2 GoutAn elevated serum urate concentrationRecurrent attacks of acute arthritis in which MSU( monosodium urate) crystals are seen in synovial fluidAggregates of MSU crystals (tophi) are deposited in & around joints leading to deformity & cripplingHyperuricemiaAn elevated level of urate in the blood > 7mg/dl in males and >6.5mg/dl in females
3 EpidemiologyThe incidence of gout varies in population with an overall prevalence of less than 1 to 15.3%PathophysiologyUric acid is the end product of the degradation of purines.The accumulation may result from either overproduction or underexecreation.
4 The purines from which uric acid is produced originate from three sources: dietary purine,conversion of tissue nucleic acid to purine nucleotides and de novo synthesis of purine bases.Overproduction of uric acid result from:Abnormalities in the enzyme system that regulate purine metabolism.An increase in the activity of phosphribosyl pyrophosphate(PRPP) synthatase, a key determinant in purine synthesis and thus uric acid overproduction.
5 3. A deficiency of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) may also result in the overproduction of uric acid.4. Increased breakdown of tissue nucleic acids, as with myeloproliferative and lymphoproliferative disorders.Drugs that decrease renal clearance:Diuretics, salicylate<2g\d, ethanol, L-dopa, cyclosporine, ethambutol……..
6 Normal individual produce mg of uric acid daily and excrete less than 600 mg in urine. Individual who excrete more than 600 mg on a purine-free diet are considered overproducers.Hyperuricemic individuals who excrete less than 600mg per 24 hours on purine-free diet are defined as underexcretors of uric acid.On regular diet, excretion of >1000 mg per 24 hours reflect overproduction , less than this is probably normal.
7 Gout once called the“Disease of Kings”isalso seen in Women,EspeciallyAfterMenopause
8 M:F - 7:1 to 9:1Women before menopause- F < MIn ages younger than 65- M:F- 4:1 ratioIn the older age groups > 65- M:F-3:1 ratioAfter 80 years of age-F > M
9 URIC ACID METABOLISM MEN Vs WOMEN Estrogen have a mild uricosuric effect; therefore, gout is unusual in premenopausal womenHigher renal clearance of urate in women possibly due to their higher plasma estrogen levelsThe declining use of HRT may further increase the frequency of gout in women at an earlier age
10 Pathogenesis of GoutHyperuricemia results from urate overproduction (10%), under excretion (90%) or often a combination of twoGout is mediated by supersaturation and crystallization of uric acid within joints ultimately, the formation of tophiInteractions of MSU crystals with the components of the innate immune system trigger acute gouty inflammation
12 Clinical Features in Gout patient Asymptomatic HyperuricemiaAcute Gouty Arthritis- Acute monoarticular arthritis- The attacks begin abruptly and reach maximum intensity in 8-12 hours- The joints are red, hot, and exquisitely tender- Untreated, the first attacks resolve spontaneously in less than 2 weeks.- Gout can initially present as a polyarticular arthritis in 10% of patients
13 Chronic tophaceous Gout Intercritical goutChronic tophaceous Gout- Attacks become more polyarticular- Inflammation may become less intense- Proximal and upper-extremity joints involved- Attacks occur more frequently and last longer- Tophi in the soft tissues (helix of the ear, fingers, toes……………)
19 Clinical Features MEN Vs WOMEN In women, polyarticular/tophaceous disease is often the first manifestation of goutA preceding recurrent mono-arthritis is found in joints other than the big toeThe duration of disease before tophi is shorterThe prevalence of tophi is higher and its localization different in female than in male patients
20 Tophi are usually indolent and show little surrounding inflammation Gout in women has higher frequency of upper limb joint involvement in comparison to menThe articular features of gout are usually similar
21 Definitive diagnosis is best established by Aspiration of joint and identification of urate crystalThe triad of acute monoarticular arthritis, hyperuricemiaand dramatic response to colchicinesPresence of 6 of the below mentioned 12 clinical,laboratory and radiographic criteriaCriteria of Acute Gouty Arthritis► More than one attack of arthritis► Maximum inflammation in one day►Monoarticular arthritis►Joint redness► First metatarsophalangeal joint involvement► Unilateral attack► Unilateral attack involving tarsal joint► Suspected tophus►Hyperuricemia► Asymmetric swelling within joint (radiograph)► Subcortical cyst without erosion (radiograph)►Negative culture of joint fluid for microorganism
22 Co morbid Conditions Renal stones Urate nephropathy & chronic kidney failureHypertensionDiabetesEndothelial dysfunctionObesityInsulin resistance syndromeAtherosclerosisCardiovascular disease related mortalityCerebrovascular diseaseHypothyroidism
