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Background: Studies have found that the ratio of total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) was associated with the development of chronic kidney disease (CKD). However, the relationship in different genders was rarely discussed. The aim of this study was to explore this relationship and assess its predictive power for both males and females., Methods: Based on a prospective cohort platform in northwest China, 32,351 participants without CKD were collected in the baseline and followed up for approximately 5 years. Cox proportional hazard model and restricted cubic spline regression analysis were performed to investigate the association between TC, HDL-C, TC/HDL-C and CKD in adult female and male. The clinical application value of the indicators in predicting CKD was evaluated by the receiver operator characteristic curve., Results: During a mean follow-up of 2.2 years, 484 males and 164 females developed CKD. After adjusted for relevant confounders, for every one standard deviation increase in TC, HDL-C and TC/HDL-C, the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for CKD were 1.17 (1.05-1.31), 0.84 (0.71-0.99), and 1.15 (1.06-1.25) for males, 0.94 (0.78-1.13), 0.58 (0.35-0.95), and 1.19 (1.01-1.40) for females, respectively. The results also showed that TC, HDL-C, and TC/HDL-C were associated with CKD in a linear dose-response relationship. The TC/HDL-C had the largest area under the curve (AUC) compared to TC and HDL-C, and the AUC among the females was larger than that among males., Conclusions: The TC/HDL-C was significantly associated with CKD in adult males and females and has better clinical value in predicting CKD than TC and HDL-C, especially in females., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Chronic Diseases and Translational Medicine published by John Wiley & Sons Ltd on behalf of Chinese Medical Association.)

Background: Hirschsprung's disease (HSCR) is a relatively common congenital disability. Accumulating extracellular matrix (ECM) prompts intestinal fibrosis remodelling in the aganglionic segments of HSCR. The contributions of various cellular subsets in the fibrogenesis of HSCR segments are poorly understood., Methods: Single-cell transcriptomics from 8 aganglionic segments and 5 normal segments of 7 HSCR subjects and 26 healthy segments of seven healthy donors were analysed. Fibrotic phenotype and alterations were explored using differential expression analysis and single-cell trajectory analysis. Fibrosis-related transcription factors were inferred through single-cell regulatory network inference. Bulk transcriptomic data, proteomic data, immunohistochemistry (IHC) and real-time polymerase chain reaction were used to validate the alterations in the HSCR intestine., Results: Various collagen, fibronectin and laminin protein-coding genes expression were up-regulated in the stromal and glial cells of the HSCR intestine. The number of fibroblasts and myofibroblasts in the aganglionic segments increased, and more myofibroblasts were activated at an earlier stage in HSCR segments, which infers that there is an intestinal fibrosis phenotype in HSCR segments. The fibrotic regulators POSTN, ANXA1 and HSP70 were highly expressed in the ECM-related cellular subsets in the transitional segments and aganglionic segments. The transcription factor regulatory network revealed that fibrosis-related and megacolon-related NR2F1 in the fibroblasts and glial subsets was up-regulated in the aganglionic segment., Conclusions: This work identifies intestinal fibrosis and related regulators in aganglionic segments of HSCR; hence, anti-fibrotic therapy may be considered to prevent HSCR-associated enterocolitis (HAEC), relieve intestinal stricture and improve cell therapy., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Biliary atresia (BA) is a devastating inflammatory and fibrosing cholangiopathy of neonates with unknown aetiology. We aim to investigate the relationship between these two main characteristics., Methods: Single-cell RNA sequencing and spatial transcriptomics were performed on liver samples from a cohort of 14 objects (BA: n = 6; control: n = 8). We conducted data integration and cell-type annotation based on gene expression profiling. Furthermore, we identified fibrosis-related immune cells according to their spatial locations, GO and KEGG analysis. Finally, SPOTlight and CIBERSORTx were used to deconvolute ST data and microarray data of the GSE46960 cohorts, respectively., Results: Immune subpopulations inhabiting the 'fibrotic niche' (areas of scarring), comprising 'intermediate' CD14 ++ CD16 + monocytes, scar-associated macrophages, natural killer T cells, transitional B cells and FCN3 + neutrophils were identified. GO and KEGG analyses showed that pathways including 'positive regulation of smooth muscle cell/fibroblast proliferation' and 'positive regulation of/response to VEGFR/VEGF/EGFR/FGF' were enriched in these cell types. Interactions analysis showed that communication among 'FGF_FGFR', 'RPS19-C5AR1', 'CD74_COPA/MIF/APP' and 'TNFRSF1A/B_GRN' was extensive. Finally, the results of deconvolution for ST data and microarray data validated that the proportions of certain identified fibrosis-related cell types we identified were increased in BA., Discussion: Fibrosis is an important feature of BA, in which the immune system plays an important role. Our work reveals the subpopulations of immune cells enriched in the fibrotic niche of BA liver, as well as key related pathways and molecules; some are highlighted for the first time in liver fibrosis. These newly identified interactions might partly explain why the rate of liver fibrosis occurs much faster in BA than in other liver diseases., Conclusion: Our study revealed the molecular, cellular and spatial immune microenvironment of the fibrotic niche of BA., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

