GOUTBy

Dr: Abd El Hameed Fureeh

MD, Lecturer of Internal Medicine, Mansoura faculty of Medicine

Diabetes, endocrinology and Metabolism unit

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What is gout? Gout is a syndrome caused by the

inflammatory response to tissue deposition of monosodium urate crystals (MSU).

Nicknamed the “Disease of Kings” because it can be caused by rich foods, alcohol, and royalty often had it.

Prevalence

The prevalence of asymptomatic hyperuricemia is 5 to 8%.

The prevalence of gout is 13 cases per 1000 men and 6.4 cases per 1000 women.

The higher the uric acid, the higher the risk to develop gout.

90% of patients with primary gout are men.

Prevalence Women rarely develop gout before the

menopause, because estrogens are thought to be uricosuric.

Peak incidence in men is in the fifth decade.

Primary gout is associated with: obesity, hyperlipidemia, diabetes mellitus, hypertension and atherosclerosis.

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Etiology

Hyperuricemia is the common denominator in gout.

Two-thirds of uric acid are excreted by the kidney and the rest in the GI tract.

90% of cases of gout are secondary to under-excretion.

Overproduction is secondary to defects in the HGPRT or PRPP.

Etiology The inflammatory response is

secondary to the response of the leukocytes to the MSU crystals.

Acute gout is most likely secondary to the formation of new crystals.

Factors that precipitate gout includes: surgery, trauma, alcohol, starvation and medications.

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GOUT RISK FACTORSGOUT RISK FACTORS

MaleMale Postmenopausal Postmenopausal

femalefemale OlderOlder HypertensionHypertension Pharmaceuticals:Pharmaceuticals:

Diuretics, ASA, Diuretics, ASA, cyclosporinecyclosporine

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GOUT RISK FACTORSGOUT RISK FACTORS

TransplantTransplant Alcohol intakeAlcohol intake

Highest with beerHighest with beer

Not increased with wineNot increased with wine High BMI (obesity)High BMI (obesity) Diet high in meat & seafoodDiet high in meat & seafood

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Pathology The most frequent sites of deposition of

MSU crystals are: cartilage, epiphyseal bone, periarticular structures and the kidney.

A tophus is a foreign body reaction that includes the MSU crystals surrounded by fibrous tissue.

In the kidney the deposition of MSU crystals causes interstitial fibrosis and arteriosclerosis.

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Clinical course

4 clinical phases if untreated: asymptomatic hyperuricemia, acute/recurrent gout, intercritical gout, chronic tophaceous gout

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Asymptomatic Hyperuricemia

elevated urate levels without symptoms of gout, nephrolithiasis, or kidney stones.

Hyperuricemia is defined: >7 mg/dL (0.42mmol/L) in men and postmenopausal

women >6 mg/dL (0..36mmol/L) in premenopausal women. urate <7 mg/dL 0.1% annual incidence of gout urate >=9 mg/dL 4.9% annual incidence. the clustering of glucose intolerance, central obesity,

dyslipidemia, hypertension, and increased prothrombotic and antifihrinolytic factors in an individual.

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Cause of hyperuricemia-- decreased renal excretion

Primary Idiopathic Familial juvenile

gouty nephropathy

Secondary Hypertension Hyperparathyroidism Myxoedema Down’s syndrome Increased level of organic level Lead nephropathy Sarcoidosis Bartter’s syndrome Beryllium poisoning Drug: diuretics, B-blocker, ACEI,

salicylates (low dose), PEA, EMB, cyclosporin, nicotinic acid

Chronic renal failure Volume depletion NDI

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Cause of hyperuricemia-- increased uric acid production

Primary Idiopathic HPRT def. PPRT overactivity Ribose-5-

phosphate overproduction

AMP-deaminase def.

Secondary Glycogen storage disease type II (G6PD), type III, V, VII Hereditary fructose intolerance Lymphoproliferative and

myeloproliferative diseases ( leukemia, Hodgkin’s d’z, lymphosarcoma, myeloma, PV, Waldenstrom’s macroglobulinemia )

Cytotoxic drugs Carcinomatosis Gaucher’s disease Chronic hemolytic anemia Severe exfoliative psoriasis

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Acute/Recurrent Gout

symptoms: sudden onset of severe pain, inflammation, limited range of motion, and warmth at the affected joint(s).

