PATHOLOGY OF GOUT—PROTEIN METABOLISM
Not only is the proximate cause of gout unknown, but the essential nature
of the disease is still shrouded in obscurity; for the obliquity in trend
of protein metabolism, manifested though it be by striking phenomena, is
clearly only the outcome of some, as yet undetermined, derangement in the
mechanism of _intermediary_ metabolic or bio-chemical change.
This is, of course, but to restate the problem we are confronted with.
Wholly to solve the enigma would postulate ability on our part to trace
ingested foodstuffs through all their vicissitudes from the moment of
entry into the blood or lymph-stream till flung out as effete matter
through the various avenues of excretion; but, unhappily, we know the
story only in part, its beginning and end, but not what lies between.
We know much of the complex changes that take place in food prior to
absorption, and of the _modus operandi_ of the latter not a little.
Comparably, too, we can gauge the quality and quantity of end-products,
the chemical outcasts, as they escape in the urine, sweat or breath, and
largely how achieved; but of the intermediate steps between absorption
and excretion we catch but a glimpse here and there. The sequestered path
by which the inanimate molecules of food uprise to Life, and anon go down
to decay and death, are still hidden.
In other words, little do we know of the relationship of _labile_, or
food-protein, to _tissue_ protein. True, the coarse fact of abnormal
protein loss in _renal_ disease may be revealed in the urine, as
likewise the waste of albumoses in _myeloma_, etc., and the incidence
of amino-acids in disease of the _liver_. Similarly, the appearance
of _cystin_ or of _alkapton_ in the urine bespeaks flaws in protein
metabolism, failures in the normal disruption of amino-acids. All these
are of the grosser anomalies of protein metabolism, but more subtle those
of gout!
Complex, in truth, the problem here presented, than which none more
subtle exists in the realm of bio-chemistry. True, _quantitative_
variations in the content of the urine as to _urea_, _uric acid_, etc.,
undoubtedly bear a direct relation to _protein_ metabolism, but they give
us little, if any, substantial clue as to the particular metabolic warp
responsible. We see this particularly in regard to uric acid, so long
accredited with an essential _rôle_ in gout.
Thus we cannot, on the basis of the _variations_ in its _excretion_ only,
presume to diagnose “gout.” This because even more extensive variations
occur in _healthy_ persons. On the other hand, attacks of gout never
occur when urates are absent from the _blood_. To reduce the amount of
these urates is clearly then of importance, and obviously to this end a
knowledge of their source is essential. We have an analogy to hand in
diabetes, in which the somewhat similar problem relating to _glycosuria_
has been partially solved.
REVELATIONS OF THE BIO-CHEMIST
But before proceeding to the more strictly biological aspect of the
relationship of uric acid to gout, we must, as in the study of any other
problem of metabolism, place ourselves in possession of the main facts
relating to the chemistry of _protein_, and more particularly of _purin_
or _nuclein_ metabolism; for it was just this same lack of even the most
rudimentary facts, especially regarding the chemistry of uric acid,
that vitiated the conclusions arrived at by the earlier workers in this
sphere. Disabilities of technique of necessity rendered inaccurate the
results obtained by these pioneers in research, while the significance of
the facts they laboriously gleaned was likewise misinterpreted.
But with the advent of highly trained organic chemists, well skilled
in the investigation of bio-chemical problems, a basis of accurate
chemical facts was established. The story of the fate of protein and
purin substances in the animal body, at one time a medley of guesses and
gaps, was brought to one of relative certitude and completeness. The
change involved has proved in truth revolutionary, and many the cherished
shibboleth that has been ruthlessly cast aside.
How vivid the light thrown upon the problems of clinical medicine by the
bio-chemists! With admiration not unmingled with awe we see them laying
well and truly the foundations upon which in the ultimate scientific
medicine must inevitably rest. Of these the very corner stones are
_chemical physiology and chemical pathology_, the rapid evolution
of which is profoundly altering our conceptions of health and alike
disease. Those vital processes of the organism that but yesterday we saw
“as through a glass darkly,” are now in great part illumined, and the
distortions wrought in them by disease made more manifest.
How pregnant, too, with warning their findings! Processes that, to our
untutored minds, seemed simple are revealed as infinitely complex.
