Download Clinical Signs of Gout

Review of Clinical Signs
Series Editor: Bernard M. Karnath, MD
Clinical Signs of Gout
Prashanth Sunkureddi, MD
Tracy U. Nguyen-Oghalai, MD
Bernard M. Karnath, MD
istorically, gout has been considered a disease
of affluent middle-aged men who eat and
drink to excess; however, gout does affect
other segments of the population. Gout is a
systemic disease characterized by manifestations of
chronic underlying hyperuricemia, resulting in the
deposition of monosodium urate crystals in various tissues. Initially, inflammatory arthropathy is episodic,
but it can become persistent if left untreated. Other
clinical signs of gout include tophi formation, renal
calculi, and urate nephropathy. This article reviews the
risk factors, clinical features, and diagnostic evaluation
of gout and discusses the management of gout and
hyperuricemia.
H
RISK FACTORS
Gout has a strong male predominance, with an estimated 2% prevalence in men over age 30 years1 and a
peak incidence in the fifth decade of life among men.2
Gout is rarely seen in premenopausal women but can
be found in postmenopausal women. The prevalence
of gout is higher in African Americans than in whites,3
and gout prevalence overall appears to have increased
in recent decades.4
Other risk factors for gout include older age, obesity,
taking certain medications (eg, diuretics), and consuming purine-rich food and alcohol. Alcoholic beverages
not only increase urate production but also decrease
urate elimination via the kidney. Beer has the highest
purine content of the alcoholic beverages and confers
the highest risk for developing gout. However, wine
does not increase the risk of developing gout. Interestingly, a recent study by Choi et al5 showed that consuming purine-rich vegetables had no correlation with gout
development and increasing dairy intake decreased
gout incidence.
PATHOPHYSIOLOGY
Hyperuricemia is defined as a serum uric acid level
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FEATURES OF GOUT
Gout has a strong male predominance.
Asymptomatic hyperuricemia may be present for
decades.
Risk factors for gout include: older age, obesity,
medications (eg, diuretics, niacin), and consumption of purine-rich foods and alcohol.
The metatarsophalangeal joint of the great toes is
involved in 50% of initial attacks.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
are typically used as first-line therapy.
Corticosteroids are an effective alternative to
NSAIDs.
greater than 6.8 mg/dL. Baseline uric acid level is
higher among men (5.1 ± 1.0 mg/dL) than among
women (4.0 ± 1.0 mg/dL).6 Common causes of overproduction or underexcretion of uric acid that can
lead to hyperuricemia are shown in Table 1. When the
limit of solubility of monosodium urate in plasma is
exceeded, urate crystals precipitate. Urate crystals are
phagocytosed by neutrophils, which subsequently
release potent inflammatory mediators, such as tumor
necrosis factor-α, interleukin-1, and interleukin-6.
These inflammatory mediators are responsible for systemic effects (eg, fever, leukocytosis) observed during
an acute attack of gout.
Dr. Sunkureddi is a rheumatology fellow, and Dr. Nguyen-Oghalai is an
assistant professor of medicine, Division of Rheumatology. Dr. Karnath
is an associate professor of medicine, Division of General Medicine. All
are at the University of Texas Medical Branch, Galveston, TX.
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Sunkureddi et al : Clinical Signs of Gout : pp. 39 – 42, 47
Table 1. Common Causes of Hyperuricemia
Overproduction
Foods with high purine content (eg, mussels, oysters, red meat, liver,
anchovies)
Alcohol
Enzyme deficiencies (eg, hypoxanthine-guanine phosphoribosyltransferase, phosphoribosyl pyrophosphate)
Obesity
Increased cell turnover
Malignancy
Psoriasis
Figure 1. Acute arthritis of the right first metatarsophalangeal joint in a patient with gout (known as podagra).
