Most of the const.i.tuents necessary for the construction of tissue or for carrying on its functions can be synthesized by the animal body from the basal foodstuffs. It has been ascertained within the past decade that certain const.i.tuents--for example, some amino-acids of the protein molecule--are building-stones which cannot be primarily elaborated by the cells, but must be supplied by the food. At present the vitamines--including the antis...o...b..tic vitamine--are included in this new and essential group of substances which the human organism cannot manufacture. Animal experiments seem to bear out this conception of the vitamine whether we regard them as dynamic or as indispensable tissue elements in the structural sense.

A closely-related but less fundamental question is that of _the ability of man to store vitamines_--whether the tissues can h.o.a.rd an excess of these factors, or whether, in this respect, we are carrying on a precarious hand-to-mouth existence in regard to cellular nutrition. It is of course clear that at all times the various organs and tissues must contain a certain amount of the vitamines. This has been shown for the water-soluble or "antineuritic vitamine" by the fact that even the organs of birds which have died of polyneuritis contain an appreciable quant.i.ty of the specific vitamine, although an insufficiency of this very factor has led to their death. That such is the case is demonstrated for the antis...o...b..tic vitamine by the fact that muscle tissue contains sufficient antis...o...b..tic to protect individuals subsisting largely on a diet of which raw meat const.i.tutes the sole antis...o...b..tic agent (Stefansson). It is very probable that some organs contain more of the vitamines than others; this has been proved for the "antineuritic" factor, and seems to hold good for the antis...o...b..tic--the liver being particularly rich. No quant.i.tative study has been carried out from this point of view regarding the antis...o...b..tic vitamine, and it would be well worth our while to ascertain the relative antis...o...b..tic potency of the various organs of the body. Some time ago we undertook experiments to determine whether the guinea-pig is capable of storing this vitamine. One series of guinea-pigs was fed daily 6 c.c. of orange juice for a period of two weeks, whereas another series, of about the same weight, was given, in addition to the basal ration, only 3 c.c.

per capita (the minimal protective dose). After this preliminary period both series were placed on a diet containing practically no antis...o...b..tic. Both groups came down with scurvy after about the same interval, leading to the conclusion that there could have been little if any storing of the excess vitamine by those which received twice the "minimal protective dose." The experiments of Harden and Zilva, who fed a concentrated lemon juice, showed that this potent agent also was unable to provide against a subsequent period of antis...o...b..tic deficiency. It should be realized that the results of these tests on guinea-pigs cannot be applied to man without tests on other species.

It might be thought that _the blood_--the purveyor of the vitamines to the tissues--would be particularly rich in these essential factors.

Such, however, was not our experience in respect to the antis...o...b..tic vitamine. The blood possibly varies greatly in this respect according to the diet of the individual, or even according to the interval elapsing after the ingestion of antis...o...b..tic food. Our opinion is based on the surprisingly poor therapeutic effect of blood transfusion in the treatment of scurvy. To ill.u.s.trate: An infant weighing about fifteen pounds received six intravenous injections of citrated blood--one of 200 c.c., given by the direct method, and a month later five smaller transfusions with citrated blood, which aggregated 205 c.c.[25] In spite of this addition of blood, the hemorrhage and congestion of the gums did not disappear, nor the general condition improve, as would have happened had 50 or 75 c.c. of orange juice been given by mouth. It seems probable that small quant.i.ties of vitamine are being transmitted at all times by the blood and supplied to the cells, but that its normal content of this factor is not great. The antis...o...b..tic potency of blood may perhaps be compared to that of milk. Animal investigation may show that various vessels--for example, those supplying or draining certain glandular organs--differ in the antis...o...b..tic quality of the blood which they carry. It is evident, therefore, that many transitory factors may influence the vitamine content of the blood, and that--as in the case of milk and fruits and vegetables--we are not dealing with a constant and unvarying agent.

[25] The dates and quant.i.ties of the transfusions were as follows: March 26th, 200 c.c.; April 27th, 30 c.c.; April 28th, 35 c.c.; April 29th, 30 c.c.; May 2nd, 75 c.c.; May 3rd, 35 c.c.

Nothing whatsoever is known concerning the _excretion_ of the antis...o...b..tic vitamine. No attempts have been made to recover it from the urine, or to ascertain if, when large amounts are ingested, the excess is thrown off by the body. This suggests the question--a corollary of that raised in connection with the vitamine content of the blood--whether it is immaterial if the vitamine is taken frequently in small amounts, or is provided only occasionally and at longer intervals in larger amounts. Is it of no moment whether the infant receive its quota of antis...o...b..tic every few hours through the medium of the breast milk, or only once a day in the form of orange juice or tomato? If we turn to studies on the other vitamines for enlightenment as to the possibility of excretion, we find that Muckenfuss recovered the water-soluble factor from ox bile and from human urine.[26] In this article he proposes the interesting question of a possible variation in the vitamine output under pathological conditions, which may be responsible for the development of functional disturbances in children.

