In the foregoing there has been frequent reference to the close relationship between scurvy and the incidence of the infectious diseases—to the fact that a scorbutic condition increases the susceptibility to infection. This is indeed one of the most characteristic, as well as one of the most important phenomena associated with scurvy and other disorders resulting from vitamine deficiency. Mention has been made of the special susceptibility to the diphtheria bacillus, and to the organisms leading to coryza and the respiratory diseases, but no doubt this applies also to invasion by other bacteria. We wish, however, to confine ourselves to the nutritional disorders, first in their relationship one to the other, and second, as a group of deficiency diseases, due to a lack of vitamines of various kinds. As is well known, in addition to scurvy, this group generally includes beriberi, a disease attributed to a lack of the water-soluble vitamine, and xerophthalmia, an eye condition which recently has been brought about in rats by placing them on a diet free from fat-soluble vitamine. These, however, form only the nucleus of the disorders which commonly are included in this category. Schaumann, the first to formulate this classification, illustrated his conception of the interrelationship by depicting the various members as spokes of a wheel surrounding a central hub. He included scurvy, rickets, osteomalacia, typical beriberi, ship-beriberi, pellagra and mehlnaerschaden. Funk made a similar classification of disorders which he termed the “avitaminosen.” There is a tendency to enlarge rather than to decrease the membership of this class, and recently war or hunger edema, infantile atrophy and diarrhoea, sprue, coeliac disease, leprosy and others have been proposed as suitable candidates. At the present time it is impossible to determine which and how many of this motley company should be associated with scurvy. Some, possibly, are the result of a lack of vitamine, but for the present it will be well to bear in mind that three vitamines only have stood the test of experiment, and only these three therefore can be definitely connected in a causal relationship with pathologic conditions. In addition to this consideration of the interrelationship of the “deficiency diseases,” the kinship of allied disorders—more particularly of rickets—must be discussed.

Although at first thought beriberi and scurvy would seem far apart from a clinical point of view, they have some important features in common. In both there is a tendency to a rapidity of the heart’s action and a marked lability of the pulse, to an enlargement of the cardiac ventricles, to an involvement of the vagus, and to an exaggeration of the deep reflexes. It is unnecessary to describe these signs and symptoms in detail, as they have been fully considered under symptomatology. It has been recorded from time to time that under certain circumstances scurvy has developed in man where one should have expected beriberi, and vice versa. Darling, who has had a large experience in this field, writes: “A deficient dietary in a tropical African negro mine laborer causes severe scurvy, in a Cape Colony African mine laborer, mild scurvy, and in some African negroes a diet that causes scurvy in one set of men causes neuritis in others.” Possibly some minor differences in the dietary can explain this difference in reaction—for we do not know all the sources of the water-soluble vitamine, but such an experience deserves to be cited as it is not an isolated instance. It is all the more worthy of attention because it harmonizes to a certain extent with the everyday experience of animal investigation. As has been stated elsewhere, a diet of decorticated grain will lead to scurvy in the guinea-pig, to polyneuritis in the pigeon, and to a combination of these diseases in the hog! Results of this kind show that there must be a relationship between the etiologic factors of scurvy and of beriberi. It is unwise at present to attempt to define the relationship more precisely. The remarkable observation, first made by Fuerst, and since confirmed by numerous investigators, that seeds and legumes are devoid of antiscorbutic potency but acquire this power on sprouting, constitutes another link in the evidence of their kinship. Funk has suggested that the antiscorbutic vitamine can be formed from the “antineuritic” vitamine, a theory which is very attractive but needs confirmation and experimental proof. It is quite evident that this change does not usually occur in animals, in view of the specificity of the vitamines for their respective diseases—of the antiscorbutic for scurvy and the water-soluble for beriberi.

It will be noted that “ship-beriberi” is included in this group of diseases. Very little is known about this condition, except what is contained in the investigation of Nocht (1903) and that of Holst and Froelich. It is a very rare condition but of interest because it is characterized by spongy, hemorrhagic gums and other signs encountered in scurvy. The feature which differentiates it sharply from scurvy, however, is an anÆsthesia of the extremities. Ship-beriberi is generally regarded as a combination of beriberi and scurvy. Where these two disorders occur concomitantly, the beriberi manifests itself some months before the scurvy, as the latter takes much longer to develop.

In considering the vitamines in connection with diseases of the nervous system, mention may be made of “central neuritis” and the “peripheral neuritis” which has been reported from the West Indies. This bears only a partial resemblance to beriberi, as there is no edema, nor dyspnoea, and its course is more chronic. Judging from the report of Edwards from Jamaica, the cases more closely resemble pellagra, terminating after many years. A degeneration of the cells of the spinal cord was found and “in some isolated patches of the cerebellum and in the roots of the optic and auditory nerves.” The disease occurs among the poor classes whose diet is inadequate chiefly in nitrogen.

