Association of long noncoding RNA H19 rs2839698 C/T with hepatitis B virus infection and hepatocellular carcinoma risk.

The intricate pathogenesis of the hepatitis B virus (HBV) and its progression to hepatocellular carcinoma (HCC) have not yet been fully elucidated. H19 is one of the earliest imprinted long noncoding RNAs (lncRNAs) associated with liver pathobiology. This study investigated the association of H19 single nucleotide polymorphisms (SNPs) rs2839698 C/T and rs217727 C/T with HBV and HBV-related HCC and their correlation with H19 expression level. A total of 230 subjects were enrolled in this study including 100 HBV-infected patients, 30 HBV-related HCC patients, and 100 apparently healthy controls. TaqMan genotyping human assays were utilized to assess allelic discrimination for H19 SNPs. H19 expression was assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Our findings showed that H19 rs2839698 was linked to a higher incidence of HBV infection and HBV-related HCC. Individuals who bear the CT genotype of rs2839698 were more susceptible to HBV infection (OR = 3.05; 95% CI 1.714-5.457; p < 0.001). Those harboring the TT genotype were more prone to develop HCC (OR = 2.625; 95% CI 1.037-6.64; p = 0.038). Our data revealed that rs2839698 could function as a promising predictor of HCC risk. Furthermore, H19 was significantly downregulated in HBV (p < 0.01) and HCC (p < 0.01) patients versus the control group. Significant upregulation of H19 in HCC patients with cirrhosis (p < 0.001) was detected. Altogether, this is considered the first prospective case-control study to address the implication of the genetic variations of H19 SNPs in HBV and HBV-related HCC in Egyptian patients.

ADAM10 Gene Polymorphism and Its Relationship to Hepatocellular Carcinoma in Egyptian HCV Patients Receiving Direct-Acting Antiviral Therapies (DAAs).

OBJECTIVE: The aim of this study was to investigate the ADAM 10 rs.653765 SNP genetic polymorphism in the hepatocellular carcinoma occurrence (de novo and post DAAs). METHODS: This study was conducted on 360 participants divided to 4 groups. Group 1: 90 chronic adult patients infected with HCV received DAAs regimens and evolved HCC during the period of follow up. Group 2: Another 90 HCV patients received the same DAAs regimens and did not show HCC manifestations during the same follow up period. Group 3 included 90 de novo HCC patients (did not receive any DAAs). Finally, 90 apparently healthy participants as group 4. Clinical and laboratory data were evaluated, and ADAM 10 genotyping were performed using qPCR. RESULTS: The study showed statistically significant between HCC de novo and HCC deterioration on top of DAAs according to three scoring systems (Child Pugh, BCLC and HKLC) with p- value <0.05. Regarding ADAM10 gene polymorphism, the study showed a significant difference between CC versus CT+TT genotypes of HCC groups according to Child Bugh, BCLC and HKLC staging systems. Yet, no significant difference was found when ADAM10 genotypes and allele frequencies were compared between the four different studied groups. No difference in the survival rate between HCC de novo and on the top of DAAs but more aggressive stages with HCC on top of DAAs. CONCLUSION: ADAM10 genotypes did not show any significant association with HCC. Also, no differences in the death rate recorded between the de novo HCC and HCC post DAAs treatment with statistical significant worse staging of HCC post DAAs and were noted. the study showed a significant difference between CC versus CT+TT genotypes of HCC groups according to Child Bugh, BCLC and HKLC staging systems.
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Biliary complications after adult to adult right-lobe living donor liver transplantation (A-ARLLDLT): Analysis of 245 cases during 16 years period at a single high centre- A retrospective cohort study.

