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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.

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goals of discussion
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
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
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
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
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 hyperplasia1
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 hyperplasia2
Congenital Adrenal Hyperplasia
  • Cortisol sufficient
    • Tolerates general anesthesia and surgery
  • Treatment
    • Steroids to suppress excess
    • Gonadal replacement
  • 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
congenital adrenal hyperplasia3
Congenital Adrenal Hyperplasia
  • Can present in puberty
    • Hyperandrogenemia
      • Hirsuitism
      • Oligomenorrhea
  • Treatment
    • Cortisol replacement
  • 3 β-Hydroxysteroid Dehydrogenase
    • Presents early infancy
    • Adrenal insufficiency
    • Females can be virilized due to DHEA
    • Males
      • Normal genital development
      • Hypospadias
      • Pseudohermaphroditism
congenital adrenal hyperplasia4
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 and Aldosterone
  • Aldosterone
    • Sodium homeostasis
    • Regulates arterial pressure
    • Regulated
      • Angiotensin 2
    • Increases
      • Renal sodium retention
      • Renal potassium excretion
    • Low Aldosterone
      • Adrenal insufficiency
        • High renin
      • Hyperkalemia
  • 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
mineralocorticoid deficiency
Mineralocorticoid Deficiency
  • Hyporeninemic Hypoaldosteronism
    • Impaired renin release
    • 50-70 years
    • Chronic assymptomatic hyperkalemia
    • Mild-moderate renal insufficiency
    • Muscle weakness
    • Cardiac arrhythmias
mineralocorticoid deficiency1
Mineralocorticoid Deficiency
  • Other diseases
    • SLE
    • Multiple myeloma
    • Renal amyloidosis
    • Cirrhosis
    • Sickle Cell
    • AIDS
    • POEMS
  • Transient with drugs
    • NSAID
    • Cyclosporin A
    • Mitomycin C
    • Cosyntropin
  • 50% of patients with Diabetes
  • Type IV RTA
    • Metabolic acidosis
    • Decreased renal ammoniagenesis
    • Decreased H ion secretion
    • Decreased bicarbonate resorbtion
mineralocorticoid deficiency primary hypoaldosteronism
Mineralocorticoid DeficiencyPrimary Hypoaldosteronism
  • Acquired
    • Heparin
      • Suppresses aldosterone
      • Increase in renin
      • Healthy person, asymptomatic
      • Critically ill, can be symptomatic
  • Aldosterone synthase deficiency (CYP11B2)
    • Autosomal recessive
    • Diagnosed in infancy
      • Recurrent dehydration
      • Failure to thrive
      • Salt wasting
  • Treatment
    • Florinef
mineralocorticoid deficiency primary hypoaldosteronism1
Mineralocorticoid DeficiencyPrimary Hypoaldosteronism
  • 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
  • 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
slide19

POSTERIOR

Adrenal Fasiculata

HYPOTHALAMUS

(-)

PITUITARY

CORTISOL

ACTH

HYPOTHALAMIC-

PITUITARY

(-)

PORTAL SYSTEM

CRH

(+)

