SOURCES OF URIC ACID
Uric acid, like the “purin bodies” (xanthine, hypoxanthine, guanine,
and adenine), is derived from _nucleins_, _i.e._, from the breaking
down of tissues rich in cells. The end-product of purin or nuclein
katabolism _uric acid_ represents but a further stage in the oxidation
of the _purin_ bodies. To the serial enzymatic transformations that mark
its derivation from _nucleic acid_ we shall allude later, but at this
juncture we are concerned not with the _mode_ of _formation_ of uric
acid, but with the sources thereof.
In this sphere we are greatly indebted to the pioneer researches of
Burian and Schur. These observers noted that on a diet rich in _nucleins_
(sweetbreads, liver, kidneys) the total daily excretion of uric acid was
considerably higher than on a milk or purin-free diet. This difference
in response to varying dietaries, in respect of the excretion of uric
acid, led Burian and Schur to the conclusion that the purins excreted
must be partly of _exogenous_ and partly of _endogenous_ origin; in other
words, the exogenous purins are derived from the nucleins ingested in the
food, whereas the endogenous are the outcome of the breaking down of the
cellular tissue of the organism itself.
Here it may be noted that all the ingested purins are not excreted in the
urine as uric acid, for some pass away as _purins_. Moreover, the amount
excreted will vary with the kind of purin ingested, and also with the
_species_ of the animal that consumes it. Thus, in man “only one half of
the hypoxanthine administered as such appears as uric acid in the urine,
and but one fourth of the purin in nuclein when that is fed. In the
dog, compared with man, about ten times as much purin disappears in its
passage through the organism; in the rabbit, about three times” (Flack
and Hill).[11]
In amount about 0·4-0·7 gramme of uric acid is excreted in _human_ urine
daily, and the purin bodies, hypoxanthine, xanthine, and adenine, in
small quantities.
Beyond exogenous and endogenous purins there is yet one other possible
source of uric acid, viz., its _synthetic formation_ within the organism.
This supposition took origin in Horbaczewski’s discovery that in the
laboratory he was able to produce uric acid by the interaction of _urea_
and _glycocine_, a finding afterwards confirmed by Latham. The theory
was then advanced that a similar synthesis might be effected by the
_kidneys_; but it was found that glycocine and urea, even when given in
excess to mammals, caused no change in the uric acid excretion.
So much by way of preface to our detailed discussion _seriatim_ of the
various sources of uric acid, and to which we now pass on.
EXOGENOUS PURINS
The foodstuffs that cause an increase in purin excretion are divisible
into three groups:—
(_a_) Amino-purins.
(_b_) Oxy-purins.
(_c_) Methyl-purins.
_Amino-purins._—In man the taking of food rich in nucleated cells and
therefore in nucleo-protein and nucleins, increases the quantity of
uric acid in the urine. Thymus gland, pig’s pancreas, and herring roe,
containing the characteristic conjugated proteins of nuclei, or Liebig’s
meat extract, rich in purin bases, when ingested, lead to a distinct
increase in purin excretion.
The researches of Kossel and Horbaczewski showed that such augmentation
was mainly due to the production of uric acid from the _nuclein_
substances of the food; in other words, it was due to the katabolism of
_nuclein_, the cleavage products of which comprise _adenine_ derived
from thymus, and _guanine_ from the pancreas, both of these bodies
being amino-purins. According to Burian and Schur, of the amino-purins
ingested, a fourth is excreted as purin.
_Oxy-purins._—To this group belong xanthine and hypoxanthine. These
substances occur in muscle, and in great abundance in meat extract, and
Minkowski noted that the ingestion of xanthine bases markedly augmented
the amount of uric acid excreted. In man, given ingestion of hypoxanthine
as such, only one half thereof appears as uric acid in the urine. It may
here be mentioned that not all the purin bases ingested exist bound up in
the nuclein substances. An appreciable amount is present in the tissues
in a _free_ state, _e.g._, hypoxanthine in the muscles; consequently,
a moiety of the intake of purin bodies, especially in the animal
constituents of the food, is to hand ready formed, and does not require
the disruption of _nucleic acid_ for its liberation.
_Methyl-purins._—The nuclei of _vegetable_ cells also contain
nucleo-protein, and, therefore, can add their quota to the purin intake.
