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The relationship of serum uric acid to risk factors in coronary heart disease
The Relationship
of Serum Uric Acid to Risk
Factors in Coronary ALLEN R. MYERS,
M.D.,? FREDERICK
Heart Disease*
H. EPSTEIN,
M.D., H. J. DODGE,
and WILLIAM M. MIKKELSEN,
M.D., M.P.H.
M.D.
Ann Arbor, Michigan Analysis of the uric acid data from the initial examination cycle of the Tecumseh Community Health Study reveals that not only age and sex but also body weight or build should be considered when evaluating serum uric acid levels in disease or relating serum uric acid levels to other physiologic variables. It was found that serum uric acid levels of persons with coronary heart disease were not significantly different from the mean of the population studied and hence cannot be considered an attribute associated with the disease. Furthermore, there appears to be no evident relationship between serum uric acid levels and serum cholesterol or blood sugar, both of which are regarded as risk factors for coronary heart disease. Although there is no consistent pattern of a relationship between uric acid levels and casual blood pressure levels, some trends are suggestive. Of the conditions and disease states studied, only gout and pregnancy differed significantly from the means of the entire population with respect to serum uric acid scores; the levels in gouty subjects, as expected, were higher and in pregnant women lower, confirming reports in the literature.
W
In the 1959-1960 examinations, the serum uric acid (SUA) concentrations in 6,000 participants were measured by the enzymatic spectrophotometric method of Liddle, Seegmiller and Laster [7]. The resulting data were discussed in an earlier paper and the need was demonstrated for standardizing the individual SUA to compensate for systematic differences associated with age and sex distributions of the population studied [6]; the adjusted or standardized SUA was called a “score” or SUAS. The scores thus computed vary about a mean of 4.5 mg. per 100 ml. with a standard deviation of +l.OO mg. per 100 ml. In succeeding analyses of the data it became evident that still another variable is associated with SUA concentrations; this variable is “relative weight,” a measure computed by a regression equation taking into account actual weight, height, biacromial and bicristal diameters of the individual subject and stated as a ratio relationship to the sex specific value for men or women of ages twenty to twenty-nine years [3]. The nature of the association of the serum uric acid score (SUAS) and relative weight can be illustrated simply as shown in Table I. As the distribution of
THE increasing interest in risk factors associated with atherosclerosis and coronary heart disease, a number of publications have contributed conflicting information as to the association of serum uric acid concentrations with established coronary heart disease and its precursors. Most of the studies are based on relatively small numbers of subjects selected by virtue of having this disease or related biochemical or physiologic abnormalities. In an effort to clarify this situation, the present study is reported. It deals with observations of a natural population selected only because they were residents of a particular community, and participants in a Tecumseh, Michigan, comprehensive prospective study of health and disease. ITH
METHODS
The genera1 objectives and the methods of the Tecumseh Community Health Study (TCHS) have been documented [ 7-61.
* From the Department of Epidemiology, School of Public Health and the Rackham Arthritis Research Unit, Department of Internal Medicine, Medical School, The University of Michigan, Ann Arbor, Michigan. This study was supported by Program Project Grant HE 6378 to the Cardiovascular Research Center, The University of Michigan (Thomas Francis, Jr., M.D., Director) from the National Heart Institute, National Institutes of Health and by Grant CD.-00005 from the U. S. Public Health Service. It is reported for the Research Staff of the Tecumseh, Michigan, Community Health Study. Requests for reprints should be addressed to H. J. Dodge, M.D.,3072 School of Public Health, University of Michigan, Ann Arbor, Michigan 48104. Manuscript received October 5, 1967. t Present address: Arthritis Unit, Massachusetts General Hospital, Boston, Massachusetts 02114. 520
AMERICAN
JOURNAL
OF
MEDICINE
Serum
Uric Acid,
Coronary
study subjects moves from the lowest class (twentieth percentile or below) to the highest class (eightieth percentile or above) for each of the three variables, the prevalence rate of hyperuricemia increases. For serum cholesterol the increase is not consistent; for blood sugar it is consistent but of low magnitude. For relative weight the increase is both consistent and of the magnitude of 8 percentage points. There is a consistent increase in mean SUAS as one moves up the percentile scale. For serum cholesterol and blood sugar the increase is modest, in the range of 0.06 to 0.07 mg. per 100 ml., whereas the increase of SUAS with relative weight is of the order of 0.53 mg. per 100 ml. This association is in keeping with the reports of O’Brien, Burch and Bunim [8] as to the relationship between SUA and a measure of body surface, and of Acheson and O’Brien IS] on the relationship between SUA and the ponderal index in men and body weight in women. It was decided to standardize the SUA values further to take relative weight into account. This was accomplished by a formula utilizing the regression of relative weight on SUAS. The resulting value is an expression of the individual’s SUA value adjusted for age, sex and relative weight simultaneously and will be called the SUAS(RW). This computed value is distributed about a mean of 4.5 mg. per 100 ml. with a standard deviation of 10.96 mg. per 100 ml. Of the 6,000 subjects with a SUAS, all but thirtythree had a relative weight determination so that the SUAS(RW) could be computed for a total of 5,967. This latter group of subjects forms the base of this report. The data are reported in two ways. First, the proportion of subjects with hyperuricemia are considered. Hyperuricemia is defined as SUA concentration, without adjustment, of greater than 7.0 mg. per 100 ml. in men and greater than 6.0 mg. per 100 ml. in women. This definition is conventional in terms of the method of SUA determination and sets the cutting points at the mean +1.53 standard deviations of the 6,000 observed SUA values of this population. These cutting points result in a slightly lower proportion of women being labeled hyperuricemic than men, 6.27 per cent as compared with 6.42 per cent. The second method of reporting the data is in terms of the mean SUAS(RW), a refined measure taking into account three variables that have significant association with SUA. RESULTS
The association of SUA with three physiologic variables will be considered first. These are serum cholesterol, blood sugar and blood pressure; all have been implicated as risk factors in coronary heart disease. The relationship of SUA (expressed in two ways) with serum cholesterol is shown in Table II. The study subjects have been divided into VOL.
45,
OCTOBER
1968
Heart
Disease-Myers
et al. ‘I’AHLE
sERm4
URIC
*CID
DISTRIBUTION
SeWIll Cholesterol
of Hypcruricumin,*
PrevalenceR&r
percentile
6.1%
(1,218H
21st to 79th Dercentile At or above
the
80th
6.0% (3,575) percentile
8.5% (1,187) 6.5% (5,980)
Total
Mew
SUAS
(Adjusted
Below or at the 20th percentile to 79th percentile
21~
At or above
the
80th
B1.00,~
WEIGH’I
1959-1960
Age-Sex Sprcific Percentile Distributmn
20th
ro PER~EN-rur
AND RELATIVE TCHS
or at the
I
RELATION
m
OF SERUM CHOLESTEROL,
SUGAR
Below
521
oercentile
R&IlW Weight
Unadjurlcd
Si ‘A
6.941: (859) 7 6% (2,54d) 9 3 cc;, (952) 7 8
9;
(4,360)
3 4 or (: ,Zli) 5 % (3,605 II 4% <: ,143)
-7
(1
4% (5,967)
forAgr and Sex)
4.481
4.461
(1,218) 4.495 (3,575) 4.539
(859) 4.498
(1,187) 4.492
Total
Blood Sugar
(5,980)
(2,549) 4.528
4 251 (1,215) 4 485 13,609) 4 777
(952) 4.497 (4,360)
(1,143) ‘l 499 (5,967)
* Unadjusted SUA greater than 7.0 mg. per 100 ml. in mak 6.0 mg. per 100 ml. in female subjects. t Number of subjects in group.
and
three groups in relation to the distribution on a percentile scale made specific for age and sex. Among the 5,947 subjects in whom both serum cholesterol and uric acid determinations were obtained, there is no evident association between the two variables. Those subjects whose cholesterol values fall in the mid-range have very slightly lower SUA values than do those at the extremes of the range. The differences between the SUA values for the two sexes are not striking and are no greater than can be accounted for by sampling variation and TABLE SEX-SPECIFIC AND
MEAN
PREVALENCE SUAS(RW)
DISTRIBUTION
IN
Below or at the 20th percentile 21st to 79th percentiles At or above centile Total
the 80th
per-
RELATION
OF HYPERURICEMIA TO
OF SERUM CHOLESTEROL TCHS
Serum Cholesterol Distribution
II
RATES
sex M F M F M F M F
PERCENTILE VALUES
1959-1960
No. of Subjects
Per cent Hyperuricemic*
Mean SUA Adjusted ior Age, Sex and Relative Weight
603 607 1,772 1.785 ‘588 592 2,963 2,984
6.0 6.1 5.6 6.0 8.8 7.3 6.3 6.3
4 516 4.500 4.497 4.492 4 495 4.535 4.500 4.502
*Unadjusted SUA greater than 7.0 mg. per 100 ml. in male and 6.0 mg. per 100 ml. in female subjects.
522
Scrurn Uric Acid, Coronary ‘I‘AIILE
SEX-SPECIFIC AND
PREVALRSCB
MEAN
SUAS(RW)
IN
DISTRIHU~I‘ION
III
RAKS
REI.AT,ON
OF HL”“”
TCIIS
OF
IIYPERURICI~MIA I’0 PERCEh’TlLE
SUGAR
“A,
UKS
1959-1960 .uran SUA
Blood Sugar Distribution -.
sex
No. of Subjects
Per cc”, Hypcruriccmic*
M F M F h4 F M 1:
417 437 1,235 1,303 444 499 2,096 2,239
6.5 7.3 8.3 6.7 8.6 9.6 8.0 7.5
Adjusted for Age, Sex and R&ilk Weight
..~
~.
Below oratthe ccntilc 21~1 to 79th Ator above ccntilc Total
20th per-
percentiles the 80thper-
* Unadjusted SUA greater 6.0 mg. per 100 ml. in female
than 7.0 subjects.
mg.
per
4.492 4.478 4.511 4.480 4.454 4.583 4.495 4.502
100 ml.
in male
md
the cutting points selected for defining hyperuricemia. The association between SUA and blood sugar, in 4,335 subjects in whom both determinations were made, is seen in Table III. There appears to be some slight positive gradient of SUA values with increasing levels of blood sugar in male subjects as to prevalence of hyperuricemia but not as to SUAS(RW), whereas the reverse is true for female subjects. The differences between the two sexes for each of the two measures within and across the blood sugar categories show no consistent pattern. From these data it is impossible to show any TABLE SEX-SPECIFIC
PREVALENCE
IN RELA’I‘ION
TO
BLOOD
TCllS
IV
RATES
(mm.
Hg)
Lcsp rhan 90
.-.Lcsl
than
140
140-159
F
4.4’Y (1,66& 4 ‘3;.
M
(I, 733) 8
hl
&f F
Total
Prcssurc
Hg) 95 or mow
90-94
Total
-
F 160 or mow
Blond (mm.
sex
GROUPINGS
1959-1960
Diastolic Systolic Blood PIYXVX-C
OF IIYPERURICEHIA*
PRESSURE
M t‘
(40) 4.8% (21) lO.u~,;
(126) 5.2%
.9
(77) 9.9% ,111) 6.0%
57;.
(363) 4.8% (2523 15.5’;;. (71) 8.4% (71) 5.5%.
12.50/,
14.3%
(120) 18.5% (65) 12 6% (151) 15.6%. (173) 1 I :(I%’
(117) 0.0% (31) 16.7”‘, ‘r (54) lO.d%’
(2,089) .5.0% (1,056)
* Unadjurtcd SUA grr;iwr rtkm 7.0 6.0 mg. per 100 ml. in fcmnlc subjects. t Numba of subjccn in group.
(268) 8.1% (248)
mg.
(311) 15.4yo (259)
prr
5.2% (1,821) 4.9% ‘:rG’ (5940) 7.1% (434) 11.9% (253) 14.1% (298) 6:770’ (2,668) 6.4% (2,563)
100 ml. in male
and
Heart
Disease-Myers
et al.
degree of Incaningful association between the two variables. Cross classification of serum cholesterol and blood sugar by percentile distributions shows no pattern that can be interprctcd as showing an association of SUA with thcsc two variables considered simultaneously. Xcxt are considered the 5,231 subjects in whom both the SLA values and blood pressure (systolic and diastolic V phase) were determined. The prevalence of hypcruriccmia, as defined, is shown in Table IV in relation to cross classification of systolic and diastolic blood pressure. This table has several interesting features. On inspection of the right hand colUII1I1, which summarizes the association between prevalence of hyperuricemia and categories of systolic blood pressure, it is seen that prevalence rises appreciably with pressure. This is true for both malt and female subjects; the only disparity is the excess prevalence in female over Inale subjects in the group with pressures of 160 mm. Hg or greater. These same cornmcnts can be made about the bottom row which summarizes the association between prevalence of hyperuricemia and the rising gradient of diastolic pressures. However, when one considers the nine cells which represent the interactions of blood pressure, no pattern whatever is seen; there are no consistent trends. The most puzzling situation is in the middle column (those with borderline of diastolic pressures) ; here the prevalence hyperuriccmia declines as the systolic pressure increases in male subjects whereas the reverse is true in female subjects. Table v displays the relationship between SUA and blood pressure in terms of the arithmetic means of SUAS(RW). In the whole of the table there is only one suggestion of a positive association between SUA and blood pressure. This appears in the bottom row which summarizes the association between SUA and diastolic blood pressure. The positive association is somewhat more notable in male subjects than in female subjects, but in neither case is the association of sufficient degree for consideration of biological significance. The rernaindcr of the table suggests only random variation of the three variables in relation to one another. Of four physiologic characteristics, all of which have been incriminated to varying degrees as risk factors in relation to coronary heart disease, only one, relative weight, is shown to have any significant degree of association with AMERICAN
JOURNAL
OF
MEDICINE
Serum
Uric Acid, Coronary
Heart
SUA. Therefore, we believe that it must be taken into account, together with age and sex, in comparing SUA levels in disease. Turning to the data on the relationship of SUA to coronary heart disease, we are prompted to report for several other diseases and for pregnancy, to afford some basis for comparison. Included are gout and diabetes because they are diseases with prominent metabolic components; hypertensive heart disease; rheumatoid arthritis (ARA grades of probable and definite) because of the problems of differentiating it from gout by the use of the American Rheumatism Association criteria; and pregnancy, a condition characterized by marked, although temporary, metabolic changes. The relationships of SUA to these conditions are set forth in Table VI and Figures 1 and 2. The subjects appearing in these representations are those who had one, but only one, of the conditions listed. There were others who had two or more of the conditions; these were relatively few in number and are not included because of the possible confounding effect of multiple conditions on SUA. In order to aid in visualizing the differences in SUA distributions between sexes and among the conditions shown in Table VI, the two figures are presented. The method of presentation is the portrayal of the sex- and condition-specific SUA statistics and the “95 per cent confidence limits” (statistic *2 standard errors). The
PREVALENCE
RATES
OF
HYPERURICEMIA
AND TCHS
Condition
Diagnosed
Sex M F M F M F M F M F F
Gout Coronary heart disease Diabetes mellitus Hypertensive Rheumatoid
heart disease arthritis
Pregnancy Total Tecumseh SUAS(RW) * Unadjusted vol..
45,
Subjects with
Both Sexes
No. of Subjects 11 7 94 53 22 34 20 22 8 49 72 5,967
MEAN
523
et al. ~‘ABLE
SEX-SPECIFIC
v
SUAS(RW)
PRESSURE
IN
RELArlON
I’0 HLOOD
GROUPINGS
1959-1960
‘TCHS
Diastolic Blood Prcssurr (mm. Hg)
Systolic Blwd Pressure (mm. Hg)
Less
than90
Sex
90-94
95 or mow
Less than 140
M
140-1.59
160 or more
Total
4.610
4 832
4.467
F
4.448 (1,655)+ 4.490
(1261 4.669
M
(1,733) 4.647
(77) 4 596
(I ,821) 4.600 (1,831) 4.622 (594) 4.453
F
(363) 4.352
(111) 4.503
M
(252) 4.573
(117) 4.339
(40) 4.948 (21) 4.570 (120) 4.754 (65) 4.607
F
(71) 4.407
(31) 4.617
(151) 4.590
(253) 4.551
M
(71) 4.487
(54) 4.573 (268) 4.579
(173) 4.621 (311) 4.660 (259)
(298) 4.511 (2,668) 4 570 (2,563)
(2,089) 4.557 (2,056)
F
*Number
of subjects
(248)
1968
(434) 4.565
in group.
statistic for the total Tecumseh subjects is plotted as a horizontal solid line and the 95 per cent confidence limits as interrupted lines paralleling it in the case of the prevalence of hyperuricemia; in the case of the mean SUAS(RW), the 95 per cent confidence band is too narrow to portray. The sex- and conditionspecific statistics are plotted as solid vertical lines with the statistic of interest plotted at the midpoint and the limits plotted as horizontal bars at the ends of the line. This mode of VI
MEAN
SUAS(RW)
IN SELECTED
MAJOR
CONDITIONS
DIAGNOSED
1959-1960
% Hyperuricemic* and Standard Error of the Proportion
SUA Adjusted for Age, Sex and Relative Weight
Mean
Standard Deviation
Standard Error of Mean
fl.829 fl.540 Al.036 ztl.202 f0.815 fl.338 ho.986 fl.114 f0.449 f0.735 fl.230
fO.304 f0.339 f0 012 ztO.027 zto.030 f0.053 fO.049 f0 056 f0.031 fO.O1l Ito .021
fl.000
fO.0002
f f f f
15.0 18.7 3.9 5.6
f f f
6.5 4.9 8.2
f f
2.0 2.0
5.791 4.985 4.722 4.704 4.027 4.541 4.330 4.268 4.112 4.306 3.843
5.7 f
0.3
4.500
45.5 42.9 17.0 20.8 0.0 17.6 5.0 18.2 0.0 2.0 2.8
SUA greater than 7.0 mg. per 100 ml. in male and 6.0 mg. per 100 ml. in female subjects
OCTOBER
Total
.__I_-___
TABLE SEX-SPECIFIC
Disease-Myers
Serum 95%
Uric Acid, Coronary
Confidence
Bend
FIG. 1. Sex- and condition-specific prevalence rates of hyperuricemia. Tecumseh Community Health Study, 1959-1960. expression permits ready visualization of the magnitude of the statistic and the variation of observations about it as well as the statistical significance of differences between the statistics. If any two of the vertical lines overlap, it is judged that the statistics which they represent do not differ from one another at the 5 per cent level of statistical significance; if a vertical line crosses or falls within the 95 per cent con5.a5.6 -
0
95%
Confidence
Bond
5.4 -
‘E 5.2. B
t
5.0
g 4.8. .E Z 5 4.6. I: 2 4.4-
I
4.24.0 3.8FIG. 2. Sex- and condition-specific mean SUA (adjusted for age, sex and relative weight). Tecumseh Community Health Study, 1959-1960.
Heart
Disease--Myers
et al.
fidence band for the total 5,967 Tecurnseh subjects, the specific statistic does not differ significantly from that of the total subjects studied as to SUA. Conversely, when two lines do not overlap at any point, they may be said to differ from one another at the 5 per cent level of statistical significance. Table VI and Figure 1 show sex- and condition-specific prevalence rates of hyperuricemia. The 0.0 per cent rates for male subjects with diabetes and with rheumatoid arthritis probably do not differ appreciably from the rate for the total 5,967 subjects studied; if there had been a single instance of hyperuricemia in each of these two groups, the rates would have been 4.5 and 12.5 per cent, respectively. There are no significant differences between the prevalence rates in the two sexes for any of the conditions in which comparison is possible nor are there significant differences between conditions except for the rates of coronary heart disease, which exceed those of rheumatoid arthritis in female subjects and of pregnancy. The prevalence rate for gout in male subjects also exceeds to a significant degree that of men with hypertensive heart disease and those of women who have rheumatoid arthritis or are pregnant. Altogether, the use of prevalence rates of hyperuricemia does not provide much discrimination as to SUA in the conditions cited. Figure 2, however, suggests that the use of the SUAS(RW) provides a high degree of discrimination both between sexes and among the conditions considered. In order to show the data on a scale of reasonably sized intervals, it is necessary to show only the lower half of the 95 per cent confidence band for men with gout. It is readily apparent that men with this condition have a mean SUAS(RW) which exceeds all others, except women with gout, to a highly significant degree statistically. Women with gout do not differ appreciably as to the magnitude of this statistic from any of the others except men with diabetes or rheumatoid arthritis and women in pregnancy. Although men with coronary heart disease have a rather high mean SUAS(RW), there is sufficient variation so that they do not differ significantly from the mean of the total 5,967 subjects considered. Men with coronary heart disease have a mean value which is higher to a significant degree than all others with a specific condition except for women with diabetes, and men and women with gout. Women AMERICAN
JOURNAL
OF
MEDICINE
Serum
Uric Acid, Coronary
with c:oronar)- heart disease show relatively little \ ariation about their mean SUAS(RW), which is lower than that of men with gout, not different from wonton with gout or men with coronary hc=art disease, but is significantly greater than all others. Wonlen with diabetes are the only ones who appear to differ very little from the totality of subjects studied as to the SUAS(RW). Men with diabetes have low mean SUAS(RW) which differs from all others except men with rheumatoid arthritis and have a high mean only by comparison with pregnant women. Men with hypertensive heart disease do not differ appreciably from women with the same condition or from wotnen with gout or rheumatoid arthritis. They have a significantly lower mean than men with gout, men and women with coronary heart disease, women with diabetes, and the generality of the group under study, but a significantly higher mean than all others. Much the same can be said for women with hypertensive heart disease except that they do not differ from men with rheumatoid arthritis. Men with rheumatoid arthritis have a significantly low mean SUAS(RW) by comparison with their female counterparts. They do not differ from male diabetic subjects or female subjects with hypertensive heart disease and have a mean SUAS(RW) which is significantly greater only than that of women in pregnancy. The only thing striking about the mean SUAS(RW) of women with rheumatoid arthritis is the small range of variation of the observations that make it up. One further comparison is needed, that of pregnant women with nonpregnant women. Seventy-two women stated that they were pregnant at the time of examination. They ranged in age frotn eighteen through forty years. All other women in the study, in this same age range, were identified for comparison. The wotnen who stated they were not pregnant, 1,135 in all, had a mean SUAS(RW) of 4.534 mg. per 100 ml. with a standard deviation of hO.827, as compared with 3.843 f 1.230 for the pregnant women; the difference is highly significant statistically. COMMENTS
A risk factor for coronary heart disease has been defined as an attribute which appears to occur more commonly among persons VOL.
45,
OCTOBER
1968
Heart
Disease-Myers
(11al.
525
with the disease than atnonq contra! subjects, although causality is not nccessaril>, implied [IO]. Numerous clinical and epidemiologic studies have elucidated the attributes associated with developing and established coronary heart disease, and among those mentioned protuinently are excesses of serum cholesterol, serum triglycerides, blood sugar, blood pressure, body weight, smoking and physical inactivity, as well as genetic, social and psychologic influences. Gertler, Garn and Levine [17] noted a statistically significant excess of hyperuricemia in a group of young patients with coronary heart disease. Kohn and Prozan [?2] subsequently suggested use of SUA levels in assessing coronary proneness. Several other reports have noted the association of hyperuricetnia with the manifestations of atherosclerosis [ 13-781. The original stimulus for some of these studies appeared to be the clinical observation that arteriosclerosis and its tnanifestations were more common in gouty patients. Yet, at least one authority, based on his longtime study of gout, believes that gouty subjects are no more prone to coronary heart disease than nongouty persons [19]. By contrast, a report from a major epidemiologic study recently concluded that there is a higher incidence of coronary heart disease in gouty subjects but that the association between the risk of coronary heart disease and hyperuricemia disappears when people with clinically overt gout are removed [ZO]. By reason of these associations, the interrelationship between hyperuricemia and specific physiolsgic variables has received recent attention. In view of our results, the relationship to obesity is of major interest. Engelhardt and Wagner [21] called attention to obesity as an integral part of a triad with gout and diabetes mellitus; others have since noted this association [22,23]. Even when diabetes is not present, there still appears to be a preponderance of obese persons in gouty populations [2&26], although Talbott [19] found it uncomtnon in his series. More extensive recent reports including population studies have confirmed a definite association between hyperuricemia and obesity or increased body size [8,9,263-281. The data here reported substantiate this interrelationship. Because of its association with clinically significant arteriosclerosis, one of the first traits to be examined for a relationship to hyperuricemia was the serum cholesterol. In 1949 Ad-
526
Serum
Uric
Acid,
Coronary
lersberg [29] reported that one third of a group of patients with hypercholesterolemia had hyperuricemia and Harris-Jones [30] later confirmed this finding. More recently, however, such an association has been found lacking [31]. Although studies of patients experiencing myocardial infarctions [ 7I] or peripheral vascular disease [ 141 revealed hyperuricemia commonly, the association with hypercholesterolemia was also evident. Becker [32] approached this problem in the reverse manner and noted that over 50 per cent of a small group of gouty patients had hypercholesterolemia. On the other hand, in a group of gouty patients without clinical evidence of arteriosclerosis, serum triglyceride levels were higher than in a control group but serum cholesterol levels in the two groups were not significantly different [33]. Others have confirmed these findings [34,35]. We are also unable to demonstrate a meaningful association between SUA and serum cholesterol. A further ill defined connection is that of blood sugar and hyperuricemia. Prevalence data vary widely depending upon the type and extent of the populations studied. Although Joslin et al. [36] and Talbott [79] found the association of gout and diabetes mellitus to be rare in each of their large series, others have found an increased prevalence of abnormal carbohydrate metabolism, when searched for, in gouty subjects [22,23,37-471. Berkowitz [47] has found, in addition, that abnormal glucose tolerance in gouty patients correlates best with elevation of serum triglycerides. On the other hand, Dunn and Moses [42] found no significant correlation between serum triglyceride, sugar and SUA levels in a population unselected for disease. Furthermore, Beckett and Lewis [43] found that SUA values were generally lower in diabetic than in nondiabetic subjects. Finally, in a recent report of the Framingham study [26] diabetes did not occur more commonly than expected in those subjects with hyperuricemia or gouty arthritis. In our study, we found no meaningful association between the two variables. The relationship between hypertension and hyperuricemia is likewise unclear. Certainly, hyperuricemia may occur secondary to renal disease of any etiology and may be associated with the concomitant hypertension but several studies have demonstrated elevation of SUA
Heart
Disease--Myers
et al.
levels in the absence of clinically significant renal disease. Dollery et al. [44] concluded that hyperuricemia in hypertensive patients was usually the result of antihypertensive therapy, but others have found elevations of SUA in 27 to 38 per cent of untreated hypertensive patients [45-471. This is significantly greater than the prevalence of hyperuricemia expected in an unselected population [6]. Furthermore, it has been noted that antihypertensive therapy in the form of drugs or surgery significantly increased the likelihood of finding hyperuricemia in a hypertensive patient [44-491. Our data lead us to conclude that there is no consistent pattern of a relationship between SUA levels and casual blood pressure determinations despite some suggestive trends. Finally, the relationship of hyperuricemia to the disease states, coronary heart disease, hypertensive heart disease and diabetes mellitus, is of interest in view of the evidence reported in the literature, as already noted. Although our data are not conclusive because of small numbers, certain generalizations can be made. The mean SUAS adjusted for age, sex and relative weight in male and female subjects with coronary heart disease are rather high and significantly greater than those found in most other conditions examined, with the exception of gout, but not significantly different from the study mean. Male and female subjects diagnosed as having hypertensive heart disease have a significantly lower SUAS(RW) than those with coronary heart disease and had lower values than the mean for the entire population. Men with diabetes have a low SUAS(RW), whereas in women with diabetes the SUAS(RW) does not differ from the mean of the study group. The results of several studies have led us to analyze our data in regard to possible other significant associations. Horvath [50] recently reported elevated SUA levels in a broad group of arthropathies, with a 9.5 per cent prevalence rate in rheumatoid arthritis. We cannot confirm such a finding but our group with rheumatoid arthritis is small. In 1956 Steenstrup [57] observed that a moderate hypouricemia occurred during the first two trimesters of pregnancy and recently Boyle et al. [52] confirmed these findings. Our data support these reports as we found a highly significant difference between pregnant and nonpregnant women in respect to SUAS. AMERICAN
JOURNAL
OF
MEDICINE
Serum
Uric Acid, Coronary
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15. 16.
17. 18. 19.
study. Pub. Health Rep., 76: 963, 1961. NAPIER, .I. A. Field methods and response rates in ttlr Tecumseh Community Health Study. Am. J. I’iii,. Health., 52: 208, 1962. EP~I.EIN, F. I-I., FRANCIS, T., JR., HAYNER, N. S., JOHNSON, B. C., KJELSBERG, M. O., NAPIER, .I. A., C)S?.RANDER,L. D., JR., PAYNE, M. W. and DODGE, H. J. Prevalence of chronic diseases and distribution of physiologic variables in a total community, Tecumseh, Michigan. Am. J. Epidemiol., 81 : 307, 1965. JOHNSON, B. C., EPSTEIN, F. H. and KJELSBERG, M. 0. Distributions and familial studies of blood pressure and serum cholesterol levels in a total community-Tecumseh, Michigan. J. Chron. Dis., 18: 147, 1965. HAYNER, N. S., KJELSBERG,M. O., EPSTEIN, F. H. and FRANCIS,T., JR. Carbohydrate tolerance and diabetes in a total community, Tecumseh, Michigan. Diabetes, 14: 413, 1965. MIKKELSEN,W. M., DODGE, H. J. and VALKENBURG, H. The distribution of serum uric acid values in a population unselected as to gout or hyperuricrmia. Am. J. Med., 39: 242, 1965. LIDDLE, L., SEEGMILLER, .I. E. and LASTER, J. The enzymatic spectrophotometric method for the detrrmination of uric acid. J. Lab. & Clin. Med., 54: 903, 1959. O’BRIEN, W. M., BURGH, T. and BUNIM,J. Genetics of hyperuricemia in Blackfeet and Pima Indians. Ann. Rheumat. Dis., 25: 117, 1966. ACHESON, R. M. and O’BRIEN, W. M. Dependence of serum-uric-acid on haemoglobin and other factors in the general population. Lancet, 1: 777,1966. EPSTEIN, F. H. The epidemiology of coronary heart disease. J. Chron. Dis., 18: 735, 1965. GERTLER,M. M., GARN, S. M. and LEVINE, S. A. Serum uric acid in relation to age and physique in health and in coronary heart disease. Ann. Int. Med., 34: 1421, 1951. KOHN, P. M. and PROZAN, G. B. Hyperuricemiarelationship to hypercholesterolemia and acute myocardial infarction. J.A.M.A., 170: 1909, 1959. ASK UPMARK, E. and ADNER, M. L. Coronary infarction and gout. Acta med. scandinau., 139: 1, 1950. KRAMER, D. W., PERILSTEIN, P. K. and DEMEDEIROS, A. Metabolic influences in vascular disorders with particular reference to cholesterol determinations in comparison with uric acid levels. Angiology, 9: 162,1958. DREYFUS, F. The role of hyperuricemia in coronary heart disease. Dir. Chest, 38: 332, 1960. SPRING, M., CAWSOGLU, M., CHU, Y. C. and ARTYMOWSKE, C. Hyperuricemia and hyperglycemia in acute myocardial infarction. (Abstract.) Circulation, 22: 817, 1960. EIDLITZ, M. Uric acid and arteriosclerosis. Lancet, 2: 1046, 1961. HANSEN, 0. E. Hyperuricemia, gout and atherosclerosis. Am. Heart J., 72: 570, 1966. TALBOTT, J. H. Gout, 2nd ed., p. 139. New York, 1964. Grune & Stratton, Inc.
VOL.
45,
OCTOBER
1968
Heart
Disease--Myrrs
rt d.
20. HALL, A. P. Correlations among hypcruricernia, hypercholesterolemia, coronary diseasr* and hypertension. Arthl&s & Rheumat., 8: 846, 1765. 21. ENGELIXARDT, H. T. and WAGNER, E. L. GolIt, diabetes rnellitus and obesity, a poorly recognized syndrome. South. 1El. J., 43: 51, 1960. 22. BARTELS, E. C., BALODIMOS,M. C. and CCXN, 1.. R. The association of gout and diabetrs _4I. Urn. North Amer~a, 44: 443, 1960.
rneliitus.
23. WHITEI-IOUSF., F. W. and CLEARY, iV. .J., JR. LXabetes mellitus in patients with gout. J.A..\I.A., 197: 73, 1966. 24. BR@CHNER-MOR.~ENSEN, K. Heberden Oration, 1957-Gout. Ann. Rheumat. Dis., 17: 1, 1958. 25. SHAPIRO, J. R., KLINENBERG, J. R., PECK, W., GOLDFINGER, S. E. and SEEGMILLER, J. E. IHyperuricemia associated with obesity and intensified by caloric restriction. Arthritis @ Rheumat., -’ : 343, 1964. 26. HALL, A. P., BARRY, P. E., DAWBER, T. R. and MCNAMARA, P. M. Epidemiology of gout and hyperuricemia. Am. J. Med., 42: 27, 1967. 27. BURCH, T. A., O’BRIEN, W. M., NISED, R. and KURLAND, L. T. Hyperuricemia and gout in the Mariana Islands. Ann. Rheumat. Dir., 25: 114, 1966. 28. KRIZEK, V. Serum uric acid in relation to body weight. Ann. Rheumat. Dis., 25: 456, 1966. 29. ADLERSBERG, D. Newer advances in gout. flull. New York Acad. Med., 25: 651, 1949. 30. HARRIS-JONES, J. N. Hyperuricemia and essential hypercholesterolemia. Lancet, 1: 857, 1957. 31. JENSEN, J., BLANKENHORN,D. H. and KORNERUP, V. Blood uric acid levels in familial hypercholestcrolemia. Lancet, 1: 298, 1966. 32. BECKER, J. H. Gout and serum cholesterol. Wuconsin M. J., 59: 735, 1960. 33. FELDMAN, E. B. and WALLACE, S. L. Hypertriglyceridemia in gout. Circulation, 20: 508, 1964. 34. BERKOWITZ, D. Blood lipid and uric acid interrelationships. J.A.M.A., 190: 856, 1964. 35. BENEDEK, T. G. Correlations of serum uric acid and lipid concentrations in normal, gouty and atherosclerotic men. Ann. Int. Med., 66: 851, 1967. 36. JOSLIN, E. P., ROOT, H. F., WHITE, P. and MARBLE, A. The Treatment of Diabetes Mellitus, 9th ed., p. 93. Philadelphia, 1952. Lea & Febiger. 37. WEISS, T. E., SEGALOFF, A. and MOORE, C. Gout and diabetes. Metabolism, 6: 103, 1957. 38. HERMAN, J. B. Gout and diabetes. Metabolism, 7: 703, 1958. 39. ISHMAEL, W. K., OWENS, J. N., PAYNE, R. W. and HONICK, M. D. Diabetes mellitus in patients with gouty arthritis. J.A.M.A., 190: 396, 1964. 40. MCKECHNIE, J. K. Gout, hyperuricemia and carbohydrate metabolism. South African M. J., 38: 182, 1964. 41. BERKOWITZ, D. Gout, hyperlipidemia and diabetes mellitus. J.A.M.A., 197: 77, 1966. 42. DUNN, J. P. and MOSES, C. Correlation of serum lipids with uric acid and blood sugar in normal males. Metabolism, 14: 788, 1965. 43. BECKETT, A. G. and LEWIS, J. G. Gout and the serum uric acid in diabetes mellitus. Quart. J. Med., 29: 443, 1960.
Serum
528
Uric Acid, Coronary
44. DOLLERY, C. T.,
DUNCAN, H. and SCHUMER, B. Hyperuricemia related to treatment of hypertension. Brit. M. J., 2: 832,196O.
45. BRECKINRIDGE,A. Hypertension and hyperuricemia. Lancet, 1: 15, 1966. 46. WALTHER, R. D., KINSEY, D., SISE, H. S., WHITELAW, G. P. and SMITHWICK, R. H. Factors inhuencing serum uric acid levels in patients with hypertension. Pm. New England Cardiovascular
Sot., 19: 36, 1960. 47. CANNON, P. J., STASON, W.
B., DEMARTINI, F. E., SOMMERS,S. C. and LARAGH, H. J. Hyperuricemia in primary and renal hypertension. New England J.
Med., 275: 457, 1966. 48. KINSEY, D. Gout and hyperuricemia in hypertensive
Heart
Disease--Myers patients 15-25 splanchnicectomy. 1963.
et al. years following lumbodorsal Arthritis & Rheumat., 6: 778,
Gout and hyperuricemia after adrenalectomy for hypertension. New England J. Med., 268: 1105, 1963. 50. HORVATH, G. Uric acid levels in the serum of arthropathies. Acta rheumat. scandinav., 12: 72, 1966. 51. STEENSTRUP,0. R. Hypouricemia during pregnancy.
49. ITSKOVITZ, H. D. and SELLERS, A. M.
Scandinau.J. Clin. tT Lab. Invest., 8: 263, 1956. 52. BOYLE, J. A., CAMPBELL, S., DUNCAN, A. M., GEIG, W. R. and BUCHANAN, W. W. Serum uric acid levels in normal pregnancy with observations on the renal excretion of urate in pregnancy. J. Clin.
Path., 19: 501, 1966.
AMERICAN
JOURNAL
OF
MEDICIPJE
of Serum Uric Acid to Risk
Factors in Coronary ALLEN R. MYERS,
M.D.,? FREDERICK
Heart Disease*
H. EPSTEIN,
M.D., H. J. DODGE,
and WILLIAM M. MIKKELSEN,
M.D., M.P.H.
M.D.
Ann Arbor, Michigan Analysis of the uric acid data from the initial examination cycle of the Tecumseh Community Health Study reveals that not only age and sex but also body weight or build should be considered when evaluating serum uric acid levels in disease or relating serum uric acid levels to other physiologic variables. It was found that serum uric acid levels of persons with coronary heart disease were not significantly different from the mean of the population studied and hence cannot be considered an attribute associated with the disease. Furthermore, there appears to be no evident relationship between serum uric acid levels and serum cholesterol or blood sugar, both of which are regarded as risk factors for coronary heart disease. Although there is no consistent pattern of a relationship between uric acid levels and casual blood pressure levels, some trends are suggestive. Of the conditions and disease states studied, only gout and pregnancy differed significantly from the means of the entire population with respect to serum uric acid scores; the levels in gouty subjects, as expected, were higher and in pregnant women lower, confirming reports in the literature.
W
In the 1959-1960 examinations, the serum uric acid (SUA) concentrations in 6,000 participants were measured by the enzymatic spectrophotometric method of Liddle, Seegmiller and Laster [7]. The resulting data were discussed in an earlier paper and the need was demonstrated for standardizing the individual SUA to compensate for systematic differences associated with age and sex distributions of the population studied [6]; the adjusted or standardized SUA was called a “score” or SUAS. The scores thus computed vary about a mean of 4.5 mg. per 100 ml. with a standard deviation of +l.OO mg. per 100 ml. In succeeding analyses of the data it became evident that still another variable is associated with SUA concentrations; this variable is “relative weight,” a measure computed by a regression equation taking into account actual weight, height, biacromial and bicristal diameters of the individual subject and stated as a ratio relationship to the sex specific value for men or women of ages twenty to twenty-nine years [3]. The nature of the association of the serum uric acid score (SUAS) and relative weight can be illustrated simply as shown in Table I. As the distribution of
THE increasing interest in risk factors associated with atherosclerosis and coronary heart disease, a number of publications have contributed conflicting information as to the association of serum uric acid concentrations with established coronary heart disease and its precursors. Most of the studies are based on relatively small numbers of subjects selected by virtue of having this disease or related biochemical or physiologic abnormalities. In an effort to clarify this situation, the present study is reported. It deals with observations of a natural population selected only because they were residents of a particular community, and participants in a Tecumseh, Michigan, comprehensive prospective study of health and disease. ITH
METHODS
The genera1 objectives and the methods of the Tecumseh Community Health Study (TCHS) have been documented [ 7-61.
* From the Department of Epidemiology, School of Public Health and the Rackham Arthritis Research Unit, Department of Internal Medicine, Medical School, The University of Michigan, Ann Arbor, Michigan. This study was supported by Program Project Grant HE 6378 to the Cardiovascular Research Center, The University of Michigan (Thomas Francis, Jr., M.D., Director) from the National Heart Institute, National Institutes of Health and by Grant CD.-00005 from the U. S. Public Health Service. It is reported for the Research Staff of the Tecumseh, Michigan, Community Health Study. Requests for reprints should be addressed to H. J. Dodge, M.D.,3072 School of Public Health, University of Michigan, Ann Arbor, Michigan 48104. Manuscript received October 5, 1967. t Present address: Arthritis Unit, Massachusetts General Hospital, Boston, Massachusetts 02114. 520
AMERICAN
JOURNAL
OF
MEDICINE
Serum
Uric Acid,
Coronary
study subjects moves from the lowest class (twentieth percentile or below) to the highest class (eightieth percentile or above) for each of the three variables, the prevalence rate of hyperuricemia increases. For serum cholesterol the increase is not consistent; for blood sugar it is consistent but of low magnitude. For relative weight the increase is both consistent and of the magnitude of 8 percentage points. There is a consistent increase in mean SUAS as one moves up the percentile scale. For serum cholesterol and blood sugar the increase is modest, in the range of 0.06 to 0.07 mg. per 100 ml., whereas the increase of SUAS with relative weight is of the order of 0.53 mg. per 100 ml. This association is in keeping with the reports of O’Brien, Burch and Bunim [8] as to the relationship between SUA and a measure of body surface, and of Acheson and O’Brien IS] on the relationship between SUA and the ponderal index in men and body weight in women. It was decided to standardize the SUA values further to take relative weight into account. This was accomplished by a formula utilizing the regression of relative weight on SUAS. The resulting value is an expression of the individual’s SUA value adjusted for age, sex and relative weight simultaneously and will be called the SUAS(RW). This computed value is distributed about a mean of 4.5 mg. per 100 ml. with a standard deviation of 10.96 mg. per 100 ml. Of the 6,000 subjects with a SUAS, all but thirtythree had a relative weight determination so that the SUAS(RW) could be computed for a total of 5,967. This latter group of subjects forms the base of this report. The data are reported in two ways. First, the proportion of subjects with hyperuricemia are considered. Hyperuricemia is defined as SUA concentration, without adjustment, of greater than 7.0 mg. per 100 ml. in men and greater than 6.0 mg. per 100 ml. in women. This definition is conventional in terms of the method of SUA determination and sets the cutting points at the mean +1.53 standard deviations of the 6,000 observed SUA values of this population. These cutting points result in a slightly lower proportion of women being labeled hyperuricemic than men, 6.27 per cent as compared with 6.42 per cent. The second method of reporting the data is in terms of the mean SUAS(RW), a refined measure taking into account three variables that have significant association with SUA. RESULTS
The association of SUA with three physiologic variables will be considered first. These are serum cholesterol, blood sugar and blood pressure; all have been implicated as risk factors in coronary heart disease. The relationship of SUA (expressed in two ways) with serum cholesterol is shown in Table II. The study subjects have been divided into VOL.
45,
OCTOBER
1968
Heart
Disease-Myers
et al. ‘I’AHLE
sERm4
URIC
*CID
DISTRIBUTION
SeWIll Cholesterol
of Hypcruricumin,*
PrevalenceR&r
percentile
6.1%
(1,218H
21st to 79th Dercentile At or above
the
80th
6.0% (3,575) percentile
8.5% (1,187) 6.5% (5,980)
Total
Mew
SUAS
(Adjusted
Below or at the 20th percentile to 79th percentile
21~
At or above
the
80th
B1.00,~
WEIGH’I
1959-1960
Age-Sex Sprcific Percentile Distributmn
20th
ro PER~EN-rur
AND RELATIVE TCHS
or at the
I
RELATION
m
OF SERUM CHOLESTEROL,
SUGAR
Below
521
oercentile
R&IlW Weight
Unadjurlcd
Si ‘A
6.941: (859) 7 6% (2,54d) 9 3 cc;, (952) 7 8
9;
(4,360)
3 4 or (: ,Zli) 5 % (3,605 II 4% <: ,143)
-7
(1
4% (5,967)
forAgr and Sex)
4.481
4.461
(1,218) 4.495 (3,575) 4.539
(859) 4.498
(1,187) 4.492
Total
Blood Sugar
(5,980)
(2,549) 4.528
4 251 (1,215) 4 485 13,609) 4 777
(952) 4.497 (4,360)
(1,143) ‘l 499 (5,967)
* Unadjusted SUA greater than 7.0 mg. per 100 ml. in mak 6.0 mg. per 100 ml. in female subjects. t Number of subjects in group.
and
three groups in relation to the distribution on a percentile scale made specific for age and sex. Among the 5,947 subjects in whom both serum cholesterol and uric acid determinations were obtained, there is no evident association between the two variables. Those subjects whose cholesterol values fall in the mid-range have very slightly lower SUA values than do those at the extremes of the range. The differences between the SUA values for the two sexes are not striking and are no greater than can be accounted for by sampling variation and TABLE SEX-SPECIFIC AND
MEAN
PREVALENCE SUAS(RW)
DISTRIBUTION
IN
Below or at the 20th percentile 21st to 79th percentiles At or above centile Total
the 80th
per-
RELATION
OF HYPERURICEMIA TO
OF SERUM CHOLESTEROL TCHS
Serum Cholesterol Distribution
II
RATES
sex M F M F M F M F
PERCENTILE VALUES
1959-1960
No. of Subjects
Per cent Hyperuricemic*
Mean SUA Adjusted ior Age, Sex and Relative Weight
603 607 1,772 1.785 ‘588 592 2,963 2,984
6.0 6.1 5.6 6.0 8.8 7.3 6.3 6.3
4 516 4.500 4.497 4.492 4 495 4.535 4.500 4.502
*Unadjusted SUA greater than 7.0 mg. per 100 ml. in male and 6.0 mg. per 100 ml. in female subjects.
522
Scrurn Uric Acid, Coronary ‘I‘AIILE
SEX-SPECIFIC AND
PREVALRSCB
MEAN
SUAS(RW)
IN
DISTRIHU~I‘ION
III
RAKS
REI.AT,ON
OF HL”“”
TCIIS
OF
IIYPERURICI~MIA I’0 PERCEh’TlLE
SUGAR
“A,
UKS
1959-1960 .uran SUA
Blood Sugar Distribution -.
sex
No. of Subjects
Per cc”, Hypcruriccmic*
M F M F h4 F M 1:
417 437 1,235 1,303 444 499 2,096 2,239
6.5 7.3 8.3 6.7 8.6 9.6 8.0 7.5
Adjusted for Age, Sex and R&ilk Weight
..~
~.
Below oratthe ccntilc 21~1 to 79th Ator above ccntilc Total
20th per-
percentiles the 80thper-
* Unadjusted SUA greater 6.0 mg. per 100 ml. in female
than 7.0 subjects.
mg.
per
4.492 4.478 4.511 4.480 4.454 4.583 4.495 4.502
100 ml.
in male
md
the cutting points selected for defining hyperuricemia. The association between SUA and blood sugar, in 4,335 subjects in whom both determinations were made, is seen in Table III. There appears to be some slight positive gradient of SUA values with increasing levels of blood sugar in male subjects as to prevalence of hyperuricemia but not as to SUAS(RW), whereas the reverse is true for female subjects. The differences between the two sexes for each of the two measures within and across the blood sugar categories show no consistent pattern. From these data it is impossible to show any TABLE SEX-SPECIFIC
PREVALENCE
IN RELA’I‘ION
TO
BLOOD
TCllS
IV
RATES
(mm.
Hg)
Lcsp rhan 90
.-.Lcsl
than
140
140-159
F
4.4’Y (1,66& 4 ‘3;.
M
(I, 733) 8
hl
&f F
Total
Prcssurc
Hg) 95 or mow
90-94
Total
-
F 160 or mow
Blond (mm.
sex
GROUPINGS
1959-1960
Diastolic Systolic Blood PIYXVX-C
OF IIYPERURICEHIA*
PRESSURE
M t‘
(40) 4.8% (21) lO.u~,;
(126) 5.2%
.9
(77) 9.9% ,111) 6.0%
57;.
(363) 4.8% (2523 15.5’;;. (71) 8.4% (71) 5.5%.
12.50/,
14.3%
(120) 18.5% (65) 12 6% (151) 15.6%. (173) 1 I :(I%’
(117) 0.0% (31) 16.7”‘, ‘r (54) lO.d%’
(2,089) .5.0% (1,056)
* Unadjurtcd SUA grr;iwr rtkm 7.0 6.0 mg. per 100 ml. in fcmnlc subjects. t Numba of subjccn in group.
(268) 8.1% (248)
mg.
(311) 15.4yo (259)
prr
5.2% (1,821) 4.9% ‘:rG’ (5940) 7.1% (434) 11.9% (253) 14.1% (298) 6:770’ (2,668) 6.4% (2,563)
100 ml. in male
and
Heart
Disease-Myers
et al.
degree of Incaningful association between the two variables. Cross classification of serum cholesterol and blood sugar by percentile distributions shows no pattern that can be interprctcd as showing an association of SUA with thcsc two variables considered simultaneously. Xcxt are considered the 5,231 subjects in whom both the SLA values and blood pressure (systolic and diastolic V phase) were determined. The prevalence of hypcruriccmia, as defined, is shown in Table IV in relation to cross classification of systolic and diastolic blood pressure. This table has several interesting features. On inspection of the right hand colUII1I1, which summarizes the association between prevalence of hyperuricemia and categories of systolic blood pressure, it is seen that prevalence rises appreciably with pressure. This is true for both malt and female subjects; the only disparity is the excess prevalence in female over Inale subjects in the group with pressures of 160 mm. Hg or greater. These same cornmcnts can be made about the bottom row which summarizes the association between prevalence of hyperuricemia and the rising gradient of diastolic pressures. However, when one considers the nine cells which represent the interactions of blood pressure, no pattern whatever is seen; there are no consistent trends. The most puzzling situation is in the middle column (those with borderline of diastolic pressures) ; here the prevalence hyperuriccmia declines as the systolic pressure increases in male subjects whereas the reverse is true in female subjects. Table v displays the relationship between SUA and blood pressure in terms of the arithmetic means of SUAS(RW). In the whole of the table there is only one suggestion of a positive association between SUA and blood pressure. This appears in the bottom row which summarizes the association between SUA and diastolic blood pressure. The positive association is somewhat more notable in male subjects than in female subjects, but in neither case is the association of sufficient degree for consideration of biological significance. The rernaindcr of the table suggests only random variation of the three variables in relation to one another. Of four physiologic characteristics, all of which have been incriminated to varying degrees as risk factors in relation to coronary heart disease, only one, relative weight, is shown to have any significant degree of association with AMERICAN
JOURNAL
OF
MEDICINE
Serum
Uric Acid, Coronary
Heart
SUA. Therefore, we believe that it must be taken into account, together with age and sex, in comparing SUA levels in disease. Turning to the data on the relationship of SUA to coronary heart disease, we are prompted to report for several other diseases and for pregnancy, to afford some basis for comparison. Included are gout and diabetes because they are diseases with prominent metabolic components; hypertensive heart disease; rheumatoid arthritis (ARA grades of probable and definite) because of the problems of differentiating it from gout by the use of the American Rheumatism Association criteria; and pregnancy, a condition characterized by marked, although temporary, metabolic changes. The relationships of SUA to these conditions are set forth in Table VI and Figures 1 and 2. The subjects appearing in these representations are those who had one, but only one, of the conditions listed. There were others who had two or more of the conditions; these were relatively few in number and are not included because of the possible confounding effect of multiple conditions on SUA. In order to aid in visualizing the differences in SUA distributions between sexes and among the conditions shown in Table VI, the two figures are presented. The method of presentation is the portrayal of the sex- and condition-specific SUA statistics and the “95 per cent confidence limits” (statistic *2 standard errors). The
PREVALENCE
RATES
OF
HYPERURICEMIA
AND TCHS
Condition
Diagnosed
Sex M F M F M F M F M F F
Gout Coronary heart disease Diabetes mellitus Hypertensive Rheumatoid
heart disease arthritis
Pregnancy Total Tecumseh SUAS(RW) * Unadjusted vol..
45,
Subjects with
Both Sexes
No. of Subjects 11 7 94 53 22 34 20 22 8 49 72 5,967
MEAN
523
et al. ~‘ABLE
SEX-SPECIFIC
v
SUAS(RW)
PRESSURE
IN
RELArlON
I’0 HLOOD
GROUPINGS
1959-1960
‘TCHS
Diastolic Blood Prcssurr (mm. Hg)
Systolic Blwd Pressure (mm. Hg)
Less
than90
Sex
90-94
95 or mow
Less than 140
M
140-1.59
160 or more
Total
4.610
4 832
4.467
F
4.448 (1,655)+ 4.490
(1261 4.669
M
(1,733) 4.647
(77) 4 596
(I ,821) 4.600 (1,831) 4.622 (594) 4.453
F
(363) 4.352
(111) 4.503
M
(252) 4.573
(117) 4.339
(40) 4.948 (21) 4.570 (120) 4.754 (65) 4.607
F
(71) 4.407
(31) 4.617
(151) 4.590
(253) 4.551
M
(71) 4.487
(54) 4.573 (268) 4.579
(173) 4.621 (311) 4.660 (259)
(298) 4.511 (2,668) 4 570 (2,563)
(2,089) 4.557 (2,056)
F
*Number
of subjects
(248)
1968
(434) 4.565
in group.
statistic for the total Tecumseh subjects is plotted as a horizontal solid line and the 95 per cent confidence limits as interrupted lines paralleling it in the case of the prevalence of hyperuricemia; in the case of the mean SUAS(RW), the 95 per cent confidence band is too narrow to portray. The sex- and conditionspecific statistics are plotted as solid vertical lines with the statistic of interest plotted at the midpoint and the limits plotted as horizontal bars at the ends of the line. This mode of VI
MEAN
SUAS(RW)
IN SELECTED
MAJOR
CONDITIONS
DIAGNOSED
1959-1960
% Hyperuricemic* and Standard Error of the Proportion
SUA Adjusted for Age, Sex and Relative Weight
Mean
Standard Deviation
Standard Error of Mean
fl.829 fl.540 Al.036 ztl.202 f0.815 fl.338 ho.986 fl.114 f0.449 f0.735 fl.230
fO.304 f0.339 f0 012 ztO.027 zto.030 f0.053 fO.049 f0 056 f0.031 fO.O1l Ito .021
fl.000
fO.0002
f f f f
15.0 18.7 3.9 5.6
f f f
6.5 4.9 8.2
f f
2.0 2.0
5.791 4.985 4.722 4.704 4.027 4.541 4.330 4.268 4.112 4.306 3.843
5.7 f
0.3
4.500
45.5 42.9 17.0 20.8 0.0 17.6 5.0 18.2 0.0 2.0 2.8
SUA greater than 7.0 mg. per 100 ml. in male and 6.0 mg. per 100 ml. in female subjects
OCTOBER
Total
.__I_-___
TABLE SEX-SPECIFIC
Disease-Myers
Serum 95%
Uric Acid, Coronary
Confidence
Bend
FIG. 1. Sex- and condition-specific prevalence rates of hyperuricemia. Tecumseh Community Health Study, 1959-1960. expression permits ready visualization of the magnitude of the statistic and the variation of observations about it as well as the statistical significance of differences between the statistics. If any two of the vertical lines overlap, it is judged that the statistics which they represent do not differ from one another at the 5 per cent level of statistical significance; if a vertical line crosses or falls within the 95 per cent con5.a5.6 -
0
95%
Confidence
Bond
5.4 -
‘E 5.2. B
t
5.0
g 4.8. .E Z 5 4.6. I: 2 4.4-
I
4.24.0 3.8FIG. 2. Sex- and condition-specific mean SUA (adjusted for age, sex and relative weight). Tecumseh Community Health Study, 1959-1960.