ANTERIOR

PITUITARY

adrenal physiology1
Adrenal Physiology
  • Increase in response to stress
    • Hypoglycemia
    • Surgery
    • Illness
    • Hypotension
    • Smoking
    • Cold exposure
  • Blunted response
    • Chronic illness
  • 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
circulation of cortisol and adrenal androgens
Circulation of Cortisol and Adrenal Androgens
  • Androgens
    • Albumin
    • Testosterone
      • Sex Hormone binding (SHBG)
  • Secreted unbound
  • In circulation bind to plasma proteins
  • Unbound is active
  • Cortisol
    • Free (10%)
    • Corticosteroid-binding globulin (CBG) (75%)
    • Albumin
cortisol effects
Cortisol Effects
  • Calcium metabolism
    • Decrease intestinal calcium absorption
    • Stimulates renal 1α-hydroxylase
      • Increases 1,25 OH vitamin D synthesis
    • Increased calciuria
    • Increased phosphaturia
  • Connective Tissue
    • Inhibit fibroblasts
    • Loss of collagen
    • Thinning of skin
  • Bone
    • Inhibit bone formation
    • Stimulate bone resorption
    • Potentiate actions of PTH
      • Increased resorption
cortisol effects1
Cortisol Effects
  • Immunologic
    • Inhibit prostaglandin synthesis
      • Phospholipase A2
    • Decreases IL-1
      • IL-1 stimulates CRH and ACTH
    • Impairs AB production and clearance
  • 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
cortisol effects2
Cortisol Effects
  • 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
  • Cardiovascular
    • Increase CO
    • Increase peripheral vascular tone
    • Hypertension
  • Renal function
    • Mineralocorticoid receptors
      • Na retention
      • Hypokalemia
      • HTN
    • Glucocorticoid receptors
      • Increased GFR
cortisol effects metabolism
Cortisol EffectsMetabolism
  • Lipids
    • Activate lipolysis in adipose tissue
    • Redistributes body fat
      • Sparing of the extremities
  • Glycogen
    • Activates glycogen production\
    • Deactivates glycogen breakdown
  • Glucose
    • Increase hepatic glucose production
    • Inhibits peripheral tissue utilization of glucose
adrenal insufficiency
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
Adrenal InsufficiencyPresentation
  • Signs and symptoms
    • Rate and degree of loss of adrenal function
    • Degree of physiologic stress
    • Primary
      • Mineralocorticoid deficiency
    • Secondary/Tertiary
      • Mineralocorticoid sufficient
adrenal insufficiency presentation1
Adrenal InsufficiencyPresentation
  • Dehydration
  • Hypotension/shock
    • Syncope
  • Abdominal pain
    • Recurrent and unexplained
  • Mental status changes
  • Nausea and vomiting
  • Weight loss
  • Fatigue
  • Hyperpigmentation
  • Vitiligo
adrenal crisis presentation
Adrenal CrisisPresentation
  • Unexplained hypoglycemia
  • Hyponatremia
  • Hyperkalemia
  • Hypercalcemia
  • Eosinophilia
  • Other autoimmune deficiencies
    • Hypothyroid
    • Hypogonadal
adrenal crisis populations at risk
Adrenal CrisisPopulations at Risk
  • Secondary adrenal insufficiency
    • Exogenous steroid use
      • Joint injections
      • Herbals from Mexico
      • High dose inhaled steroids
  • Congenital Adrenal Hyperplasia
primary adrenal insufficiency etiology
Primary Adrenal InsufficiencyEtiology
  • 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 etiology1
Primary Adrenal InsufficiencyEtiology
  • 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 etiology2
Primary Adrenal InsufficiencyEtiology
  • Bilateral adrenal hemorrhage
    • Ill patients on anticoagulants
    • Coagulopathies
    • Heparin
      • Thrombosis and thrombocytopenia
    • Primary antiphospholipid antibody syndrome
primary adrenal insufficiency etiology3
Primary Adrenal InsufficiencyEtiology
  • 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 etiology4
Primary Adrenal InsufficiencyEtiology
  • 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 etiology5
Primary Adrenal InsufficiencyEtiology
  • HIV/AIDS
    • Adrenal necrosis
      • Infiltrative etiologies
        • CMV or TB
  • Bilateral metastatic infiltration
    • Breast cancer
    • Bronchogenic carcinoma
    • Renal malignancies
primary adrenal insufficiency etiology6
Primary Adrenal InsufficiencyEtiology
  • Drugs that inhibit cortisol synthesis
    • Aminoglutethimide
    • Etomidate
    • Ketoconazole
    • Metyrapone
    • Suramin
    • Mitotane
  • Accelerate cortisol metabolism
    • Phenytoin
    • Barbituates
    • Rifampin
secondary adrenal insufficiency etiology
Secondary Adrenal InsufficiencyEtiology
  • Developmental abnormalities
    • Pit-1
    • Prop-1
    • Septo-optic dysplasia
  • Glucocorticoid use
  • Pituitary
    • Tumors
    • Hemorrhage
      • Pituitary necrosis (Sheehan Syndrome)
    • Metastatic malignancies
    • Lymphocytic hypophysitis
    • Sarcoidosis
    • Histiocytosis X
adrenal insufficiency diagnosis
Adrenal InsufficiencyDiagnosis
  • 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 diagnosis1
Adrenal InsufficiencyDiagnosis
  • 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 11β-deoxycortisol
  • Metyrapone is difficult to obtain
adrenal insufficiency diagnosis2
Adrenal InsufficiencyDiagnosis
  • 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
  • Secondary cause
    • Normal renin-angiotensin system
      • Normal kalemia
      • No hyperpigmentation
  • Baseline critical samples
    • Hypoglycemia or hypotension
    • Metabolic panel, CBC, Cortisol, ACTH
    • Thyroid function studies
adrenal crisis inpatient treatment
Adrenal CrisisInpatient Treatment
  • 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)
  • Fluid resuscitation
    • Saline and dextrose
  • Hydrocortisone (Solucortef)
    • 100 mg IV bolus then 100mg IV Q6hrs
outpatient treatment
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 treatment1
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