Fibrosis Grade Research Articles

Hepatic Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor Levels Decline in Hepatitis C but Are Not Associated with Progression of Hepatocellular Carcinoma.

Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is an antagonist of transforming growth factor (TGF)-β type 1 signaling. BAMBI functions as an anti-fibrotic protein and exerts pro- as well as anti-cancerogenic activities. Our study aimed to correlate hepatocyte BAMBI protein levels in hepatocellular carcinoma (HCC) with T stage, lymph node invasion, vessel invasion, grading, tumor size and Union for International Cancer Control (UICC) stage, as well as with liver inflammation and fibrosis stages. Hepatocyte BAMBI protein expression was assessed by immunohistochemistry in HCC tissues of 320 patients and non-tumor tissues of 51 patients. In the HCC tissues of the whole cohort and sex-specific analysis, BAMBI protein was not related to T stage, vessel invasion, lymph node invasion, histologic grade, UICC stage and tumor size. Accordingly, BAMBI was not associated with overall survival, recurrence-free and metastasis-free survival. BAMBI protein levels in tumor and non-tumor tissues were not related to inflammation and fibrosis grade. BAMBI protein levels in HCC tissues and non-tumor tissues from HCC patients, which were analyzed by immunoblot in a small cohort and by immunohistochemistry in the tissues of patients described above, were similar. Notably, BAMBI protein was low-abundant in HCC tissues of hepatitis C virus (HCV) compared to hepatitis B virus (HBV)-infected patients with comparable disease severity. Immunoblot analysis revealed reduced BAMBI protein in non-tumor tissues of patients with HCV in comparison to patients with HBV and normal human liver tissues. In summary, this analysis showed that hepatocyte BAMBI protein levels of patients with HCC are related to HCV infection rather than the severity of the underlying liver disease and cancer staging.

Significance of intrarenal vascular lesions in Ig A nephropathy prognosis

BackgroundImmunoglobulin A nephropathy (IgAN) is the predominant primary glomerulonephritis globally and remains a subject of active research with a focus on understanding its course and prognosis. Although vascular lesions are associated with IgAN, the current histopathological grading systems do not consider intrarenal vascular lesions when predicting patient prognosis. Therefore, this retrospective study conducted at Kyungpook National University Hospital between October 2016 and December 2021, aimed to elucidate the significance of intrarenal vascular lesions in IgAN by comparing the clinical data of patients with and without such lesions.MethodsData of patients with biopsy-confirmed primary IgAN between October 2016 and June 2021 at Kyungpook National University Hospital (Daegu, South Korea) were collected, and their medical records were reviewed. All slides from these 138 cases were independently pathologically reviewed by two nephropathologists (Y. J. K. and M. S. K.) using light microscope. The vascular lesions included in this study were fibrous intimal thickening, arteriolar wall thickening, and arteriolar hyalinosis. All cases were reviewed according to the Oxford Classification of IgA Nephropathy (2016) and Haas classification.ResultsOf the 138 patients, 88 exhibited at least one intrarenal vascular lesion. Patients with arteriolar wall thickening demonstrated a reduced estimated glomerular filtration rate (eGFR), elevated serum creatinine level and urine protein-to-creatinine ratio, an increased proportion of global glomerulosclerosis, and a higher histologic grade of interstitial fibrosis and tubular atrophy at the time of biopsy.ConclusionArteriolar wall thickening in IgAN are associated with reduced eGFR and global glomerulosclerosis. Moreover, reduced eGFR and global glomerulosclerosis are correlated with the progression to end-stage renal disease. Although the direct correlation between vascular lesions and end-stage renal disease is not entirely clear, a marginally significant association (log-rank test, p = 0.06) was observed with arterial wall thickening. This study suggests the potential importance of vascular lesions in the prognosis of IgAN, encouraging further investigation using larger cohort studies to establish a clearer association.

Evaluation of urinary volatile organic compounds as a novel metabolomic biomarker to assess chronic kidney disease progression

