Gout

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Chapter 169 Gout

Michael T. Murray, ND

Diagnostic Summary

• Acute onset, frequently nocturnal, with typically monoarticular joint pain, involving the metatarsophalangeal joint of the big toe in about 50% of cases

• Elevated serum uric acid level

• Asymptomatic periods between acute attacks

• Identification of urate crystals in joint fluid

• Aggregated deposits of monosodium urate monohydrate (tophi) chiefly in and around the joints of the extremities but also in subcutaneous tissue, bone, cartilage, and other tissues

• Uric acid kidney stones

• Familial disease; 95% males

General Considerations

Gout is a common type of arthritis caused by an increased concentration of uric acid (the final breakdown product of purine metabolism) in biological fluids. In gout, uric acid crystals (monosodium urate) are deposited in joints, tendons, kidneys, and other tissues, where they cause considerable inflammation and damage.¹ Gout is a condition characterized biochemically by increased serum uric acid levels, leukotriene levels, and neutrophil accumulation. Gout may lead to debilitation owing to the tophaceous deposits around the joints and tendons; renal involvement may result in kidney failure due to either parenchymal disease or urinary tract obstruction.

Gout is associated with affluence and is often called the “rich man’s disease.” Throughout history, the sufferer of gout has been depicted as a portly, middle-aged man sitting in a comfortable chair with one foot resting painfully on a soft cushion as he consumes great quantities of meat and wine. In fact, the traditional picture does have some basis in reality, as meats, particularly organ meats, are high-purine foods, whereas alcohol inhibits uric acid secretion by the kidneys. Furthermore, even today, gout is primarily a disease of adult men; more than 95% of sufferers of gout are men older than age 30. The incidence of diagnosed gout cases has been estimated at 2.13% of the 2009 U.S. population, although 10% to 20% of the adult population has hyperuricemia. Gout is a strong predictor of the metabolic syndrome and an increased risk for type 2 diabetes.¹^–⁴

Causes of Gout

Gout is classified into two major categories: primary and secondary. Primary gout accounts for about 90% of all cases, whereas secondary gout accounts for only 10%. Primary gout is usually idiopathic (i.e., the underlying metabolic defect is unknown). However, there are several genetic defects in which the exact cause of the elevated uric acid is known.¹ The synthesis and degradation of purines are summarized in Figure 169-1.

FIGURE 169-1 Purine synthesis and degradation.

(From Nutrition Foundation. Nutrition reviews’ present knowledge in nutrition, ed 5. Washington, DC: Nutrition Foundation, 1984:740-756.)

The term secondary gout refers to those cases in which the elevated uric acid level is secondary to some other disorder such as excessive breakdown of cells or some form of renal disease. Diuretic therapy for hypertension and low-dose aspirin therapy are also important causes of secondary gout because they cause decreased uric acid excretion.

The increased serum uric acid level observed in primary idiopathic gout can be divided into three categories:

• Increased synthesis of uric acid, found in a majority of individuals

• Reduced ability to excrete uric acid, typical of a smaller group (about 30%)

• Overproduction of uric acid, as well as underexcretion of uric acid—a small minority

Although the exact metabolic defect in gout is unknown in the majority of cases, gout is one of the most controllable metabolic diseases. Box 169-1 summarizes the causes of gout.

BOX 169-1 Causes of Hyperuricemia

About 200 to 600 mg of uric acid are excreted daily in the urine of an adult male. This is two thirds of the amount produced, the rest being excreted in the bile and other gastrointestinal tract secretions. The dietary component of uric acid is usually 10% to 20%, but in an individual with significant hyperuricemia, 1 mg/100 mL may be added to the serum concentration of uric acid through the diet, enough to increase precipitation into the tissues if the individual is near the saturation threshold.

Almost all of the plasma urate is filtered at the glomerulus: only the small amount bound to protein is not filtered. Renal excretion is peculiar in that about 80% of the filtered uric acid is reabsorbed in the proximal tubule of the nephron. Actually, the distal tubule secretes most of the uric acid found in the urine. Distal to this site, some postsecondary reabsorption occurs. These events are summarized in Figure 169-2.

