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In This Report

•	Highlights
•	Introduction
•	Causes
•	Symptoms
•	Complications
•	Risk Factors
•	Diagnosis
•	Treatment
•	Medications
•	Lifestyle Changes
•	Resources
•	References

Related Reports

•	Osteoarthritis
•	Rheumatoid Arthritis
•	Foot Pain

Encyclopedia

•	Acute gouty arthritis
•	Chronic gouty arthritis
•	Pseudogout

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Gout

Highlights

Disease Overview

Gout is one of the most painful forms of arthritis. It may be classified as primary or secondary (caused by other conditions).

There are four stages of the disease. With treatment, most people can avoid progression to the later stages.

• Asymptomatic hyperuricemia – increased levels of uric acid in the blood, but no symptoms. This stage may last 30 years, and does not always lead to gout. People with asymptomatic hyperuricemia do not usually require treatment.
• Acute gout, or acute gouty arthritis – uric acid crystals in the joints cause intense attacks of pain, swelling, and other symptoms. Attacks may last for hours to days, or even several weeks, although most subside within 5 to 7 days. Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are the most common treatments for acute gout.
• Intercritical gout – the periods between attacks. People do not have symptoms during intercritical periods. NSAIDs and colchicine are commonly used to prevent future attacks.
• Chronic tophaceous gout – if gout continues untreated, the intercritical periods become shorter, and pain becomes chronic. Knobby crystal deposits may form in the joints, outer ear, and other locations. Drugs such as allopurinol (which reduces the body’s production of uric acid) and uricosurics (which increase excretion of uric acid) are used to reduce blood levels of uric acid during this stage.

Recent Research

Vitamin C.Researchers have found that taking 500 mg/day vitamin C significantly reduces uric acid levels. Researchers are investigating whether vitamin C can prevent or treat gout.

Association with coronary artery disease.A mechanism involving the breakdown of cholesterol may contribute to both gout and a higher than normal risk of atherosclerosis and coronary artery disease. Allopurinol has the positive side effect of reducing “bad” cholesterol, and therefore may be better than other drugs for patients with both gout and coronary artery disease.

Introduction

Gout is an arthritic condition that causes inflammation of the joints. It mostly affects men over 40 and is usually associated with chronic hyperuricemia, a long-lasting abnormally high concentration of uric acid in the blood.

Click the icon to see an animation about gout.

The Processes Leading to Hyperuricemia and Gout

Metabolism of Purines. The process leading to hyperuricemia and gout begins with the metabolism of purines, nitrogen-containing compounds that are important for energy. Purines can be divided into two types:

• Endogenous purines are manufactured within human cells.
• Exogenous purines are obtained from foods.

All mammals except humans possess an enzyme called uricase that breaks purines down so they can be dissolved and eliminated easily from the body. In humans, however, purine breaks down into uric acid, which is not as easily eliminated and can build up in body tissues.

Uric Acid and Hyperuricemia. The path leading to high concentrations of uric acid and gout is the following:

• Uric acid is produced from purines in the liver. It then enters the bloodstream. Most uric acid then eventually passes through the kidneys and is excreted in the urine. The rest is disposed of in the intestines, where it is processed and broken down by bacteria.
• Normally these processes keep the concentration of uric acid in the blood plasma (the liquid part of the blood) at a healthy level, which is below 6.8 mg/dL.
• Under certain circumstances, however, the body produces too much uric acid or excretes too little. In either case, concentrations of uric acid increase in the blood. This condition is known as hyperuricemia.
• If concentrations of uric acid reach 7 mg/dL and above, the blood becomes supersaturated. Needlelike crystals of a salt called monosodium urate (MSU) form.
• In time, as MSU crystals accumulate in the joints, they cause inflammation and pain, the characteristic symptoms of gout.

Gout and Other Conditions Associated with Hyperuricemia

High levels of uric acid are associated not only with gout, but also with a number of other conditions. They can occur independently, but may also develop one after the other if gout is untreated.

Acute Gouty Arthritis. Acute gouty arthritis is the stage at which the first symptoms of gout appear. It most often occurs in men.

Chronic Tophaceous Gout and Tophi. After several years, persistent gout can develop into a condition called chronic tophaceous gout. This long-term condition often produces tophi, which are solid deposits of MSU crystals that form in the joints, cartilage, bones, and elsewhere in the body. In some cases, tophi break through the skin and appear as white or yellowish-white, chalky nodules that have been described as looking like crab eyes.

Without treatment, tophi develop on average about 10 years after the initial onset of gout, although their first appearance can range from three to 42 years. They are more apt to appear early in the course of the disease in older people. In the elderly population, women appear to be at higher risk for tophi than men.

Click the icon to see an image of tophi gout.

Today, drug therapy has reduced the prevalence of chronic tophaceous gout to as little as 3% of patients. Certain groups, such as transplant patients receiving cyclosporine, however, still face a high risk of developing tophi.

Uric Acid Nephrolithiasis (Kidney Stones). Uric acid nephrolithiasis occurs when kidney stones form from uric acid. In one study, patients with these stones were more likely to have elevated levels of uric acid in their blood than in their urine, suggesting that gout is responsible for these stones. Uric acid and other kidney stones are present in 10 - 25% of patients with primary gout, a prevalence more than 1,000 times that of the general population. In gout caused by other conditions (called secondary gout), the reported incidence reaches 42%.

Click the icon to see an image of nephrolithiasis.

Uric acid stones can also form in the absence of gout or hyperuricemia. Also, not all of the kidney stones in patients with gout are composed of uric acid; some are composed of calcium oxalate, calcium phosphate, or those substances combined with uric acid.

Chronic Uric Acid Interstitial Nephropathy. Chronic uric acid interstitial nephropathy occurs when crystals slowly form in the structures and tubes that carry fluid from the kidney. It is reversible and not likely to injure the kidneys.

Kidney Failure. Sudden overproduction of uric acid can occasionally block the kidneys and cause them to fail. This occurrence is very uncommon but can occur with the following conditions:

• After chemotherapy for leukemia or lymphoma.
• After severe heat stress from vigorous exercise.
• Following epileptic seizures.
• After corticosteroid therapy for severe allergic reactions.

