Chapter V: Part II: , Showing Predominance of Malarial Element . . . . 617 (4)

At present the question is under discussion whether the amyloid degeneration may affect cells of the most varied character, or whether it is limited to those of connective tissues. Eberth[35] maintains that in all cases the amyloid disturbance is seated in the connective tissue. Kyber,[36] the latest investigator, in opposition to this view maintains that this affection is not limited to the connective tissue, but may also be seated in the parenchymatous cells of organs. Whether the one of these views is to exclude the other, or whether both are not correct, remains for future investigation to decide.

[Footnote 35: _Virchow's Archiv_, 1880, lxxx. 138; 1881, lxxxiv.]

[Footnote 36: _Ibid._, 1880, lxxxi. 7, 111.]

Wherever the amyloid material may be situated, the result is a transformation of the cells into a homogeneous, glistening, colorless material, which occupies more space than the original cell, and, when abundant, is accompanied with a loss of the primitive details of the cell-structure. This material is recognized by the color it presents when acted upon by iodine alone, by iodine and sulphuric acid, or by methyl-aniline. The first produces a reddish-brown color, the second a blue, and the last a violet or purple color. These reactions are all characteristic, and the first is of special value in the macroscopic recognition of the process, while the last two are of special importance in the microscopic recognition of the earlier stages of the affection.

With the advance of the degeneration and its dissemination, the organ affected presents, in the diseased portions, pale-gray, glistening, translucent patches, and becomes increased in size and density in proportion to the quantity of amyloid material present. The change appears primarily in the vessel wall or outside the same, and there results a diminution in the calibre of the vessels, with a lessened quantity of blood in the organ.

From the homogeneous and translucent appearance of the surface and the increased density of the tissues the resemblance to bacon or wax is suggested, and the terms lardaceous, bacony, or waxy degeneration have been applied. Notable differences in degree and seat occur in connection with the organs diseased. In the spleen, for example, the change may be limited to the arteries of the Malpighian bodies and their immediate surroundings. To this condition the term sago spleen is applied, the enlarged, rounded, translucent, and projecting bodies suggesting granules of boiled sago. The appearances of the diseased part are further affected by the association of other conditions, as the presence of fat or pigment. When fat is present, it is often to be regarded as a result of the gradual and progressive increase in the obstruction to the circulation of blood in the organ.

Although so little is known of the immediate cause of amyloid degeneration, its distribution in the various organs of the body is fully ascertained, as well as certain of the conditions which are likely to be followed by its presence. It is known to occur as a localized process in cartilage, in the conjunctiva, in certain tumors, cardiac thrombi, scars, retained inflammatory products, and renal casts. The causes of this localized appearance are wholly obscure, and little or no general inconvenience results. Its presence, however, on a large scale and in various parts of {86} the body at the same time, is met with under such circumstances as indicate a distinct etiological relation. An appreciation of these circumstances is of importance, since their existence demands an investigation as to the probable presence of the degeneration. The organs thus affected are the spleen, liver, kidneys, and intestine. It is to their disturbance of function that the pathological importance of amyloid degeneration is to be especially attributed.

Other organs which may sometimes be affected are the lymphatic glands, pancreas, suprarenal capsules, omentum, uterus, bladder, prostate gland, heart, and thyroid body. In the case of a general diffused infiltration these organs are variously degenerated, now some, and again others, showing a more extensive alteration, while few or many may be simultaneously diseased. The longer the process has continued, the greater the degree of the disturbance and the larger the number of the organs infiltrated. Although, in general, a period of months and years may be demanded for these extensive changes, very serious disturbances may arise within a short time, and Cohnheim[37] records several cases which suggest that widely diffused amyloid degeneration may occur within a few months--in one instance in less than four months.

[Footnote 37: _Virchow's Archiv_, 1872, liv. 271.]

All that is at present known with regard to the etiology of this process applies to certain general diseases with which in the course of time it is likely to be associated. These have one element in common, that of chronicity, and are likewise the occasion of a progressive wasting of the body. Of these affections, that which holds the first place is chronic pulmonary consumption, especially that form in which extensive destruction of the lungs and ulcers of the intestine are present. Another disease whose effects are in like manner to be regarded as general is syphilis, and in the later stages of this disease amyloid degeneration is likely to occur, and often to represent by its resulting disturbances the immediate cause of death. Again, chronic suppurative processes, especially those due to disease of the bones and joints, are a frequent antecedent of amyloid degeneration. Finally, the process has been found in connection with leucæmia, chronic intermittent fever, rickets, gout, and certain malignant tumors. This last group, however, is one in whose sequence the degeneration is to be regarded as exceptional.

The clinical importance of this process is due to the resulting disturbances in the function of such important organs as the liver and intestines, the spleen and lymphatic glands, and the kidneys. The nature of these disturbances obviously demands detailed consideration in connection with the description of the diseases of the respective organs. It may be mentioned here that the infiltration of the walls leads to a narrowing of the calibre of blood-vessels, and thus a diminution in the supply of blood to the part or organ. The resulting impairment of nutrition becomes enhanced from the condition of the blood, which is impoverished from the simultaneous infiltration of the blood-making organs. The nutrition of the individual thus suffers as well as that of the immediately diseased organ. Fatty degeneration and atrophy of the parenchymatous cells of organs like the liver and kidneys is the constant result of long-continued and extensive infiltration of these glands.

Mention is intentionally omitted of the so-called amyloid bodies, {87} corpora amylacea, considered in connection with amyloid degeneration in most text-books on pathology and pathological anatomy. They usually present a different reaction with iodine, their origin has but little in common, their distribution is for the most part unlike, and little or no clinical importance is to be attached to their presence.

_Calcification, Ossification, Petrifaction._

When salts previously held in solution are precipitated under abnormal circumstances in the tissues of the body, the part is said to be calcified, ossified, or petrified. Although these terms are often used as equivalent, the last is to be regarded as more general than its predecessors, since it includes the deposition of other than the calcareous salts.

