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Primary Adrenal Disease
Briana Patterson, M.D. Fellow, Pediatric Endocrinology Emory University School of Medicine
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Objectives Normal adrenal physiology
Common causes of primary adrenal insufficiency Evaluation of suspected adrenal insufficiency Acute and chronic management issues
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Normal Adrenals
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Adrenal Cortex Zona Glomerulosa: Mineralocorticoids
Zona Fasiculata: Glucocorticoids Zona Reticularis: Androgens Medulla
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Adrenal Histology Reticularis Glomerulosa Capsule Medulla Fasiculata
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Adrenal physiology 1: HPA axis
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Adrenal physiology 2: Renin-angiotensin system
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Steroid Biosynthesis Androstenedione Cortisol Aldosterone ACTH
Cholesterol Progesterone Pregnenolone StAR, 20,22-desmolase 3βHSD 17α-hydroxylase 3βHSD 3βHSD 17,20-lyase 17-OH-Pregnenolone 17-OH-Progesterone DHEA Androstenedione aromatase 17βHSD Testosterone Estrone Estradiol Corticosterone DOC 18-OH-Corticosterone Aldosterone 11-deoxycortisol Cortisol 21-hydroxylase 11β-hydroxylase 18-hydroxylase 18-oxidase 21-hydroxylase 11β-hydroxylase
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Primary adrenal insufficiency: Etiologies
Acquired Autoimmune AIDS Tuberculosis Bilateral injury Hemorrhage Necrosis Metastasis Idiopathic Congenital Congenital adrenal hyperplasia Wolman disease Adrenal hypoplasia congenita Allgrove syndrome (AAA) Syndromes Adrenoleukodystrophy Kearns-Sayre Autoimmune polyglandular syndrome 1 (APS1) APS2
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Primary adrenal insufficiency: Etiologies
Acquired Autoimmune AIDS Tuberculosis Bilateral injury Hemorrhage Necrosis Metastasis Idiopathic
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Tuberculosis
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Adrenal Hemorrhage: Meningiococcemia
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Addison’s Disease 1st described in 1855 by Dr. Thomas Addison
Refers to acquired primary adrenal insufficiency Does not confer specific etiology Usually autoimmune (~80%)
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Addison’s Disease Addison’s Normal
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Primary adrenal insufficiency: Symptoms
Fatigue Weakness Orthostatsis Weight loss Poor appetite Neuropsychiatric Apathy Confusion Nausea, vomiting Abdominal pain Salt craving
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Primary adrenal insufficiency: Physical findings
Hyperpigmentation Hypotension Orthostatic changes Weak pulses Shock Loss of axillary/pubic hair (women)
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Primary adrenal insufficiency: Physical findings
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Primary adrenal insufficiency: Laboratory findings
Hyponatremia Hyperkalemia Hypoglycemia Narrow cardiac silhouette on CXR Low voltage EKG
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Primary adrenal insufficiency: Etiologies
Congenital Congenital adrenal hyperplasia Wolman disease Adrenal hypoplasia congenita Allgrove syndrome (AAA)
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21-hydroxylase deficiency: Pathophysiology
Testosterone
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CAH: Pathophysiology Androstenedione Cortisol Aldosterone Cholesterol
Progesterone Pregnenolone StAR, 20,22-desmolase 3βHSD 17α-hydroxylase 3βHSD 3βHSD 17,20-lyase 17-OH-Pregnenolone 17-OH-Progesterone DHEA Androstenedione Testosterone Estrone Estradiol Corticosterone DOC 18-OH-Corticosterone Aldosterone 11-deoxycortisol Cortisol 21-hydroxylase 11β-hydroxylase 18-hydroxylase 18-oxidase 21-hydroxylase 11β-hydroxylase
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CAH: Pathophysiology Androstenedione Cortisol Aldosterone Cholesterol
Progesterone Pregnenolone StAR, 20,22-desmolase 3βHSD 17α-hydroxylase 3βHSD 3βHSD 17,20-lyase 17-OH-Pregnenolone 17-OH-Progesterone DHEA Androstenedione Testosterone Estrone Estradiol Corticosterone DOC 18-OH-Corticosterone Aldosterone 11-deoxycortisol Cortisol 21-hydroxylase 11β-hydroxylase 18-hydroxylase 18-oxidase 21-hydroxylase 11β-hydroxylase
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21-hydroxylase deficiency: Physical exam
Females are unremarkable other than genitalia GU exam – Clitoromegaly, posterior labial fusion, no vaginal opening Males appear normal
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21-hydroxylase deficiency CAH
Classification based on enzyme activity Classic Salt wasting (Complete deficiency) Simple virilizing (Significant but partial defect) Non Classic Elevated enzyme levels (Mild deficiency)
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Primary adrenal insufficiency: Etiologies
Syndromes Adrenoleukodystrophy Kearns-Sayre Autoimmune polyglandular syndrome 1 (APS1) APS2
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Primary adrenal insufficiency: Associated conditions
