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)