Susanne Strohmaier

Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults

Initial studies have indicated diabetes and obesity to be risk factors for hepatocellular carcinoma; but the association between other metabolic risk factors and primary liver cancer (PLC) has not been investigated. The metabolic syndrome and cancer project (Me‐Can) includes cohorts from Norway, Austria and Sweden with data on 578,700 subjects. We used Cox proportional hazard models to calculate relative risks (RRs) of PLC by body mass index (BMI), blood pressure and plasma levels of glucose, cholesterol and triglycerides as continuous standardized variables (z‐score with mean = 0 and standard deviation (SD) = 1) and their standardized sum of metabolic syndrome (MetS) z‐score. RRs were corrected for random error in measurements. During an average follow‐up of 12.0 years (SD = 7.8), 266 PLCs were diagnosed among cohort members. RR of liver cancer per unit increment of z‐score adjusted for age, smoking status and BMI and stratified by birth year, sex and sub‐cohorts, was for BMI 1.39 (95% confidence interval (CI) 1.24–1.58), mid blood pressure 2.08 (0.95–4.73), blood glucose 2.13 (1.55–2.94) cholesterol 0.62 (0.51–0.76) and serum triglycerides 0.85 (0.65–1.10). The RR per one unit increment of the MetS z‐score was 1.35 (1.12–1.61). BMI, glucose and a composite MetS score were positively and cholesterol negatively associated with risk of liver cancer.

Cohort Profile: The Metabolic syndrome and Cancer project (Me-Can)

Background: A large number of prospective studies have shown that overweight and diabetes are related to an increased risk of many cancers, including colorectal cancer. In contrast, diabetes has been related to a decreased risk of prostate cancer, and overweight has been related to an increased risk of fatal, but not of incident, prostate cancer. Data from studies on metabolic factors related to overweight and diabetes, and the association with cancer risk, are limited. Aim: The aim of this thesis was to study metabolic factors in relation to risk of prostate cancer (paper I and III), colorectal cancer (paper II and V), and cancer overall (paper VI). Methods: Study designs were i) case-control studies, nested within the Northern Sweden Health and Disease Cohort (paper I and II), and ii) cohort studies of the Swedish Construction Workers cohort (paper III), and the Metabolic syndrome and Cancer project (Me-Can) comprising seven European cohorts (paper V and VI). Paper IV was a descriptive paper of Me-Can. Results, prostate cancer: In paper I, increasing levels of several factors related to insulin resistance (insulin, insulin resistance index, leptin, HbA1c, and glucose) were associated with a decreased risk of overall incident prostate cancer, and the associations were stronger for non-aggressive tumours. In paper III, increasing levels of blood pressure was associated with a significant decreased risk of overall incident prostate cancer and of non-aggressive tumours. Body mass index (BMI) was significantly positively related to fatal prostate cancer. Results, colorectal cancer: In paper II, obesity, hypertension, and hyperglycaemia, were associated with an increased risk of colorectal cancer, and presence of two or three of these factors was associated with a higher risk than the presence of one single factor. In paper V, BMI was associated with a significant linear positive association with risk of colorectal cancer in men and women, and significant positive associations were also found in men for blood pressure and triglycerides. A high metabolic syndrome score, based on levels of BMI, blood pressure, glucose, cholesterol, and triglycerides, was associated with a significant increased risk of colorectal cancer in men and women. The association was stronger than for any of the factors in single, but there was no evidence of a positive interaction between these metabolic factors. Results, cancer overall: Blood glucose was significantly positively associated with risk of incident and fatal cancer overall, and at several specific sites. The associations were stronger in women than in men, and for fatal than for incident cancer. Conclusions: Results from these studies indicate that elevated blood glucose is related to an increased risk of cancer overall and at several specific sites, and further, that overweight and metabolic aberrations increase the risk of colorectal cancer in an additive way. The association with prostate cancer seems to be more complex; insulin resistance and high blood pressure were in our studies related to a decreased risk of overall incident prostate cancer and of non-aggressive tumours, whereas overweight increased the risk of fatal prostate cancer.

