Approach to the Patient with Asymptomatic Hyperuricemia

Hyperuricemia is defined physiologically as the level above which the serum is fully saturated with uric acid (i.e., serum uric acid concentration >6.8 mg/d [>404 µmol/L]). It corresponds to the concentration above which the risks of developing gout and other complications of hyperuricemia begin to increase markedly.

Prevalence of hyperuricemia has been rising in recent decades concordant with increases in such risk factors as age and obesity. Prevalence estimates range from less than 10% up to 25% and are highest in the elderly. On average, about one in five hyperuricemic patients eventually goes on to develop clinical gout, with risk increasing in proportion to urate concentration and age.

Asymptomatic hyperuricemia became commonplace when physicians began ordering chemistry panels that routinely included measurement of the serum uric acid. The consequences of being hyperuricemic and the need for urate-lowering therapy in the absence of symptoms have been subjects of considerable debate. While lowering the serum uric acid can reduce the risk of gouty attacks and symptomatic urate kidney stones, the safety and cost-effectiveness of doing so in asymptomatic persons remains an issue. The association of elevations in serum uric acid with cardiovascular disease (CVD) and other cardiovascular risk factors (e.g., hypertension, hyperinsulinism, renal insufficiency) raises questions of cause versus effect and the potential role of urate-lowering therapy in reducing cardiovascular event risk.

The primary care physician needs to take these considerations into account as well as the costs and potential adverse effects of urate-lowering therapy when encountering the patient with asymptomatic hyperuricemia.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 and 27)

Pathophysiology of Hyperuricemia

Uric acid is the end product of purine metabolism. Humans have no pathway for the further breakdown of uric acid; it must be excreted by the kidneys or the serum level will rise. The pathogenesis of hyperuricemia involves the overproduction and/or underexcretion of urate. It is estimated that one third of hyperuricemic patients are overproducers, another one third are underexcreters, and the remainder have a combined deficit.

Overproduction of uric acid is especially marked in patients acutely undergoing treatment for myeloproliferative or lymphoproliferative malignancy (so-called tumor lysis syndrome) and in those with severe psoriasis. Rapid cellular turnover results in the production of massive amounts of nucleic acid metabolites that are converted to uric acid. Overproduction may also develop from an increase in purine synthesis de novo, as occurs in patients with inborn errors of metabolism and from consuming large quantities of beverages and foods sweetened with fructose, largely from the ubiquitous addition of high-fructose corn syrup. (High fructose intake depletes ATP, causing increase in purine production that leads to high levels of urate.) Contrary to popular belief, excessive dietary intake of purine-rich foods (fatty meats, shellfish) makes only a modest contribution to urate production (estimate: 10% of the uric acid pool). However, excessive intake of alcohol (>100 g of ethanol per day) can result in a more substantial increase in urate synthesis, especially if the patient does not eat anything at the time of alcohol consumption.

Underexcretion of uric acid occurs in association with an overall decrease in the glomerular filtration or a defect in the tubular secretion of urate; uric acid is also underexcreted if another substance competes with urate for tubular secretion. A compromise in renal blood flow secondary to aging or atherosclerotic disease reduces renal urate excretion. Hyperuricemia has been noted in hypertensive patients. Although some instances may be a consequence of hypertensive renovascular injury, epidemiologic analysis suggests that most cases are caused by thiazide use. In addition to thiazides, low doses of aspirin, niacin, and loop diuretics reduce renal urate excretion. Excretion falls in patients with an increased proximal tubular reabsorption of sodium, which has been linked to the hyperinsulinism seen in patients with the metabolic syndrome (obesity, hypertension, dyslipidemia—see Chapters 18, 27, 31,
and 102) and might account for the oft-noted, poorly understood relation between hyperuricemia and atherosclerotic CVD. Presence of the metabolic syndrome increases markedly with increase in uric acid, to as high as 70% in persons with uric acid levels in excess of 10 mg/dL. Fasting that results in ketosis seems to be capable of transiently reducing urate excretion and raising the serum uric acid. Obesity appears to be another risk factor, especially for triggering gouty attacks associated with hyperuricemia. Exposure to lead, even in the absence of toxic blood levels, is associated with increase prevalence of hyperuricemia independent of risk factors for decreased excretion or increased production, purported mechanisms of lead’s effect on urate handling.

Pathophysiology of Adverse Consequences

Serum saturation of uric acid leads to deposits of uric acid in synovial tissue and urate crystals in the synovial fluid, triggering joint inflammation that presents as acute gouty arthritis (see Chapter 158). In addition, urate kidney stone formation may ensue as the urine becomes supersaturated from increased urate excretion (see Chapter 135). Urate deposition in subcutaneous tissues leads to tophi. A sudden flooding of renal tubules with uric acid in the setting of chemotherapy for myeloproliferative or lymphoproliferative malignancy can trigger acute renal failure. Hyperuricemia has an association with atherosclerotic disease and chronic kidney disease, but the statistical relationship has yet to be proven etiologic.

Cardiovascular Risk

There has been ongoing debate about the oft-noted association between hyperuricemia and cardiovascular disease (CVD). At issue is whether or not hyperuricemia is an independent CVD risk factor and thus an important pathophysiologic determinant that requires early detection and treatment. In the landmark Framingham Study, the association with CVD risk was noted, but multivariate analysis found hyperuricemia not to be an independent determinant of risk, but rather a consequence of concurrent thiazide therapy for hypertension. As noted, others have pointed out hyperuricemia’s association with metabolic syndrome and its hyperinsulinism, a major contributor to CVD risk and an important cause of vascular endothelial dysfunction (see Chapters 31 and 102). One pathophysiologic hypothesis is that many CVD risk factors, including hyperuricemia, share a common hyperinsulinemic pathophysiology.

A small body of evidence is emerging suggesting a more etiologic CVD role for hyperuricemia. Findings such as hyperuricemia preceding onset of CVD and its more established risk factors are giving some pause to the view that hyperuricemia has minimal CVD significance. In particular, the presence of hyperuricemia before onset of hypertension, its predictiveness for development of hypertension, and its being uncommon in secondary hypertension suggest a more etiologic role or at least a common pathophysiology. Recent animal model studies find that elevations in uric acid can trigger increases in blood pressure, and endothelial function studies show that hyperuricemia is associated with increases in plasma renin activity, a precipitant of hypertension.

As intriguing as these findings are, considerably more work is needed before hyperuricemia can be considered a primary, independent CVD risk factor worth treating.

Chronic Kidney Disease Risk

Early studies suggesting that hyperuricemia can cause significant decline in renal function were confounded by high levels of lead exposure in the study populations. Subsequent investigations found chronic hyperuricemia did not appear to be a significant risk factor for the development of azotemia, nor did hyperuricemia secondary to renal failure pose an additional threat to the kidneys. In a prospective study from Kaiser Permanente in which 113 patients with asymptomatic hyperuricemia and 193 controls were followed for 8 years, no difference was found in the incidence of azotemia between the two groups (1.8% vs. 2.1%). In the same study, no relation between uric acid level and risk for azotemia was found in 168 patients with clinical gout followed for 10 years. In the Normative Aging Study, a creatinine level greater than 2.0 mg/dL developed in only 0.7% of the 94 patients with a uric acid level greater than 9.0 mg/dL during the 15 years of follow-up. One set of investigators calculated that a significant risk for renal injury from chronic hyperuricemia required that a uric acid level of 13.0 mg/dL in men and 10.0 mg/dL in women be sustained for 40 years. A 3-year prospective study of hyperuricemic patients with and without renal failure showed no change in renal function when allopurinol was used to normalize the serum urate concentration.

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