Non alcoholic fatty liver disease and risk of incident diabetes in subjects who are not obese.

BACKGROUND AND AIMS: It is not known whether non alcoholic fatty liver disease (NAFLD) is a risk factor for diabetes in non obese, non centrally-obese subjects. Our aim was to investigate relationships between fatty liver, insulin resistance and a biomarker score for liver fibrosis with incident diabetes at follow up, in subjects who were neither obese nor centrally-obese. METHODS AND RESULTS: As many as 70,303 subjects with a body mass index (BMI) < 25 kg/m2 and without diabetes were followed up for a maximum of 7.9 years. At baseline, fatty liver was identified by liver ultrasound, insulin resistance (IR) by homeostatic model assessment of insulin resistance (HOMA-IR) ≥2.0, and central obesity by waist circumference (waist circumference ≥90 cm (men) and ≥85 cm (women). The Fibrosis-4 (FIB-4 score) was used to estimate extent of liver fibrosis. Cox proportional hazards models adjusted for confounders were used to estimate hazard ratios (aHRs) for incident diabetes. As many as 852 incident cases of diabetes occurred during follow up (median [IQR] 3.71 [2.03] years). Mean ± SD BMI was 22.8 ± 1.8 and 21.7 ± 2.0 kg/m2 in subjects with and without diabetes at follow up. In subjects without central obesity and with fatty liver, aHRs (95% CI) for incident diabetes at follow up were 2.17 (1.56, 3.03) for men, and 2.86 (1.50,5.46) for women. Similar aHRs for incident diabetes occurred with fatty liver, IR and the highest quartile of FIB-4 combined, in men; and there was a non significant trend toward increased risk in women. CONCLUSIONS: In normal weight, non-centrally obese subjects NAFLD is an independent risk factor for incident diabetes.

Type 2 Diabetes and Hepatocellular Carcinoma: Risk Factors and Pathogenesis.

PURPOSE OF REVIEW: This review aims to assess the epidemiological evidence for a link between type 2 diabetes and hepatocellular carcinoma and to investigate possible pathophysiological mechanisms. RECENT FINDINGS: The presence of type 2 diabetes significantly increases the risk of developing hepatocellular carcinoma, and treatment with metformin may be associated with a lower risk. Treatment with insulin and sulphonylureas may be associated with increased risk. The pathophysiology underlying development of hepatocellular carcinoma in this context is complex and is likely to involve increased proinflammatory mediators, oxidative stress, JNK-1 activation, increased IGF-1 activity, altered gut microbiota and immunomodulation. Hepatocellular carcinoma incidence is increasing and this is likely to be linked to the increasing incidence of type 2 diabetes, obesity and the metabolic syndrome. These conditions increase the risk of developing hepatocellular carcinoma, and a greater understanding of the underlying pathophysiology may help with the development of novel treatments.

Glycaemic control and lipid concentrations in a cohort of people with diabetes over 7 years of follow-up: a regional audit of diabetes care in the UK.

AIM: To determine changes in glycaemic control and lipids over time since the introduction of the Quality and Outcomes Framework. METHODS: In adults with diabetes (Hampshire, UK), HbA1c and lipid measurements were retrieved from a regional National Health Service biochemical database in 2006 and 2013 and analysed using anova and logistic regression modelling. RESULTS: In 2006, 8568 people with diabetes were identified. In 2013, 5815 had follow-up data, 1207 people were lost to follow-up and 1546 had died. At baseline, HbA1c concentrations were 62.1 ± 16.1, 64.7 ± 16.7 and 64.5 ± 17.6 mmol/mol for those with follow-up data, those lost to follow-up and those who died, respectively. The mean age was 60.2 ± 14.5, 57.6 ± 18.0 and 73.9 ± 10.5 years, respectively, for the three groups. Total cholesterol, HDL cholesterol and triglyceride concentrations were similar between groups. The mean HbA1c concentration for those with complete follow-up data was 62.1 ± 16.1 mmol/mol in 2006 and 61.7 ± 17.3 mmol/mol in 2013. Quality and Outcomes Framework targets for cholesterol (< 5 mmol/l) were achieved by 79% of people in 2006 and 83% in 2013 (P < 0.001). Baseline age and HbA1c were associated with death at follow-up: the odds ratio per year increase in baseline age was 1.10 (95% CI 1.09-1.10; P < 0.001) and per unit increase in HbA1c it was 1.02 (95% CI 1.02-1.03; P < 0.001). CONCLUSIONS: Glycaemic control showed remarkable stability over 7 years of follow-up, despite increasing patient age and duration of diabetes. More patients achieved lipid targets in 2013 than in 2006. Although baseline HbA1c was a predictor of death at follow-up, baseline HbA1c differed little between survivors, non-survivors and those lost to follow-up.

Omega-3 fatty acids, hepatic lipid metabolism, and nonalcoholic fatty liver disease.

Long-chain omega-3 fatty acids belong to a family of polyunsaturated fatty acids that are known to have important beneficial effects on metabolism and inflammation. Such effects may confer a benefit in specific chronic noncommunicable diseases that are becoming very prevalent in Westernized societies [e.g., nonalcoholic fatty liver disease (NAFLD)]. Typically, with a Westernized diet, long-chain omega-6 fatty acid consumption is markedly greater than omega-3 fatty acid consumption. The potential consequences of an alteration in the ratio of omega-6 to omega-3 fatty acid consumption are increased production of proinflammatory arachidonic acid-derived eicosanoids and impaired regulation of hepatic and adipose function, predisposing to NAFLD. NAFLD represents a spectrum of liver fat-related conditions that originates with ectopic fat accumulation in liver (hepatic steatosis) and progresses, with the development of hepatic inflammation and fibrosis, to nonalcoholic steatohepatitis (NASH). If the adipose tissue is inflamed with widespread macrophage infiltration, the production of adipokines may act to exacerbate liver inflammation and NASH. Omega-3 fatty acid treatment may have beneficial effects in regulating hepatic lipid metabolism, adipose tissue function, and inflammation. Recent studies testing the effects of omega-3 fatty acids in NAFLD are showing promise and suggesting that these fatty acids may be useful in the treatment of NAFLD. To date, further research is needed in NAFLD to (a) establish the dose of long-chain omega-3 fatty acids as a treatment, (b) determine the duration of therapy, and (c) test whether there is benefit on the different component features of NAFLD (hepatic fat, inflammation, and fibrosis).

Late effects of childhood cancer treatment: severe hypertriglyceridaemia, central obesity, non alcoholic fatty liver disease and diabetes as complications of childhood total body irradiation.

BACKGROUND: Childhood cancer survivors may develop a number of endocrine complications linked to organ failure, such as hypogonadism, diabetes and growth hormone deficiency. However, increasing evidence now suggests that total body irradiation treatment, specifically, is linked with future risk of insulin resistance, hepatic steatosis and dyslipidaemia, possibly because total body irradiation affects adipocyte differentiation and impairs subcutaneous adipose tissue depot expansion during times of positive energy balance. CASE REPORT: We describe a 20-year-old woman who developed pancreatitis with severe hypertriglyceridaemia (serum triglycerides > 300 mmol/l) that required plasmapheresis. She had received total body irradiation prior to her bone marrow transplant at age 6 years for relapsed acute lymphoblastic leukaemia. She developed ovarian failure at age 12 years. At age 15 years she was noted to have hyperglycaemia, increased blood pressure, hepatic steatosis and mild hypertriglyceridaemia. She presented with severe hypertriglyceridaemia and eruptive xanthoma, and developed pancreatitis 12 h after admission. She was treated with plasmapheresis and intravenous insulin and made an excellent recovery. We implicate and discuss total body irradiation as the major contributing factor to her severe hypertriglyceridaemia, compounded by worsening glycaemic control, oestrogen deficiency and a changing adult lifestyle. CONCLUSION: Children who have received total body irradiation are at risk of diabetes and an exaggerated form of the metabolic syndrome with hypertriglyceridaemia, which can be life-threatening. We suggest that survivors of total body irradiation treatment require careful lifelong monitoring of their metabolic status.

External validity of randomized controlled trials of glycaemic control and vascular disease: how representative are participants?

