Meta-analysis: insulin resistance and sustained virological response in hepatitis C

Aliment Pharmacol Ther 2011; 34: 297–305

Summary

Background A higher baseline homeostasis model assessment of insulin resistance (HOMA‐IR) score has sometimes predicted a poorer sustained virological response (SVR) rate to peginterferon/ribavirin therapy in treatment‐naïve chronic hepatitis C patients. Aim To perform a meta‐analysis to evaluate the impact of HOMA‐IR on SVR in hepatitis C. Methods Relevant studies were identified by searching Medline and EMBASE. We identified 17 publications that addressed the influence of insulin resistance on SVR. The random effect model of Der Simonian and Laird method were used for heterogeneous studies using the Meta‐Disc software 1.4, Madrid, Spain. Results Normal insulin sensitivity was associated with a higher rate of SVR [odds ratio (OR) 2.86 (95%CI: 1.97–4.16)] in comparison with insulin resistance. Moreover, in separate analysis by genotype selecting studies that used HOMA‐IR > 2 as cut‐off defining insulin resistance, SVR was higher in patients with HOMA‐IR < 2 in all genotypes: HCV‐1 [OR: 2.16 (95%CI: 1.51–3.08)], HCV‐2&3 [OR: 3.06 (95%CI: 1.06–8.82)] and HCV‐4 [OR: 6.65(95%CI: 2.51–17.61)]. Studies reporting no association between HOMA and SVR included easy‐to‐cure cohorts, analysed variables strongly related with insulin resistance like body mass index, steatosis, hyper γGT, age and fibrosis and reported differences in handling and interpretation of HOMA‐IR. Conclusion Elevated HOMA‐IR was associated with a lower cure rate of patients with hepatitis C treated with Peg‐IFN‐α/ribavirin irrespective of genotype, and the more difficult‐to‐treat cohort, the better the HOMA‐IR prediction. HOMA‐IR is, as a surrogate marker of insulin resistance, susceptible to some biases derived from both handling and interpretation.     

IL28B polymorphisms, IP-10 and viral load predict virological response to therapy in chronic hepatitis C

Aliment Pharmacol Ther 2011; 33: 1162–1172

Summary

Background Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma and the identification of the predictors of response to antiviral therapy is an important clinical issue. Aim To determine the independent contribution of factors including IL28B polymorphisms, IFN‐gamma inducible protein‐10 (IP‐10) levels and the homeostasis model assessment of insulin resistance (HOMA‐IR) score in predicting response to therapy in chronic hepatitis C (CHC). Methods Multivariate analysis of factors predicting rapid (RVR) and sustained (SVR) virological response in 280 consecutive, treatment‐naive CHC patients treated with peginterferon alpha and ribavirin in a prospective multicentre study. Results Independent predictors of RVR were HCV RNA <400 000 IU/mL (OR 11.37; 95% CI 3.03–42.6), rs12980275 AA (OR 7.09; 1.97–25.56) and IP‐10 (OR 0.04; 0.003–0.56) in HCV genotype 1 patients and lower baseline γ‐glutamyl‐transferase levels (OR = 0.02; 0.0009–0.31) in HCV genotype 3 patients. Independent predictors of SVR were rs12980275 AA (OR 9.68; 3.44–27.18), age <40 years (OR = 4.79; 1.50–15.34) and HCV RNA <400 000 IU/mL (OR 2.74; 1.03–7.27) in HCV genotype 1 patients and rs12980275 AA (OR = 6.26; 1.98–19.74) and age <40 years (OR 5.37; 1.54–18.75) in the 88 HCV genotype 1 patients without a RVR. RVR was by itself predictive of SVR in HCV genotype 1 patients (OR 33.0; 4.06–268.32) and the only independent predictor of SVR in HCV genotype 2 (OR 9.0, 1.72–46.99) or genotype 3 patients (OR 7.8, 1.43–42.67). Conclusions In HCV genotype 1 patients, IL28B polymorphisms, HCV RNA load and IP‐10 independently predict RVR. The combination of IL28B polymorphisms, HCV RNA level and age may yield more accurate pre‐treatment prediction of SVR. HOMA‐IR score is not associated with viral response.     

