1 CLINICAL CHEMISTRY 3 MIDTERMS :P 1/7/14 ADRENALS: Anatomy, physiology, and pathology Normal Anatomy - 2 small, yellowish bodies - Located

d in the perirenal space, immediately anterosuperior to the upper pole of the kidneys - Also known as the suprarenal glands - Location: at the posterior 12th thoracic vertebra - Weight: approximately 4 6 grams - 2 portions: adrenal cortex and adrenal medulla 2. Zona fasciculata - Middle zone (75%), thickest and located between the zona glomerulosa and zona reticularis. - Primary secretion: Glucocorticoids -> involved in increasing blood glucose levels. - Have additional effects in protein and fat metabolism. - The naturally synthesized glucocorticoids of most importance is cortisol. * DHEA: partly released in this zone 3. Zona reticularis - Innermost zone (10%), in between the zona fasciculata and medulla; interior layer - Primary secretion: Androgen - Main androgen is Dehydroepiandrosterone sulfate (DHEAS) 4. Capsule (5%) - Lining of adrenals not capable of secreting hormones. Hormones of the Adrenal Cortex - All adrenal cortex hormones are steroids - Not stored, synthesized only when needed. (needs stimulation -> production -> effect) * Cortex steroidogenesis

Layers: A. Adrenal cortex - Outer layer - Responsible for the regulation of salt, sugar, and sexual characteristics. - Hormones produced are known as corticosteroids. * Components of Corticosteroids: a. Mineralocorticoids: regulate salt b. Glucocorticoids: regulate sugar c. Androgens: regulate sexual characteristics - Cholesterol serve as the precursor for the production of corticosteroids. Microscopic Regions of the Adrenal Cortex: 1. Zona glomerulosa - Outermost zone (10%), located just below the adrenal cortex. - Secretes mineralocorticoids * Mineralocorticoids are aptly termed as they are involved in the regulation of electrolytes in ECF. - The naturally synthesized mineralocorticoids of most importance is aldosterone.

CRH (Hypothalamus) - Stimuli: - Serum cortisol - Circadian signals - Stress

ACTH (Anterior pituitary) - Stimulates transport of free cholesterol into adrenal mitochondria

Adrenal parenchymal cells Cholesterol enters into mitochondria

Cholesterol (Mitochondria)

Minus 6 carbons (CYP450 enzyme)

Pregnenolone

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2 G Blood Pressure - mineralocorticoids - Serum Potassium Pregnenolone 3 Progesterone 21 F Blood Pressure - glucocorticoids - Glucose 17-OH Pregnenolone 3 17-OHase 3 c. Enhances reabsorption of sodium from the intestine especially in colon absence of aldosterone leads to diarrhea - no Na reabsorption -> continuous excretion of sodium with water * Regulation and control a. Renin Angiotensin System Stimulus: blood volume -> Renin secretion by juxtaglomerular cells -> reacts with angiotensinogen -> angiotensin I production (liver) -> passes through the lungs -> angiotensin converting enzyme (ACE) changes it to active form: angiotensin II: vasoconstriction, Na reabsorption by PCT, release Aldosterone Na reabsorption at DCT-> Angiotensin III -> more aldosterone release b. Potassium: K = aldosterone synthesis c. ACTH more pregnenolone = more progesterone d. Natriuretic Peptide (heart) - inhibits aldosterone secretion, promotes natriuresis by the kidneys. - decrease potassium = production by heart - decreases aldosterone to allow potassium reabsorption and sodium secretion * Disorders of Aldosterone a. Natural increase (Physiologic response) - deficiency in Na and plenty of K in the diet - heavy sweat (decreased Na) b. Natural decrease - deficiency in the diet - having large amounts of water and drinks c. Addisons disease - occurs when about 90% of cortex cells are damaged, very rare (8/million person) MHML R Vinlization - androgens - sex DHEA (S) * Effects of Aldosterone: a. Renal and circulatory effects (ECF volume regulation, sodium and potassium ECF concentration) b. Promotes reabsorption of sodium from the ducts of sweat and salivary glands during excessive sweat or saliva loss.

17-OH Progesterone 21

Deoxycorticosterone 11- Deoxycortisol Androstenedione Androstenediol 11 Corticosterone 18 OH ALDOSTERONE (15 20 mg/day) Cortisone (waste product) ESTRADIOL 11 CORTISOL 3 TESTOSTERONE

* Regulation - only free cholesterol can enter steroidogenesis - the availability is regulated by ACTH (positively) and LDL (negatively) - F-layer glucocorticoids powerfully suppress ACTH release, thus cortisol is the primary feedback regulation of ACTH - ACTH does not significantly impact G-layer aldosterone synthesis HORMONES 1. Aldosterone - Normal level: 4-9 mg/100 mL of blood - Discarded in urine at about 2-18 mg daily - Responsible for regulating Sodium reabsorption - Target cells are called principal (P) cells - Stimulates synthesis of more Sodium/Potassium ATPase pumps.

3 - Addisonian has a remarkable depression in aldosterone level - accompanied by a low BP, high temp., weight loss, decreased blood Na, and increased blood K. o Signs and symptoms of Addisons disease: - fatigue - weight loss - anorexia why? -> function of cortisol - changes in skin pigment (small black freckles, decrease in cortisol -> increased ACTH -> increased MSH) - muscular weakness (cortisol helps muscles maintain contraction and avoid fatigue) Formed in the F zone (essentially) and R zone of adrenal cortex. In circulation, cortisol is bound to corticosteroid-binding globulin (CBG) or transcortin. Exhibits diurnal variation -> highest concentration at 8 AM, lowest at late evening. Free cortisol -> biologically active form Glucocorticoids have no target gland; exert their influence throughout the body.

