Association of Sat-a and Alu methylation status with HCV-induced chronic liver disease and hepatocellular carcinoma.

BACKGROUND: The combination of epigenetic and genetic abnormalities contributes together to the development of liver cancer. The methylation status of the repetitive elements (REs) in DNA has been investigated in a variety of human illnesses. However, the methylation patterns of Sat-α and Alu REs in chronic liver disease (CLD) and hepatocellular carcinoma (HCC) caused by hepatitis C virus (HCV) have never been studied before. METHODOLOGY: In this study, 3 groups of participants including 50 patients having HCV-induced CLD, 50 patients having HCV-induced HCC, and 46 healthy subjects were subjected to measurement of Sat-α and Alu methylation using the quantitative MethyLight assay. RESULTS: Sat-α and Alu methylation percentages decreased significantly in both CLD and HCC, compared to control. Also, a significant Sat-α hypomethylation was detected in HCC, compared to CLD. In addition, Sat-α and Alu methylation showed a significant decline as lesion size grew. However, only Sat-α hypomethylation was significantly increased in association with portal vein thrombosis and the MELD score. Sat-α methylation percentage had the highest sensitivity and specificity for diagnosing HCC (100% and 84.4%) followed by α-fetoprotein (80% and 84.4%) and Alu methylation (66% and 61.5%). Furthermore, there was a strong positive correlation between Sat-α and Alu methylation. CONCLUSIONS: Measuring Sat-α and Alu methylation provides us with a new tool for early detecting HCV-induced CLD and hepatocarcinogenesis. Sat-α has the potential to be utilized as an independent predictive parameter for HCC development and progression because of its ability to distinguish between CLD and HCC with their different MELD scores.

Detection of Occult Hepatitis C Virus Infection in Egyptian Patients Who Achieved a Sustained Virologic Response to Direct-Acting Antiviral Agents.

BACKGROUND: Occult hepatitis C virus (HCV) infection (OCI) is diagnosed based on the detection of HCV-RNA in non-serum reservoirs, such as peripheral blood mononuclear cells (PBMCs) and/or hepatocytes with undetectable HCV-RNA in the serum. The current study was designed to shed more light on the presence of occult HCV in a population of cases who achieved an SVR after receiving treatments for HCV-infection and its significance. METHODS: This cross-sectional study evaluated 111 chronic HCV patients treated at Theodor Bilharz Research Institute, Egypt and achieved a sustained virological response (SVR) 12 -24 weeks after treatment with Direct acting antiviral drugs (DAAs). The treatment lasted 12 or 24 weeks using generic medications including Sofosbuvir (SOF) 400 mg/day and Daclatasvir (DCV) 60 mg/day ± weight-based Ribavirin (RBV) 600-1000 mg/day. After achieving the SVR 12 -24 weeks, all patients were subjected to clinical examination and full laboratory investigations. All the candidates were assessed for fibrosis pre/post-treatment by transient elastography (Fibroscan©). Eighty-seven patients (78.4%) received dual therapy (SOF/DCV) and 24 patients (21.6%) received triple therapy (SOF/DCV/RBV). One hundred and seven patients received the regimen for 12 weeks (96.4%) and only four patients received the regimen for 24 weeks (3.6%). All patients were examined in terms of HCV RNA in plasma and PBMCs. RESULTS: Nine patients (8.1%) were positive for PBMCs HCV RNA. The presence of Occult HCV infection (OCI) was significantly correlated with age, level of AFP, and the degree of liver stiffness. CONCLUSION: The OCI was present in 8.1% of the patients who achieved an SVR 12 - 24 weeks. These patients were mostly aged and with elevated AFP and advanced fibrosis. Monitoring and follow-up of those patients may help to assess the outcomes.

Efficacy of carvedilol versus propranolol versus variceal band ligation for primary prevention of variceal bleeding.

BACKGROUND AND AIMS: Band ligation and propranolol are the current therapies for primary prevention of variceal bleeding. Carvedilol is a rising nonselective beta-blocker used for reducing portal pressure with favorable outcome. The aim of this study to assess the efficacy of carvedilol, propranolol, and band ligation for primary prevention of variceal bleeding based on the effect of each regimen on progression of Child score and portal hypertensive gastropathy after 1 year. METHODS: The study included 264 cirrhotic patients with medium/large-sized varices who were candidates for primary prophylaxis of variceal bleeding. Patients were randomly divided into three groups: group I: band ligation; group II: propranolol; group III: carvedilol. RESULTS: Group I showed higher success rate of 75 %, followed by group III with 70.2 % and group II with 65.2 %. Risk of bleeding was comparable between the three groups, with group II carrying the highest rate of complications (34.7 %) followed by group III (14.2 %) and finally group I (5.7 %). After 1 year of follow-up, Child score did not improve in any of the studied groups, while portal hypertensive gastropathy significantly increased in group I but decreased in groups II and III. CONCLUSIONS: Band ligation is the best treatment option for primary prevention of variceal bleeding with minimal complications. Carvedilol is a good pharmaceutical alternative medicine to propranolol with lesser side-effects. Progress of liver disease as represented by Child score is not affected by any of the primary variceal prophylactic regimens, although medical treatment reduces portal hypertensive gastropathy. Choice of treatment depends on patient will, compliance with treatment, and endoscopist competence.

