Nicola Carulli

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.

Cholesterol absorption during bile acid feeding: Effect of ursodeoxycholic acid (UDCA) administration

Abstract We studied the effect of ursodeoxycholic acid (UDCA) administration (15 mg/kg/day) on cholesterol absorption in 11 volunteers. Cholesterol absorption was estimated by feeding a standard dose of cholesterol, dissolved in butter, containing 5 μCi of [ 14 C]cholesterol and 10 μCi of [ 3 H]sitosterol (as a nonabsorbable marker). Feces were then collected for 5–6 days. Cholesterol absorption with β-sitosterol, corrected for losses not due to absorption, was estimated from the recovered radioactivity. After 20 days of treatment with UDCA, the study was repeated with each patient acting as his own control. Cholesterol saturation of bile and biliary bile acid composition were also studied before and after treatment. UDCA was virtually undetectable in bile before treatment, but became the most abundant bile acid (42.0 ± 17.2% of the total) after treatment. Although the molar percentage of cholesterol in bile fell in each patient after treatment, bile saturation critically depended on the criteria adopted to calculate the saturation index. Mean cholesterol absorption was 36.7 ± 9.3% of the administered dose in basal conditions and fell to 17.5 ± 11.3% (48% decrement) after treatment (P

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.

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.

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.

Bile lipid composition and bile acid pool size in diabetes

Since the prevalence of gallstones is higher in diabetics than in controls and since cholelithiasis is often associated with supersaturated bile, we measured bile lipid composition and bile acid pool size in 8 patients with juvenile diabetes, 16 with maturity-onset diabetes, and 10 control subjects. Bile lipid composition was expressed as “saturation index.” In the maturity-onset diabetics the saturation index (1.60:±0.45SDM) was significantly higher (P<0.005) than that in the controls (0.82±0.20) and in patients with juvenile diabetes (0.75±0.24). The absolute values for biliary bile acid concentration were significantly lower (P<0.01) in the maturity-onset diabetics than in the other two groups. There were no differences in either the proportion of the individual biliary bile acids or the size of the bile acid pool between the three groups. The results suggest that the incidence of cholelithiasis in diabetes is associated with the secretion of a supersaturated bile only in the maturity-onset subgroup.

Review article: the metabolic syndrome and non‐alcoholic fatty liver disease

Metabolic syndrome represents a common risk factor for premature cardiovascular disease and cancer whose core cluster includes diabetes, hypertension, dyslipidaemia and obesity. The liver is a target organ in metabolic syndrome patients in which it manifests itself with non‐alcoholic fatty liver disease spanning steatosis through hepatocellular carcinoma via steatohepatitis and cirrhosis. Given that metabolic syndrome and non‐alcoholic fatty liver disease affect the same insulin‐resistant patients, not unexpectedly, there are amazing similarities between metabolic syndrome and non‐alcoholic fatty liver disease in terms of prevalence, pathogenesis, clinical features and outcome. The available drug weaponry for metabolic syndrome includes aspirin, metformin, peroxisome proliferator‐activated receptor agonists, statins, ACE (angiotensin I‐converting enzyme) inhibitors and sartans, which are potentially or clinically useful also to the non‐alcoholic fatty liver disease patient. Studies are needed to highlight the grey areas in this topic. Issues to be addressed include: diagnostic criteria for metabolic syndrome; nomenclature of non‐alcoholic fatty liver disease; enlargement of the clinical spectrum and characterization of the prognosis of insulin resistance‐related diseases; evaluation of the most specific clinical predictors of metabolic syndrome/non‐alcoholic fatty liver disease and assessment of their variability over the time; characterization of the importance of new risk factors for metabolic syndrome with regard to the development and progression of non‐alcoholic fatty liver disease.

Alcohol‐Drugs Interaction in Man: Alcohol and Tolbutamide*

Abstract. In man tolbutamide was shown to share certain properties with the drugs handled by the hepatic drug‐metabolizing system: its prolonged administration is capable of accelerating its own metabolism; the same effect is obtained by pretreatment with microsomal inducers such as phenobarbital, diphenylhydantoin and diazepam. — Chronic addiction to alcohol produces an enhanced rate of tolbutamide metabolism; on the other hand, prolonged treatment with tolbutamide is able to increase the rate of ethanol oxidation. The existence of a microsomal oxidation of ethanol supports the hypothesis that microsomes may be the site of the interference between alcohol and tolbutamide. — Additional evidence is provided by the observed inhibition of tolbutamide metabolism by ethanol infusion.

Review article: diabetes, genetics and ethnicity

The prevalence of insulin resistance and diabetes has increased in the past decades at an alarming rate in all Western countries and in those countries which are adopting a ‘western life style’. This trend suggests the impact of environmental factors such as diet, obesity and physical activity on the pathogenesis of diabetes. However it is known that the prevalence and variation of prevalence, as consequence of environmental changes, it is different in various ethnic groups. Studies conducted in multiethnic populations suggest that some ethnic groups, such as Hispanics or Asian Indians, might have a particular predisposition, possibly on genetic basis, to develop insulin resistance and diabetes, when exposed to adverse conditions. According to the ‘thrifty gene’ hypothesis, a clustering of different genetic defects or polymorphisms, developed as genetic advantage in some populations, could predispose some ethnic groups to insulin resistance and diabetes in presence of an increased food supply. Multiple mutations, associated with small changes in insulin sensitivity, when combined, may induce a significant reduction in insulin sensitivity. This review deals with the possible relevance of genetic factors in the expression of insulin resistance and diabetes in relation to ethnicity.