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Introduction: The relevance of plasma cells in the allograft liver is of utmost importance and objective assessment of these infiltrates and correlation with other ancillary findings needs to be evaluated. Materials and Methods: Three hundred and sixty-eight graft liver biopsies received in the department from 2012 to 2022 and 115 allograft liver biopsies with histopathological diagnosis of rejection were selected. Based on plasma cells percentage in the portal tracts, the biopsies were divided into three groups: Group 1 showing not more than an occasional plasma cell, Group 2 showing 10% plasma cells. Rejection activity index (RAI), portal/lobular inflammation, interface activity, subendothelial inflammation (portal and central vein), duct damage/loss, presence of cholestasis, apoptosis, perivenulitis, necrosis, rosette along with serial liver function tests (LFTs), and patient status at 1 year of follow-up were recorded and compared between the groups. Results: Plasma cell infiltrates were observed in 52.6% of the specimens, with the mean percentage of plasma cells in the infiltrates being 4.9. Increased plasma cell infiltrates were associated with higher RAI scores, marked duct damage, marked portal and central vein endotheliitis, marked portal inflammation, and presence of interface activity. Higher levels of transaminitis were recorded at the time of biopsy, but no significant association was observed in the fall of serial LFTs over a 2-week period with the presence of plasma cells. Conclusion: Identifying plasma cell infiltrates in liver allografts can serve as a clue toward increased severity of rejection in liver allograft biopsies. Further studies with emphasis on correlation with the clinical outcome and response to treatment are needed to validate its utility as an objective tool.

Introduction and Objectives: Hepatic proteome and gut microbiota alterations are known in alcohol-associated hepatitis (AAH). Current animal models sparsely mimic human AAH. We aimed to develop an murine model that closely resembled human AAH. Materials and Methods: Male C57BL/6N mice were pair-fed control/incremental ethanol Lieber-DeCarli diets and thioacetamide (TAA) for 12-weeks to induce AAH. Hepatic proteome was analyzed using LC-MS/MS. Gut-bacteria was determined using 16s-rRNA sequencing. Results: Mice exposed to EtOH+TAA displayed higher expression of liver triglycerides (1.5-fold, p = 0.001), pro-inflammatory (IL6, 1.5-fold, p = 0.002 and TNFα, 1.7-fold, p = 0.01), fibrotic (TGF-β, 2.7-fold, p = 0.01 and Col1α1, 2-fold, p = 0.01) and oxidative markers (GSH and SOD (-1.5 fold, p = 0.004 & 0.005 respectively)) as compared to EtOH alone. Histology of EtOH+TAA liver displayed pericellular liver fibrosis, increased steatosis, and neutrophil infiltration, which resembled human AAH. In the 12wk EtOH+TAA group, Desulfobacteria, Campylobacteria, and Patescibacteria increased by 2-fold (p = 0.02). Pathway combined score (CS, log10) in EtOH+TAA treatment showed upregulated hepatic ethanol oxidation (CS=1.93), fatty acid biosynthesis (CS=2.48), necrosis (CS=1.59), collagen formation (CS=1.28) and hypoxia (CS=0.68) and downregulated fatty acid beta-oxidation (CS=2.37), PPAR signaling (CS=1.35) fatty acid degradation (CS=2.35), bile acid metabolism (CS=1.87), and oxidative phosphorylation (CS=1.50), as observed in human disease. Conclusions: Using an ethanol-thioacetamide combination in mice results in a faster establishment of AAH with fibrosis than previously known models. Differential protein expression strongly correlates with pathways found altered in human AAH, thus making the model mimic human disease better than other known models., respectively. Thioacetamide (TAA) was administered to enhance liver fibrosis and mimic human AAH.

Aims: Autoimmune liver diseases (AILD) represent a spectrum of related yet distinct immune-mediated disorders. The literature on the prevalence of these AILDs in Indian population is scarce. This study aims to assess the prevalence and clinicopathological spectrum of various AILDs especially the overlap syndrome. Materials and Methods: A 10-year (2011–2020) cross-sectional, retrospective observational study of histological proven cases of AILD was conducted. Clinical, demographic, and laboratory parameters were retrieved. Two pathologists independently reviewed the liver biopsies and reassessed 18 histopathological parameters. Results: During the study period, 17664 liver biopsies were received, out of which 1060 (6%) biopsies of AILD were identified. After exclusion, we had 721 cases which revealed a distribution of autoimmune hepatitis (AIH)-64.7%, primary biliary cholangitis (PBC)-14.8%, primary sclerosing cholangitis (PSC)-7.6%, overlap AIH-PBC 11%, and overlap AIH-PSC 1.7%. AIH patients had significantly higher prevalence for severe lobular inflammation (27%, P ≤ 0.001), several lobular plasma cells (37%, P ≤ 0.001), central perivenulitis (30%, P ≤ 0.001), hepatic rosettes (51%, P ≤ 0.001), and necrosis (35.5%, P ≤ 0.001), while PBC patients had significantly higher frequency of florid duct lesions (11.2%, P ≤ 0.001), duct loss (83.17%, P ≤ 0.001), bile duct damage (76.6%, P ≤ 0.001), and periportal copper deposits (19.6%, P ≤ 0.001). Overlap AIH-PBC group had the highest proportion of severe portal inflammation (27.5%, P ≤ 0.001), prominent portal plasma cells (75%, P ≤ 0.001), moderate interface activity (53.7%, P ≤ 0.001), Mallory-Denk bodies (27.5%, P ≤ 0.001), and periportal cholate stasis (25%, P ≤ 0.001). Conclusion: Prevalence of biopsy-proven AILDs in our study cohort is 6%. AIH (64.7%) is the most common AILD followed by PBC (14.8%). Overlap syndrome (AIH-PBC) showed prevalence of 11%.

Objectives The objective of the study was to identify accurate site of liver biopsy under ultrasound and elastography guidance and compare the shear wave elastography (SWE) and transient elastography (TE) diagnostic accuracy with histopathological correlation.

