Waiting list mortality and 5-year transplant survival benefit of patients with MASLD: An Italian liver transplant registry study.

Background & Aims: International consensus has recently introduced a new definition of metabolic dysfunction-associated steatotic liver disease (MASLD). We sought to analyse epidemiological trends, prognostic features, and transplant survival benefits of patients with MASLD and without MASLD waiting for liver transplantation (LT) in Italy. Methods: Using the Italian Liver Transplant Registry database, we analysed data from adult patients listed for primary LT attributable to end-stage chronic liver disease between January 2012 and December 2022. Independent multivariable waiting lists and post-transplant survival models were developed for patients with and without hepatocellular carcinoma (HCC). A Monte Carlo simulation was used to create 5-year transplant benefit distributions based on the presence of MASLD, HCC, and model for end-stage liver disease (MELD)-sodium values. Results: A total sample of 1,941 patients with MASLD and 11,201 patients without MASLD was considered. A significant increase in the prevalence of MASLD as an indication for LT was observed from 2012 to 2022, for both cohorts with HCC (from 17.7 to 30%) and without HCC (from 9.5 to 11.8%) cohorts. Projections suggest that, as early as next year, MASLD will overcome HCV as the second most common indication for transplantation after alcoholic liver disease in Italy. According to univariate and multivariate analyses, MASLD was not an independent predictive factor for patient survival after transplantation. However, it increased the risk of death for patients on the waiting list without HCC (hazard ratio 1.62, p <0.001). At the same MELD-sodium, the 5-year transplant benefit was higher in patients with non-HCC MASLD, followed by patients with HCC, whereas it was lower in patients without HCC and without MASLD. Conclusions: Patients with non-HCC MASLD had an increased waitlist mortality and 5-year transplant survival benefit compared with other candidates. Impact and implications: The present research addresses the critical need to understand the evolving landscape of liver transplantation indications, mainly focusing on metabolic dysfunction-associated steatotic liver disease (MASLD) in Italy. Given the significant rise in MASLD cases, these findings highlight that patients with non-HCC MASLD face increased waitlist mortality and benefit more from liver transplantation within 5 years compared with other candidates. The significance of these results lies in their emphasis on the necessity of focusing on patients with MASLD on waiting lists to improve outcomes. By tailoring transplant eligibility criteria and resource allocation, the study provides actionable insights to improve patient survival and optimise liver transplantation practices.

Transarterial Radioembolization Can Downstage Intermediate and Advanced Hepatocellular Carcinoma to Liver Transplantation.

BACKGROUND: Transarterial radioembolization (TARE) is an effective treatment to control tumor growth and improve survival in hepatocellular carcinoma (HCC). The role of TARE in downstaging patients to liver transplantation (LT) is unclear. The aim of this study was to investigate the downstaging efficacy of TARE for intermediate and advanced HCC. METHODS: Intention-to-treat analysis with multistate modeling was performed. Patients moved through 5 health states: (1) from TARE to listing, (2) from TARE to death without listing, (3) from listing to LT, (4) from listing to death without LT, and (5) from transplant to death. Factors affecting the chance of death after TARE were considered to stratify outcomes. RESULTS: Two hundred fourteen patients underwent TARE. Of those, 43.9% had radiological response, 29.9% were listed, and 22.8% were transplanted. The probability of being alive without LT was 40.5% 1 y after TARE and 11.5% at 5 y. The chance of being listed was 9.4% at 1 y and 0.9% at 5 y. The probability of dying after TARE without LT was 38% at 1 y and 73% at 5 y. The overall survival of patients receiving LT was 61% at 5 y after transplant. Tumor beyond up-to-seven criteria, alfafetoprotein >400 ng/mL, and albumin-bilirubin ≥2 were associated with death. Three risk groups were associated with different response, chances of being listed, and receiving LT. Median survival was 3 y for low-risk, 1.9 y for intermediate-risk, and 9 mo for high-risk patients (P < 0.001). CONCLUSIONS: In intermediate and advanced HCC, TARE allows for a 44% chance of response, 30% downstaging, and 23% probability of permitting LT. Patient's and tumor's characteristics allow for risk stratification and predict survival from TARE.

Liver transplantation for organ failure following multiple locoregional treatments for breast cancer metastasis.

