Predictors of Spontaneous Bacterial Peritonitis (SBP) in Liver Cirrhosis: Current Knowledge and Future Frontiers

Spontaneous bacterial peritonitis (SBP) in patients with cirrhotic liver disease is a serious complication that contributes to the high morbidity and mortality rate seen in this population. Currently, there is a lack of consensus amongst the research community on the clinical predictors of SBP as well as the risks and benefits of prophylactic antibiotic therapy in these patients. Pharmacological gastric acid suppression (namely with PPIs and H2RAs) are frequently prescribed for these patients, many times without a clear indication, and may contribute to gut bacterial overflow and SBP development. However, this remains controversial as there are conflicting findings in SBP prevalence between PPI/H2RA-users and non-users. In addition, studies show recent antibiotic use, whether for SBP prophylaxis or for another infectious process, appear to be associated with higher rates of SBP and drug-resistant organisms. Other researchers have also explored the link between zinc, platelet indices (MPV), and macrophage inflammatory protein-1 β (MIP-1β) levels in liver cirrhosis, all of which appear to be promising markers for classifying SBP risk and diagnosis. This literature review was limited by the number and quality of studies available as most are retrospective in nature. Thus, more ongoing, prospective studies and trials are needed to judge the true value of the findings in the studies reviewed in hopes that they can guide appropriate prevention, diagnosis, and management of SBP.

Proton pump inhibitor use increases mortality and hepatic decompensation in liver cirrhosis

BACKGROUND Proton pump inhibitors(PPIs)are widely prescribed,often without clear indications.There are conflicting data on its association with mortality risk and hepatic decompensation in cirrhotic patients.Furthermore,PPI users and PPI exposure in some studies have been poorly defined with many confounding factors.AIM To examine if PPI use increases mortality and hepatic decompensation and the impact of cumulative PPI dose exposure.METHODS Data from patients with decompensated liver cirrhosis were extracted from a hospital database between 2013 to 2017.PPI users were defined as cumulative defined daily dose(cDDD)≥28 within a landmark period,after hospitalisation for hepatic decompensation.Cox regression analysis for comparison was done after propensity score adjustment.Further risk of hepatic decompensation was analysed by Poisson regression.RESULTS Among 295 decompensated cirrhosis patients,238 were PPI users and 57 were non-users.PPI users had higher mortality compared to non-users[adjusted HR=2.10,(1.20-3.67);P=0.009].Longer PPI use with cDDD>90 was associated with higher mortality,compared to non-users[aHR=2.27,(1.10-5.14);P=0.038].PPI users had a higher incidence of hospitalization for hepatic decompensation[aRR=1.61,(1.30-2.11);P<0.001].CONCLUSION PPI use in decompensated cirrhosis is associated with increased risk of mortality and hepatic decompensation.Longer PPI exposure with cDDD>90 increases the risk of mortality.

Polysomnographic sleep aspects in liver cirrhosis: A case control study

AIM: To study sleep aspects and parameters in cirrhotic patients and assess the role of liver dysfunction severity in polysomnographic results. METHODS: This was a case-control study. Patients with a diagnosis of liver cirrhosis were consecutively enrolled in the study. Clinical examinations and laboratory liver tests were performed in all patients, and disease severity was assessed using the Child-Pugh score. The control group consisted of ageand gender-matched healthy volunteers. All individuals answered a questionnaire about habits, behaviors, and complaints related to sleep and were submitted to polysomnography. Sleep parameters were compared between the two groups, and separate analyses were performed among classesof Child-Pugh classification in the cirrhotic group. RESULTS: Forty-two cirrhotic patients and forty-two controls were enrolled. Compared to the control group, the cirrhotic group exhibited lower sleep efficiency (mean ± SD: 73.89% ± 14.99% vs 84.43% ± 8.55%, P < 0.01), increased latency (151.27 ± 93.24 min vs 90.62 ± 54.74 min, P < 0.01) and a lower percentage of rapid eye movement (REM) sleep (14.04% ± 5.64% vs 20.71% ± 6.77%, P < 0.05) as well as a higher frequency of periodic limb movements (10.56 ± 2.85/h vs 2.79 ± 0.61/h, P < 0.01). The comparison of sleep parameters among Child A, B and C cirrhotic patients revealed a significant reduction of REM sleep stage occurrence in individuals with severe liver disease (Child C patients) compared to Child A/B patients (polysomnography percentage of REM sleep stage of patients Child A: 16.1% ± 1.2%; Child B: 14.9% ± 1.2%; Child C: 8.6% ± 1.6%, P < 0.05). CONCLUSION: Cirrhosis was associated with shorter sleep time, reduced sleep efficiency, increased sleep latency, increased REM latency and reduced REM sleep. Additionally, disease severity influences sleep parameters.