Causes

Gout is classified as either primary or secondary, depending on what causes the high levels of uric acid in the blood (hyperuricemia). In both types of gout, between 70 - 95% of hyperuricemia cases occur when the body doesn't get rid of (excrete) enough uric acid, rather than uric acid over-production.

Many people develop hyperuricemia, but not all people with the condition develop gout. Researchers have not yet determined the reason for this, or why gout develops in certain joints but not in others.

Primary Gout

More than 99% of primary gout cases are referred to as idiopathic, meaning that the cause of the hyperuricemia cannot be determined. They are most likely due to a combination of hormonal and genetic factors that cause metabolic abnormalities resulting in overproduction of uric acid or reduced excretion of uric acid. Consumption of certain purine-rich foods and certain alcoholic beverages may also contribute to primary gout. The remaining 1% of primary gout cases are traceable to either of two rare inherited enzyme defects that affect purine synthesis in the cells. One in five people with gout has a family history of the disease.

Secondary Gout

In secondary gout, hyperuricemia is caused by drug therapy or by medical conditions other than an inborn metabolic disorder that increase uric acid concentration.

Alcohol Use. Alcohol use, especially beer consumption, is a major contributor to gout and increases uric acid levels in three ways:

• By providing an additional dietary source of purines (the compounds from which uric acid is formed)
• By intensifying the body’s production of uric acid
• By interfering with the kidneys’ ability to excrete uric acid

Renal (Kidney) Insufficiency and Its Causes. Hyperuricemia occurs in 30 - 85% of people who have renal (kidney) insufficiency. Renal insufficiency is a major cause of gout in older people. This results in an impaired ability of the kidneys to eliminate waste products, including uric acid, which then build up in the blood. This condition, in turn, can be the result of the following:

The kidneys are responsible for removing waste from the body, regulating electrolyte balance and blood pressure, and the stimulation of red blood cell production.

• Thiazide diuretics (the “water pills” used to control hypertension). These agents are very highly associated with gout. In fact, 75% of elderly-onset gout patients report the use of diuretics.
• Organ transplantation. Kidney transplantation poses a high risk for renal insufficiency and gout. In addition, other transplantation procedures, such as heart and liver, increase the risk. The procedure itself poses a risk. In addition, cyclosporine an immunosuppressive agents used after these procedures to help prevent rejection of the implant, poses a particular risk for gout. It also interacts with indomethacin, a common gout treatment. (Alternative agents, such as tacrolimus, may be effective and pose less of a risk of gout.)

Other Medications. The list of drugs that cause hyperuricemia is long. In addition to diuretics and immunosuppressants, other agents that increase the risk for gout include the following:

• Pyrazinamide (used to treat tuberculosis).
• Aspirin. Low doses (not high doses) of aspirin reduce uric acid excretion and increase the chance for hyperuricemia. This may be a problem for older people who take baby aspirin (81 mg) to protect against heart disease. (High doses have the opposite effect.)
• Niacin.

Exposure to Lead. Chronic occupational exposure to lead is associated with build-up of uric acid and a high incidence of gout. A 2002 study suggested that persistent low-level exposure to lead may also increase the risk for gout.

Other Conditions. A number of other conditions can cause gout. They include:

• Leukemia
• Lymphoma
• Psoriasis

Symptoms

Gout is often divided into four symptomatic stages:

• Asymptomatic hyperuricemia
• Acute gouty arthritis
• Intercritical gout
• Chronic tophaceous gout

These stages may differ depending on the age of onset:

• In middle-aged adults, symptoms are more likely to occur in one joint, most often in the lower limbs. About 60% of cases in this age group first occur in the big toe.
• In elderly people, symptoms are more likely to occur in a number of joints in the upper extremities, particularly the fingers.

Asymptomatic Hyperuricemia

Asymptomatic hyperuricemia, in which MSU slowly builds up, always precedes gout and is considered the first stage of the disorder. It lasts for an average of 30 years.

Note: Hyperuricemia does not inevitably lead to gout. In fact, less than 20% of the hyperuricemic population develops the full-blown arthritic disease.

Acute Gouty Arthritis

Acute gouty arthritis occurs when the first symptoms of gout appear. Sometimes gout is heralded by brief twinges of pain (petit attacks) in an affected joint, which can precede the actual full-blown condition by several years. MSU crystals form at normal body temperature when concentrations in the blood reach 7 mg/dL. At lower temperatures, crystals form at lower concentrations. Since blood temperature falls with distance from the heart, gout strikes the toes and fingers first.

The symptoms of acute gouty arthritis are described as follows:

• The primary symptom is severe pain at and around the joint. Some patients describe it "crushing" or resembling a dislocated bone. The area can be so tender that walking and even the weight of bed sheets can be unbearable. One writer described gout in the toe as feeling like “walking on my eyeballs.” The pain usually takes 8 to 12 hours to develop. In many cases the attack occurs late at night or early in the morning and may awaken the patient from sleep.
• Swelling may extend beyond the joint, indicating fluid build-up within.
• The skin over the affected area is often red, shiny, and tense. After a few days it may start to peel.
• Chills and mild fever, loss of appetite, and feelings of ill health may occur with an attack.

Most often symptoms first start in one joint, a condition is called monoarticular gout. If more than one joint is affected, it is known as polyarticular gout. (Multiple joints are affected in only 10 - 20% of first attacks.)

Monoarticular Gout. The joint of the big toe is the site of about 60% of all f irst monoarticular gout attacks in middle-aged adults. This occurrence is known as podagra. (The site is medically referred to as the big toe’s metatarsophalangeal joint, the point where one of the five long bones of the foot meets the first digit of a toe.) Symptoms can also occur in other locations, although most often they develop somewhere on one lower limb in middle-aged men.

Polyarticular Gout. Older people are more likely to have polyarticular gout. In this condition, the joints of the foot, ankle, knee, wrist, elbow, and hand are the most frequently affected. The pain usually occurs in joints on one side of the body and it is usually, although not always, in the lower extremities. People with polyarticular gout are more likely to have a more gradual onset of pain and a longer delay between attacks. Older people are at higher risk for polyarticular gout than younger adults and it tends to occur in the upper extremities, often in the fingers. People with polyarticular gout are also more likely to experience the low-grade fever, loss of appetite, and a general feeling of poor health.

