Hypothalamus-Pituitary-Adrenal Axis Adrenal Insufficiency: Stress (physical, Current Practice 2012 psychological) Hypothalamus - CRH or Vasopressin + Lawrence S. Kirschner, MD, PhD Pituitary - Professor of Medicine ACTH: Major direct regulator Division of Endocrinology, Diabetes, and Metabolism of cortisol secretion The Ohio State University’s Wexner Medical Center + Adrenals Cortisol, Aldosterone, Androgens Overview Actions of cortisol • A very brief review of adrenal function • What is adrenal insufficiency? • Adrenal insufficiency in the outpatient setting • Adrenal insufficiency during critical illness • Therapy for adrenal insufficiency 1 What is Adrenal insufficiency? • Actions of Aldosterone – Promotes sodium/water retention • When discussing adrenal insufficiency – Promotes potassium excretion (Addison disease), we are almost always – May be involved in tissue remodeling talking about glucocorticoid (cortisol) ((ge.g. in the heart) insufficiency • Actions of adrenal androgens • However, other adrenal hormones can also – Responsible for initiation of puberty be affected in primary adrenal failure • Secondary sex characteristics in women Adrenal Insufficiency Clinical Addison disease (Addison disease) Image courtesy of Wellcome Images http://images.wellcome. ac.uk/ 2 Clinical Features of Chronic Features of Acute Adrenocortical Insufficiency Adrenocortical Insufficiency (Adrenal Crisis) • Hypotension •Weakness, fatigue 100% •Weight loss 100% • Weakness (prox. muscle), •Anorexia 100% confusion •Hyperpigmentation 92% • Nausea, vomiting , abdominal pain •Hypotension 88% • Dehydration, hypovolemia •Nausea, abdominal pain 56% • Hyperthermia •Salt craving 19% •Hypoglycemia ?? • Hypoglycemia »more common in children and women TREAT FIRST, AND DIAGNOSE LATER!! Hyperpigmentation, Adrenal Crisis toxic appearance Addison disease • Acute loss of adrenal function – Acute loss of adrenals • Surgery • Hemorrhage/thrombosis – Acute loss of pituitary function – Acute loss of steroid replacement OR • Acute stress in the setting of compensated Hyperpigmentation, including chronic adrenal failure Images courtesy of knuckles and palmar creases Wellcome Images – Precipitating event (e.g., like DKA) http://images.wellcome.ac.uk/ 3 Normal Adrenal Function Secondary Adrenal Insufficiency • Primary Hypothalamus – Adrenal gland Hypothalamus CRH – Destruction of Pituitary glands CRH Pituitary • Secondary ACTH – Pituitary ACTH – Inadequate ACTH Adrenals – NO increased Adrenals pigment Cortisol Aldosterone – Fewer electrolyte imbalances Cortisol Aldosterone (regulated by Renin/Angiotension system) Primary Adrenal Insufficiency Causes of adrenal failure • Primary Hypothalamus – Adrenal gland • Like CS, iatrogenic causes are probably most common CRH – Destruction of Pituitary glands • Inherited forms of adrenal failure – Typically presenting early in life (<1 yr) • CAH, especially salt-wasters (steroid biosynthesis defect) Adrenals • Other rare genetic diseases (lipoid CAH, AHC) – Typically presenting in childhood, and dx should be “obvious” • AAA Cortisol Aldosterone – Alacrima, Achalasia, Adrenal failure • Autoimmune Polyendocrine Syndrome (APS), Type I (APECED) – Ectodermal dysplasia, mucocutaneous candidiasis 4 Causes of adrenal failure Causes of adrenal failure • Like CS, iatrogenic causes are probably most • Like CS, iatrogenic causes are probably most common common • Inherited forms of adrenal failure • Inherited forms of adrenal failure – Typically presenting early in life (<1 yr) – Typically presenting early in life (<1 yr) • CAH, especially salt-wasters (steroid biosynthesis • CAH, especially salt-wasters (steroid biosynthesis defect) defect) • Other rare genetic diseases (lipoid CAH, AHC) • Other rare genetic diseases (lipoid CAH, AHC) – Typically presenting in childhood, and dx – Typically presenting in childhood, and dx should be “obvious” should be “obvious” • AAA • AAA – Alacrima, Achalasia, Adrenal failure – Alacrima, Achalasia, Adrenal failure • Autoimmune Polyendocrine Syndrome (APS), • Autoimmune Polyendocrine Syndrome (APS), Type I (APECED) Type I (APECED) – Ectodermal dysplasia, mucocutaneous – Ectodermal dysplasia, mucocutaneous candidiasis candidiasis Causes of adrenal failure • Presenting later in life • Like CS, iatrogenic causes are probably most – Autoimmune Polyendocrine Syndrome common (APS), Type II • Type I DM, thyroid disease • Inherited forms of adrenal failure – Typically presenting early in life (<1 yr) • May occur as sole autoimmune feature • CAH, especially salt-wasters (steroid biosynthesis (although rare) defect) – Adrenal hemorrhage • Other rare genetic diseases (lipoid CAH, AHC) – Typically presenting in childhood, and dx • Resulting from sepsis should be “obvious” – HIV, other viral diseases • AAA – Adrenalectomy – Alacrima, Achalasia, Adrenal failure • Autoimmune Polyendocrine Syndrome (APS), Type I (APECED) • Note that non-classical CAH rarely causes – Ectodermal dysplasia, mucocutaneous candidiasis adrenal insufficiency 5 Adrenal hemorrhage! Pre-bleed Post-bleed Secondary adrenal failure Diagnosis of Adrenal Insufficiency in the Outpatient setting: Static Testing • Pituitary malfunction • A GOOD HISTORY IS ESSENTIAL! – Tumor destroying normal cells – History of steroid use, including nasal steroids or injected steroids (e.g., – Autoimmune hypophysitis back injections) • May be quite specific for loss of ACTH-producing cells • 8 AM cortisol (probably NOT reliable in – Infiltrative diseases of pituitary hospitalized patients) • Histiocytosis X Strongly Very unlikely suggestive • Sarcoidosis Normal range • Metastatic disease 0 37 18 25 8am Cortisol (ug/dl) 6 Diagnosis of Adrenal Insufficiency in the Outpatient setting: Static Testing - 2 Adrenal Insufficiency: • ACTH measurements – Generally not helpful, particularly low Current Practice 2012 values – Elevated values may suggest primary Adrenal Insufficiencyyg in the right clinical setting Rami N. Khayat, MD Associate Professor • “Suggestive” findings: Pulmonary, Critical Care, and Sleep Medicine – Eosinophilia, hyperchloremia, The Ohio State University’s Wexner Medical Center acidosis, hypercalcemia, azotemia, hyponatremia/hyperkalemia and fasting hypoglycemia Diagnosis of Adrenal Insufficiency: Adrenal Insufficiency during Critical ACTH stim test Illness • Give IV/IM bolus of 250 mcg ACTH, measure blood at 0, 30, 60 min • Adrenal function during critical illness Cortisol ug/dl • Relative adrenal insufficiency • Normal response is for cortisol to reach >18 20 • Overv iew o f Cor ticos tero id th erapy i n th e mcg/dl 10 ICU • Caveat :ACTH stim test • Conclusions will be “normal” in early pituitary failure. Once adrenal atrophy sets in, test becomes subnormal 03060 7 Acute injury Adrenal Function in Critical Illness • Adrenal Gland Death Acute critical illness Recovery • Synthetic inhibition • Drugs • Cytokines Sub-acute; chronic critical • Etomidate llness • Ketoconazole » Corticosteroids • Destruction Maladaptive Adaptive • Pre-existing • Acute responses responses • Autoimmune • Hemorrhage • Infection • Infection • HIV • CMV Impaired Adrenal Decreased • TB • Fungal immune function Inflammatory • Metastasis response response The Adrenal Response to Prolonged Adrenal Function in Critical Illness Critical Illness • Hepatic metabolism of cortisol • Rifampin • Phenytoin • Phenobarbital • Glucorticoid Resistance J Clin End Met. 1995;80:1238. 8 Cortisol and Septic Shock Group % Basalbasal cortisol maxmax mortalitymortality Good 30% <34 >9 26% Intermediate1 <34 <9 50% 67% “The fact that cortical hormone therapy exerts beneficial effects in so many conditions makes it rather likely that Intermediate2 >34 >9 the hormone is not a specific antidote in any one of these cases but raises shock resistance in general because a Poor 20% >34 <9 82% condition of relative adrenal insufficiency exists in organisms exposed to non-specific damage.” Annane JAMA 2000; 283:1038-1045 Prognostic Value of Cortisol Levels and ACTH Cortisol Levels-Marker of Survival Response Venkatesh and Cohen 2011 Annane, D. et al. JAMA 2000;283:1038-1045 9 Effect of Low Dose Hydrocortisone on Mortality in Patients with Septic Shock Annane, D. et al. JAMA 2002;288:862-871 Steroids In Septic Shock Effect of Low Dose Hydrocortisone on Mortality in Patients with Septic Shock Catechlamine dependent septic shock (300) ACTH Stim Test 76% Non-Respp()onders (229) 24% Responders (70) <9 ug/dl cortisol >9 ug/dl cortisol Steroids Placebo Steroids Placebo 50 mg Hydrocortisone q6º 50 mg Hydrocortisone q6º 50 ug Fludrocortisone qd 50 ug Fludrocortisone qd Annane, D. et al. JAMA 2002;288:862-871 Annane JAMA 2002; 288:862-871 10 Steroids In Septic Shock Approach to Suspected Adrenal Insufficiency < 25 ug/dL 25 ug/dL to 40 ug/dL > 40 ug/dL Non- Responders Mortality Responders ACTH stim test Steroids Placebo Steroids Placebo 28 Day 53%* 63% 61% 53% < 9 ug/dL > 9 ug/dL ICU 58%* 70% 67% 59% Hospital 61%* 72% 69% 59% 1 Year 68%* 77% 69% 71% Persistent hypotention Vasopressor 57%* 40% 50% 53% Therapeutic Trial Withdrawal Median Median Median Median (28 days) 7 10 9 7 Steroid Replacement Treatment Annane JAMA 2002; 288:862-871 Effects of Corticosteroids on Mortality ICU Severe Sepsis and Septic Shock Concerns • High mortality in the Control group • Use of Etomidate • Design and power • Severe refractory shock required for enrollment Annane BMJ 2004;329:480 11 Hydrocortisone Therapy for Patients with Septic Shock Kaplan–Meier curves for survival at 28 days according to CORTICUS response to corticotropin test Sprung