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Asymptomatic
hyperuricemia
Author: David B Mount, MD
Section Editor: Nicola Dalbeth, MBChB, MD, FRACP
Deputy Editor: Paul L Romain, MD

All topics are updated as new evidence becomes available

and our peer review process is complete.

Literature review current through: Sep 2020. | This

topic last updated: Jun 29, 2020.

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 renal
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 renal diseases" and "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 renal 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 renal diseases" and "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 [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 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 renal
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 both men and women
[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 in both men
and women 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 renal
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 renal diseases" and "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 renal 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]. Renal 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 renal diseases".)

The extent to which chronic urate crystal

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

It has been suggested that hyperuricemia

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no clinical importance with respect to CKD until
Text
serum urate levels exceed at least 13 mg/dL
References
(773 micromol/L) in men and 10 mg/dL (595
Graphics
micromol/L) in women, levels that are
Contributor
uncommon and beyond whichDisclosures
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 renal insufficiency.
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 (medullary
cystic 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 renal
insufficiency is a hallmark of ADTKD due to
UMOD mutations [63], hyperuricemia and gout
can also be associated with cystic renal disease
due to mutations in HNF1B [64].

An elevation in the serum urate concentration

out of proportion to the degree of renal
insufficiency 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 renal 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 "Uric acid
nephrolithiasis" and "Risk factors for calcium
stones in adults".)

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 renal
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]. 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 [69].

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, renal, 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
: