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BACKGROUND@#Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.@*METHODS@#Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL).@*RESULTS@#A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69-1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension ( P < 0.001, P = 0.026 and P = 0.049, respectively). CK-18 M30 levels were positively associated with histological NAS in most centers. The area under the receiver operating characteristics (AUROC) for NASH was 0.750 (95% confidence intervals: 0.714-0.787), and CK-18 M30 at Youden's index maximum was 275.7 U/L. Both sensitivity (55% [52%-59%]) and positive predictive value (59%) were not ideal.@*CONCLUSION@#This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.
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Humans , Non-alcoholic Fatty Liver Disease/diagnosis , Keratin-18 , Biomarkers , Biopsy , Hepatocytes/pathology , Apoptosis , Liver/pathologyABSTRACT
The intestinal mucus layer is a barrier that separates intestinal contents and epithelial cells, as well as acts as the "mucus layer-soil" for intestinal flora adhesion and colonization. Its structural and functional integrity is crucial to human health. Intestinal mucus is regulated by factors such as diet, living habits, hormones, neurotransmitters, cytokines, and intestinal flora. The mucus layer's thickness, viscosity, porosity, growth rate, and glycosylation status affect the structure of the gut flora colonized on it. The interaction between "mucus layer-soil" and "gut bacteria-seed" is an important factor leading to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Probiotics, prebiotics, fecal microbiota transplantation (FMT), and wash microbial transplantation are efficient methods for managing NAFLD, but their long-term efficacy is poor. FMT is focused on achieving the goal of treating diseases by enhancing the "gut bacteria-seed". However, a lack of effective repair and management of the "mucus layer-soil" may be a reason why "seeds" cannot be well colonized and grow in the host gut, as the thinning and destruction of the "mucus layer-soil" is an early symptom of NAFLD. This review summarizes the existing correlation between intestinal mucus and gut microbiota, as well as the pathogenesis of NAFLD, and proposes a new perspective that "mucus layer-soil" restoration combined with "gut bacteria-seed" FMT may be one of the most effective future strategies for enhancing the long-term efficacy of NAFLD treatment.
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Humans , Non-alcoholic Fatty Liver Disease/therapy , Gastrointestinal Microbiome , Probiotics , Prebiotics , Fecal Microbiota Transplantation , Bacteria , Liver/pathologyABSTRACT
There are gradual increases in the incidence rates of metabolic associated fatty liver disease （MAFLD） and type 2 diabetes mellitus （T2DM）， with close relationship and mutual interaction between the two diseases， but the specific mechanism is still unclear. Studies have shown that T2DM and MAFLD may cause aggravation of each other through insulin resistance， inflammation， some hepatocyte factors， and cellular senescence and protect each other through some hepatocyte factors. Further research on the association between T2DM and MAFLD and the mechanism of comorbidity is of great significance for the clinical prevention and treatment of the two diseases.
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With the effective control of viral hepatitis around the world, nonalcoholic steatohepatitis (NASH) will become the main cause of liver transplantation in the next ten years. There is a huge number of NASH patients, but currently no drug has been approved by authorities, which represents a large unmet need in clinical practice. The complex pathogenesis of NASH, heterogeneity of this disease, difficulties in diagnosis, and selection of treatment endpoints have brought great challenges to the research and development of new drugs.
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Current studies have confirmed that liver diseases are closely related to intestinal microorganisms; however, those studies have mainly concentrated on bacteria. Although the proportion of intestinal microorganisms accounted for by colonizing fungi is very small, these fungi do have a significant effect on the homeostasis of the intestinal microecosystem. In this paper, the characteristics of intestinal fungi in patients with chronic liver diseases such as alcoholic liver disease, nonalcoholic fatty liver disease and cirrhosis are summarized, and the effects of intestinal fungi and their metabolites are analyzed and discussed. It is important to realize that not only bacteria but also intestinal fungi play important roles in liver diseases.
