Intrahepatic Vascular Resistance Research Articles

The mechanical mechanism of angiotensin II induced activation of hepatic stellate cells promoting portal hypertension

In the development of chronic liver disease, the hepatic stellate cell (HSC) plays a pivotal role in increasing intrahepatic vascular resistance (IHVR) and inducing portal hypertension (PH) in cirrhosis. Our research demonstrated that HSC contraction, prompted by angiotensin II (Ang II), significantly contributed to the elevation of type I collagen (COL1A1) expression. This increase was intimately associated with enhanced cell tension and YAP nuclear translocation, mediated through α-smooth muscle actin (α-SMA) expression, microfilaments (MF) polymerization, and stress fibers (SF) assembly. Further investigation revealed that the Rho/ROCK signaling pathway regulated MF polymerization and SF assembly by facilitating the phosphorylation of cofilin and MLC, while Ca2+ chiefly governed SF assembly via MLC. Inhibiting α-SMA-MF-SF assembly changed Ang II-induced cell contraction, YAP nuclear translocation, and COL1A1 expression, findings corroborated in cirrhotic mice models. Overall, our study offers insights into mitigating IHVR and PH through cell mechanics, heralding potential breakthroughs.

Recent Advances in the Pathogenesis and Clinical Evaluation of Portal Hypertension in Chronic Liver Disease.

In chronic liver disease, hepatic stellate cell activation and degeneration of liver sinusoidal endothelial cells lead to structural changes, which are secondary to fibrosis and the presence of regenerative nodules in the sinusoids, and to functional changes, which are related to vasoconstriction. The combination of such changes increases intrahepatic vascular resistance and causes portal hypertension. The subsequent increase in splanchnic and systemic hyperdynamic circulation further increases the portal blood flow, thereby exacerbating portal hypertension. In clinical practice, the hepatic venous pressure gradient is the gold-standard measure of portal hypertension; a value of ≥10 mm Hg is defined as clinically significant portal hypertension, which is severe and is associated with the risk of liver-related events. Hepatic venous pressure gradient measurement is somewhat invasive, so evidence on the utility of risk stratification by elastography and serum biomarkers is needed. The various stages of cirrhosis are associated with different outcomes. In viral hepatitis-related cirrhosis, viral suppression or elimination by nucleos(t)ide analog or direct-acting antivirals results in recompensation of liver function and portal pressure. However, careful follow-up should be continued, because some cases have residual clinically significant portal hypertension even after achieving sustained virologic response. In this study, we reviewed the current and future prospects for portal hypertension.

5-MTHF enhances the portal pressure reduction achieved with propranolol in patients with cirrhosis: A randomized placebo-controlled trial

β-blockers reduce hepatic venous pressure gradient (HVPG) by decreasing portal inflow, with no reduction in intrahepatic vascular resistance. 5-Methyltetrahydrofolate (5-MTHF) can prevent oxidative loss of tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase coupling. It also converts homocysteine (tHcy) into methionine and enables the degradation of asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase. The aim of this study was to evaluate the effects of 5-MTHF in combination with propranolol on HVPG and nitric oxide bioavailability markers in patients with cirrhosis and portal hypertension. Sixty patients with cirrhosis and HVPG ≥12mmHg were randomized 1:1 to receive treatment with 5-MTHF+propranolol or placebo+propranolol for 90 days under double-blind conditions. HVPG and markers of nitric oxide bioavailability (BH4, ADMA and tHcy) were measured again at the end of treatment. Groups were similar in terms of baseline clinical and hemodynamic data and nitric oxide bioavailability markers. HVPG decreased in both groups, but the magnitude of the change was significantly greater in the group treated with 5-MTHF+propranolol compared to placebo+propranolol (percentage decrease, 20 [29-9] vs. 12.5 [22-0], p=0.028), without differences in hepatic blood flow. At the end of treatment, 5-MTHF+propranolol (vs. placebo+propranolol) was associated with higher BH4 (1,101.4 ± 1,413.3 vs. 517.1 ± 242.8pg/ml, p<0.001), lower ADMA (109.3 ± 52.7 vs. 139.9 ± 46.7μmol/L, p=0.027) and lower tHcy (μmol/L, 11.0 ± 4.6 vs. 15.4 ± 7.2μmol/L, p=0.010) plasma levels. In patients with cirrhosis and portal hypertension, 5-MTHF administration significantly enhanced the HVPG reduction achieved with propranolol. This effect appears to be mediated by improved nitric oxide bioavailability in the hepatic microcirculation. 2014-002018-21. Currently, the pharmacological prevention of cirrhosis complications due to portal hypertension, such as esophageal varices rupture, is based on the use of β-blockers, but some patients still present with acute variceal bleeding, mainly due to an insufficient reduction of portal pressure. In this study, we sought to demonstrate that the addition of folic acid to β-blockers is more effective in reducing portal pressure than β-blockers alone. This finding could represent the basis for validation studies in larger cohorts, which could impact the future prophylactic management of variceal bleeding in cirrhosis. Enhancing the benefit of β-blockers with a safe, accessible, cost-effective drug could improve clinical outcomes in cirrhosis, which in turn could translate into a reduction in the rates and costs of hospitalization, and ultimately into improved survival.

