Hyperuricemia 

Uric acid is the final product of purine metabolism in human beings. Despite the fact that uric acid was first identified approximately 2 centuries ago, certain pathophysiologic aspects of hyperuricemia are still not clearly understood. For years, hyperuricemia has been identified with or thought to be the same as gout, but uric acid has now been identified as a marker for a number of metabolic and hemodynamic abnormalities

Unlike allantoin, the more soluble end product found in lower animals, uric acid is a poorly soluble end product of purine metabolism in humans. Human beings have higher levels of uric acid, in part, because of a deficiency of the hepatic enzyme, uricase, and a lower fractional excretion of uric acid. Approximately two thirds of total body urate is produced endogenously, while the remaining one third is accounted for by dietary purines. Approximately 70% of the urate produced daily is excreted by the kidneys, while the rest is eliminated by the intestines. However, during renal failure, the intestinal contribution of urate excretion increases to compensate for the decreased elimination by the kidneys.

The blood levels of uric acid are a function of the balance between the breakdown of purines and the rate of uric acid excretion. Theoretically, alterations in this balance may account for hyperuricemia, although clinically defective elimination accounts for most cases of hyperuricemia.

Uric acid in the blood is saturated at 6.4-6.8 mg/dL at ambient conditions, with the upper limit of solubility placed at 7 mg/dL. Urate is freely filtered at the glomerulus, reabsorbed, secreted, and then again reabsorbed in the proximal tubule. The recent cloning of certain urate transporters will facilitate the understanding of specific mechanisms by which urate is handled in the kidney and small intestines.

A urate/anion exchanger (URAT1) has been identified in the brush-border membrane of the kidneys and is inhibited by an angiotensin II receptor blocker, losartan. A human organic anion transporter (hOAT1) has been found to be inhibited by both uricosuric drugs and antiuricosuric drugs, while another urate transporter (UAT) has been found to facilitate urate efflux out of the cells. These transporters may account for the reabsorption, secretion, and reabsorption pattern of renal handling of urate.

Urate secretion does appear to correlate with the serum urate concentration because a small increase in the serum concentration results in a marked increase in urate excretion.

Hyperuricemia may occur because of decreased excretion (underexcretors), increased production (overproducers), or a combination of these two mechanisms.

Underexcretion accounts for most causes of hyperuricemia. Urate handling by the kidneys involves filtration at the glomerulus, reabsorption, secretion, and, finally, postsecretory reabsorption. Consequently, altered uric acid excretion can result from decreased glomerular filtration, decreased tubular secretion, or enhanced tubular reabsorption. While decreased urate filtration may not cause primary hyperuricemia, it can contribute to the hyperuricemia of renal insufficiency. Decreased tubular secretion of urate occurs in patients with acidosis (eg, diabetic ketoacidosis, ethanol or salicylate intoxication, starvation ketosis). The organic acids that accumulate in these conditions compete with urate for tubular secretion. Finally, enhanced reabsorption of uric acid distal to the site of secretion is the mechanism thought to be responsible for the hyperuricemia observed with diuretic therapy and diabetes insipidus.

Overproduction accounts for only a minority of patients presenting with hyperuricemia. The causes for hyperuricemia in overproducers may be either exogenous (diet rich in purines) or endogenous (increased purine nucleotide breakdown). A small percentage of overproducers have enzymatic defects that account for their hyperuricemia. These include a complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HGPRT) as in Lesch-Nyhan syndrome, partial deficiency of HGPRT (Kelley-Seegmiller syndrome), and increased production of 5-phospho-alpha-d-ribosyl pyrophosphate (PRPP) activity. Accelerated purine degradation can result from rapid cell proliferation and turnover (blast crisis of leukemias) or from cell death (rhabdomyolysis, cytotoxic therapy). Glycogenoses types III, IV, and VII can result in hyperuricemia from excessive degradation of skeletal muscle ATP.

Combined mechanisms (underexcretion and overproduction) can also cause hyperuricemia. The most common cause under this group is alcohol consumption,^[1] which results in accelerated hepatic breakdown of ATP and the generation of organic acids that compete with urate for tubular secretion. Enzymatic defects such as glycogenoses type I and aldolase-B deficiency are other causes of hyperuricemia that result from a combination of overproduction and underexcretion.

New findings revealed that urate crystals can engage an intracellular pattern recognition receptor, the macromolecular NALP3 (cryopyrin) inflammasome complex.^{[2, 3]} NALP3 inflammasome may result in interleukin 1 (IL-1) beta production, which, in turn, incites an inflammatory response. Inhibition of this pathway has the potential to be targeted for hyperuricemia-induced crystal arthritis.

Frequency

United States

The prevalence rate of asymptomatic hyperuricemia in the general population is estimated at 2-13%.

International

A Japanese study that used an administrative claims database to ascertain 10-year trends in the prevalence of hyperuricemia concluded that the prevalence of hyperuricemia in the overall study population increased during the 10-year follow-up. When stratified by age, the prevalence increased among groups older than 65 years in both sexes. In those younger than 65 years, men had a prevalence 4 times higher than that in women, but in those older than 65 years, the gender gap narrowed to 1:3 (female-to-male ratio) with gout and/or hyperuricemia.

Mortality/Morbidity

Hyperuricemia has been associated with increased morbidity^[4] in patients with hypertension and is associated with increased mortality in women and elderly persons. The cause for this is unknown, but hyperuricemia is probably a marker for comorbid risk factors rather than a causative factor, per se.

Although observational studies on hyperuricemia and stroke have yielded conflicting results, a meta-analysis by Kim et al suggested that hyperuricemia may modestly increase the risk of stroke incidence and mortality.^[5] The authors reviewed 16 studies that together included 238,449 adults. Investigating risk ratios (RRs) for the incidence of stroke and mortality in relation to serum uric acid levels in adults, the authors found that in studies that adjusted for known risk factors, the RR for stroke in patients with hyperuricemia was 1.47 (4 studies; 95% confidence interval [CI] 1.19, 1.76) and the RR for mortality was 1.26 (6 studies; 95% CI 1.12, 1.39). Kim et al concluded that further research is needed to determine if reducing patients' uric acid levels will have beneficial effects relating to stroke.

Race

A high prevalence of hyperuricemia exists in indigenous races of the Pacific, which appears to be associated with a low fractional excretion of uric acid. African American persons develop hyperuricemia more commonly than white persons.

Sex

Hyperuricemia, and particularly gouty arthritis, are far more common in men than in women. Only 5% of patients with gout are female, but uric acid levels increase in women after menopause.

Age

The normal serum uric acid level is lower in children than in adults. The upper limit of the reference range for children is 5 mg/dL (0.30 mmol/L). The upper limit of the reference range for men is 7 mg/dL (0.42 mmol/L) and for women is 6 mg/dL (0.36 mmol/L). The tendency to develop hyperuricemia increases with age.