Evaluation of fluvastatin in combination with the standard of care therapy (PEG-IFN/Ribavirin) in Egyptian patients with hepatitis C virus.

BACKGROUND/AIMS: Cholesterol biosynthesis suppresses the replication of HCV-1b replicons, thus influencing hepatitis C virus (HCV) natural history. This study aimed at comparing the efficacy and safety of fluvastatin (FLV) as an adjuvant therapy to the standard of care (SOC) therapy, i.e., pegylated interferon (PEG-IFN) and ribavirin, for the treatment of HCV patients. MATERIALS AND METHODS: Sixty HCV patients were enrolled and allocated to either group I, who received the triple therapy (fluvastatin + SOC), or group II, who received SOC; the duration for both treatments was 48 weeks. All patients were subjected to pretreatment liver biopsy and monthly biochemical tests (liver profile, CBC), and quantitative HCV-RNA test was performed at weeks 0, 4, 12, 48, and 72. RESULTS: All virological responses were higher in group I than in group II, with no statistical difference. Group I showed no manifestations of hepatotoxicity. CONCLUSION: Fluvastatin yielded a borderline, significantly higher complete early virological response than SOC; therefore, it is a safe adjuvant to the SOC therapy.

Evaluation of the diagnostic value of serum and tissue apoptotic cytokeratin-18 in patients with chronic hepatitis C.

BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) is considered the most common aetiology of chronic liver disease (CLD) in Egypt. The disease severity ranges from mild illness to cirrhosis and hepatocellular carcinoma. A role for apoptosis in liver damage caused by HCV chronic infection has been suggested. Cytokeratin 18 (CK-18) is the major intermediate filament protein in the liver and is a known caspase substrate in hepatocyte apoptosis. Therefore, we analysed the serum and tissue levels of CK-18 in patients with chronic HCV infection to evaluate its role in hepatocyte apoptosis. We also correlated CK-18 expression with the severity of hepatic pathology. PATIENTS AND METHODS: This study examined 80 Egyptian patients with liver disease. There were 69 patients with chronic hepatitis C and 11 patients with hepatitis C-induced cirrhotic changes. Fifteen healthy controls were also included in the study. The levels of CK-18 fragment were quantified in paired serum and liver biopsy samples. RESULTS: The serum and tissue CK-18 levels were reduced in chronic HCV patients compared to early cirrhosis patients. This result indicates that serum levels of CK-18 and the hepatic expression of CK-18 might play an important role in disease progression. The serum and tissue levels of CK-18 were significantly increased and directly correlated with inflammation severity, stage of fibrosis, and ALT levels in the chronic HCV group and the cirrhotic liver group. There was no significant difference in viral load between patient cohorts. CONCLUSION: The serum level and the hepatic expression of CK-18 are related to disease activity and are directly correlated with METAVIR scoring. This result suggests that serum CK-18 levels may be useful for monitoring disease activity in chronic HCV and liver cirrhosis patients.

SEN virus infection in Egyptian patients with chronic hepatitis C and patients undergoing hemodialysis.

The SEN virus has been tentatively linked to transfusion-associated non-A to E hepatitis. The aim of the present study was to 1) determine the prevalence of SEN virus among Egyptian patients with hepatitis C virus (HCV)-related chronic liver disease and patients undergoing hemodialysis and 2) demonstrate the clinical effect of SEN virus infection on coexistent hepatitis C in terms of severity and probability of developing hepatocellular carcinoma. Polymerase chain reaction was used to detect SEN virus-D and SEN virus-H DNA in serum samples of 74 patients with HCV-related chronic liver disease, 45 uremic patients undergoing maintenance hemodialysis, and 28 healthy controls. SEN virus-D/H DNA was detected in 13.5% of patients with chronic liver disease, 11.1% of patients undergoing hemodialysis, and 7.1% of healthy controls, with no significant differences between patients and the control group. Clinical and biochemical measures did not significantly differ between SEN virus-infected and noninfected patients in the chronic liver disease group or the hemodialysis group. The rate of SEN virus infection was significantly higher in patients with chronic liver disease and hepatocellular carcinoma (33.3%) than in those with chronic liver disease only (8.5%) (P < .05). In conclusion, SEN virus does not seem to be a common infection in Egyptian patients. It has no apparent influence on the severity of coexistent HCV-related chronic liver disease but could be a risk factor for hepatocellular carcinoma in such patients. Further studies are needed to define the etiopathogenic role of SEN virus infection in the development of hepatocellular carcinoma.

