THE PATHOLOGICAL CHANGES IN THE LIVER RE- SULTING PROM PASSIVE VENOUS CONGESTION EXPERIMENTALLY PRODUCED.

By CHARLES BOLTON, M.D., DSc., F.R.C.P., Director of Research, Umiversity College Hospital Medical School, London.

From tkc liesearch Ldoralories, University College Hos$al d f d b l School.

(PLATES XVII.-XVIII.)

FOR several years past a research dealing with the pathological factors involved in the production of the dropsy of venous stagnation has been in progress. Three papers have been published on the subject (1903-7-9 1-2-3), but the work is not yet completed, as it has been found necessary to keep the dropsical animals alive for considerable perioda of time, and also because the research has been frequently interrupted by other work.

The methods employed to produce venous stagnation are constriction of the pericardium or obstruction of the superior and inferior venae cam, or of the portal vein in the cat and the monkey. From time to time the livers of these animals have been examined microscopically, but until quite recently no very obvious differences from the changes which are usually described as occurring in the liver in uncompensated heart disease in man, were seen in them.

In the first place, it is necessary to consider one or two points in connection with obstruction of the inferior vena cava. The other veins do not concern us here. The inferior vena cava is in all cases obstructed in the chest between the heart and the liver.

Complete ligature of the vein in this situation brings about death in a few hours, the liver is found to be swollen with blood, and about 15 C.C. to 20 C.C. of free fluid, which is usually blood-stained, but not invariably so, is present in the peritoneal cavity. Incomplete obstruction to three-fifths of the normal diameter of the vein is not fatal, but leads within twenty-four hours to the presence of a considerable amount of ascites, the fluid being of a light- straw colour. The amount of fluid is greater in the same time with an increase in the degree of constriction, but when the latter amounts to less than two-fifths of the normal diameter of the vein, the animal dies, as in the case of complete ligature. No ascites results unless the obstruction amounts to at least three- fifths of the normal diameter.

[Received May, 11,1914.1 The expuiiscs of this research have been defrayed by agrant from the Graham Research Fund, University of London.

PASSIVE 1 7 ~ ~ 0 us CONGESTION: 259

The ascites due to incomplete obstruction gradually increases up to a certain point of time, persisting for about two or three months, when it disappears with the complete establishment of anastomoses.

Experimental proof of this latter point has been obtained but not yet published.

The systemic anastomoses in the body wall develop rapidly, and the veins are large in a few days, but the portal anastornoses apparently are much slower in their dilatation.

My intention was to partially obstruct the inferior vena cava, and a week or two later to attempt complete obliteration, but fortunately this wa8 accomplished naturally in one animal by the formation of cicatricial tissue round the constricting tube, the vein being completely occluded. This auimal showed remarkable changes in the liver, which have not hitherto been recognised as depending upon simple passive congestion of that organ, As this experiment definitely proves that such changes occur as the result of a high degree of passive congestion, it is published here in detail, but only a very few remarks upon the cases of incomplete obstruction are neceswry, because, as stated above, the liver changes in those cases correspond in the main with those usually recognised as occurring in uncompensated heart disease.

CHANGES OCCURRING M PASSITE CONGESTION OF THE LIVER.- Complete ligature of the inferior vena cava, which rapidly results in death, leads to engorgement of the abdominal organs with blood. This is more marked in the liver than in any other organ. It is swollen and dark in colour, the edge tends to be rounded, and it bleeds freely on section. Since the rise of venous pressure behind the obstruction extends right through the liver iuto the portal vein, one would expect both hepatic and portal capillaries to be dilated. This is precisely w h t occurs, and on microscopical examination of the liver these two sets of capillaries appear to be about equally distended with blood.

Incomplete obstr-uction of the inferior z'ena cava, in which the animal survives, leads to an increasing dilatation of the hepatic capillaries and sinusoids, which finally form wide irregular shaped spaces full of blood (Plate XVII. Fig. 1). When the capillary endothelium can be definitely made out, it is always found lining the spaces, no blood being seen between the endothelium and the liver cells.

The portal capillaries are also dilated, but are never seen to form wide spaces. The hepatic parenchyma cells in the immediate vicinity of the blood spaces have disappeared, probably by a process of gradual atrophy. There is no trace of cellular infiltration or fibrosis in coniiection with the hepatic or portal capillaries. The hepatic veins appear to be somewhat dilated, and the large and medium-sized veins undoubtedly show some thickening, but there is no fibrosis in connection with those of small size. The portal canals show slight cellular infiltration or thickening, and the liver capsule is irregularly thickened. Such c l p g e s are well marked in from two to three months.