Eijkman was the first to draw an analogy between beriberi and pellagra, and thus to suggest that the latter might be a disease due to an unidentified factor; he compared the pernicious effect of a diet of polished rice with that of decorticated corn. Of recent years, largely as the result of the investigations of Goldberger and his co-workers, pellagra has come to be regarded as a dietetic disorder primarily due to a lack of adequate protein, rather than to a lack of a specific vitamine. Its relationship to scurvy cannot, therefore, at the present time, be discussed from an etiologic viewpoint. Apart, however, from the question of etiology, the two diseases have certain clinical symptoms in common. Weston states that “distinguished physicians, who were really astute observers, have mistaken pellagra for scurvy, eczema, various kinds of intestinal troubles, syphilis, and many other diseases.” In the chapter on symptomatology, attention has been directed to the fact that an eczema which yields to antiscorbutic treatment may occur in scurvy; at times it presents the symmetrical arrangement so typical of pellagra. In other cases a fleeting erythema may be observed, another sign noted frequently in pellagrins. In some instances congestion of the gums has been recorded. In describing a little girl of three who had pellagra, Weston writes: “The gums are also red and swollen, suggesting scurvy.” This child had eaten large amounts of turnips, so that there could have been no question of complicating scurvy. Lombroso and some of the earlier authors drew attention to the fact that fragility of the bones, of the ribs and of the long bones, was often associated with pellagra. These various clinical similarities should not be construed as evidence in favor of the “avitamine” nature of pellagra. They indicate, rather, that in nutritional disorders, whatever may be their underlying cause, the vessels, the bones, and other tissues may suffer and lead to similar—but not identical—clinical pictures.58

The relation between scurvy and rickets is a subject which was discussed by Glisson. With the renewed interest in infantile scurvy which followed Barlow’s work toward the end of the last century, children’s specialists ranged themselves into opposing camps on the question of the interrelationship and interdependency of these two diseases. Some accepted Barlow’s dictum that infantile scurvy is an absolutely distinct and separate entity; others, for example, Hirschsprung, declared that the so-called scurvy was merely a form of rickets; whereas a third group considered it a combination of rickets and scurvy. This last viewpoint was actively maintained by Cheadle on the clinical side, and later by Schoedel and Nauwerk on the pathologic side—the latter declaring that rickets is “an inseparable component of infantile scurvy,” and that the entire disease should be regarded merely as “an episode in the course of rickets.” Even Barlow, in a paper published in 1894, wrote: “Rhachitic changes already present may act as a physiological determinant of the sites in which scurvy becomes manifest” and “rickets as a basis plus inadequate food gives the simplest explanation of the typical case” (of scurvy).

We had an exceptional opportunity to test this thesis in 1914, in an institution where scurvy broke out among infants who were on a diet of pasteurized milk. All these infants were receiving cod liver oil daily, as prophylactic treatment against rickets. Many infants have been seen since that time, who in spite of receiving cod liver oil developed scurvy, and others in whom large doses of this oil failed to mitigate the scurvy, although it prevented rickets. The same failure has been encountered in the treatment of scurvy in guinea-pigs. This experience has been without exception, both from a prophylactic and a curative standpoint.

Confusion between the two diseases has resulted from the fact that the majority of infants in the Temperate Zone have some degree of rickets. Thus the two diseases have been found very frequently associated in pathologic examination of the bones, leading some to infer that they are in some way interdependent. They have been also confused clinically, as mentioned in another connection, owing to the fact that beading of the ribs—the rhachitic rosary—has been mistakenly regarded as a pathognomonic sign of rickets, whereas it is also a sign common to scurvy. It is important to bear in mind that from the pathologic viewpoint scurvy and rickets present strikingly dissimilar pictures—the former is characterized by an almost complete cessation of activity of bone-forming elements, whereas the latter is distinguished by a hyperplastic condition leading to a marked overgrowth of cartilage and of abnormal bone. Viewed from the pathologic, etiologic and clinical standpoint, we believe that there is no basis for assuming an interrelationship between the two disorders, and that scurvy will develop as readily and as rapidly where rickets is absent as where it is present.59

It is premature to discuss the relationship of these two disorders from the vitamine standpoint. In 1910 Schaumann suggested that rickets was due to a lack of a specific food factor, and somewhat later Funk included it among the “avitaminosen.” Recently Mellanby, as the result of experiments on dogs, has affirmed that the fault lies in a lack of the fat-soluble or a closely-related vitamine. Investigations of the near future will probably decide the merits of this contention; our experience is that rickets develops in infants even where the diet contains adequate fat-soluble vitamine. If rickets is proved to be a disorder depending on a vitamine, it belongs, naturally, in the same group as scurvy. This would indicate relationship, but not interrelationship. Just as the mere fact that a lack of vitamines leads to scurvy and to beriberi does not signify, in theory or in practice, the existence of pathogenetic interrelationship. However, as stated, this is a subject which does not as yet rest on a secure foundation.

