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Trichosporon cholangitis associated with hyperbilirubinemia, and findings suggesting primary sclerosing cholangitis on endoscopic retrograde cholangiopancreatography.

Usually, ascending cholangitis is a bacterial process. However, in the debilitated or immunocompromised patient, mycotic cholangitis must be placed in the differential diagnosis. We report a patient with cryptogenic cirrhosis whose presenting problem in his terminal hospitalization was spontaneous bacterial peritonitis, for which he was treated with broad-spectrum antibiotics. Endoscopic retrograde cholangiopancreatogram was performed during the hospital course to explain his profound hyperbilirubinemia. The findings were grossly consistent with primary sclerosing cholangitis or cholangiocarcinoma. The patient subsequently continued to deteriorate, and died with hepatic and renal failure. At autopsy, he was found to have choledocholithiasis, marked biliary duct proliferation, and ascending cholangitis, with Trichosporon demonstrated histologically to be invading the bile ducts. To our knowledge, this is the first reported case of Trichosporon cholangitis.

Cholangiopancreatography, Endoscopic Retrograde

HLA class II genes in primary sclerosing cholangitis and chronic inflammatory bowel disease: no HLA-DRw52a association in Swedish patients with sclerosing cholangitis.

The familial predisposition to chronic inflammatory bowel disease and the increased concordance rate in monozygotic twins with Crohn's disease, suggest that genetic factors influence disease susceptibility. A 100% association with the supertypic HLA class II specificity DRw52a was recently described in white North American patients with primary sclerosing cholangitis, with or without concurrent ulcerative colitis. HLA class II alleles of the DR, DQ, and DP subregions were determined by genomic typing techniques in a large group of Swedish patients with ulcerative colitis or Crohn's disease as well as in a series of patients with primary sclerosing cholangitis. No statistically significant HLA class II association was observed in any of the investigated diseases or when the patients were subgrouped according to disease site or occurrence of extraintestinal manifestations, except an insignificant increase of the DRw17, DQw2 haplotype in patients with primary sclerosing cholangitis. The failure to confirm the well established DRw17 association in Swedish patients with sclerosing cholangitis probably represents a statistical type II error. Furthermore, this study did not verify the recently described strong DRw52a association in sclerosing cholangitis--52% of the patients were DRw52a positive compared with 28% of the controls (p less than 0.05, pc NS). This discrepancy was probably caused by different typing techniques. The DRw52a specificity was determined directly by hybridising HLA-DRB3 genes, group specifically amplified by the polymerase chain reaction, with an allele specific oligonucleotide probe, whereas in the previously mentioned study DRw52a was assigned by indirect serological criteria, which overestimate the frequency of this allele.

Blotting, Southern

Cholangitis glandularis proliferans. A histologic variant of primary sclerosing cholangitis with distinctive clinical and pathological features.

This is the first report in the American literature of a recently described histologic variant of primary sclerosing cholangitis (PSC). Only six examples of this unique entity, called cholangitis glandularis proliferans (CGP), or proliferative cholangitis, have previously been reported. This disorder typically presents as painless jaundice but differs clinically from PSC by occurring predominantly in females and lacking an association with inflammatory bowel disease. The unique histological features are characterized by florid intramural proliferation of glandular elements in addition to an intense inflammatory component. Anatomically, the lesion is confined to the extrahepatic biliary tree, which enables its successful surgical extirpation since it does not appear to be progressive.

Adult

Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas.

Pancreatic involvement in primary sclerosing cholangitis (PSC) is an extremely rare condition, and its pathologic features are poorly documented. We report two cases of an unusual lymphoplasmacytic sclerosing inflammatory disease involving the total pancreas, common bile duct, gallbladder, and, in one patient, the lip. Two elderly men presented with waxing and waning obstructive jaundice, and exhibited radiologic and ultrasonographic findings highly suggestive of pancreatic carcinoma. Gross appearance of the pancreas showed firm and mass-like enlargement with regional lymph node swelling. Histologic findings were characterized by diffuse lymphoplasmacytic infiltration with marked interstitial fibrosis and acinar atrophy, obliterated phlebitis of the pancreatic veins, and involvement of the portal vein. Similar inflammatory processes involved the bile duct and the gallbladder. Lymphoplasmacytic sclerosing pancreatitis with cholangitis is thought to be a more appropriate term for this condition, of which a similar lesion has been previously noted in a single case of "PSC involving pancreas". Differences in age, radiologic appearance, and the negative history of ulcerative colitis exist, but the two cases in this study could be considered as a variant of PSC extensively involving pancreas, which can readily be mistaken for pancreatic carcinoma.

