Billur Canbakan

Melatonin reduces dimethylnitrosamine-induced liver fibrosis in rats

Abstract:  Increased deposition of the extracellular matrix components, particularly collagen, is a central phenomenon in liver fibrosis. Stellate cells, the central mediators in the pathogenesis of fibrosis are activated by free radicals, and synthesize collagen. Melatonin is a potent physiological scavenger of hydroxyl radicals. Melatonin has also been shown to be involved in the inhibitory regulation of collagen content in tissues. At present, no effective treatment of liver fibrosis is available for clinical use. We aimed to test the effects of melatonin on dimethylnitrosamine (DMN)‐induced liver damage in rats. Wistar albino rats were injected with DMN intraperitoneally. Following a single dose of 40 mg/kg DMN, either saline (DMN) or 100 mg/kg daily melatonin was administered for 14 days. In other rats, physiologic saline or melatonin were injected for 14 days, following a single injection of saline as control. Hepatic fibrotic changes were evaluated biochemically by measuring tissue hydroxyproline levels and histopathogical examination. Malondialdehyde (MDA), an end product of lipid peroxidation, and glutathione (GSH) and superoxide dismutase (SOD) levels were evaluated in blood and tissue homogenates. DMN caused hepatic fibrotic changes, whereas melatonin suppressed these changes in five of 14 rats (P < 0.05). DMN administration resulted in increased hydroxyproline and MDA levels, and decreased GSH and SOD levels, whereas melatonin reversed these effects. When melatonin was administered alone, no significant changes in biochemical parameters were noted. In conclusion, the present study suggests that melatonin functions as a potent fibrosuppressant and antioxidant, and may be a therapeutic choice.

Efficacy of interferon α‐2b and lamivudine combination treatment in comparison to interferon α‐2b alone in chronic delta hepatitis: A randomized trial

Background and Aim:  Delta hepatitis is characterized by rapidly progressive liver disease with adverse prognosis in most patients. Patients benefit from high doses and prolonged courses of interferon (IFN) therapy; however, lamivudine as a single agent has been disappointing. Data relating to the efficacy of IFN and lamivudine in combination is limited. The aim of this study was to test the efficacy of IFN‐α 2b and lamivudine combination treatment in comparison to IFN‐α 2b alone in patients with chronic delta hepatitis.

Is alanine aminotransferase level a surrogate biomarker of hepatic apoptosis in nonalcoholic fatty liver disease

AIM To evaluate the serum alanine aminotransferase (ALT) variabilities in nonalcoholic fatty liver disease (NAFLD) and correlate it with hepatocyte apoptosis and oxidative stress parameters. METHODS 24 patients with NAFLD and normal ALT were compared with 26 subjects with NAFLD and elevated ALT. Liver oxidative stress was estimated on the basis of malondialdehyde, superoxide dismutase and glutathione. Immunohistochemistry was performed for activated caspase 3 and 8, nuclear factor-kappaB, antiapoptotic Bcl-2 protein and serum TNF receptor levels were measured. RESULTS The mean caspase 3 and 8 activity scores, oxidative stress parameters, necroinflammatory grade and prevalence of severe fibrosis were comparable across the groups with normal versus elevated ALT. Patients with nonalcoholic steatohepatitis had significantly higher caspase 3 and 8 activity (percentage of cells with positive staining per high power field), and serum malondialdehyde (mmol/l) levels than those with simple steatosis. ALT elevation was not a risk factor for advanced necroinflammatory grade and fibrosis. A receiver operating characteristic curve did not demonstrate sensitivity and specificity for discriminative power of ALT. CONCLUSION Apoptosis and oxidative stress are the main processes contributing to disease progression in NAFLD. ALT values do not correlate with the parameters of apoptosis and oxidative stress. The disease severity can only be determined by liver biopsy.

Validation of Biochemical Markers for the Prediction of Liver Fibrosis and Necroinflammatory Activity in Hemodialysis Patients with Chronic Hepatitis C

Background: Liver biopsy is an imperfect gold standard for assessing the disease severity in hemodialysis patients with chronic hepatitis C. Our purpose was to compare the accuracy of the FibroTest (FT) and ActiTest (AT) with liver biopsy and the AST-to-platelet ratio index (APRI) in determining hepatic fibrosis and necroinflammatory activity in hemodialysis patients with hepatitis C virus (HCV). Methods: The FT-AT index combining 6 biochemical markers was assessed in 33 hemodialysis patients with HCV. Liver fibrosis and necroinflammatory activity was staged and graded according to the METAVIR scoring system. Results: The accuracy of FT-AT versus biopsy was 0.46 for significant fibrosis and 0.36 for severe necroinflammatory activity. The FT index had a positive predictive value of 20% for scores greater than 0.6 and a negative predictive value of 45% for scores less than 0.2. Eleven of the 33 patients had scores ≤0.2, 6 had significant fibrosis on biopsy. Four out of 5 patients with FT scores >0.6 had mild fibrosis. APRI correlated well with the biopsy. Conclusion: The FT-AT test does not seem to be a reliable noninvasive marker for the prediction of necroinflammatory activity and fibrosis in hemodialysis patients with HCV and cannot be used as an alternative to either liver biopsy or APRI.

