Sclerosing Cholangitis and Primary Biliary Cirrhosis -a Disease Spectrum? HENRY J. FEE, M.D., HAROLD GEWIRTZ, M.D., JUAN SCHILLER, M.D., WILLIAM P. LONGMIRE, JR., M.D.
Sclerosing diseases of the biliary system encompass a spectrum ranging from primary sclerosing cholangitis (usually of the extrahepatic biliary tree) to primary biliary cirrhosis of the intrahepatic bile canaliculi. In a study of 35 patients with primary intra- and extrahepatic biliary sclerosis, age of onset, sex distribution, symptomatology, associated diseases, radiographic abnormalities and chemical profile were considered. The difficulty of differentiating sclerosing cholangitis and biliary cirrhosis from other causes of obstructive jaaundice preoperatively was stressed, in addition to points of differential clinical and laboratory findings. The etiology of these entities as well as the possibility that they represent variant clinical manifestations of the same disease process were also considered. Mechanical and pharmacological treatment alternatives that were attempted included drainage procedures, the easiest and most widely used of which was the T-tube. However, this could prove to be a source of infection and should therefore be removed early, inasmuch as cholangitis represents a major cause of morbidity. Steroids have been used with varying effectiveness; subjective improvement was generally attained, although objective improvement has been difficult to document. When choleuretics and cholestyramine were administered, we noted significant palliation. Antibiotics were reserved for treatment of cholangitis. Until the underlying etiology of this rare malignant sclerosing process is found, only symptomatic treatment can be offered. S CLEROSIS OF THE BILIARY TRACT may
involve the
extrahepatic system exclusively (sclerosing cholangitis), or the most proximal portion of the intrahepatic radicals (primary biliary cirrhosis). However, patients with fibrosis affecting both extra- and intrahepatic bile ducts6 have frequently been reported. For example, cases have been seen that first involved one system and later at autopsy or laparotomy were revealed to have progressed to fibrosis both of the extrahepatic and the intrahepatic biliary tree. Regardless of location and extent of fibrosis at the time of initial exploration, these diseases are noted for their progressive course. A review of our experience with primary sclerosing diseases of the biliary tract indicates that these may not be separate entities but rather represent a nonspecific response of the bile ducts to an insult of unknown etiology or etiologies. Not included Submitted for publication: February 11, 1977.
589
From the Department of Surgery, UCLA School of Medicine, Los Angeles, California
in this study is secondary sclerosing cholangitis of the extrahepatic biliary system from known causes, such as common bile duct stones or previous surgical trauma.9 The present review has been limited to cases of primary sclerosing cholangitis or primary biliary cirrhosis that met the following criteria: 1) absence of cholestatic jaundice from drug or viral hepatitis; 2) progressive obstructive jaundice; 3) absence of choledocholithiasis; 4) absence of previous bile duct surgery; 5) absence of malignancy as demonstrated by long-term follow-up or autopsy; 6) presence of thickening and fibrosis of the extrahepatic biliary system or of the intrahepatic cholangioles. Clinical Data All charts of patients at UCLA Hospital who were diagnosed as suffering from obstructive jaundice during the two decades between 1955 and 1975 were reviewed. The 35 patients with proven primary sclerosing cholangitis or primary biliary cirrhosis form the basis of this report and include both those who had been referred and those seen originally at UCLA Hospital. Vital factors such as the age when the first symptoms occurred, the age at death, the initial presenting symptoms and any other diseases the patient may have had, regardless of time sequence, were recorded. An evaluation of the initial laboratory values, often varying from later values, included CBC with differential count, electrolytes, indices of liver disease such as bilirubin (total and direct), SGOT, SGPT, alkaline phosphatase, cholesterol, total protein and albumin. Many of the patients had serum protein and lipoprotein electrophoreses and several underwent serologic determinations often associated with liver disease such as antinuclear antibody, anti-
FEE AND OTHERS
590
Ann. Surg. * November 1977
Discussion Although analysis of several small series has indicated male predominance, it would appear that women
develop sclerosing cholangitis as frequently as men. In our series, the ratio of male to female was almost 1:1. However, the predominance of females with primary biliary cirrhosis is unequivocal, with the ratio of male to female being 2:5. Few cases of sclerosing cholangitis or biliary cirrhosis have been reported before the second decade. The youngest patient in our series with sclerosing cholangitis was 19, yet with biliary cirrhosis the youngest was 40. The incidence appears to be highest from the third to sixth decade. In sclerosing cholangitis and biliary cirrhosis the presenting symptoms are pruritis, right upper quadrant pain, and weight loss. Physical examination usually reveals jaundice, hepatosplenomegaly, and occasionally, xanthomata. Laboratory determinations in primary sclerosing cholangitis and primary biliary cirrhosis show a similar profile. The bilirubin and alkaline phosphatase levels are markedly elevated in primary sclerosing cholangitis and moderately elevated in primary biliary cirrhosis. Cholesterol levels are often elevated and were above 300 mg% in 11 of 21 patients tested. Total lipid measurements were noted to be elevated in all patients with primary biliary cirrhosis tested by Longmire et al.6 In our series, eosinophilia was noted in seven of 21 patients with primary sclerosing cholangitis and three of 14 patients with primary biliary cirrhosis. Similar findings have been reported by others.9'13 Indices of hepatocellular damage are occasionally normal early in the course of the disease; however, hepatocellular damage from secondary biliary cirrhosis is inevitable. All patients who died of their disease were observed preterminally to have markedly elevated levels of alkaline phosphatase, bilirubin and bromosulfophthalein retention. Antimitochondrial antibodies have been found in an occasional patient with sclerosing cholangitis and not uncommonly in patients with primary biliary cirrhosis.'1'13 None of the patients experienced cholangitis initially, but after operative intervention and bile contamination, this became a major source of morbidity. For this reason, early removal of the T-tube (if drainage is slight) is recommended, as we will describe later.
