Primary Adrenal Disease Briana Patterson, M.D. Fellow, Pediatric Endocrinology Emory University School of Medicine

Objectives Normal adrenal physiology Common causes of primary adrenal insufficiency Evaluation of suspected adrenal insufficiency Acute and chronic management issues

Normal Adrenals

Adrenal Cortex Zona Glomerulosa: Mineralocorticoids Zona Fasiculata: Glucocorticoids Zona Reticularis: Androgens Medulla

Adrenal Histology Reticularis Glomerulosa Capsule Medulla Fasiculata

Adrenal physiology 1: HPA axis

Adrenal physiology 2: Renin-angiotensin system

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

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

Primary adrenal insufficiency: Etiologies Acquired Autoimmune AIDS Tuberculosis Bilateral injury Hemorrhage Necrosis Metastasis Idiopathic

Tuberculosis

Adrenal Hemorrhage: Meningiococcemia

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%)

Addison’s Disease Addison’s Normal

Primary adrenal insufficiency: Symptoms Fatigue Weakness Orthostatsis Weight loss Poor appetite Neuropsychiatric Apathy Confusion Nausea, vomiting Abdominal pain Salt craving

Primary adrenal insufficiency: Physical findings Hyperpigmentation Hypotension Orthostatic changes Weak pulses Shock Loss of axillary/pubic hair (women)

Primary adrenal insufficiency: Physical findings

Primary adrenal insufficiency: Laboratory findings Hyponatremia Hyperkalemia Hypoglycemia Narrow cardiac silhouette on CXR Low voltage EKG

Primary adrenal insufficiency: Etiologies Congenital Congenital adrenal hyperplasia Wolman disease Adrenal hypoplasia congenita Allgrove syndrome (AAA)

21-hydroxylase deficiency: Pathophysiology Testosterone

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

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

21-hydroxylase deficiency: Physical exam Females are unremarkable other than genitalia GU exam – Clitoromegaly, posterior labial fusion, no vaginal opening Males appear normal

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)

Primary adrenal insufficiency: Etiologies Syndromes Adrenoleukodystrophy Kearns-Sayre Autoimmune polyglandular syndrome 1 (APS1) APS2

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

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

Evaluation

Primary adrenal insufficiency: Evaluation 0800 cortisol level ACTH level Random cortisol in ill patient ACTH stimulation test Suspected CAH Needs special evaluation

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

Primary adrenal insufficiency: Evaluation Random cortisol in ill patient >20 mcg/dL reassuring Adrenal Autoantibodies ACA—adrenal cortex antibody Anti-21-OH-hydroxylase antibody

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

Primary adrenal insufficiency: Evaluation—ACTH Stimulation Cortisol peaks are controversial Reported normals range between 16-25 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

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

Diagnosis with 17-OH progesterone Baseline 10,000 - 90,000 Stimulated 20,000 - 100,000 Baseline 500 - 1,000 Stimulated 2,000-15,000 Baseline 20 - 1,000 Stimulated 200 - 1,000

Treatment

Primary adrenal insufficiency: Acute treatment NS volume resusitation Reverse shock Look for/treat hypoglycemia 25% dextrose New problem, suspected AI Labssteroids Established patient with AI Steroids

Stress dose steroids Loading dose 50-100 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 50-100 mg/M2/day Divide q6-8 hours May be 2-3x home dose

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 0.05-0.2 mg daily Patient education Stress coverage Emergency steroid administration IM hydrocortisone (Solucortef Actovial) Medic Alert ID

Relative Steroid Potencies Glucocorticoid Mineralocorticoid Hydrocortisone 1 ++ Prednisone/ Prednisolone 3-5 + Methylprednisone 5-6 Dexamethasone 25-50 Fludrocortisone 15-20 +++++

Relative Steroid Potencies Glucocorticoid Mineralocorticoid Hydrocortisone 1 ++ Prednisone/ Prednisolone 3-5 + Methylprednisone 5-6 - Dexamethasone 25-50 Fludrocortisone 15-20 +++++

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

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

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!