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The editorial titled "Reconsidering Persistent Somatic Symptoms: A Transdiagnostic and Transsymptomatic Approach" explores the complexity of persistent somatic symptoms, emphasizing the need for a biopsychosocial model to understand and address these symptoms effectively. The authors highlight the commonalities and differences in symptom perception across various conditions, advocating for a transdiagnostic and transsymptomatic approach to research and treatment. The editorial discusses ongoing research projects, such as SOMACROSS, aimed at identifying risk factors and mechanisms for symptom persistence in different medical conditions. The ultimate goal is to develop evidence-based interventions for patients suffering from persistent somatic symptoms. [Extracted from the article]

Background and Aim: Primary biliary cholangitis (PBC) is an autoimmune‐mediated cholestatic liver disease that can progress to biliary cirrhosis and liver‐related death. The associations between baseline myostatin levels and clinical outcomes in PBC patients are unknown. We aimed to clarify the influence of myostatin levels on the clinical outcomes of PBC patients. Methods: A total of 119 PBC patients were analyzed in this study. Myostatin levels were measured in stored sera before ursodeoxycholic acid treatment, and their associations with the clinical features and prognosis of PBC patients were analyzed. We analyzed the correlation between serum myostatin and chemokines/cytokines. Results: Serum myostatin was significantly lower in PBC patients (2343 pg/mL) than in healthy controls (4059 pg/mL, P < 0.001). The prevalence of patients with low myostatin levels increased according to the severity of histological fibrosis. The serum myostatin concentration was negatively correlated with the IL‐6 and leucine‐rich α2 glycoprotein levels, but the chemokine concentration was not correlated with the myostatin concentration. Low myostatin in PBC patients was associated with shorter survival without liver‐related complications (hazard ratio [HR], 3.598; 95% confidence interval [CI], 1.27–10.1; P = 0.015) and shorter transplant‐free survival (HR, 3.129; 95% CI, 1.02–9.56; P = 0.045) independent of pretreatment GLOBE score. Patients with both high pretreatment GLOBE scores and low myostatin levels had poor prognoses (log–rank test: P < 0.001). Conclusions: A low serum myostatin concentration at diagnosis was associated with poor clinical outcomes. Assessment of circulating myostatin levels may improve the prediction of outcomes in patients with PBC. [ABSTRACT FROM AUTHOR]

Selecting truly relevant variables contributing to the response is a fundamental problem in many scientific fields. One of major challenges in variable selection is to effectively control the false discovery rate (FDR). Most existing variable selection procedures in survival analysis neglect the FDR control. In this article, we fill such a gap and propose a new and flexible variable selection method with guaranteed FDR control for accelerated failure time models. The proposed method combines the strengths of deep knockoffs and the weighted M-estimation procedure and enjoys the FDR control for arbitrarily high dimension with finite samples. More importantly, our method does not require prior knowledge about the joint distribution of covariates. Extensive simulation studies confirm the generality, effectiveness, and power of the proposed method. Finally, the proposed method is used to analyze a primary biliary cirrhosis data to demonstrate its practical utility. [ABSTRACT FROM AUTHOR]

Background: The long-term impacts of COVID-19 on human health are a major concern, yet comprehensive evaluations of its effects on various health conditions are lacking. Methods: This study aims to evaluate the role of various diseases in relation to COVID-19 by analyzing genetic data from a large-scale population over 2,000,000 individuals. A bidirectional two-sample Mendelian randomization approach was used, with exposures including COVID-19 susceptibility, hospitalization, and severity, and outcomes encompassing 86 different diseases or traits. A reverse Mendelian randomization analysis was performed to assess the impact of these diseases on COVID-19. Results: Our analysis identified causal relationships between COVID-19 susceptibility and several conditions, including breast cancer (OR = 1.0073, 95% CI = 1.0032–1.0114, p = 5 × 10 − 4), ER + breast cancer (OR = 0.5252, 95% CI = 0.3589–0.7685, p = 9 × 10 − 4), and heart failure (OR = 1.0026, 95% CI = 1.001–1.0042, p = 0.002). COVID-19 hospitalization was causally linked to heart failure (OR = 1.0017, 95% CI = 1.0006–1.0028, p = 0.002) and Alzheimer's disease (OR = 1.5092, 95% CI = 1.1942–1.9072, p = 0.0006). COVID-19 severity had causal effects on primary biliary cirrhosis (OR = 2.6333, 95% CI = 1.8274–3.7948, p = 2.059 × 10 − 7), celiac disease (OR = 0.0708, 95% CI = 0.0538–0.0932, p = 9.438 × 10–80), and Alzheimer's disease (OR = 1.5092, 95% CI = 1.1942–1.9072, p = 0.0006). Reverse MR analysis indicated that rheumatoid arthritis, diabetic nephropathy, multiple sclerosis, and total testosterone (female) influence COVID-19 outcomes. We assessed heterogeneity and horizontal pleiotropy to ensure result reliability and employed the Steiger directionality test to confirm the direction of causality. Conclusions: This study provides a comprehensive analysis of the causal relationships between COVID-19 and diverse health conditions. Our findings highlight the long-term impacts of COVID-19 on human health, emphasizing the need for continuous monitoring and targeted interventions for affected individuals. Future research should explore these relationships to develop comprehensive healthcare strategies. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by a range of symptoms, including sleep disturbances. The present study aimed to investigate the prevalence of sleep disorders and the associations between sleep disorders and clinical outcomes in PBC. We enrolled 177 patients with PBC and 165 healthy controls (age- and sex-matched). Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Demographic and clinical data were collected from comprehensive clinical records to investigate whether sleep disorder was correlated with disease severity, therapeutic response and liver cirrhosis. The prevalence of sleep disorders in patients with PBC (50.8 ​%) was significantly higher than healthy controls (18.2 ​%). Patients with sleep disorders presented with higher levels of laboratory parameters including globulin (GLO), aspartate aminotransferase (AST), alkaline phosphatase (ALP), glutamyl transpeptidase (GGT), total bilirubin (TBIL), direct bilirubin (DBIL) and immunoglobulin M (IgM), as well as higher ratio of poor therapeutic response and liver cirrhosis (p ​< ​0.05). There was a positive correlation between global PSQI score and AST, ALP, GGT, TBIL, DBIL and IgM in patients with PBC. Patients with poor therapeutic response and liver cirrhosis in PBC had a higher proportion of sleep disorders and more chaotic sleep patterns, whereas a stronger correlation between sleep quality and laboratory parameters was found in patients with liver cirrhosis. Sleep disorders were prevalent and manifested as adverse effects in PBC. Assessment of sleep quality and intervention were essential to the overall clinical management of patients with PBC. [ABSTRACT FROM AUTHOR]

Modern data are often collected in a matrix form. In this paper, we consider modelling the varying coefficient regression with matrix valued covariate X and scalar index variable U. The proposed model simultaneously makes principal component analysis for both the row and column dimensions of the matrix objects, maintaining the matrix structure while achieving substantial dimension reduction. We develop an iterative estimation method for the involved principal parameters and nonparametric functions. Under regularity conditions, the asymptotic distributions of the estimators are derived. In addition, by incorporating the estimation with the adaptive group Lasso and the group SCAD penalties, variables of X in entire rows or columns are selected. The proximal gradient algorithm is further utilised to solve the regularised optimisation problems. The asymptotic properties of the penalised estimators are also studied. Our model and estimation methods are demonstrated by simulated experiments. Real applications to the primary biliary cirrhosis (PBC) data reveal that the effects of the blood measurements to the survival time vary with levels of age. [ABSTRACT FROM AUTHOR]