Objectives: Biliary complications (BCs) after adult to adult living donor liver transplantation (A-ALDLT) result in poor graft and patient survival. This study aimed to analyze these complications. Methods: We retrospectively analyzed BCs in 245 recipients who underwent A-ALDLT using the right-lobe graft during 16 years period in our centre. The overall male/female ratio was 215/30. Results: One hundred fifty-five BCs affected 102 of our recipients (95 early (≤3months) and 60 late (≥3months)). They were classified as 67/245(27.3%) early bile leak, 10/245(4.1%) early biliary stricture, 44/245(17.9%) late biliary stricture, 4/245(1.6%) early cholangitis, 10/245(4.1%) late cholangitis, 14/245(5.7%) early biloma, and 6/245(2.4%) late cholangitic abscesses. Multiple biliary anastomoses were independently correlated with Post liver transplantation (LT) overall BCs; moreover, post LT hepatic artery thrombosis or stenosis (HAT/S) was an independent predictor of overall BCs, strictures and leaks. The mortality affected 96(39.2%) cases mostly due to sepsis, bleeding and multi-organ failure (MOF). On the other hand, the biliary related mortality was 10.6% of cases. Multiple cholangitic hepatic abscesses were significant predictors of poor graft and patient outcomes. Conclusions: Multiple biliary anastomoses and post LT HAT/S lead to a poor biliary outcome, furthermore, cholangitis, cholangitic abscesses and sepsis lead to poor graft and patient outcomes, so proper management of those variables is mandatory to improve outcomes after A-ARLLDLT.

BAR Score Performance in Predicting Survival after Living Donor Liver Transplantation: A Single-Center Retrospective Study.

METHODS: 146 adult liver transplant recipients were included. Univariate and multivariate analyses were used to determine the independent predictors of survival at 3 months, 1 year, and 5 years. The receiver operating characteristic (ROC) curve for the BAR score was plotted, and the area under the ROC curve (AUROC) was calculated. Kaplan-Meier curve and log-rank test were used to compare survival above and below the best cutoff values. RESULTS: The mean age was 52.45 ± 8.54 years, and 59.6% were males. The survival rates were 89, 78.8, and 72% at 3 months, 1 year, and 5 years, respectively. The BAR score demonstrated a clinically significant value in the prediction of 3-month (AUROC = 0.89), 1-year (AUROC = 0.76), and 5-year survival (AUROC = 0.71). Among the investigated factors associated with survival, BAR score <10 points was the only independent predictor of 3-month (OR 7.34, p < 0.0001), 1-year (OR 3.37, p=0.001), and 5-year survival (OR 2.83, p=0.044). CONCLUSIONS: BAR is a simple and easily applicable scoring system that could significantly predict short- and long-term survival after LDLT. A large multicenter study is warranted to validate our results in the Egyptian population.

Circulating microRNA 9-3p and serum endocan as potential biomarkers for hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND: The high mortality rate of hepatocellular carcinoma (HCC) in Egypt is due mainly to the increasing prevalence of hepatitis C virus infection (HCV) and late diagnosis of the carcinoma. MicroRNAs (miRNA), which regulate tumor proliferation and metastasis in HCC, may serve as a useful diagnostic approach for the early detection of HCC, thus decreasing its mortality. Meanwhile, endocan is a protein with angiogenic and inflammatory properties that are associated with tumor progression and poor outcomes. AIM: To analyze the levels of miRNA 9-3p and endocan in HCV-infected HCC patients and correlate them with clinicopathological parameters. METHODS: We compared levels of endocan and circulating miRNA 9-3p from 35 HCV-related HCC patients to 33 patients with HCV-induced chronic liver disease and 32 age and gender matched healthy controls recruited from inpatient and outpatient clinics of the National Liver Institute, Menoufia University, Egypt in the period from January to March 2021 in a case-control study. Serum samples from all groups were analyzed for HCV. Endocan was measured by enzyme-linked immunosorbent assays, and the expression levels of circulating miRNA 9-3p were measured by real-time quantitative reverse transcriptase PCR. RESULTS: The levels of circulating miRNA 9-3p were significantly lower in the HCC group compared to the chronic liver disease (P < 0.001) and control (P < 0.001) groups, while levels in the chronic liver disease were significantly lower than those in the control group (P < 0.001). The levels of serum endocan were significantly higher in the HCC group compared to the chronic liver disease (P < 0.001) and control (P < 0.001) groups. Moreover miRNA 9-3p and endocan performed better than α-fetoprotein in discriminating HCC patients from cirrhosis and healthy patients. The levels of miRNA 9-3p were significantly inversely correlated to vascular invasion (P = 0.002), stage of advancement of Barcelona Clinical Liver Cancer (P < 0.001) and the metastatic site (P < 0.001) of the HCC group. CONCLUSION: Circulating miRNA 9-3p and endocan can be used as novel biomarkers for the early diagnosis of HCV-related HCC.

