Insulin resistance and NAFLD: Relationship with intrahepatic iron and serum TNF-α using 1H MR spectroscopy and MRI.

AIM: The association of non-alcoholic fatty liver disease (NAFLD) with insulin resistance (IR) is well established, yet little is known of their possible relationship with intrahepatic iron and serum tumour necrosis factor (TNF)-α concentrations in adults without diabetes. Thus, this study looked at the relationship of intrahepatic iron and serum TNF-α with intrahepatic triglycerides and IR in non-diabetic adults. METHODS: In this cross-sectional study of 104 healthy non-diabetic Caucasians, a quantitative magnetic resonance (MR) imaging T2 gradient-echo technique was used to measure hepatic iron, with 1H-MR spectroscopy used to measure hepatic triglycerides. HOMA-IR was calculated to determine IR. RESULTS: The prevalence of hepatic iron overload (HIOL) was 26.6% in individuals with NAFLD vs. 0% in those without. IR was present in 87.5% of subjects with both NAFLD and HIOL, in 45.4% of those with NAFLD but not HIOL, and in 4.5% of those with neither. HOMA-IR was positively correlated with hepatic triglycerides (r = 0.56, P < 0.001) and hepatic iron (r = 0.52, P < 0.001), whereas serum TNF-α concentrations correlated with intrahepatic triglyceride levels (r = 0.28, P < 0.04), but not with intrahepatic iron. Hepatic triglycerides, serum TNF-α and age were the only significant determinants of IR in regression analyses. CONCLUSION: IR is closely associated with intrahepatic triglycerides and, to a lesser extent, intrahepatic iron, with some interplay between them. High serum TNF-α concentrations may contribute to the association between NAFLD and IR, while increased hepatic triglycerides appear to be a determinant of the development of HIOL in non-diabetic subjects without haemochromatosis.

Bone mineral density and bone turnover in non-cirrhotic patients with chronic hepatitis C and sustained virological response to antiviral therapy with peginterferon-alfa and ribavirin.

UNLABELLED: Patients with chronic hepatitis C have low bone mineral density and increased bone resorption related to serum transaminase levels. Elevated serum soluble tumor necrosis factor (sTNFR-55) receptor levels may play a role in the bone mass loss in these patients. Bone mass is improved and bone turnover normalized in patients who respond to antiviral therapy with interferon and ribavirin. INTRODUCTION: Low bone mineral density (BMD) has been described in patients with chronic hepatitis C (HCV). The study objective was to evaluate the effect of antiviral therapy on BMD and bone metabolism in non-cirrhotic HCV patients with sustained virological response. METHODS: We conducted a prospective study in 36 consecutive outpatients from the general community with non-cirrhotic HCV and an early and sustained virological response to peginterferon-alfa and ribavirin therapy. Determinations of BMD (dual X-ray absorptiometry at lumbar spine and femoral neck) and biochemical measurements of bone metabolism and sTNFR-55 were made at baseline, after 24 and 48 weeks of antiviral therapy, and at 48 weeks after the end of treatment. RESULTS: Patients had a significantly reduced BMD, which significantly increased during the follow-up. Serum levels of sTNFR-55 and bone turnover markers were increased at baseline and significantly reduced at all subsequent time points. We found an inverse correlation between BMD and both serum aminotransferase levels and urine deoxypyridinoline (D-pyr) and a positive correlation between serum aminotransferases and both urine D-Pyr and serum sTNFR-55. CONCLUSIONS: Patients with chronic hepatitis C have low bone mass associated with increased bone resorption, and some relationship can be expected between serum aminotransferase levels and the degree of bone mass loss. Bone mass may be improved and bone turnover normalized in patients who respond to antiviral therapy. Elevated serum sTRFR-55 levels may play a role in the bone mass loss of these patients.