Aged

Risk factors and classification of acute suppurative cholangitis.

A prospective study was performed in 1282 patients with common bile duct stones to determine the clinical and laboratory parameters that could predict cholangitis, and the factors associated with greater severity of cholangitis. Patients were divided into two groups, with or without acute cholangitis, depending on the macroscopic appearance of bile aspirated from the common bile duct during surgery. Acute cholangitis was diagnosed when the aspirated fluid was turbid or clearly pus; the typical Charcot's triad was present in only 22 per cent of patients with acute cholangitis. Several clinical and laboratory parameters were significantly more common in these patients and, depending on their number, the probability of acute cholangitis increased significantly. The operative mortality rate was 1.2 per cent for patients without cholangitis and 11.9 per cent for patients with cholangitis. Depending on the number of factors present, patients with cholangitis were divided into three groups: mild acute cholangitis without mortality; moderate acute cholangitis with a mortality rate of 5.6 per cent; and severe acute cholangitis with a mortality rate of 27.5 per cent. The present classification allows the group of patients needing prompt endoscopic or surgical drainage to be identified.

Acute Disease

Unconjugated bilirubin in hepatic bile with brown pigment gallstones and cholangitis.

To investigate the role of cholangitis in hydrolysis of bilirubin in bile with brown pigment gallstones, bilirubin composition and bacterial growth in hepatic bile with and without cholangitis were studied. The study included 38 brown pigment gallstone cases (28 without cholangitis and 10 with cholangitis). The proportion of unconjugated bilirubin in hepatic bile with cholangitis (16.9 +/- 8.5%, mean +/- SD) was significantly higher than that without cholangitis (3.7 +/- 1.8%, P less than 0.001). A positive correlation was found between bacterial population with beta-glucuronidase activity and the proportion of unconjugated bilirubin in bile in cases of brown pigment stones with cholangitis (P less than 0.05) but not in those without cholangitis despite the fact that bacterial species and population are similar regardless of the presence of cholangitis. In cholangitis, pH of bile becomes lower toward the optimal pH of bacterial beta-glucuronidase. Together the lower concentration of bile acid and the lower pH in bile result in lower solubility of unconjugated bilirubin, promoting its precipitation. Thus occasional bouts of cholangitis may result in periodic deposition of bilirubinate on brown pigment stones with layered structures by inducing cyclic changes of bile composition in situ.

Bacteroides

Diagnosis of sclerosing cholangitis with technetium 99m-labeled iminodiacetic acid planar and single photon emission computed tomographic scintigraphy.

