Mikko Salaspuro

Carbohydrate-Deficient Transferrin as Compared to Other Markers of Alcoholism: A Systematic Review

This is a systematic review of the studies in which carbohydrate-deficient transferrin (CDT) has been compared to other laboratory markers in different experimental conditions, clinical settings, and populations. Only the studies (n = 54) in which CDT was compared either to the conventional or new biological markers of alcoholism, heavy drinking, or alcohol use were selected for further evaluation. Two prospective studies indicate that in men CDT is slightly more sensitive than gamma-GT in reflecting changes in these markers caused by drinking of a moderate and fixed amount of alcohol during three to four weeks. In one prospective study, in which the drinking history of male heavy drinking volunteers was as close the golden standard as possible; that is, obtained by a prospective anonymous drinking diary, CDT was slightly but not significantly better marker than conventional laboratory markers (ASAT, ALAT, gamma-GT and beta-Hex) in the identification of men drinking more than 400 g of alcohol daily. Similar prospective studies concerning women have not been done. Six prospective treatment outcome studies indicate that CDT may be a significantly more sensitive marker than gamma-glutamyltransferase (gamma-GT) in the detection of relapses in male alcoholics. However, these two tests can also be considered to be complementary markers. Furthermore, in the detection of relapses the baseline values of CDT and gamma-GT should be measured and compared on individual basis to the pretreatment values. Comparable data are not available from female alcoholics. In selective materials comprising male alcoholics and heavy drinkers, CDT was found to be a slightly more sensitive marker than gamma-GT in seven retrospective studies. In five studies, gamma-GT was slightly better. However, the differences between CDT and gamma-GT in general were not statistically significant. In three studies, the combined use of CDT and gamma-GT improved the sensitivity but with the expense of specificity. Only four studies included women and in three of these the sensitivity of gamma-GT was better than that of CDT, whereas in one study CDT was better than gamma-GT in the detection of female heavy drinkers. Seven studies performed in primary health care settings and among young populations demonstrate that the performance of CDT in the identification of heavy and problem drinkers in this type of populations is very low, although comparable to the poor performance of the conventional laboratory markers, too. According to seven studies, the sensitivity of gamma-GT is slightly better than that of CDT in the identification of excessive alcohol consumption among hospitalized male and female patients. However, in this type of hospital setting, the specificity of CDT is markedly higher than that of gamma-GT. There is some evidence indicating that the performance of the tests can be improved with the combined use of both tests. Eight studies indicate that both in men and women CDT is a better marker than gamma-GT in the identification of alcohol abuse among patients with alcoholic and nonalcoholic liver diseases. This is mostly due to the higher specificity of CDT as compared to that of gamma-GT.

Treatment of alcohol abuse: an evidence-based review.

This article represents the proceedings of a symposium at the 2002 annual meeting of the Research Society on Alcoholism in San Francisco, CA, organized and cochaired by Mats Berglund and Sten Thelander. The presentations were (1) Preventive interventions against hazardous consumption of alcohol, by Mikko Salaspuro; (2) Treatment of alcohol withdrawal, by Johan Franck; (3) Psychosocial treatment for alcohol problems, by Sven Andréasson and Agneta Ojehagen; and (4) Pharmacological treatment of alcohol dependence, by Mats Berglund.

Elevated blood acetaldehyde in alcoholics with accelerated ethanol elimination

Alcoholics and controls given ethanol (1.2 g/kg body weight) were analyzed for blood and breath acetaldehyde using the more sensitive and reliable semicarbazide method. The acetaldehyde levels in controls were almost undetectable (less than 2 microM), but were found to be elevated (10--10 microM) in 6 of 8 alcoholics. Breath acetaldehyde and blood acetaldehyde co-fluctuated during the experiments. Fructose infusion transiently increased blood acetaldehyde, but only in 4 of the alcoholics. The apparent discrepancy between our finding and the simultaneously reported low acetaldehyde level in alcoholics (Eriksson and Peachy, this volume) may be explained by the different status of the alcoholics tested. Our alcoholics were tested on the day after hospital admission and eliminated ethanol 5% faster than controls. It is suggested that elevated blood acetaldehyde occurs regularly after interrupted drinking in heavy alcohol abusers with fast ethanol elimination, possibly combined with reduced liver aldehyde dehydrogenase activity, but that the phenomenon may rapidly disappear upon abstinence and hospital treatment, which reduces disturbances in hepatic functions and the ethanol elimination rate.

