Aminoacyl-tRNA synthetases (ARSs) participate in tumor initiation and progression but their involvement in hepatocellular carcinoma (HCC) is not clear. This study aimed to investigate the prognostic value and underlying mechanisms of ARS in HCC.

Data were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium, Gene Expression Omnibus and Human Protein Atlas databases. The prognostic model was constructed with the use of Cox regression and least absolute shrinkage and selection operator regression. Kaplan-Meier survival analysis, enrichment analysis, single sample gene set enrichment analysis and tumor mutation burden calculation were performed with R to evaluate the model and explore the underlying mechanism. Wilcoxon tests were used for comparisons between groups.

Aspartyl-tRNA synthetase 2 (DARS2), tyrosyl-tRNA synthetase 1 (YARS1) and cysteinyl-tRNA synthetase 2 (CARS2) were identified as prognostic biomarkers and enrolled in model construction. The area under receiver operating characteristic curve of the model was 0.775. The model was used to assign patients from TCGA into low- and high-risk groups. Those in the high-risk group had a worse prognosis (p<0.001). The clinical significance of the model was tested in different clinical subgroups. Genetic mutation analysis had a higher TP53 mutation frequency in high-risk group. Enrichment analysis and study of immune-related cells and molecules found that the high-risk group was characterized by immune-cell infiltration and immunosuppression states.

A novel ARS family-based model of HCC prognosis was constructed. TP53 mutation frequency and immune-suppressive status accounted for a worse prognosis in patients included in the high-risk group.

The outbreak of coronavirus disease 2019 (COVID-19) has resulted in significant morbidity and mortality worldwide. Vaccination against coronavirus disease 2019 is a useful weapon to combat the virus. Patients with chronic liver diseases (CLDs), including compensated or decompensated liver cirrhosis and noncirrhotic diseases, have a decreased immunologic response to coronavirus disease 2019 vaccines. At the same time, they have increased mortality if infected. Current data show a reduction in mortality when patients with chronic liver diseases are vaccinated. A suboptimal vaccine response has been observed in liver transplant recipients, especially those receiving immunosuppressive therapy, so an early booster dose is recommended to achieve a better protective effect. Currently, there are no clinical data comparing the protective efficacy of different vaccines in patients with chronic liver diseases. Patient preference, availability of the vaccine in the country or area, and adverse effect profiles are factors to consider when choosing a vaccine. There have been reports of immune-mediated hepatitis after coronavirus disease 2019 vaccination, and clinicians should be aware of that potential side effect. Most patients who developed hepatitis after vaccination responded well to treatment with prednisolone, but an alternative type of vaccine should be considered for subsequent booster doses. Further prospective studies are required to investigate the duration of immunity and protection against different viral variants in patients with chronic liver diseases or liver transplant recipients, as well as the effect of heterologous vaccination.

This study evaluates the association of haplotypes of vitamin D receptor (VDR) genes (BsmI-ApaI-TaqI) with blood lead (B-Pb) levels.

The VDR polymorphism results for 100 occupationally lead-exposed (LEx) workers in the battery industry and 100 non-lead-exposed controls (controls) from the Delhi-NCR region were analyzed for haplotypes. PCR-RFLP was used to identify three VDR polymorphisms (TaqI, BsmI and ApaI), and the VDR haplotype and linkage disequilibrium (D′) were analyzed in these subjects.

B-Pb, together with the total vitamin D, calcium and phosphorus levels, were reported in the previous study conducted by the investigators. Eight possible haplotypes were observed among the three single nucleotide polymorphisms (BsmI-ApaI-TaqI). Furthermore, significant differences in haplotype frequency were observed between LEx workers and controls for the “baT” haplotype (X2 = 4.9, p = 0.02). Importantly, higher B-Pb levels were observed for the “baT” haplotype of the BsmI-ApaI-TaqI polymorphism, and BsmI and ApaI had the highest D′ and r2 values. However, significant variations in vitamin D, calcium and phosphorus levels were not observed between these haplotypes.

The “baT” haplotype of VDR polymorphisms might be a potential risk factor for lead toxicity, especially in exposed individuals. Hence, this haplotype may be considered during the screening of occupationally exposed individuals, in order to identify those who are susceptible to developing lead toxicity.

