articulo

1. REVIEWARTICLE
Asymptomatic hyperuricemia: is it time to intervene?
Binoy J. Paul1
& K. Anoopkumar1
& Vinod Krishnan1
Received: 14 July 2017 /Revised: 18 September 2017 /Accepted: 21 September 2017 /Published online: 4 October 2017
# International League of Associations for Rheumatology (ILAR) 2017
Abstract Whether to treat hyperuricemia uncomplicated by
articular gout, urolithiasis, or uric acid nephropathy is an ex-
ercise in clinical judgment and universal agreement is lacking.
Patients with coronary artery disease, chronic kidney disease,
and early onset hypertension with persistent hyperuricemia
are likely to be benefited with urate-lowering therapy. The
paradigm of the causative association of hyperuricemia with
cardiovascular and chronic kidney diseases seems to have
progressed from skepticism to increasing evidence of a true
relationship. Although such evidences are mounting, they are
not enough to support pharmacotherapy for all patients with
asymptomatic hyperuricemia. Further studies are needed to
determine which patients are likely to get beneficial effects
from pharmacotherapy and the minimum threshold of uric
acid level required to experience clinical benefits.
Keywords Chronickidneydisease .Coronaryarterydisease .
Gout . Hyper uricemia . Systemic hypertension .
Urate-lowering therapy
Asymptomatic hyperuricemia is a condition in which the se-
rum urate concentration is elevated (> 7 mg/dL in men or
> 6 mg/dL in women) but neither symptoms nor signs of urate
crystal deposition have occurred. Uricase (urate oxidase) en-
zyme present in lower animals has the unique ability to con-
vert uric acid to soluble allantoin [1]. During evolution in man
and apes (hominoids), there was inactivation of uricase gene
by mutation. In the phase of the transition to upright walking
during the evolution, the hominoids have experienced recur-
rent postural hypotension [2]. Human diet during that time
was mainly vegetarian and extremely low in salt. The eleva-
tion in serum uric acid level was a protective mechanism for
restoring normal blood pressure, primarily through urate-
induced renovascular injury [3]. Today, human diet is rich in
salt and proteins. Hence, this homeostatic adaptation is now
contributing to hyperuricemia and gout [4, 5].
Uric acid—physiological functions
Uric acid is a breakdown product of purine metabolism, a
metabolic waste molecule. Evolution has co-opted this
waste-generating process to play important physiological
functions. Uric acid has important role in organismal immu-
nity. It promotes T cell activation in response to antigens and
acts as a danger signal to promote immune responses.
Hyperuricemia promotes hominoid intellectual function,
through its activation of neuro-stimulatory adenosine recep-
tors. Subjects with elevated uric acid levels have a lower fre-
quency of Parkinson’s disease [6, 7], Alzheimer’s disease [8,
9], multiple sclerosis [10, 11], and Huntington’s disease [12].
Moreover, uric acid is a key antioxidant in plasma that may
help to prolong longevity by preventing aging-associated ox-
idative stress [13].
Risks of hyperuricemia
There are many primary and secondary causes of hyperuricemia
(Table 1). The dangers of chronic hyperuricemia are urate crystal
deposition leading to gout, urolithiasis, and uric acid nephropa-
thy. Crystal deposition unrelated problems like hypertension
[14, 15], chronic kidney disease [16, 17], cardiovascular disease
* K. Anoopkumar
dranoop6505@gmail.com
1
Department of Internal Medicine, KMCT Medical College
Manassery, Calicut, 673602, Kerala, India
Clin Rheumatol (2017) 36:2637–2644
DOI 10.1007/s10067-017-3851-y

2. [18, 19], and insulin resistance syndrome [20–22] were also
implicated with elevated uric acid level (Fig. 1). However, the
chance of developing gout or urolithiasis in people with hyper-
uricemia is fairly low in clinical practice. Ten percent of adults
are documented to have hyperuricemia at least once in their
lifetime. More than 80% of hyperuricemic individuals will re-
main asymptomatic throughout their lives. In Normative Aging
Study, 2046 initially healthy men were followed up for 15 years.
The annual incidence of gout was 0.1% in people with serum
uric acid (S.UA) level less than 7.0 mg/dL, 0.5% when S.UA is
between 7.0 and 8.9 mg/dL, and 4.9% when S.UA more than
9.0 mg/dL [23]. In the Hypertension Detection and Follow-up
Program, patients with serum uric acid levels between 7 and
7.9 mg/dL were followed up for 14 years; gout developed only
in 12% individuals [24]. Serum urate levels above 9.0 mg/dL
had a much greater predictive value for the development of gout.