In the pathological ossification, as well as its physiological prototype, the carbonates and phosphates of calcium and magnesium are present in a specially formed tissue of the nature of bone-cartilage, whereas calcification occurs independently of such a new-formed tissue. The deposition of the calcareous salts takes place either in the cells or intercellular substance of living or dead tissues, when the terms calcification or ossification are applied, or as accumulations of various size in tissues or canals, which are known as concretions and calculi.

The immediate causes of the physiological deposition in the formation of bone are so obscure that only more or less probable explanatory theories are advanced, to all of which obvious objections arise. The causes of a pathological precipitation may be regarded as equally hidden. It is apparent, however, that old age usually furnishes the necessary factors. This in part may be due to the feeble nutrition associated with impairment of function in advancing years. In part it may be the result of the numerous opportunities offered in a long life for the occurrence of inflammation, the products of which are frequently infiltrated with calcareous salts. The latter are apparently kept in solution by the action of living cells, for, though presented to all in the fluids of the body, they are precipitated most constantly in dead parts or in the vicinity of those cells whose function is presumably lessened from disease or age. The solvent action of living cells is further demonstrated by the effect of the giant-cells in removing calcium salts from living or dead bone.

The causes of calcification are therefore to be regarded as local, depending upon a destruction or weakening of the cells of a part--conditions which are directly attributable to an interference with nutrition. The deposition of calcium salts thus represents a disorder of nutrition, and may be experimentally produced by agencies which occasion a necrosis of tissues.

Although the immediate causes of the precipitation of the calcium salts must be expressed somewhat vaguely, the places and effects of their accumulation are sufficiently well known, as are the resulting appearances. The presence of these salts in sufficient quantity produces a homogeneous, granular, strongly refractive appearance of the cell or intercellular substance, in addition to a greatly increased resistance to pressure. When muriatic acid is added to the affected part, the salts are dissolved, with the escape of abundant bubbles of gas when a carbonate is present, and with a rapid fading of the glistening appearance, without effervescence, {88} when the salt is a phosphate. After the removal, the cell or intercellular substance is readily recognized, with such modifications in its appearance as may be due to the action of the strong acid. The parts in which this deposition or infiltration has taken place are either relatively normal in appearance or variously altered from disease, and the calcium salts are to be regarded as absorbed from the constituents of the food and deposited, or as taken up and transferred from the bones of the body. That both sources are drawn upon is obvious from the abnormal presence of calcareous material in the soft parts, in connection with increased density of the bones, as well as with a diminution in the density of the latter. The term calcification is more correctly applied to the presence of the salts in normal tissues other than bone, or in the products of disease not simulating bone-cartilage in structure. A pathological ossification is to be considered present when an actual new formation of bone has taken place so limited and so situated as not to suggest a tumor of bone, or when the calcium salts are deposited in a new-formed tissue whose structure stimulates that of bone-cartilage.

Tissues which may become calcified are, in the first instance, the connective tissues, and of these fibrous tissue and cartilage are especially liable. Epithelial, muscle--in particular the unstriped variety--and ganglion-cells may also become calcified. The frequency with which blood-vessels, especially arteries, are affected is such that it is regarded as almost normal in advancing years that calcareous material should be deposited within the vascular walls. A distinction is drawn between an ossification and a calcification of the blood-vessels. The former term should be limited to the osteoid plates so often found as circumscribed thickenings of the aortic intima, and which are obviously new-formed patches of fibrous tissue in which the calcium salts are accumulated. A calcified artery, on the contrary, is one usually of a size varying between that of the common iliac and the temporal arteries, whose wall has become rigid and unyielding, suggestive of a pipe-stem, from the presence of calcareous deposits in the muscular middle coat.

From the frequency with which the osseous plates of the aorta are associated with the fatty and fibrous changes in chronic inflammation of the intima, the so-called atheromatous degeneration of the same, it is customary to speak of the calcified artery at the wrist or temple as an atheromatous artery or as evincing an atheromatous degeneration. The common feature in the aortic changes and in the calcified muscular coat is the element of age. They are frequently, though not necessarily, associated. The one is the result of an inflammatory process productive of a new, fibrous, tissue in which the calcium salts are infiltrated; while the other is due to a deposition of the latter in the normal, pre-existing, muscular elements of the vessel.

Calcification and ossification of blood-vessels are frequent when the latter become dilated, as in aneurisms, whether these occur as circumscribed tumors or as a serpentine elongation and widening of the affected vessel.

Cartilage is also a tissue which presents a double relation to calcareous deposition. On the one hand, there may exist an ossification resulting from the extension of a growth of bone from the perichondrium into the cartilage. The structure of this bone presents all the details found in {89} normal bone--lacunæ, lamellæ, and marrow-spaces. On the other hand, a section of the cartilage, especially the costal cartilages, may contain opaque, gray, or grayish-yellow patches, grating under the knife, which are wholly due to the presence of calcium salts in the hyaline intercellular substance of the cartilage. This calcification of the cartilage, which may also involve the capsules of the cells, is frequently associated with an ossification, although this relation is in no way essential.

Calcification of the placenta, of the fibrous framework of the lungs, of the mucous membrane of the stomach, or of the atrophied glomeruli of the kidney, are well-recognized instances of the infiltration of calcareous material in normal or atrophied tissues. On the contrary, ossification of the fibrous inflammatory products of the pleura, pericardium, and peritoneum are instances of a pathological bone-formation, analogous in its nature to that met with in the intima of the aorta. The fibrinous and fibrino-cellular products of the inflammation of serous surfaces are favorable positions for the deposition of calcium salts, as are thrombi arising from the walls of blood-vessels. The latter are rather instances of the calcification of dead parts, analogous to the members of the group which includes the formation of calculi and concretions, the calcification of the dead foetus in abdominal parturition, of cheesy lymphatic glands, and of cheesy material in the lungs and elsewhere. Finally, there remains the calcification of tumors of the most varied nature, the salts being present either in living or dead parts of the tumor.

