Medical Progress

Current Concepts of Hyperuricemia

and Gout
JAMES R. KLINENBERG, M.D., Los Angeles

* Recent studies have confirmed that gout is an inborn error of metab-

olism. It has now become evident that the hyperuricemia associated with
gout might occur either due to overproduction of uric acid, underexcre-
tion of uric acid or a combination of these processes. Furthermore, pa-
tients with excessive purine synthesis may have a specific enzyme defect
resulting in altered feedback inhibition of purine synthesis. A neuro-
logical disease manifest by mental retardation, choreo-athetosis, aggres-
sive behavior, lip-biting and self-mutilation and associated with decidedly
increased purine biosynthesis serves as a prototype of this kind of
disorder. Other defects in regulation of purine biosynthesis have been
postulated but their existence not yet confirmed.
It has been demonstrated that urate crystals which are deposited
from hyperuricemic body fluids set up an acute inflammatory reaction
by means of a variety of chemical mediators. Thus, acute gouty arthritis
is now recognized as an example of "crystal induced" synovitis.
The treatment of gout consists of (1) the control of acute gouty
attacks, and (2) the maintenance of normal serum uric acid concentra-
tions. This latter may be achieved either with uricosuric drugs or with
xanthine oxidase inhibition. With these principles in mind, it is now
possible to avoid many of the severe crippling effects of gout and to
restore the vast majority of gouty patients to useful and productive lives.

ALTHOUGH THE FIRST clinical description of gouty
arthritis is attributed to Hippocrates, it has been
only during the past decade that concepts regarding
the pathogenesis of hyperuricemia and its relation-
ship to gout have been firmly established. Scheele
in 1776 isolated uric acid from a urinary calculus
The author is Assistant Professor of Medicine at UCLA School of
Medicine, Los Angeles.
This work partially supported by U.S.P.H.S. Grant #GM15759.
Reprint requests to: Institute of Chronic Diseases and Rehabilitation,
1000 Veteran Avenue, Los Angeles 90024.
and in 1797 Wollaston demonstrated that gouty
tophi contain uric acid. Garrod, in 1876, using
crude methods, demonstrated that the blood of
gouty patients contained excessive quantities of
uric acid and subsequently it was shown that hyper-
uricemia was also present in the normal relatives
of gouty patients. The younger Garrod in 19311
classified gout as "an inborn error of metabolism"
but noted that no enzyme deficiency characteristic
of this disease had been found. During the past

CALIFORNIA MEDICINE 231

decade, however, investigators have provided evi-
dence for a variety of biochemical and physical
abnormalities that result in hyperuricemia. Fur-
thermore, experimental findings during this period
have also provided a framework for the construc-
tion of an hypothesis for the mechanisms of the
crystal induced synovitis of acute gout. These
recent developments and concepts will be reviewed.
Biochemistry of Uric Acid
Properties of Uric Acid
Uric acid (2, 6, 8 trioxypurine) is weakly acidic
due to ionization of the hydrogen atoms at position
9 (pKa=5.75) and 3 (pKa-10.3) while the
hydrogen atoms at positions 1 and 7 do not ionize
significantly. Thus at physiologic pH (7.4) uric
acid exists almost entirely in the salt form as a
monovalent urate ion.2 Therefore urate is deposited
in tophi as monosodium urate monohydrate3 while
due to the more acidic nature of urine, renal calculi
are in the form of undissociated uric acid. Uric
acid readily forms supersaturated solutions both
in plasma and protein free buffer systems.4 This
phenomenon greatly hampers the ability to accu-
rately determine solubility of urate in biological
fluids.
Uric Acid Assay
The colorimetric assays for urate frequently
used in routine clinical laboratories depend upon
the ability of urate to reduce a reagent such as
phosphotungstic acid to a chromagen.5 Since non-
urate metabolites of methylated purines (for exam-
ple, caffeine or theophylline) and the other oxy-
purines (that is, hypoxanthine and xanthine) also
reduce phosphotungstic acid, the use of colori-
metric assays may give spuriously elevated values
in patients ingesting caffeinated beverages, the-
ophylline drugs or the xanthine oxidase inhibitor
ailopurinol. Another error inherent in colorimetric
procedures for measuring uric acid results from
the need to deproteinize serum with the consequent
coprecipitation of some uric acid.
An enzymatic spectrophotometric method for
measuring urate concentration6 eliminates these
errors. Uric acid may be measured directly in
whole serum by determining the absorbancy at
292 mu at pH 9.4 before and after reaction with
the highly specific enzyme uricase which is capable
of converting all the uric acid present to allantoin
and co2. This technique is sufficiently sensitive
232 MARCH 1969 * I 10 * 3
to detect microgram quantities of urate with an
accuracy of 2 percent. A modification of this
method for the determination of total oxypurines in
urine and plasma7 has recently been described.
During the past few years multichannel auto-
analyzers have been adapted to determine serum
urate by colorimetric techniques,8 thus allowing
hundreds of determinations to be performed daily
with a high degree of accuracy. Because such
multiphasic screening programs are in use in our
hospitals and clinics today, a great number of pa-
tients with unsuspected hyperuricemia are being
detected. The significance of such hyperuricemia
and an approach to this problem will be discussed
subsequently.
Purine Metabolism
Uric acid is truly the end product of purine
metabolism in man since through the process of
evolution there has been loss of the enzyme uricase
which is capable of catalyzing the further metab-
olism of uric acid to allantoin and Co2. Hyper-
uricemia, therefore may result from either in-
creased absorption of precursor purines, increased
production, decreased excretion or decreased
breakdown of uric acid or from some combination
of these mechanisms.
