Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH) and ultimately may lead to cirrhosis. Hepatic ...steatosis or fatty liver is defined as increased accumulation of lipids in hepatocytes and results from increased production or reduced clearance of hepatic triglycerides or fatty acids. Fatty liver can progress to NASH in a significant proportion of subjects. NASH is a necroinflammatory liver disease governed by multiple pathways that are not completely elucidated. This review describes the main mechanisms that have been reported to contribute to the pathophysiology of NAFLD and NASH.
Hereditary hemochromatosis (HH) is one of the most common genetic disorders among persons of northern European descent. There have been recent advances in the diagnosis, management, and treatment of ...HH. The availability of molecular diagnostic testing for HH has made possible confirmation of the diagnosis for most patients. Several genotype-phenotype correlation studies have clarified the differences in clinical features between patients with the C282Y homozygous genotypes and other HFE mutation patterns. The increasing use of noninvasive tests such as MRI T2* has made quantification of hepatic iron deposition easier and eliminated the need for liver biopsy in most patients. Serum ferritin of <1,000 ng/mL at diagnosis remains an important diagnostic test to identify patients with a low risk of advanced hepatic fibrosis and should be used routinely as part of the initial diagnostic evaluation. Genetic testing for other types of HH is available but is expensive and generally not useful in most clinical settings. Serum ferritin may be elevated among patients with nonalcoholic fatty liver disease and in those with alcoholic liver disease. These diagnoses are more common than HH among patients with elevated serum ferritin who are not C282Y homozygotes or C282Y/H63D compound heterozygotes. A secondary cause for liver disease should be excluded among patients with suspected iron overload who are not C282Y homozygotes. Phlebotomy remains the mainstay of therapy, but emerging novel therapies such as new chelating agents may have a role for selected patients.
MicroRNAs in Common Human Diseases Li, Yu; Kowdley, Kris V.
Genomics, Proteomics & Bioinformatics/Genomics, proteomics and bioinformatics
10, Številka:
5
Journal Article
Recenzirano
Odprti dostop
MicroRNAs (miRNAs) are a class of short non-coding RNA molecules that have attracted tremendous attention from the biological and biomedical research communities over the past decade. With over 1900 ...miRNAs discovered in humans to date, many of them have already been implicated in common human disorders. Facilitated by high-throughput genomics and bioinformatics in conjunction with traditional molecular biology techniques and animal models, miRNA research is now positioned to make the transition from laboratories to clinics to deliver profound benefits to public health. Herein, we overview the progress of miRNA research related to human diseases, as well as the potential for miRNA to becoming the next generation of diagnostics and therapeutics.
Nonalcoholic fatty liver disease is a common cause of chronic liver disease in the general population. Nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease, is ...associated with an increased risk of liver‐related mortality and cardiovascular disease. At present, a liver biopsy is the only generally acceptable method for the diagnosis of NASH and assessment of its progression toward cirrhosis. Although several treatments have shown evidence of efficacy in clinical trials of varying design, there are no approved treatments for NASH, and published trials are often too divergent to allow meaningful comparisons. There is thus a lack of established noninvasive, point‐of‐care diagnostics and approved treatment on one hand and a substantial population burden of disease on the other. These provide the rationale for developing consensus on key endpoints and clinical trial design for NASH. Conclusion: This article summarizes the consensus arrived at a meeting of the American Association for the Study of Liver Diseases on the key endpoints and specific trial design issues that are germane for development of diagnostic biomarkers and treatment trials for NASH. (HEPATOLOGY 2011;)
Nonalcoholic steatohepatitis (NASH) and the metabolic syndrome (MetS) are highly prevalent in the Western population. Their pathogenesis is closely linked to insulin resistance, which serves as a ...therapeutic target for the management of these conditions. This review article reviews the research supporting the influence of MetS on NASH and includes studies supporting their similar epidemiology, pathogenesis, and treatment.
Background and Aims
Cenicriviroc (CVC) is a C‐C chemokine receptors type 2 and 5 dual antagonist under evaluation for treating liver fibrosis in adults with nonalcoholic steatohepatitis (NASH). Year ...1 primary analysis of the 2‐year CENTAUR study showed that CVC had an antifibrotic effect without impacting steatohepatitis. Herein, we report the final data from year 2 exploratory analyses.
