Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis.

OBJECTIVE: The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration. DESIGN: We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson. RESULTS: Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I2=74.6%) and 5.7 (2.5 to 15.3, I2=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1). CONCLUSION: Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.

Comparison of transient elastography and shear wave elastography in patients with MAFLD: A single-center experience.

BACKGROUND: Metabolic-associated fatty liver disease and liver fibrosis are intimately linked to insulin resistance, type 2 diabetes, obesity, and metabolic syndrome. Transient elastography (TE) and point shear wave elastography (pSWE) were used to measure liver stiffness in patients who met the ultrasound criteria for steatotic liver diseases (SLD). This study compared two methods for estimating liver stiffness in patients with SLD, which in turn correlated with liver fibrosis. METHOD: Ultrasound B-mode imaging was used to identify SLD. In total, 250 MAFLD patients were recruited. Patient characteristics, laboratory investigations, and liver stiffness measurements using TE and pSWE were assessed on the same day. RESULTS: In the study, 56.0% of the patients were male, with a mean age of 41.5 ± 10.7 years. The correlation between TE and pSWE was significant (Spearman's r = 0.867*, p < .001). The Bland-Altman Plot analysis confirmed this, with 97.5% of variations in LSM falling within 95% agreement ranges. Cohen's κ was used to assess the agreement between TE and pSWE fibrosis stages, showing almost perfect agreement (83.5% kappa agreement) and a strong association between pSWE and TE in the assessment fibrosis stages. CONCLUSION: In patients with MAFLD, TE, and SWE are reliable methods for measuring liver stiffness and can be used as non-invasive screening tools for the assessment of fibrosis in SLD.

Low Frequency of Aflatoxin Induced TP53 Gene Codon 249 Mutation in Hepatocellular Carcinoma from Egyptian Patients Living in the Nile Delta Region.

OBJECTIVE: Study the frequency of codon 7 (c.747 G>T, p. R249S) mutation associated with Aflatoxin B1 (AFB1) exposure in Egyptian patients with hepatocellular carcinoma (HCC). METHODS: We utilized restriction fragment polymorphism and direct sequencing to assess codon 7 mutations in 104 hepatocellular carcinomas. The expression of TP53 protein in the tumors were assessed in 44 tumors by a monoclonal rabbit antibody. RESULTS: We identified a single 1/104 (1%) with c.747 G>T, p. R249S variant. 28/44 (63.6%) tumors showed no or occasional (less than < 5%) nuclear staining; 9/44 (20.4%) showed mild to moderate (5-49%) and 7/44 (15.9%) showed strong ≥ 50% staining. CONCLUSION: We observed much lower frequency of TP53 gene than previously published results suggesting geographical alterations in AFB1 exposure in Egypt.

KIR genotypic diversity can track ancestries in heterogeneous populations: a potential confounder for disease association studies.

Killer cell immunoglobulin-like receptors (KIR) are encoded by highly polymorphic genes that regulate the activation of natural killer (NK) cells and other lymphocyte subsets and likely play key roles in innate and adaptive immunity. Association studies increasingly implicate KIR in disease predisposition and outcome but could be confounded by unknown KIR genetic structure in heterogeneous populations. To examine this, we characterized the diversity of 16 KIR genes in 712 Northern Californians (NC) stratified by self-assigned ethnicities and compared the profiles of KIR polymorphism with other US and global populations using a reference database. Sixty-eight distinct KIR genotypes were characterized: 58 in 457 Caucasians (NCC), 17 in 47 African Americans (NCAA), 21 in 80 Asians (NCA), 20 in 74 Hispanics (NCH), and 18 in 54 "other" ethnicities (NCO). KIR genotype patterns and frequencies in the 4 defined ethnicities were compared with each other and with 34 global populations by phylogenetic analysis. Although there were no population-specific genotypes, the KIR genotype frequency patterns faithfully traced the ancestry of NCC, NCAA, and NCA but not of NCH whose ancestries are known to be more heterogeneous. KIR genotype frequencies can therefore track ethnic ancestries in modern urban populations. Our data emphasize the importance of selecting ethnically matched controls in KIR-based studies to avert spurious associations.

Histological versus clinical cirrhosis in chronic hepatitis C: does race/ethnicity really matter?