Instances of the deposition in the tissues of other than calcareous salts are abundantly met with in gout. In this disease cartilage, ligaments, and tendons, bone-marrow, muscle, the endocardium and aorta, the membranes of the brain and spinal cord, the skin and kidneys, may contain deposits of acicular crystals and amorphous granules. Although these deposits are largely composed of sodium urate, calcium urate may be present with other salts, as sodium chloride and calcareous compounds. According to Ebstein,[38] the earthy salts in gout are deposited in necrotic patches of previously diseased tissue. The local conditions are therefore analogous to those concerned in the formation of chalky concretions.

[Footnote 38: _Die Natur und Behandlung der Gicht_, Wiesbaden, 1882, 45.]

Concretions and calculi are collections of earthy salts, the former lying within tissues, the latter being present in canals opening externally. Both represent the results of a deposition in and upon organic material, which is often an inflammatory product, at times surrounding a foreign body acting as the exciting cause of the inflammation.

The earthy matter of which the concretion is composed consists mainly of carbonate and phosphate of calcium, while the chemical properties of the calculi often vary in accordance with the nature of the secretion which flows by them. The salivary, pancreatic, intestinal, lachrymal, and prostatic calculi are chiefly formed of calcareous salts. These salts also are an important, if not the chief, constituent of biliary and urinary calculi. In the former pigment, bile acids, and cholesterin may also be present. Urinary calculi are of still more varied composition, containing not only the calcium salts, as the oxalate, phosphate, and carbonate, but also uric acid and the urates of sodium and ammonium, in addition to the ammoniaco-magnesian phosphate.

The infiltration with calcium salts may prove beneficial as well as {90} injurious--beneficial under those circumstances where further changes might prove harmful, as in the softening of cheesy material or the maceration of a dead foetus in the abdominal cavity. The calcification of certain tumors, as the fibro-myoma of the uterus, is equally sanatory, the further growth of the calcified parts being thus checked. The calcification of an aneurismal sac may prove beneficial in strengthening a weakened blood-vessel.

The injurious effects are seen more particularly in case of the calcareous infiltration of the middle coat of arteries. Such vessels become converted into rigid and unyielding tubes at various parts of their course, and the nutrition of peripheral parts becomes correspondingly lessened. Hence, in great measure, the liability of old people to serious inflammatory processes from trivial irritation of peripheral portions of the body, such inflammations often terminating in gangrene.

The calcification and ossification of the cardiac valves and the calcification of attached thrombi, furnish frequent and constant occasion for disturbances in the functions of the heart, resulting in dilatation and hypertrophy, with the sequence of symptoms of chronic valvular endocarditis.

The great clinical importance of the presence of calcium salts in the circulatory apparatus is such that further reference in this place to its results is unnecessary, as its special relations are more important than its general features.

Calculi act as local causes of inflammation, and their presence is likely to be followed by ulceration, abscess, and stenosis, perhaps obliteration, of the smaller canals in which they may lie.

_Pigmentation._

The pathological pigmentation of the body results, presumably, from the metamorphosis of the coloring matter of the blood or from the introduction from without of pigments insoluble in the fluids of the body. The former of these methods has recently been studied by Langhans[39] and Cordua,[40] and the present views of this subject are chiefly due to their observations, as well as to the earlier investigations of Virchow and others.

[Footnote 39: _Virchow's Archiv_, 1870, xlix. 66.]

[Footnote 40: _Ueber Resorptionsmechanismus von Blutergüssen_, Berlin, 1877.]

The hæmoglobin contained in red blood-corpuscles is considered to be composed of a coloring matter, hæmatin, combined with an albuminate, globulin. When blood is removed from the body the hæmoglobin is readily separated from the corpuscles by various agents, and is then dissolved in the plasma, which becomes lac-colored. This solubility of the hæmoglobin is of importance in connection with the absorption of extravasated blood. During the time necessary for this process to take place, observable changes are apparent in the color of the affected part when its seat is superficial, especially cutaneous. These changes in color are largely dependent upon the modifications undergone by the hæmoglobin.

It is well known that a yellowish discoloration of the general surface frequently takes place when extensive internal hemorrhages have occurred, constituting a form of jaundice (hæmatogenous) attributed to the presence of the coloring matter of the blood. As yet there has been no satisfactory chemical analysis of this diffused pigment, which if not hæmatin must be regarded as its derivative, although a coexistent increase of the urobilin in the urine has been observed. The association of the stained skin and urine, {91} in the absence of causes favoring an absorption of bile-pigment, leads to the inference that the abnormal discoloration is due to the absorption into the circulating fluids of the body of a pigment dissolved out of the extravasated red blood-corpuscles. This view is confirmed by the microscopic examination of the latter, which discloses the presence of pale, shadowy, round outlines enclosing faintly granular material, which are regarded as decolorized red corpuscles. In the course of a few days glistening crystals and granules of a yellowish-red color make their appearance in the midst of the unabsorbed blood. The crystals are usually oblique rhombic prisms, varying in size from the larger symmetrical shapes to the more minute, apparently granular, forms. Acicular crystals are also to be met with, more yellow than red in color, and are sometimes present in great abundance, although they may be wholly absent. Virchow has applied the term hæmatoidin to these crystals. Owing to the resemblance in the chemical reactions of solutions of hæmatoidin and of the biliary coloring matter, bilirubin, and to the similar crystalline forms of the latter, it has been maintained that the two are identical. Late investigations indicate that solutions of crystals with the appearances of hæmatoidin are not invariably alike in their reaction. A solution of these in chloroform may become decolorized when acted upon by a dilute alkali, or it may not be thus altered. Bilirubin presents the former relation, while chloroform solutions of the coloring matter of the yelk of egg and of the corpus luteum, called lutein or hæmolutein, are not decolorized by an alkali. Although the crystalline forms of hæmatoidin and bilirubin are not to be distinguished, it is not to be conceded that the two substances are identical. As Maly,[41] the latest writer on this subject, states, the term hæmatoidin is merely indicative of a microscopical picture. Although the identity of the coloring matter of the blood and of the bile is not admitted, the intimate relation of the two is not only suggested by the similarity of crystalline form, but by the relation determined between urobilin, bilirubin, and hæmoglobin. Urobilin is the coloring matter extracted from the urine in fever by Jaffé, and it has since been obtained from bilirubin by Maly,[42] who has given it the name of hydrobilirubin. This hydrobilirubin has also been derived from hæmoglobin. According to Maly, this genetic relation between the coloring matter of the blood and bile, shown in the production of hydrobilirubin, is the only chemical evidence of the connection of the two pigments.

