Does PEEP impair the hepatic outflow in patients following liver transplantation?

Objective Evaluation of the impact of end-expiratory pressure (PEEP) ventilation on venous liver outflow, portal vein, and hepatic artery flows as well as systemic hemodynamics in patients following liver transplantation (LT).Design Prospective, interventional patient study.Setting University hospital intensive care unit.Patients 65 consecutive patients after LTInterventions All patients were intubated and mechanically ventilated with biphasic positive airway pressure (BIPAP). The effects of three levels of PEEP (0, 5, and 10 mbar) applied at random order on hepatic inflow and outflow were studied in the immediate postoperative period.Measurement and results Central venous-, arterial pressure, and cardiac index was recorded from every patient at three different PEEP levels (0, 5, and 10 mbar). Simultaneously, flow velocities in the hepatic-, portal vein, and hepatic artery were determined by Doppler ultrasound. PEEP of 10 mbar significantly increased central venous pressure in comparison with zero PEEP. Mean arterial pressure and cardiac index was not influenced. Hepatic inflow and outflow of the transplanted livers were not impaired by any of the used PEEP levels.Conclusions BIPAP ventilation with PEEP levels up to 10 mbar does not affect systemic hemodynamics. Furthermore, neither venous outflow nor portal venous or hepatic artery inflow of the liver are impaired at PEEP levels up to 10 mbar immediately following liver transplantation. Although these results suggest that PEEP ventilation up to 10 mbar does not affect liver hemodynamics, further studies are needed to determine whether these findings could be confirmed for a longer ventilation period with PEEP.     

The C-681G polymorphism of the PPAR-γ gene is associated with susceptibility to non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is defined as excessive accumulation of fatty acid in the liver, a common disease in the world. The research of single nucleotide polymorphisms (SNPs) provides a new approach for managing NAFLD. SNPs may increase or decrease the functions of the target genes and their encoding proteins. Peroxisome proliferator-activated receptor (PPAR) plays a key role in modulating metabolism of hepatic triglycerides and consequently magnitude of NAFLD. In this study, we investigated the effect of three SNPs in the PPAR-γ gene i.e. rs10865710 (C-681G), rs7649970 (C-689T) and rs1801282 (C34G, also termed Pro12Ala) on susceptibility to NAFLD. The participants were selected from our epidemiological survey. Totally 169 participants were enrolled in NAFLD group, and 699 healthy subjects were included as controls. PCR-RFLP was applied to detect the SNPs. The G allele frequency of rs10865710 in NAFLD group (41.1%) was significantly higher than that (34.8%) in controls (p = 0.03). Differences in other two loci (rs7649970 and rs1801282) were not statistically significant between the two groups (p > 0.05). This result was confirmed by haplotype analysis. The GCC haplotype (a set of 3 adjacent SNPs in linkage disequilibrium, corresponding to the three alleles of above polymorphisms in order) was a risk factor for the susceptibility to NAFLD (p = 0.03). This study has revealed that the G allele of rs10865710 in the PPAR-γ gene is associated with the increased susceptibility to NAFLD. Our findings may provide novel diagnostic biomarkers and therapeutic targets for NAFLD.     

Adipocyte fatty acid binding protein in a Caucasian population: a new marker of metabolic syndrome?

