Does asymmetric dimethylarginine (ADMA) plasma concentration predict esophageal varices in patients with cirrhosis?

BACKGROUND: In previous studies elevated Asymmetric NG, NG - dimethylarginine (ADMA) plasma levels, an endogenous nitric oxide synthase inhibitor, correlated with the severity of hepatic venous pressure gradient measurement, both in peripheral and in hepatic veins. The aim of this study was to explore whether elevated ADMA plasma levels were able to predict the presence of esophageal varices (EV) and/or large EV in patients with cirrhosis. METHODS: 74 cirrhotic patients who had undergone elective upper gastrointestinal endoscopy in order to assess the presence of portal hypertension and predictors of EV and/or large EV. ADMA levels were assayed by an ELISA test (Immundiagnostik AG, Germany). RESULTS: 53 patients had EV (26/53 had large EV). Univariate analysis of low hemoglobin (p = 0.045), PT-INR (p = 0.003), albumin (p = 0.024), bilirubin (p = 0.036), Child-Pugh score (p = 0.026), and ascites (p = 0.036) predicted the presence of EV. Multivariate analysis predicted EV for only PT-INR. The presence of large EV was predicted with univariate analysis of ADMA plasma levels (p = 0.013), low hemoglobin (p < 0.001), PT-INR (p = 0.001), albumin (p = 0.001), bilirubin (p = 0.026), Child-Pugh score (p < 0.001), ascites (p = 0.004). Sensitivity, specificity, predictive positive and negative values of ADMA plasma level > 0.5 micromol/L(-1) in predicting large EV were 0.69 (95% CI 0.53 - 0.82), 0.51 (95% CI 0.40 - 0.62), 0.43 (95% CI 0.31 - 0.56), 0.76 (95% CI 0.62 - 0.86), while the area under the ROC curve was 0.65 (95% CI 0.51 - 0.79). CONCLUSIONS: ADMA plasma levels were increased in cirrhotics with more advanced liver failure but did not prove to be a useful clinical tool for predicting the presence of esophageal varices or large esophageal varices.

Electromagnetic navigation bronchoscopy and rapid on site evaluation added to fluoroscopy-guided assisted bronchoscopy and rapid on site evaluation: improved yield in pulmonary nodules.

AIM: Electromagnetic navigation bronchoscopy (ENB) was reported to increase diagnostic yield in pulmonary nodules (PNs). The aim of this study was to assess if rapid on site evaluation (ROSE) associated with ENB could improve diagnostic accuracy in PNs after non-diagnostic fluoroscopy-guided bronchoscopy added to ROSE. METHODS: Forty patients with PNs suspected for lung cancer underwent to ENB + ROSE after non-diagnostic Fluoroscopy-guided Bronchoscopy + ROSE. Each lesion was studied with reference to size, location, presence of bronchus sign on CT. All lesions were sampled by needle and brush; if negative, by forceps and bronchoalveolar lavage. All patients were followed-up until achievement of definitive diagnosis. RESULTS: Twenty-nine out of 41 lesions (70.7%) had a definitive diagnosis. ENB sensitivity for malignancy was 76.5%, with higher rate in presence of bronchus sign on CT (86.2%) and in case of lesions located in the upper and middle lobes (87.5%). CONCLUSION: ENB is a useful tool in the evaluation of PNs. High diagnostic accuracy may be related to sampling (transbronchial needle aspiration), ROSE, location and presence of bronchus sign.

Gender and liver fibrosis in chronic hepatitis: the role of iron status.

BACKGROUND: The role of gender in the progression of fibrosis in chronic hepatitis C is still under investigation. AIM: To investigate whether gender affects the progression of liver disease and/or hides other risk factors. METHODS: A prospective series of 121 consecutive patients with chronic hepatitis C underwent liver biopsy. Grading and staging for chronic hepatitis were each evaluated according to Ishak's classification. RESULTS: In univariate and multivariate analysis on the whole group of patients, male gender was not associated either with significant liver fibrosis (Ishak's score > 2) or with cirrhosis (Ishak's score > 4). On the contrary, in univariate analysis on patients aged < or = 50 years, male gender was nearly significantly (P = 0.06) predictive of liver fibrosis, whereas it was not in patients > 50 years. Hepatic iron grading, along with age, was an independent factor associated with fibrosis. Moreover, the values of all the variables which describe iron status were significantly higher in males aged < or = 50 years in comparison with females of the same age. CONCLUSIONS: In chronic hepatitis C, male gender may be predictive of liver fibrosis only in patients aged < or = 50 years. Among fibrogenetic factors hidden by gender, iron status could play a major role.

