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Cirrhosis represents the end stage of chronic liver disease, characterized by high mortality and morbidity. The prevalence of liver disease is difficult to assess, given its clinical latency up to the late stage.We aimed to assess the prevalence of unrecognized chronic liver disease and cirrhosis using surrogate indicators from medical records of family physicians.Medical records of 139,104 subjects, collected from 99 family physicians of the Veneto region, were used. Persistently high transaminases were used as indicators of occult chronic liver disease; thrombocytopenia, unrelated to haematological malignancies, was used as indicator of occult cirrhosis. Diagnosis of chronic liver disease and cirrhosis was assessed using ICD9-CM-1997 codes.Alteration of transaminases was found in 32.7% of the subjects, and among them only one-third had an already diagnosed liver disease. Patients with diagnosis of cirrhosis were 0.3%, while thrombocytopenia, indicator of occult cirrhosis, was detected in 1.3% of the remaining population. Patients with overt and occult cirrhosis showed a higher metabolic profile, with significantly higher prevalence of arterial hypertension, obesity and diabetes than the general population.A large proportion of patients with chronic liver disease is still undiagnosed. Surrogate biochemical indicators might be useful for disease recognition.

Background Squamous cell carcinoma antigen (SCCA)-IgM complex has been described as a promising tool to identify patients with progressive liver disease at higher risk of hepatocellular carcinoma (HCC) development in retrospective studies. Aim To assess the clinical value of this biomarker in patients with cirrhosis in a prospective study. Methods Patients with overt cirrhosis were prospectively evaluated at 6-month intervals for HCC development and decompensation with clinical examination, liver ultrasound, α-fetoprotein measurement. SCCA-IgM was measured in serum by immunoenzymatic assay. Median follow-up duration was 52 months (range 12–68 months). Results 70 patients (26% male; mean age 56 ± 10 years) were enrolled. The main aetiological factors were alcohol (44%) and hepatitis C (34%). Baseline values of SCCA-IgM were significantly higher in patients who developed HCC. Positivity of the biomarker at baseline was associated with a significantly shorter HCC-free survival, while α-fetoprotein (cut off >20 ng/ml) was not significant. SCCA-IgM positivity and hepatitis C were significant prognostic factors for HCC development. The biomarker was not associated with the development of clinical complications of cirrhosis. Conclusion This prospective study demonstrates that in patients with cirrhosis SCCA-IgM is associated with HCC development and may be useful for clinical management of cirrhotic patients at higher risk of HCC development.

The detection of alcohol consumption in liver transplant candidates (LTCs) and liver transplant recipients (LTRs) is required to enable a proper assessment of transplant eligibility and early management of alcohol relapse, respectively. In this clinical setting, urinary ethyl glucuronide (uEtG), the Alcohol Use Disorders Identification Test for Alcohol Consumption (AUDIT-c), serum ethanol, urinary ethanol, carbohydrate-deficient transferrin (CDT), and other indirect markers of alcohol consumption were evaluated and compared prospectively in 121 LTCs and LTRs. Alcohol consumption was diagnosed when AUDIT-c results were positive or it was confirmed by a patient's history in response to abnormal results. Alcohol consumption was found in 30.6% of the patients. uEtG was found to be the strongest marker of alcohol consumption (odds ratio = 414.5, P

Summary Background & Aims A moderate sodium restriction diet should be indicated in patients with cirrhosis and ascites. Nevertheless, there is a lack of specific investigation on its correct application. To evaluate the adherence of patients with cirrhosis and ascites to a moderately low-salt diet and the impact on intake of total calories and serum sodium concentration. Methods A total of 120 outpatients with cirrhosis and ascites were interviewed with a pre-established questionnaire. A quantitative assessment of nutrient and salt intake was performed. Result A moderately low-salt diet was followed by 37 patients (Group A). Of the 83 patients who did not follow the diet (Group B), 54 thought that they were following it. The mean daily sodium intake was 79.5 ± 5.5 mmol/day (Group A) and 205.9 ± 14.1 mmol/day (Group B), P

A considerable proportion of patients with cirrhosis exhibit insomnia, delayed sleep habits, and excessive daytime sleepiness. These have been variously attributed to hepatic encephalopathy and impaired hepatic melatonin metabolism, but the understanding of their pathophysiology remains limited and their treatment problematic. Sleep is regulated by the interaction of a homeostatic and a circadian process. The homeostatic process determines sleep propensity in relation to sleep-wake history, thus the need to sleep increases with the duration of the waking period. The circadian process, which is marked by the 24-hour rhythm of the hormone melatonin, is responsible for the alternation of high/low sleep propensity in relation to dark/light cues. Circadian sleep regulation has been studied in some depth in patients with cirrhosis, who show delays in the 24-hour melatonin rhythm, most likely in relation to reduced sensitivity to light cues. However, while melatonin abnormalities are associated with delayed sleep habits, they do not seem to offer a comprehensive explanation to the insomnia exhibited by these patients. Fewer data are available on homeostatic sleep control: it has been recently hypothesized that patients with cirrhosis and hepatic encephalopathy might be unable, due to excessive daytime sleepiness, to accumulate the need/ability to produce restorative sleep. This review will describe in some detail the features of sleep-wake disturbances in patients with cirrhosis, their mutual relationships, and those, if any, with hepatic failure/hepatic encephalopathy. A separate section will cover the available information on their pathophysiology. Finally, etiological treatment will be briefly discussed. © 2013 by the American Association for the Study of Liver Diseases.