[Footnote 41: _Hermann's Handbuch der Physiologie_, 1880, vii. 155.]

[Footnote 42: _Op. cit._, 161.]

Hæmatoidin is to be regarded not only as directly derived from solutions of hæmoglobin, but as originating through the medium of indifferent cells. Langhans claims that this pigment is formed within movable cells which accumulate in great numbers in the vicinity of the blood-clot, and, in virtue of their amoeboid properties, take into themselves the extravasated corpuscles, entire or in fragments. The indifferent cell may become enlarged into a giant-cell, and then contain numbers of whole or disintegrated red corpuscles. In time these colored corpuscles and fragments become smaller, more glistening, and darker-colored, and eventually are transformed into granular or crystalline hæmatoidin. These granules may be set free by the fatty degeneration of the cell, or may be transferred within the cell to distant parts.

{92} The diffusion and absorption of a solution of hæmoglobin, and the formation of crystals of hæmatoidin from the same or through the medium of cells, are supplemented by an apparent inspissation and condensation of the hæmoglobin. The resulting dark-brown pigment may remain at the seat of the hemorrhage indefinitely, and may be accompanied with reddish-brown flakes, which, as shown by Kunkel,[43] are composed of hydrated ferric oxide.

[Footnote 43: _Virchow's Archiv_, 1880, lxxxi. 381.]

Another feature in the absorption of extravasated blood is to be found on examination of the nearest chain of lymphatic glands. These may be seen swollen, of a dark-red color, and homogeneous surface. In density and color, as well as shape, they suggest the small supplementary spleens so frequently met with. These glands owe their change in appearance to the presence of large numbers of unaltered red blood-corpuscles which have entered the lymphatics traversing the region of hemorrhage. Within the lymph-glands they undergo a metamorphosis similar to that taking place at the part from which they were transferred. In the course of weeks or months there remains in the place of extravasation simply pigment, either as crystals or granules. Such pigment may remain for years imbedded within the tissues, or it may become absorbed, no trace of the original disturbance remaining. Its removal may take place presumably through a local solution of the pigment or the transfer of the granules or crystals by means of wandering cells to the nearest lymphatic glands or to the more remote parts of the body. An eventual elimination may occur through the secretions, especially the urine or bile, or there may result a deposition and permanent retention of the granules.

The investigations of Langhans are especially interesting, as suggesting efficient means for the production of pigment by cells whose function is intimately connected with pigmentation, as the cells of the rete Malpighii, of the choroid, and of certain tumors. The observations of Gussenbauer,[44] however, lead to the conclusion earlier advanced by Virchow, that pigment may be produced by the diffusion into cells, outside the vessels, of a solution of the pigment of the blood in the plasma of the latter. A precipitation of this dissolved pigment into granules is considered as eventually taking place.

[Footnote 44: _Ibid._, 1875, lxiii. 322.]

The method of origin of pigment thus described applies only to those discolorations which are unquestionably due to the metamorphosis of the coloring matter of the blood. Examples are furnished not only by the extravasation of blood on a large scale, but also by the escape of red blood-corpuscles in small numbers. Such an escape takes place from the pulmonary vessels in chronic obstruction to the admission of blood into the left side of the heart. The resulting brown induration of the lungs owes its color to the metamorphosed blood-pigment which is present as hæmatoidin in the interstitial tissue of the lungs, as well as contained within amoeboid cells in the alveolar and bronchial cavities.

It is probable that a similar transformation of hæmoglobin takes place in the spleen and elsewhere in melanæmia. In this condition the black granules of pigment, although differing in color and form from hæmatoidin, contain iron, and have received the name melanin. These granules are either free in the blood or are contained within the white {93} blood-corpuscles. Their origin in the spleen is directly suggested by their frequent presence, often in considerable numbers, in the large, so-called splenic, corpuscles of the blood in the hepatic capillaries. Eventually, the pigment is found at more remote points in the circulation, and becomes fixed in the interstitial tissue of the various organs of the body.

The black pigment of the cells of melanotic tumors, also called melanin, is not to be directly traced to the hæmoglobin. Virchow[45] early called attention to the absence of iron in such pigment. Ferrated and non-ferrated varieties of melanin are thus to be recognized, the term being used in the same way as hæmatoidin, indicative of a microscopical appearance. A still further complication in the composition of melanin is suggested by Kunkel,[46] who has isolated a ferrated pigment from melanotic tumors. It shows, however, with the spectroscope, no relation to hæmatin, bilirubin, or hydrobilirubin. That its nature is similar to the normal pigment of the skin and choroid is suggested by the customary origin of the melanotic tumors in such pigmented tissues, and by the resemblance in appearance and reactions.

[Footnote 45: _Virchow's Archiv_, 1847, i. 378.]

[Footnote 46: Ziegler, _op. cit._, 100.]

That pigment of the most varied sort may be introduced into the body from without, and may remain indefinitely in the organism, is sufficiently well known from the results of tattooing. What is essential in such cases is, that the pigment shall be finely divided and insoluble in the fluids of the body. The most important of such pigmentations are those taking place through inhalation into the lungs. The reception by this channel of particles of soot is so common that it is most exceptional for the lungs of an adult to be free from the bluish-black discoloration due to this agent. Particles of coal-dust presenting the details of vegetable structure are met with in the lungs of individuals exposed to an atmosphere charged with this material. The worker compelled to inhale the dust of iron eventually accumulates a store of this substance, the quantity of which is essentially dependent upon the length of exposure, the degree of impregnation of the atmosphere, and the insufficient nature of the protectives employed.

