the hemeo box gene HESX1, combined pituitary hormone deficiency, optic-nerve hypoplasia, and midline brain defects (septo-optic dysplasia) Pituitary apoplexy Onset mainly with abrupt severe headache, visual disturbance, and nausea or vomiting Sheehan�s syndrome Pituitary apoplexy or necrosis with peripheral onset�eg, due to high blood loss or hypotension Pituitary infiltration Tuberculosis, actinomycosis, sarcoidosis, histiocytosis X, Wegener�s granulomatosis or granuloma Head trauma For example pituitary stalk lesions Previous chronic Exogenous glucocorticoid administration for more than 4 weeks endogenous glucocorticoid glucocorticoid excess hypersecretion due to Cushing�s syndrome

33. Tumor of hypothalamic-pituitary region Most frequent cause Usually associated with panhypopituitarism Caused by tumor growth or treatment with surgery or irradiation

34. Other causes Adrenal infiltration or hemorrhage-rare Congenital or neonatal adrenal insufficiency-only 1%

35. Autoimmune lymphocytic hypophysitis Less frequent Most affecting women during or shortly after pregnancy

36. Isolated ACTH insufficiency Autoimmune origin Some pts have other autoimmune disorders-most frequent thyroid disease

37. Postpartum autoimmune hypophysitis Sheehan�s syndrome-results from pituitary apoplexy-due to pronounced blood loss during delivery

39. Physiological situation Primary adrenal insufficiency Hypothalamus Hypothalamus CRH CRH Pituitary Pituitary ACTH ACTH Adrenal Adrenal Cortisol Cortisol Secondary adrenal insufficiency Hypothalamus Hypothalamus CRH CRH Pituitary Pituitary ACTH ACTH Adrenal Adrenal Cortisol Cortisol Pituitary disease Hypothalamic disease

40. Hypothalamus Reduced feedback + -- -- Corticotropin -- Corticotropin -- Stress Corticotropin Central nervous releasing releasing Cytokines releasing system disease, hormone hormone hormone corticosteroids + ++ + pituiatry apoplexy Pituitary -- -- -- corticosteroids -- Corticotropin Corticotropin Corticotropin Cytokines, + ++ + anesthetics -- antinfective agents Corticosteroids Adrenal hemorrhage, infection HIV infiltration Binding of cortisol increased cortisol and Decreased cortisol and to corticosteroid- decreased corticosteroid- decreased corticosteroid- binding globulin binding globulin binding globulin cytokine, local cytokine, corticosteroid glucocorticoid + activation - resistance

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43. Functional adrenal insufficiency Subnormal adrenal corticosteroid production during acute severe illness Relative adrenal insufficiency Cortisol in high absolute terms, are insufficient to control the inflammatory response

46. Symptoms of chronic adrenal insufficiency Main symptoms-fatigue, accompanied by lack of stamina, loss of energy, reduced muscle strength, and increased irritability Additionally, chronic glucocorticoid deficiency�leads to weight loss, nausea, and anorexia, and account for muscle and joint pain Most are non-specific 50% pts have S & S for >1yr before diagnosis

47. Secondary adrenal insufficiency Diagnosis prompted by history of pituitary disease Can also be delayed�in isolated ACTH deficiency Often have pale, alabaster-colored skin

48. Primary adrenal insufficiency More specific sign�hyperpigmentation-most pronounced in areas of the skin exposed to increased friction�palmar creases, knuckles, scars, oral mucosa Hyperpigmentation-caused by enhanced stimulation of skin MC1-receptor by ACTH and other POMC-related peptides

49. Laboratory finding in glucocorticoid deficiency Mild anemia, lymphocytosis, and eosinophilia Increased TSH Hypercalcemia-due to increased intestinal absorption and decreased renal excretion and generally coincides with autoimmune hyperthyroidism, facilitating calcium release from bone

50. Mineralocorticoid deficiency Only in primary adrenal insufficiency Leads to dehydration and hypovolemia�resulting in low BP, postural hypotension, and even prerenal azotemia Deterioration can be sudden and is often due to exogenous stress�such as infection or trauma Accounts for hyponatremia (90%), hyperkalemia (65%), and salt craving (15%)

51. Physiological situation Primary adrenal insufficiency Adrenal Adrenal AI, II AI, II Kidney Kidney Aldosterone Renin Aldosterone Renin Potassium excretion Potassium retention Sodium retention Sodium loss Fluid retention Fluid depletion Mineralocorticoid production

52. Dehydroepiandrosterone (DHEA) deficiency DHEA-major precursor of sex-steroid synthesis Loss-results in pronounced androgen deficiency in women Women with adrenal insufficiency �show loss of axillary and pubic hair (absence of pubarche in children), dry skin, and reduced libido DHEA also exerts direct action as a neurosteroid with potential antidepressant properties DHEA deficiency�contribute to the impairment of wellbeing

