Gout
March 2000
WHAT IS GOUT?
Gout
Gout is a type of arthritis (inflammation of the joints) that mostly affects men age 40 and older. It is nearly always associated with chronic hyperuricemia, a long-lasting, abnormally high concentration of uric acid in the blood. The process leading to gout begins with the metabolism of purines, nitrogen-containing compounds, that are important for energy. Purines can be divided into two types, endogenous and exogenous. Endogenous purines are synthesized within the nuclei of cells in the human body itself, whereas the exogenous purines are obtained from foods. All mammals, except humans, possess an enzyme called uricase that breaks purines down into a very soluble product called allantoin. Humans, however, lack this enzyme, and the end point of their purine metabolism is uric acid, a useless substance that can build up in tissues in the body if it is not adequately eliminated in urine.
Uric acid is produced in the liver and enters the bloodstream. Most uric acid eventually passes through the kidneys and is excreted in the urine; the rest is disposed of in the intestines, where it is processed and oxidized by bacteria. Normally these processes keep the concentration of uric acid in the blood plasma (the liquid part of the blood) below 6.8 milligrams per deciliter (6.8 mg/dL). Under certain circumstances, however, the body produces too much uric acid or excretes too little. This results in higher levels and increased concentrations of uric acid in the blood, and hyperuricemia develops. At normal body temperature and below, uric acid concentrations increase; as they approach 7 mg/dL, the blood becomes supersaturated, and needlelike crystals of a salt called monosodium urate (MSU) form. In time, as MSU crystals accumulate, they cause inflammation and pain, symptoms typical of gout.
Effects of Hyperuricemia
High levels of uric acid are basically associated with four conditions, which can occur independently but may develop one after the other if gout is untreated: acute gouty arthritis, chronic tophaceous gout, uric acid nephrolithiasis (a form of kidney stone), and, possibly, uric acid nephropathy (kidney disease).
Acute Gouty Arthritis. Acute gouty arthritis is the stage at which the first symptoms of gout appear.
Chronic Tophaceous Gout. After several years, persistent gout can produce tophi, which are solid deposits of MSU crystals that form in the joints and elsewhere in the body (hence the term chronic tophaceous gout). Without anti-hyperuricemia treatment, tophi develop on average about 10 years after the onset of the disease although their first appearance can range from three to 42 years. Bones, cartilage, tendons, soft tissue, and membranes containing synovial fluid (the lubricating fluid surrounding joints) can all harbor tophi. Common locations include the helix of the outer ear (the curved ridge along the edge of the ear), the fingers, hands, forearms, knees, and feet, and the olecranon bursa (a sac at the elbow joint filled with synovial fluid). In some cases, tophi break through the skin and appear as white or yellowish-white, chalky nodules. (They have been described as looking like "crabs eyes.") In rare cases, they can settle in regions around the heart and spine.
Today, drug therapy has reduced the prevalence of chronic tophaceous gout to as little as 3%, although certain groups, such as transplant patients receiving cyclosporine, still face a high risk of developing tophi.
Uric Acid Nephrolithiasis (Kidney Stones). Uric acid nephrolithiasis occurs when kidney stones form from uric acid. Uric acid and other kidney stones are present in 10% to 25% of patients with primary gout, a prevalence more than 1000 times that of the general population. In secondary gout, the reported incidence reaches 42%. Uric acid stones can also form in the absence of gout or hyperuricemia. 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. Kidney stones can be extraordinarily painful and can cause infection and kidney failure if untreated.
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. (Sudden overproduction of uric acid, however, can occasionally block the kidneys and cause them to fail. This most often occurs in conjunction with chemotherapy for leukemia or lymphoma and can also occur after heat stress from vigorous exercise, following epileptic seizures, and after corticosteroid therapy for severe allergic reactions.)
WHAT CAUSES GOUT?
Gout is classified as either primary (the most common type) or secondary, depending on the cause of the associated hyperuricemia. In both types of gout, between 70% and 95% of hyperuricemia cases are the result of underexcretion of uric acid, rather than uric acid overproduction.
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. The remaining 1% of primary gout cases are traceable to either of two rare inherited enzyme defects that affect purine synthesis in the cells.
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.
