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)

Hyperferritinemia, a common feature of nonalcoholic fatty liver disease (NAFLD), has been associated with steatohepatitis and fibrosis. Heterozygosity for alpha 1-antitrypsin (AAT) mutations is a cofactor of liver damage, and AAT influences inflammation and iron metabolism. This study evaluated the prevalence of the common AAT PiS/PiZ mutants in 353 patients with NAFLD, 195 of whom had hyperferritinemia, versus 114 matched controls and their influence on iron metabolism and the severity of liver damage in the 212 patients submitted to biopsy. PiS and PiZ alleles were searched for by restriction analysis. Thirty-eight patients (10.8%) carried non-MM genotypes versus 4/114 (3.5%) controls (P = .02). Patients carrying AAT mutations had higher ferritin (573 [454-966] vs. 348 [201-648]; P = .001) with similar transferrin saturation. The difference was more evident in males (P < .0001) and significant in patients not carrying HFE genotypes associated with iron overload (P = .015). The prevalence of non-MM genotypes was higher in patients with hyperferritinemia than in those without (28/195, 14% vs. 10/158, 6%, P = .016), and AAT mutations were associated with higher prevalence of sinusoidal siderosis (17/27, 63% vs. 70/180, 39%; P = .02), and sinusoidal/total iron score (46.3 +/- 38% vs. 25.1 +/- 35%, P = .01). Although ferritin was independently associated with fibrosis (P = .047), AAT mutations favoring sinusoidal iron deposition did not affect liver damage. In conclusion, AAT mutations are associated with hyperferritinemia and sinusoidal iron accumulation, but not with more severe liver damage in NAFLD.
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PMID:Alpha 1-antitrypsin mutations in NAFLD: high prevalence and association with altered iron metabolism but not with liver damage. 1700 22

There are limited data on nonalcoholic fatty liver disease (NAFLD) from India. The clinicopathological profile of Indian patients with NAFLD may be different from that of Western patients. One hundred NAFLD patients with increased liver enzymes were prospectively evaluated for clinical presentation, associated diseases, overweight/obesity, central obesity (n=54), presence of diabetes mellitus, lipid abnormalities, insulin resistance (n=39), metabolic syndrome (n=54), serum iron, serum ferritin, and transferrin saturation (n=60), and HFE gene mutations (n=30). Risk factors for the grade and stage of the disease on histology were studied in 38 biopsy-proven patients. Patients were treated with lifestyle modifications and ursodeoxycholic acid (UDCA). Seventeen nonresponder patients were treated with metformin. The majority of patients were males (n=70). Twenty percent of patients were overweight, 68% had obesity, and 78% had central obesity. Abnormal cholesterol, HDL, and triglycerides were present in 36%, 66%, and 53% of patients, respectively. Twelve percent of patients had diabetes mellitus and 16% patients had various associated diseases. All 22 (100%) patients studied by ITT and all but 1 (98%) studied by HOMA-IR were found to have reduced insulin sensitivity and 50% were found to have metabolic syndrome by the modified ATP III criteria. Two (3%) patients were found to have high serum iron, 4 (7%) patients had high ferritin, 5 (8%) patients had increased transferrin saturation, and 4 (13%) patients were found to be heterozygotes for H63D HFE gene mutation. Twenty patients of 38 (53%) had histological evidence of NASH (class 3=6, class 4=14). The other 18 (47%) qualified for class I (n=1) or class II (n=17) NAFLD. Four (10.5%) patients had bridging fibrosis and none had evidence of cirrhosis liver. Seventy-four (74%) patients achieved a biochemical response to lifestyle modification and UDCA. All 17 patients treated with metformin had a reduction in ALT level and 10 (59%) of them had normalization of their enzymes. We conclude that the clinicopathological profile of NAFLD in Indian patients is different from that in the West.
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PMID:The clinicopathological profile of Indian patients with nonalcoholic fatty liver disease (NAFLD) is different from that in the West. 1742 Sep 51

