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Serum urate in degenerative joint disease and rheumatoid arthritis.

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BRIEF REPORT
Serum Urate in Degenerative Joint Disease and
Rheumatoid Arthritis
By WALTF. WEAVER
AND CHARLEY
J. SMYTH
I
N THE DIFFERENTIAL DIAGNOSIS of patients with arthritic symptoms,
the serum urate is frequently determined, and often when gouty arthritis
is considered only as a remote possibility, Occasionally an “elevated value is
obtained. When the usual causes of an elevation in the serum mate have been
searched for and eliminated, this laboratory finding may cause considerable
concern and confusion. In these circumstances it is not unusual that patients
with rheumatoid arthritis with cystic changes in the bones are falsely interpreted as having gouty arthritis. Lockiel has suggested that the serum urate
may be increased in patients with rheumatoid arthritis. In a more recent
paper, Grayzel et a1.2 have also suggested this phenomenon.
Further difficulty in the interpretation of an elevated serum urate value
may be due to the number of different methods that are currently used, each
with a different range for normal values. The clinician is frequently not aware
of the method used nor the range of normal valces for the particular serum
urate method. In the Arthritis Clinic of the University of Colorado, the Archibald modifications of the Kern-Stransky methodl has been used since 19S5.
This study was undertaken to determine the incidence of hyperuricemia in
patients with rheumatoid arthritis, and to compare this group with the uric
acid values obtained in this same clinic in a series of patients with degenerative
arthritis who served as the control group.
METHOD
It has heen the policy in this clinic to obtain a serum urate determination on each new
patient at the time of the original examination. At times, more than one determination was
made on a single patient because the initial value was elevated. To include all of these
values or even their mean would introduce a sampling error into the study. When thc
data obtained at the time of the initial determination (the first of several measurements in
an individual patient) was compared with the data obtained as a single measurement (only
one determination per patient), there was no significant difference in any of the groups
tested. This data is not presented here but serves to validate the method of this study.
Accordingly, the first uric acid determination on each patient was the one selected for this
report. All of the new patients with rheumatoid arthritis and degenerative joint disease seen
during a 5-year period were selected for a review. The effects of salicylates and other drug
ingestion, renal status and hematologic factors were not included in this retrospective
study. The serum urate determinations, age, and sex were analyzed and the results are
summarized.
RESULTS
The serum urate values found in the different decades of both male and
female patients are present in table 1. The over-all means for males and feFront the Department of Medicine, Section of Rheumtic Diseases: UrtiVerSity of Colorado
School of Medicine, Denver, Colo.
372
ARTHRITIS
AND RHEUMATISM,VOL. 6, No. 4 (AUGUST),
1963
373
SERUM URATE VALUES
males indicate that the serum urate values were higher in the male patients
both with degenerative joint disease (5.6 mg. per cent) and with rheumatoid
arthritis (5.3 per cent) than the female patients with degenerative joint disease (5.1 mg. per cent) and with rheumatoid arthritis (4.3 mg. per cent).
When analyzed in this manner it is apparent that thce serum urate values for
the patients with degenerative joint disease and rheumatoid arthritis were
similar.
These difkerent age groups were combined into those above and
below the age of 50 years (table 2 ) and the mean serum urate levels with
their standard deviations were determined. In patients older than 50 years
the serum urate in rheumatoid arthritis was slightly but definitely lower
than in degenerative arthritis ( p = 0.002 for females and 0.05 for males). This
relationship did not hold in patients below 50 years of age. It was also apparent that while males over 50 (in either the R.A. or control groups) had
slightly higher serum urate values than females over 50, the differences were
not statistically significant. In the groups under 50 years of age, the serum
urate of males with rheumatoid arthritis was considerably higher ( p =
0,001) than females with rheumatoid arthritis. The small size of the control
(degenerative arthritis) groups under 50 years of age did not permit a similar
statistical statement.
