LIVER FAILURE/CIRRHOSIS/PORTAL HYPERTENSION

Association Between Serum Uric Acid Level and Chronic

Liver Disease in the United States
Anita Afzali,1,2,5 Noel S. Weiss,4 Edward J. Boyko,3,6 and George N. Ioannou1,2,5

Elevated serum uric acid (UA) levels strongly reect and may even cause oxidative stress,
insulin resistance, and metabolic syndrome, which are risk factors for the progression of
liver disease. We sought to determine whether serum UA levels are associated with the de-
velopment of cirrhosis or the presence of elevated serum liver enzymes. We used cohort
data from the rst National Health and Nutrition Examination Survey (NHANES I) to
determine whether the baseline serum UA level was associated with the incidence of hospi-
talization or death due to cirrhosis among 5518 participants during a mean follow-up of
12.9 years (range 5 4-21 years) after the exclusion of the rst 4 years of follow-up. We also
used cross-sectional data from NHANES 1988-1994 (n 5 10,993) and NHANES 1999-
2006 (n 5 6186) to determine whether the serum UA level was associated with elevated se-
rum alanine aminotransferase (ALT) or c-glutamyl transferase (GGT), two markers of he-
patic necroinammation. Compared to persons in the lower third of the distribution of
serum UA (<4.8 mg/dL), those in the top third (>6 mg/dL) had a higher risk of cirrhosis-
related hospitalization or death [adjusted hazard ratio (AHR) 5 2.8, 95% condence
interval (CI) 51.3-5.7], whereas the risk was not substantially increased in persons within
the middle third (serum UA level 5 2.6-4.8 mg/dL, AHR 5 1.3, 95% CI 5 0.6-2.7). A
higher serum UA level was associated with greater mean serum ALT and GGT levels and a
greater probability of elevated serum ALT and GGT. Conclusion: The serum UA level is
associated with the development of cirrhosis and the presence of elevated serum liver
enzymes after adjustments for important causes and risk factors of chronic liver disease.
(HEPATOLOGY 2010;52:578-589)

Abbreviations: AHR, adjusted hazard ratio; ALT, alanine aminotransferase; BMI, body mass index; CI, condence interval; CRP, C-reactive protein; GFR,
glomerular ltration rate; GGT, c-glutamyl transferase; HBV, hepatitis B virus; HCV, hepatitis C virus; HDL, high-density lipoprotein; HOMA-IR, homeostasis
model assessment insulin resistance; MDRD, Modication of Diet in Renal Disease; N/A, not applicable; NAFLD, nonalcoholic fatty liver disease; NASH,
nonalcoholic steatohepatitis; NHANES, National Health and Nutrition Examination Survey; NHEFS, First National Health and Nutrition Examination Survey
Epidemiologic Follow-Up Study; RIBA, recombinant immunoblot assay; UA, uric acid.
From the 1Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, WA; 2Research Enhancement Award
Program, Veterans Affairs Puget Sound Health Care System, Seattle, WA; 3Seattle Epidemiologic Research and Information Center, Veterans Affairs Puget Sound Health
Care System, Seattle, WA; 4Department of Epidemiology, University of Washington, Seattle, WA; 5Divisions of Gastroenterology; and 6 Internal Medicine, Department
of Medicine, University of Washington, Seattle, WA.
Received January 6, 2010; accepted April 7, 2010.
This study was supported by the American Liver Foundation and American Association for the Study of Liver Diseases (Jan Albrecht Award), the Veterans
Affairs Research Enhancement Award Program (to George N. Ioannou), and the National Institute of Diabetes and Digestive and Kidney Diseases (grant P30 DK-
17047) through the Diabetes Endocrinology Research Center at the University of Washington (to Edward J. Boyko).
Anita Afzali contributed to the study concept and design, the drafting of the article, and a critical revision of the article. Noel S. Weiss contributed to the study
concept and design, the interpretation of data, and a critical revision of the article for important intellectual content. Edward J. Boyko contributed to the study
concept and design, the interpretation of data, and a critical revision of the article for important intellectual content. George N. Ioannou contributed to the study
concept and design, the acquisition of data, the analysis and interpretation of data, the drafting of the article, a critical revision of the article for important
intellectual content, and the statistical analysis.
Address reprint requests to: George N. Ioannou, B.M.B.Ch., M.S., Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health
Care System, S-111-Gastro, 1660 South Columbian Way, Seattle, WA 98108. E-mail: georgei@medicine.washington.edu; fax: 206-764-2232.
Copyright V C 2010 by the American Association for the Study of Liver Diseases.

Published online in Wiley InterScience (www.interscience.wiley.com).

DOI 10.1002/hep.23717
Potential conict of interest: Nothing to report.
Additional Supporting Information may be found in the online version of this article.

