Liver.—The liver is frequently congested, as would be expected in view of the involvement of the right heart. Erdheim found congestion, however, in only nine among thirty-one necropsies, although enlargement of the heart was present twenty-one times. There may be hemorrhages in the glandular tissue or under the peritoneum. “Cloudy†and fatty degenerations occur occasionally, and in some cases an early cirrhosis. Lind found abscess of the liver, and wrote that in a few instances “the matter or corruption was hardened, as it were, into a stone.â€
Spleen.—This organ is usually somewhat enlarged and congested. Charpentier, in the Paris epidemic of 1871, found it often three to four times the normal size and very soft, and Lind tells us that “the spleen was three times bigger than natural, and fell to pieces, as if composed of congealed blood.†It must be remembered that the pathologic as well as the clinical picture of the scurvy of Lind and his time was generally complicated by infection. The enlargement is usually by no means so great, and no doubt is due in part to intercurrent infections. On section, it is found frequently to contain much reddish-brown pigment. Hemorrhage may also occur. In beriberi, Andrews observed frequent congestion of the spleen and also a loss of normal markings.
Pancreas.—There is but one reference to a lesion of the pancreas in scurvy, that of Sato and Nambu, who encountered hemorrhage of this organ in one case among the necropsies performed in the course of the Russo-Japanese War.
Kidneys.—Here again, congestion and hemorrhage arethe two lesions most commonly found. The kidneys also may show any of the forms of nephropathy ordinarily recognized, but these must be regarded as complicating conditions and not a part of the true scurvy.
Small hemorrhages may be found in the uterus, bladder or urethra. They are especially common in the bladder, both in man and in the guinea-pig, and in some instances may be the cause of the hæmaturia noted during life.
Lymph-nodes.—General enlargement of the lymph-nodes has been described, but occurs probably only in advanced cases where a general infection has been superadded. As a rule the enlargement is confined to nodes draining areas where hemorrhage has occurred. On section these nodes are reddish or brownish as the result of the pigment which they contain, the “black and red spots of different sizes†mentioned by Lind. Following infection they may become purulent, resulting in the inguinal buboes so frequently mentioned by the older authors,31or in the purulent mesenteric nodes associated with intestinal ulceration.
Organs of Internal Secretion.—Until recently these organs have received but little attention. It is probable, however, that in the near future they will be the object of close study and that new information will be acquired as to their condition in this disorder. Hemorrhages are commonly seen in the adrenals, enlarging them greatly and giving them a deep red color; the hemorrhage generallyinvolves mainly the medullary portion.32It is probable that careful scrutiny will disclose hemorrhages in the other glands of internal secretion. The question of the involvement of these glands will be again considered under the microscopic anatomy, and has been taken up from a functional standpoint in treating of the possible indirect action of the vitamines.
The brain and the spinal cordlikewise have been but little studied. It is hardly to be expected that much will be learned from an investigation of the gross pathology of these organs, but the microscopic anatomy offers a promising field of research. Hemorrhage may occur into the brain substance, into the cord or the membranes surrounding them. Pachymeningitis hemorrhagica interna has been described frequently (Meyer, Hayem, Sutherland, Sato and Nambu) and may give rise to the symptoms of meningitis. Sutherland reports an instance where thrombosis of the basal artery was found postmortem. In one case, that of Feigenbaum, hemorrhage of the cord was diagnosed during life and confirmed at necropsy.
The peripheral nerves may be the seat of hemorrhages, the blood lying between the nerve trunk and its sheath. This is particularly well illustrated in the recent work of Aschoff and Koch.
Bones.—Palpation of the body will often reveal distinct lesion of the bones, such as fractures, either ununited or healed with the formation of large calluses; subperiosteal hemorrhages, especially of the distal end of the femur or of the tibia, may be evident to the eye as well as to the touch. Crepitation of the bones may serve to further establish the break in continuity of the bones. This lesionwas well known to the older writers. Lind writes that “in some, when moved, we heard a small grating of the bones. Upon operating those bodies the epiphyses were found entirely separated from the bones; which, by rubbing against each other, occasioned this noise.†“All the young persons under 18 had in some degree their epiphyses separated from the body of the bone, this water having penetrated into the very substance of it.†Poupart was also struck by this phenomenon in young adults.
Another bony alteration which is readily palpable is “beading†of the ribs, the counterpart of the rhachitic rosary. This has not been considered a sign of scurvy, and when noted clinically or at postmortem has been passed over without comment, just as has been the case with cardiac hypertrophy. In infants the beading has been attributed to rickets, and this error has been largely responsible for the general opinion that almost all infants suffering from scurvy suffer also from rickets. If we scan the literature with this question in mind, we find numerous casual references to beading of the ribs in scurvy. Fraenkel’s frequently cited case of a child of seven who died of acute scurvy, showed beading of the ribs during life as well as after death. The true scorbutic character of these enlargements was substantiated by microscopic examination. In their pathologic studies on scurvy among soldiers, Aschoff and Koch frequently describe beading of the ribs, which they attribute to an infraction of the costochondral junctions.33There may befracture at this junction, or a separation of the cartilages from the sternum, as described by Lind.
