The study aimed to define the prevalence, char- actenstics, and clinical importance of nutritiona... more The study aimed to define the prevalence, char- actenstics, and clinical importance of nutritional disorders in pa- tients with liver cirrhosis. Nutritional status was evaluated in 120 hospitalized patients-77 with alcoholic and 43 with virus-related cirrhosis-by anthropometric, visceral, and immunologic mea- surements. Energy malnutrition, defined as triceps skinfold thick- ness (TSF) and/or midarm muscle circumference (MAMC) below the 5th percentile
Background/aims—The purpose of this study was to better define the long term prognosis of infecti... more Background/aims—The purpose of this study was to better define the long term prognosis of infection and disease in chil- dren with chronic hepatitis B treated with interferon (IFN) alpha. Patients—A total of 107 children with chronic hepatitis B who received IFN alpha for three or six months in two clini- cal trials were followed for a mean period of 69
BACKGROUND/AIMSThe purpose of this study was to better define the long term prognosis of infectio... more BACKGROUND/AIMSThe purpose of this study was to better define the long term prognosis of infection and disease in children with chronic hepatitis B treated with interferon (IFN) alpha.PATIENTSA total of 107 children with chronic hepatitis B who received IFN alpha for three or six months in two clinical trials were followed for a mean period of 69 (17) months. Response
World journal of gastroenterology : WJG, Jan 14, 2014
To investigate the agreement and prognostic value of different measures of covert hepatic encepha... more To investigate the agreement and prognostic value of different measures of covert hepatic encephalopathy (CHE). One-hundred-and-thirty-two cirrhotic outpatients underwent electroencephalography (EEG), paper-and-pencil psychometry (PHES) and critical flicker frequency, scored on the original/modified (CFFo/CFFm) thresholds. Eighty-four patients underwent Doppler-ultrasound to diagnose/exclude portal-systemic shunt. Seventy-nine were followed-up for 11 ± 7 mo in relation to the occurrence of hepatic encephalopathy (HE)-related hospitalisations. On the day of study, 36% had grade I HE, 42% abnormal EEG, 33% abnormal PHES and 31/21% abnormal CFFo/CFFm. Significant associations were observed between combinations of test abnormalities; however, agreement was poor (Cohen's κ < 0.4). The prevalence of EEG, PHES and CFFo/CFFm abnormalities was significantly higher in patients with grade I overt HE. The prevalence of EEG and CFFm abnormalities was higher in patients with shunt. The pre...
Pathogenetic mechanisms of hepatocellular carcinoma (HCC) are still unclear and new tools for dia... more Pathogenetic mechanisms of hepatocellular carcinoma (HCC) are still unclear and new tools for diagnostic and therapeutic purposes are ongoing. We have assessed whether squamous cell carcinoma antigen (SCCA), a serpin overexpressed in neoplastic cells of epithelial origin, is also expressed in liver cancer. Squamous cell carcinoma antigen was evaluated by immunohistochemistry in 65 HCCs of different aetiology and in 20 normal livers. Proliferative activity was assessed using MIB-1 antibody. In 18 surgical samples, tumour and nontumour liver tissue was available for SCCA cDNA amplification and sequencing. Squamous cell carcinoma antigen was detected in 55 out of 65 (85%) tumour specimens, but in none of the 20 controls. In the majority of the cases, the positive signal was found in the cytoplasm of more than 50% of the hepatocytes. Low or undetectable SCCA (score<or=1) was associated to lower MIB-1 labelling index, compared to cases with SCCA score >or=2 (mean+/-s.d.: 2%+/-2.4 v...
Psychometric performance has been reported to be related to brain atrophy in cirrhotics, but the ... more Psychometric performance has been reported to be related to brain atrophy in cirrhotics, but the relationship between brain atrophy and EEG findings is still unknown. The aim of this study was to ascertain the relationship among brain atrophy, EEG, and cognitive performance in cirrhotics. Sixty-eight cirrhotics (age = 55 +/- 10 years; males-66%) underwent psychometric evaluation (Symbol Digit Test, Trail Making Test-Part A, Scan test), EEG recording and spectral analysis (S-EEG), and brain CT scan. Central brain atrophy was ascertained by the following indexes of brain atrophy: the Evans' index, the bicaudate index, the cella media index, the bifrontal index, and the ventricular index; cortical brain atrophy by the sulci index. The severity of liver failure was assessed by the Child-Pugh score: 18% of patients were Child-Pugh Class A, 50% Class B, and 32% Class C. Central and cortical atrophies were found to be correlated with age, but not with the Child-Pugh score. Psychometric...
