Regression of Hepatic Fibrosis and Evolution of Cirrhosis: A Concise Review

Fibrosis is not a unidirectional, linear process, but a dynamic one resulting from an interplay of fibrogenesis and fibrolysis depending on the extent and severity of a biologic insult, or lack thereof. Regression of fibrosis has been documented best in patients treated with phlebotomies for hemochromatosis, and after successful suppression and eradication of chronic hepatitis B and C infections. This evidence mandates a reconsideration of the term “cirrhosis,” which implies an inevitable progression towards liver failure. Furthermore, it also necessitates a staging system that acknowledges the bidirectional nature of evolution of fibrosis, and has the ability to predict if the disease process is progressing or regressing. The Beijing classification attempts to fill this gap in contemporary practice. It is based on microscopic features termed “the hepatic repair complex,” defined originally by Wanless and colleagues. The elements of the hepatic repair complex represent the 3 processes of fragmentation and regression of scar, vascular remodeling (resolution), and parenchymal regeneration. However, regression of fibrosis does not imply resolution of cirrhosis, which is more than just a stage of fibrosis. So far, there is little to no evidence to suggest that large regions of parenchymal extinction can be repopulated by regenerating hepatocytes. Similarly, the vascular lesions of cirrhosis persist, and there is no evidence of complete return to normal microcirculation in cirrhotic livers. In addition, the risk of hepatocellular carcinoma is higher compared with the general population and these patients need continued screening and surveillance

Treatment of Idiosyncratic Drug-Induced Liver Injury Using Steroids

Idiosyncratic drug-induced liver injury (DILI), when severe, can be associated with significant morbidity and mortality. Currently, there are no specific therapies for DILI, apart from corticosteroids for drug-induced autoimmune hepatitis caused by drugs such as nitrofurantoin or minocycline. We present 2 cases of DILI that improved with corticosteroid therapy despite the lack of autoimmune features by serology or histology. The current observations make a strong case for formally testing corticosteroids in a controlled trial in patients with suspected DILI

Increased Mast Cell Counts and Degranulation in Microscopic Colitis

Objectives: Microscopic colitis (MC) is characterized by chronic diarrhea, normal colonoscopy findings, and mucosal inflammation in colonic biopsies and can be classified as collagenous colitis (CC) or lymphocytic colitis (LC). However, the pathogenesis of MC is largely unknown. In this study, we aimed to study mast cell counts and activation in MC. Methods: We investigated 64 biopsy samples from the surgical pathology database of Indiana University Health, which met the diagnostic criteria for CC or LC along with 20 control samples collected from 2014 to 2015. The specimens were used for the quantification of mast cells by examining the presence of intracellular and extracellular tryptase by immunohistochemistry. Results: In the lamina propria, the mast cell count was higher in both CC and LC groups than the control (mean highest count, 39/high-power field (HPF) vs. 30/HPF vs. 23/HPF; P < 0.01). Extracellular tryptase was present in 10% of control subjects as compared to 41% of CC (P < 0.01). Extracellular tryptase was present in 10% of control subjects as compared to 41% of CC (P < 0.01). Extracellular tryptase was present in 10% of control subjects as compared to 41% of CC (. Conclusions: The increased mast cell count and degranulation are identified in MC, suggesting that mast cell activation might be involved in the pathogenesis of MC

Hepatic Arterial Buffer Response: Pathologic Evidence in Non-Cirrhotic Human Liver with Portal Vein Thrombosis

poster abstractHepatic arterial buffer response (HABR) is the ability of the hepatic artery (HA) to compensate for changes in portal flow. Experimentally, occlusion of the portal vein leads to compensatory increase in HA flow with minimal parenchymal effects. Wether portal vein thrombosis (PVT) causes similar effects in the human liver is unknown. This study aims to answer this question as well as elucidate any microscopic features that may reliably assist diagnosis of PVT in the non-cirrhotic liver. We studied patients with PVT and no concomitant liver pathology. Age and gender matched livers with normal morphology served as controls. Following parameters were graded as subtle or obvious and focal or diffuse in a blinded fashion: sinusoidal dilatation, central and portal vein (PV) dilatation, PV absence, hepatic plate thinning and thickening. Outer and luminal diameters and wall thickness of HA, and outer diameter of accompanying bile ducts (BD) were measured. There were 16 patients (8 men, 8 women; mean age, 46.5 years) who presented with varices (12), ascites (8) and splenomegaly (11). Subtle and or focal dilatations of CV, PV and sinusoids as well as thinning/thickening of hepatic plates were common findings in both groups but were diffuse and obvious predominantly in cases of PVT. Absence or attenuation of PV was seen only in cases of PVT. The large HA were dilated in resection specimens of patients with PVT, p<0.05. This difference was not seen in biopsy specimens. There was no difference in the small HA in either biopsy or resection specimens or other measurements of HA or BD. In conclusion, septal branches of the HA dilate as a compensatory response to long standing thrombosis. Microscopic features of PVT are subtle but when obvious and/or diffuse in a patient with non-cirrhotic portal hypertension should raise suspicion for this diagnosis

