Association of 1-deoxy-sphingolipids with steatosis but not steatohepatitis nor fibrosis in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most important cause of chronic liver disease in the western world. Steatosis can be accompanied by inflammation and cell damage (non-alcoholic steatohepatitis, NASH), and even liver fibrosis. Sphingolipids are a heterogeneous class of lipids and essential components of the plasma membrane and plasma lipoproteins. The atypical class of deoxy-sphingolipids has been implicated in the metabolic syndrome and type 2 diabetes. AIM: To determine if circulating (deoxy)sphingolipids are associated with NAFLD and its different entities, steatosis, inflammatory changes (inflammation and ballooning) and fibrosis. METHODS: Sphingolipids were analysed by LC-MS after hydrolysing the N-acyl and O-linked headgroups in plasma of obese adults who underwent a liver biopsy in suspicion of NAFLD. RESULTS: Two-hundred and eighty-eight patients were included. There was no association between typical sphingolipids and NAFLD and its different entities. There was a significant association between the presence of steatosis and the concentrations of deoxy-sphinganine [exp(B) 11.163 with CI (3.432, 36.306) and p < 0.001] and deoxy-sphingosine [exp(B) 8.486 with CI (3.437, 20.949) and p < 0.001]. There was no association between these deoxy-sphingolipids and activity of the steatohepatitis, nor was there any association with fibrosis. Differences in deoxy-sphingolipids also correlated independently with the presence of the metabolic syndrome, but not diabetes. CONCLUSION: Deoxy-sphingolipids are elevated in patients with steatosis compared to those without fatty liver, but not different between the different NAFLD subtypes, suggesting that deoxy-sphingolipid bases might be involved in steatogenesis, but not in the further progression of NAFLD to NASH nor in fibrogenesis.

Correction: Plasma 1-deoxysphingolipids are early predictors of incident type 2 diabetes mellitus.

[This corrects the article DOI: 10.1371/journal.pone.0175776.].

Plasma 1-deoxysphingolipids are early predictors of incident type 2 diabetes mellitus.

1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids, which are formed in a side reaction during sphingolipid de-novo synthesis. Recently, we demonstrated that 1-deoxySLs are biomarkers for the prediction of T2DM in obese, non-diabetic patients. Here we investigated the relevance of 1-deoxySLs as long-term predictive biomarkers for the incidence of T2DM in an asymptomatic population. Here, we analyzed the plasma sphingoid base profile in a nested group of non-diabetic individuals (N = 605) selected from a population-based study including 5 year follow-up data (CoLaus study). 1-DeoxySLs at baseline were significantly elevated in individuals who developed T2DM during the follow-up (p<0.001), together with increased glucose (p<5.11E-14), triglycerides (p<0.001) and HOMA-IR indices (p<0.001). 1-Deoxy-sphinganine (1-deoxySA) and 1-deoxy-sphingosine (1-deoxySO) were predictive for T2DM, even after adjusting for fasting glucose levels in the binary regression analyses. The predictive value of the combined markers 1-deoxySA+glucose were superior to glucose alone in normal-weight subjects (p<0.001) but decreased substantially with increasing BMI. Instead, plasma adiponectin and waist-to-hip ratio appeared to be better risk predictors for obese individuals (BMI>30kg/m2). In conclusion, elevated plasma 1-deoxySL levels are strong and independent risk predictors of future T2DM, especially for non-obese individuals in the general population.

Can LDL cholesterol be too low? Possible risks of extremely low levels.

Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.

[Clinical importance of HDL cholesterol]. / Klinische Bedeutung des HDL-Cholesterins.

BACKROUND: Each year 16-17 million determinations of high-density lipoprotein cholesterol (HDL-C) are conducted and interpreted in Germany. Recently acquired data have led to a fundamental reassessment of the clinical significance of HDL-C. METHOD: This review article is based on a selective literature search. RESULTS: Low HDL­C levels usually indicate an increased cardiovascular risk, particularly in primary prevention but the epidemiological relationship between HDL­C and the risk is complex. The HDL plays a role in the back transport and excretion of cholesterol; however, the biological functions of HDL are dependent on the protein and lipid composition, which is not reflected by the HDL­C concentration. If the composition of HDL is pathologically altered it can also exert negative vascular effects. CONCLUSION: Compared with low-density lipoprotein cholesterol (LDL-C), HDL­C is of secondary importance for cardiovascular risk stratification and the calculation of the LDL-C:HDL­C ratio is not useful for all patients. Low HDL­C levels should prompt a search for additional metabolic and inflammatory pathologies. An increase in HDL­C through lifestyle changes (e.g. smoking cessation and physical exercise) has positive effects and is recommended; however, HDL­C is currently not a valid target for drug therapy.

