The Internet Journal of Family Practice ISSN: 1528-8358

Hyperuricemia an !out: " #e$ie% "rticle

M. Akram Faculty of Eastern Medicine, Shifa-ul-Mulk Memorial Hospital Hamdard University Karachi akistan E. Mohiuddin Faculty of Eastern Medicine, Shifa-ul-Mulk Memorial Hospital Hamdard University Karachi akistan M. !"ais Khan Faculty of Eastern Medicine, Shifa-ul-Mulk Memorial Hospital Hamdard University Karachi akistan M. #$rahim Khan Faculty of Eastern Medicine, Shifa-ul-Mulk Memorial Hospital Hamdard University Karachi akistan Syed Muhammad Ali Shah %olle&e of %onventional Medicine, Faculty of harmacy and Alternative Medicine, 'he #slamia University of (aha"alpur Khalil Ahmad Ansari %olle&e of %onventional Medicine, Faculty of harmacy and Alternative Medicine, 'he #slamia University of (aha"alpur )a*ala Shaheen %olle&e of %onventional Medicine, Faculty of harmacy and Alternative Medicine, 'he #slamia University of (aha"alpur M. Asif %olle&e of %onventional Medicine, Faculty of harmacy and Alternative Medicine, 'he #slamia University of (aha"alpur M. +ia* ur +ehman %olle&e of %onventional Medicine, Faculty of harmacy and Alternative Medicine, 'he #slamia University of (aha"alpur &itation: M. Akram, E. Mohiuddin, M. !"ais Khan, M. #$rahim Khan, S.M.A. Shah, K.A. Ansari, ). Shaheen, M. Asif, M.+. ur +ehman, Hyperuricemia and )out, A +evie" Article. The Internet Journal of Family Practice. -./. 0olume 1 2um$er /. 3!#, /..445.6-.ef 'ey%or (: Hyperuricemia, )out

")(tract
Uric acid is a chemical, created in the $ody $y the $reakin& do"n of purines. #t is e7creted out of the $ody $y the kidneys, throu&h urine, after it dissolves in the $lood. #f it is not e7creted out of the $ody properly, hi&h levels of uric acid &ets accumulated "hich causes &out and kidney stones. Hyperuricemia is usually caused due to the re&ular intake of food havin& hi&h content of purine and conditions such as hypoparathyroidism, lead poisonin&, renal failure and side effects of chemotherapy. Hyperuricemia occurs "hen serum urate levels e7ceed urate solu$ility, ie, at appro7imately 8.5 m&6d9. At serum urate levels a$ove this threshold, manifestations of &outy arthritis may occur, althou&h asymptomatic hyperuricemia often persists for many years. #ntercritical asymptomatic periods follo" the resolution of acute &out flares, $ut crystals remain in the :oint durin& these intervals and further deposition may continue silently. Ultimately this may lead to persistent attacks, chronic pain, and, in some patients, :oint dama&e.

Intro uction to !out

)out, or &outy arthritis, is a relatively common meta$olic disorder. #t is characteri*ed $y a painful, inflammatory response to deposits of sodium urate crystals in the synovial fluid of the :oints and surroundin& tissue. 'his condition may also present as deposits of urate crystals in cartila&e ;i.e., tophi<, interstitial renal disease, or kidney stones. )out is a reco&ni*ed complication of hyperuricemia. #n the acute phase it is characteri*ed $y a monoarticular arthritis that remits after one to t"o "eeks and recurs periodically. =oints of the lo"er e7tremity are most commonly affected. 'he periods $et"een flares of the disease may

shorten over time and attacks may $ecome polyarticular. %hronic tophaceous :oints develop after many years of recurrent attacks and are characteri*ed $y deposits of urate in the skin or $ursa, referred to as tophi. %ommon sites for tophi include the pinna of the ear, the olecranon $ursa and ad:acent to the small :oints of the fin&ers.

