Ten important original articles in the field of cirrhosis and portal hypertension from China

The number of patients with liver disease exceeds 400 million in China.1 All types of hepatitis can progress to cirrhosis, and the severity of portal hypertension is a crucial factor affecting patients' clinical prognosis.2 In 2022, Chinese scientific researchers have made progress in the field of cirrhosis and portal hypertension. Accordingly, the “Top 10 Original Research in Cirrhosis and Portal Hypertension from China in 2022” project was initiated by the Chinese Portal Hypertension Alliance (CHESS). The aim was to select original, profound, and challenging research in cirrhosis and portal hypertension completed by Chinese scientific research institutions. The committee from the CHESS selected 30 high-quality studies from databases and recommendations. These studies were reviewed by an international panel, and 15 were chosen for further consideration. During the final review process, the authors presented their studies to the panel members, who asked questions about the research. Ultimately, the top 10 most representative studies were selected as representing high level of basic and clinical researches in the field of cirrhosis and portal hypertension. In the study by Rao et al.,3 follistatin-like protein 1 (FSTL1) expression was increased and positively correlated with histological stages of liver fibrosis in humans and mice. Myeloid FSTL1 deficiency suppresses M1 polarization, reduces pro-inflammatory mediator expression and macrophage/neutrophil recruitment, and alleviates liver fibrosis. FSTL1 binds directly to pyruvate kinase M2 (PKM2), inhibits ubiquitin-mediated degradation, enhances the stability of cytoplasmic PKM2, and promotes PKM2 phosphorylation and nuclear translocation in macrophages. PKM2 is critical for FSTL1-mediated M1 polarization, inflammation, and glycolysis in macrophages. In conclusion, macrophage FSTL1 promoted the progression of liver fibrosis by promoting inflammation on the basis of the intracellular PKM2 reprogramming function of macrophages. This finding provides a rationale for novel therapeutic strategies to ameliorate macrophage-mediated liver inflammation and fibrosis. In the study by Zhang et al.,4 the migration of a cluster of differentiation 11b+ cells into the fibrotic liver was directly visualized. Annotation of these spleen-derived cells within livers identified a subtype of splenic monocytes (sM-1s). sM-1s preferentially migrated into livers and underwent a sequential transformation to sM-2s and to sMφs, which activated hepatic stellate cells and exacerbated liver fibrosis. This study identified spleen-derived macrophages accounting for the exacerbation of liver fibrosis. These findings revealed the precise mechanisms of the spleen–liver axis in hepatic pathogenesis and shed light on the potential of sM-1 as a candidate target for controlling liver diseases. The study by Jiang et al.5 revealed a potent sterol regulatory element-binding protein (SREBP) inhibitor, 25-hydroxylanosterol (25-HL), which binds to insulin-induced gene (INSIG) protein and promotes the interaction between INSIG and SREBP cleavage-activating protein, thereby inhibiting the SREBP pathway and lipid synthesis. In nonalcoholic steatohepatitis (NASH) mouse models, 25-HL reduced cholesterol and triglyceride levels in serum and liver, and ameliorated steatosis, inflammation, and fibrosis in the liver. This study proposed a new strategy for treating NASH by targeting INSIG to inhibit SREBP-mediated lipogenesis, indicating the translational potential of 25-HL, and demonstrating the critical role of SREBP in NASH progression. Genetic and pharmacological targeting of macrophage dopamine receptor D2 (DRD2)-attenuated liver fibrosis was also studied. In a large animal (minipig) NASH model simulating human pathology, the DRD2 antagonist blocked fibrosis and restored hepatic architecture. DRD2 antagonism selectively targets Yes-associated protein (YAP)-dependent fibrogenic crosstalk between macrophages and connective tissue growth factor-positive/vascular cell adhesion molecule 1-positive vascular niche, promoting liver regeneration over fibrosis in both rodent and large animal models. Liver fibrosis is a main histological determinant of NASH, a disease paralleling a worldwide surge in metabolic syndromes. The study by Qing et al.6 demonstrated that a macrophage-specific deficiency in YAP attenuated liver fibrosis. DRD2 antagonism selectively blocked YAP in macrophages and thwarted liver fibrosis in both rodent and large animal models, and thus holds potential for the treatment of NASH. In the study by Zhang et al.,7 the Baveno VII guideline proposed that for patients who do not meet the Baveno VI criteria, spleen stiffness measurement (SSM) ≤ 40 kPa could avoid further unnecessary endoscopic screening. Among patients whose SSM was assessed using a 50-Hz probe, the Baveno VII algorithm avoided more esophagogastroduodenoscopies (56.7% vs. 39.1%) compared with the Baveno VI criteria, respectively. Additionally, the Baveno VII algorithm with SSM assessed with a 100-Hz probe decreased the percentage of esophagogastroduodenoscopies (75.4% vs. 59.5%) compared with a 50-Hz probe, respectively. The Baveno VII algorithm was excellent in ruling out high-risk varices in individuals with hepatitis B virus-related cirrhosis. The Baveno VII algorithm will be a practical tool to triage individuals with cirrhosis in future clinical practice. The study by Cai et al.8 aimed to investigate the safety and efficacy of hydronidone in patients with chronic hepatitis B (CHB)-associated liver fibrosis. A total of 168 patients with CHB and liver fibrosis were subsequently randomized. The fibrosis improvement endpoint was achieved in 11 patients (25.6%) in the placebo group compared with the hydronidone