Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension

1. Download : Download high-res image (255KB)
2. Download : Download full-size image

     

Sildenafil does not influence hepatic venous pressure gradient in patients with cirrhosis

AIM： To investigate if sildenafil increases splanchnic blood flow and changes the hepatic venous pressure gradient （HVPG） in patients with cirrhosis. Phosphodiesterase type-5 inhibitors are valuable in the treatment of erectile dysfunction and pulmonary hypertension in patients with end-stage liver disease. However, the effect of phosphodiesterase type-5 inhibitors on splanchnic blood flow and portal hypertension remains essentially unknown. METHODS： Ten patients with biopsy proven cirrhosis （five females/five males, mean age 54：1：8 years） and an HVPG above 12 mmHg were studied after informed consent. Measurement of splanchnic blood flow and the HVPG during liver vein catheterization were done before and 80 min after oral administration of 50 mg sildenafil. Blood flow was estimated by use of indocyanine green clearance technique and Fick＇s principle, with correction for non-steady state. RESULTS： The plasma concentration of sildenafil was 222 ± 136 ng/mL 80 min after administration. Mean arterial blood pressure decreased from 77 ±7 mmHg to 66 ± 12 mmHg, P = 0.003, while the splanchnicblood flow and oxygen consumption remained unchanged at 1.14 ± 0.71 L/min and 2.3 ± 0.6 mmol/ min, respectively. Also the HVPG remained unchanged （18 ± 2 mmHg vs 16 ± 2 mmHg） with individual changes ranging from -8 mmHg to ±2 mmHg. In seven patients, HVPG decreased and in three it increased. CONCLUSION： In spite of arterial blood pressure decreases 80 min after administration of the phosphodiesterase type-5 inhibitor sildenafil, the present study could not demonstrate any clinical relevant influence on splanichnic blood flow, oxygen consumption or the HVPG.     

Comparison of Doppler ultrasonography and the hepatic venous pressure gradient in assessing portal hypertension in liver cirrhosis

BACKGROUND AND AIM: This prospective study aimed to determine whether Doppler ultrasonography can represent the hepatic venous pressure gradient (HVPG) as an assessment of the severity of portal hypertension and the response to terlipressin, which reduces the portal pressure in liver cirrhosis. METHODS: The HVPG and the Doppler ultrasonographic parameters, such as the portal venous velocity and the splenic venous velocity, the pulsatility and the resistive index of the hepatic, splenic and renal arteries were measured in 138 patients with liver cirrhosis. The changes in the HVPG and the portal venous velocity after administering terlipressin were evaluated in 43 of the 138 patients. The patients who showed a reduction in the HVPG of more than 20% of the baseline were defined as responders to terlipressin. RESULTS: None of the Doppler ultrasonographic parameters correlated with the HVPG. Both the HVPG (28.0 +/- 19.8%) and the portal venous velocity (29.7 +/- 13.2%) showed a significant reduction after terlipressin administration. However, the portal venous velocity decreased significantly, not only in the responders (31.0 +/- 12.0%) but also in the non-responders (25.2 +/- 16.4%). CONCLUSIONS: Doppler ultrasonography does not represent the HVPG, and is therefore not suitable for replacing HVPG as a means of assessing the severity of portal hypertension and the response to drugs which reduce the portal pressure in liver cirrhosis.     

Extrahepatic aneurysm of the portal venous system and portal hypertension

Portal venous aneurysm (PVA) is a rare condition characterized by dilatation of the portal venous system. PVA manifestation of symptoms is varied and depends on the aneurysm size, location and related-complications, such as thrombosis. While the majority of reported cases of PVA are attributed to portal hypertension, very little is known about the condition’s pathophysiology and clinical management remains a challenge. Here, we describe a 67-year-old woman who presented with complaint of dyspepsia and without a significant medical history, for whom PVA was incidentally diagnosed. The initial upper abdominal ultrasound revealed marked dilatation of the main portal vein, and subsequent contrast-enhanced computed tomography with angiography revealed a large aneurysm arising from the extrahepatic troncus portion of the portal vein, as well as gastroesophageal varices. A conservative approach using beta-blocker therapy was chosen. The patient was followed-up for 60 mo, during which time the asymptomatic status was unaltered and the PVA remained stable.     