!enetic an Hyperuricemia

*iochemical

*a(i(

of

'here are three different inherited defects that lead to early development of severe hyperuricemia and &out, &lucose-8-phosphatase ;&ene sym$ol > )8 '< deficiency? severe and partial hypo7anthine-&uanine phosphori$osyltransferase ;H) +', &ene sym$ol > H +'< deficiency? and elevated 4@-phosphori$osyl-/@-pyrophosphate synthetase ; + synthetase, &ene sym$ol > + S< activity. 'he familial association of &out "as reco&ni*ed hundreds of years a&o $ut definin& the e7act &enetic mechanisms "as not possi$le until the advancement of modern &enetic tools. )out and )arrod have $een linked in medical literature for more than a century. He identified uric acid as a normal constituent of the serum of healthy persons and devised a method for detectin& its increased concentration in &outy su$:ects. !veractivity of +S is also an A-linked dominant disorder that can produce hyperuricemia. #t is characteri*ed $y an overproduction of phosphori$osyl pyrophosphate ; + < and uric acid, "hich can cause hyperuricemia, nephrolithiasis, and &out at an early a&e. !veractivity of +S is related to an accelerated transcription of the +S-# &ene, actin& as a ma:or determinant of synthesis of + , purine nucleotides, and uric acid. At least three different isoforms of + synthetase have $een identified and are encoded $y three distinct, yet hi&hly homolo&ous + S &enes, identified as + S/, + S-, and + SB. 'he + S/ and + S- &enes are found on the A chromosome ;AC--DC-E and Ap--.-Dp--.B, respectively< and the + SB &ene is found on chromosome F. 'he + SB &ene appears to $e e7pressed e7clusively in the testes. All three + synthetase isoforms differ in kinetic and physical characteristics such as isoelectric points ;p#<, pH optima, activators and inhi$itors. hosphori$osylpyrophosphate synthetase ; +S< superactivity is characteri*ed $y hyperuricemia and hyperuricosuria and is divided into a severe phenotype "ith infantile or early-childhood onset and a milder phenotype "ith late-:uvenile or early-adult onset. 0aria$le com$inations of sensorineural hearin& loss, hypotonia, and ata7ia o$served in the severe type are not usually present in the mild type. #n the mild type, uric acid crystalluria or a urinary stone is commonly the first clinical findin&, follo"ed later $y &outy arthritis if serum urate concentration is not controlled. Hypo7anthine-&uanine phosphori$osyltransferase ;H) +'< is an en*yme involved in the salva&e of purine nucleotides. H) +' cataly*es the follo"in& t"o interconversions, hypo+anthine , P#PP -../ I0P , PPi 1uanine , P#PP -../ !0P , PPi A complete or virtually complete loss of H) +' activity results in the severe disorder, 2e(ch-Nyhan (yn rome. 9esch-2yhan syndrome is inherited as an 7 linked trait. ersons "ith this syndrome are missin& or are severely lackin& an en*yme called hypo7anthine &uanine phosphori$osyltransferase / ;H) <. 'he $ody needs this en*yme to recycle purines. Githout it, a$normally hi&h levels of uric acid $uild up in the $ody. Hyperuricemia results from a com$ination of increased &eneration and decreased e7cretion of uric acid "hich is &enerated "hen increased amounts of )8 are meta$oli*ed via the pentose phosphate path"ay. #t is also a $yproduct of purine de&radation. Uric acid competes "ith lactic acid and other or&anic acids for renal e7cretion in the urine. #n )S3 # increased

availa$ility of )8 for the pentose phosphate path"ay, increased rates of cata$olism, and diminished urinary e7cretion due to hi&h levels of lactic acid all com$ine to produce uric acid levels several times normal. Althou&h hyperuricemia is asymptomatic for years, kidney and :oint dama&e &radually accrue.

3iet an 4ric "ci

Foods hi&h in uric acid play a ma:or role in the development of )out. #n association "ith a healthy lifestyle and chan&es in diet, it can actually $e easier to mana&e than many people $elieve, as lon& as the sufferer is "illin& to make some si&nificant chan&es in their eatin& ha$its. 3iets that have hi&h contents of purine are e7tremely important. +estrictions of diet containin& hi&her level of purine "ill help in reducin& serum uric acid level. 2ormally, uric acid is eliminated from the $ody $y the kidneys. Ho"ever, some people are more sensitive to hi&h levels of uric acid, and their $odies "ill form crystals that accumulate in the :oints and cause painful &out symptoms. 'he main &oals of treatment for acute &out are to &et rid the pain that comes "ith this disease as "ell as prevention of future &out attacks. #f untreated, it can also lead to :oint disa$ility and, ultimately, kidney dama&e. 3iets to reduce uric acid also $enefit &out sufferers $y helpin& them lose "ei&ht, "hich has also $een sho"n to help lo"er concentrations of uric acid in the $lood. Foods containin& purine and the compounds that meta$oli*e into uric acid include most animal meats, such as $eef, pork and seafood. Ghite meat is $etter than red meat and can have some de&ree of purine content and should $e eaten very sparin&ly, $ut they are not as detrimental as the red meats. Alcohol and foods that have hi&h content purine should $e kept out of the diet. (lack cherry :uice, is recommended as her$al therapy for treatment of &out. %elery seed e7tract and $romelain are some popular alternative medicine remedies that have $een used as natural anti-inflammatories and have $een "ell tolerated $y those "ho suffer chronic inflammation. Addin& eicosapentaenoic acid ;E A< and folic acid to the diet can also assist in relievin& symptoms of &outy arthritis.
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Treatment of 1out an hyperuricemia Treatment of acute 1outy arthriti(

