Pub Date : 2024-09-01DOI: 10.1016/j.livres.2024.09.005
Haijin Lyu , Xiaomeng Yi , Yunshan Zou , Pinglan Lu , Lijuan Li , Jianrong Liu , Senbiao Chen , Xuxia Wei , Yang Yang , Huimin Yi
Liver transplantation (LT) is the only effective treatment for hepatopulmonary syndrome (HPS). Moreover, perioperative refractory hypoxemia (pRH) is a prevalent life-threatening condition and has extremely limited treatment options. Here, we report three patients with HPS who experienced pRH after LT and were consecutively treated with different salvage therapies, ephedrine inhalation, intravenous use of methylene blue with nitric oxide (NO) inhalation, and NO inhalation alone. The results showed that unresolved severe hypoxia may induce fatal morbidity such as early biliary leakage and acute kidney injury. Early initiation of NO inhalation, rather than ephedrine, can significantly improve oxygenation in patients with pRH and may help prevent hypoxia-related complications. Therefore, based on the response to these exploratory salvage treatments, we further demonstrate the unique ventilation-perfusion mismatch pathophysiology in specific lung regions during pRH in HPS. We propose that early inhalation of NO is an important treatment option to rescue severe hypoxia in patients with HPS during the perioperative period of LT.
{"title":"Inhaled nitric oxide as a salvage therapy for refractory hypoxemia in the post-transplantation period of hepatopulmonary syndrome: An explorative report of three cases","authors":"Haijin Lyu , Xiaomeng Yi , Yunshan Zou , Pinglan Lu , Lijuan Li , Jianrong Liu , Senbiao Chen , Xuxia Wei , Yang Yang , Huimin Yi","doi":"10.1016/j.livres.2024.09.005","DOIUrl":"10.1016/j.livres.2024.09.005","url":null,"abstract":"<div><div>Liver transplantation (LT) is the only effective treatment for hepatopulmonary syndrome (HPS). Moreover, perioperative refractory hypoxemia (pRH) is a prevalent life-threatening condition and has extremely limited treatment options. Here, we report three patients with HPS who experienced pRH after LT and were consecutively treated with different salvage therapies, ephedrine inhalation, intravenous use of methylene blue with nitric oxide (NO) inhalation, and NO inhalation alone. The results showed that unresolved severe hypoxia may induce fatal morbidity such as early biliary leakage and acute kidney injury. Early initiation of NO inhalation, rather than ephedrine, can significantly improve oxygenation in patients with pRH and may help prevent hypoxia-related complications. Therefore, based on the response to these exploratory salvage treatments, we further demonstrate the unique ventilation-perfusion mismatch pathophysiology in specific lung regions during pRH in HPS. We propose that early inhalation of NO is an important treatment option to rescue severe hypoxia in patients with HPS during the perioperative period of LT.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"8 3","pages":"Pages 188-192"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01DOI: 10.1016/j.livres.2024.09.004
Meng-Qi Dong , Yuan Xie , Zhi-Liang Tang , Xue-Wen Zhao , Fu-Zhen Lin , Guang-Yu Zhang , Zhi-Hao Huang , Zhi-Min Liu , Yuan Lin , Feng-Yong Liu , Wei-Jie Zhou
Background and aim
Hepatic ischemia–reperfusion injury (IRI) is a significant challenge in liver transplantation, trauma, hypovolemic shock, and hepatectomy, with limited effective interventions available. This study aimed to investigate the role of leukocyte cell-derived chemotaxin 2 (LECT2) in hepatic IRI and assess the therapeutic potential of Lect2-short hairpin RNA (shRNA) delivered through adeno-associated virus (AAV) vectors.
Materials and methods
This study analyzed human liver and serum samples from five patients undergoing the Pringle maneuver. Lect2-knockout and C57BL/6J mice were used. Hepatic IRI was induced by clamping the hepatic pedicle. Treatments included recombinant human LECT2 (rLECT2) and AAV-Lect2-shRNA. LECT2 expression levels and serum biomarkers including alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and blood urea nitrogen (BUN) were measured. Histological analysis of liver necrosis and quantitative reverse-transcription polymerase chain reaction were performed.
