Percutaneous liver biopsy in adult haemophiliacs with hepatitis C virus: safety of outpatient procedure and impact of human immunodeficiency virus coinfection on the spectrum of liver disease.

Both HCV and HIV are common in haemophiliacs previously treated with non-viral-inactivated clotting factor concentrates. Because of increased bleeding risks, little data are available on the safety of percutaneous outpatient liver biopsy (LBx) and impact of HIV coinfection in this population. This study aims at reporting our experience with percutaneous LBx in a cohort of haemophiliacs infected with HCV and describe the spectrum of disease and impact of HIV coinfection. A retrospective review of consecutive patients with haemophilia and HCV who underwent percutaneous LBx was performed. All patients were positive for HCV RNA by commercial assay and received factor concentrate prior to biopsy. A total of 29 male patients (mean age 36, 24 haemophilia A, five haemophilia B, and 44% coinfected with HIV) underwent successful outpatient percutaneous LBx without bleeding complication. Histologic activity index was 6.44 with advanced fibrosis (bridging fibrosis/cirrhosis) in 31%. When patients were stratified by HIV positive (n = 13) vs. HIV negative (n = 16), coinfected patients had higher fibrosis scores and higher proportion advanced fibrosis (54% vs. 12%; P = 0.0167) with no differences in age, demographic or other laboratory parameters. Multivariate logistic regression found that HIV positivity was independently associated with advanced fibrosis (OR = 3.7; 95% CI: 1.17-11.8; P = 0.026). Outpatient percutaneous LBx can be safely performed in patients with haemophilia. Despite similar age, HIV coinfection was an independent predictor of advanced fibrosis. These data support the hypothesis that HIV accelerates fibrosis progression in those coinfected with HCV and highlights the importance of liver histology in this population.

A prospective, randomized-controlled pilot study of ursodeoxycholic acid combined with mycophenolate mofetil in the treatment of primary sclerosing cholangitis.

BACKGROUND: Ursodeoxycholic acid has been ineffective in the treatment of primary sclerosing cholangitis. Because the pathogenesis of primary sclerosing cholangitis is related to immune destruction of bile duct epithelium, several immune suppressive agents have been evaluated. Mycophenolate mofetil is a potent immunosuppressant that is now widely used in organ transplantation. AIM: In this pilot study to determine if mycophenolate mofetil when combined with ursodeoxycholic acid could prevent evidence of clinical progression and improve the biochemical, histological and/or cholangiographic features of primary sclerosing cholangitis compared with patients treated with ursodeoxycholic acid alone. METHODS: Twenty-five patients with well-defined primary sclerosing cholangitis were randomized to ursodeoxycholic acid (13-15 mg/kg/day) with or without mycophenolate mofetil (1000 mg b.d.). Cholangiography and liver biopsy were performed at study entry and after 2 years of treatment. Symptoms, clinical features of liver disease and biochemical tests were monitored at 3-month intervals. RESULTS: The mean age 44 years, 58% male, 84% Caucasian and 64% had ulcerative colitis. After 2 years, there were no differences in laboratory values, histological stage or cholangiograms between patients treated with ursodeoxycholic acid alone and those treated with mycophenolate mofetil + ursodeoxycholic acid. CONCLUSIONS: Mycophenolate mofetil combined with ursodeoxycholic acid does not appear to provide additional benefit compared with standard doses of ursodeoxycholic acid alone in the treatment of primary sclerosing cholangitis.

Polymorphisms in cytokines and growth factor genes and their association with acute rejection and recurrence of hepatitis C virus disease in liver transplantation.

Acute rejection (AR) and recurrence of hepatitis C virus (HCV) infection are complications after liver transplantation (LTx). Genetic factors play a role in cytokine production as a consequence of polymorphisms within cytokine genes. Our goal was to identify genetic factors that might be associated with AR and recurrence of HCV in liver transplant recipients (LTxRs). We studied 77 Caucasian LTxRs and 100 Caucasian healthy individuals. We studied single-nucleotide polymorphisms (SNPs) in tumor necrosis factor-alpha[TNF-alpha, interleukin-6 (IL-6), IL-10, transforming growth factor-beta1, and angiotensin-converting enzyme genes by SNaPSHOT trade mark Multiplex assay. SNPs were classified as high producers (HP), intermediate producers (IP), or low producers (LP), and their association with AR and recurrence of HCV were studied. The frequency of TNF-alpha IP and HP genotypes was significantly higher in LTxRs with AR in comparison to patients without AR (TNF-alpha HP -238: 63 vs 20%, p < 0.001; TNF-alpha HP -308: 47.4 vs 20%, p = 0.02). The frequency of IL-6 IP and HP genotypes was higher in patients with AR episodes, but the difference was not statistically significant (p = 0.14). However, when we analyzed the simultaneous presence of pro-inflammatory genotypes in the same patient, we found a significant difference between patients with and without AR, respectively (42.1 vs 14.6%, p = 0.012). Moreover, the frequency of the IL-10 LP genotype was higher in LTx patients with AR (p = 0.001) compared to patients without AR. There was an association between pro-inflammatory genotypes and HCV recurrence. Our data suggest that cytokine gene polymorphisms might play a role in AR and HCV recurrence in LTxRs.

A randomized, controlled trial to determine whether continued ribavirin monotherapy in hepatitis C virus-infected patients who responded to interferon-ribavirin combination therapy will enhance sustained virologic response.

This study assessed the use of ribavirin monotherapy to enhance sustained virologic response in hepatitis C virus (HCV)-infected patients who achieved virologic response to interferon (IFN)-ribavirin combination therapy. Patients who had chronic HCV infection and prior relapse were retreated with IFN-ribavirin for 6 months. Patients with an end-of-treatment virologic response were assigned randomly to either stop use of both IFN and ribavirin or to continue use of ribavirin as monotherapy for an additional 6 months. HCV RNA became undetectable during treatment in 46 patients, who then entered the randomized trial. Sustained virologic response was observed in 13 of 26 patients who continued ribavirin monotherapy and in 15 of 20 patients who stopped use of both IFN and ribavirin (P, not significant). Sustained virologic response was significantly more common in patients with HCV genotype non-1 (75% vs. 56%) and in patients with a virus titer < 2 x 10(6) copies/mL (93% vs. 43%). The results indicate that continuing ribavirin monotherapy after achieving a virologic response does not improve sustained virologic response.

Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis.

Many subjects with cryptogenic cirrhosis have underlying nonalcoholic steatohepatitis (NASH). The natural history of NASH-related cryptogenic cirrhosis after orthotopic liver transplantation (OLT) is not well defined. A primarily retrospective study of patients with the clinical histological phenotype of NASH-related cirrhosis undergoing OLT was performed. Data were compared with 2 sets of age- and weight-matched controls with (1) primary biliary cirrhosis or primary sclerosing cholangitis or (2) alcoholic liver disease. After OLT, all patients were managed by a standard immunosuppressive protocol. Liver biopsies were performed at 6 and 12 months after OLT and at 1- to 2-year intervals thereafter, as well as when liver enzyme levels were elevated enough to warrant diagnostic biopsy. Twenty-seven subjects with cryptogenic cirrhosis and a clinical histological phenotype of NASH and 3 patients with a long-standing diagnosis of NASH before OLT were included. The 30-day perioperative mortality was 1 in 30 patients. During a median follow-up of 3.5 +/- 2.7 years, 2 additional patients died of sepsis. There was a time-dependent increase in the risk for allograft steatosis that approached 100% by 5 years compared with only an approximately 25% incidence of steatosis in the control groups (P <.009, log-rank test). On multivariate analysis, only the cumulative steroid dose correlated with time to development of allograft steatosis. Three patients developed histological progression from hepatic steatosis to steatohepatitis. Of these, 1 patient developed progressive fibrosis. Four patients experienced at least 1 episode of acute cellular rejection; however, no patient developed chronic rejection or graft failure. In conclusion, nonalcoholic fatty liver disease occurs frequently after OLT in patients with the phenotype of NASH-related cirrhosis. Despite the frequent histological recurrence of disease, clinical outcomes are similar to those of other groups of patients undergoing OLT.

Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities.

BACKGROUND AND AIMS: The pathogenesis of nonalcoholic steatohepatitis (NASH) is unknown. We tested the hypothesis that NASH is associated with 2 defects: (1) peripheral insulin resistance, which increases lipolysis, delivery of free fatty acids (FFA) to the liver, and hepatic fatty acid beta oxidation, thereby creating oxidative stress; and (2) an abnormality within the hepatocytes that might render them more susceptible to injury from oxidative stress. METHODS: The hypothesis was tested by evaluation of (1) insulin resistance by a 2-step hyperinsulinemic (10 and 40 mU. m(-2). min(-1)) euglycemic clamp; (2) insulin effects on lipolysis by enrichment of [U-(13)C]glycerol; (3) frequency and severity of structural defects in hepatocyte mitochondria in vivo; (4) fatty acid beta oxidation from serum [beta-OH butyrate], release of water-soluble radioactivity from (3)H-palmitate by cultured fibroblasts and urinary dicarboxylic acid excretion; and (5) hepatic lipid peroxidation by immunohistochemical staining for 3-nitrotyrosine (3-NT). Subjects with NASH (n = 6-10 for different studies) were compared with those with fatty liver (n = 6) or normal controls (n = 6). RESULTS: NASH and fatty liver were both associated with insulin resistance, with mean glucose infusion rates (normal/fatty liver/NASH) of step 1, 4.5/1.6/0.9; step 2, 9.5/7.7/4.5 (P < 0.03 for both steps). Although baseline rates of glycerol appearance were higher in those with NASH than in those with fatty liver (means, 14.6 vs. 21.6 micromol. kg(-1). min(-1); P < 0.05), neither group significantly suppressed glycerol appearance at insulin infusion rates of 10 mU. m(-2). min(-1). NASH was associated with loss of mitochondrial cristae and paracrystalline inclusions in 9 of 10 subjects, compared with 0 of 6 subjects with fatty liver. However, no evidence of a generalized defect in fatty acid beta oxidation was noted in any group. Also, mean [beta-OH butyrate] was highest in those with NASH (means, 90 vs. 110 vs. 160 micromol/L; P < 0.04). Increased staining for 3-NT was present in fatty liver, and even greater staining was seen in NASH. CONCLUSIONS: These data indicate that peripheral insulin resistance, increased fatty acid beta oxidation, and hepatic oxidative stress are present in both fatty liver and NASH, but NASH alone is associated with mitochondrial structural defects.

Chronic infection with hepatitis C virus in patients with elevated or persistently normal serum alanine aminotransferase levels: comparison of hepatic histology and response to interferon therapy.

Ninety-five patients with chronic hepatitis C virus (HCV) infection, 35 with persistently normal serum alanine aminotransferase (ALT) levels, were randomized to treatment with daily interferon (IFN) for 3 months, followed by IFN 3 times weekly (TIW) for 12 months (group A) or TIW for 18 months (group B). Patients with elevated versus normal ALT levels had similar demographic and virologic characteristics but significantly (P<.05) more advanced liver histology (bridging fibrosis and cirrhosis, 37.9% vs. 11.4%). After 3 months of treatment, 38.3% of patients in group A were HCV RNA negative versus 18.8% in group B (P<.05). When the IFN dose was reduced from daily to TIW in group A, the percentage of patients who remained HCV RNA negative declined; sustained virologic response was similar in both groups (10.6% vs. 8.3%). Response to treatment was similar in patients with elevated or normal ALT levels. Persons with chronic HCV infection and persistently normal serum ALT levels have milder liver disease than, and respond to IFN therapy similarly to, persons with elevated ALT levels.

Treatment of chronic hepatitis C in patients who failed interferon monotherapy: effects of higher doses of interferon and ribavirin combination therapy. The Virginia Cooperative Hepatitis Treatment Group.

OBJECTIVE: The present study was designed to evaluate the effectiveness of interferon-ribavirin combination therapy for treatment of chronic hepatitis C virus (HCV) in patients who failed previous treatment with interferon monotherapy. METHODS: A total of 140 patients with well-documented chronic HCV who failed to achieve a virological (if HCV-RNA was assessed) or biochemical response (if HCV-RNA was not assessed) to interferon monotherapy, 3 mU three times weekly (TIW) for 3-18 months, were randomly assigned to one of three treatment groups. Group A patients were treated with 5 mU interferon TIW for 6 months. Ribavirin (1000-1200 mg daily) was added in those patients HCV-RNA positive at month 3. Group B patients were treated with 3 mU interferon TIW plus ribavirin (1000-1200 mg daily) for 6 months. The dose of interferon was increased to 5 mU TIW in those patients HCV-RNA positive at month 3. Group C patients were treated with 5 mU interferon TIW plus ribavirin (1000-1200 mg daily) for 6 months. Serum ALT and HCV-RNA were monitored during and after treatment for a total of 15 months. RESULTS: Seventeen percent of patients in group A became HCV-RNA negative by treatment month 3. Adding ribavirin resulted in one additional patient becoming HCV-RNA negative. However, none of the patients in this group achieved sustained virological response. Twenty-six percent of patients in group B became HCV-RNA negative by treatment month 3. Increasing the dose of interferon from 3 to 5 mU TIW increased virological response to 30%. However, sustained virological response was observed in only 14%. Thirty percent of patients in group C became HCV-RNA negative, but sustained virological response was observed in only 12%. Sustained virological response was found to be significantly greater in patients with a nontype I HCV genotype (p < 0.002) and in patients who had a decline in HCV-RNA titer to a value < 100,000 copies/ml during their previous course of interferon monotherapy (p < 0.0001). None of the 12 sustained responders were African Americans (p < 0.013). CONCLUSIONS: Retreatment of nonresponders with interferon-ribavirin combination therapy results in limited benefit; only 13% of patients achieved sustained virological response. Response was extremely poor in African Americans and those with HCV genotype 1.

Chronic hepatitis C infection in patients with end stage renal disease: characterization of liver histology and viral load in patients awaiting renal transplantation.

OBJECTIVES: Hepatitis C virus (HCV) is common in patients with end stage renal disease (ESRD) awaiting renal transplantation (RT). However, few data are available on the liver histology and viral titer in these patients relative to patients with HCV and normal renal function. The aims of this study were to assess liver histology, quantitative HCV-RNA titer, and alanine aminotransferase (ALT) levels in patients with ESRD awaiting RT, and to identify clinical predictors of histological progression to advanced bridging fibrosis and/or cirrhosis. METHODS: A total of 50 consecutive patients (mean age 42 yr, 62% male) with ESRD and HCV, who were awaiting RT, underwent liver biopsy. Two HCV populations, one with persistently normal ALT and another with elevated ALT, both with normal renal function, served as controls. HCV-RNA titer was assessed by quantitative PCR. RESULTS: Of the patients with ESRD, 94% had normal ALT. Log HCV RNA titer was significantly higher in patients with ESRD (5.8+/-0.3) than in either normal ALT (5.4+/-0.1) or elevated ALT (5.3+/-0.1) controls (p < 0.05). Knodell Histological Activity Index (HAI) in patients with ESRD was similar to that observed in control patients with normal ALT (4.8+/-0.4 vs 4.9+/-0.4) but significantly less (p < 0.05) than that observed in control patients with elevated ALT (8.4+/-0.5). The percentage of patients with bridging fibrosis or cirrhosis was similar in patients with ESRD and controls with persistently normal ALT (22% vs 13%) but significantly less (p < 0.001) than that observed in control patients with elevated ALT (48%). No significant differences in ALT, HCV-RNA titer, duration on hemodialysis, or time from first possible exposure was observed between ESRD patients with advance fibrosis (n = 11) and those with mild disease (n = 39). CONCLUSIONS: Our data suggest that liver biopsy is necessary to exclude significant liver pathology in patients with HCV and ESRD, and to help define those patients in whom interferon treatment might be helpful.

A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia.