Approach and Results
This was a randomized, controlled study of adults with NASH, nonalcoholic fatty liver disease activity score ≥4, and NASH Clinical Research Network stage 1‐3 fibrosis. Participants in arms A and C received CVC 150 mg or placebo, respectively, for 2 years; arm B received placebo in year 1 and switched to CVC in year 2. Liver biopsy was performed at baseline, year 1, and year 2. Of 289 randomized participants, 242 entered year 2. At year 2, 24% of patients who switched to CVC and 17% who remained on placebo achieved ≥1‐stage fibrosis improvement and no worsening of NASH (P = 0.37). Twice the proportion on CVC who achieved fibrosis response at year 1 maintained benefit at year 2 (60% arm A versus 30% arm C), including 86% on CVC who had stage 3 fibrosis at baseline. Over 2 years, a similar proportion on CVC or placebo achieved ≥1‐stage fibrosis improvement and no worsening of NASH (15% arm A versus 17% arm C). In patients with fibrosis responses, we observed consistent reductions in levels of N‐terminal type 3 collagen propeptide and enhanced liver fibrosis scores, while increases in aspartate aminotransferase‐to‐platelet ratio index and Fibrosis‐4 scores were consistently observed in nonresponders. Safety profile was comparable across groups.
Conclusions
CVC was well tolerated, and year 2 data corroborate antifibrotic findings from year 1. The majority on CVC who achieved fibrosis response at year 1 maintained it at year 2, with greater effect in advanced fibrosis. ClinicalTrials.gov number, NCT02217475 (CENTAUR).
MicroRNAs are a group of intracellular noncoding RNA molecules that have been implicated in a variety of human diseases. Because of their high stability in blood, microRNAs released into circulation ...could be potentially utilized as noninvasive biomarkers for diagnosis or prognosis. Current microRNA isolation protocols are specifically designed for solid tissues and are impractical for biomarker development utilizing small-volume serum samples on a large scale. Thus, a protocol for microRNA isolation from serum is needed to accommodate these conditions in biomarker development. To establish such a protocol, we developed a simplified approach to normalize sample input by using single synthetic spike-in microRNA. We evaluated three commonly used commercial microRNA isolation kits for the best performance by comparing RNA quality and yield. The manufacturer’s protocol was further modified to improve the microRNA yield from 200μl of human serum. MicroRNAs isolated from a large set of clinical serum samples were tested on the miRCURY LNA real-time PCR panel and confirmed to be suitable for high-throughput microRNA profiling. In conclusion, we have established a proven method for microRNA isolation from clinical serum samples suitable for microRNA biomarker development.
Primary sclerosing cholangitis is a chronic cholestatic liver disease that can shorten life and may require liver transplantation. The cause is unknown, although it is commonly associated with ...colitis. There is no approved or proven therapy, although ursodeoxycholic acid is used by many on an empiric basis. Complications including portal hypertension, fat-soluble vitamin deficiency, metabolic bone diseases, and development of cancers of the bile duct or colon can occur.
Background and Aims
NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor‐α/γ agonist, improves ...insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH.
Approach and Results
A total of 106 patients with NAFLD/NASH with alanine aminotransferase (ALT) ≥ 50 U/L at baseline and body mass index ≥25 kg/m2 were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at week 16. Liver fat content (LFC) was assessed by MRI proton density fat fraction. The least‐squares mean percent change from baseline in ALT at week 16 was −25.5% (5.8), −27.7% (5.9), and −45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all). Compared with placebo, saroglitazar 4 mg improved LFC (4.1% 5.9 vs. −19.7% 5.6), adiponectin (−0.3 μg/mL 0.3 vs. 1.3 μg/mL 0.3), homeostatic model assessment–insulin resistance (−1.3 1.8 vs. −6.3 1.7), and triglycerides (−5.3 mg/dL 10.7 vs. −68.7 mg/dL 10.3) (P < 0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well‐tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27).
Conclusions
Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.)
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