The Journal of Pathology and Bacteriology

Vol. XXXIV., No. 6

616.36-005.3

THE PATHOLOGICAL OCCURRENCES IN THE LIVER I N EXPERIMENTAL VENOUS STRG- NATION.

CHARLES BOLTON and W. G. BARNARD.

From the Pathological Departme&, University College Hospital Medicd School.

(PLATE LXVII.)

THE research with which this communication deals is one of a Reries, which was initiated some time ago by one of us (C. B.) with the object of studying the factors which are responsible for the production of the dropsy of venous stagnation. The circulatory conditions of the congested liver and the lymph flow from it during the development and decline of ascites have already been described (l); and the present investigation deals with the histological examination of the congested liver with the object of interpreting the appearances found in the light of these demonstrated changes in circulation and lymph flow. The liver is thus intended to present a picture of interacting processes from start to finish. The research was finished in 1928 and a paper dealing with the capsular changes in the liver published in that year(2). Circumstances have interfered with the complete publication till now.

Bethod.

A constricting band was applied to the inferior vena cava in the chest after the manner already described, and the experimental animals were killed after 4, 6, 11, 25, 32, 62, 65, 72, 89 and 113 days, i.e., till the full development of anastomoses put an end to the morbid process. Ten experiments in all were performed on cats, and they thus represent the various stages during a single attack of hepatic congestion, such as occurs in uncompensated heart disease,

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702 C. BOLTON AND W. G. BARNARD

including recovery from the same. The vein was narrowed to approximately 3 mm. in diameter (almost half the normal) in each experiment. This does not represent precisely the same degree of constriction in all cases because the vein varies somewhat in size from animal to animal ; but this is a matter of no great importance and the results are exact enough for the purpose in hand.

I. Ci'rculatoyy changes and lymph $ow.

The structure of the liver and its circu- latory apparatus differ fundamentally from those of the other abdominal organs, and accordingly the effects of passive congestion present corresponding differences in the two cases. The difference as regards the circulation lies in the fact that the hepatic and portal veins react to an obstruction of the inferior vena cava as if they were one continuous tube without any intervening capillaries. Any rise of pressure in the inferior vena cava is transmitted right through the liver from the hepatic to the portal vein, the pressure in which rises exactly proportional to the pressure in the veiia cava.* This occurs with all degrees of obstruction and a t all stages of the experinierit. I n the other organs of the portal area the pressure is merely trans- mitted back to the capillaries and no further, owing to the tonic contraction of the arterioles. The conditions of circulation in the two sets of capillaries are, therefore, different in the respect that the pressure is always relatively higher in the liver capillaries. This is because every increment of pressure in the hepatic veins in front is followed by a corresponding increment behind in the portal vein, which adds to the capillary engorgement ; whereas the capillaries of the other organs are not subjected to this automatic exaggeration of their congestion when the portal pressure rises, because the volunie of blood supplied to them from behind entirely depends on the state of contraction or dilatation of the arterioles. The splaiichnic area is so capacious that any obstruc- tion t o the venous return from it is followed by a fall of general arterial pressure, and thus a lessening of the blood supply to its capillaries.

The efforts of the animal, in order to effect compensation, are directed towards raising its vena cava and portal pressures, so as to ensure a greater blood-flow through the liver and the narrowed vena cava, and also towards raising its arterial pressure. Two courses itre open to it. (1) The more rapid one of vaso-constriction raises tlie arterial pressure but further cuts off blood from the splanchnic capillaries and increases the obstruction of the vena cava by raising its pressure to some extent. The capillary pressure in the liver, therefore, becomes higher than it was before and that of the remaining organs lower. This is what occurs in the early stages of narrowing of the inferior vena cava. Immediately on applying the constriction

* The constrictor mechanism at the mouths of the hepatic veins of dogs does not

(a) Circulatory changes.

appear to exist in cats (H. H. Dale, hamet, 1929, i. 1180).

