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We evaluated the therapeutic efficacy of penicillamine in primary sclerosing cholangitis. In a randomized, prospective, double-blind trial, 39 patients received penicillamine (250 mg t.i.d.) and 31 received a placebo. The two groups were highly comparable at entry with regard to clinical, biochemical, radiologic, and hepatic histologic features. Although a predictable cupruresis and a decrease in levels of hepatic copper were achieved in patients taking penicillamine, there was no beneficial effect on disease progression within 36 mo or on overall survival. Progressive symptoms, deterioration in serial hepatic laboratory values, or histologic progression on sequential liver biopsy specimens were similar in both groups, occurring in greater than 80% of the entire study population. The development of major side effects led to the permanent discontinuation of penicillamine in 21% of the patients taking the drug. We conclude that the use of penicillamine in primary sclerosing cholangitis is not associated with a beneficial effect on disease progression or survival, and has considerable toxicity. The study also suggests that primary sclerosing cholangitis is a progressive disease in many patients.

Whipple's disease is a chronic systemic illness, the optimal treatment of which remains poorly defined. In our analysis of a 30-year, 29-patient experience with Whipple's disease at the Mayo Clinic, the frequent initial manifestations of diarrhea, weight loss, arthritis, and lymphadenopathy correlated with findings reported previously by other investigators. Antibiotic therapy yielded rapid symptomatic and biochemical improvement, and histologic changes in the small bowel occurred subsequently. Despite antimicrobial therapy, relapses in patients with Whipple's disease are common, and the central nervous system is considered the most serious site of involvement for recurrence. Administration of an antibiotic agent that is able to cross the blood-brain barrier may be more important in preventing relapse than prolonged duration of initial antimicrobial therapy.

When Wilson's disease presents as fulminant hepatic failure, it may be extremely difficult to differentiate from other causes of hepatic insufficiency. A recently described diagnostic biochemical profile (elevated serum and urine copper levels, mild transaminase elevation, very high bilirubin levels, and low hemoglobin with intravascular hemolysis) was employed to diagnose this form of Wilson's disease prior to death in a young woman without Kayer-Fleischer rings and with a normal serum ceruloplasmin level. Since hepatic transplantation now offers a possible cure for this previously uniformly fatal form of Wilson's disease, it should be considered the treatment of choice for this disease entity. Combined with the availability of hepatic transplantation, this patient's temporary improvement and unusually long survival of four months further emphasizes the importance of this diagnostic profile in recognizing Wilson's disease quickly and accurately when it presents as fulminant hepatic failure.

Successful implementation of a liver transplantation program is dependent on extensive blood bank support. Careful planning, organization, and coordination of the blood bank and other clinical services are necessary. In our first 100 orthotopic liver transplantations, our median intraoperative erythrocyte use was 12.6 units, and 30% of the erythrocytes were provided by intraoperative cell salvage. Thus, the need for homologous blood and the number of donors to whom recipients were exposed were reduced. Use of intraoperative cell salvage and expansion of our erythrocyte inventory through the use of AS-1 preservative helped us meet the demands of the liver transplant program without compromising the availability of blood products for all other surgical and medical patients.

The effect of proctocolectomy on the primary sclerosing cholangitis that frequently is associated with chronic ulcerative colitis in patients with both conditions is unknown. We have studied prospectively the progression of clinical, biochemical, cholangiographic, and hepatic histologic features in 45 patients with both primary sclerosing cholangitis and chronic ulcerative colitis to compare these variables in the 20 patients who had undergone proctocolectomy with the 25 who had not. The two groups were similar initially with regard to clinical, biochemical, cholangiographic, and hepatic histologic findings. All patients were followed for a minimum of 1 yr and overall duration of follow-up was similar in both groups (4.1 vs. 3.9 yr). Clinically, new onset of hepatomegaly, splenomegaly, esophageal varices, and ascites did not differ in patients with and without proctocolectomy. Biochemically, the serial changes in bilirubin, alkaline phosphatase, aspartate aminotransferase, prothrombin time, and albumin were similar. Histologic progression on liver biopsy did not differ between groups, nor did changes on serial cholangiograms. Proctocolectomy also had no effect on survival. We conclude that proctocolectomy for chronic ulcerative colitis has no beneficial effect on the primary sclerosing cholangitis in patients with both diseases.

A 43-year-old man underwent abdominoperineal resection of a rectal adenocarcinoma, and left hepatic lobectomy for a single metastasis. He then received hepatic artery infusions of floxuridine. The tumor did not recur, but sclerosing cholangitis and liver failure developed which necessitated orthotopic liver transplantation. In the hilus of the native liver, obstructive arteriopathy and portal venopathy were found. These lesions probably had been caused by drug-induced intravascular thrombosis. Thus, the sclerosing cholangitis that develops in many patients after floxuridine infusion may be ischemic rather than toxic. The patient described here is well, 14 months after orthotopic liver transplantation. Therefore, in some cases of floxuridine-induced cholangitis, liver transplantation appears to be indicated despite a history of metastasizing carcinoma.

