K. Beckh

Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy : results of a placebo-controlled double-blind study

BACKGROUND/AIMS In the current state of knowledge of the pathophysiology of hepatic encephalopathy, a reduction in hyperammonemia is the most important evidence of effective treatment. Therefore, the therapeutic efficacy of oral L-ornithine-L-aspartate, which improves impaired ammonia detoxification, was investigated in patients with cirrhosis, hyperammonemia and stable, overt, chronic hepatic encephalopathy, and in subclinical hepatic encephalopathy in a randomized, double-blind, placebo-controlled clinical trial. METHODS Oral L-ornithine-L-aspartate was administered three times daily at fixed times for 14 consecutive days in a total dose of 18 g per day. The design was chosen to prevent an increase in ammonia induced by a protein meal of 0.25 g/kg body weight, given at the start of the daily treatment period. Efficacy variables were: fasting and postprandial ammonia concentration, Number-Connection-Test time, mental state grades, and a Portosystemic Encephalopathy Index. Analyses were based on the total study sample of 32 placebo- and 34 L-ornithine-L-aspartate-treated patients as well as on the subgroup samples in the overt (20 placebo- and 23 L-ornithine-L-aspartate-treated) and subclinical hepatic encephalopathy (12 placebo- and 11 L-ornithine-L-aspartate-treated) patients. RESULTS Number Connection Test performance times (p<0.01) as well as fasting (p<0.01) and postprandial (p<0.05) venous blood ammonia concentrations in the L-ornithine-L-aspartate-treated group showed improvement in comparison to placebo. Also, the mental state grade (p<0.05) and the Portosystemic Encephalopathy Index (p<0.01), improved to a much greater degree in the L-ornithine-L-aspartate group than in the placebo group. Adverse events were observed in neither the placebo nor the L-ornithine-L-aspartate-treated patients. CONCLUSION Oral L-ornithine-L-aspartate is a safe, well-tolerated treatment with a good compliance rate and a beneficial therapeutic effect in patients with cirrhosis and stable, overt, chronic hepatic encephalopathy.

HCV and HGV in B-cell non-Hodgkin's lymphoma

BACKGROUND/AIMS A causative role of hepatitis C virus infection (HCV) has been discussed in the pathogenesis of mixed cryoglobulinaemia and in B-cell non-Hodgkins lymphoma. No data are available concerning the newly discovered hepatitis G virus (HGV) and extrahepatic manifestations such as haematological malignancies. But, HCV and HGV most probably belong to the same family of Flavivirus. Consequently, we looked for the prevalence of HCV, HGV and cryoglobulins in patients with B-cell non-Hodgkins lymphoma. METHODS Serum samples from 69 patients with non-Hodgkins lymphoma were studied. Diagnosis of non-Hodgkins lymphoma was established according to the Kiel classification. Active HCV- and HGV infections were investigated using polymerase chain reaction for detection of viral RNA. Cryoglobulins were detected from serum and monoclonal immunoglobulin components were analysed with immunofixation electrophoresis. In addition, we assessed the clinical course of HCV- and HGV-infected patients under chemotherapy. RESULTS Three of 69 (4.3%) patients with B-cell non-Hodgkins lymphoma were HCV-infected and nine non-Hodgkins lymphoma patients (13.0%) were positive for hepatitis G virus RNA. All HGV infected patients were suffering from low-grade non-Hodgkins lymphoma. No HGV-infected patient was co-infected by HCV and neither HCV- nor HGV-infected patients showed clinical signs of chronic liver disease before, during or after chemotherapy. Serum samples from all patients were devoid of cryoglobulins. CONCLUSIONS HCV seems to have no significance for the pathogenesis of non-Hodgkins lymphoma in Germany. The increased prevalence of hepatitis G (16.3%) in patients with low-grade non-Hodgkins lymphoma could suggest a pathological consequence of HGV infection outside of the liver. Evidence of clinically relevant hepatic disease in HGV infected patients was not obtained. Further, chemotherapy does not seem to affect the subsequent clinical course of HGV infection.