Patients with nonresectable breast cancer liver metastasis (BCLM) face a dismal prognosis. Despite liver transplantation (LT) for metastatic liver tumors having recently shown good results, BCLM represents an absolute contraindication. This study aimed to investigate the potential for long-term survival after LT for BCLMs in a patient experiencing end-stage liver disease, following multiple oncologic treatments. In July 2019, we performed a deceased donor LT on a 41-year-old female with BCLM controlled with human epidermal growth factor receptor 2 targeted therapy, who developed liver failure following multiple locoregional liver-directed treatments. The primary tumor was treated with surgical resection and adjuvant chemoradiation in 2000. The procedure was performed under a protocol approved by the local ethical committee, and by the Italian National Transplant Center. A 12-month treatment with trastuzumab was performed immediately after LT. Immunosuppression following transplantation was undertaken without steroids, and with everolimus. The patient completed 12 months of follow-up without recurrence. Trastuzumab was then withdrawn. Fifteen months after LT, a liver recurrence occurred that was treated with chemotherapy. In October 2021, she developed 2 brain lesions that were treated with stereotactic radiation. The patient is still alive, with a positron emission tomography/computed tomography performed in January 2024 showing no disease. LT for this patient with BCLM of extreme selectivity showed a good clinical outcome. Perioperative systemic treatment and tumor control are necessary. A specific protocol should be discussed within a multidisciplinary team, and with local and national authorities. Even if tumor recurrence occurs, multimodal therapy can control the disease.

Immunosuppression in liver transplant oncology: position paper of the Italian Board of Experts in Liver Transplantation (I-BELT).

Liver transplant oncology (TO) represents an area of increasing clinical and scientific interest including a heterogeneous group of clinical-pathological settings. Immunosuppressive management after LT is a key factor relevantly impacting result. However, disease-related guidance is still lacking, and many open questions remain in the field. Based on such a substantial lack of solid evidences, the Italian Board of Experts in Liver Transplantation (I-BELT) (a working group including representatives of all national transplant centers), unprecedently promoted a methodologically sound consensus conference on the topic, based on the GRADE approach. The group final recommendations are herein presented and commented. The 18 PICOs and Statements and their levels of evidence and grades of recommendation are reported and grouped into seven areas: (1) risk stratification by histopathological and bio-molecular parameters and role of mTORi post-LT; (2) steroids and HCC recurrence; (3) management of immunosuppression when HCC recurs after LT; (4) mTORi monotherapy; (5) machine perfusion and HCC recurrence after LT; (6) physiopathology of tumor-infiltrating lymphocytes and immunosuppression, the role of inflammation; (7) immunotherapy in liver transplanted patients. The interest in mammalian targets of rapamycin inhibitors (mTORi), for steroid avoidance and the need for a reduction to CNI exposure emerged from the consensus process. A selected list of unmet needs prompting further investigations have also been developed. The so far heterogeneous and granular approach to immunosuppression in oncologic patients deserves greater efforts for a more standardized therapeutic response to the different clinical scenarios. This consensus process makes a first unprecedented step in this direction, to be developed on a larger scale.

Trends in liver transplantation for primary sclerosing cholangitis.

BACKGROUND: 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. AIM: We performed a national survey to investigate the listing criteria, comorbidities, and outcomes. METHODS: In April 2022, we surveyed liver transplantation in primary sclerosing cholangitis nationwide for the last 15 years. RESULTS: 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). CONCLUSIONS: 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.

Porto-sinusoidal vascular disorder (PSVD): Application of new diagnostic criteria in a multicenter cohort of patients.

BACKGROUND AND AIM: The term porto-sinusoidal vascular disorder (PSVD) was recently proposed to replace that of idiopathic non-cirrhotic portal hypertension (INCPH) to describe patients with typical histological lesions in absence of cirrhosis, irrespective of the presence/absence of portal hypertension (PH), and new diagnostic criteria were defined. The study aimed to compare the applicability between the diagnostic criteria of PSVD and those of INCPH. MATERIALS AND METHODS: 53 patients affected by PSVD were enrolled. Biochemical, clinical, ultrasound and histological data, the presence and type of associated diseases were recorded in a database. According to the new criteria, histological data and signs of PH were divided into specific and non-specific. Percutaneous and transjugular biopsies were compared to establish the usability of the two methods for diagnostic purposes. RESULTS: In 85% of the patients the diagnosis of PSVD was obtained by applying the first criterion (25 had specific histological signs with specific signs of PH); one patient presented with specific histological signs but no PH. In 8 patients the diagnosis was obtained by applying the second criterion. 19% of patients had portal vein thrombosis. Finally, the prevalence of the various histological lesions was similar between the patients submitted to percutaneous and transjugular liver biopsy. CONCLUSIONS: The study confirms that the diagnostic criteria of PSVD lead to the inclusion of a greater number of patients than INCPH.

