Konstantinos Thomopoulos

Non-invasive predictors of the presence of large oesophageal varices in patients with cirrhosis

BACKGROUND/AIMS The usual clinical practice is to screen all patients with established cirrhosis at the time of diagnosis by upper endoscopy for the presence of varices. Patients with large varices should be treated with non-selective beta blockers to reduce the incidence of first variceal bleeding. However, fewer than 50% of cirrhotic patients have varices at screening endoscopy and most have small sized varices, with a low risk of bleeding. The aim of the present study was to determine whether clinical or laboratory non-endoscopic parameters could predict the presence of large oesophageal varices. PATIENTS/METHODS Seventeen variables considered relevant to the prevalence of oesophageal varices were tested in 184 patients with cirrhosis, who underwent screening endoscopy. Small varices were regarded as those which flatten with insufflation or slightly protrude into the lumen, while large varices are those which protrude into the lumen or touch each other. None of the patients was on beta blockers or other vasoactive drugs or had a history of variceal bleeding. RESULTS Oesophageal varices were present in 92 patients (50%), and large varices in 33 patients (17.9%). Variables associated with the presence of large oesophageal varices on univariate analysis were the presence of ascites and splenomegaly either by clinical examination or by ultrasound (p < 0.01), the presence of spiders (p = 0.02), platelet count (p < 0.0001), and bilirubin (p = 0.01). Factors independently associated with the presence of large oesophageal varices on multivariate analysis were platelet count, size of spleen and presence of ascites by ultrasound. Using mean values as cut-off points, it is noteworthy that only five out of 39 patients (12.8%) with platelets > or = 18(x 10(9)/l), spleen length < or = 135 mm and no ascites had varices. Moreover, all these patients had small sized varices. On the other hand, 15 out of 18 patients (83.3%) with a platelet count < 118 x 10(9)/l, spleen length > 135 mm and ascites had varices. Moreover, five out of those 18 patients had large varices (28.3%). CONCLUSION Thrombocytopenia, splenomegaly and ascites are independent predictors of large oesophageal varices in cirrhotic patients. We suggest that endoscopy could be avoided safely in cirrhotic patients with none of these predictive factors, as large varices are absent in this group of patients.

Prevalence of liver steatosis in patients with chronic hepatitis B: a study of associated factors and of relationship with fibrosis.

Objectives The clinical significance of hepatic steatosis in chronic hepatitis B virus patients is poorly understood. The purpose of this study was to determine risk factors for liver steatosis in chronic hepatitis B patients and its relationship with fibrosis. Methods We retrospectively evaluated liver biopsies from patients with chronic hepatitis B treated in our department. Patients co-infected with other viruses (hepatitis C virus, HIV) or suffering from liver disease of any other cause were excluded from the study, as well as patients consuming alcohol above 30 g/day for males or 20 g/day for females. Liver steatosis, necroinflammation and fibrosis were assessed. Results A total of 233 patients with chronic hepatitis B were included in the study. The mean age was 44.7±16.2 years. There were 164 men (70.4%) and 69 women (29.6%). The majority of patients were HbeAg-negative, 196/233 (84.1%). Thirty-seven patients had cirrhosis (15.9%). Steatosis was present in 42 patients (18%). Steatosis was independently associated with fasting glucose level (P=0.019) and being overweight (body mass index ≥25; P=0.021). No correlation was found with stage of fibrosis, grade of inflammation, alcohol use or other parameters. Ninety-four out of 233 patients (40.3%) had advanced fibrosis. Patients with advanced fibrosis were older than those with minimal or no fibrosis (47.6±17 versus 42.3±15.2 years, P=0.024) and more frequently had a higher grade of necroinflammation activity (57/94 (60.6%) versus 26/139 (18.7%), P<0.0001). There was no significant association between advanced fibrosis and the presence of steatosis or mild alcohol consumption. Conclusion Hepatic steatosis is present in 18% of our patients with biopsy-proven chronic hepatitis B. Steatosis is independently associated only with body mass index and fasting glucose level, risk factors for metabolic steatohepatitis, and was not correlated with the degree of fibrosis.

Changes in aetiology and clinical outcome of acute upper gastrointestinal bleeding during the last 15 years.