Since a purine-free diet results in an average
reduction of serum urate of only 1 mg per 100 m19
in gouty subjects and does not correct hyperurice-
mia, it is clear that the hyperuricemia of gout
cannot be attributed to abnormal absorption of
precursor purines. It is likely, however, that an
increased purine load may serve as a mechanism
for the secondary hyperuricemia seen in patients
with lymphoproliferative disorders with a rapid
turnover of tumor cellsI0 or with psoriasis where
there is a rapid turnover of the skin.11
Uricolysis in man occurs almost entirely by ac-
tion of intestinal flora upon uric acid entering the
gastrointestinal tract.'2 There is no evidence that
uricolysis is diminished in patients with gout and,
in fact, Sorenson'3 has demonstrated that in gouty
patients with reduced renal excretion of uric acid,
extra-renal disposal may constitute the chief excre-
tory mechanism for uric acid. There is, however,
considerable evidence that both increased produc-
tion of uric acid and reduced renal excretion of
uric acid play important roles in the pathogenesis
of hyperuricemia, both in primary gout and in
hyperuricemia secondary to other causes.
 Increased Production of Uric
Acid Associated with Gout
Evaluation of Uric Acid Synthesis
Uric acid is the end-product of purine metab-
olism. Therefore, in the steady state when urate is
not being deposited or mobilized, urate production
is approximately equal to uric acid excretion. Un-
der the standard basal conditions of a purine-free
diet and no medications, the consistent daily urinary
excretion of more than 600 mg of uric acid there-
fore is a good indication that a patient has increased
uric acid production. Approximately 25 percent
of gouty patients show such an excess in urinary
uric acid excretion. This indirect measurement,
however, does not adequately reflect uric acid
synthesis in patients with impaired renal function.
Uric acid production may be directly assessed by
measuring the incorporation of isotopically labelled
glycine into urinary uric acid and correcting such
data for the disposition of the body urate pool as
determined by simultaneous administration of iso-
topically labelled uric acid. By these techniques
Seegmiller and coworkers9 found that 67 percent
of patients with primary gout had increased uric
acid synthesis. Furthermore careful evaluation of
studies using isotopically labeled compounds has
supplied experimental evidence suggesting that
among gouty patients there is no single metabolic
defect in purine metabolism to account for the
hyperuricemia.2
Control of Purine Biosynthesis
It has long been proposed that among gouty
patients who overproduce uric acid there may be
a defect in the feedback control of purine biosyn-
thesis.2 Feedback control of purine biosynthesis
would be expected to be exerted on the first irre-
versible step of purine biosynthesis-that is, the
enzymatic reaction of glutamine with 5 phospho-
ribosyl-l-pyrophosphate (PRPP) to form 5 phos-
phoribosylamine (Chart 1). Suppression of purine
biosynthesis by the addition of preformed purines
either as free bases or ribonucleotides has been
demonstrated in cultured mammalian cells,14"l5
bacterial systems'6 and in liver slices.'7"18 An in-
creased rate of purine biosynthesis thus could re-
sult from a loss of the sensitivity of the rate con-
trolling enzymes to feedback inhibitors, from a
diminished concentration of the normal end prod-
ucts that function as feedback inhibitors, or from
an increase in concentration of one of the sub-
strates available for the rate limiting reaction.
The first evidence of a regulatory mechanism for
control of purine biosynthesis in man came from
studies using the purine precursor 4-amino-5-
imidazole carboxamide (AIC). Administration of
this compound to non-gouty subjects substantially
reduced de novo uric acid synthesis.'9 Subsequent-
ly the drug 6-diazo-5-oxy-l-norleucine (DON)
was also shown to suppress purine biosynthesis in
gouty subjects.20 Toxic side effects, however, have
precluded the clinical use of these compounds.
Recently there have been exciting new develop-
ments in this area. In 1966 Sorenson2' found that
administration of the purine analog azathioprine
(Imuran®g) to three gouty patients inhibited their
excessive purine synthesis, as measured by a de-
crease in the uric acid content of plasma and urine
as well as the glycine-l-C'4 incorporation into uri-
nary uric acid. Two normal subjects and one gout
patient who produced normal quantities of uric
acid showed no significant suppression of urate
production in response to azathioprine treatment.
Sorenson therefore proposed that azathioprine pro-
duced a unique effect in gouty patients who were
overproducers of uric acid, thus implying that the
regulation of purine synthesis may differ in different
types of gout.
Lesch and Nyhan in 1964 at the Johns Hopkins
Hospital first described a familial neurological dis-
order consisting of choreoathetosis, spasticity, men-
tal retardation, aggressive behavior and compulsive
biting resulting in mutilation of the lips and fin-
gers.22 These findings in two young brothers were
associated with hyperuricemia, urinary uric acid
excretion which was three to six times normal and
incorporation of from 100 to 200 times the normal
amount of glycine-l-C'4 into urinary uric acid.
Numerous other cases have subsequently been
described, limited to males and with a striking
familial distribution compatible with x-linked
inheritance.23 Although the degree of overproduc-
tion of uric acid found in children with the Lesch-
Nyhan syndrome was greatly in excess of that
encountered in adults with clinical gout, gouty
arthritis has remained a relatively late occurrence
in these children. Gouty nephropathy, however,
was a contributing factor to the death of some of
these patients in early puberty.24
Because of the pronounced excess of uric acid
produced by these children, Seegmiller and co-
workers25 compared the effect of azathioprine in
two children with Lesch-Nyhan syndrome and
two gouty men who were also overproducers of
CALIFORNIA MEDICINE 233
uric acid. They found that azathioprine suppressed
purine synthesis in the two gout patients but did
not diminish it in the children. Since the pharma-
cologic action of azathioprine probably results
from its degradation to 6-mercaptopurine (6MP)
the effect of 6MP on the purine synthesis of fibro-
blasts grown in vitro from biopsy specimens of skin
obtained from a child with the Lesch-Nyhan syn-
drome was compared with its effect on cells grown
from normal subjects. It was found that 6MP great-
ly inhibited purine biosynthesis in normal cells
but had no effect on cells derived from the child
with the neurological disorder. Resistance to the
action of 6MP had previously been described in
mutant mammalian tumor cells26 and leukemic
leukocytes,27 and this phenomenon was ascribed
to a deficiency of the enzyme hypoxanthine-gua-
nine phosphoribosyl transferase (HGPRTase).
