Seminars in liver disease最新文献

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Early forms of alcohol-associated liver disease (ALD) include different stages in the progression of compensated liver disease ranging from steatosis to steatohepatitis and fibrosis. ALD has been classically diagnosed at advanced stages more frequently than other liver diseases. This fact probably contributed to the scarcity of studies on early forms of ALD. Recent studies have investigated the prevalence of early ALD in the general population and have described the natural history of alcohol-induced steatosis and fibrosis, which has been linked to worse prognosis compared to early stages of other chronic liver diseases. In addition, studies of screening and early diagnosis of ALD in at-risk populations have shown that these strategies allow early detection and intervention. Of note, up to 28% of the United States population has concurrent alcohol use and metabolic syndrome, and estimated prevalence of advanced fibrosis among heavy drinkers with metabolic syndrome has increased from 3% in the 1990s to more than 10% in the 2010s. Therefore, new challenges and treatment opportunities will emerge for patients with ALD. In this review, we provide an overview of the state of the art in early ALD, focusing on natural history, diagnosis and management, and provide insights into future perspectives.

The liver is a sexually dimorphic organ. Sex differences in prevalence, progression, prognosis, and treatment prevail in most liver diseases, and the mechanism of how liver diseases act differently among male versus female patients has not been fully elucidated. Biological sex differences in normal physiology and disease arise principally from sex hormones and/or sex chromosomes. Sex hormones contribute to the development and progression of most liver diseases, with estrogen- and androgen-mediated signaling pathways mechanistically involved. In addition, genetic factors in sex chromosomes have recently been found to contribute to the sex disparity of many liver diseases, which might explain, to some extent, the difference in gene expression pattern, immune response, and xenobiotic metabolism between men and women. Although increasing evidence suggests that sex is one of the most important modulators of disease prevalence and outcomes, at present, basic and clinical studies have long been sex unbalanced, with female subjects underestimated. As such, this review focuses on sex disparities of liver diseases and summarizes the current understanding of sex-specific mechanisms, including sex hormones, sex chromosomes, etc. We anticipate that understanding sex-specific pathogenesis will aid in promoting personalized therapies for liver disease among male versus female patients.

Critically ill patients with cirrhosis and liver failure do not uncommonly have hypotension due to multifactorial reasons, which include a hyperdynamic state with increased cardiac index (CI), low systemic vascular resistance (SVR) due to portal hypertension, following the use of beta-blocker or diuretic therapy, and severe sepsis. These changes are mediated by microvascular alterations in the liver, systemic inflammation, activation of renin-angiotensin-aldosterone system, and vasodilatation due to endothelial dysfunction. Haemodynamic assessment includes measuring inferior vena cava indices, cardiac output (CO), and SVR using point-of-care ultrasound (POCUS), arterial waveform analysis, pulmonary artery pressures, and lactate clearance to guide fluid resuscitation. Fluid responsiveness reflects the ability of fluid bolus to increase the CO and is assessed effectively by POCUS, passive leg raises manoeuvre, and dynamic tests such as pulse pressure and stroke volume variation in spontaneously breathing and mechanically ventilated patients. Albumin has pleiotropic benefits through anti-inflammatory properties besides its standard action on oncotic pressure and volume expansion in patients with cirrhosis but has the potential for precipitating pulmonary oedema. In conclusion, fluid therapy in critically ill patients with liver disease is a complex and dynamic process that requires individualized management protocols to optimize patient outcomes.

Progression of liver disease is dependent on intercellular signaling, including those mediated by extracellular vesicles (EVs). Within these EVs, microRNAs (miRNAs) are packaged to selectively silence gene expression in recipient cells for upregulating or downregulating a specific pathway. Injured hepatocytes secrete EV-associated miRNAs which can be taken up by liver sinusoidal endothelial cells, immune cells, hepatic stellate cells, and other cell types. In addition, these recipient cells will secrete their own EV-associated miRNAs to propagate a response throughout the tissue and the circulation. In this review, we comment on the implications of EV-miRNAs in the progression of alcohol-associated liver disease, metabolic dysfunction-associated steatohepatitis, viral and parasitic infections, liver fibrosis, and liver malignancies. We summarize how circulating miRNAs can be used as biomarkers and the potential of utilizing EVs and miRNAs as therapeutic methods to treat liver disease.

Alcohol-associated liver disease (ALD), primarily caused by chronic excessive alcohol consumption, is a leading cause of chronic liver disease worldwide. ALD includes alcohol-associated steatotic liver, alcohol-associated hepatitis (AH), fibrosis, cirrhosis, and can even progress to hepatocellular carcinoma (HCC). Existing research indicates that the risk factors of ALD are quite numerous. In addition to drinking patterns, factors such as aldehyde dehydrogenase 2 (ALDH2) deficiency, smoking, medication administration, high-fat diet (HFD), hepatitis virus infection, and disruption of circadian rhythms can also increase susceptibility to ALD. However, there is limited understanding regarding the exacerbation of liver injury by alcohol plus additional risk factors. This review presents rodent models of EtOH + "X," which simulate the synergistic effects of alcohol and additional risk factors in causing liver injury. These models offer a further exploration of the interactions between alcohol and additional risk factors, advancing the simulation of human ALD and providing a more reliable platform for studying disease mechanisms and exploring therapeutic interventions. We summarize the modeling methods, relevant indicators of liver injury, and focus on the targets of the synergistic effects as well as the associated mechanisms.

