URATOSIS IN RELATION TO GOUT
The two salient features of the gouty diathesis are:—
(_a_) The tendency to excess of uric acid in the blood, _i.e._,
_hyper-uricæmia_, and
(_b_) The tendency to uratic deposition, _i.e._, _uratosis_.
With the former we have dealt, but before passing to discuss the latter,
it will, we think, be advisable to review both these morbid tendencies in
relation to gout.
Hyper-uricæmia and uratosis, though they both occur in gout, are
by no means of identical pathological valency or significance. In
hyper-uricæmia the uric acid, either in a free state or combined,
circulates in the blood and lymph. In uratosis the uric acid is anchored
in solid form in the substance of the tissues. In the former, then, the
uric acid, if it be noxious, acts as a chemical poison, in the latter as
a mechanical irritant.
But the more striking contrast is that while hyper-uricæmia is not
restricted to gout, but occurs in many other disorders; on the other
hand, uratosis is absolutely confined to the gouty state, constituting
its pathognomonic stigma.
Again, hyper-uricæmia may exist for prolonged periods without producing
uratosis. But uratosis cannot, as far as is ascertained, occur without a
co-existing hyper-uricæmia. From these disparities it may legitimately be
inferred that the factors responsible for the genesis of hyper-uricæmia
and of uratosis, are not identical; in other words, that in uratosis some
other agency or agencies are at work over and beyond those that beget
hyper-uricæmia.
Lastly, inasmuch as uratosis stamps the seal of specificity upon gout,
it follows, from this and the above considerations, that there is a
more intimate relation between gout and uratosis than between gout and
hyper-uricæmia, and that the factors which make for uratosis have a more
intimate bearing upon the pathogeny of gout than those which lead to
hyper-uricæmia.
CONSTITUTION OF TOPHI
“Et tophus scaber, et nigris exesa chelydris Creta.”
_Virgil, Georg._, ii., 214.
The view that tophi were composed of chalk prevailed for centuries. As
we see such was the conception of Virgil, and in our own country John
Hunter entertained the same erroneous notion, while amongst the laity
this view as to their nature is held widely even to-day as it was in the
time of Dryden.
“Knots upon his gouty joints appear,
And chalk is in his crippled fingers found.”
_Dryden, Pers._
Albeit, the term “chalk-stones” is a misnomer, as tophi, when pure,
may be wholly devoid of lime. Modern analyses, too, have failed to
demonstrate the presence of calcium carbonate, the essential ingredient
being _urate of soda_.
On the authority of Rendu, we have it that Tennant and Pierson were the
first to demonstrate the presence of uric acid in gouty deposits, which
discovery was later confirmed by Fourcroy and Wollaston (1797), these
latter observers showing that they consisted almost exclusively of urate
of soda.
Subsequently to Wollaston’s day, many analyses have been conducted, by
Marchand, Lehmann, Wurzer, and Langier, L’Heretier, Ebstein and Sprague.
Of the various findings we append those by Marchand, Lehmann and one of
later date by Ebstein and Sprague.
MARCHAND’S ANALYSIS
Urate of soda 34·20
Urate of lime 2·12
Carbonate of ammonia 7·86
Chloride of sodium 14·12
Animal matter 32·53
Water 6·80
Loss 2·37
------
100·00
======
LEHMANN’S ANALYSIS
Urate of soda 52·12
Urate of lime 1·25
Chloride of sodium 9·84
Phosphate of lime 4·32
Cellular tissue 28·49
Water, loss, etc. 3·98
------
100·00
======
EBSTEIN AND SPRAGUE’S ANALYSIS
Uric acid 59·70
Tissue, organic matter 27·88
Sodium oxide 9·30
Potassium oxide 2·95
Calcium oxide 0·17
MgO, Fe, P₂O₅, S Traces.
It will be seen that all of them agree more or less closely as to the
essential ingredients being uric acid and soda. According to Ebstein and
Sprague they consist usually of almost pure _biurate_ of _sodium_ and
_potassium_. But, as a rule, after a time _calcium_ salts are deposited.
Dunin, it may be noted, has found deposits resembling gouty tophi, which
contained only calcium salts. Kahn, again, claims that tophi do not
always consist solely or even largely of urates, but that these may be
replaced by _calcium_ salts. It may be added, too, that M. B. Schmidt has
recorded, under the designation of “Calcium gout,” a case in which there
existed a generalised deposition of calcium, and this in tissues other
than those usually involved in “metastatic calcification.” But, to sum
up, although there may be admixture of lime salts and organic matter, the
salient chemical constituent of tophi is _biurate of sodium_.
MODE OF FORMATION
Gouty tophi, like all pathological concretions, are laid down in
accordance with a definite law. In the first instance, a central nucleus
is essential. To this must be added a “binding substance” or structural
framework of different nature from the main mass of the concretion.
Garrod, discussing the intimate structure of “chalk-stones,” observes
that, “the large amount of phosphate of lime occasionally met with is
probably derived not only from the tissue in which the chalk-stones have
been developed, but likewise from secondary deposition, the result of
ordinary inflammation around the original nucleus (urate of soda) which
acts as a foreign body.”
It is, however, quite possible that some substance other than _urate of
soda_ constitutes the primary nucleus, for, as we now know, concretions
most frequently gather around masses of mucin, clumped bacteria,
desquamated cells, precipitated proteins, etc. Thus, the renal _uric acid
infarcts_, supposed to result from disruption of the nucleo-proteins
of the _fœtal nucleated red corpuscles_, take origin around injured
_epithelial_ cells, which latter form the nucleus.
As to _gouty tophi_, too, it has been suggested that they form in
response to any _toxin_, resistance to which may involve death of the
tissue cells with consequent disruption of their _nucleins_ and formation
of _urates_. Such was the view held by Woods. Hutchinson, who also
thought that the calcareous accretions might be regarded as “protective,”
analogous to the formation of shells in the invertebrates, the process
here consisting in the deposition of lime salts in cells already
saturated with uric acid and urates.
