Emerging medical therapies for non-alcoholic fatty liver disease and for alcoholic hepatitis.
ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are currently the two most common liver diseases in the world. Alcoholic hepatitis (AH), a unique clinical syndrome among ALD patients has high short-term mortality. Apart from controlling the risk factor for individual respective disease, there are no Food and Drug Administration (FDA) approved medical therapies for these diseases. Over the last 5-10 years, the field has extensively grown with many new targets being studied in randomized clinical trials for these diseases, with many of these drugs being tested in both the conditions. In this chapter, we will describe the novel therapeutic agents and current status of ongoing clinical trials with these agents for the treatment of NAFLD and/or AH.
Project description:Heavy alcohol use is the cause of alcoholic liver disease (ALD). The ALD spectrum ranges from alcoholic steatosis to steatohepatitis, fibrosis, and cirrhosis. In Western countries, approximately 50% of cirrhosis-related deaths are due to alcohol use. While alcoholic cirrhosis is no longer considered a completely irreversible condition, no effective anti-fibrotic therapies are currently available. Another significant clinical aspect of ALD is alcoholic hepatitis (AH). AH is an acute inflammatory condition that is often comorbid with cirrhosis, and severe AH has a high mortality rate. Therapeutic options for ALD are limited. The established treatment for AH is corticosteroids, which improve short-term survival but do not affect long-term survival. Liver transplantation is a curative treatment option for alcoholic cirrhosis and AH, but patients must abstain from alcohol use for 6 months to qualify. Additional effective therapies are needed. The molecular mechanisms underlying ALD are complex and have not been fully elucidated. Various molecules, signaling pathways, and crosstalk between multiple hepatic and extrahepatic cells contribute to ALD progression. This review highlights established and emerging concepts in ALD clinicopathology, their underlying molecular mechanisms, and current and future ALD treatment options.
Project description:Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple hepatic steatosis to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. Although most subjects with excessive alcohol or food intake experience simple hepatic steatosis, a small percentage of individuals will develop progressive liver disease. Notably, both ALD and NAFLD are frequently accompanied by extrahepatic complications, including cardiovascular disease and malignancy. The survival of patients with ALD and NAFLD depends on various disease-associated conditions. This review delineates the clinical characteristics and outcomes of patients with ALD and NAFLD by comparing their epidemiology, the factors associated with disease susceptibility and progression, and the predictors and characteristics of outcomes. A comprehensive understanding of the characteristics and outcomes of ALD and NAFLD is imperative in the management of these chronic liver diseases.
Project description:Alcoholic liver disease (ALD) is increasing in incidence in the UK. It is the commonest cause of liver-related deaths, predominantly in people below the age of 60. Alcoholic hepatitis (AH) is an acute form of ALD with high mortality when severe. Jaundice and coagulopathy are clinical hallmarks of severe AH. Histology findings are characterised by parenchymal inflammation and hepatocellular damage although biopsy is only required when diagnostic uncertainty exists; clinical findings are usually sufficient for accurate diagnosis. Patients with AH should be stratified as non-severe or severe using non-invasive scoring systems such as the discriminant function or the Glasgow Alcoholic Hepatitis Score. In patients with non-severe AH, abstinence is the mainstay of treatment, and it is important that steps are taken to help patients stop drinking. Severe AH requires specialist treatment. Consensus guidelines recommend the use of prednisolone although this remains subject to clinical trials. Pentoxifylline may have a survival benefit if corticosteroids are contraindicated. Nutritional support and N-acetylcysteine should be considered for use in conjunction with corticosteroids although evidence of benefit is not conclusive. Patients with severe disease who do not respond to therapy within a week have a very poor outcome. Recent data have shown a survival benefit of liver transplantation in this group although this remains experimental at present. Current and future research should focus on targeted therapies for severe AH and those who fail first-line treatment.
