Ethnicity and body mass index are associated with hepatitis C presentation and progression.

BACKGROUND & AIMS: Ethnicity and the metabolic syndrome are believed to affect progression of hepatitis C virus (HCV) infection, but the interaction between these factors is unknown. We evaluated the association between elements of the metabolic syndrome and ethnicity in the histologic progression of HCV in a large, diverse cohort. METHODS: We retrospectively evaluated clinical data and liver biopsy samples from 812 patients who had no cause of liver disease other than HCV infection. Liver biopsies were scored for steatosis, necroinflammatory activity, and fibrosis. For each patient with a known risk factor for viral acquisition, fibrosis index was calculated as an indicator of disease progression. RESULTS: Hispanics had significantly higher fibrosis index (0.13 +/- 0.09) than non-Hispanic whites (0.11 +/- 0.07) and African Americans (0.10 +/- 0.06; P = .001). Fibrosis index correlated with body mass index (BMI), older age at infection, ethnicity, and degree of steatosis. Cirrhosis was present in 50% of Hispanics, 38% of non-Hispanic whites, and 24% of African Americans (P < .001). The presence of cirrhosis was associated additionally with older age, longer duration of infection, BMI, alcohol consumption, and diabetes. In multivariate analysis, only BMI and ethnicity were associated with both fibrosis index and presentation with cirrhosis. Patients with higher BMIs, diabetes mellitus, and steatosis had higher degrees of necroinflammation. CONCLUSIONS: Ethnicity and BMI each were associated with the progression of fibrosis and the presence of cirrhosis. Hispanics had the highest fibrosis index and prevalence of cirrhosis, whereas African Americans had the lowest. Ethnic differences in fibrosis index and cirrhosis persisted after controlling for elements of metabolic syndrome.

Intracardiac migration of inferior vena cava filters: review of published data.

BACKGROUND: Intracardiac or intrapulmonary migration of inferior vena cava (IVC) filters is an uncommon although potentially life-threatening event that is poorly understood. METHODS: We searched the medical literature and extracted data detailing information concerning the event, including the cause and treatment of the filter migration. Our data were summarized with respect to the filter type, presenting symptoms, associated morbidity and mortality, and success and failure of the treatment provided. RESULTS: Ninety-eight cases of intracardiac or intrapulmonary migration of IVC filters were identified in 77 publications. CONCLUSIONS: Intracardiac and intrapulmonary migration of IVC filters is an uncommon event the etiology of which has been attributed to a variety of causes including operator error, device failure, and patient's physical attributes. Although there is no consensus on patient management, we offer that open thoracotomy has several advantages over the endovascular approach and may provide the best first option. Whenever the patient is not a surgical candidate, endovascular retrieval has been demonstrated to be a relatively safe and viable alternative.

A mathematical model of hepatitis C virus dynamics in patients with high baseline viral loads or advanced liver disease.

BACKGROUND & AIMS: Patients with baseline hepatitis C virus-RNA levels (bHCV-RNA)>6 log IU/mL or cirrhosis have a reduced probability of a sustained-virologic response (SVR). We examined the relation between bHCV-RNA, cirrhosis, and SVR with a mathematical model that includes the critical-drug efficacy (epsilonc; the efficacy required for a drug to clear HCV), the infection-rate constant (beta), and the percentage of HCV-infected hepatocytes (pi). METHODS: The relation between baseline factors and SVR was evaluated in 1000 in silico HCV-infected patients, generated by random assignment of realistic host and viral kinetic parameters. Model predictions were compared with clinical data from 170 noncirrhotic and 75 cirrhotic patients. RESULTS: The ranges chosen for beta and the viral production rate (p) resulted in bHCV-RNA levels that were in agreement with the distribution observed in US patients. With these beta and p values, higher bHCV-RNA levels led to higher epsilonc, resulting in lower SVR rates. However, higher beta values resulted in lower bHCV-RNA levels but higher pi and (epsilonc), predicting lower rates of SVR. Cirrhotic patients had lower bHCV-RNA levels than noncirrhotic patients (P=.013), and more had bHCV-RNA levels<6 log IU/mL (P<.001). Even cirrhotic patients with lower bHCV-RNA levels had lower SVR rates. An increase in beta could explain the results observed in cirrhotic patients. CONCLUSIONS: Our model predicts that higher bHCV-RNA levels lead to higher epsilonc, reducing the chance of achieving SVR; cirrhotic patients have lower SVR rates because of large pi values, caused by increased rates of hepatocyte infection.

The histologic spectrum of liver disease in African-American, non-Hispanic white, and Hispanic obesity surgery patients.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a prominent cause of chronic liver disease in African Americans, non-Hispanic whites, and Hispanics. The aim of this study was to evaluate ethnic differences in the prevalence of NAFLD and non-alcoholic steatohepatitis (NASH) and to compare the severity of histologic features of NASH in obesity surgery patients. METHODS: Subjects consisted of 238 patients who had a routine liver biopsy at the time of obesity surgery. Demographic and clinical variables pertaining to the metabolic syndrome were collected retrospectively. Liver biopsies were evaluated according to the scoring system proposed by the Nonalcoholic Steatohepatitis Clinical Research Network and NASH was defined as a NASH activity score > or =5. RESULTS: African Americans had lower rates of steatosis than non-Hispanic whites (P<0.001) and Hispanics (P=0.03). Among patients with steatosis, African Americans had lower rates of NASH than non-Hispanic whites (P=0.05) and Hispanics (P=0.02) and lower rates of fibrosis score > or =F2 than non-Hispanic whites (P=0.002) and Hispanics (P=0.04). Ethnic differences in rates of NAFLD, NASH, and fibrosis > or =F2 persisted when controlling for demographic variables and features of the metabolic syndrome in logistic regression analysis. There were no significant differences in steatosis, NASH, or fibrosis > or =F2 between non-Hispanic whites and Hispanics. CONCLUSIONS: African-American obesity surgery patients have a lower rate of NAFLD, NASH, and less severe fibrosis than non-Hispanic whites and Hispanics.

Ethnicity and nonalcoholic fatty liver disease in an obesity clinic: the impact of triglycerides.

Nonalcoholic fatty liver disease (NAFLD) is a growing problem that is associated with the metabolic syndrome. The goal of the present study was to evaluate for ethnic differences in NAFLD and clinical correlates of NAFLD. The study population consisted of 567 patients seen at an urban obesity clinic. Elevated aminotransferase levels were used as a surrogate marker for NAFLD. The prevalence of elevated aminotransferases was highest in Hispanics (39%), followed by Caucasians (28%), and African Americans (12%). In univariate analysis, elevated aminotransferase levels were associated with ethnicity (Hispanic > African American, P < 0.001, and Caucasian > African American P = 0.030), hypertriglyceridemia (P < 0.001), and male gender (P < 0.001). The pattern of results was confirmed in multivariate analysis, except that the differences between Caucasians and African Americans was no longer significant. In conclusion, in an obesity clinic population, elevated aminotransferase levels and hypertriglyceridemia were most common in Hispanics and least common in African Americans.

Hepatitis C Viral Kinetics in Special Populations.

Mathematical models of hepatitis C viral (HCV) kinetics provide a means of estimating the antiviral effectiveness of therapy, the rate of virion clearance and the rate of loss of HCV-infected cells. They have also proved useful in evaluating the extrahepatic contribution to HCV plasma viremia and they have suggested mechanisms of action for both interferon-α and ribavirin. Viral kinetic models can explain the observed HCV RNA profiles under treatment, e.g., flat partial response, biphasic and triphasic viral decay and viral rebound. Current therapy with (pegylated) interferon-α and ribavirin has a poorer success in patients having insulin resistance, hepatic fibrosis, African American ethnicity, HCV/HIV-coinfection, HCV genotype-1 and high baseline viral load. The use of mathematical modeling and statistical analysis of experimental data have been useful in understanding some of these treatment obstacles.

Diabetes and hepatic oxidative damage are associated with hepatitis C progression after liver transplantation.

BACKGROUND: Posttransplant diabetes mellitus (PTDM) is common after liver transplantation and was recently identified as a risk factor for hepatitis C progression. Increased levels of oxidative stress have been identified in diabetes and hepatitis C. The aim of this study was to evaluate the relationship among PTDM, oxidative damage in liver biopsy specimens, and fibrosis progression posttransplant. METHODS: Subjects consisted of 27 hepatitis C-infected liver transplant recipients who had liver biopsy specimens available from 49 protocol liver biopsies. Paraffin embedded liver tissue sections were stained for 8-hydroxy-2' deoxyguanosine (8-OHdG), an indicator of hydroxyl radical mediated tissue damage. The percentage of cells staining for 8-OHdG in a histologic section was categorized as high (>66%) versus low score (< or =66%). Fibrosis index was calculated as fibrosis score (0-4)/ years posttransplant. Time to bridging fibrosis or cirrhosis (F3-4) was compared as a function of PTDM and 8-OHdG score. RESULTS: Considering all 49 biopsies, fibrosis index was higher in cases with PTDM (P<0.001) and high 8-OHdG score (P=0.004). High 8-OHdG score was associated with PTDM (P=0.012). In time to event analyses, time to F3-4 was more rapid in patients with PTDM (P=0.02) and in those with high 8-OHdG scores (P<0.001). CONCLUSIONS: This study confirmed a relationship between PTDM and hepatitis C fibrosis progression and found that oxidative damage in liver biopsy specimens was associated with PTDM and more rapid development of advanced fibrosis.

Measurement of liver fat content using selective saturation at 3.0 T.

PURPOSE: To validate an MRI technique for measuring liver fat content by calibrating MRI readings with liver phantoms and comparing MRI measurements in human subjects with estimates of liver fat content on liver biopsy specimens. MATERIALS AND METHODS: The MRI protocol consisted of fat and water imaging by selective saturation using a 3.0-T scanner. A water phantom and liver phantoms were scanned before each of 10 human subjects who underwent a liver biopsy to assess for nonalcoholic fatty liver disease (NAFLD). Liver fat content in human subjects was derived from a calibration curve generated by scanning the phantoms. Liver fat was also estimated by optical image analysis and pathologists' assessment of histologic sections. RESULTS: MRI measurements of the liver phantoms were highly reproducible. Measurements of liver fat content in human subjects made by MRI in two areas of the liver were strongly correlated (r=0.98, P<0.001). MRI measurements were highly associated with estimates of liver fat content made by optical image analysis (r=0.96, P<0.001) and with estimates made by the pathologists (r=0.93, P<0.001). CONCLUSION: We validated a technique for quantifying liver fat content based on selective fat and water imaging. The technique is accurate and reproducible and provides a noninvasive method to obtain serial measurements of liver fat content in human subjects.

Viral kinetics in the treatment of chronic hepatitis C.

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatic fibrosis, and chronic infection can frequently progress to cirrhosis, end-stage liver disease and hepatocellular carcinoma. Treatment with pegylated interferons (INFs) plus ribavirin has been shown to be more effective than pegylated INFs alone or standard INFs with or without ribavirin. The early response of HCV to treatment with peg-INF has been used to predict treatment outcomes in infected patients, emphasizing the importance of viral kinetics and genotyping in their treatment. Mathematic modelling of viral dynamics has shown the importance of optimal doses of drug, with early virologic response at week 12 predictive of sustained virologic response. Maintaining INF concentration above a therapeutically effective level is necessary to prevent viral rebound and subsequent treatment failure. Once-weekly dosing with peg-INF-alpha2a, which has a longer half-life than other forms of INF, plus daily dosing with ribavirin, has been shown to be effective in reducing viral load.

