There has been a tremendous growth in data collection in hepatology over the last decade. This wealth of "big data" lends itself to the application of artificial intelligence in the development of predictive and diagnost...There has been a tremendous growth in data collection in hepatology over the last decade. This wealth of "big data" lends itself to the application of artificial intelligence in the development of predictive and diagnostic models with potentially greater accuracy than standard biostatistics. As processing power of computing systems has improved and data are made more accessible through the large databases and electronic health record, these more contemporary techniques for analyzing and interpreting data have garnered much interest in the field of medicine. This review highlights the current evidence base for the use of artificial intelligence in hepatology, focusing particularly on the areas of diagnosis and prognosis of advanced chronic liver disease and hepatic neoplasia.
Since the early trials in viral hepatitis, more and more new drugs are being tested for use in various liver diseases. Since drug hepatotoxicity is a major cause of drugs under investigation not making it to market, the...Since the early trials in viral hepatitis, more and more new drugs are being tested for use in various liver diseases. Since drug hepatotoxicity is a major cause of drugs under investigation not making it to market, the assessment of drug-induced liver injury in clinical trials of new drugs is crucial. This review will focus on the systems that are used to assess drug-induced liver injury in clinical trials and will discuss how some of these criteria are inappropriate or inaccurate in this function together with suggestions for improvement.
Semin Liver Dis
· 2022 Feb · PMID 34311471
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Metabolic rewiring is one of the hallmarks of cancer. Altered de novo lipogenesis is one of the pivotal metabolic events deregulated in cancers. Sterol regulatory element-binding transcription factor 1 (SREBP1) controls...Metabolic rewiring is one of the hallmarks of cancer. Altered de novo lipogenesis is one of the pivotal metabolic events deregulated in cancers. Sterol regulatory element-binding transcription factor 1 (SREBP1) controls the transcription of major enzymes involved in de novo lipogenesis, including ACLY, ACACA, FASN, and SCD. Studies have shown the increased de novo lipogenesis in human hepatocellular carcinoma (HCC) samples. Multiple mechanisms, such as activation of the AKT/mechanistic target of rapamycin (mTOR) pathway, lead to high SREBP1 induction and the coordinated enhanced expression of , , and genes. Subsequent functional analyses have unraveled these enzymes' critical role(s) and the related de novo lipogenesis in hepatocarcinogenesis. Importantly, targeting these molecules might be a promising strategy for HCC treatment. This paper comprehensively summarizes de novo lipogenesis rewiring in HCC and how this pathway might be therapeutically targeted.
The American College of Radiology has released the Liver Imaging Reporting and Data System (LI-RADS) scheme which categorizes focal liver lesions (FLLs) in patients at risk for hepatocellular carcinoma (HCC) according to...The American College of Radiology has released the Liver Imaging Reporting and Data System (LI-RADS) scheme which categorizes focal liver lesions (FLLs) in patients at risk for hepatocellular carcinoma (HCC) according to the degree of risk of nodules to be HCC. It subgroups FLL in LR-1 (definitely benign), LR-2 (probably benign), LR-3 (intermediate probability of malignancy), LR-4 (probably HCC), LR-5 (definitely HCC), and LR-M (probable malignancy not specific for HCC). Computed tomography/magnetic resonance imaging (CT/MRI) and contrast enhanced ultrasound (CEUS) LI-RADS diagnostic algorithm have the goal to standardize the acquisition, interpretation, reporting, and data collection for imaging examinations in patients at risk for HCC. Nevertheless, there remain controversial issues that should be dealt with. The aim of this review is to discuss the pros and cons of the interpretation and reporting part of CT/MRI and CEUS LI-RADS diagnostic algorithm to permit future refinements of the scheme and optimize patient and nodule management.