55. Biochemical diagnosis of adrenal insufficency Test Protocol Normal range Definitive Adrenal insufficiency Comment adrenal not excluded insufficiency Primary adrenal insufficiency Early morning Serum cortisol at 165-680 nmol/L Cortisol Cortisol Cortisol >500 nmol/L usually Cortisol 0700-0900h <165 nmol/L <300 nmol/L excludes primary adrenal and and insufficiency Early morning Plasma 1.1-11.0 pmol/L ACTH ACTH in most cases ACTH ACTH at >22.0 pmol/L >45.0 pmol/L 0700-0900 h Standard short Serum cortisol at Peak cortisol Peak cortisol In most cases no cortisol Corticotropin test 0, 30, and 60 min >500 nmol/L <500 nmol/L increase because of already After 250 ug intra- maximum endogenous venous or intra- ACTH stimulation Muscular 1-24 ACTH Secondary adrenal insufficiency Early morning Serum cortisol at 165-680 nmol/L Cortisol Cortisol >100 nmol/L Cortisol >500 nmol/L excludes Cortisol 0700-0900h <100 nmol/L OR <500 nmol/L secondary adrenal insufficiency Early morning Plasma ACTH 1.1-11.0 pmol/L ACTH ACTH at 0700-0900 H <11.0 pmol/L Standard short Serum cortisol at Peak cortisol Peak cortisol Peak cortisol Peak cortisol <400 nmol/L in Corticotropin test 0, 30, and 60 min >500 nmol/L <500 nmol/L <550 nmol/L most patients with secondary After 250 ug intra- adrenal insufficiency venous or intra- Muscular 1-24 ACTH Insulin tolerance Serum glucose and Peak cortisol Peak cortisol Peak cortisol Peak cortisol Test only valid if symptomatic Test cortisol 0,15, 30 >500 nmol/L <500 nmol/L <550 nmol/L hypoglycemia (serum glucose 45, 60, and 90 min <2.2 nmol/L) is achieved; gold after intravenous standard test; close insulin (0.1-0.15 U/kg) suprevision mandatory; contraindicated with history of seizures, cerebrovascular, and cardiovascular disease

56. Laboratory assessment in primary adrenal insufficiency Early morning serum cortisol & ACTH Plasma ACTH greatly increased > 22.0 pmol/L, serum cortisol <165 nmol/L Aldosterone level subnormal or low normal range Plasma renin activity increased Serum DHEA low

57. Standard short corticotropin test IV or IM 250 ug 1-24 ACTH Measure 0, 30, 60 min Healthy�serum cortisol >500 nmol/L Primary adrenal insufficiency�no further increased in serum cortisol

58. Adrenal cortex autoantibodies or antibodies against 21-hydroxylase Present in > 80% recent onset autoimmune adrenalitis Autoantibodies against other steroidogenic enzymes (P450 scc, P450c17) and steroid-producing cell antibodies are present Especially helpful in pt with isolated primary adrenal insufficiency with no family history In APS type 2�screening for concomitant disease should involve TSH and FBS

59. Isolated primary adrenal insufficiency Serum very-long-chain fatty acids (C26, C26/22, C24/C22 ratios) should be measured

60. Lab assessment in secondary adrenal insufficiency Morning cortisol <100 nmol/L Cortisol >500 mmol/L�intact H-P-A axis Insulin tolerance test-gold standard BS <2.2 mmol/L�powerful stressor Intact axis�peak cortisol>500 nmol/L or 550nmol/L

61. Overnight metyrapone test Metyrapone 30 mg/kg-maximum 3gm�administered with a snack at midnight Metyrapone inhibits 11b-hydroxylase Healthy-deoxycortisol increases, serum cortisol <230 nmol/L Secondary adrenal insufficiency�11-deoxycortisol <200 nmol/L at 0800 h

62. Low-dose corticotropin test 1ug ACTH More sensitive Successfully used However, 1ug still results in hormone conc. Greater than those for maximum cortisol release Handling difficulties by need to dilute the test amount from commercially available 250 ug 1-24 ACTH

63. Corticotropin releasing hormone test Differentiate hypothalamic from pituitary disease in secondary adrenal insufficiency Not of great help in actual condition Reponses high variable Cut-off values or normal range still not well defined

64. Special diagnostic situations Adrenal insufficiency after pituitary surgery Standard short ACTH test done 4-6 weeks after surgery In critically ill patients Random sample serum cortisol & plasma ACTH followed by immediate hydrocortisone administration