The most important are _caffeine_, _theobromine_, and _theophyllin_, the
active principles of tea, coffee, and cocoa. It may here be recalled that
of the purins administered in food, not all are excreted as uric acid,
but some as _purins_. Now it is doubtful whether the _methyl-purins_ lead
to the formation of _uric acid_ in the organism, or whether they are
excreted as purin bases in the urine. According to Stewart, a fractional
part of the _purin bases_ in the urine is composed of heteroxanthine,
1-methyl-xanthine, and paraxanthine derived from the active principles of
coffee, tea, and cocoa when consumed as beverages. As stated by Burian
and Schur, one third of the methyl-purins ingested is excreted as purin.
From the foregoing data it will be obvious that the _exogenous_ urinary
purins are derived from _nuclein_ and certain _free xanthine bases_, and
that the influence of other nitrogenous foodstuffs in this direction is
practically negligible.
EXOGENOUS URIC ACID EXCRETION
As to the amount of exogenous purins that, when administered orally,
can be recovered from the urine, it would appear that a certain rough
parallelism obtains between the purin content of the food and that of the
urine. The amount of the exogenous urinary purin differs for different
forms of food, a variation well illustrated by the following table,
giving the results of Burian and Schur’s researches.
---------------+-------------------+----------------
| Total percentage | Percentage of
Diet. | of purin | exogenous
|substances in diet.| urinary purin.
---------------+-------------------+----------------
Beef | 0·06 | 0·030
Coffee | 0·20 | 0·075
Calf’s liver | 0·12 | 0·060
Calf’s spleen | 0·16 | 0·080
Calf’s thymus | 0·40 | 0·100
---------------+-------------------+----------------
Walker Hall, experimenting with various purin-containing foods, found
that (1) with chicken 54·4 per cent., (2) with plaice 58·7 per cent., (3)
with beef 47·4 per cent., (4) with haricot beans 55 per cent. of the food
purin appears in the urine as exogenous purin. These findings of Walker
Hall’s, like Burian’s and Schur’s, reveal that, roughly speaking, 50 per
cent. of the purin content in food is excreted in the urine.[12]
These figures must be taken as a broad average relating only to healthy
individuals upon diets capable of perfect assimilation.
More recently, Mendel and Lyman found that about 60 per cent. of injected
hypoxanthine, 50 per cent. of xanthine, 19-30 per cent. of guanosine,
and 30-37 per cent. of adenine were excreted in the form of _uric acid_.
While this is true of free purins, on the other hand, when _bound_
purins, _i.e._, nucleins are administered, only a small proportion
thereof appears as uric acid in the urine. But before proceeding to
canvass the fate of the missing purin, it will, we think, be helpful
if we interpolate here a table (Taylor and Rose), illustrative of the
variations in uric acid excretion that attend a _purin_ as opposed to a
_purin-free_ diet.
The subject of the experiment was, for three days, fed on a purin-free
diet of milk, eggs, starch and sugar. At the end of this period a
portion of the total nitrogen (3 grams) was administered in the form of
_sweetbreads_, thymus gland, etc., with a high percentage content (0·482)
of purin nitrogen. During the succeeding four days still more (6 grams)
of the total nitrogen was replaced by sweetbread nitrogen. Subsequently
the person was placed on the original purin-free diet.
---------------+-------------+--------------+-------------+--------------
|First period.|Second period.|Third period.|Fourth period.
| Purin-free | | | Purin-free
| diet. | | | diet.
---------------+-------------+--------------+-------------+--------------
Total urinary N| 8·9 | 8·7 | 9·1 | 8·8
Urea N and NH₂ | 7·3 | 7·1 | 7·1 | 7·05
Creatine | 0·58 | 0·55 | 0·56 | 0·47
Purin N (total)| 0·11 | 0·17 | 0·26 | 0·10
Uric acid N | 0·09 | 0·14 | 0·24 | 0·07
Remainder N | 0·91 | 0·88 | 0·18 | 1·18
---------------+-------------+--------------+-------------+--------------
From a study of the table it will be noted that, following the
introduction of sweetbreads rich in _nucleins_, the uric acid content of
the urine markedly increased, to sink again when a purin-free diet was
substituted. But it will be seen also, as MacLeod points out, that “the
increase of uric acid accounted for less than half of the purin nitrogen
ingested. This appeared as uric acid, the excretion of purin bases being
practically unchanged.” In other words, a moiety of the bound purins,
_i.e._, nucleins ingested, appears as uric acid in the urine.
