Recent advances in promising drugs for primary prevention of gastroesophageal variceal bleeding with cirrhotic portal hypertension

Background:Gastroesophageal variceal bleeding is one of the most severe complications of patients with cirrhosis.Although primary prevention drugs,including non-selectiveβ-blockers,have effectively reduced the incidence of bleeding,their efficacy is limited due to side effects and related contraindications.With recent advances in precision medicine,precise drug treatment provides better treatment efficacy.Data sources:Literature search was conducted in PubMed,MEDLINE and Web of Science for relevant articles published up to May 2022.Information on clinical trials was obtained from https://clinicaltrials.gov/and http://www.chictr.org.cn/.Results:The in-depth understanding of the pathogenesis and advances of portal hypertension has enabled the discovery of multiple molecular targets for promising drugs.According to the site of action,these drugs could be classified into four classes:intrahepatic,extrahepatic,both intrahepatic and extrahepatic targets and others.All these classes of drugs offer advantages over traditional treatments in prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.Conclusions:This review classified and summarized the promising drugs,which prevent gastroesophageal variceal bleeding by targeting specific markers of pathogenesis of portal hypertension,demonstrating the significance of using the precision medicine strategy to discover and develop promising drugs for the primary prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.

Value of red blood cell distribution width in prediction of diastolic dysfunction in cirrhotic cardiomyopathy

BACKGROUND Clinical diagnosis of cirrhotic cardiomyopathy(CCM) often encounters challenges of lack of timeliness and disease severity, with the commonly positive indicator usually associated with advanced heart failure.AIM To explore suitable biomarkers for early CCM prediction.METHODS A total of 505 eligible patients were enrolled in this study and divided into four groups according to Child-Pugh classification: Group Ⅰ, Class A without CCM(105 cases);Group Ⅱ, Class A with CCM(175 cases);Group Ⅲ, Class B with CCM(139 cases);and Group Ⅳ, Class C with CCM(86 cases). Logistic regression and receiver operating characteristic(ROC) curve analyses were performed to determine whether red blood cell distribution width(RDW) was an independent risk factor for CCM risk. The relationships between RDW and Child-Pugh scores, Model for End-Stage Liver Disease(MELD) scores, and N-terminal pro-brain natriuretic peptide(NT-proBNP) were analyzed by Pearson correlation analysis.RESULTS A constant RDW increase was evident from Group Ⅰ to Group Ⅳ(12.54 ± 0.85, 13.29 ± 1.19, 14.30 ± 1.96, and 16.25 ± 2.13, respectively). Pearson correlation analysis showed that RDW was positively correlated with Child-Pugh scores(r = 0.642, P < 0.001), MELD scores(r = 0.592, P < 0.001), and NT-proBNP(r = 0.715, P < 0.001). Furthermore, between Group Ⅰ and Group Ⅱ, RDW was the only significant index(odds ratio: 2.175, 95% confidence interval [CI]: 1.549-3.054, P < 0.001), and it reached statistical significance when examined by ROC curve analysis(area under the curve: 0.686, 95%CI: 0.624-0.748, P < 0.001).CONCLUSION RDW can serve as an effective and accessible clinical indicator for the prediction of diastolic dysfunction in CCM, in which a numerical value of more than 13.05% may indicate an increasing CCM risk.

Cirrhotic cardiomyopathy

During the course of cirrhosis, there is a progressive deterioration of cardiac function manifested by the disappearance of the hyperdynamic circulation due to afailure in heart function with decreased cardiac output. This is due to a deterioration in inotropic and chronotropic function which takes place in parallel with a diastolic dysfunction and cardiac hypertrophy in the absence of other known cardiac disease. Other findings of this specific cardiomyopathy include impaired contractile responsiveness to stress stimuli and electrophysiological abnormalities with prolonged QT interval. The pathogenic mechanisms of cirrhotic cardiomyopathy include impairment of the b-adrenergic receptor signalling, abnormal cardiomyocyte membrane lipid composition and biophysical properties, ion channel defects and overactivity of humoral cardiodepressant factors. Cirrhotic cardiomyopathy may be difficult to determine due to the lack of a specific diagnosis test. However, an echocardiogram allows the detection of the diastolic dysfunction and the E/e′ ratio may be used in the followup progression of the illness. Cirrhotic cardiomyopathy plays an important role in the pathogenesis of the impairment of effective arterial blood volume and correlates with the degree of liver failure. A clinical consequence of cardiac dysfunction is an inadequate cardiac response in the setting of vascular stress that may result in renal hypoperfusion leading to renal failure. The prognosis is difficult to establish but the severity of diastolic dysfunction may be a marker of mortality risk. Treatment is non-specific and liver transplantation may normalize the cardiac function.

