Greetings to all experts and colleagues. In this issue of the CDM Monthly Review, we will share six recent articles in the field of portal hypertension diagnosis and treatment (four on diagnostic monitoring and two on multidisciplinary treatment). This issue features reviews by invited experts: Professor Pengyuan He from the Center for Infectious Disease Control at the Fifth Affiliated Hospital of Sun Yat-sen University, Professor Wei Gou from the Hepatology Department at the Qingdao Sixth People's Hospital, and Professor Airong Hu from the Liver Disease Center at the Ningbo No.2 Hospital.

01. Early Liver Transplant for Alcohol-Associated Liver Disease Shows Excellent Survival but Higher Rates of Harmful Alcohol Use

Musto JA, Palmer G, Nemer M, Schell T, Waclawik G, Glover Q, Lucey MR, Osman F, Rice JP. Early liver transplant for alcohol-associated liver disease has excellent survival but higher rates of harmful alcohol use. Clin Gastroenterol Hepatol. 2024 May 8.

In recent years, early liver transplantation (ELT) for alcohol-associated liver disease (ALD) has gained popularity globally, yet long-term data remains scarce. A study by Professor Jessica A. Musto and colleagues from the University of Wisconsin-Madison investigated long-term survival rates and postoperative drinking behaviors of ALD patients undergoing ELT. The retrospective study included 708 liver transplant recipients from 2010 to 2020, with a median follow-up of 4.6 years. Results showed that ELT patients were younger and had a median pre-transplant sobriety period of 61.5 days. Survival rates were similar between ELT and standard liver transplant (SLT) groups and superior to the non-ALD group. However, the ELT group had higher rates of alcohol use and harmful alcohol use compared to the SLT group. Harmful alcohol use was associated with post-transplant mortality in univariate analysis but not in multivariate analysis. The study concluded that while ELT patients had higher rates of alcohol use post-transplant, their 10-year survival rates were similar or better than other diagnostic groups, indicating potential long-term benefits for ALD patients.

Commentary by Pengyuan He, Center for Infectious Disease Control, Fifth Affiliated Hospital of Sun Yat-sen University:

Most liver transplant programs require a minimum of 6 months of sobriety as a prerequisite for liver transplant eligibility to observe patients’ voluntary commitment to abstinence. This policy might exclude patients who cannot survive more than 6 months but could benefit from liver transplantation. This single-center, retrospective study from the University of Wisconsin-Madison included 708 patients, comparing the long-term outcomes of patients with less than 6 months of sobriety (ELT), more than 6 months of sobriety (SLT), and non-ALD liver transplant patients, with a median follow-up time of 4.6 years.

The study found that ELT patients had similar 5-year survival rates to SLT patients, both superior to non-ALD patients, but post-transplant alcohol use and harmful alcohol use (defined as consuming more than 4 drinks per day for more than 3 months) were more common in ELT patients.

Whether “more than 6 months of sobriety” is an essential factor affecting post-transplant survival and quality of life or merely a moral requirement is still debatable. The study found that although harmful alcohol use was a risk factor for post-transplant mortality in univariate analysis, it was not significant in multivariate analysis. Similarly, more than 6 months of pre-transplant sobriety was a protective factor against harmful alcohol use in univariate analysis but not significant in multivariate analysis. ELT patients had shorter waiting times for transplant, were more likely to receive standard-compliant donors, and had similar 5-year survival rates to SLT patients. These findings provide valuable guidance for optimizing and potentially redefining transplant eligibility criteria.

This study focused on the impact of pre-transplant sobriety duration on post-transplant survival rates, addressing a critical clinical issue and providing thought-provoking insights. However, the study has some limitations, such as the lack of subgroup analysis for non-ALD patients. Different causes of cirrhosis, liver cancer, and cholangiocarcinoma could significantly affect post-transplant survival rates. It was also a single-center study with specific selection patterns and methods, and as a retrospective study, it could not detail patients’ drinking amounts, durations, and patterns, and follow-up time was still limited to evaluate longer-term survival and prognosis.

