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Treatment of de novo malignancies and recurrent hepatocellular carcinoma with immune checkpoint inhibitors (ICI) in liver transplant recipients (LT) is an attractive strategy that is infrequently pursued because of the lack of strong evidence regarding their safety and efficacy. In this systematic review with pooled analysis, we aimed to assess safety and efficacy of ICI therapy following LT.We performed a systematic search of case reports and series published until January 2022. We included 31 publications reporting a total of 52 patients treated with ICIs after LT and assessed in a pooled analysis the risk of graft rejection and the outcome of ICI therapy.Acute graft rejection occurred in 15 patients (28.8%) and 7 patients (13.4% of the total cohort) died because of graft loss. Rejection was associated with shorter overall survival (OS) (17.2 months, confidence interval [CI] 12.1-22.2 vs. 3.5 months, CI 1.6-5.4, p 0.001). Disease control rate was 44.2% (n = 23), and in these patients, OS was longer than in non-responders (26.4 months, CI 20.8-32.0 vs. 3.4 months, CI 2.1-4.7, p 0.001).Observational, off-label experience suggests that treatment with ICI for advanced malignancies in LT recipients might not be discarded a priori. This notwithstanding, ICI treatment in these patients is associated with a substantial risk of graft rejection and mortality. Prospective studies are needed to provide adequate safety and efficacy figures of ICI treatment in this fragile population.

Background & Aims: Information on safety and efficacy of systemic treatment in patients with hepatocellular carcinoma (HCC) under dialysis are limited due to patient exclusion from clinical trials. Thus, we aimed to evaluate the rate, prevalence, tolerability, and outcome of sorafenib in this population. Methods: We report a multicenter study comprising patients from Latin America and Europe. Patients treated with sorafenib were enrolled; demographics, dose modifications, adverse events (AEs), treatment duration, and outcome of patients undergoing dialysis were recorded. Results: As of March 2018, 6156 HCC patients were treated in 44 centres and 22 patients were concomitantly under dialysis (0.36%). The median age was 65.5years, 40.9% had hepatitis C, 75% had Child-Pugh A, and 85% were Barcelona Clinic Liver Cancer-C. The median time to first dose modification, treatment duration and overall survival rate were 2.4months (interquartile ranges [IQR], 0.8-3.8), 10.8months (IQR, 4.5-16.9), and 17.5months (95% CI, 7.2-24.5), respectively. Seventeen patients required at least 1 dose modification. The main causes of first dose modification were asthenia/worsening of Eastern Cooperative Oncology Group-Performance Status and diarrhoea. At the time of death or last follow-up, four patients were still on treatment and 18 had discontinued sorafenib: 14 were due to tumour progression, 2 were sorafenib-related, and 2 were non-sorafenib-related AE. Conclusions: The outcomes observed in this cohort seem comparable to those in the non-dialysis population. Thus, to the best of our knowledge, this is the largest and most informative dataset regarding systemic treatment outcomes in HCC patients undergoing dialysis.

Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic that encompasses three distinct clinical phenotypes: uncomplicated fatty liver, non-alcoholic steato-hepatitis (NASH) and NASH-related cirrhosis with its complications, including hepatocellular carcinoma. To date, no pharmacological treatments have been approved and lifestyle modifications including reduced caloric intake targeting a 7-10% weight loss from baseline assessment represent the standard approach. Mediterranean Diet has been recommended as the best dietary pattern since it is easy to follow and, independently of caloric intake its nutritional components have beneficial metabolic effects that not only improve steatosis but also risk factors for cardio-vascular events, the leading cause of morbidity/mortality in individuals with NAFLD. Other dietary patterns such as low carbohydrates ketogenic diet and Dietary Approach to Stop Hypertension (DASH) diet can be used in patients with NAFLD. Recently, intermittent fasting diets have gained popularity among healthy individuals and have been proposed as a safe and effective treatment for the metabolic syndrome in experimental and in a few human studies. In this narrative review, we aim to summarize the evidence for the available dietary approaches for patients with NAFLD.

