URICÆMIA IN GOUT
In the summer of 1848, Garrod made his momentous announcement that “the
blood in gout always contains uric acid in the form of urate of soda,
which salt can be obtained from it in crystalline state.” Some eleven
years later in his classic work on gout, he reiterated his affirmation,
but appended thereto the words, “in abnormal quantities.” Garrod’s
analyses were mainly _qualitative_, but, at any rate, in one instance, he
obtained from a gouty patient the equivalent of 5 mg. of uric acid per
100 gm. of blood serum, maintaining, however, that this amount was much
below that really present.
But not until 1895 was a series of _quantitative_ estimates undertaken
when Klemperer in three gouty subjects passing through an attack found
the blood content of uric acid to be 6·6 mg., 8·8 mg., and 9·5 mg. per
100 c.c. of blood. Some years later, Magnus Levy, investigating seventeen
gouty individuals, found that the amount of uric acid in the blood ranged
from 2·1-9·5 mg. per 100 c.c.
Brugsch and Schittenhelm noted that, in gouty victims, uric acid was
still present in the blood even when they had been on purin-free diet for
weeks or months. They held endogenous uricæmia to be a constant symptom
in gout. Even as late as 1913 the former investigator contended that, in
a healthy person on a purin-free diet, the presence of uric acid in the
blood cannot be satisfactorily demonstrated. But it must be recollected
that the _precipitation_ (ammonical silver and cupric bisulphite) method
was beset with disadvantages. An approximate estimate only of the blood
content of uric acid was with difficulty to be achieved even when large
quantities were available.
Fortunately, however, our powers of analysis in this direction became
greatly enlarged with the introduction in 1913 of the colorimetric method
of Folin and Denis.
FOLIN AND DENIS’S METHOD
This colour reaction is so sensitive that one part of uric acid in a
million parts of water can be detected. Moreover, unlike the older
methods which required from 75-100 c.c. of blood or more, determinations
can be made with 20 c.c., and if the blood be rich in uric acid only 10
c.c. Walker Hall observes that the procedure “has many advantages and
does not take up much more time than some of the qualitative methods
when once the technical difficulties are overcome.” He described it as
follows:—
Twenty cubic centimetres of blood are withdrawn into a wide-mouthed,
tared bottle containing 0·1 gramme of finely-powdered potassium oxalate.
The flask and contents are then weighed. Five times the weight of
_n_/100 acetic acid is heated to boiling. The oxalated blood is poured
into the boiling acetic acid solution, and the heating continued until
the solution has begun again to boil. The mixture is filtered hot.
The clear filtrate and wash waters are acidified (0·5 c.c. of 50 per
cent. acetic acid) and evaporated to 3 c.c. Five drops of a 3 per cent.
silver lactate solution, two drops of magnesia mixture, and ten to
fifteen drops of strong ammonia hydrate are next added. The mixture
is centrifugalised. The supernatant fluid is removed. To the residue
five drops of freshly-saturated hydrogen sulphide water and one drop of
strong hydrochloric acid are added. The tube is placed in a beaker of
boiling water for ten minutes in order to remove the hydrogen sulphide.
The supernatant fluid is added to 2 c.c. of a solution containing 100
grams of sodium tungstate and 80 c.c. of 85 per cent. phosphoric acid in
1,000 c.c. of water and 10 c.c. of a saturated sodium carbonate solution.
The resultant blue solution is then compared with a standard uric acid
solution, and the result obtained by the following formula:—
(20_V_)/(_RW_) mg. of uric acid per 100 grams blood,[20]
where 20 represents depth in millimetres of standard solution,
_R_, the depth of unknown solution,
_V_, the volume to which the unknown solution is diluted,
_W_, the weight of blood taken for the determination.
URIC ACID A NORMAL CONSTITUENT OF BLOOD
Up till quite recently it was held that in normal persons the amount
of uric acid in the blood was too small to be detected; also that uric
acid was not demonstrable in the blood of normal individuals when on
a _purin-free_ diet. On the other hand, if the subject’s blood was
found to contain _uric acid_, while on a purin-free diet, it was held a
characteristic feature of _gout_ and of prime diagnostic import.
But, since the introduction of Folin and Denis’s method, it has been
established that uric acid is constantly present, in demonstrable
amounts, in _human_ blood. These authorities, using their _colorimetric_
method, found that the uric acid content of the blood ranged from 0·7-3·7
mg. per 100 grams. They believe that 1-2 mg. of uric acid per 100 grams
of blood is well within the normal variations, but “are not prepared to
say that they represent the full variations.”