Objectives The diagnostic and therapeutic approaches to patients with acute upper gastrointestinal bleeding have been improved during the last decades. The aim of this study was to compare the aetiology and clinical outcome of acute upper gastrointestinal bleeding (AUGIB) between two distinct periods during the last 15 years. Methods The causes of AUGIB and clinical outcome of 668 patients hospitalised with the problem in 1986–1987 were compared to 636 patients with AUGIB in 2000–2001. Patients were admitted to our hospital or they bled while they were inpatients for other reasons. No patient was excluded because of age or concurrent diseases. Endoscopic haemostasis with adrenaline injection for bleeding peptic ulcers was performed in the second period while no endoscopic method of haemostasis was performed in the first period. Results We observed an increase in the age of patients (56.5 ± 16.9 vs 62.9 ± 17.5 years, P < 0.0001) and the percentage of patients who received non-steroidal anti-inflammatory drugs (NSAIDs) before bleeding (from 44% to 63.5%, P < 0.0001). An increase in the diagnosis rate of gastric ulcer (12% vs 19.2%, P = 0.005) and varices (13.2% vs 3.3%, P < 0.001) with a simultaneous decrease in that of erosive gastroduodenitis (18.4% vs 7.2%, P < 0.0001) and duodenal ulcer (48.7% vs 33.3%, P < 0.0001) as a cause of bleeding was also observed. In peptic ulcer bleeding, emergency surgical haemostasis was reduced from 14% to 5.3%, P < 0.001. Overall mortality was also reduced from 5.2% to 3.1% and in peptic ulcer bleeding patients from 3.3% to 2.4%, respectively, but the differences are not statistically significant. Conclusion The aetiology of AUGIB has changed during the last 15 years probably due to the better therapeutic approach to chronic duodenal ulcers and increasing use of NSAIDs in the elderly. Emergency surgical haemostasis has been reduced but the reduction of mortality was not significant.

Increased frequency of mutations in the gene responsible for familial Mediterranean fever (MEFV) in a cohort of patients with ulcerative colitis: evidence for a potential disease-modifying effect?

The MEFV gene, responsible for familial Mediterranean fever (FMF), is involved in inflammatory reactions through altered leukocyte apoptosis, secretion of interleukin (IL)-1β, and activation of the NF-κ B pathway. Ulcerative Colitis (UC) and FMF are both characterized by a recurrent pattern of presentation with periods of remission and flares associated with neutrophilic infiltration at the site of injury. The aim of this study was to investigate the possible correlation between UC and MEFV gene alterations. Twenty-five consecutive, first-diagnosed and untreated UC patients, 28 control patients with rheumatoid arthritis, and 65 normal individuals were analyzed. Nonisotopic RNase Cleavage Assay (NIRCA) was applied as a first-step mutational screening method of exons 10 and 2 of MEFV gene; direct sequencing was subsequently performed to confirm the results. MEFVmutations were identified in 7 (3 M694V/0, 2 M680I/0, 1 E148Q/E148Q, and 1 A744S/0) out of 25 UC patients versus 1 (M694V/0) out of 28 rheumatoid arthritis patients (P = .0199) and 1 (M694V/0) out of 65 healthy controls (P = .0004). Four out of 7 patients with MEFVmutations had inflammatory arthritis, a clinical finding that was not observed in the 18 UC patients with unmutated MEFV (P = .0028). Patients with UC almost universally carried the T A C G MEFV exon 2 haplotype in contrast with normal individuals (P < .0001) and FMF patients (P = .0310). In conclusion the increased frequency of mutations of MEFV in UC patients, especially in those with episodic arthritis, suggests a possible modifying effect of MEFV in the disease process and its localization within the joint. The difference in distribution of MEFV exon 2 haplotypes between UC patients and both FMF patients and normal individuals, suggests that UC patients constitute a genetically distinct population. Larger, longitudinal studies are needed to confirm these initial findings.

Altered intestinal tight junctions’ expression in patients with liver cirrhosis: a pathogenetic mechanism of intestinal hyperpermeability

Eur J Clin Invest 2012; 42 (4): 439–446

Evidence for intestinal oxidative stress in patients with obstructive jaundice

Background  Obstructive jaundice results in failure of the intestinal barrier with consequent systemic endotoxemia associated with septic complications. We have recently shown that gut barrier failure in experimental obstructive jaundice is associated with high intestinal oxidative stress. This study was undertaken to investigate whether oxidative alterations occur in the intestinal mucosa of patients with obstructive jaundice.

Neuropsychological function in Greek patients with chronic hepatitis C

Background: Research has shown that hepatitis C virus (HCV) infection is associated with subclinical neuropsychological deficits in the absence of hepatic encephalopathy.

Liver steatosis is an independent risk factor for treatment failure in patients with chronic hepatitis C.