'hree treatments are availa$le for patients "ith acute &outy arthritis. %olchicine is commonly used for treatment of acute &outy arthritis. 2onsteroidal antiinflammatory dru&s, "hich are currently prescri$ed, are rapidly effective $ut may have serious side effects. %orticosteroids administered either intraarticularly or parenterally, are used increasin&ly in patients "ith monarticular &out, especially if oral dru& therapy is not feasi$le. Urate lo"erin& dru&s should not $e initiated or chan&ed as lon& as any &outy :oint inflammation persists, $ecause such treatment may delay the recovery.

&olchicine
%olchicine is the most popular treatment for acute &out. 'he hi&h dose of colchicine, up to 8 m&, usually advised for the treatment of &out may cause unnecessary to7icity? a lo"er dose of ..4 m& every ei&ht hours may $e more appropriate. 'he to7icity of intravenous colchicine is too hi&h to :ustify its use.

Non(teroi al "ntiinflammatory 3ru1(

Most potent nonsteroidal antiinflammatory dru&s are rapidly effective in relievin& pain and reducin& inflammation in patients "ith acute &out, particularly if the dru&s are taken soon after the onset of the attack. #ndomethacin, the first of these dru&s to $e used e7tensively,

provides some pain relief "ithin t"o to four hours. 3ependin& on the severity of the attack and its duration, the appropriate dose ran&es from /4. to B.. m& per day, &iven in divided doses, "ith a &radual reduction durin& a period of five to seven days as the attack su$sides. Most other nonsteroidal antiinflammatory dru&s are effective $ut no $etter than indomethacin, althou&h fe" comparative data are availa$le. 'he usefulness of nonsteroidal antiinflammatory dru&s is limited $y their side effects, $ut in &eneral, the risks are &reatest in elderly patients, particularly those "ith renal dysfunction.

&ortico(teroi (
%orticosteroids such as prednisone can $e used as a last resort for &out therapy, "hen neither 2SA#3s nor colchicine can $e used. As "ell, intra-articular steroids can $e useful "hen medium to lar&e :oints are affected. Steroids are used to control pain and inflammation. 2ormally patients takin& corticosteroids are &iven tapered doses "hen comin& off of treatment. Ho"ever, taperin& is not usually necessary for &out patients $ecause of the short duration of therapy.

Treatment of chronic 1out

)out can $e prevented $y identifyin& and correctin& the cause of hyperuricemia or $y administerin& dru&s that inhi$it the synthesis of urate or increase its e7cretion. )out may $e prevented $y reducin& serum urate concentrations to values less than 8.. m& per deciliter ;B8. Hmol per liter<. A reduction to less than 4.. m& per deciliter ;B.. Hmol per liter< may $e reCuired for the resorption of tophi. '"o classes of dru&s are availa$le, uricosuric dru&s and 7anthine o7idase inhi$itors. Uricosuric dru&s increase the urinary e7cretion of urate, there$y lo"erin& the serum urate concentration. #n contrast, 7anthine o7idase inhi$itors $lock the final step in urate synthesis, reducin& the production of urate "hile increasin& that of its precursors, 7anthine and hypo7anthine ;the o7ypurines<. #n &eneral, a 7anthine o7idase inhi$itor is indicated in patients "ith increased urate production, and a uricosuric dru& in those "ith lo" urate clearance. A potential complication of these dru&s is the precipitation of acute attacks of &out. 'he mechanism is poorly understood, $ut it is usually attri$uted to the sudden chan&e in the serum urate concentration. 'he risk can $e minimi*ed $y concurrently administerin& prophylactic dru&s, delayin& urate-lo"erin& therapy until several "eeks after the last attack of &out, and commencin& therapy "ith a lo" dose of the dru& that is chosen.