02. Liver Fibrosis Assessed via Non-Invasive Tests is Associated with Incident Heart Failure in a General Population Cohort

Hydes TJ, Kennedy OJ, Glyn-Owen K, Buchanan R, Parkes J, Cuthbertson DJ, Roderick P, Byrne CD. Liver fibrosis assessed via non-invasive tests is associated with incident heart failure in a general population cohort. Clin Gastroenterol Hepatol. 2024 May 7.

Current research on the relationship between liver fibrosis and heart failure remains limited. A recent study by Theresa J. Hydes and colleagues from the University of Liverpool aimed to explore this association in a general population and assess the impact of genetic polymorphisms (PNPLA3 rs738409 and TM6SF2 rs58542926) on this relationship. The study used data from the UK Biobank to analyze the relationship between non-invasive fibrosis markers and heart failure hospitalization/mortality events. The results showed that liver fibrosis was associated with an increased risk of heart failure hospitalization or death, with significant associations observed across different fibrosis markers. These associations persisted in various cohorts, including those with metabolic-associated fatty liver disease (MAFLD), MAFLD with alcohol use, and harmful drinking. However, the genetic polymorphisms did not attenuate the positive association between fibrosis markers and heart failure. Significant interactions were observed between PNPLA3 rs738409, certain fibrosis markers, and heart failure. The detailed findings were published in Clinical Gastroenterology and Hepatology.

Commentary by Pengyuan He, Center for Infectious Disease Control, Fifth Affiliated Hospital of Sun Yat-sen University:

Previous genome-wide association studies (GWAS) and candidate gene studies have confirmed that single nucleotide polymorphisms (SNPs) in PNPLA3 and TM6SF2 are associated with liver fibrosis, with patients carrying the GG homozygous variant of PNPLA3 (rs738409) and the TT homozygous variant of TM6SF2 (rs58542926) being at the highest risk for liver fibrosis. However, some studies also suggest these variants protect against cardiovascular disease (CVD).

This study utilized data from the UK Biobank, including 413,860 patients, to explore the relationship between liver fibrosis and incident heart failure using FIB-4 >2.67, NFS >0.676, or APRI ≥1.0 as non-invasive fibrosis diagnostic (NIT) criteria. It aimed to determine if the GG variant of PNPLA3 and TT variant of TM6SF2 modify the association between higher fibrosis scores and incident heart failure risk.

Key findings include: 1) High FIB-4, NFS, and APRI scores were associated with increased incident heart failure risk. This association remained significant after excluding patients with harmful drinking and baseline CVD in two sensitivity analyses; 2) Patients with GG variants of PNPLA3 and TT variants of TM6SF2 with NIT-indicated fibrosis had no reduced incident heart failure risk compared to other genotypes; 3) NFS score was significantly associated with acute coronary syndrome (ACS) in multivariable analysis.

The study used Mendelian randomization and data from the UK Biobank to investigate the potential modifying effect of SNPs in two genes associated with liver fibrosis risk and the predictive value of NIT-diagnosed liver fibrosis for incident heart failure. The study’s large sample size and detailed analysis highlight the importance of screening liver fibrosis in high-risk patients and managing cardiac comorbidities in liver fibrosis patients.

However, the study has limitations: 1) Using serum marker scores for fibrosis diagnosis has a high false-positive rate and may not be the best among NIT methods, potentially leading to selection bias; 2) As data came from a database, repeated measurements were not possible, preventing comparison of fibrosis score changes over time and the assessment of whether fibrosis scores could improve existing heart failure risk prediction tools; 3) The sample was predominantly white, with a clear racial bias, making it difficult to generalize conclusions to other populations. Long-term prospective multicenter cohort studies using higher-efficiency NIT methods or liver biopsies are needed to further explore the relationship between liver fibrosis and incident heart failure.