As an initial step in testing the hypothesis that immunoregulatory abnormalities are important in the pathogenesis of primary sclerosing cholangitis, we determined the number and percentage of lymphocyte subsets in the peripheral blood of 33 patients with primary sclerosing cholangitis. In these patients, when compared with normal and diseased controls, there was a significant reduction in the total number of circulating T cells because of a disproportionate decrease in Leu-2a (suppressor/cytotoxic) cells. This decrease resulted in a significantly increased ratio of Leu-3a to Leu-2a cells. Patients with cirrhosis had significantly higher Leu-3a/Leu-2a (helper/suppressor) ratios than did noncirrhotic patients; both disease groups, however, had ratios that were significantly higher than controls. The number and percentage of B cells were significantly increased. Alterations in the percentage of B cells correlated significantly with histologic stage and concentrations of gamma globulin, serum IgG, and bilirubin. We conclude that these abnormalities are suggestive of a defect in immunoregulation in primary sclerosing cholangitis, which is not secondary to advanced liver disease alone and appears to be independent of chronic ulcerative colitis or obstructive jaundice.

No controlled trials have been performed to assess the efficacy of liver transplantation. Because of the marked improvement in survival after liver transplantation since 1981, random assignment of patients to a control group not undergoing transplantation is considered clinically inappropriate. To assess the efficacy of liver transplantation in patients with primary biliary cirrhosis, we compared survival in 161 patients with this diagnosis who had undergone a liver transplantation with survival in patients with the same diagnosis who had been treated conservatively. The comparison was performed with use of a recently developed statistical technique, the Mayo model. All patients had undergone liver transplantation between March 1980 and June 1987 and were followed for a median of 25 months. Three months after liver transplantation, the Kaplan-Meier survival probabilities in the recipients were substantially higher than the Mayo-model "simulated-control" survival probabilities (P less than 0.001). At two years, the Kaplan-Meier survival probability was 0.74, whereas the mean Mayo-model survival probability was 0.31. The patients who were at low risk according to the Mayo model had the best probability of survival after liver transplantation; however, patients at all risk levels who had undergone liver transplantation had higher probabilities of survival that those who had not. We conclude that liver transplantation is an efficacious treatment in patients with advanced primary biliary cirrhosis.

Twelve liver and 5 kidney transplant recipients with severe cytomegalovirus infection were treated with Ganciclovir (7.5 mg/kg/day, intravenously). Ten were evaluable (compatible clinical picture, organ involvement shown histopathologically or by culture, viremia, and absence of concomitant infection). All 17 patients were studied for adverse drug side effects. A total of 9 evaluable patients survived the infection; 1 died during treatment due to infection or drug toxicity. A death 19 days after completion of treatment was due to unrelated causes. Patients became afebrile after 2-9 days (mean, 5.3 days) of treatment. Liver function improved, pulmonary infiltrates cleared, and hypoxemia reversed during therapy. Viremia ceased during therapy in 9 patients; asymptomatic viruria persisted or recurred in 6 of 7 patients studied. No relapses occurred during follow-up (7-17 months; mean, 13 months). Transient neutropenia and thrombocytopenia occurred in 3 and 1 patients, respectively. Ganciclovir appears promising for treatment of severe CMV infection in patients with kidney or liver transplants.

Primary biliary cirrhosis is a chronic, progressive, cholestatic liver disease thought to be related to abnormalities in immune regulation. The disease is associated with granulomatous bile duct destruction, cholestasis, hepatic copper overloading and the development of hepatic fibrosis or cirrhosis or both. There have been numerous therapeutic trials evaluating immunosuppressive, antifibrotic and cupruretic agents. Prednisolone, D-penicillamine, azathioprine, colchicine and chlorambucil have been evaluated in controlled clinical trials, and biochemical improvement of liver function has been noted with all of the agents, except D-penicillamine. Improved survival has also been reported in patients treated long-term with azathioprine and colchicine. However, none of the therapeutic agents has been demonstrated to halt histologic progression of the disease or to induce a complete clinical, biochemical and histologic remission as has been reported in patients with autoimmune chronic active hepatitis treated with corticosteroids. Many of the trials did not use a double-blind design, failed to use the "intent to treat" rule or failed to define an objective time to analyze results. Many of the studies involved small numbers of patients with short-term follow-up and thus potentially were inadequate to appreciate drug effects that might be of clinical benefit. Currently, there is no totally effective therapy for primary biliary cirrhosis. We believe that well-designed clinical trials can provide important information to better understand this disease until a totally effective therapy is available. New clinical trials should use well-established methodologic guidelines in study design and well-accepted statistical standards in the analysis and interpretation of results.