4rico(uric(
Uricosurics like pro$enecid and sulfinpyra*one increase renal e7cretion of uric acid $y inhi$itin& tu$ular rea$sorption in the kidneys. #t is important to start at lo" doses $ecause lar&e amounts of uric acid passin& throu&h the kidneys "ill increase the risk of formin& uric acid stones. 'he anti-hypertensive dru& losartan has $een sho"n to have a uricosuric effect, $ut this effect decreases drastically once the dru& has reach steady state. #t can also "orsen pree7istin& renal impairment. Uricosuric dru&s are contraindicated for patients "ith kidney stones and renal insufficiency. 'hose patients should use a dru& that "ill function independently of kidney function.

5anthine o+i a(e inhi)itor(

Allopurinol, a 7anthine o7idase inhi$itor, is the most commonly prescri$ed of these a&ents. 'he avera&e dose is B.. m& per day, althou&h dosin& recommendations ran&e from /.. to 5.. m& per day, titrated to serum urate and creatinine clearance. 'he side effects of allopurinol, althou&h uncommon, may $e severe or life-threatenin& and occur more often in patients "ith renal insufficiency. Allopurinol has $een considered the dru& of choice for hyperuricemia $ecause it can $e conveniently administered once daily, and mi&ht prevent

urolithiasis. Allopurinol and uricosuric dru& may $e used simultaneously in a fe" patients "ho can not $e controlled "ith a sin&le medication.

3i(cu((ion
Hyperuricemia does not al"ays lead to the typical clinical manifestations of &out. 'hese symptoms usually only appear in a person sufferin& "ith hyperuricemia for -. to B. years. 'he normal course of untreated hyperuricemia, leadin& to pro&ressive urate crystal deposition, $e&ins "ith uric acid urolithiasis ;urate kidney stones< and pro&resses to acute &outy arthritis and chronic tophaceous &out. atients "ith &out tend to seek medical attention durin& &out attacks, at "hich point the standard dia&nostic procedure is to search for monosodium urate crystals in synovial fluid. (ut patients are often seen durin& the intercritical periods, "hen, in the a$sence of tophi, the dia&nosis is made on clinical &rounds $y applyin& the preliminary American %olle&e of heumatolo&y classification criteria. Ho"ever, classification criteria "ork $est in the study of &roups of patients, and they often fail in the evaluation of the individual patient. A clinical approach for the dia&nosis of &out may $e pro$lematic and may e7plain "hy other conditions are often incorrectly dia&nosed and treated as &out. Monosodium urate crystals can $e found in synovial fluid o$tained from asymptomatic &outy :oints. !ther factors that can precipitate &outy attacks such as trauma, sur&ery, e7cessive alcohol consumption, administration of certain dru&s and the in&estion of purine-rich foods. Acute &outy arthritis consists of painful episodes of inflammatory arthritis and represents the most common manifestation of &out. 'ypical manifestations include a patient "ho &oes to $ed and a"akens $y severe pain in the $i& toe $ut may also $e e7perienced in the heel, instep or ankle. 'he pain is descri$ed as that of a dislocated :oint and is often accompanied or preceded $y chills and a sli&ht fever. 'he pain can $ecome so severe even the simple act of cloth touchin& the area in un$eara$le. )outy arthritis attacks usually dissipate "ithin several hours $ut can also last for several "eeks. 9on&-standin& persistence of MSU crystals may also cause chronic neutrophilic inflammation, osteoclast activation and chronic &ranulomatous infiltration of the synovium. Micro-a&&re&ates of MSU crystals occur in all patients "ith &out, $ut in some, macroscopic a&&re&ates occur, manifested as tophus formation. 'ophi are usually considered to $e a late manifestation of &out. 'he continued development of tophi results in destructive arthropathy ;disease of a :oint<. Aside from &outy arthritis and tophus formation, renal disease is the most freCuent complication of hyperuricemia. Kidney disease in patients "ith &out is of numerous types. Uric acid stones, "hich represent 4-/.I of all renal calculi in the United States, also result from uric acid precipitation in the collectin& system. Uric acid stones are related to uric acid e7ceedin& its solu$ility in the urine? thus, patients "ith hyperuricosuria have an increased risk of uric acid nephrolithiasis. Urine oversaturation "ith uric acid and su$seCuent crystal formation is determined lar&ely $y urinary pH. #ndividuals "ho form uric acid stones tend to e7crete less ammonium, "hich contri$utes directly to lo" urinary pH. #n addition, persons "ith &out and those "ho form stones, in particular, have a reduced postprandial alkaline tide ;alkaline urinary pH<. 'reatments aimed at lo"erin& serum urate levels in hyperuricemic patients is usually only a consideration in the conte7t of &out. (ecause acute &outy arthritis is an inflammatory event, treatment "ith anti-inflammatory dru&s is often successful in reducin& the symptoms. Allopurinol is an inhi$itor of 7anthine o7idase and therefore prevents conversion of 7anthine to uric acid. 'he usual dose of B.. m&6day should $e ad:usted for renal insufficiency. atients "ith decreased renal function should $e&in takin& allopurinol at a dose of 4.-/.. m&6day and then &radually increase the dose over a fe" months if it is tolerated "ell "ithout fever, dermatitis or eosinophilia. 'he &oal of urate lo"erin& therapy is a serum uric acid level of 8

m&6dl or less. !nce achieved, such therapy should $e continued indefinitely. %are must $e taken to avoid dru& interactions of allopurinol in com$ination "ith ampicillin, cyclophosphamide, a*athioprine, "arfarin or theophylline.

&onclu(ion
)out is an inflammatory arthritis caused $y the deposition of monosodium urate crystals in a :oint, characteri*ed $y acute attacks that, over time, can $ecome a chronic arthritis. Untreated, pro&ressive :oint destruction occurs and tophaceous deposits develop. %ommon sites for tophi include the pinna of the ear, the olecranon $ursa and ad:acent to the small :oints of the fin&ers )out must $e dia&nosed $y arthrocentesis $efore initiatin& one of the many treatments that e7ist. %ontinuin& dru& therapy and lifestyle modifications can si&nificantly improve patient outcome.

#eference(
/. )ar& = , %hasan-'a$er S, (lair A,<. JEffects of sevelamer and calcium-$ased phosphate $inders on uric acid concentrations in patients under&oin& hemodialysis, a randomi*ed clinical trialJ. Arthritis and rheumatism ;=anuary, -..4, 4-, -1.D4. -. Kelley G2, Schumacher H+ =r. %rystal-associated synovitis. #n, Kelley G2, ed. 'e7t$ook of rheumatolo&y. Eth ed. hiladelphia, Saunders, /11B,/-1/-BB8. B. Mc%arty 3=. )out "ithout hyperuricemia. =AMA /11E?-F/,B.--B. E. Gortman +9. )out and other disorders of purine meta$olism. #n, Fauci AS, ed. Harrison@s rinciples of internal medicine. /Eth ed. 2e" Kork, Mc)ra"-Hill, /115,-/45-84. 4. (eutler A, Schumacher H+ =r. )out and @pseudo&out@, "hen are arthritic symptoms caused $y crystal dispositionL ost&rad Med /11E?14,/.B-8. 8. Ku =S, %hun& %, +echt M, 3ailiana', =urdi +. M+ ima&in& of tophaceous &out. A=+ Am = +oent&enol /11F?/85,4-B-F. F. Martine*-%ordero E, (essudo-(a$ani A, 'revino ere* S%, )uillermo-)ra:ales E. %oncomitant &out and rheumatoid arthritis. = +heumatol /155?/4, /B.F-//. 5. Shrestha M, %hiu M=, Martin +9, %ush ==, Gainscott MS. 'reatment of acute &outy arthritis "ith intramuscular ketoralac tromethamine. Am = Emer& Med /11E? /-,E4E-4. 1. =ohnstone A. )out M the disease and non-dru& treatment. Hosp harm -..4?/-,B1/-B. /.. Nuiceno )A,%ush ==. #atro&enic rheumatic syndromes in the elderly. %lin )eriatr Med -..4?-/,4FF-55. //. Manolis A=,)rossman E, =elakovic (, et al. Effects of losartan and candesartan monotherapy and losartan6hydrochlorothia*ide com$ination therapy in patients "ith mild to moderate hypertension. %lin 'her -...? --,//58--BB. /-. Feher M3,Hep$urn A9,Ho&arth M(. Fenofi$rate enhances urate reduction in men treated "ith allopurinol for hyperuricaemia and &out. +heumatolo&y -..B? E-? B-/-4.