Results
Serum and liver LECT2 levels were elevated during hepatic IRI. Serum LECT2 protein and mRNA levels increased post reperfusion. Lect2-knockout mice had reduced weight loss; hepatic necrosis; and serum ALT, AST, creatinine, and BUN levels. rLECT2 treatment exacerbated weight loss, hepatic necrosis, and serum biomarkers (ALT, AST, creatinine, and BUN). AAV-Lect2-shRNA treatment significantly reduced weight loss, hepatic necrosis, and serum biomarkers (ALT, AST, creatinine, and BUN), indicating therapeutic potential.
Conclusions
Elevated LECT2 levels during hepatic IRI increased liver damage. Genetic knockout or shRNA-mediated knockdown of Lect2 reduced liver damage, indicating its therapeutic potential. AAV-mediated Lect2-shRNA delivery mitigated hepatic IRI, offering a potential new treatment strategy to enhance clinical outcomes for patients undergoing liver-related surgeries or trauma.
{"title":"Leukocyte cell-derived chemotaxin 2 (LECT2) regulates liver ischemia–reperfusion injury","authors":"Meng-Qi Dong , Yuan Xie , Zhi-Liang Tang , Xue-Wen Zhao , Fu-Zhen Lin , Guang-Yu Zhang , Zhi-Hao Huang , Zhi-Min Liu , Yuan Lin , Feng-Yong Liu , Wei-Jie Zhou","doi":"10.1016/j.livres.2024.09.004","DOIUrl":"10.1016/j.livres.2024.09.004","url":null,"abstract":"<div><h3>Background and aim</h3><div>Hepatic ischemia–reperfusion injury (IRI) is a significant challenge in liver transplantation, trauma, hypovolemic shock, and hepatectomy, with limited effective interventions available. This study aimed to investigate the role of leukocyte cell-derived chemotaxin 2 (LECT2) in hepatic IRI and assess the therapeutic potential of Lect2-short hairpin RNA (shRNA) delivered through adeno-associated virus (AAV) vectors.</div></div><div><h3>Materials and methods</h3><div>This study analyzed human liver and serum samples from five patients undergoing the Pringle maneuver. <em>Lect2</em>-knockout and C57BL/6J mice were used. Hepatic IRI was induced by clamping the hepatic pedicle. Treatments included recombinant human LECT2 (rLECT2) and AAV-Lect2-shRNA. LECT2 expression levels and serum biomarkers including alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and blood urea nitrogen (BUN) were measured. Histological analysis of liver necrosis and quantitative reverse-transcription polymerase chain reaction were performed.</div></div><div><h3>Results</h3><div>Serum and liver LECT2 levels were elevated during hepatic IRI. Serum LECT2 protein and mRNA levels increased post reperfusion. <em>Lect2</em>-knockout mice had reduced weight loss; hepatic necrosis; and serum ALT, AST, creatinine, and BUN levels. rLECT2 treatment exacerbated weight loss, hepatic necrosis, and serum biomarkers (ALT, AST, creatinine, and BUN). AAV-Lect2-shRNA treatment significantly reduced weight loss, hepatic necrosis, and serum biomarkers (ALT, AST, creatinine, and BUN), indicating therapeutic potential.</div></div><div><h3>Conclusions</h3><div>Elevated LECT2 levels during hepatic IRI increased liver damage. Genetic knockout or shRNA-mediated knockdown of <em>Lect2</em> reduced liver damage, indicating its therapeutic potential. AAV-mediated Lect2-shRNA delivery mitigated hepatic IRI, offering a potential new treatment strategy to enhance clinical outcomes for patients undergoing liver-related surgeries or trauma.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"8 3","pages":"Pages 165-171"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01DOI: 10.1016/j.livres.2024.09.001
Bodil Bjørndal , Siri Lunde Tungland , Pavol Bohov , Magne O. Sydnes , Simon N. Dankel , Lise Madsen , Rolf K Berge
Background and objective
Metabolic associated fatty liver disease (MAFLD) is associated with abnormal lipid metabolism. Mitochondrial dysfunction is considered an important factor in the onset of MAFLD, whereas altered fatty acid composition has been linked to the severity of the disease. Tetradecylthioacetic acid (TTA), shown to induce mitochondrial proliferation and alter the fatty acid composition, was used to delay the accumulation of hepatic triacylglycerol. This study aimed to evaluate how impaired mitochondrial fatty acid beta-oxidation affects fatty acid composition by incorporating meldonium into a high-carbohydrate diet.