[26] This investigation was carried out by means of activating fuller's earth with these fluids. This method is inapplicable to the antis...o...b..tic vitamine, which is not adsorbed by this material. An attempt to feed concentrated human urine to guinea-pigs resulted in their death.

It would be of interest to know the _fate of the antis...o...b..tic vitamine in the gastro-intestinal tract_. How is it affected by a lack of the acid gastric juice, or by the alkaline intestinal secretions, or by the bacteria in the lumen of the gut? From which part of the intestine is it largely absorbed? May an appreciable amount undergo destruction before this is accomplished? None of these questions can be answered satisfactorily in the present state of our knowledge, but they suggest that the mere fact that an adequate quota of antis...o...b..tic vitamine is provided in the food does not necessarily insure an adequate supply for the tissues. If in addition to the question of intake we must take into account that the vitamines may suffer various vicissitudes, it may come to pa.s.s that pathological conditions at times destroy or render them partially inactive. In this way we may account for irregularities in the clinical course of disorders a.s.sociated with vitamine deficiency.

Of prime importance, however, is the effect of the vitamines _on the glands of the alimentary tract and on the digestive processes_. A diminution of gastric juice, or in some instances a total absence, has been observed in adult scurvy, and noted by us in two cases of infantile scurvy. As mentioned elsewhere, some consider the function of the water-soluble vitamine a.n.a.logous to that of secretin. In applying this hypothesis to scurvy it must be borne in mind that the sequence may be reversed, that the lack of vitamine may not lead to the gastric achylia, but that the achylia may come about secondarily as the result of the malnutrition.

We have referred to _"irregularities" in the course of the "deficiency diseases."_ A careful perusal of the literature leaves one with the impression that the most experienced observers are not entirely satisfied with the exclusively etiologic relationship of the vitamine to its respective nutritional disorder. In regard to scurvy, more particularly, there are numerous scattered reports where the disorder did not yield to antis...o...b..tic foods as might have been expected, or where, on the other hand, it suddenly and inexplicably retrogressed, although there had been no alteration in the dietary.[27] These instances are not common, but they occur from time to time, and their occurrence must be accounted for. In relation to beriberi and avian polyneuritis improvement of this kind has frequently been explained on the theory of a sudden mobilization of vitamines from the tissues. There is, however, no data on which to base such explanations, and it may be that a lack of parallelism between vitamine intake and the clinical course may be due at times to processes taking place in the alimentary tract.

[27] Neumann, for example, writes that he has seen at least four children whose condition was not improved, although in addition to the milk, they took asparagus, spinach, and other vegetables or apple sauce.

Some years ago we had a similar experience. It has likewise happened that infantile scurvy did not recur, although the diet was the same as that which originally led to the disorder.

The fat-soluble vitamine has been termed by some the growth vitamine.

All the vitamines, however, are closely a.s.sociated with the function of growth, which their deficiency tends to inhibit. In the chapter on symptomatology, it will be pointed out that infants suffering from scurvy fail to grow normally both in length and in weight. To a certain extent this may be due to a loss of appet.i.te, which is one of the characteristic phenomena accompanying the s...o...b..tic condition. On the other hand, this anorexia may be secondary and not primary to the impairment of the growth impulse, which may lead to a dysfunction of various body processes.

It is of little value to look ahead and try to foresee what the next decade will bring forth in regard to the nature of the vitamines.

Investigation has broadened remarkably during the past few years and now embraces the chemical field--chemical and adsorption methods, the large realm of biology, including studies in physiology and pharmacology; and recently pathology has once more been called upon to aid in the solution of the problem. Probably additional vitamines will be discovered. From time to time it has been suggested that a specific growth vitamine exists quite distinct from the three which are recognized, and recently Mellanby has suggested still another food factor--a specific "rachitic vitamine." When we reflect that the characteristic functions of the various organs--the kidneys, liver, etc.--must depend on essential differences in chemical structure, the complexity of the entire problem of unidentified factors becomes evident.[28]

[28] For recent and comprehensive reviews of the vitamines the reader is referred to papers by A. B. Macallum (Trans. Royal Canadian Inst.i.tute, Toronto, 1919) and by W. H. Eddy (Abstracts of Bacteriol. 1919, Vol.

iii, 313.)

