Patrizia Boccagni

Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma.

Objective:To determine the long-term results of liver transplantation for well- or moderately differentiated hepatocellular carcinoma (HCC). Summary Background Data:HCC patient selection for liver transplantation remains controversial, and deciding exclusively on the strength of criteria such as number and size of nodules appears prognostically inaccurate. Methods:Since 1991, preoperative tumor grading has been used at our center to establish whether a patient with HCC is fit for transplantation. Poorly differentiated HCC cases were excluded, while size and number of nodules were not considered as absolute selection criteria. Thirty-three patients with moderately or well-differentiated HCC were prospectively studied after liver transplantation. A group of 15 patients with incidental HCC transplanted during the same period were also evaluated and compared with the 33 patients with preoperatively diagnosed HCC. Results:On histologic examination, 38% of the entire group of 48 patients did not meet the “Milan criteria” and 42% were pTNM stages III and IV. The median follow-up was 44 months. The 5-year actuarial survival rate was 75% and recurrence-free survival was 92%. HCC recurred in only 3 patients (6%). The only histomorphologic variable differing significantly between incidental and nonincidental HCC was nodule size. The timing of diagnosis (incidental vs. nonincidental HCC), the Milan criteria, and the TNM stage revealed no statistically significant impact on overall and recurrence-free survival rates. Conclusions:The routine pre-orthotopic liver transplantation tumor grading may represent a valid tool in the selection of unresectable HCC patients for transplantation.

Prospective evaluation of anticoagulation and transjugular intrahepatic portosistemic shunt for the management of portal vein thrombosis in cirrhosis

There is no established management algorithm for portal vein thrombosis (PVT) in cirrhotic patients. The aim of our study was to prospectively evaluate anticoagulation and transjugular intrahepatic portosystemic shunt (TIPS) to treat PVT.

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.

A randomized study comparing ligation with propranolol for primary prophylaxis of variceal bleeding in candidates for liver transplantation.

Whether beta‐blockers (BB) or banding is the best therapy for primary prophylaxis of variceal bleeding is subject to debate. A randomized comparison between the 2 treatments was performed in candidates for liver transplantation (LT). A total of 62 patients with Child‐Turcotte‐Pugh B‐C cirrhosis and high risk varices received propranolol (31) or variceal banding (31). The primary endpoint was variceal bleeding. There were 2 variceal hemorrhages (6.5%) in the banding group, related to postbanding ulcers, and 3 (9.7%) in the propranolol group (P = not significant [n.s.]). Deaths and bleeding related deaths were 3 and 1 for banding and 3 and 2 for BB, respectively (P = n.s.). A total of 14 patients underwent LT in the banding group and 10 in the propranolol group (P = n.s.). Adverse events were 2 postbanding ulcer bleedings in ligated patients (1 fatal) and 5 were intolerant to propranolol (P = n.s.). Mean costs per patient were higher with banding than with propranolol treatment (4,289 ± 285 vs. 1,425 ± 460 U.S. dollars, P < 0.001). In conclusion, propranolol and banding are similarly effective in reducing the incidence of variceal bleeding in candidates for LT, but ligation can be complicated by fatal bleeding and is more expensive. Our results suggest that banding should not be utilized as primary prophylaxis in transplant candidates who can be treated with BB. Liver Transpl, 2007.

Histology predicts cirrhotic evolution of post transplant hepatitis C

Background: Hepatitis C recurring after orthotopic liver transplantation varies in severity and some patients rapidly develop fully established liver cirrhosis. Neither clinical nor biological markers of such rapid cirrhotic evolution are available. Aim: To assess the value of histology in identifying patients who will develop cirrhosis shortly after liver transplantation. Patients and methods: Only cases of recurrent hepatitis C diagnosed by both hepatitis C virus-RNA positive serum and liver changes consistent with hepatitis, with no other causes of allograft injury, were considered. A total of 128 liver biopsies were scored from 29 consecutive patients with a mean follow up of 48 (13.97) months. The histological activity index was evaluated according to Ishak et al. The time of the first histological diagnosis of recurrent hepatitis C in the absence of rejection was defined as time of histological recurrence (RHC-T). Results: First histological diagnosis of recurrent hepatitis with no features of rejection was obtained at the six month biopsy in 23 of 29 cases. By the end of follow up, nine patients had developed cirrhosis (mean follow up 38 (14.39) months (range 18–60)). The remainder (mean follow up 46 (13.40) months (24–72)) showed a spectrum of fibrosis but no cirrhosis. Severe necroinflammatory lesions at RHC-T significantly correlated with rapid development of cirrhosis. At the RHC-T biopsy, only cases evolving into cirrhosis showed confluent necrosis. The median value of the histological activity index was 11 (mean 11.11 (1.76) (range 9–14)) in patients who developed cirrhosis and four (mean 4 (1.78) (range 1–8)) in the others (p<0.0001). A histological activity index ≥9 was associated with rapid development of cirrhosis in 100% of cases. Conclusions: After liver transplantation, the histological activity of recurrent hepatitis C predicts the risk of development of cirrhosis. By adopting Ishaks scoring system, a histological activity index ≥9 was 100% sensitive/specific in identifying subjects who rapidly developed cirrhosis.