Insulin resistance is a major determinant of liver stiffness in nondiabetic patients with HCV genotype 1 chronic hepatitis

Background  In patients with chronic hepatitis C (CHC), liver stiffness measurement (LSM) by transient elastography (TE), is closely related to the stage of fibrosis, but may be affected by necroinflammation. Other factors, such as insulin resistance (IR), might influence the performance of LSM.
Aims  To evaluate in a cohort of nondiabetic patients with genotype 1 CHC, whether IR and other anthropometric, biochemical, metabolic and histological factors contribute to LSM and to identify the best cut-off values of LSM for predicting different stages of fibrosis.
Methods  Nondiabetic patients with genotype 1 CHC ( n  = 156) were evaluated by liver biopsy (Metavir score), anthropometric, biochemical and metabolic features including IR. Furthermore, all subjects underwent LSM by TE.
Results  Severe fibrosis (F3–F4) was associated with LSM (OR 1.291; 95%CI 1.106–1.508). LSM was also independently correlated with low platelets ( P  =   0.03), high γGT ( P  <   0.001) and high HOMA ( P  =   0.004) levels. A stiffness value ≥8 KPa was identified as the best cut-off for predicting severe fibrosis ( AUC 0.870); yet this cut-off still failed to rule out F3–F4 fibrosis in 22.7% of patients (false-negative rate) or rule in F3–F4 in 19.6% (false-positive rate). Platelets <200 × 10³/mmc and a HOMA of >2.7 were the major determinants of these diagnostic errors in predicting severe fibrosis.
Conclusions  In nondiabetic patients with genotype 1 CHC, insulin resistance, γGT and platelet levels contribute to LSM independently of liver fibrosis. The identification of these three factors contributes to a more correct interpretation of LSM.     

Impact on adherence and sustained virological response of psychiatric side effects during peginterferon and ribavirin therapy for chronic hepatitis C

Summary

Background

The psychiatric side effects of interferon, often responsible for dose reduction or treatment discontinuation, represent a major limitation in the treatment of chronic hepatitis C (CHC).

Aim

To prospectively assess the impact on adherence and sustained virological response (SVR) of the occurrence of psychiatric side effects during peginterferon and ribavirin therapy for CHC.

Methods

Ninety‐eight consecutive treatment‐naïve CHC patients receiving a standard course of peginterferon plus ribavirin were systematically screened for psychiatric side effects, using DSM‐IV, at baseline and both during and after treatment.

Results

Psychiatric side effects occurred in 38 patients (39%), mostly within the first 12 weeks (87%), and always consisted of mood disorders. Overall, 68% of patients achieved an SVR (71% of patients with mood disorders and 68% of those without; P = N.S.). Peginterferon and ribavirin dose reductions did not differ between patients with mood disorders and those without (46% vs. 37%, respectively; P = N.S. and 13% vs. 22%, respectively; P = N.S.). Anti‐viral therapy had to be discontinued in four patients (nonresponse: two, hyperthyroidism: one, psychiatric event: one).

Conclusion

Early detection and appropriate management of psychiatric side effects during peginterferon and ribavirin therapy for CHC allow optimizing adherence and virological efficacy.

     

Visceral adiposity index is associated with significant fibrosis in patients with non-alcoholic fatty liver disease

