Metformin in the treatment of patients with non-alcoholic steatohepatitis.

BACKGROUND: Increased insulin resistance is the major pathogenic mechanism in the development of non-alcoholic steatohepatitis. AIM: To investigate the therapeutic effect of metformin, a well-known insulin-sensitizing agent, in the treatment of non-alcoholic steatohepatitis. METHODS: Thirty-six patients with non-alcoholic steatohepatitis were randomized into two groups. The first group was given lipid and calorie-restricted dietary treatment alone, and the second group was given metformin 850 mg b.d. plus dietary treatment, for 6 months. The changes in biochemical, sonographic and histological parameters were compared. RESULTS: The mean serum alanine/aspartate aminotransferase, insulin and C-peptide levels decreased and the index of insulin resistance improved significantly from baseline in the group given metformin. The mean changes in these parameters in the metformin group were significantly greater than those in the group given dietary treatment alone. Although more patients in the metformin group showed improvement in the necro-inflammatory activity, compared with the group given dietary treatment alone, no significant differences in necro-inflammatory activity or fibrosis were seen between the groups. CONCLUSION: The data suggest that improvement of the insulin sensitivity with metformin may improve the liver disease in patients with non-alcoholic steatohepatitis.

Gonadotropin treatment increases homocysteine levels in idiopathic hypogonadotropic hypogonadism: an indirect effect mediated by changes in body composition.

The main objective of the present study was to examine the alterations in plasma total homocysteine (tHcy) concentrations during a testosterone-deficient state and after gonadotropin treatment for 6 Months in patients with idiopathic hypogonadotropic hypogonadism (IHH). Thirty-five newly diagnosed male patients with IHH (mean age 21.34+/-1.53 years) and 29 age- and body mass index-matched healthy males (mean age 21.52+/-1.77 years) were recruited into the study. Pretreatment levels of free testosterone (1.51+/-0.66 pg/ml), estradiol (21.37+/- 4.37 pg/ml), FSH (0.91+/-0.24 IU/l) and LH (1.25+/- 0.53 IU/l) were lower than controls (25.17+/-3.06 pg/ml, 31.00+/-4.96 pg/ml, 3.14+/-1.62 IU/l and 4.83+/-1.65 IU/l respectively) (P<0.001). They increased significantly after treatment (18.18+/-1.59 pg/ml, 27.97+/- 4.25 pg/ml, 2.41+/-0.27 IU/l and 2.79+/-0.19 IU/l respectively) (P<0.001). Patients with IHH had lower tHcy levels than controls (10.14+/-1.34 and 12.58+/- 2.29 micro mol/l respectively) (P<0.001). Plasma tHcy concentrations increased significantly (12.63+/-1.44 micromol/l) after 6 months of treatment (P<0.001). As compared with the controls, pretreatment levels of serum creatinine (63.54+/-13.01 vs 82.84+/-16.69 micromol/l), hemoglobin (12.98+/-0.56 vs 13.83+/-0.71 g/dl) and hematocrit (39.29+/-2.01 vs 41.38+/-1.95%) were significantly lower (P<0.001), and they increased significantly following treatment (80.24+/-11.93 micromol/l, 13.75+/-0.49 g/dl and 41.26+/-1.78% respectively) (P<0.001). The pretreatment folic acid and vitamin B(12) levels were significantly higher in patients when compared with controls (14.87+/-5.68 vs 12.52+/-4.98 nmol/l, P=0.034 and 289.75+/-92.34 vs 237.59+/-108.17 pmol/l, P=0.002 respectively). They decreased significantly after treatment (11.29+/-3.31 nmol/l and 228.51+/-54.33 pmol/l respectively) (P<0.001). The univariate and multivariate regression analysis results showed that only changes in creatinine, creatinine clearance, vitamin B12 and folic acid were independently associated with changes in tHcy levels in patients with IHH. In conclusion, the increase in plasma tHcy concentrations following gonadotropin treatment seems to be largely independent of changes in androgen levels.

Similar frequency of TT virus infection in patients with liver enzyme elevations and healthy subjects.

TT virus (TTV) is a novel DNA virus that has been identified in patients with post-transfusional hepatitis of unknown aetiology. However, its pathogenic role in liver injury remains unclear. To determine its frequency and clinical impact in cryptogenic liver diseases, we investigated the TTV prevalence in patients with liver enzyme elevations of unknown aetiology and in healthy subjects. Fifty-four patients (33 male, 21 female) who have been followed up for elevated ALT/AST levels of unknown aetiology and 118 healthy subjects (99 male and 19 female) were included in the study. TTV DNA was investigated by the polymerase chain reaction. Other possible causes of transaminase elevation were excluded in detailed biochemical and serological tests. A liver biopsy was performed in 45 patients. TTV DNA was detected in 46 patients with liver enzyme elevations (85.1%) and in 94 healthy subjects (79.6%). There was no statistical difference between the groups (p = 0.51). Histological examination of the liver revealed no specific change in TTV DNA positive patients that could be attributed to this virus infection. These results showed that TTV is a common virus in patients with liver enzyme elevation of unknown aetiology and even among healthy subjects in our geographical area. TTV infection is therefore widespread in the general population and does not seem to be associated with liver damage.

