Imad Nasser

Hepatitis C genotype 4: What we know and what we don't yet know

Hepatitis C virus genotype 4 (HCV‐4) is the most common variant of the hepatitis C virus (HCV) in the Middle East and Africa, particularly Egypt. This region has the highest prevelance of HCV worldwide, with more than 90% of infections due to genotype 4. HCV‐4 has recently spread in several Western countries, particularly in Europe, due to variations in population structure, immigration, and routes of transmission. The features of HCV‐4 infection and the appropriate therapeutic regimen have not been well characterized. This review discusses the virology, epidemiology, natural history, histology, clinical data, and treatment options for patients with HCV‐4 infections. Early reports on the treatment of patients with chronic HCV‐4 with conventional interferon (IFN)‐α monotherapy indicated poor rates of sustained viral response (SVR), which improved slightly when combined with ribavirin. Pegylated IFN and ribavirin combination therapy has dramatically improved the response rates, with recent clinical trials showing rates that exceed 60%. These data can now be used as a platform for further research to define optimal treatment duration and predictors of SVR in patients with HCV‐4 infection. Conclusion: HCV‐4 infection is spreading beyond its strongholds in Africa and the Middle East. Recent clinical trials show that HCV‐4 is not difficult to treat, as the response to treatment may be at an intermediate level compared with genotype 1 and genotypes 2 or 3. Tailored treatment options that are comparable to the treatment approaches for genotype 1, 2, and 3 patients to optimize treatment for each patient are now being developed. (HEPATOLOGY 2008.)

Hepatic CD1d Expression in Hepatitis C Virus Infection and Recognition by Resident Proinflammatory CD1d-Reactive T Cells

A subset of CD161+CD56+/− NKT cells can recognize glycolipids presented by CD1d and positively or negatively regulate inflammatory responses, including those implicated in several models of hepatitis. CD1d is expressed at very low levels in the healthy liver, but there is a large fraction of CD161+CD56+ NKT cells. There are high levels of nonclassical proinflammatory hepatic CD1d-reactive T cells in hepatitis C virus (HCV) infection. Hepatic inflammatory cells and biliary cells adjacent to portal tract fibrotic areas of HCV-infected donors specifically up-regulated CD1d. A hepatocyte cell line expressing minimal CD1d was efficiently recognized by hepatic CD1d-reactive T cells, suggesting a role for these cells in disease. Hepatic CD1d-reactive T cells from HCV-positive as well as negative donors produced large amounts of IFN-γ with some IL-13, but only rarely detectable IL-4. We confirmed large numbers of hepatic CD161+ T cells, lower levels of CD56+ T cells, and small numbers of classic invariant NKT cells. However, hepatic CD1d-reactivity was not restricted to any of these populations. We suggest virally infected hepatic cells can process potent CD1d-presented liver Ag(s), for surveillance by resident Th1 hepatic CD1d-reactive T cells. This process may be beneficial in acute viral clearance, but in chronic infection could contribute to liver injury.

High resolution anoscopy findings for men who have sex with men: Inaccuracy of anal cytology as a predictor of histologic high-grade anal intraepithelial neoplasia and the impact of HIV serostatus

We compared the pathological diagnoses obtained by anal Papanicolaou (Pap) smear with those obtained by anal biopsy or by surgical excision for 153 men who have sex with men (MSM). Analysis of these paired specimens showed that anal Pap smears were an inaccurate predictor of high-grade anal dysplasia, regardless of human immunodeficiency virus (HIV) serostatus. The presence of any abnormal anal cytological finding indicates a potential for high-grade dysplasia on histological examination of MSM.

Fibroblast Growth Factor 21 Limits Lipotoxicity by Promoting Hepatic Fatty Acid Activation in Mice on Methionine and Choline-Deficient Diets

