Degenerations

The degenerations represent disturbances in the nutrition of the tissues of the body, in consequence of which their functions become impaired, if not destroyed. The latter result obviously attends the death of cells, which may occur in the course of the degeneration. The processes concerned are called necrobiotic by Virchow, as they represent vital processes leading to death. Although in many of them the cell is decaying during their continuance, its recovery is possible with the disappearance of the conditions which have transformed physiological into pathological processes. The degenerations affect intercellular substance as well as cells, and are called metamorphoses, infiltrations, or degenerations, as a transformation of normal into abnormal material, or the addition of extraneous substances, or the functional impairment of the part assumes the greatest prominence.

Cloudy Swelling, Albuminoid Infiltration, Granular Degeneration, Parenchymatous Degeneration.

Of the various modifications in the appearance of cells under pathological conditions, there is none, perhaps, more commonly met with than that known by the above terms. A granular appearance may be regarded as an essential characteristic of protoplasm, and is an attribute of cells of epithelial origin as well as of those which belong to other groups of tissues. The abundance of granules present in a normal cell depends largely upon its shape, size, and situation. These granules present various relations to chemical agents, some being soluble in alcohol and ether, others in acids and alkalies, and many of them, especially those met with in the form of degeneration now being considered, show from the various reactions that they are of the nature of albumen. Since their exact composition, in all instances, is undetermined, they are called albuminoid, and when in excess the cell is considered to be infiltrated with these granules, and the organ presents the appearances regarded as characteristic of an albuminoid infiltration. A granular cell becomes much more granular when it is thus infiltrated, and it is therefore a matter of difficulty to recognize from the appearance of certain single cells, as those of the liver or kidney, whether or not the number of granules present is abnormally increased. When, however, a large number of cells of any given organ contain more than the normal quantity of these albuminoid granules, the appearance of the organ becomes modified. In extreme cases the latter is swollen, doughy in consistency, with ill-defined structural details, and in all instances presents an opaque appearance. The term cloudy swelling is thus purely descriptive, and was applied by Virchow to designate the optical appearances of the condition in question. The granules, which disappear on the addition of acids and alkalies, are apparently either added to the cell or result from a precipitation within the same.

Frequently associated with these albuminoid granules are others, distinctly recognizable as globules of fat. An apparent increase of nuclei is often observed, and in certain organs, as the kidneys, the cells seem less coherent than is normally the case. The study of this condition in the kidneys is further of interest as indicating that the border-line between a parenchymatous degeneration and a parenchymatous inflammation is purely arbitrary. From similar exciting causes there may be associated, with the described alterations of the epithelial lining of the tubes, the exudation of albumen, the formation of casts, the desquamation of epithelium, and the presence of leucocytes within the tubules.

When the macroscopic changes are of moderate degree, and the disturbance of function relatively slight, while the concurrent alterations elsewhere, from the simultaneous action of the same cause, are predominant and characteristic of the disease, the condition is conveniently regarded as a degeneration occurring in the course of the latter, rather than an inflammation. The latter term, on the contrary, is to be applied when the granular infiltration of the cells is associated with other evidences of an inflammatory exudation, and when the pathological disturbances are to be directly attributed to the parenchymatous changes.

It is customary to speak of cloudy swelling as a nutritive change, and the condition may be induced by those causes which interfere with the nutrition of parts or of the whole of an organ. Many authorities regard this granular or parenchymatous degeneration as closely allied to fatty degeneration, since many of the causes which produce the one occasion the other. The former is often spoken of as an earlier stage of the latter, from the frequent association of the albuminoid granules with numerous globules of fat as a result of the more prolonged or more intense action of a given cause.

Organs which give evidence of a granular degeneration contain, as a rule, a diminished quantity of blood. This feature is usually attributed to the pressure of the swollen cells upon capillary blood-vessels. The anæmic organ obviously becomes still more cloudy, gray, and opaque in appearance from the diminished quantity or impoverished quality of the blood.

The granular degenerations of the heart, liver, and kidneys, as a whole, usually occur simultaneously, and afford a most important means for the post-mortem recognition of the infective diseases. The condition is therefore to be looked for in the exanthemata, especially in small-pox and scarlet fever, also in erysipelas, septicæmia in its manifold forms, diphtheria, typhoid and typhus fevers, cerebro-spinal meningitis, etc. A common feature in all these cases is the occurrence of fever, and it has been claimed that this element is the cause of the degeneration. In opposition to this view is the well-known fact of its presence in afebrile cases of poisoning from carbonic oxide, and its absence in certain cases of pneumonia and exposure to high temperatures.