Biliary complications are a major cause of morbidity and mortality in liver transplantation. Up to 25% of patients that develop biliary complications require additional surgical procedures, re-transplantation or die in the absence of a suitable regraft. Here, we investigate the role of the primary cilium, a highly specialised sensory organelle, in biliary injury leading to post-transplant biliary complications. Human biopsies were used to study the structure and function of primary cilia in liver transplant recipients that develop biliary complications (n = 7) in comparison with recipients without biliary complications (n = 12). To study the biological effects of the primary cilia during transplantation, we generated murine models that recapitulate liver procurement and cold storage, and assessed the elimination of the primary cilia in biliary epithelial cells in the K19CreER T Kif3a fl /fl mouse model. To explore the molecular mechanisms responsible for the observed phenotypes we used in vitro models of ischemia, cellular senescence and primary cilia ablation. Finally, we used pharmacological and genetic approaches to target cellular senescence and the primary cilia, both in mouse models and discarded human donor livers. Prolonged ischemic periods before transplantation result in ciliary shortening and cellular senescence, an irreversible cell cycle arrest that blocks regeneration. Our results indicate that primary cilia damage results in biliary injury and a loss of regenerative potential. Senescence negatively impacts primary cilia structure and triggers a negative feedback loop that further impairs regeneration. Finally, we explore how targeted interventions for cellular senescence and/or the stabilisation of the primary cilia improve biliary regeneration following ischemic injury. Primary cilia play an essential role in biliary regeneration and we demonstrate that senolytics and cilia-stabilising treatments provide a potential therapeutic opportunity to reduce the rate of biliary complications and improve clinical outcomes in liver transplantation. Up to 25% of liver transplants result in biliary complications, leading to additional surgery, retransplants, or death. We found that the incidence of biliary complications is increased by damage to the primary cilium, an antenna that protrudes from the cell and is key to regeneration. Here, we show that treatments that preserve the primary cilia during the transplant process provide a potential solution to reduce the rates of biliary complications. [Display omitted] • Liver pre-transplantation ischemic conditions damage the primary cilia (PC) of biliary epithelial cells (BEC). • Elimination of PC induces cellular senescence in BEC. • Senescent BEC cannot proliferate, leading to persistent biliary injury. • Targeted PC interventions prevent biliary injury and promote regeneration. [ABSTRACT FROM AUTHOR]

AbstractThe restricted mean survival time (RMST) emerges as a crucial summary metric in survival analysis. In some cases, certain covariates may have a varying impact on RMST at one specific change-point. For instance, consider studies focusing on women’s health, where a notable shift in a patient’s lifespan might occur when the age at menopause surpasses a particular cutoff value. To tackle this complex phenomenon, we consider a regression analysis of RMST with change-point in the covariate effects. This involves building a generalized linear model that directly captures the relationship between RMST and associated covariates that may have a change-point. Using the smoothed estimating equation with pseudo-observations, we obtain parameter estimators and establish the large sample properties. Finally, we assess the finite sample performance of the proposed method through simulation studies and apply it to real data examples from primary biliary cirrhosis and rectal cancer studies. [ABSTRACT FROM AUTHOR]

Background: Although numerous studies had revealed associations between autoimmune diseases (AIDs) and thyroid cancer (TC), the potential causal associations between the two remain poorly defined. Methods: Using five approaches, two-sample Mendelian randomization (MR) analyses were carried out to determine the causal effects of 12 major AIDs on risk of TC. The sensitivity analyses were conducted to verify the reliability of the analysis. The reverse MR analysis was performed to evaluate the possibility of reverse causation. Results: The results showed a significant causal association of systemic lupus erythematosus (SLE) and primary biliary cirrhosis (PBC) on the risk of TC. Genetically predicted PBC elevated the risk of TC (OR = 1.46, 95% CI = 1.06- 2.02, p = 0.021). The risk of TC was also increased by genetically predicted SLE (OR = 6.52, 95% CI = 1.38-30.84, p = 0.018) with heterogeneity. After outlier-corrected analyses, the results still suggested that genetically predicted SLE increased the risk of TC (p = 0.019). No evidence of a causal relationship between the remaining 10 AIDs and TC was observed. No reverse causal effects of TC on AIDs were found in reverse MR analysis. Conclusion: These findings support a significant causal association of SLE/PBC on the increased risk of TC, indicating that patients with SLE/PBC should be under a close monitoring of TC. [ABSTRACT FROM AUTHOR]

Background: Extrahepatic manifestations in patients with primary biliary cholangitis (PBC) are frequently observed recently. We aimed in this study to explore the clinicopathological characteristics and prognosis of glomerulonephritis in patients with PBC. Methods: Consecutive PBC patients admitted to Peking Union Medical College Hospital from January 2002 to May 2019 were retrospectively enrolled. PBC patients with other autoimmune diseases which may have nephritis were excluded. Structured interview, systemic rheumatologic examination, and laboratory tests were conducted for each patient. Literature about patients with PBC and glomerulonephritis was reviewed and summarized. Results: Among the 330 PBC patients enrolled, glomerulonephritis were identified in 10 patients (3.0%). Eight (80.0%) were females and 2 (20.0%) were males. The mean age was 58.4 ± 9.5 years old. Membranous nephropathy (MN) was revealed in 4 patients, IgA nephropathy (IgA N) in 2 patients, minimal change disease (MCD) in 2 patients, mesangial proliferative glomerulonephritis in 1 patient, and renal amyloidosis in 1 patient. Compared to the literature reviewed, 10 cases of MN, 1 case of MCD, 1 case of IgA N, and 1 case of acute poststreptococcal glomerulonephritis (APSGN) were observed. Conclusions: Glomerulonephritis may not be a well-recognized feature of PBC and is not a rare complication and deserved to be routinely screened in clinical practice. As MN is the most common form of glomerulonephritis in PBC patients and PBC can be asymptomatic at an early stage, patients presented with MN should be screened for PBC, so to avoid cirrhosis. Key Points • Patients with primary biliary cholangitis (PBC) can be complicated with glomerulonephritis, and membranous nephropathy (MN) is the most common form. [ABSTRACT FROM AUTHOR]

Biliary atresia (BA) is a progressive fibroinflammatory disease affecting both the extrahepatic and intrahepatic bile ducts, potentially leading to chronic cholestasis and biliary cirrhosis. Despite its prevalence, the exact mechanisms behind BA development remain incompletely understood. Recent research suggests that the gut microbiota and its metabolites may play significant roles in BA development. This paper offers a comprehensive review of the changing characteristics of gut microbiota and their metabolites at different stages of BA in children. It discusses their influence on the host's inflammatory response, immune system, and bile acid metabolism. The review also explores the potential of gut microbiota and metabolites as a therapeutic target for BA, with interventions like butyrate and gut microbiota preparations showing promise in alleviating BA symptoms. While progress has been made, further research is necessary to untangle the complex interactions between gut microbiota and BA, paving the way for more effective prevention and treatment strategies for this challenging condition. [ABSTRACT FROM AUTHOR]

This article proposes a Bayesian approach for jointly estimating marginal conditional quantiles of multi-response longitudinal data with multivariate mixed effects model. The multivariate asymmetric Laplace distribution is employed to construct the working likelihood of the considered model. Penalization priors on regression parameters are incorporated into the working likelihood to conduct Bayesian high-dimensional inference. Markov chain Monte Carlo algorithm is used to obtain the fully conditional posterior distributions of all parameters and latent variables. Monte Carlo simulations are conducted to evaluate the sample performance of the proposed joint quantile regression approach. Finally, we analyze a longitudinal medical dataset of the primary biliary cirrhosis sequential cohort study to illustrate the real application of the proposed modeling method. [ABSTRACT FROM AUTHOR]