Iron, hepatic stellate cells and fibrosis in chronic hepatitis C.

BACKGROUND/AIMS: In patients with chronic hepatitis C, hepatic iron concentration correlates with liver fibrosis. However, it is not clear whether this correlation merely reflects the presence of more active disease, or iron exacerbates chronic hepatitis C virus (HCV)-induced damage through activation of hepatic stellate cells and regeneration of hepatocytes. MATERIALS AND METHODS: We studied 72 HCV-positive patients, staged according to the Ishak's score system. We measured hepatic iron concentration with spectrophotometry and evaluated the number of hepatic stellate cells (using monoclonal antibody against alpha smooth muscle actin) and proliferating hepatocytes (using monoclonal antibody against Ki67). Iron and ferritin serum levels were also determined. RESULTS: Hepatic iron concentration correlated statistically with ferritin serum level (r = 0.59, P < 0.001), with grading (r = 0.47, P < 0.001) and staging (r = 0.51, P < 0.001) scores for chronic hepatitis in the whole group of patients. Hepatic iron concentration correlated positively with stellate cell number (r = 0.55, P = 0.004) and Ki67-positive hepatocyte number (r = 0.36, P = 0.08) in patients with chronic hepatitis C and low grading score (< 3). CONCLUSIONS: In patients with chronic hepatitis C and low grading score, hepatic iron could play a role in the activation of hepatic stellate cells and in the progression of fibrosis.

Chronic hepatitis C treated with phlebotomy alone: biochemical and histological outcome.

BACKGROUND: In patients with chronic hepatitis C, the histological outcome of long term phlebotomy is unknown. AIM: To investigate biochemical and histological findings before and after phlebotomy in chronic hepatitis C. PATIENTS: Twenty-four non-haemochromatotic patients with chronic hepatitis C were treated with long-term phlebotomy alone. RESULTS: Hepatic iron concentration had decreased in all patients who underwent a second liver biopsy, two years after iron depletion was attained and maintained. Histological grading score decreased in four patients, was unchanged in two, and increased in five. Histological staging score decreased in two patients, was unchanged in five, and increased in four. Pretreatment high serum selenium level predicted the reduction of the inflammatory grading score in univariate analysis (p=0.008, while low serum aspartate aminotransferase (p=0.02) and low propeptide of procollagen III (p=0.08) levels predicted the lack of progression of liver fibrosis. Furthermore, when iron depletion was reached, significant reductions of serum levels of aminotransferase, gamma glutamyl transferase (-47%), propeptide of procollagen III, alpha foetoprotein, selenium were observed in 24 patients. No changes in serum hepatitis C virus-RNA levels were found. CONCLUSIONS: Phlebotomy alone seems to be efficacious in suppressing progression of chronic hepatitis C in some patients. Phlebotomy not only induces iron depletion, but it even modifies serum levels of other trace elements involved in the balance between oxidant and antioxidant processes.

Chronic hepatitis C is mild in menstruating women.

BACKGROUND AND AIMS: Women with chronic hepatitis C may have a slower rate of disease progression than men. We have previously demonstrated a relationship between hepatic iron concentration and liver fibrosis in patients with chronic hepatitis C. Our aim was to compare hepatic histologic findings, iron status and other factors putatively capable of determining the severity of chronic hepatitis between menstruating women and men of comparable age. METHODS: We studied 21 consecutive hepatitis C virus (HCV)-RNA positive menstruating women and 24 consecutive HCV-RNA positive men of comparable age, who underwent liver biopsy for chronic hepatitis C. Alcohol intake was recorded and blood tests, HCV genotyping, serum iron, unsaturated iron binding capacity, serum ferritin, hepatic iron concentration, and liver histology were evaluated. RESULTS: Menstruating women showed lower grading (2.7 +/- 1.5 vs 3.6 +/- 2, P = 0.09) and significantly lower staging (1.38 +/- 1.11 vs 2.42 +/- 1.64, P = 0.037) scores than men of comparable age. Among the factors putatively capable of determining the severity of chronic hepatitis, only the hepatic iron concentration correlated with the hepatic histologic staging in a multivariate analysis. Iron-depleted women (transferrin saturation < 20% and/or serum ferritin < 9 micrograms/L) showed significant lower hepatic histologic grading (1.75 +/- 0.7 vs 3.23 +/- 1.55, P = 0.027) and staging (0.75 +/- 1.03 vs 1.77 +/- 1.01, P = 0.026) scores than women with normal iron status. CONCLUSIONS: Menstruating women with chronic hepatitis C may have a milder disease compared to men of comparable age, possibly because of menstrual blood loss and lower hepatic iron concentration. Women with chronic hepatitis C and iron deficiency have a milder disease compared to women with normal iron status, suggesting that iron deficiency results in a slower rate of disease progression.

