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Postgrad Med J: first published as 10.1136/pgmj.47.552.666 on 1 October 1971. Downloaded from Postgraduate Medical Journal (October 1971) 47, 666-670.

CLINICAL REVIEW

Primary sclerosing cholangitis LAURENCE TINCKLER M.D., Ch.M., F.R.C.S., F.A.C S. Formerly Professor of Surgery, University of Singapore

Summary however, had had previous biliary surgery. Miller The literature on the subject ofsclerosing cholangitis is reported a case in 1927. reviewed. Carter & Gilletie in 1951 described fifteen patients The value of conserving the gall bladder, of opera- with strictures involving the intrahepatic biliary tive cholangiography and of the administration of system. In 1963, Bartholomew et al. reported two steroids in the management of these patients is patients and suggested an association with retro- emphasized. peritoneal fibrosis and Riedel's thyroiditis. They con- sidered the possibility that a hypersensitivity reaction PRIMARY sclerosing cholangitis, stenosing cholangitis, might be the underlying aetiological factor. In one of chronic obliterative their patients, as well as in the experience of Schwartz Protected by copyright. fibrosing cholangitis, cholangitis & Dale (1958) corticosteroids appeared to be of are all terms referring to a rare diffuse type ofchronic definite therapeutic value. inflammation of the entire common and at In 1958, Schwartz & Dale found only thirteen times of the hepatic ducts and their radicles. In most authentic cases of the primary type in the literature instances, sclerosing cholangitis is idiopathic or and added six cases of their own. The majority of primary. cases reported were examples of extensive involve- Bartholomew et al., in 1963 found only twenty ment of the entire with, at times, unequivocal cases reported in the previous 40 years involvement. They suggested that the and considered that the rarity of the syndrome and disease is commoner than previously considered and the poor results of treatment warranted reporting of therefore its recognition and therapy assume greater individual cases, particularly if they provided new significance; they noted that matters of aetiology, aetiological or therapeutic data. Although Schwartz clinical course and final prognosis remain speculative & Dale (1958) described a diffuse obliterative ductal at this stage. Involvement of the sclerosis in with intrahepatic ducts patients gall-stone disease, stenosing as in the case described by Klemperer (1937) and by http://pmj.bmj.com/ cholangitis involving only a short segment of the Shumarer (1958) is evidently exceedingly rare. common duct may occur and Baddeley & Stammers The disease is one of adult life, commonly in (1964) infer that such lesions may diffusely spread patients of middle-age, and men are affected more throughout the bile duct system. often than women. Glen & Witsell (1966) stipulate the following Manesie & Sullivan (1965) reviewed the literature criteria for making the diagnosis: progressive biliary between 1924 and 1964 and found only twenty cases obstruction, exclusion of surgical injury as a possible fulfilling the criteria. Wolubitsky & Mackenzie (1964) causative agent, operative demonstration of a diffuse found on review of the literature between 1924 and on September 29, 2021 by guest. sclerosing process involving the common duct, 1964, twenty-four acceptable cases out of 100 frequently the hepatic ducts and sometimes the gall reported and added four of their own. bladder, a fibrotic process and absence of malignant Warren, Athanassiades & Monge (1966) found the neoplasm requiring histological confirmation. records of forty-two patients at the Lahey Clinic and noted that twelve of these patients had associated Incidence ulcerative ; eleven patients had no history of The first case was reported by Delbet in 1924; gall stones or previous surgery, and there were no and the second 1 year later by Lafucade (1925). other associated diseases; a fourth group included Judd reported three patients in 1926 all of whom, four patients in whom severe periportal inflamma- tion preceded the sclerosing obliterative process. In Address for reprints: 7 Mossgiel Avenue, Ainsdale, South- one of these four patients suppuration also had port, Lancs. occurred. Clinical review 667 Postgrad Med J: first published as 10.1136/pgmj.47.552.666 on 1 October 1971. Downloaded from