The universal occurrence of cloudy swelling in fatal cases of the affections above mentioned leads to the inference of its presence in those instances terminating in recovery without obvious permanent impairment of the organs and tissues concerned. It is therefore agreed that the process may terminate in resolution—i.e. in a disappearance of the excess of granular material. On the other hand, its association, under circumstances, with fatty degeneration suggests as extremely probable that the latter condition may represent a result of the albuminoid infiltration. Even if this more serious issue exists, the possibilities are still at hand for an absorption of the degenerated material and a restitution of the destroyed protoplasm. The effect upon the individual is evidently determined by the persistence and dissemination of the condition, which, in turn, are controlled by the immediate cause and the peculiarities of the individual acted upon.

Fatty Metamorphosis, Fatty Degeneration, and Fatty Infiltration.

The fat which is present within the body under physiological conditions owes its origin primarily to the food taken. A diet which is abundantly fatty furnishes a direct source for much of the fat which appears accumulated in the various organs and tissues. Although it may now appear that such a statement needs but little confirmation, it is not long since the opinion prevailed that nearly all the fat in the body came from the hydrocarbons of the food. This seemed all the more plausible as the herbivora readily accumulated fat, although their diet might contain this element in very small quantities. Hofmann made a decisive experiment with reference to the origin of fat from fatty food by feeding a dog, made lean by starvation, with bacon in abundance, but with little meat. In the course of a few days the greater part of the fat introduced was deposited within the tissues of the animal. Other experimenters have arrived at a similar result, and it can no longer be questioned that fat, accumulated within the body, owes its origin chiefly to the absorption of fat from the food taken.

Zeitschrift für Biologie, 1872, viii. 153.

Another source for the fat of the body has long been suggested—namely, the albuminates of the food. In the admirable article on the formation of fat by Voit, from which most of the information herein presented is derived, it is claimed that he and Pettenkofer were the first to prove the origin of fat in the body, under normal conditions, from albumen. This proof was an inference, however, although presenting a high degree of probability. Valuable evidence in the same direction was furnished by Kemmerich, who found that the milk of a cow during a certain period held more fat than was contained in the food; Subbotin and Voit have shown that more milk is secreted the richer the diet in albumen. Still other observers have furnished more decisive proof that fat is formed from albuminates.

Hermann's Handbuch der Physiologie, 1881, vi. 1, 235.

Two sources for fat in the body under physiological conditions are thus recognized: 1, the free fat in the food; 2, the fat derived from the decomposition of the albuminates of the food.

Voit admits the possibility of the hydrocarbons serving as a third source, although this possibility is unnecessary in most cases. Should instances arise, however, where other sources for fat are found insufficient, the hydrocarbons must be regarded as filling the gap.

Fat which is taken into the body is considered to be either consumed or stored. That which is stored is chiefly accumulated in the great reservoirs—viz. the subcutaneous and perinephritic fat tissue, the mesentery, omentum, and bone-marrow—although it may be found elsewhere, in the fluids and tissues of the body. This accumulation serves as a source to be drawn from in case of need, and is called upon where the easily-decomposed soluble albumen is disposed of by the functional activity of the cells. An acting muscle demands food for its work, and consumes first the soluble albumen, then the fat. An excessive waste of fat is delayed by the decomposition of hydrocarbons, but the demands may become so great that albumen, fat, and hydrocarbons are consumed more rapidly and constantly than they can be supplied. It being, therefore, admitted that fat is formed from the albuminates, as well as from the fat of the food, the question readily presents itself whether fat may not be formed from the fixed albuminates of the body, especially from those contained within its cells.

It is well known that in the secretion of sebum the superficial cells of the sebaceous follicles contain fat in great quantity, while the deeper layers are comparatively free from any appearances indicative of the presence of fat. It is further admitted that when pus is retained for a time the individual corpuscles contain fat-drops in quantity and become transformed into fatty granular corpuscles. Eventually, the pus is transformed into a detritus in which fat-drops are found in great number.

