GOUT AS AN INFECTION
“The old order changeth, giving place to new,” and the uric acid
theory having failed us, it is essential that we cast round for some
other solution of the problem, carrying with us, however, this guiding
principle, that _uric acid_, having lost its _etiological_ status, be
viewed in its right perspective as not the cause, but the _consequence_,
of gout.
Happily, with the advent of bacteriology our views, or rather our
hazards, as to the nature of joint diseases underwent profound
modification. But, strange to say, though quick to apprehend the
significance of infection, its causal relation to other joint disorders,
we still seem unaccountably loth to discard our time-worn conception of
“gouty” arthritis as of purely _metabolic_ origin. This, to my mind, is
the more remarkable in that the onset, clinical phenomena, and course of
acute gout, and no less the life history of the disorder as a whole, are
emphatically indicative of the intrusion of an _infective_ element in its
genesis.
In developing this hypothesis I purpose devoting the present chapter
to consideration of the frequency with which local foci of infection
are met with in gout, the frequency, too, with which exacerbations of
the disorder are presaged by acute glandular affections of undeniably
infective source. The latter part of the text will concern itself with
the rival claims of _auto-toxæmia_ and _infection_ or _sub-infection_. In
the subsequent chapter we shall analyse critically the component elements
of the acute paroxysm of gout, their compatibility or not with an
infective origin. The affinities between gouty arthritis and the specific
infective arthritides will then be noted, and, finally, an endeavour made
to link up the specific stigmata of gout—its uratic deposits—with the
postulated infective element.
LOCAL FOCI OF INFECTION
The extreme frequency with which _infective foci_ are met with in the
victims of gout is by no means adequately realised. Moreover, we are only
now beginning to appreciate the grave significance of such “nests” of
infection and how devious are the ways in which they work their malign
influence. For our forefathers gout began, and, forsooth, often ended,
in the “stomach,” or it was the “liver” that was impeached. But the
portal to the alimentary canal was for them only a cavity, the contained
structures of which, albeit, to their mind often betrayed evidences of a
“gouty diathesis.” They distinguished “gouty” teeth, “gouty” tonsillitis,
“gouty” pharyngitis, even “gouty” parotitis; but all these they classed
as tokens or sequelæ of gout—not possible causes or excitants thereof.
Nevertheless, their observations on “gouty” teeth are of deep interest,
though their significance was misinterpreted.
Thus, Duckworth, for example, wrote: “The tendency to shed sound teeth
has been noted with some frequency in middle or later life in goutily
disposed persons, and they are more than others liable to occasional
and fugitive attacks of pain in several sound teeth at a time, with a
sensation as if these were starting from their sockets, being tender to
bite upon.” In truth, a succinct picture of _pyorrhœa alveolaris_, of
unprejudiced source, hence the more valuable.
Garrod again tells us that he saw an initial attack of gout supervene
after extraction of a tooth, a sequence attributed by him to loss of
blood. How interesting this, in light of the fact that exacerbations of
joint disease have frequently been seen to follow the removal of septic
teeth. The same authority also noted the incidence of a primary attack of
gout following _epistaxis_, and the same after copious _hæmatemesis_, and
Todd several times observed such articular outbreaks after _venesection_.
Lastly, says Garrod, “cases illustrative of the effects of the
suppression of an habitual hæmorrhoidal discharge are by no means
uncommon, and ... numerous instances arising from _boils and carbuncles_
have come under my notice.” By Garrod and his contemporaries all these
various determinants of gouty paroxysms, _i.e._, loss of blood, etc.,
were believed to exert their influence _viâ_ the _nervous_ system, with
consequent disturbed equilibrium of nutritive processes throughout
the body. But while it may be admitted that depression of the _vis
resistantiæ_ plays a part, it does so, I believe, by favouring the
occurrence of _infection_.
Let us turn now to modern findings, and we shall see that they do but
confirm those of the older clinicians. Lambert in 125 cases of gout found
the teeth unsound in 82 per cent. of males and 1 per cent. of females,
while in 9 per cent. of the former and 17 per cent. of the latter there
was associated _chronic dyspepsia_. Two years after (1909) Wynn, Wirgman
and Turner noted the invariable correlation of gout with local foci of
infection. In the majority, _pyorrhœa alveolaris_ was present. _Tonsillar
sepsis_, too, was not uncommon, and much more rarely _nasal_ disorders.