Aliment Pharmacol Ther 2012; 35: 238–247

Summary

Background Metabolic factors have been associated with liver damage in patients with non‐alcoholic fatty liver disease (NAFLD). Aims To test a new marker of adipose dysfunction, the visceral adiposity index (VAI), in NAFLD patients to assess whether or not it is associated with host factors, and to investigate a potential correlation with histological findings. Methods One hundred and forty‐two consecutive NAFLD patients were evaluated by liver biopsy, and clinical and metabolic measurements, including insulin resistance with the homeostasis model assessment (HOMA), and VAI by using waist circumference, body mass index, triglycerides and HDL. Serum levels of TNFα, IL‐6, adiponectin and leptin were also assessed. All biopsies were scored for NAFLD activity score (NAS) and its components, and for staging (Kleiner). Results By multiple linear regression analysis, VAI was independently associated with higher HOMA (P = 0.04), and fibrosis (P = 0.04). In addition, an independent association was found between higher VAI and lower adiponectin levels (P = 0.002). Higher HOMA (OR 1.149, 95% CI 1.003–1.316, P = 0.04), higher VAI (OR 1.446, 95% CI 1.023–2.043, P = 0.03), lobular inflammation (OR 3.777, 95% CI 1.771–8.051, P = 0.001), and ballooning (OR 2.884, 95% CI 1.231–6.757, P = 0.01) were correlated with significant fibrosis (F2–F4) on multiple logistic regression analysis. In particular, the prevalence of significant fibrosis progressively increased from patients with a VAI ≤ 2.1 and HOMA ≤ 3.4 (26%) to those with a VAI > 2.1 and HOMA > 3.4 (83%). Conclusions In NAFLD patients, visceral adiposity index is an expression of both qualitative and quantitative adipose tissue dysfunction and, together with insulin resistance, is independently correlated with significant fibrosis.     

Insulin resistance is increased in alopecia areata patients

Increased insulin resistance (IR) has been found in androgenetic alopecia in several studies. However, IR has not been investigated in alopecia areata (AA). We aimed to investigate IR in AA patients and the controls. Anthropometric and demographic data were obtained from 51 AA patients and 36 controls. We measured insulin, c-peptide and blood glucose and HOMA-IR. Demographic characteristics of the two groups were similar. AA group had higher insulin [12.5?±?7.01 vs. 8.3?±?3.9 µIU/mL, p = 0.001], c-peptide [2.7?±?1.07 vs. 2.1?±?0.6?ng/mL, p = 0.007] and HOMA-IR levels [2.8?±?1.6 vs. 1.9?±?0.9, p = .004] than the controls. Patient and control groups were also similar regarding lipid profiles. In this study, we found increased IR in AA patients for the first time in literature. Increased inflammatory cytokines and hypothalamic–pituitary–adrenal axis activation may be responsible for this finding. Further studies with larger sample sizes may give additional information for IR in AA.     

Randomised clinical trial: efficacy of peginterferon alfa-2a in HBeAg positive chronic hepatitis B patients with lamivudine resistance

Aliment Pharmacol Ther 2011; 34: 424–431

Summary

Background Previous studies suggested that a finite course of peginterferon alfa‐2a may offer an alternative rescue therapy for patients with lamivudine resistance. However, because of the limitation of study design and small sample size, it is difficult to make definitive conclusion. Aim To explore the role of peginterferon alfa‐2a, in the rescue treatment of HBeAg‐positive chronic hepatitis B patients with lamivudine resistance. Methods In this randomised study, chronic hepatitis B patients with lamivudine resistance were treated with peginterferon alfa‐2a for 48 weeks (n = 155) or adefovir for 72 weeks (n = 80). All enrolled patients were treated with lamivudine for the first 12 weeks. Results At 6 months posttreatment, 14.6% (18/123) of peginterferon alfa‐2a‐treated patients achieved HBeAg seroconversion, in contrast to 3.8% (3/80) of adefovir‐treated patients after 72 weeks continuous therapy (P = 0.01). For peginterferon alfa‐2a‐treated patients, the rate of HBeAg seroconversion at week 72 was significantly higher in patients who had HBsAg decline >0.5 Log₁₀ IU/mL from baseline at week 24, compared with patients with HBsAg decline ≤0.5 Log₁₀ IU/mL from baseline at week 24 (25.5% vs. 7.7%, P = 0.01). After 72 weeks continuous adefovir treatment, 22.5% of patients achieved HBV DNA <80 IU/mL, compared with 10.6% in peginterferon alfa‐2a‐treated patients at 6 months off‐treatment (P = 0.02). Conclusions Overall, the response to peginterferon alfa‐2a among patients with lamivudine resistance was suboptimal. HBeAg seroconversion rate at week 72 by 48 weeks peginterferon alfa‐2a treatment was higher than continuous adefovir therapy. Monitoring HBsAg levels can help to predict response to peginterferon alfa‐2a.     