IgM antibodies bound to different cancer antigens have shown recently a higher diagnostic value, compared with the corresponding free molecule, giving rise to a new family of biomarkers. High or increasing levels of Squamous Cell Carcinoma Antigen (SCCA)-IgM immune complexes were associated with more advanced liver disease and increased risk of development of HCC. Rheumatoid factor (RF) represents a long-standing problem of interference for immunometric assays. The aim of the present study was to examine the specificity of SCCA-IgM in relation to the presence of RF reactivity in patients infected with hepatitis C virus (HCV). Sera of 73 patients with cirrhosis, infected with HCV, (mean age ± SD: 66 ± 13 years; M/F: 45/28), including 21 patients with HCC, were studied. SCCA-IgM immune complexes levels were measured by a commercial ELISA. To evaluate the possible interfering effect of RF, the standard calibrator, positive for SCCA-IgM, was spiked with serial dilutions of a RF positive or negative serum. SCCA-IgM immune complexes were positive in 35 out of 73 (48%) patients, while RF activity was found in 10 out of 73 (14%) patients. Patients with cirrhosis with RF activity had significantly higher levels of SCCA-IgM, compared to RF negative cases; however, no significant correlation between SCCA-IgM and RF values was observed. In samples created artificially the same results in terms of reactivity for SCCA-IgM were obtained, regardless of the presence of RF activity. These findings support the lack of correlation between the two parameters found in sera of patients infected with HCV. J. Med. Virol. 85: 1005–1008, 2013. © 2013 Wiley Periodicals, Inc.

Background Most NSAIDs are thought to be able to cause hepatic injury and acute liver failure (ALF), but the event rates of those leading to transplantation (ALFT) remain uncertain. Objectives The aim of the study was to estimate population event rates for NSAID-associated ALFT Methods This was a case-population study of ALFT in 57 eligible liver transplant centres in seven countries (France, Greece, Ireland, Italy, The Netherlands, Portugal and the UK). Cases were all adults registered from 2005 to 2007 for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY). Results In the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose). Event rates per MTY were 1.59 (95 % CI 1.1–2.2) for all NSAIDs pooled, 2.3 (95 % CI 1.2–3.9) for ibuprofen, 1.9 (95 % CI 0.8–3.7) for nimesulide, 1.6 (95 % CI 0.6–3.4) for diclofenac and 1.6 (95 % CI 0.3–4.5) for ketoprofen. For paracetamol, the event rate was 3.3 per MTY (95 % CI 2.6–4.1) without overdoses and 7.8 (95 % CI 6.8–9.0) including overdoses. Conclusions ALF leading to registration for transplantation after exposure to an NSAID was rare, with no major difference between NSAID. Non-overdose paracetamol-exposed liver failure was twice more common than NSAID-exposed liver failure. Electronic supplementary material The online version of this article (doi:10.1007/s40264-012-0013-7) contains supplementary material, which is available to authorized users.

Background and Aim: Liver cirrhosis is characterized by high morbidity and mortality rates. This study was addressed to evaluate the epidemiological and economic impact of cirrhosis on hospitalizations in a large population in Italy. Methods: Epidemiological analysis was performed using hospital discharge sheets of 57,720 hospitalizations due to liver disease from 2006 to 2008, selected from the Veneto regional archive. In a sample of 100 randomly selected hospitalizations, a detailed cost analysis was performed and a comparison was made with sets of patients admitted for heart failure (HF) and chronic obstructive pulmonary disease (COPD). Results: Among patients with cirrhosis, ascites emerged as the most frequent cause of admission, followed by hepatic encephalopathy, hepatocellular carcinoma, and upper gastrointestinal bleeding. Encephalopathy and ascites were the complications with the highest rates of readmission. The detailed cost analysis of hospitalizations revealed that economic expenses in the set of patients admitted for cirrhosis were about 30% higher than those for patients admitted for HF or COPD, mainly due to the longer duration of hospitalization. Conclusions: Cirrhosis has a relevant epidemiological and economic impact on hospitalizations and preventive strategies for its clinical management are warranted.

One of the most daunting challenges of nanomedicine is the finding of appropriate targeting agents to deliver suitable payloads precisely to cells affected by malignancies. Even more complex is the ability to ensure that the nanosystems enter those cells. Here, we use 2 nm (metal core) gold nanoparticles to target human hepatocellular carcinoma (HepG2) cells stably transfected with the SERPINB3 (SB3) protein. The nanoparticles were coated with a 85:15 mixture of thiols featuring, respectively, a phosphoryl choline (to ensure water solubility and biocompatibility) and a 28-mer peptide corresponding to the amino acid sequence 21–47 of the hepatitis B virus-PreS1 protein (PreS1(21–47)). Conjugation of the peptide was performed via the maleimide–thiol reaction in methanol, allowing the use of a limited amount of the targeting molecule. This is an efficient procedure also in the perspective of selecting libraries of new targeting agents. The rationale behind the selection of the peptide is that SB3, which is undetectable in normal hepatocytes, is overexpressed in hepatocellular carcinoma and in hepatoblastoma and has been proposed as a target of the hepatitis B virus (HBV). For the latter, the key recognition element is the PreS1(21–47) peptide, which is a fragment of one of the proteins composing the viral envelope. The ability of the conjugated nanoparticles to bind the target protein SB3, expressed in liver cancer cells, was investigated by surface plasmon resonance analysis and in vitro via cellular uptake analysis followed by atomic absorption analysis of digested samples. The results showed that the PreS1(21–47) peptide is a suitable targeting agent for cells overexpressing the SB3 protein. Even more important is the evidence that the gold nanoparticles are internalized by the cells. The comparison between the surface plasmon resonance analysis and the cellular uptake studies suggests that the presentation of the protein on the cell surface is critical for efficient recognition.

The relationship between hepatic encephalopathy (HE) and the sleep-wake disturbances exhibited by patients with cirrhosis remains debated. The aim of this study was to examine the usefulness of sleep-wake interview within the context of HE assessment. One-hundred-and-six cirrhotic patients were asked three yes/no questions investigating the presence of difficulty falling asleep, night awakenings and daytime sleepiness. All underwent formal HE assessment, quantitative electroencephalography and standardised psychometry. Fifty-eight were monitored for 8 ± 6 months in relation to the occurrence of HE. Patients complaining of daytime sleepiness (n = 75, 71 %) had slower EEGs than those who did not report it (relative alpha power: 37 ± 19 vs. 48 ± 17 %, p

Multidrug-resistant infections represent an increasing problem in the management of hospitalized patients worldwide. With respect to Gram-negative infections, carbapenems are an important antimicrobial class for the treatment of infections caused by extended-spectrum beta lactamase producers enterobacteriaceae. However, the emergence of novel β-lactamases with direct carbapenem-hydrolyzing activity has contributed toward an increased prevalence of carbapenem-resistant enterobacteriaceae. Recent reports have described the spread of carbapenemase-producing Klebsiella pneumoniae across the world. There are very few existing agents that can be used against these pathogens and there are limited options on the horizon. In recent years, the epidemiology of bacterial strains involved in the pathogenesis of spontaneous bacterial peritonitis has also been changing rapidly. In this setting, we report the first case of nosocomial spontaneous bacterial peritonitis due to carbapenemase-producing K. pneumoniae.

