Course Of Liver Disease Research Articles

Liver Transplantation in Polish Children With α1-Antitrypsin Deficiency: A Single-Center Experience

Backgroundα1-Antitrypsin deficiency (ATD) is the most common genetic cause of liver injury in young children. Asymptomatic hepatitis is observed in most patients. However, the course of liver disease due to ATD is unpredictable, and some children develop liver cirrhosis. Liver transplantation (Ltx) dramatically improves their outcome and in some cases is required in the first years of life. The aim of the study was to evaluate the course of the disease in children with ATD treated with Ltx in a single center. MethodsWe retrospectively reviewed the clinical features (ascites, esophageal varices, esophageal bleeding) and laboratory parameters of liver function in children with ATD who were treated with Ltx. ResultsTwenty-two Ltxs were performed in 20 children (13 boys, 7 girls). Median age at transplantation was 12 years (range 0.5 to 17.1). Four children were transplanted in the first 2 years of life and 16 patients were over 7 years old. The indications for Ltx in younger children were progressive cholestasis with coagulopathy and ascites. In older patients, the indications were as follows: liver failure presenting with variceal bleeding in 7 patients, ascites in 5 patients, hypersplenism in all but 1 patient. In the group of children transplanted over 7 years old, the frequency of cholestasis decreased intermittently in the second year of life: 4 patients (25%) compared to 15 patients (94%) and 10 patients (63%) in the neonatal and pretransplant period, respectively. In the group of children transplanted earlier, cholestasis and hepatitis were maintained until Ltx. Of transplanted patients, 50% were malnourished at the transplantation, and 50% were followed for more than 10 years. Five-year post-transplant survival was 100% (n = 14), and 10-year survival was 90%. Two patients died as adults with biliary post-transplant complications and problems with compliance. ConclusionsOur experience suggests that transient normalization of liver parameters in some patients with ATD do not exclude the liver disease progression to cirrhosis and unfavorable outcome of liver disease in childhood. In our group of patients, median age at transplantation was high compared to other centers. The long-term prognosis in children after transplantation is very good, but early post-transplant complications and probable problems with compliance in young adults may lead to graft failure.

Effects of Eradicating Hepatitis C Virus Infection in Patients With Cirrhosis Differ With Stage of Portal Hypertension

Clearance of hepatitis C virus (HCV) via antiviral treatment changes the course of liver disease. We evaluated the benefit of sustained virologic response (SVR) in patients with HCV and cirrhosis without (stage 1) and with (stage 2) esophageal varices (EV). We performed a prospective cohort study of 444 patients with HCV and compensated cirrhosis (218 with stage 1 and 226 with stage 2 disease) treated with peg-interferon and ribavirin from June 2001 through December 2009 at the University of Palermo, Italy and followed for a median of 7.6years (range, 1-12.6 years). We used Cox regression analysis to identify variables associated with appearance or progression of EVs, development of hepatocellular carcinoma (HCC), liver decompensation, and overall survival. In the intention-to-treat analysis, 67 patients with stage 1 disease (30.7%) and 41 patients with stage 2 disease (18.1%) achieved an SVR (P= .003). Patients with stage 1 disease and an SVR were less likely to develop EVs than stage 1 patients without an SVR (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.11-0.48; P < .001). However, SVR did not affect whether patients with stage 2 disease developed further EVs (HR, 1.58; 95% CI, 0.33-1.03; P= .07, by log-rank test). An SVR was associated with lower risk for HCC (HR,0.25; 95% CI, 0.12-0.55; P < .001). Patients with stage 2 disease, regardless of SVR, were at greater risk than patients with stage 1 disease for liver decompensation (HR, 2.82; 95% CI, 1.73-4.59; P < .001) or death (HR, 1.77; 95% CI, 1.12-2.80; P=.015). A lower proportion of patients with stage 1 disease and an SVR died from HCC (2.9%), compared with those without an SVR (11.9%) (P= .03) or developed liver decompensation (none vs 7.1% without an SVR; P= .009). A lower proportion of patients with stage 2 disease and an SVR died from causes secondary to HCC (2.0%) compared with those without an SVR (18.4%) (P= .003). Death from causes secondary to liver decompensation did not differ significantly between patients with stage 2 disease with or without an SVR (12.1% vs 25.4%; P= .15). In a prospective study of 444 patients with HCV and compensated cirrhosis, HCV eradication reduced risk for liver decompensation, HCC, and death, regardless of whether the patients had EVs.

