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. 333), urolithiasis, and renal dysfunction (see below).
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. Hyperuricemia is present in between 2 and 13.2% of ambulatory adults and is even more frequent in hospitalized individuals.
Hyperuricemia may be classified as primary or secondary depending on whether the cause is innate or is the result of 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. 359-1, Table 359-2).
Table 359-2 Classification of Hyperuricemia by Pathophysiology |Favorite Table|Download (.pdf)
Table 359-2 Classification of Hyperuricemia by Pathophysiology
PRPP synthetase overactivity
Glycogenosis III, V, and VII
|Decreased Uric Acid Excretion|
Polycystic kidney disease
Toxemia of pregnancy
Salicylates (>2 g/d)
|Glucose-6-phosphatase deficiency||Fructose-1-phosphate aldolase deficiency|
Increased Urate Production
Diet contributes to the serum urate in proportion to its purine content. Strict restriction of purine intake reduces the mean serum urate level by about 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. 359-3). De novo purine biosynthesis is an 11-step process that forms inosine monophosphate (IMP). The rates of purine biosynthesis and urate production are determined, for the most part, 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. Both increased PRPP synthetase activity and HPRT deficiency are associated with overproduction of purines, hyperuricemia, and hyperuricaciduria (see below for clinical descriptions).
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 diseases types III, V, and VII (Chap. 362). 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. Gouty individuals excrete ˜40% less uric acid than nongouty individuals for any given plasma urate concentration. Uric acid excretion increases in gouty and nongouty individuals when plasma urate levels are raised by purine ingestion or infusion, but 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.
Altered 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 between serum creatinine, urea nitrogen, and urate concentration is poor. Uric acid excretion per unit of glomerular filtration rate increases progressively with chronic renal insufficiency, but tubular secretory capacity tends to be preserved, tubular reabsorptive capacity is reduced, and 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 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 organic anion transporter (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- and OAT4-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 and OAT3 are involved in the movement of uric acid through the basolateral membrane, although the detailed mechanisms are still being elucidated.
Glucose transporter 9 (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, and thus into the circulation (SLC2A9v1). This might be a mechanism for the observed association of the consumption of fructose-sweetened soft drinks with an increased risk of hyperuricemia and gout. Genomewide association scanning (GWAS) suggests that polymorphisms in SLC2A9 may play an important role in susceptibility to gout in the white 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, these polymorphisms explain <5% of the variation in serum uric acid levels in whites.
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 such as beer may also be a factor.
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 the 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. In the general population, the prevalence of hyperuricemia ranges between 2.0 and 13.2%, and the prevalence of gout is between 1.3 and 3.7%. 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% for individuals with serum urate concentrations >540 μmol/L (9.0 mg/dL) compared with 0.5% for 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 severity of hyperuricemia. For further discussion of gout, see Chap. 333.
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 nongouty individuals with 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 causes obstruction to 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 distal renal vasculature.
If recognized, uric acid nephropathy is potentially reversible. Appropriate therapy has reduced the mortality from about 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 24-h specimen is >1, and a value that high is essentially diagnostic.
Hyperuricemia and Metabolic Syndrome
Metabolic syndrome (Chap. 242) 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.
Hyperuricemia is present in ˜5% of the population and in up to 25% of hospitalized individuals. The vast majority 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, in which treatment is given 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 are at risk to develop gouty arthritis, especially those with higher serum urate levels. 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. Increased risk of stone formation in those with asymptomatic hyperuricemia is not 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.
(See Chap. 333 for treatment of gout.) 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 maximum reduction occurring within 2 weeks. The average effective dose of allopurinol is 300–400 mg/d. Allopurinol can be given once a day because of the long half-life (18 h) of its active metabolite, oxypurinol. 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 gouty patients and in nongouty individuals with hyperuricemia or hyperuricaciduria. 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 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.