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Chronic anaemia in advanced liver disease is a frequent finding. The aim was to explore the clinical impact of spur cell anaemia, a rare entity typically associated with end-stage of the disease. One-hundred and nineteen patients (73.9% males) with liver cirrhosis of any etiology were included. Patients with bone marrow diseases, nutrients deficiencies and hepatocellular carcinoma were excluded. In all patients, a blood sample was collected to check for the presence of spur cells on blood smear. A complete blood biochemical panel was recorded together with Child–Pugh (CP) score and Model for End-Stage Liver Disease (MELD) score. For each patients, clinically relevant events, such as acute-on-chronic liver failure (ACLF) and 1 year liver-related mortality, were registered. Patients were then grouped according to the percentage of spur cells at smear (> 5%, 1–5%, 5% spur cells, only 2 had evidence of haemolysis. In patients with > 5% spur cells, haemoglobin and albumin were lower compared with the other sub-group, while MELD score, CP score, International Normalized Ratio, ferritin, creatinine and unconjugated bilirubin were higher. Patients with more spur cells were more decompensated and developed more frequently ACLF. ACLF and liver-related mortality were significantly and independently associated with the presence of > 5% spur cells but not with baseline severe anaemia. Cirrhotic patients have a fairly high prevalence of spur cells, not always associated with severe haemolytic anaemia. The presence of spur red cells is per se associated with a worse prognosis and, therefore, should be always evaluated to prioritize patients for intensive management and eventually liver transplantation.

Post-resective liver failure is a frequent complication of liver surgery and it is due to portal hyperperfusion of the remnant liver and to arterial vasoconstriction, as buffer response of the hepatic artery. In this context, splenectomy allows a reduction of portal flow and increases the survival chance in preclinical models. SerpinB3 is over-expressed in the liver in oxidative stress conditions, as a mechanism of cell defense to provide survival by apoptosis inhibition and cell proliferation. In this study, the expression of SerpinB3 was assessed as predictor of liver damage in in vivo models of major hepatic resection with or without splenectomy. Wistar male rats were divided into 4 groups: group A received 30% hepatic resection, group B > 60% resection, group C > 60% resection with splenectomy and group D sham-operated. Before and after surgery liver function tests, echo Doppler ultrasound and gene expression were assessed. Transaminase values and ammonium were significantly higher in groups that underwent major hepatic resection. Echo Doppler ultrasound showed the highest portal flow and resistance of the hepatic artery in the group with > 60% hepatectomy without splenectomy, while the association of splenectomy determined no increase in portal flow and hepatic artery resistance. Only the group of rats without splenectomy showed higher shear-stress conditions, reflected by higher levels of HO-1, Nox1 and of Serpinb3, the latter associated with an increase of IL-6. In conclusion, splenectomy controls inflammation and oxidative damage, preventing the expression of Serpinb3. Therefore, SerpinB3 can be considered as a marker of post-resective shear stress.

Hepatocellular carcinoma (HCC) is the major cause of liver-related death worldwide. Interleukin 6 (IL-6) promotes the growth of the HCC microenvironment. The correlation between Child–Pugh (CP) and HCC stage and between HCC stage and sarcopenia is still not clear. Our aim was to investigate whether IL-6 is correlated with HCC stage and could represent a diagnostic marker for sarcopenia. Ninety-three HCC cirrhotic patients in different stages, according to BCLC-2022 (stages A, B, and C), were enrolled. Anthropometric and biochemical parameters, comprehensive of IL-6, were collected. The skeletal muscle index (SMI) was measured using dedicated software on computer tomography (CT) images. IL-6 level was higher in advanced (BCLC C) compared to the early-intermediate (BCLC A-B) stages (21.4 vs. 7.7 pg/mL, p < 0.005). On multivariate analysis, IL-6 levels were statistically dependent on the degree of liver disease severity (CP score) and HCC stages (p = 0.001 and p = 0.044, respectively). Sarcopenic patients presented lower BMI (24.7 ± 5.3 vs. 28.5 ± 7.0), higher PMN/lymphocyte ratio (2.9 ± 2.4 vs. 2.3 ± 1.2) and increased values of log (IL-6) (1.3 ± 0.6 vs. 1.1 ± 0.3). Univariate logistic regression between sarcopenia and log (IL-6) showed a significant odds ratio (OR 14.88, p = 0.044) with an AUC of 0.72. IL-6 appears to be an effective biomarker for the diagnosis of advanced cirrhotic HCC. In addition, IL-6 could be considered a marker of cirrhotic HCC-related sarcopenia, suggesting further investigation with BIA- or CT-dedicated software.

Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular (CV) risk. However, it is unclear whether NAFLD contributes independently to the development of CV disease. Our study aimed at assessing the differences in several indices of atherosclerosis, arterial stiffness and cardiac morphology among patients with isolated NAFLD, isolated hypertension (HT) or a combination of the two conditions.A total of 169 participants (mean age = 50.4 ± 10.2 yrs; males = 73.6%) were divided according to the presence of NAFLD and HT into three groups: only NAFLD (55 patients), only HT (49 patients), and NAFLD + HT (65 patients). Exclusion criteria were a BMI≥35 kg/mOvert atherosclerosis was significantly present only in NAFLD + HT patients, but not in patients with isolated NAFLD. This implies that the impact of NAFLD on vascular structure and function could depend on the coexistence of other major CV risk factors, such as HT.

Background Portal vein thrombosis is the most common thrombotic complication in cirrhosis. About 60% of anticoagulated patients can achieve recanalization. Despite fondaparinux (FPX) theoretical advantages, data are lacking about safety and efficacy for treatment of portal vein thrombosis in cirrhosis. Methods Cirrhotic patients with portal vein thrombosis treated with FPX or low-molecular-weight heparin (LMWH) were retrospectively included. The extension of thrombosis at baseline and its evolution during anticoagulant treatment were evaluated. Patients were treated with LMWH or FPX at therapeutic dosage and reduction was considered in selected cases. Results There were 124 patients included. Main portal vein branch, splenic, and superior mesenteric veins were involved in 84%, 13%, and 36% of cases, respectively. Forty-one patients (33%) were treated with FPX and 83 (67%) with LMWH. The probability of resolution of thrombosis at 36 months was significantly higher in patients treated with FPX than in those treated with LMWH (77% vs 51%; P = .001), particularly when prescribed at reduced dose. With multivariate analysis, the treatment with FPX (hazard ratio 2.38; P = .002) and use of a full dose (hazard ratio 1.78; P = .035) were independent predictors of portal vein full recanalization. Bleeding rate was higher in patients treated with FPX than in those treated with LMWH (27% vs 13%; P = .06). Conclusions FPX appears to be more effective than LMWH in the treatment of portal vein thrombosis when used at reduced dose, also in complete thrombosis. FPX should be considered among possible treatments for portal vein thrombosis in cirrhosis.

Aim. Nonalcoholic steatohepatitis (NASH) is the consequence of insulin resistance, fatty acid accumulation, oxidative stress, and lipotoxicity. We hypothesize that an increase in the inflammatory adipokine NOV decreases antioxidant Heme Oxygenase 1 (HO-1) levels in adipose and hepatic tissue, resulting in the development of NASH in obese mice. Methods. Mice were fed a high fat diet (HFD) and obese animals were administered an HO-1 inducer with or without an inhibitor of HO activity to examine levels of adipose-derived NOV and possible links between increased synthesis of inflammatory adipokines and hepatic pathology. Results. NASH mice displayed decreased HO-1 levels and HO activity, increased levels of hepatic heme, NOV, MMP2, hepcidin, and increased NAS scores and hepatic fibrosis. Increased HO-1 levels are associated with a decrease in NOV, improved hepatic NAS score, ameliorated fibrosis, and increases in mitochondrial integrity and insulin receptor phosphorylation. Adipose tissue function is disrupted in obesity as evidenced by an increase in proinflammatory molecules such as NOV and a decrease in adiponectin. Importantly, increased HO-1 levels are associated with a decrease of NOV, increased adiponectin levels, and increased levels of thermogenic and mitochondrial signaling associated genes in adipose tissue. Conclusions. These results suggest that the metabolic abnormalities in NASH are driven by decreased levels of hepatic HO-1 that is associated with an increase in the adipose-derived proinflammatory adipokine NOV in our obese mouse model of NASH. Concurrently, induction of HO-1 provides protection against insulin resistance as seen by increased insulin receptor phosphorylation. Pharmacological increases in HO-1 associated with decreases in NOV may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NASH.