FATE OF THE UNEXCRETED PURIN
As to what becomes of that portion of the ingested purin that, so to
speak, disappears in the body, is largely a matter of speculation. As
MacCallum states, “the liberation of guanine and adenine is well in the
line of uric acid formation,” but “the fate of the pyrimidin groups,
thymine and cytosine, is still uncertain.” According to this observer,
Levene has hitherto been unable to find an enzyme which will decompose
the _nucleoside_ in which they occur, and that since they cannot form
uric acid, they are possibly excreted as _urea_ or in other forms. He
adds that only 50 per cent. of the nucleic acid nitrogen can be counted
on for the production of _uric acid_, viz., that in the guanine and
adenine groups.
MacLeod, discussing this same point, suggests that some of the
unrecovered purin may undergo decomposition in the intestine, but why so
much should, after absorption of the blood, disappear is, as he remarks,
difficult of explanation; for while _uricase_, which can decompose uric
acid, exists in the tissues of the lower animals, no such ferment is
found in man, and uric acid is excreted as such. According to MacLeod,
too, “the destroyed purins cannot be shown to influence any of the other
well-known nitrogenous metabolites of the urine.”
Lastly, Stewart, discussing the ultimate destiny of the absorbed
products of _nucleic acid_ digestion, suggests that, when undergoing
further cleavages, “they may be in part utilised for the synthesis
of nucleo-proteins, replacing those destroyed in the process of cell
metabolism;” or, that it is “possible that they may be wholly disrupted
into their components, and these again re-synthesised.”... “Finally, and
this fate is probably not long delayed in the case of the surplus of
purin compounds contained in ordinary dietaries, both the purins of the
food and the purins arising from the waste of the tissues, are for the
most part converted into uric acid and excreted in the urine.”
Also, it should be recollected that the purin bases normally found in
human _fæces_ are in part of _exogenous_ origin, and are increased in
amount after the ingestion of meat extract or thymus.
ENDOGENOUS PURINS
Even if we entirely eliminate all purin substances, by restricting the
diet to _purin-free_ foodstuffs (bread, milk, cheese, eggs and butter),
purin in the form of _uric acid_ is still excreted in the urine.
To this moiety the term _endogenous_ purin is applied; for the continued
excretion of purin on such a diet is explicable only on the view that
they are derived from the waste of the tissues, the daily “wear and
tear” of cells. In other words, it is the outcome of the katabolism of
the _nucleo-protein_ of the body tissues.
SOURCE OF ENDOGENOUS PURINS
_Is the nuclear destruction of localised or generalised distribution?_
Mares (and subsequently many other observers), having noted that,
following the ingestion of _purin-free_ protein food, a marked increase
in endogenous uric acid excretion ensued, suggested that the said
augmentation was the outcome of the “wear and tear” entailed upon the
nuclear material of the _secretory glands of the gastro-intestinal
tract_, following such intake.
The effects yielded on uric acid excretion by those antithetic drugs,
atropine and pilocarpine, certainly seem to lend colour to Mares’
hypothesis.
Following the injection of _atropine_, the rise in uric acid output, that
normally follows the ingestion of protein, was inhibited. But in sequence
to _pilocarpine_, an _excitant_ and not like _atropine_, a depressor of
secretory activity, a marked increase in uric acid excretion followed.
The contrast in response was naturally translated as striking evidence
of the important _rôle_ played by the _digestive glands_ on uric acid
excretion; in other words, it was held that the major portion of the
endogenous uric acid was the reflex of such intensified glandular action.
In opposition, however, Burian, as the outcome of his experimental
studies, maintained that a _fractional_ portion only of the endogenous
uric acid could be derived from the _nucleo-protein of the body cells_.