Adipocyte fatty acid binding protein (A-FABP) has been suggested as playing an important role in the pathogenesis of metabolic syndrome. The aim of this study was to evaluate serum A-FABP as a marker of metabolic syndrome and to assess its predictive accuracy in a Caucasian population. Anthropometric and serum analyses were performed for body mass index (BMI), waist circumference, A-FABP, insulin, triglycerides, total cholesterol, high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c), uric acid, and glucose on 67 non-obese, healthy subjects and 71 subjects with metabolic syndrome. Quicki-quantitative insulin sensitivity check index, receiver operating characteristic curve (ROC-curve) and chi(2) analysis were completed. Compared with healthy controls, subjects with metabolic syndrome had a significantly higher A-FABP serum level (mean: 42.4 vs. 23.7 microg L(-1); P < 0.01). The A-FABP serum level correlated with fasting levels of insulin (r = 0.34; P < 0.01), glucose (r = 0.21; P = 0.01), triglycerides (r = 0.4; P < 0.01), BMI (r = 0.57; P < 0.01) and waist circumference (r = 0.51; P < 0.01), but negatively with HDL-c (r = -0.23; P < 0.01) and Quicki (r = -0.32; P < 0.01). The relationship was defined between serum A-FABP level and metabolic syndrome diagnosis with 40% sensitivity and 99% specificity at A-FABP level 16.4 microg L(-1). Serum A-FABP level might be an independent marker of metabolic syndrome in a Caucasian population.     

Early growth and non-alcoholic fatty liver disease in adulthood—the NAFLD liver fat score and equation applied on the Helsinki Birth Cohort Study

Abstract

Introduction. Prenatal and childhood growth influence the risk of developing the metabolic syndrome and type 2 diabetes. Both conditions are associated with non-alcoholic fatty liver disease (NAFLD). Our aim was to explore the associations between early growth and adult NAFLD.

Methods. We studied 1587 individuals from the Helsinki Birth Cohort Study (HBCS) born 1934–44 for whom birth, childhood, and adult clinical data were available. NAFLD was defined using the NAFLD liver fat score and equation. The score was converted into a dichotomous variable, with outcomes defined as either a positive or negative score. The equation predicts liver fat percentage.

Results. A positive score was found in 43% of men and 22.5% of women. Several measurements of birth and childhood body size were negatively associated with both NAFLD outcomes after adjustment for adult BMI. Those from the smallest BMI tertile at age 2 who were obese in adulthood had an OR of 18.5 for a positive score compared to those from the same group who were normal weight in adulthood.

Conclusions. A larger childhood body size was negatively associated with NAFLD outcomes. Individuals who are small during early childhood and obese as adults seem to be at the highest risk of developing NAFLD.     

Statin-based treatment for cardiovascular risk and non-alcoholic fatty liver disease. Killing two birds with one stone?

Cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD) share common risk factors and may have a parallel course. Statin treatment alone or in combination with other drugs has a substantially beneficial effect on CVD morbidity and mortality. The question was if these regimens were harmful for the liver. Mounting data suggest that statin monotherapy or statin-based treatments are safe in patients with NAFLD and can improve liver tests and liver ultrasonographic evidence of NAFLD. Recent data suggest that statin-based therapies are beneficial to the liver and at the same time reduce CVD morbidity and mortality in patients with NAFLD more than in subjects without it. These findings suggest that with statins we are able to get two birds with one stone.     

Does the metabolic syndrome improve identification of individuals at risk of type 2 diabetes and/or cardiovascular disease?

OBJECTIVE: The metabolic syndrome has been promoted as a method for identifying high-risk individuals for type 2 diabetes and cardiovascular disease (CVD). We therefore sought to compare this syndrome, as defined by the National Cholesterol Education Program, to the Diabetes Predicting Model and the Framingham Risk Score as predictors of type 2 diabetes and CVD, respectively. RESEARCH DESIGN AND METHODS: A population-based sample of 1,709 initially nondiabetic San Antonio Heart Study (SAHS) participants were followed for 7.5 years, 195 of whom developed type 2 diabetes. Over the same time interval, 156 of 2,570 SAHS participants experienced a cardiovascular event. A population-based sample of 1,353 initially nondiabetic Mexico City Diabetes Study (MCDS) participants were followed for 6.5 years, 125 of whom developed type 2 diabetes. Baseline measurements included medical history, age, sex, ethnicity, smoking status, BMI, blood pressure, fasting and 2-h plasma glucose levels, and fasting serum total and HDL cholesterol and triglycerides. RESULTS: The sensitivities for predicting diabetes with the metabolic syndrome were 66.2 and 62.4% in the SAHS and the MCDS, respectively, and the false-positive rates were 27.8 and 38.7%, respectively. The sensitivity and false-positive rates for predicting CVD with the metabolic syndrome in the SAHS were 67.3 and 34.2%, respectively. At corresponding false-positive rates, the two predicting models had significantly higher sensitivities and, at corresponding sensitivities, significantly lower false-positive rates than the metabolic syndrome for both end points. Combining the metabolic syndrome with either predicting model did not improve the prediction of either end point. CONCLUSIONS: The metabolic syndrome is inferior to established predicting models for either type 2 diabetes or CVD.     