BACKGROUND & AIMS: : At least half of patients with chronic hepatitis C virus (HCV) fail to respond to interferon or interferon/ribavirin therapy. Histological improvement is observed in some nonresponders. We conducted a randomized, controlled trial to determine if maintenance interferon therapy could prevent histological progression in this subset of nonresponders. METHODS: Fifty-three patients with chronic HCV were enrolled. All were HCV-RNA positive after 6 months of treatment with interferon alfa-2b but had a histological response. Twenty-seven of the patients were randomly assigned to continue interferon (3 MU 3 times weekly) for 24 months; 26 patients discontinued treatment and were observed prospectively. Alanine aminotransferase (ALT) level and HCV-RNA titer were monitored, and liver biopsy was repeated every 12 months. RESULTS: Before interferon therapy, the 2 groups were well matched for all demographic factors, serum ALT (94.0 +/- 15.6), log HCV-RNA titer (5. 85 +/- 0.15 copies/mL), histology score (9.5 +/- 0.2), and percentage with cirrhosis (25%). After 6 months of treatment, significant reductions (P < 0.05) in serum ALT level (62.6 +/- 9.6), log HCV-RNA titer (4.79 +/- 0.13 copies/mL), and hepatic inflammation (4.0 +/- 0.2) were observed. These improvements were maintained in the patients randomized to continue interferon. Stopping treatment was associated with an increase in serum ALT, log HCV-RNA, and hepatic inflammation back to baseline. After 30 months of treatment, mean fibrosis score declined from 2.5 to 1.7 and 80% of patients had histological improvement (P < 0.03). Discontinuation of interferon was associated with an increase in mean fibrosis score from 2.2 to 2.4 and worsening of hepatic histology in 30% of patients (P < 0.01). CONCLUSIONS: These data support the hypothesis that maintenance interferon may prevent histological progression of chronic HCV in patients who remain viremic.

Adenosine rinse in human orthotopic liver transplantation: results of a randomized, double-blind trial.

OBJECTIVE: The study was aimed at determining whether the vasodilator, adenosine, shown to produce dramatic improvement in liver graft and animal acute and long-term survival, would be beneficial in human liver transplantation. METHODS: A prospective, randomized, double-blind trial of an adenosine rinse preservation solution in human orthotopic liver transplantation (OLTX) was conducted in 43 consecutive transplants. Intraoperative and postoperative care was performed by a single transplant team utilizing a quadruple drug immunosuppressive protocol, with complete 5-year patient follow-up. At implantation all allografts were flushed with a 4 degrees C (pH 7.4) Normosol solution, with 0.12 mM adenosine or without adenosine. RESULTS: Recipient characteristics were similar in the treated and control groups including age, pre-OLTX diagnosis, and United Network for Organ Sharing (UNOS) status. Donor variables were equivalent in the two groups including age, weight, prothrombin time, and serum chemistries. Operative variables showed no differences except a significant (p = 0.006) reduction of veno-venous bypass time in the adenosine treated group. Liver allograft function improved in the adenosine rinse groups as measured by both postoperative bile production (218 +/- 156cc/24h adenosine vs. 116 +/- 78 cc/24 h without adenosine, p = 0.03) and Factor 7 production at day 3 (64 +/- 26% adenosine vs. 51 +/- 20% without adenosine, p = 0.08). The adenosine treated group had an insignificant 10% patient and graft improvement in survival at 6 months to 60 months compared to the control group. CONCLUSIONS: These results suggest that adenosine added to the intraoperative flush solution during human liver transplantation is safe, does not reduce cardiac stability at reperfusion, improves early liver allograft function, but has an insignificant short- and long-term affect on allograft survival.

Development of pseudointima and stenosis after transjugular intrahepatic portasystemic shunts: characterization of cell phenotype and function.

