Greetings to all experts and colleagues. In this issue of CDM Monthly Review (Issue 83), we will share five recent papers in the field of diagnosis and treatment of portal hypertension in liver cirrhosis (three on diagnostic monitoring and two on multidisciplinary treatment). The guest experts for this issue's review are Dr. Qianwen Zhao from the Department of Infectious Diseases at Nanjing Drum Tower Hospital, Dr. Yanna Liu from the Liver Disease and Gastroenterology Center at Beijing You'an Hospital , Capital Medical University, Dr. Kefeng Jia from Tianjin Third Central Hospital, and Dr. Wenhui Zhang from the Department of Gastroenterology at Beijing Daxing District People's Hospital.01 Targeting 5-Hydroxytryptamine Receptor 1A in the Portal Vein to Alleviate 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. Researchers have found elevated levels of 5-hydroxytryptamine (5-HT) in the peripheral blood of patients with cirrhosis. Recently, Zhu CP and colleagues from Changzheng Hospital of the Naval Medical University explored the effects and mechanisms of 5-HT receptor 1A (HTR1A) in the portal vein on PH. Their findings were published in the journal Gastroenterology.
The researchers used models of PH induced by thioacetamide (TAA) injection, bile duct ligation (BDL), or partial portal vein ligation (PPVL). They detected HTR1A expression using real-time PCR, in situ hybridization, and immunofluorescence staining. The effects of 5-HT, the HTR1A agonist 8-OH-DPAT, and the HTR1A antagonist WAY-100635 on portal pressure (PP) were evaluated through in situ portal vein infusion. They confirmed the role of HTR1A in PP regulation using Htr1a knockout (Htr1a-/-) rats and vascular smooth muscle cell (VSMC)-specific Htr1a knockout (Htr1a-/-ΔVSMC) mice.
The results showed that HTR1A expression was significantly elevated in PH rat models and cirrhotic patients. Additionally, 8-OH-DPAT increased PP in rats, while WAY-100635 reduced PP, without affecting liver fibrosis or systemic hemodynamics. Moreover, 5-HT or 8-OH-DPAT directly induced contraction of isolated portal veins (PV). Knockout of Htr1a in rats and VSMC-specific Htr1a knockout in mice prevented the development of PH. The researchers also confirmed that 5-HT triggers cAMP pathway-mediated PV smooth muscle cell contraction through Htr1a in the PV. Furthermore, the HTR1A antagonist alverine effectively reduced PP in TAA-, BDL-, and PPVL-induced PH rat models.
Summary by Qianwen Zhao
Nanjing Drum Tower Hospital, Department of Infectious Diseases
Portal hypertension is a common complication of chronic liver disease and the primary outcome of cirrhosis, which has become the leading cause of death in cirrhotic patients. However, the development of drugs targeting cirrhosis remains in the exploratory stage. Therefore, reducing portal pressure to prevent complications can improve patient prognosis. This study explores the specific mechanisms by which 5-hydroxytryptamine receptor 1A (HTR1A) in the portal vein reduces portal hypertension.
The study found that 5-hydroxytryptamine expression was significantly upregulated in both portal hypertension rat models and cirrhotic patients. 5-hydroxytryptamine directly acts on blood vessels, accelerating their contraction in a dose-dependent manner, suggesting that it can directly regulate portal vein pressure. Therefore, identifying 5-hydroxytryptamine receptors as therapeutic targets for portal hypertension is promising. HTR1A was identified as a key receptor in the process of vascular contraction acceleration by 5-hydroxytryptamine, with high expression detected only in cirrhotic patients and not in healthy individuals.
To further confirm HTR1A’s role in portal hypertension regulation, the researchers used the HTR1A agonist 8-OH-DPAT and the antagonist WAY-100635 to observe their effects on portal pressure. The results showed that WAY-100635 significantly inhibited TAA- and BDL-induced portal hypertension in rats, while 8-OH-DPAT accelerated vascular contraction and exacerbated the development of portal hypertension. Knockout of HTR1A in rats and VSMC-specific Htr1a knockout in mice significantly slowed the progression of portal hypertension by inhibiting cAMP signaling pathway-mediated vascular contraction, reducing portal pressure.
Therefore, the researchers believe that HTR1A could become an effective therapeutic target for portal hypertension, and designing and synthesizing HTR1A antagonists may be a potential clinical treatment strategy for portal hypertension.
