Definition

Gout is a syndrome characterised by: hyperuricaemia and deposition

of urate crystals causing attacks of acute inflammatory arthritis; tophi around
the joints and possible joint destruction; renal glomerular, tubular and
interstitial disease; and uric acid urolithiasis. The disease most commonly
affects the first toe (podagra), foot, ankle, knee, fingers, wrist, and elbow;
however, it can affect any joint.

Causes

Gout occurs when urate crystals accumulate in your joint, causing the
inflammation and intense pain of a gout attack. Urate crystals can form when
you have high levels of uric acid in your blood.

Your body produces uric acid when it breaks down purines

substances that are found naturally in your body.Purines are also found in
certain foods, such as steak, organ meats and seafood. Other foods also
promote higher levels of uric acid, such as alcoholic beverages, especially
beer, and drinks sweetened with fruit sugar (fructose).

Normally, uric acid dissolves in your blood and passes through your
kidneys into your urine. But sometimes either your body produces too much
uric acid or your kidneys excrete too little uric acid. When this happens, uric
acid can build up, forming sharp, needlelike urate crystals in a joint or
surrounding tissue that cause pain, inflammation and swelling.
Symptoms

The signs and symptoms of gout almost always occur suddenly, and often at
night. They include:

 Intense joint pain. Gout usually affects the large joint of your big toe,
but it can occur in any joint. Other commonly affected joints include the
ankles, knees, elbows, wrists and fingers. The pain is likely to be most
severe within the first four to 12 hours after it begins.

 Lingering discomfort. After the most severe pain subsides, some joint
discomfort may last from a few days to a few weeks. Later attacks are
likely to last longer and affect more joints.

 Inflammation and redness. The affected joint or joints become swollen,

tender, warm and red.

 Limited range of motion. As gout progresses, you may not be able to

move your joints normally.

Risk factors

You're more likely to develop gout if you have high levels of uric acid in
your body. Factors that increase the uric acid level in your body include:

a. Diet. Eating a diet rich in meat and seafood and drinking beverages
sweetened with fruit sugar (fructose) increase levels of uric acid, which
increase your risk of gout. Alcohol consumption, especially of beer,
also increases the risk of gout.
b. Obesity. If you're overweight, your body produces more uric acid and
your kidneys have a more difficult time eliminating uric acid.
 c. Medical conditions. Certain diseases and conditions increase your risk
of gout. These include untreated high blood pressure and chronic
conditions such as diabetes, metabolic syndrome, and heart and
kidney diseases.
d. Certain medications. The use of thiazide diuretics commonly used to
treat hypertension and low-dose aspirin also can increase uric acid
levels. So can the use of anti-rejection drugs prescribed for people
who have undergone an organ transplant.
e. Family history of gout. If other members of your family have had gout,
you're more likely to develop the disease.
f. Age and sex. Gout occurs more often in men, primarily because
women tend to have lower uric acid levels. After menopause, however,
women's uric acid levels approach those of men. Men are also more
likely to develop gout earlier usually between the ages of 30 and 50
whereas women generally develop signs and symptoms after
menopause.
g. Recent surgery or trauma. Experiencing recent surgery or trauma has
been associated with an increased risk of developing a gout attack.

Complications

People with gout can develop more-severe conditions, such as:

a. Recurrent gout. Some people may never experience gout signs and
symptoms again. Others may experience gout several times each
year. Medications may help prevent gout attacks in people with
recurrent gout. If left untreated, gout can cause erosion and
destruction of a joint.
 b. Advanced gout. Untreated gout may cause deposits of urate crystals to
form under the skin in nodules called tophi (TOE-fie). Tophi can
develop in several areas such as your fingers, hands, feet, elbows or
Achilles tendons along the backs of your ankles. Tophi usually aren't
painful, but they can become swollen and tender during gout attacks.
c. Kidney stones. Urate crystals may collect in the urinary tract of people
with gout, causing kidney stones. Medications can help reduce the risk
of kidney stones.

Prevention

During symptom-free periods, these dietary guidelines may help protect

against future gout attacks:

a. Drink plenty of fluids. Stay well-hydrated, including plenty of water.

Limit how many sweetened beverages you drink, especially those
sweetened with high-fructose corn syrup.
b. Limit or avoid alcohol. Talk with your doctor about whether any amount
or type of alcohol is safe for you. Recent evidence suggests that beer
may be particularly likely to increase the risk of gout symptoms,
especially in men.
c. Get your protein from low-fat dairy products. Low-fat dairy products
may actually have a protective effect against gout, so these are your
best-bet protein sources.
d. Limit your intake of meat, fish and poultry. A small amount may be
tolerable, but pay close attention to what types — and how much —
seem to cause problems for you.
e. Maintain a desirable body weight. Choose portions that allow you to
maintain a healthy weight. Losing weight may decrease uric acid levels
 in your body. But avoid fasting or rapid weight loss, since doing so may
temporarily raise uric acid levels.

