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PubMed2005

Nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease is emerging as the most common chronic liver condition in the Western world. It is associated with insulin resistance and frequently occurs with features of the metabolic syndrome. Disease presentation ranges from asymptomatic elevated liver enzyme levels to cirrhosis with complications of liver failure and hepatocellular carcinoma. Current treatment recommendations are limited to weight loss and exercise, although several promising medications are on the horizon. In this article we discuss the etiology, pathogenesis and diagnosis of nonalcoholic fatty liver disease as well as approaches to its management.

Biopsy↗
PubMed2000

Ruminant adaptation to negative energy balance. Influences on the etiology of ketosis and fatty liver.

Ketosis and fatty liver occur when physiologic mechanisms for the adaptation to negative energy balance fail. Failure of hepatic gluconeogenesis to supply adequate glucose for lactation and body needs may be one cause of ketosis; however, poor feedback control of nonesterified fatty acid release from adipose tissue is another likely cause of ketosis and fatty liver. The types of ketosis resulting from these two metabolic lesions may require different therapeutic and prophylactic approaches.

Adaptation, Physiological↗
PubMed2002

Update on nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease is now recognized as the most common liver disease in the United States, with a prevalence of approximately 5% in the general population and up to 25% to 75% in patients with obesity and type II diabetes mellitus. Nonalcoholic fatty liver disease is a clinicopathologic syndrome with a wide spectrum of histologic abnormalities and clinical outcomes. Hepatic steatosis has a benign clinical course. In contrast, nonalcoholic steatohepatitis (NASH) may progress to cirrhosis and liver-related death in 25% and 10% of patients, respectively. Cases occur most commonly in obese, middle-aged women with diabetes. However, NASH may also occur in children and normal-weight men with normal glucose and lipid metabolism. The pathophysiology involves two steps. The first is insulin resistance, which causes steatosis. The second is oxidative stress, which produces lipid peroxidation and activates inflammatory cytokines resulting in NASH. Liver biopsy provides prognostic information and identifies NASH patients who may benefit from therapy. Treatment consists of managing the comorbidities: obesity, diabetes, and hyperlipidemia. Although antioxidant therapy with vitamin E is often used, ursodeoxycholic acid is the only drug that has shown benefit and is the most promising of the drugs currently being investigated. Future therapies will depend on a greater understanding of the pathophysiology and should focus on diminishing fibrosis.

Diabetes Mellitus, Type 2↗
PubMed2005

Mechanisms of Disease: pathogenesis of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is associated with the metabolic syndrome. The metabolic syndrome is characterized by insulin resistance, which is produced by a complex interaction between genetic factors, macronutrient intake and lifestyle that alters the cytokine profile, cell biology and biochemical milieu of the liver, adipose tissue and striated muscle. The resultant disequilibrium in lipid homeostasis causes triglycerides to accumulate in the liver. An increase in oxidative stress, due to the generation of reactive oxygen species as a result of mitochondrial abnormalities and induction of the cytochrome P-450 system could be one mechanism by which the nonalcoholic fatty liver develops into nonalcoholic steatohepatitis. The pathogenesis of cytologic ballooning and Mallory body formation and their role in NAFLD remain to be defined. In addition, inflammation and fibrosis are likely to be secondary to hepatocyte injury and death.

Cytochrome P-450 Enzyme System↗
PubMed2004

Nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders that encompasses simple hepatic steatosis and the more serious nonalcoholic steatohepatitis (NASH) that can progress to cirrhosis. Although the prevalence of NAFLD in childhood is not clear, it is apparently more common than originally thought. The major association with NAFLD is obesity, and as the prevalence of obesity in childhood and adolescence increases, fatty liver is recognized with greater frequency. Although the factors associated with progression of liver disease have not been determined fully, the pathogenesis of NASH is a "two hit" process that includes disturbed lipid homeostasis, resistance to the effects of insulin and subsequent hyperinsulinemia, and local toxic effects of triglyceride on hepatocytes. Treatment options are currently limited.

