Efficacy and safety of pegylated (40-kd) interferon alpha-2a compared with interferon alpha-2a in noncirrhotic patients with chronic hepatitis C.

Administration of interferon (IFN) 3 times weekly in patients with chronic hepatitis C (CHC) is associated with low sustained responses, which may be, in part, related to this regimen's inability to maintain IFN concentrations sufficient to suppress viral replication. An enhanced IFN molecule produced by the covalent attachment of a branched 40-kd polyethylene glycol moiety to IFN alpha-2a (PEG[40kd] IFN alpha-2a) exhibits sustained absorption, a restricted volume of distribution, and reduced clearance compared with unmodified IFN alpha-2a. One hundred fifty-nine patients with CHC participated in a randomized, ascending-dose (45 or 90, 180, 270 microg) study comparing PEG(40kd) IFN alpha-2a administered once weekly with 3 MIU IFN alpha-2a administered 3 times weekly for 48 weeks to determine the most appropriate PEG(40kd) IFN alpha-2a dose for subsequent clinical trials. Efficacy was assessed by measuring hepatitis C virus (HCV) RNA following a 24-week treatment-free period. Sustained virological responses for PEG(40kd) IFN alpha-2a once weekly were 10% (45 microg; not significant), 30% (90 microg; P = .009), 36% (180 microg; P = .0006), and 29% (270 microg; P = .004), compared with 3% for the 3-times-weekly 3-MIU IFN alpha-2a regimen. The types and frequencies of adverse events and laboratory abnormalities were similar among all groups. In conclusion, once-weekly PEG(40kd) IFN alpha-2a was associated with a higher number of sustained virological responses compared with IFN alpha-2a 3 times weekly in patients with CHC, but had a similar safety profile. The 180-microg PEG(40kd) IFN alpha-2a dose appeared to be the optimal dose based on sustained virological response and its associated side-effect profile.

Altered mucin core peptide expression in acute and chronic cholecystitis.

Human mucin genes include membrane-bound mucins (MUC1, MUC3, MUC4) and secretory mucins (MUC2, MUC5AC, MUC5B, MUC6). Our aim was to determine mucin gene expression in human gallbladder cell lines, normal gallbladder from liver donors (N = 7) and surgical specimens with mild chronic cholecystitis (N = 29), chronic cholecystitis (N = 48), and acute and chronic cholecystitis (N = 27). MUC1 mRNA was ubiquitous; however, only rare MUC1 immunoreactivity was detected. MUC3, MUC5AC, MUC5B, and MUC6 mRNA were present in all gallbladder specimens and cell lines examined. Prominent MUC3, MUC5AC, MUC5B, and MUC6 immunoreactivity was present in 86-100% of normal gallbladders. The frequency of MUC5AC reactivity was decreased in specimens with acute cholecystitis (P < 0.05). In contrast, MUC2-reactivity was absent in normal gallbladder and present in 53.8% of acute cholecystitis specimens (P < 0.05). Surface epithelium is characterized by MUC3, MUC5AC, and MUC5B, whereas deeper mucosal folds display MUC5B and MUC6 immunoreactivity. Gallbladder epithelium demonstrates a unique and diverse pattern of mucin core proteins that becomes altered with increasing degrees of inflammation.

Transjugular intrahepatic portosystemic shunts compared with endoscopic sclerotherapy for the prevention of recurrent variceal hemorrhage. A randomized, controlled trial.

BACKGROUND: Transjugular intrahepatic portosystemic shunts (TIPS) have widened the use of portal decompression as therapy for variceal hemorrhage. However, no controlled studies have examined the efficacy of TIPS compared with that of other treatments. OBJECTIVE: To compare the efficacy and safety of TIPS with those of endoscopic sclerotherapy for the prevention of recurrent variceal hemorrhage. DESIGN: Randomized, controlled trial. SETTING: Tertiary-care academic medical center. PATIENTS: 100 patients with cirrhosis were evaluated a mean of approximately 10 days after an episode of acute variceal bleeding; 20 patients were excluded because of portal venous thrombosis (n = 6), hepatoma (n = 3), florid alcoholic hepatitis (n = 6), and refusal to give consent (n = 5). INTERVENTIONS: TIPS (n = 41) or sclerotherapy (n = 39). The latter was performed by freehand injections of 5% Na morrhuate at 2- to 3-week intervals. Recurrent variceal hemorrhage was managed by sclerotherapy followed by angiographic assessment of TIPS and dilatation of the stents (TIPS group) or crossover to TIPS (sclerotherapy group). MEASUREMENTS: Rebleeding and survival were the primary end points. Complications and rates of rehospitalization were secondary end points. RESULTS: During a mean follow-up of approximately 1000 days, recurrent gastrointestinal bleeding resulted from variceal hemorrhage (9 patients in the TIPS group and 8 in the sclerotherapy group), portal gastropathy (1 patient in each group), and gastric lipoma (0 and 1 patients, respectively). A higher mortality rate was seen with TIPS (P = 0.03). Death resulted from variceal bleeding (5 patients in the TIPS group and 3 in the sclerotherapy group), sepsis (3 and 2 patients, respectively), liver failure (2 patients in each group), hepatoma (1 and 0 patients, respectively), and hemoperitoneum (1 and 0 patients, respectively). Encephalopathy was the most common complication in the TIPS group (n = 12), and pain developing after sclerotherapy was the most common in the sclerotherapy group (n = 10). The two groups had similar rates of rehospitalization. CONCLUSIONS: Endoscopic sclerotherapy and TIPS are equivalent with respect to rebleeding developing over the long term. However, sclerotherapy may be superior to TIPS with respect to survival.

The natural history of portal hypertension after transjugular intrahepatic portosystemic shunts.

BACKGROUND & AIMS: The effects of transjugular intrahepatic portosystemic shunt (TIPS) on portal hemodynamics, esophageal and gastric varices, and hepatic function have not been fully defined. The aim of this study was to define prospectively the effects of TIPS on portal pressures and flow, variceal resolution, and hepatic function. METHODS: Pressure and flow measurements were made by angiography and Doppler sonography, respectively. Varices were assessed by endoscopy and angiography. Liver functions were evaluated by a battery of tests. RESULTS: In 100 consecutive subjects, mean portosystemic gradient decreased from 24 to 11 mm Hg (means) (P < 0.001) after TIPS. Recurrent portal hypertension caused by stent thrombosis (n = 5), stent retraction (n = 2), and stent stenosis (n = 51) occurred at 6 months but, by year 5, was not present in survivors (n = 0 of 8). Fundic gastric varices failed to resolve in 6 of 12 cases. Systemic venous pressures of >15 mm Hg, stent dysfunction, and continued alcoholism were risk factors for recurrent hemorrhage. Angiography was superior to endoscopy, which was superior to Doppler sonography for detection of recurrent portal hypertension. Progressive liver failure occurred in 8 patients. CONCLUSIONS: Recurrent portal hypertension caused by stent stenosis occurs commonly in the first 2 years after TIPS. Fundic gastric varices often fail to disappear after TIPS. The effects of TIPS on liver function are unpredictable.

Transjugular intrahepatic portosystemic shunts for patients with active variceal hemorrhage unresponsive to sclerotherapy.

BACKGROUND & AIMS: Despite urgent sclerotherapy, active variceal hemorrhage has a 70%-90% mortality rate in patients with advanced age, sepsis, renal or pulmonary compromise, tense ascites, or deep coma. The aim of this study was to test the safety and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) performed semiemergently and preceded by stabilization by balloon tamponade in such patients. METHODS: Patients with actively bleeding esophageal or contiguous gastric varices despite sclerotherapy were assessed for risk of dying after emergent portacaval shunt. Those considered to be at high risk were stabilized by balloon tamponade and vasopressin/nitroglycerin and TIPS placed semiurgently within 12 hours. Balloon tamponade and pharmacological therapy were discontinued within 24 hours after TIPS in all cases. RESULTS: Thirty-two patients met entry criteria, and 2 were excluded due to portal vein thrombosis. TIPS was successfully placed in 29 of 30 patients and achieved hemostasis in all. Thirty-day and 6-week survival rates were 63% and 60%, respectively; in those without aspiration, the 6-week survival rate was 90%. After a median follow-up period of 920 days, 46% of the original cohort was alive. Only 2 episodes of early rebleeding and 4 late rebleeds occurred. Eight patients developed encephalopathy. Stent stenosis requiring dilation occurred in 6 of 11 patients within 6 months. CONCLUSIONS: TIPS is highly effective as salvage therapy in high-risk patients with active variceal hemorrhage despite endoscopic sclerotherapy.

The hematologic consequences of transjugular intrahepatic portosystemic shunts.

Transjugular intrahepatic portosystemic shunts (TIPS) are a recent innovation in the management of portal hypertension. In 1992, we had previously described an instance of severe hemolysis associated with this procedure. This study was undertaken to define and quantify the true incidence of TIPS-associated hemolysis and its clinical spectrum, as well as to test the hypothesis that portal decompression by TIPS would ameliorate hypersplenism in patients with portal hypertension. A total of 60 patients undergoing TIPS for prevention of recurrent variceal hemorrhage (n = 40) or refractory ascites (n = 20) were studied. Forty patients with cirrhosis who were followed concurrently served as controls. At entry, both groups were comparable with the exception of increased ascites in the TIPS group. A total of 7 instances of intravascular hemolysis were identified in 60 TIPS patients, whereas none occurred in controls. Of these, 4 patients were asymptomatic and detected on routine laboratory testing. Hemolysis led to a greater than 4-g/dL decrease in hemoglobin in 2 patients, 2- to 3-g/dL decrease in 2 others and a 3- to 4-gm/dL decrease in 1 patient. Two patients were able to compensate for hemolysis and did not develop anemia. In all but 1 case, the findings of hemolysis subsided by 12 to 15 weeks; in 1 patient, orthotopic liver transplantation was associated with resolution of the hemolysis. Overall, no significant changes in white blood cell or platelet counts were observed in patients undergoing TIPS despite adequate portal decompression. We conclude that TIPS-induced hemolysis occurs in approximately 10% of subjects. However, it is self-limited and rarely requires intervention. Potential mechanisms of such hemolysis are discussed. TIPS is also not recommended as a means of improving platelet counts in patients with severe hypersplenism.

Cyclosporine: indications and use in gastrointestinal diseases.

Cyclosporine is the most important drug used in transplant medicine, and it has revolutionized the field of organ transplantation. It suppresses cytotoxic T-cell activity without producing myelosuppression. Recently, its use has been expanded to include an increasing number of immunologically mediated disorders. Many of these diseases involve the liver and the gastrointestinal tract, which is therefore of interest to practicing gastroenterologists. However, cyclosporine is associated with a number of adverse effects. A knowledge of these side effects and their management is essential for any physician who intends to use this drug. Current gastrointestinal indications and a practical approach to cyclosporine use in gastroenterology are discussed.

Oxaprozin-induced fulminant hepatitis.

OBJECTIVE: To report oxaprozin-induced fulminant hepatic failure. CASE SUMMARY: A 56-year-old woman was admitted with fulminant hepatic failure. Work-up for potential etiologies was negative except for the use of oxaprozin for the preceding two months. Results of premortem liver biopsy were consistent with drug-induced hepatic injury similar to that previously reported with diclofenac. DISCUSSION: Although the literature describes elevation in hepatic transaminase concentrations associated with oxaprozin, fulminant hepatic failure has not been described previously. CONCLUSIONS: Elevations in hepatic transaminase concentrations and now fulminant hepatic failure have been shown to occur with oxaprozin, as previously seen with other nonsteroidal antiinflammatory drugs (NSAIDs). Transaminitis is a known adverse effect of NSAID use, but is usually mild and reversible with discontinuation of drug. Transaminitis may be more likely to occur in the elderly, in patients receiving concurrent potentially hepatotoxic medications, and possibly with the newer long-acting NSAIDs. The existence of fulminant hepatitis, although rare, supports the need for monitoring liver function enzymes during NSAID therapy.