Through what a labyrinth must we thread our way if we would unravel the
intricacies of metabolism! Intricate enough, forsooth, in health, but how
much more so in disease!—for as Sir Archibald Garrod eloquently phrases
it, “It is becoming evident that special paths of metabolism exist, not
only for proteins, fats and carbohydrates as such, but that even the
individual primary fractions of the protein molecule follow their several
catabolic paths, and are dealt with in successive stages by series of
enzymes until the final products of catabolism are formed. Any of these
paths may be blocked, while others remain open.”
It is with chastening reflections such as these that we may best approach
our study of gout, that Riddle of the Ages, upon the elucidation of which
so many physicians from time immemorial have expended their dialectic
skill. Would that we could affirm that the bio-chemists of to-day had
found the “Open Sesame!” But, alas, it is not so! The chamber is still
sealed.
Vast though the increase in our knowledge of the chemical structure of
uric acid and its allies, uncertainty still dogs our steps. Doubtful of
the pathway to solution of the pathological mystery of gout, we must
perforce approach the problem in a more strictly catholic attitude. _Uric
acid_ has apparently failed us as the _causa causans_. We can, therefore,
no longer restrict our enquiry to _purin_, but must take cognisance
of _protein_ metabolism as a whole, for some, perhaps not unnaturally
despairing of the _uric acid_ hypothesis, are turning therefrom to
other end-products of metabolism, _e.g._, _creatinine_. In keeping
with this altered outlook, it will not be out of place if we, at this
juncture, allude, though in brief, to the later revelations as to protein
metabolism, before we pass on to more detailed consideration of those
relating to the _purin_ bodies.
PROTEIN METABOLISM
No longer can we, like the older physiologists, envisage _protein_
as being absorbed as such from the alimentary canal and forthwith
incorporated with the body tissue, for the researches of Fischer have
revealed that the complex _protein_ molecule must previously undergo
complete disruption into the _a-amino-acids_, its ultimate “building
stones,” this through the hydrolytic action of the digestive enzymes
of the alimentary tract. The fact that Fischer[6] was able to maintain
nitrogen equilibrium in animals fed with completely digested protein
mixtures is, of course, direct evidence in favour of his contention,
viz., that proteins undergo disruption into amino-acids.
THE FORMATION OF UREA
The question as to whether urea, the end-product of general nitrogenous
catabolism, was derived from the _amino-acids_, brought in the portal
blood to the liver, was for long a vexed one. This because the earlier
attempts to detect amino-acids in the _portal blood_, during the
digestion of copious amounts of protein, proved futile. On the other
hand, the same workers found that free _ammonia_ was present in greater
amounts in the portal vein than in the systemic circulation.
This, to their mind, seemed to indicate that the amino-acids, during
their passage through the intestinal mucous membrane, underwent
_deaminisation_. According to this view the _ammonia_, thus split off
from the amino-acids, was the precursor of _urea_.
But the claim that more free ammonia was present in the portal vein than
in the systemic circulation was disproved by Folin and Denis. Invoking
more delicate methods of hæmo-analysis, they found that the amount
of ammonia and urea in the portal blood was not increased during the
absorption of amino-acids from the lumen of the intestine. Moreover, they
found that the ammonia present was of minimal amount, produced in the
main by putrefactive bacteria. Lastly, they discovered that _amino-acids_
were actually present in the _portal blood_.
FATE OF THE AMINO-ACIDS
In the gastro-intestinal tract the complex food proteins, under the
hydrolytic action of enzymes, break down into a variety of substances,
all of which belong to the group of a-amino-acids. These same absorbed
from thence into the blood are transported to the various organs and
tissues. Arrived thither the amino-acids are subjected to a process of
sifting. Thus some are invoked for the reconstruction of broken down
proteins, _i.e._, are re-synthesised into the body’s own characteristic
tissues.
The surplus amino-acids, viz., those not required for purposes of cell
repair, undergo deaminisation. Two residues then result, one represented
by ammonia, and the other by the remaining relics of the amino-acid
molecule. The former is excreted as _urea_ and the latter is oxidised to
produce energy.
But there is yet another source of amino-acids, viz., the disintegration
of tissue protein. To this end almost all bodily tissues possess
intracellular enzymes capable of converting their proteins into the same
simple products from which they took origin.
