[Impact of chaperone-mediated autophagy on bilirubin-induced damage of mouse microglial cells]. / åˆ†å­ä¼´ä¾£ä»‹å¯¼çš„è‡ªå™¬å¯¹èƒ†çº¢ç´ è¯±å¯¼çš„å°é¼ å°èƒ¶è´¨ç»†èƒžæŸä¼¤çš„å½±å“.

OBJECTIVES: To investigate the effect of chaperone-mediated autophagy (CMA) on the damage of mouse microglial BV2 cells induce by unconjugated bilirubin (UCB). METHODS: The BV2 cell experiments were divided into two parts. (1) For the CMA activation experiment: control group (treated with an equal volume of dimethyl sulfoxide), QX77 group (treated with 20 µmol/L QX77 for 24 hours), UCB group (treated with 40 µmol/L UCB for 24 hours), and UCB+QX77 group (treated with both 20 µmol/L QX77 and 40 µmol/L UCB for 24 hours). (2) For the cell transfection experiment: LAMP2A silencing control group (treated with an equal volume of dimethyl sulfoxide), LAMP2A silencing control+UCB group (treated with 40 µmol/L UCB for 24 hours), LAMP2A silencing group (treated with an equal volume of dimethyl sulfoxide), and LAMP2A silencing+UCB group (treated with 40 µmol/L UCB for 24 hours). The cell viability was assessed using the modified MTT method. The expression levels of p65, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), and cysteinyl aspartate specific proteinase-1 (caspase-1) were detected by Western blot. The relative mRNA expression levels of the inflammatory cytokines interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were determined by real-time quantitative polymerase chain reaction. Levels of IL-6 and TNF-α in the cell culture supernatant were measured using ELISA. The co-localization of heat shock cognate protein 70 with p65 and NLRP3 was detected by immunofluorescence. RESULTS: Compared to the UCB group, the cell viability in the UCB+QX77 group increased, and the expression levels of inflammation-related proteins p65, NLRP3, and caspase-1, as well as the mRNA relative expression levels of IL-1ß, IL-6, and TNF-α and levels of IL-6 and TNF-α decreased (P<0.05). Compared to the control group, there was co-localization of heat shock cognate protein 70 with p65 and NLRP3 in both the UCB and UCB+QX77 groups. After silencing the LAMP2A gene, compared to the LAMP2A silencing control+UCB group, the LAMP2A silencing+UCB group showed increased expression levels of inflammation-related proteins p65, NLRP3, and caspase-1, as well as increased mRNA relative expression levels of IL-1ß, IL-6, and TNF-α and levels of IL-6 and TNF-α (P<0.05). CONCLUSIONS: CMA is inhibited in UCB-induced BV2 cell damage, and activating CMA may reduce p65 and NLRP3 protein levels, suppress inflammatory responses, and counteract bilirubin neurotoxicity.

Preliminary exploration of animal models of congenital choledochal cysts.

BACKGROUND: Various animal models have been used to explore the pathogenesis of choledochal cysts (CCs), but with little convincing results. Current surgical techniques can achieve satisfactory outcomes for treatment of CCs. Consequently, recent studies have focused more on clinical issues rather than basic research. Therefore, we need appropriate animal models to further basic research. AIM: To establish an appropriate animal model that may contribute to the investigation of the pathogenesis of CCs. METHODS: Eighty-four specific pathogen-free female Sprague-Dawley rats were randomly allocated to a surgical group, sham surgical group, or control group. A rat model of CC was established by partial ligation of the bile duct. The reliability of the model was confirmed by measurements of serum biochemical indices, morphology of common bile ducts of the rats as well as molecular biology experiments in rat and human tissues. RESULTS: Dilation classified as mild (diameter, ≥ 1 mm to < 3 mm), moderate (≥ 3 mm to < 10 mm), and severe (≥ 10 mm) was observed in 17, 17, and 2 rats in the surgical group, respectively, while no dilation was observed in the control and sham surgical groups. Serum levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, and total bile acids were significantly elevated in the surgical group as compared to the control group 7 d after surgery, while direct bilirubin, total bilirubin, and gamma-glutamyltransferase were further increased 14 d after surgery. Most of the biochemical indices gradually decreased to normal ranges 28 d after surgery. The protein expression trend of signal transducer and activator of transcription 3 in rat model was consistent with the human CC tissues. CONCLUSION: The model of partial ligation of the bile duct of juvenile rats could morphologically simulate the cystic or fusiform CC, which may contribute to investigating the pathogenesis of CC.

[Expression of neutrophil extracellular traps and phagocytic functions among patients with hepatic alveolar echinococcosis].