Immunohistochemical assessment of angiogenesis in hepatocellular carcinoma and surrounding cirrhotic liver tissues

AIM: To investigate whether vascular endothelial growth factor (VEGF) was over-expressed in hepatocellular carcinoma (HCC) or in surrounding cirrhotic liver tissues.METHODS: Immunohistochemistry was performed to investigate the expression of VEGF proteins in HCC tissues from 105 consecutive patients undergoing curative resection for HCC. The immunostaining results and related clinicopathologic materials were analyzed with statistical methods. Kaplan-Meier method was used to calculate survival curves, and Log-rank test was performed to compare differences in survival rates of the patients with positive HCC staining and negative VEGF.RESULTS: VEGF-positive expression was found in 72 of105 HCC patients (68.6%). Capsular infiltration (P= 0.005),vascular invasion (P = 0.035) and intrahepatic metastasis(P=0.008) were observed more frequently in patients with VEGF-positive expression than in those with VEGFnegative expression. Kaplan-Meier curves showed that VEGF-positive expression was associated with a shorter overall survival (P = 0.014). VEGF-positive expression was found in 47 of tissues 68 HCC (69.1%), and VEGF-positive expression was found in 54 of 68 surrounding cirrhotic liver tissues (79.4%). VEGF-positive expression was significantly higher in surrounding cirrhotic liver tissues than in HCC (P= 0.017).CONCLUSION: VEGF may play an important role in the angiogenesis and prognosis of HCC, as well as in the angiogenesis of liver cirrhosis.

Reduced bone mineral density and altered bone turnover markers in patients with non-cirrhotic chronic hepatitis B or C infection

AIM: Previous studies suggest that loss of bone mineral density (BMD) frequently occurs in patients with chronic viral liver disease, presenting with histologically proven liver cirrhosis. However, little is known about the occurrence of bone disease in non-cirrhotic patients with chronic hepatitis B or C. Therefore, it was the aim of this study to evaluate this particular population for BMD and bone turnover markers. METHODS: Biochemical markers of bone turnover and BMD were measured in 43 consecutive patients with HCV (n = 30) or HBV (n = 13) infection without histological evidence for liver cirrhosis. Mean age was 49 years (range 26-77 years). BMD was measured by dual X-ray absorptiometry in the femoral neck (FN) and the lumbar spine (LS) region. In addition, bone metabolism markers were measured. RESULTS: BMD was lowered in 25 (58%) of the patients with chronic hepatitis B or C (FN; 0.76 (0.53-0.99); LS: 0.96 (0.62-1.23) g/cm2). Eight (32%) osteopenic patients were diagnosed with osteoporosis. Bone-specific alkaline phosphatase (P= 0.005) and intact parathyroid hormone (iPTH) (P = 0.001) were significantly elevated in the more advanced stages of fibrosis. Mean T-score value was lower in patients with chronic hepatitis C as compared to patients suffering from chronic hepatitis B; however, the difference was not statistically significant (P= 0.09). CONCLUSION: There was a significantly reduced BMD in non-cirrhotic patients with chronic hepatitis B or C infection. Alterations of bone metabolism already occurred in advanced liver fibrosis without cirrhosis. According to our results, these secondary effects of chronic viral hepatitis should be further investigated.