The hyperdynamic circulation of cirrhosis participates in the pathophysiology of portal hypertension. P450-dependent epoxyeicosatrienoic acids (EET) are potent vasodilators. We evaluated plasma levels of EETs in cirrhotic patients and the effect of epoxygenase and nitric oxide synthase (NOS) inhibition on skin blood flow, measured by laser Doppler flowmetry, in normal subjects and cirrhotic patients with and without ascites. Free plasma EETs were increased in cirrhotic patients compared to normal subjects, while the ratio between 8,9-, 11,12-, and 14-15-EET was the same. In cirrhotic patients without ascites, skin blood flow was significantly increased compared to normal subjects. In patients with ascites skin blood flow was significantly reduced compared to control subjects and patients without ascites. Inhibition of epoxygenase with miconazole and of NOS with l -NG-Nitroarginine methyl ester ( l -NAME) decreased basal skin flow in normal subjects and in cirrhotic patients, the effect being higher in cirrhotic patients. Miconazole caused a further decrease in flow when administered with l -NAME, both in normal subjects and in cirrhotic patients. In conclusion, EETs participate in the control of peripheral circulation of normal subjects and in the pathophysiology of peripheral vasodilatation of cirrhotic patients with ascites.

Awareness of previous hepatic encephalopathy (HE) and compliance with treatment can probably reduce HE recurrence. The aim of this study was to assess the degree of awareness of previous HE and its treatment in a group of cirrhotic patients and their caregivers. Thirty-five cirrhotic patients with a history of HE and their caregivers (n = 31) were enrolled. Patients underwent evaluation of HE (clinical, psychometry and electroencephalography), quality of life (SF36 questionnaire), and awareness of HE/treatment on an ad hoc questionnaire (QAE). Caregivers underwent the QAE plus the Caregiver Burden Inventory. On the day of study, 7 patients were unimpaired, 8 had minimal and 20 low-grade overt HE. Of the patients, 37 % were aware of previous HE, 6 % of being on treatment and 6 % understood treatment effects. Of the caregivers, 48 % were aware of previous HE, 6 % of their relative being on treatment and 6 % understood treatment effects. Significant correlations were observed between neuropsychiatric status/linear HE indices and both the patients' quality of life and the caregivers' burden. In conclusion, HE awareness was poor in both patients and caregivers, most likely in relation to insufficient/inadequate provision of information.

SERPINB3 is a serine protease inhibitor with pleiotropic functions. It is involved in several physiological and pathological processes, where it appears to exert antiapoptotic effects. Little is known about its expression on immune system cells, the major players in mechanisms of viral defense and autoimmune disorders. The aim of this study was to characterize the expression of SERPINB3 on the surface of peripheral blood mononuclear cell subsets in both normal subjects and in patients with chronic viral infections and autoimmune diseases. Sixty-two patients were analyzed by flow cytometric analysis, including 45 with hepatitis C virus (HCV)-related chronic liver disease and 17 with systemic lupus erythematosus (SLE). SERPINB3 was expressed on B lymphocytes in 79% of the controls, in 32% of the HCV-infected patients and in none of the SLE patients. Surface localization of SERPINB3 was confirmed by confocal microscopy. SERPINB3 positivity was associated with CD27 reactivity ( r = 0.98), but not to other activation molecules (CD69, CD71, CD86 and CXCR3). SERPINB3 is physiologically expressed on the surface of CD27+ B lymphocytes, but its expression is reduced in HCV viral infection and not detectable in SLE patients. These results may suggest a role for SERPINB3 in B-cell defects typically found in viral infections and autoimmune disorders.

Splenic Doppler impedance indices are measurements of splenic congestion in chronic liver disease. It is not known whether they can also assess splenic congestion in patients affected by right-sided or congestive heart failure. We analyzed splanchnic hemodynamics with Doppler ultrasound and systemic hemodynamics with right-sided heart catheterization in patients with heart failure. Splenic pulsatility index (PI) was higher in patients with heart failure (48 patients) compared with healthy subjects (39 patients) (1.19 ± 0.41 vs. 0.73 ± 0.11, p0.0001) and was related to hepatic vein diameter (p = 0.02). Splenic PI was not related to systemic arterial pressure, cardiac output, systemic vascular resistance or splenic arterial resistance, whereas it was related to right atrial mean pressure (p = 0.0003) and to right ventricle end-diastolic pressure (p = 0.011) (34 patients). In conclusion, splenic PI is a measurement of splenic congestion caused by an increase in venous outflow resistance. It can estimate splenic congestion in patients with right-sided or congestive heart failure.

The aims of the study were to evaluate (i) the prevalence of MGUS in patients after liver transplantation (LT), (ii) the role of MGUS as a risk factor for malignancy and other medical complications after LT. One hundred and fifty consecutive patients were included in the study and followed prospectively after LT for more than 18 months. Eighteen patients had MGUS before LT, whereas 49 patients developed MGUS after LT ('de novo' MGUS). Thirty-six of these patients showed a MGUS along all the follow up after LT ('permanent' MGUS). In 31 patients, MGUS disappeared after LT ('transient' MGUS). No patient with MGUS developed B-malignant lymphoproliferative disorder and only one patient developed a myeloma after LT. Comparing patients with 'permanent' MGUS to patients with 'transient' MGUS or without MGUS after LT, the former group showed a higher rate of serious infections (30% versus 13%, P = 0.01), chronic kidney disease (CKD) (75% versus 44%, P = 0.001) and mortality (33% versus 17%, P = 0.04). Permanent MGUS was confirmed as an independent risk factor for serious infections and CKD by multivariate analysis. Permanent MGUS after LT does not entail a significant risk of malignancy, but it is associated with a higher risk of serious infections and CKD.

