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PubMed2004

Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver.

The mechanism(s) determining the progression from fatty liver to steatohepatitis is currently unknown. Our goal was to define the relative impact of iron overload, genetic mutations of HFE, and insulin resistance on the severity of liver fibrosis in a population of subjects with nonalcoholic fatty liver disease (NAFLD) who had low prevalence of obesity and no overt symptoms of diabetes. In a cohort of 263 prospectively enrolled patients with NAFLD, 7.4% of patients had signs of peripheral iron overload and 9% had signs of hepatic iron overload, but 21.1% had hyperferritinemia. The prevalence of C282Y and H63D HFE mutations was similar to the general population and mutations were not associated with iron overload. Although subjects were on average only moderately overweight, insulin sensitivity, measured both in the fasting state and in response to oral glucose, was lower. Univariate analysis demonstrated that the presence of severe fibrosis was independently associated with older age, female sex, overweight, aspartate/alanine aminotransferase ratio, serum ferritin level, fasting glucose and insulin levels, decreased insulin sensitivity, and with histologic features (degree of necroinflammation and steatosis). After adjustment for body mass index (BMI), age, sex, and degree of steatosis, ferritin levels (odds ratio [OR] = 1.77; 95% CI = 1.21- 2.58; P =.0032) and the oral glucose insulin sensitivity (OR = 0.53; CI = 0.33-0.87; P =.0113) were independent predictors of severe fibrosis. In conclusion, the current study indicates that insulin resistance is a major, independent risk factor for advanced fibrosis in patients with NAFLD. Increased ferritin levels are markers of severe histologic damage, but not of iron overload. Iron burden and HFE mutations do not contribute significantly to hepatic fibrosis in the majority of patients with NAFLD.

Adult↗
PubMed2004

Insulin resistance and the pathogenesis of nonalcoholic fatty liver disease.

The prevalence of obesity has reached epidemic proportions in most of the western world. Current estimates suggest that 22.5%of the population of the United States suffers from obesity and is at risk for development of obesity-related complications, including hypertension, coronary artery disease, diabetes, hyperlipidemia,increased predisposition for various cancers, and nonalcoholic fatty liver disease. Fatty liver disease is currently the most common abnormality observed in hepatology practice. Since it was first reported in the 1980s in obese diabetic females, our understanding of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) has undergone significant metamorphosis. It is now universally accepted that insulin resistance and subsequent hyperinsulinemia are key factors that lead to both NAFL and NASH.This article reviews the role of insulin resistance in the genesis of these conditions.

Carbohydrate Metabolism↗
PubMed2004

Impairment of mitochondrial oxidative phosphorylation in rat fatty liver exposed to preservation-reperfusion injury.

BACKGROUND/AIMS: As the impairment of the cellular energy metabolism contributes to the failure of fatty liver grafts after transplantation, we aimed to determine whether steatosis affects the oxidative phosphorylation activity during preservation. METHODS: Rat normal and fatty livers were preserved for 18 h and then reperfused with warm oxygenated solution. The oxidative phosphorylation, the F(0)F(1)-ATPase and the Complex I activities were assessed in isolated mitochondria before and after preservation, and during reperfusion. The ALT release and portal pressure were monitored during reperfusion. RESULTS: The baseline phosphorylation activity was similar in normal and steatotic mitochondria. After cold preservation, the respiratory control index and state 3 respiration decreased significantly only in steatotic livers. Reperfusion induced a further deterioration in either group. Contrary to normal liver, uncoupling of fatty liver mitochondria allowed the recovery of the maximal respiration rate only using succinate (Complex II-dependent substrate), but not glutamate-malate (Complex I-dependent). Complex I dysfunction was confirmed spectrophotometrically. The ATPase activity was also significantly lower in fatty livers. Finally, ALT release and portal pressure were greater in steatotic livers. CONCLUSIONS: The alteration of the oxidative phosphorylation activity during preservation is greatly exacerbated by fatty infiltration likely resulting from damage of the respiratory chain Complex I and of the F(0)F(1)-ATP synthase.

Adenosine Triphosphate↗
PubMed1996

Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein B.