Increasing insulin resistance is associated with increased severity and prevalence of gastro-oesophageal reflux disease

Aliment Pharmacol Ther 2011; 34: 994–1004

Summary

Background The diagnosis of gastro‐oesophageal reflux disease (GERD) is based on reflux symptoms. Although metabolic syndrome has been linked to erosive oesophagitis (EO), the impact of insulin resistance, the core of the metabolic syndrome, on reflux symptoms remains to be elucidated. Aim To assess the effects of insulin resistance on GERD, including both endoscopic findings and symptoms. Methods A total of 743 sonographic noncirrhotic adult subjects, who underwent an upper gastrointestinal endoscopic examination, completed a gastro‐oesophageal reflux questionnaire and had available fasting insulin data were included. Endoscopic findings were classified according to the Los Angeles classification. Homeostatic model assessment‐insulin resistance (HOMA‐IR) index was used to evaluate the status of insulin resistance. Univariate and multivariate approaches were used to evaluate the associations between insulin resistance and GERD. Results Older age, male gender, smoking and alcohol consumption increased the prevalence of EO, but not GERD symptoms. A large waist circumference, high fasting blood glucose levels and high number of metabolic syndrome components were associated with increased prevalence of both EO and GERD symptoms, while high blood pressure was associated with increased prevalence of EO only. Moreover, higher scores in the gastro‐oesophageal reflux questionnaire were associated with higher HOMA‐IR index, and higher HOMA‐IR index was associated with increased prevalence of EO (adjusted odds ratio 1.14, 95% CI 1.03–1.26, P = 0.012). Conclusions Our findings demonstrate clear associations between insulin resistance, metabolic syndrome and GERD. Whether reducing insulin resistance may improve GERD symptoms or EO deserves prospective study.     

Anti-viral therapy in haemodialysed HCV patients: efficacy, tolerance and treatment strategy

Aliment Pharmacol Ther 2011; 34: 454–461

Summary

Background In end‐stage renal disease (ESRD) patients, hepatitis C virus (HCV) eradication improves patient and graft survival. Aim To determine optimal use of erythropoietin (EPO) and ribavirin, to compare ribavirin concentrations with those of HCV patients having normal renal function and to evaluate sustained virological response (SVR) in a prospective observatory of ESRD candidates for renal transplantation. Methods Thirty‐two naïve patients were treated with Peg‐IFN‐α2a and ribavirin. Two different schedules of ribavirin and EPO administration were used: starting ribavirin at 600 mg per week and adapting EPO when haemoglobin (Hb) fell below 10 g/dL (adaptive strategy) or starting ribavirin at 1000 mg per week while increasing EPO from the start of treatment (preventive strategy). Results Patients treated with the adaptive strategy had lower median Hb levels (9.6 vs. 10.9 g/dL, P = 0.02) and more frequent median Hb levels below 10 g/dL (58 vs. 5%, P = 0.0007) despite lower median ribavirin doses (105 vs. 142 mg/day, P < 0.0001) than patients treated with the preventive strategy. There was a trend for more frequent transfusion in patients treated with the adaptive strategy than in patients treated with preventive strategy (50 vs. 20%, P = 0.08). Compared to patients with normal renal function, ESRD patients had lower ribavirin concentrations during the first month (0.81 vs. 1.7 mg/L, P = 0.007) and similar concentrations thereafter. SVR was reached in 50%. Conclusions Pegylated interferon (Peg‐IFN) and an adapted schedule of ribavirin are effective in ESRD patients. Increasing EPO from the start of treatment provides better haematological tolerance. The optimal dosage of ribavirin remains unresolved, in light of frequent side effects.     

Are decreased AdipoR1 mRNA levels associated with adiponectin resistance in coronary artery disease patients?

