Hyperuricemia can result from increased production or decreased excretion of uric acid or from a combination of the two processes. Sustained hyperuricemia predisposes some individuals to develop clinical manifestations including gouty arthritis (Chap. 395), urolithiasis, and renal dysfunction (see below).
In general, hyperuricemia is defined as a plasma (or serum) urate concentration >405 μmol/L (>6.8 mg/dL). The risk of developing gouty arthritis or urolithiasis increases with higher urate levels and escalates in proportion to the degree of elevation. The prevalence of hyperuricemia is increasing among ambulatory adults and even more markedly among hospitalized patients. The prevalence of gout in the United States more than doubled between the 1960s and the 1990s. Based on NHANES data from 2007–2008, these trends continue, with an approximate prevalence of gout among men of 5.9% (6.1 million) and among women of 2.0% (2.2 million). Mean serum urate levels rose to 6.14 mg/dL among men and 4.87 mg/dL among women, with consequent hyperuricemia prevalences of 21.2% and 21.6%, respectively (with hyperuricemia defined as a serum urate level of >7.0 mg/dL [415 μmol/L] for men and >5.7 mg/dL [340 μmol/L] for women). These numbers represent a 1.2% increase in the prevalence of gout, a 0.15-mg/dL increase in the serum urate level, and a 3.2% increase in the prevalence of hyperuricemia over figures reported in NHANES-III (1988–1994). These rises are thought to be driven by increased obesity and hypertension and perhaps also by better medical care and increased longevity.
Hyperuricemia may be classified as primary or secondary, depending on whether the cause is innate or an acquired disorder. However, it is more useful to classify hyperuricemia in relation to the underlying pathophysiology—i.e., whether it results from increased production, decreased excretion, or a combination of the two (Fig. 431e-1, Table 431e-2).
Increased Urate Production
Diet contributes to the serum urate concentration in proportion to its purine content. Strict restriction of purine intake reduces the mean serum urate level by ~60 μmol/L (~1 mg/dL) and urinary uric acid excretion by ~1.2 mmol/d (~200 mg/d). Foods high in nucleic acid content include liver, “sweetbreads” (i.e., thymus and pancreas), kidney, and anchovy.
Endogenous sources of purine production also influence the serum urate level (Fig. 431e-3). De novo purine biosynthesis is a multistep process that forms inosine monophosphate (IMP). The rates of purine biosynthesis and urate production are predominantly determined by amidophosphoribosyltransferase (amidoPRT), which combines phosphoribosylpyrophosphate (PRPP) and glutamine. A secondary regulatory pathway is the salvage of purine bases by hypoxanthine phosphoribosyltransferase (HPRT). HPRT catalyzes the combination of the purine bases hypoxanthine and guanine with PRPP to form the respective ribonucleotides IMP and guanosine monophosphate (GMP).
Abbreviated scheme of purine metabolism. (1) Phosphoribosylpyrophosphate (PRPP) synthetase, (2) amidophosphoribosyltransferase (amidoPRT), (3) adenylosuccinate lyase, (4) (myo-)adenylate (AMP) deaminase, (5) 5′-nucleotidase, (6) adenosine deaminase, (7) purine nucleoside phosphorylase, (8) hypoxanthine phosphoribosyltransferase (HPRT), (9) adenine phosphoribosyltransferase (APRT), and (10) xanthine oxidase. PRA, phosphoribosylamine; SAICAR, succinylaminoimidazole carboxamide ribotide; AICAR, aminoimidazole carboxamide ribotide; GMP, guanylate; IMP, inosine monophosphate; ATP, adenosine triphosphate.
Serum urate levels are closely coupled to the rates of de novo purine biosynthesis, which is driven in part by the level of PRPP, as evidenced by two X-linked inborn errors of purine metabolism (Table 431e-3). Both increased PRPP synthetase activity and HPRT deficiency are associated with overproduction of purines, hyperuricemia, and hyperuricaciduria (see below for clinical descriptions).
