Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twin concordance studies indicate that genetic factors influence the individual susceptibility for alcoholic liver disease (ALD). Both clinical and experimental data suggest that Kupffer cell activation by gut-derived endotoxins and other bacterial products is an important pathogenic factor. Activated Kupffer cells release proinflammatory cytokines, a process that is regulated by the CD14 endotoxin receptor (CD14). Recently, a C-->T (-159) polymorphism in the promoter region of the CD14 gene was detected and found to confer increased CD14 expression. In the present study, the association of CD14 promoter polymorphism with different forms of ALD was examined in 3 separate autopsy series. Among 442 men with valid alcohol-consumption data, 381 men had been moderate or heavy alcohol consumers. The allele frequency of the CD14 promoter genotype, determined by a modified cycle minisequencing technique, was 0.34 (CC), 0.51 (CT), and 0.16 (TT). The T allele was found to be associated with advanced ALD, i.e., with alcoholic hepatitis (odds ratio [OR]: 2.48; P = .018), and especially with cirrhosis (OR: 3.45; P = .004), but not with fatty liver, periportal fibrosis, or bridging fibrosis. The overall age-adjusted risk for cirrhosis was 3.08 (P = .01) for the carriers of the CT genotype, and 4.17 (P = .005) for the homozygous TT genotype. These results suggest that in the relatively isolated Finnish population, the T allele confers increased risk of alcoholic liver damage. In particular, TT homozygotes are at a high risk to develop cirrhosis.
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PMID:Promoter polymorphism of the CD14 endotoxin receptor gene as a risk factor for alcoholic liver disease. 1178 86

Nonalcoholic fatty liver (NAFL) is associated with fundamental issues of fat metabolism and insulin resistance. These abnormalities have been linked to impairment of ATP homeostasis, and a growing body of literature has reported mitochondrial abnormalities in various forms of hepatic steatosis. The changes are evident as structural abnormalities, including greatly increased size and the development of crystalline inclusions, and are usually regarded as pathologic, reflecting either a protective or degenerative response to injury. Although the relationships between structural changes,decreased mitochondrial function, and disease states are becoming clearer, the molecular basis for the perturbations is not well understood. Oxidative damage is the most likely causative process and may result in alterations of mitochondrial DNA (mtDNA), stimulated apoptotic pathways, and increased propensity for necrosis.Overall mitochondrial health likely depends on multiple factors including the integrity of the mtDNA, the composition of cellular lipids, lipoprotein trafficking, the balance of pro- and antioxidant factors, and the metabolic demands placed on the liver. Mitochondrial dysfunction may play a role in numerous clinical conditions associated with NAFL, such as hepatocellular carcinoma, lipodystrophy,age-related insulin resistance, gut dysmotility, cryptogenic cirrhosis, a mild form of gaze palsy, and possibly other more severe neurodegenerative diseases. The prominent role of mitochondrial dysfunction in NAFL provides a new and exciting paradigm in which to view this disorder, its complications, and potential dietary and pharmacologic intervention.
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PMID:Mitochondria in nonalcoholic fatty liver disease. 1533 Oct 66

Obesity has reached epidemic levels in industrialized countries and is increasing worldwide. This trend has serious public health consequences, since obesity increases the risk of diabetes, hypertension, heart disease, sleep apnea, cancer, arthritis, cholelithiasis, fatty liver disease, and other complications. Obesity is the result of an imbalance between energy intake and expenditure; hence, an understanding of how gastrointestinal function is integrated with the hormonal regulation of energy balance is pertinent to the pathophysiology of obesity. Nutrients, peptides, and neural afferents from the gut influence the size and frequency of meals and satiety. The long-term regulation of energy stores is mediated primarily through the actions of adiposity hormones, such as leptin and insulin, in the hypothalamus and other neuronal circuits in the brain. Efforts are underway to determine how these peripheral and central pathways may be targeted for treatment of obesity and related diseases.
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PMID:Gut peptides and other regulators in obesity. 1560 2

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.
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PMID:Recent concepts in non-alcoholic fatty liver disease. 1610 37

Nonalcoholic fatty liver disease (NAFLD) is a condition of increasing incidence in western Countries seldom associated to other diseases of high prevalence in general population (i.e. diabetes and obesity). NAFLD ranges from simple fatty liver to steatohepatitis (NASH), which may lead to cryptogenic cirrhosis and in some cases hepatocellular carcinoma (HCC). Natural history of NAFLD in humans is poorly understood and progression of liver disease seems to be due to interaction between hosting (i.e. genetic, gut flora, insulin resistance) and environmental factors (social and eating behaviours) that should be responsible of increased oxidative stress within hepatocytes. Even if we need non-invasive markers able to describe the progression of liver disease, only meaning of liver biopsy is useful to characterize the stigmata of worsening such as inflammation and fibrosis.
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PMID:The natural history and risk factors for progression of non-alcoholic fatty liver disease and steatohepatitis. 1623 89

