Hepatic Manifestation Of Obesity Research Articles

Role of Circulating Vascular Cell Adhesion Protein – 1 as a Biomarker in Non-alcoholic Fatty Liver Disease

Background As a result of the obesity pandemic, non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. NAFLD is the hepatic manifestation of obesity and a precursor of and independent risk factor for type 2 diabetes Aim of the Work To assess the level of vascular cell adhesion molecule 1 (VCAM-1) as noninvasive diagnostic tools for diagnosis of NAFLD degree of fibrosis. Patients and Methods A Case-Control clinical study in the Internal medicine and hepatology outpatient clinic at Ain Shams University Hospital for 6-month on 60 persons that were included in this study divided into 2 groups: Group A: 30 patient with NAFLD as a study group. Group B: 30 healthy subjects as a control group. Results In the present study, the mean VCAM-1 was 2.392 ± 0.3 in NAFLD group, 9.893 ± 2.3 in NASH group and 1.983 ± 0.3 in control group with high statistical significant increase in NASH followed by NAFLD than in control group. Regarding to ROC curve, VCAM-1 had excellent Diagnostic performance with an AUC of 0.994. A best cut-off criterion of VCAM-1 > 7.7 ng/mL could discriminate between patients with NASH from control group with a sensitivity of 95% and specificity of 100% In our study, there was no significant correlation in between VCAM-1 and age, AST, ALT In the present study, the significant predictors of bad outcome in patients with NAFLD and NASH were higher VCAM-1 level, GGT and higher AST levels Conclusion The significant predictors of bad outcome in patients with NAFLD and NASH were higher VCAM-1 level, GGT and higher AST levels.

Can Walnut Serve as a Magic Bullet for the Management of Non-Alcoholic Fatty Liver Disease?

Walnut contains many nutrients and bioactive components such as essential fatty acids, polyphenols, fiber, ɤ-tocopherol, folate, minerals, and vegetable protein, and has therefore been regarded as a natural functional food. Walnut-enriched diets have been demonstrated to be useful for heart health, cancer prevention, and metabolic disorders owing to their anti-oxidative and anti-inflammatory properties as well as for the maintenance of a healthy metabolism and immune function. Walnut extracts, either phenolic or lipid, also demonstrated the health effects in animal and cultured cell studies. More recently, the beneficial effects of walnut consumption on non-alcoholic fatty liver disease, which is a hepatic manifestation of obesity, hyperlipidemia, type 2 diabetes mellitus, and metabolic syndrome with substantial hepatic accumulation of triglyceride, have been proposed because walnut and a walnut-containing diet can modulate the etiologic mechanism such as ameliorating systemic and hepatic dyslipidemia, reducing lipotoxicity and inflammation, enhancing immune function, and maintaining gut microbiota balance. Through the extensive literature review we discuss the preventive roles of walnut in the development and progression of non-alcoholic fatty liver disease (NAFLD) and provide mechanistic insights into these effects.

Hepatic Mediators of Lipid Metabolism and Ketogenesis: Focus on Fatty Liver and Diabetes.

Diabetes mellitus (DM) is a chronic disorder that it is caused by the absence of insulin secretion due to the inability of the pancreas to produce it (type 1 diabetes; T1DM), or due to defects of insulin signaling in the peripheral tissues, resulting in insulin resistance (type 2 diabetes; T2DM). Commonly, the occurrence of insulin resistance in T2DM patients reflects the high prevalence of obesity and non-alcoholic fatty liver disease (NAFLD) in these individuals. In fact, approximately 60% of T2DM patients are also diagnosed to have NAFLD, and this condition is strongly linked with insulin resistance and obesity. NAFLD is the hepatic manifestation of obesity and metabolic syndrome and includes a spectrum of pathological conditions, which range from simple steatosis (NAFL), non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. NAFLD manifestation is followed by a series of hepatic lipid deregulations and the main abnormalities are increased triglyceride levels, increased hepatic production of VLDL and a reduction in VLDL catabolism. During the progression of NAFLD, the production of ketone bodies progressively reduces while hepatic glucose synthesis and output increases. In fact, most of the fat that enters the liver can be disposed of through ketogenesis, preventing the development of NAFLD and hyperglycemia. This review will focus on the pathophysiological aspect of hepatic lipid metabolism deregulation, ketogenesis, and its relevance in the progression of NAFLD and T2DM. A better understanding of the molecular mediators involved in lipid synthesis and ketogenesis can lead to new treatments for metabolic disorders in the liver, such as NAFLD.