BackgroundThere is a need to develop accurate and reliable non-invasive methods to evaluate chronic kidney disease (CKD) status and assess disease progression. Given it is recognized that dysregulation in metabolic pathways occur from early CKD, there is a basis in utilizing metabolomic biomarkers to monitor CKD progression. Volatile Organic Compounds (VOCs), a form of metabolomic biomarker, are gaseous products of metabolic processes in organisms which are typically released with greater abundance in disease conditions when there is dysregulation in metabolism. How urinary VOCs reflect the abnormal metabolic profile of patients with CKD status is unknown. Our study aimed to explore this.MethodsIndividuals aged 18–75 years undergoing kidney biopsy were included. Pre-biopsy urine samples were collected. All biopsy samples had an interstitial fibrosis and tubular atrophy (IFTA) grade scored by standardized assessment. Urine supernatant was extracted from residue and sampled for stir bar sorptive extraction followed by Gas chromatography–mass spectrometry (GC-MS) analysis. Post-processing of GC-MS data separated complex mixtures of VOCs based on their volatility and polarity. Mass-to-charge ratios and fragment patterns were measured for individual VOCs identification and quantification. Linear discriminant analysis (LDA) was performed to assess the ability of urinary VOCs in discriminating between IFTA 0 (‘no or minimal IFTA’ i.e. <10%, IFTA), IFTA 1 (‘mild IFTA’ i.e. 10–25% IFTA) and IFTA ≥ 2 (‘moderate or severe IFTA’ i.e. >25% IFTA). Linear regression analysis adjusting for age, sex, estimated glomerular filtration rate, diabetes mellitus (DM) status, and albuminuria was conducted to determine significantly regulated urinary VOCs amongst the groups.Results64 study participants (22 individuals IFTA 0, 15 individuals IFTA 1, 27 individuals IFTA ≥ 2) were included. There were 34 VOCs identified from GC-MS which were statistically associated with correct classification between the IFTA groups, and LDA demonstrated individuals with IFTA 0, IFTA 1 and IFTA ≥ 2 could be significantly separated by their urinary VOCs profile (p < 0.001). Multivariate linear regression analysis reported 4 VOCs significantly upregulated in the IFTA 1 compared to the IFTA 0 group, and 2 VOCs significantly upregulated in the IFTA ≥ 2 compared to the IFTA 1 group (p < 0.05). Significantly upregulated urinary VOCs belonged to one of four functional groups - aldehydes, ketones, hydrocarbons, or alcohols.ConclusionsWe report novel links between urinary VOCs and tubulointerstitial histopathology. Our findings suggest the application of urinary VOCs as a metabolomic biomarker may have a useful clinical role to non-invasively assess CKD status during disease progression.

6819 Adult-Onset Craniopharyngioma Patients Are at High Risk for Hepatic and Metabolic Dysfunction in the First Year After Surgery

Abstract Disclosure: O. Cooper: None. V.S. Bonert: None. M. Noureddin: Advisory Board Member; Self; GlaxoSmithKline, Novo Nordisk, Merck, Takeda, Altimmune, BI, Northsea Therapeutics, Terns, 89BIO, Madrigal, Cytodyn, Corcept. Research Investigator; Self; Bristol-Myers Squibb, Akero, BI, GlaxoSmithKline, Allergan, Galectin, Genfit, Conatus, Enanta, Madrigal, Novartis Pharmaceuticals, Novo Nordisk, Shire, Takeda, Terns, Viking, Zudus, Gilead, Corcept. Stock Owner; Self; Rivus Pharma, CIMA, Cytodyn, ChronWell. M. Ader: None. M.O. Goodarzi: Advisory Board Member; Self; Nestle Health Science, Organon Laboratories. A.N. Mamelak: None. Background: Observational studies of adult-onset craniopharyngioma (AoCP) suggest that hepatic and metabolic dysfunction begin perioperatively, but rigorous evidence is lacking. We assessed prevalence of these sequelae in AoCP to better understand their long-term impact. Methods: The retrospective study included all patients with AoCP who underwent surgery at our center from 1993 to 2017. In the prospective study, newly diagnosed patients were assessed preoperatively and at 3 and 12 months postoperatively with MRI-PDFF/elastography, frequently sampled intravenous glucose tolerance test (FSIGT), and cardiometabolic biomarkers. The primary endpoint was hepatic fat fraction change from baseline. Secondary endpoints were changes in fibrosis, glucose/insulin metabolism, hypertension (HTN), and lipids. Data are summarized as median (IQR) or mean ± SD. Results: 35 patients were followed retrospectively for a mean of 116 months. After surgery, 73% had new-onset obesity. Mean BMI increased by 5.0 ± 5.8 kg/m2 and 40% progressed from overweight to obese. 43% had new-onset type 2 diabetes mellitus (T2DM) and 39% hyperlipidemia. In 16 patients with liver imaging, 11 had metabolic dysfunction-associated steatotic liver disease (MASLD), 5 metabolic dysfunction-associated steatohepatitis (MASH), and 4 cirrhosis. In the prospective study, data from 6 patients were analyzed, 4 for ≥12 months. Median age was 48.5 (40.5, 59); 50% were female. At baseline, 17% had HTN, 50% hyperlipidemia, 67% prediabetes, 50% obesity class 1, and 17% class 2. 40% had mild steatosis and none had fibrosis. Median A1C was 5.9% (5.3, 6.1). By 3 months postop, 83% had elevated liver enzymes and median hepatic fat fraction increased 213%, with steatosis in 67%. BMI increased by 4% (-1.8, 12.5); 1 patient remained normal weight, 1 progressed to overweight, 3 remained class 1 obesity and 1 class 2. By 12 months, 50% had elevated liver enzymes and all had steatosis, with fibrosis grade 3 in 1 patient. Median hepatic fat fraction increased 670% from baseline and 62% from month 3. 50% had T2DM and 50% prediabetes. Median A1C was 6.4% (5.9, 7.3). On FSIGT, disposition index decreased by 69% (-91, 50) and insulin sensitivity decreased by 51% (-70, 46). Median BMI was 30.8 kg/m2 (25.3, 37.1); 1 patient remained normal weight, 1 was overweight, 1 class 1 obesity, and 1 class 2. 50% had HTN and 50% had hyperlipidemia. Conclusion: By 10 years after surgery, most patients with AoCP have MASLD, with some progressing to MASH, fibrosis, and cirrhosis. T2DM, hyperlipidemia, and obesity are prevalent. In our small prospective cohort, by 1 year after surgery, all patients had developed MASLD, and BMI, blood pressure, and insulin and lipid profiles worsened. These results underscore the need for early interventions to halt progression of metabolic sequelae in patients with AoCP undergoing surgical resection and impede long-term comorbidity development. Presentation: 6/3/2024