Prevalence of mutations in HBV DNA polymerase gene associated with nucleos(t)ide resistance in treatment-naive patients with Chronic Hepatitis B in Central China

ObjectiveThere are a lot of disagreements in the studies on hepatitis B virus (HBV) DNA polymerase mutation rate associated with nucleos(t)ide analogues (NAs) in treatment-naive chronic hepatitis B (CHB) patients. This is the first study aimed to investigate the prevalence of spontaneous HBV resistance mutations in Central China. MethodsThis study included treatment-naive patients with CHB from June 2012 to May 2015 receiving care at the Institute of Liver Disease in Central China. All patients completed a questionnaire covering different aspects, such as family medical history, course of liver disease, medication history, alcohol use, among others. Mutations in HBV DNA polymerase associated with NAs resistance were detected using INNO-LiPA assay. Results269 patients were infected with HBV genotype B (81.4%), C (17.9%), and both B and C (0.7%). Mutations in HBV DNA polymerase were detected in 24 patients (8.9%) including rtM204I/V (n=6), rtN236T (n=5), rtM250V (n=2), rtL180M (n=2), rtT184G (n=1), rtM207I (n=1), rtS202I (n=1), rtM204V/I & rtL180M (n=5), and rtM204I & rtM250V (n=1). ConclusionSpontaneous HBV resistance mutations in HBV DNA polymerase were found in treatment-naive patients with CHB in Central China. These findings suggest that we should analyze HBV DNA polymerase resistance mutation associated with NAs before giving antiviral therapy such as lamivudine (LAM), adefovir (ADV), and telbivudine (LdT).

The prospects for the application of the natural and preformed therapeutic factors in the treatment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is one of the most widespread diffuse liver pathologies among the patients over 40 years of age. The available algorithms for the pharmacological treatment of this disease do not always ensure the desirable results which makes their further development and improvement with the use of natural and preformed physical factors an important priority. The objective of the present study was to evaluate the effectiveness of the internal course of mineral waters of different balneological types and a bischofite aqueous solution for the treatment of the patients presenting with NAFLD. A total of 120 patients with non-alcoholic fatty liver disease were examined and treated with the use of the anamnestic, clinical, biochemical and immunochemical methods as well as sonographic studies of the digestive system and the statistical analysis. The data on the effectiveness of the use of mineral waters of different balneological types and a bischofite aqueous solution in the treatment of NAFLD are presented. It is shown that the use of an aqueous solution of bischofite improves the clinical course of the underlying disease (p<0.05), concomitant diseases of the biliary tract (p<0.02) and irritable bowl syndrome complicated by constipation (p<0.003); also, it improves the functional state of the liver and the blood lipid profile (p<0.02) and significantly reduces insulin resistance (p<0.01), primarily due to the reduction of hyperinsulinemia (p<0.01). Using the mineral waters with the predominance of sulfates can improve the clinical course of liver diseases (p<0.01), biliary tract and intestines (p<0.02), normalize the functional state of the liver including that in the patients with non-alcoholic steatohepatitis (p<0.05,) significantly improve the blood lipid profile (p<0.02) due to the substantial improvement of disordered carbohydrate metabolism including that in the patients suffering from type 2 diabetes mellitus (p<0.05). The application of mineral waters with the elevated content of hydrocarbons improves the clinical course of NAFLD with the concomitant esophagogastroduodenal pathology (p<0.001) and simultaneously reduces the severity of insulin resistance due to the lowering of the level of hyperinsulinemia (p<0.001). Moreover, the mineral water-based therapy improves tolerance to carbohydrates, in the first place in the patients with type 2 diabetes mellitus (p<0.01), and restores the background lipid profile (p<0.05). The studies has demonstrated the high efficiency of the non-pharmacological treatment resulting in the multifaceted and oppositely directional influence on the patients presenting with non-alcoholic fatty liver disease. The possibility of the differentiated application of mineral water and an aqueous solution of bischofite for the treatment of this pathology is confirmed depending on the stage of the disease, the severity of metabolic disorders, the presence of a concomitant pathology of the digestive system, type 2 diabetes mellitus, and hypertension.

