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Endocannabinoids contribute to hemodynamic abnormalities of cirrhosis. Whether this favors renal sodium retention and ascites formation is unknown. We determined whether cannabinoid type 1 receptor antagonism prevents sodium retention and ascites formation in preascitic cirrhotic rats.Once renal sodium handling was impaired, rats with carbon tetrachloride-induced cirrhosis were randomized to receive either vehicle or rimonabant (3 [group 1] or 10 [group 2] mg x kg(-1) x day(-1)) for 2 weeks. Natriuresis, sodium intake, and sodium balance were measured daily. At the end of the protocol, systemic hemodynamics, renal blood flow, ascites volume, and liver fibrosis were assessed.A significant reduction in ascites formation (group 1: 54%; group 2: 10%; vehicle: 90%) and volume (group 1: 1.6 +/- 0.3 mL; group 2: 0.5 mL; vehicle: 5.5 +/- 0.8 mL) occurred in treated rats. Rimonabant significantly improved sodium balance during week 2 (group 1: 0.98 +/- 0.08 mmol; group 2: 0.7 +/- 0.08 mmol; vehicle: 3.05 +/- 0.11 mmol). Both treated groups showed lower cardiac output and higher mean arterial pressure, peripheral vascular resistance, and renal blood flow (P.05). Liver fibrosis was reduced in group 2 by 30% (P.05 vs vehicle). Mean arterial pressure inversely correlated with sodium balance (R = -0.61; P = .003), but not with fibrosis score.Rimonabant improves sodium balance and delays decompensation in preascitic cirrhosis. This is achieved though an improvement in systemic and renal hemodynamics, although it cannot be excluded that the antifibrotic effect of the drug may play a role.

We describe an interesting case of a woman with decompensated cirrhosis, ischaemic heart disease and prolonged QT interval, who developed a new-onset atrial fibrillation. During amiodarone infusion a torsade de pointes occurred, which was immediately converted to sinus rhythm by synchronized cardioversion. A new episode of atrial fibrillation was treated with infusion of a beta-blocker (metoprolol) that restored sinus rhythm and normalized the QT interval. Delayed repolarization, frequently observed in ischaemic heart disease, cirrhosis and pro-arrhythmic drugs administration, represents the background for the development of torsade de pointes. Our report underlines that the potential harmfulness of a prolonged QT interval in cirrhotic patients is currently not perceived in its entirety, so that various categories of drugs affecting ventricular repolarization are rather thoughtlessly used in clinical practice without monitoring the QT interval. Thus, amiodarone should be avoided, if possible, or used with extreme care in arrhythmic patients with advanced liver disease. Moreover, beta-blockers may be considered the first-line treatment for rate-control during supraventricular tachyarrhythmias in cirrhotic patients with delayed repolarization.

Background/Aims Muscle wasting likely influences blood flow to muscle districts in advanced cirrhosis. Thus, we assessed systemic hemodynamics and femoral artery blood flow corrected by muscle mass of the lower limb in 13 patients (Child-Pugh classes B and C) and 11 healthy controls. Methods Systemic hemodynamics were assessed by transthoracic electrical bioimpedance, femoral artery blood flow by duplex-Doppler and muscle mass by magnetic resonance imaging. Results As expected, patients exhibited increased cardiac index and reduced peripheral vascular resistance. Femoral artery blood flow did not differ between patients and controls. However, when this parameter was indicized by the muscle mass of the lower limb, which was reduced in patients (median: 3391; range: [2546–4793] vs 5118 [3562–7077]cm 3 , p =0.0006), it proved almost doubled in patients (91.1 [59.9–119.4] vs 50.5 [38.6–69.8]μl/mincm 3 ; p =0.0001). Patient femoral blood flow indicized by muscle mass correlated inversely with peripheral vascular resistance ( r =−0.65; p =0.017) and directly with cardiac index ( r =0.57; p =0.042). Conclusions Vasodilation of muscle districts contributes to the reduced peripheral vascular resistance in advanced cirrhosis. Our findings provide a stronger rationale for the use of non-selective vasoconstrictors to treat hemodynamic-dependent complications of cirrhosis, such as hepatorenal syndrome.