AimsIncreased Ankyrin Repeat Domain 1 (ANKRD1) levels linked to gain of function mutations have been associated to total anomalous pulmonary venous return and adult cardiomyopathy occurrence in humans. The link between increased ANKRD1 level and cardiac structural and functional disease is not understood. To get insight into this problem, we have generated a gain of function ANKRD1 mouse model by overexpressing ANKRD1 in the myocardium.Methods and resultsAnkrd1 is expressed non-homogeneously in the embryonic myocardium, with a dynamic nucleo-sarcomeric localization in developing cardiomyocytes. ANKRD1 transgenic mice present sinus venosus defect, which originates during development by impaired remodelling of early embryonic heart. Adult transgenic hearts develop diastolic dysfunction with preserved ejection fraction, which progressively evolves into heart failure, as shown histologically and haemodynamically. Transgenic cardiomyocyte structure, sarcomeric assembly, and stability are progressively impaired from embryonic to adult life. Postnatal transgenic myofibrils also present characteristic functional alterations: impaired compliance at neonatal stage and impaired lusitropism in adult hearts. Altogether, our combined analyses suggest that impaired embryonic remodelling and adult heart dysfunction in ANKRD1 transgenic mice present a common ground of initial cardiomyocyte defects, which are exacerbated postnatally. Molecular analysis showed transient activation of GATA4-Nkx2.5 transcription in early transgenic embryos and subsequent dynamic transcriptional modulation within titin gene.ConclusionsANKRD1 is a fine mediator of cardiomyocyte response to haemodynamic load in the developing and adult heart. Increased ANKRD1 levels are sufficient to initiate an altered cellular phenotype, which is progressively exacerbated into a pathological organ response by the high ventricular workload during postnatal life. Our study defines for the first time a unifying picture for ANKRD1 role in heart development and disease and provides the first mechanistic link between ANKRD1 overexpression and cardiac disease onset.

Introduction and objectives: SerpinB3 is a cysteine protease inhibitor involved in several biological activities. It is progressively expressed in chronic liver disease, but not in normal liver. The role in vascular reactivity of this serpin, belonging to the same family of Angiotensin II, is still unknown. Our aim was to evaluate the in vivo and in vitro effects of SerpinB3 on systemic and splanchnic hemodynamics. Material and methods: Different hemodynamic parameters were evaluated by ultrasonography in two colonies of mice (transgenic for human SerpinB3 and C57BL/6J controls) at baseline and after chronic carbon tetrachloride (CCl4) treatment. In vitro SerpinB3 effect on mesenteric microvessels of 5 Wistar-Kyoto rats was analyzed measuring its direct action on: (a) preconstricted arteries, (b) dose–response curves to phenylephrine, before and after inhibition of angiotensin II type 1 receptors with irbesartan. Hearts of SerpinB3 transgenic mice and of the corresponding controls were also analyzed by morphometric assessment. Results: In SerpinB3 transgenic mice, cardiac output (51.6 ± 21.5 vs 30.1 ± 10.8 ml/min, p = 0.003), hepatic artery pulsatility index (0.85 ± 0.13 vs 0.65 ± 0.11, p

Hepcidin, a phase II reactant secreted by hepatocytes, regulates cellular iron levels by increasing internalization of ferroportin-a transmembrane protein facilitating egress of cellular iron. Chronic low-grade inflammatory states, such as obesity, have been shown to increase oxidative stress and enhance hepcidin secretion from hepatocytes and macrophages. Heme-heme oxygenase (HO) is a stress response system which reduces oxidative stress. We investigated the effects of HO-1 induction on hepatic hepcidin levels and on iron homeostasis in hepatic tissues from lean and obese mice. Obese mice exhibited hyperglycemia (p<0.05); increased levels of proinflammatory cytokines (MCP-1, IL-6,p<0.05); oxidative stress (p<0.05); and increased hepatic hepcidin levels (p<0.05). Enhancement of hepcidin was reflected in the reduced expression of ferroportin in obese mice (p<0.05). However, this effect is accompanied by a significant decline in ferritin expression. Additionally, there are reduced insulin receptor phosphorylation and attenuation of metabolic regulators pAMPK, pAKT, and pLKB1. Cobalt protoporphyrin- (CoPP-) induced HO-1 upregulation in obese mice reversed these alterations (p<0.05), while attenuating hepatic hepcidin levels. These effects of CoPP were prevented in obese mice concurrently exposed to an inhibitor of HO (SnMP) (p<0.05). Our results highlight a modulatory effect of HO on iron homeostasis mediated through the suppression of hepatic hepcidin.