Influence of variceal bleeding on natural history of ACLF and management options.

Patients with diagnosed and undiagnosed chronic liver diseases experience one or more acute assaults of a hepatic nature and develop a downhill course of liver diseases, a condition regarded as acute-on-chronic liver failure (ACLF). It is a medical emergency, the prognosis of ACLF is extremely bad and considerable numbers of patients with ACLF die even after diagnosis and receiving conservative treatment. ACLF is characterized by jaundice, coagulopathy, ascites and encephalopathy. ACLF patients are very sick and associated with different hemodynamic profiles and have very high 3-month mortality. As these groups of patients have high baseline hepatic venous pressure gradients, the chances of variceal bleed are also high, and the impact is also greater in comparison to stable cirrhosis; however, evidence is lacking to substantiate such effects. The aim of this review is to discuss the natural course of variceal bleeding in ACLF patients and to develop insights into the management of variceal bleeding in ACLF.

Experimental transmission of equine hepacivirus in horses as a model for hepatitis C virus.

Equine hepacivirus (EHCV; nonprimate hepacivirus) is a hepatotropic member of the Flaviviridae family that infects horses. Although EHCV is the closest known relative to hepatitis C virus (HCV), its complete replication kinetics in vivo have not been described, and direct evidence that it causes hepatitis has been lacking. In this study, we detected EHCV in 2 horses that developed post-transfusion hepatitis. Plasma and serum from these horses were used to experimentally transmit EHCV to 4 young adult Arabian horses, two 1-month-old foals (1 Arabian and 1 Arabian-pony cross), and 2 foals (1 Arabian and 1 Arabian-pony cross) with severe combined immunodeficiency (SCID). Our results demonstrated that EHCV had infection kinetics similar to HCV and that infection was associated with acute and chronic liver disease as measured by elevations of liver-specific enzymes and/or by histopathology. Although most of these animals were coinfected with equine pegivirus (EPgV), also a flavivirus, EPgV viral loads were much lower and often undetectable in both liver and blood. Three additional young adult Arabian-pony crosses and 1 SCID foal were then inoculated with plasma containing only EHCV, and evidence of mild hepatocellular damage was observed. The different levels of liver-specific enzyme elevation, hepatic inflammation, and duration of viremia observed during EHCV infection suggested that the magnitude and course of liver disease was mediated by the virus inoculum and/or by host factors, including breed, age, and adaptive immune status. This work documents the complete infection kinetics and liver pathology associated with acute and chronic EHCV infection in horses and further justifies it as a large animal model for HCV.

Alternative splicing-regulated protein of hepatitis B virus hacks the TNF-α-stimulated signaling pathways and limits the extent of liver inflammation.

Hepatitis B splicing-regulated protein (HBSP) of the hepatitis B virus (HBV) was uncovered a few years ago but its function remains unknown. HBSP expression occurs from a spliced viral transcript that increases during the course of liver disease. This study aimed at characterizing the impact of HBSP on cellular signaling pathways in vitro and on liver pathogenesis in transgenic (Tg) mice. By RT-qPCR array, NF-κB-inducible genes appeared modulated in HepG2 cells transduced with a HBSP-encoding lentivirus. Using luciferase and Western blot assays, we observed a decreased activation of the NF-κB pathway in HBSP-expressing cells following TNF-α treatment, as illustrated by lower levels of phosphorylated IκB-α. Meanwhile, the level of phosphorylated JNK increased together with the sensitivity to apoptosis. The contrasting effects on JNK and IκB-α activation upon TNF-α stimulation matched with a modulated maturation of TGF-β-activated kinase 1 (TAK1) kinase, assessed by 2-dimensional SDS-PAGE. Inhibition of the NF-κB pathway by HBSP was confirmed in the liver of HBSP Tg mice and associated with a significant decrease of chemically induced chronic liver inflammation, as assessed by immunohistochemistry. In conclusion, HBSP contributes to limit hepatic inflammation during chronic liver disease and may favor HBV persistence by evading immune response.