Although a large part of the pigmentation under such circumstances is due to the direct presence of the foreign body, the appearances are also partly the result of consequent minute hemorrhages. The coal-dust and the iron-filings are often sharp and jagged fragments, which penetrate the delicate tissues, and the escaping red blood-corpuscles are acted upon by the amoeboid cells in the air-passages, with the consequent formation of hæmatin or hæmatoidin, as are the blood-corpuscles in larger hemorrhages. The inhaled pigment finds its way, either directly or by the agency of amoeboid cells, into the lymphatics and fibrous tissue of the lungs, and remains indefinitely either in the bronchial and pulmonary lymphatic glands or in the interstitial tissue of the lungs.

Attention may be here called to that pigmentation of the skin and deeper-seated parts of the body, especially of the kidneys, known by the term argyria. The long continued internal use of nitrate of silver, in former years so extensively employed, especially in diseases of the nervous system, results in the reduction of the silver and its deposition as minute particles in the tissues. Whether the silver is first reduced in the {94} intestine and then absorbed, or whether it is absorbed as an albuminate and subsequently reduced, still remains an open question.

Although the pathological pigmentations form an extended series of alterations, the clinical importance of the condition may be regarded in many instances as trivial. The pigments resulting from extravasation produce no disturbance of function. The presence of bile-pigment does not account for the symptoms of jaundice. The clinical importance of melanæmia has perhaps been overrated. The earlier observations led directly to the inference that mechanical obstruction to the circulation in various organs might take place. The particles of pigment and the cells containing them were so numerous that this inference seemed quite probable. The evidence is still lacking, however, which proves the existence of definite symptoms and characteristic lesions as the result of the melanæmic condition.

The inhaled foreign bodies, as coal and iron, are productive of greater disturbances, and are well known as efficient causes in the production of chronic pulmonary consumption. The coal-miner's and scissors-grinder's phthises usually have, as an anatomical basis, catarrhal conditions of the aërating surfaces and interstitial inflammations of the pulmonary connective tissue. Mechanical obstruction to the aëration of the blood may also be present from the extreme quantity of the foreign material in the lungs.

Tuberculosis.

Until the investigations and discoveries of the past few years, the presence of tubercles in the various organs and tissues of the body had been regarded as the essential element of tuberculosis. The evidence to be presented in the following pages will show that the immediate cause of tubercles may produce other lesions as well, and that the presence of a specific virus as the efficient cause of whatever may be the lesion, rather than the existence of tubercles, is to be regarded as the characteristic feature of the disease tuberculosis.

The tendency of the present is to regard the latter term as including the various morbid processes connected with the origin, presence, and growth of a specific, organized virus, their dissemination, metamorphoses, and effects. Whether all those processes in connection with which the virus is found are due to the latter, or whether some may not arise and exist independently of the same, are among the questions whose answer is remote rather than at hand.

As the presence of the cause of tuberculosis is the test demanded by some authorities for the existence of the process, so the anatomical classification has depended upon the existence of the tubercle. The substitution of tubercle for organized virus in the general definition of tuberculosis represents the distinction between the anatomical and the etiological classification of this affection.

A tubercle was originally a small rounded body, a little tuberosity, and at the close of the last century the specific tubercle was distinguished from other rounded nodules.

Till the discovery of Villemin, the recognition of the tubercle was {95} essentially based upon its anatomical characteristics. Previous to the studies of Reinhardt and Virchow these related to appearances, which were attributed to a deposition of material, scrofulous or tuberculous, from the blood or lymph. The idea was eventually maintained that this material formed the basis of a growth or new formation, and Virchow showed that the tubercle was composed of a tissue, of cells and intercellular substance, growing within and from pre-existing tissues. He classified the tubercles among the tumors as circumscribed new formations whose structure resembled that of granulation-tissue. The specific tubercle was, at the outset, minute, smaller than a millet-seed, submiliary, although indefinite numbers of these minute tubercles might be grouped together and form closely massed aggregations. From this agglomeration of single tubercles, and their frequent association with inflammatory products, both of which were prone to early death and transformation into a cheese-like mass, the extensive tubercular infiltrations of organs arose. The latter were regarded as a frequent cause of the wasting disease phthisis, which was either pulmonary, intestinal, or renal according as the lungs, intestine and mesenteric glands, or kidneys were the predominant seat of the tubercular growth.

The histological features of the tubercle were further investigated by Wagner,[47] who described the resemblances and differences of the structure of the tubercle and the lymphatic gland. Schüppel[48] soon after published his monograph, essentially confirming the statements of Wagner. According to these observers, the typical tubercle, as found in lymphatic glands, presents essentially the same peculiarities of structure when seen elsewhere in the body. This structure consists of a non-vascularized network of fibres, in the meshes of which cells are imbedded. The fibrous network resembles the reticulum of a lymphatic gland, and nuclei are often found at those points where the fibres are united. This appearance has suggested that the network is formed of branching and anastomosing cells. Within the meshes are three sorts of cells--viz. giant-cells, epithelioid (endothelioid) cells, and small, round, indifferent cells. One or several giant-cells, each with its abundant nuclei, lie near the centre of the tubercle or are diffused throughout the same. These are usually immediately surrounded by the large epithelioid cells, with one or more nuclei, which are often so numerous as to compose the greater part of the tubercle. The indifferent cells, resembling lymph-corpuscles, occur singly or in groups, distributed throughout the tubercle more abundantly at the periphery, between the cells previously described, and with them completely fill the spaces of the fibrous network.