We present a retrospective case series of 3 patients with retroperitoneal kaposiform hemangioendothelioma (KHE) complicated by Kasabach-Merritt phenomenon (KMP) and biliary obstruction. We found sirolimus to be a safe and effective treatment for these patients who were refractory to other treatment modalities. However, our patients were slow to respond in comparison to published reports of sirolimus use for KHE without biliary obstruction. We postulate that therapeutic serum levels of sirolimus may be affected by biliary obstruction and improved with surgical alleviation of the obstruction., (© 2020 Wiley Periodicals, Inc.)

Objectives: To detail the effects of vitamin D (VD) deficiency and assess the relationships between VD deficiency and liver function and liver fibrosis in patients with biliary atresia (BA)., Methods: In this study, BA patients confirmed by intraoperative cholangiography were enrolled between January 2017 and February 2019. Preoperative serum 25-(OH)D level, liver function, serum biomarker levels of liver fibrosis, and histopathologic features were recorded. Deficiency, insufficiency, and sufficiency of VD were defined as serum 25-(OH)D concentrations of <10, 10-20, and >20 ng/ml, respectively. Associations between serum 25-(OH)D level and liver function and liver fibrosis were analyzed., Results: A total of 161 BA infants were included. The median (interquartile range (IQR)) serum 25-(OH)D level in all patients was 7.56 (IQR: 4.48-11.40) ng/ml. The rates of 25-(OH)D deficiency, insufficiency, and sufficiency were 67.1% (108/161), 29.2% (47/161), and 3.7% (6/161), respectively. Serum 25-(OH)D level was negatively correlated with alkaline phosphatase ( r = -0.232, P = 0.003). After adjusting for age, a decrease in serum 25-(OH)D level was correlated with the increase of the Batts-Ludwig stage score (odds ratio (OR): 0.94, 95% confidence interval (CI): 0.88-0.99; P = 0.028). Serum 25-(OH)D level was also correlated with the N-terminal propeptide of type III procollagen (PIIINP) ( r = -0.246, P = 0.002). Additionally, PIIINP ( P = 0.038) and ALP ( P = 0.031) were independently associated with serum 25-(OH)D level., Conclusions: VD deficiency was common and inversely correlated with liver fibrosis in BA patients. Furthermore, VD was not correlated with liver function except alkaline phosphatase., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Peijun Zhuang et al.)

Objective: Both exposure to heavy metals and alcohol intake have been related to the risk of type 2 diabetes (T2D). In this study, we aimed to assess the potential interactions between metal exposure and alcohol intake on the risk of T2D and prediabetes in a cohort of Chinese male workers., Methods: We conducted a cross-sectional analysis of 26,008 Chinese male workers in an occupational cohort study from 2011 to 2013. We assessed metal exposure and alcohol consumption at baseline in these workers who were aged ≥20 years. Based on occupations which were categorized according to measured urine metal levels, multiple logistic regression analyses were used to evaluate the independent and joint effects of metal and alcohol exposure on the risk of T2D and prediabetes., Results: Risks of T2D ( P trend  = 0.001) and prediabetes ( P trend  = 0.001) were significantly elevated with increasing number of standard drinks per week, years of drinking, and lifetime alcohol consumption. An adjusted odds ratio ( OR ) of 6.1 (95% confidence interval [ CI ]: 4.8-7.8) was observed for the smelting/refining workers (highest metal exposure levels) who had the highest lifetime alcohol consumption (>873 kg) ( P interaction  = 0.018), whereas no statistically significant joint effect was found for prediabetes ( P interaction = 0.515)., Conclusions: Both exposures to metal and heavy alcohol intake were associated with the risk of diabetes in this large cohort of male workers. There was a strong interaction between these two exposures in affecting diabetes risk that needs to be confirmed in future studies.

