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Studies of uric acid biosynthesis in the chronic leukemias.

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Studies of Uric Acid Biosynthesis in
the Chronic Leukemias
By IRWIN
H. KRAKOFF,M.D.
Sloan-Kettering Institute
Dr. Yii’s case material was selected from the standpoint of gout. Ours was
selected from the standpoint of neoplastic disease, hence the concentration
of gout in the group of patients we have studied is considerably less than
the number of gouty patients in her series. However, hyperuricemia is a common occurrence in the population we see with myeloproliferative disease.
We have studied the urinary excretion of uric acid and serum uric levels
in patients with leukemias and other neoplastic diseases1 and have consistently found increases in serum and urine uric acid in patients with chronic
granulocytic leukemia. This is in contrast to patients with chronic lymphocytic
leukemia, in whom serum and urine uric acid have been normal (Table 11).
In an attempt to explore the genesis of the hyperuricemia of chronic granulocytic leukemia, a group of patients with that disease was studied prior to
the institution of any therapy and again when the disease was under good
control (Table 12). It was found that there was a marked decrease in both
serum and urine acid in each patient when a satisfactory degree of control
had been achieved. It could be concluded that the overproduction of uric
acid present initially in each patient was not due to an inherent biochemical
Table 11.-Uric Acid Production in Untreated Chronic Leukemia
Mean WBC
x 10.’/mm.3
Mean Urine Uric Acid Mean Serum Uric Acid
(mg./day)
(mg. per cent)
1,071
491
452
Chronic granulocytic
Chronic lymphocytic
Nonlcukcmic
8.6
5.5
4.8
198
182
7
Table 12.- Uric Acid Excretion in Untreated and Controlled
Chronic Granulocutic Leukemia“
Untreated
Patirnt
F. S.
M. P.
M. W.
M. Y.
T. Y.
P. K.
Average
Urine
Uric Acid
mg./day
(mean)
2,044
1,055
1,217
810
891
618
1,106
Serum
Uric Acid
mg./103 ml.
(mean)
9.9
10.4
5.7
6.6
5.6
8.0
7.7
_-_
WBC
x ioy
mm:’
(mean)
116
263
212
198
228
73
177
Urine
Uric Acid
mg./day
(mean)
504
511
717
500
433
341
507
Controlled
-
Serum
Uric Acid
mg./100 ml.
(mean)
WBC
x lo3/
mm.3
(mean)
7.4
7.1
4.0
5.8
3.7
5.7
5.6
39
13
5
16
15
10
16
*These values represent the mean of 8-12 consecutive days of observation during each
phase in each patient.
772
ARTHRITISAND RHEUMATISM,VOL. 8, NO.
5-PART
1 (OCTOBER), 1965
773
URIC ACID BIOSYNTHESIS IN CHRONIC LEUKEMIAS
H.J. Chronic Granulocytic Leukemia
Urine uricacid-C14
60
50
40
Cpm /c( mol
30
2 0 L
1
x10
200
--
100
Serum uric acid
l0 o c k
Urine uric
- - -
1000
Mglday
500
Days
1
6
11
16
Fig. 72.
abnormality of those individuals but was related to the activity of the hematopoietic disease in each instance.
In order to investigate the difference in uric acid production between chronic granulocytic and chronic lymphocytic leukemia, a series of isotope studies
of the type previously reported by Gutman, Yii, Wyngaarden, and others, was
carried out, in which a carbon-14-labelled purine precursor was given to
patients with each type of leukemia and incorporation of the isotope into
the urinary uric acid measured. Figure 72 represents a study performed in a
patient with chronic granulocytic leukemia in whom hyperuricemia and excessive uricosuria were present. Following the administration of sodium formate-CI4, the curve of isotope enrichment of urinary uric acid resembled those
reported by other investigators in myeloproliferative diseases who employed
g 1 y ~ i n e - Cas~ ~a tracer. There was a prominent early peak occurring two to
three days after isotope administration, and a second maximum at about 12
days. This diphasic pattern was seen in each of five cases of chronic granulocytic leukemia and in one case of myeloid metaplasia studied. The initial peak
i y thought to represent uric acid synthesized de novo without prior incorpora-
774
GOUT AND PURINE METABOLISM
J.R.. 71
Chronic Lymphocytic Leukemia
1w
Na formate C’‘
lWIlc, I V
60
40
cpmlpmol
30
20
10
Serum uricacid
mg*
0
”t
750
mg /day
r
I
Urine uric acid
0
1963
I
I
13
18
February
I
23
I
28
I
5
I
10
March
Fig. 73.
tion into nucleic acids, and the second peak to represent isotope which has
been incorporated into the leukocyte nucleic acid purines and then released
as the leukocytes degenerate. In contrast, similar studies in patients with
chronic Iymphocytic leukemia (Fig. 73) have not shown a diphasic curve. The
pattern of isotope incorporation in each of these patients closely resembled
that seen in nonleukemic subjects. There was no discernible second phase.