Screening for hepatocellular carcinoma by Egyptian physicians

To assess the practice of Egyptian physicians in screening patients for hepatocellular carcinoma (HCC). The study included 154 physicians from all over Egypt caring for patients at risk for HCC. The study was based on a questionnaire with 20 items. Each questionnaire consisted of two parts: (1) personal information regarding the physician (name, age, specialty and type of health care setting); and (2) professional experience in the care of patients at risk for HCC development (screening, knowledge about the cause and natural course of liver diseases and HCC risk). Sixty-eight percent of doctors with an MD degree, 48% of doctors with a master degree or a diploma and 40% of doctors with a Bachelor of Medicine, Bachelor of Surgery certificate considered the hepatitis C virus (HCV) genotype as risk factor for HCC development (P < 0.05). Ninety percent of physicians specialized in tropical medicine, internal medicine or gastroenterology and 67% of physicians in other specialties advise patients to undergo screening for HCV and hepatitis B virus infection as well as liver cirrhosis (P < 0.05). Eighty-six percent of doctors in University Hospitals and 69% of Ministry of Health (MOH) doctors consider HCV infection as the leading cause of HCC in Egypt (P < 0.05). Seventy-two percent of doctors with an MD degree, 55% of doctors with a master degree or a diploma, 56% of doctors with an MBBCH certificate, 74% of doctors in University Hospitals and 46% of MOH hospital doctors consider abdominal ultrasonography as the most important investigation in HCC screening (P < 0.05). Sixty-five percent of physicians in tropical medicine, internal medicine or gastroenterology and 37% of physicians in other specialties recommend as HCC screening interval of 3 mo (P < 0.05). Seventy-one percent of doctors with an MD degree, 50% of doctors with a master degree or diploma and 60% of doctors with an MBBCH certificate follow the same recommendation. In Egypt, physicians specialized in tropical medicine, internal medicine or gastroenterology with an MD degree and working in a University Hospital are best informed about HCC.

The impact of hepatitis E in the liver transplant setting

Hepatitis E virus (HEV) infection has been identified as a cause of graft hepatitis in liver transplant recipients. The true frequency and clinical importance of HEV infections after liver transplantations is a matter of debate. It is proposed that consumption of HEV-contaminated undercooked meat is a main source for HEV infections in developed countries--which might also account for some hepatitis E cases after organ transplantation. However, HEV is also transmitted by transfusion of blood products, likely representing a previously underestimated risk particularly for patients in the transplant setting. HEV infection can take chronic courses in immunocompromised individuals, associated in some cases with rapid progression to cirrhosis within 1-2 years of infection. Diagnosis in transplanted patients is based on HEV RNA testing as antibody assays are not sensitive enough. Selection of immunosuppressive drugs is important as different compounds may influence viral replication and the course of liver disease. Ribavirin has antiviral activity against HEV and should be administered for at least three months in chronically infected individuals; however, treatment failure may occur. HEV infections have also been linked to a variety of extrahepatic manifestations both during and after resolution of infection. In this review we summarize the emerging data on hepatitis E with a particular focus on the importance of HEV infections for liver transplant recipients.

Autophagy and microRNA dysregulation in liver diseases.

Autophagy is a catabolic process through which organelles and cellular components are sequestered into autophagosomes and degraded via fusion with lysosomes. Autophagy plays a role in many physiological processes, including stress responses, energy homeostasis, elimination of cellular organelles, and tissue remodeling. In addition, autophagy capacity changes in various disease states. A series of studies have shown that autophagy is strictly controlled to maintain homeostatic balance of energy metabolism and cellular organelle and protein turnover. These studies have also shown that this process is post-transcriptionally controlled by small noncoding microRNAs that regulate gene expression through complementary base pairing with mRNAs. Conversely, autophagy regulates the expression of microRNAs. Therefore, dysregulation of the link between autophagy and microRNA expression exacerbates the pathogenesis of various diseases. In this review, we summarize the roles of autophagy and microRNA dysregulation in the course of liver diseases, with the aim of understanding how microRNAs modify key autophagic effector molecules, and we discuss how this dysregulation affects both physiological and pathological conditions. This article may advance our understanding of the cellular and molecular bases of liver disease progression and promote the development of strategies for pharmacological intervention.

