Effect of sustained virological response on long-term clinical outcome in 113 patients with compensated hepatitis C-related cirrhosis treated by interferon alpha and ribavirin.

AIM: To assess the long-term clinical benefit of sustained virological response (SVR) in patients with hepatitis C virus (HCV) cirrhosis treated by antiviral therapy using mostly ribavirin plus interferon either standard or pegylated. METHODS: One hundred and thirteen patients with uncomplicated HCV biopsy-proven cirrhosis, treated by at least one course of antiviral treatment > or = 3 mo and followed > or = 30 mo were included. The occurrence of linical events [hepatocellular carcinoma (HCC), decompensation and death] was compared in SVR and non SVR patients. RESULTS: Seventy eight patients received bitherapy and 63 had repeat treatments. SVR was achieved in 37 patients (33%). During a mean follow-up of 7.7 years, clinical events occurred more frequently in non SVR than in SVR patients, with a significant difference for HCC (24/76 vs 1/37, P = 0.01). No SVR patient died while 20/76 non-SVR did (P = 0.002), mainly in relation to HCC (45%). CONCLUSION: In patients with HCV-related cirrhosis, SVR is associated with a significant decrease in the incidence of HCC and mortality during a follow-up period of 7.7 years. This result is a strong argument to perform and repeat antiviral treatments in patients with compensated cirrhosis.

Impaired coronary endothelium-dependent vasodilation is associated with microalbuminuria in patients with type 2 diabetes and angiographically normal coronary arteries.

OBJECTIVE: Microalbuminuria and impaired endothelium-dependent vasodilation are both predictors for cardiac events in patients with type 2 diabetes. The aim of the study was to evaluate whether microalbuminuria correlated with coronary endothelium-dependent vasodilation. RESEARCH DESIGN AND METHODS: We evaluated 84 patients (47 men, mean age 50.5 +/- 5.9 years) with type 2 diabetes for 9.4 +/- 3.4 years, without angiographic coronary stenosis and without major cardiovascular risk factors or other confounding factors, for endothelium investigation. Quantitative coronary angiography was used to assess coronary artery response to cold pressor testing, used to assess endothelium-dependent vasodilation, and to isosorbide dinitrate (endothelium-independent vasodilation). RESULTS: Endothelium-dependent vasodilation differed in the patients with and without microalbuminuria (changes in coronary artery diameter during cold pressor testing: -15.0 +/- 1.9% vs. -10.2 +/- 1.3%, respectively, P < 0.05) and correlated with urinary albumin excretion rate (r = -0.39, P = 0.003), diastolic blood pressure (r = 0.29, P < 0.01), and left ventricular mass index (r = -0.24, P < 0.05). Independent predictors for endothelium-dependent vasodilation were urinary albumin excretion rate (beta -0.04 [95% CI -0.07 to -0.01], P < 0.005) and left ventricular mass index (-0.26 [-0.49 to -0.05], P < 0.05). Endothelium-independent vasodilation was similar in both groups. CONCLUSIONS: Type 2 diabetic patients with microalbuminuria have a more severely impaired coronary endothelium-dependent vasodilation than those with normoalbuminuria. These data suggest a common pathophysiological process for both coronary vasomotor abnormalities and microalbuminuria.

Predictive value of silent myocardial ischemia for cardiac events in diabetic patients: influence of age in a French multicenter study.

OBJECTIVE: Silent myocardial ischemia (SMI) in asymptomatic subjects with no history of myocardial infarction or angina is a frequent condition in diabetic patients. The aim of the study was to examine the predictive value of SMI for cardiac events in a multicenter cohort and to determine whether this value is higher in patients with a particular clinical profile. RESEARCH DESIGN AND METHODS: A total of 370 asymptomatic diabetic patients with at least two additional cardiovascular risk factors was recruited in four departments of diabetology. SMI was assessed by either exercise or dipyridamole single-photon emission-computed tomography myocardial perfusion imaging with thallium-201. If dipyridamole stress was used, an electrocardiogram stress test was performed separately on another day. Follow-up duration was 3-89 months (38 +/- 23 months). RESULTS: There was evidence of SMI in 131 patients (35.4%) on at least one positive noninvasive test. The patients with SMI were significantly older and had significantly higher serum triglycerides and lower HDL cholesterol levels. Cardiac events occurred in 53 patients (14.3%). Major cardiac events (death or myocardial infarction) occurred in 38 patients (10%) and other events (unstable angina, heart failure, or coronary revascularization) occurred in 15 patients. The patients who had cardiac events were older and had higher serum triglyceride levels at baseline. There was a significant association between SMI and cardiac events (hazard ratio 2.79 [95% CI 1.54-5.04]) and in particular major cardiac events (3 [1.53-5.87]). In the patients >60 years of age, the prevalence of SMI was higher (43.4 vs. 30.2% in those <60 years). SMI was associated with a significant risk of cardiac events (2.89 [1.31-6.39]) and in particular major cardiac events (3.66 [1.36-9.87]) for the patients >60 years old but not for those <60 years old. CONCLUSIONS: In asymptomatic diabetic patients with additional cardiovascular risk factors, SMI is a potent predictor of cardiac events and should be assessed preferably in the patients >60 years of age.