Abstract Aim: Different animals are used as experimental models for the hepatic Ischemia- Reperfusion (IR) injury investigations and for each one of these animal models, many different surgical approaches have been performed. The aim of our study was to establish a new surgical pig model in which a hemi-liver is used to study the pathophysiology of hepatic IR injury. Contro-lateral hemi-liver is used as an internal control in the same animal. Methods: Liver ischemia was performed in six pigs by clamping the hepatic artery and vein and the portal vein to isolate the left hepatic lobe. Four hours of warm ischemia were followed by 4-hourrs of reperfusion. Biochemical and hematological analyses were performed throughout the experiments. Needle biopsies were obtained prior to ischemia and then hourly during the reperfusion for evaluation of tissue damage. To assess local temperature gradients on the liver surface a focal plane array detector camera was used. Results: Four hours ischemia induced mild signs of hepatic damage on the left ischemic lobe while more dramatic changes were evidenced after 2-hours reperfusion. Absence of tissue damage was detected on the right lobe. The liver functional test reached their maximum value at 2-4 hours after reperfusion. Conclusion: Our model is easy to perform, feasible and reproducible. This surgical model minimizes biases dependent on the individual response of different animals under the same conditions. In this IR model the new technology of an infrared thermocamera was used to control temperature changes and provide clinically important real-time information during surgery. Abbreviations: IR: Ischemia/Reperfusion; IV: Intravenous; ALP: Alkaline Phosphatase; ALT: Serum Alanine Aminotrasferase; AST: Aspartate Aminotransferase; LDH: Lactate Dehydrogenase; ROI: Region of Interest Keywords: Animal model; Infrared imaging; Liver ischemia reperfusion injury, Liver transplantation

Background and aims Blood lysosomal acid lipase (LAL) is reduced in non-alcoholic steatohepatitis, which is the major cause of cryptogenic cirrhosis (CC); few data on LAL activity in CC do exist. We investigated LAL activity in a cohort of patients with liver cirrhosis. Methods This is a multicentre cohort study including 274 patients with liver cirrhosis of different aetiology from 19 centres of Internal Medicine, Gastroenterology and Hepatology distributed throughout Italy. Blood LAL activity (nmol/spot/h) was measured with dried blood spot extracts using Lalistat 2. Results Overall, 133 patients had CC, and 141 patients had cirrhosis by other causes (61 viral, 53 alcoholic, 20 alcoholic + viral, 7 autoimmune). Mean age was 64.2 ± 13.4 years, and 28.5% were women. Patients with CC were older compared to other aetiology-cirrhosis, with a lower Child-Turcotte-Pugh (CTP, p=0.003) and MELD (p=0.009) score, and a higher prevalence of cardio-metabolic risk factors and previous ischemic events. In the whole cohort, median LAL activity value was 0.58 nmol/spot/h, 0.49 and 0.65 in the groups of CC and known-aetiology cirrhosis, respectively (p=0.002). The difference remained significant after adjustment for white blood cells count (p=0.001). Multivariable linear regression analysis showed that CC (vs. known aetiology, Beta = −0.144, p=0.018), platelet count (Beta = 0.398, p < 0.001) and CTP score (Beta = −0.133, p=0.022) were associated with log-LAL activity. Similar results were found using MELD as covariate. Conclusions We found a marked reduction of LAL activity in patients with cryptogenic cirrhosis compared to the other known aetiologies. A prospective study will clarify the role of LAL in chronic liver diseases.

Cardiorenal syndrome type 1 (CRS-1) is the acute kidney disfunction caused by an acute worsening of cardiac function. CRS-1 is the consequence of renal vasoconstriction secondary to renin-angiotensin system (RAS) activation. No animal models of CRS-1 are described in literature.To characterize a murine model of CRS-1 by using a high-resolution ultrasound echo-color Doppler system (VEVO2100).Post-ischemic heart failure was induced by coronary artery ligation (LAD) in seven CD1 mice. Fifteen and thirty days after surgery, mice underwent cardiac and renal echo-color Doppler. Serum creatinine and plasma renin activity were measured after killing. Animals were compared to seven CD1 control mice.Heart failure with left ventricle dilatation (end diastolic area, p 0.05 vs. controls) and significantly reduced ejection fraction (EF; p 0.01 vs. controls) was evident 15 days after LAD. We measured a significant renal vasoconstriction in infarcted mice characterized by increased renal pulsatility index (PI; p 0.05 vs. controls) associated to increased creatinine and renin levels (p 0.05 vs. controls).The mice model of LAD is a good model of CRS-1 evaluable by Doppler sonography and characterized by renal vasoconstriction due to the activation of the renin-angiotensin system secondary to heart failure.Per sindrome cardiorenale tipo-1 (SCR-1) si intende il peggioramento acuto della funzione renale dovuto alla riduzione della funzione cardiaca. La SCR-1 è conseguenza della vasocostrizione renale dovuta all’attivazione del sistema renina-angiotensina. In letteratura non sono descritti modelli animali che riproducono tale patologia. Obiettivo di questo studio è caratterizzare mediante l’utilizzo di un sistema ecografico ad alta risoluzione (VEVO2100) un modello murino di CRS-1.lo scompenso cardiaco post ischemico è stato indotto in 7 topi CD1 mediante legatura dell’arteria coronaria sinistra discendente anteriore. 15 e 30 giorni dopo la procedura chirurgica gli animali sono stati valutati mediante ecografia ed ecoDoppler cardiaco e renale. Gli animali sono stati sacrificati il trentesimo giorno e sono stati effettuati il dosaggio della creatinina sierica e dell’attività reninica plasmatica. I risultati sono stati confrontati con quelli ottenuti da 7 topi CD1 di controllo.la presenza di scompenso cardiaco, valutato mediante misurazione ecocardiografica dell’area telediastolica del ventricolo sinistro (EDA) e della frazione di eiezione (FE), è risultata evidente già 15 giorni dopo la LAD (rispettivamenteil modello murino di legatura di coronaria è un buon modello di SCR valutabile mediante ecoDoppler e caratterizzato da vasocostrizione renale e attivazione del sistema renina angiotensina.