groups: 180 mg: 17 patients (40.5%) (p = 0.12), 270 mg: 23 patients (54.8%) (p = 0.006), and 360 mg: 18 patients (43.90%) (p = 0.08). The overall safety profile and incidence of serious adverse events were similar among the groups. In conclusion, hydronidone plus entecavir showed clinically significant histological improvement of liver fibrosis in patients with CHB. Further studies are required to assess the long-term effectiveness of hydronidone in the regression of hepatic fibrosis. The study by Liu et al.9 aimed to develop and validate a novel ready-to-use score for decompensation risk stratification. A total of 1252 patients with compensated advanced chronic liver disease were included from nine international centers. In the derivation cohort, independent predictors of hepatic decompensation were the Stiffness of liver, Albumin, Varices, and platelets, and these were fitted to develop a novel score, the “SAVE” score, for predicting hepatic decompensation. The score is calculated as follows: SAVE score = 0.036 × stiffness − 0.152 × albumin − 0.011 × platelets + 1.177 × (Varices: 0 if absent, 1 if present), with liver stiffness as kpa, albumin as g/L, and platelets as 109/L. This score performed significantly better (p < 0.05) than other assessed methods, with a time-dependent receiver operating characteristic curve of 0.83 in validation cohorts. The 5-year cumulative incidence of decompensation was 0%, 20%, and 59.6% in the low-, middle-, and high-risk groups, respectively (p < 0.001). The SAVE score also accurately predicted clinically significant portal hypertension. In conclusion, the novel SAVE score optimized the prediction of hepatic decompensation. This score could be an ideal tool to triage patients into those for routine follow-up versus those at risk of decompensation who would benefit from nonselective beta-blockers. The study by Liu et al.10 aimed to evaluate changes in skeletal muscle and fat mass using computed tomography after transjugular intrahepatic portosystemic shunt (TIPS) placement. A total of 224 patients with cirrhosis who underwent TIPS were included. In male patients with sarcopenia, the mean L3 skeletal muscle index increased from 41.8 cm2/m2 (baseline) to 49.1 cm2/m2 (5-month follow-up; p < 0.001) and 49.6 cm2/m2 (1-year follow-up; p < 0.001) after TIPS. In female patients with sarcopenia, skeletal muscle index increased from 33.7 cm2/m2 to 40.6 cm2/m2 (p < 0.001) and 42.0 cm2/m2 (p < 0.001) after TIPS (5-month and 1-year follow-ups, respectively). Additionally, patients who converted from sarcopenic to nonsarcopenic had higher cumulative survival rates compared with those who did not convert. In conclusion, in patients with sarcopenia, both skeletal muscle and fat mass increased after TIPS placement. The reversal of sarcopenia could reduce the risk of death in patients with cirrhosis. The study by Lv et al.11 was a randomized controlled trial that aimed to evaluate whether prophylactic embolization of large spontaneous portosystemic shunts (SPSS) at TIPS creation could reduce the incidence of post-TIPS hepatic encephalopathy in patients with cirrhosis and variceal bleeding. From June 2014 to August 2017, 56 patients with cirrhosis and large SPSS who were scheduled for elective TIPS to prevent variceal bleeding were randomly assigned (1:1) to receive TIPS alone (n = 29) or TIPS plus simultaneous SPSS embolization (n = 27). The results showed that in patients with cirrhosis treated with TIPS for variceal bleeding, concurrent large SPSS embolization reduced the risk of overt hepatic encephalopathy without increasing other complications. In the study by Mak et al.,12 2330 patients with CHB were recruited; 671 (28.8%) with CHB and type 2 diabetes (T2D). T2D was independently associated with hepatocellular carcinoma (HCC) (hazard ratio: 2.080) and fibrosis progression (odds ratio: 4.305) defined by transient elastography. In patients with CHB and T2D, factors reflecting glycemic burden (T2D duration, mean hemoglobin A1c, time to reach the target hemoglobin A1c, liver stiffness, and smoking) were independently associated with HCC (all p < 0.05), the same glycemic burden-related factors were independently associated with fibrosis progression at 3 years. High glycemic burden was associated with HCC development and fibrosis progression among patients with CHB and T2D, highlighting the importance of glycemic control in reducing liver-related complications. The aforementioned 10 studies focused on the pathogenesis, diagnosis, treatment, and prognosis of cirrhosis or portal hypertension. Apart from the topics covered in these studies, there are crucial areas that require further enhancement to optimize the overall management of patients with cirrhosis and portal hypertension. It is hoped that these top 10 original studies can provide ideas and directions for scientific researchers, propel the development of medical scientific research in China, and enhance the capability for scientific and technological innovation in liver diseases (Table 1). Xiaolong Qi contributed to the conception, design, draft, and revise the manuscript critically and submission. We would like to thank the members of the C10 consortium (Bin Xiong, Jiacheng Liu, Guohong Han, Yong Lv, Jinjun Chen, Xiaofeng Zhang, Ling Lv, Jianhua Rao, Lungen Lu, Xiaobo Cai, Xiaolong Qi, Chuan Liu, Wai-Kay Seto, Lung-Yi Mak, Wei Qi, Shi-You Jiang, Zhongwei Cao, Jie Qing, Zongfang Li, Shaoying Zhang) and Xiaoguo Li for their support during this project. Thanks to Hong You for the great support provided for this project. The authors have no funding to report. Xiaolong Qi is the Editor-in-Chief of Portal Hypertension & Cirrhosis. He was therefore excluded from the peer review process and all editorial decisions related to the publication of this manuscript. Institutional Review Board approval is not required.