Background: Cirrhotic portal hypertension is characterized by mesenteric arterial vasodilation and hyporeactivity to vasoconstrictors. Aim: We evaluated the role of epoxyeicosatrienoic acid (EET) and of myoendothelial gap junctions (GJ) in the haemodynamic alterations of experimental cirrhosis. Methods: Thirty-five control rats and 35 rats with carbon tetrachloride (CCl4)-induced cirrhosis were studied. Small resistance mesenteric arteries (diameter

Background: Squamous cell carcinoma antigen-immunoglobulin M (SCCA-IgM) is a useful biomarker for the risk of development of hepatocellular carcinoma (HCC) in patients with cirrhosis due to its progressive increase associated to HCC evolution. In patients with cirrhosis, other assays have been affected by interfering reactivities of IgM. In this study, the analytical specificity of the SCCA-IgM assay was assessed by evaluating SCCA-IgM measurement dependence on different capture phases, and by measuring the recovery of SCCA-IgM reactivity following serum fractionation. Methods: Serum samples from 82 patients with cirrhosis were analyzed. SCCA-IgM was measured using the reference test (Hepa-IC, Xeptagen, Italy) that is based on rabbit oligoclonal anti-squamous cell carcinoma antigen (SCCA) and a dedicated ELISA with a mouse monoclonal anti-SCCA as the capture antibody. Results: SCCA-IgM concentrations measured with the reference assay (median value=87 AU/mL) were higher than those measured with the mouse monoclonal test (median value=78 AU/mL). However, the differences in the SCCA-IgM distribution were not statistically significant (p>0.05). When SCCA-IgM concentrations measured with both tests were compared, a linear correlation was found (r=0.77, p2000 kDa) with both tests. Conclusions: The equivalence of both SCCA-IgM assays and the absence of reactivity not related to immune complexes support the analytical specificity of SCCA-IgM measurements. The results validate the assessment of SCCA-IgM for prognostic purposes in patients with cirrhosis. Clin Chem Lab Med 2010;48:217–23.

The aim of the study was to compare sequential versus combined diuretic therapy in patients with cirrhosis, moderate ascites and without renal failure.One hundred patients were randomly assigned to the two diuretic treatments. The sequential treatment provided potassium canrenoate at the initial dose of 200 mg/day, then increased to 400 mg/day. Non-responders were treated with 400 mg/day of potassium canrenoate and furosemide at an initial dose of 50 mg/day, then increased to 150 mg/day. The combined treatment provided the initial dose of 200 mg/day of potassium canrenoate and 50 mg/day of furosemide, then increased to 400 mg/day and 150 mg/day, respectively.Most patients who received sequential treatment responded to potassium canrenoate alone (19% to 200 mg/day and 52.63% to 400 mg/day, respectively). Most patients who received the combined treatment responded to the first two steps (40% to the first step and 50% to the second, ie, 400 mg/day of potassium canrenoate plus 100 mg/day of furosemide). Adverse effects (38% vs 20%, p0.05), in particular, hyperkalaemia (18% vs 4%, p0.05), were more frequent in patients who received sequential therapy. As a consequence, the per cent of patients who resolved ascites without changing the effective diuretic step was higher in those who received the combined treatment (56% vs 76%, p0.05).The combined diuretic treatment is preferable to the sequential one in the treatment of moderate ascites in patients with cirrhosis and without renal failure. NCT00741663. This work is an open randomised clinical trial.

Psychometric Hepatic Encephalopathy Score (PHES) and EEG are used to detect minimal hepatic encephalopathy (MHE). We aimed at standardizing PHES in Italy and comparing Italian, German and Spanish norms in EEG characterized cirrhotic patients.PHES was standardized on 228 normal individuals. Repeatability was studied in 128 individuals. One hundred patients with liver cirrhosis underwent EEG and PHES which was computed on the Spanish, German and the Italian norms.Age and education levels were predictors of psychometric tests; therefore, adjusted Z scores were calculated. Practice effect (p0.01) was detected. In the patients, the Italian norms were closer to the Spanish norms (difference -0.14+/-1.32, p=0.29) than to the Germans ones (difference 1.97+/-2.07, p0.001). The PHES calculated on the Italian norms was correlated with the EEG mean dominant frequency more closely than the ones calculated on the German and Spanish norms (r=0.38, r=0.31, r=0.33, respectively -p0.01). The detection of MHE on the basis of PHES and EEG showed limited agreement (73%, Cohen's K=0.32).(i) Valid norms for PHES were produced, (ii) clues for the use of common norms in Latin Countries were found, (iii) different findings between PHES and EEG possibly reflect various features of MHE.

Background In the sera of liver, colorectal and prostate cancer patients, several biomarkers may be detected as IgM immune complexes. To determine whether the presence of immune complexes was correlated to an increase of IgMs, we measured the IgM content in the sera of patients with hepatocellular carcinoma (HCC) and cirrhosis, and evaluated the occurrence of des-gamma-carboxy prothrombin (DCP) as immune complexes (DCP-IgM) compared to the levels of DCP and alpha-fetoprotein (AFP). Patients and methods Serum samples from 31 patients with cirrhosis, 33 untreated HCC patients diagnosed by ultrasound, computed tomography and/or magnetic resonance and confirmed by histopathology, when indicated, and 30 healthy controls were analysed. Concentrations of IgM and DCP-IgM were determined by ELISAs. Results Circulating IgM in patients with HCC (median level = 1·79 mg mL−1) and cirrhosis (1·09 mg mL−1) were not significantly different (P = 0·1376) while DCP-IgM were significantly higher in HCC patients (median level = 2171·2 AU mL−1) than in those with cirrhosis (1152 AU mL−1, P = 0·0047). No correlation was found between DCP-IgM and IgM in HCC (r = 0·227) and cirrhosis patients (r = 0·475). DPC-IgM was positive in 55% (18/33) of HCC patients and in 26% (8/31) of cirrhosis patients compared to 39% and 26% for DCP and 48% and 13% for AFP. DCP-IgM, DCP and AFP tests had 100% specificity in healthy controls. Conclusions DCP-IgM in HCC patients was not associated with an increase in IgM concentration. DCP-IgM was more frequently detected in HCC patients than DCP and AFP, strengthening the diagnostic role of IgM immune complexes for liver cancer.