This beading of the ribs, which involves mainly the middle tier, was described by Holst and Froelich in their classic report of guinea-pig scurvy, and has been noted by all subsequent investigators in this field. It has usually been called “rhachitic†or “pseudo-rhachitic†in spite of the fact that this junction is the site of typical scorbutic microscopic lesions. Hart and Lessing refer to the “rhachitic rosary†in monkeys, likewise not realizing that it is the product of scurvy.
The subperiosteal hemorrhage has long been recognized as a lesion characteristic of scurvy.34It occurs exceptionally in the upper extremities, and most commonly at the lower end of the femur; it may, however, involve almost any of the bones, and has been described in connection with the scapula, cranial vault, orbital plate of the frontal bone, ribs, etc. It varies greatly in its size, being confined to a small area or extending a long distance on the shaft of the bone. It rarely is as large as one would expect from external appearance, as much of the swelling is due to edema and hemorrhage into the soft parts. The periosteum rarely becomes separated at the line of junction of the epiphysis and diaphysis. The underlying blood coagulates rapidly, and the periosteum begins to calcify within a few weeks, as shown by the X-ray.
The most frequent site of fracture, or separation ofthe epiphysis, is the lower end of the femur. This may be accompanied by local swelling, or be discovered at necropsy, or during life by means of the X-ray in cases in which it has not been suspected. An interesting fracture reported by the author, and also mentioned by Kaufmann and by Schoedel, is that of the head of the femur leading to the development of coxa vara. In the author’s case, the condition was found in a scorbutic infant who had never stood on its feet. Schoedel suggests that scurvy may at times be the etiologic factor in coxa vara as well as in some cases diagnosed as congenital dislocation of the hip.
On sectioning the bones longitudinally the cortex is noted to be exceedingly thin, a mere shell and very brittle. The trabeculæ are so thin and reduced in number that the bone has become a very fragile structure. The marrow is no longer deep red at the ends of the long bones, but yellowish, frequently presenting a patchy appearance. It has a gelatinous consistency. This “Geruestmark†is one of the characteristic anatomical changes of scurvy, and will be fully described in considering the microscopic picture. Hemorrhages can be clearly distinguished in the marrow, and are of varying shades denoting their irregular occurrence. These hemorrhages were considered by Looser to be the cause of the connective-tissue formation in the marrow, but do not occur with sufficient constancy to warrant this interpretation. Moreover, this “frame-work marrow†is found where there is no evidence of previous hemorrhage.
Skin.—As pointed out by Aschoff and Koch, examination of skin which to gross appearance was the seat of typical small hemorrhages, showed various lesions. Insome, perhaps the most typical forms, there had been a fresh extravasation of red blood-cells. This condition is found usually in the subepidermal layers, especially in the papillary stratum. These small hemorrhages occur very frequently about the hair follicles and sweat glands, especially when they have been diseased. Where the bleeding has been of long standing, dark brownish pigment deposits are found and all blood-cells may have disappeared. Phagocytic cells are almost always present and may be of the “wandering†or of the more fixed connective-tissue type. Many round cells may be seen in these areas lying between the connective-tissue strands or around the blood-vessels. Rheindorf, as quoted by Tuechler, has called attention to this round-celled reaction, which in many instances gives a picture analogous to the granulomas, and which leads him to infer an infectious origin for these lesions. Other areas which appeared to be the seat of hemorrhage are shown by the microscope to be small abscesses or new connective tissue often loaded with pigment and detritus, apparently representing the final stage of these lesions. Aschoff and Koch have found that suitably-stained preparations frequently show a loss of elastic fibres, which Rheindorf states constitutes one of the earliest changes of this disorder. The blood-vessels in the vicinity of the hemorrhages are congested, especially the capillaries and small venules.
The musclesalso present a similar diverse picture of old and recent hemorrhages, pigment deposit and round-celled infiltration. Increase of connective tissue is usually found between the fibre bundles and in some cases where the hemorrhages are apparently of long standing, as evidenced by loss of contour of the red cells and pigmentation of the surrounding areas, this scar tissue formationis very marked. Changes in the muscle fibres themselves have not been encountered by all observers. Hayem describes widespread fatty degeneration and a deposit of pigment within the fibres, Leven a loss of sarcolemma, while Lasèque and Legroux found fatty changes which were equally marked in muscles showing no hemorrhage. On the other hand, Aschoff and Koch, in their careful studies, did not find noteworthy fatty change of the fibres, but observed often that the fibres within the hemorrhagic areas seemed shrunken and were stained abnormally deep with eosin.
In monkeys dying of experimental scurvy, Hart and Lessing describe granules in the muscles, which, judged by their staining affinities, evidently contained calcium and were similar to those found in the adrenal glands.
Blood-vessels.—A similar difference of opinion obtains in regard to the changes in the walls of the blood-vessels, especially of those in hemorrhagic areas. This question is of particular interest because of its bearing on the problem of the mechanism involved in the escape of the blood. Since it has been demonstrated that neither the clotting time nor the viscosity of the blood is markedly changed in scurvy but that weakness of the vessel walls exists, as demonstrated by “the capillary resistance test,†it is natural that we should seek an explanation in the microscopic pathology of the vessels. So far no change has been found. The application of some of the newer stains, such as those for mitochondria and other cell granules, has not been resorted to for this study, and might furnish valuable information.
