Gabriella Lengyel

Pathological aspects of lipid peroxidation.

Abstract Lipid peroxidation (LPO) product accumulation in human tissues is a major cause of tissular and cellular dysfunction that plays a major role in ageing and most age-related and oxidative stress-related diseases. The current evidence for the implication of LPO in pathological processes is discussed in this review. New data and literature review are provided evaluating the role of LPO in the pathophysiology of ageing and classically oxidative stress-linked diseases, such as neurodegenerative diseases, diabetes and atherosclerosis (the main cause of cardiovascular complications). Striking evidences implicating LPO in foetal vascular dysfunction occurring in pre-eclampsia, in renal and liver diseases, as well as their role as cause and consequence to cancer development are addressed.

Silymarin in the prevention and treatment of liver diseases and primary liver cancer

In chronic liver diseases caused by oxidative stress (alcoholic and non-alcoholic fatty liver diseases, drug- and chemical-induced hepatic toxicity), the antioxidant medicines such as silymarin can have beneficial effect. Liver cirrhosis, non-alcoholic fatty liver and steatohepatitis are risk factors for hepatocellular carcinoma (HCC). Insulin resistance and oxidative stress are the major pathogenetic mechanisms leading the hepatic cell injury in these patients. The silymarin exerts membrane-stabilizing and antioxidant activity, it promotes hepatocyte regeneration; furthermore it reduces the inflammatory reaction, and inhibits the fibrogenesis in the liver. These results have been established by experimental and clinical trials. According to open studies the long-term administration of silymarin significantly increased survival time of patients with alcohol induced liver cirrhosis. Based on the results of studies using methods of molecular biology, silymarin can significantly reduce tumor cell proliferation, angiogenesis as well as insulin resistance. Furthermore, it exerts an anti-atherosclerotic effect, and suppresses tumor necrosis factor-alpha-induced protein production and mRNA expression due to adhesion molecules. The chemopreventive effect of silymarin on HCC has been established in several studies using in vitro and in vivo methods; it can exert a beneficial effect on the balance of cell survival and apoptosis by interfering cytokines. In addition to this, anti-inflammatory activity and inhibitory effect of silymarin on the development of metastases have also been detected. In some neoplastic diseases silymarin can be administered as adjuvant therapy as well.

High sustained virologic response rates in rapid virologic response patients in the large real‐world PROPHESYS cohort confirm results from randomized clinical trials

The ability to predict which patients are most likely to achieve a sustained virologic response (SVR) with peginterferon/ribavirin would be useful in optimizing treatment for hepatitis C virus (HCV). The objective of this large international noninterventional cohort study was to investigate the predictive value (PV) of a virologic response (VR) by weeks 2, 4, and 12 of treatment on SVR. Treatment‐naive HCV monoinfected patients (N = 7,163) age ≥18 years were prescribed peginterferon/ribavirin at the discretion of the treating physician according to country‐specific requirements in accordance with the local label. The main outcome measure was the PV of a VR (HCV RNA <50 IU/mL) by weeks 2, 4, and 12 of treatment for SVR24 (HCV RNA <50 IU/mL after 24 weeks of untreated follow‐up) by HCV genotype. The overall SVR24 rate was 49.4% (3,541/7,163; 95% confidence interval [CI]: 48.3‐50.6%). SVR24 rates in patients with an HCV RNA titer <50 IU/mL by weeks 2, 4, and 12, respectively, were 66.2% (95% CI: 60.4‐71.7%), 68.4% (95% CI: 65.7‐71.0%), and 60.3% (95% CI: 58.5‐62.1%) among genotype 1 patients; 82.0% (95% CI: 76.8‐86.5%), 76.3% (95% CI: 73.3‐79.1%), and 74.2% (95% CI: 71.3‐76.9%) among genotype 2 patients; 67.3% (95% CI: 61.1‐73.1%), 67.3% (95% CI: 64.2‐70.3%), and 63.8% (95% CI: 61.0‐66.6%) among genotype 3 patients; and 59.4% (95% CI: 40.6‐76.3%), 63.3% (95% CI: 54.3‐71.6%), and 54.3% (95% CI: 47.5‐60.9%) among genotype 4 patients. The absence of a VR by week 12 had the highest negative PV across all genotypes. Conclusion: A VR by week 2 or 4 had the highest positive PV for SVR24 and differed according to HCV genotype. (HEPATOLOGY 2012;56:2039–2050)