Autoimmune Polyglandular Syndrome I Hypoparathyroidism Chronic mucocutaneous candidiasis Atrophic gastritis Adrenal insufficiency in childhood Pernicious anemia Vitiligo AIRE mutation Transcription factor Affects immune regulation
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Primary adrenal insufficiency: Associated conditions
Autoimmune Polyglandular Syndrome II Autoimmune thyroiditis Type I diabetes mellitus Adrenal insufficiency Pernicious anemia Premature ovarian failure Genetic associations HLA haplotype, CLTA4
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Evaluation
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Primary adrenal insufficiency: Evaluation
0800 cortisol level ACTH level Random cortisol in ill patient ACTH stimulation test Suspected CAH Needs special evaluation
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Primary adrenal insufficiency: Evaluation
0800 cortisol level Levels less than 3 mcg/dL are suggestive of AI Levels greater than 11 mcg/dL exclude AI ACTH level Elevated in adrenal insufficiency ACTH readily degraded if not properly processed
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Primary adrenal insufficiency: Evaluation
Random cortisol in ill patient >20 mcg/dL reassuring Adrenal Autoantibodies ACA—adrenal cortex antibody Anti-21-OH-hydroxylase antibody
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Primary adrenal insufficiency: Evaluation—ACTH Stimulation
Low dose (1 mcg) test Baseline and 30 minute cortisol levels More physiological ACTH level/stimulation Useful in central AI Useful for assessing recovery after chronic steroid treatment High dose (250 mcg) test Baseline, 30 and 60 minute levels Can be done IM Stronger stimulation than 1 mcg test
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Primary adrenal insufficiency: Evaluation—ACTH Stimulation
Cortisol peaks are controversial Reported normals range between mcg/dl Some providers also look at the magnitude of rise Also use ACTH to help differentiate primary vs secondary deficiency Secondary may respond to high dose, but not low Primary should fail both high and low dose
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Suspected CAH: Evaluation
Newborn screening Call endo before you treat Need special evaluation ACTH stimulation can be helpful in well patients with suspected nonclassic disease 17-OH progesterone 17-OH pregnenolone 11-deoxycortisol Deoxycorticosterone Androstenedione DHEA Aldosterone Cortisol ACTH Plasma renin activity
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Diagnosis with 17-OH progesterone
Baseline , ,000 Stimulated 20, ,000 Baseline ,000 Stimulated 2,000-15,000 Baseline ,000 Stimulated ,000
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Treatment
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Primary adrenal insufficiency: Acute treatment
NS volume resusitation Reverse shock Look for/treat hypoglycemia 25% dextrose New problem, suspected AI Labssteroids Established patient with AI Steroids
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Stress dose steroids Loading dose
mg/M2 hydrocortisone IV/IM Small/medium/large approach Infants: Hydrocortisone 25 mg Small children: Hydrocortisone 50 mg Larger children/teens: Hydrocortisone 100 mg Continue hydrocortisone with mg/M2/day Divide q6-8 hours May be 2-3x home dose
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Primary adrenal insufficiency: Long term treatment
Daily glucocorticoid replacement (hydrocortisone) 10-15 mg/m2/day divided TID Option to change to prednisone in teen years Daily mineralocorticoid replacement Fludrocortisone mg daily Patient education Stress coverage Emergency steroid administration IM hydrocortisone (Solucortef Actovial) Medic Alert ID
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Relative Steroid Potencies
Glucocorticoid Mineralocorticoid Hydrocortisone 1 ++ Prednisone/ Prednisolone 3-5 + Methylprednisone 5-6 Dexamethasone 25-50 Fludrocortisone 15-20 +++++
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Relative Steroid Potencies
Glucocorticoid Mineralocorticoid Hydrocortisone 1 ++ Prednisone/ Prednisolone 3-5 + Methylprednisone 5-6 - Dexamethasone 25-50 Fludrocortisone 15-20 +++++
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When to consider AI: Patients at risk…Primary AI
History of TB Refractory shock Particularly meningococcal disease Dehydration/shock with hyperpigmentation Neonate with vomiting/dehydration/shock Other autoimmune endocrine disease History consistent with APS1 Immunodeficiency/chronic mucocutaneous candidiasis
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When to consider AI: Patients at risk…Secondary AI
Pituitary trauma/surgery Brain tumor Craniopharyngioma Suprasellar germ cell tumor Infiltrative pituitary disease Sarcoidosis Histiocytosis Congenital pituitary abnormalities May have progressive loss of corticotroph function Chronic glucocorticoid therapy
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Adrenal Insufficiency Summary
May be primary or secondary May be congenital or acquired Treatment is relatively simple Diagnosis is often controversial Baseline cortisol/ACTH before steroids ACTH stim test if possible Additional testing if CAH is suspected Don’t forget to check the blood sugar!
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