Project description:Alcoholic liver disease (ALD) comprises a clinical-histologic spectrum including fatty liver, alcoholic hepatitis (AH), and cirrhosis with its complications. Most patients are diagnosed at advanced stages and data on the prevalence and profile of patients with early disease are limited. Diagnosis of ALD requires documentation of chronic heavy alcohol use and exclusion of other causes of liver disease. Prolonged abstinence is the most effective strategy to prevent disease progression. AH presents with rapid onset or worsening of jaundice, and in severe cases may transition to acute on chronic liver failure when the risk for mortality, depending on the number of extra-hepatic organ failures, may be as high as 20-50% at 1 month. Corticosteroids provide short-term survival benefit in about half of treated patients with severe AH and long-term mortality is related to severity of underlying liver disease and is dependent on abstinence from alcohol. General measures in patients hospitalized with ALD include inpatient management of liver disease complications, management of alcohol withdrawal syndrome, surveillance for infections and early effective antibiotic therapy, nutritional supplementation, and treatment of the underlying alcohol-use disorder. Liver transplantation, a definitive treatment option in patients with advanced alcoholic cirrhosis, may also be considered in selected patients with AH cases, who do not respond to medical therapy. There is a clinical unmet need to develop more effective and safer therapies for patients with ALD.
Project description:Background and Aim:Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) have common hepatic histological features, but few studies have compared the genomic backgrounds of these two diseases. Here, we compared the genetic differences between ALD and NAFLD. Methods:This study enrolled 318 Japanese patients with ALD (n?=?118; male, 86%; median age, 62?years; liver cirrhosis, 58%; hepatocellular carcinoma [HCC], 31%) and NAFLD (n?=?200; male, 55%; age, 61?years; cirrhosis, 19%; HCC, 12%). The genotype frequencies of 10 single nucleotide polymorphisms (SNPs) were analyzed. Results:The ADH1B genotype GG and ALDH2 genotype GG were observed more frequently, and the percentage of patients with the MTP genotype GG was lower in ALD compared with NAFLD patients (ADH1B, 16 vs 4%; ALDH2 84 vs 44%; MTP 62 vs 72%, respectively; all P?<?0.01). Comparing noncirrhosis to cirrhosis, the frequency of the potassium voltage-gated channel subfamily Q member 1 (KCNQ1) genotype TT and adrenoceptor beta 3 (ADRB3) genotype TT was increased significantly in ALD-related cirrhosis. In contrast, the patatin-like phospholipase 3 (PNPLA3) genotype CC was decreased significantly in NAFLD-related cirrhosis. A comparison of patients with and without HCC demonstrated that the KCNQ1 genotype TT was increased significantly in both HCC groups. In addition, associations between the KCNJ15 genotype GG and ALD-HCC and the G allele of PNPLA3 and NAFLD-HCC were identified. Conclusions:SNPs in genes related to ethanol and lipid metabolism clearly differed between patients with ALD and NAFLD. KCNQ1 might affect the progression and hepatocarcinogenesis in both ALD and NAFLD.
Project description:Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple steatosis to hepatitis to cirrhosis and hepatocellular carcinoma. Although most people with excessive alcohol or calorie intake display abnormal fat accumulation in the liver (simple steatosis), a small percentage develops progressive liver disease. Despite extensive research on understanding the pathophysiology of both these diseases there are still no targeted therapies available. The treatment for ALD remains as it was 50 years ago: abstinence, nutritional support and corticosteroids (or pentoxifylline as an alternative if steroids are contraindicated). As for NAFLD, the treatment modality is mainly directed toward weight loss and co-morbidity management. Therefore, new pathophysiology directed therapies are urgently needed. However, the involvement of several inter-related pathways in the pathogenesis of these diseases suggests that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination therapy towards multiple targets would eventually be required. In this review, we delineate the treatment options in ALD and NAFLD, including various new targeted therapies that are currently under investigation. We hope that soon we will be having an effective multi-therapeutic regimen for each disease.
Project description:Alcoholic liver disease (ALD) represents a spectrum of injury, ranging from simple steatosis to alcoholic hepatitis to cirrhosis. Regular alcohol use results in fatty changes in the liver which can develop into inflammation, fibrosis and ultimately cirrhosis with continued, excessive drinking. Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with significant morbidity and mortality that can occur in patients with steatosis or underlying cirrhosis. The pathogenesis of ALD is multifactorial and in addition to genetic factors, alcohol-induced hepatocyte damage, reactive oxygen species, gut-derived microbial components result in steatosis and inflammatory cell (macrophage and neutrophil leukocyte) recruitment and activation in the liver. Continued alcohol and pro-inflammatory cytokines induce stellate cell activation and result in progressive fibrosis. Other than cessation of alcohol use, medical therapy of AH is limited to prednisolone in a subset of patients. Given the high mortality of AH and the progressive nature of ALD, there is a major need for new therapeutic intervention for this underserved patient population.
