Valéria Pereira Lanzoni

Altered Glucose Homeostasis and Hepatic Function in Obese Mice Deficient for Both Kinin Receptor Genes

The Kallikrein-Kinin System (KKS) has been implicated in several aspects of metabolism, including the regulation of glucose homeostasis and adiposity. Kinins and des-Arg-kinins are the major effectors of this system and promote their effects by binding to two different receptors, the kinin B2 and B1 receptors, respectively. To understand the influence of the KKS on the pathophysiology of obesity and type 2 diabetes (T2DM), we generated an animal model deficient for both kinin receptor genes and leptin (obB1B2KO). Six-month-old obB1B2KO mice showed increased blood glucose levels. Isolated islets of the transgenic animals were more responsive to glucose stimulation releasing greater amounts of insulin, mainly in 3-month-old mice, which was corroborated by elevated serum C-peptide concentrations. Furthermore, they presented hepatomegaly, pronounced steatosis, and increased levels of circulating transaminases. This mouse also demonstrated exacerbated gluconeogenesis during the pyruvate challenge test. The hepatic abnormalities were accompanied by changes in the gene expression of factors linked to glucose and lipid metabolisms in the liver. Thus, we conclude that kinin receptors are important for modulation of insulin secretion and for the preservation of normal glucose levels and hepatic functions in obese mice, suggesting a protective role of the KKS regarding complications associated with obesity and T2DM.

Noninvasive serum markers in the diagnosis of structural liver damage in chronic hepatitis C virus infection.

Abstract: Aim: Several noninvasive markers are being used to assess the structural liver damage in patients with chronic hepatitis C (CHC). We evaluated the capacity of serum hyaluronic acid (HA), aspartate aminotransferase (AST)/ALT ratio, the AST to platelet ratio index (APRI) and γ‐glutamyltransferase (GGT) levels to predict the intensity of hepatic fibrosis in patients with CHC.

Role of γ‐glutamyl transferase activity in patients with chronic hepatitis C virus infection

Background:  Increased serum γ‐glutamyl transferase (GGT) levels are frequently observed in chronic hepatitis C virus (HCV) infection. However, the significance of this finding remains unclear. The purpose of the present paper was to assess the relationship between GGT levels and clinical, biochemical and histological features in chronic HCV‐infected carriers.

Serum laminin, type IV collagen and hyaluronan as fibrosis markers in non-alcoholic fatty liver disease

Hepatic fibrosis in patients with non-alcoholic fatty liver disease is associated with progression of the disease. In the present study, we analyzed the discriminative ability of serum laminin, type IV collagen and hyaluronan levels to predict the presence of fibrosis in these patients. In this preliminary report, we studied 30 overweight patients divided into two groups according to the absence (group I, N = 19) or presence (group II, N = 11) of fibrosis in a liver biopsy. Triglycerides, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidade, hyaluronan (noncompetitive fluoroassay), type IV collagen, and laminin (ELISA) were determined. Group II presented significantly higher mean laminin, hyaluronan, type IV collagen, and aspartate aminotransferase values, which were due to the correlation between these parameters and the stage of fibrosis in the biopsy (Spearmans correlation coefficient, rS = 0.65, 0.62, 0.53, and 0.49, respectively). Analysis of the ROC curve showed that laminin values >282 ng/ml were those with the best diagnostic performance, with 87% accuracy. Association of laminin with type IV collagen showed improvement in the positive predictive value (100%), but with reduction in diagnostic sensitivity (64%). When compared with the criteria of Ratziu et al. for the diagnosis of septal fibrosis, laminin values presented a better diagnostic accuracy (83 vs 70%). Determination of extracellular matrix components in serum, especially of laminin, may identify patients with non-alcoholic fatty liver disease and fibrosis and these components may be used as indicators for liver biopsy in these patients.

Simple blood tests as noninvasive markers of liver fibrosis in hemodialysis patients with chronic hepatitis C virus infection.

HCV infection is common among patients with end‐stage renal disease (ESRD) on hemodialysis, and it has been considered an independent risk factor for mortality in this setting. Although liver biopsy in ESRD patients with HCV infection is useful before kidney transplantation, it carries a high risk of complications. We sought to assess the diagnostic value of noninvasive markers to stage liver fibrosis in 203 ESRD HCV‐infected patients. Univariate and multivariate analysis were used to identify variables associated with significant fibrosis (METAVIR F2, F3, or F4 stages). Significant liver fibrosis was observed in 48 patients (24%). Logistic regression analysis identified AST and platelet count as independent predictors of significant fibrosis (P < 0.001 and P = 0.001, respectively). The area under the receiver operating characteristic curve of the AST to platelet ratio index (APRI) for predicting significant fibrosis was 0.801. An APRI < 0.40 accurately identified patients with fibrosis stage 0 or 1 in 93% of the cases (NPV = 93%), and all misclassified subjects were F2. A cutoff ≥ 0.95 to confirm significant fibrosis had a PPV of 66%. If biopsy indication was restricted to APRI scores in the intermediate range (≥0.40 and < 0.95), 52% of liver biopsies could have been correctly avoided. Conclusion: Stage of liver fibrosis can be reliably predicted in ESRD HCV‐infected subjects by simple and widely available blood tests such as AST levels and platelet count. These tests might obviate the requirement for a liver biopsy in a significant proportion of those patients. (HEPATOLOGY 2007.)

