Hello, esteemed experts and colleagues. In this issue of the CDM Monthly Review (Issue 80), we will share six recent articles on the diagnosis and treatment of portal hypertension (four on diagnosis and monitoring, and two on multidisciplinary treatment). We have invited the following experts to review this month’s issue: Dr. Yifei Huang from the Department of Gastroenterology at the Third Affiliated Hospital,Sun Yat-sen University, Professor Yali Xiong from the Department of Infectious Diseases at Nanjing Drum Tower Hospital, and Dr. Jiacheng Liu from the Department of Interventional Radiology at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.
01 Validation of Baveno VII Criteria and Other Non-Invasive Diagnostic Algorithms for Clinically Significant Portal Hypertension in Hepatitis Delta
JJachs M, Sandmann L, Hartl L, Tergast T, Schwarz M, Bauer DJM, Balcar L, Ehrenbauer A, Hofer BS, Cornberg M, Lenzen H, Deterding K, Trauner M, Mandorfer M, Wedemeyer H, Reiberger T, Maasoumy B. Validation of Baveno VII criteria and other non-invasive diagnostic algorithms for clinically significant portal hypertension in hepatitis delta. J Hepatol. 2024 Mar.
Non-invasive testing (NIT) tools for clinically significant portal hypertension (CSPH) in patients with hepatitis delta virus (HDV)-associated compensated advanced chronic liver disease (cACLD) have not been validated. A recent study by Jachs M and colleagues from the Medical University of Vienna explored this issue, with detailed results published in the Journal of Hepatology.
This retrospective study included 51 HDV-cACLD patients (LSM ≥10 kPa or histological METAVIR F3/F4 fibrosis) who underwent paired hepatic venous pressure gradient (HVPG) measurement and NIT evaluation at the Medical University of Vienna or Hannover Medical School between 2013 and 2023. The study assessed liver stiffness (LSM), von Willebrand factor-to-platelet count ratio (VITRO), and spleen stiffness (SSM). Individual CSPH risk was calculated based on previously published models (ANTICIPATE, 3P/5P). The diagnostic performance of Baveno-VII criteria and improved algorithms (Baveno-VII-VITRO, Baveno-VII-SSM) was evaluated in the main cohort and an independent multicenter validation cohort.
Results showed that the CSPH prevalence was 62.7%, and varices prevalence was 42.2%. CSPH patients had significantly higher LSM [25.8 (17.2–31.0) vs. 14.0 (10.5–19.8) kPa, P < 0.001], VITRO [n=31, 3.5 (2.7–4.5) vs. 1.3 (6.6–2.0) %/(G/L), P < 0.001], and SSM [n=20, 53.8 (41.7–75.5) vs. 24.0 (17.0–33.9) kPa, P < 0.001]. Comprehensive CSPH risk models showed excellent AUROC performance (ANTICIPATE: 0.885, 3P: 0.903, 5P: 0.912). The Baveno-VII criteria excluded CSPH with 100% sensitivity and confirmed CSPH with 84.2% specificity. Baveno-VII-VITRO or Baveno-VII-SSM significantly reduced the “gray zone” (41.1%) while maintaining diagnostic accuracy. Liver decompensation within two years occurred only in CSPH patients or those meeting the Baveno-VII inclusion criteria. The predictive value of NIT was confirmed in a validation cohort of 92 patients.
Thus, individual and combined NIT/diagnostic algorithms can be used for CSPH diagnosis in HDV-cACLD patients. NIT can identify CSPH patients related to chronic hepatitis D who should be prioritized for novel antiviral treatments targeting HDV.
Review by Dr. Yifei Huang
Department of Gastroenterology, Third Affiliated Hospital, Sun Yat-sen University
This study explores the value of established, widely validated models such as the ANTICIPATE model based on LSM and PLT, the 3P/5P models based on serological tests, the VITRO model based on vWF and PLT, and the SSM for non-invasive diagnosis of CSPH in chronic hepatitis D patients. These models have shown good performance.
In the population with HBV co-infected with HDV, CSPH is not only an indication for NSBB but also a contraindication for peginterferon. Moreover, CSPH assessment in such patients guides bulevirtide use, highlighting the clinical significance of CSPH evaluation in HDV-infected patients. A search for “hepatitis D virus AND clinically significant portal hypertension” in PubMed reveals that CSPH diagnostic research in hepatitis D patients is still blank. The main highlight of this study is the first exploration of non-invasive assessment methods for CSPH in HDV-infected patients. Although the study did not show interesting innovations or designs in methods, it closely follows the Baveno VII “Research agenda,” indicating that researchers should focus not only on emerging non-invasive diagnostic methods but also on verifying and applying classical non-invasive diagnostic methods across different liver cirrhosis etiologies, decompensation risks, and dynamic changes.
02 Progression of Non-Alcoholic Fatty Liver Disease and Long-Term Outcomes: A Nationwide Paired Liver Biopsy Cohort Study
Simon TG, Roelstraete B, Hagström H, Loomba R, Ludvigsson JF. Progression of non-alcoholic fatty liver disease and long-term outcomes: A nationwide paired liver biopsy cohort study. J Hepatol. 2023 Dec.
Data on the long-term impact of histological progression of non-alcoholic fatty liver disease (NAFLD) on long-term outcomes, including end-stage liver disease (ESLD) and mortality, are still insufficient. Tracey G Simon and colleagues from the Division of Gastroenterology and Hepatology at Massachusetts General Hospital explored this issue, with related content published in the Journal of Hepatology.
The study included adults diagnosed with non-cirrhotic NAFLD by liver biopsy between 1969 and 2017 in Sweden, with at least two liver biopsies spaced more than six months apart (n = 718). At the initial biopsy, NAFLD was classified as simple steatosis, non-fibrotic steatohepatitis (NASH), or non-cirrhotic fibrosis. NAFLD progression was defined as histological changes between the two biopsies (i.e., new-onset NASH, new-onset fibrosis, fibrosis progression, cirrhosis). Cox regression was used to calculate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) to assess the incidence of new-onset ESLD (i.e., hospitalization due to decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation) and mortality.
Results showed that at the initial biopsy, 497 patients (69.2%) had simple steatosis, 90 (12.5%) had non-fibrotic NASH, and 131 (18.2%) had non-cirrhotic fibrosis. The median interval between the two biopsies was 3.4 years, during which 30.4% (218/718) of patients showed NAFLD progression, including 12.5% (62/497) new-onset non-fibrotic NASH, 24.0% (141/587) new-onset fibrosis, and 5.6% (40/718) cirrhosis.
Compared to stable/remitting disease, patients with NAFLD progression had a significantly increased probability of new-onset ESLD (23.8 vs. 11.4/1000 person-years; difference = 12.4/1000 person-years; aHR: 1.65, 95% CI: 1.17-2.32). Although the incidence of ESLD was highest in patients who progressed to cirrhosis (difference vs. stable/remitting disease = 56.3/1000 person-years), early changes, including from simple steatosis to new-onset fibrosis, also significantly increased the risk of ESLD (difference vs. stable/remitting disease = 18.9/1000 person-years). In contrast, there was no difference in all-cause mortality between patients with NAFLD progression and those with stable/remitting disease (difference = 4.7/1000 person-years; aHR: 0.99, 95% CI: 0.78-1.24).
Therefore, the authors concluded that histological progression significantly increases the incidence of new-onset ESLD in a nationwide, real-world cohort with paired NAFLD biopsies but does not seem to affect all-cause mortality.
Review by Professor Yali Xiong
Department of Infectious Diseases, Nanjing Drum Tower Hospital
Previous studies have confirmed that the severity of NAFLD histology can independently predict all-cause mortality, but it remains unclear whether dynamic changes in NAFLD histology affect disease prognosis. Swedish researchers conducted a large, nationwide, paired liver biopsy cohort study to observe the relationship between NAFLD progression and long-term outcomes, including ESLD and mortality.