The aim of the present study was to investigate if circulating adiponectin levels and the expression of AdipoR1 and AdipoR2 in peripheral blood mononuclear cells (PBMC) are altered in coronary artery disease (CAD) patients, with and without significant stenosis, compared to healthy patients. The present study included 69 patients with presenting symptoms of CAD (26 patients with significant stenosis and 43 patients without significant stenosis). The control group (CG) consisted of 33 healthy patients. Circulating adiponectin levels were measured by enzyme‐linked immunosorbent assay, whereas AdipoR1 and AdipoR2 mRNA levels in PBMC were determined by real‐time polymerase chain reaction. Adiponectin levels were significantly higher in patients with and without significant stenosis compared to the CG (P < 0.001 vs P = 0.006, respectively). Both patient groups had lower AdipoR1 levels compared to the CG (P < 0.001 vs P < 0.001, respectively). There were no significant differences in these parameters between the two patient groups. Adiponectin negatively correlated with body mass index, triglycerides, insulin and homeostasis model assessment of insulin resistance index (HOMA IR), and positively with high‐denisty lipoprotein cholesterol in the CG. Glucose, insulin, and the HOMA IR index negatively correlated with adiponectin in patients. A positive correlation between adiponectin receptors was found in patients and the CG. Decreased AdipoR1 mRNA levels and increased circulating adiponectin in advanced stages of CAD, as well as in patients without significant stenosis, compared to the CG, implies that CAD could be related to ‘adiponectin resistance’. Despite increased adiponectin, its protective effects could be diminished even in early stages of atherosclerosis.     

Perinatal exposure to di‐(2‐ethylhexyl)‐phthalate leads to cognitive dysfunction and phospho‐tau level increase in aged rats

Di‐(2‐ethylhexyl)‐Phthalate (DEHP) can affect glucose and insulin homeostasis in periphery and lead to insulin resistance, especially exposure of DEHP during critical developmental period. Given the potential relationship between insulin resistance and pathogenesis of Alzheimer's disease (AD) in elderly life, we investigated the relationship between perinatal DEHP exposure and AD pathogenesis. Our results suggested that perinatal exposure to DEHP can affect the expression of insulin and insulin‐Akt‐ GSK‐3β signal pathway in hippocampus. Furthermore, impaired cognitive ability and increased level of phospho‐Tau was observed in DEHP‐exposed rat offspring (1.25 ± 0.11 vs. 0.47 ± 0.07, P < 0.05). The present study demonstrates that perinatal exposure to DEHP may be a potential risk factor for AD pathogenesis associated with insulin resistance and insulin metabolism disorder in the hippocampus. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 596–603, 2014.     

Predictors of treatment response in patients with hepatitis C 1b genotype

Background

The aim of the study was to analyse the predictive host and viral factors of sustained virological response (SVR) in Estonian patients with chronic hepatitis C genotype 1b.

Methods

A total of 76 outpatients (44 males and 32 females, aged 21–63 years) were enrolled in the single-centre prospective study. The patients received 180 µg of Peg-IFN α-2α weekly plus daily weight-based ribavirin (1000–1200 mg/day).

Results

The SVR was achieved in 50% of the patients, 43.4% of the patients were referred to as non-SVR. The SVR and the non-SVR patients differed significantly in terms of age (p=0.012), stage of fibrosis (p=0.012), grade of inflammatory activity (p=0.002), platelet count (p=0.005), gamma-glutamyltransferase (GGT) level (p=0.028), as well as a decrease of the viral load at weeks 4 and 12 more than 3.59 log10 IU/ml and 5.98 log₁₀ IU/ml (P<0.01), respectively.

Conclusion

Age below 40 years, absence of or mild and moderate fibrosis, absence of severe inflammation activity, normal platelet count and normal GGT level, and pronounced changes in viral kinetics at weeks 4 and 12, were valuable predictors of better response to peginterferon alfa plus ribavirin treatment in Estonian patients with chronic hepatitis C genotype 1b.     

