Endohepatology in clinical practice: EUS-guided portal pressure measurement combined with EUS-guided liver biopsy and variceal screening and treatment in outpatients.

Background and Objectives: EUS-guided portal pressure gradient (PPG) is a novel technique that permits a true, direct measure of portal vein pressure and hepatic vein pressure. This article details our experience and lessons learned from 20 consecutive outpatient EUS-PPG procedures performed at a single center, along with simultaneous EUS-guided liver biopsy, variceal screening, and variceal banding. Methods: Data on the first 20 patients who underwent EUS-PPG at a single center were retrospectively viewed and analyzed. The effects of various liver diseases or other patient-related factors on the clinical and technical success of EUS-PPG measurements, as well as EUS-guided liver biopsy (EUS-LB), were evaluated. During the procedure, if esophageal varices were encountered, they were assessed, and if felt to be clinically indicated, endoscopic variceal ligation was performed. Results: The 20 patients included 10 male and 10 female patients. All procedures were technically successful. In all patients, the portal vein and hepatic veins could be easily identified. One adverse event of bleeding occurred during the EUS-PPG measuring procedure. All 20 EUS-LBs were technically successful and yielded adequate samples for histological evaluations, with an average of 25 complete portal tracts per sample. Among patients with esophageal varices, 40% of patients underwent banding. The mean EUS-PPG among 5 patients with esophageal varices was 11.6 mm Hg, compared with 3.2 mm Hg among 15 patients without esophageal varices. Conclusion: This study demonstrates that EUS-PPG is a novel, safe, reproducible, and effective technique. Also, the fact that EUS-PPG, EUS-LB, variceal screening, and variceal banding could be performed in 1 session and on an outpatient basis speaks to the growing relevance and impact of the nascent field of endohepatology.

Gut Microbiota and Sinusoidal Vasoregulation in MASLD: A Portal Perspective.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common condition with heterogeneous outcomes difficult to predict at the individual level. Feared complications of advanced MASLD are linked to clinically significant portal hypertension and are initiated by functional and mechanical changes in the unique sinusoidal capillary network of the liver. Early sinusoidal vasoregulatory changes in MASLD lead to increased intrahepatic vascular resistance and represent the beginning of portal hypertension. In addition, the composition and function of gut microbiota in MASLD are distinctly different from the healthy state, and multiple lines of evidence demonstrate the association of dysbiosis with these vasoregulatory changes. The gut microbiota is involved in the biotransformation of nutrients, production of de novo metabolites, release of microbial structural components, and impairment of the intestinal barrier with impact on innate immune responses, metabolism, inflammation, fibrosis, and vasoregulation in the liver and beyond. The gut-liver axis is a conceptual framework in which portal circulation is the primary connection between gut microbiota and the liver. Accordingly, biochemical and hemodynamic attributes of portal circulation may hold the key to better understanding and predicting disease progression in MASLD. However, many specific details remain hidden due to limited access to the portal circulation, indicating a major unmet need for the development of innovative diagnostic tools to analyze portal metabolites and explore their effect on health and disease. We also need to safely and reliably monitor portal hemodynamics with the goal of providing preventive and curative interventions in all stages of MASLD. Here, we review recent advances that link portal metabolomics to altered sinusoidal vasoregulation and may allow for new insights into the development of portal hypertension in MASLD.

Hepatic Venous Pressure Gradient: Measurement and Pitfalls.

Measurement of hepatic venous pressure gradient (HVPG) effectively mirrors the severity of portal hypertension (PH) and offers valuable insights into prognosis of liver disease, including the risk of decompensation and mortality. Additionally, HVPG offers crucial information about treatment response to nonselective beta-blockers and other medications, with its utility demonstrated in clinical trials in patients with PH. Despite the widespread dissemination and validation of noninvasive tests, HVPG still holds a significant role in hepatology. Physicians treating patients with liver diseases should comprehend the HVPG measurement procedure, its applications, and how to interpret the results and potential pitfalls.

Endoscopic ultrasound-guided portal pressure gradient measurement: a systematic review and meta-analysis.