An untreated attack will typically peak 24 to 48 hours after the initial appearance of symptoms, and subside after 5 to 7 days, although it can last only hours or as long as several weeks.

Intercritical Gout

Intercritical gout is the term used to describe the periods between attacks. The first attack is usually followed by a complete remission of symptoms, but left untreated, gout nearly always recurs at some point in the future. One study reported that 62% of subjects experienced at least one further attack within a year. At the end of two years, 78% of patients experienced a recurrence. After 10 years, 93% of the patients had had repeat attacks.

Symptoms of Chronic Tophaceous Gout

Development of Chronic Pain. When gout remains untreated, the intercritical periods typically become shorter and shorter, and the attacks, although sometimes less intense, can last longer. Over the long term (about 10 to 20 years) gout becomes a chronic disorder characterized by constant low-grade pain and mild or acute inflammation. Gout may eventually affect several joints, including those that may have been free of symptoms at the first appearance of the disorder. In rare cases, the shoulders, hips, or spine are affected.

Symptoms of Tophi. Tophi, the knobby MSU crystal deposits that form during chronic gout, generally form in the following locations:

• Helix of the outer ear (the curved ridge along the edge of the ear)
• Forearms
• Elbow or knee
• Hands or feet -- older patients, particularly women, are more likely to have gout in the small joints of the fingers
• Around the heart and spine (rare)

Tophi are generally painless. However, they can cause pain and stiffness in the affected joint. Eventually, they can also erode cartilage and bone, ultimately destroying the joint. Large tophi under the skin of the hands and feet can give rise to extreme deformities.

Triggers for Gout Symptoms

Severe illness is an important trigger. Between 20 - 86% of patients with gout experience a recurrence when they are hospitalized. Gout accompanies and can be exacerbated by serious conditions that are associated with kidney and heart disease including diabetes, obesity, unhealthy cholesterol levels, insulin resistance, and high blood pressure.

Gout symptoms may be precipitated by various other conditions including:

• Stress
• Infection
• Joint injury
• Weight loss
• Surgery
• Certain drug treatment
• Overindulgence in alcohol or purine-rich foods
• Overstrenuous exercise

Symptoms occur more frequently in the spring, with the peak in April, according to some studies.

Complications

Gout rarely poses a long-term health threat if properly treated. It does, however, remain a source of short-term pain and incapacity for thousands of Americans.

Pain and Disability

Left untreated, gout can develop into a painful and disabling chronic disorder. Persistent gout can destroy cartilage and bone, causing irreversible joint deformities and loss of motion. Tophi can grow to the size of handballs and can destroy bone and cartilage in the joints, similar to the process in rheumatoid arthritis. If they lodge in the spine, tophi can cause serious damage including compression, although this is very rare. In extreme cases, joint destruction results in complete disability.

Kidney Conditions

Kidney Stones. Kidney stones occur in 10 - 40% of gout patients, and can occur at any time after the development of hyperuricemia. Although the stones are usually composed of uric acid, they may also be mixed with other materials. A 2003 study showed that although a current diagnosis of gout doubles the risk of kidney stones, a history of gout does not increase kidney stone risk. Therefore, reducing gout risk factors with dietary and other lifestyle changes may reduce the likelihood of stone formation.

Kidney stones result when urine becomes too concentrated and substances in the urine crystalize to form stones. Symptoms arise when the stones begin to move down the ureter causing intense pain. Kidney stones may form in the pelvis or calyces of the kidney or in the ureter.

Kidney Disease. About 25% of patients with chronic hyperuricemia develop progressive kidney disease, which sometimes ends in kidney failure. It should be noted, however, that many experts believe that chronic hyperuricemia is unlikely to be a common cause of kidney disease. In most cases, the kidney disease comes first and causes high concentrations of uric acid.

Gout and Heart Disease

Gout often accompanies both risk factors for heart disease and heart disease itself. It is found in higher rates in people with obesity, high blood pressure, coronary artery disease, and congestive heart failure. Hyperuricemia, in fact, has been associated with a higher risk of death from heart conditions. One 2001 study reported that disease activity in gout may even contribute to unhealthy cholesterol and lipid levels. Some interesting evidence, however, suggests that hyperuricemia may occur as a response to inflammatory damage that occurs with heart disease and may even be protective.

Click the icon to see an image of coronary artery blockage.

Other Medical Conditions Associated with Gout

The following are some conditions that are associated with long-term gout:

• Cataracts
• Dry eye syndrome
• Complications in the lungs (in rare cases, uric acid crystals occur in the lungs)

Risk Factors

Risk factors are attributes or activities associated with a greater-than-normal likelihood of developing a particular disorder. Sometimes a causal connection between the attribute or activity and the disorder can be established, but at other times there is simply a statistical correlation. The risk factors for gout, of which there are several, are identical to those for hyperuricemia.

Prevalence

Gout is the second most common inflammatory arthritic condition in older adults. Based on self-reports, gout is estimated to affect about 2.1 million Americans (1.56 million men and 550,000 women). Some experts believe, however, that this may be an overestimate. The prevalence of gout has been rising in recent decades, not only in America but in other developed countries, possibly because of dietary and lifestyle changes, greater use of medications that cause hyperuricemia, and aging populations.

Gout is very uncommon in less-developed countries, however, and in 1952 it was said to be unknown in China, Japan, and the tropics.

Age

Middle-Aged Adults. Gout usually occurs in middle-aged men, peaking in the mid-40s. It is most often associated in this age group with obesity, high blood pressure, unhealthy cholesterol levels, and heavy alcohol use.

Elderly. Gout can also first develop in older people, when it occurs equally in men and women. In this group, gout is most often associated with kidney problems and the use of diuretics. It is less often associated with alcohol use.

Children. Among children, the levels of uric acid in both girls and boys are low, averaging 3 to 4 mg/dL. Except for rare inherited genetic disorders that cause hyperuricemia, gout in children is almost unheard of.