578
HEPATOLOGY, Vol. 52, No. 2, 2010
I
n humans and higher primates, uric acid (UA) is
the nal oxidation product of purine metabolism
and is excreted in urine. Hyperuricemia has long
been recognized as a cause of gouty arthritis and kid-
ney stones. More recently, hyperuricemia has also been
implicated in the development of hypertension, kidney
disease, metabolic syndrome, and cardiovascular disease
(reviewed by Feig et al.1 and Edwards2).
Although hyperuricemia has traditionally been con-
sidered a result of these conditions or an epiphenome-
non, mechanisms have been proposed by which hyper-
uricemia could actually cause them. Such mechanisms
include the induction by hyperuricemia of endothelial
dysfunction, insulin resistance, oxidative stress, and
systemic inammation.1,2
Oxidative stress, insulin resistance, and systemic
inammation are now known to be important risk fac-
tors for the development or progression of the most im-
portant liver diseases. For example, these conditions are
considered central in the pathogenesis of nonalcoholic
fatty liver disease (NAFLD) and nonalcoholic steatohe-
patitis (NASH).3 In addition, they contribute to the pro-
gression of hepatitis C virus (HCV)related and alco-
holic liver diseases.4 Therefore, we hypothesized that
hyperuricemia, which strongly reects and may even
cause oxidative stress, insulin resistance, and systemic
inammation, is a risk factor for the development of cir-
rhosis or the presence of hepatic necroinammation. We
performed two related studies to test this hypothesis:
1. A prospective cohort study to determine whether the
baseline serum UA level is associated with the subse-
quent development of cirrhosis.
2. Cross-sectional studies to determine the association
between hyperuricemia and the levels of serum
alanine aminotransferase (ALT) and c-glutamyl
transferase (GGT), two markers of hepatic
necroinammation.
Materials and Methods
Study Design
First National Health and Nutrition Examination
Survey (NHANES I) Cohort Study of the Association
Between Serum UA Levels and Cirrhosis. Data were
derived from NHANES I, a cross-sectional study of a
nationwide probability sample from the civilian, non-
institutionalized population of the coterminous United
States conducted between 1971 and 1975.1 The survey
included 14,407 participants, 25 to 74 years old, who
completed extensive dietary questionnaires and under-
went physical examinations and laboratory investiga-
AFZALI ET AL. 579
tions. The NHANES I Epidemiologic Follow-Up
Study (NHEFS)2 sought to locate these 14,407 indi-
viduals in 1982-1984, 1986, 1987, and 1992 and col-
lected data on specic health conditions that they
developed in the intervening period through personal
interviews, hospitalization records, and death certi-
cates. We merged NHANES I and NHEFS to form a
nationally representative cohort of 14,407 persons with
approximately 20 years of follow-up.
NHANES Cross-Sectional Studies of the Associa-
tion Between Serum UA Levels and Serum Levels of
ALT and GGT. Data were derived from NHANES III
(conducted between 1988 and 1994 and henceforth
called NHANES 1988-1994) and from the more
recent NHANES studies conducted between 1999 and
2006 (henceforth called NHANES 1999-2006). These
were cross-sectional studies designed to assess the
health and nutritional status of the noninstitutional-
ized US population.3 Participants completed personal,
structured interviews at home and then attended a mo-
bile examination center at multiple locations through-
out the United States to undergo various examinations
and provide blood samples.
Study Population
NHANES I Cohort Study. Among 14,407
NHANES I participants (25-74 years old), 13,861 were
successfully traced on at least one of four follow-up
occasions (1982-1984, 1986, 1987, or 1992). We
attempted to exclude participants who suffered from
cirrhosis at the time of entry into the study by excluding
participants who, at the baseline, reported ever being
told by a physician that they had jaundice (n 886) or
hepatitis (n 47), who had hepatomegaly or spleno-
megaly at the baseline examination (n 237), or whose
level of serum albumin was less than 3 g/dL (n 10).
Serum bilirubin levels and platelet counts, which may
be abnormal in advanced cirrhosis, were available only
in a small minority of participants and therefore could
not be used to identify participants with possible cirrho-
sis. Because cirrhosis may be present for a long time
before it is clinically diagnosed, we also excluded partic-
ipants who were diagnosed with cirrhosis within the
rst 4 years of follow-up or who had less than 4 years of
follow-up (n 687). We excluded 47 participants who
had a malignant tumor and 90 with missing values in
potential confounding variables. Serum UA levels were
measured only in a subsample of participants, so 6339
participants did not have serum UA measurements; this
left 5518 participants in the current analyses.
NHANES 1988-1994 and NHANES 1999-2006
Cross-Sectional Studies. Of 16,884 NHANES 1988-
580 AFZALI ET AL.
1994 participants who were 25 years old or older, we
excluded 168 pregnant women and participants with
missing data for viral hepatitis B or C serologies (n
2861), educational attainment (n 186), alcohol con-
sumption (n 560), body mass index (BMI; n
24), waist circumference (n 474), diabetes (n 9),
coffee consumption (n 18), and serum UA (n
104). We excluded persons who fasted for
6 hours
or lacked measurements for fasting serum insulin and
plasma glucose (n 1487); this left 10,993 persons
for serum ALT analyses. Serum GGT testing was
added to the NHANES 1988-1994 protocol after the
study began, so serum GGT levels were not available
in an additional 2359 participants; this left 8634 par-
ticipants for serum GGT analyses. Identical inclusion
and exclusion criteria resulted in 6186 participants for
both serum GGT and ALT analyses in NHANES
1999-2006.
Measurement of Serum UA Levels
In NHANES I, serum UA was measured with an
automated colorimetric phosphotungstic acid proce-
dure, which had been validated against the uricase
assay, on a Technicon SMA 12-60 (Technicon Instru-
ments, Tarrytown, NY). In NHANES 1988-1994 and
NHANES 1999-2006, serum UA was measured by ox-
idation with the specic enzyme uricase to form allan-
toin and hydrogen peroxide.5 Serum UA levels meas-
ured in NHANES studies have been used in multiple
research publications.6,7
In NHANES I, we divided participants into three
groups based on tertiles of serum UA levels: 0 to 4.8,
>4.8 to 6.0, and >6.0 mg/dL. The number of hospi-
talizations or deaths due to cirrhosis during follow-up
(n 80) precluded the division of participants into
more categories.
In NHANES 1988-1994 and NHANES 1999-
2006, participants were divided into four groups based
on quartiles of serum UA levels: 0 to 4.2, >4.2 to 5.2,
>5.2 to 6.3, and >6.3 mg/dL.
Measurement of Serum ALT and GGT in
NHANES 1988-1994 and NHANES 1999-2006
and Denition of Elevated Levels
In NHANES 1988-1994, serum specimens were
frozen and shipped weekly to a central laboratory
(White Sands Research Center, Alamogordo, NM);
there, they were stored initially at 20 C and then at
70 C before they were thawed and analyzed for ALT
and GGT with a Hitachi model 737 multichannel
analyzer.
HEPATOLOGY, August 2010
In NHANES 1999-2006, serum specimens were
refrigerated at 4 to 8 C and then shipped weekly to a
central laboratory, at which they were tested upon ar-
rival.8,9 Although the central laboratory changed
between 1999-2001 (Coulston Foundation, Alamo-
gordo, NM, which used a Hitachi Model 704 multi-
channel analyzer) and 2002-2006 (Collaborative Labo-
ratory Services, Ottumwa, IA, which used a Beckman
Synchron LX20 analyzer), there was no difference in
the ALT means of samples measured at the Coulston
Foundation Laboratory in 2001 and Collaborative
Laboratory Services in 2002.8,9
We previously suggested that the method of speci-
men processing in NHANES 1988-1994 might have
led to some degradation of ALT activity.10 Although
absolute serum ALT levels are lower in NHANES
1988-1994, multiple studies by us10-12 and other
investigators13,14 have demonstrated all the expected
associations with serum ALT activity, and this suggests
a uniform reduction in ALT activity across all
specimens.
Elevated levels were dened on the basis of recom-
mended cutoffs as a serum ALT level > 30 U/L for
men and > 19 U/L for women and a serum GGT
level > 51 U/L for men and > 33 U/L for women.14
Hospitalizations and Deaths Due to Liver
Cirrhosis During Follow-Up in NHANES I
Deaths and hospitalizations due to liver cirrhosis
that occurred during follow-up were ascertained from
hospitalization records and death certicates abstracted
by specially trained NHEFS personnel. We used the
following ICD-9 codes for cirrhosis: alcoholic cirrho-
sis, 571.2; cirrhosis without mention of alcohol,
571.5; pigmentary cirrhosis, 275.0; esophageal varices,
456.0-456.2; hepatic coma, 572.2; portal hyperten-
sion, 572.3; and hepatorenal syndrome, 572.4. Esoph-
ageal varices, hepatic coma, portal hypertension, and
hepatorenal syndrome were included in the diagnosis
of liver cirrhosis because the overwhelming majority of
cases of these conditions in the United States are the
result of liver cirrhosis. If acute necrosis of the liver
(ICD-9 code 570.0) was diagnosed together with he-
patic coma or hepatorenal syndrome, then the person
was considered not to have cirrhosis. Other complica-
tions of cirrhosis such as ascites or peritonitis were not
included as evidence of cirrhosis because they are com-
monly caused by other conditions. Similar diagnostic
codes from NHANES I have been previously used by
us and other investigators to determine the incidence
of death or hospitalization related to cirrhosis.15-17
HEPATOLOGY, Vol. 52, No. 2, 2010
The date of the rst hospital admission for each
condition was used as the date of incidence. For sub-