Objective To describe auditory perceptual, pre-attentive, attention-related and cognitive processes along lifespan in normal people by a simple auditory oddball paradigm easily usable in clinical practice. Methods ERPs were recorded in 72 normal subjects. Four blocks of tones were delivered (20% rare 2000 Hz and 80% frequent 1000 Hz). In the former two blocks, subjects performed a concomitant distracting visual search task (distracted condition); in the latter two blocks, they had to attend the occurrence of the rare tones (active condition). Latency and amplitude of ERPs were analyzed according to age, gender, educational level and repetition. Results N100 amplitude was greater in active than in distracted condition. MMN amplitude decreased with age. N2b and P300 latencies increased with age, while their amplitudes decreased. Females produced greater P300 than males. In the elderly, P300 latency was found to be longer in the second block than in the first one. Conclusions N100 and MMN were found to be less affected by age than N2b and P300. When repeated, P300 showed increased latency in elderly subjects. Significance The protocol detected the higher influence of aging on late cognitive processes than on the perceptual and pre-attentive ones. Age-adjusted normative data were produced.

Portal hypertension is primarily caused by the increase in resistance to portal outflow and secondly by an increase in splanchnic blood flow, which worsens and maintains the increased portal pressure. Increased portal inflow plays a role in the hyperdynamic circulatory syndrome, a characteristic feature of portal hypertensive patients. Almost all the known vasoactive systems/substances are activated in portal hypertension, but most authors stress the pathogenetic role of endothelial factors, such as COX-derivatives, nitric oxide, carbon monoxide. Endothelial dysfunction is differentially involved in different vascular beds and consists in alteration in response both to vasodilators and to vasoconstrictors. Understanding the pathogenesis of portal hypertension could be of great utility in preventing and curing the complications of portal hypertension, such as esophageal varices, hepatic encephalopathy, ascites.

The current standard of care for the treatment of chronic hepatitis C virus (HCV) infection is combination therapy with Peg-interferon (IFN) alpha-2a or alpha-2b type plus ribavirin (RBV). This antiviral schedule can in fact avoid the three fold mortality rates associated to untreated cases with HCV infection, by inducing viral eradication and liver damage regression, so as to define the patients “definitively cured” from liver disease. This analysis describes the modalities of antiviral treatment in the Veneto region, in particular the therapy-schedule mainly used and compares the cost-effectiveness of treatment with the 2 available Peg-IFNs with strategies proposed as in the every day practice. Twelve on line hepatologic units, centralized by a network program on “Surveillance and Control of HCV Infection in the Veneto Region”, prospectively collected data and, of these, we evaluated 450 subjects that underwent antiviral therapy for chronic hepatitis or cirrhosis. A post hoc retrospective analysis of cases treated from January 2003 to December 2005 was performed, grouping the study population in 166 cases treated with Peg-IFN alpha-2a (Pegasys®, Roche, fixed-dose of 180 μg/weekly) and 284 that received Peg-IFN alpha-2b (Peg-Intron®, Schering-Plough, weight-adjusted-dose from 50 to 150 μg/weekly), both in combination therapy with ribavirin (Copegus®, Roche, or Rebetol®, Schering-Plough, weight-adjusted-dose of 15 mg/kg/daily). Epidemiological characteristics and cumulative rate of end-of-therapy response and Sustained Virological Response (SVR) were similar in the 2 groups, but 78% of cases treated with Peg-IFN alpha-2b and RBV received a significantly lower dose with respect to the weight-adjusted dose. This event conditioned efficacy to therapy as demonstrated in cases that received a < 1 μg/kg dose with respect to those treated with > 1 μg/kg (respectively SVR: 49% vs 66%, p < 0,01), particularly in genotype HCV-1 (SVR: 29% vs 51%, p = 0,01), known to be more resistant to IFN-therapy. The overall cost of antiviral therapy in this study population was about € 3,528,000/450 treated cases and considering the 269 that reached SVR (98 and 171, respectively by Peg-IFN alpha-2a or 2b and RBV therapy), the cost/SVR was € 15,632 and € 11,672 in the 2 groups. In conclusion, the optimization of Peg-IFN therapy, that is the use of the full dose, particularly in cases treated with a weight-adjusted Peg-IFN alpha-2b and RBV, at the standard of care dosage of 1.5 μg/kg/week and 15 mg/kg/day respectively, will allow a better efficacy, especially in genotype HCV-1 with an increase of 11% in SVR (43% to 54%) at a lower cost.

Patients with liver cirrhosis often exhibit sleep-wake abnormalities, which are, at least to some extent, circadian in origin. A relatively novel non-pharmacological approach to circadian disruption is appropriately timed bright light therapy. The aims of this pilot study were to investigate sleep-wake characteristics of a well-characterized population of inpatients with cirrhosis, and to evaluate the efficacy of bright light therapy in the hospital setting. Twelve consecutive inpatients with cirrhosis underwent complete sleep-wake assessment, to include qualitative and semi-quantitative (actigraphic) indices of night-time sleep quality, daytime sleepiness, diurnal preference, habitual sleep timing, quality of life, mood and circadian rhythmicity [i.e. urine collections for measurement of the melatonin metabolite 6-sulphatoxymelatonin (aMT6s)]. Patients showed extremely impaired night sleep quality (Pittsburg Sleep Quality Index global score: 16.3 ± 2.1) and daytime sleepiness was common (Epworth Sleepiness Scale: 8.3 ± 3.2). Five patients were randomly assigned to a single room in which lighting was controlled in relation to timing, spectral composition and intensity (lights on at 06:30 and off at 22:30, blue-enriched, more intense light in the morning, red-enriched, less intense light in the afternoon/evening); the others stayed in identical rooms with standard lighting. Sleep diaries revealed poor sleep quality, prolonged sleep latency (67 ± 138 min) and a reduced sleep efficiency (69 ± 21%). These features were confirmed by actigraphy (sleep efficiency: 71 ± 13%; fragmentation index: 55 ± 15%). Quality of life was globally impaired, and mood moderately depressed (Beck Depression Inventory: 19.4 ± 7.9). Seven patients underwent serial urine collections: no circadian aMT6s rhythm was detected in any of them, neither at baseline, nor during the course of hospitalization in either room (n = 4). In conclusion, sleep and circadian rhythms in hospitalized, decompensated patients with cirrhosis are extremely compromised. Treatment with bright light therapy did not show obvious, beneficial effects, most likely in relation to the severity of disturbance at baseline.