The joints are red, hot, and exquisitely tender; even a bed sheet on the swollen joint is uncomfortable, slight fever, leukocytosis, elevation of ESR, and elevation of CRP

90% of first attacks are monoarticular with first metatarsophalangeal joint, known as podagra.

Left untreated, the symptoms are self-limiting but may take up to 21 week to subside.

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90% of gout patients eventually have 90% of gout patients eventually have podagra : 1st MTP jointpodagra : 1st MTP joint

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Table. Characteristics of Classic Gout vs Atypical Gout

Classic Gout Atypical Gout

Can present at any age, including patients older than 60 years

Observed in elderly patients

Predominantly men Diagnosed in as many women as men

Monarthritis Polyarthritis

Asymmetric Symmetric or asymmetric

Usually in lower extremity Any joint, upper or lower extremity

Tophi rare at presentation Tophi common at presentation

Acute Chronic but can have acute flare-ups

Can be misdiagnosed as cellulitis or infection

Chronic form can be misdiagnosed as rheumatoid arthritis or osteoarthritis: acute flare-ups can be misdiagnosed as cellulitis or infection

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ADVANCED GOUTADVANCED GOUT

Chronic ArthritisChronic Arthritis

X-ray ChangesX-ray Changes

Tophi DevelopTophi Develop

Acute Flares continueAcute Flares continue

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ADVANCED GOUTADVANCED GOUT

Chronic ArthritisChronic Arthritis Polyarticular acute Polyarticular acute

flares with upper flares with upper extremities more extremities more involvedinvolved

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Intercritical Gout

It is the asymptomatic period between crises, but MSU crystals can still be recovered if necessary.

The duration of this period varies, but untreated patients may have a second episode within two years.

Some patients evolve to chronic polyarticular gout without pain free intercritical episodes.

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Chronic Tophaceous Gout

Tophi are usually present after 10 to 20 years of inadequately treated chronic gout.

Visible tophi occur in 12% of patients after 5 years of gout and in 55% of patients after 20 years.

most common sites of tophaceous gout: olecranon bursae (elbow) and the joints of the hand and feet.

Other sites: the helix of the ear, the Achilles tendons, and the knees.

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Chronic Tophaceous Gout

Transplant patients treated with cyclosporine and/or diuretics have an increased risk for tophaceus gout.

The most common sites for tophi are: the olecranon, prepatellar bursa, ulnar surface and Achilles tendon.

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Chronic Tophaceous Gout

Tophi in the hands can cause joint destruction.

Tophi can ulcerate the skin and excrete a chalky material composed of MSU crystals.

Tophi progress insidiously with increased stiffness and pain.

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TOPHITOPHI

Solid urate deposits Solid urate deposits in tissuesin tissues

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TOPHITOPHI

Irregular & Irregular & destructivedestructive

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TOPHI RISK FACTORSTOPHI RISK FACTORS

Long duration of hyperuricemiaLong duration of hyperuricemia

Higher serum urateHigher serum urate

Long periods of active, untreated goutLong periods of active, untreated gout

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Renal disease

Urolithiasis, Urate nephropathy (deposition of MSU

crystals in the interstitium), and Uric nephropathy ( deposition of MSU

crystals in the collecting tubes). The prevalence of urolithiasis is 22% in

primary gout and 42% in secondary gout.

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Nephrolithiasis

The prevalence of nephrolithiasis correlates with the serum and urinary uric acid levels.

Serum urate levels 13 mg/dl Urinary uric acid excretion > 1100 mg/d

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Urate Nephropathy

Deposits of monosodium urate crystals surrounded by a giant cell inflammatory reaction in the medullary intrerstitium and pyramids.

Clinically: silent or cause proteinuria, hypertension and renal insufficiency.

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Uric acid nephropaty

Precipitation in renal tubules and collecting ducts cause obstruction to urine flow.