AIMS: To describe the proportion of people with Type 2 diabetes living in Scotland who meet eligibility criteria for inclusion in several large randomized controlled trials of glycaemic control to inform physicians and guideline developers about the generalizibility of trial results. METHODS: A literature review was performed to identify large trials assessing the impact of glycaemic control on risk of macrovascular disease. Inclusion and exclusion criteria from each trial were applied to data on the population of people with a diagnosis of Type 2 diabetes living in Scotland in 2008 (n = 180,590) in a population-based cross-sectional study and the number and proportion of people eligible for each trial was determined. RESULTS: Seven trials were identified. The proportion of people with Type 2 diabetes who met the eligibility criteria for the trials ranged from 3.5 to 50.7%. Trial participants were younger at age of diagnosis of diabetes and at time of trial recruitment than in the Scottish study population. The application of upper age criteria excluded the largest proportion of patients, with up to 39% of people with Type 2 diabetes ineligible for a trial with the most stringent criteria based on age alone. CONCLUSIONS: We found that many of the large trials of glycaemic control among people with Type 2 diabetes have limited external validity when applied to a population-based cohort of people with Type 2 diabetes. In particular, the age distribution of trial participants often does not reflect that of people with Type 2 diabetes in a contemporary British population.

Lipoprotein (a), metabolic syndrome and coronary calcium score in a large occupational cohort.

BACKGROUND AND AIMS: Whether lipoprotein (a) [Lp(a)] concentration is associated with metabolic syndrome (MetS) and pre-clinical atherosclerosis in different ethnic groups is uncertain. The association between Lp(a), MetS and a measure of pre-clinical atherosclerosis was studied in a large Asian cohort. METHODS AND RESULTS: Data were analyzed from a South Korean occupational cohort who underwent a cardiac computed tomography (CT) estimation of CAC score and measurements of cardiovascular risk factors (n = 14,583 people). The key exposure was an Lp(a) concentration in the top quartile (>38.64 mg/dL)) with a CAC score >0 as the outcome variable and measure of pre-clinical atherosclerosis. Logistic regression was used to describe the associations. 1462 participants had a CAC score >0. In the lowest Lp(a) quartile (<11.29 mg/dL), 25.8% had MetS, compared with 16.1% in the highest Lp(a) quartile (>38.64 mg/dL (p < 0.001). MetS, and component features, were inversely related to Lp(a) concentration (all p < 0.0001). In the highest Lp(a) quartile group, there was an association between Lp(a) and CAC score >0 in men (OR 1.21[1.05, 1.40], p = 0.008), and women (OR 1.62[1.03, 2.55], p = 0.038), after adjustment for age, sex, lipid lowering therapy, and multiple cardiovascular risk factors. There was no evidence of an interaction between highest quartile Lp(a) and either high LDLc (>147 mg/dL) (p = 0.99), or MetS (p = 0.84) on the association with CAC score >0. CONCLUSION: Lp(a) levels are inversely related to MetS and its components. There was a robust association between Lp(a) concentration >38.6 mg/dL and marker of early atherosclerosis in both men and women, regardless of LDLc, level MetS or other cardiovascular risk factors.

Dorothy Hodgkin Lecture 2012: non-alcoholic fatty liver disease, insulin resistance and ectopic fat: a new problem in diabetes management.

Non-alcoholic fatty liver disease is now recognized as the hepatic component of the metabolic syndrome. Non-alcoholic fatty liver disease is a spectrum of fat-associated liver conditions that can result in end-stage liver disease and the need for liver transplantation. Simple steatosis, or fatty liver, occurs early in non-alcoholic fatty liver disease and may progress to non-alcoholic steatohepatitis, fibrosis and cirrhosis with increased risk of hepatocellular carcinoma. Prevalence estimates for non-alcoholic fatty liver disease range from 17 to 33% in the general populations and it has been estimated that non-alcoholic fatty liver disease exists in up to 70% of people with Type 2 diabetes. Non-alcoholic fatty liver disease increases risk of Type 2 diabetes and cardiovascular disease. In people with Type 2 diabetes, non-alcoholic fatty liver disease is the most frequent cause (∼80%) of fatty liver diagnosed by ultrasound. As non-alcoholic fatty liver disease is strongly associated with insulin resistance, the presence of non-alcoholic fatty liver disease with diabetes often contributes to poor glycaemic control. Consequently, strategies that decrease liver fat and improve whole-body insulin sensitivity may both contribute to prevention of Type 2 diabetes and to better glycaemic control in people who already have developed diabetes. This review summarizes the Dorothy Hodgkin lecture given by the author at the 2012 Diabetes UK annual scientific conference, proposing that fatty acid fluxes through the liver are crucial for the pathogenesis of non-alcoholic fatty liver disease and for increasing insulin resistance.