Changes in the etiology of liver cirrhosis and the corresponding management strategies

We read with interest the article by Xing Wang,which was published in the recent issue of the World Journal of Hepatology 2023;15:1294-1306.This article focuses particularly on the prevalence and trends in the etiology of liver cirrhosis(LC),prognosis for patients suffering from cirrhosis-related complications and hepatocellular carcinoma(HCC),and management strategies.The etiology of cirrhosis varies according to geographical,economic,and population factors.Viral hepatitis is the dominant cause in China.Vaccination and effective treatment have reduced the number of people with viral hepatitis,but the overall number is still large.Patients with viral hepatitis who progress over time to LC and HCC remain an important population to manage.The increased incidence of metabolic syndrome and alcohol consumption is likely to lead to a potential exponential increase in metabolic dysfunction-associated steatotic liver disease(MASLD)-associated LC and alcoholic liver disease in the future.Investigating the evolution of the etiology of LC is important for guiding the direction of future research and policy development.These changing trends indicate a need for greater emphasis on tackling obesity and diabetes,and implementing more effective measures to regulate alcohol consumption in order to reduce the occurrence of MASLD.In an effort to help cope with these changing trends,the authors further proposed countermeasures for healthcare authorities doctors,and patients.

Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia

A "leaky gut" may be the cutting edge for the passage of toxins, antigens or bacteria into the body, and may play a pathogenic role in advanced liver cirrhosis and its complications. Plasma endotoxin levels have been admitted as a surrogate marker of bacterial translocation and close relations of endotoxemia to hyperdynamic circulation, portal hypertension, renal, cardiac, pulmonary and coagulation disturbances have been reported. Bacterial overgrowth, increased intestinal permeability, failure to inactivate endotoxin,activated innate immunity are all likely to play a role in the pathological states of bacterial translocation. Therapeutic approach by management of the gut-liver axis by antibiotics, probiotics, synbiotics, prebiotics and their combinations may improve the clinical course of cirrhotic patients. Special concern should be paid on anti-endotoxin treatment. Adequate management of the gut-liver axis may be effective for prevention of liver cirrhosis itself by inhibiting the progression of fibrosis.

Analysis of the nitric oxide-cyclic guanosine monophosphate pathway in experimental liver cirrhosis suggests phosphodiesterase-5 as potential target to treat portal hypertension