1859-P: Hepatic NIK Augments Hepatocyte Ferroptosis and Hepatic Inflammation in Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of obesity and diabetes. Hepatocyte injury and death pathologically mark a turning point from simple liver steatosis to nonalcoholic steatohepatitis (NASH). Chronic hepatocyte injury and hepatic inflammation drive liver fibrosis, leading to liver cirrhosis, end-stage liver failure, and/or hepatocellular carcinoma. We previously reported that NAFLD is associated with a marked elevation of NF-κB-inducing kinase (NIK) in the liver. NIK in turn augments the hepatic hyperglycemic response to counterregulatory hormone glucagon, contributing to hyperglycemia and diabetes progression. Here, we demonstrate that hepatic NIK also promotes hepatocyte injury and death, exacerbating liver disease. We found that hepatocyte-specific overexpression of NIK substantially increased hepatocyte death and liver inflammation in mice treated with acetaminophen (APAP), a hepatocyte-toxic drug. Conversely, hepatocyte-specific deletion of NIK significantly blunted APAP-induced liver injury and hepatitis. In line with these findings, in primary liver cell cultures, overexpression of NIK substantially enhanced APAP sensitivity to induce cell death. Notably, NIK overexpression dramatically increased liver reactive oxygen species (ROS) levels in APAP-treated mice, and ablation of hepatocyte NIK had the opposite effects. Treatment with antioxidant N-acetylcysteine abrogated the ability of NIK and APAP to induce hepatocyte death and liver inflammation. Given that ROS drives ferroptosis, we treated primary liver cells with ferroptosis inhibitors ferrostatin 1 and liproxtatin-1. Both ferrostatin 1 and liproxtatin-1 dose-dependently suppressed NIK/APAP-induced cell death. Collectively, our data suggest that aberrant activation of hepatic NIK augments hepatocyte ferroptosis, thereby promoting liver injury, liver inflammation, and liver disease progression. Disclosure X. Zhong: None. L. Rui: None.

Lipoprotein Lipase Up-regulation in Hepatic Stellate Cells Exacerbates Liver Fibrosis in Nonalcoholic Steatohepatitis in Mice.

Lipoprotein lipase (LPL) plays a central role in incorporating plasma lipids into tissues and regulates lipid metabolism and energy balance in the human body. Conversely, LPL expression is almost absent in normal adult livers. Therefore, its physiological role in the liver remains unknown. We aimed to elucidate the role of LPL in the pathophysiology of nonalcoholic steatohepatitis (NASH), a hepatic manifestation of obesity. Hepatic stellate cell (HSC)–specific LPL‐knockout (LplHSC‐KO) mice, LPL‐floxed (Lplfl/fl) mice, or double‐mutant toll‐like receptor 4–deficient (Tlr4−/−) LplHSC‐KO mice were fed a high‐fat/high‐cholesterol diet for 4 weeks to establish the nonalcoholic fatty liver model or an high‐fat/high‐cholesterol diet for 24 weeks to establish the NASH model. Human samples, derived from patients with nonalcoholic fatty liver disease, were also examined. In human and mouse NASH livers, serum obesity‐related factors, such as free fatty acid, leptin, and interleukin‐6, dramatically increased the expression of LPL, specifically in HSCs through signal transducer and activator of transcription 3 signaling, as opposed to that in hepatocytes or hepatic macrophages. In the NASH mouse model, liver fibrosis was significantly reduced in LplHSC‐KO mice compared with that in Lplfl/fl mice. Nonenzymatic LPL‐mediated cholesterol uptake from serum lipoproteins enhanced the accumulation of free cholesterol in HSCs, which amplified TLR4 signaling, resulting in the activation of HSCs and progression of hepatic fibrosis in NASH. Conclusion: The present study reveals the pathophysiological role of LPL in the liver, and furthermore, clarifies the pathophysiology in which obesity, as a background factor, exacerbates NASH. The LPL‐mediated HSC activation pathway could be a promising therapeutic target for treating liver fibrosis in NASH.