jects who had a death certicate recording one of these
conditions but did not have a hospitalization for any
of them, the date of death was used as the date of
incidence.
Ascertainment of Potential Confounders and
Other Baseline Characteristics
NHANES I Cohort Study. The following were
studied: age; gender and menopausal status; race,
which was categorized as white (n 4812) and non-
white (n 706; 653 of these were black, and only 53
were of other race, too small a number for additional
racial categories); alcohol consumption over the previ-
ous 12 months, which was ascertained with a speci-
cally designed validated questionnaire; BMI, which
was calculated as the measured weight in kilograms di-
vided by the square of the height in meters; subscapu-
lar-to-triceps skinfold ratio, which is a measure of cen-
tral subcutaneous fat versus peripheral subcutaneous
fat (the waist circumference was not measured in
NHANES I); self-reported diabetes mellitus; coffee or
tea consumption; consumption of dietary calories, pro-
teins, carbohydrates, and fat, which was ascertained by
24-hour dietary recall; educational attainment; smok-
ing; serum creatinine level; use of antihypertensive or
diuretic medications; and geographical area of resi-
dence in the United States (Northeast, Midwest,
South, and West).
Viral hepatitis B and C testing was not available in
1971-1975 when the NHANES I participants were
recruited. We wanted to ensure that viral hepatitis, an
important cause of cirrhosis in the United States, was
not associated with serum UA levels in order to
exclude the possibility that viral hepatitis was an im-
portant source of unmeasured confounding in our
NHANES I cohort. We did this with data from
NHANES 1988-1994 and NHANES 1999-2006
[Table 3 (shown later) shows little association between
the serum UA level and the presence of viral hepatitis
B or C].
NHANES I participants were not instructed to fast;
hence, fasting plasma glucose, lipid, and serum insulin
levels were not available.
NHANES 1988-1994 and NHANES 1999-2006
Cross-Sectional Studies. The following were studied:
age; gender and menopausal status; race/ethnicity,
which was categorized as non-Hispanic white, non-
Hispanic black, Mexican American, and other; alcohol
consumption over the preceding 12 months; BMI;
AFZALI ET AL. 581
waist circumference; self-reported diabetes mellitus;
fasting plasma glucose level; homeostasis model assess-
ment insulin resistance (HOMA-IR), which was calcu-
lated as [fasting serum insulin (lU/mL)  fasting se-
rum glucose (mmol/L)]/22.5; hepatitis B virus (HBV)
infection (positive serum hepatitis B surface antigen)
and HCV infection [positive serum HCV RNA in
NHANES 1988-1994; positive HCV antibody con-
rmed by the recombinant immunoblot assay (RIBA)
in NHANES 1999-2006]; educational attainment;
smoking; physical activity, which was calculated by the
multiplication of each recreational and nonrecreational
activity by its intensity value and the addition of the
products for all activity types (data presented for
NHANES 1988-1994 only); average measured systolic
and diastolic blood pressure; use of diuretics and anti-
hypertensives; coffee intake (cups/day) in NHANES
1988-1994 or caffeine intake (mg/day) in NHANES
1999-2006; dietary intake of meat, seafood, dairy
foods, and sugar-sweetened soft drinks, which was
ascertained with a food frequency questionnaire (data
presented for NHANES 1988-1994 only), and dietary
intake of calories, protein, fat, and carbohydrates,
which was ascertained by 24-hour dietary recall; C-re-
active protein (CRP); total cholesterol and high-den-
sity lipoprotein (HDL) cholesterol; triglycerides; and
glomerular ltration rate (GFR), which was estimated
with the abbreviated Modication of Diet in Renal
Disease (MDRD) study equation and standardized cre-
atinine values.18
Statistical Analysis
NHANES I Cohort Study. The Cox proportional
hazards model was used to determine the hazard ra-
tio: persons with different levels of serum UA were
compared with respect to the risk for cirrhosis with
or without adjustments for baseline potential con-
founders. The date 4 years after the ascertainment of
serum UA levels was used as time zero because any
cases occurring within the rst 4 years were excluded.
We performed sensitivity analyses in which we varied
the number of years after entry into the cohort that
we excluded from analysis (0, 1, 2, 3, 4, 5, or 6
years).
We did not simultaneously adjust for all 18 ascer-
tained baseline variables because some of them were
ascertained only in subsets of our study population,
because the number of events (n 80) did not allow
simultaneous modeling of so many variables, and
because some are suspected but not proven to be asso-
ciated with both UA and cirrhosis and therefore we
582 AFZALI ET AL.
were not sure a priori if they were signicant con-
founders. Instead, we included all variables that are
known to be associated with both UA and cirrhosis
[alcohol consumption, gender/menstruation, race, age,
BMI, and diabetes] and then added one by one the
other variables; we retained those that resulted in a
substantial change (>10%) in the adjusted hazard ratio
(AHR) of the association between UA and cirrhosis.
We then removed individual variables and eliminated
them from the nal model if their removal resulted in
a <10% change in the AHR between UA and
cirrhosis.
We performed additional analyses limited to persons
(n 3951) who were hospitalized at least once or
who died during follow-up, so all had hospitalization
records or death certicates available in which the di-
agnosis of cirrhosis could be sought.
Because of the importance of gender, obesity, and
alcohol consumption in liver disease, we performed
analyses stratifying persons into subgroups dened by
these variables.
NHANES I employed a complex sampling design
that incorporated stratication, clustering, and weight-
ing processes. However, in NHANES I, the stratica-
tion and clustering were shown to have little effect on
estimates, whereas sample weights can be highly vari-
able and skewed. This can produce highly unstable
results, especially when relatively small subsamples of
the data are used, as in our study. Therefore, we
decided to present unweighted results; we treated the
observations as a simple sample, as recommended by
the NCHS investigators19 and Korn and Graubard.20
NHANES 1988-1994 and NHANES 1999-2006
Cross-Sectional Studies. Multivariate linear and logis-
tic regression was used to determine whether serum
UA levels were associated with the levels of serum
ALT or GGT (linear regression) or with the likelihood
of having elevated serum ALT or GGT levels (logistic
regression). As in our NHANES I analyses, we
included all variables known to be associated with
both serum UA levels and serum liver enzyme levels in
initial multivariate models and then used forward
selection and backward elimination techniques to
determine whether additional variables were important
confounders.
In contrast to NHANES I, there is a general con-
sensus that analyses employing NHANES 1988-1994
and NHANES 1999-2006 data should account for the
complex sampling design of the studies. We did so
with the survey commands of STATA 10 statistical
software and with the appropriate weight, strata, and
primary sampling unit variables.
HEPATOLOGY, August 2010
Results
NHANES I Cohort Study
Increased levels of serum UA were associated with
increased age, BMI, subscapular-to-triceps skinfold ra-
tio, serum creatinine, alcohol consumption, use of
antihypertensive medications, dietary consumption of
total calories, proteins, carbohydrates, and fat, non-
white race, male gender, smoking, and lower educa-
tional attainment (Table 1). The prevalence of diabetes
was slightly greater (4%) in persons in the top serum
UA quartile versus persons in the lower two quartiles
(3%). Serum UA levels did not appear to be associated
with US geographical location or coffee or tea
consumption.
There were 80 incident cases of death or hospitaliza-
tion due to cirrhosis, including 25 cases diagnosed only
from death certicates, during a mean follow-up of
12.9 years after the exclusion of the rst 4 years of fol-
low-up. With the forward selection and backward elimi-
nation techniques described in the Materials and Meth-
ods section, the following variables remained in the
nal multivariate models: alcohol consumption, gender/
menstruation, race, age, educational attainment, BMI,
and subscapular-to-triceps skinfold ratio. The incidence
of death or hospitalization due to cirrhosis increased
from persons in the lowest serum UA tertile (53 per
100,000 person-years) to persons in the middle tertile
[83 per 100,000 person-years, AHR 1.3, 95% con-
dence interval (CI) 0.6-2.7] to persons in the top ter-
tile (210 per 100,000 person-years, AHR 2.8, 95%
CI 1.3-5.7; Table 2). For every unit increase in serum
UA, the AHR for cirrhosis was 1.40 (95% CI 1.2-
1.7); this association did not vary substantially among
subgroups dened by gender, BMI, or alcohol con-
sumption (Table 2). Interaction terms for these variables
and serum UA were not statistically signicant.
Among a subgroup of 3951 participants who either
were hospitalized or died during follow-up, such that
they all had hospitalization records or death certi-
cates, the association between serum UA levels and the
development of cirrhosis was similar to the association
in the entire study population (AHR 1.49 and 95%
CI 0.7-3.1 for persons with a UA level of 4.8-6.0
mg/dL and AHR 2.95 and 95% CI 1.4-6.2 for
persons with a UA level > 6 mg/dL versus persons
with a serum UA level < 4.8 g/dL). Not excluding
persons who reported at the baseline ever being told
by a physician that they had jaundice or hepatitis had
almost no inuence on the results.
Increasing the number of years following entry into
the study that were excluded from analysis (in order to
HEPATOLOGY, Vol. 52, No. 2, 2010 AFZALI ET AL. 583