Hayem found fatty infiltration of the walls of the small veins and capillaries, and believed this to play an important rôle in the etiology of these bleedings. Lasèque andLegroux also found occasional fatty changes. Other authors have failed to demonstrate similar lesions, or have considered them due to postmortem change. Koch searched in vain for “rents†in the vessel walls to account for the escape of blood. Hyaline degeneration has also been described, but is believed to result from secondary infections and not to be an intrinsic lesion of scurvy (Sato and Nambu, Aschoff and Koch).
Thrombosis of vessels is found both in the neighborhood of hemorrhage and elsewhere, the thrombi at times completely occluding the vessels and giving rise to typical wedge-shaped infarcts. The lung often shows areas of this kind.
Lungs.—Hemorrhages of various size occur in the tissue of the lung or in the air spaces. Hemorrhagic infarcts also have been described, and Sato and Nambu report hyaline degeneration of the blood-vessel walls. Secondary pneumonias, usually broncho-pneumonic in type, are of common occurrence, and in many epidemics constitute the prevailing cause of death. Tuberculous lesions are also frequently present, and are stated to assume fresh activity as the result of the nutritional disorder. Edema occurs frequently, the fluid in the acini often containing red blood-cells. Subpleural hemorrhages, thickening of the pleura, purulent or fibrinous pleurisy are common lesions.
Heart.—Although hypertrophy and dilatation of the heart have been noted by several observers, microscopic changes have rarely been recorded. Meyer, and also Leven, report fatty degeneration of the muscle fibres, which, however, was found by Aschoff and Koch in only one case. Sato and Nambu described an increase of connectivetissue, and others anemia and pigmentation. Thickening of the pericardium and subserous hemorrhages also occur.
Gums.—Where it has been possible to examine the gums of early cases, where swelling, redness or bluish discoloration are the chief symptoms and before secondary infection has set in, the microscopic picture is very similar to that of the skin. Small hemorrhages, round-celled infiltration, increase of connective tissue, clumps of pigment containing cells, or a diffuse deposit of brownish granules complete the picture. Congestion and edema are usually evident. The changes are most pronounced in the deeper layers of the submucosa and about the muscles, leaving the superficial layers strikingly intact, beneath an apparently normal epithelium. In the later stages, erosion of the mucosa occurs, and the upper layers of submucosa become involved. Polynuclear cells appear in great numbers, abscesses and ulcers are formed, which with proper staining can be shown to harbor the various types of mouth bacteria, cocci, spirillæ, etc. The pigmentation becomes intense, and a marked increase of the newly-formed connective tissue takes place.
The lesions of the stomach are neither characteristic nor, as a rule, very striking. Hemorrhages occur, the larger ones generally in the subperitoneal layers, the smaller ones in any of the coats. Thickening of the wall follows or accompanies these hemorrhages. Superficial erosions of the mucosa or even ulcers may be seen.
The striking congestion of the duodenum has been fully discussed in considering the gross pathology. At any level in the intestinal tract hemorrhage may take place, with theresulting pigmentation and scar tissue formation. The lymphoid structures—solitary follicles and Peyer’s patches—are usually intensely congested and often the seat of hemorrhage. They constitute the sites of predilection for ulcerative processes of the gut. Bacteria can be demonstrated at times in the submucous layers; however, no type has been found to predominate, the flora being composed of the usual intestinal forms. Aschoff and Koch have demonstrated in these ulcers the spirilla and fusiform bacilli so commonly found in the mouth. These follicular ulcers may be found in any part of the intestine, and may be shallow erosions, or extend through the follicle into the deeper tissues. Hemorrhages are commonly located about the follicles. The epithelial layer is edematous, often showing an increased number of cells.
The lymph-nodes may be congested, or edematous and hemorrhagic. Pigment is usually present and in some cases the peripheral sinus is distended with pigment-loaded cells. Where secondary infection has occurred, extensive necrosis of the glands is seen. This is found frequently in mesenteric nodes where severe intestinal lesions are present. The nodes lying in the drainage paths of hemorrhagic areas, especially the inguinal nodes, show active resorption of blood and blood pigments, and, as noted above, may be the seat of infection.
Liver.—In this organ, likewise, no change is found with sufficient regularity to warrant its acceptance as a distinctive lesion of scurvy. Fatty infiltration is, however, very common in the centre as well as in the periphery of the lobules. It is frequently associated with congestion, which may be so great as to lead to atrophy. In one case of Aschoff and Koch the picture resembled that of primary liver atrophy. The organ frequently containsextravasated blood or depositions of old blood pigment. It should be noted that Boerich described early cirrhosis in several of his cases, and that Aschoff and Koch record that one of their severe, acute cases showed “a recent cellular cirrhosis.†An exceptional lesion is reported by Reinert—a “leucocytic†infiltration of the liver and spleen occurring in a three-year-old child, and resembling that seen in pseudoleukæmia. Finally, it should be remembered in this connection that Hart and Lessing found calcium deposits not only in the muscles and adrenal glands of their monkeys, but also in the liver.
The spleenshares the general congestion of the internal organs. Sato and Nambu invariably found large numbers of pigment granules in this organ. Hirschsprung noted many Malpighian corpuscles, Reinert describes a true hyperplasia of the splenic pulp, and others mention infarcts and subcapsular hemorrhages.