Patients with chronic hepatitis C frequently have serum and hepatic iron overload, but the mechanism is unknown. Recently identified hepcidin, exclusively synthesized in the liver, is thought to be a key regulator for iron homeostasis and is induced by infection and inflammation. This study was conducted to determine the hepatic hepcidin expression levels in patients with various liver diseases. We investigated hepcidin mRNA levels of liver samples by real-time detection-polymerase chain reaction; 56 were hepatitis C virus (HCV) positive, 34 were hepatitis B virus (HBV) positive, and 42 were negative for HCV and HBV (3 cases of auto-immune hepatitis, 7 alcoholic liver disease, 13 primary biliary cirrhosis, 9 nonalcoholic fatty liver disease, and 10 normal liver). We analyzed the relation of hepcidin to clinical, hematological, histological, and etiological findings. Hepcidin expression levels were strongly correlated with serum ferritin (P < 0.0001) and the degree of iron deposit in liver tissues (P < 0.0001). Hepcidin was also correlated with hematological parameters (vs. hemoglobin, P = 0.0073; vs. serum iron, P = 0.0012; vs. transferrin saturation, P < 0.0001) and transaminase levels (P = 0.0013). The hepcidin-to-ferritin ratio was significantly lower in HCV(+) patients than in HBV(+) patients (P = 0.0129) or control subjects (P = 0.0080). In conclusion, hepcidin expression levels in chronic liver diseases were strongly correlated with either the serum ferritin concentration or degree of iron deposits in the liver. When adjusted by either serum ferritin values or hepatic iron scores, hepcidin indices were significantly lower in HCV(+) patients than in HBV(+) patients, suggesting that hepcidin may play a pivotal role in the pathogenesis of iron overload in patients with chronic hepatitis C.
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PMID:Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. 1751 61

Persons heterozygous for Z, S and rare alpha-1-antitrypsin (AAT, SERPIN1A) polymorphisms (ca. 9% of population) are often considered 'silent' carriers with increased vulnerability to environmentally modulated liver and lung disease. They may have significantly more anxiety and bipolar spectrum disorders, nutritional compromise, and white matter disease [Schmechel DE, Browndyke J, Ghio A. Strategies for the dissection of genetic-environmental interactions in neurodegenerative disorders. Neurotoxicology 2006;27:637-57]. Given association of art and mood disorders, we examined occupation and artistic vocation from this same series. One thousand five hundred and thirty-seven consecutive persons aged 16-90 years old received comprehensive work-up including testing for AAT 'phenotype' and level, nutritional factors, and inflammatory, iron and copper indices. Occupations were grouped by Bureau of Labor Standards classification and information gathered on artistic activities. Proportion of reactive airway disease, obstructive pulmonary disease, and pre-existing anxiety disorder or bipolar disorder were significantly increased in persons carrying AAT non-M polymorphisms compared to normal MM genotype (respectively, 10, 20, 21, and 33% compared to 8, 12, 11, and 9%; contingency table, pulmonary: chi2 37, p=0.0001; affective disorder: chi2=171, p=0.0001). In persons with artistic avocation (n=189) or occupation (n=57), AAT non-M polymorphisms are significantly increased (respectively, proportions of 44 and 40% compared to background rate of 9%; contingency table, avocation: chi2=172, p=0.0001; occupation: chi2=57, p=0.0007). Artistic ability and 'anxiety/bipolar spectrum' mood disorders may represent phenotypic attributes that had selective advantage during recent human evolution, an 'intensive creative energy' (ICE) behavioral phenotype. Background proportion of ICE of 7% consists of 49 of 1312 persons with AAT MM genotype (4%), and 58 of 225 persons with non-MM genotypes (26%) (contingency table, chi2=222, p=0.0001). Penetrance of ICE increases in genotypes with lower AAT levels: PiMS, 18%; PiMZ, 44%; PiSS and PiZZ, 100% (five cases). At all ages, persons with non-MM genotype had significantly higher proportion of thiamine deficiency (50% in PiMZ), reactive hypoglycemia (20% in PiMZ), and possibly fatty liver (thiamine: chi2=28, p=0.0001; hypoglycemia: chi2=92, p=0.0001). In older persons, PiMZ genotype had significantly increased proportion (46%) of brain MRI T2 white matter abnormalities (chi2=49, p=0.003). Persons with ICE and MM genotype showed increased prevalence of pulmonary disorders and same signature as S and Z carriers and homozygotes (see above). Z polymorphism was associated with delayed age of onset (average 7 years) for persons with toxic environmental or occupational exposures (log rank, p=0.0001) and more stable cognitive change in persons with neurodegenerative illness (p<0.05). At all ages, ICE phenotype and Z polymorphism were associated with altered copper homeostasis with low or absent non-ceruloplasmin bound copper (p<0.05). AAT polymorphisms which affect iron, lipid and copper metabolism may affect early events in nervous system development, function and response to environmental exposures. AAT may also be a 'switch' for copper metabolism and low 'free' copper would be theorized to provide protection for lipid oxidation and favorably affect beta-amyloid and other aggregation, but possibly alter early 'critical' period of CNS development. AAT polymorphisms may define an important and treatable subset of persons presenting with CNS disorders. This new proposed phenotype for AAT transcends classic pattern of strictly liver and lung disease, and should be considered for proper evaluation and management of patients presenting with classic AAT-related disorders, affective disorders, persons with ICE, white matter disease or multisystem disorders of memory.
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PMID:Art, alpha-1-antitrypsin polymorphisms and intense creative energy: blessing or curse? 1765 42

