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Asymptomatic hyperuricemia

Asymptomatic hyperuricemia
Literature review current through: May 2024.
This topic last updated: Apr 11, 2023.

INTRODUCTION — Asymptomatic hyperuricemia is a term traditionally applied to settings in which the serum urate concentration is elevated but in which neither symptoms nor signs of monosodium urate (MSU) crystal deposition disease, such as gout, or uric acid kidney disease, have occurred. Although these clinical manifestations may develop in a hyperuricemic individual at any point, about two-thirds or more of such individuals remain asymptomatic, never developing gout flares, tophaceous gout, acute or chronic hyperuricemic nephropathy, or uric acid nephrolithiasis [1-5]. (See "Clinical manifestations and diagnosis of gout" and "Uric acid kidney diseases" and "Kidney stones in adults: Uric acid nephrolithiasis".)

In addition to its relationship with urate or uric acid crystal deposition, asymptomatic hyperuricemia has also been associated with other disorders that appear to be largely unrelated to crystal deposition, including hypertension, chronic kidney disease (CKD), cardiovascular disease, and the insulin resistance syndrome. (See "Overview of possible risk factors for cardiovascular disease", section on 'Urate' and "Secondary factors and progression of chronic kidney disease", section on 'Hyperuricemia' and "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Other associations'.)

The definition, etiology and management of asymptomatic hyperuricemia will be reviewed here. Gout, uric acid kidney diseases, and uric acid nephrolithiasis are discussed separately. (See "Clinical manifestations and diagnosis of gout" and "Treatment of gout flares" and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout" and "Uric acid kidney diseases" and "Kidney stones in adults: Uric acid nephrolithiasis".)

DEFINITION — There is no universally accepted definition of hyperuricemia. For purposes relating to urate crystal deposition, a physicochemical definition of hyperuricemia, based upon the solubility limit of urate in body fluids (ie, the concentration above which a state of saturation for urate is reached in the serum) is widely preferred over a statistical definition because of the non-normal distribution of serum urate concentrations in most populations [6-11]. This physicochemical definition corresponds to urate concentrations exceeding about 7 mg/dL (416 micromol/L), as measured by automated enzymatic (uricase) methods in routine clinical laboratory use. These values are approximately 1 mg/dL (60 micromol/L) lower than those obtained with colorimetric methods.

A definition of hyperuricemia appropriate to the non-crystal deposition associations with hyperuricemia (eg, cardiovascular disease) is more problematic for two reasons. One is the high prevalence of urate values exceeding saturation but within two standard deviations of the population mean (eg, an estimated 5 to 8 percent in adult White males in the United States and 25 percent in Taiwan Chinese males) [12]. The other is that putative effects of elevated serum urate levels on cardiovascular and other disorders are thought to occur at concentrations that are clearly sub-saturating [13].

An alternative suggested by some experts as a practical and clinically relevant definition of hyperuricemia is a serum urate concentration exceeding 6 mg/dL (360 micromol/L) [14,15]; this value would integrate an estimated threshold for the lifelong risk for clinical consequences of hyperuricemia with the widely recommended goal range of <6 mg/dL (under 360 micromol/L) for clinically successful urate-lowering in gout [6,7,10,11,16,17].

There appears to be little dissent from the physiochemical definition of hyperuricemia. Nevertheless, acceptance of a range of serum urate achieved and maintained at less than 6 mg/dL (360 micromol/L) as the goal for clinical management of most patients with gout is controversial, although it represents our approach and that of a number of other experts [6-11,14,15]. This controversy was illustrated by a 2016 American College of Physicians clinical practice guideline [18], which recommended pharmacologic treatment aimed at abolishing the acute intermittent symptoms of most gout patients in preference to monitored serum urate-lowering to a pre-specified goal range. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Serum urate goals and targeted therapy'.)

We use a persistent urate level of >8 mg/dL (480 micromol/L) as the threshold for initiating evaluation and, where warranted, lifestyle and/or pharmacologic intervention for management of asymptomatic hyperuricemia. (See 'Evaluation' below and 'Management' below.)

CLASSIFICATION — Persistent hyperuricemia is a common biochemical abnormality that results from excessive urate production [19], absolute or relative impairment of renal uric acid clearance [20-22], reduced intestinal secretion [23], or a combination of these mechanisms (see "Urate balance" and "Pathophysiology of gout"). Within the kidney, separate sets of transporters mediate reabsorption of filtered urate and secretion of circulating urate across the proximal tubular epithelium; serum urate is determined in large part by the relative balance of these two opposing pathways (figure 1 and figure 2). Genetically, loss of function in reabsorptive [24] or secretory pathways [25] results in hypouricemia or hyperuricemia, respectively, underscoring the bidirectional nature of transepithelial urate flux within the proximal tubule.

As the list of specific genetic, comorbid disease-related, and environmental (drug, diet, and toxic exposure-induced) influences promoting hyperuricemia have been identified (table 1 and table 2), the former categorization of hyperuricemia as either primary (idiopathic) or secondary has given way to the recognition of hyperuricemia as arising from multiple pathways that impact urate production and/or uric acid clearance. The effects upon these pathways lead to development of this risk factor for clinical expression of urate crystal formation and deposition (gout and, less frequently, uric acid-/urate crystal-related kidney disease) and, potentially, to associated non-crystal-related disorders. (See 'Potential clinical consequences' below.)