The study found that 30.4% of NAFLD patients experienced disease progression, including new-onset NASH, fibrosis, or cirrhosis. NAFLD progression was significantly associated with the risk of ESLD, especially for patients progressing to cirrhosis. However, even early changes, such as from simple steatosis to new-onset fibrosis, showed a significant increase in ESLD risk. Thus, the results have significant implications for developing NAFLD treatment strategies, emphasizing the importance of preventing NAFLD progression to reduce the burden of ESLD. Additionally, current NAFLD treatment trials mainly focus on short-term histological endpoints, and this study provides evidence supporting these trial designs.
However, the study did not observe a difference in mortality between patients with stable/regressing NAFLD and those with progressive NAFLD. This might be due to the limited inclusion of stable/regressing NAFLD patients (who are less likely to undergo repeat biopsies). It also suggests that other risk factors beyond NAFLD histological changes might affect survival, warranting further investigation.
The study’s limitations include potential selection bias due to its retrospective design (not all NAFLD patients underwent repeat biopsies), lack of detailed information on biopsy indications, individual fibrosis stages, alcohol use, or weight changes, which might lead to unmeasured confounders. The results may not apply to a broader NAFLD population without liver biopsies.
03 Simple Blood Tests to Diagnose Compensated Advanced Chronic Liver Disease and Stratify the Risk of Clinically Significant Portal Hypertension
Semmler G, Hartl L, Mendoza YP, Simbrunner B, Jachs M, Balcar L, Schwarz M, Hofer BS, Fritz L, Schedlbauer A, Stopfer K, Neumayer D, Maurer J, Szymanski R, Meyer EL, Scheiner B, Quehenberger P, Trauner M, Aigner E, Berzigotti A, Reiberger T, Mandorfer M. Simple blood tests to diagnose compensated advanced chronic liver disease and stratify the risk of clinically significant portal hypertension. Hepatology. 2024 Mar.
Patients with compensated advanced chronic liver disease (cACLD) have a risk of progressing to clinically significant portal hypertension (CSPH), leading to liver-related complications. However, due to the inconvenience of liver stiffness measurement (LSM) in non-specialist institutions, many patients at risk of cACLD/CSPH remain unidentified. Recently, Semmler G and colleagues from the Medical University of Vienna developed a new algorithm based on blood tests, using the FIB-4 index to identify cACLD and the von Willebrand factor-to-platelet ratio (VITRO) to identify CSPH. This research was published in Hepatology.
The study included 6,143 patients with compensated chronic liver disease (or suspected cACLD) who underwent FIB-4 and LSM testing in Vienna and Salzburg, forming the LSM/FIB-4 cohort. Another 247 patients who underwent hepatic venous pressure gradient (HVPG) measurement and VITRO testing formed the HVPG/VITRO cohort.
Results showed that 211 patients (3.4%) in the LSM/FIB-4 cohort experienced liver function decompensation. LSM [AUROC: 0.897 (95% CI: 0.865-0.929)] and FIB-4 [AUROC: 0.914 (95% CI: 0.885-0.944)] had similar accuracy in predicting liver function decompensation within three years. A FIB-4 ≥1.75 identified patients at risk of the first liver function decompensation (5-year cumulative incidence: 7.6%), while patients with FIB-4 <1.75 had negligible risk (0.3%).
In the HVPG/VITRO cohort, 202 patients had cACLD/FIB-4 ≥1.75. VITRO showed excellent diagnostic performance for CSPH [AUROC: 0.89 (95% CI: 0.84-0.934)], similar to LSM [AUROC: 0.856 (95% CI: 0.81-0.910), P = 0.351] and the ANTICIPATE model [AUROC: 0.910 (95% CI: 0.869-0.952), P = 0.498]. VITRO <1.0/≥2.5 could exclude (sensitivity: 100.0%) and confirm (specificity: 92.4%) CSPH, with diagnostic performance comparable to Baveno-VII criteria. The LSM/FIB-4 cohort results were externally validated in 1,560 patients, and the HVPG/VITRO cohort results were internally validated (n = 133) and externally validated (n = 55).