Semin Liver Dis
· 2021 Nov · PMID 34289507
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Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease, increasingly contributing to the burden of liver transplantation. In search for effective treatments, novel strategies addres...Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease, increasingly contributing to the burden of liver transplantation. In search for effective treatments, novel strategies addressing metabolic dysregulation, inflammation, and fibrosis are continuously emerging. Disturbed bile acid (BA) homeostasis and microcholestasis via hepatocellular retention of potentially toxic BAs may be an underappreciated factor in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) as its progressive variant. In addition to their detergent properties, BAs act as signaling molecules regulating cellular homeostasis through interaction with BA receptors such as the Farnesoid X receptor (FXR). Apart from being a key regulator of BA metabolism and enterohepatic circulation, FXR regulates metabolic homeostasis and has immune-modulatory effects, making it an attractive therapeutic target in NAFLD/NASH. In this review, the molecular basis and therapeutic potential of targeting FXR with a specific focus on restoring BA and metabolic homeostasis in NASH is summarized.
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide with high prevalence, especially in individuals with obesity and type 2 diabetes. Among individuals with type 2 diabetes...Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide with high prevalence, especially in individuals with obesity and type 2 diabetes. Among individuals with type 2 diabetes, the severe insulin resistant subgroup has the greatest risk of NAFLD, likely due to dysfunctional adipose tissue mass but also genetic factors, and may progress earlier to inflammatory and profibrotic nonalcoholic steatohepatitis (NASH). NASH has been associated with increased liver-related as well as cardiovascular morbidity and mortality. International diabetes associations recommend certain screening and treatment strategies for NASH in type 2 diabetes, which, however, bear several limitations such as lack of accurate noninvasive diagnostic tools and targeted treatments. Currently, antihyperglycemic drug concepts based on glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors offer metabolic as well as cardiorenal benefits and provide treatment options for both hyperglycemia and NASH in type 2 diabetes.
Liver failure in the context of acute (ALF) and acute on chronic liver failure (ACLF) is associated with high mortality in the absence of a liver transplant. For decades, therapeutic plasma exchange (TPE) is performed fo...Liver failure in the context of acute (ALF) and acute on chronic liver failure (ACLF) is associated with high mortality in the absence of a liver transplant. For decades, therapeutic plasma exchange (TPE) is performed for the management of immune-mediated diseases. TPE has emerged as an attractive extracorporeal blood purification technique in patients with ALF and ACLF. The basic premise of using TPE is to remove the toxic substances which would allow recovery of native liver functions by facilitating liver regeneration. In recent years, encouraging data have emerged, suggesting the benefits of TPE in patients with liver failure. TPE has emerged as an attractive liver support device for the failing liver until liver transplantation or clinical recovery. The data in patients with ALF suggest routine use of high-volume TPE, while the data for such a strategy are less robust for patients with ACLF.
Semin Liver Dis
· 2021 Nov · PMID 34261137
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The human gut harbors a dense and highly diverse microbiota of approximately 1,000 bacterial species. The interaction between the host and gut bacteria strongly influences human health. Numerous evidence suggest that int...The human gut harbors a dense and highly diverse microbiota of approximately 1,000 bacterial species. The interaction between the host and gut bacteria strongly influences human health. Numerous evidence suggest that intestinal flora imbalance is closely associated with the development and treatment of liver diseases, including acute liver injury and chronic liver diseases (cirrhosis, autoimmune liver disease, and fatty liver). Therefore, regulating the gut microbiota is expected to be a new method for the adjuvant treatment of liver diseases. Fecal microbiota transplantation (FMT) is defined as the transplantation of gut microbiota from healthy donors to sick patients via the upper or lower gastrointestinal route to restore the normal intestinal balance. In this study, we briefly review the current research on the gut microbiota and its link to liver diseases and then summarize the evidence to elucidate the clinical application and development of FMT in liver disease treatment.
