Alice Gianstefani

Criteria for diagnosing benign portal vein thrombosis in the assessment of patients with cirrhosis and hepatocellular carcinoma for liver transplantation

Malignant portal vein thrombosis is a contraindication for liver transplantation. Patients with cirrhosis and early hepatocellular carcinoma (HCC) may have either malignant or benign (fibrin clot) portal vein thrombosis. The aim of this study was to assess prospectively whether well‐defined diagnostic criteria would enable the nature of portal vein thrombosis to be established in patients with HCC under consideration for liver transplantation. Benign portal vein thrombosis was diagnosed by the application of the following criteria: lack of vascularization of the thrombus on contrast‐enhanced ultrasound and on computed tomography or magnetic resonance imaging, absence of mass‐forming features of the thrombus, absence of disruption of the walls of veins, and, if uncertainty persisted, biopsy of the thrombus for histological examination. Patients who did not fulfill the criteria for benign thrombosis were not placed on the transplantation list. In this study, all patients evaluated at our center during 2001‐2007 with a diagnosis of HCC in whom portal vein thrombosis was concurrently or subsequently diagnosed were discussed by a multidisciplinary group to determine their suitability for liver transplantation. The outcomes for 33 patients who met the entry criteria of the study were as follows: in 14 patients who were placed on the transplantation list and underwent liver transplantation, no malignant thrombosis was detected when liver explants were examined histologically; 5 patients who were placed on the transplantation list either remained on the list or died from causes unrelated to HCC; in 9 patients, liver transplantation was contraindicated on account of a strong suspicion, or confirmation, of the presence of malignant portal vein thrombosis; and 5 patients who were initially placed on the transplantation list were subsequently removed from it on account of progression of HCC in the absence of evidence of neoplastic involvement of thrombosis. In conclusion, for a patient with HCC and portal vein thrombosis, appropriate investigations can establish whether the thrombosis is benign; patients with HCC and benign portal vein thrombosis are candidates for liver transplantation. Liver Transpl 16:658‐667, 2010.

Assessment of liver fibrosis in transplant recipients with recurrent HCV infection: usefulness of transient elastography.

BACKGROUND Progression of recurrent hepatitis C is accelerated in liver transplant recipients, leading to special need of non-invasive validated methods to estimate liver fibrosis. AIM To assess the efficacy of liver stiffness measurement by transient elastography (Fibroscan) and serum parameters in predicting fibrosis stage in HCV-infected transplant recipients. METHODS The correlation between liver fibrosis, assessed at liver histology on bioptic specimens obtained for clinical indications, and stiffness or clinico-serological indexes (Benlloch, APRI, Forns, Fibrotest and Doppler resistance index), was investigated in transplant recipients with recurrence of HCV chronic hepatitis. A total of 56 patients (of which 36 with all clinico-serological indexes), presenting with the following METAVIR fibrosis stage F1=38, F2=9, F3=8, F4=1, were enrolled in the study population. Differences between fibrosis stages were calculated by non-parametric analysis. The best cut-off for identifying significant fibrosis (F2-F4) was assessed by ROC curve analysis. RESULTS Stiffness (median and range) was 7.7 KPa (range 4.2-13.9) in F1 and 17.0KPa (range 6.8-36.3) in >or=F2 (p<0.001). A stiffness cut-off of 10.1 KPa revealed 94% Sensitivity, 89% Specificity, 81% PPV and 94% NPV in differentiating F1 from F2-F4. The area under the receiver operator curve in the assessment of fibrosis was significantly higher for Liver stiffness (AUROC 0.943) than for any of the other non-invasive indexes (AUROCs ranging 0.591-0.815). CONCLUSIONS Transient elastography of the liver provides good accuracy in identifying patients with significant fibrosis and performs better than non-invasive indexes based on clinico-serological parameters in transplant recipients.

Liver AL amyloidosis as a possible cause of high liver stiffness values.

The liver is a common site of amyloid deposition in primary systemic amyloidosis. We report the case of a 52-year-old white woman complaining of hepatomegaly, high levels of alkaline phosphatase and serum gamma-glutamyl transferase. Other laboratory tests showed proteinuria with light-chain type lambda. Color Doppler ultrasonography showed an enlarged bright liver with hepatopetal portal blood flow. Fine-needle aspiration biopsy of abdominal fat, with Congo red stain, was positive for amyloid. No liver biopsy was performed, but transient elastography showed high liver stiffness values (75 kPa), suggestive of amyloid infiltration, as other causes of elevation had been ruled out by clinical, laboratory and radiological findings. Bone marrow morphology and immunoistochemistry confirmed low-grade plasmacytoma with amyloidosis.

