THE RISE OF THE INFECTIVE THEORY
With the abandonment of the uric acid theory of the causation of gout
we see a reversion, curiously enough, to the hypothesis held by the
ancient physicians as to its pathogeny. Like Cælius Aurelianus and
Paulus Ægineta, we now incline to refer the origin of the disorder to
some derangement of the _gastro-intestinal_ tract. This conception
indeed endured up to the latter half of the eighteenth century, and was
definitely maintained by Van Swieten in his commentary on the aphorisms
of his great preceptor, Boerhaave. For him the _fons et origo mali_ in
gout was disturbance of the functions of the alimentary tract.
“Indigestio viscorum pro origine proxima hujus morbi habitur.”
The English Hippocrates, too, Sydenham, in his classic treatise observes:
“The more closely I have thought upon gout, the more I have referred it
to _indigestion, or to the impaired concoction of matters both in the
parts and juices of the body_.”
Not only in regard of the initial site are we reverting to the views of
old-time physicians, but the tenor of our reflections upon the _nature_
of the disorder exhibits a like trend. Thus the older physiologists,
doubtless impressed by its fulminant onset and clinical features, ranked
gout amongst the fevers, describing it indeed as a “tertian fever
terminating in fourteen days.”
Indeed, the great Boerhaave avowed his belief that gout was
_contagious_—a forecast, we may take it, of the modern theory of
_infection_. Subsequently his pupil, Van Swieten, went a step further,
maintaining that sometimes wives, while nursing husbands afflicted with
gout, contracted the malady!
Passing now to relatively modern times, it will be noted that in 1864
Laycock classed acute gout with rheumatic fever as an “excretory fever,”
while Parkes even prior to this, in 1860, wrote: “I define gout after
Garrod as a febrile infection with inflammation about the joints leading
to a deposition of urate of soda.”
But it must be freely acknowledged that, subsequent to Garrod’s discovery
of _uric acid_ in the blood in gout, the spell exercised by the _uric
acid theory_ was such that it dominated medical thought almost to the
exclusion of all other possibilities. All energies were forthwith
centred upon endless laborious researches into possible modes of uric
acid formation, but which, alas, did little to purge men’s minds of their
obsession that _uric acid_ was the _proximate cause_ of gout.
Still it would be unfair to infer that the disabilities attaching to the
uric acid hypothesis were wholly unrealised. Indeed, it may be fairly
said of Duckworth’s reflections on the pathogeny of gout that they
definitely foreshadowed the _infective_ theory. His views postulated
what may be termed a _toxic tropho-neurosis_, wherewith to explain the
paroxysmal nature, the periodicity and protean symptomatology of the
disorder.
But in the early part of 1900 we may, I think, discern in some words of
Chalmers Watson a change coming over our thoughts as to the pathology
of gout, this as the result of some studies of a series of examples of
_acute gouty polyarthritis_. The results of his researches were such
that he challenged the accuracy of Garrod’s original observations as to
the lowered alkalinity of the blood during acute attacks, also his claim
that the uric acid content of the blood was increased and the uric acid
excretion diminished during the paroxysm. If these points be accepted, he
says we must start _de novo_ in search of the cause of the acute paroxysm.
He noted also the interesting fact that during acute attacks of gout a
very marked _leucocytosis_ was present. Another outstanding feature was
the presence in large numbers of peculiar myelocyte-like cells, half
as many in number as the ordinary finely granular oxyphil leucocytes.
Reflecting on these findings, he observes: “It would, I think, be well
if much less attention were centred on the excretion of uric acid alone
as the all-important factor in the disease, whether in its acute or
chronic form. The results obtained by the line of investigation here
followed suggest the advisability of more attention being devoted to the
histo-chemical characters of the blood, the ratios of uric acid to other
important products of metabolism, and, if opportunity be afforded, an
examination of the bone marrow.”
To other interesting features of these researches of Watson’s we shall
allude later, but, concerned here more with tracing the evolution of the
infective theory of gout, we would hasten to add that in September of
the same year Ringrose Gore, discussing the inadequacy of the uric acid
theory, boldly avowed and ably propounded his belief in the _infective_
origin of the disorder.
Thus he writes: “I consider a toxin to be the cause of this disease. If
so, such toxin must be formed in the intestine. As the symptoms of gout
are constant, it must be a definite toxin, the product of a definite
bacillus acting upon the intestinal secretion. As gout is capable of
being caused in any subject, it must be one of the bacilli normally found
in the intestinal canal.”
Nor did Gore lack supporters in his suggestion that the alimentary tract
was the primary source of the changes in the metabolism of gout. For in
the same year Minkowski, Le Gendre, and in this country Watson, hazarded
the view that intestinal derangements, through the medium of their
resultant toxins, initiate disturbances in the liver, and these in turn
determine those obliquities of metabolism typical of gout.
At the same time their contentions derive colour from the researches
of Grübe, who, despite traditional views, maintained that in gout the
hydrochloric acid of the gastric juice, far from being increased, was
in most cases _diminished or wholly lacking_, while, on the other hand,
lactic acid was present in some instances.
In 1903 Woods-Hutchinson ably contended that “gout and lithæmia are mere
symptom names for a miscellaneous group of _chronic toxæmic processes_
of widely varied origin, characterised by the production of uric acid
and the urates.” He held that the uric acid in gout as well as the
associated phosphoric acid are merely a criterion of the measure to
which the nucleins of the body cells (chiefly probably of leucocytes)
have undergone destruction in consequence of their invasion by a toxin
or toxins of organic or inorganic nature. He furthermore contended that
the _rôle_ of the _liver_ in gout was purely negative, consisting in its
inability “to absorb or transform into harmless excretory substances the
excess of toxins brought to it by the portal vein.”