Semin Liver Dis
· 2021 Nov · PMID 34243194
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The burden of obesity and metabolic syndrome has determined a sharp increase in bariatric surgery (BS) procedures, which lead to marked weight loss, improved metabolic syndrome, reduced cardiovascular risk, and even impr...The burden of obesity and metabolic syndrome has determined a sharp increase in bariatric surgery (BS) procedures, which lead to marked weight loss, improved metabolic syndrome, reduced cardiovascular risk, and even improvement in nonalcoholic steatohepatitis (NASH). Despite these promising results, BS in patients with chronic liver disease can rarely lead to worsening of liver function, progression to cirrhosis and its complications, and even liver transplantation. On the other hand, since obesity in patients with cirrhosis is a major cofactor for progression to a decompensated stage of the disease and a risk factor for hepatocellular carcinoma, BS has been used to achieve weight loss in this population. In this review, we critically analyze the existing data on outcomes of BS in patients with cirrhosis and the possible mechanisms leading to fibrosis progression and worsening liver function in patients undergoing BS. Finally, we propose a set of measures that could be taken to improve the multidisciplinary management of liver disease in patients undergoing BS, including early recognition of malnutrition and alcohol misuse.
Semin Liver Dis
· 2021 Nov · PMID 34243193
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With the recent urbanization and globalization, the adult obesity rate has been increasing, which was paralleled with a dramatic surge in the incidence and prevalence of nonalcoholic fatty liver disease (NAFLD). NAFLD po...With the recent urbanization and globalization, the adult obesity rate has been increasing, which was paralleled with a dramatic surge in the incidence and prevalence of nonalcoholic fatty liver disease (NAFLD). NAFLD poses a growing threat to human health as it represents the most common cause of chronic liver disease in developed countries. It encompasses a wide spectrum of conditions starting from a build-up of fat in hepatocytes (steatosis), to developing inflammation (steatohepatitis), and reaching up to cirrhosis. It is also associated with higher rates of cardiovascular mortalities. Therefore, proper timely treatment is essential and weight loss remains the cornerstone in the treatment of obesity-related liver diseases. When diet, exercise, and lifestyle changes are not successful, the current recommendation for weight loss includes antiobesity medications and bariatric endoscopic and surgical interventions. These interventions have shown to result in significant weight loss and improve liver steatosis and fibrosis. In the current literature review, we highlight the expected outcomes and side effects of the currently existing options to have a weight-centric NAFLD approach.
Interleukin-35 (IL-35) is a newly identified inhibitory cytokine. It has recently been found to play an extremely important role in chronic hepatitis B disease, which makes it likely to be a target for new therapies for...Interleukin-35 (IL-35) is a newly identified inhibitory cytokine. It has recently been found to play an extremely important role in chronic hepatitis B disease, which makes it likely to be a target for new therapies for hepatitis B malady. IL-35 modulates a variety of immune mechanisms to cause persistent viral infections, such as affecting the ratio of helper T cells, reducing the activity of cytotoxic T cells, hindering the antigen presentation capacity for dendritic cells, and increasing the transcription level of hepatitis B virus. On the other hand, IL-35 can control the inflammation caused by hepatitis B liver injury. Therefore, to seek a breakthrough in curing hepatitis B disease, the contradictory part of IL-35 in the occurrence and development of this sickness is worthy of further discussion and research. This article will systematically review the biological effects of IL-35 and the specific mechanisms affecting the disease.
Arrese M, Arab JP, Barrera F
… +3 more, Kaufmann B, Valenti L, Feldstein AE
Semin Liver Dis
· 2021 Nov · PMID 34233370
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The acronym nonalcoholic fatty-liver disease (NAFLD) groups a heterogeneous patient population. Although in many patients the primary driver is metabolic dysfunction, a complex and dynamic interaction of different factor...The acronym nonalcoholic fatty-liver disease (NAFLD) groups a heterogeneous patient population. Although in many patients the primary driver is metabolic dysfunction, a complex and dynamic interaction of different factors (i.e., sex, presence of one or more genetic variants, coexistence of different comorbidities, diverse microbiota composition, and various degrees of alcohol consumption among others) takes place to determine disease subphenotypes with distinct natural history and prognosis and, eventually, different response to therapy. This review aims to address this topic through the analysis of existing data on the differential contribution of known factors to the pathogenesis and clinical expression of NAFLD, thus determining the different clinical subphenotypes observed in practice. To improve our understanding of NAFLD heterogeneity and the dominant drivers of disease in patient subgroups would predictably impact on the development of more precision-targeted therapies for NAFLD.
