URIC ACID IN RELATION TO GOUT
It will be recalled that at the close of our chapter on Pathogenesis we
referred to the growing scepticism of Garrod’s views as to the pathogeny
of gout. Still, if we except Edward Liveing’s pertinent observation that
_uricæmia_ was not peculiar to gout, naught, save alternative hypotheses,
unsupported by pathological data, was advanced. Consequently, Garrod’s
facts never being seriously called in question, his position remained
unassailable, until, in the year 1898, his original observations as to
the lowered alkalinity of the blood in acute gout, and the increased uric
acid content thereof during the same, were definitely contradicted by
Magnus Levy.
Working with more modern and more reliable methods of technique, this
observer, in a series of seventeen cases of acute gout, found no evidence
of any lessening in alkalinity of the blood or of any augmentation of its
uric acid content as compared with the inter-paroxysmal period.
Again, as to Garrod’s claim that there was a diminished excretion of uric
acid during the attack, this also, while supported by Minkowski, was
called in question by Pfeiffer, Levy, and Badt, who found the reverse to
be the case, _i.e._, a notable increase in the excretion of uric acid
during the paroxysm.
These results were again in 1900 confirmed by Chalmers Watson. An
exhaustive study of a series of cases of _acute gouty polyarthritis_
convinced him that:—
(1) The alkalinity of the blood is not diminished during the
attack.
(2) The excretion of uric acid is not lessened during the
paroxysm, but the reverse; there is, therefore, no ground for
the supposition that there is a temporary diminution in the
capacity of the kidneys to excrete uric acid.
(3) The amount of the uric acid in the blood is not greater
during the attack than in the intervening period, and if these
points be accepted, we must start _de novo_ in search of the
cause of the acute paroxysm.
The iconoclastic revelations of the foregoing researches may well form a
preface to our discussion of gout from the triple aspect of:—
(1) Uric acid excretion.
(2) Uricæmia.
(3) Uratosis.
URIC ACID EXCRETION IN GOUT
The earlier investigations as to the behaviour of uric acid in the
organism were necessarily restricted to the noting of any variations in
the uric acid output in the urine. That the findings and, alike, the
deductions proved bewilderingly contradictory is not to be marvelled
at when we recall the many factors that govern the amount of uric acid
excreted in the urine.
How fallacious, it now transpires, were the assumptions based upon the
mere uric acid output in the urine, and how little understood even to-day
the many conditions that determine its variations.[17] But, fortunately,
we can now to some extent control and review our urinary findings in
light of the uric acid content of the _blood_. But we anticipate, and
meanwhile let us confine our discussion to the variations in uric acid
excretion that occur in _gout_, and this as revealed by more modern
students of the disease. This will be more conveniently dealt with if
we consider first the oscillations in uric acid output in relation to
_acute_ attacks of the disorder, and subsequently the same as met with in
its more _chronic_ manifestations.
URIC ACID VARIATIONS IN ACUTE GOUT
Generally speaking, there appears to be a consensus of opinion on the
following points:—
(1) That in the _intervals_ between _acute_ attacks of gout the
elimination of uric acid lies within the normal limits, but that
(2) For one or two days _prior_ to an acute attack an
appreciable _decline_ in the output of uric acid occurs. This,
however, is not so marked as the subsequent
(3) _Increased_ output of uric acid _during_ the acute attack.
According to Magnus Levy the increase may reach from 0·3-0·5
gram, daily, and more, and may sometimes last for a week or
even two.
(4) Following attack a tardy decline in uric acid output to
former level.
To sum up, during an attack of _acute_ gout the uric acid output stands
at a relatively low level between the paroxysms. But one or two days
before the oncoming attack a _diminution_ in uric acid output ensues.
In contrast with the outbreak of the attack, the uric acid excretion
_increases_ markedly, this enduring for a week or more, when the output
again _declines_. The augmented output _during_ the paroxysm is more
constant than the diminished excretion antecedent thereto. Now, while it
may be taken that the foregoing variations in _uric acid output_, prior,
during, and subsequent to, acute attacks, obtain as a general rule,
such behaviour is not invariable; for, unfortunately, as Wells reminds
us, instances are met with in which “the uric acid excretion shows no
variation from that of normal persons.”
