Portal hypertension in patients with nonalcoholic fatty liver disease:Current knowledge and challenges

Portal hypertension(PH)has traditionally been observed as a consequence of significant fibrosis and cirrhosis in advanced non-alcoholic fatty liver disease(NAFLD).However,recent studies have provided evidence that PH may develop in earlier stages of NAFLD,suggesting that there are additional pathogenetic mechanisms at work in addition to liver fibrosis.The early development of PH in NAFLD is associated with hepatocellular lipid accumulation and ballooning,leading to the compression of liver sinusoids.External compression and intraluminal obstacles cause mechanical forces such as strain,shear stress and elevated hydrostatic pressure that in turn activate mechanotransduction pathways,resulting in endothelial dysfunction and the development of fibrosis.The spatial distribution of histological and functional changes in the periportal and perisinusoidal areas of the liver lobule are considered responsible for the pre-sinusoidal component of PH in patients with NAFLD.Thus,current diagnostic methods such as hepatic venous pressure gradient(HVPG)measurement tend to underestimate portal pressure(PP)in NAFLD patients,who might decompensate below the HVPG threshold of 10 mmHg,which is traditionally considered the most relevant indicator of clinically significant portal hypertension(CSPH).This creates further challenges in finding a reliable diagnostic method to stratify the prognostic risk in this population of patients.In theory,the measurement of the portal pressure gradient guided by endoscopic ultrasound might overcome the limitations of HVPG measurement by avoiding the influence of the pre-sinusoidal component,but more investigations are needed to test its clinical utility for this indication.Liver and spleen stiffness measurement in combination with platelet count is currently the best-validated non-invasive approach for diagnosing CSPH and varices needing treatment.Lifestyle change remains the cornerstone of the treatment of PH in NAFLD,together with correcting the components of metabolic syndrome,using nonselective beta blockers,whereas emerging candidate drugs require more robust confirmation from clinical trials.

Liver regeneration as treatment target for severe alcoholic hepatitis

Severe alcoholic hepatitis(AH)is a distinct entity in the spectrum of alcoholrelated liver disease,with limited treatment options and high mortality.Supportive medical care with corticosteroids in selected patients is the only currently available treatment option,often with poor outcomes.Based on the insights into the pathogenetic mechanisms of AH,which are mostly obtained from animal studies,several new treatment options are being explored.Studies have implicated impaired and deranged liver regeneration processes as one of the culprit mechanisms and a potential therapeutic target.Acknowledging evidence for the beneficial effects of granulocyte colony-stimulating factor(G-CSF)on liver regeneration and immunomodulation in animal models,several human studies investigated its role in the treatment of advanced alcohol-related liver disease and AH.Contrary to the previously published studies suggesting benefits of G-CSF in the outcomes of patients with severe AH,these effects were not confirmed by a recently published multicenter randomized trial,suggesting that other options should rather be pursued.Stem cell transplantation represents another option for improving liver regeneration,but evidence for its efficacy in patients with severe AH and advanced alcohol-related liver disease is still very scarce and unconvincing,with established lack of efficacy in patients with compensated cirrhosis.In this review,we summarize the current knowledge on the pathogenesis and experimental therapies targeting liver regeneration.The lack of high-quality studies and evidence is a major obstacle in further treatment development.New insights into the pathogenesis of not only liver injury,but also liver regeneration processes are mandatory for the development of new treatment options.A reliable experimental model of the pathogenesis of AH and processes involved in liver recovery is still missing,and data obtained from animal studies are essential for future research.