In any case, whatever be the exact nature of the nucleus, the urate of
soda collects thereupon, the acicular crystals tending to assume the
form of radiating needles. But the successive depositions not being of
regular incidence, the surface of the crystals, in the intervals of
quiescence, becomes covered by _mucin_, animal or earthy matter. Hence,
the concretions display not only a _radiating_, but a _concentric_ or
_laminated_ structure.
The mucin acts as the “binding substance,” the crystals lying in its
meshes, and, moreover, remaining as the framework of the concretion even
after the crystals are dissolved out; in other words, the gouty tophus
is made up of a blend of _crystalloids_ and _colloids_, evolved from
solutions of the same character.
The importance of recognising the true nature of this binding substance,
_i.e._, mucin, merits a brief digression, in light of Ebstein’s view that
local tissue _necrosis_ is a necessary antecedent to uratic deposition.
Now, exhaustive studies of the histology of uratic deposits, both those
experimentally induced and of spontaneous gouty origin, have been
conducted by Freudweiler, His, Krause, and Rosenbach.
All their results, according to Gideon Wells, “indicate that uric acid
and urates excite some slight inflammatory reaction, cause a slight
local necrosis, and seem to act as a weak tissue poison.” According
to Rosenbach, however, this sequence is not invariable, inasmuch as
he noted that such deposits may occur without inducing necrosis. More
pertinently to our contention, however, is it that Krause’s experience
seems to indicate that errors of interpretation were possible. Thus, he
suggests that part of the material in the areas of uratic deposits merely
constituted the _framework_ of a crystalline deposit, though such were
currently regarded as _strands_ of _necrotic tissue_.
But, to resume, tophi being blends of _crystalloids_ and _colloids_, we
must recollect that the suspension capacity of _colloidal_ solutions for
crystalloids is much superior to that of simple solutions, by reason of
the fact that at the surface of each colloidal particle there exists a
zone in which the crystalloids are much more closely aggregated than
elsewhere, thus permitting more crystalloids to be dissolved in the
solvent between the colloidal particles. But, be it noted, this same
tendency to concentration of the crystalloids at the surface of the
colloidal elements leads to the colloids acting as determinants of
_precipitation_ when _crystalloids_ are in excess. Accordingly, when the
crystalloids pass out of solution, they form crystals or precipitates
intimately blended with the colloids. Thus, for example, when uric acid
crystallises out of urine it carries with it the colloidal pigments. On
the other hand, if the colloids are precipitated, the solvent capacity
of the solution being consequently depreciated, the crystalloids are
deposited in intimate relation with the colloids.
Again, Schade has pointed out that colloids may precipitate in reversible
form or not. If in irreversible (_e.g._, fibrin) form, the concretion
will remain permanent. But if the colloidal precipitate is reversible,
it may be redissolved, as happens with the uric _acid infarcts_ of the
infant’s kidney. In conclusion, we see, therefore, _re_ crystalloids and
colloids in animal juices, that the conditions of their solubility are
most complex, and though they do not explain the nature of gout, the
variations doubtless stand in intimate relation to the _formation of
tophi_.
LOCALISATION OF URATIC DEPOSITS
Uratic deposits evince a decided predilection for _cartilages_, tendons,
muscles, and skin. This localised distribution of the depositions would
seem to suggest their dependence on _local tissue peculiarities_. Now
the presence of _sodium_ salts in a solution diminishes the solubility
of urates therein. Consequently, in seeking to explain the incidence of
_tophi_, it was suggested that _cartilage_ and _tendons_, being richer
in _sodium ions_ than the _blood_, this might account for the fact that
urates tend to be precipitated in these particular structures.
Again, Almagia, working in Hofmeister’s laboratory, noted that thin
sections of _cartilage_, if left for some hours in a solution of sodium
urate, will take up _uric acid_. Direct inspection readily reveals the
presence of white foci and diffuse opacities due to uratic deposits. The
marked affinity of normal cartilage for uric acid is again attested by
the fact that, given injection thereof in quantity into the peritoneal
cavity of rabbits, the uric acid may often be detected by the murexide
reaction in _joint cartilage_, though apparently not in other tissues.
This behaviour would appear to justify the conclusion that the observed
accumulation of uric acid in the cartilages in the presence of states
of _uricæmia_, may be explicable on this same basis. In any case, this
marked affinity of even _normal_ cartilage for uric acid seems to
disprove the necessity of Ebstein’s postulate, viz., that the dissolved
uric acid sets up inflammation, and that an _antecedent necrosis_
precedes the _deposition of urates_. Still, even if we concede the fact
that _normal cartilage_ has a marked affinity for _uric acid_, how is it
that in _leukæmics_, despite their high blood content of _uric acid_,
no _uratic deposits_ ensue? Does not such disparity seem to indicate
that in gout some other factor intrudes? in other words, that the excess
of _sodium ions_ in particular tissues, while it may favour deposition
therein, is inadequate of itself to actually determine the formation of
tophi.
THE CAUSATION OF TOPHI
Many and divers are the theories that have been propounded to account
for the genesis of tophi. For some their incidence would appear to
predicate something abnormal in the conditions of uric acid solution and
circulation. Others have pinned their faith to some affinity on the part
of the bodily tissues for uric acid—an enhanced retention capacity on
their part for this substance. Some again, impressed by the objective
changes that mark the clinical evolution of tophi, have been led to
regard them as _concomitants_ or _sequels_ of _gouty inflammation_. But,
be the true explanation what it may, we may well preface our discussion
of the various theories by the obvious comment, viz., that the origin
of tophi must doubtless depend in the ultimate upon _constitutional_ or
_systemic_, as well as _local_, factors.
SOLUBILITIES OF URIC ACID
In the older conceptions of the pathology of gout the hypothesis that
found most vogue was that the separation of uric acid from the blood into
the tissues was due to _diminished alkalinity_ of the blood and tissue
juices; but, as before pointed out, it has been established that the
alkalinity of the blood is _not_ reduced, and the theory has consequently
been abandoned.