7864 Accurate Machine Learning-Based Diagnosis of At-Risk MASH and MASLD Subtypes Using Categorical Gradient Boosting and Select Clinical, Biochemical, and Metabolomic Measurements: Building Highly Robust Models With Few Variables Through a Multinational, Multi-Center, Biopsy-Proven Cohort

Abstract Disclosure: K. Stefanakis: None. E. Axarloglou: None. C.S. Mantzoros: None. Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by intrahepatic lipid accumulation, may precipitate steatohepatitis (MASH) and liver fibrosis, and is a significant cardiometabolic risk factor. Liver biopsy, though invasive and costly, is the diagnostic gold standard, thus creating an unmet clinical need for accurate and reliable non-invasive diagnostic methods to diagnose MASLD, particularly the combination of MASH and significant fibrosis, classified as “at-risk MASH” and known to markedly increase morbidity and mortality. We aimed to leverage novel machine-learning (ML) algorithms to create lightweight but highly precise models that may accurately diagnose at-risk MASH and related histological outcomes through a top-down approach. This is a study of 443 participants from two Gastroenterology-Hepatology Clinics (Greece, Australia) and one Metabolic Surgery Clinic (Italy), including healthy controls and MASLD patients across the entire spectrum of the disease. All participants underwent liver biopsies, anthropometric, standard biochemical and additional hormonal measurements, and global serum metabolomics using ultra-high-performance liquid chromatography-tandem mass spectrometry, followed by robust batch correction and quality control, eventually identifying 687 known and 152 unknown metabolites. The dataset was randomly divided into a discovery (n=353) and a validation cohort (n=90) ensuring a balanced distribution of at-risk MASH and clinic. Our main ML pipeline implemented Categorical Gradient Boosting Machines using the CatBoost package for R. We pre-specified domain knowledge variables and implemented recursive feature elimination, among additional techniques, to build models through an iterative, algorithm-based process. The models were tested in the validation and entire cohort using k-fold and leave-one-out cross-validation with random resampling, and further assessed on relevant subgroups (MASLD status, obesity, diabetes, clinic, country). The main ML model consists of three routine clinical and biochemical variables, supplemented by two aminoacid metabolites (full model to be shown), and can detect the presence of at-risk MASH with a mean AUROC of 93% and mean accuracy of 92% in the validation cohort, and AUCS&amp;gt;93% with very high sensitivities and specificities per J-statistic in all subgroups. We likewise present ML models for the detection of MASLD, MASH, and fibrosis grades, with AUCs of over 90% in the validation cohort and all subgroups. Our models significantly outperform all applicable biomarker-based indices per DeLong’s tests. Further enhancement with lipidomic and proteomic variables will fully delineate the circulating biochemical snapshot of MASLD and likely lead to even more accurate, similarly structured models. Presentation: 6/1/2024

A-040 Association of GATA-4 and Platelet Derived Growth Factor-B in Metabolic (Dysfunction) Associated Fatty Liver Disease

