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Gout
浙大医学院附属二院 任跃忠
Background
Gout is a common disorder of uric acid m
etabolism that can lead to deposition of
monosodium urate (MSU) crystals in soft
tissue, recurrent episodes of debilitating j
oint inflammation, and, if untreated, joint
destruction and renal damage.
Gout is definitively diagnosed based on t
he demonstration of urate crystals in asp
irated synovial fluid.
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Epidemiology
United States statistics---The National Health and Nutrit
ion Examination Survey (2007-2008) estimated a new pre
valence for gout and hyperuricemia. Gout rates were repo
rted as 5.9% among men and 2% among women. (estrog
enic hormones have a mild uricosuric effect). The prevale
nce rate of hyperuricemia was noted as 21.2% for men an
d 21.6% for women.
Racial differences in incidence---In the United States, t
he incidence of gout is 3.11 per 1000 person-years in Afri
can Americans and 1.82 per 1000 person years in whites;
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--------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.
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 four
th to sixth decade of life. However, onset may occur in me
n 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 y
ears after the first gout attack.
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Olaniyi-Leyimu BY. Consider gout in patients with risk factors, regardless
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of age. Am Fam Physician. Jul 15 2008;78(2):176.
Etiology
Uric acid is an end-stage by-product of purine metabolism. Human
s remove uric acid primarily by renal excretion. (the saturation level
of 6.8 mg/dL )
Ninety percent of patients with gout … underexcretion. The remaini
ng patients …overproduction.
In rare cases, overproduction .., due to a genetic disorder. ( hypoxa
nthine-guanine phosphoribosyl transferase次黄嘌呤鸟嘌呤磷酸核糖基转移酶 deficie
ncy , glucose-6-phosphatase deficiency , fructose 1-phosphate ald
olase醛缩酶 deficiency)
Chronic urate nephropathy can result from the deposition of urate c
rystals in the medullary interstitium and pyramids, resulting in an inf
lammatory 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 super
saturated, …, forming crystals. In addition, the crystals also
are less soluble under acid conditions.
reactive urate crystals are normally coated with serum protei
ns (apolipoprotein [apo] E or apo B) that physically inhibit th
e binding of the crystals to cell receptors. A gout attack may
be triggered by either a release of uncoated crystals (eg, due t
o partial dissolution of a microtophus caused by changing ser
um urate levels) or precipitation of crystals in a supersaturate
d microenvironment (eg, release of urate due to cellular dam
age).
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Clinical---History
Podagra is the initial joint manifestation in 50% of gout ca
ses. 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 intensit
y within 8-12 hours. The joints are red, hot, and exquisitel
y tender; even a bed sheet on the swollen joint is uncomf
ortable. Untreated, the first attacks resolve spontaneously
in less than 2 weeks. Gout initially presents as polyarticul
ar 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 m
ore joints may become involved, inflammation in a given j
oint may become less intense. More proximal and upperextremity joints become involved. Attacks occur more freq
uently and last longer.
Eventually, patients may develop chronic polyarticular art
hritis. Patients with gout are profoundly more likely to dev
elop renal stones .
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Clinical--Physical Examination
The classic location of tophi is along the helix of the ear …, includin
g the fingers, toes, prepatellar bursa, and along the olecranon. Rar
ely, 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
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•Gout. Chronic tophaceous gout
in an untreated patient with endstage renal disease
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Workup –Approach Considerations
Arthrocentesis关节穿刺术 of the affected joint is mandatory for all pati
ents with new onset of acute monoarthritis . Tophi also may be aspi
rated for crystal analysis under polarizing microscopy
Septic arthritis must be diagnosed and treated promptly, because ir
reversible 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 differentia
l, Gram stain, culture and sensitivity, and microscopic analysis for c
rystals.
In gout, crystals of monosodium urate (MSU) appear as needle-sha
ped intracellular and extracellular crystals. ..pseudogout shows cal
cium pyrophosphate焦磷酸盐 (CPP) crystals, which appear shorter th
an MSU crystals and are often rhomboidal.长斜方形的
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Laboratory Studies
Synovial fluid:
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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.
Gout. Strongly negative birefringent双折
射的, needle-shaped crystals diagnostic of
gout obtained from an acutely inflamed
joint
Gout. Needles of urate on polarizing microscopy偏光显微术
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Laboratory Studies
Serum uric acid
This is the most misused test in the diagnosis of gout. T
he presence of hyperuricemia in the absence of sympto
ms is not diagnostic of gout. In addition, as many as 10
% of patients with symptoms due to gout may have nor
mal 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 cryst
als in the synovial fluid or soft tissues.