03. Predictive Role of Hepatic Venous Pressure Gradient in Bleeding Events Among Patients with Cirrhosis Undergoing Orthotopic Liver Transplantation

Giabicani M, Joly P, Sigaut S, Timsit C, Devauchelle P, Dondero F, Durand F, Froissant PA, Lamamri M, Payancé A, Restoux A, Roux O, Thibault-Sogorb T, Valainathan SR, Lesurtel M, Rautou PE, Weiss E. Predictive role of hepatic venous pressure gradient in bleeding events among patients with cirrhosis undergoing orthotopic liver transplantation. JHEP Rep. 2024 Apr 28.

Significant bleeding events during orthotopic liver transplantation (OLT) are associated with poor prognosis, but the extent of risks related to portal hypertension is unclear. A study by Mikhael Giabicani and colleagues from Université Paris Cité explored the predictive ability of hepatic venous pressure gradient (HVPG) for such events in cirrhotic patients undergoing OLT. The findings were published in JHEP Reports. The researchers retrospectively analyzed a prospective database of cirrhotic patients who underwent OLT and preoperative liver and right heart catheterization from 2010 to 2020. The study included 468 patients with a median HVPG of 17 mmHg and a median MELD score of 16 on the day of OLT. Significant intraoperative bleeding events occurred in 33% of patients and were associated with HVPG, preoperative hemoglobin levels, cirrhosis severity, coagulopathy, and cirrhosis complications. Multivariable regression analysis identified HVPG, preoperative hemoglobin levels, MELD score, and tranexamic acid infusion as factors associated with bleeding events. Patients were classified into three risk categories based on HVPG: low risk (<16 mmHg), high risk (≥16 mmHg), and very high risk (≥20 mmHg).

Commentary by Wei Gou, Hepatology Department, Qingdao Sixth People’s Hospital:

The relationship between portal hypertension and intraoperative outcomes, particularly blood loss and red blood cell transfusion during OLT, has been a hot topic for many years, but the potential of HVPG to predict significant intraoperative bleeding events has not been fully studied.

This study shows that HVPG (<16 mmHg; 16–20 mmHg; >20 mmHg) is closely related to blood loss and thresholds, proposing a risk classification for significant bleeding, which helps clinicians predict intraoperative and postoperative management, and individualizes perioperative management, enabling surgical teams to anticipate blood management strategies to reduce exposure to blood products and associated complications and costs. Importantly, the study found that the predictive ability of HVPG is independent of other bleeding-related factors (e.g., preoperative hemoglobin, fibrinogen levels, and MELD score) and specific targeted interventions (e.g., tranexamic acid infusion and temporary portal vein shunt). The study also conducted subgroup analysis, confirming the association between HVPG and significant bleeding events in several subgroups (based on low and moderate MELD scores, OLT indications, and tranexamic acid use).

However, the study has limitations: 1) Its retrospective design may introduce bias in results; 2) HVPG results are inaccurate in acute events, limiting predictive ability in severe patients, such as those with high MELD scores or ACLF at OLT; 3) It is a single-center study; 4) Over more than a decade, surgical and anesthetic practices may have changed.

04. Prospective Evaluation of Patients with Non-Cirrhotic Portal Hypertension: A Single Centre Study

Mironova M, Gopalakrishna H, Viana Rodriguez GM, et al. Prospective evaluation of patients with non-cirrhotic portal hypertension: A single centre study. Aliment Pharmacol Ther. 2024 Apr 17.

