[Chronic intermittent hypoxia activates NLRP1 inflammasome and causes liver injury].

Objective To investigate the liver injury induced by chronic intermittent hypoxia (CIH) activation of NOD-like receptor pyrin domain containing protein 1 (NLRP1) inflammasome. Methods C57BL/6 male mice were randomly divided into control group and CIH group. Mice in CIH group were put into CIH chamber for molding (8 hours a day for 4 weeks). After 4 weeks of molding, liver tissue cells was observed by HE staining, and the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum of mice were detected by kit. The levels of reactive oxygen species (ROS) in liver tissue were detected by dihydroethidine (DHE). The expression and localization of NLRP1, apoptosis speck-like protein containing a caspase activation and recruiting domain (ASC) and caspase-1 were detected by immunohistochemical staining. The protein expressions of NLRP1, ASC, caspase-1, interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α) were detected by Western blot analysis. The serum levels of IL-1ß and TNF-α were detected by ELISA. Results Compared with the control group, the CIH group exhibited significant pathological changes in hepatocytes. Hepatocytes showed signs of rupture and necrosis, accompanied by inflammatory cell aggregation. Furthermore, the levels of ALT, AST, ROS, IL-1ß and TNF-α were elevated, along with increased protein expressions of NLRP1, ASC, caspase-1, IL-1ß and TNF-α. Conclusion CIH causes liver injury by activating NLRP1 inflammasome.

Current Evidence and Perspectives of Cluster of Differentiation 44 in the Liver's Physiology and Pathology.

Cluster of differentiation 44 (CD44), a multi-functional cell surface receptor, has several variants and is ubiquitously expressed in various cells and tissues. CD44 is well known for its function in cell adhesion and is also involved in diverse cellular responses, such as proliferation, migration, differentiation, and activation. To date, CD44 has been extensively studied in the field of cancer biology and has been proposed as a marker for cancer stem cells. Recently, growing evidence suggests that CD44 is also relevant in non-cancer diseases. In liver disease, it has been shown that CD44 expression is significantly elevated and associated with pathogenesis by impacting cellular responses, such as metabolism, proliferation, differentiation, and activation, in different cells. However, the mechanisms underlying CD44's function in liver diseases other than liver cancer are still poorly understood. Hence, to help to expand our knowledge of the role of CD44 in liver disease and highlight the need for further research, this review provides evidence of CD44's effects on liver physiology and its involvement in the pathogenesis of liver disease, excluding cancer. In addition, we discuss the potential role of CD44 as a key regulator of cell physiology.

The role of anoctamin 1 in liver disease.

Liver diseases include all types of viral hepatitis, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), cirrhosis, liver failure (LF) and hepatocellular carcinoma (HCC). Liver disease is now one of the leading causes of disease and death worldwide, which compels us to better understand the mechanisms involved in the development of liver diseases. Anoctamin 1 (ANO1), a calcium-activated chloride channel (CaCC), plays an important role in epithelial cell secretion, proliferation and migration. ANO1 plays a key role in transcriptional regulation as well as in many signalling pathways. It is involved in the genesis, development, progression and/or metastasis of several tumours and other diseases including liver diseases. This paper reviews the role and molecular mechanisms of ANO1 in the development of various liver diseases, aiming to provide a reference for further research on the role of ANO1 in liver diseases and to contribute to the improvement of therapeutic strategies for liver diseases by regulating ANO1.

[Role of liver sinusoidal endothelial cell damage in the developmental process of hepatic sinusoidal obstruction syndrome: a focus on the research progress of immune inflammatory mechanisms].

Hepatic sinusoidal obstruction syndrome (HSOS) is a type of secondary vascular disease of the liver that is mainly associated with the ingestion of pyrrole alkaloids (PAs) and hematopoietic stem cell transplantation (HSCT) treatment, resulting in severe liver dysfunction, multiple organ failure, and even death. Hepatic sinusoidal dilatation and obstruction, hepatocyte coagulative necrosis, and hepatic lobular inflammation are the main pathological manifestations of HSOS. The key initiating process for the pathogenesis of HSOS is damage to liver sinusoidal endothelial cells (LSECs). Currently, it is believed that LSECs are damaged by the involvement of multiple etiologies and mechanisms, and secondary coagulation and fibrinolysis disorders, oxidative stress, and inflammatory responses are the occurrence contributors to HSOS; however, the mechanism has not been fully elucidated. Therefore, the role of immune-inflammatory mechanisms has received increasing attention in LSEC damage. This article provides an overview of the epidemiology, etiology, and pathological changes of HSOS and reviews the physiological functions, common etiological damage mechanisms, and the key role of LSEC damage in the pathogenesis of HSOS, with a special focus on the role and research progress of immune-inflammatory mechanisms for LSEC damage in recent years. Furthermore, we believe that in-depth study and elucidation of the role of immune-inflammatory mechanisms in LSEC damage and the pathogenesis of HSOS and diagnosis will provide feasible research and development ideas for the screening and identification of new markers and drug treatment targets for HSOS.