The role of portal-systemic shunting and portal liver hypoperfusion in the pathophysiology of cen... more The role of portal-systemic shunting and portal liver hypoperfusion in the pathophysiology of central nervous system dysfunction (CNSD) of cirrhosis is not yet well defined. It is well known that one of the most important collateral vessels (CVs) is a patent paraumbilical vein (PUV), but there is controversy regarding its clinical significance. We have evaluated the relationships between neuropsychological and EEG alterations, ammonia plasma level (NH4), hepatic function, and portal hemodynamics (Doppler Ultrasound) in 95 cirrhotic patients. Patency, diameter, or flow of PUV or the presence of other CVs were not related to an increased prevalence of neuropsychological or EEG abnormalities. Patients with effective portal flow (EPF = portal flow - PUV flow) lower than 692 mL/min (median) had a significantly higher risk of failing the neuropsychological test, or of having an altered EEG. Low EPF and prothrombin time (<50%), and high NH4 (51 micromol/L) were independent predictors of...
It is not yet clear if benzodiazepine receptor ligands, implicated in the pathophysiology of hepa... more It is not yet clear if benzodiazepine receptor ligands, implicated in the pathophysiology of hepatic coma, also have a role in subclinical cognitive or neurophysiological alterations in cirrhotic patients. Therefore, we carried out a double-blind, placebo-controlled study to evaluate the effectiveness of flumazenil, a benzodiazepine antagonist, on brainstem auditory evoked responses and on the number connection test in cirrhotic patients with subclinical neurophysiological or cognitive alterations. Thirteen cirrhotic subjects with subclinical neurophysiological or cognitive alterations were studied. A total of 3 mg of flumazenil or saline was infused intravenously. Before and after the infusion, the number connection test was administered and brainstem auditory evoked responses recorded. After 72 h, patients were crossed over. Flumazenil did not influence brainstem auditory evoked responses or the number connection test. A screening test for benzodiazepines was negative in all subje...
The effects of iloprost, a stable analog derivative of prostacyclin, on heart rate, blood pressur... more The effects of iloprost, a stable analog derivative of prostacyclin, on heart rate, blood pressure, renal plasma flow (RPF), glomerular filtration rate, filtration fraction, urine flow, fractional excretion of sodium (FEN.), proximal fractional sodium reabsorption (PFRN,), fractional sodium resorption at the ascending limb of Henle's loop (HFRN,), plasma renin activity (PRA), and plasma aldosterone concentration (PA) were evaluated in patients with peripheral vascular disease and normal renal function. In 10 patients the drug was administered intravenously for 6 hours daily for 6 days at a rate of 1 ng/kg/min In 7 patients iloprost was also administered at a dose of 2 ng/kg/min for the same time. There was no significant change in heart rate and blood pressure at both iloprost doses. At the dose of 1 ng/kg/min the drug had no effect on renal hemodynamics and function, PRA, and PA. At the dose of 2 ng/kg/ min iloprost significantly increased RPF (p < 0.025) and FEN, < 0.025) and significantly decreased HFRN. (p < 0.025) without affecting glomerular filtration rate, filtration fraction, urine flow, PFRN., PRA, and PA. No correlation was found between the increase in RPF and FEN, (r = 0.01). We conclude that at a dose of 2 ng/kg/min, but not 1 ng/kg/min, iloprost has a natriuretic effect secondary to inhibition of sodium reabsorption at the ascending limb of the Henle's loop and not related to the renal hemodynamic effect. (PGI,), an arachidonic acid metabolite, has vasodilatory, cytoprotective, and antiplatelet activities. The hemodynamic effects of intravenous infusion of PGI2 include a decrease in both peripheral and pulmonary vascular resistances, with consequent drop in arterial blood pressure, and increase in heart rate and cardiac output." Despite conflicting data,' it is generally accepted that intravenous or intraarterial infusion of PGI2 increases renal plasma flow (RPF) with a redistribution of the flow toward the inner cortex. This effect is not accompanied by any change in glomerular filtration rate (GFR), whereas urinary sodium and water excretion is increased.5-7 Moreover, PGI, infusion stim-
The possibility of estimating portal hypertension combining splenic Doppler pulsatility index (PI... more The possibility of estimating portal hypertension combining splenic Doppler pulsatility index (PI), which has been shown strictly to be related to portal resistance, and portal blood flow (PBF) was evaluated. Hepatic venous pressure gradient, and splanchnic Doppler parameters were measured in 40 cirrhotic patients. A formula to assess the severity of portal hypertension from Doppler parameters was calculated in a training group of 19 patients, and then this formula was tested to prospectively predict the degree of portal pressure in 21 further patients. In the training group, the regression of portal resistance over splenic PI was calculated and individual values of estimated portal resistance were obtained for every patient of the test group. From them and from observed values of PBF, an estimated value of portal pressure was calculated. The following formula was obtained [(0.066*splenic PI -0.044)*PBF]. In the second group, predicted and observed portal pressure were well correlated (r = 0.71, p = .0003). A good accuracy for the prediction of mild or severe portal hypertension was obtained.