65. imaging Abdominal CT MRI

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68. Replacement regimen and treatment survelliance in chronic adrenal insufficiency Glucocorticoid replacement Hydrocortisone 15-25 mg daily (or cortisone acetate 25-37.5 mg) Given in two to three doses with half to two-thirds of the total dose given in the morning (immediately after rising) Survelliance: history of glucocorticoid dose adjustment and potential adverse events, including any crisis since last visit bodyweight , signs and symptoms suggestive of over-replacement or under-replacement, and ability to cope with daily stress (optimal, fasting glucose) Mineralocorticoid replacement (only in primary adrenal insufficiency) Fludrocortisone 0.05-0.2 mg daily taken as one dose in the morning Survelliance: blood pressure, peripheral edema, serum sodium, serum potassium, plasma renin acivity Dehydroepiandrosterone replacement (optimal) Dehydroepiandrosterone 25-50 mg daily taken as one dose in the morning Survelliance: serum dehydroepiandrosterone sulphate, in women also free testosterone (or total testosterone ans sex-hormone binding globulin) Additional monitoring requirements Primary adrenal insufficiency; thyrotropin (in patients with autoimmune adrenalitis) Secondary adrenal insufficiency: monitoring of underlying hypothalamic-pituitary disease, including replacement of other axes Yearly outpatient visits in a specialized centre Vertification of steroid emergency card or bracelet Reinstruction of patient on stress-related glucocorticoid dose adjustment

69. Frequency of signs and symptoms during chronic replacement therapy for adrenal insufficiency in a series of 53 patients Number All Men Women Primary adrenal insufficiency Secondary adrenal insufficiency (n=53) (n=23) (n=30) (n=28; 19 female, 9 male) (n=25; 11 female, 14 male) Symptoms Fatigue 21(40%) 8 (35%) 13 (43%) 10 (36%) 11 (44%) Lack of energy 14 (28%) 7 (30%) 8 (27%) 7 (25%) 8 (32%) Reduced strength 13 (26%) 6 (26%) 8 (27%) 5 (18%) 9 (36%) Insomnia 11 (20%) 4 (17%) 7 (23%) 4 (14%) 7 (28%) Muscle pain 7 (13%) 3(13%) 4 (13%) 4 (14%) 3 (12%) Recurrent infections 3 (6%) 0 3 (10%) 3 (11%) 0 Nausea 3 (6%) 0 3 (10%) 3 (11%) 0 Signs Weight gain 11(20%) 4 (17%) 7 (23%) 3 (11%) 8 (32%) Truncal obesity 10 (19%) 3 (13%) 7 (23%) 4 (14%) 6 (24%) Hyperpigmentation 9 (17%) 2 (7%) 7 (23%) 9 (32%) 0 Arterial hypotension 8 (15%) 4 (17%) 4 (13%) 3 (11%) 4 (16%) Increased serum sodium 4 (9%) 1 (4%) 4 (13%) 4 (13%) 1 (4%) Or decreased potassium Decreased serum sodium 3 (6%) 0 3 (10%) 2 (7%) 1 (4%) Or increased potassium Arterial hypertension 3 (6%) 0 3 (10%) 2 (7%) 1 (4%) Peripheral edema 2 9450 1 (4%) 1 (3%) 0 2 (8%) Weight loss 1(2%) 0 1(3%) 1 (4%) 0

71. Special therapeutic situations Thyroid dysfunction Hyperthyroidism increases cortisol clearance In pt with adrenal insufficiency and unresolved hyperthyroidism, glucocorticoid replacement should be doubled or tripled To avoid adrenal crisis, thyroxine should only be initiated after concomitant glucocorticoid deficiency been treated

72. Pregnancy Gradual increase in cortisol-binding globulin & free cortisol during the last term Serum progesterone also increase, exerting antimineralocorticoid action During third trimester, hydrocortisone replacement should be increased by 50% Mineralocorticoid should be adjusted according to BP & serum potassium Peripartum hydrocortisone replacement should follow the requirements for major surgery�100 mg/24 starting with labor and continuing until 48 hr after delivery, followed by rapid tapering

73. Drug interactions Rifampicin increases cortisol clearance, but not aldosterone clearance Glucocorticoid replacement should be doubled during rifampicin treatment Mitotane decreases bioavailable glucocorticoid conc. Due to increase in cortisol-binding globulin and enhanced glucocorticoid metabolism During chronic mitotane treatment-in adrenal carcinoma�glucocorticoid replacement should be doubled or tripled

74. Quality of life, disability, and prognosis Prospective data indicate excess mortality in hypopituitarism, including secondary adrenal insufficiency, mainly due to vascular and respiratory disease Deficiencies other hormone axes also contribute Mortality in primary adrenal insufficiency has not been studied-life expectancy may be reduced as a consequence of unrecognized adrenal crisis, underlying illness, eg, adrenomyeloneuropathy and other causes Despite adequate glucocorticoid and mineralocorticoid replacement, health-related quality of life is greatly impaired Predominant complaints-fatigue, lack of energy, depression, and anxiety

75. Quality of life, disability, and prognosis Affected women frequently complain about impaired libido 50% primary adrenal insufficiency pt�unfit to work 30% need household help The adverse effect of chronic adrenal insufficiency on health-related quality of life is comparable to that of CHF Glucocorticoid replacement do not improve wellbeing DHEA replacement in adrenal insufficiency can improve wellbeing, mood, and in women-libido, and improve quality of life