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Although hyperuricemia (high blood levels of urate) is not the same as gout, it is the major risk factor for gout. Generally speaking, anything that tends to raise the blood urate level is a risk factor for gout. However, not everyone with raised urate levels will get gout. About 95 percent of uric acid in the blood combines with sodium to form molecules of monosodium urate, which is much more soluble than uric acid in both blood and joints. Many people use the terms uric acid and urate interchangeably. Although they have different chemical structures, for everyday purposes, it does not really matter. At levels up to about 0.35 mmol/L (5.8 mg/dL) urate dissolves well in body fluids, and levels are similar in joints and blood most of the time. Above that level it can form a stable supersaturated solution. The higher the concentration, the more likely it is to crystallize out of solution. When it crystallizes out into joints and soft tissues, it may initiate an intense inflammation called gout. The easiest way to view the relationship between blood urate levels and gout is to look at the risk of developing gout in either one year or five years given a certain urate level as in the table on the next page.

RELATIONSHIP OF GOUT TO BLOOD URATE LEVELS IN MEN

Blood Urate Risk of Developing Gout

In One Year In Five Years

< 0.42mmol/L (7 mg/dL) <1 per 1,000 5 per 1,000

0.42-0.47 mmol/L (7-7.9 mg/dL) 1 per 1,000 6 per 1,000

0.48-0.53 mmol/L (8-8.9 mg/dL) 4 per 1,000 10 per 1,000

> 0.54 mmol/L (> 9.0 mg/dL) 49 per 1,000 220 per 1,000

In males, there is a significant rise in urate levels at puberty. Although this rise is less marked in women, they have a further rise after menopause. since most people probably have raised urate levels for 10 to 20 years before getting gout, this may explain the typical age of onset in men in their 30s and 40s and in women in their 60s.

Causes of hyperuricemia Either the formation of too much urate or not getting rid of it quickly enough can lead to a buildup. Two-thirds of a person's urate is eliminated in the urine. In most people there will be a variety of factors operating to cause significant hyperuricemia.

• Enzyme deficiencies can lead to overproduction of uric acid. The best-known one (that of an enzyme abbreviated as HGPRT) is extremely rare and when severe, also results in mental retardation (the Lesch-Nyhan syndrome). Minor abnormalities in this enzyme can cause high uric acid production without mental problems. Many other enzyme abnormalities have recently been discovered, but at present these account for only an extremely small number of people with gout. People developing gout under the age of 20 years are very likely to have an enzyme abnormality predisposing them to hyperuricemia.

• Many Polynesian groups of people have genetically determined hyperuricemia as well as frequent gout. Chinese and Filipino people living traditionally in their own lands have normal urate levels but are prone to hyperuricemia on modern diets or when living in Western countries. This is probably due to an interaction between diet and genetic makeup. Even in West ern populations the genetic contribution to the urate level has been calculated as 40 percent.

• Body bulk is the strongest predictor of urate level in the vast majority of people. This is true for straightforward weight measurements as well as for weight corrected for height. This is not just related to dietary intake, because weight loss will actually increase the amount of uric acid passed in the urine.

• Dietary intake of foods high in purines is important (see later under Treatment and Outcome). Regular alcohol intake (not necessarily excessive) increases urate levels in a number of ways. It slows down uric acid excretion in the urine as well as speeding up the breakdown of some purines to form urate. In addition, beer contains a large amount of purine itself.

• Many drugs may increase urate levels. The most common are the diuretics (water tablets), especially the thiazides but also furosemide and bumetanide. Low-dose aspirin is now commonly used for the prevention of heart disease and will slightly increase urate levels (although high doses lower it). Others include most cytotoxic (anticancer) drug regimens, levodopa, and the anti-tuberculous drugs ethambutol and pyrazinamide.

• Diseases such as psoriasis in which there is an increased rate of cell turnover also lead to higher urate levels. An extreme degree of this happens when treatment for leukemia and lymphoma is begun.

• Lead exposure can lead to kidney disease and high urate levels.

• Patients who have received an organ transplant, usually a kidney or heart, develop high urate levels, frequently get gout, and have particular problems with its treatment.

Given a high urate level for many years, there are many events that may precipitate an attack of gout. These include any sudden illness, trauma (even minor), surgery, a large intake of alcohol or large purine-containing meal, or starting on one of the drugs listed above. Bleeding from the gut (which may be due to taking NSAIDs to settle the previous attack) seems to be a particularly potent initiator of gout.