TABLE 431e-3Inborn Errors of Purine Metabolism ||Download (.pdf) TABLE 431e-3 Inborn Errors of Purine Metabolism
|Enzyme ||Activity ||Inheritance ||Clinical Features ||Laboratory Features |
|Hypoxanthine phosphoribosyltransferase ||Complete deficiency ||X-linked ||Self-mutilation, choreoathetosis, gout, and uric acid lithiasis ||Hyperuricemia, hyperuricosuria |
| ||Partial deficiency ||X-linked ||Gout and uric acid lithiasis ||Hyperuricemia, hyperuricosuria |
|Phosphoribosylpyrophosphate synthetase ||Overactivity ||X-linked ||Gout, uric acid lithiasis, and deafness ||Hyperuricemia, hyperuricosuria |
|Adenine phosphoribosyltransferase ||Deficiency ||Autosomal recessive ||2,8-Dihydroxyadenine lithiasis ||— |
|Xanthine oxidase ||Deficiency ||Autosomal recessive ||Xanthinuria and xanthine lithiasis ||Hypouricemia, hypouricosuria |
|Adenylosuccinate lyase ||Deficiency ||Autosomal recessive ||Autism and psychomotor retardation ||— |
|Myoadenylate deaminase ||Deficiency ||Autosomal recessive ||Myopathy with exercise intolerance or asymptomatic ||— |
|Adenosine deaminase ||Deficiency ||Autosomal recessive ||Severe combined immunodeficiency disease and chondro-osseous dysplasia ||— |
|Purine nucleoside phosphorylase ||Deficiency ||Autosomal recessive ||T cell–mediated immunodeficiency ||— |
Accelerated purine nucleotide degradation can also cause hyperuricemia—i.e., with conditions of rapid cell turnover, proliferation, or cell death, as in leukemic blast crises, cytotoxic therapy for malignancy, hemolysis, or rhabdomyolysis. Hyperuricemia can result from excessive degradation of skeletal muscle ATP after strenuous physical exercise or status epilepticus and in glycogen storage disease types III, V, and VII (Chap. 433e). The hyperuricemia of myocardial infarction, smoke inhalation, and acute respiratory failure may also be related to accelerated breakdown of ATP.
Decreased Uric Acid Excretion
More than 90% of individuals with sustained hyperuricemia have a defect in the renal handling of uric acid. For any given plasma urate concentration, patients who have gout excrete ~40% less uric acid than those who do not. When plasma urate levels are raised by purine ingestion or infusion, uric acid excretion increases in patients with and without gout; however, in those with gout, plasma urate concentrations must be 60–120 μmol/L (1–2 mg/dL) higher than normal to achieve equivalent uric acid excretion rates.
Diminished uric acid excretion could theoretically result from decreased glomerular filtration, decreased tubular secretion, or enhanced tubular reabsorption. Decreased urate filtration does not appear to cause primary hyperuricemia but does contribute to the hyperuricemia of renal insufficiency. Although hyperuricemia is invariably present in chronic renal disease, the correlation among serum creatinine, urea nitrogen, and urate concentrations is poor. Extrarenal clearance of uric acid increases as renal damage becomes more severe.
Many agents that cause hyperuricemia exert their effects by stimulating reabsorption rather than inhibiting secretion. This stimulation appears to occur through a process of “priming” renal urate reabsorption through the sodium-dependent loading of proximal tubular epithelial cells with anions capable of trans-stimulating urate reabsorption. The sodium-coupled monocarboxyl transporters SMCT1 and 2 (SLC5A8, SLC5A12) in the brush border of the proximal tubular cells mediate sodium-dependent loading of these cells with monocarboxylates. A similar transporter, SLC13A3, mediates sodium-dependent influx of dicarboxylates into the epithelial cell from the basolateral membrane. Some of these carboxylates are well known to cause hyperuricemia, including pyrazinoate (from pyrazinamide treatment), nicotinate (from niacin therapy), and the organic acids lactate, β-hydroxybutyrate, and acetoacetate. The mono- and divalent anions then become substrates for URAT1 and OAT4, respectively, and are exchanged for uric acid from the proximal tubule. Increased blood levels of these anions result in their increased glomerular filtration and greater reabsorption by proximal tubular cells. The increased intraepithelial cell concentrations lead to increased uric acid reabsorption by promoting URAT1-, OAT4-, and OAT10-dependent anion exchange. Low doses of salicylates also promote hyperuricemia by this mechanism. Sodium loading of proximal tubular cells also provokes urate retention by reducing extracellular fluid volume and increasing angiotensin II, insulin, and parathyroid hormone release. Additional organic anion transporters OAT1, OAT2, and OAT3 are involved in the movement of uric acid through the basolateral membrane, although the detailed mechanisms are still being elucidated.