Again, out of fifty-two examples of so-called “gouty” throat Edward
McCracken found _pyorrhœa alveolaris_ to be present in thirty-nine, and
Fenner also tells us that this affection is common in the subjects of
gout.
In truth, the victims of _gouty_ arthritis are no more immune from
_dental_ lesions than those of other types of joint disease. Thus, Mr.
Macdonald, dental surgeon to the Royal Mineral Water Hospital, Bath,
informs me that this form of _oral sepsis_ is extremely common in _gouty_
individuals, and in my experience it is but rarely that evidences of its
presence are not forthcoming in these subjects. The desirability of early
recognition of such foci—in light of their highly probable _etiological_
significance—can scarcely be overestimated. For their consequences, both
local and remote, are of paramount importance.
Thus, G. I. Stewart’s recent observations have conclusively demonstrated
that “bad teeth” are causally related to _tonsillar_ affections. How
illumining this, in view of McCracken’s experiences in “gouty throats.”
As we saw, _pyorrhœa alveolaris_ was present in more than half the
examples. But, more pertinently to the point at issue, he comments on the
frequency with which the victims of gout develop _acute tonsillitis_, of
lacunar or parenchymatous type, also that such attacks frequently precede
outbreaks of _arthritic_ gout. Duckworth again noted the same liability
of the gouty to unsound teeth and tonsillitis, and that the latter was
often followed by articular outbreaks. Luff also observed that “gouty”
tonsillitis was occasionally a precursor of articular gout, always
subsiding on the appearance of the latter complication.
Again, acute and chronic _pharyngitis_ are proverbially common in “gouty”
subjects. Moreover, in both types the subsidence of the throat affection
has frequently been signalised by an articular outbreak of classic site.
_Parotitis_, too, has been repeatedly met with in gout, and, according to
Luff, “rapidly subsides on the appearance of regular gout in one or more
joints.”
In truth, whether we peruse recent or older works on gout, we cannot
fail to remark the unanimity of opinion as to the frequency of incidence
of these _glandular_ affections—these states of _oral sepsis_—in the
subjects of _gout_. Equally noteworthy is their insistence on the
constancy with which such local affections have proved harbingers
of oncoming _articular_ outbreaks. Lastly, the mere fact that our
forefathers dignified these local disorders with special appellations,
“gouty” tonsillitis, pharyngitis, etc., is cogent proof that they
regarded them as among the integral features of gout.
Now, as to the true significance of these acute _glandular_ affections,
held by clinicians of repute to be of “gouty” origin. What of “gouty”
tonsillitis, pharyngitis, etc.? Still more, what of our deductions
regarding the relationship of these same when met with in association
with other joint disorders? Do we not hold them each and all as evidences
of _infection_—“acute rheumatism,” “gonorrhœal arthritis,” etc.?—and we
may well ask, Why not in _gout_?
Says Duckworth, “Angina tonsillaris—very painful but not suppurating—may
in the gouty suddenly yield to an acute articular attack.” Is it not
here more than likely that the tonsil was the initial site or portal of
_infection_, and the arthritis _secondary_ thereto? Is not this same
interpretation in all probability true also of all forms of “gouty”
throats when followed by _arthritic_ outbreaks?
The marvel, then, is that not only have we held, but apparently many
still hold, that the tonsillitis, pharyngitis, even the gingivitis—like
the subsequent articular lesions—are one and all attributable to the
underlying _gout_. We certainly would not do so in the case of any
arthritis other than “gouty,” and to my mind the time is ripe for a
change of attitude. The “gouty” throats, like the “gouty” teeth, should
be regarded not as symptomatic of gout, but _etiologically_ related
thereto. We should cease to talk of “gouty” throats, teeth, etc., should
renounce the prefix, for there is nothing _specific_ of _gout_ either
in the tonsillar, pharyngeal, or dental lesions. We should instead view
these various local disorders in their true perspective as _foci of
infection_, _causally_ related to the subsequent and _secondary_ “gouty”
arthritis.
