Hepatic venous pressure gradient-guided laparoscopic splenectomy and pericardial devascularisation versus endoscopic therapy for secondary prophylaxis for variceal rebleeding in portal hypertension (CHESS1803): study protocol of a multicenter randomised controlled trial in China
Ruoyang ShaoZhiwei LiJitao WangRuizhao QiQingbo LiuWeijie ZhangXiaorong MaoXiaojing SongLei LiYanna LiuXin ZhaoChuan LiuXun� LiChangzeng ZuoWeidong WangXiaolong Qi
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Introduction Gastro-oesophageal variceal bleeding is one of the most common and severe complications with high mortality in cirrhotic patients who developed portal hypertension. Hepatic venous pressure gradient (HVPG) is a globally recommended golden standard for the portal pressure assessment and an HVPG ≥16 mm Hg indicates a higher risk of death and rebleeding. This study aims to compare the effectiveness and safety of splenectomy and pericardial devascularisation (laparoscopic therapy) plus propranolol and endoscopic therapy plus propranolol for variceal rebleeding in cirrhotic patients with HVPG between 16 and 20 mm Hg. Methods and analysis This is a multicenter, randomised, controlled clinical trial. Participants will be 1:1 assigned randomly into either laparoscopic or endoscopic groups. Forty participants whose transjugular HVPG lies between 16 and 20 mm Hg with a history of gastro-oesophageal variceal bleeding will be recruited from three sites in China. Participants will receive either endoscopic therapy plus propranolol or laparoscopic therapy plus propranolol. The primary outcome measure will be the occurrence of gastro-oesophageal variceal rebleeding. Secondary outcome measures will include overall survival, occurrence of hepatocellular carcinoma, the occurrence of venous thrombosis, the occurrence of adverse events, quality of life and tolerability of treatment. Outcome measures will be evaluated at baseline, 12 weeks, 24 weeks, 36 weeks, 48 weeks and 60 weeks. Multivariate COX regression model will be introduced for analyses of occurrence data and Kaplan-Meier analysis with the log-rank test for intergroup comparison. Ethics and dissemination Ethical approval was obtained from all three participating sites. Primary and secondary outcome data will be submitted for publication in peer-reviewed journals and widely disseminated. Trial registration number NCT03783065 ; Pre-results. Trial status Recruitment for this study started in December 2018 while the first participant was randomised in January 2019. Recruitment is estimated to stop in October 2019.Keywords:
Portal vein thrombosis
Clinical Significance
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SUMMARY
Liver cirrhosis is frequently complicated by the development
of portal hypertension. This syndrome is characterised
by a pathological increase of the portal venous pressure,
which leads to the formation of portal-systemic collaterals.
Among these, gastroesophageal varices are of special
interest, since are responsible for the main complication
of portal hypertension, massive gastrointestinal bleeding.
The development of collaterals is due to different factors,
including the dilation of pre-existing vessels and the
action of angiogenic factors. Once formed, varices tend to
dilate as a function of time, persistence of portal hypertension,
and repeated physiological stimuli such as meals, ethanol
consumption, exercise, and increased intrabdominal
pressure which cause abrupt rises in portal pressure and/
or blood flow. The concept ofvariceal wall tension, which
combines variceal size, variceal wall thickness, and variceal
pressure correlates well with the clinical observation that
increased variceal pressure, increased variceal size and
presence of red colour signs are independent predictors of
the risk ofvariceal bleeding. Tension in the variceal wall is
probably the decisive factor determining variceal bleeding,
as when exceeding the elastic limit of the vessel, the varix
ruptures. Endoscopie and endosonographic examinations
may allow a better assessment ofvariceal pressure, size and
wall thickness, and thus a more accurate evaluation of the
individual risk ofvariceal bleeding in cirrhotic patients.
Key Words: Liver Cirrhosis, Portal hypertension, Gastroeophageal
varices, Variceal size, Variceal wall tension,
Variceal bleeding.
Varix
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The pathologic increase in the pressure gradient between portal vein and inferior venacava is called portal hypertension. Increased portal blood flow and increased resistance in the portal venous system cause portal hypertension. The structural components and the functional components contribute to the resistance. Hepatic venous pressure gradient (HVPG) reflects the degree of portal pressure in liver disease. HVPG is calculated as the difference between the wedged hepatic venous pressure (WHVP) and the free hepatic venous pressure (FHVP). Clinically significant portal hypertension (CSPH) is defined as HVPG ≥10. Different values of HVPG have been defined as threshold for different consequences of portal hypertension. Variceal hemorrhage, portal hypertensive gastropathy, ascites, colopathy, biliopathy and hepatopulmonary syndrome are main complications of portal hypertension. Besides nonselective beta blockers, other drugs like statins, antioxidants, antidiabetic, anti-inflammatory and antiapoptotic drugs have also been seen to be effective in reducing portal pressure.