Medications. The list of drugs that cause hyperuricemia is long. They include thiazide diuretics (the "water pills" used to control hypertension), pyrazinamide (used to treat tuberculosis), and the immunosuppressive drug cyclosporine (given to transplant recipients to prevent organ rejection). Low doses of aspirin decrease uric acid excretion and increase the chance for hyperuricemia; this is a particular problem for older people with heart disease who would benefit from baby aspirin. High doses have the opposite effect, however.
Kidney Problems. Renal (meaning kidney) insufficiency is the impaired ability of the kidneys to eliminate waste products, including uric acid, which then build up in the blood. It is one of the major risk factors for gout in older people. Hyperuricemia occurs in between 30% and 85% of people who have kidney transplants and who receive immunosuppressive and diuretic drugs.
Other Medical Conditions. A number of diseases, including leukemia, lymphoma, and psoriasis, can cause gout. Over exposure to lead can cause gout.
Alcohol Use. Alcohol use 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, and by interfering with the kidneys' ability to excrete uric acid.
Purine-Rich Diet. A purine-rich diet rarely causes hyperuricemia, although it may precipitate an attack in some people with existing gout. [For a list of purine-rich foods, see What Lifestyle Measures Can Help Prevent Gout? below.]
WHAT ARE THE SYMPTOMS OF GOUT?
Gout is often divided into four symptomatic stages: asymptomatic hyperuricemia, acute gouty arthritis, intercritical gout, and chronic tophaceous gout. Gout symptoms can be precipitated by stress, infection, joint injury, weight loss, surgery, certain kinds of drug treatment, overindulgence in alcohol or purine-rich foods, or even something as seemingly inconsequential as a long walk that one was not sufficiently physically fit to undertake. They tend to occur more in the spring, with the peak in April. Severe illnesses and drug treatments are probably the most significant triggers; in fact, 20% to 86% of patients with gout experienced a recurrence when they are hospitalized.
Asymptomatic Hyperuricemia
Asymptomatic hyperuricemia, in which MSU slowly builds up, always precedes gout and is considered the first stage of the disorder. It can last, however, for an average of 30 years. Hyperuricemia also 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 is the stage at which 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 begin to form at normal body temperature when concentrations reach 7 mg/dL. They can form at lower concentrations, however, at lower body temperatures, which occur in areas farther from the heart; this explains why gout tends to favor joints in fingers and toes first. Symptoms usually begin as a sudden, severe, and unexpected arthritic attack affecting a single joint in one of the lower limbs, a condition known as monoarticular gout. The joint of the big toe is the site of about half of all first gout attacks, a specific condition called podagra. The site is often medically referred to as the big toe's metatarsophalangeal (MTP) joint, the point where one of the long five bones of the foot meets the first digit of a toe.
The joints of the foot, ankle, knee, wrist, elbow, and hand are other frequently affected sites. In such cases the condition is known as polyarticular gout. More than one joint is affected in 10% to 20% of first attacks. 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. They are also more likely to experience a low-grade fever, loss of appetite, and a general feeling of poor health.
The primary symptom, which usually takes eight to 12 hours to develop, is severe, sometimes crushing pain at and around the joint. In many cases the attack occurs late at night or early in the morning and announces itself by waking the sufferer. Some patients describe it as resembling a dislocated bone and one writer described it as "like walking on my eyeballs." Chills and mild fever may follow. The area can be so tender that walking and even the weight of bed sheets can be unbearable. 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. An untreated attack will typically peak 24 to 48 hours after the initial appearance of symptoms, and subside after five to seven days, although it can last only hours to 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 in untreated cases most people can expect a recurrence. One study found that 62% of subjects experienced at least one further attack within a year. At the end of two years 78% and after 10 years 93% of patients experienced a recurrence of gout.
Symptoms of Chronic Tophaceous Gout
When gout remains untreated, the intercritical periods typically become shorter and shorter, and the attacks, although sometimes less intense, can last longer. 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. Over the long term, about 10 to 20 years, in untreated gout the intercritical periods dwindle until gout becomes a chronic disorder characterized by constant low-grade pain and mild or acute inflammation in several joints. Persistent gout, moreover, can destroy cartilage and bone, causing irreversible joint deformities and loss of motion.
Symptoms of Tophi. Tophi, the solid, knobby MSU crystal deposits that form during this process are generally painless themselves, but they often cause pain and stiffness in an affected joint and can erode cartilage and bone, ultimately destroying the joint. Large tophi under the skin of the hands and feet can give rise to extreme deformities.