Editorial introductions.

Current Opinion in Gastroenterology was launched in 1985. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of gastroenterology is divided into 12 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Don RockeyDon RockeyDr Don Rockey completed internship, residency, chief residency, and fellowship at the University of California, San Francisco, USA. He is currently Director of the Medical University of South Carolina Digestive Disease Center. He has active, basic and clinical research interests in liver disease. His basic research focuses on understanding the molecular basis of fibrosis and portal hypertension. His laboratory initially demonstrated that a key player, the hepatic stellate cell, exhibits a contractile phenotype and transforms to a myofibroblast. Further, following liver injury, stellate cells not only produce increases quantities of extracellular matrix, but also exhibit exaggerated contractility, constrict liver sinusoids, and contribute to increased intrahepatic vascular resistance typical of portal hypertension. Dr Rockey also has an active clinical research program, focused on clinical management problems in gastrointestinal bleeding, drug induced liver injury, and chronic liver diseases including complications of portal hypertension. Dr Rockey and colleagues have published some 300 peer reviewed original scientific papers and over 100 editorials, reviews, and book chapters. He has served as a mentor for over 125 trainees, including students, residents, fellows, and junior faculty members - the vast majority of whom have pursued or who are pursuing careers in academic medicine. He has had a number of editorial responsibilities, including as Associate Editor for Hepatology, Liver International, and the Journal of Investigative Medicine, and has served on multiple NIH and other study sections, and editorial boards. Reena SidhuReena SidhuProf. Reena Sidhu is a Consultant Gastroenterologist and an Honorary Professor with the University of Sheffield, UK. Her main area of interest is the small bowel and she completed a clinical MD with the University of Sheffield on modern modalities of investigation of the small bowel. She is currently the lead for the tertiary double balloon enteroscopy service at Sheffield Teaching Hospitals and co-runs one of the biggest Capsule Endoscopy services in Europe. Both of these services are established regional services which have won national awards. She runs an international capsule endoscopy course for doctors. She carries out clinical research related to the small bowel and continues to publish actively in this field with > 100 Medline publications to date. She has research fellows under her banner. She is regularly invited to speak at national and international meetings. She has led an ESGE curriculum for Capsule and Device Assisted Enteroscopy. She has also been involved in formalizing accreditation for capsule endoscopy and enteroscopy in the UK. She was awarded the Hopkins Endoscopy Prize by the BSG in 2012, the first female gastroenterologist to have ever won this. She is the first author of the British Society of Gastroenterology guidelines on capsule endoscopy and enteroscopy, published in 2008 and is also a co-author on the 2023 ESGE guidelines on small bowel endoscopy. She also led a UK wide Position Statement on the use of Propofol sedation for complex endoscopy in the UK and a co-author on the BSG Iron Deficiency Anaemia Guidelines 2021. She is the current BSG Education Chair and has curated an entirely new platform for e-learning for gastroenterology in the UK during her tenure as the BSG Web Editor.

Editorial introductions.