URIC ACID VARIATIONS IN CHRONIC GOUT
It must never be forgotten that the _elimination of uric acid_ displays
wide _variations_, this even when the subject under investigation is on
a _constant_ diet. Consequently, as Folin has pointed out, “even in the
case of gout, which is distinctly associated with uric acid, it is an
extremely difficult matter to prove by means of urine analyses that the
uric acid elimination is not entirely normal.” And he adds, “If it had
not been for the fact that uric acid, because of its insolubility, is so
easily found in the joints, it would unquestionably have been a very long
time before any definite relationship between uric acid and gout could
have been established.”
None can gainsay the truth of these reflections, for, when placed on
a fixed diet, the uric acid output in the victims of _chronic gout_
differs but little from that of _normal_ individuals on a similar regime;
save in this respect, that, following the intake of _purin-containing_
substances, the period of augmented uric acid excretion that ensues is
_prolonged_ as compared with the normal.
RETARDED EXOGENOUS URIC ACID OUTPUT
In 1901 Vogt showed that in gout the excretion of exogenous purins was
not only delayed but diminished. Giving simultaneously to a _gouty_
subject and a _healthy_ individual a diet rich in purins, he found that,
in the former, _retention_ and _delayed excretion_ of _purins_ ensued.
Vogt’s findings were confirmed by Reach, Soetbeer, Pollak, Mallory, and
others.
Brugsch and Schittenhelm also observed that, following the intake of
purin-containing substances, the exogenous uric acid excretion was
_retarded_ and _reduced_; in other words, the percentage of exogenous
nitrogen excreted as uric acid nitrogen is less than in normal
individuals, although the increased elimination extends over a longer
period of time.
On the other hand, Walker Hall finds that, though there is _retardation_,
there is _no diminution_ in the output in gouty subjects. Thus he states:
“When an adult takes a meal consisting of half a pound of beef and a
quarter of a pound of sweetbread, containing about 0·620 gram purins, the
moiety which usually occurs in the urine, say 0·300 gram, is not fully
excreted until 6-10 hours have elapsed. When a similar meal is taken by
a gouty individual the full 0·300 gram is eliminated, but the rate of
output is delayed, some 48-72 hours being necessary.”
The same observer states that, given _intravenous_ injection of acid
into a _normal_ man, its elimination is spread over several days, and
the total amount injected fails to appear in the urine. But if the
injection be administered during a course of _atophan_, then the uric
acid excretion is completed within twenty-four hours, and the whole
amount injected can be recovered from the urine. Now if in a _gouty_
subject the same method of procedure be adopted, the sequence of events
is precisely similar, and like results have been reported, following the
administration of _sodium salicylate_ to vegetarians of five or more
years’ standing. To sum up, the above findings would appear to indicate
that:—
(1) A gouty subject can excrete exogenous purins as adequately
as a normal man, but he takes longer to do so.
(2) If the extra purins be taken during a course of atophan,
even this departure from normal is obliterated, _i.e._, the
customary delay in excretion is obviated.[18]
But, unfortunately for the diagnostic valency of this symptom in gout,
viz., _retarded exogenous purin output_, it has not been found to be
_invariable_. Thus Magnus Levy has shown that, in some instances of gout,
the elimination of exogenous purin is neither reduced nor protracted.
Pratt, too, has confirmed this observer’s findings, while, as we shall
see later, this authority, also McClure, Mallory, and others, have placed
on record the still more disconcerting fact, viz., that a diminished and
retarded output of exogenous purin is _not peculiar to gout_.
The inference then would appear to be that:—
(1) Reduction and retardation of the excretion of exogenous
purin, though common in gout, is not invariable.
(2) The same is not peculiar to gout, but occurs in other
disorders.
(3) Its diagnostic valency, as a characteristic feature of
gout, is correspondingly depreciated.