Adolescent↗
PubMed2005

Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is consistently associated with features of the metabolic syndrome, a condition carrying a high risk of cardiovascular events. We measured the vasodilatory response of the brachial artery in response to ischemia (a test of endothelial function) (FMV) as well as cardiovascular risk profile in 52 NAFLD cases and 28 age- and sex-matched controls. The 10-year risk of coronary events was calculated according to the Framingham equation and the scores derived from the PROCAM study and NCEP-ATPIII proposals. FMV was 6.33% +/- 5.93% in NAFLD versus 12.22% +/- 5.05% in controls (P < .0001), and higher in pure fatty liver (9.93%) compared with nonalcoholic steatohepatitis (4.94%) (P = .010). No differences were observed in flow-independent vasodilation (response to sublingual nitroglycerin). Percent FMV was negatively associated with insulin resistance (homeostasis model assessment) in the whole population (r = -0.243; P = .030). In logistic regression analysis, NAFLD was associated with a percent FMV in the lower tertile (OR, 6.7; 95% CI, 1.26-36.1), after adjustment for age, sex, body mass index, and insulin resistance. Among NAFLD patients, low FMV was associated with nonalcoholic steatohepatitis (adjusted OR, 6.8; 95% CI, 1.2-40.2). The 10-year probability of cardiovascular events was moderately increased in NAFLD, and particularly in nonalcoholic steatohepatitis. In conclusion, our study provides evidence of endothelial dysfunction and increased risk of cardiovascular events in NAFLD. The risk of advanced liver disease is well recognized in NAFLD patients, but the large majority of cases might experience cardiovascular disease in the long term, indirectly limiting the burden of liver failure.

Adult↗
PubMedDate not supplied

Nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease is a clinicopathologic syndrome that encompasses several clinical entities. The spectrum of conditions ranges from simple steatosis to steatohepatitis, fibrosis and end stage liver disease. The condition was originally described in obese, diabetic, middle-aged females without a history of significant alcohol use with liver histology consistent with alcoholic hepatitis. It is known that this entity occurs without any particular sex predilection, in lean individuals, as well as an increasing number of obese children. Other terms have been used to describe this clinical entity such as alcohol-like hepatitis, pseudo-alcoholic hepatitis, diabetic hepatitis and steatonecrosis. Ludwig and colleagues introduced the term nonalcoholic steatohepatitis (NASH) to describe patients fitting the picture of alcoholic hepatitis but without a history of significant alcohol abuse. The term nonalcoholic fatty liver disease (NAFLD) is used more frequently to include the spectrum of conditions that range from steatosis through steatohepatitis, fibrosis and cirrhosis. NASH is reserved for patients with steatohepatitis and fibrosis. NAFLD is now being recognized as the most common cause of elevated liver enzymes in the United States. Although the exact etiology of NAFLD is not known, it may be caused by insulin resistance coupled with increased oxidative stress to the hepatocytes. No specific therapy has been approved for this condition and the mainstay of management is weight loss.

Fatty Liver↗
PubMed2004

Pathologic features associated with fibrosis in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of clinicopatholologic conditions ranging from steatosis alone to nonalcoholic steatohepatitis (NASH), with varying risks for progression to cirrhosis. Although steatosis alone seems to be nonprogressive, some patients with NASH can progress. This study focuses on the clinical and pathological characteristics of patients with NAFLD associated with the development of histological fibrosis. Patients with an established diagnosis of nonalcoholic fatty liver were identified through our NAFLD database containing extensive clinical, demographic, and laboratory data. Liver biopsy specimens were read blindly by one hepatopathologist using a 19-item pathological protocol and by another hepatopathologist using a second pathological protocol. Clinical and pathological data were matched to the presence of different types of histological fibrosis. Univariate and multivariate analyses helped determine all of the variables independently associated with histological fibrosis. Of 132 NAFLD patients, 21.2% had advanced fibrosis (septal/bridging fibrosis or well-established cirrhosis). Sinusoidal fibrosis was present in 20.3% of patients, whereas perivenular fibrosis was seen in 17.2%. Ballooning degeneration and Mallory bodies were independently associated with both sinusoidal fibrosis and perivenular fibrosis. Aspartate aminotransferase/alanine aminotransferase ratio and ballooning degeneration were also independently associated with periportal-portal fibrosis. We conclude that the presence of hepatocyte injury in NAFLD is associated with fibrosis. These pathological features can be used to establish the pathological criteria for diagnosis of the progressive form of NAFLD or NASH.