Cirrhosis after orthotopic liver transplantation in the absence of primary disease recurrence.

Liver allograft cirrhosis is a relatively uncommon complication of liver transplantation. Most cases can be attributed to disease recurrence, particularly recurrent hepatitis C. Little is known about the frequency, etiology, and natural history of liver allograft cirrhosis occurring without evidence of recurrent disease. The aim of the present study was to review the clinicopathological features in this group of patients. We retrospectively reviewed data from all adult patients who were transplanted between 1982 and 2002 and survived >12 months after orthotopic liver transplantation (n = 1,287). Cases of histologically proven cirrhosis were identified from histopathological data entered into the Liver Unit Database. A total of 48 patients (3.7%) developed cirrhosis. In 29 of them, cirrhosis could be attributed to recurrent disease (hepatitis C, 11; hepatitis B, 4; autoimmune hepatitis, 4; primary biliary cirrhosis, 2; primary sclerosing cholangitis, 3; nonalcoholic steatohepatitis, 4; alcoholic liver disease, 1). In 9 of the 19 patients without evidence of disease recurrence, another cause of cirrhosis could be identified (de novo autoimmune hepatitis, 4; biliary complications, 4; acquired hepatitis B, 1). In the remaining 10 cases, the cause of cirrhosis remained unknown; their previous biopsies had shown features of chronic hepatitis of uncertain etiology. Three patients in this group died, and the remaining 7 are alive with good graft function 3-12 years after cirrhosis was first diagnosed. The prevalence of "cryptogenic" posttransplant cirrhosis was significantly higher in patients initially transplanted for fulminant seronegative hepatitis (6%) than in those transplanted for other diseases (0.3%). In conclusion, posttransplant cirrhosis without disease recurrence is uncommon, but it is more frequent in patients transplanted for fulminant seronegative hepatitis. Chronic hepatitis is the most frequent underlying pathological process in cases where the cause of cirrhosis remains uncertain.

Denver peritoneovenous shunt in the management of refractory ascites due to chronic liver diseases: impact of patients selection on its outcome.

Forty four patients with refractory ascites due to chronic liver diseases that fulfilling the inclusion criteria of selection were divided into 2 groups. The first group (GI, n=24) was subdivided into 2 subgroups according to degree of liver condition; GIa (n=11) with Child-Pugh class B and GIb (n=13) with early class C. The patients were subjected to P-V shunt (Denver group). Similarly, patients in the second group (GII, n=20) were divided into 2 subgroups GIIa (n=10) & GIIb (n=10) respectively and treated by the repeated tapping and albumin infusion (control group). Postoperative results revealed a significant increase in urine out put (P<0.001), decrease in abdominal girth (P<0.01) and body weight (p<0.01) with more patients fitness and satisfaction than in controls. Postoperative complications were more in GIb. Ascites recurrence occurred in 3 (23%) patients in GIb due to severe infection (2 cases) and irreversible shunt obstruction (1 case) and without recurrence in GIa. So, Denver P-V shunt offers a good palliation in such patients, but its use is more justified in selected cases.

Blood lactate but not serum phosphate levels can predict patient outcome in fulminant hepatic failure.

Early identification of those patients with fulminant hepatic liver failure (FHF) who need a transplant greatly helps in their management. A number of prognostic criteria have recently been proposed, including arterial blood lactate and serum phosphate concentrations. To validate their use, we retrospectively studied 83 consecutive patients with FHF admitted to our intensive treatment unit between August 2000 and March 2003. A total of 48 patients (58%) survived with medical management only (group I) and 35 patients (42%) failed to survive spontaneously (group II). This group included 19 patients (23%) who underwent orthotopic liver transplantation (LT), and 16 patients (19%) who died without undergoing LT (group IIa). A total of 5 patients (6%) who underwent liver transplantation died. Within paracetamol overdose (POD) and non-POD subgroups, phosphate concentrations were not significantly higher in group II patients (P = 0.08 and P = 0.27, respectively), when compared to group I patients. In multivariate analysis, post admission 12-hour lactate level was the only predictor of survival for the POD subgroup, whereas in non-POD patients, 12-hour lactate and admission bilirubin levels were significant in predicting patients' outcome. In conclusion, we found that while serum phosphate concentrations have limited clinical utility as prognostic markers, persistently elevated arterial blood lactate levels despite adequate fluid resuscitation are indicators of a poor prognosis in FHF.