Portal hypertension is a clinical syndrome which leads to several clinical complications, such as... more Portal hypertension is a clinical syndrome which leads to several clinical complications, such as the formation and rupture of esophageal and/or gastric varices, ascites, hepatic encephalopathy and hepato-renal syndrome. In cirrhosis, the primary cause of the increase in portal pressure is the enhanced resistance to portal outflow. However, also an increase in splanchnic blood flow worsens and maintains portal hypertension. The vasodilatation of arterial splanchnic vessels and the opening of collateral circulation are the determinants of the increased splanchnic blood flow. Several vasoactive systems/substances, such as nitric oxide, cyclooxygenase-derivatives, carbon monoxide and endogenous cannabinoids are activated in portal hypertension and are responsible for the marked splanchnic vasodilatation. Moreover, an impaired reactivity to vasoconstrictor systems, such as the sympathetic nervous system, vasopressin, angiotensin II and endothelin-1, plays a role in this process. The opening of collateral circulation occurs through the reperfusion and dilatation of preexisting vessels, but also through the generation of new vessels. Splanchnic vasodilatation leads to the onset of the hyperdynamic circulatory syndrome, a syndrome which occurs in patients with portal hypertension and is characterized by increased cardiac output and heart rate, and decreased systemic vascular resistance with low arterial blood pressure. Understanding the pathophysiology of splanchnic vasodilatation and hyperdynamic circulatory syndrome is mandatory for the prevention and treatment of portal hypertension and its severe complications.
Introduction: Sleep-wake disturbances are common in hospitalized patients but few studies have as... more Introduction: Sleep-wake disturbances are common in hospitalized patients but few studies have assessed them systematically. The aim of the present study was to assess sleep quality in a group of medical inpatients, in relation to environmental factors, and the switch to daylight-saving time.
Clinical Cases in Mineral and Bone Metabolism, 2014
Metabolic disturbances of bone are frequent in patients with chronic liver disease. The prevalenc... more Metabolic disturbances of bone are frequent in patients with chronic liver disease. The prevalence of osteoporosis among patients with advanced chronic liver disease is reported between 12% and 55%; it is higher in primary biliary cirrhosis. All patients with advanced liver disease should be screened for osteoporosis with a densitometry, especially if the etiology is cholestatic and in the presence of other risk factors. Clinical relevance of hepatic osteodystrophy increases after liver transplantation. After liver transplant, a rapid loss of bone mineral density can be detected in the first 6 months, followed by stabilization and slight improvement of the values. At the time of transplantation, bone density values are very important prognostic factors. Therapy of hepatic osteodystrophy is based primarily on the control of risk factors: cessation of tobacco and alcohol assumption, reduction of caffeine ingestion, exercise, supplementation of calcium and vitamin D, limitation of drugs such as loop diuretics, corticosteroids, cholestyramine. Bisphosphonates have been proposed for the therapy of osteoporosis in patients with liver disease, particularly after liver transplantation. The possible side effects of oral administration of bisphosphonates, such as the occurrence of esophageal ulcerations, are of particular concern in patients with liver cirrhosis and portal hypertension, due to the risk of gastrointestinal hemorrhage from ruptured esophageal varices, although this risk is probably overestimated.
The physiological roles of the protease inhibitor SERPINB3 (SB3) are still largely unknown. The s... more The physiological roles of the protease inhibitor SERPINB3 (SB3) are still largely unknown. The study was addressed to assess the biological effects of this serpin in vivo using a SB3 transgenic mouse model. Two colonies of mice (123 transgenic for SB3 and 148 C57BL/6J controls) have been studied. Transgenic (TG) mice showed longer survival than controls and the difference was more remarkable in males than in females (18.5% vs 12.7% life span increase). In TG mice decreased IL-6 in serum and lower p66shc in the liver were observed. In addition, TG males showed higher expression of mTOR in the liver. Liver histology showed age-dependent increase of steatosis and decrease of glycogen storage in both groups and none of the animals developed neoplastic lesions. In conclusion, the gain in life span observed in SB3-transgenic mice could be determined by multiple mechanisms, including the decrease of circulating IL-6 and the modulation of ageing genes in the liver.