In this series of articles with comments and illustrations on the World Federation for Medicine and Biology (WFUMB) guidelines on contrast-enhanced ultrasound (CEUS) the topics of very rare focal liver lesions (FLL) are discussed. Improving the detection and characterization of the most common FLL are the main topics of these guidelines. The focus of this review is on the many manifestations of cystic fibrosis-related liver disease (CFLD). These include focal biliary fibrosis, liver cirrhosis, vascular manifestations with nodular regenerative hyperplasia and portal hypertension with or without cirrhosis. This article describes the diverse changes of liver involvement in cystic fibrosis and their appearance on ultrasound, duplex sonography, and contrast enhanced ultrasonography. This knowledge and the imaging should help to recognize liver manifestations in time and enable a correct interpretation of ultrasound images in CF in the corresponding clinical situation. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is a frequent complication of cirrhosis, leading to preventable hospitalizations and increased mortality. Despite the availability of validated neuro-psychometric tests to diagnose HE, only 10% of clinicians regularly screen for HE due to lack of time, equipment, and trained personnel. We studied the association between patient-reported cognitive function and the National Institutes of Health Toolbox Cognition Battery (a validated measure of HE) in patients with cirrhosis. A single-center prospective study of adult patients undergoing liver transplantation evaluation was performed from 10/2020 to 12/2021. Cognition was assessed using the National Institutes of Health Toolbox Cognition Battery and a brief Patient-Reported Outcomes Measurement Information System (PROMIS) survey. Twenty-three liver transplantation candidates were enrolled; the mean age was 56.4 (±9.7) years, 39% were female and the most common etiologies of cirrhosis were primary biliary cirrhosis/primary sclerosing cholangitis/overlap syndrome (30%), hepatitis C (22%) and alcohol-associated liver disease (22%). The mean MELD-Na was 14.9 (±6.4). The mean PROMIS Cognitive Function T-score (PROMIS CF) was 49.2 (±9.6). The mean T-scores for the List Sort Working Memory test, Flanker Inhibitory Control and Attention test, and Pattern Comparison Processing Speed test were 46.4 (±9.9), 37.8 (±6.2), and 50.22 (±16.4), respectively. PROMIS CF correlated with the List Sort Working Memory test (r = 0.45, P =.03). The mean hospitalization rate was 1.6 days admitted per month. On adjusted multivariate analysis, PROMIS CF predicted total hospitalization days (P <.001), hospital admissions (P =.01), and hospitalization rate (P <.001). A brief survey can screen for HE and predict hospitalizations in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Hemorrhage is the most common major complication after liver biopsy. Hemothorax is one type of bleeding and is very rare and dangerous. Several cases of hemothorax subsequent to liver biopsy have been documented, primarily attributed to injury of the intercostal artery or inferior phrenic artery and a few resulting from lung tissue damage; however, no previous case report of hemothorax caused by injury of musculophrenic artery after liver biopsy has been reported. Case presentation: A 45-year-old native Chinese woman diagnosed with primary biliary cirrhosis due to long-term redness in urination and abnormal blood test indicators was admitted to our hospital for an ultrasound-guided liver biopsy to clarify pathological characteristics and disease staging. A total of 2 hours after surgery, the patient complained of discomfort in the right chest and abdomen. Ultrasound revealed an effusion in the right thorax and hemothorax was strongly suspected. The patient was immediately referred to the interventional department for digital subtraction angiography. Super-selective angiography of the right internal thoracic artery was performed which revealed significant contrast medium extravasation from the right musculophrenic artery, the terminal branch of the internal thoracic artery. Embolization was performed successfully. The vital signs of the patient were stabilized after the transarterial embolization and supportive treatment. Conclusion: This case draws attention to the musculophrenic artery as a potential source of hemorrhage after percutaneous liver biopsy. [ABSTRACT FROM AUTHOR]

The effects of the obliteration of portal venules (OPV) in cirrhotic portal hypertension are poorly understood. To investigate its contribution to portal hypertension in biliary cirrhosis and its underlying mechanism, we evaluated OPV using two‐dimensional (2D) histopathology in liver explants from patients with biliary atresia (BA, n = 63), primary biliary cholangitis (PBC, n = 18), and hepatitis B‐related cirrhosis (Hep‐B‐cirrhosis, n = 35). Then, three‐dimensional (3D) OPV was measured by X‐ray phase‐contrast CT in two parallel models in rats following bile duct ligation (BDL) or carbon tetrachloride (CCl4) administration, representing biliary cirrhosis and post‐necrotic cirrhosis, respectively. The portal pressure was also measured in the two models. Finally, the effects of proliferative bile ducts on OPV were investigated. We found that OPV was significantly more frequent in patients with biliary cirrhosis, including BA (78.57 ± 16.45%) and PBC (60.00 ± 17.15%), than that in Hep‐B‐cirrhotic patients (29.43 ± 14.94%, p < 0.001). OPV occurred earlier, evidenced by the paired liver biopsy at a Kasai procedure (KP), and was irreversible even after a successful KP in the patients with BA. OPV was also significantly more frequent in the BDL models than in the CCl4 models, as shown by 2D and 3D quantitative analysis. Portal pressure was significantly higher in the BDL model than that in the CCl4 model. With the proliferation of bile ducts, portal venules were compressed and irreversibly occluded, contributing to the earlier and higher portal pressure in biliary cirrhosis. OPV, as a pre‐sinusoidal component, plays a key role in the pathogenesis of portal hypertension in biliary cirrhosis. The proliferated bile ducts and ductules gradually take up the 'territory' originally attributed to portal venules and compress the portal venules, which may lead to OPV in biliary cirrhosis. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a systemic immune-mediated disease that, in addition to the articular involvement, can have extra-articular manifestations. Even though liver damage in RA is not very common, associated autoimmune liver diseases (AILDs) may occur. The most common AILD associated with RA is primary biliary cirrhosis (PBC), followed by autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). There are common underlying mechanisms that play a role in the emergence of autoimmunity and inflammation in both rheumatic and autoimmune liver diseases. Genetic studies have revealed the existence of several common disease-associated genes shared between RA and AILDs, and infectious triggers, particularly those associated with recurrent or complicated urinary tract infections, are also speculated to be potential triggers for these conditions. Moreover, these diseases share common serologic patterns characterized by the presence of specific autoantibodies and hyper-gammaglobulinemia. In this study, we focus on reviewing the association between RA and AILDs regarding the prevalence and possible etiopathogenic link. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to examine the proportion of CD161 on CD56+ natural killer (NK) cells in peripheral blood of primary Sjögren's syndrome (pSS) and investigate its clinical relevance of pSS. Methods: The proportion of CD56+ NK cells and CD161 on CD56+ NK cells was detected by flow cytometry in 31 pSS patients and 29 healthy controls (HCs). The correlations between the proportion of CD161+CD56+ NK cells and clinical features and disease activity of pSS were further analyzed. Meanwhile, we drew the receiver operating characteristic curve to evaluate the diagnostic value of CD161+CD56+ NK cells in pSS. In addition, we evaluated the differences in the effects of CD161+ cells and CD161− cells in peripheral blood on the function of CD56+ NK cells in 5 pSS patients. Results: The proportion of CD56+ NK cells and CD161+CD56+ NK cells decreased markedly in pSS patients compared to HCs. The correlation analysis showed that the proportion of CD161+CD56+ NK cells negatively correlated with white blood cells, Immunoglobulin A (IgA), IgM, IgG, European League Against Rheumatism Sjogren's Syndrome Patient Reported Index and European League Against Rheumatism Sjogren's Syndrome Disease Activity Index, and positively correlated with complement C4. The proportion of CD161+CD56+ NK cells in pSS patients with decayed tooth, fatigue, arthralgia, skin involvement, primary biliary cirrhosis, interstitial lung disease, anti‐SSA/Ro60 positive, anti‐SSB positive and high IgG was lower than that in negative patients. Furthermore, compared with inactive patients, the proportion of CD161+CD56+ NK cells decreased obviously in active patients. The area under the curve was 0.7375 (p =.0016), the results indicated that CD161+CD56+ NK cells had certain diagnostic values for pSS. In addition, the proportion of CD86, HLA‐DR, Ki67, FasL, TNF‐α, and IFN‐γ on CD161+CD56+ NK cells was lower than that on CD161−CD56+ NK cells in the peripheral blood of pSS patients. Conclusion: This study suggested that the proportion of CD56+ NK cells and CD161+CD56+ NK cells decreased significantly in pSS patients, and the proportion of CD161+CD56+ NK cells negatively associated with the clinical features and disease activity of pSS patients. CD161 expression inhibited the function of CD56+ NK cells in peripheral blood of pSS patients. The CD161+CD56+ NK cells may present as a potential target for therapy and a biomarker of disease activity in pSS. [ABSTRACT FROM AUTHOR]

