hyperuricemia and associated diseases

Rheum Dis Clin N Am 32 (2006) 275–293

Hyperuricemia and Associated Diseases

Michael A. Becker, MDa,T, Meenakshi Jolly, MDb

aRheumatology Section, The University of Chicago Pritzker School of Medicine, Chicago, IL, USAbDepartment of Medicine, Rush University Medical Center, Chicago, IL, USA

In the years after introduction of effective urate-lowering therapy, many

persons who had hyperuricemia but no symptoms of gout were treated with

allopurinol or uricosuric agents in the belief that the previously demonstrated

association of gout with chronic structural and functional renal abnormalities

denoted a causal relationship. Epidemiologic studies in the late 1970s [1,2],

however, seemed to allay the concern that hyperuricemia and gout were in-

dependent risk factors for chronic kidney disease. These studies prompted the

current conservatism in the management of asymptomatic hyperuricemia. Never-

theless, the association of hyperuricemia and gout with other important disorders

continues to be documented and, combined with experimental data derived from

studies in rats, has led to reconsideration of a pathogenetic role for hyperurice-

mia independent of crystal deposition in hypertension, chronic kidney disease,

cardiovascular disease (coronary heart disease, stroke and peripheral artery dis-

ease, and congestive heart failure), and aberrant metabolic states, such as hyper-

triglyceridemia, obesity, insulin resistance, and metabolic syndrrome. Whether

or not hyperuricemia (or even ‘‘high normal’’ serum urate levels) plays a causal

role or simply is a marker arising in the course of each related disorder remains

unresolved. This article reviews the current status of the relationship between

hyperuricemia and associated disorders.

0889-857X/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.rdc.2006.02.005 rheumatic.theclinics.com

T Corresponding author. Rheumatology Section, MC 0930, University of Chicago Medical

Center, 5841 Maryland Avenue, Chicago, IL 60637.

E-mail address: [email protected] (M.A. Becker).

mailto:[email protected]

http://dx.doi.org/10.1016/j.rdc.2006.02.005

http://rheumatic.theclinics.com

becker & jolly276

Definition of hyperuricemia

Physicochemical and population definitions of hyperuricemia exist [3]. The

physicochemical definition (serum urate concentration in excess of 6.8 mg/dL,

the limit of urate solubility in serum) is preferable in the context of gout, to stress

that the risk for crystal deposition disease imparted by urate supersaturation of

extracellular fluids begins at approximately this concentration and probably is

equivalent in comparably affected men and women. Hyperuricemia without

gout (asymptomatic hyperuricemia) is more common with this definition, with

prevalence rates of 5% to 8% in men in the United States [4–6] and up to 25% in

adult men of Polynesian derivation [7], than with a definition of hyperuricemia

based on serum urate values 2 standard deviations or more above the mean

population value.

With respect to the issue of crystal deposition and independent roles of

hyperuricemia, however, it is important to acknowledge the results of popu-

lation studies of serum urate, showing that values are higher in men than

in women before menopause and are more comparable thereafter. Furthermore,

children have lower serum urate levels, with adult male levels reached at the

time of puberty and female levels changing little before menopause. In fact, as

exemplified by the studies of juvenile-onset hypertension and cardiovascular

disease (discussed later), it may become necessary to frame new definitions

of ‘‘high’’ serum urate levels as distinct from physicochemical or population-

based hyperuricemia.

Hyperuricemia and hypertension

An association of hyperuricemia and hypertension [8–12] long has been rec-

ognized and is supported by the following observations:

1. Prevalences of hyperuricemia of approximately 20% to 40% in untreated

hypertensive patients and approximately 50% to 70% in treated or renally

impaired hypertensive patients

2. Gout prevalences of 2% to 12% in hypertensive patients

3. 25% to 50% hypertension prevalences in groups of patients who have

documented gout

4. Increasing prevalence of hyperuricemia with increasing blood pressure in

the general population

5. Increasing risk for development of hypertension with increasing baseline

serum urate levels

Despite these findings, conflicting results of epidemiologic studies and

the existence of multiple potentially confounding variables preclude establish-

hyperuricemia & associated diseases 277

ment of a cause-effect relationship in either direction. For example, the high

prevalence of hypertension in patients who have classical gout is related more

closely to obesity than to the duration of gout [13,14]. Moreover, only 1% of

blood pressure variation could be accounted for by serum urate values in

the Israel Ischemic Heart Disease Study of 10,000 men ages 40 or older [15].

These findings contrast with longitudinal studies in which the risk for future

hypertension is correlated with serum urate levels [9,10,12] and a trial of in-

dividuals, who initially were normotensive, in whom serum urate levels re-

mained positively and significantly associated with systolic and diastolic blood

pressures for 12 years and, when high, predicted the development of hyperten-

sion [8].

Because of difficulty in distinguishing epidemiologically between causal and

epiphenomenologic bases for the hyperuricemia-hypertension association, in-

creasing attention is devoted to mechanistic and experimental studies. Renal uric

acid clearances depend on tubular secretory and postsecretory reabsorption rates,

which are reported to be inappropriately low relative to glomerular filtration

rates in adult and childhood essential hypertension [3,16], and may be regu-

lated, in part, by renal blood flow. In fact, selectively increased renal vascular

resistance and total peripheral resistance are documented in subjects who have

essential hypertension and hyperuricemia, raising the possibility that hyper-

uricemia is a consequence of early nephrosclerosis in patients who have essential

hypertension [17]. A similar argument is made for the early appearance of

hyperuricemia in patients who have familial juvenile hyperuricemic nephropathy

(FJHN) [18].

In contrast, a causal role for hyperuricemia in hypertension is suggested by

the results of other experimental and clinical studies. Urate is reported to ac-

tivate critical proinflammatory pathways in vascular smooth muscle cells and,

hence, may have a role in the vascular changes associated with hypertension and

vascular disease [19,20]. Urate stimulates monocyte chemoattractant protein-1

production in vascular smooth muscle cells via mitogen-activated protein kinase

and cyclooxygenase 2. In Sprague-Dawley rats with serum urate levels raised

by oxonate inhibition of uricase activity, a direct correlation is observed between

serum urate level and the development of salt-resistant, allopurinol-reversible

high blood pressure [21]. Also demonstrated is increased juxtaglomerular renin

content and decreased macula densa neuronal nitric oxide synthase content,

implicating the respective mediator systems in the dysregulation of blood pres-

sure. Preglomerular arteriolopathy [22] accompanying these changes may ac-

count for the subsequent development of a salt-sensitive hypertensive state, not

reversible by lowering of serum urate levels [23]. Feig and Johnson recently

demonstrated a linear relationship between serum urate levels and systolic blood

pressure (r=0.8, Pb0.001) in adolescents who have new-onset hyperten-

sion [24]. Furthermore, in a pilot study of such individuals, allopurinol admin-

istration results in urate lowering and normalization of blood pressure [25].