* Physiological actions of cortisol 1/9/14 * Anti-inflammatory effects of cortisol Reduces phagocytic action of WBC Reduces fever Suppresses allergic reactions Wide spread therapeutic use Promotes gluconeogenesis Promotes breakdown of skeletal muscle proteins Enhances fat breakdown (lipolysis) Suppresses immune system (immune system uses a lot of sugar) Breakdown of bone matrix (high doses)

d. Conns syndrome - Primary: due to tumor (adenoma), nodularity, hyperplasia - Secondary: due to excess stimulation by angiotensin - Most common cause: Aldosterone producing adenoma -> not controlled by negative feedback - Incidence: Females > Males, 30-60 y/o, 7% of patients investigated for hypertension. * Investigations a. Blood - Na and K levels - Plasma aldosterone - Plasma renin activity b. Urine - urinary potassium and sodium c. Imaging - ultrasound - CAT scan - MRI - Iodo-cholesterol isotope scan

2. Cortisol - Major glucocorticoid hormone - Secretion: 25 mg/day; no normal range because production depends on the need.

* Regulation of Cortisol Release > Enhanced release can be caused by: - Physical trauma - Infection - Extreme heat and cold - Exercise to the point of exhaustion - Extreme mental anxiety * Disorders of Cortisol a. Glucocorticoid Deficiency i. Loss of cortisol - disruption of glucose concentration - reduction in metabolism of fats and proteins - patient is susceptible to different types of stress MHML

4 - sluggishness of energy mobilization result in weak muscle even when glucose and other nutrients are available cortisol is needed for metabolic function ii. Hyperadrenalism Cushings syndrome - caused by exogenous glucocorticoids and by tumors (adrenal/pituitary) - zona glomerulosa tumor increases aldosterone -> increased sodium, blood pressure -> 80% suffer from hypertension - zona reticularis tumor increases cortisol -> excess protein catabolism, redistribution of fat o Characteristics Buffalo torso - Redistribution of fat from lower parts of the body to the thoracic and upper abdominal areas. Moon face - Edematous appearance of face - Acne and hirsutism (excess growth of facial hair) b. Dehydroepiandrosterone (DHEA) c. Androstenedione Small amounts of testosterone (T) and Dihydrotestosterone (DHT) Peak production of androgens between 20 30 years old, then falls off gradually DHEA and DHEAS levels decrease during illness, depression and other stresses (impotency and infertility)

* Disorders of Androgens a. Androgen Excess - Androgen stimulates organ development and linear growth and epiphyseal fusion. - Virilization in boys include penile enlargement, androgen dependent hair growth and other secondary sex characteristics. - Girls develop hirsutism, acne, and clitorimegaly * Diagnosis of Androgen Excess - High DHEA production strongly suggests adrenal hyperandrogenism. - Elevated testosterone values are seen with either adrenal or gonadal hyperandrogenism. - Plasma DHEA or urine 17 Ketosteroids can identify adrenal causes of pathologic masculinization and feminization.

b. Effects on carbohydrate metabolism i. Adrenal Diabetes - hypertension of cortisol results in increase blood glucose levels up to 2x normal (200mg/dL) - prolonged oversecretion of insulin burns out the Beta cells of the pancreas resulting in life long DM. c. Other effects i. High blood pressure (secondary) ii. Osteoporosis due to increased protein breakdown. * Diagnosis a. 24 - hours urine free cortisol or salivary cortisol b. Low dose dexamethasone suppression test c. Plasma ACTH d. Imaging studies 3. Adrenal Androgens - Predominant androgens produced at the adrenal cortex are: a. Dehydroepiandrosterone sulfate (DHEAS)

B. Adrenal Medulla - Devoted to synthesis of cathecolamines which includes adrenaline (epinephrine) and noradrenaline (norepinephrine) - Both hormones are secreted in stressful situations - Function as an atypical sympathetic ganglion - Its products serve as first responders to stress by acting within seconds to promote a fight flight response.

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5 Physiologic Effects of Cathecolamines - Cathecolamines causes general physiological changes that prepare the body for physical activities. - In case of (fight or flight), cathecolamines cause: Elevation of blood pressure Increasing blood sugar Increasing heart rate Increased metabolic rate Affects peripheral nervous system Cathecolamines Production Cytoplasm Phenylalanine -> Tyrosine -> DOPA -> Dopamine -> Vesicle transporters (VMAT) -> Dopamine in lipid vesicles Norepinephrine VMAT Epinephrine in secretory vesicles (active form) * Diagnosis PNMT Cortisol 24 hour urine VMA (metabolite of epinephrine) Urinary cathecolamines Plasma cathecolamines Urinary metanephrine Plasma metanephrine CT to locate tumor failed to involute after birth and secretes excessive amounts of cathecolamines. Extra adrenal paragangliomas (extra adrenal pheochromocytomas) are closely related, less common.

* Symptomatology - symptoms may be sporadic and paroxysmal against a background of continuing high concentration of cathecolamines and chronic physiological changes such as: Hypovolaemia Palpitation Hypertension Sweating and pallor Anxiety Chest pain and weakness

Cathecolamine Degradation 3 Mechanisms: a. Reuptake into secretory vesicles b. Uptake in nonneuronal cells (mostly liver) c. Degradation -> metabolites such as metanephrines and Vanillylmandelic acid (VMA) Metabolites and free cathecolamines are eliminated by direct filtration into urine. Epinephrine is converted from norepinephrine by renal PNMT enzyme.

b. Adrenal Incidentaloma - Incidental finding of adrenal masses during diagnostics - Usually non-functioning and benign ..

Disorder of the Adrenal Medulla a. Pheochromocytoma Neuroendocrine tumor of the medulla originating in the chromaffin cells or extra adrenal chromaffin tissue that MHML