Dear experts, this CDM monthly review (83rd issue) will share 5 recent articles in the field of diagnosis and treatment of portal hypertension in liver cirrhosis (3 in diagnostic monitoring and 2 in multidisciplinary treatment). Invited experts in this issue: Professor Zhao Qianwen from the Department of Infectious Diseases of Nanjing Drum Tower Hospital, Professor Liu Yanna from the Liver Disease and Digestive Center of Beijing You'an Hospital Affiliated to Capital Medical University, Professor Jia Kefeng from the Third Central Hospital of Tianjin, and Professor Zhang Wenhui from the Department of Gastroenterology of Beijing Daxing District People's Hospital.
01 Targeting serotonin receptor 1A in the portal vein can slow down portal hypertension
Zhu CP, Liu SQ, Wang KQ, et al. Targeting 5-Hydroxytryptamine Receptor 1A in the Portal Vein to Decrease Portal Hypertension. Gastroenterology. 2024 Jun 19.
Portal hypertension (PH) is one of the most common complications of chronic liver disease. Some researchers have found that serotonin (5-HT) levels in the peripheral blood of patients with cirrhosis are elevated. Recently, Zhu CP et al. from Changzheng Hospital of the Naval Medical University discussed the effect of portal vein serotonin receptor 1A (HTR1A) on PH and its mechanism of action. The content was published in the journal Gastroenterology.
The investigator used thioacetamide (TAA) injection, bile duct ligation (BDL) or partial portal vein ligation (PPVL) to induce PH model; Real-time PCR, in situ hybridization and immunofluorescence staining were used to detect the expression of HTR1A. To assess the effects of 5-HT, HTR1A agonist 8-OH-DPAT, and HTR1A antagonist WAY-100635 on portal venous pressure (PP) by intraportal in situ infusion; The regulatory effect of HTR1A on PP was confirmed in Htr1a knockout (Htr1a-/-) rats and vascular smooth muscle cell (VSMC)-specific Htr1a knockout (Htr1a-/-ΔVSMC) mice.
The results showed that the expression of HTR1A was significantly increased in PH rat model and patients with liver cirrhosis. In addition, 8-OH-DPAT increased PP in rats, while WAY-100635 decreased PP in rats, but neither affected liver fibrosis and systemic hemodynamic changes. In addition, 5-HT or 8-OH-DPAT can directly induce contraction of the isolated portal vein (PV). Htr1a gene deletion in rats and VSMCs-specific Htr1a knockout in mice prevent the development of PH. Moreover, 5-HT triggers cAMP-mediated contraction of PV smooth muscle cells through Htr1a in PV. The investigators also confirmed that the HTR1A antagonist alverine has the ability to reduce PP in rats with TAA-, BDL-, and PPVL-induced portal hypertension.
Therefore, the results of this study suggest that 5-HT promotes PH by inducing PV contraction, and HTR1A is a promising therapeutic target. As an HTR1A antagonist, alvirin is expected to be a candidate for clinical PH therapy.
Brief comment丨Zhao Qianwen
Department of Infectious Diseases, Nanjing Drum Tower Hospital
Portal hypertension is one of the most common complications of chronic liver disease and the primary outcome of cirrhosis, which has become the leading cause of death in patients with cirrhosis. However, the development of drugs for cirrhosis is still in the exploratory stage, so it can improve patient outcomes by reducing portal venous pressure to prevent complications. The research team investigated the specific mechanism of action of serotonin receptor 1A (HTR1A) in the portal vein in reducing portal hypertension.
The researchers found that the expression of serotonin was significantly up-regulated in both the rat model of portal hypertension and in patients with liver cirrhosis, and serotonin could directly act on blood vessels to accelerate their constriction in a dose-dependent manner, suggesting that serotonin can directly regulate portal venous pressure. Therefore, it was confirmed that serotonin-acting receptors can be used as effective targets for the treatment of portal hypertension. HTR1A was screened as a key receptor in the process of serotonin accelerating vasoconstriction, and high expression of HTR1A was also detected only in people with liver cirrhosis, and almost no expression in healthy people.