OBJECTIVE: To investigate the expression of neutrophil extracellular traps (NETs) and phagocytic function in the peripheral blood of patients with hepatic alveolar echinococcosis (HAE), and to examine their correlations with clinical inflamma tory indicators and liver functions. METHODS: A total of 50 patients with HAE admitted to Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qinghai University from August 2022 to June 2023 were enrolled, while 50 age- and gender-matched healthy individuals from the Centre for Healthy Examinations of the hospital during the same period served as controls. The levels of NETs markers neutrophil myeloperoxidase (MPO) and neutrophil elastase (NE) were measured using enzyme-linked immunosorbent assay (ELISA). Peripheral blood neutrophils were isolated using density gradient centrifugation, stimulated in vitro using phorbol 12-myristate 13 acetate (PMA), and the levels of MPO and citrullination histone H3 (CitH3) released by neutrophils were quantified using flow cytometry. The phagocytic functions of neutrophils were examined using flow cytometry. In addition, the correlations of MPO and NE levels with clinical inflammatory indicators and liver biochemical indicators were examined using Spearman correlation analysis among HAE patients. RESULTS: The peripheral blood plasma MPOï¼»(417.15 ± 76.08) ng/mL vs. (255.70 ± 80.84) ng/mL; t = 10.28, P < 0.05ï¼½, NEï¼»(23.16 ± 6.75) ng/mL vs. (11.92 ± 3.17) ng/mL; t = 10.65, P < 0.05ï¼½and CitH3 levelsï¼»(33.93 ± 18.93) ng/mL vs. (19.52 ± 13.89) ng/mL; t = 4.34, P < 0.05ï¼½were all significantly higher among HAE patients than among healthy controls, and a lower phagocytosis rate of neutrophils was detected among HAE patients than among healthy controlsï¼»(70.85 ± 7.32)% vs. (94.04 ± 3.90)%; t = 20.18, P < 0.05ï¼½, and the ability to produce NETs by neutrophils was higher among HAE patients than among healthy controls following in vitro PMA stimulation. Pearson correlation analysis showed that the phagocytosis rate of neutrophils correlated negatively with platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), interleukin-6 (IL-6) level and C-reactive protein (CRP) level (rs = -0.515 to -0.392, all P values < 0.05), and the MPO and NE levels positively correlated with inflammatory markers NLR, PLR, CRP and IL-6 (rs = 0.333 to 0.445, all P values < 0.05) and clinical liver biochemical indicators aspartic transaminase, alanine aminotransferase, direct bilirubin and total bilirubin among HAE patients (rs = 0.290 to 0.628, all P values < 0.001). CONCLUSIONS: Excessive formation of NETs is found among HAE patients, which affects the phagocytic ability of neutrophils and results in elevated levels of inflammatory indicators. NETs markers may be promising novel biomarkers for early diagnosis, monitoring, and severity assessment of liver disease.

Role of albumin-bilirubin score in non-malignant liver disease.

The albumin-bilirubin (ALBI) score, which was proposed to assess the prognosis of patients with hepatocellular carcinoma, has gradually been extended to other liver diseases in recent years, including primary biliary cholangitis, liver cirrhosis, hepatitis, liver transplantation, and liver injury. The ALBI score is often compared with classical scores such as the Child-Pugh and model for end-stage liver disease scores or other noninvasive prediction models. It is widely employed because of its immunity to subjective evaluation indicators and ease of obtaining detection indicators. An increasing number of studies have confirmed that it is highly accurate for assessing the prognosis of patients with chronic liver disease; additionally, it has demonstrated good predictive performance for outcomes beyond survival in patients with liver diseases, such as decompensation events. This article presents a review of the application of ALBI scores in various non-malignant liver diseases.

Impact of Omicron variant infection on the liver, kidney, and coagulation system in patients undergoing elective surgery: a retrospective case-control study.

Purpose: We aimed to investigate the impact of Omicron variant infection on the perioperative organ function in patients undergoing elective surgery. Methods: A total of 5029 patients who underwent elective surgery between October 2022 and January 2023 at our hospital were enrolled. Among them, the patients who underwent elective surgery between October 2022 and November 2022 composed Group 1 (not infected with the Omicron variant) the control group; those who underwent elective surgery between December 2022 and January 2023 composed Group 2 (one month after Omicron variant infection) the experimental group. We further divided the patients into two subgroups for analysis: the tumor subgroup and the nontumor subgroup. Data on organ system function indicators, including coagulation parameters, liver function, complete blood count (CBC), and kidney function, were collected before and after surgery. Differences between the two groups were subsequently analyzed via binary logistic regression analysis. Results: Compared with those in the uninfected patient group, the following changes were observed in patients with Omicron variant infection who underwent elective surgery one month after infection: prothrombin activity (PTa), prothrombin time (PT), fibrinogen, albumin/globulin, alanine aminotransferase (ALT), mean corpuscular hemoglobin concentration (MCHC), platelet (PLT), and anemia were increased AST/ALT, indirect bilirubin (IBILI), eosinophils, and uric acid were decreased before surgery; and lung infection/pneumonia and fibrinogen were increased, while AST/ALT, globulin, total bilirubin (TBIL), white blood cell count (WBC), and uric acid were decreased after surgery. There was no significant difference in the mortality rate or length of hospital stay (LOS) between the two groups. Subgroup analysis revealed elevated monocyte, PLT, and fibrinogen classification, levels and decreased globulin, prealbumin (PBA), eosinophil, and uric acid levels in the tumor subgroup of patients who underwent elective surgery one month after Omicron infection compared with those in the uninfected patients. Compared with the nontumor subgroup, fibrinogen levels, lung infection/pneumonia, TBIL, and PLT count were increased in the uninfected patients, while the globulin and eosinophil levels were decreased. Conclusion: Compared with uninfected patients, patients who underwent elective surgery one month after Omicron variant infection exhibited minimal changes in perioperative coagulation parameters, liver function, CBC counts, and kidney function. Additionally, no significant differences in postoperative mortality or LOS were observed between the two groups.