TABLE 2. Symptoms at Time of Initial Presentation
Differential Diagnosis
TABLE 1. Distribution by Sex and Age of Onset
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
Age
Males
Females
Males
Females
10-20 21-30 31-40 41-50 51-60 61-70 71-80
0 0 0 3 1 0 0
0 0 1 4 2 2 1
0 1 1 6 1 1 0
1 4 2 2 1 1 0
mitochondrial antibody, smooth muscle antibody, and lupus erythematous preparation. We reviewed all plain x-rays and all dye studies of the biliary tree, paying special attention to intraoperative cholangiograms, and we recorded the use of steroids, choleuretics and cholestyramine. However, it was frequently difficult to determine whether such therapy ameliorated the patient's condition. Various modes of surgical treatment were also undertaken, and the results documented. The pathologic records of each patient indicated that in all of those with primary sclerosing cholangitis, the pathologic diagnosis was confirmed at operation. Liver biopsy verified all cases of primary biliary cirrhosis. Inasmuch as several of the patients were first seen elsewhere, their diagnoses depended upon material obtained from other hospitals. Of the 21 patients with primary sclerosing cholangitis, 47% were male. Age of onset averaged 40-50 years in males and 20-40 in females. The major presenting complaints were jaundice and pruritis; abdominal pain and nausea were less commonly cited. Of the 14 patients with primary biliary cirrhosis, 21% were male; age of onset averaged 50 years among the males and 40-60 among the females. Common presenting complaints included pruritis, jaundice, abdominal pain and lethargy (Tables 1 and 2).
Pruritis Jaundice Right upper quadrant pain Nausea Weight loss
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
8 5
12 14
5 1 3
7 6 3
The diagnosis of primary sclerosing cholangitis implies the absence of neoplasia, stones, infection and prior trauma in a patient with obstructive jaundice and fibrosis of the extrahepatic biliary tree. However, primary sclerosing cholangitis and primary biliary cirrhosis are similar in presentation to these causes of obstructive jaundice, and therefore final diagnosis
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591
SCLEROSING CHOLANGITIS
often must await exploratory laparotomy. One group of patients (not used in this study) was clinically diagnosed as having primary sclerosing cholangitis, but long-term follow-up or autopsy revealed adenocarcinoma. Similar cases have been described by Peck et al. and Altemeier and Culbertson.18 This raises the question of whether the carcinoma might be secondary to scarring, as seen in other areas of the body. Several of our patients had undergone prior cholecystectomy when they were referred for biliary decompression or reconstruction. However, these patients were noted to have extrahepatic fibrosis and no stones at the prior procedure. Many had undergone prior biliary tree biopsies which were consistent with primary sclerosing cholangitis when reviewed by our pathology department. The distinction between primary sclerosing cholangitis and primary biliary cirrhosis is sometimes difficult to establish. One-third of our patients with primary sclerosing cholangitis had liver biopsy results that were consistent with primary biliary cirrhosis. Although the symptom complexes of the two diseases are similar and represent obstructive jaundice, primary sclerosing cholangitis was rated as having a slightly higher incidence of associated autoimmune disease in our series. While the laboratory findings were also similar, there were helpful indications: (a) hyperbilirubinemia (usually mixed) was greater in primary sclerosing cholangitis, (b) patients with primary sclerosing cholangitis had a marked incidence of eosinophilia which occurred less commonly among patients with primary biliary cirrhosis, and (c) patients suffering from primary sclerosing cholangitis exhibited more pronounced hypercholesterolemia. It is also difficult to distinguish between these two diseases in terms of course and prognosis; both are characterized by a subgroup of slowly progressive or remitting disease as well as a subgroup with rapidly progressive disease. Among the patients who died, similar end-state hepatic failure was involved in both groups (Table 3). Associated Diseases
Contrary to the opinion of Sherlock10 and other authors, the majority of patients with primary sclerosing cholangitis do not have ulcerative colitis; only three of the 21 patients in our series were afflicted. Such a low incidence has been substantiated by other reports, thus undermining the theory that the mucosal barrier is disrupted by colitis, and bacteria invade the portal system, damaging the bile ducts.12 In view of the possible autoimmune etiology of sclerosing diseases of the biliary tract, one might
TABLE 3. Cause of Death
Hepatic failure Hepato-renal syndrome Pericarditis Cerebrovascular accident Unknown Ascending cholangitis
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
4 1 0 0 1 0
3 I 1 1 0 1
expect to see concomitant disease having a similar etiology. Among the 21 patients with primary sclerosing cholangitis, three had thyroiditis and one had granulomatous colitis. Among the 14 patients with primary biliary cirrhosis, one suffered from Hashimoto's thyroiditis, two had idiopathic myopathies and one had retroperitoneal fibrosis. Another interesting finding was the occurrence of xanthomata in three of the patients with primary sclerosing cholangitis, but this is not surprising in view of the marked hypercholesterolemia of these patients (mean 697). One of the patients with primary biliary cirrhosis had xanthelasma, but all had lower levels of serum cholesterol (mean 324), lower than those observed in past cases of primary biliary cirrhosis. Six of the 21 individuals with primary sclerosing cholangitis had associated histologically proven primary biliary cirrhosis. Intrahepatic biliary stasis causing secondary biliary cirrhosis might easily be explained by extrahepatic disease, but these six patients had lipid-laden macrophages and granulomatous changes of classic primary biliary cirrhosis. Several authors have eliminated patients with primary biliary cirrhosis from the group of those suffering from primary sclerosing cholangitis. We believe that these patients represent primary sclerosis at both levels of the hepatobiliary system (Table 4).
