Download Adrenal Physiology and Hypofunctioning States

Adrenal Physiology and
Hypofunctioning States
Heidi Chamberlain Shea, MD
Endocrine Associates of Dallas
Goals of Discussion
Review Adrenal Physiology
 Identify the clinical features of Adrenal
Insufficiency
 Etiologies of Adrenal Insufficiency
 Understand testing of adrenal function
 Treatment of Adrenal Insufficiency

Adrenal Development

Derived
– Neuroectodermal cells
(medulla)
– Mesenchymal cells (cortex)

Fetal adrenal is present
by 2 months gestation
– Mostly cortex
– Glomerulosa and fasiculata
are present at birth
– Reticularis develops during
first year of life
Adrenal Anatomy

Adult adrenal
– 2-3cm wide
– 1cm thick
– 4-6 grams

Located
– Upper pole of kidneys

Vascular supply
– 12 small arteries from
aorta
Adrenal Physiology

Glomerulosa
– 15% of cortex
– Aldosterone
 Renin-Angiotensin

Fasciulata
– 75% of cortex
– Cortisol
– DHEA
 ACTH

Reticularis
– Androgens and estrogens
 ACTH

Medulla
– Catecholamines
Congenital Adrenal Hyperplasia

Most adrenal
biosynthetic defects
result in
– Virilized female
– Normally virilized male
– Deficiencies
 Mineralocorticoid
 Glucocorticoid
– 21-OH deficiency
– 11-OH deficiency
Congenital Adrenal Hyperplasia

Deficiency of CYP 17
– 17α- hydroxylase and 1720 lyase deficiency
– Rare cause
– Diagnosed due to delayed
pubertal development
– 46xx




Hypertensive
+/- Hypokalemic
Primary amenorrhea
Absent secondary sex
characteristics
Congenital Adrenal Hyperplasia

Deficiency of CYP 17

– 46XY
 Complete male
pseudohermaphroditism
 Female external genitalia
 Blind-ended vagina
 No mullerian structures
 Testes intra-abdominal
– Leydig cell hyperplasia
 Hypertensive
 +/- Hypokalemic
Cortisol sufficient
– Tolerates general
anesthesia and
surgery

Treatment
– Steroids to suppress
excess
– Gonadal replacement
Congenital Adrenal Hyperplasia

3 β-Hydroxysteroid
Dehydrogenase
– Presents early infancy
– Adrenal insufficiency
– Females can be virilized
due to DHEA
– Males
 Normal genital
development
 Hypospadias
 Pseudohermaphroditism

Can present in
puberty
– Hyperandrogenemia
 Hirsuitism
 Oligomenorrhea

Treatment
– Cortisol replacement
Congenital Adrenal Hyperplasia
Congenital Lipoid Adrenal
Hyperplasia
 StAR Deficiency

– Transports cholesterol to
inner mitochondrial
membrane






Rarest form
Autosomal recessive
All adrenal steroids are
deficient
Present with adrenal
insufficiency
Typically fatal infancy
Males
– Female external genitalia
Renin and Aldosterone

Renin
– Enzyme released from the
kidneys (macula densa)
– Activates Angiotensinogen
Angiotensin 1
Angiotensin 2
– Increased secretion




Low blood pressure
Low sodium
High potassium
Upright posture

Aldosterone
– Sodium homeostasis
– Regulates arterial pressure
– Regulated
 Angiotensin 2
– Increases
 Renal sodium retention
 Renal potassium excretion
– Low Aldosterone
 Adrenal insufficiency
– High renin
 Hyperkalemia
Renin and Aldosterone
Mineralocorticoid Deficiency

Hyporeninemic
Hypoaldosteronism
– Impaired renin release
– 50-70 years
– Chronic assymptomatic
hyperkalemia
– Mild-moderate renal
insufficiency
– Muscle weakness
– Cardiac arrhythmias
Mineralocorticoid Deficiency


50% of patients with
Diabetes
Type IV RTA
– Metabolic acidosis
– Decreased renal
ammoniagenesis
– Decreased H ion secretion
– Decreased bicarbonate
resorbtion

Other diseases
–
–
–
–
–
–
–

SLE
Multiple myeloma
Renal amyloidosis
Cirrhosis
Sickle Cell
AIDS
POEMS
Transient with drugs
–
–
–
–
NSAID
Cyclosporin A
Mitomycin C
Cosyntropin
Mineralocorticoid Deficiency
Primary Hypoaldosteronism

Aldosterone synthase
deficiency (CYP11B2)
– Autosomal recessive
– Diagnosed in infancy
 Recurrent dehydration
 Failure to thrive
 Salt wasting

Treatment
– Florinef

Acquired
– Heparin
 Suppresses aldosterone
 Increase in renin
 Healthy person,
asymptomatic
 Critically ill, can be
symptomatic
Mineralocorticoid Deficiency
Primary Hypoaldosteronism

Pseudohypoaldosteronism

– Salt wasting syndrome
– Infancy
– Renal tubular insensitivity to
mineralocorticoids
– Autosomal Dominant
–
–
–
–
 Resistance to aldosterone at

the renal tubule
– Autosomal Recessive
 Severe
 Also affects sweat and
salivary glands
 Colon
Features of
hypoaldosteronism