Portosystemic encephalopathy after transjugular intrahepatic portosystemic shunt: results of a prospective controlled study.

Portosystemic encephalopathy is a common complication of surgical portacaval shunts. Recently, transjugular intrahepatic portosystemic shunts have been proposed to produce portal decompression in a manner analogous to a side-to-side portacaval shunt, but with less morbidity. The incidence and clinical spectrum of portosystemic encephalopathy after transjugular intrahepatic portosystemic shunts, however, had not been previously prospectively defined. We therefore prospectively studied portosystemic encephalopathy in 30 patients undergoing transjugular intrahepatic portosystemic shunts and compared these findings with 25 patients concurrently undergoing sclerotherapy (controls). At entry, both study groups were comparable. Portosystemic encephalopathy was assessed by examining and grading mental status, asterixis, plasma ammonia and trail making tests. The portosystemic encephalopathy index was calculated from these parameters. Nine of 30 patients with transjugular intrahepatic portosystemic shunts experienced 24 episodes of acute portosystemic encephalopathy during follow-up; 6 of 9 had a history of portosystemic encephalopathy before transjugular intrahepatic portosystemic shunts and 5 of these 6 patients had Child C cirrhosis. Mental status and asterixis scores as well as portosystemic encephalopathy index worsened significantly in the first month after transjugular intrahepatic portosystemic shunts but showed some improvement thereafter. Increasing age, a medical history of portosystemic encephalopathy and trail scores for part B greater than 100 sec were predictors of portosystemic encephalopathy after transjugular intrahepatic portosystemic shunts. Portosystemic encephalopathy could be managed medically in all but one patient who underwent liver transplant. In contrast, there were no significant changes in mental status, asterixis, ammonia or trail scores over time in sclerotherapy controls. Only six episodes of encephalopathy occurred in endoscopic sclerotherapy patients over the duration of the study. Thus, overall risk of portosystemic encephalopathy after transjugular intrahepatic portosystemic shunts was higher than during sclerotherapy.

Hepatic lidocaine metabolism and liver histology in patients with chronic hepatitis and cirrhosis.

Recent advances in the medical and surgical treatment of chronic hepatitis and cirrhosis have made it increasingly important to develop noninvasive tests of liver function. Our study has evaluated the hepatic conversion of lidocaine to its primary metabolite monoethylglycinexylodide and compared this with liver histological findings in 225 patients with chronic hepatitis (161 with hepatitis C, 23 with hepatitis B, 21 with autoimmune hepatitis and 20 with cryptogenic hepatitis). One hundred seven (47.7%) patients had cirrhosis at the time of evaluation. A decline in monoethylglycinexylodide production was observed with worsening liver histological conditions from a mean of 81.5 +/- 7.0 ng/ml in patients with chronic persistent hepatitis to 61.2 +/- 5.5 ng/ml for chronic active hepatitis and 20.9 +/- 1.5 ng/ml in patients with cirrhosis (p < 0.05). A further stepwise decline in monoethylglycine xylodide production was observed with worsening Child class: from 25.5 +/- 2.2 ng/ml for class A patients to 8.9 +/- 1.4 ng/ml for patients with Child class C disease (p < 0.05). All patients with monoethylglycinexylodide production less than 20 ng/ml had cirrhosis confirmed on histological examination. In contrast, no relationship was observed between liver histological status and serum transaminases (AST or ALT), bilirubin, albumin and prothrombin time. Thirty-five patients underwent repeat histological evaluation and monoethylglycinexylodide testing after receiving at least 6 mo treatment for chronic hepatitis (interferon for hepatitis B and C and corticosteroids for autoimmune hepatitis). The change in monoethylglycinexylodide production observed in these patients was a linear function of the change in Knodell histological index (r = 0.73, p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Biochemical and histologic evaluation of recurrent hepatitis C following orthotopic liver transplantation.