In order to further confirm the regulatory role of HTR1A in portal hypertension, the investigators used HTR1A's agonist 8-OH-DPAT and antagonist WAY-100635 to observe the effect on portal venous pressure. The results showed that WAY-100635 could significantly inhibit the occurrence of portal hypertension in rats induced by TAA and BDL, and similarly, 8-OH-DPAT accelerated vasoconstriction and aggravated the development of portal hypertension in rats. In order to further confirm whether HTR1A is a potential target gene for the treatment of portal hypertension, the researchers constructed systemic knockout HTR1A rats (KO) and vascular smooth muscle cell-specific knockout HTR1A rats (CKO), respectively, and the results showed that KO mice and CKO mice could significantly slow down the development of portal hypertension, which was achieved by inhibiting vasoconstriction mediated by cAMP signaling pathway activation and reducing portal pressure.
Therefore, the investigators believe that HTR1A is expected to be an effective target gene for the treatment of portal hypertension, and the design and synthesis of HTR1A antagonistic drugs may be an important means for the potential clinical treatment of portal hypertension.
02 The role of spleen stiffness measurement in the exclusion of high-risk varicose veins in patients with portal sinus vascular disease
Moga L, Paradis V, Ferreira-Silva J, et al. Performance of spleen stiffness measurement to rule out high-risk varices in patients with porto-sinusoidal vascular disorder. Hepatology. 2024 Jul 2.
The Baveno VII consensus recommends that patients with compensated cirrhosis have a lower rate of high-risk varices (HRV) when the spleen stiffness (SSM) measured by vibration-controlled transient elastography (VCTE) is ≤ 40 kPa and therefore can be exempted from endoscopic screening. In contrast, all patients with portal sinus vascular disease (PSVD) require endoscopic screening. Recently, Lucile Moga et al. from the University of Paris-Cité discussed the effect of SSM-VCTE in excluding HRV in patients with PSVD and portal hypertension. Details were published in the journal Hepatology.
This retrospective study included 309 patients with PSVD at 21 VALDIG centers who had at least one or more signs of portal hypertension, had no history of variceal bleeding, and received SSM-VCTE within 2 years before and after upper endoscopy. A total of 154 patients were enrolled in the training cohort and 155 patients were included in the validation cohort.
The results showed that 43% of patients in the training cohort had HRV. Multivariate logistic regression analysis showed that SSM-VCTE>40 kPa and serum bilirubin≥1 mg/dL were associated with HRV. SSM-VCTE ≤40 kPa and bilirubin < 1 mg/dL had a sensitivity of 96% to rule out HRV, which could eliminate endoscopy in 38% of cases, with a missed HRV rate of 4% and a negative predictive value (NPV) of 95%. In the validation cohort, SSM in combination with bilirubin resulted in a 21% reduction in endoscopic screening (4% missed HRV and 94% NPV).
Thus, SSM-VCTE≤40 kPa plus bilirubin <1 mg/dL) can identify patients with PSVD and portal hypertension with a <5% HRV probability, and such patients are exempt from endoscopic screening.
Brief comment丨Liu Yanna
Liver Disease and Digestive Center, Beijing You'an Hospital, Capital Medical University
This study investigated the accuracy of noninvasive exclusion of high-risk varicose veins (HRV) based on vibration-controlled transient elastography (VCTE) detection of spleen stiffness (SSM) in patients with PSVD and portal hypertension. Finally, a model based on SSM and serum total bilirubin level (TBIL) was proposed, that is, the probability of HRV in patients with SSM ≤ 40 kPa and TBIL < 17 μmol/L was <5%, so this model can be used to rule out the occurrence of HRV and save patients from endoscopy.
Portal venous sinusoidal vascular disease (PSVD) is a new concept proposed by the European Hepatic Angiopathy Study Group (VALDIG) in 2019, which is based on the background of patients with clinical liver biopsy pathology consistent with non-cirrhotic portal hypertension characteristics, but no clinical, experimental, and imaging manifestations related to portal hypertension. At present, for patients with PSVD with portal hypertension, the management is mainly carried out in accordance with the relevant guidelines for portal hypertension in liver cirrhosis. However, due to the different pathogenesis, the criteria proposed for diagnosing clinically significant portal hypertension and HRV in patients with cirrhosis may not be applicable to people with PSVD.