Therefore, simple and widely available laboratory tests (FIB-4/VITRO) can help screen for cACLD and stratify the risk of CSPH in liver disease patients. These blood-based tests are suitable for primary care settings outside specialized institutions and may facilitate early disease intervention.
Review by Dr. Yifei Huang
Department of Gastroenterology, Third Affiliated Hospital,Sun Yat-sen University
The researchers focused on two key concerns for doctors and patients regarding chronic liver disease: “disease progression” and “portal hypertension risk.” They conducted a non-invasive diagnostic study based on serological indicators to explore the value of the classic liver fibrosis score FIB-4 for cACLD and the VITRO model for CSPH diagnosis.
The study’s main highlights are:
- It “breaks away” from LSM and HVPG, which may require higher-level hospitals and specialized doctors, using simple blood tests to classify patients with cACLD and CSPH, showing good diagnostic performance.
- Particularly, the FIB-4 score, validated in a large sample, reflects good research and clinical application prospects against the backdrop of the European Association for the Study of the Liver (EASL) raising the question “Should the compensated advanced chronic liver disease (cACLD) concept replace cirrhosis.”
- This study does not merely innovate and challenge existing non-invasive diagnostic methods for cACLD and CSPH but combines FIB-4 and VITRO to provide a possible, simple method for evaluating the disease status of all suspected CLD patients.
However, the study’s results face the following issues: although the study population includes viral hepatitis, alcoholic hepatitis, and steatohepatitis, it does not explain or subgroup analyze etiological treatment. Whether the conclusions apply to patients at different stages of etiological treatment, especially those emphasizing early liver disease treatment, remains to be explored.
04 Development and Validation of the Nonalcoholic Fatty Liver Disease Familial Risk Score to Detect Advanced Fibrosis: A Prospective, Multicenter Study
Huang DQ, Ahlholm N, Luukkonen PK, Porthan K, Amangurbanova M, Madamba E, Bettencourt R, Siddiqi H, Cervantes V, Hernandez C, Lopez SJ, Richards L, Nemes K, Isoniemi H, Yki-Järvinen H, Loomba R. Development and Validation of the Nonalcoholic Fatty Liver Disease Familial Risk Score to Detect Advanced Fibrosis: A Prospective, Multicenter Study. Clin Gastroenterol Hepatol. 2024 Jan.
Nonalcoholic fatty liver disease (NAFLD)-related fibrosis is heritable, but it is unclear how to use family history to identify first-degree relatives at risk for advanced fibrosis. Recently, Daniel Q Huang and colleagues from the University of California, San Diego School of Medicine developed and validated a simple risk score to identify individuals at higher risk of advanced fibrosis among first-degree relatives of probands who underwent liver fibrosis evaluation. This study was published in Clinical Gastroenterology and Hepatology.
The study consisted of a training cohort from San Diego, California, and a validation cohort from Helsinki, Finland. The study included consecutive adult probands (n = 242), including those with NAFLD and advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD individuals, all with at least one first-degree relative. All enrolled probands and first-degree relatives underwent liver fibrosis evaluation, mostly using magnetic resonance elastography.
Results showed that among the 396 first-degree relatives (64% male), the median age and BMI were 47 years (interquartile range, 32-62 years) and 27.6 kg/m² (interquartile range, 24.1-32.5 kg/m²). Age (1 point), type 2 diabetes (1 point), obesity (2 points), and having a proband with NAFLD and advanced fibrosis (2 points) were predictors of advanced fibrosis in first-degree relatives in the training cohort (n = 220), forming the NAFLD Familial Risk Score. The AUROC for detecting advanced fibrosis in the validation cohort (n = 176) was 0.94, outperforming the FIB-4 index (AUROC = 0.70, P = 0.02).
Thus, the NAFLD Familial Risk Score is a simple and accurate clinical tool for identifying first-degree relatives at risk for advanced liver fibrosis. The data generated in this study may have important implications for NAFLD monitoring.
Review by Professor Yali Xiong
Department of Infectious Diseases, Nanjing Drum Tower Hospital
NAFLD is a global health issue affecting many people worldwide. Advanced liver fibrosis is a critical factor for poor prognosis in NAFLD patients, making it essential to identify high-risk individuals for early intervention and improved patient management. This study aimed to develop a simple risk score tool to identify first-degree relatives of probands who underwent liver fibrosis evaluation and who are at higher risk for advanced fibrosis associated with NAFLD.