GLUT9 (SLC2A9) is an electrogenic hexose transporter with splicing variants that mediate co-reabsorption of uric acid along with glucose and fructose at the apical membrane (GLUT9ΔN/SLC2A9v2) as well as through the basolateral membrane (SLC2A9v1) and thus into the circulation. GLUT9 has recently been identified as a high-capacity urate transporter, with rates 45–60 times faster than its glucose/fructose transport activity. GLUT9 may be responsible for the observed association of the consumption of fructose-sweetened soft drinks with an increased risk of hyperuricemia and gout. Genome-wide association scanning suggests that polymorphisms in SLC2A9 may play an important role in susceptibility to gout in the Caucasian population. The presence of one predisposing variant allele increases the relative risk of developing gout by 30–70%, most likely by increasing expression of the shorter isoform, SLC2A9v2 (GLUT9ΔN). Notably, though, genetic polymorphisms explain only ~6% of the differences in serum uric acid levels in Caucasians. Clearly, gout is polygenic and complex, and at this time the utility of genetic testing for relevant polymorphisms remains investigational and of no clinical utility.
Alcohol promotes hyperuricemia because of increased urate production and decreased uric acid excretion. Excessive alcohol consumption accelerates hepatic breakdown of ATP to increase urate production. Alcohol consumption can also induce hyperlacticacidemia, which blocks uric acid secretion. The higher purine content in some alcoholic beverages may also be a factor. Consumption of beer confers a greater risk of gout than liquor, and moderate wine intake does not increase gout risk. Intake of red meat and fructose increases the risk of gout, whereas intake of low-fat dairy products, purine-rich vegetables, whole grains, nuts and legumes, less sugary fruits, coffee, and vitamin C reduces the risk.
Hyperuricemia does not necessarily represent a disease, nor is it a specific indication for therapy. The decision to treat depends on the cause and the potential consequences of hyperuricemia in each individual.
Quantification of uric acid excretion can be used to determine whether hyperuricemia is caused by overproduction or decreased excretion. On a purine-free diet, men with normal renal function excrete <3.6 mmol/d (600 mg/d). Thus, the hyperuricemia of individuals who excrete uric acid above this level while on a purine-free diet is due to purine overproduction; for those who excrete lower amounts on the purine-free diet, it is due to decreased excretion. If the assessment is performed while the patient is on a regular diet, the level of 4.2 mmol/d (800 mg/d) can be used as the discriminating value.
The most recognized complication of hyperuricemia is gouty arthritis. NHANES 2007–2008 found a prevalence of gout among U.S. adults of 3.9%, with figures of ~6% for men and ~2% for women. The higher the serum urate level, the more likely an individual is to develop gout. In one study, the incidence of gout was 4.9% among individuals with serum urate concentrations >540 μmol/L (>9.0 mg/dL) as opposed to only 0.5% among those with values between 415 and 535 μmol/L (7.0 and 8.9 mg/dL). The complications of gout correlate with both the duration and the severity of hyperuricemia. For further discussion of gout, see Chap. 395.
