Gout

浙大医学院附属二院 任跃忠

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Background

Gout is a common disorder of uric acid metabolism that can lead to deposition of monosodium urate (MSU) crystals in soft tissue, recurrent episodes of debilitating joint inflammation, and, if untreated, joint destruction and renal damage.

Gout is definitively diagnosed based on the demonstration of urate crystals in aspirated synovial fluid.

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Epidemiology

United States statistics---The National Health and Nutrition Examination Survey (2007-2008) estimated a new prevalence for gout and hyperuricemia. Gout rates were reported as 5.9% among men and 2% among women. (estrogenic hormones have a mild uricosuric effect). The prevalence rate of hyperuricemia was noted as 21.2% for men and 21.6% for women.Racial differences in incidence---In the United States, the incidence of gout is 3.11 per 1000 person-years in African Americans and 1.82 per 1000 person years in whites;

--------Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: The National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. Oct 2011;63(10):3136-41.

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Epidemiology

As a rule, uric acid levels are elevated for 20 years before the onset of gout.

In men, the peak age of onset of gout in men is in the fourth to sixth decade of life. However, onset may occur in men in their early 20s who have a genetic predisposition and lifestyle risk factors. In women, peak age of onset is in the sixth to eighth decade of life.

Tophi are typically detectable clinically approximately 10 years after the first gout attack.

Olaniyi-Leyimu BY. Consider gout in patients with risk factors, regardless of age. Am Fam Physician. Jul 15 2008;78(2):176.

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Etiology

Uric acid is an end-stage by-product of purine metabolism. Humans remove uric acid primarily by renal excretion. (the saturation level of 6.8 mg/dL )

Ninety percent of patients with gout … underexcretion. The remaining patients …overproduction.

In rare cases, overproduction .., due to a genetic disorder. ( hypoxanthine-guanine phosphoribosyl transferase 次黄嘌呤鸟嘌呤磷酸核糖基转

移酶 deficiency , glucose-6-phosphatase deficiency , fructose 1-phosphate aldolase 醛缩酶 deficiency)Chronic urate nephropathy can result from the deposition of urate crystals in the medullary interstitium and pyramids, resulting in an inflammatory reaction that can lead to fibrotic changes

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Pathophysiology

Gout can be considered a disorder of metabolism that allows uric acid/urate to accumulate in blood and tissues. When tissues become

supersaturated, …, forming crystals. In addition, the crystals also are less soluble under acid conditions.

reactive urate crystals are normally coated with serum proteins (apolipoprotein [apo] E or apo B) that physically inhibit the binding of the crystals to cell receptors. A gout attack may be triggered by either a release of uncoated crystals (eg, due to partial dissolution of a microtophus caused by changing serum urate levels) or precipitation of crystals in a supersaturated microenvironment (eg, release of urate due to cellular damage).

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Clinical---History

Podagra is the initial joint manifestation in 50% of gout cases. Eventually, it is involved in 90% of cases. Other than the great toe, the most common sites of gouty arthritis are the ankle, wrist, and knee. In early gout, only 1 or 2 joints are usually involved.

Gout attacks begin abruptly and reach maximum intensity within 8-12 hours. The joints are red, hot, and exquisitely tender; even a bed sheet on the swollen joint is uncomfortable. Untreated, the first attacks resolve spontaneously in less than 2 weeks. Gout initially presents as polyarticular arthritis in 10% of patients.

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Clinical---History

The pattern of symptoms in untreated gout changes over time. The attacks become more polyarticular. Although more joints may become involved, inflammation in a given joint may become less intense. More proximal and upper-extremity joints become involved. Attacks occur more frequently and last longer.

Eventually, patients may develop chronic polyarticular arthritis. Patients with gout are profoundly more likely to develop renal stones .

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Clinical--Physical Examination

The classic location of tophi is along the helix of the ear …, including the fingers, toes, prepatellar bursa, and along the olecranon. Rarely, a creamy discharge may be present .