Background: In liver transplant patients with hypoplastic portal vein (PV), when the narrowed segment is extended too deep into the dorsal side of the pancreas, it is difficult and dangerous to reconstruct the interposition graft from the upper part of the pancreas. Herein, we present a case of PV reconstruction with the autologous mesosystemic shunt vessel from the caudal side of the pancreas in a situation where the narrowed PV was deep, and we discuss the technical details. Case presentation: A 25-year-old woman presented with cholestatic liver cirrhosis due to biliary atresia after Kasai procedure. Since her jaundice progressed, she was referred to our hospital for liver transplantation. Laboratory tests showed that her total bilirubin was elevated to 7.6 mg/dL. The Model for End-Stage Liver Disease score was 18, and the Child–Pugh score was 9 (Grade B). She underwent living donor liver transplantation (LDLT) using a right hemi-liver graft procured from her 54-year-old mother. The conventional approach from the cephalad side to the superior mesenteric vein (SMV) and splenic vein (SpV) confluence behind the pancreas was extremely difficult in this case because the confluence of SMV and SpV was close to the lower edge of the pancreas. Therefore, we decided to perform PV reconstruction from the caudal side. The main trunk of PV was documented as narrow (5 mm in diameter), for which retro-pancreatic pull-through PV reconstruction was successfully performed using her own mesosystemic shunt vessel. A contrast computed tomography (CT) scan was performed on postoperative day 5 because of an elevation of D-dimer and found a partial thrombus in the left pulmonary artery, as well as in the PV and left renal vein. Thereafter, thrombolytic therapy with low-molecular-weight heparin was started immediately and switched to a direct oral anticoagulant. The follow-up CT taken 3 months after liver transplantation revealed a patent PV without thrombus; therefore, anticoagulant therapy was discontinued. Currently, the patient has been well and active with a patent PV without anticoagulant therapy for 3 years after LDLT. Conclusions: Retro-pancreatic pull-through reconstruction of the hypoplastic PV is a feasible and effective method when conventional reconstruction is not indicated. [ABSTRACT FROM AUTHOR]

Cholestasis describes bile secretion or flow impairment, which is clinically manifested with fatigue, pruritus, and jaundice. Neutrophils play a crucial role in many diseases such as cholestasis liver diseases through mediating several oxidative and inflammatory pathways. Data have been collected from clinical, in vitro, and in vivo studies published between 2000 and December 2021 in English and obtained from the PubMed, Google Scholar, Scopus, and Cochrane libraries. Although nitric oxide plays an important role in the pathogenesis of cholestatic liver diseases, excessive levels of NO in serum and affected tissues, mainly synthesized by the inducible nitric oxide synthase (iNOS) enzyme, can exacerbate inflammation. NO induces the inflammatory and oxidative processes, which finally leads to cell damage. We found that natural products such as baicalin, curcumin, resveratrol, and lycopene, as well as chemical likes ursodeoxycholic acid, dexamethasone, rosuvastatin, melatonin, and sildenafil, are able to markedly attenuate the NO production and iNOS expression, mainly through inducing the nuclear factor κB (NF-κB), Janus kinase and signal transducer and activator of transcription (JAK/STAT), and toll like receptor-4 (TLR4) signaling pathways. This study summarizes the latest scientific data about the bile acid signaling pathway, the neutrophil chemotaxis recruitment process during cholestasis, and the role of NO in cholestasis liver diseases. Literature review directed us to propose that suppression of NO and its related pathways could be a therapeutic option for preventing or treating cholestatic liver diseases. [ABSTRACT FROM AUTHOR]

Background: People all around the world are affected by primary liver cancers like hepatocellular carcinoma (HCC), which is usually associated with cirrhosis. Early HCC detection is crucial for better prognosis, but effective biomarkers are still needed. Hepcidin, a hormone-regulating iron homeostasis, has been implicated in liver diseases. In this study, blood hepcidin levels were evaluated in cirrhotic individuals as a possible biomarker for HCC. Methods: There were three groups involved in this case-control study: cirrhotic patients with no HCC (group I), cirrhotic patients diagnosed with HCC (group II), and healthy controls (group III). Clinical and laboratory data, such as those from tests indicating the liver function, hepcidin levels, and imaging, were all analyzed using a number of statistical tests. Results: When compared to those with cirrhosis, serum hepcidin levels were significantly lower in HCC patients, but there was no significant difference statistically between the two studies involved: cirrhotic groups and the controls. Serum alpha-fetoprotein (AFP) was also significantly greater in HCC patients. Conclusions: The start and progression of liver diseases, such as HCC in cirrhotic people, appear to be influenced by hepcidin. It can be utilized as a potential HCC biomarker when cirrhotic liver is present, despite the fact that it cannot be used to diagnose cirrhosis by itself. [ABSTRACT FROM AUTHOR]

Background: An association between primary biliary cholangitis (PBC) and connective tissue diseases (CTDs) [rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), systemic sclerosis (SSc)] has been found in observational studies. However, the direction causality is unclear. The aim of this study was to assess the causality between PBC and CTDs and to promote early screening, pre-emptive therapy, and accurate stratification. Methods: A two-sample Mendelian randomization (MR) analysis was performed to assess the causal relationship between PBC [Genome-Wide Association Study (GWAS) meta-analysis, 8021 cases/16498 controls], and SLE (GWAS meta-analysis, 8021 cases/16489 controls), RA(FinnGen, 6236 cases/14727 controls), SS(FinnGen, 2495 cases/365533 controls), SSc (FinnGen, 302 cases/213145 controls). Inverse variance weighting (IVW) was used as the primary analysis method, supplemented by four sensitivity analyses to assess the robustness of the results. Results: The IVW revealed that genetically predicted PBC increased the risk of SLE [odd's ratio (OR) = 1.43, 95% confidence interval (CI) 1.30–1.58, P < 0.001]), RA (OR = 1.09, 95%CI1.04–1.14, P<0.001), and SS (OR = 1.18, 95%CI1.12–1.24, P<0.001), but not that of SSc. In addition, no association was observed between CTDs as an exposure and PBC. Sensitivity analyses did not reveal horizontal pleiotropy. Conclusions: Our study provided new genetic evidence for a causal relationship between PBC and CTDs. PBC increased the risk of SLE, RA, and SS. Our findings highlighted the importance of active screening and intervention for CTDs in patients with PBC. [ABSTRACT FROM AUTHOR]

Background: Molecular mimicry is hypothesized to be a mechanism by which autoimmune diseases are triggered. It refers to sequence or structural homology between foreign antigens and self-antigens, which can activate cross-reactive lymphocytes that attack host tissues. Elucidating the role of molecular mimicry in human autoimmunity could have important clinical implications. Objective: To review evidence for the role of molecular mimicry in major autoimmune diseases and discuss potential clinical implications. Methods: Comprehensive literature review of clinical trials, observational studies, animal models, and immunology studies on molecular mimicry in multiple sclerosis, type 1 diabetes, rheumatoid arthritis, lupus, Guillain-Barre syndrome, autoimmune myocarditis, and primary biliary cirrhosis published from 2000-2023. Results: Substantial indirect evidence supports molecular mimicry as a contributor to loss of self-tolerance in several autoimmune conditions. Proposed microbial triggers include Epstein-Barr virus, coxsackievirus, Campylobacter jejuni, and bacterial commensals. Key mechanisms involve cross-reactive T cells and autoantibodies induced by epitope homology between microbial and self-antigens. Perpetuation of autoimmunity involves epitope spreading, inflammatory mediators, and genetic factors. Conclusions: Molecular mimicry plausibly explains initial stages of autoimmune pathogenesis induced by infection or microbiota disturbances. Understanding mimicry antigens and pathways could enable improved prediction, monitoring, and antigen-specific immunotherapy for autoimmune disorders. However, definitive proof of causation in humans remains limited. Further research should focus on establishing clinical evidence and utility. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many malignancies in recent years. However, immune--related adverse events (irAE) are a frequent concern in clinical practice. The safety profile of ICI for the treatment ofmalignancies in patients diagnosedwith autoimmune and cholestatic liver disease (AILD) remains unclear. Due to this uncertainty, these patients were excluded from ICI clinical trials and ICI are withheld from this patient group. In this retrospective multicenter study, we assessed the safety of ICI in patients with AILD. Methods: We contacted tertiary referral hospitals for the identification of AILD patients under ICI treatment in Europe via the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Fourteen centers contributed data on AILD patients with malignancies being treated with ICI, another three centers did not treat these patients with ICI due to fear of irAEs. Results: In this study, 22 AILD patients under ICI treatment could be identified. Among these patients, 12 had primary biliary cholangitis (PBC), five had primary sclerosing cholangitis (PSC), four had autoimmune hepatitis (AIH), and one patient had an AIH-PSC variant syndrome. Eleven patients had hepatobiliary cancers and the other 11 patients presented with non-hepatic tumors. The applied ICIs were atezolizumab (n=7), durvalumab (n=5), pembrolizumab (n=4), nivolumab (n=4), spartalizumab (n=1), and in one case combined immunotherapy with nivolumab plus ipilimumab. Among eight patients who presented with grade 1 or 2 irAEs, three demonstrated liver irAEs. Cases with grades ≥ 3 irAEs were not reported. No significant changes in liver tests were observed during the first year after the start of ICI. Discussion: This European multicenter study demonstrates that PD-1/PD-L1 inhibitors appear to be safe in patients with AILD. Further studies on the safety of more potent dual immune checkpoint therapy are needed. We conclude that immunotherapy should not categorically be withheld from patients with AILD. [ABSTRACT FROM AUTHOR]