Cirrhotic cardiomyopathy: Implications for the perioperative management of liver transplant patients

Cirrhotic cardiomyopathy is a disease that has only recently been recognised as a definitive clinical entity. In the setting of liver cirrhosis, it is characterized by a blunted inotropic and chronotropic response t o s t r e s s, i m p a i r e d d i a s t o l i c r e l a x a t i o n o f t h e myocardium and prolongation of the QT interval in the absence of other known cardiac disease. A key pathological feature is the persistent over-activation of the sympathetic nervous system in cirrhosis, which leads to down-regulation and dysfunction of theβ-adrenergic receptor. Diagnosis can be made using a combination of echocardiography(resting and stress), tissue Doppler imaging, cardiac magnetic resonance imaging, 12-lead electrocardiogram and measurement of biomarkers. There are significant implications of cirrhotic cardiomyopathy in a number of clinical situations in which there is an increased physiological demand, which can lead to acute cardiac decompensation and heart failure. Prior to transplantation there is an increased risk of hepatorenal syndrome, cardiac failure following transjugular intrahepatic portosystemic shunt insertion and increased risk of arrhythmias during acute gastrointestinal bleeding. Liver transplantation presents the greatest physiological challenge with a further risk of acute cardiac decompensation. Peri-operative management should involve appropriate choice of graft and minimization of large fluctuations in preload and afterload. The avoidance of cardiac failure during this period has important prognostic implications, as there is evidence to suggest a long-term resolution of the abnormalities in cirrhotic cardiomyopathy.

Clinical research on navel application of Shehuang Paste combined with Chinese herbal colon dialysis in treatment of refractory cirrhotic ascites complicated with azotemia

AIM: To explore the efficacy and mechanism of a novel therapeutic method of traditional Chinese medicine in patients with refractory cirrhotic ascites complicated with azotemia. METHODS: Seventy-five cases of refractory cirrhotic ascites complicated with azotemia were randomly divided into 3 groups: comprehensive treatment (n = 29), simple treatment (n = 24), and control (n = 22). The basic treatment methods were the same in all groups, including liver protecting medicines, diuretics and supportive drugs. The control group underwent only the basic treatment. Shehuang Paste (SHP) was applied to the navels of the two treatment groups once a day for 30 d. Colon dialysis with Chinese herbs was administered to the comprehensive treatment group once every two days. Before and after treatment, we measured abdominal circumference, BUN, Cr, serum Na+, urine Na+/K+, liver function, endotoxin content, NO, and ET-1. Color Doppler ultrasonography was conducted to measure the portal vein blood flow. RESULTS: The total effective rate for ascites was 72.4% in the comprehensive treatment group, 45.8% in the simple treatment, contrasting with 18.2% in the controls. Between the two treatment groups and the controls, there were significant differences in the effective rates (P < 0.01, and P < 0.05). There was also a significant difference (P < 0.05) between the two treatment groups. Measurements of Cr and BUN showed higher values for the treatment groups, with the comprehensive better than the simple group (P < 0.05). Sera Na, urineNa/K were different, P < 0.01 between pre- and post- treatment in the comprehensive group, and P < 0.05 in the simple group. The treatment groups’ endotoxin content was also significantly reduced (P < 0.01, and P < 0.05), with the comprehensive group better than the simple group (P < 0.05). Portal vein blood flow and NO content significantly reduced (P < 0.05), as did ET-1 content (P < 0.01). There were no significant changes in the control group (P > 0.05). The comprehensive treatment group’s pre- and post-treatment portal vein and splenic vein blood flows showed a positive correlation to NO, ET-1 and endotoxin contents.CONCLUSION: When treating refractory cirrhotic ascites complicated with azotemia, Shehuang Paste combined with Chinese herbal dialysis is better than Shehuang Paste alone for ascites resolution, azotemia, and endotoxin elimination. However, both methods on their own were also effective for reducing portal and splenic vein blood flow, and lowering the contents of NO, ET-1 in the two treatment groups.

Diagnostic non-invasive model of large risky esophageal varices in cirrhotic hepatitis C virus patients