The purpose of this study was to determine whether 99mTc-iminodiacetic acid planar biliary scintigraphy combined with single photon emission computed tomography could detect sclerosing cholangitis and provide additional information regarding the extent and severity of disease. Thirteen patients with sclerosing cholangitis and 13 normal control subjects were studied. Scintigraphic results were also compared with previously reported studies of patients with isolated common bile duct obstruction and with primary biliary cirrhosis. The planar scintigraphy in patients with sclerosing cholangitis showed beading or bandlike constrictions of the biliary tract corresponding to lesions seen on cholangiography, and the image pattern was distinctly different from images obtained from patients with isolated common bile duct obstruction or primary biliary cirrhosis. The single photon emission computed tomography images of the liver in patients with sclerosing cholangitis demonstrated multiple focal areas of 99mTc-iminodiacetic acid retention, representing bile stasis in intrahepatic bile ducts. Compared to controls, the mean hepatic clearance half-time of 99mTc-iminodiacetic acid was markedly delayed in patients with sclerosing cholangitis (6-10 times normal). Individual patients with sclerosing cholangitis had wider variation in isotope clearance half-time from three regions of the liver than patients with isolated common bile duct obstruction, consistent with regional difference in disease severity and variable impairment of bile flow. In 4 patients with sclerosing cholangitis with incomplete filling of the right and left hepatic ducts at cholangiography, planar and single photon emission computed tomographic scintigraphy provided evidence of significant intrahepatic sclerosing cholangitis. In conclusion, combined 99mTc-iminodiacetic acid planar and single photon emission computed tomographic scintigraphy is a sensitive noninvasive test for the diagnosis of sclerosing cholangitis and reliably differentiates sclerosing cholangitis from isolated common bile duct obstruction or primary biliary cirrhosis. Measurement of isotope clearance half-time provides quantitative physiologic data that may be useful in the longitudinal follow-up of patients with sclerosing cholangitis.

Adult

Ischemic cholangitis in hepatic allografts.

In this report, our objectives are to introduce the term "ischemic cholangitis" as an etiologic designation and to describe its manifestations. Herein we use the label "ischemic cholangitis" as a collective term for ischemic bile duct necrosis, cholangitis caused by ischemia but without necrosis, and biliary fibrosis as a manifestation of ischemic damage. The condition was observed in 12 allografts, either at the time of retransplantation (9 cases) or at autopsy (3 cases). Ischemic cholangitis involved primarily perihilar extrahepatic and intrahepatic bile ducts. The findings included duct necroses (eight cases), strictures (four cases), and cholangiectases (four cases); some of these features coexisted. In addition, complicating ascending cholangitis and cholangitic abscesses were noted in three cases. Ischemic cholangitis was caused by hepatic artery thrombosis (in nine patients) or stenosis (in one) or by occlusion of parabiliary arteries by fibrointimal proliferations, probably attributable to old thromboses (in two, in conjunction with associated foam cell arteriopathy in one). Biopsy specimens before retransplantation or autopsy were obtained in 11 patients, only 1 of whom had an infarct as direct evidence of ischemia. Nine patients had evidence of biliary obstruction or bile flow impairment; in two cases, specimens were normal or nondiagnostic relative to cholangitis. Features of cellular rejection associated with the manifestations of bile flow impairment and ischemia were noted in five cases. Thus, biopsy features that suggest biliary obstruction, with or without cellular rejection, may be a manifestation of ischemic cholangitis. We conclude that ischemic cholangitis is an important cause of cholestatic graft failure but that this type of cholangitis is difficult to diagnose because of its misleading biopsy manifestations.

Adult

Serum autoantibodies, ulcerative colitis and primary sclerosing cholangitis.

The aetiology of primary sclerosing cholangitis is unknown, but it is closely associated with ulcerative colitis. Serum anticolon antibodies, crossreacting with portal tracts, have been reported in patients with ulcerative colitis but no studies have been carried out in primary sclerosing cholangitis. The frequency of serum anticolon antibodies and portal tract antibodies have been measured in 24 patients with primary sclerosing cholangitis and ulcerative colitis; 15 patients with primary sclerosing cholangitis without ulcerative colitis; 77 patients without primary sclerosing cholangitis: 25 patients with Crohn's colitis; 10 patients with primary biliary cirrhosis; 22 patients with extrahepatic biliary obstruction and 20 normal controls. Serum anticolon and portal tract antibodies were detected using immunoperoxidase techniques on normal colon and obstructed human liver. Tissue typing was undertaken using a standard microcytotoxicity technique. The frequency of anticolon antibodies was markedly increased in primary sclerosing cholangitis patients with ulcerative colitis (62.5%) compared with patients with ulcerative colitis (17%) and Crohn's colitis (16%) (chi 2 = 17.9; p less than 0.001). The antibodies were almost entirely of IgG and IgA classes in all groups. Anticolon antibodies were not found in sera from any other group. Sera from eight of 15 patients with primary sclerosing cholangitis, ulcerative colitis and anticolon antibody reacted with portal tracts of human obstructed liver. This reaction was also seen in four of nine patients with ulcerative colitis and primary sclerosing cholangitis and in three of 15 patients with primary sclerosing cholangitis alone. Portal tract antibody was of IgG class and was not present in sera from any other groups. Unlike anticolon antibody, there was a close relationship between HLA-B8 phenotype and the portal tract antibody (p<0.02; chi 2 = 6.04). Absorption studies confirmed that the anticolon antibody is distinct from portal tract antibody.

