Development and validation of a model to predict incident chronic liver disease in the general population: The CLivD score.

BACKGROUND & AIMS: Current screening strategies for chronic liver disease focus on detection of subclinical advanced liver fibrosis but cannot identify those at high future risk of severe liver disease. Our aim was to develop and validate a risk prediction model for incident chronic liver disease in the general population based on widely available factors. METHODS: Multivariable Cox regression analyses were used to develop prediction models for liver-related outcomes with and without laboratory measures (Modellab and Modelnon-lab) in 25,760 individuals aged 40-70 years. Their data were sourced from the Finnish population-based health examination surveys FINRISK 1992-2012 and Health 2000 (derivation cohort). The models were externally validated in the Whitehall II (n = 5,058) and Copenhagen City Heart Study (CCHS) (n = 3,049) cohorts. RESULTS: The absolute rate of incident liver outcomes per 100,000 person-years ranged from 53 to 144. The final prediction model included age, sex, alcohol use (drinks/week), waist-hip ratio, diabetes, and smoking, and Modellab also included gamma-glutamyltransferase values. Internally validated Wolbers' C-statistics were 0.77 for Modellab and 0.75 for Modelnon-lab, while apparent 15-year AUCs were 0.84 (95% CI 0.75-0.93) and 0.82 (95% CI 0.74-0.91). The models identified a small proportion (<2%) of the population with >10% absolute 15-year risk for liver events. Of all liver events, only 10% occurred in participants in the lowest risk category. In the validation cohorts, 15-year AUCs were 0.78 (Modellab) and 0.65 (Modelnon-lab) in the CCHS cohort, and 0.78 (Modelnon-lab) in the Whitehall II cohort. CONCLUSIONS: Based on widely available risk factors, the Chronic Liver Disease (CLivD) score can be used to predict risk of future advanced liver disease in the general population. LAY SUMMARY: Liver disease often progresses silently without symptoms and thus the diagnosis is often delayed until severe complications occur and prognosis becomes poor. In order to identify individuals in the general population who have a high risk of developing severe liver disease in the future, we developed and validated a Chronic Liver Disease (CLivD) risk prediction score, based on age, sex, alcohol use, waist-hip ratio, diabetes, and smoking, with or without measurement of the liver enzyme gamma-glutamyltransferase. The CLivD score can be used as part of health counseling, and for planning further liver investigations and follow-up.

Hemodynamic Effects of Intravenous, High-Dose Lipid Emulsion With and Without Metoprolol Infusion in Healthy Volunteers: A Randomized Clinical Trial.

In a double-blinded, randomized, crossover trial, we investigated the hemodynamic effects of high-dose intravenous lipid emulsion (ILE) with/without metoprolol. Ten healthy volunteers each completed 4 trial days (placebo + ILE; metoprolol + placebo; metoprolol + ILE; placebo + placebo) in random order. Metoprolol was administered as an initial bolus (10 mg), followed by an infusion (50 mg) from 5 to 30 minutes. ILE was administered as a bolus at 12.5 minutes (2.5 mL/kg), followed by a 15-minute infusion (0.25 mL/kg per minute). On metoprolol + ILE days (compared with metoprolol + placebo) after 120 minutes, mean heart rates were significantly higher (difference, 5.5 beats per minute (bpm); 95% confidence interval (CI), 3.0-8.1 bpm; P < 0.001), and average relative cardiac output was higher (difference, 10 percentage points; 95% CI, 5-15 percentage points; P < 0.001). The hemodynamic effect of ILE developed gradually. ILE had no effect on plasma metoprolol or major adverse events. In conclusion, high-dose ILE has relatively marginal and delayed hemodynamic effects that may have limited clinical relevance in the short-term clinical toxicological setting.

[Limited evidence for effect and safety of propranolol for exam-related anxiety].

Propranolol is often prescribed to younger people with exam-related performance anxiety. Evidence for effect as well as safety is, however, sparse for this non-approved indication. Furthermore, only relatively large pack sizes are available in Denmark. This may spur an unnecessary, permanent overuse and increase the risk of overdosing and poisoning. The aim of this review is to examine the evidence for the effect as well as safety of propranolol for exam-related performance anxiety and to discuss, whether the use of this drug for this unapproved indication is rational.

Hemodynamic Effects of Glucagon: A Literature Review.

