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

Alcoholic liver disease includes steatosis, alcoholic hepatitis and cirrhosis. Other liver diseases of genetic origin, but with a curious association with alcohol intake, are hemochromatosis and porphyria cutanea tarda. The attribution of chronic hepatitis to alcohol intake remains speculative, and the association may reflect hepatitis C infection. Hepatic injury attributed to alcohol includes the changes reported in the fetal alcohol syndrome. Steatosis, the characteristic consequence of excess alcohol intake, is usually macrovesicular and rarely microvesicular. Acute intrahepatic cholestasis, which in rare instances accompanies steatosis, must be distinguished from other causes of intrahepatic cholestasis (e.g., drug-induced) and from mechanical obstruction of the intrahepatic bile ducts (e.g., pancreatitis, choledocholithiasis) before being accepted. Alcoholic hepatitis (steatonecrosis) is characterized by a constellation of lesions: steatosis, Mallory bodies (with or without a neutrophilic inflammatory response), megamitochondria, occlusive lesions of terminal hepatic venules, and a lattice-like pattern of pericellular fibrosis. All these lesions mainly affect zone 3 of the hepatic acinus. Other changes, observed at the ultrastructural level, are of importance in progression of the disease. They include widespread cytoplasmic shedding, and capillarization and defenestration of sinusoids. Progressive fibrosis complicating alcoholic hepatitis eventually leads to cirrhosis that is typically micronodular but can evolve to a mixed or macronodular pattern. Hepatocellular carcinoma occurs in 5 to 15% of patients with alcoholic liver disease. The clinical syndrome of alcoholic liver disease is the result of three factors--parenchymal insufficiency, portal hypertension and the clinical consequences of extrahepatic damage produced by alcohol. At the several phases of the life history of alcoholic liver disease, the individual factors play a different role. The clinical manifestations of alcoholic steatosis are mainly extrahepatic in origin. Those of alcoholic hepatitis reflect mainly parenchymal insufficiency and those of cirrhosis are mainly those of portal hypertension. Alcoholic liver injury appears to be generated by the effects of ethanol metabolism and the toxic effects of acetaldehyde, perhaps the immune responses to alcohol- or acetaldehyde-altered proteins, and questionably enhanced by viral hepatitis. Alcoholic hepatitis may be mimicked histologically, and to a varying degree clinically, by a number of conditions (obesity, diabetes, several drug-induced injuries, jejunoileal bypass, and related "shortcircuiting" of the bowel). Perhaps the most important facet of the hepatotoxicity of alcohol is its enhancement of the effects of a number of other hepatotoxic agents, among which acetaminophen is the prime example.
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PMID:Alcoholic liver disease: pathologic, pathogenetic and clinical aspects. 205 45

Alcoholic liver disease (ALD) is a serious and potentially fatal consequence of alcohol use. The diagnosis of ALD is based on drinking history, physical signs and symptoms, and laboratory tests. Treatment strategies for ALD include lifestyle changes to reduce alcohol consumption, cigarette smoking, and obesity; nutrition therapy; and pharmacological therapy. The diagnosis and management of the complications of ALD are important for alleviating the symptoms of the disease, improving quality of life, and decreasing mortality.
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PMID:Diagnosis and treatment of alcoholic liver disease and its complications. 1553 53

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.
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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

Alcoholic liver disease (ALD) is characterized by accumulation of neutral lipids in hepatocytes leading to micro and macro-vesicular steatosis and balloon cell degeneration. Hypercaloric alimentation and resultant obesity also cause similar changes as evident in non-alcoholic fatty liver disease (NAFLD). Thus, accumulation of lipids in hepatocytes is a pathologic hallmark of ALD and NAFLD. In contrast, quiescent hepatic stellate cells (HSC) are characterized by the intracellular content of not only vitamin A but also triglycerides, and HSC activation is associated with depletion of these lipids. In fact, our recent work demonstrates that adipogenic/ lipogenic transcriptional regulation rendered by PPARgamma, LXRa, and SREBP-1c is essential for the maintenance of the fat-storing, quiescence phenotype of HSC. Expression of these adipogenic transcription factors is lost in activated HSC and the treatment of the cells with the adipocyte differentiation cocktail or ectopic expression of PPARgamma or SREBP-1c causes a reversal of activated cells to the quiescent phenotype. In steatotic livers from ALD and NAFLD mouse models, the expression of these adipogenic transcription factors is induced while the normal control livers lack such expression. Thus, adipogenic regulation is essential for HSC quiescence while it makes hepatocytes steatotic. Interestingly, under the adipogenic conditions of ALD and NAFLD, HSC are still activated to cause fibrosis. This fat paradox in hepatocytes and HSC highlights contrasted significance of fat in these two cell types that depend on each other for their homeostatic control. It further suggests, activated HSC in steatotic livers may have defective insulin signaling or lipogenic regulation.
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PMID:Fat paradox in liver disease. 1645 29