Journal of Clinical and Experimental Hepatology, 2014
The Mini-Mental State Examination (MMSE) has been utilized for the diagnosis of hepatic encephalo... more The Mini-Mental State Examination (MMSE) has been utilized for the diagnosis of hepatic encephalopathy (HE). However, its threshold of abnormality has not been formally tested in patients with cirrhosis and its diagnostic/prognostic validity remains unknown. The aim of this study was to assess it in a large group of well-characterized outpatients with cirrhosis and no overt HE. One-hundred-and-ninety-one patients underwent clinical assessment, MMSE, electroencephalography (EEG) and paper-and-pencil psychometry (PHES); 117 were followed up for 8 ± 5 months in relation to the occurrence of HE-related hospitalizations. On the day of study, 81 patients (42%) had abnormal EEG and 67 (35%) abnormal PHES; 103 (60%) had a history of HE. Average MMSE was 26.6 ± 3.5; 22 (19%) patients had abnormal MMSE based on the standard threshold of 24. Patients with abnormal EEG/PHES/history of HE had worse MMSE performance than their counterparts with normal tests/negative history (25.7 ± 4.2 vs. 27.3 ± 2.7; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01; 25.5 ± 3.2 vs. 27.9 ± 1.8, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001; 26.3 ± 3.7 vs. 27.4 ± 2.6, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05, respectively). Based on the above results, MMSE thresholds of 26 and 27 were tested against abnormalities in clinical/EEG/PHES indices and significant associations were observed. An MMSE threshold of 26 was also a predictor of HE-related hospitalization (Cox-Mantel: P = 0.001); patients with MMSE &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;26 were significantly older than those with MMSE ≥26 but comparable in terms of liver dysfunction and ammonia levels. When MMSE items were considered separately, those which correlated most significantly with standard HE indices where spatial orientation and writing. In conclusion, an MMSE &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;26 identifies older patients with cirrhosis who are more prone to manifest HE signs.
Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortalit... more Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the reversal of HRS. Where terlipressin is not available, as in the United States, midodrine and octreotide with albumin are used as an alternative treatment of HRS. The aim was to compare the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in a randomized controlled trial. Twenty-seven patients were randomized to receive terlipressin with albumin (TERLI group) and 22 to receive midodrine and octreotide plus albumin (MID/OCT group). The TERLI group received terlipressin by intravenous infusion, initially 3 mg/24 hours, progressively increased to 12 mg/24 hours if there was no response. The MID/OCT group received midodrine orally at an initial dose of 7.5 mg thrice daily, with the dose increased to a maximum of 12.5 mg thrice daily, together with octreotide subcutaneously: initial dose 100 μg thrice daily and up to 200 μg thrice daily. Both groups received albumin intravenously 1 g/kg of body weight on day 1 and 20-40 g/day thereafter. There was a significantly higher rate of recovery of renal function in the TERLI group (19/27, 70.4%) compared to the MID/OCT group (6/21, 28.6%), P = 0.01. Improvement in renal function and lower baseline Model for End-Stage Liver Disease score were associated with better survival. Conclusion: Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS (Hepatology 2015).
Angeli P, Ferna´ndez-Varo G, Dalla Libera V, Fasolato S, Galioto A, Arroyo V, Sticca A, Guarda S,... more Angeli P, Ferna´ndez-Varo G, Dalla Libera V, Fasolato S, Galioto A, Arroyo V, Sticca A, Guarda S, Gatta A, Jime´nez W. The role of nitric oxide in the pathogenesis of systemic and splanchnic vasodilation in cirrhotic rats before and after the onset of ascites. Liver International 2005: 25: 429-437. r Blackwell Munksgaard 2005
To evaluate the most cost-effectiveness strategy for preventing variceal growth and bleeding in p... more To evaluate the most cost-effectiveness strategy for preventing variceal growth and bleeding in patients with cirrhosis and small esophageal varices. A stochastic analysis based on decision trees was performed to compare the cost-effectiveness of beta-blockers therapy starting from a diagnosis of small varices (Strategy 1) with that of endoscopic surveillance followed by beta-blockers treatment when large varices are demonstrated (Strategy 2), for preventing variceal growth, bleeding and death in patients with cirrhosis and small esophageal varices. The basic nodes of the tree were gastrointestinal endoscopy, inpatient admission and treatment for bleeding, as required. All estimates were performed using a Monte Carlo microsimulation technique, consisting in simulating observations from known probability distributions depicted in the model. Eight-hundred-thousand simulations were performed to obtain the final estimates. All estimates were then subjected to Monte Carlo Probabilistic sensitivity analysis, to assess the impact of the variability of such estimates on the outcome distributions. The event rate (considered as progression of varices or bleeding or death) in Strategy 1 [24.09% (95%CI: 14.89%-33.29%)] was significantly lower than in Strategy 2 [60.00% (95%CI: 48.91%-71.08%)]. The mean cost (up to the first event) associated with Strategy 1 [823 £ (95%CI: 106 £-2036 £)] was not significantly different from that of Strategy 2 [799 £ (95%CI: 0 £-3498 £)]. The cost-effectiveness ratio with respect to this endpoint was equal to 50.26 £ (95%CI: -504.37 £-604.89 £) per event avoided over the four-year follow-up. When bleeding episodes/deaths in subjects whose varices had grown were included, the mean cost associated with Strategy 1 was 1028 £ (95%CI: 122 £-2581 £), while 1699 £ (95%CI: 171 £-4674 £) in Strategy 2. Beta-blocker therapy turn out to be more effective and less expensive than endoscopic surveillance for primary prophylaxis of bleeding in patients with cirrhosis and small varices.