Background: Endoscopic ultrasound-guided portal pressure gradient measurement (EUS-PPG) is a new modality where the portal pressure is measured by directly introducing a needle into the hepatic vein and portal vein. This is the first systematic review and meta-analysis to evaluate the efficacy and safety of EUS-PPG. Methods: A comprehensive literature search was performed to identify pertinent studies. The primary outcomes assessed were the technical and clinical success of EUS-PPG. Technical success was defined as successful introduction of the needle into the desired vessel, while clinical success was defined as the correlation of the stage of fibrosis on the liver biopsy to EUS-PPG, or concordance of HVPG and EUS-PPG. The secondary outcomes were pooled rates for total and individual adverse events related to EUS-PPG. Pooled estimates were calculated using random-effects models with a 95% confidence interval (CI). Results: Eight cohort studies with a total of 178 patients were included in our analysis. The calculated pooled rates of technical success and clinical success were 94.6% (95%CI 88.5-97.6%; P=<0.001; I2=0) and 85.4% (95%CI 51.5-97.0%; P=0.042; I2=70), respectively. The rate of total adverse events was 10.9% (95%CI 6.5-17.7%; P=<0.001; I2=4), and 93.7% of them were mild, as defined by the American Society for Gastrointestinal Endoscopy. Abdominal pain (11%) was the most common adverse event, followed by bleeding (3.6%). There were no cases of perforation or death reported in our study. Conclusions: EUS-PPG is a safe and effective modality for diagnosing portal hypertension. Further randomized controlled trials are needed to validate our findings.

Transjugular intrahepatic portosystemic shunt: A promising therapy for recompensation in cirrhotic patients.

This is a retrospective study focused on recompensation after transjugular intrahepatic portosystemic shunt (TIPS) procedure. The authors confirmed TIPS could be a treatment for recompensation of patients with cirrhosis according to Baveno VII. The paper identified age and post-TIPS portal pressure gradient as independent predictors of recompensation in patients with decompensated cirrhosis after TIPS. These results need to be validated in a larger prospective cohort.

Laparoscopic treatment of congenital portosystemic shunts with portal pressure measurement and portal angiography in 36 dogs.

Introduction: Laparoscopic surgery is used for canine congenital extrahepatic portosystemic shunts (CEHPSS). However, outcomes of laparoscopic surgery involving simultaneous portal vein angiography and portal pressure measurement to attenuate or completely occlude the shunt vessel in canines remain unclear. This study aimed to evaluate outcomes and complications of laparoscopic portosystemic shunt occlusion (LAPSSO) for CEHPSS. Methods: Between June 2014 and March 2021, data on dogs undergoing cellophane banding (CB) and complete occlusion of laparoscopically treated congenital extrahepatic port shunts were collected from hospital records. Cases in which complete occlusion was laparoscopically performed, or a CB was used for gradual occlusion were included. A total of 36 dogs (14 males; median age 32.5 months [range, 5-99] with median body weight, 4.2 kg [range, 1.5-7.9]) that underwent LAPSSO for CEHPSS were included. All the dogs underwent computed tomographic angiography (CTA), and data on blood and radiological examinations were collected. Shunt vessel morphology was categorized using CTA findings. Portal pressure measurements and portal angiography were performed by accessing mesenteric and splenic veins in 30 and 6 cases, respectively. Results: The most common shunt types were spleno-phrenic shunts 16/36 (44.4%), followed by spleno-azygos 9/36 (25.0%), spleno-caval 4/36 (11.1%), right gastric-caval 6/36 (16.6%), and right gastric-caval with caudal loop shunts 1/36 (2.7%). The median portal pressure after complete occlusion was 11.5 mmHg (range, 4-16); portal pressures in the two dogs undergoing CB attenuation were 22 and 24 mmHg. The median operating time in the dogs with right (n = 25) and left (n = 11) recumbent positioning was 55 min (range, 28-120) and 54 min (range, 28-88), respectively. One dog had pneumothorax due to injury to the diaphragm. Another dog developed postoperative hypernatremia and succumbed 5 h post-procedure. Nevertheless, no other dogs exhibited signs of portal hypertension within 72 h. Blood tests and abdominal ultrasounds performed 1-2 months postoperatively revealed no residual shunts. Discussion: LAPSSO, coupled with portal pressure measurement and portal angiography, was shown as safe and effective approach that facilitated successful occlusion of CEHPSS. Further large-scale prospective studies and analyses of perioperative complications are needed.