Alcoholic liver disease (ALD) is a lifestyle disease with its pathogenesis and individual predisposition governed by gene-environment interactions. Based on the "second hit" or "multiple hits" hypothesis, patients are predisposed to progressive ALD when a magic combination of gene and environmental interactions exists. Reproduction of second or multiple hits in animal models serves to test a combination and to gain mechanistic insights into synergism achieved by such combination. Numerous environmental factors have been incorporated into animal models, largely classified into nutritional, xenobiotic/pharmacologic, hemodynamic, and viral groups. A loss or gain of function genetic model has become a popular experimental approach to test the role of a gene as a second hit. Future research will need to test more subtle or natural hits combined with excessive alcohol intake to test multiple hits in the genesis of ALD. Additionally, animal models of comorbidities are urgently needed particularly for synergistic liver disease and oncogenesis caused by alcohol, obesity, and hepatitis virus.
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PMID:"Second hit" models of alcoholic liver disease. 1938 17

Alcoholic liver disease remains a frequent and serious problem for increasing numbers of patients. Research has expanded our molecular understanding of the cellular basis of disease progression; however, translation into therapy is still hampered by a lack of suitable animal models for alcoholic liver disease, as well as from consequences of related liver damage due to malnutrition, hepatitis C virus infection, or abuse of other substances. Many patients with liver disease do not simply consume too much alcohol; they also suffer from comorbidities such as obesity or viral hepatitis, and/or may be addicted to other drugs besides alcohol. This review will summarize the currently available animal models to study liver disease due to either single causes or combinations of liver toxic substances/infections and alcohol.
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PMID:Alcoholic liver disease and exacerbation by malnutrition and infections: what animal models are currently available? 2118 34

Alcoholic liver disease (ALD) accounts for the majority of chronic liver disease in Western countries. The spectrum of ALD includes steatosis with or without fibrosis in virtually all individuals with an alcohol consumption of >80 g/day, alcoholic steatohepatitis of variable severity in 10-35% and liver cirrhosis in approximately 15% of patients. Once cirrhosis is established, there is an annual risk for hepatocellular carcinoma of 1-2%. Environmental factors such as drinking patterns, coexisting liver disease, obesity, diet composition and comedication may modify the natural course of ALD. Twin studies have revealed a substantial contribution of genetic factors to the evolution of ALD, as demonstrated by a threefold higher disease concordance between monozygotic twins and dizygotic twins. With genotyping becoming widely available, a large number of genetic case-control studies evaluating candidate gene variants coding for proteins involved in the degradation of alcohol, mediating antioxidant defence, the evolution and counteraction of necroinflammation and formation and degradation of extracellular matrix have been published with largely unconfirmed, impeached or even disproved associations. Recently, whole genome analyses of large numbers of genetic variants in several chronic liver diseases including gallstone disease, primary sclerosing cholangitis and non-alcoholic fatty liver disease (NAFLD) have identified novel yet unconsidered candidate genes. Regarding the latter, a sequence variation within the gene coding for patatin-like phospholipase encoding 3 (PNPLA3, rs738409) was found to modulate steatosis, necroinflammation and fibrosis in NAFLD. Subsequently, the same variant was repeatedly confirmed as the first robust genetic risk factor for progressive ALD.
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PMID:Genetic determinants of alcoholic liver disease. 2211 53

Alcoholic liver disease (ALD) remains a major cause of chronic liver diseases and liver failure. Population-based prospective studies and patient cohort studies have demonstrated that obesity and the metabolic syndrome exacerbate progression of ALD and increase hepatocellular carcinoma (HCC) incidence and mortality. Emerging evidence also suggests a synergism between alcohol and obesity in mortality and HCC incidence. Recognition of these increased risks and detection of early-stage liver disease may offer the opportunity to address these modifiable risk factors and prevent disease progression in these patients.
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PMID:The impact of obesity and metabolic syndrome on alcoholic liver disease. 2427 71

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are significant causes of chronic liver disease worldwide. Both are characterized by histological lesions that can include steatosis, and each can lead to cirrhosis. It might be possible for pathologists to identify lesions and patterns of ALD and NAFLD; we review these lesions and propose methods to distinguish between the disorders. Any form of ALD can lead to end-stage liver disease, according to long-term studies of biopsy specimens and patient outcomes. Although steatosis can be a significant cofactor in progression of established chronic liver disease, or even development of hepatocellular carcinoma, only steatohepatitis indicates the presence of progressive liver disease in patients with NAFLD. Pediatric and adolescent NAFLD differ from adult nonalcoholic steatohepatitis and should be recognized as distinct conditions. Benign and malignant liver tumors have been more frequently reported with the increasing prevalence of obesity and diabetes. Histological scoring systems for ALD and NAFLD have been proposed to monitor efficacy in clinical trials and serve as prognostic factors. We review what we have learned from pathological analyses about the development of these disorders and how this information might be used to detect and treat them.
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PMID:Pathological features of fatty liver disease. 2510 84

Alcoholic liver disease (ALD) accounts for the majority of chronic liverdiseases in Occidental countries and remains a major cause of liver-related mortality in worldwide. The spectrum of ALD includes steatosis in patients which consume over 80g of alcohol per day, alcoholic steatohepatitis and liver cirrhosis in approximately 15% of patients. Once cirrhosis is established, the annual risk for hepatocellular carcinoma is about 1-2%. Environmental factors such as drinking patterns, coexisting liver disease, obesity, diet and co-medication may affect the natural course of ALD. Abstinence is the hallmark of therapy for ALD, and nutritional therapy is the first line in therapeutical intervention.
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PMID:Alcoholic liver disease--epidemiology and risk factors. 2558 47


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