Introduction: The utilization of large-scale claims databases has greatly improved the management, accessibility, and integration of extensive medical data. However, its potential for systematically identifying comorbidities in the context of skin diseases remains unexplored. Methods: This study aims to assess the capability of a comprehensive claims database in identifying comorbidities linked to 14 specific skin and skinrelated conditions and examining temporal changes in their association patterns. This study employed a retrospective case-control cohort design utilizing 13 million skin/skin-related patients and 2 million randomly sampled controls from Optum's de-identified Clinformatics® Data Mart Database spanning the period from 2001 to 2018. A broad spectrum of comorbidities encompassing cancer, diabetes, respiratory, mental, immunity, gastrointestinal, and cardiovascular conditions were examined for each of the 14 skin and skin-related disorders in the study. Results: Using the established type-2 diabetes (T2D) and psoriasis comorbidity as example, we demonstrated the association is significant (P values< 1x10-15) and stable across years (OR=1.15-1.31). Analysis of the 2014- 2018 data reveals that celiac disease, Crohn's disease, and ulcerative colitis exhibit the strongest associations with the 14 skin/skin-related conditions. Systemic lupus erythematosus (SLE), leprosy, and hidradenitis suppurativa show the strongest associations with 30 different comorbidities. Particularly notable associations include Crohn's disease with leprosy (odds ratio [OR] =6.60, 95% confidence interval [CI]: 3.09-14.08), primary biliary cirrhosis with SLE (OR=6.07, 95% CI: 4.93-7.46), and celiac disease with SLE (OR=6.06, 95% CI: 5.49-6.69). In addition, changes in associations were For instance, the association between atopic dermatitis and lung cancer demonstrates a marked decrease over the past decade, with the odds ratio decreasing from 1.75 (95% CI: 1.47-2.07) to 1.02 (95% CI: 0.97-1.07). The identification of skin-associated comorbidities contributes to individualized healthcare and improved clinical management, while also enhancing our understanding of shared pathophysiology. Moreover, tracking these associations over time aids in evaluating the progression of clinical diagnosis and treatment. Discussion: The findings highlight the potential of utilizing comprehensive claims databases in advancing research and improving patient care in dermatology. [ABSTRACT FROM AUTHOR]

Background: Primary biliary cirrhosis (PBC) and psoriasis are frequently observed to co-occur in clinical settings. However, the causal associations and underlying mechanisms between PBC and psoriasis remain poorly defined. Methods: In this study, we conducted bidirectional MR analysis to explore the causal relationship between PBC and psoriasis using four MR methods: inversevariance weighted, MR-Egger regression, weighted median, and weighted mode. Sensitivity analyses were carried out, employing different models and testing methods for comparison to assess the influence of heterogeneity and pleiotropy on our findings and to confirm the robustness of these results. Results: A causal relationship between the risk of PBC and psoriasis was identified, as confirmed by IVW analysis (OR: 1.081, 95%CI: 1.028~1.137, P<0.05). The other three MR methods also produced similar results. However, psoriasis did not have a causal effect on PBC risk (OR: 1.022, 95%CI: 0.935~1.118, P>0.05). The intercept of MR-Egger regression was 0.0013 (P>0.05), indicating that genetic pleiotropy did not influence the results. Additionally, the leave-oneout analysis demonstrated the robustness of our MR findings. Conclusion: This study reveals a causal relationship between PBC and psoriasis, with PBC increasing the risk of psoriasis, but not the reverse. This potential causal relationship offers a new perspective on the etiology of PBC. [ABSTRACT FROM AUTHOR]

Objective: Function loss, for whatever reason, of the graft used for liver transplantation requires re-transplantation. This study is an evaluation of all re-transplantations performed at our center. Material and Method: All liver re-transplantation patients whose surgeries had been performed at our clinic, whether at an early or late stage, were included in the study. Demographic information, details related to the surgery, and complications were evaluated retrospectively. Result: From 2018 to 2023, 236 liver transplantations were performed on 228 recipients in our institution. Of these patients, a total of 18 underwent re-transplantation, 10 of whom were from external centers and 8 of whom had had their first liver transplantation performed at our center. Of these patients, 12 were male and 6 were female, with a mean age of 6.7 years (±4.8) for pediatric patients and 49 years (±14.32) for adult patients. The mean weight for pediatric patients was 19.76 kg (±8.86), and for adult patients it was 70.48 kg (±11.83). The mean body mass index for pediatric patients was 17.41 kg/m² (±2.84), and for adult patients it was 22.33 kg/m² (±2.65). Six of these patients underwent early re-transplantation (7.6±5.4 days) and 12 underwent late re-transplantation (7.6±5.3 years). In terms of re-transplantation etiology, primary non-function was prominent for the early period, while secondary biliary cirrhosis, disease recurrence, and chronic rejection were detected for the late period. Seven recipients (39%) died during the perioperative period, and 1-year survival was calculated as 61% in this patient group. Conclusion: Re-transplantation has high mortality and morbidity rates. Although early re-transplantation seems to overcome high mortality rates, especially in primary non-function cases, organ shortage and the need for living donors are significant problems. [ABSTRACT FROM AUTHOR]

This research paper focuses on the development of advanced mathematical models for disease diagnosis and prediction, and the subsequent creation of automated systems based on these models. These systems leverage a range of mathematical models and incorporate cutting-edge information technology achievements to provide medical professionals with valuable decision-making support. By amalgamating mathematical rigor and technological innovation, this research endeavors to enhance the accuracy and efficiency of medical diagnoses, thereby improving patient care and healthcare outcomes. This study delves into the persistent need for contemporary information systems, where information plays a crucial role in decision-making. It aims to provide an objective approach to addressing pressing medical challenges, particularly in disease diagnosis and prediction, enhancing the effectiveness of these critical tasks. Automated medical information systems, built on advanced mathematical models, significantly empower physicians. Machine diagnostics, relying on deterministic logic, the phase interval method, and information-probabilistic logic, bolster diagnostic capabilities. Functional entropy enables individuals to handle vague information, aiding decision-making. Assessing imprecision and uncertainty computationally diminishes subjectivity, while employing fuzzy set theory enhances diagnostic modeling. Mathematical models assess diagnostic indicators, and linguistic variables quantify resemblance. The diagnostic model for primary biliary cirrhosis and active hepatitis utilizes a diagnostic table and gradient projection. This comprehensive study advances medical diagnostics through mathematical models and automated systems, addressing critical healthcare challenges. [ABSTRACT FROM AUTHOR]

Aims: To investigate the impact of endovascular (EV) treatment on liver cirrhosis in Chinese patients with Budd–Chiari syndrome (BCS). Methods: From September 2011 to March 2022, 97 patients from four hospitals in China who were diagnosed with primary BCS complicated with liver cirrhosis and received EV treatment were retrospectively enrolled in this study for clinical analysis. In addition, liver tissues for basic research were acquired from 25 patients between June 2022 and March 2023, including six with benign liver tumors, 11 with BCS before EV treatment, and eight with EV‐treated BCS. Liver cirrhosis was assessed by clinical outcomes, histological studies, and the expression of related genes at the mRNA and protein levels. Results: The patients with BCS had better liver function after EV treatment, evidenced by an increased albumin level and reduced total bilirubin, ALT, and AST. The imaging findings suggested an amelioration of liver cirrhosis and portal hypertension, including increased portal vein velocity (13.52 ± 8.89 cm/s vs. 17.51 ± 6.67 cm/s, p < 0.001) and decreased liver stiffness (30.37 ± 6.39 kPa vs. 23.70 ± 7.99 kPa, p < 0.001), portal vein diameter (14.97 ± 3.42 mm vs. 13.36 ± 2.89 mm, p < 0.001), and spleen volume (870.00 ± 355.61 cm3 vs. 771.36 ± 277.45 cm3, p < 0.001). Furthermore, histological studies revealed that EV treatment resulted in a restoration of liver architecture with reduced extracellular matrix deposition. Meanwhile, hepatic angiogenesis and inflammation, which have a close relationship with cirrhosis, were also inhibited. In addition, the state of hepatocytes switches from apoptosis to proliferation after EV treatment. Conclusions: BCS‐induced liver cirrhosis could be reversed by EV treatment from macroscopic to microscopic dimensions. Our study may provide further insights into understanding BCS and treating cirrhosis. [ABSTRACT FROM AUTHOR]