However, before applying their colorimetric method to human subjects,
Folin and Denis conducted some researches into the uric acid blood
content of a variety of animals, the results of which appear in the
following table:—
URIC ACID, TOTAL NON-PROTEIN NITROGEN AND UREA NITROGEN IN BLOOD
(The Figures represent Milligrams per 100 grams of Blood.)
------------------------------------+-----+-----------+---------
|Uric |Non-protein| Urea
|acid.| nitrogen. |nitrogen.
------------------------------------+-----+-----------+---------
Rabbit (6 cases) |0·05 | 31 | 13
Sheep (mixed blood) |0·05 | 28 | 13
Pig (mixed blood) |0·05 | 32 | 14
Horse (1 case, anti-toxin animal) |0·05 | 54 | 28
Monkey (1 case, poliomyelitis) |0·05 | 60 | 38
Beef (mixed blood) |0·2 | 24 | 14
Cat (2 cases, diet, liver) |0·2 | 60 | 34
Cat (2 cases, diet, milk and eggs) |0·2 | 67 | 37
Cat (2 cases, diet, rice and cream) |0·2 | 31 | 20
Chicken (6 cases, mixed blood) |4·9 | 32 | 8
Duck (4 cases, mixed blood) |4·8 | 34 | 7
Goose (1 case) |4·8 | 26 | 8
------------------------------------+-----+-----------+---------
The most striking feature of these findings is the marked contrast
between the uric acid blood content of _mammals_ as opposed to avians. In
the former the amount is minimal—0·2 mg. or less per 100 grams of blood.
On the other hand, in the blood of _birds_, in whose instance the origin
of uric acid is so different, it is present in relatively large amounts.
As Folin and Denis observe, the small amounts of _urea_ in the blood of
birds, as compared with that of mammals, is also worthy of note.
Reverting now to the findings in human subjects, as observed by Folin and
Denis, these have been summarised as follows by Walker Hall:—
URIC ACID, TOTAL NON-PROTEIN NITROGEN AND UREA NITROGEN IN BLOOD
(The Figures represent Milligrams per 100 grams of Blood.)
-----------------------------------+----------+-----------+---------
|Uric acid.|Non-protein| Urea
| | nitrogen. |nitrogen.
-----------------------------------+----------+-----------+---------
Human, group 1 | 0·8 | 36 | 19
Human, group 2 | 1·5 | 34 | 18
Human, group 3 | 2·8 | 36 | 19
Human, with blood pressures of 160 | 2·9 | 50 | 33
Human, with blood pressures of 200 | 1·2 | 50 | 22
Human, with blood pressures of 220 | 2·7 | 40 | 19
Human, with blood pressures of 260 | 3·9 | 52 | 20
Human, alcoholic | 1·0 | 43 | 29
Human, chronic gout | 3·9 | 25 | 13
Human, chronic gout | 4·4 | 30 | 15
Human, chronic gout | 5·2 | 20 | 13
Human, lead poisoning | 4·7 | 50 | 31
Human, lead poisoning | 4·8 | 52 | 32
Human, leukæmia | 3·1 | 33 | 14
Human, acute nephritis with | | |
arterio-sclerosis | 2·7 | 40 | 19
Human, chronic nephritis with | | |
arterio-sclerosis | 2·5 | 38 | 19
-----------------------------------+----------+-----------+---------
Interesting and valuable as are the above findings, Folin and Denis are
careful to point out that, even as regards the first three groups in the
above table, “the figures can scarcely be said to represent the strictly
normal variations, for no attempt was made to select physically normal
persons.” The samples of blood were drawn from patients newly admitted to
the Boston _Psychopathic_ Hospital.
It may be noted that of all the _mammals_ examined the blood of _man_
contains by far the greatest amount of uric acid. Also that in humans the
uric acid blood content varies in different persons, and, moreover, as
Walker Hall points out, “the figures lend support to the view that there
may be groups or families exhibiting similar features.” It will be seen,
too, that the blood uric acid in _gout_ and _lead poisoning_ stands at a
high level, though not so elevated as was formerly maintained. From the
figures, too, it may be gleaned that apparently no relationship obtains
between the amount of uric acid and that of the urea or total non-protein
nitrogen in the blood.
At the same institution in Boston, Adler and Ragle conducted a similar
series of investigations, though on a more extended scale. These
observers, taking 156 unselected _psychopathic_ patients, found that in
107 examples the uric acid content of the blood was from 1-2 mg., in
thirty-eight more than 2 mg., and in eleven instances less than 1 mg. To
sum up, the uric acid content varied from 0·7-4·5 mg. per 100 grams of
blood, an average of 1·7 mg.