Methods
C57BL/6 mice (n = 40) were fed high-carbohydrate diets supplemented with meldonium, TTA, or a combination of meldonium and TTA for 21 days. Lipid levels were determined in liver samples, and fatty acid composition was measured in both liver and plasma samples. Additionally, desaturase and elongase activities were estimated. The hepatic activities and gene expression levels of enzymes involved in fatty acid metabolism were measured in liver samples, whereas carnitines, their precursors, and acylcarnitines were measured in plasma samples.
Results
The meldonium-induced depletion of L-carnitine and mitochondrial fatty acid oxidation was confirmed by reduced plasma levels of L-carnitine and acylcarnitines. Principal component analyses of the hepatic fatty acid composition revealed clustering dependent on meldonium and TTA. The meldonium-induced increase in hepatic triacylglycerol levels correlated negatively with estimated activities of elongases and was associated with higher estimated activities of delta-6 desaturase (D6D; C18:4n-3/C18:3n-3 and C18:3n-6/C18:2n-6), and increased circulating levels of C18:4n-3 and C18:3n-6 (gamma-linolenic acid). TTA mitigated meldonium-induced triacylglycerol levels by 80% and attenuated the estimated D6D activities, and elongation of n-6 polyunsaturated fatty acids (PUFAs). TTA also attenuated the meldonium-mediated reduction of C24:1n-9 (nervonic acid), possibly by stimulating Elovl5 and increased elongation of erucic acid (C22:1n-9) to nervonic acid. The hepatic levels of nervonic acid and the estimated activity of n-6 PUFA elongation correlated negatively with the hepatic triacylglycerol levels, while the estimated activities of D6D correlated positively.
Conclusion
Circulating levels of gamma-linolenic acid, along with reduced estimated elongation of n-6 PUFAs and D6D desaturation activities, were associated with hepatic triacylglycerol levels.
{"title":"Meldonium-induced steatosis is associated with increased delta 6 desaturation and reduced elongation of n-6 polyunsaturated fatty acids","authors":"Bodil Bjørndal , Siri Lunde Tungland , Pavol Bohov , Magne O. Sydnes , Simon N. Dankel , Lise Madsen , Rolf K Berge","doi":"10.1016/j.livres.2024.09.001","DOIUrl":"10.1016/j.livres.2024.09.001","url":null,"abstract":"<div><h3>Background and objective</h3><div>Metabolic associated fatty liver disease (MAFLD) is associated with abnormal lipid metabolism. Mitochondrial dysfunction is considered an important factor in the onset of MAFLD, whereas altered fatty acid composition has been linked to the severity of the disease. Tetradecylthioacetic acid (TTA), shown to induce mitochondrial proliferation and alter the fatty acid composition, was used to delay the accumulation of hepatic triacylglycerol. This study aimed to evaluate how impaired mitochondrial fatty acid beta-oxidation affects fatty acid composition by incorporating meldonium into a high-carbohydrate diet.</div></div><div><h3>Methods</h3><div>C57BL/6 mice (<em>n</em> = 40) were fed high-carbohydrate diets supplemented with meldonium, TTA, or a combination of meldonium and TTA for 21 days. Lipid levels were determined in liver samples, and fatty acid composition was measured in both liver and plasma samples. Additionally, desaturase and elongase activities were estimated. The hepatic activities and gene expression levels of enzymes involved in fatty acid metabolism were measured in liver samples, whereas carnitines, their precursors, and acylcarnitines were measured in plasma samples.</div></div><div><h3>Results</h3><div>The meldonium-induced depletion of L-carnitine and mitochondrial fatty acid oxidation was confirmed by reduced plasma levels of L-carnitine and acylcarnitines. Principal component analyses of the hepatic fatty acid composition revealed clustering dependent on meldonium and TTA. The meldonium-induced increase in hepatic triacylglycerol levels correlated negatively with estimated activities of elongases and was associated with higher estimated activities of delta-6 desaturase (D6D; C18:4n-3/C18:3n-3 and C18:3n-6/C18:2n-6), and increased circulating levels of C18:4n-3 and C18:3n-6 (gamma-linolenic acid). TTA mitigated meldonium-induced triacylglycerol levels by 80% and attenuated the estimated D6D activities, and elongation of n-6 polyunsaturated fatty acids (PUFAs). TTA also attenuated the meldonium-mediated reduction of C24:1n-9 (nervonic acid), possibly by stimulating <em>Elovl</em><em>5</em> and increased elongation of erucic acid (C22:1n-9) to nervonic acid. The hepatic levels of nervonic acid and the estimated activity of n-6 PUFA elongation correlated negatively with the hepatic triacylglycerol levels, while the estimated activities of D6D correlated positively.</div></div><div><h3>Conclusion</h3><div>Circulating levels of gamma-linolenic acid, along with reduced estimated elongation of n-6 PUFAs and D6D desaturation activities, were associated with hepatic triacylglycerol levels.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"8 3","pages":"Pages 152-164"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01DOI: 10.1016/j.livres.2024.09.003
Chenhao Xu , Xixi Fang , Xiao Xu , Xuyong Wei
Compared with the widely used rodents, pigs are anatomically, physiologically, and genetically more similar to humans, making them high-quality models for the study of liver diseases. Here, we review the latest research progress on pigs as a model of human liver disease, including methods for establishing them and their advantages in studying cystic fibrosis liver disease, acute liver failure, liver regeneration, non-alcoholic fatty liver disease, liver tumors, and xenotransplantation. We also emphasize the importance of genetic engineering techniques, mainly the CRISPR/Cas9 system, which has greatly enhanced the utility of porcine models as a tool for substantially advancing liver disease research. Genetic engineering is expected to propel the pig as one of the irreplaceable animal models for future biomedical research.
{"title":"Genetic engineering drives the breakthrough of pig models in liver disease research","authors":"Chenhao Xu , Xixi Fang , Xiao Xu , Xuyong Wei","doi":"10.1016/j.livres.2024.09.003","DOIUrl":"10.1016/j.livres.2024.09.003","url":null,"abstract":"<div><div>Compared with the widely used rodents, pigs are anatomically, physiologically, and genetically more similar to humans, making them high-quality models for the study of liver diseases. Here, we review the latest research progress on pigs as a model of human liver disease, including methods for establishing them and their advantages in studying cystic fibrosis liver disease, acute liver failure, liver regeneration, non-alcoholic fatty liver disease, liver tumors, and xenotransplantation. We also emphasize the importance of genetic engineering techniques, mainly the CRISPR/Cas9 system, which has greatly enhanced the utility of porcine models as a tool for substantially advancing liver disease research. Genetic engineering is expected to propel the pig as one of the irreplaceable animal models for future biomedical research.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"8 3","pages":"Pages 131-140"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01DOI: 10.1016/j.livres.2024.07.001
Lina Wu , Jiadi Lai , Qiumin Luo , Yeqiong Zhang , Chaoshuang Lin , Dongying Xie , Youming Chen , Hong Deng , Zhiliang Gao , Liang Peng , Wenxiong Xu
Background and aim
Few studies have reported hepatitis B surface antigen (HBsAg) kinetics after nucleos(t)ide analog (NA) discontinuation in patients with noncirrhotic chronic hepatitis B (CHB). The study specifically investigated long-term HBsAg kinetics after NA discontinuation.
Methods
Between January 2014 to January 2024, this study prospectively enrolled 106 outpatients with noncirrhotic CHB who met the discontinuation criteria after NA consolidation treatment. Demographic, clinical, and laboratory data were collected and analyzed after NA discontinuation.
Results
Ninety-six patients who finished 5 years of follow-up were included. HBsAg remained undetectable in 29 patients with end of treatment (EOT) HBsAg negativity. Among 67 patients with EOT HBsAg positivity, HBsAg seroclearance occurred in 12 (17.9%) patients with an estimated annual incidence of HBsAg seroclearance of 3.6%. Patients with EOT HBsAg levels of ≤1000 IU/mL had a higher HBsAg seroclearance rate than those with EOT HBsAg levels of >1000 IU/mL (33.3% vs. 5.4%). The proportion of patients with HBsAg ≤1000 IU/mL increased during follow-up. Logistic regression analysis indicated that the EOT HBsAg level was an independent factor for HBsAg seroclearance and an HBsAg level decline exceeding 1 log10 IU/mL. The optimal EOT HBsAg cutoff for both HBsAg seroclearance and an HBsAg level decline exceeding 1 log10 IU/mL was 359 IU/mL.
Conclusions
Patients with EOT HBsAg negativity experienced no relapse and maintained HBsAg seroclearance during 5 years of follow-up after NA discontinuation. A higher HBsAg seroclearance rate can be obtained in patients with EOT HBsAg levels of ≤1000 IU/mL during 5 years of follow-up after NA discontinuation. Close monitoring and proper NA retreatment are recommended to guarantee the safety of NA discontinuation.