Non-cirrhotic portal hypertension (NCPH) refers to liver diseases, including portal sinus vascular disorders, that exhibit portal hypertension without cirrhosis. The natural progression and diagnostic methods of NCPH remain unclear. A study by Marina Mironova and colleagues from Maryland, USA, evaluated the progression and outcomes of NCPH, with findings published in Alimentary Pharmacology & Therapeutics. The single-center, prospective study included patients with NCPH or at risk of NCPH, divided into two groups based on the presence of specific portal hypertension features. All participants underwent baseline liver biopsy, with liver stiffness measurement (LSM) and imaging repeated every 6–12 months. Results showed that patients with specific features had higher hepatic venous pressure gradient (HVPG), non-invasive portal hypertension indicators, and lower platelet counts (PLT) than those without. Survival and decompensation rates were similar between groups. Patients with PLT ≤1×10^5/μL had lower survival rates, and those with LSM ≥10 kPa had shorter overall and decompensation-free survival. Regardless of specific features, all patients had similar survival rates and should be closely monitored, as thrombocytopenia and increased LSM were associated with disease severity and prognosis.

Commentary by Wei Gou, Hepatology Department, Qingdao Sixth People’s Hospital:

NCPH is a rare chronic liver disease characterized by elevated portal vein pressure without cirrhosis. In this prospective, single-center study, longitudinal data were collected from patients without specific portal hypertension features and those at risk of at least one specific feature. Researchers used a prospective and standardized follow-up evaluation method to assess patients at risk for NCPH, categorized them based on the presence or absence of specific portal hypertension features, and provided timely intervention when needed. While NCPH management appears in vascular liver disease guidelines, most current portal hypertension management guidelines are based on cirrhosis recommendations. This study aims to expand understanding of NCPH progression and outcomes, potentially aiding tailored clinical guidance for NCPH.

The study found that patients with specific features of portal hypertension had higher HVPG, non-invasive portal hypertension indicators, and lower platelet counts than those without specific features. Survival and decompensation rates were similar between groups. Patients with PLT ≤1×10^5/μL had lower survival rates than those with PLT >1×10^5/μL. Patients with LSM ≥10 kPa had shorter survival and were more prone to decompensation compared to those with LSM <10 kPa.

The study has three main limitations: 1) The National Institutes of Health Clinical Center in the USA is a research institution and does not provide continuous care for some patients requiring higher-level care; 2) The patient cohort was relatively small; 3) The COVID-19 pandemic significantly affected enrollment rates.

05. Clinical Risk Factors for Portal Hypertension-Related Complications in Systemic Therapy for Hepatocellular Carcinoma

Fujiwara K, Kondo T, Fujimoto K, Yumita S, Ogawa K, Ishino T, Nakagawa M, Iwanaga T, Tsuchiya S, Koroki K, Kanzaki H, Inoue M, Kobayashi K, Kiyono S, Nakamura M, Kanogawa N, Ogasawara S, Nakamoto S, Chiba T, Koizumi J, Kato J, Kato N. Clinical risk factors for portal hypertension-related complications in systemic therapy for hepatocellular carcinoma. J Gastroenterol. 2024 Apr 7.

Systemic antitumor therapy is crucial in treating advanced hepatocellular carcinoma (HCC), but managing portal hypertension-related complications is vital. Adequate evaluation of portal hypertension, preferably through regular endoscopic screening for esophagogastric varices, remains a concern due to low compliance. Identifying clinical risk factors and feasible evaluation methods for HCC patients undergoing systemic therapy is necessary. A retrospective study by Kazuhiro Fujiwara and colleagues from Japan, published in the Journal of Gastroenterology, included 669 HCC patients receiving systemic antitumor therapy. Results showed that systemic antitumor therapy negatively impacted esophageal varices worsening and bleeding, with atezolizumab/bevacizumab potentially leading to rapid progression in patients without pre-existing varices. Predictors of varices bleeding included esophageal lower wall veins diameter ≥3.1 mm and portal vein tumor thrombosis. Predictors of hepatic encephalopathy and ascites worsening were also identified.