The impact of insulin resistance, serum adipocytokines and visceral obesity on steatosis and fibrosis in patients with chronic hepatitis C

Aims To assess whether host metabolic factors influence the degree of hepatic steatosis and fibrosis in patients infected with hepatitis C virus, and to evaluate the impact of anti‐viral therapy on insulin resistance and serum levels of adipocytokines. Methods Clinical and biochemical features, anthropometrical characteristics, and levels of fasting insulin, leptin, adiponectin and resistin were measured in ‘naïve’ patients with chronic hepatitis C, before, during and after therapy with Peg‐Interferon‐alpha 2a plus Ribavirin. Results Forty‐eight patients were included (M/F 28/20; mean age 50.0 ± 12.6 years; 62.5% genotype‐1). Body mass index was 26.4 ± 4.0 kg/m², and visceral obesity was present in 24 patients. At multivariate analysis (RR; 95% CI), steatosis was associated to older age (1.08; 1–1.18), necroinflammatory activity (17.67; 1.6–194.46), and raised insulin levels (1.39; 1.1–1.77). Fibrosis was related to necroinflammatory activity (25.73; 2.54–261.11), and steatosis (6.47; 1.09–38.29). Sustained viral response was achieved by 62.5% of patients and was associated with younger age (0.92; 0.85–0.99), genotype non‐1 (10.61; 1.52–73.76) and absence of visceral obesity (13.78; 2.36–80.29). At the end of follow‐up, insulin and the homeostasis model assesment for insulin resistance were reduced and adiponectin increased when compared with baseline, all unrelated to the outcome of treatment. Conclusions Visceral obesity correlates with the degree of steatosis and fibrosis, and it negatively affects treatment response. Significant changes of insulin resistance and adipocytokines occur under treatment, irrespective of virological outcome.     

Liver stiffness diminishes with antiviral response in chronic hepatitis C

Aliment Pharmacol Ther 2011; 34: 656–663

Summary

Background Transient elastography measures liver stiffness, which correlates with the hepatic fibrosis stage and has excellent accuracy for the diagnosis of cirrhosis in patients with chronic hepatitis C. Aim To assess prospectively the kinetics of liver stiffness in treated patients with chronic hepatitis C and compare them with the viral kinetics on treatment and with the final outcome of therapy. Methods 91 patients with chronic hepatitis C with significant fibrosis (>7.0 kPa) at baseline were included. They received therapy with pegylated interferon‐α and ribavirin. The kinetics of liver stiffness were characterized during therapy and thereafter by means of Fibroscan, and compared with the virological responses at weeks 4, 12, 24, end of treatment and 12 and 24 weeks after. Results A significant liver stiffness decrease was observed during therapy, which continued after treatment only in patients who achieved a sustained virological response. In this group, the median intra‐patient decrease relative to baseline at the end of follow‐up was ?3.4 kPa, vs?1.8 kPa in the patients who did not achieve an SVR. Similar dynamics were observed in cirrhotic and non‐cirrhotic patients. In multivariate analysis, only the SVR was associated with long‐term improvement of liver stiffness (odds ratio: 3.10; 95% confidence interval: 1.20–8.02, P = 0.019). Conclusions In patients with advanced fibrosis at the start of therapy, liver stiffness is significantly reduced during treatment, but improvement continues off treatment only in patients who achieve a sustained virological response. Liver stiffness assessment earlier than 6 months after the end of therapy does not appear to be clinically meaningful.

     

Changes in quality of life and sexual health are associated with low‐dose peginterferon therapy and disease progression in patients with chronic hepatitis C

