Project description:Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide, with an estimated prevalence of 25% in the Western World. NAFLD is a broad spectrum of disease states and while most people with NAFLD do not have progressive disease, 10-20% of patients develop histological features of inflammation (non-alcoholic steatohepatitis), fibrosis, cirrhosis and its complications. Despite this large disease burden of significant clinical impact, most people living with NAFLD are undiagnosed, disease course prediction is imprecise and there are no treatments licensed for this condition. In this review, we discuss some of the recent developments in NAFLD, focusing on disease definition and diagnosis, risk stratification and treatments.
Project description:Ten years ago, there was an emerging view that the molecular basis for adult mitochondrial disorders was largely known and that the clinical phenotypes had been well described. Nothing could have been further from the truth. The establishment of large cohorts of patients has revealed new aspects of the clinical presentation that were not previously appreciated. Over time, this approach is starting to provide an accurate understanding of the natural history of mitochondrial disease in adults. Advances in molecular diagnostics, underpinned by next generation sequencing technology, have identified novel molecular mechanisms. Recently described mitochondrial disease phenotypes have disparate causes, and yet share common mechanistic themes. In particular, disorders of mtDNA maintenance have emerged as a major cause of mitochondrial disease in adults. Progressive mtDNA depletion and the accumulation of mtDNA mutations explain some of the clinical features, but the genetic and cellular processes responsible for the mtDNA abnormalities are not entirely clear in each instance. Unfortunately, apart from a few specific examples, treatments for adult mitochondrial disease have not been forthcoming. However, the establishment of international consortia, and the first multinational randomised controlled trial, have paved the way for major progress in the near future, underpinned by growing interest from the pharmaceutical industry. Adult mitochondrial medicine is, therefore, in its infancy, and the challenge is to harness the new understanding of its molecular and cellular basis to develop treatments of real benefit to patients.
Project description:Alcohol consumption is one of the leading causes of the global burden of disease and results in high healthcare and economic costs. Heavy alcohol misuse leads to alcohol-related liver disease, which is responsible for a significant proportion of alcohol-attributable deaths globally. Other than reducing alcohol consumption, there are currently no effective treatments for alcohol-related liver disease. Oxidative stress refers to an imbalance in the production and elimination of reactive oxygen species and antioxidants. It plays important roles in several aspects of alcohol-related liver disease pathogenesis. Here, we review how chronic alcohol use results in oxidative stress through increased metabolism via the cytochrome P450 2E1 system producing reactive oxygen species, acetaldehyde and protein and DNA adducts. These trigger inflammatory signaling pathways within the liver leading to expression of pro-inflammatory mediators causing hepatocyte apoptosis and necrosis. Reactive oxygen species exposure also results in mitochondrial stress within hepatocytes causing structural and functional dysregulation of mitochondria and upregulating apoptotic signaling. There is also evidence that oxidative stress as well as the direct effect of alcohol influences epigenetic regulation. Increased global histone methylation and acetylation and specific histone acetylation inhibits antioxidant responses and promotes expression of key pro-inflammatory genes. This review highlights aspects of the role of oxidative stress in disease pathogenesis that warrant further study including mitochondrial stress and epigenetic regulation. Improved understanding of these processes may identify novel targets for therapy.
Project description:Background/aimsAlcohol-related liver disease (ALD) is the medical manifestation of alcohol use disorder, a prevalent psychiatric condition. Acute and chronic manifestations of ALD have risen in recent years especially in young people and ALD is now a leading indication of liver transplantation (LT) worldwide. Such alarming trends raise urgent and unanswered questions about how medical and psychiatric care can be sustainably integrated to better manage ALD patients before and after LT.MethodsCritical evaluation of the interprofessional implications of broad and multifaceted ALD pathophysiology, general principles of and barriers to interprofessional teamwork and care integration, and measures that clinicians and institutions can implement for improved and integrated ALD care.ResultsThe breadth of ALD pathophysiology, and its numerous medical and psychiatric comorbidities, ensures that no single medical or psychiatric discipline is adequately trained and equipped to manage the disease alone.ConclusionsEarly models of feasible ALD care integration have emerged in recent years but much more work is needed to develop and study them. The future of ALD care is an integrated approach led jointly by interprofessional medical and psychiatric clinicians.
Project description:Fatty liver disease constitutes a spectrum of liver diseases which begin with simple steatosis and may progress to advance stages of steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The two main etiologies are-alcohol related fatty liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). NAFLD is a global health epidemic strongly associated with modern dietary habits and life-style. It is the second most common cause of chronic liver disease in the US after chronic hepatitis C virus (HCV) infection. Approximately 100 million people are affected with this condition in the US alone. Excessive intakes of calories, saturated fat and refined carbohydrates, and sedentary life style have led to explosion of this health epidemic in developing nations as well. ALD is the third most common cause of chronic liver disease in the US. Even though the predominant trigger for onset of steatosis is different in these two conditions, they share common themes in progression from steatosis to the advance stages. Oxidative stress (OS) is considered a very significant contributor to hepatocyte injury in these conditions. Mitochondrial dysfunction contributes to this OS. Role of mitochondrial dysfunction in pathogenesis of fatty liver diseases is emerging but far from completely understood. A better understanding is essential for more effective preventive and therapeutic interventions. Here, we discuss the pathogenesis and therapeutic approaches of NAFLD and ALD from a mitochondrial perspective.
Project description:Backgruound and aims: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). However, the mechanisms and the impact of hepatocyte reprogramming in liver disease are poorly understood. Here we show that both hepatocytes expressing KRT7 (hepatobiliary (HB) cells) and ductular reaction cells were increased in decompensated cirrhotic patients and AH, but only HB cells correlated with poor liver function, reduced liver synthetic capacity and poor outcome. Transcriptomic analysis of microdissected HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming together with inflammatory, stemness and cancer gene programs. In this context, CXCR4 pathway was highly enriched in HB cells, and CXCR4 correlated with disease severity and reduced expression of hepatocyte transcription factors and albumin. Mechanistically, TGFβ induced the expression of CXCR4 in primary hepatocytes, and its ligand CXCL12 promoted hepatocyte reprogramming. Liver overexpression of CXCR4 in chronic liver injury decreased hepatocyte gene expression and promoted liver injury. Pharmacological inhibition of CXCR4 reverted hepatocyte loss of identity and reduced ductular reaction and fibrosis progression. Conclusions: This study shows the association of hepatocyte reprogramming with disease progression and poor outcome in AH. Moreover, we identify CXCR4 as a driver of hepatocyte reprogramming as well as a potential therapeutic target in chronic liver injury.
Project description:Alcohol-related liver disease (ALD) represents a major public health problem worldwide. According to the World Health Organization, the highest levels of per capita alcohol consumption are observed in countries of the European Region. Alcohol consumption is also alarmingly increasing in developing countries. ALD is one of the main contributors to the burden of alcohol-attributable deaths and disability. In the United States, severe forms of ALD such alcoholic hepatitis have increased in the last decade and in the United Kingdom, three-quarters of liver-related mortality results from alcohol consumption. Besides genetic factors, there is strong evidence that the amount of alcohol consumed plays a major role in the development of advanced ALD. Establishing effective public health policies is therefore mandatory to reduce the burden of ALD. Since the 90s, major public health institutions and governments have developed a variety of policies in order to reduce the harm caused by excessive drinking. These policies encompass multiple factors, from pricing and taxation to advertising regulation. Measures focused on taxation and price regulation have been shown to be the most effective at reducing alcohol-related mortality. However, there are few studies focused on the effect of public policies on ALD. This review article summarises the factors influencing ALD burden and the role of different public health policies.