Rifampicin test in the diagnosis of Gilbert's syndrome.

Gilbert's syndrome (GS) is characterised by the existence of chronic mild unconjugated hyperbilirubinaemia. The value of rifampicin as a provocative test for the diagnosis of GS was evaluated and compared with a fasting test. Twenty-two patients with GS, 15 patients with chronic liver disease and 20 healthy controls were included. Both rifampicin and fasting tests were applied to all subjects. In the fasting test, the subjects were given a 400 calorie/day diet for 24 hours; in the rifampicin test, unconjugated bilirubin levels was measured before and four hours after taking 600 mg of rifampicin. Both tests achieved a significant increase in mean unconjugated bilirubin levels in patients with GS but not in the controls. The sensitivity and specificity of a rifampicin test in the diagnosis of GS were comparable with the fasting test. However, both tests caused a significant increase in unconjugated bilirubin levels in nearly half the patients with chronic liver disease. A rifampicin test may be used in the diagnosis of suspected GS instead of a fasting test, as it is simpler and more practical. However, its specificity for GS is not sufficient, because it also causes an increase in unconjugated bilirubin levels in some patients with chronic liver disease.

Insignificant role of hepatitis G virus infection in patients with liver enzyme elevations of unknown etiology.

Hepatitis G virus (HGV) may cause acute and chronic infection in humans but its role in parenchymal liver injury and chronic hepatitis is obscure. In this study, the importance of HGV was investigated in patients with elevated aminotransferases alanine transaminase/aspartate transaminase (ALT/AST) levels of unknown etiology. We included 56 patients with elevated ALT/ AST levels of unknown etiology and 81 healthy controls in the study. HGV RNA was investigated by the reverse transcription polymerase chain reaction. The other possible causes of transaminase elevation were excluded with detailed biochemical and serologic tests. Liver biopsy was performed on 47 patients for histologic examination. HGV RNA was detected in only two patients (3.3%) and in one control (1.2%). There was no statistical difference between the groups. Liver biopsy revealed minimal inflammatory changes and steatosis in HGV RNA-positive patients. These observations indicated that HGV prevalence is not different from that of the general population in patients with liver transaminases elevation of unknown etiology. The role of this novel virus in the pathogenesis of chronic liver injury of unknown etiology appears insignificant in our geographic area.

Serum leptin levels in patients with nonalcoholic steatohepatitis.

OBJECTIVE: Leptin is a peptide hormone that mainly regulates food intake and energy expenditure of human body. A close correlation between serum leptin levels and the percentage of body fat stores is well known. Nonalcoholic steatohepatitis (NASH) is a common disorder which causes serum liver enzyme elevation. In this study, the serum leptin levels were investigated in patients with NASH to determine a possible role in the pathogenesis and in patients with chronic viral hepatitis to ascertain the effect of hepatic inflammation on serum leptin level. METHODS: Forty-nine patients (38 men, 11 women) with NASH diagnosed by biopsy, 32 patients with biopsy-proven chronic viral hepatitis (21 men and 11 women), and 30 healthy adults (17 men, 13 women) enrolled in the study. Fasting blood samples were obtained, and serum leptin levels were measured by ELISA. Body mass index (BMI) was calculated for all subjects, and serum insulin, C-peptide, and lipoprotein levels were also detected. RESULTS: The mean serum leptin levels (+/-SEM) were 6.62 +/- 0.71, 4.24 +/- 1.0, and 4.02 +/- 0.46 ng/ml in NASH, chronic hepatitis, and the control group, respectively. Mean serum leptin level in the NASH group was significantly higher than those in the other groups tested. BMI was also slightly higher in the NASH group when compared to the other groups (26.7 +/- 0.3, 23.7 +/- 0.6, and 24.6 +/- 0.3, respectively). There was a significant correlation between BMI and serum leptin levels when all the subjects were evaluated together (NASH, hepatitis, and control groups, r = 0.337, p = 0.012) but not in the NASH group when evaluated alone (r = 0.238, p = 0.1). Of the predisposing factors for NASH, obesity was observed in 24% of patients and hyperlipidemia in 67%. Serum cholesterol and triglyceride levels were significantly higher in the NASH group than those in controls (p < 0.05). It has been detected that most of these patients consumed high amounts of fat in their dietary habits. CONCLUSIONS: The serum leptin levels were significantly higher in patients with NASH, while they were not affected by chronic hepatitis. This elevation is out of proportion to BMI of these patients and may be related to hyperlipidemia in most. Elevated serum leptin levels, therefore, may promote hepatic steatosis and steatohepatitis.