EPIDEMIOLOGY — Hyperuricemia is a very common biochemical aberration, detectable in a single determination of serum urate in 20 to 25 percent of adult men and a smaller proportion of women in some populations [12,26]. Hyperuricemia in men frequently begins at puberty, when the lower serum urate levels characteristic of children rise into the adult male range. Normal adult male values exceed those in women of reproductive age due to enhancement of renal uric acid clearance by estrogenic compounds. Thus, uric acid variation during the menstrual cycle indicates an inhibitory influence of higher endogenous estradiol [27]. Additionally, hyperuricemia in women is usually delayed until after menopause; at that point, serum urate values in normal women increase and approximate those in normal men of corresponding age [28]. There is a lesser rise in urate levels in postmenopausal women treated with hormone replacement therapy [28,29]. Although the underlying mechanisms for this effect of estrogenic compounds are not characterized, estrogen treatment of human cell lines causes post-transcriptional downregulation of the ABCG2 [30] and GLUT9 [31] urate transporters.

Although the incidence of gout increases with increasing age in all individuals [32,33], the incidence rate is appreciable from age 30 in men and only after about age 50 in women. Thus, the urate crystal-related manifestations of hyperuricemia occur, on average, about two decades later than the initial physiologic increase in serum urate concentration. This observation suggests that there is a lengthy period of asymptomatic hyperuricemia preceding the occurrence of gout.

POTENTIAL CLINICAL CONSEQUENCES — There are three major crystal deposition-related disorders associated with hyperuricemia: gout, urate nephropathy, and nephrolithiasis. Substantial evidence supports the view that persistent asymptomatic hyperuricemia imparts risks for the development of urate or uric acid crystal-related clinical events and that the respective risks are, at least in part, related to the magnitude as well as the duration of hyperuricemia. (See 'Gout' below and 'Chronic kidney disease' below and 'Nephrolithiasis' below.)

With the exception of acute uric acid nephropathy [34], the initial clinical manifestations of urate or uric acid crystal deposition are not life-threatening and are readily treatable. (See "Uric acid kidney diseases", section on 'Acute uric acid nephropathy'.)

In addition, hyperuricemia has also been associated with conditions that are not due to crystal deposition, but the role of hyperuricemia in these conditions is less well-defined. (See 'Non-crystal deposition disorders' below.)

Urate crystal deposition disorders — Asymptomatic hyperuricemia was historically regarded as the initial state in the classically defined progression of gout, preceding the presentation of acute inflammatory arthritis (gout flare), intercritical gout, chronic gouty arthritis, and tophi; however, epidemiologic studies have demonstrated that gout flares, tophus formation, chronic urate nephropathy, and uric acid nephrolithiasis are relatively infrequent, occurring in aggregate in a third or less of individuals with longstanding hyperuricemia [1-3]. Longitudinal studies have documented an elevated risk of gout and nephrolithiasis with increasing degrees of hyperuricemia and hyperuricosuria, respectively. (See "Clinical manifestations and diagnosis of gout" and "Uric acid kidney diseases" and "Kidney stones in adults: Uric acid nephrolithiasis".)

Gout — There is clear evidence of an association between the degree of hyperuricemia and the risk of gout. As examples:

One study followed serial serum urate concentrations in 2046 initially healthy men for 15 years [1]. The annual incidence of gout was 4.9, 0.5, and 0.1 percent for serum urate levels of at least 9, 7 to 8.9, and less than 7 mg/dL (greater than 535, between about 529 and 416, and less than 416 micromol/L), respectively. The cumulative incidence of gout with serum urate levels of 9 mg/dL (535 micromol/L) or greater was 22 percent after five years.

Similar findings were noted in a second report in which gout occurred in only 12 percent of patients with urate levels between 7 and 7.9 mg/dL (416 and 470 micromol/L) over a 14-year period [2]. Serum urate levels above 9 mg/dL (535 micromol/L) had a much greater predictive value for the development of gout. However, this degree of hyperuricemia was uncommon in both series, occurring in less than 20 percent of individuals with hyperuricemia.

Tophi can occur in patients with chronic hyperuricemia, usually in those with antecedent gout flares. However, hyperuricemic older adults and patients with asymptomatic hyperuricemia who are being treated with nonsteroidal antiinflammatory drugs (NSAIDs) or glucocorticoids for some other reason can develop tophi in the absence of gout flares.

Risk factors for increasing hyperuricemia and/or raising the likelihood of incident gout include: increased amounts of beer and distilled spirits [35] (and of wine as well in established gout [36]); high levels of meat and seafood ingestion [37]; diuretic, beta blocker, angiotensin-converting enzyme inhibitor, and non-losartan angiotensin II receptor blocker use [38]; hypertension; and obesity [39,40]. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Management principles and initial postdiagnostic assessment'.)

Monosodium urate (MSU) crystal deposition in joints and tendons can be detected by ultrasonography [41-46], by dual-energy computed tomography (DECT) [47], and by direct observation during arthroscopic examination [48]. Crystal deposition in joints and tendons may be present in a substantial proportion of persons with traditionally defined asymptomatic hyperuricemia, especially hyperuricemia of long duration [14,44]. Ultrasound and DECT studies have indicated that approximately one-quarter of patients with asymptomatic hyperuricemia have detectable MSU crystal deposition [42,49-51], albeit with much lower volumes of deposition than in patients with symptomatic gout [49]. However, there is a lack of compelling evidence to address whether such "asymptomatic hyperuricemia with MSU crystal deposits" predicts an earlier onset and/or worsened outcomes of clinical gout, which might provide an indication for initiation of urate-lowering pharmacotherapy [14,52]; nor has it been proven that such changes influence the onset or severity of hyperuricemia-associated comorbid diseases.

