Chapter XI: 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Twenty cubic centimetres of blood are withdrawn into a wide-mouthed, tared bottle containing 0·1 gramme of finely-powdered potassium oxalate.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.”