Table 1. Baseline Characteristics of NHANES I Participants Stratied by Serum Uric Acid Levels
Serum UA (mg/dL)

0-4.8 (n 5 1834) >4.8-6.0 (n 5 1850) >6.0 (n 5 1834)

Age (years) 45.4 (0.3) 48.2 (0.3) 49.7 (0.3)

Men (%) 14 (0.8) 47 (1) 73 (1)
Premenopausal women (%) 51 (1) 23 (1) 7 (0.6)
Postmenopausal women (%) 36 (1) 30 (1) 20 (0.9)
Nonwhite race (%) 11 (0.7) 12 (0.8) 15 (0.8)
Geographical region (%)
Northeast 22 (1) 24 (1) 25 (1)
Midwest 25 (1) 25 (1) 25 (1)
South 27 (1) 25 (1) 24 (1)
West 26 (1) 27 (1) 26 (1)
High-school graduate (%) 62 (1) 58 (1) 55 (1)
Alcohol consumption (%)
None 44 (1) 37 (1) 28 (1)
>0-1 drinks/day 47 (1) 48 (1) 45 (1)
>1-2 drinks/day 6 (0.6) 8 (0.6) 13 (0.8)
>2 drinks/day 3 (0.4) 6 (0.6) 14 (0.8)
BMI (kg/m2) 23.7 (0.1) 25.6 (0.1) 27.7 (0.1)
Subscapular-to-triceps skinfold ratio 0.84 (0.02) 1.1 (0.01) 1.4 (0.01)
Smoking (%)
Never 49 (1) 45 (1) 35 (1)
Former 13 (0.8) 16 (0.9) 23 (1)
Current 38 (1) 38 (1) 42 (1)
Self-reported diabetes (%)* 3 (0.5) 3 (0.5) 4 (0.6)
Serum creatinine (mg/dL)* 0.9 (0.008) 1.0 (0.01) 1.1 (0.008)
Antihypertensive medications taken over the preceding 6 months (%) 7 (0.8) 10 (1) 19 (1)
Diuretic medications taken over the preceding 6 months (%) 7 (0.6) 7 (0.6) 9 (0.7)
Dietary calories/day 1663 (21) 1859 (29) 1970 (32)
Dietary protein (g/day) 66 (1) 76 (1) 81 (1)
Dietary fat (g/day) 69 (2) 78 (1) 81 (2)
Dietary carbohydrate (g/day) 188 (3) 202 (3) 202 (3)
Coffee or tea consumption (%)*
<1 cup/day 12 (1) 11 (1) 14 (1)
1-2 cups/day 43 (2) 45 (2) 46 (2)
>2 cups/day 45 (2) 43 (2) 40 (2)

The values are means or percentages and standard errors.

*Data were available for a subset of the study population.

Table 2. Association Between Serum Uric Acid Levels and Hospitalization or Death Due to Cirrhosis
Deaths or Hospitalizations
Serum UA Number of Subjects Deaths or Hospitalizations Related to Cirrhosis per Unadjusted Hazard
(mg/dL) (n 5 5518) Person-Years Related to Cirrhosis (n 5 80) 100,000 Person-Years Ratio (95% CI) Adjusted Hazard Ratio (95% CI)*

0-4.8 1834 24,619 13 53 1 1

>4.8-6.0 1850 24,046 20 83 1.6 (0.8-3.2) 1.3 (0.6-2.7)
>6.0 1834 22,354 47 210 4.0 (2.2-7.4) 2.8 (1.3-5.7)

Hazard Ratio per Unit Increase in Serum UA

All persons 1.50 (1.3-1.7) 1.40 (1.2-1.7)
Men 1.33 (1.1-1.6) 1.29 (1.03-1.6)
Women 1.66 (1.3-2.1) 1.55 (1.2-2.0)
Normal-weight persons 1.64 (1.3-2.1) 1.54 (1.2-2.0)
Obese or overweight persons 1.45 (1.2-1.7) 1.32 (1.1-1.6)
Persons consuming < 1 alcoholic drink/day 1.45 (1.2-1.7) 1.39 (1.1-1.7)
Persons consuming 1 alcoholic drink/day 1.45 (1.1-1.9) 1.42 (1.04-1.9)

The data were obtained from NHANES I.