We retrospectively reviewed the results of preoperative hematology-coagulation studies in 66 patients who underwent orthotopic liver transplantation-24 with the primary diagnosis of chronic active hepatitis (CAH), 22 with primary sclerosing cholangitis (PSC), and 20 with primary biliary cirrhosis (PBC). The mean prothrombin time was above normal in all three diagnostic groups, patients with CAH having the highest values. The mean activated partial thromboplastin time was normal in patients with PSC or PBC but elevated in those with CAH. Fibrinogen levels were above normal in patients with PBC but decreased in 1 patient (5%) with PSC and 10 (42%) with CAH. Mean platelet counts were below normal in 68% and 55% of patients with PSC and PBC, respectively, but in 96% of those with CAH. The mean Ivy bleeding time was normal in patients with PSC or PBC but prolonged in those with CAH. Patients with PSC or PBC had normal mean activity levels of factors II, V, VII, IX, and X, whereas those with CAH had below normal mean values for factors II and VII. The antithrombin III activity level was normal in patients with PSC or PBC but reduced in those with CAH. Thus, patients with CAH have a greater derangement in results of clotting studies in comparison with those who have PSC or PBC, but the use of blood did not differ among the three diagnostic groups.

To analyze the correlations between the presence of cirrhosis and hepatocellular inflammation and the serum concentrations of the amino-terminal peptide of procollagen type III in chronic liver disease, we measured procollagen type III concentrations in paired serum samples from 46 patients (17 had cirrhosis) with severe chronic active hepatitis during a therapeutic treatment trial. Coded sera were analyzed for procollagen type III concentrations using both a standard and a recently described Fab radioimmunoassay to compare their relative diagnostic accuracy. Mean procollagen type III levels were elevated to the same extent in the cirrhotic and noncirrhotic groups at entry into the study. In response to immunosuppressive therapy, the initially elevated procollagen type III levels improved to normal values at remission in both groups. Qualitatively, the results were similar using either assay, but the standard assay was more sensitive for identifying the clinical stage of disease (i.e., active disease vs. disease in remission) than the Fab assay. Since both procollagen type III levels and standard liver function tests correlated well individually with the presence or absence of active disease, they also correlated with each other when both entry and remission values were considered. However, procollagen type III levels correlated poorly with indicators of inflammation (histologic grade and serum transaminase levels) during active disease. It is concluded that procollagen type III levels change in concert with standard liver function tests but do not quantitatively reflect inflammation or static measurements of hepatic fibrosis in severe chronic active hepatitis. However, these preliminary results suggest that procollagen type III can distinguish active disease from chronic active hepatitis in remission.(ABSTRACT TRUNCATED AT 250 WORDS)

Monoclonal antibodies were used to identify T-helper cells (TH) and T-suppressor/cytotoxic cells (TS/C) in biopsy specimens obtained 7, 21, 90, 180, and 365 days postoperatively, and during episodes of graft dysfunction, from 34 consecutive liver transplant patients treated with cyclosporine and steroids. Rejection was diagnosed by the presence of appropriate laboratory and light microscopic findings and at least 8 weeks of follow-up to exclude other causes of graft dysfunction. Four immunohistologic patterns were seen--no labeled cells (No), only lobular TS/C, only portal TH, and a portal mixture of TH and TS/C (mix). Of 36 specimens with the No or only lobular TS/C pattern, 29 were not associated with rejection. Of the 39 specimens with the portal TH or portal Mix pattern, 33 were associated with a rejection episode. In addition, in nine specimens from patients with no biochemical or routine histologic evidence of rejection, the presence of portal TH or a portal mix indicated immunologic rejection 5 days to 5 weeks before biochemical and routine histologic evidence of it was manifested. Immunohistologic labeling appears to be an early indicator of liver allograft rejection.

A detailed coagulation and thromboelastographic study was done on the first 50 liver transplantation procedures performed at the Mayo Clinic between March 1985 and June 1986. Most of the patients suffered from primary sclerosing cholangitis, primary biliary cirrhosis, or chronic active hepatitis. Seven patients required a second liver transplantation, and six patients died, none intraoperatively. Most of the patients had distorted hemostatic mechanisms preoperatively, as would be expected because the liver generates most of the clotting factors. The outstanding exception was factor VIII, which was usually in the high-normal range or even more elevated. Substantial deterioration of coagulation factors occurred regularly during reperfusion of the donor liver. In some instances, this trend was corrected within 1 hour, but platelet counts continued to decrease, and some coagulation factors rebounded only partially. Because thromboelastographic tracings are quickly available to the liver transplant team and because they tend to forewarn of impending hemostatic problems, we believe that thromboelastography is a reasonably effective procedure for monitoring coagulation during liver transplantation.

The aims of our prospective study were to determine the development and natural history of esophageal varices and variceal bleeding in patients with primary biliary cirrhosis. As part of a controlled clinical study, 265 patients with primary biliary cirrhosis who did not have esophageal varices at entry were followed for a median of 5.6 yr. The mean age was 49 yr (range 26-75 yr), 89% were women, and 69% had advanced histologic stage disease (stage 3-4) on liver biopsy at study entry. All patients were screened annually for esophageal varices by barium esophogram or endoscopy, or both; endoscopy was used to diagnose all episodes of esophageal variceal bleeding. Esophageal varices developed in 83 (31%) patients, and 40 (48%) of those with esophageal varices experienced one or more episodes of esophageal variceal bleeding. Cox regression analysis indicated that only serum bilirubin and histologic stage were associated independently with time to development of esophageal varices. In patients who developed esophageal varices, 33% and 41% developed esophageal variceal bleeding at 1 and 3 yr, respectively. After development of esophageal varices, 1- and 3-yr survival estimates were 83% and 59%, respectively. After the initial variceal bleeding episode, survival estimates were 65% and 46% at 1 and 3 yr and were dependent on Child's classification. These findings are important in considering indications for prophylactic therapy for esophageal varices in primary biliary cirrhosis and may influence timing of liver transplantation.