With the introduction of new concepts, PSVD-related research has become one of the "niche" hotspots in the field of liver diseases in recent years. The advantage of this study is that on the one hand, it focuses on a type of portal hypertension that is rarely seen in clinical practice, and on the other hand, it has the largest sample size and the highest accuracy in excluding HRV diagnosis among the published studies on HRV-related topics. In addition, the validation cohort of the study came from 20 units in Europe, which confirmed the reliability of the model to a certain extent. Unlike the cirrhosis portal hypertension population, the model did not ultimately include platelets (PLT) but rather TBIL, possibly because 25% of patients in the study population had a hematologic disease that may affect PLT levels. Compared with the Baveno VII standard, which has been extensively validated, the accuracy of this model needs to be further validated in other population backgrounds and in larger sample cohorts. For patients with PSVD, non-invasive diagnosis-related prognostic events, such as clinically significant portal hypertension and HRV, will be one of the hot spots of future research.
03 Transjugular intrahepatic portosystemic shunt with small-diameter stent combined with variceal embolization for gastric varices: a multicenter cohort study
Xia Y, Tie J, Wang G, et al. Small Transjugular Intrahepatic Portosystemic Shunt Plus Variceal Embolization for Gastric Varices: A Multicenter Cohort Study. Clin Gastroenterol Hepatol. 2024 May 16.
At present, the efficacy of transjugular intrahepatic portosystemic shunt (TIPS) combined with variceal embolization (VE) in the treatment of gastric varices (GV) remains controversial. Recently, Xia Y et al. from Shandong Provincial Hospital investigated whether the combination of VE on small-diameter (8 mm stent) TIPS can reduce the incidence of rebleeding in patients with different types of GV. This article was published in the journal Clin Gastroenterol Hepatol.
This retrospective cohort study included 629 patients in seven medical centers who received 8 mm stent TIPS for gastric varices. The primary endpoint was all-cause rebleeding, with secondary endpoints including overt hepatic encephalopathy (OHE) and all-cause mortality.
A total of 629 patients were enrolled, of whom 429 (68.2%) had type 1 gastroesophageal varices (GOV1), 145 (23.1%) had type 2 gastroesophageal varices (GOV2), and 55 (8.7%) had type 1 isolated gastric varices (IGV1). Across the cohort, combined assisted embolization reduced rebleeding rates compared with TIPS alone (6.2% vs. 13.6%; P=0.005) and OHE (31.0% vs. 39.4%; P=0.02）。 However, there was no statistically significant difference in mortality (12.0% vs. 9.7%; P=0.42）。 In subgroup analysis of GOV2 and IGV1 patients, TIPS plus VE reduced rebleeding rates (GOV2: 7.8% vs. 25.1%; P=0.01；IGV1：5.6% vs. 30.8%； P=0.03) and OHE rate (GOV2: 31.8% vs. 51.5%; P=0.008；IGV1：11.6% vs. 38.5%； P=0.04）。 However, in patients with GOV1, the combination of VE did not reduce the rate of rebleeding after TIPS (5.9% vs. 8.7%; P=0.37) or OHE rate (33.1% vs. 35.3%; P=0.60）。
Thus, TIPS with an 8 mm stent combined with VE reduced postoperative rebleeding and OHE in patients with GOV2 and IGV1 compared with TIPS alone. These findings suggest that patients with GOV2 and IGV1 may benefit from TIPS combined with embolization compared to patients with GOV1.
Brief comment丨Jia Kefeng
The Third Central Hospital of Tianjin
In the past, intraoperative TIPS combined with variceal vein embolization has been a routine clinical practice, but the use of intraoperative variceal vein embolization in the stent graft era, especially when the portal venous pressure gradient (PPG) drops below 12 mmHg, has been a controversial topic. In clinical practice, gastric venous bleeding still exists when the PPG is less than 12 mmHg, indicating that TIPS combined with gastric variceal embolization can effectively avoid rebleeding, but there is a lack of large-scale clinical research data.
The national multicenter study included a total of 629 patients treated with TIPS, with all-cause rebleeding as the primary endpoint and overt hepatic encephalopathy (OHE) occurrence and mortality as secondary endpoints. Compared with 6 mm, 8-10 mm, and 12 mm diameter stents, 8 mm stents are more commonly used in TIPS surgery in China. The addition of variceal embolization to small-diameter (8 mm) TIPS was found to significantly reduce rebleeding and OHE episodes in patients with GOV2 and IGV1, with no evidence of additional benefit in patients with GOV1. Suggests that clinicians can choose TIPS or TIPS+E depending on the type of gastric varice.