The clinical utility of transjugular intrahepatic portasystemic shunts (TIPS) is frequently complicated by the ingrowth of tissue into the stent lumen, causing stent stenosis. These studies were undertaken to define the cellular and matrix components of the pseudointima, define the phenotype and function of the mesenchymal cells in the pseudointima and maintain them in culture, and to study the differences between stenotic and nonstenosed stents. A total of 35 stents were evaluated. TIPS pseudointima were examined histologically, by immunohistochemistry and in situ hybridization to determine the cellular and connective tissue constituents. Mesenchymal cells were grown from tissue within the TIPS and around it, and their phenotype was studied and compared with control smooth muscle cells and fibroblasts. Masson's trichrome staining of histological sections demonstrated that TIPS tissue was composed of collagen and palisades of mesenchymal cells and was lined by an endothelium. Immunostaining demonstrated strong and uniform alpha-smooth muscle staining in TIPS mesenchymal cells and peri-TIPS cells. Type I procollagen mRNA expression was demonstrated in mesenchymal cells in and around the stent by in situ hybridization. TIPS mesenchymal cells secreted less radiolabeled fibronectin, and far more type III, relative to type I, collagen compared with peri-TIPS cells. TIPS cells also expressed high levels of type III procollagen mRNA compared with peri-TIPS cells. There was no difference between stenotic stents and nonstenosed stents with respect to clinical features, time from stenting, gross morphology, histology, presence of bile fistulae, and cell phenotype. However, smooth muscle cells (SMC) from stenotic stents demonstrated both greater cell proliferation and collagen I and III secretion compared with those from nonstenosed stents. These data demonstrate that TIPS stenosis results from an accumulation of collagen and proliferation of SMC within the stent lumen.

Relationship between biochemical, virological, and histological response during interferon treatment of chronic hepatitis C.

The present study was conducted to evaluate the relationship between biochemical, virological, and histological response during the course of interferon therapy. Ninety consecutive patients with well-documented chronic hepatitis C virus (HCV) were treated with 5 MU of interferon alfa-2b three times weekly for 6 months. Liver biopsy was performed, and serum HCV RNA titer was measured before and at the completion of interferon treatment. Normalization of serum alanine transaminase (ALT) concentration (biochemical response) was observed in 50% of patients. In these patients, Knodell score declined significantly from 9.6 +/- 0.5 to 5.0 +/- 0.5 (P < .01), and 75% became HCV RNA negative. The remaining patients (50%) were biochemical nonresponders; mean Knodell score declined from 9.6 +/- 0.5 to 7.7 +/- 0.5 (P < .01), and 11% became HCV RNA negative. For both biochemical responders and nonresponders, the decline in Knodell score was confined to the components of hepatic inflammation (piecemeal necrosis + lobular + portal inflammation); no change in fibrosis was observed. Hepatic inflammation declined by 5 points or more in 69% of biochemical responders and 48% of biochemical nonresponders, and by at least 50% from pretreatment values in 74% and 38% of biochemical responders and biochemical nonresponders, respectively. For all patients (both biochemical responders and nonresponders) who remained viremic at the conclusion of interferon therapy, the reduction in hepatic inflammation was a linear function of the decline in HCV RNA titer. We conclude that more than one third of patients who had no biochemical response after 6 months of interferon therapy achieved a similar improvement in hepatic histology as was observed in patients with biochemical response. This improvement in hepatic histology appeared to correlate with a reduction in HCV RNA titer, especially in patients who remained viremic.

Malignant lymphoma can present as hepatobiliary disease.

BACKGROUND: Liver involvement by non Hodgkin's lymphoma usually represents systemic progression of a low grade lymphoma. Sixteen patients without palpable lymphadenopathy who presented with features suggesting hepatic inflammation were found to have non Hodgkin's lymphoma involving the liver. METHODS: Tissue sections stained with hematoxylin and eosin were examined by light microscopy. Immunohistochemical studies were performed on formalin-fixed paraffin embedded tissue to determine phenotype. Patients' medical records were reviewed for clinical details. RESULTS: Clinical presentation included fever, jaundice, and elevated liver enzymes. Peripheral lymphadenopathy was absent. Hepatomegaly and splenomegaly were common. Imaging studies revealed a homogeneous pattern of liver involvement without a discrete mass. Histologically, infiltration of the liver was predominantly portal consisting of large, atypical cells scattered within a background of small lymphoid cells. By immunohistochemistry, it was determined that eight were T-cell and eight were B-cell lymphomas. Of the eight patients who had lymph node sampling, three showed involvement by diffuse mixed, small cleaved, and large cell lymphomas. Each of these three involved lymph nodes was located near the liver. Bone marrow infiltration was demonstrated in 10 of the 11 patients in whom it was sampled. Eleven of the 16 patients died 2 days to 31 months after diagnosis, and at last follow-up, 5 patients were alive 2 weeks to 13 months after diagnosis. CONCLUSIONS: Patients with non-Hodgkin's lymphoma can present with hepatic dysfunction and without peripheral lymphadenopathy. This presentation of lymphoma is associated with extensive disease and an aggressive course.