Objectives Hepatic steatosis is a common feature of chronic hepatitis C. The purpose of this study was to determine factors related to the presence of steatosis and to define the role of steatosis in the response to antiviral treatment in chronic hepatitis C patients. Methods We retrospectively analysed all patients with chronic hepatitis C treated in a 5 year period in our department. Patients were included in the study only if a pretreatment liver biopsy specimen was available for evaluation. All patients treated either with interferon in combination with ribavirin, or with pegylated interferon in combination with ribavirin were included irrespectively of their response (early, end of treatment and/or sustained) to antiviral therapy. Results A total of 116 patients with chronic hepatitis C were included in the study with a mean age of 45.5±14.1 years. Steatosis was present in 52 patients (44.8%). On univariate analysis age, P=0.04 and body mass index ⩾25, P=0.004 were correlated with the presence of steatosis and on multivariate analysis only body mass index ⩾25, P=0.032. Advanced fibrosis was not found associated with steatosis. Sixty patients out of 116 (51.7%) had sustained virological response (SVR). In particular 42 out of 64 patients with no steatosis (65.6%) had SVR compared to 20 out of 52 patients (38.4%) with any degree of steatosis (P=0.009). Patients with genotype 2 or 3 had a more favourable outcome compared to patients with 1 or 4 genotypes, 63.2% vs 49.2%, P=0.032. Also increased age (P=0.0001), gamma glutamyltransferase (GGT) (P=0.029), no history of intravenous drugs use (P=0.001) and advanced fibrosis on pretreatment biopsy (P=0.046) were correlated with treatment failure. On multivariate analysis significant independent association with SVR was found with the presence of steatosis on pretreatment biopsy (P=0.004), increased GGT (P=0.005) and genotype (P=0.017). Conclusion Steatosis in the liver biopsy performed before the beginning of antiviral treatment was found to be associated only to the body mass index of the patients and to be a strong independent factor for treatment failure.

Potential Role of Bcl-2 and Bax mRNA and Protein Expression in Chronic Hepatitis Type B and C: A Clinicopathologic Study

Bcl-2 oncoprotein regulates programmed cell death by providing a survival advantage to rapidly proliferating cells, and bax protein promotes apoptosis by enchanting cell susceptibility to apoptotic stimuli. In this study, we assessed the expression of bcl-2 and bax in liver biopsies from patients with chronic hepatitis (CH) Type B (HBV) and C (HCV). The study comprised 65 liver biopsies from 65 patients with HBV (n = 37) and HCV (n = 28) and 10 normal liver biopsies as controls. The HAI score ranged from 3/18–13/18, and the fibrosis Stage, from 1–6 (7 HBV/10 HCV). Pathologic examination included the following: (1) immunohistochemical stains in paraffin sections for bcl-2 and bax protein expression, (2) Western blot analysis (bcl-2 and bax protein levels evaluation), (3) ISH (detection of bcl-2 and bax mRNA), and (4) ISH (TUNEL-ABI [apoptotic body index]). In CH cases, both bcl-2 and bax protein and mRNA were detected in portal and intralobular lymphocytes and in cholangiolar epithelial cells in interface areas and fibrous bands. Bax protein and mRNA was expressed within hepatocytes and epithelial cells of interlobular ducts in portal tracts. Bcl-2 mRNA was present in periportal hepatocytes only in cases with Stage 5–6 fibrosis. Western blot analysis showed a decreased bcl-2 and an increased bax expression toward advanced fibrotic stages. In CH cases, ABI was reverse correlated with the percentage of bcl-2 expression and was correlated directly with the percentage of bax expression (P < .001). The results of this study suggest that in cases of chronic HBV or HCV infection, bax may be involved in the hepatocyte cycle regulation during infection, whereas its expression in intraportal bile duct epithelium implies that this protein enhances susceptibility of these particular cells to apoptosis. The increased bax expression and ABI in fibrosis Stages 1–5, imply that they are responsible for hepatocytes depletion through apoptosis, during progress of liver fibrosis and fibrous tissue accumulation, until cirrhosis is established. Bcl-2 mRNA expression in periportal hepatocytes only in Stages 5 and 6 suggests that this oncogene is involved in the late stages of progressive liver fibrosis and failure and furthermore that periportal hepatocytes are resistant to apoptosis. Bcl-2 expression, in cholangioles of interface area, suggests that this oncoprotein may be involved in growth regulation of these epithelial cells. Further research is warranted to specify the exact role of apoptosis and apoptotic genes involved in liver fibrosis process in cases of chronic HBV and HCV infection. This may lead to new strategies in the management of human liver disease to prevent the progression to chronic liver failure.

Potential role of hepatic progenitor cells expression in cases of chronic hepatitis C and their relation to response to therapy: a clinicopathologic study

Abstract: Background: This study investigates the correlation of hepatic progenitor cells (HPC) expression with treatment response in patients with chronic hepatitis C.