Limitations of the study: (1) the study excluded patients with portal vein with thrombosis, and the proportion of patients with clinical portal vein thrombosis was not low, limiting the application of the results; (2) Patients with large shunts were not excluded in the study, because for patients with GOV2 and IGV1 with larger shunts, the effect of embolization may be greater, which will significantly affect the onset of postoperative rebleeding and OHE.
04 High prevalence and clinical relevance of intrapulmonary vasodilation in patients after TIPS
Mauz JB, Rieland H, Berliner D, et al. High Prevalence and Clinical Relevance of Intrapulmonary Vascular Dilatations in Patients Undergoing TIPS Implantation. Clin Gastroenterol Hepatol. 2024 May 9.
Selecting the right patient is critical to ensure the best outcome after transjugular intrahepatic portosystemic shunt (TIPS) is performed. However, there is a lack of data on the effect of intrapulmonary vasodilation (IPVD) or hepatopulmonary syndrome (HPS) on the clinical course of TIPS placement. Recently, Mauz JB et al. from Hanover, Germany, discussed the association between IPVD and HPS in patients undergoing TIPS implantation, and the related content was published in the journal Clin Gastroenterol Hepatol.
A total of 265 patients were included in the study; Echocardiography and blood gas analysis were used to detect the presence of IPVD and HPS, of which 136 cases had IPVD and 71 cases met the criteria of HPS. Multivariate competitive risk analysis was used to assess cardiac decompensation (CD), hepatic decompensation (HD) and liver transplantation-free (LTx) survival within 1 year of follow-up.
The results showed that patients with IPVD had lower Freiburg survival index (FIPS) scores, lower creatinine, and more frequent TIPS due to variceal bleeding. The presence of IPVD was significantly associated with a significantly higher incidence of CD (HR: 1.756, 95%CI: 1.011-3.048, P=0.046) and HD (HR: 1.841, 95%CI: 1.255-2.701, P=0.002). However, LTx-free survival was comparable between patients with IPVD and non-IPVD patients (HR: 1.081, 95%CI: 0.630-1.855, P=0.780). Patients with HPS showed more trends in CD (HR: 1.708, 95%CI: 0.935-3.122, P=0.082) and HD (HR: 1.458, 95%CI: 0.934-2.275, P=0.097), but did not reach statistical significance. There was no difference in LTx-free survival between patients with HPS and patients without HPS (HR: 1.052, 95%CI: 0.577-1.921, P=0.870).
Therefore, pre-TIPS screening for IPVD can help to further identify patients at higher risk of cardiac and hepatic decompensation.
Brief comment丨Jia Kefeng
The Third Central Hospital of Tianjin
Treatment options are limited for patients with complications due to cirrhosis and portal hypertension, such as ascites or variceal bleeding. If liver transplantation is not possible, TIPS has become the most commonly used treatment in clinical practice. The aim is to reduce the risk of further decompensation and improve survival by reducing portal pressure. However, a considerable number of patients are prone to complications such as cardiac decompensation (CD) and hepatic decompensation (HD) after TIPS, and the proportion of pulmonary vasodilation (IPVD) and hepatopulmonary syndrome (HPS) in these patients is not low. For example, 51% of patients with IPVD and 36% with HPS were reported in the study. Whether the postoperative treatment of TIPS in these patients will lead to a further increase in the risk of decompensation, which will affect the survival of these patients, is a concern and concern for clinicians.
The study found that patients with IPVD had a significantly increased incidence of CD and HD after TIPS, with 85% of CD severity being mild to moderate, which could be controlled clinically with intensive diuretics. The predominant forms of HD are ascites and hepatic encephalopathy, and some patients require adjustment of the TIPS stent diameter, although this does not result in increased mortality. Patients with HPS also had an increased incidence of CD and HD after TIPS, but not statistically significant, and there was no difference in liver transplant-free survival between patients with HPS and those without HPS. This study provides clinicians with a warning that preoperative screening for IPVD with TIPS can help to further identify patients at higher risk of cardiac and hepatic decompensation.