But, with the advent of Gudzent’s findings, viz., that uric acid
existed in two forms—one soluble and unstable, and the other insoluble
and stable, and that the former is constantly changing into the
latter—another conception of the origin of tophi arose. It was supposed
that, by reason of the disparity in solubility of these _tautomeric_
types of _uric acid_, the blood in gouty subjects must at times be
in a state of _super-saturation_ with uric acid; and, moreover, that
equilibrium could only be restored through abstraction of the urates by
crystallisation.
Unfortunately for this theory, it has been shown that the blood of gouty
subjects is not _super-saturated_ therewith; indeed, over and above the
highest increments hitherto met with in gouty blood, a considerable
margin of solubility for uric acid is still available. In truth, the
problem is by no means so simple; for the conditions governing the
solvency of uric acid in the blood are bewilderingly complex, subject
as they are to the manifold variations in solubility exhibited by
crystalloids in the presence of the many divers colloids.
But, to resume, Minkowski, it will be recalled, noted that from a
mixed solution of _uric_ and _nucleinic acids_ the former cannot be
precipitated by either acetic acid or alkaline ammonio-silver-magnesia
mixture. Accordingly he advanced the view that uric acid “primarily
exists in the blood and the tissue juices in combination with nucleinic
acid, and that, not only the conversion of the purin bases into uric
acid, but also the solubility and transportation, as well as the further
changes of the uric acid in the living body, is regulated by this linking
with a nucleinic acid rest.”
But, unfortunately for the value of this hypothesis, there is no proof
that _nucleinic acid_ is actually present in the blood; for, as Fürth
remarks, is this inhibition of the precipitation of uric acid, in the
presence of nucleinic acid, “necessarily indicative of a true acid
combination with nucleinic acid,” “but such inhibition of precipitation
is rather to be referred to the general group of variations of solubility
which are manifested by crystalloid substances in the presence of all
sorts of colloids.”
Complex phenomena of solubility of this nature must be considered in
connection with the circulating uric acid. Nucleinic acid is not the only
important substance, but “the general mass of the blood proteins must be
particularly thought of.”
Continuing, Fürth reminds us that uric acid is much more soluble in
_blood serum_ than in water, and forthwith envisages this disparity in
light of the factors that affect solubility of uric acid in the _urine_.
The latter is markedly influenced by the presence of urea and di-sodium
phosphate, and the relation of this to mono-sodium phosphate. Nor, he
reflects, is there any doubt “of the importance of such inter-relations,
too, in the formation of _uric acid deposits in the tissues_.” But he
adds, “Although the importance of these complex conditions of solubility
as they prevail among colloid and crystalloid substances in the animal
juices may be accepted in relation to the formation of uric acid
concretions, there is no real reason for seeking the explanation of gout
in this sphere.”
TOPHI IN RELATION TO URICÆMIA
It might be thought that some relationship might be established between
uratic deposits and the degrees of uricæmia, but the data to hand give
no countenance to the assumption. Thus, His has recorded the case of a
gouty subject with multiple tophi whose blood did not yield an excess
of uric acid. Pratt, again, could trace no relation between the amount
of uric acid in the blood and the severity or character of the disease.
Two of his patients had numerous and widely distributed large deposits
of sodium urate beneath the skin, yet the _blood content_ of _uric
acid_ in both was less than the average amount found in gout. Thus, on
a purin-free diet, one had 2·4, the other 2·2 mg. These findings, he
considers, show that the presence of _multiple tophi_ is no indication
that a state of _hyper-uricæmia_ exists.
Walker Hall, discussing this same question, holds that there is but
little evidence “as to the relation of uricæmia to the formation of
tophi.” He asks the question whether the deposition is the outcome of
abnormal purin combination in the blood and lymph stream? which latter at
present, he states, are regarded as passive carriers of the urates. For,
he says, the small purin increase in gouty blood cannot surely make all
the difference, seeing the large volume of solubility still available.
The physico-chemical hypothesis, he claims, is inadequate to explain the
relationship between uricæmia and the tophi, and hazards the suggestion
that after all it may be that “the uricæmia plays little or no part in
the depositions, and that these are due to the defective removal of
substances resultant from local nuclear activities.” He asks, moreover,
whether such substances differ in type from those of normal nuclein
metabolism and so fail to be suspended in the surrounding lymph in such
a way as to ensure their entrance into the blood-stream? Like others,
he notes that atophan brings about a removal of some of the deposited
urates. But such diminution of the tophi may, of course, he says, be
due to increased flow of serum to the inflamed part; though, on the
other hand, the more massive deposits “are surrounded by layers of young
granulation tissue and phagocytes and peritophal fibrous tissue, and
these in turn offer some hindrance to the permeation of serum or drugs.”
In reviewing the foregoing views as to the formation of tophi, it is
obvious we stand in urgent need of more knowledge. Neither the chemical
nor the physical theory or a combination of the twain seems adequate.
This for the salient reason that, as far as the existing evidence permits
us to draw conclusions, it would seem probable that not only local but
constitutional or systemic conditions play an important _rôle_ in tophi
formation.
But as far as our discussion has advanced, we may, we think, be justified
in the following deductions:—
(1) That tophi are blends of crystalloids and colloids and
subject to the complex conditions of solubility attaching to
such combinations.
(2) That the relatively high sodium content of certain tissues,
_e.g._, cartilage, favours the incidence of uratic deposits
therein.
(3) That tissue necrosis is not necessarily an antecedent to
uratic deposits.
(4) That no relationship can be established between the
incidence or multiplicity of tophi and uricæmia.
It will be seen from these conclusions that the proximate cause
responsible for the genesis of tophi is yet to seek, and in pursuance of
our quest we turn to another aspect of this complex subject.
TISSUE AFFINITIES FOR URIC ACID
Injecting uric acid intravenously into _gouty_ subjects, Umber noted
that at times the whole was retained, but on some occasions was excreted
in fractional portions. On the other hand, a _normal_ individual under
similar circumstances eliminates it completely. In explanation thereof,
he proffered the opinion that this failure on the part of gouty persons
to excrete exogenous uric acid was due to a _special affinity of their
tissues for uric acid_.