Chronic kidney disease — There is an association between hyperuricemia and chronic kidney disease (CKD), although the deterioration in kidney function has generally been attributed to risk factors other than chronic hyperuricemia, and a causal role of hyperuricemia in CKD has not been established [4,13,53]. CKD is a significant comorbidity in gout; analysis of the National Health and Nutrition Examination Survey (NHANES) data from 2007 to 2008 revealed a 16 percent prevalence of stage ≥CKD3 in male gout patients and 31.4 percent in female gout patients [54]. Kidney dysfunction is also a major risk factor for presentation with tophaceous gout early in the disease course [55,56].

The hyperuricemia that is nearly invariable in CKD is due to a reduction in the efficiency of uric acid excretion and is unaccompanied by hyperuricosuria. This is in contrast to acute uric acid nephropathy as part of the tumor lysis and related syndromes in which urate overproduction is the primary abnormality, leading to enhanced uric acid excretion. (See "Uric acid kidney diseases".)

The extent to which chronic urate crystal deposition contributes to the association of hyperuricemia and chronic kidney function impairment remains uncertain. Historically, persistent hyperuricemia was regarded as an infrequent cause of slowly progressive chronic kidney failure called urate nephropathy, in which the deposition of urate in the kidney interstitium was thought to result in an inflammatory reaction and in progressive tubulointerstitial injury. Many of these patients had tophi, and the kidney pathologic changes could be viewed as tophi. (See "Uric acid kidney diseases".)

It has been suggested that hyperuricemia is of no clinical importance with respect to CKD until serum urate levels exceed at least 13 mg/dL (773 micromol/L) in men and 10 mg/dL (595 micromol/L) in women, levels that are uncommon and beyond which insufficient data were available to exclude a nephrotoxic effect of hyperuricemia [4]. However, tophaceous gout has become a less frequent problem, and the CKD that is still relatively frequent over time in gout patients could reflect consequences of chronic hyperuricemia unrelated to crystal deposition [13].

Some patients with gout and CKD have a bland urine sediment and hyperuricemia out of proportion to the degree of kidney function impairment. Although these findings are compatible with urate or a "hyperuricemic" nephropathy, such patients may have lead intoxication [57]. (See "Lead nephropathy and lead-related nephrotoxicity".)

Patients with a strong family history of CKD and gout should be evaluated for autosomal dominant tubulointerstitial kidney disease (ADTKD) (see "Autosomal dominant tubulointerstitial kidney disease"). ADTKD is most commonly caused by mutations in uromodulin, a membrane-associated protein unique to the thick ascending limb of the loop of Henle (TALH). These ADTKD-associated mutations are associated with intracellular retention of uromodulin protein in TALH cells, with reduced expression at the apical membrane [58]; the associated endoplasmic reticulum stress may be pathogenic [59]. To the extent that uromodulin is a key regulatory factor for ion transporters in the TALH [60,61], a reduction of TALH-associated salt transport may cause hyperuricemia due to neurohumoral activation. Notably, gout is also reported in patients with Bartter syndrome [62], which is characterized by much greater loss of function in TALH ion transport. Although hyperuricemia out of proportion to the degree of kidney function impairment is a hallmark of ADTKD due to UMOD mutations [63], hyperuricemia and gout can also be associated with cystic kidney disease due to mutations in HNF1B [64].

An elevation in the serum urate concentration out of proportion to the degree of kidney function impairment has been defined as follows [65]:

Greater than 9 mg/dL (535 micromol/L) if the serum creatinine concentration is ≤1.5 mg/dL (132 micromol/L)

Greater than 10 mg/dL (595 micromol/L) if the serum creatinine concentration is between 1.5 and 2 mg/dL (132 to 176 micromol/L)

Greater than 12 mg/dL (714 micromol/L) with more advanced kidney failure

Nephrolithiasis — Increased urinary uric acid excretion is associated with a higher risk of uric acid but not calcium oxalate stone formation [66]. The incidence of urolithiasis approaches 50 percent in patients in whom daily urinary uric acid excretion exceeds 1100 mg (6.5 micromol) [67]. However, this degree of uric acid overexcretion is uncommon. Reduced urine pH is also a major factor in uric acid nephrolithiasis. (See "Kidney stones in adults: Uric acid nephrolithiasis" and "Kidney stones in adults: Epidemiology and risk factors".)

Non-crystal deposition disorders — Hyperuricemia, although clearly associated with hypertension, CKD, cardiovascular disease, and components of the insulin resistance syndrome, has not been established as a causal factor in any of these disorders. The possible relationship between hyperuricemia and cardiovascular disease is discussed in detail separately. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Hyperuricemia' and "Overview of possible risk factors for cardiovascular disease", section on 'Urate' and "Effect of antihypertensive treatment on kidney function in primary (essential) hypertension", section on 'Chronic effects'.)

Over the course of several decades, the results of largely observational studies, and a few experimental studies as well, have supported the concept that higher levels of urate may (through an antioxidant effect) reduce the risk of degenerative/inflammatory neurologic disorders such as Alzheimer and Parkinson diseases [68,69]. Proof of this concept is, of course, important with respect to these neurologic disorders but also pertinent with regard to an increasing number of gout patients in whom the recommended long-term management is pharmacologic lowering of urate concentrations to sub-saturating levels. As an example, an observational study supporting the view that incident gout is inversely associated with the risk for developing Alzheimer disease points to the importance of prospectively assessing this relationship [70].

EVALUATION — We suggest performing an evaluation to determine the cause of asymptomatic hyperuricemia in persons with a urate level in excess of 8 mg/dL (approximately 480 micromol/L). Evaluation to determine the cause of asymptomatic hyperuricemia should proceed only following repeat urate determination to confirm its presence after an interval of at least a week. (See 'Initial evaluation' below.)