Densidad mineral ósea y remodelado ósea en mujeres posmenopáusicas con cirrosis hepática vírica / Bone Mineral density an bone remodeling in postmenopausal women with liver cirrohosis with viral origin

Introducción. Se conoce que la cirrosis hepática, tanto vírica como alcohólica, provoca pérdida de masa ósea en hombres. Sin embargo, poco se conoce del efecto de la cirrosis hepática sobre la masa ósea y remodelado óseo de mujeres posmenopáusicas con cirrosis vírica. Igualmente, se desconoce si realmente empeora aún más la masa ósea, ya deteriorada, de estas mujeres. Objetivo: Nuestro objetivo fue estudiar la masa ósea, remodelado óseo y factores hormonales relacionados con el metabolismo óseo en 49 mujeres con cirrosis hepática de etiología vírica y 22 controles sanas. Resultados: La ingesta etílica era inferior a 30 g a la semana. En todas ellas, se midió la densidad mineral ósea (DMO) entre las pacientes cirróticas y controles sanas (expresadas como Z-score) en LS (-0,13±0,025 vs 0,17±1,18; p<0,3) y FN (0,15±1,17 vs. 0,01±1,10; p<0,6). Las concentraciones séricas de estradiol eran más elevadas en mujeres con cirrosis que en las sanas (11,89±15,64 ng/ml vs. 6,54±5,30 ng/ml; p<0,04), existiendo una correlación positiva entre los valores séricos de estradiol y la gravedad de la cirrosis (r=0,49; p<0,001), Además, existía una correlación inversa entre los valores séricos de FSH y DMO (r= -0,31; p<0,03) y positiva de SHBG con la DMO (r=0.48; p<0,03), e inversa entre los valores de SHBG y estradiol (r=-0,29; p<0,05). Los valores séricos de insulina eran significativamente más elevados en las pacientes cirróticas (20,94 ± 15,21 µU/ml) que en los controles (12,96 ± 10,96 µU/ml); p<0,02 y había correlación positiva entre la insulinemia y la DMO (r=0,40; p<0,02) en pacientes cirróticas.Conclusiones: Los parámetros bioquímicos de remodelado óseo mostraban alto turnover, tanto en pacientes como en controles sin diferencias entre ellas. Nuestros hallazgos muestran que las mujeres posmenopáusicas con cirrosis hepática vírica no presentan mayor pérdida de masa ósea que las mujeres posmenopáusicas sanas. A ello, parece contribuir los niveles séricos elevados de estradiol e insulina que presentan las pacientes. No hay diferencias en el remodelado óseo, que es de alto turnover, tanto en las pacientes como en los controles

Introduction: Liver cirrohosis both with viral and alcoholic origin causes bone mass loss in males. However, the effect of liver cirrohosis on bone mass and bone remodeling in postmenopausal women with liver cirrhosis with viral origin is little know. Likewise, it is not known if it worsens even more the already damaged bone mass of these women. Aim: Our aim was to study the bone mass, bone remodeling, and other hormonal factors related to bone metabolism in 29 women with liver cirrhosis of viral etiology and 22 healthy controls. Results: Alcohol consumption was below 30g/week. Bone mineral density (BMD) was measured by dual x-ray absorptiometry in the lumbar spine (LS) and the femoral week (FN) in all the patients. Significant differences in BMD were not found between cirrhotic patients and healthy controls (expressed as Z-score) in LS (-0,13±0.025 vs. 0,17±1,18; p<0.3) and FN (0,15±1.17 vs. 0.01±1.10; p<0.6). Serum estradiol concentrations were higher in the cirrohotic women than in the healthy ones (11.89±15.64 ng/ml vs. 6.54±5.30ng/ml; p<0,04), being a positive correlation between the serum estradiol values and the cirrhosis seriousness (r=0,49; p<0.001) Besides, there was an opposite correlation between the serum values of FSM and BMD (r=0.31; p<0.03); a positive correlation of SHBG and BMD (r=0,48; p<0,03); and an opposite correlation between SHBG and estradiol values (r=-0.29; p<0.05). Serum insulin values were significantly higher in the cirrohotic patients (20.94±15.21 µU/ml) than in the controls (12.06±10.96 µU/ml), (p<0.02). There was a positive correlation between insulinemia and BMD in cirrhotic patients (r=0.40; p<0.02). Conclusion: Biochemical parameters of bone remodeling showed a high turnover both in patients and controls without differences between them. Our finds show postmenopausal women with liver cirrhosis with viral origin do not have a higher bone mass loss than healthy postmenopausal women do. The high serum insulin and serum estradiol levels seem to contribute to it. There are no differences in bone remodeling, which shows a high turnover both in patients and controls

