Liver Biopsy Research Articles

Revisiting Mac-2-Binding Protein Glycosylation Isomer (M2BPGi) for Diagnosing High-Risk Liver Fibrosis: A Stepwise Diagnostic Analysis

Abstract* Background The level of liver fibrosis is the basis for the treatment of chronic hepatitis B (CHB), and it is necessary to adapt non-invasive liver fibrosis modalities. We aimed to investigate the use of M2BPGi as a single or combined diagnostic modality for liver fibrosis in CHB patients through a stepwise diagnostic analysis. Methods Cross-sectional data were taken from patients between October 2021 and August 2022. Demographic data, blood profile, liver function, and liver stiffness were measured in CHB patients over 18 years old, willing to take part in the research, and had complete data. APRI, FIB-4, and AAR were calculated using the well-known formulas. Serum M2BPGi-levels were converted into a cut-off index (COI). The patients were divided into low-risk (LR) and high-risk fibrosis (HR) groups. A cut-off for each predictor variable to differentiate between the LR and HR groups was determined. The obtained cut-off was assessed for its association with the grouping of liver elastography results. Models to diagnose the liver stiffness measurement (LSM) ≥8 kPa were created and compared through multivariate and ROC analyses. Results The number of patients that met the inclusion and exclusion criteria was 143 (HR = 65, LR = 78). The cut-off for diagnosing LSM ≥8kPa was 0.311, 0.742, 0.635, and 1.434 for APRI, FIB-4, AAR, and M2BPGi, respectively. This cut-off was significantly associated with the results of the HR and LR groupings. A multivariate analysis found that FIB4, AAR, and M2BPGi added significantly to the model. Statistically, the most optimal use of M2BPGi was combined with FIB-4, with an AUC of 0.835. Conclusions The optimal cut-off of M2BPGi for diagnosing high-risk liver fibrosis in this study was 1.434. M2BPGi should be used with FIB-4 as a diagnostic tool for diagnosing liver fibrosis, especially in the absence of a liver biopsy or elastography.

Serum autotaxin is a prognostic indicator of liver-related events in patients with non-alcoholic fatty liver disease.

Circulating autotaxin (ATX) levels have been reported to correlate with liver inflammation activity and liver fibrosis severity in patients with non-alcoholic fatty liver disease (NAFLD). The objective of this study is to investigate whether serum ATX could predict liver-related events (LRE) in NAFLD patients. This retrospective investigation includes 309 biopsy-proven NAFLD patients registered at Shinshu University Hospital. All patients are followed for at least 1 year, during which time the prevalence of LRE, including newly developing hepatocellular carcinoma, hepatic encephalopathy, ascites, and esophagogastric varices, is investigated in relation to ATX levels at the time of liver biopsy. During the median follow-up period of 7.0 years, LRE are observed in 20 patients (6.5%). The area under the receiver operating characteristic curve and cut-off value of serum ATX for predicting LRE are 0.81 and 1.227 mg/l, respectively. Multivariate Cox proportional hazards models for LRE determine ATX and advanced fibrosis as independently associated factors. Furthermore, in a competing risk analysis that considered non-liver-related death as a competing event, ATX (HR 2.29, 95% CI 1.22-4.30, p = 0.010) is identified as an independent factor associated with LRE, along with advanced fibrosis (HR 8.01, 95% CI 2.10-30.60, p = 0.002). The predictive utility of ATX for LRE is validated in an independent cohort. Serum ATX may serve as a predictive marker for LRE in patients with NAFLD.

Prediction of Non-Alcoholic Fatty Liver Disease (NAFLD) in Both Lean and Obese Patients Utilizing the Waist to Height Ratio (WHR) and Fatty Liver Index (FLI)