Therefore, Seegmiller examined the activity of this
enzyme in the fibroblasts grown in vitro as well as
in hemolysates of washed erythrocytes and found
that the enzyme activity from cells of affected
children was less than 0.05 percent of normal.25
It was thus enticing to attempt to explain both
the neurological disease and the increased purine
synthesis on the basis of this enzyme defect.
Rosenbloom and coworkers28 demonstrated HG-
PRTase deficiency in the brain and liver as well as
fibroblasts and erythrocytes of these affected chil-
dren. They noted that the absence of this enzyme
activity in the basal ganglia where it is normally
of highest activity could be correlated with the
fact that the major clinical symptoms are attribut-
able to basal ganglia dysfunction. It was also ob-
served that the concentration of oxypurines in the
cerebrospinal fluid (CSF) was four times normal
and was greater than in the plasma, thus suggesting
that the brain also had an increase in purine
synthesis. No detectable increase in CSF uric acid
concentration was noted. Thus the neurological
dysfunction could be secondary to increased con-
centration of oxypurines or other metabolites of
enhanced purine biosynthesis or possibly due to
a failure to maintain adequate intracellular con-
centration of certain purine nucleotides necessary
for normal brain function.
The existence of a causal relationship between
the deficiency in HGPRTase and accelerated
purine biosynthesis is suggested by the following
evidence: (a) there is an inverse relationship be-
tween the degree of enzyme deficiency and the
rate of purine biosynthesis,25'29 (b) both the en-
234 MARCH 1969 * 10 * 3
zyme deficiency and either the neurological disease
of children or the gouty arthritis in appropriate
kindreds are inherited in an x-linked manner,23,30
(c) all patents with HGPRTase deficiency to date
have been shown to have accelarated purine bio-
synthesis.
This relationship between HGPRTase deficiency
and accelerated purine biosynthesis was studied in
detail, using fibroblast cultures.31 Lack of HGPRT-
ase had no detrimental effect on the rate of growth
of the fibroblasts. The enzyme deficient fibroblasts
had accelerated rates of purine biosynthesis and
elevated levels of PRPP, although the rate of syn-
thesis of this compound was not increased. These
cells were sensitive to feedback inhibition of purine
synthesis by nucleotides of adenine and 6 methyl-
mercaptopurine ribonucleoside but the rate of
purine synthesis was increased rather than de-
creased by hypoxanthine and guanine. Based on
these studies it was concluded that the acceleration
of purine biosynthesis is probably due to an in-
crease in the activity of phosphoribosyl pyrophos-
phate glutamine amidotransferase, the enzyme cat-
alyzing the first irreversible step of purine biosyn-
thesis (Chart 1).
PRPP + Glutamine
,- _ N
, 5-Phosphoribosyl-l-Amine "
/ \ C Glycine
I
'
FGAR
Guanylic - iosiuic Acid * Adenylic
Acid Acid
Guanosine Inosine -Adenosine
jK (HGPRTase Adenine
Guanine'R aypoxanthine
Xanthine
Uric Acid
PRPP ....phosphoribosyl pyrophosphate
FGAR . ...formyl glycinamide ribonucleotide
HGPRTase . hypoxanthine - guanine phosphoribosyltransferase
indicates inhibition
Chart 1.-Pathways of purine metabolism. The first ir-
reversible step of purine biosynthesis, PRPP + gluta-
mine, is catalyzed by phosphoribosyl pyrophosphate glu-
tamine amidotransferase.
Abnormalities of Purine Biosynthesis heterogeneity of the causes of hyperuricemia, even
In Patients with Gout in patients with gout and excessive purine biosyn-
In addition to the complete deficiency of HGP- thesis and suggest that only within given families
RTase described in patients with the Lesch-Nyhan may common causes for hyperuricemia be found.
syndrome, Kelly and coworkers described a partial Numerous investigations are under way in an at-
deficiency of this enzyme in five affected members tempt to delineate additional specific defects in
of two families with gout.29'32 Ten other gouty purine metabolism in patients with increased uric
patients with excessive purine biosynthesis simi- acid production.