Do the epidemiology, physiological mechanisms and characteristics of hepatocellular carcinoma in HIV-infected patients justify specific screening policies?

Reducing the incidence of hepatocellular carcinoma (HCC) in HIV-infected patients has become a serious problem when managing these patients. There are many explanations for this disease evolution, which notably include their longer survival under effective antiviral therapy and also the more rapid evolution of chronic liver disease. Despite recent advances in the management of hepatitis B (HBV) and hepatitis C (HCV) viral diseases, which will probably increase the number of patients achieving a virological response, HIV-infected patients with cirrhosis are still at risk of the onset of HCC. This evolution to HCC is also correlated to other comorbidities such as excessive alcohol consumption and nonalcoholic steatohepatitis (NASH). HCC thus remains a public health issue in this population. The poor prognosis and aggressiveness of HCC have been fully demonstrated, but the mechanisms underlying this aggressiveness are not yet well defined. As well as underlying mechanisms that contribute to accelerating hepatocarcinogenesis in HIV-infected patients, there are other reasons why HIV-infected patients should be considered a higher risk population. This review discusses the principal epidemiological determinants; the mechanisms of pathogenesis; and the treatment of HCC in HIV/HBV and HIV/HCV coinfected patients. It also discusses the probable need to develop a specific screening policy for HCC in this population in order to prevent the rapid development and to make them more amenable to a curative treatment.

Low prevalence of hepatitis C infection among HIV-infected individuals in Slovenia: a nationwide study, 1985–2013

After introduction of highly active antiretroviral therapy and consecutive successful control of HIV infection hepatitis C virus (HCV) has become an important pathogen in HIV infected patients. HIV infection in a person who is also HCV infected results in reduced rate of spontaneous HCV RNA clearance, faster liver disease progression and more aggressive course of liver disease. A total of 639 individuals were cumulatively reported as HIV-infected in Slovenia until the end of 2013. The majority of HIV-infected were men (553/639; 86.5%) and among them 68.2% were men who have sex with men. The predominant HIV-1 subtype in Slovenia is subtype B, which is present in 85.8% of the infected individuals. We tested 575 (90.0%) of 639 Slovenian individuals who were confirmed as HIV positive by the end of 2013 for HCV infection. All individuals included in a study were tested for both anti-HCV and HCV RNA. Out of 575 HIV-infected individuals 44 (7.6%) had anti-HCV specific antibodies, and 32 of them (72.7%) were also HCV RNA positive. We didn’t detect HCV RNA alone in any of the 531 anti-HCV-negative individuals. Anti-HCV positivity was significantly more frequent in HIV-infected individuals who acquired HIV by parenteral route (73.3%) comparing with those who acquired HIV by sexual route (2.6%). The most prevalent HCV genotype among HIV-infected individuals was genotype 1 (70.8%), followed by genotype 3 (16.7%), genotype 4 (8.3%) and genotype 2 (4.2%). HCV genotypes distribution didn’t significantly differ between HIV-positive and HIV-negative, HCV-positive Slovenian patients. Our study which was performed on the highest proportion per entire population of HIV-infected individuals from a certain country identified Slovenia as the country with the lowest prevalence of HCV infection among HIV-infected individuals. The predominance of sexual transmission of HIV (79.2%) in Slovenia and the fact that HIV has not yet entered the intravenous drug users’ community in Slovenia are the two most likely reasons for low prevalence of HIV-HCV co-infection. However, the present epidemiological situation in Slovenia needs to be monitored closely since it could quickly change in a case of an increase in the incidence of acute hepatitis C among HIV-infected men who have sex with men and/or increase of HIV infection among intravenous drug users in the country, as it happened recently in some neighboring countries.