Eicosapentaenoic acid attenuates obesity-related hepatocellular carcinogenesis.

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity, is an emerging risk factor for hepatocellular carcinoma (HCC). Accumulating evidence has shown that chronic inflammation represents a plausible link between obesity and HCC and that the pro-inflammatory cytokine interleukin (IL)-6 contributes to the development of obesity-related HCC. In the present study, we aimed to examine the therapeutic potential of the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA), which exerts anti-inflammatory effects. The results showed that the development of carcinogen-induced HCC was significantly less in mice fed a high-fat diet (HFD) supplemented with EPA than in those fed HFD only, suggesting that EPA attenuates the development of obesity-related HCC. Although EPA did not appear to affect obesity-linked inflammation, it suppressed the activation of the pro-tumorigenic IL-6 effector STAT3, contributing to the inhibition of tumor growth. These findings suggest a clinical implication of EPA as a treatment for obesity-related HCC.

Liver transplantation for nonalcoholic steatohepatitis in young patients.

Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of obesity and insulin resistance. The aim of this study was to determine the frequency of NASH as an indication for liver transplantation (LT) in children and young adults and to characterize patient and graft survival. The study included all children and young adult patients (up to the age of 40years) who underwent LT in the United States for NASH cirrhosis from the 1987 to 2012 United Network for Organ Sharing (UNOS) database. Kaplan-Meier analysis was used to assess patient and graft survival. A total of 330 patients were included, 68% were Caucasian, and the mean BMI was 33.6±6.3. Age at time of LT ranged between 4 and 40years (mean 33.9±6.6years). Fourteen subjects were <18years of age at time of LT and 20 were between the ages of 18 and 25years. Median follow-up after 1st LT was 45.8months [10.7, 97.3]. During this time, 30% of subjects (n=100) died and 11.5% (n=38) were retransplanted including 13 for NASH recurrence. In conclusion, NASH can progress to end-stage liver disease requiring LT in childhood and early adulthood. A significant number of young patients transplanted for NASH cirrhosis required retransplantation.

Decaffeinated green tea extract rich in epigallocatechin-3-gallate prevents fatty liver disease by increased activities of mitochondrial respiratory chain complexes in diet-induced obesity mice

Nonalcoholic fatty liver disease has been considered the hepatic manifestation of obesity. It is unclear whether supplementation with green tea extract rich in epigallocatechin-3-gallate (EGCG) influences the activity of mitochondrial respiratory chain complexes and insulin resistance in the liver. EGCG regulated hepatic mitochondrial respiratory chain complexes and was capable of improving lipid metabolism, attenuating insulin resistance in obese mice. Mice were divided into four groups: control diet+water (CW) or EGCG (CE) and hyperlipidic diet+water (HFW) or EGCG (HFE). All animals received water and diets ad libitum for 16weeks. Placebo groups received water (0.1ml/day) and EGCG groups (0.1ml EGCG and 50mg/kg/day) by gavage. Cytokines concentrations were obtained by ELISA, protein expression through Western blotting and mitochondrial complex enzymatic activity by colorimetric assay of substrate degradation. HFW increased body weight gain, adiposity index, retroperitoneal and mesenteric adipose tissue relative weight, serum glucose, insulin and Homeostasis Model Assessment of Basal Insulin Resistance (HOMA-IR); glucose intolerance was observed in oral glucose tolerance test (OGTT) as well as ectopic fat liver deposition. HFE group decreased body weight gain, retroperitoneal and mesenteric adipose tissue relative weight, HOMA-IR, insulin levels and liver fat accumulation; increased complexes II-III and IV and malate dehydrogenase activities and improvement in glucose uptake in OGTT and insulin sensitivity by increased protein expression of total AKT, IRα and IRS1. We did not find alterations in inflammatory parameters analyzed. EGCG was able to prevent obesity stimulating the mitochondrial complex chain, increasing energy expenditure, particularly from the oxidation of lipid substrates, thereby contributing to the prevention of hepatic steatosis and improved insulin sensitivity.

