Liver and atherosclerotic risks of patients with cryptogenic steatotic liver disease.

BACKGROUND AND AIMS: In 2023, a new nomenclature of "metabolic associated steatotic liver disease" (MASLD) has emerged by incorporating cardio-metabolic criteria to redefine "non-alcoholic fatty liver disease" (NAFLD). Among steatotic liver disease (SLD), those having no known causes and without any one of cardio-metabolic criteria are deemed to have cryptogenic SLD. This study aims to compare the liver and atherosclerotic risks between MASLD and cryptogenic SLD patients. APPROACH: We analyzed participants with liver ultrasound data from the Taiwan Bio-Bank cohort, excluding those with positive HBsAg, positive anti-HCV, or "frequent drinker". MASLD involves hepatic steatosis and any of five cardiometabolic risk factors, whereas cryptogenic SLD features hepatic steatosis without these risk factors. Liver fibrosis severity was assessed by using NAFLD fibrosis score (NFS), while atherosclerosis was determined by carotid plaques on duplex ultrasound. RESULTS: Among 17,595 subjects (age 55.47 ± 10.41; males 31.8%), 7538 participants (42.8%) had SLD, comprising 96.5% of MASLD and 3.5% of cryptogenic SLD. Cryptogenic SLD patients are younger and had a lower percentage of male than those with MASLD. After propensity score matching for age and sex, patients with cryptogenic SLD exhibited milder glucose and lipid profiles, fewer carotid plaques, lower liver steatosis, inflammation, and fibrosis markers than those with MASLD. CONCLUSIONS: In this large population-based study, cryptogenic SLD, the excluded group, occupy only 3.5% in NAFLD patients. It has lower liver and atherosclerotic risks than MASLD, supporting its exclusion from NAFLD and justifying the rationale for the new disease name and diagnostic criteria of MASLD.

Prevalence and clinical outcomes in subtypes of metabolic associated fatty liver disease.

BACKGROUND/PURPOSE: In 2020, metabolic Associated Fatty Liver Disease (MAFLD) was proposed to replace non-alcoholic fatty liver disease (NAFLD) with new diagnostic criteria. The prevalence and clinical outcomes of MAFLD subtypes remained unclear. METHODS: The participants from Taiwan bio-bank cohort were included. MAFLD was defined as the presence of fatty liver, plus any of the following three conditions: overweight/obesity, diabetes mellitus (DM), or metabolic dysfunction. The patients with positive HBsAg or anti-HCV were considered as chronic HBV or HCV infection. NAFLD fibrosis score (NFS) > 0.676 plus fibrosis 4 (FIB-4) score > 2.67 was defined as advanced liver fibrosis. Atherosclerosis was diagnosed as having carotid plaques on duplex ultrasounds. The clinical outcomes were assessed among four subtypes of MAFLD including DM, obesity, chronic HBV infection, and chronic HCV infection. RESULTS: A total of 21,885 participants (mean age 55.34 ± 10.31; 35.69% males) were included in the final analysis. Among them, 38.83% were diagnosed with MAFLD. The prevalence of MAFLD was 66.95% in DM patients, 65.07% in obese participants, 33.74% in chronic HBV patients, and 30.23% in chronic HCV patients. Logistic regression analysis showed that the subtypes of DM and chronic HCV infection were associated with an increased risk of advanced liver fibrosis in MAFLD patients. Additionally, the subtypes of DM and lean were associated with an increased risk of atherosclerosis, but a decreased risk of atherosclerosis in the subtype of chronic HBV infection. CONCLUSION: This population-based study proves the concept that subtypes of MAFLD can help risk stratification of clinical outcomes.

Erratum to 'Impact of HBV infection on clinical outcomes in patients with metabolic dysfunction-associated fatty liver disease' (JHEP Reports 5 [2023] 100836).

[This corrects the article DOI: 10.1016/j.jhepr.2023.100836.].

The impact of concomitant hepatitis C virus infection on liver and cardiovascular risks in patients with metabolic-associated fatty liver disease.

