Hello experts and colleagues, in this 75th issue of the CDM Monthly Review for November 2023, we share six recent publications in the field of portal hypertension diagnosis and treatment (three on diagnosis and monitoring, and three on multidisciplinary treatment). This issue features guest experts: Dr. Bingtian Dong from the Department of Ultrasound at the First Affiliated Hospital of Anhui Medical University, Dr.Ningning Wang from the Department of Gastroenterology at the First Affiliated Hospital of China Medical University, Dr.Lei Zheng from the Department of General Surgery at the Ninth People’s Hospital affiliated with Shanghai Jiao Tong University School of Medicine, and Dr. Sheng Wang from the Department of Gastroenterology at the Third Affiliated Hospital of Sun Yat-sen University.
01
Spleen Stiffness: A New Tool to Predict High-Risk Varices in Cirrhotic Patients
Rui Gaspar, Marco Silva, Pedro Cardoso, Raquel Goncalves, Patrícia Andrade, Guilherme Macedo. Spleen stiffness: a new tool to predict high-risk varices in cirrhotic patients. J Gastroenterol Hepatol. 2023 Sep 1.
Portal hypertension is a major cause of complications related to liver cirrhosis, defined as a hepatic venous pressure gradient (HVPG) >5 mmHg. Traditional measurement of HVPG is invasive, difficult, and expensive, thus only feasible at specialized centers. Measuring liver stiffness with transient elastography is one of the most studied non-invasive markers of portal hypertension, and recently, spleen elastography has emerged as an important adjunct tool. A newly developed probe (100 Hz) can more reliably reflect spleen stiffness and thereby assess the degree of portal hypertension, enhancing accuracy. Recently, Rui Gaspar et al. from the Faculty of Medicine of the University of Porto assessed the accuracy of this new specialized probe in detecting spleen stiffness to predict the presence of high-risk varices and determine the ideal cut-off value for prediction. The findings were published in the J Gastroenterol Hepatol journal.
The study conducted a prospective analysis of 209 cirrhotic patients undergoing upper gastrointestinal endoscopy (average age 61.9±9.9 years, 77.0% male), who also underwent liver and spleen elastography at a tertiary center by the same blinded operator using a 100 Hz probe.
The results showed that the most common etiology was alcoholic liver disease (72.7%). The median liver elastography value was 25.3 (4.5–75) kPa, and the median spleen elastography value was 42.4 (7.6–100) kPa. At a cut-off value of 53.25 kPa for spleen stiffness, the sensitivity for predicting high-risk varices was 100%, with a specificity of 72.6%. According to this threshold, it was possible to avoid 133/175 esophagogastroduodenoscopy (EGD) examinations (76.0%); whereas, based on the Baveno guidelines, only 51/175 patients could avoid EGD (29.1%).
Therefore, in the era of non-invasive examinations, spleen elastography using a 100 Hz probe is an excellent tool for predicting the presence of high-risk varices. At a cut-off value of 53.25 kPa, spleen elastography can avoid upper gastrointestinal endoscopy screening for high-risk varices, potentially becoming a part of routine practice for liver disease specialists.
Brief Review | Dr. Bingtian Dong
Department of Ultrasound, First Affiliated Hospital of Anhui Medical University
Variceal bleeding is one of the most severe complications of portal hypertension. The Baveno VI consensus recommends regular esophagogastroduodenoscopy (EGD) screenings for cirrhosis patients to enable appropriate prophylactic treatment; however, only a minority of compensated patients develop high-risk varices. Moreover, EGD assessments of varices are somewhat invasive, expensive, and carry significant risk of complications. In recent years, ultrasound elastography techniques, including transient elastography and shear wave elastography, have rapidly evolved, garnering widespread attention for their clinical application in liver diseases. Increasing evidence suggests that liver stiffness measurement (LSM) and spleen stiffness measurement (SSM) correlate with liver fibrosis, significant portal hypertension, and varices.
This study, through prospective analysis using EGD as the gold standard for evaluating variceal severity, measured LSM (based on M or XL probes) and SSM (based on a 100-Hz M probe) using the FibroScan Expert 630 (Echosens®) device to assess varices. The results demonstrated that SSM has excellent predictive capability for high-risk varices, superior to LSM. The study proposes a new cut-off value for SSM diagnosis of high-risk varices, potentially avoiding about 76% of EGD examinations, outperforming the Baveno VI guidelines. The study has limitations: the diverse etiology of the study subjects might influence LSM and SSM, leading to some bias; the use of the 100-Hz M probe for measuring SSM lacks a consistent evaluation; and the newly proposed cut-off value lacks external validation. Nevertheless, this study is clinically significant, helping improve the management of cirrhotic patients.