Effect of Twice-Yearly Denosumab on Prevention of Bone Mineral Density Loss in De Novo Kidney Transplant Recipients: A Randomized Controlled Trial.

We conducted an open-label, prospective, randomized trial to assess the efficacy and safety of RANKL inhibition with denosumab to prevent the loss of bone mineral density (BMD) in the first year after kidney transplantation. Ninety kidney transplant recipients were randomized 1:1 2 weeks after surgery to receive denosumab (60 mg at baseline and 6 months) or no treatment. After 12 months, total lumbar spine areal BMD (aBMD) increased by 4.6% (95% confidence interval [CI] 3.3-5.9%) in 46 patients in the denosumab group and decreased by -0.5% (95% CI -1.8% to 0.9%) in 44 patients in the control group (between-group difference 5.1% [95% CI 3.1-7.0%], p < 0.0001). Denosumab also increased aBMD at the total hip by 1.9% (95% CI, 0.1-3.7%; p = 0.035) over that in the control group at 12 months. High-resolution peripheral quantitative computed tomography in a subgroup of 24 patients showed that denosumab increased volumetric BMD at the distal tibia and radius (all p < 0.05). Biomarkers of bone turnover (C-terminal telopeptide of type I collagen, procollagen type I N-terminal propeptide) markedly decreased with denosumab (all p < 0.0001). Episodes of cystitis and asymptomatic hypocalcemia occurred more often with denosumab, whereas graft function, rate of rejections, and incidence of opportunistic infections were similar. In conclusion, denosumab increased BMD in the first year after kidney transplantation but was associated with more frequent episodes of urinary tract infection.

Gender-Related Differences in Patients Presenting with Suspected Acute Coronary Syndromes: Clinical Presentation, Biomarkers and Diagnosis.

OBJECTIVES: Gender differences in patients presenting with suspected acute coronary syndromes (ACS) have not yet been fully characterized. The aim of this study was to assess gender-related disparities in clinical profiles, biomarkers and diagnoses of patients with suspected ACS. METHODS: This single-centre, prospective cohort study included 377 consecutive patients presenting with suspected ACS to the emergency department. Suspected ACS was defined as a request for conventional troponin T (c-cTnT) measurements on clinical grounds. RESULTS: Women were older than men (p = 0.004), and had a lower prevalence of known coronary artery and peripheral vascular disease (p < 0.05). c-cTnT was positive in 8% of female and in 14% of male patients (p = 0.16), TIMI risk score and cardiac biomarkers including c-cTnT, hs-cTnT, myoglobin, creatine kinase, N-terminal pro-brain natriuretic peptide, myeloid-related protein 8/14 and pregnancy-associated plasma protein A were lower in women (p < 0.05). Women were less frequently diagnosed with ACS (30 vs. 51%), and were not referred for urgent coronary angiography as often as men (p < 0.001). In multivariate analysis, female gender was associated with a lower referral for coronary angiography (HR 0.41, 95% CI 0.23-0.78, p = 0.006). CONCLUSIONS: In patients with suspected ACS, women presented with different biomarker profiles, and were less often diagnosed with ACS and referred to coronary angiography.

[New AHA and ACC guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk : Statement of the D•A•CH Society for Prevention of Cardiovascular Diseases, the Austrian Atherosclerosis Society and the Working Group on Lipids and Atherosclerosis (AGLA) of the Swiss Society for Cardiology]. / Neue AHA- und ACC-Leitlinie zur Risikoreduktion von Herz-Kreislauf-Erkrankungen durch Cholesterinsenkung : Stellungnahme der D•A•CH-Gesellschaft Prävention von Herz-Kreislauf-Erkrankungen e. V., der Österreichischen Atherosklerose Gesellschaft und der Arbeitsgruppe Lipide und Atherosklerose (AGLA) der Schweizer Gesellschaft für Kardiologie.

Guidelines for the reduction of cholesterol to prevent atherosclerotic vascular events were recently released by the American Heart Association and the American College of Cardiology. The authors claim to refer entirely to evidence from randomized controlled trials, thereby confining their guidelines to statins as the primary therapeutic option. The guidelines derived from these trials do not specify treatment goals, but refer to the percentage of cholesterol reduction by statin medication with low, moderate, and high intensity. However, these targets are just as little tested in randomized trials as are the cholesterol goals derived from clinical experience. The same applies to the guidelines of the four patient groups which are defined by vascular risk. No major statin trial has included patients on the basis of their global risk; thus the allocation criteria are also arbitrarily chosen. These would actually lead to a significant increase in the number of patients to be treated with high or maximum dosages of statins. Also, adhering to dosage regulations instead of cholesterol goals contradicts the principles of individualized patient care. The option of the new risk score to calculate lifetime risk up to the age of 80 years in addition to the 10-year risk can be appreciated. Unfortunately it is not considered in the therapeutic recommendations provided, despite evidence from population and genetic studies showing that even a moderate lifetime reduction of low-density lipoprotein (LDL) cholesterol or non-HDL cholesterol has a much stronger effect than an aggressive treatment at an advanced age. In respect to secondary prevention, the new American guidelines broadly match the European guidelines. Thus, the involved societies from Germany, Austria and Switzerland recommend continuing according to established standards, such as the EAS/ESC guidelines.