Commentary by Airong Hu, Liver Disease Center, Ningbo No.2 Hospital:

Systemic antitumor therapy, including molecular targeted therapy, immune checkpoint inhibitors, chemotherapy, and traditional Chinese medicine, is widely used in inoperable advanced HCC, controlling disease progression, prolonging survival, and achieving partial or complete tumor remission in some patients. Besides familiar common adverse reactions (e.g., hypertension, proteinuria, liver function abnormalities, diarrhea, decreased appetite, thrombocytopenia, hand-foot syndrome, hypothyroidism), attention should be paid to the increased risk of gastrointestinal bleeding (increased portal hypertension-induced bleeding risk) from systemic antitumor therapy. Therefore, high-risk varices or other gastrointestinal bleeding risks should be assessed before treatment.

Regarding CECT evaluation of esophagogastric varices bleeding, many reports indicate its certain diagnostic value (morphological assessment of varices). Compared to endoscopy, its advantage is non-invasiveness, while its disadvantage is the inability to assess varices’ nature. As pointed out in the study, morphology-based EV assessment alone is incomplete. Endoscopy can also assess varices’ nature (red signs, blue signs, straight, serpentine, beaded, nodular, tumor-like).

Moreover, the study lacks comparative data between systemic antitumor therapy and non-systemic therapy groups, making it unclear if portal hypertension-related complications are directly related to systemic antitumor therapy.

06. Precirrhotic Primary Biliary Cholangitis with Portal Hypertension: Bile Duct Injury Correlate

Hu YF, Li SX, Liu HL, Du ZX, Wang SS, Chen MY, Wang L, Xiong QF, Zhong YD, Liu DX, Yang YF. Precirrhotic Primary Biliary Cholangitis with Portal Hypertension: Bile Duct Injury Correlate. Gut Liver. 2024 Apr 16.

Primary biliary cholangitis (PBC) is an autoimmune liver disease that can lead to biliary cirrhosis and complications like portal hypertension. Some PBC patients develop portal hypertension and related complications before histological cirrhosis, but the mechanisms are unclear. A retrospective study by Professor Yongfeng Yang and colleagues from the Second Hospital of Nanjing included 165 precirrhotic PBC patients, divided into portal hypertension and non-portal hypertension groups. Results showed that 24.2% of precirrhotic PBC patients had portal hypertension, positively correlated with bile duct loss, cytokeratin-7 positivity, and portal area fibrosis. The portal hypertension group had higher incidences of obliterative portal venopathy, incomplete septal fibrosis, and poorer responses to UDCA treatment. High ALP levels, low white blood cell counts, high Mayo scores, and high FIB-4 index levels were independent risk factors for predicting portal hypertension in precirrhotic PBC.

Commentary by Airong Hu, Liver Disease Center, Ningbo No.2 Hospital:

Studies using HVPG “gold standard” in PBC patients for portal hypertension assessment found that about 34% of precirrhotic PBC patients have high-risk portal hypertension, possibly related to portal and sinusoidal damage. Therefore, clinicians should focus on screening for portal hypertension in chronic progressive liver disease patients (regardless of etiology). Due to the high specificity of serum AMA, especially AMA-M2 subtype, in diagnosing PBC, liver biopsy is not necessary for diagnosis, and there are risks associated with liver biopsy in cirrhotic or portal hypertension patients. Few studies have focused on the pathological mechanisms of PBC-related cirrhosis or portal hypertension.

The study’s unique aspect is analyzing the clinical characteristics, pathological mechanisms, and risk factors of portal hypertension in precirrhotic PBC patients through liver histopathological changes. The progression of PBC remains associated with bile duct injury (chronic non-suppurative cholangitis). For PBC patients, if ALP and FIB-4 levels are high, white blood cell counts are low, and UDCA treatment response is poor, attention should be given to liver disease progression, including portal hypertension.

However, the study has some limitations: (1) It did not include histologically advanced (cirrhotic) PBC patients; (2) The diagnosis of portal hypertension was based on esophagogastric varices, portal hypertensive bleeding, imaging-indicated portal collateral circulation, ascites, platelet count <150×10^9/L, splenic length diameter ≥13 cm, without measuring HVPG.