Similar appearances may be present in the protoplasm of muscular tissue, the cells of the liver, kidneys, and gastric glands, when poisonous doses of phosphorus or arsenic are given. The occurrence of an acute fatty metamorphosis of the cells of various organs in new-born children has repeatedly been observed. The presence of fat in various organs of the body in pernicious anæmia, and in the heart in connection with stenosis of the coronary artery, is universally recognized. The abuse of alcohol, long-continued obstruction to the flow of venous blood, exposure to high temperatures, are all known to be conditions in connection with which fat-drops are found in the various cells of the body. The effects of poisoning with phosphorus and arsenic are of special importance, as showing that the abundance of fat present in the cells represents a result of the degeneration of these cells, since it takes place when the animal is deprived of food. Although there is an evident destruction of albumen, there is also a diminished elimination of carbonic acid and admission of oxygen. These facts are explicable on the ground that the fat present is not consumed, and the accumulation in the cells is evidence of this lack of consumption. The fat is not simply stored, as none is taken in, nor is any food received from which fat might be formed. Its presence, therefore, must be regarded as due to degeneration.

Since fat may be formed in the body as a result of the metamorphosis of cell-protoplasm, it is desirable to ascertain whether there are any means by which stored fat may be distinguished from that present as the result of a degeneration of the cell. The term fatty infiltration has been used to indicate the presence of stored fat, the latter being regarded as simply taken into the cell and retained for a longer or shorter time, without any necessary interference with other functions possessed by the cell.

In fatty degeneration, on the contrary, it is considered that the quantity of fat present indicates a corresponding diminution in the albuminates of the cell, and is connected with a diminution in the function of the latter, all the greater the more abundant the fat.

It is found that in fatty infiltration, as a rule, the fat is present in large drops, the size of the cell being increased in proportion to the quantity of fat present. Although there may be several drops present, they tend to run together, as is suggested by their different size, varying proximity, and the constant presence of a considerable quantity of protoplasm. In organs, on the contrary, whose function is seriously, even fatally, impaired, the fat, as a rule, assumes rather a granular form. Many minute fat-drops are present, and the cell is not particularly, if at all, increased in size. The more abundant the fat the less the protoplasm. Appearances are met with indicating a transition between cells with few fat-granules and those with many.

If the morphological appearances of fatty infiltration and of fatty degeneration were constant, there would obviously be little or no difficulty in determining the nature of the process manifested by the presence of fat. The exceptions occur both in fatty infiltration and fatty degeneration. In the cells of the liver of an animal poisoned with phosphorus fat makes its appearance in large drops, while in the heart and kidneys of the same animal the fat is present in a granular form.

During absorption from the intestine in the process of digestion fat is present in the epithelium in a finely granular form. When digestion is completed fat is no longer met with in these cells. The presence of large or small drops, therefore, cannot be regarded as a sufficient test of the origin of the fat. It is of equal, if not greater, importance to bear in mind the organ concerned.

In the heart, liver, kidneys, and gastric glands, as well as elsewhere, with the exception, perhaps, of the mammary gland, the presence of many small fat-drops in the cells indicates a degeneration of its protoplasm. The presence of large fat-drops, on the contrary, in the organs and tissues, with the exception of the liver, indicates an infiltration. Large fat-drops, then, may be present in the cells of the liver as the result of an infiltration or of a degeneration. In order to form a satisfactory opinion of the nature of the appearances in the liver in doubtful cases, it is important to note the condition of those organs which may be simultaneously in a state of fatty degeneration.

The accumulation of fat under physiological conditions is obviously brought about, on the one hand, by those causes which permit a free introduction, absorption, and deposition, and, on the other, by those which check its oxidation or elimination with the secretions of the body, as the bile, in which it may be present to a considerable extent. A diet rich in fat, or in albuminates readily converted into fat, offers a favorable element for the absorption of fat by the healthy individual. If the organism demands but little of this fat for oxidation, as in the case of the sedentary person, an accumulation is likely to occur. This may become so considerable that obesity results. Tissues in which normally but little fat is accumulated may become infiltrated to a large extent. The intermuscular fibrous tissue thus becomes loaded, and the activity, as well as the nutrition, of the muscles is impaired. This accumulation may be manifested not only in the voluntary muscles, but in the heart as well, which may present abundant sub-pericardial and sub-endocardial fat, the myocardium also being interlarded with streaks of fat, the so-called fatty infiltration of the heart. The abdominal walls may become thickened to the extent of a couple of inches, and the mesentery, omentum, perinephritic tissue, and liver may become enormously increased in weight from the mass of accumulated fat.