Current Opinion in Gastroenterology was launched in 1985. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of gastroenterology is divided into 12 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Chantal HoussetChantal HoussetChantal Housset is Professor of Cell Biology at Sorbone Université, Paris, France, since 2000. She is Course Director of molecular and cellular biology at Sorbonne Université Medical School & Life Science Department. She is Hepatologist in the Reference Center for Inflammatory Biliary Diseases and Auto-immune Hepatitis, in Saint-Antoine Hospital, and of the Rare Liver Disease National Network (FILFOIE). She is the Head of an INSERM-Sorbonne Université Laboratory of translational research on metabolic and biliary diseases of the liver in Centre de Recherche Saint-Antoine (CRSA), Paris. Dr Housset is member of the University National Council (CNU) in Cell Biology. She published 193 articles. Her main scientific contributions relate to the pathophysiology of bile secretion and biliary diseases, the progression of metabolic and biliary diseases towards fibrosis, the origins and functions of myofibroblasts in the liver. Don C. RockeyDon C. RockeyDr Don Rockey completed internship, residency, chief residency, and fellowship at the University of California, San Francisco, USA. He is currently Director of the Medical University of South Carolina Digestive Disease Center. He has active, basic and clinical research interests in liver disease. His basic research focuses on understanding the molecular basis of fibrosis and portal hypertension. His laboratory initially demonstrated that a key player, the hepatic stellate cell, exhibits a contractile phenotype and transforms to a myofibroblast. Further, following liver injury, stellate cells not only produce increases quantities of extracellular matrix, but also exhibit exaggerated contractility, constrict liver sinusoids, and contribute to increased intrahepatic vascular resistance typical of portal hypertension. Dr Rockey also has an active clinical research program, focused on clinical management problems in gastrointestinal bleeding, drug induced liver injury, and chronic liver diseases including complications of portal hypertension. Dr Rockey and colleagues have published some 300 peer reviewed original scientific papers and over 100 editorials, reviews, and book chapters. He has served as a mentor for over 125 trainees, including students, residents, fellows, and junior faculty members - the vast majority of whom have pursued or who are pursuing careers in academic medicine. He has had a number of editorial responsibilities, including as Associate Editor for Hepatology, Liver International, and the Journal of Investigative Medicine, and has served on multiple NIH and other study sections, and editorial boards.

Editorial introductions.

Current Opinion in Gastroenterology was launched in 1985. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of gastroenterology is divided into 12 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Editor and Section Editors for this issue. EDITOR Don RockeyDon RockeyDr Don Rockey completed internship, residency, chief residency, and fellowship at the University of California, San Francisco, USA. He is currently Director of the Medical University of South Carolina Digestive Disease Center. He has active, basic and clinical research interests in liver disease. His basic research focuses on understanding the molecular basis of fibrosis and portal hypertension. His laboratory initially demonstrated that a key player, the hepatic stellate cell, exhibits a contractile phenotype and transforms to a myofibroblast. Further, following liver injury, stellate cells not only produce increases quantities of extracellular matrix, but also exhibit exaggerated contractility, constrict liver sinusoids, and contribute to increased intrahepatic vascular resistance typical of portal hypertension. Dr Rockey also has an active clinical research program, focused on clinical management problems in gastrointestinal bleeding, drug induced liver injury, and chronic liver diseases including complications of portal hypertension. Dr Rockey and colleagues have published some 300 peer reviewed original scientific papers and over 100 editorials, reviews, and book chapters. He has served as a mentor for over 125 trainees, including students, residents, fellows, and junior faculty members - the vast majority of whom have pursued or who are pursuing careers in academic medicine. He has had a number of editorial responsibilities, including as Associate Editor for Hepatology, Liver International, and the Journal of Investigative Medicine, and has served on multiple NIH and other study sections, and editorial boards. SECTION EDITOR Anthony BuckleyAnthony BuckleyDr Anthony Buckley, PhD, is a Lecturer in Microbiology at the University of Leeds, UK, and leads the Microbiome & Nutritional Sciences group. He also holds an honorary position at the Leeds Teaching Hospital Trust, NHS, UK. Dr Buckley obtained his PhD in Molecular Microbiology at the University of Birmingham, UK, where he investigated the role of efflux pumps towards Salmonella Typhimurium in vivo pathogenicity under the supervision of Professor Laura J. V. Piddock. Dr Buckley is passionate about student education and supporting early career researchers, and he sits on the steering committees for the Leeds Biofilm Network and [email protected] Network. The research interests of his group centers on influencing disease outcome by manipulating the human microbiota through probiotics and prebiotics. His group develops novel models of the human digestive tract to study the interactions between xenobiotics, microbe, and host, and determine the efficacy of novel drugs and biotherapeutics. He is an author on over 40 primary research articles, review articles, and book chapters. Russell D. CohenRussell D. CohenRussell D. Cohen, MD. FACG, AGAF is a Professor of Medicine at the Pritzker School of Medicine, in the Department of Medicine, Section of Gastroenterology at the University of Chicago, USA. Currently he is Director of the IBD Center and the Co-Director of the Advanced IBD Fellowship Program, and serves as Illinois Governor for the American College of Gastroenterology, USA. Dr Cohen earned his BS at Cornell University, USA, his MD with honors at Mount Sinai School of Medicine, USA, and his residency in internal medicine at Beth Israel Hospital/Harvard Medical School, USA, and his fellowship in gastroenterology and senior fellowship in IBD at the University of Chicago. He has been Principal or Co-Investigator for more than 185 research projects. He is an editor of three medical textbooks, and has authored more than 200 articles, abstracts, reviews, books, book chapters, and audiotapes. He is published in prestigious journals such as Gastroenterology, American Journal of Gastroenterology, and Inflammatory Bowel Diseases. He also is a reviewer for multiple journals, including New England Journal of Medicine, Gastroenterology, Gut, and American Journal of Gastroenterology, and is a member of multiple prestigious medical societies. Dr Cohen is named in Best Doctors in America, America's Top Gastroenterologists, Top Doctors in the Chicago Metro Area, and Chicago Magazine's Top Doctor in Gastroenterology.