Abstract Background Metabolic (dysfunction) associated fatty liver disease is a global concern as its prevalence is rising steeply ranging from 38.7% to 50.7%. MAFLD is a multifaceted burden of diseases such as diabetes, obesity, and cardio-metabolic diseases. It is the leading cause of hepatocellular carcinoma. GATA-4 is a zinc finger transcription factor located in liver sinusoidal endothelial cells and plays a critical role in liver regeneration. Platelet-derived growth factor-B (PDGF-B) plays a role in the profibrogenic trans-differentiation of Hepatic stellate cells and is actively involved in the development of hepatic fibrosis. Therefore, the study hypothesized that GATA-4 and PDGF-B are dysregulated and involved in the progression of MAFLD. Thus, the study aimed to assess the association of GATA 4 and PDGF-B in MAFLD, disease control, and healthy control. Methods 80 subjects were recruited after exclusion criteria from Gastroenterology and Medicine OPD at AIIMS, New Delhi, and divided into 3 groups: Group 1 (healthy control)-20, Group 2 (disease control)-20, and Group 3 (MAFLD)-40. Institutional ethical committee approval was obtained. The demographic and anthropometric details, blood investigations, Non-invasive scores (AST/ALT ratio, APRI &amp; FIB-4), and Transient elastography findings were illustrated in all the groups. The correlation between the GATA-4, PDGF-B, and platelet indices (MPV, P-LCR, PDW, and PCT) was done. STATA version 15 software was used for statistical analysis. Results GATA 4 was significantly decreased (p&amp;lt;0.001) and PDGF-B (p&amp;lt;0.001) was significantly increased in MAFLD subjects compared to healthy controls. However, no significant correlation was observed between GATA-4 and PDGF-B with platelet indices (P-LCR, PCT, and PDW). In contrast, mean platelet volume (MPV) was statistically significant (p&amp;lt;0.001) but it was clinically insignificant between the study groups. Similarly, HOMA-IR and GATA-4 did not show any significant correlation among MAFLD. However, CAP, LSM parameters of Transient elastography, APRI, and FIB-4 scores were statistically significant (p&amp;lt;0.001) in MAFLD when compared to healthy control. AUROC of non-invasive scores were found with weak discrimination and clinically not robust to distinguish the fibrosis grading. Conclusions GATA-4 and PDGF-B could be potential biomarkers, as no drugs are available so far to fill the global gap. However, pharmacological aspects need to be formulated for the treatment of MAFLD.

The Role of Strain Wave Elastography in The Evaluation of Renal Fibrosis in Patients with Kidney Diseases

Background: A renal biopsy represents the gold standard in the diagnosis, prognosis and management of patients with chronic kidney disease and glomerulonephritis. Strain wave elastography (SE) is a developing technique to assess tissue elasticity. The aim of this study was to correlate between the strain index value of renal parenchyma and degree of renal fibrosis detected with renal biopsy.Method: For 68 patients who were referred for a kidney biopsy, SE test was performed. The Banff scoring system was utilized to classify the IFTA grading of kidney fibrosis that assigns a severity level of mild, moderate, or severe. Receiver operating characteristic curve (ROC) was utilized to correlate between the severity of renal fibrosis and the grade of renal elasticity determined by SE.Results: In total, 38 males and 30 females, the echogenicity, qualitative and semiquantitative elastography showed significant positive correlation with serum creatinine, percentage of fibrosis, G score and tubular atrophy and significant negative correlation with eGFR. ROC curve of SE for diagnosis of interstitial fibrosis shown that echogenicity has sensitivity 100.0%, Specificity 62.5%, positive predictive value (PPV) 75.0%, negative predictive value (NPV) 100.0% with area under curve (AUC) 0.906, while qualitative elastography has sensitivity 77.8%, specificity 75.0%, PPV 77.8%, NPV 75.0% AUC 0.833, semi quantitative elastography has sensitivity 83.3%, specificity 93.8%, PPV 93.8%, NPV 83.3% with AUC 0.915.Conclusion: SE approach is simple to use, and can differentiate between varying stages of renal fibrosis. However, further research is required before it can be frequently used in clinical practice.

Essential thrombocythemia (ET) presenting as a combined cilioretinal artery occlusion (Cil.RAO) and central retinal vein occlusion (CRVO)

A 35-year-old male presented with sudden vision loss in his left eye for 1 day and was diagnosed with combined cilioretinal artery occlusion (Cil.RAO) and central retinal vein occlusion (CRVO). A multidisciplinary clinical work up was conducted to determine the underlying cause. A full blood count revealed a very high platelet count (1,147,000/mm3), prompting further hematologic investigation. Peripheral blood smear showed abundant platelet clumps, and bone marrow trephine biopsy indicated megakaryocytic hyperplasia and reticulin fibrosis (grade 1). The patient tested heterozygous for the JAK2 V617F mutation, a genetic marker for myeloproliferative disorders, and was diagnosed with essential thrombocythemia (ET). After a month of treatment with hydroxyurea 500 mg daily, his platelet count returned to normal. Thrombocythemia is associated with systemic and ocular thrombotic and embolic complications. A full blood count was pivotal in diagnosing and managing ET in this patient with combined retinal vascular disease.

Ultrasound viscoelastic imaging in the noninvasive quantitative assessment of chronic kidney disease

Background This study aims to evaluate the clinical application value of ultrasound viscoelastic imaging in noninvasive quantitative assessment of chronic kidney disease (CKD). Methods A total of 332 patients with CKD and 190 healthy adults as a control group were prospectively enrolled. Before kidney biopsy, ultrasound viscoelastic imaging was performed to measure the mean stiffness value (Emean), mean viscosity coefficient (Vmean), and mean dispersion coefficient (Dmean) of the renal. CKD patients were divided into three groups based on estimated glomerular filtration rate. The differences in clinic, pathology, ultrasound image parameters between the control and patient groups, or among different CKD groups were compared. The correlation between viscoelastic parameters and pathology were analyzed. Results Emean, Vmean, and Dmean in the control group were less than the CKD group (p < 0.05). In the identification of CKD from control groups, the area under curve of Vmean, Dmean, Emean, and combining the three parameters is 0.90, 0.79, 0.69, 0.91, respectively. Dmean and Vmean were increased with the decline of renal function (p < 0.05). Vmean and Dmean were positively correlated with white blood cell, urea, serum creatinine, and uric acid (p < 0.05). Vmean is positively correlated with interstitial fibrosis and inflammatory cell infiltration grades (p < 0.001). Conclusions Ultrasound viscoelastic imaging has advantages in noninvasive quantitative identification and evaluating renal function of CKD. Emean > 6.61 kPa, Vmean > 1.86 Pa·s, or Dmean > 7.51 m/s/kHz may suggest renal dysfunction. Combining Vmean, Dmean, and Emean can improve the efficiency of identifying CKD.

Spleen shear wave elastography measurements do not correlate with histological grading of liver fibrosis in Fontan physiology: a preliminary investigation.

Elevated spleen stiffness may be seen in patients with portal hypertension due to cirrhosis. In patients with Fontan physiology, elevated liver stiffness has been shown to correlate poorly with liver fibrosis. It is unknown whether spleen stiffness may instead serve as a surrogate marker of liver fibrosis in these patients. To compare spleen stiffness determined by shear wave elastography (SWE) with histological findings of an ultrasound-guided liver biopsy in patients who had undergone Fontan palliation as a potential surrogate for Fontan-associated liver disease. This was an IRB-approved single-center, retrospective study. Patients with Fontan palliation who had undergone both a spleen SWE study and a percutaneous liver biopsy between 2016 and 2020 were included. Biopsy, performed during cardiac catheterization, within 3months of the SWE was required for inclusion. Using Kruskal-Wallis tests, spleen stiffness was compared with three liver biopsy scoring methods: Ishak, METAVIR, and congestive hepatic fibrosis score (CHFS). When available, Pearson's correlation was also used to compare collagen deposition determined using Sirius Red stain (%SR) with SWE values. A P-value < 0.05 was considered statistically significant. Twenty-two patients (15 males) were included in the study, with a median age of 17years (IQR is 14.8-20.5years; age range: 7years to 30.2years). The median spleen stiffness was 2.94m/s (IQR: 2.57-3.61m/s; range: 1.48-4.27m/s). The median Fontan pressure was 11mm Hg (IQR: 10-13.3mm Hg; range: 7-19mm Hg) obtained within a median of 10days (IQR: 1-41days) of SWE. Splenic stiffness did not correlate with the extent of fibrosis determined by histology (all P > 0.05). There was also no statistically significant correlation between the %SR staining and SWE-determined spleen stiffness (Pearson's correlation of 0.165, P = 0.59, n = 13). In this preliminary study, SWE spleen stiffness values did not correlate with biopsy-determined scoring of liver fibrosis in patients with Fontan physiology.

Akkermansia muciniphila improve cognitive dysfunction by regulating BDNF and serotonin pathway in gut-liver-brain axis

BackrgroundAkkermansia muciniphila, a next-generation probiotic, is known as a cornerstone regulating the gut-organ axis in various diseases, but the underlying mechanism remains poorly understood. Here, we revealed the neuronal and antifibrotic effects of A. muciniphila on the gut-liver-brain axis in liver injury.ResultsTo investigate neurologic dysfunction and characteristic gut microbiotas, we performed a cirrhosis cohort (154 patients with or without hepatic encephalopathy) and a community cognition cohort (80 participants in one region for three years) and validated the existence of cognitive impairment in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced hepatic injury mouse model. The effects of the candidate strain on cognition were evaluated in animal models of liver injury. The expression of brain-derived neurotrophic factor (BDNF) and serotonin receptors was accessed in patients with fibrosis (100 patients) according to the fibrosis grade and hepatic venous pressure gradient. The proportion of A. muciniphila decreased in populations with hepatic encephalopathy and cognitive dysfunction. Tissue staining techniques confirmed gut-liver-brain damage in liver injury, with drastic expression of BDNF and serotonin in the gut and brain. The administration of A. muciniphila significantly reduced tissue damage and improved cognitive dysfunction and the expression of BDNF and serotonin. Isolated vagus nerve staining showed a recovery of serotonin expression without affecting the dopamine pathway. Conversely, in liver tissue, the inhibition of injury through the suppression of serotonin receptor (5-hydroxytryptamine 2A and 2B) expression was confirmed. The severity of liver injury was correlated with the abundance of serotonin, BDNF, and A. muciniphila.ConclusionsA. muciniphila, a next-generation probiotic, is a therapeutic candidate for alleviating the symptoms of liver fibrosis and cognitive impairment.Graphical

Amyloid precursor protein as a fibrosis marker in infants with biliary atresia.