In general, health screening practices do not include testing for serum urate levels; nor does the laboratory evaluation of most medical conditions unrelated to symptomatic urate crystal deposition diseases routinely include serum urate measurement. This may be the case because despite increasing clinical, epidemiologic, and experimental evidence that hyperuricemia is a risk factor for important metabolic, kidney, and CV diseases, a causal role for hyperuricemia in these disorders remains to be established. Nevertheless, incidental recognition of patients with urate levels over 8 mg/dL (480 micromol/L) provides an opportunity for reducing the risk of several symptomatic disorders and their potential complications.

The aim of evaluating the cause of confirmed asymptomatic hyperuricemia is to identify the following:

Patients at particularly high risk for gout or urolithiasis who warrant antihyperuricemic treatment.

Hyperuricemia-inducing drugs or toxins that can be removed or substituted, with relief or diminution of the hyperuricemic state. This aim may be especially important in patients with or at high risk for disorders (such as hypertension, chronic kidney disease [CKD], and ischemic heart disease) which are commonly associated with hyperuricemia and for which lifestyle modifications and/or pharmacologic alternatives to hyperuricemia-inducing medications are usually available.

Individuals whose hyperuricemia is a sign of an underlying disorder or environmental exposure requiring specific treatment.

In patients with a urate level between 7 and 8 mg/dL (416-476 micromol/L) on confirmatory testing, we generally repeat testing to determine if it is greater than 8 mg/dL (approximately 480 micromol/L) in 6 to 12 months before initiating a more detailed evaluation. In patients with a value less than 7 mg/dL (416 micromol/L) on confirmatory testing, we generally do not pursue further evaluation of this isolated laboratory value.

The decision not to evaluate persons with urate levels ≤8 mg/dL [≤480 micromol/L] is a practical compromise, based upon the low rate of incident gout in the many hyperuricemic individuals with urate levels between 7 and 8 mg/dL [416 to 476 micromol/L] [71,72]. Hyperuricemia is a very common laboratory finding [12,26], and is an established causal risk factor only in urate crystal deposition-related events that are nearly always readily treatable. (See 'Definition' above and 'Potential clinical consequences' above.)

Initial evaluation — We initiate the evaluation of persons with asymptomatic hyperuricemia in excess of 8 mg/dL (480 micromol/L) with a focused clinical evaluation and limited biochemical screening. The initial evaluation should include a thorough history and physical examination, with particular attention to intercurrent medical conditions, diet or lifestyle choices, drug therapies, toxin exposure, or a known familial disorder that may result in hyperuricemia. Laboratory testing should include a complete blood count and differential leukocyte counts; a chemical profile, including measurement of kidney function, electrolytes, calcium, and liver chemistries; and a urinalysis. Further laboratory determinations are directed to the specific causative factor suspected to confirm or deny the relationship.

In our experience, initial evaluation will identify one or more of the many causes of hyperuricemia due to increased urate production (table 1) or decreased renal uric acid clearance (table 2) in approximately 80 to 90 percent of patients. Modification or extension in the evaluation scheme is sometimes warranted by circumstances such as patient age and the extent to which the urate level exceeds normal. For example, marked hyperuricemia (exceeding 10 mg/dL [600 micromol/L] in a child) or 12 mg/dL [720 micromol/L] in an adolescent might prompt concern over an underlying lymphoproliferative or myeloproliferative state, a previously unappreciated congenital cardiac or pulmonary disorder, or a previously undiagnosed inherited enzyme defect resulting in urate overproduction. Such results would thus prompt appropriate imaging studies and/or pathologic, genetic, or biochemical measurements. Similarly, additional evaluation may be warranted among some patients with multiple possible explanations for their hyperuricemia, often including dietary or lifestyle choices or the use of medications affecting urate balance.

Further evaluation — A determination of the fractional urinary excretion of uric acid (FEur), which represents the percent of urinary uric acid excretion per unit of the glomerular filtration rate (GFR), should be performed in both men presenting prior to age 25 and women prior to menopause who are without an identifiable cause of hyperuricemia on their initial evaluation (see 'Initial evaluation' above) and have stable and normal kidney function; such testing can help to differentiate between causes resulting from overproduction of urate (table 1) and causes resulting from reduced uric acid clearance (table 2). The distinction between overproduction and underexcretion can guide further investigation of the underlying cause of hyperuricemia and will be useful in directing the choice of antihyperuricemic medication in those needing treatment.

The FEur can be determined by measurement of the urate and creatinine concentration in a mid-morning spot urine collection and the serum urate and creatinine; this calculation will help to distinguish between urate overproduction with hyperuricosuria (FEur is usually >10 percent) and reduced urinary uric acid clearance (FEur is usually <6 percent) [73]. (See "Fractional excretion of sodium, urea, and other molecules in acute kidney injury".)

The information gained by calculating the FEur using a spot urine is similar to that achieved by measurement of 24-hour urinary uric acid excretion, which, although a much more cumbersome procedure, is preferred by some investigators and clinicians. In this case, urinary uric acid excretion greater than 800 mg/day (4.8 mmol/day) or 12 mg/kg/day (71 micromol/kg per day) is defined as hyperuricosuria, while daily excretion below this level is indicative of reduced urinary uric acid clearance (with normal or reduced urinary uric acid excretion) [74]. The urine collections for these studies should be done while the individual is receiving a standard diet, excluding alcohol and drugs known to affect uric acid metabolism. (See "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)".)