It is well recognized that hepatitis recurs in virtually all patients who undergo orthotopic liver transplantation for cirrhosis secondary to chronic hepatitis C (HCV). The present report describes the biochemical and histologic findings of recurrent hepatitis in 25 such patients. One patient was found to have hepatocellular carcinoma at the time of OLT and was excluded from further analysis. All post-OLT laboratory values were reviewed. Liver biopsies were performed on protocol 6, 12, 24, and 36 months following OLT. Additional biopsies were performed as necessary to evaluate abnormalities in serum liver chemistries. A total of 104 biopsies was obtained; hepatitis consistent with recurrent HCV was present in 68 (65%). Other biopsy findings included cytomegalovirus hepatitis; acute, chronic, or resolving rejection; cholestasis with or without an underlying hepatitis; steatosis, and centrilobular necrosis. Histologic hepatitis appeared in all patients within 12 months following OLT. Despite these histologic findings, serum ALT was normal for prolonged periods in over 50% of such patients. In all cases this hepatitis was mild and did not progress over a mean follow-up of 22 months (maximum 44 months), as judged by Knodell histologic activity score (mean score: 4.0 +/- 0.3). Five patients developed cholestatic jaundice, far out of proportion to the degree of histologic hepatitis. In 2 patients this was secondary to chronic rejection. The other 3 patients had drug-induced cholestasis that resolved after various medications were discontinued. HCV did not contribute to graft dysfunction in any of the 24 patients. To date, our data suggest that post-OLT hepatitis in patients with preexisting HCV is a relatively benign process. Severe cholestatic jaundice in such patients is not secondary to HCV, and should stimulate a search for other possible causes of graft dysfunction. The long-term consequences of recurrent HCV following hepatic transplantation remain to be determined.

Complications of transjugular intrahepatic portosystemic shunt: a comprehensive review.

It is generally accepted that the transjugular intrahepatic portosystemic shunt (TIPS) procedure has lower morbidity and mortality rates than those of surgical shunting. Nevertheless, complications occur. The authors have reviewed their experience and that of other institutions in compiling an extensive list of complications. Complications are categorized according to those related to transhepatic needle puncture, transvenous access to the portal vein, portal venous cannulation, the stent, the puncture site, portosystemic shunting, and contrast material. Excluding hepatic encephalopathy and delayed stenosis or occlusion of the shunt, an overall complication rate of less than 10% can be expected for TIPS. The prevalence of aggravated or new cases of encephalopathy is 5%-35%, and over the long term, up to 75% of shunts may undergo stenosis or occlusion. The direct procedural mortality rate is less than 2%, and the 30-day mortality rate ranges from 4% to 45%, depending on several factors. The role to which TIPS is relegated will be influenced by the long-term success rate in the prevention of recurrent variceal hemorrhage.

Hepatic lidocaine metabolism and complications of cirrhosis. Implications for assessing patient priority for hepatic transplantation.