260 CHARLES BOLTON;

The spleens of these animals do not show any definite changes, and the peritoneum is not thickened except over the liver. Jaundice develops in a certain proportion of the cases, but I have not been able to connect its occurrence with any definite alterntion in the liver.

The dilatation of the hepatic capillaries into caveruous spaces is not due to mere mechanical pressure, because it only occurs in advanced cases in which the venous pressure differs very little from the normal. I n fact it is commonly, ns I showed in a former paper (19093), quite normal after the first twenty-four hours after the establishment of venous obstruction. The dilatation is due to atrophy of the liver cells, as a result of the nutritive disturbance consequent upon the venous stagnation ; the vessel wall being unsupported, dilataticrn occurs. This point will be more fully discussed in a future paper.

Complete obliteration of the inferior vena cam, with sur.L.ivul.-The animal was a monkey (Rheszts macnciis), and at the time of t h e operation weighed 1 9 0 0 grms.

The inferior vena cava in its course through the chest from the diaphragni to the heart was constricted to about half ite normal diameter. The operation was performed in the same manner as I have described previously in the case of the cat.

The chest was opened in an intercostal space, and the lower lobe of the right lung drawn aside by a spatula, artificial respiration being maintained by a pump, the air being blown through an ether chamber. The vein mas cleared and a piece of Jacque's rubber catheter about $ in. in length and 3 mm. in diameter, cut open longitudinally and having a piece of silk attached to each cut margin, was passed round i t and tied on. The lungs were well blown up, and the two ribs brought together with silk sutures.

Seven days later a small nbclominal incision was made just above the pubes in order to ascertain whether ascites was present or not. A considerable quantity of fluid inimedi- ately escaped, and the wound mas dosed, the fact of tho presence of free fluid being established. I hardly expected that oederua of the lower extremities would occur, because the attitude of sitting on its haunches with the thighs bent on the abdomen, which a monkey assumes, is not such as would favour the occurrence of edema of the legs. Large nnastomotic veins were present in the abdominal subcutaneous tissue. The animal grew, became fat, and was perfectly healthy in every respect.

Exactly one year after the operation, the animal was killed. Its weight w a ~ 2570 grms. The ascitcs had completely disappeared. There was no jaundice, neither were there any signs of tuberculosis in any part of the body. All the abdominal organs were healthy except the liver, which will be described below. The peritoneum was not generally thickened and the spleen had a perfectly normal appearance. ( In opening the thorax the constricting tube was found to be in position and surrounded by white fibrous tissue, to which the lower lobe of the right lung was adherent. The inferior vena cava was ligatured at the upper surface of bhe diaphragm and the thoracic viscera removed. The right auricle and the inferior vena cava below the obstruction were opened, and both portions of the vein found to contain liquid blood. There was no thrombosis. On looking into the vein it was found to be com- pletely occluded at the level of the constriction ; B probe would not pass the constriction, and water could not be forced through it with a syringe connected to the vein by a cannula.

The animal soon recovered from the operation.

There mns no cedema of the legs.

PASSIVE YEN0 US CONGESTlOiV 261

The anastomoses were completely established. The veins of the abdominal wall, the lumbar veins, veins in the suspensory ligament of the liver, and accessory portid veins communicated above with the phrenic, the azygos, the internal mammary, the comes nervi phrenici, nnd the lower intercostnl veine. There were dilated veins in the small omentuni and on the surface of the liver, the latter in places communicating with the dinphragniatic veiiis by loose adhesions between the liver and the diaphragm.

!Z7Le liver was enlarged, and weighed 145 grme. The weight of t.he liver of a monkey of 2570 grnis should be about 100 gms. The whole organ was rounded in shape and generally enlarged, one lobe probably corresponding to the human Spigelian lobr, showing a very great contrast with the normal. The Rurface was irregular, pirrticularly the upper one, the appearance of the latter being very similar to that of a human hob-nailed liver (Plate XVLI. Fig. 2). Dilated veins mere present on the surface under the capsule. These were very sniall on the posterior surface and corresponded with depressions in the surface of the. liver. On the upper aspect they were larger and in places passed into loo~e adheRions with the diaphragm. The capsule waR irregularly thickened, and the anterior edge of the liver was shrunken ant1 in p1acc.s looked like a mere tag of fibrous tisaue. Loose adhesions were also present on the front part of the under surface of the organ in the region of the small omentum and gall-bladder.

Tliu cut surface of the liver showed that the morbid changes were most marked towards the upper portion and the sides of the organ, the central and lower aspects presenting an appearance differing very little from the normal.

MICROBCOPICAL EXAB~INATION.-T~O sections were stained with eosin and hoematoxylin, by van Gieson's method, and also far fat and bacteria.