In 1904 Falkenstein furnished collateral evidence that the starting
point of gout lay in a diseased condition of the _gastric glands_, those
responsible for the secretion of _hydrochloric acid_. The supply of
hydrochloric acid being deficient in the gouty, their digestive capacity
is distinctly lowered. Abnormal fermentation ensues with insufficient
oxidation, and “the substances containing quantities of nuclein are
partly prevented from being further split up, and partly favour the
synthetic formation of uric acid.” He would thus refer the excessive
formation of this latter directly to the diseased glands. He further
observes that, despite the deficiency of hydrochloric acid, the gastric
juice is often hyperacid, this being due to the presence therein of
organic acids, such as butyric, lactic, and acetic acids.
In the same year Chalmers Watson, as the outcome of investigations into
gout as it occurs in the _fowl_, held that:—
(_a_) There is ample evidence to prove that the uric acid in
the blood is not the primary factor in gout, and
(_b_) Uric acid can be deposited in cartilages and other
tissues, even in considerable amount, without the association
of any inflammatory phenomena.
He concludes that the last-mentioned point clearly proves that:—
(_c_) Uric acid is not the factor which causes the inflammatory
phenomena characteristic of the acute attack.
He then proceeds to inquire as to the nature of the toxic principles in
the blood, and the factors that influence their passage thence into the
tissues. In connection with these queries he emphasises the necessity
of envisaging the all-important part played by the _alimentary canal_,
holding that herein doubtless resides the clue to the solution of the
problem.
_Post-mortem_ examination of the fowl revealed marked catarrh of _ileum_,
_duodenum_ and _large intestine_, while the pancreatic duct was filled
with catarrhal products. The congested _spleen_, apart from proliferation
of its endothelial elements, exhibited a marked increase in the number
of _granular leucocytes_ in the capillaries and sinuses as compared with
the features of the control sections, which, as Chalmers Watson observes,
is the characteristic reaction of this organ to invasion by bacteria or
their products. The kidneys on examination revealed here and there uratic
deposits surrounded by inflammatory tissue. The relationship of these to
the inter-lobular arteries was such as to suggest an _infection_ by the
_blood stream_.
The collecting tubules in the deeper part of the cortex and medulla
were markedly dilated and choked with granular leucocytes. Sections of
the organs were examined bacteriologically by Muir, the necrosed areas
revealing the presence of “rod-like bodies of the size of large bacilli
massed together in dense clusters; the appearance suggested that these
rods were either degenerated cell products of an unusual character,
degenerated bacteria, or crystalline in nature.” Examination of the
same by polariscope by Marshall disposed of the possibility that they
were crystalline. Finally it was thought that the appearances generally
favoured the view that the rods in question were bacteria which had
lost their reaction to bacterial stains owing to bacteriolytic or other
changes.
As to the inference that the defunct fowl fell a victim to acute
gout, Watson based it on the existence of the _uratic deposits_ in
the tissues, the changes in the synovia, the widespread thromboses,
and the renal necroses. As to the other lesions, the chief interest
centres in those located in the intestine, pancreas and kidney. The
state of the _pancreatic duct_ raises the question as to whether it
points to any connection between these changes and the common occurrence
of _glycosuria_ in gouty subjects. The alteration in the _leucocytes_
merits notice in that similar changes were found by Watson in the blood
in _acute gouty polyarthritis_, the same, moreover, being subsequently
confirmed by Bain.
Chalmers Watson’s final conclusion was that “the clinical features
of gout—regular or irregular, acute or chronic—are more adequately
explained by the light of our present knowledge of infections, relapses,
and immunity than by any other theory. The distinctive feature of this
infection in gout is that the toxin or toxins have a special property of
disturbing nitrogenous metabolism in a manner favourable to the deposit
of uric acid in certain tissues.”
SUGGESTION OF A SPECIFIC INFECTION
It will have been noted that, despite the growing number of adherents
to the infective theory, no attempt had been made to saddle any
particular organism with the responsibility of initiating gout. But
in 1905 Trautner, holding _mucous colitis_ to be one of the initial
manifestations of gout, affirmed his belief that the _bacillus coli
communis_ was the responsible microbic agent.
He claimed that this particular organism, during its passage through the
system, gives rise to a reducing agent which is subsequently transmuted
into _xanthin_ and _uric acid_. This is, of course, but a variant of
Gore’s original view that the toxin of gout is a product of certain
bacteria normally present in the intestine, but which under certain
conditions take on a pathogenic action.
The microbic theory fast gained ground. Thus Luff, who in the first
edition of his work advocated the renal origin of gout, subsequently
renounced the same in favour of its infective origin. To sum up,
the opinion generally was that it was more than probable that
_gastro-intestinal derangements_, with their altered secretions, exert
an influence on the intestinal flora with resultant formation of toxins,
and that these same, acting chiefly on the liver, put in motion those
obliquities of metabolism which eventuate in gout.
Sikes, however, in 1907, discussing the _rôle_ of gastro-intestinal
disorders, expressed a doubt as to whether the same are primarily or
secondarily related “to the actual chemical processes at the base of the
disease.”
He thinks it at least as probable that the gastro-intestinal disorders
are due to an alteration in the intestinal secretions from an internal
cause as that they are due to bacteria in the formation of toxins, or, he
suggests, to some alteration in the epithelial cells, so that they take
up chemical compounds of different nature from the ordinary. To him it
does not seem at all probable that gout will ever be found affiliable
to any specific micro-organism, inclining rather to the belief that a
solution of the riddle will only be found in a closer and more extended
study of that most difficult subject, the actual _chemistry of the cell
protoplasm_.