We read with interest the report published in Liver International by Colaneri et al who presented a case of acute Hepatitis B Virus (HBV) infection occurring during the course of coronavirus disease 2019 (COVID-19), highlighting how difficult can be disentangling the responsibility of liver enzyme alteration in a patient with COVID-19, and more importantly how treatment decisions can be affected by both liver disease and severe acute respiratory syndrome coronavirus-2 infection

Background Growing evidence indicates tissue inhibitors of matrix metalloproteinases (TIMPs) as potential players in inflammatory bowel disease (IBD), but, no prospective data are available in IBD remission/relapse. Material & methods In this prospective pilot study, a cohort of IBD patients (n = 32) was enrolled and treated with monoclonal anti-TNF-α antibodies. Patients were clinically followed up for a median period of 54 weeks. Serum circulating levels of C-reactive protein (CRP), TIMP-1 and -2, matrix metalloproteinase (MMP)-9 and -8, myeloperoxidase (MPO) and neutrophil elastase (NE) were assessed by ELISA at enrolment and at the end of the treatment. Results The percentage (%) TIMP-2 reduction from baseline to end of treatment was independently associated with IBD remission at the end of treatment and follow-up as well. ROC curve analysis further confirmed the good prognostic accuracy of % TIMP-2 reduction over the treatment period. Conversely, no other change in inflammatory molecule concentrations was able to predict short- or long-term IBD remission. Conclusions This study indicates TIMP-2 reduction during IBD treatment with monoclonal anti-TNF-α antibodies as a potential prognostic parameter of short and long term remission. To understand if TIMP-2 is an innocent biomarker or an active pathophysiological factor in IBD remains to be clarified.

BACKGROUND α-Fetoprotein (AFP) is a biomarker commonly used in the management of patients with hepatocellular carcinoma (HCC), although the possible determinants of its serum levels in these patients have not been adequately explored. For this study, the authors evaluated the relevance of demographic, clinical, and oncologic factors to the presence of elevated AFP levels in large cohort of patients with HCC. METHODS In 4123 patients with HCC who were managed by the Italian Liver Cancer Group, AFP levels were assessed along with their association with demographic, biochemical, clinical, and oncologic characteristics. Patients were subdivided according to the presence of elevated AFP (ie, >10 ng/mL). RESULTS AFP levels were elevated in 62.4% of patients with HCC. Multivariate logistic regression analysis indicated that being a woman (odds ratio [OR], 1.497; 95% confidence interval [95%CI], 1.250-1.793; P 2 cm (OR, 1.346; 95% CI, 1.135-2.596; P = .001), multinodular HCC (OR, 1.641; 95% CI, 1.403-1.920; P

BACKGROUND The outcome of patients with chronic hepatitis C virus infection (HCV) and advanced, compensated liver disease after sustained virological response (SVR) to direct-acting antivirals (DAAs) has not yet been completely depicted. We aimed to assess the clinical, biochemical and instrumental outcome of patients with advanced, compensated chronic HCV-related liver disease with DAA-induced SVR to DAAs and who had at least 1-year follow-up. MATERIALS AND METHODS Fifty-two patients with cirrhosis (n = 27) and fibrosis stage F3 (n = 25) followed up for a median of 60 weeks after successful DAA treatment were included. Laboratory work-up, including APRI and FIB-4 scores, liver transient elastography and measurement of the spleen bi-polar diameter were carried out before treatment and at the end of follow-up. RESULTS Liver stiffness decreased (P

Background: Chronic hepatitis B virus (HBV) infection is one of the most frequent aetiological factors associated with the development of hepatocellular carcinoma (HCC). Aim: This study evaluated the temporal trend in the aetiological role played by HBV infection alone in patients diagnosed with HCC during the last 20 years in Italy. Methods: Among the 2042 HCC patients included in the Italian Liver Cancer (ITA.LI.CA.) database, 346 had chronic HBV infection alone. We assessed the proportion of HCC patients with HBV infection in four quinquennia (1987–1991, 1992–1996, 1997–2001, 2002–2006) and evaluated their main clinical, virological and oncological characteristics across these periods. Results: Although the absolute number increased, the proportion of HBV-related HCC relatively decreased over time from 26.7% (47/176 patients) in 1987–1991 to 14.7% (127/862 patients) in 2002–2006 (P=0.0005). Patients' demographical, clinical and virological characteristics were similar across the four quinquennia. A greater proportion of patients was diagnosed with non-advanced HCC in more recent years (from 26% in 1987–1991 to 48% in 2002–2006, P=0.025), likely owing to a growing use of semiannual surveillance (from 63% in 1987–1991 to 80% in 2002–2006). Conclusions: We observed a significant, relative decrease in the role played by chronic HBV infection alone in the determinism of HCC during the last 20 years. In recent years, more patients are diagnosed with non-advanced HCC probably owing to improvements in HCC detection.