Johnson and colleagues [26–29] review in detail the evidence for a role of urate in

human hypertension.

becker & jolly278

Hyperuricemia and chronic kidney disease

Despite the nearly invariable occurrence of hyperuricemia in chronic kidney

disease in humans and the high frequency of chronic renal impairment in patients

who have gout, evidence for a pathogenetic role of hyperuricemia in the initiation

or progression of chronic renal impairment comes mainly from animal studies

[30]. Mild oxonate-induced increases in serum urate levels in Sprague-Dawley

rats result in glomerular hypertension, hypertrophy, and, ultimately, sclerosis;

renin-dependent systemic hypertension and afferent arteriolosclerosis; and

interstitial renal inflammation, terminating in fibrosis [21,22,31–35]. All of these

changes occur at high but subsaturating urate levels and are independent of urate

crystal deposition. A role for increased urate levels in worsening structural and

functional renal disease also is demonstrated in the cyclosporine-induced [36]

and remnant kidney [33] models of chronic kidney disease in rats. Few studies in

humans are available to support the potential implications of the rat studies.

As discussed previously, earlier studies [1,2] in subjects who have gout and

hyperuricemia failed to corroborate a renal risk of hyperuricemia or gout, at least

at serum urate levels (b13 mg/dL in men; b10 mg/dL in women) commonly

encountered in clinical practice. Although a pathologically demonstrable in-

terstitial urate crystal deposition nephropathy (called urate nephropathy) does

exist, this entity only rarely is of clinical consequence [37]. The shift of in-

vestigative focus to crystal-unrelated effects of urate on the kidney holds more

promise for resolution of the question of a causal role of hyperuricemia in pro-

gressive renal disease.

FJHN is an autosomal dominantly inherited hyperuricemic disorder, commonly

progressing to end-stage renal disease, and allopurinol treatment is reported by

some investigators [38,39], but not all [18], to retard or prevent progression.

Although gout occurs in some patients who have FJHN, there is little evidence

for crystal deposition as a mediator of renal impairment [18], so that confirmation

of a benefical effect of allopurinol in this process is important in assessing the

role of hyperuricemia in the renal disease, for which alternative mechanisms are

proposed [40]. Most families who have the FJHN phenotype have mutations in

the UMOD gene encoding uromodulin (Tamm-Horsfall protein) [41], a fact that

should allow early identification of at-risk family members in whom the benefits

of early urate-lowering therapy can be assessed.

In epidemiologic studies, urate levels are reported to correlate with develop-

ment of chronic renal insufficiency in patients who have hypertension [42,43],

and patients who have impaired renal function have higher serum urate levels

[44–46]. Recently, a reciprocol relationship between serum urate levels and renal

vascular responsiveness to angiotensin II administration was reported [47], sug-

gesting that increased urate levels may, as in rats, activate the renin-angiotensin

system. Finally, the incidence of end-stage renal disease developing over 7 years

in Okinawan women who had serum urate levels greater than or equal to

6.0 mg/dL at baseline was significantly higher than in their counterparts who had

lower urate levels [48].


Hyperuricemia and cardiovascular disease

Coronary heart disease

The weight of recent evidence supports the view that hyperuricemia is an

important risk factor for ischemic heart disease and probably other forms of

cardiovascular disease [49,50]. Whether or not hyperuricemia is only a marker or

is a pathogenetic factor in cardiovascular diseases remains uncertain (Table 1),

and resolution of this issue will likely require large interventional trials assessing

the proposition that prevention or reversal of hyperuricemia has beneficial effects

on the course of cardiovascular disorders in at-risk patients.

The issue of hyperuricemia as an independent risk factor for atheroscle-

rotic cardiovascular disease is controversial [49]. Multivariate analysis of cardiac

risk factors in the original Framingham cohort did not identify an independent

predictive role for serum urate values in coronary heart disease [51] but did

show a 60% excess of coronary disease in gouty men never treated with di-

uretics [52]. Additional study of the Framingham cohort [53] supports the con-

tention that risk factors other than hyperuricemia are causal in atherosclerotic

heart disease. In 6763 subjects who had baseline serum urate levels established

from 1971 to 1976, hyperuricemia was not associated (by 1994) with an increased

risk for adverse outcome (coronary heart disease, death from cardiovascular

disease, or death from all causes) in men or, after adjustment for other cardiovas-

cular risk factors, in women. Similarly, Wannamethee and coworkers did not find

hyperuricemia a risk factor for coronary heart disease in men, independent of pre-

existing myocardial infarction, atherosclerosis, and the cluster of risk factors

associated with the insulin resistance syndrome [54]. Clustering of hyperuricemia

with cardiovascular risk factors also is reported by others [55].

Other published studies, however, favor a more direct role for hyperuricemia

in cardiovascular events or mortality [26,27,50,56–68]. In the National Health

and Nutrition Examination Survey (NHANES) I study, increasing serum urate

concentration was related to increasing cardiovascular mortality in both sexes and

in blacks and whites [56]. Death rates resulting from ischemic heart disease

increased in relation to serum urate quartile (relative risk 1.77 in men and 3.00 in

women), and cardiac and overall cardiovascular mortality risks of hyperuricemia

persisted even after adjustment for age, race, body mass index (BMI), smoking

status, alcohol intake, cholesterol, hypertension, and diabetes. In the NHANES III

study, serum urate levels greater than or equal to 6 mg/dL were found to be an

independent predictor of coronary heart disease [61]. Also, in two studies in-

cluding more than 2600 patients who had angiographically confirmed coronary

artery disease [57,62], overall mortality rates in patients either whose serum urate

was greater than 7.1 mg/dL (compared with those whose had serum urate was

b5.1) [57] or who were in the highest quintile for serum urate (N6.4 mg/dL) were

increased substantially and independently. Finally, the Losartan Intervention for

Endpoint Reduction in Hypertension (LIFE) study reported a significant

association between baseline serum urate level and risk for a morbid or fatal

Table

1

Studiesrelatingserum

urate

concentrationsandcardiovasculardisease

Author,year[ref.]

Subjects/studynam

eLongitudinal

study

Outcomevariables

Serum

urate

asindependent

predictorofCVD

Brand,1985[51]

Framingham

cohort

Yes

CHD

No

Culleton,1999[53]

Framingham

cohort

Yes

IncidentCHD,allcause

and

CVD

mortality

No

6763Participants

Wannam

ethee,1997[54]

7688Men,40–59years

Yes

Fatal/nonfatalCHD

events

No

Moriarity,

2000[63]

ARIC

cohort;13,504healthysubjects

Yes

CHD

events(fatal/nonfatal)

No

Lin,2004[139]

391Men

withhyperuricemia

Yes

CVD

Abbott,1988[52]

5209,Framingham

cohortwithgout

CHD

Yes,in

men

Freedman,1995[64]

5,421(N

HANES1)25–74years

Yes

Mortality(allcause,ischem

ic

heartdisease)

Yes,in

women

Alderman,1999[50]

7978Mild–moderateHTN

subjects

Yes

CVevents

Yes

Liese,1999[65]

MONICA

cohort,1044subjects,45–64years

Yes

CHD,allcause/CV

mortality

Yes

Fang,2000[56]

5926,Subjects25–74years

(NHANES1

follow-up)

Yes

CHD,allcause/CV

mortality

Yes

Franse,2000[66]

4327SystolicHTN

subjects�60years

(SHEP)

Yes

CVevents,allcause

mortality

Yes

Verdecchia,2000[67]

1720SubjectswithuntreatedHTN

Yes

CVevents,allcause/CV

mortality

Yes

Tuttle,2001[60]