Starvation in Mice Induces Liver Damage Associated with Autophagy.

Anorexia nervosa (AN) induces organ dysfunction caused by malnutrition, including liver damage leading to a rise in transaminases due to hepatocyte damage. The underlying pathophysiology of starvation-induced liver damage is poorly understood. We investigate the effect of a 25% body weight reduction on murine livers in a mouse model and examine possible underlying mechanisms of starvation-induced liver damage. Female mice received a restricted amount of food with access to running wheels until a 25% weight reduction was achieved. This weight reduction was maintained for two weeks to mimic chronic starvation. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured spectrophotometrically. Liver fat content was analyzed using an Oil Red O stain, and liver glycogen was determined using a Periodic acid-Schiff (PAS) stain. Immunohistochemical stains were used to investigate macrophages, proliferation, apoptosis, and autophagy. Starvation led to an elevation of AST and ALT values, a decreased amount of liver fat, and reduced glycogen deposits. The density of F4/80+ macrophage numbers as well as proliferating KI67+ cells were decreased by starvation, while apoptosis was not altered. This was paralleled by an increase in autophagy-related protein staining. Increased transaminase values suggest the presence of liver damage in the examined livers of starved mice. The observed starvation-induced liver damage may be attributed to increased autophagy. Whether other mechanisms play an additional role in starvation-induced liver damage remains to be investigated.

Native and engineered extracellular vesicles: novel tools for treating liver disease.

Liver diseases are classified as acute liver damage and chronic liver disease, with recurring liver damage causing liver fibrosis and progression to cirrhosis and hepatoma. Liver transplantation is the only effective treatment for end-stage liver diseases; therefore, novel therapies are required. Extracellular vesicles (EVs) are endogenous nanocarriers involved in cell-to-cell communication that play important roles in immune regulation, tissue repair and regeneration. Native EVs can potentially be used for various liver diseases owing to their high biocompatibility, low immunogenicity and tissue permeability and engineered EVs with surface modification or cargo loading could further optimize therapeutic effects. In this review, we firstly introduced the mechanisms and effects of native EVs derived from different cells and tissues to treat liver diseases of different etiologies. Additionally, we summarized the possible methods to facilitate liver targeting and improve cargo-loading efficiency. In the treatment of liver disease, the detailed engineered methods and the latest delivery strategies were also discussed. Finally, we pointed out the limitations and challenges of EVs for future development and applications. We hope that this review could provide a useful reference for the development of EVs and promote the clinical translation.

Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis.

Maximizing the potential of human liver organoids (LOs) for modeling human septic liver requires the integration of innate immune cells, particularly resident macrophage Kupffer cells. In this study, we present a strategy to generate LOs containing Kupffer cells (KuLOs) by recapitulating fetal liver hematopoiesis using human induced pluripotent stem cell (hiPSC)-derived erythro-myeloid progenitors (EMPs), the origin of tissue-resident macrophages, and hiPSC-derived LOs. Remarkably, LOs actively promote EMP hematopoiesis toward myeloid and erythroid lineages. Moreover, supplementing with macrophage colony-stimulating factor (M-CSF) proves crucial in sustaining the hematopoietic population during the establishment of KuLOs. Exposing KuLOs to sepsis-like endotoxins leads to significant organoid dysfunction that closely resembles the pathological characteristics of the human septic liver. Furthermore, we observe a notable functional recovery in KuLOs upon endotoxin elimination, which is accelerated by using Toll-like receptor-4-directed endotoxin antagonist. Our study represents a comprehensive framework for integrating hematopoietic cells into organoids, facilitating in-depth investigations into inflammation-mediated liver pathologies.

Morphological findings in different subtypes of hepatic amyloid.