Su1038 Liver Transplantation for Nonalcoholic Steatohepatitis (NASH) in Children and Young Adults: The True Burden of Pediatric Nonalcoholic Fatty Liver Disease

Background: Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of obesity and can progress to liver cirrhosis even during childhood and early adulthood. The aim of this study was to determine the frequency of NASH as an indication for liver transplantation (LT) in children and young adults and to characterize patient and graft survival in this cohort using a comprehensive large national liver transplantation registry in the U.S. Methods: The study included all children and young adult patients (up to the age of 40 years) who underwent LT in the U.S. from the 1987-2012 United Network for Organ Sharing and Organ Procurement and Transplantation Network (UNOS/OPTN) database. We created a modified NASH category that included LT recipients who were given a primary diagnosis of NASH plus obese patients with primary diagnosis of cryptogenic cirrhosis (CC). KaplanMeier analysis was used to assess patient and graft survival. Results: A total of 330 patients were included (111 with NASH and 219 with CC and BMI ≥ 30 kg/m2). 52% were male, 68% were Caucasian, the mean BMI was 33.6 ± 6.3 and diabetes was present in 18%. Age at time of LT ranged between 4 and 40 years with a mean of 33.9 ± 6.6 years. 14 subjects were < 18 years of age at time of LT and 20 were between the ages of 18-25 years. A progressive increase in NASH as the primary indication for LT in young subjects is seen from 2001 to 2012 (Figure). Median follow-up after 1st LT was 45.8 months [10.7, 97.3]. During this time 30% of subjects (n = 100) died and 11.5% (n = 38) were re-transplanted including 13 for NASH recurrence. Conclusion: NASH can progress to end-stage liver disease requiring LT in childhood and early adulthood. A significant number of young patients transplanted for NASH cirrhosis required re-transplantation with one third being done for NASH recurrence.

Su1039 The Longitudinal Association Between Alcohol Consumption and Fatty Liver in Japanese Subjects

Background: Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of obesity and can progress to liver cirrhosis even during childhood and early adulthood. The aim of this study was to determine the frequency of NASH as an indication for liver transplantation (LT) in children and young adults and to characterize patient and graft survival in this cohort using a comprehensive large national liver transplantation registry in the U.S. Methods: The study included all children and young adult patients (up to the age of 40 years) who underwent LT in the U.S. from the 1987-2012 United Network for Organ Sharing and Organ Procurement and Transplantation Network (UNOS/OPTN) database. We created a modified NASH category that included LT recipients who were given a primary diagnosis of NASH plus obese patients with primary diagnosis of cryptogenic cirrhosis (CC). KaplanMeier analysis was used to assess patient and graft survival. Results: A total of 330 patients were included (111 with NASH and 219 with CC and BMI ≥ 30 kg/m2). 52% were male, 68% were Caucasian, the mean BMI was 33.6 ± 6.3 and diabetes was present in 18%. Age at time of LT ranged between 4 and 40 years with a mean of 33.9 ± 6.6 years. 14 subjects were < 18 years of age at time of LT and 20 were between the ages of 18-25 years. A progressive increase in NASH as the primary indication for LT in young subjects is seen from 2001 to 2012 (Figure). Median follow-up after 1st LT was 45.8 months [10.7, 97.3]. During this time 30% of subjects (n = 100) died and 11.5% (n = 38) were re-transplanted including 13 for NASH recurrence. Conclusion: NASH can progress to end-stage liver disease requiring LT in childhood and early adulthood. A significant number of young patients transplanted for NASH cirrhosis required re-transplantation with one third being done for NASH recurrence.