02 Role of Spleen Stiffness Measurement in Excluding High-Risk Varices in Patients with Porto-Sinusoidal Vascular Disorder
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 suggests that when spleen stiffness measurement (SSM) by vibration-controlled transient elastography (VCTE) is ≤40 kPa, the rate of high-risk varices (HRV) in compensated cirrhosis patients is low, allowing them to avoid endoscopic screening. Conversely, all patients with porto-sinusoidal vascular disorder (PSVD) require endoscopic screening. Recently, Lucile Moga and colleagues from Université Paris Cité explored the efficacy of SSM-VCTE in excluding HRV in PSVD and portal hypertension patients. Their detailed findings were published in the journal Hepatology.
This retrospective study included 309 PSVD patients from 21 VALDIG centers who had at least one sign of portal hypertension, no history of variceal bleeding, and underwent SSM-VCTE within two years before or after upper gastrointestinal endoscopy. Of these, 154 patients were included in the training cohort, and 155 in the validation cohort.
The results showed that 43% of patients in the training cohort had HRV. Multivariate logistic regression analysis revealed that SSM-VCTE >40 kPa and serum bilirubin ≥1 mg/dL were associated with HRV. SSM-VCTE ≤40 kPa combined with bilirubin <1 mg/dL had a sensitivity of 96% for ruling out HRV, sparing 38% of endoscopies, with a missed HRV rate of 4% and a negative predictive value (NPV) of 95%. In the validation cohort, combining SSM with bilirubin could save 21% of endoscopic screenings (missed HRV rate of 4%, NPV of 94%).
Summary by Yanna Liu
Liver Disease and Gastroenterology Center, Beijing You’an Hospital,Capital Medical University
This study investigated the accuracy of non-invasive exclusion of high-risk varices (HRV) using spleen stiffness measurement (SSM) by vibration-controlled transient elastography (VCTE) in patients with PSVD combined with portal hypertension. The study proposed a model based on SSM and serum total bilirubin (TBIL) levels, showing that patients with SSM ≤40 kPa and TBIL <17 μmol/L had an HRV probability of <5%, allowing them to avoid endoscopic screening.
Porto-sinusoidal vascular disorder (PSVD) is a new concept introduced by the European Liver Vascular Disease Group (VALDIG) in 2019. It was established based on the clinical background of patients with liver biopsy pathology consistent with non-cirrhotic portal hypertension characteristics but lacking clinical, laboratory, or imaging evidence of portal hypertension. For PSVD patients combined with portal hypertension, management currently follows the guidelines for cirrhotic portal hypertension. However, given the differences in pathogenesis, the standards for diagnosing clinically significant portal hypertension and HRV in cirrhotic patients may not apply to the PSVD population.
With the emergence of this new concept, PSVD-related research has become a niche hotspot in the field of liver disease in recent years. The advantages of this study are its focus on a rare type of portal hypertension and being the largest sample size study on SSM diagnosis of HRV, with the highest accuracy in excluding HRV. Additionally, the validation cohort came from 20 European centers, which somewhat confirms the reliability of the model. Unlike the cirrhotic portal hypertension population, the final model did not include platelet count (PLT) but instead included TBIL, possibly because 25% of the study population had hematological diseases, potentially affecting PLT levels. Compared to the extensively validated Baveno VII criteria, the model’s accuracy still requires further validation in other population backgrounds and larger sample cohorts. Non-invasive diagnosis of prognostic events like clinically significant portal hypertension and HRV in PSVD patients will be a research hotspot in the future.
03 Small Transjugular Intrahepatic Portosystemic Shunt Plus 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.
The effectiveness of transjugular intrahepatic portosystemic shunt (TIPS) combined with variceal embolization (VE) for gastric varices (GV) remains controversial. Recently, Xia Y and colleagues from Shandong Provincial Hospital explored whether combining VE with small-diameter (8 mm) TIPS could reduce the rebleeding rate in patients with different types of GV. Their findings were published in the journal Clinical Gastroenterology and Hepatology.
This retrospective cohort study included 629 patients treated with 8 mm stent TIPS for gastric varices from seven medical centers. The primary endpoint was all-cause rebleeding, while secondary endpoints included overt hepatic encephalopathy (OHE) and all-cause mortality.