Quantile regression has emerged as a useful and effective tool in modeling survival data, especially for cases where noises demonstrate heterogeneity. Despite recent advancements, non‐smooth components involved in censored quantile regression estimators may often yield numerically unstable results, which, in turn, lead to potentially self‐contradicting conclusions. We propose an estimating equation‐based approach to obtain consistent estimators of the regression coefficients of interest via the induced smoothing technique to circumvent the difficulty. Our proposed estimator can be shown to be asymptotically equivalent to its original unsmoothed version, whose consistency and asymptotic normality can be readily established. Extensions to handle functional covariate data and recurrent event data are also discussed. To alleviate the heavy computational burden of bootstrap‐based variance estimation, we also propose an efficient resampling procedure that reduces the computational time considerably. Our numerical studies demonstrate that our proposed estimator provides substantially smoother model parameter estimates across different quantile levels and can achieve better statistical efficiency compared to a plain estimator under various finite‐sample settings. The proposed method is also illustrated via four survival datasets, including the HMO (health maintenance organizations) HIV (human immunodeficiency virus) data, the primary biliary cirrhosis (PBC) data, and so forth. [ABSTRACT FROM AUTHOR]

Disturbance in the production and excretion of bile acid causes cholestatic liver disease. Liver cirrhosis is a disease that occurs if cholestasis continues. This study evaluated the protective effect of gallic acid (GA) on liver damage caused by biliary cirrhosis. Rats were randomly divided into 4 groups, each with 8 subjects: 1) control, 2) BDL, 3) BDL + GA 20, and 4) BDL + GA 30. The rats were anesthetized 28 days after the BDL, followed by collecting their blood and excising their liver. Their serum was used to measure liver enzymes, and the liver was used for biochemical analysis, gene expression, and histopathological analysis. Serum levels of liver enzymes, total bilirubin, liver Malondialdehyde level (MDA), expression of inflammatory cytokines and caspase-3, necrosis of hepatocytes, bile duct proliferation, lymphocytic infiltration, and liver fibrosis showed an increase in the BDL group compared to the control group (p < 0.05). In addition, BDL decreased the activity of liver antioxidant enzymes and glutathione (GSH) levels compared to the control group (p < 0.05). The groups receiving GA indicated a decrease in liver enzymes, total bilirubin, MDA, the expression of inflammatory cytokines and caspase-3, and a reduction in liver tissue damage compared to the BDL group (p < 0.05). The level of GSH in the BDL + GA 20 group showed a significant increase compared to the BDL group (p < 0.05). Moreover, it was found that GA, with its anti-fibrotic and anti-inflammatory properties, reduces liver damage caused by biliary cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Two-dimensional shear wave elastography (2D-SWE) has been proposed for detecting liver fibrosis in biliary atresia. Objectives: To assess the performance of 2D-SWE for detecting advanced liver fibrosis and cirrhosis in patients with biliary atresia. Materials and Methods: Five electronic databases were searched to identify studies investigating the performance of 2D-SWE for diagnosing liver fibrosis in biliary atresia in children. We constructed the summary receiver operating characteristic (SROC) curves of 2D-SWE for detecting advanced liver fibrosis and cirrhosis, and then calculated the area under the SROC curves (AUROCs). Results: Six studies with 470 patients (ages 55 days to 6.6 years) were included. The median correlation coefficient of 2D-SWE with pathological liver fibrosis stages was 0.779 (range: 0.443‒0.813). The summary AUROCs for advanced liver fibrosis and cirrhosis were 0.929 and 0.883, respectively. The summary sensitivity and specificity of 2D-SWE for advanced liver fibrosis were 88% (95% confidence interval [CI]: 80‒94%) and 85% (95% CI: 77‒91%) with I values of 0% and 45.6%, respectively, and for cirrhosis were 80% (95% CI: 72‒87%) and 82% (95% CI: 77‒86%) with I values of 12.9% and 0%, respectively. The diagnostic odds ratio (DOR) of 2D-SWE for advanced liver fibrosis and cirrhosis were 40.3 (95% CI: 18.2‒89.4) and 18.9 (95% CI: 11.2‒31.7), respectively. For preoperative detection of cirrhosis, the pooled AUROC, sensitivity, specificity, and DOR based on the four 2D-SWE studies were 0.877, 79% (95% CI: 71‒86%), 82% (95% CI: 77‒86%), and 17.58 (95% CI: 10.35‒29.85), respectively. Conclusions: Results show that 2D-SWE has potential as a non-invasive tool for detecting advanced liver fibrosis and cirrhosis in patients with biliary atresia. [ABSTRACT FROM AUTHOR]

Background: ASC42 is a non-steroidal farnesoid X receptor agonist currently in clinical development for chronic liver diseases, such as nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) and primary biliary cirrhosis (PBC). Objective: The objective of this study was to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ASC42 in healthy subjects. Methods: We conducted the first-in-human study of ASC42 following single and multiple ascending doses (SAD/MAD) and food effect in healthy subjects. The SAD study included five cohorts receiving 5–200 mg ASC42 or placebo and one cohort that was given 15 mg ASC42 with a high-fat meal. The MAD study included three cohorts receiving 5–50 mg ASC42 or placebo once-daily (QD) for 14 days. Results: A total of 65 healthy subjects were enrolled and one subject in the MAD study (cohort 8, ASC42 50 mg) withdrew from the study due to an unrelated serious adverse event (SAE) of atrial fibrillation. Pruritus was observed at the highest doses (200 mg cohort in SAD and 50 mg cohort in MAD). Most AEs were mild or moderate. No life-threatening or fatal AEs occurred. ASC42 showed a proportional increase in exposure and elimination half-life following both single and multiple dosing. There was a 21% and 37% decrease in area under the curve (AUC) and maximum plasma concentration (Cmax) when ASC42 was coadministered with food. The steady state was reached on day 4 with a mild accumulation (1.02–1.74-fold). ASC42 showed dose-dependent increases in fibroblast growth factor 19 and decreases in 7α-hydroxy-4-cholesten-3-one. Cholesterol remained within normal limits during study. Conclusion: ASC42 was well tolerated with a pharmacokinetic profile suitable for QD dosing, and demonstrated dose-dependent targets engagement without altering plasma cholesterol in healthy subjects. Trial registration number: NCT04679129. [ABSTRACT FROM AUTHOR]

Bile duct injury (BDI) is an infrequent but serious complication of cholecystectomy, often with life-changing consequences. Liver transplantation (LT) may be required following severe BDI, however given the rarity, few large studies exist to guide management for complex BDI. A systematic review was performed to assess post-operative complications, 30-day mortality, retransplant rate and 1-year and 5-year survival following LT for BDI in Medline, EMBASE, Web of Science or Cochrane Clinical Trials Database. Seven articles met inclusion criteria, describing 179 patients that underwent LT for BDI. Secondary biliary cirrhosis (SBC) was the main indication for LT (82.2% of patients). Median model for end-stage liver disease (MELD) scores at time of LT ranged from 16 to 20.5. Median 30-day mortality was 20.0%. The 1-year and 5-year survival ranges were 55.0–84.3% and 30.0–83.3% respectively, and the overall retransplant rate was 11.5%. BDI is rarely indicated for LT, predominantly for SBC following multiple prior interventions. MELD scores poorly reflect underlying morbidity, and exception criteria for waitlisting may avoid prolonged LT waiting times. 30-day mortality was higher than for non-BDI indications, with comparable long term survival, suggesting that LT remains a viable but high risk salvage option for severe BDI. [ABSTRACT FROM AUTHOR]