Autoantibodies

Significance and specificity of antibodies to neutrophils detected by western blotting for the serological diagnosis of primary sclerosing cholangitis.

Antibodies against neutrophils have been detected in sera from patients with primary sclerosing cholangitis and inflammatory bowel diseases either by immunofluorescence or by enzyme-linked immunosorbent assay. To assess primary sclerosing cholangitis-specific antibodies, we examined sera from 30 patients with clinically and morphologically well-established primary sclerosing cholangitis by Western blotting against neutrophils and compared these results with those obtained by testing sera from patients with inflammatory bowel diseases. By Western blot using sonified neutrophils, 24 (80%) of 30 primary sclerosing cholangitis sera were positive. Five antigenic determinants at 95, 60, 55, 40 and 30 kD were visualized. Twenty-eight of the primary sclerosing cholangitis sera also showed the characteristic perinuclear fluorescence pattern by immunofluorescence on neutrophils. Thus a serological diagnosis of primary sclerosing cholangitis could be made in 80% of patients based on these two methods. In contrast, only 9% of 23 patients with ulcerative colitis and 10% of 60 patients with Crohn's disease were positive by Western blot, and these patients also showed positive perinuclear fluorescence pattern by immunofluorescence, suggesting an overlap between inflammatory bowel diseases and primary sclerosing cholangitis. Although some patients with classical primary biliary cirrhosis and autoimmune chronic active hepatitis had antibodies against primary sclerosing cholangitis epitopes, none of the patients with obstructive bile duct disorders, collagen diseases, Wegener's granulomatosis or other hepatic and nonhepatic disorders were positive by Western blot, indicating the specificity of these five primary sclerosing cholangitis-related neutrophilic epitopes.

Adolescent

[The clinical and pathologic correlations in acute cholangitis].

The liver histology of acute cholangitis was studied in order to determine whether microscopic changes correspond to clinical status. Patients with acute cholangitis were divided into mild cholangitis (1st group, n = 18) and severe cholangitis (2nd, 3rd and 4th groups) accompanied by hypotension. The 2nd group consisted of 6 surviving patients who underwent liver biopsy during hypotension. The 3rd group consisted of 3 non-surviving patients with biopsy during hypotension. The 4th group consisted of 7 patients with biopsy during autopsy. The frequency of endotoxemia, gram negative bacteremia, disseminated intravascular coagulopathy and hepatic failure were significantly higher in severe cholangitis than in mild cholangitis. The incidence of neutrophilic infiltration in the sinusoid and microabscess in lobule were significantly higher in severe cholangitis than in mild one. The incidence of portal thrombosis and massive necrosis of hepatic cells were also significantly higher in severe cholangitis, especially in the 3rd and 4th groups. It was suggested that the neutrophilic infiltration in the sinusoid and microabscess in lobules which proved the existence of endotoxemia or bacteremia were characteristic findings in severe cholangitis.