277Patientsundergoingcardiaccatheterization

Yes

SUA

andCHD

Yes,in

women

Bickel,2002[57]

1,017CHD

(angiographic)

Yes

Mortality

Yes

Athyros,2004[71]

GREACEstudy,

1600withCHD

Yes

Allvascularevents

Yes

Niskanen,2004[68]

1423Middle-aged,healthyFinnishmen

Yes

CV/allcause

mortality

Yes

Hoieggen,2004[69]

9193Subjects,55–80years

old

withuntreated

HTN

andLVH

(LIFEstudy)

Yes

Fatal/nonfatalMI,CV

mortality,

fatal/nonfatalstroke

Yes

Tomita,

2000[45]

49,413HealthyJapanese25–60years

Yes

CHD

andstrokeevents,all

cause

mortality

Yes

Madsen,2005[62]

1,595Angiographically

defined

CAD

patients

Yes

Mortality

Yes

Abbreviations:

CAD,coronaryartery

disease;CHD,coronaryheartdisease;CV,cardiovascular;CVD,cardiovasculardisease;HTN,hypertension.

becker & jolly280


cardiovascular event (hazard ratio 1.024 per 10 mmol/L increment in baseline

serum urate) [69].

Data supporting a role for serum urate as a determinant of coronary heart

disease also have emerged from two cardiovascular disease interventional stud-

ies. In the LIFE study [69], which compares losartan-based and atenolol-based

therapy in high-risk hypertensive patients who had left ventricular hypertrophy,

losartan therapy is associated with lower rates of cardiovascular morbidity and

death [70]. Analysis of baseline and in-trial serum urate levels indicates that

29% of the cardiovascular benefit of losartan-based therapy could be ascribed

to the urate-lowering (uricosuric) effect of losartan (not shared by atenolol)

therapy, which prevented increases in serum urate levels during the 4.8 years

of the trial. Similarly, in the Greek Atorvastatin and Coronary-Heart-Disease

Evaluation (GREACE) study [71], patients who had coronary heart disease

treated with atorvastatin showed an in-trial 8.2% reduction in serum urate levels

compared with a 3.3% mean increase in urate in patients who were untreated. The

risks of recurrent coronary disease events were correlated significantly with the

serum urate levels, such that serum urate was regarded an independent predictor

of recurrent coronary heart disease events.

Mechanisms by which hyperuricemia may promote vascular occlusive dis-

ease are under study. A direct relationship between plasma homocysteine

and serum urate levels is reported in patients who have atherosclerosis [72]. A

mutation in the methyl tetrahydrofolate reductase (MTHFR) gene is correlated

with hyperuricemia and hyperhomocysteinemia, the latter a state associated with

thrombotic disease [73]. In a recent study [74], flow-mediated arterial dilation

(FMD) in healthy hyperuricemic and normouricemic control patients who hade

high cardiovascular risk was determined before and after 3 months of allopurinol

treatment. Allopurinol (300 mg daily) reduced serum urate levels in both groups

of subjects, and the significantly lower baseline FMD in the hyperuricemic

group was normalized, suggesting that restoration of normal serum urate levels

improved this measure of vascular function [74]. Other possible mechanisms

relating hyperuricemia and cardiovascular disease are reviewed by Gavin and

Struthers [75].

Stroke and peripheral artery disease

Uric acid administration is protective against experimental ischemic stroke in

rats [76]. In humans, however, there is only one report of a more favorable

outcome of stroke in individuals who are hyperuricemic [77]. In fact, higher

serum urate levels are associated with poorer outcomes in stroke, and serum urate

greater than or equal to 7 mg/dL is described as an independent risk factor for

stroke [61]. Lehto and coworkers [78] found hyperuricemia a predictor (hazard

ratio 1.93) of nonfatal and fatal stroke in a population-based study of middle

aged, non–insulin-dependent diabetics. Similar findings are reported by others

[79,80]. In the Cardiovascular Study in the Elderly (CASTEL) study [79], serum

becker & jolly282

urate also was an independent predictor of stroke mortality [79,59], poor out-

come, and subsequent vascular events, especially in diabetics [81]. Even though

levels of antioxidants, such as ascorbate, are reduced immediately after acute

ischemic stroke, patients who have the worst early outcome are those who have

higher plasma urate levels [82], raising the speculation that under circumstances

of alternative antioxidant depletion, urate may become prooxidant [82,83].

In patients in the LIFE study who were hyperuricemic [69], the cardiovascular

benefits of losartan extended to a reduced incidence of cerebrovascular events.

Whether or not the increased risk of stroke in individuals who are hyperuricemic

is mediated by increased predilection for the development of hypertension or

through a urate effect on the vascular endothelium is unclear, but these potential

mechanisms are under investigation [84].

Hyperuricemia also is a significant and independent risk factor for peripheral

arterial disease in Taiwanese men who have type 2 diabetes [84] and for carotid

artery atherosclerosis. Nieto and coworkers, in their prospective case control

study [85], find baseline serum urate levels associated significantly and in-

dependently with increased carotid artery atherosclerosis 13 years later. The

serum antioxidant capacity, however, was elevated unexpectedly in individuals

who had atherosclerosis, suggesting that hyperuricemia may be a compensatory

rather than a causative factor.

Congestive heart failure

Hyperuricemia is a common finding in congestive heart failure [86], and

higher serum urate levels are associated with increasing severity and poorer

outcomes in heart failure [87,88]. Anker and colleages [87] found high serum

urate levels an independent marker for impaired prognosis in patients who have

moderate to severe congestive heart failure. Urate also may contribute to more

severe heart failure via its role in hypertension [89]. Thus, there is evidence for

direct and indirect pathophysiologic roles of abnormal urate metabolism in con-

gestive heart failure [90].

In animal models, allopurinol decreases myocardial oxygen consumption [91]

and improves systolic function [92]. Endothelial damage resulting from local

xanthine oxidase-generated oxygen free radicals is proposed as a basis of cardiac

dysfunction in hyperuricemic states, and allopurinol inhibition of xanthine oxi-

dase is reported to improve endothelial dysfunction in patients who have heart

failure [86,93]. Ongoing interventional trials [89] assessing cardiovascular out-

comes resulting from inhibition of urate production with allopurinol and oxypuri-

nol should provide useful information relative to these proposed relationships.

Overall, a causal role for hyperuricemia in cardiovascular disease events and

mortality is not established unequivocally [26,58]. There seem to be more than

sufficient grounds, however, to support new clinical (interventional) and ex-

perimental initiatives for studying the potential causal mechanisms by which

hyperuricemia may promote cardiovascular disease [27].


Hyperuricemia, metabolic syndrome, and its components

Metabolic syndrome

Complexity in defining the role of hyperuricemia in chronic diseases, such

as hypertension and atherosclerotic cardiovascular disease, is underlined by

additional associations of hyperuricemia with the clinical and biochemical ab-

normalities of the metabolic syndrome: obesity, hyperlipidemia, and insulin re-

sistance. Included in the diagnostic criteria for the metabolic syndrome are waist

circumference, triglyceride levels, high-density lipoprotein (HDL) cholesterol

levels, blood pressure, and fasting blood glucose levels. Emmerson [94] has

reviewed evidence supporting inclusion of hyperuricemia resulting from impaired

renal uric acid clearance [95,96] as an intrinsic component of the metabolic

syndrome of hyperinsulinemia and resistance to insulin action [97]. The fact that

acute elevations of serum triglycerides, plasma free fatty acids, or serum insulin

do not effect serum urate levels in health volunteers supports this view [96].