Influence of nutrients on cardiac autonomic function in nondiabetic overweight subjects.

The current study sought to determine whether there is a link between cardiac autonomic dysfunction and food intake in overweight subjects. One hundred five nondiabetic overweight (body mass index >27 kg/m2) subjects were studied. Heart rate variations were analyzed during 3 bedside standard tests investigating mainly vagal control: deep breathing, lying-to-standing, and Valsalva tests. The resting metabolic rate and substrate oxidation rates were measured by indirect calorimetry. Dietary intake was estimated from a 3-day recall of food intake. Cardiac parasympathetic dysfunction (PSD) was found in 39 subjects. The sex ratio, age, anthropometric parameters, biochemical parameters and insulin resistance index, resting metabolic rate, and substrate oxidation rates did not differ in the subjects with or without PSD. The total 24-hour energy intake was similar, but the carbohydrate intake was significantly higher in the subjects with PSD (P = .006), and the fat and protein intakes were significantly lower (P = .026 and .045, respectively). In the logistic regression analyses, PSD correlated with carbohydrate and fat intake, independently of serum insulin levels. Glucose oxidation rate correlated negatively with fasting and postglucose serum insulin levels only in the subjects with PSD (P = .006 and .005, respectively). Cardiac parasympathetic dysfunction is associated with higher carbohydrate intake and lower fat and protein intakes in overweight subjects. A sympathetic override may contribute to reducing the glucose oxidation rate in subjects with PSD.

Serum albumin and platelet count but not portal pressure are predictive of death in patients with Child-Pugh A hepatitis C virus-related cirrhosis.

AIM: The presence of esophageal varices has been reported to be a prognostic factor in patients with compensated hepatitis viral C induced cirrhosis. We studied the prognostic value of hepatic venous pressure gradient in addition to epidemiological and clinical parameters in these patients. METHODS: Among patients with Child-Pugh A hepatitis C induced cirrhosis, prospectively followed in two Parisian centres, 100 had measurement of occluded and free hepatic venous pressures. We evaluated hepatic venous pressures as a predictive factor of death by Cox models (survival) and Fine and Gray models (liver-deaths). RESULTS: Median hepatic occluded pressure and gradient were 21.5 (15-24) and 13 mm Hg (9-15), respectively. The median duration of follow-up was 85 months (range: 70-112); 38 deaths or liver transplantation were registered. Hepatic venous pressure gradient was not significantly related to survival in the studied population but as a continuous variable was predictive of death from liver disease. On multivariable analysis serum albumin <40 g/L and platelet count <90,000 /mm(3) were the only selected prognostic factors. CONCLUSION: Hepatic venous pressure gradient has a limited value for assessing the prognosis of patients with Child-Pugh A hepatitis C virus induced cirrhosis; prognosis is accurately predicted by serum albumin and platelet count.

Liver insulin-like growth factor 2 methylation in hepatitis C virus cirrhosis and further occurrence of hepatocellular carcinoma.

AIM: To assess the predictive value of the insulin-like growth factor 2 (Igf2) methylation profile for the occurrence of Hepatocellular Carcinoma (HCC) in hepatitis C (HCV) cirrhosis. METHODS: Patients with: (1) biopsy-proven compensated HCV cirrhosis; (2) available baseline frozen liver sample; (3) absence of detectable HCC; (4) regular screening for HCC; (5) informed consent for genetic analysis were studied. After DNA extraction from liver samples and bisulfite treatment, unbiased PCR and DHPLC analysis were performed for methylation analysis at the Igf2 locus. The predictive value of the Igf2 methylation profile for HCC was assessed by Kaplan-Meier and Cox methods. RESULTS: Among 94 included patients, 20 developed an HCC during follow-up (6.9 +/- 3.2 years). The methylation profile was hypomethylated, intermediate and hypermethylated in 13, 64 and 17 cases, respectively. In univariate analysis, two baseline parameters were associated with the occurrence of HCC: age (P = 0.01) and prothrombin (P = 0.04). The test of linear tendency between the three ordered levels of Igf2 methylation and probability of HCC occurrence was significant (Log Rank, P = 0.043; Breslow, P = 0.037; Tarone-Ware, P = 0.039). CONCLUSION: These results suggest that hypomethylation at the Igf2 locus in the liver could be predictive for HCC occurrence in HCV cirrhosis.