Obesity; epiphenomenon or cause of metabolic syndrome?

Metabolic syndrome is a combination of metabolic-related health issues such as hypertension, hyperlipidaemia and hyperinsulinaemia that together increase significantly the risk of cardiovascular disease and type 2 diabetes. Its prevalence has dramatically increased over the last several decades throughout the world following that of obesity. Insulin resistance and abdominal obesity are considered its core, while the latter may generate via complex metabolic and biochemical pathways the rest parameters of metabolic syndrome. The current approach of treatment is based on treating the chronic cardiovascular malfunctions but there is increasing interest in approaches to managing abdominal obesity as the underlying cause.     

Are psychosocial factors associated with the pathogenesis and consequences of cardiovascular disease in the elderly?

It is well known that older individuals are at higher risk of developing cardiovascular disease (CVD). In addition, evidence exists for the relationship between psychosocial factors and the pathogenesis and cognitive consequences of CVD. However, less is known about the effect of psychosocial factors on the development and consequences of CVD in older individuals. Using a biopsychosocial framework, this article examines the influence of psychosocial factors, specifically depression, anxiety, and social isolation on older persons with CVD as well as the influence of CVD on psychosocial factors. The effectiveness of interventions for modifying adverse psychosocial factors is also discussed.     

Are the lipid-modifying effects of fibrates mediated by alterations in plasma lipid transfer activity?

Fenofibrate, a PPAR-alpha (peroxisome-proliferator-activated receptor-alpha) agonist, has been shown to modify plasma lipid and lipoprotein composition and metabolism by a variety of mechanisms. In addition, fenofibrate has been shown to increase the activity of PLTP (phospholipid transfer protein) and to reduce the activity of CETP (cholesteryl ester transfer protein). It is not known, however, whether the changes in PLTP and CETP plasma activity play an active role in the lipid changes observed with fenofibrate therapy, and this is investigated by Watts and co-workers in the present issue of Clinical Science.     

Low insulin sensitivity (S(i) = 0) in diabetic and nondiabetic subjects in the insulin resistance atherosclerosis study: is it associated with components of the metabolic syndrome and nontraditional risk factors?