Bone metabolism and gonad function in male patients undergoing liver transplantation: a two-year longitudinal study.

Osteodystrophy is a major complication of end-stage liver disease, especially in postmenopausal women. Our aim in this study was to evaluate bone metabolism and gonad function in men undergoing orthotopic liver transplantation (OLTx). Twenty-three consecutive men (mean age 48 ± 13 years) evaluated for OLTx were studied, assessing the following parameters at baseline and 3, 6, 12 and 24 months after OLTx: lumbar spine (L2–L4) bone mineral density (BMD), parathyroid hormone (PTH), osteocalcin (BGP), 25-hydroxyvitamin D (25OHD), free testosterone (FT) and gonadotropins (FSH, LH). At baseline, 12 patients (52%) had a T-score <–2.5 SD and the mean BMD was 0.806 ± 0.11 g/cm2 (range 0.470–1.045 g/cm2). The BMD was lower 3 months after OLTx and significantly higher 12 and 24 months after OLTx. A significant increase in serum BGP was observed at 6, 12 (p<0.05) and 24 months (p<0.005) after OLTx. The mean serum PTH level was 26.6 ± 3.1 pg/ml at baseline and increased significantly at 12 and 24 months (to 49.4 ± 9.9 and 61.2 ± 10.1 pg/ml, respectively; p<0.05). 25OHD serum levels were low at baseline and returned to the normal range after 12 and 24 months (baseline, 8.73 ± 1.54 ng/ml; 12 months, 16.4 ± 2.6 ng/ml; 24 months, 17.67 ± 3.1 ng/ml; p<0.05). FT was significantly lower at baseline than in a group of 10 healthy controls (5.09 ± 10.99, vs 10.3 ± 1.1 pg/ml; p<0.0001). After OLTx a significant increase in FT was recorded at 6, 12 (p<0.05) and 24 months (p<0.005). FT was not correlated with BMD, however. After OLTx an increase in FSH and LH was observed (but failed to reach statistical significance) at 3 and 6 months, followed by a slight reduction at 12 and 24 months. Thus a high proportion of men with end-stage liver disease do have osteoporosis. After OLTx, an early recovery of gonad function is observed, followed by an increase in bone mass, which occurs from the sixth month onward.

Viral load in HCV RNA-positive pregnant women

Abstract OBJECTIVES: The risk of hepatitis C virus (HCV) infection in the newborn is estimated to be around 5%, but becomes very high in the case of coinfection with HIV. One of the main factors associated with the vertical transmission of HCV is the viral load. Our objective was to investigate the behavior of HCV viral load during pregnancy in relation to HIV coinfection, liver enzymes, and vertical transmission. METHODS: Three thousand seven hundred forty-eight women seen consecutively in their first trimester of pregnancy were screened for HCV infection. Sixty-five were found to be anti-HCV+/HCV RNA+ and were followed up with clinical and serological assessment ( i.e., transaminases and quantitative polymerase chain reaction [PCR] for viral load) in their second and third trimesters and 6 months after delivery. All were anti-HIV and hepatitis B surface antigen negative. HCV RNA was 12.0 ± 19.9 × 10 6 copies/ml in the first trimester and 10.9 ± 13.3 × 10 6 in the second, but increased to 19.5 ± 25.1 × 10 6 in the third trimester. Six months after delivery the viral load returned to the baseline levels; the changes in viral load did not reach any statistical significance, however. Transaminases tended toward a reduction from the baseline during the second and third trimesters, and then an increase in both AST and ALT was recorded 6 months after delivery. However, when the group whose AST/ALT were found abnormal at the first test was considered, no significant changes were recorded during the follow-up. The overall rate of vertical transmission was 4.6%. CONCLUSIONS: With HCV+ mothers monitoring transaminases during pregnancy is unnecessary, and testing liver enzymes at the beginning of pregnancy is sufficient. Qualitative PCR should be done once during the pregnancy, but any staging of the liver disease should be taken after delivery. Quantitative PCR testing is expensive and pointless. Any decision for elective cesarean section in HCV RNA+ mothers should be confirmed by other studies.

