Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide. We estimated the global prevalence, incidence, progression, and outcomes of NAFLD and nonalcoholic steatohepatitis (NASH). PubMed/MEDLINE were searched from 1989 to 2015 for terms involving epidemiology and progression of NAFLD. Exclusions included selected groups (studies that exclusively enrolled morbidly obese or diabetics or pediatric) and no data on alcohol consumption or other liver diseases. Incidence of hepatocellular carcinoma (HCC), cirrhosis, overall mortality, and liver-related mortality were determined. NASH required histological diagnosis. All studies were reviewed by three independent investigators. Analysis was stratified by region, diagnostic technique, biopsy indication, and study population. We used random-effects models to provide point estimates (95% confidence interval [CI]) of prevalence, incidence, mortality and incidence rate ratios, and metaregression with subgroup analysis to account for heterogeneity. Of 729 studies, 86 were included with a sample size of 8,515,431 from 22 countries. . Fibrosis progression proportion, and mean annual rate of progression in NASH were 40.76% (95% CI: 34.69-47.13) and 0.09 (95% CI: 0.06-0.12). HCC incidence among NAFLD patients was 0.44 per 1,000 person-years (range, 0.29-0.66). Liver-specific mortality and overall mortality among NAFLD and NASH were 0.77 per 1,000 (range, 0.33-1.77) and 11.77 per 1,000 person-years (range, 7.10-19.53) and 15.44 per 1,000 (range, 11.72-20.34) and 25.56 per 1,000 person-years (range, 6.29-103.80). Incidence risk ratios for liver-specific and overall mortality for NAFLD were 1.94 (range, 1.28-2.92) and 1.05 (range, 0.70-1.56). Conclusions: As the global epidemic of obesity fuels metabolic conditions, the clinical and economic burden of NAFLD will become enormous. (HEPATOLOGY 2016;64:73-84)
BackgroundHepatic expression of Sonic Hedgehog (SHH) is associated with Non-alcoholic fatty liver disease (NAFLD) and development of Non-alcoholic steatohepatitis (NASH). Hepatic SHH detection increases with the diagnosis of NASH. This pilot study was designed to confirm that staining for SHH is useful in NASH diagnosis and determine whether quantification of staining by computer assisted morphometry (CAM) can be used to assess severity of ballooning degeneration.MethodsSHH was detected by immunohistochemistry (IHC) on paraffin-embedded liver sections in subjects (N = 69) with biopsy proven NAFLD and no liver disease (control). Serum samples were also available for these subjects. Post-staining, a digitized image of the section was acquired and an area quantification algorithm was used to quantify the degree of SHH expression. Additionally, circulating M30, M65, and SHH were measured by ELISA.ResultsNotably, hepatic SHH expression correlated with histologic ballooning degeneration (rho = 0.62, p < 0.0001), steatosis grade (rho = 0.554, P < 0.001), Mallory-Denk bodies (rho = 0.54, P < 0.001), pericellular fibrosis (rho = 0.527, P < 0.001), and lymphocytic infiltration (rho = 0.435, P < 0.0002). Additionally, hepatic SHH expression correlated with circulating M65 (rho = 0.588, p < 0.0001), and circulating M30 (rho = 0.375, p = 0.001), as well as AST and ALT (rho = 0.43, p = 0.0004, and rho = 0.27, p = 0.03, respectively). Further, serum M30 was almost twice as high in NASH patients compared to non-NASH (539.1 ± 290.8 U/L vs. 287.6 ± 190.5 U/L; p = 0.0002), while M65 was almost three times higher in NASH patients compared to non-NASH (441.2 ± 464.2 U/L vs. 162.8 ± 353.1 U/L, P = 0.0006). Logistic modeling indicates hepatic SHH expression and presence of type 2 diabetes as independent predictors of advanced fibrosis (defined as portal and pericellular fibrosis > 2: OR = 1.986, p = 0.01, and OR = 3.280, p = 0.03, respectively).ConclusionThus, our findings show quantitation of SHH expression by CAM can provide a tool for quantifying changes in hepatocyte injury and assist in unambiguous staging/grading of NASH. Our study showed minimal interobserver variability using CAM based quantification. Once validated, CAM assessment of hepatic SHH could benefit clinical trials or long term outcomes studies of NASH subjects.
