HYPERURECIMIA and GOUTBy: SUNSHINE A. BACLAAN

HYPERURECIMIA V.S.GOUTHyperuricemia - a serum uric acid level that is elevated more than 2 std. deviations above the population mean.-serum urate level of >7mg/dlGout - 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 ExcretionURIC 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 therapy1. 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 acidb. 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 acidd. Ethambutol & Nicotinic acid

inc. uric acid conc. by competing with urate for tubular secretion sites, thereby dec. uric acid excretione. Heavy alcohol consumption - by forming lactate

4. Miscellaneous disorders- Diabetic Ketoacidosis - Psoriasis- Chronic lead poisoning

PATHOPHYSIOLOGYGOUTY 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 PRESENTATION1. 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 Criteria1. Demonstration of monosodium urate crystals in the synovial fluid of affected joints. 2. Serum analysis reveals above normal uric acid level3. 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 dayb. More than one arthritic attackc. Oligaoarthritis attack (limited to a few joints)d. Painful / swollen first metatarsophalangeal jointe. Unilateral attack involving the tarsal jointsf. Unilateral attack involving the fist metatarsophalangeal jointg. Redness over the affected jointh. Tophusi. Asymptomatic swelling in one jointj. Hyperuricemia

TREATMENT GOALS1. Relieve pain and inflammation2. Terminate the acute attack3. Restore normal function to the affected joints

For INTERCRITICAL & CHRONIC TOPHACEOUS GOUT:1. Reduce the frequency and severity of recurrent attacks2. Minimize urate deposition in body tissues and thus prevent progression to chronic tophaceous gout

THERAPY

GENERAL:1. The affected joint should be immobilized2. 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.