{"title":"Long-term hepatitis B surface antigen kinetics after nucleos(t)ide analog discontinuation in patients with noncirrhotic chronic hepatitis B","authors":"Lina Wu , Jiadi Lai , Qiumin Luo , Yeqiong Zhang , Chaoshuang Lin , Dongying Xie , Youming Chen , Hong Deng , Zhiliang Gao , Liang Peng , Wenxiong Xu","doi":"10.1016/j.livres.2024.07.001","DOIUrl":"10.1016/j.livres.2024.07.001","url":null,"abstract":"<div><h3>Background and aim</h3><div>Few studies have reported hepatitis B surface antigen (HBsAg) kinetics after nucleos(t)ide analog (NA) discontinuation in patients with noncirrhotic chronic hepatitis B (CHB). The study specifically investigated long-term HBsAg kinetics after NA discontinuation.</div></div><div><h3>Methods</h3><div>Between January 2014 to January 2024, this study prospectively enrolled 106 outpatients with noncirrhotic CHB who met the discontinuation criteria after NA consolidation treatment. Demographic, clinical, and laboratory data were collected and analyzed after NA discontinuation.</div></div><div><h3>Results</h3><div>Ninety-six patients who finished 5 years of follow-up were included. HBsAg remained undetectable in 29 patients with end of treatment (EOT) HBsAg negativity. Among 67 patients with EOT HBsAg positivity, HBsAg seroclearance occurred in 12 (17.9%) patients with an estimated annual incidence of HBsAg seroclearance of 3.6%. Patients with EOT HBsAg levels of ≤1000 IU/mL had a higher HBsAg seroclearance rate than those with EOT HBsAg levels of >1000 IU/mL (33.3% <em>vs</em>. 5.4%). The proportion of patients with HBsAg ≤1000 IU/mL increased during follow-up. Logistic regression analysis indicated that the EOT HBsAg level was an independent factor for HBsAg seroclearance and an HBsAg level decline exceeding 1 log10 IU/mL. The optimal EOT HBsAg cutoff for both HBsAg seroclearance and an HBsAg level decline exceeding 1 log10 IU/mL was 359 IU/mL.</div></div><div><h3>Conclusions</h3><div>Patients with EOT HBsAg negativity experienced no relapse and maintained HBsAg seroclearance during 5 years of follow-up after NA discontinuation. A higher HBsAg seroclearance rate can be obtained in patients with EOT HBsAg levels of ≤1000 IU/mL during 5 years of follow-up after NA discontinuation. Close monitoring and proper NA retreatment are recommended to guarantee the safety of NA discontinuation.</div></div><div><h3>Clinical trial number</h3><div><span><span>Clinicaltrials.gov</span><svg><path></path></svg></span> number NCT02883647.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"8 3","pages":"Pages 179-187"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141690926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hepatocellular carcinoma (HCC) is the sixth most prevalent form of cancer globally and the third leading cause of cancer-related mortality. The incidence of portal vein tumor thrombosis (PVTT) in HCC patients is 21% at one year and 46% at three years. The presence of PVTT has consistently been associated with a poor prognosis for HCC patients over the past decades. Notably, HCC prognosis is influenced not only by the presence of PVTT but also by the degree or extent of PVTT. Currently, there is a lack of global consensus or established protocols regarding the optimal management of HCC with associated PVTT. The Barcelona Clinic for Liver Cancer classifies HCC patients with PVTT as stage C, indicating an advanced stage, and limiting treatment recommendations for these patients to systemic therapy. In recent years, there has been an increase in the availability of therapeutic options for HCC patients with PVTT. Treatment modalities include systemic therapy, transarterial chemoembolization, surgical resection, stereotactic body radiotherapy, transarterial radioembolization, and liver transplantation. An ideal therapy for each patient necessitates a multidisciplinary approach. This review article presents the latest updates in managing HCC patients with PVTT.