Objective: To analyze the levels of fat-soluble vitamins (FSVs) in pediatric patients with biliary atresia (BA) before and after the Kasai procedure., Methods: Pediatric patients with obstructive jaundice were enrolled in this study. The FSV levels and liver function before, 2 weeks after, and 1, 3, and 6 months after the Kasai procedure were measured., Results: FSV deficiency was more obvious in patients with BA than in patients with other cholestatic liver diseases, especially vitamin D deficiency. 25-Hydroxy vitamin D (25-(OH)D) deficiency was more pronounced in younger patients before surgery. The 25-(OH)D level was significantly higher in patients with than without resolution of jaundice 3 months after surgery. At 6 months after surgery, the 25-(OH)D level was abnormally high at 8.76 ng/ml in patients with unresolved jaundice., Conclusions: Preoperative FSV deficiency, particularly vitamin D deficiency, is common in patients with BA. 25-(OH)D deficiency is more pronounced in younger children before surgery. Postoperative FSV deficiency was still prevalent as shown by the lower 25-(OH)D levels in patients with BA and unresolved jaundice. This required long-term vitamin AD supplementation for pediatric patients with BA and unresolved jaundice after surgery.

Objectives: The aim of the study was to analyze the value of gamma-glutamyl transpeptidase (GGT) for distinguishing biliary atresia (BA) from non-BA for patients suspected of having neonatal obstructive jaundice by correlation with age., Methods: From January 2003 to March 2014, cholangiography and/or surgical exploration were undertaken in 1469 patients with suspicion of having neonatal obstructive jaundice. A total of 1338 patients were diagnosed with BA intraoperatively. Preoperative medical records were compared between BA and non-BA patients., Results: Preoperative levels of total bilirubin, direct bilirubin, and GGT were significantly higher in the BA group (P < 0.05), whereas the non-BA group had higher alkaline phosphatase levels (P = 0.0003). The area under the receiver operating characteristic curve of total bilirubin, direct bilirubin, GGT, and alkaline phosphatase was 0.584, 0.614, 0.843, and 0.398, respectively. In all age groups (i: 31-60 days; ii: 61-90 days; iii: 91-120 days; iv: ≥121 days), BA groups had higher GGT levels (in IU/L) (i: 725.3 ± 549.9; ii: 927.0 ± 679.8; iii: 1114.3 ± 823.1; iv: 767.5 ± 666.7). The level of GGT in patients with BA younger than 30 days was 834.2 ± 475.3 IU/L. GGT levels had the highest diagnostic value (0.869) in group ii (61-90 days) and the lowest diagnosis value (0.712) in group iv (≥121 days). At a cutoff of >303 IU/L in group ii (61-90 days), GGT had 82.8% sensitivity and 81.6% specificity for the discrimination of BA., Conclusions: GGT levels contribute to the diagnosis of BA before 120 days. Age must be considered if using GGT levels as a diagnostic test for BA.

Objective: Biliary atresia (BA) is a devastating liver disease in infants. Progressive hepatic fibrosis is often observed in postoperative patients with BA even after a successful Kasai portoenterostomy procedure. MicroRNA-222 (miRNA) has been linked to the activation of stellate cells and the progression of liver fibrosis., Methods: In this study, the miR-222 expression profile in BA and infants with anicteric choledochal cyst (CC) was determined. The functional effect of miR-222 inhibition on the growth of the human hepatic stellate cell line LX-2 was also evaluated. The downstream signaling pathways and target of miR-222 were determined by coupling gene expression profiling and pathway analysis and by in silico prediction, respectively. In addition, we demonstrated miR-222 overexpression in patients with BA compared with choledochal cyst controls., Results: Inhibition of miR-222 in the LX-2 cell line significantly decreased cell proliferation. We also identified protein phosphatase 2A subunit B as a target of miR-222. The downstream signaling pathway, Akt, was also influenced by miR-222. A consistent reduction of Akt phosphorylation and Ki67 in the LX-2 line was shown following miR-222 suppression., Conclusions: Our results show that miR-222 overexpression is common in BA and contributes to LX-2 cell proliferation by targeting protein phosphatase 2A subunit B and Akt signaling.

Objectives: Biliary atresia (BA) is a devastating pediatric cholestatic liver disease. Increasing evidence indicates that nuclear factor (NF)-κB signaling plays a key role in the pathogenesis of BA. Leucine zipper downregulated in cancer 1 (LDOC1) may control the expression of NF-κB. The aim of this study was to evaluate the relation between LDOC1 and inflammation/apoptosis mediated by NF-κB in the human intrahepatic biliary epithelial cells (HIBECs)., Methods: HIBECs were divided into 3 treatment groups: control, mock transfection group, and LDOC1 transfection. Immunofluorescence, reverse transcription polymerase chain reaction, Western blot, and flow cytometry analysis were used to investigate the effectiveness of LDOC1-transfected HIBECs and the expression of NF-κB. Apoptosis was detected by Hochest/ propidium iodide staining. Interleukin (IL)-2 and tumor necrosis factor (TNF)-α levels were evaluated by enzyme-linked immunosorbent assay., Results: The expression of NF-κB was higher in the LDOC1-transfected group when compared with the control and mock-transfected groups as evaluated by immunofluorescence, reverese transcription polymerase chain reaction, and Western blot analysis. The rate of apoptosis was significantly lower in the LDOC1-transfected group when compared with the control and mock-transfected groups. The levels of IL-2 and TNF-α were significantly higher in the LDOC1-transfected group when compared with the control and mock-transfected groups., Conclusions: Upregulation of LDOC1 in HIBEC increases the expression of NF-κB, which may promote the activation of IL-2 and TNF-α secretion and inhibit cell apoptosis.