Comparably with those of exogenous origin, these amino-acids of
_endogenous_ formation undergo a like deaminisation; in other words, the
bulk of their carbon, oxygen, and hydrogen is oxidised to form CO₂ and
water, the residue combining with nitrogen to form _urea_, etc.
The main end-product, then, of protein metabolism is _urea_, with traces
of its forerunner _ammonia_. But there are also other waste nitrogenous
metabolites. Thus, of the various amino-acids that become built up into
tissue protein, some subsequently break down into products not belonging
to the amino-acid category, viz., _creatine_ and _creatinine_. Some of
the amino-acids, too, are excreted unchanged in the urine. Lastly, to
these must be added those closely related substances, the _purin_ bodies,
the end-products of _nuclein_ as opposed to general protein metabolism,
of which latter _urea_ is the terminal product. To sum up, in a man on
ordinary diet about 90 per cent. of his total nitrogen is excreted as
urea, about 3 per cent. as ammonia, the residue of the nitrogen appearing
in the form of other nitrogenous metabolites.
SEAT OF FORMATION OF UREA
The _liver_, it is generally held, is the main centre wherein urea is
produced from the amino-acids; but not exclusively so, for it has been
definitely established that, _even after removal of the entire liver in
animals_, its production may not cease.
Moreover, some researches of Otto Folin and W. Denis into _urea
formation_ seem to indicate that the older views call for revision.
Experimenting on cats, they injected them with _alanine_ and _glycocoll
nitrogen_ and other amino-acids as well as Witte’s _peptone_. They
were able to prove definitely that, at the end of an hour or more, the
formation of _urea_ from the absorbed amino-acids was unmistakably
demonstrable. Also they noted that interesting fact, that the “_urea
nitrogen_ obtained from the _hepatic blood_ is not larger than the urea
in the blood obtained at about the same time from the _iliac artery_.”
This they claim indicates that “_the liver has not brought about any
demonstrable specialised deaminisation_.”
The experimental data forthcoming in their researches, while they prove
that the absorption of _amino-acids_ is very swiftly followed by the
formation of urea, does not afford any definite evidence as to the _site_
of urea formation; but, as they rightly contend, we have no satisfactory
proof that _deaminisation_ and _urea formation_ is _localised_.
Consequently “we are not justified in assuming that the process is a
specialised process in the sense of being confined to some particular
organ.”
Indeed, they bring forward evidence that the process of urea formation,
far from being localised to any particular organ, _i.e._, the liver, is
almost ubiquitous.
Thus, experimenting with the injection of _alanine_, they noted that
prior to the same the muscle content of _non-protein nitrogen_ and _urea
nitrogen_ was respectively 194 and 26 mg.; but 180 minutes after the
injection the non-protein content in muscle had risen to 232 and that of
urea nitrogen to 41 mg. Working with _glycocoll_, the non-protein and
urea nitrogen in muscle before injection of the same was 248 and 42 mg.
respectively, while 240 minutes after injection the figures were 304 and
54 mg.
The significance of these figures is more striking when contrasted with
the fact that in the same subjects the urea nitrogen content of the
_hepatic_ blood did not exceed that obtained almost simultaneously from
the _iliac_ artery. The deduction made by Folin and Denis is that—
(1) “_The urea-forming process is one characteristic of all the tissues,
and by far the greatest amount of the urea is, therefore, probably formed
in the muscles._”
(2) “_The negative results, so far as any localised urea formation is
concerned, is almost satisfactory proof that there is none, for if
there were one central focus from which all or nearly all of the urea
originated we could scarcely fail to find it._”
AMINO-ACIDS IN RELATION TO GOUT
The vista opened up by these advances in physiology suggested
investigations into the _amino-acids_, their association with the output
of _uric acid_ in _gouty_ patients. No less than eighteen different
amino-acids enter into the constitution of protein, but of these the most
interesting from our point of view is _glycocoll_ or amino-acetic-acid.
Now, glycocoll plays a great _rôle_ in the organism as a _detoxicating_
agent, rendering innocuous, _e.g._, benzoic and cholic acids by
transmuting them into _hippuric_ and _glycocholic_ acids. In short, the
body always has glycocoll at its disposal for coupling or combination
purposes.