Rectal Mucosal Adrenergic Innervation and Enterochromaffin Cells in Ulcerative Colitis and Irritable Colon

Rectal mucosal biopsies of 13 patients suffering from ulcerative colitis, 7 patients presenting symptomatology typical of irritable colon, and 7 control persons were studied by the recently introduced glyoxylic-acid-induced fluorescence histochemical method. In ulcerative colitis, compared to control specimens: 1) the density of the adrenergic nerve network was significantly pronounced; 2) the mean diameter of the varicosities and the proportional share of large varicosities were increased, as well as the number of varicosities per a given length of an axon; 3) the intensity of the fluorescence of varicosities of comparable size was significantly increased; 4) the number of enterochromaffin cells was significantly decreased. In irritable colon, compared to control specimens, the number of enterochromaffin cells was significantly increased. These findings suggest that biogenic amines are somehow involved in both ulcerative colitis and irritable colon. The fluorescence histochemical method used was found sensitive, specific, and suitable for comparative studies on human clinical material.

Blood acetaldehyde concentration gradient between hepatic and antecubital venous blood in ethanol-intoxicated alcoholics and controls.

Abstract. After ethanol (0·8 g kg‐1 body weight orally) significant concentrations of acetaldehyde (2–20 μmol l‐1) were found in hepatic venous blood of moderately intoxicated non‐alcoholic male Caucasians in spite of the absence of detectable levels (<2 μmol l‐1) in simultaneously taken antecubital blood. In thirteen chronic lcoholics the elevation of blood acetaldehyde was more constant in the hepatic than in the peripheral vein.

Rationale in diagnosis and screening of atrophic gastritis with stomach-specific plasma biomarkers

Abstract Background and aims. Atrophic gastritis (AG) results most often from Helicobacter pylori (H. pylori) infection. AG is the most important single risk condition for gastric cancer that often leads to an acid-free or hypochlorhydric stomach. In the present paper, we suggest a rationale for noninvasive screening of AG with stomach-specific biomarkers. Methods. The paper summarizes a set of data on application of the biomarkers and describes how the test results could be interpreted in practice. Results. In AG of the gastric corpus and fundus, the plasma levels of pepsinogen I and/or the pepsinogen I/pepsinogen II ratio are always low. The fasting level of gastrin-17 is high in AG limited to the corpus and fundus, but low or non-elevated if the AG occurs in both antrum and corpus. A low fasting level of G-17 is a sign of antral AG or indicates high intragastric acidity. Differentiation between antral AG and high intragastric acidity can be done by assaying the plasma G-17 before and after protein stimulation, or before and after administration of the proton pump inhibitors (PPI). Amidated G-17 will rise if the antral mucosa is normal in structure. H. pylori antibodies are a reliable indicator of helicobacter infection, even in patients with AG and hypochlorhydria. Conclusions. Stomach-specific biomarkers provide information about the stomach health and about the function of stomach mucosa and are a noninvasive tool for diagnosis and screening of AG and acid-free stomach.

Acetaldehyde as a common denominator and cumulative carcinogen in digestive tract cancers

The key issue in cancer prevention is the identification of specific aetiologic factors. Acetaldehyde, the first metabolite of ethanol oxidation, is carcinogenic in animals. ADH and ALDH2 gene mutations provide an exceptional human model to estimate the long-term effects of acetaldehyde exposure in man. These models provide strong evidence for the local carcinogenic potential of acetaldehyde also in humans. Ethanol is metabolized to acetaldehyde by both mucosal and microbial enzymes. Many microbes produce acetaldehyde from ethanol, but their capacity to eliminate acetaldehyde is low, which leads to the accumulation of acetaldehyde in saliva during an alcohol challenge. Acetaldehyde is the most abundant carcinogen in tobacco smoke, and it readily dissolves into saliva during smoking. Fermented food and many alcoholic beverages can also contain significant amounts of acetaldehyde. Thus acetaldehyde, derived from mucosal or microbial oxidation of ethanol, tobacco smoke, and/or diet, appears to act as a cumulative carcinogen in the upper digestive tract of humans. The evidence strongly suggests the importance of world-wide screening of acetaldehyde and ethanol levels in many beverages and foodstuffs, as well as an urgent need for regulatory measures and consumer guidance. Screening of the risk groups with enhanced acetaldehyde exposure, e.g. people with ADH and ALDH2 gene polymorphisms and hypochlorhydric atrophic gastritis, should also be seriously considered. Most importantly, the GRAS (generally regarded as safe) status of acetaldehyde, which allows it to be used as a food additive, should be re-evaluated, and the classification of acetaldehyde as a carcinogen should be upgraded.