The kidneysare often normal. On the other hand, various forms of nephritis are found, with cloudy swelling or interstitial change—a not infrequent complication of scurvy. More typical of the primary disease are congestion and hemorrhages, the bleedings occurring either under the capsule, into the interstitial tissues, or into the lumina of the tubules. Hayem found fatty infiltration of this organ and Aschoff and Koch a slight change of this kind in one case.
Adrenals.—A new interest in the study of the adrenals in diseases of the “deficiency†group has been created by the recent work of McCarrison. This author found the adrenals increased in size and weight in guinea-pigs dying of scurvy, whereas the adrenalin content of these glands was markedly decreased. On section there was hemorrhagic infiltration, “usually circumscribed in extent andsituated around the periphery of the adrenal cortex.†This was seen even in early cases before hemorrhage had occurred elsewhere in the body. He describes also “degenerative changes in the cellular elements of cortex and medulla†consisting of vacuolation and disintegration of the cells with disappearance or loss of staining reactions of their nuclei. Rondoni, some years previously, had called attention to this increase in size and hyperæmia of the adrenals in guinea-pigs fed exclusively cereal diets. He, as well as McCarrison, noted an increase, though much less marked, as the result of starvation. LaMer and Campbell recently have confirmed McCarrison’s report of an augmentation in the weight of the adrenal glands in guinea-pigs fed on diets deficient in the antiscorbutic factor.
Comparable lesions have as yet not been found in human scurvy. These glands have been found normal by Jacobsthal, Schoedel and Nauwerk, Ingier and Epstein. In the cases of Aschoff and Koch no abnormality was noted except an almost constant increase in lipoid content. In those of Boerich the glands were normal in all but one case; in this instance the medulla was somewhat increased in size. In passing, we may repeat that Hart and Lessing found calcium deposits in the adrenals of four of their five monkeys, a lesion which has never been recorded in man.
It is valuable in this connection to compare the adrenal in scurvy with that of beriberi. In this disorder, Albert found the adrenal normal in one case, and Andrews describes only congestion in his eighteen necropsies. Ono found an increased adrenalin content in nine fatal cases, and states that the medulla appeared “fatter†than normal. More data will have to be obtained before it can be determined whether characteristic changes occur inscurvy, and how to interpret the hypertrophy described by several authors as common to guinea-pig scurvy.
Pancreas.—Sato and Nambu appear to be the only investigators who have described lesions in the pancreas. They found hemorrhages in one case among thirteen.
Thymus.—This organ has rarely been examined. Aschoff and Koch found no abnormalities in adults, nor did Jacobsthal in a case of infantile scurvy. Boerich noted enlargement in one instance.
Other Organs of Internal Secretion.—Very little attention has been paid to these organs. Aschoff and Koch state that the thyroids and hypophyses were normal in their cases.
Generative Organs.—No abnormalities have been described.
Central Nervous System.—The most frequent abnormality of the central nervous system is, as would be expected, hemorrhage; this has been discussed in the section dealing with gross pathology. No specific changes have been found in nerve-cells or fibres of the brain.
In a case of fatal scurvy in an infant a “focal degeneration of the lumbar cord†has been described, extending for a distance of about a quarter of an inch (Hess). The lesion differed from that of poliomyelitis in the absence of round-celled infiltration and of the characteristic changes in the anterior horn cells (Figs. 3 and 4). The outstanding feature was a loss of cells in the lateral groups of the left anterior horn; there were also fewer nerve fibres in this region, but this diminution was less striking. No definite interpretation of this case can be made as the data are insufficient to permit a conclusion as to whether the lesion was truly scorbutic or the result of an associated process. Schoedel and Nauwerkfound no change in the spinal cord stained by Marchi’s method.
Peripheral Nerves.—The sheaths of the large nerves as well as those of the vessels are very often invaded by hemorrhage. The extravasated blood is found to lie around but rarely among the nerve fibres, which do not show any pathological alteration. Ingier is one of the very few to describe a degeneration of the nerve fibres. In one guinea-pig in which scurvy was induced she found “many marked degenerated fibrillar bundles of both sciatic and peroneal nerves, slight degeneration of the phrenic nerves and one vagus and its cardiac branch.†Another animal is referred to as having shown “very marked and well-developed degeneration of the nerves of the lower extremities.†It is open to question whether starvation played a rôle in the causation of these lesions. Schoedel and Nauwerk, and Aschoff and Koch examined these nerves but failed to find any lesions; the latter directed their attention especially to the vagus of twenty-two cases.
Retinal hemorrhageswere found by Jacobsthal, and by Kitamura, who records “decided edema of the retina, marked bleeding and circumscribed hypertrophy of the nerve fibres†such as is found in albuminuric retinitis. These changes are considered again under the symptomatology of scurvy.
Bones.—Our knowledge of the minute pathology of the bones is far more complete and detailed than that of any other structure. This was to be expected in view of the fact that this is the only tissue in which the lesions are diagnostic. In considering the microscopic pathology it must be remembered that all the bones are rarely affected by scurvy, and that those that are involved showthe scorbutic changes to a varying degree. One of the peculiarities of the lesion is that it involves the end of the diaphysis or rather the junction of the diaphysis and the cartilage. The bones most apt to show typical changes are the ribs; we shall therefore describe a section made through a costochondral junction.