Thrombin inhibition with dabigatran protects against high-fat diet-induced fatty liver disease in mice.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome. Robust coagulation cascade activation is common in obese patients with NAFLD. We identified a critical temporal relationship between thrombin generation and the manifestation of hepatic steatosis, inflammation, and injury in C57BL/6J mice fed a high-fat diet (HFD) for 1, 2, and 3 months. Mice fed a HFD exhibited dramatic increases in hepatocellular injury and inflammation over time. Hepatic fibrin deposition preceded an increase in serum alanine aminotransferase, and the most dramatic changes in liver histopathology occurred in conjunction with a detectable increase in plasma thrombin-antithrombin levels at 3 months. To directly determine whether thrombin activity promotes NAFLD pathogenesis, mice were fed a HFD and simultaneously treated with the direct thrombin inhibitor dabigatran etexilate for 3 months. Notably, dabigatran treatment significantly reduced hepatic fibrin deposition, hepatic inflammation, hepatocellular injury, and steatosis in mice fed a HFD. Of interest, dabigatran treatment also significantly attenuated HFD-induced body weight gain. Gene expression analysis suggested that thrombin potentially drives NAFLD pathogenesis by altering the expression of genes associated with lipid metabolism and bile acid synthesis. Collectively, the results suggest that thrombin activity is central to HFD-induced body weight gain, liver injury, and inflammation and provide the proof-of-principle evidence that pharmacological thrombin inhibition could be effective in limiting NAFLD and associated pathologies.

Abstract 18552: The Thrombin Inhibitor Dabigatran Inhibits High Fat Diet-induced Obesity and Fatty Liver Disease in Mice

Inflammation associated with non-alcoholic fatty liver disease (NALFD) increases the risk of adverse cardiovascular events. NAFLD is the hepatic manifestation of obesity and the metabolic syndrome and significantly contributes to liver-related morbidity. We have shown previously that the thrombin receptor protease activated receptor-1 (PAR-1) is essential for hepatic inflammation and steatosis in mice fed a high fat diet (HFD), but PAR-1 deficiency does not affect weight gain in mice fed a HFD. To determine whether pharmacologic inhibitors of thrombin could reduce the progression of NAFLD in mice on a HFD, we utilized the direct thrombin inhibitor, dabigatran etexilate. Wild type C57Bl/6 mice were fed a HFD formulated to contain dabigatran (10 mg/g chow) or an identical HFD with starch substituted for drug for 3 months. Plasma thrombin time was significantly prolonged in mice fed HFD+dabigatran, but no adverse bleeding events were observed. Despite consuming a similar amount of chow, mice fed HFD+dabigatran gained significantly less body weight compared to mice fed HFD alone. Induction of inflammatory genes including TNFα, MCP-1, and the lipogenic genes SCD-1 and CD36, was significantly reduced in livers of mice fed HFD+dabigatran compared to mice fed HFD alone. In agreement, hepatic steatosis was dramatically reduced by dabigatran in mice fed a HFD. In summary, pharmacologic inhibition of thrombin with dabigatran reduced various features of NAFLD in mice fed a HFD. In contrast to PAR-1-deficient mice, dabigatran administration also dramatically reduced diet-induced obesity. Taken together, the results indicate that thrombin contributes to NAFLD in mice fed a HFD, and that thrombin promotes diet-induced obesity in a PAR-1-independent manner. Clinical evaluation of the potential for thrombin inhibition to reduce systemic and hepatic inflammation in obese patients taking dabigatran for another indication, such as atrial fibrillation, could reveal novel beneficial effects of oral thrombin inhibitors in metabolic disease.

