A CASE OF CATARRHAL CHOLANGITIS AND CHRONIC PERICHOLANGITIS, ON WHICH SUPPURATIVE SUPERVENED IN THE PORTAL SPACES. Ey H. D. ROLLESTON,M.D., F.R.C.P., Senior Assistant Physician and Lecturer on Pntlaology, St. George’s Hospital ; aid T. STRANGEWAYS PIGG,Demonstrator of Pathology in tlze University qf Cambridge.

(PLATESXXV. AND XXVI.)

ABSTRACTOF CLIXICAL HISTORY.-Aman, at. 44, was admitted into St. George’s Hospital on 24th March 1896, under one of US (R.), with a history that he had passed a quart of blood by the bowel. He was deaf, very blanched, and with a low tension pulse, the arterial walls being distinctly thickened. The heart was hypertrophied ; there was albuminuria, old optic neuritis, and a trace of edema of the legs. He evidently had renal disease, and it was thought that the melaena was due to hamorrhage taking place into the submucous layer of the intestine, leading to the condition of albuminuric ulceration, first described by Dr. W. H. Dickinson (I). With rest in bed he improved temporarily, but subsequently severe abdomiiial pain, , and hamorrhage from the bowels came on. Death was preceded by a rash, which was thought to be uraemic. At no time was he jaundiced, and no history,of a past attack of jaundice was obtained. AT THE nuToPsY.-The skin was generally anaemic, and showed the remains of a rash which in places was petechial. There was no cedema of the feet. Slight uratic deposit was present on the cartilages of the first metatarso- phalangeal joints. Head.-On removing the skull-cap the Pacchionian bodies were present in excess. The vessels at the base of the brain were healthy. The brain weighed 44 oz., and was remarkably anaemic, the lateral ventr&les were sonie- what dilated, but there was nothing else abnormal. The margins of the optic discs were indistinct, but there were no hemorrhages in the retina. Thorax.-The pleura were healthy, as were the lungs, except for some edema. The larynx, thjroid body, and pericardizeiiz were healthy. The heart weighed 14 oz., and showed simple hypertrophy of the left ventricle ; the valves were healthy, and the myocardium, though palc, did not show any “ tabby-cat ’’ striation, indicating fatty degeneration. The aorta was healthy. Abdonzea.-There was no ascites. The was healthy, but the mucous membrane of the stomach was rugose and pigmented, as if from past of some standing, though free from ulceration. The and commencement of the jejununi were also pigmented. 223 H. D. ROLLESTON AND I: STRANGEKAYS PIGG. The vermiform was curled up to the right of and behind the ascend- ing colon, and for the greater part of its extent was impervious. The mucous membrane of the and colon was normal, and no ulceration or source for the hemorrhage either there or in the was forthcoming. Peyer’s patches were normal. The , just before it entered the caecum, was adherent to the signioid flexure. To the right of the second part of the duodenum, and extending up into the lesser omentum, there was a whitish soft mass of enlarged glands, which, though close to the common , did not obstruct the passage of bile through it. The adjacent aortic, and to a lesser extent the mesenteric, glands, were similarly enlarged. The portal fissure contained large glands, and a white growth was seen tracking along the portal vein into the substance of the liver. After following the portal canal for some distance, the white growth generally faded away, but in part of the right lobe became continuous, with suppnra- tion resembling pylephlebitis. To the naked eye the hepatic artery and bile duct could be seen in the growth, and a ragged space apparently representing the situation of the portal vein. Near the bifurcation of the portal vein into the two main branches there had evidently been some thrombosis, for attached to its wall was a parietal clot ; there was no complete thrombosis of the portal vein, and it was quite pervious. The liver, though but little increased in size, weighed 80 oz. There were old adhesions between the upper surface of the right lobe and the diaphragm, and surrounded by these fibrous adhesions was a firm, oval body, rather smaller than a Barcelona nut. Microscopically it was seen to be composed of a fibrous capsule enclosing structureless material, and was thought to be the remains of a necrosed lymphatic gland which had become pednnculated and finally loose in the peritoneal cavity (”. The oval body had formed for itself a smooth depression on the surface of the liver. On the upper surface of the left lobe there was an old cicatrix. On section the larger portal spaces showed the packing of white growth, already referrcd to. This gradually disappeared, and the liver tissue in most prts then showed no abnormality except cloudy swelling. In psrt of the right lobe there were multiple small abscesses, resembling what is seen in pylephlebitis. This affected area was close to the place where the loose body was embedded. There does not, however, appear to be any association between the two. The gall bladder was large and full of bile, which by pressure could be made to issue from the biliary papilla in the dnudenurn. There were no calculi. The spleeib weighed 12 oz., and was healthy on section. 