This, inasmuch as it would entail a far too extensive katabolism of
nuclear substance. Accordingly he propounded the view that the endogenous
uric acid in the main was derived from the _hypoxanthine_ of the
_inosinic_ acid present in _muscular_ tissue. In this connection it may
be noted that, on a diet approximating to Voit’s standard, 0·5 gram of
purin is excreted daily. This, it is calculated, is equivalent to nearly
100 grams of thymus or allied tissue, which probably far exceeds the
amount that could be gleaned from cellular katabolism.
PROTEINS AND THEIR DERIVATIVES
A comparison of the influence of _proteins_ as contrasted with that of
their digested products, the _amino-acids_, it was thought, might furnish
a clue as to the extent of which the alleged activity of the _digestive
glands_ was responsible for the increased uric acid output that followed
the intake of non-purin protein food.
Such was the supposition entertained by H. B. Lewis, M. S. Dunn, and E.
A. Doisy. Alive, moreover, to the deficiency of the older procedure in
use for the determination of small amounts of uric acid, Lewis and his
collaborators invoked the more accurate colorimetric method of Folin and
Denis (as modified by Benedict and Hitchcock).
The experiments were conducted with great care, and with as complete
control as possible of the variable factors concerned. The investigators
realised that, if any significance was to be attached to fluctuations
in uric acid excretion following the intake of proteins and their
derivatives, it was essential that accurate information be obtained as to
the extent of the _variations_ to be expected _normally_ in the subjects
when _fasting_. “Controls,” therefore, in which no food was consumed
throughout the experiments, were instituted at frequent intervals so as
to make sure that the level of endogenous uric acid metabolism was not
altered by the long-continued _purin-free_ diet.[13]
Passing now to the results obtained, it was noted that, after the intake
of three types of _purin-free_ protein food (egg white, cottage cheese,
and glidine), there ensued _a rise in uric acid output_, reaching
its maximum during the third or fourth hour after their intake. No
quantitative differences in the uric acid output after ingestion of these
three types of protein were observed; in short, the findings did but
confirm what had been repeatedly demonstrated, viz., that the _excretion
of the endogenous uric acid is increased by purin-free protein food_.
AMINO-ACIDS AND DICARBOXYLIC AMINO-ACIDS
But the further interesting fact emerged, viz., that _glycocoll_ and
_alanine_, end-products of protein digestion, also _augmented_ uric acid
excretion; moreover, this even more swiftly than _proteins_, the maximum
being reached within two hours after their intake.
In addition, like results followed the ingestion of the _dicarboxylic_
amino-acids (glutaminic and aspartic acids), the increase in endogenous
uric acid excretion being even more pronounced than with glycocoll or
alanine.
Now, it must be recalled that the _amino-acids_ represent the
_end-products_ of protein digestion. Accordingly, Lewis and his
co-workers argue that “since no digestive processes are required for
the utilisation of amino-acids, it can hardly be considered that the
_rises in endogenous uric acid_ observed following the ingestion of four
different amino-acids can be attributed to the _work of the digestive
glands_.” The effect, they held, is more probably attributable to “a
direct stimulation of the body cells by amino-acids or their katabolism
products, a stimulation of nuclear metabolism,” for it is known that
amino-acids disappear very swiftly from the _blood-stream_ to be stored
up temporarily in the _tissues_.
The question that now confronted the observers was whether the
stimulation of nuclear metabolism was an _inherent_ property of
amino-acids. If so, “_substituted_ amino-acids might be expected to exert
a similar influence.” But, if on the contrary, it was due not to the
amino-acids as such but “either to the cellular work of their katabolism
or to the intermediary products of their breakdown, a substituted
amino-acid which does not follow the normal path of amino-acid catabolism
would in all probability be devoid of the power of stimulation.”
To this end, they selected _sarcosine_ or _methyl-glycocoll_ to elucidate
the point at issue; this, inasmuch as it has been found to pass through
the organism for the most part unchanged. The result justified their
inference, for _no_ perceptible influence on uric acid excretion was
noted. Hence, on the basis of this experiment, they inferred that the
stimulation of uric acid metabolism was not an _inherent_ property of
_amino-acids_; in other words, that if an amino-acid when ingested does
not undergo disruptive katabolism, it is without effect on uric acid
excretion.