It is important to appreciate that "underexcretors" actually have a normal rate of urinary uric acid excretion since this is required to maintain the steady state in which production and clearance are relatively equal. It is the reduced efficiency of uric acid excretion that obligates a higher serum urate concentration to achieve a rate of urinary uric acid excretion that matches production. Similar considerations apply to diuretic therapy. (See "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'The steady state' and "Diuretic-induced hyperuricemia and gout".)

Most patients with underexcretion of uric acid and with a normal GFR have no other demonstrable abnormality in kidney function. The defect in renal urate transport (which could be manifested functionally either as reduced secretion or as enhanced reabsorption) may be inherited (often associated with one or more polymorphisms ["risk alleles"] in urate transporter genes); acquired (eg, related to a drug or toxin); or secondary to reduced kidney perfusion (eg, diuretics). (See "Urate balance".)

The vast majority of hyperuricemic individuals (80 to 90 percent) demonstrate excess dietary purine or purine precursor consumption, uric acid underexcretion, or both. The remainder exhibit overproduction of urate from endogenous sources. The distinction between exogenously (dietary) and endogenously determined urate overproduction can be accomplished in the following way in patients with hyperuricosuria (defined as an FEur exceeding 10 percent):

A 24-hour urine collection should be carried out after the patient has been on an isocaloric, reduced purine diet for three to five days containing 1 gram/kg protein daily from dairy sources and excluding alcohol, meat, seafood, and medications known to affect urate metabolism.

In patients with uric acid excretion greater than 600 mg/day (3.6 mmol/day) on such a diet, inherited causes of overproduction (eg, various enzyme defects, disordered adenosine triphosphate [ATP] metabolism, or disorders resulting in increased rates of cell turnover) should be considered (table 1). This historical, accepted threshold is two standard deviations higher than the reported value for urinary uric acid excretion in healthy males on a purine-restricted diet [75].

Excess dietary purine consumption is confirmed as the cause of hyperuricosuria in patients whose uric acid excretion and serum urate levels decline to normal levels (less than 600 mg/day [4 mmol/day]) on a reduced purine diet.

To the extent that instituting a purine-restricted diet is cumbersome, uric acid excretion of >800 mg/day is typically chosen as the threshold for overproduction on a self-selected diet. Notably, however, the chosen reference value varies dramatically in various publications, from 700 to 1000 mg/day [76-78].

MANAGEMENT — Decisions regarding institution of particular nonpharmacologic (lifestyle-based) or pharmacologic therapies for asymptomatic hyperuricemia should be individualized based upon estimates of the risk of clinical events related to the hyperuricemia and the potential benefits and risks of intervention (see 'Urate crystal deposition disorders' above). We do not recommend pharmacologic management for the vast majority of patients with asymptomatic hyperuricemia, despite the high prevalence of this biochemical aberration. In part, this reflects the view that the established clinical consequences of hyperuricemia are almost always readily manageable if and when such symptoms or signs arise. Moreover, in the absence of studies to address this issue, there is insufficient evidence in most circumstances to confirm the benefit of pharmacologic intervention in the asymptomatic state. Nevertheless, in a few situations discussed below, pharmacologic intervention appears warranted.

General measures — In all persons with persistent asymptomatic hyperuricemia in whom treatable causes have either been excluded or, if present, appropriately treated, we take the following approach:

All patients with persistent asymptomatic hyperuricemia (serum urate >8 mg/dL [480 micromol/L]) and without evidence of urate crystal deposition should be offered a plan for management with nonpharmacologic (lifestyle) measures to reduce the degree of hyperuricemia and educated with regard to the potential effects on urate levels of medical interventions for other conditions.

The lifestyle interventions, largely overlapping those used for the prevention of gout, include reduction to ideal body weight by adjustment of dietary volume and composition, avoidance of alcohol and sugar-sweetened beverages, and regular exercise [7,79-81]. Mention should be made of the fact that treatment indications may change over time as new data are published. These interventions and evidence of their benefit are described in detail separately. (See "Nonpharmacologic strategies for the prevention and treatment of gout".)

When there are acceptable alternatives for the management of diseases accompanying hyperuricemia, we prefer the use of medications that reduce serum urate levels and/or decrease the risk for incident gout and the avoidance of medications/additives promoting hyperuricemia. Examples of the former include the use of fenofibrate for hyperlipidemia [82] and losartan [38,83] or calcium channel blockers [38] for hypertension. Likewise, agents that may promote hyperuricemia/incident gout that should be avoided, when possible, include thiazide or loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, non-losartan angiotensin II receptor blockers, and beta blockers [38]. (See "Nonpharmacologic strategies for the prevention and treatment of gout", section on 'Treating comorbid conditions'.)

We consider pharmacologic urate-lowering therapy (with xanthine oxidase inhibitors or uricosuric agents) as generally unwarranted for upper normal range serum urate values or for asymptomatic hyperuricemia. (See 'Sustained marked hyperuricemia' below and 'Marked asymptomatic hyperuricosuria' below.)

For persons with asymptomatic hyperuricemia in the presence of monosodium urate (MSU) crystal deposition (as by the finding of the double-contour sign or a suspected tophus) demonstrated only on imaging [49,50], we take the same approaches as for other asymptomatic individuals with hyperuricemia and do not view asymptomatic MSU crystal deposition detected on imaging alone as an indication for pharmacologic treatment (see 'Urate crystal deposition disorders' above), although patients should be advised of the finding and its potential implications.

These approaches are based upon their effects on hyperuricemia and in the management of gout and uric acid nephrolithiasis, and on our experience and that of other experts; however, we acknowledge that there have not been any randomized trials or large observational studies of these interventions in patients with asymptomatic hyperuricemia designed to determine whether they provide clinically important benefit.

