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Clinicians in both the developed and also the newer industrial economies in the Asia-Pacific region will encounter non-alcoholic fatty liver disease (NAFLD) with increasing frequency. Although the region has been a significant contributor to the current state of knowledge, the spectrum of NAFLD, its severity and the potential for significant future morbidity and health costs are not widely recognized. Lifestyle changes, the epidemic of childhood and adult obesity and type 2 diabetes sweeping the Asia-Pacific represent the key substrates for the rising prevalence of NAFLD. Physicians in all disciplines need to be aware of clinical clues to the presence of NAFLD in the absence of other liver disease and in those with chronic viral hepatitis and they should be able to identify subsets at risk for liver-related morbidity. Given the scope of the problem, efforts should focus primarily on preventing or ameliorating the impact of risk factors; the key one is insulin resistance and its associates of diabetes and central obesity. Pharmacotherapy may play a role in selected individuals. A regional agenda for case definition, future study and public health initiatives is urgently required.
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PMID:Non-alcoholic steatohepatitis in the Asia-Pacific region: future shock? 1501 72

Non alcoholic fatty liver disease is a disease of emerging identity and importance. It is frequently associated with obesity, especially visceral fat, and is intimately related to fatty liver and markers of insulin resistance. Both the prevalence and the severity of liver steatosis are related to body mass index, waist circumference, hyperinsulinaemia, hypertriglyceridaemia and impaired glucose tolerance or type 2 diabetes. The identification fatty liver disease in obese patients, is very important in order to prevent complications such as steathohepatitis and cirrhosis. The pathogenesis of non alcoholic fatty liver disease is very complex, there are mitochondrial morphologic and functional alterations, as well as, high sensitivity to injurious stimulus, an increased inflammatory activity, and modifications in cellular metabolism at post-receptor level. Weight reduction is one of the first steps in the treatment of patients with non alcoholic fatty liver disease, as well as the management of associated conditions such as obesity, diabetes mellitus and hyperlipidaemia. Antioxidants, and others drugs such as ursodeoxycholic acid may be beneficial in the treatment of non alcoholic fatty liver disease. These medications, however, need first to be tested in well-controlled trials with clinically relevant end-points and extended follow-up. In this review, we analyze the new concepts in epidemiology, pathophysiology and treatment of this disease.
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PMID:[An update on non-alcoholic fatty liver disease]. 1514 45

Cryptogenic cirrhosis (CC) is diagnosed in 5-30% of cirrhotic patients overall and 7% of patients who undergo liver transplantation for cirrhosis. In our series of patients transplanted for CC, pre-transplant clinical and histological data and the post-transplant course were reexamined in an attempt to identify the aetiology. Among the 881 patients transplanted in our centre between 1987 and 2000, 28 patients with a median age of 46 yr (range: 18-69) at transplantation were initially classified as having CC. Two patients were excluded because of intense ischaemic lesions caused by chemoembolization prevented histological analysis of the native liver (n = 1) and because of cryptic HBV infection (n = 1). Among the remaining 26 patients, four groups were individualized: (i) patients with chronic inflammatory liver disease with autoimmune features (n = 14, 54%); (ii) patients with features suggestive of non-alcoholic fatty liver disease (n = 3, 11.5%); (iii); patients with incomplete septal cirrhosis (ISC) and vascular liver disease (n = 3), and (iv) patients with unresolved CC (n = 6, 23%). In the autoimmune liver disease group, the median International Autoimmune Hepatitis score was 12.5 (range: 11-19) after reevaluation and review of the post-transplantation course was helpful to confirm the diagnosis with the occurrence of active graft hepatitis in nine patients, with autoantibodies in five patients. The vascular group was characterized by lesions of obliterative portal venopathy and ISC in all native livers. Diagnosis of NAFLD was based on the clinical background of obesity and/or type 2 diabetes and the presence of steatosis or steatohepatitis in native livers and graft biopsies. A definite aetiological diagnosis can be achieved in the majority of patients initially diagnosed with CC. Autoimmune liver disease emerged as the main aetiology (14 of 26 patients, 54%) and frequently recurred on the grafted liver (nine cases). In all cases a precise diagnosis is obviously of practical interest for better management of post-transplant survey and treatment.
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PMID:Could post-liver transplantation course be helpful for the diagnosis of so called cryptogenic cirrhosis? 1710 Jul 32