Before and after hip fracture, vitamin D deficiency may not be treated sufficiently.

UNLABELLED: Our findings show that only about 20% of seniors receive vitamin D supplementation prior to their index hip fracture or after the event. We further confirm the high prevalence of severe vitamin D deficiency in this population and show that those who receive supplementation have significantly higher 25-hydroxyvitamin D (25(OH)D) status. INTRODUCTION: The aim of this study is to assess current practice in pre- and post-hip fracture care practice with respect to vitamin D supplementation. METHODS: We surveyed 1,090 acute hip fracture patients age 65 and older admitted to acute care for hip fracture repair; 844 had serum 25-hydroxyvitamin D levels measured upon admission to acute care, and 362 agreed to be followed at 12 month after their hip fracture. Prevalence of vitamin D supplementation was assessed upon admission to acute care (at the time of hip fracture), upon discharge from acute care, and at 6 and 12 months follow-up. RESULTS: Of 1,090 acute hip fracture patients (mean age 85 years, 78% women, 59 % community-dwelling), 19% had received any dose of vitamin D prior to the index hip fracture, 27% (of 854 assessed) at discharge from acute care, 22 % (of 321 assessed) at 6 month, and 21% (of 285 assessed) at 12 month after their hip fracture. At the time of fracture, 45% had 25(OH)D levels below 10 ng/ml, 81% had levels below 20 ng/ml, and 96% had levels below 30 ng/ml. Notably, 25(OH)D levels did not differ by season or gender but were significantly higher among 164 hip fracture patients, with any vitamin D supplementation compared with 680 without supplementation (19.9 versus 10.8 ng/ml; p < 0.0001). CONCLUSION: Only about 20% of seniors receive vitamin D at the time of their fracture and after the event. This is despite the documented 81% prevalence of vitamin D deficiency. Interdisciplinary efforts may be warranted to improve vitamin D supplementation in seniors both before a hip fracture occurs and after.

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

AIMS/HYPOTHESIS: Sphingolipid synthesis is typically initiated by the conjugation of L-serine and palmitoyl-CoA, a reaction catalysed by serine palmitoyltransferase (SPT). SPT can also metabolise other acyl-CoAs (C(12) to C(18)) and other amino acids such as L-alanine and glycine, giving rise to a spectrum of atypical sphingolipids. Here, we aimed to identify changes in plasma levels of these atypical sphingolipids to explore their potential as biomarkers in the metabolic syndrome and diabetes. METHODS: We compared the plasma profiles of ten sphingoid bases in healthy individuals with those of patients with the metabolic syndrome but not diabetes, and diabetic patients (n = 25 per group). The results were verified in a streptozotocin (STZ) rat model. Univariate and multivariate statistical analyses were used. RESULTS: Deoxysphingolipids (dSLs) were significantly elevated (p = 5 × 10⁻6) in patients with the metabolic syndrome (0.11 ± 0.04 µmol/l) compared with controls (0.06 ± 0.02 µmol/l) but did not differ between the metabolic syndrome and diabetes groups. Levels of C(16)-sphingosine-based sphingolipids were significantly lowered in diabetic patients but not in patients with the metabolic syndrome but without diabetes (p = 0.008). Significantly elevated dSL levels were also found in the plasma and liver of STZ rats. A principal component analysis revealed a similar or even closer association of dSLs with diabetes and the metabolic syndrome in comparison with the established biomarkers. CONCLUSIONS/INTERPRETATION: We showed that dSLs are significantly elevated in patients with type 2 diabetes mellitus and non-diabetic metabolic syndrome compared with healthy controls. They may, therefore, be useful novel biomarkers to improve risk prediction and therapy monitoring in these patients.

Excellent agreement between genetic and hydrogen breath tests for lactase deficiency and the role of extended symptom assessment.