Long-Term Impact of Hepatitis C Virus Eradication on Liver Stiffness in Egyptian Patients.

Methods: Liver stiffness measurements (LSM) have been serially assessed 1, 3, and 5 years after HCV clearance in 655 patients who have been treated with DAAs. Results: The mean age was 51.44 ± 10 years. 73% of patients were males. 48% were cirrhotics. In noncirrhotics, the mean LSM was significantly decreased from 8.29 ± 2.3 kPa to 4.03 ± 1.0 kPa (p < 0.0001) at the end of the follow-up. Likewise, LSM decreased in cirrhotics from 29.66 ± 14.25 kPa to 22.50 ± 11.16 kPa (p < 0.0001). The proportions of F1, F2, F3, and F4 patients at the baseline were 17.7%, 17.9%, 16.6%, and 47.8%, which became 56.5%, 4.1%, 4.9%, and 34.5%, respectively, with a substantial reversal of cirrhosis in 87 patients (27.7%) at the end of follow-up. Conclusions: There was an overall significant regression of liver stiffness in all patients after sustained HCV eradication. Liver stiffness reflecting mild fibrosis (F0-F2) usually improves shortly after treatment, while measurements reflecting advanced fibrosis (F3-F4) take a longer time to regress to lower fibrosis stages.

HCV treatment with direct acting antivirals improves the insulin sensitivity.

Background: There is strong link between hepatitis C virus (HCV) infection and the insulin resistance panel. Homeostatic model assessment (HOMA) ß is an indirect measurement of insulin secretion from pancreatic ß cells, while HOMA-S accounts for insulin sensitivity. Aim: We examined the impact of HCV treatment with direct acting antivirals (DAAs) on HOMA-ß and HOMA-S results. Methods: HOMA-IR, HOMA-ß, and HOMA-S were calculated before and 12 weeks after treatment in 511 treatment eligible patients with HCV. Five DAA treatment protocols were used. Values before and after treatment were compared. Results: The mean age of patients was 50.63 years with a 3.2:1 male: female ratio. A total of 29.7% of patients were treatment experienced and 24.7% had diabetes. HCV sustained virological response (SVR) was achieved in 91% of patients. Unlike non-responders, SVR patients showed significantly decreased post-treatment HOMA-Β. Delta HOMA-Β was comparable between groups. HOMA-S increased significantly in patients with SVR compared to in non-responders, as did delta HOMA-S. HOMA-S and HOMA-ß improved significantly under 5 and 2 DAA protocols, respectively. The treatment status did not affect the HOMA-ß and S dynamics during treatment. Conclusions: Insulin sensitivity improved markedly in patients who achieved HCV SVR.

Validation of modified albumin-bilirubin-TNM score as a prognostic model to evaluate patients with hepatocellular carcinoma.