Expert management of congenital portosystemic shunts and their complications.

Congenital portosystemic shunts are often associated with systemic complications, the most challenging of which are liver nodules, pulmonary hypertension, endocrine abnormalities, and neurocognitive dysfunction. In the present paper, we offer expert clinical guidance on the management of liver nodules, pulmonary hypertension, and endocrine abnormalities, and we make recommendations regarding shunt closure and follow-up.

Liver-targeted nanoparticles delivering nitric oxide reduce portal hypertension in cirrhotic rats.

Nitric oxide (NO) is a small vasodilator playing a key role in the pathogenesis of portal hypertension. Here, we assessed the potential therapeutic effect of a NO donor targeted to the liver by poly(beta-amino ester) nanoparticles (pBAE NPs) in experimental cirrhosis. Retinol-functionalized NO donor pBAE NPs (Ret pBAE NPs) were synthetized with the aim of actively targeting the liver. Administration of Ret pBAE NPs resulted in uptake and transfection by the liver and spleen. NPs were not found in other organs or the systemic circulation. Treatment with NO donor Ret pBAE NPs (30 mg/ kg body weight) significantly decreased aspartate aminotransferase, lactate dehydrogenase and portal pressure (9.75 ± 0.64 mmHg) compared to control NPs (13.4 ± 0.53 mmHg) in cirrhotic rats. There were no effects on mean arterial pressure and cardiac output. Liver-targeted NO donor NPs reduced collagen fibers and steatosis, activation of hepatic stellate cells and mRNA expression of profibrogenic and proinflammatory genes. Finally, Ret pBAE NPs displayed efficient transfection in human liver slices. Overall, liver-specific NO donor NPs effectively target the liver and mitigated inflammation and portal hypertension in cirrhotic rats. The use of Ret pBAE may prove to be an effective therapeutic strategy to treat advanced liver disease.

Analysis of transjugular intrahepatic portosystemic shunt by hemodynamic simulation.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS), which artificially creates a portocaval shunt to reduce portal venous pressure, has gradually become the primary treatment for portal hypertension (PH). However, there is no prefect shunting scheme in TIPS to balance the occurrence of postoperative complications and effective haemostasis. OBJECTIVE: To construct cirrhotic PH models and compare different shunting schemes in TIPS. METHODS: Three cases of cirrhotic PH with different liver volumes were selected for enhanced computed tomography scanning. The models for different shunting schemes were created using Mimics software, and following FLUENT calculation, all the models were imported into the software computational fluid dynamic-post for processing. In each shunting scheme, the differences in portal vein pressure, hepatic blood perfusion and blood flow from the superior mesenteric vein in the shunt tract were compared. The coefficient G was adapted to evaluate the advantages and disadvantages. RESULTS: (1) Concerning the precise location of the shunt tract, the wider the diameter of the shunt tract, the lower the pressure of the portal vein and the lesser the hepatic blood perfusion. Meanwhile, the pressure drop objective was not achieved with the 6 mm-diameter shunting scheme. (2) The 8 mm-diameter shunting scheme through the left portal vein (LPV) had the highest coefficient G. CONCLUSION: The 8 mm-diameter shunting scheme through the LPV may demonstrate a superior effect and prognosis in TIPS procedures.

Resveratrol protects against Schistosoma mansoni-induced liver fibrosis by targeting the Sirt-1/NF-κB axis.

Hepatic schistosomiasis is a prevalent form of chronic liver disease that drastically affects human health. Nevertheless, an antifibrotic drug that could suppress the development of hepatic fibrosis does not exist yet. The current study aimed to evaluate the effect of resveratrol, a natural polyphenol with multiple biological activities, on Schistosoma mansoni (S. mansoni)-induced hepatic fibrosis and delineate the underlying molecular mechanism. Swiss male albino mice were randomly assigned into infected and non-infected groups. Hepatic schistosomiasis infection was induced via exposure to S. mansoni cercariae. 6 weeks later, resveratrol was administrated either as 20 mg/kg/day or 100 mg/kg/day for 4 weeks to two infected groups. Another group received vehicle and served as infected control group. At the end of the study, portal hemodynamic, biochemical, and histopathological evaluation of liver tissues were conducted. Remarkably, resveratrol significantly reduced portal pressure, portal and mesenteric flow in a dose-dependent manner. It improved several key features of hepatic injury as evidenced biochemically by a significant reduction of bilirubin and liver enzymes, and histologically by amelioration of the granulomatous and inflammatory reactions. In line, resveratrol reduced the expression of pro-inflammatory markers; TNF-α, IL-1ß and MCP-1 mRNA, together with fibrotic markers; collagen-1, TGF-ß1 and α-SMA. Moreover, resveratrol restored SIRT1/NF-κB balance in hepatic tissues which is the main switch-off control for all the fibrotic and inflammatory mechanisms. Taken together, it can be inferred that resveratrol possesses a possible anti-fibrotic effect that can halt the progression of hepatic schistosomiasis via targeting SIRT1/ NF-κB signaling.