This infiltration of fat may take place under pathological as well as physiological conditions. It is apparent that those causes which check oxidation are likely also to prevent the consumption of fat, and it is well known that the destructive processes in the lung, grouped under the term pulmonary consumption, accomplish this result. Something more, however, is necessary than the obliteration of pulmonary blood-vessels and the destruction of an aërating surface. There may be, as in emphysema of the lung, a diminished respiratory and vascular surface, yet evidences of fatty infiltration, particularly of the liver, are wanting. It seems probable that the constant anæmia, with the loss of the blood-corpuscles, of pulmonary phthisis is an important additional factor in checking oxidation in this disease. This factor, it is needless to say, is not a necessary occurrence in pulmonary emphysema.

Litten has shown that when certain animals are exposed to high temperatures the appearances of fatty infiltration and degeneration are present in various organs of the body. He attributes the fatty degeneration to a direct poisoning of the red blood-corpuscles and a resulting diminution of the oxidizing processes.

Virchow's Archiv, 1877, lxx. 10.

It is universally admitted that in chronic alcoholism a fatty liver is frequently met with, even in the absence of those chronic interstitial tissue-changes usually characterized under the name cirrhosis. Alcohol is known to check the reception of oxygen and the elimination of carbonic acid, and, whatever other disturbance of cell-activity it may produce, its effect in favoring the accumulation of fat is directly attributable, in part at least, to this disturbance of oxidation.

In those conditions known as cachexiæ, the constant accompaniment of progressive and wasting diseases, as cancer, leucæmia, chronic dysentery, etc., a fatty infiltration, particularly of the liver, is a frequent accompaniment. A cachexia is dependent upon a complex series of processes, many of which tend to check oxidation, and in this respect is to be grouped with the conditions previously mentioned. That the associated fatty infiltration is intimately connected with the deficient oxidation is not to be doubted, although the agents producing this deficiency may vary in detail.

The causes which favor fatty degeneration are numerous, and the result represents one of the most serious conditions which can affect an organ. As oxidation represents the chief means of normally disposing of fat, so, pathologically, deficient oxidation favors the retention of fat due to degeneration. Were a constant renewal of protoplasm to take place, the degenerated fat might be displaced into the circulation or retained within the cell. If the latter event should occur, the result would be apparent as an infiltration, owing to the increased size of the cell, although the condition giving rise to the presence of the fat is a degenerative process. The importance of impairment of nutrition as the chief cause for fatty degeneration is thus obvious. It may readily be produced, experimentally, by measures which check the flow of blood to a part. The same measures necessarily prevent the presence of abundant oxygen, as fewer red blood-corpuscles are presented.

Fatty degeneration resulting from impaired nutrition is apparent in the heart in consequence of stenosis of its coronary arteries, in the kidneys as a result of interstitial processes obstructing the capillary circulation, in the brain from obliterative processes in the arteries at the base or within the organ, and in blood-vessels from the effect of age.

The cause of fatty degeneration may be general as well as local. In poisoning from phosphorus and arsenic the appearances in most of the organs indicate an actual destruction of protoplasm. Analysis of the secretions confirms this inference, as the production of urea is largely increased. Furthermore, there is less oxygen taken in and less carbonic acid eliminated. As has been previously stated, these conditions may be present in the starving animal. The fatty degeneration is thus easily explained as a metamorphosis of cell-protoplasm, and the deficient oxidation of the fat calls direct attention to its accumulation rather than elimination.

In acute yellow atrophy of the liver and in cases of severe jaundice fatty degenerations are constantly met with. That the origin and accumulation of fat in these affections is also due to rapid tissue-metamorphosis and checked oxidation is highly probable. Although the elimination of urea diminishes rather than increases, as shown by Schultzen and Riess, there are other links in the chain of retrograde changes, as the appearance of leucin and tyrosin, indicative of the extensive destruction of albuminates.

