Giorgio Soardo

Portal vein thrombosis in hepatocellular carcinoma: age and sex distribution in an autopsy study

Abstract The purpose of this work was to investigate the prevalence, associated features and effect on survival of portal vein thrombosis (PVT) complicating hepatocellular carcinoma (HCC). The autopsy data of a series of 72 consecutive patients (57 male, 15 female) with HCC were reviewed. PVT was found in 32/72 patients (44%), and tended to be more common in female patients (10/15 versus 22/57, P = 0.052). Stratifying the data according to gender, it appeared that the mean age of patients with PVT compared to those without was greater in woman (71.9 ± 5.9 versus 63.2 ± 6.9 years, P = 0.024) and younger in men (58.8 ± 8.9 versus 66.0 ± 9.9 years, P = 0.007). When PVT was present, it was more likely that a definite diagnosis of HCC had been obtained before autopsy (P = 0.0001) and that death had been caused by bleeding complications (P = 0.007). Median survival times were similar, irrespective of the presence of PVT. During the natural history of HCC, PVT occurs in a substantial proportion of patients. Hormonal factors may have a permissive role in thrombus formation or neoplastic vascular invasion. Although in the presence of PVT a diagnosis of HCC is rarely missed and bleeding complications are likely to occur, patient survival does not seem to be significantly affected.

Blood lipids of patients with chronic hepatitis: differences related to viral etiology

In order to investigate whether a difference might exist in blood cholesterol and its subtractions between patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, serum cholesterol, HDL-cholesterol, triglycerides and common liver function tests were measured in 138 patients (92 male, 46 female) with biopsy-proven chronic viral hepatitis without cirrhosis. Twenty-four had hepatitis B and 114 hepatitis C. Mean serum cholesterol was lower in HCV-infected in comparison to HBV-infected patients (175 +/- 36 mg/dl vs. 189 +/- 28 mg/dl, p < 0.05). On multivariate analysis, etiology of hepatitis appeared to be associated with the value of serum cholesterol, independently of age, sex and liver synthetic function (improvement of chi-square 4.40, p < 0.05). In patients with HBV infection, circulating tumor necrosis factor-alpha demonstrated a correlation with serum triglycerides (p = 0.618) and an inverse correlation with serum HDL-cholesterol (p = -0.456); in the group of patients with HCV infection, interleukin-6 correlated with triglycerides (p = 0.370) and HDL-cholesterol (p = -0.355). Thus, differences in the mechanisms of liver damage and of viral clearance in hepatitis C in comparison to hepatitis B, reflected in these patients by the levels of circulating cytokines, may be mirrored by differences in their blood lipid composition.

Non-alcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in essential hypertension

BACKGROUND AND AIM Insulin resistance is recognized as the pathophysiological hallmark of non-alcoholic fatty liver disease (NAFLD). A relation between insulin sensitivity and left ventricular morphology and function has been reported in essential hypertension, where a high prevalence of NAFLD has been recently found. We investigated the inter-relationship between left ventricular morphology/function, metabolic parameters and NAFLD in 86 never-treated essential hypertensive patients subdivided in two subgroups according to the presence (n = 48) or absence (n = 38) of NAFLD at ultrasonography. METHODS AND RESULTS The two groups were similar as to sex, age and blood pressure levels. No patient had diabetes mellitus, obesity, hyperlipidemia, or other risk factors for liver disease. Body mass index, waist circumference, triglycerides, glucose, insulin, homeostasis model of assessment index for insulin resistance (HOMA-IR), aspartate aminotransferase and alanine aminotransferase were higher and adiponectin levels were lower in patients with NAFLD than in patients without NAFLD, and were associated with NAFLD at univariate analysis. Patients with NAFLD had similar prevalence of left ventricular hypertrophy compared to patients without NAFLD, but a higher prevalence of diastolic dysfunction (62.5 vs 21.1%, P < 0.001), as defined by E/A ratio <1 and E-wave deceleration time >220 ms. Diastolic dysfunction (P = 0.040) and HOMA-IR (P = 0.012) remained independently associated with NAFLD at backward multivariate analysis. CONCLUSIONS Non-alcoholic fatty liver disease was associated with insulin resistance and abnormalities of left ventricular diastolic function in a cohort of patients with essential hypertension, suggesting a concomitant increase of metabolic and cardiac risk in this condition.