To investigate whether the C-type natriuretic peptide (CNP) has a role in the regulation of fluid and sodium homeostasis in normal subjects and in pre-ascitic cirrhotic patients.The daily profile of CNP plasma levels was assessed by serial measurements (0700 h, 0900 h, 1800 h, 2300 h) in 10 pre-ascitic cirrhotic outpatients (age 56+/-4 years) and in 10 age-matched healthy controls (54+/-2 years) on a normal sodium diet (150 mmol/day) while carrying on their usual activities (mobile from 0700 h to 2200 h), after an equilibration period of 5 days. Daily diuresis and natriuresis were also monitored.Mean daily CNP was comparable in cirrhotic and healthy subjects (3.64+/-0.32 versus 3.20+/-0.20 pg/ml; p=0.139); CNP concentration showed a tendency towards a circadian fluctuation in healthy subjects (p=0.053) but not in patients (p=0.171). Mean daily CNP concentration significantly correlated with 24-h natriuresis (r=0.709; p=0.022) and urine volume (r=0.745; p=0.013) in patients but not in healthy subjects.CNP plasma levels appear to play a role in the water-sodium balance regulation in patients with pre-ascitic cirrhosis.

Abnormalities in cardiac electrophysiology are well documented in patients with liver cirrhosis. The mechanisms underlying their occurrence are not fully understood, although it is likely that some of these defects have common pathophysiogical alterations at molecular level. In order to attribute the electrophysiological abnormalities found in a patient to cirrhosis, it is important to exclude other causes of cardiac disease, such as ischemic, valvular, restrictive or congenital heart disease, as well as conduction abnormalities, arterial hypertension, lung disease or the use of anti-arrhythmic drugs. Patients who are actively drinking alcohol may have cardiac abnormalities due to alcohol abuse, and, as with cardiac abnormalities in patients with hemochromatosis, it may be difficult, if not impossible, to attribute an electrophysiologial abnormality to cirrhosis per se in these contexts. This review will deal with the three abnormalities of cardiac electrophysiology most frequently encountered in cirrhosis: (1) chronotropic incompetence; (2) electromechanical uncoupling, and (3) electrocardiographic QT interval prolongation.

The iatrogenic form of Kaposi's sarcoma (KS) is typically observed among transplant recipients, and the most appropriate therapeutic approach (usually including reduction of immunosuppression, specific chemotherapy, and/or administration of antiviral agents against human herpes virus-8) is still controversial. Available experiences on the effect of the anti-herpes viruses drug cidofovir provide conflicting results. Herein, we report the clinical, histological, and virological features of a liver transplant recipient successfully treated with a combined therapy of cidofovir and liposomal daunorubicin, associated with a reduction of the immunosuppressive regimen, for an advanced cutaneous and visceral KS.

Although the etiology of liver disease affects the features of hepatocellular carcinoma (HCC) diagnosed during surveillance, it is not known whether it influences patients' survival. We analyzed the impact of etiology on the characteristics and outcome of HCC detected during surveillance.In this cohort study, 742 patients with HCC detected during semiannual or annual surveillance were selected from the ITA.LI.CA database, including 1,834 consecutive patients observed in three primary and seven tertiary care settings for HCC. Patients were grouped according to etiology: hepatitis B virus (HBV, 87), hepatitis C virus (HCV, 461), alcohol (59), and multietiology (135).In all etiologic groups, most HCCs were unifocal (51-68%) and most of them wereor=3 cm (60-69%). Unifocal HCCs were less common in the multietiology group (P=0.050) and slightly more frequent in the HCV group (P=0.087). Besides etiology, only age was associated with gross pathology (P=0.023). About two-thirds of HCCs in all groups were discovered at Cancer of the Liver Italyn Program (CLIP) stage 0 or 1. The 1-, 3-, and 5-yr survival rates were comparable among groups (HBV 81%, 47%, and 22%; HCV 86%, 49%, and 24%; alcohol 76%, 41%, and 25%; multietiology 75%, 37%, and 24%; P=0.446). The surveillance interval did not influence survival, which was independently predicted by serum alpha-fetoprotein, Child-Pugh class, gross pathology, cancer size, vascular invasion, and treatment.In patients with HCC diagnosed during surveillance: (a) single nodules are less common in multietiology cases and (b) prognosis is independent of etiology, being dictated by liver function, oncologic features, and treatment.