Hyperuricemia also causes several renal problems: (1) nephrolithiasis; (2) urate nephropathy, a rare cause of renal insufficiency attributed to monosodium urate crystal deposition in the renal interstitium; and (3) uric acid nephropathy, a reversible cause of acute renal failure resulting from deposition of large amounts of uric acid crystals in the renal collecting ducts, pelvis, and ureters.
Uric acid nephrolithiasis occurs most commonly, but not exclusively, in individuals with gout. In gout, the prevalence of nephrolithiasis correlates with the serum and urinary uric acid levels, reaching ~50% with serum urate levels of 770 μmol/L (13 mg/dL) or urinary uric acid excretion >6.5 mmol/d (1100 mg/d).
Uric acid stones can develop in individuals with no evidence of arthritis, only 20% of whom are hyperuricemic. Uric acid can also play a role in other types of kidney stones. Some individuals who do not have gout but have calcium oxalate or calcium phosphate stones have hyperuricemia or hyperuricaciduria. Uric acid may act as a nidus on which calcium oxalate can precipitate or lower the formation product for calcium oxalate crystallization.
Urate nephropathy, sometimes referred to as urate nephrosis, is a late manifestation of severe gout and is characterized histologically by deposits of monosodium urate crystals surrounded by a giant-cell inflammatory reaction in the medullary interstitium and pyramids. The disorder is now rare and cannot be diagnosed in the absence of gouty arthritis. The lesions may be clinically silent or cause proteinuria, hypertension, and renal insufficiency.
This reversible cause of acute renal failure is due to precipitation of uric acid in renal tubules and collecting ducts that obstructs urine flow. Uric acid nephropathy develops following sudden urate overproduction and marked hyperuricaciduria. Factors that favor uric acid crystal formation include dehydration and acidosis. This form of acute renal failure occurs most often during an aggressive “blastic” phase of leukemia or lymphoma prior to or coincident with cytolytic therapy but has also been observed in individuals with other neoplasms, following epileptic seizures, and after vigorous exercise with heat stress. Autopsy studies have demonstrated intraluminal precipitates of uric acid, dilated proximal tubules, and normal glomeruli. The initial pathogenic events are believed to include obstruction of collecting ducts with uric acid and obstruction of the distal renal vasculature.
If recognized, uric acid nephropathy is potentially reversible. Appropriate therapy has reduced the mortality rate from ~50% to practically nil. Serum levels cannot be relied on for diagnosis because this condition has developed in the presence of urate concentrations varying from 720 to 4800 μmol/L (12–80 mg/dL). The distinctive feature is the urinary uric acid concentration. In most forms of acute renal failure with decreased urine output, urinary uric acid content is either normal or reduced, and the ratio of uric acid to creatinine is <1. In acute uric acid nephropathy, the ratio of uric acid to creatinine in a random urine sample or a 24-h specimen is >1, and a value that high is essentially diagnostic.
HYPERURICEMIA AND METABOLIC SYNDROME
Metabolic syndrome (Chap. 422) is characterized by abdominal obesity with visceral adiposity, impaired glucose tolerance due to insulin resistance with hyperinsulinemia, hypertriglyceridemia, increased low-density lipoprotein cholesterol, decreased high-density lipoprotein cholesterol, and hyperuricemia. Hyperinsulinemia reduces the renal excretion of uric acid and sodium. Not surprisingly, hyperuricemia resulting from euglycemic hyperinsulinemia may precede the onset of type 2 diabetes, hypertension, coronary artery disease, and gout in individuals with metabolic syndrome.
TREATMENT Hyperuricemia ASYMPTOMATIC HYPERURICEMIA
Hyperuricemia is present in ~21% of the population and in at least 25% of hospitalized individuals. The vast majority of hyperuricemic persons are at no clinical risk. In the past, the association of hyperuricemia with cardiovascular disease and renal failure led to the use of urate-lowering agents for patients with asymptomatic hyperuricemia. This practice is no longer recommended except for individuals receiving cytolytic therapy for neoplastic disease, who are treated with urate-lowering agents in an effort to prevent uric acid nephropathy. Because hyperuricemia can be a component of the metabolic syndrome, its presence is an indication to screen for and aggressively treat any accompanying obesity, hyperlipidemia, diabetes mellitus, or hypertension.