BackgroundNon-alcoholic steatohepatitis (NASH) is among the leading causes of liver disease worldwide. It is increasingly recognized that the phenotype of NASH may involve a number of different pathways, of which each could become important therapeutic targets. The aim of this study is to use high resolution mass spectrometry (MS) and phosphoproteomics techniques to assess the serum proteome and hepatic phosphoproteome in subjects with NASH-related fibrosis.MethodsSixty-seven biopsy-proven NAFLD subjects with frozen sera and liver tissue were included. Reverse phase protein microarray was used to quantify the phosphorylation of key signaling proteins in liver and nano-liquid chromatography (LC)-MS was used to sequence target biomarkers in the serum. An image analysis algorithm was used to quantify the percentage of collagen (% collagen) using computer-assisted morphometry. Using multiple regression models, serum proteomes and phosphorylated hepatic proteins that were independently (p ≤ 0.05) associated with advanced fibrosis (stage ≥ 2) and higher % collagen were assessed.ResultsPhosphorylated signaling pathways in the liver revealed that apoptosis signal-regulating kinase 1, mitogen-activated protein kinase (ASK1-MAPK pathway involving ASK1 S38 (p < 0.02) and p38 MAPK (p = 0.0002)) activated by the inflammatory cytokine interleukin (IL-10) (p < 0.001), were independently associated with higher % collagen. LC-MS data revealed that serum alpha-2 macroglobulin (α2M) (p = 0.0004) and coagulation factor V (p = 0.0127) were independently associated with higher % hepatic collagen.ConclusionsSimultaneous profiling of serum proteome and hepatic phosphoproteome reveals that the activation of ASK1 S38, p38 MAPK in the liver, and serum α2M and coagulation factor V are independently associated with hepatic collagen deposition in patients with NASH. These data suggest the role of these pathways in the pathogenesis of NASH-related fibrosis as a potential therapeutic target.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1136-1) contains supplementary material, which is available to authorized users.
Major histocompatibility complex class I-related chain A (MICA) is a highly polymorphic gene that modulates immune surveillance by binding to its receptor on natural killer cells, and its genetic polymorphisms have been associated with chronic immune-mediated diseases. The progressive form of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), is characterized by accumulation of fat and inflammatory cells in the hepatic parenchyma, potentially leading to liver cell injury and fibrosis. To date, there are no data describing the potential role of MICA in the pathogenesis of NAFLD. Therefore, our aim was to assess the association between MICA polymorphism and NASH and its histologic features. A total of 134 subjects were included. DNA from patients with biopsy-proven NAFLD were genotyped using polymerase chain reaction-sequence-specific oligonucleotide for MICA alleles. Liver biopsies were assessed for histologic diagnosis of NASH and specific pathologic features, including stage of fibrosis and grade of inflammation. Multivariate analysis was performed to draw associations between MICA alleles and the different variables; P ≤ 0.05 was considered significant. Univariate analysis showed that MICA*011 (odds ratio [OR], 7.14; 95% confidence interval [CI], 1.24-41.0; P = 0.04) was associated with a higher risk for histologic NASH. Multivariate analysis showed that MICA*002 was independently associated with a lower risk for focal hepatocyte necrosis (OR, 0.24; 95% CI, 0.08-0.74; P = 0.013) and advanced fibrosis (OR, 0.11; 95% CI, 0.02-0.70; P = 0.019). MICA*017 was independently associated with a higher risk for lymphocyte-mediated inflammation (OR, 5.12; 95% CI, 1.12-23.5; P = 0.035). Conclusion: MICA alleles may be associated with NASH and its histologic features of inflammation and fibrosis. Additional research is required to investigate the potential role of MICA in increased risk or protection against NAFLD. (Hepatology Communications 2021;5:63-73).