Among the 629 patients, 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, combining TIPS with VE reduced rebleeding rates (6.2% vs. 13.6%; P=0.005) and OHE (31.0% vs. 39.4%; P=0.02) compared to TIPS alone. However, there was no significant difference in mortality (12.0% vs. 9.7%; P=0.42). Subgroup analysis of GOV2 and IGV1 patients showed that TIPS combined with VE reduced rebleeding rates (GOV2: 7.8% vs. 25.1%; P=0.01; IGV1: 5.6% vs. 30.8%; P=0.03) and OHE rates (GOV2: 31.8% vs. 51.5%; P=0.008; IGV1: 11.6% vs. 38.5%; P=0.04). However, for GOV1 patients, combining VE did not reduce the rebleeding rate (5.9% vs. 8.7%; P=0.37) or OHE rate (33.1% vs. 35.3%; P=0.60) after TIPS.
Summary by Kefeng Jia
Tianjin Third Central Hospital
In the past, combining variceal embolization with TIPS was a routine clinical practice, but in the era of covered stents, the necessity of combining variceal embolization during TIPS, especially when the portal pressure gradient (PPG) is reduced below 12 mmHg, has been a topic of debate. In clinical practice, gastric variceal bleeding can still occur when PPG is below 12 mmHg, indicating that combining variceal embolization with TIPS can effectively prevent rebleeding. However, large-scale clinical data supporting this are lacking.
This national multicenter study included 629 patients undergoing TIPS, with all-cause rebleeding as the primary endpoint, and OHE and mortality as secondary endpoints. Compared to 6 mm, 8-10 mm, and 12 mm stents, 8 mm stents are more commonly used in TIPS procedures in China. The study found that adding variceal embolization to small-diameter (8 mm) TIPS significantly reduced rebleeding and OHE in GOV2 and IGV1 patients, with no evidence of additional benefits for GOV1 patients. This suggests that clinicians can choose TIPS or TIPS+VE based on the type of gastric varices.
The study’s limitations include (1) the exclusion of patients with portal vein thrombosis, a condition that is not uncommon in clinical practice, limiting the applicability of the results; and (2) the failure to exclude patients with large shunts, as variceal embolization might have a greater effect on reducing rebleeding and OHE in GOV2 and IGV1 patients with large shunts.
04 High Prevalence and Clinical Relevance of Intrapulmonary Vascular Dilatations in Patients Undergoing TIPS Implantation
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 appropriate patients is crucial for ensuring optimal outcomes after transjugular intrahepatic portosystemic shunt (TIPS) implantation. However, there is a lack of data on the impact of intrapulmonary vascular dilatations (IPVD) or hepatopulmonary syndrome (HPS) on the clinical course following TIPS placement. Recently, Mauz JB and colleagues from Hannover, Germany, explored the association between IPVD, HPS, and the clinical course of patients undergoing TIPS implantation. Their findings were published in the journal Clinical Gastroenterology and Hepatology.
The study included 265 patients, and IPVD and HPS were detected using contrast-enhanced echocardiography and arterial blood gas analysis. Of these, 136 had IPVD, and 71 met the criteria for HPS. A multivariate competing risk analysis was used to assess cardiac decompensation (CD), hepatic decompensation (HD), and liver transplant-free (LTx-free) survival within one year of follow-up.
The results showed that patients with IPVD had lower Freiburg survival index (FIPS) scores, lower creatinine levels, and more frequent TIPS placement for variceal bleeding. The presence of IPVD was significantly associated with increased rates 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 similar between IPVD and non-IPVD patients (HR: 1.081, 95% CI: 0.630-1.855, P=0.780). HPS patients showed trends toward more 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 these were not statistically significant. LTx-free survival did not differ between HPS and non-HPS patients (HR: 1.052, 95% CI: 0.577-1.921, P=0.870).
Summary by Kefeng Jia
Tianjin Third Central Hospital
Treatment options for patients with complications of cirrhosis and portal hypertension, such as ascites or variceal bleeding, are limited. If liver transplantation is not feasible, TIPS has become the most commonly used clinical treatment. The goal is to reduce portal pressure, lower the risk of further decompensation, and improve survival. However, a significant proportion of patients experience complications such as cardiac decompensation (CD) and hepatic decompensation (HD) after TIPS, with a considerable number of these patients having intrapulmonary vascular dilatations (IPVD) or hepatopulmonary syndrome (HPS). For example, this study reported that 51% of patients had IPVD and 36% had HPS. Clinicians are concerned about whether TIPS will further increase the risk of decompensation in these patients, affecting survival.