Background: Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health issue with a global prevalence that mirrors the rise in obesity and metabolic syndrome. Non-invasive diagnostic indices like the Waist to Height Ratio (WHtR) and the Fatty Liver Index (FLI) are crucial for early detection and management, offering an alternative to the invasive liver biopsy. These indices are particularly pertinent for populations with distinctive body compositions, such as those seen in Asian countries, where traditional measures like Body Mass Index (BMI) may not accurately reflect metabolic risk. Objective: To evaluate the efficacy of WHtR and FLI as non-invasive diagnostic tools for NAFLD in both lean and obese populations, and to identify the most reliable indicator for predicting the presence of fatty liver disease across different body compositions. Methods: This cross-sectional study was approved by the Ethical Review Board (ERC-771) and conducted at the Sindh Institute of Urology and Transplantation. It included 757 participants aged 18-70 years, with 559 lean and 298 obese individuals based on BMI classifications. Exclusion criteria included other forms of hepatitis, use of steatogenic medication, and significant gastrointestinal disorders. Diagnostic measures included abdominal ultrasonography performed by an expert radiologist and calculation of WHtR and FLI. Statistical analyses were performed using SPSS version 25, and diagnostic accuracy was assessed through sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Area Under the Receiver Operating Characteristic (AUROC) curves. Results: Fatty liver was detected in 49% of obese patients and 33% of lean patients. The obese cohort demonstrated a WHtR >0.63 with a diagnostic accuracy of 94.63%, whereas the FLI had a diagnostic accuracy of 83.6% for a cutoff >74. In lean patients, FLI >16.5 was more predictive of NAFLD with a diagnostic accuracy of 96.96%, as opposed to WHtR, which was less effective. The AUROC for WHtR and FLI in obese patients was 0.847 and 0.704, respectively, while in lean patients, the AUROC for FLI was 0.875, suggesting superior diagnostic performance over WHtR. Conclusion: The study confirms that WHtR and FLI are valuable non-invasive tools for predicting NAFLD, with WHtR being more effective in obese patients and FLI showing greater reliability in lean patients. These findings highlight the need for tailored approaches in diagnosing NAFLD according to body composition. Further large-scale, multicentric research is needed to generalize these diagnostic cut-offs.

Turner syndrome with isochromosome Xq as a cause of granulomatous hepatitis: a case report

Introduction: Turner syndrome (TS) is the most common sex chromosome abnormality in women, caused by a complete or partial absence of the second sex chromosome. The karyotype 46, X,i(Xq) is the underlying cause in about 10% of the cases of TS. Hepatic abnormalities are frequent in Turner syndrome. Granulomas are relatively common in liver samples but are very rarely reported in Turner syndrome. Case Presentation: a 15-year-old female with Turner syndrome attended a consultation for evaluation of elevated liver enzymes. Her chromosomal analysis showed mosaicism 46, X (iso xq)100%. There were no stigmata of chronic liver disease. A liver biopsy showed granulomatous hepatitis. Other causes of hepatic granulomas have been excluded. Ursodeoxycholic Acid (UDCA) therapy leads to the normalization of transaminases. Clinical Discussion: Although Hepatic involvement is common and mostly asymptomatic in Turner syndrome, the mechanism of liver injury is not well understood. The hepatic histological changes in these cases are variable and range from minimal abnormalities to nonalcoholic steatohepatitis (NASH), liver architectural changes, and biliary lesions. Hepatic granulomas are associated with a wide range of systemic disorders but are very rarely reported in tuner syndrome. Normalization of liver enzymes after treatment with Ursodeoxycholic Acid (UDCA) was previously reported, but the importance of this approach is to be determined. Conclusion: Granulomatous hepatitis may be associated with Turner syndrome and may be added to the histological patterns encountered in this disorder.

Liver biopsy in the post-hepatitis C virus era in Japan

In Japan, liver biopsies were previously crucial in evaluating the severity of hepatitis caused by the hepatitis C virus (HCV) and diagnosing HCV-related hepatocellular carcinoma (HCC). However, due to the development of effective antiviral treatments and advanced imaging, the necessity for biopsies has significantly decreased. This change has resulted in fewer chances for diagnosing liver disease, causing many general pathologists to feel less confident in making liver biopsy diagnoses. This article provides a comprehensive overview of the challenges and potential solutions related to liver biopsies in Japan. First, it highlights the importance of considering steatotic liver diseases as independent conditions that can coexist with other liver diseases due to their increasing prevalence. Second, it emphasizes the need to avoid hasty assumptions of HCC in nodular lesions, because clinically diagnosable HCCs are not targets for biopsy. Third, the importance of diagnosing hepatic immune-related adverse events caused by immune checkpoint inhibitors is increasing due to the anticipated widespread use of these drugs. In conclusion, pathologists should be attuned to the changing landscape of liver diseases and approach liver biopsies with care and attention to detail.

Progress and Prospects of Elastography Techniques in the evaluation of fibrosis in chronic liver disease

The precise assessment of liver fibrosis degree is imperative for monitoring and managing chronic liver diseases. Traditionally, liver biopsy and quantitative blood biomarkers have been the mainstays for fibrosis assessment, albeit each with its inherent limitations. However, the emergence of elastography presents a promising non-invasive alternative, potentially supplanting or complementing traditional biomarkers. In contrast to conventional biomarkers, elastography offers several advantages. Firstly, it is non-invasive, sidestepping the risks and discomfort associated with liver biopsy. Secondly, this technique provides real-time and intuitive fibrosis assessments, characterized by user-friendly operation and high reproducibility. Thirdly, elastography excels in diagnosing moderate to severe fibrosis, vital for determining treatment strategies and monitoring disease progression. Notably, MRE stands out as the most accurate non-invasive method for fibrosis assessment, especially suitable for advanced fibrotic stages. This article provides an overview of the advancements in elastography as a viable quantitative biomarker for chronic liver disease fibrosis burden.