Aliment Pharmacol Ther 2010; 32: 1000–1006 Summary Background Abnormal intestinal clearance is involved in the pathogenesis of small intestinal bacterial overgrowth (SIBO). It is known that partially hydrolysed guar gum affects intestinal motility. Eradication therapy of SIBO is based on antibiotic treatment: no data are available on the role of fibre supplementation in eradicating SIBO. Aim To assess whether the combination of partially hydrolysed guar gum and rifaximin is more effective than rifaximin alone in the treatment of SIBO. Methods A 50 g-glucose breath test was given to 500 consecutive patients. Patients with a positive glucose breath test and predisposing conditions to SIBO entered into the study, and were randomized to receive rifaximin 1200 mg/day or rifaximin 1200 mg/day plus partially hydrolysed guar gum 5 g/day for 10 days. Patients completed a symptom questionnaire and glucose breath test both in basal condition and 1 month after withdrawal of therapy. Results Seventy-seven patients had SIBO. Eradication rate of SIBO was 62.1% in the rifaximin group (both on per-protocol and intention-to-treat analyses), and 87.1% (per-protocol, P = 0.017) and 85.0% (intention-to-treat, P = 0.036) in the rifaximin-plus-partially hydrolysed guar gum group. Clinical improvement was observed in 86.9% and 91.1% of eradicated cases in rifaximin and rifaximin-plus-partially hydrolysed guar gum groups respectively (P = 0.677). Conclusion The combination of rifaximin with partially hydrolysed guar gum seems to be more useful in eradicating SIBO compared with rifaximin alone.

Aberrant squamous cell carcinoma antigen (SCCA) expression is an early event in hepatocarcinogenesis, and increasing serum levels of SCCA variants IgM immune complexes (SCCA-IgM IC) have been found in cirrhotic patients developing hepatocellular carcinoma (HCC). We longitudinally evaluated a cohort of cirrhotic patients with hepatitis C virus infection (HCV) who underwent pegylated interferon (PEG-IFN) and ribavirin treatment. SCCA-IgM IC levels were assessed in the sera of 33 cirrhotic patients with HCV (21 males, median age 57 years) before, at the end and at 6-month and 1-year follow-up after treatment with PEG-IFN and ribavirin. SCCA-IgM IC serum levels (arbitrary units/mL, AU/mL) were evaluated according to treatment outcome: sustained virological response (SVR) vs nonresponse (NR). Overall, 15 patients obtained a SVR to antiviral therapy (45%). There was no significant difference in baseline SCCA-IgM IC serum levels between SVR and NR patients. When compared to baseline (451.2 AU/mL), SVR patients showed a significant decrease in median SCCA-IgM IC serum levels at the end of treatment (186.8 AU/mL, P = 0.013) and at both 6-month (96.8 AU/mL, P < 0.001) and 1-year follow-up (52.4 AU/mL, P < 0.001), while no significant modification was observed in NR patients. In patients with HCV-related liver cirrhosis, successful antiviral therapy is associated with a dramatic and significant decrease in SCCA-IC serum levels. Because of the pathophysiological correlation between SCCA and liver carcinogenesis, it is hypothesized that in patients with liver cirrhosis, SVR may be accompanied by a decreased proliferative stimulation.

Objectives. Noninvasive evaluation of fibrosis is an on-going effort in the management of chronic hepatitis C. This study was planned to noninvasively evaluate fibrosis staging. Design. We evaluated the biochemical, functional [aminopyrine breath test (ABT)] and ultrasonographic variables of 75 chronic hepatitis C patients. Results. Clinical [body mass index (BMI)], biochemical [aspartate aminotransferase (AST), alanine aminotransferase (ALT) and platelets (PLT)] and ratio indexes, together with the ABT, showed a higher relationship with fibrosis: initial (score ≤ 2) versus evident (score > 2) fibrosis: BMI (24 ± 2 vs. 26 ± 2, P = 0.0007), AST (56 ± 36 vs. 88 ± 65, P = 0.0159), ALT (92 ± 54 vs. 139 ± 108, P = 0.0290), PLT (220 ± 64 vs. 173 ± 61, P = 0.0007), PLT/spleen diameter ratio (PLT/SPD) (2133 ± 786 vs. 1540 ± 681, P = 0.0003), AST/platelet count ratio index (APRI) (0.80 ± 0.87 vs. 1.51 ± 1.47, P = 0.0010), ABT%d/h30 min (10.8 ± 4.5 vs. 7.6 ± 3.8, P = 0.0007), ABT%d/cum120 min (8.9 ± 3.3 vs. 6.5 ± 3.1, P = 0.0007). Considering the differences between fibrosis score 2 and 3 patients, BMI, ABT and PLT/SPD ratio proved to be statistically significant. Multivariate stepwise analysis (with and without BMI) identified two models for distinguishing between initial and evident fibrosis: Model 1: −0.569 +(BMI × 0.107) + (APRI × 0.169)−(PLT/SPD × 0.304), and Model 2: 2.376 + (APRI × 0.152)−(ABTd/h30 × 0.043)−(PLT/SPD × 0.249). These models showed concordance in identifying or ruling out evident fibrosis in 76% and 78.7% of the patients respectively. The PLT/SPD ratio also showed 78.7% concordance with the histological score. Conclusion. These results suggest that noninvasive evaluation of fibrosis in chronic hepatitis C may be considered an effective tool thanks to the use of an inexpensive, reproducible ratio index.

Background/Aim: To evaluate the relationship between hyaluronic acid/aminopyrine breath test (HA/ABT) ratio and fibrosis score in chronic hepatitis, and between HA/ABT and clinical staging (child-turcotte-pugh'score, CTP; and model for end stage liver disease, MELD) in cirrhosis, as well as to evaluate the aspartate aminotransferase (AST)/ABT in relation to the HA/ABT. Methods: We studied 48 patients with histologically proven chronic hepatitis C (CHC) and 35 patients with compensated cirrhosis (CIR). Results: HA/ABT and AST/ABT showed a more significant correlation with the fibrosis score than HA or ABT or AST alone in the 48 CHC patients: r=0.568 (P

Summary Background Helicobacter pylori treatment failure is becoming an emergent problem in clinical practice. Shorter treatment duration should improve compliance to therapy and keep an acceptable H. pylori eradication rate. Aims To evaluate the efficacy of two rabeprazole, high-dose levofloxacin and tinidazole-based regimens as ‘rescue’ treatment for H. pylori eradication in an open-label, randomized, pilot study carried out in a clinical practice setting. Methods Eighty-five consecutive patients who have previously failed at least one H. pylori eradication attempt were randomized to receive rabeprazole (20 mg, b.d.), levofloxacin (500 mg, b.d.) and tinidazole (500 mg, b.d.) either for 4 (4-day RLT, n = 42) or 7 days (7-day RLT, n = 43). Cure of H. pylori infection was assessed by means of 13C-urea breath test. Results The 7-day RLT achieved 84% (95% CI: 69–93%) and 86% (95% CI: 72–95%) eradication rates in intention-to-treat and per-protocol analyses respectively. The shorter treatment obtained an 83% (95% CI: 69–93%) eradication rate in both intention-to-treat and per-protocol analysis. Both regimens were well tolerated, although patients who received the 4-day RLT reported fewer side-effects. Conclusions In patients who have previously failed at least one H. pylori eradication attempt, both 4- and 7-day rabeprazole, high-dose levofloxacin, tinidazole-based regimens are effective in curing the infection in more than 80% of patients.

