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Bacterial infections are a common complication in patients with decompensated liver cirrhosis. The complex landscape of cirrhosis, characterized by immune paralysis and an exhausted response to exogenous triggers, explains the higher prevalence of such infections, particularly in advanced disease stages. In clinical practice, the onset of a bacterial infection can lead to further deterioration of hepatic and extra-hepatic function, potentially resulting in acute decompensation or acute-on-chronic liver failure. This has significant clinical implications, particularly for patients awaiting a transplant. In this review, we will discuss the latest evidence on the diagnosis and therapy of bacterial infections in patients with decompensated cirrhosis. Additionally, we will analyze the impact of bacterial infections in the context of liver transplantation, discussing debated topics such as the timing of transplantation in patients with infections, potential implications for prioritization, effects on post-operative recovery, grafts, and patient survival. [ABSTRACT FROM AUTHOR]

Sarcopenia and frailty are common complications in patients with cirrhosis evaluated for liver transplantation (LT). Although the negative impact of sarcopenia on patient's outcome has been well studied, the prognostic role of frailty is not as clear. We assessed the prevalence of sarcopenia and frailty and the clinical impact of frailty in a prospective cohort of cirrhosis patients with and without hepatocellular carcinoma (HCC) listed for LT. Patients with cirrhosis were prospectively recruited at the time of admission into the waiting list. Clinical and lab values were collected. Physical frailty was assessed by liver frailty index (LFI) and patients were categorized into robust (< 3.2); pre-frail (between 3.2 and 4.5), and frail (> 4.5). Skeletal muscle mass was evaluated via skeletal muscle index (SMI) obtained from last CT scan before LT; sarcopenia was defined by SMI < 50 cm2/m2 in males and < 39 cm2/m2 in females. 105 patients were included, of which 42 (40%) had hepatocellular carcinoma (HCC). In patients without HCC (63.5% males, median age 61 years), 36.5% were frail, 50.8% were pre-frail and 12.7% were robust. Frail patients were older than non-frail patients (63 vs. 56; p = 0.008) and had more severe liver disease (Child C: 65% vs. 37.5%; p = 0.02). Prevalence of sarcopenia in patients without HCC was 63%, with similar value of median SMI between frail and not frail patients (p = 0.454). Patients with HCC (78.6% males, 65 years old) were 21.4% frail, 61.9% pre-frail, and 16.7% robust. Frail patients had more severe liver disease (Child C: 77% vs. 18.2%; p = 0.004), whereas age was comparable to non-frail patients; among patients without HCC, during a median follow-up of 263 days, 17% died (of which 72% were frail) and 10 patients were delisted due to clinical improvement (none of whom were frail). Among those with HCC, during a median follow-up of 289 days, 4 (9%) patients died of which 50% were frail. Frailty and sarcopenia are common complications in patients with cirrhosis awaiting LT. Frailty appears to be associated with an increased risk of mortality during wait-list time especially in those with decompensated cirrhosis. At univariate analysis Meld score, Child score and presence of frailty were found to be associated with shorter survival, however, at multivariate analysis presence of frailty and Child C vs. A/B were the only independent predictor of death. Larger cohorts are required to confirm these results. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis is a cholestatic disease with a low prevalence in Italy. Indications for liver transplantation and the time of listing are not stated. We performed a national survey to investigate the listing criteria, comorbidities, and outcomes. In April 2022, we surveyed liver transplantation in primary sclerosing cholangitis nationwide for the last 15 years. From 2007 to 2021, 445 patients were included on waiting lists, and 411 had undergone liver transplants. The median age at transplantation was 46 years (males 63.9%); 262 patients (59%) presented an inflammatory bowel disease. Transplants increased over the years, from 1.8 % in 2007 to 3.0 % in 2021. Cholangitis (51%) and hepatic decompensation (45%) were the main indications for listing. The disease recurred in 81 patients (20%). Patient survival after the first transplant was 94 %, 86% and 84% at one, five, and ten years. Twenty-four died in the first year (50% surgical complications, 25% infections); 33 between one to five years (36% recurrence, 21% cholangiocarcinoma recurrence) and nine after five years (56% de novo cancer, 44% recurrence). Primary sclerosing cholangitis has been an increasing indication for transplantation in Italy. Cholangitis and decompensation were the main indications for listing. Recurrence and cancer were the leading causes of death. [ABSTRACT FROM AUTHOR]