Now _deaminisation_ is the first stage in the katabolism of
_amino-acids_, yielding as products _ammonia_ and _a-ketonic_ or _hydroxy
acids_. The ammonia thus formed normally undergoes conversion into _urea_
and is excreted as such. In order to ascertain whether the _ammonia_
stimulated uric acid excretion, _ammonium chloride_ was administered,
but no rise in the uric acid output above the normal level ensued.
Also, the ingestion of _urea_ seemed to entail no appreciable increase
in the uric acid elimination; in other words, these katabolic products
of the _nitrogenous_ moiety of the amino-acids are without effect.
As to the _non-nitrogenous_ intermediary products of the katabolism
of amino-acids, _i.e._, the _a-ketonic_ or _hydroxy acids_, it was
impossible to investigate the influence of these on the endogenous uric
acid elimination.[14]
Lusk also has brought forward evidence that in the presence of
amino-acids cellular activities are intensified markedly. According to
Taylor and Rose, too, not only _nuclear katabolism_, but also _nuclear
anabolism_, may be accelerated by the presence of large amounts of
amino-acids.
Lewis and his collaborators consider that the results of their researches
militate against Mares’ hypothesis, viz., that the origin of the
increased amounts of endogenous uric acid that follow the intake of
purin-free protein stuffs is referable to _intensified activity of the
digestive glands_.
_They hold that “it can be accounted for equally well as the result of
a general stimulation of all cellular metabolism by the products of
digestion of proteins the amino-acids.”_
The recorded increases in endogenous urinary purin are, they consider,
far too great to be the outcome of the stimulation of so small a
proportion of the cells of the body as those of the digestive tract. On
the other hand, they do not deem it necessary to assume that the whole
of the endogenous uric acid is the outcome of _nuclear_ disruption,
concurring with Burian’s view, that a moiety thereof may be derived from
the _hypoxanthine_ of _muscular_ tissue.
ENDOGENOUS URIC ACID EXCRETION
The researches of Leathes and his collaborators permit the deduction that
endogenous uric acid excretion bears a definite relation to the activity
of cellular processes. Given unchanged physiological conditions, _e.g._,
muscular exercise, the amount of the endogenous uric acid excreted is,
for the same individual, fairly _constant_, and this _irrespective of
diet_; but it is not the same for _different_ individuals, even those of
identical body weight.
According to MacLeod, the endogenous excretion in an adult man fluctuates
between 0·12 and 0·20 per cent. purin nitrogen. The average daily
endogenous uric acid output of a normal adult, as stated by Walker Hall,
is about 0·5 gram, while that of a gouty individual is 0·45 gram.
Now Burian and Schur’s original contention was that, in a given
individual on a _purin-free_ diet, the endogenous purin output was
_constant_, and this despite _marked_ variations in the amount of the
purin-free food digested.
Recent researches, however, of Folin and of Hopkins and Hope, indicate
that this dictum must be modified to this extent, viz., that although it
is true that the endogenous excretion continues remarkably constant, with
_moderate_ variations in the amount of purin-free food, it is not so in
the presence of _marked_ variations.
The subject (Hopkins and Hope), after a fast of six hours, was given a
meal of bread and potatoes, and at every subsequent hour estimates were
made of the amount of _urea_ and _uric acid_ excreted in the urine.
------------------+--------------+--------------+--------------
| | Uric acid. | Amount of
Time. | Urea. Grams. | Milligrams. | urine. C.C.
------------------+--------------+--------------+--------------
10-11 | 1·07 | 26 | 175
11-12 | 1·13 | 27 | 118
12-1 p.m. | 1·07 | 24 | 164
1-2 (meal). | 0·64 | 21 | 60
2-3 | 1·12 | 22 | 43
3-4 | 1·16 | 38 | 41
4-5 | 0·84 | 40 | 53
5-6 | 1·16 | 56 | 59
6-7 | 1·20 | 39 | 56
7-8 | 1·37 | 30 | 95
8-9 | 1·47 | 33 | 183
9-10 | 1·33 | 24 | 155
10-11 | 1·33 | 23 | 180
------------------+--------------+--------------+--------------
It is clear from the results obtained that a very definite increase of
endogenous purin excretion ensued, and that the said increase occurred
sooner as regards _uric acid_ than urea. This bears out what Mares
demonstrated many years ago, viz., that the greatest increase in uric
acid excretion occurs in a few hours after a meal, whereas the increase
in the case of urea comes more tardily, not reaching its maximum until
some hours after.