*Adjusted for daily alcohol consumption, gender/menstruation, race, age, educational attainment, BMI, and subscapular-to-triceps skinfold ratio.
584 AFZALI ET AL.
exclude prevalent cases of cirrhosis) from 0 to 6 years
led to an increasing hazard ratio in the association
between serum UA and cirrhosis (see the supporting
information). The Kaplan-Meier curves (Fig. 1) show
little difference between persons in different UA cate-
gories in the incidence of cirrhosis-related hospitaliza-
tion or death due to cirrhosis in the rst 7 years after
enrollment into NHANES I, but there is a marked
separation of the cumulative incidence curves after
approximately 7 years. These ndings suggest that the
associations that we describe between serum UA levels
and cirrhosis are truly due to the development of inci-
dent cases during follow-up rather than the presence
of undiagnosed cases of cirrhosis at the baseline.
NHANES 1988-1994 and NHANES 1999-2006
Cross-Sectional Studies
In both NHANES studies, persons in increasing
quartiles of serum UA had higher age, BMI, waist cir-
cumference, HOMA-IR, plasma triglycerides, plasma
cholesterol, CRP, alcohol consumption, and consump-
tion of dietary calories, protein, fat, and carbohydrates
and lower HDL cholesterol, and they were more likely
to be male and diabetic (Table 3). There was little dif-
ference between persons in different serum UA quar-
tiles with respect to race/ethnicity or the prevalence of
viral hepatitis B or C.
With the forward selection and backward elimina-
tion techniques described in the Materials and Meth-
ods section, the following variables remained in our
fully adjusted models predicting serum ALT or GGT
levels: age, gender/menstruation, race/ethnicity, alcohol
HEPATOLOGY, August 2010
Fig. 1. Serum UA level and cir-
rhosis-related hospitalization or
death.
consumption, HBV infection, HCV infection, BMI,
waist circumference, HOMA-IR, self-reported diabetes,
fasting plasma glucose, serum CRP, diuretic medica-
tion use, hypertension, GFR, plasma triglycerides,
plasma HDL cholesterol, and coffee consumption (or
caffeine consumption in NHANES 1999-2006). In
both NHANES studies, mean serum ALT and GGT
levels both increased with increasing levels of serum
UA (Table 4). The prevalence of elevated serum ALT
or GGT also increased with increasing serum UA levels
(Table 5).
Despite the differences in mean serum ALT and the
prevalence of elevated ALT between NHANES 1988-
1994 and NHANES 1999-2006, which were attrib-
uted largely to differences in specimen processing (see
the Materials and Methods section), the associations
between serum UA and serum ALT and GGT levels
were consistent in the two studies.
The associations between serum UA and ALT or
GGT were not substantially different among subgroups
dened by gender, obesity, and alcohol consumption
(Table 5); interaction terms for these variables and se-
rum UA were not statistically signicant.
Discussion
Increased serum UA levels were associated with a
greater risk of cirrhosis-related hospitalization or death
and with elevated levels of serum markers of hepatic
necroinammation (ALT and GGT) even after adjust-
ments for important causes and risk factors for
cirrhosis.
HEPATOLOGY, Vol. 52, No. 2, 2010 AFZALI ET AL. 585

Table 3. Characteristics of Participants from NHANES 1999-2006 (n 5 6186, Shown in Bold) and NHANES 1988-1994
(n 5 10,993, Shown in Normal Font) Stratied According to Serum UA Levels
Serum UA Level (mg/dL)

0-4.2 >4.2-5.2 >5.2-6.3 >6.3

Age (years) 44.7 (0.6) 47.0 (0.5) 47.5 (0.6) 49.1 (0.5)
46.4 (0.5) 48.7 (0.5) 49.5 (0.5) 50.0 (0.5)
Men (%) 12 (0.9) 40 (1) 63 (1) 77 (1)
13 (1) 35 (1) 61 (2) 77 (1)
Premenopausal women (%) 59 (2) 33 (2) 15 (1) 7 (0.9)
54 (2) 33 (2) 15 (1) 6 (0.7)
Postmenopausal women (%) 29 (1) 27 (1) 22 (1) 17 (0.9)
33 (2) 32 (2) 24 (1) 17 (1)
Race/ethnicity (%)
Non-Hispanic white 80 (1.2) 80 (1.5) 80 (1.5) 79 (1.5)
74 (2) 74 (2) 75 (2) 76 (2)
Non-Hispanic black 9.5 (0.7) 8.5 (0.5) 8.9 (0.7) 9.9 (0.7)
9.7 (1) 9.1 (1) 9.9 (1) 11 (1)
Mexican American 4.5 (0.3) 4.6 (0.6) 4.2 (0.4) 4.4 (0.5)
7.5 (0.8) 7.2 (0.8) 6.4 (0.8) 5.6 (0.7)
Other 6.6 (0.9) 7.3 (1.1) 6.6 (0.9) 6.6 (1.0)
8.6 (1) 10 (1) 8.9 (2) 7.8 (1)
Number of school years completed (years) 12.6 (0.1) 12.5 (0.1) 12.5 (0.1) 12.4 (0.1)
Completed high school (%) 81 (2) 81 (1) 82 (1) 82 (1)
Alcohol consumption (%)
None 53 (2) 48 (2) 43 (2) 40 (2)
57 (2) 55 (2) 48 (2) 43 (2)
>0-1 drinks/day 40 (2) 40 (2) 41 (2) 36 (1)
35 (2) 35 (2) 36 (2) 37 (2)
>1-2 drinks/day 4.5 (0.7) 8.8 (1.0) 8.9 (0.9) 12 (0.1)
5.2 (0.8) 6.3 (0.7) 8.9 (0.8) 11 (0.8)
>2 drinks/day 2.1 (0.4) 3.0 (0.6) 7.0 (0.8) 12 (1.1)
2.5 (0.6) 4.0 (0.6) 6.6 (0.9) 10 (1)
BMI (kg/m2) 24.3 (0.1) 26.3 (0.1) 27.6 (0.2) 29.1 (0.2)
25.3 (0.2) 27.6 (0.2) 29.2 (0.2) 30.8 (0.2)
Waist circumference (cm) 83.7 (0.4) 91.1 (0.4) 96.2 (0.4) 101.1 (0.4)
87.3 (0.5) 94.3 (0.4) 100.2 (0.4) 106.1 (0.5)
Smoking (%)
Never 53 (1) 45 (1) 42 (1) 38 (2)
53 (2) 50 (2) 47 (2) 46 (1)
Former 20 (1) 28 (1) 30 (1) 37 (1)
22 (2) 27 (2) 30 (2) 35 (1)
<1 pack/day 12 (0.9) 10 (1) 11 (1) 11 (0.9)
12 (1) 12 (1) 12 (0.9) 10 (0.9)
1 pack/day 14 (1) 16 (1) 16 (1) 14 (1)
12 (1) 11 (1) 12 (1) 10 (1)
HCV infection, RNA-positive (%) 1.7 (0.3) 1.5 (0.3) 1.6 (0.4) 2.1 (0.5)
HCV infection, antibody-positive and RIBA-positive (%) 2.0 (0.6) 1.2 (0.3) 2.1 (0.4) 2.5 (0.4)
HBV infection (%) 0.6 (0.3) 0.4 (0.1) 0.4 (0.1) 0.4 (0.1)
0.2 (0.1) 0.5 (0.3) 0.4 (0.2) 0.4 (0.1)
Self-reported diabetes (%)* 3.3 (0.5) 4.0 (0.6) 4.0 (0.4) 5.3 (0.6)
6.0 (0.7) 7.1 (0.8) 7.4 (0.9) 8.7 (0.9)
Fasting plasma glucose (mg/dL)
0 to <100 85 (1) 78 (1) 70 (1) 65 (1)
78 (2) 66 (2) 55 (2) 49 (1)
(Continued)
586 AFZALI ET AL. HEPATOLOGY, August 2010

