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Background and Aims: Circulating albumin in cirrhosis can be dysfunctional because of accumulating structural damages, leading to the concept of effective albumin concentration (eAlb), referring to the albumin portion presenting structural and functional integrity. We aimed to estimate eAlb in patients with decompensated cirrhosis and analyze its relationships with albumin function and clinical outcomes as compared to total albumin concentration (tAlb). Approach and Results: We evaluated 319 patients with cirrhosis hospitalized for acute decompensation (AD) with and without acute-on-chronic liver failure (ACLF) and 18 age- and sex-comparable outpatients with compensated cirrhosis. tAlb was quantified by standard assay, whereas eAlb was estimated combining liquid chromatography/electrospray ionization/mass spectrometry and standard methods. Albumin binding and detoxification efficiency were evaluated by electron paramagnetic resonance analysis. Circulating albumin in patients with decompensated cirrhosis displayed multiple structural abnormalities, with reversible oxidation and glycation being the most frequent. As a result, eAlb progressively declined with the worsening of cirrhosis and was superior to tAlb in stratifying patients between compensated cirrhosis, AD, and ACLF, as well as patients with and without complications. Moreover, eAlb, but not tAlb, was closely associated with binding capacities in ACLF. Finally, eAlb at admission predicted the occurrence of ACLF within 30 days and mortality at 90 days better than tAlb. Conclusions: This large, observational study provides the evidence in patients with decompensated cirrhosis that eAlb can be quantified and differentiated from tAlb routinely measured in clinical practice. As compared to tAlb, eAlb is more closely associated with disease severity and albumin dysfunction and carries a greater prognostic power. These results prompt future research assessing eAlb as a biomarker for predicting prognosis and treatment response.

The current epidemic of non-alcoholic fatty liver disease (NAFLD) is reshaping the field of hepatology all around the world. The widespread diffusion of metabolic risk factors such as obesity, type2-diabetes mellitus, and dyslipidemia has led to a worldwide diffusion of NAFLD. In parallel to the increased availability of effective anti-viral agents, NAFLD is rapidly becoming the most common cause of chronic liver disease in Western Countries, and a similar trend is expected in Eastern Countries in the next years. This epidemic and its consequences have prompted experts from all over the word in identifying effective strategies for the diagnosis, management, and treatment of NAFLD. Different scientific societies from Europe, America, and Asia-Pacific regions have proposed guidelines based on the most recent evidence about NAFLD. These guidelines are consistent with the key elements in the management of NAFLD, but still, show significant difference about some critical points. We reviewed the current literature in English language to identify the most recent scientific guidelines about NAFLD with the aim to find and critically analyse the main differences. We distinguished guidelines from 5 different scientific societies whose reputation is worldwide recognised and who are representative of the clinical practice in different geographical regions. Differences were noted in: the definition of NAFLD, the opportunity of NAFLD screening in high-risk patients, the non-invasive test proposed for the diagnosis of NAFLD and the identification of NAFLD patients with advanced fibrosis, in the follow-up protocols and, finally, in the treatment strategy (especially in the proposed pharmacological management). These difference have been discussed in the light of the possible evolution of the scenario of NAFLD in the next years.