Total serum cholesterol and cancer incidence in the Metabolic syndrome and Cancer Project (Me-Can).

Objective To investigate the association between total serum cholesterol (TSC) and cancer incidence in the Metabolic syndrome and Cancer project (Me-Can). Methods Me-Can consists of seven cohorts from Norway, Austria, and Sweden including 289,273 male and 288,057 female participants prospectively followed up for cancer incidence (n = 38,978) with a mean follow-up of 11.7 years. Cox regression models with age as the underlying time metric were used to estimate hazard ratios (HR) and their 95% confidence intervals (CI) for quintiles of cholesterol levels and per 1 mmol/l, adjusting for age at first measurement, body mass index (BMI), and smoking status. Estimates were corrected for regression dilution bias. Furthermore, we performed lag time analyses, excluding different times of follow-up, in order to check for reverse causation. Results In men, compared with the 1st quintile, TSC concentrations in the 5th quintile were borderline significantly associated with decreasing risk of total cancer (HR = 0.94; 95%CI: 0.88, 1.00). Significant inverse associations were observed for cancers of the liver/intrahepatic bile duct (HR = 0.14; 95%CI: 0.07, 0.29), pancreas cancer (HR = 0.52, 95% CI: 0.33, 0.81), non-melanoma of skin (HR = 0.67; 95%CI: 0.46, 0.95), and cancers of the lymph−/hematopoietic tissue (HR = 0.68, 95%CI: 0.54, 0.87). In women, hazard ratios for the 5th quintile were associated with decreasing risk of total cancer (HR = 0.86, 95%CI: 0.79, 0.93) and for cancers of the gallbladder (HR = 0.23, 95%CI: 0.08, 0.62), breast (HR = 0.70, 95%CI: 0.61, 0.81), melanoma of skin (HR = 0.61, 95%CI: 0.42, 0.88), and cancers of the lymph−/hematopoietic tissue (HR = 0.61, 95%CI: 0.44, 0.83). Conclusion TSC was negatively associated with risk of cancer overall in females and risk of cancer at several sites in both males and females. In lag time analyses some associations persisted, suggesting that for these cancer sites reverse causation did not apply.

Blood pressure and other metabolic syndrome factors and risk of brain tumour in the large population-based Me-Can cohort study

Objectives: Brain tumour has few established determinants. We assessed to which extent risk of brain tumour was related to metabolic syndrome factors in adults. Methods: In the Me-Can project, 580 000 individuals from Sweden, Austria, and Norway were followed for a median of 10 years after baseline measurement. Data on brain tumours were obtained from national cancer registries. The factors of metabolic syndrome (BMI, SBP and DBP, and blood levels of glucose, cholesterol, and triglycerides), separately and combined, were analysed in quintiles and for transformed z-scores (mean transformed to 0 and standard deviation to 1). Cox proportional hazards multivariate regression models were used, with corrections for measurement error. Results: During follow-up, 1312 primary brain tumours were diagnosed, predominantly meningioma (n = 348) and high-grade glioma (n = 436). For meningioma, the hazard ratio was increased for z-scores of SBP [hazard ratio = 1.27 per unit standard deviation, 95% confidence interval (CI) 1.03–1.57], of DBP (hazard ratio = 1.29, 95% CI 1.04–1.58), and of the combined metabolic syndrome score (hazard ratio = 1.31, 95% CI 1.11–1.54). An increased risk of high-grade glioma was found for DBP (hazard ratio = 1.23, 95% CI 1.01–1.50) and triglycerides (hazard ratio = 1.35, 95% CI 1.05–1.72). For both meningioma and high-grade glioma, the risk was more than double in the fifth quintiles of DBP compared to the lowest quintile. For meningioma this risk was even larger for SBP. Conclusion: Increased blood pressure was associated with risk of brain tumours, especially of meningiomas.

A prospective study on metabolic risk factors and gallbladder cancer in the metabolic syndrome and cancer (Me-Can) collaborative study.