Metabolic regulation during constant moderate physical exertion in extreme conditions in Type 1 diabetes.

BACKGROUND: Constant moderate intensity physical exertion in humid environments at altitude poses a considerable challenge to maintaining euglycaemia with Type 1 diabetes. Blood glucose concentrations and energy expenditure were continuously recorded in a person trekking at altitude in a tropical climate to quantify changes in glucose concentrations in relation to energy expenditure. CASE REPORT: Blood glucose concentrations and energy expenditure were continuously monitored with a Guardian® real-time continuous glucose monitoring system (CGMS) and a SenseWear® Pro3 armband (BodyMedia Inc., USA), in a 27-year-old woman with Type 1 diabetes, during her climb up Mount Kinabalu in Borneo (c. 4095 m). Comparative control data from the same person was collected in the UK (temperate climate at sea level) and Singapore (tropical climate at sea level). Maximum physical effort during the climb was < 60% VO(2MAX) (maximal oxygen consumption). Mean daily calorific intakes were 2300 kcal (UK), 2370 kcal (Singapore) and 2274 kcal (Mount Kinabalu), and mean daily insulin doses were 54 U (UK), 40 U (Singapore) and 47 U (Mount Kinabalu). Despite markedly increased energy expenditure during the climb [4202 kcal (Mount Kinabalu) vs. 2948 kcal (UK) and 2662 kcal (Singapore)], mean blood glucose was considerably higher during the trek up Mount Kinabalu [13.2 ± 5.9 mmol/l, vs. 7.9 ± 3.8 mmol/l (UK) and 8.6 ± 4.0 mmol/l (Singapore)]. CONCLUSION: Marked unexpected hyperglycaemia occurred while trekking on Mount Kinabalu, despite similar calorie consumption and insulin doses to control conditions. Because of the risk of unexpected hyperglycaemia in these conditions, we recommend that patients embarking on similar activity holidays undertake frequent blood glucose monitoring.

Association between increased plasma ceramides and chronic kidney disease in patients with and without ischemic heart disease.

AIM: Plasma levels of certain ceramides are increased in patients with ischemic heart disease (IHD). Many risk factors for IHD are also risk factors for chronic kidney disease (CKD), but it is currently uncertain whether plasma ceramide levels are increased in patients with CKD. METHODS: We measured six previously identified high-risk plasma ceramide concentrations [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] in 415 middle-aged individuals who attended our clinical Cardiology and Diabetes services over a period of 9 months. RESULTS: A total of 97 patients had CKD (defined as e-GFRCKD-EPI<60ml/min/1.73m2 and/or urinary albumin-to-creatinine ratio≥30mg/g), 117 had established IHD and 242 had type 2 diabetes. Patients with CKD had significantly (P=0.005 or less) higher levels of plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/24:1) compared to those without CKD. The presence of CKD remained significantly associated with higher levels of plasma ceramides (standardized beta coefficients ranging from 0.124 to 0.227, P<0.001) even after adjustment for body mass index, smoking, hypertension, diabetes, prior IHD, plasma LDL-cholesterol, hs-C-reactive protein levels and use of any lipid-lowering medications. Notably, more advanced stages of CKD and abnormal albuminuria were both associated (independently of each other) with increased levels of plasma ceramides. These results were consistent in all subgroups considered, including patients with and without established IHD or those with and without diabetes. CONCLUSION: Increased levels of plasma ceramides are associated with CKD independently of pre-existing IHD, diabetes and other established cardiovascular risk factors.

Improvements in glycaemic control and cholesterol concentrations associated with the Quality and Outcomes Framework: a regional 2-year audit of diabetes care in the UK.