Background & Aims The use of contrast enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis was questioned because of the risk of a false positive diagnosis in cases of cholangiocarcinoma. The American College of Radiology has recently released a scheme (CEUS Liver Imaging Reporting and Data System [LI-RADS®]) to classify lesions at risk of HCC investigated by CEUS. The aim of the present study was to validate this LI-RADS scheme for the diagnosis of HCC. Methods A total of 1,006 nodules from 848 patients with chronic liver disease at risk of HCC were collected in five Italian centers and retrospectively analyzed. Nodules were classified as LR-5, (HCC) if ≥1 cm with arterial phase hyperenhancement, and late washout (onset ≥60 s after contrast injection) of mild degree. Rim enhancement and/or early and/or marked washout qualified lesions as LR-M (malignant, but not specific for HCC). Other combinations qualified lesions at intermediate risk for HCC (LR-3) or probable HCC (LR-4). Diagnostic reference standard was CT/MRI diagnosis of HCC (n = 506) or histology (n = 500). Results The median nodule size was 2 cm. Of 1,006 nodules, 820 (81%) were HCC, 40 (4%) were cholangiocarcinoma, 116 (11%) regenerative nodules (±dysplastic). The LR-5 category (52% of all nodules) was 98.5% predictive of HCC, with no risk of misdiagnosis for pure cholangiocarcinoma. Sensitivity for HCC was 62%. All LR-M nodules were malignant and the majority of non-hepatocellular origin. Over 75% of cholangiocarcinomas were LR-M. The LR-3 category included 203 lesions (HCC 96 [47%]) and the LR-4 202 (HCC 173 [87%]). Conclusions The CEUS LI-RADS class LR-5 is highly specific for HCC, enabling its use for a confident non-invasive diagnosis. Lay summary This is a retrospective study of approximately 1,000 focal lesions at risk for hepatocellular carcinoma (HCC). Herein, we demonstrate that the refined definition of the typical contrast enhanced ultrasound pattern of HCC introduced by the Liver Imaging Reporting and Data System (LI-RADS®) practically abolishes the risk of misdiagnosis of other malignant entities ( e.g. cholangiocarcinoma) for HCC with negligible reduction in sensitivity. These data support the use of contrast enhanced ultrasound to diagnose HCC in cirrhosis.

SUMMARY Contrast-enhanced ultrasound (CEUS) is a sure, noninvasive, repeatable imaging technique widely used in the characterization of benign and malignant liver lesions. The European Federation of Societies for Ultrasound in Medicine and Biology guidelines suggest the typical CEUS features of liver lesions as criteria for the noninvasive diagnosis in cirrhotic and not-cirrhotic patients. The clinical application of CEUS in the liver study is summarized in this review; the contrast-enhanced patterns of the most frequent liver lesions are described (hepatocellular and cholangiocellular carcinoma, liver metastases, hemangioma, focal nodular hyperplasia, adenoma). The role of this imaging technique in the diagnostic algorithm of liver malignancy is illustrated and the CEUS application in hepatologic and oncological settings is depicted.

Background Few data exist on real-life adherence to international guidelines for the treatment of hepatocellular carcinoma. We analysed the rate of adherence to American Association for the Study of Liver Diseases guidelines, to identify reasons for discrepancy with treatments performed in our centre. Methods 227 consecutive cirrhotics with a first hepatocellular carcinoma diagnosis (2005–2010) were retrospectively evaluated and stratified based on Barcelona Clinic Liver Cancer system: 126 early, 50 intermediate, 40 advanced, and 11 end stage. Results Early hepatocellular carcinomas were theoretically eligible for resection ( n = 27), liver transplantation ( n = 36), and percutaneous treatment ( n = 63). In practice, 15/27 (55.5%), 31/36 (86.1%), and 22/63 (34.9%) respectively were treated as recommended. Reasons for discrepancy were age/comorbidity, tumour location, ultrasound visibility, surgical contraindications. Transarterial chemoembolisation was performed in 25/126 early hepatocellular carcinomas (19.8%), resection in 11/63 early hepatocellular carcinomas eligible for percutaneous treatment (17.5%). Transarterial chemoembolisation was excluded in 16/50 intermediate hepatocellular carcinomas (32%). Resection or transarterial chemoembolisation was performed in 6/40 advanced hepatocellular carcinomas (15%). Conclusion Overall, 60% of patients were treated according to American Association for the Study of Liver Diseases guidelines. Approximately 28% of hepatocellular carcinomas were “under-treated” and 7% treated more aggressively than recommended. Peculiarities of individual patients can lead the multidisciplinary team to personalise real-life treatments.

