Liver Transplantation in People Living with HIV: Still an Experimental Procedure or Standard of Care?

Liver transplantation (LT) is the only curative treatment for various liver diseases, including acute liver failure, end-stage liver disease, and selected unresectable liver malignancies. Combination antiretroviral therapy has improved outcomes for people living with HIV (PLWH), transforming the status of acquired immune deficiency syndrome from a fatal disease to a chronic and manageable condition. These powerful antiviral therapies have not only increased the number of HIV+ enlisted patients by improving their survival but also made the use of HIV+ organs a viable option. In this review, we summarise current knowledge on the peculiarities of liver transplantation in PLWH. In particular, we focus on the indications, contraindications, specific considerations for treatment, and outcomes of LT in PLWH. Finally, we present available preliminary data on the use of HIV+ liver allografts.

Long-Term Impact of Direct-Acting Antivirals on Liver Fibrosis and Survival in HCV-Infected Liver Transplant Recipients.

(1) Background: Little is known about the long-term impact of sustained virological response (SVR) on fibrosis progression and patient survival in liver transplantation (LT) recipients treated with direct-acting antivirals (DAAs). We investigated liver fibrosis evolution and patient survival in hepatitis C virus (HCV)-infected patients receiving DAAs after LT. (2) Methods: All consecutive HCV-infected patients treated with DAAs after LT between May 2014 and January 2019 were considered. The clinical and virological features were registered at the baseline and during the follow-up. The liver fibrosis was assessed by liver biopsy and/or transient elastography (TE) at the baseline and at least 1 year after the end of treatment (EoT). (3) Results: A total of 136 patients were included. The SVR12 was 78% after the first treatment and 96% after retreatment. After the SVR12, biochemical tests improved at the EoT and remained stable throughout the 3-year follow-up. Liver fibrosis improved after the SVR12 (p < 0.001); nearly half of the patients with advanced liver fibrosis experienced an improvement of an F ≤ 2. The factors associated with lower survival in SVR12 patients were the baseline platelet count (p = 0.04) and creatinine level (p = 0.04). (4) Conclusions: The long-term follow-up data demonstrated that SVR12 was associated with an improvement in hepatic function, liver fibrosis, and post-LT survival, regardless of the baseline liver fibrosis. The presence of portal hypertension before the DAAs has an impact on patient survival, even after SVR12.

Main factors influencing long-term outcomes of liver transplantation in 2022.

Liver transplant (LT) outcomes have markedly improved in the recent decades, even if long-term morbidity and mortality are still considerable. Most of late deaths are independent from graft function and different comorbidities, including complications of metabolic syndrome and de novo neoplasms, seem to play a key role in determining long-term outcomes in LT recipients. This review discusses the main factors associated with late mortality and suggests possible strategies to improve long-term management and follow-up after liver transplantation. In particular, the reduction of drug toxicity, the use of tools to identify high-risk patients, and setting up a multidisciplinary team also for long-term management of LT recipients may further improve survival after liver transplantation.

Correlation of Ultrasound Scores with Endoscopic Activity in Crohn's Disease: A Prospective Exploratory Study.

BACKGROUND AND AIMS: Intestinal ultrasound [IUS] is widely accepted as a reliable tool to monitor Crohn's disease [CD]. Several IUS scores have been proposed, but none has been formally accepted by international organizations. Our aim here was to compare the available scores regarding their correlation with endoscopic activity. METHODS: Consenting CD patients undergoing ileocolonoscopy at our Unit between September 2021 and February 2023 were included. Endoscopic activity was defined as SES-CD ≥ 3 or Rutgeerts score ≥ i2b for operated patients. IUS was performed within 6 weeks of endoscopy and scored with IBUS-SAS, BUSS, Simple-US and SUS-CD scores. All correlations were performed using Spearman's rank coefficient [rho = ρ]. Receiver operating characteristic [ROC] curves were compared with the Hanley and McNeil method. RESULTS: Of 73 CD patients, 45 [61.6%] presented endoscopic activity, of whom 22 were severe [30.1%]. All IUS scores showed a significant positive correlation with endoscopy [p < 0.0001], with IBUS-SAS ranking the highest [ρ = 0.87]. Similarly, IBUS-SAS was the most highly correlated with clinical activity [ρ = 0.58]. ROC analysis of IBUS-SAS for any endoscopic activity showed the highest area under the curve (0.95 [95% confidence interval 0.87-0.99]), with sensitivity of 82.2% and specificity of 100% for a cut-off value of 25.2. IBUS-SAS was statistically superior to all the other scores in detecting severe endoscopic activity [SES-CD ≥ 9 or Rutgeerts i4]. CONCLUSIONS: All IUS scores provided solid correlation with endoscopy and clinical symptoms. IBUS-SAS outperformed the others due to a more granular description that might help in stratifying different levels of disease activity. Therefore, the use of IBUS-SAS in centres with well-founded expertise in IUS can be suggested.

