PROLIFERATION OF ENDOTHELIUM ON THE LIVER I N EXPERIMENTAL VENOUS STAG- NATION.

CHARLES BOLTON AND w. G. BARNARD. Vniversity College Hospital Medical School, London.

(PLATE IX.)

FOR some years one of us (C. B.) has been conducting a research dealing with the pathological factors involved in the production of dropsy due to venous stagnation. Several methods have been employed t o produce this condition but the particular one that concerns us in the present communication is that of partial obstruction of the inferior vena cava above the diaphragm (for details see this Journal, 1909, xiv. 51).

Ascites results from the obstruction and persists for a variable time, eventually disappearing with the establishment of anastomoses. The ascitic fluid comes entirely from the portal system and more particularly from the liver which is considerably enlarged and may show patchy thickening and adhesions of the capsule. The fluid exudes through the capsule of the liver and a t the same time the lymph flow along the lymphatics from the liver is greatly increased. On the surface of the liver a non-inflammatory proliferation of its endothelium leading to the formation of fibrous polyps and tags was found; and so far as we are aware proliferation of this type occurring independently of any inflammatory change or mechanical irritation has not been described before. Tsunoda (Frank. Zed. f. Path., 1909, iii. 220) produced milk-spots on the pericardium by mechanical irritation and stated that these occurred without inflammatory reaction or deposition of fibrin but in our cases mechanical irritation is also excluded.

All the operations were performed on cats under strict antiseptic precautions and the peritoneal cavity was in no case opened. The animals were killed a t periods varying from 21 hours to 113 days after the operation and showed no sign of infection. The livers were in varying stages of central degeneration necrosis and engorgement and the histological changes of their cells were characteristic of the condition of passive venous congestion. Post-mortem examinations were made

45

46 C. BOLTON A N D W. G. BARNARD

immediately after killing the animals and the livers were fixed whole in saline formalin. Some ascites was found in six cases out of eleven but in none was there any evidence of peritonitis.

Macroscopic. On examination after fixation it was found that the degeneration

was not uniform throughout the livers, the parts nearest to the anterior free borders being always the most severely affected. The polyps could be identified in the earliest cases as a slight roughening of the surface and in the more advanced as a shaggy coat of milky-white threads ; both being most conspicuous over the contact surfaces of the lobes and over the degenerate areas. Under a dissecting microscope milky-white dots, small buttons, ridges, pockets, tags and along the free borders of the lobes fringes could be identified. For the most part the arrangement appeared to be haphazard but in a few places it seemed to be orderly, buttons appearing on either side of each portal canal.

Microscopic. Normally the surface of a cat’s liver is smooth and its capsule

consists of a thin sheet of fibrous tissue covered by a single layer of endothelium. The surface of the majority showed slight undulations, the depressions corresponding to the centres of lobules and the pro- jections to portal canals. I n the earliest cases the subcapsular zone was greatly congested and small collections of fluid were noted between the fibrous capsule and the endothelial layer. I n this way small groups of endothelial cells were pushed up from the underlying fibrous tissue, as can be seen in fig. 3. This separation of the endothelial cells from the fibrous capsule only occurs in the early stages; later the two layers are again in contact. The endothelial cells change from flat to cubical or columnar and this change persists ; it is best seen over the surface depressions. The next chaiige observed was that the endothelial cells had proliferated to form buds varying in height from two to five cells ; and a t this stage although the buds were very numerous there was no proliferation of the fibrous tissue. The reaction was confined to the endothelial cells, neither inilammation nor the deposition of fibrin being associated with it. Later fibrous tissue was found at the base of the buds, later still the buds had a fibrous tissue core and finally fibrous tissue polyps covered by a single layer of endothelium were produced. The endothelium covering the polyps was continuous with that covering the rest of the capsule and the fibrous core with the fibrous tissue of the capsule. I n the later stages irregular patchy thickening of the capsule also occurred.

JOURNAL OF PATHOLOGY-VOL. XXXI. PLATE IX.

FIG. 1.-Polyps, buttons and ridges. x 6. FIG. 2.-Small pockets. x 6.

FIG. 3.-Separation of endothelium from capsule.

FIG. 4.-Endothelial buds.

FIG. 5.-Buttons and polyp with fibrous FIG. &-Cubical endothelium over a cores. surface depression.

ENDOTNELIAL PROLlFERd TION 47

:at No.

4 2

12

11

7

5

1

9 6 3

a x be1

lays after )peration.

4 6

11

25

62

72

113

32 65 a9

21 hrs.

.ed nor1 as a control

Summary of post-mortem findings.

Ascites in C.C.

25

15

20

3

nil

35

I killed

Severe central degeneration. The endothelium is in places lifted up from the fibrous tissue of the capsule by small collections o f fluid. In both the endothelium tends to be cubical and in 2 it is in places columnar.

Severe central degeneration. The endothelium is cubical or columnar particularly over the de- pressions where it has proliferated to form very numerous endothelial buds. Although these con- sist of cubical and columnar cells up to five or SO high there is no fibrous tissue proliferation in their bases.

Severe central degeneration. The surface is covered with papille consisting of proliferated endothelial buds in the base of many of which is a little young fibrous tissue.

Severe central degeneration. Numerous papi lh most of which have a fibrous tissue core.

Severe central degeneration. Numerous large papillie, buttons, ridges and tags all of which consist of a central core of fibrous tissue covered by a simple layer of endothelium. There is patchy thickening of the capsule.

Severe central degeneration. Numerous fibrous papillae, buttons, ridges and tags in some of which the fibrous tissue has become hyaline.

In these cases there was only slight central de- generation. In 9 there were small polyps over the degenerate areas. In the other two there was no proliferation of the endothelium but it was cubical over the surface depressions.

Very great congestion. The endothelium was of the normal flattened type.

The endothelium consists of a single layer of flattened cells. No abnormality found post- mortem.

Discussion.

At operation it is impossible to produce exactly the same degree of stenosis in each case, so that too much importance must not be attached to the actual times after operation a t which the changes took place. Even so it would appear that the process is very much slower than a similar one taking place in the course of an ordinary inflamma- tion. An indication of the severity of the obstruction is given by the degree and the distribution of the central degeneration and since the polyps are more numerous over the degenerate areas it follows that the more severe the obstruction the more numerous will be the polyps. The presence of fibrous tissue in the polyps probably depends on the age of the polyp and the older it is the more likely is it to become hyaline.

The explanation of the endothelial proliferation is not clear though the lifting of the endothelium described in cases 2 and 4, the observa-

48 C. BOLTON AN11 W. G. BARNARD

tion that the polyps are most numerous over the areas of maximum degeneration and the association with ascites are all suggestive.

The fact of this occurrence in cases in which inflammation can definitely be excluded and in which there is no evidence of deposition of fibrin and subsequent organisation is of itself of considerable importance. Not the least of which is that it provides evidence that the buttons ridges pockets tags and fringes found so commonly in connection with endothelium elsewhere are not of themselves conclusive proof of an antecedent inflammation. That such structures are fre- quently the sequela: of inflammation is not disputed, but it has long been suspected that in some cases they may have a different origin. This is particularly so in the case of the heart where the lesions are especially common and as there is no essential difference between the structure of the capsule of the liver with its covering endothelium and that of the pericardium and endocardium the non-inflammatory pro- liferation in the one case makes it easy to believe in its occurrence in the other.

SUMMARY. Proliferation of the endothelium over the surface of the liver

occurring independently of inflammation and leading to the production of polyps has been found in experiniental venous obstruction.