Quimioprevención del cáncer colorrectal (CCR) con antiinflamatorios no esteroides (AINES) / Chemoprevention of gastrointestinal malignancies with nonsteroidal antiinflammatory drugs

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Bone mineral density, serum insulin-like growth factor I, and bone turnover markers in viral cirrhosis.

Previous studies suggest that low bone mass is a complication of alcoholic liver disease. Nevertheless, little is known about bone mass and bone metabolism in viral cirrhosis. To evaluate the prevalence and magnitude of hepatic osteopenia in these patients, bone remodeling status, and its relationship with the severity of liver disease and serum levels of insulin-like growth factor I (IGF-I), we studied 32 consecutive patients with viral cirrhosis and no history of alcohol intake. Bone mineral density (BMD) was measured by dual x-ray absorptiometry in the lumbar spine (LS) and femoral neck (FN), and the values were expressed as the z score. Bone metabolism markers and hormone profiles were measured. Patients with viral cirrhosis showed reduced BMD in all sites (LS: -1.27 +/- 1.06, P < .001; FN: -0.48 +/- 0.96; P < .01). Of the 32 patients, 53% met the diagnostic criteria for osteoporosis. In patients, urine deoxypyridinoline (D-Pyr) as a marker of bone resorption and serum bone alkaline phosphatase (b-AP) as a marker of bone formation were significantly higher than in control subjects (P < .001 and P < .01, respectively). Serum IGF-I was lower than in control subjects (P < .001), and significant differences were also found between patients with and without osteoporosis (P < .05). BMD in LS correlated with severity of the disease, with serum levels of IGF-I, and with urine D-Pyr. Our findings show that viral cirrhosis is a major cause of osteoporosis in men, and that low serum IGF-I levels seem to play a role in the bone mass loss in these patients. The biochemical markers of bone remodeling suggest high-turnover osteoporosis in patients with viral cirrhosis.

Effect of acute alcohol ingestion on mineral metabolism and osteoblastic function.

Alcohol abuse can induce osteopenia in some subjects. In order to study the effect of a single dose of alcohol on mineral metabolism and osteoblastic function, we have measured calcium, phosphate, parathyroid hormone midmolecule (PTHm), parathyroid hormone intact molecule (PTHi) and bone-gla-protein (BGP) in serum of 8 healthy men after the ingestion of a single dose of alcohol (0.6 g/kg body weight). Urinary calcium and magnesium were also measured. After alcohol intake, both serum PTHm and PTHi were decreased, as well as serum BGP. Serum phosphate and urinary calcium and magnesium were increased. An inverse significant correlation was found between PTHi and serum phosphate (r = 0.42; p < 0.02). Our data show that acute alcohol ingestion lowers serum PTH and BGP in humans, suggesting an inhibitory effect on parathyroid and osteoblastic function. These changes and the alcohol-induced transient hypercalciuria could contribute to the development of bone disease associated with chronic alcohol abuse.

Mineral metabolism, osteoblastic function and bone mass in chronic alcoholism.