CHAPTER IV

PATHOLOGY

Physicians have had a general knowledge of the pathology of scurvy for a great many years. Lind, in his "Treatise on the Scurvy," published in 1772, included a chapter on "dissections" and a postscript on "Appearances on Dissections of s...o...b..tic Bodies," based on a large, although indefinite, number of postmortem examinations. In the century which followed, there are to be found many reports of scurvy, especially in connection with the frequent wars, but it is surprising how little detailed pathologic information they furnish. Barlow's publication in 1883, establishing the ident.i.ty of the scurvy of adults and of infants, must be regarded as the modern milestone in the study of the pathology of this disorder. This work did not contribute richly to the data of the subject, or suggest novel interpretations, but directed attention to a new source of material--the increasing number of cases of infantile scurvy--at a critical moment when the opportunity for the study of scurvy in the adult was rapidly becoming less. At the time of Barlow's exposition of the true nature of "acute rickets," scientific medicine was concentrating its interest on pathology. Tissues were being carefully studied by means of the microscope, and scurvy was subjected to this new method of investigation. As a result of intensive application of this technic, a lesion of the bones was identified and established as characteristic of scurvy. Study was focussed so exclusively on the bones, that for many years, indeed until very recently, the other organs of the body were neglected. This is true of the gross as well as of the microscopic anatomy. Protocol after protocol gives a hasty account of the appearance of the various organs, merely as a routine introduction to a careful and often minute study of the bones (Table 2). As the result of this myopic vision, enlargement of the heart, for example, which should have been noted many years ago, was, until recently, un.o.bserved--indeed, the heart is but occasionally mentioned in the protocols.

TABLE 2 NECROPSY REPORTS OF SCURVY ====================================================================== Number

of

Author

Date

Gross

Microscopic Cases

------+------------------+----+---------------+----------------------- ADULTS Many

Lind

1772

Brief summaries

51

von Himmelstein

1843

Brief summaries

8

Hayem

1871

Resume

Brief resume.

7

Laseque & Legroux

1871

Fairly detailed

7

Charpentier

1871

Brief summaries

13

Sato & Nambu

1908

Fairly detailed

Fairly detailed.

2

Urizio

1917

Brief summaries

Brief summaries.

1

Feigenbaum

1917

Brief summary

Brief summary.

23

Aschoff & Koch

1919

Very complete

Very complete.

INFANTS AND CHILDREN 1

Smith

1876

Brief report

3

Barlow

1883

Fairly detailed

Bones, brief report.

1

MacKenzie

1883

Brief summary

1

Northrup

1892

Brief report

1

Ca.s.sel

1893

Brief report

2

Sutherland

1894

Fairly detailed

Brain and liver, 1 case 1

Reinert

1895

Very complete

Fairly complete.

1

Hirschsprung

1896

Summary

3

Meyer

1896

Fairly detailed

1

Baginsky

1897

Fairly detailed

Brief, bones more in

detail.

1

Naegeli

1897

Fairly detailed

Bones only.

1

Manz

1899

Summary

5

Schoedel & Nauwerk

1900

Very complete

Very complete.

1

Jacobsthal

1900

Very complete

Very complete.

1

Stoos

1903

Fairly complete

Bones only.

1

Looser

1905

Summary

1

Hoffmann

1905

Summary

Bones only.

1

Stoeltzner

1906

Bone only

Bone only.

22

Fraenkel

1908

Resume

Bones only.

1

n.o.becourt et al

1913

Brief report

Bone only.

3

Ingier

1913

Brief report

Bones, very complete.

1

Bahrdt & Edelstein

1913

Complete

Bones, brief report.

31

Erdheim

1918

Brief summaries

Brief resume.

1

Epstein

1918

Very detailed

----------------------------------------------------------------------

A new era in the pathology of scurvy was inaugurated by the availability of experimental scurvy and also by the stimulation occasioned by the recent conception of vitamines and the so-called deficiency diseases. In endeavoring to elucidate this fascinating problem, it has gradually been realized that pathology may be of service--for example, in relation to the involvement of the endocrine glands. Accordingly, studies of the minute pathology of the various organs have been undertaken in many laboratories throughout the world (Italy, India, England, Germany and the United States). An additional stimulus to investigation in pathology has been furnished by the recent war, which, as shown elsewhere, led to a great increase in scurvy among both the military and civilian population. The excellent report of Aschoff and Koch from Roumania was made possible by this catastrophe, and will no doubt soon be followed by others of similar character.

