Supplements Update on the Diagnosis and Treatment of Gout
Understanding Treatments for Gout
Gout is one of the most readily manageable of the rheumatic diseases. This article reviews basic pathways in purine metabolism, uric acid handling, and the pathogenic mechanism of clinical gout, as well as the areas in those pathways amenable to intervention. Attention is also given to associated comorbidities, such as hyperuricemia and obesity, hypertension, hyperinsulinemia, and coronary artery disease. The significance of lifestyle modifications, such as weight loss and alcohol reduction, is discussed as an important adjunct to pharmacotherapy in gout. Current and investigational agents used in gout management are also reviewed. Finally, treatment recommendations for acute and chronic gout are suggested.
(Am J Manag Care. 2005;11:S451-S458)
The clinical description of gout dates back to antiquity, and evidence of the disease has been found in early skeletal remains.1 Physicians since the time of Hippocrates have sought to understand the origin of gout and alleviate its suffering. Modern medicine has led to a clearer understanding of the biochemical pathway of purine nucleotide metabolism, leading to the formation of monosodium urate (MSU) crystals and the pathogenesis of clinical gout.2,3 As a result, advances in therapy have made gout one of the most readily manageable rheumatic diseases.
Although a complete review of purine metabolism, uric acid handling, and the pathogenic mechanism of clinical gout is beyond the scope of this article, a brief overview of each is warranted to better comprehend current therapeutic strategies for gout. Figure 1 illustrates a simplified schematic of urate handling and the factors that can have both a negative and positive impact in the context of gout management.
Purine Metabolism and Hyperuricemia
Purines are crucial for a range of normal physiologic functions. They are the essential building blocks for nucleic acids (deoxyribonucleic and ribonucleic acid), extra- and intracellular messengers (adenosine triphosphate and G-protein coupled reactions), metabolic regulators (cyclic adenosine monophosphate), coenzymes, antioxidants, and neurotransmitters. In humans, uric acid is the end product of purine degradation. It exists as the urate ion at physiologic pH and has a very narrow window of solubility. The enzyme xanthine oxidase is required for the conversion of xanthine to urate. Humans lack the enzyme urate oxidase (uricase), which converts urate in other species to the highly soluble compound allantoin. This may have conferred a survival advantage because of the function of uric acid as an antioxidant. Urate oxidase is present in most fish, amphibians, and nonprimate mammals.4
About one third of the daily urate load comes from dietary sources, with the remainder generated endogenously. Once urate has been formed, it can be eliminated by the gastrointestinal tract or kidneys, or deposited in tissue. Enteric excretion is responsible for handling one third of the daily urate load.5 The remainder is handled primarily by the kidneys. Approximately 95% of urate is filtered by the glomerulus and subsequently undergoes bidirectional proximal convoluted tubule (PCT) movement with presecretory reabsorption (99%), secretion (50%), and postsecretory reabsorption (40%-50%). The movement of urate is accomplished via several recently described anion transmembrane channels.4,6,7 The balance between the PCT's secretory and reabsorptive activities exerts a major influence on renal excretion of uric acid. Although the secretory capacity of the kidneys can increase with hyperuricemia, the compensation is often not enough. Therefore, in the majority (90%) of patients with primary gout, hyperuricemia results from relative renal underexcretion, whereas in 10% of patients there is overproduction of endogenous uric acid.8
Gout Risk Factors and Disease Comorbidity
The transition from hyperuricemia to the formation of uric acid crystals and subsequent inflammation is dependent on several factors in the local microenvironment, including both pH and temperature. Once crystals form, an intense inflammatory response is triggered. There is an initial interaction with mononuclear cells, which results in a release of inflammatory cytokines and chemokines, resulting in neutrophil recruitment and activation. Once neutrophils migrate to the site of inflammation, there is aggressive phagocytosis of the uric acid crystals, delayed phagocytic apoptosis, and, ultimately, neutrophil death with massive enzyme and mediator release, which leads to the clinical acute gouty attack.2,4
Although it is clear that hyperuricemia is the harbinger of gout, both genetic and environmental factors are recognized contributors to the development of hyperuricemia.9 Hypertension, the use of thiazide or loop diuretics, obesity, a high alcohol intake, and certain dietary factors (ie, high meat intake) all contribute in an additive manner to the risk of developing hyperuricemia and gout.10-13 These are modifiable risk factors, and targeting lifestyle and health behaviors is important not only for secondary prevention and treatment of gout, but also for the overall health of the patient.