Aliment Pharmacol Ther 31 , 719–734

Summary

Background Primary analysis of the Hepatitis C Antiviral Long‐Term Treatment against Cirrhosis (HALT‐C) Trial showed long‐term peginterferon therapy did not reduce complications in patients with chronic hepatitis C and advanced fibrosis or cirrhosis. Aim To assess the effects of long‐term peginterferon therapy and disease progression on health‐related quality of life (HRQOL), symptoms and sexual health in HALT‐C patients. Methods A total of 517 HALT‐C patients received peginterferon alfa‐2a (90 μg/week); 532 received no additional treatment for 3.5 years. Patients were followed up for outcomes of death, hepatocellular carcinoma and hepatic decompensation. Sexual health, SF‐36 scores and symptoms were serially assessed by repeated‐measures analyses of covariance. Results Patients with cirrhosis (n = 427) reported lower general well‐being and more fatigue (P < 0.001) than patients with fibrosis (n = 622). Physical scores declined significantly over time, independent of treatment, and patients with cirrhosis reported lower scores. Vitality scores were lower in those with cirrhosis, and treated patients experienced a greater decline over time than untreated patients; HRQOL rebounded after treatment ended. Patients with a clinical outcome had significantly greater declines in all SF‐36 and symptom scores. Among men, Sexual Health scores were significantly worse in treated patients and in those with a clinical outcome. Conclusion Clinical progression of chronic hepatitis C and maintenance peginterferon therapy led to worsening of symptoms, HRQOL and, in men, sexual health in a large patient cohort followed up over 4 years (NCT00006164).     

Factors that affect the diagnostic accuracy of liver fibrosis measurement by Fibroscan in patients with chronic hepatitis B

Aliment Pharmacol Ther 2010; 32: 498–505

Summary

Background Interquartile range/median value (IQR/M) of liver stiffness measurement (LSM) is a factor in chronic hepatitis C (CHC) leading to over estimation of fibrosis by Fibroscan. Aim To investigate factors that affect the accuracy of LSM in chronic hepatitis B (CHB). Methods One hundred and ninety‐nine patients were enrolled. Only procedures yielding ≥10 valid measurements were considered reliable. Liver fibrosis was evaluated using the Batts and Ludwig system. Liver biopsy (LB) specimens <15 mm were considered ineligible. Results The mean age (142 men and 57 women) was 40.1 years. A significant discordance (discordance of at least two stages between LB and LSM) was identified in 38 (19.1%) and 47 (23.6%) patients respectively, according to Marcellin et al. and Chan et al.’s cutoff values. In multivariate analyses, BMI and fibrosis stage (F0–2 vs. F3–4) were identified as independent predictors for significant discordance (P = 0.040; hazard ratio [HR], 1.126; 95% confidence interval [CI], 1.005–1.261 and P = 0.036; HR, 0.450; 95% CI, 0.213–0.949 respectively) with Marcellin et al.’s cutoffs, whereas fibrosis stage was the only independent predictor (P = 0.004; HR, 0.300; 95% CI, 0.131–0.685) with Chan’s cutoffs. Conclusions Success rate and IQR/M were not predictive factors of the accuracy for diagnosing liver fibrosis by Fibroscan in CHB. Fibrosis stage (F0‐2) was the only factor to predict significant discordance between LB and LSM.     

Development of a refractory gastro-oesophageal reflux score using an administrative claims database

Aliment Pharmacol Ther 2011; 34: 555–567

Summary

Background Approximately one‐third of gastro‐oesophageal reflux disease (GERD) patients demonstrate refractory symptoms following treatment with proton pump inhibitor (PPI) therapy. Aim To develop a refractory GERD score that can be applied to predict patients’ healthcare utilisation. Methods We enrolled adults (≥18 years) with a diagnosis of GERD. Refractory GERD was evaluated on an 8‐point scale where 1 point was given for each of the following criteria: doubling, addition, or switching of GERD medication dose, receipt of a GERD‐related endoscopic procedure or surgery, or ≥3 GERD‐related outpatient visits. Refractory GERD was defined as the presence of two or more points. Results A total of 135 139 GERD patients (44% male) were analysed with a mean (±s.d.) age of 52.9 ± 15 years. The mean overall refractory GERD score was 1.12 ± 1.2 (range 0–8 on an 8‐point scale); 31% of patients had refractory GERD with a mean score of 2.56 ± 0.82. Among patients with refractory GERD, 31% doubled their GERD medication, 28% added a new GERD medication, 60% switched GERD medications, 54% had a GERD‐related procedure and 1% had a GERD‐related surgery. Patients with refractory GERD were more likely to be female (59% vs. 55%, P < 0.001) and had a higher co‐morbidity score (0.78 vs. 0.56, P < 0.001). The overall mean costs for refractory patients during the study period were significantly higher compared with treatment‐responsive patients ($18 088 ± $36 220 vs. $11 044 ± $22 955, P < 0.001). Conclusions Refractory GERD was present in approximately one‐third of the GERD patients. We created a GERD refractory score that could define need for increased anti‐reflux therapy and predict higher healthcare resource utilisation.     

