NAFLD (non-alcoholic fatty liver disease) refers to a wide spectrum of liver damage, ranging from simple steatosis to NASH (non-alcoholic steatohepatitis), advanced fibrosis and cirrhosis. NAFLD is strongly associated with insulin resistance and is defined by accumulation of liver fat >5% per liver weight in the presence of <10 g of daily alcohol consumption. The exact prevalence of NAFLD is uncertain because of the absence of simple non-invasive diagnostic tests to facilitate an estimate of prevalence. In certain subgroups of patients, such as those with Type 2 diabetes, the prevalence of NAFLD, defined by ultrasound, may be as high as 70%. NASH is an important subgroup within the spectrum of NAFLD that progresses over time with worsening fibrosis and cirrhosis, and is associated with increased risk for cardiovascular disease. It is, therefore, important to understand the pathogenesis of NASH and, in particular, to develop strategies for interventions to treat this condition. Currently, the 'gold standard' for the diagnosis of NASH is liver biopsy, and the need to undertake a biopsy has impeded research in subjects in this field. Limited results suggest that the prevalence of NASH could be as high as 11% in the general population, suggesting there is a worsening future public health problem in this field of medicine. With a burgeoning epidemic of diabetes in an aging population, it is likely that the prevalence of NASH will continue to increase over time as both factors are important risk factors for liver fibrosis. The purpose of this review is to: (i) briefly discuss the epidemiology of NAFLD to describe the magnitude of the future potential public health problem; and (ii) to discuss extra- and intra-hepatic mechanisms contributing to the pathogenesis of NAFLD, a better understanding of which may help in the development of novel treatments for this condition.

The epidemic of obesity is largely responsible for the high prevalence of metabolic syndrome in the developed world. Since 2001 with the development of the NCEP metabolic syndrome classification, simple pragmatic criteria have been available that can be applied in primary care across all continents to diagnose the syndrome. Although there is an ongoing debate about the level of thresholds that should be applied to individual features of the syndrome, it is likely that with further research a consensus will be reached in the near future. It is now clear that metabolic syndrome represents a condition of insulin resistance and ectopic fat accumulation associated with a proinflammatory and procoagulant phenotype. The syndrome is sometimes associated with other conditions such as non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome, type 2 diabetes and cardiovascular disease. The purpose of this review is to discuss the clinical and laboratory diagnosis of the metabolic syndrome. The review discusses the various approaches to the investigation of people with the metabolic syndrome. Simple tools for clinical and laboratory diagnosis of metabolic syndrome are described. Some of the more complex biochemical tests that are now being applied in research to the diagnosis of associated conditions, such as NAFLD, are also described.

There is a considerable body of evidence supporting an association between hypertriglyceridaemia, a hypercoagulable state and atherothrombosis. A disorder of triglyceride metabolism is a key feature of the metabolic syndrome that increases risk of both ischaemic heart disease and type 2 diabetes approximately 3-fold. An increasing prevalence of obesity and metabolic syndrome is likely to contribute markedly to the prevalent ischaemic heart in the foreseeable future, and therefore it is crucial to understand mechanisms linking hypertriglyceridaemia and a hypercoagulable state. Activation of platelets and the coagulation cascade are intertwined. VLDL and remnant lipoprotein concentrations are often increased with the metabolic syndrome. These lipoproteins have the capacity to activate platelets and the coagulation pathway, and to support the assembly of the prothrombinase complex. VLDL also upregulates expression of the plasminogen activator inhibitor-1 gene and plasminogen activator inhibitor-1 antigen and activity, a process accompanied by platelet aggregation and clot formation. The surface membrane of activated platelets also supports the assembly and activity of the prothrombinase complex, resulting in further thrombin generation and amplification of the coagulation cascade. Fibrinolysis is also less efficient when thrombin is generated. Thrombin induces thrombin activatable fibrinolysis inhibitor. Thrombin activatable fibrinolysis inhibitor is a carboxypeptidase that cleaves the carboxylic lysine residues on fibrin, thereby abolishing the critical binding site for tPA-plasminogen decreasing plasmin formation. Thus the evidence is supportive of dysregulated coagulation, and impaired fibrinolysis with a predisposition to atherothrombosis, in conditions such as the metabolic syndrome, in which there are increased concentrations of VLDL and remnant lipoproteins. The purpose of this review is to describe the current evidence supporting a procoagulant state induced by VLDL and remnant lipoproteins. The role of these lipoprotein classes in (1) platelet activation; (2) the intrinsic coagulation cascade, and (3) clot formation and fibrinolysis is discussed.

Background: Introduction of inductively coupled plasma mass spectrometry (ICP-MS) into clinical laboratories has led to an increasing application of analyses to risk assessment for toxicity from environmental exposure to trace elements, and in occupational monitoring. Interpretation of results from random urine samples may be problematic and measurement of excretion over 24 h is sometimes preferable. Recent reference data are sparse. Methods: Twenty-four-hour urine samples from 111 healthy adults from the renal stones clinic in Southampton, UK, were analysed for 31 trace elements using ICP-MS and for zinc using atomic absorption spectroscopy. Non-parametric 0.95 coverage intervals were determined for trace element excretion per 24 h and as a ratio to creatinine, for the full study cohort and separately for men (n ¼ 77) and women (n ¼ 34). Results: Beryllium was undetectable in 95% of samples, bismuth in 87% and uranium in 75%. In comparison with published ranges, reference intervals for this cohort were higher for molybdenum, tin and vanadium, and for arsenic due to inclusion of fish arsenicals. Aluminium, chromium, iron, lead and mercury were lower. In our cohort, 24-h excretion of 17 elements was significantly higher in men than in women. However, when expressed as trace element to creatinine ratios, the situation reversed strikingly. Because of their lower creatinine excretion, ratios for 18 elements were significantly higher for women. Conclusions: New adult reference intervals were obtained for 24-h urine trace element excretion. Trace element:creatinine ratios must be used cautiously, with separate ranges for men and women.

Cholesterol is packaged into lipoprotein particles in the liver and intestine and transported to peripheral tissues for normal cellular function. Reverse cholesterol transport is the mechanism by which excess cholesterol is transported back to the liver and is facilitated by high‐density lipoproteins (HDLs). Increased plasma concentrations of cholesterol within the low‐density lipoprotein (LDL) molecule contribute to atherosclerotic vascular disease that commonly affects the coronary, cerebral and peripheral vascular circulation. There is now strong evidence to support the use of the statin class of drugs to decrease the risk of cardiovascular disease. Statins inhibit hepatic cholesterol synthesis, increase hepatic low‐density lipoprotein cholesterol (LDLc) receptor expression and consequently decrease plasma LDLc, to reduce the risk of myocardial infarction in people at widely varying risk of heart disease. At present, there is limited evidence to support the use of alternative classes of lipid‐lowering medications to reduce the risk of cardiovascular disease. Clinical trials are currently ongoing to assess the safety and efficacy of new types of medications to treat dyslipidaemias, the most promising of which are targeted against proprotein convertase subtilysin kexin 9 (PCSK9). Key Concepts Endogenous and exogenous lipid pathways exist within the body. There are both inherited and acquired forms of hypercholesterolaemia. Low‐density lipoprotein cholesterol (LDLc) is associated with the development of coronary heart disease. Disordered lipid metabolism plays a crucial role in the development of atherosclerotic vascular disease. There is much clinical trial evidence now showing the effectiveness of certain classes of lipid‐lowering medication in lowering cholesterol levels and reducing the risk of cardiovascular disease.