a b s t r a c t Background: The frequency with which patients in Child-Pugh B having hepatocellular carcinoma are treated following the international guidelines according to the Barcelona Clinic Liver Cancer stages is unknown. Aims: To investigate treatment allocation for Child-Pugh B patients in different tumour stages, with particular interest in the intermediate stage. Methods: Patients were retrospectively identified from a consecutively collected series. Treatment was carried out primarily according to the guidelines. Results: Of 86 Child-Pugh B patients, 45 were Barcelona early stage, of which the Child-Pugh scores were 46.7% B7, 33.3% B8, 20.0% B9; 27 patients were intermediate stage (B7 59.3%, B8 37.0% and B9 3.7% respectively), 12 were advanced (41.7% B7, 25.0% B8 and 33.3% B9) and 2 were terminal (both B9). In the intermediate stage, transarterial chemoembolization (or ablation) was performed in 68.8% of the Child- Pugh B7 patients, 50% of the B8 patients and 0% of the B9 patients. Median survival of the intermediate patients was 8.0 months (9.0 in B7 vs. 6.0 in -B8/B9, P = 0.048). Survival of the intermediate stage patients undergoing chemoembolisation was 22.0 months in Child-Pugh B7 and 6.0 in B8. Conclusions: Approximately half of the intermediate stage patients can undergo locoregional treatment with good survival when in the Child-Pugh B7. The Child-Pugh numeric score impacts survival, suggesting that this tumour stage be refined. © 2013 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.

Noninvasive criteria for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis, recommended by the European Association for the Study of Liver (EASL) in 2001 and by the American Association for the Study of Liver Diseases (AASLD) in 2005, have left a number of small liver neoplastic nodules undefined. We designed this prospective study in 2003 with the aims of assessing the diagnostic contribution of vascular contrast-enhanced techniques and investigating the possible additional contribution of superparamagnetic iron oxide magnetic resonance (SPIO-MR) in this setting.Between 2003 and 2005, 75 consecutive small (10-30 mm) liver nodules detected at ultrasonography in 60 patients with cirrhosis were prospectively submitted to contrast-enhanced ultrasound (CEUS), helical-computed tomography (helical-CT), and gadolinium magnetic resonance (gad-MR), each blinded to the other. A total of 68 nodules were also studied with SPIO-MR at the same time as gad-MR.Using the EASL noninvasive criteria, the diagnosis of HCC was established in 44 of 55 (80%) nodules with a final diagnosis of HCC. Gad-MR was the most sensitive technique for detecting the typical vascular pattern. SPIO-MR showed a pattern consistent with HCC in 5 of 10 HCCs, not satisfying the EASL noninvasive criteria, and was negative in 17 of 18 (94.4%) nonmalignant nodules. The review of the present case series according to the AASLD criteria for the noninvasive diagnosis of HCC yielded a sensitivity rate of 81.8%.This study shows that both EASL and AASLD noninvasive recall strategies for nodules of 10-30 mm in the cirrhotic liver, based on the vascular pattern of nodules, have a false-negative rate of approximately 20%. SPIO-MR may increase the diagnostic potential of noninvasive techniques, contributing to the diagnosis of HCC lacking a typical vascular pattern.

The best prioritization of patients with hepatocellular carcinoma (HCC) waiting for liver transplantation under the model for end-stage liver disease (MELD) allocation system is still being debated. We analyzed the impact of a MELD adjustment for HCC, which consisted of the addition of an extra score (based on the HCC stage and waiting time) to the native MELD score. The outcome was analyzed for 301 patients with chronic liver disease listed for liver transplantation between March 1, 2001 and February 28, 2003 [United Network for Organ Sharing (UNOS)-Child-Turcotte-Pugh (CTP) era, 163 patients, 28.8% with HCC] and between March 1, 2003 and February 28, 2004 (HCC-MELD era, 138 patients, 29.7% with HCC). In the HCC-MELD era, the cumulative dropout risk at 6 months was 17.6% for patients with HCC versus 22.3% for those patients without HCC (P = NS), similar to that in the UNOS-CTP era. The cumulative probability of transplantation at 6 months was 70.3% versus 39.0% (P = 0.005), being higher than that in the UNOS-CTP era for patients with HCC (P = 0.02). At the end of the HCC-MELD era, 12 patients with HCC (29.3%) versus 57 without HCC (58.8%) were still on the list (P = 0.001). Both native and adjusted MELD scores were higher (P < 0.05) and progressed more in patients with HCC who dropped out than in those who underwent transplantation or remained on the list (the initial-final native MELD scores were 17.3-23.1, 15.5-15.6, and 12.8-14.1, respectively). The patients without HCC remaining on the list showed stable MELD scores (initial-final: 15.1-15.4). In conclusion, the present data support the strategy of including the native MELD scores in the allocation system for HCC. This model allows the timely transplantation of patients with HCC without severely affecting the outcome of patients without HCC. Liver Transpl 13:857–866, 2007. © 2007 AASLD.