Background & Aims: Lymphatic vessels (LVs) are crucial for maintaining abdominal fluid homoeostasis and immunity. In cirrhosis, mesenteric LVs (mLVs) are dilated and dysfunctional. Given the established role of vascular endothelial growth factor-C (VEGF-C) in improving LVs, we hypothesised that VEGF-C treatment could ameliorate the functions of mLVs in cirrhosis. Methods: In this study, we developed a nanoformulation comprising LV-specific growth factor, recombinant human VEGF-C (Cys156Ser) protein (E-VEGF-C) and delivered it orally in different models of rat cirrhosis to target mLVs. Cirrhotic rats were given nanoformulation without VEGF-C served as vehicles. Drainage of mLVs was analysed using tracer dye. Portal and systemic physiological assessments and computed tomography were performed to measure portal pressures and ascites. Gene expression and permeability of primary mesenteric lymphatic endothelial cells (LyECs) was studied. Immune cells in mesenteric lymph nodes (MLNs) were quantified by flow cytometry. Endogenous and exogenous gut bacterial translocation to MLNs was examined. Results: In cirrhotic rats, mLVs were dilated and leaky with impaired drainage. Treatment with E-VEGF-C induced proliferation of mLVs, reduced their diameter, and improved functional drainage. Ascites and portal pressures were significantly reduced in E-VEGF-C rats compared with vehicle rats. In MLNs of E-VEGF-C animals, CD8+CD134+ T cells were increased, whereas CD25+ regulatory T cells were decreased. Both endogenous and exogenous bacterial translocation were limited to MLNs in E-VEGF-C rats with reduced levels of endotoxins in ascites and blood in comparison with those in vehicle rats. E-VEGF-C treatment upregulated the expression of vascular endothelial-cadherin in LyECs and functionally improved the permeability of these cells. Conclusions: E-VEGF-C treatment ameliorates mesenteric lymph drainage and portal pressure and strengthens cytotoxic T-cell immunity in MLNs in experimental cirrhosis. It may thus serve as a promising therapy to manage ascites and reduce pathogenic gut bacterial translocation in cirrhosis. Impact and Implications: A human recombinant pro-lymphangiogenic growth factor, VEGF-C, was encapsulated in nanolipocarriers (E-VEGF-C) and orally delivered in different models of rat liver cirrhosis to facilitate its gut lymphatic vessel uptake. E-VEGF-C administration significantly increased mesenteric lymphatic vessel proliferation and improved lymph drainage, attenuating abdominal ascites and portal pressures in the animal models. E-VEGF-C treatment limited bacterial translocation to MLNs only with reduced gut bacterial load and ascitic endotoxins. E-VEGF-C therapy thus holds the potential to manage ascites and portal pressure and reduce gut bacterial translocation in patients with cirrhosis.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is an uncommon form of primary liver carcinoma. It is heterogenous in terms of morphology, immunohistochemistry, radiology, and clinical features; making it a challenging entity for diagnosis. Aims: The purpose of the present study was to evaluate clinicopathological characteristics of patients with cHCC-CCA. Settings and Design: Retrospective observational study. Materials and Methods: The patients diagnosed with cHCC-CC were identified from hepatic surgical specimens and were evaluated. Statistical Analysis: Survival was estimated as per Kaplan–Meier method. Results: Out of six patients, five had undergone resection while one had liver transplant. Five were male and one was female and the mean age was 52 years. Tumor markers revealed raised serum alfa-fetoprotein and CA19.9 in four and three patients, respectively. Five of the liver specimens were cirrhotic. Diagnosis was predominantly based on tumor morphology. All cases were of Allen and Lisa type B and cHCC-CCA as per WHO (2019) classification. Stem cell features

Dilated and dysfunctional gut lymphatic vessels (LVs) have been reported in experimental cirrhosis. Here, we studied LVs in duodenal (D2)-biopsies of liver cirrhosis patients and investigated the prognostic role of a LV marker, podoplanin (PDPN), in predicting the mortality of patients with cirrhosis. A prospective, single-center cohort study was performed in liver cirrhosis patients (n = 31) and matched healthy controls (n = 9). D2-biopsies were obtained during endoscopy procedure, immunostained with PDPN, and scored based on 1) intensity and 2) density of positively-stained LVs per high power field. Gut and systemic inflammation were estimated by quantifying duodenal CD3+ intraepithelial lymphocytes (IELs), CD68+ macrophages, and serum TNF-α and IL-6 levels, respectively. Gut permeability and inflammation as assessed by quantifying gene expression of TJP1, OCLN, TNF-α, and IL-6 in D2-biopsies. Gene expression of LV markers, PDPN (8-fold), and LYVE1 (3-fold) was enhanced in D2-biopsies of cirrhosis patients compared to control (p < 0.0001). The mean PDPN score in decompensated cirrhosis patients (6.91 ± 1.26, p < 0.0001) was significantly increased as compared to those with compensated (3.25 ± 1.60). PDPN score positively and significantly correlated with the number of IELs (r = 0.33), serum TNF-α (r = 0.35), and IL-6 (r = 0.48) levels, while inversely correlated with TJP1 expression (r = -0.46, p < 0.05 each). In Cox regression, the PDPN score was a significant and independent 3-month-mortality predictor in patients (HR: 5.61; 1.08-29.109; p = 0.04). The area under the curve for the PDPN score was 84.2, and cutoff value for predicting mortality was ≥6.5 with 100% sensitivity and 75% specificity. Collectively, dilated LVs with high PDPN expression in D2-biopsies is a characteristic feature of patients with decompensated cirrhosis. PDPN score correlates with enhanced gut and systemic inflammation and also associates with 3-month mortality in cirrhosis.

Background: Liver biopsy plays a crucial role in evaluating allograft dysfunction. Comprehensive analysis of the histological spectrum of complications, particularly rejection, in different time zones is lacking. Aim: To evaluate the histological spectrum of rejection, in four time zones, in a large Living donor liver transplant series. Patients and Methods: Retrospective analysis of 313 biopsies for the last 10 years of living donor liver transplantation (LDLT) recipients. 123 of which had rejection as diagnosis, were redistributed in four time zones [1-early ( 12) months] and were assessed for sixteen histological parameters. Results: Biopsies in time zone 1 (26.5%), 2 (20.7%), 3 (24.6%), and 4 (28.1%)] were nearly equal. Multiple coexistent complications existed in 12% of the cases. Rejection diagnosed in time zone groups: 1 = 22 (17.9%), 2 = 27 (22%), 3 = 36 (29.3%), and 4 = 38 (30.9%). Portal inflammation mixed type (P < 0.000), portal vein (P = 0.001) and hepatic vein endothelialitis (P < 0.000), portal eosinophils (P = 0.001), and lymphocytic bile duct damage (P = 0.01) were most pronounced in group 1. Perivenulitis without hepatic vein endothelialitis was observed (P = 0.03) in groups 3, whereas bile duct atypia (P = 0.01) and duct loss (P < 0.000) were observed in group 4. Multiple episodes of rejection displayed significant association with central perivenulitis (P = 0.002) and bile duct loss (P < 0.001). Conclusions: Histological analysis in large series of LDLT recipients highlights the spectrum of complications in different time zones. Late acute and chronic rejection occurred as early as 3 months posttransplant. Central perivenulitis and bile duct atrophy were associated with repeated episodes of rejection and deterioration.

