Stefania Lorenzini

Stem cell mobilization and collection in patients with liver cirrhosis

Background  Bone marrow‐derived stem cells (BMSC) and granulocyte colony‐stimulating factor (G‐CSF) have been proved to contribute to tissue regeneration after liver injury.

Stem cell therapy for human liver cirrhosis : A cautious analysis of the results

End‐stage liver disease, and in particular human liver cirrhosis, represents a worldwide health problem. Currently, liver transplant is the only effective treatment, but it is affected by many problems, including relative lack of donors, operative damage, risk of rejection, and high costs. Stem cell therapy is very attractive in this setting because it has the potential to help tissue regeneration while providing minimally invasive procedures and few complications. Only a few clinical studies on the administration of bone marrow‐derived stem cells to cirrhotic patients have been published up to now. Although preliminary results seem to be encouraging, the number of treated patients is too small and the study design not completely appropriate to demonstrate safety and efficacy of stem cell therapy in liver cirrhosis. Well designed, randomized, controlled studies are needed to confirm preliminary results and eventually clear doubts.

Transcatheter Arterial Chemoembolization Therapy for Patients With Hepatocellular Carcinoma: A Case-Controlled Study

BACKGROUND & AIMS Transcatheter arterial chemoembolization (TACE) currently is used as a palliative treatment for patients with unresectable hepatocellular carcinoma (HCC), but its efficacy still is debated. Our aim was to assess the impact of TACE on patient survival and to identify prognostic factors for survival. METHODS Fifty-six cirrhotic patients with unresectable HCC undergoing at least 1 course of TACE were matched 1:1 for sex, age (in 5-year periods), parameters of Child-Pugh score, Okuda stage, and tumor type with a control group who had received only supportive care. RESULTS The 2 groups were comparable for cause of cirrhosis, alpha-fetoprotein serum levels, and Cancer of the Liver Italian Program (CLIP) score. The 56 patients in the TACE group received a total of 123 treatment courses. The median follow-up period was 16 months (range, 1-67 mo) in the TACE group and 5 months (range, 1-77 mo) in the supportive care group. Survival rates at 12, 24, and 30 months in patients receiving TACE were 74.3%, 52.1%, and 38.8%, respectively, with a median survival time of 25 months, whereas in supportive care patients the rates were 39.4%, 25.4%, and 19%, respectively, with a median survival time of 7 months (P = .0004). At univariate analysis, TACE, tumor type, presence of ascites, alpha-fetoprotein serum level, CLIP score, and Okuda stage were associated significantly with survival. Only TACE and CLIP score proved to be independent predictors of survival at multivariate analysis. CONCLUSIONS TACE is an effective therapeutic option for cirrhotic patients with unresectable HCC and a CLIP score of 3 or less.

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.

Thymosin-alpha 1 plus interferon-alpha for naive patients with chronic hepatitis C: results of a randomized controlled pilot trial.

Summary.  In this pilot study, we evaluated the efficacy of interferon‐α (IFN) plus Thymosin‐α 1 (TA1) to that of IFN alone in naive patients with chronic hepatitis C. Twenty‐two patients were randomized to receive interferon‐α2b (3 million units three times a week) plus thymosin‐α l (900 μg/m2 body surface area) and 19 received interferon‐α2b alone at the same dose. Patients were treated for 6 months and followed up for another 6 months. Biochemical (alanine aminotransferase values) and virological (hepatitis C virus‐RNA) responses to treatment were determined. Combination treatment showed significantly higher efficacy than monotherapy in achieving virological end‐of‐treatment response (P = 0.03). At 6‐month follow up, the sustained biochemical and virological response was not different between the two groups. Our results indicate that the immune modulator TA1 may enhance the end‐of‐treatment response in naive patients with chronic hepatitis C. Higher doses and/ore more prolonged courses as well as the association with new interferon formulation such as pegylated interferons could improve the sustained response rates to this treatment.

A randomized trial of induction doses of interferon alone or in combination with ribavirin or ribavirin plus amantadine for treatment of nonresponder patients with chronic hepatitis C

BackgroundEfficacy and safety of interferon induction therapy alone or in combination with ribavirin or ribavirin plus amantadine were evaluated in chronic hepatitis C patients who were nonresponders to primary antiviral treatment.MethodsThe study was designed to have 225 HCV nonresponder patients, but at an interim analysis the response rate difference between groups was lower than expected and the enrollment was stopped when 75 patients had been randomized to receive interferon-α2a (group A, n = 26), interferon-α2a plus 15 mg/kg per day of ribavirin (group B, n = 24), or interferon-α2a plus ribavirin plus 200 mg/day of amantadine hydrochloride (group C, n = 25). Treatment duration was 48 weeks. The dose of interferon was 6 MU/day for 4 weeks followed by 3 MU/day for the remaining 44 weeks.ResultsOn intention-to-treat, the sustained virological response at 24 weeks of follow-up was 11.5% in group A, 12.5% in group B, and 12% in group C. Therapy was discontinued because of adverse effects in three patients in group A (11.5%), three in group B (12.5%), and two in group C (8%).ConclusionsNonresponders with chronic hepatitis C may achieve a sustained virological response rate of approximately 12% if retreated with interferon induction treatment followed by administration of a daily dose. The addition of ribavirin or amantadine did not seem to improve the response rates.

