Metabolic dysfunction outperforms ultrasonographic steatosis to stratify hepatocellular carcinoma risk in patients with advanced hepatitis C cured with direct-acting antivirals.

BACKGROUND AND AIMS: Metabolic dysfunction (MD)-associated fatty liver disease has been proposed to identify individuals at risk of liver events irrespectively of the contemporary presence of other liver diseases. The aim of this study was to examine the impact of MD in patients cured of chronic hepatis C (CHC). PATIENTS AND METHODS: We analysed data from a real-life cohort of 2611 Italian patients cured of CHC with direct antiviral agents and advanced liver fibrosis, without HBV/HIV, transplantation and negative for hepatocellular carcinoma (HCC) history (age 61.4 ± 11.8 years, 63.9% males, median follow-up 34, 24-40 months). Information about ultrasonographic steatosis (US) after sustained virological response was available in 1978. RESULTS: MD affected 58% of patients, diagnosed due to the presence of diabetes (MD-diabetes, 19%), overweight without diabetes (MD-overweight, 37%) or multiple metabolic abnormalities without overweight and diabetes (MD-metabolic, 2%). MD was more frequent than and not coincident with US (32% MD-only, 23% MD-US and 13% US-only). MD was associated with higher liver stiffness (p < 0.05), particularly in patients with MD-diabetes and MD-only subgroups, comprising older individuals with more advanced metabolic and liver disease (p < 0.05). At Cox proportional hazard multivariable analysis, MD was associated with increased risk of HCC (HR 1.97, 95% CI 1.27-3.04; p = 0.0023). Further classification according to diagnostic criteria improved risk stratification (p < 0.0001), with the highest risk observed in patients with MD-diabetes. Patients with MD-only appeared at highest risk since the sustained virological response achievement (p = 0.008), with a later catch-up of those with combined MD-US, whereas US-only was not associated with HCC. CONCLUSIONS: MD is more prevalent than US in patients cured of CHC with advanced fibrosis and identifies more accurately individuals at risk of developing HCC.

Histological and serological features of acute liver injury after SARS-CoV-2 vaccination.

Background & Aims: Liver injury with autoimmune features after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is increasingly reported. We investigated a large international cohort of individuals with acute hepatitis arising after SARS-CoV-2 vaccination, focusing on histological and serological features. Methods: Individuals without known pre-existing liver diseases and transaminase levels ≥5x the upper limit of normal within 3 months after any anti-SARS-CoV-2 vaccine, and available liver biopsy were included. Fifty-nine patients were recruited; 35 females; median age 54 years. They were exposed to various combinations of mRNA, vectorial, inactivated and protein-based vaccines. Results: Liver histology showed predominantly lobular hepatitis in 45 (76%), predominantly portal hepatitis in 10 (17%), and other patterns in four (7%) cases; seven had fibrosis Ishak stage ≥3, associated with more severe interface hepatitis. Autoimmune serology, centrally tested in 31 cases, showed anti-antinuclear antibody in 23 (74%), anti-smooth muscle antibody in 19 (61%), anti-gastric parietal cells in eight (26%), anti-liver kidney microsomal antibody in four (13%), and anti-mitochondrial antibody in four (13%) cases. Ninety-one percent were treated with steroids ± azathioprine. Serum transaminase levels improved in all cases and were normal in 24/58 (41%) after 3 months, and in 30/46 (65%) after 6 months. One patient required liver transplantation. Of 15 patients re-exposed to SARS-CoV-2 vaccines, three relapsed. Conclusion: Acute liver injury arising after SARS-CoV-2 vaccination is frequently associated with lobular hepatitis and positive autoantibodies. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. A close follow-up is warranted to assess the long-term outcomes of this condition. Impact and implications: Cases of liver injury after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have been published. We investigated a large international cohort of individuals with acute hepatitis after SARS-CoV-2 vaccination, focusing on liver biopsy findings and autoantibodies: liver biopsy frequently shows inflammation of the lobule, which is typical of recent injury, and autoantibodies are frequently positive. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. Close follow-up is warranted to assess the long-term outcome of this condition.

