Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs.Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.

Hepatocellular carcinoma incidence post direct-acting antivirals in hepatitis C-related advanced fibrosis/cirrhosis patients in Australia

Background:Despite efficacy in HCV eradication,direct-acting antiviral(DAA)therapy has raised controversies around their impact on hepatocellular carcinoma(HCC)incidence.Herein we reported the first Australian data on HCC incidence in DAA-treated HCV patients with advanced fibrosis/cirrhosis.Methods:We conducted a retrospective single center study of DAA-treated HCV patients with advanced fibrosis/cirrhosis from April 2015 to December 2017.Patients with prior HCC were included if they had complete response to HCC treatment.Results:Among 138 patients who completed DAA therapy,133(96.4%)achieved sustained virologic response(median follow-up 23.8 months).Ten had prior HCC and 5/10(50.0%)developed recurrence,while de novo HCC developed in 7/128(5.5%).Median time from DAA to HCC diagnosis was 34 weeks in recurrent HCC vs.de novo 52 weeks(P=0.159).In patients with prior HCC,those with recurrence(vs.without)had shorter median time between last HCC treatment and DAA(12 vs.164 weeks,P<0.001).On bivariate analysis,failed sustained virologic response at 12 weeks(SVR12)(P=0.011),platelets(P=0.005),model for end-stage liver disease(MELD)score(P=0.029),alpha fetoprotein(AFP)(P=0.013),and prior HCC(P<0.001)were associated with HCC post-DAA.On multivariate analysis,significant factors were prior HCC(OR=4.80;95%CI:1.47–48.50;P=0.010),failed SVR12(OR=2.83;95%CI:1.71–16.30;P=0.016)and platelets(OR=0.97;95%CI:0.95–0.99;P=0.009).Conclusions:Our study demonstrates a high incidence of recurrent HCC in HCV patients with advanced fibrosis/cirrhosis treated with DAA.Factors associated with HCC development post-DAA were more advanced liver disease,failed SVR12 and prior HCC,with higher rates of recurrence in those who started DAA earlier.

Serum 25-hydroxyvitamin D deficiency and hepatic encephalopathy in chronic liver disease

To investigate the relationship between 25-hydroxyvitamin D (25-OHD) deficiency and hepatic encephalopathy (HE) in patients with chronic liver disease (CLD). METHODSA retrospective analysis of the results of 392 adult patients with chronic liver disease who were assessed for liver transplantation between 2006 and 2010 was undertaken. HE, severity of CLD, nutritional status and 25-OHD were analysed in patients assessed for liver transplantation between 2006 and 2010. Patients who presented with acute, fulminant or subacute disease, with a primary diagnosis of liver cancer, were assessed for re-transplantation or who did not have a 25-OHD measurement were excluded from the analysis. RESULTSOne hundred and sixty-five patients were included in this analysis. The mean age of all patients was 53 ± 8 years. Moderate to severe 25-OHD deficiency was identified in 49 patients of whom 36 had grade 2-3 HE compared with 13 patients who were not encephalopathic (P ≤ 0.0001). Mild 25-OHD deficiency was not associated with HE. There was a significant correlation between the severity of 25-OHD deficiency and the severity of liver disease (r = 0.39, P ≤ 0.0001) and disease severity and the presence of HE (P ≤ 0.0001). Importantly, individuals with 25-OHD deficiency were more likely to have a diagnosis of overt HE (OHE) at a significantly lower model for end stage liver disease (MELD) score than individuals without OHE (P ≤ 0.0001). This significant difference was observed with MELD scores from 10 to 38. CONCLUSION25-OHD deficiency was observed in the majority of patients with CLD and for the first time was found to be significantly worse in patients with OHE.