In a prospective study, we examined the impact of arterial hypervascularity, as established by the European Association for the Study of the Liver (EASL) recommendations, as a criterion for characterizing small (1-3 cm) nodules in cirrhosis. A total of 72 nodules (1-2 cm, n = 41; 2.1-3 cm, n = 31) detected by ultrasonography in 59 patients with cirrhosis were included in the study. When coincidental arterial hypervascularity was detected at contrast perfusional ultrasonography and helical computed tomography, the lesion was considered to be hepatocellular carcinoma (HCC) according to EASL criteria. When one or both techniques showed negative results, ultrasound-guided biopsy was performed. In cases with negative results for malignancy or high-grade dysplasia, biopsy was repeated when an increase in size was detected at the 3-month follow-up examination. Coincidental hypervascularity was found in 44 of 72 nodules (61%; 44% of 1-2-cm nodules and 84% of 2-3-cm nodules). Fourteen nodules (19.4%) had negative results with both techniques (hypovascular nodules). Biopsy showed HCC in 5 hypovascular nodules and in 11 of 14 nodules with hypervascularity using only one technique. All nodules larger than 2 cm finally resulted to be HCC. Not satisfying the EASL imaging criteria for diagnosis were 38% of HCCs 1 to 2 cm (17% hypovascular) and 16% of those 2 to 3 cm (none hypovascular). In conclusion, the noninvasive EASL criteria for diagnosis of HCC are satisfied in only 61% of small nodules in cirrhosis; thus, biopsy frequently is required in this setting. Relying on imaging techniques in nodules of 1 to 2 cm would miss the diagnosis of HCC in up to 38% of cases. Any nodule larger than 2 cm should be regarded as highly suspicious for HCC.

To the Editor: The study by Suh and coworkers [1] addresses a hot topic, namely the possibility to predict prognosis (recurrence and survival) in patients submitted to curative treatments for early hepatocellular carcinoma (HCC). The authors conclude that patients submitted to radiofrequency ablation are at higher risk of local intrahepatic recurrence in comparison to surgery and that survival is compromised in case of increased production of a-fetoprotein (AFP) by prothrombin, induced by vitamin K absence-II (PIVKA-II), compared to all other groups (not increased AFP by PIVKA-II product or surgical resection). We agree with the conclusion of the higher risk of recurrence, as we recently demonstrated [2], but in our view the second conclusion is not sufficiently supported by evidence. Moreover, some incorrect reporting of data prevent a full understanding of the study. Regarding the latter point, results about AFP and PIVKA-II were reported as mean values. This is unacceptable, as such data are not expected to follow a Gaussian distribution, thus, mean values are poorly or totally non-informative or may even be misleading under these circumstances. Median values have to be reported. Moreover, readers cannot understand how many patients had normal values of these two parameters. Secondly, the authors themselves point out that patients submitted to ablation had a slightly more compromised liver function than surgical patients. It is evident that cirrhotic patients with poorer liver function have a worse overall survival, regardless of the tumours status. We have recently shown in this Journal that resection may apparently provide better survival in early HCC, but only when entire patient series are analysed [2]. Such difference disappeared in very early HCC when patients were balanced in terms of background liver function and tumour features [2]. Suh and colleagues [1] did not show whether the four subgroups were superimposable in terms of highly relevant factors, such as liver function variables, tumour size and number, thus making the issue of survival questionable. This would be recommendable, especially in the two groups of patients, submitted to ablation, for which the information, derived from histology on which prognosis was designed, was not available. Thus, a re-analysis of the Korean data appears to be well-deserved before the conclusions, proposed by the authors, can be adopted.