Quantification of enhancement of focal liver lesions during contrast-enhanced ultrasound (CEUS). Analysis of ten selected frames is more simple but as reliable as the analysis of the entire loop for most parameters

The aim of the study was to evaluate the reliability of the analysis of only 10 frames rather than of a whole clip in performing quantitative assessment of tumor enhancement of focal liver lesions (FLLs) following ultrasound contrast injection. Contrast-enhanced ultrasonography (CEUS) examinations of 31 FLLs (median diameter: 30mm) were performed. All clips were analyzed and quantified with an early prototype of the SonoLiver software (TomTec GmbH, Munich and Bracco Research SA, Geneva), first evaluating the entire clip then selecting only 10 frames at different time intervals. Enhancement measurements obtained from the analysis of the entire clip or of only 10 frames were closely correlated (r=0.931 and p<0.0001 for Area Under the Curve; r=0.944 and p<0.0001 for Perfusion Index). In conclusion, enhancement quantification of FLLs can be reliably obtained from only 10 frames, rather than the entire clip, at least for most parameters, making such procedure easier for potential routine use.

Imaging Diagnosis of Hepatocellular Carcinoma: Recent Advances of Contrast-Enhanced Ultrasonography with SonoVue®

Due to the ability to detect the typical contrast-imaging pattern for hepatocellular carcinoma (HCC), that is hyperenhancement in the arterial phase and hypoenhancement in the late phase on a cirrhotic background, contrast-enhanced ultrasonography (CEUS) was included in the American diagnostic algorithm for HCC in 2005. However, its role has been questioned because of the possibility of misdiagnosis of cholangiocarcinoma. The present review aims to describe the advantages and disadvantages of CEUS applications using Sonovue® for HCC. In particular there is focus on the accuracy of CEUS in detecting the typical HCC pattern, the CEUS patterns of intrahepatic cholangiocarcinoma (ICC), the risk of misdiagnosis with HCC, the diagnostic use of CEUS in cases of locoregional and systemic treatments, and the evaluation of response to antiangiogenic treatment using dedicated software.

Selecting patients with hepatocellular carcinoma for transplantation.

The article by Otto et al., published in Liver Transplantion in the August 2006 issue, provides intriguing results concerning the possibility to select patients with hepatocellular carcinoma for transplantation according to an indirect assessment of tumor biology, namely the response to transarterial chemoembolization, regardless of the initial radiologic staging. The widely accepted Milan criteria, based on imaging findings of size and number of tumor nodules, were also selected because considered indirect markers of the tumor biology and thus predictors of the risk of posttransplantation hepatocellular carcinoma recurrence. Indeed, on a general basis, the larger the tumor (and, similarly, the higher the number of tumors) the poorer the differentiation and the higher the rate of microvascular invasion, both parameters being features related to the risk of recurrence. The approach of Otto et al. consisted in judging the biology of the tumor following the response to repeat transarterial chemoembolization treatments. Although this is a reasonable approach, it should be acknowledged that technical problems might prevent adequate treatment of tumors in various instances, in otherwise biologically suitable candidates for transplantation. For instance, hepatic artery stenosis after initial transarterial chemoembolization sessions, progression of liver failure, and anatomical variants of liver arterial vascularization, may all limit the possibility to perform or repeat transarterial chemoembolization treatments. Interestingly, an information on the grading of the tumors, obtained by means of liver biopsy, was available in the vast majority of the patients studied by Otto et al. Despite the possible intrinsic limitation of percutaneous biopsy in comparison to whole nodule pathologic analysis, in establishing the exact tumor grading, due to the risk of undergrading in bioptic specimens, we believe that a reanalysis of data of Otto et al., could provide additional interesting results. In particular, we would suggest a further analysis, with patients grouped according to tumor grading, assessing: 1) the outcome of patients in terms of transplantations on an intentionto-treat basis; 2) the outcome of transplanted patients in terms of recurrence rate; and 3) the rate of dropout due to tumor progression during the waiting time. Possible findings to be tested should also be whether patients with well differentiated tumors have lower dropout rates for tumor progression or have lower recurrence rates, regardless of the initial tumor size. This would make them potentially transplantable also in those instances in which technical feasibility of repeated transarterial chemoembolization is lacking. On the other hand, it may also be tested whether patients with poorly differentiated tumors are poor transplant candidates, even when they respond adequately to transarterial chemoembolization treatments. Since an answer on these points might be of particular relevance for the liver transplant community, a further analysis by Otto et al. is warranted.