Hepatitis B virus DNA quantification with the three-in-one (3io) method allows accurate single-step differentiation of total HBV DNA and cccDNA in biopsy-size liver samples

BackgroundHepatitis B virus (HBV) replicates via reverse transcription converting its partially double stranded genome into the covalently closed circular DNA (cccDNA). The long-lasting cccDNA serves as a replication intermediate in the nuclei of hepatocytes. It is an excellent, though evasive, parameter for monitoring the course of liver disease and treatment efficiency. ObjectiveTo develop and test a new approach for HBV DNA quantification in serum and small-size liver samples. Study designThe p3io plasmid contains an HBV fragment and human β-actin gene (hACTB) as a standard. Respective TaqMan probes were labeled with different fluorescent dyes. A triplex real-time PCR for simultaneous quantification of total HBV DNA, cccDNA and hACTB could be established. ResultsThree-in-one method allows simultaneous analysis of 3 targets with a lower limit of quantification of 48 copies per 20μl PCR reaction and a wide range of linearity (R2>0.99, p<0.0001) for all measured sequences. The method showed a pan-genotypic specificity among genotypes A–F with serum DNA samples from HBV infected patients. Total HBV DNA and cccDNA could be quantified in 32 and 22 of 33 FFPE preserved liver specimens, respectively. Total HBV DNA concentrations quantified by the 3io method remained comparable with Cobas TaqMan HBV Test v2.0. ConclusionsThe three-in-one protocol allows the single step quantification of viral DNA in samples from different sources. Therefore lower sample input, faster data acquisition, a lowered error and significantly lower costs are the advantages of the method.

Patient-important benefits of clearing the hepatitis C virus through treatment: A simulation model

Given an appreciable risk of adverse-effects, current therapies for chronic hepatitis C virus (HCV) infection pose a dilemma to patients. We explored, via simulation modelling, patient-important benefits of attaining a sustained viral response (SVR). We created the HCV Individualised Treatment-decision model (the HIT-model) to simulate, on a per patient basis, the lifetime course of HCV-related liver disease according to two distinct scenarios: (i) SVR attained, and (ii) SVR not attained. Then, for each model subject, the course of liver disease under these alternative scenarios was compared. The benefit of SVR was considered in terms of two patient-important outcomes: (1) the percent-probability that SVR confers additional life-years, and (2) the percent-probability that SVR confers additional healthy life-years, where "healthy" refers to years spent in compensated disease states (i.e., the avoidance of liver failure). The benefit of SVR varied strikingly. It was lowest for patients aged 60 years with initially mild fibrosis; 1.6% (95% CI: 0.8-2.7) and 2.9% (95% CI: 1.5-4.7) probability of gaining life-years and healthy life-years, respectively. Whereas it was highest for patients with initially compensated cirrhosis aged 30 years; 57.9% (95% CI: 46.0-69.0) and 67.1% (95% CI: 54.1-78.2) probability of gaining life-years and healthy life-years, respectively. For older patients with less advanced liver fibrosis, SVR is less likely to confer benefit when measured in terms of averting liver failure and premature death. These data have important implications. Foremost, it may inform the contemporary patient dilemma of immediate treatment with existing therapies (that have poor adverse effect profiles) vs. awaiting future regimens that promise better tolerability.

English

AIM: To evaluate resistive index in various stages of liver cirrhosis and to determine its significance in developing hepatorenal syndrome. METHODS: Study included 60 cirrhotic patients divided into 4 groups (15 patients each): compensated liver cirrhosis (group A), diuretic responsive ascites (group B), refractory ascites (group C), hepatorenal syndrome (group D) and ten healthy persons as control group (E). All patients subjected to detailed history taking and clinical examination. Laboratory investigations included simple urine analysis, complete blood picture, liver function tests, blood urea and serum creatinine, serum sodium and serum potassium, and protein concentration. Ultrasonographic examination and renal duplex Doppler were under taken to assess the Resistive index. RESULTS: The RI of interlobar and arcuate arteries were significantly higher in all patient groups than in control group (p <0.05), the RI was significantly higher in patients with refractory ascites than in patients with diuretic responsive ascites, and also in patient of diuretic responsible ascites than in patients with compensated cirrhosis (p < 0.05), in patient with hepatorenal syndrome than in patient with diuretic responsive ascites and patients with compensated cirrhosis (p<0.05). Also Creatinine levels & blood urea levels in patients with the hepatorenal syndrome was significantly higher than that of other different groups (p<0.05) but there was no significant change in creatinine levels between patients with compensated cirrhosis and control group. While creatinine levels in patient with diuretic responsive ascites was significantly higher than that in patient with compensated cirrhosis (p<0.05) there was no significant change between patient with diuretic responsive ascites and patient with refractory ascites. CONCLUSION: Resistive index increases with degree of hepatic decompensation. Renal duplex ultrasound is a non- invasive, simple and easy method to study intrarenal hemodynamics in patients with liver cirrhosis INTRODUCTION: Renal hemodynamic changes with intense intrarenal vasoconstriction begin early in the course of liver disease before changes in the level of serum urea and serum creatinine1. Patients with liver cirrhosis and portal hypertension develop circulatory dysfunction characterized by disturbance in systemic and renal hemodynamics. Hepatorenal syndrome (HRS) is a functional and reversible form of renal failure that occurs in patients with advanced chronic liver disease. The distinctive hallmark feature of HRS is the intense renal vasoconstriction caused by interactions between systemic and portal hemodynamics. This results in inactivation of vasoconstrictors and suppression of vasodilators in the renal circulation. Although the assessment of kidney function is of great clinical importance in patients with liver cirrhosis and ascites, serum creatinine and even

Thrombocytopenia, Liquor Use and Marijuana are Associated with Noninvasive Markers of Liver Fibrosis in People Living with HIV

Objective and aims: Liver disease is currently one of the leading causes of death among people living with HIV. Although platelets alterations are well recognized in the course of liver disease, the impact of thrombocytopenia (TCP: platelet counts <150,000 per microliter), which is highly prevalent among Hazardous Alcohol Users (HAU), is unclear. This lack of information limits the possibility to identify those at risk and to create targeted interventions. Methods: In this study, a total of 400 people living with HIV underwent laboratory assessments to determine if in addition to alcohol, TCP or its related factors (i.e., serotonin) were associated with non-invasive markers of liver fibrosis. The FIB-4 and the APRI scores were calculated using the Sterling’s and the Wai’s formulas, respectively. Results: Liver fibrosis was present in almost half of the study population (47%). As expected, APRI values of Hepatitis C co-infected subjects were higher than in HIV mono-infected patients (0.96 ± 0.18 vs. 0.5 ± 0.45, p=0.01). Notably, the risk was higher among marijuana users (OR= 9 95% CI 1.3-9.5, p=0.02). The risk of moderate fibrosis was also higher in the HAU (OR = 1.3; 95% CI, 1-2.5, p=0.04) when compared to non-HAU. Additional analyses indicated that consumption of liquor even 1-2 drinks per day, and high daily intakes of beer or wine (> 3 drinks per day) increases the risk of liver fibrosis. Thrombocytopenia, which is still prevalent (HAU=15% versus Hep C=22%) significantly increased the odds of moderate fibrosis (OR = 9; 95% CI, 3.6-23; p=0.0001). The odds of having severe fibrosis were 52% higher in the TCP group (95% CI, 13-97; p=0.0000). Serotonin, which is stored in the platelets, was also reduced among subjects with liver fibrosis levels (55.7 ± 6.7 vs. 87.3 ± 7.8 ng/mL, p=0.003). Multivariate analysis identified gender, hepatitis C, liquor use, TCP, marijuana and serotonin alterations as risk factors associated with liver fibrosis. Conclusion: Liver fibrosis is a condition that was associated with modifiable risk factors such as HAU, marijuana, TCP and viral hepatitis C. These results indicated that health care providers must be attentive for signs of these conditions to avert the risk of this terminal liver disease. From the clinical perspectives, analyses suggest that platelet-based interventions and serotonin agonist could be potential therapeutic targets.