Serum urate levels contribute significantly to levels of HDL cholesterol and

total cholesterol, BMI, and systolic blood pressure in children and adolescents

who are obese and may be a reliable marker of ‘‘premetabolic syndrome’’ [98].

The inverse correlation of serum urate and insulin sensitivity and the positive

correlation of urate and triglyceride levels may explain up to 50% of urate var-

iation [96]. It also is suggested that hyperuricemia may be used as a simple

marker of insulin resistance [96]. In addition, studies of weight loss-inducing

medications, such as sibutramine and orlistat, confirm reductions in BMI, fasting

and postprandial glucose levels, waist circumference, insulin resistance, blood

pressure, and serum levels of cholesterol, triglycerides, lipoprotein a, apolipo-

protein B, and urate uric acid [99] (ie, all the features of metabolic syndrome).

A corollary of these observations is that individuals who are hyperuricemic

and hyperlipidemic, in particular those who have abdominal obesity, may be a

high-risk group for the cardiovascular correlates of insulin resistance.

Obesity

Epidemiologic studies have established a strong positive correlation between

body weight and serum urate concentration, but the basis of the relationship is

complex and multifactorial [100–108]. Obesity is associated with decreased renal

uric acid clearance and increased urate production [109,110]. Direct and indi-

rect evidence for excessive body weight promoting hyperuricemia and gout is

presented in many studies [56,111–115], but a role of hyperuricemia influencing

development of obesity emerges from a few other studies (Table 2).

In interventional studies, weight reduction is associated with a modest low-

ering of serum urate concentration and a decrease in the rate of de novo pu-

rine synthesis [109]. In addition, the weight loss associated with moderate calorie

and carbohydrate restriction and increased proportional intake of protein and

unsaturated fat (as recommended for insulin-resistant states) is accompanied by a

Table

2

Characteristicsofselected

studiesonrelationship

ofhyperuricemia

andobesity

Author,year[ref.]

Studydesign

Subjects

Questionaddressed

Observations

Rem

arks

Loenen,1990[107]

Cross

sectional

460HealthyDutch

ages

65–79

Dem

ographic

correlates

ofobesity

Average7-kgdifference

betweenlowestandhighest

tertiles

ofSUA

formen,

and5kgforwomen

Anassociationbetweenbody

weightandSUA

present

Studyincluded

whites

only,

diabeticswereexcluded,and

30%

participantswereon

prescribed

dietary

restrictions

Fang,2000[56]

Longitudinal

5926Subjects

ages

25–74

Cardiovascularandall

cause

mortality

BMIandBPincreasedwith

increasingquartilesofSUA

in

men

andwomen

atbaseline

Independentrisk

factorstatus

notevaluated

Masuo,2003[114]

Longitudinal

433Young,nonobese,

norm

otensivemen

Relationbetweenserum

urate,weightgain,and

bloodpressure

elevation

SUA

predictssubsequent

weightgainandBPelevation

SUAwas

anindependentrisk

factorforweightgainandBP

Ogura,2004[113]

Longitudinal

17,155Students

SUA

andobesityor

relatedfactors

Serum

uricacid

levels

tightlyrelatedto

BMI

Independentassociation

betweenSUA

andBMInot

clear.Studyincluded

only

men

Abbreviations:

BMI,bodymassindex;BP,

bloodpressure;SUA,serum

urate.

becker & jolly284


decrease in serum urate levels and dyslipidemia in patients who have gout [116].

Furthermore, amelioration of insulin resistance by a low-energy diet decreases

serum urate levels in individuals who are overweight and hypertensive [117].

Finally, the weight-reduction agents, sibutramine and orlistat, lower serum urate

levels [99,118,119], and, in the prospective Swedish Obese Subjects Study [120],

2- and 10-year hyperuricemia and hypertriglyceridemia incidence rates were

lower in patients who had undergone bariatric surgery than in unoperated obese

control subjects.

Leptin, the hormone product of the obese (ob) gene, is expressed in adipo-

cytes and acts through the hypothalamus to regulate food intake and energy

expenditure. Most persons who are obese show leptin resistance, and increased

leptin levels are associated with insulin resistance in individuals who are non-

diabetic [121]. Insulin response, triglyceride levels, and BMI are associated in-

dependently and significantly with leptin concentrations [122].

Serum urate and leptin levels correlate in healthy male adolescents [123] and

in women who are moderately obese [124], and an independent relation between

serum leptin and urate was found in 822 Japanese women, even after adjust-

ing for BMI and percent body fat [125]. Women have a higher mean leptin

and lower mean urate and triglyceride concentrations than men even after adjust-

ment for BMI [126]. Similar findings are observed in children who are obese

[127]. Creatinine, leptin, insulin, and triglyceride levels account for significant

variability in serum urate in men and women [126]. These studies suggest that the

association of serum urate, obesity, and insulin resistance may be mediated, at

least in part, by leptin expression and that leptin levels may prove to be a link

between obesity and hyperuricemia.

Hyperlipidemia

The issue of hypertriglyceridemia and hyperuricemia is addressed in many

studies [56,98,128–131]. Hyperuricemia is observed in up to 80% of patients

who have hypertriglyceridemia. Furthermore, hypertriglyceridemia also may

be seen in 50% to 75% of patients who have gout. In humans, fasting serum

triglyceride levels may be the most important determinant of serum urate levels

[132]. Obesity and excessive alcohol intake confound these issues. Reductions in

serum HDL-C and HDL2-C concentrations also are observed in individuals who

are hyperuricemic [125,133]. By regression analysis, no association between

gout and HDL levels or BMI index was seen, suggesting that reduced HDL

levels are attributable to altered triglyceride metabolism [133]. Concentrations of

serum Lp(a) lipoprotein, triglycerides, and apolipoproteins AII, B, CII, CIII, and

E reportedly were increased, and HDL-C was decreased in patients who had gout

[134]. The prevalence of apolipoprotein E2 allele was greater in patients who had

gout, and its presence was associated with higher triglyceride levels in very low-

density and intermediate-density lipoproteins and with reduced renal uric acid

excretion [135].

becker & jolly286

In the prospective GREACE study, addition of atorvastatin to the standard

treatment of coronary heart disease patients resulted in serum urate reduction

averaging 8.2% compared with an average 3.3% increase in patients receiving

standard care without atorvastatin [71]. In the atorvastatin treatment group, tri-

glyceride levels fell by 31%, HDL-C rose by 7%, and the LDL-C/HDL-C ratio

decreased by 50%. Similarly, in another prospective study [120], lower 2- and

10-year incidence rates of hypertriglyceridemia and hyperuricemia were observed

in obese patients who underwent bariatric surgery.

Insulin resistance

The relationship between hyperuricemia and insulin resistance may be indi-

rect and mediated through increased fasting plasma triglyceride levels or BMI

[96,136]. In experimental animals, urate suppresses basal insulin release in iso-

lated rat pancreatic islets and inhibits glucose-stimulated insulin secretion [137].