Risk Factors for Immune Checkpoint Inhibitor-Induced Liver Injury and the Significance of Liver Biopsy.

Immune checkpoint inhibitor (ICI)-induced liver injury (LI) is a common adverse event, but the clinical characteristics based on the classification of hepatocellular injury and cholestatic types are not fully evaluated. This study aims to analyze risk factors and histological findings in relation to the classification of ICI-induced LI. In total, 254 ICI-induced LI patients among 1086 treated with ICIs between September 2014 and March 2022 were classified according to the diagnostic criteria for drug-induced LI (DILI), and their risk factors and outcomes were evaluated. Kaplan-Meier analyses showed that overall survival in patients with hepatocellular-injury-type LI was significantly longer than others (p < 0.05). Regarding pre-treatment factors, the lymphocyte count was significantly higher in patients with ICI-induced LI, especially in hepatocellular-injury-type LI. Gamma glutamyl transferase (γGTP) and alkaline phosphatase (ALP) were also significantly lower in patients with ICI-induced LI (p < 0.05). Multivariate analyses revealed that malignant melanoma, high lymphocyte count, and low ALP levels were extracted as factors contributing to hepatocellular-injury-type LI. The histological findings among 37 patients diagnosed as ICI-induced LI via liver biopsy also revealed that the spotty/focal necrosis was significantly frequent in hepatocellular-injury-type LI, whereas ductular reactions were frequently observed in cholestatic-type LI. It is suggested that the histological inflammation pattern in patients with LI is closely correlated with the type of DILI.

Endoscopic ultrasound-guided fine needle biopsy diagnosis of circumferentially extraluminal mucosa-associated lymphoid tissue lymphoma in the transverse colon: a case report.

A 61-year-old man present to us with continued abdominal pain without abdominal tenderness for 1month. Blood testing showed elevated biliary enzymes and inflammation. Contrast-enhanced computed tomography (CT) revealed thickening of the transverse colon with relatively strong enhancement but no bile duct dilatation. Colonoscopy revealed localized edema and granular mucosa in the transverse colon. Fluoroscopic endoscopy exhibited the absence of haustra. Multiple biopsies were performed, but differentiation between mild inflammation and mucosa-associated lymphoid tissue (MALT) lymphoma was inconclusive. To establish a definitive diagnosis, transgastric endoscopic ultrasound-guided fine needle biopsy of the hypoechoic mass was performed. Histopathological analysis exhibited the proliferation of small-sized lymphocytes. Fluorescence in situ hybridization revealed the characteristic API2-MALT1 translocation of MALT lymphoma. We performed liver biopsy to investigate biliary enzyme elevation. Histopathology confirmed lymphocytic infiltration within Glisson's capsule. Immunohistochemistry showed positive for CD20 and negative for CD3 and CD5, signifying the infiltration of MALT lymphoma in the liver. Based on these findings, we diagnosed MALT lymphoma, Lugano classification Stage IV. We performed bendamustine-rituximab (BR)-combined therapy. After six courses of BR-combined therapy, colonoscopy revealed improvement in the lead pipe sign and CT revealed disappearance of the mass.

Hepatic steatosis modeling and MRI signal simulations for comparison of single- and dual-R2* models and estimation of fat fraction at 1.5T and 3T

Background and objectiveMagnetic resonance imaging (MRI) has emerged as a noninvasive clinical tool for assessment of hepatic steatosis. Multi-spectral fat-water MRI models, incorporating single or dual transverse relaxation decay rate(s) (R2*) have been proposed for accurate fat fraction (FF) estimation. However, it is still unclear whether single- or dual-R2* model accurately mimics in vivo signal decay for precise FF estimation and the impact of signal-to-noise ratio (SNR) on each model performance. Hence, this study aims to construct virtual steatosis models and synthesize MRI signals with different SNRs to systematically evaluate the accuracy of single- and dual-R2* models for FF and R2* estimations at 1.5T and 3.0T. MethodsRealistic hepatic steatosis models encompassing clinical FF range (0–60 %) were created using morphological features of fat droplets (FDs) extracted from human liver biopsy samples. MRI signals were synthesized using Monte Carlo simulations for noise-free (SNRideal) and varying SNR conditions (5–100). Fat-water phantoms were scanned with different SNRs to validate simulation results. Fat water toolbox was used to calculate R2* and FF for both single- and dual-R2* models. The model accuracies in R2* and FF estimates were analyzed using linear regression, bias plot and heatmap analysis. ResultsThe virtual steatosis model closely mimicked in vivo fat morphology and Monte Carlo simulation produced realistic MRI signals. For SNRideal and moderate-high SNRs, water R2* (R2*W) by dual-R2* and common R2* (R2*com) by single-R2* model showed an excellent agreement with slope close to unity (0.95–1.01) and R2 > 0.98 at both 1.5T and 3.0T. In simulations, the R2*com-FF and R2*W-FF relationships exhibited slopes similar to in vivo calibrations, confirming the accuracy of our virtual models. For SNRideal, fat R2* (R2*F) was similar to R2*W and dual-R2* model showed slightly higher accuracy in FF estimation. However, in the presence of noise, dual-R2* produced higher FF bias with decreasing SNR, while leading to only marginal improvement for high SNRs and in regions dominated by fat and water. In contrast, single-R2* model was robust and produced accurate FF estimations in simulations and phantom scans with clinical SNRs. ConclusionOur study demonstrates the feasibility of creating virtual steatosis models and generating MRI signals that mimic in vivo morphology and signal behavior. The single-R2* model consistently produced lower FF bias for clinical SNRs across entire FF range compared to dual-R2* model, hence signifying that single-R2* model is optimal for assessing hepatic steatosis.