Underexcretion
Renal disease
Lead intoxication (“saturnine gout”)
Medications (eg, diuretics, cyclosporine, low-dose aspirin, pyrazinamide, niacin, ethambutol)
Metabolic acidosis (eg, ketoacidosis, lactic acidosis)
Alcohol
CLINICAL FEATURES
Gout can be described in 4 stages: asymptomatic
hyperuricemia, intermittent acute gout, intercritical
gout, and advanced or chronic tophaceous gout. The
first stage, asymptomatic hyperuricemia, may be present
for decades and is characterized by silent urate deposition in tissue. The degree of hyperuricemia correlates
with the development of a gout attack in the second
stage.7 Acute gout attacks occur abruptly with severe
joint pain and inflammation and are typically monoarticular. In 50% of the initial attacks, the metatarsophalangeal joint of the great toes is involved, commonly
known as podagra (Figure 1). Over time, attacks may
become polyarticular and involve the ankles, knees,
wrist, and joints in the hands. Impressive erythema of
the surrounding area may also occur. Although the
attack is often dramatic and painful, it is usually selflimited and lasts only several days. After each attack,
long asymptomatic intervals may occur, which are referred to as the intercritical period.8 This stage may last
many years and, in some cases, patients have persistent
hyperuricemia and low-grade inflammation in the
joints.9 Gout attacks can be precipitated by rapid
changes in the serum urate level caused by trauma,
alcohol consumption, medications, and increased consumption of purine-rich foods (eg, hospitalized patients such as those admitted for a myocardial infarction or surgery who are not on their usual diet).
As the disease progresses, the intercritical periods of
gout become shorter and attacks occur more often,
40 Hospital Physician January 2006
Figure 2. Arthritis of the hands. Note the distribution of the
arthritis. The metacarpophalangeal and proximal interphalangeal joints are predominantly affected, as in rheumatoid
arthritis.
eventually leading to the last stage, advanced or chronic
tophaceous gout. Patients often complain of constant
pain and swelling in the joints. The clinical features of
chronic gouty arthritis can be similar to rheumatoid
arthritis (Figure 2), but in gouty arthritis, plain radiographs of the joints show distinctive submarginal erosions with “overhanging edges,” atrophic and hypertrophic features, and minimal periarticular osteopenia
(Figure 3). Also, deposition of clusters of urate crystals
in soft tissues, known as tophi, can occur (Figure 4).
While tophi can form anywhere in the body, commonly
involved sites are the olecranon bursa, fingers, wrists,
and sometimes the helix of the ear.
In chronic gout, urate deposition in the kidneys can
also cause renal problems, such as urate renal stones
(10%–25% of all patients with gout) and urate nephropathy, which can lead to progressive renal failure.6
DIAGNOSTIC EVALUATION
The definitive diagnosis of gout is made by verifying
the presence of monosodium urate crystals in neutrophils from synovial fluid obtained from the affected
joint (via aspiration). Uric acid crystals are needleshaped and, under a compensated polarizing microscope, are yellow and negatively birefringent when
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Sunkureddi et al : Clinical Signs of Gout : pp. 39 – 42, 47
Figure 4. A large tophus at the olecranon in a patient with
chronic gouty arthritis.
Figure 3. Radiograph of the left hand in a patient with
chronic gouty arthritis showing erosions in the second metacarpophalangeal joint, third proximal interphalangeal joint,
and the distal radius. Note the joint space narrowing, the cystic lesions, the lack of periarticular osteopenia, and the submarginal location of the erosions. (Reprinted with permission
from American College of Rheumatology. ACR slide collection on the rheumatic diseases. 3rd ed. Atlanta: The College;
2004. Copyright © 1972 – 2004 American College of
Rheumatology Clinical Slide Collection.)
parallel to the plane of the polarizing lens (Figure 5).
Cell count of the synovial fluid typically shows an inflammatory exudate, with leukocyte counts ranging
from 5000 to 80,000 cells/µL and with neutrophilic predominance. The synovial fluid should also be evaluated
for infection with Gram stain and culture because septic
arthritis can rarely occur with acute gouty arthritis.