Horbaczewski referred such increase in uric acid excretion to a digestive
_leucocytosis_; in other words, that the uric acid was the outcome of
destruction of the leucocytes, and consequent formation of purin from the
released nucleic acid. Unfortunately for this theory, the period of most
marked augmentation in uric acid excretion ensues when the leucocytes are
most in evidence in the blood-stream, not _after_ they have disappeared,
as would be the case if uric acid was derived from the purin product of
the nucleic acid liberated by leucocytic destruction. We have a parallel
instance in the case of _pneumonia_, in which it has been shown that
the elimination of uric acid and other purins is at its acme when the
leucocytes are most abundant; in other words, the highest uric acid
output coincides with the period of most marked leucocytosis, whereas
during the post-critical stage, viz., when leucocytes are being destroyed
in great numbers, the output of uric acid is very markedly lowered.
Discussing Horbaczewski’s theory in light of the above criticisms,
MacLeod suggests, “that the facts appear to indicate that the purin
substance is a metabolic product of the living leucocytes,” and not, so
to speak, the chemical outcast of their disruption and death.
Lastly, Walker Hall, discussing endogenous uric acid excretion,
emphasises the necessity of discriminating between the _uric acid_
output and the _total purin_ output. He reminds us that the actual cell
nucleins belong chiefly to the group of amino-purins, _i.e._, guanine
and adenine, and that the oxypurines, xanthine and hypoxanthine, are
intermediate products on their way to excretion, another and more
advanced intermediate product being uric acid. Now, only a proportion of
these intermediary products appears in the urine, this commonly cited to
be approximately 50 per cent.
But this, as Walker Hall states, must be taken only as a very broad
estimate, for in the same individual the output varies with the number of
conditions, not as yet fully determined. But the point most emphasised
by him is, that though “the _uric acid_ output varies considerably, the
_total purin_ output does not show similar variations; for when the
uric acid excretion wanes that of the purin bases usually rises. As a
consequence, the total purin output is more constant, less influenced by
circumstances, than the output of _uric acid_.”
This being so, we shall now pass on to consider other conditions
influencing endogenous uric acid excretion.
FACTORS INFLUENCING ENDOGENOUS URIC ACID EXCRETION
The output of endogenous uric acid excretion is influenced by (1)
Physiological conditions, (2) Pathological states, and (3) The ingestion
of certain drugs.
PHYSIOLOGICAL CONDITIONS
It is now recognised that the purin bases of the body exist not only in
the bound form (nucleic acid), but also _free_, especially in _muscular_
tissue. Also, that from such free purin bases uric acid can be readily
formed as from those liberated by the disruption of nucleic acid. Thus,
_inosinic_ acid, a nucleotid first isolated from meat extract, yields
phosphoric acid and the purin base, _hypoxanthine_. In possession of
these facts, we shall be better able to appreciate the significance of
the researches of Burian and others.
(_a_) _Muscular Exercise._—According to Burian a large increase in the
excretion of uric acid was found to follow _muscular exercise_. The same
observer also noted the presence of _hypoxanthine_ in defibrinated
blood after its perfusion through the hind legs of a dog whose muscles
had been thrown into tetanus. Moreover, subsequent to contraction, the
muscles themselves contained an increased amount of oxypurine. From these
findings Burian concluded that hypoxanthine was a product of _muscular
action_, and that this substance or its precursor, _inosinic acid_, was
an important source of _endogenous uric acid_. The uric acid thus formed
by oxidation was then partly destroyed in the liver and partly excreted
by the kidneys. But Burian noted also during activity of the muscles
that a certain amount of the _purin bases_ failed of oxidation, and
consequently a larger amount of the same, as compared with uric acid,
passed into the circulation.
Kennaway, discussing the effect of _muscular exercise_ on the excretion
of endogenous purins, noted that during unaccustomed exercise the _uric
acid output_ of the kidneys diminished, but that of the purin bases is
relatively augmented, but, on the whole, he found that the total purin
output (bases plus uric acid) was not very much increased.
Leathes and others, investigating the effects on uric acid excretion of
strenuous exercise, established the occurrence of a distinct increase.
