Primary sclerosing cholangitis

Primary

Sclerosing

Cholangitis

A Study of Forty-Two KENNETH

W.

M.D., Boston, Massachusetts, SOCRATES ATHANASSIADES, Athens, Greece, AND JUAN I. MONGE, M.D.,Santiago, Chile

WARREN,

sc~~R0s1NG CHOLANGITIS is a rare disease characterized by total or partial involvement of the extrahepatic biliary ducts. It often _ involves the intrahepatic biliary radicles by a progressive inflammatory sclerosing and obliterative process, which results in chronic biliary obstruction followed by secondary biliary cirrhosis and eventually liver failure and coma. Less often portal hypertension and bleeding esophageal varices occur as terminal events. Primary sclerosing cholangitis is associated in a large number of cases with chronic, moderately severe ulcerative colitis, often with gallwith severe periportal stones, occasionally inflammation or suppuration, and rarely with Riedel’s struma and fibrous retroperitonitis. It exists many times without any apparent associated intra-abdominal or general disease. It should not be confused with acute obstructive suppurative cholangitis and should be carefully differentiated from cholangiocarcinoma which simulates primary sclerosing cholangitis clinically and in gross appearance. Many names have been used for this disease but we prefer the term primary sclerosing cholangitis. The wide variation in the pathologic features of the disease invites a wide choice of appellation. The first well documented case was reported by Delbet [I] in 1924, and one year later a second case was reported by Lafourcade [2]. In the English literature Judd [3] first wrote about “obliterative cholangitis” in 1926 and reported on three patients, all of whom had had previous biliary surgery. He claimed that the long interRIMARY

Vol. 111, January

1966

M.D.,

val between previous cholecystectomy and the appearance of cholangitis, thirteen years in one patient, suggests that the pathologic findings in these patients were not the result of traumatic strictures. In 1927 Miller [P] reported the first well documented case in the English literature. Manesis and Sullivan [5 ] reviewed the literature during the forty year period from 1924 to 1964 and found only twenty cases fulfilling their criteria; in about the same period of time, however, Holubitsky and McKenzie [6] found twenty-five acceptable cases of 100 reported and added four of their own. The criteria considered essential by several authors for inclusion in this group are: (1) absence of previous biliary surgery; (2) absence of gallstones; (3) diffuse generalized involvement of the extrahepatic biliary ducts ; (4) exclusion of cholangiocarcinoma by reasonably long follow-up study. It is obvious that many cases of primary sclerosing cholangitis will be excluded from this group by applying the first three criteria indiscriminately. In reviewing the records of the Lahey Clinic Foundation we found forty-two patients who had a diagnosis of primary sclerosing cholangitis. A number of these patients had biopsies of the biliary ducts; however, since there is nothing specific in the microscopic appearance of the inflammatory process present in primary sclerosing cholangitis, the decision to include a case in this group was made on the basis of the history and the description of the gross pathologic appearance of the biliary ducts found in the operative notes. It is interesting that twelve of these patients had associated ulcerative colitis. A second group of eleven patients had no history of gall-

From the Department of Surgery, Lahey Clinic Foundation, Boston, Massachusetts.

P

Cases

23

24

Warren, Athanassiades, and Monge TABLE SEX

Group A (12 Patients)

Data

AGE

Group C (15 Patients)

Group D (4 Patients)

Total (42 Patients)

6 6

7 4

5 10

4 0

22 20

0 10 2

0 3 8

0 5 10

0 0 4

0 18 24

stones or previous surgery, or if surgery had been performed, the diagnosis of primary sclerosing cholangitis was made at the first operation, and there were no other associated diseases. A third group of titeen patients had either a history of gallstones or previous biliary surgery, or both, but no other associated disease. The fourth group included four patients in whom severe periportal inflammation preceded the sclerosing obliterative process. In one of these four patients suppuration also occurred. Because of these distinctive characteristics we thought it appropriate to present these cases by dividing them into the four above-mentioned groups. CLINICAL

I

DISTRIBUTION

Group B (11 Patients)

Sex:

Males Females Age: O-19 2040 Over 40

AND

MATERIAL

Group A. These twelve patients had had ulcerative colitis several years before the appearance of biliary symptoms. The majority (83 per cent) had a moderately severe type of ulcerative colitis usually under good control with medical treatment. In ten patients the interval between onset of ulcerative colitis and development of biliary symptoms varied from three to twenty-five years, with an average of twelve years. In one patient symptoms of ulcerative colitis preceded the appearance of jaundice by only two weeks, and in a second patient jaundice preceded the appearance of symptoms of ulcerative colitis by three years. The majority of the patients in this group were between twenty and forty years of age, in the usual age distribution of ulcerative colitis. (Table I.) Pain, associated with the attacks, was present intermittently in nine patients. Usually it was located in the right upper quadrant and less often in the epigastrium. Nausea and vomiting were present in half of the patients.

All twelve patients had had jaundice whit was intermittent in two-thirds and constant i the others. It was associated with. pruritus i eleven patients. Chills and fever occurring E variable times in nine patients completed th clinical picture of biliary obstruction. Anorexia, malaise, and fatigability wer present in all patients, and eight had lo: weight, three over 20 pounds. No history c hematemesis, diabetes mellitus, or alcoholisr was present in this group. (Table II.) The duration of biliary symp&oms ‘befo7 examination of these patients varied from 14 than one month to over ten years, with fi patients having symptoms for less than o year, five patients for one to five years, a two for more than five years. One patient h had an operation for common dud stones a three others for both gallstones and comn duct stones. However, in two of them the di nosis of primary sclerosing chhgitis \ made at the first operation, thus favoring ’ hypothesis that cholelithiasis developed : cause of chronic biliary obstruction, bile sta: and infection accompanying the prim: sclerosing cholangitis. In the other two information was available about the con&it: of the bile ducts at the first operation. ~i.ai III.)