Gender

Men. Men are significantly at higher risk for gout. In males, uric acid levels rise substantially at puberty, with the result that the level exceeds 7 mg/dL (considered to indicate hyperuricemia) in about 5 - 8% of American men. Gout typically strikes only after 20 to 40 years of persistent hyperuricemia, however, so men who develop it usually experience their first attack between the ages of 30 and 50 years. In one study that followed male medical students for 28 years, the prevalence of gout was 5.8% in Caucasian men and 10.9% in African American men.

Women. Before menopause, women have a significantly lower risk for gout than men, possibly because of the actions of estrogen. This female hormone appears to facilitate uric acid excretion by the kidneys. (Only about 15% of female gout cases occur before menopause.) After menopause the risk increases in women so that after age 60 the incidence is equal in men and women, and after 80, gout occurs actually more often in women.

Family History

A fairly substantial proportion of patients with gout (10 - 20%) has a family history of gout. According to a 2001 Taiwanese study, patients with possible inherited conditions were more likely to have an earlier onset (about 41 years) compared to those whose gout is due to other factors (48 years). They were also more likely to have family histories of obesity, type 2 diabetes, and kidney insufficiencies.

Other Risk Factors

Obesity. Researchers report a clear link between body weight and uric acid levels. In one Japanese study, overweight people had between two and over three times the incidence of hyperuricemia as those of normal or low weights. Obesity may be an especially important risk factor for gout in men. Children who are obese may have a higher risk for gout in adulthood.

Hypertension and Diuretics. The use of diuretics, which are agents used to treat high blood pressure, is highly associated with gout. Hypertension (high blood pressure) itself is found in 25 -50% of patients with gout, but whether it causes hyperuricemia is uncertain.

Consumption of purine-rich foods. A 2004 study showed that higher consumption of purine-rich foods such as meat and seafood was associated with a significantly increased risk of gout. However, purine-rich vegetables did not increase gout risk. Interestingly, the same study showed that consumption of dairy products had a protective effect against gout. A 2005 study confirmed these results and found that total protein intake was not associated with increased uric acid levels

Alcohol Use. Alcohol use is highly associated with gout in younger adults. Binge drinking particularly increases uric acid levels. It appears to play less of role among elderly patients, especially among women with gout. A major 2004 study showed that among alcoholic beverages, beer is the most strongly linked with gout, followed by spirits. However, moderate wine consumption does not appear to increase the risk of developing gout.

Thyroid Dysfunction. Some studies have reported a higher prevalence of gout in people with hypothyroidism (low levels of thyroid hormone). Hypothyroidism may even trigger gout. There is also some evidence to suggest that hyperthyroidism (high levels of thyroid hormone) can increase uric acid levels, although not to the degree that low thyroid hormones levels do.

Although the thyroid gland releases the hormones which govern growth and metabolism, the brain (the pituitary and the hypothalamus) manages the release and the balance of the amount of hormones circulated.

Diagnosis

Determining which joints are affected is the first step. A physical examination and medical history can reveal a number of significant indictors that help confirm or rule out gout. The following are some examples:

• Gout is more likely if arthritis first appears in the big toe than if it first appears elsewhere.
• The speed of the onset of pain and swelling is relevant; symptoms that take days or weeks rather than hours to develop probably indicate a disorder other than gout.
• Abnormal enlargements in joints that had been affected by previous injury or osteoarthritis are possible signs of gout. This is particularly significant in older women on diuretics.

Examination of Synovial Fluid

Examination of synovial fluid is the most accurate method for diagnosing gout. It may even be helpful in detecting gout during intercritical periods. The synovial fluid is the lubricating liquid that fills the synovium (the membrane that surrounds a joint and creates a protective sac). The fluid cushions joints and supplies nutrients and oxygen to cartilage, the slippery tissue that coats the ends of bones.

Procedure. The procedure for taking a sample of synovial fluid from an affected joint is called aspiration:

• A needle attached to a syringe is inserted into the joint and suction is used to draw the fluid into the syringe.
• Local anesthesia is avoided because it can reduce the effectiveness of aspiration, but normally the procedure is only mildly uncomfortable.
• Following the procedure there can be some minor discomfort in the area where the needle was inserted, but it usually dissipates quickly.

Synovial fluid analysis is a series of tests performed on synovial (joint) fluid to help diagnose and treat joint-related abnormalities. To obtain a synovial fluid sample, a needle is inserted into the knee between the joint space. When the needle is in place, the synovial fluid is then withdrawn. The sample is sent to the lab for analysis.

Aspiration can cause infection, though this occurs in less than 0.1% of patients. Aspiration sometimes eases a patient’s symptoms by reducing swelling and pressure on the tissue surrounding the joint.

Analyzing the Fluid. After the sample is taken, it is sent to a laboratory, where a specialist examines the sample through a microscope under polarized light. This special light will reveal the presence of monosodium urate (MSU) crystals, which will nearly always confirm a diagnosis of gout. The laboratory can also test the sample for infection.

Blood Test for Uric Acid Levels

A blood test is usually given for measuring uric acid and detecting hyperuricemia. A low level of uric acid in the blood makes a diagnosis of gout much less probable, and a very high level increases the likelihood of gout. Some experts argue, however, that such measurements are not very useful, given what is known about the variability of uric acid levels in people with gout:

• Uric acid levels in the blood during an attack of gout can lie within or below the normal range.
• Even if hyperuricemia is present, it is very common in the population and does not necessarily indicate the presence of gout.

Determining Uric Acid Excretion in Urine

It is sometimes helpful to gauge the amount of uric acid excreted by the patient, particularly if the patient is young and has pronounced hyperuricemia that might be related to a metabolic disorder. If uric acid exceeds a particular value in the urine, further tests for an enzyme defect or other identifiable cause of gout arising from uric acid overproduction are justified. Greater-than-normal amounts of uric acid in the urine also indicate that the patient faces a greater risk of developing uric acid kidney stones, and can guide the physician in his or her choice of drug therapy for chronic gout.