Prognostic value of virtual portal pressure gradient response in compensated cirrhotic patients treated with carvedilol.

AIM: This study aimed to assess the prognostic significance of virtual portal pressure gradient (vPPG) response to carvedilol in patients with compensated cirrhosis (CC). METHODS: Compensated cirrhosis patients with high-risk varices were prospectively enrolled to receive carvedilol for prevention of first variceal hemorrhage (VH) and followed up for 1 year. The vPPG response was defined as a reduction of vPPG >10% from baseline after 1-month therapy. Logistic and Cox regression analyses were performed to identify independent predictors for vPPG response and first decompensation, respectively. Competitive risk models were constructed to predict disease progression, and validated using the C-index, Kaplan-Meier analysis, competitive risk analysis, and calibration curves. RESULTS: A total of 129 patients completed this study, of whom 56 (43.4%) achieved vPPG response and were referred as vPPG responders. Baseline vPPG, red color sign, Model for End-stage Liver Disease score, serum monocyte chemoattractant protein-1 (MCP-1), and laminin levels significantly correlated with vPPG response, which itself was further documented as an independent predictor of VH, ascites, and overall decompensation events in CC. Moreover, the red color sign or Child-Turcotte-Pugh score effectively predicted VH, while ascites correlated well with portal flow velocity or MCP-1. The predictive models for VH and ascites showed a good discrimination with C-index values of 0.747 and 0.689 respectively, and the high consistency on calibration curves. CONCLUSION: The vPPG response could be used as a noninvasive tool for prediction of disease progression in patients with CC.

An Open-label Randomized Controlled Trial of Early Initiation of Nasogastric Feeding After Endotherapy in Variceal Bleeding: A Proof-of-concept Study.

Background and aims: Limited data exist on the safety of early nasogastric (NG) feeding in patients with cirrhosis after endotherapy for variceal bleeding (VB). We studied the impact of early NG tube feeding in these patients in this proof-of-concept open-label randomized controlled trial. Methods: Eligible patients with cirrhosis undergoing endotherapy for VB were randomized to receive either a liquid diet through a 14 Fr NG tube (commencing 1 h after endotherapy) (early feeding [EF] group) or sips of water and lemon water orally (standard-of-care [SOC] group) for total duration of 48 h. The primary outcome was 5-day rebleeding in both arms. Other outcomes included 5-day infection rate, hepatic encephalopathy during hospitalization, and 6-week mortality. Results: Eighty patients (Mean age: 41 ± 11.5 years; males [82.5%]; alcohol etiology [55%]) were included. Baseline median Child-Pugh and MELD scores were similar (CTP: 8 [IQR: 8-9] vs 9 [8-9.25]; P = 0.47 and MELDNa: 13 [10.75-16.25] vs 15 [12-18.25]; P = 0.16). The 5-day rebleeding rates in EF and SOC groups were 2.5% and 5%, respectively (P = 0.55), and non-inferiority or superiority of either could not be demonstrated. The incidence of infection (2.5% [EF] vs 2.5% [SOC]; P = 1.00) and development of HE (5% [EF] vs 2.5% [SOC]; P = 0.36) during hospitalization were comparable. The average daily calorie and protein intake in the EF group during the 48 h was 1318 ± 240 Kcals and 43.4 ± 9.2 g of proteins. No patient in the EF group had feed intolerance. Conclusion: Early initiation of NG tube-based feeding after endotherapy in VB appears safe and well tolerated without the additional risk of rebleeding or encephalopathy.