It is unnecessary in a work of the present character to call attention to all the possible circumstances under which fat is present in the body as the result of degeneration. Mention may be made of the acute parenchymatous (fatty) degeneration of new-born children, of the results of excessive bleeding, and of pernicious anæmia otherwise occasioned. The fatty degeneration of the uterus after parturition, of paralyzed muscles, and of tumors, the atrophic fatty degeneration of the liver in chronic passive congestion (nutmeg liver), are all well-known examples. To these may be added the fatty degenerations associated with amyloid and interstitial processes. It is apparent that in most of these instances the common features of rapid tissue-metamorphosis and deficient oxidation are present, and, being present, offer a ready explanation for the appearance of the fat.

The clinical importance of fatty metamorphosis requires consideration in connection with the description of the diseases in which its occurrence is a constant feature. As the presence of fat in cells is not necessarily pathological, so an interference with the function of the cell is not invariably implied by its presence. When its existence is suggestive of a local destruction of albuminates, a diminution of cell-activity is a necessary consequence. Such diminished activity must produce different results as the cells are those of muscles, of vessels, or of glandular organs.

Even if fat is found in cells under conditions favoring such a suggestion, it does not follow that the destruction of the cell must result. Not only is it possible that the fat may be reserved for eventual oxidation, and its place in the protoplasm be filled by normal constituents, but it is also possible that the fat may be eliminated, as such, from the body. The latter event is made apparent by the experiments of numerous observers referred to by Cohnheim, who have found free fat in the urine after its introduction into the venous current.

Cheesy Metamorphosis, Cheesy Degeneration, Caseation.

Virchow introduced the term cheesy metamorphosis, tyrosis, to designate the process resulting in the incomplete absorption of pus and the production of apparently similar changes in certain other occasional constituents of the body. The characteristic cheesy appearances were regarded as due to the inspissation of the material concerned, in consequence of the absorption of its fluid. With this inspissation there was frequently associated a partial fatty degeneration, and the cheesy matter represented dead material, which might undergo further changes, of which softening and calcification were the more important.

Inflammatory products, as pus and fibrin, were especially prone to become thus transformed, as well as other relatively transitory materials of new formation—viz. tubercle and parts of various tumors. The type of the cheesy metamorphosis was found in the enlarged lymphatic glands, commonly called scrofulous.

The importance of a clear understanding of the cheesy metamorphosis is now a matter of history. It is merely necessary to allude to the fact that these cheesy products were formerly regarded as indicative of the presence of tubercle, and were the tubercles. Tuberculization and the cheesy condition were synonymous terms, and their indiscriminate use led to much confusion with reference to the nature of tubercle.

Quite recently Weigert has called attention to the conditions present in necrosis resulting from the intermediate stoppage of the blood-current in a part. The effect is manifested, under favoring circumstances, by a cheesy appearance of the affected region, to which the terms decolorized hemorrhagic infarction, anæmic or ischæmic necrosis, have been applied. Weigert lays stress upon the existence of a coagulation of the protoplasm of the cells, with an early disappearance of the nuclei, as the essential feature of this form of necrosis, the conditions present being regarded as analogous to those met with in the coagulation of the blood. The term coagulative necrosis has consequently been introduced by Cohnheim to represent the process first fully described in detail by Weigert. The optical and physical properties of the ischæmic or coagulative necroses of tissue are often manifested as cheesy appearances, although the term coagulative necrosis includes conditions which do not present a suggestion of cheese. It is thus apparent that cheesy appearances may result in two ways: 1, by the inspissation of material in a state of partial fatty degeneration; 2, by a coagulation of the constituents of cells whose blood-supply is suddenly and completely cut off. In the more restricted sense these caseous appearances are regarded as indicative of a cheesy metamorphosis which arises by the former of these methods. Cheesy appearances, on the contrary, dependent upon the sudden death of a part, indicate an ischæmic or coagulative necrosis.

Virchow's Archiv, 1880, lxxix. 87.

Whatever may be the origin of the cheesy condition, the material presenting this appearance is liable to further changes, known as softening and calcification. The former event results from the soaking of the dead part with liquid, in consequence of which a detritus results. The softening usually begins at the oldest part of the cheesy mass, and advances toward the periphery. The sanatory evacuation of the emulsive detritus is permitted when a surface continuous with that of the external surface of the body is reached, as instanced by the escape of softened cheesy material from the lungs through a bronchus. The possibility of the complete removal of the dead mass is thus at hand, and an eventual obliteration of the resulting cavity may take place by an adhesive inflammation of its walls.