Objective This study aims to evaluate the efficiency of top-down and bottom-up processes in the extrastriate cortex of cirrhotic patients without overt hepatic encephalopathy (HE). Methods Reaction times (RTs), accuracy and event-related potentials (ERPs) were recorded during the execution of a visual Simon task in 17 cirrhotic patients and 10 healthy controls. Amplitude and latency of the P1 and N1 (indexes of bottom-up processes) and of the N2pc (index of top-down processes) were measured. Results Patients were slower than controls, and patients with minimal HE (MHE) were slower than patients without MHE. The distribution analysis of RTs showed that the Simon effect decays with slower RTs in all the groups and that the shape of the distribution was different in MHE patients. No differences were found between cirrhotic patients and controls for P1 and N1 amplitude and latency. In contrast, N2pc latency was delayed in cirrhotic patients compared to controls independently of MHE. Conclusions In the extrastriate cortex of cirrhotic patients without HE, top-down processes are altered whereas bottom-up processes are preserved. Significance The analysis of exogenous and endogenous visual components of ERPs provides a model to study the functional dissociation between top-down and bottom-up processes inside the extrastriate cortex.

Minimal hepatic encephalopathy (MHE) is the earliest stage of hepatic encephalopathy and is associated with changes in cognitive functions, in electrophysiological parameters, and in cerebral neurochemical/neurotransmitter homeostasis. MHE can be observed in patients with cirrhosis who have no clinical evidence of hepatic encephalopathy (HE). At present, no data are available on a possible olfactory dysfunction in such a syndrome, although the pathophysiology of HE may alter olfactory functions since some of the neurotransmitters impaired in the syndrome are involved in the transmission of olfactory information. In the present paper, we performed a preliminary study aimed at detecting whether identification and recognition odor memory is altered in patients with MHE. Twelve patients diagnosed as MHE on the basis of their scores at the portosystemic encephalopathy (PSE)-syndrome test battery, and 12 age-matched controls were studied. Consistent with the hypothesis, patients performed significantly worse than controls for both odor identification and recognition tasks. In addition, a significant correlation between the two olfactory tests and the PSE-syndrome test score was found. This pattern supports the notion that olfactory alterations related to cognitive dysfunction in patients with MHE may be linked to the pathophysiology of HE.

Background. No gold standard exists to detect minimal hepatic encephalopathy. Event-related evoked potentials (P300 latency) were proposed as the best tool to assess this condition. EEG spectral analysis and psychometric evaluation are also used to assess minimal hepatic encephalopathy. Aims. The present study aims at comparing these three techniques. Patients. Eighty-six cirrhotic patients without overt hepatic encephalopathy were studied. Methods. Patients underwent EEG spectral analysis, psychometric evaluation and P300. P300 latency was age-adjusted; psychometric tests were age- and education-adjusted. Values >2Z were considered to be altered. The alteration of at least two psychometric tests was considered for cognitive impairment. Results. At least one of the three indexes was altered in 61% (CI95% = 49–71) patients; EEG spectral analysis was altered in 41% (CI95% = 30–52%) patients, psychometric performance in 34% (CI95% = 24–45%) and P300 latency in 13% (CI95% = 7–22%). P300 latency was altered only in the patients having EEG spectral analysis or psychometric alterations, but for two cases. Psychometric performance and EEG spectral analysis, but not P300 latency, were correlated with indexes of liver function. Conclusions. P300 latency provided little additional information and was less related to liver function than EEG spectral analysis and psychometrical investigation.

Summary Background : The acute effects of β-blockers may be different from chronic; mechanisms underlying this difference are poorly elucidated. Aim : To assess portal pressure and its pathophysiological determinants after acute and chronic administration of nadolol. Methods : In 24 patients with cirrhosis and portal hypertension hepatic venous pressure gradient, portal blood flow and resistance to portal blood flow were measured before, 60–90 min after acute administration of nadolol, and after 1 month. Patients were good-responders if hepatic venous pressure gradient was ≤12 mmHg, or decreased by at least 20%. Results : Eleven and 13 patients were good- and poor-responders to acute administration, respectively. Acute poor-responders showed a lower decrease in portal blood flow (P = 0.04) and a less evident decrease in mean arterial pressure (P

To prospectively evaluate accuracy and predictive values of Doppler ultrasonographic (US) measurement of portal blood velocity (PBV) and splenic pulsatility index (SPI) in diagnosis of clinically relevant acute rejection in patients with clinicobiochemical hepatic dysfunction after orthotopic liver transplantation (OLT).Study was approved by the institutional review board, and protocol conformed to ethical guidelines of Declaration of Helsinki. Patient informed consent was obtained. In 27 patients with OLT (23 men, four women; mean age, 48 years; range, 27-64 years), PBV and SPI were measured at Doppler US within 48 hours before or after liver biopsy for clinically suspected acute rejection. Biopsy specimens were assigned scores according to Banff method, and rejection activity index (RAI) was calculated. RAI score of 4 or greater was considered clinically relevant acute rejection. Doppler US parameters were analyzed as absolute values and as percentage point changes with respect to values obtained at last examination before rejection was suspected. Information from two Doppler US parameters was combined; Doppler US composite index was calculated. Statistical tests were conducted to assess accuracy, sensitivity, specificity, and predictive values of Doppler US parameters in diagnosis of graft rejection.Clinically relevant acute rejection was diagnosed in nine patients. Median time from OLT until histologic diagnosis of acute rejection was 8 days (range, 5-20 days). Rejection was associated with a marked reduction in mean PBV (-43% +/- 5 [standard error of the mean]) and a slight increase in SPI (+12% +/- 16). The calculated Doppler US composite index was strictly related to severity of rejection (P.001). When applied retrospectively, this index had good accuracy (88%) for prediction of rejection (specificity, 89%; sensitivity, 86%; negative predictive value, 94%).During the first weeks after OLT, a marked decrease in PBV associated with increased SPI supports suspicion of clinically relevant acute rejection.