A Unique Presentation of Familial Idiopathic Colonic Varices.

Colonic varices typically occur in the setting of portal hypertension, and patients may present with rectal bleeding or occult anemia. Idiopathic colonic varices occur infrequently in the absence of cirrhosis and can involve the entire colon. We present a case of a 54-year-old Eastern European woman who had undergone diagnostic colonoscopy for newly diagnosed sigmoid adenocarcinoma and was incidentally found to have colonic varices with normal portal pressure gradients. Her 38-year-old daughter was found to have similar varices, raising concerns for hereditary etiology.

Candesartan cilexetil ameliorates NOSTRIN-NO dependent portal hypertension in cirrhosis and ACLF.

In decompensated cirrhosis, the severity of portal hypertension (PHT) is associated with increased hepatic endothelial nitric oxide synthase (eNOS) trafficking inducer (Nostrin), but the mechanism remains unclear. AIM: To investigate: (1) Whether in cirrhosis-PHT models, ± superimposed inflammation to mimic acute-on-chronic liver failure (ACLF) modulates hepatic nitric oxide synthase trafficking inducer (NOSTRIN) expression, nitric oxide (NO) synthesis, and/or endothelial dysfunction (ED); and (2) Whether the "angiotensin II type 1 receptor blocker" candesartan cilexetil (CC) affects this pathway. CD-1 mice received intraperitoneal carbon tetrachloride injections (CCl4 15% v/v in corn oil, 0.5 mL/kg) twice weekly for 12 wk to induce cirrhosis. After 12 wk, mice were randomized to receive 2-wk oral administration of CC (8 mg/kg) ± LPS. At sacrifice, plasma (biochemical indicators, cytokines, and angiotensin II) and liver tissues (histopathology, Sirius-red stains, and molecular studies) were analysed. Moreover, Nostrin gene knockdown was tested in human umbilical vein endothelial cells (HUVECs). When compared to naïve animals, CCl4-treated animals showed markedly elevated hepatic Nostrin expression (P < 0.0001), while hepatic peNOS expression (measure of eNOS activity) was significantly reduced (P < 0.05). LPS challenge further increased Nostrin and reduced peNOS expression (P < 0.05 for both) in cirrhotic animals. Portal pressure and subsequent hepatic vascular resistance were also increased in all cirrhotic animals following LPS challenge. In CCl4 ± LPS-treated animals, CC treatment significantly reduced Nostrin (P < 0.05) and increased hepatic cGMP (P < 0.01). NOSIP, caveolin-1, NFκB, and iNOS protein expression were significantly increased in CCl4-treated animals (P < 0.05 for all). CC treatment non-significantly lowered NOSIP and caveolin-1 expression while iNOS and NFκB expression was significantly reduced in CCl4 + LPS-treated animals (P < 0.05 for both). Furthermore, Nostrin knockdown significantly improved peNOS expression and associated NO synthesis and reduced inflammation in HUVECs. This study is the first to indicate a potential mechanistic role for the Nostrin-eNOS-NO pathway in cirrhosis and ACLF development. Moreover, this pathway provides a potential therapeutic target given the ameliorative response to Candesartan treatment.

The influence of static portal pressure on liver biophysical properties.

