Current status and future trends of the global burden of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common chronic liver disease globally, affecting more than a third of the world's adult population. This comprehensive narrative review summarizes the global incidence and prevalence rates of MASLD and its related adverse hepatic and extrahepatic outcomes. We also discuss the substantial economic burden of MASLD on healthcare systems, thus further highlighting the urgent need for global efforts to tackle this common and burdensome liver condition. We emphasize the clinical relevance of early interventions and a holistic approach that includes public health strategies to reduce the global impact of MASLD.

A multicomponent holistic care pathway for people who use drugs in Tayside, Scotland.

BACKGROUND: People Who Use Drugs (PWUD) are at high risk of non-fatal overdose and other drug-related harms. The United Kingdom drugs policy landscape makes it challenging to support those at risk. Tayside, in East Scotland, has a sizeable population at risk of drug-related harms. In 2021, the National Health Service implemented a care pathway for PWUD to provide multidimensional healthcare interventions. We aimed to quantify drug-related harms; assess wider health and well-being; and understand substance use trends and behaviours, among those engaged in the pathway. METHODS: Existing community-embedded blood-borne virus pathways were adapted to provide multiple healthcare assessments over three visits. We undertook an observational cohort study to analyse uptake and outcomes for the initial cohort of PWUD engaged at appointment one. RESULTS: From August 2021-September 2022, 150 PWUD engaged with the pathway. Median age was 39 (34-42) years, 108 (72%) were male, and 124 (83%) lived in deprived areas. Seventy (47%) had been disengaged from healthcare for over a year. Polysubstance use was reported by 124 (83%), 42 (28%) disclosed injecting daily, and 54 (36%) shared equipment. Fifty-four (36%) experienced recent non-fatal overdose, and there were six overdose fatalities (4.1 [1.5-9.0] per 100PY). The offer of take-home naloxone was accepted by 108 (72%). Fourteen (9%) were diagnosed with Hepatitis C and two (1%) with HIV. Renal, hepatological, and endocrine impairment were observed among 30 (20%), 23 (15%), and 11 (7%), people respectively. Ninety-six (65%) had high risk of clinical depression. Forty-eight (32%) declined Covid-19 vaccination. CONCLUSION: The pathway engaged PWUD with high exposure to recent non-fatal overdose and other drug-related harms, alongside co-morbid health issues. Our results suggest multi-dimensional health assessments coupled with harm reduction in community settings, with appropriate linkage to care, are warranted for PWUD. Service commissioners should seek to integrate these assessments where possible.

Alcohol consumption and metabolic syndrome: Clinical and epidemiological impact on liver disease.

Alcohol use and metabolic syndrome are highly prevalent in the population and frequently co-exist. Both are implicated in a large range of health problems, including chronic liver disease, hepatocellular carcinoma, and liver-related outcomes (i.e. decompensation or liver transplantation). Studies have yielded mixed results regarding the effects of mild-moderate alcohol consumption on the risk of metabolic syndrome and fatty liver disease, possibly due to methodological differences. The few available prospective studies have indicated that mild-moderate alcohol use is associated with an increase in liver-related outcomes. This conclusion was substantiated by systems biology analyses suggesting that alcohol and metabolic syndrome may play a similar role in fatty liver disease, potentiating an already existing dysregulation of common vital homeostatic pathways. Alcohol and metabolic factors are independently and jointly associated with liver-related outcomes. Indeed, metabolic syndrome increases the risk of liver-related outcomes, regardless of alcohol intake. Moreover, the components of metabolic syndrome appear to have additive effects when it comes to the risk of liver-related outcomes. A number of population studies have implied that measures of central/abdominal obesity, such as the waist-to-hip ratio, can predict liver-related outcomes more accurately than BMI, including in individuals who consume harmful quantities of alcohol. Many studies even point to synergistic interactions between harmful alcohol use and many metabolic components. This accumulating evidence showing independent, combined, and modifying effects of alcohol and metabolic factors on the onset and progression of chronic liver disease highlights the multifactorial background of liver disease in the population. The available evidence suggests that more holistic approaches could be useful for risk prediction, diagnostics and treatment planning.

Incorporating fatty liver disease in multidisciplinary care and novel clinical trial designs for patients with metabolic diseases.