Superiority of the new sex-adjusted models to remove the female disadvantage restoring equity in liver transplant allocation.

BACKGROUND AND AIMS: Model for End-stage Liver Disease (MELD) and MELDNa are used worldwide to guide graft allocation in liver transplantation (LT). Evidence exists that females are penalized in the present allocation systems. Recently, new sex-adjusted scores have been proposed with improved performance respect to MELD and MELDNa. GEMA-Na, MELD 3.0, and sex-adjusted MELDNa were developed to improve the 90-day dropout prediction from the list. The present study aimed at evaluating the accuracy and calibration of these scores in an Italian setting. METHODS: The primary outcome of the present study was the dropout from the list up to 90 days because of death or clinical deterioration. We retrospectively analysed data from 855 adults enlisted for liver transplantation in the Lazio region (Italy) (2012-2018). Ninety-day prediction of GEMA-Na, MELD 3.0 and sex-adjusted MELDNa with respect to MELD and MELDNa was analysed. Brier score and Brier Skill score were used for accuracy, and the Greenwood-Nam-D'Agostino test was used to evaluate the calibration of the models. RESULTS: GEMA-Na (concordance = .82, 95% CI = .75-.89), MELD 3.0 (concordance = .81, 95% CI = .74-.87) and sex-adjusted MELDNa (concordance = .81, 95% CI = .74-.88) showed the best 90-day dropout prediction. GEMA-Na showed a higher increase in accuracy with respect to MELD (p = .03). No superiority was shown with respect to MELDNa. All the tested scores showed a good calibration of the models. Using GEMA-Na instead of MELD would potentially save one in nine dropouts and could save one dropout per 285 patients listed. CONCLUSIONS: Validation and reclassification of the sex-adjusted score GEMA-Na confirm its superiority in predicting short-term dropout also in an Italian setting when compared with MELD.

Association between gut-derived endotoxins and porto-sinusoidal vascular disorder with portal hypertension.

BACKGROUND: Porto-sinusoidal vascular disorder (PSVD) is characterised by lesions involving portal veins and sinusoids in absence of cirrhosis with an unclear pathophysiology. However, its association with immunodeficiency, bowel disorders and abdominal bacterial infections supports the role of altered intestinal permeability and gut-derived endotoxins. The study aimed at assessing the association between serological markers of increased intestinal permeability, pro-aggregating/procoagulant state and liver injury in PSVD and portal hypertension. METHODS: Thirty-three patients with biopsy-proven PSVD and portal hypertension and 33 healthy subjects were submitted to a venous blood sampling for the measurement of zonulin and lipopolysaccharides (LPS) as markers of intestinal permeability, of s-Glycoprotein VI, sP-selectin, ADAMTS13 and von Willebrand factor (vWF), as markers of platelet aggregation and microvascular inflammation, factor VIII and F1 + 2 as markers of hypercoagulability. In 17 PSVD patients, histomorphological and immunohistochemical study on liver biopsies was performed. RESULTS: Compared with controls, PSVD patients had higher levels of LPS, zonulin, vWF, factor VIII and sP-selectin, F1 + 2. ADAMTS13 was reduced. Serum LPS correlated with zonulin, sP-selectin, FVIII and vWF. At histological analysis, PSVD specimens had increased LPS localisation, toll-like receptor-4(TLR4)-positive macrophages and platelet number compared with samples from healthy liver donors. TLR4+ macrophage number correlated with portal inflammation and fibrosis. Sinusoid dilation and capillarisation were observed. PSVD biopsies showed signs of biliary damage and reduced ductular reaction without alteration in Sox9+ cell population. CONCLUSIONS: PSVD patients display an altered intestinal permeability and endotoxemia correlated to a pro-aggregating/procoagulant state; histologically, PSVD was associated with increased TLR4+ cell involvement and platelet clumps within sinusoids. Our study suggests that LPS-TLR4 pathway could contribute to the pathophysiological basis of PSVD with portal hypertension.

Liver ischemia-reperfusion injury: From trigger loading to shot firing.

An ischemia-reperfusion injury (IRI) results from a prolonged ischemic insult followed by the restoration of blood perfusion, being a common cause of morbidity and mortality, especially in liver transplantation. At the maximum of the potential damage, IRI is characterized by 2 main phases. The first is the ischemic phase, where the hypoxia and vascular stasis induces cell damage and the accumulation of damage-associated molecular patterns and cytokines. The second is the reperfusion phase, where the local sterile inflammatory response driven by innate immunity leads to a massive cell death and impaired liver functionality. The ischemic time becomes crucial in patients with underlying pathophysiological conditions. It is possible to compare this process to a shooting gun, where the loading trigger is the ischemia period and the firing shot is the reperfusion phase. In this optic, this article aims at reviewing the main ischemic events following the phases of the surgical timeline, considering the consequent reperfusion damage.

