The Adrenals דר. אביטל נחמיאס

The Adrenals Structure and function Cortex  Hypofunction – Addison  Hyperfunction – Cushing 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

GlomerulosaFasciculataReticularisMedulla Morphology of the Adrenal Aldosterone Cortisol DHEA Cathecholeamines

Adrenal Cortex Zona glomerulosa- 15% Mineralocorticoid - Aldosterone Zona fasciculata- 75% Glucocorticoid - Cortisol and DHEA Zona reticularis- 10% Androgens - DHEA (DeHydroEpiAndrosterone), DHEAS DHEAS הוא 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 deficiency  Suppression – for suspected excess

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) Primary (Addison’s Disease) A drenal dysfunction Both GC and MC deficiency;  ACTH. Secondary 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" The first description of Addison’s disease Thomas Addison

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

Iatrogenic Abrupt 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 DM type 1 Vitiligo Graves or hashimoto Addison Pernicious anemia

Clinical Features of Adrenal Insufficiency Chronic syndrome Symptoms (not specific): Weakness & fatigue100% Anorexia100% Gastrointestinal symptoms92% Signs: Weight loss100% Hyperpigmentation (primary)92% Hypotension88% Salt craving (primary)19% Postural hypotension symptoms 12% Asthenia

Hyperpigmentation ל ACTH ברמות גבוהות יש פעילות של MSH הורמון 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  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  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 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 mg in the morning & 5-10 mg at 4-6 PM or prednisone mg orally once a day Fludrocortisone 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 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- Symptoms Feature% Weight gain91 Hirsutism, acne82 Menstrual disturbances/Dec. libido76 Psychiatric dysfunction60 Back pain43 Muscular weakness29 Fractures (osteoporosis)  Infections

Cushing’s Syndrome- Signs Feature% Central obesity (viceral fat)97 Plethora 94 Moon face 88 HTN74 Easy bruising (colagen fibroblasts)62 Red striae56 Muscle weakness56 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 dependentACTH 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 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

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 ACTH The 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. Cushing's disease Suppression of urinary cortisol excretion by more than 90%→100% specific for Cushing'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

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 DrugMechanism MetyraponeCYP11B1 inhibitors KetoconazoleCYP11A1+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)