AIM To build a diagnostic non-invasive model for screening of large varices in cirrhotic hepatitis C virus(HCV) patients. METHODS This study was conducted on 124 post-HCV cirrhotic patients presenting to the clinics of the Endemic Medicine Department at Mansoura University Hospital for evaluation before HCV antiviral therapy: 78 were Child A and 46 were Child B(score ≤ 8). Inclusion criteria for patients enrolled in this study was presence of cirrhotic HCV(diagnosed by either biopsy or fulfillment of clinical basis). Exclusion criteria consisted of patients with other etiologies of liver cirrhosis, e.g., hepatitis B virus and patients with high MELD score on transplant list. All patients were subjected to full medical record, full basic investigations, endoscopy, and computed tomography(CT), and then divided into groups with no varices, small varices, or large risky varices. In addition, values of Fibrosis-4 score(FIB-4), aminotransferase-to-platelet ratio index(APRI), and platelet count/splenic diameter ratio(PC/SD) were also calculated.RESULTS Detection of large varies is a multi-factorial process, affected by many variables. Choosing binary logistic regression, dependent factors were either large or small varices while independent factors included CT variables such coronary vein diameter, portal vein(PV) diameter, lieno-renal shunt and other laboratory noninvasive variables namely FIB-4, APRI, and platelet count/splenic diameter. Receiver operating characteristic(ROC) curve was plotted to determine the accuracy of non-invasive parameters for predicting the presence of large esophageal varices and the area under the ROC curve for each one of these parameters was obtained. A model was established and the best model for prediction of large risky esophageal varices used both PC/SD and PV diameter(75% accuracy), while the logistic model equation was shown to be(PV diameter ×-0.256) plus(PC/SD ×-0.006) plus(8.155). Values nearing 2 or more denote large varices.CONCLUSION This model equation has 86.9% sensitivity and 57.1% specificity, and would be of clinical applicability with 75% accuracy.

Cirrhotic cardiomyopathy:Isn't stress evaluation alwaysrequired for the diagnosis?

AIM:To describe the proportion of patients with cirrhotic cardiomyopathy(CCM) evaluated by stress echocardiography and investigating its association with the severity of liver disease.METHODS:A cross-sectional study was conducted.Cirrhotic patients without risk factors for cardiovascular disease were included.Data regarding etiology and severity of liver disease(Child-Pugh score and model for end-stage liver disease),presence of ascites and gastroesophageal varices,pro-brain natriuretic peptide(proBNP) and corrected QT(QTc) interval were collected.Dobutamine stress echocardiography(conventional and tissue Doppler imaging) was performed.CCM was considered present when diastolic and/or systolic dysfunction was diagnosed at rest or after pharmacological stress.Therapy interfering with cardiovascular system was suspended 24 h before the examination.RESULTS:Twenty-six patients were analyzed,17(65.4%) Child-Pugh A,mean model for end-stage liver disease(MELD) score of 8.7.The global proportion of patients with CCM was 61.5%.At rest,only 2(7.7%)patients had diastolic dysfunction and none of the patients had systolic dysfunction.Dobutamine stress echocardiography revealed the presence of diastolic dysfunction in more 6(23.1%) patients and of systolic dysfunction in 10(38.5%) patients.QTc interval prolongation was observed in 68.8%of the patients and increased pro-BNP levels in 31.2%of them.There was no association between the presence of CCM and liver impairment assessed by Child-Pugh score or MELD(P= 0.775,P= 0.532,respectively).Patients with QTc interval prolongation had a significant higher rate of gastroesophageal varices comparing with those without QTc interval prolongation(95.0%vs 50.0%,P= 0.028).CONCLUSION:CCM is a frequent complication of cirrhosis that is independent of liver impairment.Stress evaluation should always be performed,otherwise it will remain an underdiagnosed condition.

VEGF in hepatocellular carcinoma and surrounding cirrhotic liver tissues

We read with a great interest the recent work of Deli and colleagues. in the World Journal of Gastroenterology reporting vascular endothelial growth factor （VEGF） expression in hepatocellular carcinoma （HCC） and cirrhotic liver tissues. This well-documented work shows that VEGF was significantly higher in surrounding cirrhotic liver tissues than in HCC. Authors assessed VEGF expression using immunohistochemistry. The immunohistochemical staining is an efficient tool to assess the percentage of cells stained positively for VEGF but is not really efficient to estimate their true VEGF content. Evaluation of the VEGF protein by an enzyme-linked immunosorbent assay 0ELISA） has been reported, by us and others, to be an efficient tool in order to assess tissue VEGF expression. We have, thus, tested whether the ELISA method might be an efficient tool in order to confirm data reporting higher amounts of VEGF in surrounding cirrhotic liver tissues than in HCC. Deli and colleagues. also correctly pointed out that basic fibroblast growth factor （bFGF） has been reported to act cooperatively on VEGF expression. We have, thus, also assessed bFGF tissue levels in order to search for a putative link between VEGF and bFGF levels in cirrhotic tissues.

