Advanced Stages Of Liver Cirrhosis Research Articles

Portal vein thrombosis in patients with liver cirrhosis

Background/Aim. Portal vein thrombosis (PVT) in patients with liver cirrhosis (LC) has a prevalence of 0.6- 26%. It is most commonly discovered incidentally as part of the evaluation of LC or in the context of acute decompensation of LC due to portal hypertension. The aim of the study was to determine the prevalence of PVT in patients with LC in relation to the severity of the disease and individual elements of portal hypertension. Methods. A total of 326 patients treated for LC decompensation were included in a retrospective study. Standard laboratory analyses, abdominal ultrasonography and/or computed tomography, and esophagogastroduodenoscopy were performed. Results. The diameter of the portal vein (PV) differed between patients without esophageal varices (12.2 mm) and those with large varices (13.6 mm), p = 0.026. PVT was identified in 6.1% of patients with LC. The patients were classified according to the Child-Pugh scoring system, which has the A, B, and C categories used to assess the severity of liver disease. PVT was present in 3.0% of patients in class C and 12.0% in class B, while none of the patients in class A had PVT (p = 0.005). PVT was present in 4.4% of patients with small varices and 16.7% with large varices (p < 0.001). There was no difference in the presence of PVT between the groups of patients with and without variceal bleeding nor between groups with different degrees of ascites. A fatal outcome occurred in 29.4% of patients, but there was no difference between patients with and without PVT. Conclusion. PVT is present in more advanced stages of LC and predominantly in patients with large esophageal varices. There was no higher prevalence of PVT observed with the occurrence of variceal bleeding or with the death outcome in patients with LC.

Expression profile of microRNAs in patients with decompensated cirrhosis by small RNA deep sequencing

Introduction and objectiveDecompensated cirrhosis (DCC) is a more advanced stage of liver cirrhosis (LC). It is important to identify biomarkers to predict DCC progression. The aim of this study was to analyze microRNA (miRNA) profiles of whole blood involved in the DCC process to gain a better understanding of the molecular mechanisms underlying its development. Materials and methodsRNA-Seq analysis of blood samples from a discovery set, including four DCC patients and four LC individuals, was performed to identify differentially expressed miRNAs. The selected differentially expressed miRNAs were validated by using an independent validation set. ResultsIn this study, a total of 1,036 miRNAs were identified in whole blood samples. Forty differentially expressed miRNAs were identified, including 24 upregulated and 16 downregulated miRNAs. The expression levels of three upregulated miRNAs (hsa-miR-20b-5p, hsa-miR-421, and hsa-miR-1307-3p) and two downregulated miRNAs (hsa-miR-139-5p and hsa-miR-150-5p) were validated by quantitative reverse transcriptase polymerase chain reaction. The receiver operator characteristic curve for the logistic regression model based on hsa-miR-20b-5p, hsa-miR-421, and hsa-miR-150-5p could distinguish DCC patients with excellent diagnostic accuracy (area under the curve: 0.981, p < 0.01). ConclusionThe miRNA expression profiles in patients with DCC and LC controls suggested that miR-20b-5p, miR-421, and miR-150-5p could be potential biomarkers and therapeutic targets for this condition.

Elevated serum levels of methylglyoxal are associated with impaired liver function in patients with liver cirrhosis

Methylglyoxal (MGO) is a highly reactive dicarbonyl species that forms advanced glycation end products (AGEs). The binding of these AGEs to their receptor (RAGE) causes and sustains severe inflammation. Systemic inflammation is postulated to be a major driver in the progression of liver cirrhosis. However, the role of circulating MGO levels in liver cirrhosis remains unknown. In this study, we investigated the serum levels of two dicarbonyl species, MGO and glyoxal (GO) using tandem mass spectrometry (HPLC–MS/MS) and evaluated their association with disease severity. A total of 51 inpatients and outpatients with liver cirrhosis of mixed etiology and different disease stages were included. Elevated MGO levels were seen in an advanced stage of liver cirrhosis (p < 0.001). High MGO levels remained independently associated with impaired liver function, as assessed by the model for end-stage liver disease (MELD) (β = 0.448, p = 0.002) and acute decompensation (AD) (β = 0.345, p = 0.005) scores. Furthermore, MGO was positively correlated with markers of systemic inflammation (IL-6, p = 0.004) and the development of ascites (p = 0.013). In contrast, no changes were seen in GO serum levels. Circulating levels of MGO are elevated in advanced stages of liver cirrhosis and are associated with impaired liver function and liver-related parameters.