The liver is a highly vascularized organ where fluid properties, including vascular pressure, vessel integrity and fluid viscosity, play a critical role in gross mechanical properties. To study the effects of portal pressure, liver confinement, fluid viscosity, and tissue crosslinking on liver stiffness, water diffusion, and vessel size, we applied multiparametric magnetic resonance imaging (mpMRI), including multifrequency magnetic resonance elastography (MRE) and apparent diffusion coefficient (ADC) measurements, to ex vivo livers from healthy male rats (13.6±1.6 weeks) at room temperature. Four scenarios including altered liver confinement, tissue crosslinking, and vascular fluid viscosity were investigated with mpMRI at different portal pressure levels (0-17.5 cmH2O). Our experiments demonstrated that, with increasing portal pressure, rat livers showed higher water content, water diffusivity, and increased vessel sizes quantified by the vessel tissue volume fraction (VTVF). These effects were most pronounced in native, unconfined livers (VTVF: 300±120%, p<0.05, ADC: 88±29%, p<0.01), while still significant under confinement (confined: VTVF: 53±32%, p<0.01, ADC: 28±19%, p<0.05; confined-fixed: VTVF: 52±20%, p<0.001, ADC: 11±2%, p<0.01; confined-viscous: VTVF: 210±110%, p<0.01, ADC: 26±9%, p<0.001). Softening with elevated portal pressure (-12±5, p<0.05) occurred regardless of confinement and fixation. However, the liver stiffened when exposed to a more viscous inflow fluid (11±4%, p<0.001). Taken together, our results elucidate the complex relationship between macroscopic-biophysical parameters of liver tissue measured by mpMRI and vascular-fluid properties. Influenced by portal pressure, vascular permeability, and matrix crosslinking, liver stiffness is sensitive to intrinsic poroelastic properties, which, alongside vascular architecture and water diffusivity, may aid in the differential diagnosis of liver disease. STATEMENT OF SIGNIFICANCE: Using highly controllable ex vivo rat liver phantoms, hepatic biophysical properties such as tissue-vascular structure, stiffness, and water diffusivity were investigated using multiparametric MRI including multifrequency magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI). Through elaborate tuning of the experimental conditions such as the static portal pressure, flow viscosity, amount and distribution of fluid content in the liver, we identified the contributions of the fluid component to the overall imaging-based biophysical properties of the liver. Our finding demonstrated the sensitivity of liver stiffness to the hepatic poroelastic properties, which may aid in the differential diagnosis of liver diseases.

Endoscopic ultrasound-guided portal pressure gradient measurement in managing portal hypertension.

Portal hypertension (PH) is still a challenging clinical condition due to its silent manifestations in the early stage and needs to be measured accurately for early detection. Hepatic vein pressure gradient measurement has been considered as the gold standard measurement for PH; however, it needs special skill, experience, and high expertise. Recently, there has been an innovative development in using endoscopic ultrasound (EUS) for the diagnosis and management of liver diseases, including portal pressure measurement, which is commonly known as EUS-guided portal pressure gradient (EUS-PPG) measurement. EUS-PPG measurement can be performed concomitantly with EUS evaluation for deep esophageal varices, EUS-guided liver biopsy, and EUS-guided cyanoacrylate injection. However, there are still major issues, such as different etiologies of liver disease, procedural training, expertise, availability, and cost-effectiveness in several situations with regard to the standard management.

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

BACKGROUND & AIMS: ß-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. METHOD: Sixty patients with cirrhosis and HVPG ≥12 mmHg 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. RESULTS: 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 ± 242.8 pg/ml, p <0.001), lower ADMA (109.3 ± 52.7 vs. 139.9 ± 46.7 µmol/L, p = 0.027) and lower tHcy (µmol/L, 11.0 ± 4.6 vs. 15.4 ± 7.2 µmol/L, p = 0.010) plasma levels. CONCLUSION: 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. CLINICAL TRIAL EUDRACT NUMBER: 2014-002018-21. IMPACT AND IMPLICATIONS: Currently, the pharmacological prevention of cirrhosis complications due to portal hypertension, such as esophageal varices rupture, is based on the use of ß-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 ß-blockers is more effective in reducing portal pressure than ß-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 ß-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.

Close Relationship between Systemic Arterial and Portal Venous Pressure in an Animal Model with Healthy Liver.