Resistin and resistin-like molecules (RELMs) are a family of proteins reportedly related to insulin resistance and inflammation. Because the serum concentration and intestinal expression level of RELMbeta were elevated in insulin-resistant rodent models, in this study we investigated the effect of RELMbeta on insulin signaling and metabolism using transgenic mice and primary cultured hepatocytes. First, transgenic mice with hepatic RELMbeta overexpression were shown to exhibit significant hyperglycemia, hyperlipidemia, fatty liver, and pancreatic islet enlargement when fed a high fat diet. Hyperinsulinemic glucose clamp showed a decreased glucose infusion rate due to increased hepatic glucose production. In addition, the expression levels of IRS-1 and IRS-2 proteins as well as the degrees of insulin-induced phosphatidylinositol 3-kinase and Akt activations were attenuated in RELMbeta transgenic mice. Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated (for 24 h) with RELMbeta, suggesting the insulin resistance-inducing effect of RELMbeta to be direct. Furthermore, it was shown that RELMbeta acutely and markedly activates ERK and p38, while weakly activating JNK, in primary cultured hepatocytes. This increased basal p38 phosphorylation level was also observed in the livers of RELMbeta transgenic mice. In conclusion, RELMbeta, a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of RELMbeta may be involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. Thus, RELMbeta is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic agents.
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PMID:Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet. 1624 41

Plasma levels of gut-derived endotoxins (lipopolysaccharides, LPS) are often elevated in cirrhotics and are thought to contribute to hepatic encephalopathy. Circulating LPS activates macrophages to produce tumor necrosis factor alpha (TNF-alpha) and other potentially cytotoxic proinflammatory mediators. A pathogenic role for endotoxins is supported by studies showing that treatment with Lacto-bacillusor antibiotics, both of which reduce LPS-producing intestinal Gram-negative bacteria, alleviates experimental liver damage. To mimic the "leaky gut" syndrome with endotoxin translocation into the circulation in cirrhotics, a new animal model was developed. Rats were chronically exposed to ethanol and for the four last weeks also infused with endotoxin into the jugular vein from subcutaneously implanted osmotic minipumps. Animals receiving endotoxin had elevated hepatic expression of both pro- and anti-inflammatory cytokines, but compared to ethanol treatment alone hepatic steatosis and inflammatory changes were only marginally increased. This demonstrates marked endotoxin tolerance, probably as a consequence of a counteracting anti-inflammatory cytokine response. The role of gut-derived endotoxin in hepatic encephalopathy has recently received considerable attention. To further delineate the role and actions of endotoxin and its extrahepatic effects, studies applying both acute challenge and chronic infusion seem warranted. The chronic endotoxin model, mimicking the "leaky gut," may best be combined with more robust ways to impair liver function, such as carbon tetrachloride treatment, bile duct ligation, or galactosamine administration.
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PMID:Chronic systemic endotoxin exposure: an animal model in experimental hepatic encephalopathy. 1638 49

When specimens of the newt Triturus carnifex, under anaesthesia by submersion in a 0.2% chlorbutol solution for 25 min, are isolated in a respiratory chamber at 18 degrees C containing water with only 1.3 ppm of oxygen, they consume the oxygen completely in about 3 hr, but they can stay alive for many more hours and wake up with no apparent exterior consequences. Hypoxia induces rapid onset of hepatic steatosis and melanosis, as well as a controlled haemolytic process involving a pool of red blood cells of the same order of size as that held as a reserve in the spleen by animals in an aerial habitat. At the origin of the phenomena is an intense response by the hypophysis, histologically detectable 1 hr from the onset of treatment and confirmed 2 hr later by a highly significant increase in the plasma thyroidstimulating hormone (TSH) concentration compared with the controls (41.5 +/- 13.7 microU/L vs. 15.5 +/- 6.2; P < 0.005). The thyroid follicles react by reabsorbing their colloid, but instead of an increase in the plasma free T3 and T4 concentrations, fT3 falls significantly (1.5 +/- 0.3 pg/mL vs., the 2.4 +/- 0.7; P < 0.05), whereas fT4 remains stationary (4.0 +/- 0.5 pg/mL vs. 4.6 +/- 0.8; N.S.). After 6 hr, the plasmatic TSH concentration is still higher than in the controls (27.0 +/- 3.0 microU/L vs. 15.5 +/- 6.2; P < 0.05), whereas fT3 and fT4 remain stable (1.5 +/- 0.3 and 4.4 +/- 0.5 pg/mL, respectively). If T3 or T4 labelled with 125I is administered prior to hypoxia, after 6 hr of treatment the radioactivity is found to be limited exclusively to the liver and kidney; the thyroid, gall bladder and gut result negative, and this does not agree with hypotheses of hormone inactivation by deiodination, sulphation or glucuronidation. This apparently peculiar endocrine path has not been observed in previous studies on hypoxia in vertebrates, because the experiments were always designed to analyse plasma hormone levels after at least 24 hr of hypoxia or during chronic treatments, losing the most interesting phases of the endocrine response. The possibility that the hypoxic newt possesses alternative or complementary metabolic pathways to anaerobic glycolysis to sustain steatogenesis and melanogenesis and maintain the same cardiac activity as the controls is briefly discussed.
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PMID:Thyroid and hypoxic stress in the newt Triturus carnifex. 1643 85