AIM: Primary aim was to validate the percentage of intrahepatic cholangiocarcinomas (ICC) which have a contrast vascular pattern at contrast enhanced ultrasound (CEUS) at risk of misdiagnosis with hepatocellular carcinoma (HCC) and, secondary aim, to verify if any characteristics in the CEUS pattern helps to identify ICC. METHODS: All ICC on cirrhosis seen in three Italian centres (Bologna, Milan and Pavia) between 2003 and 2011, in which CEUS and at least another imaging technique (CT or MRI) had been performed, were retrospectively identified. Those patients with ICC size comparable to the early HCC stage (Milan criteria, considered as small ICC) were enrolled for this study. The enhancement pattern at CEUS was analysed and compared with CT or MRI. RESULTS: A total of 25 small ICC made this study group. CEUS was at risk of misdiagnosis of ICC for HCC in a significantly higher number of cases than in CT (performed in 24 ICC) (52% vs. 4.2%, P = 0.009) and MRI (11 ICC) (52% vs. 9.1%, P = 0.02). A different contrast pattern among all techniques was found in 6 of 10 ICC lesions submitted to the three imaging methods. In the arterial phase, ICC lacked global hyperenhacement in approximately 50% of cases at CEUS and the degree of intensity of wash-out in the late phase was marked in 24% of nodules. CONCLUSIONS: CEUS misdiagnosed as HCC a significantly higher number of ICC lesions in cirrhotic patients than CT and MRI. However, some CEUS contrast features can help suspect ICC, especially in some cases with inconclusive CT or MRI.

Background & Aims Aim of the study was to assess the clinical impact of conventional transarterial chemoembolization (cTACE) repeated "on demand" on HCC outcome. Outcome measures were: response rate to first and repeated cTACE, recurrence rates and overall survival. Methods The outcome of 151 consecutive HCC patients submitted to a first cTACE from January 2004 to December 2005 was retrospectively analyzed. Results Complete radiological response (CR) was observed in 72/151 (48%), 34/60 (52%) and 12/22 (55%) patients after first, second and third cTACE, respectively. Recurrence rates at 6 and 12months were 37% and 61% after the first cTACE, and 40% and 59% after the second cTACE, respectively. Patients not achieving CR or with a recurrence after CR not treated with curative therapies were 94 and 84 after first and second cTACE, respectively. Of these, 60/94 (64%) and 22/84 (26%) were submitted to a second and third cTACE, respectively. Median overall survival was 32.0months but 25.0months excluding transplanted patients. Factors at the time of first cTACE associated with overall shorter survival at multivariate analysis were higher bilirubin, higher AFP and not achieving CR. Conclusions CR and recurrence rates after first and second cTACE were similar. About 64% of patients were submitted to second cTACE, while only few patients (26%) were submitted to third cTACE using an "on demand" policy. These figures may be also useful for planning trials for the evaluation of the efficacy of repeated TACE vs . TACE combined with adjuvant treatments or vs . systemic treatments.