LOWERED ENDOGENOUS URIC ACID OUTPUT
As a rule, gouty subjects, on a _purin-free_ diet, excrete less
endogenous uric acid than _normal_ persons. Thus, according to Walker
Hall, the average daily endogenous urinary uric acid output of a _normal_
adult is about 0·5 gramme, while that of a gouty subject is about 0·45
gramme. Brugsch and Schittenhelm hold that in about 80 per cent. of cases
the average endogenous excretion is lower than normal.[19]
According to these same observers, “the maximum fluctuation during
attack-free periods was at first believed to be less than in the normal
cases; more recent examinations, however, have shown that in the
same case of gout there may be _periods of high, and periods of low,
endogenous uric acid excretion_.” These variations, they hold, are not to
be accounted for by either mild or severe attacks of gout, for they occur
in the _attack-free_ period.
Again Laird, investigating the elimination of endogenous uric acid in a
case of _chronic_ gout, noted that the output thereof was _sub-normal_,
and, as Brugsch and Schittenhelm observed, the same presented marked
_variations_. The leucocyte counts he found normal, but the phosphorus
output and the acidity were sub-normal. Bloch again, while he agrees
that endogenous purin excretion is usually below the average in _gouty_
subjects, found that the output thereof is at its minimum before an acute
attack of gout.
The foregoing observations would suggest that the _retention_ or delayed
excretion of uric acid applies both to _exogenous_ and _endogenous_
purins. But, when we come to analyse the foregoing findings as to
the variations in uric acid output, both in acute and chronic gout,
one feels inclined to agree with O. Folin, “that the clinically
useful contributions obtained by _urine analysis_ have not been very
numerous.” Thus we cannot, on the basis of the _variations_ in _uric
acid excretion_, presume to diagnose gout; in other words, if we take
_urine analysis_ alone, it is extremely difficult to prove that the uric
acid elimination in gout is really and truly abnormal. Our uncertainty,
moreover, is the more pronounced when we realise that in some cases
of _rheumatoid arthritis_, etc., there is a disturbance of _purin_
metabolism which in some of its features is reminiscent of that obtaining
in typical gout. But, before proceeding to discuss this interesting
resemblance, it will, we think, be convenient here to recall that the
obliquities in metabolism found in gout are not wholly restricted to
_uric acid_.
OTHER ANOMALIES IN EXCRETION IN GOUT
As Levene and Kristeller have shown, side by side with the delayed
excretion of ingested purins, there occurs also a tardy elimination
of the other nitrogenous products of protein food. Vogt observed that
fluctuations in nitrogen retention and nitrogen loss are quite typical
of gouty subjects. As to the why and wherefore, however, of this
variability, it remains a mystery. Nor do we know the form in which the
nitrogen is retained, though Vogt maintains that the uneliminated moiety
takes the form of purin bodies. According to Brugsch, it is during the
acute attacks of gout that the nitrogen loss reaches its zenith, and he
suggests that the nitrogen retention in the inter-paroxysmal periods is
in part compensatory. On the other hand, the gain in weight that ensues
is not adequate to account for the sum total of the nitrogen retention;
while, as before observed, in gout there occurs, not only retarded
elimination of exogenous purins, but also of other nitrogenous products
of protein food. Yet, according to Heffter, the ratio of _purin bases_ to
uric acid is unaltered in the urine of gouty subjects.
Again, all _nucleins_ contain a _phosphoric_ acid group, and
Futcher found that the curve of the uric acid output ran in a
striking parallel with that of phosphoric acid. But the attempts of
subsequent investigators to show that the two end-products of nuclein
disintegration—uric acid and phosphoric acid—go hand-in-hand prove
contradictory. Hence Wells, in regard to phosphoric elimination, observes
that, “it seems probable that it shows no characteristic alterations
in gout.” Lastly, we will recall to the reader that in the chapter on
protein metabolism it was pointed out that the _amino-acids_, especially
_glycocoll_, are found in excess in “gouty” urines.
In conclusion, it must, we fear, be admitted that the results of
_urinary analyses_ have proved insufficient of themselves to unravel the
intricacies of metabolism in gout, and, after a brief digression, we
shall proceed to ascertain whether, on the other hand, chemical analysis
of the _blood_ by modern methods can in any way shed further light on
this obscure problem.