The costochondral junction is generally swollen, somewhat beaded, and when cut longitudinally shows on gross examination a transverse yellowish bar, corresponding to the area of disorganization which will be described below. Under the microscope the line of juncture is not sharp and straight as is normally the case, but presents a wavy or irregular contour, the cartilage jutting into the bony end of the rib, instead of abutting in neat apposition to it. The bone is hollowed out and irregularly concave, whereas the cartilage presents a convex appearance. At the site of the junction is theTruemmerfeld area, where the normal tissue is splintered and fragmented. Everything in a state of disorder—trabeculæ of bone of various shapes and sizes lie scattered about, the cells irregularly arranged and much distorted, signs of recent hemorrhage, unrecognizable detritus. The picture is that of weakened bone having been crushed by the pressure of the more compact cartilage. Higher magnification shows that there are few osteoblasts (generally associated with the deeper fragments of bone), a varying number of intact red cells, according to the occurrence of hemorrhage, and occasional spindle- and star-shaped connective-tissue cells. Covering this mass of detritus there is frequently, as Aschoff and Koch have emphasized, more or less protective fibrin which has undergone some hyaline or connective-tissue organization.
The cartilage is also not normal. Its cells do not presentan orderly arrangement, the proliferating columns having disappeared in the central convex portion, and being present to a varying extent near the periosteal borders. If we judge from sections of early scurvy in guinea-pigs, this disturbance of the columnar formation of the proliferating cartilage is one of the early signs of scurvy, and is associated with an unevenness and irregularity in shape and size of the bone trabeculæ. In young individuals, where cartilage activity is great, these changes are most marked and the entire zone of active cells may be somewhat widened.
Bone in scurvy. Microscopic pathologyFig. 5.—Infantile scurvy. Epiphyseal junction of lower end of femur: (a) calcified cartilage at “Truemmerfeld†(b) hemorrhage in the fibrous marrow (Gernest-mark). Bone cortex and trabeculae abnormally thin. McCallums’ Text Book of Pathology. W. B. Saunders Co.
Below the Truemmerfeld is theGeruestmark or framework marrow, another distinguishing feature of scurvy. This extends for about 5 to 10 mm. toward the lymphoid marrow, where it ends more or less abruptly. It is composed of a loosely-constructed fibrillar tissue on a gelatinous-appearing groundwork, of sparsely scattered cells, and bony trabeculæ which are markedly thin and weak. Here and there are hemorrhages and blood pigment, especially adjacent to the “Truemmerfeld.†Another feature which strikes one at first glance is that the entire marrow area is incompletely filled by the thin and greatly-depleted trabeculæ of the spongiosa. The question has been raised whether this rarification is to be considered entirely of scorbutic origin. It is due evidently to a lack of function of the osteoblasts, which are diminished in number, and are represented by a layer of shrivelled spindle cells along the walls of the atrophied bony columns. They may fail almost entirely, as may its osteoid border, which is significant of active bone tissue. The lack of bony structure and rarification clearly is not due to an increase in the number or the function of the osteoclasts, for these do not appear in excess. It is mainly the result of normal boneresorption with a lack of normal bone regeneration. Aschoff and Koch suggest that the framework marrow may be able to manufacture bone, but cannot accomplish this because there is a lack of material from which to make osteoid tissue. This, they believe, constitutes the primary deficiency—a lack or faulty development of cement substance, which in turn may depend on an alteration of colloid material. Regarded in this light, the lesions of the bones resulting in fracture and those of the blood-vessels resulting in rupture and hemorrhage are dependent on a deficiency of the same basic material.
Hemorrhage occurs in the bone as elsewhere; it is almost never lacking. It appears either as large hemorrhages in the spongiosa, especially where the normal marrow joins either the Geruestmark or the Truemmerfeld, or merely as scattered cells, possibly the result of diapedesis. The blood-vessels in these areas are narrow and extremely thin-walled. The most typical site of hemorrhage is beneath the periosteum, a lesion widely known on account of its clinical significance (Fig. 16). Here the blood may extend for a considerable distance along the shaft, but rarely beyond the epiphyseal line. The clot forms readily, demonstrating that the nature of the hemorrhage is not a defect in coagulation, and in its midst may be seen fibrin, pigment, granulation tissue, and more or less firm connective tissue—constituting the callus. The inner surface of the periosteum is frequently lined with newly-formed bone and with a more or less dense deposition of lime salts, which becomes heavier in the course of the healing process, and is readily observed in radiographs. This periostitis ossificans may result in the clot being surrounded by a perfect shell of bone, with bony columns penetrating the deeper layers.
As the result of the lack of bone formation and the consequent weakening of the corticalis and the spongiosa, frequently a separation of the diaphysis from the epiphysis results. This lesion should not be regarded as a true separation, for, as Barlow pointed out, the line of cleavage is not at the junction, but below it, involving the uppermost region of the diaphysis. It is therefore correct to speak of a fracture or infraction. This lesion is generally accompanied by a deformity of the surface contour of the junction, due to a displacement of the cartilage, as a result of which “angular beading†of the rib is brought about. In some instances the cartilage is “telescoped†into the crushed end of the bone. To a varying extent fibrin covers the end of the fractured bone; the angles adjacent to the periosteum contain blood which becomes organized into dense connective tissue, thus serving as a splint for the fractured parts. In the course of healing a large number of foreign body giant-cells appear, blood-vessels sprout from the periosteum as well as the bony surface, and the necrosed tissue gives place to an active formation of callus, which generally leads to complete regeneration and restitution. It is remarkable how quickly and perfectly an epiphysis may become reunited to its shaft (Figs. 6 and 7). Sometimes, however, this takes place with resulting deformity, as in the development of coxa vara of the femur.