Hyopnatremia
Hyperkalemia
Hyper-reninemia
Increased aldosterone
levels
Many kindreds
– Homozygous mutation in
amiloride-sensitive
epithelial sodium channel
Treatment
– NaCl
– K+ binding resins
HYPOTHALAMUS
(-)
HYPOTHALAMICPITUITARY
PORTAL SYSTEM
(-)
CRH
(+)
ANTERIOR
PITUITARY
POSTERIOR
PITUITARY
ACTH
Adrenal Fasiculata
CORTISOL
Adrenal Physiology

ACTH and cortisol

– Pulsatile secretion
– Highest in AM at wakening
– Lowest late afternoon and
evening
– Nadir is 1-2 hrs after the
start of sleep
– Circadian
 Blind patient
 Reverts to a 24.5-25hr
– DHEA and Androstenedione
regulated by ACTH
Increase in response to
stress
–
–
–
–
–
–

Hypoglycemia
Surgery
Illness
Hypotension
Smoking
Cold exposure
Blunted response
– Chronic illness
Circulation of Cortisol and Adrenal
Androgens
Secreted unbound
 In circulation bind to
plasma proteins
 Unbound is active
 Cortisol

– Free (10%)
– Corticosteroid-binding
globulin (CBG) (75%)
– Albumin

Androgens
– Albumin
– Testosterone
 Sex Hormone binding
(SHBG)
Cortisol Effects

Connective Tissue
– Inhibit fibroblasts
– Loss of collagen
– Thinning of skin

Bone
– Inhibit bone formation
– Stimulate bone
resorption
– Potentiate actions of
PTH
 Increased resorption

Calcium metabolism
– Decrease intestinal
calcium absorption
– Stimulates renal 1αhydroxylase
 Increases 1,25 OH
vitamin D synthesis
– Increased calciuria
– Increased
phosphaturia
Cortisol Effects

Growth
– Accelerate development of
fetal tissues
 Lung maturity
– Inhibit linear growth
 Decreased growth
hormone

Erythrocytes
– Minimal effect

Leukocytes
– Increase PMN by increasing
release from bone marrow
– Decreases lymphocytes,
monocytes and eosinophils

Immunologic
– Inhibit prostaglandin
synthesis
 Phospholipase A2
– Decreases IL-1
 IL-1 stimulates CRH and
ACTH
– Impairs AB production
and clearance
Cortisol Effects

Cardiovascular
– Increase CO
– Increase peripheral
vascular tone
– Hypertension

Renal function
– Mineralocorticoid receptors
 Na retention
 Hypokalemia
 HTN
– Glucocorticoid receptors
 Increased GFR

Nervous system
– Enters the brain
– Euphoria
– Irritability, depression and
emotional lability
– Hyperkinetic or manic
behavior
– Overt psychosis
– Increased appetite
– Impaired memory or
concentration
– Decreased libido
– Insomnia
 Decreased REM and
increased Stage II sleep
Cortisol Effects
Metabolism

Glycogen
– Activates glycogen
production\
– Deactivates glycogen
breakdown

Glucose
– Increase hepatic
glucose production
– Inhibits peripheral
tissue utilization of
glucose

Lipids
– Activate lipolysis in
adipose tissue
– Redistributes body fat
 Sparing of the
extremities
Adrenal Insufficiency

Incidence
– 6 cases per 1 million
adults/year

Prevalence
– 40-110 cases per 1 million
adults

More common in females
– 2.6:1

Diagnosed in the 3-5th
decades
Adrenal Insufficiency
Presentation

Signs and symptoms
– Rate and degree of
loss of adrenal
function
– Degree of physiologic
stress
– Primary
 Mineralocorticoid
deficiency
– Secondary/Tertiary
 Mineralocorticoid
sufficient
Adrenal Insufficiency
Presentation


Dehydration
Hypotension/shock
– Syncope

Abdominal pain
– Recurrent and unexplained
Mental status changes
 Nausea and vomiting
 Weight loss
 Fatigue
 Hyperpigmentation
 Vitiligo

Adrenal Crisis
Presentation






Unexplained
hypoglycemia
Hyponatremia
Hyperkalemia
Hypercalcemia
Eosinophilia
Other autoimmune
deficiencies
– Hypothyroid
– Hypogonadal
Adrenal Crisis
Populations at Risk

Secondary adrenal
insufficiency
– Exogenous steroid use
 Joint injections
 Herbals from Mexico
 High dose inhaled
steroids

Congenital Adrenal
Hyperplasia
Primary Adrenal Insufficiency
Etiology

Autoimmune adrenalitis
– 70% of cases
– Polyendocrinopathy-candidiasis-ectodermal
dystrophy (APECED)- PGA I
 Autosomal recessive disorder
 Mutation in zinc finger protein
 Adrenal failure, hypoparathyroidism, mucocutaneous
candidiasis, dental enamel hypoplasia, dystrophy of
the nails
Primary Adrenal Insufficiency
Etiology
 Autoimmune adrenalitis
– Polyglandular autoimmune II
 Primary adrenal insufficiency, Autoimmune thyroid
disease (hypo and hyper), Type I Diabetes,
hypogonadism

