Vol. 13 Issue 1
On the cover: This figure showns a liver histology of a patient with massive hepatocellular necroses due to Halothane hepatitis.
Introduction. Bacterial infection in cirrhotic patients is a severe complication that requires early recognition and specific therapeutic care. Material and methods. In this review the various aspects of diagnosis and management of infections that may impact survival in cirrhosis are analyzed. Results. Active search for infections allows early detection and its treatment with suitable antibiotics has reduced mortality rates in spontaneous bacterial peritonitis, the main infection in patients with decompensated cirrhosis. Other common infections, such as bacteremia and septicemia or urinary tract, lung, skin and soft tissue infections must be thoroughly investigated so that antibiotic treatment can be started early. As intestinal bacterial translocation is one of the most important mechanisms for development of bacterial infections, selective intestinal decontamination is able to prevent these infections in populations at risk. After the first episode of spontaneous bacterial peritonitis, poorly absorbed oral antibiotics, such as quinolones, must be started and continued. Moreover, when there is upper gastrointestinal bleeding, infection prevention should be based on oral administration of quinolones or intravenous administration of cephalosporins, both for seven days, to avoid morbidity and early lethality. With the advent of resistance to commonly used antibiotics and recent reports of multiresistant bacteria, there is a need for stricter control when administering antibiotics to cirrhotic patients. Conclusion. Existing knowledge of therapy and prophylaxis for bacterial infections in cirrhotic patients, which undoubtedly improve survival, should be disseminated and applied in clinical practice for the benefit of the population at large.
Introduction. In patients with chronic hepatitis C it is still debated whether previous exposure to the hepatitis B virus, diagnosed from the presence of the anti-HBc antibody, is linked to a greater risk of severe hepatitis. The aim of the study was to evaluate whether the presence of anti-HBc antibodies is associated with cirrhosis in patients with HBsAg-negative chronic hepatitis C. Material and methods. Two hundred twenty-two consecutive HBsAg-negative patients with HCV-related chronic hepatitis were enrolled at their first liver biopsy. Ishak's scoring system was used to grade necroinflammation and fibrosis and the patients with stage 5 or 6 were considered as having histological cirrhosis. Results. Patients with histological cirrhosis had a higher mean age, AST, ALT, a lower platelet count and prothrombin activity compared to those with milder fibrosis. The presence of anti-HBc was identified in 21 (63.6%) of the 33 patients with fibrosis score 5 or 6 and in 56 (29.6%; p < 0.001) of the 189 with score ≤ 4. Patients with cirrhosis had a significantly higher grading than those without cirrhosis (median = 8, IQR 6-11 vs. Median = 6, IQR = 4-8, respectively, p < 0.001). A multivariate logistic regression analysis showed that age, sex and anti-HBc positivity were independent predictors of histological cirrhosis. Conclusion. Our data support the idea that in patients with chronic hepatitis C the presence in serum of anti-HBc is associated with histological cirrhosis and is therefore a marker of clinical value.
Background & Aim. The mechanisms by which type 2 diabetes mellitus (T2DM) worsen liver function are not yet established. Tissue factor (TF) is a protein that participates in hemostatic, immune and inflammatory processes. To test the hypothesis that T2DM contributes to clinical outcome through changes of TF expression on monocytes and to investigate the association between antidiabetic therapies and monocytic TF expression in HCV-related cirrhotic patients with T2DM. Material and methods. In HCV-related cirrhotic patients (139 diabetics and 130 non diabetics) compared with 100 matched diabetic patients and 100 Controls; the flowcytometric analysis of CD14, TF (CD142), costimulatory molecules; CD86 and HLA-DR on monocytes were determined. Results. Cirrhotic patients with T2DM have increase in the expression of monocytic TF and CD86 in comparison with cirrhotic non-diabetic, diabetic and healthy control; which increase significantly with increase of the stage of the Child-Pugh score. The expression of HLA-DR is significantly lower in cirrhotic patients than controls. Albeit, there were no significant differences in the HbA1c levels between the three groups, the use of exogenous insulin were associated with significantly higher monocytic TF expression than those in sulphonylurea and insulin sensitizer group (P < 0.03 for both). Conclusions. The monocytic TF as a significant link connecting inflammatory and immunological phenomena can partially explain a lot of events in HCV- related cirrhotic patients with T2DM. The use of exogenous insulin was associated with significantly higher TF expression than sulphonylurea and insulin sensitizer. Future target therapy against TF may be beneficial for T2DM cirrhotic patients.