Gallstone Prevalence in Germany: The Ulm Gallbladder Stone Study

The Ulm Gallbladder Stone Study is the first ultrasound-based epidemiologic survey of cholecystolithiasis in the former West Germany. A study population of 1116 blood donors (656 men, age 38.0 ± 12.0 years; 460 women, age 34.1 ± 11.2 years) at the Central Blood Bank of the German Red Cross in Ulm was examined between April 1994 and February 1995. Based on age, subjects were assigned to one of four groups (18-30, 31-40, 41-50, and 51-65 years). Following a structured interview of each study subject, an ultrasound examination was carried out and a blood sample obtained for laboratory study. Overall, 6.0% (95% (95% CI: 4.8%-7.6%) of all study subjects (5.8% of the men and 6.3% of the women) exhibited evidence of current or past gallbladder disease (cholelithiasis or history of cholecystectomy). The prevalence of gallbladder disease correlated positively with age, reaching a maximum of 13.7% (9.5-20.0) in the 51- to 65-year-old age group, and also correlated as with body mass index (BMI). Female subjects with previous full-term pregnancies showed a higher prevalence of cholelithiasis, but this difference was not statistically significant for age-adjusted analysis. Subjects with a family history of cholelithiasis were found to suffer from gallstones in 11.5% (8.0-16.7) of cases compared with 4.6% (3.4%-6.3%) of subjects without such family history. Autopsy studies conducted in Germany have shown the prevalence of gallstones to be about 13.1% in men and 33.8% in women. Our sonographic data are relatively low in comparison. This may be due, in part, to the specific selection characteristics inherent in retrospective autopsy studies, such as age distribution and the presence of other pathologic factors associated with increased risk for cholelithiasis. The Ulm data rank in the lower third of the prevalence range reported for European sonographic studies to date. Age, positive family history, and increased BMI all correlated positively with the prevalence of gallbladder disease (P < 0.05). For the study population as a whole, there was no gender-specific increased risk for the development of gallstones.

Diagnosis of Echinococcus multilocularis infection by reverse-transcription polymerase chain reaction

Alveolar echinococcosis is a life-threatening parasitosis occurring in countries in the Northern hemisphere. The diagnosis of an Echinococcus multilocularis infection is routinely performed by radiological techniques and by the detection of specific antibodies in the sera of infected patients. However, because serodiagnosis fails in 5%-10% and radiological techniques are difficult to interpret in some cases, we developed a polymerase chain reaction for the detection of echinococcal-specific messenger RNA from fine-needle biopsy specimens. This technique was applied to the diagnosis of alveolar echinococcosis in a 20-year-old seronegative woman. Detection of messenger RNA not only allowed the diagnosis of echinococcal disease but also proved to be a reliable measure for determining the efficacy of an antiparasitic therapy.

Oligoclonal CD8+ T-Cell Expansion in Patients with Chronic Hepatitis C Is Associated with Liver Pathology and Poor Response to Interferon-α Therapy

The role of CD8+ T lymphocytes in chronic hepatitis C virus (HCV) infection and in liver injury with subsequent development of fibrosis and cirrhosis is poorly understood. To address this #x003Fion, we performed a follow-up study including 27 chronically HCV-infected individuals. We determined clonality and phenotypes of circulating CD8+ T cells employing TCRBV spectratyping. Antigen specificity was tested by rMHC-peptide tetramer staining and stimulation with recombinant HCV antigens. In addition, T-cell clonality and phenotypes were followed during the variable clinical response of interferon- (IFN) α treatment. We could demonstrate that CD8+ T-cell expansions were significantly associated with liver fibrosis and cirrhosis. Likewise, increased oligoclonality of circulating CD8+ T cells in chronic HCV infection was identified as an indicator for poor clinical response to IFN-α therapy. Moreover, we also found that IFN-α therapy enhanced the differentiation of CD8+ T cells towards a late differentiation phenotype (CD28− CD57+). In cases of virus elimination the disappearance of expanded terminally differentiated CD8+ cells was observed. Thus, this study identifies an association of clonal expansions of circulating CD8+ T cells with liver pathology and provides a possible explanation for the fact that response to IFN-α therapy diminishes with the duration of infection.

Proximal Gastric Motility Functions Are Normal in Severe Obesity

The role of altered gastric motor functions for the development of obesity is still unclear. In this study, we investigated whether severe obesity is related to gastric dysfunctions or to abnormal perception in response to distension. 31 obese patients and 20 healthy volunteers were studied using an electronic barostat. Basal gastric tone, gastric accommodation, and perception in response to distension were not altered in obese patients. The median minimal distending pressure, reflecting the intra-abdominal pressure, was significantly elevated in obese patients, being 12 versus 7 mm Hg, respectively (p < 0.0001). We conclude that the proximal gastric motility, including perception and accommodation in response to intragastric distension, is not impaired in severe obesity. Whether disturbances of gastric reflex relaxation in response to a meal are involved in the pathogenesis of obesity remains to be established.

Gastric Hypersensitivity in Nonulcer Dyspepsia An Inconsistent Finding

Visceral hypersensitivity is claimed to beinvolved in the pathogenesis of nonulcer dyspepsia(NUD). We evaluated whether gastric hypersensitivity isa consistent finding in an unselected group of NUDpatients. In 11 patients and 20 healthy controls, astandardized gastric distension was performed using agastric barostat. Perception was scored by aquestionnaire and compared between the two groups. Therewas a linear pressure/volume relationship duringgastric distension in both groups. The pain threshold inNUD patients was significantly lower compared tocontrols [5.5 ± 4.0 mm Hg above minimaldistending pressure (mdp) and 10.2 ± 2.2 mm Hg above mdp,respectively, P < 0.004], irrespective of the H.pylori status. However, more than 50% of the NUDperception scores were in the control range at mostdistension levels. Gastric hypersensitivity could be confirmed inNUD patients as a group. However, there is aconsiderable overlap concerning perception in responseto distension between unselected NUD patients andcontrols.