Elevated blood acetate as indicator of fast ethanol elimination in chronic alcoholics

The concentration of acetate was determined in the hepatic and peripheral blood of 10 chronic alcoholics and six healthy non-alcoholic controls after a peroral dose of ethanol (0.8 g/kg b.wt.). The blood acetate concentration was significantly higher in the hepatic vein than peripherally and remained at a rather constant level both in alcoholics and controls during the course of ethanol elimination. However, the level of acetate was significantly (p less than 0.005) higher in alcoholics than in controls both in the hepatic vein (1.79 and 1.15 mM) and peripherally (0.91 and 0.52 mM) (alcoholics and controls respectively). The alcoholics also eliminated ethanol 54% faster than the controls (159 mg/kg b.wt./hr and 103 mg/kg b.wt./hr; alcoholics and controls respectively). Furthermore a highly significant correlation was found between the rate of ethanol elimination and blood acetate level both in the hepatic (r = 0.877, p less than 0.001) and in the peripheral vein (r = 0.799, p less than 0.001). Our results suggest that an increased level of blood acetate during ethanol oxidation may be used as an indicator of enhanced ethanol elimination.

Eliminating Carcinogenic Acetaldehyde By Cysteine From Saliva During Smoking

Tobacco smoking is one of the strongest risk factors not only for lung cancer but also for cancers of the upper gastrointestinal tract. Acetaldehyde has been shown to dissolve into the saliva during smoking and to be a local carcinogen in the human upper digestive tract. Cysteine can bind to acetaldehyde and eliminate its toxicity. We developed a tablet that releases cysteine into the oral cavity during smoking and could therefore be a potential chemopreventive agent against toxicity of tobacco smoke. In this study, the efficacy of l-cysteine–containing tablets to reduce the carcinogenic acetaldehyde in the saliva during tobacco smoking was examined. Seven volunteers smoked five cigarettes. During every smoking period, each volunteer sucked a blinded tablet containing 0, 1.25, 2.5, 5, or 10 mg of l-cysteine. Acetaldehyde was analyzed from salivary samples gas chromatographically at 0, 5, and 10 minutes from the beginning of the smoking. All tablets containing l-cysteine reduced highly significantly the salivary acetaldehyde; 5 mg of l-cysteine was the minimum concentration to totally eliminate the acetaldehyde from saliva. The mean salivary acetaldehyde concentrations in samples collected immediately after smoking with 0, 1.25, 2.5, 5, or 10 mg of l-cysteine were 228 ± 115 μmol/L, 85 ± 42 μmol/L (P = 0.007), 9 ± 7 μmol/L, 0.09 ± 0.2 μmol/L, 0 ± 0 μmol/L (P < 0.001), respectively. In conclusion, carcinogenic acetaldehyde could be totally inactivated in the saliva during smoking by sucking tablet containing 5 mg of l-cysteine. Even a small reduction of the carcinogenicity of cigarette smoke could gain benefit at the population level. Hence, this finding warrants for further clinical trials for l-cysteine tablet in the prevention of upper digestive tract cancers in smokers. (Cancer Epidemiol Biomarkers Prev 2006;15(1):146–9)

Characteristics of Helicobacter pylori alcohol dehydrogenase

BACKGROUND Helicobacter pylori shows alcohol dehydrogenase activity, which in the presence of ethanol leads to in vitro production of acetaldehyde, a toxic and highly reactive substance. The present study was undertaken to further define H. pylori-related ethanol and acetaldehyde metabolism by characterizing H. pylori alcohol dehydrogenase and by determining whether the organism possesses aldehyde dehydrogenase. METHODS Cytosolic alcohol and aldehyde dehydrogenase activities were determined spectrophotometrically. Acetaldehyde produced by cytosol during incubation with ethanol was measured by head space gas chromatography. Isoenzyme pattern was studied using isoelectric focusing. RESULTS Significant alcohol dehydrogenase activity was observed at a neutral pH known to occur in gastric mucus. The Km for ethanol oxidation was approximately 100 mmol/L for the two strains tested. Acetaldehyde was formed already from a low ethanol concentration known to prevail in the stomach endogenously. Isoelectric focusing of the enzyme showed activity bands with pI at 7.1-7.3, a pattern different from that of gastric mucosal alcohol dehydrogenase. 4-methylpyrazole inhibited enzyme activity in a competitive manner and suppressed the growth of the organism during culture. Neither Helicobacter strain studied showed aldehyde dehydrogenase activity and can thus not remove acetaldehyde by that pathway. CONCLUSIONS Acetaldehyde production by H. pylori from exogenous or endogenous ethanol may be a pathogenetic mechanism behind mucosal injury associated with the organism.