Liver transplantation is now a well-established therapeutic strategy for irreversible acute and chronic liver diseases. There is a broad spectrum of complications encountered in early and late period after transplantation and these contribute to significant morbidity and mortality. Distinguishing among these complications often requires interpretation of allograft biopsies. Histology is the gold standard for the diagnosis of rejection. However, interpretation of these biopsies is quite challenging due to the atypical and complex histomorphology. Multiple simultaneous insults, effects of immunosuppression (IMS), de novo complications, and presentations distinct from non-transplant setting are a few cardinal concerns. Awareness of the time period of occurrence of various complications, the most characteristic histological features or patterns, and distinguishing features between various complications are crucial. The management can be completely divergent; hence, recognition of dominant problem and interpretation in appropriate clinical context is much needed. This review focuses on histopathology of major complications accountable for early and late graft dysfunction. Tabulation of clinico-pathological features to distinguish various complications helps to solve the conundrums and arrive at the correct diagnosis.

Abstract Background There is limited scientific evidence on the potential of spectral computed tomography (SCT) for differentiation of nodules in the cirrhotic liver. We aimed to assess SCT-generated material density (MD) parameters for nodule characterisation in cirrhosis. Methods Dynamic dual-energy SCT scans of cirrhotic patients performed over 3 years were retrospectively reviewed. They were classified as hepatocellular carcinoma (HCC), regenerative or indeterminate, according to the European Association for the Study of the Liver criteria. MD maps were generated to calculate the area under the curve (AUC) and cutoff values to discriminate these nodules in the hepatic arterial phase (HAP) and portal venous phase (PVP). MD maps included iodine concentration density (ICD) of the liver and nodule, lesion-to-normal liver ICD ratio (LNR) and difference in nodule ICD between HAP and PVP. Results Three hundred thirty nodules belonging to 300 patients (age 53.0 ± 12.7 years, mean ± standard deviation) were analysed at SCT (size 2.3 ± 0.8 cm, mean ± SD). One hundred thirty-three (40.3%) nodules were classified as HCC, 147 (44.5%) as regenerative and 50 (15.2%) as indeterminate. On histopathology, 136 (41.2%) nodules were classified as HCC, 183 (55.5%) as regenerative and 11 (3.3%) as dysplastic. All MD parameters on HAP and the nodule difference in ICD could discriminate pathologically proven HCC or potentially malignant nodules from regenerative nodules (p < 0.001). The AUC was 82.4% with a cutoff > 15.5 mg/mL for nodule ICD, 81.3% > 1.8 for LNR-HAP and 81.3% for difference in ICD > 3.5 mg/mL. Conclusion SCT-generated MD parameters are viable diagnostic tools for differentiating malignant or potentially malignant from benign nodules in the cirrhotic liver.

Introduction: The aim of the study was to assess the peripheral blood lymphocyte subsets as immune markers for acute cellular rejection (ACR) in the living donor liver-transplant (LDLT) recipients using high-dimensional flow cytometry. Materials and Methods: This is a prospective observational study in which 19 LDLT recipients undergoing liver biopsy for suspected rejection were enrolled after informed and written consent. They were divided into two groups as rejection group (11/19) and no rejection group (6/19). In addition to this, nine healthy subjects were also enrolled as controls. Biochemical and immune parameters were analyzed among these groups. Results: It was observed that hematocrit, total protein, and serum albumin levels were significantly higher in rejection group as compared to no rejection group (P = 0.021, 0.006, and 0.044, respectively), whereas aspartate transaminase was significantly lower in rejection group compared to no rejection group (P = 0.027). It was seen that central memory (CM) helper T (TH) cells and CM cytotoxic T (TC) cells were significantly lower in no rejection group when compared to healthy controls (P = 0.02 and 0.009, respectively). The effector TH cells and TH1 cells were significantly higher in the rejection group when compared to healthy controls (P = 0.03 and 0.04, respectively). However, the effector CD8+ T cell and memory B cell subsets were significantly higher in rejection and no rejection group compared with healthy controls (P = 0.03, 0.01 and P = 0.02, 0.009 respectively). The activated regulatory T cells (TREG) and plasmablasts were significantly higher in no rejection group when compared with healthy control (P = 0.038 and 0.016, respectively). The naïve B cells were significantly lower in rejection and no rejection group compared to healthy controls (P = 0.001 and 0.01, respectively). However, when immune profile was compared among the rejection and no rejection group, we could not arrive at statistically significant results owing to the small sample size. Conclusion: The data in this study show that there is difference in immune profile of lymphocyte subsets among rejection and no rejection groups compared to healthy controls and hence can be used to characterize these patients. The promising immune subsets that can serve as biomarkers for ACR post-LDLT are TH1 cells, CM TH cells, effector TH cells, CM TC cells, effector TC cells, activated TREG cells, naïve B cells, memory B cells, and plasmablasts.

The Indian Association of Pathologists and Microbiologists (IAPM) and Indian Society of Gastroenterology (ISG) decided to make a joint consensus recommendation for handling, processing, and interpretation of SI biopsies for the diagnosis and management of celiac disease (CD) recognizing the inhomogeneous practice of biopsy sampling, orientation, processing, and interpretation. A modified Delphi process was used to develop this consensus document containing a total of 42 statements and recommendations, which were generated by sharing the document draft, incorporating expert's opinion, followed by three cycles of electronic voting as well as a full-day face-to-face virtual ZOOM meeting and review of supporting literature. Of the 42 statements, 7 statements are on small intestinal (SI) biopsy in suspected patients of CD, site and the number of biopsies; 7 on handling, fixative, orientation, processing, and sectioning in pathology laboratories; 2 on histological orientation; 13 statements on histological interpretation and histological grading; 3 on the assessment of follow-up biopsies; 2 statements on gluten-free diet (GFD)-nonresponsive CD; 4 on challenges in the diagnosis of CD; 2 statements each on pathology reporting protocol and training and infrastructure in this area. The goal of this guideline document is to formulate a uniform protocol agreed upon both by the experienced pathologists and gastroenterologists to standardize the practice, improve the yield of small bowel biopsy interpretation, patients' compliance, overall management in CD, and generate unified data for patient care and research in the related field.

