Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The spectrum of pathological lesions observed in non-alcoholic fatty liver disease (NAFLD) is wide and strongly resembles that of alcohol-induced liver disease. It ranges from fatty liver to steatohepatitis, progressive fibrosis and cirrhosis. Hepatocellular carcinoma is a possible complication of NAFLD, but whether it is related to frequently associated metabolic disorders (e.g., overweight, diabetes) or to underlying cirrhosis is unclear. This disease is the result of a multi-factorial process in which insulin resistance seems to play a major role in the initial accumulation of fat in the liver, whereas multiple causes of mitochondrial dysfunction and oxidative stress can induce the secondary occurrence of necroinflammatory lesions and fibrosis. Genetic factors might explain why only some patients with simple steatosis will develop steatohepatitis and fibrosis. Due to the increasing prevalence of obesity in Western countries, NAFLD will possibly be a public health problem and the liver disease of the future.
 ...
PMID:Non-alcoholic fatty liver disease: an emerging pathological spectrum. 1468 53

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

The role of insulin resistance in non-alcoholic fatty liver disease is suggested by laboratory data (hyperinsulinemia and decreased sensitivity to endogenous and exogenous insulin). The clinical association with features of the metabolic syndrome, particularly in the most aggressive stages of the disease, further confirms a causative role. Fat accumulation in the liver may stem either from genetic defects, primarily responsible for insulin resistance, or excessive calorie intake and visceral obesity, and is mediated by adipocytokines (leptin, adiponectin, tumour necrosis factor-alpha). Progression of fatty liver to steatohepatitis may be the result of an imbalance between pro-inflammatory and anti-inflammatory cytokines, triggering the formation of reactive oxygen species and intrahepatic lipid peroxidation. This process may also be promoted or accelerated by pro-oxidant xenobiotics or environmental factors. Insulin resistance provides a target for specific treatment of non-alcoholic fatty liver, and insulin-sensitising agents (metformin or thiazolidinediones) as well as lifestyle changes to reduce visceral adiposity are the most promising therapeutic options. Future trials need to be performed in order to test the long-term effectiveness of these treatments on the basis of clinically relevant histological outcomes.
 ...
PMID:Non-alcoholic fatty liver and insulin resistance: a cause-effect relationship? 1504 83

Obesity, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are becoming increasingly common medical problems in the developed world, often in the setting of the metabolic or insulin resistance syndrome (IRS). It is predicted that by the year 2025 > 25 million Americans may have NASH-related liver disease. NASH and NAFLD also affect the donor population. The use of steatotic donor livers for liver transplantation (LT) is associated with an increased risk of primary nonfunction (PNF) in the allograft. There is particular reluctance to use steatotic livers for living donor LT. There is indirect evidence to suggest that patients undergoing LT for cirrhosis resulting from NASH may have poorer outcome, despite careful selection of LT candidates. Indeed it is likely that many potential LT candidates with NASH are excluded from LT due to co-morbid conditions related to IRS. The post-LT patient is at risk of several components of IRS, such as diabetes mellitus, hypertension, hyperlipidaemia and obesity and there is increasing recognition of de novo and recurrent NAFLD and NASH after LT. Thus NAFLD and NASH affect all aspects of LT including donors, patients in evaluation and the LT recipient.
 ...
PMID:Non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and orthotopic liver transplantation. 1508 61

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

Obesity has emerged as a significant new health problem in the pediatric population. Non-alcoholic steatohepatitis (NASH) is an entity in the spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from fat in the liver -- simple steatosis, NASH/ steatohepatitis -- fat with inflammation and/or fibrosis to advanced fibrosis and cirrhosis when fat may no longer be present. NASH is associated with obesity, diabetes, insulin resistance (IR), and hypertriglyceridemia. While majority of individuals with risk factors like obesity and IR have steatosis only a minority develop steatohepatitis, possible mechanisms have been discussed. Clinical experience with pediatric NASH is limited. Children generally present in the prepubertal age group, have a male predominance with a higher incidence in children of Hispanic origin. Body mass index (BMI) of 25-29.9 is considered to be overweight and that > or =30 obese. Acanthosis nigricans as a marker of IR should be looked for. As NASH is a diagnosis of exclusion, other causes of chronic liver disease must be excluded. Increased echogenicity in the liver is noted on ultrasound. Liver biopsy is considered the gold standard in establishing the diagnosis. Histopathological lesions thought to be necessary for diagnosis of NASH include steatosis (macrovesicular > microvesicular), mixed mild lobular inflammation and hepatocyte ballooning. A system of grading depending on degree of steatosis and/or inflammation and staging depending on the extent of fibrosis has also been proposed. Although there is no consensus for the treatment for NASH, effort needs to be made to prevent development of fibrosis, which results in cirrhosis and portal hypertension. Slow, consistent weight loss has been shown to be effective in childhood NAFLD, based on improvement of serum aminotransferases or liver sonogram. A low glycemic index diet has been shown to be more effective than a low fat diet in lowering BMI. Family based behavioral intervention may also enhance success with diet. Several pharmacological agents have been used including ursodeoxycholic acid, vitamin E, betaine, n-acetyl cysteine, and insulin sensitizing agents like metformin, rosiglitazone, and pioglitazone. Transplantation for overt NASH is rare, accounting for < 1% of liver transplantations in the USA. The disease can recur after liver transplantation. A strong association exists between the presence of steatosis in a donor liver and poor graft function. As a result, cadaveric donor livers with macrovesicular steatosis >40% are not used routinely. Prognosis in NASH is dependent not only on severity and number of risk factors but also on the degree of histological damage. Clinical trials are needed to identify an effective treatment that halts the progression of NAFLD to NASH in both pretransplantation and post-transplantation patients.
 ...
PMID:Non-alcoholic steatohepatitis in children. 1559 36