Measurement of portal pressure is pivotal in the evaluation of patients with liver cirrhosis. The measurement of the hepatic venous pressure gradient represents the reference method by which portal pressure is estimated. However, it is an invasive procedure that requires significant hospital resources, including experienced staff, and is associated with considerable cost. Non-invasive methods that can be reliably used to estimate the presence and the degree of portal hypertension are urgently needed in clinical practice. Biochemical and morphological parameters have been proposed for this purpose, but have shown disappointing results overall. Splanchnic Doppler ultrasonography and the analysis of microbubble contrast agent kinetics with contrast-enhanced ultrasonography have shown better accuracy for the evaluation of patients with portal hypertension. A key advancement in the non-invasive evaluation of portal hypertension has been the introduction in clinical practice of methods able to measure stiffness in the liver, as well as stiffness/congestion in the spleen. According to the data published to date, it appears to be possible to rule out clinically significant portal hypertension in patients with cirrhosis (i.e., hepatic venous pressure gradient ≥ 10 mmHg) with a level of clinically-acceptable accuracy by combining measurements of liver stiffness and spleen stiffness along with Doppler ultrasound evaluation. It is probable that the combination of these methods may also allow for the identification of patients with the most serious degree of portal hypertension, and ongoing research is helping to ensure progress in this field.

To develop quantitative imaging biomarkers of synovial tissue perfusion by pixel-based contrast-enhanced ultrasound (CEUS), we studied the relationship between CEUS synovial vascular perfusion and the frequencies of pathogenic T helper (Th)-17 cells in psoriatic arthritis (PsA) joints. Eight consecutive patients with PsA were enrolled in this study. Gray scale CEUS evaluation was performed on the same joint immediately after joint aspiration, by automatic assessment perfusion data, using a new quantification approach of pixel-based analysis and the gamma-variate model. The set of perfusional parameters considered by the time intensity curve includes the maximum value (peak) of the signal intensity curve, the blood volume index or area under the curve, (BVI, AUC) and the contrast mean transit time (MTT). The direct ex vivo analysis of the frequencies of SF IL17A-F(+)CD161(+)IL23(+) CD4(+) T cells subsets were quantified by fluorescence-activated cell sorter (FACS). In cross-sectional analyses, when tested for multiple comparison setting, a false discovery rate at 10%, a common pattern of correlations between CEUS Peak, AUC (BVI) and MTT parameters with the IL17A-F(+)IL23(+) - IL17A-F(+)CD161(+) - and IL17A-F(+)CD161(+)IL23(+) CD4(+) T cells subsets, as well as lack of correlation between both peak and AUC values and both CD4(+)T and CD4(+)IL23(+) T cells, was observed. The pixel-based CEUS assessment is a truly measure synovial inflammation, as a useful tool to develop quantitative imaging biomarker for monitoring target therapeutics in PsA.

In liver cirrhosis, portal hypertension is a consequence of enhanced intrahepatic vascular resistance and portal blood flow. Significant vasodilation in the arterial splanchnic district is crucial for an increase in portal flow. In this pathological condition, increased levels of circulating endogenous vasodilators, including nitric oxide, prostacyclin, carbon monoxide, epoxyeicosatrienoic acids, glucagon, endogenous cannabinoids, and adrenomedullin, and a decreased vascular response to vasoconstrictors are the main mechanisms underlying splanchnic vasodilation. In this review, the molecular pathways leading to splanchnic vasodilation will be discussed in detail.