Vitamin E Improves Transplant‐free Survival and Hepatic Decompensation among Patients with NASH and Advanced Fibrosis

Vitamin E improves liver histology in non‐diabetic adults with nonalcoholic steatohepatitis (NASH), but its impact on long‐term patient outcomes is unknown. We evaluated whether vitamin E treatment improves clinical outcomes of NASH patients with bridging fibrosis or cirrhosis. Two hundred and thirty‐six patients with biopsy‐proven NASH and bridging fibrosis or cirrhosis seen at Indiana University Medical Center between October 2004, and January 2016 were included. Ninety of them took 800 IU/day of vitamin E for ≥ 2 years (vitamin E users) and were propensity matched to 90 adults who did not take vitamin E (controls) after adjusting for fibrosis severity, age, gender, body mass index, comorbidities and their treatment, LDL cholesterol, liver biochemistries and length of follow‐up on vitamin E. Covariate‐adjusted cox and competing risk regression models were assessed to evaluate association between vitamin E treatment and patient outcomes. The median follow‐up was 5.62 (IQR: 4.3‐7.5) and 5.6 (IQR: 4‐6.9) years for vitamin E users and controls respectively. Vitamin E users had higher adjusted transplant‐free survival (78% vs. 49%, P<.01) and lower rates of hepatic decompensation (37% vs. 62%, P=.04) than controls. After controlling for severity of fibrosis, calendar year of patient enrollment and other potential confounders, vitamin E treatment decreased the risk of death or transplant (adj. HR: 0.30, 95% CI: 0.12‐0.74, P<.01) and hepatic decompensation (adj. sHR: 0.52, 95% CI: 0.28‐0.96, P=.036). These benefits were evident in both diabetics as well as non‐diabetics. Adjusted 10‐year cumulative probability of HCC, vascular events and non‐hepatic cancers were not different between vitamin E exposed and controls

Hepatic lipid peroxidation and cytochrome P-450 2E1 in pediatric nonalcoholic fatty liver disease and its subtypes

GOAL: To compare hepatic lipid peroxidation and cytochrome P-450 2E1 (CYP2E1) protein content in liver biopsies from children with nonalcoholic fatty liver disease (NAFLD) and 2 control groups. BACKGROUND: Elevated hepatic lipid peroxidation resulting from increased hepatic CYP2E1 enzyme activity is involved in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) in adults, but studies in children are lacking. STUDY: Liver biopsies from 59 children with NAFLD (49 with NASH), 10 children with normal liver histology, and 9 children with mild chronic hepatitis C (HCV) infection were examined. Hepatic malondialdehyde (a measure of lipid peroxidation) levels and CYP2E1 protein content were quantitated, as a percentage of the total area, by immunohistochemical staining of liver biopsy material followed by digital image quantitation. RESULTS: Lipid peroxidation was significantly greater in NAFLD liver biopsies (46.7 ± 20.8%) compared with biopsies from children with normal liver histology (7.6 ± 9.4%; P<0.001) or HCV infection (7.7 ± 7.6%; P<0.001). However, hepatic CYP2E1 expression was not different across the NAFLD, normal liver histology, and HCV groups (60.7 ± 8.7%, 53.5 ± 10.7%, and 60.0 ± 11.9%, respectively; P=0.116). Among children with NAFLD, lipid peroxidation and CYP2E1 protein content did not differ between biopsies with and without NASH. Body mass index was independently associated with hepatic lipid peroxidation levels (r=0.549; P<0.001). CONCLUSIONS: Hepatic lipid peroxidation is increased in children with NAFLD but this is not related to hepatic CYP2E1 expression. No difference in lipid peroxidation in pediatric NAFLD versus NASH argues against a role in disease progression

Metabolomic Characterization of Human Model of Liver Rejection Identifies Aberrancies Linked to Cyclooxygenase (COX) and Nitric Oxide Synthase (NOS)

