the adrenals דר. אביטל נחמיאס. the adrenals structure and function cortex hypofunction...
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The Adrenals
דר. אביטל נחמיאס
The Adrenals
Structure and function Cortex
Hypofunction – AddisonHyperfunction – Cushing
Adrenal incidentaloma
The Adrenal Glands
בלוטת יותרת הכליה היא איבר רטרופריטוניאלי שנראה כמו כובע משולש מעל כל כליה
X 4-6 cm 2-3 גרם והמידות הן 4המשקל של כל בלוטה הוא כ-
The Adrenal Glands
Retroperitoneal4 gr weight
2X4X1 cm
The Adrenal Glands
GlomerulosaFasciculataReticularisMedulla
Morphology of the Adrenal
Ald
ostero
ne
Co
rtisol
DH
EA
Cath
echo
leamin
es
Adrenal Cortex
Zona glomerulosa- 15%
Mineralocorticoid - Aldosterone
Zona fasciculata- 75%
Glucocorticoid - Cortisol and DHEA
Zona reticularis- 10%
Androgens - DHEA (DeHydroEpiAndrosterone), DHEAS
DHEASהוא ההורמון הפעיל שאחראי על כל סימני הויריליזציה
Actions of glucocorticoids Immune system
• ↑ WBC, ↓Eos, ↓ phagocytosis, anti inflammatory
• Metabolic• Increase gluconeogenesis
• Inhibit glucose uptake and utilization (NOT in brain, heart, liver, RBC)
• Increase lipolysis, increase protein catabolism - myopathy
• Impaired wound healing (less colagen production, impaired fibroblast function)
• Inhibit osteoblasts (osteoporosis), ↓ intestinal and renal calcium absorption – increases PTH
• Developmental• Differentiation of organs in the fetus
• Complex action on the brain - arousal and cognition
Action of mineralocorticoids
Increased Na absorption in the kidney – water comes with the Na – fluid overload – hypertention and edema
K+ secreted instead of the Na – hypokalemia
Action of androgens
Regulation of cortisol secretion
Regulation of aldosterone secretion
•RAS•K+
•ACTH
Regulation of androgen secretion
Adrenal androgen secretion is regulated by ACTH
In males – adrenal androgens have minimal effects
In females – adrenal androgens convert to testosterone in extraglandular tissues
Laboratory evaluation of adrenal function
What’s the problem?
Cortisol circadian rhythm
Laboratory evaluation of adrenal function
Point measurements – at peak or trough Urinary excretion Dynamic testing
Stimulation – for suspected deficiencySuppression – for suspected excess
Stimulation tests
CortisolACTH (synacthen test)
AldosteroneVolume depletion
Salt restriction Diuretic administration Upright posture
Suppression test
CortisolDexamethasone suppression test
AldosteroneSaline infusion test
Addison’s disease
Adrenal Failure
Primary Primary ((Addison’s DiseaseAddison’s Disease))
AAdrenal dysfunction drenal dysfunction Both GC and MC deficiency; ACTH.
SecondarySecondaryPituitary DysfunctionPituitary DysfunctionOnly GC deficiency; ACTH.
“general languor and debility, feebleness of the heart's action,
irritability of the stomach, and a peculiar change of
the color of the skin"
The first description of Addison’s disease
Thomas Addison
Etiology of Addison’s DiseaseAutoimmune (80%)Isolated, Autoimmune polyglandular syndrome Type 1&2
InfectionsTB (calcifications), Histoplasmosis, CMV, HIV, syphillis, coccidioidomycosis, and cryptococcosis.
