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The Use of Fish Oil Lipid Emulsion in the Treatment of Intestinal Failure Associated Liver Disease (IFALD)  [PDF]
Melissa I. Chang,Mark Puder,Kathleen M. Gura
Nutrients , 2012, DOI: 10.3390/nu4121828
Abstract: Since 2004, fish oil based lipid emulsions have been used in the treatment of intestinal failure associated liver disease, with a noticeable impact on decreasing the incidence of morbidity and mortality of this often fatal condition. With this new therapy, however, different approaches have emerged as well as concerns about potential risks with using fish oil as a monotherapy. This review will discuss the experience to date with this lipid emulsion along with the rational for its use, controversies and concerns.
Lack of effect of apolipoprotein C3 polymorphisms on indices of liver steatosis, lipid profile and insulin resistance in obese Southern Europeans
Federica Sentinelli, Stefano Romeo, Cristina Maglio, Michela Incani, Maria A Burza, Francesca Scano, Federica Coccia, Efisio Cossu, Frida Leonetti, Marco G Baroni
Lipids in Health and Disease , 2011, DOI: 10.1186/1476-511x-10-93
Abstract: To determine if the APOC3 variants alter the susceptibility of obese subjects to develop liver damage, hypertrigliceridaemia, and insulin-resistance.The study was carried out on 585 unrelated obese Italians (median body mass index BMI = 41 kg/m2) who were genotyped for the rs2854116 and rs2854117 variants. All participants underwent oral glucose tolerance tests (OGTT), with measurement of glucose, insulin, lipid parameters. Indices of insulin-resistance (HOMA and ISI) were calculated. Alanine transaminase (ALT) and aspartate transaminase (AST) were used as markers of liver injury.The study subjects were divided into two groups: those homozygous for the wild-type alleles at both SNPs (-482C and -455T alleles) and those who were carriers of at least one variant allele or both (-482T, -455C or both). Also each SNP was analysed independently. No significant differences were found in ALT and AST levels and in the lipid profile between the two groups. Insulin concentrations, glucose tolerance and insulin sensitivity were similar in the two groups.We did not identify any significant association between APOC3 polymorphisms and fatty liver disease, lipids, and insulin-resistance in obese subjects, thus not confirming the suggested role of these APOC3 gene sequence variants.Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disorder arising from the interplay between genetic susceptibility and environmental influences. A large body of evidence shows that NAFLD is highly related to obesity and its metabolic consequences such as insulin resistance and dyslipidaemia [1]. In addition to altering metabolic risk, hepatic steatosis is also associated with significant liver disease in some patients. As many as 10-20% of patients with NAFLD develop steatohepatitis [1] and approximately 5% proceed to liver cirrhosis within 10 years of diagnosis [2].The hallmark of hepatic steatosis is the presence of triglycerides (TGs) stored as large lipid droplets in the cytoplasm of hepa
Nonalcoholic Fatty Liver Disease: Focus on Lipoprotein and Lipid Deregulation  [PDF]
Klementina Fon Tacer,Damjana Rozman
Journal of Lipids , 2011, DOI: 10.1155/2011/783976
Abstract: 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. 1. Introduction Nonalcoholic fatty liver disease (NAFLD) is progressively diagnosed worldwide and is considered to be the most common liver disorder in Western countries, estimated to affect at least one-quarter of the general population [1, 2]. NAFLD used to be almost exclusively a disease of adults but is now becoming a significant health issue also in obese children. The prevalence of childhood obesity has significantly increased over the past three decades [3, 4] and boosted the prevalence of NAFLD in adolescents (reviewed in [5]). NAFLD covers a spectrum of hepatic pathologies, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). It strongly associates with obesity, insulin resistance, hypertension, and dyslipidaemia and is now regarded as the liver manifestation of metabolic syndrome [6]. Simple steatosis is largely benign and nonprogressive whereas NASH is characterized by hepatocyte injury, inflammation, and fibrosis and can lead to cirrhosis, liver failure, and hepatocellular carcinoma [7]. Lipid accumulation in the liver is the major hallmark of NAFLD. A comprehensive understanding of the mechanisms leading to liver steatosis and further transition to nonalcoholic steatohepatitis (NASH) still remains elusive. There is no simple solution to understand the multi-factorial nature of NAFLD appearance and progression, presumably due to the nonlinear interactions of those factors. Abnormalities in lipid and lipoprotein metabolism accompanied by chronic inflammation are considered to be the central pathway for the development of several obesity-related co-morbidities such as NAFLD and cardio-vascular disease (CVD) [8, 9]. NAFLD
Systemic abnormalities in liver disease  [cached]
Masami Minemura, Kazuto Tajiri, Yukihiro Shimizu
World Journal of Gastroenterology , 2009,
Abstract: Systemic abnormalities often occur in patients with liver disease. In particular, cardiopulmonary or renal diseases accompanied by advanced liver disease can be serious and may determine the quality of life and prognosis of patients. Therefore, both hepatologists and non-hepatologists should pay attention to such abnormalities in the management of patients with liver diseases.
Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing  [PDF]
Dan Xu,Toshi Nishimura,Sachiko Nishimura,Haili Zhang,Ming Zheng,Ying-Ying Guo,Marylin Masek,Sara A. Michie,Jeffrey Glenn ,Gary Peltz
PLOS Medicine , 2014, DOI: 10.1371/journal.pmed.1001628
Abstract: Background Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers. Methods and Findings Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers. Conclusions FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve the safety of candidate medications selected for testing in human participants. Please see later in the article for the Editors' Summary
Dietary Conjugated Linoleic Acid and Hepatic Steatosis: Species-Specific Effects on Liver and Adipose Lipid Metabolism and Gene Expression  [PDF]
Diwakar Vyas,Anil Kumar G. Kadegowda,Richard A. Erdman
Journal of Nutrition and Metabolism , 2012, DOI: 10.1155/2012/932928
Abstract: Objective. To summarize the recent studies on effect of conjugated linoleic acid (CLA) on hepatic steatosis and hepatic and adipose lipid metabolism highlighting the potential regulatory mechanisms. Methods. Sixty-four published experiments were summarized in which trans-10, cis-12 CLA was fed either alone or in combination with other CLA isomers to mice, rats, hamsters, and humans were compared. Summary and Conclusions. Dietary trans-10, cis-12 CLA induces a severe hepatic steatosis in mice with a more muted response in other species. Regardless of species, when hepatic steatosis was present, a concurrent decrease in body adiposity was observed, suggesting that hepatic lipid accumulation is a result of uptake of mobilized fatty acids (FA) from adipose tissue and the liver's inability to sufficiently increase FA oxidation and export of synthesized triglycerides. The potential role of liver FA composition, insulin secretion and sensitivity, adipokine, and inflammatory responses are discussed as potential mechanisms behind CLA-induced hepatic steatosis. 1. Introduction Obesity is a chronic metabolic nutritional disorder that has increased at an alarming rate in the last 20 years [1]. In the US, 68% of the adults (age ≥ 20 years) and 18% of children (2–19 years) are either obese or overweight as per the National Health and Nutrition Examination Survey [2, 3]. Incidence of obesity is associated with many health complications such as hypertension, hyperlipidemia, cardiovascular disease, type 2 diabetes [4], and a range of lipid abnormalities, the most common being nonalcoholic fatty liver disease (NAFLD) [4]. NAFLD is an important health concern due to its high prevalence (~20% of adult population) and its association with insulin resistance and metabolic syndrome [5]. It is characterized by hepatic lipid accumulation primarily in the form of triglycerides (TG) [6]. Some of the potential steps involved in the progression of NAFLD may involve increased uptake of circulating fatty acids (FA) [7], increased hepatic denovo lipogenesis (DNL) [8], reduced rate of FA oxidation [9], or reduced FA secretion [10, 11]. When NAFLD is associated with inflammation and fibrosis, it is termed as nonalcoholic steatohepatitis (NASH), a serious condition that could lead to liver cirrhosis, hepatic carcinoma, and liver failure [12]. The pathogenesis of NAFLD can be explained by “two hit” hypothesis suggesting steatosis as the “first hit” which increases the vulnerability of liver to various second hits like oxidative stress and inflammation leading to NASH [13]. Although no
When the heart kills the liver: acute liver failure in congestive heart failure
FH Saner, M Heuer, M Meyer, A Canbay, GC Sotiropoulos, A Radtke, J Treckmann, S Beckebaum, C Dohna-Schwake, SW Oldedamink, A Paul
European Journal of Medical Research , 2009, DOI: 10.1186/2047-783x-14-12-541