Intestinal failure-associated liver disease develops in 40% to 60% of infants who require long-term total parenteral nutrition (TPN) for intestinal failure and 15% to 40% of adults on home parenteral nutrition. The clinical spectrum includes hepatic steatosis, cholestasis, cholelithiasis, and hepatic fibrosis. Progression to biliary cirrhosis and the development of portal hypertension and liver failure occurs in a minority but is more common in infants and neonates than in adults. The pathogenesis is multifactorial. In infants it is related to prematurity, low birth weight, duration of PN, short bowel syndrome requiring multiple laparotomies, and recurrent sepsis. Other important mechanisms include lack of enteral feeding, which leads to reduced gut hormone secretion; reduction of bile flow and biliary stasis, which leads to the development of cholestasis; and biliary sludge and gallstones, which exacerbate hepatic dysfunction. In adults, IFALD is less common and related to age, length of time on PN, total caloric intake, and lipid or glucose overload. In preterm infants, a deficiency of taurine or cysteine may play a role, whereas in both adults and children, choline deficiency may exacerbate IFALD. Lipid emulsions, choline deficiency, and manganese toxicity are associated with both hepatic steatosis and cholestasis in adults and children. Management strategies for the prevention of intestinal failure-induced liver disease include early enteral feeding, a multidisciplinary approach to the management of parenteral nutrition, and aseptic catheter techniques to reduce sepsis. The addition of choline, taurine, and cysteine to PN solutions may also play a role. Oral administration of ursodeoxycholic acid may improve bile flow and reduce gallbladder stasis. Survival after either isolated small bowel or combined liver and small bowel transplantation is approximately 50% at 5 years, making this an acceptable therapeutic option in adults and children with irreversible liver and intestinal failure.
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PMID:Intestinal failure-associated liver disease: what do we know today? 1647 75

Total parenteral nutrition is a life saving therapy for patients with chronic gastrointestinal failure, being an effective method for supplying energy and nutrients when oral or enteral feeding is impossible or contraindicated. Clinical epidemiological data indicate that total parenteral nutrition may be associated with a variety of problems. Herein we reviewed data on the gastroenterological tract regarding: (i) total parenteral nutrition-related hepatobiliary complications; and (ii) total parenteral nutrition-related intestinal complications. In the first group, complications may vary from mildly elevated liver enzyme values to steatosis, steatohepatitis, cholestasis, fibrosis and cirrhosis. In particular, total parenteral nutrition is considered to be an absolute risk factor for the development of biliary sludge and gallstones and is often associated with hepatic steatosis and intrahepatic cholestasis. In general, the incidence of total parenteral nutrition-related hepatobiliary complications has been reported to be very high, ranging from 20 to 75% in adults. All these hepatobiliary complications are more likely to occur after long-term total parenteral nutrition, but they seem to be less frequent, and/or less severe in patients who are also receiving oral feeding. In addition, end-stage liver disease has been described in approximately 15-20% of patients receiving prolonged total parenteral nutrition. Total parenteral nutrition-related intestinal complications have not yet been adequately defined and described. Epidemiological studies intended to define the incidence of these complications, are still ongoing. Recent papers confirm that in both animals and humans, total parenteral nutrition-related intestinal complications are induced by the lack of enteral stimulation and are characterised by changes in the structure and function of the gut. Preventive suggestions and therapies for both these gastroenterological complications are reviewed and reported in the present review.
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PMID:Total parenteral nutrition-related gastroenterological complications. 1676 37


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