Hepatocellular carcinoma in non-alcoholic fatty liver disease: An emerging menace

Hepatocellular carcinoma (HCC) is a common cancer worldwide that primarily develops in cirrhosis resulting from chronic infection by hepatitis B virus and hepatitis C virus, alcoholic injury, and to a lesser extent from genetically determined disorders such as hemochromatosis. HCC has recently been linked to non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity and related metabolic disorders such as diabetes. This association is alarming due to the globally high prevalence of these conditions and may contribute to the rising incidence of HCC witnessed in many industrialized countries. There is also evidence that NAFLD acts synergistically with other risk factors of HCC such as chronic hepatitis C and alcoholic liver injury. Moreover, HCC may complicate non-cirrhotic NAFLD with mild or absent fibrosis, greatly expanding the population potentially at higher risk. Major systemic and liver-specific molecular mechanisms involved include insulin resistance and hyperinsulinemia, increased TNF signaling pathways, and alterations in cellular lipid metabolism. These provide new targets for prevention, early recognition, and effective treatment of HCC associated with NAFLD. Indeed, both metformin and PPAR gamma agonists have been associated with lower risk and improved prognosis of HCC. This review summarizes current evidence as it pertains to the epidemiology, pathogenesis, and prevention of NAFLD-associated HCC.

Protease-Activated Receptor 1 and Hematopoietic Cell Tissue Factor Are Required for Hepatic Steatosis in Mice Fed a Western Diet

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome and contributes to increased risk of cardiovascular disease and liver-related morbidity and mortality. Indeed, obese patients with metabolic syndrome generate greater amounts of thrombin, an indication of coagulation cascade activation. However, the role of the coagulation cascade in Western diet-induced NAFLD has not been investigated. Using an established mouse model of Western diet-induced NAFLD, we tested whether the thrombin receptor protease-activated receptor 1 (PAR-1) and hematopoietic cell-derived tissue factor (TF) contribute to hepatic steatosis. In association with hepatic steatosis, plasma thrombin-antithrombin levels and hepatic fibrin deposition increased significantly in C57Bl/6J mice fed a Western diet for 3 months. PAR-1 deficiency reduced hepatic inflammation, particularly monocyte chemoattractant protein-1 expression and macrophage accumulation. In addition, PAR-1 deficiency was associated with reduced steatosis in mice fed a Western diet, including reduced liver triglyceride accumulation and CD36 expression. Similar to PAR-1 deficiency, hematopoietic cell TF deficiency was associated with reduced inflammation and reduced steatosis in livers of low-density lipoprotein receptor-deficient mice fed a Western diet. Moreover, hematopoietic cell TF deficiency reduced hepatic fibrin deposition. These studies indicate that PAR-1 and hematopoietic cell TF are required for liver inflammation and steatosis in mice fed a Western diet.

Nonalcoholic Fatty Liver Disease: Focus on Lipoprotein and Lipid Deregulation

Obesity with associated comorbidities is currently a worldwide epidemic and among the most challenging health conditions in the 21st century. A major metabolic consequence of obesity is insulin resistance which underlies the pathogenesis of the metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome. It comprises a disease spectrum ranging from simple steatosis (fatty liver), through nonalcoholic steatohepatitis (NASH) to fibrosis, and ultimately liver cirrhosis. Abnormality in lipid and lipoprotein metabolism accompanied by chronic inflammation is the central pathway for the development of metabolic syndrome-related diseases, such as atherosclerosis, cardiovascular disease (CVD), and NAFLD. This paper focuses on pathogenic aspect of lipid and lipoprotein metabolism in NAFLD and the relevant mouse models of this complex multifactorial disease.