Abstract: Although the pathophysiology is poorly understood, there is rising evidence, that low cardiac output with consecutive reduction in hepatic blood flow is a main causing factor, rather than hypotension. In the setting of acute liver failure due to congestive heart failure, clinical signs of the latter can be absent, which requires an appropriate diagnostic approach.As a reference center for acute liver failure and liver transplantation we recorded from May 2003 to December 2007 202 admissions with the primary diagnoses acute liver failure. 13/202 was due to congestive heart failure, which was associated with a mortality rate of 54%. Leading cause of death was the underlying heart failure. Asparagine transaminase (AST), bilirubin, and international normalized ratio (INR) did not differ significantly in surviving and deceased patients at admission. Despite both groups had signs of cardiogenic shock, the cardiac index (CI) was significantly higher in the survival group on admission as compared with non-survivors (2.1 L/min/m2 vs. 1.6 L/min/m2, p = 0.04). Central venous - and pulmonary wedge pressure did not differ significantly. Remarkable improvement of liver function was recorded in the group, who recovered from cardiogenic shock.In conclusion, patients with acute liver failure require an appropriate diagnostic approach. Congestive heart failure should always be considered as a possible cause of acute liver failure.Acute liver failure (ALF) is defined as an abrupt onset of jaundice, hepatic encephalopathy, and coagulopathy in the absent of pre-existing liver disease [11]. Cardiomyopathy as the underlying cause of ALF is rare and only a few case reports are documented in the literature [5,7,8,18]. Cardiac decompensation can initially be undetected, and the usual signs of congestive heart failure may be absent [5,18]. Both, chronic and acute congestive heart failure can lead to hepatic dysfunction [10,17]. Although there is no classic pattern of abnormalities, a cholesta
Hemostatic abnormalities in liver cirrhosis
Dicle Medical Journal , 2009,
Abstract: In this study, 44 patients with liver cirrhosis were investigated for hemostatic parameters. Patients with spontaneous bacterial peritonitis, hepatocellular carcinoma, hepatorenal syndrome and cholestatic liver diseases were excluded. Patients were classified by Child-Pugh criterion and according to this 4 patients were in Class A, 20 in Class B and 20 in C. Regarding to these results, it was aimed to investigate the haematological disturbances in liver cirrhotic patients.In the result there was a correlation between activated partial thromboplastin time, serum iron, ferritin, transferrin, haptoglobin and Child-Pugh classification. Besides there was no correlation between prothrombin time, factor 8 and 9, protein C and S, anti-thrombin 3, fibrinogen, fibrin degradation products, serum iron binding capacity, hemoglobin, leukocyte, mean corpuscular volume and Child-Pugh classification.There were significant difference, in terms of AST, ferritin, haptoglobulin, sex and presence of ascites between groups (p<0.05). In all groups there were abnormalities and dysfunctions in prothrombin time, fibrinogen, factor 8 and 9, serum iron, ferritin, transferrin, haptoglobin, protein C and S, anti-thrombin 3, hemoglobin and platelets, where there was no in activated partial thromboplastin time, fibrin degradation products, serum iron binding capacity, leucocytes and mean corpuscular volume (p>0.05). In the summary, we have found correlation between hemostatic abnormalities and disease activity and clinical prognosis in patients with liver cirrhosis which is important in the management of these patients. This is also important for identification of liver transplant candidiates earlier.