{"title":"Portal vein tumor thrombosis in hepatocellular carcinoma patients: Is it the end?","authors":"Walaa Abdelhamed , Hend Shousha , Mohamed El-Kassas","doi":"10.1016/j.livres.2024.09.002","DOIUrl":"10.1016/j.livres.2024.09.002","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is the sixth most prevalent form of cancer globally and the third leading cause of cancer-related mortality. The incidence of portal vein tumor thrombosis (PVTT) in HCC patients is 21% at one year and 46% at three years. The presence of PVTT has consistently been associated with a poor prognosis for HCC patients over the past decades. Notably, HCC prognosis is influenced not only by the presence of PVTT but also by the degree or extent of PVTT. Currently, there is a lack of global consensus or established protocols regarding the optimal management of HCC with associated PVTT. The Barcelona Clinic for Liver Cancer classifies HCC patients with PVTT as stage C, indicating an advanced stage, and limiting treatment recommendations for these patients to systemic therapy. In recent years, there has been an increase in the availability of therapeutic options for HCC patients with PVTT. Treatment modalities include systemic therapy, transarterial chemoembolization, surgical resection, stereotactic body radiotherapy, transarterial radioembolization, and liver transplantation. An ideal therapy for each patient necessitates a multidisciplinary approach. This review article presents the latest updates in managing HCC patients with PVTT.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"8 3","pages":"Pages 141-151"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01DOI: 10.1016/j.livres.2024.06.001
Yazheng Wang, Conor Fahy, Hong Lu
Background and aim
Glucocorticoids are the only first-line drugs for severe alcoholic hepatitis (AH), with limited efficacy and various side effects on extrahepatic tissues. Liver-targeting glucocorticoid therapy may have multiple advantages over systemic glucocorticoid for AH. The aim of this study was to determine the role of hepatocellular glucocorticoid receptor (GR) in alcohol-associated steatosis (AS) and AH.
Materials and methods
AS was induced by a high-fat diet plus binge alcohol in adult male and female mice with liver-specific knockout (LKO) and heterozygote of GR. AH was induced by chronic-plus-binge in middle-aged male mice with liver-specific knockin of GR. Changes in hepatic mRNA and protein expression were determined by quantitative real-time polymerase chain reaction and Western blot.
Results
GR-LKO aggravated steatosis and decreased hepatic expression and circulating levels of albumin in both genders of AS mice but only increased markers of liver injury in male AS mice. Marked steatosis in GR-LKO mice was associated with induction of lipogenic genes and down-regulation of bile acid synthetic genes. Hepatic protein levels of GR, hepatocyte nuclear factor 4 alpha, and phosphorylated signal transducer and activator of transcription 3 were gene-dosage-dependently decreased, whereas that of lipogenic ATP citrate lyase was increased in male GR heterozygote and LKO mice. Interestingly, hepatic expression of estrogen receptor alpha (ERα) was induced, and the essential estrogen-inactivating enzyme sulfotransferase 1e1 was gene-dosage-dependently down-regulated in GR heterozygote and knockout AS mice, which was associated with induction of ERα-target genes. Liver-specific knockin of GR protected against liver injury and steatohepatitis in middle-aged AH mice.
Conclusions
Hepatic GR deficiency plays a crucial role in the pathogenesis of AS induced by high-fat diet plus binge, and liver-specific overexpression/activation of GR protects against chronic-plus-binge-induced AH in middle-aged mice. Hepatocellular GR is important for protection against AS and AH.
{"title":"Liver-specific glucocorticoid action in alcoholic liver disease: Study of glucocorticoid receptor knockout and knockin mice","authors":"Yazheng Wang, Conor Fahy, Hong Lu","doi":"10.1016/j.livres.2024.06.001","DOIUrl":"10.1016/j.livres.2024.06.001","url":null,"abstract":"<div><h3>Background and aim</h3><p>Glucocorticoids are the only first-line drugs for severe alcoholic hepatitis (AH), with limited efficacy and various side effects on extrahepatic tissues. Liver-targeting glucocorticoid therapy may have multiple advantages over systemic glucocorticoid for AH. The aim of this study was to determine the role of hepatocellular glucocorticoid receptor (GR) in alcohol-associated steatosis (AS) and AH.</p></div><div><h3>Materials and methods</h3><p>AS was induced by a high-fat diet plus binge alcohol in adult male and female mice with liver-specific knockout (LKO) and heterozygote of GR. AH was induced by chronic-plus-binge in middle-aged male mice with liver-specific knockin of GR. Changes in hepatic mRNA and protein expression were determined by quantitative real-time polymerase chain reaction and Western blot.