Dysmetabolism, Diabetes and Clinical Outcomes in Patients Cured of Chronic Hepatitis C: A Real-Life Cohort Study.

The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real-life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE-Lombardia registry). In a subset (n = 748), liver stiffness measurement (LSM) was available at baseline and follow-up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m2 , 1.03-1.09) and diabetes (OR 2.01 [1.65-2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35-0.60]; P < 0.0001 for all). The impact of BMI was greater in those without diabetes (P = 0.003). Diabetes was independently associated with less pronounced LSM improvement after viral eradication (P = 0.001) and in patients with advanced fibrosis was an independent predictor of the most frequent clinical events, namely de novo hepatocellular carcinoma (HCC; hazard ratio [HR] 2.09 [1.20-3.63]; P = 0.009) and cardiovascular events (HR 2.73 [1.16-6.43]; P = 0.021). Metformin showed a protective association against HCC (HR 0.32 [0.11-0.96]; P = 0.043), which was confirmed after adjustment for propensity score (P = 0.038). Diabetes diagnosis further refined HCC prediction in patients with compensated advanced chronic liver disease at high baseline risk (P = 0.024). Conclusion: Metabolic comorbidities were associated with advanced liver fibrosis at baseline, whereas statins were protective. In patients with advanced fibrosis, diabetes increased the risk of de novo HCC and of cardiovascular events. Optimization of metabolic comorbidities treatment by a multi-disciplinary management approach may improve cardiovascular and possibly liver-related outcomes.

Surveillance for hepatocellular carcinoma at the community level: Easier said than done.

Surveillance for hepatocellular carcinoma (HCC) in high-risk patients with semiannual ultrasound examinations is advocated by all international guidelines. However, as long as the identification of the population to be screened and the surveillance programs are not well implemented, the real-life impact of HCC surveillance in reducing mortality for HCC cannot be known. We propose a new approach that promotes the identification of cirrhotic patients by primary care physicians (PCPs) and referral of patients to the hepatologist for surveillance. Surveillance should be incorporated, when feasible, in a hub and spoke model of comprehensive hepatology care. Training PCPs to identify cirrhotic patients and performing surveillance in a subspecialist setting are equally important to improve the effectiveness of real-life surveillance and to decrease HCC mortality over time.

Immune and cellular damage biomarkers to predict COVID-19 mortality in hospitalized patients.

Early prediction of COVID-19 in-hospital mortality relies usually on patients' preexisting comorbidities and is rarely reproducible in independent cohorts. We wanted to compare the role of routinely measured biomarkers of immunity, inflammation, and cellular damage with preexisting comorbidities in eight different machine-learning models to predict mortality, and evaluate their performance in an independent population. We recruited and followed-up consecutive adult patients with SARS-Cov-2 infection in two different Italian hospitals. We predicted 60-day mortality in one cohort (development dataset, n = 299 patients, of which 80% was allocated to the development dataset and 20% to the training set) and retested the models in the second cohort (external validation dataset, n = 402). Demographic, clinical, and laboratory features at admission, treatments and disease outcomes were significantly different between the two cohorts. Notably, significant differences were observed for %lymphocytes (p < 0.05), international-normalized-ratio (p < 0.01), platelets, alanine-aminotransferase, creatinine (all p < 0.001). The primary outcome (60-day mortality) was 29.10% (n = 87) in the development dataset, and 39.55% (n = 159) in the external validation dataset. The performance of the 8 tested models on the external validation dataset were similar to that of the holdout test dataset, indicating that the models capture the key predictors of mortality. The shap analysis in both datasets showed that age, immune features (%lymphocytes, platelets) and LDH substantially impacted on all models' predictions, while creatinine and CRP varied among the different models. The model with the better performance was model 8 (60-day mortality AUROC 0.83 ± 0.06 in holdout test set, 0.79 ± 0.02 in external validation dataset). The features that had the greatest impact on this model's prediction were age, LDH, platelets, and %lymphocytes, more than comorbidities or inflammation markers, and these findings were highly consistent in both datasets, likely reflecting the virus effect at the very beginning of the disease.

