Marco Bertolotti

Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes

Background and Aim:  Studies have shown monounsaturated oleic acid to be less toxic than palmitic acid and to prevent/attenuate palmitic acid hepatocites toxicity in steatosis models in vitro. However, to what degree these effects are mediated by steatosis extent is unknown.

Non-organ-specific autoantibodies in nonalcoholic fatty liver disease: prevalence and correlates.

Eighty-four consecutive subjects with nonalcoholic fatty liver disease (NAFLD) were tested for non-organ-specific autoantibodies (NOSA) by indirect immunoflorescence. Indices of insulin resistance and biochemical and anthropometric parameters were assessed. The overall prevalence of anti-nuclear-antibodies (ANA), smooth muscle antibodies (SMA) and anti-mitochondrial-antibodies (AMA) was 35.7% (30/84), 18 subjects (21.4%) being positive for ANA, 4 (4.7%) for SMA, 6 for ANA and SMA, and 2 for AMA. NOSA-positive subjects were older (P < 0.01) and mostly females (63.3%). No significant difference was found in the age-corrected parameters studied, except for copper and ceruloplasmin, which was more elevated in NOSA-positive patients. The subset of high titer (≥1:100) ANA-positive patients had significantly (P < 0.05) greater insulin resistance than ANA-negative patients. In contrast, SMA-positive patients had higher gammaglobulin and significantly lower insulin resistance as compared to high-titer ANA-positive patients. In 3 NOSA-positive but not in NOSA-negative patients, liver biopsy disclosed features of overlapping NASH with autoimmune hepatitis, partially responding to diet combined with steroid treatment. In conclusion, NOSA positivity in NAFLD is more prevalent than in the general population. High-titre ANA but not SMA positivity is associated with insulin resistance.

Effects of acute changes of bile acid pool composition on biliary lipid secretion.

To elucidate the mechanism responsible for the bile acid-induced changes of biliary lipid secretion, we evaluated bile flow and biliary output of bile acids, cholesterol, phospholipids, and alkaline phosphatase activity in seven cholecystectomized subjects with a balloon occludable T-tube during two experimental periods: (a) depletion of the endogenous bile acid pool and (b) replacement of the pool by means of duodenal infusion with individual bile acids, such as deoxycholic (DCA), chenodeoxycholic (CDCA), cholic (CA), and ursodeoxycholic (UDCA) acids. Bile flow, cholesterol, and phospholipid output were linearly related to bile acid secretion in all experimental periods. During the replacement periods, the amount of cholesterol and phospholipids coupled to bile acids was significantly different (at 1% level at least) for each individual bile acid secreted; it was the highest during DCA secretion (slope value: 0.209 for cholesterol and 0.434 for phospholipids) followed, in the order, by CDCA (0.078 and 1.794), CA (0.044 and 0.127), and UDCA (0.030 and 0.122). The phospholipid to cholesterol ratio was higher during secretion of CA and UDCA as compared with DCA and CDCA. The secretion of CA seemed to stimulate a greater bile flow than the other bile acids did. The infusion of all bile acids, except UDCA, induced an increase of biliary alkaline phosphatase activity as compared with the values of the depletion period. The mean highest increase (13-fold the pretreatment value) was observed during DCA secretion followed by CDCA (fivefold) and CA (1.5-fold). These results would suggest that the physical chemical properties, namely the lipid-solubilizing capacity, of bile acids could directly contribute to the regulation of biliary lipid secretion. The observed changes in biliary alkaline phosphatase activity lend support to the view that bile acid-induced lipid secretion may be, at least in part, contributed by membrane solubilization.

Endocrine and liver interaction: the role of endocrine pathways in NASH

This article reviews evidence that causally links hormonal disorders with hepatobiliary disease, and gives particular focus to nonalcoholic steatohepatitis (NASH). The downstream mechanisms by which endocrine disturbances cause liver disease might be similar to those involved in the development of primary liver disease. Hypothyroidism, for example, might lead to NASH, cirrhosis and potentially liver cancer via the development of hyperlipidemia and obesity. Patients with growth hormone deficiency have a metabolic-syndrome-like phenotype that is also associated with the development of NASH. Polycystic ovary syndrome is a common endocrine disorder that is often associated with insulin resistance, the metabolic syndrome, altered levels of liver enzymes and the development of NASH. Recent findings support a role of dehydroepiandrosterone sulfate deficiency in the development of advanced NASH. In addition, adrenal failure is increasingly reported in patients with end stage liver disease and in patients who have received a liver transplant, which suggests a bidirectional relationship between liver and endocrine functions. Clinicians should, therefore, be aware of the potential role of endocrine disorders in patients with cryptogenic liver disease and of the effects of liver function on the endocrine system.