Biodistribution Profile of Magnetic Nanoparticles in Cirrhosis-Associated Hepatocarcinogenesis in Rats by AC Biosusceptometry

Since magnetic nanoparticles (MNPs) have been used as multifunctional probes to diagnose and treat liver diseases in recent years, this study aimed to assess how the condition of cirrhosis-associated hepatocarcinogenesis alters the biodistribution of hepatic MNPs. Using a real-time image acquisition approach, the distribution profile of MNPs after intravenous administration was monitored using an AC biosusceptometry (ACB) assay. We assessed the biodistribution profile based on the ACB images obtained through selected regions of interest (ROIs) in the heart and liver position according to the anatomical references previously selected. The signals obtained allowed for the quantification of pharmacokinetic parameters, indicating that the uptake of hepatic MNPs is compromised during liver cirrhosis, since scar tissue reduces blood flow through the liver and slows its processing function. Since liver monocytes/macrophages remained constant during the cirrhotic stage, the increased intrahepatic vascular resistance associated with impaired hepatic sinusoidal circulation was considered the potential reason for the change in the distribution of MNPs.

Patency of spleno-pancreatorenal shunt in infant with portal hypertension, case series and literature review

Introduction: Portal hypertension is the main cause of morbidity and mortality in infant diagnosed of biliary atresia (BA) and cavernous deformation of the portal vein. Portal hypertension evolves as a result of increased intrahepatic vascular resistance, most commonly caused by a chronic liver disease. The clinical manifestations are ascites and bleeding owing the esophageal and gastric varices. The mortality rate per acute episode of bleeding is 5% to 19% in children. The aim of this work was to evaluate the clinical influence of rebleeding, refractory ascites, child-Pugh class (C.P) and shunt patency in infant underwent spleno-pancreatorenal (SPR) shunt in a case series in a pediatric reference medical center. Patients and Methods: Retrospective and observational work was performed owing clinical surveillance of C.P, shunt patency, rebleeding and ascites formation after SPR shunt procedure from December 2017 to November 2020. Of 16 shunts performed in this period, 3(18.7%) patients had SPR shunt. The three patients were females and the mean weight was 6.5kg. Outcomes and Results: The search identified three patients underwent surgical shunts of SPR less than 2-year-old. All of three patients had shunt patency in the first three months from the procedure. One patient had thrombosis of the shunt at fourth month from the operation. The three patients had improvement in the C.P class, 1 patient had infectious, rebleeding and ascites between 4 months from the procedure. Conclusion: The three patients had no experienced shunt complications in the first three months from the procedure.

Portal Hypertension in Nonalcoholic Fatty Liver Disease: From Pathogenesis to Clinical Practice.

Portal hypertension in nonalcoholic fatty liver disease (NAFLD) mostly occur in cirrhotic stage. However, several experimental and clinical studies showed evidence of portal hypertension in NAFLD without significant or advance fibrosis. This early development of portal hypertension in NAFLD is associated with liver sinusoidal contraction by hepatocellular lipid accumulation and ballooning, which is also accompanied by capillarization and dysfunction of liver sinusoidal endothelial cells. Both of these impaired mechanical and molecular components can cause an increase in intrahepatic vascular resistance which lead to the increase of portal pressure in the absence of significant liver fibrosis. Extrahepatic factors such as insulin resistance and gut dysbiosis may also contribute to liver sinusoidal endothelial dysfunction and early portal hypertension in NAFLD. The clinical impact of early portal hypertension in NAFLD is still unclear. However, clinical tools for diagnosis and monitoring of portal hypertension in NAFLD are being investigated to predict high-risk patients and to guide therapy.