Operative Approach Inasmuch as sclerosing diseases of the biliary tract present in a manner similar to other causes of obstrucTABLE 4. Associated Diseases
Primary biliary cirrhosis Thyroiditis Xanthoma Ulcerative colitis Retroperitoneal fibrosis Idiopathic myopathy Granulomatous colitis
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
1 1 0 1 2 0
6 3 3 3 0 0 1
FEE AND OTHERS
592 TABLE 5. Medical Treatment Modalities
Steroids Choleuretics Cholestyramine Immuran
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
No ImImproved provement
No ImImproved provement
1 1 0 0
4 1 0 1
2 3 5 0
5 0 2 0
tive jaundice, the surgeon should perform several operative maneuvers. Although the diagnosis can be suspected at the time of initial exploration of the right upper quadrant if the common duct is thickened and hard,4 other diseases may appear to be sclerosing cholangitis in a localized area, and therefore the common duct should be explored through a longitudinal incision. In typical sclerosing cholangitis, the common duct will be markedly thickened along its entire course, free of stones, and will contain highly viscous bile. If one is dealing with biliary cirrhosis, the common bile duct may appear completely normal. Attempts to pass a common duct dilator proximally and distally will be difficult or impossible in sclerosing cholangitis. It is important to obtain a biopsy, but a report of "sclerosing changes" or "fibrosis and chronic inflamation" does not rule out carcinoma.1 A diagnosis of carcinoma on frozen section can sometimes be erroneous and a cholangiogram should therefore always be obtained. The cholangiogram is diagnostic when it shows uneven narrowing of the intrahepatic ducts with stenosis of the extrahepatic duct down to the ampulla of Vater, indicating probable sclerosing cholangitis. It may also show that the area of operative intervention is an isolated segment of stenosis and that the ducts are markedly dilated proximally. This would be more consistent with the diagnosis of bile duct carcinoma.1 If the extrahepatic ducts are normal and small intrahepatic radicals can not be demonstrated, then it is likely that biliary cirrhosis is the diagnosis. We recommend that after common duct exploration, biopsy, and cholangiogram have been carried out, a T-tube be left in place regardless of diagnosis. Pathological Description Primary sclerosing cholangitis grossly consists of dense fibrosis of the extrahepatic tree presenting in several patterns: diffuse fibrosis (including the gallbladder and head of pancreas, making identification of the biliary system very difficult); segmental disease, which produces the classic beaded appearance on a cholangiogram; or fibrosis, extending from the ampulla
Ann. Surg. * November 1977
of Vater to the smallest biliary radicles. The fibrosis may on occasion present as a discrete nodular mass in the region of the common or hepatic ducts and mimic carcinoma.8'13 Regional lymphadenopathy is seen frequently. Histologically, the extrahepatic biliary tree shows marked fibrosis and chronic inflammation with lymphocytes, histocytes, plasma cells and eosinophils. The epithelium is rarely effaced. Vasculitis and metaplasia are not seen. Distortion of periluminal glands by fibrosis and inflammation can complicate differentiation from sclerosing adenocarcinoma. 1,13
In isolated primary biliary cirrhosis, the extrahepatic biliary ducts are usually normal. Intrahepatic bile accumulation occurs at the periphery of the lobule along with lipid-laden hepatocytes. Lipid-filled microphages may also be seen along with an epitheliomatous reaction that leads to a granulomatous picture.10
Treatment Alternatives Jaundice and pruritis can be ameliorated with the use of cholestyramine, a drug that blocks the intestinal absorption of bile and prevents its entry into the enterohepatic circulation.6 Corticosteroids have been used by several authors with varying results.5'6'9 It is our opinion that the patient's sense of well-being is improved by steroids and when the steroids are taken every other day at low levels, side effects are minimal. Objective evaluation has been difficult to document without improvement in level of jaundice, cholangiogram or episodes of cholangitis. Choleuretic drugs act to decrease the viscosity of bile and may improve biliary drainage.9 These drugs have low morbidity and may help to minimize the episodes of cholangitis (Table 5). Use of the T-tube has remained controversial, although the majority of authors cite this device as having some efficacy in treating patients who have biliary cirrhosis or sclerosing cholangitis. 4,6,7 9 The T-tube can be used effectively following common duct exploration and biopsy, but if the bile drainage is minimal, it is best to remove the tube early. Not only does the T-tube cause some obstruction and perhaps increase the fibrotic reaction in the common duct, but it also serves as an avenue for contamination. In reviewing our 35 cases it was found that cholangitis was a significant cause of hospitalization. This point is not emphasized in previous publications and many clinicians assume that hepatic encephalopathy is the major risk factor. Choledochoenteric bypass should be reserved for those unusual cases in which there is isolated distal extrahepatic fibrosis with proximal dilatation.