Table 3. Continued
Serum UA Level (mg/dL)

0-4.2 >4.2-5.2 >5.2-6.3 >6.3

100 to <126 12 (0.9) 19 (1) 25 (2) 29 (1)

17 (1) 27 (1) 38 (2) 40 (2)
126 3.5 (0.5) 3.2 (0.5) 5.2 (0.6) 5.7 (0.5)
5.9 (0.7) 7.0 (0.8) 7.1 (0.8) 11 (0.9)
HOMA-IR 1.9 (0.06) 2.3 (0.08) 2.9 (0.1) 3.3 (0.1)
2.1 (0.09) 2.6 (0.09) 3.1 (0.09) 4.0 (0.1)
Serum total cholesterol (mg/dL) 198 (1) 206 (1) 212 (1) 215 (1)
197 (1) 204 (2) 204 (1) 207 (1)
Serum HDL cholesterol (mg/dL) 57 (0.6) 53 (0.5) 48 (0.6) 45 (0.6)
60 (0.6) 56 (0.5) 51 (0.5) 47 (0.4)
Serum triglycerides (mg/dL) 105 (4) 128 (3) 153 (3) 190 (6)
111 (3) 139 (4) 151 (4) 187 (6)
CRP > 0.3 mg/dL (%) 22 (2) 27 (1) 30 (2) 36 (2)
CRP (mg/dL) 0.35 (0.02) 0.40 (0.02) 0.46 (0.03) 0.50 (0.03)
GFR (mL/minute1/1.73 m2) 96 (0.6) 92 (0.7) 90 (0.8) 84 (0.6)
90 (0.7) 85 (0.7) 83 (0.7) 80 (0.7)
Hypertension or antihypertensive medications (%) 21 (1) 31 (1) 39 (2) 51 (2)
29 (2) 40 (1) 46 (2) 57 (2)
Systolic BP (mm Hg) 115 (0.6) 119 (0.4) 123 (0.6) 126 (0.5)
118 (0.7) 122 (0.5) 124 (0.6) 127 (0.5)
Diastolic BP (mm Hg) 70 (0.4) 73 (0.3) 75 (0.4) 77 (0.3)
70 (0.4) 71 (0.4) 72 (0.4) 74 (0.4)
Diuretic medications (%) 3.3 (0.5) 4.7 (0.4) 6.9 (0.6) 15 (1)
5.0 (0.9) 7.7 (0.8) 11 (1) 20 (1)
Physical activityk 106 (4) 107 (4) 110 (4) 111 (4)
Meat intake (servings/day) 1.0 (0.02) 1.0 (0.02) 1.1 (0.02) 1.1 (0.02)
Seafood intake (servings/day) 0.2 (0.007) 0.2 (0.009) 0.2 (0.008) 0.2 (0.008)
Dairy food intake (servings/day) 1.6 (0.04) 1.5 (0.05) 1.4 (0.03) 1.4 (0.03)
Sugar-sweetened soft drinks (drinks/day) 0.3 (0.02) 0.4 (0.03) 0.5 (0.04) 0.5 (0.02)
Protein intake (g/day) 69 (0.8) 79 (2) 87 (2) 89 (2)
72 (1) 79 (1) 85 (1) 93 (2)
Fat intake (g/day) 74 (1) 82 (2) 92 (3) 90 (2)
76 (1) 81 (1) 88 (2) 90 (1)
Carbohydrate intake (g/day) 235 (3) 259 (5) 274 (5) 280 (4)
243 (3) 256 (3) 278 (5) 277 (4)
Dietary calories/day 1893 (19) 2118 (41) 2319 (45) 2367 (31)
1962 (25) 2105 (25) 2290 (34) 2392 (35)
Coffee intake (cups/day) 1.2 (.07) 1.3 (.06) 1.4 (.06) 1.3 (.05)
Caffeine intake (mg/day) 204 (9) 221 (11) 219 (10) 211 (7)

This table should not be used to evaluate temporal trends in listed characteristics between 1988-1994 and 1999-2006 because of possible differences in the
ascertainment of each characteristic between the two NHANES studies (which are beyond the scope of this work). The values are means or percentages and stand-
ard errors.
*Diabetes was dened as self-reported diabetes (diabetics on insulin were instructed not to fast; hence, they were not included in this sample of fasting
NHANES participants).
HOMA-IR was calculated as follows:
[Fasting serum insulin (l U/mL)  Fasting serum glucose (mmol/L)]/22.5
Hypertension was dened as a systolic blood pressure > 130 mm Hg, a diastolic blood pressure > 85 mm Hg, or the use of antihypertensive medications.
GFR was estimated with the abbreviated MDRD study equation27:
GFR (mL/minute/1.73m2) 175  [Standardized serum creatinine level (mg/dL)]1.154  (Age)0.203  (0.742 if female)  (1.212 if black)
Standardized serum creatinine was derived from the measured serum creatinine. For NHANES 1988-1994
Standard creatinine 0.184 0.960  Uncalibrated serum creatinine.
For NHANES 1999-2000
Standard creatinine 0.147 1.013  Uncalibrated serum creatinine
No correction was needed for 2001-2006.18
k
Physical activity is calculated as the sum of the products of the activity frequency in the previous month and the intensity rating for nine common activities.
HEPATOLOGY, Vol. 52, No. 2, 2010 AFZALI ET AL. 587