Aminotransferase Levels and 20-Year Risk of Metabolic Syndrome, Diabetes, and Cardiovascular Disease

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome (MetS). Alanine aminotransferase (ALT) levels are used to detect NAFLD and have also been associated with increased risk for MetS, diabetes mellitus, and cardiovascular disease (CVD). We studied the relationship between ALT levels and these disorders in a long-term follow-up study. Framingham Offspring Heart Study participants (n = 2812; mean age, 44 years; 56% women) were followed for the development of MetS, diabetes, CVD, and all-cause mortality using logistic regression (MetS, diabetes) or Cox proportional hazards models (CVD, all-cause mortality). Among individuals at baseline, per 1 standard deviation increase in log ALT level, there were increased odds of the development of MetS (odds ratio [OR] 1.21, P < .001) and diabetes (OR, 1.48; P < .0001) over 20 years of follow-up. These findings also applied to participants with ALT levels within the normal range (MetS OR, 1.17; P = .006; diabetes OR, 1.34; P =.002). There was an increased risk of CVD in age/gender-adjusted models (hazard ratio, 1.23; P < .0001), but this was attenuated in multivariable-adjusted models (hazard ratio 1.05; P = .27); no association was observed for all-cause mortality. Aspartate aminotransferase levels were found to be associated with an increased risk of only diabetes. Both normal and increased levels of ALT are associated with long-term development of multiple metabolic disorders. These results indicate the potential for ALT values as biomarkers for the risk of metabolic disease.

Nonalcoholic Fatty Liver Disease: Hepatic Manifestation of Obesity and the Metabolic Syndrome

Obesity is currently a worldwide epidemic, and will likely only increase in prevalence in the coming years. The incidence of the metabolic syndrome (MetS) seems to be paralleling obesity. The MetS is strongly linked to insulin resistance, abdominal obesity, diabetes mellitus, and dyslipidemia. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and the MetS. Although not currently a formal component of the MetS, data suggest a very strong correlation between NAFLD and the MetS; insulin resistance appears to be the common factor. Nonalcoholic steatohepatitis (NASH) is a more advanced stage in the spectrum of NAFLD, which can progress to cirrhosis. Management strategies for NAFLD are conceivably similar to those for the MetS, which focus on lifestyle measures aimed at weight reduction and maintenance. The purpose of this review is to highlight the growing epidemic of obesity and the MetS, and the strong likelihood of an increase in the prevalence of the already widely existent combination of NAFLD/NASH. This article describes pharmacological treatments including novel therapies aimed at the hepatic pathophysiologic process, as well as surgical options. The increasing prevalence of obesity and the MetS places a large population at risk for developing hepatic failure. Therefore, NAFLD must be acknowledged as a major worldwide public health concern.

Liver fat is reproducibly measured using computed tomography in the Framingham Heart Study

Fatty liver is the hepatic manifestation of obesity, but community-based assessment of fatty liver among unselected patients is limited. We sought to determine the feasibility of and optimal protocol for quantifying fat content in the liver in the Framingham Heart Study using multidetector computed tomography (MDCT) scanning. Participants (n = 100, 49% women, mean age 59.4 years, mean body mass index 27.8 kg/m(2)) were drawn from the Framingham Heart Study cohort. Two readers measured the attenuation of the liver, spleen, paraspinal muscles, and an external standard from MDCT scans using multiple slices in chest and abdominal scans. The mean measurement variation was larger within a single axial computed tomography (CT) slice than between multiple axial CT slices for the liver and spleen, whereas it was similar for the paraspinal muscles. Measurement variation in the liver, spleen, and paraspinal muscles was smaller in the abdomen than in the chest. Three versus six measures of attenuation in the liver and two versus three measures in the spleen gave reproducible measurements of tissue attenuation (intraclass correlation coefficient [ICCC] of 1 in the abdomen). Intra reader and interreader reproducibility (ICCC) of the liver-to-spleen ratio was 0.98 and 0.99, the liver-to-phantom ratio was 0.99 and 0.99, and the liver-to-muscle ratio was 0.93 and 0.86, respectively. One cross-sectional slice is adequate to capture the majority of variance of fat content in the liver per individual. Abdominal scan measures as compared to chest scan measures of fat content in the liver are more precise. The measurement of fat content in the liver on MDCT scans is feasible and reproducible.