As before stated, it was until recently maintained that in the blood
of _normal_ individuals, on a _purin-free_ diet, _uric acid_ was
undemonstrable. But McLester, utilising Folin’s method, found uric
acid in the blood of fifteen _healthy_ individuals, who had been on a
_purin-free_ diet for at least three days, and this in amounts ranging
from 0·5-2·9 mg. per 100 grams of blood, an average of 1·4, as contrasted
with 1·7, the average amount in Adler and Ragle’s series. Pratt,
discussing these findings, considers that the fact that the _average_
amounts approximate so nearly in the two series is worthy of emphasis.
This especially as all McLester’s examples were young healthy adults on a
_purin-free diet_, while the patients studied by Adler and Ragle were of
all ages and on a _mixed_ diet.[21]
EFFECT OF EXOGENOUS PURINES
As we are aware, the amount of uric acid excreted in the _urine_
increases markedly on a _purin-rich diet_. But recent researches appear
to raise doubts as to whether the uric acid content of the _blood_ rises
correspondingly. Thus, according to Walker Hall, “a state of _uricæmia_
is said to exist if the amount of uric acid in the blood exceeds 0·8 mg.
per 100 c.c.” The figure he considers is probably too low for, after an
average meat breakfast, the blood uric acid rises to 1 or 2 mg. per 100
c.c. _in normal_ adults, or even higher after an excessive intake of
_purin-rich_ foods.
On the other hand, Denis, investigating the effect of ingested purin on
the uric acid content of the blood, found that in _normal_ individuals
_no increase in the circulating uric acid_ follows the intake; in other
words, the kidney, in _normal_ persons, is quite capable of excreting any
excess of uric acid presented to it, thereby keeping the uric acid of
the blood at the same level as obtains when only the _endogenous_ moiety
thereof has to be eliminated.
Moreover, another factor, according to Folin and Denis, that operates
in the same direction is the _binding capacity of the tissues for uric
acid_. Pratt of Boston’s observations, too, appear to indicate “That the
uric acid derived from exogenous purin does not accumulate in the blood
unless there is a disturbance in the uric acid metabolism.”
On the other hand, given damage to the _kidney_ (even when this has not
progressed to the point when nitrogen retention is apparent, as shown
by the non-protein nitrogen values), an accumulation of uric acid takes
place in the blood after a short period of purin feeding.[22]
Now, as to the second regulating factor, the _retention capacity_ of the
_tissues_ for _uric acid_, it may be said that the amount, in _normal_
subjects, would appear to be small. But Fine, it may be noted, found that
the uric acid content in divers tissues was relatively proportionate to
that of the blood, whether normal or increased in amount.
But, to resume, Denis also demonstrated that the uric acid content of
the blood in patients suffering from various _chronic diseases other
than gout_ was also not increased on a purin-rich diet. To sum up, the
researches of Denis would appear to indicate that:—
(1) In _normal_ subjects _no increase_ in the _uric_ acid
content of the _blood_ follows exogenous purin intake.
(2) The uric acid content of the blood in patients suffering
from chronic diseases, other than _gout_ or _renal_ disease, is
similarly _not_ augmented on a _purin-rich_ diet.
(3) The _uric acid content_ of the _blood_ is _increased_ more
or less markedly, after a short period of purin feeding, in the
presence of defective _renal elimination_.
In amplification of the second of the foregoing postulates some
observations by Pratt may be quoted. This authority is of opinion
that the low amount of uric acid present in the blood of unselected
_psychiatric_ patients on a mixed diet (Folin and Denis, Adler and Ragle)
shows that a retention of uric acid in the blood in any considerable
amount for twenty-four to twenty-eight hours rarely occurs. For, as he
informs us, these patients at the Boston Psychopathic Hospital, when on
ordinary diet, are eating purin-containing food daily, and they might
take as much or more purin during the forty-eight hours preceding the
blood analysis as is contained in a single sweetbread meal. Now, as Pratt
argues, if the uric acid thus derived accumulated in the blood, the
amount found would be considerably greater than that of individuals on a
_purin-free_ diet. But, on the contrary, it transpires that the average
amount of uric acid found by Adler and Ragle in the blood of patients on
an ordinary diet was only 0·3 mg. more than that found by McLester in
normal individuals on a _purine-free_ diet. The diagnostic significance
of these observations will be better appreciated when we come to discuss
the sequential increase of the uric acid content of the blood in _gouty_
subjects after the ingestion of purin-rich substances.
URIC ACID CONTENT OF BLOOD IN GOUT
Taking 1-3 mg. per 100 c.c. as the normal, the uric acid content of the
blood, in typical cases of gout, according to MacLeod, rises to nearly 10
mg. Gudzent, from his studies, maintains that the blood, in almost all
cases of gout, contains as much or even more _mono-sodium urate_ than
it can hold in solution (1-8 mg.), in other words, it is in effect a
supersaturated solution of the relatively insoluble _lactim_ urate.