The study used a prospective, multicenter, familial study design, including adult probands and their first-degree relatives of different races and ethnicities, increasing the study’s diversity, representativeness, and generalizability. Using multivariate logistic regression analysis, the researchers identified age, obesity, type 2 diabetes, and a history of advanced fibrosis in the proband as independent predictors. The resulting NAFLD Familial Risk Score is simple, easy to calculate, and demonstrated good discriminative ability and calibration in the validation cohort, showing robust predictive performance in an independent sample. This score provides clinicians with a quick tool to assess the risk of advanced liver fibrosis in NAFLD first-degree relatives without laboratory tests.
However, the study has limitations, such as the high rate of advanced fibrosis in the derivation cohort, which may limit its general applicability to the broader population. The study did not include genetic or environmental factors, which could provide additional predictive power to the risk score. Additionally, the study did not assess the risk score system’s application in real clinical settings and its impact on patient management. Further long-term follow-up studies are needed to evaluate the risk score system’s practical application.
05 Transjugular Intrahepatic Portosystemic Shunt for Portal Hypertension with Chronic Portal Vein Occlusion
Luo J, Li M, Wu J, Wang H, Pan T, Wu C, Chen J, Huang M, Jiang Z. Transjugular intrahepatic portosystemic shunt for portal hypertension with chronic portal vein occlusion. Eur J Radiol. 2024 Feb.
A recent retrospective cohort study by the team from the Department of Interventional Radiology at the Third Affiliated Hospital of Sun Yat-sen University, published in the European Journal of Radiology, examined the use of transjugular intrahepatic portosystemic shunt (TIPS) for treating portal hypertension with chronic portal vein occlusion (CPVO).
The study included 106 patients with portal hypertension and CPVO who underwent TIPS between December 2010 and December 2020. Among them, 71 were male, and 35 were female, with an average age of 45.3 ± 13.6 years. 82.1% had a history of variceal bleeding, 10.4% had refractory ascites, and 7.5% had recurrent diarrhea. 45 patients (42.5%) had cirrhosis. Based on preoperative imaging, 85.8% of patients were classified as having adequate inflow (maximum inflow diameter ≥8 mm), and 14.2% as having inadequate inflow (maximum inflow diameter <8 mm).
Results showed that TIPS was successful in 100 patients (94.3%), with no 30-day postoperative mortality. Post-TIPS, the average portosystemic pressure gradient (PPG) decreased from 24.3 ± 4.9 mmHg to 10.5 ± 3.1 mmHg. During a median follow-up of 52.5 months (range: 1.8-144 months), 37 (37%) of the 100 successfully treated patients experienced shunt dysfunction. The overall stent patency rates at 6, 12, 24, and 36 months post-TIPS were 88.9%, 86.8%, 83.6%, and 81.2%, respectively.
Univariate and multivariate regression analyses showed that inadequate inflow and platelet count ≥300×10⁹/L were independent predictors of shunt dysfunction. The risk score was calculated as (0.914 × inflow status) + (3.119 × platelet count). Based on the median risk score, patients were divided into high-risk and low-risk groups. Kaplan-Meier curves showed significantly lower stent patency rates in the high-risk group compared to the low-risk group (P < 0.001). The authors created a nomogram based on multivariate analysis results, showing good predictive performance, with AUROCs of 0.77 and 0.72 for 1-year and 2-year stent dysfunction prediction, respectively.
Review by Dr. Jiacheng Liu
Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
This study shows that TIPS is effective for treating portal hypertension with CPVO. Despite a 37% occurrence of shunt dysfunction, which is higher than in patients without CPVO, further analysis identified inadequate inflow and platelet count ≥300×10⁹/L as significant predictors of shunt dysfunction. This indicates that TIPS may not be suitable for treating portal hypertension with CPVO in patients with inadequate inflow or a high platelet count.