larly studied had normal concentrations of this
enzyme.29 These patients with gout and a partial Renal Excretion of Uric Acid
enzyme deficiency not only had some residual A diminished renal excretion of uric acid in
enzyme activity but also showed different amounts gouty patients was suggested as a possible cause
of activity depending upon whether hypoxanthine of hyperuricemia nearly a century ago. Gutman
or guanine served as the substrate, suggesting that and Yii4 failed to show significant differences in the
the HGPRTase which is present in these patients urate/inulin clearance ratios between normal and
may be structurally different from both the normal gouty subjects. Nugent and Tyler,42 however,
enzyme and from other affected patients. Other showed that six gouty subjects had urate/inulin
instances of partial deficiencies of HGPRTase in clearance ratios significantly lower than those of
patients with gout and minimal neurological ab- normal subjects made comparably hyperuricemic
normality have been reported33 including a 21- with a high purine diet. This finding was confirmed
year-old man who had onset of gout at age 15 and by Seegmiller and coworkers,43 who found a
has very low residual HGPRTase activity but diminished urate/inulin clearance ratio in all five
nevertheless has only a minimal neurological deficit gouty subjects who showed normal uric acid pro-
and had no evidence of self-mutilation.34 duction, while among patients who produced ex-
The demonstration of an enzyme defect in cessive amounts of uric acid the urate/inulin clear-
patients with primary gout and excessive purine ance ratios were identical with those of normal
synthesis has indeed confirmed Garrod's original control subjects in whom hyperuricemia was in-
proposal that gout is "an inborn error of metab- duced by dietary means. Other gouty patients
olism."' Furthermore it affords a possible explana- showed some degree of both overproduction and
tion as to why these patients have excessive purine diminished renal excretion of uric acid, again sug-
biosynthesis35 and abnormal resistance to the sup- gesting the heterogeneity of causes for hyperurice-
pressive effects of azathioprine36 and allopurinol37 mia among gouty patients. Diminution in renal
on purine production. However, this single enzyme clearance of uric acid may be produced by a
defect occurs in less than 30 percent of patients variety of chemical substances and drugs. It may
with primary gout and excessive purine synthesis account for the hyperuricemia seen after the in-
and therefore different metabolic defects are prob- gestion of low doses of salicylates,44 chlorothia-
ably present in these other patients. Rosenbloom zides45'46 or an association with the lactic acidemia
and coworkers38 recently demonstrated decreased of glycogen storage disease47 or the ketoacidosis of
sensitivity to feedback inhibition of purine biosyn- diabetes mellitus or starvation.48
thesis in cultured fibroblasts from two patients with The mechanism for the excretion of uric acid by
increased purine production and normal HGPRT- the kidney was originally thought to consist of
ase concentrations. They suggested that the first complete filtration of uric acid at the glomerulus
enzyme of the de novo purine pathway, 5-phos- followed by tubular reabsorption of 90 to 95 per-
phoribosyl-1-pyrophosphate glutamine amidotrans- cent of the filtered load4l without appreciable
ferase (Chart 1), may be abnormal in the gouty tubular secretion. However, evidence for tubular
patients and thus less sensitive to feedback inhibi- secretion of uric acid now includes: (a) studies of
tion.39 However, Seegmiller and coworkers,40 a patient with hypouricemia in whom urate/inulin
studying similar patients, found normal suppression clearance ratios exceed 1: 1,49 (b) induction of
of glycine-l-C'4 incorporation into urinary uric clearance ratios of urate to insulin greater than 1:1
acid following adenine administration, thus sug- by administration of uricosuric drugs during man-
gesting that feedback inhibition is intact. These in- nitol diuresis,50 (c) the paradoxical effects of
vestigations all provide additional evidence for salicylates which causes urate retention when given
CALIFORNIA MEDICINE 235
in low doses (attributed to inhibition of tubular
secretion) and uricosuria when given at high doses
(attributed to inhibition of tubular reabsorption).44
Tubular secretion has also been shown to play
a role in the renal excretion of the oxypurines
(hypoxanthine and xanthine).51 Although the
exact sites of tubular secretion have not been
elucidated there is at least some indirect evidence
for competition between uric acid and oxypurines
for renal tubular secretion.51'52
Thus, it is currently believed that uric acid is
filtered at the glomerulus, and that the filtered uric
acid is completely reabsorbed in the proximal
tubules and that excreted uric acid is the result al-
most entirely of a tubular secretory process. This
concept presumes that urate is entirely filterable
and therefore not bound to protein. Evidence sug-
gesting that there may, in fact, be some binding
of urate to proteins, as discussed below, may neces-
sitate additional alterations in our concept of the
mechanisms of renal excretion of uric acid.
Acute Gouty Arthritis
The Inflammatory Reaction
Recent concepts of the mechanisms responsible
for attacks of acute gouty arthritis really represent
rediscoveries of early hypotheses proposed by
Garrod,53 Freudweiler54 and Roberts.55 Garrod
considered acute gouty arthritis to be an inflam-
matory reaction to crystals of sodium urate de-
posited from hyperuricemic body fluids in and
about the joints during an acute attack. However,
evidence against Garrod's proposals included:
(a) the reported failure of injected urate to give
rise to an inflammatory response, (b) the general-
ly painless nature of tophi which were shown to
be deposits of urate crystals, (c) the poor correla-
tion between acute attacks of gout and the serum
urate concentration, and (d) the paradox whereby
colchicine, which has a remarkable therapeutic
effect on acute gouty arthritis, does not alter the
serum urate concentration while uricosuric agents,
which lower the serum urate may, in fact, trigger
acute gouty attacks. Therefore this hypothesis was
abandoned, even after Roberts in 189255 found
that synovial fluid obtained from patients with
acute gouty arthritis was "laden with crystals of
sodium biurate."
The above concepts were reassessed beginning
in 1961 when McCarty and Hollander56 again
identified urate crystals in gouty synovial fluid.
Additional evidence was obtained when Seegmiller
236 MARCH 1969 * 110 * 3
and coworkers57 showed that intra-articular injec-
tions of microcrystalline monosodium urate mono-
hydrate in gouty and non-gouty volunteers pro-
duced warmth, swelling and pain indistinguishable
from the signs and symptoms of acute gout. Similar
injections of an amorphous urate suspension pro-
duced little reaction. Independently, Faires and
McCarty58 confirmed this work and also produced
synovitis in dogs with intra-articular urate injec-
tions.
Based on these experimental findings, Seegmilier
and Howell59 proposed the following mechanism
for the development of acute gouty arthritis: (a)
there is intra-articular deposition of microcrystal-
line monosodium urate monohydrate from hyper-
uricemic body fluids, (b) there develops an acute
inflammatory reaction to the crystals with local
infiltration, predominately by granulocytes, which
phagocytize the urate crystals, (c) propagation of
the acute inflammatory reaction by continued in-
troduction of new crystals possibly due in part to
alterations in local factors (such as decreasing pH)
with further decrease in urate solubility.