MILD SIALOADENITIS : A COMMON FINDING IN PATIENTS WITH HEPATITIS C VIRUS INFECTION

BACKGROUND Sjögrens syndrome (SS) is an autoimmune disease of presumed viral origin; sialoadenitis has been reported to occur in hepatitis C virus (HCV) infection. METHODS Lip biopsy specimens were graded in 32 consecutive patients with either HCV-related chronic liver disease or SS. RESULTS Seventeen of 22 HCV-positive patients had sialoadenitis, although generally mild (15 of 17, grades I-II). Severe inflammation (grades III-IV) was observed in 8 of 10 patients with SS (chi-square = 12.6; P < 0.0005). Moreover, HCV-positive patients with sialoadenitis differed from patients with SS in female sex prevalence (6 of 17 versus 10 of 10; chi-square = 10.9; P = 0.0001) and presence of serum antinuclear autoantibodies (0 of 17 versus 9 of 10; chi-square = 23.0; P < 0.0001). Five of 13 HCV-positive patients and 7 of 8 patients with SS were HLA-DR3-positive (chi-square = 4.9; P < 0.05). CONCLUSIONS Sialoadenitis of HCV-related liver disease is common but differs from SS with regard to predisposing genetic factors, expression of autoimmune markers, and histopathologic severity.

New risk factors for atherosclerosis in hypertension: focus on the prothrombotic state and lipoprotein(a).

Although adequate control of blood pressure is of basic importance in cardiovascular prevention in hypertensive patients, correction of additional risk factors is an integral part of their management. In addition to classical risk factors, epidemiological research has identified a number of other conditions that might significantly contribute to cardiovascular risk in the general population and might achieve specific relevance in patients with high blood pressure. In fact, more than 20% of patients with premature cardiovascular events do not have any of the traditional risk factors and, although effective intervention on blood pressure and additional risk factors has significantly reduced cardiovascular morbidity and mortality, the contribution to stroke, coronary artery disease and renal failure is still unacceptably high. Evaluation of new risk factors may further expand our capacity to predict atherothrombotic events when these factors are included along with the traditional ones in the assessment of global cardiovascular risk in hypertensive patients. Because it could be anticipated that the role of these novel factors will become increasingly evident in the future, researchers with an interest in hypertension and physicians dealing with problems related to cardiovascular prevention should give them appropriate consideration. This review summarizes the basic biology and clinical evidence of two emerging risk factors that are reciprocally related and contribute to the development and progression of organ damage in hypertension: the prothrombotic state and lipoprotein(a).

Iron Deposition and Progression of Disease in Chronic Hepatitis C Role of Interface Hepatitis, Portal Inflammation, and HFE Missense Mutations

Histologically detectable iron (HDI) and HFE mutations were searched for in liver biopsy specimens from 58 Italian patients with chronic hepatitis C, and morphologic features were compared to examine their reciprocal relation and their contribution to disease progression. HDI was evident in 48% of cases with features of nonhemochromatosis iron overload. Total, sinusoidal, and portal HDI increased with stage; grade was related to all iron scores because of the contribution of portal inflammation and interface hepatitis. HFE mutations were seen in 47% of patients with chronic hepatitis C and in 28% of control subjects; they were related to stage and the His63Asp mutation to portal HDI. On multivariate analysis, grade but not stage or HFE mutations was associated with HDI in all sites. Interface hepatitis with its sequelae (sinusoidal capillarization and microshunting) represents a major factor in iron deposition in chronic hepatitis C and justifies the features of HDI. HFE mutations are not responsible for HDI deposition but could favor the progression of virus-induced damage independently from interference with iron metabolism.

Oxidative Stress Is Activated by Free Fatty Acids in Cultured Human Hepatocytes

BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is strongly associated to oxidative stress, metabolic syndrome, and cardiovascular risk. Hepatocytes overloaded with fatty acids (FA) could generate substances that interfere with endothelial function, providing a potential explanation for this association. We have investigated the response of cultured human hepatoblastoma cells (Hep-G2) that were exposed to FA by measuring markers of oxidative stress and thrombosis and expression of the insulin receptor. METHODS Hep-G2 cells were conditioned with a mixture of FA with or without N-acetyl-L-cysteine (NAC), glutathione (GSH), or adiponectin (ADN). After 7 days, we measured intracellular GSH (iGSH), nitric oxide (NO), malondialdehyde (MDA), and tissue plasminogen inhibitor-1 (PAI-1). Real-time polymerase chain reaction (PCR) was used to determine gene expression of inducible nitric oxide synthase (iNOS) and insulin receptor (INS-R). RESULTS Exposure to FA decreased iGSH and NO levels in Hep-G2 cells and increased MDA and PAI-1 production. Gene expression of iNOS and INS-R in Hep-G2 cells was decreased by exposure to FA. Co-incubation with NAC and GSH prevented the change of iNOS mRNA levels, but not of INS-R; co-incubation with ADN restored the gene expression of INS-R, but not of i-NOS. ADN prevented also the FA-induced increase in MDA in cultured human endothelial cells. CONCLUSION Exposure to FA activates oxidative stress and production of prothrombotic markers and decreases expression of insulin receptors in cultured human hepatocytes. These effects of FA are partially prevented by ADN and might contribute to the increased cardiovascular risk in patients with NAFLD and metabolic syndrome.