Objective To investigate the association between metabolic risk factors (individually and in combination) and risk of gallbladder cancer (GBC). Methods The metabolic syndrome and cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden with data on 578,700 men and women. We used Cox proportional hazard regression models to calculate relative risks of GBC by body mass index (BMI), blood pressure, and plasma levels of glucose, cholesterol, and triglycerides as continuous standardised variables and their standardised sum of metabolic syndrome (MetS) z-score. The risk estimates were corrected for random error in measurements. Results During an average follow-up of 12.0 years (SD = 7.8), 184 primary gallbladder cancers were diagnosed. Relative risk of gallbladder cancer per unit increment of z-score adjusted for age, smoking status and BMI (except for BMI itself) and stratified by birth year, sex and sub-cohorts, was for BMI 1.31 (95% confidence interval 1.11, 1.57) and blood glucose 1.76 (1.10, 2.85). Further analysis showed that the effect of BMI on GBC risk is larger among women in the premenopausal age group (1.84 (1.23, 2.78)) compared to those in the postmenopausal age group (1.29 (0.93, 1.79)). For the other metabolic factors no significant association was found (mid blood pressure 0.96 (0.71, 1.31), cholesterol 0.84 (0.66, 1.06) and serum triglycerides 1.16 (0.82, 1.64)). The relative risk per one unit increment of the MetS z-score was 1.37 (1.07, 1.73). Conclusion This study showed that increasing BMI and impaired glucose metabolism pose a possible risk for gallbladder cancer. Beyond the individual factors, the results also showed that the metabolic syndrome as an entity presents a risk constellation for the occurrence of gallbladder cancer.

Antibody dynamics and spontaneous viral clearance in patients with acute hepatitis C infection in Rio de Janeiro, Brazil

BackgroundThe anti-HCV antibody response has not been well characterized during the early phase of HCV infection and little is known about its relationship to the clinical course during this period.MethodsWe analyzed serial anti-HCV antibodies longitudinally obtained from a prospective cohort of 65 patients with acute HCV infection by using a microparticle enzyme immunoassay AxSYM HCV 3.0 (Abbott Diagnostics) during the first 12 months from HCV acquisition in Rio de Janeiro, Brazil. Spontaneous viral clearance (SVC) was defined as undetectable HCV RNA in serum, in the absence of treatment, for three consecutive HCV PCR tests within 12-months of follow-up.ResultsBaseline antibody values were similar among patient groups with self-limiting HCV evolution (n = 34) and persistent viremia (n = 31) [median (interquartile range) signal/cut-off ratio (s/co) 78.7 (60.7-93.8) vs. 93.9 (67.8-111.9), p = 0.26]. During 12-months follow-up, patients with acute spontaneous resolving HCV infection showed significantly lower serial antibody response in comparison to individuals progressing to chronic infection [median (interquartile range) s/co 62.7 (35.2-85.0) vs. 98.4 (70.4-127.4), p < 0.0001]. In addition, patients with self-limiting HCV evolution exhibited an expeditious, sharp decline of serial antibody values after SVC in comparison to those measured before SVC [median (interquartile range) s/co 56.0 (25.4-79.3) vs. 79.4 (66.3-103.0), p < 0.0001].ConclusionOur findings indicate a rapid short-term decline of antibody values in patients with acute spontaneous resolving HCV infection.