Fatty liver has been anecdotally associated with heterozygous hypobetalipoproteinemia. The aim of this study was to characterize the molecular defect in a subject with heterozygous hypobetalipoproteinemia (low-density lipoprotein cholesterol, 52 mg/dL; apolipoprotein [apo] B, 15 mg/dL) and otherwise unexplained fatty liver. Plasma lipoproteins were separated by ultracentrifugation, and apo B was analyzed by electrophoresis and immunoblotting. A fragment of genomic DNA corresponding to the 5' end of exon 26 of the apo B gene was amplified by polymerase chain reaction and sequenced. The plasma lipoproteins of the proband contained, besides normal apo B-100, a 200-kilodalton truncated apo B whose size suggested the presence of a mutation in exon 26 of the apo B gene. The nucleotide sequence of a fragment of the 5' end of exon 26 revealed that the proband was a heterozygote for a 14-nucleotide deletion, producing a frameshift resulting in a premature stop codon at residue 1768. This truncated apo B was named apo B-38.95. The proband's father was a carrier of the same mutation. Fatty liver in this subject with familial heterozygous hypobetalipoproteinemia most likely results from the inability of apo B-38.95 to export lipids from hepatocytes into the blood stream. Heterozygous hypobetalipoproteinemia should be considered in a hypolipidemic subject with an otherwise unexplained fatty liver.

Adult↗
PubMed2003

Decreased hepatic triglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid-binding protein gene.

Liver fatty acid-binding protein (L-Fabp) is an abundant cytosolic lipid-binding protein with broad substrate specificity, expressed in mammalian enterocytes and hepatocytes. We have generated mice with a targeted deletion of the endogenous L-Fabp gene and have characterized their response to alterations in hepatic fatty acid flux following prolonged fasting. Chow-fed L-Fabp-/- mice were indistinguishable from wild-type littermates with regard to growth, serum and tissue lipid profiles, and fatty acid distribution within hepatic complex lipid species. In response to 48-h fasting, however, wild-type mice demonstrated a approximately 10-fold increase in hepatic triglyceride content while L-Fabp-/- mice demonstrated only a 2-fold increase. Hepatic VLDL secretion was decreased in L-Fabp-/- mice suggesting that the decreased accumulation of hepatic triglyceride was not the result of increased secretion. Fatty acid oxidation, as inferred from serum beta-hydroxybutyrate levels, was increased in response to fasting, although the increase in L-Fabp-/- mice was significantly reduced in comparison to wild-type controls, despite comparable induction of PPAR alpha target genes. Studies in primary hepatocytes revealed indistinguishable initial rates of oleate uptake, but longer intervals revealed reduced rates of uptake in fasted L-Fabp-/- mice. Oleate incorporation into cellular triglyceride and diacylglycerol was reduced in L-Fabp-/- mice although incorporation into phospholipid and cholesterol ester was no different than wild-type controls. These data point to an inducible defect in fatty acid utilization in fasted L-Fabp-/- mice that involves targeting of substrate for use in triglyceride metabolism.

Adaptation, Physiological↗
PubMed1984

Focal fatty liver change by sonography.

Focal fatty liver change (FFLC) is a poorly characterized entity whose ultrasound pattern has not yet been properly defined. From our experience based on 12 cases and from the few cases reported in the literature, the following conclusions can be made: (1) FFLC can be of increased and decreased echogenicity with map-like or clearcut margins; (2) rounded lesions with defined margins are indistinguishable from other focal pathology; according to the case, fine needle biopsy, arteriography, computed tomography or nuclear scan should be used; (3) FFLC can change in size or disappear in a short span of time, and (4) a hypoechogenic area with map-like margins in the quadrate lobe (even if it turns out to be a false focal defect in that it corresponds to residual normal liver tissue) of a patient with abnormal values for gamma-glutamyltransferase (GGT) and serum glutamic oxaloacetic transaminase (SGOT) is reasonably indicative of FFLC.

Fatty Liver↗
PubMed2004

Nonalcoholic fatty liver disease: is all the fat bad?

