Giovanni Vizzini

TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.

BACKGROUND & AIMS Budd-Chiari syndrome (BCS) is a rare and life-threatening disorder secondary to hepatic venous outflow obstruction. Small series of BCS patients indicate that transjugular intrahepatic portosystemic shunt (TIPS) may be useful. However, the influence of TIPS on patient survival and factors that predict the outcome of TIPS in BCS patients remain unknown. METHODS One hundred twenty-four consecutive BCS patients treated with TIPS in 6 European centers between July 1993 and March 2006 were followed until death, orthotopic liver transplantation (OLT), or last clinical evaluation. RESULTS Prior to treatment with TIPS, BCS patients had a high Model of End Stage Liver Disease and high Rotterdam BCS prognostic index (98% of patients at intermediate or high risk) indicating severity of liver dysfunction. However, 1- and 5-year OLT-free survival were 88% and 78%, respectively. In the high-risk patients, 5-year OLT-free survival was much better than that estimated by the Rotterdam BCS index (71% vs 42%, respectively). In the whole population, bilirubin, age, and international normalized ratio for prothrombin time independently predicted 1-year OLT-free survival. A prognostic score with a good discriminative capacity (area under the curve, 0.86) was developed from these variables. Seven out of 8 patients with a score >7 died or underwent transplantation vs 5 out of 114 patients with a score <7. CONCLUSIONS Long-term outcome for patients with severe BCS treated with TIPS is excellent even in high-risk patients, suggesting that TIPS may improve survival. Furthermore, we identified a small subgroup of BCS patients with poor prognosis despite TIPS who might benefit from early OLT.

Short- and long-term effects of the transjugular intrahepatic portosystemic shunt on portal vein thrombosis in patients with cirrhosis

Background and aims Portal vein thrombosis (PVT) negatively impacts the prognosis in patients with cirrhosis. The aim of our study was to evaluate the effects of transjugular intrahepatic portosystemic shunt (TIPS) placement in patients with cirrhosis complicated by PVT. Methods Seventy consecutive cirrhotic patients with non-tumoural PVT treated with TIPS for portal hypertension complications from January 2003 to February 2010 in a tertiary-care centre were followed until last clinical evaluation, liver transplantation, or death. Results TIPS was successfully placed without major procedure-related complications. After TIPS, the portal venous system was completely recanalised in 57% of patients, a marked decrease in thrombosis was observed in 30%, and no improvement was seen in 13%. 95% of patients with complete recanalisation after TIPS maintained a patent portal vein. Predictors of complete recanalisation were a less severe and extensive PVT, de novo diagnosis of PVT, and absence of gastro-oesophageal varices. At follow-up, 1 patient had recurrence of bleeding, and 2 had spontaneous bacterial peritonitis. The rate of TIPS dysfunction at 12 and 24 months was 38% and 85% for bare stent and 21% and 29% for covered stent (p=0.001), respectively. Occurrence of encephalopathy at 12 and 24 months was 27% and 32%, respectively. Fifteen patients underwent liver transplantation. Survival at 1, 12 and 24 months was 99%, 89% and 81%, respectively. Conclusion Long-term outcome of non-tumoural PVT in patients with cirrhosis treated with TIPS placement is excellent. Prospective randomised studies should investigate whether TIPS placement is the best therapeutic option in patients with cirrhosis who develops non-tumoural PVT.

