Maurizio Biselli

Review article: alcoholic liver disease – pathophysiological aspects and risk factors

Alcoholic liver disease has a known aetiology but a complex and incompletely known pathogenesis. It is an extremely common disease with significant morbidity and mortality, but the reason why only a relatively small proportion of heavy drinkers progress to advanced disease remains elusive.

High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?

Background: Interferon may trigger autoimmune disorders, including autoimmune hepatitis, in immunocompetent patients. To date, no such disorders have been described in liver transplanted patients. Methods: 9 of 44 liver transplanted patients who had been receiving pegylated-interferon alpha-2b and ribavirin for at least 6 months for hepatitis C virus (HCV) recurrence, developed graft dysfunction despite on-treatment HCV-RNA clearance in all but one case. Laboratory, microbiological, imaging and histological evaluations were performed to identify the origin of graft dysfunction. The International Autoimmune Hepatitis scoring system was also applied. Results: In all cases infections, anastomoses complications and rejection were excluded, whereas the autoimmune hepatitis score suggested a “probable autoimmune hepatitis” (score from 10 to 14). Three patients developed other definite autoimmune disorders (overlap anti-mitochondrial antibodies (AMA)-positive cholangitis, autoimmune thyroiditis and systemic lupus erythematosus, respectively). In all cases, pre-existing autoimmune hepatitis was excluded. Anti-lymphocyte antibodies in immunosuppressive induction treatment correlated with the development of the disorder, whereas the use of granulocyte colony-stimulating factor to treat interferon-induced neutropenia showed a protective role. Withdrawal of antiviral treatment and treatment with prednisone resulted in different outcomes (five remissions and four graft failures with two deaths). Conclusions: De novo autoimmune hepatitis should be considered in differential diagnosis along with rejection in liver transplanted patients developing graft dysfunction while on treatment with interferon.

Efficacy of transarterial targeted treatments on survival of patients with hepatocellular carcinoma. An Italian Experience

Background. Most patients with hepatocellular carcinoma (HCC) are not suitable for surgical therapy. Systemic chemotherapy, immunotherapy, and hormonotherapy have not had convincingly acceptable results. Therefore, transarterial catheter‐targeted therapies such as intraarterial chemotherapy (IAC), possibly followed by transcatheter arterial chemoembolization (TACE), have been proposed.

Cytokine profile of peripheral blood mononuclear cells from patients with different outcomes of hepatitis C virus infection

Summary.  The relationship between the balance of helper T‐cell type 1 (Th1) or type 2 (Th2) cytokines and the clinical course of hepatitis C virus (HCV) infection is unclear. We evaluated Th1 [interleukin (IL)‐2, interferon‐gamma (IFN‐γ)] and Th2 cytokine (IL‐4, IL‐10) and 2,5‐oligoadenylate synthetase (OAS, an IFN‐induced antiviral protein) production by peripheral blood mononuclear cells from 10 healthy anti‐HCV‐positive individuals (group A), 10 HCV‐RNA‐positive with persistently normal alanine aminotransferase (ALT) levels (group B), 10 HCV‐RNA‐positive with abnormal ALT (group C) and 10 uninfected healthy controls. IL‐2 production was significantly increased in group B when compared with all the other groups. No difference was found for IFN‐γ. IL‐4 was significantly higher in group C than in both group B (P = 0.0006) and controls (P = 0.004). Compared with controls, IL‐10 was significantly decreased in group A (P = 0.013) and B (P = 0.004). The production of 2,5‐OAS was significantly higher in group B than in A (P = 0.04) and in C (P = 0.004). Finally, in all HCV‐RNA‐positive patients, a significant correlation was found between ALT and both IL‐2 (r = −0.78; P = 0.0008) and IL‐4 (r = 0.75; P = 0.0008). In conclusion: (i) subjects who cleared HCV showed a cytokine profile similar to controls; (ii) a preferential shift towards a Th1 profile seems associated with a more favourable clinical outcome in chronic hepatitis C; and (iii) a prevalent Th2 profile seems implicated in HCV pathogenesis and severity of liver disease.

High risk of hepatocellular carcinoma in anti-HBe positive liver cirrhosis patients developing lamivudine resistance

Summary.  The emergence of drug‐resistant virus in hepatitis B virus patients treated with lamivudine is well documented. However, its clinical impact in the long‐term treatment of anti‐HBe positive compensated cirrhotic patients is not well known. In this study, we treated 22 consecutive patients with anti‐HBe compensated cirrhosis with lamivudine for a median period of 42 months. All patients responded to lamivudine, but viral breakthrough occurred in 13 patients (59%) between 9 and 42 months of therapy due to the emergence of a mutant strain. During the follow‐up, 11 developed hepatocellular carcinoma. Of these, 10 occurred soon after the emergence of viral resistance, generally showing aggressive behaviour, and one in the nine long‐term responder patients (P = 0.013). Lamivudine resistance was the only independent predictor of hepatocellular carcinoma development (risk ratio: 10.4; 95% CI: 1.3–84.9). Our study suggests that the occurrence of lamivudine resistance increases the risk of hepatocellular carcinoma in anti‐HBe positive cirrhosis and warrants further research.