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.

We found splenic artery aneurysms in 6 of 71 consecutive patients who underwent orthotopic liver transplantation at the Mayo Clinic. The incidence of splenic artery aneurysms in cirrhotic patients with portal hypertension was 10%. Five of the aneurysms were found in patients suffering from chronic active hepatitis, whereas no aneurysms were encountered in patients with primary sclerosing cholangitis or primary biliary cirrhosis. One patient ruptured a splenic artery aneurysm shortly after liver transplantation, and 1 patient developed an aneurysm 3 months after transplantation. We recommend coeliac angiography to be performed prior to liver transplantation, and if splenic artery aneurysms are found, ligation of the splenic artery should be performed at the time of transplantation to prevent possible rupture.

We describe three adult patients who had chronic cholestatic liver disease associated with unexplained loss of interlobular bile ducts; two of these patients eventually required orthotopic liver transplantation. We have named this condition 'idiopathic adulthood ductopenia' because (1) the etiology is unknown, (2) the age of the patients may be the only distinguishing feature between this newly described condition and neonatal or infantile nonsyndromatic paucity of intrahepatic bile ducts, and (3) morphologic demonstration of ductopenia is an indispensable finding. Our three patients, all males, had a negative drug history, absence of antimitochondrial antibodies, normal cholangiographic findings, and no evidence of inflammatory bowel disease. Idiopathic adulthood ductopenia may be a representation of (1) late onset of infantile paucity of intrahepatic bile ducts, (2) destructive viral cholangitis, and (3) isolated small-duct primary sclerosing cholangitis - that is, 'pericholangitis' unassociated with inflammatory bowel disease.

The association of primary sclerosing cholangitis and celiac disease was observed in three patients, an association not previously reported. All three patients were men who presented with chronic cholestatic liver disease at ages 32, 46, and 62 years, respectively. In each patient, endoscopic retrograde cholangiography showed the typical findings of primary sclerosing cholangitis. Histologic features of liver biopsy were compatible with the diagnosis. Two patients had associated chronic ulcerative colitis. All three patients complained of frequent loose stools and weight loss; subsequent testing showed severe steatorrhea (204 to 323 mmol/d of fecal fat on a 100 g fat diet). Total villous atrophy was found in all three patients on histologic examination of the small bowel. Celiac disease was diagnosed at the time of presentation in two patients who had primary sclerosing cholangitis and was diagnosed three years after the onset of primary sclerosing cholangitis in the third patient. The celiac disease responded to a gluten-free diet in each patient whereas the primary sclerosing cholangitis was not affected by dietary treatment. The possibility of a chance association of primary sclerosing cholangitis and celiac disease cannot be accurately assessed but seems unlikely given the rarity of both diseases. The relationship between the two diseases remains unknown, although an immunologic connection is suspected. Celiac disease should be considered in the differential diagnosis of severe steatorrhea in patients with primary sclerosing cholangitis.

A 52-year-old woman with primary biliary cirrhosis who had never had hepatic coma developed it while taking propranolol. The coma receded when the propranolol was stopped and 2 days later gastrointestinal bleeding did not precipitate hepatic coma. This raises the question whether propranolol and other beta blockers lead to hepatic encephalopathy.

PSC is a progressive chronic hepatobiliary disorder of unknown etiology for which no effective medical or surgical therapy now exists. This syndrome occurs most commonly in young men and is frequently associated with CUC. The diagnosis is best made utilizing endoscopic retrogradecopic retrograde cholangiography. Although liver histologic findings alone are infrequently diagnostic of PSC, it remains important to exclude other causes of chronic cholestasis. Although the etiology remains unknown, preliminary studies suggest that PSC is related to immunologic damage. Although viral infections can induce obliterative cholangitis in children, their role in the cause of PSC remains undefined. PSC progresses slowly from an asymptomatic stage to cirrhosis, portal hypertension, and premature death secondary to liver failure. Bile duct cancer appears to be a frequent complication of long-standing PSC. Since no therapy is of established efficacy, controlled clinical trials of both medical and surgical therapy should be encouraged. Fat-soluble vitamin deficiencies commonly occur in the advanced stages of PSC, and therefore serum levels of vitamins A, D, E, and prothrombin time should be monitored on a regular basis to prevent complications associated with these deficiencies. Liver transplantation is now a therapeutic option for the treatment of end-stage PSC. Palliative surgical biliary drainage procedures, proctocolectomy, and surgical decompressive shunts that increase the risk of liver transplants, therefore, should be avoided, if possible, in young PSC patients. If a total proctocolectomy is surgically indicated, we would strongly recommend performing a ileoanal pull-through procedure, thus, avoiding the formation of an abdominal ileostoma and the risk of developing bleeding peristomal varices.