Liver resections are performed for acute and chronic end stage liver failure, primary and secondary liver malignancies as well as for several other neoplastic and non-neoplastic conditions. Hepatectomy specimens can be total, partial, or wedge resections. These specimens are relatively rare and complex. Meticulous handling, orientation, dissection, margin assessment, and reporting as per the latest guidelines, often require a multidisciplinary approach. This article discusses the approach to grossing of hepatectomy specimens, and the most important macroscopic considerations for specific conditions.

Troxerutin (TXR) is a phytochemical reported to possess anti-inflammatory and hepatoprotective effects. In this study, we aimed to exploit the antiarthritic properties of TXR using an adjuvant-induced arthritic (AIA) rat model. AIA-induced rats showed the highest arthritis score at the disease onset and by oral administration of TXR (50, 100, and 200 mg/kg body weight), reduced to basal level in a dose-dependent manner. Isobaric tags for relative and absolute quantitative (iTRAQ) proteomics tool were employed to identify deregulated joint homogenate proteins in AIA and TXR-treated rats to decipher the probable mechanism of TXR action in arthritis. iTRAQ analysis identified a set of 434 proteins with 65 deregulated proteins (log2 case/control≥1.5) in AIA. Expressions of a set of important proteins (AAT, T-kininogen, vimentin, desmin, and nucleophosmin) that could classify AIA from the healthy ones were validated using Western blot analysis. The Western blot data corroborated proteomics findings. In silico protein–protein interaction study of tissue-proteome revealed that complement component 9 (C9), the major building blocks of the membrane attack complex (MAC) responsible for sterile inflammation, get perturbed in AIA. Our dosimetry study suggests that a TXR dose of 200 mg/kg body weight for 15 days is sufficient to bring the arthritis score to basal levels in AIA rats. We have shown the importance of TXR as an antiarthritic agent in the AIA model and after additional investigation, its arthritic ameliorating properties could be exploited for clinical usability.

Objectives The purpose of this study is to determine the diagnostic efficacy of enzyme-linked immunosorbent assay (ELISA) in radiologically confirmed liver mass lesions for the diagnosis of hepatic hydatid disease (HHD) and to compare the diagnostic performance of ELISA with fine needle aspiration cytology (FNAC) (taken as standard) for HHD diagnosis. Materials and Methods This retrospective study included blood samples of 223 patients with radiologically confirmed liver mass lesions in which immunoglobulin G (IgG) anti-Echinococcus antibodies were tested using a commercial IgG ELISA (RIDASCREEN, R-Biopharm AG, Darmstadt, Germany). Results of ELISA, ultrasonography, FNAC, and liver function tests were obtained from the hospital information system. ELISA results were compared with those of FNAC to analyze the diagnostic efficacy of ELISA for HHD diagnosis. Statistical Analysis Comparison of the results obtained from ELISA was performed with respect to FNAC results (taken as standard) to analyze the diagnostic efficacy of ELISA for HHD detection. Data has been represented as median (range) or in frequencies. Wilson score was used to assess 95% confidence interval of diagnostic parameters. The analysis was performed using SPSS Version 22.0 (IBM Corp.) and Open Epi (version 3.01). Results Out of 223 cases with liver mass lesions, Echinococcus IgG was reactive in 62 (28%) cases and FNAC was positive in 16 (7.2%) cases. Since two cases were FNAC-positive but IgG-nonreactive, total HHD cases were 64 (28.7%). Echinococcus IgG reactive cases were seen more in the extremes of age group, that is, 1 to 10 years and 81 to 90 years. Taking FNAC as the standard, the sensitivity, specificity, positive predictive value, and negative predictive value of ELISA were 87.5, 76.8, 22.6, and 98.7%, respectively. Cytology-positive cases demonstrated a mean ELISA optical density/cut-off (OD/CO) of 4.2 ± 3 standard deviation. Conclusion ELISA in radiologically confirmed liver mass cases is highly sensitive in detecting HHD and hence should be used along with ultrasonography for the screening of HHD followed by confirmation with cytology even in cases with a higher OD/CO of ELISA.

Introduction: Portal cavernoma cholangiopathy (PCC)’ refers to abnormalities of the extrahepatic and intrahepatic bile ducts in patients with portal hypertension. Although there is data on clinical and imaging aspects of PCC, the description of liver pathology has been strikingly deficient. The purpose of this study was to examine the histopathological characteristics of PCC. Patients and Methods: A retrospective study of patients clinically diagnosed with extrahepatic portal vein obstruction (EHPVO) with portal cavernoma cholangiopathy, was conducted. Vascular anatomy was characterized by computerized tomographic angiography, and endoscopic retrograde cholangiography (ERC) and magnetic resonance cholangiography (MRC) were used to characterize the biliary anatomy. Histological features were analyzed by two hepatopathologists in a blinded manner, with mutual discussion to resolve any discrepancies. Results: A total of 50 patients with portal cavernoma cholangiopathy were included in the study. The mean age of the patients was 26.2 ± 11.6 years. Radiologically, bilobar intrahepatic biliary dilatation was seen in 98% with common bile duct abnormality in 100% of patients, along with extrinsic ductal impressions in 77 % of cases. Liver tests were deranged total bilirubin 1.5 mg/dL (IQR 0.8–2.4) and alkaline phosphatase 109.5 IU/L (IQR 70–193). Histologically; dilated multiple portal venous channels (72%), hepatic artery thickening (70%). The presence of aberrant vascular channels around portal tracts (54%), elastosis of portal veins (50%), and bile ductular reaction in (44%) were the other prominent findings. A 12% of cases show focal thin bridges. Advanced fibrosis was not seen in any of the cases. One-fourth of the cases showed concomitant minimal to mild hepatocyte steatosis. Conclusions: Histologically, intrahepatic portal vein and portal tract abnormalities were noted in cases with portal cavernoma cholangiopathy, associated with mild derangement of liver tests.