BACKGROUND: Chronic hepatitis C virus (HCV)-infected patients with hepatic steatosis are excluded from the diagnosis of nonalcoholic fatty liver disease (NAFLD). The new name and diagnostic criteria of metabolic-associated fatty liver disease (MAFLD) were proposed in 2020 to replace the original term NAFLD. The clinical outcome of MAFLD patients with concomitant chronic HCV infection requires further investigation. METHODS: The participants from Taiwan bio-bank cohort were included. MAFLD is defined as the presence of fatty liver, plus any of the following three conditions: overweight/obesity, type 2 diabetes, or metabolic dysfunction. The patients with positive anti-HCV were considered chronic HCV infections. The severity of liver fibrosis was determined using the fibrosis-4 index and NAFLD fibrosis score (NFS). The risk of cardiovascular disease (CVD) was assessed using intima-media thickness (IMT) or plaques of carotid duplex ultrasound. RESULTS: A total of 18 907 participants (age 55.79 ±â€…10.42; males 31.9%) were included for final analysis. The prevalence of MAFLD and chronic HCV infections were 39.2% and 2.6%, respectively. According to the status of MAFLD and chronic HCV infection, they were distributed to four groups: 'dual etiology group', 'MAFLD alone', 'HCV alone', and healthy controls. Compared with the 'MAFLD alone' group, the 'dual etiology' group had a lower frequency of the male sex, reduced levels of serum triglyceride, total cholesterol, and LDL; but overall older age, a higher percentage of hypertension history. In addition, they had higher levels of serum aspartate aminotransferase, fibrosis-4 index, and NFS; but no difference in levels of alanine aminotransferase, gamma-glutamyl transferase, fatty liver index, IMT, and the percentage of carotid plaques. Using binary logistic regression, chronic HCV infection was associated with more severe liver fibrosis, but not with carotid plaques in MAFLD patients. CONCLUSION: MAFLD patients with concomitant HCV infection, a specific phenotype of MAFLD may include a higher risk of advanced liver fibrosis, but a similar risk of atherosclerotic cardiovascular disease compared to those without.

Impact of HBV infection on clinical outcomes in patients with metabolic dysfunction-associated fatty liver disease.

Background & Aims: The new name and diagnostic criteria of metabolic-associated fatty liver disease (MAFLD) was proposed in 2020. Although chronic HBV infection has protective effects on lipid profiles and hepatic steatosis, the impact of chronic HBV infection on clinical outcomes of MAFLD requires further investigation. Methods: The participants from a Taiwan bio-bank cohort were included. MAFLD is defined as the presence of hepatic steatosis plus any of the following three conditions: overweight/obesity, type 2 diabetes mellitus, and metabolic dysfunction. The patients with positive glycated haemoglobin were considered as having chronic HBV infection. Atherosclerosis was determined as having carotid plaques on duplex ultrasound. Advanced liver fibrosis was defined as Fibrosis-4 >2.67. Based on the status of MAFLD and HBV infection, the participants were distributed into four groups: 'dual aetiology', 'MAFLD alone', 'HBV alone', and 'healthy controls'. Results: A total of 20,460 participants (age 55.51 ± 10.37; males 32.67%) were included for final analysis. The prevalence of MAFLD and chronic HBV infections were 38.8% and 10.3%, respectively. According to univariate analysis, 'HBV alone' group had lower levels of glycated haemoglobin, lipid profiles, and intima media thickness than healthy controls. The 'dual aetiology' group had lower levels of triglycerides, cholesterol, γ-glutamyl transferase, intima media thickness, and percentage of carotid plaques than 'MAFLD alone' group. Using binary logistic regression, chronic HBV infection increased the overall risk of advanced liver fibrosis; and had a lower probability of carotid plaques in MAFLD patients, but not in those without MAFLD. Conclusions: The large population-based study revealed chronic HBV infection increases the overall risk of liver fibrosis, but protects from atherosclerosis in patients with MAFLD. Impact and implications: Patients with metabolic-associated fatty liver disease can also be coinfected with chronic HBV. Concomitant HBV infection increases the overall risk of liver fibrosis, but protects from atherosclerosis in patients with MAFLD.

Predictors of Liver Dysfunction After Transhepatic Arterial Chemo-embolization in Hepatocellular Carcinoma Patients.