High rates of sustained virological response despite premature discontinuation of directly acting antivirals in HCV-infected patients treated in a real-life setting.

In routine clinical practice, hepatitis C virus-infected patients can prematurely discontinue the prescribed regimen for several reasons. The aim of our study was to investigate sustained virological response (SVR12) rates in patients who prematurely discontinued directly acting antiviral (DAA) regimens and to assess the shortest effective duration of DAA able to lead to SVR12. We retrospectively collected the SVR rates of patients, registered in the NAVIGATORE-Lombardia Network database from January 2015, who discontinued DAAs before the predefined end of treatment. Overall, we included 365 patients, males were the majority (213, 58.4%), mean age was 60.5 years, and 53 (14.5%) patients were HIV-co-infected. Liver cirrhosis was observed in 251 (68.8%) subjects, and the most represented genotypes were 1b (n = 168, 46%) and 3 (n = 59, 16.2%). DAA was discontinued a median of 1 (IQR 1-4) weeks before the predefined EOT, with 164 (44.9%) patients stopping DAAs at least 2 weeks before the planned schedule. In patients with F0-F3 liver fibrosis, lower rates of SVR12 were observed in patients treated for <4 weeks: 50% (n = 2/4) vs. 99.1% (n = 109/110) for ≥4 weeks, p = 0.003. In patients with liver cirrhosis, lower rates of SVR12 were observed in patients treated <8 weeks: 83.3% (n = 25/30) vs. 94.6% (n = 209/221) for ≥8 weeks, p = 0.038. Despite premature discontinuation of DAA, high SVR12 rates were observed in a real-life setting for treatment lasting at least 4 weeks in patients with liver fibrosis F0-F3 and 8 weeks in those with liver cirrhosis. On this basis, feasibility of reducing DAA treatment duration should be explored in randomized clinical trials.

High rates of 30-day mortality in patients with cirrhosis and COVID-19.

BACKGROUND & AIMS: Coronavirus disease 2019 (COVID-19) poses a major health threat to healthy individuals and those with comorbidities, but its impact on patients with cirrhosis is currently unknown. Herein, we aimed to evaluate the impact of COVID-19 on the clinical outcome of patients with cirrhosis. METHODS: In this multicentre retrospective study, patients with cirrhosis and a confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection were enrolled between 1st and 31th March 2020. Clinical and biochemical data at diagnosis of COVID-19 and at the last outpatient visit were obtained through review of medical records. RESULTS: Fifty patients with cirrhosis and confirmed SARS-CoV-2 infection were enrolled (age 67 years, 70% men, 38% virus-related, 52% previously compensated cirrhosis). At diagnosis, 64% of patients presented fever, 42% shortness of breath/polypnea, 22% encephalopathy, 96% needed hospitalization or a prolonged stay if already in hospital. Respiratory support was necessary in 71%, 52% received antivirals, 80% heparin. Serum albumin significantly decreased, while bilirubin, creatinine and prothrombin time significantly increased at COVID-19 diagnosis compared to last available data. The proportion of patients with a model for end-stage liver disease (MELD) score ≥15 increased from 13% to 26% (p = 0.037), acute-on-chronic liver failure and de novo acute liver injury occurred in 14 (28%) and 10 patients, respectively. Seventeen patients died after a median of 10 (4-13) days from COVID-19 diagnosis, with a 30-day-mortality rate of 34%. The severity of lung and liver (according to CLIF-C, CLIF-OF and MELD scores) diseases independently predicted mortality. In patients with cirrhosis, mortality was significantly higher in those with COVID-19 than in those hospitalized for bacterial infections. CONCLUSION: COVID-19 is associated with liver function deterioration and elevated mortality in patients with cirrhosis. LAY SUMMARY: Coronavirus disease 2019 (COVID-19) poses a major health threat to healthy individuals and those with comorbidities. Herein, we assessed its impact on patients with cirrhosis. Infection with COVID-19 was associated with liver function deterioration and elevated mortality in patients with cirrhosis.