BACKGROUND: An ideal staging system for hepatocellular carcinoma (HCC) should rely on the hepatic reserve function and tumor burden. With the improvement in diagnostic and treatment strategies for HCC, in addition to recent treatment of viral hepatitis, finding a suitable assessment tool for hepatic reserve has become mandatory. AIM: To validate a recently proposed modified albumin-bilirubin-TNM (mALBI-T) grade as a prognostic model for patients with HCC in Egypt. METHODS: For patients diagnosed with HCC, Child-Turcotte-Pugh (CTP) score, Barcelona Clinic Liver Cancer (BCLC) stage, albumin-bilirubin (ALBI), plateltet-albumin-bilirubin (PALBI), ALBI-based BCLC, ALBI-T and mALBI-T grades were estimated. Patients were followed from time of diagnosis to date of death or date of data collection if they remained alive. Overall survival and received treatments were determined. Survival data were analyzed. RESULTS: A total of 1910 patients were included (mean age, 57 years; 1575 males). At presentation, 50.6% had CTP A, 36.1% had CTP B and 13.4 % had CTP C; 12% had ALBI grade 1, 62.3% had ALBI grade 2 and 24.7% had ALBI grade 3. Overall median survival was 13 mo; survival was better in patients with ALBI 1 than in those with ALBI 2 and 3 (28.6 vs 14 and 5.8 mo, respectively, P < 0.001). Patients with ALBI-T grades 0 and 1 had better survival than those with ALBI-T grades 2, 3, 4 and 5 (P < 0.001). The modified ALBI-T showed better stratification and significant improvement in prediction of survival. CONCLUSION: ALBI-T grade is a superior prognostic tool that selects patients with HCC who have better liver reservoir and tumor stage. mALBI-T is a better prognostic model in patients with HCC.

Insulin resistance is not a risk factor for oesophageal varices development in hepatitis C.

Chronic hepatitis C (HCV) patients commonly have insulin resistance which is a risk factor for disease progression. Oesophageal varices may bleed with high mortality. We aimed to assess the relationship between insulin resistance and oesophageal varices. HCV-related compensated liver cirrhosis patients (n = 146) underwent gastroscopy and homeostasis model assessment (HOMA)-IR, HOMA-ß and HOMA-S calculations. Their average age was 54.98 years; most (84.9%) patients were men and non-diabetic (60.3%). Patients with oesophageal varices had higher median Model for End-Stage Liver Disease (MELD) scores and comparable Child-Pugh class. Patients with and without oesophageal varices had comparable (P > 0.05) HOMA scores and insulin resistance percentage of 82.9% versus 85.5%. We therefore conclude that insulin resistance is unrelated to the presence of oesophageal varices.

Insulin resistance does not impair response of chronic hepatitis C virus to direct-acting antivirals, and improves with the treatment.

BACKGROUND: Insulin resistance (IR) is a common complication in chronic hepatitis C virus (HCV) patients. The impact of IR on outcome of therapy with direct antivirals has not been studied. AIM: The aim was to assess the impact of direct-acting antiviral (DAA) therapy on IR status in chronic HCV patients. PATIENTS AND METHODS: A total of 511 patients [mean age: 50.7±10.4 years, 29.7% pegylated interferon and ribavirin (RBV) experienced] were enrolled. Patients with uncontrolled diabetes, decompensated liver disease, or previous nonresponse to DAAs were excluded. Homeostatic model assessment (HOMA) was calculated before and 12 weeks after treatment, and IR was defined as HOMA greater than 1.9. Patients were treated according to the treating physician's choice, and received 12 weeks of either ombitasvir/ritonavir/paritaprevir/RBV (n=28); sofosbuvir (SOF)/simeprevir (n=36); SOF/ravidasvir (n=101); SOF/pegylated interferon/RBV (n=192); or 24 weeks of SOF/RBV (n=154). RESULTS: Most patients received IR pretreatment (80.6%); 51.3% had fibrosis stage F4 and 24.7% had diabetes. A sustained virological response (SVR) at 12 weeks after treatment (SVR12) was achieved in 465 (91%) patients. SVR12 was achieved in 90.5% of patients with IR and in 92.9% of patients without IR (P=0.560), and pretreatment HOMA was not different in responders and nonresponders (P=0.098). The number of patients with IR decreased significantly in patients who achieved an SVR much more than in nonresponders (P<0.0001) and HOMA improved significantly more in patients with SVR than in nonresponders (P=0.001). All treatment protocols were associated with a comparable improvement in HOMA (P=0.101). Predictors of SVR12 included age, platelets, and liver stiffness, but not pretreatment IR. CONCLUSION: IR does not impair the response of patients with HCV treated with DAAs, and improves significantly in patients who achieve an SVR.

