Seven gene signature explores the impact of DAAs on the appearance of hepatocellular carcinoma in HCV infected patients.

HCV damages the hepatocytes ending with hepatocellular carcinoma (HCC). The direct-acting antivirals (DAAs) treatment has raised hopes for reducing the incidence of HCC. However, several scientific debate regarding the impact of DAAs on the occurrence of HCC in patients with cirrhosis. We aimed to study the Cirrhosis Risk Score (CRS), several clinical factors and tumor characteristics between patients who developed HCC either with or without DAAs treatment "DAA-exposed HCC patients" and "DAA-unexposed HCC patients". Methods: CRS was assessed via genotyping by allelic discrimination assays in HCV patients who developed de novo HCC (with DAAs (DAA-exposed HCC patients, n = 50), and without DAAs treatment (DAA-unexposed HCC patients, n = 40)). APRI, FIB-4 scores, and tumor characteristics were assessed. Results: Around 60% and 48% of DAA-exposed HCC patients and DAA-unexposed HCC patients; respectively had high CRS scores without significant difference. DAA-exposed HCC patients showed elevated Albumin, Hemoglobin and decreased ALT, AST compared with DAA-unexposed HCC patients (P = 0.002, 0.04, <0.001 and 0.006; respectively). FIB4 and APRI didn't reach the statistical difference between the studied groups. DAA-exposed HCC patients have higher overall survival (OS) than DAA-unexposed HCC patients (median: 30 & 15 months; respectively (p = 0.019)). Moreover, no significant differences were observed between the two groups in their focal lesion characteristics. Conclusion: All studied patients are genetically predisposed to develop HCC. Moreover, DAAs significantly improved the OS and the biochemical parameters. No differences between the two groups were detected regarding their tumor characteristics. Accordingly, the appearance of HCC after treatment is attributed to the natural course of cirrhosis.

The Impact of COVID-19 on Liver Injury.

The current coronavirus disease outbreak of 2019 (COVID-19) has led to a global pandemic. The principal cause of mortality in COVID-19 is represented lung injury with the development of acute respiratory distress syndrome (ARDS). In patients with COVID-19 infection, liver injury or liver dysfunction has been reported. It may be associated with the general severity of the disease and serve as a prognostic factor for ARDS development. In COVID-19, the spectrum of liver damage may range from direct SARS-CoV-2 viral proteins, inflammatory processes, hypoxemia, the antiviral drugs induced hepatic injury and the presence of the preexisting liver disease. We highlight in this review important topics such as the epidemiological features, potential causes of liver injury, and the strategies for management and prevention of hepatic injury in COVID-19 patients.

Evaluation of seven gene signature for predicting HCV recurrence post-liver transplantation.

BACKGROUND: Orthotropic liver transplantation (OLT) offers a therapeutic choice for hepatocellular carcinoma (HCC) patients. The poor outcome of liver transplantation is HCV recurrence. Several genome-wide associated studies (GWAS) have reported many genetic variants to be associated with HCV recurrence. Seven gene polymorphisms formed a cirrhosis risk score (CRS) signature that could be used to distinguish chronic HCV patients at high risk from those at low risk for cirrhosis in non-transplant patients. This study aims to examine the association of CRS score and other clinical parameters with the probability for HCC emergence and/or the rate of HCV recurrence following liver transplantation. RESULTS: Seven gene polymorphisms, forming the CRS, were genotyped by real-time PCR using allelic discrimination protocol in 199 end-stage liver disease patients (79 child A, 43 child B, and 77child C), comprising 106 patients who encountered liver transplantation. Recipient CRS scores were correlated with HCV recurrence (HCV-Rec) at the end of the third year after OLT. Around 81% (39) recipients with low steatosis (LS; < 3.5%) donor percentage revealed no HCV recurrence (non-Rec) (p<0.001). CRS score could distinguish between child A, child B, and child C only at the low-risk group. Among the HCV Rec group 27% (8/30), 40% (12/30), and 33% (10/30) fell into the high, moderate, and low CRS risk groups, respectively. Stepwise logistic regression evinced two features more likely to be seen in HCV-Rec patients: abnormal ALT [OR, 1.1; 95% CI, 1.02-1.2] and donor steatosis >3.5% [OR, 46.07; 95% CI, 1.5-1407.8]. CONCLUSIONS: Accordingly, the CRS score seems to be less useful to predict HCV recurrence after OLT. ALT and donor steatosis (exceed 3.5%) can significantly promote the HCV recurrence post-OLT. Moreover, the combination of MMF and CNI positively heightens HCV recurrence.

Development of a gene signature for predicting cirrhosis risk score of chronic liver disease associated with HCV infection in Egyptians.