Nonalcoholic fatty liver disease is now a major cause of liver disease in developed countries, largely as a result of an epidemic of obesity, diabetes and sedentary lifestyles. This has resulted in raised clinical awareness and diagnostic refinement. The entity encompasses several histologic patterns from benign steatosis to nonalcoholic steatohepatitis, the latter having a significant risk of progressive fibrosis and the development of cirrhosis. Laboratory tests and imaging are not able to distinguish steatosis from steatohepatitis, which requires liver biopsy. However following an assessment of several risk factors, patients can be stratified for the potential risk of fibrosis, allowing the rational use of liver biopsy. This review will describe the various patterns of nonalcoholic fatty liver disease and relate this to disease pathogenesis and progression. Strategies for management, including experimental interventions, will be discussed.

Biopsy↗
PubMed2005

Management of fatty liver disease with vitamin E and C compared to ursodeoxycholic acid treatment.

BACKGROUND/AIMS: Despite a proposed role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis, antioxidant approaches have not been investigated sufficiently in the therapy of nonalcoholic steatohepatitis. Our aim was to determine whether vitamin E plus C therapy is effective in normalization of liver enzymes compared to ursodeoxycholic acid treatment in patients with fatty liver disease. METHODS: This was an open-labeled, prospective, randomized study enrolling patients with histologically proven fatty liver disease who had chronically elevated alanine aminotransferase, despite a three-month reducing diet. Patients consuming alcohol (more than 20 g/day) were excluded. The patients were randomly prescribed either oral vitamin E (600 IU/day) plus vitamin C (500 mg/day) or ursodeoxycholic acid (10 mg/kg/day). Patients were randomized as two groups to receive vitamin E plus vitamin C combination (28 patients, 10 F) or ursodeoxycholic acid treatment (29 patients, 13 F). RESULTS: There was no significant change in body mass index before and after the treatment in both groups. At the end of six months of therapy, serum aspartate aminotransferase and aminotransferase levels significantly decreased in both treatment options. Vitamin E and C combination was more efficacious on serum aminotransferase levels than ursodeoxycholic acid, but the difference was not significant. Alanine aminotransferase decreased to normal levels in 17 of 27 (63%) and in 16 of 29 patients (55%), respectively, in the two groups. Gamma-glutamyl transpeptidase decreased in patients receiving ursodeoxycholic acid, but no change was obtained in the vitamin-treated patients. CONCLUSIONS: Vitamin E plus C combination treatment is a safe, inexpensive and effective treatment option in patients with fatty liver disease, with results comparable to those obtained with ursodeoxycholic acid. Since more effective new therapeutic options are lacking, patients with fatty liver disease should be encouraged to take vitamin E and C supplements, which are safe and affordable.

Administration, Oral↗
PubMed1979

Abnormalities of hepatic mitochondrial urea-cycle enzyme activities and hepatic ultrastructure in acute fatty liver of pregnancy.

Two patients presenting with acute fatty liver of pregnancy were studied. Because of similarities between acute fatty liver of pregnancy and Reye's syndrome, we investigated hepatic ultrastructure, urea-cycle enzyme activities, and plasma amino acids. Initial liver biopsies obtained 12 and 21 days after the onset of illness demonstrated microvesicular fat deposition and mitochondrial ultrastructural changes, including pleomorphism and abundant crystalline inclusions. In both biopsies, activity of the mitochondrial urea-cycle enzyme OTC was markedly below normal limits. Activity of the other mitochondrial urea-cycle enzyme, CPS, was low in one patient. Abnormalities of these enzymes persisted in second biopsies obtained at 9 and 28 weeks, respectively. By 44 weeks all urea-cycle enzyme activities had returned to normal in one patient. However, in the other patient OTC activity was still reduced at 52 weeks, although it had doubled in comparison to previous biopsies. Morphological changes of the mitochondria generally improved in parallel with the urea-cycle enzymes. Plasma amino acids, obtained at the time of the initial biopsies, demonstrated a generalized hypoaminoacidemia with the exception of glutamate. Serial observations in patients with this rare disease indicate that there are similarities with Reye's syndrome, in particular, reduced activity of the mitochondrial urea-cycle enzymes. But there are important differences. (1) Enzymatic and ultrastructural abnormalities of mitochondria persist for a longer period of time than in Reye's syndrome. (2) Mitochondrial ultrastructure is different. (3) Plasma amino acid profiles are different.