The Italian compassionate use of sofosbuvir in HCV patients waitlisted for liver transplantation: A national real-life experience

This study aimed to assess the real‐life clinical and virological outcomes of HCV waitlisted patients for liver transplantation (LT) who received sofosbuvir/ribavirin (SOF/R) within the Italian compassionate use program.

Development and validation of a nomogram based on clinical factors and standard laboratory tests for prediction of clinically significant liver fibrosis in chronic hepatitis C virus infection.

Objectives Staging liver fibrosis in chronic viral hepatitis C (HCV) patients is essential for prompting surveillance and treatment. The aim of this study was to develop a nomogram, on the basis of simple clinical and laboratory variables, to predict three clinically significant stages of fibrosis (nil–mild, moderate, advanced/cirrhosis), using histology as reference, and to compare its performance with that of FibroTest, a widely used noninvasive fibrosis score. Materials and methods Nomograms are graphical representations of a mathematical formula, used as predictive tools. The study retrospectively recruited 406 HCV patients undergoing liver biopsy. Nomogram was developed in a training set of 252 patients and tested in a validation set of 154 patients. Histology was staged according to the Metavir system. Fibrosis stages were subgrouped as follows: advanced fibrosis/cirrhosis (F3/F4, 24%), nil–mild (F0/F1, 36%), and moderate (F2, 40%). Age at biopsy, aspartate aminotransferase, &ggr;-glutamyl transpeptidase, albumin, platelet count, and prothrombin activity formed the basis for the so-called Fibro-Nomogram, which, in one graphical representation, estimates probability for different stages of fibrosis. Results Areas under the receiver-operating characteristic curves for advanced fibrosis/cirrhosis were similar for training (0.86) and validation sets (0.87). For nil–mild fibrosis, area under the receiver-operating characteristics were 0.81 and 0.79. Compared with FibroTest, Fibro-Nomogram performed slightly better at predicting severe fibrosis (F3/F4) with positive likelihood ratio (LR+) 5.07 (95% confidence interval 3.08–8.37) versus LR+ 3.82 (95% confidence interval 2.56–5.71) for FibroTest. For nil–mild fibrosis, the two tests showed limited but comparable performances. Conclusion In HCV patients, Fibro-Nomogram, an inexpensive and readily available predictive tool, could enable clinicians to interpret patients’ profile, concurrently stratifying patients into three clinically relevant probability categories with good overall performance.

Widen NomoGram for multinomial logistic regression: an application to staging liver fibrosis in chronic hepatitis C patients.

The interpretation of regression models results can often benefit from the generation of nomograms, ‘user friendly’ graphical devices especially useful for assisting the decision-making processes. However, in the case of multinomial regression models, whenever categorical responses with more than two classes are involved, nomograms cannot be drawn in the conventional way. Such a difficulty in managing and interpreting the outcome could often result in a limitation of the use of multinomial regression in decision-making support. In the present paper, we illustrate the derivation of a non-conventional nomogram for multinomial regression models, intended to overcome this issue. Although it may appear less straightforward at first sight, the proposed methodology allows an easy interpretation of the results of multinomial regression models and makes them more accessible for clinicians and general practitioners too. Development of prediction model based on multinomial logistic regression and of the pertinent graphical tool is illustrated by means of an example involving the prediction of the extent of liver fibrosis in hepatitis C patients by routinely available markers.

Stiffness and amyloidosis: to be continued…

We have recently published a paper dealing with the use of transient elastography in a case of liver amyloidosis [1]. We would like to enrich our report by describing a case similar to the one reported earlier which occurred recently in our Institution in a patient with Castleman’s disease. Castleman’s disease (also known as ‘giant lymph node hyperplasia’) is a rare clinicopathological entity belonging to the group of atypical lymphoproliferative disorders [2]. It is well known that this disease can be complicated by the occurrence of secondary systemic and renal amyloid A (AA) amyloidosis [3]. Furthermore, some authors reported a case of hepatic amyloidosis and Castleman’s disease diagnosed with liver biopsy [4].