Diammonium glycyrrhizinate ameliorates portal hypertension by regulating portal macrophage oxidation and superoxide dismutase 3

Portal hypertension (PHT) is a complication of liver diseases. Increased intrahepatic vascular resistance is attributed to reduced bioavailability of vasodilator substances. The macrophage activation and superoxide dismutase 3 (SOD3) involve in the pathogenesis of PHT. Diammonium glycyrrhizinate (DG) is the salt form of glycyrrhizin derived from Radix glycyrrhizae, exerting anti-oxidant activities and be beneficial for liver injury. Here, we aimed to investigate effects of DG on PHT and explore its underlying mechanisms on regulation of macrophages and SOD3. The carbon tetrachloride induced PHT rats received administration of liposome-encapsulated clodronate for hepatic macrophage depletion, or PBS liposomes for matched control. DG (25 mg/kg) or vehicle was gavaged. Portal pressure in vivo, and serum biomarkers of macrophage activation were measured. The nitric oxide (NO) and prostacyclin (PGI2) bioavailability was evaluated in the isolated portal perfused rat livers. Liver tissues were collected to evaluate cirrhosis, macrophage oxidation, and SOD3 activity. Depletion of hepatic macrophages decreased portal pressure, increased bioavailability of NO and PGI2, and restored SOD3 activity. DG effectively decreased portal pressure, relieved cirrhosis, inhibited macrophage activation. DG increased bioavailability of NO and PGI2 to relax portal veins. DG relieved portal macrophage oxidation through decreasing nicotinamide adenine dinucleotide phosphate oxidase 2 and inducible NO synthase expressions, elevated SOD3 activities and increased SOD3 expressions at portal triads. These findings indicated that DG restored SOD3 activity, against portal macrophage oxidation, protected bioavailability of NO and PGI2, thereby reduced portal pressure. It suggested a potential use of DG for PHT treatment.

Cirrhotic portal hypertension reversal mechanism and its therapy

Portal hypertension is one of the most serious complications in patients with liver cirrhosis, and its prevention and treatment are essential to improve patient outcomes. The main pathophysiological basis of cirrhotic portal hypertension is increased intrahepatic vascular resistance and/or increased portal blood flow. In recent years, studies have suggested that liver sinusoid endothelial cells dysfunction, hepatic microvascular thrombosis, pathological angiogenesis, and gut-liver axis imbalance play critical roles in the development of portal hypertension. With respect to this, targeted therapy drugs have made significant advances. This article discusses the cirrhotic portal hypertension reversal mechanism and the current status of its treatment.

Correlation of pressure gradient in three hepatic veins with portal pressure gradient.

BACKGROUNDThe liver is one of the most important organs in the human body, with functions such as detoxification, digestion, and blood coagulation. In terms of vascular anatomy, the liver is divided into the left and the right liver by the main portal vein, and there are three hepatic efferent veins (right, middle, and left) and two portal branches. Patients with impaired liver function have increased intrahepatic vascular resistance and splanchnic vasodilation, which may lead to an increase in the portal pressure gradient (PPG) and cause portal hypertension (PHT). In order to measure the increased pressure gradient of portal vein, the hepatic venous pressure gradient (HVPG) can be measured to reflect it in clinical practice. The accuracy of PPG measurements is directly related to patient prognosis.AIMTo analyze the correlation between HVPG of three hepatic veins and PPG in patients with PHT.METHODSFrom January 2017 to December 2019, 102 patients with PHT who met the inclusion criteria were evaluated during the transjugular intrahepatic portosystemic shunt procedure and analyzed.RESULTSThe mean HVPG of the middle hepatic vein was 17.47 ± 10.25 mmHg, and the mean HVPG of the right and left hepatic veins was 16.34 ± 7.60 and 16.52 ± 8.15 mmHg, respectively. The average PPG was 26.03 ± 9.24 mmHg. The correlation coefficient and coefficient of determination of the right hepatic vein, middle hepatic vein, and left hepatic vein were 0.15 and 0.02 (P = 0.164); 0.25 and 0.05 (P = 0.013); and 0.14 and 0.02 (P = 0.013), respectively. The mean wedged hepatic vein/venous pressure (WHVP) of the middle and left hepatic veins was similar at 29.71 ± 12.48 and 29.1 ± 10.91 mmHg, respectively, and the mean WHVP of the right hepatic vein was slightly lower at 28.01 ± 8.95 mmHg. The mean portal vein pressure was 34.11 ± 8.56 mmHg. The correlation coefficient and coefficient of determination of the right hepatic vein, middle hepatic vein, and left hepatic vein were 0.26 and 0.07 (P = 0.009); 0.38 and 0.15 (P < 0.001); and 0.26 and 0.07 (P = 0.008), respectively. The average free hepatic venous pressure (FHVP) of the right hepatic vein was lowest at 11.67 ± 5.34 mmHg, and the average FHVP of the middle and left hepatic veins was slightly higher at 12.19 ± 4.88 and 11.67 ± 5.34 mmHg, respectively. The average inferior vena cava pressure was 8.27 ± 4.04 mmHg. The correlation coefficient and coefficient of determination of the right hepatic vein, middle hepatic vein, and left hepatic vein were 0.30 and 0.09 (P = 0.002); 0.18 and 0.03 (P = 0.078); and 0.16 and 0.03 (P = 0.111), respectively.CONCLUSIONMeasurement of the middle hepatic vein HVPG could better represent PPG. Considering the high success rate of clinical measurement of the right hepatic vein, it can be the second choice.

Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis, cirrhosis and hepatocellular carcinoma.

Intercellular crosstalk among various liver cells plays an important role in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Capillarization of liver sinusoidal endothelial cells (LSECs) precedes fibrosis and accumulating evidence suggests that the crosstalk between LSECs and other liver cells is critical in the development and progression of liver fibrosis. LSECs dysfunction, a key event in the progression from fibrosis to cirrhosis, and subsequently obstruction of hepatic sinuses and increased intrahepatic vascular resistance (IHVR) contribute to development of portal hypertension (PHT) and cirrhosis. More importantly, immunosuppressive tumor microenvironment (TME), which is closely related to the crosstalk between LSECs and immune liver cells like CD8+ T cells, promotes advances tumorigenesis, especially HCC. However, the connections within the crosstalk between LSECs and other liver cells during the progression from liver fibrosis to cirrhosis to HCC have yet to be discussed. In this review, we first summarize the current knowledge of how different crosstalk between LSECs and other liver cells, including hepatocytes, hepatic stellate cells (HSCs), macrophoges, immune cells in liver and extra cellular matrix (ECM) contribute to the physiological function and the progrssion from liver fibrosis to cirrhosis, or even to HCC. Then we examine current treatment strategies for LSECs crosstalk in liver fibrosis, cirrhosis and HCC.

Management of Liver Decompensation in Advanced Chronic Liver Disease: Ascites, Hyponatremia, and Gastroesophageal Variceal Bleeding

Portal hypertension is a major complication of cirrhosis characterized by a pathological hepatic venous pressure gradient (HVPG) ≥ 5 mmHg. The structural changes observed in the liver leading to intrahepatic vascular resistance and, consequently, portal hypertension appear in the early stages of cirrhosis. Clinically significant portal hypertension (HVPG ≥ 10 mmHg) is associated with several clinical consequences, such as ascites, hyponatremia, gastroesophageal variceal bleeding, hepatorenal syndrome, cardiopulmonary complications, adrenal insufficiency, and hepatic encephalopathy. The diagnosis and management of these complications depend on their early identification and treatment. Regarding ascites, diuretics are a useful treatment, although plasma sodium levels must be properly controlled to avoid hyponatremia. The management of hypovolemic hyponatremia usually consists in stopping diuretics and the administration of volume. On the contrary, hypervolemic hyponatremia is managed with fluid and sodium restriction. Transjugular intrahepatic portosystemic shunt (TIPS) should be considered in patients with refractory ascites. Primary prophylaxis of variceal bleeding should be based mainly on non-selective beta-blockers. Management of acute gastroesophageal variceal bleeding includes vasoactive drugs and endoscopic band ligation and, in patients at high risk of failure and rebleeding, preemptive use of TIPS. Secondary prophylaxis with a combination of non-selective beta-blockers and endoscopic band ligation is the treatment of choice. This article focuses on the management of ascites, hyponatremia, and gastroesophageal variceal bleeding.

Microbiota transplantation in portal hypertension: promises and pitfalls.