The complete absorption of the cheesy material of an ischæmic necrosis may occur by the extension into the latter of a granulation-tissue from the periphery. Whenever cheesy appearances are found on surfaces, as the degenerated tubercles of mucous membranes or the circumscribed necroses in diphtheritic inflammation or in typhoid fever, healing may be accomplished by their detachment as sloughs, a clean ulcer being left. Cheesy material is frequently encapsulated—i.e. imbedded in a layer of dense connective tissue, a condition which indicates a local cessation of the process through which the cheesy appearances arose. The same may be said of the infiltration of the cheesy mass with earthy salts—calcification—an event which will again be referred to in connection with the consideration of the general subject.

Hyaline Degeneration, Fibrinous Degeneration, Croupous Metamorphosis.

Certain of the conditions now regarded as indicative of a coagulative necrosis or a hyaline degeneration were previously described by Wagner as the result of a croupous or fibrinous metamorphosis. According to this observer, the cell-contents were transformed, under certain circumstances, into a substance resembling externally clotted fibrin. The formation of croupous and diphtheritic membranes, especially of the larynx, pharynx, and trachea, was thus explained, also the hyaline casts of the kidney.

The results of this metamorphosis presented a hyaline appearance under the microscope, and the term hyaline degeneration is now applied more especially to indicate the production of microscopic changes, while the hyaline appearances visible to the eye are rather included under mucous, colloid, or amyloid metamorphoses.

The limitations in the use of the term hyaline degeneration are but ill defined. On the one hand, there is included the transformation of muscular tissue, first discovered by Zenker; on the other, the various changes described by Recklinghausen and others, among which are embraced the results of Wagner's croupous metamorphosis. As the hyaline appearances are a frequent result of coagulative necrosis, these terms are frequently used to indicate the same condition, according as the optical or etiological features are uppermost in the mind of the observer.

The hyaline or waxy degeneration of muscular fibre described by Zenker represents a metamorphosis of the protoplasm of striated muscle in particular, although the fusiform cells of the muscular coat of the stomach and intestine may present a similar transformation.

The microscopic appearances are more characteristic than those visible to the naked eye. To the latter the muscle appears paler, more translucent, and homogeneous, and proves to be more brittle than normal. The muscular fibres are found with the microscope to be swollen, irregular in outline, the myosin transformed into flaky, glistening masses, without evidence of the normal transverse striation. These appearances have given rise to the term waxy degeneration, which suggests a possibility of confusion with the earlier recognized waxy degeneration of organs, due to the presence of amyloid material. The waxy transformation of muscular fibre, however, does not present the reaction with iodine characteristic of amyloid substance. The degeneration of the muscle is usually regarded as the result of a coagulation of the myosin, and it is claimed by Cohnheim that the latter takes place only in dead muscle, either during the life of the individual or as a post-mortem appearance.

The hyaline degeneration of muscular fibre is found in certain febrile diseases, as typhoid and typhus fevers, scarlatina, variola, and cerebro-spinal meningitis. It may also be met with when a muscle has been exposed to violence, as in the insane who have been placed under mechanical restraint. It has further been found in the vicinity of tumors, especially where muscles have been invaded by their growth. Cohnheim and Weil describe a similar condition in the tongue of frogs after ligature of the lingual artery.

The pathological importance of the above-mentioned degeneration of muscle is most prominent in cases of typhoid fever. The occurrence in this disease of the hæmatoma or blood-tumor of the rectus abdominis is thus explained, the degenerated muscle and its contained blood-vessels being ruptured. The muscles of the thigh and the diaphragm frequently undergo this degeneration; the change is more rarely met with in other muscles of the body.

Recklinghausen regards a hyaline substance, hyalin, as a normal constituent of cell-protoplasm which escapes in drops when the cell dies. Its presence indicates a diminution in the vitality of the cell from various causes. Under the microscope it appears as a sharply defined, highly refractive meshwork, enclosing spaces of irregular shape and size, in which are frequently found nuclei, more rarely cells or granules. Langhans has described this appearance as channelled fibrin. It has been met with in the placenta, diphtheritic membranes, blood-vessels, tubercles, and gummata.