UNLABELLED: Liver fibrosis progression in hepatitis C virus (HCV) infection has been in part associated with race/ethnicity. Little is known of the frequency of clinical cirrhosis in Asian patients in the US. AIM: To compare histological and clinical features of chronic hepatitis C (CHC) in a multiethnic cohort of patients. METHODS: Retrospective query of an electronic medical registry for CHC patients evaluated from 1999 to 2005. Histological cirrhosis was defined as advanced METAVIR fibrosis score at biopsy. Clinical cirrhosis was defined as any of: varices, ascites, or splenomegaly. Liver cirrhosis was defined as either histological or clinical cirrhosis. Chi-square tests, t tests, and logistic regression method were used for data analysis. RESULTS: Six hundred and ninety-two patients were categorized into four racial-ethnic groups: 292 Caucasian (C), 145 Hispanic (H), 121 African American (AA), and 134 Asian (As) patients. Median age of AA (54 years) and As (53) was higher than C (52), or H (50) (p < 0.05). H patients had a higher percentage of alcohol abuse (60%) than AA and C (42-44%) and As (14%; p < 0.0001). Body mass index (BMI) was significantly lower in Asians compared to all other groups (p < 0.0001). Features of the metabolic syndrome were common, ranging from 28% in As to 72% in H patients. Liver cirrhosis was found in 53% H, 35% C, 29% As, and 19% AA. In multivariable analysis, only alcohol abuse, BMI, diabetes mellitus (DM), and age were significantly associated with liver cirrhosis. There was a trend for AA to have less cirrhosis, either histological or clinical (p = 0.08). CONCLUSIONS: Using only histology, liver cirrhosis was significantly underestimated. In our cohort, severity of CHC was not clearly affected by race when alcohol use and features of the metabolic syndrome were taken into consideration. However, there was a trend for African Americans to have lower cirrhosis rates.

Racial differences in prevalence and severity of non-alcoholic fatty liver disease.

The aim of this review is to assess the evidence regarding racial differences in the prevalence and severity of nonalcoholic fatty liver disease (NAFLD). We reviewed the published literature that reported prevalence, severity, and genetic associations of NAFLD in different ethnic groups. The metabolic syndrome (MetS) has been associated with NAFLD, but each component of the MetS is present in various races in different percentages and their effect on NAFLD appears to be dissimilar. An elevated triglyceride (TG) level seems to have the strongest association with NAFLD. The latter is more prevalent in Hispanic patients; Blacks have lower TG levels and a lower NAFLD prevalence, compared to Caucasians or Hispanics. The severity of liver fibrosis is lower in some, but not all biopsy-based studies of Black patients. No study has evaluated the severity of liver disease controlling for the individual components of MetS, especially TG. Important racial differences in the prevalence of selected genetic polymorphisms, particularly PNPLA-3 and MBOAT7 have been documented, together with their effects on the prevalence of liver steatosis and fibrosis. Data on overall and liver mortality have found no significant differences according to race/ethnicity, with the possible exception of one paper reporting lower cirrhosis mortality in Black patients. We conclude that NAFLD is more prevalent in Hispanics and less in Blacks. This is supported by differences in key genetic polymorphisms associated with hepatic fat storage. However, there is presently insufficient evidence to firmly conclude that race, per se, plays a role in the development of liver fibrosis and its complications. Further studies, appropriately controlled for diet, exercise, and individual MetS parameters are needed.

Red cell distribution width as a predictor of outcome in hospitalized cirrhotic patients.

BACKGROUND: A systemic inflammatory response syndrome (SIRS) is linked to red cell distribution width (RCDW), which produces pro-inflammatory signals that act directly on hematopoietic stem cells in the bone marrow. This stimulation may cause alterations in the membrane of red blood cells (RBCs), as assessed by RCDW, which have been linked to increased morbidity and death in a number of systemic disorders. AIM: This study aims to evaluate RCDW as a predictor of outcome in hospitalized cirrhotic patients. METHODS: This prospective cross-sectional study was conducted on 1000 patients. The outcome was assessed by days of hospitalization; mortality in hospitalized patients or during short-term follow-up (3 months) and rehospitalization during follow-up of 6 months. RESULTS: Male represented 69.6%. Mean age was 57.67 ± 13.07 years old. Baseline co-morbidities were recorded as the presence of diabetes mellitus (200 patients) and hypertension (400 patients). Hepatitis C virus was the commonest etiology of the diseased liver (90%). Child-Pugh classes A, B and C of studied patients represented (21.2%, 38.8% and 40%). The survived patients during follow-up represented 63.3%. Area under the curve for RCDW was 0.923 (95% CI, 0.904-0.943), 0.910 for C-reactive protein (95% CI, 0.890-0.930), 0.904 for Hb (95% CI, 0.883-0.925) and 0.903 for platelets (95% CI, 0.882-0.924). RCDW cutoff point at 21.35 for predicting survival had sensitivity 93%, specificity 91%, accuracy 92%, positive predictive value 85 and negative predictive value 96. Regression analysis revealed a significant positive association between both RCDW and white blood cells with mortality. CONCLUSION: RCDW could provide useful information for predicting the length of hospitalization and survival in hospitalized cirrhotic patients.