BACKGROUND Acute liver rejection (ALR), a significant complication of liver transplantation, burdens patients, healthcare payers, and the healthcare providers due to an increase in morbidity, cost, and resources. Despite clinical resolution, ALR is associated with an increased risk of graft loss. A unique protocol of delayed immunosuppression used in our institute provided a model to characterize metabolomic profiles in human ALR. MATERIAL AND METHODS Twenty liver allograft biopsies obtained 48 hours after liver transplantation in the absence of immunosuppression were studied. Hepatic metabolites were quantitated in these biopsies by liquid chromatography and mass spectroscopy (LC/MS). Metabolite profiles were compared among: 1) biopsies with reperfusion injury but no histological evidence of rejection (n=7), 2) biopsies with histological evidence of moderate or severe rejection (n=5), and 3) biopsies with histological evidence of mild rejection (n=8). RESULTS There were 133 metabolites consistently detected by LC/MS and these were prioritized using variable importance to projection (VIP) analysis, comparing moderate or severe rejection vs. no rejection or mild rejection using partial least squares discriminant statistical analysis (PLS-DA). Twenty metabolites were identified as progressively different. Further PLS-DA using these metabolites identified 3 metabolites (linoleic acid, γ-linolenic acid, and citrulline) which are associated with either cyclooxygenase or nitric oxide synthase functionality. CONCLUSIONS Hepatic metabolic aberrancies associated with cyclooxygenase and nitric oxide synthase function occur contemporaneous with ALR. Additional studies are required to better characterize the role of these metabolic pathways to enhance utility of the metabolomics approach in diagnosis and outcomes of ALR

Autotaxin expression and its connection with the TNF-alpha-NF-κB axis in human hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Autotaxin (ATX) is an extracellular lysophospholipase D that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Both ATX and LPA have been shown to be involved in many cancers. However, the functional role of ATX and the regulation of ATX expression in human hepatocellular carcinoma (HCC) remain elusive.</p> <p>Results</p> <p>In this study, ATX expression was evaluated in tissues from 38 human HCC and 10 normal control subjects. ATX was detected mainly in tumor cells within tissue sections and its over-expression in HCC was specifically correlated with inflammation and liver cirrhosis. In addition, ATX expression was examined in normal human hepatocytes and liver cancer cell lines. Hepatoma Hep3B and Huh7 cells displayed stronger ATX expression than hepatoblastoma HepG2 cells and normal hepatocytes did. Proinflammtory cytokine tumor necrosis factor alpha (TNF-α) promoted ATX expression and secretion selectively in Hep3B and Huh7 cells, which led to a corresponding increase in lysophospholipase-D activity. Moreover, we explored the mechanism governing the expression of ATX in hepatoma cells and established a critical role of nuclear factor-kappa B (NF-κB) in basal and TNF-α induced ATX expression. Further study showed that secreted enzymatically active ATX stimulated Hep3B cell invasion.</p> <p>Conclusions</p> <p>This report highlights for the first time the clinical and biological evidence for the involvement of ATX in human HCC. Our observation that links the TNF-α/NF-κB axis and the ATX-LPA signaling pathway suggests that ATX is likely playing an important role in inflammation related liver tumorigenesis.</p

Evaluation of 11C-Acetate and 18 F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2−/− mice in order to facilitate therapeutic translational studies from bench to bedside. Methods 18F-FDG and 11C-acetate PET/CT was performed on 12 m MDR2−/− mice (n = 3/tracer) with HCC and 12 m MDR2−/+ control mice (n = 3/tracer) without HCC. To compare PET/CT to biological markers of HCC and cellular function, serum alpha-fetoprotein (AFP), lysophosphatidic acid (LPA), cAMP and hepatic tumor necrosis factor α (TNFα) were quantified in 3-12 m MDR2−/− (n = 10) mice using commercially available ELISA analysis. To translate results in mice to patients 11C-acetate PET/CT was also performed in 8 patents suspected of HCC recurrence following treatment and currently on the liver transplant wait list. Results Hepatic18F-FDG metabolism was not significantly increased in MDR2−/− mice. In contrast, hepatic 11C-acetate metabolism was significantly elevated in MDR2−/− mice when compared to MDR2−/+ controls. Serum AFP and LPA levels increased in MDR2−/− mice contemporaneous with the emergence of HCC. This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα. In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11C-acetate negative. Conclusions Hepatic 11C-acetate PET/CT tracks well with HCC in MDR2−/− mice and patients with underlying liver disease. Consequently 11C-acetate PET/CT is well suited to study 1) HCC emergence/progression in patients and 2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC