Donatella Magalotti

Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is consistently associated with features of the metabolic syndrome, a condition carrying a high risk of cardiovascular events. We measured the vasodilatory response of the brachial artery in response to ischemia (a test of endothelial function) (FMV) as well as cardiovascular risk profile in 52 NAFLD cases and 28 age‐ and sex‐matched controls. The 10‐year risk of coronary events was calculated according to the Framingham equation and the scores derived from the PROCAM study and NCEP‐ATPIII proposals. FMV was 6.33% ± 5.93% in NAFLD versus 12.22% ± 5.05% in controls (P < .0001), and higher in pure fatty liver (9.93%) compared with nonalcoholic steatohepatitis (4.94%) (P = .010). No differences were observed in flow‐independent vasodilation (response to sublingual nitroglycerin). Percent FMV was negatively associated with insulin resistance (homeostasis model assessment) in the whole population (r = −0.243; P = .030). In logistic regression analysis, NAFLD was associated with a percent FMV in the lower tertile (OR, 6.7; 95% CI, 1.26–36.1), after adjustment for age, sex, body mass index, and insulin resistance. Among NAFLD patients, low FMV was associated with nonalcoholic steatohepatitis (adjusted OR, 6.8; 95% CI, 1.2–40.2). The 10‐year probability of cardiovascular events was moderately increased in NAFLD, and particularly in nonalcoholic steatohepatitis. In conclusion, our study provides evidence of endothelial dysfunction and increased risk of cardiovascular events in NAFLD. The risk of advanced liver disease is well recognized in NAFLD patients, but the large majority of cases might experience cardiovascular disease in the long term, indirectly limiting the burden of liver failure. (HEPATOLOGY 2005.)

Efficacy of a Surveillance Program for Early Detection of Hepatocellular Carcinoma

Contrasting data have so far been reported on the utility and efficacy of screening patients with cirrhosis for early detection of hepatocellular carcinoma (HCC). The goal of this study was to evaluate the efficacy of a regular ultrasonographic and laboratory follow‐up for the early detection of small HCC, and to identify parameters correlated with a higher risk of developing HCC.

Prognostic indicators of risk for first variceal bleeding in cirrhosis: a multicenter study in 711 patients to validate and improve the North Italian Endoscopic Club (NIEC) index

OBJECTIVE:The best known indicator of risk for first bleeding in patients with cirrhosis without previous bleeding is the index devised by the North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices (NIEC index), which results from the combination of size of esophageal varices, severity of red wale marks, and Child-Pugh class. Its efficiency is far from optimal, and validation studies have reported sensitivities and specificities markedly lower than those reported in the original study. In the present study we analyzed the efficiency of NIEC index in a large series of cirrhotic patients with varices without previous bleeding. In addition, we tried to improve the effectiveness of the index by modifying it, and to validate the modifications in an independent group of patients.METHODS:A total of 627 patients were enrolled and followed until either a variceal bleeding or for a maximum of 2 yr. During this time, 117 experienced a first variceal bleeding.RESULTS:Using Coxs regression analysis, size of varices, severity of red wale marks, and Child-Pugh score were significant and independent predictors of first bleeding, as already noted in the original report of the NIEC group. However, coefficients and standard errors were markedly different, and the importance of size of esophageal varices in the regression was much larger, whereas that of Child-Pugh score was much lower. According to these data, a revised index was developed (Rev-NIEC). Using receiver operating characteristic (ROC) curve analysis, the revised index showed a larger efficiency, and the area under the curve was significantly larger (0.80 ± 0.02 vs 0.74 ± 0.02; p < 0.01). In particular, the curve showed that for a specificity of 75%, the new index had a sensitivity of 72% compared to that of 55% of the NIEC index. Validation in an independent sample of 84 patients showed good agreement between predicted and observed risk for bleeding. Validation with the bootstrap technique also showed adequate stability of the results.CONCLUSIONS:The revised index seems to be superior to the traditional index, and may turn out to be more useful in the selection of patients for different therapeutic procedures and in the stratification of patients in clinical trials.

