5-fold, but only 16-fold in Cyp7a1-tg mice In fatty acid synthe

5-fold, but only 1.6-fold in Cyp7a1-tg mice. In fatty acid synthesis pathway, a FXR target gene fatty acid synthase (FAS) was strongly induced, but the rate-limiting enzyme acetyl-CoA carboxylase (ACC) was induced only 90% in Cyp7a1-tg mice versus WT mice. However, microarray analysis did not indicate differential expression of any fatty acid synthesis genes, and IPA did not identify fatty acid metabolism as a top regulated pathway. Interestingly, mRNA levels of CD36, a major hepatic fatty Panobinostat acid transporter, were reduced in Cyp7a1-tg. Peroxisome proliferator-activated

receptor gamma (PPARγ), involved in the induction of hepatic fatty acid synthesis, was markedly reduced in both chow- and WD-fed Cyp7a1-tg mice. Liver pyruvate kinase (L-PK) and carbohydrate

response element-binding protein (ChREBP), involved in lipogenesis, were increased in chow-fed, but this website decreased in WD-fed, Cyp7a1-tg mice, compared to respective WT mice. These data suggest that reduced free fatty transport to hepatocytes and fatty acid synthesis in hepatocytes may prevent hepatic steatosis in Cyp7a1-tg mice. Given that induction of hepatic bile acid synthesis in Cyp7a1-tg mice is associated with increased expression of cholesterologenic and lipogenic genes, we injected 14C-labeled sodium acetate to chow-fed WT and Cyp7a1-tg mice to study hepatic fatty acid and cholesterol synthesis rate. As estimated by pmole of 14C-acetate incorporated into fatty acids and sterols, Fig.

1A shows that acetyl-CoA was mainly used for fatty acid synthesis in WT liver. Interestingly, cholesterol synthesis rate was increased ∼12-fold, whereas fatty acid synthesis rate was decreased ∼60% in Cyp7a1-tg mice, resulting in approximately equal incorporation of 14C-acetate into cholesterol and fatty acids. During the postprandial state, acetyl-CoA derived from glycolysis is used for both lipogenesis and cholesterologenesis. Induction acetylcholine of cholesterol synthesis provides cholesterol substrate to stimulate CYP7A1 activity and bile acid synthesis and, subsequently, stimulates fecal excretion of cholesterol and bile acids. To test the potential contribution of this route to hepatic lipid metabolism, we administered 14C-glucose to mice and measured 14C radioactivity in fecal neutral and acidic sterols. Figure 1B shows that fecal 14C radioactivity in neutral, acidic, and total sterols was markedly and rapidly increased in day 1 in Cyp7a1-tg mice, compared to WT mice. Fecal samples from Cyp7a1-tg mice contained significantly higher 14C radioactivity, accounting for ∼15% of 14C-glucose administered, compared to WT mice feces, which contained only ∼2% of 14C-glucose administered. In addition, the majority of fecal 14C radioactivity was recovered as neutral sterols. Fecal acidic sterols (bile acids) were increased 2-fold in Cyp7a1-tg mice.

5-fold, but only 16-fold in Cyp7a1-tg mice In fatty acid synthe

5-fold, but only 1.6-fold in Cyp7a1-tg mice. In fatty acid synthesis pathway, a FXR target gene fatty acid synthase (FAS) was strongly induced, but the rate-limiting enzyme acetyl-CoA carboxylase (ACC) was induced only 90% in Cyp7a1-tg mice versus WT mice. However, microarray analysis did not indicate differential expression of any fatty acid synthesis genes, and IPA did not identify fatty acid metabolism as a top regulated pathway. Interestingly, mRNA levels of CD36, a major hepatic fatty LDE225 order acid transporter, were reduced in Cyp7a1-tg. Peroxisome proliferator-activated

receptor gamma (PPARγ), involved in the induction of hepatic fatty acid synthesis, was markedly reduced in both chow- and WD-fed Cyp7a1-tg mice. Liver pyruvate kinase (L-PK) and carbohydrate

response element-binding protein (ChREBP), involved in lipogenesis, were increased in chow-fed, but find more decreased in WD-fed, Cyp7a1-tg mice, compared to respective WT mice. These data suggest that reduced free fatty transport to hepatocytes and fatty acid synthesis in hepatocytes may prevent hepatic steatosis in Cyp7a1-tg mice. Given that induction of hepatic bile acid synthesis in Cyp7a1-tg mice is associated with increased expression of cholesterologenic and lipogenic genes, we injected 14C-labeled sodium acetate to chow-fed WT and Cyp7a1-tg mice to study hepatic fatty acid and cholesterol synthesis rate. As estimated by pmole of 14C-acetate incorporated into fatty acids and sterols, Fig.