AIM To investigate the potential effect of inhibitors of phosphodiesterase-5(PDE-5) for therapy of portal hypertension in liver cirrhosis.METHODS In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the nitric oxide-cyclic guanosine monophosphate(NO-cGMP) pathway was investigated. Expression and localization of PDE-5, the enzyme that converts vasodilating cGMP into inactive 5'-GMP, was in the focus of the study. Hepatic gene expression of key components of the NO-cGMP pathway was determined by qRT-PCR: Endothelial NO synthase(eNOS), inducible NO synthase(iNOS), soluble guanylate cyclase subunits α1 and β1(sGCa1, sGCb1), and PDE-5. Hepatic PDE-5 protein expression and localization were detected by immunohistochemistry. Serum cGMP concentrations were measured using ELISA. Acute effects of the PDE-5 inhibitor Sildenafil(0.1 mg/kg or 1.0 mg/kg) on portal and systemic hemodynamics were investigated using pressure transducers.RESULTS Hepatic gene expression of eNOS(2.2-fold; P = 0.003), sGCa1(1.7-fold; P = 0.003), sGCb1(3.0-fold; P = 0.003), and PDE-5(11-fold; P = 0.003) was increased in cirrhotic livers compared to healthy livers. Overexpression of PDE-5(7.7-fold; P = 0.006) was less pronounced in fibrotic livers. iNOS expression was only detected in fibrotic and cirrhotic livers. In healthy liver, PDE-5 protein was localized primarily in zone 3 hepatocytes and to a lesser extent in perisinusoidal cells. This zonation was disturbed in cirrhosis: PDE-5 protein expression in perisinusoidal cells was induced approximately 8-fold. In addition, PDE-5-expressing cells were also found in fibrous septa. Serum cGMP concentrations were reduced in rats with cirrhotic livers by approximately 40%. Inhibition of PDE-5 by Sildenafil caused a significant increase in serum cGMP concentrations [+ 64% in healthy rats(P = 0.024), + 85% in cirrhotic rats(P = 0.018)]. Concomitantly, the portal venous pressure was reduced by 19% in rats with liver cirrhosis. CONCLUSION Overexpression and abrogated zonation of PDE-5 likely contribute to the pathogenesis of cirrhotic portal hypertension. PDE-5 inhibition may therefore be a reasonable therapeutic approach for portal hypertension.

Arrhythmia risk in liver cirrhosis

Interactions between the functioning of the heart and the liver have been described, with heart diseases affecting the liver, liver diseases affecting the heart, and conditions that simultaneously affect both. The heart is one of the most adversely affected organs in patients with liver cirrhosis. For example, arrhythmias and electrocardiographic changes are observed in patients with liver cirrhosis. The risk for arrhythmia is influenced by factors such as cirrhotic cardiomyopathy, cardiac ion channel remodeling, electrolyte imbalances,impaired autonomic function, hepatorenal syndrome, metabolic abnormalities, advanced age, inflammatory syndrome, stressful events, impaired drug metabolism and comorbidities. Close monitoring of cirrhotic patients is needed for arrhythmias, particularly when QT intervalprolonging drugs are given, or if electrolyte imbalances or hepatorenal syndrome appear. Arrhythmia risk may persist after liver transplantation due to possible QT interval prolongation, persistence of the parasympathetic impairment, post-transplant reperfusion and chronic immunosuppression, as well as consideration of the fact that the transplant itself is a stressful event for the cardiovascular system. The aims of the present article were to provide a review of the most important data regarding the epidemiology, pathophysiology, and biomarkers of arrhythmia risk in patients with liver cirrhosis, to elucidate the association with long-term outcome, and to propose future research directions.

Clinical study on the relationship between liver cirrhosis,ascites,and hyponatremia

BACKGROUND Cirrhosis is a common liver disease,and ascites is one of the common clinical conditions.However,the clinical manifestations of ascites combined with hyponatremia as a high-risk condition and its relationship to patient prognosis have not been fully studied.AIM To explore the clinical manifestations,prognostic factors,and relationships of ascites with hyponatremia in patients with cirrhosis to provide better diagnostic and treatment strategies.METHODS In this study,we retrospectively analyzed the clinical data of 150 patients diagnosed with cirrhosis and ascites between 2017 and 2022.Patients were divided into two groups:ascites combined with hyponatremia group and ascites group.We compared the general characteristics,degree of hyponatremia,complications,treatment,and prognosis between the two groups.RESULTS In the study results,patients in the ascites combined with hyponatremia group showed an older average age(58.2±8.9 years),64.4%were male,and had a significantly longer hospitalization time(12.7±5.3 d).Hyponatremia was more severe in this group,with a mean serum sodium concentration of 128.5±4.3 mmol/L,which was significantly different from the ascites group of 137.6±2.1 mmol/L.Patients with ascites and hyponatremia were more likely to develop hepatic encephalopathy(56.2%vs 39.0%),renal impairment(45.2%vs 28.6%)and infection(37.0%vs 23.4%).Regarding treatment,this group more frequently used diuretics(80.8%vs 62.3%)and salt supplements(60.3%vs 38.9%).Multiple logistic regression analysis identified older age[Odds ratio(OR)=1.06,P=0.025]and male gender(OR=1.72,P=0.020)as risk factors for hyponatremia combined with ascites.Overall,patients with ascites and hyponatremia present a clear high-risk status,accompanied by severe complications and poor prognosis.CONCLUSION In patients with cirrhosis,ascites with hyponatremia is a high-risk condition that is often associated with severe complications.