Diagnosis

Tests to help diagnose gout may include:

 Joint fluid test. Your doctor may use a needle to draw fluid from your
affected joint. Urate crystals may be visible when the fluid is examined
under a microscope.

 Blood test. Your doctor may recommend a blood test to measure the
levels of uric acid and creatinine in your blood. Blood test results can be
misleading, though. Some people have high uric acid levels, but never
experience gout. And some people have signs and symptoms of gout,
but don't have unusual levels of uric acid in their blood.

 X-ray imaging. Joint X-rays can be helpful to rule out other causes of
joint inflammation.

 Ultrasound. Musculoskeletal ultrasound can detect urate crystals in a

joint or in a tophus. This technique is more widely used in Europe than in
the United States.

 Dual energy CT scan. This type of imaging can detect the presence of
urate crystals in a joint, even when it is not acutely inflamed. This test is
not used routinely in clinical practice due to the expense and is not
widely available.
Treatment

Gout is the result of monosodium urate crystals in joints, which trigger

the NALP3 (cryopyrin) inflammasome and release of pro-inflammatory
cytokines, especially IL-1β. Gouty arthritis is often intermittent, but can be
chronic, joint destructive and deforming, and persistently painful. Tophi (large
crystal deposits) can form in longstanding disease. Gout affects 1–4% of
adults (it is more common in the USA) and its prevalence is increasing,
probably due to changes in diet, increases in CKD (gout has a higher
prevalence in CKD , obesity, and a longer lifespan. Subjects with serum urate
between 7 and 8 mg/dL (0.40-0.48 mmol/L) have an accumulated risk of
developing gout of 3%, while those above 9 mg/dL (>0.54 mmol/L) have an
accumulated risk of 22%. The American College of Rheumatology guidelines
recommend a serum urate target level of <6 mg/dL (<0.35 mmol/L) in all gout
cases and <5 mg/dL (<0.3 mmol/L) in gout with tophi. The recommendation in
Japan also includes reducing hyperuricaemia, even in the absence of gout,
with lifestyle guidance or drugs if >8 mg/dL (>0.48 mmol/L) and certain
conditions apply . Gout is costly to Society, since those affected are often
absent from work.

Standard treatment consists of acute anti-inflammatory drugs for gouty

flares, followed by the long-term urate-lowering therapy. Anti-inflammatory
treatment aims at reducing the pain and swelling. Established treatments are
NSAIDs and sometimes corticosteroids. Colchicine can be used as gout
prophylaxis, especially when urate-lowering therapy is first introduced, but it
is also used for acute gout. Drugs targeting IL-1β are also effective in acute
gout (e.g. rilonacept and canakinumab).

Primary urate-lowering therapy (Figure 1) is often initiated with a XO

inhibitor such as allopurinol or febuxostat, but the number of patients
achieving serum urate levels <6 mg/dL (<0.35 mmol/L) is in the range of 20-
40% for allopurinol and 45–67% for febuxostat (Phase III data, indicating the
need for additional therapies. Moreover, allopurinol can have both dose-
related (e.g., gastrointestinal intolerance, rashes) and idiosyncratic side
effects, which can be life-threatening and may by more frequent in Asians.
Examples of non-specific uricosuric drugs are the older URAT1 inhibitors
probenecid (which also inhibits OAT1 and 3), which is still available in some
countries, and benzbromarone, which has largely been withdrawn because of
liver toxicity. Uricosuric drugs in clinical development are mainly URAT1
inhibitors, i.e., lesinurad (Phase III), arhalofenate (Phase II and also in
development for diabetes), levotofisopam (Phase II and the S-enantiomer of
RS-tofisopam, an anxiolytic agent used in some countries) and RDEA3170
(Phase I). Lesinurad can achieve target serum urate levels when given with
allopurinol or febuxostat in 60-100% of the patients, according to available
Phase II data. Use of the non-absorbable phosphate binder sevelamer can
also decrease serum urate in haemodialysis patients, most likely the result of
increased gastrointestinal elimination. BCX4208, an inhibitor of purine
nucleotide phosphorylase (an enzyme ‘higher up’ in the purine metabolic
pathway), is in Phase II trial . There are two pegylated uricase derivatives:
pegloticase is approved for patients refractory to conventional treatments
(mainly used in severe tophaceous gout) and pegadricase has been in Phase
I trial and may still be in development . These emerging therapies are aiming
to improve efficacy and reduce side effects.