PORTAL STAGNATlON 703

the portal pressure is raised by almost 30 per cent. of its original height; it soon tends to fall owiiig to swelling of the liver; but rises again when vaso-constriction occurs, and stands a t its original level after 24 hours. At this stage there is considerable stagnation in the liver capillaries but only a moderate rise of pressure. (2) The next course open to the animal of raising its pressures is by an increase in the volume of its blood. This is a slower process and is demonstrable after about ten clays. It is rendered possible by exaggerated absorption of lymph in the clepleted areas of the body with a diminished output of urine a t the beginning, and also bccause the ascitic fluid is being constantly absorbed. The average increase in blood volume is a little over 25 per cent. of the normal. The portal and inferior veiia cava pressures now staiid a t about twice their original height, that is to say a t a height comparable to that inimecliately following complete ligation of the vein. The capillary pressures in the entire splanchnic area go up, but the pressure is still rnuch higher relatively in the liver than in the other organs. Owing to the higher pressure in the portal vein with the same degree of obstruction the blood flow through the liver is increased arid the capillary stagnation lessened (l).

I t was shown by Starling that, when the inferior vena cava is completely obstructed above the diaphragm, the lymph flow through the thoracic duct is greatly increased, and that the lyniph comes entirely from the liver(3). In such a state of affairs as this the venous pressure is more than doubled and the arterial pressure sinks to zero. The pressure in the liver is, therefore, very high in cornparison with that in the other abdoniiiial organs. This state of the circulatioii is fundamentally the same in a grossly exaggerated form as that described above. In the early stages of narrowing of the vena cava the pressure in the liver is only moderate, although there is considerable stagnation of blood in it. I n such an animal with ascites there is no demonstrable alteration in the lymph flow through the thoracic duct. At a later stage when the blood volume is increased and the pressure in the liver high the lymph flow is increased to about three times the norrnal(l). Not only is the blood flow through the liver improved a t this late stage of the experiment but the flow of lymph from it is increased, that is to say the liver is better drained.

(13) Lymph j o w .

11. Histological changes in the 6lood vessels.

Both hepatic and portal veins are dilated in some measure and all the capillaries, both portal and hepatic, are equally distended at the beginning. Later when cellular necrosis or degeneration has removed many hepatic cells near the centre of the lobule, the capillaries in this region dilate into irregular spaces from loss of support and many rupture leading t o extravasation. Such a condition of dilated

704 C. BOLTON AND W. G. BARAJARD

capillaries is well marked under the capsule, but the regions surrounding the portal canals are free from it. The blood in the portal veins is always in a normal condition, and individual corpuscles are well defined and well stained and no fibrin is seen indicating thronibosis; and the same may be said generally of the blood in the capillaries surrounding them. The blood in the capillaries towards the centre of the lobules in the necrotic areas is different : there is no fibrin but the capillary contains a red hyaline mass composed of red corpuscles welded together, so that the outlines are lost in the uniform red or pink mass. The hepatic vein in to which these capillaries drain contains plasma stained a uniform pink wit11 eosin and almost devoid of red corpuscles except here and there where may be seen one or two small groups of normally staining and well-defined corpuscles. There is no fibrin indicating intravascular clotting. The high venous stagnation and slowing of the blood stream, the damaged capillary endothelium and the rapid leakage of fluid from the capillaries has led to aggregation of the corpuscles. Such a condition is well known in necrotic and inflammatory states(‘). The capillaries are not blocked so that the blood flow is stopped, but corpuscles are entangled arid the plasma carried forward into the hepatic venules. Outside the necrotic areas the blood in the veins is normal. When the cells round the hepatic vein do not necrose but disappear more slowly by degenerative changes, the same dilatation of the sinusoids into irregular rounded spaces of various shapes occurs. Such dilatation is well marked in a zone under the capsule, but we repeat that it never occurs around the portal canals, the capillaries in this region remaining regularly and moderately dilated as a t first. A few haeniorrhages may occur under the capsule and as already described around the hepatic vein. Whether necrosis has occurred or a slower degeneration in the hepatic cells, the same final changes are seen in the later specimens of a few weeks’ duration. Around the central vein and under the capsule are irregular spaces, formed of dilated sinusoids and by their rupture, which are full of normal blood and which form, as it were, permanent new channels for the blood on recovery from the condition. In this permanent stage they may resemble in some specimens naevoid spaces. Fatty degeneration of liver cells occurs in the areas outside these spaces. All these appearances are in keeping with those observed in passive congestion of the liver in human heart failure and we have not found the extensive fibrosis around the hepatic veins described recently by Zimmerman and Hillsrnan (”.