With the global epidemics of obesity and associated conditions, including type 2 diabetes, metabolic dysfunction-associated fatty liver disease, chronic kidney disease, hypertension, stroke, cardiovascular disease, osteoporosis, cancer, and cognitive changes, the prevalence of multimorbidity is rapidly increasing worldwide. In this Review, a panel of international experts from across the spectrum of metabolic diseases come together to identify the challenges and provide perspectives on building a framework for a virtual primary care-driven, patient-centred, multidisciplinary model to deliver holistic care for patients with metabolic dysfunction-associated fatty liver disease and associated metabolic diseases. We focus on clinical care and innovative trial design for metabolic dysfunction-associated fatty liver disease and associated metabolic diseases. This work represents a call to action to promote collaboration and partnerships between stakeholders for improving the lives of people with, or at risk of, metabolic dysfunction-associated fatty liver disease and associated metabolic diseases.

Non-alcoholic fatty liver disease: a multisystem disease requiring a multidisciplinary and holistic approach.

Non-alcoholic fatty liver disease (NAFLD) is a public health problem worldwide. This narrative Review provides an overview of the current literature to support the notion that NAFLD is a multisystem disease. Convincing evidence shows a strong association between NAFLD and the risk of developing multiple extrahepatic complications such as type 2 diabetes, cardiovascular disease (ie, the predominant cause of mortality in people with NAFLD), chronic kidney disease, and some types of extrahepatic malignancies. The magnitude of this risk parallels the severity of NAFLD (especially the stage of liver fibrosis). There are probably multiple underlying mechanisms by which NAFLD might increase the risk of cardiovascular disease, type 2 diabetes, and extrahepatic complications. Addressing the growing burden of NAFLD will require setting up a multidisciplinary working group and framework to progress and embrace novel collaborative ways of working to deliver holistic, person-centred care and management of people with NAFLD.

Managing hyperlipidaemia in patients with COVID-19 and during its pandemic: An expert panel position statement from HEART UK.

The emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes Coronavirus Disease 2019 (COVID-19) has resulted in a pandemic. SARS-CoV-2 is highly contagious and its severity highly variable. The fatality rate is unpredictable but is amplified by several factors including advancing age, atherosclerotic cardiovascular disease, diabetes mellitus, hypertension and obesity. A large proportion of patients with these conditions are treated with lipid lowering medication and questions regarding the safety of continuing lipid-lowering medication in patients infected with COVID-19 have arisen. Some have suggested they may exacerbate their condition. It is important to consider known interactions with lipid-lowering agents and with specific therapies for COVID-19. This statement aims to collate current evidence surrounding the safety of lipid-lowering medications in patients who have COVID-19. We offer a consensus view based on current knowledge and we rated the strength and level of evidence for these recommendations. Pubmed, Google scholar and Web of Science were searched extensively for articles using search terms: SARS-CoV-2, COVID-19, coronavirus, Lipids, Statin, Fibrates, Ezetimibe, PCSK9 monoclonal antibodies, nicotinic acid, bile acid sequestrants, nutraceuticals, red yeast rice, Omega-3-Fatty acids, Lomitapide, hypercholesterolaemia, dyslipidaemia and Volanesorsen. There is no evidence currently that lipid lowering therapy is unsafe in patients with COVID-19 infection. Lipid-lowering therapy should not be interrupted because of the pandemic or in patients at increased risk of COVID-19 infection. In patients with confirmed COVID-19, care should be taken to avoid drug interactions, between lipid-lowering medications and drugs that may be used to treat COVID-19, especially in patients with abnormalities in liver function tests.