_Gastro-Intestinal Disorders._—It is a matter of common experience
that acute attacks of gout are often preceded by or associated with
flatulence, heartburn, acidity, loss of appetite, confined bowels,
scanty, high-coloured urine, and a feeling of lassitude. In short,
nothing is more certain than that exacerbations or relapses very commonly
follow symptoms referable to gastro-intestinal and hepatic disorders.
How well established is it that these subjects after unusual, though
not necessarily excessive, indulgence at the table, almost inevitably,
and sometimes almost immediately, suffer twinges in the big toe, if
not frank outbreaks of gout. Such reaction seems to indicate clearly
that the functional disturbances in the alimentary tract stand in some
causal relation to the subsequent arthritic phenomena. The assumption
gains colour, too, from the very certainty with which freedom from such
gouty manifestations is attained by abstinence from, or more moderate
indulgence in, articles of diet predisposing to such ebullitions.
So much by way of prelude as to the probability—attested by clinical
observation and the results of treatment—that the _intestinal canal_ is
often the source of the responsible microbe or toxin. Let us now pass
to consider what factors other than an _oral sepsis_ may favour the
incidence of _functional_ disorders of the _alimentary_ tract.
_Variations in Free HCL._—Some years ago Grübe and Falkenstein found
that in gout the hydrochloric acid of the gastric juice, far from being
increased, was in most cases _diminished or wholly wanting_.
Now, as we know, the gastric juice when of normal acidity is quite
capable of dealing with moderate quantities of pathogenic bacteria. But
in the presence of _oral sepsis_ it is probable that a greater number are
swallowed than can be satisfactorily coped with.
Given therefore excess of pathogenic organisms and _relative
insufficiency of free HCL_, conditions favourable to the growth of
bacteria ensue, while incidentally the chance of such reaching the
intestine is materially enhanced.
When, however, the defensive barrier is wholly withdrawn, viz. when there
is an absence of free HCL, then of course the necessary inhibition of
microbic growth fails of achievement. Moreover, also owing to diminished
acidity, ill-digested protein substances gain access to the intestine,
and their subsequent putrefaction is favoured.
In opposition to the foregoing, many hold that an _excess of free HCL_
in gout is not uncommon, and unquestionably some are thus troubled. The
pernicious effects of the hyperchlorhydria are accentuated by the fact
that intestinal indigestion ensues secondarily, owing to the acid chyme
completely antagonising pancreatic secretion and thus impairing digestive
capacity.
_Intestinal_ rather than gastric indigestion is, I think, more typical
of the gouty subject. It will be recalled that the food nucleins are
unaffected by the gastric juice, and though the protein moiety is split
off from the nucleinic acid by the pancreatic ferments, yet neither the
poly- nor the mono-nucleotides are thereby acted upon. It is in truth the
_succus entericus_ with its nucleotidase that plays the most important
digestive _rôle_ as regards nucleins, breaking them up into nucleosides
which are, to a large extent, absorbed as such.
To resume, this condition of _intestinal indigestion_ may arise from
a variety of causes: excess or deficiency of gastric juice, defective
motility, and diminished secretion of intestinal juices, and in all cases
improper food may determine such _intestinal derangement_.
The clinical features presented are very variable. It is often
difficult, if not impossible, on the basis purely of the subjective
symptoms, to decide in any given instance how far the symptoms are
referable to _intestinal stasis_, or to a _chronic infection_, with a
resultant catarrhal state of the mucosa, or to both causes combined in
varying proportions.
But, be the explanation what it may, in our experience the most common
antecedent or concomitant of gout is _intestinal dyspepsia_. Its
secondary consequences are far reaching, especially if the small bowel be
involved, catarrh of which may lead to _reduction_ in the secretion of
_bile_ and _pancreatic juice_.
How commonly in these cases do we meet with symptoms indicative of
sluggishness of the hepatic functions, such as turbidity of the urine, a
pale or abnormally dark colour of the alvine evacuations. Also, whatever
be its true etiology, they exhibit not so uncommonly _sugar_ in the
urine, the so-called “gouty” _glycosuria_.