In the case of pharmacologic urate-lowering therapy, the estimated risk of clinical consequences from hyperuricemia should be weighed against the potential benefits and risks of lifelong drug treatment since hyperuricemia often persists indefinitely. The risks of urate-lowering pharmacotherapy and associated treatments include rare but potentially severe and even life-threatening toxic reactions to agents such as allopurinol and colchicine [84,85]. (See "Overview of cutaneous small vessel vasculitis".)

In the absence of unequivocal evidence for a causal role of this chemical aberration in one or more of the non-crystal deposition disorders associated with hyperuricemia (see 'Non-crystal deposition disorders' above), our view is that asymptomatic hyperuricemia is not a disease but can be regarded as a necessary (although not usually sufficient) predisposing factor for the narrow range of clinical manifestations of urate or uric acid crystal deposition. This view is supported by the fact that monosodium urate or uric acid crystal deposition, not soluble urate, is the essential pathophysiologic link between hyperuricemia and clinical manifestations such as gout flares, uric acid urolithiasis, and tophus formation [74].

There is a lack of evidence regarding the outcomes of patients whose clinically asymptomatic hyperuricemia is accompanied by MSU crystal deposition demonstrated only by imaging with respect to incident gout or the range or severity of hyperuricemia-associated diseases. However, a gout flare is readily treatable and reversible if it occurs (see "Treatment of gout flares" and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout"). Similarly, urate-lowering pharmacotherapy for prophylaxis against uric acid stone disease is not warranted in most individuals, but appropriate therapy should be started after discovery of a stone, as discussed elsewhere (see "Kidney stones in adults: Uric acid nephrolithiasis"). The primary therapeutic modality in hyperuricemic but non-gouty individuals who experience a uric acid urinary tract stone is hydration (fluid intake >2 liters daily) and urinary alkalinization with potassium citrate or potassium bicarbonate, rather than allopurinol. The treatment of uric acid nephrolithiasis is discussed in detail separately. (See "Kidney stones in adults: Uric acid nephrolithiasis".)

In patients without a clinically evident hyperuricemia-associated disorder, lifestyle initiatives appropriate to gout have additional value in terms of general health and wellbeing [7], in addition to modest urate-lowering effects with potential lessening of the increased incident risks for gout and comorbid diseases imparted by hyperuricemia [80].

Sustained marked hyperuricemia — Selected patients with sustained marked asymptomatic hyperuricemia (>13 mg/dL [>773 micromol/L]) benefit or potentially benefit from the use of pharmacologic urate-lowering therapy (eg, allopurinol or febuxostat) rather than only providing advice regarding diet, lifestyle, and the treatment of comorbid conditions alone. Among these infrequently encountered patients are some individuals with purine and/or urate overproduction due to inherited monogenic defects in purine, sugar, or ATP metabolism, or due to clinical disorders associated with accelerated cell turnover (table 1). Patients with autosomal dominant tubulointerstitial kidney disease due to mutations in uromodulin frequently (approximately 75 percent) develop hyperuricemia due to a reduced fractional excretion of urate. Approximately 65 percent also develop gout, typically with an early onset (table 2); in our opinion, these patients should be considered for urate-lowering therapy in the setting of marked hyperuricemia [86].

As is the case in patients with non-tophaceous gout, the aim of urate-lowering therapy in patients with sustained marked but asymptomatic hyperuricemia and a urate-related medical condition very likely to result ultimately in recurrent urolithiasis and/or obstructive uropathy is serum urate <6 mg/dL (360 micromol/L). By contrast, in patients whose sustained asymptomatic hyperuricemia is unaccompanied by an identifiable urate-related medical condition likely to present such predictable renal risks, we suggest that a urate-lowering goal range <8 mg/dL (480 micromol/L) might suffice.

As an example:

Hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) deficiency is an X chromosome-linked inherited disorder of purine metabolism in which purine nucleotide and urate overproduction is accompanied biochemically by severe hyperuricemia and hyperuricosuria and clinically by recurrent uric acid urolithiasis, gout, and, in more severe forms of this enzyme deficiency, neurobehavioral abnormalities characterizing the spectrum of Lesch-Nyhan disease and its variants [87]. Hyperuricemia in HGPRTase-deficient patients often exceeds 13 mg/dL [780 micromol/L]) and hyperuricosuria is often >12 mg/kg/day. In general, the severity of deficiency in HGPRTase activity correlates with the magnitudes of the metabolic abnormalities and with the extent of accompanying neurological and behavioral signs. (See "Kidney stones in children: Epidemiology and risk factors", section on 'Hyperuricosuria' and "Hyperkinetic movement disorders in children", section on 'Lesch-Nyhan syndrome'.)

Because of the high incidence of urolithiasis and obstructive uropathy in severely affected male children, treatment with allopurinol, titrated to reduce both hyperuricemia (to <6 mg/dL [360 micromol/L]) and hyperuricosuria, is initiated upon diagnosis of such patients or prior to disease expression in affected male family members. In milder forms of HGPRTase deficiency, later childhood or even adult-onset gout may be the predominant clinical manifestation, and allopurinol-induced reductions in serum urate and urinary uric acid most often control gout progression and prevent recurrent urolithiasis. Allopurinol treatment does not, however, alter or prevent the neurologic features in patients with severe HGPRTase deficiency. Moreover, maintenance of an optimal allopurinol dose in such patients is often difficult to achieve because allopurinol increases blood and urine xanthine levels by blocking conversion of xanthine to urate, resulting in a markedly increased risk for xanthine urolithiasis.