Efficacy and tolerance of interferon-alpha in the treatment of chronic Hepatitis C in end-stage renal disease patients on hemodialysis

Abstract: Background: Patients with end‐stage renal disease (ESRD) show a high prevalence of hepatitis C, with a negative impact on the survival on hemodialysis and after renal transplantation. We evaluated the efficacy and tolerance of interferon‐α (IFN‐α) in HCV‐infected ESRD patients on dialysis.

Optimized cutoffs improve performance of the aspartate aminotransferase to platelet ratio index for predicting significant liver fibrosis in human immunodeficiency virus/hepatitis C virus co‐infection

Aim: To assess the diagnostic value of modified cutoffs for aspartate aminotransferase to platelet ratio index (APRI) to predict significant liver fibrosis in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) patients.

Iron overload in patients with chronic hepatitis C virus infection: clinical and histological study.

Background:  Recently it has been found that iron is an important element in the natural history of hepatitis C. Serum markers of iron stores are frequently increased in chronic hepatitis C virus (HCV)‐infected carriers but the real impact of the hepatic iron overload is poorly understood. The purpose of the present paper was to determine the prevalence of iron overload and to study the relationship between hepatic iron concentration (HIC) and clinical, biochemical and histological characteristics in chronic HCV‐infected carriers.

A randomized double-blind study of the short-time treatment of obese patients with nonalcoholic fatty liver disease with ursodeoxycholic acid

In order to determine the effect of ursodeoxycholic acid on nonalcoholic fatty liver disease, 30 patients with body mass indices higher than 25, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) or gamma-glutamyltransferase (gamma-GT) at least more than 1.5 times the upper limit of normality, and hepatic steatosis demonstrated by ultrasonography were randomized into two groups of 15 patients to receive placebo or 10 mg kg-1 day-1 ursodeoxycholic acid for three months. Abdominal computed tomography was performed to quantify hepatic fat content, which was significantly correlated with histological grading of steatosis (r s = -0.83, P < 0.01). Patient body mass index remained stable for both groups throughout the study, but a significant reduction in mean ( +/- SEM) serum levels of ALT, AST and gamma-GT was observed only in the treated group (ALT = 81.2 +/- 9.7, 44.8 +/- 7.7, 48.1 +/- 7.7 and 52.2 +/- 6.3 IU/l at the beginning and after the first, second and third months, respectively, N = 14, P < 0.05). For the placebo group ALT values were 66.4 +/- 9.8, 54.5 +/- 7, 60 +/- 7.6 and 43.7 5 IU/l, respectively. No alterations in hepatic lipid content were observed in these patients by computed tomography examination (50.2 +/- 4.2 Hounsfield units (HU) at the beginning versus 51.1 +/- 4.1 HU at the third month). These results show that ursodeoxycholic acid is able to reduce serum levels of hepatic enzymes in patients with nonalcoholic fatty liver disease, but this effect is not related to modifications in liver fat content.

Serum levels of YKL‐40 and hyaluronic acid as noninvasive markers of liver fibrosis in haemodialysis patients with chronic hepatitis C virus infection

Summary.  Hepatitis C virus (HCV) infection is highly prevalent among end‐stage renal disease (ESRD) patients undergoing haemodialysis and it is an important cause of morbidity and mortality in this population. The aim of this study was to evaluate the diagnostic value of YKL‐40 and hyaluronic acid (HA) as noninvasive markers of liver fibrosis in 185 ESRD HCV‐infected patients. Significant liver fibrosis was defined as METAVIR F2, F3 or F4 stages. Significant fibrosis was observed in 45 patients (24%). By univariate analysis, higher levels of YKL‐40, HA, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma‐glutamyltransferase (GGT) as well as reduced platelet count were associated with fibrosis. However, by multivariate analysis, only AST (P = 0.001), platelet count (P = 0.004) and HA (P = 0.042) were independently associated with significant fibrosis. For the prediction of significant fibrosis, the areas under receiver operating characterictic curve (AUROC) of the regression model (0.798) was significantly higher than the AUROC of YKL‐40 (0.607) and HA (0.650). No difference was noted between the AUROC of the regression model and AST to platelet ratio index (APRI) (0.787). Values <8.38 of the regression model showed a negative predictive value of 94% and scores ≥9.6 exhibited a positive predictive value of 65%. If biopsy indication was restricted to scores in the intermediate range of the regression model, it could have been correctly avoided in 61% of the cases. In conclusion, APRI and a model based on AST, platelet count and HA showed better accuracy than YKL‐40 and HA (when used solely) for the prediction of significant fibrosis in ESRD HCV‐infected patients.