AIMS: To determine whether there have been changes in glycaemic control and lipids in a cohort of people with repeated glycated haemoglobin (HbA(1c)) measurements since the implementation of the Quality and Outcomes Framework (QOF) for diabetes care. METHODS: Retrospective retrieval of computer-held biochemical measurements of glycaemic control (HbA(1c)) and lipid profiles in adults in Hampshire, UK between 2006 and 2008. Routine data on age, sex, HbA(1c) and plasma lipids were available on an NHS database on 8997 adults with data available for HbA(1c) in both 2006 and 2008. RESULTS: In 2006, 39.7% of adults had glycaemic control within the QOF threshold (HbA(1c) < 7.5%); by 2008, this proportion had risen to 52.1% (P < 0.001). In 2006, 11.8% of subjects had poor glycaemic control (HbA(1c) > 10.0%); by 2008, this proportion had decreased to 10.1% (P < 0.001). The proportion of subjects achieving HbA(1c) and cholesterol targets (both HbA(1c) < 7.5% and total cholesterol < or = 5.0 mmol/l) was 30.2% in 2006; in 2008, this proportion had increased to 43.7% (P < 0.001). Individuals with poorer glycaemic control (HbA(1c) > 10.0%) were younger and had higher cholesterol concentrations than people with good (HbA(1c) < 7.5%) or moderate (HbA(1c) 7.5-10.0%) glycaemic control (P value for trend, both P < 0.001). CONCLUSION: Since the introduction of performance indicators for primary care and the incorporation of pay for performance in 2004, there has been marked improvement in the management of hyperglycaemia and hypercholesterolaemia among people with diabetes with data available in 2006 and 2008. It remains to be seen whether the new HbA(1c) audit target (HbA(1c) < 7.0%) introduced in 2009 will result in a further improvement in glycaemic control.

Potential therapeutic uses for ezetimibe beyond lowering LDL-c to decrease cardiovascular events.

Ezetimibe is a relatively new drug that inhibits the absorption of dietary cholesterol in the small intestine. It is a low density lipoprotein-cholesterol (LDL-C) lowering medication that acts directly on the intestine by inhibiting Niemann-Pick C1 Like1 (NPC1L1). Recently, results of the ARBITER 6-HALTS trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) and the ENHANCE trial (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) showed that ezetimibe had no effect on atherosclerosis despite producing a marked decrease in LDL-C. Recent studies show a potential benefit of ezetimibe in treating insulin resistance, non-alcoholic fatty liver disease (NAFLD), gallstones and dyslipidaemia associated with chronic renal failure and organ transplantation. All of these conditions are known to be associated with an increase in risk of cardiovascular disease (CVD) and further studies are needed to assess the potential benefits of ezetimibe in these therapeutics areas.

Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: An updated systematic review of randomized controlled trials.

AIM: There are no approved drugs for the treatment of non-alcoholic fatty liver disease (NAFLD). However, many randomized controlled trials (RCT) have examined the effect of anti-hyperglycaemic agents on NAFLD in patients with and without type 2 diabetes mellitus (T2DM), since both T2DM and insulin resistance are closely linked to this burdensome liver disease. METHODS: We systematically searched publication databases using predefined keywords to identify head-to-head or placebo-controlled RCTs (published until September 30, 2019) of NAFLD individuals testing the efficacy of anti-hyperglycaemic drugs to specifically treat NAFLD or non-alcoholic steatohepatitis (NASH). Outcomes of interest included changes in serum liver enzyme levels, liver fat, liver fibrosis, or histologic resolution of NASH. RESULTS: We included 29 RCTs involving a total of 2,617 individuals (∼45% had T2DM) that have used metformin (n=6 studies), glitazones (n=8 studies), glucagon-like peptide-1 receptor agonists (n=6 studies), dipeptidyl peptidase-4 inhibitors (n=4 studies) or sodium-glucose cotransporter-2 inhibitors (n=7 studies) to treat NAFLD. Although most anti-hyperglycaemic drugs improved serum liver enzyme levels, only glitazones (especially pioglitazone) and liraglutide showed an improvement of histologic features of NAFLD, with a mild beneficial effect also on liver fibrosis for pioglitazone only. CONCLUSION: RCT evidence supports the efficacy of some anti-hyperglycaemic agents (especially pioglitazone) in patients with NAFLD or NASH, though weight gain with pioglitazone may warrant caution. Further well-designed RCTs are needed to better characterize the efficacy and safety of monotherapy and combination therapy with anti-hyperglycaemic agents in patients with NAFLD.