Cholangiograms from 104 patients (and serial cholangiograms in 66 patients) with primary sclerosing cholangitis (PSC) were reviewed. In 13 patients the additional diagnosis of cholangiocarcinoma was made at biopsy or autopsy. Cholangiograms from patients with both PSC and carcinoma were compared with cholangiograms from patients with PSC alone. Marked dilatation of ducts or ductal segments (100% vs. 24%) and the appearance of a polypoid mass (46% vs. 7%) were common findings in the group of patients whose disease was complicated by malignancy. In the malignant group, polypoid masses were larger, measuring 1 cm or greater in diameter. On serial cholangiograms, four of 15 patients with progressive stricture formation and four of five with progressive ductal dilatation proved to have carcinomas. The frequent occurrence of bile duct carcinoma as a complication of PSC in this group of patients indicates that PSC has a strong tendency to undergo malignant degeneration. Cholangiographic findings which suggest malignant degeneration include markedly dilated ducts or ductal segments, presence of a polypoid mass 1 cm or greater in diameter, and progressive stricture formation or ductal dilatation.

A retrospective review of 30 patients with documented Budd-Chiari syndrome disclosed an overall mortality of 57%. Medical treatment alone was associated with an 86% mortality; hepatic failure was the most common cause of death. Mortality was 31% overall for the surgical group, but there were long-term survivors among patients undergoing portacaval shunting. From this series, no single surgical procedure was found to be clearly superior. Surgical treatment with a side-to-side portacaval shunt seems to be the preferred operation when it can be performed. Surgical intervention should proceed soon after the diagnosis is made, lest extension of thrombus occur. Medical therapy most often is ineffective.

We report 12 cases of primary sclerosing cholangitis (confirmed by cholangiography) in which the serum alkaline phosphatase activity was normal. The enzyme activity remained normal during follow-up in 7 cases and fluctuated in 5 cases (it returned to normal in 4). The presence of advanced histologic stage (fibrosis/cirrhosis) with marked cholangiographic changes in 4 patients establishes that cirrhotic-stage primary sclerosing cholangitis can occur without a concomitant increase in serum alkaline phosphatase activity. Therefore, primary sclerosing cholangitis may exist in an occult state without symptoms or increase in serum alkaline phosphatase activity. Our findings suggest that primary sclerosing cholangitis may be more prevalent than realized, especially in patients who have inflammatory bowel disease. A normal value for serum alkaline phosphatase activity should not preclude further investigation for primary sclerosing cholangitis in patients with inflammatory bowel disease when symptoms or signs suggest liver disease.

Among the first 52 recipients of primary liver allografts with follow-up of 2 weeks or greater, 6 patients had biopsy-confirmed vanishing bile duct syndrome (VBDS) and required retransplantation. Five of these six patients had positive lymphocyte crossmatches. Of the 46 remaining liver transplant recipients, 11 had positive crossmatches. Thus, the incidence of VBDS was 5/16 in recipients with a positive crossmatch and 1/36 in recipients with a negative crossmatch. The positive-crossmatch group was significantly more likely to develop VBDS than the negative-crossmatch group (P less than 0.004, log rank test). Additional HLA studies comparing degree of donor-recipient mismatch at the various HLA loci showed no significant difference between the groups for class I disparity. However, class II mismatch was of borderline significance (P less than 0.056). When evaluated individually, the DQ mismatch (P less than 0.04) appeared to be more important than the DR mismatch (P = NS). Our data suggest that a positive lymphocyte crossmatch and a class II mismatch, in particular HLA DQ disparity, may play an important role in the pathogenesis of VBDS.

Blastogenesis of autoreactive T lymphocytes in the autologous mixed lymphocyte reaction has been shown to be decreased in patients with primary biliary cirrhosis, but the mechanisms underlying this abnormality are not known. To investigate further the abnormal autologous mixed lymphocyte reaction in primary biliary cirrhosis, we measured the activation of autoreactive helper/inducer and suppressor/cytotoxic T lymphocytes concurrently with blastogenesis in 35 patients with primary biliary cirrhosis and 18 healthy controls. Blastogenesis was diminished in autologous mixed lymphocyte reaction cultures from primary biliary cirrhosis patients compared to the control subjects (25,273 +/- 20,259 dpm vs. 36,004 +/- 14,951 dpm, p less than 0.02), but cultures from patients with primary biliary cirrhosis contained significantly increased percentages of activated helper/inducer and suppressor/cytotoxic T lymphocytes: 20.6 +/- 7.9 vs. 15.5 +/- 5.3%, p less than 0.008, and 9.8 +/- 7.8 vs. 5.4 +/- 3.0%, p less than 0.02, respectively. These findings were not related to the histologic stage of liver disease or to the serum bilirubin concentration and were not associated with abnormalities of lymphocyte subsets in fresh peripheral blood specimens. We conclude that the percentage of autoreactive T lymphocytes in autologous mixed lymphocyte reaction cultures from peripheral blood is increased in patients with primary biliary cirrhosis and diminished blastogenesis in autologous mixed lymphocyte reaction cultures is not due to the loss of autoreactive T lymphocytes from peripheral blood. Diminished blastogenesis reflects a diminished proliferative response of activated, autoreactive T lymphocytes in primary biliary cirrhosis. Possible mechanisms that may account for the paradoxical findings of decreased blastogenesis and increased activation of autoreactive T lymphocytes in primary biliary cirrhosis are discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