Association of thromboelastography profile with severity of liver cirrhosis and portal venous system thrombosis

Background and aimHemostasis profile is often complicated in liver cirrhosis. Thromboelastography is a global viscoelastic test recommended by the current practice guideline and consensus. This cross-sectional study aimed to evaluate the association of thromboelastography profile with severity of liver cirrhosis and presence of portal venous system thrombosis (PVST).MethodsOverall, 116 and 50 cirrhotic patients were included in the Shenyang and Xi’an cohorts, respectively. Thromboelastography parameters were compared between cirrhotic patients with Child–Pugh class A and B/C, those with and without decompensated events, and those with and without PVST. Hypercoagulability would be considered if at least two of the following thromboelastography parameters were met: shortened reactive time (R), shortened coagulation time (K), increased angle, and increased maximum amplitude (MA).ResultsIn the Shenyang cohort, 16 patients had shortened R, of whom seven (43.75%) had prolonged K and 11 (68.75%) decreased MA. In the Xi’an cohort, 24 patients had shortened R, of whom seven (29.17%) had prolonged K and 15 (62.50%) decreased MA. In the Shenyang cohort, the prevalence of hypercoagulability was not significantly different between cirrhotic patients with Child–Pugh class A and B/C (3.85% vs. 6.25%, P = 0.873), those with and without decompensated events (5.49% vs. 4.00%, P = 1.000), and those with and without PVST (4.17% vs. 5.88%, P = 1.000), which were similar to the results obtained in the Xi’an cohort.ConclusionThere is a high rate of discordance between R and other thromboelastography parameters. In addition, hypercoagulability may not be related to more advanced stage of liver cirrhosis or presence of PVST.

Transfusion-associated circulatory overload in gastroenterology.

Transfusion-associated circulatory overload (TACO) is a rare life-threatening event associated with transfusion. This study aimed to identify any case of TACO in a large cohort of highly transfused patients with gastrointestinal tract (GI) bleeding. Data from patients who underwent an oesophago-gastro-duodenoscopy (OGD) were collected over one year from the gastroenterology service of a regional hospital. A total of 278 patients were identified, of which 81 required transfusion. In total, 811 blood components were transfused (red cell concentrate, platelets, plasma), leading to a cumulative TACO incidence of 12.3%. The probability of developing TACO was greater for patients aged ≥80 years (OR=3.9%; p=0.0058), with renal disease (OR=1.9%, p=not significant) and with cardiac disease (OR 11.1%; p=0.003). Patients with TACO had a lower overall survival (52 vs 20% at 3 years, p=0.034, HR=2.19, 95% CI: 1.04-4.63) compared to patients with cirrhosis without TACO (57 vs 28% at 3 years, p=0.003, HR=2.20, 95% CI: 1.30-3.72). Patients with an advanced stage of liver cirrhosis (Child Pugh c10 or more) were most likely to develop TACO. This study shows that within the GI setting TACO may be markedly under-reported. Clinical awareness for potential TACO development in GI patients with cardiac or renal disease or age &gt;80 years is now required.

Association of liver cirrhosis severity with anemia: does it matter?

BackgroundThe etiology of anemia in liver disease is diverse and often multifactorial. Anemia is more severe in advanced stages of liver cirrhosis and can be a predictor of the severity of liver disease.MethodsIn this cross-sectional observational study, we included 181 cirrhotic patients with anemia owing to liver cirrhosis and its complications. The population was divided into 2 groups based on the model for end-stage liver disease (MELD) score and the severity of anemia was assessed in the 2 groups. Similarly, hemoglobin levels were assessed in 3 groups based on the Child-Turcotte-Pugh (CTP) classification.ResultsThere was a statistically significant correlation between CTP class and hemoglobin (P<0.001), with the lowest hemoglobin levels in CTP C patients. The correlation coefficient between hemoglobin and MELD score was -0.671 and was statistically significant, establishing that hemoglobin levels decrease with increasing severity of liver cirrhosis. Of 58 patients with macrocytosis, 45 (77.6%) had a MELD score of >12, whereas only 13 patients (22.4%) had a MELD score of <12. This difference was statistically significant (P<0.0001).ConclusionsThis study shows that hemoglobin levels decrease with increasing severity of liver disease; thus, this measure can be used in the initial assessment of patients to give a picture of the severity of the disease. A larger prospective trial is needed to establish the use of hemoglobin levels for assessing severity and predicting mortality in patients with liver cirrhosis.