Fasting insulin and uric acid levels but not indices of iron metabolism are independent predictors of non-alcoholic fatty liver disease. A case-control study

BACKGROUND Non-alcoholic fatty liver disease is a common reason for hepatological consultation and may herald severe hepatic and extra-hepatic disease. The aetiopathogenesis of this condition is an area of increasing interest. AIM To evaluate anthropometric and biochemical factors associated to non-alcoholic fatty liver disease in a case-control study. Methods. Demographic and biochemical data of 60 consecutive patients with bright liver absent-to-low alcohol consumption, no evidence of viral, genetic and autoimmune diseases, were compared to those of 60 age- and gender-matched historical controls without fatty liver by univariate and multiple logistic regression analysis. RESULTS Patients were more often hypertriglyceridaemic, obese and diabetic than controls (p<.01). Mean values of alanine transaminase, gammaglutamyltranspeptidase, triglycerides, uric acid, fasting and log insulin, transferrin percent saturation and ferritin were significantly higher in the patients, while transferrin and quantitative insulin sensitivity check index, a quantitative insulin sensitivity index, were lower. No iron storage was found in those who underwent liver biopsy At univariate analysis the relative risk for non-alcoholic fatty liver disease significantly increased (p<0. 05) with increasing body mass index, fasting insulin, alanine transaminase, uric acid, triglycerides and gammaglutamyltranspeptidase; it decreased with increasing transferrin and quantitative insulin sensitivity check index. Multiple logistic regression analysis disclosed only fasting insulin and uric acid to be independent predictors of non-alcoholic fatty liver disease (p<0.05). CONCLUSIONS Fasting insulin and serum uric acid levels indicating insulin resistance, but not indices of iron overload, are independent predictors of non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease and aging: epidemiology to management.

Nonalcoholic fatty liver disease (NAFLD) is common in the elderly, in whom it carries a more substantial burden of hepatic (nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma) and extra-hepatic manifestations and complications (cardiovascular disease, extrahepatic neoplasms) than in younger age groups. Therefore, proper identification and management of this condition is a major task for clinical geriatricians and geriatric hepatologists. In this paper, the epidemiology and pathophysiology of this condition are reviewed, and a full discussion of the link between NAFLD and the aspects that are peculiar to elderly individuals is provided; these aspects include frailty, multimorbidity, polypharmacy and dementia. The proper treatment strategy will have to consider the peculiarities of geriatric patients, so a multidisciplinary approach is mandatory. Non-pharmacological treatment (diet and physical exercise) has to be tailored individually considering the physical limitations of most elderly people and the need for an adequate caloric supply. Similarly, the choice of drug treatment must carefully balance the benefits and risks in terms of adverse events and pharmacological interactions in the common context of both multiple health conditions and polypharmacy. In conclusion, further epidemiological and pathophysiological insight is warranted. More accurate understanding of the molecular mechanisms of geriatric NAFLD will help in identifying the most appropriate diagnostic and therapeutic approach for individual elderly patients.

Gallstone disease in non-alcoholic fatty liver: Prevalence and associated factors

Background:  Insulin resistance is a risk factors for non‐alcoholic fatty liver disease (NAFLD) and for gallstone disease (GD). Aims of the present study were to assess the prevalence of and factors associated with GD in unselected patients with NAFLD.