Thiazolidinediones (TZDs) are peroxisomal proliferator-activated receptor (PPAR)-gamma agonists. They increase insulin action through several mechanisms including: stimulation of the expression of genes that increase fat oxidation and lower plasma free fatty acid levels; increased expression, synthesis and release of adiponectin; and stimulation of adipocyte differentiation resulting in more and smaller fat cells. TZDs lower blood sugar comparably to sulfonylureas and metformin. The clinical use of TZDs is limited due to the long duration of time required before they reach their full blood sugar-lowering action (3-4 months) and adverse effects such as fluid retention, resulting in excessive weight gain and occasionally in peripheral and/or pulmonary oedema and congestive heart failure. Troglitazone, a TZD that has since been removed from the market because of hepatoxicity, has been demonstrated to decrease the progression from normal or impaired glucose tolerance to overt Type 2 diabetes mellitus. Pioglitazone, another TZD, marginally decreased the incidence of cardiovascular complications in patients with Type 2 diabetes mellitus (PROactive trial). Other, as yet, unapproved uses of TZDs include: non-alcoholic fatty liver disease, in which TZDs reduced hepatic fat accumulation and improved liver function tests; polycystic ovary syndrome, where TZDs improved ovulation, hirsutism and endothelial dysfunction; and lipodystrophies, where TZDs increased body fat (marginally) and decrease liver size. Lastly, because PPAR-alpha and -gamma agonists improve atherosclerotic vascular disease and insulin sensitivity, respectively, dual PPAR-alpha/gamma agonists, which are currently undergoing clinical trials, may be useful in treating patients with the metabolic syndrome.
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PMID:Recent findings concerning thiazolidinediones in the treatment of diabetes. 1650 61

Alanine aminotransferase (ALT) is a marker of non-alcoholic fatty liver disease (NAFLD) and predicts incident type 2 diabetes mellitus (DM2). Recently, ALT was shown to be also associated with endothelial dysfunction and carotid atherosclerosis. We studied the predictive value of ALT for all-cause mortality, incident cardiovascular disease (CVD) and coronary heart disease (CHD) events in a population-based cohort of Caucasian men and women aged 50-75 years, at baseline. The 10-year risk of all-cause mortality, fatal and non-fatal CVD and CHD events in relation to ALT was assessed in 1439 subjects participating in the Hoorn Study, using Cox survival analysis. Subjects with prevalent CVD/CHD and missing data were excluded. As compared with the first tertile, the age- and sex-adjusted hazard ratios (95% confidence intervals) for all-cause mortality, CVD events and CHD events were 1.30 (0.92-1.83), 1.40 (1.09-1.81) and 2.04 (1.35-3.10), respectively, for subjects in the upper tertile of ALT. After adjustment for components of the metabolic syndrome and traditional risk factors, the association of ALT and CHD events remained significant for subjects in the third relative to those in the first tertile, with a hazard ratio of 1.88 (1.21-2.92) and 1.75 (1.12-2.73), respectively. In conclusion, the predictive value of ALT for coronary events, seems independent of traditional risk factors and the features of the metabolic syndrome in a population-based cohort. Further studies should confirm these findings and elucidate the pathophysiological mechanisms.
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PMID:Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. 1855 46

Obesity is a major risk factor for the development of the metabolic syndrome, a cluster of diseases including insulin resistance, type 2 diabetes, dyslipidemia, hypertension, microalbuminuria, atherosclerosis, and non-alcoholic steatohepatitis. On the other hand, it is now generally accepted that adipose tissue acts as an endocrine organ producing a number of substances with an important role in the regulation of food intake, energy expenditure and a series of metabolic processes. Adiponectin is a recently discovered hormone produced exclusively by adipocytes. In fact, adiponectin is considered currently as a major factor in obesity-related insulin resistance and atherosclerosis. This new hormone differs from other adipocytokines in that its production and concentrations are actually decreased in insulin resistant subjects. The aim of this review is to summarize the current knowledge about the chemistry and physiology of adiponectin and to discuss its implications in the pathophysiology and potential treatment of insulin resistance and non-alcoholic fatty liver disease.
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PMID:Adiponectin, structure, function and pathophysiological implications in non-alcoholic fatty liver disease. 1678 75