In a study of the relationship of insulin-mediated glucose disposal and serum

urate in 36 healthy nondiabetic volunteers [95], renal uric acid clearance de-

creased in proportion to increased insulin resistance, resulting in increased se-

rum urate concentration. An association between hyperinsulinemia and decreased

renal uric acid clearance also is reported in another study [96].

Increased serum urate concentration is among the significant risk factors as-

sociated with non–insulin-dependent diabetes mellitus in Japanese Americans

living in Hawaii and Los Angeles [138]. Persistent hyperuricemia in postmeno-

pausal women in the Kinmen study also is associated with subsequent devel-

opment of diabetes [139,140]. In a longitudinal study of Japanese male office

workers, a strong association between serum urate and subsequent development

of hypertension or type 2 diabetes was found [141]. The relationship with dia-

betes was stronger in men who had BMI less than 24.2 kg/m2 compared with

higher BMI, but the absolute risk was greater in more men who were obese.

In another prospective study, however, hyperuricemia is associated with the

development of hypertension but not type 2 diabetes [10]. Finally, metformin

administration not only reduces postprandial and fasting blood glucose levels but

also serum urate levels [99].

Summary

It is the authors’ belief that the literature to date has not established a causal

link between hyperuricemia and the previously discussed disorders that justify

the use in clinical practice of urate-lowering treatment in aymptomatic hyper-

uricemia to avoid or modify the course of the associated diseases. Relationships

between hyperuricemia and each of these morbid states do, however, exist and

may, in one or more of these disorders, prove causal and, thus, exploitable by

urate-lowering intervention. Although experimental studies performed in animals


have limitations set by differences between humans and other mammals in purine

metabolism and in renal uric acid handling, and an entirely suitable mammalian

model for hyperuricemia remains to be created, additional experimental studies

and, especially, interventional clinical studies aimed at evaluating the effects of

urate-lowering on the courses of these disorders are warranted.

References

[1] Fessel JW. Renal outcomes of gout and hyperuricemia. Am J Med 1979;67:74–82.

[2] Liang MH, Fries JF. Asymptomatic hyperuricemia: the case for conservative management. Ann

Intern Med 1978;88:666–70.

[3] Wyngaarden JB, Kelley WN. Gout and hyperuricemia. New York7 Grune & Stratton; 1976.

[4] Gibson T, Waterworth R, Hatfield P, et al. Hyperuricemia, gout and kidney function in New

Zealand Maori men. Br J Rheumatol 1984;23:276–82.

[5] Darmavan J, Valkenburg HA, Muirden KD, et al. The epidemiology of gout and hyperuri-

cemia in a rural population of Java. J Rheumatol 1992;19:1595–9.

[6] Ko YC, Wang TN, Tsai LY, et al. High prevalence of hyperuricemia in adolescent Taiwan

aborigenes. J Rheumatol 2002;29:837–42.

[7] Klemp P, Stansfield SA, Castle B, et al. Gout is on the increase in New Zealand. Ann Rheum

Dis 1997;56:22–6.

[8] Jossa F, Farinaro E, Panico S, et al. Serum uric acid and hypertension: the Olivetti heart study.

J Hum Hypertens 1994;8:677–81.

[9] Masuo K, Kawaguchi H, Mikami H, et al. Serum uric acid and plasma norepinephrine

concentrations predict subsequent weight gain and blood pressure elevation. Hypertension

2003;42:474–80.

[10] Taniguchi Y, Hayashi T, Tsumura K, et al. Serum uric acid and the risk of hypertension and

type 2 diabetes in Japanese men. The Osaka health study. J Hypertens 2001;19:1209–15.

[11] Nakanishi N, Okamato M, Yoshida H, et al. Serum uric acid and risk for development of

hypertension and impaired fasting glucose or type II diabetes in Japanese male office workers.

Eur J Epidemiol 2003;18:523–30.

[12] Hunt SC, Stephenson SH, Hopkins PN, et al. Predictors of an increased risk of future hyper-

tension in Utah. A screening analysis. Hypertension 1991;17:969–76.

[13] Grahame R, Scott JT. Clinical survey of 354 patients with gout. Ann Rheum Dis 1970;29:

461–8.

[14] Rapado A. Relationship between gout and arterial hypertension. Adv Exp Med Biol 1974;41B:

451–9.

[15] Kahn HA, Medalie JH, Neufeld HN, et al. The incidence of hypertension and associated

factors: the Israel ischemic heart disease study. Am Heart J 1972;84:171–82.

[16] Prebis JW, Gruskin AB, Polinsky MS, et al. Uric acid in childhood essential hypertension.

J Pediatr 1981;98:702–7.

[17] Messerli FH, Frohlich ED, Dreslinski GR, et al. Serum uric acid in essential hypertension:

an indicator of renal vascular involvement. Ann Intern Med 1980;93:817–21.

[18] Puig JG, Miranda ME, Mateos FA, et al. Hereditary nephropathy associated with hyperuri-

cemia and gout. Arch Intern Med 1993;153:357–65.

[19] Kanellis J, Watanabe S, Li JH, et al. Uric acid stimulates monocyte chemoattractant protein-1

production in vascular smooth muscle cells via mitogen activated protein kinase and cyclooxy-

genase-2. Hypertension 2003;41:1287–93.

[20] Kanellis J, Kang DH. Uric acid as a mediator of endothelial dysfunction, inflammation, and vas-

cular disease. Semin Nephrol 2005;25:39–42.

[21] Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid increases blood pressure in the rat by

a novel crystal independent mechanism. Hypertension 2001;38:1101–6.

becker & jolly288

[22] Mazzali M, Kanellis J, Han L, et al. Hyperuricemia induces a primary renal arteriolopathy

in rats by a blood pressure independent mechanism. Am J Physiol Renal Physiol 2002;282:

F991–7.

[23] Watanabe S, Kang DH, Feng L, et al. Uric acid, hominoid evolution and the pathogenesis

of salt- sensitivity. Hypertension 2002;40:355–60.

[24] Feig DI, Johnson RJ. Hyperuricemia in childhood essential hypertension. Hypertension 2003;

42:247–52.

[25] Feig DI, Nakagawa T, Karumanchi SA, et al. Hypothesis: uric acid, nephron number, and the

pathogenesis of essential hypertension. Kidney Int 2004;66:1–8.

[26] Johnson RJ, Tuttle KR. Much ado about nothing, or much to do about something? The

continuing controversy over the role of uric acid in cardiovascular disease. Hypertension 2000;

35:E10.

[27] Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension

and cardiovascular and renal disease? Hypertension 2003;41:1183–90.

[28] Johnson RJ, Rodriguez-Iturbe B, Kang DH, et al. A unifying pathway for essential hyper-

tension. AJH 2005;18:431–40.

[29] Feig DI. Uric acid and hypertension in adoloscents. Semin Nephrol 2005;25:32–8.

[30] Kang DH, Nakagawa T. Uric acid and chronic renal disease: possible implication of hyperuri-

cemia on progression of renal disease. Semin Nephrol 2005;25:43–9.