Serum Dipeptidyl Peptidase-4 Activity in Insulin Resistant Patients with Non-Alcoholic Fatty Liver Disease: A Novel Liver Disease Biomarker

Background In a cross-sectional study we studied the fasting serum DPP-4 enzymatic activity (sDPP-4) and the insulin resistance index (HOMA2-IR) in gliptin naïve patients with type 2 diabetes and in non-alcoholic fatty liver disease (NAFLD) and in healthy controls (CNTRL). Methods and Findings sDPP-4 was measured by kinetic assay in 39 NAFLD (F/M:19/20, mean age: 47.42 yrs) and 82 type 2 diabetes (F/M:48/34, 62.8 yrs) patients and 26 (F/M:14/12, 35.3 yrs) controls. Definition of T2D group as patients with type 2 diabetes but without clinically obvious liver disease created non-overlapping study groups. Diagnosis of NAFLD was based on ultrasonography and the exclusion of other etiololgy. Patients in T2D and NAFLD groups were similarly obese. 75 g CH OGTT in 39 NAFLD patients: 24-NGT, 4-IGT or IFG (“prediabetes”), 11-type 2 diabetes. HOMA2-IR: CNTRL: 1.44; T2D-group: 2.62 (p = 0.046 vs CNTRL, parametric tests); NAFLD(NGTonly): 3.23 (p = 0.0013 vs CNTRL); NAFLD(IFG/IGT/type 2 diabetes): 3.82 (p<0.001 vs CNTRL, p = 0.049 vs 2TD group). sDPP-4 activity was higher in NAFLD both with NGT (mean:33.08U/L) and abnormal glucose metabolism (30.38U/L) than in CNTRL (25.89U/L, p<0.001 and p = 0.013) or in T2D groups (23.97U/L, p<0.001 and p = 0.004). Correlations in NAFLD among sDPP-4 and ALT: r = 0.4637,p = 0.0038 and γGT: r = 0.4991,p = 0.0017 and HOMA2-IR: r = 0.5295,p = 0.0026 and among HOMA2-IR and ALT: r = 0.4340,p = 0.0147 and γGT: r = 0.4128,p = 0.0210. Conclusions The fasting serum DPP-4 activity was not increased in T2D provided that patients with liver disease were intentionally excluded. The high serum DPP-4 activities in NAFLD were correlated with liver tests but not with the fasting plasma glucose or HbA1C supporting that the excess is of hepatic origin and it might contribute to the speedup of metabolic deterioration. The correlation among γGT, ALT and serum DPP-4 activity and also between serum DPP-4 activity and HOMA2-IR in NAFLD strongly suggests that serum DPP-4 activity should be considered as a novel liver disease biomarker.

Oxidative Stress in the Liver and Biliary Tract Diseases

Oxidative stress plays an important role in the pathogenesis of toxic liver diseases and of other hepatic alterations. We summarize the pathomechanism of free radical reactions in liver diseases and the results of experimental and clinical observations. Most of the hepatoprotective drugs belong in the group of free-radical scavengers, their mechanism of action involving membrane stabilization, neutralization of free radicals and immunomodulation. We demonstrate the effects of the different drugs used in the therapy of liver diseases in animal experiments and in human clinicopharmacological studies. The scavenger effect of these drugs has been demonstrated in the subcellular fractions of liver cells in animal experiments. In vitro incubation with some hepatoprotective drugs inhibit lectin-induced lymphocyte transformation while others decrease the antibody-dependent, spontaneous, and lectin-induced lymphocytotoxicity. Dihydroquinolin-type antioxidants and silymarin enhanced the superoxide dismutase activity of erythrocytes and lymphocytes. In addition, in a 6-month double-blind clinical trial of patients with chronic alcoholic liver disease, we studied the effects of silymarin therapy on liver function tests, on the parameters characterizing the oxidative stress and immune reaction, on serum procollagen III peptide level, and on liver histology. A wide range of methods was used. The silymarin preparate corrected the altered immune reaction and the decreased superoxide-dismutase activity of erythrocytes and lymphocytes in patients with alcoholic liver cirrhosis. The results indicate that these drugs exert hepatoprotective activity and can improve liver functions in alcoholic patients and in toxic liver diseases. We found a correlation between the bilirubin concentration and lipid peroxidation in cases with toxic liver and biliary tract diseases, and assume that there are two kinds of bilirubin, an antioxidant and a prooxidant form, on the basis of diene conjugates in the bile.