24-Hour Urine Sample. Typically, urine samples are taken over the course of 24 hours. To provide a urine sample, the following steps are taken:

• The urine is collected during an intercritical period, after the patient has been placed on a purine-reduced diet. The patient is also asked to temporarily stop using alcohol and any medications that can interfere with the test.
• The patient should not change any of his or her usual eating or drinking patterns when performing this test.
• The patient discards the first urination on the day of the test.
• Afterward all urine passed over the next 24 hours is collected, including the first urination on the morning of day two.
• The container is then delivered to the patient’s physician or sent directly to the laboratory.

Click the icon to see an image of a uric acid test.

Imaging Techniques

X-Rays. For the most part, x-rays do not reveal any abnormalities during the early stages of gout, and their usefulness where gout is concerned lies in assessing the progress of the disorder in its chronic phase and in identifying other health problems whose symptoms may resemble those of gout. Tophi can be seen on x-rays before they become apparent on physical examination.

Advanced Imaging Techniques. Advanced imaging techniques being investigated for identifying tophi include computed tomography (CT), magnetic resonance imaging (MRI), and Doppler ultrasonography. A 2002 study comparing these approaches found that CT scans offered the best images.

Ruling Out Other Disorders

As part of the diagnosis, other disorders that produce gout-like symptoms or cause hyperuricemia should be ruled out. In general, it is easy to distinguish acute gout that occurs in one joint from other arthritic conditions. The two disorders that may confuse this diagnosis are pseudogout and septic arthritis. Chronic gout can often resemble rheumatoid arthritis. A number of other conditions may at some point in their course resemble gout.

Pseudogout. Pseudogout is a condition most likely to be confused with gout.

Rheumatoid Arthritis. Rheumatoid arthritis can cause distortion in the joints of the fingers, inflammation, and pain that may mimic gout. It is particularly difficult to distinguish chronic gout in older people from rheumatoid arthritis. A proper diagnosis can be made with a detailed medical history, laboratory tests, and identification of MSU crystals.

Osteoarthritis. Gout can coincide and be confused with osteoarthritis in older people, particularly when it occurs in arthritic finger joints in women. In general, gout should be suspected if the joints in the fingertips are unusually enlarged.

Click the icon to see an image of osteoarthritis.

Infections. Joint infections can have features that resemble gout and a correct diagnosis is critical for appropriate treatment. For example, some cases of gout have been confused with infection after joint replacement. On the other hand, joint infection not associated with surgery might indicate sepsis, which is a widespread and potentially life-threatening bacterial infection that can cause inflamed joints, chills, and spiking fever. The severity of the fever and a high white-blood cell count in the joint fluid helps diagnose a septic infection, while identifying urate crystals in the joint is a good indicator of gout.

Charcot Foot. Between 1 -  2.5% of people with diabetes suffer from Charcot foot or Charcot joint (medically referred to as neuropathic arthropathy). This condition is caused by abnormalities in the nerves in the feet. Early changes may resemble gout, with the foot becoming swollen, red, and warm. Recognition and treatment of this condition is very important. A seriously affected foot can become deformed. The bones may crack, splinter, and erode, and the joints may shift, change shape, and become unstable.

Bunions. A bunion is a deformity that usually occurs at the head of the first of five long bones (the metatarsal bones) that extend from the arch and connect to the toes, and may be confused with gout. The first metatarsal bone is the one that attaches to the big toe. A bunion begins to form when the big toe is forced in toward the rest of the toes, causing the head of the first metatarsal bone to jut out and rub against the side of the shoe; the underlying tissue becomes inflamed, and a painful bump forms. As this bony growth develops, the bunion is formed as the big toe is forced to grow at an increasing angle towards the rest of the toes.

Click the icon to see an illustrated series detailing bunion removal.

Treatment

Acute attacks of gout and long-term treatment of gout and its associated hyperuricemia require different approaches. All phases are treated mainly with drugs. There are also specific treatment regimes for conditions associated with gout, including uric acid nephropathy and uric acid nephrolithiasis.

Lifestyle Measures

Many patients do not require medications. During the period between gout attacks, patients are advised to avoid foods high in purines and to maintain a healthy weight. Patients should also avoid alcohol and reduce any stress.

Treatments for Asymptomatic Hyperuricemia

Experts do not recommend treatment for hyperuricemia that causes no symptoms. For one, asymptomatic hyperuricemia usually does not lead to gout or other health problems. In addition, the drugs used to treat it are expensive and carry certain risks. In unusual circumstances treatment may be justified, for example in patients with very high uric acid levels that threaten the kidney or those with a personal or strong family history of gout, kidney stones, or kidney damage.

Treatment of an Acute Attack of Gout

Drug treatments for acute attacks of gout are aimed at relieving pain and reducing inflammation. They should be started as early as possible.

• NSAIDs. Powerful forms of nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs of choice for an acute attack in younger, healthy patients with no serious health problems, particularly problems that affect the kidneys, liver, or heart. Usually indomethacin is prescribed for 2 to 7 days.
• Colchicine. Colchicine may be given within 48 hours of an attack to healthy adults. It is typically administered hourly to a maximum of six doses. It should not be used in patients with kidney or liver problems or in pregnant women.
• Corticosteroids. Corticosteroids may be used in patients who cannot tolerate NSAIDs and they may be particularly beneficial for elderly patients. Injections into an affected joint provide effective relief for many patients, but this is not useful for patients who have multiple joints that are effected. Oral steroids may be used for patients who cannot take NSAIDs or colchicine and who have gout in more than one joint.

Rest and protecting the affected joint with a splint can also promote recovery. A 2002 study reported that applying ice packs for 30 minutes four times daily significantly reduced pain. Interestingly, one 2001 study recommended applying warm water continuously and moving the joint. The theory behind this advice was that the pain in a gout attack is due to grinding from the crystals and that warmth would help dissolve the crystals and relieve pain.

After the first attack, some physicians advise their patients to keep a supply of medications on hand so that self-medication can begin at the first sign of symptoms of a second acute attack.

Treatments to Prevent Attacks During Intercritical Gout

After an acute attack some patients remain at high risk for another for several weeks during the intercritical period. (Such patients include those with kidney insufficiency or with congestive heart failure who are on diuretics.) In such cases, low doses of either of the following agents may be used to during this period for prevention.

• Colchicine
• NSAIDs

These agents should be taken in low doses for 1 to 2 months after an attack or longer in patients who have experienced frequent attacks. These are simply anti-inflammatory drugs, however, and have no effect on hyperuricemia.