[31] Sanchez-Lozada LG, Tapia E, Avila-Casado C, et al. Mild hyperuricemia induces glomerular

hypertension in normal rats. Am J Physiol Renal Physiol 2002;283:F1105–10.

[32] Nakagawa T, Mazzali M, Kang DH, et al. Hyperuricemia causes glomerular hypertrophy in the

rat. Am J Nephrol 2003;23:2–7.

[33] Kang DH, Nakawaga T, Feng L, et al. A role of uric acid in the progression of renal disease.

J Am Soc Nephrol 2002;13:2888–97.

[34] Kang DH, Nakagawa T. Uric acid and chronic renal disease: possible implication of hyper-

uricemia on progression of renal disease. Semin Nephrol 2005;25:43–9.

[35] Sanchez-Lozada L, Tapia E, Rodriguez-Iturbe B, et al. Hemodynamics of hyperuricemia.

Semin Nephrol 2005;25:19–24.

[36] Mazzali M, Kim Y-G, Suga S, et al. Hyperuricemia exacerbates chronic cyclosporine ne-

phropathy. Transplantation 2001;71:900–5.

[37] Reif MC, Constantiner A, Levitt MF. Chronic gouty nephropathy: a vanishing syndrome.

N Engl J Med 1981;304:535–6.

[38] Fairbanks LD, Cameron JS, Venkat-Raman G, et al. Early treatment with allopurinol in familial

juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal

disease. Q J Med 2002;95:597–607.

[39] McBride MB, Simmonds HA, Ogg CS, et al. Efficacy of allopurinol in ameliorating the pro-

gressive renal disease in familial juvenile hyperuricaemic nephropathy (FJHN). A six-year

update. Adv Exp Med Biol 1998;431:7–11.

[40] Cameron JS, Simmonds HA. Hereditary hyperuricemia and renal disease. Semin Nephrol

2005;25:9–18.

[41] Dahan K, Vuyst D, Smaers M, et al. A cluster of mutations in the UMOD gene causes familial

juvenile hyperuricemic nephropathy with anornal expression of uromodulin. J Am Soc Nephrol

2003;14:2883–93.

[42] Segura J, Campo C, Ruilope LM. How relevant and frequent is the presence of mild renal

insufficiency in essential hypertension? J Clin Hypertens 2002;4:332–6.

[43] Leoncini G, Viazzi F, Parodi D, et al. Mild renal dysfunction and subclinical cardiovascular

damage in primary hypertension. Hypertension 2003;42:14–8.

[44] Staessen J for members of the European working party on high blood pressure in the elderly.

The determinants and prognostic significance of serum uric acid in elderly patients of the

European working party on high blood pressure in the elderly trial. Am J Med 1991;90:50s–4s.

[45] Tomita M, Mizuno S, Yamanaka H, et al. Does hyperuricemia affect mortality? A prospective

cohort study of Japanese male workers. J Epidemiol 2000;10:403–9.


[46] Iseki K, Oshiro S, Tozawa M, et al. Significance of hyperuricemia on the early detection of

renal failure in a cohort of screened subjects. Hyprtens Res 2001;24:691–7.

[47] Perlstein TS, Gumieniak O, Hopkins PN, et al. Uric acid and the state of the intrarenal renin

angiotensin system in humans. Kidney Int 2004;66:1465–70.

[48] Iseki K, Ikemiya Y, Inoue T, et al. Significance of hyperuricemia as a risk factor for developing

ESRD in a screened cohort. Am J Kidney Dis 2004;44:642–50.

[49] Johnson RJ, Kivlighn SD, Kim YG, et al. Reappraisal of the pathogenesis and consequences

of hyperuricemia in hypertension, cardiovascular, and renal disease. Am J Kidney Dis 1999;

33:225–34.

[50] Alderman MH, Cohen H, Madhavan S, et al. Serum uric acid and cardiovascular events in

successfully treated hypertensive patients. Hypertension 1999;34:144–50.

[51] Brand FN, McGee DL, Kannel WB, et al. Hyperuricemia as a risk factor of coronary heart

disease: the Framingham study. Am J Epidemiol 1985;121:11–8.

[52] Abbott RD, Brand FN, Kannel WB, et al. Gout and coronary heart disease: the Framingham

study. J Clin Epidemiol 1988;41:237–42.

[53] Culleton BF, Larson M, Kannel WB, et al. Serum uric acid and risk for cardiovascular disease

and death: the Framingham heart study. Ann Intern Med 1999;131:7–13.

[54] Wannamethee SG, Shaper AG, Whincup PH. Serum urate and the risk of major coronary heart

disaese events. Heart 1997;78:147–53.

[55] Nagahama K, Iseki K, Inoue T, et al. Hyperuricemia and cardiovascular risk factor clustering in

a screened cohort in Okinawa, Japan. Hypertens Res 2004;27:227–33.

[56] Fang J, Alderman MH. Serum uric acid and cardiovascular mortality. The NHANES I epide-

miologic follow up study, 1971–1992. JAMA 2000;283:2404–10.

[57] Bickel C, Rupprecht HJ, Blankenberg S, et al. Serum uric acid as an independent predictor

of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol

2002;89:12–7.

[58] Yusuf S, Bosch J. Urate levels as predictor of cardiac deaths: causal relation or mere asso-

ciation? Eur Heart J 2002;23:760–1.

[59] Wong KY, MacWalter RS, Fraser HW, et al. Urate predicts subsequent cardiac death in stroke

survivors. Eur Heart J 2002;23:788–93.

[60] Tuttle KR, Short RA, Johnson RJ. Sex differences in uric acid and risk factors for coronary

artery disease. Am J Cardiol 2001;87:1411–4.

[61] Rich MW. Uric acid: is it a risk factor for cardiovascular disease? Am J Cardiol 2000;1018–21.

[62] Madsen TE, Muhlestein JB, Carlquist JF, et al. Serum uric acid independently predicts mor-

tality in patients with significant, angiographically defined coronary disease. Am J Nephrol

2005;25:45–9.

[63] Moriarity JT, Folsom AR, Iribarren C, et al. Serum uric acid and risk of coronary heart disease:

Atherosclerosis Risk In Communities (ARIC) Study. Ann Epidemiol 2000;10:136–43.

[64] Freedman DS, Williamson DF, Gunter EW, et al. Relation of serum uric acid to mortality and

Ischemic heart disease. The NHANES 1 Epidemiologic Follow-up study. Am J Epidemiol

1995;141:637–44.

[65] Liese AD, Hense HW, Lowel H, et al. Association of serum uric acid with allcause and

cardiovascular disease mortality and incident myocardial infarction in the MONICA Augsburg

Cohort. Epidemiology 1999;10:391–7.

[66] Franse LV, Pahor M, Bari MD, et al. Serum uric acid, diuretic treatment and risk of cardio-

vascular events in the Systolic Hypertension in the Elderly Program (SHEP). J Hypertens

2000;18:1149–54.

[67] Verdecchia P, Schillaci G, Reboldi G, et al. Relation between serum uric acid and risk of car-

diovascular disease in essential hypertension. The PIUMA study. Hypertension 2000;36:1072–8.

[68] Niskanen LK, Laaksonen DE, Nyyssonen K, et al. Uric acid level as a risk factor for cardio-

vascular and all-cause mortality in middle aged men. Arch Intern Med 2004;164:1546–51.