Hyperuricemic individuals, especially those with higher serum urate levels, are at risk for the development of gouty arthritis. However, most hyperuricemic persons never develop gout, and prophylactic treatment is not indicated. Furthermore, neither structural kidney damage nor tophi are identifiable before the first attack. Reduced renal function cannot be attributed to asymptomatic hyperuricemia, and treatment of asymptomatic hyperuricemia does not alter the progression of renal dysfunction in patients with renal disease. An increased risk of stone formation in those with asymptomatic hyperuricemia has not been established.
Thus, because treatment with specific antihyperuricemic agents entails inconvenience, cost, and potential toxicity, routine treatment of asymptomatic hyperuricemia cannot be justified other than for prevention of acute uric acid nephropathy. In addition, routine screening for asymptomatic hyperuricemia is not recommended. If hyperuricemia is diagnosed, however, the cause should be determined. Causal factors should be corrected if the condition is secondary, and associated problems such as hypertension, hypercholesterolemia, diabetes mellitus, and obesity should be treated. SYMPTOMATIC HYPERURICEMIA
See Chap. 395 for treatment of gout, including urate nephrosis. Nephrolithiasis
Antihyperuricemic therapy is recommended for the individual who has both gouty arthritis and either uric acid– or calcium-containing stones, both of which may occur in association with hyperuricaciduria. Regardless of the nature of the calculi, fluid ingestion should be sufficient to produce a daily urine volume >2 L. Alkalinization of the urine with sodium bicarbonate or acetazolamide may be justified to increase the solubility of uric acid. Specific treatment of uric acid calculi requires reducing the urine uric acid concentration with a xanthine oxidase inhibitor, such as allopurinol or febuxostat. These agents decrease the serum urate concentration and the urinary excretion of uric acid in the first 24 h, with a maximal reduction within 2 weeks. Allopurinol can be given once a day because of the long half-life (18 h) of its active metabolite, oxypurinol. In the febuxostat trials, the generally recommended dose of allopurinol (300 mg/d) was effective at achieving a target serum urate concentration below 6.0 mg/dL (357 μmol/L) in <50% of patients; this result suggested that higher doses should be considered. The drug is effective in patients with renal insufficiency, but the dose should be reduced. Allopurinol is also useful in reducing the recurrence of calcium oxalate stones in patients with gout and in individuals with hyperuricemia or hyperuricaciduria who do not have gout. Febuxostat (40–80 mg/d) is also taken once daily, and doses do not need to be adjusted in the presence of mild to moderate renal dysfunction. Potassium citrate (30–80 mmol/d orally in divided doses) is an alternative therapy for patients with uric acid stones alone or mixed calcium/uric acid stones. A xanthine oxidase inhibitor is also indicated for the treatment of 2,8-dihydroxyadenine kidney stones. Uric Acid Nephropathy
Uric acid nephropathy is often preventable, and immediate appropriate therapy has greatly reduced the mortality rate. Vigorous IV hydration and diuresis with furosemide dilute the uric acid in the tubules and promote urine flow to ≥100 mL/h. The administration of acetazolamide (240–500 mg every 6–8 h) and sodium bicarbonate (89 mmol/L) IV enhances urine alkalinity and thereby solubilizes more uric acid. It is important to ensure that the urine pH remains >7.0 and to watch for circulatory overload. In addition, antihyperuricemic therapy in the form of allopurinol in a single dose of 8 mg/kg is administered to reduce the amount of urate that reaches the kidney. If renal insufficiency persists, subsequent daily doses should be reduced to 100–200 mg because oxypurinol, the active metabolite of allopurinol, accumulates in renal failure. Despite these measures, hemodialysis may be required. Urate oxidase (rasburicase) can also be administered IV to prevent or to treat tumor lysis syndrome.