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Nonalcoholic steatohepatitis (NASH)/nonalcoholic fatty liver disease (NAFLD) has gradually become one of the main causes of hepatocellular carcinoma (HCC) in Western developed countries. Different from the typical evolution process of hepatitis, liver cirrhosis, and liver cancer, nearly 40% NAFLD patients can progress into HCC without experiencing liver cirrhosis, suggesting other mechanisms may play a role in this process. This article elaborates on the latest research advances in the pathogenesis of NAFLD-related HCC.
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Objective@#To preliminary, explore the effect of small intestinal epithelial dendritic cells on the occurrence and development of nonalcoholic fatty liver disease in mice.@*Methods@#Thirty-two (half male and half female) 4-week-old C57BL/6 mice were randomly divided into two groups. The mice were fed with normal diet (SD group) and high-fat diet (HFD group). Eight mice (half male and half female) were randomly killed from each group over the 14 and 20-weeks feeding period to observe their body weight, liver and small-intestine wet weight. Alanine aminotransferase, aspartate aminotransferase, blood glucose, high-density lipoprotein, low-density lipoprotein, total cholesterol and triglyceride were determined by eyeball blood samples. Pathological diagnosis and alcoholic fatty liver disease activity score were collected. The number of mice small intestinal dendritic cells was observed under a microscope. Statistical analysis was performed to compare two groups of independent samples with homogeneity test of variance, t test, and covariance analysis.@*Results@#The body weight, liver wet weight, serum alanine aminotransferase and aspartate aminotransferase of mice in HFD group were significantly higher than those of control group at 20 weeks (P < 0.05), and the serum high density lipoprotein of mice in HFD group was significantly higher than that of SD group at 14 weeks (P < 0.05). At 14th weeks, the liver tissue of mice in HFD group had early pathological manifestations of hepatitis (fatty degeneration, punctate necrosis and balloon-like degeneration). Of which 87.5% (7/8) of them were diagnosed as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease, while only a few mice in SD group had early pathological manifestations of hepatitis. At 20th weeks, all mice in HFD group were diagnosed with non-alcoholic steatohepatitis or non-alcoholic fatty liver disease, while none of the mice in SD group was diagnosed with non-alcoholic fatty liver disease. At both time points, the percentage of small intestinal dendritic cells in HFD group was significantly higher than that in SD group (14 weeks: 4.181 ± 4.314 vs. 15.099 ± 10.349; 20 weeks: 9.615 ± 8.267 vs. 32.839 ± 24.475, both P < 0.05). Statistical analysis combined with the alcoholic fatty liver disease activity score showed that there was no linear correlation between the two groups (regression coefficient was 20.196%).@*Conclusion@#The number and different staging of small intestinal dendritic cells in mice is associated with the occurrence and development of NAFLD.
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Currently, there is no randomized controlled clinical trial of immunoglobulin (Ig) G4-related diseases in the world. Therefore, the best-known evidence-based medical treatment plan for this disorder is unavailable. The goal of IgG4-related hepatobiliary diseases treatment is to alleviate symptoms, prevent disease-related complications and fibrosis progression. A definite diagnosis is warranted before treatment. Hormonal therapy has become the basis of induction of remission in IgG4-related hepatobiliary disease. An initial prednisone dose is 30 ~ 40mg/d or 0.6 mg.kg-1.d-1 for 2 to 4 weeks, thereafter, gradually the dose is reduced within 2-3 months. Maintenance therapy with low-dose glucocorticoids hormone (prednisone 2.5 to 5.0 mg/d) is recommended for 1 to 3 years to prevent disease recurrence. In addition, immunosuppressive agents are equally effective, and in most cases, hormone combined immunosuppressive therapy may respond. Rituximab, a monoclonal antibody is a promising drug for treatment of this kind of diseases.