[69] Hoieggen A, Alderman MH, Kjeldsen SE, et al. The impact of serum uric acid on cardio-

vascular outcomes in the LIFE study. Kidney Int 2004;65:1041–9.

becker & jolly290

[70] Dahlof B, Devereux R, de Faire U, et al. The Losartan Intervention For Endpoint reduction

(LIFE) in Hypertension study: rationale, design, and methods. The LIFE Study Group. Am J

Hypertens 1997;10:705–13.

[71] Athyros VG, Elisaf M, Papageorgiou AA, et al. Effect of statins versus untreated dyslipidemia

on serum uric acid levels in patients with coronary artery disease: a subgroup analysis of the

Greek atorvastatin and coronary heart disease evaluation (GREACE) study. Am J Kidney Dis

2004;43:589–99.

[72] Malinow MR, Levenson J, Giral P, et al. Role of blood pressure, uric acid, and hemorheo-

logical parameters on plasma homocyteine concentration. Atherosclerosis 1995;114:175–83.

[73] Hong YS, Lee MJ, Kim KH, et al. The C677 mutation in methylene tetrahydrofolate reductase

gene: Correlation with uric acid and cardiovascular risk factors in elderly korean men. J Korean

Med Sci 2004;19:209–13.

[74] Mercuro G, Vitale C, Cerquetani E, et al. Effect of hyperuricemia upon endothelial function in

patients with increased cardio vascular risk. Am J Cardiol 2004;94:932–5.

[75] Gavin AR, Struthers AD. Hyperuricemia and adverse outcomes in cardiovascular disease. Am J

Cardiovasc Drugs 2005;3:309–14.

[76] Yu ZF, Bruce-Keller AJ, Goodman Y, et al. Uric acid protects neurons against excitotoxic and

metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J Neurosci Res

1998;53:613–25.

[77] Chamorro A, Obach V, Cervera A, et al. Prognostic significance of uric acid serum con-

centration in patients with acute ischemic stroke. Stroke 2002;33:1048–52.

[78] Lehto S, Niskanen L, Ronnemaa T, et al. Serum uric acid is a strong predictor of stroke in

patients with non-insulin dependent diabetes mellitus. Stroke 1998;29:635–9.

[79] Mazza A, Pessina AC, Pavei A, et al. Predictors of stroke mortality in elderly people from the

general population. Eur J Epidemiol 2001;17:1097–104.

[80] Wang JG, Staessen JA, Fagard RH, et al. Prognostic significance of serum creatinine and

uric acid in older chinese patients with isolated systolic hypertension. Hypertension 2001;37:

1069–74.

[81] Weir CJ, Muir SW, Walters MR, et al. Serum urate as an independent predictor of poor outome

and future vascular events after acute stroke. Stroke 2003;34:1951–6.

[82] Abuja PM. Ascorbate prevents pro oxidant effects of urate in oxidation of human low density

lipoprotein. FEBS Lett 1999;446:305–8.

[83] Cherubini A, Polidori MC, Bregnocchi M, et al. Antioxidant profile and early outcome in stroke

patients. Stroke 2000;31:2295–300.

[84] Tseng CH. Independent association of uric acid levels with peripheral arterial disease in

Taiwanese patients with Type 2 diabetes. Diabet Med 2004;21:724–9.

[85] Nieto FJ, Iribarren C, Gross MD, et al. Uric acid and serum antioxidant capacity: a reaction to

atherosclerosis? Atherosclerosis 2000;148:131–9.

[86] Doehner W, Schoene N, Rauchhaus M, et al. Effects of xanthine oxidase inhibition with

allopurinol on endothelialfunction and peripheral blood flow in hyperuricemic patients with

chronic heart failure: results from 2 placebo controlled studies. Circulation 2002;105:2619–24.

[87] Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure.

Circulation 2003;107:1991–7.

[88] Cicoira M, Zanolla L, Rossi A, et al. Elevated serum uric acid levels are associated with

diastolic dysfunction in patients with dilated cardiomyopathy. Am Heart J 2002;143:1107–11.

[89] Hare JM, Johnson RJ. Uric acid predicts clinical outcomes in heart failure. Insights regard-

ing the role of xanthine oxidase and uric acid in disease pathophysiology. Circulation 2003;

107:1951–3.

[90] Cappola TP, Kass DA, Nelson GS, et al. Allopurinol improves myocardial efficiency in pa-

tients with idiopathic dilated cardiomyopathy. Circulation 2001;104:2407–11.

[91] Ekelund UE, Harrison RW, Shokek O, et al. Intravenous allopurinol decreases myocardial

oxygen consumption and increases mechanical efficiency in dogs with pacing induced heart

failure. Circ Res 1999;85:437–45.


[92] Ukai T, Cheng CP, Tachibana H, et al. Allopurinol enhances the contractile response to dobu-

tamine and exercise in dogs with pacing induced heart failure. Circulation 2001;103:750–5.

[93] Struthers AD, Donnan PT, Lindsay P, et al. Effect of allopurinol on mortality and hos-

pitalisations in chronic heart failure: a retrospcetive cohort study. Heart 2002;87:229–34.

[94] Emmerson B. Hyperlipidaemia in hyperuricaemia and gout. Ann Rheum Dis 1998;58:509–10.

[95] Facchini F, Chen Y-D, Hollenbeck CB, et al. Relationship between resistance to insulin-

mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA

1991;266:3008–11.

[96] Vuorin-Markkola H, Yki-Jarvonen H. Hyperuricemia and insulin-resistance. J Clin Endocrinol

Metab 1994;78:25–9.

[97] Reaven GM. Role of insulin-resistance in human disease. Diabetes 1988;37:1596–607.

[98] Denzer C, Muche R, Mayer H, et al. Serum uric acid levels in obese children and ado-

lscents:linkage to testosterone levels and pre metabolic syndome. J Pediatr Endocrinol 2003;

16:1225–32.

[99] Gokcel A, Gumurdulu Y, Karakose H, et al. Evaluation of the safety and efficacy of sibutramine,

orlistat and metformin in the treatment of obesity. Diabetes Obes Metab 2002;4:49–55.

[100] Brauer GW, Prior IAM. A prospective study of gout in New Zealand Maoris. Ann Rheum Dis

1978;37:466–72.

[101] Fessel WJ, Bar GD. Uric acid, lean body weight and creatine interactions: results from re-

gression analysis of 78 variables. Semin Arthritis Rheum 1977;7:115–21.

[102] Glynn RJ, Campion EW, Silbert JE. Trends in serum uric acid levels 1961–1980. Arthritis

Rheum 1983;26:87–93.

[103] Scott JT. Obesity and hyperuricaemia. Clin Rheum Dis 1977;3:25–35.

[104] Sturge RA, Scott JT, Kennedy AC, et al. Serum uric acid in England and Scotland. Ann Rheum

Dis 1977;36:420–7.

[105] Seidell JC, Bakx KC, Deurenberg P, et al. Overweight and chronic illness: a retrospective

cohort study with a follow-up of 6–17 years, in men and women of initially 20–50 years of age.

J Chronic Dis 1986;39:585–93.

