Stefano Gitto

Enoxaparin Prevents Portal Vein Thrombosis and Liver Decompensation in Patients With Advanced Cirrhosis

BACKGROUND & AIMS We performed a randomized controlled trial to evaluate the safety and efficacy of enoxaparin, a low-molecular-weight heparin, in preventing portal vein thrombosis (PVT) in patients with advanced cirrhosis. METHODS In a nonblinded, single-center study, 70 outpatients with cirrhosis (Child-Pugh classes B7-C10) with demonstrated patent portal veins and without hepatocellular carcinoma were assigned randomly to groups that were given enoxaparin (4000 IU/day, subcutaneously for 48 weeks; n = 34) or no treatment (controls, n = 36). Ultrasonography (every 3 months) and computed tomography (every 6 months) were performed to check the portal vein axis. The primary outcome was prevention of PVT. Radiologists and hepatologists that assessed outcomes were blinded to group assignments. Analysis was by intention to treat. RESULTS At 48 weeks, none of the patients in the enoxaparin group had developed PVT, compared with 6 of 36 (16.6%) controls (P = .025). At 96 weeks, no patient developed PVT in the enoxaparin group, compared with 10 of 36 (27.7%) controls (P = .001). At the end of the follow-up period, 8.8% of patients in the enoxaparin group and 27.7% of controls developed PVT (P = .048). The actuarial probability of PVT was lower in the enoxaparin group (P = .006). Liver decompensation was less frequent among patients given enoxaparin (11.7%) than controls (59.4%) (P < .0001); overall values were 38.2% vs 83.0%, respectively (P < .0001). The actuarial probability of liver decompensation was lower in the enoxaparin group (P < .0001). Eight patients in the enoxaparin group and 13 controls died. The actuarial probability of survival was higher in the enoxaparin group (P = .020). No relevant side effects or hemorrhagic events were reported. CONCLUSIONS In a small randomized controlled trial, a 12-month course of enoxaparin was safe and effective in preventing PVT in patients with cirrhosis and a Child-Pugh score of 7-10. Enoxaparin appeared to delay the occurrence of hepatic decompensation and to improve survival.

Reproductive status is associated with the severity of fibrosis in women with hepatitis C.

Introduction Chronic hepatitis C is the main cause of death in patients with end-stage liver disease. Prognosis depends on the increase of fibrosis, whose progression is twice as rapid in men as in women. Aim of the study was to evaluate the effects of reproductive stage on fibrosis severity in women and to compare these findings with age-matched men. Materials and Methods A retrospective study of 710 consecutive patients with biopsy-proven chronic hepatitis C was conducted, using data from a clinical database of two tertiary Italian care centers. Four age-matched groups of men served as controls. Data about demographics, biochemistry, liver biopsy and ultrasonography were analyzed. Contributing factors were assessed by multivariate logistic regression analysis. Results Liver fibrosis was more advanced in the early menopausal than in the fully reproductive (P<0.0001) or premenopausal (P = 0.042) group. Late menopausal women had higher liver fibrosis compared with the other groups (fully reproductive, P<0.0001; premenopausal, P = <0.0001; early menopausal, P = 0.052). Multivariate analyses showed that male sex was independently associated with more severe fibrosis in the groups corresponding to premenopausal (P = 0.048) and early menopausal (P = 0.004) but not late menopausal pairs. In women, estradiol/testosterone ratio decreased markedly in early (vs. reproductive age: P = 0.002 and vs. premenopausal: P<0.0001) and late menopause (vs. reproductive age: P = 0.001; vs. premenopausal: P<0.0001). In men age-matched with menopausal women, estradiol/testosterone ratio instead increased (reproductive age group vs. early: P = 0.002 and vs. late M: P = 0.001). Conclusions The severity of fibrosis in women worsens in parallel with increasing estrogen deprivation and estradiol/testosterone ratio decrease. Our data provide evidence why fibrosis progression is discontinuous in women and more linear and severe in men, in whom aging-associated estradiol/testosterone ratio increase occurs too late to noticeably influence the inflammatory process leading to fibrosis.

Alcohol and viral hepatitis: A mini-review

Due to their high prevalence in the general population, alcohol use and abuse can be associated with hepatitis B and C virus infections and it has been demonstrated that alcohol plays a role as a co-morbid factor in the development of liver disease. There is evidence that alcohol abuse accelerates the progression of liver fibrosis and affects the survival of patients with chronic hepatitis C. The mechanism by which alcohol worsens hepatitis C virus-related liver disease has not been fully clarified, but enhanced viral replication, increased oxidative stress, cytotoxicity and impairment of immune response could play a relevant role. Alcohol abuse also seems to reduce both sensitivity to interferon and adherence to treatment. It sounds reasonable to presume that the mechanisms enhancing liver damage in patients affected by hepatitis B are similar to those involved in hepatitis C virus infection. However, more studies are warranted to improve our knowledge about the interaction between alcohol intake and hepatitis B virus infection. In conclusion alcohol abuse is associated with an accelerated progression of liver injury, leading to an earlier development of cirrhosis, higher incidence of hepatocellular carcinoma, and higher mortality. Abstinence could reverse some of these deleterious effects.