When first examined at the Lahey Ci’ ;ic I of these patients were jaundiced; in fc lr 1 tients only the liver was palpable, and in additional four both the liver and spleen WF palpable. Tenderness in the right upper qm rant was present in about 42 per cent. T\ patients had a T tube in place. (Table IV.) At operation eleven patients wae found have a diffuse sclerosing and stenting proce involving all the extrahepatic bilia%y ducts; one patient this was limited to t& left, rig! American

J-d

of SW,

Y

Primary

Sclerosing

Cholangitis

25

TABLE II SXGNSAND SYMPTOMS Group A (12 Patients)

History

Group B (11 Patients)

Group C (15 Patients)

Group D (4 Patients)

Total (42 Patients)

Pain (intermittent)

9

6

14

3

32

Location of pain Bight upper quadrant Epigastric

7 2

1 5

13 1

2 1

23 9

11

9

10

2

32

Nausea and vomiting

5

5

11

2

23

Nausea alone

1

2

0

1

Jaundice Intermittent Constant

12 8 4

11 6 5

15 15 0

Pruritus

Anorexia, malaise, andifatigability

3” 1

4 42 32 10

11

7

5

2

Chills and fever

7

4

9

1

25 21

Weight loss (pounds) O-9 lo-20 Over 20

8

9 2 3 4

10 1 2 7

2 1 0 1

29 9 5 15

Hematemesis

0

1

0

0

1

Diabetes mellitus

0

1

1

0

2

0

0

0

0

0

12

0

0

0

12

: 3

Alcoholism Ulcerative colitis

TABLE III DURATIONOF BILIARY SYMPTOMSAND PRESENCEOF GALLSTONES

History

Group A (12 Patients)

Group B ( 11 Patients)

Duration of symptoms: Less than 1 mo. l-3 mo. 4-6 mo. 7-12 mo. 12-24 mo. 2-5 yr. 5-10 yr. Over 10 yr. History of gallstones or stones found at operation: Gallstones Common duct stones Both gallbladder and common duct stones

January 1966

Group D (4 Patients)

Total (42 Patients)

0 2 2 2 1 3 1 0

6 6 12 6 4

0 1

0 0

8 1

3

0

11

and common hepatic ducts. The severity of this process varied. In eight patients with complete or almost complete obstruction of the ducts and with marked induration and thickening of the ductal wall up to 0.5 cm., fine probes only could be admitted. In four patients with less severe nduration and thickening of the wall, the ‘01.III.

Group C ( 15 Patients)

1

3

ductal lumen was decreased to the point where only the smallest Bakes dilator could be passed with difficulty. Common duct stones were found in three patients. No gallstones were found in the gallbladder, and the pathologic examination of eight gallbladder specimens showed only chronic

26

Warren, Athanassiades, and Monge TABLE IV FINDINGSAT PHYSICALEXAMINATION Group A (12 Patients)

Jaundice Tenderness in right upper quadrant Only liver palpable Both liver and spleen palpable T tube in place External biliary fistula Chills and fever

Group B (11 Patients)

10 5 4 4 2 0 0

Group C (15 Patients)

10 4 7 3 1 1 1

Group D (4 Patients)

7 10 10 0 1 1 2

31 1 2 1 0 1

Total (42 Patients)

2”:: 22 9 5 2 4

TABLE v OPERATIVEE FINDINGS

Operative Findings

Sclerosing process involving: All extrahepatic ducts Left, right, and common hepatic ducts Entire common duct Proximal common duct Distal common duct Left and right hepatic ducts Left, right, and common hepatic ducts plus proximal common duct Involvement : Severe: duct admitted only probes Moderately severe: duct admitted small dilator with difficulty Gallstones: Gallbladder Common duct Gallbladder and common duct Liver enlarged Spleen enlarged Portal hypertension Enlarged lymph nodes around bile ducts

Group A (12 Patients)

Group B (11 Patients)

11

Group C

Group D

Total

(15 Patients)

(4 Patients)

(42 Patients)

9

4

30

0 0 0 0

5 2 1 2 1

2 0 0 2 1

.o

0

0

1

0

1

8

6

5’

4

23

4

5

10

19

0

3 0 11

0 0 0 10

4 3

3 3

2 1 1 8 (1 small) 2 3

2 4 1 32 (1 small) 11 10

8

6

2

16

cholecystitis. In the operative notes the bile was described as thick, dark, or inspissated, but in no case was pus drained from the bile ducts. The liver was enlarged in eleven patients and the spleen in four. In three patients portal hypertension was manifested by the presence of dilated veins and profuse venous bleeding during the operation, but in no case was ascitic fluid found. Enlarged lymph nodes in the periportal area were encountered in eight patients. (Table v.) After the diagnosis was established at operation on the basis of the gross appear-

ante of the bile duct, little else could be done surgically except decompression of the biliauy system. This was accomplished by chokdochostomy in fourteen of seventeen biliary procedures, combined with cholecystectomy in eight, and sphincterotomy in two. Because of recurrence of symptoms months after the original cholecystectomy and choledoch&y and because of severe involvement of the c&&al duct, hepaticojejunostomy was performed in one patient. This patient needed two man operative procedures for revision of the haputic;?oAmerican Jourltal ej w

27

Primary Sclerosing Cholangitis TABLEVI TYPE OF

OPERATION

Operation

Group A

Cholecystostomy Cholecystectomy Cholecystectomy, common duct exploration, and choledochostomy Common duct exploration and choledochostomy Common duct exploration, choledochostomy, and sphincterotomy Cholecystojejunostomy Hepaticojejunostomy plus jejunojejunostomy Revision of hepaticojejunojejunostomy Cholecystectomy, choledochojejunostomy, and jejunojejunostomy Common duct exploration and choledochostomy pluscholecystojejunostomy and jejunojejunostomy Common duct exploration and insertion of Y tube Transduodenal exploration of common duct Cholecystectomy, common duct exploration, cholecystostomy plus duodenostomy, and closure of perforated duodenal ulcer Exploratory laparotomy and common duct biopsy Exploratory laparotomy Excision of echinococcus cvst of left lobe of liver External drainage of pancreatic pseudocyst Hemigastrectomy and vagotomy Ileostomy Subtotal colectomy Right colectomy Total colectomy in 2 stages Total colectoms in 3 stages Total number if opera&s Total number of biliarv ooerations Total number of opera&ok other than bilisry ink-abdominal operations

* Two duodenal

patients who had cholecystectomy ulcer (one) at the same opera&n.

OR OTHER

FOR BILIARY

Previous Operations------? Group Group Group B C D

1966

Total

OBSTRUCTION

-------Operations Group Group A B

at Lahey Clinic--Group Group D Total C

0 2

2 0

2 9

0 2

4 13

0 0

0 0

0 0

0 0

3

2

3

1

9

8

2

0

26

5

0

9

1

15

4

14

4

26

1 3

0 1

1 0

k

3 4

2 0

1 0

0 0

3 0

0 0

0 0

0 0

0 0

0 0

1 1

1 0

0 0

4 1

0

0

0

0

0

0

1

0

2

0

0

0

0

0

0

1

0

0

1

0

0

0

0

.O

0

0

1

0

1

0

0

1

0

1

0

0

0

0

0

0

0

0

0

0

0

0

0

1

1

0 0

1 1

0 1

0 2

1 4

0 0

8

0 0

0 0

8

0

0

0

1

1

0

0

0

0

0

0 0 1 1 1 0 0 16* 14

0 0 0 0 0 0 0 7 7

0 1 0 0 0 0 0 27 25

1 0 0 0 0 0 0 9 8

1 1 1 1 : 0 0 0

0 0 1 1 0 2 1 26 17

0 0 0 0 0 0 0 14 14

: 0 0 0 0 0 20 20

3

0

1

1

0

9

0

0

and common

duct

jejunostomy with removal of stones in one of them. (Table VI.) Either because of the severity of the ulcerative colitis or as an attempt at amelioration of the biliary disease, five patients had nine operative procedures on the colon. One patient had a three stage total colectomy, two had two stage total colectomy, one had subtotal colectomy, and one an ileostomy. There were two operative deaths in this group. One patient died from hepatorenal failure on the fifth postoperative day, with pulmonary edema as the terminal event. Another died on the fourth postoperative day from massive upper gastrointestinal bleeding, but no source of bleeding could be found at autopsy. No significant hepatobiliary complications Vol. 111, Januavy