Assessment of Von Willebrand Factor in Hepatitis C Patients as Biomarker for Liver Fibrosis and Predictor of HCC

Background:Hepatitis C virus (HCV) infection is a progressive disease that may result in chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. Itis estimated that about 160 million individuals are chronically infected with HCV. Hepatocellular carcinoma (HCC), the fifth most common cancer in men and the ninth in women, represents an urgent clinical problem, being the second leading cause of cancer-related death worldwide. Aim of the study: To determine whether VWF is a potential biomarker for liver fibrosis in comparison to other markers of fibrosis and predictor for development of Hepatocellular Carcinoma in comparison with Alpha-feto protein and Des Gamma carboxy prothrombin. Patients and Methods: This study had been carried out on 50 subjects, age range 34-77 year selected from Virology and Hepatology outpatient clinics at Ain shams university hospitals in Cairo after informed consent were taken from the patients. Subjects were divided as follows: Group I: Include 20 HCC patients diagnosed by imaging and alpha- fetoprotein. Group II: Include 20 matched cirrhotic patients without HCC divided according to child – pugh scoring system. Group III: Include 10 apparently healthy subjects, age and sex matched, having no acute or chronic illness and taking no medications were taken as control group. Results: In our study, VW factor was statistically significant higher in cirrhotic patients than control group and in patients with HCC than cirrhotic group without HCC, with weak positive correlation with other markers of liver fibrosis (FIB4, APRI), and weak positive correlation with other markers of hepatocellular carcinoma (alpha feto protein, des gamma carboxy prothrombin). VW factor was statistically significant higher in advanced stages of liver cirrhosis. Conclusion:In conclusion; VWfactor is statistically significant higher in patients with Hepatocellular carcinoma than in cirrhotic patients without HCC. There is weak positive correlation between VW factor as a biomarker for liver fibrosis and other scores assessing stage of fibrosis. There is a strong correlation between VW factor and child score used to classify stage of liver cirrhosis, so VW factor is valuable predictor for hepatocellular carcinoma and advanced stages of liver cirrhosis. Background:Hepatitis C virus (HCV) infection is a progressive disease that may result in chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. Itis estimated that about 160 million individuals are chronically infected with HCV. Hepatocellular carcinoma (HCC), the fifth most common cancer in men and the ninth in women, represents an urgent clinical problem, being the second leading cause of cancer-related death worldwide. Aim of the study: To determine whether VWF is a potential biomarker for liver fibrosis in comparison to other markers of fibrosis and predictor for development of Hepatocellular Carcinoma in comparison with Alpha-feto protein and Des Gamma carboxy prothrombin. Patients and Methods: This study had been carried out on 50 subjects, age range 34-77 year selected from Virology and Hepatology outpatient clinics at Ain shams university hospitals in Cairo after informed consent were taken from the patients. Subjects were divided as follows: Group I: Include 20 HCC patients diagnosed by imaging and alpha- fetoprotein. Group II: Include 20 matched cirrhotic patients without HCC divided according to child – pugh scoring system. Group III: Include 10 apparently healthy subjects, age and sex matched, having no acute or chronic illness and taking no medications were taken as control group. Results: In our study, VW factor was statistically significant higher in cirrhotic patients than control group and in patients with HCC than cirrhotic group without HCC, with weak positive correlation with other markers of liver fibrosis (FIB4, APRI), and weak positive correlation with other markers of hepatocellular carcinoma (alpha feto protein, des gamma carboxy prothrombin). VW factor was statistically significant higher in advanced stages of liver cirrhosis. Conclusion:In conclusion; VWfactor is statistically significant higher in patients with Hepatocellular carcinoma than in cirrhotic patients without HCC. There is weak positive correlation between VW factor as a biomarker for liver fibrosis and other scores assessing stage of fibrosis. There is a strong correlation between VW factor and child score used to classify stage of liver cirrhosis, so VW factor is valuable predictor for hepatocellular carcinoma and advanced stages of liver cirrhosis.