Comparison of three therapeutic regimens for genotype-3 hepatitis C virus infection in a large real-life multicentre cohort.

BACKGROUND & AIMS: In the direct-acting antiviral era, treatment of genotype-3 HCV (HCV-GT3) is still challenging. Real-life comparisons between recommended regimens, sofosbuvir (SOF)+daclatasvir (DAC), SOF/velpatasvir (VEL), glecaprevir/pibrentasvir (GLE/PIB), are scarce. We aimed at filling this data gap. METHODS: Sustained virological response 12 weeks after treatment completion (SVR12) was assessed for all HCV-GT3 patients consecutively treated within the Lombardia web-based Navigatore HCV-Network; differences in SVR12 across regimens were evaluated by logistic regression. RESULTS: Of the 2082 subjects with HCV-GT3, 1544 were evaluable for comparisons between regimens: SOF + DAC (1023, 66.2%), SOF/VEL (369, 23.9%), GLE/PIB (152, 9.8%). Patients treated with former regimens were more frequently male, cirrhotic, HIV-positive, pretreated, used ribavirin in their regimen, and had lower baseline HCV-RNA. SVR12 was similar across groups: 94.8% in SOF + DAC, 97.6% in SOF/VEL, 96.7% in GLE/PIB (P = .065). At univariate analysis, SVR12 was associated with female gender (97.9% vs 94.8%, P = .007) and lower median pretreatment Log10 HCV-RNA (5.87 vs 6.20, P = .001). At multivariate logistic regression analysis, treatment with SOF/VEL was associated with a higher likelihood of SVR12 than SOF + DAC, but only in the absence of ribavirin (98% vs 90.3%). Female gender and lower pretreatment HCV-RNA were independently associated with SVR12. CONCLUSIONS: In a large real-life setting of HCV-GT3-infected patients with a high proportion of cirrhosis, the success rate was remarkable. The slight advantage of SOF/VEL on SOF + DAC was significant only without ribavirin. The current prescription shift towards novel regimens (ie SOF/VEL and GLE/PIB) in easier-to-treat patients allows ribavirin-free and shorter schedules without mining SVR12 in this <> genotype.

Real-world effectiveness and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C.

BACKGROUND AND AIMS: The efficacy and safety of glecaprevir/pibrentasvir (G/P) for patients infected with hepatitis C virus (HCV) have only been investigated in clinical trials, with no real-world data currently available. The aim of our study was to investigate the effectiveness and safety of G/P in a real-world setting. METHODS: All patients with HCV consecutively starting G/P between October 2017 and January 2018 within the NAVIGATORE-Lombardia Network were analyzed. G/P was administered according to drug label (8, 12 or 16 weeks). Fibrosis was staged either histologically or by liver stiffness measurement. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks after the end of treatment. RESULTS: A total of 723 patients (50% males) were treated with G/P, 89% for 8 weeks. The median age of our cohort was 58 years, with a median body mass index of 23.9 kg/m2, and median liver stiffness measurement of 6.1 kPa; 84% were F0-2 and 16% were interferon-experienced. Median HCV-RNA was 1,102,600 IU/ml, and 49% of patients had HCV genotype 1 (32% 1b), 28% genotype 2, 10% genotype 3 and 13% genotype 4. The median estimated glomerular filtration rate was 90.2 ml/min, platelet count 209x103/mm3 and albumin 4.3 g/dl. The SVR rates were 94% in intention-to-treat and 99.3% in per protocol analysis (8-week vs. 12 or 16-week: 99.2% vs. 100%). Five patients failed therapy because of post-treatment relapse; a post-treatment NS5A resistance-associated substitution was detected in 1 case. SVR rates were lower in males (p = 0.002) and in HCV genotype-3 (p = 0.046) patients treated for 8 weeks, but independent of treatment duration, fibrosis stage, baseline HCV-RNA, HIV co-infection, chronic kidney disease stage and viral kinetics. Mild adverse events were reported in 8.3% of the patients, and 0.7% of them prematurely withdrew treatment. Three patients died of drug-unrelated causes. CONCLUSIONS: In a large real-world cohort of Italian patients, we confirmed the excellent effectiveness and safety of G/P administered for 8, 12 or 16 weeks. LAY SUMMARY: A large number of patients with hepatitis C virus have been treated with glecaprevir/pibrentasvir (G/P) within the NAVIGATORE-Lombardia Network, in Italy. This is the first real-world study evaluating effectiveness and safety of G/P in patients with hepatitis C virus treated according to international recommendations. This study demonstrated excellent effectiveness (with sustained virological response rates of 99.3%) and safety profiles.