Natural history of cirrhotic patients with small esophageal varices: a prospective study

OBJECTIVE:Contrasting data are available on the natural history and bleeding risk of small esophageal varices. The aim of this prospective study was to evaluate a large series of consecutive cirrhotics with a first endoscopic diagnosis of small varices.METHODS:Between 1987 and 1992, 258 patients with small varices and no previous bleeding were enrolled. Patients were clinically examined every 6 months and were followed until a first episode of bleeding and/or death, or until June 1998. None received any treatment to prevent bleeding. Endoscopies were planned at 18-month intervals.RESULTS:The cumulative risk of bleeding was low (3% at 2 yr and 8% at 4 yr) and remained low in patients in whom varices remained small at 2nd endoscopy, whereas it increased significantly when varices enlarged. The increase of varices appeared to be rather linear in time: at the 2nd endoscopy varices remained small in 79% of patients and increased in 21%; at the 3rd endoscopy varices remained small in 55%, whereas at the 4th 33% of patients still had small varices. Clinical and biochemical data at the 1st and 2nd endoscopy were included in a multiple logistic regression analysis. Only the increase in Child-Pugh score appeared to be a significant predictor of enlarged varices; the risk of aggravation increased by 37.5% for every unit of impairment of the score.CONCLUSIONS:The present study shows that patients with small varices have a low bleeding risk. An increase in Child-Pugh score during follow-up suggests enlargement of varices, thus an increase in bleeding risk. In these patients closer endoscopic surveillance is recommended.

Impact of interferon therapy on the natural history of hepatitis C virus related cirrhosis

BACKGROUND The role of interferon treatment on the natural history of hepatitis C virus related cirrhosis is under debate. AIM To evaluate the effect of interferon on the clinical course of compensated hepatitis C virus related cirrhosis. PATIENTS AND METHODS Seventy two cirrhotic patients treated with interferon and 72 untreated controls matched treated patients with for quinquennia of age, sex, and Child-Pughs score were enrolled in a prospective non-randomised controlled trial. Treated patients received leucocytic interferon alfa, with an escalating schedule for 12 months. The incidence and risk (Cox regression analysis) of clinical complications (hepatocellular carcinoma, ascites, jaundice, variceal bleeding, and encephalopathy) and death were calculated. RESULTS Over median follow up periods of 55 months for treated and 58 for untreated subjects, seven and nine patients, respectively, died, and 20 and 32, respectively, developed at least one clinical complication (ns). Hepatocellular carcinoma developed in six treated and 19 untreated patients (p=0.018). Seven treated patients showed sustained aminotranferase normalisation and none died or developed complications. Clinical complications were significantly associated with low albumin, bilirubin, and prothrombin activity while hepatocellular carcinoma was significantly related to no treatment with interferon, oesophageal varices, and high α fetoprotein levels. By stratified analysis, the beneficial effect of interferon was statistically evident only in patients with baseline α fetoprotein levels ⩾20 ng/ml. CONCLUSIONS Interferon does not seem to affect overall or event free survival of patients with hepatitis C virus related cirrhosis while it seems to prevent the development of hepatocellular carcinoma. Patients who achieved sustained aminotransferase normalisation survived and did not develop any complications during follow up.

Serum C3 is a stronger inflammatory marker of insulin resistance than C-reactive protein, leukocyte count, and erythrocyte sedimentation rate: comparison study in an elderly population.

OBJECTIVE—This study was performed to ascertain the relative relevance of some inflammatory markers in insulin resistance. RESEARCH DESIGN AND METHODS—Four inflammatory markers (leukocyte count, erythrocyte sedimentation rate [ESR], high-sensitivity C-reactive protein [CRP], and C3 complement) were assessed as possible determinants of the homeostasis model assessment (HOMA) index, together with the five elements of the metabolic syndrome (National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel III] definition), total cholesterol, physical activity, and four indicators of adiposity (BMI, waist circumference, percent body fat, and hepatic steatosis) in an unselected population of 990 subjects aged 65–91 years (the Pianoro Study). RESULTS—In univariable analysis, C3, CRP, and leukocyte count, but not ESR, were significantly correlated with HOMA index. In multivariable analysis, C3 remained associated with insulin resistance with the highest partial R2 value (0.049), independently of all other covariates. The other most significant (P < 0.0001) determinants of HOMA index were total cholesterol (inverse association, R2 = 0.026), waist circumference (R2 = 0.023), triglycerides (R2 = 0.022), and hepatic steatosis (R2 = 0.021) (R2 = 0.450 for the whole model). The adjusted relative risks of having the metabolic syndrome for the subjects with inflammatory markers in the high tertile, with respect to those with lower values, were (prevalence ratio [95% CI]): 1.77 (1.41–2.22) for C3, 1.38 (1.12–1.70) for leukocyte count, 1.17 (0.94–1.46) for CRP, and 1.13 (0.91–1.40) for ESR. CONCLUSIONS—Of the four inflammatory markers simultaneously assessed in our elderly population, only C3 was strongly associated with insulin resistance, independently of the components of the metabolic syndrome and the main indexes of abdominal and general obesity.