However, this degree of hyperuricemia was uncommon, occur-
ring in less than 20% of individuals with chronic hyperuricemia.
Progression of hyperuricemia to acute gout is more common
when associated other risk factors were present [25]. Risk factors
of developing gout are alcohol consumption, high levels of meat
and seafood ingestion, diuretic use, obesity, and usage of drugs
like low-dose aspirin or pyrazinamide [26–28]. Uric acid stones
account for 5–10% of all renal stones, but the annual incidence
of urolithiasis was 0.3% in patients with asymptomatic
hyperuricemia and 0.9% in patients with hyperuricemia and gout
[29, 30]. Uric acid stones develop in only 20% of hyperuricemic
patients [31]. Asymptomatic hyperuricemia was regarded as the
initial state preceding acute gouty arthritis or urolithiasis. But
epidemiologic studies have demonstrated that acute gout, uro-
lithiasis, or tophi are relatively infrequent events in individuals
with long-standing hyperuricemia. The initial clinical manifesta-
tions of urate deposition are not life-threatening and are readily
treatable. Prolonged antihyperuricemic pharmacotherapy has its
own risks. Hence, routine prophylactic urate-lowering drug ther-
apy is not indicated in the vast majority of individuals with
asymptomatic hyperuricemia [31]. However, it is recommended
that patients presenting with tophi should be treated promptly,
even if they have no history of gout symptoms [32].
But there are other problems with sustained hyperuricemia.
Soluble urate is biologically active, with effects on renal and
vascular function. Uric acid may have numerous other delete-
rious roles. It inhibits endothelial function, stimulates vascular
smooth muscle cell proliferation, activates the renin-
angiotensin system, and stimulates adipocytes [14].
Hyperuricemia and systemic hypertension
Various studies and meta-analysis have shown that hyperurice-
mia is associated with an increased risk for incident hypertension,
independent of traditional hypertension risk factors [33, 34] (See
Table 2). It is also found that this risk appears more pronounced
in younger individuals and women [47, 48]. Uric acid inhibits
Fig. 1 Pathogenesis of hyperuricemia causing hypertension, coronary
artery disease, and chronic kidney disease
Table 1 Causes of hyperuricemia
Primary (innate) hyperuricemia
■ Idiopathic (90% of these are due to under excretion of uric acid)
■ Inherited enzyme defects
Hypoxanthine-guanine phosphoribosyl transferase deficiency
(Lesch–Nyhan syndrome/Seegmiller syndrome)
Glucose-6-phosphatase deficiency
Phosphoribosyl pyrophosphate synthetase overactivity
Secondary hyperuricemia
Increased urate production
■ Myeloproliferative disorders
■ Psoriasis
■ Hemolytic diseases
■ Malignancies and tumor lysis syndrome
■ High-purine diet
■ Alcohol
Decreased renal clearance
■ Renal: chronic renal failure, polycystic kidney disease, lead
nephropathy
■ Endocrine: hyperparathyroidism, hypothyroidism, diabetes insipidus
■ Metabolic: lactic acidosis, ketoacidosis, starvation, severe dehydration
■ Metabolic syndrome: obesity, dyslipidemia, hypertension
■ Drugs: diuretics, low-dose aspirin, pyrazinamide, cyclosporin,
ethambutol
■ Miscellaneous: sarcoidosis, toxemia of pregnancy, down syndrome
2638 Clin Rheumatol (2017) 36:2637–2644

3. synthesis of the potent vasodilator nitric oxide, induces smooth
muscle cell proliferation, and stimulates platelet-derived growth
factor synthesis leading to arterial vasoconstriction. Soluble urate
has been shown to directly stimulate the renin-angiotensin sys-
tem in the kidney. It also induces renal interstitial and tubular
inflammation causing hypertension. Hyperuricemia was found
to precede the development of hypertension in nearly 90% of
newly diagnosed hypertensive adolescents [49], and lowering
uric acid with allopurinol has been found to reduce blood pres-
sure in these patients in few studies [50]. Whether serum uric
acid has a direct pathophysiological role in the development of
hypertension in older adults is less clear because allopurinol use
is associated with only a small reduction in blood pressure in
adults [51]. Hyperuricemia may promote insulin resistance in
adipose cells, potentially serving as a risk factor for diabetes
and metabolic syndrome [52, 53]. However, treatment of hyper-
uricemia does not improve insulin sensitivity in these patients.