It was concluded that in chronic lymphocytic leukemia, in contrast to chronic
granulocytic leukemia, leukocyte “turnover” does not significantly contribute
to uric acid production.
These observations and their interpretations are consistent with data presented by Hamilton2 and others concerning the incorporation and retention
of adenine-CI4 in the nucleic acids of leukemic granulocytes and lymphocytes. In those studies it was shown that adenine was promptly incorporated
into the nucleic acids of both types of cells but that it was retained much
longer in the nucleic acids of lymphocytes than of granulocytes. This was
thought to indicate that either the leukemic lymphocyte survives much longer
than the granulocyte or that its nucleic acids are partially degraded, with
URIC ACID BIOSYNTHESIS IN CHRONIC LEUKEMIAS
775
reutilization of large polynucleotide fragments for nucleic acid synthesis.
Either mechanism could result in a failure of lymphocyte nucleic acid purines
to be degraded to uric acid, with the result that total uric acid production
would be normal. The absence of retention of C-14 adenine in the granulocyte
nucleic acid suggests that granulocyte degradation is more complete and
that this degradation accounts for the second peak of isotope enrichment
and is largely responsible for the overproduction of uric acid found in patients with chronic granulocytic leukemia. One could further extrapolate from
these data an interpretation of the failure of chronic lymphocytic leukemia
to respond to antimetabolites ( 6-mercaptopurine and methotrexate) which
are known to be inhibitors of purine biosynthesis, as contrasted with the susceptibility of chronic granulocytic leukemia. Chronic lymphocytic leukemia,
in which lymphocyte production is not dependent on de novo purine synthesis
to such a large extent, is not affected by such compounds while chronic granulocytic leukemia, which is more dependent on d e novo purine synthesis, can
be satisfactorily treated with them.
Secondary gout has not been a common problem in the management of patients with chronic granulocytic leukemia and myeloid metaplasia in our
experience. We believe that this is probably because the average survival
of patients with chronic granulocytic leukemia is slightly less than 40 months
and many of these patients therefore do not have sufficiently prolonged hyperuricemia to produce secondary gout. In contrast, patients with polycythemia
Vera, such as described by Dr. Yii, usually survive for longer periods. The incidence of secondary gout in our series of patients with chronic granulocytic
leukemia is about 6 per cent.
An additional problem that should be considered apropos of hyperuricemia
in hematopoietic diseases is uric acid nephropathy. This has been, in our experience, a much more serious clinical problem. In patients with leukemia
or lymphoma given radiotherapy or cytolytic chemicals, large amounts of
uric acid can be produced very rapidly. Figure 74 illustrates such a case, in
which marked hyperuricemia and azotemia occurred in a child with acute
lymphoblastic leukemia treated with adrenal cortical steroids. As a result
of vigorous regulation of his fluid balance, his urine volume remained adequate and he recovered; however, his survival was threatened by the renal
problem in spite of his prompt hematologic remission. We have recently
reviewed3 the experience with this problem on the Chemotherapy Service of
Memorial and James Ewing Hospitals during a five-year period in which 203
patients with all kinds of leukemia were followed to the end of their clinical
courses. Twenty-three per cent were found to have serum uric acid levels
of more than 12 mg. per cent at some time during the course of the disease.
In four patients uric acid nephropathy with urinary obstruction was a direct
or contributing cause of death. W e have attempted to cope with this problem
by cautious initiation of cytolytic therapy in patients whose disease is expected to respond rapidly, maximum administration of oral and parenteral
fluids to insure a large urine volume, administration of sodium bicarbonate
776
GOUT AND PURINE METABOLISM
J M 9 YRS d ACUTE LEUKEMIA
METICORTEN 75 MG
P
%NORMAL MYeLOlD
7'ERYTHROlD
?.STEM CELLS, LYMPHOCYTES
BONE MARROW
12
5 29
PLATELETS% POLYS-
'1
16
E
A 4
46
44
108
125
115
54
58
\.,p--.d~---."------________/*-
r
2
h
:L
!60
p
4
hb:250 CC PACKED CELLS
0
50
MG %
SERUM URIC ACID
25
0
ML 4 4 HR
3000-
70007
2400
URINARY URIC ACID
:
:
0
MG124HR
6
1800
1956
APRIL
MAY
Fig. 74.
or Diamox in an attempt to alkalinize the urine and, in a few patients, extracorporeal hemodialysis to remove uric acid from the blood in cases in which
severe, life-threatening hyperuricemia had developed. Although each of these
measures can be useful in preventing or treating uric acid nephropathy, they
are not invariably successful and the clinical situations in which they are indicated are often extremely complex. The recent availability of an effective xanthine oxidase inhibitor has added substantially to success in the management
of this problem, as discussed elsewhere.