As to intravenous injection of uric acid, however, modern investigation
has established that, both in normal as well as gouty subjects, its
excretion is spread over several days, and the _whole_ is _not_
recoverable from the urine. Now this incomplete excretion or _retention_
of uric acid was attributed to _defective elimination by the renal
cells_; but, as shown in a previous chapter, this conception fails of
demonstration. Nor, for that matter is there any proof either that the
retention is due to _fixation of the uric acid in the blood serum_.
Accordingly, to our minds, it is permissible then to canvass the further
possibility adumbrated by Umber, viz., that an _increased affinity of
the tissues for uric acid_ may haply account for the diminished purin
excretion, the excess of uric acid in the blood, lymph, and tissues, and
that these same may lead to _uratic deposition_.
This last hypothesis derives colour from the findings of Schmoll, Magnus
Levy, Vogt, Reach and Bloch, who noted that, after giving thymus to
_gouty_ persons, they found far less uric acid in the urine than in
the case of normal subjects. Also, that the ingestion of thymus by the
victims of _chronic_ gout repeatedly resulted in acute outbursts of
the disease. Moreover, as we saw when discussing the _sources_ of uric
acid, there are cogent reasons for avoiding a too restricted conception
which would make the leucocytes, the muscles, or the digestive glands
alone responsible for the _endogenous production of uric acid_; in other
words, that a more catholic attitude on our part is indicated, one which
would envisage it as the outcome of continuous and _general cellular_
wear and tear. That an _increased cellular destruction_, as induced
experimentally, _e.g._, by exposure to Röntgen rays, is capable of
raising the _blood content_ of _uric acid_ in a _gouty_ subject, and of
precipitating a gouty paroxysm, may be inferred from the researches of P.
Linsen.
RETENTION CAPACITY OF TISSUES FOR URIC ACID
It may be recalled that Wiechowski and others observed that in man, of
_parenterally_ introduced uric acid, 80-90 per cent. reappears in the
urine. Accordingly, Schittenhelm and Wiener argued that, if uric acid is
indestructible in the human body, then, given _retarded elimination_, the
_tissues_ should contain considerable quantities thereof. Subsequently,
in 1914, they sought to investigate human tissues as to their content
of uric acid. Their studies were conducted on three examples, a case of
anuria, one of pernicious anæmia, and one of gout.
The case of _anuria_ occurred in a male, aged sixty-two, in sequence to
thrombosis of both renal veins following operation. Two-hundred gram
samples of the following tissues, lung, heart, spleen and liver, were
examined for uric acid with wholly negative results. The residue of
the organ was worked up together, but only 0·01 gram of uric acid was
isolated.
In the case of _pernicious anæmia_ no uric acid was demonstrable. The
_gouty_ subject had for twenty-five years suffered from typical attacks
and exhibited many auricular tophi. The following organs, in their
entirety, were analysed, the _liver_ (1,550 gram), no uric acid; _spleen_
(290 gm.), 10 mg. uric acid (3·5 mg. per 100 gm.); _kidney_ (270 gm.),
no uric acid; _lung_ (930 gm.), 15 mg. uric acid (1·6 mg. per 100 gm.);
_muscle_ (440 gram), no uric acid; and _intestine_ (420 gram), no uric
acid.
It will be seen that _uric acid was either absent or present in minimal
amounts_, and these results Schittenhelm and Wiener interpreted as
confirming their long advocated contention as to the _destructibility of
uric acid_ in the human organism.
Morris S. Fine, from the results of similar investigations, considered
the failure of these observers to isolate _uric acid_ in these cases of
_anuria_ and _gout_ as most remarkable. He considers “their results may
in part be ascribed to the use of hot sodium hydroxide previous to the
precipitation of the proteins in the extraction of the tissues, as the
instability of uric acid in alkaline solutions is a well-known property.”
In this criticism Fine would appear to be fully justified, in view of the
marked contrast between the findings of Schittenhelm and Wiener, and his
own data is recorded in the tables on p. 159.
While it is unfortunate that Fine’s theory contained no instances
of _gout_, his findings are a definite proof that, to quote his own
words, _uric acid can be demonstrated in considerable concentrations
in human tissues_. Incidentally, also, his tissue analyses are flatly
contradictory to Schittenhelm and Weiner’s persistent contention, viz.,
that the human organism _can decompose uric acid_.
Gideon Wells states that in normal individuals the tissues contain but
little uric acid, and this not in quantities sufficient to permit readily
of its isolation in a pure state. Albeit, Wells found considerable
amounts of uric acid in the tissues of a young woman who, in sequence to
poisoning with HgCl₂, died after complete suppression of urine for nine
days.
TABLE I.—CONCENTRATION OF URIC ACID IN HUMAN TISSUES AND FLUIDS PER 100
GRAMS OF MATERIAL
------------------+-------+-------+-------+---------+---------+
Case. | E. E. | T. D. | S. H. | M. F. | C. M. |
|Uremia.|Uremia.|Uremia.|Diabetes.|Diabetes.|
------------------+-------+-------+-------+---------+---------+
| mg. | mg. | mg. | mg. | mg. |
Blood | 15·4 | 14·3 | 17·0 | 0·7 | 0·7 |
Pleural fluid | 16·7 | 15·9 | | | |
Ascitic fluid | 18·0 | | | | |
Pericardial fluid | | 14·3 | 18·0 | | |
Subcutaneous fluid| 18·0 | | | | |
Spinal fluid | 2·8 | 2·0 | 4·7 | | |
Skeletal muscle | 8·0 | 3·9 | 5·8 | 0·7 | 2·6 |
Heart muscle | 10·0 | 7·3 | 8·8 | | 1·2 |
Liver | 18·0 | 15·6 | 11·5 | | 5·0 |
Spleen | 12·6 | 14·3 | 9·1 | | 1·2 |
Skin | | 13·0 | | | |
------------------+-------+-------+-------+---------+---------+
------------------+-----------+----------
Case. | S. T. | H. J.
|Amputation.|Pneumonia.
