METABOLISM
Studies of the chemical exchanges in scurvy have been surprisingly few.
It is a field that should repay investigation, promising to afford a
clearer insight into the intermediary metabolism in this disorder. One
of the first to touch upon this question was Garrod, who in 1848
reported that there was a diminution of potassium salts in the urine and
in the blood of scurvy patients. In 1877 Ralfe confirmed the potassium
deficiency in the urine, but denied its importance from an etiologic
standpoint, as he was unable to benefit scurvy patients by administering
potassium nitrate. He reported an increase of uric acid in the urine, a
diminution of the total acidity, and a reduction of the alkaline
phosphates. Litten found the analyses of the urine very contradictory in
respect to potassium, but stated that beyond a doubt its uric acid
content is increased at the height of the disease, although this
diminishes rapidly with convalescence. These few and scattered articles
comprise the sum of metabolic studies up to the last decade, and even
during the succeeding period they have been very few--so few, indeed,
that they furnish insufficient data from which to draw conclusions.
The first careful study of the mineral metabolism in a case of scurvy is
that of Baumann and Howard, published in 1912. Its conclusions are not
very definite. They may be summed up by their statement that "chlorin
and sodium were retained during the fruit-juice period, but excreted in
excess of the intake during the preliminary period," and that "more
potassium, calcium and magnesium were retained during the fruit-juice
period."
This same year Lust and Klocman published the first metabolism study of
a case of infantile scurvy. The baby was 18 months old and the metabolic
changes were investigated during the active, convalescent, and "the
healing stage" of the disorder. This study seems to have been carefully
carried out. The fact, however, that the infant received 800 c.c. daily
of slightly-boiled milk during the active stage, and was improving at
this time, may also have had a beneficial effect on the metabolism in
respect to scurvy. The results of these writers are surprising--quite
different from what they expected or what we should have expected. They
write: "The balance of the mineral metabolism, including the total ash,
the calcium, phosphorus and chlorin during the florid stage of the
disease must be regarded not only as not damaged, compared to that of
the healthy child, but indeed as somewhat increased." "All the more
striking, on the contrary, are the results found during the stage of
convalescence. Here the balances were all markedly negative, and only
after a lapse of weeks was the tendency manifested to a return to normal
conditions." The authors regard these results as indicating a sort of
washing out of "dead material" during convalescence--of material which
had gathered during the florid stage of the disease. According to their
interpretation the disease is due, not to a primary or secondary salt
deficiency, but to a disturbance in salt elimination, and in the first
place, of a calcium excretion. This is shown by the fact that even in
the "stage of healing," when the total ash and the phosphorus balance
once more had become positive, the calcium balance nevertheless remained
somewhat negative. The metabolism of infantile scurvy, they believe, far
from showing a resemblance to rickets, manifests quite the contrary
tendency. The study of this case of infantile scurvy and that of Baumann
and Howard of a case of adult scurvy, comprise the total investigation
of the metabolism in human scurvy.
In the course of a recent discussion on rickets before the Medical
Society of Vienna, Moll states briefly that in a case of infantile
scurvy, at the height of the disease, he found a positive calcium
balance, which became poor and later negative on giving fruit juice; in
other words, a partial confirmation of the work which has just been
cited.
In 1913 Bahrdt and Edelstein reported the analyses of the organs of an
infant almost nine months old who died of scurvy; an examination of the
tissues, especially of the bones, should be most valuable in checking up
determinations of the metabolism during life. This investigation runs
absolutely contrary to that of Lust and Klocman. The bones showed a
decrease of ash, especially of calcium and of phosphorus, and also a
lack of calcium in the muscles, but normal amounts in the liver and in
the kidneys. These conditions resemble the deficiency of ash and of lime
commonly associated with rickets, and it seems quite possible that this
infant had rickets as well as scurvy, and that in this way the
discrepancy between the two reports is to be explained. The fact that
the water content of the bones was two to three times the normal, also
lends emphasis to this interpretation. _In any metabolism study of
infantile scurvy, great care will have to be exercised that the disorder
is not complicated by rickets_, and the issue thereby confused. It will
be very difficult to avoid this pitfall, for there is no test by which
early rickets can be diagnosed. The danger of this complication may be
realized when we bear in mind that the majority of infants have rickets
to some degree. An investigation of the chemistry of adult scurvy has an
advantage from this point of view.