Table 4. Association Between Serum Uric Acid Levels and Levels of Serum ALT or GGT, Data from NHANES 1999-2006 are
Shown in Bold; Data From NHANES 1988-1994 are Shown in Normal Font
Adjusted Mean
Unadjusted Mean Difference in Unadjusted Mean Adjusted Mean
Serum UA Difference in ALT Versus ALT Versus the 0-4.2 Difference in GGT Versus Difference in GGT Versus
Level (mg/dL) Mean ALT (U/L) the 0-4.2 Category (U/L) Category (U/L)* Mean GGT (U/L) the 0-4.2 Category (U/L) the 0-4.2 Category (U/L)*

0-4.2 14.0 (13.0-14.9) 0 0 19.8 (18.5-21.1) 0 0

20.2 (19.5-21.0) 0 0 20.3 (18.7-21.8) 0 0
>4.2-5.2 16.3 (15.4-17.2) 2.4 (1.4-3.3) 0.3 (0.7 to 1.2) 27.3 (24.7-29.8) 7.5 (4.6-10.3) 3.1 (0.9-5.3)
23.4 (22.5-24.2) 3.1 (1.9-4.4) 1.2 (0.02-2.3) 27.2 (24.3-30.1) 6.9 (3.4-10.4) 3.8 (0.7-6.9)
>5.2-6.3 18.9 (17.7-20.1) 5.0 (3.9-6.1) 1.1 (0.02-2.2) 31.1 (29.2-33.1) 11.4 (9.3-13.4) 2.8 (0.2-5.4)
27.4 (26.1-28.8) 7.2 (5.7-8.7) 2.9 (1.3-4.5) 31.5 (29.2-33.9) 11.2 (8.4-14) 4.2 (0.5-8)
>6.3 22.6 (21.2-24.1) 8.6 (7.5-9.8) 3.6 (2.6-4.5) 41.9 (38.8-45.0) 22.1 (18.7-25.5) 10.3 (7-14)
34.2 (30.9-37.6) 14.0 (10.6-17.4) 7.6 (3.4-12) 40.3 (36.6-44.0) 20.3 (19-22) 7.8 (4-12)

*Adjusted for age, gender/menstruation, race/ethnicity, alcohol consumption, HBV infection, HCV infection, BMI, waist circumference, HOMA-IR, self-reported dia-
betes, fasting plasma glucose, serum CRP, diuretic medication use, hypertension, GFR, plasma triglycerides, plasma HDL cholesterol, and coffee consumption (or
caffeine intake).

A study from China reported that among 8925
employees of a chemical company, the serum UA level
was associated with ultrasonographic NAFLD after
adjustments for 10 anthropometric and metabolic
potential confounders (although insulin resistance was
not estimated).21 In an Italian study, 60 patients with
ultrasonographic NAFLD had higher serum UA levels
than 60 historical controls without NAFLD after
adjustments for serum insulin; the investigators did
not simultaneously adjust for all potential confound-
ers.22 These studies suggest that hyperuricemia is asso-
ciated with NAFLD; this would be expected because
hyperuricemia is associated with many risk factors for
NAFLD, such as obesity, insulin resistance, and

Table 5. Association Between Serum UA Levels and the Presence of Elevatedy Levels of Serum ALT or GGT, Data from
NHANES 1999-2006 are Shown in Bold; Data From NHANES 1988-1994 are Shown in Normal Font
Unadjusted Odds Adjusted Odds Ratio of Unadjusted Odds Adjusted Odds
Serum UA Ratio of Elevated ALT Elevated ALT Versus Ratio of Elevated GGT Ratio of Elevated GGT
Level (mg/dL) Elevated ALT (%)y Versus the 0-4.2 Category the 0-4.2 Category* Elevated GGT (%)y Versus the 0-4.2 Category Versus the 0-4.2 Category*

0-4.2 10.0 (7.9-12.0) 1 1 7.6 (6.3-9.0) 1 1

32.2 (29-36) 1 1 9.7 (8-12) 1 1
>4.2-5.2 12.9 (10.8-14.9) 1.3 (1.0-1.7) 1.3 (1.0-1.7) 12.3 (10.5-14.1) 1.7 (1.4-2.2) 1.6 (1.3-2.0)
36.9 (34-40) 1.2 (1.01-1.5) 1.3 (1.1-1.6) 11.1 (9-13) 1.2 (0.9-1.6) 1.1 (0.8-1.4)
>5.2-6.3 15.5 (12.8-18.2) 1.7 (1.4-2.1) 1.5 (1.1-2.1) 15.0 (12-18) 2.1 (1.6-2.8) 1.9 (1.3-2.6)
39.9 (37-43) 1.4 (1-1.7) 1.6 (1.3-2.1) 14.4 (12-17) 1.6 (1.2-2.1) 1.4 (1.0-1.9)
>6.3 22.3 (18.1-26.5) 2.6 (1.9-3.5) 2.3 (1.6-3.4) 22.9 (20.1-25.7) 3.6 (2.6-4.6) 3.1 (2.2-4.3)
46.7 (44-49) 1.8 (1.5-2.2) 2.2 (1.7-2.9) 20.8 (18-23) 2.5 (2.0-3.1) 1.8 (1.3-2.5)
Odds Ratio per Unit Increase in Serum UA
All persons 1.26 (1.2-1.4) 1.22 (1.1-1.3) N/A 1.36 (1.3-1.4) 1.30 (1.2-1.4)
1.17 (1.1-1.2) 1.22 (1.1-1.3) N/A 1.32 (1.2-1.4) 1.24 (1.1-1.4)
Men 1.34 (1.2-1.5) 1.22 (1.1-1.4) N/A 1.40 (1.3-1.5) 1.34 (1.2-1.5)
1.40 (1.3-1.5) 1.26 (1.1-1.4) N/A 1.35 (1.2-1.5) 1.30 (1.1-1.5)
Women 1.35 (1.3-1.5) 1.20 (1.1-1.4) N/A 1.58 (1.5-1.7) 1.26 (1.1-1.4)
1.30 (1.2-1.4) 1.1 (1.04-1.3) N/A 1.42 (1.3-1.5) 1.2 (1.04-1.3)
Normal-weight persons 1.09 (1.0-1.2) 1.22 (1.06-1.4) N/A 1.50 (1.3-1.7) 1.35 (1.1-1.6)
1.0 (0.9-1.1) 1.19 (1.0-1.4) N/A 1.40 (1.2-1.6) 1.23 (1.0-1.5)
Obese or overweight persons 1.23 (1.1-1.3) 1.23 (1.1-1.4) N/A 1.23 (1.2-1.3) 1.26 (1.1-1.4)
1.12 (1.06-1.2) 1.22 (1.1-1.3) N/A 1.25 (1.2-1.3) 1.23 (1.1-1.4)
Persons consuming < 1 alcoholic drink/day 1.25 (1.2-1.3) 1.24 (1.1-1.4) N/A 1.36 (1.3-1.4) 1.34 (1.2-1.5)
1.16 (1.1-1.2) 1.22 (1.1-1.3) N/A 1.27 (1.2-1.4) 1.20 (1.1-1.3)
Persons consuming  1 alcoholic drink/day 1.26 (1.01-1.6) 1.08 (0.8-1.4) N/A 1.20 (1.06-1.4) 1.22 (1.0-1.5)
1.20 (1.04-1.4) 1.18 (1.0-1.4) N/A 1.32 (1.2-1.5) 1.37 (1.1-1.6)

Abbreviation: N/A, not applicable.

*Adjusted for age, gender/menstruation, race/ethnicity, alcohol consumption, HBV infection, HCV infection, BMI, waist circumference, HOMA-IR, self-reported
diabetes, fasting plasma glucose, serum CRP, diuretic medication use, hypertension, GFR, plasma triglycerides, plasma HDL cholesterol, and coffee consumption.
An elevated ALT was a level > 30 U/L for men and > 19 U/L for women; an elevated GGT level was a level > 51 U/L for men and > 33 U/L for women.
588 AFZALI ET AL.
metabolic syndrome, including each of metabolic syn-
dromes ve components.6 We are not aware of studies
other than ours investigating the associations between
hyperuricemia and the development of cirrhosis.
A crucial question raised by our ndings is whether
hyperuricemia plays any role in directly causing he-
patic necroinammation and cirrhosis or whether it is
just a marker for an adverse metabolic prole that
leads to NAFLD/NASH or promotes progression of
viral or alcoholic hepatitis. Observational studies such
as ours cannot denitively distinguish between these
two possibilities, but it is tempting and potentially
useful to speculate whether hyperuricemia is a cause or
a marker. Although hyperuricemia has been clearly
associated with alcohol consumption, obesity, insulin
resistance, systemic inammation, and metabolic syn-
drome,1,6 the associations that we describe with ele-
vated liver enzymes persisted after adjustments for
these conditions. However, we cannot exclude the pos-
sibility of residual confounding by conditions such as
insulin resistance and systemic inammation, which
are likely not captured completely even after adjust-
ments for HOMA-IR, CRP, and a host of related met-
abolic parameters that we included in our regression
models. Nonetheless, even if hyperuricemia proves in
the future to be only a marker for the presence of he-
patic necroinammation or the development of cirrho-
sis and not a cause, it is likely to be a useful marker
because it can predict these outcomes independently of
other currently available predictors. Furthermore, the
associations that we describe were robust and occurred
in all three NHANES studies for different outcomes
(cirrhosis or elevated liver enzymes) and among differ-
ent subgroups (by gender, obesity, and alcohol con-
sumption) as well as the entire population. It has been
proposed recently that hyperuricemia, rather than
being simply a marker, might contribute to the cause
of insulin resistance, oxidative stress, systemic inam-
mation, and metabolic syndrome.1,2 Because these
conditions can cause NAFLD, promote its progression
to steatohepatitis, or even promote the progression of
viral and alcoholic hepatitis, they represent mecha-
nisms by which hyperuricemia can directly cause cir-
rhosis (Fig. 2). Hyperuricemia can induce endothelial
dysfunction and reduced bioavailability of endothelial
nitric oxide in rats,23 whereas treatment with allopuri-
nol can improve endothelial function in patients with
hyperuricemia.24 Glucose uptake in skeletal muscle
depends in part on increases in blood ow mediated
by the insulin-stimulated release of nitric oxide from
endothelial cells. Therefore, hyperuricemia-induced en-
dothelial dysfunction can potentially promote insulin
HEPATOLOGY, August 2010
Fig. 2. Schematic representation of pathogenetic mechanisms
potentially underlying the associations between hyperuricemia and cir-
rhosis. aThe arrow is bidirectional to indicate that it is unclear whether
hyperuricemia causes or is caused by these conditions.
resistance by impairing insulin-stimulated release of ni-
tric oxide. Furthermore, hyperuricemia induces inam-
matory and oxidative changes in adipocytes, and this
process is crucial in causing metabolic syndrome in
obese mice.25 Whether hyperuricemia is a cause or a
result of conditions that promote the progression of
liver disease is of considerable signicance because
pharmacological reduction of serum UA levels is possi-
ble but will be useful only if hyperuricemia is a cause
rather than a result of these conditions. Similar argu-
ments about the role of hyperuricemia as a cause or
effect of cardiovascular diseases are currently
ongoing.1,2
Our NHANES I cohort study is limited by the fact
that the diagnosis of cirrhosis is based on hospitaliza-
tion records and death certicates. These diagnoses are
likely to be accurate because cirrhosis that is advanced
enough to lead to hospitalization or death presents
with very typical symptoms, signs, and laboratory nd-
ings. A large review of autopsy studies found that a
clinical diagnosis of cirrhosis made during life has
nearly 100% specicity in comparison with autopsy
data.26 Furthermore, the fact that 96.2% of the study
participants were successfully traced suggests that the
ascertainment of deaths or hospitalizations due to cir-
rhosis was nearly complete. However, cases of undiag-
nosed cirrhosis or diagnosed cirrhosis that did not lead
to hospitalization or death were not captured. This
misclassication tends to drive hazard ratios toward
the null, so the hazard ratios that we report might be
underestimates of the true hazard ratios; because
HEPATOLOGY, Vol. 52, No. 2, 2010
cirrhosis is a rare outcome, such misclassication is
expected to have little effect. The absence of HCV
serologies is another potential limitation of our
NHANES I study. However, the lack of a substantial
association between HCV infection and serum UA lev-
els (in NHANES 1988-1994 and NHANES 1999-
2006) suggests that HCV infection is unlikely to be an
important source of unmeasured confounding. Finally,
the presence of diabetes might have been underre-
ported in the 1970s, and fasting plasma glucose levels
were not available.
Our cross-sectional NHANES 1988-1994 and
1999-2006 analyses are limited by reliance on a single
measurement of serum ALT and GGT. Because serum
ALT and GGT levels may uctuate with time, this can
result in nondifferential misclassication in comparison
with multiple measurements over time. Such misclassi-
cation would most likely bias our results toward the
null, so if multiple measurements of ALT or GGT
were available, the associations between hyperuricemia
and serum ALT or GGT would most likely be even
greater than what we report.
We have reported novel associations between serum
UA levels and the incidence of cirrhosis-related hospi-
talization or death or the presence of elevated serum
ALT or GGT. These associations are largely independ-
ent of other known liver disease risk factors. The se-
rum UA level might be a risk factor for the incidence
of chronic liver disease. Future studies should investi-
gate whether this association is causal or has clinical
utility in the prediction of the presence or incidence of
liver disease. If this is conrmed, further consideration
should be given to measures that reduce the serum UA
levels as a means of preventing cirrhosis in persons
with elevated levels.
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