Given that the same kind of exercise is practised on the day following,
the said increase is much less marked. If, however, some different
form of muscular activity is undertaken, another increase in uric acid
follows. It would appear, therefore, that, despite conflicting evidence,
the balance of opinion favours the view that muscular activity does lead
to increase in endogenous uric acid excretion.
(_b_) _Periodic Variations._—Leathes noted _diurnal_ and _nocturnal_
variations in the excretion of endogenous uric acid, the maximum
occurring within the early waking hours, and sinking to a minimum towards
the evening. His experiments, he held, indicated a variation in the
actual formation of endogenous uric acid at different periods of the day.
Rockwood also found that an increase occurred during the daytime, and
Pfeil, that there was a morning rise in the amount of uric acid passed.
The fact that doubt still obtains as to whether muscular exercise has any
effect on endogenous uric acid excretion, renders explanation of this
diurnal variation difficult. This especially as there are no fluctuations
in the urinary functions that could in any way account for it.
PATHOLOGICAL STATES
Endogenous uric acid is increased under certain pathological conditions.
Leathes’ recent work confirmed the view that there is an increased
production of nitrogenous waste in _fevers_. After taking a large dose
of anti-typhoid serum his temperature rose to 103° F. Experimenting
on himself, he found his output of urea, uric acid, and creatinine
all increased, but of all three _uric acid_ showed the most marked
alteration. The question now arises as to whether such is due to
increased production or diminished destruction. Some further experiments
conducted by Leathes on himself may serve to elucidate this point.
Subjecting himself for a prolonged period to cold baths, a similar
increase in his _uric acid_ output ensued. This would appear to indicate
that, through increased loss of heat, the bodily processes of combustion
were augmented to maintain the body temperature, with, as a consequence,
increased uric acid excretion.
In _leukæmia_ protein-destroying forces are at work, and the urine
contains large quantities of _uric acid_. The same is attributed to the
formation and destruction of enormous numbers of _leucocytes_, but the
urinary findings in this respect have been extremely variable. While
increased uric acid elimination has been vouched for by many authors,
some have noted increase in the _purin bases_, sometimes with, and
sometimes without increase in the uric acid; while others again have even
noted a decrease in uric acid and _phosphoric acid_ excretion.
Apart from these contradictory findings, it would appear, according to
Magnus-Levy, that in _acute_ leukæmias the relation between the number
of leucocytes and the uric acid output is most variable. Lastly, the
different types of leukæmia present differences in regard of their uric
acid output, the increase in the _myelogenous_ variety being much more
marked than in the _lymphatic_ form.
Wells, discussing these conflicting data, considers that they are but
the reflex of the “known fluctuations in the course of the pathological
processes of leukæmia; the number of leucocytes, the size of the
lymphatic organs, and the general condition of the patient all vary
greatly from time to time, often with remarkable rapidity and the
excretion of products of metabolic activity must vary likewise.”
Continuing, he observes that the enormous increase in the amount of
lymphoid tissue in the body and blood must give rise to a greatly
augmented _nuclein katabolism_, with sequential appearance of _uric
acid_, _purin bases_, and _phosphoric acid_ in the urine. This he holds
to be well demonstrated by the increased elimination of uric acid and
purin bases, together with a general increase in the nitrogen output such
as has been frequently noted in sequence to the therapeutic use of X-rays
in leukæmia, this attributable to the increased autolysis known to be
induced by X-rays.
As to this question of the relationship of _leucocytosis_ to _uric acid
excretion_, it must be borne in mind that the number of leucocytes and
the excretion of uric acid do not always vary directly. Parallel studies
of the blood and urine have shown that _leucocytosis does not invariably
accompany increased uric acid excretion_. Indeed, Hutchison and MacLeod
have recorded cases of _leucopenia_ without any reduction in the amount
of uric acid eliminated.
Also, we have to recall that on a _purin-free_ diet the amount of
endogenous uric acid is more than can come from _nuclein_ destruction
in the body. As suggested by Burian, some may be derived from the
_hypoxanthine_ in muscular tissue. In short, while nuclein disintegration
is the outstanding source of endogenous purin, yet, for the reason cited,
it cannot be regarded as the sole source, for the exact origin of all the
endogenous purin is not as yet established.