INTRAHEPATIC

exploration

also had right

colectomy

(one)

and closure

0 1 1 1 0 2 1 8 2

0

of perforated

occurred immediately after operation except in one patient who became lethargic with deepening jaundice, but who gradually improved with medical treatment. Chills and fever developed in two patients in the immediate postoperative period. Other complications were wound infection in one patient and peritonitis with pelvic abscess secondary to perforation of the colon and wound infection in another. The follow-up period was complete, ranging from 18 to 207 months, with an average of 53 months. In nine patients secondary biliary cirrhosis developed, ascertained by liver examination at autopsy, liver biopsy, liver function tests, or clinical signs and symptoms. Portal hypertension developed in four of these nine patients, and one of the four had bleeding

28

Warren, Athanassiades, TABLE OPERATIVE

Results

Operative deaths Late complications: Biliary cirrhosis Portal hypertension Bleeding esophageal varices Follow-up results : Excellent Good Poor Death : Related to disease Unrelated to disease Length of follow-up study (average)

DEATHS,

Group A (12 Patients)

LATE

VII

COMPLICATIONS,

Group B (11 Patients)

2

and Monge AND FOLLOW-UP

Group C (15 Patients)

STUDY

Group D (4 Patients)

0

2

0

3 1 1 1 lost to follow-up 5 4 6*

2 1 0 Complete

2 0 10

6 3 1 1 lost to follow-up 3 0 7

5 1

4 2 69 mo.

9 4 1 Complete

53 mo.

* One natient with a poor result when last seen had follow-up lost to foiiow-up study.

from esophageal varices for which a splenorenal shunt was performed successfully elsewhere. Two patients obtained an excellent result, but in ten patients the result was poor. Four of them are alive with jaundice and six are dead. The cause of death in five of the six patients was related to the hepatobiliary disease, and the sixth patient, still with jaundice, and having a twenty-five year history of ulcerative colitis, died from a colonic carcinoma, with disseminated metastases. (Table VII.) Of the two patients who had excellent results, one had had ulcerative colitis for ten years and biliary symptoms for six months, and the other had had ulcerative colitis for twenty years and biliary symptoms for four to five years before colectomy was performed, effecting cures in both. However, total colectomy performed in three other patients, in one of whom it was carried out soon after the onset of biliary symptoms, failed to control the progress of the biliary disease, although there was some evidence of improvement in one of them. This patient had to have two additional operations for stenosis of the hepaticojejunostomy one and two years after the colectomy, and at the last operation it was the surgeon’s opinion that the biliary ducts looked less inflamed and thickened and the lumen more patent. Colectomy was performed on this patient ten years after the onset of biliary symptoms. The second patient had a

Total (42 Patients) 4

1 1 2

20 9 3 2 lost to follow-up 11 5 25

2 1

1 0

12 4

48 mo.

49 mo.

studies for only six months and is thus counted

twenty year history of ulcerative colitis and biliary symptoms for only a few months before undergoing subtotal colectomy. The rectosigmoid was removed five years later. The third patient had a thirty-two year history of ulcerative colitis and biliary symptoms for seven years before ileostomy was performed, followed by total colectomy one year later. Ileostomy was performed in another patient as a first step for a total colectomy because of her poor general condition, without any change in the patient’s biliary symptoms. If we exclude the two operative deaths and the patient who died from colonic carcinoma, the interval between the onset of biliary symptoms and death was seven, six, and two and a half years, respectively, in the three other patients who died. Biopsies taken of the liver in seven patients, of the common duct in two, and of the periportal lymph nodes in three, eight gallbladder specimens, and three colon specimens were used for microscopic study. Of the seven liver biopsies, biliary cirrhosis was demonstrated in one, bile stasis in five (two of them with chronic periportal inflammation and fibrosis), and bile stasis with subacute hepatitis in another. One common duct biopsy revealed acute and chronic inflammation and fibrosis and the other, chronic inflammation. Of the three lymph node biopsies, one showed chronic inflammation and

Primary Sclerosing Cholangitis hyperplasia and the other two were hyperplastic lymph nodes. All eight gallbladder specimens demonstrated chronic cholecystitis, and all three colon specimens showed chronic ulcerative colitis. Bile cultured from seven patients demonstrated several organisms in varying combinations. Aerobacter aerogenes and Escherichia coli were cultured from three patients, Pseudomonas aeruginosa and Proteus from two, and enterococci and alpha hemolytic streptocorci from one. The white blood cell count recorded on admission was within normal limits in six of nine cases and was between 10,000 and 20,000 per cu. mm. in the three other patients. The sedimentation rate was over 50 mm. per hour in all four patients in whom it was recorded. The bilirubin level was increased in ten patients, above 10 mg. per cent in seven, and the alkaline phosphatase was increased in all eleven patients in whom it was recorded, being more than 20 Bodansky units in eight patients. Transaminase, checked in only two patients, was 118 and 262 units. Liver function tests performed in eleven patients were equivocal in two and abnormal in five, while of the four patients in whom the results of liver tests were normal on first admission, abnormalities had developed in two patients on admission one and two years later. Hemoglobin was found to be above 12.5 gm. per cent in four patients and below 12.5 gm. per cent in eight patients, and the fasting blood sugar was within normal limits in all twelve. The x-ray findings are usually characteristic; however, because of the impaired liver function, intravenous cholangiograms are not successful, and in no case was percutaneous cholangiography attempted. Five patients had operative and postoperative T tube cholangiograms which showed diffuse narrowing of the intrahepatic radicles in four patients and a markedly narrowed common duct with a thread-like channel into the duodenum in one patient. Group B. In the eleven patients included in this group, the prominent characteristics were absence of gallstones, ulcerative colitis or other intra-abdominal or general disease, and no history of previous biliary surgery. If a surgical procedure had been performed, the diagnosis of primary sclerosing cholangitis was established at the first operation. The majority were male patients and over Vol,lIl,