111. Histological changes in the lymphatics.

These livers are peculiarly suitable for studying the normal lymphatic system of the liver, because the channels are distended with cedema fluid. The blood capillaries lying between the columns

JOURXAIJ OF PATHOLOGY.-Vor.. KXXI\’.

J?Xl’ERIM EXTAL PO IlTAL ST-AB N ATION

PLATE LXVII

FIB. 1.-After 6 clays. c =.:capillaries. s =extracapillary lymph spaces.

PIG. 2.-Same cat. hccuniulation of wdeina fluid under capsule and between endothelium and capsule.

PORTAL STAGNATION 705

of liver cells have everywhere completely formed walls of endothelial cells: this applies to the capillaries round both the hepatic venules and portal canals in every part of the liver. The capillary wall lies directly upon the column of liver cells but there is a potential space between the two, across which pass a t intervals delicate protoplasmic threads, which become visible when the space is distended with lymph. These spaces partake, therefore, more of the nature of lymph spaces than lymphatics, since they have no definite walls of their OWII. I n no part of the liver parenchyma have we seen any other arrange- ment. These extracapillary spaces thus form in reality small potential channels entirely surrounding the capillaries, and they open into lymph spaces of the areolar tissue of the portal canal. In the portal canals lie walled lymphatics running outwards towards the portal fissure along the portal vein. When distended with lymph, these lymphatics can be traced up in the smallest portal canals with the bile ducts and small branches of the portal vein, and communicate with the extracapillary spaces described and the lymph spaces of the areolar tissue of the portal canals. I n places the distended extra- capillary spaces can be seen definitely opening into the distended lymphatic spaces of the portal canals. The main lymphatics of the liver drain into the cisterna chyli, though some of the superficial lymphatics under the capsule drain into the thoracic lymphatics. All the channels mentioned above as constituting the lymphatic apparatus are distended with lymph during the first few days. The intact capillary wall containing Kuppfer nuclei is detached from its position contiguous to the liver cells by lymph which distends the extracapillary spaces and renders visible the fine strands of fibres passing across the space from one wall to the other (fig. 1). As the hepatic cells disappear either by necrosis or atrophy the extracapillary spaces blend with the empty spaces left by the disappearance of the cells, allowing dilatation of the blood capillaries, which become bulged out into these newly formed spaces in quite an irregular fashion and by rupture cause hizmorrhage into them. It is quite clear that the lymph from the central parts of the liver chiefly flows out in the portal lymphatics, and that the lymph from the superficial parts of the liver finds a more ready exit between the endothelial cells of the capsule into the peritoneal cavity (fig. 2) contributing, perhaps chiefly, to the ascitic fluid contained therein. Some lymph from the spaces between the endothelium and the liver cells no doubt finds its way into the capillaries and passes along these to mix with the plasma in the central hepatic veins. All these appearances denote defective lymph drainage and are seen in the early cases only (up to eleven days). After the first few days have passed and the lymph flow increases, the extracapillary spaces disappear and are seen no more. The only channels now dilated are the lymph spaces here and there in the portal canals and the walled lymphatics.

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706 C. BOLTON AND W. G. BARNARD

IV. Distyihtion of the odema fluid.

(Edema fluid, that is to say fluid which has collected outside the walled lymphatics, is found in the following positions. (1) In those early cases showing extensive necrohis of the liver cells it occurs in the extracapillary spaces a d sometimes between the individual liver cells, which appear to be separated from each other. I t also occurs extravasated in places as the result of rupture and more particulayly under the capsule. Otherwise it is present in the areolar spaces of the portal canals. (2) When there is no severe necrosis it is largely confined to the capsular region aud the portal canals, and is also to be seen in the meshwork resulting froiri atrophied and degenerated liver cells.

The interpretation of all these changes we have described in the blood vessels and lymph channels can only be, that in the early stages there is great stagnation of blood in the liver a i d also defective drainage of lymph by the lymphatics. This is in keeping with the relatively moderate pressure in the portal and hepatic veins and the normal lymph flow. In the latcr stages when the venous pressures are high and the pressure in the liver high, the blood volume increased and the lymph flow excessive, tlie histological changes are also in keeping with these altered conditions, and indicate better drainage of lymph from the liver and greater volume of blood flow through the organ and the narrowed veiia cava.