Management of sotorasib-related adverse events and hepatotoxicities following anti-PD-(L)1 therapy: Experience with sotorasib in two French anti-cancer centers and practical guidance proposal

IntroductionSotorasib is a first-in-class KRASG12C inhibitor that showed significant clinical activity in KRASG12C-mutated non-small cell lung cancer (NSCLC). The most frequent grade 3 or 4 sotorasib-related adverse events (AEs) were diarrhea (4–12 %) and hepatotoxicity (10.1–15.1 %). Data is lacking about the management of these AEs, especially in patients receiving sequential anti-PD-(L)1 and sotorasib therapy. Our aim was to report the management of grade ≥ 2 sotorasib-related AEs in real-world setting and to propose practical guidance for the management of grade ≥ 2 sotorasib-related AEs and more generally KRASG12C inhibitors-related AEs. Materials and methodsRecords from all consecutive patients who initiated sotorasib through expanded access program in two French anti-cancer centers from January 1st 2021 to April 1st 2023 were reviewed to identify and grade sotorasib-related AEs, according to NCI-CTCAE v5.0., and to collect AEs management data. Patients were included in the analysis if they presented a grade ≥ 2 sotorasib-related AE. ResultsFrom 57 patients identified, 21 met inclusion criteria including eighteen (86 %) who received sequential anti-PD-(L)1 and sotorasib therapy. Hepatotoxicity (76 %) and diarrhea (24 %) were the most common grade ≥ 2 sotorasib-related AEs. Among the 16 patients with a grade ≥ 2 hepatotoxicity, 12 (75 %) definitely discontinued sotorasib, among which 9 (56 %) after dose reductions and rechallenge, and five (32 %) received corticosteroids, allowing only one patient to resume sotorasib. Diarrhea and nausea were usually manageable and not associated with sotorasib discontinuation. We propose a step-by-step management practical guidance for sotorasib-related hepatotoxicity based on dose-reduction and careful monitoring. Liver biopsy is strongly encouraged for grade 3 and 4 hepatotoxicity to assess candidates for corticosteroids. DiscussionThe experience with sotorasib might help better prevent, screen and manage sotorasib-related and other KRASG12C inhibitors-related AEs, particularly hepatotoxicity.

Comparative and Predictive Significance of Serum Leptin Levels in Non-alcoholic Fatty Liver Disease.

Background Non-alcoholic fatty liver disease (NAFLD) has emerged as the single most common chronic non-viral liver disease. The burden of the disease on healthcare-providing services has increased tremendously. Although a liver biopsy is the most authentic laboratory investigation for scoring the disease progression, it is an invasive technique. Researchers are vigorously working to find alternate markers for the scoring purpose. Despite the importance and association of leptin with metabolic syndrome and its related disorders, there have been relatively fewer studies on serum leptin and its association with NAFLD. Objective This study aimed to investigate variations in serum leptin levels between subjects with and without fibrosisin NAFLD and to assess the predictive value of serum leptin levels in NAFLD subjects. Materials and methods The study comprised 130 NAFLD subjects from two tertiary care hospitals in Lahorealong with 86 healthy controls that were age, gender, and BMI matched with the subjects. Based on the NAFLD fibrosis score (NFS), the subjects were divided into two sub-groups, subjects withsimple steatosis and those with fibrosis. Fasting serum leptin, glucose, and insulin levels were measured using enzyme-linked immunosorbent assay (ELISA). The Kruskal-Wallis test was applied to find differences between the three groups and Fisher's exact test for categorical comparison. To assess the predictive value of serum leptin for steatosis and fibrosis in NAFLD subjects, receiver operation characteristic (ROC) curve analysis was implemented. Results The difference in serum leptin level was statistically highly significant(p-value <0.001), with leptin levels of 10 (17.1) ng/mL among controls, 20.5 (21) ng/mL in simple steatosis, and 21 (28.6) ng/mL in fibrosis. The area under the ROC curve was 0.67 and 0.52 for steatosis and fibrosis, respectively. The cut-off value of 12.2 ng/mL showed 70% sensitivity and 50% specificity for steatosis, while at a threshold of 18 ng/mL, leptin demonstrated 40% sensitivity and specificity for fibrosis. Conclusion In conclusion, this study found that serum leptin levels are higher in NAFLD subjects compared to healthy controls, and it is a good independent predictor for the detection of liver steatosis.