Development and validation of a nomogram for predicting in-hospital mortality of intensive care unit patients with liver cirrhosis

BACKGROUND Liver cirrhosis patients admitted to intensive care unit(ICU)have a high mortality rate.AIM To establish and validate a nomogram for predicting in-hospital mortality of ICU patients with liver cirrhosis.METHODS We extracted demographic,etiological,vital sign,laboratory test,comorbidity,complication,treatment,and severity score data of liver cirrhosis patients from the Medical Information Mart for Intensive Care IV(MIMIC-IV)and electronic ICU(eICU)collaborative research database(eICU-CRD).Predictor selection and model building were based on the MIMIC-IV dataset.The variables selected through least absolute shrinkage and selection operator analysis were further screened through multivariate regression analysis to obtain final predictors.The final predictors were included in the multivariate logistic regression model,which was used to construct a nomogram.Finally,we conducted external validation using the eICU-CRD.The area under the receiver operating characteristic curve(AUC),decision curve,and calibration curve were used to assess the efficacy of the models.RESULTS Risk factors,including the mean respiratory rate,mean systolic blood pressure,mean heart rate,white blood cells,international normalized ratio,total bilirubin,age,invasive ventilation,vasopressor use,maximum stage of acute kidney injury,and sequential organ failure assessment score,were included in the multivariate logistic regression.The model achieved AUCs of 0.864 and 0.808 in the MIMIC-IV and eICU-CRD databases,respectively.The calibration curve also confirmed the predictive ability of the model,while the decision curve confirmed its clinical value.CONCLUSION The nomogram has high accuracy in predicting in-hospital mortality.Improving the included predictors may help improve the prognosis of patients.

Contemporary concepts of prevention and management of gastroesophageal variceal bleeding in liver cirrhosis patients

This editorial describes the contemporary concepts of prevention and management of gastroesophageal variceal bleeding in liver cirrhosis(LC)patients according to the current guidelines.Gastroesophageal variceal bleeding is the most dangerous complication of portal hypertension in LC patients.Risk stratification and determination of an individual approach to the choice of therapeutic measures aimed at their prevention and management has emerged as one of the top concerns in modern hepatology.According to the current guidelines,in the absence of clinically significant portal hypertension,etiological and nonetiological therapies of LC is advisable for the primary preventing gastroesophageal variceal bleeding,whereas its presence serves as an indication for the administration of non-selectiveβ-blockers,among which carvedilol is the drug of choice.Non-selectiveβ-blockers,as well as endoscopic variceal ligation and transjugular intrahepatic portosystemic shunt can be used to prevent recurrence of gastroesophageal variceal bleeding.Pharmacotherapy with vasoactive drugs(terlipressin,somatostatin,octreotide),endoscopic variceal ligation,endovascular techniques and transjugular intrahepatic portosystemic shunt are recommended for the treatment of acute gastroesophageal variceal bleeding.Objective and accurate risk stratification of gastroesophageal variceal bleeding will allow developing individual strategies for their prevention and management,avoiding the first and further decompensation in LC,which will improve the prognosis and survival of patients suffering from it.