Range of Normal Liver Stiffness and Factors Associated With Increased Stiffness Measurements in Apparently Healthy Individuals.

BACKGROUND & AIMS: Transient elastography (TE) is a noninvasive technique used to measure liver stiffness to estimate the severity of fibrosis. The range of liver stiffness measurements (LSMs) in healthy individuals is unclear. We performed a systematic review to determine the range of LSMs, examined by TE, in healthy individuals and individuals who are susceptible to fibrosis. METHODS: We collected data from 16,082 individuals, in 26 cohorts, identified from systematic searches of Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for studies of liver stiffness measurements. Studies analyzed included apparently healthy adults (normal levels of liver enzymes, low-risk alcohol use patterns, and negative for markers of viral hepatitis). The presence of diabetes, hypertension, dyslipidemia, or steatosis, based on ultrasound examination, was known for most participants. We performed a meta-analysis of data from individual participants. The cohort was divided into 4 groups; participants with a body mass index <30 kg/m2 were examined with the medium probe and those with a body mass index ≥30 kg/m2 were examined with the extra-large probe. Linear regression models were conducted after adjusting for potential confounding factors of LSMs. We performed several sensitivity analyses. RESULTS: We established LSM ranges for healthy individuals measured with both probes-these did not change significantly in sensitivity analyses of individuals with platelets ≥150,000/mm3 and levels of alanine aminotransferase ≤33 IU/L in men or ≤25 IU/L in women. In multivariate analysis, factors that modified LSMs with statistical significance included diabetes, dyslipidemia, waist circumference, level of aspartate aminotransferase, and systolic blood pressure at examination time. Significant increases in LSMs were associated with the metabolic syndrome in individuals examined by either probe. Diabetes in obese individuals increased the risk of LSMs in the range associated with advanced fibrosis. CONCLUSIONS: In a systematic review and meta-analysis of data from individual participants, we established a comprehensive set of LSM ranges, measured by TE in large cohorts of healthy individuals and persons susceptible to hepatic fibrosis. Regression analyses identified factors associated with increased LSMs obtained by TE with the medium and extra-large probes.

A training program for primary care physicians improves the effectiveness of ultrasound surveillance of hepatocellular carcinoma.

BACKGROUND AND AIMS: Cirrhosis is the main risk factor of hepatocellular carcinoma (HCC), but only a minority of cirrhotic patients are referred to the hepatologist by primary care physicians (PCP) and receive regular ultrasound surveillance. The aim of this study was to determine whether a training program targeted to PCP could enhance the effectiveness of surveillance in a real-life setting. PATIENTS AND METHODS: A total of 120 PCP in an Italian area with a high incidence of HCC were trained to identify cirrhotic patients, to refer them to the Hepatology Centers of the area, and to start regular ultrasound surveillance. Clinical characteristics, outcome of treatments, and survival of 190 consecutive HCC patients in the same centers after training were compared with 244 HCC referred from the same area before training, and to 232 HCC referred by untrained PCP from other areas. RESULTS: Trained PCP referred significantly more HCC patients detected under surveillance and at an early stage (Barcelona Clinic Liver Cancer-A), suitable for radical treatments. In the intervention area, the 3 and 5-year survival of HCC patients increased after training from 35 to 48% and from 20 to 40%, respectively (P<0.05). In contrast, survival was unchanged in the other areas. At multivariate analysis, independent predictors adversely affecting survival were Child-Pugh B-C, α-fetoprotein more than 10 ng/dl, nonviral etiology, intermediate/advanced Barcelona Clinic Liver Cancer stage, and referral by an untrained PCP. CONCLUSION: Specific training of PCP aimed at the identification and referral of cirrhotic patients efficiently improves HCC survival.