02
A Novel Nomogram Predicting Overt Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt in Portal Hypertension Patients
Liao Y, Zhang L, Wang JT, Yue ZD, Fan ZH, Wu YF, Zhang Y, Dong CB, Wang XQ, Cui T, Meng MM, Bao L, Chen SB, Liu FQ, Wang L. Sci Rep. 2023 Sep 14.
Recently, Liao Y and colleagues from the Capital Medical University in China developed a nomogram based on demographic/clinical indicators such as age, creatinine, blood ammonia, 15-minute indocyanine green retention rate (ICG-R15), and the percentage decrease in portal pressure gradient (PPG) to predict overt hepatic encephalopathy (OHE) in patients with portal hypertension undergoing transjugular intrahepatic portosystemic shunt (TIPS). The study was published in the Sci Rep journal.
This retrospective study included 296 portal hypertension patients treated with selective TIPS at Beijing Shijitan Hospital from June 2018 to June 2020. Patients were randomly divided into a training group (n=207) and a validation group (n=89). Based on the occurrence of OHE, patients were classified into OHE and non-OHE groups. Independent variables predicting OHE post-TIPS were identified through univariate and multivariate analyses. The new model was compared with traditional Child-Pugh and MELD scoring models for accuracy and advantage using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA).
The results showed that age (OR 1.036, 95% CI: 1.002–1.070, P=0.037), creatinine (OR 1.011, 95% CI: 1.003–1.019, P=0.009), blood ammonia (OR 1.025, 95% CI: 1.006–1.044, P=0.011), ICG-R15 (OR 1.030, 95% CI: 1.009–1.052, P=0.004), and the percentage decrease in PPG (OR 1.068, 95% CI: 1.029–1.109, P=0.001) were independent risk factors for OHE post-TIPS. A nomogram was constructed using these five covariates with a well-fitting calibration curve. Compared to the Child-Pugh score and MELD score, the new nomogram showed better predictive value (C-index= 0.828, 95% CI: 0.761–0.896). The results were consistent in the validation cohort and confirmed by DCA.
This study developed a new predictive model using these five variables, which showed better predictive value compared to traditional scoring systems and was replicable in the validation cohort.
Brief Review | Dr. Ningning Wang
Department of Gastroenterology, First Affiliated Hospital of China Medical University
Portal hypertension (PTH) is a manifestation of decompensated liver cirrhosis, clinically presenting as esophageal and gastric variceal bleeding, and even refractory ascites, making it challenging to treat. In recent years, TIPS has been widely used in patients with PTH, offering advantages like minimally invasive procedure, clear therapeutic effects, and quick postoperative recovery. However, there are many complications after TIPS, such as hepatic encephalopathy (HE). Previous studies have shown that the incidence of HE post-TIPS can be as high as 5%–35%. Many risk factors, such as advanced age, Child-Pugh score, and history of HE can predict the occurrence of HE in PTH patients after TIPS. However, traditional models do not include surgery-related factors, such as stent diameter, puncture site, and intraoperative pressure measurement, and thus cannot accurately predict the risk of HE post-TIPS.
This study utilized variables like age, creatinine, and blood ammonia to build a model that more intuitively predicts overt hepatic encephalopathy (OHE) after TIPS. This model will help assess high-risk patients for OHE, implementing preventive and treatment measures post-TIPS, thereby providing strategies for the treatment of PTH.
However, this study also has certain limitations. Being a retrospective study, it uses the change in PPG as one of the model parameters, so the model cannot predict the occurrence of OHE before TIPS. Additionally, this study only underwent internal validation and lacks external validation.
03
Surgical Treatment of Portal Hypertension in Children
Abdumanap Alkhasov, Elena Komina, Sergey Ratnikov, Maria Saveleva, Ekaterina Romanova, Aleksey Gusev, Maksim Lochmatov, Sergey Yatsyk, Elena Dyakonova. J Laparoendosc Adv Surg Tech A. 2023 Oct 16.
Portal hypertension is a syndrome characterized by elevated pressure in the portal venous system, caused by impaired blood flow in the portal vein, hepatic vein, or inferior vena cava. The main complications of this condition are esophageal variceal bleeding (in 100% of the patients in this study), splenomegaly with hypersplenism (in 98% of the patients in this study), and ascites (in one patient in this study). The primary goal of treating portal hypertension is to prevent esophageal variceal bleeding. However, the goal of surgical treatment of portal hypertension in children today is not only to prevent bleeding but also potentially to restore intrahepatic blood flow.