Summary Background: Trans-catheter arterial chemoembolisation (TACE) is the most common palliative treatment for hepatocellular carcinoma (HCC). The therapeutic options depend both on the characteristics of the tumour and on functional staging of the cirrhosis. Aim: To evaluate the effects of TACE on the survival of cirrhotic patients with HCC according to different staging systems [Okuda score, Cancer Liver Italian Program (CLIP) score, Model for End-stage Liver Disease (MELD) score] and in relation to the side-effects of TACE. Methods: Fifty cirrhotic patients, 36 CTP class A and 14 class B, underwent 106 TACE treatments with mitoxantrone. Survival at 12, 24, and 36 months was evaluated. Results: MELD at 12 months and CLIP at 24 months were identified as significant variables associated with survival. Combined cut-offs of CLIP and of MELD identified four subgroups of patients with different survivals, at 12, 24 and 36 months, respectively: CLIP ≥ 2 and MELD ≥ 10 (63%, 20% and 0%), CLIP

Background: There are few data on the use of the 13C-aminopyrine breath test to evaluate the severity of disease in patients with hepatitis C virus-related chronic liver disease, although these patients represent one of the most important problems in clinical hepatology. Aims: To compare 13C-aminopyrine breath test results of patients with hepatitis C virus-related chronic hepatitis and Child–Pugh class A cirrhosis with those of normal subjects, and to evaluate different methods of expressing 13C-aminopyrine breath test results. Methods: Twenty-four patients with hepatitis C virus-related chronic hepatitis and 17 patients with Child–Pugh class A cirrhosis underwent 13C-aminopyrine breath test. Breath samples were collected every 30 min up to 2 h after 13C-aminopyrine administration. 13C-Aminopyrine breath test results were expressed as a percentage of the administered dose of 13C recovered per hour (% dose/h) and the cumulative percentage of administered dose of 13C recovered over time (% dose cum). Nineteen healthy subjects served as controls. Patients with hepatitis C virus-related chronic hepatitis were divided into subgroups on the basis of histological staging and grading. Results: The 13C-aminopyrine breath test result (% dose/h) at 30 min was significantly different among the three subgroups of subjects (normal subjects, 11.5 ± 3.5; chronic hepatitis patients, 8.1 ± 4.1; cirrhosis patients, 5.0 ± 3.1; P 2) fibrosis scores to be distinguished. The 13C-aminopyrine breath test results (% dose cum) at 30, 60 and 90 min allowed discrimination between normal subjects and chronic hepatitis and cirrhosis patients. The 13C-aminopyrine breath test result (% dose cum) was also able to distinguish between normal subjects and chronic hepatitis patients with high but not low fibrosis scores. Both 13C-aminopyrine breath test results (% dose/h and % dose cum) at 120 min allowed the differentiation between normal subjects and chronic hepatitis patients with high (≥ 6) necro-inflammatory activity. Conclusions: In patients with hepatitis C virus-related chronic liver disease, the 13C-aminopyrine breath test proved to be safe and easy to perform, and was able to evaluate different degrees of liver function impairment which were partly correlated to clinical and histological evaluation. In future studies, 13C-aminopyrine breath test results should be expressed in a standardized fashion to permit comparison.

Background: Helicobacter pylori gastric infection has been associated with various digestive and extra-digestive diseases. The systemic influence of gastric H. pylori infection seems to be mediated by the release of various cytokines. In liver disease, bacterial infections have been associated with the impairment of liver metabolic function. Aims: To evaluate the influence of H. pylori infection on liver function as assessed by means of the monoethylglycinexylidide test, which depends upon liver blood flow and cytochrome P-450 activity, and the 13C-galactose breath test, which depends on cytosolic enzymatic activity and is correlated with hepatic functional mass. Moreover, to evaluate whether H. pylori-associated modifications of liver function may be related to tumour necrosis factor-α serum levels. Patients and methods: Thirty-five patients with liver cirrhosis of various aetiologies, who underwent monoethylglycinexylidide and 13C-galactose breath tests, were retrospectively evaluated for H. pylori infection by means of anti-H. pylori immunoglobulin G. The main clinical, biochemical and functional characteristics of the patients as well as their tumour necrosis factor-α serum levels were then analysed on the basis of the presence of H. pylori infection. Results: Twenty-one patients tested positive for H. pylori infection (60%), and 11 tested negative (31.4%). No clinical or biochemical differences were observed between H. pylori-infected and non-infected patients. H. pylori infection showed no difference in distribution according to Child–Pugh classes (A, 55%; B and C, 67%). The monoethylglycinexylidide test results were significantly lower at each sampling time in H. pylori-positive patients compared to H. pylori-negative patients (MEGX15, P=0.027; MEGX30, P=0.014; MEGX60, P=0.028), while 13C-galactose breath test showed no significant differences considering both cumulative percentage dose and percentage dose/h. The median tumour necrosis factor-α serum levels were no different between H. pylori-positive (16.1 pg/mL, 95% confidence interval, 8.7–28.7) and H. pylori-negative (12.3 pg/mL, 95% confidence interval, 8.7–23.4) patients. Conclusions: In cirrhotic patients, H. pylori infection seems to selectively affect cytochrome P-450 liver activity, while hepatic functional mass does not seem to be impaired. Tumour necrosis factor-α does not seem to be the mediator of this impairment. Further studies are needed to evaluate the impact of H. pylori eradication on parameters of liver function.