January 1966

29

forty years of age, differing from group A in which the majority were younger. (Table I.) Pain in six patients was present intermittently, usually coincidental with the attacks. It was located in the epigastrium in five and right upper quadrant in one patient. Nausea and vomiting were present in five patients, while two complained only of nausea. All eleven patients had a history of jaundice which was intermittent in six and constant in five. Seven patients had pruritus. Chills and fever were present in four patients. Nine patients had had anorexia, malaise, easy fatigability, and also weight loss, seven having lost more than 10 pounds and four more than 20 pounds. There was no history of alcoholism in this group of patients; only one patient had diabetes mellitus and another had had hematemesis. (Table II.) The duration of biliary symptoms varied from one month to several years, with six patients having had biliary symptoms for less than one year, four patients from one to five years, and one patient more than five years. There was no history of cholelithiasis or ulcerative colitis in any patient. (Table III.) When examined at the Lahey Clinic ten of these patients had jaundice. Tenderness in the right upper quadrant was present in four, the liver was palpable in seven, and both the liver and spleen were palpable in three. One patient had a T tube in place and another had an external biliary fistula which had been present since the removal of the T tube. One patient was febrile on admission. (Table IV.) Five of these patients had had one operation, and one patient had had two previous operations because of biliary symptoms; however, in no case were stones found in the gallbladder or common duct, and the diagnosis of primary sclerosing cholangitis was established by either biopsy or the characteristic macroscopic appearance of the biliary ducts in each of the previous operations. The first biliary procedure was performed at the Lahey Clinic in the remaining five patients in this group. At the Lahey Clinic, fourteen surgical procedures were performed on these patients. Nine patients had one operation, one had two, and one had three operations. Decompression of the biliary system was accomplished in these fourteen procedures by external drainage in ten and by internal drainage in four, and was combined with cholecystectomy in seven. (Table VI.)

30

Warren,

Athanassiades,

At operation six patients were found to have a sclerosing and stenosing process involving all the extrahepatic ducts, and five had only partial involvement of the ducts. Two had involvement of the left, right, and common hepatic ducts; in two the process involved only the common duct, and in one the common duct was involved only in its proximal extrapancreatic segment, as was judged by the fact that dilators entered the duodenum easily once they had passed the proximal stenosed area. Using the same criteria to judge the severity of involvement in this group, as was done in group A, six patients had severe involvement, that is, thickening of the ductal wall and narrowing of the lumen, so that only fine probes could be admitted, and five patients had moderately severe involvement, that is, admission of the smallest Bakes dilators with difficulty. Stones werenot found in either the gallbladder or the common duct in any of these patients. The liver was enlarged in ten patients and the spleen in three. The presence of portal hypertension was indicated by dilated veins and profuse venous bleeding during the operation in three patients, and in six patients enlarged lymph nodes were found in the periportal area. (Table v.) There were no operative deaths in this group of patients and no early hepatobiliary or general complication except for melena which developed in one patient in the postoperative period from an undetermined source and for which transfusions were needed. Ten patients had follow-up periods ranging from 18 to 122 months, with an average length of 69 months. One patient, examined four months after operation, was well but subsequently was lost to follow-up study. Of the ten patients who had follow-up studies for long periods of time, biliary cirrhosis ultimately developed in six, three had portal hypertension, one had bleeding varices. Three patients obtained an excellent result without further attacks. Seven had a poor result; four of these are dead, and three are alive but have symptoms of the disease. Six patients have’ died; two patients free of biliary symptoms died from unrelated causes and in the previously mentioned four cases the death was directly attributed to the biliary disease. One patient died from bleeding esophageal varices and two from advanced biliary cirrhosis, with ascites and hydrothorax in one. In the fourth

and Monge

patient, who had severe hepatic cirrhosis, an abscess of the left lobe of the liver developed six months after operation at the clinic. Rupture of this abscess led to the development of a subdiaphragmatic abscess with necrosis of the diaphragm, empyema, and death. (Table VII.) The length of time between onset of biliary symptoms and death in these four patients was sixteen, five, five, and four years, respectively. Liver biopsies were performed on seven patients. One showed intracanalicular bile stasis, five intracanalicular bile stasis, chronic pericholangitis, and portal fibrosis, and one intracanalicular bile stasis and chronic interstitial hepatitis. All four biopsies of the common duct revealed chronic inflammation and fibrosis, with granulation tissue in two. Four of the five lymph nodes examined were hyperplastic, and one was normal. All six gallbladder specimens showed chronic cholecystitis. The white blood cell count taken on admission in eight patients was normal in all. The sedimentation rate in three patients was normal in one and abnormal in two (47 and 82 mm. per hour). The bilirubin level was increased in ten patients, above 10 mg. per cent in five, and the alkaline phosphatase level was increased above 10 Bodansky units in all eight recorded and above 20 Bodansky units in two. The transaminase, tested in only three patients, was 56, 155, and 172 units. Results of the liver function tests on ten patients at admission were normal in five, equivocal in four, and abnormal in one. Two patients, one with normal and the other with slightly disturbed tests on first admission, were found to have abnormal test results on subsequent admissions one year later. Hemoglobin was above 12.5 gm. per cent in four and below 12.5 gm. per cent in seven, and one patient was found to have diabetes mellitus. Only one bacteriologic study of the bile was made and this gave negative results. T tube cholangiograms performed in six patients showed narrowing of the extrahepatic ducts, extending to the intrahepatic radicles in three of them. Group C. In this group, a controversial one perhaps, we have included those patients with no history of ulcerative colitis or other intraabdominal inflammatory or general disease, but with a positive history of gallstones, previous surgery, or both. In these patients stricture of the ducts secAmerican