CASE REPORT: Cytomegalovirus Infection of Gastrointestinal Tract with Multiple Ulcers and Strictures, Causing Obstruction in a Patient with Common Variable Immunodeficiency Syndrome

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by panhypogammaglobulinemia (especially decreased production of IgG but frequently also IgA and IgM, recurrent bacterial infections, and different gastrointestinal appearances), especially inflammatory bowel disease and granulomatous enteropathy, and increased incidence of malignant and autoimmune disease. A small subpopulation of these patients has reduced numbers of circulating B lymphocytes, suggesting a central failure of the development of this cell line (1–3). In 80–90% of the patients there are normal numbers of B lymphocytes, with immature phenotype, because these cells fail to differentiate into immunoglobulin-secreting plasma cells (4). Most patients with this disorder appear to have an intrinsic B-cell defect. Consistent with the evidence that B lymphocytes are able to recognize the antigens and proliferate but fail to differentiate to plasma cells is the fairly common finding of lymphoid hyperplasia, including splenomegaly and nodular hyperplasia of the gut. In some patients, an increase in T-suppressor activity, quantitative deficiency of helper T cells, and production of abnormal immunoglobulins, which are degraded in cytoplasm, have been observed. Two thirds of patients with common variable immunodeficiency have a normal CD4/CD8 ratio, one third has increased relative and absolute numbers of CD3 and CD8 peripheral blood lymphocytes, resulting in a decreased CD4/CD8 ratio. Less than 10% of the patients with normal ratios and 40% with a decreased ratio are anergic, and 30% of the patients with normal ratios and 70% with decreased ratios have splenomegaly (5). Most of the CD8 T cells expressed the CD57 antigen and activation antigens (HLA-DR) (6). Cytomegalovirus (CMV) is a member of the herpesvirus group and causes a wide spectrum of disorders, ranging from an asymptomatic, subclinical infection to a mononucleosis syndrome in healthy individuals to disseminated disease in the immunocompromised host (7). CMV contains doublestranded DNA, a protein capsid, and a lipoprotein envelope and replicates in the cell nucleus. Virus replication is associated with the production of large intranuclear inclusions and smaller cytoplasmic inclusions. Once infected, an individual probably carries the virus for life. Most commonly these infections remain latent. However, with compromise of Tlymphocyte-mediated immunity, CMV reactivation syndromes frequently develop (8). These cells in vivo Manuscript received April 10, 1999; accepted January 31, 2000. From the Internal Medicine Department, Gastroenterology Department, General Surgery Department, Department of Pathology, and Infectious Diseases Department, Cerrahpasa Medical Faculty, University of Istanbul; and Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Pittsburgh, Pennsylvania. Address for reprint requests: Dr. Veysel Tahan, Cerrahpasa Medical Faculty, Internal Medicine Department, 34303 Aksaray, Istanbul, Turkey. Digestive Diseases and Sciences, Vol. 45, No. 9 (September 2000), pp. 1781–1785

Role of oxidative stress and insulin resistance in disease severity of non-alcoholic fatty liver disease.

BACKGROUND/AIMS Oxidative stress and insulin resistance (IR) are major contributors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to find the relation between oxidative stress parameters and histopathological findings in NAFLD patients with and without insulin resistance (IR). MATERIALS AND METHODS Thirty-two patients with no alcohol intake and biopsy-proven diagnosis of NAFLD were studied (M/F: 17/15; mean age 46.5±11.4 years). Twenty-one NAFLD patients with IR were compared with 11 patients without IR. The fasting insulin level was measured, and the insulin resistance index was calculated using the homeostasis model assessment (HOMA) method. Malondialdehyde (MDA) and superoxide dismutase (SOD) activities were measured in tissue and serum specimens. Glutathione (GH) was measured in tissue homogenates. Nitric oxide (NO), vitamin E and C levels were measured in serum. RESULTS Patients with IR had significantly higher tissue MDA levels (p=0.001) and significantly decreased tissue SOD and GH levels (p=0.001 and 0.002, respectively) than those without IR. The steatosis grade, necroinflammatory grade and stage were significantly higher in patients with IR (p=0.035, 0.003 and 0.001, respectively). HOMA IR significantly correlated with the necroinflammatory grade, stage, tissue MDA, SOD and GH (p=0.013, 0.001, 0.008, 0.001 and 0.001, respectively). Serum MDA (β=1.88, p=0.002), serum SOD (β=0.57, p=0.006), tissue MDA (β=0.22, p=0.006), tissue SOD (β=1.48, p=0.071) and stage (β=2.81, p=0.003) were independently associated with increased HOMA IR. Increased MDA [OR: 1.51; 95% CI: (1.03-2.22); p=0.034] was a risk factor for non-alcoholic steatohepatitis (NASH), and increased SOD activity had a preventive effect against NASH [OR: 0.008; 95% CI: (0.001-0.98); p=0.04]. CONCLUSION This study shows that insulin resistance in NAFLD correlates with enhanced oxidative stress. Histopathological disease severity significantly correlated with oxidative stress parameters. These data show that NAFLD patients with IR may have increased risk for disease progression.