Hyperuricemia is associated with histological liver damage in patients with non-alcoholic fatty liver disease

Aliment Pharmacol Ther 2011; 34: 757–766

Summary

Background Hyperuricemia has been associated with metabolic disorders. In this line recent studies observed an independent link between higher uric acid serum levels and clinical diagnosis of non‐alcoholic fatty liver disease (NAFLD). Aims We aimed to assess the potential association between uric acid serum levels and histological liver damage in a homogeneous cohort of biopsy‐proven NAFLD patients. Methods Consecutive NAFLD patients (n = 166), assessed by liver biopsy (Kleiner score), anthropometric, biochemical and metabolic features, were included. Enzymatic colorimetric test was used for serum uric acid assays (Roche Diagnostics GmbH, Mannheim, Germany). Hyperuricemia was diagnosed when uric acid serum levels were >7 mg/dL in men, and >6 mg/dL in women. Results Mean uric acid serum level was 5.75 mg/dL, and about 20% of patients had hyperuricemia, that was independently associated with younger age (OR 0.951, 95% CI 0.918–0.984, P = 0.004), lobular inflammation (OR 2.144, 95% CI 1.055–4.357, P = 0.03) and steatosis grade (OR 1.859, 95% CI 1.078–3.205, P = 0.02), by multivariate logistic regression analysis. Female gender (OR 2.656, 95% CI 1.190–5.928, P = 0.01), higher HOMA index (OR 1.219, 95% CI 1.043–1.426, P = 0.01), and hyperuricemia (OR 4.906, 95% CI 1.683–14.296, P = 0.004) were linked to NAFLD activity score (NAS) ≥ 5 by multiple logistic regression analysis. Conversely, higher HOMA index (OR 1.140, 95% CI 1.001–1.229, P = 0.04), and NAS (OR1.954, 95% CI 1.442–2.649, P < 0.001) were independently associated with significant fibrosis by logistic regression analysis. Conclusions In NAFLD patients, hyperuricemia is independently associated with the severity of liver damage, representing, in this setting of patients, together with insulin resistance, a potential new therapeutic target in future intervention trials.     

Sustained virological response to peginterferon plus ribavirin in chronic hepatitis C genotype 1 patients is associated with a persistent Th1 immune response

Summary

Background

An impairment of cellular immune response may contribute to the persistency of hepatitis C virus infection.

Aim

To analyse the Th1/Th2 cytokine profile in peripheral blood CD4+ and CD8+ T cells from patients with chronic hepatitis C (CHC) during treatment with pegylated interferon‐α2a plus ribavirin and to correlate the Th1/Th2 balance with virological response (SVR).

Methods

Prospective longitudinal study: 44 naïve genotype 1 CHC patients received PEG‐IFNα2a plus ribavirin for 48 weeks: 26 (59.1%) achieved a SVR, 13 relapsed (29.5%) and 5 (11.4%) were non‐responders. Sixteen healthy controls were analysed. The production of IL‐4, IFNγ and TNFα by CD4+ and CD8+ T cells was measured using flow cytometry, both in resting and phorbol‐ester‐stimulated cells.

Results

First three months of treatment: the synthesis of TNFα by phorbol‐ester‐stimulated‐CD4+ T cells was higher in patients with SVR (P < 0.01). At the end of treatment, SVR was associated with higher intracellular expression of IFNγ by stimulated‐CD4+ and CD8+ T cells (P < 0.05). At the end of follow‐up, a higher intracellular expression of IFNγ by CD4+ T cells was associated with a SVR.

Conclusions

A Th1‐type immune response was associated with achievement of a SVR, as indicated by the persistent elevation of intracellular IFNγ and TNFα.