CONTEXT: Inflammatory pseudotumor (IPT) of the liver is a rare, tumor-like lesion that is considered to be biologically benign but often mimics malignancy. AIMS: The aim of the study was construe clinicopathological features, imaging findings, differential diagnosis, management, and follow-up of IPT involving the liver. SETTINGS AND DESIGN: It is a retrospective study. SUBJECTS AND METHODS: Cases included were of IPT, diagnosed on histopathology, at our center from June 2009 to December 2016. Details studied were clinical presentation, imaging studies, laboratory investigations, pathological features, treatment, and follow-up of the cases and compared with reports in the literature. RESULTS: A total of cases of IPT included were 17. The age of the patients ranged from 21 to 62 years. Common presenting features were intermittent fever, upper abdominal pain, and weight loss. Radiological diagnosis varied from neoplastic (13) to infectious etiologies (4), with hepatocellular carcinoma being the most common differential (7/17). Laboratory investigations revealed leukocytosis, hyperbilirubinemia, raised transaminases, and raised serum alkaline phosphatase. Core biopsy of a tumor conceded increased fibrosis along with mixed inflammatory cell infiltrates. Eleven cases were managed conservatively and showed regression or complete recovery. Six patients underwent surgical resection. None of these had any recurrence in median follow-up of 22 months. CONCLUSIONS: IPT of the liver can masquerade as a fatality, either primary or metastatic. It will be well managed with conservative modalities and can avoid redundant hepatectomy, reserved for complicated cases. For this intent, accurate preoperative diagnosis is the requisite, and needle biopsy with or without fine-needle aspiration cytology plays as a significant rescuer in this field.

Background and Aims: Non-dividing hepatocytes in end-stage liver disease indicates permanent growth arrest similar to senescence. Identifying senescence in vivo is often challenging and mechanisms inhibiting senescence are poorly understood. In lower organisms mitochondrial unfolded protein response (UPRMT) helps in increasing longevity; however, its role in senescence and liver disease is poorly understood. Aim of this study was to identify hepatocyte senescence and the role of UPRMT in cryptogenic cirrhosis. Methods: Doxorubicin was used to induce senescence in non-neoplastic hepatocytes (PH5CH8) and hepatoma cells (HepG2 and Huh7). Senescence-associated markers and unfolded protein response was evaluated by fluorescence microscopy, immunoblotting and gene expression. Explants/biopsies from normal, fibrosis, compensated and decompensated cirrhosis without any known etiology were examined for presence of senescence and UPRMT by immunohistochemistry and gene expression. Results: Accumulation of senescent hepatocytes in cryptogenic cirrhosis was associated with reduced proliferation, increased expression of γH2AX and p21, together with loss of LaminB1. Dysfunctional mitochondria and compromised UPRMT were key features of senescent hepatocytes both in vitro and also in decompensated cirrhosis. Intriguingly, compensated cirrhotic liver mounted strong UPRMT, with high levels of mitochondrial protease, CLPP. Overexpression of CLPP inhibited senescence in vitro, by reducing mitochondrial ROS and altering oxygen consumption. Conclusions: Our results implicate a role of hepatocyte senescence in cryptogenic cirrhosis together with a crucial role of UPRMT in preventing hepatocyte senescence. A compromised UPRMT may shift the fate of cirrhotic liver toward decompensation by exaggerating hepatocyte senescence. Restoring CLPP levels at least in cell culture appears as a promising strategy in mitohormesis, thereby, preventing senescence and possibly improving hepatocyte function. Keywords: Cryptogenic Liver Cirrhosis, Mitochondrial Respiration, Mitochondrial Unfolded Protein Response, Oxidative Stress

Introduction: Early and accurate diagnosis is paramount for improving the therapeutic efficacy of pancreatic cancers. Endoscopic ultrasonography–fine needle aspiration (EUS-FNA) cytology has come up with the advantage of an early and accurate diagnosis of pancreatic cancers. This study was conducted to analyze the spectrum of pancreatic lesions cytology, and appraise the diagnostic accuracy of EUS-FNA cytology for pancreatic solid and cystic lesions. Materials and Methods: This retrospective study includes 288 EUS-guided pancreatic FNA cases. Clinical data, laboratory tests, cytopathology, histopathology, and imaging reports were retrieved. The final diagnosis was based on EUS-FNA cell block and/or pathology in surgical specimens, with immunohistochemistry support. The results of EUS-guided FNA were compared with the final diagnoses to calculate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Among 288 EUS-guided pancreatic FNA cases, 175 (62.0%) were malignant. The mean age was 57.8 ± 13.5 years and 50.1 ± 13.7 years, and the mean size of the lesion was 4.1 ± 1.8 cm and 2.2 ± 1.1 cm in malignant and benign groups, respectively. Sensitivity, specificity, PPV, and NPV of EUS-FNA cytology for solid malignant lesions were 98.3%, 95.1%, 98.3%, and 95.1%, and those for cystic lesions were 88%, 92.3%, 100%, and 100%. Diagnostic accuracy of EUS-FNA cytology for solid and cystic pancreatic lesions is 97.4% and 95.0%, respectively. In conclusion of the above; diagnosis of pancreatic solid and cystic malignancy can be assigned from a composite of the EUS-FNA cytology, cell block preparation and immunohistochemistry Diagnosis of pancreatic solid and cystic malignancy can be assigned from a composite of the EUS-FNA cytology, cell block preparation, and immunohistochemistry.

Objective: To analyze and evaluate the diagnostic performance of conventional diagnostic (qualitative) imaging features versus LI-RADSv2018 lexicon for indeterminate and atypical Hepatocellular carcinoma (HCC) on dynamic liver imaging with reference to histopathology. Patients and methods: This retrospective study (June 2009–June 2019) evaluated the performance characteristics of conventional imaging findings, versus the Liver Imaging Reporting and Data System (LIRADS) v2018, for interpretation of indeterminate and atypical HCC, in patients who underwent subsequent histopathological analysis (gold standard). A total of 100,457 dynamic hepatobiliary CT and MR examinations were performed over ten years at our institute. Using current international imaging guidelines, 3218 patients were found to have suspected liver cancer lesions on imaging. Classical enhancement pattern of typical HCC was seen in 2916 of these patients. These patients did not require further biopsy. We enrolled, the remaining (n = 302) patients, who underwent biopsy, into our study group. Two radiologists, blinded to pathology findings, reviewed and classified these lesions, in consensus, according to LI-RADS® lexicon and as per ‘conventional’ (Indeterminate, Atypical HCC, Classical HCC, other malignancies) imaging. The histopathology diagnosis was considered as the final diagnosis. Alpha feto protein (AFP) levels amongst various subgroups were compared. Statistical analysis was performed to calculate the efficacy of LIRADS versus qualitative imaging parameters in comparison with histopathology. Results: A total of n = 302 patients, [89 % men (n = 269), mean age 57.08 ± 12.43 years] underwent biopsy for suspected liver lesions. Qualitative imaging had 92.3 % (CI 88.53–94.91) sensitivity, 41.4 % (CI 25.51–59.26) specificity, positive predictive value (PPV) of 93.7 % (CI 90.11–96.02), negative predictive value (NPV) of 36.4 % (CI 22.19–53.38), positive likelihood ratio (PLHR) of 1.575 (CI 1.40–1.77) and negative likelihood ratio of (NLHR) 0.19 (CI 0.13-0.26). It correctly classified 87.4 % of lesions diagnosed on pathology. In comparison, LI-RADS was found to have 92 % sensitivity, 55.5 % specificity, 97 % PPV, 30.3 %, NPV, PLHR 2.068 (CI 1.62–2.64), NLHR 0.15 (CI 0.11-0.18) and 89.7 % diagnostic accuracy. A total of 38 patients (17 false negative, 21 false positive lesions) had discordant diagnoses on imaging versus histopathology. The kappa agreement between LIRADs and qualitative Imaging was found to be 0.77 ± .07 (p < 0.001). LIRADS and qualitative imaging collectively had 97 % sensitivity, 30 % specificity, 91.9 % PPV, 55.6 % NPV, PLHR of 1.39 (CI 1.27–1.51) and NLHR of 0.09 (0.048-0.19) which was better than, either reporting system, independently. Conclusion: It was observed that the LI-RADS v2018 lexicon with qualitative imaging as a combination technique added extra value in interpretation of atypical HCC or indeterminate lesions on dynamic CT and MRI compared to either as ‘stand- alone’ reporting systems.

Bone loss is common in advanced cirrhosis, although the precise mechanisms underlying bone loss in cirrhosis are unknown. We studied the profile and functionality of bone‐forming cells and bone‐building proteins in bone marrow (BM) of individuals with cirrhosis (n = 61) and individuals without cirrhosis as normal controls (n = 50). We also performed dual energy X‐ray absorptiometry for clinical correlation. BM mesenchymal cells (MSCs) were analyzed for colony‐forming units‐fibroblasts and their osteogenic (fibronectin‐1 [FN1], insulin‐like growth factor binding protein 3 [IGFBP3], collagen type 1 alpha 1 chain [COL1A1], runt‐related transcription factor 2 [RUNX2], and alkaline phosphatase, liver [ALPL]) and adipogenic ( adiponectin, C1Q, and collagen domain containing [ADIPOQ], peroxisome proliferator‐activated receptor gamma [PPARγ], and fatty acid binding protein 4 [FABP4]) potentials. Colony‐forming units‐fibroblasts were lower in patients with cirrhosis (P = 0.002) than in controls. Cirrhotic BM‐MSCs showed >2‐fold decrease in osteogenic markers. Compared to controls, patients with cirrhosis showed fewer osteocytes (P = 0.05), osteoblasts, chondroblasts, osteocalcin‐positive (osteocalcin+) area, clusters of differentiation (CD)169+ macrophages (P < 0.001, each), and nestin+ MSCs (P = 0.001); this was more apparent in Child‐Turcotte‐Pugh (CTP) class C than A (P < 0.001). Multivariate logistic regression showed low nestin+ MSCs (P = 0.004) as a predictor of bone loss. Bone‐resolving osteoclasts were comparable among CTP groups, but >2‐fold decreased anti‐osteoclastic and increased pro‐osteoclastic factors were noted in patients with CTP C compared to CTP A. Bone‐building proteins (osteocalcin [P = 0.008], osteonectin [P < 0.001], and bone morphogenic protein 2 [P = 0.001]) were decreased while anti‐bone repair factors (fibroblast growth factor 23 [P = 0.015] and dipeptidyl peptidase 4 [P < 0.001]) were increased in BM and peripheral blood; this was more apparent in advanced cirrhosis. The dual energy X‐ray absorptiometry scan T score significantly correlated with the population of osteoblasts, osteocytes, MSCs, and CD169+ macrophages. Conclusion: Osteoprogenitor cells are substantially reduced in patients with cirrhosis and more so in advanced disease. Additionally, increased anti‐bone repair proteins enhance the ineffective bone repair and development of osteoporosis in cirrhosis. Hepatology Communications 2018;0:0‐0)

We report a case of 18F fluorodeoxyglucose (FDG) positron emission tomography (PET)–computed tomography-avid histologically confirmed inflammatory hepatic adenoma in a 77-year-old male patient without any history of steroid, alcohol use. This is the first case report of inflammatory hepatic adenoma in a male patient documented in the published literature showing uptake on 18F-FDG PET. Previous single case report of 18F-FDG PET-avid hepatic adenoma in a male patient was of hepatocyte nuclear factor-1-α subtype.

Purpose: To study the imaging findings in gangrenous acute cholecystitis. Materials and Methods: Retrospective analysis of imaging findings in 31 histopathologically confirmed cases of gangrenous cholecystitis was done. The following imaging findings were analyzed: wall thickness, gallbladder distension, intraluminal membranes, mural striation, edema, wall enhancement, gallstones, gas, pericholecystic fluid, stranding, hemorrhage, hyperaemia in adjacent liver, mucosal/wall irregularity, complications. Statistical Analysis: Appropriate statistical tests were used using SPSS.22.0 software. The two proportions were compared using Chi-square or Fisher exact test and two means were compared using student t test. Results: Mean gallbladder wall thickening was 6 ± 1.93 mm. Gallstones, mural edema, mural striation, pericholecystic fluid, intraluminal membranes, gas were seen in 30, 27, 18, 20, 14 and 3 cases respectively. The mean short-axis distension of gallbladder lumen was 4.24 ± 0.91 cm. Gallbladder wall enhancement was studied in only 10 cases. Complete absence of enhancement was seen in 1, focal decreased enhancement in 8 cases. Mucosal/wall irregularity was seen in 28 cases. 74.2% cases had ≥4 cm gallbladder distension. Intraluminal membranes were present in 14 cases with mean short-axis distension of 4.6 cm and absent in 17 (P = 0.041), in 11 cases with mural striation (P = 0.036). Mean wall thickening was 6.69mm in patients with intraluminal membranes and 5.46 mm with absence of membranes (P = .078). Conclusion: Presence of more than one of these findings - gallbladder distension (short axis diameter of ≥4 cm), intraluminal membranes, mural striation, absent or decreased enhancement of gallbladder wall suggest high probability of gangrenous change in acute cholecystitis.