Carbamazepine-induced hypogammaglobulinemia

Carbamazepine is used to control seizures. Its common side effects are sleep disorders, anorexia, nausea, vomiting, polydipsia, irritability, ataxia, and diplopia. Involvement of the immune system is rare, and few cases of decreased immunoglobulin levels have been reported. We describe a patient with low immunoglobulin levels due to carbamazepine use who presented with recurrent urinary tract infection. Intravenous immunoglobulin was administered, and immunoglobulin levels increased to safer levels after discontinuation of carbamazepine. Previous reports describe severe infection after carbamazepine-induced hypogammaglobulinemia. Therefore, in patients using antiepileptics, particularly carbamazepine, serum immunoglobulin levels should be checked in those with recurrent infections.

Liver steatosis in hepatitis C positive hemodialysis patients and factors affecting IFN-2a treatment

Objective. Hepatitis C virus (HCV) infection is endemic among hemodialysis (HD) patients. It is well known that HCV causes approximately 50% of hepatosteatosis in patients with normal renal function and that this rate is higher in patients infected with genotype 3. The aim of this study was to investigate the rate of steatosis, the regression in steatosis with interferon (IFN) treatment and factors affecting IFN treatment in hemodialysis patients with chronic hepatitis C (CHC). Material and methods. Thirty-seven HD patients with CHC were included in the study. All patients received hemodialysis treatment three times a week during the follow-up period. Patients were treated with 3 million units (MU) of IFN-α 2a monotherapy for at least 6 months. All patients were evaluated by liver biopsy before therapy and 16 were evaluated at 12-month follow-up. Results. Mean age of the 37 patients (23 M, 14 F) was 44±11.6 years and body mass index was 21.8±1.8 kg/m2. Twenty-eight of the patients included in the study (75.7%) were of genotype 1b. RNA response after treatment was 78.4% and sustained response after the follow-up period of 14.9±8 months was 54%. Total cholesterol values were directly proportional to RNA response (p<0.003) and inversely correlated with resistance to treatment (p<0.008). Triglyceride values were inversely correlated with resistance to treatment (p<0.041). At evaluation of steatosis scores in baseline liver biopsy, severe and mild to moderate steatosis was found in 3 (8.1%) and 16 (43.2%) patients, respectively. In 18 patients (48.7%) there was no steatosis. The rate of steatosis was found to be 44% in control biopsies. While there was no regression in the rates of steatosis (p=0.499), it was found that steatosis regressed after IFN treatment in two patients infected with genotype 3. No correlations were observed between HCV genotype, sustained response and liver steatosis. Conclusions. Response and sustained response rates of HD patients with HCV in a Turkish population were found to be high after IFN monotherapy. With the exception of two patients infected with genotype 3a, the rate of liver steatosis was found to be high and did not change after IFN treatment in HD patients with CHC.

Reliability of caspase activity as a biomarker of hepatic apoptosis in nonalcoholic fatty liver disease

A letter in response to: Yilmaz Y, Kurt R, Kalayci C. Apoptosis in nonalcoholic steatohepatitis with normal aminotransferase values: zooming in on cytokeratin 18 fragments. Biomarkers Med. 4(5), 743–745 (2010).

Fatty liver disease might increase the risk of abdominal operation in patients with fatty liver and the prevalence of cancer in first-degree relatives.

BACKGROUND/AIMS We investigated the risk of abdominal operation in patients with fatty liver and the risk of any cancer in first-degree relatives of patients with fatty liver. MATERIALS AND METHODS We evaluated 105 patients with nonalcoholic fatty liver disease (NAFLD), 121 patients with biopsy-proven hepatitis C (61 patients with fatty liver and 60 patients without fatty liver), 50 patients with inflammatory bowel disease (IBD), and 109 patients with dyspepsia. RESULTS There was no difference in sex, mean age, and marital status among the groups except that patients with IBD were younger than the others (p<0.001). The frequency of cancer among family members was 18% in IBD, 9% in dyspepsia, 28% in hepatitis C with steatosis, 21.5% in hepatitis C without steatosis, and 27% in NAFLD (p=0.006). Then, we divided the study group into two groups as follows: group 1: (IBD+dyspepsia+hepatitis C without steatosis) and group 2: (hepatitis C with steatosis+NAFLD). We found that the frequency of cancer was 16% in group 1 versus 24.4 % in group 2 (p=0.037). We also investigated the risk of abdominal operation in patients with fatty liver. The results were as follows: 33% in group without fatty liver versus 43% in group with fatty liver (p=0.043). CONCLUSION Understanding the underlying causes of fatty liver forms might decrease the cancer frequency in the population and number of operations in patients with fatty liver.