Serum Zonulin in HBV-Associated Chronic Hepatitis, Liver Cirrhosis, and Hepatocellular Carcinoma.

Background The gut microbiota is involved in the occurrence and development of chronic liver diseases. Zonulin is considered a marker of intestinal permeability. The purpose of this study was to assess zonulin levels in patients with chronic hepatitis B (CHB), HBV-associated liver cirrhosis (LC), and HBV-associated hepatocellular carcinoma (HCC). Materials and Methods The study population consisted of 90 HBV-associated HCC patients, 90 HBV-associated LC patients, 90 CHB patients, and 90 healthy subjects. Serum levels of zonulin and AFP were determined. The diagnostic accuracy of each marker was evaluated using receiver operating characteristic (ROC) curve analysis (AUC). Results Serum zonulin levels were significantly higher in patients with HCC than in patients with LC or CHB or healthy subjects (p < 0.001). Moreover, the zonulin levels were increased in the advanced stage of LC and HCC. ROC curve analysis revealed that serum zonulin could be used to differentiate CHB from cirrhosis. In addition, the combination of zonulin and AFP exhibited a significantly larger AUC compared with zonulin or AFP alone. Conclusions Serum zonulin levels were significantly increased both in LC and in HCC and correlated with the advanced stage of LC and HCC. Moreover, the combination of zonulin and AFP confers significant benefit to diagnostic accuracy in differentiating LC from HCC.

Validation of insulin-like growth factor-1 as a prognostic parameter in patients with hepatocellular carcinoma in a European cohort

BackgroundIn hepatocellular carcinoma (HCC), the third leading cause of cancer-related mortality worldwide, the Child-Turcotte-Pugh score (CTP) is one of the most established tools to assess hepatic reserve and determine survival. Serum levels of insulin-like growth factor-1 (IGF-1) are decreased in patients with chronic liver disease or HCC. A modified score combining circulating IGF-1 with the CTP score (IGF-CTP) was recently proposed.MethodsIGF-CTP scoring was evaluated in 216 patients diagnosed with HCC between 2007 and 2017 to assess the predictive value of serum IGF-1 levels for patient risk stratification and overall survival (OS).ResultsLiver cirrhosis was identified in 80.1% of the study cohort, and alcohol-induced liver disease was the most frequent underlying cause of HCC (44.4%). Serum IGF-1 levels were significantly lower in patients with HCC in cirrhosis compared with non-cirrhotic HCC (p < 0.01). A lower serum level of IGF-1 was associated with more advanced stages of liver cirrhosis (p < 0.05) and cancer stages (p < 0.001). Median OS in the cohort was 11.4 months (range 0.5–118.2 months). OS was significantly higher (10.9 vs. 7.9 months; p < 0.05) in patients with a serum IGF-1 level above the median of 43.4 ng/mL. Patient reassignment using IGF-CTP scoring reclassified 35.6% of patients. Through reassignment, stratification regarding OS was comparable to CTP.ConclusionsThis study is the first to investigate IGF-1 and the IGF-CTP classification in a European cohort of HCC patients. Serum IGF-1 correlates with OS in patients with HCC. However, the IGF-CTP classification was not superior compared to CTP score regarding OS.