Alcoholic liver disease is a major cause of illness and death in the United States. In the initial stages of the disease, fat accumulation in hepatocytes leads to the development of fatty liver (steatosis), which is a reversible condition. If alcohol consumption is continued, steatosis may progress to hepatitis and fibrosis, which may lead to liver cirrhosis. Alcoholic fatty liver has long been considered benign; however, increasing evidence supports the idea that it is a pathologic condition. Blunting of the accumulation of fat within the liver during alcohol consumption may block or delay the progression of fatty liver to hepatitis and fibrosis. To achieve this goal, it is important to understand the underlying biochemical and molecular mechanisms by which chronic alcohol consumption leads to fat accumulation in the liver and fatty liver progresses to hepatitis and fibrosis. In addition to alcohol consumption, dietary fatty acids and obesity have been shown to affect the degree of fat accumulation within the liver. Again, it is important to know how these factors modulate the progression of alcoholic liver disease. The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on "Role of Fatty Liver, Dietary Fatty Acid Supplements, and Obesity in the Progression of Alcoholic Liver Disease" in Bethesda, Maryland, USA, October 2003. The following is a summary of the symposium. Alcoholic fatty liver is a pathologic condition that may predispose the liver to further injury (hepatitis and fibrosis) by cytochrome P450 2E1 induction, free radical generation, lipid peroxidation, nuclear factor-kappa B activation, and increased transcription of proinflammatory mediators, including tumor necrosis factor-alpha. Increased acetaldehyde production and lipopolysaccharide-induced Kupffer cell activation may further exacerbate liver injury. Acetaldehyde may promote hepatic fat accumulation by impairing the ability of peroxisome proliferator-activated receptor alpha to bind DNA, and by increasing the synthesis of sterol regulatory binding protein-1. Unsaturated fatty acids (corn oil, fish oil) exacerbate alcoholic liver injury by accentuating oxidative stress, whereas saturated fatty acids are protective. Polyenylphosphatidylcholine may prevent liver injury by down-regulating cytochrome P450 2E1 activity, attenuating oxidative stress, reducing the number of activated hepatic stellate cells, and up-regulating collagenase activity. Nonalcoholic steatohepatitis may develop through several mechanisms, such as oxidative stress, mitochondrial dysfunction and associated impaired fat metabolism, dysregulated cytokine metabolism, insulin resistance, and altered methionine/S-adenosylmethionine/homocysteine metabolism. Obesity (adipose tissue) may contribute to the development of alcoholic liver disease by generating free radicals, increasing tumor necrosis factor-alpha production, inducing insulin resistance, and producing fibrogenic agents, such as angiotensin II, norepinephrine, neuropeptide Y, and leptin. Finally, alcoholic fatty liver transplant failure may be linked to oxidative stress. In vitro treatment of fatty livers with interleukin-6 may render allografts safer for clinical transplantation.
 ...
PMID:Role of fatty liver, dietary fatty acid supplements, and obesity in the progression of alcoholic liver disease: introduction and summary of the symposium. 1567 Jun 59