=Gross Pathology.--General Appearance.=--The skin usually is pale, livid, and dotted with numerous petechiae. These vary in size from the tiniest pin-points, barely recognizable to the naked eye, to ecchymoses of moderately large size. The most frequent site is the lower extremities. The trunk is always less affected, hemorrhages tending to occur along the mid-line and especially around the umbilicus. There may be also larger superficial hemorrhages, showing great differences in color, from the redder tone of the more recent, to the blues, browns and greens of the older lesions. Bleeding from the nose and mouth is not uncommon in fatal scurvy, and occasionally exophthalmos is present, usually unilateral, and due to subperiosteal hemorrhage of the orbital plate of the frontal bone. Rigor mortis is generally slight, and, according to Lind and to von Opitz, decomposition takes place rapidly.

There may be great emaciation, especially where secondary infection has supervened. General wasting occurs, however, in uncomplicated scurvy due to starvation--the result of lack of appet.i.te or a deficiency of the general food supply. Children, especially infants, are undersized, as ill.u.s.trated in treating of the symptomatology, and their bones may be decidedly smaller than normal. Generally there is some edema about the ankles, and in children a somewhat characteristic puffiness about the eyes. General anasarca also occurs, in some cases a.s.sociated with renal involvement. Peculiar boggy, "tumor-like" ma.s.ses of localized edema may be present, which were considered by the earlier writers (Lind) to be one of the typical lesions of this condition.

=Hemorrhages.=--Hemorrhage is such a striking manifestation that it is not surprising to find it was regarded by the older writers as the pathognomonic sign of scurvy. The bleeding may take place into almost any organ, and vary from small petechiae to very extensive extravasations. The hair follicles and sweat glands are particularly susceptible, as Laseque and Legroux noticed in cases occurring in the French prisons. Aschoff and Koch, during the recent war, noted the same peculiarity of involvement, calling attention also to the fact that previous skin diseases such as keratosis or seborrhea seemed to predispose to this localization.

Trauma plays a very important role in determining the location of the deeper as well as of the superficial hemorrhages. In adults, especially in soldiers, in whom the greater number of cases have been recorded, the lower extremity is the commonest site, between the knee and ankle, the area most exposed to blows as well as acted upon by static congestion.

In infants, the inner aspect of the thighs is a frequent site due to the trauma of the diaper.

The most characteristic hemorrhage, the subperiosteal, will be fully discussed when considering the bone lesions. The deeper hemorrhages may be very extensive. They tend to follow the connective-tissue strata, and in the muscles are usually limited by the muscle sheaths. The blood surrounds the muscle fibres, which appear quite intact. The neighboring blood-vessels are congested and may contain thrombi, both venous and arterial. Such thrombi are found also in areas where extravasation has not taken place, and conversely, hemorrhages occur where no thrombi are demonstrable, so that a mutual causal relationship cannot be proved.

Further evidence in regard to the mechanism of these extravasations is presented in the discussion of the minute anatomy. Brownish pigment, undoubtedly derived from the blood, is frequently found in the neighborhood of the hemorrhagic areas. New connective tissue also grows in these areas, so that in healing cases a marked formation of scar tissue will be found. Bizarre forms of hemorrhage at times have given rise to confusion in diagnosis; hemorrhage involving the right lower abdominal quadrant may simulate appendicitis; when occurring in the region of the transverse colon it has been mistaken for an epigastric new-growth.

Certain parts of the body seem less predisposed to hemorrhage. The central nervous system is often spared, notwithstanding extensive bleeding elsewhere, the meninges being somewhat more frequently involved. Hemorrhage of the lungs is also less common than might be expected, and it is probably true as Laseque and Legroux suggested, that previous pulmonary disease, particularly tuberculosis, is an important predisposing factor.

=Anasarca.=--This comprises the second characteristic lesion found in scurvy at necropsy and was referred to in the earliest records of the disease. In the account of his dissections Lind writes: "The breast, belly and several other parts of the body were filled with this water or serum," mentioning also the pericardium and ventricles of the brain.

He also noted that all the tissues seemed to contain an excessive amount of fluid, a condition which may be so striking that the muscles appear bathed in serum. In one of his first cases with postmortem verification, Barlow described this appearance as follows: "The muscular walls of the thorax were pale yellow and watery, as though they had been bathed in serum." In many cases this edema is most marked in the neighborhood of the hemorrhages, for example, in the muscles of the thigh when subperiosteal hemorrhage has taken place; less frequently it is produced by venous thrombosis.