Current knowledge on gamma glutamyl transpeptidase (gammaGTP) was reviewed. This enzyme, which is mainly expresses on the cell surface, is thought to participate in catalyzing glutathione breakdown, resulting in the formation of cystein, a thiol compound exerting antioxidant effects. The most important role of this enzyme in vivo seems to recover cystein from extracellular glutathione to preserve intracellular homeostasis of oxidative stress. Increase in environmental oxidative stress may induce this enzyme via NFkB. However, its excessive induction may contrary raise oxidative stress and cause subsequent organ injuries since cysteinylglycine, an intermediate of the glutathione breakdown, affects the iron metabolism, resulting in the production of free radicals. Recently, there are multiple lines of evidence that the development of hypertension, hyperlipidemia, diabetes mellitus is associated with increased serum gammaGTP levels. The oxidative stress derived from gammaGTP may participate in the development of these morbid conditions and would account for these associations. However, since subjects associated with excessive drinking and overweight, two major factors increasing serum gammaGTP level are usually suffering from hypertension, hyperlipidemia, diabetes mellitus, it is most likely that the associations are attributed to excessive drinking and overweight. We recently demonstrated that level of serum gammaGTP is inversely associated with that of serum adiponectin, a sort of adipocytokines. In that abnormalities of adipocytokines including adiponectin cause hypertension, hyperlipidemia, diabetes mellitus as well as fatty liver that is associated with increased gammaGTP level, the status of adipocytokines may stand behind the associations among these factors in obese subjects. Moreover, we demonstrated that serum gammaGTP level is inversely associated with subjects' statuses of lifestyles evaluated by Breslow's lifestyle index, suggesting that serum gammaGTP activity could be a tool for screening of subjects with unhealthy lifestyles. In that unhealthy lifestyles cause various morbid conditions designated as lifestyle-related diseases that is thought to comprehend metabolic syndrome and/or alcohol-related diseases, such screening and intervention in their correction should be significant to prevent their development. The consensus currently reached is that increased serum gammaGTP activity is associated with increased mortality. In that excessive drinking, obesity, as well as improper lifestyle elevate serum gammaGTP activity meanwhile cause various morbid conditions that make lifespan shorter, the view is not surprising.
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PMID:[Gamma glutamyl transpeptidase (gammaGTP) in the era of metabolic syndrome]. 1766 41

Chronic hepatitis B virus (HBV) infection is the most common cause of hepatic fibrosis and hepatocellular carcinoma (HCC), mainly as a result of chronic necroinflammatory liver disease. A characteristic feature of chronic hepatitis B infection, alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD) is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which, in turn, activates hepatic stellate cells (HSCs). HSCs are the primary target cells for inflammatory and oxidative stimuli, and these cells produce extracellular matrix components. Chronic hepatitis B appears to progress more rapidly in males than in females, and NAFLD, cirrhosis and HCC are predominately diseases that tend to occur in men and postmenopausal women. Premenopausal women have lower hepatic iron stores and a decreased production of proinflammatory cytokines. Hepatic steatosis has been observed in aromatase-deficient mice, and has been shown to decrease in animals after estradiol treatment. Estradiol is a potent endogenous antioxidant which suppresses hepatic fibrosis in animal models, and attenuates induction of redox sensitive transcription factors, hepatocyte apoptosis and HSC activation by inhibiting a generation of reactive oxygen species in primary cultures. Variant estrogen receptors are expressed to a greater extent in male patients with chronic liver disease than in females. These lines of evidence suggest that the greater progression of hepatic fibrosis and HCC in men and postmenopausal women may be due, at least in part, to lower production of estradiol and a reduced response to the action of estradiol. A better understanding of the basic mechanisms underlying the sex-associated differences in hepatic fibrogenesis and carciogenesis may open up new avenues for the prevention and treatment of chronic liver disease.
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PMID:Female hepatology: favorable role of estrogen in chronic liver disease with hepatitis B virus infection. 1770