Background Which is the least expensive recall policy for nodules in the cirrhotic liver remains unclear. Aim Aim of the study was to analyze the costs of different recall diagnostic strategies of hepatocellular carcinoma (HCC) on cirrhosis on a real series of patients. Methods 75 consecutive small liver nodules (10–30 mm) detected at conventional ultrasonography in 60 patients with cirrhosis were submitted to contrast-enhanced ultrasound, computed tomography and gadolinium-magnetic resonance imaging with a final diagnosis established according to the latest guidelines which include different strategies for nodules 10–19 mm or ≥20 mm. The actual costs required to fully characterise any nodule and staging HCC in every patient, if one or the other imaging modality had been used as the first diagnostic step, were calculated. The theoretical hypothesis that each nodule was present in each patient was also investigated from an economical point of view. Results The recall strategy starting with contrast-enhanced ultrasound plus computed tomography is the least expensive strategy for patients with at least one nodule 10–19 mm in size, in nearly all combinations (single or double nodules). In patients with single 20–30 mm nodules the least expensive strategy is to start with computed tomography and to use contrast-enhanced ultrasound as a second step technique. Conclusions wider use of contrast-enhanced ultrasound has the potential to save healthcare costs after first ultrasound detection of a single small nodule in cirrhosis.

The aim of this study was to identify the most common patterns of various common liver lesions at real-time contrast-enhanced ultrasonography with second-generation contrast agents and their role in the differentiation of malignant from benign lesions.The enhancement pattern in the arterial phase and its modifications in subsequent portal and sinusoidal phases were separately evaluated in (i) 171 liver lesions detected at conventional ultrasonography in 125 noncirrhotic patients (87 metastases, six cholangiocellular carcinoma, 38 focal nodular hyperplasia, 30 hemangiomas, seven focal fatty sparing/changes, two hepatocellular adenomas and one hepatocellular carcinoma) and (ii) 75 lesions detected in 67 cirrhotic patients (66 hepatocellular carcinoma and nine dysplastic nodules). The final diagnosis was made by contrast-enhanced helical computed tomography and/or magnetic resonance imaging or by ultrasonography-guided biopsy when the diagnosis was equivocal at conventional imaging techniques (45 lesions).In noncirrhotic patients, the hypoechoic pattern in portal and sinusoidal phase (rapid washout) or the markedly hypoechoic or anechoic pattern in sinusoidal phase (marked late washout) showed a sensitivity, specificity and accuracy of 96.8, 100 and 98.2% for the diagnosis of malignancy. In cirrhotic patients, early arterial enhancement showed a sensitivity of 93.9% for the diagnosis of malignancy, with a specificity as low as 55.5% given the presence of arterial enhancement in 5/9 nodules resulted dysplastic at histological analysis.Real-time contrast-enhanced ultrasonography provides sensitive and specific criteria for the differential diagnosis between benign and malignant liver lesions, and in most cases it may replace more expensive and invasive imaging techniques.

The action pathways of nitrates are hypothesised to be deranged in cirrhosis.In order to confirm it, the acute haemodynamic effects of isosorbide-5-mononitrate in cirrhotic patients and controls was investigated.Nine cirrhotics and nine healthy controls.Evaluation in the fasting state, 90 min after isosorbide-5-mononitrate or placebo (double-blind on two different days) and then 30 and 120 min after eating a standard meal. Various systemic and splanchnic haemodynamic parameters, including arterial impedance, assessed as Doppler pulsatility index, were measured.isosorbide-5-mononitrate reduced arterial pressure and increased heart rate and mesenteric pulsatility index both in controls and in cirrhotics, whereas the following parameters behaved differently in the two groups (P0.05): hepatic pulsatility index decreased (-9%) and the portal velocity increased (+13%) in controls, whereas hepatic pulsatility increased (+18%) and portal velocity decreased (-18%) in cirrhotics. The two groups presented a similar pattern of changes in most variables under placebo after a meal. In controls, the administration of isosorbide-5-mononitrate blunted the postprandial mesenteric vasodilation and related changes in splanchnic and systemic circulation, expected at 30 min, in comparison to those observed under placebo. In cirrhotics, instead, the postprandial pattern was similar under placebo and isosorbide-5-mononitrate.The acute administration of isosorbide-5-mononitrate produces different haemodynamic effects in healthy and diseased livers, both in the fasting state and after a meal, consistent with the hypothesis of a deranged response of the intrahepatic microcirculation to nitrates in cirrhosis.