BACKGROUND: Complex diseases such as fibrosis are likely polygenic. Lately, cirrhosis risk score (CRS) clearly discriminated Chronic HCV patients with high-risk versus those with low-risk for cirrhosis better than clinical factors. METHODS: Herein, the CRS was assessed via genotyping by allelic discrimination assays in 243 HCV Egyptian patients categorized into 164 patients didn't develop HCC (93 mild, 71 advanced fibrosis); and 79 patients developed HCC. APRI and FIB-4 scores were calculated, compared with CRS and correlated with degree of fibrosis progression. RESULTS: Median of the three CRS, APRI and FIB-4 scores were significantly elevated in late fibrotic and HCC patients (p < 0.001); however CRS displayed proper discrimination (mild fibrosis (0.59; 0.4-0.75), advanced fibrosis (0.75; 0.7-0.86) and HCC (0.73; 0.57-0.77); (p < 0.001)). The ROC analysis of CRS score displayed modest accuracy to discriminate between mild and advanced fibrotic patient; AUC was 0.73; p < 0.0001), while AUC was only 0.57 (p = 0.05) for the discrimination between HCC and no HCC. Moreover, the combination of CRS, APRI and FIB4 lessened the power of correlation (AUC, 0.63 (p < 0.0001)) in fibrosis prognosis. In HCC prognosis, the combination of CRS, APRI and FIB4 in HCC patients showed modest accuracy with AUC, 0.59 (p = 0.0001). CONCLUSION: The diagnostic accuracy of FIB-4 for predicting liver fibrosis was nearly identical to that of CRS, however the strength of CRS score stemmed from that it is built on 7 SNPs host genetic factor. Our study validates non invasive algorithms for fibrosis prognosis purposes which may aid in decision making for therapeutic intervention.

Reactivation of human cytomegalovirus inhibits expression of liver fibrosis related cytokines in patients chronically infected with hepatitis C virus genotype 4a.

BACKGROUND: The impact of human cytomegalovirus (HCMV) reactivation on the expression pattern of matrix metalloproteinases, their inhibitors and related cytokines during HCV infection poorly understood. METHODS: Reactivation of CMV in 95 subjects (75 chronically infected HCV patients and 20 healthy subjects) was examined. All studied subjects had detectable IgG antibodies for CMV, but only 35/75 of HCV patients (46.7%) had detectable CMV DNA. The expressions of 11 fibrosis related genes by quantitative real-time PCR were analyzed in subjects' PBMCs. The serum levels of TGFß2 and PDGFα have been measured by ELISA. RESULTS: Chronically infected HCV patients with reactivated CMV had less expression of TGF-ß1, TGF-ß2, PDGFα and STAT1 transcripts than HCV patients with latent CMV (p = 0.037, 0.006, 0.001 and 0.009; respectively) and normal controls (TGF-ß2, p = 0.008). Moreover the expression of (TGFß2 and PDGFα) genes decreased significantly in CMV-reactivated patients during the early stage of fibrosis relative to the comparable stage of HCV infection (p = 0.004 and 0.008; respectively). Besides, the mRNA abundance of STAT1 gene in CMV-reactivated patients decreased dramatically as compared to HCV infections during the late stage of fibrosis (p = 0.014). The TGFß2 protein level has been declined dramatically in CMV-reactivated patients compared to HCV infected patients and control group (p = 0.001 and 0.033; respectively). Our results suggest that CMV reactivation disrupts the expression of several cytokines as compared to solitary infection with HCV. Noticeably, the expressions of matrix metalloproteinases genes and their inhibitors have not been significantly influenced by reactivation of CMV. CONCLUSION: The current data reveal that reactivation of CMV partially blocks the upregulation of 2 important pro-inflammatory cytokines i.e. TGFß 2 and PDGFα at early stages of fibrosis, moreover this CMV mediated blockage of the STAT1 shows statistical significance at late stage of fibrosis.

Dysregulation of fibrosis related genes in HCV induced liver disease.

BACKGROUND: Liver fibrosis results from a wound healing response to chronic injury, which leads to excessive matrix deposition. Genome wide association studies have showen transcriptional dysregulation in mild and severe liver fibrosis. Recent studies suggested that genetic markers may be able to define the exact stage of liver fibrosis. AIM: To define genes or genetic pathways that could serve as markers for staging or as therapeutic targets to halt progression of liver fibrosis. METHODS: The study was performed on 105 treatment naïve HCV genotype 4 infected patients [F0-F2, n = 56; F3-F4, n = 49] and 16 healthy subjects. The study included PCR array on 84 fibrosis related genes followed by customization of a smaller array consisting of 11 genes that were designed on the bases of results obtained from the larger array. Genes that displayed significant dysregulation at mRNA levels were validated at protein levels. RESULTS AND DISCUSSION: Two major pathways exhibited high dysregulation in early fibrosis as compared with controls or when compared with late fibrosis, these were the TGFß - related pathway genes and Matrix - deposition associated genes. Hepatic stellate cell (HSC) activators i.e. TGFß pathway genes [TGFß1, 2 and 3, their receptors TGFßR1 and 2, signaling molecules SMAD genes and PDGF growth factors] were considerably over-expressed at transcriptional levels as early as F0, whereas expression of their inhibitor TGIF1 was simultaneously down regulated. Matrix proteins including collagen and MMPs were upregulated in early fibrosis whereas tissue inhibitors TIMPs 1 and 2 began over expression in late fibrosis. Expression at protein levels was concordant with RNA data excluding dysregulation at post transcriptional levels. CONCLUSION: Since these 2 gene sets are closely interrelated regarding HSC activation and proliferation, we assume that the current findings suggest that they are favorable targets to further search for stage specific markers.