In this commentary, we discuss new findings indicating that microbiota transplantation has favorable impact on portal hypertension (PH) in the experimental model of cirrhosis induced by bile duct ligation (BDL) (Huang et al.; Clin Sci (Lond) (2021) 135(24): 2709-2728, doi: 10.1042/CS20210602). Sinusoidal PH is an ominous outcome of advanced chronic liver disease, characterized by increased intrahepatic vascular resistance (IHVR), splanchnic hyperemia, and the development of portosystemic collaterals. In the work of Huang et al., microbiota transplantation not only alleviated splanchnic hyperdynamic circulation by improving vascular responsiveness and decreasing mesenteric angiogenesis, but also reduced blood flow in portosystemic collaterals. Surprisingly, however, microbiota transplantation had no effect on intrahepatic vasoconstriction in this experimental model. We discuss these observations in the context of recent literature showing that manipulation of the gut microbiota (either by transplantation or through the use of probiotics) may improve IHVR, which is one of the earliest abnormalities in the pathogenesis of sinusoidal PH. Further research is needed to explore the specific molecular and cellular targets associated with the correction of dysbiosis in liver disease.

Use of the volume-averaged Murray's deviation method for the characterization of branching geometry in liver fibrosis: a preliminary study on vascular circulation.

Vascular changes in liver fibrosis can result in increased intrahepatic vascular resistance and impaired blood circulation. This can hinder the recovery from fibrosis and may eventually lead to portal hypertension, a major cirrhosis complication. This report proposed a volume-averaged Murray's deviation method to characterize intrahepatic circulation in the liver during fibrosis and its subsequent regression via X-ray phase-contrast computed tomography (PCCT). Liver fibrosis was induced in 24 Sprague-Dawley rats by exposure to carbon tetrachloride (CCl4) for up to 10 weeks, after which, spontaneous regression commenced and continued until week 30. High-resolution three-dimensional (3D) imaging of the livers was performed with PCCT. The values of Murray's deviation based on the volume-averaged and the conventional diameter-based methods were compared. After that, the intrahepatic circulation at different stages of fibrosis was evaluated using the volume-averaged method. The increase in collagen during liver fibrosis was assessed by pathological analyses. A comparison of the 2 methods showed that with an increase in the number of diameter measurements, the value of Murrary's deviation obtained using the diameter-based method gradually approaches those of the volume-averaged method, with minimal variations. The value of Murray's deviation increased with the development of fibrosis. After reversal, the value rapidly decreased and approached that of the normal state in both the main branches (1.05±0.17, 1.17±0.21, 1.34±0.18, and 1.17±0.19 in the normal, moderate, severe, and regressive groups, respectively; P<0.05 between the severe group and other groups) and the small branches (1.05±0.09, 1.42±0.48, 1.79±0.57, and 1.18±0.28 in the normal, moderate, severe, and regressive group, respectively; P<0.05 between adjacent groups). An analysis of Murray's deviation and the pathological results showed that the vascular circulation in this disease model was consistent with the progression and recovery from fibrosis. This study showed the validity of the volume-averaged method for calculating Murray's deviation and demonstrated that it could accurately evaluate the blood circulation state of the liver during fibrosis and its subsequent regression. Thus, the volume-averaged method of calculating Murray's deviation may be an objective and valuable staging criterion to evaluate intrahepatic circulation during liver fibrosis.

Study of the effect of vascular endothelial growth factor (VEGF) C(+405)G (rs2010963) single nucleotide polymorphism on the development of esophageal and gastric varices and risk of variceal bleeding in cirrhotic hepatitis C virus (HCV) patients (VEGF) C(+405)G IN esophageal and gastric varices

BackgroundHCV infection is a major worldwide cause of chronic liver diseases. Esophageal and gastric varices are common in cirrhotic patients due to concomitant portal hypertension. Variceal hemorrhage is a major decompensating event with high morbidity and mortality. Endothelial dysfunction, occurring in cirrhosis, facilitates the development of liver cirrhosis, portal hypertension and contributes to increased intrahepatic vascular resistance..VEGF family members are major regulators of blood vessel development and function.ResultsThe study was conducted on 90 subjects admitted to Tropical Medicine Department, Alexandria Main University Hospital: 30 cirrhotic patients with endoscopically proven varices (group A), 30 cirrhotic patients without varices (group B), and 30 healthy controls (group C). All patients was subjected to detailed history taking and thorough clinical examination, laboratory investigations, ultrasound abdomen, upper gastrointestinal endoscopy, and genotyping for VEGF C(+405)G (rs2010963) by 5′ nuclease assay. The VEGF C(+405)G (rs2010963) GG genotype was associated with higher prevalence of esophageal and gastric varices and higher bleeding risk.ConclusionVEGF C(+405)G (rs2010963) is an important genetic determinant of esophageal varices, gastric varices, and correlates with variceal bleeding risk. Genetic testing of this SNP would be useful in prediction of esophageal and gastric varices and bleeding risk.