Journal of Surgery

Primary Sclerosing Cholangitis ondary to gallstones or injury at the time of previous surgery is a possibility. It should be remembered, however, that the extent of stricture secondary to gallstones is much less than that seen in primary sclerosing cholangitis. In addition, symptoms of bile duct injuries appear within a few days or weeks from the time of injury, and in most of these patients an interval of several years elapsed between previous biliary surgery and onset of biliary symptoms attributed to primary sclerosing cholangitis. Of these fifteen patients, ten were female and ten were more than forty years old, following the age and sex distribution of biliary calculous disease. (Table I.) Fourteen patients had had intermittent pain in the right upper quadrant, which was associated with nausea and vomiting in eleven. All fifteen had had intermittent jaundice, with pruritus in five. Chills and fever accompanied the attacks in nine patients, and ten had lost weight, seven more than 20 pounds. Anorexia, malaise, and fatigability were present to some degree in ten patients. One patient had diabetes mellitus, but none of the patients had had ulcerative colitis, alcoholism, or hematemesis. (Table II.) The duration of biliary symptoms was much longer than in groups A and B. While about one-half the patients in groups A and B had had symptoms for less than one year, only two patients in group C had such a short history. Six patients had symptoms for one to five years, seven for more than five years, and three for more than ten years. A probable explanation of this difference is that in the majority of these patients gallstones had been found at previous operation, leaving no doubt in the surgeon’s mind about the pathologic changes behind the symptoms of biliary obstruction. In contrast, the absence of gallstones in groups A and B made the surgeon suspicious as to the cause of the biliary symptoms, and the patient was referred soon for further study and treatment. (Table III.) On admission seven of these patients had jaundice, ten had tenderness in the right upper quadrant, ten had a palpable liver, and one had chills and fever. One patient had a T tube in place and another had an external biliary fistula. (Table IV.) A total of twenty-five biliary operations had been performed in twelve of these patients before being admitted to the Vol. 111, January

1966

31

Lahey Clinic. Three patients had not had a previous operation, but all had had gallstones demonstrated by cholecystograms. It is not known whether gallstones were found at each of the twenty-five previous biliary procedures; however, four of these twelve patients had gallstones, seven had stones in both the gallbladder and common duct, and one patient, who had had two previous biliary operations, was found to have no gallstones. These fifteen patients had a total of twenty biliary operations at the Lahey Clinic, seventeen of which were external drainage procedures, and three internal drainage, combined with cholecystectomy in three patients. (Table VI.) At operation, nine patients were found to have a sclerosing process involving all the extrahepatic ducts, while six patients had only partial involvement of the ducts. Two of these six had involvement of the left, right, and common hepatic ducts; one only the left and right hepatic ducts; one the left, right, common hepatic, and proximal common duct with dilators passing easily into the duodenum; and the last two had narrowing of the distal common duct only without even the smallest dilator passing into the duodenum and without evident disease of the head of the pancreas to account for the obstruction. Five patients had severe involvement of the ducts with marked thickening of the wall and narrowing of the lumen to complete obstruction or to admission of fine probes only. Ten patients had less severe thickening and narrowing of the lumen so that the smallest dilators could be passed, but only with difficulty. Gallstones were found in two patients; one patient had stones in both the gallbladder and common duct and one had common duct stones, an incidence similar to that found in group A. The liver was very small in an advanced stage of cirrhosis in one patient and enlarged in eight, and the spleen was enlarged in two patients. Three patients had evidence of portal hypertension. Only in two patients was mention made in the operative notes of the presence of enlarged periportal lymph nodes in contrast to eight of twelve in group A and six of eleven in group B. Whether this difference in the incidence of enlarged periportal lymph nodes is indicative of a lesser degree of infection in this group is difficult to determine. (Table v.) Two patients died from upper gastrointestinal bleeding on the second and ninth postop-

32

Warren, Athanassiades,

erative days, respectively. The source of bleeding was found to be ruptured esophageal and gastric varices in one patient and probably ruptured esophageal varices in the other also. Follow-up study was complete in fourteen patients, ranging from 13 to 120 months with an average length of 48 months. One patient who was seen five months postoperatively in poor condition with recurrent symptoms was subsequently lost to follow-up study. Five patients in this group had an excellent result with no further attacks. However, we performed three operations on one of these before he became completely free of symptoms. Three of these five patients had partial and two had widespread involvement of the extrahepatic ducts. Four patients having only occasional mild attacks of cholangitis were classified as having a good result, and in six patients the result was considered poor because of recurrent symptoms in four and because of death related to biliary disease in two. Three patients died, two in the immediate postoperative period because of the disease, and one patient who was free of biliary symptoms for fifty-nine months died from an unrelated cause. (Table VII.) Elevated white blood cell count was found in two of twelve patients tested on admission, and the sedimentation rate was increased to more than 40 mm. per hour in four patients in whom this test was carried out. The bilirubin was within normal limits in eight patients and abnormal in seven, being over 10 mg. per cent in two patients. The alkaline phosphatase level was increased in nine of ten patients in whom it was determined; it was more than 10 Bodansky units in six patients and more than 20 Bodansky units in two patients. The transaminase level was determined in three patients and was found to be 59, 120, and 128 units. Hemoglobin was more than 12.5 gm. per cent in eight and less than 10 gm. per cent in one. Blood sugar level was abnormal in one patient. The results of liver function tests performed in eleven patients were normal in five, equivocal in four, and abnormal in two. Bacteriologic study of bile in seven patients was positive in six with varying combinations of E. coli, cultured four times, Paracolobactrum, Proteus, Streptococcus hemolyticus, A. aerogenes, cultured twice, and enterococci,

and Monge

Streptococcus faecalis and gram-positive cocci, cultured once. Operative and postoperative T tube cholangiograms in six patients showed generalized narrowing in three and narrowing of the distal common duct in the other three. The intrahepatic radicles were described as slightly dilated in one and slightly narrowed in another. Group D. This group consisted of four men, all over forty years of age, who had had severe inflammation around the portal area. One patient without cholelithiasis had a perforated, sealed-off duodenal ulcer. He was not operated on at the time of perforation but he had had two exploratory laparotomies and liver biopsies because of jaundice. More than a year after the perforation he was treated at the Lahey Clinic by cholecystectomy, common duct exploration, and choledochostomy, plus closure of the duodenal perforation. The extrahepatic biliary ducts were found to be diffusely involved by a sclerosing and stenosing inflammatory process. No stones were present. Five months later he underwent hemigastrectomy and vagotomy; six months after the second operation he had to be reoperated on for recurrent biliary symptoms, and exploration of the common duct with dilatation and choledochostomy were performed. No stones were present. Now almost two years after his last operation he still has jaundice. The second patient had excision of an echinococcus cyst of the left lobe of the liver, and three months later an exploratory operation was performed because of jaundice, chills, and fever. At this operation an acutely inflamed gallbladder without stones was removed, and about 50 cc. of pus was drained from the porta hepatis. The common duct was inflamed and thickened, and a diagnosis of sclerosing cholangitis was made. Culture of the drained material showed streptococci. Because of recurrence of the biliary symptoms this patient was referred about a year later to the Lahey Clinic where a common duct exploration with dilatation of the duct and choledochostomy were performed. No stones were present but there was a diffuse involvement of the extrahepatic ducts by an inflammatory stenosing and sclerosing process, completely obliterating the common hepatic and common bile ducts and involving the left and right hepatic ducts to a lesser degree. Five months after operation at the clinic this patient died deeply jaundiced and with ascites. The third patient who had undergone choleAmerican