This study retrospectively analyzed the treatment outcomes of 75 children (41 boys and 34 girls) with portal hypertension who underwent surgery at the center from 2019 to 2022. The average age of the patients was 7±1 years. Sixty-nine patients had extrahepatic portal hypertension, and six had intrahepatic type (liver fibrosis). Fourteen cases (18.6%) were reoperations (previous shunt operations were done in another hospital; four children underwent multiple reoperations).
The results found that all children achieved good outcomes, eliminating the risk of esophageal variceal bleeding. All cases underwent vascular bypass surgery: 17 patients (22.7%) underwent portal vein bypass, 37 patients (49.3%) underwent splenorenal shunt, and 21 patients (28%) underwent caval shunt. In 10 cases (13%), reoperations were needed due to dysfunction or thrombosis of the previous bypass. In 14 patients (18.6%) who underwent portal systemic shunting, hepatic blood flow was fully restored.
Therefore, the current main method of surgical treatment for portal hypertension is portosystemic shunting, effectively preventing esophageal variceal bleeding. Portal systemic shunting is a definitive treatment for extrahepatic portal hypertension, capable of restoring hepatic portal perfusion.
Brief Review | Dr. Lei Zheng
Department of Hepatobiliary Surgery, The Ninth People’s Hospital Affiliated with Shanghai Jiao Tong University School of Medicine
Extrahepatic portal vein obstruction (EHPVO) causing pre-hepatic portal hypertension is the most prevalent type of pediatric portal hypertension in developing countries, accounting for 54%-76%. With the advent of Rex shunt and liver transplant techniques, the treatment of EHPVO has significantly evolved. The Baveno VI consensus of 2015 recommends considering Rex shunt for all children with EHPVO when complications arise. Unlike traditional shunting or portosystemic shunt surgeries, Rex shunt not only alleviates portal hypertension but also restores hepatic portal vein blood flow, addressing issues like growth retardation, coagulation disorders, hepatic encephalopathy, and hepatopulmonary syndrome, hence considered a curative surgery.
For children who cannot undergo Rex shunt, if severe clinical symptoms like variceal bleeding, severe splenomegaly, or significant varices are present, Warren shunt should be considered the optimal alternative. In cases where Warren shunt is not feasible, such as post-splenectomy, mesocaval shunt can be performed. For children without severe clinical symptoms, observation is advisable. However, portosystemic shunt surgery might worsen clinical symptoms and is not suitable for these patients, warranting consideration of other methods like endoscopic treatment, shunting, or liver transplantation. According to the author, 87% of cases achieved complete bleeding control after the first surgery, and with repeated interventions, bleeding was completely controlled in 100% of cases. However, Rex shunt was performed in only 22.7% of patients. This might be related to a higher frequency of umbilical vein catheterization and the incidence of infectious complications such as omphalitis and sepsis.
This article, primarily based on case-control study analyses and the author’s experience, combined with current international understanding, lacks high-quality randomized controlled trials, presenting certain limitations.
04
Reversal of Fibrosis and Portal Hypertension by Empagliflozin Treatment of CCl4-Induced Liver Fibrosis: Emphasis on gal-1/NRP-1/TGF-β and gal-1/NRP-1/VEGFR2 Pathways
Noah AA, El-Mezayen NS, El-Ganainy SO, Darwish IE, Afify EA. Eur J Pharmacol. 2023 Nov 15.
Currently, there are no approved clinical treatments for liver fibrosis. Empagliflozin (EMPA), a highly selective sodium-glucose cotransporter-2 (SGLT2) inhibitor, shows potential in improving liver diseases, but its complete mechanism remains undisclosed. Neuropilin-1 (NRP-1) is a novel modulator of fibrogenic signaling pathways associated with hepatic stellate cells (HSCs) and hepatic sinusoidal endothelial cells (HSECs), regulating intrahepatic fibrogenic and angiogenic pathways.
Recently, Noah AA and colleagues from Alexandria, Egypt, evaluated different EMPA doses for their anti-fibrotic potential in a rat model of liver fibrosis and their impact on the galectin-1 (Gal-1)/NRP-1 signaling pathway, as published in the Eur J Pharmacol journal. The study revealed that EMPA treatment led to a dose-dependent decrease in hepatic Gal-1/NRP-1 expression. This corresponded with the inhibition of fibrogenic pathways in HSCs: decreased transforming growth factor-β (TGF-β)/TGF-β RI/Smad2, platelet-derived growth factor-β (PDGF-β), and hepatic Col 1A1 levels. Furthermore, EMPA significantly inhibited angiogenic pathways and vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2)/Src homology 2 domain-containing adaptor protein-b (Shb) pathways, reversing altered portal hypertension (PHT) markers: endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS). Liver fibrosis improvement was accompanied by significant improvement in liver transaminases and histological liver fibrosis Ishak score. The highest dose of EMPA demonstrated good safety, with minimal effects on renal function and blood glucose control.