Following sudden urate overproduction and marked hyperuricaciduria:

Dehydration and acidosis Lymphoma Cytolytic therapy

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Complication of gout

Joint: destruction Soft tissue nerve entrapment syndrome: CTS,

tarsal tunnel syndromes kidney: uric acid calculi(10-15%),

chronic urate nephropathy, and acute uric acid nephropathy

Heart: ischemic heart disease

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GOUTY ARTHRITIS & TOPHI

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Diagnosis of gout

Clinical diagnosis: Triad of

1- hyperurecemia

2- Acute monoarticular arthritis

3- Response to colchicine Laboratory diagnosis Differential diagnosis

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Criteria for clinical diagnosisAmerican Rheumatism Association sub-committe on classification criteria for gout 1977

presence of characteristic urate crystals in the joint fluid Tophus proved to contain urate crystals by negative polarized light

microscopic study If none of above, diagnosis is 6/12 clinical, radiographic, and

laboratory criteria include: 1. more than one attack of acute arthritis 2. Maximum inflammation within 24 hours 3. Attack of monoaricular arthritis 4. Joint redness observed 5. first MTP joint painful or swollen 6. Unilateral attack involving first MTP 7. Unilateral attack involving tarsal joint 8. Suspected tophus 9. Hyperuricemia 10. Asymmetric swelling within a joint ( roentgenogram ) 11. Subcortical bone cysts without erosions ( roentgenogram ) 12. Negative synovial culture during attack of joint inflammation

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Laboratory Diagnosis

Even the clinical appearance strongly suggests gout. The diagnosis should be confirmed by needle aspiration of acute or chronically inflamed joints or tophaceous deposits.

Acute septic arthritis several of the other crystalline – associated arthropathies, and psoriatic arthritis may present with similar clinical features.

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SYNOVIAL FLUID ANALYSISSYNOVIAL FLUID ANALYSIS (Polarized Light Microscopy)(Polarized Light Microscopy)

The Gold standardThe Gold standard

Crystals intracellular during attacksCrystals intracellular during attacks

Needle & rod shapesNeedle & rod shapes

Strong negative birefringence meaning that Strong negative birefringence meaning that the crystals are yellow when aligned parallel the crystals are yellow when aligned parallel to the slow ray of the compensator and that to the slow ray of the compensator and that they are blue when they are perpendicular.they are blue when they are perpendicular.

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SYNOVIAL FLUIDSYNOVIAL FLUID

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SYNOVIAL FLUIDSYNOVIAL FLUID Presence of MSU crystals do not

exclude the possibility of septic arthritis, for this reason it is also recommended to request a Gram smear.

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SYNOVIAL FLUIDSYNOVIAL FLUID

- Cloudy due to leukocytes and a large amounts crystals ocassionally produce a thick pasty or chalky joint fluid.

-Increased leukocytes: >15,000/cc WBCs, primarily PMNs

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SERUM URATIC ACID LEVELSSERUM URATIC ACID LEVELS

This is the most misused test in the diagnosis This is the most misused test in the diagnosis

of gout.of gout. Not reliableNot reliable

May be normal with flaresMay be normal with flares

May be high with joint Sx from other causesMay be high with joint Sx from other causes

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Serum uric acid

-Normal range: male 3-8 mg/dl

female 1.5-6 mg/dl

children 3-4 mg/dl

("normal" values may vary between laboratories)

-False elevation by: levodopa if colorimetric method used

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Uric acid in 24-hour urine sample

24 urine collection for uric acid determination is useful in assessing the risk of renal stones and planning for therapy.

Urinary levels above 750 mg/dl in 24h in gout or > 1100 mg/dl in asymptomatic hyperuricemia indicates urate overproduction.

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Radiographic Features

Cystic changes, well-defined erosions described as punched-out lytic lesion.

Soft tissue calcified masses (chronic tophaceous gout)

Is helpful to exclude other kinds of arthritis.

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RADIOLOGIC SIGNSRADIOLOGIC SIGNSWww.MansFans.coM

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Blood chemistry

Renal function before deciding on therapy Plasma glucose: Patients with gout are at an increased

risk of developing diabetes mellitus. Abnormal liver function tests need to be considered

when therapy is selected. CBC count: The WBC count may be elevated in patients

during the acute gouty attack, particularly if it is polyarticular.

Lipids: Hypertriglyceridemia and low high-density lipoproteins are associated with gout.

Urinalysis: Patients with gout are at an increased risk of renal stones

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Differential diagnosis

Acute Infective arthritis Bursitis, cellulitis, tenosynovitis Other crystal arthropathy

( pseudogout, apatite or brushite arthritis or periarthritis )

Traumatic arthritis Hemoarthrosis RA with palindromic onset Reactive arthritis Spondarthritis with peripheral

involvement Psoriatic arthritis Sarcoid arthritis Rheumatic fever

Chronic Nodular rheumatoid

arthritis Psoriatic arthritis Osteoarthritis with

Heberden’s and Bouchard’s nodes

Sarcoid arthritis xanthomatosis

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Gout vs. CPPDGout vs. CPPD

Similar Acute attacksSimilar Acute attacks Different crystals under Micro;Different crystals under Micro;

Rhomboid, irregular in CPPDRhomboid, irregular in CPPDPseudogout crystals are positively birefringent. Pseudogout crystals are positively birefringent.