Pratt, working in Folin’s laboratory, investigated a series of cases of
gout, selecting only those in which (1) Tophi were found, (2) A history
of characteristic attacks of acute gout was obtained, or (3) Typical
symptoms developed while under observation.
At the time of examination the average uric acid content, irrespective of
the diet or condition, was 3·7 mg. In three patients on _ordinary diet_,
who were seen during attacks, the amounts were 4·5, 4·8 and 5·7 mg. of
uric acid. In two other patients, also seen during attacks, and while on
a _purin-free_ diet, the uric acid in four estimates ranged from 2·4-5·1
mg., viz., an average of 3·6 mg. None of these patients were taking
atophan.
Seven patients, on a _mixed_ diet, and free at the time from symptoms of
gout, contained on the average 4·3 mg. of uric acid in their blood.
On the other hand, examination of the blood in six patients on a
_purin-free_ diet, at the time manifesting no acute symptoms of gout,
revealed an average uric acid content of 3 mg.
From the foregoing considerations it may be deduced that:—
(1) In gout there is a condition not of uricæmia, but of
_hyper-uricæmia_.
(2) That on the average the blood in _gouty_ subjects contains
twice as much uric acid as that of _non-gouty_ subjects, as
evidenced by comparison of the average uric acid content of the
blood in Pratt’s series of gouty cases (4·5 mg.) with Adler and
Ragle’s non-gouty examples (1·7 mg.).
(3) In contrast with non-gouty subjects, the uric acid content
of the blood in _gouty_ subjects is augmented on a purin-rich
diet.
(4) Both in the inter-paroxysmal periods and during attacks
the uric acid content of the blood, when on a _mixed_ diet, is
higher than when on a purin-free diet.
HYPER-URICÆMIA IN NON-GOUTY ARTHRITIS
Pratt, of Boston, has found that a condition of hyper-uricæmia is
sometimes demonstrable in joint disorders other than gouty; but he
maintains that the following distinction obtains, viz., that while in
gout the hyper-uricæmia is generally _constant_, in other forms of
arthritis it appears to be _transient_.
He cites a case of _infective_ arthritis, not exhibiting the clinical
features of gout, in which the first analysis of the blood by Denis
revealed a uric acid content of 7·6 mg.; but on a subsequent examination,
seven months later, only 0·8 mg. was found, this, though the patient
at the time was on a _purin-rich_ diet. This difference is response to
exogenous purins in gouty, as opposed to _non-gouty_ arthritics, is well
illustrated in the following table.
According to Walker Hall, the following example illustrates the
effect of purin-free as opposed to purin diet on the uric acid
blood content in a gouty subject:—
--------------------------------+-------+-------------+-------------
| Uric | Non-protein | Urea
| acid. | nitrogen. | nitrogen.
--------------------------------+-------+-------------+-------------
Mgs. per 100 gms. of blood.
Gout with purin dietary | 5·5 | 52 | 36
Gout with purin-free food | 3·4 | 40 | 18
--------------------------------+-------+-------------+-------------
GOUTY POLYARTHRITIS (PRATT).
---------------------------+----------+-----------------------+----------
|Milligrams| |Milligrams
| of | | of
|uric acid | |uric acid
| in 100 | | in 100
| gms. of | | gms. of
| blood. | | blood.
---------------------------+----------+-----------------------+----------
D. N. Gout. Purin-free | 3·1 |52 hours after eating | 5·8
diet. | | 280 grams haddock |
| | roe. |
| |3 days after eating | 6·2
| | 300 grams roast beef.|
K. Gout. Purin-free diet. | 2·4 |24 hours after eating | 3·0
| | 270 grams roast beef.|
H. Gout. Purin-free diet. | 1·7 |3 days after eating | 3·6
| | 150 grams thymus. |
P. Gout. Purin-free diet. | 2·1 |3 days after eating | 3·4
| | 160 grams thymus. |
J. N. Gout. Purin-free | 2·2 |48 hours after eating | 8·7
diet. | | 190 grams thymus. |
| --- | | ---
Average | 2·2 | Average | 5·1
---------------------------+----------+-----------------------+----------
NON-GOUTY POLYARTHRITIS (PRATT).
---------------------------+----------+-----------------------+----------
|Milligrams| |Milligrams
| of | | of
|uric acid | |uric acid
| in 100 | | in 100
| gms. of | | gms. of
| blood. | | blood.
