Fabrizio Bar

Hyperdynamic circulation in patients with cirrhosis: direct measurement of nitric oxide levels in hepatic and portal veins

BACKGROUND/AIMS Peripheral vasodilation represents the main vascular dysfunction associated with the hyperdynamic circulation of liver cirrhosis. This study was intended to measure directly regional and systemic levels of nitric oxide, a potent vasorelaxing mediator, in order to assess its role in the development of hemodynamic changes of cirrhosis. METHODS We compared nitric oxide levels in the splanchinic and systemic circulation of 25 patients with cirrhosis undergoing transjugular intrahepatic portosystemic stent shunt and in the hepatic vein and peripheral blood of 10 patients without cirrhosis submitted to venous catheterization. Nitric oxide levels were measured through electron paramagnetic resonance spectroscopy as nitrosylhemoglobin complexes. RESULTS Significantly higher nitric oxide levels were calculated in patients with cirrhosis with respect to controls, both in the peripheral and hepatic veins. In patients with cirrhosis, nitric oxide levels in the portal vein (3.44 +/- 2.17, expressed in arbitrary units) were higher than in the systemic circulation (1.89 +/- 1.15), but lower than in the hepatic vein (4.75 +/- 2.53; p < 0.001 by variance analysis). CONCLUSIONS These data suggest that nitric oxide synthetic pathway activity as well as nitric oxide release are enhanced at the level of splanchnic vasculature and, more important, in the hepatic tissue, confirming evidence of the predominant role of nitric oxide in the pathogenesis of hemodynamic changes in patients with cirrhosis with portal hypertension.

Evaluation of Hepatic Function in Liver Cirrhosis Clinical Utility of Galactose Elimination Capacity, Hepatic Clearance of D-Sorbitol, and Laboratory Investigations

Assessment of hepatic function is based on bothliver blood tests and functional tests, the extensiveapplication of which is still controversial. The aim ofthis study was to evaluate the clinical utility of a few selected tests as discriminatory andprognostic indexes: serum albumin, pseudocholinesterase,prothrombin time, as well as galactose eliminationcapacity and hepatic sorbitol clearance. Two separate studies were performed: Study I to investigatehow well these tests assessed severity, and Study II toevaluate their prognostic value. A total of 128consecutive cirrhotic patients classified according to the Child-Pugh score were included in StudyI; Study II was carried out on 47 of these 128 during atwo-year follow-up period. Pairwise correlations betweenall tests and Child-Pugh score yielded higher significant values for liver blood tests thanfor the functional ones. In Study I functional testssuch as galactose elimination capacity and hepaticsorbitol clearance did not appear to be better than conventional biochemical tests indiscriminating clinical severity of cirrhotic patients,as defined by Child-Pugh classification. Results ofStudy II confirmed that in severe liver cirrhosisChildPugh score remains the best method for medium- andlong-term prognosis and for planning livertransplantation. Functional tests should be reserved fordefining the residual functioning liver mass or forstudies about functional liver plasma flow.

Evidence of an increased nitric oxide production in primary biliary cirrhosis.

OBJECTIVE:Although possible implications of nitric oxide in the pathophysiology of liver cirrhosis have been extensively studied, until now few articles have addressed the assessment of nitric oxide production in primary biliary cirrhosis. This study was directed to evaluate circulating nitrosyl-hemoglobin levels as well as neutrophil elastase and soluble adhesion molecule concentrations in this condition, by assuming these parameters as possible markers of either inflammatory response or neutrophil activation.METHODS:Laboratory investigations were performed in 30 patients with primary biliary cirrhosis, in 13 patients with postviral and/or alcoholic cirrhosis, and in a group of eight subjects with chronic hepatitis.RESULTS:Although no difference was detected with respect to chronic hepatitis subjects, higher levels of nitrosyl-hemoglobin adducts were found in primary biliary cirrhosis patients than in postviral or alcoholic cirrhotics and in normal subjects (3.55 ± 1.75 arbitrary units vs 1.95 ± 0.57 and 0.84 ± 0.34, p = 0.0004 and p < 0.0001, respectively). Similarly, more elevated concentrations of neutrophil elastase (213.7 ± 192.0 μg/L vs 51.1 ± 34.3 and 38.0 ± 11.5, p < 0.0001 and p < 0.0001, respectively) as well as of soluble forms of intercellular adhesion molecule 1 and endothelial-leukocyte adhesion molecule 1 were shown in primary biliary cirrhosis patients than in subjects with cirrhosis of other etiologies and in controls.CONCLUSIONS:Highly enhanced nitric oxide production in primary biliary cirrhosis could be related to the development of strong inflammation and at least partially to neutrophil activation, thus suggesting a putative role of these cellular mediators in the development of liver damage owing to their ability to synthesize and release a wide variety of important factors, including elastase and nitric oxide.