Liver transplantation (LT) has significantly transformed the prognosis of patients with end-stage liver disease and hepatocellular carcinoma (HCC). The traditional epidemiology of liver diseases has undergone a remarkable shift in indications for LT, marked by a decline in viral hepatitis and an increase in metabolic dysfunction-associated steatotic liver disease (MASLD), along with expanded indications for HCC. Recent advancements in surgical techniques, organ preservation and post-transplant patients' management have opened new possibilities for LT. Conditions that were historically considered absolute contraindications have emerged as potential new indications, demonstrating promising results in terms of patient survival. While these expanding indications provide newfound hope, the ethical dilemma of organ scarcity persists. Addressing this requires careful consideration and international collaboration to ensure equitable access to LT. Multidisciplinary approaches and ongoing research efforts are crucial to navigate the evolving landscape of LT. This review aims to offer a current overview of the primary emerging indications for LT, focusing on acute-on-chronic liver failure (ACLF), acute alcoholic hepatitis (AH), intrahepatic and perihilar cholangiocarcinoma (i- and p-CCA), colorectal liver metastasis (CRLM), and neuroendocrine tumor (NET) liver metastases. [ABSTRACT FROM AUTHOR]

Background and Aims: Porto‐sinusoidal vascular disease (PSVD) has been described as the prominent pathology in liver explants of patients with cystic fibrosis (CF), but data outside the transplant setting are lacking. We aimed to investigate the prevalence of portal hypertension (PH) in CF‐associated liver disease (CFLD) and develop an algorithm to classify liver involvement in CF patients. Methods: This is a cross‐sectional study of consecutive paediatric and adult patients in a tertiary centre between 2018 and 2019, who underwent ultrasound, liver (LSM) and spleen stiffness (SSM) measurement. CFLD was defined according to physical examination, liver tests and ultrasound findings. PSVD was likely if there were PH signs in the absence of advanced chronic liver disease (CF‐ACLD, LSM <10 kPa). A historical cohort was used to validate the prognostic significance of the new definitions. Results: Fifty (27.5%) patients met CFLD criteria. At least one sign of PH was found in 47 (26%) patients, but most (81%) had LSM <10 kPa and were likely to have PSVD; only 9 (5%) had CF‐ACLD. PSVD and CFLD (LSM <10 kPa) co‐existed in most (23/36) cases. In the historical cohort (n = 599 patients), likely PSVD and CFLD+PH were independently associated with a 2‐fold and 3.5‐fold increase in mortality compared to patients without PH, respectively. In 34 patients with SSM, values <21 and >50 kPa accurately diagnosed specific signs of PH. Conclusions: PSVD is the prevailing cause of PH in CF patients. We developed a new diagnostic algorithm based on clinical and elastosonography criteria to classify liver involvement in patients with CF. [ABSTRACT FROM AUTHOR]

The editorial discusses the importance of assessing the prognosis of patients with hepatitis B virus (HBV) and acute on chronic liver failure (ACLF), emphasizing the impact of comorbidities on patient outcomes. A new scoring system, the age-adjusted Charlson Comorbidity Index (aCCI)-HBV ACLF score, was proposed to improve prognostic accuracy in HBV-related ACLF patients. While the score showed promising results in predicting short- and mid-term mortality, it has limitations in terms of generalizability across different ethnicities and the exclusion of certain comorbidities. Further research is needed to evaluate the effectiveness of the aCCI in identifying the impact of comorbidities on short-term prognosis in ACLF patients. [Extracted from the article]

(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. [ABSTRACT FROM AUTHOR]