Journal

of Surgery

Primary

Sclerosing

cystectomy twenty years previously was operated on because of epigastric pain radiating to the back and jaundice of short duration. An exploratory operation on the common duct effected negative results, and the abdomen was closed. Pancreatitis developed postoperatively resulting in the formation of a pancreatic cyst which was drained externally three weeks after the first operation. Five years later this patient was examined at the Lahey Clinic because of pain and intermittent jaundice since his last operation. Exploration of the common duct with dilatation and choledochostomy were performed. No stones were present, but all the extrahepatic ducts were diffusely thickened and narrowed. The liver was described as nodular in places and hardened throughout. At the time of this writing, six months after operation, he is free of biliary symptoms but complains of general discomfort. The last patient was operated on for a gangrenous gallbladder and a stone impacted in the common duct; cholecystectomy and removal of the stone with choledochostomy were performed. After this operation he had intermittent jaundice and pain with chills and fever, and because of these symptoms he underwent common duct exploration, sphincterotomy, and choledochostomy two and a half years later. No stones were found. Three and a half months later, when the T tube was removed, jaundice, pain, chills, and fever recurred and he was referred to the Lahey Clinic eight months after his second operation. Common duct exploration and dilatation of the ducts were performed, and a long-limb T tube was placed in the common duct. No gallstones were present, but the extrahepatic ducts were considerably thickened throughout, with the left and right hepatic ducts and distal common duct more seriously involved to a point of almost complete obstruction. The T tube was left in place for sixteen months. This patient had an excellent result with no recurrence of his symptoms 124 months after the clinic operation. In summary, two of these patients had a poor outcome and biliary cirrhosis ultimately developed; one died because of hepatobiliary disease. One patient, presently free of symptoms of bile duct obstruction, had a good result but the liver is badly damaged and the prognosis poor. Finally, one patient had an excellent result and is free of symptoms 124 months after operation. Vol. 111, January 1966

Cholangitis

33 COMMENTS

The cause of primary sclerosing cholangitis is unknown. In this series of patients, the disease existed by itself or in association with other diseases, such as ulcerative colitis, biliary calculous disease, and severe inflammation around the porta hepatis. No proof exists to date for a causal relation between primary sclerosing cholangitis and other associated diseases. However, the presence of ulcerative colitis in twelve patients in this series makes the possibility of a causal relation very strong and supports the view that low grade bacterial infection with the large bowel as a source, which reaches the biliary tract through the portal circulation, might be responsible for the chronic inflammation of the biliary tract and, therefore, fibrosis and obliteration of the ducts. The inflamed large bowel in ulcerative colitis with an extensively ulcerated mucosal surface and an abundance of bacteria could certainly be the source of a continuous or intermittent portal bacteremia. Studies carried out by Dineen [7] in guinea pigs to determine the importance of the route. of infection in experimental biliary tract obstruction showed that the portal circulation is the most important route by which bacteria reach the biliary tract, and it is much more important than the systemic circulation. Also, Brooke and Slaney [8] indicated that portal bacteremia may complicate diseases of the colon, ulcerative colitis in particular. They were able to culture organisms in five of ten times in which blood was taken from the portal radicles of nine patients undergoing colectomy for ulcerative colitis. Schatten, Desprez, and Holden [9], in a bacteriologic study of blood from the portal vein of man, obtained positive cultures in eight of twenty-five patients undergoing laparotomy for reasons other than inflammatory lesions of the gastrointestinal tract, while negative cultures of blood from the peripheral veins were obtained concomitantly. They concluded that there is continuous passage of bacteria from the gastrointestinal tract to the liver through the portal vein even without operative manipulation of the bowel. Further support of this view comes from the clinical observation that slight jaundice, usually of short duration, or deepening of preexisting jaundice appears in certain patients soon after colectomy for ulcerative colitis. It is believed to be related to increased portal

34

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Athanassiades,

bacteremia produced by manipulating the large bowel at operation. Also, we have observed simultaneous reactivation of both the colonic and biliary disease in one patient. Furthermore, two patients were cured of the biliary disease and a third patient was improved after total colectomy. Although total colectomy in patients in this series did not always produce cure, its occurrence in two patients seems to favor an etiologic relation of ulcerative colitis to primary sclerosing cholangitis on the basis of portal bacteremia. It is difficult, however, to understand how these bacteria produce an inflammation of the extrahepatic bile ducts in the absence of bile duct obstruction and with free flow of the bile to the duodenum, as seems to be the case in patients of groups A and B. Although it is not a specific lesion for ulcerative colitis according to Popper and Szanto [lo], the intrahepatic damage associated with ulcerative colitis seems easier to understand, with cholestasis, pericholangitis, and periductal fibrosis [IO-121 developing in these patients as a result of bacterial infection. Whether the intrahepatic lesion in ulcerative colitis constitutes by itself a different disease from primary sclerosing cholangitis or whether the two are simply stages of the same process is difficult to determine because of the histologic changes produced in the liver secondary to usually long-standing biliary obstruction. However, the histologic picture seen in liver biopsies seems to be different from the one expected in uncomplicated biliary obstruction [13]. It usually consists of inflammation and periductal fibrosis with intrahepatic obstruction, indicated by the common finding of increased serum level of alkaline phosphatase [11,12] without extrahepatic biliary obstruction. This similarity of the microscopic picture of the liver parenchyma and the extrahepatic ducts gives support to the consideration that both the liver changes and the extrahepatic biliary lesions are probably parts or stages of the same syndrome, as was postulated by Schwartz and Dale [14]. The involvement of the extrahepatic ducts by this sclerosing, obliterative, chronic inflammatory process, although present in association with ulcerative colitis in twelve of our patients, is an uncommon complication of ulcerative colitis. These twelve patients represent only 0.8 per cent of the 1,474 patients with ulcerative colitis seen at about the same time at the Lahey Clinic, and this percentage is actually

and Monge

even smaller when we consider that the majority of these patients were seen at the clinic because of this complication. Primary sclerosing cholangitis in this series was not associated with regional enteritis, although the number of patients with regional enteritis treated at the clinic is similar to the number with ulcerative colitis. This is in accordance with a study done elsewhere of 168 patients with regional enteritis, in which sclerosing cholangitis was neither seen nor suspected [15]. As far as we know there is no published report of primary sclerosing cholangitis associated with regional enteritis, although there are reports of liver damage attributed to regional enteritis. This again occurs less often with regional enteritis than with ulcerative colitis [16,17]. The possible explanation of this difference is that ulceration of the mucosa does not develop in patients with regional enteritis until the late stages of the disease, and that the bacterial flora of the small bowel differs in amount from that of the large bowel. Furthermore, the pathologic change of regional enteritis, characterized by thickening of the bowel wall, often results in obstruction for which resection is performed early in the disease, in contrast to ulcerative colitis for which a long trial of medical treatment is usually given before total colectomy and the associated problems of a permanent ileostomy will be accepted. Whether the length of time, activity, extent of involvement, loss of weight, or malnutrition associated with ulcerative colitis are factors in the development and severity of biliary tract disease is unknown. In our series a long history of mild or moderately severe ulcerative colitis was present in the majority of cases. However, microscopic studies of the liver by Kleckner et al. 1181in patients with ulcerative colitis and regional enteritis [16] showed no correlation between these factors and the severity of liver damage, although Ross of this clinic found the liver damage related to the malnutrition state present in patients with severe ulcerative colitis [19]. In patients in whom primary sclerosing cholangitis is associated with cholelithiasis, particularly when common duct stones are present, the bacterial cause of the disease seems probable. Bile stasis favors multiplication of bacteria present in the bile and sets up an infection which might become acute with pus formation presenting as acute suppurative American