Heart
Disease--Myers
et al.
fidence band for the total 5,967 Tecurnseh subjects, the specific statistic does not differ significantly from that of the total subjects studied as to SUA. Conversely, when two lines do not overlap at any point, they may be said to differ from one another at the 5 per cent level of statistical significance. Table VI and Figure 1 show sex- and condition-specific prevalence rates of hyperuricemia. The 0.0 per cent rates for male subjects with diabetes and with rheumatoid arthritis probably do not differ appreciably from the rate for the total 5,967 subjects studied; if there had been a single instance of hyperuricemia in each of these two groups, the rates would have been 4.5 and 12.5 per cent, respectively. There are no significant differences between the prevalence rates in the two sexes for any of the conditions in which comparison is possible nor are there significant differences between conditions except for the rates of coronary heart disease, which exceed those of rheumatoid arthritis in female subjects and of pregnancy. The prevalence rate for gout in male subjects also exceeds to a significant degree that of men with hypertensive heart disease and those of women who have rheumatoid arthritis or are pregnant. Altogether, the use of prevalence rates of hyperuricemia does not provide much discrimination as to SUA in the conditions cited. Figure 2, however, suggests that the use of the SUAS(RW) provides a high degree of discrimination both between sexes and among the conditions considered. In order to show the data on a scale of reasonably sized intervals, it is necessary to show only the lower half of the 95 per cent confidence band for men with gout. It is readily apparent that men with this condition have a mean SUAS(RW) which exceeds all others, except women with gout, to a highly significant degree statistically. Women with gout do not differ appreciably as to the magnitude of this statistic from any of the others except men with diabetes or rheumatoid arthritis and women in pregnancy. Although men with coronary heart disease have a rather high mean SUAS(RW), there is sufficient variation so that they do not differ significantly from the mean of the total 5,967 subjects considered. Men with coronary heart disease have a mean value which is higher to a significant degree than all others with a specific condition except for women with diabetes, and men and women with gout. Women AMERICAN
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with c:oronar)- heart disease show relatively little \ ariation about their mean SUAS(RW), which is lower than that of men with gout, not different from wonton with gout or men with coronary hc=art disease, but is significantly greater than all others. Wonlen with diabetes are the only ones who appear to differ very little from the totality of subjects studied as to the SUAS(RW). Men with diabetes have low mean SUAS(RW) which differs from all others except men with rheumatoid arthritis and have a high mean only by comparison with pregnant women. Men with hypertensive heart disease do not differ appreciably from women with the same condition or from wotnen with gout or rheumatoid arthritis. They have a significantly lower mean than men with gout, men and women with coronary heart disease, women with diabetes, and the generality of the group under study, but a significantly higher mean than all others. Much the same can be said for women with hypertensive heart disease except that they do not differ from men with rheumatoid arthritis. Men with rheumatoid arthritis have a significantly low mean SUAS(RW) by comparison with their female counterparts. They do not differ from male diabetic subjects or female subjects with hypertensive heart disease and have a mean SUAS(RW) which is significantly greater only than that of women in pregnancy. The only thing striking about the mean SUAS(RW) of women with rheumatoid arthritis is the small range of variation of the observations that make it up. One further comparison is needed, that of pregnant women with nonpregnant women. Seventy-two women stated that they were pregnant at the time of examination. They ranged in age frotn eighteen through forty years. All other women in the study, in this same age range, were identified for comparison. The wotnen who stated they were not pregnant, 1,135 in all, had a mean SUAS(RW) of 4.534 mg. per 100 ml. with a standard deviation of hO.827, as compared with 3.843 f 1.230 for the pregnant women; the difference is highly significant statistically. COMMENTS
A risk factor for coronary heart disease has been defined as an attribute which appears to occur more commonly among persons VOL.
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with the disease than atnonq contra! subjects, although causality is not nccessaril>, implied [IO]. Numerous clinical and epidemiologic studies have elucidated the attributes associated with developing and established coronary heart disease, and among those mentioned protuinently are excesses of serum cholesterol, serum triglycerides, blood sugar, blood pressure, body weight, smoking and physical inactivity, as well as genetic, social and psychologic influences. Gertler, Garn and Levine [17] noted a statistically significant excess of hyperuricemia in a group of young patients with coronary heart disease. Kohn and Prozan [?2] subsequently suggested use of SUA levels in assessing coronary proneness. Several other reports have noted the association of hyperuricetnia with the manifestations of atherosclerosis [ 13-781. The original stimulus for some of these studies appeared to be the clinical observation that arteriosclerosis and its tnanifestations were more common in gouty patients. Yet, at least one authority, based on his longtime study of gout, believes that gouty subjects are no more prone to coronary heart disease than nongouty persons [19]. By contrast, a report from a major epidemiologic study recently concluded that there is a higher incidence of coronary heart disease in gouty subjects but that the association between the risk of coronary heart disease and hyperuricemia disappears when people with clinically overt gout are removed [ZO]. By reason of these associations, the interrelationship between hyperuricemia and specific physiolsgic variables has received recent attention. In view of our results, the relationship to obesity is of major interest. Engelhardt and Wagner [21] called attention to obesity as an integral part of a triad with gout and diabetes mellitus; others have since noted this association [22,23]. Even when diabetes is not present, there still appears to be a preponderance of obese persons in gouty populations [2&26], although Talbott [19] found it uncomtnon in his series. More extensive recent reports including population studies have confirmed a definite association between hyperuricemia and obesity or increased body size [8,9,263-281. The data here reported substantiate this interrelationship. Because of its association with clinically significant arteriosclerosis, one of the first traits to be examined for a relationship to hyperuricemia was the serum cholesterol. In 1949 Ad-
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lersberg [29] reported that one third of a group of patients with hypercholesterolemia had hyperuricemia and Harris-Jones [30] later confirmed this finding. More recently, however, such an association has been found lacking [31]. Although studies of patients experiencing myocardial infarctions [ 7I] or peripheral vascular disease [ 141 revealed hyperuricemia commonly, the association with hypercholesterolemia was also evident. Becker [32] approached this problem in the reverse manner and noted that over 50 per cent of a small group of gouty patients had hypercholesterolemia. On the other hand, in a group of gouty patients without clinical evidence of arteriosclerosis, serum triglyceride levels were higher than in a control group but serum cholesterol levels in the two groups were not significantly different [33]. Others have confirmed these findings [34,35]. We are also unable to demonstrate a meaningful association between SUA and serum cholesterol. A further ill defined connection is that of blood sugar and hyperuricemia. Prevalence data vary widely depending upon the type and extent of the populations studied. Although Joslin et al. [36] and Talbott [79] found the association of gout and diabetes mellitus to be rare in each of their large series, others have found an increased prevalence of abnormal carbohydrate metabolism, when searched for, in gouty subjects [22,23,37-471. Berkowitz [47] has found, in addition, that abnormal glucose tolerance in gouty patients correlates best with elevation of serum triglycerides. On the other hand, Dunn and Moses [42] found no significant correlation between serum triglyceride, sugar and SUA levels in a population unselected for disease. Furthermore, Beckett and Lewis [43] found that SUA values were generally lower in diabetic than in nondiabetic subjects. Finally, in a recent report of the Framingham study [26] diabetes did not occur more commonly than expected in those subjects with hyperuricemia or gouty arthritis. In our study, we found no meaningful association between the two variables. The relationship between hypertension and hyperuricemia is likewise unclear. Certainly, hyperuricemia may occur secondary to renal disease of any etiology and may be associated with the concomitant hypertension but several studies have demonstrated elevation of SUA
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levels in the absence of clinically significant renal disease. Dollery et al. [44] concluded that hyperuricemia in hypertensive patients was usually the result of antihypertensive therapy, but others have found elevations of SUA in 27 to 38 per cent of untreated hypertensive patients [45-471. This is significantly greater than the prevalence of hyperuricemia expected in an unselected population [6]. Furthermore, it has been noted that antihypertensive therapy in the form of drugs or surgery significantly increased the likelihood of finding hyperuricemia in a hypertensive patient [44-491. Our data lead us to conclude that there is no consistent pattern of a relationship between SUA levels and casual blood pressure determinations despite some suggestive trends. Finally, the relationship of hyperuricemia to the disease states, coronary heart disease, hypertensive heart disease and diabetes mellitus, is of interest in view of the evidence reported in the literature, as already noted. Although our data are not conclusive because of small numbers, certain generalizations can be made. The mean SUAS adjusted for age, sex and relative weight in male and female subjects with coronary heart disease are rather high and significantly greater than those found in most other conditions examined, with the exception of gout, but not significantly different from the study mean. Male and female subjects diagnosed as having hypertensive heart disease have a significantly lower SUAS(RW) than those with coronary heart disease and had lower values than the mean for the entire population. Men with diabetes have a low SUAS(RW), whereas in women with diabetes the SUAS(RW) does not differ from the mean of the study group. The results of several studies have led us to analyze our data in regard to possible other significant associations. Horvath [50] recently reported elevated SUA levels in a broad group of arthropathies, with a 9.5 per cent prevalence rate in rheumatoid arthritis. We cannot confirm such a finding but our group with rheumatoid arthritis is small. In 1956 Steenstrup [57] observed that a moderate hypouricemia occurred during the first two trimesters of pregnancy and recently Boyle et al. [52] confirmed these findings. Our data support these reports as we found a highly significant difference between pregnant and nonpregnant women in respect to SUAS. AMERICAN
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