Of 83 patients who underwent 100 orthotopic liver transplantations, 53 had a single transplant procedure and at least 6 months of follow-up. In this main study group of 53 patients, major infections developed in 28 (53%) (a mean of 1.8 major episodes per infected patient). Of 51 major infections, 27 were bacterial, 19 were viral, 3 were protozoan, and 2 were fungal. Of the 27 bacterial infections, 22 (81%) occurred in the first 2 months after transplantation. Of the 40 bacterial isolates in the 27 bacterial infections, gram-positive aerobic bacteria were isolated in 26 (65%), anaerobic bacteria in 8 (20%), and aerobic gram-negative bacteria in 6 (15%). Only 1 of 16 bacteremic episodes was due to a gram-negative aerobic bacterium. Cytomegalovirus (CMV) infection occurred in 30 of the 53 patients (57%) and was symptomatic and invasive in 18. CMV infection was diagnosed a mean of 26 days after transplantation. Infections due to Pneumocystis carinii occurred later (2 to 3 months after transplantation). Death from infection occurred in 4 of the 53 patients (8%). In the group of 16 patients with two or more liver transplantations, fungal infection occurred in 2 and CMV infection in 13. In all 16 patients who underwent more than one liver transplantation, a major infection developed. The observations made in the main study group were consistent with findings in 13 patients with one liver transplantation but less than 6 months of follow-up. Infection is a major complication after liver transplantation, generally occurring in the first 2 months. Our observations suggest that the use of selective bowel decontamination may be associated with a relatively lower incidence of gram-negative aerobic bacterial infections.

Endotheliitis (EN) is a feature of hepatic allograft rejection, characterized by the adherence of immunocytes to the endothelium of veins, often leading to endothelial damage, endophlebitis, and, sometimes, panphlebitis. We found EN at least once in 28 of 41 allografts (68%) that had survived 6 months or longer. In approximately half the affected cases, the condition recurred. The EN was mild in most instances; moderate or severe manifestations were found in only 13% of the cases. The histologic changes were present for about 1 week in approximately half the cases; a duration of more than 2 weeks was noted in 17%, and then EN usually persisted. After retransplantation, recurrence of EN was observed in all of nine cases. We were unable to establish specific clinicopathologic and laboratory correlations for EN. The immunocytes in EN consisted mainly of helper and suppressor/cytotoxic T cells as well as natural killer cells. Sometimes, the immunocytes assumed a blastlike appearance; in these instances, the condition was severe. Such blastlike changes may be specific for EN. The immunocytes were attached to the endothelium by pseudopodia, broad bases, or both; some also were interconnected by cytoplasmic bridges. Underlying endothelial cells often showed evidence of cytoplasmic damage. The pathogenesis of EN is not completely understood; the immunocytes probably attach themselves to antigenic epitopes. Their nature, however, has not been clearly identified; HLA-A, B, and C and HLA-DR were displayed in areas of EN, but the antigens also were found in vessels without EN.

We studied intrahepatic bile ducts of five patients with chronic ulcerative colitis and primary sclerosing cholangitis. The livers had been obtained at the time of orthotopic liver transplantation. After specimen cholangiography and perfusion fixation, sequential blocks and sections from portal tracts were studied, combining light microscopy with scanning electron microscopy. In vivo cholangiograms were studied also. The specimens revealed: absence of normal bile ducts; presence of thin-walled tubular or saccular cholangiectases with semicircular and annular fibrous crests, without evidence of superinfection; cholangiectases with secondary acute or chronic-cellular cholangitis, with or without cholangitic abscesses; fibrous cholangitis without ductal dilatation; transformation of bile ducts into fibrous cords which were either solid or contained remnants of bile duct epithelium, and complete loss of bile ducts. The shape and distribution of the cholangiectases suggested that these lesions were manifestations of the disease process and not passively dilated normal ducts. Fibrous-obliterative cholangitis with formation of fibrous cords was found not only at the level of interlobular and adjacent septal bile ducts but also at the level of segmental bile ducts that normally would have been demonstrable in cholangiograms. The "pruned-tree" appearance in cholangiograms appears to result from the transition between patent and often cholangiectatic ducts, and duct obliteration. At present, intrahepatic cholangiectases in association with duct obliteration can be considered pathognomonic morphologic features of primary sclerosing cholangitis.

