Dorothy Hodgkin Lecture 2012: non-alcoholic fatty liver disease, insulin resistance and ectopic fat: a new problem in diabetes management.
ABSTRACT 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.
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ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) has been linked to cardiovascular disease (CVD) but it is largely unknown if such a relationship between NAFLD and CVD risk relates to severity of liver disease or if it is independent. We aimed to study the severity of NAFLD in a well characterized non-obese population and to compare this to prevalence of CVD risk factors and Framingham risk score. This study included 30,172 subjects. Based on the presence or absence of steatosis on ultrasound and serum alanine aminotransferase (ALT), subjects were divided into controls, an increased serum ALT group without steatosis and a group with presumed nonalcoholic fatty liver disease (NAFLD), which included a steatosis alone group and a group with presumed nonalcoholic steatohepatitis (NASH) with steatosis and an elevated ALT. The odds ratio for 10-year risk by total Framingham risk scores > or =10% was 5.3 times higher in NASH groups. The prevalence of diabetes, hypertension, elevated CRP and metabolic syndrome were all increased up to 15-fold over controls, independent of age, BMI, smoking and exercise habits. Overall CVD risk was significantly greater in NASH than in either steatosis or raised ALT alone. Young, non-obese subjects with NAFLD are at significantly increased CVD risk, especially those with NASH. As well as specific therapy for liver disease, a diagnosis of NAFLD should lead to targeted risk assessment and risk factor modification.Atherosclerosis 07/2008; 203(2):581-6. · 3.71 Impact Factor
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ABSTRACT: The metabolic syndrome (MetS) represents a combination of cardiometabolic risk determinants including obesity (central adiposity), insulin resistance, glucose intolerance, dyslipidaemia, non-alcoholic fatty liver disease and hypertension. MetS is rapidly increasing in prevalence worldwide as a consequence of the continued obesity "epidemic", and as a result will have a considerable impact on the global incidence of cardiovascular disease and type 2 diabetes. Currently, there is debate concerning whether the risk of cardiovascular disease is greater in patients diagnosed with MetS than that of the sum of the individual risk factors. At present, no unifying origin that can explain the pathogenesis of MetS has been identified and therefore no unique pharmacological treatment is available. This review summarises and critically evaluates the current clinical and scientific evidence supporting the existence of MetS as a multifactorial endocrine disease, for which maternal nutrition may be a common pathogenic mechanism. In addition, we suggest that ectopic fat accumulation (such as visceral and hepatic fat accumulation) and the proinflammatory state are central to the development of the MetS.Postgraduate medical journal 11/2009; 85(1009):614-21. · 1.38 Impact Factor
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ABSTRACT: 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.Clinical Science 04/2009; 116(7):539-64. · 4.86 Impact Factor