Long-term survival analysis of ultrasound-guided percutaneous microwave ablation for hepatocellular carcinoma conforming to the Milan criteria: primary versus recurrent HCC.

BACKGROUND: This study compared long-term outcomes between patients with initial hepatocellular carcinoma (IHCC) and those with recurrent HCC (RHCC) treated with microwave ablation (MWA). METHODS: This retrospective study included 425 patients with HCCs (294 IHCCs and 131 RHCCs) within the Milan criteria who were treated with ultrasound-guided percutaneous MWA between January 2008 and November 2021. All patients with RHCC had previously undergone MWA for initial HCC. Overall survival (OS) and recurrence-free survival (RFS) rates were compared between the IHCC and RHCC groups before and after propensity score matching (PSM). RESULTS: Before matching, the 1-, 3-, 5-, and 10-year OS rates in the IHCC group were 95.9%, 78.5%, 60.2%, and 42.5%, respectively, which were significantly higher than those in the RHCC group (93.8%, 70.0%, 42.0%, and 6.6%, respectively). This difference remained significant after PSM. However, subgroup analyses suggested that there were no significant differences in OS rates between IHCC and RHCC in patients with solitary HCC ≤3.0 cm, AFP ≤200 ng/mL, ablative margins ≥0.5 cm, or Albumin-Bilirubin (ALBI) grade 1. RFS was significantly higher in IHCC than in RHCC before and after PSM, as well as in subgroup analyses. ALBI grade (hazard ratio (HR), 2.38; 95% CI: 1.46-3.86; p < 0.001), serum AFP level (HR, 2.07; 95% CI: 1.19-3.62; p = 0.010) and ablative margins (HR, 0.18; 95% CI: 0.06-0.59; p = 0.005) were independent prognostic factors for OS of RHCC. Serum AFP(HR, 1.29; 95% CI: 1.02-1.63, p = 0.036) level was the only factor associated with RFS in RHCC. CONCLUSIONS: MWA yielded comparable OS in IHCC and RHCC patients with solitary HCC ≤3.0 cm, AFP ≤200 ng/mL, ablative margins ≥0.5 cm, or ALBI grade 1.

[Surgical treatment and prognosis analysis of hilar cholangiocarcinoma].