Alagille syndrome (ALGS) is an autosomal dominant disorder caused by pathogenic variants in or , which encode fundamental components of the Notch signaling pathway. Clinical features span multiple organ systems includin...Alagille syndrome (ALGS) is an autosomal dominant disorder caused by pathogenic variants in or , which encode fundamental components of the Notch signaling pathway. Clinical features span multiple organ systems including hepatic, cardiac, vascular, renal, skeletal, craniofacial, and ocular, and occur with variable phenotypic penetrance. Genotype-phenotype correlation studies have not yet shown associations between mutation type and clinical manifestations or severity, and it has been hypothesized that modifier genes may modulate the effects of and pathogenic variants. Medical management is supportive, focusing on clinical manifestations of disease, with liver transplant indicated for severe pruritus, liver synthetic dysfunction, portal hypertension, bone fractures, and/or growth failure. New therapeutic approaches are under investigation, including ileal bile acid transporter (IBAT) inhibitors and other approaches that may involve targeted interventions to augment the Notch signaling pathway in involved tissues.
Patients with primary sclerosing cholangitis (PSC) constitute 5 to 15% of patients listed for liver transplantation worldwide. Although post-transplant outcomes are favorable, recurrent PSC (rPSC) occurs in an important...Patients with primary sclerosing cholangitis (PSC) constitute 5 to 15% of patients listed for liver transplantation worldwide. Although post-transplant outcomes are favorable, recurrent PSC (rPSC) occurs in an important subset of patients, with higher prevalence rates reported with increasing time from transplant. Given its association with poor graft outcomes and risk of retransplant, effort has been made to understand rPSC, its pathophysiology, and risk factors. This review covers these facets of rPSC and focuses on implicated risk factors including pretransplant recipient characteristics, inflammatory bowel-disease-related factors, and donor-specific and transplant-specific factors. Confirming a diagnosis of rPSC requires thoughtful consideration of alternative etiologies so as to ensure confidence in diagnosis, management, subsequent risk assessment, and counseling for patients. Unfortunately, no cure exists for rPSC; however, future large-scale efforts are underway to better characterize the natural history of rPSC and its associated risk factors with hopes of identifying potential key targets for novel therapies.
Antiviral therapy has greatly improved the survival and reduced the incidence of adverse liver events such as hepatic decompensation and hepatocellular carcinoma in chronic hepatitis B patients with cirrhosis (hepatitis...Antiviral therapy has greatly improved the survival and reduced the incidence of adverse liver events such as hepatic decompensation and hepatocellular carcinoma in chronic hepatitis B patients with cirrhosis (hepatitis B virus [HBV]-cirrhosis). However, hepatitis B surface antigen loss, regarded as the ultimate goal of therapy or functional cure, was rarely achieved during long-term indefinite nucleos(t)ide analogues (Nuc) treatment. Emerging issues such as medication adherence and loss-to-follow-up may lead to increased risk of hepatic decompensation, even catastrophic life-threatening events. Studies have shown that finite therapy is feasible and reasonably safe, even in patients with HBV-cirrhosis. This review critically assesses the scientific evidence of the pros and cons for finite Nuc therapy in HBV-cirrhosis and proposes how to stop Nuc therapy and monitor the off-therapy patients. It also proposes the perspective and unsolved issues to be investigated in the future.
Pruritus (itch) is a debilitating symptom in liver diseases with cholestasis, which severely affects patients' quality of life. Limited treatment options are available for cholestatic itch, largely due to the incomplete...Pruritus (itch) is a debilitating symptom in liver diseases with cholestasis, which severely affects patients' quality of life. Limited treatment options are available for cholestatic itch, largely due to the incomplete understanding of the underlying molecular mechanisms. Several factors have been proposed as pruritogens for cholestatic itch, such as bile acids, bilirubin, lysophosphatidic acid, and endogenous opioids. Recently, two research groups independently identified Mas-related G protein-coupled receptor X4 (MRGPRX4) as a receptor for bile acids and bilirubin and demonstrated its likely role in cholestatic itch. This discovery not only opens new avenues for understanding the molecular mechanisms in cholestatic itch but provides a promising target for developing novel anti-itch treatments. In this review, we summarize the current theories and knowledge of cholestatic itch, emphasizing MRGPRX4 as a bile acid and bilirubin receptor mediating cholestatic itch in humans. We also discuss some future perspectives in cholestatic itch research.