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Objective@#To establish overfed zebrafish model for non-alcoholic steatohepatitis.@*Methods@#The wild-type zebrafish was fed 3 times a day with normal diet. Body length, weight, and triglyceride levels were measured after 20 days of feeding. The changes in expression of genes associated with cholesterol metabolism, lipid metabolism, endoplasmic reticulum stress, and inflammation were detected by quantitative PCR. Liver tissue sections were stained with H&E. Statistical analyses between groups were compared using t-test.@*Results@#The body length (0.71±0.014) cm and body weight (44.83±1.833) mg of model group were higher than that of control group (0.50±0.009) cm and body weight (19.33±2.753) mg (total body length = 12.36, total body weight = 7.71, P < 0.01). Triglyceride content in the model group was (59.15 ± 0.5612) μmol / L, higher than the control group (16.71 ± 0.3562) μmol / L (t = 63.84, P < 0.001). Quantitative PCR results showed that the expression of genes related to cholesterol synthesis in the model group was higher than that in the control group (P < 0.01). The expression levels of lipid production and lipid oxidation related factors in the model group were higher than the control group. The difference between the two groups was statistically significant (P < 0.05). The expression of inflammation-related factors in the model group was higher than that in the control group (P < 0.001), and the expression of genes related to endoplasmic reticulum stress in the model group was higher than that to control group (P<0.001). Liver H&E staining showed that the model group had pathological changes such as large bulla and vesicles compared to the control group.@*Conclusion@#A continuous 3 times 20 days of normal diet can simulate the disease characteristics of human non-alcoholic steatohepatitis in a zebrafish.
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Objective To investigate the value of hydrogen proton MR spectroscopy (1H-MRS) and Dixon sequence for the quantitative diagnosis and classification of steatosis in patients with non-alcoholic fatty liver disease (NAFLD). Methods Sixty seven patients with NAFLD confirmed by liver biopsy were prospectively collected from October 2015 to May 2017 in Hangzhou Normal University Hospital. All patients underwent 1H-MRS and Dixon sequence scan within 7 days after liver biopsy, 1H-MRS-based hydrogen proton density fraction (MRS-PDFF) and Dixon-based hydrogen proton density fraction (MRI-PDFF) were obtained. Fat grading based on the fat percentage obtained from liver biopsy. Pearson correlation analysis was performed to analyze the correlation among pathological steatosis and MRS-PDFF, MRI-PDFF. One-way ANOVA analysis was performed to compare the difference of PDFF between patients with different degrees of severity of fatty liver. And the ROC curve analysis was performed to generate the thresholds of MRS-PDFF and MRI-PDFF for determining the presence of fatty liver. Results The steatosis grade of pathological biopsy showed grade S1 in 36 cases, grade S2 in 16 cases, grade S3 in 15 cases, the MRS-PDFF values of S1, S2 and S3 patients were (8.25 ± 4.32)％, (15.67 ± 4.54)％, (23.46 ± 5.82)％and the MRI-PDFF values were (6.31 ± 2.94)％, (15.42 ± 5.07)％, (24.47 ± 6.31)％. Statistically significant differences were observed among them (P<0.01). Both MRS-PDFF and MRI-PDFF were positively correlated with histological fat percentage (r values were 0.840 and 0.892,all P<0.01), there was also a correlation between MRS-PDFF and MRI-PDFF (r=0.930, P<0.01). Area under ROC curve of MRS-PDFF and MRI-PDFF for differential diagnosis of grade S1 steatosis were 0.955 and 0.976, and area under ROC curve for differential diagnosis of grade S3 steatosis were 0.972 and 0.978. Conclusion 1H-MRS and Dixon sequces have high value in liver fat content detection and classification of patients with NAFLD, and both have similar diagnostic efficacy.