Symptoms

Typically the patient awakes in the early hours of the morning with pain in the great toe, less commonly the heel, ankle, or midfoot. This becomes progressively worse and is often excruciating. in severe attacks there may be fever and chills. Most first attacks (90 percent) occur in the great toe. This is probably because of the frequent minor trauma this toe suffers as well as the fact that cold precipitates gout (the urate becomes less soluble) and feet are often the coolest part of the body. only one joint is affected in 90 percent of first attacks, but as time goes on, more and more joints are likely to be affected during an attack. Somebody having a first attack of gout has a 60 percent chance of having another within one year and a 90 percent chance of having another within five years. Ankles, knees, and hands are commonly affected. Not all attacks are severe and may be put down to sprained ankles or bruised heels because they do not appear to be a typical gout attack.

Even if untreated, most attacks of gout will settle down after 10 to 14 days. Initially there are no abnormalities to see once the attack has settled. However, after years of gout with no treatment to lower the urate levels, it may become chronic; that is, the gaps between attacks become shorter and shorter until it is continuous. When this happens there are always many joints affected and it may occasionally look very like rheumatoid arthritis. By this time damage has occurred to the joints with loss of cartilage and cysts in the bone.

Tophi may also develop in longstanding gout. Tophi are collections of urate crystals that steadily grow larger if the urate level remains high. if close to the skin surface they may periodically break open and discharge chalky, white material (the urate crystals). They may also cause pressure symptoms on nerves and other deeper tissues. The spine, heart, eyes, and voicebox are among the unusual places to be affected by tophi. Tophi seldom develop within 10 years of first developing gout and are becoming much less common with better treatment of hyperuricemia.

Gout may be difficult to diagnose when attacks are not typical. Women develop gout later than men (usually in their 60s), and it more frequently affects more than one joint from the beginning. in older patients, attacks may be less severe but longer lasting, and frequently other forms of arthritis are suspected. Gout has a tendency to develop in damaged joints and may not be suspected if these are joints not commonly affected by gout. Gout in the shoulder and hip joints is particularly difficult to diagnose. Some people with osteoarthritis of the hands develop gout there that causes intermittent pain and swelling that should be distinguished from erosive osteoarthritis. in these situations the danger is that the intermittent gout will accelerate the damage to the joint if unrecognized. in severe gout the joint is fiery red and hot, hugely swollen, and exquisitely painful. This is exactly what an acute joint infection looks like. in addition the sufferer is likely to have sweats and chills, and it is not surprising, therefore, that they are frequently treated as infective arthritis initially.

High urate levels can lead to two kinds of kidney disease, and these can occur in patients who have not had gout as well. in the first, uric acid crystals form in the small tubules of the kidney or the ureters that drain urine from the kidney to the bladder and, often together with calcium crystals, form kidney stones. This can lead to intense pain (renal colic) as well as blockage of tubules or ureter. in the second type, uric acid crystals form in the tissues of the kidney and cause inflammation there. These patients may go on to develop kidney failure.

A number of conditions are closely associated with gout and should be addressed or looked for as part of the management plan:

Obesity Nearly 80 percent of people with gout are more than 10 percent overweight, and nearly 60 percent are 30 percent overweight. Not only does this indicate a poor health outcome, but increased weight has a direct effect on raising urate levels.

Diabetes This association may simply be because of the obesity since there is some disagreement about the strength of the association in different studies.

Hyperlipidemia A risk factor for heart disease, this is especially likely to be present in those who drink alcohol. About 80 percent of gout patients have hyperlipidemia.

Hypertension Approximately 30 percent of gout patients are hypertensive, and nearly 30 percent of hypertensives have a high urate level.

Atherosclerosis patients with gout develop atherosclerotic problems (angina, heart attacks, strokes, and poor circulation to the legs) at a younger age than others. However, the high urate levels and gout do not cause this but probably a combination of the other associated conditions mentioned above do.

Diagnosis

It is necessary to take fluid from a joint or material from a tophus and see urate crystals under a po-larized-light microscope to diagnose gout definitely. This not always possible, however, and in typical presentations not necessary. When the setting is not typical, however, every effort should be made to find the crystals. in long-standing gout, the X rays show bony damage that is very typical of gout and useful in the diagnosis.

The blood urate levels are not very useful in making the diagnosis during a sudden attack. First, many people with mildly raised urate levels will never develop gout, and second 40 percent of people with acute gout will have a normal level during the attack. All of this second group will, however, have a raised urate level later on when the attack has settled. Because the diagnosis may still sometimes be difficult, the American College of Rheumatology has developed criteria for the diagnosis that relies on at least three of 12 suggestive symptoms, signs, and investigations being present.