Validation of the BCLC Prognostic System in Surgical Hepatocellular Cancer Patients

BACKGROUND/AIM Prognosis assessment in surgical patients with hepatocellular carcinoma (HCC) remains controversial. The most widely used HCC prognostic tool is the Barcelona Clinic Liver Cancer (BCLC) classification, but its prognostic ability in surgical patients has not been yet validated. The aim of this study was to investigate the value of known prognostic systems in 400 Italian HCC patients treated with radical surgical therapies. METHODS We analyzed a prospective database collection (400 surgical, 315 nonsurgical patients) observed at a single institution from 2000 and 2007. By using survival times as the only outcome measure (Kaplan-Meier method and Cox regression), the performance of the BCLC classification was compared with that of Okuda, Cancer of the Liver Italian Program, United Network for Organ sharing TNM, and Japan Integrated Staging Score staging systems. RESULTS Two hundred twenty-five patients underwent laparotomy resection; 55, laparoscopic procedures (ablation and/or resection); and 120, liver transplantations. In the surgical group, BCLC proved the best HCC prognostic system. Three-year survival rates of patients in BCLC Stages A, B, and C were 81%, 56%, and 44% respectively, (P < .01); whereas all other tested staging systems did not show significant stratification ability. When all 715 HCC patients were considered, surgery proved to be a significant survival predictor in each BCLC stage (A, B, and C). CONCLUSIONS BCLC staging showed the best interpretation of the survival distribution in a surgical HCC population. The BCLC treatment algorithm should consider the role of surgery also for intermediate-advanced stages of liver disease.

Killer cell immunoglobulin-like receptor genotype and killer cell immunoglobulin-like receptor-human leukocyte antigen C ligand compatibility affect the severity of hepatitis C virus recurrence after liver transplantation

In 20% to 30% of infected individuals, hepatitis C virus (HCV) can cause cirrhosis and hepatocellular carcinoma, for which liver transplantation is the best treatment available. HCV re‐infection is universal, and hepatitis disease recurrence occurs in most cases with a 30% probability of progression to graft cirrhosis at 5 years post‐transplant. The immunological response to HCV involves natural killer (NK) cells and killer cell immunoglobulin‐like receptors (KIRs), which specifically recognize human leukocyte antigen (HLA) class I antigens present on target cells. The effector functions of NK cells are influenced by inhibitory KIR interaction with self‐HLA class I ligands, with HLA‐C being the most predominant. This study examines the roles of KIR genotypes and their HLA ligands in both HCV disease recurrence and its progression. A total of 151 patients were included in the cohort, and their clinical details were recorded. Liver biopsies were used to define the absence/presence of recurrent hepatitis, the degree of fibrosis, and the progression to cirrhosis over a 10‐year period. Mismatching of KIR–HLA‐C ligands between donor‐recipient pairs was associated with the recurrence of hepatitis (P = 0.008). The presence of KIR2DL3 in the recipient correlated with progression to liver fibrosis (P = 0.04). The mismatching of HLA‐KIR ligands favored the progression of the recurrent hepatitis to fibrosis only in the presence of KIR2DL3 (P = 0.04). These preliminary results indicate that the KIR genotype and KIR–HLA‐C ligand compatibility play roles in the recurrence and progression of hepatitis C disease in liver transplant recipients. Liver Transpl 15:390–399, 2009.

Heterophilic antibody interference in a non-endogenous molecule assay: an apparent elevation in the tacrolimus concentration.

BACKGROUND In drug monitoring assays the most common interferences are due to hematocrit, other drugs or their metabolites, while the interference by heterophilic antibodies has been reported only when measuring endogenous molecules. In the present paper a heterophilic antibody interference in the tacrolimus measurement is described. METHODS Samples from a patient treated with tacrolimus were analyzed on RxL Dimension analyzer. Ranging drug concentrations from 49 to 12.5 microg/L, even after the interruption of the treatment, confirmation analysis were performed using heterophilic blocking tubes before tacrolimus measurement on the same analyzer, then testing the samples on V-Twin System, finally incubating the samples with chlorophenol red beta-d-galactopyranoside, beta-galactosidase, polyclonal mouse IgG, protein A and Protein G resin. RESULTS The elevated tacrolimus concentrations were due to the presence of an interference attributable to heterophilic antibodies, as confirmed by treating the samples with heterophilic blocking tubes and protein G resin. CONCLUSIONS a) The interference caused by heterophilic antibodies can be found not only in immunoassays measuring endogenous molecules, but also in those for exogenous molecules; b) the pre-treatment sample procedure, which represent the main difference between the methods affected and unaffected by the interference, is a fundamental step in removing the antibodies responsible of the interference.