8uprarenals.-The right was quite free from the enlarged glands. The left was normal; close to it there was a large accessory gland. On section, both appeared healthy, though ansmic. Kidne?js.-The right weighed 54 oz. and the left 5 oz. The capsules were slightly adherent, and on being removed exposed a finely granular surface with a few scattered cysts. On section the organs resembled a contracting white kidney. Microscopically the tubules were dilated, and contained fatty debris. There were alternating areas of recent fibrosis and of dilated tubules in the cortex, the glomeruli in many places were undergoing fibrotic atrophy, but there was no proliferation from the inside of Bowman’s capsule. The vessels showed some, but by no means excessive, arterio-sclerosis. MICROSCOPICALEXAMINATION.-A careful microscopical examination of the liver was made by means of both frozen and paraffin sections. Of the latter a large number were cut and stained in various ways. Sections of one of the larger portal spaces, which contained the abnormal CHOLANGITIS AND CHRONIC .PERICHOLAArGITIS. 223 formation, spoken of as “new growth,” show that the portal space is much enlarged, and that its increase in size is due to a packing of fibrous and inflammatory tissue. In this are embedded the hepatic artery, the bile ducts, and nerves. The portal vein is not seen, but what appears to have been its site is taken by an abscess cavity (Plate XXV. Fig. 1, a and F). The outlines of the space are fairly well preserved, and in places sharply limited by what is evidently the remains of Glisson’s capsule (Fig. 1, c). Outside this limiting membrane there is some little infiltration of the peripheral parts of the hepatic lobules ; in places the liver cells are flattened and atrophied from pressure, and between the liver cells and other parts there is a prominence and increase of Kupffer’s cells. The liver cells contain some yellow pigment, probably biliary in origin. There is a complete absence of any microscopic biliary calculi or inspissated bile- stained masses. The added tissue of the portal space is composed of well-formed fibrous tissue, between the strands of which small round cells and developing connective tissue cells are packed (Plate XXV. Fig. 2). This evidently in- flammatory process is much more recent around the central cavity, the wall of which is composed of inflammatory cells (Plate XXV. Fig. 3). This space, from the absence of the portal vein elsewhere, probably represents its site, but the walls of the vein have completely disappeared. There is no throm- bosis or remains of blood clot in the cavity, but in some sections liver cells can be seen, though these are probably of post-mortem origin, and due to handling of the liver. In several of the sections remains of the larger bile ducts can be seen lying at the edge of the cavity, and in one there is a duct cut transversely and lined with large columnar cells ; it would seem probable that these represent the remains of a bile duct which has only been partially destroyed by the sup- purative process, but they may possibly be of similar origin to the liver cells before mentioned, namely, artefacts. The hepatic artery has lying between the blood corpuscles in its lumen some spindle cells, probably derived about the time of death from the intima. That the cells have not long been detached is shown by the fact that their nuclei stain well, and by the absence of signs of degeneration in the cells or of their nuclei. In this vessel also some liver cells are seen. These, again, are probably accidental phenomena of post-mortem origin, and not of any significance. The bile ducts are extremely prominent objects in the section. They are markedly increased in number, and vary greatly in size, from very small canals, with hardly any lumen, to enormous ducts with cyst-like cavities. The mucous membrane of many of the larger ducts is thrown into folds, and presents a papillomatous arrangement (Plate XXV. Figs. 4, 5) resembling the appear- ances seen in the liver of a rabbit affected with psorospermosis. Their lumen is distended, and the ducts are tortuous (Plate XXV. Figs. 4A and 4B). In these characteristics the bile ducts resemble the illustrations of biliary given in Janowski’s paper(3). A few of the narrow columns of cubical cells, the pseudo-bile canaliculi, which are generally present in biliary cirrhosis and are not uncommon in ordinary cirrhosis, are seen around the outer part of the space. In some spaces where the bile ducts are dilated, the lining epithelium is flattened as if from the internal pressure of some materials in their lumen, but no trace of microscopic calculi of inspissated bile is to be seen. Around all the bile ducts there is a marked fibrosis, pointing to a past pericholangitis (Plate XXVI. Fig. 5). On staining for micro-organisnis, streptococci were easily found, though they are not present in great numbers. They are seen lying amongst the inflammatory tissue forming the walls of the abscess, and bear no special rela- tion either to the vein or to the bile ducts, though in a few places they are seen lying in small vessels, which might be either lymphatics or capillaries.

