Gudrun Høiseth

Cohort Profile Update: The Norwegian Mother and Child Cohort Study (MoBa)

This is an update of the Norwegian Mother and Child Cohort Study (MoBa) cohort profile which was published in 2006. Pregnant women attending a routine ultrasound examination were initially invited. The first child was born in October 1999 and the last in July 2009. The participation rate was 41%. The cohort includes more than 114 000 children, 95 000 mothers and 75 000 fathers. About 1900 pairs of twins have been born. There are approximately 16 400 women who participate with more than one pregnancy. Blood samples were obtained from both parents during pregnancy and from mothers and children (umbilical cord) after birth. Samples of DNA, RNA, whole blood, plasma and urine are stored in a biobank. During pregnancy, the mother responded to three questionnaires and the father to one. After birth, questionnaires were sent out when the child was 6 months, 18 months and 3 years old. Several sub-projects have selected participants for in-depth clinical assessment and exposure measures. The purpose of this update is to explain and describe new additions to the data collection, including questionnaires at 5, 7, 8 and 13 years as well as linkages to health registries, and to point to some findings and new areas of research. Further information can be found at [www.fhi.no/moba-en]. Researchers interested in collaboration and access to the data can complete an electronic application available on the MoBa website above.

Comparison between the urinary alcohol markers EtG, EtS, and GTOL/5-HIAA in a controlled drinking experiment

AIM Urinary ethyl glucuronide (EtG), ethyl sulfate (EtS), and the ratio between 5-hydroxytryptophol-glucuronide and 5-hydroxyindole-3-acetic acid (GTOL/5-HIAA) are all suggested as biomarkers for recent alcohol ingestion with longer detection times than measurement of ethanol itself. The aim of this controlled study was to compare the sensitivities and detection times of EtG, EtS, and GTOL/5-HIAA, after a single ingestion of ethanol. METHODS 0.5 g ethanol/kg body weight was ingested by 10 healthy male volunteers in a fasted state. Ethanol, EtG, EtS, and GTOL/HIAA levels were measured in urine samples collected during a 45-50 h period. The total amount of ethanol excreted as EtG and EtS was also determined. RESULTS Urinary EtG, EtS, and GTOL/5-HIAA showed 100% sensitivity as biomarkers for recent drinking. Compared to ethanol testing in urine, the detection times for GTOL/5-HIAA were approximately 5 h longer and for EtG and EtS approximately 25 h longer. The maximum EtG concentrations were higher than for EtS in all subjects, and a higher fraction of the ethanol dose was excreted as EtG (median 0.019%) compared with EtS (median 0.011%). CONCLUSIONS This study is the first controlled experiment comparing the time-courses for ethanol, EtG, EtS, and GTOL/5-HIAA in urine. In cases where surveillance of alcohol relapse is needed, measurements of urinary EtG and EtS are sensitive and specific alternatives to ethanol testing. The GTOL/5-HIAA ratio is equally sensitive but with a much shorter window of detection.

Controlling for High-Density Lipoprotein Cholesterol Does Not Affect the Magnitude of the Relationship Between Alcohol and Coronary Heart Disease

Background— This study tested the hypothesis that moderate alcohol intake exerts its cardioprotective effect mainly through an increase in the serum level of high-density lipoprotein cholesterol. Methods and Results— In the Cohort of Norway (CONOR) study, 149 729 adult participants, recruited from 1994 to 2003, were followed by linkage to the Cause of Death Registry until 2006. At recruitment, questionnaire data on alcohol intake were collected, and the concentration of high-density lipoprotein cholesterol in serum was measured. Using Cox regression, we found that the adjusted hazard ratio for men for dying from coronary heart disease was 0.52 (95% confidence interval, 0.39–0.69) when consuming alcohol more than once a week compared with never or rarely. The ratio changed only slightly, to 0.55 (0.41–0.73), after the regression model included the serum level of high-density cholesterol. For women, the corresponding hazard ratios were 0.62 (0.32–1.23) and 0.68 (0.34–1.34), respectively. Conclusions— Alcohol intake is related to a reduced risk of death from coronary heart disease in the follow-up of a large, population-based Norwegian cohort study with extensive control for confounding factors. Our findings suggest that the serum level of high-density cholesterol is not an important intermediate variable in the possible causal pathway between moderate alcohol intake and coronary heart disease.