Vasculitides associated with malignancies: analysis of sixty patients.

OBJECTIVE: To describe characteristics and outcomes of vasculitides associated with malignancies. METHODS: The requirement for inclusion in this retrospective, 10-year study was development of vasculitis in patients with a progressing malignancy. Malignancies secondary to immunosuppressants used to treat vasculitis were excluded. The main characteristics of vasculitides were analyzed and compared according to the type of malignancy. RESULTS: Sixty patients were included (male/female sex ratio 2.53, mean age 62.4 years). Mean followup duration was 45.2 months. Vasculitides were cutaneous leukocytoclastic (45%), polyarteritis nodosa (36.7%), Wegener's granulomatosis (6.7%), microscopic polyangiitis (5%), and Henoch-Schönlein purpura (5%). Malignancies were distributed as follows: hematologic in 63.1%, myelodysplastic syndrome (MDS) in 32.3%, lymphoid in 29.2%, and solid tumor in 36.9%. Vasculitides were diagnosed concurrently with malignancy in 38% of the cases. Manifestations of vasculitides were fever (41.7%), cutaneous involvement (78.3%), arthralgias (46.7%), peripheral neuropathy (31.7%), renal involvement (23.3%; 11.7% glomerulonephritis, 11.7% microaneurysms, 6.7% renal insufficiency), and antineutrophil cytoplasmic antibody (20.4%). Vasculitis treatments were corticosteroids (78.3%) and immunosuppressant(s) (41.7%). Vasculitis was cured in 65% of patients, but 58.3% died, with 1 death secondary to vasculitis. Independent of subtype, patients with vasculitides associated with MDS more frequently had renal manifestations (P = 0.02) and steroid dependence (P = 0.04) and achieved complete remission less often (P = 0.04) than patients with vasculitides associated with other malignancies. Patients with vasculitides associated with a solid tumor more frequently had peripheral neurologic involvement (P = 0.05). Patients with vasculitides associated with lymphoid malignancy had less frequent arthralgias (P = 0.01) and renal involvement (P = 0.02). CONCLUSION: Vasculitides occurring during malignancies present distinctive features according to the vasculitis subtype and nature of the malignancy.

Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis.

BACKGROUND & AIMS: Influence of being overweight and diabetes mellitus on the occurrence of hepatocellular carcinoma (HCC) in patients with cirrhosis has not been evaluated prospectively. The aim of this study was to show the predictive value of these factors in a cohort of 771 patients with well-compensated alcohol- or hepatitis C (HCV)-related cirrhosis who were screened prospectively for HCC. METHODS: The predictive value for HCC occurrence was assessed by using the log-rank test and the Cox proportional hazards model. At enrollment, the mean age was 61.4 +/- 10 years and 431 patients were men. Cirrhosis was caused by alcohol (n = 478), HCV (n = 220), or the association of both factors (n = 73). The mean body mass index (BMI) was 25.4 kg/m(2) and 231 patients were diabetic. RESULTS: During a mean follow-up period of 4.2 +/- 3 years, 220 patients developed HCC. In univariate analysis, a BMI of 25 kg/m(2) or more, diabetes, male sex, age older than 60 years, and HCV infection were risk factors for HCC. In multivariate analysis, predictive factors were a BMI between 25-30 kg/m(2) (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.4-2.7), BMI of 30 kg/m(2) or more (HR, 2.8; 95% CI, 2.0-4.0), diabetes (HR, 1.6; 95% CI, 1.2-2.1), age 60-70 years (HR, 2.4; 95% CI, 1.3-4.3), age older than 70 years (HR, 3.0; 95% CI, 1.7-5.5), male sex (HR, 2.0; 95% CI, 1.4-2.7), HCV (HR, 1.6; 95% CI, 1.1-2.2), and mixed (HR, 2.6; 95% CI, 1.7-4.0) etiology. We found a positive linear relationship between BMI level and HCC incidence during follow-up evaluation. CONCLUSIONS: Overweight and diabetes mellitus are associated with an increased risk of HCC occurrence in patients with HCV- or alcohol-related cirrhosis.