Long-term antiviral treatment for recurrent hepatitis C after liver transplantation

BACKGROUND AND AIMS The management of patients treated for hepatitis C recurrence after liver transplantation and not achieving virological response following treatment with interferon plus ribavirin is controversial. METHODS A retrospective analysis of the outcomes of 70 patients non-responders to antiviral treatment after liver transplantation was performed. Twenty-one patients (30.0%; Group A) were treated for ≤ 12 months and 49 (70.0%; Group B) for more than 12 months. RESULTS The 2 groups were comparable for main demographic, clinical and pathological variables. Median duration of antiviral treatment was 8.2 months in Group A and 33.4 months in Group B. No patient achieved a complete virological response. The 5-year patient hepatitis C-related survival rate was 49.2% in Group A and 88.3% in Group B (P=0.002), while the 5-year graft survival rate was 49.2% in Group A and 85.9% in Group B (P=0.007). The median yearly fibrosis progression rate was 1.21 per year in Group A and 0.40 per year in Group B (P=0.001). CONCLUSIONS Prolonged antiviral treatment showed an overall beneficial effect in transplanted patients with a recurrent hepatitis C infection and not responding to conventional therapy. The treatment should be continued as long as it is permitted, in order to improve clinical and histological outcomes.

Acquired intestinal lymphangiectasia successfully treated with a low-fat and medium-chain triacylglycerol-enriched diet in a patient with liver transplantation.

Intestinal lymphangiectasia is defined as a dilatation of small bowel lymphatic capillaries and a loss of lymph into the bowel lumen. Clinically it is characterized by hypoproteinaemia and oedema. We present here a case of protein-losing enteropathy due to intestinal lymphangiectasia after liver transplantation in a 57-year-old man who was transplanted for hepatitis C virus. Four years after liver transplantation, the patient developed hypoalbuminaemia and ascites associated with recurrence of cirrhosis. The sudden fall in serum albumin led us to look for a cause of reduction other than or in addition to cirrhosis. Duodenal biopsies showed tall villi with dilated lymphatic vessels and widening of the villi caused by oedema, demonstrating intestinal lymphangiectasia. In this case a low-fat diet supplemented with medium-chain triacylglycerols achieved an early clinical improvement with increased serum albumin levels and ascites disappearance. Intestinal lymphangiectasia should be suspected in liver-transplanted patients developing hypoproteinaemia and hypoalbuminaemia after the recurrence of cirrhosis.

Allocation priority in non-urgent liver transplantation: An overview of proposed scoring systems.

Given the lack of donors, a correct organ allocation system for candidates to liver transplantation is essential to increase graft and patient survival. The most used organ allocation tools are Child-Turcotte-Pugh and model for end-stage liver disease. It is generally accepted that model for end-stage liver disease score is superior to the Child-Turcotte-Pugh classification in predicting the short-term survival of cirrhotic patients awaiting liver transplantation. Since 2002, model for end-stage liver disease is widely used for liver allocation. In recent years, to overcome limitations of the consolidated scores, some adjustments to the original model for end-stage liver disease formula and new scoring systems have been proposed. Published data suggest that integrating serum sodium and model for end-stage liver disease may improve the score prognostic accuracy but further studies are necessary to confirm this issue. The updated model for end-stage liver disease, obtained through a revision of traditional model for end-stage liver disease parameters and tested in a large cohort of patients, is of great interest at the moment. In conclusion, several scoring systems have been described for organ allocation, but today, none is definitely able to overcome the limitations of the Child-Turcotte-Pugh and model for end-stage liver disease systems.

Regenerative medicine and liver injury: what role for bone marrow derived stem cells?

In recent years, great interest has been aroused by the discovery of the ability of adult stem cells to contribute to regeneration processes and repair of damaged tissues. In particular, bone marrow derived stem cells (BMSCs), the most well known population of multipotent stem cells in adults, have been shown to be able to generate many different committed cellular types. In this review, we systematically organize the numerous hypotheses emerging from the most recent studies, in animal and humans, which evaluated the potentiality of BMSCs to contribute to tissue repair in different types of liver damage. Our aim is to give scientists and clinicians who are interested in regenerative medicine the rational basis for planning future studies on stem cell therapy for liver diseases.