Marine omega-3 fatty acid supplementation in non-alcoholic fatty liver disease: Plasma proteomics in the randomized WELCOME* trial.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a liver condition characterised by liver fat accumulation and often considered to be the liver manifestation of metabolic syndrome. The aim of this study was to examine in patients with NAFLD the system-wide effects of treatment with docosahexaenoic acid + eicosapentaenoic acid (DHA + EPA) versus placebo on the plasma proteome. METHODS: Plasma from patients that participated in a 15-18 months randomised, double-blind placebo-controlled trial testing the effects of 4 g DHA + EPA daily was analysed using depletion-free quantitative proteomics. RESULTS: Bioinformatics interpretation of the proteomic analysis showed that DHA + EPA treatment affected pathways involving blood coagulation, immune/inflammatory response and cholesterol metabolism (p < 0.05). Two key proteins of cardiovascular risk, prothrombin and apolipoprotein B-100, were shown to decrease as a result of DHA + EPA supplementation [Prothrombin: Males DHA + EPA Mean iTRAQ log2ratio (SD) = -0.13 (0.20) p = 0.05, Females DHA + EPA Mean iTRAQ log2ratio (SD) = -0.48 (0.35) p = 0.03; Apo B-100: Males DHA + EPA Mean iTRAQ log2ratio (SD) = -0.24 (0.16) p = 0.01, Females DHA + EPA Mean iTRAQ log2ratio (SD) = -0.15 (0.05) p = 0.02]. CONCLUSIONS: Plasma proteomics applied in a randomised, placebo-controlled trial showed that high dose DHA + EPA treatment in patients with NAFLD affects multiple pathways involved in chronic non-communicable diseases.

Omega-3 fatty acids and non-alcoholic fatty liver disease: Evidence of efficacy and mechanism of action.

For many years it has been known that high doses of long chain omega-3 fatty acids are beneficial in the treatment of hypertriglyceridaemia. Over the last three decades, there has also been a wealth of in vitro and in vivo data that has accumulated to suggest that long chain omega-3 fatty acid treatment might be beneficial to decrease liver triacylglycerol. Several biological mechanisms have been identified that support this hypothesis; notably, it has been shown that long chain omega-3 fatty acids have a beneficial effect: a) on bioactive metabolites involved in inflammatory pathways, and b) on alteration of nuclear transcription factor activities such as peroxisome proliferator-activated receptors (PPARs), sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP), involved in inflammatory pathways and liver lipid metabolism. Since the pathogenesis of non alcoholic fatty liver disease (NAFLD) begins with the accumulation of liver lipid and progresses with inflammation and then several years later with development of fibrosis; it has been thought in patients with NAFLD omega-3 fatty acid treatment would be beneficial in treating liver lipid and possibly also in ameliorating inflammation. Meta-analyses (of predominantly dietary studies and small trials) have tended to support the assertion that omega-3 fatty acids are beneficial in decreasing liver lipid, but recent randomised controlled trials have produced conflicting data. These trials have suggested that omega-3 fatty acid might be beneficial in decreasing liver triglyceride (docosahexanoic acid also possibly being more effective than eicosapentanoic acid) but not in decreasing other features of steatohepatitis (or liver fibrosis). The purpose of this review is to discuss recent evidence regarding biological mechanisms by which long chain omega-3 fatty acids might act to ameliorate liver disease in NAFLD; to consider the recent evidence from randomised trials in both adults and children with NAFLD; and finally to discuss key 'known unknowns' that need to be considered, before planning future studies that are focussed on testing the effects of omega-3 fatty acid treatment in patients with NAFLD.

Platelet rich Plasma in Achilles Tendon Healing 2 (PATH-2) trial: protocol for a multicentre, participant and assessor-blinded, parallel-group randomised clinical trial comparing platelet-rich plasma (PRP) injection versus placebo injection for Achilles tendon rupture.

BACKGROUND: Achilles tendon injuries give rise to substantial long-lasting morbidity and pose considerable challenges for clinicians and patients during the lengthy healing period. Current treatment strategies struggle to curb the burden of this injury on health systems and society due to lengthy rehabilitation, work absence and reinjury risk. Platelet-rich plasma (PRP) is an autologous preparation that has been shown to improve the mechanobiological properties of tendons in laboratory and animal studies. The use of PRP in musculoskeletal injuries is on the increase despite the lack of adequately powered clinical studies. METHODS AND DESIGN: This is a multicentre randomised controlled trial to evaluate the efficacy and mechanism of PRP in patients with acute Achilles tendon rupture (ATR). All adults with acute ATR presenting within 12 days of the injury who are to be treated non-operatively are eligible. A total of 230 consenting patients will be randomly allocated via a remote web-based service to receive PRP injection or placebo injection to the site of the injury. All participants will be blinded to the intervention and will receive standardised rehabilitation to reduce efficacy interference.Participants will be followed up with blinded assessments of muscle-tendon function, quality of life, pain and overall patient's functional goals at 4, 7, 13, 24 weeks and 24 months post-treatment. The primary outcome is the heel-rise endurance test (HRET), which will be supervised by a blinded assessor at 24 weeks. A subgroup of 16 participants in one centre will have needle biopsy under ultrasound guidance at 6 weeks. Blood and PRP will be analysed for cell count, platelet activation and growth factor concentrations. ETHICS AND DISSEMINATION: The protocol has been approved by the Oxfordshire Research Ethics Committee (Oxfordshire Research Ethics Committee A, reference no 14/SC/1333). The trial will be reported in accordance with the CONSORT statement and published in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: ISRCTN: 54992179, assigned 12 January 2015. ClinicalTrials.gov: NCT02302664, received 18 November 2014. UK Clinical Research Network Study Portfolio Database: ID 17850.