[Footnote 47: "Das tuberkelähnliche Lymphadenom," _Archiv der Heilkunde_, 1870, xi. 6; xii. 1.]

[Footnote 48: _Untersuchungen über Lymphdrüsen-Tuberkulose_, 1871.]

Although the typical tubercle is thus constituted, the structural features depend somewhat upon its age. It is generally admitted that the freshest tubercles, as found in the external coat of the smaller arteries of the pia mater, are composed of little else than a circumscribed accumulation of small, round cells, without a distinct reticulum. The giant-cells, the epithelioid cells, and the well-characterized reticulum appear as the tubercle increases in age. It is thought probable that the giant-cells represent the agglomeration of the small, round cells in pre-existing cavities, lymphatics, blood-vessels, or secretory canals. The epithelioid cells in like {96} manner are considered to result from the enlargement or fusion of the smaller cells, while the reticulum represents either a secretion from, or a transformation of, the cellular elements of which the tubercle is composed.

The subsequent history of the tubercle is dependent upon its metamorphoses. These are known as cheesy degeneration, calcification, and fibrous transformation.

The absence of blood-vessels, already stated, and the abundantly cellular nature of the growth, with the possible action of micro-organisms, result in a tendency to the early death of the cells and a necrosis of the tubercle. This is the cheesy degeneration, and is regarded as a form of coagulative necrosis, which begins at the centre, advances toward the periphery, and results in the transformation of the gray into a yellow tubercle. This termination in cheesy degeneration likewise affects inflammatory products surrounding the tubercle, and even relatively normal tissues in which numerous tubercles may lie. This cheesy material either softens or becomes infiltrated with lime salts, calcified. The softening of the tubercle results in the formation of a material capable of removal as a discharge from the surfaces of the body or by absorption through the lymphatics and blood-vessels. In the former event ulcers arise upon, and cavities communicate with, the surfaces of the body opening externally.

The cheesy material frequently becomes calcified, thus remaining as a comparatively inert mass. The earthy salts may be diffused throughout a uniformly cheesy basis, or they may be deposited in a partially softened, cheesy menstruum, when a mortar-like material results.

The tubercle becomes fibrous with the diminution in the number of its cells and the increase in the thickness of the reticulum, with the transformation of the latter into a homogeneous hyaline substance. The cornified, horn-like tubercle is one whose size is diminished from the shrinkage of its cells into glistening flakes, without an evident associated cheesy or fatty degeneration.

The intimate relation of scrofula to tuberculosis has been variously expressed from time to time in accordance with the amount and accuracy of the existing knowledge. At the outset the enlargement of the lymphatic glands, especially of the neck, characterized the scrofulous affection. As the enlargements of the glands were found to present intrinsic differences connected with differing clinical histories, only those glands were regarded as scrofulous which presented the cheesy appearances. With the recognition of the cheesy condition of tubercles the latter were identified with the scrofulous gland, from the cheesy condition common to both.

This identification of scrofula and tubercle prevailed till Virchow showed that cheesy material might have a different origin, and maintained that there were cheesy lymphatic glands without tubercle, as well as tuberculous lymphatic glands which might become cheesy. A distinction was thus drawn between scrofula and tuberculosis. The former term was applied to that condition of the individual which favored the retention and cheesy degeneration of inflammatory products, not only in the lymphatic glands, but elsewhere in the body. Tuberculosis, on the contrary, was characterized by the production of tubercles which were often accompanied by retained inflammatory products, both of which were prone to undergo cheesy degeneration.

{97} The frequent association of well-defined tubercles with what were regarded as antecedent scrofulous disturbances also suggested an intimacy of relation between scrofula and tuberculosis. Virchow[49] had always maintained the possibility of regarding tuberculosis as a heteroplastic or metastatic scrofula. The occurrence of cases of tuberculosis without evidence of an antecedent scrofula prevented him from making a more absolute statement of the above relation.

[Footnote 49: _Die Krankhaften Geschwülste_, 1864-65, ii. 629.]

The views with regard to the connection between scrofula and tuberculosis have become essentially modified of late years as a result of the investigations concerning the etiology of tuberculosis.

In 1856, Buhl[50] first published his view, although he had for several years been impressed with the idea, that miliary tuberculosis was an infective disease resulting from the absorption of a specific virus. He based his theory upon the almost constant coexistence of one or several cheesy collections and miliary tubercles. The former were recognized as the remains of previous inflammatory processes, and the tubercles were looked upon as the immediate result of the absorption of this cheesy material. The individual thus infected himself. Buhl[51] claimed that the simultaneous occurrence of tubercles and inflammatory products was the co-effect of the same cause, and that the acute miliary tuberculosis, as a localized process, was merely an inflammation with the development of tubercles. He restricted the term tuberculous inflammation, however, to those forms which necessarily and from the beginning, produced tubercles whose presence was limited to the tissue inflamed. The tuberculous inflammation was regarded as a primary condition, while the acute miliary tuberculosis was a secondary process resulting from infection.

[Footnote 50: _Lungenentzündung, Tuberkulose und Schwindsucht_, 1872, iii.]

[Footnote 51: _Op. cit._, 123.]

The tuberculous inflammation of this author was largely characterized by those features which, with the exception of the constant presence of tubercles, were recognized by others as attributes of a scrofulous inflammation. At the same time, he objected to the latter term as a substitute, since its use would imply that no other cheesy product than that from a tuberculous inflammation would serve as the origin of tubercles. Buhl strictly maintained that the absorption of any cheesy material, whatsoever its source, might give rise to a general growth of tubercle in the body.

The views of this author were popularized mainly through the teachings of Niemeyer[52] concerning pulmonary consumption. The latter adhered to Virchow's views relating to scrofulous inflammation, but maintained that most consumptives were in imminent danger of becoming tuberculous in accordance with the doctrines of Buhl.

[Footnote 52: _Klinische Vorträge über die Lungenschwindsucht_, 1867.]