1A shows that acetyl-CoA was mainly used for fatty acid synthesis in WT liver. Interestingly, cholesterol synthesis rate was increased ∼12-fold, whereas fatty acid synthesis rate was decreased ∼60% in Cyp7a1-tg mice, resulting in approximately equal incorporation of 14C-acetate into cholesterol and fatty acids. During the postprandial state, acetyl-CoA derived from glycolysis is used for both lipogenesis and cholesterologenesis. Induction Clomifene of cholesterol synthesis provides cholesterol substrate to stimulate CYP7A1 activity and bile acid synthesis and, subsequently, stimulates fecal excretion of cholesterol and bile acids. To test the potential contribution of this route to hepatic lipid metabolism, we administered 14C-glucose to mice and measured 14C radioactivity in fecal neutral and acidic sterols. Figure 1B shows that fecal 14C radioactivity in neutral, acidic, and total sterols was markedly and rapidly increased in day 1 in Cyp7a1-tg mice, compared to WT mice. Fecal samples from Cyp7a1-tg mice contained significantly higher 14C radioactivity, accounting for ∼15% of 14C-glucose administered, compared to WT mice feces, which contained only ∼2% of 14C-glucose administered. In addition, the majority of fecal 14C radioactivity was recovered as neutral sterols. Fecal acidic sterols (bile acids) were increased 2-fold in Cyp7a1-tg mice.

Fresh frozen plasma and cryoprecipitates were traditionally the p

Fresh frozen plasma and cryoprecipitates were traditionally the principal treatments for patients with inherited clotting factor deficiencies. The revolutionary development of plasma-derived clotting factor concentrates (pdCFCs), via the fractionation of plasma [66], provided benefits for both haemophilia treaters and patients and enabled the widespread adoption of home treatment [67]. Large blood donor pools of up to 30 000 donations were used as a source of plasma to manufacture pdCFCs

and at the time there were no virucidal procedures or specific tests for infectious agents [68]. This led to an epidemic in the 1970s and early 1980s, with large numbers NVP-AUY922 of people with bleeding disorders becoming infected with blood-borne viruses such as hepatitis C virus (HCV) and HIV ERK inhibitor [66]. High infection rates were seen among haemophilia patients, particularly in those with severe haemophilia. Approximately 60% of patients were reported to have been infected with HIV [69] and almost 100% of patients treated with CFCs derived from pooled blood products developed non-A non-B hepatitis (today known as hepatitis C) [70]. Some countries with a national plasma supply had better

control of plasma and donors, and therefore were able to limit these epidemics. During this time, patients were also exposed to hepatitis B virus (HBV) infection, although symptomatic infection remains uncommon in haemophilia patients [71]. The high rates of infection observed within the haemophilia population had a significant impact on mortality rates. In the UK, prior to 1984, annual mortality for patients with haemophilia was Thymidine kinase 0.9% for severe disease and 0.4% for mild/moderate haemophilia. Post-1984 this remained relatively constant for patients without HIV, but increased progressively in patients infected with HIV to a maximum

of 12.7% for severe patients in 1994 and 13.1% for mild/moderate patients in 1996 (Fig. 4). The decrease in annual mortality rates after this period was due in part to the introduction of highly active antiretroviral therapy [72], and also to the introduction of screening procedures for HIV infection, starting from 1986. HCV complications also affected mortality rates. For example, in a UK cohort study, the mortality rates due to liver disease and liver cancer were found to be 16.7-times and 5.6-times higher, respectively, for haemophilia patients than in the general population [73]. Overall, the infection of haemophilia patients with HIV and HCV has placed severe health, economic and emotional burdens on affected patients and families, as well as on the wider bleeding disorders community [74]. The viral epidemic associated with pdCFCs acted as a trigger within the patient community and industry to drive the improvement of the processes involved in their manufacture.