Two-dimensional echocardiographic evaluation in liver cirrhosis patients in prediction of cirrhotic cardiomyopathy

Background/Aim. Cirrhotic cardiomyopathy (CCM) is a clinical syndrome in liver cirrhosis (LC) patients, which is characterized by the abnormal cardiovascular (CV) response to physiologic, pathologic, or pharmacologic stress provocation, but normal to increased cardiac output and contractility at rest. The aim of the study was to identify the structural and functional myocardial changes in patients with LC of various origins in advanced stages of the disease, by transthoracic two-dimensional echocardiography Doppler imaging evaluation in the prediction of CCM. Methods. The research was performed as a prospective, nest case-control study, on carefully selected 40 patients in the advanced stage of LC and negative personal medical history on previous CV disease and 40 healthy subjects as the control, from January 2012?December 2014. There were determining significant echocardiographic parameters in LC patients as predictors for the development and/or presence of CCM. Results. Most of the LC patients were alcoholic (80%), dominantly in Child-Pough C stage of the disease (70%). The average value of QT interval in the LC patients was significantly higher (0.44 ? 0.03 ms vs 0.42 ? 0.01 ms; p &lt; 0.001), as well as brain natriuretic peptide (BNP) serum level (284.61 ? 181.44 ng/L vs 69.41 ? 31.08 ng/L; p &lt; 0.001) compared to those in the healthy subjects. A significant association with serum BNP level in LC patients was shown with left atrial diameter (p = 0.031), left ventricular ejection fraction (p = 0.014), pulmonary artery systolic pressure (PASP) (p = 0.000) and the presence of tricuspid valve regurgitation of 2+ (p = 0.000), affecting its change of 41.6%. Conclusion. The obtained results suggest that LC patients have significant echocardiographic signs of myocardial dysfunction, as well as the increased BNP serum level. Left atrial diameter, left ventricular ejection fraction, PASP and tricuspid valve regurgitation are valuable echocardiographic predictors of CCM.

A Rare Case of Salmonella Bacteremia in a Patient with Cryptogenic Liver Cirrhosis

Introduction: Nontyphoid salmonella infections are most often associated with contaminated food products. Most cases of salmonella bacteremia in liver cirrhosis have been associated with an advanced stage of liver cirrhosis and hepatocellular carcinoma. Case: A 54 year old female with past medical history significant for cryptogenic liver cirrhosis, gastroesophageal reflux disease and hypertension presented with complaint of fever for the last 3 days. She had associated diffuse abdominal pain and 10-15 episodes of non-bloody, non-mucus diarrhea. Her temperature was 39.1 C, BP 134/79 mmHg, pulse 96/min and oxygen saturation 100% on room air. Physical exam was pertinent for soft, moderately distended abdomen with tenderness to deep palpation in all quadrants and 2+ edema in bilateral lower extremities. Lab work revealed a white blood cell count of 7000/μL, platelets 74,000/ μL, creatinine 0.8 mg/dL, albumin 2.2 g/dL, AST 78 IU, ALT 29 IU and total bilirubin 2 mg/dL. Ultrasound abdomen was concerning for hepatic cirrhosis, large amount of ascites and thickened gall bladder wall without stones or sludge. Bedside diagnostic paracentesis was done to evaluate for spontaneous bacterial peritonitis, which revealed only 378 white blood cells (10% polynuclear and 90% mononuclear) but no organisms. However, the blood and the stool cultures drawn at admission were finalized as growing Salmonella species. The patient was then treated with IV ciprofloxacin and responded appropriately. Discussion: Bacteremia is a poor prognostic sign in patients with liver cirrhosis because of its occurrence late in the course of cirrhosis. Escherichia coli and Klebsiella pneumoniae are the most commonly isolated organisms. Only seldom cases of Salmonella bacteremia have been reported. Nontyphoid salmonellosis is associated with immunocompromised conditions, including extremes of age, alteration of the endogenous bowel flora, malignancy, autoimmune disorders and reticuloendothelial blockade. Patients with liver cirrhosis have defects in both humoral and cell-mediated immunity. The rediculoendothelial cells represent a potent filtering mechanism for portal bloodborne pathogens which is impaired in patients with liver cirrhosis. The occurrence of nontyphoid Salmonella bacteremia has been reported patients with an advanced stage of liver cirrhosis and hepatocellular carcinoma. The Model for end stage liver disease score was calculated as 17 in above case.Figure 1

Daclatasvir plus sofosbuvir, with or without ribavirin, in real-world patients with HIV-HCV coinfection and advanced liver disease.