BACKGROUND AND AIMS: Although transhepatic arterial chemo-embolization (TACE) is beneficial for the survival of intermediate stage hepatocellular carcinoma (HCC) patients, its cost is the damage of liver reserve. Liver dysfunction is one of factors associated with TACE refractory status and poor prognosis. The study aims to determine the prevalence and predictors of liver dysfunction in HCC patients after TACE.. METHODS: Using the ASUS EMR search 3.0 system, the patients with discharge codes "HCC (C22.0)" plus "TACE" were collected since 2016 till 2021 in Taipei Tzu Chi Hospital. Liver reserve was determined by modified albumin-bilirubin (mALBI) grade. The liver dysfunction was defined as mALBI grade migration within 1-3 months after TACE.. RESULTS: A total of 220 HCC patients with 314 TACE were found in 5-year duration. Those with TACE-experienced tumors, incomplete laboratory data for mALBI grade and incorrect diagnosis coding were excluded. 91 HCC patients (62 male; mean age 65.86 ± 11.61 year-old) were recruited for final analysis. 10 (11%) patients with baseline mALBI grade 3 were excluded. The percentage of mALBI grade migration was 27.2% (22/81) after TACE. Binary logistic regression discovered "up-to-seven out" and "up-to-eleven out" were associated with mALBI grade migration after TACE. CONCLUSION: In this retrospective study, liver dysfunction occurred in 27.2% of HCC patients after TACE. "Up-to-seven out" and "up-to-eleven out" were predictors for liver dysfunction after TACE, suggesting early switch to systemic therapy to reduce the risk of liver dysfunction for HCC patients with high tumor burden.

Metabolic associated fatty liver disease better identifying patients at risk of liver and cardiovascular complications.

BACKGROUND/PURPOSE: A nomenclature of "metabolic associated fatty liver disease" (MAFLD) with a new definition was proposed in 2020 instead of the previous "non-alcoholic fatty liver disease" (NAFLD). Whether it better coheres with the clinical demand remains controversial. METHODS: The participants with fatty liver on ultrasonography in Taiwan bio-bank cohorts were included. MAFLD is defined as the presence of fatty liver, plus any of the following three conditions: overweight/obesity, type 2 diabetes mellitus (DM), or metabolic dysfunction. The severity of liver fibrosis was determined using fibrosis-4 (FIB-4) index and NAFLD fibrosis score (NFS). The risk of atherosclerotic cardiovascular disease was assessed using intima-media thickness (IMT) or plaques of carotid duplex ultrasound. RESULTS: A total of 9,719 subjects (ages 55.9 ± 10.8; males 42.6%) were distributed among 4 groups: "overlapping group", "MAFLD only", "NAFLD only", and "neither fatty liver disease (FLD)" with the percentages of 79.7, 12, 7.1, and 1.2%, respectively. Compared with NAFLD patients, MAFLD patients had a greater percentage of males, higher levels of BMI, waist circumference, HbA1c, and triglyceride. In addition, they had higher levels of serum ALT, AST, GGT, fatty liver index (FLI), NFS, and IMT, but no difference in FIB-4 index and the percentage of carotid plaques. To note, "MAFLD only group" had greater levels of AST, ALT, GGT, FLI, FIB-4, NFS, IMT and a higher percentage of carotid plaques than the "NAFLD only group". CONCLUSION: The grand, population-based study showed MAFLD with new diagnostic criteria to aid in identifying a greater number of high-risk patients of metabolic, liver, and cardiovascular complications, suggesting MAFLD may be a better nomenclature than NAFLD in clinical practice.

The metabolic profiles and body composition of lean metabolic associated fatty liver disease.

BACKGROUND/PURPOSE: Metabolic associated fatty liver disease (MAFLD) is the commonest cause of chronic liver disease, which is associated with obesity and diabetes. However, it also occurs in lean individuals especially in Asian populations. METHODS: The participants of Tzu Chi MAFLD cohort (TCMC) including health controls or MAFLD patients were enrolled. MAFLD was defined as fatty liver in imaging without hepatitis B virus, hepatitis C virus infection, drug, alcohol or other known causes of chronic liver disease. Lean MAFLD was defined as MAFLD in lean subjects (BMI < 23 kg/m2). RESULTS: A total of 880 subjects were included for final analysis. Of 394 MAFLD patients, 65 (16.5%) patients were diagnosed as lean MAFLD. Lean MAFLD patients were elder, higher percentage of female gender, lower ALT, diastolic blood pressure, triglyceride, and waist circumference but higher HDL than non-lean MAFLD patients. Using binary regression analysis, elder age and lower waist circumference were associated with lean MAFLD. Compared with lean healthy controls, lean MAFLD patients had higher BMI, waist circumference, and percentage of hypertension. In body composition, fatty tissue index (FTI), lean tissue index (LTI) ,and total body water (TBW) were lower in lean MAFLD than non-lean MAFLD patients; but they were comparable with lean healthy controls. CONCLUSIONS: The prevalence of lean MAFLD was 16.5% in this study population and it was higher in elder age, especially of female subjects. Lean MAFLD patients had different metabolic profiles compared with lean healthy controls, but different body composition compared with non-lean MAFLD patients.