Therefore, truncated Bid may preferentially activate Bak rather t

Therefore, truncated Bid may preferentially activate Bak rather than Bax in the liver. However, the present study also reveals that, in the absence of Bak, Bax plays an essential role in mediating the early onset of hepatocellular apoptosis. The most important finding of this study is that Bak/Bax deficiency failed to protect against the late onset of liver injury after Jo2 anti-Fas injection as well as Fas agonist injection. Wei et al.,32 in their historical paper establishing the importance of Bak and Bax in the mitochondrial pathway of apoptosis, reported

that hepatocytes were protected from Jo2-induced apoptosis in traditional Bak/Bax DKO mice (bak−/−bax−/−). Because perinatal lethality occurs with most CHIR-99021 nmr traditional Bak/Bax DKO mice, they could only analyze three animals, which did not enable detailed analysis of cell death due to Jo2 stimulation. The present study is the first to (1) thoroughly examine the impact of Bak and Bax in the liver using conditional KO mice and (2) demonstrate that Bak/Bax deficiency can protect against Fas-induced severe

injury in the early phase but not in the late phase. The late onset of liver injury Z VAD FMK observed in Bak/Bax DKO appeared to be apoptosis based on biochemical and morphological observations, including caspase activation, oligonucleosomal DNA breaks and, most importantly, identification of cell death with caspase dependency. In Tangeritin addition, the well-established necrotic pathway mediated by RIP kinase and/or CypD was not involved. However, the difference from apoptosis observed in Bak KO mice was the absence of mitochondrial alteration or cytochrome c–dependent caspase-9 processing in Bak/Bax DKO mice. We also confirmed that Bak/Bax-deficient mitochondria were not capable of releasing cytochrome c in the presence of truncated Bid (Supporting Fig. 5). These data support the idea that activation of the mitochondrial pathway of apoptosis is fully dependent on either Bak or Bax even in the late phase,

indicating at the same time that late onset of apoptosis takes place through an extrinsic pathway rather than the mitochondrial pathway. Although hepatocytes are generally considered to be type II cells, recent work has shown that the requirement of the mitochondrial pathway may be overcome through changes induced by in vitro culture conditions33, 34 or the strength of Fas stimulation.23 Schüngel et al.23 demonstrated that hepatocytes act as type II cells with a low-dose Jo2 injection (0.5 mg/kg) and act as type I cells with an extremely high-dose Jo2 injection (5 mg/kg). This agrees with the generally accepted idea that type I cells exhibit strong activation of DISC and caspase-8, which itself is sufficient to induce apoptosis, whereas type II cells exhibit weak activation and therefore require amplification of the apoptosis signal through the mitochondrial loop. In the present study, we used 1.5 mg/kg or 0.

Importantly, we implicate a putative role for the hepatic innate

Importantly, we implicate a putative role for the hepatic innate immune

system. The experimental design allowed us to investigate the relative influence of maternal obesity versus a postnatal obesogenic environment on progression of the NAFLD phenotype. The postweaning Chk inhibitor obesogenic diet had the greater influence on adiposity, hepatosteatosis, and markers of liver injury and fibrosis; however, there was an independent effect of maternal diet and a significant interaction between maternal and postweaning environments, which led to the most profound degree of liver injury observed. Moreover, we also observed that this disorder progressed with age. At 3 months, there was evidence of offspring obesity, adiposity, hepatosteatosis, and up-regulation of IL-6, TNF-α, and α-SMA as biochemical

markers of liver injury and fibrosis. By 12 months, there was more-profound evidence of hepatosteatosis, as assessed by the biochemical Selleckchem FDA-approved Drug Library markers and histological evidence of liver injury and fibrosis. We previously reported that offspring of obese mouse dams, when weaned onto standard chow, despite displaying hypertensive and dysmetabolic characteristics, did not exhibit a robust fatty liver phenotype.3 Here, we report similar hepatic tissue TG content Meloxicam in OffOb-SC, compared to controls, corroborated by histological steatosis assessment. Our findings parallel the findings of Bruce et al.,5 who reported hepatosteatosis in offspring exposed to maternal high-fat diet and weaned onto high-fat chow. OffOb-OD display