Pragmatically, this means that their colors are Pragmatically, this means that their colors are opposite those of gout. Thus, pseudogout crystals opposite those of gout. Thus, pseudogout crystals are blue when aligned parallel to the slow ray of are blue when aligned parallel to the slow ray of the compensator and yellow when they are the compensator and yellow when they are perpendicular.perpendicular.

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Gout Gout vs vs CPPD CPPD

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Crystal-Induced Arthritis

Characteristic Gout Pseudogout

Prevalence 1.5 to 2.6 cases per 1000 individuals; increases with age in men and postmenopausal women; 15/1000 at age 58; men:28/1000, women:11/1000

<1 case per 1000 individuals; increases with age

Crystals

Chemistry Monosodium urate Calcium pyrophosphate dihydrate

Appearance Negatively birefringent; needle-shaped Weakly positively birefringent; linear or rhomboidal

Articular involvement Monoarticular > oligoarticular; polyarticular < 30%

Monoarticular > oligoarticular

Most frequently affected joints First MTP joint

　－ initially 50%

　－ eventuall 90%

Ankles, knees, other

Knee, wrist other

Predisposing conditions/risk factors Hyperuricemia*, obesity, hypertension, hyperlipidemia, alcohol ingestion, lead ingeation, hereditary enzyme defect (rare)

Hypothyroidism, hemochromatosis, OA, chronic renal insufficiency, diabetes, hyperparathyroidism, hereditary (rare)

Therapeutic options Acute attacks:

　－ NSAIDs, corticosteroids, colchicine

Chronic management

　－ Urate-lowering agents, colchicine

Acute attacks:

　－ NSAIDs, corticosteroids, colchicine

Chronic management

　－ NSAIDs colchicine

*Drugs associated with hyperuricemia include diuretios, low-dose salicylates, nicotinic acid, oyclosporine, ethanol and ethambutol.

Adapted from Am J Med 1997; 103 : 68S.

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RA vs GoutRA vs Gout

Both have polyarticular, symmetric Both have polyarticular, symmetric arthritisarthritis

Tophi can be mistaken for RA nodulesTophi can be mistaken for RA nodules

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RA RA vs vs Gout Gout

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Treatment of gout

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TREATMENT GOALSTREATMENT GOALS

Rapid and safe pain relieve (end Rapid and safe pain relieve (end acute flares)acute flares)

Protect against future flaresProtect against future flares Prevent disease progressionPrevent disease progression Correct metabolic causeCorrect metabolic cause

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ENDING ACUTE FLARESENDING ACUTE FLARES

Control inflammation & pain & resolve Control inflammation & pain & resolve the flarethe flare

Not a cureNot a cure Crystals remain in jointsCrystals remain in joints Don’t try to lower serum urate during a Don’t try to lower serum urate during a

flareflare Choice of med not as critical as alacrity Choice of med not as critical as alacrity

& duration& duration

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Acute Flare Med ChoicesAcute Flare Med Choices

NSAIDSNSAIDS

ColchicineColchicine

CorticosteroidsCorticosteroids

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Colchicine

1. Mechanism of action

-decreases inflammatory response through binding of microtubular proteins which interferes with granulocyte mobility

2. Efficacy: somewhat diagnostic for gout because

-90% respond to colchicine if treatment is initiated within a few hours after onset, response rates decline if acute attack is >24hrs old

-colchicine is relatively specific therapy for acute gout

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ColchecineDosing:

-colchicine has a narrow therapeutic index

-doses should be decreased in renal and hepatic

dysfunction, but there are no standard guidelines

-PO: 1.2mg stat, then 0.6mg every hour until:

response is achieved, or gastrointestinal toxicity (diarrhea, abd. pain), or maximum dose of 12 tablets is taken

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Colchecine

-IV: 2mg in 20cc NS infused slowly, may repeat with 1mg after 6hrs but no more than 4mg in 24hours