Marked asymptomatic hyperuricosuria — In patients evaluated for sustained asymptomatic hyperuricemia who have urinary uric acid excretion in excess of 1100 mg (6.5 mmol) daily, we suggest treatment with interventions to reduce levels of urine uric acid. Based upon a reported 50 percent incidence of urolithiasis among the small proportion of gout patients with urinary uric acid excretion exceeding 1100 mg (6.5 mmol) daily [67], treatment with hydration (≥2 liters of fluids) and allopurinol has long been recommended for prevention or treatment of urinary tract stones in gouty individuals with this level hyperuricosuria [88] (see "Kidney stones in adults: Uric acid nephrolithiasis"). In patients with asymptomatic hyperuricemia and hyperuricosuria of similar degree, we believe that a 90-day trial [89] of restricted dietary purine and purine precursor intake should precede initiation of allopurinol, with the aim of reducing daily renal urinary uric acid excretion to <1000 mg (6.0 mmol).

Failure to reach this goal or patient objection should lead to either of two robust alternatives for stone prophylaxis: first, hydration (>2 liters of fluids daily) and urinary alkalinization (goal: urinary pH ≥6.5 for at least several hours daily) (see "Kidney stones in adults: Uric acid nephrolithiasis"); or second, hydration and allopurinol. In the event urolithiasis occurs on the first regimen, substitution for potassium citrate by allopurinol, with reduction of serum urate levels (goal: <6 mg/dL, or <360 micromol/L) and urinary uric acid excretion (goal: <800 mg daily), can be done (see 'Evaluation' above and 'Initial evaluation' above and 'Further evaluation' above). The use of urate-lowering therapy can result in substantial reduction of stone risk among hyperuricosuric gout patients [88]; a comparable benefit of alkalinization appears the case in our experience and that of other experts, compared with historical experience [67,88].

Recurrent uric acid urolithiasis — In hyperuricemic and/or hyperuricosuric patients with recurrent uric acid urolithiasis despite adequate hydration and urinary alkalinization therapy, urate-lowering pharmacotherapy with a xanthine oxidase inhibitor is employed regardless of the baseline serum urate level. The management of uric acid nephrolithiasis is described in detail separately. (See "Kidney stones in adults: Uric acid nephrolithiasis".)

Tumor lysis — Patients about to receive radiotherapy or chemotherapy that is likely to result in extensive tumor cytolysis should be treated to prevent acute uric acid nephropathy and other manifestations of tumor lysis syndrome [34]. The management of patients with or at risk of tumor lysis syndrome is described in detail separately. (See "Tumor lysis syndrome: Prevention and treatment".)

Hyperuricemia and conditions unassociated with crystal deposition — Despite the high prevalence of hyperuricemia in patients with conditions (such as hypertension or metabolic syndrome) in which hyperuricemia does not clearly play a causal role, our approach to management of such patients is in accord with those used for most other patients with asymptomatic hyperuricemia, such as life-style interventions and optimization of medication choices for other conditions. (See "Secondary factors and progression of chronic kidney disease", section on 'Hyperuricemia'.)

With the exception of acute uric acid nephropathy [34], the initial clinical manifestations of urate or uric acid crystal deposition are not life-threatening and are readily treatable. This observation, plus the lack of an established causal role of hyperuricemia in chronic kidney disease (CKD) [4,53,90] and the other associated disorders [91], has restrained enthusiasm in the United States for prophylactic antihyperuricemic drug therapy in the vast majority of individuals with asymptomatic hyperuricemia. However, experts in some countries (eg, Japan) recommend antihyperuricemic drug therapy for asymptomatic hyperuricemic persons, especially those with associated diseases such as hypertension [10].

Systematic reviews have emphasized the lack of adequate evidence to support the use of urate-lowering therapy for the treatment of hypertension and/or CKD in patients with hyperuricemia [13,92]. Notably, randomized placebo-controlled trials on the effects of urate lowering in hypertension [93] and CKD [94] have been negative. Two randomized trials published in 2020, Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase (CKD-FIX) and Preventing Early Renal Loss in Diabetes (PERL), addressed the effect of treatment with allopurinol on estimated glomerular filtration rate (GFR) decline:

In the CKD-FIX trial, 369 patients with stage 3 or 4 CKD determined to be at high risk for progression (either a decrease in GFR of 3 mL/min/1.73 m2 in the preceding 12 months or a urinary albumin/creatinine ratio of 265 mg/g or greater) were randomized. Despite a significant reduction in serum urate, there was no evidence of slower GFR decline in the allopurinol group over the two-year follow-up period [95].

In the PERL trial, 530 type 1 diabetic patients with evidence of diabetic kidney disease (defined as the presence of albuminuria or evidence of GFR decline of 3 mL/min/1.73 m2 per year) and a minimum serum urate of 4.5 mg/dL were randomized. Changes in GFR during the study period was measured through an iohexol-based method. Despite sustained lowering of serum urate over a three-year period in the allopurinol group, there was no appreciable change in GFR slope [96].

Given the results of CKD-FIX, PERL, and other studies, we do not recommend the use of urate-lowering therapy for the treatment of hypertension and/or CKD in patients with hyperuricemia. Of note, however, patients with severe gout have been shown to demonstrate renal medullary echogenicity on ultrasound scans [97], potentially due to MSU crystalluria [98] and the development of medullary tophi; therefore, we advocate for the aggressive management of gout in patients with CKD [99].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gout and other crystal disorders".)