Hepatitis C virus genotype 1a NS5A pretreatment sequence variation and viral kinetics in African American and white patients.

In hepatitis C virus (HCV) infection, race is a determinant of treatment response and interferon (IFN) effectiveness. Here, we investigated whether there were differences in the pretreatment viral strains between African American patients and white patients and whether these differences correlated with viral kinetics. IFN effectiveness was calculated using a viral kinetic model. The HCV NS5A region from 21 treated patients with HCV genotype 1a was sequenced and analyzed. White patients displayed more mutations in the V3 region (mean+/-SD, 4.5+/-1.4 vs. 2.9+/-1.6; P=.016), and treatment responders tended to have more mutations in this region than did nonresponders. There was a significant positive correlation between IFN effectiveness and the number of mutations in the V3 region (P=.03). There was no clustering of strains by race, treatment response, or IFN effectiveness in phylogenetic analyses. The results of this study, in conjunction with those of a previous study illustrating the impaired IFN effectiveness in African Americans, suggest a role for host-related factors.

p53, Ki-67, and serum alpha feto-protein as predictors of hepatocellular carcinoma recurrence in liver transplant patients.

Patients with hepatocellular carcinoma who undergo orthotopic liver transplantation (OLT) are at risk for post-transplant tumor recurrence. The aim of this study was to evaluate whether expression of p53 and Ki-67 in hepatocellular carcinoma lesions present in explanted liver tissue was associated with time to tumor recurrence after OLT. Subjects consisted of 20 consecutive patients who underwent OLT and were found to have hepatocellular carcinoma in the liver explant. Immunostaining for p53 and Ki-67 was performed by standard methods. The presence of nuclear immunostaining in >10% of the tumor tissue was considered positive. Time to recurrence of hepatocellular carcinoma after OLT was compared between patients with positive and negative immunostaining by the log rank test. Multivariate analysis was performed using a Cox regression model to control for potentially confounding clinical factors. Time to post-transplant hepatocellular carcinoma recurrence was significantly more rapid in p53+ (P=0.0007) and Ki-67+ cases (P=0.001). These associations remained significant in multivariate analysis. Furthermore, time to recurrent hepatocellular carcinoma was significantly shorter in patients with a serum alpha feto-protein (AFP) level >or=100 ng/ml at time of diagnosis, compared to those with an AFP level <100 ng/ml (P=0.003). In conclusion, expression of p53 and Ki-67 in hepatocellular carcinoma lesions, and a serum AFP level >or=100 ng/ml were associated with more rapid recurrence of hepatocellular carcinoma after OLT. Identification of patients at risk for early post-transplant recurrence could be used to guide surveillance and adjuvant treatment strategies.

Modelling how ribavirin improves interferon response rates in hepatitis C virus infection.

Nearly 200 million individuals worldwide are currently infected with hepatitis C virus (HCV). Combination therapy with pegylated interferon and ribavirin, the latest treatment for HCV infection, elicits long-term responses in only about 50% of patients treated. No effective alternative treatments exist for non-responders. Consequently, significant efforts are continuing to maximize response to combination therapy. However, rational therapy optimization is precluded by the poor understanding of the mechanism(s) of ribavirin action against HCV. Ribavirin alone induces either a transient early decline or no decrease in HCV viral load, but in combination with interferon it significantly improves long-term response rates. Here we present a model of HCV dynamics in which, on the basis of growing evidence, we assume that ribavirin decreases HCV infectivity in an infected individual in a dose-dependent manner. The model quantitatively predicts long-term response rates to interferon monotherapy and combination therapy, fits observed patterns of HCV RNA decline in patients undergoing therapy, reconciles conflicting observations of the influence of ribavirin on HCV RNA decline, provides key insights into the mechanism of ribavirin action against HCV, and establishes a framework for rational therapy optimization.