Acute Disease↗
PubMed2005

Recent concepts in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is present in up to one-third of the general population and in the majority of patients with metabolic risk factors such as obesity and diabetes. Insulin resistance is a key pathogenic factor resulting in hepatic fat accumulation. Recent evidence demonstrates NAFLD in turn exacerbates hepatic insulin resistance and often precedes glucose intolerance. Once hepatic steatosis is established, other factors, including oxidative stress, mitochondrial dysfunction, gut-derived lipopolysaccharide and adipocytokines, may promote hepatocellular damage, inflammation and progressive liver disease. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies, however, staging the disease requires a liver biopsy. NAFLD is associated with an increased risk of all-cause death, probably because of complications of insulin resistance such as vascular disease, as well as cirrhosis and hepatocellular carcinoma, which occur in a minority of patients. NAFLD is also now recognized to account for a substantial proportion of patients previously diagnosed with 'cryptogenic cirrhosis'. Diabetes, obesity and the necroinflammatory form of NAFLD known as non-alcoholic steatohepatitis, are risk factors for progressive liver disease. Current treatment relies on weight loss and exercise, although various insulin-sensitizing medications appear promising. Further research is needed to identify which patients will achieve the most benefit from therapy.

Fatty Liver↗
PubMed2006

Nonalcoholic fatty liver disease of obesity.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are part of the same continuum. They are a major, under-recognized cause of chronic liver disease. Good medical treatment options do not exist to date. The mainstay of treatment is weight loss. Bariatric surgery offers weight loss and improvement of NAFLD and NASH.

Fatty Liver↗
PubMed2003

Quantitative diagnosis of fatty liver with dual-energy CT. An experimental study in rabbits.

OBJECTIVES: To explore the correlation between fatty content of fatty liver and the difference of CT attenuation value in dual-energy CT, and to evaluate the value of dual-energy CT in the quantitative diagnosis of fatty liver in rabbits. MATERIAL AND METHODS: Dual-energy CT at 120 kVp and 90 kVp was performed in 16 rabbits of experimental groups that were induced to various degrees of fatty liver by feeding carbon tetrachloride (CCl4). Four healthy rabbits in the control group underwent dual-energy CT at the same time. The CT attenuation values of liver tissues at 120 kVp (H120), 90 kVp (H90) and the difference (Delta H) between them were obtained. The specimens of liver tissues were examined with freeze section (9 microm) and an oil red O stain histologically. The ratio of fatty content in liver to the liver volume (VP value) was measured using the image analyzer system. RESULTS: The change of CT attenuation values between 120 kVp and 90 kVp was not obvious (Delta H between -0.4 HU and 1.4 HU) in the control group. The density of the liver in the experimental groups decreased differently, and the change in CT attenuation values between high and low energy levels were very clear. H120 values were between 51.0 HU and 91.7 HU and H90 values were between 37.0 HU and 89.2 HU. Delta H values were between 2.5 HU and 14.0 HU. Significant negative linear correlation (r = -0.92, -0.93, t = 8.51, 9.76, p < 0.001, 0.001, respectively) were found between VP values and H120 and H90, respectively, while significant positive linear correlation (r = 0.95, t = 11.89, p < 0.001) was found between VP values and Delta H. CONCLUSION: The amount and degree of fat in the fatty liver can be assessed exactly by dual-energy CT. It will be a potential new effective method for quantitative diagnosis of fatty livers.

Animals↗
PubMed2004

Activities of the enzymes of hepatic gluconeogenesis in periparturient dairy cows with induced fatty liver.