The role of sarcopenia in predicting decompensation other than hepatic encephalopathy is unclear. We aimed to evaluate the prognostic role of sarcopenia, assessed by computed tomography (CT), in the development of ascites and mortality in patients with advanced chronic liver disease (ACLD) outside the liver transplantation (LT) setting. We retrospectively evaluated ACLD patients with liver stiffness measurement (LSM) >10 kPa and an available CT scan within 6 months. Sarcopenia was defined as skeletal muscle index (SMI) <50 and <39 cm2/m2, respectively, in men and women. Competing risk regression models were used to assess the variables associated with the main outcomes. 209 patients were included in the final analysis and sarcopenia was present in 134 (64.1%). During a median follow-up of 37 (20–63) months, 52 patients developed ascites, 24 underwent LT, and 30 died. Sarcopenia was found a predictive factor of decompensation with ascites (SHR 2.083, 95%-CI: 1.091–3.978), independently from the features of clinically significant portal hypertension (LSM≥21 kPa or portosystemic shunts). Sarcopenia (SHR: 2.744, 95%-CI: 1.105–6.816) and LSM≥21 kPa (SHR: 3.973, 95%-CI: 1.548–10.197) were independent risk factors for increased mortality. Sarcopenia and portal hypertension are two major and independent risk factors for decompensation with ascites and mortality in cirrhotic patients outside the LT context. [ABSTRACT FROM AUTHOR]

Background: Management of infections due to carbapenemase‐resistant Enterobacterales (CRE) in solid organ transplant (SOT) recipients remains a difficult challenge. The INCREMENT‐SOT‐CPE score has been specifically developed from SOT recipients to stratify mortality risk, but an external validation is lacking. Methods: Multicenter retrospective cohort study of liver transplant (LT) recipients colonized with CRE infection who developed infection after transplant over 7‐year period. Primary endpoint was all‐cause 30‐day mortality from infection onset. A comparison between INCREMENT‐SOT‐CPE and other selected scores was performed. A two‐level mixed effects logistic regression model with random effects for the center was fitted. Performance characteristics at optimal cut‐point were calculated. Multivariable Cox regression analysis of risk factors for all‐cause 30‐day mortality was carried out. Results: Overall, 250 CRE carriers developed infection after LT and were analyzed. The median age was 55 years (interquartile range [IQR]: 46–62) and 157 were males (62.8%). All‐cause 30‐day mortality was 35.6%. A sequential organ failure assessment (SOFA) score ≥ 11 showed a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 69.7%, 76.4%, 62.0%, 82.0%, and 74.0%, respectively. An INCREMENT‐SOT‐CPE ≥ 11 reported a sensitivity, specificity, PPV, NPV, and accuracy of 73.0%, 62.1%, 51.6%, 80.6% and 66.0%, respectively. At multivariable analysis acute renal failure, prolonged mechanical ventilation, INCREMENT‐SOT‐CPE score ≥ 11 and SOFA score ≥ 11 were independently associated with all‐cause 30‐day mortality, while a tigecycline‐based targeted regimen was found to be protective. Conclusions: Both INCREMENT‐SOT‐CPE ≥ 11 and SOFA ≥ 11 were identified as strong predictors of all‐cause 30‐day mortality in a large cohort of CRE carriers developing infection after LT. [ABSTRACT FROM AUTHOR]

Gastroenterology, Digestive Endoscopy and Hepatology have faced significant improvements in terms of diagnosis and therapy in the last decades. However, many fields still remain poorly explored, and many questions unanswered. Moreover, basic-science, as well as translational and clinical discoveries, together with technology advancement will determine further steps toward a better, refined care for many gastroenterological disorders in the future. Therefore, the Young Investigators of the Italian Society of Gastroenterology (SIGE) joined together, offering a perspective on major future innovations in some hot clinical topics in Gastroenterology, Endoscopy, and Hepatology, as well as the current pitfalls and the grey zones. [ABSTRACT FROM AUTHOR]