Screening for non-alcoholic fatty liver disease using liver stiffness measurement and its association with chronic kidney disease and cardiovascular complications in patients with type 2 diabetes.

AIM: Despite the high prevalence and serious clinical implications of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM), NAFLD is usually overlooked during routine diabetes care. This study explored the proportion of NAFLD cases and increased liver fibrosis (LF), and the association between LF and either chronic kidney disease (CKD) or cardiovascular complications in T2DM patients. METHODS: The study included 137 patients with non-insulin-treated T2DM and no known liver disease consecutively attending our diabetes outpatients' service who underwent liver ultrasonography and liver stiffness measurement (LSM) using vibration-controlled transient elastography (FibroScan®). RESULTS: The proportion of patients with hepatic steatosis on ultrasonography was 73.7%, and the proportion with significant LF was 17.5% with an LSM cut-off ≥7kPa or 10.2% with an LSM cut-off ≥8.7kPa. The presence of CKD (estimated GFR <60mL/min/1.73m2 and/or abnormal albuminuria) increased significantly across LSM tertiles (from around 15% in tertile 1 to 45% in tertile 3). Cardiovascular complications (previous ischaemic heart disease, ischaemic stroke, permanent atrial fibrillation) also tended to increase across LSM tertiles (from around 15% to 30%). After adjusting for established risk factors and potential confounders, LSM tertile 3 remained significantly associated with an approximately threefold higher risk of prevalent CKD (adjusted OR: 3.28, 95% CI: 1.22-8.90; P=0.019), but not for cardiovascular complications. CONCLUSION: These results suggest that NAFLD and significant LF (as assessed by FibroScan®) are very commonly seen in T2DM outpatients with no known liver disease attending a secondary-care diabetes service, and that increased LF is associated with a greater proportion of chronic vascular complications, especially CKD.

Associations between specific plasma ceramides and severity of coronary-artery stenosis assessed by coronary angiography.

AIM: Recent prospective studies have identified distinct plasma ceramides as strong predictors of major adverse cardiovascular events in patients with established or suspected coronary artery disease (CAD). Currently, it is uncertain whether higher levels of distinct plasma ceramides are associated with greater angiographic severity of coronary-artery stenoses in this patient population. METHODS: We measured six previously identified high-risk plasma ceramide species [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] in 167 consecutive patients with established or suspected CAD, who underwent urgent or elective coronary angiography. RESULTS: Approximately 77% of patients had a significant stenosis (≥50%) in one or more of the main coronary arteries, the majority of whom (∼60%) had a significant stenosis in the left anterior descending (LAD) artery. Of the six measured plasma ceramides, higher levels of plasma Cer(d18:1/20:0) (adjusted-odds ratio 1.39, 95%CI 1.0-1.99), Cer(d18:1/22:0) (adjusted-odds ratio 1.57, 95%CI 1.08-2.29) and Cer(d18:1/24:0) (adjusted-odds ratio 1.59, 95%CI 1.08-2.32) were significantly associated with the presence of LAD stenosis≥50%, after adjustment for age, sex, smoking, pre-existing CAD, hypertension, diabetes, dyslipidaemia, lipid-lowering therapy, estimated glomerular filtration rate and plasma C-reactive protein levels. Almost identical results were found even after excluding patients (n=15) with acute ST-elevation myocardial infarction. Similar results were also found when patients were categorized according to the Gensini severity score. CONCLUSION: Our cross-sectional study shows for the first time that higher levels of specific plasma ceramides are independently associated with a greater severity of coronary-artery stenoses in the LAD artery in patients who had suspected or established CAD.

Higher liver stiffness scores are associated with early kidney dysfunction in patients with histologically proven non-cirrhotic NAFLD.