HIV-HCV-coinfected patients respond just as well to modern direct-acting antiviral HCV therapy as HCV-monoinfected patients. However, clinical data for all-oral HCV treatments are sparse in HIV-HCV-coinfected patients with an advanced stage of liver cirrhosis. A subanalysis of efficacy and safety for a daclatasvir (DCV) and sofosbuvir (SOF) regimen, with or without ribavirin (RBV), was undertaken in HIV-HCV-coinfected patients with advanced liver disease and no other treatment options enrolled into a European DCV compassionate use programme. Fifty five HIV-HCV (mostly genotypes 1, 3, 4) coinfected patients were treated with DCV+SOF with (n=16) or without RBV (n=39), mostly for 24 weeks. Patients were predominantly (95%) cirrhotic (50% were Child-Pugh class B or C) and were receiving a wide range of antiretrovirals; 40% were injection drug users and 25% were receiving oral opioid substitution. Sustained virological response at post-treatment week 12 (SVR12) by modified intention-to-treat analysis (n=52) was 92% overall (95% CI 81.5, 97.9), and was similar with (94% [95% CI 69.8, 99.8]) or without RBV (92% [95% CI 77.5, 98.2]). Only one patient relapsed (Child-Pugh class B). The overall SVR12 rate after excluding non-virological failures (n=49) was 98% (95% CI 89.1, 99.9). Four patients discontinued treatment for adverse events and one died during treatment (not treatment-related). No patient lost opioid maintenance or required a change of antiretrovirals due to drug-drug interactions. DCV+SOF, with or without RBV, showed high SVR12 rates and was well tolerated in this real-world cohort of HIV-HCV-coinfected patients with very advanced liver disease. ClinicalTrials.gov ID NCT02097966 (Study AI444-237).

New therapies for hepatic fibrosis

Liver fibrosis is an outcome of many chronic diseases, and often results in cirrhosis, liver failure, and portal hypertension. Liver transplantation is the only treatment available for patients with advanced stages of liver cirrhosis. Therefore, alternative methods are required to develop new strategies for anti-fibrotic therapy. Various kinds of hepatocyte injuries cause inflammatory reactions, which lead to activation of hepatic stellate cells (HSCs). Continuous liver injuries maintain these activated HSCs, and they are called as myofibroblasts. Myofibroblasts proliferate in response to various kinds of cytokines and produce extracellular matrix proteins (ECMs). Myofibroblasts undergo apoptosis and inactivation when the underlying causative etiologies are cleared. Here, we describe the current knowledge of targeting the activated HSCs as a therapeutic target for liver fibrosis.

Regression effect of hepatocyte nuclear factor 4α on liver cirrhosis in rats

The aim of this study was to determine whether cirrhosis could be reversed after treated with hepatocyte nuclear factor 4α (HNF4α), a key transcriptional regulator of hepatocyte differentiation and function. Early and advanced stages of liver cirrhosis were induced by thioacetamide (TAA) administration. The adenovirus carrying HNF4α gene was injected into cirrhotic rats via the tail vein. The effect of HNF4α on cirrhosis was evaluated by histological and immunohistochemical examination. Early stage of cirrhosis was remarkably resolved by HNF4α to a nearly-normal extent and advanced cirrhosis was partially ameliorated in vivo. The enforced expression of HNF4α downregulated profibrogenic factors remarkably including α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β1, fibroblast-specific protein (FSP)-1, collagen I and III. In vivo and in vitro studies revealed that HNF4α administration inhibited extracellular signal-regulated kinase (ERK) signaling pathway through the downregulation of phosphorated ERK and phosphorated JunD. In addition, HNF4α readjusted the balance between extracellular matrix deposition and degradation through the upregulation of matrix metalloproteinase and downregulation of its inhibitors. Moreover, HNF4α treatment inhibited angiogenesis as determined by CD31 and CD34 immunostaining. Our findings broaden the knowledge on the reversibility of different stages of cirrhosis as HNF4α could present a promising alternative for the treatment of liver cirrhosis.