Now, as a mere glance will show, diminution and impairment of the biliary
and pancreatic secretions have far-reaching consequences. Foodstuffs
undergo abnormal changes, are less easily absorbed, and simultaneously
chemical products are formed which irritate the intestinal mucosa. Nor
do the baneful effects cease here, for, owing to the unusual nature and
reaction of the intestinal content, the _bacterial flora_ in the bowel
undergo modifications.
Thus, organisms normally present only in small numbers in the small
intestine find the altered medium more suitable for their growth and
multiplication; while others, whose usual habitat is the large bowel,
migrate upwards, and infect the ileum and duodenum, and ultimately the
biliary and pancreatic passages.
In the presence of such deficiency in the intestinal juices, proteins are
imperfectly digested, and putrefaction under microbic action favoured. At
the same time the digestion of carbohydrates is impaired, organic acids
are formed, and gases in larger amounts liberated. Ultimately, owing to
absorption of these irritating products, a condition of _chronic toxæmia_
results.
SUMMARY
It now devolves upon us to decide whether the phenomena of gout are best
explicable as the outcome of _auto-intoxication_, or of _infection_ or
_sub-infection_. The uric acid theory was in truth one of _auto-toxæmia_,
the varied manifestations of gout being attributed to mechanical or toxic
irritation by _uric acid_, the end-product of purin metabolism. But, as
we hope to have shown conclusively, uric acid is _not toxic_, and _per
se_ is apparently as innocuous as those other and intermediary products
of metabolism which give rise to cystinuria and alkaptonuria.
The question then arises, Is gout haply due to a retention of other
metabolites? That outbreaks of gout follow fast on the heels of dietetic
irregularities is proverbially true. But there is no certain evidence
that the symptoms generally ascribed to auto-toxæmia are referable to
substances derived from the foodstuffs under the action of the digestive
juices. Toxic as are peptones and primary proteoses when they gain direct
access to the tissues, the symptoms produced in no way resemble those
affiliated to alimentary toxæmia, much less those of _gout_. Rather,
according to Adami, do they approximate to those typical of _anaphylactic
shock_.
Normally, too, the mucous membrane proves an efficient barrier, these
poisonous bodies during their passage through it being transmuted
into harmless substances. Nor can we refer the symptoms of gout to a
toxæmia secondary to _intestinal stasis_ or other causes. In other
words, it cannot be attributed to assumed toxic action on the part of
the intermediary and terminal products of protein disintegration. For
seemingly these chemical outcasts of the economy become progressively
less toxic on their downward path to effete matter.
The diamines, too, produced by bacterial action on foodstuffs, are so
minimal as to be negligible, while the toxicity of cholin and neurin is
unestablished; and as for indol and skatol, they are with difficulty
absorbed from the healthy colon. Experimental researches on carbohydrate
and fatty disintegration have likewise proved sterile, while there is
no evidence that the anaerobes present in the digestive tract produce
ecto-toxins, or undergo lysis with release and absorption of their
endo-toxins.
In short, it is but too clear from the foregoing brief _résumé_ of recent
experimental findings that, if _uric acid_ cannot be held responsible for
the causation of _gout_, there is no evidence likewise that the disorder
owes its genesis to any other of the as yet isolated _chemical_ products
of gastro-intestinal digestive activities. Having dealt with this aspect
of the question, we shall now pass on to consider whether the phenomena
of gout can be more adequately explained on a basis of _infection_ or
_sub-infection_.
_Infection or Sub-infection._—Our knowledge as to the exact manner in
which _local foci of infection_ work their malign effects almost daily
undergoes expansion. It will be recalled that Stewart has shown that “bad
teeth” are often etiologically responsible for tonsillar inflammation. It
further is well established that _streptococci_ are of common incidence
in the _tonsils_, and Rosenow and Brown from experimental observation
have established that these hemolysing organisms, migrating _viâ_ the
blood stream, exhibit a marked predilection for forming a fresh nidus
in the _gall bladder_. Here they may initiate a _cholecystitis_, and
secondly gallstones, and in sequence thereto the symptoms associated
with _gall-bladder-dyspepsia_. The same formidable list of sequels may
follow infection of the gall bladder from the _teeth_, _stomach_, or
_intestines_, notably from the vermiform appendix.