</p></div><div><h3>Results</h3><p>GR-LKO aggravated steatosis and decreased hepatic expression and circulating levels of albumin in both genders of AS mice but only increased markers of liver injury in male AS mice. Marked steatosis in GR-LKO mice was associated with induction of lipogenic genes and down-regulation of bile acid synthetic genes. Hepatic protein levels of GR, hepatocyte nuclear factor 4 alpha, and phosphorylated signal transducer and activator of transcription 3 were gene-dosage-dependently decreased, whereas that of lipogenic ATP citrate lyase was increased in male GR heterozygote and LKO mice. Interestingly, hepatic expression of estrogen receptor alpha (ERα) was induced, and the essential estrogen-inactivating enzyme sulfotransferase 1e1 was gene-dosage-dependently down-regulated in GR heterozygote and knockout AS mice, which was associated with induction of ERα-target genes. Liver-specific knockin of GR protected against liver injury and steatohepatitis in middle-aged AH mice.</p></div><div><h3>Conclusions</h3><p>Hepatic GR deficiency plays a crucial role in the pathogenesis of AS induced by high-fat diet plus binge, and liver-specific overexpression/activation of GR protects against chronic-plus-binge-induced AH in middle-aged mice. Hepatocellular GR is important for protection against AS and AH.</p></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"8 2","pages":"Pages 91-104"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2542568424000205/pdfft?md5=e4fec752111b323ab3a04da91784f562&pid=1-s2.0-S2542568424000205-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141414252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01DOI: 10.1016/j.livres.2024.05.004
Walaa Abdelhamed , Mohamed El-Kassas
Hepatitis B virus (HBV) infection is a significant health problem that can result in progression to liver cirrhosis, decompensation, and the development of hepatocellular carcinoma (HCC). On a country level, the prevalence of chronic HBV infection varies between 0.1% and 35.0%, depending on the locality and the population being investigated. One-third of all liver cancer fatalities worldwide are attributable to HBV. The adoption of standard birth-dose immunization exerted the most significant impact on the decline of HBV prevalence. HCC incidence ranges from 0.01% to 1.40% in noncirrhotic patients and from 0.9% to 5.4% annually, in the settings of liver cirrhosis. Although antiviral therapy significantly reduces the risk of developing HBV-related HCC, studies have demonstrated that the risk persists, and that HCC screening is still essential. This review discusses the complex relationship between HBV infection and HCC, recent epidemiological data, different aspects of clinical disease characteristics, and the impact of antiviral therapy in this context.
{"title":"Hepatitis B virus as a risk factor for hepatocellular carcinoma: There is still much work to do","authors":"Walaa Abdelhamed , Mohamed El-Kassas","doi":"10.1016/j.livres.2024.05.004","DOIUrl":"10.1016/j.livres.2024.05.004","url":null,"abstract":"<div><p>Hepatitis B virus (HBV) infection is a significant health problem that can result in progression to liver cirrhosis, decompensation, and the development of hepatocellular carcinoma (HCC). On a country level, the prevalence of chronic HBV infection varies between 0.1% and 35.0%, depending on the locality and the population being investigated. One-third of all liver cancer fatalities worldwide are attributable to HBV. The adoption of standard birth-dose immunization exerted the most significant impact on the decline of HBV prevalence. HCC incidence ranges from 0.01% to 1.40% in noncirrhotic patients and from 0.9% to 5.4% annually, in the settings of liver cirrhosis. Although antiviral therapy significantly reduces the risk of developing HBV-related HCC, studies have demonstrated that the risk persists, and that HCC screening is still essential. This review discusses the complex relationship between HBV infection and HCC, recent epidemiological data, different aspects of clinical disease characteristics, and the impact of antiviral therapy in this context.</p></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"8 2","pages":"Pages 83-90"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2542568424000199/pdfft?md5=d802d7bd2e6321fa394f3007326cb461&pid=1-s2.0-S2542568424000199-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141281964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01DOI: 10.1016/j.livres.2024.05.003
Huan Wei , Songhao Luo , Yanhua Bi , Chunhong Liao , Yifan Lian , Jiajun Zhang , Yuehua Huang
Background and aims
Hepatocellular carcinoma (HCC), which is prevalent worldwide and has a high mortality rate, needs to be effectively diagnosed. We aimed to evaluate the significance of plasma microRNA-15a/16-1 (miR-15a/16) as a biomarker of hepatitis B virus-related HCC (HBV-HCC) using the machine learning model. This study was the first large-scale investigation of these two miRNAs in HCC plasma samples.
