Renal impairment and anemia during triple therapy

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Relationship between adipose tissue dysfunction, Vitamin D deficiency and the pathogenesis of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease ( NAFLD) is the most common chronic liver disease worldwide. Its pathogenesis is complex and not yet fully understood. Over the years many studies have proposed various pathophysiological hypotheses, among which the currently most widely accepted is the "multiple parallel hits" theory. According to this model, lipid accumulation in the hepatocytes and insulin resistance increase the vulnerability of the liver to many factors that act in a coordinated and cooperative manner to promote hepatic injury, inflammation and fibrosis. Among these factors, adipose tissue dysfunction and subsequent chronic low grade inflammation play a crucial role. Recent studies have shown that vitamin D exerts an immune-regulating action on adipose tissue, and the growing wealth of epidemiological data is demonstrating that hypovitaminosis D is associated with both obesity and NAFLD. Furthermore, given the strong association between these conditions, current findings suggest that vitamin D may be involved in the relationship between adipose tissue dysfunction and NAFLD. The purpose of this review is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to adipose tissue dysfunction, and in the pathophysiology linking vitamin D deficiency with NAFLD and adiposity, together with an overview of the evidence available on the clinical utility of vitamin D supplementation in cases of NAFLD

Liver involvement in the course of thymoma-associated multiorgan autoimmunity: The first histological description

Thymoma-associated multiorgan autoimmunity (TAMA) is a rare paraneoplastic syndrome described in patients with thymoma and characterized by multiorgan failure and graft-versus-host disease (GVHD) like pathology affecting the skin, the gastrointestinal tract, and the liver. To date, only 21 cases are reported in literature [1], with some patients presenting gastrointestinal and hepatic manifestations, mainly colitis, diarrhea, and abnormal liver enzymes, but the hepatic involvement has not been histologically characterized yet. In the present study, we describe for the first time that liver involvement in a patient affected by TAMA resembles GVHD

Portal and interface chronic inflammation are associated with the progenitor cell compartment activation during NAFLD

Background and aim: During nonalcoholic fatty liver disease (NAFLD), portal and interface chronic inflammation (PCI and ICI) are strongly associated with fibrosis by activation of hepatic stellate cell (HSC)s (Brunt et al., 2009; Vespasiani-Gentilucci et al., 2014). However, the determinants of PCI and ICI observed in NAFLD remain to be elucidated. Since portal and periportal ductular reaction is related to disease progression, we aimed to investigate if PCI and ICI are associated with hepatic progenitor cell (HPC) compartment activation. Methods: Fifty-two NAFLD patients were studied. NAFLD activity score, fibrosis, PCI and ICI were histologically evaluated. HPCs, intermediate hepatobiliary cells and bile ductules/interlobular bile ducts were evaluated by immunohistochemistry for CK-7, CK-19 and EpCAM. HSC and myofibroblast (MF) activity were determined by immunohistochemistry for α-SMA. Results: PCI and ICI strongly correlated with HPC compartment activation and with the activity of MFs (p≤0.001). Lobular inflammation, ballooning and HPC compartment activation were all associated with both PCI (p<0.01) and ICI (p<0.05) by univariate analysis. In the multivariate models, HPC compartment activation was independently associated with PCI and ICI (OR 4.4, 1.7-11.5; OR 3.4, 1.5-7.9, respectively). Conclusions: During NAFLD, PCI and ICI are strongly associated with HPC compartment activation and this association is likely one determinant subtending the strong association between PCI/ICI and fibrosis

Toll-like receptor-4 is involved in hepatic fibrogenesis in the course of non-alcoholic fatty liver disease

Toll-like receptor-4 (TLR4) is actively involved in liver in the response to injury from a variety of etiologies. Recently TLR4 expression by hepatic progenitor cells (HPC) and biliary epithelial cells has been associated to the progression of liver damage in chronic HCV-related hepatitis (1). HPC compartment activation in ductular reaction (DR) is a feature of progressive disease also in non-alcoholic fatty liver disease (NAFLD) (2). We aimed to investigate the association among TLR4 expression, HPC compartment activation and histopathologic features of fibrotic disease progression in NAFLD. Seventy-four patients who had undergone liver biopsy were included and immunohistochemistry for TLR4 was performed on hepatic tissue samples. CK-7 was used to evaluate HPC, bile ducts (BD)/ductules of DR and intermediate hepatocytes; α-smooth muscle actin was used to quantify the activation of hepatic stellate cells (HSC) and of portal/septal myofibroblasts (MF). HPC in BD/DR were responsible for the highest TLR4 intensity of staining. TLR4-positive HPC and BD/ DR correlated with fibrosis (p<0.01 and p<0.05), activity of MF (p<0.001 and p<0.05) and HSC (p<0.001 and p<0.001), portal and interface chronic inflammation (p<0.01 and p=0.01). The present study indicates the activation of the TLR4 expressing HPC compartment as important determinant of the progressive liver damage in NAFLD. TLR4 stimulation could represent one of the mechanisms directly linking the activation of HPC to inflammation and fibrosis in NAFLD

Diagnostic value of Virtual Touch Quantification (VTQ®) for differentiation of hemangiomas from malignant focal liver lesions

Aim: To evaluate the diagnostic value of Virtual Touch Quantification (VTQ®) for characterizing benign vs. malignant focal liver lesions (FLLs).Material and methods: From January 2015 to January 2016 all consecutive FLLs visualized during a conventional abdominal ultrasound (US), underwent VTQ® evaluation, taking five measurements of both the lesion and the surrounding parenchyma.Results: We studied 119 FLLs, consisting of 52 hemangiomas (HEs), 39 hepatocellular carcinomas (HCCs), and 28 liver metastases (METs). HEs showed a significantly lower shear wave velocity (SWV) values compared to malignant FLLs (HEs SWV median value 1.34 m/sec, IQR 0.9; malignant lesions SWV median value 2.69 m/sec, IQR 1.6; p<0.001). Moreover, a nodule-to-parenchyma SWV ratio showed a significant difference in HEs and METs (p<0.001) but not in HCCs (p=0.03). SWV values were able to correctly differentiate malignant lesions with c-statistics of 0.82 (95 % CI 0.74- 0.90) and sensitivity of 74.6%/specificity of 80.7% at a cut-off of 2 m/sec.Conclusions: Our results suggest that VTQ® is able to distinguish HEs from malignant lesions (HCCs and METs) at a SWV cut-off of 2 m/sec

Reelin expression in liver and pancreas and its correlation with liver fibrosis

Reelin is an extracellular glycoprotein secreted by a variety of cell types in both embryonic and adult tissue and plays a critical role during brain development (1,2). Reelin is up-regulated in experimental liver cirrhosis of rats in hepatic stellate cell(HSC)s, the cell type mainly implicated in liver fibrogenesis, supporting that reelin is involved in the pathogenesis of liver fibrosis (3). Pancreatic stellate cell(PSC)s share similar morphology and function to HSCs, in pancreatic fibrosis setting (4). Currently, the role of reelin in human liver and pancreas is still unclear. We investigated reelin expression in different stages of chronic liver disease in 81 liver biopsies of HCV affected patients and in pancreatic tissue near to tumoral lesions. The expression of Reelin, HSC markers (CRBP1, alpha-SMA) and Dab1, a Reelin adaptor protein, was investigated by immunohistochemistry and immunofluorescence. Reelin protein was expressed by HSCs and a strong correlation was found between Reelin expression and liver fibrosis stage (

Liver vitamin D receptor, CYP2R1 and CYP27A1 expression related to progression of metabolic and viral chronic liver damage

Background and aim: Low serum 25(OH)vitamin D3 levels were associated with the presence and prognosis of liver diseases [1]. The biological effects of 1,25(OH)2 vitamin D3 are mediated by the vitamin D receptor (VDR) and VDR has been widely detected in liver, but its expression in the course of liver disease has never been investigated [2]. We aimed to evaluate the hepatic expression of VDR and vitamin D 25-hydroxylases in patients with chronic hepatitis C (CHC) or non-alcoholic steatohepatitis (NASH) and its relationship with liver histology and serum 25(OH) vitamin D3 levels. Methods: Patients affected by CHC or NASH who had undergone liver biopsy and subjects without liver disease were included. Expression of VDR, CYP2R1 and CYP27A1 was evaluated by immunohistochemistry. Results: In CHC subjects, fibrosis stage was associated with low hepatic CYP27A1 expression, whereas in patients with VDR-negative inflammatory cells and low VDR expression on hepatocytes, the portal inflammation was significantly higher (p&lt;0.009 and p&lt;0.03). In NASH patients, VDR expression on cholangiocytes was inversely correlated with steatosis severity (p&lt;0.02), lobular inflammation (p&lt;0.01) and NAS score (p&lt;0.03). Conclusions: The liver of patients with viral and metabolic chronic liver disease expresses VDR in a manner inversely proportional to the severity of histological lesions and a role of the vitamin D/VDR system in the progression of chronic liver damage is suggested

The hepatic expression of GH/IGF1 axis components is impaired with fibrosis progression in patients with HCV-related chronic hepatitis

Background and aim: Resistance to the action of growth hormone (GH), characterized by low serum levels of insulin-like growth factor-1 (IGF1) in the face of high concentrations of GH, frequently complicates cirrhosis (Assy et al., 2008). Physiologically, the activation of GH receptor (GHR) determines phosphorylation of signal transducer and activator of transcription (STAT)-5 and the consequent induction of IGF-1 expression. The suppressor of cytokine signalling (SOCS)-3 negatively regulates this intracellular cascade. Since, to date, the hepatic expression of the GH/IGF1 axis components has been studied mainly in animal models (Blaas L et al., 2010), we aimed to evaluate their expression in the liver of patients with HCV-related chronic hepatitis. Methods: Fifty HCV patients were studied and liver samples were histologically re-evaluated for grading and staging. The expression of GH/IGF1 axis components was assessed by immunohistochemistry. Results: At the hepatocyte level, IGF-1 and phospho-STAT5 showed a negative correlation with fibrosis stage, while SOCS3 a positive one (p&lt;0,05 for all). Furthermore, the hepatocyte expression of IGF1 was negatively correlated with its expression by hepatic stellate cells (p&lt;0,05). Conclusions: IGF1 expression by hepatocytes was reduced with fibrosis progression, probably due to the impairment of GHR intracellular cascade. The inverse correlation between IGF1 expressed by hepatocytes and hepatic stellate cells suggests specific roles for IGF-I produced by different hepatic cells