Early fibrosis regression by shear wave elastography after successful direct-acting anti-HCV therapy.

Shear wave elastography (SWE) is a noninvasive ultrasound-based marker of hepatic fibrosis not requiring a special device. Successful direct-acting anti-HCV therapy was associated with hepatic fibrosis regression assessed by transient elastography (FibroScan). Data on the utility of SWE in these patients and how early fibrosis can regress after treatment are still lacking. To assess liver fibrosis by SWE before and after direct-acting antiviral treatment of chronic hepatitis C (CHC), we enrolled 165 CHC genotype 4 Egyptian patients treated with different Sofosbuvir-based regimens. Patients' laboratory characteristics, fibrosis biomarkers, namely Fibrosis-4 (FIB-4) index and AST/platelet ratio index (APRI) and liver stiffness measurements (LSM) by SWE were evaluated at baseline, end of treatment (EOT at week 12), week 24 and week 36. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels as well as FIB-4 and APRI indices decreased significantly at EOT, week 24 and week 36 in comparison to baseline (P value < 0.001). Although platelet counts did not significantly differ between baseline and EOT, they increased significantly from EOT to week 24 and week 36 with a P value < 0.001. The mean LSM showed improvement at EOT (7.01 ± 3.59 kpa), week 24 (6.18 ± 3.39 kpa) and week 36 (5.74 ± 3.21 kpa) in comparison to baseline (8.49 ± 0.83 kpa) (P value < 0.001). There is early liver fibrosis regression at EOT and throughout the time after successful treatment with direct-acting antiviral agents (DAAs). SWE is a feasible, easily applicable noninvasive relatively inexpensive assessment method of liver fibrosis.

Assessment of liver fibrosis with acoustic radiation force impulse imaging versus liver histology in patients with chronic hepatitis C: a pilot study.

BACKGROUND: Acoustic radiation force impulse imaging (ARFI) involves the mechanical excitation of tissues using short-duration acoustic pulses to generate localized displacements in tissue. The displacements results in shear-wave propagation, tracked by ultrasonography (US) correlation-based methods and recorded in meters per seconds. AIM: To compare (ARFI) integrated into a conventional US with the standard histological examination of liver biopsy specimens for the assessment of liver fibrosis. MATERIALS AND METHODS: Histological fibrosis staging with standard liver biopsy using the Metavir scoring system as well as fibrosis assessment using ARFI were performed to 80 patients with chronic hepatitis C over a 3-month period. RESULTS: ARFI findings were identical to the biopsy findings in 61 (76.25%) patients.Fifty-eight (67.5%) patients with an early fibrosis stage (F0, F1, and F2) by histology had identical fibrosis stages using ARFI.Only 20 out of 26 patients with an advanced fibrosis stage (F3 and F4) using ARFI had advanced fibrosis histologically. In the advanced fibrosis stages, the sensitivity of ARFI was 70% and specificity was 80%, with positive and negative predictive values of 53.8 and 88.9%, respectively. The accuracy of detection of advanced fibrosis by ARFI was 77.5%. CONCLUSION: ARFI imaging is a promising noninvasive US-based method for the assessment of liver fibrosis.

Impact of nitazoxanide on sustained virologic response in Egyptian patients with chronic hepatitis C genotype 4: a double-blind placebo-controlled trial.

BACKGROUND: Nitazoxanide, approved for the treatment of Cryptosporidium parvum and Giardia lamblia, was found to inhibit hepatitis C virus replication. AIM: The aim of this study was to assess the impact of nitazoxanide as an add-on therapy to pegylated interferon α-2a and ribavirin on sustained virologic response (SVR) in patients with chronic hepatitis C. PATIENTS AND METHODS: A total of 200 patients with chronic hepatitis C were enrolled in the study, assigned randomly in a 1 : 1 ratio to two groups: group A (placebo group) and group B (nitazoxanide group). Five patients withdrew from the study after they signed the consent form.A total of 195 patients were evaluated: 97 patients in group A versus 98 patients in group B at a dose of 500 mg twice daily. Placebo and nitazoxanide were administered as an add-on therapy to pegylated interferon α-2a plus ribavirin following a 12-week lead-in phase. SVR was evaluated. Statistical analysis was carried out using the SPSS software. RESULTS: The mean age of the patients in group A was 46.5 versus 45.7 years in group B. In group A, 85 out of 97 (87.6%) patients were men and in group B, 84 out of 98 (85.7%) patients were men.In group A, 59 out of 97 (60.82%) patients achieved an SVR versus 57 out of 98 (58.16%) patients in group B (P=0.70); this difference was not significant. CONCLUSION: Our data did not show any significant impact of nitazoxanide on SVR.