Biliary atresia (BA) is a rare condition of unknown origin in newborns with jaundice. In BA bile ducts are non-functional, causing neonatal cholestasis and following liver fibrosis and failure. This retrospective study included liver biopsies of 14 infants with BA aged [mean ± SD] 63 ± 23 days. Patients were grouped according to the clinical course (jaundice-free vs recurrent jaundice vs required liver transplantation or liver fibrosis (Ishak fibrosis score)) and followed for 1.61-5.64 years (mean 4.03). Transcriptome profiles were assessed using a panel of 768 fibrosis-specific genes, reanalyzed via qRT-PCR, and confirmed via immunostaining. Plasma from an additional 30 BA infants and 10 age-matched controls were used for amyloid precursor protein (APP) quantification by ELISA. Different clinical outcome groups showed a homogeneous mRNA expression. Altered amyloid-metabolism-related gene expression was found between cases with Ishak fibrosis score greater than 4. Immunostaining confirmed a distinct presence of APP in the livers of all BA subjects. APP plasma levels were higher in BA than in age-matched controls and correlated with the histological fibrosis grade. These results suggest that amyloidosis may contribute to BA and liver fibrosis, indicating that APP could serve as a potential liquid biomarker for these conditions. Biliary atresia patients with higher fibrosis scores according to Ishak have higher hepatic expression of amyloid-related genes while amyloid precursor protein accumulates in the liver and increases in the circulation. After a recent study revealed beta-amyloid deposition as a mechanism potentially involved in biliary atresia, we were able to correlate amyloid-metabolism-related transcript levels as well as amyloid precursor protein tissue and plasma levels with the degree of hepatic fibrosis. These findings suggest that amyloid precursor protein is a fibrosis marker in infants with biliary atresia, reinforcing the role of amyloid metabolism in the pathogenesis of this serious disease.

Associated Factors for Liver Fibrosis and Histological Activity Index in Treatment-Naïve HBeAg-Positive Chronic Hepatitis B Infection: Insights from a Retrospective Analysis.

The study aimed to identify predictors of advanced fibrosis score and histological activity index (HAI) in HBeAg-positive patients to facilitate early disease detection and reduce the need for invasive biopsies. The single-center retrospective study included treatment-naïve HBeAg-positive chronic hepatitis B (CHB) patients. Patients with HAI ≥6 and/or fibrosis ≥2 were considered to have significant liver damage. Independent determinants were identified by univariate and multivariate logistic regression analysis. Cut-off values for variables were determined by receiver operating characteristics (ROCs) curve analysis. The study enrolled a cohort of 66 patients, with 51.5% male and a median age of 26 (22.7-34.2) years. In assessing necroinflammation, no significant differences were observed in age and gender between patients with HAI <6 and HAI ≥6. However, patients with HAI ≥6 exhibited higher aspartate aminotransferase (AST) levels compared to those with HAI <6. Furthermore, lower albumin levels and platelet (PLT) counts, along with higher fibrosis-4 (FIB-4) scores, were associated with HAI ≥6. In the evaluation of fibrosis, while gender distribution did not differ significantly, patients with fibrosis grade ≥2 were older and had higher HAI scores, HAI ≥6 ratios, and FIB-4 scores compared to those with fibrosis grade <2. Multivariate analysis identified albumin as a significant predictor for both HAI ≥6 and fibrosis grade ≥2. The area under ROC (AUROC) values of albumin for predicting HAI ≥6 and fibrosis ≥2 were 0.696 and 0.698, respectively, indicating moderate predictive ability. Albumin was found to be an independent predictor of liver damage in HBeAg-positive CHB patients. The fact that the optimal threshold values detected for both HAI ≥6 and fibrosis ≥2 in this patient group were close to normal values suggests that clinicians should be more cautious in monitoring albumin levels and other pre-defined parameters to avoid delays in diagnosis.