Viral kinetics in hepatitis C virus: special patient populations.

The evolution in therapy for chronic hepatitis C virus (HCV) infection to the more recent use of peginterferons in combination with ribavirin has dramatically increased the sustained virological response (SVR) rates versus standard interferon/ ribavirin combination therapy. However, although peginterferon and ribavirin therapy has markedly improved treatment responses overall, factors such as high viral load, genotype 1 infection, obesity, HIV co-infection and African American race continue to pose challenges to optimizing SVR rates. Application of mathematical models may be helpful in understanding why these groups and/or individuals appear to be resistant to interferon (IFN)-based therapy. This article focuses on the viral kinetics and viral kinetic differences among patients infected with HCV genotypes 1 and 2, obese and nonobese patients, and African Americans and Whites.

Dynamics of alanine aminotransferase during hepatitis C virus treatment.

Studies of the kinetics of hepatitis C virus (HCV) decline during interferon (IFN)-based therapy have led to insights into treatment efficacy. However, the kinetics of serum alanine aminotransferase (ALT), an enzyme used as a surrogate of liver damage, have not been closely monitored, and it is not known if they correlate with those of HCV RNA. Here we describe the associations between ALT and HCV dynamics. We analyzed 35 patients treated daily with 10 mIU IFN-alpha 2b with or without ribavarin for 28 days followed by standard IFN/ribavirin therapy. Patients exhibited 4 patterns of ALT change: (1) exponential decay of ALT, (2) transient increase in ALT followed by a decrease to pretreatment or normal levels, (3) increase in ALT to a new level, and (4) no significant change. By simultaneously modeling HCV and ALT dynamics, we successfully fit the observed changes. We found ALT decays with t(1/2) = 12.7 hours. The transient increase in ALT observed in some patients suggested a mild hepatotoxic effect of IFN. However, patients with a smaller initial ALT increase achieved higher rates of viral negativity by week 72 (P =.02). The week-4 ALT decline correlated with the HCV log drop (P =.006) and the efficacy of therapy (P =.025). In conclusion, our results suggest the use of ALT as a surrogate marker for treatment effect in patients with elevated ALT.

Viral dynamics and response differences in HCV-infected African American and white patients treated with IFN and ribavirin.

Studies have suggested that African American patients infected with hepatitis C virus (HCV) do not respond as well to treatment with interferon (IFN) as white patients. Here we analyzed the difference in the viral kinetic response between genotype 1 HCV-infected African American patients (n = 19) and white patients (n = 16). Patients were treated with 10 mIU IFN-alpha2b daily with or without ribavirin for 1 month followed by 3 mIU IFN-alpha2b 3 times a week with ribavirin. The kinetic parameters (epsilon, treatment effectiveness at inhibiting virion production; delta, loss rate of virus-producing cells; c, clearance rate of free virions; tau, delay until viral decline starts) were estimated from the viral load decay profiles using a previously described mathematical model. Differences in early kinetic parameters and viral negativity frequencies at weeks 4, 12, and 48 were compared. Ribavirin did not appear to enhance any of the viral kinetic parameters, although this may have been due to the high dose of IFN used. African American patients exhibited significantly (P =.005) lower drug effectiveness (88.6% vs. 98.2%) compared with white patients, accounting for a 0.8 log lower HCV RNA decrease in the first 24 hours of treatment. Significant differences (P =.006) were also noted for delta. There was no correlation between any of the viral kinetic parameters and either age, body mass index (BMI), or genotype 1 subtype. No patient achieved viral negativity at weeks 4, 12, or 48 without an epsilon greater than 90%. The mean viral decline and viral negativity rates were statistically different between the two races; however, when controlling for treatment effectiveness, these differences were no longer apparent. In conclusion, the failure of IFN response in African American patients infected with genotype 1 HCV is in part due to an impaired ability to inhibit viral production.