Robert J. de Knegt

Association Between Sustained Virological Response and All-Cause Mortality Among Patients With Chronic Hepatitis C and Advanced Hepatic Fibrosis

CONTEXT Chronic hepatitis C virus (HCV) infection outcomes include liver failure, hepatocellular carcinoma (HCC), and liver-related death. OBJECTIVE To assess the association between sustained virological response (SVR) and all-cause mortality in patients with chronic HCV infection and advanced hepatic fibrosis. DESIGN, SETTING, AND PATIENTS An international, multicenter, long-term follow-up study from 5 large tertiary care hospitals in Europe and Canada of 530 patients with chronic HCV infection who started an interferon-based treatment regimen between 1990 and 2003, following histological proof of advanced hepatic fibrosis or cirrhosis (Ishak score 4-6). Complete follow-up ranged between January 2010 and October 2011. MAIN OUTCOME MEASURES All-cause mortality. Secondary outcomes were liver failure, HCC, and liver-related mortality or liver transplantation. RESULTS The 530 study patients were followed up for a median (interquartile range [IQR]) of 8.4 (6.4-11.4) years. The baseline median (IQR) age was 48 (42-56) years and 369 patients (70%) were men. The Ishak fibrosis score was 4 in 143 patients (27%), 5 in 101 patients (19%), and 6 in 286 patients (54%). There were 192 patients (36%) who achieved SVR; 13 patients with SVR and 100 without SVR died (10-year cumulative all-cause mortality rate, 8.9% [95% CI, 3.3%-14.5%] with SVR and 26.0% [95% CI, 20.2%-28.4%] without SVR; P < .001). In time-dependent multivariate Cox regression analysis, SVR was associated with reduced risk of all-cause mortality (hazard ratio [HR], 0.26; 95% CI, 0.14-0.49; P < .001) and reduced risk of liver-related mortality or transplantation (HR, 0.06; 95% CI, 0.02-0.19; P < .001), the latter occurring in 3 patients with SVR and 103 without SVR. The 10-year cumulative incidence rate of liver-related mortality or transplantation was 1.9% (95% CI, 0.0%-4.1%) with SVR and 27.4% (95% CI, 22.0%-32.8%) without SVR (P < .001). There were 7 patients with SVR and 76 without SVR who developed HCC (10-year cumulative incidence rate, 5.1%; 95% CI, 1.3%-8.9%; vs 21.8%; 95% CI, 16.6%-27.0%; P < .001), and 4 patients with SVR and 111 without SVR experienced liver failure (10-year cumulative incidence rate, 2.1%; 95% CI, 0.0%-4.5%; vs 29.9%; 95% CI, 24.3%-35.5%; P < .001). CONCLUSION Among patients with chronic HCV infection and advanced hepatic fibrosis, sustained virological response to interferon-based treatment was associated with lower all-cause mortality.

Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus.

Recent studies suggest that diabetes mellitus increases the risk of developing hepatocellular carcinoma (HCC). The aim of this study is to quantify the risk of HCC among patients with both diabetes mellitus and hepatitis C in a large cohort of patients with chronic hepatitis C and advanced fibrosis. We included 541 patients of whom 85 (16%) had diabetes mellitus. The median age at inclusion was 50 years. The prevalence of diabetes mellitus was 10.5% for patients with Ishak fibrosis score 4, 12.5% for Ishak score 5, and 19.1% for Ishak score 6. Multiple logistic regression analysis showed an increased risk of diabetes mellitus for patients with an elevated body mass index (BMI) (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.00‐1.11; P = 0.060) and a decreased risk of diabetes mellitus for patients with higher serum albumin levels (OR, 0.81; 95% CI, 0.63‐1.04; P = 0.095). During a median follow‐up of 4.0 years (interquartile range, 2.0‐6.7), 11 patients (13%) with diabetes mellitus versus 27 patients (5.9%) without diabetes mellitus developed HCC, the 5‐year occurrence of HCC being 11.4% (95% CI, 3.0‐19.8) and 5.0% (95% CI, 2.2‐7.8), respectively (P = 0.013). Multivariate Cox regression analysis of patients with Ishak 6 cirrhosis showed that diabetes mellitus was independently associated with the development of HCC (hazard ratio, 3.28; 95% CI, 1.35‐7.97; P = 0.009). Conclusion: For patients with chronic hepatitis C and advanced cirrhosis, diabetes mellitus increases the risk of developing HCC. (HEPATOLOGY 2008;47:1856–1862.)

Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians

Background Hepatocellular carcinoma (HCC) risk-scores may predict HCC in Asian entecavir (ETV)-treated patients. We aimed to study risk factors and performance of risk scores during ETV treatment in an ethnically diverse Western population. Methods We studied all HBV monoinfected patients treated with ETV from 11 European referral centres within the VIRGIL Network. Results A total of 744 patients were included; 42% Caucasian, 29% Asian, 19% other, 10% unknown. At baseline, 164 patients (22%) had cirrhosis. During a median follow-up of 167 (IQR 82–212) weeks, 14 patients developed HCC of whom nine (64%) had cirrhosis at baseline. The 5-year cumulative incidence rate of HCC was 2.1% for non-cirrhotic and 10.9% for cirrhotic patients (p<0.001). HCC incidence was higher in older patients (p<0.001) and patients with lower baseline platelet counts (p=0.02). Twelve patients who developed HCC achieved virologic response (HBV DNA <80 IU/mL) before HCC. At baseline, higher CU-HCC and GAG-HCC, but not REACH-B scores were associated with development of HCC. Discriminatory performance of HCC risk scores was low, with sensitivity ranging from 18% to 73%, and c-statistics from 0.71 to 0.85. Performance was further reduced in Caucasians with c-statistics from 0.54 to 0.74. Predicted risk of HCC based on risk-scores declined during ETV therapy (all p<0.001), but predictive performances after 1 year were comparable to those at baseline. Conclusions Cumulative incidence of HCC is low in patients treated with ETV, but ETV does not eliminate the risk of HCC. Discriminatory performance of HCC risk scores was limited, particularly in Caucasians, at baseline and during therapy.

Abundant numbers of regulatory T cells localize to the liver of chronic hepatitis C infected patients and limit the extent of fibrosis

BACKGROUND & AIMS Weak hepatitis C virus (HCV) specific immunity in peripheral blood has been shown to be partially controlled by regulatory T cells (Treg). However, little is known about Treg present in livers of HCV-infected patients, their association with clinical parameters, and immunopathology resulting in disease progression. METHODS The frequency and phenotype of CD4+FoxP3+ Treg, conventional CD4+ T cells, and the distribution of lymphocytes and leukocytes were studied by multi-color flowcytometry in liver and peripheral blood of 43 chronic HCV patients at different phases of liver disease. Comparisons between healthy blood and liver and correlations with disease parameters were made. RESULTS An extensive lymphocyte infiltration containing abundant numbers of CD4+FoxP3+ Treg was present in HCV-infected livers, while absent from healthy liver. Moreover, in all patients, intrahepatic CD4+FoxP3+ Treg showed a fully differentiated and highly activated phenotype on the basis of the surface markers CD45RO, CCR7, CTLA-4 and HLA-DR. These Treg were more numerous in those HCV-infected livers showing only limited fibrosis. However, HCV RNA loads or alanine transaminase levels did not correlate with CD4+FoxP3+ Treg frequencies. CONCLUSIONS Our data demonstrate that large numbers of highly activated and differentiated CD4+FoxP3+ Treg localize to the infiltrated chronic HCV-infected liver and may result in limiting the extent of fibrosis. This suggests that CD4+FoxP3+ Treg play a pivotal role in limiting collateral damage by suppressing excessive HCV-induced immune activation.

Extracellular brain glutamate during acute liver failure and during acute hyperammonemia simulating acute liver failure: An experimental study based on in vivo brain dialysis

Hyperammonemia is thought to be important in the pathogenesis of hepatic encephalopathy. However, the mechanism leading to ammonia toxicity is still not known. Since the metabolism of the most important excitatory neurotransmitter, glutamate, is closely linked to that of ammonia, it has been postulated that hyperammonemia lowers the availability of the neurotransmitter glutamate. To study this hypothesis, we used brain dialysis to measure glutamate levels in extracellular cerebral fluid from rabbits with acute ischemic liver failure or acute hyperammonemia. The basal glutamate concentration was found to be increased during both acute liver failure (start of experiments 4.9 +/- 1.7 mumol/l; end of experiments 9.5 +/- 2.1 mumol/l, n = 6, difference p < 0.05) and acute hyperammonemia (start of experiments 4.4 +/- 1.2 mumol/l; end of experiments 7.3 +/- 1.8 mumol/l, n = 7, difference p > 0.05) (mean +/- SEM). Both the veratridine- and the potassium-evoked glutamate release were increased during acute liver failure but appeared normal during hyperammonemia. We conclude that during acute liver failure and acute hyperammonemia in the rabbit there is no decreased glutamate availability in the extracellular space of the cortical brain; on the contrary, we found evidence for increased extracellular glutamate concentrations in the cortical brain, which were more pronounced in acute liver failure. Experimental hepatic encephalopathy is thus not due to cerebral glutamate deficiency.

Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.

BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) is reduced but not eradicated among patients with hepatitis C virus (HCV)-induced advanced hepatic fibrosis who attained sustained viral response (SVR). We aimed to assess the risk of cirrhosis-related complications in this specific group of patients. METHODS Data from previously reported Western cohort studies including patients with chronic HCV infection and bridging fibrosis or cirrhosis who attained SVR were pooled for survival analyses on the individual patient level. The primary endpoint was HCC and the secondary endpoint was clinical disease progression, defined as liver failure, HCC or death. RESULTS Included were 1000 patients with SVR. Median age was 52.7 (IQR 45.1-59.7) years, 676 (68%) were male and 842 (85%) had cirrhosis. Median follow-up was 5.7 (IQR 2.9-8.0) years. Fifty-one patients developed HCC and 101 had clinical disease progression. The cumulative 8-year HCC incidence was 1.8 (95% CI 0.0-4.3) among patients with bridging fibrosis and 8.7% (95% CI 6.0-11.4) among those with cirrhosis (p=0.058). Within the cirrhosis group, the 8-year HCC incidence was 2.6% (95% CI 0.0-5.5) among patients <45years, 9.7% (95% CI 5.8-13.6) among patients from 45-60years, and 12.2% (95% CI 5.3-19.1) among patients >60years of age at start of therapy (p=0.006). Multivariable Cox analyses indicated that higher age, lower platelet count and diabetes mellitus were independently associated with development of HCC. After 8years 4.2% (95% CI 0.1-8.3) of patients with bridging fibrosis and 15.8% (95% CI 12.3-19.3) of patients with cirrhosis experienced clinical disease progression (p=0.007). CONCLUSIONS Patients with HCV-induced cirrhosis and SVR showed an annual risk of approximately 1% for HCC and 2% for clinical disease progression. Therefore, to prevent HCC surveillance, chronic HCV infection should preferably be treated before cirrhosis has developed. LAY SUMMARY Patients with cirrhosis who were able to eradicate their chronic HCV infection remain at substantial risk of primary liver cancer. The risk of liver cancer increases with higher age, laboratory makers suggesting more severe liver disease, and presence of diabetes mellitus. Also after successful antiviral therapy patients with HCV-induced cirrhosis should thus remain included in follow-up for early detection of liver cancer.

Immunological Analysis During Interferon-Free Therapy for Chronic Hepatitis C Virus Infection Reveals Modulation of the Natural Killer Cell Compartment

BACKGROUND Chronic hepatitis C virus (HCV) infection is a global health problem, resulting in liver failure, hepatocellular carcinoma, and liver-related death. Natural killer (NK) cells are innate immune cells, and their activity is known to correlate to viral treatment response of HCV. In this study, we investigate the immune effects of viral load decline with direct-acting antivirals (DAAs) in blood. METHODS Twelve patients with chronic HCV were treated with asunaprevir and daclatasvir, and peripheral blood was analyzed at various time points during therapy. RESULTS In line with previous studies, we confirmed restoration of HCV-specific T-cell frequency upon viral load decline. In addition, we show that serum interferon (IFN)-γ inducible-protein 10, interleukin (IL)-12p40, and IL-18 levels decreased early after start of therapy. Surface expression of activation receptors NKp30, NKp46, and inhibitory receptor NKG2A on blood NK cells reduced during therapy. In addition, the expression of TRAIL on NK cells was reduced during IFN-free therapy, suggesting a decrease in TRAIL-mediated killing by NK cells. CONCLUSIONS We show that viral load decline as a consequence of treatment with novel DAAs in chronic HCV patients reduces serum levels of NK cell-stimulating cytokines and causes correction of the altered NK cell phenotype observed in chronic HCV patients. CLINICAL TRIALS REGISTRATION NCT02282709.

Biochemical and biophysical assessment of MTX-induced liver fibrosis in psoriasis patients: Fibrotest predicts the presence and Fibroscan predicts the absence of significant liver fibrosis.

Background: Methotrexate (MTX) use is associated with hepatic fibrosis in psoriasis patients. To monitor this serial liver biopsies were performed. The Fibroscan® and the Fibrotest are two novel, non‐invasive methods that might be able to assess MTX‐induced hepatic fibrosis.

EFSUMB Guidelines and Recommendations on the Clinical Use of Liver Ultrasound Elastography, Update 2017 (Long Version)

We present here the first update of the 2013 EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) Guidelines and Recommendations on the clinical use of elastography with a focus on the assessment of diffuse liver disease. The short version provides clinical information about the practical use of elastography equipment and interpretation of results in the assessment of diffuse liver disease and analyzes the main findings based on published studies, stressing the evidence from meta-analyses. The role of elastography in different etiologies of liver disease and in several clinical scenarios is also discussed. All of the recommendations are judged with regard to their evidence-based strength according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. This updated document is intended to act as a reference and to provide a practical guide for both beginners and advanced clinical users.

Evaluation of transient elastography for fibrosis assessment compared with large biopsies in chronic hepatitis B and C

Fibrosis determines prognosis and management in patients with chronic hepatitis B and C (CHB and CHC). Transient elastography (TE) is a promising non‐invasive method to assess fibrosis. We prospectively studied the performance of TE compared to histology and also whether there are differences between CHB and CHC. Only large biopsies (≥25 mm) were used.