BCLC stage B hepatocellular carcinoma and transcatheter arterial chemoembolization: a 20-year survey by the Italian Liver Cancer group.

BACKGROUND & AIMS: Significant proportion of Hepatocellular Carcinoma (HCC) cases are diagnosed in stage B of Barcelona Clinic Liver Cancer (BCLC) algorithm, in which the standard of care is Transcatheter Arterial ChemoEmbolization (TACE). We aimed to ascertain adherence to current guidelines, survival and prognostic factors in BCLC stage B patients. METHODS: From 3027 HCC cases recruited from 1986 to 2008 by the Italian Liver Cancer group (2430 with data allowing a correct allocation in the BCLC system), a retrospective analysis was conducted on those diagnosed in BCLC stage B (405 patients, 17%). Statistics were performed with Kaplan-Meier (log rank) method and Cox multivariate analysis. RESULTS: Median overall survival in BCLC stage B patients was 25 months (Confidence Interval - C.I. - 22-28 months) with a 5-year survival of 18%. Child-Pugh class, oesophageal varices and Alpha-foetoprotein (AFP) were the independent predictors of survival. TACE was applied in 40% of cases and did not offer the longest survival in comparison with surgical or percutaneous treatments (median 27 months vs. 37 and 36 months, respectively) (P < 0.001). BCLC stage B patients undergoing radical treatments were more frequently in Child-Pugh class A and had a significantly lower number of lesions; patients undergoing best supportive care were frequently in Child-Pugh class B and had a multifocal disease. Survival after TACE did not significantly increase over time. CONCLUSIONS: In clinical practice, TACE cannot be considered the best approach for BCLC stage B patients who represent a heterogeneous population and are often suitable for more aggressive therapies, which lead to a better survival.

Factors that affect efficacy of ultrasound surveillance for early stage hepatocellular carcinoma in patients with cirrhosis.

BACKGROUND & AIMS: Ultrasound surveillance does not detect early stage hepatocellular carcinomas (HCCs) in some patients with cirrhosis, although the reasons for this have not been well studied. We assessed the rate at which ultrasound fails to detect early stage HCCs and factors that affect its performance. METHODS: We collected information on 1170 consecutive patients included in the Italian Liver Cancer (ITA.LI.CA) database who had Child-Pugh A or B cirrhosis and were diagnosed with HCC during semiannual or annual ultrasound surveillance, from January 1987 through December 2008. Etiologies included hepatitis C virus infection (59.3%), alcohol abuse (11.3%), hepatitis B virus infection (9%), a combination of factors (15.6%), and other factors (4.7%). Surveillance was considered to be a failure when patients were diagnosed with HCC at a stage beyond the Milan criteria (1 nodule ≤5 cm or ≤3 nodules each ≤3 cm). RESULTS: HCC was found beyond Milan criteria in 34.3% of surveilled patients (32.2% during semi-annual surveillance and 41.3% during annual surveillance; P < .01). Nearly half of surveillance failures were associated with at least one indicator of aggressive HCC (levels of AFP >1000 ng/mL, infiltrating tumors, or vascular invasion and metastases). Semiannual surveillance, female sex, Child-Pugh class A, and α-fetoprotein levels of 200 ng/mL or less were associated independently with successful ultrasound screening for HCC. CONCLUSIONS: Based on our analysis of surveillance for HCC in patients with cirrhosis, the efficacy of ultrasound-based screening is acceptable. Ultrasound was least effective in identifying aggressive HCC, and at surveillance intervals of more than 6 months.

Hepatocellular carcinoma in patients without cirrhosis in Italy.