Mulberry-extract improves glucose tolerance and decreases insulin concentrations in normoglycaemic adults: Results of a randomised double-blind placebo-controlled study.

BACKGROUND: High sugar and refined carbohydrate intake is associated with weight gain, increased incidence of diabetes and is linked with increased cardiovascular mortality. Reducing the health impact of poor quality carbohydrate intake is a public health priority. Reducose, a proprietary mulberry leaf extract (ME), may reduce blood glucose responses following dietary carbohydrate intake by reducing absorption of glucose from the gut. METHODS: A double-blind, randomised, repeat measure, phase 2 crossover design was used to study the glycaemic and insulinaemic response to one reference product and three test products at the Functional Food Centre, Oxford Brooks University, UK. Participants; 37 adults aged 19-59 years with a BMI ≥ 20kg/m2 and ≤ 30kg/m2. The objective was to determine the effect of three doses of mulberry-extract (Reducose) versus placebo on blood glucose and insulin responses when co-administered with 50g maltodextrin in normoglycaemic healthy adults. We also report the gastrointestinal tolerability of the mulberry extract. RESULTS: Thirty-seven participants completed the study: The difference in the positive Incremental Area Under the Curve (pIAUC) (glucose (mmol / L x h)) for half, normal and double dose ME compared with placebo was -6.1% (-18.2%, 5.9%; p = 0.316), -14.0% (-26.0%, -2.0%; p = 0.022) and -22.0% (-33.9%, -10.0%; p<0.001) respectively. The difference in the pIAUC (insulin (mIU / L x h)) for half, normal and double dose ME compared with placebo was -9.7% (-25.8%, 6.3%; p = 0.234), -23.8% (-39.9%, -7.8%; p = 0.004) and -24.7% (-40.8%, -8.6%; p = 0.003) respectively. There were no statistically significant differences between any of the 4 groups in the odds of experiencing one or more gastrointestinal symptoms (nausea, abdominal cramping, distension or flatulence). CONCLUSIONS: Mulberry leaf extract significantly reduces total blood glucose rise after ingestion of maltodextrin over 120 minutes. The pattern of effect demonstrates a classical dose response curve with significant effects over placebo. Importantly, total insulin rises were also significantly suppressed over the same time-period. There were no statistically significant differences between any of the treatment groups (including placebo) in the odds of experiencing one or more gastrointestinal symptoms. Mulberry extract may have multiple modes of action and further studies are necessary to evaluate ME as a potential target for the prevention of type 2 diabetes and the regulation of dysglycaemia.

Higher body fat percentage is associated with enhanced temperature perception in NAFLD: results from the randomised Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD with OMacor thErapy trial (WELCOME) trial.

