Alcohol biomarker screening in medical and surgical settings.

This article highlights the proceedings of a symposium presented at the 28th Annual Meeting of the Research Society on Alcoholism in Santa Barbara, CA, on June 28, 2005, organized and chaired by Peter Miller. The presentations included (1) Screening for Alcohol Use Disorders in Surgical and Trauma Patients, presented by Claudia Spies; (2) Are Serum Levels of %CDT and GGT Related to Severity of Liver Biopsy Inflammation, Fibrosis, and Steatohepatitis in Patients with Hepatitis C? by Martin Javors; (3) Biochemical Alcohol Screening in the Treatment of Hypertension, presented by Peter Miller; and (4) The Cost-Effectiveness of a New Biomarker, CDT, in a Primary Care Sample, by Michael Fleming. Presentations were discussed by Raymond Anton.

Rabeprazole: pharmacokinetics in patients with stable, compensated cirrhosis.

This single-center, open-label study was undertaken to compare the tolerability and pharmacokinetic profiles of rabeprazole, a new proton-pump inhibitor (PPI), in healthy volunteers and in subjects with chronic cirrhosis. Thirteen healthy men and 10 men with stable, compensated cirrhosis documented by biopsy or liver/spleen scan received a single 20-mg rabeprazole dose. Blood samples were drawn before and up to 24 hours after drug administration for the determination of plasma rabeprazole concentrations using high-performance liquid chromatography. Adverse events, vital signs, electrocardiograms, physical findings, and clinical laboratory test results were monitored before and during treatment to determine how rabeprazole was tolerated. Chronic liver disease substantially altered the pharmacokinetic profile of rabeprazole. The maximum rabeprazole concentration (+/- SD) in subjects with cirrhosis (635+/-199 ng/mL) was approximately 50% higher than that in the healthy volunteers (401+/-246 ng/mL), and both area under the curve and elimination half-life were increased by approximately 100%. Oral clearance in subjects with cirrhosis was 38% of that in the healthy volunteers. Rabeprazole was well tolerated by both groups. Three subjects reported a total of 5 clinical adverse events that were judged as definitely or possibly related to rabeprazole treatment. Some minor changes in laboratory values were judged to be clinically insignificant. In patients with mild-to-moderate liver dysfunction, clearance of this PPI, as with other members of the class, was markedly reduced and plasma levels were increased. Although caution is always warranted in patients with severe liver disease, drug accumulation is unlikely with rabeprazole 20 mg once daily, and dose adjustment does not appear to be indicated in patients with mild-to-moderate liver dysfunction.

Fetal alcohol syndrome: overview of pathogenesis.

The pathogenesis of Fetal Alcohol Syndrome (FAS) has been reviewed briefly in terms of factors which can influence its development and specific mechanisms. FAS was defined arbitrarily to include a wide spectrum ranging from the fully expressed clinical syndrome to growth and developmental impairment seen in fetal and neonatal animals exposed to ethanol. The available evidence suggests that ethanol per se in the absence of nutritional deficit can cause some from of FAS. Acetaldehyde may contribute to the FAS, but there is lack of knowledge concerning the levels of acetaldehyde needed to achieve fetal damage and the effect of this agent on the placenta and its placental transfer to the fetal organs. There is no specific data at this time to incriminate nutritional impairment, although further studies in animal models and man of the role of possible deficiencies of certain vitamins (i.e., folate) and of trace minerals (i.e., zinc) are needed. There is some evidence that alcohol or its metabolites may alter placental transport function. The relevance of this to FAS needs further investigation. The possible additive roles of caffeine, nicotine and other drugs on fetal development and viability deserve more consideration. The specific mechanism(s) of FAS are unknown. Of those considered--mutagenic (paternal) effect, abnormal protein synthesis, altered cerebral neurotransmitter balance, hormonal and other effects--impairment of protein synthesis at present seems best documented, but all clearly require further evaluation. When specific mechanisms are investigated it will be essential also to determine the dose-response relationship and the effects of a given dose of alcohol at various stages of gestation.

Mechanisms of thiamin deficiency in chronic alcoholism.

In the United States and other developed countries thiamin deficiency is often related to chronic alcoholism. A number of mechanisms may be involved in the pathogenesis of thiamin deficiency in the alcoholic population. An important cause is inadequate intake of thiamin. Moreover, there may be decreased converstion of thiamin to the active coenzyme, reduced hepatic storage of the vitamin in patients with fatty metamorphosis, ethanol inhibition of intestinal thiamin transport, and impaired thiamin absorption secondary to other states of nutritional deficiency. The present discussion focuses on the mechanism of ethanol-related thiamin malabsorption. Under normal conditions thiamin transport in animals and humans is biphasic. At low or physiological thiamin concentrations, transport is a saturable, carrier-mediated, active process; but at higher concentrations, the transport of thiamin is predominantly passive. Ethanol reduces the rate of intestinal absorption and the net transmural flux of thiamin. Furthermore, ethanol inhibits only the active and not the passive component of thiamin transport by impeding the cellular exit of thiamin across the basolateral or serosal membrane. The impairment of thiamin movement out of the enterocyte correlates with a fall in the activity of Na-K ATPase. Bound to the basolateral membrane, Na-K ATPase is believed to be involved in the kinetics of active transport. Ethanol also increases the fluidity of enterocyte brush border and basolateral membranes. Since ethanol increases membrane fluidity it is possible that tahe impairment of thiamin transport and the diminution of Na-K ATPase activity may be related, at least partly, to a physical perturbation of the enterocyte membrane.

Gastric varices. Problem in diagnosis.

Gastric varices may appear in association with esophageal varices secondary to portal-hypertension or as an independent manifestation of splenic vein obstruction. Since gastric varices often manifest as radiologic filling defects in the gastric fundus or cardia, differentiation from tumors and many other diseases becomes imperative. Unfortunately, routine diagnostic pprocedures may be of limited value. The difficulties in the diagnosis of gastric varices are illustrated with three specific cases. Correct diagnosis is best established with the aid of endoscopy and such special procedures as celiac angiography or splenoportography. With the help of three cases, the characteristics of gastric varices are reviewed and their evaluation and management are outlined.

Liver-lung scan in the diagnosis of right subphrenic abscess.

To assess the value of liver-lung scanning in the diagnosis of right subphrenic abscess, 148 scans were reviewed against corresponding charts. Of 91 scans with adequate clinical data, overall scanning error was 19.3% with 14 false positive and 3 false negative scans. Among 49 scans (of the initial group of 91 studies) with presence or absence of actual pathology proved by surgery and/or autopsy, there were 3 true positive, 12 false positive, 29 true negative, and 3 false negative scans. Analysis of data indicated (1) lower accuracy of scan interpretations than generally reported, (2) low specificity for positive scans and high specificity for negative scans, (3) correlations of false interpretations with atypical degrees of liver-lung separation and with scanning defects in liver and lung, and (4) failure of rereading significantly to improve accuracy of interpretation.