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OBJECTIVE To explore the role of Wnt/β-catenin signaling in hair cell regeneration using zebrafish lateral line system. METHODS Zebrafish larval were incubated in cisplatin solution to induce lateral line hair cells loss and then regenerated for 48 hrs. Supporting cells were sorted, and QPCR was taken to detect the expression change of Wnt/β-catenin signaling factors. Whole mount in situ hybridization was used to show the expression pattern of dkks. Wnt/β-catenin signalinginhibitors(FH535 and XAV939) and enhancer(BIO) was added to the medium to observe the influences on hair cell regeneration. RESULTS RT-PCR and Q-PCR showed that the expressions of wnt2, wnt3a and ctnnb1 in sorting supporting cells were elevated(P＜0.05). Whole mount in situ hybridization showed that the expression of dkk1a and dkk2 in lateral lines sub-supporting cellsreduced. The addition of Wnt/β-catenin signaling inhibitors reduced the regenerated hair cells to 40％ of normal, and even to 10％ when the concentration of inhibitor was elevated.And the first 12 hrs Wnt/β-catenin signaling inhibition also led to the reduced regenerated hair cells(P＜0.001). However, regeneratedhair cells have no significant change compared between BIO-treated and nontreated group(P＞0.05). CONCLUSION Wnt/β-catenin signaling is necessary whilenot sufficient for zebrafish lateral line hair cell regeneration.
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Nonalcoholic fatty liver disease (NAFLD) has become one of the research hotspots in the field of liver disease. However, so far, no drugs have been approved by the U.S. Food and Drug Administration for the treatment of nonalcoholic steatohepatitis, which brings opportunities and challenges to the clinical trials on the treatment of NAFLD. Liver histology is currently considered a reliable surrogate endpoint for tracking the progression of NAFLD, but its invasiveness has limited the development of drugs for the treatment of NAFLD. In recent years, some noninvasive measurement methods have gradually been used as secondary or exploratory endpoints in existing clinical trials.
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Objective@#We aimed, in our prospective study, to assess the predictive value of serum non-invasive and biochemical markers for clinical diagnosis of significant fibrosis (including early stages).@*Methods@#We measured sH2a levels in serum, comparing with routine liver function markers. We compared blindly pretreatment serum samples from a cohort of hepatitis B patients without non-alcoholic fatty liver disease(NAFLD), which had histological grades of liver fibrosis, with NAFLD individuals and CHB with NAFLD patients. Statistical analysis was by Student′s t test, and receiver-operating characteristic (ROC) curves were drawn.@*Results@#ROC curves showed that serum sH2a had greater diagnostic performance than routine liver function markers compared with histological grades of liver fibrosis(S0, S1-2, S3-4). ROC curves showed that using a sH2a cut-off point of 0.79 was with highest sensitivity as 63% and highest specificity as 80%. And sensitivity as 96.7% and specificity as 75.5% when using a sH2a cut-off point of 0.77.@*Conclusions@#sH2a has the potential to be a uniquely sensitive and specific novel marker for liver fibrosis and function.
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Objective@#To investigate the value of 1H-magnetic resonance spectroscopy (1H-MRS) in determining the content of liver triglyceride in patients with fatty liver disease (FLD), as well as its influencing factors.@*Methods@#A total of 124 patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis B (CHB), or hepatitis B complicated by FLD who underwent liver biopsy in the Affiliated Hospital of Hangzhou Normal University were enrolled, and the clinical data, serological markers, FibroScan results, and 1H-MRS results were collected. A correlation analysis was performed with the results of liver biopsy as the gold standard, and the influence of factors including hepatitic B virus (HBV) infection and obesity on accuracy was analyzed. A one-way analysis of variance was used for comparison of means between the three groups, and the LSD or SNK test (for homogeneity of variance) or the Tamhane’s or Dunnett’s test (heterogeneity of variance) was used for comparison between any two groups. The t-test was used for comparison of continuous data between groups, and the chi-square test was used for comparison of categorical data. The MRS-PDFF receiver operating characteristic (ROC) curve was plotted, the area under the ROC curve (AUC) was calculated, the optimal cut-off points for the diagnosis of NAFLD were estimated, and sensitivity and specificity were calculated.@*Results@#The NAFLD group (42 patients) and the CHB + NAFLD group (40 patients) had a significantly higher proton density fat fraction (PDFF, the content of triglyceride in the liver) than the CHB group (42 patients) (16.84±9.76/9.39 ± 5.50 vs 3.45 ± 1.63, P < 0.001). The results were significantly correlated with the degree of steatosis confirmed by liver biopsy (P < 0.001), but it was not significantly correlated with inflammation or fibrosis grade. The correlation analysis showed that the MRS-PDFF value measured by 1H-MRS was significantly correlated with body mass index (BMI), blood lipids, alkaline phosphatase, and blood glucose, while it was not significantly correlated with age, sex, or the presence or absence of hepatitis B. The ROC curve analysis showed that the AUCs of PDFF measured by 1H-MRS were 0.93, 0.974, and 0.976, respectively, for the diagnosis of steatosis S1(≥5%), S2(≥34%), and S3(≥66%), and the corresponding optimal thresholds were 5.14%, 11.16%, and 16.7%, respectively.@*Conclusion@#1H-MRS has a high diagnostic value in quantitative evaluation of the degree of liver steatosis in patients with FLD and is not affected by the factors such as HBV infection, age, and sex, while it is correlated with BMI and lipid metabolism.