Vol. 186 * No. 5
SCLEROSING CHOLANGITIS
Prognosis While the fibrosing process in primary sclerosing cholangitis and primary biliary cirrhosis may be selflimiting, it usually follows an unrelenting course leading to death of the patient due to hepatic failure. In fact, life expectancy of such patients is difficult to determine; palliation may range from two months to 19 years, and therefore aggressive treatment of the complications of biliary sclerosis should be pursued. Eighteen of the 21 patients with sclerosing cholangitis were followed for one year or longer. Five of these 18 patients died of their disease from one to six years after the first symptoms became apparent and two died of unrelated causes. The other 11 patients were alive when seen at periods from one to 14 years. Among the group, 17 T-tube placements were performed with symptomatic palliation from one to eight years. The 11 patients who were alive at last follow-up demonstrated a similar slow progressive decline in clinical status and worsening of liver function tests. None had spontaneous remission. The patients who died had followed a similar but accelerated course. The presenting symptoms, laboratory data, and associated diseases did not correlate with rate of survival. Thirteen of the 14 patients with primary biliary cirrhosis were followed for one year or longer. Five of these 13 died of their disease from one to 22 years after their first symptoms occurred, and one died of unknown causes. The surviving seven patients have been observed for periods ranging from one to 13 years. Those with biliary cirrhosis demonstrated a slowly progressive course. Among the patients who died, survival after the onset of symptoms lasted for a longer time than those with primary sclerosing cholangitis (2.5 versus 9.5 years). Survival time did not correlate with initial laboratory values or associated diseases (Table 6).
TABLE 6. Prognosis
Primary Biliary Cirrhosis Total number of patients studied Patients dead at time of study Mean time from symptoms to death
14
Primary Sclerosing Cholangitis 21
6(43%)
4(33%)
9.5 yrs
2.5 yrs
autoimmune disease, (e.g., retroperitoneal fibrosis, thyroiditis, and ulcerative colitis);3 (b) improvement with steroids; (c) eosinophilia;2 (d) biliary tract autoantibodies ;8 and (e) occasional serum globulin abnormalities such as elevated IgM. Although this theory is attractive, it is far from conclusive. While these diseases classically occur in different areas of the biliary duct system, there are many cases that seem to exhibit the characteristics of both. Thus, biliary sclerosis of intralobular cholangioles, extrahepatic bile ducts, or of the entire bile duct system may represent varying degrees of response to a common etiologic agent. References 1. Altemeier, W. A. and Culbertson, W. R.: Sclerosing Car-
2. 3.
4. 5. 6.
Etiology
The etiology or etiologies of sclerosing cholangitis and primary biliary cirrhosis are not known. Suggested possibilities have included syphilis, toxins such as polyvinyl chloride and carbon tetrachloride, or a post-viral Schwartzmann reaction.2 Portal bacteremia has also been considered in view of the common finding of E. coli in the bile and the association with ulcerative colitis.12 In our series, no organisms was consistently found in the bile and several have been sterile. Significant consideration has been given to the possibility of an autoimmune etiology on the basis of indirect evidence including (a) association with other
593
7. 8. 9. 10. 11.
12. 13.
cinoma of the Hepatic Bile Ducts. Surg. Clin. North Am., 53:1229, 1973. Atkinson, A. J. and Carroll, W. W.: Sclerosing Cholangitis: Association with Rlegional Enteritis. J.A.M.A., 188:183, 1964. Bartholomew, L. G., Cain, J. C., Waciner, L. B. and Utz, D. C.: Sclerosing Cholangitis: Its Possible Association with Riedel's Struma and Fibrous Retroperitonitis. Report of Two Cases. N. Engl. J. Med., 269:8, 1963. Culter, B. and Donaldson, G. A.: Primary Sclerosing Cholangitis and Obliterative Cholangitis. Am. J. Surg., 117:502, 1969. Grua, 0. E. and McMurrin, J. A.: Sclerosing Cholangitis: Review and Presentation of an Unusual Pathologic Variant. Am. J. Surg., 116:659, 1968. Longmire, W. P., Jr., Joseph, W. L., Levin, P. M. and Mellinkoff, S. M.: Diagnosis and Treatment of Cholangiolitic Hepatitis (Primary Biliary Cirrhosis). Ann. Surg., 162:356, 1965. Oviedo, M. A., Volkmer, D. and Scanlon, E. F.: Primary Sclerosing Cholangitis. Arch. Surg., 109:747, 1974. Peck, J. J., Kern, W. H. and Mikkelsen, W. P.: Sclerosis of the Extra-hepatic Bile Ducts. Arch. Surg., 108:798, 1974. Schwartz, S. I.: Primary Sclerosing Cholangitis: A Disease Revisited. Surg. Clin. North Am., 53:1161, 1973. Sherlock, S.: Chronic Cholangitides: Aetiology, Diagnosis and Treatment. Br. Med. J., 3:515, 1968. Walker, J. G., Doniach, D., Roitt, I. M. and Sherlock, S.: $erological Tests in Diagnosis of Primary Biliary Cirrhosis. Lancet, 6:827, 1965. Warren, K. W., Athanassiades, S. and Monge, J. I.: Primary Sclerosing Cholangitis: A Study of 42 Cases. Am. J. Surg., 111:23, 1966. Whelton, M. J.: Sclerosing Cholangitis. Clinics in Gastroenterology, 2:163, 1973.