Blood kinetics of ethyl glucuronide and ethyl sulphate in heavy drinkers during alcohol detoxification

Studies of ethyl glucuronide (EtG) blood kinetics have so far been performed on healthy volunteers with ingestion of low to moderate doses of ethanol. These data are not necessarily transferable to heavy drinkers where the consumed doses of ethanol are much higher. The aim of this study was to investigate the pharmacokinetics of EtG and ethyl sulphate (EtS) in blood in heavy drinkers after termination of alcohol ingestion. Sixteen patients from an alcohol withdrawal clinic were included directly after admission. Time of end of drinking, estimated daily intake of ethanol (EDI) and medical history were recorded. Three to five blood samples over 20-43 h were collected from each patient subsequent to admission. The median EDI was 172 g (range 60-564). The first sample was collected median 2.5 h after end of drinking (range 0.5-23.5). Two patients had levels of EtG and EtS below LOQ in all samples, the first collected 19.25 and 23.5 h after cessation of drinking, respectively. Of the remaining 14 patients, one subject, suffering from both renal and hepatic disease, showed concentrations of EtG and EtS substantially higher than the rest of the material. This patients initial value of EtG was 17.9 mg/L and of EtS 5.9 mg/L, with terminal elimination half lives of 11.9 h for EtG and 12.5 h for EtS. Among the remaining 13 patients, the initial median values were 0.7 g/L (range 0-3.7) for ethanol, 1.7 mg/L (range 0.1-5.9) for EtG and 0.9 mg/L (range 0.1-1.9) for EtS. Elimination occurred with a median half-life of 3.3 h for EtG (range 2.6-4.3) and 3.6 h for EtS (range 2.7-5.4). In conclusion, elimination of EtG in heavy drinkers did not significantly differ from healthy volunteers, and EtS appeared to have similar elimination rate. In the present work, there was one exception to this, and we propose that this could be explained by the patients renal disease, which would delay excretion of these conjugated metabolites.

Ethyl glucuronide in hair compared with traditional alcohol biomarkers--a pilot study of heavy drinkers referred to an alcohol detoxification unit.

BACKGROUND Traditional biomarkers for heavy alcohol use include serum carbohydrate-deficient transferrin (CDT), the enzymes aspartate aminotransferase (AST), and alanine aminotransferase (ALT) as well as gamma-glutamyl transferase (GGT). Measurement of the nonoxidative ethanol metabolite, ethyl glucuronide (EtG) in hair, has been proposed as a new marker with superior qualities. The aim of this study was to investigate the sensitivity of EtG in hair to detect heavy alcohol use compared with CDT, AST, ALT, and GGT. We also wanted to study the quantitative relation between alcohol intake and the different biomarkers. METHODS Sixteen patients with a history of heavy alcohol use over the previous 3 months were recruited directly after admission to a withdrawal clinic. They were thoroughly interviewed about their drinking pattern as well as relevant diseases and use of medicines or drugs. Serum was sampled and analyzed for %CDT, AST, ALT, and GGT. Hair samples were collected and analyzed for EtG. RESULTS The mean estimated daily intake (EDI) over the previous 3 months was 206 +/- 136 g pure alcohol. All patients fulfilled the criteria for heavy alcohol use. The sensitivity to detect heavy alcohol use was 64% for %CDT, 67% for AST, 67% for ALT, 93% for GGT, and 94% for EtG. There was no correlation between the quantitative values of EDI and %CDT, AST, ALT, and GGT. There was a positive, statistically significant correlation between EDI and the level of EtG in hair. CONCLUSIONS In this study, EtG in hair and GGT showed the best sensitivity to detect heavy alcohol use and there was a positive correlation between EDI and the concentrations of EtG in hair. Before giving recommendations for clinical practice, further studies should be carried out on larger materials and populations with a wider range of alcohol intake.

Divergent associations of drinking frequency and binge consumption of alcohol with mortality within the same cohort

Background Observational studies show beneficial effects of moderate alcohol drinking on all-cause and cardiovascular disease (CVD) mortality, while binge drinking has been linked with increased mortality. The aim of this study was to assess the associations of alcohol use with mortality in a population with a hybrid of drinking patterns. Method Participants in a population based cardiovascular health survey in Finnmark county in 1987–1988, aged 20–62 years, constituted the study cohort. Alcohol use was self-reported by use of questions on frequency of beer, wine and liquor intake, and one question on intake of around five drinks or more per occasion (binge drinking). Information on education, income and use of alcohol in an earlier and in a later survey was linked to the file. Mortality was assessed throughout 2009 by Cox regression, with adjustment for potential confounding factors. In the analysis of mortality by frequency of any alcohol use, we adjusted for binge consumption and vice versa. Results Two opposite trends appeared: a higher all-cause mortality in both sexes, and higher CVD mortality in men, with increasing frequency of binge drinking, compared with non-bingers. Second, in both sexes low-frequent use of any alcohol was associated with lower all-cause and CVD mortality, compared with abstention. The combination of any use of alcohol at least weekly and binge consumption at least monthly was common, particularly in men. Conclusions Questions on drinking frequency and a specific question on binge drinking capture different effects of alcohol use on all-cause and CVD mortality.

Higher levels of hair ethyl glucuronide in patients with decreased kidney function.