Any or all of the serous cavities may be involved in this hydrops, the order of frequency being pericardium, pleurae, peritoneum, and joint surfaces, especially the knee. The fluid is clear and straw-colored, or, in the event of secondary infection, becomes cloudy and fibrino-purulent. Later the exudate may become organized so that the entire cavity is filled with a solid ma.s.s, which binds the organs together and obliterates the cavity. The exudate may be blood-stained or apparently consist entirely of clotted blood.

=Heart.=--In the protocols of most necropsies, the heart is pa.s.sed over with scant mention. For example, Lind's only statement in this regard is that "all those who died suddenly, without any visible cause of their death, had the auricles of their heart as big as one's fist, and full of coagulated blood." Barlow accords it no attention, nor do most of the writers who immediately followed him. The first careful description of the heart is to be found in the excellent work of Schoedel and Nauwerk, which contains the following record in regard to three of the five necropsies on infantile scurvy: (1) Pericardial fluid somewhat increased, both ventricles moderately dilated, the right somewhat hypertrophic. (2) The heart showed a hypertrophy of the right and left ventricles, as well as dilatation of the right ventricle. (3) The right ventricle is dilated and slightly hypertrophied, the muscles pale and tough. There is no word of comment relative to these cardiac changes, which evidently were considered fortuitous. The same observation holds true in regard to a necropsy on an eight-year-old child reported by Ingier, which showed a moderate hypertrophy of the left ventricle. We look in vain, likewise, for information on the subject in the work on guinea-pig scurvy by Holst and Froelich, and that on scurvy in the monkey by Hart and Lessing. The first linking of cardiac enlargement with scurvy is found in a paper by Darling, who described "right-sided hypertrophy and degenerative changes in the vagus and all its branches."

Hess described and demonstrated by means of roentgenograms the enlarged heart in infantile scurvy. Recently Erdheim, in an article ent.i.tled "Das Barlowherz," reported the occurrence of enlargement of the heart, especially of the right ventricle, in 21 out of 31 necropsies of infantile scurvy, and concluded that a direct ratio exists between the degree of enlargement and the intensity of the disorder. These reports gain added interest in view of the enlargement of the right heart so frequently encountered in beriberi, and described by Andrews in infants dying of this condition. In addition to the definite statement of Darling regarding adults, mention may be made of the observation of Aschoff and Koch, that in two cases of uncomplicated scurvy there were fatty degeneration and dilatation of the heart. Fatty degeneration of the muscle is frequent, brown atrophy exceptional. Sato and Nambu also found hyperaemia and atrophy with increase of connective tissue between the muscle fibres.

The pericardial cavity contains almost invariably an increased quant.i.ty of fluid, which may be so great as to impede the heart's action.

Adhesive pericarditis has been described. The cardiac valves are normal, unless previously damaged.

=Lungs.=--The lungs are almost always congested, but apart from this are remarkably free from abnormality. Smaller or larger hemorrhages are described occasionally, which are usually considered truly s...o...b..tic; Andrews, however, found similar lesions in beriberi. In the necropsy of Stephen Mackenzie's case, described by Barlow, these small hemorrhages are stated to have resembled small red tubercles scattered throughout the lung. There may be pulmonary infarcts. Edema of the lungs is not uncommon, as we should expect, especially as a terminal condition.

Pneumonia, lobular or lobar, is one of the most frequent complications and causes of death. Active tuberculosis is a not uncommon secondary manifestation.

Subserous hemorrhages are almost the rule; if infection supervenes, the pleurae become thickened and covered with an exudate of pus and fibrin.

=Alimentary Tract.=--The lesions of the gums so well recognized clinically are fully discussed under symptomatology. The remarkable fact that these hemorrhages do not appear in edentulous gums has been the centre of the controversy as to the ident.i.ty of adult scurvy and Barlow's disease. This same lack of involvement is noted in adults whose teeth have been extracted. Where teeth are present, the gums are swollen and edematous, often of a livid, reddish color; less frequently, pale and pouting. Hemorrhage is seen at the edge of the gum adjacent to the teeth. In advanced cases the gums are enormously swollen, fungous, ulcerated and covered with a foul, greenish, necrotic ma.s.s, which may extend widely over the buccal mucous membrane. The teeth become loosened and fall out. Secondary infection undoubtedly plays the chief role in producing this condition, for the most severe forms are found only where caries and pyorrhoea preexisted. This seat of infection may serve as the source of dissemination throughout the body, giving rise to many of the lesions found at postmortem, especially in the lower part of the intestinal tract.

The _stomach_ shows no characteristic changes. Congestion of the mucosa is frequent, at times a.s.sociated with small superficial erosions; the latter gain added interest in view of their occurrence in guinea-pig scurvy. Hemorrhages occur here also and may involve any of the mural coats.