The study aimed to define the prevalence, char- actenstics, and clinical importance of nutritiona... more The study aimed to define the prevalence, char- actenstics, and clinical importance of nutritional disorders in pa- tients with liver cirrhosis. Nutritional status was evaluated in 120 hospitalized patients-77 with alcoholic and 43 with virus-related cirrhosis-by anthropometric, visceral, and immunologic mea- surements. Energy malnutrition, defined as triceps skinfold thick- ness (TSF) and/or midarm muscle circumference (MAMC) below the 5th percentile
Background/aims—The purpose of this study was to better define the long term prognosis of infecti... more Background/aims—The purpose of this study was to better define the long term prognosis of infection and disease in chil- dren with chronic hepatitis B treated with interferon (IFN) alpha. Patients—A total of 107 children with chronic hepatitis B who received IFN alpha for three or six months in two clini- cal trials were followed for a mean period of 69
BACKGROUND/AIMSThe purpose of this study was to better define the long term prognosis of infectio... more BACKGROUND/AIMSThe purpose of this study was to better define the long term prognosis of infection and disease in children with chronic hepatitis B treated with interferon (IFN) alpha.PATIENTSA total of 107 children with chronic hepatitis B who received IFN alpha for three or six months in two clinical trials were followed for a mean period of 69 (17) months. Response
World journal of gastroenterology : WJG, Jan 14, 2014
To investigate the agreement and prognostic value of different measures of covert hepatic encepha... more To investigate the agreement and prognostic value of different measures of covert hepatic encephalopathy (CHE). One-hundred-and-thirty-two cirrhotic outpatients underwent electroencephalography (EEG), paper-and-pencil psychometry (PHES) and critical flicker frequency, scored on the original/modified (CFFo/CFFm) thresholds. Eighty-four patients underwent Doppler-ultrasound to diagnose/exclude portal-systemic shunt. Seventy-nine were followed-up for 11 ± 7 mo in relation to the occurrence of hepatic encephalopathy (HE)-related hospitalisations. On the day of study, 36% had grade I HE, 42% abnormal EEG, 33% abnormal PHES and 31/21% abnormal CFFo/CFFm. Significant associations were observed between combinations of test abnormalities; however, agreement was poor (Cohen's κ < 0.4). The prevalence of EEG, PHES and CFFo/CFFm abnormalities was significantly higher in patients with grade I overt HE. The prevalence of EEG and CFFm abnormalities was higher in patients with shunt. The pre...
Pathogenetic mechanisms of hepatocellular carcinoma (HCC) are still unclear and new tools for dia... more Pathogenetic mechanisms of hepatocellular carcinoma (HCC) are still unclear and new tools for diagnostic and therapeutic purposes are ongoing. We have assessed whether squamous cell carcinoma antigen (SCCA), a serpin overexpressed in neoplastic cells of epithelial origin, is also expressed in liver cancer. Squamous cell carcinoma antigen was evaluated by immunohistochemistry in 65 HCCs of different aetiology and in 20 normal livers. Proliferative activity was assessed using MIB-1 antibody. In 18 surgical samples, tumour and nontumour liver tissue was available for SCCA cDNA amplification and sequencing. Squamous cell carcinoma antigen was detected in 55 out of 65 (85%) tumour specimens, but in none of the 20 controls. In the majority of the cases, the positive signal was found in the cytoplasm of more than 50% of the hepatocytes. Low or undetectable SCCA (score<or=1) was associated to lower MIB-1 labelling index, compared to cases with SCCA score >or=2 (mean+/-s.d.: 2%+/-2.4 v...
Psychometric performance has been reported to be related to brain atrophy in cirrhotics, but the ... more Psychometric performance has been reported to be related to brain atrophy in cirrhotics, but the relationship between brain atrophy and EEG findings is still unknown. The aim of this study was to ascertain the relationship among brain atrophy, EEG, and cognitive performance in cirrhotics. Sixty-eight cirrhotics (age = 55 +/- 10 years; males-66%) underwent psychometric evaluation (Symbol Digit Test, Trail Making Test-Part A, Scan test), EEG recording and spectral analysis (S-EEG), and brain CT scan. Central brain atrophy was ascertained by the following indexes of brain atrophy: the Evans' index, the bicaudate index, the cella media index, the bifrontal index, and the ventricular index; cortical brain atrophy by the sulci index. The severity of liver failure was assessed by the Child-Pugh score: 18% of patients were Child-Pugh Class A, 50% Class B, and 32% Class C. Central and cortical atrophies were found to be correlated with age, but not with the Child-Pugh score. Psychometric...