15---JL. OF PATE,-VOL. V. 224 H. D.ROLLESTON AND T. STRANGE Wd YS PIGG. To sum up the changes in the larger portal spaces-There is evidence of catarrhal cholangitis and past pericholangitis of some duration. In addition to this, there is a suppurative inflammation of a more recent date, with the forma- tion of abscesses around and involving the portal vein, Microscopic examination of that part of the right lobe of the liver, where there were multiple minute abscesses, shows that the portal spaces were affected in much the same way as the larger ones, but not to a corresponding extent. There is a marked fibrosis of the connective tissue of the space, especially around the bile ducts. This fibrosis extends in many places into the peripheral parts of the surrounding lobules, so that there is a distinct new formation of connective tissue between the liver cells, which near the portal spaces has led to their compression and atrophy. In other places there is a prominence ant1 increase of Kupffer's cells to even a greater extent than in the lobules surround- ing the larger spaces. There is, in fact, an intercellular cirrhosis. In the smaller portal spaces it is again seen that the bile ducts are more numerous than in sections of a normal liver, and, in addition, that there are columns of cubical cells exactly resembling the pseudo-bile canaliculi before spoken of, which have been regarded as a compensatory hyperplasia of the hepatic cells. In many of the portal spaces, in addition to the above changes, there is a diffuse small-celled infiltration, involving and in many places obscuring the whole portal space, and spreading from thence into the surrounding lobules of the liver. The invasion of the lobules by this inflammatory change is more extensive here than around the large portal spaces previously described. The inflammation is suppurative in character, as is seen by the minute abscesses in various parts of the section. All these abscesses appear to rise in the portal space, but do not bear any distinct relation to the portal vein, the vein of the space being in many cases quite free. In places the liver cells around these small abscesses are distorted and so flattened as to imitate connective tissue cells. In this part of the liver also, streptococci are found, and as before they bear no relation to the bile ducts or veins, but lie in the inflammatory tissue and smaller vessels, which appear to be lymphatics. REMABKS. Under this heading we propose to discuss briefly the nature of the lesion and its probable origin. In the larger portal spaces it has been shown that there is a considerable increase of coniiective tissue, and added to this a distinct acute inflammation, which has gone on to the formation of an abscess in the situation of the portal vein. The inflammatory process there has been intense, and has destroyed the portal vein so coinpletely that no traces of it remain. The bile ducts are both more numerous and larger than natural, while their epithelium is papillomatous, and there is very considerable fibrosis around them. This fibrous tissue is well formed, and contrasts with the recent inflammation around the position of the portal vein. The hepatic artery is practically healthy, and may therefore be acquitted of any causal part in the morbid changes found. The changes in the smaller portal spaces appear to be of much the same nature as those of the larger, but less advanced. It will be noticed that the micro-organisms (streptococci) are distributed in the portal spaces lying amongst the inflammatory tissue, CHOLANGITIS AND CHRONIC PERICHOLANGITIS. 225 and in a few spots only are they seen in small vessels, but nowhere in the portal veins or bile ducts. The above appearances seem to show that the first change in the liver began as a cholangitis and a pericholangitis. This process seems to have been of some duration and to have been fairly well advanced when the second lesion supervened, namely, a septic inflam- mation and suppuration following the coiirse of the portal spaces ; the micro -organisms probably finding their way through the mucous membrane of the bile duct, which being in a state of catarrh would allow this to take place. The streptococci once having obtained a suitable nidus in the portal space, the resulting changes are easily understood. Acute inflammation leading to the suppuration was set up, the organisms passed either along the lymphatics of the space or the portal vein to a more distant part of the liver, and there set up the changes which led to the formation of minute multiple abscesses. At the same time they caused inflammation and enlargement of the lymphatic glands which drain the liver, and thus their presence around the portal fissure and the second part of the duodenum is explained. It might, however, be suggested that the morbid changes began in the portal vein as a pylephlebitis, and set up secondary changes in the bile ducts. The more extensive changes in their walls and in the immediate neighbourhood of the portal vein might be thought to suggest this, while the localised partial thrombosis in the extraportal part of the portal vein, and clinically the melzna, might be urged in support of this view. The absence of the jaundice, often seen in pyle- phlebitis, could be explained by the inflammation (as shown by the enlarged glands of the portal fissure) having markedly affected the lymphatics of the liver, and so blocked the exit for the bile absorbed by the lymphatic radicles. There is, however, the evidence of past pericholangitis to be accounted for; this being older than the sup- purative inflammation around the portal vein, must have been due to some antecedent cause, so that pylephlebitis alone will not satisfactorily explain the lesions found. To sum up- Nature of the lesion.