-Decrease total dose to 2mg/24hrs in elderly patients

or patients who have been on colchicine maintenance

-Give only to patients who cannot tolerate the oral

tablets

-Avoid extravasation because it causes soft tissue necrosis

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ColchecineAdverse reactions

-Gastrointestinal: diarrhea, nausea, vomiting, hemorrhagic

colitis, occurs in 70-80% of patients on oral therapy, less

frequent with IV therapy but may see with high doses

-Bone marrow depression: cumulative toxicity

-Renal dysfunction: toxic side effect seen after large doses,

hematuria, oliguria

-Necrosis of soft tissue after extravasation: do not give IM/SC

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NSAIDMechanism of action:

-anti-inflammatory effects through inhibition of prostaglandin

synthesis and inhibition of motility of PMNs

-not specific for gout—adequate doses will relieve inflammation from any cause

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NSAIDAgents and Dosing

-Indomethacin: 75mg stat, 25-50mg q6hr, taper as symptoms resolve

-avoid in elderly

-Any non-salicylate NSAID should be effective if given in anti-inflammatory doses

-avoid salicylates because of effect on uric acid elimination

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NSAIDSNSAIDS

NSAIDS : NSAIDS :

Interaction with Interaction with warfarinwarfarin

Contraindicated in:Contraindicated in:

Renal diseaseRenal disease

PUDPUD

GI bleedersGI bleeders

ASA-induced RADASA-induced RAD

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Intra-articular Steroids

-Effective anti-inflammatory agents

-Reserve for patients who cannot tolerate oral colchicine or NSAID therapy and who are not candidates for IV colchicine

-Limited to 4 injections per joint per year

Can use:

-Methylprednisolone (Depomedrol)

-Triamcinolone hexocetanide

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Syst. Corticosteroids

-IM injection of depot corticosteroid product

(e.g. DepoMedrol ) or ACTH

-Tapering effect of depot product prevents rebound gout attacks

-Efficacy comparable to NSAID in studies

-Limited toxicity due to short term use

- Worse glycemic control- Worse glycemic controlMay need to use mod-high dosesMay need to use mod-high doses

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PROTECTION VS. FUTURE PROTECTION VS. FUTURE FLARESFLARES

Colchicine : 0.5-1.0 mg/dayColchicine : 0.5-1.0 mg/day Low-dose NSAIDSLow-dose NSAIDS

Both decrease freq & severity of flaresBoth decrease freq & severity of flares Prevent flares with start of urate-lowering RXPrevent flares with start of urate-lowering RX

Best with 6 mos of concommitant RXBest with 6 mos of concommitant RX

EBMEBM

Won’t stop destructive aspects of goutWon’t stop destructive aspects of gout

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PREVENT DISEASE PREVENT DISEASE PROGRESSIONPROGRESSION

Lower urate to < 6 mg/dl : DepletesLower urate to < 6 mg/dl : Depletes

Total body urate poolTotal body urate pool

Deposited crystalsDeposited crystals RX is lifelong & continuousRX is lifelong & continuous MED choices :MED choices :

Uricosuric agentsUricosuric agents

Xanthine oxidase inhibitorXanthine oxidase inhibitor

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PREVENT THISPREVENT THIS

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Uricosuric agents

Indicated in patients with normal renal function, under-excretion and no evidence of tophi.

Patients taking uricosuric agents are at risk for urolithiasis. This can be decreased by ensuring high urinary output and by adding sodium bicarbonate 1 gram TID.

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Uricosuric agents The available agents include:

probenecid (1-2 g/day) and sulfinpyrazone (50-400 mg BID).

Dose should be increased to decrease uric acid < 6.0 mg/ml

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Sulfinpyrazone (Anturane)Uricosuric: has Increased potency vs probenecid

Has antiplatelet effect at doses of 600-800mg/day

Dosing: 50mg bid-400mg/day, may go up to 800mg/day

Adverse reactions:

-Hypersensitivity reactions (uncommon): rash, may cause bronchoconstriction in patients with ASA intolerance, contraindicated in patients allergic to phenylbutazone/pyrazoles

-Gastrointestinal irritation: take with food or milk

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XANTHINE OXIDASE XANTHINE OXIDASE INHIBITORINHIBITOR

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Allopurinol

Blocks conversion of hypoxanthine to Blocks conversion of hypoxanthine to uric aciduric acid

Decreases uric acid in overproducers and underexcreters; it is also indicated in patients with a history of urolithiasis, tophaceus gout, renal insufficiency and in prophylaxis of tumor lysis syndrome.