Glen & Witsell (1966) reported seven patients sclerosing cholangitis clinically and in gross appear. under their care at the New York Hospital. Operative ance. findings were similar in all patients. The gall bladder in each patient exhibited some degree of fibrosis but Pathology calculi were present in only three. Enlargement of Great thickening of the wall of the involved duct lymph nodes along the common duct was fre- or ducts associated with marked luminal narrowing quently accompanied by oedema and fibrosis in the characterizes the lesion. In most cases the common region of Calot's triangle. The external diameter of duct lumen has been between 3 and 5 mm in diameter the common duct although not increased and even (Jackson & MacVey, 1962), it being possible to sometimes reduced was firm and thickened to palpa- insert a fine probe only into the lumen. The wall of tion in every patient. Narrowing of various portions the ducts may be up to eight times the normal of the biliary tree was demonstrated by operative thickness (Roberts, 1955) and on palpation the cholangiography in six of the seven patients. Radio- common duct is cord-like throughout. Lymph nodes logical visualization of the biliary system could not about the duct are usually enlarged and at times the be accomplished in the remaining patient because entire area is encased in dense adhesions (Schwartz almost complete obliteration of the lumen of the & Dale, 1958). The duct mucosa is normal, the duct common duct made introduction of the contrast thickening involving the sub-mucosa and sub-serosa agent impossible. Common duct exploration was in a diffuse fibrotic process with oedema inter- accomplished in five patients and in each was vening. Biopsy of the liver shows bile stasis and demonstrated either localized segmental or general periportal fibrosis. The diagnosis is made on the diffuse involvement of the ductal system. When the basis of findings at operation which may be of a lumen was narrowed there was a corresponding dense inflammatory reaction in the region of the increase in the thickness of the wall. The process was gall bladder and gastro-hepatic ligament. This may so marked in one patient that common duct explora- be so intense that demonstration of the common Protected by copyright. tion was not feasible. Biopsy of the common duct duct is difficult; its size is not diagnostic because this was performed on four patients: dense vascular represents the sum of the narrowed lumen and fibrous tissue was demonstrated in three of the thickened wall (Schwartz & Dale, 1958). Palpation biopsies, while the fourth showed only common duct of the common duct imparts the sensation of a cord- mucosa. like structure which may feel like a thrombosed blood vessel. When the wall of the common duct is Clinical picture incised the diagnosis should be clear; the wall is The usual clinical picture is one of slowly progres- obviously thickened, cuts with difficulty and the sive jaundice often associated with discomfort in the edges of the incision pout outwards. It is possible to or upper lumbar region. True biliary insert a fine probe only into the lumen. is unusual. The age range has been from 21-67 years, It is of interest that in all cases in which operative patients in the fourth and fifth decade being more cholangiograms were obtained, radio-opaque ma- common. The ratio of males to females has been terial was seen to enter the thus indicating about 3:1. Laboratory findings have invariably been that obstruction is not always complete. http://pmj.bmj.com/ those of obstructive jaundice. Symptoms of scleros- k Bartholomew et al (1963) say that essentially there ing cholangitis are indistinguishable from those is inflammatory fibrosis quite comparable to, if not associated with chronic gall-bladder disease, the identical with that seen in Riedel's struma. The most frequent sign being a slowly deepening jaundice histological similarity of Riedel's struma and idio- over a period of weeks or months. Hepatomegaly is pathic fibrous mediastinitis has been emphasized, not usual. A definitive diagnosis is established by and it seems logical to infer that Riedel's struma,