Objective Neuromuscular re-education (NMRE) therapy including bracing, containment, facilitation techniques, joint compression, weight (WT) bearing, and myofascial release has been shown to improve neurodevelopmental maturation in premature infants. This study aimed to examine the association of NMRE with growth parameters including WT and length (L) at 36 weeks postmenstrual age (PMA) and at discharge. Study Design We analyzed data of infants <34 weeks gestational age (GA) or <1,800 g birth weight (BW) to examine the association of NMRE with growth parameters using correlation coefficient analysis. The effect of potential confounders was examined using multilinear regression models. Results Study includes 253 premature infants. Average GA was 300/7 weeks (±23/7) and BW was 1,315 g (±416), 49.8% were females and 65% were African Americans. NMRE has inverse correlation with WT at birth and at 36 weeks PMA, −0.66 (<0.001) and −0.21 (<0.001), respectively, but not at the time of discharge. NMRE has direct correlation with change in WT from birth to 36 weeks PMA and time of discharge, 0.50 (<0.001) and 0.62 (<0.001), respectively, and from the time of starting therapy to 36 weeks PMA or discharge, 0.25 (<0.001) and 0.51 (<0.001), respectively. There was no negative correlation between NMRE with daily WT gain from birth to 36 weeks PMA or to discharge, −0.05 (0.43) and −0.07 (0.23), respectively, or from the time of starting therapy to 36 weeks PMA, −0.09 (0.14). There was an inverse correlation between NMRE with average WT gain per day from the time of starting therapy to discharge, −0.26 (<0.001), Similar findings were found examining the correlation between NMRE and changes in L. Multilinear regression analysis examining the relationship while controlling for GA, BW, sex, and race; socioeconomic variables; and concurrent massage therapy and sensory integration revealed similar results. Conclusion NMRE, aimed to enhance neurodevelopmental outcomes of premature infants, may not have a negative impact on their physical growth. Key Points
Objective Cue-based feeding aims at matching introduction of per oral (PO) feeding with physiological readiness of preterm infants to facilitate PO intake and avoid oral aversion. It was claimed that cue-based feeding may lead to delay in the initiation or achieving full PO feeding in clinical setting primarily using bubble nasal continuous positive airway pressure (CPAP). The study aimed to examine the association of cue-based feeding with time of introduction and completing oral feeding in infants primarily managed with bubble CPAP. Study Design A retrospective analysis where outcomes of preterm infants ≤32 weeks' gestational age (GA) and ≤2,000 g birth weight (BW) were compared after a practice change from volume-based feeding advancement to cue-based feeding. Continuous variables were compared by using t-test and multilinear regression analysis to control for confounding variables. Results Of the 311 preterm infants who met inclusion and exclusion criteria, 194 were in the cue-based feeding group and 117 were in the volume-based advancement historical comparison group. There were no differences between groups regarding demographic or clinical variables. Postmenstrual age (PMA) of initial feeding assessment was less in the cue-based feeding group. Age of first PO feeding and when some PO was achieved every feed was mildly delayed in the cue-based feeding compared with comparison group, 34 (±1.3) versus 33.7 (±1.2) weeks, and 36.2 (±2.3) versus 36.0 (±2.4) weeks, (p < 0.01) respectively. However, the age of achieving full PO did not differ between groups, 36.8 (±2.2) versus 36.4 (±2.4) weeks (p = 0.13). There was no difference between groups regarding growth parameters at 36 weeks' PMA or at discharge. Similar results were obtained when examining subcategories of infants ≤1,000 g and 1,001 to 2,000 g. Conclusion Cue-based feeding may not be associated with a delay in achieving full oral feeding or prolongation of the length of stay in preterm infants managed with CPAP. Key Points
Background: Dexamethasone has been associated with early extubation and shorter duration of mechanical ventilation in preterm infants. High doses or prolonged courses of dexamethasone may be associated with poor neurodevelopmental outcomes. Methods: This is an observational cohort study assessing the efficacy of a low dose short dexamethasone course combined with post-extubation bubble continuous positive airway pressure (CPAP) strategy on rates of successful extubation and reduction of the duration of invasive mechanical ventilation in extremely preterm infants. We compared the short term outcomes of implementing such strategy on a group of infants with birth weight <750g to a historical cohort. Results: Among infants intubated for at least 10 days, median time to extubation from starting the dexamethasone course was 2 days (IQR: 1-3). Total duration of intubation was significantly shorter in infants received dexamethasone compared to the control groups (21 +/-6 days vs. 30 +/-10 days, p= 0.03), and although statistically non-significant, duration to wean to 21% bCPAP was shorter compared to the control group (48 +/-13 days vs. 74 +/-29 days, p= 0.06). Conclusions: A low-dose short dexamethasone course combined with post extubation bubble CPAP intervention may be associated with successful early extubation and shorter duration of mechanical ventilation.
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