As Czerny and Keller have stated, it is difficult to define sharply the relation of bone fragility to scurvy. Histologically there is great similarity between the “osteotabes infantum†described by Ziegler and conditions sometimes found in infantile scurvy. The main distinction is that in the latter disorder the lesion is less generally distributed throughout the skeleton, and is particularlymarked in a limited area of the bones (epiphyses). In considering this question it should be borne in mind that, experimentally, osteoporosis and scurvy can be brought about by diets which are absolutely dissimilar. For example, Bartenstein showed that young guinea-pigs develop osteoporosis and multiple fractures on a diet of raw milk containing an adequate quota of antiscorbutic vitamine.
Ricketsand infantile scurvy are commonly found associated, although they bear no causal relationship to each other. The distinctive characteristic of rickets is the broad area of osteoid tissue which is formed at the epiphyseal junction, a broad band of incompletely calcified cartilage not found in scurvy. In the latter disease osteoblastic bone growth is greatly inhibited, but what growth does take place occurs in a normal and orderly manner. The osteophytes, for example, which so commonly develop at right angles to the axis of the bone in the subperiosteal hemorrhages, are composed of apparently normal bone. Another marked distinction between the two conditions is the paucity of blood-vessels in the cartilaginous area and in the marrow in scurvy, compared with the increased vascularity so generally encountered in rickets. It is evident, therefore, that although these two nutritional disorders bear a superficial resemblance to each other pathologically, they are radically different and almost antithetical.
There is no mention whatsoever of scurvy in animals previous to 1895, when Theobald Smith wrote: “When guinea-pigs are fed with cereal (it has been observed for some years in this laboratory), with bran and oats mixed, without any grass, clover, or succulent vegetable, such as cabbage, a peculiar disease, chiefly recognizable by subcutaneous extravasations of blood, carries them off in from four to eight weeks.†Smith did not pursue the subject further.
Coincident with the appreciation of the value of experimental methods, one would have expected attempts to produce scurvy in animals. The disorder had been recognized for a great many years, the fact that it was occasioned by a dietary deficient in fresh food was widely known, so that it would seem natural for clinicians or laboratory workers to have tried to induce the disease in animals by a similar restricted diet. There is, however, no suggestion of such an experiment in the voluminous literature on scurvy. The explanation of the neglect of an experimental study of scurvy appears to be that this was considered a disorder which required little investigation—its etiology, its prevention and its cure seemed thoroughly understood. It is strange that the mere fact that such a severe disturbance responded, as if by magic, to the administration of simple foodstuffs should not have awakened curiosity as well as wonder, and stimulated inquiry into the nature and significance of the curative agent.
In 1903 Bolle published the results of experiments on guinea-pigs which had been fed for various periods on raw or sterilized milk. He reported that the animals developed a marked fragility of the bones, varying in intensity in proportion to the degree of heat to which the milk had been subjected. These changes Bolle interpreted as typical scurvy, but it is difficult to decide whether the disorder was actually true scurvy, in view of the indefinite description of the bone lesions.
Bartenstein repeated Bolle’s work and described in detail the changes in the bones. From his work we learned that it was of little moment whether the animals were fed raw or sterilized milk—their nutrition failed within about the same length of time, and they died within a month. The chief pathologic change was a marked fragility of the bones, leading to spontaneous fractures, or to breaking of the bones in the course of ordinary manipulation. Bartenstein described the disorder as “beginning with the degeneration of the marrow, and secondarily leading to an atrophy of the bone due to increased absorption and deficient new formation of bone, especially at the endochondral lines of ossification. As the result of the osteoporosis, spontaneous fractures occur without noticeable hemorrhagic diathesis.†He found a deficiency of calcium in the bones of animals suffering from even a mild degree of this disorder. Hart and Lessing are of the opinion that we cannot accept Bartenstein’s diagnosis of scurvy. They compare this disorder to that described by Ziegler as “osteotabes infantum,†in which there is a more or less pronounced “jelly marrow†which has replaced the lymphoid cells in scattered areas. They sum up their analysis of the question with the statement that “the primary marrow changesin the diaphysis, the marked lacunar absorption by osteoclasts, the absence of subperiosteal hemorrhages, do not indicate typical scurvy.†Schmorl produced comparable lesions in dogs and came to the conclusion that the disorder was one “very similar†to scurvy but not identical with it, the essential difference being that in all animals there was a most marked absorption of bone by osteoclasts.
Similar results were obtained by others. In 1904 Peiper and Eichloff attempted to produce scurvy in dogs by means of a diet composed exclusively of raw or of sterilized milk. The following year we find a report by Esser of feeding goats on sterilized milk. None of these studies hits the mark; a condition of fragilitas ossium was produced rather than typical scurvy.