------------------+-----------+----------
| mg. | mg.
Blood | 0·7 |
Pleural fluid | |
Ascitic fluid | |
Pericardial fluid | |
Subcutaneous fluid| |
Spinal fluid | |
Skeletal muscle | 2·0 |
Heart muscle | |
Liver | | 4·0
Spleen | | Trace
Skin | |
------------------+-----------+----------
TABLE II.—CONCENTRATION OF URIC ACID IN MISCELLANEOUS HUMAN TISSUES PER
100 GRAMS OF MATERIAL
-----------------+------------
Tissue. | Uric acid.
-----------------+------------
| mg.
Pectoral muscle | 2·5
Uterine muscle | 2·0
Uterine muscle | 2·5
Uterine muscle | 1·2
Mixed tonsils | 1·7
Thyroid | 0·0
-----------------+------------
Again, as before alluded to, Bass and Herzberg found that intravenous
injection of uric acid caused less _uricæmia_ in the _gouty_, despite
diminished renal excretion. Hence, they concluded that _in gout the
retention capacity of the tissues for uric acid is augmented_.
Fürth, an ardent advocate of Umber’s hypothesis, emphasises the fact
that Wiechowski was never able to detect any evidence of _uricolysis_
in the human body. Continuing, he observes, if we reject all idea of
_uric acid retention in the tissues_, “It would be a particularly
difficult thing to understand why gouty patients do not simply expel by
a compensatory hyper-excretion the uric acid which is accumulated from
a supposed failure of uricolysis; precisely as in leukæmia the patient
compensates simply by an exaggerated excretion of the excessive uric acid
which is mobilised in the body from the excessive purin decomposition.”
His conclusion, therefore, is that, “_In the gouty individual there
must exist some cause which makes a compensatory uric acid excretion
impossible; and that is plainly a retention affinity of the tissues,
because of which the uric acid is actually held in the tissues._”
In light of Fine’s revelations the retention capacity of the bodily
tissue for uric acid may, we take it, be considered as fairly well
established. But, in view of the _precipitation or anchoring of urates
in the tissues in gout_ it is most desirable that further investigations
be made to discover whether in _gouty_ subjects the _tissue retention
capacity_ for _uric acid_ is _enhanced_.
“The impression,” says Fürth, “grows on one that this hitherto little
considered factor, of an increased affinity of the tissues for uric acid
in the gouty subject is very much closer to the real kernel of the gout
problem than, for example, the question of the fixation of uric acid in
the blood about which there has been so much contention, and with which
of necessity we are compelled, at least, to some little extent to concern
ourselves.” The results of modern researches tend to support this more
catholic conception. We would recall that Lewis and his co-workers,
seeking the source of the _increased endogenous purin excretion_ that
follows ingestion of _purin-free_ food, were forced to reject the view
that it was solely derived from katabolism of the _nuclear_ substance
of the _digestive glands_, and to refer it instead to “wear and tear”
of the _body cells as a whole_. Precisely the same change in attitude,
we may remind our readers, has overtaken us in regard to the site of
_urea_ formation, viz., that not only the _liver_ cells, but those of the
muscles also participate in its production.
While admitting that dogmatism is out of place, still to our mind this
theory of _tissue retention_ makes strong appeal. In light of it the
nebulous “gouty diathesis” seems on its way to become incarnate in some
_inborn peculiarity_ of _tissue-function_, a falling short of full
physiological activity, or, as M. Rendu termed it, a “_primordial vice of
nutrition_.”
In other words, in gout there is no rift nor lack of finish in the
orderly sequence of enzymatic reactions that eventuate in _uric acid_.
Uric acid is formed and, as far as we know, after a normal fashion.
But, here comes the flaw, viz., the uric acid, when formed, fails of
transport and elimination. It is _precipitated_ and _anchored_ in the
_tissues_, from whose grip it fails to detach itself. In short, it is not
the formation of uric acid, or its failure of further metamorphosis, but
the _retention_ of uric acid, and more pertinently, its _fixation in the
tissues_ that constitutes the salient feature of gout.
Now, all modern research tends to indicate that uric acid is not an
intermediary, but a _terminal_ product of metabolism, and, moreover,
that there are no _uricolytic_ ferments within the body whereby its
destruction can be accomplished.
If we grant that—
(1) Uric acid is not an intermediate but an end-product of
metabolism; and
(2) That the human body is devoid of uric acid-destroying
enzymes,
then it follows that man, _ipso facto_, is _potentially liable to uric
acid retention and deposition_, the same objectivated as _tophi_. In this
innate potentiality of and to _uratosis_ resides the “gouty” diathesis.
If the postulates (1) and (2) be established, then, though it sound rank
heresy, it follows that gout is not, chemically speaking, an “error of
metabolism.” Not, at any rate, in the ordinary acceptation, viz., not
a failure in the transmutation of uric acid into urea and intermediate
products. If uric acid be an _end-product_, then no further cleavage into
_urea_, etc., occurs, and in this connection the failure to discover
_uricolytic enzymes_ is significant.
We have before proffered the suggestion that not only local, but
_constitutional_, or systemic influences also play a part in the origin
of tophi. Provisionally, therefore, we would infer that—
(1) The tissues of gouty subjects display an abnormal affinity
for uric acid, _i.e._, an increased retention capacity for the
same;
(2) That certain chemico-physical factors, previously alluded
to (content of sodium ions, etc.), favour the incidence of
uratic deposits in particular tissues.
In other words, we have in these two elements haply the constitutional
and local factors that we postulate as essential to the formation of
tophi. Albeit, they represent but _latent tissue potentialities_,
inadequate of themselves to determine the eruption of _tophi_.
Moreover, be it recalled that the _causa causans_ of gout must be
responsible not only for the incidence of _tophi_, but also for the more
dramatic features of gout, its _arthritic_ outbreaks, etc. To dissociate
the cause or causes of the uratic deposits from that of the joint
inflammations would indeed appear impermissible.