abdominal exploration, by X-ray and by histological idiopathic fibrous mediastinitis, sclerosing cho- on September 29, 2021 by guest. study of the biliary tree. langitis and retroperitoneal fibrosis represent a The disease results in chronic biliary obstruction basically similar pathological process occurring in followed by secondary biliary sclerosis, eventual different sites. and terminal coma. Less often portal According to Glen & Witsell (1966) the operative hypertension and bleeding oesophageal varices occur findings seem to vary with stages of the disease but as terminal events. It is associated in a significant the characteristic changes are located in the gall number of cases with chronic, moderately severe bladder and especially in the common duct. , often with stones, occasionally with Although the gall bladder is frequently calculus free, Riedel's struma and peri-ureteric fibrosis. It should stones are occasionally found. The wall of the gall not be confused with acute obstructive suppurative bladder is thickened and fibrotic, less markedly in cholangitis and should be differentiated from the region of the ampulla and cystic duct. Similar cholangiocarcinoma which simulates primary and usually more pronounced changes are present Postgrad Med J: first published as 10.1136/pgmj.47.552.666 on 1 October 1971. Downloaded from 668 Clinical review in the common duct. Instead of the soft, pliable, A hypersensitivity response has been postulated easily compressible structures which one normally by Schwartz & Dale (1958) since cortisone appears finds, the common duct in patients with this condi- to have a strikingly favourable therapeutic effect. tion is firm and rigid and rolls between the examining Cole (1958) has mentioned the possibility of the fingers like a pencil. Opening the common duct con- existence of a Schwartzman type reaction; Gold- firms the fact that the lumen has been reduced to a grabber & Kirsner (1960) have reported a case of point which frequently will hardly admit the ulcerative colitis with granulomatous smallest probe. This process may be localized or and fibrosing choledochitis and discussed the may involve the entire common duct and major possibility that a hypersensitivity reaction accounts portions of the intrahepatic biliary system. The use for these wide-spread tissue changes. of operative cholangiography is valuable in deter- Because, in the two cases reported by Bartholo- mining the extent of the disease process. Histological mew et al. (1963), there was eosinophilia with study of sections of the wall of the common duct associated fibrosing retroperitonitis (which is known and hepatic ducts both by frozen sections at the time to be frequently accompanied by eosinophilia) they of operation and by permanent sections later is also considered the role of an allergic or hyper- important, as it has been pointed out by Thorb- sensitivity reaction and diffuse disturbance of colla- jarnarson (1958) and Altmeir et al. (1957) that car- gen tissue in the pathogenesis of sclerosing cholan- cinoma of the can be a slow-growing gitis. lesion which produces symptoms clinically indis- In the series of patients reported by Warren et al. tinguishable from those of chronic sclerosing (1966) the disease existed by itself or in association cholangitis. Gross findings at operation are not with another disease such as ulcerative colitis, biliary diagnostic and interpretation of frozen sections from calculus disease or severe inflammation around the In of No exists to date for a causal this area is notoriously difficult. spite every porta hepatis. proof Protected by copyright. effort, carcinoma may not be recognized until per- relation between primary sclerosing cholangitis and manent sections are available, and occasionally the other associated diseases. However, the presence of correct diagnosis is not made until necropsy. ulcerative colitis in twelve patients in the series, Although the occasional patient may experience makes it possible that a causal relation exists between an apparent remission of the disease and enjoy a long the two conditions, and supports the view that low- asymptomatic interval, the long-term prognosis for grade bacterial infection, with the large bowel as the most patients is dismal, the usual clinical course source, reaching the biliary tract through the portal being gradual progressive biliary obstruction, circulation might be responsible for chronic inflam- deepening jaundice, physical wasting and finally mation of the biliary tract and consequent fibrosis death from biliary . and obliteration of the ducts. In support of this view, they quoted studies by Denien (1964), Brooks & Slaney (1958) and Schatten, Ouprez & Holden Aetiology (1955) concerned with the passage of bacteria from