Correlation of routinely used coagulation parameters and presence of portal vein thrombosis in patients with liver cirrhosis

Portal vein thrombosis (PVT) is a serious complication in patients with liver cirrhosis. In patients with advanced stages of liver cirrhosis plasmatic coagulation and platelet count are often reduced. However, patients with normal coagulation status might carry a high risk for developing PVT. A correlation between coagulation status used in clinical routine and the incidence of PVT in patients with liver cirrhosis has been evaluated in the present retrospective analysis. 88 patients with liver cirrhosis were identified by screening a database. Of these patients, 23 suffered from PVT. Patients were classified according to the Child-Pugh classification. Patients were subdivided into early stages (Child A) and advanced stages (Child B/C) of liver cirrhosis. In patients with Child-Pugh A cirrhosis, there was no difference in activated partial thromboplastin time (apTT), international normalized ratio (INR), and platelet count between the PVT (n = 7) and the control group (n = 35). In contrast, the median apTT and INR were significantly lower in patients with Child B/C cirrhosis and PVT (n = 16) in comparison with patients without PVT (37 s vs 43 s [P = 0.017] and 1.25 vs 1.40 [P = 0.022]), respectively. Platelet count did not differ significantly in patients with advanced liver cirrhosis and PVT from those without PVT. Patients with advanced liver cirrhosis and PVT displayed lower apTT and INR compared with those without PVT. Therefore, patients with advanced liver cirrhosis and almost normal coagulation parameters might be at particular risk of developing PVT. The results suggest that regular monitoring using Doppler-ultrasound should be carried out in these patients, especially when liver transplantation is intended.

Validation of connective tissue growth factor (CTGF/CCN2) and its gene polymorphisms as noninvasive biomarkers for the assessment of liver fibrosis

Clinical and experimental studies have demonstrated that connective-tissue growth factor (CTGF) expression is increased in fibrotic human liver and experimental animal models of liver fibrogenesis. CTGF has been linked to transforming growth factor-beta (TGF-beta) pathways in fibroproliferative diseases and specific polymorphisms within the CTGF gene may predispose for fibrosis in systemic sclerosis. As CTGF is detectable in various human fluids (serum, plasma and urine), it may provide information about fibrotic remodelling processes and reflect hepatic TGF-beta bioactivity. We established a novel ELISA for the measurement of serum CTGF and tested its clinical value in patients with chronic hepatitis C virus (HCV) infection and chronic liver disease (CLD). HCV infected patients (n = 138) had significantly higher serum CTGF levels than healthy controls. CTGF was linked to the histological degree of liver fibrosis. To expand the results to other aetiologies, a separate cohort of CLD patients (n = 129) was evaluated, showing higher serum CTGF than healthy controls and again an association with advanced stages of liver cirrhosis (Child B and C). Although independent of the underlying aetiology, serum CTGF was most powerful in indicating fibrosis/advanced disease states in HCV-related disorders. The genotyping of six polymorphisms (rs6917644, rs9399005, rs6918698, rs9493150, rs2151532 and rs11966728) covering the CTGF locus in 365 patients suffering from chronic hepatitis C revealed that none of these polymorphisms showed a genotypic or allelic association with the severity of hepatic fibrosis. Taken together, serum CTGF is suitable for determination of hepatic fibrosis and most powerful in patients with chronic HCV infection.

Elevation of Nε-(carboxymethyl)lysine-modified advanced glycation end products in chronic liver disease is an indicator of liver cirrhosis

Objectives: Progression of liver fibrosis to cirrhosis is a dire consequence of chronic liver diseases (CLD). Nε-(carboxymethyl)lysine (CML)-modified advanced glycation end products (AGEs) in patients with CLD could reflect the degree of severity of the disease. Design and methods: In 110 patients with CLD and 124 healthy controls, CML serum levels and their diagnostic sensitivity and specificity were determined and compared to hyaluronan (HA). Results: Serum levels of CML were significantly affected by the stage of liver cirrhosis and were closely associated with liver function capacity. CML correlated positively with HA ( r = 0.639, P < 0.0001). In ROC analysis, the diagnostic sensitivity and specificity in distinguishing healthy controls from liver disease patients for CML (AUC 0.908; 95%-CI 0.863–0.942, cut-off 640 ng/mL, sensitivity 74.5% and specificity 97.6%) resembled HA (AUC 0.948; 95%-CI 0.907–0.974; cut-off 50 ng/mL, sensitivity 80.7% and specificity 97.9%). The combination of CML and HA shows an AUC of 0.932; 95%-CI 0.888–0.962; sensitivity 82.6%; and specificity 95.8%. Conclusions: Our data suggest that serum levels of CML could provide a supplementary diagnostic marker for advanced stages of liver cirrhosis. However, the quality of interaction needs further investigation.