Acute Disease

Enhanced autoreactivity of T-lymphocytes in primary sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic, cholestatic liver disease in which immune mechanisms are thought to play a role in the pathogenesis. We have determined the frequencies and functional phenotypes of autoreactive T-lymphocytes in peripheral blood specimens from patients with primary sclerosing cholangitis and healthy adults as an indicator of autoreactivity in primary sclerosing cholangitis. We found a significant increase in the percentage of autoreactive suppressor/cytotoxic T-lymphocytes that become activated in the T-, non-T-autologous mixed lymphocyte reaction in primary sclerosing cholangitis patients (p less than 0.002). Blastogenesis in autologous mixed lymphocyte reaction cultures from primary sclerosing cholangitis patients was significantly decreased (p less than 0.02), and the magnitude of the decrease correlated directly with the percentage of activated suppressor/cytotoxic T-lymphocytes (r = 0.56, p less than 0.01). The percentage of autoreactive, suppressor T-lymphocytes was increased in autologous mixed lymphocyte reaction cultures from primary sclerosing cholangitis patients (p less than 0.0001); and suppression of mitogen-induced blastogenesis by autologous concanavalin A-treated mononuclear cells was significantly enhanced. These results, which were unrelated to the histologic stage of liver disease and the presence or absence of active colitis, document the presence of an expanded population of T-lymphocytes in the peripheral blood of patients with primary sclerosing cholangitis that became activated on exposure to autologous major histocompatibility antigens in the autologous mixed lymphocyte reaction. We hypothesize that these autoreactive cells may be a marker or may participate as effector cells in cell-mediated autoimmunity in primary sclerosing cholangitis.

Adult

Endoscopic sphincterotomy as a therapeutic measure in cholangitis and as prophylaxis against recurrent biliary tract stones.

Our purpose was to analyse the results of endoscopic sphincterotomy in patients with advanced cholangitis, and to assess the potential of this method in the prevention of recurrent biliary tract stones. Advanced cholangitis certainly predisposes to microlith formation, and we believe that the increased biliary drainage produced by sphincterotomy counteracts this process. Our grading of cholangitis was an intraoperative cholangioscopic assessment corresponding to Nishimura grades III and IV (erosions in the duct walls, patchy stone ulceration, biliary gravel, fibro-purulent plaques densely adherent to the biliary walls etc. 62 patients with grades III and IV cholangitis (as defined at choledochoscopy) underwent endoscopic sphincterotomy (GP-A). This group underwent a controlled prospective study with review at: one year, between 2 and 3 years, 5 years following surgery. The control group (GP-B) constituted 20 patients with comparable cholangitis who did not undergo sphincterotomy. Group A had no recurrent lithiasis, 4.8% revealed persistent cholangitis. In control group (GP-B) 6 patients (30%) revealed recurrent lithiasis, on average 4.6 years following initial surgery. In addition, 35% of this group had clinical symptoms of cholangitis. These results indicate that endoscopic sphincterotomy is a worthwhile method in the treatment of cholangitis and prophylaxis against recurrent biliary tract stones.

Ampulla of Vater

Nonoperative dilatation of dominant strictures in primary sclerosing cholangitis.

While most cases of primary sclerosing cholangitis are characterized by multifocal bile duct strictures, a few have a localized high-grade stricture (dominant stricture) superimposed on diffuse disease. This dominant stricture may cause jaundice or bacterial cholangitis in some patients. Dominant strictures were percutaneously dilated in 14 patients with primary sclerosing cholangitis and jaundice or bacterial cholangitis. Stricture dilatation produced a significant decrease in the frequency of cholangitis and a significant decrease in serum bilirubin in those with recent onset of jaundice. The only complication was bacteremia or cholangitis in five patients. Three of nine patients with successful dilatations developed recurrent strictures at 6-18 months. Balloon dilatation should be considered the treatment of choice for dominant strictures in symptomatic patients with primary sclerosing cholangitis who have recent onset of jaundice (less than 6 months' duration) or recurrent episodes of bacterial cholangitis.

Cholangiography

Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis.

All patients greater than or equal to 16 years old with a diagnosis of ulcerative colitis were identified in five well-defined catchment areas, representing 12.7% of the Swedish population. Exactly 1500 patients were retrieved, giving a point prevalence of 170/10(5) inhabitants. It was possible to obtain liver function test results less than 2 years old in 94% of the patients and to obtain endoscopic retrograde cholangiographic results in 65 of the 72 patients with abnormal serum alkaline phosphatase values. Primary sclerosing cholangitis was diagnosed in 55 of the patients (3.7%). The prevalence of the disease was 5.5% in patients with substantial colitis and 0.5% in patients with distal colitis. There was a marked male predominance in cholangitis patients compared with colitis patients without cholangitis. Ninety-five percent of the patients with cholangitis had substantial colitis, which was more than the 62% of patients without cholangitis who had colitis. Female patients with cholangitis were older than male patients at the time of diagnosis of both cholangitis and colitis, which contrasted to the equal age at diagnosis of colitis in male and female patients without cholangitis.