The classic findings have been well described for light-chain amyloid involving the liver. In addition to light chain, however, many additional proteins are now known to be amyloidogenic and can involve the liver. A total of 58 surgical pathology specimens with amyloid deposits were analyzed for patterns of amyloid deposition, including amyloid from light chain lambda (N = 17), light chain kappa (N = 15), transthyretin (N = 15), serum amyloid A (N = 4), apolipoprotein A1 (N = 4), fibrinogen alpha (N = 2), LECT2 (N = 1). Amyloid deposits predominately targeted the liver vasculature, including the walls of the hepatic arteries, portal veins, and sinusoids. While there was overlap, light chain amyloid predominately involved the sinusoids, while transthyretin amyloid predominately targeted the hepatic arteries, especially the larger ones in the hilum and larger portal tracts. Serum amyloid A formed nodular deposits that started in the portal vasculature but then extended into the portal tract stroma, leading to large, bulbous, portal-based amyloid deposits. Apolipoprotein A amyloid also formed large portal-based nodules. Fibrinogen was mild and subtle on H&E and predominately affected portal veins. Amyloid deposits in hilar nerves were prominent with amyloid light chain, transthyretin, and apolipoprotein A1. In conclusion, the histology of hepatic amyloid is diverse and shows several distinct clusters of findings that can aide in recognition in surgical pathology specimens.

The Role of miRNA and Long Noncoding RNA in Cholestatic Liver Diseases.

Cholestatic liver diseases encompass a range of organic damages, metabolic disorders, and dysfunctions within the hepatobiliary system, arising from various pathogenic causes. These factors contribute to disruptions in bile production, secretion, and excretion. Cholestatic liver diseases can be classified into intrahepatic and extrahepatic cholestasis, according to the location of occurrence. The etiology of cholestatic liver diseases is complex, and includes drugs, poisons, viruses, parasites, bacteria, autoimmune responses, tumors, and genetic metabolism. The pathogenesis of cholelstatic liver disease is not completely clarified, and effective therapy is lacking. Clarifying its mechanism to find more effective therapeutic targets and drugs is an unmet need. Increasing evidence demonstrates that miRNA and long noncoding RNA are involved in the progression of cholestatic liver diseases. This review provides a comprehensive summary of the research progress on the roles of miRNA and long noncoding RNA in cholestatic liver diseases. The aim of the review is to enhance the understanding of their potential diagnostic, therapeutic, and prognostic value for patients with cholestasis.

Comparison of Fibroscan, Shear Wave Elastography, and Shear Wave Dispersion Measurements in Evaluating Fibrosis and Necroinflammation in Patients Who Underwent Liver Biopsy.

OBJECTIVE: Our aim was to predict these stages of hepatic fibrosis and necroinflammation using measurements from two-dimensional shear wave elastography (2D-SWE), transient elastography (Fibroscan, TE), and shear wave dispersion (SWD). MATERIALS AND METHODS: In this prospectively designed study, chronic liver patients with nonspecific etiology whose biopsy was performed for up to 1 week were included. Two-dimensional SWE, SWD, and TE measurements were performed. The METAVIR and F-ISHAK classification was used for histopathological evaluation. RESULTS: Two-dimensional SWE and TE were considered significant for detecting hepatic fibrosis. In distinguishing ≥F2, for 2D-SWE, area under the receiver operating characteristics (AUROC) was 0.86 (confidence interval [CI], 0.75-0.96) for the cutoff value of 8.05 kPa ( P = 0.003); for TE, AUROC was 0.79 (CI, 0.65-0.94) for the cutoff value of 10.4 kPa ( P < 0.001). No significance was found for TE in distinguishing ≥F3 ( P = 0.132). However, for 2D-SWE, a cutoff value of 10.45 kPa ( P < 0.001), with AUROC = 0.87 (CI, 0.78-0.97) was determined for ≥F3. Shear wave dispersion was able to determine the presence of necroinflammation ( P = 0.016) and a cutoff value of 15.25 (meter/second)/kiloHertz ([m/s]/kHz) ( P = 0.006) and AUROC of 0.71 (CI, 0.57-0.85) were calculated for distinguishing ≥A2. In addition, a cutoff value of 17.25 (m/s)/kHz ( P = 0.023) and AUROC = 0.72 (CI, 0.51-0.93) were found to detect severe necroinflammation. The cutoff value for SWD was 15.25 (m/s)/kHz ( P = 0.013) for detecting ≥A2 in the reversible stage of fibrosis (F0, F1, and F2), and AUROC = 0.72 (CI, 0.56-0.88). CONCLUSIONS: Two-dimensional SWE and TE measurements were significant in detecting the irreversible stage and the stage that should be treated in hepatic fibrosis noninvasively. Shear wave dispersion measurements were significant in detecting necroinflammation noninvasively.