Khat-induced liver injuries: A report of two cases.

Khat is consumed for recreational purposes in many countries, including Yemen, where >50% of adults chew khat leaves regularly. A wide spectrum of khat-induced liver injuries has been reported in the literature. Herein, we report two patients with khat-induced liver injury. Both patients clinically presented with acute hepatitis, one of whom showed radiological evidence of hepatic outflow obstruction. Based on the histological tests, both patients had acute hepatitis, which indicated drug-induced liver injury (DILI) on a background of chronic hepatitis and portal fibrosis; of the two, one presented with symptoms of immune-mediated liver injury.

Predictors of hepatic decompensation after TACE for hepatocellular carcinoma.

AIM: To study predictive factors for hepatic decompensation after transarterial chemoembolisation (TACE) for hepatocellular carcinoma (HCC). METHODS: Between November 2009 and August 2010, of 254 patients with HCC who presented to our multidisciplinary HCC clinic for evaluation, 102 (40%) were amenable for TACE. In this prospective study, there were 102 patients with compensated cirrhosis with HCC and Child-Pugh Class A cirrhosis who underwent TACE at the National Liver Institute, Menoufiya University, Egypt. We excluded all patients with prior locoregional therapy, systemic therapy and/or surgical intervention. At baseline and at 1 month postprocedure, laboratory criteria, tumour criteria (size, number) and Child-Pugh score were recorded. Patients were classified into group 1 (no Child-Pugh point increase after TACE) and group 2 (one or more added Child-Pugh points after TACE, defining hepatic decompensation). Univariate and multivariate analyses were performed to identify factors predictive of hepatic decompensation. RESULTS: Patients were mostly males (82.4%) of mean age 58.4±8.1 years. The only significant changes in laboratory findings at 1 month after TACE were increased international normalised ratio, serum total bilirubin, alanine transaminase and aspartate transaminase and decreased serum albumin and α-fetoprotein (AFP). The statistically significant predictive factors for hepatic decompensation using univariate analysis were found to be baseline lower serum albumin, higher serum α-fetoprotein, more advanced Barcelona Clinic Liver Cancer (BCLC) stage, larger tumour size and a greater number of tumour nodules; with logistic regression, multivariate analysis found that at baseline larger tumour size (p=0.004 at 95% CI), higher serum AFP (p=0.046 at 95% CI) and lower serum albumin (p=0.033 at 95% CI) predicted decompensation; BCLC stage, number of tumour nodules and pre-TACE bilirubin did not predict changes in liver function. CONCLUSIONS: Lower serum albumin and increased tumour burden (larger tumour size/more nodules and higher α-fetoprotein) at baseline may help predict post-TACE decompensation.

Portal and splanchnic hemodynamics after partial splenic embolization in cirrhotic patients with hypersplenism.

To assess the acute effects of partial splenic embolization (PSE) on portal and splanchnic hemodynamics in patients with cirrhosis. Ninety-five patients with hypersplenism were included in the study. Duplex examinations were performed before and 3 and 7 days after PSE. Portal and splanchnic hemodynamics including vessel cross-sectional area (CSA), mean flow velocities (cm/s), blood flows (mL/min), Doppler indices as portal congestion index (CI), liver vascular index, hepatic artery and superior mesenteric artery (SMA) pulsatility and resistive indices (PI and RI), were performed before and after PSE. In our study, 69 of 95 patients were males (72.6%) and 26 females (27.3%). Chronic hepatitis C virus infection was the main cause of cirrhosis (81.1%). PSE failed technically in six patients (6.3%). After PSE, both CSA and CI significantly decreased (p < 0.05 and <0.01). The portal vein velocity significantly increased (p < 0.01). The portal flow volume (892.4 ± 151 mL/min) did not show significant changes. The hepatic artery RI and PI showed a steady increase that became significant 7 days post-PSE (p < 0.05). The RI and PI of SMA increased significantly after 7 days of PSE (p < 0.05). PSE has an immediate portal decompression effect in patients with portal hypertension without reduction in portal flow. This effect on portal pressure should be investigated in future studies as a potential tool for management of acute variceal bleeding when other medical procedures fail.