Adolescent

Different immune mechanisms leading to autoimmunity in primary sclerosing cholangitis and autoimmune chronic active hepatitis of childhood.

Children with primary sclerosing cholangitis or autoimmune chronic active hepatitis have similar high levels of immunoglobulin G and non-organ-specific autoantibodies and may have similar histological features. To investigate a possible immunopathogenesis of primary sclerosing cholangitis, we have studied a series of regulatory and/or effector immune mechanisms in eight children with primary sclerosing cholangitis, comparing them to 14 children with autoimmune chronic active hepatitis and 24 healthy children as controls. Antibodies to a liver membrane protein preparation were found in all children with autoimmune chronic active hepatitis tested and in seven of eight with primary sclerosing cholangitis, whereas antibodies against the hepatic asialoglycoprotein receptor were present in three of six patients with autoimmune chronic active hepatitis and in two of the eight with primary sclerosing cholangitis. Lymphocyte cytotoxicity values to autologous hepatocytes were similarly elevated in primary sclerosing cholangitis (median: 50%; range: 38 to 83%) and in autoimmune chronic active hepatitis (median: 52%; range 37 to 87%) compared to controls (median: 8%; range: 0 to 27%) (p less than 0.01 for both). In contrast, T suppressor cell number and function were normal in patients with primary sclerosing cholangitis (median: 23%; range: 19 to 28%; and median: 54%; range: 44 to 61%), but significantly decreased in patients with autoimmune chronic active hepatitis (median: 15%; range: 9 to 21%; and median: 9%; range: -40 to +21%) when compared to controls (median: 24%; range: 16 to 29%; and median: 53%; range: 8 to 77%) (p less than 0.01 for both).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent

Acute cholangitis.

Cholangitis is an infection of the biliary ductal system that results from the combination of bactibilia and biliary obstruction. Choledocholithiasis has been the leading cause of cholangitis. However, in recent years, especially at tertiary referral centers, nonoperative biliary manipulations, often in patients with unresectable malignancies, have become the most common cause of cholangitis. As a result, the complete triad of fever and chills, jaundice, and abdominal pain, as originally described by Charcot, is now seen less frequently. Most patients still have leukocytosis and abnormal liver function tests, but many patients with indwelling tubes may develop cholangitis without significant jaundice. E. coli, Klebsiella species, and the enterococci remain the most frequently isolated organisms, and anaerobes including Bacteroides fragilis are recovered in 15% to 30% of patients. However, Enterobacter and Pseudomonas species, as well as yeasts, are now being isolated more frequently from patients with indwelling tubes, who often have been treated previously with antibiotics. Computed cholangiography usually is necessary to determine the cause and site of biliary obstruction. In the majority of patients with cholangitis, cholangiography can be delayed until the patient has been afebrile for a minimum of 24 to 48 hours. Initial therapy includes bowel rest, intravenous fluids, and antibiotics. Many antibiotic regimens are now available to cover the gram-negative aerobes, the enterococcus, and the anaerobes that are likely to be causing the biliary infection. The combination of a penicillin and an aminoglycoside has been the gold standard. However, recent studies suggest that the newer broad-spectrum penicillins provide adequate therapy for these patients. Only a small percentage (5%-10%) of patients with toxic cholangitis require emergency biliary decompression. The choice of percutaneous or endoscopic drainage should be made on the basis of the presumed site and cause of obstruction as well as local expertise. The nature of the biliary obstruction may be the most important determinant of outcome. At present, patients with end-stage malignant obstruction account for most of the deaths, whereas approximately 95% of patients survive an episode of cholangitis.

Acute Disease