FIGURE 169-2 Normal uric acid excretion.

Uric acid is a highly insoluble molecule; at pH 7.4 and body temperature, the serum is saturated at 6.4 to 7 mg/100 mL. Although higher concentrations do not necessarily result in urate deposition (some unknown factor in serum appears to inhibit urate precipitation), the chance of an acute attack is greater than 90% when the level is above 9 mg/100 mL (Table 169-1). Lower temperatures decrease the saturation point of uric acid, which may explain why urate deposits tend to form in areas such as the pinna of the ear, where the temperature is lower than the mean body temperature (Table 169-2). Uric acid is insoluble below pH 6 and can precipitate as the urine is concentrated in the collecting ducts and passed to the renal pelvis.

TABLE 169-1 Prevalence of Gouty Arthritis by Maximum Urate Level

SERUM URATE (mg/100 mL)	MEN (%)	WOMEN (%)
<6	0.6	0.08
6-6.9	1.9	3.3
7-7.9	16.7	17.4
8-8.9	25	0
9+	90	0

Data from Faller J, Fox IH. Ethanol-induced hyperuricemia: evidence for increased urate production by activation of adenine nucleotide turnover. N Engl J Med 1982;307:1598-1602.

TABLE 169-2 Solubility of Urate Ion as a Function of Temperature in 140 mM Na+

TEMPERATURE (°C)	MAXIMUM SOLUBILITY (mg/100 mL)
37	6.8
35	6
30	4.5
25	3.3
20	2.5
15	1.8
10	1.2

Data from Faller J, Fox IH. Ethanol-induced hyperuricemia: evidence for increased urate production by activation of adenine nucleotide turnover. N Engl J Med 1982;307:1598-1602.

Signs and Symptoms

The first attack of gout is characterized by intense pain, usually involving only one joint. The first joint of the big toe is affected in nearly one half of the first attacks and is at some time involved in more than 90% of individuals with gout. If the attack progresses, fever and chills will appear. The first attacks usually occur at night and are generally preceded by a specific event such as dietary excess, alcohol ingestion, trauma, certain drugs, or surgery.

The classic description of gout was offered in 1683 by Sydenham, an English physician who suffered from gout. Little has changed in the clinical picture of gout in more than 300 years. Sydenham’s classic description is as follows:

The victim goes to bed and sleeps in good health. About two o’clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle, or instep. The pain is like that of a dislocation, and yet parts feel as if cold water were poured over them. Then follows chills and shivers, and a little fever. The pain which at first was moderate, becomes more intense. With its intensity the chills and fever increase. After a time this comes to a height, accommodating itself to the bones and ligaments of the tarsus and metatarsus. Now it is a violent stretching and tearing of the ligaments—now it is a gnawing pain and now a pressure and tightening. So exquisite and lively meanwhile is the feeling of the part affected, that it cannot bear the weight of bedclothes nor the jar of a person walking in the room. The night is passed in torture, sleeplessness, turning the part affected, and perpetual change of posture; the tossing about of the body being as incessant as the pain of the tortured joint, and being worse as the fit comes on. Hence the vain effort by change of posture, both in the body and the limb affected, to obtain an abatement of pain.

Subsequent attacks are common, with the majority of such individuals having another attack within 1 year. However, nearly 7% never have a second attack. Chronic gout rarely is an issue owing to the advent of dietary therapy and drugs that lower uric acid levels. When it does occur, chronic gout is due to poor compliance or inadequate response to treatment, or it may arise in patients with high flare frequency, tophi, and the inability to maintain serum urate levels below 6 mg/dL.² Some degree of kidney dysfunction occurs in nearly 90% of subjects with gout, and there is a higher risk of kidney stones.

Therapeutic Considerations

The current standard medical treatment of acute gout is administration of colchicine, the antiinflammatory drug originally isolated from the plant Colchicum autumnale (autumn crocus, meadow saffron). Colchicine has no effect on uric acid levels; rather, it stops the inflammatory process by inhibiting neutrophil migration into areas of inflammation.