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The correct treatment of portal hypertension associated with myeloproliferative disorders remains uncertain. Splenectomy has been advocated by some to eliminate the forward flow component of the portal hypertension and thus reduce portal pressure. The authors describe three recent cases of myeloproliferative disorder in whom splenectomy failed to achieve any significant amelioration of portal hypertension, with in-depth hemodynamic studies in one patient. Based on these experiences, the authors suggest that splenectomy is not the optimum treatment of the portal hypertension associated with myeloproliferative disorders.
Myeloproliferative Disorders
Myeloproliferative neoplasm
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Presentation (obstetrics)
Varix
Case presentation
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Portal hypertension is a major consequence of any chronic liver disease and it represents the main mechanism of complication occurrence. Therefore, the assessment of portal hypertension presence is one of the most important steps in the management of any chronic liver diseases. The most accurate tool for portal pressure assessment is hepatic venous pressure gradient (HVPG) measurement, which has diagnostic and prognostic relevance. In this paper we review the methodology of HVPG measuring, together with the clinical relevance of this technique. Portal hypertension is defined as a HVPG higher than 5 mmHg, but clinically significant portal hypertension that predisposes to clinical decompensation is defined as HVPG higher than 10 mmHg. HVPG is useful for portal hypertension treatment monitoring. A decrease in HVPG greater than 20% or under the threshold of 12 mmHg is considered to be protective against portal hypertension-related events. Even if HVPG measurement is a safe procedure, it is still considered an invasive technique and not widely available. Therefore, non-invasive markers of portal hypertension were searched for. Until now only liver stiffness measurement by transient elastography has proved to be sufficiently accurate but there is still heterogeneity among the cut-off values for portal hypertension diagnosis.
Transient elastography
Decompensation
Chronic liver disease
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INTRODUCTION :
Portal hypertension can occur due to many reasons. One of the commonest causes for portal hypertension is cirrhosis. Other important causes are non cirrhotic portal fibrosis (NCPF) and extra hepatic portal vein obstruction (EHPVO). Portal pressure increases in cirrhosis initially as a result of an increased resistance to portal flow. This mostly results from fibrous tissue and regenerative nodules formation within the hepatic parenchyma which leads to distortion of the architecture of the liver.
Along with this structural resistance to blood flow, there is an intra-hepatic constriction of the vessels that accounts for twenty to thirty percent of the increase in resistance within the liver. This happens because there is decreased synthesis of nitric oxide endogenously. The obstruction to the portal flow is at perisinusoidal level in NCPF but in EHPVO the obstruction is extra hepatic, which is commonly due to the formation of thrombosis in the portal vein.
Porto-systemic collaterals are formed due to the development of portal hypertension. Although the collaterals are formed to relieve the portal pressure portal hypertension persists due to two causes: (1) an increase in portal venous inflow due to splanchnic arteriolar vasodilatation along with the formation of collaterals and (2) inadequate decompression of the portal venous system through the collaterals since they have a higher resistance than the normal liver. Therefore, an increased portal pressure gradient results from both an increase in portal blood inflow and increase in resistance to portal flow.
Gastroesophageal varices are commonly seen in up to 50% of patients with cirrhosis.6 Gastric varices are seen in 20-25% of patients with portal hypertension. If the patient is not having varices it will develop at the rate of 8% per annum and one who have small varices will develop larger varices at 8% per year.. In few subsets of patients such as in primary biliary cirrhosis and hepatitis C with bridging fibrosis, even in the absence of overt cirrhosis they have propensity to develop varices in up to 16 % of the patients. Irrespective of the aetiology, the important and dreadful complication of varices is upper gastrointestinal bleeding.
Prevalence of gastric varices is low when compared to esophageal varices. They are present in 6%-35% of patients with portal hypertension. The incidence of bleeding is about twenty-five percent in 2 years and highest bleeding rate is for fundal varices. Risk factors for gastric variceal haemorrhage include fundal varices size (large varices defined as >10 mm, medium -5-10 mm and small >5 mm), Child-Turcotte-Pugh score, particularly Child C status and endoscopic presence of variceal red spots (defined as localized reddish mucosal area or spots on the mucosal surface of a varix).