Background: De novo metabolic syndrome (MS) is a frequent complication after liver transplantation (LT). The aim of this prospective study is to identify potential risk factors longitudinally associated to post‐LT de novo MS. Patients without pre‐LT MS who underwent LT between April 2013 and October 2017 were prospectively included. Metabolic variables were collected at LT and at 6, 12, and 24 months post‐LT. Results: Sixty‐three patients fulfilled the inclusion criteria (76% male, mean age 53.6±9.5 years). The prevalence of de novo MS was 46%, 43%, and 49% at 6, 12, and 24 months after LT, respectively. Among other MS components, the prevalence of type 2 diabetes, hypertension and hypertriglyceridemia significantly increased after LT. Considering the baseline characteristics at the adjusted analysis, alcoholic liver disease (OR 4.17, 95%CI 1.20‐14.51; p =.03) and hypertension pre‐LT (OR 11.3, 95% CI 1.49‐85.46; p =.02) were confirmed as independent risk factors of post‐LT de novo MS. In the time‐varying analysis, only eGFR (OR.97, 95% CI.97‐.98; p <.0001) was found associated with post‐LT de novo MS. Conclusions: De novo MS frequently occurs shortly after LT, affecting nearly half of patients at 24 months post‐LT. Lifestyle modifications should be recommended starting early post‐LT, particularly for patients with established risk factors. [ABSTRACT FROM AUTHOR]

Background Patients colonized with carbapenem-resistant Enterobacteriaceae (CRE) are at higher risk of developing CRE infection after liver transplantation (LT), with associated high morbidity and mortality. Prediction model for CRE infection after LT among carriers could be useful to target preventive strategies. Methods Multinational multicenter cohort study of consecutive adult patients underwent LT and colonized with CRE before or after LT, from January 2010 to December 2017. Risk factors for CRE infection were analyzed by univariate analysis and by Fine-Gray subdistribution hazard model, with death as competing event. A nomogram to predict 30- and 60-day CRE infection risk was created. Results A total of 840 LT recipients found to be colonized with CRE before (n = 203) or after (n = 637) LT were enrolled. CRE infection was diagnosed in 250 (29.7%) patients within 19 (interquartile range [IQR], 9–42) days after LT. Pre- and post-LT colonization, multisite post-LT colonization, prolonged mechanical ventilation, acute renal injury, and surgical reintervention were retained in the prediction model. Median 30- and 60-day predicted risk was 15% (IQR, 11–24) and 21% (IQR, 15–33), respectively. Discrimination and prediction accuracy for CRE infection was acceptable on derivation (area under the curve [AUC], 74.6; Brier index, 16.3) and bootstrapped validation dataset (AUC, 73.9; Brier index, 16.6). Decision-curve analysis suggested net benefit of model-directed intervention over default strategies (treat all, treat none) when CRE infection probability exceeded 10%. The risk prediction model is freely available as mobile application at https://idbologna.shinyapps.io/CREPostOLTPredictionModel/. Conclusions Our clinical prediction tool could enable better targeting interventions for CRE infection after transplant. [ABSTRACT FROM AUTHOR]

Objective: To investigate the rate of and the risk factors for breakthrough‐IFI (b‐IFI) after orthotopic liver transplantation (OLT) according to the new definition proposed by Mycoses‐Study‐Group‐Education‐and‐Research‐Consortium (MSG‐ERC) and the European‐Confederation‐of‐Medical‐Mycology (ECMM). Methods: Multicenter prospective study of adult patients who underwent OLT at three Italian hospitals, from January 2015 to December 2018. Targeted antifungal prophylaxis (TAP) protocol was developed and shared among participating centers. Follow‐up was 1‐year after OLT. B‐IFI was defined as infection occurring during exposure to antifungal prophylaxis. Risk factors for b‐IFI were analyzed among patients exposed to prophylaxis by univariable analysis. Results: We enrolled 485 OLT patients. Overall compliance to TAP protocol was 64.3%, 220 patients received antifungal prophylaxis, 172 according to TAP protocol. Twenty‐nine patients were diagnosed of IFI within 1 year after OLT. Of them, 11 presented with b‐IFI within 17 (IQR 11‐33) and 16 (IQR 4‐30) days from OLT and from antifungal onset, respectively. Then out of 11 patients with b‐IFI were classified as having high risk of IFI and were receiving anti‐mould prophylaxis, nine with echinocandins and one with polyenes. Comparison of patients with and without b‐IFI showed significant differences for prior Candida colonization, need of renal replacement therapy after OLT, re‐operation, and CMV infection (whole blood CMV‐DNA >100 000 copies/mL). Although non‐significant, a higher rate of b‐IFI in patients on echinocandins was observed (8.2% vs 1.8%, P =.06). Conclusions: We observed 5% of b‐IFI among OLT patients exposed to antifungal prophylaxis. The impact of echinocandins on b‐IFI risk in this setting should be further explored. [ABSTRACT FROM AUTHOR]