However, there are some limitations to the study, for example, most decompensation in patients treated with TIPS occurs within the first 3 months after surgery, such as the median time to CD and HD after surgery was 32 days and 33 days, respectively. Many studies have reported that small-diameter TIPS scaffolds can reduce the occurrence of short-term decompensation events. However, the vast majority of patients in this study used stents with a diameter of 8-10 mm, and it is necessary to distinguish whether the postoperative decompensation event is caused by the choice of stent diameter or preoperative IPVD and HPS.
05 In patients with hepatitis C virus-associated cirrhosis, the ratio of vascular hematologic factors to ADAMTS13 is a valid predictor of esophagogastric varices progression after sustained virologic response
Iwai S, Akahane T, Takaya H, et al. Ratio of von Willebrand factor to ADAMTS13 is a useful predictor of esophagogastric varices progression after sustained virologic response in patients with hepatitis C virus-related liver cirrhosis. Hepatol Res. 2024 Jun 5.
Esophageal and gastric varices (EGV) are a serious complication of hepatitis C virus (HCV)-associated cirrhosis (HCV-LC). In most cases, portal hypertension improves after achieving a sustained virologic response (SVR) with direct antiviral (DAA) therapy. However, in some cases, EGV exacerbation can still occur after HCV elimination. Recently, Satoshi Iwai et al., from Nara Medical University, Japan, investigated whether vascular hematologic factor (VWF) and disintegrin-like metalloproteinase (ADAMTS13) with thrombospondin type 1 motif 13 can predict EGV progression in HCV-LC after reaching SVR. Details were published in the journal Hepatol Res.
The retrospective study included 47 patients with HCV-LC who achieved SVR after DAA therapy. Eighteen patients developed EGV progression after achieving the SVR (EGV progression group). Twenty-nine patients did not progress to EGV after achieving the SVR (no EGV progression group). Plasma VWF antigen levels and ADAMTS13 activity are measured one day before DAA treatment.
The results showed that the plasma VWF antigen level (P=0.00331) and VWF/ADAMTS13 ratio (P=0.000249) in the EGV progression group were significantly higher than those in the non-EGV progression group. Multivariate logistic regression models showed that VWF/ADAMTS13 ratio >2.3 was the only risk factor for EGV progression after SVR (HR: 18.4, 95%CI: 3.08-109, P=0.00138). During the observation period, the cumulative incidence of EGV progression after achieving SVR was significantly higher in patients with a VWF/ADAMTS13 ratio of > 2.3 than in patients with a ratio ≤of 2.3 (HR: 6.4, 95% CI: 1.78-22.96, P=0.0044).
Therefore, the ratio of VWF to ADAMTS13 before HCV DAA treatment predicts EGV progression after SVR is achieved.
Brief comment丨Zhang Wenhui
Department of Gastroenterology, Daxing District People's Hospital, Beijing
Esophagogastric varices (EGV) are a serious complication of cirrhosis, with up to 85% of patients with cirrhosis developing EGV at some point in time. The same is true for hepatitis C virus-associated cirrhosis (HCV-LC). In most cases, HCV-LC portal hypertension improves after achieving a sustained virologic response (SVR) with DAA treatment; However, in some cases, EGV worsens even after HCV clearance. However, both HVPG and endoscopy are invasive procedures, and how to predict the appearance and deterioration of EGV through minimally invasive or non-invasive methods is still a hot issue for clinicians and researchers.
The study featured the measurement of plasma VWF antigen levels and ADAMTS13 activity one day before DAA treatment, along with endoscopic assessment of EGV. The results showed that the cumulative incidence of EGV progression after SVR was significantly higher in patients with baseline VWF/ADAMTS13>2.3 than in patients with a ratio of ≤ 2.3, so it was concluded that the VWF/ADAMTS13 ratio before DAA treatment for HCV could predict EGV progression after SVR was achieved. At the same time, considering the difference in the hemodynamics of EV and GV, the study also found that the ratio was significantly higher in both the EV and GV progression groups. Stratification of patients through this indicator can avoid unnecessary endoscopy in low-risk patients.
However, the study also had some limitations: (1) the sample size was small (47 patients in total, 18 with EGV progression and 29 without progression); (2) it was a single-center retrospective and observational study, and no confirmatory cohort study was conducted; (3) The diagnosis of portal hypertension was based on physical examination, laboratory results and imaging, and the patient's HVPG was not measured.