PURIN METABOLISM IN OTHER DISORDERS
Working at the Research Hospital for the Study of Special Diseases at
Cambridge, Strangeways (1910) commented on the striking resemblance that
obtained between certain cases of so-called _rheumatoid arthritis_ and
gout, as evidenced by X-ray findings and section of the joints. Their
similitude in these respects suggested that the nature of the apparent
kinship of the two disorders might be elucidated by a study of _purin
metabolism_ in instances of rheumatoid arthritis.
To this end Ackroyd studied the purin metabolism in eleven persons, the
victims of rheumatoid arthritis. His conclusion was that there was no
important variation from the normal. To quote his own words, he states
that “it may be (1) completely normal, or (2) while normal as regards
endogenous excretion, the period of increased uric acid excretion which
follows the administration of hypoxanthine may be prolonged for more than
four days. It is more likely that this effect is individual, than that it
is characteristic of any particular form of the disease, excepting those
cases in which the prolongation is accompanied by active manifestation of
the disease.”
W. J. Mallory, critically analysing Ackroyd’s cases, points out that he
used only _hypoxanthine_ in his studies; also that, while _hypoxanthine_
has this advantage, that it is of definite and known chemical
composition, furnishing a known quantity of basic nitrogen, it labours
under this drawback: “It is by simple oxidation converted into uric acid,
and probably calls into action only a limited part of the ferment system
concerned in the formation of uric acid.” As a consequence, therefore,
the amount of information on metabolism that can be gleaned through its
usage is more restricted than if _nucleinic acid_ were invoked in its
place; for this substance, on the other hand, calls into action all the
various enzymes concerned in the disruption of nuclein or nucleic acid.
Alive to these advantages, Mallory, in addition to hypoxanthine, used
_nucleinic acid_ in his investigations of purin metabolism in a series of
eight “undoubted cases of so-called rheumatoid arthritis.” The value of
the inclusion of nucleinic acid is revealed by the fact that some of the
cases, when given exogenous purin in the form of _hypoxanthine_, showed
no deviation from the normal. On the other hand, when given _nucleinic
acid_, a prolongation of the period of increased uric acid excretion
ensued; this even though the total amount of basic nitrogen in nucleinic
acid is less than in hypoxanthine. Thus 4 grams of nucleinic acid have
0·2632 gram of basic nitrogen, while 0·75 gram hypoxanthine has 0·309
gram of basic nitrogen.
Apart from his own series of cases, Mallory analysed those of other
observers, and his conclusions are as follows: “Of nineteen cases of
rheumatoid arthritis in which the purin metabolism has been studied
by three different observers, nine cases, or 47·3 per cent., show a
marked variation from the normal in their reaction to purin-containing
substances while they are on a purin-free diet.
“In these cases the period of increased uric acid excretion which
follows the administration of purin-containing substances is much
_prolonged_. Following the administration of purin-containing substances,
a considerable number of cases suffer from attacks of _sub-acute
arthritis_, accompanied in some cases by an increased uric acid
excretion.”
It will be seen that in virtue of:—
(1) The prolongation of the period of exogenous uric acid
excretion, and
(2) Increased uric acid excretion during attacks of sub-acute
arthritis,
certain cases of _rheumatoid arthritis_ manifest a certain resemblance to
gout, though, as Mallory remarks, “other features characteristic of that
disease are lacking.”
It may be observed that the attacks of _sub-acute arthritis_ that ensued
in rheumatoid subjects followed the administration of _hypoxanthine_,
as shown in Ackroyd’s series. That this reaction to exogenous purin
is suggestive of a relationship between rheumatoid arthritis and gout
derives colour from the fact that it has been repeatedly induced in
_gouty_ subjects by the same means. Thus, Brugsch and Mallory (1910),
after giving 0·5 gram of hypoxanthine to a gouty patient, noted a typical
outbreak of gout. Again, Brugsch and Schittenhelm, in the same year,
reported attacks of arthritis following the administration of _nucleinic_
acid to gouty subjects.
Another feature worthy of note is that, in the cases of _rheumatoid
arthritis_ investigated by Ackroyd and Mallory, the percentage of
exogenous purin nitrogen excreted as uric acid nitrogen largely exceeds
that observed in any case of _gout_ available for comparison by these
authors.
Mallory’s final conclusions were that “there seemed to be sufficient
data to show that, in certain cases of so-called rheumatoid arthritis,
the purin metabolism is not normal. Whether these cases are real gout,
or only resemble that disease in certain features, must be determined by
further studies.”