Treatment for gout usually involves medications. What medications

you and your doctor choose will be based on your current health and your
own preferences.Gout medications can be used to treat acute attacks and
prevent future attacks. Medications can also reduce your risk of complications
from gout, such as the development of tophi from urate crystal deposits.
Medications to treat gout attacks

Drugs used to treat acute attacks and prevent future attacks include:

 Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs include over-

the-counter options such as ibuprofen (Advil, Motrin IB, others) and
naproxen sodium (Aleve), as well as more-powerful prescription NSAIDs
such as indomethacin (Indocin) or celecoxib (Celebrex).

Your doctor may prescribe a higher dose to stop an acute attack,

followed by a lower daily dose to prevent future attacks.

NSAIDs carry risks of stomach pain, bleeding and ulcers.

 Colchicine. Your doctor may recommend colchicine (Colcrys, Mitigare),

a type of pain reliever that effectively reduces gout pain. The drug's
effectiveness may be offset, however, by side effects such as nausea,
vomiting and diarrhea, especially if taken in large doses.

After an acute gout attack resolves, your doctor may prescribe a low
daily dose of colchicine to prevent future attacks.

 Corticosteroids. Corticosteroid medications, such as the drug

prednisone, may control gout inflammation and pain. Corticosteroids
may be in pill form, or they can be injected into your joint.

Corticosteroids are generally used only in people with gout who can't
take either NSAIDs or colchicine. Side effects of corticosteroids may
include mood changes, increased blood sugar levels and elevated blood
pressure.
Medications to prevent gout complications

If you experience several gout attacks each year, or if your gout attacks
are less frequent but particularly painful, your doctor may recommend
medication to reduce your risk of gout-related complications. If you already
have evidence of damage from gout on joint X-rays, or you have tophi,
chronic kidney disease or kidney stones, medications to lower your body's
level of uric acid may be recommended. Options include:

 Medications that block uric acid production. Drugs called xanthine

oxidase inhibitors (XOIs), including allopurinol (Aloprim, Lopurin,
Zyloprim) and febuxostat (Uloric), limit the amount of uric acid your body
makes. This may lower your blood's uric acid level and reduce your risk
of gout.

Side effects of allopurinol include a rash and low blood counts.

Febuxostat side effects include rash, nausea, reduced liver function and
an increased risk of heart-related death.

 Medication that improves uric acid removal. These drugs, called

uricosurics, include probenecid (Probalan) and lesinurad (Zurampic).
Uricosuric drugs improve your kidneys' ability to remove uric acid from
your body. This may lower your uric acid levels and reduce your risk of
gout, but the level of uric acid in your urine is increased. Side effects
include a rash, stomach pain and kidney stones. Lesinurad can be taken
only along with an XOI.
Education

Lifestyle and home remedies

Medications are often the most effective way to treat acute gout and can
prevent recurrent attacks of gout. However, making certain lifestyle changes
also are important, such as:

 Limiting alcoholic beverages and drinks sweetened with fruit sugar

(fructose). Instead, drink plenty of nonalcoholic beverages, especially
water.

 Limiting intake of foods high in purines, such as red meat, organ meats
and seafood.

 Exercising regularly and losing weight. Keeping your body at a healthy

weight reduces your risk of gout.

Alternative medicine

If gout treatments aren't working as well as you'd hoped, you may be

interested in trying an alternative approach. Before trying such a treatment on
your own, talk with your doctor — to weigh the benefits and risks and learn
whether the treatment might interfere with your gout medication.

Because there isn't a lot of research on alternative therapies for gout,

however, in some cases the risks aren't known.Certain foods have been
studied for their potential to lower uric acid levels, including:
  Coffee. Studies have found an association between coffee drinking
both regular and decaffeinated coffee and lower uric acid levels, though
no study has demonstrated how or why coffee may have such an effect.

The available evidence isn't enough to encourage noncoffee drinkers to

start, but it may give researchers clues to new ways of treating gout in
the future.

 Vitamin C. Supplements containing vitamin C may reduce the levels of

uric acid in your blood. However, no studies have demonstrated that
vitamin C affects the frequency or severity of gout attacks.

Talk to your doctor about what a reasonable dose of vitamin C may be.
And don't forget that you can increase your vitamin C intake by eating
more vegetables and fruits, especially oranges.

 Cherries. Cherries have been reported to lower levels of uric acid, as

well as reduce the number of gout attacks. However, more research
needs to be done to confirm this. Eating more cherries and drinking
cherry extract may be a safe way to supplement your gout treatment, but
discuss it with your doctor first.