REFERENCES
1. Krakoff, I. H., and Balis, M. E.: Abnorinalities of Purine Metabolism in Human Leukemia. Ann. N . Y. Acad. Sci.
113:1043, 1964.
2. Hamilton, L. D.: Metabolic Stability of
PNA and DNA. Human Leukemic
Leukocytes; The Function of Lymphocytes, in The Leukemim: Etiology,
Pathophysiology and Treatment. J. W.
Rebuck, F. H. Bethell, and R. W.
Monto (eds.) N. Y., Academic Press,
1957, pp. 381.
3. Krakoff, I. H., and Meyer, R. L.: Prevention of Hyperuricemia in Leukemia and Lymphoma: Use of a
Xanthine Oxidase Inhibitor, Allopurinol. J. A. M . A. 193:1, 1965.
Figs. 72 a n d 73 are reprinted from: Krakoff, I. H., a n d Balis, M. E.: Abnormalities
of Purine Metabolism in Human Leukemia. Ann. N . Y. Acad. Sci. 113:1043, 1964.
URIC ACID BIOSYNTHESIS IN CHRONIC LEUKEMIAS
777
Discussion
DR. BAUM:I would like to ask Dr. Yu and Dr. Krakoff how often clinical
onset of gout occurred prior to diagnosis of the myeloproliferative disease
in their cases. Put it another way, how often is the onset of gout an early
indication of the subsequent development of one or another form of mydoproliferative disease?
DR. Yu: Very occasionally, a patient with overt primary gout may subsequently develop one of the myeloproliferative disorders, like any one else,
but this association appears to be coincidental and we have no evidence that
primary gout should be considered premonitory to polycythemia Vera or
leukemia. There were about five of our more than 1,000 patients with primary
gout who later turned up with polycythemia Vera, the clinical onset of gout
clearly antedating the myeloproliferative disorder; these cases are excluded
from our series of secondary gout. In two further instances acute gouty
arthritis preceded recognition of polycythemia Vera but this precedence was
equivocal and these two patients are included among those with secondary
gout, perhaps erroneously. It is not uncommon to find a modest relative
polycythemia in patients with primary gout.
We have defined secondary gout as an acquired disorder but it is admittedly impossible rigorously to exclude an underlying latent gouty trait in
any one instance. As already mentioned, three of our patients classified as
secondary gout were found to have familial gout or hyperuricemia but were
nevertheless so classified because the blood disorder developed long before
any symptoms of gout appeared. Conversely, we have not encountered any
patients classified as primary gout who gave a familial history of hemopoietic
disorder.
DR.SEEGMILLER:
We have encountered several gout patients with a family
history not of gout but of one of the myeloproliferative diseases, perhaps
six or seven of 100 or so gout patients. I don’t know what this means, perhaps it is not significant.
DR.WYNGAARDEN:
I would like to ask about the purine bases, the so-called
trace purine bases in secondary gout. We studied the incorporation of glycine-N15 into purine bases in a case of myeloid metaplasia and, with Dr.
Seegmiller, in a case of leukemia. We were impressed with the appreciable
labeling of 7-methyl-8-hydroxyguanine, which is excreted in the urine in
greater than normal quantities in secondary gout. Also, I would like to ask
about the current status of 7-methyl-8-hydroxyguanine in relation to the acute
gouty attack, in which an increased excretion of this compound was described by Gutman and associates some years ago.
DR.Yu: We have studied the urinary excretion of purine bases in ten cases
of secondary gout. As reported elsewhere, there is a small but quite consistent increase in the urinary elimination of 8-hydroxy-7-methylguanine in
secondary gout, and some decrease in the excretion of hypoxanthine and
xanthine.
As to the possible relationship between 8-hydroxy-7-methylguanine and
acute gouty arthritis, some years ago we obtained a small amount of this
778
GOUT AND PURINE METABOLISM
compound and injected it into the knee joint of a patient, without inducing
any inflammatory response. This was before the effect of microcrystals was
known to us, and the material was injected in solution. We have not done
anything further along these lines.
DR. DEMARTINI:
Dr. Yii, do you know how the increased load of uric acid
is handled by the kidney in secondary gout as compared to primary gout? IS
the renal clearance of uric acid different in primary and secondary gout?
DR. Yu: We have not carried out many renal clearance measurements in
patients with secondary gout so I cannot answer this question in any detail.
As already pointed out, both plasma urate concentrations and urinary excretion of uric acid tend to be higher in secondary gout than in most patients
with primary gout. In this respect, patients with secondary gout resemble
the patient with primary gout who is an overexcretor of uric acid, and I
assume that the kidneys handle the large excess loads of uric acid in much the
same way. When the uric acid loads are inordinately high, kidney function
may deteriorate, in part because of uric acid precipitation in the urinary
tract, and the urinary excretion of uric acid decreases, hyperuricemia increases,
and the renal clearance of uric acid declines.