All manifestations of gout in the eye are secondary to deposition of

urate crystals within the ocular tissue

•Gout. Tophaceous deposits on elbow•Gout. Tophaceous deposits

in ear

•Gout. Chronic tophaceous gout in an untreated patient with end-stage renal disease

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Workup –Approach Considerations

Arthrocentesis 关节穿刺术 of the affected joint is mandatory for all patients with new onset of acute monoarthritis . Tophi also may be aspirated for crystal analysis under polarizing microscopy

Septic arthritis must be diagnosed and treated promptly, because irreversible damage can occur within 4-6 hours, and the joint can be completely destroyed within 24-48 hours.

Send joint fluid for fluid analysis, including cell count and differential, Gram stain, culture and sensitivity, and microscopic analysis for crystals.

In gout, crystals of monosodium urate (MSU) appear as needle-shaped intracellular and extracellular crystals. ..pseudogout shows calcium pyrophosphate 焦磷酸盐 (CPP) crystals, which appear shorter than MSU crystals and are often rhomboidal. 长斜方形的

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Laboratory Studies

Synovial fluid:

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Gout. Needles of urate on polarizing microscopy 偏光显微术

Gout. Strongly negative birefringent 双折射的 , needle-shaped crystals diagnostic of gout obtained from an acutely inflamed joint

The sensitivity of a synovial fluid analysis for crystals is 84%, with a specificity of 100%. If gout remains a clinical consideration after negative analysis findings, the procedure can be repeated in another joint or with a

subsequent flare. Crystals may be absent very early in a flare.

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Laboratory Studies

Serum uric acid

This is the most misused test in the diagnosis of gout. The presence of hyperuricemia in the absence of symptoms is not diagnostic of gout. In addition, as many as 10% of patients with symptoms due to gout may have normal serum uric acid levels at the time of their attack.---

only 5-20% of patients with hyperuricemia develop gout. Gout is diagnosed based on the discovery of urate crystals in the synovial fluid or soft tissues.

Asymptomatic hyperuricemia should generally not be treated. The level of serum uric acid correlates with risk for developing gout. The 5-year risk for developing gout is approximately 0.6% if the level is less than 7.9 mg/dL, 1% if 8-8.9 mg/dL, and 22% if higher than 9 mg/dL.

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Laboratory Studies

Uric acid in 24-hour urine sample If patients excrete more than 800 mg of uric acid in 24 hours on a regular diet, these patients (approximately 10% of patients with gout) require allopurinol instead of probenecid to reduce uric acid levels.

In patients in whom probenecid is contraindicated (eg, those with a history of renal stones or renal insufficiency).

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Laboratory Studies

Blood chemistry Obtaining an accurate measure of the patient's renal function before deciding on therapy for gout is important.. 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; therefore, these patients may have a history of hematuria.

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Imaging Studies

Gout. Radiograph of erosions with overhanging悬垂的 edges.

typical changes of gout in the first metatarsophalangeal joint and fourth interphalangeal joint.

showing chronic tophaceous 痛风石 gouty arthritis in the hands.

Erosions with maintenance of the joint space Erosions without periarticular osteopenia Erosions with overhanging edgesErosions with sclerotic borders, sometimes called cookie-cutter or punched-out borders Erosions that are distributed asymmetrically among the joints, with strong predilection for distal joints, especially in the lower extremities

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Male sexPrevious arthritis attackOnset within 1 dayJoint rednessFirst metatarsophalangeal joint involvementHypertension or one or more cardiovascular diseasesA serum uric acid level of more than 5.88 mg/dL

In a study of this rule in 328 patients, the positive predictive value of gout diagnosis by family physicians was 0.64; the negative predictive value was 0.87.

---Janssens HJ, Fransen J, van de Lisdonk EH, van Riel PL, van Weel C, Janssen M. A diagnostic rule for acute gouty arthritis in primary care without joint fluid analysis. Arch Intern Med. Jul 12 2010;170(13):1120-6.