Thromboelastography can be performed with native or citrated blood (a surrogate to native blood in healthy controls, surgical and cirrhotic patients). Activators such as kaolin are increasingly used to reduce the time to trace generation. To compare kaolin-activated thromboelastography with nonkaolin-activated thromboelastography of native and citrated blood in patients with liver disease, patients undergoing treatment with warfarin or low-molecular weight heparin and healthy volunteers. We studied thromboelastography parameters in 21 healthy volunteers (group 1) and 50 patients, including 20 patients with liver cirrhosis with a nonbiliary aetiology (group 2), 10 patients with primary biliary cirrhosis or primary sclerosing cholangitis (group 3), 10 patients on warfarin treatment (group 4) and 10 patients with enoxaparin prophylaxis (group 5). Thromboelastography was performed using four methods: native blood (kaolin-activated and nonkaolin-activated) and citrated blood (kaolin-activated and nonkaolin-activated). For all thromboelastography parameters, correlation was poor (Spearman correlation coefficient < 0.70) between nonkaolin-activated and kaolin-activated thromboelastography, for both citrated and native blood. In healthy volunteers, in patients with liver disease and in those receiving anticoagulant treatment, there was a poor correlation between nonkaolin-activated and kaolin-activated thromboelastography. Kaolin-activated thromboelastography needs further validation before routine clinical use in these settings, and the specific methodology must be considered in comparing published studies.

QT interval prolongation is frequent in cirrhosis, predicts a poor prognosis and may trigger severe ventricular arrhythmias. Our aim was to evaluate the effect of chronic beta-blockade on QT prolongation.Clinical and laboratory evaluation, ECG and hepatic vein pressure gradient (HVPG) measurement were performed in 30 cirrhotic patients before and 1-3 months after prophylactic nadolol. QT was corrected for heart rate by the cirrhosis-specific formula and other formulas.QT(cirrhosis) was prolonged in 10 patients (33%); HVPG was increased in all cases. QT(cirrhosis) was correlated with the Child-Pugh score (r=0.40; p=0.027). Nadolol shortened QT interval only with the Bazett formula (p=0.01), remaining unchanged with the other formulas. The QT interval shortened only if prolonged at baseline (from 473.3+/-5.5 to 458.4+/-6.5 ms; p=0.007), while it lengthened when normal (from 429.8+/-3.1 to 439.3+/-2.9 ms; p=0.01). QTc changes were directly related to the baseline value (p0.001). HVPG decreased from 19.4+/-0.8 to 15.6+/-1.3 mmHg (p=0.004). The HVPG changes did not correlate with QTc changes.Chronic beta-blockade shortens the QT interval only in patients with prolonged baseline values, and this is likely due to a direct cardiac effect.

Introduction: QT interval prolongation is a common electrophysiological abnormality in patients with cirrhosis. As QT interval varies with the heart rate, many QT correction formulas have been proposed, the Bazett's one being the most criticized because it overcorrects the QT interval and may be misleading. This study focused on the QT-RR relationship in patients with cirrhosis to derive a population-specific QT correction formula. Methods: One hundred cirrhotic patients of different etiology and severity and 53 healthy controls comparable for age and sex were enrolled. The QT-RR relationship was analyzed in patients by five regression analysis models to derive the population-specific QT-RR equation. The QTc was calculated and compared with those calculated by four common QT correction formulas (Bazett, Fridericia, Framingham, and Hodges). The correlation coefficient QTc-RR was calculated as a measure of the independence of QTc from the original RR interval. Results: In patients the QT-RR relationship was best described by the power equation “QT = 453.65 × RR1/3.02” (R2= 0.41), similar to the Fridericia's formula. Bazett's formula led to the longest QTc (P < 0.0001), which was still significantly influenced by the RR interval (R =−0.39; P < 0.0001), while the estimated equation led to a QTc value not influenced by RR (R =−0.014). Conclusion: Bazett's correction should be avoided in patients with cirrhosis because it still provides a rate-dependent QTc value and might be misleading, particularly when assessing the overall preoperative cardiac risk and the effect of drugs affecting the QT interval. In its place, our formula or that of Fridericia can be confidently employed.