Liver disease in the alcoholic is due not only to malnutrition but also to ethanol's hepatotoxicity linked to its metabolism by means of the alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1) pathways and the resulting production of toxic acetaldehyde. In addition, alcohol dehydrogenase-mediated ethanol metabolism generates the reduced form of nicotinamide adenine dinucleotide (NADH), which promotes steatosis by stimulating the synthesis of fatty acids and opposing their oxidation. Steatosis is also promoted by excess dietary lipids and can be attenuated by their replacement with medium-chain triglycerides. Through reduction of pyruvate, elevated NADH also increases lactate, which stimulates collagen synthesis in myofibroblasts. Furthermore, CYP2E1 activity is inducible by its substrates, not only ethanol but also fatty acids. Their excess and metabolism by means of this pathway generate release of free radicals, which cause oxidative stress, with peroxidation of lipids and membrane damage, including altered enzyme activities. Products of lipid peroxidation such as 4-hydroxynonenal stimulate collagen generation and fibrosis, which are further increased through diminished feedback inhibition of collagen synthesis because acetaldehyde forms adducts with the carboxyl-terminal propeptide of procollagen in hepatic stellate cells. Acetaldehyde is also toxic to the mitochondria, and it aggravates their oxidative stress by binding to reduced glutathione and promoting its leakage. Oxidative stress and associated cellular injury promote inflammation, which is aggravated by increased production of the proinflammatory cytokine tumor necrosis factor-alpha in the Kupffer cells. These are activated by induction of their CYP2E1 as well as by endotoxin. The endotoxin-stimulated tumor necrosis factor-alpha release is decreased by dilinoleoylphosphatidylcholine, the active phosphatidylcholine (PC) species of polyenylphosphatidylcholine (PPC). Moreover, defense mechanisms provided by peroxisome proliferator-activated receptor alpha and omega fatty acid oxidation are readily overwhelmed, particularly in female rats and also in women who have low hepatic induction of fatty acid-binding protein (L-FABPc). Accordingly, the intracellular concentration of free fatty acids may become high enough to injure membranes, thereby contributing to necrosis, inflammation, and progression to fibrosis and cirrhosis. Eventually, hepatic S-adenosylmethionine and PCs become depleted in the alcoholic, with impairment of their multiple cellular functions, which can be restored by PC replenishment. Thus, prevention and therapy opposing the development of steatosis and its progression to more severe injury can be achieved by a multifactorial approach: control of alcohol consumption, avoidance of obesity and of excess dietary long-chain fatty acids, or their replacement with medium-chain fatty acids, and replenishment of S-adenosylmethionine and PCs by using PPC. Progress in the understanding of the pathogenesis of alcoholic fatty liver and its progression to inflammation and fibrosis has resulted in prospects for their better prevention and treatment.
 ...
PMID:Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. 1567 Jun 60

The prevalence of and the risk factors for fatty liver have not undergone a formal evaluation in a representative sample of the general population. We therefore performed a cross-sectional study in the town of Campogalliano (Modena, Italy), within the context of the Dionysos Project. Of 5,780 eligible persons aged 18 to 75 years, 3,345 (58%) agreed to participate in the study. Subjects with suspected liver disease (SLD), defined on the basis of elevated serum alanine aminotransferase (ALT) and gamma-glutamyl-transferase (GGT) activity, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV)-RNA positivity, were matched with randomly selected subjects of the same age and sex without SLD. A total of 311 subjects with and 287 without SLD underwent a detailed clinical, laboratory, and anthropometrical evaluation. Fatty liver was diagnosed by ultrasonography, and alcohol intake was assessed by using a 7-day diary. Multinomial logistic regression was used to detect risk factors for normal liver versus nonalcoholic fatty liver disease (NAFLD) and for alcoholic fatty liver (AFLD) versus NAFLD. The prevalence of NAFLD was similar in subjects with and without SLD (25 vs. 20%, P = .203). At multivariable analysis, normal liver was more likely than NAFLD in older subjects and less likely in the presence of obesity, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and systolic hypertension; AFLD was more likely than NAFLD in older subjects, males, and in the presence of elevated GGT and hypertriglyceridemia, and less likely in the presence of obesity and hyperglycemia. In conclusion, NAFLD is highly prevalent in the general population, is not associated with SLD, but is associated with many features of the metabolic syndrome.
 ...
PMID:Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. 1589 1

Non-alcoholic steatohepatitis (NASH) represents only a part of a wide spectrum of non-alcoholic fatty liver disease (NAFLD) and its prevalence is only 2 - 3% in the general population. Obesity, diabetes, hyperlipidemia and female sex are important risk factors for NASH. Two hit theory describes very well the pathogenesis of NASH wherein hepatic steatosis, the first hit is followed up by the second hit, one of which may be reactive oxygen species. Mitochondria is the main source of reactive oxygen species which may trigger steatohepatitis by lipid peroxidation, cytokine induction or induction of fas-ligand. Insulin resistance syndrome is the only metabolic syndrome that has been consistently associated with NASH. The diagnosis rests on the hallmark histological features and rigorous exclusion of significant alcohol consumption. Most patients are asymptomatic, have mild-to-moderate elevations of serum aminotransferase levels, clinical hepatomegaly and features of fatty liver on imaging. Liver biopsy is essential for positive diagnosis and prognostication of NASH. Histologically, fat deposition is typically macrovesicular and inflammation of steatohepatitis is predominantly lobular. Neutrophilic cells in lobular inflammatory infilterate are a distinguishing feature of steatohepatitis and differentiate it from other chronic hepatitis. The pattern of collagen deposition is perivenular & peri-sinusoidal spaces in zone 3. NASH is a progressive disease in more than one in four and has spontaneous regression in less than one in six. Therapy options include weight reduction in obese, good control in diabetics and exercise. Ursodeoxycholic acid has membrane stabilizing, cytoprotective and immunological effect and normalizes raised transaminases. Liver transplantation has been done in NASH but transplanted liver shows re-development in more than two thirds. Many more therapies are in the pipeline and show promise for the future.
 ...
PMID:Non-alcoholic steatohepatitis. 1592 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>