Other complementary and alternative medicine treatments may help you

cope until your gout pain subsides or your medications take effect. For
instance, relaxation techniques, such as deep-breathing exercises and
meditation, may help take your mind off your pain.

THE PHYSICAL EXAMINATION FOR GOUT

Examination of patients with a history suggestive of gout should

include not only the joints but also the extensor surface of the forearms and
feet. When patients are seen for a visit and gout is suspected, they should be
instructed to remove their shoes and socks and roll up their sleeves to allow
examination for evidence of tophi, which would suggest a past history of
gouty arthritis. The ear, knee, and olecranon bursa are other common sites
for tophi, so patients should also be asked to roll up their pants and sleeves
and remove any head coverings. In the late stages of gouty arthritis, multiple
joints may be involved, which can cause the condition to be confused with
other diagnoses such as psoriatic arthritis or erosive osteoarthritis.

Pathophysiology

The initial trigger of the ‘inflammasome’ is from the effect of

monosodium urate crystals on cells of the monocyte/macrophage lineage.
This leads (via the NALP3 inflammasome) to secretion of IL-1β, which then
acts to recruit more inflammatory cells. The detailed mechanism underlying
the secretion of IL-1β is not known, but cell damage leading to ATP release
and activation of the P2X7 receptor may be involved. Potassium efflux may
also be important, as well as generation of reactive oxygen species (ROS).
Released IL-1β recruits other inflammatory cells and so amplifies the
inflammatory reaction. The result is a burst of inflammatory mediator release.
The inflammation spontaneously resolves, perhaps mediated by release of
the anti-inflammatory cytokine TGF-β. The inflammasome is considered to be
essential in gout and other crystalopathies, but its role in any associated
pathology is less clear. It is also unclear if hyperuricaemia alone can initiate
other pathological processes. What information is available, will be included
with the discussion of various diseases associated with hyperuricaemia.

Multivariate analysis has been used to assess if serum urate is an

independent risk factor for disease. A positive association has been found
between urate levels and a number of important disorders, including
hypertension, CKD, CHF, the metabolic syndrome, T2DM, endothelial cell
dysfunction, cardiovascular events, and fatty liver disease. The strength of
these associations will be discussed below. There are also a few intervention
studies, mostly with allopurinol, but these are small and may not be
representative of the effects of lowering urate by different mechanisms.

It is important to mention that urate also plays an essential function in

humans. The loss of uricase in higher primates parallels the similar loss of
our ability to synthesize ascorbic acid, an important anti-oxidant, leading to
the suggestion that urate may partially substitute for ascorbate in humans.
Both uric acid and ascorbic acid are strong reducing agents (electron donors)
and potent antioxidants. In humans, the major extracellular antioxidant
capacity of blood comes from urate, but urate can also be pro-oxidant
depending on the conditions (see also below under the metabolic syndrome).
Epidemiological data suggest that urate may be important in neuroprotection.
The brain is vulnerable to oxidative stress due to its high metabolic rate and
high levels of unsaturated fatty acids. Thus, increased lipid peroxidation could
be one explanation for the association found between reduced serum urate
levels and CNS disorders such as multiple sclerosis (MS), AML, Parkinson’s,
Alzheimer’s and Huntington’s diseases. Patients with MS have significantly
lower serum urate levels and there seem to be no reported cases of patients
suffering from both MS and gout.

Conclusion

The present review of the available literature shows that there is an

association between serum urate levels and hypertension, CKD, heart failure,
the metabolic syndrome, obesity and cardiovascular events. However, as is
often the case in the published literature, support is not unanimous.
Understanding in the field is hampered by the difference in urate metabolism
between laboratory animals and man, which makes animal studies difficult to
interpret. Thus, there is limited evidence for a causal relationship. The
interventional studies in man can be considered more as hypothesis-
generating, since design quality, duration, and sample size are often
insufficient to clarify the role of urate in cardiovascular disease. In addition,
most interventional studies are with allopurinol, which is lowering urate via
inhibition of XO, leading to decreased production of ROS, which may have
contributed to any apparent beneficial effect. A definitive answer to the
question of whether urate-lowering therapy can reduce cardiovascular
morbidity and mortality will, in the end, require large interventional trials, but it
is doubtful that the safety profile of allopurinol is sufficient for such large-scale
studies. The recently approved and emerging novel urate-lowering agents
may have a better safety profile for these much needed larger and longer-
term studies. Ideally, these studies would compare cardiovascular endpoints
in patients treated with placebo versus XO and/or URAT1 inhibition, to
establish both the benefits and mechanisms of treating hyperuricaemia.
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