-These divide themselves into two- 1. Catarrhal cholangitis with extreme papillomatous changes iii the mucous membrane, and increased size and number of the bile ducts, which are very tortuous. Combined with the cholangitis there is pericholangitis of old standing, as shown by the well-formed character of the resulting fibrous tissue. 2. Suppurative inflammation, having its intensity in the region of the larger portal spaces, in which also the most advanced changes in the bile ducts are found. The inflammation and suppuration has spread to some of the smaller and peripheral portal spaces. Relation of these lesions.-The changes in the liver are mixed, and 226 U: D. ROLLESTON AND I: STRANGE WAYS PIGG. do not conforin to any single recognised lesion, such as biliary cirrhosis or pylephlebitis. At first we endeavoured to fit the changes into one of these two categories, but it is plain that cholangitis and peri- cholangitis was the first, and for a considerable time, as shown by the well-marked fibrosis round the ducts, the only lesion. Subsequently a secondary infection, as shown by the presence of streptococci, took place in the portal spaces and gave rise to a suppurative inflammation, which has resulted in an abscess apparently replacing the portal vein. Whether this secondary infection travelled by the portal vein, or in its surrounding lymphatics, it is now difficult to decide dogmatically, since both of them are undoubtedly involved. Pylephlebitis is a well- established condition, while portal lymphangitis is not generally described, though no doubt it must occur. In this instance, however, it seems more probable that streptococci leaving the inflamed bile ducts would settle in the thin-walled lymphatics, into which they would almost necessarily penetrate, than that they would at once attack the comparatively thick walls of the portal vein. In other words a suppurative lymphangitis, affecting first the sheath of the portal vein, and subsequently leading to an extensive abscess destroying the portal vein, is a more satisfactory explanation thaii pylephlebitis with subsequent affection of the lymphatics. That the lymphatics were undoubtedly affected is shown by the existence of swollen glands near the portal fissure, and that the branches of the portal vein were not universally affected is proved by examination of the suppurative area in the peripheral part of the right lobe. Possibly some cases described as pylephlebitis, secondary to gall stones, are, as we believe this case to be, examples of hepatic lymphangitis, secondary to calculous cholangitis, with suppuration eventnally invading and destroy- ing the portal vein. As to the probable etiology of the lesions. The stomach and duodenum showed evidence of past inflammation in pigmentation of their mucous membrane. This would explain an ascending catarrhal cholangitis and pericholangitis, though it is true there was no history of jaundice. On this catarrhal cholangitis, just as on catarrhal , a secondary infection, possibly of the lymphatics, has we believe ensued and gone on to suppuration. In this connection it is interesting to note that Doyen (4) has recently insisted on the importance of lymphangitis in appendicitis. The hepatic arteries being healthy, the affection can hardly have arrived through the general circulation. With regard to the possibility that a suppurative pylephlebitis has supervened in a liver previously the subject of cholangitis, and that there was no direct connection between these two events, it is to be borne in mind that there was no ulceration of the intestines or appendix to give rise to suppurative pylephlebitis, and that although there was CHOLANGITIS AND CHRONIC PERICHOLANGITIS. 2 27 evidence of past gastritis and duodenitis, the rarity of these lesions giving rise to pylephlebitis inakes one hesitate before assuming that there was an independent pylephlebitis. On the other hand, Senimola and Gioffredi (5) say that exceptionally puruleii t pylephlebitis may be primary, and it is known that micro-organisms can pass through inflamed mucous membrane without there being any gross lesion. It is conceivable that, in the present case, micro-organisms thus entering the portal vein found a specially suitable nidus in the portal spaces, whose resistance was already impaired by pre-existing perichblangitis ; but, as we have already seen (p. 224), the portal vein is on the peripheral area of suppuration by no means universally affected ; in places indeed it is free from suppuration. This fact is strongly against the view that suppurative inflammation spread vid the portal vein, and is in favour of the conclusion that, on a pre-existing catarrhal cholangitis, a streptococcal infection supervened, which spread along the lymphatics and subsequently affected the portal vein. It seems more reasonable to believe that the streptococci spread out of the bile ducts, the mucous membrane of which being inflamed would allow of the passage of micro-organisms, than that the lymphatics became infected in some other way. The points of pathological interest are- 1. The unusual naked-eye appearances-masses of a white new formation in the portal spaces resembling carcinoma or lymphadenoma, but manifestly due to inflammation. 2. The coexistence of two distinct lesions of different dates in the portal spaces-(a) catarrhal cholangitis and pericholaiigitis of some standing ; (b) acute suppurative inflammation in and around the situation of the portal vein. 3. The discussion of the question whether this suppurative inflammation is due to acute lymphangitis or pylephlebitis ; our conclusion being in favour of acute lymphangitis, due to streptococcal infection through the walls of the catarrhally inflamed bile duets. 4. The presence of marked cholangitis without jaundice, which wa8 possibly due to the efYerent lymphatics being pressed upon, and so unable to convey the bile into the thoracic duct.