Liver biopsy findings from healthy potential living liver donors: Reasons for disqualification, silent diseases and correlation with liver injury tests

BACKGROUND/AIMS Liver biopsies detect silent donor disease in potential living liver donors and provide material for studies of subclinical non-alcoholic fatty liver disease (NAFLD). Our primary goal was to determine the contribution of biopsy findings to potential donor evaluation. Factors contributing to pre-clinical NAFLD and correlations between liver injury tests and histopathology have been also determined. METHODS Patient records, laboratory tests and results of the histopathologic examination and diagnoses of 284 patients from 2001 to 2005 were retrospectively extracted from the EDIT database. Hepatic histology was correlated with liver injury tests and with general demographic characteristics in an otherwise normal healthy population. RESULTS A minority (n=119; 42%) of biopsies from this population of 143 males/141 females (average age=36.8years; mean BMI=26.6) were completely normal. The remainder showed steatosis (n=107; 37%), steatohepatitis (n=44; 15%), or unexplained low-grade/early stage chronic hepatitis, primary biliary cirrhosis, or nodular regenerative hyperplasia (n=16; 6%). Biopsy findings disqualified 29/56 donors. Independent risk factors for NAFLD by multivariate modeling, which differed by sex, included: BMI (p=0.0001), age (p=0.003), iron (p=0.01), and ALT (p=0.004). CONCLUSIONS Liver biopsies provide valuable information about otherwise undetectable liver disease in potential liver donors. Obesity, age and iron, which are influenced by sex, contribute to NAFLD pathogenesis. Blood tests other than standard liver profiles are needed to detect early NAFLD.

Can the serological status of anti-HBc alone be considered a sentinel marker for detection of occult HBV infection?

Some individuals have “occult” infection with hepatitis B virus (HBV), defined as presence of HBV genome in the serum or liver tissue without HBV surface antigen (HBsAg) in the serum. The aim of this study was to investigate whether serum antibodies against HBV core antigen in isolation (“anti‐HBc alone”) are a useful marker of “occult” HBV in patients with or without hepatitis C virus (HCV) infection. “Anti‐HBc alone” was detected in the sera of 119/6,544 (1.8%) asymptomatic outpatients referred to the diagnostic laboratory for routine testing for viral hepatitis, 62/607 (10.2%) drug users, and 42/195 (21.5%) patients with hepatocellular carcinoma. Using three in‐house nested‐PCR amplification assays to detect HBV preS‐S (S), precore‐core (C), and Pol viral regions, respectively, “occult” HBV sequences were found in 9 of the 223 sera (4.0%) with “anti‐HBc alone.” The highest prevalence of “occult” HBV sequences (5.9%) was detected in “anti‐HBV alone” sera of individuals referred to the diagnostic laboratory without HCV antibodies. Direct sequencing of all PCR products confirmed the specificity of the PCR reactions and revealed the predominance of HBV genotype D. The data presented in this study suggest that detection of “anti‐HBc alone” could reflect unrecognized “occult” HBV infection and that physicians should consider investigating such patients with HBV molecular tests. J. Med. Virol. 80:577–582, 2008.

Efficient human fetal liver cell isolation protocol based on vascular perfusion for liver cell–based therapy and case report on cell transplantation

Although hepatic cell transplantation (CT) holds the promise of bridging patients with end‐stage chronic liver failure to whole liver transplantation, suitable cell populations are under debate. In addition to hepatic cells, mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) are being considered as alternative cell sources for initial clinical cell work. Fetal liver (FL) tissue contains potential progenitors for all these cell lineages. Based on the collagenase incubation of tissue fragments, traditional isolation techniques yield only a fraction of the number of available cells. We report a 5‐step method in which a portal vein in situ perfusion technique is used for tissue from the late second trimester. This method results in the high viabilities known for adult liver vascular perfusion, addresses the low cell yields of conventional digestion methods, and reduces the exposure of the tissue to collagenase 4‐fold. We used donated tissue from gestational weeks 18 to 22, which yielded 1.8 ± 0.7 × 109 cells with an average viability of 78%. Because HSC transplantation and MSC transplantation are of interest for the treatment of hepatic failure, we phenotypically confirmed that in addition to hepatic progenitors, the resulting cell preparation contained cells expressing typical MSC and HSC markers. The percentage of FL cells expressing proliferation markers was 45 times greater than the percentage of adult hepatocytes expressing these markers and was comparable to the percentage of immortalized HepG2 liver hepatocellular carcinoma cells; this indicated the strong proliferative capacity of fetal cells. We report a case of human FL CT with the described liver cell population for clinical end‐stage chronic liver failure. The patients Model for End‐Stage Liver Disease (MELD) score improved from 15 to 10 within the first 18 months of observation. In conclusion, this human FL cell isolation protocol may be of interest for further clinical translation work on the development of liver cell–based therapies. Liver Transpl 18:226–237, 2012.