23 Treatment of GoutTreat acute arthritic attack promptlyPrevent recurrence of acute gouty arthritisLower urate levelsPrevent or reverse complications of the disease resulting from deposition of MSU crystal in joint, kidney, or other sitesPrevent or reverse co-morbid conditions like obesity, HT & triglycerdemia & renal complications
24 Treatment of Acute Gouty Arthritis NSAIDs are preferred in patients with uncomplicated goutIntraarticular corticosteroid for gout affecting one or two large jointsColchicine is preferred for patients in whom the diagnosis of gout is not confirmedIt is most effective during the first hours of an attack, effectiveness declines with the duration of inflammation
25 Long-Term or Prophylactic Therapy Lowering uric acid with either allopurinol or probenecid can precipitate attacks of goutNSAIDs and colchicine are frequently used as prophylaxis against recurrent acute goutA standard practice is to use low-dose oral colchicine (0.6 mg orally twice a day in patients with intact renal function) for the first six months of antihyperuricemic therapyLong-term use of colchicine can lead to a muscle weakness with elevated levels of creatine kinase particularly in patients with renal insufficiencyNSAIDs can be used for prophylaxis, such as indomethacin at 25 mg bid
26 Approaches to Lowering Uric Acid Levels Asymptomatic HyperuricemiaRarely an indication for specific drug therapySymptomatic HyperuricemiaLife long therapy with anti-hyperuricemic therapy is indicated in following situation>2 or 3 acute attacksRenal stonesTophaceous goutChronic gouty arthritis with bony erosions.
27 Antihyperuricemic Therapy In many cases, patients who have a first attack of gout should undergo therapy with agents that lower uric acidSome rheumatologists advocate waiting for the second attack to begin therapy to lower uric acid levels because not all patients have a second attackAntihyperuricemic therapy should be started a few weeks after the attack has resolved and with the institution of colchicine to prevent another attack
28 Indications for Allopurinol (Xanthine Oxidase inhibitor) Hyperuricemia associated overproducers of uric acidIn patients at risk of tumor lysis syndrome to prevent renaltoxicity during therapy for malignanciesUric acid excretion of 1000mg or more in 24 hoursHyperuricemia associated with HGPRT deficiency or PRPPsynthetase over activityUric acid nephropathyNephrolithiasisIntolerance or reduced efficacy of space uricosuric agentsGout with renal insufficiency (GFR<60ml/min)Allergy to uricosurics
29 Candidates for uricosuric drugs Who is younger than 60 years of age and normal renal function (creatinine clearance greater than 80ml/min)Uric acid excretion of less than 800 mg/24 hours on a general dietNo h/o of renal calculi
30 ProbenecidReduce serum urate levels by enhancing the renal excretion of UAFewer significant adverse effects than allopurinolCan be used in the majority of middle-agedMaintenance dose ranges from 500 mg to 3 g per day & is administered on twice daily or thrice daily schedulePrecipitation of gout, urolithiasis, and impairment of renal function are common side effects
31 SulfinpyrazoneSulfinpyrazone is an alternative uricosuric agent that has antiplatelet activity but is seldom used because of the added risk of bone marrow suppressionStarting dose, 50 mg orally twice daily; gradually increased to mg dailyPrecipitation of gout, urolithiasis, and impairment of renal function are common side effects
32 Dietary Management of Hyperuricemia Alcohol consumption must be avoidedDiets like butter, red meat, pasta sweets, white rice, potatoes, white bread, wine beer, liquor, fish poultry and sea food increase the risk of goutHigher level of consumption of dairy products is associated with a decreased riskModerate intake of purine-rich vegetables or protein is not associated with an increased risk of goutThose who consumes milk 1 or more times per day have a lower serum uric acid level
33 Recent Advances in Treatment Recombinant uricase can promote accelerated tophus dissolutionOxipurinol is the active metabolite of allopurinol. Patients with allopurinol hypersensitivity can often tolerate oxypurinolFebuxostat is an orally administered selective inhibitor of xanthine oxidase. It inhibits both the oxidized and reduced forms of xanthine oxidase. It is a potential alternative to allopurinol for patients with gout.Anti-tumour necrosis factor as a new therapeutic option
34 Treatment of Co morbid conditions The ARBs like losartan, Amlodipine & the triglyceride-lowering agent fenofibrate - Uricosuric effectsWeight loss is protectiveThe amelioration of insulin resistance by either a low-energy diet or troglitazone & Metformin therapy can also lower uric acid and attenuate the articular syndrome
35 Role of HRT in GoutThe effect of exogenously administered oestrogens, produce a fall in plasma uric acid concentration through a uricosuric effectHowever, there is no conclusive evidence is available for the use of estrogen replacement for such cases; however it remains the potential area of research