Protective effect of omeprazole on gastric mucosal of cirrhotic portal hypertension rats

Objective:To observe the protective effect of omeprazole on gastric mucosal of cirrhotic portal hypertension rats.Methods:All rats were randomly divided into normal control group,cirrhosis and treatment group.Thioacetamide was used to establish rat model of cirrhotic portal hypertension.The necrotic tissue of gastric mucosa ulcer focus,degree of neutrophils infiltration at the ulcer margin,portal pressure,portal venous flow,abdominal aortic pressure,abdominal aortic blood flow at front end,gastric mucosal blood flow（GMBF）,glycoprotein（GP）of gastric mucosa,basal acid secretion,H’ back-diffusion,gastric mucosal damage index,NO,prostaglandin E2（PGE2） and tumor necrosis factor-α（TNF-α） were determined respectively,and the pathological changes of gastric mucosa were also observed by microscope.Results:Compared with cirrhosis group and the control group,the ulcer bottom necrotic material,gastric neutrophil infiltration and UI of the treatment group were all decreased significantly（P【0.01）,GMBF value,GP values,serum NO,PGE2,TNF- a were all significantly increased.Conclusions:Omeprazole has an important protective effect on gastric mucosal and it can increase gastric mucosal blood flow and related to many factors.

Preoperative trans-jugular porto-systemic shunt for oncological gastric surgery in a cirrhotic patient

Abdominal surgery in cirrhotic patients with portal hypertension is associated with high incidence ofdisease and mortality.In these patients,oncological gastric procedures with lymph-nodes dissection show much higher complication rates than in normotensive portal vein patients.Thus,normalization of portal vein pressure may be a favorable determinant factor to reduce complications.We report a case of a patient with hepatitis C virus-related hepatic cirrhosis,esophageal varices,portal hypertension and gastric cancer.We demonstrated the efficacy of a preoperative trans-jugular porto-systemic shunt to perform oncological radical resection more safely.We retained preoperative the trans-jugular porto-systemic shunt in the patients with elevated portal pressure and gastric cancer to perform a gastrectomy more safely and to decrease morbidity and mortality of these cases.

Non-Invasive Vibration-Stress of the Cirrhotic Liver of Patients Waiting for Transplantation Induces of Circulating CD133+ Stem Lymphocytes Committed Phenotypically toward the Liver

Background: Numerous studies of tissues’ regeneration have confessed the recovery of damaged liver by hematopoietic stem cells. The cells act not only by cell replacement in the target organ but also by delivering trophic factors that support endogenous liver regeneration. A little is known of how organ-derived signals recruit such committed cells into circulation. Objective: We investigated the roles of noninvasive mechanical percutaneous stress of cirrhotic human liver in numbers fluctuation of trophic, liver-specific alpha-fetoprotein-positive fraction of CD133-positive hematopoietic stem cells in lymphocytes of patients waiting for liver transplantation. Methods: To promote in blood the number of the alpha-fetoprotein-positive fraction of CD133-positive hematopoietic stem cells, committed to liver’ tissue, we activated mechanically the cirrhotic liver of patient by transcutaneous micro vibration received from skin-contacted electro-magnetic vibraphones generated mechanical pulses with amplitude 10 μm and smoothly changing frequency from 0.03 kHz to 18 kHz and back forth during one cycle duration 1 minute. The number of the alpha-fetoprotein-positive fraction of CD133-positive hematopoietic stem cells in lymphocytes of potential recipients was controlled by flow cytometry before and during daily sonication of skin area, which corresponds to liver projection on it. The 15 minutes cyclic sonication of the liver area performed daily for three weeks. Results: The sonication increased significantly averaged number of liver-specific alpha-fetoprotein-positive CD133-positive blood lymphocytes in 2 - 3 times compared to a base lane. The second similar sonication, the same zone after three weeks break showed differences with baseline, but it was statistically insignificant. The result was specifically related to the liver as it showed the control sonication of the backbone’s projection on the skin of a separate group of patients with cirrhotic liver from the waiting list. Conclusion: The stem cells committed to the liver recruit from the bone marrow into circulation, when organ mechanically stresses and secretes specific humoral signals to provoke of lymphopoiesis on host liver repair.