Journal of Surgery

Primary

Sclerosing

FIG. 1. Operative T tube cholangiogram showing fuse involvement of the entire biliary tree.

Cholangitis

35

dif-

FIG. 2. Operative T tube cholangiogram showing diffuse involvement of the entire biliary tree with extreme narrowing of the intrahepatic biliary radicles.

cholangitis or a more chronic form as seen in primary sclerosing cholangitis, depending probably on the degree of obstruction and also on the number and toxicity of bacteria present. When primary sclerosing cholangitis was associated with severe periportal inflammation, the process is probably one of direct invasion of the bile ducts by the bacteria present in this area. The question of etiology appears more difficult with no evidence supporting the bacterial theory in the group in which primary sclerosing cholangitis was present in patients without gallstones, ulcerative colitis, or other intraabdominal or general diseases. Viral, allergic, and toxic origins of the disease have been suggested, but from our study we see no better evidence supporting any of these theories than that of a bacterial origin. In groups A and C the sex and age of patients with primary sclerosing cholangitis was similar to that of patients with the associated disease. Primary sclerosing cholangitis appeared more often in male patients over the age of forty years in the group without associated diseases. The patient reported on by Manesis and Sullivan [5 ] and one of the patients reported on by Roberts [ZO] were alcoholic addicts, and in the latter patient the symptoms recurred after a period of heavy drinking; however, we found no history of alcoholism in any of our patients. The coexistence of alcoholism and primary

sclerosing cholangitis in. these two patients probably was accidental. The usual history of jaundice associated in the majority of cases with intermittent pain in the right upper quadrant and in about one-half of the cases with nausea and vomiting, chills, and fever, in no way helps to establish a preoperative diagnosis of primary sclerosing cholangitis which can be suspected only in the presence of ulcerative colitis. Physical examination usually shows a jaundiced patient with an enlarged, often tender liver and less often an enlarged spleen, but nothing specific to sclerosing cholangitis. The laboratory offers no real help except for the intravenous cholangiogram which reveals stenosis of the bile ducts if the patient is not jaundiced and has liver function adequate to excrete the dye. Operative or postoperative cholangiograms showed no appearance characteristic of any one group, but they contributed to the diagnosis at operation and demonstrated that involvement of the biliary tree in the sclerosing process may be either regional or complete. (Fig. 1, 2, 3, and 4.) Percutaneous cholangiograms were not attempted in our patients, and it is obvious that the thickened wall and the narrowed lumen of the bile duct make the chances of success very meager. The diagnosis usually is made at operation from the characteristic macroscopic appearance of the bile ducts which will be involved

Vol. 111, January 1966

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Warren, Athanassiades, and Mange

FIG. 3. Operative T tube cholangiogram showing involvement of the extrahepatic biliary ducts with more marked involvement of the proximal half. There was no history of biliary surgery or gallstones.

completely in the majority of cases or sometimes only partially by the obliterative process. The wall of the bile duct is hard and thickened, and in severe cases the entire duct looks like a cord with a pinpoint lumen. The microscopic picture is that of chronic inflammation and fibrosis, and in the cases studied by Roberts [ZO] the duct was eight times normal thickness. He also found that the fibrotic areas are in the submucosal and subserosal areas with an edematous field between them and with a normal mucosa. The various phases of this chronic inflammatory process are illustrated in Figures 5 through 8. Before any decision is made to carry out the indicated operative procedure, primary sclerosing cholangitis should be differentiated from cholangiocarcinoma which infiltrates the ductal wall and whose gross appearance resembles primary sclerosing cholangitis. Frozen sections of tissue taken from the ductal wall and of lymph nodes which might be present usually will help to make a correct diagnosis. However, in one of our patients with ulcerative colitis and jaundice a diagnosis of primary sclerosing cholangitis was made on the basis of microscopic examination of tissue taken from the common duct, and only choledochostomy was performed. Five months later this patient died, and autopsy showed metastatic cholangiocarcinoma.

FIG. 4. Operative T tube cholangiogram showing involvement of the intrahepatic and extrahepatic biliary ducts with marked dilatation of a branch of the left hepatic duct and extreme narrowing of the common hepatic duct. There was no history of biliary surgery or gallstones.

Whether cases of regional involvement of the bile ducts are true cases of primary sclerosing cholangitis is a point of controversy. They could certainly represent traumatic strictures or stenosis secondary to gallstones if there is a history of cholelithiasis or previous biliary surgery. However, six of twelve patients with partial involvement of the bile ducts in this series had not had cholelithiasis or previous biliary surgery. Therefore, we think that a diagnosis of primary sclerosing cholangitis is justified even when there is regional involvement of the bile ducts, although diffuse involvement is more common, being present in 71 per cent in this series. At operation common duct stones are sometimes present even in patients without previous history of cholelithiasis and without stones in the gallbladder. They are probably formed secondarily because of stasis and infection present in primary sclerosing cholangitis. Once the diagnosis of primary sclerosing cholangitis is established little can be done surgically to treat the disease itself. Treatment is directed toward decompression of the biliary system to protect the liver from further damage and to offer symptomatic relief to the patient. Exploration and dilatation of the duct and Amevican

Journal

of Surgery

Primary Sclerosing Cholangitis

FIG. 5. Biopsy of common duct wall showing chronic inflammatory process of the mucosa and desquamation of the epithelium.

FIG. 6. Granulation ing into the lumen.

choledochostomy with external drainage of the bile are the indicated treatment. If the distal duct is completely obstructed and no dilatation is feasible, the proximal ducts are dilated and hepaticojejunostomy or cholecystojejunostomy with jejunojejunostomy is performed over a T or Y tube for internal drainage of the bile. Cholecystostomy could be used for decompression if the patient is a poor risk and the proximal ducts and cystic ducts are not obstructed. It is obvious that this procedure does not allow for the possibility of dilating the ducts and the advantage of finding and removing stones, if present, in the common duct. The T tube should be kept in place for a long period of time and removed only if obstructed, as indicated by recurrent symptoms, or if a T tube cholangiogram shows improvement in the appearance of the ducts.