Liver transplantation from hepatitis B surface antigen positive donors: A safe way to expand the donor pool

BACKGROUND & AIMS The main limitation of orthotopic liver transplantation (OLT) is the scarcity of available donor organs. A possibility to increase the organ pool is to use grafts from hepatitis B virus surface antigen (HBsAg) positive donors, but few data are currently available in this setting. We assessed the clinical, serovirological, and immunological outcomes of liver transplant from HBsAg positive donors in a single centre study. METHODS From 2005 to 2009 10 patients underwent OLT from HBsAg positive donors, for HBV-related disease (n=6) or HBV-unrelated disease (n=4). The median follow-up was 42 months (range 12-60). All recipients were HBcAb positive and were given antiviral prophylaxis. RESULTS Patients transplanted for HBV-related disease never cleared HBsAg. Two HBsAg negative patients never tested positive for HBsAg, whereas the others experienced an HBsAg appearance, followed by spontaneous production of anti-HBs, allowing HBsAg clearance. No patient ever had any sign of HBV hepatitis. HBV replication was effectively controlled by antiviral therapy. The immunologic sub-study showed that a most robust anti-HBV specific T cell response was associated with the control of HBV infection. CONCLUSIONS OLT from HBsAg positive donors seems to be a safe procedure in the era of highly effective antiviral therapy.

Six score systems to evaluate candidates with advanced cirrhosis for orthotopic liver transplant: Which is the winner?

Many prognostic systems have been devised to predict the outcome of liver transplantation (LT) candidates. Today, the Model for End‐Stage Liver Disease (MELD) is widely used for organ allocation, but it has shown some limitations. The aim of this study was to investigate the performance of MELD compared to 5 different score models. We evaluated the prognostic ability of MELD, modified Child‐Turcotte‐Pugh, MELD‐sodium, United Kingdom MELD, updated MELD, and integrated MELD in 487 candidates with cirrhosis for LT at the Bologna Transplant Centre, Bologna, Italy, between 2003 and 2008. Calibration analysis by Hosmer‐Lemeshow test, calibration curves, and concordance c‐statistics (area under the receiver operating characteristic curve [AUC]) were calculated at 3, 6, and 12 months. Actual cumulative survival curves, taking into account the event of interest in the presence of competing risk, were obtained using the best cutoffs identified by AUC. For each score, the Hosmer‐Lemeshow test revealed a good calibration. Integrated MELD showed calibration curves closer to the line of perfect predicting ability, followed by MELD‐sodium at 3 months and modified Child‐Turcotte‐Pugh at 6 months. MELD‐sodium AUCs at 3 and 6 months (0.798 and 0.765, respectively) and integrated MELD AUC at 6 months (0.792) were better than standard MELD (P < 0.05). Actual survival curves showed that these 2 scores were able to identify the patients with the highest drop‐out risk. In conclusion, MELD‐sodium and integrated MELD were the best prognostic models to predict drop‐out rates among patients awaiting LT. Liver Transpl 16:964‐973, 2010.

Influence of Age and Gender Before and After Liver Transplantation

Women constitute a particular group among patients with chronic liver disease and in the post–liver transplantation (LT) setting: they are set apart not only by traditional differences with respect to men (ie, body mass index, different etiologies of liver disease, and accessibility to transplantation) but also by factors related to hormonal changes that characterize first the fertile age and subsequently the postmenopausal period (eg, disease course variability and responses to therapy). The aim of this review is, therefore, to evaluate the role of the interplay of factors such as age, gender, and hormones in influencing the natural history of chronic liver disease before and after LT and their importance in determining outcomes after LT. As the population requiring LT ages and the mean age at transplantation increases, older females are being considered for transplantation. Older patients are at greater risk for nonalcoholic steatohepatitis, osteoporosis, and a worse response to antiviral therapy. Female gender per se is associated with a greater risk for osteoporosis because of metabolic changes after menopause, the bodily structure of females, and, in the population of patients with chronic liver disease, the prevalence of cholestatic and autoimmune liver diseases. With menopause, the fall of protective estrogen levels can lead to increased fibrosis progression, and this represents a negative turning point for women with chronic liver disease and especially for patients with hepatitis C. Therefore, the notion of gender as a binary female/male factor is now giving way to the awareness of more complex disease processes within the female gender that follow hormonal, social, and age patterns and need to be addressed directly and specifically. Liver Transpl 19:122–134, 2013.

Liver transplantation for patients with alcoholic liver disease: An open question

End-stage alcoholic liver disease is a recognised indication for liver transplantation but some questions on the matter remain open. It is difficult to quantify alcohol consumption, and a single definition of post-transplant relapse is lacking. Moreover, there are no internationally accepted criteria for the selection of candidates for liver transplantation and the eligibility parameters for these patients are controversial. Additional clinical and psychological evaluations are necessary in this setting, especially to establish the risk of alcohol relapse. Nevertheless, patient and graft survival rates after liver transplantation in alcoholic liver disease are comparable to those after transplant for other aetiologies, alcohol consumption relapse being one of the most important problems in the post-transplant phase. In conclusion, alcohol-related liver disease is a good indication for liver transplantation. The main future goals are to formulate a well-defined pre-transplant approach and a single definition of alcohol relapse and to improve prevention strategies.

Serum hepatitis B surface antigen monitoring in long-term lamivudine-treated hepatitis B virus patients

Summary.  Serum hepatitis B virus surface antigen (HBsAg) levels have been suggested to predict interferon response in chronic hepatitis B. A few data are available on the role of HBsAg measurement in nucleos(t)ide analogues (NA) treatment. We retrospectively investigated the relation between HBsAg changes and main treatment outcomes during long‐term lamivudine treatment in hepatitis e antigen (HBeAg)‐negative chronic hepatitis B. A total of 42 HBeAg‐negative patients were consecutively enrolled in an open‐label study on long‐term lamivudine monotherapy (150 mg/die). Serum HBsAg levels were quantified every 6 months by Architect assay (Abbott Diagnostics). HBV‐DNA was quantified quarterly by real‐time PCR (Roche Diagnostics). The median duration of lamivudine treatment was 66 months (20–153). One patient (2%) was a primary nonresponder, 35 (83%) developed virological breakthrough (VB) and the remaining six patients (14%) were classified as long‐term on‐treatment responders. During treatment, HBsAg levels decreased only in long‐term on‐treatment responders, while no changes were observed in resistant patients. Failure to achieve a decrease of 0.7 log10 IU/mL in serum HBsAg at month six of lamivudine had a positive predictive value of developing VB of 90% and a negative predictive value of 100%. These high predictive values were also maintained in the subgroup of patients negative for HBV‐DNA at month six. The results of this study with a small sample size suggest a role of on‐treatment HBsAg quantification in the management of lamivudine‐treated patients. If validated prospectively in a larger patient cohort, HBsAg measurements would be a useful adjunct to optimize antiviral therapy.

Long term follow-up and outcome of liver transplantation for alcoholic liver disease: A single center case-control study

Background Alcoholic liver cirrhosis (ALC) is a leading indication for orthotopic liver transplantation (OLT). Goals To investigate the long-term outcome of OLT for ALC compared with patients transplanted for hepatitis C virus (HCV) infection. Study From 1987 to 2001, 49 OLT were performed for ALC and 173 for HCV. From these contemporary groups we matched 1:2 ALC patients (cases) to 98 HCV (controls). The following variables were analyzed: survival, retransplantation, rejection, primary nonfunction, infections, de novo tumors, cardiovascular and neurologic complications, and alcoholic recurrence. Results Actuarial survival rate at 9 years was comparable for cases and controls. Actuarial graft survival rate at 9 years was significantly higher in cases (78% vs. 60%; P=0.026). The retransplantation rate was higher in controls (21% vs. 4%; P=0.007). Post-OLT complications were not significantly different. The alcoholic recidivism rate was 28% without influence on patients or graft survival, whereas relapse of HCV caused the majority of death in controls (30%; P=0.042). At multivariate analysis retransplantation was the only predictor of patient survival (odds ratio: 4.35; 95% confidence interval: 2.16-8.74; P<0.001), whereas HCV was associated with a 2-fold probability of graft failure (odds ratio: 1.97; 95% confidence interval: 1.02-3.81; P=0.032). Conclusions The long-term outcome of OLT for ALC is comparable to that for HCV, even if graft survival is significantly better among ALC. These data support ALC as an excellent indication for OLT.

Hepatitis C Virus-related chronic liver disease in elderly patients: an Italian cross-sectional study

Summary.  Chronic hepatitis C virus (HCV) infection has been poorly investigated in the elderly. The aim of this study was to identify the age‐specific characteristics of chronic hepatitis C by comparing patients ≥65 years with those <65 years. A cross‐sectional study was performed on data collected from consecutive outpatients referred for the first time to two tertiary outpatient clinics for liver diseases located in Bologna (Northern Italy) and Paola, Cosenza (Southern Italy) over a two‐year period. A total of 560 anti‐HCV and HCV‐RNA positive patients were enrolled, of whom 174 (31%) were 65 years or older. The proportion of older patients was significantly higher in the Southern Italy centre, accounting for more than 40%. Comparison of younger and older groups showed that 51% patients ≥65 years had advanced liver disease (liver cirrhosis or hepatocellular carcinoma) compared with 26% younger patients (P < 0.0001). About half of the patients ≥65 years were not aware of their anti‐HCV positive status, even if they tended to be more symptomatic than the younger group. By multivariate analysis, age ≥ 65 years, alcohol consumption and diabetes were independently associated with advanced liver disease. Overall, 34 out of 174 patients (20%) ≥65 years had received antiviral treatment compared with 122 out of 386 (32%) younger patients (P = 0.003). Our results further emphasize the notion that chronic hepatitis C is becoming a disease of the elderly and that elderly patients with chronic HCV infection often have severe and underestimated disease.