InfiltrationAmyloidosis, Hemochromatosis
HemorrhageAnticoagulants, trauma, sepsis, surgery, pregnancy, Meningococcemia causes waterhouse friderichsen syndrome – adrenal crisis)
Infarction (bilateral – rare)
Etiology of Addison’s Disease
Bilateral Metastasis, Lymphoma (rare)
Bilateral adrenalectomy
Drugs•Inhibitors of steroidogenesis (ketoconazol)•Increase metabolism of steroid hormones (tegretol)
Congenital Adrenal Hyperplasia
Familial GC deficiency
IatrogenicAbrupt withdrawal of Chronic steroid Rx
Pituitary •Tumor (stalk effect)•Radiation•Surgery•Infarct•Hemorrhage•Sheehan syn – low BP during birth +/- hemorrhage
Secondary Hypoadrenalism (ACTH)
Autoimmune Addison’s Disease
Autoimmune Polyglandular Syndrome Type 1
•AR inheritance
•More common in Iranian Jews
•Hypoparathyroidism•Chronic Mucocutaneous Candidiasis•Gonadal failure•Addison
•Ab in serum can be sent abroad
Autoimmune Addison’s Disease
Autoimmune Polyglandular Syndrome Type 2
•50:1,000,000 rare
•More common in women, age 30-50
•DM type 1•Vitiligo•Graves or hashimoto•Addison•Pernicious anemia
Clinical Features of Adrenal Insufficiency
Chronic syndromeChronic syndrome
Symptoms Symptoms (not specific):(not specific):Weakness & fatigue 100%Anorexia 100%Gastrointestinal symptoms 92%
Signs:Weight loss 100% Hyperpigmentation (primary) 92%Hypotension 88% Salt craving (primary) 19%Postural hypotension symptoms 12% Asthenia
Hyperpigmentation
הורמון המפעיל מלנוציטיםMSH ברמות גבוהות יש פעילות של ACTHל
Pigmented Scar
Buccal Hyperpigmentation
Laboratory Findings
• Normocytic normochromic anemia (chronic disease)
• Neutropenia and eosinophilia, relative lymphocytosis
• Hyponatremia (SIADH, MC def) (90%)
• Hyperkalemia (65%)
• Hypoglycemia (rare)
• Hypercalcemia (rare)
Diagnosis
Primary adrenal insufficiency:•Rapid ACTH test (Synacthen 250 g)Post-stimulation cortisol (30’ 60’) above 550 nmol/l (20 g/dl)
is normal, Below 200 could be addison
•Plasma ACTH levels
Secondary/ tertiary adrenal insufficiency:•CRH test
Acute Syndrome (Addisonian Crisis) Withdrawal Acute stress
Infection traumaSurgeryDehydration
Acute syndrome Hemorrhage Infarct Meningococcemia (Waterhouse-Friderichsen
syndrome) Rare in secondary adrenal insufficiency.
Acute Syndrome (Addisonian Crisis)
• Manifestations:• Shock and hypotension• Weakness, fatigue, lethargy• Muscle, joint and abdominal pain (acute
abdomen)• Fever, anorexia, vomiting• Apathy, Clouded sensorium• Hypoglycemia is rare
• The diagnosis should always be considered in any patient with unexplained shock
Treatment
Acute Crisis
• Hydrocortisone 100 mg IV, every 6-8 hours for 24 hr not PO !!!• Correct volume depletion, dehydration, hypotension and hypoglycemia with IV saline and glucose
• Correct precipitating factors, especially infection
• As soon as the patient is eating and drinking and off IV fluids add fludrocortisone.
This is a life threatening emergency!!!
Maintenance
• Hydrocortisone 15-20 mg in the morning & 5-10 mg at 4-6 PM or prednisone 5-7.5 mg orally once a day
• Fludrocortisone 0.05-2 mg/day (primary)
• Follow clinical symptoms, weight, B.P., electrolytes
• Educate patient to increase cortisol dose during stress
Cushing’s disease
Harvey Williams Cushing
Cushing’s diseaseCushing’s disease
Exogenous: (Iatrogenic, Factitious)
Endogenous:ACTH dependent: Pituitary (68%)
Ectopic ACTH (SCLC)(15%) CRH rare
ACTH independent: Adenoma (9%)Carcinoma (8%)Nodular hyperplasia rare
Etiology of Cushing’s syndrome (CS)
Pituitary tumor
Adrenal tumor
Ectopic ACTH secretion
*hypokalemia
Symptoms and signs
Cushing’s Syndrome- SymptomsFeature %
Weight gain 91
Hirsutism, acne 82
Menstrual disturbances/Dec. libido 76
Psychiatric dysfunction 60
Back pain 43
Muscular weakness 29
Fractures (osteoporosis)
Infections
Cushing’s Syndrome- SignsFeature %
Central obesity (viceral fat) 97Plethora 94Moon face 88HTN 74Easy bruising (colagen fibroblasts) 62Red striae 56Muscle weakness 56Edema 50
Moon Face and Plethora
Moon Face, hirsutism & Supraclavicular Fat Pads
Centripetal ObesityProximal Muscle Wasting
Buffalo Hump Hirsutism & Acne
Striae
Easy Bruisability
Cushing’s Syndrome- Lab DM +IGT• Osteoporosis (hypercalciuria, inc.