Lipid Abnormalities and Cardiometabolic Risk in Patients with Overt and Subclinical Thyroid Disease  [PDF]
Melpomeni Peppa,Grigoria Betsi,George Dimitriadis
Journal of Lipids , 2011, DOI: 10.1155/2011/575840
Abstract: Dyslipidemia is a common finding in patients with thyroid disease, explained by the adverse effects of thyroid hormones in almost all steps of lipid metabolism. Not only overt but also subclinical hypo- and hyperthyroidism, through different mechanisms, are associated with lipid alterations, mainly concerning total and LDL cholesterol and less often HDL cholesterol, triglycerides, lipoprotein (a), apolipoprotein A1, and apolipoprotein B. In addition to quantitative, qualitative alterations of lipids have been also reported, including atherogenic and oxidized LDL and HDL particles. In thyroid disease, dyslipidemia coexists with various metabolic abnormalities and induce insulin resistance and oxidative stress via a vice-vicious cycle. The above associations in combination with the thyroid hormone induced hemodynamic alterations, might explain the increased risk of coronary artery disease, cerebral ischemia risk, and angina pectoris in older, and possibly ischemic stroke in younger patients with overt or subclinical hyperthyroidism. 1. Introduction Thyroid disease, namely hypothyroidism and hyperthyroidism, constitutes the most common endocrine abnormality in recent years, diagnosed either in subclinical or clinical form. According to the 6-year duration NHANES III Study, the prevalence of hypothyroidism was 4.6% (0.3% clinical and 4.3% subclinical) and of hyperthyroidism 1.3% (0.5% clinical and 0.7% subclinical), in population aged at least 12 years, showing an age and sex dependence [1]. Thyroid disease is associated with various metabolic abnormalities, due to the effects of thyroid hormones on nearly all major metabolic pathways. Thyroid hormones regulate the basal energy expenditure through their effect on protein, carbohydrate, and lipid metabolism. This might be a direct effect or an indirect effect by modification of other regulatory hormones such as insulin or catecholamines [2]. Dyslipidemia is a common metabolic abnormality in patients with thyroid disease, either in the overt or subclinical forms of the disease, and constitutes the end result of the effect of thyroid hormones in all aspects of lipid metabolism leading to various quantitative and/or qualitative changes of triglycerides, phospholipids, cholesterol, and other lipoproteins [3]. In thyroid disease, dyslipidemia and the coexisting metabolic abnormalities, in combination with the thyroid hormone-induced hemodynamic alterations, explain the high risk for cardiovascular disease [4–7]. 2. Effects of Thyroid Hormones on Lipid Metabolism Thyroid hormones influence all aspects of lipid
Nonalcoholic fatty liver disease and mitochondrial dysfunction  [cached]
Yongzhong Wei, R Scott Rector, John P Thyfault, Jamal A Ibdah
World Journal of Gastroenterology , 2008,
Abstract: Nonalcoholic fatty liver disease (NAFLD) includes hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. NAFLD is the most common liver disorder in the United States and worldwide. Due to the rapid rise of the metabolic syndrome, the prevalence of NAFLD has recently dramatically increased and will continue to increase. NAFLD has also the potential to progress to hepatocellular carcinoma (HCC) or liver failure. NAFLD is strongly linked to caloric overconsumption, physical inactivity, insulin resistance and genetic factors. Although significant progress in understanding the pathogenesis of NAFLD has been achieved in years, the primary metabolic abnormalities leading to lipid accumulation within hepatocytes has remained poorly understood. Mitochondria are critical metabolic organelles serving as “cellular power plants”. Accumulating evidence indicate that hepatic mitochondrial dysfunction is crucial to the pathogenesis of NAFLD. This review is focused on the significant role of mitochondria in the development of NAFLD.
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