This study is aim to investigate concurrent long-term psychiatric, cognitive and neurophysiological measures of alpha-IFN neurotoxicity in the treatment of chronic viral hepatitis.Twenty patients with HCV hepatitis were enrolled while treated with alpha-IFN (3-6 MU t.i.w. for 6-12 months). Neurotoxicity was evaluated by psychiatric [Hamilton Depression Rating Scale (HAM-D), Hamilton Scale for Anxiety (HAM-A), Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI-Y)], complete cognitive and neurophysiological assessments (EEG spectral analysis, P300). Patients were assessed at baseline (t0), 2 (t1) and 6 months (t2) since the beginning of therapy.Depression scores significantly increased (HAM-D: t0=4.4+/-2.6; t1=8.9+/-3.9, p0.001; and t2=7.7+/-3.8, p0.001). A concurrent increase was shown also for anxiety (HAM-A: t0=6.0+/-3.2; t1=9.6+/-4.5, p0.005; and t2=9.1+/-4.5, p0.005). Significant neurophysiological effects were also detected: increase of alpha power (p0.05) in frontal derivations, reduction of the mean dominant frequency (p0.005) and increase of theta power (p0.05) in parietal derivations. In contrast, no significant cognitive changes occurred.The study was performed on a relative small sample of patients mainly with observational intentions. Biological data (e.g. blood cytokines samples) are not available: they could have given useful information about biological mechanisms related to the alterations observed.Alpha-IFN treatment caused a time-dependent induction of symptoms of mild depression, concurrent anxiety and EEG changes. These psychiatric and neurophysiological changes can better explain the pharmacological profile of alpha-IFN and could help to address research on at risk population and, particularly, during pegylated-IFN therapy.

We assessed the presence of alpha-fetoprotein (AFP) complexed with IgM (AFP-IgM IC) in serum of patients af- fected by hepatocellular carcinoma (HCC), cirrhosis and chronic hepatitis as well as in healthy subjects by means of a ded- icated ELISA assay. The amount of AFP-IgM IC was expressed in arbitrary units (AU) on a reference standard curve. Free AFP (FAFP) levels were determined in parallel in each sample by means of an automated immunoassay system. The mean serum concentration of AFP-IgM IC was significantly higher in HCC patients (mean ± SD: 1378.3 ± 2935.7 AU/mL) than in cirrhotic patients (129.8 ± 261.4 AU/mL) and in patients with chronic hepatitis (80.9 ± 168.9 AU/mL) (p

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 performance and the EEG mean dominant frequency (MDF) were found to be correlated with brain atrophy. Multivariate analysis showed that a poor psychometric performance was independently predicted by EEG slowing (MDF: p < 0.01) and by central brain atrophy (cella media index: p < 0.01). In conclusion, brain atrophy was associated with a poor psychometric performance and EEG alterations in cirrhosis. Both brain atrophy and EEG alterations independently predicted cognitive dysfunction in cirrhotic patients.

Information on changes in splanchnic hemodynamics after liver transplantation is incomplete. In particular, data on long-term changes are lacking, and the relationship between changes in arterial and portal parameters is still under debate. The effect of liver transplantation on splanchnic hemodynamics was analyzed with echo-Doppler in 41 patients with cirrhosis who were followed for up to 4 years. Doppler parameters were also evaluated in 7 patients transplanted for acute liver failure and in 35 controls. In cirrhotics, portal blood velocity and flow increased immediately after transplantation (from 9.1 plus minus 3.7 cm/sec to 38.3 plus minus 14.6 and from 808 plus minus 479 mL/min to 2,817 plus minus 1,153, respectively, P

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 (

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. Methods: Between March and April 2013, 118 consecutive inpatients were screened and 99 (76 ± 11 years; hospitalization: 8 ± 7 days) enrolled. They slept in double or quadruple rooms, facing South/South-East, and were qualified as sleeping near/far from the window. They underwent daily sleep assessment by standard questionnaires/diaries. Illuminance was measured by a luxmeter at each patient’s eye-level, four times per day. Noise was measured at the same times by a phonometer. Information was recorded on room lighting, position of the rolling shutters and number/type of extra people in the room. Results: Compliance with sleep-wake assessment was poor, with a range of completion of 2–59%, depending on the questionnaires. Reported sleep quality was sufficient and sleep timing dictated by hospital routine; 33% of the patients reported one/more sleepless nights. Illuminance was generally low, and rolling shutters half-way down for most of the 24 h. Patients who slept near the window were exposed to more light in the morning (i.e., 222 ± 72 vs. 174 ± 85 lux, p

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.

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.

Background/Aims : The electroencephalogram (EEG) is frequently altered in cirrhotic patients. We, therefore, performed a study to ascertain the features and the prognosis of cirrhotic patients without current overt hepatic encephalopathy (OHE) who have EEG alterations. Methods : A series of 296 consecutive cirrhotic patients who had undergone quantified-EEG was studied. The median follow-up was 442 days, 128 patients had bouts of OHE and 78 patients died from liver-related causes. Another group of 124 cirrhotic patients with a median follow-up of 223 days was examined to validate the prognostic model. Results : EEG alterations were detected in 38% of the patients. The prevalence of EEG alterations was associated with the severity of cirrhosis (class B: odds ratio (OR)=2.3, 95% confidence interval (CI)=1.2–4.7; class C: OR=3.5, 95% CI=1.6–7.7), but not with the aetiology (alcoholic vs. non-alcoholic: OR=0.9; 95% CI=0.5–1.5). The EEG predicted the occurrence of OHE ( χ 2 =26; P 0.001) and mortality ( χ 2 =34; P 0.001), also adjusting for Child–Pugh class by a multivariate analysis. In the patients with a Child–Pugh score of ≥ 8, the EEG discriminated between those patients with a higher 1-year risk of OHE (hazard ratio (HR)=3.3, 95% CI=1.8–6.1) and death (HR=3.1, 95% CI=1.7–5.6). Conclusions : In conclusion, quantified-EEG had a prognostic value for the occurrence of bouts of OHE and mortality in cirrhotic patients.