But, taking this view, it is clear that, apart from the constitutional
and local factors above postulated, tophi and, alike, the arthritic
phenomena of gout, demand for their production the intrusion of some
further element, some _tertium quid_, vital and biological. To this end,
therefore, we purpose reviewing tophi in their _clinical_ aspects, as
herein possibly we may find some further clue to their exact mode of
genesis.
CLINICAL EVOLUTION OF TOPHI
As to the clinical characters that mark the genesis and maturation
of tophi not a little conflict of opinion seems to obtain. Do tophi
arise painlessly or not? Do the uratic depositions occasion any local
inflammatory reaction? Or, are they merely concomitants or sequels
thereof?
With what wearisome iteration has the same question been propounded in
regard of _gouty arthritis_. Are the attacks of pain and inflammation due
to deposits, or do the deposits take place at the site of inflammation?
But, restricting our enquiries to tophi, we may remind the reader
that Aretæus, writing in the second century, A.D., made the following
observations: “Callosities also form in the joints; at first they
resemble abscesses, but afterwards they get more condensed, and the
humour being condensed is difficult to dissolve; at last they are
converted into hard white tophi (Πῶροι στερροὶ λευκοὶ), and over the
whole there are small tumours like _vari_ and larger, but the humour is
thick white and like hailstones” (Περὶ Αρθριτιδος). To our mind, it would
be difficult to emulate, much less to surpass, the succinct and, as we
believe, accurate picture here drawn of the various stages that mark the
life history of tophi. It will be noted that Aretæus says that in their
initial stages they “resemble abscesses,” and, turning to the writings of
the elder Garrod and others, we find abundant evidence that it is so.
Discussing the more frequent incidence of tophi in the hands than in
the feet, Garrod describes the physical characters presented by tophi
in the making as seen in one of his examples of gout. “On the dorsal
surface of the second phalangeal joints of three fingers, small rounded
protuberances were observed, the skin over them being red; these
bulgings appeared soft, as if containing a thick fluid, but not the
slightest indication of white matter could be seen through the skin;
they might have been either gouty concretions in their early stage of
formation or some other form of swelling; from a simple inspection
I could form no opinion as to their true nature, but their history
convinced me that they arose from a deposit of urate of soda. Upon
puncturing one of the little swellings, full light was thrown upon
the case, as a thick white fluid immediately exuded, a drop of which
placed, under the microscope, with the use of polarised light, gave the
appearance represented in Fig. 1; the crystals were proved by analysis to
consist of urate of soda.”
We see, therefore, that Aretæus and Garrod were at one in their
observation that tophi in their initial stages are betokened by _small
red swellings_; in other words, as Aretæus says, they “resemble
abscesses.” Garrod also held that uratic deposits probably form during an
attack of gout, but occasionally they appear shortly afterwards. Thus,
in one of his cases no auricular tophi were found when the subject left
hospital, but within ten days, on re-examination, a deposit was detected.
“Perhaps,” he reflects, “some fluid was effused during the fit, but being
at first transparent, could not easily be distinguished.”
That Garrod held the swellings to be _inflammatory_ in nature is clear
from his writings. Thus, he says, “When tissues little liable to take
on inflammatory action become infiltrated (with urate of soda), but
slight vascular disturbance is produced. This is especially the case with
the fibro-cartilage of the ear, and although we now and then meet with
patients aware of the formation of these little nodules, who experience
in fact a gouty fit in the ear, yet in the majority of cases attention
has never been directed to the part, so slight has been the inflammation
caused by the effusion.”
Again, James Moore, whose graphic description of tophi formation is
quoted by Garrod, also held that “this process is usually preceded and
accompanied by inflammation.” Hilton Fagge, too, says, “it appears
probable that the deposition of lithate of soda causes inflammation in
other tissues besides the joints. It does, as we have seen, in the ear
and occasionally in the skin.” But, he also states, “in the pinna of the
ear, in fact, gouty concretions commonly form without any indications of
previous inflammatory action. In some instances the patient experiences
sensations of heat and pricking, and the part is tender, but more often
he is quite unconscious of the fact that such concretions in the pinna
are present.”
Duckworth also noted that uratic deposits are _not always painless_
during their formation, and he noted that not only may auricular tophi
be painful at this stage, but that, following the subsidence of acute
gout in a joint, painful swellings may develop in its vicinity, which
subsequently proved to have been tophi in process of formation.
For myself, I am of opinion that each and every process of tophus
formation is preceded by local inflammatory reaction of varying grades
of severity. In a matter of this sort, positive is more valuable than
negative evidence. We see that all the authorities quoted admit that
_tophi_ are associated with _inflammation_ and some measure of _pain_,
though they add the reservation that in many instances, if not the
majority, these phenomena have apparently been absent. Apparently, we
say advisedly, for conceding that the pain attending the formation of
auricular tophi is but slight, how all too easy for the subject to have
wholly forgotten it when he comes later under notice. By this time
the tophi, from being latent, have become overt. The initial soft red
swellings, their nature probably misinterpreted at their initiation, are
now transmuted into pearly concretions of hard or semi-solid consistence.
Small wonder, then, that attempts to elicit the history of slight pain
and pricking or tenderness often prove barren; for, be it noted, tophi
take months to mature, as Garrod long since pointed out.
Moreover, we would emphasise the fact that _tophi_, more often than is
thought, occasionally precede by some years the outbreak of _arthritic_
attacks. Both Duckworth and Garrod are quite definite on this, and we can
confirm them.
In such instances, then, even granted that our attention be drawn to them
in their initial stages, how easy to misinterpret their true nature!
Thus, we have known tophi in their early stages of formation confused
with _chilblains_. In this connection we might remind the reader that,
according to Duckworth, amongst the peculiarities of tissue in those
goutily disposed is feebleness of the peripheral capillary circulation,
“a condition leading to disorders of chilblain-type, the vessels filling
slowly after being emptied.”