The latest contribution to the history and nature of this form of degeneration has been furnished by Vallat, from whose article many of the above data have been obtained.

Virchow's Archiv, 1882, lxxxix. 193.

Mucous Degeneration, Mucous Metamorphosis, Mucous Softening.

Of the various degenerations presenting a colloid—i.e. gelatinous—condition, the mucous variety is one of the most striking. Its gross appearances may not differ materially from those to be described under the head of colloid degeneration, but the diagnostic characteristic of the change is to be found in the presence of mucin. The presence of this substance is readily detected by the addition of acetic acid to mucus, the effect being a fibrillated appearance of the latter, the fibres presenting a more or less parallel distribution. This fibrillation of mucus is regarded as the result of a coagulation of its mucin, previously held in solution by an alkali. Mucin is thus present in the body as a normal constituent, and, in the secretions from mucous membranes, owes its origin to the existence of epithelial cells, whether these represent gland-cells, as in the case of the muciparous glands of the bronchial mucous membranes, or whether they are superficial cells, as those of the gastric and intestinal mucous membranes.

In the origin of mucus as a secretion from glands Heidenhain claims that a destruction of gland-cells accompanies the continuance of the secretion. At the outset, however, the mucin escapes from the cells, the latter remaining relatively intact. With the persistence of the secretion there results a destruction and a new formation of the muciparous cells. In the pathological production of mucus from mucous membranes, as in catarrh, there is no reason to doubt that the persistence of an irritation is the cause of abundant mucus, and that the latter is dependent upon the rapid formation and destruction of epithelial cells.

Hermann's Handbuch der Physiologie, 1880, v. 64.

The origin of mucus from epithelial cells under physiological and pathological conditions being apparent, it readily follows that the epithelioid cells of tumors might be supposed to be liable to a similar metamorphosis. It is well known that cancerous tumors, especially those of the stomach and large intestine, are frequently met with, which present an abundant gelatinous material, more or less completely filling the spongy, fibrous meshwork. These are the alveolar, gelatinous, or colloid cancers.

The gelatinous or colloid material often gives the reaction of mucin, and the microscopic appearances of the tumor show that the jelly-like substance lies in that part of the tumor which corresponds with the position of the epithelioid cells. The latter are found in various stages of degeneration, the appearances being similar to those observed in the mucous degeneration of true epithelium.

The prevailing theory of the origin of cancer from epithelial structures readily suggests an explanation for the frequency of the mucous variety of cancer in connection with those parts from which mucus normally arises from the degeneration of the epithelium.

The mucous metamorphosis affects connective tissues as well as epithelium. The Whartonian jelly of the umbilical cord and the vitreous humor of the eye are known, through the investigations of Virchow, to owe their gelatinous condition to the presence of mucin. The latter lies in the intercellular substance; that is, between the cells. The appearance of these indicates no degenerative process, but the presence of mucin is obviously an essential constituent of the tissue. Whether this mucin represents a transformation of the gelatin of the intercellular substance, or a secretion from the fixed cells, or a metamorphosis of the migratory cells of the tissue, is not known. In mucous tissue, however, there is present mucin, wholly independent of any epithelial degeneration. Mucous tissue is present in the eye as a normal constituent of the adult, and in the umbilical cord as a normal constituent of the infant at full term. It is also abundantly met with in the subcutaneous and intermuscular tissues of the foetus. Its pathological occurrence in the adult as a circumscribed tumor, the myxoma, may also be mentioned.

A gelatinous substance containing mucin is found in the adult independent of the mucous tissue, but obviously arising from a transformation of intercellular substance. The most striking example of this occurrence is the cystoid softening of cartilage, especially of the costal cartilages of old people, the basis substance being transformed into a fluid containing mucin. A similar metamorphosis is of frequent occurrence in the intervertebral disks and in the destruction of cartilage in acute and chronic inflammations of the joints. The intercellular substance of cartilaginous tumors also becomes softened and converted into a liquid containing mucin.

In osteomalacia and in the absorption of bone the mucous degeneration of the bone-cartilage plays an important part. The lime salts are first set free, and the cartilage then undergoes a mucous degeneration; the product is either absorbed or remains as a liquid within cavities of large or small size. The mucous metamorphoses of fibrous and fat-tissues, likewise of bone-marrow, are well recognized instances of the occurrence of a mucous transformation of the intercellular substance of connective tissues. Finally, clotted fibrin, so often met with as the product of the inflammation of serous surfaces, may undergo a mucous metamorphosis, and, thus transformed, offer a suitable material for absorption.