Serum uric acid levels should be checked, but an
elevated serum uric acid level is not required to establish the diagnosis of acute gout. Although most patients will demonstrate hyperuricemia, a small number
of patients may have a normal uric acid level at the
time of an attack.10 A 24-hour urine collection for uric
acid is not routinely performed in the initial evaluation
but can be done when uricosuric therapy is being considered. Radiography of the affected joint in acute gout
may reveal soft tissue swelling but no characteristic
bone or joint abnormalities.
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Figure 5. Under a compensated polarizing microscope, urate
crystals are needle-shaped, and they appear blue when perpendicular to the plane of the polarizing lens compensator (A), disappear when in the plane (B), and are yellow when parallel to the
plane (C). (Reprinted with permission from American College of
Rheumatology. ACR slide collection on the rheumatic diseases.
3rd ed. Atlanta: The College; 2004. Copyright © 1972 – 2004
American College of Rheumatology Clinical Slide Collection.)
The American College of Rheumatology criteria for
the classification of acute gouty arthritis state that the
diagnosis of gout can be made based on clinical, laboratory, and/or radiographic findings without demonstration of crystals (Table 2).11 However, if a synovial
fluid analysis is not performed, other conditions that
can mimic acute gout, such as rheumatoid arthritis,
pseudogout, septic arthritis, trauma, and avascular
necrosis, cannot be definitively ruled out.
MANAGEMENT OF ACUTE GOUT
Nonsteroidal anti-inflammatory drugs (NSAIDs)
can effectively treat acute gout attacks and are typically
used as first-line therapy. Oral indomethacin has traditionally been the NSAID of first choice, initially administered at a dose of 50 to 75 mg and then 50 mg every
6 hours thereafter (maximum of 200 mg in 24 h). However, other NSAIDs, including the cyclooxygenase-2
selective agents, are effective as well.12 In general,
NSAIDs should be started as soon as possible after a
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Table 2. Criteria for the Classification of Acute Gouty
Arthritis
A.
The presence of characteristic urate crystals in the joint fluid,
or
B.
A tophus proved to contain urate crystals by chemical means
or polarized light microscopy, or
C.
The presence of 6 of the following clinical, laboratory, and/or
radiographic features:
More than 1 attack of acute arthritis
Maximal inflammation developed within 1 day
Attack of monoarticular arthritis
Joint redness
First metatarsophalangeal joint painful or swollen
Unilateral attack involving first metatarsophalangeal joint
Unilateral attack involving tarsal joint
Suspected tophus
Hyperuricemia
Asymmetric swelling within a joint (shown on radiography)
Subcortical cysts without erosions (shown on radiography)
D.
Negative culture of joint synovial fluid for microorganisms
during attack of joint inflammation
Adapted with permission from Wallace SL, Robinson H, Masi AT, et al.
Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum 1977;20:895–900.
gout attack occurs and continued for 24 to 48 hours
after the inflammation subsides. Because of the increased risk for gastrointestinal (GI) toxicity and renal
damage with NSAIDs, caution must be exercised in
high-risk patients, such as the elderly and those with
underlying GI or renal disease.
For patients unable to tolerate NSAIDs, corticosteroids are an effective alternative and can be given orally,
intra-articularly, or intramuscularly. Intra-articular injection of trimacinolone (10–40 mg) with lidocaine can
provide prompt relief in monoarticular gout. Systemic
corticosteroids (triamcinolone 80 mg given intramuscularly or 3–5 days of prednisone 20–40 mg) can be used
in patients with polyarticular gout. Adrenocorticotropic
hormone has also been used to treat acute gout.13
Although effective for treating acute gout, the use of
colchicine is limited by serious side effects and a frequent administration schedule. Colchicine 0.6 mg orally must be given every hour until symptoms have resolved, side effects have developed, or a maximum
dose of 6 g has been given. Most patients develop GI
side effects, such as nausea, vomiting, abdominal pain,
and diarrhea, prior to resolution of the arthritis. Use of
intravenous colchicine can avoid some GI toxicity, but
the risk for toxicity is still high; it is contraindicated in
patients with hepatic disease, renal failure, prior use of
colchicine, or bone marrow suppression. For prophylaxis against recurrent attacks, colchicine 0.6 mg daily
is effective and is usually continued until the serum
uric level is below 6.0 mg/dL or after 6 months.