Post-acute sequelae of SARS-CoV-2 (PASC) or long COVID is a major public health problem. The underlying mechanism(s) of this disease remains unclear, and there is a lack of effective therapies. We report a case of a 47-year-old patient who experienced breakthrough acute COVID-19 with PASC after two doses of COVID-19 vaccination, and its symptom resolution following a course of the novel combination of antiviral nirmatrelvir-ritonavir. One of several leading hypotheses on the pathogenesis of PASC is a persistent viral reservoir. This case report raises important questions on the potential role of antiviral therapies in long COVID, and the need for further research and clinical trials in this field of study.

As liquid biopsy attracts more attention for the clinical detection and diagnosis of cancer, the need to establish reliable biomarkers has emerged. Plasma has received extensive study. However, for genitourinary (GU) cancers, urine can be the ideal body fluid. Urine can be collected in large quantities for frequent biomarker analysis and disease monitoring with relative ease. New biomarker studies are of great importance due to the limitations of the present diagnostic tests used for cancer detection and monitoring. Recently, many promising studies have investigated the role of cell-free DNA, DNA methylation, extracellular RNAs, and exosome cargos as biomarkers for GU cancer detection. This review explores the recent literature on the discovery of novel urinary biomarkers and their utility in detecting GU cancers. In small-scale studies, several novel biomarkers have shown preliminary evidence of superior clinical sensitivity and specificity compared to conventional GU cancer screening methods. With the use of these new urinary biomarkers, routine non-invasive screening and tumor monitoring may be possible.

The COVID-19 pandemic has caused symptoms of anxiety, distress, and depression in the general population. In order to develop interventions that target psychological problems, it is necessary to determine individual factors that have an impact on the development of psychological problems. The present study examined the effects of emotion dysregulation, attachment style and perceived social support on psychological problems in the context of COVID-19 using a sample of people living in Türkiye.

The sample consisted of 517 participants. In addition to the Demographic and COVID-19-related Information Form, a number of questionnaires were used, including the Depression, Anxiety and Stress Scale (DASS-21), Experiences in Close Relationships Revised (ECR-R), Impact of Event Scale Revised (IES-R), Difficulties in Emotion Regulation Scale-Brief Form (DERS-16), and Multidimensional Scale of Perceived Social Support (MSPSS).

The findings revealed that perceived social support, emotion dysregulation and attachment anxiety did not have serial mediation effects in the relationship between the impact of COVID-19, and depression or stress. However, there were serial mediating effects of perceived social support, emotion dysregulation, and attachment anxiety in the relationship between the impact of COVID-19 and anxiety. That is, the effects of the impact of COVID-19 (X) on anxiety (Y) through emotion dysregulation (M2) and attachment anxiety (M3) (bootstrap = 0.007, 95% CI = −0.001, 0.015), and through perceived social support, emotion dysregulation, and attachment anxiety (bootstrap = 0.005, 95% CI = 0.001, 0.013) were significant.

These findings suggest the role of individual appraisals in the initial stages of the COVID-19 outbreak.

Growing scientific evidence has suggested the disrupted regulation of host cell cycle proteins in hepatitis C virus (HCV)-associated liver disease. Since the regulation of cell cycle proteins is closely associated with the control of the proliferation and survival of hepatocytes, any alteration in the regulation of these proteins would significantly contribute to the progression of the HCV disease and development of hepatocellular carcinoma (HCC). This mini-review aims to provide an overview of available information on hepatic cell cycle modulations during chronic HCV infection.

The recently proposed concept of metabolic dysfunction-associated fatty liver disease (MAFLD) has remained controversial. We aimed to describe the features and associated outcomes to examine the diagnostic ability of MAFLD for identifying high-risk individuals.

In this retrospective cohort study, we enrolled 72,392 Chinese participants between 2014 and 2015. Participants were classified as MAFLD, nonalcoholic fatty liver disease (NAFLD), non-MAFLD-NAFLD, and a normal control group. The primary outcomes were liver-related and cardiovascular disease (CVD) events. Person-years of follow-up were calculated from enrolment to the diagnosis of the event, or the last date of data (June, 2020).

Of the 72,392 participants, 31.54% (22,835) and 28.33% (20,507) qualified the criteria for NAFLD or MAFLD, respectively. Compared with NAFLD, MAFLD patients were more likely to be male, overweight, and have higher biochemical indices including liver enzyme levels. Lean MAFLD diagnosed with ≥2 or ≥3 metabolic abnormalities presented similar clinical manifestations. During the median follow-up of 5.22 years, 919 incident cases of severe liver disease and 2,073 CVD cases were recorded. Compared with the normal control group, the NAFLD and MAFLD groups had a higher cumulative risk of liver failure and cardiac-cerebral vascular diseases. There were no significant differences in risk between the non-MAFLD-NAFLD and normal group. Diabetes-MAFLD group had the highest incidence of liver-related and cardiac-cerebral vascular diseases, lean MAFLD came second, and obese-MAFLD had the lowest incidence.