Drugs Used to Reduce Uric Acid Levels in Chronic Gout

In some cases, patients will use agents (antihyperuricemic drugs) to reduce uric acid levels. The goals of antihyperuricemic therapy are to reduce the frequency of attacks and to dissolve monosodium urate (MSU) crystals and tophi. In fact, a 2001 study suggested that patients with chronic gout must maintain uric acid levels at or below 6 mg/dL in order to prevent further attacks.

Candidates. Long-term treatment of hyperuricemia may be recommended for the following situations:

• There is a risk for tophaceous gout.
• The patient has suffered more than two or three acute attacks of gout.
• Attacks are unusually severe or affect more than one joint.
• X-rays show joint damage from gout.
• Hyperuricemia is caused by an identifiable inborn metabolic deficiency.

Normal kidney function is essential for taking these drugs. This therapy, then, may not be as beneficial in many elderly patients, who often have some kidney insufficiency.

Agents Used to Reduce Uric Acid. A number of effective antihyperuricemic agents are available. In general, their effects differ depending on whether a patient's high uric acid is due to overproduction or a failure to eliminate enough in the urine. They including the following:

• Allopurinol. Allopurinol inhibits uric acid production and is useful for those who overproduce uric acid, who have kidney disorders, or who have kidney stones.
• Uricosurics. (Most often probenecid and sulfinpyrazone.) They are appropriate when gout is caused by under-excretion of uric acid, which occurs in about 80% of cases. They are not used for patients with reduced kidney function or those with tophaceous gout.

Certain steps must be made in undertaking hyperuricemic therapy:

• Some experts recommend a 24-hour collection sample in patients with frequent gout attacks to determine whether they are over-producers or under-excretors of uric acid.
• Before starting one of these drugs, any previous acute attack should be completely controlled and the joints should not be inflamed. Some physicians prefer to wait about a month after an attack.
• Low doses of NSAIDs or colchicine are used during several months after introducing anti-hyperuricemic therapies to prevent gout attacks that can occur. It should be noted that NSAIDs, particularly aspirin, as well as other salicylate drugs, interfere with uricosuric drugs and reduce effectiveness, so they should be avoided if possible by patients taking these agents.

The decision to use anti-hyperuricemic and if so, at what point, is not entirely clear, however. Some physicians do not prescribe them if hyperuricemia is mild or until a patient has had two attacks. Others prescribe them immediately after a single attack. Most of the time, antihyperuricemic therapy means taking a drug routinely throughout life, which many people find difficult.

Surgery

Surgery is sometimes used to remove large tophi that are draining, infected, or interfering with the movement of joints. When infection is present, the procedure carries a high risk for complications. People most likely to have surgery also tend to have other medical conditions that might worsen the outlook. In one study, experts suggested that better preventive measures, such as the use of allopurinol, could reduce the need for surgery.

Several other surgical procedures are available for relieving pain in and improving the function of affected joints. It is sometimes necessary to replace joints.

Medications

Nonsteroidal Anti-inflammatory Drugs (NSAIDs). Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandins, the substances that dilate blood vessels and cause inflammation and pain. They are the drugs of choice for young, healthy adults without any other serious medical condition. NSAIDs are usually taken orally at their highest safe dosage as long as gout symptoms persist and for 3 or 4 days after. Low doses of NSAIDs may be used to prevent gout attacks, including in patients who are starting anti-hyperuricemic therapies.

NSAIDs Used. There are dozens of NSAIDs available.

There are dozens of NSAIDs. The most common are the following:

• Over-the-counter NSAIDs include aspirin, ibuprofen (Motrin IB, Advil, Nuprin, Rufen), naproxen (Aleve), ketoprofen (Actron, Orudis KT).
• Prescription NSAIDs include ibuprofen (Motrin), naproxen (Naprosyn, Anaprox), flurbiprofen (Ansaid), diclofenac (Voltaren), tolmetin (Tolectin), ketoprofen (Orudis, Oruvail), dexibuprofen (Seractil), indomethacin (Indocin).

Indomethacin (Indocin) is typically the first choice for patients who have no medical conditions that would preclude its use. Usually 2 to 7 days of high-dose indomethacin will be sufficient to treat a gout attack. The first dose of indomethacin usually begins to act against the pain and inflammation within 24 hours and often much sooner.

Ibuprofen, naproxen, sulindac, or others are good alternatives, particularly for elderly patients who might experience confusion or bizarre sensations with indomethacin. (Aspirin is an NSAID, but is associated with a higher risk for gout and should be avoided.)

Regular use of even over-the-counter NSAIDs may be hazardous for anyone and has been associated with the following side effects:

• Ulcers and gastrointestinal bleeding. This is the major danger with long-term use of NSAIDs. (indomethacin poses a higher risk than many others for this adverse effect.)
• Increased blood pressure. Most NSAIDs appear to pose this risk, with higher risks observed with piroxicam (Feldene), naproxen (Aleve), and indomethacin (Indocin). (Sulindac has the smallest effect and aspirin as no risk.) People with hypertension, severe vascular disease, kidney, or liver problems and those taking diuretics must be closely monitored if they need to take NSAIDs.
• May delay the emptying of the stomach, which could interfere with the actions of other drugs. The elderly are at special risk.
• Dizziness.
• Tinnitus (ringing in the ear).
• Headache.
• Skin rash.
• Depression has also been noted.
• Confusion or bizarre sensation (in some higher-potency NSAIDs, notably indomethacin).
• As with acetaminophen, high daily doses of aspirin have been associated with an increased risk of kidney failure, although the risk remains low in those with healthy kidney function. Kidney abnormalities have been reported in people taking other NSAIDs as well, which resolve when the drugs are withdrawn. Any sudden weight gain or swelling should be reported to a physician. Anyone with kidney disease should avoid these drugs.
• Patients with diabetes who take oral hypoglycemics may need to adjust the dosage if they also need to take NSAIDs because of possible harmful interactions between the drugs.

Note: Some studies have reported that ibuprofen (but not other NSAIDs) may blunt the heart-protective effects of low-dose aspirin, Additional research is needed to confirm these findings.