The study found that patients with IPVD had significantly increased rates of CD and HD after TIPS, with 85% of CD cases being mild to moderate, which can be managed with diuretics. The main HD complications were ascites and hepatic encephalopathy, and some patients required adjustments to the TIPS stent diameter. However, these patients did not experience increased mortality. HPS patients also had higher rates of CD and HD after TIPS, but the differences were not statistically significant, and there was no difference in LTx-free survival between HPS and non-HPS patients. This study alerts clinicians that screening for IPVD before TIPS can help identify patients at higher risk of cardiac and hepatic decompensation.
However, there are some limitations to this study. For example, most decompensations in patients undergoing TIPS occur within the first three months post-surgery, as mentioned in the study, with the median time to CD and HD being 32 days and 33 days, respectively. Many existing studies suggest that small-diameter TIPS stents can reduce the incidence of short-term decompensation events. However, in this study, most patients used stents with a diameter of 8-10 mm, making it necessary to discern whether the occurrence of postoperative decompensation events was due to stent diameter selection or pre-existing IPVD and HPS.
05 Ratio of von Willebrand Factor to ADAMTS13 as an Effective Predictor of Esophagogastric Varices Progression After Sustained Virologic Response in Hepatitis C Virus-Related Liver Cirrhosis Patients
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.
Esophagogastric varices (EGV) are severe complications of hepatitis C virus-related liver cirrhosis (HCV-LC). In most cases, portal hypertension improves after achieving sustained virologic response (SVR) with direct-acting antiviral (DAA) therapy. However, in some cases, EGV progression occurs even after HCV elimination. Recently, Satoshi Iwai and colleagues from Nara Medical University in Japan studied whether von Willebrand factor (VWF) and a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) could predict EGV progression in HCV-LC after achieving SVR. Their detailed findings were published in the journal Hepatology Research.
This retrospective study included 47 HCV-LC patients who achieved SVR after DAA therapy. Eighteen patients experienced EGV progression after SVR (EGV progression group), while 29 did not (no EGV progression group). Plasma VWF antigen levels and ADAMTS13 activity were measured the day before DAA treatment.
The results showed that plasma VWF antigen levels (P=0.00331) and VWF/ADAMTS13 ratios (P=0.000249) were significantly higher in the EGV progression group than in the no EGV progression group. Multivariate logistic regression analysis found that a 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, patients with a VWF/ADAMTS13 ratio >2.3 had a significantly higher cumulative incidence of EGV progression after achieving SVR than those with a ratio ≤2.3 (HR: 6.4, 95% CI: 1.78-22.96, P=0.0044).
Summary by Wenhui Zhang
Beijing Daxing District People’s Hospital, Department of Gastroenterology
Esophagogastric varices (EGV) are severe complications of liver cirrhosis, with up to 85% of cirrhosis patients developing EGV at some point. Hepatitis C virus-related liver cirrhosis (HCV-LC) is no exception. In most cases, portal hypertension in HCV-LC improves after achieving sustained virologic response (SVR) with DAA therapy. However, in some cases, EGV may worsen even after clearing HCV. Both hepatic venous pressure gradient (HVPG) and endoscopy are invasive procedures, and finding minimally invasive or non-invasive methods to predict the occurrence and worsening of EGV remains a hot topic for clinicians and researchers.
The highlight of this study is the measurement of plasma VWF antigen levels and ADAMTS13 activity the day before DAA therapy, along with endoscopic evaluation of EGV. The results showed that patients with a baseline VWF/ADAMTS13 ratio >2.3 had a significantly higher cumulative incidence of EGV progression after achieving SVR than those with a ratio ≤2.3, leading to the conclusion that the VWF/ADAMTS13 ratio before DAA therapy could predict EGV progression after achieving SVR. Considering the hemodynamic differences between esophageal and gastric varices, the study also found that this ratio was significantly elevated in both the esophageal and gastric varices progression groups. Stratifying patients based on this ratio could help avoid unnecessary endoscopies in low-risk patients.
However, this study has some limitations: (1) The sample size is small (47 patients in total, with 18 experiencing EGV progression and 29 without progression); (2) It is a single-center, retrospective, observational study without a validation cohort; (3) The diagnosis of portal hypertension was based on physical examination, laboratory results, and imaging, without measuring HVPG.
