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

Capsule

Glomerulosa

Fasiculata

Reticularis

Medulla

Adrenal physiology 1:HPA axis

Adrenal physiology 2:Renin-angiotensin system

Steroid Biosynthesis

ACTH

Cholesterol

Progesterone

Pregnenolone

Corticosterone

DOC

18-OH-Corticosterone

Aldosterone

StAR, 20,22-desmolase

3βHSD

21-hydroxylase

11β-hydroxylase

18-hydroxylase

18-oxidase

17-OH-Pregnenolone

17-OH-Progesterone

DHEA

Androstenedione

17α-hydroxylase

17α-hydroxylase3βHSD

Testosterone

Estrone

Estradiol

aromatase

aromatase

17βHSD

17βHSD

3βHSD17,20-lyase

17,20-lyase

11-deoxycortisol

Cortisol

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

CAH: PathophysiologyCholesterol

Progesterone

Pregnenolone

Corticosterone

DOC

18-OH-Corticosterone

Aldosterone

StAR, 20,22-desmolase

3βHSD

21-hydroxylase

11β-hydroxylase

18-hydroxylase

18-oxidase

17-OH-Pregnenolone

17-OH-Progesterone

DHEA

Androstenedione

17α-hydroxylase

17α-hydroxylase3βHSD

Testosterone

Estrone

Estradiol

3βHSD17,20-lyase

17,20-lyase

11-deoxycortisol

Cortisol

21-hydroxylase

11β-hydroxylase

CAH: PathophysiologyCholesterol

Progesterone

Pregnenolone

Corticosterone

DOC

18-OH-Corticosterone

Aldosterone

StAR, 20,22-desmolase

3βHSD

21-hydroxylase

11β-hydroxylase

18-hydroxylase

18-oxidase

17-OH-Pregnenolone

17-OH-Progesterone

DHEA

Androstenedione

17α-hydroxylase

17α-hydroxylase3βHSD

Testosterone

Estrone

Estradiol

3βHSD17,20-lyase

17,20-lyase

11-deoxycortisol

Cortisol

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 20 - 1,000Stimulated 200 - 1,000

Baseline 10,000 - 90,000Stimulated 20,000 - 100,000

Baseline 500 - 1,000Stimulated 2,000-15,000

Treatment

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

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/

Prednisolone3-5 +

Methylprednisone 5-6 0Dexamethasone 25-50 0Fludrocortisone 15-20 +++++

Relative Steroid Potencies

Glucocorticoid Mineralocorticoid

Hydrocortisone 1 ++Prednisone/

Prednisolone3-5 +

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!