Advancing hepatic recompensation:Baveno VII criteria and therapeutic innovations in liver cirrhosis management

The Baveno VII criteria redefine the management of decompensated liver cirrhosis,introducing the concept of hepatic recompensation marking a significant departure from the conventional view of irreversible decline.Central to this concept is addressing the underlying cause of cirrhosis through tailored therapies,including antivirals and lifestyle modifications.Studies on alcohol,hepatitis C virus,and hepatitis B virus-related cirrhosis demonstrate the efficacy of these interventions in improving liver function and patient outcomes.Transjugular intrahepatic portosystemic shunt(TIPS)emerges as a promising intervention,effectively resolving complications of portal hypertension and facilitating recompensation.However,optimal timing and patient selection for TIPS remain unresolved.Despite challenges,TIPS offers renewed hope for hepatic recompensation,marking a significant advancement in cirrhosis management.Further research is needed to refine its implementation and maximize its benefits.In conclusion,TIPS stands as a promising avenue for improving hepatic function and patient outcomes in decompensated liver cirrhosis within the framework of the Baveno VII criteria.

Liver cirrhosis-effect on QT interval and cardiac autonomic nervous system activity

AIM To examine the impact of liver cirrhosis on QT interval and cardiac autonomic neuropathy(CAN). METHODS A total of 51 patients with cirrhosis and 51 controls were examined. Standard 12-lead electrocardiogram recordings were obtained and QT as well as corrected QT interval(QTc) and their dispersions(dQT, dQTc) were measured and calculated using a computer-based program. The diagnosis of CAN was based upon the battery of the tests proposed by Ewing and Clarke and the consensus statements of the American Diabetes Association. CAN was diagnosed when two out of the four classical Ewing tests were abnormal. RESULTS QT, QTc and their dispersions were significantly longer(P < 0.01) in patients with cirrhosis than in controls. No significant differences in QT interval were found among the subgroups according to the etiology of cirrhosis. Multivariate regression analysis after controlling for age, gender and duration of cirrhosis demonstrated significant association between QT and presence of diabetes mellitus [standardized regression coefficient(beta) = 0.45, P = 0.02] and treatment with diuretics(beta = 0.55, P = 0.03), but not with the Child-Pugh score(P = 0.54). Prevalence of CAN was common(54.9%) among patients with cirrhosis and its severity was associated with the Child-Pugh score(r = 0.33, P = 0.02). Moreover, patients with decompensated cirrhosis had more severe CAN that those with compensated cirrhosis(P = 0.03). No significant association was found between severity of CAN and QT interval duration.CONCLUSION Patients with cirrhosis have QT prolongation. Treatment with diuretics is associated with longer QT. CAN is common in patients with cirrhosis and its severity is associated with severity of the disease.

PAI-1 4G-4G and MTHFR 677TT in non-hepatitis C virus/hepatitis B virus-related liver cirrhosis