We repeat that the cause or causes of tophi and, alike, of the arthritic
phenomena of gout are, and must be, one and indivisible, for the process
of tophus formation is but an attack in miniature of gout. Although he
may never have had an arthritic outbreak, the individual who exhibits
a tophus undeniably has gout. More certainly so than if he had had an
inflammatory outbreak in his great toe; for this, at any rate, may be of
_non-gouty_ origin, but the tophus, never!
Reflecting on the foregoing considerations, we would submit—
(1) That tophi are always preceded by local inflammatory
reaction of varying grades of severity, and that the uratic
deposits are sequels thereto;
(2) That in their early stages their presence is betokened by
soft red swellings associated often with sensations of pricking
and tenderness;
(3) That their transmutation into white pearly concretions is a
process that takes months to mature;
(4) That tophi and arthritic outbreaks have a common causal
origin.
The question that now thrusts itself upon us is,—What, then, is the cause
of the inflammatory phenomena which determines the eruption of tophi, and
alike of the arthritic outbreaks?
THE CAUSE OF THE INFLAMMATORY PHENOMENA
Garrod’s discovery that uric acid was present in the blood in gout not
unnaturally led to the assumption that herein lay the origin of its
symptomatology, and what else than confirmatory could be the deposition
of uratic deposits here and there in the body. The corollary seemed
obvious that, given the presence of a certain proportion of uric acid
in the blood, then gout must result. But, unfortunately, it was not so;
for, lo! and behold, an excess of uric acid in the blood is in no sense
pathognomonic of gout.
Thus, the blood in _leukæmia_ contains a high percentage of uric acid,
in some cases exceeding that found in gout, and enduring, moreover, for
a longer period. Yet no symptoms distinctive of gout appear, nothing
that can be referred to _uric acid_. But it was contended the reason why
gout does not ensue is because simultaneously with increased formation
there is increased elimination of uric acid. But, unfortunately, despite
augmented excretion, the percentage of uric acid in the blood is still
maintained at a high level, and still no gout occurs.
Moreover, it is met with also in nephritis, simple and pernicious anæmia,
intestinal inflammation, certain fevers, notably in malaria between
attacks, and in typhus after the febrile stage, pneumonia, plumbism, etc.
Indeed, the ubiquitousness with which uric acid is found in the blood,
and this in conditions wholly distinct from gout, would of itself seem
sufficient to dissipate any lingering doubts as to its being anything
more than a symptom of gout and not its proximate cause.
Obviously, with these revelations the uric acid theory was within
measurable distance of being uprooted. Deposed from its high estate as a
causal agent, and accredited with only a symptomatic value, the question
arose whether indeed this bogey, “uric acid,” was even capable of
fulfilling a minor _rôle_, of originating any symptoms, much less gout,
in its entirety. In other words, is uric acid toxic or non-toxic?
NON-TOXICITY OF URIC ACID
The adherents of the uric acid theory did not hesitate to attribute to
its toxic action, not only the severe phenomena of acute attacks, but
even all the functional disorders of so-called _irregular_ or _visceral_
gout. By the more ardent advocates, such as Haig, we were treated to
a word picture of how solid crystals of uric acid erupted out of the
blood-stream, and anchoring themselves in nerve sheathes, the renal
substance and the mucous membrane, gave birth to chronic neuralgias,
nephritis, rhinitis, and so forth. But, alas, there is very serious doubt
as to whether uric acid or the urates are capable of acting even as
mechanical, much less as true _toxic_ irritants.
Perhaps the most cogent evidence of the slight toxic effects of uric
acid or urates is that derived from a study of the _uric acid infarcts_
so frequently noted in infants dying within the first two weeks of
birth. According to Gideon Wells, “little or no change occurs in the
renal tubule as a result of these depositions, except such as can be
attributed to their mechanical effect.” This same observer, discussing
this question of the toxicity of uric acid, observes, “It may be safely
stated that at the present time there exists no good evidence which makes
it probable that uric acid is responsible for any pathological conditions
whatever, except uric acid calculi, uric acid infarcts in the kidneys,
and certain manifestations of gout.” His further conclusion is that uric
acid possesses but a very slight degree of toxicity, and that an actual
intoxication of the organism with this substance probably never occurs.
Again, we have the fact that in instances of _malnutrition in children_
excess of uric acid may occasionally be found in the blood. Yet no
symptoms comparable to _gout_ occur, even though uric acid _calculi_
form. Also, as has been pointed out, showers of uric acid may be present
in their urine, and yet no symptoms arise, save those referable to
_mechanical_ irritation of the renal or vesical tissues.
Turning to experimental researches, the evidence is cumulative as to the
_non-toxicity_ of uric acid. Rabbits and dogs seem quite irresponsive,
either to its ingestion in large quantities in their food, or to repeated
intravenous injections of 1 or 2 grammes thereof, save only that the
urine showed a large increase in uric acid.
Again, Ransom, of New York, found that no systemic disturbance ensued in
two cases of _chronic nephritis_, following the taking by the mouth of
3 grammes of uric acid per diem for three days in succession. All that
resulted was a notable increase in the uric acid output. In one case, he
went further, and on the fourth day administered 6 grammes, but nothing
happened.
Walker Hall, with commendable devotion, took large doses of uric acid
with resultant headache and malaise, which endured for some hours. But
as Luff shrewdly observes, “almost any substance, however (common salt
for example), will produce toxic effects if taken in very excessive
quantities.” Despite his brief indisposition, Walker Hall maintains that
uric acid is rather a symptom of, than the precise _materies morbi_ in
gout.
Nor, apparently, even in gouty subjects can aggravation of the condition
be induced by intravenous injection of uric acid. Bass and Herzberg did
so until the blood content of uric acid reached the high level of 10 mg.,
and yet no joint attack supervened. Neither, for that matter, has it been
possible to establish any relationship between degrees of uricæmia and
the incidence or severity of gouty paroxysms.