OBJECTIVE: To determine the meaning of S(i) = 0 derived from the frequently sampled intravenous glucose tolerance test. RESEARCH DESIGN AND METHODS: The issue of assessing insulin resistance in large studies is important because the most definitive method ("gold standard"), the hyperinsulinemic-euglycemic clamp, is expensive and invasive. The frequently sampled intravenous glucose tolerance test (FSIGTT) has been widely used, but in insulin-resistant subjects (especially diabetic subjects), it yields considerable numbers of subjects whose S(i) is zero. The interpretation of an S(i) equaling zero is unknown. RESULTS:-To address this issue, we examined 1482 subjects from the Insulin Resistance Atherosclerosis Study (IRAS) using an insulin-modified FSIGTT and minimal model calculation of S(i). The proportion of insulin-resistant subjects (S(i) < 1.61 x 10(-4) [min(-1). microU(-1) x ml(-1)] based on the median of the nondiabetic population) was 38.6% in subjects with normal glucose tolerance (NGT), 74% in subjects with impaired glucose tolerance (IGT), and 92% in subjects with type 2 diabetes. The proportion of subjects with S(i) = 0 was 2.2% in subjects with NGT, 13.2% in subjects with IGT, and 35.7% in subjects with type 2 diabetes. In subjects with IGT, those with S(i) = 0 had significantly lower HDL cholesterol levels and higher BMI, waist circumference, fibrinogen, plasminogen-activator inhibitor 1 (PAI-1), C-reactive protein (CRP), and 2-h insulin levels than insulin-resistant subjects with S(i) > 0. In type 2 diabetes, subjects with S(i) = 0 had significantly greater BMI and waist circumference and higher triglyceride, PAI-1, CRP, fibrinogen, and fasting and 2-h insulin levels than insulin-resistant subjects with S(i) > 0. In addition, diabetic subjects with S(i) = 0 had more metabolic disorders related to the insulin resistance syndrome than diabetic insulin-resistant subjects with S(i) > 0. CONCLUSIONS: We found very few subjects with S(i) = 0 among subjects with NGT and few subjects with S(i) = 0 among subjects with IGT. In contrast, S(i) = 0 was common in subjects with diabetes. Subjects with S(i) = 0 tended to have more features of the insulin resistance syndrome than other insulin-resistant subjects with S(i) > 0, as would be expected of subjects with almost no insulin-mediated glucose disposal, thus suggesting that subjects with S(i) = 0 are correctly classified as being very insulin resistant rather than having failed the minimal model program.     

Abdominal obesity and metabolic syndrome: exercise as medicine?

Background

Metabolic syndrome is defined as a cluster of at least three out of five clinical risk factors: abdominal (visceral) obesity, hypertension, elevated serum triglycerides, low serum high-density lipoprotein (HDL) and insulin resistance. It is estimated to affect over 20% of the global adult population. Abdominal (visceral) obesity is thought to be the predominant risk factor for metabolic syndrome and as predictions estimate that 50% of adults will be classified as obese by 2030 it is likely that metabolic syndrome will be a significant problem for health services and a drain on health economies.Evidence shows that regular and consistent exercise reduces abdominal obesity and results in favourable changes in body composition. It has therefore been suggested that exercise is a medicine in its own right and should be prescribed as such.

Purpose of this review

This review provides a summary of the current evidence on the pathophysiology of dysfunctional adipose tissue (adiposopathy). It describes the relationship of adiposopathy to metabolic syndrome and how exercise may mediate these processes, and evaluates current evidence on the clinical efficacy of exercise in the management of abdominal obesity. The review also discusses the type and dose of exercise needed for optimal improvements in health status in relation to the available evidence and considers the difficulty in achieving adherence to exercise programmes.

Conclusion

There is moderate evidence supporting the use of programmes of exercise to reverse metabolic syndrome although at present the optimal dose and type of exercise is unknown. The main challenge for health care professionals is how to motivate individuals to participate and adherence to programmes of exercise used prophylactically and as a treatment for metabolic syndrome.

     

What is the metabolic syndrome? Prediabetes and cardiovascular risk

The metabolic syndrome has been referred to as a clustering of cardiovascular risk factors, including abdominal obesity, atherogenic dyslipidemia, increased blood pressure, insulin resistance, proinflammatory state, and a prothrombotic state. The metabolic syndrome has become one of the leading clinical issues discussed by physicians and the media, leading to increased public awareness to this potentially catastrophic multiplex risk factor for cardiovascular disease. With increasing prevalence in the United States, the metabolic syndrome has been equated to cigarette smoking as a contributing factor to premature cardiovascular heart disease and one of the underlying causes of type 2 diabetes. The identification and modification of the root causes, overweight/obesity, physical inactivity, and the closely associated condition, insulin resistance, needs to be one of the initial strategies that are addressed by the clinician.     

Does the association of habitual physical activity with the metabolic syndrome differ by level of cardiorespiratory fitness?