Oxidative damage in alcoholic liver disease

Objective The metabolic effects of alcohol are due both to its direct action and to that of its first metabolite, and can also be connected with the changes in redox state. Differences in ethanol distribution, bioavailability and hepatic metabolism can provide insight into the protective and predisposing factors in alcoholism, as well as gender differences of alcohol toxicity. Oxidative stress occurs following various conditions of ethanol consumption. Design Twenty-six Caucasian patients with alcoholism and 32 healthy, abstinent controls of both sexes were investigated with special regard to reduction–oxidation status and ad hoc free-radical–antioxidant balance. Method Plasma free SH-group concentration, H-donating ability, and reducing power property were measured by simple spectrophotometric methods. Total scavenger capacity was determined by a newly developed chemiluminometric method in plasma and erythrocytes. Results Alcoholics showed a decrease of free SH-group concentration, hydrogen-donating ability and an increase of reducing power property in plasma. A decreased total scavenger capacity of erythrocytes and plasma of alcoholic patients, combined with gender differences, could be detected. Conclusions Alcoholic dependence causes gradual exhaustion of the antioxidant capacity of erythrocytes, therefore this non-invasive measurement may be useful as a follow-up of the evolution of alcoholic liver disease. The results also suggest a gender susceptibility of alcohol toxicity.

Silymarin in the treatment of chronic liver diseases: past and future.

In the treatment of chronic liver diseases adequate therapy can be chosen only in the knowledge of pathogenetic processes. In the liver diseases caused by oxidative stress (alcoholic and non-alcoholic fatty liver and steatohepatitis, drug and compound induced liver toxicity) the antioxidant drugs, like silymarin, in chronic hepatitis caused by hepatitis B and hepatitis C virus, combined peginterferon and nucleosid treatments are the primary therapy modalities to be selected. The main effects of silymarin are the membrane stabilising and antioxidant effects, it is able to help the liver cell regeneration, it can decrease the inflammatory reaction and inhibit the fibrogenesis in the liver. These results have been established by experimental and clinical trials. According to open studies, the long administration of silymarin significantly increased the survival time of patients with alcohol-induced liver cirrhosis. Recently it was demonstrated that high-dosage silibinin infusion treatment could significantly decrease the number of hepatitis C viruses after four-week application. On the basis of the results with the methods of molecular biology, silymarin is able to decrease significantly tumor cell proliferation, angiogenesis as well as insulin resistance. These results support the administration of silymarin preparations in the therapy of chronic liver diseases, especially in alcoholic and non-alcoholic steatohepatitis in current clinical practice, and as it can be awaited, also in the future. In some neoplastic diseases they could also be administered as adjuvant therapy.

Cytokine (IL-10, IL-28B and LT-A) gene polymorphisms in chronic hepatitis C virus infection

Abstract Background Since the clearance of hepatitis C virus (HCV) infection depends on the cytokines which are under genetic control, we have studied genetic polymorphisms of two pro-inflammatory interleukin-28B (IL-28B) (also named as interferon λ-3) and lymphotoxin-A (LT-A) as well as of one anti-inflammatory cytokine interleukin-10 (IL-10) genes in patients with HCV infection. We examined the allele frequencies of these genes in HCV patients as compared with healthy controls, and determined their association with sustained virological response (SVR) on PEG-IFN α-2a + ribavirin (RBV) (P/R) treatment, to assess the predictive value of these genetic variants. A total of 292 chronic HCV genotype 1 infected patients and 104 healthy controls have been studied. The samples were genotyped using PCR-RFLP and ABI Taqman genotyping assay. Results IL-28B — The C/C genotype in HCV patients occurred with lower frequency than in healthy controls (28.11% vs. 51.92%, p = 0.0001, OD 2.76), suggesting a protective role ...

Relationship Between Hepatitis C Virus Recurrence and De Novo Diabetes After Liver Transplantation: The Hungarian Experience