Introduction. High activity antiretroviral therapy (HAART) has allowed people infected with human immunodeficiency virus (HIV) to live longer. In the course of time, hepatocellular carcinoma (HCC) began to be found in these patients. Investigations have suggested that, as it has been described for other tumors, HIV infection raises the risk of developing HCC. However, convincing evidence is still required. Our aim was to quantify the incidence of HCC in hepatitis C cirrhotic patients with and without human immunodeficiency virus infection in the HAART era. Material and methods. This prospective cohort study was conducted in hepatitis C cirrhotic patients with and without HIV co-infection, between june 1, 1999 and May 21, 2010. Ultrasound screening for HCC was performed every 6 to 12 months to all the patients until January 15, 2011. Incidence rate and cumulative incidence (Kaplan-Meier) were calculated. Results. One hundred and forty eight patients (69 hepatitis C virus mono-infected and 79 HIV/hepatitis C virus co-infected) were followed for a median time of 43 months, with a total follow-up of 555 person-years (324 for co-infected and 231 for mono-infected patients). Twelve patients developed HCC (5 co-infected and 7 mono-infected). The incidence of HCC in co-infected patients and mono-infected patients was 1.54 (95% confidence interval = 0.5 to 3.6) and 3.03 (95% confidence interval = 1.22 to 6.23) cases per 100 person-year respectively (log-rank p = 0.3225). Conclusion. In the HAART era, HIV co-infection is not associated with a higher incidence of HCC in hepatitis C cirrhotic patients.
Background. The liver possesses two distinct mechanisms for healing. Wound healing via hepatic stem cells recapitulates early development (hepatoblast proliferation), while liver regeneration resembles late embryonic growth (hepatocyte proliferation). Loss of control over both of these processes have been proposed as mechanisms that may contribute to poor outcomes in HCC. Material and methods. We used microarray gene expression profiles to examine the involvement of hepatic stem cell and hepatocyte proliferation markers and regulators in HCV-induced cirrhosis and HCC. We compared 30 cirrhosis and 49 HCC samples to 12 disease-free control livers. Results. Cirrhosis and HCC expressed markers of stem cell. Inhibitors of hepatocyte proliferation (HP) were highly expressed in cirrhosis. Loss of these HP inhibitors in HCC patients was associated poor prognosis (94 vs. 38% 2-year recurrence- free survival, p = 0.0003). Principal Components Analysis discriminated cirrhotic and HCC tissues, and HCC patients with poor (< 2 year) vs. good (> 2 year) recurrence-free survival. Loss of CDH1 expression correlated with up-regulation of hepatocyte proliferation promoters MET and YAP1. CDH1, MET, and YAP1 were independent predictors of recurrence-free survival by Cox regression when corrected for tumor stage (p < 0.0001). Conclusion. HCV-cirrhosis is characterized by proliferation of liver stem cells and inhibition of hepatocyte proliferation. HCC tumors in which this pattern persists have superior outcomes to those which acquire a hepatocyte proliferation signature. Genes in this signature should be studied further for potential as tissue or serum biomarkers for patient risk stratification. CDH1 and MET are candidates for personalized therapies with targeted pharmaceutical agents.
Introduction. Splanchnic hypoperfusion appears to play a key role in the failure of functional recovery of the graft after orthotopic liver transplantation (LT). The aim of this study was to determine if alterations of tonometric parameters, which are related to splanchnic perfusion, could predict poor graft function in patients undergoing LT. Materials and methods: After Ethics Committee approval, 68 patients undergoing LT were enrolled. In all the patients, regional-arterial CO2 gradient (Pr-aCO2) was recorded; in addition, the difference between Pr-aCO2 recorded at anhepatic phase (T1) and at the end of surgery (T2) (T2- T1 = ΔPr-aCO2) was calculated. Poor graft function was determined on the basis of Toronto's classification 72 hours after LT. Student t-test and logistic regression analysis were used for statistical purpose. Results. ΔPr-aCO2 was significantly greater in patients with poor graft function (3.5 ± 13.2) compared to patients with good graft function (-5.8 ± 12.3) (p = 0.014). The logistic regression analysis showed that the ΔPr-aCO2 was able to predict the onset of poor graft function (p = 0.037). A value of ΔPr-aCO2 ≥ -4 was associated with poor graft function with a sensibility of 93.3% and a specificity of 42.3%. Conclusion. Our study suggests that the change of Pr-aCO2 may be a valuable index of graft dysfunction. Gastric tonometry might give early prognostic information on the graft outcome, and it may aid clinicians in planning a more strict follow-up and proper interventions in order to improve graft survival.
Introduction. Chronic liver disease (CLD) is becoming a major cause of mortality in patients who are positive with human immunodeficiency virus (HIV). Our aim was to assess the prevalence of CLD in HIV+ individuals. Material and methods. We utilized the National Health and Nutrition Examination Survey (1999-2008) to assess the association of CLD with HIV infection. In eligible participants (18-49 years), HIV infection was defined as positive anti-HIV by enzyme immunoassay further confirmed by Western blot. The diagnosis of CLD included chronic hepatitis C (CH-C), alcohol-related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Clinic-demographic and laboratory parameters were used to assess differences between those with and without HIV infection. Results. 14,685 adults were included. Of those, 0.43 ± 0.08% were HIV-positive and 13.8% had evidence of CLD, including 26.3% in HIV-positive individuals and 13.7% in HIV-negative controls (p = 0.0341). In the U.S. population, independent predictors of CLD included HIV positivity [OR = 1.96 (1.02-3.77), p = 0.04], older age [OR = 1.03 (1.02-1.03), p < 0.0001], male gender [OR = 2.15 (1.89- 2.44), p < 0.0001] and obesity [OR = 2.10 (1.82-2.43), p < 0.0001], while African American race/ethnicity was associated with lower risk for CLD [OR = 0.68 (0.58-0.80), p < 0.0001]. Conclusions. CLD is common in HIV positive individuals. With successful long term treatment of HIV, management of CLD will continue to remain very important in these patients.
Introduction and aim. There is scarce information about primary prophylaxis in cirrhotic patients. The aim was to assess the efficacy of ciprofloxacin for primary prophylaxis for bacterial infections in patients with cirrhosis of the liver and ascites. Material and methods. A randomized, double-blind placebo-controlled clinical trial was conduced. Patients were randomized to receive oral ciprofloxacin 500 mg/day or placebo for one month. A basal evaluation and repeated assessments at 4, 6, 12, 18, and 24 weeks afterwards, or whenever a primary endpoint occurred were done. Statistical analysis: probability curves were constructed with the Kaplan-Meier method and compared by the log-rank test. Results. 95 patients were randomized to ciprofloxacin group (n = 49; 51.6%) and placebo group (n = 46; 48.4%). Six-teen (32.6%) patients in the ciprofloxacin group developed bacterial infections and thirteen (28.2%) patients developed bacterial infections in the placebo group (p = NS). The probability to remain free of bacterial infections did not reach statistical significance (p = 0.38). Probability of survival at 24 weeks was 91% in placebo group and 98% in the ciprofloxacin group (p = 0.28). The absolute risk reduction was 5%, the relative risk reduction was 6% and the NNT was 20 patients. Conclusion. Primary prophylaxis with ciprofloxacin for one month in cirrhotic patients with ascites who do not have a currently accepted indication, did not show a preventive effect on the development of bacterial infections at one month follow-up. Moreover in women could increases the odds for UTI. The administration of ciprofloxacin seemed to decrease the risk of mortality.
Background. Treatment of gastric varices (GV) implies a number of several difficulties and sometimes entails complications. The best endoscopic success rate was attributed until now to the use of tissue adhesives(N-Butyl-2-Cyanoacrylate) and band ligation. Aim. To assess the therapeutic efficacy and safety of cyanoacrylate injection compared to band ligation in patients with acute GV hemorrhage. Material and methods. Thirty-seven patients with upper gastrointestinal bleeding from GV were included in the study, treated with cyanoacrylate injection (GVO)-19 patients or band ligations (GVL)-18 patients. They were followed up for overall results, complications and survival rate. Results. The mean age of the study group was 60.22 ± 9.34 years, with a male/female ratio of 21:16. The mean follow-up period was 427.26 ± 214.16 days in the GVO group and 406.21 ± 213.23 days in the GVL group (p = 0.76). Initial hemostasis was achieved in all patients treated with cyanoacrylate and in 88.88% from the GVL group (p = 0.43). Rebleeding occurred in 72.22% of the GVL group and in 31.57% of the GVO patients (p = 0.03). Patients in the GVO group had a significantly larger rebleeding-free period(p = 0.006). No difference was found in survival rates(p = 0.75). The Child Class (p = 0.003 for Class C) and treatment method (p = 0.01) were independently associated with the rate of rebleeding. No differences were found regarding the rate of complications. Conclusion. The use of cyanoacrylate in acute GV bleeding had better results when compared with band ligation in terms of controlling the hemorrhage and recurrence of bleeding. The overall survival rate was not influenced by the method used for the treatment of complicated GV.
Background and Aim. Statins are commonly used medications for the treatment of dyslipidemia. Although there are reported cases of hepatotoxicity related to statins, very few are associated with severe course and liver failure. Material and methods. We used the Third National Health and Nutrition Examination Survey (NHANES III)-mortality linked files to assess the association between statin use and liver-related mortality. Patients with established causes of liver disease (HCV RNA-positive, HBs-Ag-positive, NAFLD by hepatic ultrasound, iron overload and excessive alcohol use of > 20 g of alcohol per day with elevated liver enzymes) were excluded. Results. Of all adult NHANES III participants enrolled in 1988-1994 (n = 20,050), 9,207 individuals had sufficient demographic, clinical and medical information making them eligible for this study (age 41.26 ± 0.38, 46.76% male, 76.67% Caucasian, BMI 26.39 ± 0.38, 16.99% had diabetes or insulin resistance, 16.97% had hypertension, 65.28% had dyslipdemia). Of the entire study cohort, 90 (1.25%) participants reported using statins at the time of the interview. Median mortality follow-up for the study cohort was 175.54 months. During this period, 1,330 individuals (11.25%) died with 26 (0.17%) being liver-related deaths. For the cohort using statins, there were 37 deaths (40.15%) after a median follow-up of 143.35 months. In fact, the top cause of death for statin users was cardiac related (16 cases, 33.62%). However, after adjusting for major demographic, clinical and metabolic confounders, statin use was not associated with cardiovascular deaths in males (Hazard Ratio, 0.79, 95% Confidence Interval, 0.30-2.13), but was associated with higher risk of cardiovascular deaths in females (odds ratio, 2.32, 95% confidence interval, 1.58-3.40). Furthermore, the rate of liver-related mortality was significantly lower (p = 0.0035) among statin users compared to non-statin users. Conclusions. After a decade of follow up, there was no association between statin use and liver-related mortality.
Background. In the management of chronic hepatitis C (CHC) patients, liver biopsy is the gold standard for liver fibrosis assessment despite some technical limits and risks. Non-invasive approaches have been proposed as alternative methods to evaluate structural liver damage. Aim. To investigate the diagnostic accuracy of transient elastography, 13C-aminopyrine breath test (13C-ABT), serum hyaluronic acid (HA) and cytokeratin 18 Asp396 fragment (CK-18) as non-invasive methods of liver fibrosis assessment ad their correlation to METAVIR score. Material and methods. In a cohort of 57 CHC patients, liver stiffness, cumulative percentage of administered dose of 13C-aminopyrine at 120 min, serum HA and serum CK-18 concentration were determined. Diagnostic accuracy in detecting significant fibrosis (F ≥ 2), severe fibrosis (F ≥ 3) and cirrhosis (F = 4) was assessed by the area under the receiver operating characteristic curve. Results. Liver fibrosis score showed a strong correlation with liver stiffness (r = 0.667; p < 0.0001) and a significant inverse correlation with 13C-ABT results (r = -0.418; p = 0.0012). A weaker correlation was found with CK18 (r = 0.329; p = 0.0126) and no correlation with HA. Areas under the curve of elastography, 13C-ABT, HA and CK18 were: 0.98, 0.75, 0.69, 0.64, respectively, for F ≥ 2; 0.97, 0.69, 0.80, 0.66, respectively, for F ≥ 3; 0.95, 0.64, 0.70, 0.56, respectively, for F = 4. Conclusion. Elastography has the best diagnostic accuracy for the assessment of the degree of liver fibrosis in CHC patients. Its application can provide an alternative useful tool for monitoring the disease evolution.
Background and Aims. Acute-on-chronic liver failure has been recognized as a sudden deterioration of cirrhosis, with a high short-term mortality. Prognostic scores are used to assess liver dysfunction. However, there is not enough information on a score to predict short term mortality in those patients. We aimed to investigate the prognostic value of bilirubin concentration in predicting the 1-week outcome of patients with acute-on-chronic liver failure. Material and methods. We performed a retrospective analysis with a cohort of 65 patients (33 women/32 men), age average of 64 years, diagnosed with acute-on-chronic liver failure with at least 1 week follow-up. Demographics, clinical and biochemical variables were analyzed. Most patients died (59 %) within 1 week of follow-up. Results. In univariate logistic regression analysis, admission to the intensive care unit, use of vasoactive drugs, need for parenteral nutrition, and levels of conjugated, unconjugated, and total bilirubin at the time of hospital admission were significantly associated with 1-week mortality; in a multivariate logistic regression, conjugated (p = 0.01), unconjugated (p = 0.01), and total bilirubin (p = 0.009) were independently associated with 1-week mortality. In ROC curve analysis, conjugated (0.751, p < 0.05) and total bilirubin (0.746, p < 0.05) levels were significantly the best short-term mortality predictors. Conclusions. High levels of bilirubin are able to predict short-term mortality in these patients. Also, we suggest that bilirubin can be used as a biochemical marker to improve triage of patients with acute-on-chronic liver failure especially with emerging interventions such as extracorporeal liver assist devices and possibly improved early phase pharmacological therapies.
Background. Bile acid sequestration (BAS) with resins has shown antidiabetic effects in both humans and animals. Since hepatic steatosis is commonly associated with type 2 diabetes mellitus and the effects of BAS on steatosis have not been explored in detail, we evaluated the effects of cholestyramine (CTM) administration on fatty liver development in the leptin-deficient obese mice. Aim. To study the effects of BAS on fatty liver development in obese (ob/ob) mice. Material and methods. 4 week-old ob/ob mice (B6.V-Lepob/ J, n = 4-6 per group) were fed with or without CTM (control group) during 8 weeks. Serum and biliary parameters, glucose tolerance test (GTT), hepatic triglyceride content, liver histology and hepatic gene expression of relevant genes related to bile secretion, lipid and glucose metabolism were assessed. Results. Control 12-week-old mice exhibited marked obesity and hepatic steatosis. CTM administration expectedly determined a marked de-repression of 7-α-hydroxylase and decreased biliary bile acid secretion as well as improved GTT. CTM feeding showed no effects on hepatic triglyceride content or in the degree of steatosis on liver histology. CTM was associated with increased levels of serum alanine-aminotransferase. Conclusion. Although CTM administration positively affects glucose tolerance it does not prevent hepatic steatosis development in obese mice. Moreover, CTM feeding was associated to liver enzyme elevation in this model of NAFLD. Thus, the effects BAS on NAFLD need to be specifically addressed since this therapy might not be beneficial for this condition.