DR. DEMARTINI:
What I am getting at is, does the kidney in patients with
secondary gout handle the very large urate loads like that of a normal individual, or is there indication of some subtle injury to the kidney as a result
of the prolonged hyperuricemia?
DR. GUTMAN:I don’t believe there is any simple answer to your question
because the circumstances in secondary gout can be very complex and in
acute situations like that described by Dr. Krakoff the patient may be in an exceedingly unsteady state. I would picture the situation something like this.
The patient with secondary gout presumably starts with a normal kidney
which can handle any moderate degree of overproduction of uric acid in the
usual way by filtering the plasma urate at the glomerulus, reabsorbing virtually
all of moderately increased filtered urate load, and secreting more or less
urate into the tubular fluid. If overproduction of uric acid is very rapidly and
markedly increased, in response to cytolytic therapy or otherwise, the filtered
urate load may suddenly increase to proportions beyond the capacity of the
tubules to reabsorb (the reabsorptive Tm for urate), and tubular secretion
of urate presumably also increases. This may result in such an outpouring
of uric acid in the urine that precipitation occurs and kidney damage results,
in extreme cases with clcgging of the collecting tubules and ureters if large
urine volumes are not maintained. The urinary excretion of uric acid falls,
the plasma urate rises, and the renal clearance of uric acid drops.
The renal clearance of uric acid will remain unchanged if the urinary
excretion of uric acid increases in proportion to the increase in plasma urate
concentration, it will rise if the rate of increase in urinary excretion of uric
acid exceeds that in the plasma urate concentration, and will fall if the reverse
occurs. I suspect that the renal clearance of uric acid in secondary gout
may be normal, high or low, and in some cases probably all three in one or
another sequence, depending not only on the intrinsic condition of the kidneys
URIC ACID BIOSYNTHESIS IN CHRONIC LEUKEMIAS
719
but as much or more upon the rate of production of uric acid, the rate of urine
flow, and other factors.
DR. KRAKOFF:In the child I described, the serum urate rose to 52 or
54 mg. per cent and during that 24-hour period he excreted 7 Gm. of uric acid
in the urine (Fig. 74).
DR. MUDGE:The concept of Tm dies hard, Dr. Gutman, but I don’t know
what it means when a substance is transported across the tubules in both
directions. In reference to Dr. Krakoffs case, the child excreted 7 Gm. of
uric acid a day, with a plasma urate of 54 mg. per cent, and so had a uric acid
clearance of about 10 ml. per minute, which is not far from normal. I don’t
know what the glomerular filtration rate was in this child but his kidneys
were handling the huge load imposed by a plasma urate concentration of 54
mg. per cent without any evidence that a Tm had been reached.
DR. GUTMAN:I fully agree with your reactions about the validity of any
estimate of the reabsorptive Tm for urate in view of concomitant tubular
secretion of urate, and that is why we refer to it as the “apparent” reabsorptive
Tm for urate. However, I think the clearance data demonstrate that the
capacity of the tubules for reabsorption of urate in man is limited, even if
we cannot measure the limits. In Dr. Krakoffs case, I should think that such
an extraordinary renal excretion of uric acid, 7 Gm. a day, would of itself
indicate that the capacity of the tubules to reabsorb urate had been greatly
exceeded.
DR. NUGENT:Dr. Krakoff, what was the average plasma urate concentration in your group of patients with chronic granulocytic leukemia?
DR. KRAKOFF:
Before treatment it was 7.7 mg. per cent.
DR. NUGENT:That is a level commonly encountered in primary gout, and
yet what was the average urinary urate excretion per day in these patients?
DR. KRAKOFF:
About 1,100 mg. per day.
DR. DEMARTINI:In Talbott’s review of the renal pathology in gout, including secondary gout, he pointed out the prevalence of pathologic changes in
the kidney. It would seem to me that there might be some change in the
handling of urate by the kidneys in consequence of the prolonged hyperuricemia and resulting renal damage.
DR. GUTMAN:I think the point that Dr. Nugent wanted to make was that
Dr. Krakoffs data in leukemia give evidence that there is something wrong
with the kidney in primary gout. As Dr. Yii pointed out, the findings in secondary gout resemble more closely those obtained in patients with primary
gout who are habitual overexcretors of uric acid.
DR. DECKER:
I am interested in the idea that one can have an acute attack
of gout only if one has a certain genetic constitution, although the appropriate
control series has not been mentioned. It should be established whether or
not there is a family history of gout in patients with chronic granulocytic
leukemia who do not get attacks of acute gouty arthritis.
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