R.M. Iemmolo

Randomized trial of lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation

BACKGROUND/AIMS The long-term prophylaxis of hepatitis B after liver transplantation requires further optimization. In a randomized trial we investigated a regimen where the initially given hepatitis B immunoglobulin (HBIg) is replaced by long-term lamivudine treatment. METHODS Twenty-four liver transplant recipients (all HBsAg-positive/HBV DNA-negative before transplantation), who had received HBIg for at least 6 months without HBV recurrence, were randomized to receive lamivudine (n = 12) or HBIg (n = 12) for 52 weeks. The efficacy criteria involved seronegativity for HBsAg and undetectable HBsAg/ HBcAg in the liver. RESULTS Twenty-one of 24 patients completed the study without hepatitis B virus (HBV) recurrence (11 on HBIg, ten on lamivudine), while three patients became HBsAg-positive. Amongst those without HBV recurrence HBV DNA was detectable only by polymerase chain reaction, intermittently in serum and lymphocytes, and in liver specimens from six of eight patients receiving HBIg and five of seven receiving lamivudine. YMDD variant was found in four cases with no viral antigen expression. Eight patients continued lamivudine after the study and during an additional 6-22 months remained HBsAg-negative with normal graft function. CONCLUSIONS Substitution of HBIg with lamivudine is effective for prevention of HBV recurrence in low-risk liver transplant recipients and offers a convenient and cost-effective alternative for long-term HBV prophylaxis.

The impact of liver disease and medical complications on quality of life and psychological distress before and after liver transplantation.

BACKGROUND/AIM The impact of liver disease and medical complications on quality of life (QOL) and psychological distress before and after orthotopic liver transplantation (OLT) is a matter of growing interest. METHODS Perceived QOL (LEIPAD Quality of Life test) and psychological distress (Brief Symptom Inventory, BSI) were assessed in 40 cirrhotic patients listed for OLT (Group A) and in 101 liver transplant recipients (Groups B to G=0-6, 7-12, 13-24, 25-36, 37-48, 49-60 months post-OLT). Patients were also evaluated for medical complications, blood levels of immunosuppressive agents and recurrence of liver disease. RESULTS QOL and psychological distress were significantly better in most of the post-OLT groups than in cirrhotic patients. Among post-OLT patients, a significantly worse QOL was perceived at 13-24 months (Life Satisfaction: Group D vs G, p=0.024; Cognitive Functioning: Group D vs F, p=0.024), while significantly greater psychological distress was detected at 7-12 months (Anxiety and Interpersonal Sensitivity: Group C vs Group B, p=0.032 and p=0.023, respectively). Medical complications and immunosuppressive therapy did not influence QOL or psychological distress after OLT. Within 6 months after OLT, patients with HCV recurrence showed significantly greater Depression (p=0.023), Anxiety (p=0.038), Phobic Anxiety (p=0.001), and Paranoid Ideation (p=0.033) than anti-HCV negative patients. CONCLUSIONS Liver transplantation improves psychological distress and most, but not all, QOL domains. Recurrent HCV infection is associated with greater psychological distress.

Study on the Sternberg Paradigm in Cirrhotic Patients Without Overt Hepatic Encephalopathy

Memory dysfunction is reported in cirrhotics. The aim of this paper was to increase insight into memory function of cirrhotic patients without overt hepatic encephalopathy. Eighty-six consecutive cirrhotics without overt hepatic encephalopathy (aged 54±10 yr., mean±s.d.) and 28 controls (52±10 yr.) with comparable education level were enrolled. Seventeen patients were class A, 55 class B, 14 class C according to Child-Pugh classification; 29 had alcoholic cirrhosis. The presence of subclinical signs of central nervous system dysfunction were assessed by Number Connection Test (NCT) and quantified EEG analysis. Memory scanning was evaluated by reaction times (RTs) in the Sternberg paradigm. MANOVA analysis showed that RTs were higher (F1,99=11, p<0.01) and time outs (TOs) more frequent (F1,110=10, p<0.01) in cirrhotics than in controls, whereas button press errors (BPEs) did not differ significantly (F1,110=2, p=n.s.). In cirrhotics, an interaction Child-Pugh class x memory set size was found (F2,146=4, p<0.05), showing exceedingly delayed RTs with greater memory set size in class C patients. Patients with altered NCT had significantly prolonged RTs (F1,71=4, p<0.05) and more TOs (F1,82=11, p<0.01) than patients with normal NCT. Cirrhotics with altered EEG had significantly prolonged RTs (F2,70=6, p<0.01). RTs were found to be correlated to alpha relative power (r=−0.4, p<0.01) and theta relative power (r=0.4, p<0.01). In conclusion, cirrhotics without over encephalopathy, but with NCT or EEG alterations, perform a computerized digit recognition task more slowly and with higher TOs than cirrhotic patients with normal NCT or EEG. In severe liver insufficiency (class C cirrhotics) also an impairment of memory scanning was detected. Sternberg test performance correlates with NCT and quantitative EEG parameters.