Combination of squamous cell carcinoma antigen immunocomplex and alpha-fetoprotein in mid-and long-term prediction of hepatocellular carcinoma among cirrhotic patients

BACKGROUND The combination of alpha-fetoprotein(AFP)and squamous cell carcinoma antigen immunocomplex(SCCA-IgM)have been proposed for its use in the screening of hepatocellular carcinoma(HCC).Current screening programs for all cirrhotic patients are controversial and a personalized screening is an unmet need in the precision medicine era.AIM To determine the role of the combination of SCCA-IgM and AFP in predicting mid-and long-term appearance of HCC.METHODS Two-hundred and three cirrhotic patients(Child A 74.9%,B 21.2%,C 3.9%)were followed-up prospectively every six months to screen HCC by ultrasound and AFP according to European Association for the Study of the Liver guidelines.The estimation cohort was recruited in Italy(30.5%;62/203)and validation cohort from Spain(69.5%;141/203).Patients underwent to evaluate SCCA-IgM by enzyme-linked immunosorbent assay(Hepa-IC,Xeptagen,Italy)and AFP levels at baseline.Patients were followed-up for 60 mo,being censored at the time of the appearance of HCC.RESULTS There were 10.8%and 23.1%of HCC development at two-and five-years followup.Patients with HCC showed higher levels of SCCA-IgM than those without it(425.72±568.33 AU/mL vs 195.93±188.40 AU/mL,P=0.009)during the fiveyear follow-up.In multivariate analysis,after adjusting by age,sex,aspartate transaminase and Child-Pugh,the following factors were independently associated with HCC:SCCA-IgM[Hazard ratio(HR)=1.001,95%CI:1.000-1.002;P=0.003],AFP(HR=1.028,95%CI:1.009-1.046;P=0.003)and creatinine(HR=1.56495%CI:1.151-2.124;P=0.004).The log-rank test of the combination resulted in 7.488(P=0.024)in estimation cohort and 11.061(P=0.004)in the validation cohort,and a 100%of correctly classified rate identifying a low-risk group in both cohorts in the two-year follow-up.CONCLUSION We have constructed a predictive model based on the combination of SCCA-IgM and AFP that provides a new HCC screening method,which could be followed by tailored HCC surveillance for individual patients,especially for those cirrhotic patients belonging to the subgroup identified as low-risk of HCC development.

Prolonged QTc Interval Is an Electrophysiological Hallmark of Cirrhotic Cardiomyopathy

BACKGROUND: Cirrhotic Cardiomyopathy is a relatively ill-characterized condition, which is often under-diagnosed due to absence of defined diagnostic criteria. ECG showing corrected QT Interval prolongation is the most suitable available option for diagnosis of this condition. OBJECTIVE: To determine the frequency of corrected QT interval prolongation in patients with liver cirrhosis. METHODOLOGY: Patients (n = 166) with confirmed cirrhosis, 30 years or older, presented in the outpatient and emergency department of medicine at Capital Hospital Islamabad between 1 October 2011 and 30 September 2012, were enrolled in this cross-sectional study after taking consent. ECG was done using calibrated ECG machine, and the QT Interval was measured. Corrected QT was calculated using Bazett’s formula and a QTc of more than 0.44 seconds was considered as being prolonged. RESULTS: The mean age of the patients was 57.05 ± 12.03 years. The corrected QT Interval varied from 337 ms to 560 ms. The mean QTc Interval was 429.92 ms ± 45.11. QTc was prolonged in 41 out of 166 patients (24.7%). Frequency of QTc prolongation was 4.5% in Child Pugh Grade A, 23.2% in Child Pugh Grade B, and 32.0% in Child Pugh Grade C. Association of Child Pugh Scoring with QTc prolongation was determined and found to be statistically significant (P < 0.05). CONCLUSION: QTc interval was prolonged in 24.7% of cirrhotic patients in our study. There was a significant increase in frequency with worsening of Child Pugh Grade, thereby indicating an association between QTc prolongation and the severity of cirrhosis.