Nitric oxide level profile in human liver transplantation

The aim of this study was to monitor nitric oxide blood levels at various times intraoperatively and following liver transplantation in humans. Nitric oxide production was assessed directly as circulating nitrosyl-hemoglobin adducts by electron paramagnetic resonance spectroscopy in 22 patients undergoing orthotopic liver transplantation. Two significant peaks in nitrosyl-hemoglobin levels were detected at 5 and 60 min after reperfusion (5.02 ± 3.33 arbitrary units and 5.75 ± 4.19, respectively, vs 3.33 ± 2.28 under basal state; P < 0.05 for both comparisons). Postoperative nitrosyl-hemoglobin levels remained elevated, up to 5.42 ± 0.89 arbitrary units (P < 0.05 vs basal values). Neither soluble intercellular adhesion molecule- 1 or soluble endothelial-leukocyte adhesion molecule concentrations were altered intraoperatively. Only the former was significantly raised after transplantation. Neutrophil elastase levels showed an early increase and remained high throughout surgery, returning to basal values after transplantation. No correlations were found among studied parameters. These data suggest that nitric oxide may play a role in ischemia–reperfusion phases in human liver transplantation. Mechanisms other than leukocyte-endothelial adhesion and neutrophil activation seem to affect nitric oxide production under these conditions.

Hepatic arterial infusion chemotherapy for unresectable confined liver metastases: prediction of systemic toxicity with the application of a scintigraphic and pharmacokinetic approach.

Purpose: The incorrect positioning of the arterial Port-a-Cath or the presence of anatomic or functional hepatic arteriovenous shunting may explain the occurrence of systemic toxicity of hepatic arterial infusion of floxuridine in patients with liver metastases. The aim of our study was to predict the occurrence of systemic toxic effects from this treatment using a scintigraphic and pharmacokinetic approach. Methods: A group of 26 patients were studied. Before treatment, Tc-99m-labelled macroaggregated albumin arterial perfusion scintigraphy was performed to verify the correct positioning of the catheter, to evaluate the percentage of pulmonary uptake of the tracer, reflecting intrahepatic arteriovenous anatomic shunting, and to qualitatively assess the perfusion pattern of the metastases with respect to the normal liver parenchyma (SPECT images). Hepatic arteriovenous functional shunting was assessed through the bioavailability of intraarterially administered D-sorbitol. Treatment was then started and systemic toxic effects were evaluated according to WHO recommendations. Results: No correlation was found between anatomic shunting (≤10% in all patients) and systemic toxicity of treatment. The 9 patients with hypoperfused metastases experienced a significantly lower level of toxic effects (1 low-grade toxicity and 8 no toxicity) than the 17 with hyperperfused metastases (6 high-grade toxicity, 5 low-grade and 6 no toxicity; χ2 = 7.170, P = 0.028). Functional shunting was significantly different in patients with high-grade, low-grade and no toxicity (46.5 ± 19.9%, 15.8 ± 12.7% and 16.5 ± 10.3%, respectively; P<0.001 by analysis of variance). Moreover, functional shunting was significantly greater only in patients with hyperperfused metastases who developed high-grade toxicity. Conclusions: A protocol combining scintigraphic and pharmacokinetic methods is of value in the individual patient in assessing the risk of high-grade systemic toxicity during hepatic arterial infusion of floxuridine. A flow-chart used in our ongoing prospective study for the evaluation of patients undergoing regional chemotherapy for liver metastases is included.

Sorbitol removal by the metastatic liver: a predictor of systemic toxicity of intra-arterial chemotherapy in patients with liver metastases

BACKGROUND/AIM Hepatic arteriovenous shunting in the metastatic liver reduces the advantages of intraarterial infusion of chemotherapeutic agents because of the passage of drugs into the systemic circulation. The aim of this study was to quantitatively assess spontaneous functional hepatic arteriovenous shunting in patients with liver metastases and to determine its implication in the increase in systemic toxic effects of intra-arterial infusion chemotherapy with floxuridine. METHODS Twenty-five patients who underwent implantation of arterial ports for regional chemotherapy of liver metastases were studied. Functional hepatic arterio-venous shunting was evaluated through the bioavailability of intra-arterially administered D-sorbitol, a safe, natural compound whose kinetic features make its hepatic clearance flow dependent. In addition, D-sorbitol hepatic clearance (a parameter reflecting functional liver blood flow) and common liver function tests were evaluated for each studied patient. Patients were then grouped with respect to the percentage of medically-assessed liver occupation by metastases and with respect to systemic toxicity of the chemotherapeutic treatment. Both univariate and multivariate analyses by Students t-test and stepwise logistic regression, respectively, were performed in both groups for each of the evaluated parameters (age, liver function tests, D-sorbitol hepatic clearance and arterial bioavailability). RESULTS Arterial bioavailability of D-sorbitol ranged between 0.05 and 0.72 and was significantly greater in patients with more than 50% liver occupation (0.39+/-0.19) compared with those with minor liver involvement (0.17+/-0.13; p = 0.003); it was also significantly greater in patients experiencing high-grade systemic toxicity (0.40+/-0.19) compared with those with low-grade toxicity (0.16+/-0.11; p<0.001). Multivariate analysis showed that arterial bioavailability of D-sorbitol was the only parameter among those evaluated which was able to predict systemic toxicity of this kind of chemotherapy. CONCLUSIONS Our results show that, in the metastatic liver, arterial bioavailability of D-sorbitol, an index of functional arteriovenous shunting, varies widely, is significantly greater in patients with massive liver occupation and it is a good predictor of systemic toxicity of intra-arterial regional chemotherapy with floxuridine.