Serum time course of naltrexone and 6β-naltrexol levels during long term treatment in drug addicts

The pharmacokinetics of naltrexone have been scarcely explored in patients during chronic treatment despite the observation that the pharmacological effect of the drug is related to its plasma concentrations. In this study we investigated the time course of serum levels of naltrexone and its active metabolite, 6 beta-naltrexol, in 13 heroin addicts (3 F, 10 M; age 22-32 years) in the 24 h after 100 mg of naltrexone orally. Six patients were studied once, at different times during chronic treatment, whereas in seven patients the study was done at the beginning and after 1 month of naltrexone treatment. Four of these patients also repeated the study after 3 months of naltrexone treatment. Serum naltrexone and 6 beta-naltrexol were assayed by GLC with a nitrogen-phosphorus detector. Our results showed large differences among patients in serum naltrexone and 6 beta-naltrexol levels. On the other hand, there were no differences in serum time course of both substances in the same patient over 3 months. Peak levels and AUCs of naltrexone were lower than those of 6 beta-naltrexol in ten addicts and higher than those of the metabolite in three patients. No significant differences in the apparent half-lives of the two drugs were detected among groups. These data are consistent with the occurrence of a decreased first-pass metabolism of naltrexone in three patients leading to a larger availability of an oral dose. The increased bioavailability of the drug is not very important for opioid receptor antagonist activity but may play a role in naltrexone treatment safety.

Multidisciplinary Approach to the Treatment of Metabolic and Morphologic Alterations of HIV-Related Lipodystrophy

Abstract Background: Treatment for metabolic and morphologic alterations in HIV-related lipodystrophy include medical therapy, physical exercise, and surgical interventions. Method: We assessed the efficacy and safety of a comprehensive multidisciplinary approach for treating morphological and metabolic alterations of the lipodystrophy syndrome in consecutive patients attending the Metabolic Clinic (MC) of the University of Modena and Reggio Emilia who had at least 2 evaluations over a 48-week period. 245 patients were evaluated: 143 (62.4%) were men, 74 (36.1%) presented with lipoatrophy, 10 (4.9%) with fat accumulation, 93 (45%) with mixed forms, 24 (11.3%) had hypercholesterolemia (LDL >160 mg/dL), 87 (38%) had hypertriglyceridemia (TG >150 mg/dL), 13 (5.7%) had diabetes (glucose >126 mg/dL), and 78 (44%) had insulin resistance (HOMA-IR >4). Results: At follow-up, a significant improvement was observed in both objective and subjective variables. Anthropometric improvement was observed in waist to hip ratio, waist circumference, and right and left cheek dermal thickness measurements. A nonsignificant improvement was observed in fat and lean regional mass by DEXA; CT showed improvement in visceral and subcutaneous adipose tissue. Glucose, HOMA-IR, total cholesterol, and APO B improved. Subjective variables improved in aesthetic satisfaction. Conclusion: We conclude that the medical and surgical interventions proposed in this multidisciplinary therapeutic approach are efficacious and safe in the management of lipodystrophy.

Prevalence rates of gallstone disease in Italy - The Chianciano population study

The prevalence of gallstone disease and associated factors in the entire population of subjects aged 15–65 years born and resident in Chianciano Terme (Siena — Tuscany) was examined in the years 1985 and 1986. The investigation included gallbladder ultrasonography, administration of a questionnaire on personal and family history, physical examination and blood chemistry. A total of 1809 subjects (attendance rate 87.7%) participated in the study. Personal history and physical examination showed that Chianciano inhabitants have a low prevalence of obesity (4.3%) and only 4.4% of the female population had more than two pregnancies. Overall prevalence of gallstone disease (cholecystectomy + cholelithiasis) was 5.9% (3.7% for males and 8.4% for females). Age standardized relative risk of gallstone disease for females was 2.25 (95% confidence limits=1.68−2.68). Prevalence of cholelithiasis was 3.5% (2.7% for males and 4.2% for females). Prevalence of gallstone disease increased with increasing age in both sexes, being extremely low in the age interval of 15–29 years (0.25%). The overall gallstones/cholecystectomy ratio was found to be lower (1:1) in females than in males (2.7:1). Although subjects with gallstones reported more frequently biliary colics and nonspecific dyspeptic symptoms, the diagnostic power of all symptoms in identifying cholelithiasis was very poor due to low sensitivity. Only one third of subjects with gallstones was aware of having the disease. Age, obesity and number of pregnancies were positively associated with gallstone disease in univariate analyses. The association with obesity and parity disappeared in multivariate analysis. Blood lipids and glucose were not associated with the disease both in univariate and multivariate analyses. Our data show that the prevalence of gallbladder disease in Chianciano is lower than that previously reported in Italy. This difference could be related to a lower prevalence of obesity and to a smaller number of pregnancies or to the effect of environmental and genetic factors.