Epstein-Barr virus-associated post-transplant lympho-proliferative disease of donor origin in liver transplant recipients

BACKGROUND/AIMS Post-transplant lymphoproliferative disease, a potential complication of solid organ transplantation, occurs in about 3% of orthotopic liver transplant recipients. We report the genetic and virological characterization of two cases of post-transplant lymphoproliferative disease that occurred early (4 and 6 months) after orthotopic liver transplant as large-cell non-Hodgkins lymphomas located at the hepatic hilum. METHODS Lymphomatous tissues were analyzed for clonality and presence of Epstein-Barr virus (EBV) sequences by Southern blot, polymerase chain reaction, and in situ hybridization techniques. RESULTS The tumors in both cases were sustained by a clonal proliferation of B lymphocytes containing type A EBV DNA. Moreover, in situ hybridization with a digoxigenin-labeled EBV-specific probe evidenced a strong nuclear signal in most of the neoplastic cells. DNA microsatellite analysis at three different loci detected alleles of donor origin in both tumor samples, suggesting that the neoplastic B cells were of donor origin. CONCLUSIONS EBV-infected donor B lymphocytes might be responsible for intragraft post-transplant lymphoproliferative disease in orthotopic liver transplant recipients. As 20 to 30% of post-transplant lymphomas involve the graft itself, donor-derived post-transplant lymphoproliferative disease might be more frequent than presently appreciated. Prospective studies are needed to assess its real incidence and identify possible risk factors.

Vertebral morphometry by X-ray absorptiometry before and after liver transplant: a cross-sectional study.

Objectives To evaluate bone density and fracture prevalence in patients with end-stage liver diseases (ESLD) awaiting liver transplant and in orthotopic liver-transplant (OLTx) recipients by using dual energy X-ray absorptiometry. Design In a cross-sectional study 27 patients (16 males and 11 females, mean age 49.9 ± 1.7 years) with ESLD, and 36 subjects (26 males and 10 females, mean age 50.5 ± 1.6 years) who had undergone OLTx 1–70 months before, were recruited. Methods All patients underwent biochemical assessment of mineral metabolism. Bone density measurement of the spine and femur and morphometric X-ray absorptiometry (MXA) of the vertebrae were also obtained. Results Bone density was decreased in both groups as compared to the expected normal values. Spinal density did not differ between the two groups, while femoral bone mass was lower in OLTx than in ESLD patients (T-scores of: femoral neck −1.91 ± 0.16 vs −1.12 ± 0.22, P < 0.01; total femur −1.62 ± 0.16 vs −0.94 ± 0.23, P < 0.02). Bone alkaline phosphatase was the only independent predictor of femoral density (R2 = −0.21, P < 0.05). Symptomatic fractures were reported by 25% of OLTx and 15% of ESLD patients. MXA vertebral fractures were present in 28% of OLTx and 7.5% of ESLD (P < 0.05) patients. Most of these fractures had been asymptomatic. Total methylprednisolone intake was higher in patients with MXA vertebral fractures than in non-fractured patients (P < 0.05). Conclusions Fragility fractures, especially of the spine, occur more frequently after liver transplantation, with corticosteroid treatment being the most important risk factor. Morphometric X-ray absorptiometry represents a useful technique for identifying vertebral fractures even in liver transplanted patients.

The effect of recurrence of HCV infection of life after liver transplantation

Abstract The present study evaluated the quality of life (QOL) of adult cirrhotic patients before orthotopic liver transplantation (OLT), the effect of OLT on QOL in the long‐term and the effect of HCV recurrence within medical complications on QOL. Three groups of patients were studied: 19 pre‐OLT, 33 during the first year post‐OLT and 41 1 to 5 years post‐OLT. The patients completed questionnaires on QOL and underwent liver function tests, immunosuppressive drug blood level determinations and medical complications evaluation. Somatization and depression and anxiety scores improved significantly during the first year post‐OLT compared with pre‐OLT, but they worsened again during the 1–5‐year period post‐OLT. Physical functioning and life satisfaction scores improved significantly during the first year post‐OLT compared with pre‐OLT and the improvement persisted 1–5‐year during the period post‐ OLT. Patients with HCV recurrence compared with patients without HCV recurrence during the first year post‐OLT showed a significant worsening of most of the domains of QOL. In conclusion, OLT improved most of the domains of QOL by the end of the first post‐transplant year, though the improvements did not all persist in the long‐term. Recurrence of HCV infection plays a major role in the impairment of QOL after OLT.

Cerebral aspergillosis in a liver transplant recipient: a case report of long-term survival after combined treatment with liposomal amphotericin B and surgery

Cerebral aspergillosis is a life-threatening complication in liver transplant recipients, with mortality rates approaching 100%; treatment with amphotericin B is of limited efficacy because of its poor distribution in the cerebrospinal fluid and its systemic side effects. We report the case of a liver transplant recipient who developed recurrent cerebral Aspergillus fumigatus infection, and was successfully treated by combined surgical excision of the lesion and administration of liposomal amphotericin B. This first report of long-term complication-free survival in a liver transplant recipient suggests that therapy with liposomal amphotericin B may reduce the risk of recurrence of cerebral aspergillosis in these immunocompromised patients.