TPGS-1000 exhibits potent anticancer activity for hepatocellular carcinoma in vitro and in vivo.

D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS1000) is the most active water-soluble derivative of vitamin E and has been widely used as a carrier of solvents, plasticizers, emulsifiers, absorbent agents and refractory drug delivery systems. However, its anti-hepatocellular carcinoma (HCC) properties have not been explored. HCC cells were treated with different concentrations of TPGS1000. Cell survival was tested by CCK8 assay, and cell migration was tested by wound healing and Transwell assay. EdU staining verified cell proliferation, and signalling pathway was assayed by Western blot analysis. The BALB/c-nu mouse xenograft model was established to test HCC cell growth in vivo. In vitro TPGS1000 significantly inhibited the viability and mobility of HCC cells (HepG2, Hep3B and Huh7) in a dose-dependent manner. Cell cycle analysis indicated that TPGS1000 treatment arrested the HCC cell cycle in the G0/G1 phase, and induction of cell apoptosis was confirmed by TUNEL and Annexin V-7-AAD staining. Further pharmacological analysis indicated that collapse of the transmembrane potential of mitochondria, increased ROS generation, PARP-induced cell apoptosis and FoxM1-p21-mediated cell cycle arresting, were involved in the anti-HCC activity of TPGS1000. Moreover, treatment in vivo with TPGS1000 effectively impaired the growth of HCC xenografts in nude mice.

Mesalazine-related lung disease in a patient with ulcerative colitis: A case report.

RATIONALE: Mesalazine is widely used to treat inflammatory bowel disease (IBD). However, discriminating between pulmonary manifestations of IBD and drug-related lung disease remains a challenge. There were few case reports of mesalazine-related organizing pneumonia so far. PATIENT CONCERNS: A 75-year-old female was diagnosed with ulcerative colitis and took mesalazine over a period of 2 years and 8 months. She presented with progressive shortness of breath for 3 days and visited our emergency department. Chest radiography showed increased bilateral infiltrates. During hospitalization her clinical condition deteriorated, and she was transferred to our intensive care unit under noninvasive ventilator support. DIAGNOSIS: Computed tomography (CT) scan showed diffuse peribronchial and subpleural consolidations in bilateral lungs. Possible etiologies of interstitial lung disease were surveyed, including various infectious diseases and connective tissue diseases. Transbronchial lung biopsy showed characteristic features of organizing pneumonia. INTERVENTIONS: Under the consideration of mesalazine-related lung disease, mesalazine was discontinued early in disease course and steroid therapy was given. OUTCOMES: The patient was discharged from hospital with improved clinical symptoms and radiographic images. LESSONS: Although this patient suffered a life-threatening adverse event, prompt diagnosis with proper management can result in a favorable outcome.

Light-Switchable Self-Assembly of Non-Photoresponsive Gold Nanoparticles.

Herein, an interesting light-induced self-assembly behavior from non-photoresponsive gold nanoparticles (Au NPs) was reported. Specifically, a pH-responsive amphiphile SPBwas developed that contained a particular phenylboronic acid moiety and showed excellent surface activity at the neutral and basic conditions, thereby stabilizing Au NPs well. Accordingly, the SPB-functionalized Au NPs showed strong pH dependence that there presented the pH-induced reversible self-assembly behavior. Furthermore, the introduction of a small amount of commercially available photoacid generator named diphenyliodonium nitrate (DIN) into the system could endow it with apparent light-switchable self-assembly behavior. The pH- and light-induced self-assembly behaviors of SPB-functionalized Au NPs in the absence and presence of DIN, respectively, were systematically studied by various techniques including UV-vis spectrum, transmission electron microscope, nuclear magnetic resonance, and Fourier transform infrared spectroscopy, which evidently confirmed that the stimuli-responsive self-assembly was controlled by the hydrogen-bonding interactions between phenylboronic acid moieties. Attributing to the light-induced obvious color change from bright-red to deep purple, the system was applied in particle imprinting successfully.

Development of novel anionic Gemini surfactants and application in fabricating hierarchical silver microparticles for surface-enhanced Raman spectroscopy.