In addition to decompression of the biliary system, total colectomy is indicated in patients with associated ulcerative colitis [Zl] as the only hope for cure regardless of the duration and severity of the colitis, Colectomy seems to have the same beneficial effect in some patients with intrahepatic disease associated with ulcerative colitis [ll,22]. Medical treatment with steroids and broad spectrum antibiotics has been suggested [6,11, 14,22-241 and proved to have a beneficial effect, although usually temporary. The follow-up study of these patients shows that biliary cirrhosis will eventually develop in the majority, and particularly those in groups A and B. They will die from either liver failure or bleeding esophageal varices, with an average of six years between onset of biliary symptoms and death.

FIG. 7. Biopsy of common duct wall showing fibrosis with scattered inflammatory cells.

FIG. 8. Biopsy of common duct showing late stage of the fibrotic process with predominance of hyaline tissue.

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tissue of the common duct protrud-

Warren, Athanassiades, and Monge

38 SUMMARY

AND CONCLUSIONS

Forty-two patients with primary sclerosing cholangitis were studied in four groups: twelve patients who also had ulcerative colitis; fifteen who had had biliary surgery, with gallstones found in fourteen; four who had severe periportal inflammation; eleven who had no other intra-abdominal or general disease. Study of the clinical material supports the hypothesis of bacterial etiology of the disease. The diagnosis is usually made at operation from the characteristic gross appearance of the bile ducts, namely, thickening and induration of the duct wall and narrowing of the ductal lumen, involving the entire extrahepatic biliary tract in the majority of cases. The resemblance of the gross pathologic changes of primary sclerosing cholangitis to those of cholangiocarcinoma is pointed out, and the importance of differential diagnosis of these two diseases at operation is emphasized. Surgical treatment is limited to decompression of the biliary tree by external or internal drainage, removal of stones if present, and total colectomy if the primary sclerosing cholangitis is associated with ulcerative colitis. The disease carries an unfavorable prognosis, progressing in the majority of cases to biliary cirrhosis and death from liver failure or bleeding esophageal varices within several years from its onset. REFERENCES 1. DELBET, P. Retrecissement

2.

3. 4. 5.

6.

du choledoque. Cholecysto-duodenostomie. Bull. et m&-z. Sot. nat. cbir., 50: 1144, 1924. LAFOURCADE, J. Deux observations d’obliteration cicatricielle du choledoque. Anastomose laterale entre le choledoque et le duodenum dans le premier cas. Reconstitution par proth&e avec tube de caoutchouc dans le second. Bull. et m&n. Sot. nut. chir., 51: 828, 1925. JUDD, E. S. Stricture of common bile duct. Ann. Swg., 84: 404, 1926. MILLER, R. T., JR. Benign stricture of bile ducts. Ann. Surg., 86: 296, 1927. MANESIS, J. G. and SULLIVAN, J. F. Primary sclerosing cholangitis. Arch. Int. Med., 115: 137, 1965. HOLUBITSKY, I. B. and MCKENZIE, A. D. Primary

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sclerosing cholangitis of the extrahepatic bile ducts. Caned. J. Surg., 7: 277, 1964. DINEEN, P. The importance of the route of infection in experimental biliary tract obstruction. Surg. Gynec. & Obst., 119: 1001, 1964. BROOKE, B. N. and SLANEY, G. Portal bacteraemia in ulcerative colitis. Lance& 1: 1206, 1958. SCHATTEN, W. E., DESPREZ, J. D., and HOLDEN, W. D. Bacteriological study of portal-vein blood in man. Arch. Surg., 61: 404, 1955. POPPER, H. and SZANTO, P. B. Intrahepatic cholestasis (cholangiolitis). Gustroenterology, 31: 683, 1956. STAUFFER, M. H., SAUER, W. G., DEARING, W. H., and BAGGENSTOSS,A. H. The spectrum of cholestatic hepatic disease. J.A.M.A., 191: 829, 1965. BODEN, R. W., RANKIN, J. G., GOULSTON, S. J., and MORROW, W. The liver in ulcerative colitis; the significance of raised serum-alkaline-phosphatase levels. Lance& 2: 245, 1959. Case records of Massachusetts General Hospital (Case 4-1964). Niw England J. Med., 270: &IQ,* 1964.

14. SCHWARTZ, S. I. and DALE, W. A. Prim$&ulerosing cholangitis; review and report of si?i:cases. Awh. Surg., 77: 439, 1958. 15. RICHTER, H. S. Personal communication. 16. KLECKNER, M. S., JR. The liver in regional enteritis. Gustroenterology, 30: 416, 1956. 17. Ross, J. R. and HEFFERNON, E. W. Hepatobiliary disease and ulcerative colitis. S. C&z. Nortb Anaericu, 38: 729, 1958. 18. KLECKNER, M. S., STAUFFER, M. H., BARGEN, J. A., and DOCKERTY, M. B. Hepatic lesions in the living patient with chronic ulcerative colitis as demonstrated by needle biopsy. Gustroenterology, 22: 13, 1952. 19. Ross, J. R. The relationship of hepatic insufficiency to chronic ulcerative colitis. S. Clin. North America, 28: 701, 1948. 20. ROBERTS, J. M. Stenosing cholangitis. W’est.J. Surg., 63: 253, 1955. 21. BRAASCH, J. W. and Ross, J. R. The colon surgeon looks at jaundice. Dis. Colon 6” Rectum, 1: 405, 1958. 22. RANKIN, J. G., BODEN, R. W., GOULSTON, S. J., and MORROW, W. The liver in ulcerative colitis; treatment of pericholangitis with tetracycline. Luncet, 2: 1110, 1959. 23. BARTHOLOMEW,L. G., CAIN, J. C., WOLLNER, L. B., UTZ, D. C., and FERRIS, D. Q. Sclerosing cholangitis: its possible association with Riedel’s struma and fibrous retroperitonitis. Report of two cases. New England J. Med., 269: 8, 1903. 24. VINNIK, I. E. and KERN, F., JR. Biliary cirrhqsis in a patient with chronic ulcerative c&is. Gustroenterology, 45: 529, 1963.

ReprInted from the January 1966 w.ue of The American Journal of Surgery Volume 1 11, number 1, pages 23-38, copyrtght 1966 and prmted in the U.S.A. Published by The Reuben H. Donnelley Corporation. 466 Lexington Ave., New York 10017