Transcript The Adrenal Cortex

‫‪The Adrenals‬‬
‫דר‪ .‬אביטל נחמיאס‬
The Adrenals
Structure and function
 Cortex

– Addison
 Hyperfunction – Cushing
 Hypofunction

Adrenal incidentaloma
‫‪The Adrenal Glands‬‬
‫בלוטת יותרת הכליה היא איבר רטרופריטוניאלי שנראה כמו כובע משולש מעל כל כליה‬
‫המשקל של כל בלוטה הוא כ‪ 4-‬גרם והמידות הן ‪2-3 X 4-6 cm‬‬
The Adrenal Glands
Retroperitoneal
4 gr weight
2X4X1 cm
The Adrenal Glands
Morphology of the Adrenal
Fasciculata
Aldosterone
Reticularis
Cortisol
DHEA
Cathecholeamines
Medulla
Glomerulosa
Adrenal Cortex
Zona glomerulosa- 15%
Mineralocorticoid - Aldosterone
Zona fasciculata- 75%
Glucocorticoid - Cortisol and DHEA
Zona reticularis- 10%
Androgens - DHEA (DeHydroEpiAndrosterone), DHEAS
‫ הוא ההורמון הפעיל שאחראי על כל סימני הויריליזציה‬DHEAS
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

– for suspected deficiency
 Suppression – for suspected excess
 Stimulation
Stimulation tests

Cortisol
 ACTH

(synacthen test)
Aldosterone
 Volume
depletion
Salt restriction
 Diuretic administration
 Upright posture

Suppression test

Cortisol
 Dexamethasone

suppression test
Aldosterone
 Saline
infusion test
Addison’s disease
Adrenal Failure
 Primary
(Addison’s Disease)
Adrenal dysfunction
Both GC and MC deficiency; ACTH.
 Secondary
Pituitary Dysfunction
Only 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"
Thomas Addison
The first description of Addison’s disease
Etiology of Addison’s Disease
Autoimmune
(80%)
Isolated, Autoimmune polyglandular syndrome Type 1&2
Infections
TB (calcifications), Histoplasmosis, CMV, HIV, syphillis,
coccidioidomycosis, and cryptococcosis.
Infiltration
Amyloidosis, Hemochromatosis
Hemorrhage
Anticoagulants, 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
Secondary Hypoadrenalism (ACTH)
Iatrogenic
Abrupt withdrawal of Chronic steroid Rx
Pituitary
•Tumor (stalk effect)
•Radiation
•Surgery
•Infarct
•Hemorrhage
•Sheehan syn – low BP
during birth +/- hemorrhage
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 syndrome
Symptoms (not specific):
Weakness & fatigue
Anorexia
Gastrointestinal symptoms
100%
100%
92%
Signs:
Weight loss
Hyperpigmentation (primary)
Hypotension
Salt craving (primary)
Postural hypotension symptoms
100%
92%
88%
19%
12%
Asthenia
‫‪Hyperpigmentation‬‬
‫ל ‪ ACTH‬ברמות גבוהות יש פעילות של ‪ MSH‬הורמון המפעיל מלנוציטים‬
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 mg)
Post-stimulation cortisol (30’ 60’) above 550 nmol/l (20 mg/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
 trauma
 Surgery
 Dehydration
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
This is a life threatening emergency!!!
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.
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
Etiology of Cushing’s syndrome (CS)
Exogenous: (Iatrogenic, Factitious)
Endogenous:
ACTH dependent:
Cushing’s disease
Pituitary
(68%)
Ectopic ACTH (SCLC)(15%)
CRH
rare
ACTH independent: Adenoma
(9%)
Carcinoma
(8%)
Nodular hyperplasia rare
Pituitary tumor
Adrenal tumor
Ectopic ACTH secretion
*hypokalemia
Symptoms and signs
Cushing’s Syndrome- Symptoms
Feature
%
Weight gain
91
Hirsutism, acne
82
Menstrual disturbances/Dec. libido 76
Psychiatric dysfunction
60
Back pain
43
Muscular weakness
Fractures (osteoporosis)
 Infections
29
Cushing’s Syndrome- Signs
Feature
%
Central obesity (viceral fat)
97
Plethora
94
Moon face
88
HTN
74
Easy bruising (colagen fibroblasts) 62
Red striae
56
Muscle weakness
56
Edema
50
Moon Face and Plethora
Moon Face, hirsutism &
Supraclavicular Fat Pads
Centripetal Obesity
Proximal 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
Does the patient have Cushing’s syndrome?


–
–
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?
Low dose dexamethasone tests

0.5mg X4 for 2 days (2mg/d).

8 AM cortisol on day 3 <50 nmol/l
Pituitary Cushing’s vs. Ectopic ACTH
The High Dose Dexamethasone Test

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
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 disease
Pituitary Cushing’s vs. Ectopic ACTHInferior 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
IPSS
Measure cortisol and ACTH simultaneously from:
Right petrosal sinus
 Left petrosal sinus
 Peripheral vein
Before 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 syndrome
Pituitary CS:
Trans-sphenoidal adenomectomy (80-90% cure)
Irradiation (conventional, proton beam)
Medical treatment
Bilateral adrenalectomy
Ectopic ACTH
Tumor resection (if possible)
Medical treatment
Bilateral adrenalectomy
Adrenal CS
Tumor resection
Medical Treatment of CS
Drug
Mechanism
Metyrapone
Ketoconazole
CYP11B1 inhibitors
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.


Determine whether the tumor is functioning


metastasis in about one-half of the patients.
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)