Objective. The dosage, duration, and the benefits of high-dose steroid treatment and outcome in biliary atresia (BA) remain controversial. In this study, we evaluated the impact of high-dose steroid therapy on the outcome of BA after the Kasai procedure. Methods. Intravenous prednisolone administration was started 1 week after surgery, followed by 8 to 12 weeks of oral prednisolone. Total bilirubin (TB) levels (3, 6, and 12 months after surgery), early onset of cholangitis, and two-year native liver survival were evaluated. Results. 53.4%, 56.9%, and 58.1% of the patients in the high-dose steroid group were jaundice-free 3, 6, and 12 months after surgery, respectively; these values were significantly higher than the 38.7%, 39.4%, and 43.3% of the low-dose steroid group. One year after surgery, the incidence of cholangitis in the high-dose group (32.0%) was lower than that in the low-dose group (48.0%). Infants with native liver in the high-dose group had a better two-year survival compared to those in the low-dose steroid group (53.7% versus 42.6%). Conclusions. The high-dose steroid protocol can reduce the incidence of cholangitis, increase the jaundice-free rate, and improve two-year survival with native liver after the Kasai operation.

Objective: The mechanisms responsible for increased collagen production and hepatic fibrosis in biliary atresia (BA) remain largely unknown. We evaluated α-smooth muscle actin (α-SMA) expression in liver and the porta hepatis in infants with BA., Methods: Immunohistochemical staining for α-SMA and CD68 in the BA liver and porta hepatis was performed. A semiquantitative 3-grade staging system was employed to estimate liver fibrosis. The densities of CD68 in BA liver and the levels of direct bilirubin were assessed in relation to α-SMA expression., Results: α-SMA was found to be overexpressed in epithelial cells and in periductular collagen fibers. The expression in infants with BA was higher than that in the control group (P < 0.05). The amount of α-SMA in BA was positively correlated with liver fibrosis scores (r = 0.549, P = 0.022). The levels of α-SMA in the liver of BA were negatively related with improvements in direct bilirubin levels, 3 months postoperatively (r = -0.653, P = 0.029). The correlation between the α-SMA and CD-68 expression was not significantly different (r = 0.444, P = 0.057)., Conclusions: The expression of α-SMA in BA liver is higher than that in contro1 group. α-SMA expression is negatively correlated with the reduction of direct bilirubin, 3 months postoperatively, probably due to fibrosis or cirrhosis affecting the entire biliary system.

Objective: There is an urgent need to identify noninvasive and convenient biomarkers for early diagnosis of biliary atresia (BA). The aim of the present study was to identify potential protein biomarkers for BA., Methods: Serum samples from 42 infants with BA, 38 infants with non-BA neonatal cholestasis (NC), and 36 healthy controls (HC) were randomly divided into a training set and a test set. Serum proteomic profiles were measured using surface-enhanced desorption/ionization time-of-flight mass spectrometry. Candidate biomarkers were purified using high-performance liquid chromatography, identified using liquid chromatography tandem mass spectrometry, and validated using enzyme-linked immunosorbent assay., Results: A total of 2 protein peaks (m/z with 8697 and 9098  Da) with differential expression levels were found using surface-enhanced desorption/ionization time-of-flight mass spectrometry. These peaks were then analyzed by a support vector machine to construct a classification model in the training set. The sensitivity and specificity of the model were 94.1% and 91.8%, respectively, in the test set. One candidate biomarker (9098  Da) was identified as Apo C-II, and was found to be downregulated in BA samples compared with HC samples, and upregulated in BA samples compared with NC samples. The other candidate biomarker (8697  Da) was identified as Apo C-III, and was found to be upregulated in BA compared with NC and HC., Conclusions: Apo C-II and Apo C-III may be potential protein biomarkers of BA and may be useful in distinguishing infants with BA from healthy and NC infants. Further studies with additional populations or using prediagnostic serum are needed to confirm the importance of these findings as diagnostic markers of infants with BA.