Improved sustained response following treatment of chronic hepatitis C by gradual reduction in the interferon dose.

Interferon (IFN) treatment of chronic hepatitis C virus (HCV) is associated with a high rate of relapse. IFN is thought to exert its effect against HCV via direct viral inhibition and immune stimulation. We have hypothesized that relapse following termination of therapy results from the sudden withdrawal of this immune modulatory effect and that gradual reduction in the IFN dose may decrease the incidence of relapse. One hundred six patients with chronic HCV were enrolled into this 24-month controlled, randomized prospective trial. All were treated with 5 mU of interferon-alpha-2b three times a week for 6 months. Patients who achieved biochemical response were randomized to either stop or taper IFN gradually at monthly intervals as follows; 3 mu, 2 mU, 1 mU, and 0.5 mU (all three times a week). 0.5 mU twice weekly and then once weekly. Liver histology was assessed by Knodell index and HCV RNA was measured by a quantitative polymerase chain reaction (PCR) assay. Of the 92 patients who completed the initial 6 months of IFN treatment, 47 (51%) achieved biochemical response. Twenty-one of these patients were randomized to stop IFN treatment and 25 to taper (1 drop-out). At randomization patients were well matched with respect to age, sex, race, serum alanine transaminase (ALT), and liver histology. Biochemical relapse was observed in 19 of 21 (91%) patients who stopped IFN treatment compared with only 60% who tapered IFN (P= .04). Virological relapse occurred in 90% of patients who stopped and only 48% of persons who tapered IFN therapy. At completion of the 24-month study patients who achieved long-term sustained biochemical response had a significantly lower mean Knodell score (3.5 vs. 6.5) and a significantly greater number were HCV RNA negative in serum (85% vs. 18%) compared with relapsers. We conclude that gradual reduction in IFN dose is associated with a significant higher rate of sustained response and clearance of HCV RNA from serum compared with abruptly stopping treatment. This in turn is associated with a significant improvement in hepatic histology supporting the premise that response to IFN therapy can prevent progression to cirrhosis.

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.

The utility of CD20 and CD43 in subclassification of low-grade B-cell lymphoma on paraffin sections.

To identify phenotypic differences among the low-grade lympho-proliferative disorders in paraffin-embedded tissue, we studied 49 cases. All 22 follicular small cleaved cell lymphomas (FSC) were CD43 negative and CD20 positive. In contrast, of 20 small lymphocytic lymphomas (SL), 90% were CD20 positive, 85% were CD43 positive, and 75% were positive for both. Of three lymphomas of intermediate differentiation (IDL), two were CD20 positive and two were CD43 positive. All four monocytoid B-cell lymphomas were positive for CD20 and 50% (two cases) were positive for CD43. Some 86% of 14 chronic lymphocytic leukemias (CLL) (on cytospins) were positive for CD43; all nine of the CLL studied for CD20 were positive and 89% (8/9) expressed both antibodies CD5 expression (on frozen sections or cytospin preparations) was compared to CD43 in 21 cases of SL and CLL. Some 77% were positive for both CD5 and CD20. All seven of the CD5-positive SL also expressed CD43. The antibody MT2 was also examined with the following results: FSC, 16/20 (80%) positive; SL, 18/19 (94%) positive; MBC, 3/3 positive; and ILL, 2/3 positive. All 56 cases tested were CD45RO (UCHL1) negative. We conclude that CD43 is expressed on most cases of low-grade lymphoproliferative disorders with the exception of FSC. Its pattern of expression seems similar to CD5; however, unlike CD5, CD43 can be studied in formalin-fixed tissue. MT2 is not helpful in distinguishing among these lesions.