Sclerosing diseases of the biliary system encompass a spectrum ranging from primary sclerosing cholangitis (usually of the extrahepatic biliary tree) to primary biliary cirrhosis of the intrahepatic bile canaliculi. In a study of 35 patients with primary intra- and extrahepatic biliary sclerosis, age of onset, sex distribution, symptomatology, associated diseases, radiographic abnormalities and chemical profile were considered. The difficulty of differentiating sclerosing cholangitis and biliary cirrhosis from other causes of obstructive jaaundice preoperatively was stressed, in addition to points of differential clinical and laboratory findings. The etiology of these entities as well as the possibility that they represent variant clinical manifestations of the same disease process were also considered. Mechanical and pharmacological treatment alternatives that were attempted included drainage procedures, the easiest and most widely used of which was the T-tube. However, this could prove to be a source of infection and should therefore be removed early, inasmuch as cholangitis represents a major cause of morbidity. Steroids have been used with varying effectiveness; subjective improvement was generally attained, although objective improvement has been difficult to document. When choleuretics and cholestyramine were administered, we noted significant palliation. Antibiotics were reserved for treatment of cholangitis. Until the underlying etiology of this rare malignant sclerosing process is found, only symptomatic treatment can be offered. S CLEROSIS OF THE BILIARY TRACT may
involve the
extrahepatic system exclusively (sclerosing cholangitis), or the most proximal portion of the intrahepatic radicals (primary biliary cirrhosis). However, patients with fibrosis affecting both extra- and intrahepatic bile ducts6 have frequently been reported. For example, cases have been seen that first involved one system and later at autopsy or laparotomy were revealed to have progressed to fibrosis both of the extrahepatic and the intrahepatic biliary tree. Regardless of location and extent of fibrosis at the time of initial exploration, these diseases are noted for their progressive course. A review of our experience with primary sclerosing diseases of the biliary tract indicates that these may not be separate entities but rather represent a nonspecific response of the bile ducts to an insult of unknown etiology or etiologies. Not included Submitted for publication: February 11, 1977.
589
From the Department of Surgery, UCLA School of Medicine, Los Angeles, California
in this study is secondary sclerosing cholangitis of the extrahepatic biliary system from known causes, such as common bile duct stones or previous surgical trauma.9 The present review has been limited to cases of primary sclerosing cholangitis or primary biliary cirrhosis that met the following criteria: 1) absence of cholestatic jaundice from drug or viral hepatitis; 2) progressive obstructive jaundice; 3) absence of choledocholithiasis; 4) absence of previous bile duct surgery; 5) absence of malignancy as demonstrated by long-term follow-up or autopsy; 6) presence of thickening and fibrosis of the extrahepatic biliary system or of the intrahepatic cholangioles. Clinical Data All charts of patients at UCLA Hospital who were diagnosed as suffering from obstructive jaundice during the two decades between 1955 and 1975 were reviewed. The 35 patients with proven primary sclerosing cholangitis or primary biliary cirrhosis form the basis of this report and include both those who had been referred and those seen originally at UCLA Hospital. Vital factors such as the age when the first symptoms occurred, the age at death, the initial presenting symptoms and any other diseases the patient may have had, regardless of time sequence, were recorded. An evaluation of the initial laboratory values, often varying from later values, included CBC with differential count, electrolytes, indices of liver disease such as bilirubin (total and direct), SGOT, SGPT, alkaline phosphatase, cholesterol, total protein and albumin. Many of the patients had serum protein and lipoprotein electrophoreses and several underwent serologic determinations often associated with liver disease such as antinuclear antibody, anti-
FEE AND OTHERS
590
Ann. Surg. * November 1977
Discussion Although analysis of several small series has indicated male predominance, it would appear that women
develop sclerosing cholangitis as frequently as men. In our series, the ratio of male to female was almost 1:1. However, the predominance of females with primary biliary cirrhosis is unequivocal, with the ratio of male to female being 2:5. Few cases of sclerosing cholangitis or biliary cirrhosis have been reported before the second decade. The youngest patient in our series with sclerosing cholangitis was 19, yet with biliary cirrhosis the youngest was 40. The incidence appears to be highest from the third to sixth decade. In sclerosing cholangitis and biliary cirrhosis the presenting symptoms are pruritis, right upper quadrant pain, and weight loss. Physical examination usually reveals jaundice, hepatosplenomegaly, and occasionally, xanthomata. Laboratory determinations in primary sclerosing cholangitis and primary biliary cirrhosis show a similar profile. The bilirubin and alkaline phosphatase levels are markedly elevated in primary sclerosing cholangitis and moderately elevated in primary biliary cirrhosis. Cholesterol levels are often elevated and were above 300 mg% in 11 of 21 patients tested. Total lipid measurements were noted to be elevated in all patients with primary biliary cirrhosis tested by Longmire et al.6 In our series, eosinophilia was noted in seven of 21 patients with primary sclerosing cholangitis and three of 14 patients with primary biliary cirrhosis. Similar findings have been reported by others.9'13 Indices of hepatocellular damage are occasionally normal early in the course of the disease; however, hepatocellular damage from secondary biliary cirrhosis is inevitable. All patients who died of their disease were observed preterminally to have markedly elevated levels of alkaline phosphatase, bilirubin and bromosulfophthalein retention. Antimitochondrial antibodies have been found in an occasional patient with sclerosing cholangitis and not uncommonly in patients with primary biliary cirrhosis.'1'13 None of the patients experienced cholangitis initially, but after operative intervention and bile contamination, this became a major source of morbidity. For this reason, early removal of the T-tube (if drainage is slight) is recommended, as we will describe later.