For example, a strong correlation exists between obesity, hyperuricemia,8,14,15 and gout.16 Furthermore, hyperinsulinemia and insulin resistance syndrome (metabolic syndrome) have been estimated to occur in 95% and 76% of gout sufferers, respectively.17 Hyperinsulinemia stimulates the renal tubular sodium-hydrogen exchanger to reabsorb sodium and uric acid, resulting in hypertension and hyperuricemia, respectively.18-20 In addition to centripetal obesity, hypertension, and hyperuricemia, insulin resistance syndrome is often associated with hypertriglyceridemia, type 2 diabetes, and coronary artery disease. Indeed, numerous studies have shown an association of hyperuricemia with both cardiovascular morbidity and mortality.21 Thus, even in the absence of clinical gout, hyperuricemia may serve as an important surrogate marker of insulin resistance and warrant screening and treatment for its comorbidities.8
Gout Treatment: Lifestyle and Health Factors
Dietary Factors. Consumption of highpurine meats and shellfish has been associated with an increased risk of gout, but consumption of purine-rich vegetables, such as spinach, has not.22
Traditional low-purine diets, once a mainstay of gout management, are difficult for patients to adhere to and less crucial now that potent and effective urate-lowering therapy is available.8 Dietary intervention has received recent attention, however, because of the association of hyperuricemia with insulin resistance. In a pilot study of men with gout, serum levels of urate and the rate of acute gouty attacks significantly decreased by 17.5% and 71%, respectively, with a diet moderately restricted in calories and carbohydrates and increased proportional intake of protein and unsaturated fats. Additionally, weight and triglycerides decreased significantly. The beneficial effects of this diet are likely mediated via improved insulin sensitivity, reduction of plasma insulin levels, and increased renal excretion of urate with concomitant lowering of serum urate levels.17
Alcohol Intake. Alcohol consumption is also closely associated with gout, and it is estimated that more than one half of gout sufferers drink excessively.23-25 Several factors contribute to this relationship: transient lactic acidemia from acute alcohol excess reduces renal urate excretion26; long-term alcohol ingestion stimulates purine production27; alcohol (especially beer28) contains purines26,27; and lead-contaminated beverages (ie, moonshine) reduce renal urate excretion.29 In patients with hyperuricemia, an alcohol history should be sought, with strong recommendations to reduce or discontinue drinking.8
Hypertension and Medications. Hypertension reduces renal excretion of urate4,30 leading to hyperuricemia. Thiazide and loop diuretics, often used in the treatment of hypertension, further increase serum urate levels by interfering with renal tubular ion transport and lead to effective volume depletion, which causes PCT urate reabsorption.31 Cyclosporine, an immunosuppressant commonly used to prevent graft rejection in patients undergoing solid organ transplantation, substantially reduces the renal clearance of serum urate, leading to both hyperuricemia and an increased risk of gout.32 Other commonly used medications that influence renal handling of uric acid are aspirin and estrogen. Low-dose aspirin (up to 1-2 g/day) decreases renal urate excretion, especially in the setting of low albumin. Paradoxically, high-dose aspirin actually has a uricosuric effect, leading to an increase in urate excretion. Estrogen also exerts a uricosuric effect. It is possible that declining use of postmenopausal estrogen replacement may lead to an increase in postmenopausal gout and an earlier age of onset.2,33 As discussed below, 2 cardiovascular drugs, losartan and fenofibrate, also have uricosuric effects.
Gout Treatment: Pharmacotherapy
Although nondrug therapy certainly plays an important role in gout management, pharmacologic therapy remains the mainstay. Most people with asymptomatic hyperuricemia do not develop clinical gout; therefore, in most cases, treatment is not necessary.34,35 However, hyperuricemia should be thought of as a marker for associated comorbidities, as outlined above, and these comorbidities should be screened for and treated.
Although somewhat controversial, possible treatment exceptions include uric acid levels >13 mg/dL (733 µmol/L) in men and >10 mg/dL (595 µmol/L) in women because of a possible nephrotoxic risk; urinary uric acid excretion of >1100 mg/day (6.5 mmol/day), which increases the risk of nephrolithiasis. Additionally, urate-lowering therapy is indicated in patients at risk for tumor lysis syndrome because of high cell turnover, such as those undergoing treatment for leukemia.36
Treatment of Acute Gout. The goal of therapy is rapid resolution of pain and inflammation (Figure 2). Nonsteroidal antiinflammatory drugs (NSAIDs) are the treatment of choice in most patients with acute gout who are otherwise healthy. A number of head-to-head studies have shown most NSAIDs to be equivalent; thus, the choice of NSAID is not as important as initiating therapy early in an attack. More than 90% of patients will experience complete resolution of the attack within 5 to 8 days.37,38 Higher doses may be needed in the first 24 to 48 hours and should be tapered as symptoms allow. Unfortunately, the use of NSAIDs is limited by adverse effects, and they should be used cautiously or not at all in patients with any of the following: significant renal impairment, poorly controlled congestive heart failure, history of or active peptic ulcer disease, anticoagulation therapy, or hepatic dysfunction.38,39
Colchicine is derived from the autumn crocus and has been in widespread use since the early 1800s,40 first as a plant extract and later in pill form. The mechanism of action is due to interference of tubulin dimers40 and subsequent leukocyte functions, including diapedesis, lysosomal degranulation, and chemotaxis. Colchicine is most effective during the first 12 to 24 hours of an attack. It can be given orally or intravenously; however, it has the smallest benefit-to-toxicity ratio of all the drugs used in the management of gout and should therefore be used with caution.41