This real-world study provided evidence for rationally assessing the benefit and practicability of the change in terminology from NAFLD to MAFLD. MAFLD may be better than NAFLD in identifying fatty liver with worse clinical features and risk profile.

Phenethyl isothiocyanate (PEITC), a phytochemical from cruciferous vegetables, is known to modulate detoxification enzymes. Fortification of PEITC into a complete nutrition gel, Nutri-PEITC jelly, has been shown to improve its bioavailability. This work aimed to study the effect of Nutri-PEITC jelly on active smokers’ detoxification of tobacco-derived carcinogens.

This pre-post trial was conducted on 30 healthy, male, regular smokers. During the pre-intervention period, they smoked regularly for three days. During the postintervention period, they smoked regularly and consumed Nutri-PEITC jelly for three days (40 mg PEITC/day). The total amounts of N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol metabolites in 24-hour urine were measured by liquid chromatography-tandem mass spectrometry after deconjugation with β-glucuronidase and normalized to the urinary creatinine level. To ensure the consistency of smoking and the actual consumption of Nutri-PEITC jelly, the levels of urinary cotinine and PEITC were measured by using an enzyme-linked immunosorbent assay and liquid chromatography-tandem mass spectrometry, respectively.

After consuming Nutri-PEITC jelly, the level of total urinary NNN metabolites (mainly glucuronide conjugates) was significantly increased by up to 4-fold (p < 0.01). In contrast, the level of total urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol metabolites was not significantly altered (p = 0.325). The urinary cotinine level was similar (p = 0.8832), while the urinary PEITC level was greater than that of the pre-intervention period (p < 0.001).

The findings suggest that intake of Nutri-PEITC jelly may increase the detoxification of NNN, a tobacco-specific oral carcinogen, likely by promoting glucuronide conjugation. Future randomized controlled trials are warranted to confirm its potential for the primary prevention of smoking-related oral cancer.

Insulin is the cornerstone of type 1 diabetes therapy and a crucial component for controlling type 2 diabetes. Despite significant advancements in insulin therapy research, including the creation of innovative insulin formulations and delivery systems, there are still numerous difficulties and unknowns surrounding insulin therapy. The main issues with more recent pharmacological and technological methods are biocompatibility, degradation/clearance of delivery materials, immunogenicity, stability, the precision of dosing, reproducibility of an effect similar to that of endogenous insulin, predictability of performance, and safety over time. In order to achieve a protracted, flatter profile, with fewer instances of hypoglycemia and an improvement in postprandial glucose level, more recent insulin mutants have been developed. The “meal” (glucose-responsive) insulins, which are supplied in accordance with an endogenous glucose-sensing feedback mechanism, best represent the future generation of insulin treatment. Insulin delivery methods with novel jet injectors, smart pens, patch pumps, and other needle-free tools for subcutaneous doses are another area of ongoing advancements. Digital health has significantly advanced treatments in recent years. As such, insulin treatments should become more scalable and potentially more cost-effective.

Distinguishing alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) with biopsy alone is often difficult without a reliable clinical context. A novel finding on liver imaging, perivascular branching heterogeneity, has shown promise in distinguishing between these chronic liver diseases. Our study investigated the role of this finding on imaging to differentiate between ASH and NASH. The aim of this study was to determine the utility and reproducibility of this novel radiographic marker to help distinguish ASH from NASH.

This was a retrospective cohort study conducted between 2016 and 2020 in patients with both liver biopsy-confirmed steatohepatitis/chronic hepatitis and abdominal magnetic resonance imaging within 13 months of each other. Two radiologists, blinded to patient clinical history and diagnosis, categorized the appearance of the liver as: 1- homogeneity, 2- mild heterogeneity, 3- moderate heterogeneity, 4- possible perivascular branching, 5- definite perivascular branching.

Of the 90 patients in the study, 60 were identified as NASH and 30 as ASH. The area under the curve (AUC) for both reader 1 and 2 when using the 5-point scale was 0.69 (CI: 0.56–0.82, p=0.006) and 0.72 (CI: 0.60–0.85, p=0.001), respectively. The positive predictive value (PPV) for identification of ASH when scoring 5 was 64.7% and 66.7% for reader 1 and 2, respectively. Interclass correlation coefficient was 0.74 in patients with ASH, indicating moderate reliability among both readers.