BACKGROUND & AIMS Nonalcoholic fatty liver disease is a common consequence of human and rodent obesity. Disruptions in lipid metabolism lead to accumulation of triglycerides and fatty acids, which can promote inflammation and fibrosis and lead to nonalcoholic steatohepatitis. Circulating levels of fibroblast growth factor (FGF)21 increase in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis; therefore, we assessed the role of FGF21 in the progression of murine fatty liver disease, independent of obesity, caused by methionine and choline deficiency. METHODS C57BL/6 wild-type and FGF21-knockout (FGF21-KO) mice were placed on methionine- and choline-deficient (MCD), high-fat, or control diets for 8-16 weeks. Mice were weighed, and serum and liver tissues were collected and analyzed for histology, levels of malondialdehyde and liver enzymes, gene expression, and lipid content. RESULTS The MCD diet increased hepatic levels of FGF21 messenger RNA more than 50-fold and serum levels 16-fold, compared with the control diet. FGF21-KO mice had more severe steatosis, fibrosis, inflammation, and peroxidative damage than wild-type C57BL/6 mice. FGF21-KO mice had reduced hepatic fatty acid activation and β-oxidation, resulting in increased levels of free fatty acid. FGF21-KO mice given continuous subcutaneous infusions of FGF21 for 4 weeks while on an MCD diet had reduced steatosis and peroxidative damage, compared with mice not receiving FGF21. The expression of genes that regulate inflammation and fibrosis were reduced in FGF21-KO mice given FGF21, similar to those of wild-type mice. CONCLUSIONS FGF21 regulates fatty acid activation and oxidation in livers of mice. In the absence of FGF21, accumulation of inactivated fatty acids results in lipotoxic damage and increased steatosis.

Thyroid hormone-related regulation of gene expression in human fatty liver

CONTEXT Fatty liver is an important complication of obesity; however, regulatory mechanisms mediating altered gene expression patterns have not been identified. OBJECTIVE The aim of the study was to identify novel transcriptional changes in human liver that could contribute to hepatic lipid accumulation and associated insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis. DESIGN We evaluated gene expression in surgical liver biopsies from 13 obese (nine with type 2 diabetes) and five control subjects using Affymetrix U133A microarrays. PCR validation was performed in liver biopsies using an additional 16 subjects. We also tested thyroid hormone responses in mice fed chow or high-fat diet. SETTING Recruitment was performed in an academic medical center. PARTICIPANTS Individuals undergoing elective surgery for obesity or gallstones participated in the study. RESULTS The top-ranking gene set, down-regulated in obese subjects, was comprised of genes previously demonstrated to be positively regulated by T(3) in human skeletal muscle (n = 399; P < 0.001; false discovery rate = 0.07). This gene set included genes related to RNA metabolism (SNRPE, HNRPH3, TIA1, and SFRS2), protein catabolism (PSMA1, PSMD12, USP9X, IBE2B, USP16, and PCMT1), and energy metabolism (ATP5C1, COX7C, UQCRB). We verified thyroid hormone regulation of these genes in the liver after injection of C57BL/6J mice with T(3) (100 microg/100 g body weight); furthermore, T(3)-induced increases in expression of these genes were abolished by high-fat diet. In agreement, expression of these genes inversely correlated with liver fat content in humans. CONCLUSIONS These data suggest that impaired thyroid hormone action may contribute to altered patterns of gene expression in fatty liver.

Expression of the Splicing Factor Gene SFRS10 is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis

Alternative mRNA splicing provides transcript diversity and may contribute to human disease. We demonstrate that expression of several genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. We evaluated a representative splicing factor, SFRS10, downregulated in both obese human liver and muscle and in high-fat-fed mice, and determined metabolic impact of reduced expression. SFRS10-specific siRNA induces lipogenesis and lipid accumulation in hepatocytes. Moreover, Sfrs10 heterozygous mice have increased hepatic lipogenic gene expression, VLDL secretion, and plasma triglycerides. We demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10; reduced SFRS10 favors the lipogenic β isoform of LPIN1. Importantly, LPIN1β-specific siRNA abolished lipogenic effects of decreased SFRS10 expression. Together, our results indicate that reduced expression of SFRS10, as observed in tissues from obese humans, alters LPIN1 splicing, induces lipogenesis, and therefore contributes to metabolic phenotypes associated with obesity.

