Induction of HGF and VEGF in hepatic regeneration after hepatotoxin-induced cirrhosis in mice.

BACKGROUND/AIMS: Liver cirrhosis is the irreversible end-result of fibrous scarring and hepatocellular regeneration, characterized by diffuse disorganization of normal hepatic structure by regenerative nodules and fibrotic tissue. In this study, we elucidated the role of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) in liver regeneration. METHODOLOGY: The study was conducted as an experimental laboratory investigation using a mouse model of lethal liver cirrhosis induced by carbon tetrachloride (CCl4), dimethylnitrosamine (DMN) and D-galactosamine (D-gal) administrations. RESULTS: Liver morphology showed fibrosis/cirrhosis in all groups, but to a different extent, as confirmed by the rise in serum transaminase levels. The immunolocalization of VEGF and HGF, and homogenate levels of HGF and serum levels of VEGF, were also analyzed. Liver fibrosis/cirrhosis was more severe in CCl4-treated mice. In cirrhotic livers, immunostaining for HGF was weak and the HGF content of liver tissue was lower. Strong immunoreactivity for VEGF was observed when hepatotoxins were administered, however as cirrhosis became apparent immunoreactivity was reduced. Blood VEGF levels increased gradually. CONCLUSIONS: Our results suggest possible involvement of VEGF in angiogenesis of cirrhotic liver. VEGF might be required for reconstruction of hepatic cells and sequentially participates in liver regeneration by facilitating hepatocyte proliferation. HGF production is supposed to be induced in the necrotic liver during regeneration and severe tissue damage followed by cirrhosis might account for low homogenate HGF levels.

Electron microscopic findings in non-alcoholic fatty liver disease: is there a difference between hepatosteatosis and steatohepatitis?

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease has long been accepted as benign; however, recent evidence suggests that the disease may progress to cirrhosis and hepatocellular carcinoma, although the natural course of the disease is still unclear. This study was designed to comparatively evaluate electron microscopic features of non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). METHODS: Quantitative and semi-quantitative ultrastructural evaluations were performed on liver biopsies from 23 patients, 10 with NAFL and 13 with NASH. RESULTS: No statistically significant difference was noted between NAFL and NASH patients in ultrastructural features of hepatocytes including megamitochondria, intramitochondrial crystalline inclusions, mitochondrial matrix granules, foamy cytoplasmic appearance, electron-lucent and glycogen-containing nuclear regions, lipofuscin granules, or an increased frequency of vesicles containing electron-dense material in peribiliary Golgi zone; however, the mitochondrial diameter was significantly higher in the NASH patients. Intercellular distance and microvilli between hepatocytes, collagen and electron-dense material accumulation in the space of Disse, electron-dense material accumulation and microvillus density in bile canaliculi did not differ significantly between the groups. CONCLUSIONS: Our data show that, although NAFL and NASH can be distinguished by their distinct light microscopic features, ultrastructural characteristics are similar, which suggests that NAFL may also have the potential to progress to fibrosis and cirrhosis like NASH.

A new agent for tumour necrosis factor-alpha inhibition: In vitro effects of dipyridamole in Crohn's disease.

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) plays a central role in inflammatory cascade in Crohn's disease (CD). Our study aims to investigate the in vitro effects of dipyridamole (DP) on the TNF-alpha and interleukin-10 (IL-10) production in the intestinal mononuclear cells of CD patients. MATERIAL AND METHODS: Thirteen patients with CD and in 17 healthy individuals underwent colonoscopy and biopsy samples were taken. Cultured mononuclear cells were preincubated with DP1 (0.7 microg/ml), DP2 (1.25 microg/ml), methotrexate (MTX)1 (0.5 nmol/L) and MTX2 (1.5 nmol/L). These cells were then stimulated with lipopolysaccaride (LPS) and phytohemagglutinin (PHA). The levels of TNF-alpha and IL-10 in supernatants were measured with standard immunoassay monoclonal antibody method. RESULTS: An appropriate cell culture could be obtained in 10 patients with CD and 12 healthy individuals. In LPS stimulated cells, MTX1 and MTX2 were superior to DP1 and DP2 in suppressing TNF-alpha in both groups. In PHA stimulated cells, while MTX1 was superior to DP1, MTX2 and DP2 had an equivalent effect in CD patients (p<0.05, p>0.05, respectively). In LPS-stimulated cells DP2 was significantly superior to MTX2 in increasing IL-10 levels in both groups (p<0.05). In PHA stimulated cells, DP1 and DP2 caused a higher increase in IL-10 levels compared with MTX1 and MTX2 in CD group (p<0.05). CONCLUSIONS: Dipyridamole suppresses TNF-alpha similar with MTX. It seems to be superior to MTX in increasing IL-10 levels. Addition of DP to anti-TNF medications may create a synergy in cytokine modulation.

Intestinal metaplasia in portal hypertensive gastropathy: a frequent pathology.