TABLE 2. Symptoms at Time of Initial Presentation
Differential Diagnosis
TABLE 1. Distribution by Sex and Age of Onset
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
Age
Males
Females
Males
Females
10-20 21-30 31-40 41-50 51-60 61-70 71-80
0 0 0 3 1 0 0
0 0 1 4 2 2 1
0 1 1 6 1 1 0
1 4 2 2 1 1 0
mitochondrial antibody, smooth muscle antibody, and lupus erythematous preparation. We reviewed all plain x-rays and all dye studies of the biliary tree, paying special attention to intraoperative cholangiograms, and we recorded the use of steroids, choleuretics and cholestyramine. However, it was frequently difficult to determine whether such therapy ameliorated the patient's condition. Various modes of surgical treatment were also undertaken, and the results documented. The pathologic records of each patient indicated that in all of those with primary sclerosing cholangitis, the pathologic diagnosis was confirmed at operation. Liver biopsy verified all cases of primary biliary cirrhosis. Inasmuch as several of the patients were first seen elsewhere, their diagnoses depended upon material obtained from other hospitals. Of the 21 patients with primary sclerosing cholangitis, 47% were male. Age of onset averaged 40-50 years in males and 20-40 in females. The major presenting complaints were jaundice and pruritis; abdominal pain and nausea were less commonly cited. Of the 14 patients with primary biliary cirrhosis, 21% were male; age of onset averaged 50 years among the males and 40-60 among the females. Common presenting complaints included pruritis, jaundice, abdominal pain and lethargy (Tables 1 and 2).
Pruritis Jaundice Right upper quadrant pain Nausea Weight loss
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
8 5
12 14
5 1 3
7 6 3
The diagnosis of primary sclerosing cholangitis implies the absence of neoplasia, stones, infection and prior trauma in a patient with obstructive jaundice and fibrosis of the extrahepatic biliary tree. However, primary sclerosing cholangitis and primary biliary cirrhosis are similar in presentation to these causes of obstructive jaundice, and therefore final diagnosis
VOl. 186 . NO. 5
591
SCLEROSING CHOLANGITIS
often must await exploratory laparotomy. One group of patients (not used in this study) was clinically diagnosed as having primary sclerosing cholangitis, but long-term follow-up or autopsy revealed adenocarcinoma. Similar cases have been described by Peck et al. and Altemeier and Culbertson.18 This raises the question of whether the carcinoma might be secondary to scarring, as seen in other areas of the body. Several of our patients had undergone prior cholecystectomy when they were referred for biliary decompression or reconstruction. However, these patients were noted to have extrahepatic fibrosis and no stones at the prior procedure. Many had undergone prior biliary tree biopsies which were consistent with primary sclerosing cholangitis when reviewed by our pathology department. The distinction between primary sclerosing cholangitis and primary biliary cirrhosis is sometimes difficult to establish. One-third of our patients with primary sclerosing cholangitis had liver biopsy results that were consistent with primary biliary cirrhosis. Although the symptom complexes of the two diseases are similar and represent obstructive jaundice, primary sclerosing cholangitis was rated as having a slightly higher incidence of associated autoimmune disease in our series. While the laboratory findings were also similar, there were helpful indications: (a) hyperbilirubinemia (usually mixed) was greater in primary sclerosing cholangitis, (b) patients with primary sclerosing cholangitis had a marked incidence of eosinophilia which occurred less commonly among patients with primary biliary cirrhosis, and (c) patients suffering from primary sclerosing cholangitis exhibited more pronounced hypercholesterolemia. It is also difficult to distinguish between these two diseases in terms of course and prognosis; both are characterized by a subgroup of slowly progressive or remitting disease as well as a subgroup with rapidly progressive disease. Among the patients who died, similar end-state hepatic failure was involved in both groups (Table 3). Associated Diseases
Contrary to the opinion of Sherlock10 and other authors, the majority of patients with primary sclerosing cholangitis do not have ulcerative colitis; only three of the 21 patients in our series were afflicted. Such a low incidence has been substantiated by other reports, thus undermining the theory that the mucosal barrier is disrupted by colitis, and bacteria invade the portal system, damaging the bile ducts.12 In view of the possible autoimmune etiology of sclerosing diseases of the biliary tract, one might
TABLE 3. Cause of Death
Hepatic failure Hepato-renal syndrome Pericarditis Cerebrovascular accident Unknown Ascending cholangitis
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
4 1 0 0 1 0
3 I 1 1 0 1
expect to see concomitant disease having a similar etiology. Among the 21 patients with primary sclerosing cholangitis, three had thyroiditis and one had granulomatous colitis. Among the 14 patients with primary biliary cirrhosis, one suffered from Hashimoto's thyroiditis, two had idiopathic myopathies and one had retroperitoneal fibrosis. Another interesting finding was the occurrence of xanthomata in three of the patients with primary sclerosing cholangitis, but this is not surprising in view of the marked hypercholesterolemia of these patients (mean 697). One of the patients with primary biliary cirrhosis had xanthelasma, but all had lower levels of serum cholesterol (mean 324), lower than those observed in past cases of primary biliary cirrhosis. Six of the 21 individuals with primary sclerosing cholangitis had associated histologically proven primary biliary cirrhosis. Intrahepatic biliary stasis causing secondary biliary cirrhosis might easily be explained by extrahepatic disease, but these six patients had lipid-laden macrophages and granulomatous changes of classic primary biliary cirrhosis. Several authors have eliminated patients with primary biliary cirrhosis from the group of those suffering from primary sclerosing cholangitis. We believe that these patients represent primary sclerosis at both levels of the hepatobiliary system (Table 4).