肝静脉压梯度对食管曲张静脉出血的预测价值

目的探讨肝静脉压梯度(HVPG)对预测肝硬化食管曲张静脉出血(EVB)的临床价值。方法对26例有出血史和20例无出血史的肝硬化食管静脉曲张患者进行了HVPG测量,平均随访18个月观察HVPG值与EVB发生率之相关性。结果出血组HVPG值平均为15.13±3.57mmHg,明显高于非出血组11.07±2.21mmHg,两组相比差异显著(P<0.05);HVPG值>12mmHg者EVB或EVB再发率为73％,而HVPG值<12mmHg者EVB发生率为10％(P<0.01)。结论HVPG测定有预测首次EVB或EVB再发的价值。     

Cirrhosis and portal hypertension: The importance of risk stratification,the role of hepatic venous pressure gradient measurement

Portal hypertension is the main prognostic factor in cirrhosis. The recent emergence of potent antiviral drugs and new algorithm of treatment for the management of complications due to portal hypertension have sensibly changed our perception of cirrhosis that can be now considered as a multistage liver disease whose mortality risk can be reduced by a tailored approachfor any stage of risk. Experts recommend to move toward a pathophysiological classification of cirrhosis that considers both structural and functional changes. The hepatic venous pressure gradient HVPG, is the reference gold standard to estimate the severity of portal hypertension in cirrhosis. It correlates with both structural and functional changes that occur in cirrhosis and carries valuable prognostic information to stratify the mortality risk. This article provides a general overview of the pathophysiology and natural course of cirrhosis and portal hypertension. We propose a simplified classification of cirrhosis based on low, intermediate and high mortality stage. The prognostic information provided by HVPG is presented according to each stage. A comparison with prognostic models based on clinical and endoscopic variables is discussed in order to evidence the additional contribute given by HVPG on top of other clinical and instrumental variables widely used in clinical practice.     

非肝硬化门脉高压患者临床特点分析

目的 总结非肝硬化门脉高压症(NCPH)患者的临床特点和肝静脉压力梯度(HVPG)的变化.方法 2017年1月～2019年12月南京市第二医院住院的28例NCPH患者,采用Seldinger法穿刺右侧颈内静脉,使用一次性球囊导管测定肝静脉压力,计算HVPG,接受肝活检检查.结果 在本组28例NCPH患者中,诊断特发性门...     

Effect of viral suppression on hepatic venous pressure gradient in hepatitis C with cirrhosis and portal hypertension

Portal hypertension is a predictor of liver‐related clinical events and mortality in patients with hepatitis C and cirrhosis. The effect of interferon‐free hepatitis C treatment on portal pressure is unknown. Fifty patients with Child‐Pugh‐Turcotte (CPT) A and B cirrhosis and portal hypertension (hepatic venous pressure gradient [HVPG] >6 mm Hg) were randomized to receive 48 weeks of open‐label sofosbuvir plus ribavirin at Day 1 or after a 24‐week observation period. The primary endpoint was sustained virologic response 12 weeks after therapy (SVR12) in patients who received ≥1 dose of treatment. Secondary endpoints included changes in HVPG, laboratory parameters, and MELD and CPT scores. A subset of patients was followed 48 weeks posttreatment to determine late changes in HVPG. SVR12 occurred in 72% of patients (33/46). In the 37 patients with paired HVPG measurements at baseline and the end of treatment, mean HVPG decreased by ‐1.0 (SD 3.97) mm Hg. Nine patients (24%) had ≥20% decreases in HVPG during treatment. Among 39 patients with pretreatment HVPG ≥12 mm Hg, 27 (69%) achieved SVR12. Four of the 33 (12%) patients with baseline HVPG ≥12 mm Hg had HVPG <12 mm Hg at the end of treatment. Of nine patients with pretreatment HVPG ≥12 mm Hg who achieved SVR12 and completed 48 weeks of follow‐up, eight (89%) had a ≥20% reduction in HVPG, and three reduced their pressure to <12 mm Hg. Patients with chronic HCV and compensated or decompensated cirrhosis who achieve SVR can have clinically meaningful reductions in HVPG at long‐term follow‐up. (EudraCT 2012‐002457‐29).     