Outcomes and Follow-Up after Hepatitis C Eradication with Direct-Acting Antivirals.

Treatment of hepatitis C (HCV) has been revolutionized with the introduction of direct-acting antivirals (DAAs). Patients can be treated at more advanced stages of liver disease, with a growing number of cirrhotic patients achieving sustained virological response (SVR). Long-term outcomes for cured patients and the optimal follow-up care of patients after SVR are yet to be defined, because most studies on cirrhotic patients cured with DAAs have a short follow-up period. There are many open questions related to patient management after viral eradication with DAAs, such as which could be the most reliable non-invasive tool to predict liver-related complications, or to what extent viral eradication reduces the risk of liver disease progression in the long term. Growing evidence supports the personalization of follow-up care based on individual risk. The aim of this narrative review is to analyze the impact of viral eradication with DAAs on clinically significant portal hypertension, hepatocellular carcinoma, and extrahepatic manifestations, as well as to summarize indications for optimal follow-up care of HCV patients treated with DAAs.

Diagnostic delay in adult coeliac disease: An Italian multicentre study.

BACKGROUND: There are few data regarding the diagnostic delay and its predisposing factors in coeliac disease (CD). AIMS: To investigate the overall, the patient-dependant, and the physician-dependant diagnostic delays in CD. METHODS: CD adult patients were retrospectively enroled at 19 Italian CD outpatient clinics (2011-2021). Overall, patient-dependant, and physician-dependant diagnostic delays were assessed. Extreme diagnostic, i.e., lying above the third quartile of our population, was also analysed. Multivariable regression models for factors affecting the delay were fitted. RESULTS: Overall, 2362 CD patients (median age at diagnosis 38 years, IQR 27-46; M:F ratio=1:3) were included. The median overall diagnostic delay was 8 months (IQR 5-14), while patient- and physician-dependant delays were 3 (IQR 2-6) and 4 (IQR 2-6) months, respectively. Previous misdiagnosis was associated with greater physician-dependant (1.076, p = 0.005) and overall (0.659, p = 0.001) diagnostic delays. Neurological symptoms (odds ratio 2.311, p = 0.005) and a previous misdiagnosis (coefficient 9.807, p = 0.000) were associated with a greater extreme physician-dependant delay. Gastrointestinal symptoms (OR 1.880, p = 0.004), neurological symptoms (OR 2.313, p = 0.042), and previous misdiagnosis (OR 4.265, p = 0.000) were associated with increased extreme overall diagnostic delay. CONCLUSION: We identified some factors that hamper CD diagnosis. A proper screening strategy for CD should be implemented.

MiRNA-Based Therapies for the Treatment of Inflammatory Bowel Disease: What Are We Still Missing?

Micro-RNAs (miRNAs) are noncoding RNAs usually 24-30 nucleotides long that play a central role in epigenetic mechanisms of inflammatory diseases and cancers. Recently, several studies have assessed the involvement of miRNAs in the pathogenesis of inflammatory bowel disease (IBD) and colitis-associated neoplasia. Particularly, it has been shown that many members of miRNAs family are involved in the pathways of inflammation and fibrogenesis of IBD; therefore, their use as inflammatory and fibrosis biomarkers has been postulated. In light of these results, the role of miRNAs in IBD therapy has been proposed and is currently under investigation with many in vitro and in vivo studies, murine models, and a phase 2a trial. The accumulating data have pushed miRNA-based therapy closer to clinical practice, although many open questions remain. With this systematic review, we discuss the current knowledge about the therapeutic effects of miRNAs mimicking and inhibition, and we explore the new potential targets of miRNA family for the treatment of inflammation and fibrosis in IBD.