Operative Approach Inasmuch as sclerosing diseases of the biliary tract present in a manner similar to other causes of obstrucTABLE 4. Associated Diseases
Primary biliary cirrhosis Thyroiditis Xanthoma Ulcerative colitis Retroperitoneal fibrosis Idiopathic myopathy Granulomatous colitis
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
1 1 0 1 2 0
6 3 3 3 0 0 1
FEE AND OTHERS
592 TABLE 5. Medical Treatment Modalities
Steroids Choleuretics Cholestyramine Immuran
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
No ImImproved provement
No ImImproved provement
1 1 0 0
4 1 0 1
2 3 5 0
5 0 2 0
tive jaundice, the surgeon should perform several operative maneuvers. Although the diagnosis can be suspected at the time of initial exploration of the right upper quadrant if the common duct is thickened and hard,4 other diseases may appear to be sclerosing cholangitis in a localized area, and therefore the common duct should be explored through a longitudinal incision. In typical sclerosing cholangitis, the common duct will be markedly thickened along its entire course, free of stones, and will contain highly viscous bile. If one is dealing with biliary cirrhosis, the common bile duct may appear completely normal. Attempts to pass a common duct dilator proximally and distally will be difficult or impossible in sclerosing cholangitis. It is important to obtain a biopsy, but a report of "sclerosing changes" or "fibrosis and chronic inflamation" does not rule out carcinoma.1 A diagnosis of carcinoma on frozen section can sometimes be erroneous and a cholangiogram should therefore always be obtained. The cholangiogram is diagnostic when it shows uneven narrowing of the intrahepatic ducts with stenosis of the extrahepatic duct down to the ampulla of Vater, indicating probable sclerosing cholangitis. It may also show that the area of operative intervention is an isolated segment of stenosis and that the ducts are markedly dilated proximally. This would be more consistent with the diagnosis of bile duct carcinoma.1 If the extrahepatic ducts are normal and small intrahepatic radicals can not be demonstrated, then it is likely that biliary cirrhosis is the diagnosis. We recommend that after common duct exploration, biopsy, and cholangiogram have been carried out, a T-tube be left in place regardless of diagnosis. Pathological Description Primary sclerosing cholangitis grossly consists of dense fibrosis of the extrahepatic tree presenting in several patterns: diffuse fibrosis (including the gallbladder and head of pancreas, making identification of the biliary system very difficult); segmental disease, which produces the classic beaded appearance on a cholangiogram; or fibrosis, extending from the ampulla
Ann. Surg. * November 1977
of Vater to the smallest biliary radicles. The fibrosis may on occasion present as a discrete nodular mass in the region of the common or hepatic ducts and mimic carcinoma.8'13 Regional lymphadenopathy is seen frequently. Histologically, the extrahepatic biliary tree shows marked fibrosis and chronic inflammation with lymphocytes, histocytes, plasma cells and eosinophils. The epithelium is rarely effaced. Vasculitis and metaplasia are not seen. Distortion of periluminal glands by fibrosis and inflammation can complicate differentiation from sclerosing adenocarcinoma. 1,13
In isolated primary biliary cirrhosis, the extrahepatic biliary ducts are usually normal. Intrahepatic bile accumulation occurs at the periphery of the lobule along with lipid-laden hepatocytes. Lipid-filled microphages may also be seen along with an epitheliomatous reaction that leads to a granulomatous picture.10
Treatment Alternatives Jaundice and pruritis can be ameliorated with the use of cholestyramine, a drug that blocks the intestinal absorption of bile and prevents its entry into the enterohepatic circulation.6 Corticosteroids have been used by several authors with varying results.5'6'9 It is our opinion that the patient's sense of well-being is improved by steroids and when the steroids are taken every other day at low levels, side effects are minimal. Objective evaluation has been difficult to document without improvement in level of jaundice, cholangiogram or episodes of cholangitis. Choleuretic drugs act to decrease the viscosity of bile and may improve biliary drainage.9 These drugs have low morbidity and may help to minimize the episodes of cholangitis (Table 5). Use of the T-tube has remained controversial, although the majority of authors cite this device as having some efficacy in treating patients who have biliary cirrhosis or sclerosing cholangitis. 4,6,7 9 The T-tube can be used effectively following common duct exploration and biopsy, but if the bile drainage is minimal, it is best to remove the tube early. Not only does the T-tube cause some obstruction and perhaps increase the fibrotic reaction in the common duct, but it also serves as an avenue for contamination. In reviewing our 35 cases it was found that cholangitis was a significant cause of hospitalization. This point is not emphasized in previous publications and many clinicians assume that hepatic encephalopathy is the major risk factor. Choledochoenteric bypass should be reserved for those unusual cases in which there is isolated distal extrahepatic fibrosis with proximal dilatation.
