[Detection of TT virus (TTV) in non-B, non-C hepatitis patients with hepatocellular carcinoma, and clinical features of these patients].

A novel human DNA virus, TTvirus (TTV), was identified from a patient with posttransfusion hepatitis of unknown etiology. It is thought to be a new hepatitis virus, but the clinical significance of this virus is uncertain. We investigated the frequency of TTV viremia by PCR in 39 non-B, non-C hepatitis (NBNC) patients with hepatocellular carcinoma (HCC), and clinical features of these patients. TTV viremia was detected in 20 (51.3%) of 39 NBNC hepatitis patients with HCC. Liver cirrhosis (LC) were found in 11 (55%) of 20 TTV-positive patients and 16 (84%) of 19 TTV-negative patients (p < 0.05). The levels of AST, LDH, LAP, gamma GTP in TTV-positive patients were significantly higher than those in TTV-negative patients (p < 0.05). (AST: 58 +/- 26 vs 42 +/- 23 IU/l, LDH: 468 +/- 127 vs 366 +/- 123 IU/l, LAP: 339 +/- 242 vs 206 +/- 80 IU/l, gamma GTP: 207 +/- 207 vs 105 +/- 107 IU/l) These results suggest clinical differences between TTV-positive and TTV-negative patients in NBNC hepatitis patients with HCC.

Serum gamma-glutamyl transferase levels and blood pressure falls after alcohol moderation.

Drinkers showing higher serum gamma-glutamyl transferase (GGT) levels tend to have higher blood pressure (BP), independent of the volume of alcohol consumed. To further evaluate the link between alcohol consumption and elevated serum GGT and BP, we observed BP, serum biochemical parameters, plasma pressor hormones and intraplatelet free calcium (Plt. [Ca2+]i) in 40 moderate drinkers who were composed of four categories of 10 each with or without hypertension (> or = 140/90 mmHg) or high serum GGT level (> or = 50 U/L) during four-week alcohol moderation. BP and serum hepatic enzymes including GGT decreased more conspicuously in both normotensive and hypertensive drinkers with high serum GGT. Serum triglyceride was higher and potassium was lower in the drinkers with high serum GGT, and were normalized during alcohol moderation. Serum calcium, Plt. [Ca2+]i and plasma renin activity and cortisol showed some decreases during alcohol moderation, but were not different in the drinkers with different serum GGT and BP levels. No significant changes were observed in plasma catecholamines and aldosterone. These results suggest that BP elevations in moderate drinkers are closely related to hepatic, lipid and electrolyte metabolic alterations induced by alcohol rather than specific pressor agents.

Genotype of cytochrome P450 2E1 and alcohol-related blood pressure elevation in Japanese men.

Three-hundred-and-sixty-seven unrelated Japanese male workers aged between 36 and 61 years were analysed for the genotypes of cytochrome P450 2E1 (CYP2E1), and the association with alcohol-related health effects including blood pressure (BP) elevation. Homozygous for the c1 (wild) gene was found in 204 men (55%), homozygous for the c2 (variant) gene in 17 (5%), and heterozygous in 146 (40%). Arithmetic means of alcohol consumed per week in the genotypes of c1/c1, c1/c2 and c2/c2 were 218, 257 and 211 g, respectively, and were not statistically different. BP was elevated with the increase in alcohol consumption, and was significantly higher in the c2/c2 genotype than in the other genotypes among the subjects consuming 200 g or more of alcohol per week. Serum uric acid did not correlate with alcohol consumption in the whole subjects, but it was also higher in drinkers having the c2/c2 genotype. Although the number of subjects was too small for a definite conclusion to be drawn, these results suggest to some extent that Japanese men having the c2/c2 genotype of CYP2E1 are more sensitive to the pressor effect of alcohol. Further studies are required to confirm this.

Genetic polymorphisms in alcohol metabolizing enzymes as related to sensitivity to alcohol-induced health effects.

Three hundred sixty-seven middle-aged Japanese men were analyzed for genotypes of low K(m) aldehyde dehydrogenase (ALDH2) and cytochrome P450 2E1, and for the association with alcohol-induced health effects. Homozygotes for the normal ALDH2 gene (NN) and for the mutant gene (MM) and heterozygotes (NM) were found in 60, 6 and 33%, and homozygotes for the c1 gene (c1/1) and c2 gene (c2/2) of P450 2E1, and heterozygotes (c1/2) in 55, 5 and 40% of subjects, respectively. Mean alcohol consumption significantly differed in the three ALDH2 genotypes: 297 g per week in NN, 158 g in NM and 18 g in MM. It was not different in the three P450 2E1 genotypes, but tended to increase from cl/1 to c2/2 in the NN subjects while there was an inverse relationship in the subjects having the M gene. No difference in alcohol-induced health effects was observed in ALDH2 genotypes, but c2/2 genotype showed higher blood pressure and serum uric acid than the other P450 2E1 genotypes in the subjects consuming 200 g or more of alcohol per week. These results suggest an interactive effect of ALDH2 and P450 2E1 genes on alcohol consumption and a higher sensitivity to alcohol-induced health effects in c2/2 genotypes, although larger scale studies are required to confirm these findings.