In this study, we retrospectively analyzed the intraoperative hemodynamic, laboratory, and coagulation data on the first 83 patients who underwent an initial liver transplantation procedure at our institution. The major hemodynamic changes at the time of reperfusion of the donor liver were significant decreases in arterial blood pressure, systemic vascular resistance, and pulmonary artery temperature and significant increases in cardiac output and pulmonary capillary wedge pressure. The alterations in laboratory values reflected intraoperative therapeutic manipulations. Citrate toxicity is a concern, and the amount of calcium chloride administered reflected the volume of blood transfused. On reperfusion, the fibrinogen concentration decreased and both the prothrombin time and the activated partial thromboplastin time increased. This coagulopathy was also evident in the thromboelastographic values. Aggressive monitoring and prompt intervention are necessary to maintain hemodynamic and metabolic homeostasis in these patients.

Primary sclerosing cholangitis is a chronic cholestatic liver disease that is commonly associated with chronic ulcerative colitis. We observed the development of varices in the abdominal wall surrounding the ileostomy stoma of patients with primary sclerosing cholangitis who underwent proctocolectomy and ileostomy for chronic ulcerative colitis. In 10 of 19 patients, the development of peristomal varices was documented 12-133 mo after operation. Risk factors for the development of peristomal varices included splenomegaly, esophageal varices, advanced histologic stage at liver biopsy, low serum albumin, thrombocytopenia, and an increased prothrombin time. Recurrent bleeding from peristomal varices was a major problem; 7 of 10 patients required repeated blood transfusions. The only therapy of long-term benefit was surgical decompression of the portal venous system in 1 patient and liver transplantation in a second patient. In contrast, there was no perirectal bleeding in 4 patients with primary sclerosing cholangitis who underwent proctocolectomy with an ileoanal anastomosis.

High performance liquid chromatography (HPLC), coupled with an amalgamated gold electrochemical detector, to measure plasma and urine concentrations of D-penicillamine, was used to determine the pharmacokinetics of this drug following both its intravenous and oral administration in doses of 800 mg. After iv administration, plasma elimination half-life (T 1/2 beta) was 62.7 +/- 5.3 min; plasma clearance (CI) 560.7 +/- 42.8 ml/min; volume of distribution (Vd), 57.0 +/- 9.3 l; and % D-penicillamine excreted within 24 h, 42.1% +/- 6.2%. Following oral administration, T 1/2 beta was 60.7 +/- 8.2 min, % D-penicillamine excreted within 24 h, 21.2 +/- 2.3%; and fraction of absorption (f) 41.2 +/- 5.5%. Urinary copper excretion paralleled urine and plasma D-penicillamine concentrations.

Cholangiograms of 86 patients with primary sclerosing cholangitis (PSC) were compared with those of 82 patients with primary bile duct carcinoma and 16 with primary biliary cirrhosis. Multifocal strictures involving both intra- and extra-hepatic bile ducts were most common in PSC; they were diffusely distributed, short, and annular, alternating with normal or slightly dilated segments to produce a "beaded" appearance. Very short, band-like strictures occurred in 18 patients; 9 also had diverticulum-like out-pouchings. Fourteen patients had "diverticula" without band strictures. Both findings appear to be specific for PSC. Inflammatory bowel disease was seen in 57 patients (66%), who could not be distinguished cholangiographically from other PSC patients. Of 40 patients with adequate retrograde pancreatograms, 3 had abnormalities of the pancreatic ducts.