OBJECTIVE: Cardiovascular fitness (VO(2max)) and physical activity are both related to risk of metabolic disease. It is unclear, however, whether the metabolic effects of sedentary living are the same in fit and unfit individuals. The purpose of this study was, therefore, to describe the association between physical activity and the metabolic syndrome and to test whether fitness level modifies this relationship. RESEARCH DESIGN AND METHODS: Physical activity was measured objectively using individually calibrated heart rate against energy expenditure. VO(2max) was predicted from a submaximal exercise stress test. Fat mass and fat-free mass (FFM) were calculated using impedance biometry. A metabolic syndrome score was computed by summing the standardized values for obesity, hypertension, hyperglycemia, insulin resistance, hypertriglyceridemia, and the inverse level of HDL cholesterol and was expressed as a continuously distributed outcome. To correct for exposure measurement error, a random subsample (22% of cohort) re-attended for three repeat measurements in the year following the first assessment. RESULTS: The relationship of VO(2max) (ml O2.kg(FFM)(-1).min(-1)) and the metabolic syndrome score was of borderline significance after adjusting for age, sex, physical activity, and measurement error (beta = -0.58, P = 0.06). The magnitude of the association between physical activity (kJ.d(-1).kg(FFM)(-1)) and the metabolic syndrome was more than three times greater than for VO(2max) (standardized beta = -1.83, P = 0.0042). VO(2max), however, modified the relationship between physical activity energy expenditure and metabolic syndrome (P = 0.036). CONCLUSIONS: This study demonstrates a strong inverse association between physical activity and metabolic syndrome, an association that is much steeper in unfit individuals. Thus, prevention of metabolic disease may be most effective in the subset of unfit inactive people.     

Semaglutide might be a key for breaking the vicious cycle of metabolically associated fatty liver disease spectrum?

Metabolically associated fatty liver disease (MAFLD) is a liver manifestation of metabolic syndrome potentially related to unfavorable hepatic and extrahepatic outcomes and progression to cirrhosis. Up to date, there are no approved pharmacotherapies for the treatment of MAFLD, so management focused on lifestyle interventions to encourage weight loss, and treatment of coexisting conditions is the only available option. Unfortunately, the aforementioned is often not potent enough to offer reversal or slow down hepatic inflammation and fibrosis. Glucagon-like peptide-1 receptor agonists have a favorable effect on glycemic management and weight loss of patients with type 2 diabetes mellitus and recently published data suggest their potential in MAFLD treatment. In addition, some of the agents have proven cardiovascular and renal benefits in dedicated cardiovascular outcome trials, making them an interesting therapeutic option. In this opinion review, we discuss the role of semaglutide in MAFLD.     

Is visceral obesity the cause of the metabolic syndrome?

Despite the fact that controversy remains around the underlying pathophysiological processes leading to the development of the metabolic syndrome (insulin resistance and/or hyperinsulinemia versus abdominal obesity), there is increased recognition that abdominal obesity is the most prevalent form of the metabolic syndrome. Although it has been well established that there is a greater prevalence of chronic metabolic diseases such as diabetes and cardiovascular diseases in obese patients than among normal weight individuals, obesity is a remarkably heterogeneous condition and not every obese patient is characterized by co-morbidities. In this regard, body fat distribution, especially visceral adipose tissue accumulation, has been found to be a major correlate of a cluster of diabetogenic, atherogenic, prothrombotic and proinflammatory metabolic abnormalities referred to as the metabolic syndrome. Due to its anatomic location and peculiar metabolic, hyperlipolytic activity, the expanded visceral adipose depot is a key correlate of the altered cardiometabolic risk profile observed among individuals with a high-risk abdominal obesity phenotype. Evidence suggests that this dysmetabolic profile is predictive of a substantially increased risk of coronary heart disease even in the absence of classical risk factors. Finally, a moderate weight loss in initially abdominally obese patients is associated with a preferential mobilization of visceral adipose tissue, which in turn leads to substantial improvements in the metabolic risk profile predictive of a reduced risk of coronary heart disease and of type 2 diabetes.