Treatment and Outcome

There are several quite different aspects to the treatment of gout:

• Treatment of the sudden painful attack of gout

• Prophylactic or preventative treatment of the gout

• Treatment to lower the urate levels

• Transplant gout

• Management of the associated conditions listed above, which will not be discussed here

The acute attack Rest has been shown to shorten the sudden attack of gout. Cold compresses help relieve pain but do not shorten the attack. colchicine has been used for 200 years and is still an effective drug. The traditional high doses used for acute attacks are, however, not well tolerated mainly because of the severe diarrhea. in lower doses it also does not work as quickly as the NSAIDs and is therefore usually used only when these drugs cannot be used or for prophylaxis (see below). All the traditional NSAIDs work in gout. phenylbutazone should not be used because of its severe side effects, especially on the blood-forming parts of the bone marrow. indomethacin is often preferred by gout patients because it is very powerful. However, it also causes more side effects than the others. ibuprofen, diclofenac, naproxen, pirox-icam, tenoxicam, and sulindac have all been used with success. The most important factor in using colchicine or the NSAIDs is to take them as early as possible in the attack. it is usual to start with a high dose and reduce it as the attack comes under control. There is limited experience with the newer cox-2 inhibitors, although one study with highdose rofecoxib (Vioxx) shows that it is effective.

corticosteroids may be used when colchicine and the NSAIDs are contraindicated. They are most effective if injected directly into the affected joint but can be taken orally as well. on average, an acute attack will get better in seven days. The more joints involved, the longer before improvement.

Prophylactic treatment When there is a large urate load in the body, urate-lowering therapy may take some time to reduce this load sufficiently to prevent gout. The initial period of urate-lowering therapy may also increase the frequency of attacks in a quarter of patients. For these reasons, many patients are given prophylactic or preventative treatment during the initial urate-lowering phase.

Low-dose colchicine (one to two tablets a day) is very effective, preventing attacks in 85 percent of such patients. The NSAIDs may also be used. Typically this therapy will be continued for six to 12 months but possibly longer in those with numerous tophi. It is usual to continue this treatment until the patient reaches the target urate level and remains free of attacks for three months at this level.

Urate-lowering treatment In severe or frequent gout or gout with complications, lowering the urate level to less than 0.35 mmol/L (5.8 mg/dL) is essential for good management. If this can be achieved, tophi will resolve and the risk of further attacks will be very small. There are drug and nondrug means to achieve this, and a combination of the two is usually required. Urate-lowering treatment has been shown to be cost-effective if an individual is having more than two attacks of gout a year.

(a) Nondrug Urate-Lowering Therapy Weight loss will lower the urate level by 0.05 mmol/L (0.83 mg/dL) for every 10 kg lost. It will also improve blood pressure, diabetes, and hyperlipidemia if present. A low-protein diet will reduce urate levels by 0.06 mmol/L (1mg/dL). A high fluid intake assists urate loss in the urine and prevents kidney stone formation. The urate-lowering effect is small, however. Reducing alcohol intake and giving up beer altogether is very effective at lowering urate levels because of the mechanisms discussed under Cause above. Avoiding foods high in purines should be part of every gout patient's management plan. These are listed below in three groups according to their purine content. The first two groups should be avoided altogether and the third eaten in moderation.

• Very high purines—heart, herring, meat extracts, mussels, yeast

• High purines—anchovies, bacon, liver, mutton, salmon, venison, wild fowl, cod, haddock

• Moderate purines—asparagus, brains, chicken, beef, eel, kidney beans, lentils, lima beans, lobster, mushroom, peas, spinach, oysters, other fish, and meat products

(b) Drug Therapy allopurinol partially blocks the enzyme that forms uric acid from xanthine.

This leads to higher levels of xanthines. However, these are more soluble than urate and do not cause the same problems. it is the most effective urate-lowering drug and is commonly used first whether the patient is forming too much urate or not getting rid of it quickly enough. it is important to start at low doses and slowly build up so as not to cause increased attacks of gout during the early stages of treatment (see Prophylactic Treatment above). Allopurinol is also used to treat patients about to start chemotherapy for certain kinds of tumors (especially lymphomas and leukemias) since they can get massive release of uric acid. Unfortunately, somewhere between 5 and 20 percent of patients develop side effects on allopurinol that requires stopping it. Allopurinol also interacts with several other drugs, and patient and doctor need to be aware of these. This can be a particular problem in transplant patients.

if allopurinol is not tolerated, there are a number of drugs that increase the amount of uric acid passed in the urine. These are known as uricosuric drugs. The most effective is benzbromarone, which causes a similar degree of urate lowering to allo-purinol. it is also a very useful drug in transplant patients. Although used in Europe for many years, it is not available in the United States. probenecid is somewhat less effective, although reasonably well tolerated, with only 2 percent of patients stopping the drug because of side effects. it too has a number of interactions with other drugs (mainly in blocking their excretion by the kidneys), which can lead to serious problems if not taken into account. sulfinpyrazone is probably more effective than probenecid, but more people have side effects with it. it also has an anticlotting effect by reducing platelet function. This can be an advantage if someone needs antiplatelet treatment because of heart disease and the low-dose aspirin is being stopped while the urate levels are being lowered. once urate levels are stable at the required level, low-dose aspirin can usually be restarted without any problems. Sulfinpyrazone and benzbromarone are more effective than probenecid when there is poor kidney function.