an accelerated and exaggerated liver phenotype, compared to offspring exposed only to a postweaning obesogenic diet. Therefore, taken together, the evidence suggests that developmental programming by diet-induced maternal obesity sensitizes the liver to the deleterious consequences of a second postnatal dietary challenge. Whereas Bruce et al. implicated phenotypic propagation of the liver phenotype by hepatic mitochondrial dysfunction and lipogenesis gene priming, we now suggest that maternal diet-induced obesity may also program offspring susceptibility to NAFLD by perturbation of the innate immune system. Offspring of obese dams reared on a hypercalorific diet, despite demonstrating increased KC numbers, showed impaired KC phagocytic activity and increased KC ROS production, which also revealed an apparent interaction between the maternal and postnatal environments. The current paradigm for the pathogenesis of NAFLD holds fat accumulation as a prerequisite for disease development.

Importantly, we implicate a putative role for the hepatic innate

Importantly, we implicate a putative role for the hepatic innate immune

system. The experimental design allowed us to investigate the relative influence of maternal obesity versus a postnatal obesogenic environment on progression of the NAFLD phenotype. The postweaning http://www.selleckchem.com/products/Adriamycin.html obesogenic diet had the greater influence on adiposity, hepatosteatosis, and markers of liver injury and fibrosis; however, there was an independent effect of maternal diet and a significant interaction between maternal and postweaning environments, which led to the most profound degree of liver injury observed. Moreover, we also observed that this disorder progressed with age. At 3 months, there was evidence of offspring obesity, adiposity, hepatosteatosis, and up-regulation of IL-6, TNF-α, and α-SMA as biochemical

markers of liver injury and fibrosis. By 12 months, there was more-profound evidence of hepatosteatosis, as assessed by the biochemical Stem Cells inhibitor markers and histological evidence of liver injury and fibrosis. We previously reported that offspring of obese mouse dams, when weaned onto standard chow, despite displaying hypertensive and dysmetabolic characteristics, did not exhibit a robust fatty liver phenotype.3 Here, we report similar hepatic tissue TG content Nintedanib (BIBF 1120) in OffOb-SC, compared to controls, corroborated by histological steatosis assessment. Our findings parallel the findings of Bruce et al.,5 who reported hepatosteatosis in offspring exposed to maternal high-fat diet and weaned onto high-fat chow. OffOb-OD display

an accelerated and exaggerated liver phenotype, compared to offspring exposed only to a postweaning obesogenic diet. Therefore, taken together, the evidence suggests that developmental programming by diet-induced maternal obesity sensitizes the liver to the deleterious consequences of a second postnatal dietary challenge. Whereas Bruce et al. implicated phenotypic propagation of the liver phenotype by hepatic mitochondrial dysfunction and lipogenesis gene priming, we now suggest that maternal diet-induced obesity may also program offspring susceptibility to NAFLD by perturbation of the innate immune system. Offspring of obese dams reared on a hypercalorific diet, despite demonstrating increased KC numbers, showed impaired KC phagocytic activity and increased KC ROS production, which also revealed an apparent interaction between the maternal and postnatal environments. The current paradigm for the pathogenesis of NAFLD holds fat accumulation as a prerequisite for disease development.

Importantly, we implicate a putative role for the hepatic innate

Importantly, we implicate a putative role for the hepatic innate immune

system. The experimental design allowed us to investigate the relative influence of maternal obesity versus a postnatal obesogenic environment on progression of the NAFLD phenotype. The postweaning learn more obesogenic diet had the greater influence on adiposity, hepatosteatosis, and markers of liver injury and fibrosis; however, there was an independent effect of maternal diet and a significant interaction between maternal and postweaning environments, which led to the most profound degree of liver injury observed. Moreover, we also observed that this disorder progressed with age. At 3 months, there was evidence of offspring obesity, adiposity, hepatosteatosis, and up-regulation of IL-6, TNF-α, and α-SMA as biochemical