Contribution of mammalian target of rapamycin in the pathophysiology of cirrhotic cardiomyopathy

AIM: To explore the role of mammalian target of rapamycin(m TOR) in the pathogenesis of cirrhotic cardiomyopathy and the potential of rapamycin to improve this pathologic condition.METHODS: Male albino Wistar rats weighing 100-120 g were treated with tetrachloride carbon(CCl_4) for 8 wk to induce cirrhosis. Subsequently, animals were administered rapamycin(2 mg/kg per day). The QT_c intervals were calculated in a 5-min electrocardiogram. Then, the left ventricular papillary muscles wereisolated to examine inotropic responsiveness to β-adrenergic stimulation using a standard organ bath equipped by Powerlab system. Phosphorylated-m TOR localization in left ventricles was immunohistochemically assessed, and ventricular tumor necrosis factor(TNF)-α was measured. Western blot was used to measure levels of ventricular phosphorylated-m TOR protein.RESULTS: Cirrhosis was confirmed by hematoxylin and eosin staining of liver tissues, visual observation of lethargy, weight loss, jaundice, brown urine, ascites, liver stiffness, and a significant increase of spleen weight(P < 0.001). A significant prolongation in QTc intervals occurred in cirrhotic rats exposed to CCl_4(P < 0.001), while this prolongation was decreased with rapamycin treatment(P < 0.01). CCl_4-induced cirrhosis caused a significant decrease of contractile responsiveness to isoproterenol stimulation and a significant increase in cardiac TNF-α. These findings were correlated with data from western blot and immunohistochemical studies on phosphorylated-m TOR expression in left ventricles. Phosphorylated-m TOR was significantly enhanced in cirrhotic rats, especially in the endothelium, compared to controls. Rapamycin treatment significantly increased contractile force and myocardial localization of phosphorylated-m TOR and decreased cardiac TNF-α concentration compared to cirrhotic rats with no treatment. CONCLUSION: In this study, we demonstrated a potential role for cardiac m TOR in the pathophysiology of cirrhotic cardiomyopathy. Rapamycin normalized the inotropic effect and altered phosphorylated-m TOR expression and myocardial localization in cirrhotic rats.

Antibody and complement levels in patients with hypersplenism associated with cirrhotic portal hypertension and therapeutic principles

BACKGROUND Hypersplenism associated with cirrhotic portal hypertension is a common condition often resulting from hepatitis B-related cirrhosis.However,the levels of immunoglobulin(Ig)and complement in patients with hypersplenism associated with cirrhotic portal hypertension remain unclear.This study was undertaken to determine the levels of Ig and complement in these patients,the relationship between these levels and Child-Pugh class and their clinical significance.AIM To investigate the antibody(Ig)and complement levels in patients with hypersplenism associated with cirrhotic portal hypertension and their clinical significance.METHODS Clinical data of 119 patients with hypersplenism associated with cirrhotic portal hypertension were statistically analyzed and compared with those of 128 control patients.RESULTS IgA and IgG levels in patients with hypersplenism were significantly higher than controls(P<0.001).There was no significant difference in IgM between the two groups(P=0.109).C3 and C4 levels in patients with hypersplenism were significantly lower than controls(P<0.001).As liver function decreased,IgA and IgG levels increased(P<0.001),and C3 and C4 levels decreased(P<0.001).CONCLUSION Patients with hypersplenism associated with cirrhotic portal hypertension have significantly higher antibody(IgA and IgG)levels and significantly lower complement(C3 and C4)levels,which are both related to liver damage.Clinically,the administration of anti-hepatitis virus agents and protection of liver function should be strengthened.

MR Features of Regenerative Nodules and Dysplastic Nodules in the Cirrhotic Liver

Summary： In order to study MR features of the regenerative nodule （RN） and dysplastic nodule （DN） of the cirrhotic liver, 26 cases of cirrhotic liver with RNs and DNs, of which 8 cases accompanied with hepatocellular carcinoma, were subjected to MRI. Eighteen of 26 cases underwent additional enhanced MRI with administration of Gd-DTPA on T1WI and 10 of the 18 cases did additional SPIO （Feridex） enhancement on T2W1. Clinical data showed normal level of α-fetoprotein in 18 cases except 8 cases accompanied with HCC. The results showed that 12 cases had RNs with nodules measuring 〈1 cm. The MR appearance of those RNs showed isointensity on T1WI and hypointensity on T2WI. The intensity of those RNs was isointense to the surrounding hepatic parenchyma on enhanced MRI with administration of Gd-DTPA or SPIO. Among the 14 cases of DNs, 8 cases had nodules measuring 1-3 cm in size and 6 had macroregenerative nodule measuring 〉3 cm. In 8 cases with DNs measuring 1-3 cm in size, 5 cases appeared hyperintense on T1W1 and hypointense on T2W1 as well as the enhancement as that of nodules with （1 cm in size; and the remaining 3 cases appeared hypointense on T1WI and hyperintense on T2WI, and were not isointense to the surrounding hepatic parenchyma on enhanced MRI but hyperintense on SPIO enhanced MRI. In 6 cases of macroregenerative nodule measuring 2〉3 cm in size, 2 cases appeared hyperintense to the surrounding hepatic parenchyma on T1, T2WI and enhanced MRI; 4 cases showed hyperintense on TlWI, and hypointense on T2WI and enhanced MRI. Sometimes, normal vessels were seen to pass through the surface of macroregenerative nodules. It was suggested that RNs of cirrhosis had features on MRI that usually allow distinction from hepatocellular carcinoma but not always from dysplastic nodules （DNs）. A helpful distinction between HCC and DNs is that the latter are almost never hyperintense on T2WI. Additionally, low grade DNs appear hypoimense on SPIO enhanced MR1.