The most prominent and striking change, which is at once noticeable in sections of the most diseased part, is the presence of irregular areas of cellular degeneration commencing round the smaller hepatic veins in the centres of the lobules and extending outwards, so that in positions where the change is most advanced the whole liver tissue has dieappeared over extensive tracts, the hepatic veins and portal canals being easily recognisable in the mass of diseased tissue (Plate XVlI. Fig. 3).

The hepatic veins show some dilatation, although this is not such a striking feature as perhaps might he expected. The larger veins show some cellular infiltration and slight1 thickening of their walls (Plate XTII. Fig. 4), but no trace of any such change is to be seen in connection with the small veins. No thrombosis can be seen in any of the veins.

The cnp'l2ary vessels are dilated throughout the liver, both hepatic and portal being affected to similar extente, but this condition is not so easily seen in the degenerated parts, as will he explained later. The capillaries are, however, not dilated into the large sinuses which have been described above in the case of incomplete obliteration of the Venn cava. No htemorrhages can be seen anywhere except those which will be described in connection with the degenerated areas.

T ~ M cellular degeneration can be easily studied at various poinls, and more particularly at the margins of the affected area. The latter are sharply defined in most instances, and the liver cells in the noii-degenerate areas are of normal appearance, though on the whole small and compressed.

The process of degeneration appears to begin with swelling of the liver cell, which beconies more or less globular in shape. The protoplasm stains feebly, and clear spaces appear in it ; the whole cell finally appearing as if distended with cedenirr fluid, only a few protoplasmic strands remaining (Plate XVII. Fig. 5). The cell disappears, but apparently the nucleus remains for some time at all events. Bile pigment may be seen in places deposited in the liver cells, but this is nct a marked feature.

The result of this disappearance of the liver cells is that a fino reticuliim There is very little fat to be seen.

263 CHARLES BOLTON;

containing capillary vessels is left, in which are to be seen many nuclei, some belonging to the capillary walls and others to the vanished liver cells (Plate XVIlI . Figs. 6 and 7). This tissue is found in some places, perhaps in those of most recent formation, more or less collapsed and infiltrated through and through with blood. The hsmorrhage is no doubt secondary to the cellular degeneration and disappearance. I n other places, in which the process is older, the reticular spaces are dilated and filled with a slightly granular and practically unstained substance, probably edema fluid. I n other places these spaces contain some blood corpuscles and fibrin.

I n no part of these degenerate areas is there any trace of inflammatory reaction or of micro-organisms. There is no cellular infiltration and no fibrosis. Neither are there any signs of proliferation and regeneration of the more or less healthy liver cells in the regions of the degenerate areas.

I n those parts of the liver which appear normal to the naked eye there can be seen, on microscopical examination, a distinct difference between the zone of cells surrounding the central hepatic vein and those of the peripheral zone of the lobule next to the portal canals. The capillaries are more evident in the latter situation, and the liver cells are smaller and more deeply staining. I n the former situation they are swollen and stain more faintly, and in some places the dropsical degcneration described above can be seen t o be commencing.

The portal canals are infiltrated with cells, and in the more advanced parts are in a condition of early fibrosis and show definite thickening (Plate XVIII. Fig. 8).

The cupsule is thickened to different degrees. In some parts, particularly the upper surfaces of both lobes, it is very considerably thickened, and formed of organised fibrous tissue (Plate XVIII. Fig. 9).

At those points where there are loose adhesions, dilated vessels are present in the capsule. The extreme edge of the liver is thin, and in section is composed entirely of fibrous tissue. Local thickenings occur all over the capsule, and the origin of these thickenings isi best seen on the posterior surface, where alI tho changes are less advanced They consist in the latter situation of collections of cells of a triangular shape in the section, the base spreading out in the capsule and the apex being connected in the depth of the liver with either a portal canal or the tissue around a hepatic vein. I n these thickenings can be seen dilated vessels connected with either the portal or hepatic veasels. Around the dilated superficial vessels collections of cells appear, and this infil- tration spreads to the adjacent portions of the capsule (Plate XVIII. Fig. 10). Adhesions to the neighbouring parts form from these patches, and so anastomoses are eRtablished. These patches evidently form the origins of the chronic inflammatory thickenings of the capsule.

SUMMARY OF CHANGES RESULTING FROM EXTREME COWGESTION OF THE LIVER.

1. There is widespread degeneration of the liver cells beginning around the central hepatic vejne, with secondary hxmorrhage into the resulting reticular network.

2. The liver cells in the portal areas to which the degeneration has not spread show the ordinary atrophic changes of a congested liver.

3. There is no fibrosis of the liver in connection with the small hepatic veins or capillaries nor anywhere in the degenerate areas.

4. The walls of the large hepatic veins are slightly thickened. 5. There is an inflammatory infiltration of the portal canals leading

to some degree of cirrhosis.