Background. The information available on time and dose effects of the exposure of hepatocytes to free fatty acids (FFA) in vitro is controversial, and very few studies have assessed the hepatocyte inflammatory response in an in vitro model. Aim. To analyze the effect of treatment with FFA on cell viability and on the kinetics of cytokine expression using hepatic cell lines. Material and methods. Hepatic cell lines, IHH and HuH7, were cultured for 3 h, 6 h, 12 h and 24 h in an enriched medium with palmitic and oleic acids. The cytotoxicity of the FFA was assessed by the MTT test and the intracellular fat content determined cytofluorimetrically and by fluorescence microscopy using Nile Red staining. The expression of mRNA for interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α was assessed by real time reverse transcription– polymerase chain reaction (RT–PCR). Results. Treatment with 600 μM FFA did not affect the viability of either cell line despite a significant increase in the intracellular content of lipid droplets already evident after 3 h of treatment. A time- and dose-dependent upregulation of the expression of IL-6 and IL-8 mRNA was observed during the treatment at 3 and 24 h. In contrast, TNF-α mRNA expression was highly upregulated at 3 h after FFA exposure but returned to control values at 24 h. In conclusion, hepatocytes exposed in vitro for a short time to low FFA concentrations showed a significant upregulation of IL-6 and IL-8 to, and a rapid but transitory elevation of TNF-α.
For the pathologist, the diagnosis of drug induced liver injury (DILI) is challenging, because histopathological features mimic all primary hepatic and biliary diseases, lacking changes that are specific for DILI. Therefore, in any patient of suspected DILI who underwent liver biopsy, the pathologist will assure the clinician that the observed hepatic changes are compatible with DILI, but this information is less helpful due to lack of specificity. Rather, the pathologist should assess liver biopsies blindly, without knowledge of prior treatment by drugs. This will result in a detailed description of the histological findings, associated with suggestions for potential causes of these hepatic changes. Then, it is up to the physician to reassess carefully the differential diagnoses, if not done before. At present, liver histology is of little impact establishing the diagnosis of DILI with the required degree of certainty, and this shortcoming also applies to herb induced liver injury (HILI). To reach at the correct diagnoses of DILI and HILI, clinical and structured causality assessments are therefore better approaches than liver histology results obtained through liver biopsy, an invasive procedure with a low complication rate.
We retrospectively investigated the characteristics, patterns of disease progression, outcome and difficulties in the management in 11 patients with concurrent autoimmune hepatitis (AIH) and HBV or HCV infections (5 HCV and 6 HBV including 2 with HDV co-infection) since there are scarce data on this issue. HCV or HBV diagnosis preceded that of AIH in all patients by many years. At initial clinical and histological assessment almost half of patients had cirrhosis (45.5%) with the group of AIH and HCV carrying the highest frequency (4/5; 80%). In two thirds of patients, mostly with HCV and HBV/HDV, AIH was assumed to be IFNalpha- induced and experienced difficulties in achieving sustained virological response. On the contrary, the outcome of patients with HBV and AIH was better compared to those with AIH and HCV or HDV. In conclusion, chronic viral hepatitis infections concomitant with AIH are often very difficult to recognize and therefore, a significant delay in AIH diagnosis in this specific group of patients is usual. HBV patients with concomitant AIH seem to carry the most favorable outcome compared to those with HCV probably because of the use of nucleos(t)ide analogues which contrary to IFN-alpha can control HBV replication with no adjacent effect, related to exacerbation of autoimmune phenomena.
Autoimmune liver diseases (AILD) are a group of immunologically induced hepatic disorders that can lead to liver cirrhosis and end-stage liver disease. Extra-hepatic involvement and association with rheumatic diseases (such as Sjögren's syndrome, systemic sclerosis and rheumatoid arthritis) are well known, whereas the coexistence of AILD with small-vessel vasculitis in the same patients have been only occasionally reported. In the present paper we report four such cases and an extensive review of the literature. Clinical features of autoimmune-liver diseases associated with small-vessel vasculitis are discussed, as well as possible common pathogenic pathways including HLA genomics, costimulatory molecules and autoantibodies. In conclusion, knowledge about this association can help physicians in recognising and treating an aggressive disease which could otherwise result in severe and multiple organ damage, compromising the overall prognosis and the indication to liver transplantation.
Hepatic involvement in primary amyloidosis is an infrequent challenge to the hepatologist. Although usually asymptomatic, amyloidosis may have unusual manifestations. Liver biopsy is an important diagnostic tool for this condition. Herein, we report three cases of portal hypertension related to primary hepatic amyloidosis, one of them in the form of acute liver failure.