Transjugular intrahepatic portosystemic shunt with radioactive seed strand for main portal vein tumor thrombosis with cirrhotic portal hypertension

BACKGROUND Patients with hepatocellular carcinoma complicated with main portal vein tumor thrombosis(mPVTT) and cirrhotic portal hypertension(CPH) have an extremely poor prognosis, and there is a lack of a clinically effective treatment paradigm.AIM To evaluate the efficacy and safety of transjugular intrahepatic portosystemic shunt(TIPS)combined with radioactive seed strand for the treatment of mPVTT patients with CPH.METHODS The clinical data of 83 consecutive patients who underwent TIPS combined with 125I seed strand placement for mPVTT and CPH from January 2015 to December 2018 were retrospectively reviewed. Procedure-related data(success rate, relief of portal vein pressure and CPH symptoms,and adverse events), PVTT response, and patient survival were assessed through a 2-year followup.RESULTS The success rate was 100.0% without perioperative death or procedure-related severe adverse events. The mean portal vein pressure was significantly decreased after the procedure(22.25 ± 7.33mmHg vs 35.12 ± 7.94 mmHg, t = 20.61, P < 0.001). The symptoms of CPH were all effectively relieved within 1 mo. The objective response rate of PVTT was 67.5%. During a mean follow-up of 14.5 ± 9.4 mo(range 1-37 mo), the cumulative survival rates at 6, 12 and 24 mo were 83.1%, 49.7%,and 21.8%, respectively. The median survival time was 12.0 ± 1.3 mo(95% confidence interval: 9.5-14.5). In multivariate Cox regression analysis, body mass index, Child-Pugh grade, cTNM stage,and PVTT response were independent prognostic factors(P < 0.05).CONCLUSION TIPS combined with radioactive seed strand might be effective and safe in treating mPVTT patients with CPH.

Portal Vein Thrombosis in Non Cirrhotic Patients: Experience of Gastroenterology and Hepatology Department University Hospital Hassan II

Portal thrombosis (PT) is a rare condition of heterogeneous etiologies. The aim of our work is to study the epidemiological and etiological profile of portal thrombosis in non cirrhotic patients through the experience of our department. Patients and Methods: This is a retrospective study over a 9-year period (January 2009-July 2018), 54 cases of PT in non cirrhotic patients were collected in the department of Hepato-Gastro-Enterology of the HASSAN II Fez Hospital, 73 cases of PT were excluded among cirrhotic patients. Results: We collected 54 cases of PT cases;the average age was 45 years, with an F/M ratio of 1.42. PT was revealed by abdominal pain in 20 cases, complications of portal hypertension in 24 cases, and ultrasound discovery in 10 asymptomatic cases. Main underlying causes of PT were: A proteine S deficiency in 7 cases, Acute pancreatitis in 5 cases, colonic cancer in 4 cases, pancreatic cancer in 4 cases, Hydatic liver Echinococcoses (3 cases), anti phospholipid syndrom (3 cases), myeloproliferative syndrom (2 cases) and jak mutation 2 in 1 case, non identified etiology was reported in 20 cases (37%). Treatment was based on anticoagulation, treatment of portal hypertension complications, and etiological treatment in cases where etiological diagnosis was certainly posed. Conclusion: PT is a rare but serious condition, according to our study neoplastic causes are predominant followed by protein S deficiency. Etiological investigations have to be wide and early treatment is the best option to avoid extension and complication.