In conclusion, it would appear that some _drugs_ influence more or less
markedly the excretion of endogenous uric acid, notably, atophan; but
discussion of these will, we think, be best postponed to the section
dealing with the medicinal treatment of gout. Meanwhile we shall proceed
to consider the vexed question of the formation within the organism of
uric acid by synthesis.
SYNTHETIC FORMATION OF URIC ACID
Birds eliminate most of their nitrogen in the form of uric acid, and,
undoubtedly, in their instance synthetic formation of uric acid in the
liver takes place on a large scale. Thus, when blood containing ammonium
lactate is perfused through the liver of the goose, an increase in the
uric acid content of the blood occurs. Also the ingestion of lactic,
pyruvic and other organic acids leads to augmented output of uric acid;
in short, it is generally agreed that in birds _synthesis_ is the chief
mode of formation of uric acid, homologous with the formation of _urea_
in the liver of mammals.
If this be true of birds, on the other hand, _splitting_ and _oxidation_
of _nucleins_ is in _mammals_ the most important source of uric acid,
but there is evidence that it cannot all be accounted for in this way.
As before remarked, the old belief that purin excretion remains almost
constant on a _purin-free_ diet, despite great variations in the amount
of the ingests, is not strictly true. Thus, using swifter and more
reliable methods for the estimation of nitrogenous metabolites, Folin
noted, on an absolutely purin-free diet, that an increase in purin
excretion ensued, given _marked_ variations in the intake of food. Again,
the Dalmatian dog, as we have seen, excretes uric acid in his urine.
S. R. Benedict was therefore able to demonstrate that a very distinct
increase in his uric acid output ensued in sequence to increase in the
amount of his _non-purin_ food; moreover, that even when such non-purin
foods were continued for a year, “the total amount of uric acid excreted
was at least ten times greater than could have come from the traces
unavoidably included in the food” (MacLeod).
Also Ascoli and Izar, experimenting with dog livers, noted on incubation
thereof and passage through the same of oxygen that the uric acid
disappeared; but on the substitution of carbon dioxide an accumulation
thereof ensued. Wells, however, was unable to confirm this re-synthesis
of uric acid by dog livers, and Spiers also failed to corroborate their
findings.
On the other hand, there is evidence pointing to the fact that a certain
small percentage of synthetic formation does take place in the organism.
Thus certain chemical substances, and these not purin, do cause an
appreciable though slight increase in the purin excretion of mammals,
and a very marked augmentation of the same in birds, viz., _lactic_,
_tartronic_ and _B-oxybutyric acids_.
But, as MacLeod, discussing these experimental and clinical findings,
observes, there are to hand even more direct proofs that _purin
synthesis_ occurs in mammals. Thus, as McCallum has pointed out, we
cannot escape the admission that young mammals are able to synthetise
the purins essential for their growth, and this from food containing no
purin, _e.g._, milk. Again, prior to incubation, a hen’s egg contains
practically no nucleic acid, whereas after development its content in
the same increases by great strides. The eggs of insects, too, with the
progress of development, amass purin very rapidly.
Again, Miescher noted long since that salmon, on leaving the sea
to ascend rivers for the object of spawning, have at that time
well-developed muscles; but on arriving at the upper reaches, marked
muscular wasting ensues, while the testes undergo enormous enlargement.
MacLeod, reflecting on these observations, argues that, “as the fish
takes no food during the migration, there must be conversion of the
protein of the muscles into the cellular tissue of the sexual glands,
and _nucleic acid_ must be produced.” MacLeod’s conclusion is that
“Purin synthesis undoubtedly occurs in the mammalian body, but it is
difficult to recognise in metabolism investigation, because it is a
slow continuous process ... whether or not changes in the activity of
purin synthesis occur in conditions of disease, is a question which
awaits investigation.” Lastly, the opinion of most authorities is that,
while they concede the possibility of synthetic formation, the amount
of uric acid produced in this manner is negligible, and that by far the
most important mode of formation in mammals is by the _splitting_ and
_oxidation_ of _nucleins_; in other words, that uric acid in the main
is derived from the _amino-purins_ by _deaminisation_ and subsequent
oxidation, and from the _oxy-purins_ directly by oxidation.