The role of portal-systemic shunting and portal liver hypoperfusion in the pathophysiology of cen... more The role of portal-systemic shunting and portal liver hypoperfusion in the pathophysiology of central nervous system dysfunction (CNSD) of cirrhosis is not yet well defined. It is well known that one of the most important collateral vessels (CVs) is a patent paraumbilical vein (PUV), but there is controversy regarding its clinical significance. We have evaluated the relationships between neuropsychological and EEG alterations, ammonia plasma level (NH4), hepatic function, and portal hemodynamics (Doppler Ultrasound) in 95 cirrhotic patients. Patency, diameter, or flow of PUV or the presence of other CVs were not related to an increased prevalence of neuropsychological or EEG abnormalities. Patients with effective portal flow (EPF = portal flow - PUV flow) lower than 692 mL/min (median) had a significantly higher risk of failing the neuropsychological test, or of having an altered EEG. Low EPF and prothrombin time (<50%), and high NH4 (51 micromol/L) were independent predictors of...
It is not yet clear if benzodiazepine receptor ligands, implicated in the pathophysiology of hepa... more It is not yet clear if benzodiazepine receptor ligands, implicated in the pathophysiology of hepatic coma, also have a role in subclinical cognitive or neurophysiological alterations in cirrhotic patients. Therefore, we carried out a double-blind, placebo-controlled study to evaluate the effectiveness of flumazenil, a benzodiazepine antagonist, on brainstem auditory evoked responses and on the number connection test in cirrhotic patients with subclinical neurophysiological or cognitive alterations. Thirteen cirrhotic subjects with subclinical neurophysiological or cognitive alterations were studied. A total of 3 mg of flumazenil or saline was infused intravenously. Before and after the infusion, the number connection test was administered and brainstem auditory evoked responses recorded. After 72 h, patients were crossed over. Flumazenil did not influence brainstem auditory evoked responses or the number connection test. A screening test for benzodiazepines was negative in all subje...
The effects of iloprost, a stable analog derivative of prostacyclin, on heart rate, blood pressur... more The effects of iloprost, a stable analog derivative of prostacyclin, on heart rate, blood pressure, renal plasma flow (RPF), glomerular filtration rate, filtration fraction, urine flow, fractional excretion of sodium (FEN.), proximal fractional sodium reabsorption (PFRN,), fractional sodium resorption at the ascending limb of Henle's loop (HFRN,), plasma renin activity (PRA), and plasma aldosterone concentration (PA) were evaluated in patients with peripheral vascular disease and normal renal function. In 10 patients the drug was administered intravenously for 6 hours daily for 6 days at a rate of 1 ng/kg/min In 7 patients iloprost was also administered at a dose of 2 ng/kg/min for the same time. There was no significant change in heart rate and blood pressure at both iloprost doses. At the dose of 1 ng/kg/min the drug had no effect on renal hemodynamics and function, PRA, and PA. At the dose of 2 ng/kg/ min iloprost significantly increased RPF (p < 0.025) and FEN, < 0.025) and significantly decreased HFRN. (p < 0.025) without affecting glomerular filtration rate, filtration fraction, urine flow, PFRN., PRA, and PA. No correlation was found between the increase in RPF and FEN, (r = 0.01). We conclude that at a dose of 2 ng/kg/min, but not 1 ng/kg/min, iloprost has a natriuretic effect secondary to inhibition of sodium reabsorption at the ascending limb of the Henle's loop and not related to the renal hemodynamic effect. (PGI,), an arachidonic acid metabolite, has vasodilatory, cytoprotective, and antiplatelet activities. The hemodynamic effects of intravenous infusion of PGI2 include a decrease in both peripheral and pulmonary vascular resistances, with consequent drop in arterial blood pressure, and increase in heart rate and cardiac output." Despite conflicting data,' it is generally accepted that intravenous or intraarterial infusion of PGI2 increases renal plasma flow (RPF) with a redistribution of the flow toward the inner cortex. This effect is not accompanied by any change in glomerular filtration rate (GFR), whereas urinary sodium and water excretion is increased.5-7 Moreover, PGI, infusion stim-
The possibility of estimating portal hypertension combining splenic Doppler pulsatility index (PI... more The possibility of estimating portal hypertension combining splenic Doppler pulsatility index (PI), which has been shown strictly to be related to portal resistance, and portal blood flow (PBF) was evaluated. Hepatic venous pressure gradient, and splanchnic Doppler parameters were measured in 40 cirrhotic patients. A formula to assess the severity of portal hypertension from Doppler parameters was calculated in a training group of 19 patients, and then this formula was tested to prospectively predict the degree of portal pressure in 21 further patients. In the training group, the regression of portal resistance over splenic PI was calculated and individual values of estimated portal resistance were obtained for every patient of the test group. From them and from observed values of PBF, an estimated value of portal pressure was calculated. The following formula was obtained [(0.066*splenic PI -0.044)*PBF]. In the second group, predicted and observed portal pressure were well correlated (r = 0.71, p = .0003). A good accuracy for the prediction of mild or severe portal hypertension was obtained.