To investigate the effects of unfractionated heparin (UFH), low molecular weight heparin (LMWH) and danaparoid (DPD) added to whole blood in vitro on standard and heparinase-modified thromboelastogram (TEG) parameters compared with conventional assays of coagulation. The effects of UFH, LMWH and DPD on standard TEG parameters were compared with the prothrombin time, activated partial thromboplastin time, thrombin time and anti-activated factor X (anti-FXa) activity, at concentrations of these anticoagulants ranging from 0.025 to 1 U/ml. In the second part of the study, the effects of very low concentrations (0.005-0.05 U/ml) of UFH, LMWH and DPD on the difference between standard and heparinase-modified TEG parameters were compared with the prothrombin time, activated partial thromboplastin time, thrombin time and anti-FXa activity. Standard TEG parameters were outside the reference range at lower concentrations of UFH, LMWH and DPD than most conventional coagulation assays were able to detect. Only anti-FXa activity was more sensitive to the presence of these anticoagulants than the standard TEG alone. The lowest concentration of UFH, LMWH and DPD used in this study (0.005 U/ml) caused significant differences between the standard and heparinase-modified alpha-angles of the TEG. In addition, the difference between standard and heparinase-modified TEG parameters distinguished between low concentrations (0.005-0.05 U/ml) of UFH with greater sensitivity than anti-FXa activity, but were less sensitive to LMWH and DPD. The standard TEG is more sensitive to UFH, LMWH and DPD than most conventional coagulation tests, with the exception of anti-FXa activity. Calculation of the difference between standard and heparinase-modified TEG parameters greatly increases the sensitivity of the assay for the effects of these anticoagulants, and is more sensitive to very low quantities of UFH than anti-FXa activity.

Bacterial infections have been proposed as a trigger for portal hypertensive bleeding in cirrhotic patients. Endogenous low molecular weight heparinoids have been previously detected in vitro by heparinase-modified thromboelastography, but it is not known what type of heparinoids they are. The aim of this study was to assay anti-Xa concentrations to detect heparin activity in infected cirrhotics in vivo.We evaluated 30 cirrhotic patients (15 with bacterial infection, 15 not infected) and 9 non-cirrhotic patients with bacterial infection. The anti-Xa assay was performed at the start of infection in all patients and after resolution of infection in 8 cirrhotics (5 to 10 days after starting antibiotics); thromboelastography (native and heparinase I-modified TEG) was performed in a subgroup of 11 cirrhotic patients with infection, 8 cirrhotics without infection and 8 non-cirrhotics with infection.Anti-Xa activity was detected in 9 of the 15 infected cirrhotics (60%) and only in 1 of 15 non-infected cirrhotics (6.7%) (P0.01). In the infected cirrhotic patients, a heparinase effect was shown in the heparinase I-modified TEG: k time (P0.01), alpha-angle (P0.01) and r time (P = 0.05), with no effect in the non-infected cirrhotics. Four of 9 (44%) infected non-cirrhotics were positive with the anti-Xa assay.In cirrhotic patients, bacterial infections modify haemostasis by producing endogenous heparin-like substances which can inhibit the activated clotting factor X (factor Xa). In infected non-cirrhotics, anti-Xa activity can also be found.

Background/Aims : A prolonged QT interval is frequent in chronic liver disease and its aetiology remains unsettled. The study's aim was to assess the role of portal hypertension in the pathogenesis of QT prolongation. Methods : We measured the QT interval in: (1) 10 patients with non-cirrhotic portal hypertension (NCPH) and preserved liver function; (2) 19 cirrhotic patients before, 1–3 and 6–9 months after transjugular intrahepatic porto-systemic shunt (TIPS) insertion. Results : Baseline corrected maximum QT interval (QTcmax) was prolonged (>440ms) in eight NCPH and 16 cirrhotic patients, and its value did not differ between the two groups (453±8 vs. 465±6ms, P =NS). No patients showed an abnormal baseline QT dispersion. In cirrhotic individuals, QTcmax further increased 1–3 months after TIPS ( P =0.042), thereafter remaining steadily elevated. QT dispersion only increased at the second post-TIPS determination ( P =0.030). Such changes occurred despite no deterioration of liver function, plasma electrolytes and haemoglobin. Conclusions : QT interval is frequently prolonged in patient with both non-cirrhotic and cirrhotic portal hypertension and portal decompression by TIPS worsens this abnormality. These results suggest that the porto-systemic shunting is responsible for the altered ventricular repolarisation possibly through a dumping into the systemic circulation of splanchnic-derived cardioactive substances.

We report a case of a 65-year-old woman with hepatitis C virus-related decompensated cirrhosis with hepatorenal syndrome, treated by high dose of terlipressin. Few hours after the highest dose was started, the patient complained burning pain in breasts, followed by the development of extensive bilateral cyanosis of breast's skin. When terlipressin was immediately stopped, pain and skin cyanosis rapidly disappeared. The peculiarity of our case is that cyanosis did not develop in common peripheral sites (e.g. fingers, toes, etc.) but in an atypical area, as skin of the breasts. Probably, this particular behaviour could be explained by the anatomical position of her large size breasts, that resulting as an extremely sloping and stretching region thus filling the maximum effect of gravity. (c) 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

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