SUMMARY AND RECOMMENDATIONS

Definition – Hyperuricemia itself is not a disease, but persistent asymptomatic hyperuricemia imparts risks for the development of urate or uric acid crystal deposition-related clinical events such as gout and uric acid nephrolithiasis. For these disorders, the risks are, at least in part, related, respectively, to the magnitude of hyperuricemia and hyperuricosuria (excessive urinary uric acid excretion). For purposes relating to urate crystal deposition in gout, the physiochemical definition of hyperuricemia is based upon the solubility limit of urate in body fluids, with hyperuricemia defined as serum urate concentrations exceeding about 7 mg/dL (416 micromol/L), as measured by automated enzymatic (uricase) methods. Hyperuricemia is also associated with important chronic kidney, cardiovascular, and metabolic disorders that are not due to urate crystal deposition, but a causal role of hyperuricemia in these conditions is less well defined, and, thus, a definition of hyperuricemia in this setting is less well established. (See 'Definition' above.)

Classification – Persistent hyperuricemia is a common biochemical abnormality that results from excessive urate production, absolute or relative impairment of renal uric acid clearance, or a combination of these mechanisms. Multiple genetic, comorbid disease-related, and environmental (drug, diet, and toxic exposure-induced) influences (table 1 and table 2) promote hyperuricemia. (See 'Classification' above.)

Epidemiology – Hyperuricemia in men frequently begins at puberty. Normal adult male values exceed those in women of reproductive age due to enhancement of renal uric acid clearance by estrogenic compounds. Thus, hyperuricemia in women is usually delayed until after menopause, when serum urate values in normal women increase and become comparable to those in normal men of a similar age. (See 'Epidemiology' above.)

Potential clinical consequences

Urate crystal deposition disorders – There are three major crystal deposition-related disorders associated with hyperuricemia: gout, urolithiasis, and urate nephropathy. The risk of gout and urolithiasis is elevated with increasing degrees of hyperuricemia and hyperuricosuria, respectively. However, tophus formation, uric acid urolithiasis, and chronic urate nephropathy are relatively infrequent occurrences even in individuals with longstanding hyperuricemia. With the exception of acute uric acid nephropathy, the initial clinical manifestations of urate or uric acid crystal deposition are readily treatable. (See 'Gout' above and 'Nephrolithiasis' above and 'Chronic kidney disease' above and 'Potential clinical consequences' above.)

Non-crystal deposition disorders – Hyperuricemia is clearly associated with hypertension, chronic kidney disease (CKD), cardiovascular disease, and components of the metabolic syndrome but has not been established as a causal factor in any of these disorders. We do not use urate-lowering pharmacotherapy for treatment of such conditions. (See 'Non-crystal deposition disorders' above.)

Evaluation

Initial evaluation – We advise that evaluation of patients with persistent asymptomatic hyperuricemia in excess of 8 mg/dL (480 micromol/L) should include a thorough history, physical examination, and limited laboratory testing to identify the following: those who are at particularly high risk for gout flares, tophi, or urolithiasis and warrant urate-lowering treatment; individuals whose hyperuricemia is a sign of an underlying disorder or environmental exposure requiring specific treatment; and hyperuricemia-inducing drugs or toxins that can be removed or substituted, with relief or diminution of the hyperuricemic state. Examples of potentially treatable causes of hyperuricemia include lymphoproliferative and myeloproliferative disorders, psoriasis, vitamin B12 deficiency, preeclampsia, and lead toxicity. (See 'Evaluation' above and 'Initial evaluation' above.)

Further evaluation – In a man presenting before age 25 or a woman presenting before menopause with asymptomatic hyperuricemia (serum urate >8 mg/dL, or >480 micromol/L) and whose initial evaluation fails to identify a cause of hyperuricemia, further evaluation should include determination of the fractional excretion of uric acid using a spot urine or a 24-hour urine specimen that is collected while the individual is receiving a standard diet, excluding alcohol and drugs known to affect urate metabolism. The distinction between overproduction and underexcretion serves to guide further investigation of the underlying cause of hyperuricemia, and, if treatment is necessary, it will be useful in directing the choice of antihyperuricemic medication. (See 'Further evaluation' above and 'Marked asymptomatic hyperuricosuria' above.)

Management

General measures – We provide counseling regarding the use of nonpharmacologic (lifestyle) interventions to reduce the degree of hyperuricemia for all people with persistent asymptomatic hyperuricemia in whom treatable secondary causes have been excluded and those with evidence of monosodium urate (MSU) crystal deposition only on imaging. These lifestyle interventions include reduction to ideal body weight by means of adjustment of dietary volume and composition, avoidance of alcohol and sugar-sweetened beverages, and regular exercise. In patients with persistent asymptomatic hyperuricemia requiring medical therapy for another condition, we avoid medications for the coexisting condition that may promote hyperuricemia (eg, thiazide diuretics for hypertension), and we prefer the use of medications for coexisting conditions that reduce serum urate levels and/or decrease the risk for incident gout when these choices are acceptable therapeutic alternatives. (See 'General measures' above.)

Marked asymptomatic hyperuricosuria – In patients evaluated for sustained asymptomatic hyperuricemia who have urinary uric acid excretion in excess of 1100 mg (6.5 mmol) daily, we suggest treatment with interventions to reduce levels of urine uric acid (Grade 2C). Dietary purine restriction should be tried initially in such patients. We use hydration and alkalinization of the urine or hydration and allopurinol if dietary restriction does not reduce uric acid excretion to less than 1000 mg/day (5.9 mmol/day), and the dose of allopurinol should be adjusted to reduce uric acid excretion below 800 mg/day (4.8 mmol/day). (See 'Marked asymptomatic hyperuricosuria' above.)

Tumor lysis syndrome – The management of patients either with or at risk of tumor lysis syndrome is described in detail separately. (See "Tumor lysis syndrome: Prevention and treatment".)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Michael A Becker, MD, who contributed to an earlier version of this topic review.

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Topic 1669 Version 36.0

References

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