Long-term temporal trends in cardiovascular and metabolic risk factors

ZusammenfassungZIELE: Kardiovaskuläre Risikofaktoren wie Adipositas, Bluthochdruck, erhöhte Blutfette und Blutzucker wurden in den letzten Jahren zunehmend mit dem Auftreten von Krebserkrankungen in Verbindung gebracht. Das MeCan (Metabolic Syndrome and Cancer) Projekt untersucht diese Zusammenhänge unter Verwendung österreichischer und skandinavischer Kohortendaten. Diese Daten wurden nun in der vorliegenden Studie genutzt, um langfristige Trends in den genannten Risikofaktoren zu untersuchen. METHODEN: Daten aus Gesundenuntersuchungen mit Nüchternblutabnahme im Zeitraum 1975 bis 2004 von insgesamt 239.602 Personen (Alter 25–64 Jahre) wurden für die Schätzung der Prävalenzveränderungen verwendet. ERGEBNISSE: Die Prävalenz der Adipositas und der Hyperglykämie zeigte einen deutlichen Anstieg im Untersuchungszeitraum. Die Adipositas stieg dabei um einen Faktor von 1,54 (95% KI: 1,42–1,66) pro Jahrzent bei Männer und um einen Faktor von 1,48 (95% KI: 1,41–1,56) bei Frauen. Noch deutlicher war der Anstieg bei der Hyperglykämie mit einem Anstieg um das 1,62-fache (95% KI: 1,49–1,76) bei Männern und um das 1,66-fache (95% KI: 1,57–1,75) bei Frauen. Bluthochdruck sank um den Faktor 0,71 (95% KI: 0,68–0,74) bei Männern und 0,83 (95% KI: 0,79–0,86) bei Frauen. Die Prävalenz der Hyperlipidämie (gemessen durch Gesamtcholesterin und Triglyceride) stieg bis Ende der achtziger Jahre und ging anschließend zurück. Als Proxy für das Metabolische Syndrom wurde eine Kombination aus drei oder mehr dieser Risikofaktoren untersucht, diese verzeichnete einen moderaten Anstieg um das 1,15-fache (95% KI: 1,08–1,22) bei Männern und um das 1,20–fache (95% KI: 1,15–1,27) pro Dekade bei Frauen. SCHLUSSFOLGERUNGEN: Über die letzten drei Jahrzehnte zeigten sich sowohl in Österreich als auch in Schweden deutliche Umschichtungen in den untersuchten Risikofaktoren. Im Hinblick auf die Prävention von Herzkreislauferkrankungen aber auch Krebserkrankungen verdienen vor allem die besorgniserregenden Entwicklungen bei Übergewicht und Diabetes besondere Aufmerksamkeit.SummaryOBJECTIVES: Metabolic factors such as obesity, hypertension, dyslipidemia and hyperglycemia have consistently been associated with increased risk of cardiovascular disease. There is also growing evidence that these factors are linked to cancer incidence and mortality. The aim of this study was to investigate long-term trends in major metabolic risk factors in three large cohorts. MATERIALS AND METHODS: Data from 239,602 individuals aged 25–64 years participating in health examinations between 1976 and 2005 were used to estimate prevalence and trends in five risk factors. RESULTS: Irrespective of geographic location, individual metabolic risk factors showed divergent trends across the observation period. Whereas obesity and hyperglycemia in men increased by a per decade ratio of 1.54 (95% CI: 1.42–1.66) and 1.62 (95% CI: 1.49–1.76), respectively, and in women by 1.48 (95% CI: 1.41–1.56) and 1.66 (95% CI: 1.57–1.75), hypertension decreased by 0.71 (95% CI: 0.68–0.74) in men and 0.83 (95% CI: 0.79–0.86) in women. Dyslipidemia increased from the 1970s to the 1980s but declined in the succeeding decade. A combination of three or more of these risk factors increased significantly in men by a ratio of 1.15 (95% CI: 1.08-1.22) per decade and in women by 1.20 (95% CI: 1.15–1.27). CONCLUSION: The study shows that individual metabolic risk factors followed divergent trends over the period of three decades even though the combination of three or more risk factors used as a proxy for the metabolic syndrome appeared to be stable over the last two of the decades. The two key components of the syndrome, namely BMI and glucose levels, increased significantly and deserve professional attention.

Mediation analysis of the relationship between sex, cardiovascular risk factors and mortality from coronary heart disease: Findings from the population-based VHM&PP cohort.