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

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.

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.

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

Heme oxygenase (HO) plays a critical role in attenuating the production of reactive oxygen species through its ability to degrade heme in an enzymatic process that leads to the production of equimolar amounts of carbon monoxide and biliverdin/bilirubin and the release of free iron. The present review examines the beneficial role of HO-1 (inducible form of HO) that is achieved by increased expression of this enzyme in renal tissue. The influence of the HO system on renal physiology, obesity, vascular dysfunction, and blood pressure regulation is reviewed, and the clinical potential of increased levels of HO-1 protein, HO activity, and HO-derived end products of heme degradation is discussed relative to renal disease. The use of pharmacological and genetic approaches to investigate the role of the HO system in the kidney is key to the development of therapeutic approaches to prevent the adverse effects that accrue due to an impairment in renal function.

Background Abdominal ultrasound can detect non-invasively the presence of abdominal portal-systemic collaterals in patients with liver cirrhosis. Abdominal portal-systemic collaterals may be protective from the formation and growth of oesophageal varices, but available data are inconclusive. Aim We aimed at investigating the relationship between abdominal portal-systemic collaterals and variceal formation and growth. Methods We studied 126 cirrhotic patients without (n = 43) or with small (n = 83) oesophageal varices who entered a protocol of serial ultrasonographic and endoscopic examinations for a median of 55 months. Presence and kind of abdominal portal-systemic collaterals was recorded on first ultrasonography and on each control thereafter. Results At inclusion, abdominal portal-systemic collaterals were found in 19/43 patients without varices and in 23/83 patients with small varices (NS). There was no difference in variceal formation and growth between patients with and without abdominal portal-systemic collaterals at inclusion. However, patients developing new abdominal portal-systemic collaterals during follow-up had a significantly higher rate of variceal formation (56.2% vs. 22.2%; p = 0.024) and growth (52.9% vs. 30.6%; p = 0.041) compared with patients with unchanged ultrasonography. Conclusions Abdominal collaterals are not protective from the formation or growth of oesophageal varices. Conversely, new abdominal portal-systemic collaterals emergence is a non-invasive clue of formation and progression of varices. Therefore, endoscopy is probably indicated whenever new abdominal portal-systemic collaterals are detected in cirrhotic patients.

Patients with cirrhosis present with hemostatic alterations secondary to reduced availability of pro-coagulant and anti-coagulant factors. The net effect of these changes is a rebalanced hemostatic system. The Italian Association of the Study of the Liver (AISF) and the Italian Society of Internal Medicine (SIMI) promoted a consensus conference on the hemostatic balance in patients with cirrhosis. The consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Rome in December 2014. The statements were graded according to quality of evidence and strength of recommendations, and approved by an independent jury. The statements presented here highlight strengths and weaknesses of current laboratory tests to assess bleeding and thrombotic risk in cirrhotic patients, the pathophysiology of hemostatic perturbations in this condition, and outline the optimal management of bleeding and thrombosis in patients with liver cirrhosis.

UNLABELLED In cirrhosis, 11,12-epoxyeicosatrienoic acid (EET) induces mesenteric arterial vasodilation, which contributes to the onset of portal hypertension. We evaluated the hemodynamic effects of in vivo inhibition of EET production in experimental cirrhosis. Sixteen control rats and 16 rats with carbon tetrachloride-induced cirrhosis were studied. Eight controls and eight rats with cirrhosis were treated with the specific epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH; 20 mg/kg/day) for 3 consecutive days. Portal blood flow and renal and splenic resistive indexes were calculated through echographic measurements, while portal and systemic pressures were measured through polyethylene-50 catheters. Small resistance mesenteric arteries were connected to a pressure servo controller in a video-monitored perfusion system, and concentration-response curves to phenylephrine and acetylcholine were evaluated. EET levels were measured in tissue homogenates of rat liver, kidney, and aorta, using an enzyme-linked immunosorbent assay. Urinary Na(+) excretion function was also evaluated. In rats with cirrhosis, treatment with MS-PPOH significantly reduced portal blood flow and portal pressure compared to vehicle (13.6 ± 5.7 versus 25.3 ± 7.1 mL/min/100 g body weight, P < 0.05; 9.6 ± 1.1 versus 12.2 ± 2.3 mm Hg, P < 0.05; respectively) without effects on systemic pressure. An increased response to acetylcholine of mesenteric arteries from rats with cirrhosis (50% effect concentration -7.083 ± 0.197 versus -6.517 ± 0.73 in control rats, P < 0.05) was reversed after inhibition of EET production (-6.388 ± 0.263, P < 0.05). In liver, kidney, and aorta from animals with cirrhosis, treatment with MS-PPOH reversed the increase in EET levels. In both controls and rats with cirrhosis, MS-PPOH increased urinary Na(+) excretion. CONCLUSION In rats with cirrhosis, in vivo inhibition of EET production normalizes the response of mesenteric arteries to vasodilators, with beneficial effects on portal hypertension. (Hepatology 2016;64:923-930).