Therefore, this study brings new insights into the potential treatment of liver fibrosis by EMPA targeting the NRP-1 signaling pathway.
Brief Review | Dr. Lei Zheng
Department of Hepatobiliary Surgery, The Ninth People’s Hospital Affiliated with Shanghai Jiao Tong University School of Medicine
Liver fibrosis, a disease with a high global incidence and poor prognosis, lacks effective intervention measures to delay its progression, leading to various end-stage complications such as gastrointestinal bleeding, hepatic encephalopathy, and portal hypertension. Empagliflozin (EMPA), as a monotherapy, has shown to alleviate hepatic steatosis in diabetic patients with metabolic associated fatty liver disease (MASLD). Additionally, EMPA has demonstrated promising anti-fibrotic effects in studies of diabetes with non-alcoholic fatty liver disease.
This study aims to explore the beneficial intervention effects of EMPA on the progression and mechanisms of liver fibrosis in non-diabetic models. The model used the classic CCl4-induced liver fibrosis rat model, evaluating serum levels of liver fibrosis diagnostic markers at RNA and protein levels and assessing liver stellate cell-related signaling pathways critical in liver fibrosis at the tissue level. The results broadly demonstrated the beneficial effects of EMPA in alleviating liver fibrosis and elevated liver enzymes in the rat model of liver fibrosis, suggesting EMPA, as a highly selective sodium-glucose cotransporter-2 (SGLT2) inhibitor, may function through the galectin-1 (Gal-1)/NRP-1 signaling pathway.
This study is innovative, revealing the potential therapeutic effects of the drug in a heterologous living model, providing insights for clinical treatment of early to mid-stage liver fibrosis. However, the study has limitations, being restricted to rat tissue for tissue analysis and not further exploring the drug’s effect on signaling pathways in target cells. Additionally, the methods for RNA and protein detection are somewhat superficial and could be improved. Future studies could consider including these aspects for a more comprehensive exploration.
05
Proton Pump Inhibitor Treatment Aggravates Bacterial Translocation in Patients with Advanced Cirrhosis and Portal Hypertension
Sturm L, Hirose M, Stolz L, Schultheiss M, Zoldan K, Reincke M, Huber JP, Kaeser R, Boettler T, Thimme R, Albert E, Busch H, Künstner A, Bettinger D. mBio. 2023 Aug 25.
Recent studies suggest that proton pump inhibitors (PPIs) are associated with an increase in complications of liver cirrhosis, such as bacterial infections and hepatic encephalopathy. However, the underlying pathophysiological mechanisms are not clear. Recently, Sturm L and colleagues from the University of Freiburg, Germany, explored the possibility that PPI treatment may promote adverse outcomes in patients with advanced cirrhosis by affecting subclinical bacterial translocation (BT) from the intestine into the portal bloodstream, as published in the mBio journal.
Researchers collected portal vein blood samples from cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) who were treated with PPIs (PPI group, n = 57) and those not treated with PPIs (non-PPI group, n = 23). BT was identified using 16S RNA gene (V1V2 region) polymerase chain reaction (PCR). The microbial community composition in portal vein blood samples was further analyzed using deep sequencing.
The results showed that the BT rate was significantly higher in the PPI group compared to the non-PPI group (86.0% vs. 52.2%, P=0.001). This effect was not due to differences in the severity of cirrhosis, portal hypertension status, or drug treatment between groups. Microbiome analysis indicated a significant increase in α-diversity (Shannon) in the portal blood of patients in the PPI group. Taxonomic analysis revealed a significant increase in the abundance of Streptococcus in these patients. The increase in BT may be an important pathologic mechanism leading to adverse reactions in cirrhotic patients treated with PPIs.
Therefore, the study suggests that bacterial translocation is significantly aggravated in cirrhotic patients treated with PPIs, potentially linking PPI treatment with adverse outcomes in cirrhosis.
Brief Review | Dr. Sheng Wang
Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University
Proton pump inhibitors (PPIs) are widely used in the treatment of liver cirrhosis, primarily for ulcer formation and to prevent rebleeding after endoscopic band ligation. However, recent studies suggest that PPI use may increase the risk of spontaneous bacterial peritonitis, hepatic encephalopathy, and even death. It remains unclear whether PPIs bring clinical benefits to patients with decompensated cirrhosis.