Nontyphoid Salmonella Bacteremia in Patients with Liver Cirrhosis

Bacteremia is reported to occur in 4% to 9% of hospitalized patients with liver cirrhosis. Escherichia coli and Klebsiella pneumoniae are the most commonly isolated organisms. Only sporadic cases of nontyphoid Salmonella bacteremia are reported in the literature. In this study, we sought to determine the clinical features and prognosis of patients with liver cirrhosis and bacteremia due to nontyphoid Salmonella. Data were collected by retrospective chart review. From December 1996 to May 2003, we identified 23 patients (18 males, 5 females) with a median age of 58 years. The Child classification for liver cirrhosis was A in 4, B in 9, and C in 10 patients. Solid organ cancers were present in 14 patients: hepatocellular carcinoma in 13 patients and gastric carcinoma in 1 patient. Hospital death occurred in 11 patients (48%): 7 died of sepsis and 4 of hepatic failure. Using a logistic regression model, the independent risk factors for death in patients with nontyphoid Salmonella bacteremia were young age and an advanced stage of liver cirrhosis. Most nontyphoid Salmonella bacteremia in patients with liver cirrhosis was community-acquired. An advanced stage of liver cirrhosis and hepatocellular carcinoma were common. The prognosis for young patients was unfavorable; this was seemingly due to hepatocellular carcinoma producing more unfavorable results in younger cirrhotic patients.

Effect of liver cirrhosis on body composition: Evidence of significant depletion even in mild disease

Malnutrition is common in liver cirrhosis patients. However, it is under-diagnosed because liver disease affects the traditional nutritional assessment. An understanding of changes in body composition and the establishment of the tissue-loss pattern in liver cirrhosis patients could help practitioners to better manage malnutrition in this setting. The aims of this study were: to quantify body composition changes, to determine tissue loss pattern, and to assess the relation of these to the severity of hepatic dysfunction. Seventy-nine patients and 17 controls were studied. Total body water and extracellular water were measured using dilution techniques. Intracellular water and body cell mass were calculated from these parameters. Total body fat was obtained using absorptiometry. Extracellular water was increased and intracellular water was decreased in patients. The two major compartments (body cell mass and body fat) were significantly reduced, mainly in patients with moderate and severe disease. However, significant losses occurred even in Child-Pugh class A patients. We established a tissue-loss pattern. In Child-Pugh class A patients body fat loss predominated. Child-Pugh class B patients had losses in at least one of the two compartments. Most Child-Pugh class C patients had simultaneous depletion in both compartments. Liver cirrhosis was characterized by a significant reduction in body cell mass and body fat and by a redistribution of body water. Significant losses occurred even in patients with mild disease. There was a more pronounced loss of fat in the initial stages, followed by an accelerated loss of body cell mass in the advanced stages of liver cirrhosis.

Diagnosis and treatment of hepatic encephalopathy

Hepatic encephalopathy arises from the combination of hepatocellular dysfunction and portal-systemic shunting. Encephalopathy is more prominent in advanced stages of liver cirrhosis and signals the presence of fulminant hepatic failure in patients with acute liver injury. As important as the extent of shunting is the presence of large spontaneous collaterals. Ammonia continues to be a leading toxin influencing brain function. Endogenous benzodiazepines and cytokines may contribute to one of ammonia’s key effects in the brain: astrocyte swelling. The diagnosis of hepatic encephalopathy is a diagnosis of exclusion; the search for a precipitating factor should be started immediately in all cases of encephalopathy. The treatment of hepatic encephalopathy has three aims: decrease the nitrogenous load from the gut, improve the extra-intestinal elimination of ammonia and counteract central abnormalities of neurotransmission. The mainstay of treatment is directed at the colon. Newer approaches targeting the brain, such as flumazenil, have become available.