Time-course analysis of liver and serum galectin-3 in acute liver injury after alpha-galactosylceramide injection.

Galectin-3 is a beta-galactoside-binding lectin that plays important roles in diverse physiological functions, such as cell proliferation, apoptosis, and mRNA splicing. This protein is expressed on inflammatory cells and acts as a local inflammatory mediator. Recently, galectin-3 has been detected in several diseases, such as chronic liver, heart, and kidney diseases, diabetes, viral infection, autoimmune and neurodegenerative diseases, and tumors, and its role as a biomarker has attracted attention. Alpha-galactosylceramide is an artificially synthesized sphingolipid that can induce acute liver injury via the natural killer T pathway. However, the pathophysiological roles and kinetics of galectin-3 in acute liver injury are not fully understood. This study aimed to elucidate the expression and time course of galectin-3 in liver tissues during acute liver injury following alpha-galactosylceramide injection. Animals were histologically examined on days 1, 2, 4, and 7 after intraperitoneal injection of alpha-galactosylceramide, and the expressions of galectin-3 and ionized calcium-binding adaptor molecule 1 were analyzed. Notably, galectin-3 formed characteristic cluster foci, particularly on day 2 after injection. Cluster formation was not observed in chronic liver disease. Simultaneously, ionized calcium-binding adaptor molecule 1-positive cells were observed in the cluster foci. Serum galectin-3 levels increased on day 2 of treatment and correlated well with the number of galectin-3-positive cell clusters in the liver. Moreover, galectin-3 expression was an important mediator of the early phase of liver injury after alpha-galactosylceramide injection. These results suggest that serum galectin-3 may be a biomarker for the early diagnosis of acute liver injury and that clusters of galectin-3-positive cells may be a specific finding in acute liver injury.

Histopathological findings from the investigation of paediatric acute hepatitis of unknown aetiology, United Kingdom 2022.

In 2022, there were global reports of increased numbers of acute hepatitis not explained by hepatitis A-E virus infection in children. This manuscript summarises histopathology results from 20 patients in the United Kingdom who underwent liver transplant or had a liver biopsy as part of aetiological investigations. All available histopathological samples were reviewed centrally as part of the outbreak investigation. A working group comprised of infection specialists, hepatologists and histopathologists met virtually to review the cases, presentation, investigations and histopathology. All 20 liver samples had evidence of inflammation without significant interface activity, and submassive confluent pan-lobular or multilobular hepatocellular necrosis. Overall, the predominant histopathological findings were of acute nonspecific hepatitis with submassive hepatic necrosis and central vein perivenulitis and endothelitis. Histopathological findings were a poor indicator of aetiology.

Hepatoprotective impact of Nigella sativa silver nanocomposite against genotoxicity, oxidative stress, and inflammation induced by thioacetamide.

Protection from liver damage and the repercussion of that harm is thought to be crucial for reducing the number of deaths each year. This work was developed to evaluate the possible role of silver nanocomposite prepared using Nigella sativa (N. sativa) aqueous extract against the hepatic damage brought on by thioacetamide (TAA), with particular attention to how they affect the NF-κß, TNF-α, IL-1ß, and COX-2 signaling pathways. There were seven groups of male Wistar rats used as follows: control, saline, N. sativa aqueous extract (NSAE; 200 mg/kg/d), N. sativa silver nanocomposite (NS-AgNC; 0.25 mg/kg/d), TAA (100 mg/kg; thrice weekly), NSAE + TTA, and NS-AgNC + TAA, respectively. The experiment continued for six weeks. The results showed that NS-AgNPs significantly enhanced liver functions (p<0.05) (albumin, ALP, LDH, AST, total protein, ALT, and globulin) and oxidant/antioxidant biomarkers (p<0.05) (H2O2, MDA, PCC, NO, SOD, CAT, GPx, GR, GST and, GSH), contrasted with TAA group. Moreover, a significant (p<0.05) downregulation of the gene expressions (COX-2, TNF-α, IL-1ß, and NF-κß) was also achieved by using silver nanocomposite therapy. These findings have been supported by histological analysis. Collectively, NS-AgNC exhibits more prominent and well-recognized protective impacts than NSAE in modulating the anti-inflammatory, genotoxicity and oxidative stress effects against TAA-induced liver injuries.

Granulomas in Pediatric Liver Biopsies: Single Center Experience.