The acute vanishing bile duct syndrome can be defined as an irreversible, rejection-related condition that affects hepatic allografts within 100 days after orthotopic liver transplantation and whose presence requires retransplantation. We have observed the acute vanishing bile duct syndrome in 5 of 48 consecutive patients (approximately 10%) who underwent orthotopic liver transplantation. In 4 cases, the condition progressed relentlessly within approximately 7 to 11 weeks after orthotopic liver transplantation from mild rejection to severe rejection to acute vanishing bile duct syndrome. A fifth patient had severe rejection in the first week and required retransplantation after 17 days because of thrombotic venoocclusive disease complicating the acute vanishing bile duct syndrome. Clinically, signs of impending acute vanishing bile duct syndrome included abrupt onset of fever and jaundice and marked elevation of serum bilirubin and alkaline phosphatase levels which persisted despite antirejection treatment. Biopsy specimens revealed destructive cholangitis (rejection cholangitis), ductopenia, and, if retransplantation was delayed, presence of noninflammatory, "burnt-out" portal tracts without bile ducts. We recommend to base the diagnosis of acute vanishing bile duct syndrome on documentation of severe ductopenia in at least 20 portal tracts which may require several consecutive needle biopsies. Rejection arteriopathy which was found in 3 of our 5 cases might have been another important diagnostic clue but could not be recognized prior to retransplantation. The pathogenesis of acute vanishing bile duct syndrome is not clear; until the condition had manifested itself, we found no qualitative differences between acute reversible and irreversible rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Monoclonal antibodies were used to identify helper T cells (TH) and suppressor/cytotoxic T cells (TS/C) in liver allograft biopsy specimens obtained 7,21,90,180, and 365 days postoperatively and then annually or during episodes of graft dysfunction and after treatment of rejection episodes. Biopsy specimens were obtained from 70 hepatic allografts from patients treated with cyclosporine and corticosteroids. Rejection was diagnosed by the presence of appropriate laboratory and light microscopic findings and at least 16 weeks of follow-up to exclude other causes of graft dysfunction. Three immunohistologic patterns were noted: no or only a trace of T lymphocytes, predominantly TH infiltrate with or without a small amount of TS/C cells (portal TH), and a mixture of TH with an equal or greater number of TS/C infiltrate (portal mix). Of 68 biopsy specimens obtained during quiescent periods, only 3 had a portal tract T-lymphocyte infiltrate. Of 30 protocol biopsy specimens, 24 contained such an infiltrate a mean of 12.4 days before biochemical and routine histologic indications of rejection in the allograft. At the time of the rejection episode, 33 biopsy specimens were immunohistologically labeled; portal tract T-lymphocyte infiltrate was predominantly TH in 8 and a mixture of TH and TS/C in 25. All rejection episodes with a predominantly TH pattern responded to methylprednisolone. Of the 25 rejection episodes with a portal mix pattern, only 3 responded to methylprednisolone. Eighty-seven biopsy specimens were obtained more than 10 days after treatment of rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Histologic, ultrastructural, chemical, and statistical methods were used to study liver biopsy and autopsy specimens from 43 patients who had primary sclerosing cholangitis (PSC), with or without chronic ulcerative colitis (CUC), and from 19 patients who had CUC without PSC. In all study groups, essentially the same abnormalities were found in the hepatic parenchyma outside the major bile ducts, although nondiagnostic tissue samples were observed also. Specimens from patients with extrahepatic PSC were indistinguishable from those patients with combined extra- and intrahepatic PSC. Common findings included periductal fibrosis and inflammation, portal edema and fibrosis, focal proliferation of bile ducts and ductules, focal bile duct obliteration and loss of bile ducts, copper deposition, and cholestasis. Proliferation of bile ducts in some portal tracts and obliteration or absence of bile duct in others were the most characteristic changes. In most specimens, inflammatory changes appeared mild, yet biliary cirrhosis had developed in 34% of the patients. Specimens from patients with PSC, with or without CUC, more often contained bile and strikingly increased stainable copper (Grades 2 and 3) than did specimens from patients with CUC without PSC. Hepatic copper contents, measured by atomic absorption spectrophotometry, also were higher in specimens from patients with PSC. Study of PCS specimens by transmission electron microscopy and by energy-dispersive X-ray microanalysis revealed that most copper was sequestered in lipolysosomes. The recognition of strikingly similar morphologic features in many liver specimens from patients with either PSC or CUC or both suggests that the causes of these conditions are closely related.

Between March 1985 and June 1987, the first 100 liver transplantations at the Mayo Clinic were performed in 83 patients (primarily adults). The most frequent diagnoses were chronic active hepatitis (in 24 patients), primary sclerosing cholangitis (in 22), and primary biliary cirrhosis (in 20). The median operating time was 406 minutes, and the median usage of erythrocytes was 13.2 units. A venovenous bypass was used in all patients older than 10 years of age. Hepatic artery thrombosis occurred in 10% of the 100 transplants. A choledochocholedochostomy was done in 58 patients and a choledochojejunostomy in 25 patients. Revision of the biliary anastomosis was necessary in 9 of the 83 patients (11%). Rejection, diagnosed by clinical and histologic criteria, occurred in 50 patients (60%) and was treated with a corticosteroid bolus, followed by OKT3 (monoclonal antibody) treatment if necessary. Selective bowel decontamination helped prevent infections; only 16 bacteremias occurred, 1 of which was caused by a gram-negative organism. Fungal infections were rare. Cytomegalovirus infection occurred in 47 patients (57%). Of the 83 patients, 16 required retransplantation, in 11 of whom graft rejection had occurred. One- and 2-year patient survival was 83% and 70%, respectively. Although problems still remain, liver transplantation is a reasonable option for patients with end-stage liver disease.

Liver transplantation is considered lifesaving for selected patients with end-stage primary biliary cirrhosis (PBC). A mathematical model to predict survival in the patient with PBC who has not undergone transplantation would be valuable for improving selection of patients for and timing of transplantation and for providing control information for assessment of the efficacy of transplantation. The Cox regression method and data from 312 Mayo Clinic patients with PBC were used to develop a model based on age, total serum bilirubin, serum albumin, prothrombin time, and severity of edema. When cross-validated on an independent set of 106 Mayo patients, the model accurately predicted their survival. It was similar to two other published survival models in terms of risk measurement but had the advantage of not necessitating liver biopsy. The model was used to assess the efficacy of liver transplantation by comparing the Kaplan-Meier survival of 32 Mayo patients after transplantation with the average model prediction of survival without transplantation. Beyond 3 months after transplantation, Kaplan-Meier survival probabilities were significantly greater than control survival predicted by the model (P less than 0.001). Examples of using the model for aiding in selection of patients for and timing of transplantation are provided.