Identification of this perivascular branching pattern on imaging is a promising novel diagnostic marker that can be used with other methods to help distinguish between ASH and NASH.

Syntaxin 5 (STX5) is a member of the syntaxin or target-soluble SNAP receptor (t-SNARE) family and plays a critical role in autophagy. However, its function and molecular mechanism in tumor cell migration are still unknown. The role of STX5 in influencing hepatocellular carcinoma (HCC) is an important topic in our research.

By using quantitative reverse transcription polymerase chain reaction (qPCR), western blotting, and immunohistochemical analysis of RNA and protein in tissues, we comprehensively evaluated data sets from public databases and clinical patient cohorts for STX5. The correlation of STX5 expression with the clinicopathological characteristics of HCC patients were assessed. In addition, we predicted signal pathways from differentially expressed genes (DEGs) and the Cancer Genome Atlas (TCGA) databases, and confirmed the prediction using integrated transcriptome and RNA-seq. We further investigated the underlying mechanisms of STX5 in the migration and adhesion of HCC cells both in vitro and in vivo.

In the TCGA dataset and our patient cohort, STX5 levels were significantly higher in HCC tissues than in adjacent normal liver tissues. At the same time, high expression of STX5 predicted worse prognosis in patients with liver cancer. High expression of STX5 indicates the decrease of adhesion and the increase of migration of HCC cells, and the conversion of epithelial-mesenchymal transition (EMT) in vitro via PI3K/mTOR pathway activation. Conversely, when Sirolimus, a phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) inhibitor acts on cells simultaneously, STX5 overexpression-mediated enhancement of HCC metastasis is reversed. Double-negative regulation of STX5 and mTOR further enhanced the inhibitory effect of STX5 on HCC metastasis. In vivo, STX5 knockdown inhibited the metastasis of HCC cells.

Our study demonstrates a novel research result that STX5 promotes HCC metastasis through PI3K/mTOR pathway. We believe that combined inhibition of STX5 and mTOR is a potential treatment for effectively prolonging patient survival and inhibiting HCC metastasis.

To investigate the safety and efficacy of double plasma molecular adsorption system (DPMAS) with sequential low-dose plasma exchange (LPE) in treating early hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF).

Clinical data of patients with HBV-ACLF were prospectively collected, including patients in a DPMAS with sequential LPE (DPMAS+LPE) group and those in a standard medical treatment (SMT) group. The primary endpoint was death or liver transplantation (LT) at 12 weeks of follow-up. Propensity-score matching was performed to control the effects of confounding factors on prognosis between the two groups.

After 2 weeks, total bilirubin, alanine aminotransferase, blood urea nitrogen levels, and Chinese Group on the Study of Severe Hepatitis B score, were significantly lower in the DPMAS+LPE group than those in the SMT group (p<0.05). After 4 weeks, laboratory parameters of the two groups were similar. The cumulative survival rate of the DPMAS+LPE group was significantly higher than that of the SMT group at 4 weeks (97.9% vs. 85.4%, p=0.027), but not at 12 weeks (85.4% vs. 83.3%, p=0.687). Cytokine levels were significantly lower in 12-week survival group than in the death-or-LT group (p<0.05). Functional enrichment analysis showed that downregulated cytokines were mainly involved in positive regulation of proliferation and activation of lymphocytes and monocytes, regulation of immune effect response, regulation of endotoxin response, and glial cell proliferation.

DPMAS+LPE significantly improved the 4-week cumulative survival rate, and ameliorated the inflammatory response in patients. DPMAS+LPE may be a promising modality for patients with early HBV-ACLF.