Evaluation of iron status in patients with chronic hepatitis C.

AIM: To evaluate the prevalence of iron overload in chronic hepatitis C and its relationship with liver histology. PATIENTS AND METHODS: Serum iron, unsaturated iron binding capacity and ferritin levels were determined in 204 consecutive anti-hepatitis C virus positive subjects, whereas hepatic iron concentration, hepatic histological grading and staging, hepatitis C virus genotypes were further assessed in a subgroup of 50 patients who underwent liver biopsy for chronic hepatitis. RESULTS: An increase in the serum markers of iron metabolism was more frequently found in subjects with aminotransferase activities above the normal range, whereas hepatic iron overload, established by direct hepatic iron determination, was found only in 9/50 (18%) patients with chronic hepatitis C. No serum iron marker could reliably predict hepatic iron stores. Patients with mild iron overload usually showed active hepatitis and fibrosis, whereas iron overload was not present in patients without fibrosis or with very mild fibrosis. Two out of nine patients with iron overload were shown to be beta thalassaemia heterozygous, and two were heterozygous carriers of a putative haemochromatosis gene mutation (His63Asp). CONCLUSIONS: Many anti-hepatitis C virus positive patients with elevated aminotransferase activities have serum ferritin levels above the normal range, but only a minority of patients with chronic hepatitis C have a mild iron overload. In chronic hepatitis C, a relationship does exist between hepatic iron content and liver fibrosis.

High prevalence of hepatitis C virus (HCV) genotype 2 in Italian patients with chronic liver disease.

The prevalence of different genotypes of Hepatitis C virus may vary between geographic areas and it is possible that various genotypes have different pathogenic characteristics. Therefore, 90 consecutive Italian patients anti-Hepatitis C Virus positive with a broad spectrum of chronic liver disease, have been analysed to observe prevalence of various genotypes of Hepatitis C Virus. Genotyping was performed by polymerase chain reaction with a set of nested biotinylated primers, located in 5'UTR region. Genotype 1b and genotype 2a were the most commonly encountered (respectively, 50% and 37%) whereas other genotypes were rare. The unexpected high prevalence of genotype 2a allowed direct comparison of clinical characteristics and response to therapy between patients with genotype 2a and those with 1b. Genotype 1b was more prevalent than 2a in patients over 60 years (29 vs 12) and in those with more severe liver disease (34 vs 16). In a univariate analysis, genotype 2a was associated with less severe liver disease (p = 0.02) and younger age (p = 0.018), in comparison with genotype 1b. Patients with genotype 2a responded to interferon alpha therapy better than those with 1b (p = 0.007). In a multivariate analysis, only younger age was associated with genotype 2a. Genotype 2a (in comparison with 1b) and absence of cirrhosis were independent predictors of response to interferon alpha. In conclusion, genotype 2a is playing an emerging role in younger Italian patients and seems more sensitive than 1b to interferon alpha therapy.

Diagnostic paracentesis. A two-step approach.