Infectious
– Tuberculosis
 5% of cases
 Rifampin will increase cortisol metabolism-higher
dose needed
– Histoplasmosis
 Ketoconazole inhibits steroid synthesis
Primary Adrenal Insufficiency
Etiology

Bilateral adrenal hemorrhage
– Ill patients on anticoagulants
– Coagulopathies
– Heparin
 Thrombosis and thrombocytopenia
– Primary antiphospholipid antibody syndrome
Primary Adrenal Insufficiency
Etiology

Adrenoleukodystrophy and
adrenomyeloneuropathy
– X-linked
– Defect in β-oxidation
– Mutations in gene encoding a peroxisomal
membrane protein of the ABC superfamily of
membrane transporters
– Demyelination of central and peripheral nervous
system
– High levels of very long chain fatty acids
(VLCFA)
Primary Adrenal Insufficiency
Etiology

Familial glucocorticoid
Deficiency
– Autosomal recessive
– ACTH resistance
 High plasma ACTH concentrations
– Cortisol and androgen
deficiency
– Aldosterone is normal
– Presents in childhood




Hyperpigmentation
Muscle weakness
Hypoglycemia and seizures
Low epinephrine
Primary Adrenal Insufficiency
Etiology

HIV/AIDS
– Adrenal necrosis
 Infiltrative etiologies
– CMV or TB

Bilateral metastatic infiltration
– Breast cancer
– Bronchogenic carcinoma
– Renal malignancies
Primary Adrenal Insufficiency
Etiology

Drugs that inhibit cortisol
synthesis
–
–
–
–
–
–

Aminoglutethimide
Etomidate
Ketoconazole
Metyrapone
Suramin
Mitotane
Accelerate cortisol
metabolism
– Phenytoin
– Barbituates
– Rifampin
Secondary Adrenal Insufficiency
Etiology
Glucocorticoid use
 Pituitary

– Tumors
– Hemorrhage
 Pituitary necrosis
(Sheehan Syndrome)
– Metastatic
malignancies
– Lymphocytic
hypophysitis
– Sarcoidosis
– Histiocytosis X

Developmental
abnormalities
– Pit-1
– Prop-1
– Septo-optic dysplasia
Adrenal Insufficiency
Diagnosis


Always test for thyroid
sufficiency
Insulin Hypoglycemia test
– Tests anterior pituitary
function
– Insulin 0.15U/kg/body
– Cortisol and growth
hormone drawn at baseline
– Repeat when glucose <35
mg/dl

Contraindicated
– Elderly, CAD, seizures
Adrenal Insufficiency
Diagnosis

Overnight Metyrapone
testing
– Tests for secondary or
tertiary abnormalities
– Blocks 11β-deoxycortisol to
cortisol
– Can initiate adrenal crisis
– Useful in determining
return of function from
steroid suppression

Normal result
– Increased ACTH
– Increased 11βdeoxycortisol

Metyrapone is difficult to
obtain
Adrenal Insufficiency
Diagnosis

Secondary cause

–
–
–
–
– Normal renin-angiotensin
system
 Normal kalemia
 No hyperpigmentation

Baseline critical samples
– Hypoglycemia or
hypotension
– Metabolic panel, CBC,
Cortisol, ACTH
– Thyroid function studies
High dose-

250 mcg ACTH
Evaluates primary disease
Critically ill
Inpatient setting
Low dose
– 1 mcg ACTH
– Evaluates primary
 Secondary if long standing
 Outpatient setting
 Evaluating for return of
adrenal function
Steroids
Potency
Steroid
AntiHPA
Inflammatory Suppression
Action
Salt
Retention
Cortisol
1
1
1
Prednisolone
3
4
0.74
Methylprednisolone
6.2
4
0.5
Dexamethasone
26
17
0
Fludrocortisone
12
12
125
Adrenal Crisis
Inpatient Treatment

Fluid resuscitation
– Saline and dextrose

Once stable
 Wean hydrocortisone

Hydrocortisone
(Solucortef)
– 100 mg IV bolus then
100mg IV Q6hrs
– 50 mg IV Q6-8hrs
– Taper and transition to
oral therapy

If primary
– Once saline heplocked
– Start Florinef
(fludrocortisone 0.1
mg PO QD)
Outpatient Treatment

Cortisol
– Hydrocortisone
 10mg AM and 5 mg PM
 6-8 mg/m2/day
 Stress dosing
–
–
–
–

Fever, illness, surgery
20 mg/m2/day
Double or triple daily dose
100 mg x1 then 25-50 mg
Q6-8hrs
All adrenal insufficient
patients need a medic
alert bracelet
Outpatient Treatment

Alternative glucocorticoid replacement
– Dexamethasone 0.5 mg (0.25-0.75) per day
– Prednisone 5 mg (2.5-7.5) per day

Florinef dosing
– Usual production 100mcg per day
– 0.05-0.2 mg (50-200mcg) per day
Questions?