Clinical manifestations of lactase (LCT) deficiency include intestinal and extra-intestinal symptoms. Lactose hydrogen breath test (H2-BT) is considered the gold standard to evaluate LCT deficiency (LD). Recently, the single-nucleotide polymorphism C/T(-13910) has been associated with LD. The objectives of the present study were to evaluate the agreement between genetic testing of LCT C/T(-13910) and lactose H2-BT, and the diagnostic value of extended symptom assessment. Of the 201 patients included in the study, 194 (139 females; mean age 38, range 17-79 years, and 55 males, mean age 38, range 18-68 years) patients with clinical suspicion of LD underwent a 3-4 h H2-BT and genetic testing for LCT C/T(-13910). Patients rated five intestinal and four extra-intestinal symptoms during the H2-BT and then at home for the following 48 h. Declaring H2-BT as the gold standard, the CC(-13910) genotype had a sensitivity of 97% and a specificity of 95% with a κ of 0.9 in diagnosing LCT deficiency. Patients with LD had more intense intestinal symptoms 4 h following the lactose challenge included in the H2-BT. We found no difference in the intensity of extra-intestinal symptoms between patients with and without LD. Symptom assessment yielded differences for intestinal symptoms abdominal pain, bloating, borborygmi and diarrhoea between 120 min and 4 h after oral lactose challenge. Extra-intestinal symptoms (dizziness, headache and myalgia) and extension of symptom assessment up to 48 h did not consistently show different results. In conclusion, genetic testing has an excellent agreement with the standard lactose H2-BT, and it may replace breath testing for the diagnosis of LD. Extended symptom scores and assessment of extra-intestinal symptoms have limited diagnostic value in the evaluation of LD.

Lack of association between iron metabolism and depressive mood in an elderly general population.

BACKGROUND: Alterations in iron metabolism have been suggested as potential pathological markers in patients with manifest depression. No data on the association between iron and depression exist from population-based studies, in which milder forms of depressive symptoms are much more common. The aim of this study was to analyze the relationship between six parameters of iron metabolism and depressive mood in a population-based cross-sectional study in Germany. METHODS: A total of 374 participants, aged 65-83 years, of the Memory and Morbidity in Augsburg Elderly (MEMO) Study were assessed using the Center for Epidemiologic Studies - Depression Scale (CES-D) for depression. Iron, ferritin, transferrin, soluble transferrin receptor, iron binding capacity, transferrin saturation and C-reactive protein were analyzed with standard laboratory methods. Linear and logistic regression analyses were applied to evaluate the relationship between iron parameters and depressive mood. RESULTS: The 7-day prevalence of depressive mood was 10.2%, with a higher risk in women compared to men [odds ratio (OR) = 2.04; 95% confidence interval (95% CI) = 1.04-4.0]. Correlation and linear regression analyses adjusted for age, gender, hypertension and smoking yielded no significant relationship between any of the iron parameters and the CES-D scores. In gender-stratified analyses a statistically significant association between serum iron and depressive mood was observed in men only. This finding disappeared after applying a Bonferroni correction for multiple testing. CONCLUSIONS: The lack of association of iron metabolism and depressive mood reported in this population-based study does not support previous findings in patients with major depression. This negative finding in milder forms of depression in elderly people indicates either the absence or a more complex nature of the interactions between iron metabolism, low-grade inflammation and depression.

[Comparison of international recommendations for the recognition of asymptomatic high risk patients for a heart attack in Germany]. / Vergleich internationaler Konsensus-Empfehlungen zur Erkennung des präsymptomatischen Hochrisikopatienten für den Herzinfarkt in Deutschland.

The recommendations of the International Task Force for the Prevention of Coronary Heart Disease/International Atherosclerosis Society (ITF/IAS), the US-American Adult Treatment Panel III of the National Cholesterol Education Programs (ATP III) and the 3rd Joint European Guidelines (3JE) for the prevention coronary heart disease (CHD) show good agreement in tertiary prevention. All three guidelines recommend that patients with manifest CHD should have a blood pressure below 140/90 mm Hg and LDL-cholesterol below 2.6 mmol/l (100 mg/dl). By contrast, the three recommendations differ with respect to the prevention of cardiovascular events in asymptomatic high risk patients (secondary prevention), notably in the strategy to be used for risk assessment. Both the ITF/IAS guidelines and the 3JE guidelines can be adapted and realized in the various European countries. We therefore compared the prognostic values of the three recommendations by applying them to the data of male participants of the Prospective Cardiovascular Munster (PROCAM) Study. The ITF/IAS recommendations show the highest specificity (94.5%), positive predictive value (32.0%) and diagnostic efficacy (90.5%); the 3JE guidelines have the highest sensitivity (64.6%) but lowest specificity (77.9%), positive predictive value (17.5%) and diagnostic efficacy (77.0%). The application of the 3JE recommendations would target 25% of German men aged 35-65 years as cardiovascular high risk patients, by contrast to 7.5% through application of the ITF/IAS guidelines. In view of the limited resources in the public health systemthe application of the ITF/IAS guidelines in Germany appears more appropriate.