2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody‐mediated liver allograft rejection at the 11th (Paris, France, June 5–10, 2011), 12th (Comandatuba, Brazil, August 19–23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5–10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody‐mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Levels of Alanine Aminotransferase Confound Use of Transient Elastography to Diagnose Fibrosis in Patients With Chronic Hepatitis C Virus Infection

BACKGROUND & AIMS Hepatic elastography (HE) is a noninvasive technique that measures liver stiffness and is used to diagnose hepatic fibrosis. It can help patients who are thought to have early-stage disease avoid a staging liver biopsy, but only when confounding variables that increase liver stiffness are excluded. Chronic inflammation from hepatitis C virus (HCV) infection is not considered to be one of these variables. METHODS We identified 684 patients with HCV and METAVIR fibrosis scores of 0-2 from a prospective, multi-institutional study of liver stiffness in 2880 patients with chronic liver disease. Patients were 49.6 ± 9.0 years old, 64.3% were male, and they had an average body mass index of 26.7 ± 4.1 kg/m(2). RESULTS In a multivariate analysis, inflammation (based on histologic analysis) and level of alanine aminotransferase (ALT) were associated with liver stiffness. The chances of a patient having a level of stiffness that indicates cirrhosis increased with grade of inflammation and level of ALT. By using a conservative 14.5-kPa cutoff for the diagnosis of cirrhosis, grade 3 inflammation had an odds ratio of 9.10 (95% confidence interval, 2.49-33.4). Likewise, levels of ALT greater than 80 and 120 IU/L had odds ratios of 3.84 (95% confidence interval, 2.10-7.00) and 4.10 (95% confidence interval, 2.18-7.69), respectively. The effect of the level of ALT persisted when analysis was restricted to patients with fibrosis scores of F0 to F1. CONCLUSIONS In patients with HCV infection and early-stage fibrosis, increased levels of ALT correlate with liver stiffness among patients in the lowest strata of fibrosis (METAVIR scores 0-2). Patients without fibrosis but high levels of ALT could have liver stiffness within the range for cirrhosis. Inflammation should be considered a confounding variable in analysis of liver stiffness.

The clinical utility of biomarkers and the nonalcoholic steatohepatitis CRN liver biopsy scoring system in patients with nonalcoholic fatty liver disease

Background and Aims:  We identified patients with nonalcoholic fatty liver disease (NAFLD) to determine the predictive value of serum markers to diagnose histological steatohepatitis (NASH).

Accuracy of Fibroscan, Compared With Histology, in Analysis of Liver Fibrosis in Patients With Hepatitis B or C: A United States Multicenter Study

BACKGROUND & AIMS Liver biopsy is invasive and associated with complications, sampling errors, and observer variability. Vibration-controlled transient elastography (VCTE) with FibroScan can be used to immediately assess liver stiffness. We aimed to define optimal levels of liver stiffness to identify patients with chronic viral hepatitis and significant fibrosis, advanced fibrosis, or cirrhosis. METHODS In a prospective, 2-phase study, patients with chronic hepatitis C or B underwent VCTE followed by liver biopsy analysis from January 2005 through May 2008 at 6 centers in the United States. In phase 1 we identified optimal levels of liver stiffness for identification of patients with stage F2-F4 or F4 fibrosis (the development phase, n = 188). In phase 2 we tested these cutoff values in a separate cohort of patients (the validation phase, n = 560). All biopsies were assessed for METAVIR stage by a single pathologist in the phase 1 analysis and by a different pathologist in the phase 2 analysis. Diagnostic performances of VCTE were assessed by area under the receiver operating characteristic curve (AUROC) analyses. RESULTS In phase 1 of the study, liver stiffness measurements identified patients with ≥ F2 fibrosis with AUROC value of 0.89 (95% confidence interval, 0.83-0.92) and identified patients with F4 fibrosis with AUROC value of 0.92 (95% confidence interval, 0.87-0.95). Liver stiffness cutoff values (kPa) in phase 1 were 8.4 for ≥ F2 (82% sensitivity, 79% specificity) and 12.8 for F4 (84% sensitivity, 86% specificity). In the phase 2 analysis, the liver stiffness cutoff values identified patients with ≥ F2 fibrosis with 58% sensitivity (P < .0001 vs phase 1) and 75% specificity (nonsignificant difference vs phase 1); they identified patients with F4 fibrosis with 76% sensitivity (P < .0001 vs phase 1) and 85% specificity (nonsignificant differences vs phase 1). VCTE had an interobserver agreement correlation coefficient of 0.98 (n = 26) and an intraobserver agreement correlation coefficient of 0.95 (n = 34). CONCLUSIONS In a large U.S. multicenter study, we confirmed that VCTE provides an accurate assessment of liver fibrosis in patients with chronic viral hepatitis. Our findings are similar to those from European and Asian cohorts.