More than 75% of patients with gout show a major improvement in symptoms within the first 12 hours after receiving colchicine. However, up to 80% of patients are unable to tolerate an optimal dose because of gastrointestinal side effects, which may precede or coincide with clinical improvement.

Colchicine may also cause bone marrow depression, hair loss, liver damage, depression, seizures, respiratory depression, and even death. Other antiinflammatory agents are also used in acute gout, including various nonsteroidal antiinflammatory drugs, indomethacin, phenylbutazone, naproxen, and fenoprofen.

Once the acute episode has resolved, a number of measures are taken to reduce the likelihood of recurrence:

• Drugs like allopurinol or febuxostat to keep uric acid levels within a normal range

• Controlled weight loss in obese individuals

• Avoidance of known precipitating factors such as heavy alcohol consumption or a diet rich in purines or refined carbohydrates

• Low doses of colchicine to prevent further acute attacks

Several dietary factors are known to cause gout: consumption of alcohol, especially beer and hard liquor; foods high in purine content (e.g., organ meats, meat, yeast, poultry); fats; refined carbohydrates, especially high-fructose corn syrup; and overconsumption of calories.⁵ Individuals with gout are typically obese; they are prone to hypertension, the metabolic syndrome, and diabetes and are at a greater risk for cardiovascular disease. Obesity is probably the most important dietary factor. Thiazide and loop diuretics are also associated with a higher risk of incident gout and higher rate of gout flares.⁵

In concept, the naturopathic approach for chronic gout does not differ substantially from the standard medical approach. However, naturopaths focus on dietary and herbal measures to keep uric acid levels within the normal range rather than on the use of drugs. In the conventional medical treatment of gout, drugs that inhibit xanthine oxidase are often too much relied upon. Allopurinol, a structural isomer of hypoxanthine (a naturally occurring purine in the body), has been the mainstay treatment for decades. However, in February 2009, the U.S. Food and Drug Administration approved febuxostat (Uloric), another xanthine oxidase inhibitor; it is a more effective treatment for lowering and maintaining serum urate levels.⁶ Febuxostat is beginning to supplant allopurinol in the conventional management of gout. Uricosuric agents (probenecid, sulfinpyrazone, and benzbromarone) are used as second-line therapy for patients with underexcretion of uric acid.

Lead Toxicity

An additional item of concern relates to lead toxicity. A secondary type of gout, sometimes called saturnine gout, can result from lead toxicity. Historically, saturnine gout was due to the consumption of alcoholic beverages stored in containers with lead in them. An unexpected and fairly common source of lead appears to be leaded crystal, because port wine elutes lead when stored in a crystal decanter.⁶ Lead concentration increases with storage time, reaching toxic levels after several months. Even a few minutes in a crystal glass results in a measurable increase in the level of lead in the wine. Lead promotes hyperuricemia as a result of decreasing renal urate excretion.

Dietary Considerations

The dietary treatment of gout involves the following guidelines:

• Elimination of alcohol intake

• Low purine intake

• Achievement of ideal body weight

• Liberal consumption of complex carbohydrates

• Low fat intake

• Low protein intake

• Liberal fluid intake

Alcohol

Alcohol increases uric acid production by accelerating purine nucleotide degradation; it also reduces uric acid excretion by increasing lactate production (a result of ethanol oxidation), which impairs kidney function. The net effect is a significant increase in serum uric acid levels. This explains why alcohol consumption is often a precipitating factor in acute attacks of gout. In many individuals, elimination of alcohol is all that is necessary to reduce uric acid levels and prevent gouty arthritis.