Successful treatment of small‐for‐size syndrome in adult‐to‐adult living‐related liver transplantation: single center series

Abstract:  The portal hyperperfusion, or small‐for‐size syndrome (SFSS), is a widely recognized clinical complication that may occur after segmental liver transplantation. Several surgical strategies have been proposed to reduce portal blood inflow and portal pressure after partial liver transplantation. In particular, splenic artery ligation and splenectomy have been used without a firm hemodynamic basis for these procedures. Our group recently demonstrated that, in patients with cirrhosis and portal hypertension, the occlusion of the splenic artery causes a significant reduction in the portal pressure gradient, which is directly related to the spleen volume and indirectly related to the liver volume. This concept is at the center of our strategy for performing early splenic artery embolization (SAE) for the treatment of SFSS after living‐related liver transplantation (LRLT). Six patients developed small‐for‐size syndrome, defined as: onset within the first week after LRLT of progressive hyperbilirubinemia without mechanical cause; marked cholestasis; centrilobular sinusoidal dilatation and hepatocyte atrophy at liver biopsy; and refractory ascites in the absence of vascular complications. All six patients who underwent SAE rapidly improved their clinical condition, with an evident decrease in the value of bilirubin in the serum, in the production of ascites, and improvement in condition of pancytopenia. Coagulopathy expressed by the international normalized ratio value (INR) was not a reliable early marker of SFSS in this series; in fact a slight improvement in the result of this test was already present immediately after LRLT and before SAE. Because splenic flow clearly contributes to portal hyperperfsion, an early SAE can relieve the partial graft from the deleterious effect of this portal overflow.

Contribution of transjugular liver biopsy in patients with the clinical presentation of acute liver failure

PurposeAcute liver failure (ALF) treated with conservative therapy has a poor prognosis, although individual survival varies greatly. In these patients, the eligibility for liver transplantation must be quickly decided. The aim of this study was to assess the role of transjugular liver biopsy (TJLB) in the management of patients with the clinical presentation of ALF.MethodsSeventeen patients with the clinical presentation of ALF were referred to our institution during a 52 month period. A TJLB was performed using the Cook Quick-Core needle biopsy. Clinical data, procedural complications, and histologic findings were evaluated.ResultsCauses of ALF were virus hepatitis B infection in 7 patients, drug toxicity in 4, mushroom in 1, Wilson’s disease in 1, and unknown origin in 4. TJLB was technically successful in all patients without procedure-related complications. Tissue specimens were satisfactory for diagnosis in all cases. In 14 of 17 patients the initial clinical diagnosis was confirmed by TJLB; in 3 patients the initial diagnosis was altered by the presence of unknown cirrhosis. Seven patients with necrosis <60% were successfully treated with medical therapy; 6 patients with submassive or massive necrosis (≥85%) were treated with liver transplantation. Four patients died, 3 had cirrhosis, and 1 had submassive necrosis. There was a strict statistical correlation (r = 0.972, p < 0.0001) between the amount of necrosis at the frozen section examination and the necrosis found at routine histologic examination. The average time for TJLB and frozen section examination was 80 min.ConclusionIn patients with the clinical presentation of ALF, submassive or massive liver necrosis and cirrhosis are predictors of poor prognosis. TLJB using an automated device and frozen section examination can be a quick and effective tool in clinical decision-making, especially in deciding patient selection and the best timing for liver transplantation.

Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients

The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant. However, despite the long use of tacrolimus in clinical practice, the best way to use this agent is still a matter of intense debate. The start of the genomic era has generated new research areas, such as pharmacogenetics, which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body. This variability seems to be correlated with the presence of genetic polymorphisms. Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus; also, unlike phenotypic tests, the genotype is a stable characteristic that needs to be determined only once for any given gene. However, prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication. At present, research has been able to reliably show that the CYP3A5 genotype, but not the CYP3A4 or ABCB1 ones, can modify the pharmacokinetics of tacrolimus. However, it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity. For these reasons, pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing.

Changing picture of central nervous system complications in liver transplant recipients

Central nervous system (CNS) complications are common after liver transplantation (LT). According to the literature, the most common causes are infections and the neurotoxicity of immunosuppressive drugs (cyclosporine and tacrolimus). The aim of this study was to evaluate the incidence, clinical presentations, etiologies, and outcomes of CNS complications in a series of 395 consecutive LT recipients whose immunosuppression regimen was designed for low tacrolimus blood levels. An analysis of the 12‐hour trough concentrations of tacrolimus in the study population showed that the target drug levels, which were designed to maintain minimal immunosuppression, were usually achieved. In all, 64 patients (16.2%) developed major neurological symptoms (37 within 30 days of LT). None of the observed CNS complications were caused by infections (viral, bacterial, or fungal), and only 3 of the 395 patients (0.8%) received a diagnosis of tacrolimus‐related leukoencephalopathy. Cerebrovascular disease was identified in 15 patients (3.8%; 8 had cerebral hemorrhages, 5 had ischemic strokes, and 2 had subdural hemorrhages). Pontine myelinolysis was found in 2 patients (0.5%). Notably, no clear cause was identified for the remaining 44 cases (11.1%): brain imaging was negative for 22 cases, and diffuse hypoxic changes were present for the other 22. CNS complications were significantly associated with a reduction in 3‐month patient survival (88.8% versus 95.4%) and 5‐year patient survival (57.3% versus 84.1%). Among the pretransplant variables that were analyzed, the incidence of portosystemic encephalopathy, the peak serum bilirubin levels, and the lowest serum total cholesterol levels were significantly different between the 64‐patient group with CNS complications and the asymptomatic group of 331 patients. Liver Transpl 17:1279–1285, 2011.

Critical use of extended criteria donor liver grafts in adult-to-adult whole liver transplantation: A single-center experience

This study presents our experience with the use of extended criteria donor (ECD) liver grafts. One hundred fifteen liver transplants were divided into 2 groups: standard (S) and nonstandard (NS). Fifty‐eight patients in group S received a liver procured from an ideal donor, whereas 57 patients in group NS received an organ from an ECD. On the basis of the number of risk factors, patients were divided into 3 subgroups: the S group with 58 receiving a standard graft, the NS1 group with 44 receiving a graft with 1 or 2 risk factors, and the NS2 group with 13 receiving a graft with 3 to 4 risk factors. Patient survival was not different at 6, 12, and 24 months (P > 0.05), whereas graft survival was different (P = 0.0079). Both patient survival and graft survival were influenced by the cumulative number of risk factors. The univariate analysis of the donor risk factors detected hemodynamic factors as predictive of graft failure (P = 0.024) and death (P = 0.018). In the multivariate analysis, which was adjusted for recipient age and donor and recipient gender, hemodynamic risk factors and Model for End‐Stage Liver. Disease score in the recipient were the only variables independently associated with graft failure (P = 0.006, P = 0.012, negatively). Finally, we observed a reduction of dropout from the list to 9% from 14.1% (P = 0.04) and of mortality on the list to 32.55% from 41.01% (P = 0.11). Critical use of ECD liver grafts allowed recipients in the waiting list to have a greater chance of being transplanted. Liver Transpl 14:220–227, 2008.