Objective: To investigate the surgical treatment effect and prognostic factors of hilar cholangiocarcinoma. Methods: This is an ambispective cohort study. From August 2005 to December 2022,data of 510 patients who diagnosed with hilar cholangiocarcinoma and underwent surgical resection at the Hepatobiliary Center of the First Affiliated Hospital of Nanjing Medical University were retrospectively collected. In the cohort,there were 324 males and 186 females,with an age of (M (IQR)) 63(13)years (range:25 to 85 years). The liver function at admission was Child-Pugh A (343 cases,67.3%) and Child-Pugh B (167 cases,32.7%). Three hundred and seventy-two(72.9%) patients had jaundice symptoms and the median total bilirubin was 126.3(197.6) µmol/L(range: 5.4 to 722.8 µmol/L) at admission. Two hundred and fourty-seven cases (48.4%) were treated with percutaneous transhepatic cholangial drainage or endoscopic nasobiliary drainage before operation. The median bilirubin level in the drainage group decreased from 186.4 µmol/L to 85.5 µmol/L before operation. Multivariate Logistic regression was used to identify the influencing factors for R0 resection,and Cox regression was used to construct multivariate prediction models for overall survival(OS) and disease-free survival(DFS). Results: Among 510 patients who underwent surgical resection,Bismuth-Corlett type Ⅲ-Ⅳ patients accounted for 71.8%,among which 86.1% (315/366) underwent hemi-hepatectomy,while 81.9% (118/144) underwent extrahepatic biliary duct resection alone in Bismuch-Corlett type Ⅰ-Ⅱ patients. The median OS time was 22.8 months, and the OS rates at 1-,3-,5-and 10-year were 72.2%,35.6%,24.8% and 11.0%,respectively. The median DFS time was 15.2 months,and the DFS rates was 66.0%,32.4%,20.9% and 11.0%,respectively. The R0 resection rate was 64.5% (329/510), and the OS rates of patients with R0 resection at 1-,3-,5-and 10-year were 82.5%, 48.6%, 34.4%, 15.2%,respectively. The morbidity of Clavien-Dindo grade Ⅲ-Ⅴ complications was 26.1%(133/510) and the 30-day mortality was 4.3% (22/510). Multivariate Logistic regression indicated that Bismuth-Corlett type Ⅰ-Ⅲ (P=0.009), hemi-hepatectomy and extended resection (P=0.001),T1 and T2 patients without vascular invasion (T2 vs. T1:OR=1.43 (0.61-3.35),P=0.413;T3 vs. T1:OR=2.57 (1.03-6.41), P=0.010;T4 vs. T1, OR=3.77 (1.37-10.38), P<0.01) were more likely to obtain R0 resection. Preoperative bilirubin,Child-Pugh grade,tumor size,surgical margin,T stage,N stage,nerve infiltration and Edmondson grade were independent prognostic factors for OS and DFS of hilar cholangiocarcinoma patients without distant metastasis. Conclusions: Radical surgical resection is necessary to prolong the long-term survival of hilar cholangiocarcinoma patients. Hemi-hepatectomy and extended resection,regional lymph node dissection and combined vascular resection if necessary,can improve R0 resection rate.

Perioperative outcomes after open biliary bypass for malignant biliary obstruction (MBO) in resource-limited setups; a multicenter prospective cohort study, 2023.

INTRODUCTION: Obstructive jaundice is the most common symptom of malignant diseases of the extrahepatic biliary system and necessitates either non-operative or operative biliary bypass. Because of percutaneous and endoscopic approaches, the use of palliative surgical procedures has decreased in recent years. However, in resource-limited situations, open biliary bypasses remain a viable option. This study aimed to identify factors associated with adverse perioperative outcomes following open biliary bypass. METHODS: From June 2022 to May 2023, 69 patients underwent open biliary bypass for malignant biliary obstruction. Postoperative morbidity and mortality within 30 days of surgery were assessed. A Kaplan-Meier was used for categorical variables, and a log-rank test was used to determine the statistically significant difference between variables. A Cox regression analysis was conducted to identify factors associated to time to develop complications. RESULTS: The hazard of developing complications among those with preoperative cholangitis was 2.49 times higher than those without preoperative cholangitis (HR 2.49, 95% CI [1.06, 5.84]). For every hour increment in the length of surgery, the hazard of getting complications increased by 2.47 times (HR 2.47, 95% CI [1.28, 4.77]). As serum bilirubin increased by 1 mg/dl, the hazard of developing complications increased by 14% (HR 1.14, 95% CI [1.03, 1.17]). CONCLUSION: Patients who had long operation times, preoperative cholangitis, and elevated total bilirubin levels are at increased risk for poor perioperative outcomes. Clinicians may use these results to optimize these patients to decrease their elevated risk of serious morbidity and mortality.

Clinical criteria accurately diagnose severe but not moderate alcohol-associated hepatitis: A systematic review and meta-analysis.

BACKGROUND: The precision of clinical criteria and the utility of liver biopsy for diagnosis or prognosis remain unclear in patients with alcohol-associated hepatitis (AH). We systematically reviewed the literature to answer these questions. METHODS: Four databases were searched for studies describing the precision of clinical criteria (National Institute on Alcohol Abuse and Alcoholism, European Association for Study of Liver, or classical) and the role of histology in AH. The precision(positive predictive value) of criteria was pooled through random-effects meta-analysis, and its variation was investigated through subgroups and meta-regression of study-level factors with their percent contribution to variation (R2). The risk of bias among studies was evaluated through the QUADAS2 tool (PROSPERO-ID-CRD4203457250). RESULTS: Of 4320 studies, 18 in the systematic review and 15 (10/5: low/high risk of bias, N=1639) were included in the meta-analysis. The pooled precision of clinical criteria was 80.2% (95% CI: 69.7-89.7, I2:93%, p < 0.01), higher in studies with severe AH (mean-Model for End-Stage Liver Disease > 20) versus moderate AH (mean-Model for End-Stage Liver Disease < 20): 92% versus 67.1%, p < 0.01, and in studies with serum bilirubin cutoff 5 versus 3 mg/dL (88.5% vs.78.8%, p = 0.01). The factors contributing to variation in precision were Model for End-Stage Liver Disease (R2:72.7%), upper gastrointestinal bleed (R2:56.3%), aspartate aminotransferase:aspartate aminotransferase ratio (R2:100%), clinical criteria (R2:40.9%), bilirubin (R2:22.5%), and Mallory body on histology (R2:19.1%).The net inter-pathologist agreement for histologic findings of AH was variable (0.33-0.97), best among 2 studies describing AH through simple and uniform criteria, including steatosis, ballooning, and neutrophilic inflammation. Few studies reported the utility of histology in estimating steroid responsiveness (N = 1) and patient prognosis (N = 4); however, very broad septa, pericellular fibrosis, and cholestasis were associated with mortality. Bilirubinostasis was associated with infection in 1 study. CONCLUSIONS: Clinical criteria are reasonably precise for diagnosing severe AH, while there is an unmet need for better criteria for diagnosing moderate AH. Histologic diagnosis of AH should be simple and uniform.