Again, taking a typical instance of acute gout in the big toe, how
difficult to conceive that the same owes its origin to uric acid
circulating in the blood especially when we realise that the blood
content of uric acid in gout exceeds but by a few milligrammes that in
_normal_ blood. Moreover, if it does so, then why does it fail to ensue
in leukæmia and in other states associated with uricæmia. Also, we
like to think that the penchant of acute gout for the toe is that the
circulation is inefficient at this peripheral site. But how often is the
circulation all too vigorous in gout, and for that matter frequently
feeble in leukæmia and in ill-nourished children. But, notwithstanding
that in the two latter conditions, _uricæmia_ exists yet, despite
favouring circulatory conditions, they develop no gout.
Garrod contended that the violent pain, intense inflammation, and
profound constitutional disturbance of acute gout were due to
_mechanical_ irritation occasioned by the sudden deposition of biurate
crystals in the delicate interior of the implicated joint. Also, that the
absence of constitutional disturbance in the inter-paroxysmal periods was
because the deposition of urates, being gradual, the tissues acquired
tolerance, and yet, forsooth, this same substance is held responsible for
the fulminant outbreak that ensues anon.
But it is, as Ringrose Gore shrewdly observed, “against the usual laws
of nature that, if an irritant foreign body remains in any organ the
symptoms should quickly subside, while the irritant actually increases,
for after each attack, and during the intervals between the attacks, the
deposits of such biurate enlarge.” In conclusion, is it not infinitely
more probable, as Gore states, that the inflammatory reaction _precedes_
the deposition of urates and that these latter, in short, are the
_consequence_ and not the cause of the gouty arthritis?
Reverting to tophi, their experimental production, it is claimed,
has been achieved by His.[24] Administering alcohol to dogs and
simultaneously injecting them locally with sodium mono-urate, he produced
deposits which seemed identical with tophi produced spontaneously in
gout. But, unfortunately, up to the present, it has been found impossible
to induce their formation by flooding the circulation with urates. The
utmost, indeed, that His and other workers in this sphere feel able to
postulate is that uric acid is a “weak tissue poison.”[25] Scarcely the
words in which to describe the poison responsible for gout! for, as we
have before stated, the agent that is responsible for _tophi_ must also
be capable of inducing the arthritic phenomena and other features of the
disorder.
The sum of our reflections is that the _toxicity_ of uric acid has
been grossly over-estimated, and that, like its relative _urea_, it is
practically _non-irritating_ and _inert_; in other words, it cannot any
longer be regarded as the _essential cause_ of the _acute_ or _chronic_
forms of _gout_, whether of _articular_ or _ab-articular_ site. Moreover,
far from its presence in excess in the blood being pathognomonic of gout,
it must, as Walker Hall contends, be held merely “as symptomatic of
conditions which help or prevent its solubility and excretion and does
not itself cause lesions which accompany uricacidæmia.”
ARE THE PRECURSORS OF URIC ACID TOXIC?
Naturally the upholders of the uric acid theory were loth to find their
fetish uric acid was allotted a meaningless _rôle_. That it should be
deemed inert was to dislodge the very corner-stone of the imposing
superstructure they had been at such pains to raise. Uric acid not
responsible for the genesis of gout! But, haply, maybe their position was
still unassailable; for what of the purin _bases_, the forerunners of
uric acid? Might not the blame lie with these?
Straightway _xanthin_, _hypoxanthin_, _adenin_, etc., were credited with
pernicious potencies.[26] Nor did they lack apparent support from the
experimental side. Thus, Mandel affirmed that purin bases, apart from
infection, might originate pyrexia. Others, again, noted that in dogs and
rabbits fed on adenin, degenerative changes in the _kidneys_ ensued, with
deposits resembling uric acid and urates in their substance. The fact,
too, that _guanin-gout_ was occasionally met with in swine, also lent
colour to their views.
Moreover, that ingestion of these congeners of uric acid led in animals
to renal lesions, seemed to support the contention of many, that renal
disorder might be the primary cause of gout. But, unfortunately, Kolisch
and Weintrand’s assertion that the alloxur bases were found in increased
quantities in the urine of gouty patients was contradicted by Schmoll,
His, Laquer, and others.
Still more cogent, apparently, the announcement in 1910, by Brugsch and
Mallory, that they had seen a typical attack of gout ensue in a gouty
patient in sequence to a dose of 0·5 gram of _hypoxanthin_. Nor did this
reaction of gouty persons fail of confirmation, as in the same year,
Brugsch and Schittenhelm, in gouty patients, noted attacks of arthritis,
after the administration of _nucleinic acid_.
Nevertheless, we must beware of laying too much stress on isolated
experiments of this nature, so hypersensitive are some of the victims
to any strange or unaccustomed ingesta. Were all the myriad other
determinants of gouty attacks eliminated, over-drinking, trauma,
mental disturbances, etc.? for be it recollected, all the victims of
these experiments with _hypoxanthin_ and _nucleinic acid_ were _gouty_
subjects, _i.e._, potentially liable to attacks at any moment.
Even admitting the ingestion of, _e.g._, hypoxanthin was followed by a
gouty outbreak, it must be insisted that mere sequence does not establish
causation. Clinically, on the whole, there is little or nothing to
support the contention that the _purin bases_ have much to do with the
pathogeny of gout. “The proof of the pudding is in the eating,” and
contrary to the view, at one time so prevalent, that purin foodstuffs
were most deleterious, it has been found that, for the average gouty
person, a purin-free dietary is not only not essential, but prejudicial.
Those, therefore, who may be inclined to see in the above sequence proof
of a _causal_ connection, would do well to recall Bacon’s dictum that
“there is in the human mind a peculiar tendency to dwell on affirmative
and to overlook negative instances.”
In conclusion, we must affirm our belief that _neither uric acid nor
its precursors_ is responsible for the fever, local inflammation, and
general constitutional disturbance in gout, for uric acid and the urates
are themselves practically non-toxic. Albeit, though holding this view,
I do not for one moment suggest that _uric acid_ has nothing whatever
to do with gout. The fact that _tophi_, its pathognomonic stigmata, are
compounded of biurate of soda, would _per se_ stamp such an attitude as
untenable. On the other hand, _uric acid_ must be viewed in its proper
perspective as a concomitant or sequel of gout, the essential _cause_ of
which must be sought elsewhere.