University of Modena Experience in HIV-Positive Patients Undergoing Liver Transplantation

INTRODUCTION Highly effective antiretroviral therapy in the last decade has increased the survival rates of HIV-positive patients, yielding a greater number of HIV patients suffering from liver-related disease. Liver transplantation (LT) is the only curative treatment for end-stage liver disease (ESLD) associated or not with hepatocellular carcinoma (HCC). PATIENTS AND METHODS From June 2003 to September 2010, 23 patients underwent cadaveric donor LT for ESLD at our institution. Inclusion criteria followed the Italian Protocol for LT in HIV-positive patients. Immunosuppressive regimens were based on cyclosporine or tacrolimus, eventually switched to Rapamycin. RESULTS The median CD4 T-cell count was 275/mmc (range=119-924). All patients were affected by ESLD, which was associated with HCC in 14 cases. Ten patients were within the Milan criteria and four patients exceeded them but were within the San Francisco criteria. Conversion from calcineurin inhibitors (CNI) to rapamycin occurred in ten cases. Hepatitis C virus (HCV) recurrence occurred in 13/21 HCV-positive patients. Acute cellular rejection occurred in eight patients with one developing chronic cellular rejection. Overall patient and graft survivals at 80 months were 50% and 45% respectively. DISCUSSION LT in HIV-positive patients is a feasible procedure, even if in our experience was burdened by a greater incidence of complications including HCV recurrence and infection compared with HIV-negative patients.

Prevention of hepatitis C recurrence by bridging sofosbuvir/ribavirin from pre to post liver transplant: a real life strategy

Hepatitis C virus (HCV) re‐infection following liver transplant (LT) is associated with reduced graft and patient survival. Before transplant, Sofosbuvir/Ribavirin (SOF/R) treatment prevents recurrent HCV in 96% of those patients achieving viral suppression for at least 4 weeks before transplant. We evaluated whether a bridging SOF‐regimen from pre‐ to post‐transplant is safe and effective to prevent HCV recurrence in those patients with less than 4 weeks of HCV‐RNA undetectability at the time of transplant.

Is advanced hepatocellular carcinoma amenable of cure by liver transplantation with sorafenib as a neoadjuvant approach plus m-TOR inhibitors monotherapy?

Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of death from cancer, resulting in more than 600,000 deaths per year [1]. While, on one hand we have different therapeutic opportunities at our disposal for early stage hepatocellular carcinoma (resection, local ablation either with radiofrequency or percutaneous ethanol injection, liver transplantation), on the other hand advanced stage represents yet a challenge due to the paucity of effective treatment options. The introduction of targeted therapies represents a new era in drug development and implies the choice to attack pathways that are critical for cancer survival and progression. In particular angiogenic signalling factors, growth signalling pathways mediated through tyrosine kinase seem to have a peculiar role in the pathogenesis of hepatocellular carcinoma [2]. Sorafenib acts by inhibiting the serine-threonine kinase Raf-1 and BRaf and the receptor tyrosine kinase activity of vascular endothelial growth factors receptors (VEGFRs) 1, 2 and 3 and platelet-derived growth factor receptor b (PDGFR-b) [3]. The results of a multicenter, phase 3, double-blind, placebo control trial reported by Llovet et al. [4] showed a benefit in overall survival obtained by the use of sorafenib over placebo of nearly 3 months but with a limited partial response rate of 2% in the sorafenib arm. Sirolimus is reported [5] to inhibit the growth of lung metastases in mice given murine colon cancer cells; it is further reported a decreased tumour growth and tumour neovascularisation in sirolimus-treated mice. Furthermore Sirolimus markedly inhibits vascular endothelial growth factor-dependent human umbilical vein endothelial cell proliferation and completely abrogates tubule formation, a crucial component of angiogenesis, with the potential for important impact on cancer recurrence and progression [6,7]. Schumacher et al. [8] recently reported in vitro suppression of human hepatoma cells by sirolimus. The impact of sirolimus on angiogenesis may theoretically alter tumour progression and so overall survival more so than the rate of tumour recurrence. We report the impressive results obtained by the use of sorafenib in a man who developed hepatocellular carcinoma in the context of a cirrhosis related to hepatitis C virus infection. In January 2004 a 44-year-old man due to the onset of a massive ascitis was found positive for hepatitis C virus infection (genotype 3) markers. An ultrasonography (US) and a CT scan showed an enlarged liver with irregular margins, a disomogeneous structure, a patent portal vein in a picture compatible with cirrhosis. The disease was rated as Child-Pugh class A, reflecting a preserved liver function with modest signs of portal hypertension (varices F1-F2) and moderate leuko-thrombocytopenia. He went on in a strict clinical and radiological follow up. In April 2007 a therapy with Ribavirin and Interferon was started. After 7 months, a nodule of 4.2 cm 3.3 cm, localised in the Vand VI liver segment was detected and a biopsy was performed that showed a moderately differentiated hepatocellular carcinoma. This discovery was accompanied by an important increase