The objective was to measure the activities of all the enzymes essential for hepatic gluconeogenesis in dairy cows with induced fatty liver. We aimed to induce severe fatty liver in ten experimental cows by overfeeding them during the dry period while seven control cows were maintained on a restricted diet. To induce a marked negative energy balance, the experimental cows were deprived of feed for 8 h immediately after parturition. In addition, the experimental cows were given a restricted amount of diet during the first 5 d of lactation. Liver samples were collected 1 week before and 1, 2 and 4 weeks after parturition. Before parturition, liver triacylglycerol concentrations did not differ between the two groups. After parturition, the experimental cows developed marked fatty liver as indicated by a higher level of triacylglycerols in the liver compared with the control cows. Before parturition, all gluconeogenic enzymes in the liver were lower in experimental cows than in control cows. Phosphoenolpyruvate carboxykinase, pyruvate carboxylase and propionyl-CoA carboxylase were significantly lower and fructose 1,6-bisphosphatase and glucose 6-phosphatase tended to be lower in the experimental cows. The activities of two crucial enzymes for gluconeogenesis in ruminants, i.e., phosphoenolpyruvate carboxykinase and propionyl-CoA carboxylase, remained low throughout the sampling period post partum. Activities of pyruvate carboxylase and glucose 6-phosphatase in the experimental cows post partum were upgraded to values similar to those of the control cows. The results showed that the capacity for hepatic gluconeogenesis before parturition was lower in cows with induced fatty liver than in control cows. After parturition, the low activities of crucial gluconeogenic enzymes indicated insufficient production of glucose. It is suggested that the low gluconeogenic capacity leads successively to low blood glucose concentrations, low insulin levels and high rates of mobilization of fatty acid, causing severe hepatic lipidosis.

3-Hydroxybutyric Acid↗
PubMed1997

Fatty liver in a case with heterozygous familial hypobetalipoproteinemia.

We herein present a case of fatty liver in a patient with heterozygous familial hypobetalipoproteinemia. A 34-yr-old male presented with abnormally elevated levels of transaminases and a fatty liver. He was asymptomatic, and the physical examination showed nothing remarkable. The serum total cholesterol, triglyceride, LDL-cholesterol, and apolipoprotein B levels all ranged from low normal to one-half normal. His other laboratory data were all in the normal range. The patient's body mass index measured was 25.7 kg/m2, and he did not demonstrate obesity. He had no history of alcohol consumption. It was thus thought that the fatty liver in this case might be associated with heterozygous hypobetalipoproteinemia. Heterozygous hypobetalipoproteinemia with a bright liver by ultrasound was also found in several of the patient's family members. Based on these rare findings, heterozygous hypobetalipoproteinemia should thus be considered as a possible cause in patients presenting with an unexplained fatty liver.

Adult↗
PubMed2006

Treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is common and may progress to cirrhosis and its complications. The pathogenesis of steatosis and cellular injury is thought to be related mostly to insulin resistance and oxidative stress. Therefore, management entails identification and treatment of metabolic risk factors, improving insulin sensitivity, and increasing antioxidant defences in the liver. Weight loss and exercise improve insulin sensitivity. Bariatric surgery may improve liver histology in patients with morbid obesity. Insulin sensitising drugs showed promise in pilot trials as have a number of hepatoprotective agents. Further randomised, well controlled trials are required to determine the efficacy of these drugs.

Antioxidants↗
PubMed1997

Multiple biochemical effects in the pathogenesis of alcoholic fatty liver.

The pathogenesis of alcoholic fatty liver is unknown, but several causes have been proposed based on biochemical findings. These include the metabolism of alcohol leading to a shift in the cytosolic [NAD+]/ [NADH] ratio to reduction, which in turn causes a direct inhibition of beta-oxidation and enhanced triacylglycerol formation via the [glycerol-3-phosphate]/[dihydroxyacetone phosphate] ratio. There are also chronic effects of ethanol on hepatic enzyme activities. Thus, increased activity of phosphatidate phosphohydrolase, an increased amount of fatty acid binding protein, decreased secretion of very low-density lipoprotein and impairment of the respiratory chain as a result of decreased protein synthesis or decreased amounts of ubiquinone could all lead to fat accumulation and steatosis. The interplay of each of these with nutritional and genetic factors would then lead to the heterogeneity of the severity and characteristics of the steatosis observed in human alcoholics.