Methods
Using quantitative polymerase chain reaction, we measured the plasma miR-15a/16 levels in a total of 766 participants, including 74 healthy controls, 335 with chronic hepatitis B (CHB), 47 with compensated liver cirrhosis, and 310 with HBV-HCC. The diagnostic performance of miR-15a/16 was examined using a machine learning model and compared with that of alpha-fetoprotein (AFP). Lastly, to validate the diagnostic efficiency of miR-15a/16, we performed pseudotemporal sorting of the samples to simulate progression from CHB to HCC.
Results
Plasma miR-15a/16 was significantly decreased in HCC than in all control groups (P < 0.05 for all). In the training cohort, the area under the receiver operating characteristic curve (AUC), sensitivity, and average precision (AP) for the detection of HCC were higher for miR-15a (AUC = 0.80, 67.3%, AP = 0.80) and miR-16 (AUC = 0.83, 79.0%, AP = 0.83) than for AFP (AUC = 0.74, 61.7%, AP = 0.72). Combining miR-15a/16 with AFP increased the AUC to 0.86 (sensitivity 85.9%) and the AP to 0.85 and was significantly superior to the other markers in this study (P < 0.05 for all), as further demonstrated by the detection error tradeoff curves. Moreover, miR-15a/16 impressively showed potent diagnostic power in early-stage, small-tumor, and AFP-negative HCC. A validation cohort confirmed these results. Lastly, the simulated follow-up of patients further validated the diagnostic efficiency of miR-15a/16.
Conclusions
We developed and validated a plasma miR-15a/16-based machine learning model, which exhibited better diagnostic performance for the early diagnosis of HCC compared to that of AFP.
{"title":"Plasma microRNA-15a/16-1-based machine learning for early detection of hepatitis B virus-related hepatocellular carcinoma","authors":"Huan Wei , Songhao Luo , Yanhua Bi , Chunhong Liao , Yifan Lian , Jiajun Zhang , Yuehua Huang","doi":"10.1016/j.livres.2024.05.003","DOIUrl":"10.1016/j.livres.2024.05.003","url":null,"abstract":"<div><h3>Background and aims</h3><p>Hepatocellular carcinoma (HCC), which is prevalent worldwide and has a high mortality rate, needs to be effectively diagnosed. We aimed to evaluate the significance of plasma microRNA-15a/16-1 (miR-15a/16) as a biomarker of hepatitis B virus-related HCC (HBV-HCC) using the machine learning model. This study was the first large-scale investigation of these two miRNAs in HCC plasma samples.</p></div><div><h3>Methods</h3><p>Using quantitative polymerase chain reaction, we measured the plasma miR-15a/16 levels in a total of 766 participants, including 74 healthy controls, 335 with chronic hepatitis B (CHB), 47 with compensated liver cirrhosis, and 310 with HBV-HCC. The diagnostic performance of miR-15a/16 was examined using a machine learning model and compared with that of alpha-fetoprotein (AFP). Lastly, to validate the diagnostic efficiency of miR-15a/16, we performed pseudotemporal sorting of the samples to simulate progression from CHB to HCC.</p></div><div><h3>Results</h3><p>Plasma miR-15a/16 was significantly decreased in HCC than in all control groups (<em>P</em> < 0.05 for all). In the training cohort, the area under the receiver operating characteristic curve (AUC), sensitivity, and average precision (AP) for the detection of HCC were higher for miR-15a (AUC = 0.80, 67.3%, AP = 0.80) and miR-16 (AUC = 0.83, 79.0%, AP = 0.83) than for AFP (AUC = 0.74, 61.7%, AP = 0.72). Combining miR-15a/16 with AFP increased the AUC to 0.86 (sensitivity 85.9%) and the AP to 0.85 and was significantly superior to the other markers in this study (<em>P</em> < 0.05 for all), as further demonstrated by the detection error tradeoff curves. Moreover, miR-15a/16 impressively showed potent diagnostic power in early-stage, small-tumor, and AFP-negative HCC. A validation cohort confirmed these results. Lastly, the simulated follow-up of patients further validated the diagnostic efficiency of miR-15a/16.</p></div><div><h3>Conclusions</h3><p>We developed and validated a plasma miR-15a/16-based machine learning model, which exhibited better diagnostic performance for the early diagnosis of HCC compared to that of AFP.</p></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"8 2","pages":"Pages 105-117"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2542568424000187/pdfft?md5=1f363a82844e27afef2899a66bb34c27&pid=1-s2.0-S2542568424000187-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141131450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号