Colloid Degeneration, Colloid Metamorphosis.

Laennec used the term colloid in a descriptive sense to indicate a gelatinous appearance, and for a long time its use was thus restricted. As the colloid appearances were found to differ in their chemical reaction, their distribution, and their pathological importance, and as the term was further extended to include appearances seen with the microscope, it obviously became necessary to subdivide the colloid series of changes according to the observed differences. Its use is now limited to those gelatinous conditions or appearances due to the presence of a fixed albuminate, homogeneous or finely granular, translucent, colorless or pale yellow, of varying consistency, which does not become fibrillated on the addition of acetic acid, and which does not change in color when acted upon by iodine. This albuminate is considered in most instances to represent the result of a transformation, a metamorphosis of cells, and is associated with an impairment of their function—a degeneration which is progressive, and leads, sometimes, to the destruction of the organ, as occurs in certain instances of colloid degeneration of the thyroid body. Usually, the process is limited, affecting particular parts rather than the whole of an organ. The reaction presented by a solution of sodium albuminate in the presence of neutral salts leads to the view that colloid material may represent a coagulation of an albuminous substance or substances under favoring conditions. The presence of colloid masses in the kidney thus meets with a plausible explanation.

The place of its typical occurrence is the thyroid body in certain cases of goitre, and it is early met with as a homogeneous substance replacing the granular cell-protoplasm. With its increase the latter disappears, and the entire cell is transformed into a homogeneous sphere. At times the colloid substance may be seen to project from the surface of the cell as a pale rounded clump. The aggregation of these clumps results in the presence of masses of various size, in which may be found granules of fat or pigment and crystals of cholesterin, which are accidental, not essential. Colloid masses are sometimes met with—in lymphatic glands, for instance—as concretions, mulberry-like aggregations of stratified colloid bodies, which may be infiltrated with earthy salts. Colloid material may eventually become liquefied, transformed into a sodium albuminate; and the presence of cysts in certain varieties of goitre is thus explained. The coexistence in the kidney of colloid accumulations and watery cysts has led to the view that the latter may, under certain circumstances, result from the former through the liquefaction of the colloid material. The same view is held with regard to the origin of cysts frequently met with in the choroid plexuses.

The colloid metamorphosis of cells is also to be found in the epithelium of mucous membranes and their glands, in the prostate, suprarenal capsule, sebaceous glands of the skin, and in the cells of certain tumors.

Amyloid Degeneration, Amyloid Infiltration, Waxy Degeneration, Lardaceous Degeneration.

The colloid appearances due to the amyloid degeneration of cells are of the greatest clinical importance from their frequent occurrence and the gravity of the symptoms connected with their presence. In amyloid degeneration there is the transformation of the cell-protoplasm into an albuminous material different from other albuminates found in the body. This transformation is at the expense of the functional activity of the cell, and the latter becomes inert. Amyloid degeneration represents no mere substitution, but an addition, since the affected tissue is increased in volume. The albuminate was called amyloid by Virchow in consequence of its color-reaction with iodine. Its method of origin is wholly unknown, never being found in the circulating fluids nor in articles of food. It is met with chiefly in the cell, although its presence in the intercellular substance of old people is recognized, and its occurrence in the midst of the thrombotic deposition on inflamed valves and in the results of inflammatory processes is also recorded.

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 maintains that in all cases the amyloid disturbance is seated in the connective tissue. Kyber, 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.

Virchow's Archiv, 1880, lxxx. 138; 1881, lxxxiv.

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 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 records several cases which suggest that widely diffused amyloid degeneration may occur within a few months—in one instance in less than four months.

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, 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, 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 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, 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.

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 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 and Cordua, and the present views of this subject are chiefly due to their observations, as well as to the earlier investigations of Virchow and others.

Virchow's Archiv, 1870, xlix. 66.

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, 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, 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, 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.

Hermann's Handbuch der Physiologie, 1880, vii. 155.

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.

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, are composed of hydrated ferric oxide.

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, 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.

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 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 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, 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.

Virchow's Archiv, 1847, i. 378.

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 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.