Diagnostic paracentesis is usually considered the first test to be performed in the assessment of the ascitic patient and a large number of investigations on ascitic fluid have been proposed. To assess the value of a simplified procedure, serum to ascites albumin gradient and ascitic white blood cell counts were employed as a first step. One hundred and fifty-three paired serum and ascitic fluid samples were analysed and allowed patients to be divided into three groups: 1) serum to ascites albumin gradient > = 11 g/L and white blood cells < 0.5 x 10(9)/L predicted cirrhosis (or liver carcinoma) without peritonitis with 83% efficacy, 96% positive predictive value and 65% negative predictive value; 2) serum to ascites albumin gradient > = 11 g/L and white blood cells > = 0.5 x 10(9)/L predicted cirrhosis (or liver carcinoma) with peritonitis with 86% efficacy, 45% positive predictive value and 99% negative predictive value; 3) serum to ascites albumin gradient < 11 g/L predicted the other diagnoses with 92% efficacy, 77% positive predictive value and 95% negative predictive value. As serum to ascites albumin gradient > = 11 g/L and white blood cells < 0.5 x 10(9)/L predicted cirrhosis (or liver carcinoma) without peritonitis in 96% of the cases and excluded peritonitis in 99% of the cases, further fluid ascitic analyses could be considered as a second step only in patients with serum to ascites albumin gradient < 11 g/L and/or white blood cells > = 0.5 x 10(9)/L. In a group of ascitic patients where the prevailing diagnosis is cirrhosis (or liver carcinoma) without peritonitis, this simplified approach could provide a favourable cost/benefit ratio.

Assessment of interferon cardiotoxicity with quantitative radionuclide angiocardiography.

Three different types of cardiovascular sequelae attributed to interferon therapy have been reported: arrhythmia, ischaemic heart disease and cardiomyopathy. We evaluated the left ventricular ejection fraction (LVEF) during alpha interferon therapy (3 MU administered subcutaneously three times a week for 6 months) in 11 patients with chronic viral hepatitis. LVEF was within the normal range in all patients (mean value +/- SD 64.6 +/- 10.7%) before interferon was started, but decreased after 1 month of therapy (mean value +/- SD 59.7 +/- 8.3%) (P = 0.015). An LVEF reduction of more than 10% was observed in five of the 11 patients. Three months after therapy was stopped, nine of the 11 patients showed an LVEF close to the pre-treatment level (mean value +/- SD 62.1 +/- 8.3%). In our patients with chronic C hepatitis, low subcutaneous doses of interferon alpha often decreased the LVEF. It is not clear whether this finding is due to the direct effect of interferon on cardiac cells, or to the peripheral vascular effects of the drug. As LVEF reduction could be critical in patients with previously reduced myocardial contractility, our results further highlight the need for careful cardiac analysis before starting interferon therapy.

A comparison of two GM-CSF schedules to counteract the granulo-monocytopenia of carboplatin-etoposide chemotherapy.

In order to obtain the beneficial effects from granulocyte-macrophage colony-stimulating factor (GM-CSF) on granulo-monocyte recovery with the minimum dose and toxicity, we compared the effect of two different GM-CSF schedules (5 micrograms/kg/day subcutaneously, days 5 to > 18 versus days 12 to > 18 on the cytopenias which follow cytostatic treatment with carboplatin (400 mg/m2 intravenous (i.v.) day 1) and etoposide (100 mg/m2 i.v. days 1 to > 3). 13 patients entered the study for a total of 36 evaluable cycles. The cytostatic treatment produced a neutropenia that persisted for up to day 22 (absolute neutrophil count (ANC) < 1000/microliters in 25% and ANC < 2000 in 50% of control cycles). Early GM-CSF administration markedly increased the leucocyte nadir and produced two waves of leucocytosis: an early one, linked to marrow reserve release and presumably of no value to the patients; and a delayed one, due to marrow precursor and progenitor cell proliferation, in which the granulomonocytosis was associated with a marked eosinophilia. The delayed GM-CSF administration markedly increased the leucocyte nadir and accelerated granulo-monocyte recovery (with an only modest eosinophilia), so that chemotherapy could be repeated every 21 days in all the patients.

[A sustained response in chronic hepatitis C treated with interferon]. / La risposta sostenuta nella epatite cronica C trattata con interferone.

We analyzed 27 subjects with long-term response, from a group of 110 interferon treated patients with biopsy-proven chronic hepatitis and serum anti-HCV antibodies. The following variables were assessed as potential predictors: sex, age, ALT level before the therapy was started, liver structure, type of interferon, total amount of interferon. Total amount of administered interferon statistically correlated with long-term response by univariate analysis. Nevertheless upon stepwise logistic multivariate analysis none of them was independently predictive of long-term response. Additional studies would be needed in order to develop a model capable of predicting from pre-treatment features which patients are likely to have long-term response.