Vol. 186 * No. 5
SCLEROSING CHOLANGITIS
Prognosis While the fibrosing process in primary sclerosing cholangitis and primary biliary cirrhosis may be selflimiting, it usually follows an unrelenting course leading to death of the patient due to hepatic failure. In fact, life expectancy of such patients is difficult to determine; palliation may range from two months to 19 years, and therefore aggressive treatment of the complications of biliary sclerosis should be pursued. Eighteen of the 21 patients with sclerosing cholangitis were followed for one year or longer. Five of these 18 patients died of their disease from one to six years after the first symptoms became apparent and two died of unrelated causes. The other 11 patients were alive when seen at periods from one to 14 years. Among the group, 17 T-tube placements were performed with symptomatic palliation from one to eight years. The 11 patients who were alive at last follow-up demonstrated a similar slow progressive decline in clinical status and worsening of liver function tests. None had spontaneous remission. The patients who died had followed a similar but accelerated course. The presenting symptoms, laboratory data, and associated diseases did not correlate with rate of survival. Thirteen of the 14 patients with primary biliary cirrhosis were followed for one year or longer. Five of these 13 died of their disease from one to 22 years after their first symptoms occurred, and one died of unknown causes. The surviving seven patients have been observed for periods ranging from one to 13 years. Those with biliary cirrhosis demonstrated a slowly progressive course. Among the patients who died, survival after the onset of symptoms lasted for a longer time than those with primary sclerosing cholangitis (2.5 versus 9.5 years). Survival time did not correlate with initial laboratory values or associated diseases (Table 6).
TABLE 6. Prognosis
Primary Biliary Cirrhosis Total number of patients studied Patients dead at time of study Mean time from symptoms to death
14
Primary Sclerosing Cholangitis 21
6(43%)
4(33%)
9.5 yrs
2.5 yrs
autoimmune disease, (e.g., retroperitoneal fibrosis, thyroiditis, and ulcerative colitis);3 (b) improvement with steroids; (c) eosinophilia;2 (d) biliary tract autoantibodies ;8 and (e) occasional serum globulin abnormalities such as elevated IgM. Although this theory is attractive, it is far from conclusive. While these diseases classically occur in different areas of the biliary duct system, there are many cases that seem to exhibit the characteristics of both. Thus, biliary sclerosis of intralobular cholangioles, extrahepatic bile ducts, or of the entire bile duct system may represent varying degrees of response to a common etiologic agent. References 1. Altemeier, W. A. and Culbertson, W. R.: Sclerosing Car-
2. 3.
4. 5. 6.
Etiology
The etiology or etiologies of sclerosing cholangitis and primary biliary cirrhosis are not known. Suggested possibilities have included syphilis, toxins such as polyvinyl chloride and carbon tetrachloride, or a post-viral Schwartzmann reaction.2 Portal bacteremia has also been considered in view of the common finding of E. coli in the bile and the association with ulcerative colitis.12 In our series, no organisms was consistently found in the bile and several have been sterile. Significant consideration has been given to the possibility of an autoimmune etiology on the basis of indirect evidence including (a) association with other
593
7. 8. 9. 10. 11.
12. 13.
cinoma of the Hepatic Bile Ducts. Surg. Clin. North Am., 53:1229, 1973. Atkinson, A. J. and Carroll, W. W.: Sclerosing Cholangitis: Association with Rlegional Enteritis. J.A.M.A., 188:183, 1964. Bartholomew, L. G., Cain, J. C., Waciner, L. B. and Utz, D. C.: Sclerosing Cholangitis: Its Possible Association with Riedel's Struma and Fibrous Retroperitonitis. Report of Two Cases. N. Engl. J. Med., 269:8, 1963. Culter, B. and Donaldson, G. A.: Primary Sclerosing Cholangitis and Obliterative Cholangitis. Am. J. Surg., 117:502, 1969. Grua, 0. E. and McMurrin, J. A.: Sclerosing Cholangitis: Review and Presentation of an Unusual Pathologic Variant. Am. J. Surg., 116:659, 1968. Longmire, W. P., Jr., Joseph, W. L., Levin, P. M. and Mellinkoff, S. M.: Diagnosis and Treatment of Cholangiolitic Hepatitis (Primary Biliary Cirrhosis). Ann. Surg., 162:356, 1965. Oviedo, M. A., Volkmer, D. and Scanlon, E. F.: Primary Sclerosing Cholangitis. Arch. Surg., 109:747, 1974. Peck, J. J., Kern, W. H. and Mikkelsen, W. P.: Sclerosis of the Extra-hepatic Bile Ducts. Arch. Surg., 108:798, 1974. Schwartz, S. I.: Primary Sclerosing Cholangitis: A Disease Revisited. Surg. Clin. North Am., 53:1161, 1973. Sherlock, S.: Chronic Cholangitides: Aetiology, Diagnosis and Treatment. Br. Med. J., 3:515, 1968. Walker, J. G., Doniach, D., Roitt, I. M. and Sherlock, S.: $erological Tests in Diagnosis of Primary Biliary Cirrhosis. Lancet, 6:827, 1965. Warren, K. W., Athanassiades, S. and Monge, J. I.: Primary Sclerosing Cholangitis: A Study of 42 Cases. Am. J. Surg., 111:23, 1966. Whelton, M. J.: Sclerosing Cholangitis. Clinics in Gastroenterology, 2:163, 1973.