Low-Purine Alkaline-Ash Diet

A low-purine diet has been the mainstay of the dietary therapy of gout for many years. However, with the advent of potent drugs that lower uric acid levels, many physicians lower serum urate levels without subjecting the patient to the inconvenience and deprivation associated with a purine-free diet. However, dietary restriction of purines is recommended to reduce metabolic stress. Foods with high purine levels should be entirely omitted. These include organ meats, meats, shellfish, yeast (brewer’s and baker’s), herring, sardines, mackerel, and anchovies. Foods with moderate levels of protein should be curtailed as well. These include dried legumes, spinach, asparagus, fish, poultry, and mushrooms.

An alkaline-ash diet is recommended in the dietary treatment of gout, because a more alkaline pH increases uric acid solubility. An alkaline-ash diet was shown to increase uric acid excretion from 302 mg/day at pH 5.9 to 413 mg/day at pH 6.5.⁸

Weight Reduction

Excess weight is associated with an increased rate of gout. Weight reduction in obese individuals significantly reduces levels of serum uric acid levels.⁹ Weight reduction should involve the use of a low glycemic diet designed to improve insulin sensitivity. Such a diet also helps to manage the elevated cholesterol and triglycerides that are common in obesity.

Carbohydrates, Fats, and Protein

Refined carbohydrates and saturated fats should be kept to a minimum, as the former increase uric acid production, whereas the latter increase uric acid retention. In addition, one of the key dietary goals in the treatment of gout appears to be the enhancement of insulin sensitivity.⁹

Protein intake should not be excessive (i.e., >0.8 g/kg per day), because it has been shown that uric acid synthesis may be accelerated in both normal and gouty patients by a high protein intake.⁵ Adequate protein is necessary (0.8 g/kg daily); however, amino acids decrease the resorption of uric acid in the renal tubules, thus increasing uric acid excretion and reducing serum uric acid concentrations.⁷

Fluid Intake

Liberal fluid intake keeps the urine dilute and promotes the excretion of uric acid. Furthermore, dilution of the urine reduces the risk of kidney stones.

Nutritional Supplements

Eicosapentaenoic Acid

Eicosapentaenoic acid (EPA) supplementation may prove useful in the treatment of gout. EPA limits the production of the proinflammatory leukotrienes, the mediators of much of the inflammation and tissue damage observed in gout.

Folic acid has been shown to inhibit xanthine oxidase, the enzyme responsible for producing uric acid.¹⁰ Research has demonstrated that a derivative of folic acid is an even greater inhibitor of xanthine oxidase than allopurinol, suggesting that folic acid at pharmacologic doses may be an effective treatment for gout.¹¹ Positive results in the treatment of gout have been reported, but the data are incomplete and uncontrolled.¹²

Botanical Medicines

Cherries

Consuming one-half pound of fresh or canned cherries per day has been shown to be effective in lowering uric acid levels and preventing attacks of gout.¹⁸ To assess the physiologic effects of cherry consumption, one study measured plasma urate, antioxidant, and inflammatory markers in 10 healthy women who consumed two servings (280 g) of cherries after an overnight fast.¹⁹ Blood and urine samples were taken before the cherry dose and at 1.5, 3, and 5 hours afterward. Plasma urate decreased 5 hours after the cherry consumption by an average of 30 mmol/L. This reduction correlated with an increase in urine urate excretion. Plasma C-reactive protein and nitric oxide concentrations decreased slightly after the 3-hour mark.

Cherries, hawthorn berries, blueberries, and other dark red and blue berries are rich sources of anthocyanidins and proanthocyanidins. These compounds are flavonoid molecules, which give these fruits their deep red-blue color, and are remarkable in their ability to prevent collagen destruction. Anthocyanidins and other flavonoids affect collagen metabolism in many ways:

• They have the unique ability to actually cross-link collagen fibers, resulting in reinforcement of the natural cross-linking of collagen that forms the collagen matrix of connective tissue (e.g., ground substance, cartilage, tendon).

• They prevent free radical damage through their potent antioxidant and free radical scavenging action.

• They inhibit enzymatic cleavage of collagen by enzymes secreted by leukocytes during inflammation.

• They prevent the release and synthesis of compounds that promote inflammation, such as histamine, serine proteases, prostaglandins, and leukotrienes.