The epidemiology of non‐alcoholic fatty liver disease
TL;DR: An international consensus conference on the definition, natural history, policies of surveillance and new pharmacological treatments of NAFLD and NASH is urgently needed.
Abstract: The increase in Non-alcoholic Fatty Liver Disease (NAFLD) and the imminent disappearance of chronic viral hepatitis thanks to new and effective therapies is motivating hepatologists to change their clinical approach to chronic liver disease. NAFLD-cirrhosis or NAFLD-Hepatocellular Carcinoma (HCC) are now the second cause of liver transplantation in the USA. This short-review is focused to the epidemiology of NAFLD/Non-alchoholic Steatohepatitis (NASH), including the definition of this disease which should be revised as well discussing the prevalence, risk factors for progression, natural history and mortality. NAFLD is considered to be the hepatic manifestation of the metabolic syndrome (MS). It affects 25-30% of the general population and the risk factors are almost identical to those of MS. The natural history involves either the development of cardiovascular diseases or cirrhosis and HCC. HCC can also develop in NASH in the absence of cirrhosis (45% of cases). We conclude that an international consensus conference on the definition, natural history, policies of surveillance and new pharmacological treatments of NAFLD and NASH is urgently needed.
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TL;DR: The effects of NAFLD on the regulation, expression and activity of major DMEs and transporters are summarized and the potential mechanisms underlying these alterations are discussed.
Abstract: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption. Insulin ...
358 citations
TL;DR: A narrative review provides an overview of the literature on the evidence for an association and causal link between NAFLD and CKD and the underlying mechanisms by which NA FLD (and factors strongly linked withNAFLD) may increase the risk of developing CKD.
209 citations
TL;DR: A new isoform of human manganese superoxide dismutase was isolated and obtained in a synthetic recombinant form designated rMnSOD, shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis.
Abstract: Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC). Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the "Two Hit Theory" to the "Multiple Hit Theory". However, the general consensus is that the gut microbiota, oxidative stress, and mitochondrial damage play key roles in the pathogenesis of NASH. The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of reactive oxygen species (ROS). The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis. This problem represents the first "Achilles' heel" of the new molecules being evaluated in most ongoing clinical trials. The second is the inability of these molecules to reach the mitochondria, the primary sites of energy production and ROS generation. Recently, a variety of non-pharmacological and pharmacological treatment approaches for NASH have been evaluated including vitamin E, the thiazolidinediones, and novel molecules related to NASH pathogenesis (including obeticholic acid and elafibranor). Recently, a new isoform of human manganese superoxide dismutase (MnSOD) was isolated and obtained in a synthetic recombinant form designated rMnSOD. This protein has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis. Based on these distinctive characteristics, it can be hypothesized that this novel recombinant protein (rMnSOD) potentially represents a new and highly efficient adjuvant therapy to counteract the progression from NASH to HCC.
179 citations
TL;DR: Available mouse models of NASH address different aspects of the disease, have varying clinical translatability, and, therefore, also show different utility in drug discovery.
165 citations
TL;DR: Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholAngiogenesis.
Abstract: Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. Although most cases in Western countries are sporadic, large population-based studies have identified a number of risk factors. This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development. Cholestatic liver diseases (e.g. primary sclerosing cholangitis and fibropolycystic liver diseases), liver cirrhosis, and biliary stone disease all increase the risk of cholangiocarcinoma. Certain bacterial, viral or parasitic infections such as hepatitis B and C and liver flukes also increase cholangiocarcinoma risk. Other risk factors include inflammatory disorders (such as inflammatory bowel disease and chronic pancreatitis), toxins (e.g. alcohol and tobacco), metabolic conditions (diabetes, obesity and non-alcoholic fatty liver disease) and a number of genetic disorders. Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-ɑ, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-κB pathways that encourage cell proliferation, migration and survival. Other mediators upregulated in cholangiocarcinoma include Transforming Growth Factor-β, Vascular Endothelial Growth Factor, Hepatocyte Growth Factor and several microRNAs. Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. Stromal changes are also observed, resulting in alterations to the extracellular matrix composition and recruitment of fibroblasts and macrophages that create a microenvironment promoting cell survival, invasion and metastasis. Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease.
157 citations
References
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TL;DR: A strong scoring system and NAS for NAFLD and NASH with reasonable inter‐rater reproducibility that should be useful for studies of both adults and children with any degree ofNAFLD are presented.
8,253 citations
Journal Article•
TL;DR: Findings in 20 patients with nonalcoholic steatohepatitis of unknown cause found the patients were moderately obese, and many had obesity-associated diseases, such as diabetes mellitus and cholelithiasis.
2,484 citations
TL;DR: Growing evidence suggests that nonalcoholic fatty liver disease is associated with an increased risk of cardiovascular disease beyond that conferred by established risk factors.
Abstract: Growing evidence suggests that nonalcoholic fatty liver disease is associated with an increased risk of cardiovascular disease beyond that conferred by established risk factors.
1,584 citations
TL;DR: Data indicate that obesity plays a greater role than excessive alcohol intake in inducing fatty liver, and the relative roles of obesity and alcohol abuse, alone and in combination, in inducing steatosis are explored.
Abstract: Steatosis frequently occurs in healthy persons and is almost always present in obese persons who drink more than 60 g of alcohol per day. This condition is more strongly associated with obesity tha...
1,249 citations
TL;DR: Based on a meta-analysis of studies of paired liver biopsy studies, liver fibrosis progresses in patients with NAFL and NASH.
1,165 citations