In this work, a new category of anionic Gemini surfactants with a rigid space, disodium 2,2'-(1, 4-phenylene bis (methylene)) bis (alkane-1-sulfate) (CmArCm, m=8, 10, 12, 14), were developed. They showed excellent surface activity and remarkable micellization tendency in aqueous solutions as measured by the equilibrium surface tension method. It was noticed that both the surface activity and micellization ability of CmArCm were gradually strengthened upon increasing the hydrophobic chain length m. Those Gemini surfactants were employed as capping reagents to fabricate three-dimensional (3D) hierarchical silver microparticles (AgMPs) successfully even in a large-scale of gram-level. The morphological evolution of these microparticles in different conditions was investigated systematically by various techniques including scanning electron microscopy (SEM), high-resolution transmission electron microscope (HRTEM), powder X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). The possible formation mechanism of surfactant assisted AgMPs was also proposed. It was found that the morphology of AgMPs could be tailored from nut-like, lichi-like, to coral-like microparticles by simply varying the concentration of surfactant. However, the hydrophobic chain length m of CmArCm showed a little influence on the morphology of AgMPs. Moreover, the surface-enhanced Raman scattering of Rhodamine 6G results evidently confirmed the superior surface activity of synthesized AgMPs.

Silk Gland Gene Expression during Larval-Pupal Transition in the Cotton Leaf Roller Sylepta derogata (Lepidoptera: Pyralidae).

The cotton leaf roller, Sylepta derogata, is a silk-producing insect pest. While young larvae feed on the underside of leaves, the older ones roll cotton leaves and feed on the leaf edges, which defoliates cotton plants. The larvae produce silk to stabilize the rolled leaf and to balloon from used to new leaves. Despite the significance of silk in the biology of pest insect species, there is virtually no information on the genes involved in their silk production. This is a substantial knowledge gap because some of these genes may be valuable targets for developing molecular pest management technologies. We addressed the gap by posing the hypothesis that silk gland gene expression changes during the transition from larvae to pupae. We tested our hypothesis using RNA-seq to investigate changes in silk gland gene expression at three developmental stages, 5th instar larvae (silk producing; 15,445,926 clean reads), prepupae (reduced silk producing; 13,758,154) and pupae (beyond silk producing; 16,787,792). We recorded 60,298 unigenes and mapped 50,158 (larvae), 48,415 (prepupae) and 46,623 (pupae) of them to the NCBI database. Most differentially expressed genes in the 5th instar larvae/prepupae libraries were relevant to nucleotide synthesis and maintenance of silk gland function. We identified down-regulated transcriptional factors and several genes involved in silk formation in the three libraries and verified the expression pattern of eight genes by qPCR. The developmental- and tissue-specific expression patterns of the fibroin light chain gene showed it was highly expressed during the larval silk-producing stage. We recorded highest expression of this gene in the larval silk gland, compared to other tissues, including midgut, hindgut, epidermis, Malpighian tubes, hemolymph and fat body. These data are a genetic resource to guide selection of key genes that may be targeted for in planta and other gene-silencing technologies for sustainable cotton agriculture.

Hepatitis B virus surface antigen selectively inhibits TLR2 ligand-induced IL-12 production in monocytes/macrophages by interfering with JNK activation.

It is widely accepted that chronic hepatitis B virus (HBV) infection is the result of an ineffective antiviral immune response against HBV infection. Our previous study found that the hepatitis B surface Ag (HBsAg) was related to decreased cytokine production induced by the TLR2 ligand (Pam3csk4) in PBMCs from chronic hepatitis B patients. In this study, we further explored the mechanism involved in the inhibitory effect of HBsAg on the TLR2 signaling pathway. The results showed that both Pam3csk4-triggered IL-12p40 mRNA expression and IL-12 production in PMA-differentiated THP-1 macrophage were inhibited by HBsAg in a dose-dependent manner, but the production of IL-1ß, IL-6, IL-8, IL-10, and TNF-α was not influenced. The Pam3csk4-induced activation of NF-κB and MAPK signaling were further examined. The phosphorylation of JNK-1/2 and c-Jun was impaired in the presence of HBsAg, whereas the degradation of IκB-α, the nuclear translocation of p65, and the phosphorylation of p38 and ERK-1/2 were not affected. Moreover, the inhibition of JNK phosphorylation and IL-12 production in response to Pam3csk was observed in HBsAg-treated monocytes/macrophages (M/MΦs) from the healthy donors and the PBMCs and CD14-positive M/MΦs from chronic hepatitis B patients. Taken together, these results demonstrate that HBsAg selectively inhibits Pam3csk4- stimulated IL-12 production in M/MΦs by blocking the JNK-MAPK pathway and provide a mechanism by which HBV evades immunity and maintains its persistence.