DISCUSSION
It is apparent from a statistical viewpoint that the serum urate by the
method employed is not elevated in patients with rheumatoid arthritis. The
data also substantiate the well-known fact that serum urate values for males
and females are similar in the age groups after the menopause. Prior to the
menopause, males have higher serum urate values than females (with exception of the years prior to the menarche).5,6
In the article by Grayzel et aL2 it is stated that, “in a series of 57 male
patients with rheumatoid arthritis admitted to the Clinical Center of the
National Institutes of Health, 10 (18 per cent) were found to have serum
urate levels greater than 6 mg. per 100 ml. after patients with renal disease,
as shown by nitrogen retention, had been eliminated.” In an earlier paper,
it would appear that at least ten per
Lockiel makes a similar statement:
cent of patients with well-developed rheumatoid arthritis will have a uric
acid concentration greater than 6 mg./100 ml.” These statements might suggest to the reader that the serum urate is elevated in rheumatoid arthritis.
However, other authors, using a variety of methods, have reported serum mate
levels greater than 6 mg. per cent in 13.1 per cent (spectrophotometric),’
17.6 per cent ( enzymatic spectrophotometric),8 32 per cent (enzymatic
spectrophotometric),8 and 40 per cent (enzymatic spectrophotometric)O of
apparently normal individuals. Had we reported our data in this manner, it
would show that 48 of 222 (21.6 per cent) of our patients with rheumatoid
arthritis had serum urate values of 6 mg. per cent or greater. In our control
group (degenerative arthritis), 47 of 172 (27.4 per cent) had serum mate
levels of 6 mg. per cent or greater. These statements might imply that 6
“. . .
50-59
80-89
70-
14-29
30-39
4WD
Age Groups
5
9
21
31
37
103
5.4
5.1
4.5
4.3
5.4
4.9
1.4
30
26
141
28
19
25
13
~
_
4.1
3.9
4.0
4.4
4.4
4.8
4.3
~
_
_
_
3
16
19
29
69
2
.
5.6
5.6
7.0
4.6
4.1
6.4
_ _ ~ -
1.5
_
1.5
Mean serum
No.of
uratein Standard
patients mg./100 cc. deviation
Mean serum
No. of
urate in Standard
patients mg./100 ec deviation
Mean serum
No.of
uratein
Standard
Datients m g . / l O O cc. deviation
Ostmwthritis
Rheumatoid Arthritis
- . .
Urate in Degenerative and Rheumatoid Adwitis
(Distribution b y Decades)
Ostemrthritis
Females
Table 1.-Serum
lala
4.9
4.2
5.7
5.7
3.1
6.0
.
1.8
4.9
-.
-
mg./100 cc. deviation
Meart B e r u m
urate in Standard
81._ _ 5.3
10
8
19
21
11
12
No.of
patients
Rheumatoid Arthritis
375
SERUM URATE VALUES
-
Table 2.--Serum Urate in Degenerative and Rheumatoid Arthritis
and
_ _ _ (Distribution
~ _ _ _ _ _under
___
_ over Age_50_Years)
~ - -__.Females
osteo.
-~
Males
RA
Osteo.
RA
Under 50
yrs.
4.4 f 0.9
4.0 & 1.4
Sample too small
5.6 2 1.8
Over 50
yrs.
5.2 f 1.5
4.5 r+ 1.6
5.6
* 1.5
5.0 & 1.6
69pts. 5.6 f 1.5
81 pts. 5.3 1.8
___141 pts. 4.3 & 1.5
-__mg. per cent is the upper limit of normal, Presentation of data in this fashion
is misleading and should be avoided if possible. Why the figure of 6 mg. per
cent is chosen as the reference point in so many studies is unclear. Certainly
males, females and patients of various ages should not be compared in terms
of one single serum urate value.
It is important to recall a common clinical practice: namely, that laboratory
values are usually reported as the mean plus or minus one standard deviation.
Thus, in most hospitals the laboratory reports give the range for only 68 per
cent of the patients. As a result of this general practice, 32 per cent of normal
patients will fall outside this “normal” range. Since it is difficult to assign
limits for normal ranges, some authorslOJ1 in writing about serum urate levels
suggest that t w o times the standard deviation of a single observation (95.4
per cent of all observations) would make desirable limits. On cursory inspection, this might appear to be the practical solution to the reporting of
normal and elevated serum urate levels. However, one must also enlarge the
frequency distribution curve of the patients with abnormal purine metabolism
by this one standard deviation in each direction. A greater percentage of the
area of the two frequency distribution curves is thus allowed to overlap. It
is to be emphasized that a single determination is not sufficient to establish a
distribution curve for a given patient. Thus, using our data, if a female patient
has a single serum urate determination of 7.2 mg./100 cc., she may be normal
or abnormal as regards purine metabolism. A single high value such as this
should prompt the clinician to obtain additional determinations before a
diagnosis of hyperuricemia is made on this patient. Jf further determinations
were much lower, a “t” test or other significance test would not show a difference between the curve for normal patients and this patient and the high
value could be disregarded. However, if further determinations were also
elevated (and yet within 1 or 2 standard deviations of normal), a test of
significance could show a definite difference between the normal distribution
curve and the one for the patient in question. In this latter instance, the
clinician must make the final decision regarding normality versus abnormality.
These concepts must be taken into consideration when evaluating or reporting data based upon single measurements. Thus, when reporting a
serum urate on a group of patients with a given condition, a frequency distribution curve should be calculated for that group and this compared to a
similar curve for normal patients. It would be far less valid to take the single
value for each patient and individually compare it to the normal value or
range of values.
Total
103 pts. 5.1 k 1.4
376
WEAVER AND SMYTH
SUMMARY
A brief report of the serum urate values in patients with degenerative and
rheumatoid arthritis using the Archibald modification of the Kern-Stransky
method has been presented.
The serum urate by this method is not elevated in rheumatoid arthritis.
Recognition of the fact that in the usual frequency distribution curve, 32 per
cent of normal patients will be outside the “normal” range (mean 1 S.D.) is
stressed.
To establish that an individual patient has a significant hyperuricemia,
several determinations may be required.
*
ACKNOWLEDGMENT
Statistical analyses of the data were made by Charles J. Hlad, Jr. of the Denver
Veterans Administration Hospital.
REFERENCES
1. Lockie, L. M.: Symposium on gout:
Diagnosis. Metabolism 6:269-276,
1957.
2. Grayzel, A. I., Liddle, L., and Seegmiller, J. E.: Diagnostic significance
of hyperuricemia in arthritis. New
England J. Med. 265:761-768, 1961.
3. Archibald, R. M.: Colorimetric measurenient of uric acid. Clin. Chem.
3:102-105, 1957.
4. Kern, A., and Stransky, E.: Beitrag zur
Kolorimetrischen Bestimmung der
Harnsaiire. Biochemi. Ztschr. 230:
419-427, 1937.
5. Smyth, C. J., Cotterman, C. W., and
Freyberg, R, H,: The genetics
gout and hypermicemia--an analysis
of nineteen families. J. Clin. Invest.
27:749-759, 1948.
6 . Wolfson, W. Q., Levine, R., Cohn, C.,
Huddleston, B., Hunt, H. O., Guterman, H. S., Rosenberg, E. F., and
Kadota, K.: The transport and excretion of uric acid in man; V. A
sex difference in mate metabolism:
J. Clin. Endocrinol. 9:749-767, 1949.
7. Gertler, M. M., and Oppenheimer: Serum uric levels in men and women
past the age of 65 years. J. Gerontol
8:465-471, 1953.
8. Praetorius, E.: Plasma uric acid in
aged and young persons. J. Gerontol
6~135-137, 1951.
9. Cob,,, s., Dunn,
p,, Brooks, G,, and
Rodnan, G. P.: Serum urate levels
in males by social class (abstract).
1961 Annual Meeting of American
Rheumatism Assoc., June 1961, New
York City. Arth. R Rheumat. 4:412,
1961.
10. Alper, c., and Seitchik, J.: Comparison of the Archibald-Kern and Stransky colorimetric procedure and the
Praetorius enzymatic procedure for
the determination of uric acid. Clin.
Chem. 3:95-101, 1957.
11. GjoruP, s., Poulsen, H.,and Praetorius,
E. The uric acid concentration in
serum determined by enzymatic spectrophotometry. Scandinav. J. Clin. &
Lab. Invest. 7:201-203, 1955.
Walt F . Weauer, M.D., formerly Clinical Assistant in Medicine,
Department of Medicine, Section of R h & k Diseases, University o j Colorado School of Medicine, Denuer, COO.;present
address. Lincoln, Neb.
Charley 1. Smyth, M.D., Associate Professor of Medicine,
Department of Medicine, Section of Rheumatic Diseases, University of C o h a d o School of Medicine, Denver, C o b .
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