markers of liver injury and fibrosis. By 12 months, there was more-profound evidence of hepatosteatosis, as assessed by the biochemical Sorafenib molecular weight markers and histological evidence of liver injury and fibrosis. We previously reported that offspring of obese mouse dams, when weaned onto standard chow, despite displaying hypertensive and dysmetabolic characteristics, did not exhibit a robust fatty liver phenotype.3 Here, we report similar hepatic tissue TG content Buspirone HCl in OffOb-SC, compared to controls, corroborated by histological steatosis assessment. Our findings parallel the findings of Bruce et al.,5 who reported hepatosteatosis in offspring exposed to maternal high-fat diet and weaned onto high-fat chow. OffOb-OD display

an accelerated and exaggerated liver phenotype, compared to offspring exposed only to a postweaning obesogenic diet. Therefore, taken together, the evidence suggests that developmental programming by diet-induced maternal obesity sensitizes the liver to the deleterious consequences of a second postnatal dietary challenge. Whereas Bruce et al. implicated phenotypic propagation of the liver phenotype by hepatic mitochondrial dysfunction and lipogenesis gene priming, we now suggest that maternal diet-induced obesity may also program offspring susceptibility to NAFLD by perturbation of the innate immune system. Offspring of obese dams reared on a hypercalorific diet, despite demonstrating increased KC numbers, showed impaired KC phagocytic activity and increased KC ROS production, which also revealed an apparent interaction between the maternal and postnatal environments. The current paradigm for the pathogenesis of NAFLD holds fat accumulation as a prerequisite for disease development.

Dynamics of the gene expression profiles responsible for the carc

Dynamics of the gene expression profiles responsible for the carcinogenesis are not fully understood.

The current study was designed to determine the serial changes of gene expression profiles and genetic and epigenetic modifications responsible for hepatocarcinogenesis in the model of chronic immune-mediated hepatitis. METHODS: Three-month-old HBV transgenic mice were immunologically reconstituted with bone marrow cells and splenocytes from syngeneic nontransgenic donors. Liver tissues were obtained every PD-332991 three months until 18 months at which time all mice developed multiple liver tumors. Oxi-dative DNA damage and hepatocyte turnover were assessed immunohistochemically. Gene expression profiles were developed by extracting total RNA from the tissues and analyzing by microarray (44 K genes, Agilent). Genomic DNA was enriched for methylated fragments and the epigenetic changes were detected, and targeted gene exomes were captured and sequenced using next-generation sequencing technology (HiSeq 2000, Illumina). RESULTS: Oxidative DNA damage (8-OHdG and 4-HNE) and hepatocyte turnover (PCNA) were increased during the progression of chronic liver disease. In a gene expression profile analysis of liver samples, nine of

gene groups with different time courses were identified by K-means clustering (P < 0.01). Although the expression levels of one group with 119 genes (cluster #2) were not changed PJ34 HCl in inflamed tissue at early time points (< 3 months) and chronic Selleck RG 7204 phases (6 – 12 months), the levels were decreased in noncan-cerous tissues in the late phase (15 – 18 months) and further

reduced in liver tumors. Of the cluster #2 genes, the hyper-methylated sites were seen at CpG islands around the coding sequences and multiple non-synonymous mutations above 1% frequency were detected in Cyp26a1, Nr2f6 and Hsd3b7 genes, all of which were involved in the catalytic and binding activity of iron, DNA or steroid. CONCLUSIONS: Chronic immune-mediated hepatitis enhances oxidative DNA damage and hepatocellular turnover in which hypermethylation and non-synonymous mutations were induced in three genes with catalytic properties of a cluster down-regulated in the late phase of liver disease. The resulting molecules may be primarily involved in malignant transformation of hepatocytes in the process of tumor development. Disclosures: Shuichi Kaneko – Grant/Research Support: MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Ajinomoto Co., Inc, MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Ajinomoto Co.

Dynamics of the gene expression profiles responsible for the carc

Dynamics of the gene expression profiles responsible for the carcinogenesis are not fully understood.