Asymptomatic hyperuricemia should generally not be tr
eated. The level of serum uric acid correlates with risk f
or developing gout. The 5-year risk for developing gout
is approximately 0.6% if the level is less than 7.9 mg/d
L, 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 aci
d in 24 hours on a regular diet, these patients
(approximately 10% of patients with gout) requi
re allopurinol instead of probenecid to reduce ur
ic acid levels.
In patients in whom probenecid is contraindicat
ed (eg, those with a history of renal stones or r
enal insufficiency).
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Laboratory Studies
Blood chemistry
Obtaining an accurate measure of the patient's renal fun
ction 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 whe
n therapy is selected.
CBC count: The WBC count may be elevated in patie
nts during the acute gouty attack, particularly if it is
polyarticular.
Lipids: Hypertriglyceridemia and low high-density lipo
proteins are associated with gout.
Urinalysis: Patients with gout are at an increased ris
k 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.
Erosions with maintenance of the joint space
Erosions without periarticular osteopenia
Erosions with overhanging edges
Erosions 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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typical changes of gout
in the first
metatarsophalangeal
joint and fourth
interphalangeal joint.
showing chronic tophaceous痛
风石gouty arthritis in the hands.
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Male sex
Previous arthritis attack
Onset within 1 day
Joint redness
First metatarsophalangeal joint involvement
Hypertension or one or more cardiovascular diseases
A serum uric acid level of more than 5.88 mg/dL
In a study of this rule in 328 patients, the positive pr
edictive value of gout diagnosis by family physicians was
0.64; the negative predictive value was 0.87.
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---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 arthritis
Secondary infections
Urate or uric acid nephropathy
Nerve or spinal cord impingement
Increased susceptibility to infection
Renal stones
Fractures
影响
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Treatment
Medical Care
Gout 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 de
position of urate crystals.
As mentioned above, asymptomatic hyperuricemia should generally not
be treated. However, patients with levels higher than 11 mg/dL who ove
rexcrete uric acid are at risk for renal stones and renal impairment; ther
efore, 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 ..Mo
derate wine intake is not associated with an increased go
ut flares.
Increasing dairy intake, folic acid intake, and coffee consu
mption may reduce gout flares.
21
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 im
prove hyperuricemia.
Ingestion of fructose-containing beverages should
be reduced, and ingestion of milk and calcium sho
uld be increased .
Maintaining a high level of hydration with water (at
least 8 glasses of liquids per day) is helpful in avoi
ding attacks of gout.
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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
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controlled trial. Rheumatology (Oxford). Feb 2009;48(2):195-7.
Treatment ---Acute gout
Options for treatment of acute gout include non
steroidal anti-inflammatory drugs (NSAIDs), cor
ticosteroids, and colchicine秋水仙碱(a classic treatm
ent that is now rarely indicated). The choice is b
ased primarily on any concomitant health proble
ms (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 w
ho do not have underlying health problems.
most NSAIDs can be used. Cyclooxygenase-2 (COX-2) inhib
itors 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 fo
r 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, pati
ents 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 NS
AIDs cautiously in patients with diabetes and those who are r
eceiving concomitant angiotensin-converting enzyme (ACE) i
nhibitors.
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Consultation may be helpful in patients with an acute gout attack that does
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not respond to NSAIDs within 2 days or to colchicine within 1 day .
Nonsteroidal anti-inflammatory drugs
Use of concomitant misoprostol gastric protection or consid
eration of a cyclooxygenase 2 (COX-2)–specific NSAID mi
ght be considered if the patient has gastrointestinal risk or i
s older than 51 years.
To control the attack as quickly and safely as possible , con
sider using an NSAID with a short half-life.
Use the maximum dose of NSAID and taper over approxim
ately 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, intrave
nously, intramuscularly, intra-articularly, or indirectly via adren
ocorticotropic 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 o
f oral steroids.
ACTH at 40 IU IM can be given to induce corticosteroid produc
tion 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 corticost
eroids exists unless the patient cannot take oral m
edications.
The short-burst corticosteroid regimen used to tre
at an acute flare of gout is generally well tolerated
In patients with only 1 or 2 involved joints, intra-arti
cular corticosteroids are a safe and effective treat
ment option
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Treatment --- Acute gout --Colchicine
• colchicine is now a second-line approach because of its narrow th
erapeutic 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 eve
ry 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 (GF
R) 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 dysfun
ction, biliary obstruction, or an inability to tolerate diarrhea.
• In February 2008, intravenous colchicine is no longer advocated f
or 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 af
fected joints, thereby reducing acute inflammation and pai
n; it also decreases uric acid levels in blood.