Clinical and biological features associated with taste loss in internal medicine patients. A cross-sectional study of 100 cases.

Which are the main features associated with taste loss in patients exposed to a wide range of drugs and diseases? In 100 consecutive patients admitted to a ward of internal medicine, we assessed taste complaints, performance status, alcohol and tobacco consumptions, diseases, drugs and laboratory data, measuring the electrical taste threshold as primary outcome. After adjusting for age, taste thresholds were not associated with sex, body mass index, tobacco, thrush, drugs, aliageusia and phantogeusia. Features associated with threshold increase included alcohol intake>or=10 gd-1, impaired performance status, complaint of taste loss, atrophic glossitis, cerebral disease, and an erythrocyte mean corpuscular volume. A multivariate analysis identified age, alcohol intake, complaint of loss or altered taste, mean corpuscular volume, and performance status as independent factors associated with taste loss. Inpatients may be screened for taste loss by a few features, to identify those for whom a nutritional intervention should be focused.

Cardiovascular vagosympathetic activity in rats with ventromedial hypothalamic obesity.

OBJECTIVE: Rats with ventromedial hypothalamic lesion (VMH) are massively obese with endogenous hyperinsulinemia, insulin resistance, low sympathetic activity, and high parasympathetic activity, which are likely to induce hypertension. The goal was to follow in this model the long-term hemodynamic changes and to investigate the role of autonomic nervous system and insulin resistance in these changes. RESEARCH METHODS AND PROCEDURES: Heart rate and blood pressure were monitored for 12 weeks after operation using a telemetric system in VMH and sham rats. Plasma catecholamines and heart beta-adrenoceptors were measured. Glucose tolerance was studied after an intravenous glucose injection and insulin sensitivity during a euglycemic hyperinsulinemic clamp test. RESULTS: A marked bradycardia and only a mild increase in blood pressure occurred in VMH rats compared with sham animals. Response to autonomic-acting drugs showed an increase in heart vagal tone and responsiveness to a beta-agonist drug. Plasma catecholamine levels were markedly increased, and the density and affinity of heart beta-adrenoceptors were similar in VMH, sham, and control rats. Muscle glucose use was reduced by 1 week after operation in VMH animals. DISCUSSION: These results show the following in this model of massively obese rats with sympathetic impairment: 1). adrenal medulla secretion is increased, probably as a result of hyperinsulinemia and increased vagal activity; 2). cardiac responsiveness to beta-agonist stimulation is increased; and 3). despite these changes and suspected resistance to the vasodilative effect of insulin, blood pressure does not increase. We conclude that high vagal activity may be protective against hypertension associated with obesity.

Hypovitaminosis C in hospitalized patients.

BACKGROUND: In recent years, cases of scurvy have mainly been described in populations at risk. The prevalence and risk factors for hypovitaminosis C among hospitalized patients in a department of internal medicine are largely unknown. METHODS: We determined serum ascorbic acid level (SAAL) and searched for clinical and biological signs of scurvy in 184 patients hospitalized during a 2-month period. RESULTS: The prevalence of hypovitaminosis C (depletion: SAAL<5 mg/l or deficiency: SAAL<2 mg/l ) was 47.3%. Some 16.9% of the patients had vitamin C deficiency. There was a strong association between hypovitaminosis C and the presence of an acute phase response (p=0.002). Other univariate risk factors for vitamin C depletion were male sex (p=0.02), being retired (p=0.037), and infectious diseases (p=0.002). For vitamin C deficiency, the significant univariate risk factors included the same ones found for vitamin C depletion, plus being unemployed (p=0.003) and concomitant excessive alcohol and tobacco consumption (p<0.0001). Logistic regression showed that being retired (p=0.015) and concomitant excessive alcohol and tobacco consumption (p=0.0003) were significant independent risk factors. Hemorrhagic syndrome and edema were described more often in patients with vitamin C deficiency than in those with vitamin C depletion or without hypovitaminosis. Clinical signs were more frequent for an ascorbic acid level below 2.5 mg/l. CONCLUSION: Hypovitaminosis C is frequent in hospitalized patients but should be interpreted according to the presence or absence of an acute phase response. The main risk factors are living conditions and excessive alcohol and tobacco consumption.