Micro-RNAs are involved in the pathogenesis of IBD, both during inflammation and fibrosis. Upregulation or downregulation of these RNA targets may be a therapeutic option, but several pathways are still under investigation. This review describes the main findings in the field and speculates on potential future implications.

Pregnancy outcomes in inflammatory bowel disease: Data from a large cohort survey.

OBJECTIVES: Inflammatory bowel disease (IBD) can affect young and reproductively active patients. Our aim was to analyze pregnancy outcomes in a large cohort of women with IBD. METHODS: All women with at least one pregnancy were given a questionnaire regarding the outcome of their pregnancy. They were divided into IBD pregnancies and controls depending on whether pregnancy occurred within or over 10 years prior to the diagnosis of IBD. RESULTS: Three hundred questionnaires were analyzed for a total of 478 pregnancies that led to live-born babies. Age at conception was older in IBD women than in the controls. Active smoking was more frequent in the control group. The risk of intrauterine growth restriction (IUGR) was higher in IBD pregnancies (odds ratio [OR] 3.028, 95% confidence interval [CI] 1.245-7.370, P = 0.013). The week of gestation at delivery was lower in the IBD population. And the risk of cesarean section was higher in IBD pregnancies (OR 1.963, 95% CI 1.274-3.028, P = 0.002). Among women with IBD pregnancy, the risk of preterm birth was higher in patients with active disease at the time of conception (OR 4.088, 95% CI 1.112-15.025, P = 0.030), but lower in patients who continued regular therapy during pregnancy. Similarly, the risk of urgent cesarean section was reduced in the case of disease remission, while the risk of a planned cesarean delivery was higher in patients with perianal disease (OR 11.314, 95% CI 3.550-36.058, P < 0.01). CONCLUSIONS: Our study shows a higher risk of IUGR, cesarean section, and poor blood pressure control in IBD pregnancies. We emphasize the importance of achieving disease remission before considering pregnancy.

Understanding fatigue in primary biliary cholangitis: From pathophysiology to treatment perspectives.

Fatigue is considered one of the most frequent and debilitating symptoms in primary biliary cholangitis (PBC), affecting over 50% of PBC patients. One in five patients with PBC suffer from severe fatigue, which significantly impairs quality of life. Fatigue is made up of a central and a peripheral component, whose pathophysiology is still greatly unresolved. Central fatigue is characterised by a lack of self-motivation and can manifest both in physical and mental activities (lack of intention). Peripheral fatigue includes neuromuscular dysfunction and muscle weakness (lack of ability). Peripheral fatigue could be explained by an excessive deviation from aerobic to anaerobic metabolism leading to excessive lactic acid accumulation and therefore accelerated decline in muscle function and prolonged recovery time. As opposed to itching, and with the exception of end-stage liver disease, fatigue is not related to disease progression. The objective of this review is to outline current understanding regarding the pathophysiology of fatigue, the role of comorbidities and contributing factors, the main tools for fatigue assessment, the failed therapeutic options, and future treatment perspectives for this disabling symptom. Since fatigue is an extremely common and debilitating symptom and there is still no licensed therapy for fatigue in PBC patients, further research is warranted to understand its causative mechanisms and to find an effective treatment.

Higher volume growth rate is associated with development of worrisome features in patients with branch duct-intraductal papillary mucinous neoplasms.

BACKGROUND: Branch duct-intraductal papillary mucinous neoplasms (BD-IPMNs) are the most common pancreatic cystic tumours and have a low risk of malignant transformation. Current guidelines only evaluate cyst diameter as an important risk factor but it is not always easy to measure, especially when comparing different methods. On the other side, cyst volume is a new parameter with low inter-observer variability and is highly reproducible over time. AIM: To assess both diameter and volume growth rate of BD-IPMNs and evaluate their correlation with the development of malignant characteristics. METHODS: Computed tomography scans and magnetic resonance imaging exams were retrospectively reviewed. The diameter was measured on three planes, while the volume was calculated by segmentation: The volume of the entire cyst was determined by manually drawing a region of interest along the edge of the neoplasm on each consecutive slice covering the whole lesion; therefore, a three-dimensional volume of interest was finally obtained with the calculated value expressed in cm3. Changes in size over time were measured. The development of worrisome features was evaluated. RESULTS: We evaluated exams of 98 patients across a 40.5-mo median follow-up time. Ten patients developed worrisome features. Cysts at baseline were significantly larger in patients who developed worrisome features (diameters P = 0.0035, P = 0.00652, P = 0.00424; volume P = 0.00222). Volume growth rate was significantly higher in patients who developed worrisome features (1.12 cm3/year vs 0 cm3/year, P = 0.0001); diameter growth rate was higher as well, but the difference did not always reach statistical significance. Volume but not diameter growth rate in the first year of follow-up was higher in patients who developed worrisome features (0.46 cm3/year vs 0 cm3/year, P = 0.00634). CONCLUSION: The measurement of baseline volume and its variation over time is a reliable tool for the follow-up of BD-IPMNs. Volume measurement could be a better tool than diameter measurement to predict the development of worrisome features.