In most instances, sclerosing cholangitis is idio- the large bowel to the biliary tract. According to http://pmj.bmj.com/ pathic or primary although some reporters have Popper & Szanto (1956) intrahepatic damage associ- described diffuse obliterative ductal sclerosis in ated with ulcerative colitis resulting in , patients with gall-stone disease (Schwartz & Dale, pericholangitis and periductal fibrosis develops as a 1958) the cause is essentially unknown. result of bacterial infection, and raises the possibility Ransom & Malcolm (1934) mentioned that an that the intrahepatic lesions in ulcerative colitis con- occasional patient with congenital stricturing of the stitute a different disease from primary sclerosing bile ducts might survive to adult life, but support for cholangitis or that the two may be simply stages of this is lacking. According to Ralston, syphilis might the same process. on September 29, 2021 by guest. give rise to a congenital stricture of the common bile Gravane, Bogetti & Iovine (1958) have suggested duct. that chronic sclerotic cholecystitis and chronic Biliary tract lithiasis, chronic sclerosing pan- relapsing may be manifestations of a creatitis and duct injury cannot be incriminated as localized collagen disease for which a course of causes. Viral infection has been considered but no steroid therapy would be justified. proof has been forthcoming. The involvement is not Although low-grade bacterial infection has been primarily mucosal so that chemical injury from bile considered, there has been no consistent demonstra- or pancreaticjuice seems unlikely. Bacterial infection tion or identification of an organism. has been dismissed as a primary factor by most Rolleston & Hayne (1901) and Mathew (1924) observers. Any infective agent occurring in associa- have suggested that some ofthe cases represented the tion with the disease would probably be carried by later results of congenital biliary stenosis due to the periductal lymphatics. during the intra-uterine state; Postgrad Med J: first published as 10.1136/pgmj.47.552.666 on 1 October 1971. Downloaded from Clinical review 669

however the appearance of manifestations of the With decompression of the biliary tract combined disease in middle and late years of life rules against with steroid therapy the prognosis of primary this concept. sclerosing cholangitis has improved strikingly in Primary hepatic disease cannot be implicated as an recent years, Schwartz & Dale (1958) for instance, aetiological factor as biopsy of the liver in these reporting only one fatality among their six patients. cases shows that the liver is involved secondarily with an obstructive biliary cirrhosis. Laboratory Acknowledgments tests of liver function do not always demonstrate I would like to acknowledge with thanks help given by hepato-cellular dysfunction and when abnormal they Professor K. Evans, Cardiff Royal Infirmary, for post- operative radiological studies, Dr Hunt, Royal Gwent have returned to normal rapidly after the biliary Hospital, for the histological sections and Mr R. Marshall obstruction has been relieved. and staff of the Department of Medical Illustration, Cardiff The possibility that an auto-immune process may Royal Infirmary, for the illustrations. be operating exists, and the occasional apparent favourable response of this condition to cortico- References steroids is consistent with auto-immunity being an ALTEMEIER, W.A., GALL, E.A., ZINNINGER, N.N. & Nox- WORTH, P.I. (1957) Sclerosing carcinoma of the major aetiological factor. intra-hepatic bile duct. Archives of Surgery, 75, 450. BADDELEY, R.M. & STAMMERS, F.A.R. (1964) Benign, non- Treatment traumatic stricture of the extra-hepatic bile duct. British As the cause of chronic sclerosing cholangitis Journal of Surgery, 59, 25. remains unknown, treatment is ofnecessity empirical. BARTHOLOMEW, L.G., CAIN, J.C., WOOLNER, L.B., UTZ, D.C. Operation is necessary to establish the diagnosis by & RERRis, D.O. (1963) Sclerosing cholangitis; its possible surgical exploration; biliary calculi when found must association with Riedel's stroma and fibrous retroperi- be removed but the gall bladder should be left intact tonitis; report of two cases. New England Journal ofMedi- as