Biliary atresia is an idiopathic, progressive fibroinflammatory cholangiopathy involving the extrahepatic biliary tree in infants. It is one of the most important causes of neonatal cholestasis. If left untreated; can progress to micronodular biliary cirrhosis and death can occur in very early years. Therefore, early diagnosis and timely administration of Kasai portoenterostomy are important for the long-term functioning of the native liver. Liver biopsy is the most reliable tool for the prelaparotomy diagnosis of biliary obstruction. The diagnostic histopathological features are mild to moderate portal edema with mixed inflammation, ductular reaction, and bile plugs. The ethiological spectrum of neonatal cholestasis is wide and there are more than 100 diseases identified. Because early diagnosis and treatment is crucial, distinguishing biliary atresia from other causes of neonatal cholestasis is very important. For this reason, the diseases included in the differential diagnosis should be examined correctly with a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

Introduction: For a large variety of liver pathologies, the plasma unconjugated (UB) and conjugated (CB) bilirubin concentrations appear to be coupled. For example, in alcoholic cirrhosis, UB and CB are roughly the same over a large range of total bilirubin, requiring an initial massive increase (about 40-fold) in plasma CB to reach the level of UB and then similar increases in UB and CB as the disease progresses. This coupling has been either unrecognized or ignored and this paper is the first attempt to try to explain it quantitatively in terms of known hepatic cell metabolic and membrane transport properties.Methods: A simplified pharmacokinetic model is developed and applied to a variety of hyperbilirubinemic pathologies. A central feature of the model is based on the recent observation that double knockout of the rat OATP1A and OATP1B hepatic transporters produces a roughly 400-fold increase in plasma CB, indicating that there is a normal rapid recycling of CB from the cell to the plasma with reuptake via OATP. We use the experimental rat Km of OATP CB transport to show that OATP uptake becomes saturated at relatively low plasma CB concentrations, decreasing uptake, and producing massive (up to 1000-fold) increases in CB in some pathologies. It is assumed that UB and CB are competing for the OATP transporter, producing the increased plasma UB that is observed in "pure" CB pathologies.Results: The model accurately describes the clinically observed UB and CB for pure UB (Gilbert's, hemolytic anemia) and CB (Dubin-Johnson, Rotor syndrome, biliary atresia) pathologies as well as in cirrhosis.Conclusion: This model is a preliminary, first attempt to quantitatively describe UB and CB pharmacokinetics. It is hoped that it will stimulate more detailed measurements and analysis. [ABSTRACT FROM AUTHOR]

Joint models and statistical inference for longitudinal and survival data have been an active area of statistical research and have mostly coupled a longitudinal biomarker‐based mixed‐effects model with normal distribution and an event time‐based survival model. In practice, however, the following issues may standout: (i) Normality of model error in longitudinal models is a routine assumption, but it may be unrealistically violating data features of subject variations. (ii) Data collected are often featured by the mixed types of multiple longitudinal outcomes which are significantly correlated, ignoring their correlation may lead to biased estimation. Additionally, a parametric model specification may be inflexible to capture the complicated patterns of longitudinal data. (iii) Missing observations in the longitudinal data are often encountered; the missing measures are likely to be informative (nonignorable) and ignoring this phenomenon may result in inaccurate inference. Multilevel item response theory (MLIRT) models have been increasingly used to analyze the multiple longitudinal data of mixed types (ie, continuous and categorical) in clinical studies. In this article, we develop an MLIRT‐based semiparametric joint model with skew‐t distribution that consists of an extended MLIRT model for the mixed types of multiple longitudinal data and a Cox proportional hazards model, linked through random‐effects. A Bayesian approach is employed for joint modeling. Simulation studies are conducted to assess performance of the proposed models and method. A real example from primary biliary cirrhosis clinical study is analyzed to estimate parameters in the joint model and also evaluate sensitivity of parameter estimates for various plausible nonignorable missing data mechanisms. [ABSTRACT FROM AUTHOR]

Background: Metabolic risk factors in primary biliary cholangitis (PBC) have not been well described in China. Additionally, it is unclear whether these factors have an impact on the prognosis of PBC patients. Therefore, this study aimed to investigate the prevalence of main metabolic risk factors in PBC, and to evaluate their prognostic values for liver-related outcomes. Methods: A cohort of 789 PBC patients was retrospectively studied between July 2008 and September 2019 by investigating the main metabolic risk factors and analyzing liver-related outcomes. Results: At presentation, 271 (34.3%) patients had concomitant hyperlipidemia, 126 (16.0%) had hypertension, 94 (11.9%) had type 2 diabetes mellitus (T2DM), and 17 (2.2%) had nonalcoholic fatty liver disease (NAFLD). Hyperlipidemia was found to be associated with the lower risk of liver-related death [P<0.0001, hazard ratio (HR): 0.397, 95% confidence interval (CI): 0.268–0.588] and adverse outcomes (P<0.0001, HR: 0.487, 95% CI:0.367–0.646), while hypertension was noted as a risk factor for liver-related death (P=0.001, HR: 1.788, 95% CI:1.268– 2.521) and adverse outcomes (P=0.014, HR: 1.417, 95% CI:1.074–1.869). Moreover, age ≥ 55 years old (P=0.005) and cirrhosis (P<0.0001) had superimposition effects on hypertension as a risk factor for liver-related death, while only cirrhosis (P<0.0001) had an effect on hypertension as a risk factor for adverse outcomes. Additionally, anti-sp100 was associated with adverse outcomes (P=0.013) in PBC patients with hypertension in univariate Cox regression analysis. Conclusion: Hyperlipidemia, hypertension, and T2DM were found as main metabolic risk factors in PBC in China. Hyperlipidemia indicated a benign clinical outcome of PBC, while hypertension indicated a poor outcome of PBC. Older age and cirrhosis had superimposition effects on hypertension for liverrelated poor outcomes. Anti-sp100 might be associated with adverse outcomes, especially in PBC patients with hypertension. [ABSTRACT FROM AUTHOR]

Background The most common cause of benign biliary stricture is bile duct injury after cholecystectomy. Benign biliary strictures are associated with a broad spectrum of signs and symptoms, ranging from subclinical disease with mild elevation of liver enzymes to complete obstruction with jaundice, pruritis, and cholangitis ultimately leading to biliary cirrhosis. The average duration for stricture development after cholecystectomy is around 7 months. This is a case report of a benign biliary stricture presenting 14 years after laparoscopic conversion to open cholecystectomy without the development of recurrent cholangitis and secondary biliary cirrhosis. [ABSTRACT FROM AUTHOR]

Cholangiopathies are defined as focal or extensive damage of the bile ducts. According to the pathogenetic mechanism, it may be immune-mediated or due to genetic, infectious, toxic, vascular, and obstructive causes. Their chronic evolution is characterized by inflammation, obstruction of bile flow, cholangiocyte proliferation, and progression toward fibrosis and cirrhosis. Immune-mediated cholangiopathies comprise primary sclerosing cholangitis (PSC), autoimmune cholangitis and IgG4-associated cholangitis in adults and biliary atresia (BA), neonatal sclerosing cholangitis (NSC) in children. The main purpose of this narrative review was to highlight the similarities and differences among immune-mediated cholangiopathies, especially those frequent in children in which cholangiocyte senescence plays a key role (BA, NSC, and PSC). These three entities have many similarities in terms of clinical and histopathological manifestations, and the distinction between them can be hard to achieve. In BA, bile duct destruction occurs due to aggression of the biliary cells due to viral infections or toxins during the intrauterine period or immediately after birth. The consequence is the activation of the immune system leading to severe inflammation and fibrosis of the extrahepatic biliary tract, lumen stenosis, and impairment of the biliary flow. PSC is characterized by inflammation and fibrosis of intra- and extrahepatic bile ducts, leading to secondary biliary cirrhosis. It is a multifactorial disease that occurs because of genetic predisposition [human leukocyte antigen (HLA) and non-HLA haplotypes], autoimmunity (cellular immune response, autoantibodies, association with inflammatory bowel disease), environmental factors (infections or toxic bile), and host factors (intestinal microbiota). NSC seems to be a distinct subgroup of childhood PSC that appears due to the interaction between genetic predisposition (HLA B8 and DR3) and the disruption of the immune system, validated by elevated IgG levels or specific antibodies [antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA)]. Currently, the exact mechanism of immune cholangiopathy is not fully understood, and further data are required to identify individuals at high risk of developing these conditions. A better understanding of the immune mechanisms and pathophysiology of BA, NSC, and PSC will open new perspectives for future treatments and better methods of preventing severe evolution. [ABSTRACT FROM AUTHOR]