A FAPα-activated MRI nanoprobe for precise grading diagnosis of clinical liver fibrosis

Molecular imaging holds the potential for noninvasive and accurate grading of liver fibrosis. It is limited by the lack of biomarkers that strongly correlate with liver fibrosis grade. Here, we discover the grading potential of fibroblast activation protein alpha (FAPα) for liver fibrosis through transcriptional analysis and biological assays on clinical liver samples. The protein and mRNA expression of FAPα are linearly correlated with fibrosis grade (R2 = 0.89 and 0.91, respectively). A FAPα-responsive MRI molecular nanoprobe is prepared for quantitatively grading liver fibrosis. The nanoprobe is composed of superparamagnetic amorphous iron nanoparticles (AFeNPs) and paramagnetic gadoteric acid (Gd-DOTA) connected by FAPα-responsive peptide chains (ASGPAGPA). As liver fibrosis worsens, the increased FAPα cut off more ASGPAGPA, restoring a higher T1-MRI signal of Gd-DOTA. Otherwise, the signal remains quenched due to the distance-dependent magnetic resonance tuning (MRET) effect between AFeNPs and Gd-DOTA. The nanoprobe identifies F1, F2, F3, and F4 fibrosis, with area under the curve of 99.8%, 66.7%, 70.4%, and 96.3% in patients’ samples, respectively. This strategy exhibits potential in utilizing molecular imaging for the early detection and grading of liver fibrosis in the clinic.

Clinical implications of linking microstructure, spatial biochemical, spatial biomechanical, and radiological features in ligamentum flavum degeneration.

The ligamentum flavum (LF) degeneration is a critical factor in spinal stenosis, leading to nerve compression and pain. Even with new treatment options becoming available, it is vital to have a better understanding of LF degeneration to ensure the effectiveness of these treatments. This study aimed to provide insight into LF degeneration by examining the connections between various aspects of LF degeneration, including histology, microstructure, chemical composition, and biomechanics. We analyzed 30 LF samples from 27 patients with lumbar vertebrae, employing magnetic resonance imaging (MRI) to link lumbar disc degeneration grades with fibrosis levels in the tissue. X-ray diffraction (XRD) analysis assessed microstructural alterations in the LF matrix component due to degeneration progression. Instrumented nanoindentation combined with Raman spectroscopy explored the spatial microbiomechanical and biochemical characteristics of the LF's ventral and dorsal regions. Our outcomes revealed a clear association between the severity of LF fibrosis grades and increasing LF thickness. XRD analysis showed a rise in crystalline components and hydroxyapatite molecules with progressing degeneration. Raman spectroscopy detected changes in the ratio of phosphate, proteoglycan, and proline/hydroxyproline over the amide I band, indicating alterations in the extracellular matrix composition. Biomechanical testing demonstrated that LF tissue becomes stiffer and less extensible with increasing fibrosis. Notably, the micro-spatial assessment revealed the dorsal side of the LF experiencing more significant mechanical stress, alongside more pronounced biochemical and biomechanical changes compared to the ventral side. Degeneration of the LF involves complex processes that affect tissue histology, chemical composition, and biomechanics. It is crucial to fully understand these changes to develop new and effective treatments for spinal stenosis. These findings can improve diagnostic accuracy, identify potential biomarkers and treatment targets, guide personalized treatment strategies, advance tissue engineering approaches, help make informed clinical decisions, and educate patients about LF degeneration.

Plasma fibrinogen degradation products with salivary coagulopathy in OSMF among Indians.

Oral submucous fibrosis (OSMF) produces changes localized to oral cavity. Hence, it is reasonable to assume that saliva may have an important role in its etiology. This prospective case control study included 37 patients with OSMF which were compared with age and gender matched healthy controls. Salivary coagulopathy procedures as described by Chatuvedi et al. and quantification of plasma fibrinogen degradation products using a commercially available kit were carried out. The obtained data was analyzed using Chi-square tests and Tukey HSD test. The salivary coagulopathy was strongly indicated in saliva of OSMF patients and was dependent on the severity of disease. There were also increased levels of plasma fibrinogen degradation products compared to the controls and were found to have a statistically significant correlation with increasing clinical grades of oral submucous fibrosis (p≤ 0.05).

Unveiling the link: hepatitis C virus and Parkinson’s disease

BackgroundParkinson disease (PD) is one of the disabling neurological disorders. The etiology of Parkinson disease is still unknown. Hepatitis C virus is one of the neurotropic viruses which is incriminated in the pathogenesis of Parkinson disease. Hepatitis C virus might affect the dopaminergic neurons, affecting the advancement of PD.MethodsThis study is observational, cross-sectional study done on 2 phases: one phase on PD patients without history of HCV and another phase on HCV patients with no history of PD. 104 PD patient were tested for HCV antibodies and 40 HCV patients with various grades of liver fibrosis were assessed for early pre-motor symptoms of parkinsonism.ResultsAmong patients with parkinsonism, HCV Abs testing was negative in all the studied patients. On the other hand, chronic HCV group included 40 patients, 27.5% were cirrhotic (11/40). Child C patients showed significantly higher percentages of non-motor parkinsonian symptoms, and regarding the HCV group, the majority (85%) of the patients show cognitive impairment, (27.5%) were at stage 1 of anxious mood, while half (50%) of the patients were at stage 1 of fatigue as evaluated by UPDRS Score. Cirrhosis was a significant factor for having non-motor (early) parkinsonism.ConclusionHere we show that advanced cirrhosis is associated with a variety of neurological symptoms including parkinsonian, which needs awareness for better preventive and therapeutic measures for early treatment of hepatitis avoiding the occurrence of cirrhosis, which can lead to parkinsonism.