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Complications

Complications of gout include the following:Severe degenerative arthritisSecondary infectionsUrate or uric acid nephropathyNerve or spinal cord impingement 影响 Increased susceptibility to infectionRenal stonesFractures

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Treatment

Medical CareGout is managed in 3 stages:

(1) treating the acute attack, (2) providing prophylaxis 预防 to prevent acute flares, and (3) lowering excess stores of urate to prevent

flares of gouty arthritis and to prevent tissue deposition of urate crystals.

As mentioned above, asymptomatic hyperuricemia should generally not be treated. However, patients with levels higher than 11 mg/dL who overexcrete uric acid are at risk for renal stones and renal impairment; therefore, renal function should be monitored in these individuals.

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Diet and Activity

high-purine foods should be avoided, or consumed only in moderation. Foods very high in purines include hearts,

sweetbreads (eg, pancreas, thymus), smelt 香鱼 , sardines, and mussels 淡菜 .Overall, purine restriction reduces serum uric acid levels by only 1 mg/ml, Patients with gout should avoid beer and hard liquor ..Moderate wine intake is not associated with an increased gout flares.Increasing dairy intake, folic acid intake, and coffee consumption may reduce gout flares.

Choi HK, Atkinson K, Karlson EW, et al. Alcohol intake and risk of incident gout in men: a prospective study. Lancet. Apr 17 2004;363(9417):1277-81. Singh JA, Reddy SG, Kundukulam J. Risk factors for gout and prevention: a systematic review of the literature. Curr Opin Rheumatol. Mar 2011;23(2):192-202.

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Diet and Activity

Weight reduction in patients who are obese can improve hyperuricemia.

Ingestion of fructose-containing beverages should be reduced, and ingestion of milk and calcium should be increased .

Maintaining a high level of hydration with water (at least 8 glasses of liquids per day) is helpful in avoiding attacks of gout.

Dalbeth N, Horne A, Gamble GD, Ames R, Mason B, McQueen FM, et al. The effect of calcium supplementation on serum urate: analysis of a randomized controlled trial. Rheumatology (Oxford). Feb 2009;48(2):195-7.

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Treatment ---Acute gout

Options for treatment of acute gout include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and colchicine 秋水仙碱 (a classic treatment that is now rarely indicated). The choice is based primarily on any concomitant health problems (eg, renal insufficiency, peptic ulcer disease)

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Treatment --- Acute gout

Nonsteroidal anti-inflammatory drugs NSAIDs are the drugs of choice in most patients with gout who do not have underlying health problems. most NSAIDs can be used. Cyclooxygenase-2 (COX-2) inhibitors have been used with success.

Start with the highest dose for 2-3 days and taper down over approximately 2 weeks. Gout symptoms should be absent for at least 2 days before the NSAID is discontinued.

Avoid NSAIDs in patients who have a history of peptic ulcer disease or GI bleeding, patients with renal insufficiency, patients with abnormal hepatic function, patients taking warfarin (selective COX-2 inhibitors can be used), and patients in the intensive care unit who are predisposed to gastritis. Use NSAIDs cautiously in patients with diabetes and those who are receiving concomitant angiotensin-converting enzyme (ACE) inhibitors.

Consultation may be helpful in patients with an acute gout attack that does not respond to NSAIDs within 2 days or to colchicine within 1 day .

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Nonsteroidal anti-inflammatory drugs

Use of concomitant misoprostol gastric protection or consideration of a cyclooxygenase 2 (COX-2)–specific NSAID might be considered if the patient has gastrointestinal risk or is older than 51 years.

To control the attack as quickly and safely as possible , consider using an NSAID with a short half-life.

Use the maximum dose of NSAID and taper over approximately 2 weeks, depending on patient's response.

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Treatment --- Acute gout

Corticosteroids Corticosteroids can be given to patients with gout who cannot use NSAIDs or colchicine. Steroids can be given orally, intravenously, intramuscularly, intra-articularly, or indirectly via adrenocorticotropic hormone (ACTH).