The field of ribonucleic acid (RNA) biology has revealed an array of noncoding RNA species, particularly long noncoding RNAs (lncRNAs), which play crucial roles in liver disease pathogenesis. This review explores the diverse functions of lncRNAs in liver pathology, including metabolic-associated steatotic liver disease, hepatocellular carcinoma, alcohol-related liver disease, and cholangiopathies such as primary sclerosing cholangitis and cholangiocarcinoma. We highlight key lncRNAs that regulate lipid metabolism, inflammation, fibrosis, and oncogenesis in the liver, demonstrating their diagnostic and therapeutic potential. Emerging RNA-based therapies, such as mRNA therapy, RNA interference, and antisense oligonucleotides, offer approaches to modulate lncRNA activity and address liver disease at a molecular level. Advances in sequencing technologies and bioinformatics pipelines are simultaneously enabling the identification and functional characterization of novel lncRNAs, driving innovation in personalized medicine. In conclusion, this review highlights the potential of lncRNAs as biomarkers and therapeutic targets in liver disease and emphasizes the need for further research into their regulatory mechanisms and clinical applications.

There continues to be an ongoing need for fair and equitable organ allocation. The Model for End-Stage Liver Disease (MELD) score has evolved as a calculated framework to evaluate and allocate patients for liver transplantation objectively. The original MELD score has undergone multiple modifications as it is continuously scrutinized for its accuracy in objectively representing the clinical context of patients with liver disease. Several refinements and iterations of the score have been developed, including the widely accepted MELD-Na score. In addition, the most recent updated iteration, MELD 3.0, has been created. The MELD 3.0 calculator incorporates new variables such as patient sex and serum albumin levels and assigns new weights for serum sodium, bilirubin, international normalized ratio, and creatinine levels. It is anticipated that the use of MELD 3.0 scores will reduce overall waitlist mortality and enhance access for female liver transplant candidates. However, despite the emergence of the MELD score as one of the most objective measures for fair organ allocation, various countries and healthcare systems employ alternative methods for stratification and organ allocation. This review article will highlight the origins of the MELD score, its iterations, the current MELD 3.0, and future directions for managing liver transplantation organ allocation. LAY SUMMARY: Organ donation is crucial for the management of patients unwell with liver disease, but organs must be allocated fairly and equitably. One method used for this is the Model for End-Stage Liver Disease (MELD) score, which helps objectively decide which patient is a candidate for liver transplant. Over time, the MELD score has been refined to better reflect patients' needs. For example, the latest version, MELD 3.0, now considers factors like nutrition and gender. This should ensure that more patients, especially females, are candidates and receive appropriate access to liver transplantation. However, not every country uses the MELD score. Some countries have created their own scoring systems based on local research. This review will explain where the MELD score came from, how it has changed, the current characteristics of the MELD 3.0 score, and what the future might hold for organ allocation in liver transplants.

The Wilson disease (WD) research field is rapidly evolving, and new diagnostic and therapeutical approaches are expected to be change-gamers in the disease for the incoming years, after decades of slow changing options. Non-ceruloplasmin-bound copper assays for circulating bioavailable copper are being tested for use in monitoring therapy and may also help in the diagnosis of new cases of WD. Other diagnostic advances include the use of quantitative detection of ATP7B peptides in dried blood spots, a method that is being tested for use in the newborn screening for WD, and the use of metallothionein immunostaining of liver biopsy specimens to differentiate WD from other liver diseases. Ongoing and future trials of gene therapy and use of methanobactin are expected to restore biliary copper excretion from the liver, thus making a cure for WD a plausible therapeutic objective. With the aim of helping updating physicians, this review summarizes the novel methods for WD diagnosis and future therapies. Advancing understanding of the scientific advances that can be applied to WD will be critical for ensuring that our patients will receive the best current and future care.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and can progress to serious complications, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Predisposing risk factors for MASH include obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome. Patients with MASH often experience significant impairments in their health-related quality of life and other patient-reported outcomes (PROs), particularly in physical functioning domains, fatigue, and vitality. Incorporating PROs offers valuable insights into patients' perspectives on their symptoms, treatment efficacy, and overall well-being, thereby guiding more holistic and patient-centered care strategies. This review aims to investigate the utilization of patient-reported outcome measures (PROMs) in the context of MASLD and MASH care, identify which PROMs are employed, and summarize the outcomes reported.