AIMS/HYPOTHESIS: The effect of n-3 fatty acid treatment on temperature perception as a sensory nerve function modality is uncertain. In patients with non-alcoholic fatty liver disease (NAFLD) both with and without type 2 diabetes, we: (1) tested whether 15-18 months' treatment with 4 g/day of docosahexaenoic plus eicosapentaenoic acid (DHA+EPA) improved hot (HPT) and cold (CPT) temperature perception thresholds and (2) explored factors associated with HPT and CPT, in a randomised, double-blind, placebo-controlled trial. METHODS: The effect of treatment (n = 44) on HPT, CPT and temperature perception index (TPI: difference between HPT and CPT) was measured at the big toe in 90 individuals without neuropathy (type 2 diabetes; n = 30). Participants were randomised 1:1, using sequential numbering, by personnel independent from the trial team. All participants and all members of the research team were blinded to group assignment. Data were collected in the Southampton National Institute for Health Research Biomedical Research Centre. Treatment effects and the independence of associations were testing by regression modelling. RESULTS: Mean ± SD age was 50.9 ± 10.6 years. In men (n = 53) and women (n = 37), HPTs (°C) were 46.1 ± 5.1 and 43.1 ± 6.4 (p = 0.02), CPTs (°C) were 22.7 ± 3.4 and 24.5 ± 3.6 (p = 0.07) and TPIs (°C) were 23.4 ± 7.4 and 18.7 ± 9.5 (p = 0.008), respectively. In univariate analyses, total body fat percentage (measured by dual-energy x-ray absorptiometry [DXA]) was associated with HPT (r = -0.36 p = 0.001), CPT (r = 0.35 p = 0.001) and TPI (r = 0.39 p = 0.0001). In multivariable-adjusted regression models, adjusting for age, sex and other potential confounders, only body fat percentage was independently associated with HPT, CPT or TPI (p = 0.006, p = 0.006 and p = 0.002, respectively). DHA+EPA treatment did not modify HPT, CPT or TPI (p = 0.93, p = 0.44 and p = 0.67, respectively). There were no important adverse effects or side effects reported. CONCLUSIONS/INTERPRETATION: Higher body fat percentage is associated with enhanced temperature perception. There was no benefit of treatment with high-dose n-3 fatty acids on the thresholds to detect hot or cold stimuli. TRIAL REGISTRATION: ClinicalTrials.gov NCT00760513 FUNDING: This work was supported by the National Institute for Health Research through the NIHR Southampton Biomedical Research Unit grant and by a Diabetes UK allied health research training fellowship awarded to KMcC (Diabetes UK. BDA 09/0003937).

Omega-3 fatty acids: Mechanisms of benefit and therapeutic effects in pediatric and adult NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is currently considered the most common liver disease in industrialized countries, and it is estimated that it will become the most frequent indication for liver transplantation in the next decade. NAFLD may be associated with moderate (i.e. steatosis) to severe (i.e. steatohepatitis and fibrosis) liver damage and affects all age groups. Furthermore, subjects with NAFLD may be at a greater risk of other obesity-related complications later in life, and people with obesity and obesity-related complications (e.g. metabolic syndrome, type 2 diabetes and cardiovascular disease) are at increased risk of developing NAFLD. To date, there is no licensed treatment for NAFLD and therapy has been mainly centered on weight loss and increased physical activity. Unfortunately, it is often difficult for patients to adhere to the advised lifestyle changes. Therefore, based on the known pathogenesis of NAFLD, several clinical trials with different nutritional supplementation and prescribed drugs have been undertaken or are currently underway. Experimental evidence has emerged about the health benefits of omega-3 fatty acids, a group of polyunsaturated fatty acids that are important for a number of health-related functions. Omega-3 fatty acids are present in some foods (oils, nuts and seeds) that also contain omega-6 fatty acids, and the best sources of exclusively omega-3 fatty acids are oily fish, krill oil and algae. In this review, we provide a brief overview of the pathogenesis of NAFLD, and we also discuss the molecular and clinical evidence for the benefits of different omega-3 fatty acid preparations in NAFLD.

Mulberry extract to modULate Blood glucosE Responses in noRmoglYcaemic adults (MULBERRY): study protocol for a randomised controlled trial.

BACKGROUND: Worldwide sugar consumption has tripled during the last fifty years. High sugar intake is associated with weight gain and increased incidence of diabetes and has been linked with increased cardiovascular mortality. Reducing the health impact of dietary sugar and poor quality carbohydrate intake is a public health priority. IminoNorm®, a proprietary mulberry leaf extract (ME), may reduce blood glucose responses following dietary sugar and carbohydrate intake by reducing absorption of glucose from the gut. Previous research has shown that ME can reduce blood glucose and improve insulin responses in healthy subjects and also in subjects with raised fasting blood glucose levels. Mulberry leaf has an excellent safety profile. This pilot study will test a novel, safe, water soluble product in normoglycaemic adults in the UK to determine if it can reduce glucose absorption without increasing plasma insulin concentration. METHODS/DESIGN: The trial will be a double-blind, individually randomised, four-arm single-dose crossover design to test the effect of three doses of ME in order to determine efficacy, dose response relationship and gastrointestinal side effects with respect to placebo. A total of 40 subjects will participate in this study and attend for four visits receiving each of the four interventions in random order. DISCUSSION: We aim to test the evidence that mulberry leaf extract can reduce blood glucose without a disproportionate increase in blood insulin responses in healthy individuals in a high-quality research study based in the UK. It is hoped that this will lead to further randomised controlled trials and an effective dietary supplement to lower blood glucose concentrations. ISRCTN: ISRCTN14597438 (21 April 2015).

Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: Results from the WELCOME trial.

BACKGROUND & AIMS: Genetic variation in both patatin-like phospholipase domain-containing protein-3 (PNPLA3) (I148M) and the transmembrane 6 superfamily member 2 protein (TM6SF2) (E167K) influences severity of liver disease, and serum triglyceride concentrations in non-alcoholic fatty liver disease (NAFLD), but whether either genotype influences the responses to treatments is uncertain. METHODS: One hundred three patients with NAFLD were randomised to omega-3 fatty acids (DHA+EPA) or placebo for 15-18months in a double blind placebo controlled trial. Erythrocyte enrichment with DHA and EPA was measured by gas chromatography. PNPLA3 and TM6SF2 genotypes were measured by PCR technologies. Multivariable linear regression and analysis of covariance were undertaken to test the effect of genotypes on omega-3 fatty acid enrichment, end of study liver fat percentage and serum triglyceride concentrations. All models were adjusted for baseline measurements of each respective outcome. RESULTS: Fifty-five men and 40 women (Genotypes PNPLA3 I148M, 148I/I=41, 148I/M=43, 148M/M=11; TM6SF2 E167K 167E/E=78, 167E/K+167K/K=17 participants) (mean ± SD age, 51 ± 11 years) completed the trial. Adjusting for baseline measurement, measured covariates and confounders, PNPLA3 148M/M variant was independently associated with percentage of DHA enrichment (B coefficient -1.02 (95% CI -1.97, -0.07), p=0.036) but not percentage of EPA enrichment (B coefficient -0.31 (95% CI -1.38, 0.75), p=0.56). This genotype was also independently associated with end of study liver fat percentage (B coefficient 9.5 (95% CI 2.53, 16.39), p=0.008), but not end of study triglyceride concentration (B coefficient -0.11 (95% CI -0.64, 0.42), p=0.68). CONCLUSIONS: PNPLA3 148M/M variant influences the changes in liver fat and DHA tissue enrichment during the trial but not the change in serum triglyceride concentration.

Impact of high dose n-3 polyunsaturated fatty acid treatment on measures of microvascular function and vibration perception in non-alcoholic fatty liver disease: results from the randomised WELCOME trial.

AIMS/HYPOTHESIS: The effect of n-3 fatty acid treatment on vibration perception thresholds (VPTs) and cutaneous microvascular reactivity is not known. We tested whether: (1) a 15-18 month treatment with high dose (4 g/day) docosahexaenoic (DHA) plus eicosapentaenoic (EPA) acid improved VPT and microvascular reactivity in patients with non-alcoholic fatty liver disease; and (2) there are associations between VPT, microvascular reactivity and metabolic variables. METHODS: In the completed single centre, randomised, parallel group, placebo controlled Wessex Evaluation of fatty Liver and Cardiovascular markers in non-alcoholic fatty liver disease with OMacor thErapy (WELCOME) trial, we tested the effect of DHA+EPA on VPT at 125 Hz (big toe) and the cutaneous hyperaemic response (forearm) to arterial occlusion (ratio of maximum to resting blood flux [MF/RF]). Allocation and dispensing was carried out by an independent research pharmacist; all participants and research team members were blinded to group assignment. RESULTS: In all, 51 and 49 patients were randomised to placebo and DHA+EPA, respectively (mean age 51.4 years). Of these, 32 had type 2 diabetes. Forty-six (placebo) and 47 (DHA+EPA) patients completed the study; there were no important adverse (or unexpected) effects or side effects. In multivariable-adjusted regression models (intention-to-treat analyses), DHA+EPA treatment was associated with an increase in VPT (ß coefficient 1.49 [95% CI 0.04, 2.94], p = 0.04). For VPT, the adjusted mean differences (95% CIs) in the placebo and DHA+EPA treatment groups were -0.725 (-1.71, 0.25) and 0.767 (-0.21, 1.75) m/s(2), respectively. With DHA+EPA treatment, there was no change in MF/RF (ß coefficient 0.07 [95% CI -0.56, 0.70], p = 0.84), the adjusted mean differences (95% CIs) in the placebo and DHA+EPA treatment groups were -0.549 (-1.03, -0.07) and -0.295 (-0.77, 0.18) respectively. VPT was independently associated with age (ß coefficient 0.019 [95% CI 0.010, 0.029], p < 0.0001) and MF/RF (ß coefficient -0.074 [95% CI -0.132, -0.016], p = 0.013), but not with diabetes (p = 0.38). CONCLUSIONS/INTERPRETATION: High dose n-3 fatty acid treatment did not improve measures of microvascular function or vibration perception. Ageing and microvascular reactivity are associated with a measure of peripheral nerve function. TRIAL REGISTRATION: ClinicalTrials.gov NCT00760513. FUNDING: The study was funded by the National Institute for Health Research UK and Diabetes UK.