For a long time, hepatic steatosis was believed to be a benign condition. Only recently, liver steatosis, also termed non-alcoholic fatty liver disease (NAFLD), has gained much interest. In most cases of NAFLD, a condition regarded as the hepatic component of the metabolic syndrome, the enzyme alanine aminotransferase (ALT) is elevated and consequently has been used as a marker for NAFLD. More recently, several cross-sectional and prospective studies have demonstrated associations of this liver enzyme with features of the metabolic syndrome and type 2 diabetes mellitus. This review discusses the biochemical and metabolic properties of ALT, its applicability as a marker of NAFLD and describes its possible role in the pathogenesis of the metabolic syndrome and type 2 diabetes mellitus and subsequent cardiovascular disease. In addition, treatment strategies to ameliorate NAFLD and the associated risks are discussed.
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PMID:Alanine aminotransferase as a marker of non-alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease. 1682 76

We examined the effects of the angiotensin-II receptor antagonist candesartan on non-alcoholic fatty liver (NAFL) and circulating adiponectin concentrations in KKAy obese mice with type 2 diabetes mellitus. The KKAy mice were randomly assigned to receive either candesartan at a once-daily dose of 10 mg/kg (n = 5) or placebo (n = 5). The differences in liver weight, histological evaluation of hepatic lipid infiltration, serum adiponectin concentration and hepatic adiponectin mRNA levels between the two groups were determined on day 7 after treatment was initiated. Candesartan-treated mice demonstrated significantly lower liver weights and reduced lipid droplets in hepatic cells compared with control mice. The circulating adiponectin levels and hepatic expression of adiponectin mRNA were significantly higher in candesartan-treated mice than control mice. These results suggest that candesartan might alleviate NAFL through elevation of circulating adiponectin levels in KKAy obese mice with type 2 diabetes mellitus.
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PMID:Angiotensin-II receptor antagonist alleviates non-alcoholic fatty liver in KKAy obese mice with type 2 diabetes. 1686 24

The prevalence of obesity and diabetes has reached pandemic proportions. Obesity, particularly in association with high waist circumference and high BMI, is an independent risk factor for coronary heart disease (CHD) and diabetes. Several large studies have shown that marginal (5 lb) to moderate (11 to 22 lb) weight gain in adulthood (age 20 to 50 years) increases the risk of chronic disease and negatively affects CHD risk status. The metabolic syndrome, a clustering of cardiovascular and metabolic risk factors that includes abdominal obesity, is increasing among adults and children and is strongly associated with the development of diabetes and CHD. Recent evidence suggests that elevated liver enzymes, an indicator of non-alcoholic fatty liver disease, may comprise an additional component of the metabolic syndrome and may serve as a surrogate marker for type 2 diabetes, particularly if used in conjunction with C-reactive protein.
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PMID:Relationship of metabolic risk factors and development of cardiovascular disease and diabetes. 1693 93

The metabolic syndrome is a crucial factor in causation of type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) in South Asians. Approximately 20-25 per cent of urban South Asians have evidence of the metabolic syndrome. Furthermore, insulin resistance was reported to be present in nearly 30 per cent of children and adolescents in India, more so in girls. At the same time many young individuals have clustering of other risk factors/conditions related to insulin resistance (e.g., non-alcoholic fatty liver disease, obstructive sleep apnoea, etc.). Rapid nutritional and lifestyle transition in urbanized areas in various countries in South Asia are prime reasons for increasing prevalence of obesity and the metabolic syndrome. It is particularly important to effectively implement and strengthen population-based primary prevention strategies for the prevention of 'epidemic' of obesity and the metabolic syndrome. The lifestyle factor modification to prevent the metabolic syndrome and T2DM in South Asians should start in early childhood. Finally, there is an urgent need to conduct research studies regarding the correct definitions of the metabolic syndrome and genetic and perinatal factors related to insulin resistance in South Asians.
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PMID:The metabolic syndrome in South Asians: continuing escalation & possible solutions. 1749 60


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