Now it appears likely that glycocoll can be split off from all the
amino-acids, a probability reinforced by the results of the researches
of Embden and Reese and Lipstein, these observers having shown that
amino-acids are present in all urines to about 1 per cent. of the total
nitrogen output.
Ignatowski, working with the urine of _gouty_ patients, found
_amino-acids_ present in large amounts; not that it was peculiar to
such subjects, for he found it in other diseases, but only traces were
detectable in the urine of _healthy_ individuals. Again, Walker Hall,
investigating urines drawn from the subjects of gout, the victims of
other diseases, as well as healthy and diseased children, determined
the presence of _glycocoll_ in about 70 per cent. of the cases. His
researches, to his mind, confirmed the conclusion that “normally a
certain amount of glycocoll escapes through or is eliminated by the renal
filter.”
Burger and Schweriner, from their researches on gouty subjects, have
confirmed Walker Hall’s findings as to the excretion in excess of
amino-acids, especially _glycocoll_. Lastly, Almagia has in gouty urines
detected the presence of _glyoxylic_ acid. What its significance may be
is uncertain, but it is at least interesting to note that, as MacLeod
suggests, the synthetic formation within the body of glycocoll may very
probably result from the interaction of ammonia and glyoxylic acid.
THE GLYCOCOLL THEORY OF GOUT
Excessive meat feeding in dogs, according to Kochmann, induces
degenerative changes in the liver and kidneys. Similar tissue
alterations were noted by Walker Hall in rabbits, after injection with
_hypoxanthine_, while the same was observed by Kionka in mice. These
findings suggest that, although _anatomical lesions_ are not apparent in
the _livers_ of “gouty” men, it is at least probable that _functional_
damage results from the overeating of meat.
Now, if glycocoll be added to a solution of (neutral) dialkali-urate,
it expedites the appearance of the (acid) mono-alkali-urate, a reaction
more noticeable with the sodium salt. _Urea_, in contrast to glycocoll,
markedly inhibits the formation of the acid salt. But if _glycocoll_
be added to a solution of the (neutral) dialkali-urate and urea, the
latter parts to some extent with its powers in this respect, and the
mono-alkali-urate is deposited.
It is reasonable, then, to suppose that if, as testified by Ignatowski
and Walker Hall, glycocoll is present in gouty _urine_, it is also
present in the _tissue fluids_ of the gouty individual, and so the
_precipitation_ of _uric acid_ is favoured. Glycocoll, normally, is
almost entirely transmuted into _urea_ by the urea-forming ferment of the
liver.
Impressed by these considerations, Kionka advances the hypothesis that
gout is due to:
(1) Functional changes in the liver, a depressed urea-ferment
action.
(2) A deficient uric acid excretion by the kidney, possibly due
to the changed uric acid combinations in the blood.
(3) These pathological conditions may be “hereditary” or
“acquired,” from overeating, alcohol, lead, etc.
In other words, given deficient action of the urea ferment in the liver,
then more glycocoll will be present in the blood-stream, and the uric
acid may be thrown out of solution.[7]
For it is possible, as Kionka suggests, that normally uric acid, on its
way to urea, may pass through a _glycocoll_ stage. Now, in the gouty
individual the glycocoll may not be entirely transformed to _urea_, and
its excess in the _tissue fluids_ may lead to _uric acid deposits_.
Perhaps, as Walker Hall observes, “since hepatic deficiency is generally
admitted in the gouty, diminished destruction of uric acid and glycocoll
may go hand in hand.”
In healthy _cartilage_ glycocoll is undemonstrable. But, according to
Kionka, if bruised or damaged, a considerable amount thereof is formed.
Now, when blood, rich in uric acid, circulates through injured cartilage,
the presence of glycocoll favours precipitation of the urates, a possible
explanation of the formation of _tophi_. Unfortunately for the valency of
this theory, Aberhalden and Schittenhelm show that the methods employed
by Frey, to isolate glycocoll from cartilage, were such as yield errors
which would quite account for the amount obtained by this worker. They,
therefore, deny the presence of glycocoll in damaged cartilages. But, in
conclusion, Kionka’s plea for a primary _hepatic functional disability_
derives colour from the fact that the drugs which have gained most
approval in the treatment of gout are those which increase the quantity
of bile without augmenting the amount of bile acids; and the which are
excreted in combination with _glycocoll_, for instance, salicyclic acid
combines with glycocoll, and is excreted as salicyluric acid, and benzoic
acid, which combines with glycocoll to form hippuric acid. Albeit, we
must not overlook the fact that the presence of glycocoll is not peculiar
to _gouty_ urine, but, as shown by Walker Hall and Embden, is met with in
other disorders. The glycocoll hypothesis as to the origin of gout is,
though attractive, therefore still unproven.