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Objective@#To investigate the role of neutrophil elastase inhibitor, sivelestat, in preventing and treating nonalcoholic steatohepatitis (NASH) and its underling mechanisms.@*Methods@#A total of forty 4-week-old male C57BL/6J ApoE-/-mice were equally divided into the following four groups: standard chow (SC)+isotonic saline; SC+sivelestat; high-fat, high-cholesterol (HFHC) diet+isotonic saline; and HFHC+sivelestat. These mice were treated with above methods for 12 weeks. Blood and liver tissue samples were collected to measure biochemical parameters, hepatic steatosis and non-alcoholic fatty liver disease (NAFLD) activity score (inflammation) were evaluated by oil red O staining and HE staining, respectively. The mRNA and protein expression levels of hepatic inflammatory cytokines, CD68, and F4/80 were determined by quantitative RT-PCR and immunohistochemistry, respectively. Comparison of means between the four groups was made by one-way analysis of variance, and comparison between any two groups was made by the LSD or SNK method (for data with homogeneity of variance) or the Tamhane or Dunnett method (for data with heterogeneity of variance).@*Results@#Mice fed with an HFHC diet for 12 weeks developed typical pathological features of NASH compared with those fed with SC. Compared with mice fed with HFHC diet without sivelestat, those treated with HFHC and sivelestat exhibited the following features: (1) significantly reduced fast blood glucose, blood cholesterol, and hepatic biochemical parameters, as well as increased insulin sensitivity; (2) significantly reduced NAFLD activity score (5.71±1.11 vs 3.16±1.16, P < 0.05); (3) reduced monocyte chemoattractant protein-1 and tumor necrosis factor -α; (4) significantly reduced mRNA levels of CD68 and F4/80; and (5) reduced expression of CD68 in the liver.@*Conclusion@#Sivelestat alleviates the hepatic steatosis and inflammation of NASH in mice by inhibiting the activation of Kupffer cells.
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Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by fatty degeneration of hepatocytes due to nonalcoholic reasons. Liver cirrhosis and hepatocellular carcinoma are two important outcomes of NAFLD. Cell senescence is a relatively stable state in which cells deviate from the normal cell cycle and experience an irreversible loss of proliferative capacity, which is an objective law in cell life. Research shows that cell senescence is closely associated with the progression of liver fibrosis and the development and progression of hepatocellular carcinoma in NAFLD, and provides a new perspective for the prevention and treatment of liver fibrosis and hepatocellular carcinoma.
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With the prevalence of obesity around the world, the incidence rate of hepatitis B virus (HBV) infection complicated by metabolic syndrome (MS) is increasing year by year, and such patients have become a special population in patients with chronic HBV infection. In recent years, the research on the features of this disease and diagnosis and treatment strategies has become a hot topic in the field of liver disease. MS not only increases the risk of liver fibrosis and cirrhosis in chronic hepatitis B (CHB) patients, but also reduces the response to antiviral therapy. Therefore, as for patients with HBV infection, especially CHB patients with suboptimal response to antiviral therapy, MS and its components should be considered. Screening and monitoring of liver cirrhosis should be performed for patients with HBV infection complicated by MS to guide the development of proper treatment regimens.