This study, by collecting portal vein blood samples, investigates the effect of PPI use on direct bacterial translocation into the liver bloodstream and bacterial load. This approach differs markedly from previous studies based on intestinal flora translocation, providing new insights and evidence for bacterial translocation post-PPI use. However, the study has limitations, including a small sample size of only 80 cases, and its endpoints—serum bacterial load and other non-direct endpoints—do not directly correlate with clinical outcomes such as spontaneous bacterial peritonitis and hepatic encephalopathy. Therefore, it’s unclear whether PPI use is a primary risk factor for increased bacterial translocation. Additionally, the study presents inconsistencies with previous research, such as the lack of a significant link between the severity of cirrhosis and bacterial translocation, and known surrogate markers for bacterial translocation, like LBP and TNF-α, showing no significant correlation with translocation levels. Further research is needed to confirm these findings and assess their generalizability and extrapolation.
06
How does alcohol use impact morbidity and mortality of liver cirrhosis? A systematic review and dose-response meta-analysis
Llamosas-Falcón L, Probst C, Buckley C, Jiang H, Lasserre AM, Puka K, Tran A, Zhu Y, Rehm J. Hepatol Int. 2023 Sep 8.
Alcohol consumption is the most important risk factor for liver cirrhosis (LC). Existing risk assessments distinguish neither cirrhosis from different causes (such as alcohol-related LC or hepatitis related LC) nor morbidity and mortality as a result. Recently, Llamosas-Falcon L et al. from Canada explored the dose-response relationship between alcohol consumption and LC, as published in Hepatol Int.
The study systematically reviewed the literature from PubMed/Medline and Embase to identify studies that reported an association between alcohol consumption and LC. A total of 44 studies and 1 secondary data source were included, with a total of 5,122,534 participants and 15,150 cases. A meta-regression model was used to evaluate dose-response relationships and control for heterogeneity.
The results found that the researchers identified a non-linear dose-response relationship that weakened as the level of alcohol intake increased. For incidence, the relative risk (RR) of drinking 25 grams per day was 1.81 (95%CI: 1.68 to 1.94) compared with lifetime abstainers. The RR corresponding to 50 g/d and 100 g/d were 3.54 (95%CI: 3.29-3.81) and 8.15 (95%CI: 7.46-8.91), respectively. For mortality, the RR of 25 g/ day was 2.65 (95%CI: 2.22-3.16). The RR of 50 g/d was 6.83 (95%CI: 5.84-7.97). The RR of 100 g/d was 16.38 (95%CI: 13.81-19.42). Alcohol-related LC and all-cause LC are associated with a higher risk compared to hepatitis C-related LC.
As a result, the findings suggest that mortality rates are increasing at a higher rate than morbidity. The findings will help quantify the burden of LC caused by alcohol consumption.
Brief Review | Dr. Sheng Wang
Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University
Alcohol is one of the most common causes of chronic liver disease worldwide, leading to direct liver damage including steatohepatitis, alcoholic hepatitis, cirrhosis, and hepatocellular carcinoma. Annually, about a quarter of global cirrhosis deaths are directly related to alcohol, with nearly a fifth of liver cancer deaths linked to alcohol. With the increasing per capita alcohol consumption globally, alcohol-related cirrhosis and hepatocellular carcinoma are expected to grow.
This systematic review included 44 studies exploring the relationship between alcohol consumption and the incidence and mortality of liver cirrhosis. The study found a nonlinear relationship between alcohol use and both the incidence and mortality of liver cirrhosis, with increases in alcohol consumption correlating with increases in both. Moreover, in stratified analyses of cirrhosis etiology, alcohol consumption posed the highest risk for alcohol-related cirrhosis, followed by all-cause cirrhosis.
The study’s conclusions align with clinical observations, such as higher alcohol consumption increasing the risk of cirrhosis incidence and mortality, and the impact of the same amount of alcohol being greater in women than in men. The dose-response analysis provides a more precise reference for quantifying the impact of alcohol on the development of liver cirrhosis. However, the study has unresolved issues, such as the lack of quantitative analysis of the relationship between alcohol consumption and hepatitis B-related cirrhosis, prevalent in Asia, and only providing consumption data without duration data. Also, the precise calculation of alcohol consumption in clinical research has always been a challenge. The study approximated alcohol consumption from literature in its methodology, which could affect the accuracy of the consumption data and the reliability of the calculated dose-response relationship. Despite these issues, the study scientifically assesses the impact of alcohol consumption on the development of liver cirrhosis, providing more scientific evidence to understand this increasingly serious global disease.