Other Investigative Alternatives to NSAIDs

NO-NSAIDs. Experimental agents are being developed that combine nitric oxide (NO) with NSAIDs. These treatments are called NO-NSAIDs. NO increases blood flow in the mucous lining and secretions of mucus and bicarbonate. Combining nitric oxide with NSAIDs may reduce the adverse effects on the GI tract. In addition, according to one study, an experimental NO-aspirin also had the heart protective properties of aspirin without its gastrointestinal problems. (COX-2 inhibitors may have adverse effects on the heart.)

Arthrotec. Arthrotec is a combination of misoprostol and the NSAID diclofenac that may reduce the risk for gastrointestinal bleeding. One study found that patients taking Arthrotec had 65 - 80% fewer ulcers than those who took NSAIDs alone.

Colchicine

Colchicine, a derivative of the autumn crocus (also called the meadow saffron), has been used against gout attacks for centuries. It is highly effective though no longer the first drug of choice because of its frequent, unpleasant, and sometimes very serious side effects.

Oral Regimen. The oral regimen requires doses every hour until the symptoms either improves or side effects develop; improvement should be evident by the tenth dose. Oral colchicine usually eliminates the pain of an acute attack within 48 hours.

The drug is generally appropriate only for healthy adults. It should not be used by elderly patients or those with kidney, liver, or bone marrow disorders. It can also affect fertility and should not be used during pregnancy.

Colchicine is unsuitable for many other patients as well, because of gastrointestinal side effects, which occur at the high doses necessary to relieve symptoms. They include nausea, vomiting, diarrhea, or abdominal cramps. Low doses do not pose as high a risk for gastrointestinal symptoms, and can prevent further attacks, including in patients who are starting anti-hyperuricemic therapies. Low dosescause virtually no GI side effects. Note: The antibiotic erythromycin or H2 blockers, such as famotidine (Pepcid AC), cimetidine (Tagamet), ranitidine (Zantac), may intensify the gastrointestinal side effects of colchicine. A 2004 study showed that long-term colchicine therapy may also weaken the respiratory muscles, especially among patients with renal failure. Colchicine also interacts with a number of other medications.

Intravenous. Intravenous administration of colchicine relieves episodes of gout without gastrointestinal effects and for a time, physicians hoped it could be used routinely. The intravenous route has some serious side effects, however, and poses an increased risk for injury to the kidney, liver, central nervous system, and bone marrow.

Warning Note: Overdose of colchicine can be dangerous, and there have even been reports of death. The agent may also suppress blood cell production and cause nerve and muscular injury in certain people, sometimes even in those not taking high doses.

Corticosteroids

Corticosteroids, known commonly as steroids, are used when patients cannot tolerate other anti-inflammatory drugs or they prove ineffective for an attack of gout. They are becoming popular in elderly people.

Corticosteroids can be administered in different ways:

• If only one joint is affected, an injection of the steroid triamcinolone directly into the affected joint can often bring rapid pain relief.
• A single muscular injection of ACTH or triamcinolone may be the most rapid and reliable method for terminating an attack. Oral doses of prednisone are usually given for seven to 10 days after the injection in tapered doses. This is to prevent a rebound attack, which can occur after the injection.

These drugs should only be administered for short periods and not used for long-term treatment. Corticotropin (ACTH), a drug that converts to a steroid, is effective and safe, according to some evidence, but is not widely available.

Uricosuric Drugs

The uricosurics prevent the kidney from reabsorbing uric acid and so increase the amount excreted in the urine. They are usually the choice for preventing gout in the following patients:

• Those under 60 years old
• Those with normal diets
• Those who have normal kidney function
• Those who have no risk of kidney stones

Uricosuric drug candidates should produce no more than 700 to 800 mg of uric acid in urine over a 24-hour period.

Specific Uricosurics. Probenecid (Benemid, Parbenem, Probalan) and sulfinpyrazone (Anturane) are the standard uricosurics. A more potent uricosuric, benzbromarone, may work for people with severe tophaceous gout and renal impairment when other drugs do not. In some studies, benzbromarone was equal to or even more effective than allopurinol, the other standard maintenance drug. Because it can cause liver failure in some patients, however, benzbromarone is available in the U.S. only with special authorization. A uricosuric combined with allopurinol may be beneficial in cases where using just one drug is not.

Probenecid is taken two to three times a day and sulfinpyrazone begins at twice a day and increases to three or four times daily. The initial doses should be low and then gradually built up. Probenecid combined with colchicine is more effective than probenecid alone, but patients respond differently to this regimen depending on the dosage balance, so it needs to be carefully individualized.

Side Effects. The possible side effects of these two drugs include skin rashes, gastrointestinal problems, anemia, and kidney stone formation. To help reduce acidity and the risk for kidney stones, patients should drink plenty of fluids (ideally water, not caffeinated beverages). Sodium bicarbonate supplemented by acetazolamide can also reduce acidity and the risk for stones.

Interactions. Adding low-dose colchicine or an NSAID may help prevent gout attacks, but NSAIDs, particularly aspirin, as well as other salicylate drugs, interfere with uricosuric drugs and reduce effectiveness, so they should be avoided if possible. Patients who require minor pain relief should instead take acetaminophen (Tylenol and others). Uricosurics interact with many other drugs, and a patient should be sure to inform the physician of any medications they are taking.

Xanthine Oxidase Inhibitors

Allopurinol (Lopurin, Zyloprim) is a xanthine oxidase inhibitor that blocks uric acid production and is the drug most often used in long-term treatment for older patients and overproducers of uric acid (levels of excreted uric acid of more than 800 mg during a 14-hour period). It is also considered the drug of choice for patients with impaired kidney function, a history of kidney stones, and for tophaceous gout. Its use in patients with tophaceous gout can help reduce the need for later surgery.

Administration. Allopurinol is taken orally once a day in doses of 100 mg to 600 mg, depending on the patient's response to treatment. When it is first used, allopurinol can trigger further attacks of gout, and thus during the first months (or longer) of therapy the patient is also given a NSAID or colchicine to forestall that possibility.