NAFLD in the 21st Century: Current Knowledge Regarding Its Pathogenesis, Diagnosis and Therapeutics.

Non-alcoholic fatty liver disease (NAFLD) is a major public health issue worldwide. It is the most common liver disease in Western countries, andits global prevalence is estimated to be up to 35%. However, its diagnosis may be elusive, because liver biopsy is relatively rarely performed and usually only in advanced stages of the disease. Therefore, several non-invasive scores may be applied to more easily diagnose and monitor NAFLD. In this review, we discuss the various biomarkers and imaging scores that could be useful in diagnosing and managing NAFLD. Despite the fact that general measures, such as abstinence from alcohol and modulation of other cardiovascular disease risk factors, should be applied, the mainstay of prevention and management is weight loss. Bariatric surgery may be suggested as a means to confront NAFLD. In addition, pharmacological treatment with GLP-1 analogues or the GIP agonist tirzepatide may be advisable. In this review, we focus on the utility of GLP-1 analogues and GIP agonists in lowering body weight, their pharmaceutical potential, and their safety profile, as already evidenced inanimal and human studies. We also elaborate on other options, such as the use of vitamin E, probiotics, especially next-generation probiotics, and prebiotics in this context. Finally, we explore future perspectives regarding the administration of GLP-1 analogues, GIP agonists, and probiotics/prebiotics as a means to prevent and combat NAFLD. The newest drugs pegozafermin and resmetiron, which seem to be very promising, arealso discussed.

Adipokine (adiponectin-rs1501299) Gene Variant and Patient Characteristics in Relation to Metabolic-associated Fatty Liver Disease

BackgroundSeveral genetic and metabolic variables, most notably the variation in the adipokine gene rs1501298, have been linked to metabolic-associated fatty liver disease etiopathogenesis (MAFLD). Liver biopsy, the gold standard for diagnosing MAFLD, is an invasive procedure; therefore, alternative diagnostic methods are required. Consequently, the integration of these metabolic variables with some of the patients’ characteristics may facilitate the development of non-invasive diagnostic methods that aid in the early detection of MAFLD, identification of at-risk individuals, and planning of management strategies. MethodsThis study included 224 Egyptians (107 healthy individuals and 117 MAFLD patients). Age, sex, BMI, clinical and laboratory characteristics, and rs1501299 adipokine gene polymorphisms were examined. The Rs1501299 variant, insulin resistance, hypertension, obesity, blood pressure, lipid profile, hemoglobin A1C level, and hepatic fibrosis predictors were evaluated for MAFLD risk. The feasibility and effectiveness of developing non-invasive MAFLD diagnostic models will be investigated. ResultsThe +276G/T (rs1501299) polymorphism (GG vs GT/TT) was linked with MAFLD (OR: 0.43, CI: 0.26-0.69, p=0.002). The GG variants had lower MAFLD rates than those of the GT and TT variants. In addition to altered lipid profiles, patients with MAFLD showed increased gamma-glutamyl transferase levels (GGT: 56 IU/L vs. 36 IU/L). Genetic diversity also affects the accuracy of hepatic fibrosis and steatosis prediction. Hepatic fibrosis and steatosis predictors had ROC AUCs of 0.529%, 0.846%, and 0.700–0.825%, respectively. We examined a diagnostic model based on these variables, and demonstrated its effectiveness. ConclusionThe Adipokine variant rs1501299 increased the risk of MAFLD. Identifying and genotyping this variation and other metabolic variables allows for a non-invasive diagnostic model for early MAFLD diagnosis and identification of those at risk. This study illuminates the prevention and management of MAFLD. Further research with more participants is needed to verify these models and to prove their MAFLD diagnostic efficacy.

Nephronophthisis 13 caused by WDR19 variants with pancytopenia: case report.