Colchicine is now considered a second-line agent in the tr
eatment of acute gout flares because of its narrow therap
eutic window.
More often, it is used at a lower dose as a prophylactic ag
ent to prevent flares of gout when adding agents that low
er uric acid.
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Treatment of Chronic Gout
some rheumatologists advocate waiting for the second att
ack to initiate therapy to lower uric acid levels because no
t 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 ye
ars. The decision to begin therapy depends partly on the
baseline serum uric acid levels (>9 mg/dL denotes a high
er risk for recurrent gouty arthritis and tophi).
The goal of therapy is to lower serum uric acid levels to a
pproximately 6 mg/dL or less.
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Treatment of Chronic Gout
If the patient excretes less than 600 mg of uric aci
d per 24-hour period on a purine-free diet or less t
han 800 mg per 24-hour period on an unrestricted
diet, the patient is considered a hypoexcreter.
Gout patients who have a 24-hour urinary excretio
n of uric acid above 1100 mg have a 50% risk of d
eveloping 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 f
luid daily at the inception of therapy in order to red
uce their urinary concentration and thereby reduce
the risk of renal stones
Indications for the use of allopurinol instead of pro
benecid include renal insufficiency (GFR < 50 mL/
min), renal stones, use of aspirin (blocks the effect
of probenecid), overproduction of uric acid, and un
responsiveness to probenecid.
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Uricosuric agents
Uricosuric agents lower uric acid levels by inhibitin
g the renal tubular reabsorption of uric acid, thereb
y 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 a
pproximately 5-6 mg/dL without causing renal ston
es.
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Benzbromarone is an effective uricosuric agent that may
eventually become available. However, it can cause fulmi
nant hepatotoxicity.
The angiotensin receptor blocker losartan and the triglyce
ride-lowering agent micronized fenofibrate(200 mg/d redu
ces 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 ri
sk of tumor lysis syndrome to prevent renal toxicity. It is the most ef
fective urate-lowering agent .
Less frequently, .. allopurinol hypersensitivity, which carries a mort
ality rate of 20-30%.... include fever, toxic epidermal necrolysis, bo
ne marrow suppression, eosinophilia, leukocytosis, renal failure, he
patic failure, and vasculitis. Corticosteroids ….
the drug rash with eosinophilia and systemic symptoms (DRESS) s
yndrome affects the liver, kidney, and skin. It is a delayed-hypersen
sitivity response occurring 6-8 weeks after beginning allopurinol. ..
a cell-mediated immunity to allopurinol and its metabolites. Althoug
h 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.
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Markel A. Allopurinol-induced DRESS syndrome. Isr Med Assoc J. Oct 2005;7(10):656-60.
Allopurinol
In most patients, start at 100 mg per day (50 mg in patient
s 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 xa
nthine oxidase, is a potential alternative to allopurinol in p
atients 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 mo
re soluble product, allantoin尿囊素, thus preventing a
cute renal failure. (Pegloticase (Krystexxa) Rasburicase (Elite
k))
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Nonrecombinant urate-oxidase (uricase尿酸酶 ) is used i
n Europe to prevent severe hyperuricemia induced by che
motherapy in patients with malignancies, as well as in sel
ected patients with treatment-refractory gout.
In 2009, the FDA approved recombinant Aspergillus flavu
s黄曲霉 uricase (rasburicase [Elitek]) for the prevention of t
umor lysis syndrome. A polyethylene聚乙烯 -glycol乙二醇 –con
jugated共轭的 uricase (pegloticase [Krystexxa]) was appro
ved by the FDA in 2010.
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Long-Term Monitoring
If uric acid–lowering therapy is begun, patients sh
ould 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 mont
hs.
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Medication Summary
Acute inflammation due to gout can be treated with NSAI
Ds, corticosteroids, or colchicine. NSAIDs are generally th
e drugs of choice unless the patient has a risk factor that
contraindicates these agents.
Ultimately, gout is treated by decreasing tissue stores of u
ric acid with allopurinol or probenecid.
Because agents that lower uric acid can precipitate attack
s 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 fro
m all causes and cardiovascular diseases. Analysis of 1,3
83 deaths among 61,527 Taiwanese subjects showed tha
t the hazard ratio (HR) of all-cause mortality was 1.46, an
d the adjusted HR of cardiovascular mortality was 1.97 in
individuals with gout compared with those who had norma
l uric acid levels .
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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.
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Rheumatology (Oxford). Jan 2010;49(1):141-6.
总
结
血糖达标强调空腹、餐后血糖、HbA1c
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
血糖，减少低血糖,减少胰岛素用量
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