---------------------------+----------+-----------------------+----------
McC. Chronic polyarthritis.| 1·7 |24 hours after eating | 2·2
Purin-free diet. | | 100 grams of thymus. |
M. Chronic polyarthritis. | 2·0 |24 hours after eating | 1·8
Ordinary diet. | | 225 grams of thymus. |
H. Chronic polyarthritis. | 2·9 |47 hours after eating | 2·5
Ordinary diet. | | 190 grams of thymus. |
| --- | | ---
Average | 2·1 | Average | 2·2
---------------------------+----------+-----------------------+----------
As Pratt points out, if the figures in the two tables be compared,
it will be seen that, prior to the sweetbread meal, the average uric
acid content of the blood in the gouty and the non-gouty patients was
identical. But twenty-four hours to three days, after the purin intake,
the average uric acid content of the blood in the _gouty_ was 5·1 mg.,
while in the _non-gouty_ subjects it was only 2·2 mg.; in other words,
in the five gouty individuals a pronounced hyper-uricæmia was produced
from one to three days after a purin meal. On the other hand, in the
_non-gouty_ subjects the uric acid content was found to be practically
unaltered twenty-four to forty-eight hours after the same purine intake.
It would seem, therefore, that some _diagnostic_ importance may be
attached to the _hyper-uricæmia_ that is induced in _gouty_ subjects
after exogenous purines, as compared with its non-occurrence in non-gouty
subjects.
Another interesting point elicited by Pratt was that in his _gouty_
examples, although, after a purin meal, the uric acid content of the
_blood_ rose markedly, yet there was no apparent _delay_ or _diminution_
in the output of _exogenous purin_ in the _urine_. Thus, in one example,
after the intake of 190 grams of thymus gland, the uric acid in the
blood, in the first twenty-four hours, rose from 2·2 mg. to 4·4 mg.,
reaching, on the third day, a maximum of 8·7 mg., which, on the fourth
day, sunk to 2·7 mg. Nevertheless, 26·2 per cent. of the ingested purin
nitrogen was excreted as uric acid. Now, as pointed out in the preceding
chapter, it has been shown by many observers that in _gouty_ subjects
the excretion of _exogenous_ purin is _diminished_ and _retarded_. But
Pratt’s study of the blood shows that a marked increase and retention of
uric acid in the _blood_ may result from the ingestion of purin bases,
even when no evidence of retention is found on the examination of the
_urine_.[23]
The clear inference from this is that it is desirable that our _urinary_
findings in respect of _uric acid_ should be reviewed and controlled in
light of _blood examinations_ to the same end.
VARIATIONS IN URIC ACID CONTENT OF BLOOD INDEPENDENTLY OF DIET
Considerable variations in the uric acid content of the blood, according
to Pratt, may occur both in _gouty_ and _non-gouty_ subjects, and which
cannot be attributed to any _purin intake_. Such oscillations, moreover,
may ensue within a short time. A patient of his, admitted to hospital
suffering from a severe attack of _gout_, was placed upon a _purin-free_
diet. Twenty-four hours afterwards examination revealed only 2·7 mg. of
uric acid in his blood. Subsequently, after having had no food containing
purins for fifteen days, it contained 5·1 mg.
Marked variations in the uric acid content of the blood may likewise
occur in _non-gouty_ subjects. After being on a _purin-free_ diet for two
days, a patient of Pratt’s, with _recurrent iritis_, had 2·2 mg., while a
few months after, when on a mixed diet, his blood contained only 0·8 mg.
Again, great oscillations in the blood content of uric acid, independent
of diet, are sometimes found in cases of _non-gouty arthritis_. Thus, in
one chronic case of this nature, the blood when first examined contained
7·6 mg. of uric acid, but a few months later, when on a purin-rich diet,
only 0·8 mg. were present. In another instance of _primary polyarthritis_
the same was strikingly exhibited. Aged twenty-two years, the subject in
October was on ordinary diet. His blood at that period showed 2·7 mg. of
uric acid per 100 mg. of blood; in December, on a purin-free diet, 5·0;
and in May, on a similar dietary, 1·6 mg.
As to whether in healthy individuals, on a purin-free diet, similar
variations in the uric acid content of the blood occur, is not
sufficiently ascertained. The solitary example that may be cited is
by McLester, who, as a result of four examinations of the blood in a
normal person on a purin-free diet, found that its uric acid content was
practically constant.
The deductions that may be drawn from the foregoing findings are:—
(1) That in _gouty_ subjects pronounced variations of the uric
acid content of the blood may occur which are not attributable
to the purin content of the food.
(2) That in _non-gouty_ arthritis similar fluctuations in the
blood content of uric acid, irrespective of diet, also occur.