Advancements in nanomedicine have effectively overcome the issues of solubility, absorption, and cytotoxicity of conventional drugs. In recent years, phytoproducts rich in bioactive constituents have been exploited as green-, herb-, or phytosynthesized metal or nonmetal nanocarriers. Of these, alkaloids, flavonoids, polyphenols, sterols, lignans, tannins, and saponins efficiently contribute to the enhanced stability of such nanocarriers or nanoparticles by reducing metal ions. In addition, phytosynthesized silver and gold nanoparticles have received much interest due to their less hazardous, eco-friendly, and cost-effective properties. Owing to these properties, phytosynthesized silver and gold nanoparticles also have been developed as effective antiviral drug delivery carriers against human immunodeficiency virus, herpes simplex virus, influenza virus, dengue virus, chikungunya virus, hepatitis B virus, bovine diarrhea virus, and foot and mouth disease virus infections. Although experimental studies have shown that such phytonanoparticles can inhibit viral replication in infected cells, the underlying mechanism of their antiviral activities is poorly understood. Importantly, compared to herbal antivirals or metal-based antiviral nanoparticles, the novel approach of phytosynthesis of antiviral nanoparticles seems to be in its infancy. In view of the emerging viral outbreaks and pandemics like coronavirus disease 2019, this area of drug research needs special attention.

Hepatocellular carcinoma (HCC) surveillance in patients at risk is strongly recommended and usually performed by ultrasound (US) semiannually with or without alfa-fetoprotein (AFP) measurements. Quality parameters except for surveillance intervals have not been strictly defined. We aimed to evaluate surveillance success and risk factors for surveillance failure.

Patients with ≥1 US prior to HCC diagnosis performed at four tertiary referral hospitals in Germany between 2008 and 2019 were retrospectively analyzed. Surveillance success was defined as HCC detection within Milan criteria.

Only 47% of 156 patients, median age 63 (interquartile range: 57–70) years, 56% male, and 96% with cirrhosis, received recommended surveillance modality and interval. Surveillance failure occurred in 29% and was significantly associated with lower median model for end-stage liver disease (MELD) score odds ratio (OR) 1.154, 95% confidence interval (CI): 1.027–1.297, p=0.025) and HCC localization within right liver lobe (OR: 6.083, 95% CI: 1.303–28.407, p=0.022), but not with AFP ≥200 µg/L. Patients with surveillance failure had significantly more intermediate/advanced tumor stages (93% vs. 6%, p<0.001), fewer curative treatment options (15% vs. 75%, p<0.001) and lower survival at 1 year (54% vs. 75%, p=0.041), 2 years (32% vs. 57%, p=0.019) and 5 years (0% vs. 16%, p=0.009). Alcoholic and non-alcoholic fatty liver disease (OR: 6.1, 95% CI: 1.7–21.3, p=0.005) and ascites (OR: 3.9, 95% CI: 1.2–12.6, p=0.021) were independently associated with severe visual limitations on US.

US-based HCC surveillance in patients at risk frequently fails and its failure is associated with unfavorable patient-related outcomes. Lower MELD score and HCC localization within right liver lobe were significantly associated with surveillance failure.

Hepatocellular carcinoma (HCC) is one of the most common types of cancer, often resulting in death. Augmenter of liver regeneration (ALR), a widely expressed multifunctional protein, has roles in liver disease. In our previous study, we reported that ALR knockdown inhibited cell proliferation and promoted cell death. However, there is no study on the roles of ALR in HCC.

We used in vitro and in vivo models to investigate the effects of ALR in HCC as well as its mechanism of action. We produced and characterized a human ALR-specific monoclonal antibody (mAb) and investigated the effects of the mAb in HCC cells.

The purified ALR-specific mAb matched the predicted molecular weight of IgG heavy and light chains. Thereafter, we used the ALR-specific mAb as a therapeutic strategy to suppress tumor growth in nude mice. Additionally, we assessed the proliferation and viability of three HCC cell lines, Hep G2, Huh-7, and MHC97-H, treated with the ALR-specific mAb. Compared with controls, tumor growth was inhibited in mice treated with the ALR-specific mAb at 5 mg/kg, as shown by hematoxylin and eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling. Simultaneous treatment with the ALR-specific mAb and adriamycin promoted apoptosis, whereas treatment with the ALR-specific mAb alone inhibited cell proliferation.

The ALR-specific mAb might be a novel therapy for HCC by blocking extracellular ALR.

Occult HBV infection (OBI) in children has proven to be associated with their immune response to hepatitis B vaccine (HepB). This study aimed to investigate the effect of a booster HepB on OBI, which is rarely investigated.

This study enrolled 236 maternal HBsAg-positive children who were followed up annually until 8 years of age and were hepatitis B surface antigen (HBsAg) negative. Of those 100 received a booster HepB between 1 and 3 years of age (booster group), and 136 were never boosted (non-booster group). Serial follow-up data of children and baseline data of their mothers were collected and between-group differences were analyzed.