Currently, most primary hospitals cannot routinely perform liver stiffness measurements (LSMs) and spleen stiffness measurements (SSMs), which are recommended by guidelines to exclude high-risk varices (HRVs). We tried to find more convenient indicators for HRV screening. We enrolled 213 cirrhosis patients as the training cohort (TC) and 65 primary biliary cirrhosis patients as the validation cohort (VC). We included indicators such as SSM by two-dimensional shear wave elastography, LSM by transient elastography, and other imaging and laboratory tests. Variable analysis revealed SSM, platelets (PLT), and spleen thickness (ST) as independent risk indicators for HRV. In TC, ST+PLT (ST < 42.2 mm and PLT > 113.5 × 109/L) could avoid 35.7% of the esophagogastroduodenoscopies (EGDs), with a 2.4% missed HRV rate. Although the proportion of EGDs spared by ST+PLT was less than SSM+PLT (SSM < 29.89 kPa + PLT > 113.5 × 109/L) (35.7% vs. 44.1%), it was higher than that of the Baveno VI criteria (B6) (35.7% vs. 28.2%). We did not validate SSM+PLT in VC considering our aims. ST+PLT safely spared 24.6% of EGDs in VC, identical to B6. Conclusions: The ability of ST+PLT to exclude HRVs was superior to B6 but slightly inferior to SSM+PLT. When SSM cannot be routinely performed, ST+PLT provides an extra option for patients to exclude HRVs as a more convenient model. [ABSTRACT FROM AUTHOR]

Background: Whether the positive associations of gastric cancer (GC) with autoimmune diseases are causal has always been controversial. This study aims to estimate the causal relationship between GC and 12 autoimmune diseases by means of Mendelian randomization (MR) analysis. Methods: After rigorous evaluation, potential candidate single nucleotide polymorphisms (SNPs) for GC and 12 autoimmune diseases were extracted from genome-wide association study (GWAS) datasets. We performed the MR analyses using the inverse variance weighted (IVW) method as the primary approach to the analysis. Three sensitivity analysis methods were added to assess the robustness of the results. In addition, heterogeneity was measured using Cochran's Q-value, and horizontal pleiotropy was assessed using MR-Egger regression and leave-one-out analysis. Results: The IVW result, which is the main method of analysis, shows no evidence of a causal association between GC and any autoimmune disease. The results of IVW analysis show the relationship between rheumatoid arthritis (p = 0.1389), systemic lupus erythematosus (p = 0.1122), Crohn's disease (p = 0.1509), multiple sclerosis (p = 0.3944), primary sclerosing cholangitis (p = 0.9022), primary biliary cirrhosis (p = 0.7776), type 1 diabetes (p = 0.9595), ulcerative colitis (p = 0.5470), eczema (p = 0.3378), asthma (p = 0.7436), celiac disease (p = 0.4032), and psoriasis (p = 0.7622) and GC susceptibility. The same result was obtained with the weighted median and the MR-egger (p > 0.05). Conclusion: Our study did not find a genetic causal relationship between susceptibility to these autoimmune diseases and GC, which suggests that unmeasured confounders (e.g., inflammatory processes) or shared genetic architecture may be responsible for the reported epidemiologic associations. Further studies of ancestral diversity are warranted to validate such causal associations. [ABSTRACT FROM AUTHOR]

Introduction: This study compares the clinical characteristics of dry eye secondary to primary biliary cholangitis (PBC), drug-induced liver injury (DILI), and viral hepatitis B(HBV) to evaluate the ocular surface damage caused by different types of liver diseases. Methods: Thirty healthy people were included as control group. Sixty patients with dry eye secondary to different types of liver disease were included, including 19 cases of PBC, 18 cases of DILI, and 23 cases of HBV. All patients were evaluated by the SPEED questionnaire, corneal fluorescein staining (CFS), noninvasive tear breakup time (NIBUT), Schirmer I test (SIt), tear meniscus height test (TMH), the area of meibomian glands dropout (MG dropout), partial blinking rate (PBR), lipid layer thickness (LLT), meibum expressibility, and meibum quality. Results: There are statistical differences in ophthalmic examination results between different types of liver diseases and normal people (P < 0.05). Compared with DILI and HBV groups, the CFS score of PBC group score was higher (P < 0.05), the PBR was higher (P < 0.05), and the SIt was lower (P < 0.01). The TMH of PBC and DILI groups were significantly lower than the HBV group, and the difference was statistically significant (P < 0.05). Compared with the PBC group, the LLT of the DILI group decreased (P < 0.01). The area of meibomian glands dropout of the three groups had mild-to-moderate defects, but there was no significant statistical difference between groups (P > 0.05).The Meibum quality score in the DILI group was significantly higher than the HBV group (P < 0.05). Conclusions: The PBC group was more prone to aqueous-deficient dry eye. The DILI group was more prone to obstructive meibomian gland dysfunction (MGD).The HBV group was more prone to nonobstructive MGD. The symptoms of dry eye in the PBC group are mild-to-moderate discomfort, but the degree of corneal damage is higher, indicating that the corneal sensitivity is reduced, which may be related to the high rate of partial blinking. [ABSTRACT FROM AUTHOR]

X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, although AAV8-mediated gene transfer therapy has shown promise in animal models and preliminarily in patients. However, 4 patients with XLMTM treated with gene therapy have died from progressive liver failure, and hepatobiliary disease has now been recognized more broadly in association with XLMTM. In an attempt to understand whether loss of MTM1 itself is associated with liver pathology, we have characterized what we believe to be a novel liver phenotype in a zebrafish model of this disease. Specifically, we found that loss-of-function mutations in mtm1 led to severe liver abnormalities including impaired bile flux, structural abnormalities of the bile canaliculus, and improper endosomemediated trafficking of canalicular transporters. Using a reporter-tagged Mtm1 zebrafish line, we established localization of Mtm1 in the liver in association with Rab11, a marker of recycling endosomes, and canalicular transport proteins and demonstrated that hepatocyte-specific reexpression of Mtm1 could rescue the cholestatic phenotype. Last, we completed a targeted chemical screen and found that Dynasore, a dynamin-2 inhibitor, was able to partially restore bile flow and transporter localization to the canalicular membrane. In summary, we demonstrate, for the first time to our knowledge, liver abnormalities that were directly caused by MTM1 mutation in a preclinical model, thus establishing the critical framework for better understanding and comprehensive treatment of the human disease. [ABSTRACT FROM AUTHOR]

This document is a letter to the editor of the journal Alimentary Pharmacology & Therapeutics. The authors express their interest in a recent article that explored the association of circulating myokines with disease progression in alcohol-associated liver disease (ALD). They discuss their own research on primary biliary cholangitis (PBC) and how previous studies have shown sarcopenia and elevated inflammation in PBC patients. The authors conducted a study on 72 PBC patients and found that myostatin levels increased and decorin levels decreased as the disease progressed. They suggest that myokines may be potential biomarkers in chronic liver diseases, but further studies are needed for validation. [Extracted from the article]

This document discusses the diagnostic and prognostic value of quantitative detection of antimitochondrial antibodies subtype M2 (AMA-M2) using chemiluminescence immunoassay in primary biliary cholangitis (PBC). PBC is an autoimmune liver disease that can lead to liver cirrhosis and failure if left untreated. AMA-M2 is the most specific autoantibody used for diagnosing PBC. The study conducted involved 158 PBC patients and 20 negative controls, and the results showed that the chemiluminescence immunoassay had good diagnostic efficacy and consistency with other detection methods. Additionally, there was a significant correlation between AMA-M2 and the occurrence of liver cirrhosis in PBC patients. [Extracted from the article]

This article discusses a case of pityriasis rotunda (PR) associated with hepatocellular carcinoma (HCC) in a 67-year-old man with primary biliary cirrhosis. PR is a rare dermatosis characterized by circular, scaly patches with no inflammatory changes. It can be idiopathic or associated with underlying diseases such as malignancy or chronic infection. The article provides clinical information, including dermoscopic features and histology correlates, and mentions other comorbidities associated with PR. The diagnosis of PR is based on clinical manifestations, as histologic findings are not specific. [Extracted from the article]