Osteogenesis imperfecta and osteomalacia are disorders of dietetic or metabolic origin characterized by fragility of the bones. The latter has developed new significance and importance due to its increased occurrence in almost epidemic form in the Central Empires at the close of the World War. The etiology of both disorders is most obscure. In the future in considering their pathogenesis it will be well to draw a sharp distinction between them. Osteogenesis imperfecta is a disease in which an injury occurs to the foetus without any manifest illness in the mother, which seems to indicate a primary lesion of the foetus (perhaps metabolic); osteomalacia, on the other hand, attacks the mother who gives birth to an apparently healthy foetus. The latter gains added interest because it is a disease of the bones which is attributed to dysfunction of the endocrine glands, to a disturbance especially of the parathyroid. If this observation is confirmed, it furnishes another anatomical basis for associating the glands of internal secretion with pathologic conditions of the bones.

One cannot survey the various diseases of the bones—scurvy, rickets, osteoporosis, osteogenesis imperfecta, osteomalacia, etc.,—without realizing that this group is at present in a state of great confusion and will have to be rearranged and winnowed. The differentiation between some of these diseases is not in every instance clear morphologically—for instance, early cases of scurvy and osteoporosis—so that it is difficult to consider them satisfactorily from the standpoint of pathogenesis. Clinical differentiation is still more difficult and uncertain. It seems probable that new entities will be established, as has happened in the past. It is not so long since rickets included almost all the bone diseases of infants. Gradually congenital syphilis, scurvy, and achondroplasia were segregated as distinct diseases. Probably a similar separation of other pathologic conditions, now so entangled as to be indistinguishable, will be evolved.

Among the diseases which have been attributed to a vitamine deficiency are “war or hunger edema,” sprue, the “mehlnaerschaden” of infants, and the “exudative diathesis” described by Czerny and Keller. Future investigation will disclose whether any of these disorders belong in the group with scurvy. The hunger edema, noted in the late war and in previous wars, seems to be a complex condition, quite dissociated from scurvy, as many of the sufferers consumed comparatively large quantities of potatoes or other vegetables. The “mehlnaerschaden” resembles scurvy and the other vitamine disorders in its tendency to produce hydremia and susceptibility to infection. It also develops in spite of a liberal supply of antiscorbutic foodstuff in the dietary. As its name implies, it comes about on a diet containing large quantities of carbohydrate, of the cereal paps so commonly fed to infants. It is conceivable that an unbalanced diet of this kind may not provide a sufficiency of all the vitamines.

It does not seem probable that exudative diathesis, a term which implies a predisposition to develop exudations or denudations of the skin and mucous membranes, is the result of a lack of vitamine. This condition does, however, predispose to scurvy. The association was very evident in the group of cases reported by Hess and Fish in 1914. It is not without significance that the blood-vessels in exudative diathesis also show a decided weakness, an increased permeability, as judged by the “capillary resistance test.” In both scurvy and in exudative diathesis eczema and petechial hemorrhages are encountered.

There may be nutritional diseases due to an excess of food rather than to a deficiency. A superfluity may be harmful by hindering the proper utilization of the food, or may possibly lead to the formation of deleterious products. Disturbances of this kind do occur. For example, it is by no means uncommon for an infant which has been overfed with milk to show the typical signs of rickets. Young guinea-pigs which are fed liberal amounts of cow’s milk develop a disease characterized by fragility of the bones. The experience of Lubarsch, who produced osteogenesis imperfecta in rabbits by means of a diet consisting mainly of liver, or adrenal gland, is of interest, especially as this condition did not come about when they were fed muscle tissue.

From what has been stated, it must be evident that this subject not only is in a state of flux but that it is in a state of great confusion. This applies not only to the relationship of vitamines to these disorders, but to their identification and demarcation pathologically as well as clinically. During the past few years we have begun to regard these diseases from a new viewpoint, which no doubt will be helpful, but it is probable that they will not be sharply defined and their relationships determined until it is possible to bring about each disease definitely and regularly in an experimental animal. Until this time we should proceed slowly, and not bring about “confusion worse confounded” by yielding to the vogue, and grouping together heterogeneous and little-understood clinical conditions under the caption of deficiency diseases. There is a growing danger of attributing every unexplained nutritional disorder to the new, overworked, but ill-defined vitamines—of their sharing with the secretions of the endocrine glands the fate of becoming the dumping-ground for every unidentified disorder.