Side Effects. Between 3 - 5% of patients experience severe side effects including diarrhea, headache, and fever. Among the more serious are blood cell abnormalities, including leukopenia (a reduction in the number of white blood cells) and thrombocytopenia (a reduction in the number of platelets). The drug may also increase the risk for cataracts. About 2% of patients experience an allergic reaction to allopurinol that causes a rash. In rare cases, the rash can become severe and widespread enough to be life threatening (called Toxic epidermal necrolysis, or TEN). Allergic individuals who experience only a mild rash may be able to build up their tolerance for the drug by undergoing a desensitization process.

Of note: People with gout are at increased risk of atherosclerosis, or “hardening of the arteries,” and coronary artery disease. A mechanism involving the metabolism of cholesterol plays a role in causing both atherosclerosis and gout. Because allopurinol has positive effects on “bad” cholesterol levels, it may be better than other drugs for patients with both gout and coronary artery disease.

Interactions. Allopurinol interacts with certain other drugs, such as azathioprine.

Other Agents

Hypertensive Agents. People with gout have a higher risk for high blood pressure. Some of the agents used to treat hypertension, such as thiazide diuretics, can increase the risk for gout attacks. Newer agents, such as losartan (an angiotensin II receptor antagonist), and amlodipine (a calcium channel blocker), may have beneficial effects on both high blood pressure and gout.

Investigative Agents

Xanthine Oxidase Inhibitors. Febuxostat is the first drug to emerge in many decades as a potential new treatment for chronic gout. It may prove to be an alternative for patients who are allergic to allopurinol. Phase II trial data reported significant reductions in serum uric acid levels. The drug's manufacturer submitted a new drug application to the FDA in December 2004.

Urate Oxidase. Recombinant urate oxidase (rasburicase) is being investigated for treatment of hyperuricemia in adult and pediatric cancer patients. In a Phase II trial, pegylated urate oxidase (Puricase) dramatically decreased uric acid levels in patients with severe, refractory gout. Both drugs are administered by injection.

COX-2 Inhibitors. Etoricoxib (Arcoxia) is being investigated as a treatment for acute gout. However, the FDA has delayed approval of etoricoxib pending safety considerations. Etoricoxib is a successor to the COX-2 inhibitor rofecoxib (Vioxx) which was withdrawn from the market in 2004 due to substantial cardiovascular (heart attack and stroke) risks. The FDA is currently evaluating all COX-2 inhibitors to determine their relative risks versus benefit.

Alternative Agents

Some people use herbal or other natural remedies for gout. Patients should be very cautious when using such agents and do so only after checking with their physicians.

Lifestyle Changes

Any activities that increase energy demands also increase metabolism or purines that produce uric acid. Avoiding stress and staying healthy are important for preventing attacks.

Dietary Recommendations

Because uric acid levels are only minimally affected by diet, dietary therapy does not play a large role in the prevention of gout. Still, people who have suffered an attack of gout may benefit from reducing their intake of purine-rich foods if they habitually eat unusually large quantities of such foods.

Recent research has suggested that not all purine-rich foods are associated with gout. Meat and certain types of seafood and shellfish have high purine levels and do produce high levels of serum uric acid. However, moderate consumption of purine-rich vegetables (spinach, cauliflower, mushrooms, legumes) does not appear to increase the risk of gout. Dairy products, especially low-fat products (low-fat yogurt, skim milk) may actually protect against gout.

Foods to Avoid:

• Organ meats (liver, kidneys, sweetbreads)
• Red meat (beef, pork, lamb)
• Meat extracts (soup, broth, gravies)
• Seafood (anchovies, sardines, herring, fish roe, canned tuna fish, shrimp, lobster, scallops, mussels)
• Yeast products (beer and baked goods)

Maintain Healthy Weight

A supervised weight-loss program may be a very effective way to reduce uric acid levels if the patient is overweight. Crash dieting, on the other hand, is counterproductive because it can increase uric acid levels and can cause an acute attack.

Maintain Fluids

Drinking plenty of water and other nonalcoholic beverages helps remove MSU crystals from the body.

Avoid Alcohol

Alcohol should be avoided, since it promotes purine metabolism and uric acid production; it also may reduce excretion of uric acid. Heavy drinking, especially binge drinking of beer or distilled spirits, should especially be avoided.

Avoid Joint Injury

People with gout should also attempt to identify and avoid activities that cause repetitive joint trauma, such as wearing tight shoes.

Preventing an Attack During Travel

Travel is an example of an activity that increases the risk for gout. It not only increases stress, but eating and drinking patterns may change. Before traveling, patients should discuss preventive measures with their physicians. The doctor may prescribe a prednisone tablet to be taken immediately at the first sign of a gout attack; in most cases this stops the episode.

Resources

• www.nih.gov/niams -- National Institute of Arthritis and Musculoskeletal and Skin Diseases
• www.rheumatology.org -- American College of Rheumatology
• www.arthritis.org -- The Arthritis Foundation

References

Huang HY, Appel LJ, Choi MJ et al. The effects of vitamin C supplementation on serum concentrations of uric acid: results of a randomized controlled trial. Arthritis Rheum. 2005 Jun;52(6):1843-7.

Chen VC, Ho PL, Yuen KY. Two probable cases of serious drug interaction between clarithromycin and colchicine. South Med J. 2005 Aug;98(8):811-3.

Saxena R, Loghmanee F. Fatal drug reaction due to allopurinol therapy in a 72-year-old man. Arch Pathol Lab Med. 2005 Aug;129(8):e183-4.

Tsutsumi Z. Oxidized low-density lipoprotein autoantibodies in patients with primary gout: effect of urate-lowering therapy. Clin Chim Acta - 01-JAN-2004; 339(1-2): 117-22.

Bardin T. Current management of gout in patients unresponsive or allergic to allopurinol. Joint Bone Spine. 2004; 71(6):481-5.

Akkasilpa S. The efficacy of combined low dose of Allopurinol and benzbromarone compared to standard dose of Allopurinol in hyperuricemia. J Med Assoc Thai.  2004; 87(9): 1087-91.

Russmann S. Life-threatening adverse effects of pharmacologic antihyperuricemic therapy. Ther Umsch. 2004; 61(9):575-7.

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