We present a case of nephronophthisis 13 that resulted from WDR19 variants. The patient, a nine-year-old Japanese boy, had detection of mild proteinuria during a school urine screening. Urinalysis revealed mild proteinuria without hematuria. Blood tests indicated pancytopenia, mild elevation of liver enzymes, and kidney dysfunction. Ultrasound examination disclosed hepatosplenomegaly. Abdominal computed tomography and bone marrow assessments ruled out malignant tumors. Subsequent kidney and liver biopsies suggested nephronophthisis and congenital hepatic fibrosis. Furthermore, comprehensive genetic analysis through next-generation sequencing revealed compound heterozygous variants in WDR19 (NM_025132.4), including the previously reported c.3533G>A, p.(Arg1178Gln), and c.3703G>A, p.(Glu1235Lys) variants, confirming the diagnosis of nephronophthisis 13. There is potential need for liver and kidney transplantation in patients with nephronophthisis and hepatic fibrosis. Early diagnosis is therefore crucial to mitigate delays in treating complications associated with kidney and hepatic insufficiency and to facilitate preparation of transplantation. To achieve early diagnosis of nephronophthisis, it is imperative to consider it as a differential diagnosis when extrarenal symptoms and kidney dysfunction coexist, particularly when mild proteinuria is observed through opportunistic urinalysis. Genetic testing is important because nephronophthisis manifests as diverse symptoms, necessitating an accurate diagnosis. Next-generation sequencing was shown to be invaluable for the genetic diagnosis of nephronophthisis, given the numerous identified causative genes.

Clinicopathological features of Sjogren's syndrome complicated with liver injury

Objective: To study the clinicopathological features of Sjogren's syndrome (SS) with liver injury and to improve the understanding of this disease. Methods: Forty-nine patients with SS complicated with liver injury were collected from Beijing Ditan Hospital, Capital Medical University from October 2008 to January 2022. All patients underwent ultrasound-guided liver biopsy, and all specimens were stained with HE. The histopathologic characteristics were observed and the pathologic indexes were graded. Immunohistochemical stains for CK7, CK19, CD38, MUM1 and CD10 were performed by EnVision method; and special histochemical stains for reticulin, Masson's trichrome, Rhodanine, Prussian blue, periodic acid Schiff (PAS) and D-PAS stains were conducted. Results: The age of patients ranged from 31 to 66 years, including 3 males and 46 females. SS combined with drug-induced liver injury was the most common (22 cases, 44.9%), followed by autoimmune liver disease (13 cases, 26.5%, including primary biliary cholangitis in eight cases, autoimmune hepatitis in 3 cases, and PBC-AIH overlap syndrome in 2 cases), non-alcoholic fatty liver disease (NAFLD, 9 cases, 18.4%) and other lesions (5 cases, 10.2%; including 3 cases of nonspecific liver inflammation, 1 case of liver amyloidosis, and 1 case of porto-sinusoidal vascular disease). Among them, 28 cases (57.1%) were associated with obvious interlobular bile duct injury, mainly in SS combined with PBC group and drug-induced liver injury group. Twenty-three cases (46.9%) were associated with hepatocyte steatosis of varying degrees. In SS with autoimmune liver disease group, ISHAK score, degree of fibrosis bile duct injury, bile duct remodeling, lymphocyte infiltration of portal area, and plasma cell infiltration, MUM1 and CD38 expression; serum ALP and GGT, IgM; elevated globulin; positive AMA, proportion of AMA-M2 positive and IgM positive were all significantly higher than those in other groups(all P<0.05). Serum ALT, direct bilirubin and SSA positive ratio in SS combined with drug liver group were significantly higher than those in other groups(all P<0.05). The serum total cholesterol level in SS combined with PBC group (P=0.006) and NALFD group (P=0.011) were significantly higher than those in other groups (P<0.05). Conclusions: The pathologic manifestations of SS patients with liver injury are varied. The inflammatory lesions of SS patients with autoimmune liver disease are the most serious, and the inflammatory lesions of SS patients with non-alcoholic fatty liver disease and non-specific inflammation are mild. Comprehensive analysis of liver histopathologic changes and laboratory findings is helpful for the diagnosis of SS complicated with different types of liver injury.

Accumulation of Non-Pathological Liver Fat Is Associated with the Loss of Glyoxalase I Activity in Humans.