Portal hypertension is a clinical syndrome which leads to several clinical complications, such as... more Portal hypertension is a clinical syndrome which leads to several clinical complications, such as the formation and rupture of esophageal and/or gastric varices, ascites, hepatic encephalopathy and hepato-renal syndrome. In cirrhosis, the primary cause of the increase in portal pressure is the enhanced resistance to portal outflow. However, also an increase in splanchnic blood flow worsens and maintains portal hypertension. The vasodilatation of arterial splanchnic vessels and the opening of collateral circulation are the determinants of the increased splanchnic blood flow. Several vasoactive systems/substances, such as nitric oxide, cyclooxygenase-derivatives, carbon monoxide and endogenous cannabinoids are activated in portal hypertension and are responsible for the marked splanchnic vasodilatation. Moreover, an impaired reactivity to vasoconstrictor systems, such as the sympathetic nervous system, vasopressin, angiotensin II and endothelin-1, plays a role in this process. The opening of collateral circulation occurs through the reperfusion and dilatation of preexisting vessels, but also through the generation of new vessels. Splanchnic vasodilatation leads to the onset of the hyperdynamic circulatory syndrome, a syndrome which occurs in patients with portal hypertension and is characterized by increased cardiac output and heart rate, and decreased systemic vascular resistance with low arterial blood pressure. Understanding the pathophysiology of splanchnic vasodilatation and hyperdynamic circulatory syndrome is mandatory for the prevention and treatment of portal hypertension and its severe complications.
Introduction: Sleep-wake disturbances are common in hospitalized patients but few studies have as... more Introduction: Sleep-wake disturbances are common in hospitalized patients but few studies have assessed them systematically. The aim of the present study was to assess sleep quality in a group of medical inpatients, in relation to environmental factors, and the switch to daylight-saving time.
Clinical Cases in Mineral and Bone Metabolism, 2014
Metabolic disturbances of bone are frequent in patients with chronic liver disease. The prevalenc... more Metabolic disturbances of bone are frequent in patients with chronic liver disease. The prevalence of osteoporosis among patients with advanced chronic liver disease is reported between 12% and 55%; it is higher in primary biliary cirrhosis. All patients with advanced liver disease should be screened for osteoporosis with a densitometry, especially if the etiology is cholestatic and in the presence of other risk factors. Clinical relevance of hepatic osteodystrophy increases after liver transplantation. After liver transplant, a rapid loss of bone mineral density can be detected in the first 6 months, followed by stabilization and slight improvement of the values. At the time of transplantation, bone density values are very important prognostic factors. Therapy of hepatic osteodystrophy is based primarily on the control of risk factors: cessation of tobacco and alcohol assumption, reduction of caffeine ingestion, exercise, supplementation of calcium and vitamin D, limitation of drugs such as loop diuretics, corticosteroids, cholestyramine. Bisphosphonates have been proposed for the therapy of osteoporosis in patients with liver disease, particularly after liver transplantation. The possible side effects of oral administration of bisphosphonates, such as the occurrence of esophageal ulcerations, are of particular concern in patients with liver cirrhosis and portal hypertension, due to the risk of gastrointestinal hemorrhage from ruptured esophageal varices, although this risk is probably overestimated.
The physiological roles of the protease inhibitor SERPINB3 (SB3) are still largely unknown. The s... more The physiological roles of the protease inhibitor SERPINB3 (SB3) are still largely unknown. The study was addressed to assess the biological effects of this serpin in vivo using a SB3 transgenic mouse model. Two colonies of mice (123 transgenic for SB3 and 148 C57BL/6J controls) have been studied. Transgenic (TG) mice showed longer survival than controls and the difference was more remarkable in males than in females (18.5% vs 12.7% life span increase). In TG mice decreased IL-6 in serum and lower p66shc in the liver were observed. In addition, TG males showed higher expression of mTOR in the liver. Liver histology showed age-dependent increase of steatosis and decrease of glycogen storage in both groups and none of the animals developed neoplastic lesions. In conclusion, the gain in life span observed in SB3-transgenic mice could be determined by multiple mechanisms, including the decrease of circulating IL-6 and the modulation of ageing genes in the liver.