UREA EXCRETION IN GOUT
According to Tilden Brown, the rhythm of urea excretion constitutes a
warning as to the approach of gout. A very lowered elimination thereof he
holds to be an excellent and pathognomonic symptom. The excretion of urea
may at times run so low as to lead to a suspicion of _renal_ disease. He
considers that this sign may find a place in the prophylaxis of gout,
a signal for the initiation of treatment with the object of lessening
the severity of symptoms (viz., extent of toxic action as manifested by
destruction of proteid, etc.).
This point was advanced by Brown (1905) during a discussion at the
Harvard Medical Society, but as far as we know it has not been confirmed.
Presumably it rested upon the assumed existence of a normal ratio of
uric acid elimination to that of urea with the corollary that every
deviation therefrom was due to a pathological cause. Haig held this view,
which was, however, disproved by Herringham, Groves and Luff. The latter
authority estimated the daily eliminations of uric acid and urea in a
healthy adult man on a mixed diet for a period of fifty days, and clearly
showed that no constant ratio exists in a given individual between the
excretion of uric acid and urea.
Also, it is obvious that, before attaching any valency to Tilden Brown’s
dictum, it is essential that it be established that the cases were
instances of pure gout, unaccompanied by _nephritis_. Moreover, modern
workers tend more and more to rely not on analyses of the urine but
of the _blood_, especially in the unravelling of so-called metabolic
disorders. Also, it may be added, that their findings in this sphere
indicate no harmony between the urea and the uric acid content of the
blood. Thus, Otto Folin observes, “One most interesting fact which we
constantly meet with in blood analysis is that there is no correspondence
between uric acid and the total non-protein nitrogen in the blood. In
gout or lead poisoning, or leukæmia, the blood is uniformly rich in
uric acid, yet the total non-protein nitrogen or _urea_ nitrogen may be
normal.”
CREATINE AND CREATININE
As before pointed out, it has been suggested that these substances may
be in some obscure way related to the genesis of _gout_. To this end a
great amount of research has been expended on the metabolism of creatine
and creatinine. But although, as far as I am aware, the revelations
hitherto forthcoming have disclosed no link between these substances and
the development of gout, still, by reason of the potentialities possibly
resident therein, a brief digression is permissible.
The exact origin of creatine and creatinine is still obscure. All we know
is that they are, in the main, the outcome of chemical processes in the
tissues, viz., products of _endogenous_ metabolism. Also of the creatine
and creatinine present in food a moiety may appear as creatine in the
urine.
_Creatinine_ occurs in the urine of adults, and is practically
independent of the protein intake. The amount excreted varies with the
size, and not with the weight of the body. In other words, it varies
with the _volume_ or _mass_ of the _voluntary muscles_, which structures
have the highest content of creatinine and creatine. MacLeod, discussing
this relationship, tells us that, “in the muscular atrophies creatine
excretion is distinctly below normal.” It must, he adds, be the “mass
of the muscles rather than their activities that is the determining
factor, for the creatine excretion does not become increased by
muscular exercises.” Otto Folin, discussing the clinical application
of pathological chemistry, observes, “Nothing definite is as yet known
concerning the creatinine output in abnormal metabolism, except that in
fevers and other diseases there is an increase, sometimes a very large
increase.” But this much we do know that creatine, after ingestion, is
almost quantitatively excreted in the urine. _Creatine_, in considerable
amount, is a normal constituent of children’s urine, but in normal adults
hardly a trace occurs, though in some diseases it is met with even in
their case. In boys it gradually dwindles and disappears at about seven
years of age. On the contrary, in girls creatine is excreted until
puberty. Subsequently, its presence in the urine is intermittent, its
incidence confined to the menstrual cycles, the period of pregnancy, and
for some days after parturition.