Transplant gout Cyclosporine is used to prevent rejection in most transplant patients. Unfortunately, it causes high uric acid levels by altering blood flow through the kidneys, and many transplant patients get gout. There are several special problems in this situation. Allopurinol causes much higher-than-usual levels of azathioprine, another commonly used transplant drug, and this combination can lead to serious side effects. Colchicine very rarely causes damage to nerves and muscles, but this side effect becomes more frequent if cyclosporine is also being used. In addition, some of the uricosuric drugs may not be effective if kidney function is not adequate. Treatment of transplant gout is best undertaken in consultation with an experienced rheumatologist. Some strategies to overcome these problems include:

• Reducing the dose of azathioprine to about a third and monitoring carefully when starting allopurinol

• using urate oxidase to break uric acid down; this needs to be given into the veins once a month and is still experimental

• Using mycophenolate mofetil instead of aza-thioprine

• Using benzbromarone, which is an excellent urate-lowering drug in this situation

Gulf War syndrome A collection of symptoms occurring in veterans of the Gulf War. In January and February 1991, a coalition army led by the United States fought a war against Iraq. The war was unusual in that the risk of exposure of soldiers to biological agents was thought to be high and because burning oil wells exposed soldiers to potentially toxic substances. Approximately 700,000 U.S. troops were deployed in the Gulf War. In January 1992, reports appeared of an increased frequency of unexplained, unusual illnesses in soldiers who had returned. The term Gulf War syndrome appeared to come into usage more as a result of media attention than scientific definition of a unique constellation of symptoms that constituted a new syndrome. Much research has focused on the question of whether Gulf War syndrome exists as a unique illness. Although the answers are not clear, the weight of scientific evidence does not indicate the existence of a unique syndrome or illness.

Cause

The cause of Gulf War syndrome is not known. There are several conflicting opinions that can be divided into three main camps.

First, Gulf War syndrome does not exist as a discrete entity and was created by the media, not medical evidence. The term syndrome implies a unique grouping of symptoms, but no such grouping has been found in Gulf War veterans. In most studies of U.S., U.K., and Canadian soldiers, almost every symptom studied occurred more frequently in veterans of the Gulf War than in soldiers who were not deployed. There was no unique pattern to the increased symptoms. opponents of this position argue that the word syndrome is a semantic definition and that the absence of a defined syndrome does not imply the absence of illness. Renaming the condition Gulf War illness would overcome the inability of researchers to define reproducibly a clear syndrome. However, the term illness also requires a definition, something that has been difficult to establish.

Second, Gulf War syndrome is a poorly defined entity that is caused by psychological stress. Similar syndromes have been reported after many wars and was variously named shell shock, soldier's heart, and neurasthenia. The level of psychological stress resulting from the Gulf War may not have been as great as in previous wars if one considers the duration and intensity of fighting or the numbers of casualties; however, the type of stress was different. The risk of exposure to biological or chemical weapons was greater and may have resulted in prolonged anxiety and psychological stress, particularly in those people who believed they were exposed to harmful substances.

Third, Gulf War syndrome was caused by exposure to infectious or toxic substances, either alone or in combination. Several candidates have been proposed and studied. There is no reproducible relationship between exposure to depleted uranium, smoke from oil fires, vaccines, insecticides, and chemicals such as pyridostigmine that were used to protect against nerve gas and risk of developing Gulf War illness. However, many studies, particularly those examining the role of multiple vaccinations and exposure to potentially harmful agents, are ongoing. No infectious agent has repro-ducibly been associated with the illness. Some researchers reported finding an atypical myco-plasma and clinical response to treatment with an antibiotic, doxycyline, but others found no evidence of infection. clinical trials with doxycycline are being conducted.

Symptoms

Many symptoms have been reported, but the most common are fatigue, poor memory, myalgia, arthral-gia, diarrhea, rash, weakness, and neuropathy. Many of the symptoms overlap with fibromyalgia and chronic fatigue syndrome, and some patients fulfill diagnostic criteria for these conditions.

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