HYPERURECIMIA and GOUT By: SUNSHINE A. BACLAAN HYPERURECIMIA V.S.

GOUT Hyperuricemia - a serum uric acid level that is elevated more than 2 std. deviations above the population mean. -serum urate level of >7mg/dl Gout - Disease characterized by recurrent acute attacks of urate crystal-induced arthritis. -may include tophi in and around the joints and cartilage and in the kidneys as well as uric acid nephrolithiasis Uric Acid Production and Excretion URIC ACID end product of purine metabolism Xanthine oxidase catalyzes the reaction that occurs as the final step in the degradation of purines to uric acid Uric acid has no known biologic function Total uric acid content in body: 1.0 1.2g @ pH = 4-5 (in urine) uric acid exist as a poorly soluble free acid at physiologic pH. It exist primarily as monosodium urate crystal The body ultimately excretes uric acid via: Kidneys (300-600mg/day) Gastrointestinal tract (100 300mg/day) ETIOLOGY: *PRIMARY HYPERURECEMIA and GOUT Results from an innate effect in purine metabolism and/or uric acid excretion. Exact cause = UNKNOWN Hyperuricemia may result from Uric acid overproduction Impaired renal clearance of uric acid Combination Classified as overproducers or underexcretors of uric acid *SECONDARY HYPERURECEMIA and GOUT Develop during the course of another disease or as a result of drug therapy 1. Hematologic causes: Lymphoproliferative disorders Myeloproliferative disorders Certain hemolytic anemias and Hemoglobinopathies 2. Chronic renal failure (reduced renal clearance of uric acid can lead to Hyperuricemia) 3. Drug induced a. Aspirin and other salicylates inhibit tubular secretion of uric acid b. Cytotoxic drugs = inc. urice acid conc. c. Diuretics cause hyperuricemia (due to volume depletion which increases proximal tubular absorption or via impaired tubular secretion of uric acid d. Ethambutol & Nicotinic acid inc. uric acid conc. by competing with urate for tubular secretion sites, thereby dec. uric acid excretion e. Heavy alcohol consumption by forming lactate 4. Miscellaneous disorders - Diabetic Ketoacidosis - Psoriasis - Chronic lead poisoning

PATHOPHYSIOLOGY GOUTY ARTHRITIS develops when monosodium urate crystals are deposited in the synovium of involved joints An inflammatory response to monosodium urate crystals leads to an attack of gouty arthritis characterized by painful joint swelling that is red, warm and tender. If gout progresses untreated Tophi / tophaceous deposits (deposits of monosodium urate crystals) may eventually lead to deformity & disability Renal Complications Acute tubular obstruction. - develops secondary to uric acid production in the collecting tubules and ureters, with subsequent blockage and renal failure. Urolithiasis - characterized by formation of uric acid sotnes in the urinary tract. (contributing factor = Low urine pH) - risk of urolithiasis rises as serum and urinary uric acid levels increases Chronic urate nephropathy - urate deposits arise in the renal interstitum

CLINICAL PRESENTATION 1. ASYMPTOMATIC HYPERURICEMIA 2. ACUTE GOUTY ARTHRITIS 3. INTERCRITICAL GOUT 4. CHRONIC TOPHACEOUS GOUT ASYMPTOMATIC HYPERURICEMIA Characterized by an elevated serum uric acid level but has no sign or symptoms of deposition disease (arthritis, tophi, or urolithiasis) Clinicians cannot predict which asymptomatic patients will develop gout symptoms or hyperuricemia-related complicaitons Although some asymptomatic patients may receive drug therapy, MOST do not require treatment. ACUTE GOUTY ARTHRITIS Characterized by painful arthritic attacks of sudden onset Monosodium urate crystals form in articular tissues; this process sets off an inflammatory reaction. Trauma, exposure to cold, or another triggering event may be involved in the development of the acute attack Signs & Symptoms Initial attack comes abruptly w/ severe, progressively worsening arthritic pain (involving one/few joints) Usually occur at NIGHT / EARLY MORNING as synovial fluid is reabsorbed Affected joint Hot, swollen and extremely tender Metatarsophalangeal joint (most common sight of attack) a.k.a. PODAGRA Others: Instep, ankle, heel, knee, wrist, elbow and fingers First few untreated attacks typically last 3-14 days. Later attacks may affect more joints and take several weeks to resolve. During recovery as edema subsides, local desquamation, and pruritis may occur Systematic symptoms: Fever, chills, malaise INTERCRITICAL GOUT The symptom-free period after the first attack. This phase may be interrupted by the recurrence of acute attacks. Onset of subsequent attacks varies. In most patients, the second attack occurs within 1 year of the first, but in some it may be delayed for 5-10 years. A small % of patients never experience a second attack. If hyperuricemia is insufficiently treated, subsequent attacks may become progressively longer ad more severe and may involve more than one joint. CHRONIC TOPHACEOUS GOUT Rare clinical presentation May develop if hyperuricemia and gout remain untreated for many years PATHOGENESIS: Persistent hyperuricemia leads to the development of tophi in the synovia or other various periarticular locations. Eventually, articular cartilage may be destroyed, resulting in joint deformities, bony erosions, deposition of tophi within tissues and renal disease Diagnostic Criteria 1. Demonstration of monosodium urate crystals in the synovial fluid of affected joints. 2. Serum analysis reveals above normal uric acid level 3. Because uric acid crystals may not be found in the affected joints of all acute gout patients, a probable diagnosis of acute gouty arthritis can be made using the criteria developed by the Americal Rheumatism Association. The presence of a minimum of 6 of the following ten criteria warrants a suggestive diagnosis: a. Development of maximum inflammation within 1 day b. More than one arthritic attack c. Oligaoarthritis attack (limited to a few joints) d. Painful / swollen first metatarsophalangeal joint e. Unilateral attack involving the tarsal joints f. Unilateral attack involving the fist metatarsophalangeal joint g. Redness over the affected joint h. Tophus i. Asymptomatic swelling in one joint j. Hyperuricemia TREATMENT GOALS 1. Relieve pain and inflammation 2. Terminate the acute attack 3. Restore normal function to the affected joints For INTERCRITICAL & CHRONIC TOPHACEOUS GOUT: 1. Reduce the frequency and severity of recurrent attacks 2. Minimize urate deposition in body tissues and thus prevent progression to chronic tophaceous gout THERAPY