From our point of view, the most interesting of the above revelations is
the fact that the largest percentage amount of creatine and creatinine is
located in the _muscular tissues_. On this point we cannot do better than
quote the following words of Otto Folin:—
“It is to be noted that we are as yet entirely ignorant of the origin and
significance of the creatine which is so abundant in muscles, and it is
scarcely to be doubted that fundamentally important metabolism problems
somehow are connected with the muscle creatine and urinary creatinine,
but these are as yet problems of normal metabolism, and it is too early
to say whether, or in what way, light may be thrown on clinical problems
by studies of these products. The fact that the muscles of mammals,
including man, contain 0·3-0·4 per cent. of creatine, and only traces of
the chief nitrogenous waste product urea, constitutes to my mind strong
presumptive evidence that creatine serves some important function, and it
is quite conceivable that metabolism diseases of one kind or another may
be associated with this curious substance, but investigations rather than
hypotheses are needed in the study of such obscure problems.”
INBORN ERRORS OF METABOLISM
Apart from its intrinsic fascination, the tracing out of analogies,
clinical or pathological, between diseases apparently diverse has often
proved a fruitful source of enlightenment, for the natural history of
disease is such that one disorder trenches upon the clinical territory of
another, symptoms overlap and similarity if not community of origin is
revealed.
Few will gainsay that gouty individuals are the victims of some inborn
defect or eccentricity of metabolism, and instinctively the thought
arises, are there no other disorders of like character? Immediately
we bethink ourselves of alkaptonuria, cystinuria and pentosuria. Sir
Archibald Garrod, as we know, classed these disorders as “chemical
malformation” of hereditary origin. In other words, all are the outcome
of an abnormality in intermediary metabolism.
In alkaptonuria the metabolic warp concerns the _aromatic_ groups, in
cystinuria the sulphur-containing radicles of the _protein_ molecule.
On the other hand, in pentosuria the origin of the endogenous pentose
is variously ascribed to the _nucleo-protein_ of the cell nuclei or to
galactose. Lastly, in gout it is in the metabolism of _nucleo-protein_,
or rather of the _nucleic acids_ of the cell nuclei that the flaw resides.
We see, therefore, that Langdon Brown, discussing gout, is well justified
in observing that, “We may look upon a person who is readily poisoned by
purins in the same light as the person who has cystinuria, alkaptonuria,
or pentosuria, _i.e._, they all lack a link in the chain of protein
katabolism, so that intermediate products appear in the urine instead of
the usual end-products.” In other words, they all display a pathological
kinship, viz., in that they are all due to inborn errors of metabolism.
Certain broad clinical resemblances also obtain. All members of the
group, including gout, display _hereditary_ tendencies. All occur much
more often in _males_ than in females. They all alike tend to persist
through life. Lastly, their distinctive chemical products, including uric
acid, are all apparently of _low toxicity_.
But when we pass to the realm of their symptomatology, resemblance, if it
does not cease, becomes relatively obscured. Cystinuria and pentosuria
appear to be “harmless anomalies,” and the same is true of alkaptonuria.
The cystinuric, albeit, does suffer with _urinary_ concretions, and we
may recall that some authorities hold that gout and uric acid _calculi_
are not unrelated. As to alkaptonuria, it has this attenuated link
with gout that in its later stages the victims thereof tend to develop
a degenerative type of _arthritis_, while the frequently associated
pigmentary change, _ochronosis_, has a predilection for deposition in the
cartilages of the ears and _joints_.
But how colourless the clinical features of alkaptonuria, etc., as
contrasted with the vivid arresting phenomena of gout! how remote the
latter disorder from these “harmless anomalies”!
Apart from this general distinction, before gout could with justice be
relegated to the same category of disorders, it would be necessary to
prove that uric acid was an _intermediary_ and not a terminal product of
metabolism. All modern research, however, tends to indicate that uric
acid is an _end-product_, and, moreover, that there are no _uricolytic_
ferments within the body whereby its destruction can be accomplished. The
term “chemical malformation,” therefore, though strictly applicable to
alkaptonuria, cystinuria, etc., is inapplicable to gout. In other words,
though, for example, the _homogentisic acid_ met with in alkaptonuria is
a “chemical malformation,” _uric acid_ cannot be regarded as such. We
see, therefore, that though gout may, superficially regarded, appear to
have kinship with alkaptonuria and its congeners, yet in reality there is
a profound and essential difference between it and this fascinating group
of disorders.