V. Changes in the liver cells.

(a) Necrotic changes. Necrosis occurs in the central part of the lobule and extends from one central hepatic vein to another. There are thus left unaffected islancls of norinal liver cells arouiitl the portal canals, and these are never affected. This extreme change is seen only in the marked stagnation of the early stages ; the necrotic tissue has disappeared by about eight days, and after twelve days at the most none is present. All the cells in this area are uniformly affected and the patch is sharply marked off froni the surrouncling liver tissue, grossly affected cells lying next to normal cells. The earliest change is swelling of the cell, which becomes cloudy and stains diffusely. Vacuoles appear in many ; the nucleus becomes invisible and the cell breaks up into debris. The Kupffer nuclei stain normally in the necrotic area. There is no leucocytic reaction. The necrosis is limited sharply and none is present in the cells outside the necrotic area. As the cells disappear the sinusoids adjacent to them dilate into spaces and replace them. This dilatation is due to losv of support, the necrosis of the cell being the primary event and due to interference with the normal blood supply, which falls below the minimal requirements

PORTAL STAGNATION 707

of the cell. the popular idea, for the following reasons :-

The cell changes are not due to pressure which is perhaps

(i) The cells swell a t the beginning and occupy more space. (ii) The cells around the portal venule are quite unaffected and

yet the capillary pressure around theni is somewhat higher than that in the capillaries of the necrotic area.

(iii) The distension of the sinusoids is limited to those of the necrotic area, in which the pressure is lower than i t is in those capillaries peripheral to it, which are not dilated.

(iv) The sharp transition from necrotic to normal cells is not in keeping with the notion that the change is due to pressure.

(v) The necrotic change is seen only in the early stages with a high degree of blood stagnation and only a moderately raised intracapillary pressure. It disappears in the later stage when the capillary pressure is highly raised and the blood stream accelerated.

The condition in a nionkey with complete occlusion of the inferior vena cava of one year’s duration, described by one of us (C. €3.) corresponds to the late stages of this condition after disappearance of the cells and the establishment of anastomoses (”.

(b) Depzwative changes occur in late cases and in those with a less degree of venous stagnation. A few scattered necrotic cells may be present, but the alteration in these less severe congestions is typically atrophy and fatty change owing to deficient nutritive exchange. A little fa t may be seen in the first few days, but atrophy and fatty degeneration are best marked a t the end of a week. These changes progressively increase 1111 ti1 compensation is established by improved blood flow and anastomoses. The distribution of these changes is the same as that of the necrosis ; the more normal liver cells are always found surrounding the portal veiiules. The cells disappear towards the centre of the lobule and dilated sinusoids appear as in necrotic cases. The degree of change varies in different animals from patches here and there to large tracts around all the hepatic veins. The atrophied cells are shrunken and narrow and frequently appear as columns radiating from the central vein. No localised regeneration of the liver cells has been seen. Fatty change is typically found in the cells peripheral to the region of atrophied cells and to the spaces formed by their disappearance. In the late stages there is slight increaseof fibrous tissue in and beneath the capsule, in the walls of the hepatic veins and in the portal canals, but iiot t o be compared in amount with that found in the monkey mentioned above.

VI. Chuiyes in thc livm capsule. Brief reference need only be made to these changes because they

have already been described (”. They consist of proliferation of

708 C. BOLTON AND W. G. BARNARD

the endothelium into buds and eventually the formation of polypoid like excrescences and tags with fibrous cores. These are of non- inflammatory origin and eventually give rise to adhesions as occurred in the monkey above mentioned.

VII. Changes in other oyans.

(a) Portal area. We have already referred to the circulatory changes in the capillaries of the remainder of the portal area and showed that the pressure in these vessels is a t all stages relatively lower than it is in the capillaries of the liver. The microscopic changes are in keeping with this state of affairs, and as a fact it is difficult to make out any great difference from the normal in the later stages, but in the early stages in which the high degree of stagnation in the liver has led to necrosis, the splenic sinuses are observed to be definitely congested and more blood is present in the organ than normal, but otherwise the appearances are normal. The blood corpuscles are normal and there is no agglutination. In the later stages some proliferation of the endothelium of the capsule occurs, but no polypoid outgrowths have been seen. It is, therefore, quite clear that the liver acts as a buffer, so to speak, and by its distension prolects the remaining capillaries of the portal area from the excessive effects which it itself shows. The changes in these remaining organs are, therefore, siniply those of moderate passive oongestioii with excessive lymph production giving rise to dropsical effusion into the peritoneum.