The concept that patients with cirrhosis are at increased risk of bleeding events is probably out of date. Liver failure is accompanied by multiple changes in the hemostatic system, because of reduced plasma levels of procoagulative and anticoagulative clotting factors synthesized by the intact liver. Thrombocytopenia is very frequent ranking first among the altered hematological tests but Von Willebrand factor is elevated and ADAMTS-13 instead decreased, counterbalancing/compensating in some way the thrombocytopenia. The hemostatic system is then in a delicate balance between prothrombotic and antithrombotic processes. Since the global effect of liver disease on the hemostatic system is complex, patients with end-stage liver disease (ESLD) can experience severe bleeding or, at the opposite, thrombotic complications. Conventional coagulation tests such as prothrombin time (PT) and international normalized ratio (INR) are not able to provide information on the actual coagulation status of the patient as well as to predict possible bleeding or thrombotic events in patients with liver disease. Standard hemostatic tests which are inadequate to evaluate the so-called rebalanced hemostatic profile of the cirrhotic patient may provide misleading information regarding the risk of bleeding: in particular, clinicians have to be aware that unneeded, useless, or even dangerous pro-hemostatic factors might be administered with no demonstrated benefit. Because of the limits of conventional coagulation tests, in recent years, the viscoelastic tests (Thromboelastography/thromboelastomatry) have gained increasing importance. A more dynamic and targeted approach to the overall hemostatic process is at the base of their success providing a visual information on fibrinolysis, on the presence of endogenous heparinoids and tendency to hypercoagulability: these characteristics make these tests ideal for a rapid diagnosis of the type of coagulopathy and for an appropriate choice of the therapeutic option in patients with acute or chronic liver disease.

Increased resistance to portal flow and increased portal inflow due to mesenteric vasodilatation represent the main factors causing portal hypertension in cirrhosis. Endothelial cell dysfunction, defined as an imbalance between the synthesis, release, and effect of endothelial mediators of vascular tone, inflammation, thrombosis, and angiogenesis, plays a major role in the increase of resistance in portal circulation, in the decrease in the mesenteric one, in the development of collateral circulation. Reduced response to vasodilators in liver sinusoids and increased response in the mesenteric arterioles, and, viceversa, increased response to vasoconstrictors in the portal-sinusoidal circulation and decreased response in the mesenteric arterioles are also relevant to the pathophysiology of portal hypertension. Arachidonic acid (AA) metabolites through the three pathways, cyclooxygenase (COX), lipoxygenase, and cytochrome P450 monooxygenase and epoxygenase, are involved in endothelial dysfunction of portal hypertension. Increased thromboxane-A2 production by liver sinusoidal endothelial cells (LSECs) via increased COX-1 activity/expression, increased leukotriens, increased epoxyeicosatrienoic acids (EETs) (dilators of the peripheral arterial circulation, but vasoconstrictors of the portal-sinusoidal circulation), represent a major component in the increased portal resistance, in the decreased portal response to vasodilators and in the hyper-response to vasoconstrictors. Increased prostacyclin (PGI2) via COX-1 and COX-2 overexpression, and increased EETs/heme-oxygenase-1/K channels/gap junctions (endothelial derived hyperpolarizing factor system) play a major role in mesenteric vasodilatation, hyporeactivity to vasoconstrictors, and hyper-response to vasodilators. EETs, mediators of liver regeneration after hepatectomy and of angiogenesis, may play a role in the development of regenerative nodules and collateral circulation, through stimulation of vascular endothelial growth factor (VEGF) inside the liver and in the portal circulation. Pharmacological manipulation of AA metabolites may be beneficial for cirrhotic portal hypertension.

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.