OBJECTIVES: Diagnostic utility of cytomegalovirus (CMV) DNA quantitative polymerase chain reaction (qPCR) in inflammatory bowel disease (IBD) has not been established. We aimed to compare diagnostic utility of qPCR for CMV in biopsy specimens with blood, serology, and histopathology. MATERIALS AND METHODS: A total of 132 patients were included (92 ulcerative colitis [UC], 9 Crohn's disease, and 31 unclassified IBD). Comparison between CMV IgM, CMV DNA qPCR in biopsy, in blood and histopathology was done. Positive result in any of the test was considered as CMV infection. Various risk factors for CMV association with IBD were analyzed. RESULTS: Confirmed CMV infection was seen in 41 (31.1%) patients. Diagnostic sensitivity of different assays was: DNA in biopsy seen in 37 (90.2%), DNA in blood in 19 (46.3%), CMV IgM in 15 (36.5%), and histopathology in 8 (19.5%). Thirty-two UC cases were further followed up for a median time of 14.0 (R: 3–31) months. They were grouped as group I – biopsy and blood DNA both positive (14, 43.7%), Group II – biopsy positive and blood negative (17, 53.1%), and Group III – biopsy negative but blood positive (1, 3.1%). CMV DNA viral load in Group I was significantly higher (mean: 4.2 ± 1.0 log10 copies/mg) than Group II (mean: 3.2 ± 0.6 copies/mg) and Group III (viral load: 2.69 log10 copies/ml), P < 0.001. Steroid refractoriness was seen more in Group I cases (n = 9) P < 0.001. A cutoff of ≥2.5 log10 copies/mg of DNA in tissue was predictive for steroid refractoriness (AUROC = 0.84). CONCLUSIONS: Quantitation of CMV DNA in intestinal biopsy is a useful diagnostic tool and can predict response to steroid treatment in patients with UC.

Ductal plate malformations are a heterogenous group of congenital fibrocystic liver diseases resulting from insult to the ductal plate at various stages of embryogenesis. As a result various biliary malformations, cysts, hamartomas and congenital hepatic fibrosis may be seen. We present a radiological pictorial of ductal plate malformations, accurate diagnosis of which is important for clinical management.

Objective: To investigate dual-energy spectral CT in characterization of hepatocellular Carcinoma (HCC) in patients with chronic liver disease. Methods: Dynamic computed tomography (CT) was performed in 3600 patients (2879 males; 721 females, mean age 50.9 ± 11.9 years) with working clinical diagnosis of liver cirrhosis for hepatocellular carcinoma screening and other clinical indications. The study was conducted over a period of 3 years. During dynamic CT scanning, spectral (monochromatic) and routine (polychromatic) CT acquisitions were obtained on a single tube, dual energy, 64 slice multi-detector CT scanner. Imaging findings were studied on routine CT. On the basis of routine CT findings, indeterminate lesions (lesions not showing characteristic hypervascularity followed by washout on dynamic routine CT scan) that were referred for biopsy or surgery were segregated. A retrospective blinded review of the lesions, acquired by the spectral CT acquisitions was done with the help of gem stone imaging (GSI) software to characterize these lesions. All the above lesions were analyzed qualitatively in the arterial phase for lesion conspicuity as well as quantitatively using the monochromatic data sets and nodule Iodine concentration on material density maps, respectively. This data was studied with respect to predictability of HCC using the spectral CT technique. Iodine density of the lesion, surrounding liver parenchyma, and lesion to liver parenchyma ratio (LLR) were derived and statistically analyzed. Histopathology of the lesion in question was treated as gold standard for analysis. Results: It was observed via statistical analysis that the value of iodine density of the lesion on material density sets of ≥29.5 mg/dl, enabled a discriminatory power of 86.5%, sensitivity of 90.5% with 95% confidence Interval (CI) (69.2–98.8%) and specificity of 81.2% with 95% Confidence Interval (54.4–95.9%) in predicting HCC. Qualitative assessment also showed higher lesion conspicuity with spectral CT image sets as compared to routine CT data. Conclusion: This study reveals that spectral imaging is an excellent qualitative as well as a quantitative tool for assessing and predicting hepatocellular carcinoma in cirrhotic patients. Keywords: Hepatocellular carcinoma, Dual energy computed tomography, Material density images, Spectral computed tomography, Functional imaging, Iodine quantification

BackgroundNeutrophils serve as critical players in the pathogenesis of liver diseases. Chemokine receptors CXCR1 and CXCR2 are required for neutrophil chemotaxis to the site of inflammation/injury and are crucial in hepatic inflammatory response. However, key mechanism of neutrophil-mediated liver injury in acute-on-chronic liver failure (ACLF) remains highly elusive; which could be targeted for the development of new therapeutic interventions.MethodsTo demonstrate the role of CXCR1/CXCR2-expressing neutrophils in hepatic injury, we investigated CXCR1/CXCR2 receptor expression in 17 hepatitis B virus-related ACLF patients in comparison to 42 chronic hepatitis B and 18 healthy controls. Mechanism of neutrophil-mediated cell death was analyzed by in vitro coculture assays and correlated with the patient data. In addition, to find out any etiological-based variations in ACLF, 19 alcohol-related ACLF patients were also included.ResultsIn ACLF, neutrophils have high expression of CXCR1/CXCR2 receptors, which potentially participate in hepatocyte death through early apoptosis and necrosis in contact-dependent and -independent mechanisms. Importantly, blockade of CXCR1/CXCR2 with SCH 527123 antagonist significantly reduced cell death by targeting both the mechanisms. No etiology-based differences were seen between ACLF groups. Importantly, absolute neutrophil count was particularly higher in clinically severe ACLF patients and non-survivors (p 73.5% (sensitivity: 76.5% and specificity: 76.5%) and CXCL8/IL-8 >27% (sensitivity: 70% and specificity: 73%) in prediction of mortality.ConclusionBlockade of CXCR1/CXCR2 diminished the production of inflammatory mediators and reduced cell death; therefore, pharmacological neutralization of CXCR1/CXCR2 could provide novel therapeutic target in the management of ACLF.