The role of ethanol as a risk factor for osteopenia was studied in alcoholic subjects without liver cirrhosis. The study was carried out in 58 male subjects classified into three groups: (1) 26 heavy drinkers, alcohol intake more than 100 g ethanol/day for more than 10 years; (2) 13 moderate drinkers, 60-100 g ethanol/day; (3) 19 healthy non-drinkers who served as control subjects. None of the drinkers had liver cirrhosis (normal clinical and biochemical data and/or liver biopsy). Mineral metabolism and serum bone Gla-protein (BGP) were studied while they were active drinkers and after they had abstained from ethanol for 7 days. Bone mineral density (BMD) was determined at the beginning of the study. Osteopenia was observed in 23% of the heavy drinkers. We found a significant inverse correlation between BMD and an index of cumulative alcohol intake. Heavy and moderate drinkers had significantly lower mean BGP values (1.6 +/- 0.4 and 1.9 +/- 0.3 ng/ml) (P < 0.01 for both) than controls (3.5 +/- 0.4 ng/ml); these values increased significantly (2.9 +/- 0.4 ng/ml; P < 0.01) after 7 days of abstinence. The data show that chronic ethanol ingestion can induce osteopenia regardless of the absence of liver cirrhosis, and that some relationship can be expected between the amount and duration of ethanol consumption and the degree of bone loss. The low serum BGP levels in drinkers are reversible upon withdrawal of ethanol, suggesting that reduction of osteoblastic activity is probably the main factor responsible for alcohol-associated bone disease.

Effects of ethanol administration on rat liver plasma membrane-bound enzymes.

Changes in the properties of rat liver plasma membranes were examined in studies designed to differentiate between direct and metabolic effects of acute and chronic ethanol ingestion. One hour after a single dose of ethanol (3 g/kg body weight) there were increases in Na+,K+-ATPase (32%) and 5'-nucleotidase (36%), and hepatic concentrations of ethanol and acetaldehyde were approximately 23 mM and 50 microM, respectively. Na+,K+-ATPase and 5'-nucleotidase activities in liver plasma membranes from control rats were not significantly changed by in vitro addition of 30 microM acetaldehyde or 50 mM ethanol. Increases in Na+,K+-ATPase (approximately 20%) and 5'-nucleotidase (approximately 30%) were also observed in liver plasma membranes isolated from rats 16 hr after feeding ethanol or sucrose supplements for 17 days. The intake of calories from dietary protein and lipid was decreased by about 25% in both the ethanol and sucrose-fed animals. Na+,K+-ATPase activities in liver plasma membranes isolated from control rats were inhibited (approximately 20%) by 100 mM ethanol in vitro, whereas no inhibition was observed using membrane preparations from rats fed ethanol or sucrose supplements. Our results show that changes in liver plasma membrane enzyme activities associated with a single dose of ethanol are not a direct effect correlated with blood, hepatic or plasma membrane concentrations of ethanol or acetaldehyde. Chronic ingestion of ethanol or sucrose supplements had similar effects on liver plasma membrane enzyme characteristics and parallel changes in nutrient intake may be a more feasible explanation of these results than any analogous direct effects of the two compounds.

Effects of ethanol and acetaldehyde on hepatic plasma membrane ATPases.

To elucidate possible causes of the hepatocyte swelling and necrosis found in alcoholic liver disease, the effects of ethanol and acetaldehyde on the activities of two hepatic plasma membrane ATPases--(Na+K+) ATPase and Mg2+ ATPase--were investigated. The activity of another plasma membrane-bound enzyme, 5' nucleotidase, was also determined to assess the specificity of these effects. Over concentrations ranging from 8 to 90 mM ethanol did not cause significant inhibition of any of the three enzymes. At 120 mM ethanol (Na+K+) ATPase activity was inhibited by 20% (P less than 0.01) and at higher concentrations there was progressive inhibition of all three enzymes that was non-competitive in type. Acetaldehyde produced non-competitive inhibition of (Na+K+) ATPase and Mg2+ ATPase at concentrations of 6 and 56 mM respectively and 5' nucleotidase activity was also inhibited at these concentrations. We conclude that ethanol and acetaldehyde inhibit (Na+K+) ATPase and Mg2+ ATPase activities as part of a generalised effect on the liver plasma membrane. Because the inhibitory concentrations of both substances are higher than are usually found in alcoholic subjects or in experimental animals after alcohol feeding, it seems unlikely that direct suppression of ATPase activity by ethanol or acetaldehyde is responsible for the morphological abnormalities of alcohol-induced liver disease. It could, however, be implicated in the development of hepatocellular necrosis in severe ethanol poisoning.