Use of portal pressure studies in the management of variceal haemorrhage

Portal hypertension occurs as a complication of liver cirrhosis and complications such as variceal bleeding lead to significant demands on resources. Endoscopy is the gold standard method for screening cirrhotic patients however universal endoscopic screening may mean a lot of unnecessary procedures as the presence of oesophageal varices is variable hence a large time and cost burden on endoscopy units to carry out both screening and subsequent follow up of variceal bleeds. A less invasive method to identify those at high risk of bleeding would allow earlier prophylactic measures to be applied. Hepatic venous pressure gradient (HVPG) is an acceptable indirect measurement of portal hypertension and predictor of the complications of portal hypertension in adult cirrhotics. Varices develop at a HVPG of 10-12 mmHg with the appearance of other complications with HPVG > 12 mmHg. Variceal bleeding does not occur in pressures under 12 mmHg. HPVG > 20 mmHg measured early after admission is a significant prognostic indicator of failure to control bleeding varices, indeed early transjugular intrahepatic portosystemic shunt (TIPS) in such circumstances reduces mortality significantly. HVPG can be used to identify responders to medical therapy. Patients who do not achieve the suggested reduction targets in HVPG have a high risk of rebleeding despite endoscopic ligation and may not derive significant overall mortality benefit from endoscopic intervention alone, ultimately requiring TIPS or liver transplantation. Early HVPG measurements following a variceal bleed can help to identify those at risk of treatment failure who may benefit from early intervention with TIPS. Therefore, we suggest using HVPG measurement as the investigation of choice in those with confirmed cirrhosis in place of endoscopy for intitial variceal screening and, where indicated, a trial of B-blockade, either intravenously during the initial pressure study with assessment of response or oral therapy with repeat HVPG six weeks later. In those with elevated pressures, primary medical prophylaxis could be commenced with subsequent close monitoring of HVPG thus negating the need for endoscopy at this point. All patients presenting with variceal haemorrhage should undergo HVPG measurement and those with a gradient greater than 20 mmHg should be considered for early TIPS. By introducing portal pressure studies into a management algorithm for variceal bleeding, the number of endoscopies required for further intervention and follow up can be reduced leading to significant savings in terms of cost and demand on resources.     

肝静脉压力梯度在肝硬化门静脉高压症患者中的临床应用

测量肝静脉压力梯度（HVPG）是评估门静脉高压症最常用的方法。大量研究表明,HVPG可作为食管静脉曲张出血的预测因子,此外,HVPG还可作为一个预后指标,可方便临床医生以其做参考为静脉曲张出血的一级预防和二级预防来制定合适的治疗策略。现阶段的治疗目标是使HVPG下降到12 mm Hg以下或比基线值下降20%,达到此目标的患者其食管静脉曲张的首次出血和再出血的风险均大大降低。对于一级预防,非选择性的β受体阻滞剂,如心得安,临床已广泛应用;然而,再出血的发生率仍然很高,临床上常用包括非选择性β受体阻滞剂在内的药物联合治疗和内镜干预,如经颈静脉肝内门体静脉分流术（TIPS）、内镜下硬化剂注射和内镜下套扎。主要探讨目前HVPG的测量方法及其临床应用,并重点对在肝硬化中HVPG对食管静脉曲张出血和再出血及治疗反应的预测作用做详细阐述。     