Chemical examination of the blood has yielded such valuable information
regarding metabolic diseases, that it might be expected to shed light on
the disturbances of scurvy. The only investigation from this standpoint
is that of Hess and Killian, who have reported estimations of the urea,
creatinine, sugar, CO_{2} combining power, diastase, cholesterol,
chlorine and calcium.[57] The urea content was normal, varying between
12 and 14 mg. per 100 c.c. of blood; this is the average of twenty-one
tests on ten cases of infantile scurvy. (In severe cases of beriberi
Yano and Nemoti have recently reported that the blood contains an
increase of urea, and that its excretion is frequently disturbed.) The
creatinine was estimated in two cases and was found to be 2.0 mg. and
1.7 mg. per cent., respectively,--also normal figures. The blood sugar
varied from 0.12 to 0.14 per cent. and was examined in almost all the
cases in which urea was estimated; these figures are at the upper level
of normality (no attention was paid to the interval elapsing between the
feeding and the withdrawal of the blood). The diastatic activity was
likewise normal. The CO_{2} combining power showed figures under 40 to
45, according to the Van Slyke method, and indicated therefore a mild
degree of acidosis. In six cases the chlorides were estimated, the
figures being remarkably constant at about 0.42 or 0.43. Cholesterol was
a little below normal in the four cases examined. Contradictory results
were obtained in regard to calcium. Earlier tests showed a definite
deficiency of this salt, but those carried out more recently have
generally yielded normal results. Further studies of the blood calcium
are highly desirable to ascertain whether it varies in amount in the
circulation, and especially in different stages of the disease. This
aspect is worthy of particular attention in view of the positive calcium
balance noted by Lust and Klocman during the active stage of scurvy, and
the negative balance during the period of convalescence.
[57] Almost all of these cases were receiving liberal daily amounts of
cod liver oil, which should exclude the possibility of complicating
rickets.
It is evident from the limited data concerning the blood chemistry of
scurvy that it is a field which has been inadequately explored and will
repay more intensive study. Investigations of this kind have recently
been made possible by the introduction of accurate methods requiring
only small quantities of blood.
Studies of the metabolism of animals suffering from scurvy are almost as
few as those on man. The work of Morgan and Beger, which is frequently
quoted in this connection, is not applicable, as it concerns rabbits,
which do not develop scurvy. They found that rabbits fed solely on oats
and water suffered in their nutrition (loss of appetite, emaciation,
paralysis of hind legs), and could be cured by the addition of sodium
bicarbonate to the dietary. In 1916 Lewis and Karr published a paper on
the constituents of the blood and the tissues of guinea-pigs fed on an
exclusive oat diet. They found the urea content several times greater
than normal, but that it fell to normal once more if cabbage or orange
juice was given. From the standpoint of scurvy, this investigation is
open to the criticism that the diet was too incomplete, and also, as the
authors suggest, that the animals suffered from partial starvation and a
lack of water.
In the following year Karr and Lewis published a paper on a different
phase of this subject, and came to the following conclusions: "No
changes in urinary elimination of phenols, nor in the degree of
conjugation of the phenols, were observed, provided the factor of
partial starvation was ruled out. This is believed to indicate that no
increased bacterial action occurs in the intestine of scorbutic
guinea-pigs despite the difficulty of evacuation of the fæces." These
results are in harmony with the bacteriological study of Torrey and
Hess, who found that there was no increase in the proteolytic flora of
the intestine in infants or in guinea-pigs suffering from scurvy.
In 1917 Baumann and Howard published the only metabolism study which has
been carried out on guinea-pigs suffering from scurvy, and they are of
the opinion that this disorder has a profound effect on the mineral
metabolism of this animal. The calcium was excreted in notably large
amount; potassium was also lost, and to a greater extent than sodium;
the only element which was consistently retained during the active stage
as well as during the period of recovery, was magnesium. This study was
followed shortly by one from the same laboratory, by Howard and
Ingvaldsen, carried out on a monkey suffering from scurvy. It was
inconclusive, not conforming to the experiments on the guinea-pigs; the
authors state that the "changes in the mineral excretion of the monkey
during the scorbutic period were not sufficiently significant to admit
of easy interpretation." "The marked loss of the various mineral
substances encountered in experiments with man and guinea-pig was not
observed in the present series." It should be remembered, however, that
the diets of the guinea-pigs and the monkeys were quite different, the
former consisting mainly of oats, and the latter of condensed milk. It
is quite possible that the basic diet may play a rôle in the metabolism
of this disease, although, as stated elsewhere, its effect cannot be
noted clinically. Special attention should be paid to this factor in
metabolic studies, in view of the widely-held opinion that the
carbohydrates exert a potent influence in the development of beriberi.
The investigations of the nitrogen metabolism in man and in animals have
been most unsatisfactory. The two on human beings--an infant and an
adult--were negative; that on guinea-pig scurvy cannot be utilized on
account of the restricted diet of oats, which contained insufficient
nitrogen, whereas the one on the monkey showed some loss of nitrogen,
which led the authors to suggest an increased nitrogenous catabolism in
scurvy. This comprises the total data on this subject.
Summarizing the results of these few metabolic studies, it may be stated
that they harmonize on one point only--the positive balance of calcium
during the active stage of the disease. The investigation of Baumann
and Howard on adult scurvy, of Lust and Klocman and of Moll on infantile
scurvy, and of Howard and Ingvaldsen on the monkey, are all in agreement
in this important conclusion.