Serum biomarkers have suboptimal accuracy for the early diagnosis of bacterial infection (BI) in cirrhosis. The aim of the study was to evaluate the diagnostic and prognostic accuracy of presepsin (PSP) in a cohort of hospitalized patients with cirrhosis. All adult cirrhotics admitted between 03.2016 and 06.2019 were consecutively evaluated. PSP was measured using chemiluminescent enzyme immunoassay, and its accuracy was compared with that of common biomarkers. A total of 278 cirrhotic patients for a total of 448 hospitalizations were prospectively collected. Prevalence of BI at admission was 28.3%. Median (range) Log10PSP in the whole cohort was 2.83 (2.48–3.19) ng/L, significantly higher in patients with BI than in patients without (p<0.001). For a cutoff value of 2.87 ng/L, Log10PSP showed sensitivity, specificity and AUC-ROC of 0.66 (95% CI 0.57–0.74), 0.63 (95% CI 0.57–0.68) and 0.69 (95% CI 0.63–0.73), lower than that of C-reactive protein (p=0.002), but similar to procalcitonin (p=0.18) Patients with BI at hospitalization had higher probability of 28-day mortality (sub-hazard ratio [sHR] 2.65;95% CI 1.49–4.70; p=0.001). At multivariate Cox's regression analysis, Log10PSP (sHR 2.4; 95% CI 1.22–4.82; p=0.01) together with age and severity of liver disease, was an independent predictor of short-term mortality. PSP shows low diagnostic accuracy for BI in cirrhosis, but it is an independent predictor of short-term mortality. PSP may be a biomarker of systemic inflammation, commonly seen in end-stage liver disease. [ABSTRACT FROM AUTHOR]

SUMMARY: Patients with hepatocellular carcinoma (HCC) are at high risk of second primary malignancies. As HCC has become the leading indication of liver transplant (LT), the aim of this study was to investigate whether the presence of HCC before LT could influence the onset of de novo malignancies (DNM). A cohort study was conducted on 2653 LT recipients. Hazard ratios (HR) of DNM development for patients transplanted for HCC (HCC patients) were compared with those of patients without any previous malignancy (non‐HCC patients). All models were adjusted for sex, age, calendar year at transplant, and liver disease etiology. Throughout 17 903 person‐years, 6.6% of HCC patients and 7.4% of non‐HCC patients developed DNM (202 cases). The median time from LT to first DNM diagnosis was shorter for solid tumors in HCC patients (2.7 vs 4.5 years for HCC and non‐HCC patients, respectively, P < 0.01). HCC patients were at a higher risk of bladder cancer and skin melanoma. There were no differences in cumulative DNM‐specific mortality by HCC status. This study suggests that primary HCC could be a risk factor for DNM in LT recipients, allowing for risk stratification and screening individualization. [ABSTRACT FROM AUTHOR]

Summary: Machine learning has recently been proposed as a useful tool in many fields of Medicine, with the aim of increasing diagnostic and prognostic accuracy. Models based on machine learning have been introduced in the setting of solid organ transplantation too, where prognosis depends on a complex, multidimensional and nonlinear relationship between variables pertaining to the donor, the recipient and the surgical procedure. In the setting of liver transplantation, machine learning models have been developed to predict pretransplant survival in patients with cirrhosis, to assess the best donor‐to‐recipient match during allocation processes, and to foresee postoperative complications and outcomes. This is a narrative review on the role of machine learning in the field of liver transplantation, highlighting strengths and pitfalls, and future perspectives. [ABSTRACT FROM AUTHOR]