BIBLIOGRAPHY. 1. DICKINSON,W. H. . . . Brit. Men. Journ., London, 22nd April 1876, p. 560; and Med.-Chir. Truns., London, 1894, vol. Ixxvii. p. 111. 2. ROLLESTON...... Trans. Path. SOC.London, 1896, vol. xlvii. p. 68. 3. JANOWSKI...... Beitr. z. path. Anat. u. z. allg. Path., Jena, 1892, Bd. xi. S. 344. 4. DOYEN...... XkZ. mod., Paris, 26th May 1897. 5. SEMMOLAAND GIOFFREDI . “ Twentieth Century Practice of Medicine,” 1897, vol. ix. p. 570. 228 CHOLANGITIS AND CHRONIC PERICHOLANGITIS.

DESCRIPTION OF PLATES XXV. AXD XXVI.

PLATE XxV.

FIG. 1 shows a portion of one of the larger portal spaces under low power- (a)The abscess cavity. (b) Its walls. (c) Remains of Glisson’s capsule. (d) Bile ducts. (e) Liver tissue. FIG. 2 shows the well-formed fibrous tissues, with inflammatory cells lying in its strands.

FIG. 3 shorn wall of abscess under high power. ( x 400.)

PLATEXXVI.

FIG. 4.1 shows a large bile duct under low power. ( x 70.)

FIG. 4~ shows the same bile duct under a high power. ( x 400.) FIG. 5 show a large bile duct cut transversely, with well-marked fibrosis of its walls.

The photographs from which the illustrations v-ere prepared we one to the skill of A. Norman, Esq. JOURNAL OF PATHOLOGY.--VOL. V PLATEXXV. JOURNAL OF PATHOLOGY.--V~L. V. PLATEXXVI.