it may be invaluable later for biliary diverting cine, 269, 8. Protected by copyright. procedures. Should it be CARTER, R.F. & GILLETTE, L. (1918) Benign stricture of the possible to insert a T-tube intra-hepatic biliary ducts. Surgery, Gynecology and into the common bile duct, this should be done to Obstetrics, 26, 81. decompress the biliary tract but in most cases the COLE, W.H. (1958) Discussion of paper of Schwartz & Dale. lumen of the common bile duct will not permit DELBET, P. (1924) Retrecissement du choledoque: chole- intubation. Where communication of the bile-duct cysto-duodenostomie. Bulletin et menmoires de la Societe system permits, decompression of the biliary tract de Meddcine de Paris, 50, 1144. can be affected by cholecystostomy for prolonged GLENN, F. & WHITSELL, J.C. (1966) Primary sclerosing drainage. Operative cholangiography at the time of cholangitis. Surgery Gynecology and Obstetrics, 123, surgical exploration is advisable in order to confirm 1037. GOLDGRABER, M.B. & KIRSNER, J.B. (1960) Chronic granulo- the suspected diagnosis. matous cholecystitis and chronic ulcerative colitis. Gastro- Drugs such as dehydrocholic acid (Decolen) 250 enterology, 38, 821. mg three times daily, can be used to increase the GRAVANO, L., BOGETTI, H. & IOVINE, J.R. (1958) Colangitis fluidity of the bile and therefore facilitate flow. A cronica estenosante, pancreatitis cronica recidivante: http://pmj.bmj.com/ broad spectrum antibiotic such as tetracycline which expression de una colangenosis localizada. Prensa medica achieves high levels in the bile may be added to the argentinia, 45, 1613. postoperative treatment to HOLUBITSKY, M.D. & MCKENZIE, A.D. (1964) Primary protect against secondary sclerosing cholangitis and of the extrahepatic bile ducts. bacterial cholangitis. The administration of cortico- Canadian Journal of Surgery, 7, 277. steroids is indicated, the drugs acting in two ways; JUDD, E.S. (1926) Stricture of the common bile duct. Annals firstly as anti-inflammatory agents having a direct of Surgery, 84, 404. action on the disease process leading to decrease in KLEMPERER, P. (1937) Chronic intrahepatic obliterating the thickness of the walls of the bile ducts and an cholangiolis. Journal of the Mount Sinai Hospital, 4, 279. on September 29, 2021 by guest. increase in the lumen; secondly, decreasing the LAFOURCADE, J. (1925) Beux observations D'obliteration bilirubinaemia by a direct action. Administration of cicatricielle de choledoque. Bulletin et memoires de la cortisone 100-300 Societe' de Mid6cine de Paris, 50, 828. mg daily is initiated promptly in MANESIS, J.G. & SULLIVAN, J.F. (1965) Primary sclerosing the postoperative period changing to prednisone cholangitis. Archives of Internal Medicine, 115, 137. 40-50 mg daily for long-term use. POPPER, H. & SZANTO, P.B. (1956) Intrahepatic cholestasis Corticosteroid treatment should be continued for (cholangiolitis). , 31, 683. several months and re-introduced should recurrence ROBERTS, J.M. (1955) Stenosing cholangitis. Western Journal of symptoms and/or jaundice take place. Sodium of Surgery, 63, 253. dehydrocholate may be given intravenously for ROLLESTON, H.D. & HAYNE, L.B. (1901) The care ofcongeni- several days to increase the fluidity of the bile and tal hepatic cirrhosis with obliterative cholangitis. British later by Medical Journal, 1, 758. mouth in tablets of 0-25 g and one or two ROLLESTON, H. & MCNEE, J.W. (1929) Disease of Liver, tablets after meals. Gall-bladder and Bile Ducts. Macmillan, London. Postgrad Med J: first published as 10.1136/pgmj.47.552.666 on 1 October 1971. Downloaded from 670 Clinical review

RANSOM, H.K. & MALCOLM, K.D. (1934) Obstructive jaun- SCHATTEN, W.E., DESPREZ, J.D. & HOLDEN, W.D. (1955) dice due to diffuse contracture of extra-hepatic bile ducts. Bacteriological study of portal-vein blood in man. Archives Archives of Surgery, 28, 713. of Surgery, 61, 404. SCHWARTZ, S.I. & DALE, W.A. (1958) Primary sclerosing THORBJARNARSON, B. (1958) Carcinoma of the intra-hepatic cholangitis: review and report of six cases. Archives of bile ducts. Archives of Surgery, 77, 908. Surgery, 77, 439. WARREN, K.W., ATHANASSIADES, S. & MONGE, J.I. (1966) HUMARER, W.B. (1958) Discussion of paper of Schwartz & Primary sclerosing cholangitis. American Journal of Dale. Surgery, 3, 23. Protected by copyright. http://pmj.bmj.com/ on September 29, 2021 by guest.