The theory of an infectious origin of tuberculosis, advanced from time to time by others, but most forcibly presented and maintained by Buhl, was first demonstrated by Villemin[53] in 1865. This observer showed that certain animals, especially rabbits and guinea-pigs, might be successfully inoculated, beneath the skin, with fragments of gray tubercle, cheesy products, sputum, and blood from cases of phthisis. The development of tubercles took place within three weeks after the {98} inoculation, and became general within four weeks. He also demonstrated that rabbits became tuberculous when inoculated with bits of the tumors occurring in the pearly distemper of cattle.

[Footnote 53: _Etudes sur la Tuberculose_, Paris, 1868, 528.]

Villemin's observations have been repeatedly confirmed and extended; although subjected to the severest criticism and control, their results are so constant that the law of the inoculability of tubercle is almost universally regarded as fixed. Its value as a test is evident from the statement of Cohnheim,[54] who regards as tuberculous only that which produces tuberculosis when transferred to suitable animals. The transfer may be made in various ways. Chauveau and others were successful in producing an intestinal tuberculosis by the introduction of tuberculous material into the intestinal canal of animals, especially the Herbivora. Tappeiner[55] succeeded in producing pulmonary tuberculosis, with or without general tuberculosis, in dogs, by compelling them to breathe air in which were contained minute particles of sputa from tuberculous pulmonary cavities.

[Footnote 54: _Die Tuberkulose vom Standpunkte der Infections-Lehre_, 1880, 13.]

[Footnote 55: _Virchow's Archiv_, 1878, lxxiv. 393.]

The production of a tuberculosis of the iris, as well as of remote organs, by the inoculation of tuberculous material into the anterior chamber of the eye, was an ingenious method devised by Cohnheim and Salomonsen.[56] It permitted the direct observation of the several steps in the process of absorption of the inoculated material and development of the tubercles.

[Footnote 56: Cohnheim's _Vorlesungen über Allgemeine Pathologie_, 2te Auflage, 1882, i. 707.]

The objections to the various experiments above alluded to are based upon the assumption that the results of the inoculation are not tubercles, but inflammatory products resembling tubercles. It is further advocated that the inoculation of indifferent material, as bits of glass or hairs, as well as other foreign substances, will produce the so-called artificial tuberculosis, especially in rabbits and guinea-pigs. It is admitted that these animals readily become tuberculous when exposed to simple inflammatory irritants, the local action of which frequently results in the production of cheesy material. This termination is now regarded as due to faults in the method of experimentation, the animals not being thoroughly protected from the influence of the virus of tuberculosis.

The objection on the ground of structure loses its force in connection with the well known differences in the structure of miliary tubercles in the human body, already mentioned. The tubercles resulting from inoculation often resemble in structure the meningeal tubercles of the brain rather than the type presented by tubercles in lymphatic glands. The development of tubercles in the iris may take place without any permanent inflammatory reaction. The association of evidences of inflammation with the development of the tubercle is therefore unnecessary.

The experiments of Villemin have not only demonstrated the infectious nature of tuberculosis, but have also led to a more accurate knowledge of the relation between tuberculosis and its allied affections, scrofula and pearly distemper.

The anatomical characteristics of scrofula have obviously proved insufficient in determining the relation presented by this affection to tuberculosis. The tendency to cheesy degeneration of its inflammatory {99} products was the feature of chief importance. Villemin showed that portions of a scrofulous (cheesy) gland when inoculated were followed by tuberculosis, and that the inoculation of cheesy material from non-tuberculous or non-scrofulous sources was not followed by this result. The assumption of Buhl, that the absorption of cheesy material, as such, was the cause of tuberculosis, was thus disproved. The frequency with which the inoculation of cheesy material, from what were regarded as scrofulous sources, was followed by tuberculosis, led to more exact studies concerning the anatomical peculiarities of scrofulous inflammation. Köster[57] called attention to the regularity of the occurrence of miliary tubercles in the fungous granulations of the inflamed joints of scrofulous and tuberculous individuals. Wagner[58] and Schüppel[59] discovered that scrofulous glands, in most if not in all instances, were tuberculous glands. The regularity of the presence of tubercles in scrofulous abscesses and ulcers of the skin and in scrofulous caries was shown by Friedländer.[60] This observer likewise called attention to the presence of agglomerated tubercles as the chief constituent of the new formation of lupus. These anatomical discoveries resulted in uniting more closely the affections scrofula and tuberculosis from the histological standpoint, and the union has become more firmly cemented from the etiological investigations.

[Footnote 57: _Virchow's Archiv_, 1869, xlviii. 95.]

[Footnote 58: _Loc. cit._]

[Footnote 59: _Op. cit._]

[Footnote 60: _Volksmann's klinische Vorträge_, 1873, lxiv.]

Schüller[61] has shown that the introduction of finely divided material from a scrofulous joint--that is, from one containing tubercles--into the lungs of rabbits was followed by a tuberculosis of the tracheal wound, the lungs, and liver. Similar experiments with reference to the introduction of lupus-tissue produced results suggestive of tubercle, if not actually tuberculous.

[Footnote 61: _Untersuchungen über die Enstehung und Ursachen der Skrophulösen und Tuberkulösen Gelenkleiden_, 1880.]

The intimacy of relation between tuberculosis and pearly distemper is a necessary result of Villemin's[62] experiment, in which the rabbit became tuberculous after inoculation with fragments of the pearly tumor. Gerlach,[63] and especially Schüppel,[64] showed that the structure of the nodules of the pearly distemper is the same as that of the tubercles of man, and that the two diseases are identical from the histological point of view.

[Footnote 62: _Op. cit._, 537.]

[Footnote 63: _Virchow's Archiv_, 1870, li. 290.]

[Footnote 64: _Ibid._, 1872, lvi. 38.]

From the anatomical identification and the etiological connection, as shown by Villemin, Gerlach, and Aufrecht, the pearly distemper became designated as a bovine tuberculosis.