Background: Obesity is an important risk factor for non-alcoholic fatty liver disease (NAFLD); however, NAFLD does occur in lean subjects. This study was aimed to evaluate the magnitude, clinical, pathological, and metabolic profiles of NAFLD in normal body mass index (BMI) subjects (defined as lean NAFLD) in comparison to overweight or obese NAFLD and lean healthy control. Materials and Methods: 336 subjects (205 consecutive NAFLD, and 131 healthy controls) were studied. Results: Among 205 NAFLD patients, 27 (13.2%) were lean, while 141 (68.8%) and 37 (18%) patients were obese and overweight, respectively. The lean NAFLD compared to obese NAFLD had significantly lesser degree of fasting hyperinsulinemia ( P < 0.001), homeostasis model assessment insulin resistance (HOMA-IR, P < 0.001), and lower prevalence of diabetes mellitus ( P = 0.01) and metabolic syndrome ( P < 0.001). The profiles of serum lipids were similar between all 3 BMI categories, and 89% of lean NAFLD were dyslipidemic. Compared to obese subjects, patients with lean NAFLD had less hepatic necro-inflammation ( P = 0.05) and fibrosis ( P < 0.001). However, the proportion of steatohepatitis and advanced fibrosis were similar between all BMI categories. The profiles of overweight NAFLD were similar to those of lean NAFLD, except for higher HOMA-IR, uric acids and male gender in overweight group. Despite being lean, the mean BMI of lean NAFLD were still higher than unselected lean healthy controls ( P = 0.02). Conclusions: Lean NAFLD patients have less severe disease, minor, or no insulin resistance, but are frequently dyslipidemic and have BMI higher than lean healthy control.

Background and Aims: Hepatic steatosis (HS) is highly prevalent in chronic hepatitis C and is an important variable predicting progression of histological injury, insulin resistance, and reduced response to antiviral therapy. There are limited data on HS in patients with chronic hepatitis B (CHB). This is relevant since response to current antiviral therapies for CHB is rather limited. We investigated the spectrum and predictors of HS in CHB patients. Materials and Methods: Liver biopsies of consecutive patients of chronic Hepatitis B Virus (HBV) infection were studied and were categorized as: Group I - hepatosteatosis (>5%) and Group II - no steatosis (£5%). Anthropometric, histological, biochemical, virological, and metabolic determinants were compared. Logistic regression analysis was applied to identify variables that were independently associated with the presence of steatosis. Results: Of the 350 patients, 118 (33.7%) liver biopsies showed steatosis (Group I); 65 (55.1%) had mild (6 to

Sickle cell trait is considered as a benign condition as these individuals carry only one defective gene and typically have their life span similar to the normal population without any health problems related to sickle cell. Only under extreme conditions, red cells become sickled and can cause clinical complications including hematuria and splenic infarction. Although twofold increased risk of venous thrombosis has been described in African Americans, there is no data available from Indian population. We here report a case of sickle cell trait from India whose index presentation was thrombosis of unusual vascular territory.

Adenomyoma can be misdiagnosed as an adenocarcinoma, leading to needless and extensive surgical resections. A 45-year-old woman presented with right hypochondrial pain. Magnetic resonance imaging showed a choledochal cyst. Excision of choledochal cyst with Roux-en-Y hepaticojejunostomy was performed. A segment of dilated common bile duct and an attached nodule was received. Sections from the choledochal cyst showed a cyst wall composed of dense fibrous tissue lined by partially ulcerated columnar epithelium. Sections from the nodule showed interlacing whorls of smooth muscle bundles with entrapped glands. The glands were lined by cuboidal to columnar cells without nuclear atypia. This was recognized as an adenomyoma. To the best of our knowledge, this is the first reported case in which an adenomyoma was found associated with a type 1 choledochal cyst. A review of the existing literature and discussion of theories of genesis and the diagnostic pitfalls are presented.

Tumors of the pancreas that contain substantial cystic components include mainly mucinous cystic neoplasm, intraductal papillary mucinous neoplasm, solid pseudopapillary tumor, and cystadenomas (which encompass microcystic, macrocystic/oligocystic, and rare solid serous adenomas). Microcystic adenoma of the pancreas is a tumor that is benign in nature. Malignant transformation in the tumor with metastases is rare and only about 26 cases have been reported so far. Here we present a giant microcystic adenoma of the pancreas, possibly the largest ever malignant type in this group ever reported in the literature with extensive metastases to the liver and causing extensive compression and encasement on surrounding structures.

Introduction. Liver disease patients have complex hemostatic defects leading to a delicate, unstable balance between bleeding and thrombosis. Conventional tests such as PT and APTT are unable to depict these defects completely. Aims. This study aimed at analyzing the abnormal effects of liver disease on sonoclot signature by using sonoclot analyzer (which depicts the entire hemostatic pathway) and assessing the correlations between sonoclot variables and conventional coagulation tests. Material and Methods. Clinical and laboratory data from fifty inpatients of four subgroups of liver disease, including decompensated cirrhosis, chronic hepatitis, cirrhosis with HCC and acute-on-chronic liver failure were analyzed. All patients and controls were subjected to sonoclot analysis and correlated with routine coagulation parameters including platelet count, PT, APTT, fibrinogen, and D-dimer. Results. The sonoclot signatures demonstrated statistically significant abnormalities in patients with liver disease as compared to healthy controls. PT and APTT correlated positively with SONACT (P

Gastric adenocarcinoma with yolk sac tumor (YST) differentiation has rarely been reported. We report a case of primary gastric adenocarcinoma with yolk sac tumor differentiation and liver metastases of the YST component in a 50-years-old patient. This was suspected due to high serum level of alpha fetoprotein in the presence of a gastric fundal tumor. Gastric carcinoma with yolk sac tumor component is a rare entity with a poor prognostic outcome.