AIM To evaluate the different roles of thrombophiliain patients with and without viral etiology. The thrombophilicgenetic factors （THRGFs）, PAI-1 4G-4G, MTHFR677TT, V Leiden 506Q and prothrombin 20210A,were studied as risk factors in 1079 patients with livercirrhosis （LC）, enrolled from January 2000 to January2014.METHODS： All Caucasian LC patients consecutivelyobserved in a seven year period were included; thepresence of portal vein thrombosis （PVT） and BuddChiari syndrome （BCS） was registered. The differencesbetween the proportions of each THRGF with regardto the presence or absence of viral etiology and thefrequencies of the THRGF genotypes with those predictedin a population by the Hardy-Weinberg equilibriumwere registered.RESULTS： Four hundred and seventeen/one thousandand seventy-six patients （38.6%） showed thrombophilia：217 PAI-1 4G-4G, 176 MTHFR C677TT, 71 V Leidenfactor and 41 prothrombin G20210 A, 84 with morethan 1 THRGF; 350 presented with no viral liver cirrhosis（NVLC） and 729 with, called viral liver cirrhosis （VLC）,of whom 56 patients were hepatitis C virus ＋ hepatitisB virus. PAI-1 4G-4G, MTHFR C677TT, the presence ofat least one TRHGF and the presence of 〉 1 THRGF,were statistically more frequent in patients with NVLC vspatients with VLC： All χ 2 〉 3.85 and P 〈 0.05. Patientswith PVT and/or BCS with at least one TRHGF were189/352 （53.7%）. The Hardy-Weinberg of PAI-1 andMTHFR 677 genotypes deviated from that expectedfrom a population in equilibrium in patients with NVLC（respectively χ 2 = 39.3; P 〈 0.000 and χ 2 = 27.94; P 〈0.05）, whereas the equilibrium was respected in VLC.CONCLUSION： MTHFR 677TT was nearly twofold andPAI-1 4G-4G more than threefold more frequently foundin NVLC vs patients with VLC; the Hardy-Weinbergequilibrium of these two polymorphisms confirms thisdata in NVLC. We suggest that PAI-1 4G-4G and MTHFR677TT could be considered as factors of fibrosis andthrombosis mechanisms, increasing the inflammationresponse, and causing the hepatic fibrosis and augmentedintrahepatic vascular resistance typical of LC. PAI-14G-4G and MTHFR 677TT screening of LC patientscould be useful, mainly in those with NVLC, to identifypatients in which new drug therapies based on theattenuation of the hepatic stellate cells activation orother mechanisms could be more easily evaluated.

Hepatocardiorenal syndrome in liver cirrhosis:Recognition of a new entity?

Emerging evidence and perspectives have pointed towards the heart playing an important role in hepatorenal syndrome(HRS),outside of conventional understanding that liver cirrhosis is traditionally considered the sole origin of a cascade of pathophysiological mechanisms directly affecting the kidneys in this context.In the absence of established heart disease,cirrhotic cardiomyopathy may occur more frequently in those with liver cirrhosis and kidney disease.It is a specific form of cardiac dysfunction characterized by blunted contractile responsiveness to stress stimuli and altered diastolic relaxation with electrophysiological abnormalities.Despite the clinical description of these potential cardiac-related complications of the liver,the role of the heart has traditionally been an overlooked aspect of circulatory dysfunction in HRS.Yet from a physiological sense,temporality(prior onset)of cardiorenal interactions in HRS and positive effects stemming from portosystemic shunting demonstrated an important role of the heart in the development and progression of kidney dysfunction in cirrhotic patients.In this review,we discuss current concepts surrounding how the heart may influence the development and progression of HRS,and the role of systemic inflammation and endothelial dysfunction causing circulatory dysfunction within this setting.The temporality of heart and kidney dysfunction in HRS will be discussed.For a subgroup of patients who receive portosystemic shunting,the dynamics of cardiorenal interactions following treatment is reviewed.Continued research to determine the unknowns in this topic is anticipated,hopefully to further clarify the intricacies surrounding the liver-heart-kidney connection and improve strategies for management.

Renal resistive index measurements by ultrasound in patients with liver cirrhosis:Magnitude and associations with renal dysfunction

BACKGROUND The hemodynamic alterations seen in liver cirrhosis lead to renal vasoconstriction,ultimately causing acute kidney injury(AKI).The renal resistive index(RRI)is the most common Doppler ultrasound variable for measuring intrarenal vascular resistance.AIM To evaluate the association of the RRI with AKI in patients with liver cirrhosis and to identify risk factors for high RRI.METHODS This was a prospective observational study,where RRI was measured using Doppler ultrasound in 200 consecutive hospitalized patients with cirrhosis.The association of RRI with AKI was studied.The receiver operating characteristic(ROC)curve analysis was utilized to determine discriminatory cut-offs of RRI for various AKI phenotypes.Multivariate analysis was conducted to determine the predictors of high RRI.RESULTS The mean patient age was 49.08±11.68 years,with the majority(79.5%)being male;the predominant etiology of cirrhosis was alcohol(39%).The mean RRI for the study cohort was 0.68±0.09,showing a progressive increase with higher Child-Pugh class of cirrhosis.Overall,AKI was present in 129(64.5%)patients.The mean RRI was significantly higher in patients with AKI compared to those without it(0.72±0.06 vs 0.60±0.08;P<0.001).A total of 82 patients(41%)had hepatorenal syndrome(HRS)-AKI,29(22.4%)had prerenal AKI(PRA),and 18(13.9%)had acute tubular necrosis(ATN)-AKI.The mean RRI was significantly higher in the ATN-AKI(0.80±0.02)and HRS-AKI(0.73±0.03)groups than in the PRA(0.63±0.07)and non-AKI(0.60±0.07)groups.RRI demonstrated excellent discriminatory ability in distinguishing ATN-AKI from non-ATN-AKI(area under ROC curve:93.9%).AKI emerged as an independent predictor of high RRI(adjusted odds ratio[OR]:11.52),and high RRI independently predicted mortality among AKI patients(adjusted OR:3.18).CONCLUSION In cirrhosis patients,RRI exhibited a significant association with AKI,effectively differentiated between AKI phenotypes,and predicted AKI mortality.

Spontaneous porto-systemic shunts in liver cirrhosis:Clinical and therapeutical aspects

Spontaneous porto-systemic shunts(SPSS)are frequent in liver cirrhosis and their prevalence increases as liver function deteriorates,probably as a consequence of worsening portal hypertension,but without achieving an effective protection against cirrhosis'complications.Several types of SPSS have been described in the literature,each one associated with different clinical manifestations.In particular,recurrent or persistent hepatic encephalopathy is more frequent in patients with splenorenal shunt,while the presence of gastric varices and consequently the incidence of variceal bleeding is more common in gastrorenal shunt.In the advanced stage,the presence of large SPSS can lead to the so called“portosystemic shunt syndrome”,characterized by a progressive deterioration of hepatic function,hepatic encephalopathy and,sometimes,portal vein thrombosis.The detection of SPSS in patients with liver cirrhosis is recommended in order to prevent or treat recurrent hepatic encephalopathy or variceal bleeding.

Yiguanjian decoction enhances fetal liver stem/progenitor cell-mediated repair of liver cirrhosis through regulation of macrophage activation state

AIM To investigate whether Yiguanjian decoction(YGJ) has an anti-liver cirrhotic effect and whether it regulates hepatic stem cell differentiation.METHODS A rat model of liver cirrhosis was established via subcutaneous injection of carbon tetrachloride(CCl4) for8 wk. From the beginning of the ninth week, the rats received 2-acetylaminofluorene(2-AAF) by oral gavage and a DLK-1+ fetal liver stem/progenitor cell(FLSPC)transplant or an FLSPC transplant in combination with YGJ treatment for 4 wk. In vitro, lipopolysaccharide(LPS)-activated macrophages were co-cultured with WB-F344 cells, and the differentiation of WB-F344 cells was observed in the presence and absence of YGJ treatment.RESULTS FLSPC transplantation improved liver function and histopathology, and inhibited the activation of the noncanonical Wnt signaling pathway, while activating the canonical Wnt signaling pathway. YGJ enhanced the therapeutic effects of FLSPCs and also promoted the liver regeneration differentiation of FLSPCs into hepatocytes.In vitro, LPS-activated macrophages promoted the differentiation of WB-F344 cells into myofibroblasts, and the canonical Wnt signaling was inhibited while the noncanonical Wnt signaling was activated in WB-F344 cells.YGJ suppressed the activation of macrophages and then inhibited non-canonical Wnt signaling and promoted canonical Wnt signaling.CONCLUSION YGJ enhances FLSPC-mediated repair of liver cirrhosis through regulation of macrophage activation state, and YGJ in combination with stem cell transplantation may be a suitable treatment for end-stage liver cirrhosis.