Adult↗
PubMed2006

The association between increased alanine aminotransferase activity and metabolic factors in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has been associated with metabolic disorders, including central obesity, dyslipidema, hypertension, and hyperglycemia. Metabolic syndrome, obesity, and insulin resistance are major risk factors in the pathogenesis of NAFLD. The aim of this study was to identify the relative contribution of the metabolic syndrome, obesity, and insulin resistance to alanine aminotransferase (ALT) activity in NAFLD. A total of 3091 subjects diagnosed with fatty liver by ultrasonography were enrolled. All components of metabolic syndrome criteria, anthropometric parameters, fasting insulin levels, high-sensitivity C-reactive protein (hs-CRP) as an inflammation marker, and ALT were measured in each subject. Homeostasis model assessment--insulin resistance (HOMA-IR) as a measure of insulin resistance and body mass index (BMI) as a measure of obesity were calculated. The prevalence of increased ALT levels (>40 IU/L) was 26.7%. Increased ALT activity was significantly associated with the following characteristics: male sex, young age, increased triglycerides, fasting glucose, fasting insulin, HOMA-IR, hs-CRP, waist circumference, BMI and diastolic blood pressure, and decreased high-density lipoprotein cholesterol (HDL-C). According to the increase in the number of metabolic syndrome components, BMI, HOMA-IR, and hs-CRP, the prevalence and odds ratio for having increased ALT activity were significantly increased. Central obesity, raised triglycerides, reduced HDL-C, and raised fasting glucose were strongly associated with increased ALT activity. In conclusion, a number of metabolic syndrome components, obesity, insulin resistance, and hs-CRP, are strong predictors of increased ALT activity in NAFLD. Central obesity, raised triglycerides, reduced HDL-C, and raised fasting glucose are metabolic syndrome components that contributed to increased ALT activity.

Adult↗
PubMedDate not supplied

[Non-alcoholic fatty liver].

Non alcoholic fatty liver disease (NAFLD) and its more agressive form, non alcoholic steatohepatitis (NASH) are entities that are becoming subject of interest of the medical community in general, especially because of the increased prevalence of diabetes and obesity in the world population. There is solid evidence linking NAFLD with the so called metabolic syndrome or syndrome X, to the point of accepting hepatic steatosis and its spectrum as one more element of the latter, along with diabetes, hipertension, hypertriglyceridemia and obesity. Insulin resistance seems to be the common link between these entities. Clinical evaluation of every patient with abnormal aminotransferase levels should take into account non alcoholic fatty liver and its spectrum, especially if the subject is obese or diabetic. Despite the important developments in the field of imaging, currenty the only way to differentiate NASH from simple NAFLD is by performing a liver biopsy, which should be discussed extensively with the patient. The prognosis of simple NAFLD is generally benign, but if there is fibrosis, ballooning of the hepatocytes, inflammation and Mallory bodies there is risk to progression to cirrhosis. Liver histology in NAFLD is indistinguishable from alcoholic hepatitis, although the clinical course is generally more benign. Despite this long and protracted clinical course, an important number of subjects have complications of cirrhosis including hepatocellular carcinoma, and many patients require a liver transplantation. There is no specific treatment for this condition, although every therapeutic regimen should include a gradual and supervised weight reduction, a balanced diet and exercise, as well as correction of precipitant factors. There is currently no specific pharmacologic treatment for NASH or NAFLD. Current body of evidence and some pilot studies suggest that the future might be concentrated in agents improving insulin resistance. Meanwhile, we should do our best to study the prevalence of NAFLD in our country and, when clinically pertinent, study histologically those patients with high risk of fibrosis.

Disease Progression↗
PubMed1999

Hepatocyte growth factor leads to recovery from alcohol-induced fatty liver in rats.

A fatty liver is characterized by the hyperaccumulation of lipids within hepatocytes and is often caused by excessive alcohol intake. Rats fed ethanol-containing diets for 37 days showed remarkable increase in hepatic lipids and lipid droplet accumulation in the hepatocytes, indicating the onset of alcoholic fatty liver. Administration of hepatocyte growth factor (HGF) for the last seven days of ethanol treatment markedly decreased hepatic lipids to a level lower than that seen before HGF treatment. In contrast, serum levels of lipids and lipoproteins increased with HGF administration. Primary cultured hepatocytes prepared from the fatty liver retained lipid droplets during a 48-hour culture. However, when cultured in the presence of HGF, intracellular lipid concentrations decreased and lipid secretion was enhanced. Consistent with these events, HGF stimulated the rate of protein synthesis of apolipoprotein B (apoB) and enhanced subsequent mobilization of lipids into the medium. These results indicate that HGF administration induced recovery from the fatty liver, at least in part, by enhancing apoB synthesis and the subsequent mobilization of lipids from hepatocytes with fatty change. The possibility that HGF can be therapeutic for subjects with an alcohol-related fatty liver warrants further attention.

Animals↗
PubMed1999

Peroxisomal and mitochondrial fatty acid beta-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor alpha and peroxisomal fatty acyl-CoA oxidase. Genotype correlation with fatty liver phenotype.