BACKGROUND Hair levels of ethyl glucuronide (EtG) are often used to differentiate social drinking from heavy drinking. Patients with decreased kidney function have delayed excretion of EtG, and increased incorporation into hair could be suspected. The aim of this study was to compare hair EtG levels in patients with decreased kidney function to those seen in healthy volunteers. METHODS Twelve patients with renal disease were included. The levels of EtG in hair were adjusted to estimated daily intake of ethanol (EDI) and compared to 21 previously published healthy individuals. RESULTS The levels of hair EtG in the 12 patients ranged between < limit of detection and 134 pg/mg, and the EDI ranged between 0.1 and 12 g. The levels of EtG in hair were significantly higher in the patients compared to healthy volunteers (p = 0.009). CONCLUSIONS These preliminary results indicate that hair levels of EtG in a population of patients with decreased kidney function should be interpreted with caution.

Prolonged Urinary Detection Times of EtG and EtS in Patients with Decreased Renal Function

BACKGROUND The aims of this study were to investigate detection times for ethyl glucuronide (EtG) and ethyl sulphate (EtS) in urine samples of patients with decreased kidney function and to compare these with those previously reported for healthy volunteers. METHODS Fourteen patients were included, each delivering 10 urine samples after a nonsupervised intake of 0.1 to 1.4 g ethanol/kg body weight. The urinary detection times of EtG and EtS in these patients were adjusted for doses and compared to previously published healthy volunteers. RESULTS Detection times were significantly longer in patients with decreased renal function compared with healthy volunteers (p < 0.01 for both EtG and EtS). CONCLUSIONS Even after very minor alcohol intakes, these patients could fail alcohol tests based on the detection of conjugated ethanol metabolites for several days and wrongly be suspected of higher or more recent alcohol intakes than actually have found place.

Long-term stability of morphine, codeine, and 6-acetylmorphine in real-life whole blood samples, stored at −20 °C

PURPOSE Stability of drugs during storage is important in forensic toxicology. For the analytes detected after intake of heroin (6-acetylmorphine (6-AM), morphine and codeine), long-time stability in real life whole blood samples are studied in only a small number of cases. METHODS Whole blood post mortem (n=37) and whole blood samples from living persons (n=22) containing morphine and codeine as well as 6-AM in blood or urine were selected. All cases represented intake of heroin. All samples contained fluoride and were initially analysed and stored in normal conditions (-20°C) for 4-9 years. All samples were then reanalysed using the same analytical methods and the results were compared. RESULTS For samples from living persons, the median change in concentration was -3.7% for morphine and -5.3% for codeine. For post mortem samples, the median change in concentration was -12% for morphine and -11% for codeine. Both for samples from living persons and post mortem samples, the decrease in the concentrations from the original analysis to reanalysis were statistically significant for morphine and codeine. Regarding 6-AM, all living samples were negative at reanalysis. For post mortem samples, four cases still tested positive for 6-AM at reanalysis with a median change in the concentrations of -81%. There was no significant change in the morphine to codeine concentration ratios neither for living nor post mortem samples. CONCLUSION This study showed that in real life whole blood samples, the concentrations of morphine and codeine are relatively stable during long-term storage at -20°C. 6-AM on the other hand, shows a considerable decrease in concentrations that is important to consider when interpreting results from reanalyses of forensic cases.

The effect of scheduling and withdrawal of carisoprodol on prevalence of intoxications with the drug

The centrally acting muscle relaxant carisoprodol has previously been shown to cause psychomotor impairment and to have a narrow therapeutic range. In Norway, carisoprodol was therefore reclassified to the highest scheduling level from 1 August 2007 and withdrawn from the market on 1 May 2008. The aim of this study was to examine to what extent this action resulted in reduced numbers of driving under the influence (DUI) cases and forensic autopsies concerning carisoprodol, as well as reduced numbers of contacts to the National Poisons Information Centre (NPIC) in Norway regarding carisoprodol. From 2004 to 2008, carisoprodol (and/or its metabolite meprobamate) was detected in a total of 1261 DUI cases, decreasing from 312 in 2004 to 47 in 2008. During the same period, carisoprodol was detected in 194 forensic autopsies, also here decreasing, from 53 cases in 2004 to 11 cases in 2008. The NPIC received 1180 contacts primarily concerning carisoprodol over this period, decreasing from 267 contacts in 2004 to 87 contacts in 2008. During the same period, the sales figures for carisoprodol decreased dramatically, and we observed a relation between the numbers of DUI cases, forensic autopsies and contacts to the NPIC concerning carisoprodol and the sales figures for the drug. This study showed that the rescheduling and withdrawal of carisoprodol from the Norwegian market had a positive effect on the prevalence of carisoprodol in impaired driving, deaths and contacts regarding intoxications. This, together with previous publications, indicates that the population reflected in our data uses regularly prescribed carisoprodol and, to a lesser degree, drug from an illegal street market.