MANAGEMENT OF HYPERURICEMIA
The management of hyperuricemia is an essential
component of the overall treatment of gout. Uratelowering agents not only control hyperuricemia but also
can reverse urate deposition. Many experts recommend
treatment of hyperuricemia with urate-lowering agents
if a patient has tophi, 2 or more arthritis attacks per year,
erosive arthritis seen on radiography, or renal calculi.14
Allopurinol lowers serum urate levels by inhibiting
urate production and is a competitive inhibitor of xanthine oxidase, the last enzyme in the purine metabolism pathway that generates urate. The typical starting
dose of allopurinol is 300 mg/d, and the dose can be
titrated up to 800 mg/d to achieve the desired serum
urate level of 6 mg/dL. Patients with renal insufficiency
should be started at a lower dose (50–100 mg/dL)
with slow titration as tolerated. There is a risk of precipitating an acute gout attack when initiating allopurinol.
It is recommended that patients start or continue prophylactic therapy with either NSAIDs or colchicine
when starting urate-lowering therapy.15 One option is
to continue colchicine 0.6 mg daily for 6 months for
prophylaxis in addition to allopurinol. Febuxostat, a
new nonpurine xanthine oxidase inhibitor, has been
reported to be efficacious and safe; US Food and Drug
Administration approval is pending.16
A less commonly used treatment of hyperuricemia
is probenecid, a uricosuric agent. The typical starting
dose is 500 mg/d, titrated up to 3000 mg/d. Prior to
starting therapy with a uricosuric agent, a 24-hour
urine collection for uric acid should be performed.
Typical indications for probenecid are urinary uric
acid excretion of below 800 mg/24 h, age 60 years or
younger, normal renal function, and no history of
renal calculi.6 Xanthine oxidase inhibitors and uricosuric agents can be combined if serum urate levels are
not reduced below 6 mg/dL on a single agent. Typically, patients continue on urate-lowering therapy indefinitely. Currently, urate-lowering therapy is not indicated for asymptomatic hyperuricemia.
ADVERSE EFFECTS OF GOUT THERAPY
Adverse reactions reported with allopurinol include
GI intolerance, bone marrow suppression, and skin
rashes. Another severe adverse effect is the allopurinol
hypersensitivity syndrome, which is characterized by a
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Sunkureddi et al : Clinical Signs of Gout : pp. 39 – 42, 47
(from page 42)
skin rash, hepatitis, eosinophilia, fever, renal failure,
and possibly death. Patients with underlying renal insufficiency and those taking diuretics are mostly likely to
develop the allopurinol hypersensitivity syndrome. Also,
patients taking azathioprine or 6-mercaptopurine
should avoid allopurinol or substantially reduce their
dose because of the risk of bone marrow suppression.
Chronic colchicine therapy has been associated with
rhabdomyolysis and a painful axonal neuromyopathy
and should be avoided in patients with significant renal
or hepatic disease.17 Probenecid is generally well tolerated, with GI distress being the most common adverse
effect; however, it alters the metabolism of many drugs,
including penicillin, heparin, and indomethacin.
10.
CONCLUSION
11.
Gout is a systemic disease characterized by manifestations of hyperuricemia, such as inflammatory arthritis,
tophi formation, nephropathy, and nephrolithiasis.
When possible, diagnosis should be made by identifying
characteristic urate crystals in synovial fluid. Therapy for
gout is effective and can dramatically change the course
of the disease. New drugs that are currently under development may provide additional options to treat gout in
HP
patients not amenable to current therapies.
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