The risk of bleeding with gastric varices is half that of esophageal varices. The transfusion requirement and mortality are high once the bleeding has occurred particularly for isolated gastric varices (IGV). Large gastric varices patients have a lower portal pressure compared to esophageal varices, which is due to the development of gastrorenal portosysytemic shunts, or large size of the varices resulting in increased wall tension. The type and prevalence of gastric varices varies greatly.
AIM :
The aim of this study is to assess
1. The prevalence of gastroesophageal varices in patients with portal hypertension in a tertiary referral centre
2. Characteristics of the gastric varices and
3. Natural history of gastric varices in portal hypertension.
CONCLUSION :
In conclusion, the results of our study confirm that the prevalence of gastroesophageal varices was low but within the range when compared with various studies.
The type of the varices in Our study tallies with the international classification and the common type is GOV1 as denoted by many studies.
GOV1 is relatively have a benign course and requires treatment only in the form of gastric variceal sclerotherapy if they bleed.
For most GOV2 varices, endoscopic variceal obliteration therapy with N-Butyl 2- Cyanoacrylate is quite useful in arresting the bleeding and achieving the variceal obliteration.
Although endoscopic therapy was effective in treating some patients with IGV1 varices, surgery was required in significant no. of patients to prevent re bleeding.
In our study, the surgery was contemplated for such patients and also for other type of gastric varices because those patients were from far remote places where the immediate endoscopic intervention may not be feasible always.
IGV2 cases were less in Our study and it might require long term follow up to identify such patients. Because the gastric varices have the potential to cause severe upper GI bleeding, its recognition is very important to manage the cases appropriately.
Portal vein thrombosis
Gastric varices
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Cirrhosis is the most common cause of portal hypertension. When the portal venous pressure gradient exceeds a certain threshold, collaterals develop at sites of communication between the portal and systemic circulations. Three-dimensional computed tomography (CT) and magnetic resonance imaging (MRI) are very useful modalities to image the portal vein and assess for the presence of portosystemic collaterals. The most commonly used method to measure portal venous pressure is an indirect approach in which the hepatic venous pressure gradient (HVPG) is determined. Portal venous pressure is directly related to vascular resistance and portal venous blood flow. Increased intrahepatic vascular resistance occurs in cirrhosis due to both structural changes and endothelial dysfunction, which results in intrahe-patic vasoconstriction. In splanchnic and systemic circulations, endothelial dysfunction leads to arterial vasodilation, which increases splanchnic flow and worsens portal hypertension. Gastroesophageal collaterals are of important clinical significance due to the risk of rupture and variceal hemorrhage.
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It is now well established that portal hypertension is not a purely mechanical phenomenon. Primary hemodynamic alterations develop in the hepatic and systemic circulatory systems; these alterations in combination with mechanical factors contribute to the development of portal hypertension. In the hepatic circulation, these hemodynamic alterations are characterized by vasoconstriction and impaired hepatic vasodilatory responses, whereas in the systemic circulation, particularly in the splanchnic bed, vessels are hyperemic with increased flow. Thus, an increase in intrahepatic resistance in conjunction with increased portal venous inflow, mediated through splanchnic dilation, contributes to the development of portal hypertension. The ensuing development of elevated flow and transmural pressure through collateral vessels from the hypertensive portal vasculature into the lower pressure systemic venous circulation accounts for many of the complications, such as bleeding esophageal varices, observed with portal hypertension. The importance of the primary vascular origin of portal hypertension is emphasized by the utility of current therapies aimed at reversing these hemodynamic alterations, such as nitrates, which reduce portal pressure through direct intrahepatic vasodilatation, and ,B blockers and octreotide, which reduce splanchnic vasodilatation and portal venous inflow. New evidence concerning relevant molecular mechanisms of contractile signaling pathways in hepatic stellate cells and the complex regulatory pathways of vasoactive molecules in liver endothelial cells makes a better understanding of these processes essential for developing further experimental therapies for portal hypertension. This article examines the current concepts relating to cellular mechanism that underlie the hemodynamic alterations that characterize and account for the development of portal hypertension.
Hyperdynamic circulation
Splanchnic Circulation
Collateral circulation
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