Iron depletion improves insulin resistance in patients with nonalcoholic fatty liver disease and diabetes and also stabilizes the hypoxia-inducible factor (HIF)-1, resulting in increased glucose uptake in vitro. This study investigated the effect of iron depletion by deferoxamine on insulin signaling and glucose uptake in HepG2 hepatocytes and in rat liver. In HepG2 cells, deferoxamine stabilized HIF-1alpha and induced the constitutive glucose transporter Glut1 and the insulin receptor. Up-regulation of insulin receptor by deferoxamine was mimicked by the intracellular iron chelator deferasirox and the hypoxia inducer CoCl2 and required the HIF-1 obligate partner ARNT/HIF-1beta. Iron depletion increased insulin receptor activity, whereas iron supplementation had the opposite effect. Deferoxamine consistently increased the phosphorylation status of Akt/PKB and its targets FoxO1 and Gsk3beta, which mediate the effect of insulin on gluconeogenesis and glycogen synthesis, and up-regulated genes involved in glucose uptake and utilization. Iron depletion of Sprague-Dawley rats increased HIF-1alpha expression, improved glucose clearance, and was associated with up-regulation of insulin receptor and Akt/PKB levels and of glucose transport in hepatic tissue. Conversely, gluconeogenic genes were not affected. In rats with fatty liver because of a high-calorie and high-fat diet, glucose clearance was increased by iron depletion and decreased by iron supplementation. Thus, iron depletion by deferoxamine up-regulates glucose uptake, and increases insulin receptor activity and signaling in hepatocytes in vitro and in vivo.
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PMID:Iron depletion by deferoxamine up-regulates glucose uptake and insulin signaling in hepatoma cells and in rat liver. 1824 13

Iron homeostasis disturbances are associated with liver disease. Non-alcoholic steatohepatitis is part of the spectrum of non-alcoholic fatty liver disease, which can progress to hepatic cirrhosis and end-stage liver disease. Increasing information supports that multiple factors underlie the development and progression of nonalcoholic steatohepatitis. However, the relation between non-alcoholic steatohepatitis and iron metabolism/ overload is still controversial. We review the recent literature, both basic and clinical, regarding iron homeostasis as it pertains to the pathogenesis of nonalcoholic fatty liver disease.
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PMID:Importance of iron and iron metabolism in nonalcoholic fatty liver disease. 1828

Emerging scientific evidence suggests that increases in body iron represent a risk factor for the development of metabolic syndrome and diabetes. The aim of our study was to determine the body iron stores in patients with metabolic syndrome, and to evaluate the potential relationship of iron overload with specific features of the metabolic syndrome, such as fatty liver. A total of 490 individuals were enrolled. The diagnosis of metabolic syndrome was based on National Cholesterol Education Program-Adult Treatment Panel III (ATPIII) criteria. The metabolic syndrome group was consisted of 185 patients having three or more criteria, whereas individuals with less than three criteria constituted the control group. Metabolic syndrome patients displayed higher ferritin concentration as compared to control individuals. Ferritin levels were positively correlated with insulin concentration, as well as with Homeostasis Model Assessment (HOMA) index values. Multiple regression analysis revealed that ferritin was the most important independent determinant of insulin resistance indices. Patients with metabolic syndrome also exhibited increased concentrations of alanine aminotransferase and gamma-glutamyltranspeptidase compared to controls. Multiple regression analysis revealed that ferritin concentration was the most important determinant of gamma-glutamyltranspeptidase levels. Patients with the metabolic syndrome exhibit an increase in body iron stores as well as elevated concentrations of liver enzymes compared to the individuals who do not fulfill the criteria for the diagnosis of this syndrome. Our data support a direct role of increased body iron in the pathogenesis of insulin resistance, whereas iron overload may also contribute to the development of specific features of the metabolic syndrome, such as fatty liver.
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PMID:Increased serum ferritin concentrations and liver enzyme activities in patients with metabolic syndrome. 1837 Jul 38

The aim of this study was to investigate HFE gene mutations, blood iron indices, and their clinical correlates in a Korean population. In 484 prospectively enrolled health-check examinees, HFE gene mutations and iron indices with clinical and laboratory variables were analyzed. Although neither the C282Y nor S65C gene mutation were found, the H63D heterozygote was detected in 41 subjects (8.5%). The mean serum ferritin and transferrin saturation (TS) were 136.2 +/- 129.8 microg/dl and 39.2 +/- 15.7%, respectively. The H63D genotype was not significantly associated with iron indices. High serum ferritin was associated with old age, the male gender, high body mass index (BMI), and the presence of nonalcoholic fatty liver disease (NAFLD). High TS was associated with the male gender and alcohol drinking. HFE gene mutation is rare; however, TS seems to be higher in Koreans compared to Caucasians or other ethnic groups. Serum ferritin reflects iron store as well as the presence of NAFLD.
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PMID:HFE gene mutations, serum ferritin level, transferrin saturation, and their clinical correlates in a Korean population. 1868 48


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