Chronic endurance exercise training prevents aging-related cognitive decline in healthy older adults: a randomized controlled trial

To evaluate the effects of endurance exercise training (EET) on the cognitive status of healthy community‐dwelling older adults.

Prognostic significance of portal hemodynamics in patients with compensated cirrhosis

The prognostic value of portal hemodynamics, measured by pulsed echo-Doppler, was prospectively evaluated, together with clinical, biochemical and endoscopic parameters, in a series of 50 consecutive patients with compensated cirrhosis. After a mean follow-up of 6 years, 25 patients had died, all from complications of liver disease. Among conventional variables, the step-wise Cox model showed that only the Child-Pugh score independently predicted death (chi 2 = 18.66; p < 0.001). When hemodynamic parameters were added to the Child-Pugh score in the same model, portal blood velocity was shown to add prognostic significance (improvement in chi 2 = 14.06; p = 0.0002; Wald test). The present study shows that a portal blood velocity below the lower limit of controls (10 cm/s) characterizes patients with shorter survival, and suggests that this non-invasive parameter should be associated to the Child-Pugh score in the evaluation of patients with cirrhosis.

Determinants of mean platelet volume (MPV) in an elderly population: Relevance of body fat, blood glucose and ischaemic electrocardiographic changes

Mean platelet volume (MPV) is increased in patients with coronary heart disease or at risk for stroke. However, MPV determinants have never been assessed in a population study. The present investigation is a cross-sectional study involving 366 non-selected subjects (both sexes, mean age 72.9 +/- 5.5 [1 SD] years). The main cardiovascular risk factors, several indexes of adiposity (including percent body fat as estimated by skinfold measurement, and ultrasound detection of hepatic steatosis and thickness of abdominal subcutaneous and visceral fat) and ischaemic electrocardiographic (ECG) changes were assessed in all subjects. Platelet parameters were determined by a Bayer ADVIA 120 counter. In addition to being associated directly with platelet distribution width (PDW) and inversely with platelet count (p < 0.0001 for both), MPV values were associated with subcutaneous abdominal fat (p = 0.02), fasting blood glucose (p = 0.002) and the prevalence of ischaemic ECG changes (p = 0.004), and tended to be higher in the subjects with a greater prevalence of hepatic steatosis (p = 0.07) and higher Homeostasis Model Assessment (HOMA) index (p = 0.09). In multiple logistic regression, of the non-platelet parameters only percent body fat (p = 0.006), ischaemic ECG changes (p = 0.01) and blood glucose (p = 0.03) remained independently associated with an MPV < or =8.4 fl (high tertile). The relative risk (odds ratio) of having ischaemic ECG changes for the subjects with MPV < or =8.4 fl was 4.2 (95% confidence interval: 2.5-7.1; p = 0.006) with respect to the subjects with lower MPV values. Blood glucose, percent body fat and ischaemic ECG changes were the main MPV determinants in our elderly population.

Functional hepatic flow and Doppler-assessed total hepatic flow in control subjects and in patients with cirrhosis

Functional hepatic flow and total hepatic flow were determined by non-invasive techniques in 32 patients with cirrhosis and in 32 paired control subjects. Functional hepatic flow was measured by the hepatic clearance of D-sorbitol, while total hepatic flow was determined by pulsed echo-Doppler, as the sum of portal and hepatic arterial blood flow. Functional hepatic flow was significantly reduced in patients with cirrhosis (927 +/- 314 vs. 1287 +/- 315; p < 0.0001), while total hepatic flow was slightly increased (1511 +/- 540 vs. 1261 +/- 321 in controls; p = 0.028). In control subjects functional hepatic flow significantly correlated with total hepatic flow (r = 0.823; p < 0.001), while no correlation was observed in cirrhosis. Functional hepatic flow and the difference between total hepatic flow and functional hepatic flow significantly correlated with the Child-Pugh score in patients with cirrhosis. The data obtained in control subjects support the measurement of functional hepatic flow and total hepatic flow by non-invasive techniques. The finding that in cirrhosis functional hepatic flow is significantly decreased, while Doppler-assessed total hepatic flow is preserved or even increased, confirms that a relevant part of blood flowing through the liver is diverted by intrahepatic shunts. The simultaneous assessment of these two parameters by non-invasive techniques may be proposed as a reliable tool for the study of functional shunting of cirrhosis.