Plasma Nogo-A and placental growth factor levels are associated with portal hypertension in patients with liver cirrhosis

BACKGROUND Clinically significant portal hypertension(CSPH) and severe portal hypertension(SPH) increase the risk for decompensation and life-threatening complications in liver cirrhosis. Pathologic angiogenesis might contribute to the formation of these conditions. Placental growth factor(PlGF) and Nogo-A protein are biomarkers of pathological angiogenesis, but data on their role in liver cirrhosis and portal hypertension is scarce.AIM To determine plasma levels of PlGF and Nogo-A in patients with liver cirrhosis,CSPH, SPH and potential to predict portal hypertension.METHODS A cohort of 122 patients with hepatitis C virus and/or alcohol-induced liver cirrhosis with characterized hepatic venous pressure gradient(HVPG) were included in the study. Demographic data, medical history, Child-Turcotte-Pugh and Model of End Stage liver disease score, clinical chemistry, liver stiffnessvalues were recorded on the day of the procedure prior HVPG measurement. The degree of portal hypertension was determined by the invasive HVPG measurement. Nogo-A and PlGF plasma levels were evaluated using enzyme linked immunosorbent assay. The control group consisted of 30 healthy age-and sex-matched individuals.RESULTS Peripheral PlGF levels were higher and Nogo-A levels were lower in patients with liver cirrhosis(23.20 vs 9.85;P < 0.0001 and 2.19 vs 3.12;P = 0.004 respectively). There was a positive linear correlation between peripheral levels of PlGF and HVPG(r = 0.338, P = 0.001) and negative linear correlation between the peripheral Nogo-A levels and HVPG(r =-0.267, P = 0.007). PlGF levels were higher in CSPH and SPH(P = 0.006;P < 0.0001) whereas Nogo-A levels were lower(P = 0.01;P < 0.033). Area under the curve for the diagnosis of CSPH for PlGF was 0.68(P = 0.003) and for Nogo-A-0.67(P = 0.01);for SPH 0.714(P <0.0001) and 0.65(P = 0.014) respectively. PlGF levels were higher and Nogo-A levels were lower in patients with esophageal varices(P < 0.05). PlGF cut-off value of 25 pg/mL distinguished patients with CSPH at 55.7% sensitivity and76.7% specificity;whereas Nogo-A cut-off value of 1.12 ng/mL was highly specific(93.1%) for the diagnosis of CSPH.CONCLUSION Plasma PlGF levels were higher while Nogo-A levels were lower in patients with liver cirrhosis and portal hypertension. Biomarkers showed moderate predictive value in determining CSPH and SPH.

Prediction of liver cirrhosis, using diagnostic imaging tools

Early diagnosis of liver cirrhosis is important. Ultrasoundguided liver biopsy is the gold standard for diagnosis of liver cirrhosis. However, its invasiveness and sampling bias limit the applicability of the method. Basic imaging for the diagnosis of liver cirrhosis has developed over the last few decades, enabling early detection of morphological changes of the liver by ultrasonography(US), computed tomography, and magnetic resonance imaging(MRI). They are also accurate diagnostic methods for advanced liver cirrhosis, for which early diagnosis is difficult. There are a number of ways to compensate for this difficulty, including texture analysis to more closely identify the homogeneity of hepatic parenchyma, elastography to measure the stiffness and elasticity of the liver, and perfusion studies to determine the blood flow volume, transit time, and velocity. Amongst these methods, elastography using US and MRI was found to be slightly easier, faster, and able to provide an accurate diagnosis. Early diagnosis of liver cirrhosis using MRI or US elastography is therefore a realistic alternative, but further research is still needed.

Advances in gene therapy of liver cirrhosis: a review

INTRODUCTIONLiver fibrosis or cirrhosis is a common progressively pathological lesion of chronic liver diseases in response to various liver-damaging factors. The main mechanisms of fibrotic or cirrhotic initiation and progression at the level of cellular and molecular events have been elucidated in the past two decades[1,2].