The relationship between serum gamma-glutamyl transpeptidase levels and hypertension: common in drinkers and nondrinkers.

A significant association between elevations of serum gamma-glutamyl transpeptidase (gamma-GTP) levels and those of blood pressure and hypertension has been reported separately in drinkers and nondrinkers. The aim of the present study is to evaluate whether the relationship between serum gamma-GTP and the prevalence of hypertension is the same or similar in both drinkers and nondrinkers. The study subjects comprised 4,920 male nondrinkers, 9,390 male daily drinkers, 8,081 female nondrinkers, and 278 female daily drinkers, who were aged 40 to 59 years. The prevalence of hypertension in the male and female daily drinkers was 1.5 and 1.3 times, respectively, higher than in the nondrinkers. Mean systolic blood pressure in the male and female drinkers was 4.4 and 3.1 mmHg, respectively, higher than in the nondrinkers. After adjusting for age, body mass index, and serum gamma-GTP levels, the differences in the prevalence of hypertension and the mean systolic blood pressure level between the drinkers and nondrinkers decreased to 1.2 times and 2.7 mmHg, respectively. Although these small differences remained statistically significant, the association between serum gamma-GTP and hypertension appears to be quite similar in both drinkers and nondrinkers, suggesting that hepatic steatosis may play a common, pathogenetic role in the development of hypertension.

Polymorphism in ALDH2-genotype in Japanese men and the alcohol-blood pressure relationship.

Aldehyde dehydrogenase with a low Michaelis constant (Km), ALDH2, is a major enzyme involved in the conversion of acetaldehyde, a toxic metabolite of ethanol, into acetic acid in the liver. Inherited deficiency of ALDH2 activity is found in half of Japanese, and is characterized by "Oriental flushing" after alcohol consumption. The aim of the present study is to evaluate the influence of the genetic polymorphism in alcohol metabolism on the sensitivity to the pressor effect of alcohol. Genotypes of ALDH2 were determined in 403 middle-aged Japanese men using genomic DNA extracted from white blood cells. Two hundred and forty-three (60%) of the subjects were shown to be homozygotes for the normal ALDH2 gene, 25 (6%) of the subjects were homozygotes for the mutant ALDH2 gene, and the remaining 135 (33%) were heterozygotes. None of the homozygotes for the mutant gene drank enough to show the pressor effect of alcohol. Elevations of blood pressure associated with increasing alcohol consumption or with elevations of serum gamma-glutamyl transpeptide (GTP) level were not different between the other two ALDH2-genotypes. It can be concluded that polymorphism in the ALDH2-genotype found in Japanese men does not affect the individual sensitivity to the pressor effect of alcohol.

Intraplatelet free calcium concentrations and alcohol-related blood pressure elevation in a middle-aged male population.

Elevated intracellular free calcium (Ca2+) has been proposed as a mechanism of alcohol-induced hypertension from animal experimental studies, but this has not been confirmed in man. In the present study, intraplatelet Ca2+ concentration (plt.[Ca2+]i) was measured in 83 middle-aged men, and the associations between alcohol consumption, age, body mass index (BMI), hematological and serum biochemical variables, plt.[Ca2+]i and blood pressure were analyzed. Plt.[Ca2+]i did not show a significant univariate correlation with alcohol consumption or with blood pressure, but did so with serum gamma-glutamyl transpeptidase (gamma-GTP) levels. Age, BMI and serum gamma-GTP were selected as independent contributors to blood pressure, and gamma-GTP alone was selected as the determinant of plt.[Ca2+]i by multiple regression analyses. The association between gamma-GTP and plt.[Ca2+]i was shown to be common or at least very similar in both drinkers and nondrinkers by generalized linear model analysis. Therefore, chronic alcohol consumption in humans may relate to elevations of plt.[Ca2+]i, not mainly by the direct action of alcohol but by some metabolic alterations after alcohol consumption. The significance of elevated plt.[Ca2+]i in drinkers in the development of hypertension, however, remains obscure.

Association between hepatic steatosis, insulin resistance and hyperinsulinaemia as related to hypertension in alcohol consumers and obese people.

The presence of hepatic steatosis was determined in 180 middle-aged male workers by ultrasonography and was found in 39 (22%) of them. Body mass index (BMI), systolic and diastolic blood pressure (BP) and serum levels of asparate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (gamma-GTP) were higher in the subjects with hepatic steatosis. Although the volume of alcohol consumed in a week did not differ between the subjects with and without hepatic steatosis, the hepatic steatosis was thought to relate to both increased body mass and alcohol consumption because the elevations of serum AST and gamma-GTP in the subjects depended largely on alcohol consumption but not on BMI. The results of 75 g oral glucose tolerance test showed a higher blood glucose at 120 minutes and a higher plasma immunoreactive insulin at baseline, 60 and 120 minutes in the subjects with hepatic steatosis, being adjusted for age, BMI and alcohol consumption. The significant association between serum gamma-GTP and BP, which had been often observed in alcohol consumers, was no longer significant after adjustment for plasma insulin levels whereas plasma insulin showed a significant association with BP. These results suggest the possibility that hypertension in alcohol consumers, and also in obese people, relates at least partly to hyperinsulinaemia associated with progression in hepatic steatosis.