BACKGROUND In Europe, annually about 77,000 women, but 253,000 men die prematurely from coronary heart disease (CHD) before the age of 65 years. This gap narrows with increasing age and disappears after the eighth life decade. However, little is known regarding the contribution of cardiovascular risk factors to this sex difference. OBJECTIVE We investigated to what extent mens higher risk of dying from CHD is explained through a different risk factor profile, as compared to women. METHODS Mediation analysis technique was used to assess the specific contributions of blood pressure, cholesterol, glucose, and smoking to the difference between men and women regarding CHD mortality in a large Austrian cohort consisting of 117,264 individuals younger than 50 years (as a proxy for pre-menopausal status) and 54,998 older ones, with 3892 deaths due to CHD during a median follow-up of 14.6 years. RESULTS Adjusting for age and year of examination, we observed a male versus female CHD mortality hazard ratio (HR) of 4.7 (95% CI: 3.4-5.9) in individuals younger than 50 years, of which 40.9% (95% CI: 27.1%-54.7%) was explained through risk factor pathways, mainly through blood pressure. In older participants, there was a HR of 1.9 (95% CI: 1.8-2.0) of which 8.2% (95% CI: 4.6%-11.7%) was mediated through the risk factors. CONCLUSION The extent to which major risk factors contribute to the sex difference regarding CHD mortality decreases with age. The female survival advantage was explained to a substantial part through the pathways of major risk factors only in younger individuals.

Comparison of arterial versus venous parameters of Rotational thromboelastometry and multiple platelet function analyzer: Results of a pilot study

Abstract Background. In the operating room and at the ICU, Rotational thromboelastometry (ROTEM®) and multiple platelet function analyzer (Multiplate®) are frequently performed on arterial blood samples while known reference ranges refer to venous blood only. To evaluate whether there are clinical important differences between parameters measured in arterial and venous blood, we performed a prospective study in patients undergoing orthopedic surgery. Methods. Arterial and venous blood samples were drawn simultaneously after line insertion (T0), intraoperatively (T1), at the end of surgery (T2) and the INTEM®, EXTEM® and FIBTEM® ROTEM assays, as well as the ASPI®, ADP® and TRAP® assays were performed in arterial and venous samples using the ROTEM® and the Multiplate® device, respectively. Results. After informed consent, 52 patients were enrolled and data of 50 patients remained for final analysis. Venous and arterial measurement results correlated significantly with a coefficient of 0.519–0.977. At the three measurement points only a few statistically significant deviations were detected for some of the ROTEM® and Multiplate® parameters. The magnitude of differences was small and most likely without clinical relevance. Pathological conditions were detected with similar frequency regardless of the sampling site. Only Multiplate® TRAP at T0 indicated low platelet aggregation more frequently in venous than in arterial samples (p = 0.0455); however, values were only narrow below reference range. Conclusion. The observed differences between arterial and venous results were within the range of variability of the methods reported for venous blood. Pathological values that might be clinically relevant could be detected at similar rates regardless of the sampling site.

Dynamic path analysis – a useful tool to investigate mediation processes in clinical survival trials

When it comes to clinical survival trials, regulatory restrictions usually require the application of methods that solely utilize baseline covariates and the intention-to-treat principle. Thereby, much potentially useful information is lost, as collection of time-to-event data often goes hand in hand with collection of information on biomarkers and other internal time-dependent covariates. However, there are tools to incorporate information from repeated measurements in a useful manner that can help to shed more light on the underlying treatment mechanisms. We consider dynamic path analysis, a model for mediation analysis in the presence of a time-to-event outcome and time-dependent covariates to investigate direct and indirect effects in a study of different lipid-lowering treatments in patients with previous myocardial infarctions. Further, we address the question whether survival in itself may produce associations between the treatment and the mediator in dynamic path analysis and give an argument that because of linearity of the assumed additive hazard model, this is not the case. We further elaborate on our view that, when studying mediation, we are actually dealing with underlying processes rather than single variables measured only once during the study period. This becomes apparent in results from various models applied to the study of lipid-lowering treatments as well as our additionally conducted simulation study, where we clearly observe that discarding information on repeated measurements can lead to potentially erroneous conclusions.