There is no dropsical effusion into the subcutaneous tissues and, corresponding with what occurs in the portal area, it was shown by one of us (C. B.) that the venous pressure in the peripheral parts of the body is relatively lower than in the inferior vena cava and its immediate tributaries (l). I n this central region the kidney shows changes and not uncommonly dropsical effusion occurs into the retroperitoneal tissues.

(c) Kidney. The changes in the kidney are similar to those in the liver except that they are slight in comparison and necrosis of the cells has not been seen. Congestion of the veins and capillaries particularly in the cortex is marked in the early stages, and aggregation of the red corpuscles may occur here and there in a few of the capillaries. There is distension of the lymphatics running with the vessels. The changes in the cells of the convoluted tubules are limited to swelling and slight cloudiness, but the nuclei are preserved and the cells do not die. I n the late stages there is some congestion as before, the cells in most being normal.

(b) Systemic capillaries.

Now and then cellular degeneration may be seen.

Summary.

When any obstacle is interposed to the return of blood through the inferior vena cava to the heart, whether it be due to right-sided heart failure from one of its numerous causes or to increased pressure in the

PORTAL STAGNATION 709

chest in any of its forms, the resulting increase of venous pressure passes back through the liver to the portal vein, but, owing to distension of the capacious splanchnic area, a high portal pressure sufficient t o maintain compensation is impossible and the arterial pressure falls. Arterial constriction does not relieve the condition. At this stage there is marked venous stagnation in the liver with resulting necrosis and cellular degeneration ; there is an increase of lymph production and the lymph stagnates in the liver and leaks out of the capsule as ascites. The other organs, to which the liver acts as a buffer, do not show such extensive changes, their capillaries are congested and excessive lymph productiorl leads t o dropsical effusion. At a later stage the blood increases in volume and the pressures go up in all parts; the flow of blood through the liver and the lymph-flow from its lymphatics are increased. I n this way compensation is partially effected, and in local obstruction of the inferior vena cava anastomoses, niore readily established in the systemic than the portal area, complete the process of compensation, although the liver contains permaiiently dilated channels round the hepatic venules. In the condition of congestive heart failure, recovery of the heart entirely removes the obstruction and compensation is completely restored ; after repeated attacks the liver and great veins remain permanently dilated. Any subsequent necrosis of the cells must be looked upon as the result of an acute exacerbation of the congestion.

A t first sight it appears anomalous that a higher portal pressure should be associated with less severe cellular change in the liver. But such is not the case. I n 1904 it was proved by one of us (C. U . ) that raised intracapillary pressure was merely a contributing factor in the causation of passive cedema and had not the importance usually ascribed to it (7). If it were possible to raise the portal pressure high enough to ensure a normal blood flow through the obstruction the changes in the liver would be limited to dilatation of the vessels and a minimal degree of pressure atrophy.

The expenses of this research have been defrayed by a grant from the Graham fund, University of London.

The same is true of these liver changes.

REFERENCES. 1. BOLTON, C. . . . . . . Froc. Roy. SOC. B., 1907, Ixxix. 267; this

Journal, 1910, xiv. 49 ; 1916, xx. 290 ; Heart, 1924, xi. 343.

2. BOLTON AND BARNARD . . this Journal, 1928, xxxi. 45. 3. STARLING, E.. . . . . . ~70uv.n. ofPhysiol., 1894, xvi. 224. 4. THOMA . . . . . . . . General Pathology, 1896, i. 26.

LEVY, A. G. . . . . . . this Journal, 1929, Xxxii. 387 (contains refer- ences to modern work).

5. ZIMYERMAN AND HILLSMAN Archives of Path., 1930, ix. 1154. 6. BOLTON, C. . . . . . . this Jozcrnal, 1914, x k . 258. 7 . BOLTON, C. . . . , . . this Journal, 1904, ix. 67.