BACKGROUND: Granulomas in pediatric liver biopsies (GPLB) are rare with the largest pediatric cohort reported over 25 years ago. METHODS: Single-center retrospective study of GPLB. RESULTS: Seventeen liver biopsies from 16 patients with granulomas were identified (9 boys, 56%) with a median age of 13 years (range: 1-18) for which the most common indication was the presence of a nodule/mass (47%). Significant comorbidities were seen in 13 patients (81%) and included: liver transplant (25%), history of a neoplasm (25%), autoimmune hepatitis (6%), Crohn disease (6%), bipolar disorder (6%), severe combined immunodeficiency (6%), and sickle cell disease (6%). Eleven patients were taking multiple medications at the time of biopsy. Granulomas were more commonly pan-acinar (11 cases) followed by subcapsular (4 cases), portal (1 case), and periportal (1 case). Necrosis was seen in 10 cases (59%). GMS stain was positive in 2 cases for Histoplasma-like yeast; microbiological cultures were negative in all cases (no: 4). A 18S and 16S rRNA gene sequencing performed in 15 cases revealed only 1 with a pathogenic microorganism, Mycobacterium angelicum. CONCLUSION: In our experience, GPLB are heterogenous with only 3 cases having an identifiable infectious etiology and many of the remaining cases being associated to multiple medications, suggesting drug-induced liver injury as possible etiology.

Mallory-Denk bodies and hepatocellular senescence: a causal relationship?

Mallory-Denk bodies (MDBs) are hepatocellular cytoplasmic inclusions, which occur in certain chronic liver diseases, such as alcohol-related (ASH) and metabolic dysfunction-associated (MASH) steatohepatitis, copper toxicosis, some drug-induced liver disorders, chronic cholangiopathies, and liver tumors. Our study focused on the expression of the senescence markers p21WAF1/cip1 and p16INK4a in hepatocytes containing MDBs in steatohepatitis, chronic cholangiopathies with fibrosis or cirrhosis, Wilson's disease, and hepatocellular carcinomas. Cytoplasm and nuclei of MDB-containing hepatocytes as well as MDB inclusions, except those associated with carcinoma cells, were strongly p16-positive, p21-positive, as well as p21-negative nuclei in MDB-containing hepatocytes which were observed whereas MDBs were p21-negative. Expression of the senescence marker p16 suggests that MDB formation reflects an adaptive response to chronic stress resembling senescence with its consequences, i.e., expression of inflammation- and fibrosis-prone secretome. Thus, senescence can be regarded as "double-edged sword" since, on the one hand, it may be an attempt of cellular defense, but, on the other, also causes further and sustained damage by inducing inflammation and fibrosis related to the senescence-associated secretory phenotype and thus progression of chronic liver disease.

Is iron overload associated with worse outcomes in patients with chronic liver disease undergoing liver transplantation?

Background: Iron overload is frequent in patients with chronic liver disease, associated with shorter survival after liver transplantation in patients with hereditary hemochromatosis. Its effect on patients without hereditary hemochromatosis is unclear. The aim of the study was to study the clinical impact of iron overload in patients who underwent liver transplantation at an academic tertiary referral center. Methods: We performed a retrospective cohort study including all patients without hereditary hemochromatosis who underwent liver transplantation from 2015 to 2017 at an academic tertiary referral center in Mexico City. Explant liver biopsies were reprocessed to obtain the histochemical hepatic iron index, considering a score ≥ 0.15 as iron overload. Baseline characteristics were compared between patients with and without iron overload. Survival was estimated using the Kaplan-Meier method, compared with the log-rank test and the Cox proportional hazards model. Results: Of 105 patients included, 45% had iron overload. Viral and metabolic etiologies, alcohol consumption, and obesity were more frequent in patients with iron overload than in those without iron overload (43% vs. 21%, 32% vs. 22%, p = 0.011; 34% vs. 9%, p = 0.001; and 32% vs. 12%, p = 0.013, respectively). Eight patients died within 90 days after liver transplantation (one with iron overload). Complication rate was higher in patients with iron overload versus those without iron overload (223 vs. 93 events/100 personmonths; median time to any complication of 2 vs. 3 days, p = 0.043), without differences in complication type. Fatality rate was lower in patients with iron overload versus those without iron overload (0.7 vs. 4.5 deaths/100 person-months, p = 0.055). Conclusion: Detecting iron overload might identify patients at risk of early complications after liver transplantation. Further studies are required to understand the role of iron overload in survival.

Mitochondrial dysfunction is associated with the severity of liver fibrosis in patients after the Fontan operation.