Effect of Liver Dysfunction on S-1 Therapy Induced Adverse Effects: A Retrospective Cohort Study.

BACKGROUND/AIM: Renal dysfunction necessitates S-1 dose reduction. However, decreased dihydropyrimidine dehydrogenase (DPD) activity may lead to adverse events due to 5-FU. The guidelines provided by pharmaceutical companies state that total bilirubin (T-Bil) should be ≤upper limit of normal (ULN)×1.5 as a reference value for safely taking S-1. Nevertheless, the relationship between the degree of liver dysfunction and S-1 dose reduction has not been clearly established. PATIENTS AND METHODS: This study focused on patients who received S-1 monotherapy for various types of cancer. The primary outcome was defined as the variation between blood sampling results on the test day and the subsequent test. The variation data were categorized based on the difference in T-Bil: Low T-Bil group (≤2.25) and High T-Bil group (>2.25). RESULTS: The number of patients that underwent S-1 monotherapy was 883 and the running number was 7,511; Low T-Bil group included 7,245 and High T-Bil group included 266. Examination of the effect of the T-Bil Group on clinical outcomes revealed a correlation with red blood cell (RBC) count, platelet (PLT) count, and T-Bil level. When the impact of the interaction between the T-Bil Group and any of the clinical outcomes, such as the RBC count, PLT count, and T-Bil level, was determined, each outcome showed a significant decrease in the High T-Bil group compared with the Low T-Bil group. CONCLUSION: S-1 administration in patients with liver dysfunction accompanied by elevated T-Bil levels may cause thrombocytopenia.

Histological characteristics in patients admitted to the hospital with alcoholic hepatitis complicated by acute-on-chronic liver failure.

OBJECTIVES: Alcoholic hepatitis (AH) is a frequent precipitating event for the development of acute-on-chronic liver failure (ACLF), a syndrome characterised by organ failures due to immune dysfunction. The histological features of this complication are not well characterized. We investigated whether ACLF has specific histological characteristics. METHODS: Prospective cohort study in consecutive adult patients admitted between 03-2008 and 04-2021 to a tertiary referral centre with suspected AH. Diagnosis of AH was based on clinical presentation and confirmed by transjugular liver biopsy. All biopsies were assessed by a dedicated liver pathologist, blinded for clinical data and outcome. Diagnosis of ACLF was based on EASL-CLIF criteria. Histological and clinical characteristics of patients with and without ACLF at baseline were compared. RESULTS: 184 patients with biopsy-proven AH were enrolled. Median time from hospital admission to transjugular biopsy was 4.5 days (IQR 2-8). At baseline, ACLF was present in 73 patients (39.7%). Out of the 110 patients without ACLF at baseline, 30 (27.3%) developed ACLF within 28 days (median 7.5 days (IQR 2-20)). At baseline, ductular bilirubinostasis (DB) was the only histological feature significantly more frequently present in patients with ACLF compared to patients without ACLF (50.7% vs. 30.6%, p = 0.003). No clear association between histological features and the development of ACLF later on could be demonstrated. CONCLUSIONS: In this well-defined cohort of patients with biopsy-proven AH, DB was associated with the presence of ACLF. This finding fits with the pathophysiology of this syndrome, which is characterized by systemic inflammation and an increased risk of infections.

Identification of complicated and non-complicated appendicitis: a new alvarado-based scoring system.

BACKGROUND: In the presence of non-complicated appendicitis, treatment typically involves a simple appendectomy and can even be managed medically. However, in cases of complicated appendicitis, surgery becomes more difficult, and the morbidity and mortality rates increase. This study aims to develop a method for recognizing complicated acute appendicitis operatively. METHODS: This retrospective study developed a scoring system based on the Alvarado score. Several variables were scored in this new scoring system, including the Alvarado score, female gender, elevated direct bilirubin, increased appendicitis thickness, and the presence of complications as evidenced by imaging or appendicoliths. RESULTS: The study included a total of 404 patients with a mean age of 38.50±12.94 years, all operated on for acute appendicitis. Of these, 45.8% were female. Complicated acute appendicitis was present in 25% of the patients. The presence of complicated acute appendicitis was identified with a sensitivity of 86.1% and a specificity of 90.4% in patients who scored 10.5 or above. CONCLUSION: It is critical to identify perioperative and postoperative complications, provide appropriate patient counseling, and consider medical treatment when appropriate to diagnose acute complex appendicitis effectively. The new scoring system is an effective method for recognizing acute complicated appendicitis.