High efficacy of generic and brand direct acting antivirals in treatment of chronic hepatitis C.

BACKGROUND: Direct acting antivirals (DAAs) are highly effective for treatment of hepatitis C (HCV) but brand products are priced beyond the means of most low and middle income countries (LMICs). Although a few DAAs are offered at reduced prices in access programs, they are still beyond affordability in limited resource settings with a large HCV infected population. Cheap generics might fill this economic need, but studies comparing their clinical efficacy to that of original products are limited. AIM: To compare efficacy of brand and generic DAAs used in the national treatment program in Egypt. METHODS: HCV treatment eligible patients (n=971) were enrolled. They were treated with 12 weeks of either sofosbuvir-daclatasvir (SOF-DCV) or SOF-ledipasvir (SOF-LDV). Ribavirin (RBV) was added to patients with cirrhosis and to SOF experienced patients. Patients with cirrhosis who were RBV intolerant were treated for 24 weeks without RBV. RESULTS: Most patients were males (61.4%), treatment naïve (88.6%), without cirrhosis (61.7%), and the mean age was 51.3±11.31 years. Baseline characteristics were not different in patients treated with brand or generic medications regarding age, liver tests, creatinine, platelets, MELD score, baseline HCV-RNA and transient elastography. Overall sustained virologic response (SVR) rate was 98.1%, which was similar for generic and brand drugs (98.2% vs. 98.1%; p=1), and similar with both regimens used (SOF-DCV±RBV: brand: 98.1%, generic 97.8%; p=0.729, SOF-LDV±RBV: brand 98.2%, generic 100%; p=0.729). AST and ALT decreased significantly with initiation of therapy with both generic and original drugs. CONCLUSION: Generic and brand DAAs are equally effective for achieving SVR and improving aminotransferases.

Platelets-to-lymphocyte ratio is a good predictor of liver fibrosis and insulin resistance in hepatitis C virus-related liver disease.

BACKGROUND: Hepatitis C virus (HCV) is a global health problem that is complicated by liver fibrosis and insulin resistance (IR). AIM: The aim of this study was to validate neutrophils-to-lymphocytes ratio (NLR) and platelets-to-lymphocytes ratio (PLR) as indirect biomarkers of liver fibrosis and IR in HCV patients. PATIENTS AND METHODS: One hundred and fifty patients were enrolled. Physical examination, BMI, liver function tests, serum creatinine, complete blood count, serum HCV RNA count by PCR, and abdominal ultrasonography were performed. Transient elastography measurement using FibroScan was performed. Patients were classified into those with mild fibrosis (F1-F3) and significant fibrosis (F4). IR was defined as homeostasis model assessment of IR more than 2. NLR and PLR were calculated. RESULTS: The average age of the patients was 47.21±10.51 years, mainly men (n=119; 79.3%), and 87.3% (n=131) had IR and 44.7% (n=67) had significant fibrosis. PLR was lower in patients with IR (74.95±37.90 vs. 94.71±31.45; P=0.032) unlike the NLR, which was comparable (P>0.05). Patients with significant fibrosis had lower PLR (66.43±39.38 vs. 86.35±33.85; P=0.001) unlike NLR (P>0.05). PLR (cutoff≥77.47) had 78.9% sensitivity, 60.3% specificity, 22.4% positive predictive value, and 95.2% negative predictive value for non-IR (P=0.008). At a cutoff of at least 63.71, PLR had 73.5% sensitivity, 61.2% specificity, 70.1% positive predictive value, and 65.1% negative predictive value for nonsignificant fibrosis (P=0.001). Age and PLR (odds ratio=0.99; 95% confidence interval=0.976-0.999) were predictors of IR, whereas age, total bilirubin, serum albumin, liver stiffness, and PLR (odds ratio=0.98; 95% confidence interval=0.974-0.994) were predictors of significant fibrosis. CONCLUSION: PLR is useful in distinguishing the patients with significant fibrosis or IR unlike NLR.