PNPLA3 I148M Polymorphism, Clinical Presentation, and Survival in Patients with Hepatocellular Carcinoma

Background & Aims Aim of this study was to evaluate whether the PNPLA3 I148M polymorphism, previously associated with hepatocellular carcinoma (HCC) risk, influences the clinical presentation of HCC and survival. Methods we considered 460 consecutive HCC patients referred to tertiary care centers in Northern Italy, 353 with follow-up data. Results Homozygosity for PNPLA3 148M at risk allele was enriched in HCC patients with alcoholic liver disease or nonalcoholic fatty liver disease (ALD&NAFLD: relative risk 5.9, 95% c.i. 3.5–9.9; other liver diseases: relative risk 1.9, 95% c.i. 1.1–3.4). In ALD&NAFLD patients, the PNPLA3 148M allele was associated with younger age, shorter history of cirrhosis, less advanced (Child A) cirrhosis at HCC diagnosis, and lower HCC differentiation grade (p<0.05). Homozygosity for PNPLA3 148M was associated with reduced survival in the overall series (p = 0.009), and with a higher number of HCC lesions at presentation (p = 0.007) and reduced survival in ALD&NAFLD patients (p = 0.003; median survival 30, 95% c.i. 20–39 vs. 45, 95% c.i. 38–52 months), but not in those with HCC related to other etiologies (p = 0.86; 48, 95% c.i. 32–64 vs. 55, 95% c.i. 43–67 months). At multivariate Cox regression analysis, homozygosity for PNPLA3 148M was the only negative predictor of survival in ALD&NAFLD patients (HR of death 1.57, 95% c.i. 1.12–2.78). Conclusions PNPLA3 148M is over-represented in ALD&NAFLD HCC patients, and is associated with occurrence at a less advanced stage of liver disease in ALD&NAFLD. In ALD&NAFLD, PNPLA3 148M is associated with more diffuse HCC at presentation, and with reduced survival.

Nonalcoholic fatty liver disease, adiponectin and insulin resistance in dipper and nondipper essential hypertensive patients.

Objective The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is multifactorial, and the presence of insulin resistance is recognized as the pathophysiological hallmark of this condition. Arterial hypertension is referred as an insulin-resistant state, and insulin resistance may substantially contribute to the cardiovascular risk in this disorder. We examined the inter-relationship between insulin sensitivity, adiponectin levels, and NAFLD in hypertensive patients with different circadian blood pressure profiles. Methods Eighty never-treated patients with essential hypertension were selected for having a nocturnal decrement of blood pressure that was at least 10% (dippers, n = 47) or less than 10% (nondippers, n = 33) of daytime values. No patient had diabetes mellitus, obesity, hyperlipidemia, or other risk factors for hepatic disease. The two groups were similar as to sex, age, and BMI. Abdominal fat distribution and NAFLD were assessed by ultrasonography. Results Hepatic steatosis was detected in 57.5% of all patients. Nondippers showed a higher prevalence of NAFLD than dippers (81.8 vs. 40.4%, P < 0.005). Insulin and the homeostasis model of assessment index were higher (P < 0.001) and adiponectin was lower (P < 0.001) in nondippers than in dippers, whereas no difference was found in regional fat, liver enzymes, and other metabolic parameters. At multivariate analysis, factors independently associated with nondipping were insulin (P < 0.05) and adiponectin (P < 0.01) with the homeostasis model of assessment index being of borderline significance. Conclusion In the absence of major risk factors for the development of NAFLD, a high prevalence of liver steatosis was associated with insulin resistance and low adiponectin levels in essential hypertensive patients with a nondipping profile.

Thrombocytopenia of chronic liver disease corrected by erythropoietin treatment

To investigate the possibility of correcting thrombocytopenia of chronic liver disease, 19 patients (6 male and 13 female) with long-term chronic liver disease and platelet count ≤85 000/ μ l were studied. Either a short-term course (7–20 days) of recombinant human erythropoietin, 4000 U daily SQ (12 patients) or placebo (7 patients) was administered. Treatment was interrupted if the platelets rose to ≥100 000/ μ l or if no significant increase was noted after 14 days. After treatment, platelets increased in the recombinant human erythropoietin group (from a baseline value of 70 000±11 184 to 101 250±37 625/ μ l), while no difference was noted in the placebo group (70 714±9928 vs 70 000±10 231/ μ l). The increase in the platelet count in the recombinant human erythropoietin group was significant, both compared to baseline values (paired Students t -test, t =−3.80, p t -test, t =2.71, p μ l platelets while four (33%) did not. In comparison to responders, non-responders had a significantly lower baseline platelet count (58 500±7937 vs 75 750±7498/ μ l, t =−3.69, p =0.004) and failed more frequently than responders to improve their haematocrit in response to recombinant human erythropoietin (Pearson χ 2 =4.687, p =0.03). When treatment was discontinued, the platelet count reverted to baseline in a few weeks. In conclusion, recombinant human erythropoietin treatment transiently corrected mild thrombocytopenia in patients with chronic liver disease. The failure to increase circulating thrombocytes with recombinant human erythropoietin treatment occurred in patients with a lower steady-state value in the balance between excessive platelet destruction and compensatory production.