Hyperuricemia and chronic kidney disease
Hyperuricemia is nearly invariable in chronic kidney disease
(CKD) due to the reduction in the renal efficiency of urate ex-
cretion and is unaccompanied by hyperuricosuria. It is also found
that elevated uric acid can also cause or worsen CKD [54]. An
elevation in the serum urate concentration out of proportion to
the degree of renal insufficiency has been defined when the
serum uric acid level is more than 9 mg/dL if the serum (S.)
creatinine is ≤ 1.5 mg/dL, more than 10 mg/dL if the S. creatinine
is between 1.5–2.0 mg/dL, and more than 12 mg/dL with more
advanced renal failure [55]. There is increasing evidence,
supporting hyperuricemia as a true risk factor of CKD [56].
But there are still discrepancies regarding the contributing role
of uric acid in the onset or worsening of kidney disease [56, 57].
As of yet, there is still no agreement as to whether treating
asymptomatic hyperuricemia in renal dysfunctions will offer
more renoprotection. Large prospective trials are needed to solve
the issue. However, it is clear that very high levels of uric acid
can cause further renal damage. It was suggested that hyperuri-
cemia is of definite clinical importance if the serum urate levels
exceed at least 13 mg/dL in men and 10 mg/dL in women [58,
59]. However, recent studies have shown that those with S. uric
acid above 9 mg/dL had three times the risk of developing kidney
disease compared to those with normal uric acid levels [60].
Several other studies also show a linear relationship between S.
Uric acid level and kidney function [61–63].
Hyperuricemia and coronay artery disease
The relation between hyperuricemia and coronary artery disease
(CAD) is more complex. Studies have linked hyperuricemia to
Table 2 Major studies showing association between hyperuricemia and hypertension
Study Population Relative risk
Normative Aging Study
(2006) [35]
2062 healthy men age 40–60 years 1.5-fold at 21 years
ARIC (2006) [36] 9104 mixed race (black and white) 1.5-fold at 9 years
MRFIT (2007) [37] Men and women age 45–64 years 1.8-fold at 6 years
Nurses health (2009) [38] 3073 men age 35–57 years 1.9-fold at 6 years
Leite et al. (2010) [39] 1410 men and women, young cohort Increased risk in middle age, not in elderly
42–59 years, older cohort 60–74 years
Grayson et al. (2010) [40] 55,607 adults, meta-analysis of 18 prospective studies 1.41-fold risk each 1 mg/dL uric acid
Silverstein et al. (2011) [41] 108 racially diverse children, age 6–18 in
Texas and Washington, DC
Linear association between systolic BP and
uric acid in children on renal replacement therapy
Fadrowski et al. (2012) [42] 6036 adolescents, age 11–17 years. Uric acid
> 5.5 mg/dL,
evaluated in the National Health and Nutrition
Examination Survey
2.03-fold risk
Gaffo et al. (2013) [43] 4752 individuals (2135 men and 2617 women),
age 18–30 years
1.25-fold risk per each mg/dL in men but no
significant increase in women
Kuwabara M et al. (2014)
[44]
90,143 Japanese people 1.7- and 3.4-fold prevalence of hypertension in
male and female patients
Cui LF et al. (2017) [45] 39,233 Chinese subjects followed up for 4 years Elevated S. uric acid is associated with increased risk of
hypertension
Kuwabara M et al. (2017)
[46]
5899 Japanese subjects followed up for 4 years Hyperuricemia was associated with increased cumulative
incidence of hypertension, chronic kidney disease,
dyslipidemia, and obesity
Clin Rheumatol (2017) 36:2637–2644 2639

4. numerous associations which are risk factors of CAD. Uric acid
levels correlate with hypertension, atherosclerosis,
microalbuminuria, obesity, hypertriglyceridemia, low HDL,
hyperinsulinemia, peripheral and carotid artery disease, endothe-
lial dysfunction, renin levels, endothelin level, and CRP level.
The association of uric acid with almost all risk factors for CAD
(with smoking the only real exception) has made it very difficult
to determine whether uric acid has a causal role in these condi-
tions or whether it is simply a marker for individuals at increased
risk. In the 1950s, one of the founding objectives of the
Framingham Heart Study was to test the hypothesis that gout is
associated with CAD. The first modern article linking gout and
CAD was published in 1988 based on data from Framingham
study which showed significant association [64]. The National
Health and Nutrition Examination Survey I (NHANES I) follow-
ed up 5421 patients from 1971 through 1987. No association
between hyperuricemia and coronary artery disease was seen in
men, but in women, the rates of all-cause mortality and CAD
rose with serum uric acid levels. This association persisted after
excluding the first 10 years of follow-up and was independent of
diastolic blood pressure, obesity, and the use of antihypertensive
agents and diuretics [65]. In 1999, the Framingham Heart Study
published the results of their ancillary study on the association of
serum urate with cardiovascular disease. A total of 6763
Framingham study participants contributed a total of 117,376
person-years of follow-up. No significant associations were
found in men or women after adjustment for cardiovascular risk
factors and diuretic use [66]. Several large epidemiological stud-
ies investigating the association between serum urate levels and
cardiovascular mortality have since been published [67, 68]. The
majority had results in support of the association, but many
good studies reported negative results [69–71]. Current data
suggests that hyperuricemia could increase the risk of develop-
ing cardiovascular disease. Some of the recent studies suggest
that hyperuricemia is a strong independent risk factor for major
cardiac events (MACE) and should be included in cardiovas-
cular prevention strategies. But it is too early to make clinical
recommendations with regard to the benefits of pharmacother-
apy in patients with asymptomatic increase in uric acid levels
as it is not clear whether hypouricemic drug treatment can
decrease cardiovascular disease risk. Further prospective con-
trol studies are warranted to address this issue [72].
Hyperuricemia is a common finding in congestive heart failure
and high levels of uric acid is associated with poor outcome. In
patients with heart failure, there is significant confirmation that
elevated uric acid levels predict an increase in morbidity and
mortality [73]. Some of the recent studies also showed that
asymptomatic hyperuricemia is independently associated with
coronary artery calcification in the absence of overt coronary
artery disease [74]. Epidemiological studies have also
established strong positive correlation between serum urate
concentration with obesity, dyslipidemia, insulin resistance, ce-
rebrovascular, and peripheral vascular diseases. Further studies
are needed to assess the exact role of uric acid reduction in the
prevention of progression of these diseases [75].
Approach to asymptomatic hyperuricemia
Mere presence of high levels of uric acid in the blood is not an
indication for pharmacotherapy with urate-lowering agents.
Instead, upon diagnosing hyperuricemia, the following ques-
tions should be answered by detailed history, physical exam-
ination, and laboratory investigations [76] (Fig. 2).
1. What is the cause of the hyperuricemia? Hyperuricemia
may be the initial clue to the presence of a previously
unsuspected disorder. In 70% of hyperuricemic patients,
an underlying cause can be readily defined by history and
physical examination. Look for possible correctable
causes like sedentary lifestyle, alcohol abuse, obesity,
high-purine diet, usage of drugs like thiazides, low-dose
aspirin, or pyrazinamide.
2. Are associated findings present? Hyperuricemia does not
necessarily represent a disease state. It is often only a
coincidental laboratory finding. A high S. uric acid level
should alert the physician to look for underlying illnesses
like hypothyroidism, metabolic syndrome, psoriasis, or
myeloproliferative disease.
3. Has damage to tissues or organs occurred? Whether the
patient has associated renal calculi, urate nephropathy, or
tophi which may need intervention
4. What are the co-morbidities? Co-morbid illnesses like
systemic hypertension, CAD, heart failure, or CKD which
may get worsened by persistent hyperuricemia
5. What, if anything, should be done? The cause of hyper-
uricemia to be determined and any associated factors re-
lated to the process to be addressed (Table 3). Lifestyle
modification with diet and exercise is often enough to
control asymptomatic hyperuricemia in majority, and
pharmacotherapy is not needed in these people.
Antihypertensive drugs like losartan can reduce hyperuri-
cemia and modify the development of gout and cardio-
vascular events in hypertensive patients. In hyperuricemic
patients with dyslipidemia, fenofibrate is an option which
can control both lipids and serum uric acid.
Non-pharmacological measures
Diet restriction Low-purine diet can reduce the S. uric acid
level by 10–15%. Avoidance of alcohol (especially beer and
spirits), sugar-sweetened drinks, heavy meals, and excessive
intake of meat and seafood is useful [77]. Bing cherry and
2640 Clin Rheumatol (2017) 36:2637–2644

5. coffee have beneficiary role [78, 79]. Low-fat dairy products
should also be encouraged [77]. Fructose-rich beverages are
better avoided (Table 4). Protein-rich vegetables like nuts,
legumes, beans, spinach, cauliflower, and mushroom can be
taken in moderation. Due to the low bioavailability of urate
and high-fiber content, they will not increase the serum uric
acid unlike animal protein or sea foods. All spirits including
wine and beer will increase uric acid production by accelerat-
ing the ATP turnover and decreasing renal excretion of urate.
Lifestyle modifications The risk of gout is lower in men who
are more physically active, maintaining ideal body weight.
Extremely strenuous exercise can lead to dehydration and in-
crease ATP turnover; both can precipitate gout.
Vitamin supplementation Ascorbic acid increases the ex-
cretion of uric acid in the urine. It is a weak uricosuric
agent [80]. Vegetables and fruits rich in vitamin C can be
useful in asymptomatic hyperuricemia. Vitamin C at a
dose of 500–1000 mg/day can also be used as an adjuvant
to diet and exercise. Studies also show that folic acid
Table 4 Dietary factors in hyperuricemia
Causative Protective
Meat, especially organ meat
Sea foods
Sugar sweetened
Soft drinks
Fructose-rich beverages
Honey
Alcohol
Bing cherry
Coffee
Low-fat dairy
products
Intact cow’s milk
Vitamin C
Folic acid
Fig. 2 Investigations in asymptomatic hyperuricemia
Table 3 Correctable factors contributing to hyperuricemia
• Obesity
• Hypertriglyceridemia
• High-purine diet
• Alcohol consumption
• Uncontrolled hypertension
• Drugs: thiazides, low-dose aspirin therapy, pyrazinamide
• Suboptimal urine flow (< 1400 ml/day)
Clin Rheumatol (2017) 36:2637–2644 2641

6. supplementation is also useful to lower the serum urate
concentration [81]. Majority of asymptomatic hyperurice-
mia can be managed well with dietary modification, cor-
rection of risk factors, exercise, and supplementation of
vitamin C and folate.
Pharmacotherapy
There are three rare exceptions that need drug therapy
even in asymptomatic people with elevated serum uric
acid. In order to prevent uric acid nephropathy, pharma-
cotherapy is warranted in patients about to receive radio-
therapy or chemotherapy for malignancies. Preventive
therapy in these patients at risk of urate nephropathy in-
cludes intravenous hydration and xanthine oxidase
inhibitors.
Second indication of urate-lowering drug therapy is in
the relatives of patients with a hereditary enzyme deficien-
cies causing uric acid overproduction like deficiency of
hypoxanthine/guanine phosphoribosyl transferase (Lesch–
Nyhan syndrome and Kelly–Seegmiller syndrome), glu-
cose-6-phosphotase, or fructose-1-phosphate aldolase.
Rarely, overactivity of phosphoribosyl pyrophosphotase
synthetase can also cause hyperuricemia. Relatives of pa-
tient with younger onset gout should be screened for in-
crease in urinary excretion of uric acid. Excretion of uri-
nary uric acid > 1100 mg daily is associated with a 50%
risk of uric acid calculi. Management of these individuals
should begin with dietary purine restriction. Xanthine ox-
idase inhibitors should be used if dietary restriction does
not reduce uric acid excretion to less than 1000 mg/day.
The dose should be adjusted to reduce uric acid excretion
below 800 mg/day.
Lastly, an infrequent patient with persistently high uric acid
level in spite of non-pharmacological measures may also require
urate-lowering drugs. Avalue greater than 13 mg/dL in men and
10 mg/dL in women carries a definite nephrotoxic risk and def-
initely requires intervention [59]. However, the upper limit of
urate level for pharmacotherapy is showing a declining trend as
the recent studies demonstrating that the nephrotoxic risk is es-
calating three times with S.UA level more than 9 mg/dL in
comparison with people with normal serum urate levels [60].
Further studies are needed to determine which patients are likely
to get beneficial effects from pharmacotherapy and the ideal
serum levels of uric acid required to experience this clinical ben-
efits [82]. In some of the countries like Japan, treatment of
asymptomatic hyperuricemia is recommended to prevent Bnon-
gout diseases^ like hypertension, CAD, and CKD [83]. The
serum urate-lowering effect of newer xanthine oxidase inhibitors
like febuxostat and topiroxostat was found to have a dose–re-
sponse relationship in hyperuricemic patients with or without
gout.
Summary
Whether to treat or not to treat asymptomatic hyperuricemia is
still a debatable entity. The causative association of hyperuri-
cemia with cardiovascular and chronic renal diseases gets
stronger with recent studies. Patients with CAD, CKD, and
early onset hypertension with persistent hyperuricemia may
likely to improve with urate-lowering therapy [84, 85].
However, using observational data alone is not sufficient to
support regular drug therapy, noting the frequent discordance
between observational studies and randomized controlled tri-
als [83]. Hence, it is too early to make clinical recommenda-
tions of the benefits of urate-lowering drug therapy in every
patient with asymptomatic hyperuricemia. However, there is
sufficient data today, to warrant well-designed clinical trials to
determine whether urate-lowering therapies would be of ben-
efit in the treatment or prevention of cardiovascular and renal
diseases.
Compliance with ethical standards
Disclosures None.
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