PURIN METABOLISM IN CHRONIC ALCOHOLISM AND PLUMBISM
Quoting from Mallory’s contribution, we note that Pollak investigated the
purin metabolism in a series of cases of _chronic alcoholism_. In five
of the examples a marked derangement of _purin metabolism_ was noted and
manifested, “partly in retention, and partly in delayed excretion, or a
combination of the two.” Having observed these variations in cases of
what he considered were _non-gouty_ alcoholics, Pollak felt justified in
attaching but limited diagnostic import to the results of the examination
of uric acid metabolism in gout, this though he realises the importance
of alcoholic excess as a cause of disturbed purin metabolism.
Mallory’s observations, too, on uric acid excretion in gout complicated
by _lead poisoning_ are highly interesting. In two cases of this
nature he noted that the percentage of uric acid nitrogen excreted
was relatively small—in this respect in full accord with previous
observations of Brugsch and Schittenhelm on a gouty patient with a
history of plumbism, with this reservation, that in the latter observers’
example there were indications of early _renal_ disease, while in
Mallory’s two cases such was absent, the urine being normal, and likewise
the blood pressure.
Again, Pollak in a case of _lead gout_ noted an extremely _low endogenous
average_, viz., a daily average endogenous excretion of 0·06 gram uric
acid in a period of five days. Eschemburg, quoted by Pollak, has recorded
an instance of gout with plumbism in which the excretion fell as low as
0·02-0·04 grams. It may be noted that Pollak’s was the victim also of
incipient _renal_ disease.
Reverting to Mallory’s conclusions, this observer’s studies of examples
of _gout_ with _lead poisoning_ seem to indicate that “these cases differ
from normal persons to a greater degree than do other cases of gout.” It
may, he thinks, be affirmed that the subjects of gout and plumbism, as a
rule, show “some or all of the following characteristics in a much more
marked degree than do cases unassociated with lead”:—
(1) Slight fluctuation in the endogenous excretion.
(2) Low endogenous average.
(3) Small percentage of exogenous purin nitrogen excreted as
uric acid nitrogen.
To sum up, then, we see that poisons, other than those responsible for
gout, may engender obliquities of general metabolism, with disturbances
of purin assimilation and output, viz., lead, alcohol, and the _causa
causans_ of rheumatoid arthritis. Also, in respect of lead poisoning and
alcoholism, further affinities with gout are discernible in that, like
the latter disorder, they tend in their later stages to be associated
with arterio-sclerosis and renal inadequacy.
INFANTILE GOUT
Apart from the fact that gouty arthritis may occur in young children,
Comby and other observers have noted that children born of _gouty_
parents display a tendency to inflammatory changes in the cutaneous
tissues and also in the mucous membranes.
These proclivities are difficult of explanation, but some further
observations by Czerny, Paltauf, Escherich, and Pfaunder are also
worthy of note. Under the headings of “exudative diathesis” or
“neuro-lymphatismus” they have described a symptom complex marked
by lymphatism with asthma, occasional vomiting, defective nervous
equilibrium, and eosinophilia. These varied phenomena also are common in
the descendants of _gouty_, diabetic, and arthritic subjects.
The clue to the true nature of these phenomena may possibly reside in
the fact noted and emphasised by Uffenheimer, viz., that these children
exhibit a _purin metabolism_ identical with that met with in _gouty_
patients.
From the foregoing consideration it is clear that further observations
are called for in the sphere of purin metabolism, and it is, perhaps, not
too much to hope that extended investigations of the uric acid content of
the _blood_ may clarify and illumine the conflicting results obtained by
urine analysis.
As before stated, we had intended in the next chapter dealing with
the question of “Uricæmia in Gout,” but on second thoughts it appears
desirable to us to interpolate a chapter devoted to discussion of the
primary _renal_ origin of gout; for we take it that, with the phenomena
of _uric acid excretion_ in _gout_ fresh in our minds, it will be more
easy at this juncture to attempt solution of this very intricate problem.
This achieved, we shall resume our thread and pass to the consideration
of uricæmia and subsequently uratosis in gout.