PTH)• Hypercalciuira• LH & FSH• TSH
• GH
• TC; TG• K
Diagnosis of Cushing’s Syndrome
Does the patient have Cushing’s syndrome?
If the answer is yes: What is the cause of the hypercortisolism?
ACTH dependent
ACTH independent
Does the patient have Cushing’s syndrome?
Loss of circadian rhythm of plasma cortisol and ACTH.
Peak 8-9 AM; Nadir 24:00
Midnight cortisol >200 nmol/l suggests Cushing’s;
<50nmol/l R/O Cushing’s
24 Hour Urinary Free Cortisol (UFCX3) Inexpensive, outpatient suspicion if X3-4 ULN
1mg Overnight Dexamethasone suppression test (ONDST)
– 1 mg dexamethasone PO @ midnight– 8 AM cortisol <50 nmol/l
Does the patient have Cushing’s syndrome?
Does the patient have Cushing’s syndrome?
Low dose dexamethasone tests
0.5mg X4 for 2 days (2mg/d).
8 AM cortisol on day 3 <50 nmol/l
ACTH secretion by pituitary adenomas is only relatively resistant to negative feedback regulation by GC’s.
Most tumors associated with the ectopic ACTH syndrome are completely resistant to feedback inhibition
Pituitary Cushing’s vs. Ectopic ACTHThe High Dose Dexamethasone Test
High Dose Dexamethasone Suppression Test- Liddle’s test
One baseline 24-hour urine specimen
2 mg of dexa X4 (8mg/d) for 2 days.
Suppression of urinary cortisol excretion by more than 90%→100% specific for Cushing's diseaseCushing's disease
Pituitary Cushing’s vs. Ectopic ACTH- Inferior Petrosal Sinus Sampling
• Some pituitary Cushing’s don’t suppress with HDDST
• Some ectopic ACTH syndrome suppress with HDDST
• MRI sensitivity in pituitary imaging is only 50%-60%
• 10-20% incidental pituitary tumors in the general population
IPSSMeasure cortisol and ACTH simultaneously from: Right petrosal sinus Left petrosal sinus Peripheral veinBefore and after stimulation with CRH (100 ucg).
Central/Peripheral >3 → Pituitary Cushing’s
Central/Peripheral <2 → Ectopic ACTH
Cushing’s Syndrome
Treatment of Cushing’s syndromePituitary CS: Trans-sphenoidal adenomectomy (80-90% cure)Irradiation (conventional, proton beam)Medical treatmentBilateral adrenalectomy
Ectopic ACTHTumor resection (if possible)Medical treatmentBilateral adrenalectomy
Adrenal CSTumor resection
Medical Treatment of CS
Drug Mechanism
Metyrapone CYP11B1 inhibitorsKetoconazole CYP11A1+B1inhibitors
Adrenal incidentaloma
Evaluation of Asymptomatic Adrenal Masses ~6% of adult/elderly subjects at autopsy have adrenocortical
adenomas. Determine whether the patient has a history of prior
malignancy. metastasis in about one-half of the patients.
Determine whether the tumor is functioning 70–80% are non-secretory.
CT Features suggestive of malignancy include large size (>4–6 cm) irregular margins tumor inhomogeneity soft tissue calcifications visible on CT high unenhanced CT attenuation values (>10 HU)