Diagnosis and Management of Esophageal and Gastric Variceal Bleeding: Focused on 2019 KASL Clinical Practice Guidelines for Liver Cirrhosis

Varices are a frequent complication of liver cirrhosis and a major cause of mortality in patients with liver cirrhosis. Patients with decompensated cirrhosis complications have a poor prognosis and require careful management. Portal hypertension is the most common complication of liver cirrhosis, which is the key determinant for varices development. Increased intrahepatic vascular resistance to portal flow leads to the development of portal hypertension. Collateral vessels develop at the communication site between the systemic and portal circulation with the progression of portal hypertension. Varices are the representative collaterals, develop gradually with the progression of portal hypertension and may eventually rupture. Variceal bleeding is a major consequence of portal hypertension and causes the death of cirrhotic patients. The present paper reviews the latest knowledge regarding the diagnosis and management of esophageal and gastric variceal bleeding.

Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses….

Portal hypertension (PHT) and hepatocellular carcinoma (HCC) are major complication of cirrhosis which significantly contribute to morbidity and mortality. In this review, we aim to describe the consequences of both angiogenesis and inflammation in the pathogenesis of PHT and HCC, but also the difficulty to propose adapted treatment when PHT and HCC coexist in the same patients. Studies for review in this article were retrieved from the PubMed database using literature published in English until March 2021. Portal hypertension occurs secondary to an increase of intrahepatic vascular resistances, the opening of portosystemic collateral vessels and the formation of neovessels, related to vascular endothelial growth factor (VEGF). Recently, bacterial translocation-mediated inflammation was also identified as a major contributor to PHT. Interestingly, VEGF and chronic inflammation also contribute to HCC occurrence. As PHT and HCC often coexist in the same patient, management of PHT and its related complications as well as HCC treatment appear more complex. Indeed, PHT-related complications such as significant ascites may hamper the access to HCC treatment and the presence of HCC is also independently associated with poor prognosis in patients with acute variceal bleeding related to PHT. Due to their respective mechanism of action, the combination of Atezolizumab and Bevacizumab for advanced HCC may impact the level of PHT and its related complications and to date, no real-life data are available. Appropriate evaluation and treatment of PHT remains a major issue in order to improve the outcome of HCC patients.

Regulation of hepatic stellate cell contraction and cirrhotic portal hypertension by Wnt/β-catenin signalling via interaction with Gli1.

Portal hypertension is a lethal complication of cirrhosis. Its mechanism and therapeutic targets remain largely unknown. Hepatic stellate cell (HSC) contraction increases intrahepatic vascular resistance contributing to portal hypertension. We investigated how HSC contraction was regulated by Wnt signalling and the therapeutic implications. Liver tissues from cirrhotic patients were examined. Cirrhotic mice with genetic or pharmacological treatments were used for in vivo assessments, and their primary cells were isolated. Cellular functions and signalling pathways were analysed in human HSC-LX2 cells using real-time PCR, Western blotting, siRNA, luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation and site-directed mutagenesis. Wnt/β-catenin correlated with HSC contraction in human cirrhotic liver. Wnt3a stimulated Smo-independent Gli1 nuclear translocation followed by LARG-mediated RhoA activation leading to HSC contraction. Suppressor of fused (Sufu) negatively mediated Wnt3a-induced Gli1 nuclear translocation. Wnt/β-catenin repressed transcription of Sufu dependent on β-catenin/TCF4 interaction and TCF4 binding to Sufu promoter. Molecular simulation and site-directed mutagenesis identified the β-catenin residues Lys312 and Lys435 critically involved in this interaction. TCF4 binding to the sequence CACACCTTCC at Sufu promoter was required for transrepression of Sufu. In cirrhotic mice, short-term liver-targeting β-catenin deficiency or acute treatment with β-catenin inhibitors reduced portal pressure via restriction of HSC contraction rather than inhibiting HSC activation. Long-term deficiency or treatments also ameliorated liver injury, fibrosis and inflammation. Interaction between Wnt/β-catenin and Smo-independent Gli1 pathways promoted HSC contraction via TCF4-dependent transrepression of Sufu. HSC-specific inhibition of β-catenin may have therapeutic benefits for cirrhotic portal hypertension.