Ethanol↗
PubMed2004

A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats.

Fatty livers of obese fa/fa rats are vulnerable to injury when challenged by insults such as endotoxin, ischemia-reperfusion or acute ethanol treatment. The objective of this study was to evaluate whether a high-fat diet can act as a "second hit" and cause progression to liver injury in obese fa/fa rats compared with lean Fa/? rats. Accordingly, obese fa/fa rats and their lean littermates were fed a diet low in fat (12% of total calories) or a diet with 60% calories as lard for 8 weeks. Hyperglycemia and steatohepatitis occurred in the fa/fa rats fed the high-fat diet. This was accompanied by liver injury as assessed by alanine aminotransferase, hematoxilin and eosin staining, increased TNFalpha and stellate cell-derived TGFbeta, collagen deposition, and up-regulation of alpha-smooth muscle actin. Active MMP13 decreased in fa/fa rats independently of the diet, and TIMP1 expression increased with the high-fat diet, especially in fa/fa rats. Although UCP2 expression was higher in fa/fa rats regardless of the diet, minor changes in ATP levels were observed. Oxidative stress occurred in the fa/fa rats fed the high-fat diet as lipid peroxidation and protein carbonyls were elevated, while glutathione and antioxidant enzymes were very low. Expression and activity of cytochrome P450 2E1 and xanthine oxidase activity were down-regulated in fa/fa compared with Fa/? rats, and no effect was seen by the high-fat diet. However, NADPH oxidase activity increased 2.5-fold in fa/fa rats fed with the high-fat diet. In summary, a high-fat diet induces liver injury in fa/fa rats leading to periportal fibrosis. A role for oxidative stress is suggested via increased NADPH oxidase activity, lipid peroxidation, protein carbonyl formation, and low antioxidant defense.

Adenosine Triphosphate↗
PubMed2005

Assessment of lipid peroxidation and antioxidant capacity in non-alcoholic fatty liver disease.

BACKGROUND/AIMS: Lipid peroxidation/oxidative stress and/or endotoxin-induced cytokine release are implicated in the non-alcoholic fatty liver disease pathogenesis. Studies in the literature are experimental in nature and are based on histopathological evaluation and peripheral blood findings. In this study, we aimed to investigate the relationships between lipid peroxidation and antioxidant capacity in non-alcoholic fatty liver disease. METHODS: Twenty-six patients with an ethanol consumption of less than 20 g/day who were diagnosed ultrasonographically and histopathologically as non-alcoholic fatty liver disease and 16 healthy control subjects with normal ultrasonographical findings were included in the study. All viral and autoimmune markers in patient and control groups included in the study were negative. Non-alcoholic steatohepatitis samples obtained by fine needle aspiration were evaluated according to Brunt et al. The levels of glutathione, catalase, superoxide dismutase, and malonyldialdehyde in peripheral blood and liver biopsy samples were measured. RESULTS: Of patients with non-alcoholic fatty liver disease, 17 (65%) were detected to have mild, 7 (27%) moderate and 2 (8%) severe steatosis; portal inflammation was found in 17 patients (65%) and stage I fibrosis in 21 patients (80%). Minimal lobular inflammation was observed in all patients. In the patient group, the levels of erythrocytic glutathione, catalase, and superoxide dismutase were significantly lower but malonyldialdehyde levels were higher compared to the control group. It was revealed that hepatocytic reduced glutathione, catalase, and malonyldialdehyde levels were not correlated with peripheral blood levels, but there was a positive correlation between liver malonyldialdehyde level and liver reduced glutathione level. Plasma malonyldialdehyde level and liver glutathione had a negative correlation. CONCLUSIONS: It was discovered that lipid peroxidation and antioxidant capacity suppression due to its overuse were important in the non-alcoholic fatty liver disease pathogenesis, but antioxidant capacity was maintained well at tissue level in the early stages of the disease. Furthermore, it was identified that tissue lipid peroxidation and changes in antioxidant capacity were not reflected in the peripheral blood to the same extent.

Adult↗