The experiments of Villemin were further productive in leading to the discovery by Koch of the bacillus tuberculosis. It was early obvious that certain cheesy material and gray tubercles possessed the infectious qualities, and Villemin[65] maintained that the immediate cause of the latter was a germ introduced from without, which propagated and perpetuated itself in man and certain animals. This view acquired prominence through the investigations of Klebs, who in 1877 claimed to have isolated the micrococci which produced tubercles when injected into animals. Three years later Schüller[66] confirmed the statements of Klebs, and asserted that he had been enabled to obtain infective micrococci by cultivation from {100} miliary tubercles, scrofulous glands and joints, and from the tissue of lupus. Aufrecht[67] found micrococci, single and in chains, and short glistening rods, within tubercles resulting from inoculation with material from pearly tumors. The same organisms were found in tubercles produced by the inoculation of tubercles from man, and he regarded these rod-shaped bodies as the specific element productive of miliary tuberculosis.

[Footnote 65: _Op. cit._, 620.]

[Footnote 66: _Op. cit._, 55.]

[Footnote 67: _Pathologische Mittheilungen_, 1881, p. 43.]

The isolation of the virus of tubercle was thus regarded as an open question till the announcement by Koch[68] of the constant presence of a hitherto unknown, characteristic, well defined organism in all tuberculous affections, which, when isolated and introduced into animals, produced tuberculosis, the resulting tubercles likewise containing the organism.

[Footnote 68: _Berliner klinische Wochenschrift_, 1882, p. 15.]

The latter, the bacillus tuberculosis, was to be seen in preparations methodically treated and carefully stained with aniline colors, by all of which, excepting the browns, the bacillus was tinged. It was found in miliary tubercles of the lung, cerebral and intestinal tubercle, cheesy bronchitis and pneumonia, phthisical sputa, scrofulous glands, and fungous inflammation of the joints. It was also seen in the nodules of pearly distemper and in the cheesy masses from the lungs of cattle. It was furthermore met with in the cheesy lymphatic glands of swine, in the tubercular nodules of a fowl, and in the tubercles of guinea-pigs, rabbits, and monkeys. The bacilli were likewise found in the tubercles resulting from the inoculation of animals with tubercular virus from its various sources.

The microphytes were described as very slender rods, varying in length from one-fourth the diameter of a red blood-corpuscle to its entire diameter, and spores were occasionally seen within the rods. In shape and size they resembled the bacilli of leprosy, but the latter were narrower and pointed at the ends. They were found in greatest abundance when the tuberculous process was recent and rapidly advancing, and were present within, as well as between, cells. The younger giant-cells contained them in larger numbers than the older forms. They were present at the periphery of cheesy nodules rather than at the centre.

The bacilli were cultivated through successive generations and required a temperature of between 30° C. and 41° C. (86° F.-105.8° F.) for their development, one of 37° C. or 38° C. (98.6° F. or 100.4° F.) being the most favorable. The crop first became apparent on the tenth day after sowing, and the growth extended through a period of three to four weeks, forming a compact scale. The cultivated bacilli, even propagated through several generations, when inoculated, produced the same positive results as follow the inoculation of fragments of tuberculous material, although animals might be used which are not easily infected with tuberculosis.

Koch's publication was immediately followed by a statement from Baumgarten[69] of his discovery of rod-like bacteria in the tubercles of rabbits resulting from the inoculation with pearly masses, and in the pleural and pericardial tubercles of man. They were made evident by treating the sections for microscopic examination with very dilute solutions of soda or potash.

[Footnote 69: _Centralblatt für die med. Wissenschaften_, 1882, xv. 257.]

{101} The discoveries of Koch thus show that the production of tuberculosis is dependent upon the presence of distinctive bacilli, and that these bacilli are present not only in miliary tubercles, but in scrofulous glands and joints, in cheesy inflammation of the lungs, and in the pearly distemper of animals. The identification of tuberculosis with the pearly distemper and certain scrofulous affections is thus established from the etiological as well as the histological point of view.

As the bacilli are to be regarded as the virus of tuberculosis, so their introduction into the human body is necessary for the production of this disease in man. It is obvious, however, that other factors than the virus are necessary, for not every one exposed to the reception of tubercular bacilli becomes tuberculous. It may well be that scrofula is still to be regarded as that condition of the solids and liquids of the body which offers favorable opportunities for the retention and growth of the bacilli, and thus for the production of tuberculosis. Formad[70] claims that he has discovered structural peculiarities of tissue as a cause for the scrofulous habit, which he regards as synonymous with a predisposition to tuberculosis. These peculiarities are manifested by a narrowness of the lymph-spaces and their partial obliteration by cellular elements. He also maintains that these features are not only of congenital origin, but may be acquired through malnutrition and confinement.

[Footnote 70: _Studies from the Pathological Lab. of the Univ. of Penna._, reprint, 1882, xi. 3.]

The occurrence of a local, circumscribed tuberculosis in extreme old age, without antecedent or other concurrent evidence of scrofulous disturbances, suggests that favorable opportunities for the development of the tubercular bacillus may arise in advancing years. In like manner, the frequent termination in phthisis of cases of diabetes suggests the likelihood of tuberculous inflammation arising in the absence of any evidence of previous scrofulous or tuberculous disease. The scrofulous condition or constitution, as indicated by vulnerable tissues, with a protracted course of inflammations, and a persistence of their products, with a tendency to cheesy degeneration, may still exist without a sign of tuberculosis. Those who claim that scrofula and tuberculosis are identical must, in the light of Koch's discovery, demonstrate the presence of the bacillus in all scrofulous inflammations, and deny the existence of scrofula apart from indisputable manifestations of the activity of the bacilli of tuberculosis. It may be that such evidence will be presented; until it is collected scrofula and tuberculosis are to be regarded as distinct though often coexistent. The scrofulous person is frequently tuberculous, the tuberculous person is usually scrofulous; the non-scrofulous person, however, may die of tuberculosis, while the individual may be scrofulous without containing tubercle.