HOW SERIOUS IS GOUT?
Left untreated, gout can develop into a painful and disabling chronic disorder. Tophi are capable of growing 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, they can cause serious damage including compression, although this is a very rare event. In extreme cases, joint destruction results in complete disability. But now, after several decades of research into the causes of gout and the development of drugs for controlling hyperuricemia, gout rarely poses a long-term threat to health if properly treated. Still, it remains a source of short-term pain and incapacity for thousands of Americans. Kidney stones occur in between 10% and 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. About 25% of patients with chronic hyperuricemia develop
progressive kidney disease, which, in some cases, ends in kidney failure. Many experts believe, however, that chronic hyperuricemia is unlikely to be a common cause of kidney disease, and that, in most cases, the kidney abnormalities come first and cause high concentrations of uric acid. Gout also accompanies and can be exacerbated by other serious conditions that are associated with kidney and heart disease including diabetes, obesity, unhealthy cholesterol levels, insulin resistance, and high blood pressure. Hyperuricemia has also been associated with a higher risk of death from heart and circulatory diseases, although it is unknown whether hyperuricemia is a risk factor independent of the high-risk conditions it often accompanies.
WHAT ARE THE RISK FACTORS FOR GOUT?
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 one of the most common types of arthritis. In the United States there were an estimated 2.2 million cases of self-reported gout in 1986, and a 1991 publication noted that Americans lost an estimated 37 million working days a year to gout. It is estimated that approximately 15 of every 1,000 American males between 35 and 45 years of age have gout and some experts believe that one in 100 men may be at risk for it. It is very uncommon in less developed countries and in 1952 it was said to be unknown in China, Japan, the tropics, and rare among African Americans. The prevalence of gout not only in America but in other developed countries has, however, been rising in recent decades, possibly because of dietary and lifestyle changes, greater use of medications that cause hyperuricemia, and aging populations.
Gender and Age Differences
Among children, the levels of uric acid in both girls and boys are low, (on average 3 to 4 mg/dL). Except for rare inherited genetic disorders that cause hyperuricemia, gout in children is almost unheard of. In males, levels rise substantially at puberty, with the result that the level exceeds 7 mg/dL (considered to indicate hyperuricemia) in about 5% to 8% of American men. Gout typically strikes only after 20 to 40 years of persistent hyperuricemia, so men usually experience their first attack between the ages of 30 and 50 years old. Men over 40 years old account for about 90% of the population affected by gout. Less than 5% of patients with gout are female. The female hormone estrogen appears to facilitate uric acid excretion by the kidneys, so levels in women remain essentially stable until menopause, after which they approach male levels. Premenopausal women are thus much less likely than men of the same age to be hyperuricemic. Women are more likely to experience gout
between the ages of 50 and 70.
Family History
A fairly substantial proportion of patients with gout (10% to 20%) has a family history of the arthritic condition.
Other Risk Factors
Obesity. Researchers report a clear link between body weight and uric acid levels; obesity may be an especially important risk factor for gout in men. In one Japanese study, overweight people had between 2 and 3.4 times the incidence of hyperuricemia as those of normal or low weights.
Hypertension. Hypertension (high blood pressure) is found in 25% to 50% of patients with gout, but whether it causes hyperuricemia is uncertain.
Alcohol Use. Alcohol use is associated with gout and in one study, it was the only notable risk factor for women with gout.
HOW IS GOUT DIAGNOSED?
Standard diagnostic tools for gout may include a medical history and physical examination, a blood test for hyperuricemia, and urine sample. For a definitive diagnosis of gout, a sample of synovial fluid from the affected joint is required, which is examined for signs of the characteristic crystals. X-rays can provide helpful information in some cases.
Ruling Out Other Disorders
As part of the diagnostic process other disorders that resemble gout 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, a potentially life-threatening condition. Chronic gout can often resemble rheumatoid arthritis.
Pseudogout. Pseudogout is a condition most likely to be confused with gout. It is caused by deposits of calcium pyrophosphate dihydrate crystals in and around the joints. Though pseudogout resembles gout in some ways, the first attack typically strikes the knee rather than the joint of the big toe, and at least two-thirds of cases affects more than one joint. The symptoms of pseudogout also appear more slowly than those of gout, taking days rather than hours to develop. In addition pseudogout is more likely to occur in the autumn while gout