In vitro effect of thymosin-α1 and interferon-α on Th1 and Th2 cytokine synthesis in patients with chronic hepatitis C

Current evidence suggests that increased expression of Th1‐associated cytokines is important for immune‐mediated eradication of hepatitis C infection, while an increase in Th2‐associated cytokines is associated with persistence of infection. In this study we evaluated the effects of thymosin‐α1 (TA1), a naturally occurring thymic peptide, and interferon‐α (IFN‐α) on cytokine production in peripheral blood mononuclear cells from untreated patients with chronic hepatitis C. We examined the effect of incubation with TA1, IFN‐α, or both, on production of Th1‐associated cytokines (IL‐2, IFN‐γ), Th2‐associated cytokines (IL‐4, IL‐10), and synthesis of the antiviral protein 2′,5′‐oligoadenylate synthetase. TA1 treatment induced a significant increase in production of IL‐2 and 2′,5′‐oligoadenylate synthetase. Smaller increases were also seen after treatment with IFN‐α, while incubation with TA1 and IFN‐α together led to an additive or synergistic effect. Incubation with TA1 resulted in a decrease in IL‐4 and IL‐10, whereas IFN‐α increased these cytokines. The addition of TA1 to IFN‐α significantly reversed this IFN‐α‐induced increase. Hence, TA1 treatment could benefit patients with hepatitis C infection by increasing the Th1‐type response, fundamental for sustained clearance of hepatitis C; and by decreasing the Th2‐type response, associated with persistence of viraemia.

Posttranscriptional changes of serum albumin: Clinical and prognostic significance in hospitalized patients with cirrhosis

Beside the regulation of fluid distribution, human serum albumin (HSA) carries other activities, such as binding, transport, and detoxification of many molecules. In patients with cirrhosis, HSA exhibits posttranscriptional alterations that likely affect its functions. This study aimed at identifying the structural HSA alterations occurring in cirrhosis and determining their relationship with specific clinical complications and patient survival. One hundred sixty‐eight patients with cirrhosis, 35 with stable conditions and 133 hospitalized for acute clinical complications, and 94 healthy controls were enrolled. Posttranscriptional HSA molecular changes were identified and quantified by using a high‐performance liquid chromatography/electrospray ionization mass spectrometry technique. Clinical and biochemical parameters were also recorded and hospitalized patients were followed for up to 1 year. Seven HSA isoforms carrying one or more posttranscriptional changes were identified. Altered HSA isoforms were significantly more represented in patients than in healthy controls. Conversely, the native, unchanged HSA isoform was significantly reduced in cirrhosis. Native HSA and most altered isoforms correlated with both Child‐Pugh and Model for End‐Stage Liver Disease scores. In hospitalized patients, oxidized and N‐terminal truncated isoforms were independently associated with ascites, renal impairment, and bacterial infection. Finally, the native HSA and cysteinylated/N‐terminal truncated isoforms were predictors of 1‐year survival, with greater prognostic accuracy than total serum albumin concentration. Conclusions: Extensive posttranscriptional changes of HSA, involving several molecular sites and increasing in parallel with disease severity, occur in patients with cirrhosis. Altered isoforms are independently associated with specific clinical complications, whereas the residual, native HSA isoform independently predicts patient survival. These findings support the concept of the “effective albumin concentration,” which implies that the global HSA function is related not only to its serum concentration, but also to the preservation of its structural integrity. (Hepatology 2014;60:1850–1859)

Vitamin E as treatment for chronic hepatitis B: results of a randomized controlled pilot trial.

BACKGROUND AND AIMS Interferon-alpha treatment has been the treatment of choice for chronic hepatitis with unpredictable results. Recently, Lamivudine has been licensed for use against HBV infection with good results. Unfortunately, recurrence of viremia after lamivudine withdrawal is common and prolonged treatment can induce the emergence of resistant mutant strains. It has been shown that vitamin E can increase the host immune response, and this may provide protection against infectious diseases. METHODS We evaluated vitamin E supplementation as therapy for chronic hepatitis B in a pilot study including 32 patients. Patients were randomly allocated to receive vitamin E at the dose of 300 mg twice daily for 3 months (15 patients) or no treatment (17 patients). They were seen monthly during the first 3 months and thereafter quarterly for additional 12 months. RESULTS The two groups were comparable at enrollment. At the end of the study period, alanine aminotransferase (ALT) normalization was observed in 7 (47%) patients in vitamin E group and only in 1 (6%) of the controls (P=0.011); HBV-DNA negativization was observed in 8 (53%) patients in the vitamin E group as compared to 3 (18%) in the control group, respectively (P=0.039). A complete response (normal ALT and negative HBV-DNA) was obtained in 7 (47%) patients taking vitamin E and in none of the controls (P=0.0019). CONCLUSION Vitamin E supplementation might be effective in the treatment of chronic hepatitis B.

Clinical trial: peg-interferon alfa-2b and ribavirin for the treatment of genotype-1 hepatitis C recurrence after liver transplantation

Background  Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is difficult with low response rates.

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.