Faculty Bibliography

AIMS: Hepatocyte proliferation (HP) is an adaptive response to liver injury. The relationships between HP and necroinflammation, fibrosis, and serum alpha-fetoprotein (AFP) levels in chronic hepatitis C virus (HCV) infection, however, are not well understood. METHODS: Proliferative hepatocytes (Ki-67+) were identified using immunohistochemical staining in formalin-fixed, paraffin-embedded liver tissue from 156 HCV RNA-positive patients with different degrees of liver histopathology. Twenty high-power fields (HPFs) in lobular areas were counted in each specimen. RESULTS: HP increased by 1.22 +/- 0.25 cells/HPF per increase in necroinflammation from grade 0 (median: 0.13; range: [0.1-0.5] cells/HPF) through grade 3 (median: 1.80; range: [0.0-25.2] cells/HPF; P=0.002). HP increased by 0.81 +/- 0.20 cells/HPF per increase in fibrosis from stage 0 (median: 0.33; range: [0.0-1.3] cells/HPF) through stage 3 (median: 1.70; range: [0.0-25.2] cells/HPF) and then decreased in stage 4 (to median: 0.90; range: [0.0-5.3] cells/HPF). HP also increased with advancing age (P=0.03). Among patients with advanced liver disease, HP was no higher in patients with elevated serum AFP levels (median: 1.68; range: [0.1-5.3] cells/HPF) than in those with normal serum AFP levels (median: 1.70; range: [0.0-25.2] cells/HPF; P=0.26). CONCLUSIONS: In patients with chronic HCV infection, HP increases with histologic progression of liver disease, but is impaired in cirrhosis. HP was not increased in patients with elevated serum AFP levels

BACKGROUND AND AIMS: Chronic hepatitis B is an important public health problem worldwide and in the United States. A treatment algorithm for chronic hepatitis B virus (HBV) infection was developed by a panel of US hepatologists based on new developments in the understanding of the virology of HBV, availability of more sensitive molecular diagnostic testing, and advantages and disadvantages of currently approved therapies. METHODS: This algorithm is based on available evidence, but where data are lacking, the panel relied on clinical experience and consensus expert opinion. RESULTS: Serum HBV DNA can be detected at levels as low as 100-1000 copies/mL by using molecular assays and should be determined to establish a baseline level before treatment, monitor response to antiviral therapy, and survey for the development of drug resistance. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to the lowest level possible. The threshold level of HBV DNA for determination of candidacy for therapy is >/=10(5) copies/mL for patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. A lower serum HBV DNA threshold is appropriate for patients with HBeAg-negative chronic hepatitis B and those with decompensated cirrhosis, and the panel recommends thresholds of 10(4) copies/mL and 10(3) copies/mL, respectively. CONCLUSIONS: Interferon alfa-2b, lamivudine, and adefovir dipivoxil are all approved as initial therapy for chronic hepatitis B and have certain advantages and disadvantages. Issues for consideration include efficacy, safety, incidence of resistance, method of administration, and cost. Studies are under way to explore the safety and efficacy of combination therapy, which may prove to be more effective than monotherapy in suppressing viral replication and may decrease or delay the incidence of drug resistance

The absence of expanded numbers of hepatitis C virus (HCV)-reactive CD8(+) T lymphocytes (CTLs) in patients chronically infected with HCV has led to the investigation of dendritic cell (DC) function in this population as a potential cause for this defect. Several studies have shown evidence for impaired monocyte-derived DCs in chronically infected patients. As it is difficult to reconcile these data with the fact that patients with chronic HCV are immune competent, we re-evaluated this finding, carefully assessing phenotypic markers and functional activity of patient DCs as compared with noninfected controls. In contrast to these prior studies, DCs from 13 of 13 chronic HCV patients expressed typical maturation markers. These mature DCs were capable of priming allogeneic T lymphocytes, as well as stimulating influenza-specific memory T cells. This finding is consistent with clinical and immunologic data that the deficit in the patient's immune repertoire is HCV-specific and suggests that refined models are required for understanding the role of DCs in HCV pathogenesis

OBJECTIVES: Transjugular intrahepatic portosystemic shunt (TIPS) is frequently used to treat patients with refractory ascites, but its role is controversial. We sought to determine from the literature the efficacy, morbidity, and mortality associated with TIPS for refractory ascites. METHODS: We searched MEDLINE and identified studies published in English from January, 1985, to March, 2003, that evaluated the effect of TIPS in patients with refractory ascites. Outcomes that were analyzed included complete resolution of ascites, reduction in ascites, mortality, encephalopathy, stenosis, and renal function. Data were analyzed on an intention to treat basis. RESULTS: Of 25 studies identified, 16 were included in the analysis. The pooled estimate for complete response at 6 months was 45% and for any response (complete and partial) was 63%. Pooled 6-month mortality after TIPS was 36%. Risk factors for mortality included renal insufficiency (serum creatinine >1.5 mg/dl), hyperbilirubinemia (total bilirubin >3 mg/dl), advanced age (>60 yr), and poor response to TIPS. The pooled rate of new or worsening encephalopathy after TIPS was 32%. In most cases, encephalopathy was managed medically or by reduction in shunt size; however, refractory cases were associated with 100% mortality in most studies. Studies reporting the effect of TIPS on kidney function showed improvement in creatinine clearance and urinary sodium excretion. CONCLUSIONS: TIPS is effective in eliminating ascites or substantially reducing ascites in cases refractory to medical therapy. Renal insufficiency, refractory encephalopathy, and hyperbilirubinemia were consistently associated with mortality after TIPS. In individuals with risk factors for mortality, alternative strategies should be recommended.