Context: Glucagon's effects on hemodynamic parameters, most notably heart rate and cardiac contractility, are often overlooked. The glucagon receptor is a central target in novel and anticipated type 2 diabetes therapies, and hemodynamic consequences of glucagon signaling have therefore become increasingly important. In this review, we summarize and evaluate published studies on glucagon pharmacology with a focus on clinical hemodynamic effects in humans. Evidence Acquisition: PubMed, Embase, and the Cochrane Library were searched for clinical studies concerning hemodynamic effects of glucagon (no year restriction). Papers reporting effects of a defined glucagon dose on any hemodynamic parameter were included. Reference searches were conducted in retrieved articles. Evidence Synthesis: Hemodynamic effects of glucagon have been investigated mainly in cohort studies of patients suffering from heart failure receiving large glucagon bolus injections. The identified studies had shortcomings related to restricted patient groups, lack of a control group, randomization, or blinding. We identified no properly conducted randomized clinical trials. The majority of human studies report stimulating effects of pharmacological glucagon doses on heart rate, cardiac contractility, and blood pressure. The effects were characterized by short duration, interindividual variation, and rapid desensitization. Some studies reported no measurable effects of glucagon. Conclusions: The level of evidence regarding hemodynamic effects of glucagon is low, and observations in published studies are inconsistent. Actual effects, interindividual variation, dose-response relationships, and possible long-term effects of supraphysiological glucagon levels warrant further investigation.

The effect of smoking on the urinary excretion of 8-oxodG and 8-oxoGuo in patients with type 2 diabetes.

Over the past decades, attention has been paid to understanding the impact of oxidative stress and related modifications of DNA and RNA on various human health risks. A recent meta-analysis comprising 1915 smokers and 3462 non-smokers found a significantly higher level of DNA oxidation measured as urinary 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG) excretion in smokers compared with non-smokers in a healthy population. We aimed to investigate if an increased urinary excretion of 8-oxodG in smokers versus never smokers and former smokers could be verified in a population with type 2 diabetes. Additionally, we measured RNA oxidation levels through urinary excretion of 8-oxo-7, 8-dihydroguanosine (8-oxoGuo). Our study included urinary samples from 2721 type 2 diabetic patients, analyzed using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Logistic regression was used to examine the relationship between daily smokers (n = 462) versus former (n = 1341) and never smokers (n = 918) regarding the RNA and DNA oxidation, respectively. We did not find any significant effect of smoking on urinary excretion of 8-oxodG or 8-oxoGuo in our study. Due to a sparse study area, it is still too early to draw any conclusions on smoking and RNA-oxidation. Regarding DNA oxidation, our study suggests that the effect of smoking seen in healthy populations might be attenuated in patients with type 2 diabetes.

Simvastatin and oxidative stress in humans: A randomized, double-blinded, placebo-controlled clinical trial.

Simvastatin reduces the blood concentration of cholesterol by inhibiting hydroxymethylglutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis, and thereby reduces the risk of cardiovascular disease. In addition, simvastatin treatment leads to a reduction in fluxes in mitochondrial respiratory complexes I and II and might thereby reduce the formation of reactive oxygen species, which have been implicated in the pathogenesis of arteriosclerosis. Therefore, we hypothesized that simvastatin may reduce oxidative stress in humans in vivo. We conducted a randomized, double-blinded, placebo-controlled study in which subjects were treated with either 40mg of simvastatin or placebo for 14 days. The endpoints were six biomarkers for oxidative stress, which represent intracellular oxidative stress to nucleic acids, lipid peroxidation and plasma antioxidants, that were measured in urine and plasma samples. A total of 40 participants were included, of which 39 completed the trial. The observed differences between simvastatin and placebo groups in the primary outcomes, DNA and RNA oxidation, were small and nonsignificant (p=0.68), specifically, 3% in the simvastatin group compared to 7.1% in the placebo group for DNA oxidation and 7.3% in the simvastatin group compared to 3.4% in the placebo group. The differences in biomarkers related to plasma were not statistically significant between the treatments groups, with the exception of total vitamin E levels, which, as expected, were reduced in parallel with the reduction in plasma cholesterol. In healthy young male volunteers, short-term simvastatin treatment, which considerably reduces cholesterol, does not lead to a clinically relevant reduction in a panel of measures of oxidative stress. Whether simvastatin has effects on oxidative stress in diseased populations, such as diabetes or hemochromatosis, where oxidative stress is prominent, is unknown but seems unlikely.