Transcript adrenal_physiology_hypofun_states

D-Adrenal Physiology and
Hypofunctioning States
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

Deficiency of CYP 17
– 17α- hydroxylase and 17-20
lyase deficiency
– Rare cause
– Diagnosed due to delayed
pubertal development
– 46xx
Hypertensive
+/- Hypokalemic
Primary amenorrhea
Absent secondary sex
characteristics
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

– 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
–
–
–
–

Hyopnatremia
Hyperkalemia
Hyper-reninemia
Increased aldosterone levels
Many kindreds
– Homozygous mutation in
amiloride-sensitive epithelial
sodium channel
– Autosomal Recessive
Severe
Also affects sweat and salivary
glands
Colon
Features of
hypoaldosteronism

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
– Hypoglycemia
– Surgery
– Illness
– Hypotension
– Smoking
– Cold exposure
Blind patient
Reverts to a 24.5-25hr
– DHEA and Androstenedione
regulated by ACTH
Increase in response to
stress

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
– Inhibit linear growth
Erythrocytes
– Decreases IL-1
Decreased growth hormone

Immunologic
– Inhibit prostaglandin
synthesis
Lung maturity


– Minimal effect
Leukocytes
– Increase PMN by increasing
release from bone marrow
– Decreases lymphocytes,
monocytes and eosinophils
Phospholipase A2
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

Metyrapone is difficult to
obtain
– Increased ACTH
– Increased 11β-deoxycortisol
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
AntiInflammatory
Action
HPA
Suppression
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

Hydrocortisone
(Solucortef)
– 100 mg IV bolus then
100mg IV Q6hrs
Once stable
 Wean hydrocortisone

– 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