It is unclear to what extent systemic arterial blood pressure influences portal pressure. This relationship is clinically important as drugs, which are conventionally used for therapy of portal hypertension, may also influence systemic arterial blood pressure. This study investigated the potential correlation between mean arterial (MAP) and portal venous pressure (PVP) in rats with healthy livers. In a rat model with healthy livers, we investigated the effect of manipulation of MAP on PVP. Interventions consisted of 0.9% NaCl (group 1), 0.1 mg/kg body weight (bw) Sildenafil (low dose), an inhibitor of phosphodiesterase-5 (group 2), and 1.0 mg/kg bw Sildenafil (high dose, group 3) in 600 µL saline injected intravenously. Norepinephrine was used to increase MAP in animals with circulatory failure while PVP was monitored. Injection of the fluids induced a transient drop in MAP and PVP, probably due to a reversible cardiac decompensation. The drop in MAP and drop in PVP are significantly correlated. The time lag between change in MAP and change in PVP by 24 s in all groups suggests a cause-and-effect relationship. Ten minutes after the injection of the fluid, cardiac function was normalized. Thereafter, MAP gradually decreased. In the NaCl group, PVP decreases by 0.485% for a 1% drop of MAP, by 0.550% in the low-dose sildenafil group, and by 0.651% in the high-dose sildenafil group (p < 0.05 for difference group two vs. group one, group three vs. group one, and group three vs. group two). These data suggest that Sildenafil has an inherent effect on portal pressure that exceeds the effect of MAP. Injection of norepinephrine led to a sudden increase in MAP followed by an increase in PVP after a time lag. These data show a close relationship between portal venous pressure and systemic arterial pressure in this animal model with healthy livers. A change in MAP is consequently followed by a change in PVP after a distinct time lag. This study, furthermore, suggests that Sildenafil influences portal pressure. Further studies should be performed in a model with cirrhotic livers, as these may be important in the evaluation of vasoactive drugs (e.g., PDE-5-inhibitors) for therapy of portal hypertension.

Correlation between hepatic venous pressure gradient and portal pressure gradient in patients with autoimmune cirrhotic portal hypertension and collateral branches of the hepatic vein.

AIM: To assess the correlation and agreement between hepatic venous pressure gradient (HVPG) and portal pressure gradient (PPG) in patients with autoimmune liver diseases (ALD) and portal hypertension, and to investigate the extent to which hepatic vein collateralization affects the accuracy of this assessment. METHODS: Ninety-eight patients with ALD between 2017 and 2021 who underwent transjugular intrahepatic portosystemic shunt with conventional and innovative 15 mL pressurized contrast were selected to measure wedged hepatic venous pressure (WHVP) and portal venous pressure and to calculate the HVPG and PPG. Pearson's correlation was used for correlation analysis between the two groups. Bland-Altman plots were plotted to estimate the agreement between paired pressures. RESULTS: The r values of PPG and HVPG in the early, middle, late, and portal venous visualization were 0.404, 0.789, 0.807, and 0.830, respectively, and the R2 values were 0.163, 0.622, 0.651, and 0.690, respectively. The p value for the r and R2 values in the early group was 0.015, and the p values in the remaining groups were less than 0.001. Bland-Altman plots showed that patients in the portal venous visualization group had the narrowest 95% limits of agreement. The mean value of the difference was close to the zero-scale line. CONCLUSIONS: In patients with ALD, the correlation between the HVPG and PPG was good, and the later the collateral development, the better the correlation. Hepatic vein collateral was an essential factor in underestimating WHVP and HVPG, and the earlier the collateral appeared, the more obvious the underestimation.

Endoscopic ultrasound-guided vascular interventions: An expanding paradigm.

Endoscopic ultrasound (EUS) has expanded its arena from a mere diagnostic modality to an essential therapeutic tool in managing gastrointestinal (GI) diseases. The proximity of the GI tract to the vascular structures in the mediastinum and the abdomen has facilitated the growth of EUS in the field of vascular interventions. EUS provides important clinical and anatomical information related to the vessels' size, appearance and location. Its excellent spatial resolution, use of colour doppler with or without contrast enhancement and ability to provide images "real-time" helps in precision while intervening vascular structures. Additionally, structures such as venous collaterals or varices can be dealt with optimally using EUS. EUS-guided vascular therapy with coil and glue combination has revolutionized the management of portal hypertension. It also helps to avoid radiation exposure in addition to being minimally invasive. These advantages have led EUS to become an upcoming modality to complement traditional interventional radiology in the field of vascular interventions. EUS-guided portal vein (PV) access and therapy is a new kid on the block. EUS-guided portal pressure gradient measurement, injecting chemotherapy in PV and intrahepatic portosystemic shunt has expanded the horizons of endo-hepatology. Lastly, EUS has also forayed into cardiac interventions allowing pericardial fluid aspiration and tumour biopsy with experimental data on access to valvular apparatus. Herein, we provide a comprehensive review of the expanding paradigm of EUS-guided vascular interventions in GI bleeding, portal vein access and its related therapeutic interventions, cardiac access, and therapy. A synopsis of all the technical details involving each procedure and the available data has been tabulated, and the future trends in this area have been highlighted.