AIM To evaluate the long-term functional outcome of chronic hepatitis C (CHC) patients treated with interferon (IFN) therapy. METHODS Thirty-six patients with CHC were followed up for a mean of 36 months (+/- 19, SD) after a course of IFN therapy. Biochemical, virological (qualitative hepatitis C virus (HCV)-RNA and HCV genotype), and functional (monoethylglycinexylidide (MEGX) test) evaluations were carried out at the time of liver biopsy. Patients were divided into long-term responders (LTR), relapsers (RR), or non-responders (NR) according to IFN therapy outcome. At the end of follow up, patients were non-invasively re-evaluated by means of biochemistry, qualitative HCV-RNA, MEGX test, and liver ultrasonography. RESULTS A significant decrease in MEGX values was observed in all patients. However, when patients were examined according to treatment outcome, only NR and RR showed a significant decrease in liver function as compared to pretreatment levels (MEGX30, 80.5 +/- 26.8-62.9 +/- 24.2 ng/mL, P< 0.01; MEGX60, 72.9 +/- 18.1-60.5 +/- 19.7 ng/mL, P< 0.05; MEGXAUC, 3,816 +/- 1,243-3,095 +/- 1,205 ng/mL per h, P< 0.05). On the contrary, LTR patients showed no significant modifications in MEGX values at each sampling time (MEGX,5, 72.9 +/- 31.4-70.3 +/- 29.7 ng/mL; MEGX30, 84.0 +/- 27.6-71.5 +/- 21.8 ng/ mL; MEGX60, 69.5 +/- 26.8-63.2 +/- 14.4 ng/mL; MEGXAUC 4028 +/- 1,378-3,620 +/- 1,041 ng/mL per h). At the end of follow up, LTR patients showed normal liver biochemistry and negativity of serum HCV-RNA, while NR and RR patients showed a significant decrease in platelets. CONCLUSIONS In CHC patients long-term response to IFN therapy, besides favoring positive clinical and virologic long-term outcome, results in maintaining preserved liver function. Furthermore, IFN therapy seems to determine a decrease in the rate of functional disease progression, even in NR and RR. The MEGX test may be considered as a useful tool for performing serial follow up of CHC patients.

Summary. Thrombocytopenia is likely the most common haematological abnormality that can be diagnosed in patients affected by chronic liver disease. In these patients, the presence of thrombocytopenia may have significant clinical implications. In fact, it can be a limiting factor when considering invasive procedures and may hamper the outcome of antiviral therapy with interferon. The prevalence of decreased platelet count in patients with chronic hepatitis C has been assessed in various studies that evaluated heterogenous patient populations and used various platelet count threshold to identify thrombocytopenia. This review shows that the prevalence of thrombocytopenia in these patients is variable and mainly depends upon the severity of the underlying liver disease and the criterion used to identify this haematological abnormality. Furthermore, the results of this epidemiological review provide an indirect evidence that confirms the multiplicity of aetiological factors underlying the pathophysiology of thrombocytopenia in chronic hepatitis C patients. Lastly, this study shows that up to 25% of patients treated with interferon may develop some degree of thrombocytopenia, and this may be associated with decreased sustained virological response rates.

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