GENERAL: 1. The affected joint should be immobilized 2. Anti-inflammatory drug therapy should begin immediately. 3. Urate lowering drugs should not be given until the acute attack is controlled SPECIFIC DRUGS: Colchicine (Goutnil) 500mcg tab Traditional drug of choice for relieving pain and inflammation and ending the acute attack Most effective when initiated 12-36 hours after symptoms begin MOA: impairs leukocyte migration to inflamed areas and disrupts urate deposition and the subsequent inflammatory response IV: single dose = 2-3mg in 20-30mL of normal saline solution by slow push. Patient should not receive more than 6mg over a period of 24 hours. (may cause tissue irritation) Not to be given IM/ SC ORAL: Initial attack = 0.5 to 0.6 mg every hour a response occurs A total of 6 to 8 mg is administered Intolerable GI distress (NVD) develops NSAIDs Preferred when treatment is delayed after symptom onset or when the Ptx. cannot tolerate the adverse GI effects of colchicine. Indomethacin (oral: 75mg followed by 50mg every 6 hrs for 2 days, then 50mg every 8 hours for 1-2 days) Others: Ibuprofen (Advil 500mg), Naproxen (Flanax 275mg, 550mg), Sulindac, Piroxicam (Feldene 20mg cap)

For INTERCRITICAL GOUT: 1. Conservative Intervention: Restriction of alcohol consumption and dietary purine High volume fluid intake and increased urinary output Weight reduction Colchicine therapy (0.5 to 1.5mg/day) / Indomethacin 2. Urate reducing drug therapy Uricosurics increase renal uric acid excretion Xanthine oxidase inhibitors reduce uric acid production Uricosurics (Probenecid) MOA: block uric acid reabsorption at the proximal convulated tubule, thereby increasing the rate of uric acid excretion Indication: generally used to reduce hyperuricemia in patients who excrete <600mg of uric acid per day Probenecid is given initially in two daily oral doses of 250mg, then increased to 500mg twice daily every 1-2 weeks until the serum uric acid level drops below 6mg/dl. Max dose: 3g Precautions: CI in patients with urinary tract stones, aspirin and other salicylates antagonize the action of uricosurics. Should not be initiated during an acute gout attack. Xanthine Oxidase Inhibitors (Allopurinol) MOA: block the final steps in uric acid synthesis by inhibiting xanthine oxidase, an enzyme that converts xanthine to uric acid. Thus reducing serum uric acid level while increasing the renal excretion of the more soluble oxypurine precursors which, in turn, decreases the risk of uric acid stones and nephropathy. Indications: patient who excrete <600mg of uric acid per day; with recurrent tophaceous deposits or uric acid stones; with renal impairment Allopurinol (Llanol, Purinase 100mg & 300mg) Initial: 100 200 mg single dose, then increase in weekly increments to 300mg/day. Precautions: Hypersensitivity, Minor skin rashes may occur, concurrent ampicillin use may inc. risk of developing rash. Patient should maintain high fluid intake and urine output during Allopurinol therapy.