In like fashion the origin of _appendicitis_ may be traced back to
_septic foci_ in the _mouth_, _tonsils_, _naso-pharynx_, or to the
_gastro-intestinal tract_. Here again there ensue the symptoms of
so-called _appendix-dyspepsia_. As in the case of the gall-bladder
variety, the _primary lesion_ in the _appendix_ may be _latent_, and the
exact diagnosis may be a matter of great difficulty, often indeed only
to be achieved _retrospectively_, viz., when abatement of the symptoms
follows ablation of the appendix.
We see, therefore, how far-reaching are the consequences of _local foci
of infection_ in the _mouth_ or elsewhere. Now, the _gouty_ subject
enjoys no immunity from the remote sequels of local sepsis. But as a
rule, unfortunately, whatever be the nature of his _dyspeptic_ symptoms,
they are, like his _dental anomalies_, his _tonsillar inflammations_,
forthwith dismissed as _symptomatic_ of gout, not etiologically related
thereto.
Now, I have seen pyorrhœa and chronic appendix-dyspepsia running side
by side in the same subject with recurring classical attacks of gout in
the big toe. The faulty teeth were extracted, and later the chronically
inflamed appendix removed; and though he had an attack of gout shortly
after the operation, there has as yet been no recurrence thereof.
Again, by the older writers “gout in the liver” was most firmly believed
in—as one authority puts it, “a subacute catarrh of the intrahepatic
biliary system which may lead to a subacute parenchymatous hepatitis”!
But more pertinent to my point is the insistence of older authors upon
the frequent association of gout and _gall-stones_. Senac, of Vichy,
claimed indeed that out of 166 cases of _biliary lithiasis_ 95 had gout
or an hereditary predisposition thereto. Judging by modern experience,
this is probably a gross over-estimate. In contrast, our own countryman
Murchison dwelt upon the frequency of jaundice in gout independently of
biliary colic. And, as we shall see later, Brinton held that many of the
dramatic phenomena accredited to “retrocedent gout” were unrecognised
examples of _biliary colic_.
But, controversy aside, the point I would lay stress on is, that we
should refrain from labelling offhand “dyspeptic” symptoms in a “gouty”
subject as _gouty_, this when we are so constantly confronted with
_local foci of infection_ in the _mouth_, or elsewhere, which afford
us an explanation of the gastro-intestinal symptoms at once more
obvious and more rational. This also the more especially in that—as
far as subjective symptoms go—those deemed typical of so-called “gouty”
dyspepsia are indistinguishable from those met with in _appendix-_ or
_gall-bladder-dyspepsia_. Indeed, I might go further and point out
that the _variations in free HCL_ in the gastric juice—as observed in
_gout_—conform to those met with in the above disorders. Thus, in “gouty”
dyspepsia, the free HCL may be normal, in excess, or wholly absent, as
in gall-bladder or appendix-dyspepsia. I would therefore plead that in
any “dyspepsia” arising in a genuinely _gouty_ subject we endeavour to
elucidate the exact nature of the _underlying lesion_, but to this we
shall return again when discussing diagnosis.
Again, the fact that gall-bladder or appendix lesions may be the outcome
of septic foci in the mouth enables us the more easily to explain the
not infrequent co-existence of gout and _glycosuria_. For an infected
gall-bladder may by extension determine a chronic _pancreatitis_.
Lastly, what of the relationship of local foci of infection to _“gouty”
synovitis_ and _arthritis_? Is one focal infection more than another
particularly related to arthritides? Whatever be the true inference,
if we take _arthritides_ as a whole, nothing seems so efficient a
cause of their production as _oral sepsis_. Accordingly, some are
inclined to think that organisms, _e.g._, _streptococcus viridans_, at
the roots of the teeth or others in the tonsillar crypts, pass, _viâ_
the blood-stream, _direct_ to the _joints_. Others, again, hold that,
given oral sepsis, infection of the stomach and lower levels of the
alimentary tract and its accessory cavities ensues. And in sequence
thereto infection of the joints may take place from local foci throughout
gastro-intestinal tracts.