Prednisone can be given at a dose of approximately 40 mg for 1-3 days and then tapered over approximately 2 weeks. . Intra-articular corticosteroids are particularly useful in patients with a monoarticular flare to help reduce the systemic effects of oral steroids.

ACTH at 40 IU IM can be given to induce corticosteroid production by the patient's own adrenal glands. Such a regimen does not depend on the patient to taper prednisone properly.

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Corticosteroids

No intrinsic advantage to treating with IV corticosteroids exists unless the patient cannot take oral medications.

The short-burst corticosteroid regimen used to treat an acute flare of gout is generally well tolerated

In patients with only 1 or 2 involved joints, intra-articular corticosteroids are a safe and effective treatment option

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Treatment --- Acute gout --Colchicine • colchicine is now a second-line approach because of its narrow

therapeutic window and risk of toxicity.

• --- colchicine dosing in acute gout of 0.5 mg tid (0.6 mg tid in the United States). or1 mg loading dose followed by 0.5 (0.6) mg every 6 hours, up to a maximum of 2.5 mg/24 hours and 6 mg over 4 days.

• Colchicine should not be used if the glomerular filtration rate (GFR) is less than 10 mL/min, and the dose should be decreased by at least half if the GFR is less than 50 mL/min.

• Colchicine should also be avoided in patients with hepatic dysfunction, biliary obstruction, or an inability to tolerate diarrhea.

• In February 2008, intravenous colchicine is no longer advocated for the treatment of acute gout in the United States.

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Anti-inflammatory agents

Colchicine reduces the formation of uric acid crystals in affected joints, thereby reducing acute inflammation and pain; it also decreases uric acid levels in blood.

Colchicine is now considered a second-line agent in the treatment of acute gout flares because of its narrow therapeutic window.

More often, it is used at a lower dose as a prophylactic agent to prevent flares of gout when adding agents that lower uric acid.

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Treatment of Chronic Gout

some rheumatologists advocate waiting for the second attack to initiate therapy to lower uric acid levels because not all patients experience a second attack .

The risk of a second attack of gout after the first attack is 62% after 1 year, 78% after 2 years, and 93% after 10 years. The decision to begin therapy depends partly on the baseline serum uric acid levels (>9 mg/dL denotes a higher risk for recurrent gouty arthritis and tophi).

The goal of therapy is to lower serum uric acid levels to approximately 6 mg/dL or less.

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Treatment of Chronic Gout

If the patient excretes less than 600 mg of uric acid per 24-hour period on a purine-free diet or less than 800 mg per 24-hour period on an unrestricted diet, the patient is considered a hypoexcreter.

Gout patients who have a 24-hour urinary excretion of uric acid above 1100 mg have a 50% risk of developing urate and oxalate 草酸盐 kidney stones.

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Treatment of Chronic Gout

Patients who use probenecid need to drink 2 L of fluid daily at the inception of therapy in order to reduce their urinary concentration and thereby reduce the risk of renal stones

Indications for the use of allopurinol instead of probenecid include renal insufficiency (GFR < 50 mL/min), renal stones, use of aspirin (blocks the effect of probenecid), overproduction of uric acid, and unresponsiveness to probenecid.

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Uricosuric agents

Uricosuric agents lower uric acid levels by inhibiting the renal tubular reabsorption of uric acid, thereby increasing net renal excretion of uric acid.

These agents increase the risk of renal stones.

The goal of therapy is to lower serum uric acid to approximately 5-6 mg/dL without causing renal stones.

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Benzbromarone is an effective uricosuric agent that may eventually become available. However, it can cause fulminant hepatotoxicity.

The angiotensin receptor blocker losartan and the triglyceride-lowering agent micronized fenofibrate(200 mg/d reduces serum urate 19% and increases clearance by 36%. ) have moderately potent uricosuric effects.

Vitamin C, with its uricosuric effect …

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Allopurinol

Allopurinol blocks xanthine oxidase 黄嘌呤氧化酶 and thus reduces the generation of uric acid. .. overproduce uric acid and in patients at risk of tumor lysis syndrome to prevent renal toxicity. It is the most effective urate-lowering agent .