The histological grading of fibrosis in Budd Chiari Syndrome: a chronic liver disease, different from others

The histological grading of fibrosis in Budd Chiari Syndrome: a chronic liver disease, different from others

The Derivation and External Validation of a Fibrosis Risk Model for Colorectal Tumours Undergoing Endoscopic Submucosal Dissection.

Background: Endoscopic submucosal dissection (ESD) is an advanced technique that can become more challenging in the presence of submucosal fibrosis. Predicting the grade of fibrosis is important in order to identify technically difficult ESD. Aims and Methods: Our study aimed to derive and validate a prediction model to determine the preoperative degree of submucosal fibrosis in colorectal tumours undergoing ESD. A predictive model was developed to derive the probability of an increasing submucosal fibrosis in the derivation cohort and then externally validated. Results: 309 patients (age: 68 ± 10.9 years) underwent colorectal ESD between January 2016 and June 2020. F0, F1, and F2 fibroses were reported in 196 (63.4%), 70 (22.6%), and 43 (13.9%) cases, respectively. R0 resection was found in 266 (87%) lesions. At multivariable analysis in the derivation cohort, lesion morphology (OR = 0.37 and CI = 0.14-0.97 for LST-NG vs. 0-Is; OR = 0.29 and CI = 0.1-0.87 for the LST mixed type vs. 0-Is; and OR = 0.32 and CI = 0.1-1.03 for LST-G vs. 0-Is) and increasing size (OR = 1.02 and CI = 1.01-1.04 for a 1 mm increase) were significantly associated with an increasing degree of fibrosis. The model had fair discriminating ability in the derivation group (AUROC = 0.61 and CI = 0.52-0.69 for F1-F2 vs. F0 fibroses; AUROC = 0.61 and CI = 0.45-0.77 for F2 vs. F0-F1 fibroses) and in the validation group (AUROC = 0.71 and CI = 0.59-0.83 for F1-F2 vs. F0 fibroses; AUROC = 0.65 and CI = 0.52-0.77 for F2 vs. F0-F1 fibroses). Conclusions: Our findings introduce a new tool for the stratification of ESD technical difficulty based on lesion size and morphological characteristics which could become crucial during the procedure's planning process.

Liver and spleen shear-wave elastography in the diagnosis and severity staging of myeloproliferative diseases and myelofibrosis.

Spleen and liver stiffness, investigated by VCTE (Vibration-Controlled Transient Elastography), have been associated with marrow fibrosis in patients with myeloproliferative neoplasms (MPNs). Tissue stiffness can be assessed by shear wave point (pSWE) and bidimensional elastography (2DSWE). Spleen stiffness (SS)values were higher in Myelofibrosis (MF) and Polycythemia Vera (PV) compared to Essential Thrombocythemia (ET). We aimed to identify SWE differences between MPN patients and healthy volunteers; to evaluate specific SWE features in patients with MF, PV and ET; to establish a correlation with bone marrow fibrosis in patients with myeloproliferative disease. Patients with myeloproliferative disease and healthy volunteers performed evaluation of spleen and liver stiffness (LS)by pSWE and 2DSWE. A total of 218 subjects were included: 143 with myeloproliferative disease (64 MF, 29.4%, 33 PV, 15.1% and 46 ET, 21.1%), and 75 (34.4%) healthy volunteers. Compared to volunteers, MF patients had greater spleen (pSWE 40.9 vs. 26.3kPa, p < 0.001; 2DSWE 34.9 vs. 20.1kPa, p < 0.001), and liver stiffness (pSWE 7.72 vs. 5.52kPa, p < 0.001; 2DSWE 6.96 vs. 5.01kPa, p < 0.001). In low (0-1) (n = 81, 60.4%) versus high-grade bone marrow fibrosis (2-3) (n = 42, 39.6%), is evident a higher median stiffness in patients with higher grades of fibrosis both for liver (pSWE 5.2 vs. 6.65kPa; 2DSWE 5.1 vs. 6.05kPa) and spleen (pSWE 27.2 vs. 37.9kPa, 2DSWE 21.7 vs 30.75kPa-p < 0.001 in both). SWE evaluation distinguishes MF patients from HV and ET/PV and may help in MPN diagnosis. LS and SS values are associated with bone marrow fibrosis grade.