De novo diabetes mellitus is a common complication after liver transplantation. It is strongly associated with hepatitis C virus (HCV) infection. We analyzed the relationship between HCV recurrence and de novo diabetes among the Hungarian liver transplant population. This retrospective study included cases from 1995 to 2009 on 310 whole liver transplantations. De novo diabetes was defined if the patient had a fasting plasma glucose ≥126 mg/dL permanently after the third month post liver transplantation, and/or required sustained antidiabetic therapy. De novo diabetes occured in 63 patients (20%). The cumulative patient survival rates at 1, 3, 5, and 8 years were 95%, 91%, 88%, and 88% in the control group, and 87%, 79%, 79%, and 64% in the de novo group, respectively (P=.011). The majority of the patients in the de novo group were HCV positive (66% vs 23%). Early virus recurrence within 5 months was associated with the development of diabetes (80% vs 20% non-diabetic controls; P=.017). The fibrosis (2.05 ± 1.5 vs 1 ± 1; P=.039) and Knodell scores (3.25 ± 2 vs 1.69 ± 1.2; P=.019) were higher among the de novo group after antiviral therapy. Rapid recurrence, more severe viremia, and fibrosis showed significant roles in the developement of de novo diabetes after liver transplantation.

New-onset diabetes mellitus after liver transplantation

A de novo diabetes mellitus a majatultetes gyakori szovődmenye. Celkitűzes: A de novo diabetes gyakorisagat, jelentőseget es a kockazati tenyezők szerepet vizsgaltuk. Modszer: 1995 es 2009 kozott 310 majatultetett beteg adatait dolgoztuk fel retrospektiv modszerrel. De novo diabetest allapitottunk meg, ha az ehomi vercukor a 3. posztoperativ honapon tul ismetelten >6,8 mmol/l volt, es/vagy a majatultetes utan tartos, a 3. posztoperativ honapot meghaladoan is fenntartott antidiabetikus terapia indult. Eredmenyek: De novo diabetes a betegek 20%-anal (63 beteg) alakult ki. A de novo es a kontrollcsoport kozott az alabbiakban talaltunk kulonbseget. Donor-testtomegindex (24±3 vs. 22,4±3,6 kg/m 2 , p = 0,003), ferfi nem (58% vs. 33%, p = 0,002). Recipienseletkor (47,6±7,2 vs. 38,3±14,6 ev, p<0,001), -testtomegindex (26,7±3,8 vs. 23,3±5,6 kg/m 2 , p<0,001), ferfi nem (60% vs. 44%, p = 0,031). A de novo diabetesesek csoportjaban a betegek 66%-at HCV talajan kialakult cirrhosis miatt transzplantaltak, a kontrollcs...UNLABELLED New-onset diabetes is a common complication after liver transplantation. AIM We aimed to analyze the incidence and rate of known risk factors and the impact of new-onset diabetes mellitus on postoperative outcome. METHODS We retrospectively evaluated the files of 310 patients who underwent liver transplantation between 1995 and 2009. Definition of new-onset diabetes included: repeated fasting serum glucose >6.8 mmol/l and/or sustained antidiabetic therapy that was present 3 months after transplantation. RESULTS New-onset diabetes occurred in 63 patients (20%). Differences between the new-onset and the control group were the donor body mass index (24+/-3 vs. 22.4+/-3.6 kg/m 2 , p = 0.003), donor male gender (58% vs. 33%, p = 0.002), and recipient age (47.6+/-7.2 vs. 38.3+/-14.6 year, p<0.001), body mass index (26.7+/-3.8 vs. 23.3+/-5.6 kg/m 2 , p<0.001), male gender (60% vs. 44%, p = 0.031). The 66% of patients with new-onset diabetes were transplanted with cirrhosis caused by hepatitis C virus infection, while in the control group the rate was 23% (p<0.001). Cumulative patient survival rates at 1, 3, 5 and 8 year were 95%, 90.6%, 88% and 88% in the control group, and 87%, 79%, 79% and 64% in the de novo group, respectively (p = 0.011). Cumulative graft survival rates at 1, 3, 5 and 8 year in the control group were 92%, 87%, 86% and 79%, in the de novo diabetes group the rates were 87%, 79%, 79%, 65%, respectively (p = NS). In case of early recurrence (in 6 months), majority of patients developed new-onset diabetes (74% vs. control 26%, p = 0.03). More patients had more than 10 times higher increase of the postoperative virus titer correlate to the preoperative titer in the de novo diabetes group (53% vs. 20%, p = 0.028). Mean fibrosis score was higher in new-onset group one year after the beginning of antiviral therapy (2.05+/-1.53 vs. 1.00+/-1.08, p = 0.039). CONCLUSIONS Risk factors for new-onset diabetes after transplantation are older age, obesity, male gender and cirrhosis due to hepatitis C infection. The early recurrence, viremia and more severe fibrosis after antiviral therapy have an impact on the occurrence of new-onset diabetes in hepatitis C positive patients.