(3) That in _normal_ persons, on a purin-free diet, the blood
content of uric acid, as far as is ascertained, does not show
such variations.
WHAT RELATION, IF ANY, EXISTS BETWEEN THE URIC ACID CONTENT OF THE BLOOD
AND ATTACKS OF GOUT?
If uric acid be _causally_ related to gout, it would seem reasonable to
expect that the blood content thereof would stand in some clear relation
to the _incidence_ or _intensity_ of attacks.
But, according to Pratt and others, no variations indicative of such
a relationship obtain. For, independently of _acute_ attacks, and,
moreover, in the absence of any pronounced _renal inadequacy_, the blood
of gouty subjects, even on a _purin-free_ diet, contains, as a rule, 4-9
mg. of uric acid.
More pertinently to our point, in the experience of Daniels and
McCrudden, it transpires that, contrary to the usually accepted teaching,
typical _acute_ attacks might occur without any variation in the _uric
acid content of the blood_ or its _excretion_.
Nor did their iconoclastic findings cease here, for, _mirabile
dictu_! attacks ensued even when the uric acid blood content was at a
_sub-normal_ level; this latter, owing to the victims being at the time
on _atophan_, which increases uric acid elimination. In this connection
it is worthy of note that, according to Pratt, the uric acid content of
the blood may at times be low, even when atophan has not been taken. In
one of his cases, on a purin-free diet, only 1·7 mg. was present, and in
another case, on a mixed diet, 1·9 mg.
Daniels and McCrudden, too, note that the uric acid content of the blood
in gouty subjects may be _persistently_ lowered, _even under the normal
average_. His, again, has recorded an instance of a gouty subject,
with multiple tophi, whose blood did not contain an excess of uric
acid. Bloch, also, took 200 c.c. of blood from a man, aged twenty-five,
suffering at the time from a typical attack of gout in the big toe; but
uricæmia was not present.
Bass and Herzberg injected uric acid into the blood of gouty subjects
until its content thereof reached 10 mg. per 100 c.c., this without
any joint symptoms supervening. The same observers, aspirating _joint
fluids_ in _non-gouty_ subjects, noted that the uric acid content was
approximately the same as that of the blood. But, in contradistinction
thereto, in two _gouty_ subjects, victims of _uræmia_, they found in the
joint fluids 18·5 and 20·8 mg. of uric acid, while the blood content was
only 10 mg. and 8·2 mg.
Furthermore, intravenous injection of uric acid engendered a lesser
degree of _uricæmia_ in the gouty—this despite _impaired renal
excretion_. To their mind, therefore, the inference was that the _bodily
tissues_ in gout display an enhanced capacity for taking up uric acid.
Lastly, Walker Hall, discussing the question as to whether any relation
obtains between the degree of uricæmia and the onset of acute attacks,
observes that, “the evidence is more general than specific.” Thus he
reminds us that excessive intake of purin food has sometimes been
followed by, or associated with, an acute outbreak. Also, that the
leucocytic destruction which occurs during acute lobar pneumonia and
after the use of X-rays has occasionally coincided with an acute
paroxysm. To this, again, must be added the fact that atophan curtails
the duration of acute attacks, apparently by exciting an increased
uric acid output. Superficially regarded, these facts might appear to
be conclusive; but, as Walker Hall states, it must be recalled that
overeating, overdrinking, trauma, mental disturbances, atmospheric
vicissitudes, and bacterial infections have also preceded acute outbreaks.
To sum up, the main conclusions deducible from the foregoing clinical and
experimental findings would appear to be that:—
(1) No constant relation has as yet been established between
the uric acid content of the blood and acute attacks of gout.
(2) No variations in the same apparently herald or accompany
typical acute paroxysms.
(3) Attacks may occur with a _sub-normal_ uric acid blood
content.
(4) The tissues of gouty subjects apparently possess an
enhanced binding capacity in respect of uric acid.
(5) _Given impaired renal excretion in gouty subjects_,
the uric acid content of the _joint fluid_ rises markedly,
exceeding that of the blood.
DISCUSSION OF THE FOREGOING DATA
While the researches of the past decade have proved distinctly
encouraging, yet we must not blind ourselves to the fact that the
foregoing findings, and alike our deductions therefrom, are largely
provisional; for we stand in grave danger of over-emphasising the
significance of the results forthcoming from the investigation of
isolated samples of blood from different individuals. The recorded
estimates of the uric acid content of the blood in _strictly normal
persons_ are all too few, the findings in _diseased_ subjects too
conflicting, to warrant dogmatic inferences, wide generalisations. In
truth, the problem is by no means as simple as may at first sight appear,
and this but a slight digression will suffice to make clear.
_The Significance of Uricæmia._—It is generally maintained that the
blood content of uric acid in gout is above normal. Yet the _excretion_
of _uric acid_, save during acute attacks, rests within physiological
limits. Again, _à propos_ of our claim that the _blood_ is _surcharged_
therewith, we have the awkward fact, as yet inexplicable on chemical or
physico-chemical grounds, that the blood-stream can hold in suspension
far more uric acid than has ever yet been met with in gout, according to
Bechhold and Ziegler no less than 50 mg. of _uric acid_ per 100 c.c. of
blood serum before deposition tends to occur. On the other hand, _urates_
are less soluble therein, not exceeding 2·5 mg. per 100 c.c. How remote
from the limit of saturation the highest figures observed in gout! What a
large margin of solubility is still available!
Again, the uric acid blood content in gout is far less than was formerly
thought. Only by a few milligrams does it transcend that found in normal
individuals. Can this slight disparity have such profound potentialities
as to determine the incidence or not of _gout_? and this with the
saturation point still so remote. The urates, too, being practically
non-toxic, how difficult to conceive that the almost trivial excess of
the uric acid blood content over the normal is adequate to produce the
fulminant and dramatic phenomena of acute gout.
Again, though we speak of uricæmia as a dominant characteristic of
gout, we are uncertain whether the alleged increase in the uric acid
content of the blood is _real_ or merely _apparent_. We can, it is true,
extract _uric acid_ and _urates_ from the blood-stream, but it does not
necessarily follow that it is as such that they circulate _in vivo_.
We need walk circumspectly here for, despite the most modern methods
of blood analysis, we are still ignorant as to the exact form in which
uric acid exists in the blood-stream; whether the purins of the food
appear in the blood-stream as _sodium monourate_, or in _organic fusion_.
Accordingly, in the interests of progress, it were well to bear in mind
the pitfalls that beset uric acid estimation, the insufficiently eclectic
capacity of even the most modern tests, and to consideration of these
more chastening aspects we now proceed.
_Sources of Fallacy in Uric Acid Estimation._—With Folin’s findings as
his basis, Walker Hall estimates that, excluding the lymphatics and
lymph spaces, the entire blood-stream contains normally 70 mg. of uric
acid, _i.e._, 2 mg. of uric acid per 100 grams of blood, 3,500 c.c.
(total quantity of blood).
Thence he argues that, inasmuch as about 1 litre of blood traverses
the kidney per minute, the total content thereof of _uric acid_ would
gain access to the renal organs in three and a half minutes. Now the
average total output of the kidneys is 500 mg. per twenty-four hours.
Accordingly, assuming that the blood arriving at the kidneys contains as
a constant the above 70 mg. uric acid, the total daily output would pass
through these organs in twenty-five minutes.
Now, given immediate extraction of all the uric acid by the renal cells,
then the blood in the renal veins will become _free of uric acid_. If so,
the estimates of the uric acid content of the blood will reflect exactly
the measure of the _endogenous_ or _exogenous_ nuclein metabolism. But,
“if the renal vein blood is not _purin-free_, then the _estimations will
fail to yield a true picture of the activities of nuclein exchange_.”
Again, as to the precise import of isolated estimates of the uric acid
blood content, we must recollect that the _excretion of purins_ is
not distributed evenly over the twenty-four hours, varying as it does
under the influence of food, exercise, sleep, and other factors. _A
propos_ of this, Pratt’s observations clearly show that both in _gouty_
and _non-gouty subjects fluctuations in the uric acid blood content_
also occur, and this independently of _diet_. To what, then, may these
variations be referred? Obviously a question of great moment, especially
when we recall the eccentric behaviour of the _blood uric acid_ in
relation to the incidence of _acute gouty attacks_. For, until the inward
meaning of these vagaries is revealed, the value of recorded estimates
must necessarily be discounted considerably.
We must recall, too, that a certain moiety of the purins derived from
nuclein metabolism lags in the _lymph_ spaces and _lymphatics_, and
this, as Walker Hall reminds us, must reduce the quantity present in the
blood-stream at any one time. Also, as the same authority reflects, the
lymph stream being probably richer in _sodium ions_ than the blood, the
entry of the nucleins therein may be retarded and so lead to a still
further reduction of the blood content.
There is yet another possibility, he reminds us, viz., “that the
purin content of the blood varies in the peripheral pulmonary hepatic
and osseous streams, and that, while in some parts the purins are
being carried to the kidneys for excretion, in others they are being
transported from one organ to another for further metabolism.”
For, as before pointed out, the enzymes responsible for the ultimate
disruption of the _nucleosides_ are scattered in different organs, and
Walker Hall suggests that “a transport of half metabolised nucleotides
from one organ to another may form a part of the normal processes of
nuclein metabolism.” This may well lead us on to consider the limitations
that beset even the most modern tests in use for uric acid determination.
_Disabilities of Modern Tests._—With all its outstanding advantages, even
the Folin method of uric acid estimation has its drawbacks. As Curtman
and Lehrman have pointed out, different workers have, even on _identical
blood samples_, arrived at results which vary widely. Nor, disconcerting
though it be, do the limitations of this mode of hæmo-analysis cease here.
Thus we know from Gudzent and Apolant that the soluble but unstable
biurate is constantly being transmuted into an insoluble stable type,
in other words, metamorphosis from one _isomer_ into another. But,
unhappily, the tests to hand fail of differentiation of the several
_tautomeric_ forms of uric acid. Also, as isomers of uric acid actually
exist, then _quâ_ Walker Hall, why not isomers of _purins_ and
_pyrimidins_ also? But here again our tests are insufficiently eclectic.
They give us no clue as to the affinities or blends of purins or
pyrimidins for or with other substances.
Again, as our criteria fall short of identifying the exact form of the
“purin combinations” it follows, therefore, that they tell us nothing as
to whether “the increase is due to a more active transport of purins from
one organ to another for further metabolism or simply to a transport to
the kidneys for elimination.”
In other words, hampered by the above disabilities in our tests, it is
beyond our power to determine whether “the increases denote a supernormal
nuclein metabolism or an unusual type of nuclein cleavage.” Should it
ultimately transpire that the increase in the purin blood content is a
_real_ one, viz., made up of “an excess of normally formed and normally
bound purins,” a great step forward will have been achieved. For, to
account for the same it will, as Walker Hall observed, be necessary to
postulate a _supernormal nuclear activity_ of _generalised or_ localised
distribution.
_Need for Further Investigations._—While none can doubt that, by means of
chemical investigation of the _blood_, the clinical problem of gout will
be elucidated to a much greater extent than has been possible by means of
_urine analysis_, still much remains to be done before recent findings
can be applied to the solution of the etiology of _gout_.
The results of _blood analyses_ up to now have afforded us no clue as to
the intimate nature of the warp in _nuclein metabolism_. At the most,
the researches in this sphere do but make it increasingly clear that
uricæmia is _not the cause but the result_ of gout.
Albeit, this conclusion does not justify us in putting out of court all
thought of _uric acid_ in connection with gout. Any tendency thereto
will be immediately checked when we recall that uratic deposits, _i.e._,
_tophi_ constitute the solitary unequivocal token of gout, and to this
aspect of the question the ensuing chapter will be devoted.
Meanwhile, systematic investigations of the purin content of the blood,
not only in gouty but in _normal_ subjects, would surely dissipate much
of the obscurity that envelops this complex question. It were well, too,
that _blood_ and _urine_ analyses go hand in hand in our investigations.
How illumining these have been in connection with _atophan_, the
increased urinary output of uric acid having been found to be correlated
with a simultaneous sinking in the level of the uric acid of the blood.
Again, the _excretion of urinary purin_ ebbs and flows with the intake
of food and the degree of muscular activity, while sleep also exerts an
influence, not to mention constitutional disturbances, _e.g._, fever
infections, etc.
Can it be doubted that the _blood_ content of uric acid varies with these
same vicissitudes? Walker Hall tells us that the data to hand, “as to
the rapidity of the appearance of purins in the blood-stream after food,
infections, fever, etc.,” though few in number, yet suggest that “the
excretion by the kidney is _tidal_ in character, and that the blood uric
acid has similar characteristics.” In light of these possibilities, we
may well pause before attempting to appraise exactly the significance of
isolated blood examinations.
What, too, as the above authority observes, of the influence on the
_gouty uricæmia_ of infancy, puberty, the menopause, and for that matter
the pre-senile and senile periods of life with their associated vascular
lesions? The researches of Uffenheimer prove that even in young children
the disorders of purin metabolism distinctive of gout are to be met with,
_i.e._, “infantile gout.”
We stand also in urgent need of knowledge as to the uric acid blood
content in the _early_ as opposed to the late stages of gout; in need,
too, of further examinations of the blood to this end, not only during
the passage of _acute_ attacks, but even more under those conditions
which are presumed to determine their incidence.
But, despite these gaps in knowledge, these disabilities of technique,
there is no need for despair. “It is a slow progress along the zigzag
which leads to the centre of the ‘gouty maze,’ but the researches of the
last decade have opened up many new and possible pathways thereto.”