The underlying molecular mechanisms for the development of non-alcoholic fatty liver (NAFL) and its progression to advanced liver diseases remain elusive. Glyoxalase 1 (Glo1) loss, leading to elevated methylglyoxal (MG) and dicarbonyl stress, has been implicated in various diseases, including obesity-related conditions. This study aimed to investigate changes in the glyoxalase system in individuals with non-pathological liver fat. Liver biopsies were obtained from 30 individuals with a narrow range of BMI (24.6-29.8 kg/m2). Whole-body insulin sensitivity was assessed using HOMA-IR. Liver biopsies were analyzed for total triglyceride content, Glo1 and Glo2 mRNA, protein expression, and activity. Liquid chromatography-tandem mass spectrometry determined liver dicarbonyl content and oxidation and glycation biomarkers. Liver Glo1 activity showed an inverse correlation with HOMA-IR and liver triglyceride content, but not BMI. Despite reduced Glo1 activity, no associations were found with elevated liver dicarbonyls or glycation markers. A sex dimorphism was observed in Glo1, with females exhibiting significantly lower liver Glo1 protein expression and activity, and higher liver MG-H1 content compared to males. This study demonstrates that increasing liver fat, even within a non-pathological range, is associated with reduced Glo1 activity.

Hepatocellular carcinoma surveillance among people living with hepatitis B in Senegal (SEN-B): insights from a prospective cohort study

Chronic hepatitis B virus (HBV) infection is the predominant cause of hepatocellular carcinoma in west Africa, yet data on the incidence of HBV-related hepatocellular carcinoma remain scarce. We aimed to describe the uptake and early outcomes of systematic ultrasound-based hepatocellular carcinoma screening in SEN-B, which is a prospective HBV cohort in Senegal. In this prospective cohort study, we included treatment-naive, HBsAg-positive individuals who were referred to the two infectious diseases clinics (the Department of Tropical and Infectious Diseases and Ambulatory Treatment Center) at Fann University Hospital of Dakar, Senegal, between Oct 1, 2019, and Oct 31, 2022. All participants resided within the Dakar region. Participants underwent abdominal ultrasound, transient elastography, and clinical and virological assessments at inclusion and every 6 months. Liver lesions at least 1 cm in diameter on ultrasound were assessed using four-phase CT, MRI, or liver biopsy. Adherence to hepatocellular carcinoma surveillance was measured using the proportion of time covered, calculated by dividing the cumulative months covered by abdominal ultrasound examinations by the overall follow-up time, defined as the number of months from the date of cohort entry until the last recorded visit, hepatocellular carcinoma diagnosis, or death. Optimal adherence was defined as a proportion of time covered of 100%. Overall, 755 (99·6%) of 758 participants had at least one abdominal ultrasound performed. The median age of the enrolled participants was 31 years (IQR 25-39), 355 (47·0%) of 755 participants were women, and 82 (10·9%) had a family history of hepatocellular carcinoma. 15 (2·0%) of 755 individuals were HBeAg positive, 206 (27·3%) of 755 individuals had HBV DNA of more than 2000 IU/mL, and 27 (3·6%) of 755 had elastography-defined liver cirrhosis. Of ten (1·3%) participants with a focal lesion at least 1 cm at initial assessment, CT or MRI ruled out hepatocellular carcinoma in nine, whereas imaging and subsequent liver biopsy confirmed one patient with hepatocellular carcinoma. Two further patients with hepatocellular carcinoma were diagnosed at study presentation due to the presence of portal thrombosis on ultrasound. Excluding the three participants with hepatocellular carcinoma identified at baseline, 752 participants were eligible for screening every 6 months. Median follow-up time was 12 months (IQR 6-18) and the median number of ultrasounds per patient was 3 (2-4). During 809·5 person-years of follow-up, one incident hepatocellular carcinoma was reported, resulting in an incidence rate of 1·24 cases per 1000 person-years (95% CI 0·18-8·80). Overall, 702 (93·0%) of 755 participants showed optimal hepatocellular carcinoma surveillance, but this proportion decreased to 77·8% (42 of 54 participants) after 24 months. Hepatocellular carcinoma screening is feasible in HBV research cohorts in west Africa, but its longer-term acceptability needs to be evaluated. Long-term hepatocellular carcinoma incidence data are crucial for shaping tailored screening recommendations. Swiss National Science Foundation, the Swiss Cancer Research Foundation, the National Cancer Institute, and Roche Diagnostics. For the French translation of the abstract see Supplementary Materials section.

A Validation Study of Non-invasive Scoring Systems for Assessing Severity of Hepatic Fibrosis in a Cohort of South Indian Patients With Non-alcoholic Fatty Liver Disease