BACKGROUND: In the Western world, hepatocellular carcinoma seldom develops in patients without cirrhosis, and reports describing the characteristics of non-cirrhotic patients with hepatocellular carcinoma are rather infrequent. METHODS: We evaluated the main clinical characteristics, treatment options, and survival of patients with hepatocellular carcinoma developed in non-cirrhotic liver among the 3027 consecutive cases of hepatocellular carcinoma accrued in the Italian Liver Cancer database during the last 20 years. RESULTS: We identified 52 patients with hepatocellular carcinoma in non-cirrhotic livers (1.7% of all hepatocellular carcinomas), 42 with (80.8%) and 10 without (19.2%) chronic liver disease. In patients without chronic liver disease, median tumour diameter was greater compared to patients with chronic liver disease (7.8 versus 4.0 cm, P=0.046). Curative treatment was feasible in 20 patients (38.5%). Median overall survival was 26 months and 5-year survival rate was 23.7%. Detection of hepatocellular carcinoma outside surveillance (P=0.036), advanced hepatocellular carcinoma stage (P<0.0001), and non-curative treatment (P=0.007) were associated with worse prognosis, but tumour stage was the only independent predictor of survival. CONCLUSIONS: In Italy, less than 2% of hepatocellular carcinomas develop in a non-cirrhotic liver, and almost never in a normal liver. These patients frequently present with advanced tumours, have low eligibility rates for curative treatment, and have a dismal prognosis despite their preserved liver function.

Alpha-fetoprotein has no prognostic role in small hepatocellular carcinoma identified during surveillance in compensated cirrhosis.

UNLABELLED: Alpha-fetoprotein is a tumor marker that has been used for surveillance and diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. The prognostic capability of this marker in patients with HCC has not been clearly defined. In this study our aim was to evaluate the prognostic usefulness of serum alpha-fetoprotein in patients with well-compensated cirrhosis, optimal performance status, and small HCC identified during periodic surveillance ultrasound who were treated with curative intent. Among the 3,027 patients included in the Italian Liver Cancer study group database, we selected 205 Child-Pugh class A and Eastern Cooperative Group Performance Status 0 patients with cirrhosis with a single HCC ≤ 3 cm of diameter diagnosed during surveillance who were treated with curative intent (hepatic resection, liver transplantation, percutaneous ethanol injection, radiofrequency thermal ablation). Patients were subdivided according to alpha-fetoprotein serum levels (i.e., normal ≤ 20 ng/mL; mildly elevated 21-200 ng/mL; markedly elevated >200 ng/mL). Patient survival, as assessed by the Kaplan-Meier method, was not significantly different among the three alpha-fetoprotein classes (P = 0.493). The same result was obtained in the subgroup of patients with a single HCC ≤ 2 cm (P = 0.714). An alpha-fetoprotein serum level of 100 ng/mL identified by receiver operating characteristic curve had inadequate accuracy (area under the curve = 0.536, 95% confidence interval = 0.465-0.606) to discriminate between survivors and deceased patients. CONCLUSION: Alpha-fetoprotein serum levels have no prognostic meaning in well-compensated cirrhosis patients with single, small HCC treated with curative intent.

Head-to-head comparison of transient elastography (TE), real-time tissue elastography (RTE), and acoustic radiation force impulse (ARFI) imaging in the diagnosis of liver fibrosis.