Diagnostic and predictive ability of hyperbilirubinemia severity in cats: A multicenter retrospective study.

BACKGROUND: Total serum bilirubin concentration (TBIL) can provide useful information on several pathophysiological conditions in cats. Nevertheless, whether the variable severity classification of hyperbilirubinemia can reliably indicate certain disease processes or predict a biliary obstruction (BO) has not been investigated. HYPOTHESIS/OBJECTIVE: Determine if hyperbilirubinemia of variable severity can assist clinicians to identify BO, which often is considered a surgical emergency. ANIMALS: Two-hundred sixteen client-owned cats. METHODS: Data were retrospectively collected from all cats (January 2015-August 2022) with an increased TBIL (>0.58 mg/dL [>10 µmol/L]) presented to 3 referral centers in the United Kingdom (UK). Presenting clinical features and diagnostic outcomes were collected. The predictive ability of TBIL to indicate BO was evaluated by multivariable binary logistic regression modeling and receiver operating characteristic (ROC) curves. RESULTS: Median TBIL was 1.73 mg/dL (range, 0.59-26.15; 29.5 µmol/L; range, 10.1-447.1) with severity classification of hyperbilirubinemia categorized as mild (>0.58-2.92 mg/dL; >10-50 µmol/L; 68.1%), moderate (>2.92-5.85 mg/dL; >50-100 µmol/L; 17.6%), severe (>5.85-11.70 mg/dL; >100-200 µmol/L; 9.7%) and very severe (>11.70 mg/dL; >200 µmol/L; 4.6%). Biliary obstruction was present in 17 (7.9%) cats, all of which received recommendation for emergency surgery. Median TBIL in cats with BO (9.69 mg/dL; 165.7 µmol/L) differed significantly from those without obstruction (1.51 mg/dL; 25.8 µmol/L; P < .01). The optimal TBIL cut-off to discriminate between cats with and without BO was ≥3.86 mg/dL (≥66 µmol/L) with a sensitivity of 94.1% and specificity of 82.4%. Using multivariable logistic regression, as age increased, the odds of BO increased significantly (odds ratio, 1.20; 95% confidence interval, 1.01-1.42; P = .04). CONCLUSIONS AND CLINICAL IMPORTANCE: As part of a thorough clinical assessment, the severity classification of hyperbilirubinemia has the potential to predict the likelihood of a BO and to discriminate between cats that may or may not require surgery for BO at a suggested cut-off of ≥3.86 mg/dL (≥66 µmol/L). Alongside TBIL, age is also useful when assessing for the likelihood of BO in a cat presented with hyperbilirubinemia.

Albumin-bilirubin score is a useful predictor of worsening liver reserve after stereotactic body radiation therapy in elderly Japanese patients with hepatocellular carcinoma.

The prognosis of patients with hepatocellular carcinoma (HCC) is closely related to their liver reserves. The Child-Pugh (CP) score has traditionally been used to evaluate this reserve, with CP Grade B (CP score ≥ 7) associated with a higher risk of radiation-induced liver disease after stereotactic body radiation therapy (SBRT). However, the CP score has limitations, as it does not accurately assess liver reserve capacity. The albumin-bilirubin (ALBI) score has been introduced as a meticulous indicator of liver reserve for the treatment of HCC. We retrospectively evaluated the role of the ALBI score in estimating the worsening liver reserve in 42 patients with HCC treated with SBRT using CyberKnife between 2015 and 2023. The median biologically effective dose (α/ß = 10 Gy) was 100 Gy. For a median follow-up duration of 17.4 months, the 1-year overall survival (OS), local control (LC) and progression-free survival (PFS) rates were 100, 98 and 62%, respectively. Worsening liver reserve was defined as an increase in the modified ALBI grade or CP score within 1 year after SBRT. Univariate and multivariate analyses showed that the baseline ALBI score (≥-2.7 vs <-2.7) was the only significantly different predictor of worsening liver reserve. The OS and LC rates after SBRT for HCC were satisfactory. However, the PFS was poor, and recurrent HCC will require additional treatment. It is clinically important to predict the liver reserve capacity after SBRT, and the baseline ALBI score is a useful predictor.

Transport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain.

Bilirubin is mainly generated from the breakdown of heme when red blood cells reach the end of their lifespan. Accumulation of bilirubin in human body usually leads to various disorders, including jaundice and liver disease. Bilirubin is conjugated in hepatocytes and excreted to bile duct via the ATP-binding cassette transporter ABCC2, dysfunction of which would lead to Dubin-Johnson syndrome. Here we determine the structures of ABCC2 in the apo, substrate-bound and ATP/ADP-bound forms using the cryo-electron microscopy, exhibiting a full transporter with a regulatory (R) domain inserted between the two half modules. Combined with substrate-stimulated ATPase and transport activity assays, structural analysis enables us to figure out transport cycle of ABCC2 with the R domain adopting various conformations. At the rest state, the R domain binding to the translocation cavity functions as an affinity filter that allows the substrates of high affinity to be transported in priority. Upon substrate binding, the R domain is expelled from the cavity and docks to the lateral of transmembrane domain following ATP hydrolysis. Our findings provide structural insights into a transport mechanism of ABC transporters finely tuned by the R domain.

Validity of BiliDx as a point-of-care bilirubin measurement device to diagnose and monitor neonatal jaundice at Muhimbili National Hospital, an observational study.

BACKGROUND: Neonatal jaundice is a condition caused by elevated levels of bilirubin in the bloodstream. Laboratory determination of serum bilirubin concentration by total serum bilirubin (TSB) test is still considered as gold standard for clinical guidance and practice. In developed countries, diagnosis of neonatal jaundice is shifting towards point-of-care medical devices. BiliDx is a device developed to allow a fast, blood-based determination of bilirubin levels at the point of care. This study aimed to determine the accuracy of the BiliDx device relative to a standard laboratory total serum bilirubin to diagnose and monitor jaundice among neonates admitted at Muhimbili National Hospital (MNH). MATERIAL AND METHODOLOGY: This was a prospective hospital-based observational study conducted at the Neonatal Ward - MNH, Dar-es-Salaam, Tanzania from November 2022 to January 2023. A total of 180 neonates admitted at the neonatal ward with jaundice and whose parents consented were enrolled in the study. Blood samples were collected; 2 ml of venous blood into the vacutainer bottle for standard laboratory measurement of total serum bilirubin (TSB) and 25µL blood collected into a transfer pipette tube and applied to BiliDx. STATA version 15.1 was used for data analysis. RESULTS: Out of 180 neonates, 39.4% (71/180) had birth weight between 1500 - 2499.9 g, approximately 2/3rd (120/180) were preterm, 92/180 (51.1%) were males and 100/180 (55.6%) were undergoing phototherapy treatment the moment sample taken. The mean bilirubin concentration was 92 mmol/l for BiliDx and 118 mmol/l for standard laboratory TSB. The minimum and maximum values obtained with BiliDx were, 3.4 and 427.5 mmol/l respectively, compared with 10.7 and 382.1 mmol/l using standard laboratory TSB. A linear relationship and correlation coefficient of 0.8408 (p = 0.000) between BiliDx and standard laboratory TSB was found. The regression analysis showed the presence of constant error [coefficient of BiliDx/slope = 0.91, 95% CI (0.82-0.99), p = 0.000] and random error exclusively [coefficient of constant/y-intercept = 48.52, 95%CI (37.70-59.34), p = 0.000]. The Bland-Altman plot showed an acceptable mean difference of 39.1mmol/l, limits of agreement of -48.3mmol/l to 126.4mmol/l, and 179 points (179/180 = 99.4%) lying inside the limits of agreement. CONCLUSION: The results support the use of BiliDx for rapid and accurate testing of elevated levels of bilirubin in the bloodstream among neonates since 99.4% of the differences between BiliDx and standard laboratory TSB lie between the lines of agreement.

Distinct bile acid alterations in response to a single administration of PFOA and PFDA in mice.

Per- and polyfluoroalkyl substances (PFASs), a group of synthetic chemicals that were once widely used for industrial purposes and in consumer products, are widely found in the environment and in human blood due to their extraordinary resistance to degradation. Once inside the body, PFASs can activate nuclear receptors such as PPARα and CAR. The present study aimed to investigate the impact of perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) on liver structure and functions, as well as bile acid homeostasis in mice. A single administration of 0.1 mmole/kg of PFDA, not PFOA, elevated serum ALT and bilirubin levels and caused cholestasis in WT mice. PFDA increased total and various bile acid species in serum but decreased them in the liver. Furthermore, in mouse livers, PFDA, not PFOA, down-regulated mRNA expression of uptake transporters (Ntcp, Oatp1a1, 1a4, 1b2, and 2b1) but induced efflux transporters (Bcrp, Mdr2, and Mrp2-4). In addition, PFDA, not PFOA, decreased Cyp7a1, 7b1, 8b1, and 27a1 mRNA expression in mouse livers with concomitant hepatic accumulation of cholesterol. In contrast, in PPARα-null mice, PFDA did not increase serum ALT, bilirubin, or total bile acids, but produced prominent hepatosteatosis; and the observed PFDA-induced expression changes of transporters and Cyps in WT mice were largely attenuated or abolished. In CAR-null mice, the observed PFDA-induced bile acid alterations in WT mice were mostly sustained. These results indicate that, at the dose employed, PFDA has more negative effects than PFOA on liver function. PPARα appears to play a major role in mediating most of PFDA-induced effects, which were absent or attenuated in PPARα-null mice. Lack of PPARα, however, exacerbated hepatic steatosis. Our findings indicate separated roles of PPARα in mediating the adaptive responses to PFDA: protective against hepatosteatosis but exacerbating cholestasis.

Prognostic Nutritional Index as a Prognostic Factor for Very Early-Stage Hepatocellular Carcinoma.

INTRODUCTION: Field factors play more important roles in predicting the outcomes of patients compared with tumor factors in early-stage hepatocellular carcinoma (HCC). However, the prognostic ability of noninvasive serum marker scores for hepatic fibrosis and liver functional reserve on very early-stage HCC is still not yet determined. We aimed to investigate the performance of these serum marker scores in predicting the prognoses of patients with very early-stage HCC. METHODS: A total of 446 patients with very early-stage HCC from 2012 to 2022 were retrospectively enrolled. Serum biomarkers and prognostic scores determining overall survival (OS) were analyzed by Cox proportional hazards model. We compared the Akaike information criterion among the prognostic nutritional index (PNI), aspartate aminotransferase-to-platelet ratio index, albumin-bilirubin (ALBI) score, EZ (easy)-ALBI score, modified ALBI score, fibrosis-4 score, and lymphocyte-to-monocyte ratio to determine the predictability on the OS. RESULTS: After a median follow-up of 41.0 months (interquartile range 36.9-45.1 months), 81 patients died, with a 5-year OS rate of 71.0%. Among the noninvasive serum marker scores, PNI had the best performance in predicting the OS with the lowest Akaike information criterion (846.407) compared with other scores. Moreover, we stratified the patients into high-risk (PNI <45) and low-risk (PNI ≥45) groups. It showed that the 5-year OS rates were 83.4% and 60.8% in the low-risk and high-risk PNI groups, respectively ( P < 0.001). DISCUSSION: PNI had the best performance in predicting the OS for patients with very early-stage HCC.

An algorithm for simplified hepatitis C virus treatment with non-specialist care based on nation-wide data from Taiwan.

BACKGROUND: Both European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (AASLD-IDSA) guidelines recommend simplified hepatitis C virus (HCV) treatment with pan-genotypic sofosbuvir/velpatasvir or glecaprevir/pibrentasvir for eligible patients. This observational study used real-world data to assess these regimens' safety in eligible patients and develop an algorithm to identify patients suitable for simplified treatment by non-specialists. METHODS: 7,677 HCV-infected patients from Taiwan Hepatitis C Registry (TACR) who received at least one dose of sofosbuvir/velpatasvir or glecaprevir/pibrentasvir, and fulfilled the EASL/AASLD-IDSA criteria for simplified treatment were analyzed. Multivariate analysis was conducted on patient characteristics and safety data. RESULTS: Overall, 92.8% (7,128/7,677) of patients achieved sustained virological response and only 1.9% (146/7,677) experienced Grades 2-4 laboratory abnormalities in key liver function parameters (alanine aminotransferase, aspartate aminotransferase, and total bilirubin), with only 18 patients (0.23%) experiencing Grades 3-4 abnormalities. Age > 70 years old, presence of hepatocellular carcinoma, total bilirubin > 1.2 mg/dL, estimated glomerular filtration rate < 60 mL/min/1.73 m2, and Fibrosis-4 > 3.25 were associated with higher risks of Grades 2-4 abnormalities. Patients with any of these had an odds of 4.53 times than that of those without in developing Grades 2-4 abnormalities (p < 0.01). CONCLUSIONS: Real-world data from Taiwan confirmed that simplified HCV treatment for eligible patients with pan-genotypic regimens is effective and well tolerated. The TACR algorithm, developed based on this study's results, can further identify patients who can be safely managed by non-specialist care.

Gilbert's syndrome leads to elevated bilirubin after initiation of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis.

Nine people with cystic fibrosis (pwCF) were found to have isolated elevations in serum total bilirubin after starting elexacaftor/tezacaftor/ivacaftor (ETI) that were associated with Gilbert's Syndrome. In longitudinal examination, total bilirubin levels increased substantially after initiation of ETI without elevations in liver transaminases in those with this syndrome. Because elevated bilirubin levels in Gilbert's Syndrome are benign, ETI was able to be continued in these individuals. Genetic testing for this relatively common syndrome should be strongly considered for pwCF experiencing isolated hyperbilirubinemia after starting ETI, since appropriate diagnosis may help pwCF avoid unnecessary interruption in this therapy with significant health benefits in CF.