Arterial-venous shunting in liver cirrhosis

Controversial data exist in the literature aboutthe presence and clinical relevance of hepaticarterial-venous shunting. An interesting opportunity forreconsidering the problem has been provided by the use, in the study of liver function, ofD-sorbitol, a substance whose first-pass hepaticextraction is very high in normal subjects, while beingdirectly related to circulatory alterations in livercirrhosis. Because of this property, the systemicbioavailability of D-sorbitol during hepatic arterialinfusion can be assumed to reflect arterial-venousshunting. Thirteen biopsy-proven cirrhotic patients(ages 35- 66 years), who required diagnostic arterialcatheterization, entered the study. Patients werestudied on two subsequent days, in which a sterilepyrogen-free solution (1.5%) of D-sorbitol wasadministered by direct low-rate infusion (15 mg/min for 20min) into the hepatic artery and the systemiccirculation, respectively. Urine samples werespontaneously collected for 8-hr periods before andduring/after each infusion. The hepatic arterialbioavailability of D-sorbitol was calculated as theratio between the net cumulative urinary outputs ofD-sorbitol after infusions into the hepatic artery andthe systemic vein. Observed values confirm the existence andthe large variability (0-88.7%) of hepaticarterial-venous shunting in cirrhoticpatients.

Primary leiomyosarcoma of the diaphragm in a 23-year-old male: a case report.

Primary neoplasms of the diaphragm are extremely rare and their diagnosis is often difficult. We present a case of leiomyosarcoma of the diaphragm in a 23-year-old male presenting with aspecific abdominal discomfort. The final diagnosis was achieved on the basis of histopathological findings after surgery. The role of different imaging techniques as diagnostic tools is also discussed.

Prediction by mathematical simulation of different pathophysiological effects on d-sorbitol bioavailability

In this study a mathematical model was applied to predict how changes in hepatic extraction ratio (E), fractional portal inflow (P) and renal elimination ratio (R) may affect fractional D-sorbitol bioavailability in cirrhotic patients. D-sorbitol bioavailability was computed as the ratio between cumulative urinary outputs measured after infusion into the superior mesenteric (Uma) or the hepatic artery (Uha) and a systemic vein (Usv). The present work was aimed at explaining by mathematical simulation the very large difference observed in the regression lines when plotting Uma or Uha against Usv values. The study was performed by considering a pathophysiological model of the hepatic circulation and simulating independent variations of the above considered parameters or assuming particular pathophysiological conditions like hepatic arterialization and hepatofugal flow. Computational results account for the wide dispersion of experimental data obtained in previous studies and provide reasonable explanations of unexpected findings.

Original contributionEvidence of an increased nitric oxide production in primary biliary cirrhosis

Abstract OBJECTIVE: Although possible implications of nitric oxide in the pathophysiology of liver cirrhosis have been extensively studied, until now few articles have addressed the assessment of nitric oxide production in primary biliary cirrhosis. This study was directed to evaluate circulating nitrosyl-hemoglobin levels as well as neutrophil elastase and soluble adhesion molecule concentrations in this condition, by assuming these parameters as possible markers of either inflammatory response or neutrophil activation. METHODS: Laboratory investigations were performed in 30 patients with primary biliary cirrhosis, in 13 patients with postviral and/or alcoholic cirrhosis, and in a group of eight subjects with chronic hepatitis. RESULTS: Although no difference was detected with respect to chronic hepatitis subjects, higher levels of nitrosyl-hemoglobin adducts were found in primary biliary cirrhosis patients than in postviral or alcoholic cirrhotics and in normal subjects (3.55 ± 1.75 arbitrary units vs 1.95 ± 0.57 and 0.84 ± 0.34, p = 0.0004 and p CONCLUSIONS: Highly enhanced nitric oxide production in primary biliary cirrhosis could be related to the development of strong inflammation and at least partially to neutrophil activation, thus suggesting a putative role of these cellular mediators in the development of liver damage owing to their ability to synthesize and release a wide variety of important factors, including elastase and nitric oxide.