In 1907 the first systematic and convincing experimental study of scurvy appeared. In this year Holst and Froelich published a preliminary account of their classic work, undertaken in an endeavor to fathom the nature of “ship beriberi,†a disorder which disabled so many of the sailors in the Norwegian navy. We must remember that until recently attention has been focussed on the infectious diseases, and little thought given to the investigation of nutritional disorders. Although experimental investigation in this field may be stated to have been initiated by this work, it in turn had been stimulated by a conception of dietary diseases which had just begun to be realized. This new viewpoint was the result of the work of Eijkman. As has been mentioned in considering the pathogenesis of human scurvy, Eijkman demonstrated that hens developed polyneuritis, a disease resembling beriberi, when fed on polished rice, and that the simple change to a diet of unpolished rice, or the addition of rice polishings to the dietary, sufficed to protect or tocure. This work had been repeated and substantiated. It was evident to those who considered the question that the old lines of thought in regard to food and dietetics inadequately explained remarkable phenomena of this kind. It was also clear that nutritional disorders were subject to experimental investigation in a way similar to the infectious diseases, which were absorbing the interest of the various laboratories. It is unnecessary to review the rapid rise of investigative work in this field. It may be stated, in general, that during the past few years the investigations of scurvy have become so numerous that an established research technic may be said to have developed in connection with its study.
Attempts have been made to produce scurvy in various animals, but it has been brought about regularly only in the guinea-pig and in the monkey. Experiments on the dog are as yet too few to justify our regarding this animal as definitely available for this study. The nutrition of rats, mice, rabbits, hogs, pigeons, fowl, receiving a diet identical with that which regularly occasions scurvy in guinea-pigs, either progresses normally or a state of malnutrition develops which cannot be identified with scurvy. Recently Hart, Steenbock and Smith have reported that cattle can be reared to maturity on a diet which will produce scurvy in the guinea-pig in four to five weeks. We are therefore confronted with the remarkable and inexplicable phenomenon, a fact concurred in by almost all investigators, that a diet induces either normal nutrition or malnutrition, according to the experimental animal employed. A diet of polished rice, or other decorticated grain, will lead to the development of scurvy in the guinea-pig, to polyneuritis in the pigeon or fowl, or, according to Holst and Froelich, to a combination of these disordersin the hog.35The basis of these divergent results cannot be surmised, and is worthy of the most thorough investigation. It may well be that the elucidation of this problem—for example, why we are able to bring about scurvy in the guinea-pig but not in the rabbit, will shed light on the pathogenesis of this disorder. Are we to conclude that some of these animals have the power to synthesize the vitamine whereas others must depend upon the food for it, or are we to presuppose an ability to maintain normal life and function without any or with a minimal amount of this vitamine? The difference between these two groups, the susceptible and non-susceptible animals, probably is not as absolute as we have been wont to regard it. Recently Harden and Zilva have shown that although rats are able to thrive on a diet free from antiscorbutic vitamine, they show an appreciable gain in weight when this factor is added to the dietary. If such be proved to be the case, we must regard the non-susceptibility of the rat, the rabbit, etc., as relative rather than absolute.
From time to time a doubt has been raised as to whether we should accept guinea-pig scurvy as the counterpart of human scurvy. This question can be answered only by comparing the disorder in the one species with that in the other—as to mode of production, pathology, symptomatology, means of cure and all other phenomena. Viewed from these standpoints it is found that in almost every respect the disorder is identical in man and in the guinea-pig. The outstanding distinction is the difference in the length of time elapsing before the development of symptoms. In the child or in the adult it takes aboutsix months of the deficient diet before clinical symptoms are manifest and a diagnosis can be established; in the guinea-pig the disorder can be recognized two weeks after restricting the diet. In the one instance we seem to be dealing with a nutritional disorder which is chronic or at least subacute, and in the other with a markedly acute condition. This distinction is open, however, to certain qualifications. In the first place, we must consider the duration of life of the two species, the comparatively short span of the guinea-pig compared with that of man. It must be borne in mind, furthermore, that the guinea-pig is placed on a diet absolutely devoid of all antiscorbutic vitamine, whereas this rarely obtains in human beings. For example, the diet which is most markedly scorbutic for infants is the “malt soup†previously mentioned, but even this food contains an amount of the antiscorbutic factor which is not negligible. But after taking these differences into consideration, it is nevertheless evident that the guinea-pig is far more sensitive to scurvy than man. This does not indicate that the guinea-pig is an unsuitable experimental animal, any more than the fact that the pigeon is more susceptible to polyneuritis than man indicates that it is unsuited to investigations of beriberi. It merely prevents our carrying out delicate quantitative experiments, and cautions against drawing too finely-spun deductions. In all nutritional investigations it should never be forgotten that conclusions drawn from experiments on animals are merely provisional, and must await substantiation on man, and, furthermore, that where differences in reaction are noted, the clinical data should be accorded full consideration.