IntroductionLiver biopsy is the gold standard for diagnosing and staging NAFLD. But liver biopsy has its limitations. Non-invasive tests (NITs) eliminate many of the drawbacks of liver biopsy. We did a retrospective observational study to validate the non-alcoholic fatty liver disease Fibrosis Score (NFS score) and Fibrosis Score 4 (FIB-4 index) against the gold standard liver biopsy in a cohort of south Indian patients with NAFLD. Material and MethodsA retrospective observational analytical study of patients who had a liver biopsy with a diagnosis of NAFLD and had all the data for aetiology assessment and NIT calculation within 4 weeks of biopsy were included in the study. On liver biopsy NAFLD was scored as per NIH’s NASH committee (NASH CRN) grading system. NAFLD Fibrosis Score (NFS) and FIB-4 index were calculated and scores more than 0.676 and 2.67 respectively was taken as the cut-off to predict advanced fibrosis. The sensitivity, specificity, positive predictive value, negative predictive value and area under the ROC curve for NFS score and FIB-4 score to diagnose advanced fibrosis were calculated. ResultsA total of 147 patients were included in the study. Of these 56 (38.1%) patients had advanced fibrosis (Stage 3, 4). Patients with advanced fibrosis were more likely to be older and have DM. Patients with advanced fibrosis had lower platelet count, higher AST, lower albumin and higher AST/ALT ratio. The NFS of > 0.676 had a sensitivity of 68% and specificity of 100% and FIB-4 index of >2.67 had a sensitivity of 67% and specificity of 95.6 % in diagnosing advanced fibrosis in our study. ConclusionThe non-invasive scoring systems NAFLD Fibrosis Score (NFS) and FIB-4 index, can be used as a bedside tool for diagnosing Liver fibrosis in NAFLD allowing liver biopsy to be used in a more targeted manner for patients diagnosed with advanced fibrosis on NITs.

Inverse relationship between HBV DNA levels and liver histopathological changes in immune-tolerant CHB patients.

Limited data exist regarding the association between hepatitis B virus (HBV) DNA levels and liver histopathological changes in patients with chronic hepatitis B (CHB) during the immune tolerant (IT) phase. In this study, we retrospectively analysed liver biopsy results from 150 adult IT-CHB patients. The liver tissue necroinflammation and fibrosis were evaluated by the Scheuer scoring system. Multivariate logistic regression, smooth curve fitting, and segmented regression models were used to examine the association between HBV DNA levels and liver histopathological changes. A total of 26%, 30.67% and 42% of IT patients had significant necroinflammation (≥G2), significant fibrosis (≥S2) and significant histopathological changes (≥G2 and/or ≥S2), respectively. HBV DNA levels were independently and non-linear inversely associated with significant necroinflammation and histopathological changes in IT-CHB patients. Patients with HBV DNA levels <107 IU/mL had a higher risk of significant histopathological changes compared to those with levels >107 IU/mL. The findings were further confirmed by smooth curve fitting analyses, subgroup and sensitivity analyses. In segmented regression model analyses, the optimal DNA value for the lowest odds ratio of significant histopathological changes was 7.26 log10 IU/mL. A non-linear inverse association between HBV DNA levels and significant histopathological changes in IT-CHB patients. DNA 7.26 log10 IU/mL may serve as a potential cut-off point to define a 'true immune tolerant phase' with minimal liver histopathological changes.

A multiple variable index and extracardiac-Fontan associated hepatic fibrosis

BackgroundThe serial follow-up of Fontan-associated liver disease is challenging, as laboratory values are frequently normal, especially with mild to moderate liver disease. ObjectiveWe investigated a composite index's correlation with hepatic biopsy total fibrosis scores in extracardiac Fontan patients. MethodsWe identified extracardiac Fontan patients undergoing cardiac catheterization and transvenous hepatic biopsies between June 2013 and September 2023 and liver shear wave elastography between January 2017 and July 2023. We developed a composite index from the following: 1) elastography values, 2) sex, 3) history of a neonatal aortopulmonary shunt for pulmonary flow obstruction, 4) pacemaker, 5) Fontan duration, 6) bilirubin values, 7) univentricular dysfunction, 8) atrioventricular valvar regurgitation, 9) mean Fontan pressures, and 10) venovenous collaterals presence. We correlated the index with hepatic total fibrosis scores (0–8), the sum of pathology grading (0 to 4) performed for sinusoidal and portal fibrosis. We defined a hepatic total fibrosis score of 0–3 as none to mild and 4–8 as moderate to severe fibrosis. ResultsWe identified 62 patients who underwent 92 transvenous liver biopsies, with 30 patients undergoing 2 biopsies. The average age at biopsy was 15 ± 2 years. We found a strong correlation (rho = 0.8, p = .00001) between liver total fibrosis scores and composite index values. A receiver operating characteristic analysis demonstrated that an index cut-off value of ≥26 predicted a total fibrosis score of ≥4 with a sensitivity of 71 % and a specificity of 75 % (AUC = 0.73, 95 % CI 0.63, 0.83, p = .0001). ConclusionsWe developed a composite index with a moderate predictive ability to discriminate none to mild from moderate to severe hepatic fibrosis. Nevertheless, additional data is needed to assist further validation and determine its clinical utility in the serial follow-up of Fontan associated liver disease.