Wedged hepatic venous pressure reflects portal venous pressure during vasoactive drug administration in nonalcoholic cirrhosis

Hepatic venous catheterization is widely used to assess portal pressure. However, it remains unclear whether wedged hepatic venous pressure is a close indicator of portal venous pressure during vasoactive drug administration in nonalcoholic cirrhosis. To address this issue, we analyzed the data from our previous published studies. Forty patients with nonalcoholic cirrhosis (HBV infection in five, HCV infection in 28, and cryptogenic in seven) were available in this analysis. A vasoconstrictor (N=14), vasodilator (N=10), or combination (N=16) was administered. The agreement of the changes between portal and wedged hepatic venous pressures during pharmacological manipulation was assessed by an intraclass correlation coefficient. The intraclass correlation coefficient in each subgroup was more than 0.60 (0.62 in vasoconstrictor group, 0.87 in vasodilator group, and 0.73 in combination group). When the analysis was performed according to the cause of liver disease, the values were 0.67 in HBV infection, 0.73 in HCV infection, and 0.74 in cryptogenic cirrhosis. These results suggest that wedged hepatic venous pressure reflects portal venous pressure during vasoactive drug administration in patients with nonalcoholic cirrhosis.     

探讨肝硬化测定肝静脉压梯度和门静脉血管阻力与食管静脉曲张再出血之关系

对有食管静脉曲张 (EV)出血后 ,肝硬化并门静脉高压之患者 2 1例 ,测定肝静脉压梯度 (HVPG)为 (2 2 6± 0 34)kPa;继之对其中之 18例又测门静脉血管阻力 (PVR)为 (0 2 3± 0 0 6 )kPa·ml 1·min·kg。治疗分两组 :手术组(n =10 )和介入组 (n =11) ,前者其HVPG和PVR之两值显著低于后者 ,随访 18个月内再出血率 ,手术组 (30 % )显然低于介入组 (5 4 6 % ) ,但两组之再出血例如以两值中位数相对比则无差异 ,均发生于高值者。再出血例与未再出血例就两值相对比 ,前者显著高于后者 ,差异非常显著 ,PVR尤著 (P <0 0 0 1)。本研究提示HVPG >2 33kPa ,PVR >0 2 2kPa·ml 1·min·kg是EV再出血危险的域值。HVPG与PVR呈正相关。     

Percutaneous transhepatic measurement of the pressure gradient between the portal and hepatic veins

Abstract Background: Knowledge of the portal pressure may be of value in the assessment of patients with chronic liver disease but its measurement is problematic. Aims: To evaluate the ease and safety of percutaneous transhepatic measurement of the pressure gradient between the portal and hepatic veins and to determine directly the need for an internal zero. Methods: Sixty-one patients undergoing liver biopsy for suspected liver disease had pressures in branches of portal and hepatic veins measured using a flexible 22G (Chiba) needle. Results: The procedure was successful in all patients, took less than ten minutes in most, and was associated with minimal discomfort. Post-procedure morbidity was similar to that of liver biopsy. Portal pressure using an external zero (either puncture site or sternal angle) was inaccurate compared with pressures obtained using the generally accepted gold standard internal zero, hepatic venous pressure, and led to incorrect classification of the presence or absence of portal hypertension in at least 10% of patients. Variations in hepatic venous pressure were not predictable on clinical grounds. The only histopathological feature predictive of portal hypertension was cirrhosis, 20 of 25 patients with and four of 36 patients without cirrhosis having portal hypertension. Of routine biochemical and haematological tests, only plasma albumin and platelet count jointly (and negatively) predicted hepatic venous pressure gradient on multiple regression analysis (R²= 0.40). Conclusions: The use of an internal zero is essential for accurate measurement of portal pressure and this can be achieved safely using the percutaneous, transhepatic route in patients with well compensated liver disease.     