About 350 million people worldwide have chronic hepatitis B virus (HBV) infection. Up to 40% of persons infected with the virus may go on to have complications related to cirrhosis or hepatocellular carcinoma. Antiviral therapy can suppress viral replication and halt the progression of liver disease in persons with chronic infection. In this article, the authors explore the modes of HBV transmission, describe the characteristics of chronic infection, and review the drugs available to treat it.

OBJECTIVE: Hepatitis C virus (HCV) is prevalent in patients with end stage renal disease who are on dialysis. Liver disease from HCV is a cause of substantial morbidity and mortality after kidney transplantation in infected recipients. Effective treatment of chronic HCV is needed in this group of patients. We aimed to determine from the literature the efficacy and safety of interferon monotherapy in dialysis patients with chronic HCV. METHODS: We reviewed the literature from 1986 to 2001 on the efficacy of interferon monotherapy in patients with HCV and end stage renal disease who were on dialysis. The outcomes measured were sustained viral response (SVR) and drop-out rate. RESULTS: We reviewed 17 studies, of which 11 studies with a total of 213 patients met criteria for our analysis. Eight studies evaluated 3 million units (MU) three times/wk (t.i.w.), and three studies evaluated higher doses. The pooled SVR for 3 MU was 33% (95% CI = 21-51%). The pooled SVR for genotype 1 patients was 26% (95% CI = 15-37%). Of 152 patients in eight studies treated with 3 MU t.i.w. of interferon monotherapy, 45 patients (29.6%) discontinued therapy because of side effects. CONCLUSIONS: Our analysis suggests that interferon monotherapy is more effective in patients on dialysis than in patients with normal renal function. Interferon monotherapy is associated with more adverse events in dialysis patients. The optimal dose and duration of interferon monotherapy and selection criteria of dialysis patients need to be studied further in clinical trials.

BACKGROUND: The purpose of this study was to compare linear array endoscopic ultrasound (EUS) and helical computed tomography (CT) scan in the preoperative local staging evaluation of patients with periampullary tumors. METHODS: Patients evaluated with EUS and CT for suspected periampullary malignancies from 1996 to 2000 were analyzed. Surgical/pathology staging results were the reference standard. RESULTS: Forty-eight patients (28 men and 20 women; mean age, 62 +/- 4.9 years; range, 18-90 years) were identified. Malignancy was histologically confirmed in 44 patients. Parameters evaluated included tumor size, lymph node metastases, and major vascular invasion. EUS was significantly more sensitive (100%), specific (75%), and accurate (98%) than helical CT (68%, 50%, and 67%, respectively) for evaluation of the periampullary mass (P <.05). In addition, EUS detected regional lymph node metastases in more patients than helical CT. Sensitivity, specificity, and accuracy of EUS were 61%, 100%, and 84%, in comparison to 33%, 92%, and 68%, respectively, with CT. Major vascular involvement was noted in 9 of 44 patients. EUS correctly identified vascular involvement in 100% compared with 45% with CT (P <.05). CONCLUSIONS: Linear array EUS was consistently superior to helical CT in the preoperative local staging of periampullary malignancies.

Chronic infection with hepatitis C virus (HCV) is associated with disturbances of B lymphocyte activation and function: autoantibody production, mixed cryoglobulinemia, and B cell lymphomas. It has been proposed that these abnormalities reflect chronic antigenic stimulation or aberrant signaling through the B cell coreceptor, the latter mediated by binding of the HCV E2 glycoprotein to CD81. To test this hypothesis, we measured expression of activation and differentiation markers on peripheral blood B cells from patients with chronic HCV infection. Thirty-six HCV patients with and without mixed cryoglobulinemia were compared with 18 healthy control volunteers and 17 sustained virologic responders who had cleared HCV infection. Ten of the 36 HCV patient samples showed increased B cell frequencies; B cell frequency was higher in patients with more severe hepatic fibrosis. However, these samples lacked evidence of Ag-driven activation or proliferation. The expanded cells were low in the activation markers CD25, CD69, CD71, CD80, and CD86. Proliferation of circulating B cells was unchanged in HCV patients. These cells did not express the differentiation marker CD27, suggesting that they were not enriched in memory B cells. Furthermore, the expanded B cells expressed both IgD and IgM, suggesting that they were antigenically naive. Together, these results indicate that B cell expansion in the peripheral blood of HCV patients is not associated with Ag-mediated activation and differentiation. Instead, factors other than antigenic stimulation may promote the accumulation of peripheral blood B cells with a naive phenotype in a subset of HCV patients

BACKGROUND: Premature stent clogging is the major limitation with plastic stents used in the treatment of malignant biliary structures. A pilot study suggested improved duration of patency of the Tannenbaum stent compared with polyethylene stents. The aim of this prospective, multicenter randomized trial was to compare the Tannenbaum Teflon stent with a conventional polyethylene endoprosthesis (Cotton-Leung biliary stent set) for the treatment of malignant biliary strictures. METHODS: Patients over age 18 years with symptoms caused by nonhilar malignant biliary strictures were enrolled. Patients were randomized to receive a 10F Tannenbaum or polyethylene stent after a guidewire was passed beyond the stricture. One hundred six patients (mean age 72 years and 71 years, respectively) were enrolled (54 Tannenbaum, mean age 72 years; 52 polyethylene, mean age 71 years). RESULTS: Tannenbaum and polyethylene stent placement was successful in, respectively, 100% and 96% of procedures without complications. The mean (SD) 90-day stent patency of the Tannenbaum stent was 67% (7%) compared with 73% (7%) for the polyethylene stents. CONCLUSIONS: The present study demonstrated no difference in ease of implantation or stent patency between Tannenbaum and polyethylene stents.