The incidence of OBI varied dynamically during follow-up, with 37.14% (78/210), 19.09% (42/220), 20.85% (44/211), 31.61% (61/193), 8.65% (18/208) and 12.71% (30/236) at 7 months, 1, 2, 3, 4, and 8 years of age. At 8 years of age, the negative conversion rate of HBV DNA in the booster group was significantly higher than that in non-booster group [57.89% (11/19) vs. 30.51% (18/59), p=0.032]. For children without OBI at 7 months old, the incidence of OBI in booster group was significantly lower than that in non-booster group [25.64% (10/39) vs. 67.74% (63/93), p<0.001].

The incidence of OBI in maternal HBsAg-positive children was high, serum HBV DNA in children with OBI was intermittently positive at low levels, and a booster HepB in infancy reduced the incidence of OBI in children with HBsAg-positive mothers.

Topoisomerase I (TOP1) participates the repair of DNA double-strand breaks (DSBs) upon radiation therapy (RT). RNF144A mediates ubiquitination of catalytic subunit of DNA protein kinase (DNA-PKcs), a critical factor in DSB repair. This study aimed to investigate the natural killer (NK) cell-mediated radiosensitization with TOP1 inhibition and the mechanism by DNA-PKcs/RNF144A.

In vitro synergism with TOP1i or cocultured NK cells and RT were evaluated in human hepatocellular carcinoma (HCC) cell lines (Huh7/PLC5) by clonogenic survivals. Orthotopic xenografts were treated with Lipotecan and/or RT. Protein expression was analyzed by western blotting, immunoprecipitation, subcellular fractionation, and confocal microscopy.

Lipotecan/RT had a superior synergistic effect to RT on HCC cells. Combined RT/Lipotecan reduced the xenograft size by 7-fold than RT (p<0.05). Lipotecan caused more radiation-induced DNA damage and DNA-PKcs signaling. The expression of major histocompatibility complex class I-related chain A and B (MICA/B) on tumor cells is associated with the sensitivity to NK cell-mediated lysis. Cocultured NK and HCC cells with Lipotecan radiosensitized HCC cells/tissues with the expression of MICA/B. RNF144A increased more in Huh7 cells with combined RT/TOP1i, and reduced the prosurvival function of DNA-PKcs. The effect was reversed by inhibiting the ubiquitin/proteasome system. In comparison, RNF144A decreased through nuclear translocation with the cumulated DNA-PKcs and radio-resistance of PLC5 cells.

TOP1i reinforces NK cell-activated anti-HCC effect of RT through RNF144A mediated DNA-PKcs ubiquitination. RNF144A provides a reason for differentiating radiosensitization effect between HCC cells.

Metabolic dysfunction and obesity commonly coexist with both alcoholic and nonalcoholic fatty liver disease (AFLD and NAFLD). The association of AFLD and NAFLD with incident diseases in individuals with different metabolic phenotypes are unclear.

UK Biobank study participants were screened for the presence of fatty liver at baseline. Body mass index and metabolic dysfunction were used to define metabolic phenotypes. Cox regression model was performed to examine the associations of AFLD and NAFLD with incident significant liver diseases (SLDs), cardiovascular diseases (CVDs), chronic kidney diseases (CKDs), and cancers, respectively.

A total of 43,974 AFLD and 103,248 NAFLD cases were identified. Both AFLD and NAFLD were associated with an increased risk of diseases of interest. The effects were amplified by obesity and metabolic abnormalities and modified by metabolic phenotypes. Compared to individuals free of fatty liver and with phenotype of metabolically healthy-normal weight, AFLD [hazard ratio (HR) 3.27; 95% CI: 1.95–5.47)] and NAFLD (HR 2.25; 95% CI: 1.28–3.94) cases with phenotype of metabolically obese-normal weight had the greatest risk of SLDs. For CVDs, CKDs, and cancer, the greatest risks were detected in AFLD and NAFLD cases with phenotype of metabolically obese-overweight/obesity. In this subpopulation, AFLD and NAFLD conferred a 2.75-fold (95% CI: 2.32–3.25) and 4.02-fold 95% CI: (3.64–4.43) increased risk of CVDs, 4.37-fold 95% CI: (3.38–5.64) and 6.55-fold 95% CI: (5.73–7.48) increased risk of CKDs, and 1.19-fold 95% CI: (1.08–1.27) and 1.21-fold 95% CI: (1.14–1.28) increased risk of cancers, respectively.

Metabolic phenotypes modified the association of AFLD and NAFLD with intrahepatic and extrahepatic diseases.