Assessment of the agreement between wedge hepatic vein pressure and portal vein pressure in cirrhotic patients

BACKGROUND: Measuring wedged hepatic venous pressure and hepatic venous pressure gradient as indices of portal pressure is being increasingly used in assessing the prognosis and response to pharmacological treatment for portal hypertension in cirrhotic patients. AIM: To re-evaluate the agreement and correlation between wedged hepatic pressures and directly measured portal pressures. METHODS: Medline search for studies comparing direct portal with wedged hepatic pressure measurement and assessment of correlation and agreement of the pooled data. RESULTS: Eleven suitable studies included 320 patients. Coefficient of determination (r2) was 0.87 in all patients, 0.87 in 102 patients with alcoholic liver disease, 0.83 in 88 patients with non-alcoholic liver disease and 0.75 in 53 patients with hepatitis C-related liver disease. Coefficient of determination was 0.85 in the 194 patients in whom a wedge catheter and 0.90 in the 113 patients in whom a balloon catheter was used. Agreement according to the method of Bland and Altman was also found to be good, with only 4-8% of the measurements outside 2 standard deviations. CONCLUSIONS: Wedged hepatic pressure measurement correlates well with direct portal pressure measurement and the agreement is sufficiently good to use this as a surrogate measurement.     

Risk factors for hepatic steatosis in adults with cystic fibrosis: Similarities to non-alcoholic fatty liver disease

AIM To investigate the clinical, biochemical and imaging characteristics of adult cystic fibrosis(CF) patients with hepatic steatosis as compared to normal CF controls.METHODS We performed a retrospective review of adult CF patients in an academic outpatient setting during 2016. Baseline characteristics, genetic mutation analysis as well as laboratory values were collected. Abdominal imaging(ultrasound, computed tomography, magnetic resonance) was used to determine presence of hepatic steatosis. We compare patients with hepatic steatosis to normal controls.RESULTS Data was collected on 114 patients meeting inclusion criteria. Seventeen patients(14.9%) were found to have hepatic steatosis on imaging. Being overweight(BMI 25)(P = 0.019) and having a higher pp FEV1(75 vs 53, P = 0.037) were significantly associated with hepatic steatosis. Patients with hepatic steatosis had a significantly higher median alanine aminotransferase level(27 vs 19, P = 0.048). None of the hepatic steatosis patients had frank CF liver disease, cirrhosis or portal hypertension. We found no significant association with pancreatic insufficiency or CF related diabetes.CONCLUSION Hepatic steatosis appears to be a clinically and phenotypically distinct entity from CF liver disease. The lack of association with malnourishment and the significant association with higher BMI and higher pp FEV1 demonstrate similarities with non-alcoholic fatty liver disease. Long term prospective studies are needed to ascertain whether CF hepatic steatosis progresses to fibrosis and cirrhosis.     

内镜超声引导下门静脉压力梯度测定在动物实验中的应用初探

目的探究内镜超声引导下门静脉压力梯度（EUS-PPG）测定在正常小型猪模型中的应用及安全性。方法选取4只小型猪，雌雄各2只，月龄8~12个月，体重20~30 kg，在全麻下经线阵内镜超声引导，使用22 G穿刺针穿刺门静脉、肝静脉、下腔静脉，再使用中心静脉压模块测压，每条血管测3次取平均值。术中及术后监测生命体征，记录门静脉压力梯度（PPG）结果（PPG为门静脉压力与肝静脉或下腔静脉压力差值）以及操作相关并发症情况。结果4只猪均成功测压，门静脉压力（11.0±1.0）mmHg（1 mmHg=0.133 kPa），肝静脉或下腔静脉压力（7.3±1.1）mmHg，计算PPG为（3.8±0.9）mmHg。术中、术后无并发症发生。结论EUS-PPG测定技术成功率高，反映门静脉压力准确，且安全性好。