Accurate risk prediction for hepatocellular carcinoma (HCC) among patients with chronic hepatitis B (CHB) may guide treatment strategies including initiation of antiviral therapy and also inform implementation of HCC sur...Accurate risk prediction for hepatocellular carcinoma (HCC) among patients with chronic hepatitis B (CHB) may guide treatment strategies including initiation of antiviral therapy and also inform implementation of HCC surveillance. There have been 26 risk scores developed to predict HCC in CHB patients with ( = 14) or without ( = 12) receiving antiviral treatment; all of them invariably include age in the scoring formula. Virological biomarkers of replicative activities (i.e., hepatitis B virus DNA level or hepatitis B envelope antigen status) are frequently included in the scores derived from patients with untreated CHB, whereas measurements that gauge severity of liver fibrosis and/or reserve of hepatic function (i.e., cirrhosis diagnosis, liver stiffness measurement, platelet count, or albumin) are essential components in the scores developed from treated patients. External validation is a prerequisite for clinical application but not yet performed for all scores. For the future, higher predictive accuracy may be achieved with machine learning based on more comprehensive data.
Hepatic alveolar echinococcosis (HAE) is a rare but severe zoonosis caused by the pseudotumoral intrahepatic development of the larval stage of the tapeworm HAE is present only in the Northern Hemisphere, predominantly...Hepatic alveolar echinococcosis (HAE) is a rare but severe zoonosis caused by the pseudotumoral intrahepatic development of the larval stage of the tapeworm HAE is present only in the Northern Hemisphere, predominantly in China. Currently, there is a significant resurgence of cases in historically endemic areas associated with emergence of HAE in countries not previously concerned. Today, in European countries, HAE is often discovered by chance; however, clinicians should be made aware of opportunistic infections that progressively emerged recently as a result of therapeutic or pathological immunosuppression. Ultrasonography is the key first-line diagnostic procedure, with specific serology providing confirmation in 95% of the cases. Albendazole, only parasitostatic, is the mainstay for treatment. Surgical resection, if feasible, is the gold standard for treatment, and more patients are currently eligible for this option because of an earlier diagnosis. The prognosis has considerably improved but remains poor in countries where access to care is less favorable.
We conducted a meta-analysis to investigate the effects of the Mediterranean Diet (Med-Diet) on hepatic steatosis and insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). Six randomized controlle...We conducted a meta-analysis to investigate the effects of the Mediterranean Diet (Med-Diet) on hepatic steatosis and insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). Six randomized controlled trials were selected for the meta-analysis (sample size: 250 participants). In the meta-analysis, there was no significant difference in body mass index and waist circumference between the Med-Diet and control groups. Med-Diet significantly reduced fatty liver index (FLI) compared with the control diet (standard mean difference [SMD]: -1.06; 95% CI: -1.95 to -0.17; = 0.02). Med-Diet significantly reduced homeostasis model assessment of insulin resistance (HOMA-IR) compared with the control diet (SMD: -0.34; 95% CI: -0.65 to -0.03; = 0.03). Similarly, a meta-regression analysis using age showed that Med-Diet significantly reduced FLI and HOMA-IR (95% CI: -0.956 to -0.237, = 0.001 and 95% CI: -0.713 to -0.003, = 0.048, respectively). This meta-analysis demonstrated that Med-Diet improved hepatic steatosis and insulin resistance in patients with NAFLD. Thus, Med-Diet is a beneficial pharmaconutritional therapy in patients with NAFLD.