AIM: The association between Liver fibrosis (LF), as assessed by either histology or Liver stiffness measurement (LSM), and the presence of Early kidney dysfunction (EKD) was investigated in this study, as was also the diagnostic performance of LSM for identifying the presence of EKD in patients with Non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: A total of 214 adults with non-cirrhotic biopsy-proven NAFLD were recruited from two independent medical centres. Their histological stage of LF was quantified using Brunt's criteria. Vibration-controlled Transient elastography (TE), using M-probe (FibroScan®) ultrasound, was performed in 154 patients and defined as significant when LSM was≥8.0kPa. EKD was defined as the presence of microalbuminuria with an estimated glomerular filtration rate≥60mL/min/1.73 m2. Logistic regression modelling was used to estimate the likelihood of having EKD with NAFLD (LSM-EKD model). RESULTS: The prevalence of EKD was higher in patients with vs without LF on histology (22.14% vs 4.82%, respectively; P<0.001) and, similarly, EKD prevalence was higher in patients with LSM≥8.0kPa vs LSM<8.0kPa (23.81% vs 6.59%, respectively; P<0.05). The area under the ROC curve of the LSM-EKD model for identifying EKD was 0.80 (95% CI: 0.72-0.89). LF detected by either method was associated with EKD independently of established renal risk factors and potential confounders. CONCLUSION: LF was independently associated with EKD in patients with biopsy-proven NAFLD. Thus, TE-measured LSM, a widely used technique for quantifying LF, can accurately identify those patients with NAFLD who are at risk of having EKD.

PNPLA3 polymorphism influences the association between high-normal TSH level and NASH in euthyroid adults with biopsy-proven NAFLD.

AIM: We aimed to evaluate the association between serum thyroid stimulating hormone (TSH) levels, within the reference range, and the histological severity of nonalcoholic fatty liver disease (NAFLD), and whether this association was modulated by the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism. MATERIALS AND METHODS: We enrolled 327 euthyroid individuals with biopsy-proven NAFLD, who were subdivided into two groups, i.e., a 'strict-normal' TSH group (TSH level 0.4 to 2.5mIU/L; n=283) and a 'high-normal' TSH group (TSH level 2.5 to 5.3mIU/L with normal thyroid hormones; n=44). Logistic regression analyses were performed to assess the association between TSH status and presence of nonalcoholic steatohepatitis (NASH) after stratifying subjects by PNPLA3 genotypes. RESULTS: Compared to strict-normal TSH group, patients with high-normal TSH levels were younger and had a greater prevalence of NASH and higher histologic NAFLD activity score. After stratifying by PNPLA3 genotypes, the significant association between high-normal TSH levels and presence of NASH was restricted only to carriers of the PNPLA3 G risk allele and remained significant even after adjustment for potential confounding factors (adjusted-odds ratio: 3.279; 95% CI: 1.298-8.284; P=0.012). CONCLUSION: In euthyroid individuals with biopsy-proven NAFLD, we found a significant association between high-normal TSH levels and NASH. After stratifying by PNPLA3 rs738409 genotypes, this association was observed only among carriers of the PNPLA3 G risk allele.

Skeletal muscle microvascular exchange capacity is associated with hyperglycaemia in subjects with central obesity.

AIMS: Poor glycaemic control is associated with increased risk of microvascular disease in various organs including the eye and kidney, but the relationship between glycated haemoglobin (HbA(1c)) and microvascular function in skeletal muscle has not been described. We tested the association between HbA(1c) and a measure of microvascular exchange capacity (K(f)) in skeletal muscle in people with central obesity at risk of developing Type 2 diabetes. METHODS: Microvascular function was measured in 28 women and 19 men [mean (+/- sd) age 51 +/- 9 years] with central obesity who did not have diabetes. We estimated insulin sensitivity by hyperinsulinaemic-euglycaemic clamp, visceral and total fatness by magnetic resonance imaging, fitness (VO(2) max by treadmill testing), physical activity energy expenditure [metabolic equivalents of tasks (METS) by use of the SenseWear Pro armband] and skeletal muscle microvascular exchange capacity (K(f)) by venous occlusion plethysmography. RESULTS: In regression modelling, age, sex and fasting plasma glucose accounted for 30.5% of the variance in HbA(1c) (r(2) = 0.31, P = 0.001). Adding K(f) to this model explained an additional 26.5% of the variance in HbA(1c) (r(2) = 0.57, P = 0.0001 and K(f) was strongly and independently associated with HbA(1c) (standardized B coefficient -0.45 (95% confidence interval -0.19, -0.06), P = 0.001). CONCLUSIONS: We found a strong negative independent association between a measure of skeletal muscle microvascular exchange capacity (K(f)) and HbA(1c). K(f) was associated with almost as much of the variance in HbA(1c) as fasting plasma glucose.