Background : Chronic hepatitis C virus (HCV) infection is associated with a variety of extrahepatic disorders that may relate to direct or indirect effects of virus infection. Increased levels of soluble forms of tumor necrosis factor (TNF) receptors I and II, found in lymphoproliferative and infectious diseases, can interfere with TNF induced apoptotic cell death. The aim of the present study was to evaluate soluble TNF family receptors levels in lymphoproliferative disorders associated with HCV infection. Methods : One hundred and forty-nine subjects were studied, including 120 anti-HCV positive patients (60 without lymphoproliferative manifestations, 47 with type II cryoglobulinemia and 13 with low-grade B-cell non-Hodgkin's lymphoma (B-NHL)) and 29 anti-HCV negative subjects (19 with low-grade B-NHLs and ten normal controls). Results : Soluble forms of TNF receptor I, TNF receptor II and Fas were significantly higher in HCV positive patients compared with normal controls. The highest levels were found in patients affected by type II cryoglobulinemia or HCV positive lymphoplasmacytoid lymphomas (LP-NHLs), while HCV positive patients without type II cryoglobulinemia or with other B-NHLs had lower values ( P Conclusions : Among HCV infected individuals, very high levels of soluble TNF receptors are significantly associated with type II cryoglobulinemia and LP-NHLs, suggesting that they may be involved in these proliferative disorders.

The best known indicator of risk for first bleeding in patients with cirrhosis without previous bleeding is the index devised by the North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices (NIEC index), which results from the combination of size of esophageal varices, severity of red wale marks, and Child-Pugh class. Its efficiency is far from optimal, and validation studies have reported sensitivities and specificities markedly lower than those reported in the original study. In the present study we analyzed the efficiency of NIEC index in a large series of cirrhotic patients with varices without previous bleeding. In addition, we tried to improve the effectiveness of the index by modifying it, and to validate the modifications in an independent group of patients.A total of 627 patients were enrolled and followed until either a variceal bleeding or for a maximum of 2 yr. During this time, 117 experienced a first varicealUsing Cox's regression analysis, size of varices, severity of red wale marks, and Child-Pugh score were significant and independent predictors of first bleeding, as already noted in the original report of the NIEC group. However, coefficients and standard errors were markedly different, and the importance of size of esophageal varices in the regression was much larger, whereas that of Child-Pugh score was much lower. According to these data, a revised index was developed (Rev-NIEC). Using receiver operating characteristic (ROC) curve analysis, the revised index showed a larger efficiency, and the area under the curve was significantly larger (0.80 +/- 0.02 vs 0.74 +/- 0.02; p0.01). In particular, the curve showed that for a specificity of 75%, the new index had a sensitivity of 72% compared to that of 55% of the NIEC index. Validation in an independent sample of 84 patients showed good agreement between predicted and observed risk for bleeding. Validation with the bootstrap technique also showed adequate stability of the results.The revised index seems to be superior to the traditional index, and may turn out to be more useful in the selection of patients for different therapeutic procedures and in the stratification of patients in clinical trials.

To evaluate the usefulness of routine ultrasonographic (US) evaluation of the hepatic arterial resistive and pulsatility indexes and of the direction of portal venous blood flow for the diagnosis of intrahepatic arterioportal fistulas (APFs) in patients with liver cirrhosis.In all patients with cirrhosis examined at one center over 4 years, the resistive (RI) and the pulsatility (PI) indexes in the right and left branches of the hepatic artery were evaluated with Doppler US. An APF was suspected when an RI decrease of at least 20% and a PI decrease of at least 30% were present in one hepatic lobe relative to values in the other lobe and portal blood flow in the lobe with the decreased values was reversed. The RI and PI in patients with an APF were compared with those in 75 patients with cirrhosis and without APFs at angiography.Seven patients with an APF were identified. APFs suspected at Doppler US were always confirmed with angiography. The percent differences +/- SD in the RI and the PI between the two intrahepatic branches of the hepatic artery in patients with versus in patients without an APF were as follows: RI, 35% +/- 6 (range, 27%-42%) versus 5% +/- 4 (range, 0%-15%) (P:.001); PI, 50% +/- 5 (range, 41%-58%) versus 11% +/- 7 (range, 0%-26%) (P:.001).The intrahepatic arterial resistive and pulsatility indexes and the direction of portal blood flow should be evaluated in routine screening for APFs in patients with liver cirrhosis.

Background & Aims: The clinical importance of portal hypertensive gastropathy (PHG) as a source of gastrointestinal bleeding in patients with cirrhosis is poorly defined. We investigated the natural history of this condition in a large series of patients. Methods: All patients with cirrhosis seen at 7 hospitals during June and July 1992 were followed up with clinical and endoscopic examinations every 6 months for up to 3 years. Gastropathy was classified according to the classification of the New Italian Endoscopic Club. Results: The prevalence of gastropathy was 80% and was correlated with the duration of disease, presence and size of esophagogastric varices, and a previous history of endoscopic variceal sclerotherapy. During 18 ± 8 months of follow-up, gastropathy was stable in 29% of patients, deteriorated in 23%, improved in 23%, and fluctuated with time in 25%. The evolution of gastropathy with time was identical in patients with and without previous or current sclerotherapy. Acute bleeding from gastropathy occurred in 8 of 315 patients (2.5%). The bleeding-related mortality rate was 12.5%. Chronic bleeding occurred in 34 patients (10.8%). Conclusions: PHG is common in patients with cirrhosis, and its prevalence parallels the severity of portal hypertension. Gastropathy can progress from mild to severe and vice versa or even disappear completely. Bleeding from this lesion is relatively uncommon and rarely severe. Sclerotherapy of esophageal varices does not seem to influence the natural history of this condition. GASTROENTEROLOGY 2000;119:181-187