Journal of Clinical and Experimental Hepatology, 2014
The Mini-Mental State Examination (MMSE) has been utilized for the diagnosis of hepatic encephalo... more The Mini-Mental State Examination (MMSE) has been utilized for the diagnosis of hepatic encephalopathy (HE). However, its threshold of abnormality has not been formally tested in patients with cirrhosis and its diagnostic/prognostic validity remains unknown. The aim of this study was to assess it in a large group of well-characterized outpatients with cirrhosis and no overt HE. One-hundred-and-ninety-one patients underwent clinical assessment, MMSE, electroencephalography (EEG) and paper-and-pencil psychometry (PHES); 117 were followed up for 8 ± 5 months in relation to the occurrence of HE-related hospitalizations. On the day of study, 81 patients (42%) had abnormal EEG and 67 (35%) abnormal PHES; 103 (60%) had a history of HE. Average MMSE was 26.6 ± 3.5; 22 (19%) patients had abnormal MMSE based on the standard threshold of 24. Patients with abnormal EEG/PHES/history of HE had worse MMSE performance than their counterparts with normal tests/negative history (25.7 ± 4.2 vs. 27.3 ± 2.7; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01; 25.5 ± 3.2 vs. 27.9 ± 1.8, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001; 26.3 ± 3.7 vs. 27.4 ± 2.6, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05, respectively). Based on the above results, MMSE thresholds of 26 and 27 were tested against abnormalities in clinical/EEG/PHES indices and significant associations were observed. An MMSE threshold of 26 was also a predictor of HE-related hospitalization (Cox-Mantel: P = 0.001); patients with MMSE &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;26 were significantly older than those with MMSE ≥26 but comparable in terms of liver dysfunction and ammonia levels. When MMSE items were considered separately, those which correlated most significantly with standard HE indices where spatial orientation and writing. In conclusion, an MMSE &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;26 identifies older patients with cirrhosis who are more prone to manifest HE signs.
Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortalit... more Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the reversal of HRS. Where terlipressin is not available, as in the United States, midodrine and octreotide with albumin are used as an alternative treatment of HRS. The aim was to compare the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in a randomized controlled trial. Twenty-seven patients were randomized to receive terlipressin with albumin (TERLI group) and 22 to receive midodrine and octreotide plus albumin (MID/OCT group). The TERLI group received terlipressin by intravenous infusion, initially 3 mg/24 hours, progressively increased to 12 mg/24 hours if there was no response. The MID/OCT group received midodrine orally at an initial dose of 7.5 mg thrice daily, with the dose increased to a maximum of 12.5 mg thrice daily, together with octreotide subcutaneously: initial dose 100 μg thrice daily and up to 200 μg thrice daily. Both groups received albumin intravenously 1 g/kg of body weight on day 1 and 20-40 g/day thereafter. There was a significantly higher rate of recovery of renal function in the TERLI group (19/27, 70.4%) compared to the MID/OCT group (6/21, 28.6%), P = 0.01. Improvement in renal function and lower baseline Model for End-Stage Liver Disease score were associated with better survival. Conclusion: Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS (Hepatology 2015).
Angeli P, Ferna´ndez-Varo G, Dalla Libera V, Fasolato S, Galioto A, Arroyo V, Sticca A, Guarda S,... more Angeli P, Ferna´ndez-Varo G, Dalla Libera V, Fasolato S, Galioto A, Arroyo V, Sticca A, Guarda S, Gatta A, Jime´nez W. The role of nitric oxide in the pathogenesis of systemic and splanchnic vasodilation in cirrhotic rats before and after the onset of ascites. Liver International 2005: 25: 429-437. r Blackwell Munksgaard 2005
To evaluate the most cost-effectiveness strategy for preventing variceal growth and bleeding in p... more To evaluate the most cost-effectiveness strategy for preventing variceal growth and bleeding in patients with cirrhosis and small esophageal varices. A stochastic analysis based on decision trees was performed to compare the cost-effectiveness of beta-blockers therapy starting from a diagnosis of small varices (Strategy 1) with that of endoscopic surveillance followed by beta-blockers treatment when large varices are demonstrated (Strategy 2), for preventing variceal growth, bleeding and death in patients with cirrhosis and small esophageal varices. The basic nodes of the tree were gastrointestinal endoscopy, inpatient admission and treatment for bleeding, as required. All estimates were performed using a Monte Carlo microsimulation technique, consisting in simulating observations from known probability distributions depicted in the model. Eight-hundred-thousand simulations were performed to obtain the final estimates. All estimates were then subjected to Monte Carlo Probabilistic sensitivity analysis, to assess the impact of the variability of such estimates on the outcome distributions. The event rate (considered as progression of varices or bleeding or death) in Strategy 1 [24.09% (95%CI: 14.89%-33.29%)] was significantly lower than in Strategy 2 [60.00% (95%CI: 48.91%-71.08%)]. The mean cost (up to the first event) associated with Strategy 1 [823 £ (95%CI: 106 £-2036 £)] was not significantly different from that of Strategy 2 [799 £ (95%CI: 0 £-3498 £)]. The cost-effectiveness ratio with respect to this endpoint was equal to 50.26 £ (95%CI: -504.37 £-604.89 £) per event avoided over the four-year follow-up. When bleeding episodes/deaths in subjects whose varices had grown were included, the mean cost associated with Strategy 1 was 1028 £ (95%CI: 122 £-2581 £), while 1699 £ (95%CI: 171 £-4674 £) in Strategy 2. Beta-blocker therapy turn out to be more effective and less expensive than endoscopic surveillance for primary prophylaxis of bleeding in patients with cirrhosis and small varices.
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