Prognostic Marker for Liver Disease due to Alpha1-Antitrypsin Deficiency

Only some Alpha1-antitrypsin deficiency (A1ATD) PiZZ patients develop liver cirrhosis and portal hypertension. Aim of the study was to investigate the course of liver disease associated with PiZZ A1ATD and to determine prognostic factors. We retrospectively reviewed the clinical and laboratory data of all PiZZ children up to 18 years of age admitted to our centre since 1978. 53 patients (age at first visit 2 days to 12 years) met our criteria. The children were divided into 2 groups: group 1 'bad prognosis', meaning the patients which were on the waiting list for liver transplantation (LTx), had a liver transplantation or had died, and group 2 'good prognosis', containing the patients they were living with their own liver. We analysed family history including smoking, gestational age, maternal age at delivery, date of birth, sex, neonatal history, breast-feeding, symptoms at presentation, clinical and laboratory data and date of LTx and/or death. Various anamnesis parameters such as manifestation of neonatal cholestasis showed no prognostic significance. In contrast the laboratory parameters thrombocytes (p=0.008), bilirubin (p<0.001), prothrombin time (p<0.001), choline-sterase (p<0.001), gamma-GT (p=0.001) and GOT (p=0.002) showed a correlation with a liver transplantation and/or death. Prognosis is difficult to determine at an early stage of this disease, but various laboratory parameters can help to predict an outcome. Therefore a regular follow-up is necessary for the children.

Hematologic Manifestations of Liver Disease

The liver plays a key role in both protein biosynthesis and lipid metabolism. As a result, hepatic synthetic dysfunction can have adverse effects on both cellular and soluble components of blood. Anemia may occur due to the hemolysis of acanthocytes (spur cells), which is ultimately due to abnormal lipid composition of the red blood cell membrane. Thrombocytopenia may result from several different mechanisms. Cytopenias also may be a consequence of hypersplenism. The liver is the primary site for synthesis of most procoagulant and anticoagulant proteins. The coagulopathy of liver disease is therefore complex. Early in the course of liver disease, thrombocytopenia and a coagulopathy associated with a prothrombotic state are not uncommon, whereas with more advanced disease pancytopenia and coagulopathy associated with hemorrhage become manifest. Fresh frozen plasma and adjuncts to hemostasis may be used as temporizing measures in bleeding patients. However, definitive management of many of the defects due to fulminant hepatic failure requires liver transplantation.

Association between dental infections and the clinical course of chronic liver disease

Dental infections are implicated in several systemic diseases due to bacteremia and pro-inflammatory effects, but their possible role in liver disease is unclear. We retrospectively analyzed the clinical course of liver disease in relation to dental health among 116 patients with liver cirrhosis who underwent dental examination before liver transplantation. The need for multiple tooth extractions, a surrogate marker of dental infections, was associated with reduced time from diagnosis of liver disease to the need for liver transplantation (P = 0.02). The association was independent of age, sex, liver disease etiology and Model for End-Stage Liver Disease (MELD) score (P = 0.04). Among 38 patients with accurate laboratory follow-up data, the number of tooth extractions correlated with the change in MELD score during the year preceding dental examination (r = 0.43, P = 0.03). Spontaneous bacterial peritonitis caused by Streptococcus viridans occurred only among patients with multiple dental infections. Dental infections may influence the clinical course of liver disease, but prospective studies are needed.

The three-in-one (3io) method for total and cccDNA quantification in small-size samples from HBV infected patients

Aims: Hepatitis B virus (HBV) is a member of Hepadnaviridae family comprising viruses replicating via particular reverse transcription mechanism. The first step in HBV replication is filling the single stranded fragments of the viral genome into the completely double stranded form and formation of covalently closed circular DNA (cccDNA). cccDNA exists in the liver as an independent episomal molecule serving as a long-lasting reservoir of the virus. It acts as a template for all genomes of viral progeny. It is an excellent though evasive parameter for monitoring the course of liver disease and treatment efficiency.