Interventional treatment of portal hypertension with CPVO requires considering multiple factors, including the type of portal hypertension (prehepatic, intrahepatic, and posthepatic), whether the portal vein inflow and outflow tracts are occluded. For prehepatic portal hypertension patients, if the portal vein inflow tract (superior mesenteric vein or splenic vein) and outflow tract (intrahepatic portal vein branches) are not occluded, percutaneous portal vein recanalization (PVR) should be the first choice. If the outflow tract is completely occluded and the inflow tract is not occluded, PVR-TIPS treatment can be considered. For intrahepatic portal hypertension patients, as long as the portal vein inflow tract is not occluded, regardless of outflow tract occlusion, PVR-TIPS treatment can be performed. If both the outflow and inflow tracts are completely occluded and cannot be recanalized, anticoagulation and partial splenic artery embolization may be considered.
06 Predictors and Outcomes of Post-Transjugular Intrahepatic Portosystemic Shunt Liver Failure in Patients with Cirrhosis
Mukund A, Aravind A, Jindal A, Tevethia HV, Patidar Y, Sarin SK. Predictors and Outcomes of Post-transjugular Intrahepatic Portosystemic Shunt Liver Failure in Patients with Cirrhosis. Dig Dis Sci. 2024 Mar.
A recent retrospective cohort study by the team from the Department of Interventional Radiology at the Institute of Liver and Biliary Sciences in New Delhi, India, published in Digestive Diseases and Sciences, analyzed the predictors and outcomes of post-transjugular intrahepatic portosystemic shunt (TIPS) liver failure (PTLF) in cirrhotic patients.
The study included 352 cirrhotic patients who underwent TIPS between May 2012 and June 2022, with 30 (8.5%) developing PTLF within 30 days post-TIPS.
Univariate analysis showed that TIPS indication (P = 0.05), history of hepatic encephalopathy (P < 0.0001), history of variceal bleeding (P = 0.024), preoperative serum creatinine level (P = 0.039), hemoglobin level (P = 0.017), MELD score (P = 0.008), and Child-Pugh score (P = 0.001) were significantly associated with PTLF. Multivariate logistic regression analysis identified history of hepatic encephalopathy and baseline Child-Pugh score as independent predictors of PTLF. AUROC analysis showed that a Child-Pugh score >9 (AUROC: 0.685) had a sensitivity of 83.3% and specificity of 43.2% for predicting PTLF. A MELD score >14 (AUROC: 0.646) had a sensitivity of 60.0% and specificity of 66.5%. There was no significant difference in the diagnostic performance between Child-Pugh and MELD scores (P = 0.533).
Additionally, the study compared survival outcomes between patients with and without PTLF, showing that 90-day transplant-free survival was significantly lower in PTLF patients (40% vs. 96%, P < 0.001).
This study indicates that nearly 10% of cirrhotic patients may develop liver failure after TIPS, significantly associated with early mortality. For patients with a high baseline Child-Pugh score and a history of hepatic encephalopathy, close monitoring of liver function and preventive measures to avert liver failure are crucial post-TIPS.
Review by Dr. Jiacheng Liu
Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
PTLF is a severe complication post-TIPS, potentially leading to patient death. Therefore, identifying predictors of PTLF is crucial for guiding clinicians in risk stratification and early warning for high-risk patients.
This study shows that history of hepatic encephalopathy and baseline Child-Pugh score are independently associated with PTLF. Especially for patients with a Child-Pugh score >9, caution is needed when performing TIPS. However, this does not mean that a Child-Pugh score >9 is a contraindication for TIPS.
For acute gastroesophageal variceal bleeding patients, early TIPS treatment is recommended within three days post-bleeding for high-risk patients with a Child-Pugh score of C (≤13 points) or Child-Pugh B with endoscopic evidence of active bleeding. However, these patients should be closely followed post-TIPS for changes in liver and kidney function and strengthened with liver-protective drugs.
For hemodynamically stable portal hypertension patients, if the Child-Pugh score is >9, medications or other interventions should be used to adjust the score to A or B before performing TIPS to avoid PTLF.