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Objective To evaluate the clinical efficacy and adverse reactions of alizarin combined with anti-tuberculosis therapy for multidrug resistant pulmonary tuberculosis (MDR-PTB).Methods A total of 200 confirmed MDR-PTB patients admitted in the Affiliated Hospital of Hangzhou Normal University during June 2013 and June 2015 were enrolled in the study.Patients were randomly divided into study group and control group (100 in each).Both groups were given standard anti -tuberculosis treatment for 8 months, and additional alizarin was given to study group .Chi-square test was used to assess the differences in clinical efficacy, sputum negative conversion rate, cavity closure and lesion absorption rate , as well as the incidence of adverse reactions between two groups ( including patients categorized according to TCM syndrome ). Results There were 39 markedly effective cases, 51 improved cases, 10 ineffective cases in study group, and 22 markedly effective cases, 35 improved cases, 43 ineffective cases in the control group.The total effective rate in study group was significantly higher than that in control group (90% vs.57%, χ2 =28.262, P 0.05). There was no significant difference in sputum negative conversion rate between two groups (76% vs.55%,χ2 =2.190, P >0.05).The cavity closure and lesion absorption rate in study group ( 91%) was significantly higher than that in the control group (54%,χ2 =38.294, P <0.01).The adverse reaction rate in study group was 27%, which was significantly lower than that in control group (66%, χ2 =30.570, P <0.01).Conclusion Alizarin in combination with standard anti -tuberculosis therapy can improve the clinical efficacy and reduce adverse reactions in treatment of MDR -PTB.
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OBJECTIVE To explore cell death type of lateral line hair cellsinduced by cisplatin in zebrafish. METHODS Zebrafish larva were incubated in 1mM cisplatin solution for 6 hrs to induce about 90%lateral line hair cells loss. Time lapse imaging was used to detect the morphology of cisplatin-incubated hair cells in wildtypezebrafish pre-labelled by live dyes Bodipy TR C5-ceramide and Sytogreen 24. TUNEL assay and In situ anti-active Caspase-3 antibody staining were performed to detect nuclei fragmentation and Caspase-3 activity respectively. RESULTS Compared to control group, hair cells condensationand nuclei fragmentation (P<0.05) were detected in cisplatin-incubated group, and active Caspase-3 activity was also observed after cisplatin addition. CONCLUSION Cisplatinmay induced zebrafish lateral line hair cells loss by Caspase-3-dependent apoptotic pathway.
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Objective:To investigate the utilization of total parenteral nutrition ( TPN) in a hospital to provide reference for the clinical rational drug use. Methods:The utilization and trend of TPN in the surgical inpatients during August 2012 to July 2013 in the hospital were analyzed statistically. Results:Totally 116 patients received TPN with 1 013 times, and the patients with gastrointestinal malignant tumor accounted for 48. 3%. The average use day was (8. 7 ± 3. 2) d and the total energy was within the range of 900-1 500 kcal. The number of prescription with glycolipid ratio below 1 was 878 (86. 7%), that with hot nitrogen ratio of 100-150 was 689 (68. 0%), that with monovalent cation concentration below 150 mmol·L-1 was 1 008 (99. 5%), that with divalent cation concentra-tion below 5 mmol·L-1 was 879 (86. 8%), that with glutamine was 765 (75. 5%) and that with sugar and insulin ratio (g:u) be-low 3 was 42 (4. 1%). Conclusion:The maln problem in the TPN application in the hospital is that glycolipid ratio in the majority of prescriptions is low, and irrational hot nitrogen ratio, excessive cation concentration and insulin dosage appeared in the minority of pre-scriptions. Clinicians should strengthen the learning of parenteral nutrition knowledge and clinical pharmacists should actively perform reasonable intervention in the TPN prescriptions to promote the reasonable TNP therapy and improve the therapeutic effect.