Interferon treatment for thrombocytopenia associated with chronic HCV infection.

Thrombocytopenia is commonly seen in patients with chronic liver disease, due mainly to hypersplenism secondary to portal hypertension. We report a case of chronic hepatitis C admitted with thrombocytopenia of unknown cause. The patient s symptoms and platelet count improved markedly with interferon treatment. We conclude that interferon treatment in chronic C hepatitis may improve HCV-induced thrombocytopenia.

The effect of Helicobacter pylori eradication on duodenal gastric metaplasia.

We investigated the incidence of duodenal gastric metaplasia and its response to Helicobacter pylori eradication in patients with duodenal ulcer or erosive duodenitis. Gastric and duodenal biopsies were taken from patients with endoscopically detected H. pylori positive duodenal ulcer or erosive duodenitis, and the presence and extent of duodenal gastric metaplasia was recorded. Patients were given omeprazole 20 mg twice daily for 2 weeks, and amoxicillin 1 g and clarithromycin 500 mg twice daily for 10 days, and then ranitidine for a further 8 weeks. Biopsies were repeated 6 months after the start of treatment. Duodenal gastric metaplasia was initially present in 22 patients (52%) and was more frequent in ulcer patients than in duodenitis patients, but not significantly so (69% versus 45%). After treatment, H. pylori was eradicated in 68% of duodenal gastric metaplasia patients and the duodenum was normal endoscopically in 85% of these patients. Duodenal gastric metaplasia was improved or eliminated in 12/15 H. pylori eradicators (80%) and in 5/7 H. pylori non-eradicators (71%), a non-significant difference. The improvement in duodenal gastric metaplasia appeared to be independent of H. pylori eradication.

Efficacy of omeprazole plus two antimicrobials for the eradication of Helicobacter pylori in a Turkish population.

Omeprazole combined with 2 antimicrobials has been suggested as a first-line option for Helicobacter pylori eradication in recent years. However, controversy exists regarding the efficacy of this protocol. This open-label, prospective clinical study investigated the efficacy of omeprazole-based triple therapy for H pylori eradication in 518 patients with H pylori-positive functional dyspepsia with or without duodenal ulcer. Amoxicillin, macrolides (clarithromycin or roxithromycin), and nitroimidazoles (metronidazole, ornidazole, or tinidazole) were the antibiotics used in the study. Nonulcer patients were randomly assigned to 1 of 8 different treatment protocols and duodenal ulcer patients were randomly assigned to 1 of 4 different treatment protocols consisting of omeprazole (20 mg once daily for nonulcer patients, 20 mg twice daily for ulcer patients for 14 days) with a combination of 2 of the above antimicrobials (for 10 days). H pylori infection was assessed by histologic findings and a rapid urease test before therapy and 4 weeks after therapy ended. Four hundred fifty-nine patients completed their regimens; 327 had functional dyspepsia (180 men, 147 women; median age, 39 years; range, 18 to 70 years) and 132 had ulcers (81 men, 51 women; median age, 40 years; range, 18 to 70 years). Eradication of H pylori was achieved in 58.8% (270 of 459) of all patients, 58.1% (190 of 327) of nonulcer dyspeptic patients, and 60.6% (80 of 132) of duodenal ulcer patients. The eradication rate varied from 47.2% to 69.4% in different treatment protocols. There were no statistically significant differences in eradication rates in any treatment group. All drugs were generally well tolerated in all groups, and no patient discontinued treatment because of side effects. Therapy with omeprazole and 2 antimicrobials for H pylori had limited efficacy in a Turkish population. The reason for these results, which conflict with those of other studies, is not clear. Further investigations of regimens for the eradication of H pylori in our population are necessary.

Distribution of the adult lactase phenotypes in Turkey.

The adult lactase phenotype, lactose absorber or malabsorber, was determined using the lactose tolerance test with breath hydrogen assay in a group of young, healthy, male Turks. Out of a total of 470 subjects, 135 (28.7%) were lactose absorbers and 335 (71.3%) lactose malabsorbers. The frequency of the 'lactase suppression gene' in this population sample was 0.844 (S.D. 0.012). The frequency of lactase suppression in Turkey is intermediate between that in southeast Europe and that in agricultural Arab populations and thus compatible with a genetic cline extending from Europe to southwest Asia.