Practical insights into chronic management of hepatic Wilson's disease.

Wilson's disease (WD) is a rare inherited disorder of human copper metabolism, with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric manifestations. In healthy individuals, the bile is the main route of elimination of copper. In WD patients, copper accumulates in the liver, it is released into the bloodstream, and is excreted in urine. Copper can also be accumulated in the brain, kidneys, heart, and osseous matter and causes damage due to direct toxicity or oxidative stress. Hepatic WD is commonly but not exclusively diagnosed in childhood or young adulthood. Adherent, non-cirrhotic WD patients seem to have a normal life expectancy. Nevertheless, chronic management of patients with Wilson's disease is challenging, as available biochemical tests have many limitations and do not allow a clear identification of non-compliance, overtreatment, or treatment goals. To provide optimal care, clinicians should have a complete understanding of these limitations and counterbalance them with a thorough clinical assessment. The aim of this review is to provide clinicians with practical tools and suggestions which may answer doubts that can arise during chronic management of patients with hepatic WD. In particular, it summarises current knowledge on Wilson's disease clinical and biochemical monitoring and treatment. It also analyses available evidence on pregnancy and the role of low-copper diet in WD. Future research should focus on trying to provide new copper metabolism tests which could help to guide treatment adjustments.

Quality of life in liver transplant recipients during the Corona virus disease 19 pandemic: A multicentre study.

BACKGROUND: Liver transplant recipients require specific clinical and psychosocial attention given their frailty. Main aim of the study was to assess the quality of life after liver transplant during the current pandemic. METHODS: This multicentre study was conducted in clinically stable, liver transplanted patients. Enrollment opened in June and finished in September 2021. Patients completed a survey including lifestyle data, quality of life (Short Form health survey), sport, employment, diet. To examine the correlations, we calculated Pearson coefficients while to compare subgroups, independent samples t-tests and ANOVAs. To detect the predictors of impaired quality of life, we used multivariable logistic regression analysis. RESULTS: We analysed data from 511 patients observing significant associations between quality of life's physical score and both age and adherence to Mediterranean diet (p < .01). A significant negative correlation was observed between mental score and the sedentary activity (p < .05). Female patients scored significantly lower than males in physical and mental score. At multivariate analysis, females were 1.65 times more likely to report impaired physical score than males. Occupation and physical activity presented significant positive relation with quality of life. Adherence to Mediterranean diet was another relevant predictor. Regarding mental score, female patients were 1.78 times more likely to show impaired mental score in comparison with males. Sedentary activity and adherence to Mediterranean diet were further noteworthy predictors. CONCLUSIONS: Females and subjects with sedentary lifestyle or work inactive seem to show the worst quality of life and both physical activity and Mediterranean diet might be helpful to improve it.

Effectiveness and Safety of Nonmedical Switch From Adalimumab Originator to SB5 Biosimilar in Patients With Inflammatory Bowel Diseases: Twelve-Month Follow-Up From the TABLET Registry.

BACKGROUND: Few data are currently available about SB5 in inflammatory bowel diseases (IBD). The aim of this study was to assess the effectiveness and safety of SB5 in a cohort of patients with IBD in stable remission switched from the adalimumab (ADA) originator and in a cohort of patients with IBD naïve to ADA. METHODS: We prospectively enrolled patients with IBD who started ADA treatment with SB5 (naïve cohort) and those who underwent a nonmedical switch from the ADA originator to SB5 (switching cohort). Clinical remission and safety were assessed at baseline and at 3, 6, and 12 months. In addition, in a small cohort of patients who were switched, we assessed the ADA serum trough levels and antidrug antibodies at baseline, 3, and 6 months. RESULTS: In the naïve cohort, the overall remission rate at 12 months was 60.42%, whereas in the switching cohort it was 89.02%. Fifty-three (36.3%) patients experienced an adverse event, and injection site pain was the most common; it was significantly more frequent in the switching cohort (P = 0.001). No differences were found in terms of ADA serum trough levels at baseline, 3, and 6 months after switching. No patient developed antidrug antibodies after the switch. CONCLUSIONS: We found that SB5 seemed effective and safe in IBD, both in the naïve cohort and in the switching cohort. Further studies are needed to confirm these data in terms of mucosal healing.

Infectious risk of vedolizumab compared with other biological agents in the treatment of inflammatory bowel disease.

BACKGROUND AND AIMS: Vedolizumab is a gut-selective anti-integrin (α4ß7) antibody for the treatment of inflammatory bowel disease with a well-known optimal safety profile. We aimed to compare its risk of infections with that of anti-TNF drugs and ustekinumab in patients with both ulcerative colitis and Crohn's disease. METHODS: All Crohn's disease and ulcerative colitis patients undergoing biological treatment at our centre between 2013 and 2019 were retrospectively included. All infectious complications were registered, considering both inpatient and outpatient events. A comparison of the exposure-adjusted infection rates of vedolizumab, anti-TNF drugs and ustekinumab was carried out, with a specific focus on the rate of gut infections. All infection rates were expressed in events per patient-years (PYs). RESULTS: The overall exposure-adjusted infection rate was 11.5/100 PYs. The most common infections were respiratory tract infections, cutaneous infections, HSV infections/reactivations and gut infections. The rate of serious infections was 1.3/100 PYs. The infection rate of vedolizumab was 17.5/100 PYs, with Crohn's disease patients having a lower infection risk compared with ulcerative colitis patients (P = 0.035). Gut infections were observed in 3.0% of the whole patient population (1.5/100 PYs) and were more common in the vedolizumab group (P = 0.0001). CONCLUSIONS: Our study confirms the good safety profile of vedolizumab. Among patients treated with vedolizumab, those with ulcerative colitis have a higher risk of developing infectious complications. Patients treated with vedolizumab have a higher risk of gut infections compared with patients treated with anti-TNF drugs or ustekinumab. Presumably, this is due to the gut-selective mechanism of action of vedolizumab.

Hepatocellular carcinoma risk in patients with HBV-related liver disease receiving antiviral therapy.

Hepatitis B virus (HBV) is a major health problem worldwide, with approximatively 240 million people living with a chronic HBV infection. HBV chronic infection remains the major cause of hepatocellular carcinoma worldwide, with more than half of HCC patients being chronic HBV carriers, even if underlying mechanisms of tumorigenesis are not totally understood. HBV-related HCC can be prevented by reducing the exposure to HBV by vaccination or by treatment of CHB infection. Current treatment of CHB are Peg-IFN alpha and oral NUCs. Treating HBV infection, either with IFN or NUCs, substantially reduces the risk of HCC development, even if antiviral therapy fails to completely eliminate HCC risk. Among treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC. The reduction of the risk of developing HCC during antiviral therapy is largely dependent upon the maintenance of virological remission, since viral load is found to be the most important factor leading to cirrhosis and its complications, including liver cancer development. The question whether Peg-IFN-alpha is superior to NUCs and whether there is a superior agent among NUCs is still controversial. Several studies demonstrated that antiviral therapy with NUCs could reduce the risk of HCC recurrence after curative treatment of HBV-related HCC.

Stevens-Johnson Syndrome and Herpes Simplex Type 1 Infection during Adalimumab Therapy for Crohn's Disease.

Stevens-Johnson syndrome (SJS) is a severe mucocutaneous adverse drug reaction with a relatively high mortality rate. SJS is described during herpes simplex virus type 1 (HSV1) infection and, rarely, even during adalimumab therapy. We report the case of a patient with Crohn's disease who developed SJS during an HSV1 infection and a contemporaneous anti-TNFα therapy with adalimumab. Remission was achieved with suspension of adalimumab and high doses of intravenous steroids and antivirals. Patients with HSV1 infection and on adalimumab therapy have a combined risk of SJS and should be monitored closely.

Cholangiocarcinoma as an Indication for Liver Transplantation in the Era of Transplant Oncology.

Cholangiocarcinoma (CCA) arises from the biliary tract epithelium and accounts for 10-15% of all hepatobiliary malignancies. Depending on anatomic location, CCA is classified as intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA). The best treatment option for pCCA is liver resection and when a radical oncological surgery is obtained, 5-year survival rate are around 20-40%. In unresectable patients, following a specific protocol, liver transplantation (LT) for pCCA showed excellent long-term disease-free survival rates. Fewer data are available for iCCA in LT setting. Nevertheless, patients with very early unresectable iCCA appear to achieve excellent outcomes after LT. This review aims to evaluate existing evidence to define the current role of LT in the management of patients with CCA.

Increased Risk of Liver Cirrhosis during Azathioprine Therapy for Crohn's Disease.

Azathioprine is a cornerstone of the therapy of Crohn's disease. Unfortunately, infections and malignancies are relatively common adverse effects related to this drug; however, cirrhosis is exceptionally reported as a side effect. We report the case of a 49-year-old male patient with ileocolonic steno-penetrating Crohn's disease who developed hepatic cirrhosis while treated with azathioprine. After taking azathioprine for 3 years with regular follow-up, he developed pancytopenia, and liver cirrhosis was diagnosed with ultrasound, abdomen computed tomography scan, transient elastography, and liver biopsy. As all other causes of liver damage were excluded, azathioprine was believed to be the cause of liver injury and therefore was interrupted.

Hepatitis C virus eradication with direct-acting antiviral improves insulin resistance.

Sustained virological response (SVR) after interferon-based therapy is associated with improvement of insulin resistance (IR) in HCV-infected patients. Few data are available in the direct-acting antivirals (DAAs) era, especially in cirrhotic patients. We prospectively evaluated the long-term effect of DAAs on IR. Patients treated with DAAs between May 2015 and December 2016 in 3 tertiary care centres were recruited. Patients with diabetes were excluded. Biochemical and virological data were collected at baseline, 12/24/48 weeks (W) after the end of therapy (EOT). Presence of IR was defined by a 'homeostasis model assessment index for IR' [HOMA-IR])> 2.5. Liver fibroscan was performed at baseline, at 24/48W after EOT. Hundred and thirty-eight patients were enrolled (mean age 58 years, M/F 85/53, GT1 61%, 68.8% cirrhotic). Sixty-eight patients (94/138) had IR. Patients with IR had significantly higher stiffness than patients without it (23 ± 12 vs 15 ± 8; P < .0001). SVR12 was achieved in 135 (98%) patients, and 124 (90%) patients reached the 48W post-EOT. At this time point, the percentage of patients with IR significantly decreased to 49% (P = 0,01). HOMA-IR was significantly lower than baseline (1.8 vs 3; P < .001), and this was related to a significant reduction of insulin level (11.7 ± 6.3 vs 16.4 ± 8.3). High BMI was associated with a significantly lower probability of achieving a non-IR status at 24W (P = .05) and 48W (P = .03).In conclusion, SVR following DAAs led to a significant reduction of IR, even in patients with cirrhosis. Nevertheless, IR can persist after the achievement of SVR, especially in patients with high BMI.

When and how should we perform a biopsy for HCC in patients with liver cirrhosis in 2018? A review.

The role of liver biopsy in the diagnosis of hepatocellular carcinoma (HCC) has changed over time. The diagnostic algorithm for this tumor is nowadays mainly based on radiological imaging, relegating histology to controversial cases, in which imaging techniques cannot establish a clear-cut diagnosis. This most commonly happens in small lesions, where biopsies frequently become mandatory, or in larger hypovascularized lesions. In this case however, the histological examination may not be reliable enough to grade the lesion, as different cell clones, deriving from sequential mutations, can originate heterogeneous cell populations. The risk of complications of liver biopsy, such as tumor seeding and intra-abdominal bleeding, needs to be reconsidered in light of new scientific evidence and of the technical improvements that have been introduced. Furthermore, increasing knowledge of the immunohistochemical and molecular characteristics of hepatocellular carcinoma opens a new scenario in which biopsy may play a decisive role in defining prognosis, and even treatment, by identifying the patient populations who could most benefit from target-driven hepatocellular carcinoma treatments, and therefore improving the success rate of experimental therapies. All the above reasons suggest that, overall, the role of liver biopsy in the management of HCC needs a reappraisal.