Those who favour the view that _direct infection viâ_ the blood from foci
of oral sepsis is the more probable _modus operandi_ are wont to produce
the following points in support of their view. Arthritis, they say, is
relatively rare in _enteric fever_. In yet another disorder, _dysentery_,
which gives every chance of absorption from the intestine, arthritis when
it occurs is seldom very acute, while in _appendicitis_ it is distinctly
uncommon.
On the other hand, we must recall that even in normal animals the
alimentary and respiratory tracts, and alike the liver and kidneys,
constantly afford cultures of pathogenic and non-pathogenic bacteria.
Such was established by Adami and his co-workers, who moreover found that
such organisms, through the agency of leucocytes, continually pass into
the system, where subsequently in the healthy animal they as constantly
undergo destruction.
If, however, inflammatory processes are at work, their migration into the
tissues is favoured. For under such conditions leucocytes aggregate at
the reactive focus, and concurrently, their migration being more active,
larger numbers of bacteria achieve entry into the system. The subsequent
course of events is determined by the number and virulence of the
organisms that effect a lodgment in the tissues, where under favourable
conditions they originate other foci of infection or sub-infection.
By _sub-infection_ is understood the fact that microbes carried into
the system undergo slight, if any, numerical increase, and do not set
up _foci of suppuration_. Here we may note that “gouty” inflammation,
however intense, never ends in _pus formation_. But, to resume, the
bacteria, instead of multiplying, undergo lysis, and, their endo-toxins
being released, the more highly specialised tissue cells in the vicinity
are destroyed. Coincidently the lower grade connective tissue elements
are by the self-same poisons stimulated to proliferate, and an area of
_chronic interstitial fibrosis_ is formed.
Incidentally this is interesting, inasmuch as the _visceral_ organs in
gout evince a tendency to _fibrosis_. But, as Gideon Wells observes,
“the actual increase of uric acid in the blood and tissues in gout is
so slight that we are not warranted in saying that the usual tendency
to sclerosis in all the organs in gout is due to the action of uric
acid rather than to some other unknown agent or agents.” In view of
these revelations, is it not infinitely more likely that the chronic
interstitial fibroses in gout are the outcome of such _sub-infection_?
The assumption gathers weight in light of the experimental proof adduced
by Adami that not only tubercle bacilli, but _streptococci_ and other
organisms, _taken orally_, can gain an entrance into the system. Upon
this basis we get a clear conception of the possible relationship of gout
to _local foci of infection_. Thus, whether it be a condition of oral
sepsis—pyorrhœa alveolaris, tonsillar sepsis, sinus disease, intestinal
disorders, constipation, and so forth—we see that it is highly probable
that organisms at any one of such infective foci may gain access to the
blood-stream with subsequent installation of local lesions in _joints_ or
other structures.
Now, as pointed out, inflammatory states or _functional_ derangements
of the _alimentary_ tract, whether focal or diffuse, favour the ingress
into the tissues of organisms. Is it not reasonable, therefore, we ask,
to suppose that the functional derangements which so commonly precede
or accompany gout may modify the character of the _intestinal flora_,
and promote their migration inwards in greater numbers? The inevitable
swiftness with which relapses or exacerbations of this disorder follow
even venial dietetic indiscretions distinctly favours this assumption,
one, moreover, substantiated by the amelioration or immunity which
follows abstention from the offending foodstuffs. The often prolonged
course, too, of gout, and its marked liability to periodic recurrence,
would be explicable as the outcome of a continued or intermittent series
of sub-infections.
My conclusions then are that:—
(1) The majority of cases of gout are marked by the presence
of _local foci of infection_, pyorrhœa alveolaris, tonsillar,
pharyngeal or nasal sepsis, etc., or by gastro-intestinal
derangements, constipation, etc.
(2) The said local foci should be regarded not as symptomatic
of, but _etiologically_ related to, gouty arthritis, and that
the same is strongly indicated by the fact that
(3) Acute _glandular_ affections of undeniably _infective_
source—tonsillitis, pharyngitis, etc.—frequently and
immediately _precede_ acute paroxysms of _articular_ gout, and,
lastly,
(4) The gastro-intestinal defects, secretory or motor, which
chequer the course of gout, enhance the pathological activities
of the intestinal flora, and incidentally the liability to
infection, at various sites of the alimentary tract.