The number of patients awaiting hepatic transplantation continues to exceed organ donation. As a result, many liver transplant candidates will develop life-threatening complications of their liver disease and not survive the pretransplant waiting period. Recent studies have demonstrated that hepatic lidocaine metabolism into monoethylglycinexylidide (MEG-X) can predict pretransplant survival. The present study was performed to determine if MEG-X could also predict pretransplant complications and thereby be useful in stratifying persons being evaluated for hepatic transplantation. A total of 57 patients with biopsy-proven cirrhosis underwent MEG-X testing. Of 57 patients, 30 (53%) developed life-threatening complications of their liver disease--i.e., variceal bleeding, grade II hepatic encephalopathy or worse, and spontaneous bacterial peritonitis. MEG-X values were greater in persons without complications of liver disease than in persons with complications (25.7 +/- 2.9 versus 14.7 +/- 1.4 ng/ml, respectively). No patients with MEG-X greater than 30 ng/ml developed a major complication. No significant difference in any of the standard liver function tests existed between persons who developed complications and patients who did not. In this group of 57 patients, 4 (7%) died from complications of cirrhosis. Mean MEG-X for patients who died (5.5 +/- 1.6 ng/ml) was significantly less (P < 0.05) than observed for other patient groups. All patients who died had MEG-X values below 10 ng/ml. This suggests that MEG-X testing could be an extremely useful test in the evaluation of patients for hepatic transplantation by identifying persons at increased risk for developing complications of chronic liver disease.

Cultured human gallbladder epithelia. Methods and partial characterization of a carcinoma-derived model.

BACKGROUND: Gallstone disease remains a leading cause of morbidity and mortality in humans. Despite extensive research into the physiology of the gallbladder, little is known about mucosal events that precede and contribute to stone formation. Here, we describe and partially characterize a cultured epithelial model of human gallbladder mucosa. EXPERIMENTAL DESIGN: Cells originally obtained from a well-differentiated gallbladder mucosal carcinoma were cultured in modified Eagle's minimum media (supplemented with fetal calf serum and antibiotics) on polycarbonate supporting matrices. RESULTS: Cell cultures were observed to come to confluence with 6 to 9 days. Light and transmission electron microscopy demonstrated the resultant epithelia to be predominantly one cell thick, to be polar in orientation, and to have apical villi. Epithelia exhibited cytokeratin markers consistent with their epithelia origin, functionally acidified the mucosal bathing solutions, and secreted mucin. Further experiments demonstrated transepithelial potential differences, mucosal-to-serosal transfer of sodium which could be inhibited with amiloride and 4-acetamido-4'-isothiocyanatostilbene-2-2'-disulfonic acid, and paracellular movement of neutral molecular probes inversely related to size. CONCLUSIONS: This culture model of human gallbladder mucosal carcinoma cells exhibits parameters consistent with native gallbladder and may offer a convenient new research tool for the study of the pathophysiology of gallstone formation.

In vivo studies of biliary ceftriaxone excretion and solubility in guinea pig hepatic bile.

Ceftriaxone (CFTX), a third-generation cephalosporin, has occasionally been reported to produce biliary sludge composed of its calcium salt. We performed studies in guinea pigs to (1) investigate the hepatic route of CFTX excretion, (2) determine ceftriaione's effects on bile flow and composition, and (3) quantify the solubility and metastability of the calcium salt as a function of administered dose. Our results show that even at high doses ceftriaxone has only minimal effects on bile flow and biliary electrolyte secretion, either alone or in combination with bile salt (taurocholate) infusion. A significant increase in total calcium concentration was observed without change in free Ca2+ concentration, this is compatible with formation of a soluble calcium salt of ceftriaxone, as previously demonstrated in vitro. Ion products of Ca2+ and ceftriaxone as high as 3.5 times the solubility product constant without crystal formation were observed, confirming the presence of a metastable state for the calcium salt of ceftriaxone in the living animal. Biliary excretion of ceftriaxone inhibited excretion of indocyanine green, suggesting that ceftriaxone and indocyanine green share a common anionic excretory pathway in this species.

Short-bowel syndrome: a review of the role of nutrition support.

Advances in long-term venous access devices and in parenteral nutrition solutions have made it possible for patients with severe short bowel syndrome to survive and to live in our society. The spectrum of this disease is such that some patients may be able to lessen their dependence or even become free from parenteral therapy. This review will discuss the role of nutrition support in the patient with short bowel syndrome.