Project description:MicroRNAs (miRNAs) are small non-coding RNAs that regulate multiple physiological and pathological functions through the modulation of gene expression at the post-transcriptional level. Accumulating evidence has established a role for miRNAs in the development and pathogenesis of liver disease. Specifically, a large number of studies have assessed the role of miRNAs in alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), two diseases that share common underlying mechanisms and pathological characteristics. The purpose of the current review is to summarize and update the body of literature investigating the role of miRNAs in liver disease. In addition, the potential use of miRNAs as biomarkers and/or therapeutic targets is discussed. Among all miRNAs analyzed, miR-34a, miR-122 and miR-155 are most involved in the pathogenesis of NAFLD. Of note, these three miRNAs have also been implicated in ALD, reinforcing a common disease mechanism between these two entities and the pleiotropic effects of specific miRNAs. Currently, no single miRNA or panel of miRNAs has been identified for the detection of, or staging of ALD or NAFLD. While promising results have been shown in murine models, no therapeutic based-miRNA agents have been developed for use in humans with liver disease.
Project description:Alcoholic liver disease (ALD) is the most common liver disease in the Western world. For many reasons, it is underestimated and underdiagnosed. An early diagnosis is absolutely essential since it (1) helps to identify patients at genetic risk for ALD; (2) can trigger efficient abstinence namely in non-addicted patients; and (3) initiate screening programs to prevent life-threatening complications such as bleeding from varices, spontaneous bacterial peritonitis or hepatocellular cancer. The two major end points of ALD are alcoholic liver cirrhosis and the rare and clinically-defined alcoholic hepatitis (AH). The prediction and early diagnosis of both entities is still insufficiently solved and usually relies on a combination of laboratory, clinical and imaging findings. It is not widely conceived that conventional screening tools for ALD such as ultrasound imaging or routine laboratory testing can easily overlook ca. 40% of manifest alcoholic liver cirrhosis. Non-invasive methods such as transient elastography (Fibroscan), acoustic radiation force impulse imaging or shear wave elastography have significantly improved the early diagnosis of alcoholic cirrhosis. Present algorithms allow either the exclusion or the exact definition of advanced fibrosis stages in ca. 95% of patients. The correct interpretation of liver stiffness requires a timely abdominal ultrasound and actual transaminase levels. Other non-invasive methods such as controlled attenuation parameter, serum levels of M30 or M65, susceptometry or breath tests are under current evaluation to assess the degree of steatosis, apoptosis and iron overload in these patients. Liver biopsy still remains an important option to rule out comorbidities and to confirm the prognosis namely for patients with AH.
Project description:Cirrhosis is a heterogeneous clinical condition that includes patients at wide-ranging stages of severity. The role of the underlying liver disease on patient prognosis remains unclear.To assess the impact of the underlying liver disease on the occurrence of hepatocellular carcinoma (HCC) and death.Data related to the occurrence of HCC and death were collected during a 21-year period among patients with cirrhosis related to alcoholic liver disease (ALD) (n = 529), chronic hepatitis C virus (HCV) infection (n = 145) or non-alcoholic fatty liver disease (NAFLD) (n = 78).At inclusion, ALD patients were younger than HCV and NAFLD patients (56 vs. 67 vs. 63 years; p<0.001) and had worse liver function (percent of patients with Child-Pugh stages B or C: 48% vs. 8% vs. 17%; p<0.001). During follow-up, 85 patients developed HCC and 379 died. The 10-year cumulative incidence rate of HCC was lower in ALD patients than in HCV and NAFLD patients (8.4% vs. 22.0% vs. 23.7%; p<0.001). The 10-year cumulative incidence rates of mortality were not statistically different between ALD, HCV and NAFLD patients (58.1% vs. 47.7% vs. 49.9%; p = 0.078). Alcohol abstinence and viral eradication were associated with reduced mortality among ALD and HCV patients, respectively. In multivariate analyses, ALD was associated with a reduced risk of HCC (0.39; 95% CI, 0.20-0.76; p = 0.005) but with a higher risk of mortality (1.53; 95% CI, 1.20-1.95; p<0.001). ALD patients died more frequently from decompensation of cirrhosis.Despite a lower incidence of HCC, patients with ALD-related cirrhosis have a worse outcome than those with chronic HCV infection or NAFLD-related cirrhosis.