Less frequently, .. allopurinol hypersensitivity, which carries a mortality rate of 20-30%.... include fever, toxic epidermal necrolysis, bone marrow suppression, eosinophilia, leukocytosis, renal failure, hepatic failure, and vasculitis. Corticosteroids ….

the drug rash with eosinophilia and systemic symptoms (DRESS) syndrome affects the liver, kidney, and skin. It is a delayed-hypersensitivity response occurring 6-8 weeks after beginning allopurinol. .. a cell-mediated immunity to allopurinol and its metabolites. Although occurrence is 0.4 %, the rate of organ failure and death is high.

Treatment is with intravenous N- acetyl cysteine 半胱氨酸 and steroids. Markel A. Allopurinol-induced DRESS syndrome. Isr Med Assoc J. Oct 2005;7(10):656-60.

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Allopurinol

In most patients, start at 100 mg per day (50 mg in patients with renal insufficiency) and adjust the dose monthly Once the target uric acid level is achieved and maintained for 6 months, discontinue colchicine prophylaxis.

Febuxostat 非布索坦 , a nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol in patients with gout. Febuxostat is administered orally and is metabolized mainly in the liver .

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Uric acid oxidizers

These agents facilitate conversion of urate to a more soluble product, allantoin 尿囊素 , thus preventing acute renal failure. (Pegloticase (Krystexxa) Rasburicase (Elitek))

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Nonrecombinant urate-oxidase (uricase 尿酸酶 ) is used in Europe to prevent severe hyperuricemia induced by chemotherapy in patients with malignancies, as well as in selected patients with treatment-refractory gout.

In 2009, the FDA approved recombinant Aspergillus flavus 黄曲霉 uricase (rasburicase [Elitek]) for the prevention of tumor lysis syndrome. A polyethylene 聚乙烯 -glycol 乙二醇 – conjugated 共轭的 uricase (pegloticase [Krystexxa]) was approved by the FDA in 2010.

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Long-Term Monitoring

If uric acid–lowering therapy is begun, patients should be seen every 1-2 months while adjusting the dose of medications to achieve the target uric acid level of 5-6 mg/dL. Once this level is achieved and maintained, patients can be seen every 6-12 months.

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Medication Summary

Acute inflammation due to gout can be treated with NSAIDs, corticosteroids, or colchicine. NSAIDs are generally the drugs of choice unless the patient has a risk factor that contraindicates these agents.

Ultimately, gout is treated by decreasing tissue stores of uric acid with allopurinol or probenecid.

Because agents that lower uric acid can precipitate attacks of gout, low-dose colchicine is used as prophylaxis 预防 when such therapy is initiated.

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Prognosis

gout that is treated early and properly carries an excellent prognosis if patient compliance is good.

In a 2010 study, Kuo et al demonstrated that gout, but not hyperuricemia, is associated with higher risk of death from all causes and cardiovascular diseases. Analysis of 1,383 deaths among 61,527 Taiwanese subjects showed that the hazard ratio (HR) of all-cause mortality was 1.46, and the adjusted HR of cardiovascular mortality was 1.97 in individuals with gout compared with those who had normal uric acid levels .

Kuo CF, See LC, Luo SF, Ko YS, Lin YS, Hwang JS, et al. Gout: an independent risk factor for all-cause and cardiovascular mortality. Rheumatology (Oxford). Jan 2010;49(1):141-6.

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总 结总 结

血糖达标强调空腹、餐后血糖、血糖达标强调空腹、餐后血糖、 HbA1cHbA1c和平稳血糖和平稳血糖

强化降糖有利于减少糖尿病的慢性并发症

拜唐苹在与胰岛素联合使用显著降低高拜唐苹在与胰岛素联合使用显著降低高血糖，减少低血糖血糖，减少低血糖 ,, 减少胰岛素用量减少胰岛素用量