Serum gamma-glutamyl transpeptidase level and blood pressure in nondrinkers: a possible pathogenetic role of fatty liver in obesity-related hypertension.

Relationships between body mass index, blood pressure (BP) and serum gamma-glutamyl transpeptidase levels were analysed in 859 male and 2,456 female nondrinkers aged 18-59 years. Serum gamma-GTP levels correlated with BP independently of age and body mass index in both men and women. The changes in BP of 391 male nondrinkers aged 35-54 years during a five year period correlated with the changes in serum gamma-GTP levels, independently of BP levels, age, body mass index and serum gamma-GTP at the beginning of the follow-up, and of the changes in body mass index. As the rise in serum gamma-GTP levels in nondrinkers depends largely on the progression in fatty change in the liver cells accompanying increases in the size of body mass, these results suggest a close association between the development of fatty liver and hypertension in obese persons.

Serum gamma-glutamyl transpeptidase levels and hypertension in non-drinkers: a possible role of fatty liver in the pathogenesis of obesity related hypertension.

The relationships between increases in body mass index (BMI) and increases in hypertension were compared between non-drinkers with elevated serum gamma-glutamyl transpeptidase (gamma-GTP) levels (> or = 50 U/l) and those with normal levels, who comprised 10,952 men and 22,107 women aged 40-59 years recruited from an occupational health clinic. Hypertension was found in 16.1% and 13.5% of the men and women, and elevated serum g-GTP was found in 10.8% and 2.8% of the men and women, respectively. The prevalences of hypertension and elevated serum gamma-GTP levels were both increased with increased BMI. Hypertension was, however, shown to be 1.5 times more prevalent in the persons with elevated serum gamma-GTP levels than in those with normal levels in both sexes, even after adjusting for BMI by a multiple logistic analysis. It can be concluded that elevations of serum gamma-GTP, which are probably a reflection of fatty liver in the non-drinkers, are closely related to the development of hypertension associated with increased obesity.

Elevated cytosolic free calcium concentrations in platelets of hypertensive drinkers: a weak association with alcohol consumption.

Although the mechanisms of alcohol related hypertension remain unknown, it has been hypothesised that alcohol causes the accumulation of calcium ions (Ca2+) in vascular smooth muscle cells, resulting in the elevation of vascular tonus. To evaluate this contention, intra platelet free calcium concentrations (platelet [Ca2+]i) were determined in 20 young adult men, i.e. five each of hypertensive heavy drinkers, hypertensive light drinkers, normotensive heavy drinkers, and normotensive light drinkers. Platelet [Ca2+]i were higher in the ten hypertensives than in the ten normotensives, irrespective of alcohol consumption. The hypertensive drinkers also showed higher levels of serum gamma-glutamyl transpeptidase (gamma-GTP) and parathyroid hormone (PTH). Platelet [Ca2+]i in the total 20 subjects did not correlate with alcohol consumption, but correlated positively with serum gamma-GTP levels and SBP. These preliminary study results do not support the contention that Ca2+ accumulates in the vascular smooth muscle cells of humans as a result of chronic alcohol consumption. The significance of elevated platelet [Ca2+]i observed in the hypertensive heavy drinkers in the pathogenesis of alcohol related hypertension remains obscure.

Alcohol, high blood pressure, and serum gamma-glutamyl transpeptidase level.

The influence of the level of serum gamma-glutamyl transpeptidase, a biological marker of alcohol consumption, on elevations of blood pressure and on the development of hypertension related to increases in alcohol consumption was determined in a cross-sectional study of 1,492 middle-aged male workers and in a subsequent 5-year follow-up study of 1,393 workers. Blood pressure levels, as well as the prevalence and incidence of hypertension, were higher in the subjects with serum gamma-glutamyl transpeptidase levels above 50 units/l than in those with normal levels. These differences were more marked in drinkers who consumed 30 ml or more of alcohol per day. Thus, elevated serum gamma-glutamyl transpeptidase activity may identify drinkers at higher risk for the development of alcohol-related hypertension.

Elevations of serum angiotensin-converting enzyme and gamma-glutamyl transpeptidase activities in hypertensive drinkers.

Serum angiotensin-converting enzyme (ACE) activity was measured in 70 middle-aged male drinkers with or without elevated serum gamma-glutamyl transpeptidase (gamma-GTP) activity and high BP. Serum ACE activity in hypertensive drinkers with elevated serum gamma-GTP was higher than that in drinkers, both normotensive and hypertensive, with normal serum gamma-GTP. Serum ACE levels were strongly correlated with alcohol consumption and serum gamma-GTP levels. Since the induction of ACE by alcohol in hepatic cells has been disputed, the coincident elevation of serum ACE and gamma-GTP activities in hypertensive drinkers may support the contention that the close association between gamma-GTP levels and BP found in drinkers is not mainly related to the induction of gamma-GTP in the hepatic cells, but related to the hepatic cell damage caused by alcohol.