[106] Must A, Jacques PF, Dallal GE, et al. Long term morbidity and mortality of overweight

adolescents. A follow up of the Harvard Growth Study of 1922 to 1935. N Engl J Med 1992;

327:1379–80.

[107] Loenen HM, Eshuis H, Lowik MR, et al. Serum uric acid correlates in elderly men and women

with special reference to body composition and dietary intake (Dutch Nutrition Surveillance

System). J Clin Epidemiol 1990;43:1297–303.

[108] Bray GA. Complications of obesity. Ann Intern Med 1985;103:1052–62.

[109] Emmerson BT. Alteration of urate metabolism by weight reduction. Aust N Z J Med 1973;3:

410–2.

[110] Gibson T, Waterworth R, Hatfield P, et al. Hyperuricaemia, gout and kidney function in New

Zealand Maori men. Br J Rheumatol 1984;23:276–82.

[111] Kannel WB, Gordon T. Physiological and medical concomittants of obesity: the Framingham

study. In: Bray GA, editor. Obesity in America. Bethesda (MD)7 DHEW (PHS) Publication

79-359; 1979. p. 125–63.

[112] Roubenoff R, Klag MJ, Mead LA, et al. Incidence and risk factors for gout in white men.

JAMA 1991;266:3004–7.

[113] Ogura T, Matsuura K, Matsumoto Y, et al. Recent trends of hyperuricemia and obseity in

Japanese male adolescents, 1991 through 2002. Metabolism 2004;53:448–53.

[114] Masuo K, Kawaguchi H, Mikami H, et al. Serum uric acid and plasma norepinephrine con-

centrations predict subsequent weight gain and blood pressure elevation. Hypertension 2003;

42:474–80.

[115] Reynolds PP, Knapp MJ, Baraf HSB, et al. Moonshine and lead. Relationship to the patho-

genesis and hyperuricemia in gout. Arthritis Rheum 1983;26:1057–64.

[116] Dessein PH, Shipton EA, Stanwix AE, et al. Beneficial effects of weight loss associated with

moderate calorie/carbohydrate restriction, and increased proportional intake of protein and

becker & jolly292

unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study. Ann Rheum Dis

2000;59:539–43.

[117] Tsunoda S, Kamide K, Minami J, et al. Decreases in serum uric acid by amelioration of insulin

resistance in overweight hypertensive patients: Effect of a low energy diet and an insulin

sensitizing agent. Am J Hypertens 2002;15:697–701.

[118] Tambascia MA, Geloneze B, Repetto EM, et al. Sibutramine enhances insulin sensitivity ame-

liorating metabolic parameters in a double blind, randomised controlled trial. Diabetes Obes

Metab 2003;5:338–44.

[119] Krejs GJ. Metabolic benefits associated with sibutramine therapy. Int J Obes Relat Metab

Disord 2002;26:S34–7.

[120] Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors

10 years after bariatric surgery. N Engl J Med 2004;351:2683–93.

[121] Donahue RP, Prineas R, Donahue DC, et al. Is fasting leptin associated with insulin resistance

among nondiabetic individuals? The Miami community health study. Diabetes Care 1999;22:

1092–6.

[122] Ruige JB, Dekker J, Blum WF, et al. Leptin and variables of body adiposity, energy balance,

and Insulin resistance in a population based study: the Hoorn study. Diabetes Care 1999;22:

1097–104.

[123] Ogura T, Matsura K, Otsuka F, et al. Serum leptin correlates with serum uric acid but not with

serum testosterone in non obese male adolescents. Res Commun Mol Pathol Pharm 2000;

107:55–63.

[124] Garcia-Lorda P, Bullo M, Vila R, et al. Leptin concentrations do not correlate with fat mass nor

with metabolic risk factors in morbidly obese females. Diab Nutr Metab 2001;14:329–36.

[125] Matsubara M, Chiba H, Maruoka S, et al. Elevated serum leptin concentrations in women with

hyperurecemia. J Atheroscler Thromb 2002;9:28–34.

[126] Bedir A, Topbas M, Tanyeri F, et al. Leptin might be a regulator of serum uric acid concen-

trations in humans. Jpn Heart J 2002;44:527–36.

[127] Moreno LA, Pineda I, Rodriguez G, et al. Leptin and metabolic syndrome in obese and non

obese children. Horm Metab Res 2002;34:394–9.

[128] Barlow KA. Hyperlipidemia in primary gout. Metabolism 1968;17:289–99.

[129] Gibson JT, Grahame R. Gout, hypertriglyceridemia, and alcohol consumption. Ann Rheum Dis

1974;33:109–10.

[130] Naito HK, Mackenzie AH. Secondary hypertriglyceridemia and hyperlipoproteinemia in pa-

tients with primary asymptomatic gout. Clin Chem 1979;25:371–5.

[131] Jiao S, Kameda K, Matsuzawa Y, et al. Hyperlipoproteinemia in primary gout: hyper-

lipoproteinemic phenotype and influence of alcohol intake and obesity in Japan. Ann Rheum

Dis 1986;45:308–13.

[132] Daskalopoulou SS, Mikhailidis DP, Elisaf M. Prevention and treatment of the metabolic

syndrome. Angiology 2004;55:589–612.

[133] Takahashi S, Yamamoto T, Moriwaki Y, et al. Impaired lipoprotein metabolism in patients with

primary gout: influence of alcohol intake and body weight. Br J Rheumatol 1994;33:731–4.

[134] Takahashi S, Yamamoto T, Moriwaki Y, et al. Increased concentrations of serum Lp(a)

lipoprotein in patients with primary gout. Ann Rheum Dis 1995;54:90–3.

[135] Cardona F, Tinahones FJ, Collantes E, et al. The elevated prevalence of apolipoprotein E2 in

patients with gout is associated with reduced renal excretion of urates. Rheumatol 2003;

42:468–72.

[136] Clausen JO, Borch-Johnsen K, Ibsen H, et al. Analysis of the relationship between fasting seum

uric acid and the insulin sensitivity index in a population based sample of 380 young healthy

caucasians. Eur J Endocrinol 1998;138:63–9.

[137] Rocic B, Vucic-Lovrencic M, Poje N, et al. Uric acid may inhibit glucose induced insulin

secretion via binding to an arginine residue in rat pancreatic beta cells. Bioorg Med Chem Lett

2005;15:1181–4.

[138] Hara H, Egusa G, Yamakido M. Incidence of non insulin dependent diabetes mellitus and its


risk factors in Japanese Americans living in Hawaii and Los Angeles. Diabet Med 1996;

13:S133–42.

[139] Lin KC, Tsai ST, Lin HY, et al. Different progressions of hyperglycemia and diabetes among

hyperuricemic men and women in the Kinmen study. J Rheumatol 2004;31:1159–65.

[140] Chou P, Lin-Chia L, Wu GS, et al. Progression of type 2 diabetes among high risk groups in

Kin-Chen kinmen. Diabetes Care 1998;21:1183–7.

[141] Nakanishi N, Okamato M, Yoshida H, et al. Serum uric acid and risk for development of

hypertension and impaired fasting glucose or type II diabetes in Japanese male office workers.

Eur J Epidemiol 2003;18:523–30.

hyperuricemia and associated diseases

Documents