OBJECTIVE: To compare the frequency of intestinal metaplasia (IM) in patients with portal hypertensive gastropathy (PHG) to the control group with functional dyspepsia. METHODS: Two-hundred and eighty-nine cases were prospectively evaluated in three groups (controls:group I--123 patients; cirrhotics: group II--135 patients; noncirrhotic portal hypertensives: group III--31 patients). Mucosal biopsies (three antrum, one angulus, two corpus) were taken and examined for atrophy, IM, dysplasia, Helicobacter pylori (Hp) and histologic PHG. RESULTS: Frequencies of IM in groups I, II and III were 17.1% (type I, 3.3%; type II, 10.6%; type III, 3.3%), 34.3% (type I, 9.6%; type II, 17%; type III, 6.7%) and 33.3% (type I, 9.7%; type II, 12.9%; type III, 9.7%), respectively. In patients with PHG, frequency of IM was significantly higher than in control group (P<0.05) and correlated with the severity of PHG (P<0.05). The frequency of type III IM was not statistically different among the three groups. Frequency of atrophy in cirrhotic patients was higher than in control group (17.9% in group I, 32.6% in group II, 25.8% in group III; P<0.05). In the control group, Hp prevalence was significantly higher than in patients with PHG (P<0.05) and there was a positive correlation between Hp and atrophy (P<0.05). In multivariate analysis, PHG and age were found as independent predictors for IM; PHG, age and Hp for atrophy. CONCLUSION: Frequencies of atrophy and IM are higher in patients with PHG. PHG is a reliable marker for IM and atrophy in gastric mucosa.

A case of Aeromonas hydrophila enteritis in the course of ulcerative colitis.

A 24-year-old man with a previous diagnosis of ulcerative pancolitis presented with severe malabsorption with watery diarrhea, malaise, and weight loss. Physical examination revealed paleness, hypotension, tachycardia, edema, ascites, and left-sided pleural effusion. Laboratory analysis revealed hypoalbuminemia and hypocalcemia. Further examination revealed that malabsorption was related to Aeromanas hydrophila infection. Clinical improvement was observed upon oral ciprofloxacin treatment. No clinical or laboratory activation of ulcerative colitis was detected during this infection.

Evaluation of malignancy risk and endoscopic follow up in achalasia: case report.

Achalasia is an esophageal motility disorder that is accepted as a risk factor for the development of cancer. Especially in megaesophagus, chronic irritation of foods and bacterial overgrowth may contribute to the formation of high-grade dysplasia and squamous cell carcinoma. We present a case of advanced stage achalasia with high-grade dysplasia detected three years after a cardiomyotomy operation. Cancer risk continues after surgical operation in achalasia, like in this case. In conclusion, endoscopic follow up is necessary for these patients even after surgical treatment.

Primary malignant melanoma of the esophagus.

Primary malignant melanoma of the esophagus (PMME) comprises only 0.1-0.2% of all malignant esophageal tumors. PMME tumors are highly aggressive and metastasize early via hematogenic and lymphatic pathways. Treatment outcome is poor because the cancer has often advanced at the time of diagnosis. Inoperability, unsuccessful treatment with radiotherapy and chemotherapy in advanced tumors and metastases have contributed to its poor prognosis. Here, we present the endoscopic features, endoscopic ultrasonography findings and management of a PMME case.

Response to hepatitis B vaccination in patients with celiac disease.

Abnormal immune response to gliadin, genetic, and environmental factors play a role in the pathogenesis of celiac disease (CD). Non-responsiveness to hepatitis B virus (HBV) vaccination is related to genetic features. Certain human leukocyte antigen (HLA) genotypes are more prevalent among non-responders to HBV vaccination. There is also a strong relationship between CD and these HLA genotypes. This study investigates the relationship between CD and non-responsiveness to HBV vaccination, with an emphasis on genotypic co-incidence. No statistically significant difference was noted between the ages and gender of CD patients and control subjects. Baseline serum IgA, IgM, and IgG levels of all CD patients were normal. Responsiveness to HBV vaccination was observed in 17 (68%) CD patients and all (100%) control subjects (P = 0.006). In conclusion, CD should also be sought in unresponders to HBV vaccine who are not immunosuppressed.

Prevalence and clinical significance of SEN-H virus in chronic hepatitis B, C and delta infections in Turkey.

BACKGROUND/AIMS: SEN viruses are transmitted parenterally and can cause post-transfusion hepatitis. The prevalence and clinical significance of SEN viruses have been investigated in patients with chronic hepatitis C and B but not in D. We aimed to determine the prevalence and clinical significance of SEN viruses- H in patients with chronic hepatitis C, B and delta in Turkey. METHODS: SEN viruses-H was analyzed in 85 patients with chronic viral hepatitis (30 HCV, 30 HBV and 25 HDV) and 43 non-professional blood donors. HBV DNA, HCV RNA and HDV RNA were positive in patients with hepatitis B, C and D, respectively. SEN viruses-H DNA was detected by semi-nested polymerase chain reaction method (L2AS, C5S primer in first step, L2AS, D11 in second step) after extraction of DNA from sera (NucleoSpin blood; Macherey-Nagel GmbH & Co KG, Germany). RESULTS: SEN viruses-H DNA was found to be positive in 7/30 (23.3%), 10/30 (33.3%), 6/25 (24%), and 7/43 (16.2%) of patients with chronic C, B, and D hepatitis and healthy blood donors, respectively. There was no significant difference in clinical features and treatment response between SEN viruses- H-positive and -negative patients with chronic viral hepatitis. CONCLUSIONS: SEN viruses is more frequent in chronic hepatitis patients than in healthy blood donors. These results indicate that SEN viruses has no effect on the clinical course and treatment response of chronic viral hepatitis.

The role of thrombopoietin and spleen volume in thrombocytopenia of patients with noncirrhotic and cirrhotic portal hypertension.

BACKGROUND/AIMS: To determine the role of thrombopoietin and spleen volume in thrombocytopenia diagnosed in cirrhotic and noncirrhotic portal hypertensive patients. METHODS: Seventy- four portal hypertensive patients (group 1: 28 noncirrhotic; group 2: 46 cirrhotic) were enrolled into this study. Spleen volume was measured by magnetic resonance imaging. Thrombopoietin and hyaluronic acid were detected by ELISA in sera. RESULTS: Splenic volume was significantly higher in group 1 (1375+/-658.74 ml) than group 2 (981.78+/-512.39 ml). In group 1, thrombopoietin and hyaluronic acid levels were 76.6+/-30.39 pg/ml and 78.17+/-66.67 ng/ml, respectively. These values were significantly higher in group 2, at 99.89+/-38.5 pg/ml and 271.97+/-197.34 ng/ml, respectively (p<0.05). Platelet counts and thrombopoietin levels had a negative correlation with spleen volume in both groups (p<0.05). Serum thrombopoietin levels were not correlated with platelet counts in cirrhotic and noncirrhotic groups; however, thrombopoietin levels were negatively correlated with splenic volume in the whole group (p= 0.044, r= - 0.23). Although spleen volume was significantly larger in noncirrhotic patients, platelet counts were similar in both groups. CONCLUSIONS: This study confirms that splenic sequestration is the main factor in the thrombocytopenia in portal hypertensive patients. The balance of thrombopoietin production and degradation may be more important for platelet counts than decreasing synthesis.

The effects of rosiglitazone, metformin, and diet with exercise in nonalcoholic fatty liver disease.

Our aim was to evaluate effects of metformin, rosiglitazone, and diet with exercise in nonalcoholic fatty liver disease. Forty-seven patients (mean age, 44+/-10 years; 17 female) whose ALT levels had been high for at least 6 months and with hepatosteatosis detected by liver biopsy and/or USG were enrolled in this study. Of these, 12 were treated with 850 mg/day metformin (group 1), 11 with 4 mg/day rosiglitazone (group 2), and 24 with diet and exercise (group 3) for 1 year. ALT normalization at months 6 and 12 was accepted as treatment response. Liver biopsy was performed in all patients in groups 1 and 2 before treatment and 12 patients (4 in group 1, 8 in group 2) after treatment; but in group 3 it was performed only in patients who approved this procedure (12 patients). Body mass index did not change in groups 1 and 2, but it decreased significantly in group 3 (30+/-3 to 28+/-2 kg/m(2)) at month 12. Treatment response rate was 33.3, 54.5, and 54.2% in groups 1, 2, and 3, respectively, at month 6. This rate was 22.2, 37.5, and 41.2 in groups 1, 2, and 3, respectively, at month 12. Rate of steatosis and stage of fibrosis did not change after treatment. Diet with exercise seems to be superior to metformin and rosiglitazone. Decreasing treatment response at month 12 compared to month 6 may be due to fluctuations of ALT levels. Treatment response should be evaluated histologically.

Treatment of hepatic hydrothorax with terlipressin in a cirrhotic patient.

Hepatic hydrothorax is a complication of cirrhosis that is uncommon and difficult to treat. Diuretic therapy, thoracentesis, transjugular intrahepatic portosystemic shunt and liver transplantation are the main therapeutic options. Here, we report on a 47-year-old man with decompensated liver cirrhosis related to hepatitis B and D virus infections and who had complications of hepatic hydrothorax and hepatorenal syndrome. In this case, the hepatic hydrothorax, which was refractory to thoracic tube drainage and octreotide treatment, could be controlled with 5 days of terlipressin therapy associated with albumin. Terlipressin administration resulted in both improvement in renal function and successful resolution of hepatic hydrothorax. Splanchnic vasoconstrictor agents that reduce splanchnic blood flow, increase both central volume and effective renal blood flow. Thus they improve renal function. In our case, terlipressin, known to be beneficial in hepatorenal syndrome, was also effective in the treatment of hepatic hydrothorax probably by similar mechanisms. This is the first case in the literature.