Urate Deposition
A key point in this hypothesis is the deposition
of urate crystals from hyperuricemic body fluids
and therefore there has been considerable interest
in factors that might be responsible for urate depo-
sition. Since physical chemical properties are of
great importance we studied the solubility of uric
acid and sodium urate in serum.4 When uric acid
rather than sodium urate is incubated with serum
for one hour and the excess crystals then removed
by passing the serum through a millipore filter of
0.22 mu, it was found that a urate concentration
in the filtrate of approximately 400 mg per 100 ml
could be achieved. Immediately after filtration
there was spontaneous crystallization of monoso-
dium urate monohydrate from the supersaturated
solution. Concentrations of urate in solution
diminished rapidly at first and then more slowly,
reaching an ultimate concentration of 8.5 mg per
100 ml after about three days' incubation. With
lower concentrations 'of uric acid in the serum there
was greater stability of these supersaturated solu-
tions such that at urate concentrations of approx-
imately 50 mg per 100 ml the solutions would be
stable for as long as four days without evidence of
spontaneous crystal formation. Only when crystals
of sodium urate were added to seed the system was
there precipitation. Therefore we explored the
possibility that sodium urate may exist in super-
saturated solutions in the range of serum urate con-
centrations commonly encountered in clinical prac-
tice. Serum obtained from gouty and non-gouty
subjects was incubated with crystals of monoso-
dium urate. After two hours' incubation the
crystals were filtered off and the concentration of
urate in the solution was determined. At initial
serum urate values of less than 7 mg per 100 ml,
sodium urate went into solution, while at initial
values greater than this, urate precipitated from
solution during the incubation period. This pro-
vided an in vitro model of the deposition of
tophaceous deposits at high serum urate levels
and the resolution at low serum urate concentra-
tions. It further illustrated the central importance
of bringing the serum urate concentration of a
gouty patient into the normal range for effective
management of their disease. It also allowed
some speculation that one of the essential differ-
ences between the gouty patient and his equally
hyperuricemic brother could be the chance forma-
tion of the first crystal of sodium urate.
Urate Binding to Plasma Proteins
In addition to the primarily physical chemical
considerations there has also been increasing in-
terest that other factors might be responsible for
increased uric acid deposition seen in patients with
gouty arthritis. It has been noted, for example,
that in certain conditions associated with extremely
high serum urate concentrations, such as lympho-
proliferative disorders and chronic renal disease,
acute gouty attacks are infrequent, while patients
with primary gout have only modest elevations of
the serum urate. This might then suggest other
factors, peculiar to patients with gout, that would
afford an increased propensity to urate deposition.
One prime possibility is that urate in biological
fluids exists in combination with other substances
which might help to solubilize the urate.
The possibility that urate is bound to plasma pro-
teins has been extensively investigated in the past
with conflicting results. Recently, however, Alvs-
aker, using the methods of gel filtration and im-
munoelectrophoresis followed by autoradiography,
demonstrated a reversible interaction between urate
and albumin,60 low density beta lipoprotein, beta
2-macroglobulin and an alpha 1-alpha 2 globulin.61
Furthermore, he noted the absence of this alpha
1-alpha 2 globulin in seven out of eight patients
with primary gout. He therefore concluded that
the alpha 1-alpha 2 globulin serves as a specific
transport protein for uric acid in blood, is absent
in patients with primary gout, and is in some way
associated with the pathogenesis of this disease.
Subsequently, Alvsaker noted that low concentra-
tions of this urate-binding protein are present in
gouty patients and has suggested genetic control
over the concentrations of this protein.62 Using the
method of equilibrium dialysis, we have been able
to confirm a decreased binding of uric acid to
plasma proteins in three patients with severe topha-
ceous gout.63 We have found normal uric acid
binding in plasma from patients with non-topha-
ceous gout, asymptomatic hyperuricemia, and sec-
ondary hyperuricemia. Urate binding to plasma
proteins was also significantly decreased by sali-
cylates. Effects of other drugs on this phenome-
non are being investigated. Katz and Ehrlich64
recently isolated from serum an acid mucopoly-
saccharide which may be bound to alpha or beta
globulin and which has the ability to significantly
increase the solubility of urate and to prevent uric
acid crystallization. The possible significance of
this substance in the pathogenesis of acute gout has
not yet been determined.
Chemical Mediators of Inflammation
According to the unitary concept of gout previ-
ously described, deposition of crystals of sodium
urate are involved, not only in tophaceous aspects
of the disease, but also in the pathogenesis of the
acute gouty attack. A possible relation between
urate crystal deposition and chemical mediators
of inflammation has therefore been intensively
evaluated. During the past few years, there has
been considerable evidence that a group of vaso-
active polypeptides called kinins are mediators of
a wide variety of inflammatory reactions. Melmon
and coworkers65 demonstrated that very small
quantities of purified bradykinin injected intra-
articularly in dogs produced signs of inflammation
within 20 minutes. This effect could be completely
abolished by injection of carboxypeptidase, an en-
zyme capable of destroying bradykinin, immediate-
ly after the bradykinin injection. Significantly
elevated kinin concentrations were also found in
synovial fluid obtained from the knee joints of
patients with spontaneous gouty arthritis, synovitis
induced by injection of microcrystalline sodium
urate and patients with other types of acute inflam-
matory synovitis. Thus, it has been concluded that
kininR may be mediators of some of the inflamma-
tory synovial reactions, not only in gouty arthritis,
but in some other forms of arthritis as well.
CALIFORNIA MEDICINE 237
 Kellermeyer66 showed that Hageman factor, a
plasma protein which serves as the initial compo-
nent of the intrinsic blood clotting mechanism, as
well as the initiator of a series of reactions relating
to mediation of inflammation, is activated by urate
crystals. He therefore proposed that when a suf-
ficient number of urate crystals are present within
the joint space, Hageman factor is activated to a
level adequate to initiate the formation of inflam-
matory mediators-that is, permeability factor,
kallikrein, and kinin-like substances. These in-
flammatory mediators increase capillary permeabil-
ity and induce margination of leukocytes along
venular walls and emigration into the synovial
space. The leukocytes then phagocytize the urate
crystals. During the process of phagocytosis, the
leukocytes may enhance the inflammatory response
by producing additional inflammatory mediators.
On this basis it has been proposed that there are
two major components for the inflammatory mech-
anism of acute gouty arthritis: (a) activation of
Hageman factor by urate crystals which, in turn,
enhances the accumulation of leukocytes in the
joint space and (b) prolongation and accentuation
of the inflammatory process by the accumulated
leukocytes.
The current status of the role of chemical me-
diators in the inflammatory reaction associated
with gout has been summarized as follows67: Kinins
are present in the synovial fluid of the inflamed
gouty joint in concentrations which are biologically
effective. They may be formed by an established
action of monosodium urate crystals on Hageman
factor and also possibly by various modes depend-
ent on leukocytes. The finding that arthritis in-
duced by urate crystals may develop and persist
in the presence of high concentrations of kinin-
destroying carboxypeptidase suggests that other
pathogenetic factors are important, but it does not
exclude the possibility that the kinin-forming sys-
tem also plays a role. In gout, the crystals deposit-
ed in synovial tissues may induce kinin formation
in the interstitial fluid where the kinins will be
relatively protected from destroying enzymes and
in a particularly good position to cause pain and
vascular changes. Furthermore, kinin-forming en-
zymes and similar proteases may also attack tissues,
not only through the release of kinins, but also by
direct action. These actions would not be affected
directly by kinin-destroying enzymes. This kinin-
forming system is, then, one of the mechanisms
through which urate and other microcrystals might
238 MARCH 1969 * 110 * 3
produce synovitis. Other pathogenetic processes
independent of kinin formation undoubtedly also
contribute to this reaction.
The Treatment of Gout
Colchicine was first used for "rheumatism" in
the 6th century A.D. but it was not until the 18th
century that it was found to be quite specific for
acute attacks of gouty arthritis. Nevertheless, for
many centuries colchicine shared its popularity
for the treatment of gout with many herbs, medical
concoctions, mechanical devices, ointments, coun-
ter-irritants, acupuncture, blood-letting and gal-
vanic current. Our new concepts regarding mech-
anisms of hyperuricemia and the pathophysiology
of acute gouty arthritis have made it possible to
consider treatment of gout on a more rational basis.
The management of a patient with gout requires
from the outset that two aspects be considered
independently: One is the acute attack of gouty
arthritis; the other is hyperuricemia with possible
tophaceous deposits, renal calculi or renal insuffi-
ciency. Clearly this point cannot be overempha-
sized since the approach to each is entirely differ-
ent; the drugs utilized are different and therapy
aimed at one phase may, in fact, exacerbate the
other. Undoubtedly, the failure to understand these
basic tenets caused much of the early confusion
surrounding the pathogenesis of gout, since it
seemed difficult to implicate an abnormality related
to uric acid as the cause of gout when colchicine,
the most specific therapeutic agent for gout, did
not alter the serum urate concentration, and urico-
suric agents which did lower the serum urate did
not relieve attacks of gout and, in fact, often
worsened the attacks. Our current understanding
of the pathogenesis of gout has resolved these para-
doxes.
Management of Acute Gouty Arthritis
Colchicine remains the most specific and most
valuable drug for an acute attack of gout. For
the fully developed acute attack, one tablet (0.6
mg) of colchicine should be given every hour,
either until the patient experiences relief of pain or
side effects such as nausea or diarrhea develop,
but probably no more than 12 tablets should be
given for any single attack. Colchicine may also
be administered intravenously (2 mg colchicine
diluted with normal saline solution to a total vol-
ume of 20 ml and injected slowly intravenously
over a 5-minute period) and produce a more
prompt and effective response, with fewer gastro-
intestinal side effects. No more than 5 mg of col-
chicine should be given intravenously during a
24-hour period. Patients with renal insufficiency
should be given even smaller doses, for they ex-
crete colchicine very slowly.
The mechanism of action of colchicine in pa-
tients with acute gouty arthritis is still not entirely
clear. Seegmiller and coworkers proposed68.69 that
colchicine has its effect on white cell metabolism,
since they demonstrated that colchicine diminished
the metabolic activity of leukocytes during phago-
cytosis. They suggested that colchicine's action in
acute gouty arthritis is mediated through inter-
ference with lactic acid production by phagocytes,
thus preventing a significant pH gradient and in-
hibiting the reseeding of urate crystals necessary
for continuation of gouty inflammation. Wallace,70
however, using an in vitro system, demonstrated
that trimethylcolchicine acid, an analogue of col-
chicine with approximately equal efficacy to the
parent compound in the treatment of acute gout,
has no effect on acid production by leukocytes.
Thus, by inference, he argued that this cannot be
the mechanism of action for colchicine. Suggested
mechanisms include: That colchicine may inhibit
chemotaxis of normal polymorphonuclear leuko-
cytes71,72; that colchicine interferes with leukocyte
migration by inhibiting ameboid motility73; and
that colchicine interferes with the process by which
phagosomes fuse with lysosomal membranes.74'75
Although Weissmann has proposed that most anti-
inflammatory drugs act by stabilization of lyso-
somes, there is no evidence that colchicine has any
direct effect on isolated lysosomes.76 All of these
proposals may be partially correct and each could
explain the effect of colchicine relative to the hy-
pothesis for crystal induced synovitis which has
been reviewed.
F.or patients intolerant or unresponsive to col-
chicine, the use of indomethacin (IndocinQ) in
doses of 50 mg three times daily for four to seven
days is recommended. This therapy has been
found to be quite effective and free from major
toxicity.77 Neither colchicine nor indomethacin
have any significant effect on the serum uric acid
concentration. Probenecid, however, has been
shown to decrease the renal excretion of indo-
methacin,78 and therefore special attention must be
paid to potential toxicity when these drugs are used
in combination.
Phenylbutazone (Butazolidin®) remains an ef-
fective anti-inflammatory and analgesic drug
which, although not specific is still of considerable
value in the management of acute gout. The dosage
is 200 mg four times daily for two to three days,
with gradual tapering over the next two to three
days. Kuzell79 has reported 93 percent major im-
provement in patients with acute gout receiving
phenylbutazone. In one double blind crossover
trial80 600 mg of phenylbutazone was found to be
more effective than 100 mg of indomethacin for
the treatment of acute gout. Although the toxic
effects of phenylbutazone are minimal in the short
term use of this agent for acute gout, potentially
serious toxicity, such as bone marrow depression,
forces even the staunchest advocates to advise
caution in its long term use for this disorder. In
addition to its anti-inflammatory properties,
phenylbutazone is also a uricosuric agent, a fact
which must be kept in mind whenever balance
studies are being done on patients receiving this
drug.
Oxyphenbutazone (Tandearil®) is a closely re-
lated compound with similar anti-inflammatory,
but no uricosuric properties. It is administered in
initial doses of 400 mg with maintenance of 100
mg every four hours for a period of about four
days.
There is no indication for the use of systemic
corticosteroids in the management of gout. ACTH
is occasionally used for very severe attacks of gout
when all other agents have failed or if the patient
is intolerant to all other agents.
Treatment of Hyperuricemia
In Patients with Gout
Despite the fact that it has been shown that the
hyperuricemia associated with gout might arise
from a variety of causes, it seems quite clear that
the hyperuricemia of gout still provides an accept-
able explanation of the development of tophaceous
deposits. It is also a source of hyperuricemic body
fluids from which crystals may precipitate to bring
about an attack of acute gouty arthritis as discussed
previously. This, in essence, is the basis for the
treatment of hyperuricemia. Today, with adequate
means available for diagnosing hyperuricemia in
gout and with potent drugs available to decrease
the serum urate concentration, there is no longer
any excuse for the development of progressive to-
phaceous gout.
Therapy aimed at lowering the serum urate con-
centration is indicated in any of the following
CALIFORNIA MEDICINE 239
conditions: ( 1 ) presence of tophaceous deposits as
noted either on physical or roentgenological exam-
ination; (2) serum urate concentration which is
consistently 1 to 1.5 mg per 100 ml above normal
in a patient with gouty arthritis; (3) persistence of
joint symptoms despite a modest increase in the
serum urate concentration.
There are now two types of therapy available
to decrease the serum urate concentration; the
first is uricosuric therapy which has, until recently,
been the only kind of therapy available; second, a
newer kind of treatment involves the use of an
enzyme inhibitor to block uric acid production.
The objective of uricosuric therapy is to increase
the renal excretion of uric acid and thereby reduce
the serum urate concentration to normal.8' Fre-
quent determination of the serum urate concentra-
tion is essential, as this is the only guide to effective
management. To avoid the sudden exposure of the
kidney to large quantities of uric acid and to pre-
vent precipitation of an acute attack of gouty
arthritis, uricosuric drugs should be started at low
doses and gradually increased over a period of
seven to ten days.
Probenecid (Benemid®) has been available for
clinical use since 1950, and has proved to be a
very effective uricosuric agent in most patients
with gout.82 83 With 1 gin daily dosage, there is a
mean increase of approximately 50 percent in the
renal excretion of uric acid in gouty subjects and
a mean fall of about one-third of the serum urate
concentration. Because the biological half-life of
probenecid in man is six to twelve hours, it is ad-
visable to administer this drug in divided doses.
Maximum recommended daily dosage is 3 gm.
In instances where toxicity occurs with pro-
benecid, or if this drug is ineffective, then the
administration of sulfinpyrazone (Anturan@) is
suggested. This phenylbutazone derivative has
potent uricosuric but no anti-inflammatory proper-
ties. When given to gouty subjects in daily dosage
of 800 mg, it will almost double the 24-hour uri-
nary output of uric acid, with reduction of the
serum urate to about half the initial concentra-
tion.83 Again, the dosage of the drug should be
increased until the desired serum urate concentra-
tion is achieved, the maximum dosage being 800
mg daily in divided doses.
Both probenecid and sulfinpyrazone have rela-
tively few side effects and are usually well tolerated.
The most common adverse reaction is gastric in-
tolerance, although drug fever and drug rashes are
240 MARCH 1969 * 110 * 3
occasionally encountered. Concomitant adminis-
tration of salicylates in any dosage nullifies the uri-
cosuric effect on both of these agents. Acetamino-
phen (Tylenolg) has no effect on the serum urate
concentration and may be used as an analgesic or
antipyretic in patients with hyperuricemia even
when they are taking uricosuric drugs.
Allopurinol in the Treatment of Gout
For many years it has been felt that the most
rational approach to the therapy of hyperuricemia
would be to inhibit uric acid production, rather
than to increase urate excretion. Attempts to find
such a drug, however, resulted only in substances
which were too toxic for human use. Recently,
however, Elion, Hitchings and their colleagues84
investigated allopurinol (4-hydroxy pyrazolo py-
rimidine) in relation to the metabolic inactivation
by xanthine oxidase of 6-mercaptopurine. They
noted that this potent inhibitor of xanthine oxidase,
which could be given to humans without adverse
effect, decidedly decreased uric acid production.