Fatty acid beta-oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also metabolized by the cytochrome P450 CYP4A omega-oxidation enzymes to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal beta-oxidation. Synthetic peroxisome proliferators interact with peroxisome proliferator activated receptor alpha (PPARalpha) to transcriptionally activate genes that participate in peroxisomal, microsomal, and mitochondrial fatty acid oxidation. Mice lacking PPARalpha (PPARalpha-/-) fail to respond to the inductive effects of peroxisome proliferators, whereas those lacking fatty acyl-CoA oxidase (AOX-/-), the first enzyme of the peroxisomal beta-oxidation system, exhibit extensive microvesicular steatohepatitis, leading to hepatocellular regeneration and massive peroxisome proliferation, implying sustained activation of PPARalpha by natural ligands. We now report that mice nullizygous for both PPARalpha and AOX (PPARalpha-/- AOX-/-) failed to exhibit spontaneous peroxisome proliferation and induction of PPARalpha-regulated genes by biological ligands unmetabolized in the absence of AOX. In AOX-/- mice, the hyperactivity of PPARalpha enhances the severity of steatosis by inducing CYP4A family proteins that generate DCAs and since they are not metabolized in the absence of peroxisomal beta-oxidation, they damage mitochondria leading to steatosis. Blunting of microvesicular steatosis, which is restricted to few liver cells in periportal regions in PPARalpha-/- AOX-/- mice, suggests a role for PPARalpha-induced genes, especially members of CYP4A family, in determining the severity of steatosis in livers with defective peroxisomal beta-oxidation. In age-matched PPARalpha-/- mice, a decrease in constitutive mitochondrial beta-oxidation with intact constitutive peroxisomal beta-oxidation system contributes to large droplet fatty change that is restricted to centrilobular hepatocytes. These data define a critical role for both PPARalpha and AOX in hepatic lipid metabolism and in the pathogenesis of specific fatty liver phenotype.

Acyl-CoA Oxidase↗
PubMed2003

Review article: Non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease is a clinicopathological condition that comprises a wide spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. Non-alcoholic steatohepatitis represents only a stage within the spectrum of non-alcoholic fatty liver disease and is defined pathologically by the presence of steatosis together with necro-inflammatory activity. The true prevalence of non-alcoholic fatty liver disease is unknown, but it is estimated that it affects 10-24% of the general population in different countries. The diagnosis of non-alcoholic fatty liver disease is based upon convincing evidence of absent or minimal alcohol consumption, compatible histological changes in liver biopsy and the exclusion of other liver diseases. The natural history of non-alcoholic fatty liver disease remains to be defined. Patients with pure steatosis on liver biopsy follow a relatively benign course, whereas patients with histological necro-inflammatory changes and/or fibrosis may progress to end-stage liver disease. An initial step in the treatment of non-alcoholic fatty liver disease is the management of associated conditions, such as obesity, diabetes mellitus and hyperlipidaemia. Non-alcoholic fatty liver disease patients with steatohepatitis and/or fibrosis on liver biopsy may benefit from investigational pharmacological therapy. Patients with decompensated cirrhosis from non-alcoholic fatty liver disease may be candidates for liver transplantation.

Alcohol Drinking↗
PubMed1999

Ischemia-reperfusion injury in rat fatty liver: role of nutritional status.

Fatty livers are more sensitive to the deleterious effects of ischemia-reperfusion than normal livers. Nutritional status greatly modulates this injury in normal livers, but its role in the specific setting of fatty liver is unknown. This study aimed to determine the effect of nutritional status on warm ischemia-reperfusion injury in rat fatty livers. Fed and fasted rats with normal or fatty liver induced by a choline deficient diet underwent 1 hour of lobar ischemia and reperfusion. Rat survival was determined for 7 days. Serum transaminases, liver histology and cell ultrastructure were assessed before and after ischemia, and at 30 minutes, 2 hours, 8 hours, and 24 hours after reperfusion. Survival was also determined in fatty fasted rats supplemented with glucose before surgery. The preischemic hepatic glycogen was measured in all groups. Whereas survival was similar in fasted and fed rats with normal liver (90% vs. 100%), fasting dramatically reduced survival in rats with fatty liver (14% vs. 64%, P <.01). Accordingly, fasting and fatty degeneration had a synergistic effect in exacerbating liver injury. Mitochondrial damage was a predominant feature of ultrastructural hepatocyte injury in fasted fatty livers. Glucose supplementation partially prevented the fasting-induced depletion of glycogen and improved the 7-day rat survival to 45%. These data indicate that rat fatty livers exposed to normothermic ischemia-reperfusion injury are much more sensitive to fasting than histologically normal livers. Because glucose supplementation improves both the hepatic glycogen stores and the rat survival, a nutritional repletion procedure may be part of a treatment strategy aimed to prevent ischemia-reperfusion injury in fatty livers.

Alanine Transaminase↗