Pathogenesis of Guinea-pig Scurvy.—From a pathogenetic point of view guinea-pig scurvy and human scurvyshow remarkable points in common. Any diet that leads to the development of scurvy in man likewise brings it about in the guinea-pig, and contrariwise, any food which cures the disorder has the same beneficent effect on both species. This similarity extends so far that, as will be shown in the chapter on antiscorbutics, the relative potency of the various foods is approximately the same for man and for the guinea-pig. The parallelism generally is striking. The dietary which has been commonly employed in experimental scurvy has been that first suggested by Holst and Froelich, namely, oats, hay and water. Recently, however, this dietary has been enlarged in order to make it more complete, so as to include adequate protein, water-soluble and fat-soluble vitamine, and inorganic salts. To this end the group of workers at the Lister Institute (Chick and co-workers, Harden and Zilva) place their animals on a basal diet of one part of crushed oats and two of wheaten bran, and a daily ration of 50 to 60 c.c. of milk autoclaved for one hour at 120° C. This milk still retains a small amount of antiscorbutic vitamine. Cohen and Mendel have employed, apparently with good result, a “soy bean cracker,†containing soy bean flour which has been heated for 30 minutes at 15 pounds’ pressure (120° C.), 3 per cent. of sodium chloride, the same percentage of calcium lactate and of dried brewers’ yeast, and raw milk sufficient to supply 5 per cent. of butter-fat.
The use of raw milk was introduced by Jackson and Moore, and adopted by McCollum and Pitz and again by Pitz in a series of interesting experiments. The milk was givenad libitum. The results of these investigations were puzzling at first, until it was shown by Chick, Hume and Skelton that the dietary on which they were based contained a fundamental error which accounted for their lackof consistence. Although milk is not rich in the antiscorbutic factor, it possesses it in moderate degree, so that the outcome will be quite different according to whether a guinea-pig takes, for example, 50 c.c. or 100 c.c. daily. It is quite evident, therefore, that a food of this kind cannot be offeredad libitum, and that if this rule is not observed, most disconcerting results will follow.36This basic error in framing the dietary has made it impossible to accept the deductions of these authors. The conclusions of McCollum and Pitz are so striking and have led to such wide discussion, that they require consideration, in spite of the fact that the error in the dietary is now recognized. These authors found that the cæcum of their animals was greatly distended with putrefying fæces. As the cæcum is extraordinarily large and delicate in this species, they drew the deduction that the development of scurvy in the guinea-pig was due principally to the retention of fæces. “An impacted cæcum, the seat of putrefaction, may cause injury to the cæcal wall, sufficient to permit the invasion of the tissues by bacteria, or the animals may perhaps be injured primarily by the absorption of toxic products of bacterial origin.†Accessory dietary factors or vitamines, according to this theory, are supposed to play no part in the disorder, and antiscorbutics, such asorange juice, are considered to owe their efficacy mainly to their laxative properties, and to be replaceable by other laxatives such as phenolphthalein or oleum petrolatum. The efficacy of orange juice is supposed to be due to its content of citrates, and to be replaceable by what was termed “artificial orange juice,†a mixture composed of the various salts, citric acid and sucrose, in the proportions in which they are found in the natural juice.
These reports stimulated renewed interest in experimental scurvy, suggesting new aspects, and therefore directing attention to points requiring investigation. There were no data at hand on the consistency of the contents of the bowel in guinea-pigs, so that it was necessary to make appropriate observations in normal and in scorbutic animals. It was soon reported by various workers, Rappleye, Cohen and Mendel, Hess and Unger, and others, that there was no definite relationship between the occurrence of scurvy and impaction of the cæcum. InFig. 8we see portrayed the stool output of a guinea-pig during the period in which it was developing scurvy, and during a subsequent period when it was being cured by means of orange juice. It is clear that there was no significant variation in the output during these divergent periods. A similar conclusion was arrived at by those who examined the cæcums of animals postmortem. Cohen and Mendel write: “Summarizing our experience with nearly one hundred scorbutic animals, we conclude that actual impaction of the fæces in the cæcum occurred in about one-quarter of the cases, and visible damage to wall,i.e., congestion or hemorrhage, or impaction, or both, was found in perhaps half of the cases. It should be noted that this statement covers all the diets we have tried.†We concur in this conclusion. Not infrequently we foundthe cæcums of markedly scorbutic pigs to contain semi-fluid fæces, the consistency of its contents depending on the character of the diet, quite apart from its adequacy and lack of the antiscorbutic factor. For example, a diet rich in milk, containing 100 c.c. or more, led to the formation of rather solid fæces; if oats were added to the milk diet the fæces in the cæcum were found to be still more solid, and this portion of the gut more often impacted. This condition could be detected by palpation even during life. Just as we encountered scorbutic animals on an oat, hay and water diet, who had semi-fluid fæces in the cæcums, so we met with others which were on a milk diet, and showed no signs of scurvy, although their cæcums were impacted with fæces of a putty-like consistence. Guinea-pigsdo not seem to be able to tolerate a diet containing a large quantity of the fat of cow’s milk. Such a diet leads to impaction of the large intestine resulting in death, but does not induce scurvy. Jackson and Moore produced a condition of this kind by feeding pigs with cream containing 26 to 28 per cent. fat. “In every case,†they write, “the large intestine was distended with light mustard-colored semi-solid fæces.†This pathological condition is not understood, but is quite distinct from scurvy, and remarkable in view of the fact that the milk of the guinea-pig contains as high as 25 per cent. of fat. It is an interesting illustration of the marked biological difference in the butter-fat of various species.