Introduction Liver cirrhosis is characterized by structural and hemodynamic changes that affect mainly the liver, the kidney and the vascular system. Cytochrome P-450 (CYP) is a variegated family of enzymes that, among many other activities, metabolize arachidonic acid to the vasoactive epoxyeicosatrienoic acids (EETs). Aim To investigate in an animal model of cirrhosis the m-RNA expression of CYPs in liver, kidney and aorta and to evaluate the effect of epoxygenase inhibition by N -(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH). Methods In aorta, liver and kidney from 3 control, 3 cirrhotic and 6 cirrhotic rats treated with MS-PPOH, quantitative real-time PCR reactions were performed and the m-RNA expression of CYP2J3, CYP2J4, CYP2J10, CYP2C11, CYP2C12 and CYP2C23 was calculated. Results In cirrhotic rats, the gene expression of hepatic CYP2C11 and CYP2J10 was increased, of aortic CYP2J4 was increased, of aortic CYP2C12 was reduced and of renal CYP2C11 was increased. In cirrhotic rats, MS-PPOH reduced CYP2J10 hepatic and CYP2C11 renal gene expression to levels similar to the ones of control rats. Conclusions Changes in CYPs gene expression may contribute to the hemodynamic alterations typical of cirrhosis. The altered gene expression of CYPs can, in some cases, be reversed by epoxygenase inhibition.

Objective Nonalcoholic fatty liver disease is very frequent in both type 2 diabetes mellitus (T2DM) and the metabolic syndrome (MS), which share clinical and metabolic characteristics. Whether and to which extent these characteristics can predict the degree of liver steatosis are not entirely clear. Patients and methods We determined liver fat (divided into four classes) by standard sonographic images, and clinical and biochemical variables, in 60 consecutive patients with T2DM and with features of the MS. We examined both simple and multiple correlations between the degree of liver steatosis and the variables measured. Results Increased liver fat (defined as >5% of liver mass) was detected in 88% of the participants. Using simple regression analysis, the class of steatosis correlated positively with BMI, waist, number of factors of the MS, sex (female > male), diastolic blood pressure, insulin resistance, metabolic control, inflammation, C-reactive protein, fibrinogen, and leptin, whereas it correlated negatively with high-density lipoprotein-cholesterol. Using multiple regression analysis, only metabolic control, insulin resistance and/or plasma insulin, and waist, remained correlated significantly with the degree of steatosis. Using an ordered probit statistical model, metabolic control, waist, and insulin concentration predicted the steatosis class in 58% of the cases (¡Ü97% with allowance for one class in either excess or deficit). Conclusion In patients with T2DM, the extent of liver steatosis is correlated with variables associated with metabolic control and features of the MS. The combination of metabolic control, visceral obesity, and insulin resistance may reasonably predict the degree of liver steatosis in T2DM. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

The purpose of the study was to assess the relationship of the continuous mode contrast-enhanced harmonic ultrasound (CEUS) imaging with the histopathological and immunohistochemical (IHC) quantitative estimation of microvascular proliferation on synovial samples of patients affected by sustained psoriatic arthritis (PsA). A dedicated linear transducer was used in conjunction with a specific continuous mode contrast enhanced harmonic imaging technology with a second-generation sulfur hexafluoride-filled microbubbles C-agent. The examination was carried out within 1 week before arthroscopic biopsies in 32 active joints. Perfusional parameters were analyzed including regional blood flow (RBF); peak (PEAK) of the C-signal intensity, proportional to the regional blood volume (RBV); beta (β) perfusion frequency; slope (S), representing the inclination of the tangent in the origin; and the refilling time (RT), the reverse of beta. Arthroscopic synovial biopsies were targeted in the hypervascularity areas, as in the same knee recesses assessed by CEUS; the synovial cell infiltrate and vascularity (vessel density) was evaluated by IHC staining of CD45 (mononuclear cell) and CD31, CD105 (endothelial cell) markers, measured by computer-assisted morphometric analysis. In the CEUS area examined, the corresponding time-intensity curves demonstrated a slow rise time. Synovial histology showed slight increased layer lining thickness, perivascular lymphomonocyte cell infiltration, and microvascular remodeling, with marked vessel wall thickening with reduction of the vascular lumen. A significant correlation was found between RT and CD31+ as PEAK and CD105+ vessel density; RT was inversely correlated to RBF, PEAK, S, and β. The study demonstrated the association of the CEUS perfusion kinetics with the histopathological quantitative and morphologic estimation of synovial microvascular proliferation, suggesting that a CEUS imaging represents a reliable tool for the estimate of the synovial hypervascularity in PsA.