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Allopurinol

usual dose is 300 mg/day. Maximal recommended dose is 800 mg/day.

In renal insufficiency dose should be decreased to 200 mg/day for creatinine clearance < 60ml/min and to 100 mg/day if clearance < 30 ml/min).

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Allopurinol Start with small doses of allopurinol to

reduce the risk of precipitating an acute gout attack.

Most common side effects are rash (2% of patients) but rarely patients can develop exfoliative dermatitis that can be lethal.

Chronic use of colchicine (0.6-1.2 mg/day) is used as prophylaxis for acute attacks.

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Allopurinol Dosing

-Start at 100mg per day, increase weekly as needed

-70% of patients will be controlled on 300mg/day

-May give up to 1200mg/day if necessary

-May be given once daily because of long half life of active metabolite, but divided doses recommended if total daily dose >300mg

-Renal disease requires dose adjustment

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Allopurinol Adverse ReactionsHypersensitivity rash:

maculopapular/purpuric: usually occurs within

1st5weeks , resolves with drug DC . rechallenge

cautiously, may cause fatal reactions

severe hypersensitivity more common in pts with

impaired renal function & ampicillin treatment

Gastrointestinal:

nausea, vomiting,abdominal pain, hepatomegaly.

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Febuxostat

Potent new xanthine oxidase inhibitor Metabolized by the liver (used in RI) No hypersensitivity reaction Dose: 80-120 mg/d

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WHICH AGENTWHICH AGENT

Base choice on above considerations & Base choice on above considerations & whether pt is an overproducer or whether pt is an overproducer or underexcretor : Need to get a 24-hr. underexcretor : Need to get a 24-hr. urine for urate excretion:urine for urate excretion:

< 700 --- underexcretor < 700 --- underexcretor (uricosuric)(uricosuric)

> 700 --- overproducer > 700 --- overproducer (allopurinol)(allopurinol)

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Purine nucleotides

hypoxanthine

xanthine

Uric acid

Xanthine oxidase

Alimentary excretion

Urinary excretion

Tissue deposition in excess

Urate crystal microtophi

Phagocytosis with acute inflammation and arthritis

uricosurics

colchicine NSAID

Allopurinol

Oxypurinol

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NEW AGENTSNEW AGENTS

RX gaps : RX gaps : Can’t always get urate < 6Can’t always get urate < 6 AllergiesAllergies Drug interactionsDrug interactions Allopurinol intoleranceAllopurinol intolerance Worse Renal diseaseWorse Renal disease

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URICASE ENZYMESURICASE ENZYMES (Stay Tuned)(Stay Tuned)

Catabolize urate to allantoin:Catabolize urate to allantoin:More soluble, excretable formMore soluble, excretable form

Currently approved for hypoeruricemia in Currently approved for hypoeruricemia in tumor lysis syndrometumor lysis syndrome

Some concerns: fatal immunogenicity & Some concerns: fatal immunogenicity & unknown long-term effectsunknown long-term effects

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Treating the Asymptomatic Hyperuricemic Patient:

Controversial, no set guidelines, but consider in the following patient groups:

A. Develops symptoms

B. Excretes >900mg of uric acid/24hr: risk for kidney stones

C. Serum uric acid >12mg/dl,

D. Patient with malignancy using chemotherapy

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Diet

Usually impractical, ineffective and rarely adhered to in clinical practice.

Indications for pharmacological therapy includes: inability to reverse secondary causes, tophaceus gout, recurrent acute gout and nephrolithiasis.

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Prophylaxis A. When to treat

1. Recurrent attacks: choice of treatment will depend on the frequency of the attacks. Attacks once yearly may be better treated with colchicine/NSAID acutely rather than exposing the patient to yearlong therapy. Frequency of attacks >1-2/year are a good indication for prophylactic or uric acid lowering therapy.

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Prophylaxis A. When to treat

2. Tophi: indicator of long-standing disease, will regress/disappear with uric acid lowering therapy, patients with tophi should be treated e even if gout attacks are not frequent

3. Uric acid nephrolithiasis: treatment will prevent further stones (and development of renal dysfunction due to gouty nephropathy?)

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QUESTIONSQUESTIONS

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