Effects of Tropisetron, a 5-HT3 Receptor Antagonist, on Proximal Gastric Motor and Sensory Function in Nonulcer Dyspepsia

Background: Visceral hypersensitivity is claimed to be involved in the pathogenesis of nonulcer dyspepsia (NUD). In a double-blind crossover study, we evaluated the effects of tropisetron, a 5-HT3 receptor antagonist, on gastric accommodation, reflex relaxation, and sensitivity in NUD patients. Methods: Eight patients and 10 healthy controls received placebo or 5 mg tropisetron on separate days. On each day, gastric accommodation and relaxation were investigated using a gastric barostat. The perception during gastric distension and relaxation was scored by a verbal perception score. Results: Under both medications, gastric accommodation and postprandial gastric reflex relaxation were not impaired in the NUD patients. The visceral perception was increased in the NUD patients and not substantially influenced by tropisetron. Conclusions: Tropisetron does not influence gastric accommodation, reflex relaxation, or gastric sensitivity in NUD patients and healthy controls.

Enhancement of hepatic glucose release and bile flow by the phosphodiesterase-III-inhibitor enoximone in the perfused rat liver

The use of phosphodiesterase-III-inhibitors (PDI) as inotropic substances in the treatment of cardiac failure can be associated with hyperglycaemia. This phenomenon could be caused by hepatic events induced by PDI. The purpose of our study was to investigate the effects of the PDI enoximone on hepatic carbohydrate metabolism and bile flow. In the rat liver perfusion model, hepatic glucose and lactate production, portal flow and bile flow were determined. Administration of enoximone (1, 10, 100 microM) increased hepatic glucose output and bile acid-independent bile flow in a dose-dependent manner. The PDI enhanced the glycogenolytic effects of glucagon (from 15.7 to 38.6 mumol glucose/g/20 min), of epinephrine (from 7.1 to 38.7 mumol glucose/g/20 min), of norepinephrine (from 9.8 to 32 mumol/g/20 min) and of phenylephrine (from 25.5 to 40.8 mumol glucose/g/20 min). Furthermore, lactate production was significantly reduced by enoximone. The effect of epinephrine and phenylephrine on portal flow was blocked or diminished by enoximone administration. In summary, it was shown that the PDI enoximone is able to enhance hepatic glucose production. Bile acid-independent bile flow was increased by the inhibition of phosphodiesterase-III. The effects of enoximone and glycogenolytic hormones on glucose release were synergistic. The vasoconstrictive action of catecholamines was reduced or completely prevented by enoximone. In conclusion, enoximone has glycogenolytic, vasodilatory and choleretic properties in the liver.

The role of nitric oxide in hemodynamic and metabolic alterations induced by prostaglandin F2α in the perfused rat liver

Abstract In the liver prostaglandins have been shown to be potent regulators of portal blood flow, carbohydrate metabolism and bile secretion. It is not known whether these effects represent a direct action of prostaglandins, and it has been suggested that nitric oxide (NO) might be a critical mediator for prostaglandin induced hepatic events. We have studied whether nitric oxide formation or inhibition alters the action of prostaglandin F2α (PG F2α) in a single-pass liver perfusion model. The liver of untreated rats (constitutive NO-synthase) or after pretreatment with endotoxin (inducible form of NO-synthase) was perfused at a constant pressure via the portal vein. Effluate were collected in 1-min intervals and bile in 5-min intervals. In both groups the addition of PG F2α (10 μM) to the perfusate for 5 min resulted in a significant increase of glucose and lactate production, and in a significant decrease in portal blood flow (−0.56 ± 0.04 ml/g per min), in bile flow (−60.7%) and in bile acid release (−60.6%). Inhibition of NO synthase by adding N G - monomethyl- l -arginine ( l -NMMA, 100 μM) to the perfusate did not affect any of the alterations induced by PG F2α. Substitution of the endogenous substrate for the NO synthase l -arginine (500 μM) in the perfusate completely prevented the hemodynamic alterations induced by PG F2α in endotoxin pretreated livers and limited the flow reduction (0.15 ± 0.04 ml/g per min) in the untreated group. The substitution of l -arginine in the perfusate of endotoxin pretreated livers raised nitrite (from 1.5 ± 0.3 to 3.6 ± 0.7 nmol/g per min) and urea release (from 65 ± 25 to 294 ± 68 nmol/g per min), but had no effect on any of the other metabolic parameters and bile secretion. We conclude that PG F2α increases glucose and lactate production in the perfused rat liver and decreases portal flow and bile secretion. The metabolic effects induced by PG F2α appear to be independent of NO mediation and hemodynamic alterations. Portal flow alone can be influenced by endogenous NO formation.