The gold standard for determining the severity of liver disease in Fontan patients is now liver biopsy. Since it is an invasive procedure, this study determined the possibility of applying mitochondrial function from isolated peripheral blood mononuclear cells (PBMCs) as a non-invasive indicator of liver fibrosis. Fontan patients (n = 37) without known liver disease were analysed cross-sectionally. Patients were classified according to their histology using the METAVIR score as follows; F0/F1-no/mild fibrosis; F2-moderate fibrosis; and F3/F4-cirrhosis. Peripheral blood mononuclear cells were assessed for mitochondrial activity and apoptosis. This study did not find any significant differences in cardiac function among the groups according to liver histology. Interestingly, our findings indicated a significant decrease in maximal respiration and spare respiratory capacity, in both the moderate (F2) and cirrhosis (F3/F4) groups compared with the group without significant fibrosis (F0/F1). Moreover, the cirrhosis group exhibited higher levels of apoptosis and lower levels of live cells, compared with both the moderate and no significant fibrosis groups. In conclusion, the degree of liver fibrosis in Fontan patients is strongly correlated with mitochondrial dysfunction in PBMCs. Mitochondrial function and apoptosis could potentially serve as novel markers for tracking the progression of liver fibrosis in these patients.

Clinical, histopathological, and immunohistochemical spectrum of hepatolithiasis: a tertiary care center-based study from north India.

Hepatolithiasis (HL), an uncommon disease among Indians, occurs due to a complex interplay of various structural and functional factors. We retrospectively evaluated the clinical and histopathological spectrum of HL (N = 19) with immunohistochemical evaluation for biliary apomucins and canalicular transporter proteins, both crucial for lithogenesis. Nineteen surgically resected cases were included. Histopathology was systematically evaluated. Immunohistochemistry for apomucins (MUC1, MUC2, MUC4, MUC5AC, and MUC6) and canalicular transporter proteins (BSEP and MDR3) was applied to all cases. The median age was 51 years with female preponderance (F:M = 1.4:1). The stone was cholesterol-rich in 71.4% and pigmented in 28.6% (n = 14). Histopathology showed variable large bile-duct thickening due to fibrosis and inflammation with peribiliary gland hyperplasia. Structural causes (Caroli disease, choledochal cyst, and post-surgical complication) were noted in 15.8% of cases (secondary HL). Expression of gel-forming apomucin MUC1, MUC2, and MUC5AC was seen in either bile duct epithelia or peribiliary glands in 84.2%, 10.5%, and 84.2% cases respectively. Loss of canalicular expression of MDR3 was noted in 42.1% of cases while BSEP was retained in all. Primary HL in the north Indian population can be associated with the loss of MDR3 expression (with retained BSEP) and/ or a shift in the phenotype of biliary apomucins to gel-forming apomucins. The former factor alters the bile acid/ phospholipid ratio while the latter parameter promulgates crystallization. In conjunction, these factors are responsible for the dominantly cholesterol-rich stones in the index population.

Pathologic approach to Neonatal cholestasis with a simple scoring system for biliary atresia.

A liver biopsy is essential for the diagnostic workup of persistent neonatal cholestasis (NC). The differential diagnosis of NC is broad, including obstructive and non-obstructive causes. In addition, histologic features of certain disorders may be non-specific in the early course of the disease. To evaluate liver biopsies using a practical histopathologic approach for NC and to define a simple scoring system for biliary atresia (BA) for routine clinical practice. From June 2006 to December 2021, liver biopsy specimens from infants with persistent NC were examined by two independent pathologists. The cases diagnosed as BA were correlated with clinical, radiologic, and laboratory data to calculate the final score. Four hundred and fifty-nine cases were enrolled in the study. They had a mean age of 63.94 ± 20.62 days and were followed for a median time of 58 (1-191) months. They included 162 (35.3%) cases of BA. On multivariate analysis, portal edema, ductular proliferation, cholangiolitis, and bile duct/ductular plugs were the histopathologic predictors of BA. A liver biopsy did perform well with a 95.1% sensitivity, 91.6% specificity, 86% PPV, and 97.1% NPV. At a cutoff of 5 of the scoring system, diagnosis of BA could be done with a sensitivity of 95.1% and a specificity of 100%. We have shown detailed histopathologic features of BA with more depth to infants aged ≤ 6 weeks. We have developed a simple scoring system using a combination of liver biopsy with non-invasive methods to increase the diagnostic accuracy of BA.