Nonalcoholic fatty liver disease and reduced serum vitamin D(3) levels.

Nonalcoholic fatty liver disease (NAFLD) and vitamin D3 deficiency are two highly prevalent pathologic conditions worldwide that share several cardiometabolic risk factors. In addition to its traditional calcium-related effects on the skeleton, vitamin D3 deficiency has now been recognized to exert nonskeletal adverse effects on several other organ systems. Accumulating epidemiological evidence suggests that low levels of serum 25-hydroxyvitamin D3 are associated with the presence and severity of NAFLD, independently of several potential confounders, including features of the metabolic syndrome. The molecular mechanisms of this association remain incompletely understood. A variety of biologically plausible mechanisms may mediate a hepato-protective role for the active metabolite of vitamin D3. 1α,25-dihydroxyvitamin D3 modulates the insulin signaling pathway/insulin resistance, suppresses fibroblast proliferation and collagen production, exerts anticoagulant and profibrinolytic effects, and modulates macrophage activity and inflammatory cytokine generation. Overall, the high prevalence of vitamin D3 deficiency and the plausible biological mechanisms linking this to NAFLD suggest that treatment of vitamin D3 deficiency to prevent and/or treat NAFLD is a promising field to explore. Large placebo-controlled randomized clinical trials are urgently needed to determine whether vitamin D3 supplementation could have any potential benefit in reducing the development and progression of NAFLD.

Functional dilator capacity is independently associated with insulin sensitivity and age in central obesity and is not improved by high dose statin treatment.

OBJECTIVE: To test the hypothesis that: (i) functional microvascular dilator capacity is independently associated with insulin sensitivity and age in individuals with central adiposity at risk of cardiovascular disease (CVD); and (ii) functional microvascular dilator capacity is improved by high dose statin treatment. METHODS: Functional dilator capacity (measured as change in laser Doppler blood flux from baseline during post occlusive reactive hyperemia [peak flux%resting flux; PF%RF] and flowmotion (power spectral density [PSD] analysis)) were assessed in 40 people with central adiposity and one or more other CVD risk factors. Measurements were made at rest and during acute hyperinsulinaemia before and six months after high dose atorvastatin (40 mg daily) or placebo. RESULTS: Insulin-induced change in PF%RF was independently associated with insulin sensitivity (M/I) (r = 0.46 p = 0.02) and age (r = -0.46 p = 0.02), which together explained almost half of the variance in PF%RF (adjusted r² = 0.37, p = 0.008). Whilst atorvastatin decreased LDL cholesterol by 51% (p < 0.001), PF%RF and flowmotion remained unchanged. CONCLUSIONS: Insulin sensitivity and age are independently associated with an insulin-induced change in functional microvascular dilator capacity in individuals with central adiposity at risk of CVD. Dilator capacity is not improved by six months high dose statin treatment.

Fatty liver: role of inflammation and fatty acid nutrition.

Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver damage, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), 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 <10g of daily alcohol consumption. The exact prevalence of NAFLD is uncertain because of the absence of simple noninvasive diagnostic tests to facilitate an estimate of prevalence but in subgroups of people such as those with type 2 diabetes, the prevalence 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 NASH is associated with increased risk for cardiovascular disease. It is, therefore, important to understand the pathogenesis of NASH specifically, to develop strategies for interventions to treat this condition. The purpose of this review is to discuss the roles of inflammation, fatty acids and fatty acids in nutrition, in the pathogenesis and potential treatment of NAFLD.