The current study was designed to determine the serial changes of gene expression profiles and genetic and epigenetic modifications responsible for hepatocarcinogenesis in the model of chronic immune-mediated hepatitis. METHODS: Three-month-old HBV transgenic mice were immunologically reconstituted with bone marrow cells and splenocytes from syngeneic nontransgenic donors. Liver tissues were obtained every Nutlin-3 three months until 18 months at which time all mice developed multiple liver tumors. Oxi-dative DNA damage and hepatocyte turnover were assessed immunohistochemically. Gene expression profiles were developed by extracting total RNA from the tissues and analyzing by microarray (44 K genes, Agilent). Genomic DNA was enriched for methylated fragments and the epigenetic changes were detected, and targeted gene exomes were captured and sequenced using next-generation sequencing technology (HiSeq 2000, Illumina). RESULTS: Oxidative DNA damage (8-OHdG and 4-HNE) and hepatocyte turnover (PCNA) were increased during the progression of chronic liver disease. In a gene expression profile analysis of liver samples, nine of

gene groups with different time courses were identified by K-means clustering (P < 0.01). Although the expression levels of one group with 119 genes (cluster #2) were not changed Pyruvate dehydrogenase lipoamide kinase isozyme 1 in inflamed tissue at early time points (< 3 months) and chronic Acalabrutinib datasheet phases (6 – 12 months), the levels were decreased in noncan-cerous tissues in the late phase (15 – 18 months) and further

reduced in liver tumors. Of the cluster #2 genes, the hyper-methylated sites were seen at CpG islands around the coding sequences and multiple non-synonymous mutations above 1% frequency were detected in Cyp26a1, Nr2f6 and Hsd3b7 genes, all of which were involved in the catalytic and binding activity of iron, DNA or steroid. CONCLUSIONS: Chronic immune-mediated hepatitis enhances oxidative DNA damage and hepatocellular turnover in which hypermethylation and non-synonymous mutations were induced in three genes with catalytic properties of a cluster down-regulated in the late phase of liver disease. The resulting molecules may be primarily involved in malignant transformation of hepatocytes in the process of tumor development. Disclosures: Shuichi Kaneko – Grant/Research Support: MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Ajinomoto Co., Inc, MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Ajinomoto Co.

Kowdley – Advisory Committees or Review Panels: AbbVie, Gilead, M

Kowdley – Advisory Committees or Review Panels: AbbVie, Gilead, Merck, Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria, Janssen, Merck, Mochida, Vertex Stefan Zeuzem – Consulting: Abbvie, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen, Roche Pharma AG, Vertex Pharmaceuticals The following people have nothing to disclose: Zobair Younossi, Maria Ste-panova, Sharon L. Hunt

Hepatitis C is the commonest cause of hepatocellular cancer (HCC) in the US and the incidence is expected to increase further as the HCV population ages and develops more cirrhosis. Management of HCC is GPCR Compound Library clinical trial very heterogenous with multiple non-surgical and surgical options. The true cost of care of the HCV patient with HCC is unknown. AIMS: To evaluate the total direct health care costs of different approaches to HCC care in HCV patients in a major referral and transplant center. METHODS: 101 patients were randomly selected by computer from a list of all HCC patients with HCV between 2003 and 2013. All patients were biopsy-proven HCC or met UNOS OPTN criteria. Patients were categorized by the primary treatment

modality of TACE, Cyberknife radiotherapy, radiofrequency abalation (RFA), chemotherapy or resection. Patients could have multiple

treatment modalities and also go on to liver transplant, which is considered as a separate modality for cost determination. MAPK inhibitor The direct cost includes the cost of the procedure, imaging, hospitalizations and all subsequent care of the HCC patient until either death or transplant including cost of HCV treatment and immunosuppression post-transplant. Costs were derived from the Medicare fee schedule abstracted SPTBN5 from the HCUP NIS sample 2011. Medication costs used were wholesale acquisition costs (Redbook 2014). RESULTS: 101 patients, 82 male mean age 59years (range 49-82) were included. All had HCV cirrhosis at diagnosis with a median CTP score of 7 ( range 5-11) and a median MELD of 8. Genotype 1 (74%) and genotype 3 (16%) were predominant. 31 patients were HCV treatment naïve, 65 treatment failures and 4 had had a prior SVR. Majority of HCC were detected through cross-sectional radiological screening programs. Liver staging using the Barcelona score was A1 20%; A2 18%; A3 16% and A4 27%; B 12% and C 7%. Tumor size was mean 2.8cms with a range from 1 – 14cms. Mean follow up was 32 months with a range from 4 – 118 and 37 patients have died. Initial primary treatment modalities were RFA 53%; TACE 26%; Cyberknife 10%, resection 8% and chemotherapy 2%. 43 patients went on to liver transplantation.