BACKGROUND: Real-time tissue elastography (RTE), acoustic radiation force impulse (ARFI) imaging, and transient elastography (TE) are new technologies that are used for liver stiffness evaluation. The aim of this study was to compare these methods in the same population and to determine their diagnostic accuracy in the prediction of liver fibrosis. METHODS: Forty-five consecutive, previously biopsied, patients with chronic liver disease and 27 normal subjects underwent TE, RTE, and ARFI on the right liver lobe. Correlation coefficients between measurements, Metavir fibrosis stage, and histological necro-inflammatory activity (adjusted for fibrosis stage) were evaluated via Spearman's rank order correlation coefficients. Areas under the receiver operating characteristic curve (AUROCs) were calculated to predict each fibrosis stage. RESULTS: Failure or inconsistent results occurred in 12.5% of the attempts at TE, but in none of the attempts at RTE and ARFI. The three methods showed high correlation with fibrosis and poor correlation with necro-inflammatory activity. TE and ARFI exhibited high diagnostic accuracy (AUROCs ≥0.9) in diagnosing cirrhosis (F4 Metavir). All three methods presented fair (AUROCs >0.7) to good (AUROCs >0.8) diagnostic accuracy in diagnosing fibrosis (F1-4 Metavir) and significant fibrosis (F2-4 Metavir), with TE showing the best performance (AUROCs were 0.878 for fibrosis and 0.897 for significant fibrosis). CONCLUSIONS: TE and ARFI provide high diagnostic accuracy in the diagnosis of cirrhosis. When feasible, TE may perform better than RTE and ARFI in predicting fibrosis and significant fibrosis, but larger studies are needed.

The changing scenario of hepatocellular carcinoma over the last two decades in Italy.

BACKGROUND & AIMS: This study investigates whether the aetiologic changes in liver disease and the improved management of hepatocellular carcinoma (HCC) have modified the clinical scenario of this tumour over the last 20 years in Italy. METHODS: Retrospective study based on the analysis of the ITA.LI.CA (Italian Liver Cancer) database including 3027 HCC patients managed in 11 centres. Patients were divided into 3 groups according to the period of HCC diagnosis: 1987-1996 (year of the "Milano criteria" publication), 1997-2001 (year of release of the EASL guidelines for HCC), and 2002-2008. RESULTS: The significant changes were: (1) progressive patient ageing; (2) increasing prevalence of HCV infection until 2001, with a subsequent decrease, when the alcoholic aetiology increased; (3) liver function improvement, until 2001; (4) increasing "incidental" at the expense of "symptomatic" diagnoses, until 2001; (5) unchanged prevalence of tumours diagnosed during surveillance (around 50%), with an increasing use of the 6-month schedule; (6) favourable HCC "stage migration", until 2001; (7) increasing use of percutaneous ablation; (8) improving survival, until 2001. CONCLUSIONS: Over the last 20 years, several aetiologic and clinical features regarding HCC have changed. The survival improvement observed until 2001 was due to an increasing number of tumours diagnosed in early stages and in a background of compensated cirrhosis, and a growing and better use of locoregional treatments. However, the prevalence of early cancers and survival did not increase further in the last years, a result inciting national policies aimed at implementing surveillance programmes for at risk patients.

Liver transplantation for hepatocellular carcinoma in clinical practice: the lesson from a 20-year multicentre experience in Italy.

INTRODUCTION: Hepatocellular carcinoma (HCC) is an established indication for liver transplantation (LT), but the selection criteria and priority are still debated. AIMS: To ascertain the number and features of patients with HCC who undergo transplantation in a Western country, the number of patients eligible for LT according to the American Association for the Study of Liver Diseases (AASLD) guidelines, the number of patients who actually undergo transplantation and whether adherence affects survival. METHODS: This is a retrospective analysis from a multicentre Italian database of 2042 cases of HCC, recruited prospectively and consecutively. Kaplan-Meier (log rank) and Cox multivariate analysis estimated survival. RESULTS: Patients who had undergone transplantation (50, 2.5%, with no change over time) had a median survival of 133 months, significantly influenced by the number of lesions and alpha-fetoprotein levels, which were found to be independent predictors of survival on multivariate analysis. Milan criteria were fulfilled in 68%, impacting on survival, whereas 48% fulfilled AASLD guidelines, without such an impact. Two hundred and twenty-eight (11%) patients were eligible for LT according to AASLD; in this group, alpha-fetoprotein levels and Child-Pugh class were independent predictors of survival. CONCLUSION: Among patients with HCC, those undergoing LT represent a small minority; even fewer (1%) are those who undergo transplantation according to AASLD guidelines, adherence to which only marginally affects survival. Overall, LT impact on HCC patients' treatment is very limited.