This compound is structurally similar to hypo-
xanthine, differing only by transposition of a car-
bon and nitrogen in the purine ring. As a xanthine
oxidase inhibitor, it prevents the conversion of
hypoxanthine to xanthine and of xanthine to uric
acid. Thus, these other oxypurines accumulate in
the blood and are subsequently excreted. Admin-
istered in doses of 300 to 800 mg a day, allopurinol
has been very well tolerated by most patients.85 It
has now been administered to thousands of patients
with occasional instances of drug rashes, transient
leukopenia and transient aberrations of liver func-
tion tests but few serious side effects noted. One
fatal case of exfoliative dermatitis was recently re-
ported.86 Attacks of acute gouty arthritis are also
occasionally aggravated during the early stages of
treatment. This is similar to the effect of the insti-
tution of uricosuric therapy and may be prevented
by starting with low dosages of allopurinol and
gradually increasing the dose. Since it has been
shown that the renal clearance of oxypurines is
much greater than that of uric acid,5' and the solu-
bility of xanthine and hypoxanthine exceed that of
uric acid,85 it would appear that the inhibition of
xanthine oxidase is indeed advantageous. Despite
some of these apparent advantages of allopurinol,
it still remains a relatively new drug and there is
some concern about potential toxicity, such as de-
velopment of xanthine stones in the kidneys. This
is based primarily on the fact that xanthine calculi
have developed in aproximately 50 percent of the
patients with the metabolic defect xanthinuria,
which has been shown to be due to the congenital
absence of the enzyme xanthine oxidase.87 Thus, it
is generally felt that conventional uricosuric ther-
apy is sufficient for most patients with gout and
hyperuricemia and that allopurinol should be re-
served for specific indications.88 If it is demon-
strated at some future time that increased renal
excretion of uric acid has some deleterious effect
on the kidneys, then allopurinol will have undis-
puted claim as the drug of choice. At present, we
must weigh the benefits of this effective agent
against the hazards both real and potential. The
primary indications for the use of allopurinol in
patients with hyperuricemia and gout include: (1)
patients who respond poorly to maximal uricosuric
therapy. This is most likely to occur in patients
with renal impairment who cannot excrete an in-
creased uric acid load. Allopurinol administration
may afford the only means by which such patients
may achieve normal serum urate concentrations.
(2) Patients who have allergic sensitivity or an
intolerance for uricosuric drugs. (3) Patients with
demonstrated uric acid renal calculi. (4) Patients
with massive tophaceous involvement. (5) Patients
with hyperuricemia secondary to myeloprolifera-
tive disorders, especially before treatment with
cytotoxic agents. These are the patients in whom,
otherwise, acute uric acid tubular blockade might
develop.
Although it has frequently been suggested that
allopurinol and uricosuric drugs may be used to-
gether, it has recently been shown52 that the com-
bined use of these drugs is indicated only when
patients have good renal function and when the aim
of therapy is to unload a maximal amount of urate,
as for example in patients with severe tophaceous
involvement. In other situations it appears that
uricosuric drugs, as well as salicylates, impair the
renal excretion of oxypurines.
The use of allopurinol in patients with overpro-
duction of uric acid and neurological deficiency has
also been questioned. Since it has been shown that
allopurinol does not decrease total purine syn-
thesis in these patients37 and since it is possible that
the neurological dysfunction in patients with the
Lesch-Nyhan syndrome is a result of increased
concentration of oxypurines, it therefore follows
that allopurinol therapy may, in fact, have a
deleterious effect in such patients.28 Recently it
was reported that an infant with this syndrome
was treated from four days of life with allopurinol
and that such therapy was not successful in pre-
venting the appearance of mental retardation,
spasticity or self mutilation in this patient.89
Interval Treatment
The interval treatment of gout is concerned pri-
marily with lowering serum urate concentration
and preventing acute attacks. This therapy usually
consists of the use of a uricosuric drug and prophy-
lactic colchicine, usually in doses of 2 or 3 tablets
daily.82 As previously discussed, to be effective the
uricosuric drug must be given in a sufficient dosage
to lower the serum urate concentration to within
the normal range. This aspect of therapy should
help decrease the incidence of gouty nephropathy,
as well as prevent the development of tophaceous
complications. The prophylactic use of colchicine
is very helpful in preventing recurrent acute at-
tacks.90 The only consideration currently given to
diet is in the avoidance of those foods which are
known to be very high in purine content. If sig-
nificant hyperuricemia is a problem, it is usually
better controlled with uricosuric drugs than by
dietary means alone. Obviously those medications
or situations known to produce hyperuricemia or
provoke acute attacks of gout should be avoided in
patients with known gout. This would include such
drugs as thiazides and salicylates and would also
include alcohol ingestion,91 total caloric restric-
tion92 and physical or emotional stress.93
Treatment of Asymptomatic Hyperuricemia
With the increased use of multiphasic screening
programs in hospitals and clinics, the incidence of
unanticipated or asymptomatic hyperuricemia is
continually increasing.94 In patients with hyper-
uricemia associated with gout where deposition of
urate either in joints or other tissues has been dem-
onstrated it is quite clear that the lowering of the
serum uric acid concentration in the blood is a
rational basis for treatment. However, there is no
definitive study to show the fate of untreated pa-
tients with asymptomatic hyperuricemia and there-
fore there are no firm guidelines as to which, if
any, of these patients should be treated. There is,
however, some suggestion that patients with
asymptomatic hyperuricemia may have some spe-
cific types of renal tubular dysfunction95 and there-
fore it is quite. possible that such patients could
have deterioration of renal function, possibly re-
lated to hyperuricemia even before they have clin-
CALIFORNIA MEDICINE 241
ical evidence of gout. Furthermore there is evi-
dence that the likelihood of acute gouty arthritis
increases proportionally to the serum urate con-
centration.96 Thus, it has been recommended that
all patients with sustained serum urate concentra-
tions greater than 9 mg per 100 ml should be
treated regardless of the cause of the hyperuri-
cemia.97 It is hoped that within the next decade
definitive studies will be completed to answer this
most important question.
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SHOCK FROM AN INFECTED CATHETER

"A patient [who] has been on IV fluids through a catheter for four or five days
suddenly [and mysteriously] goes into shock; and you don't know what it's all
about. Perhaps he has a little bit of fever. If you get that little tip-off, take the
catheter out, and you may have a miraculous cure right then and there. No treat-
ment will succeed that does not include early ... removal of the infected catheter."
-EDWARD D. FRANK, M.D., Boston
Extracted from Audio-Digest Anesthesiology,
Vol. 10, No. 19, in the Audio-Digest Founda-
tion's subscription series of tape-recorded pro-
grams.

CALIFORNIA MEDICINE 243