PASSIVE YEN0 US CONGESTZOiV. 263

6. The capsule shows inflammatory thickening, owing chiefly to a spread of the portal infiltration to the superficial dilated portal vessels, and also to infiltration around the dilated superficial hepatic veins.

In this way adhesions form with neighbouring parts, and nnastomotic channels are established.

CONCLUSIONS.

There is no doubt whatever that the cellular degeneration is the direct result of rz severe passive congestion of the liver. In an animal otherwise healthy the pathological condition of passive hepatic con- gestion was mechanically produced. The animal continued healthy, increased in weight, and exhibited no other symptoms than those resulting from the venous hypersmia. The liver changes are, there- fore, the result of this isolated pathological condition.

The cellular degeneration is, moreover, the result of a nutritive disturbance, because the increased venous pressure in the hepatic capil- laries cannot be held responsible for the production of a pressure atrophy, since the capillaries in the degenerated area are no more distended than are those in neighbouring areas aud the rise of pressure extends right through the liver to the portal vein, and does not remain permanently a t its initial height. Neither are the changes such as would be expected to result from pressure. The hsmorrhage into the area is the result of, and not the primary cause of, theicellular dieappearance.

The changes cannot be regarded as the result of a secondary bacterial infection of the liver. It is not likely that such widespread bacterial necrosis would occiir whilst the animal was quite healthy and gaining weight; moreover, there is no inflammatory reaction of the tissues in the neighbourhood of the diseme. The absence of organisms from a lesion, however, affords no proof that the latter is of non-bacterial origin.

A similar condition has been shown to occur in man. Oertel (1904-6-10-12 * - I ) has described five cases of severe congestion of the liver showing similar changes, but the difficulty in human pathology is to exclude a terminal bacterial infection. The patients were suffering from heart failure resulting from disease of that organ or of the lung, with or without kidney dinease. He was unable to find organisms, and finally concluded that the changes were the direct result of the congestion, and suggested that they resulted from the action of a cytolytic ferment following on edema. His cases developed jaundice.

Mallory (1 9 11 s), on the other hand, states that the disappearance of the liver cells in passive congestion of the liver is the result of a bacterial necrosis. He thinks it is doubtful whether atrophy ever occurs in simple uncomplicated congestion.

264 PASSZVE VENOUS CONGESTION

The experiment described above, however, decides the point in favour of the cellular degeneration being, due directly to passive congestion and not to a secondary bacterial infection.

The frequency of occurrence of such changes in man remains at present unsettled, as only the isolated cases mentioned have hitherto been described.

1. HO1:lOh' . 2. ,, .

4. OERTEL . 5. 2, -

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DESCRIPTION OF PLATES XVII.-XVIII.

PLATE XVII.

FIG. I.-Microphotograph of a section of the liver of a cat, the inferior vena cava of which was constricted to threc-fifths of its normal diameter. The animal developed escites, which disappeared after eleven weeks. Tho section shows dilatation of the capillaries into irregular spaces, and thickening of the capsule. ( x 220. )

FIQ. 2.-l'liotograph of a portion of the left lobe of the liver of the monkey referred to ie the text. The oapsule is thickened and puckered. ( x la.)

FIGS. 3 t o 10 are microphotographs of Bections of different portions of the liver of the monkey referred to in the text.

YIG. 3.-Shows the distribution of the cellular degeneration in tlie ceiltre of a lobule. The capillaries are generally dilated.

FIG. c.-Shows the thickening of a large hepatic vcin. ( x 80.) Fro. 5.-A group of cells showing the early degenerative changes. They are swollen, some

( x 60.)

are granular, and others quite clear. ( x 220.)

PLATE XVIII.

FIG. &-The liver cells are disappearing, leaving the capillaries and reticulum. ( x 150.) FIQ. 7.-Sliows the reticular spacce distended with cedema fluid and a few scattered nuclei

]cia. 8.-Shows a porhl canal infiltrated with small cells. ( x 200.) Fro. %-The capsule is greatly thickened and composed of fibrous tissue containingdilated

vessels. ( x 70.) ~ I Q , lO.--r)ilated vessels on the surface of the h e r . They are embedded in a triangular

shqed mass of small cells, the base of which reaches the capnle, and the apex ofivliich communicates deeply with an infiltrated poi.tal canal. ( x 70.)

( x ZOO.)

JOURNAL OF PATHOLO0Y.-VOL. XfZ

FIQ. 1.

PLATE XVII.

FIG. 2.

FIQ. 4. BIQ. 6.

JOURXAL OF PATHOLOQY.-VOL XTX.

FIG. 6.

PLATE XVIII.

FIG. 7.

Fra. 8.

FIG. 9. FIG. 10.