The Italian data on SARS-CoV-2 infection in transplanted patients support an organ specific immune response in liver recipients.

Introduction: The study of immune response to SARSCoV-2 infection in different solid organ transplant settings represents an opportunity for clarifying the interplay between SARS-CoV-2 and the immune system. In our nationwide registry study from Italy, we specifically evaluated, during the first wave pandemic, i.e., in non-vaccinated patients, COVID-19 prevalence of infection, mortality, and lethality in liver transplant recipients (LTRs), using non-liver solid transplant recipients (NL-SOTRs) and the Italian general population (GP) as comparators. Methods: Case collection started from February 21 to June 22, 2020, using the data from the National Institute of Health and National Transplant Center, whereas the data analysis was performed on September 30, 2020.To compare the sex- and age-adjusted distribution of infection, mortality, and lethality in LTRs, NL-SOTRs, and Italian GP we applied an indirect standardization method to determine the standardized rate. Results: Among the 43,983 Italian SOTRs with a functioning graft, LTRs accounted for 14,168 patients, of whom 89 were SARS-CoV-2 infected. In the 29,815 NL-SOTRs, 361 cases of SARS-CoV-2 infection were observed. The geographical distribution of the disease was highly variable across the different Italian regions. The standardized rate of infection, mortality, and lethality rates in LTRs resulted lower compared to NL-SOTRs [1.02 (95%CI 0.81-1.23) vs. 2.01 (95%CI 1.8-2.2); 1.0 (95%CI 0.5-1.5) vs. 4.5 (95%CI 3.6-5.3); 1.6 (95%CI 0.7-2.4) vs. 2.8 (95%CI 2.2-3.3), respectively] and comparable to the Italian GP. Discussion: According to the most recent studies on SOTRs and SARS-CoV-2 infection, our data strongly suggest that, in contrast to what was observed in NL-SOTRs receiving a similar immunosuppressive therapy, LTRs have the same risk of SARS-CoV-2 infection, mortality, and lethality observed in the general population. These results suggest an immune response to SARS-CoV-2 infection in LTRS that is different from NL-SOTRs, probably related to the ability of the grafted liver to induce immunotolerance.

Resolution of primary hepatic marginal zone lymphoma in a hepatitis C virus-infected patient treated with a direct-acting antiviral.

The favorable impact of antiviral therapy on low-grade hepatitis C virus (HCV)-related non-Hodgkin lymphoma manifesting as marginal zone lymphoma (MZL) has been reported in some clinical studies. However, primary HCV-related marginal zone lymphomas (MZLs) confined to the liver have not been described in the literature nor have the resolution of liver lymphoma through anti-HCV eradication treatment. The authors report a genotype 1b HCV-positive patient with chronic hepatitis who exhibited lesions involving both hepatic lobes resembling hepatocellular carcinoma. Liver biopsy revealed an MZL of the liver. Antiviral treatment using sofosbuvir associated with simeprevir as unique treatment was started and resulted in complete haematological response. In HCV-related MZL isolated to the liver, antiviral treatment has led to the eradication of viral infection and a complete haematological response. Antiviral therapy should be considered as a first-line treatment for HCV-related primary MZLs of the liver.

Sarco-Model: A score to predict the dropout risk in the perspective of organ allocation in patients awaiting liver transplantation.

BACKGROUND & AIMS: Sarcopenia in liver transplantation (LT) cirrhotic candidates has been connected with higher dropouts and graft losses after transplant. The study aims to create an 'urgency' model combining sarcopenia and Model for End-stage Liver Disease Sodium (MELDNa) to predict the risk of dropout and identify an appropriate threshold of post-LT futility. METHODS: A total of 1087 adult cirrhotic patients were listed for a first LT during January 2012 to December 2018. The study population was split into a training (n = 855) and a validation set (n = 232). RESULTS: Using a competing-risk analysis of cause-specific hazards, we created the Sarco-Model2 . According to the model, one extra point of MELDNa was added for each 0.5 cm2 /m2 reduction of total psoas area (TPA) < 6.0 cm2 /m2 . At external validation, the Sarco-Model2 showed the best diagnostic ability for predicting the risk of 3-month dropout in patients with MELDNa < 20 (area under the curve [AUC] = 0.93; P = .003). Using the net reclassification improvement, 14.3% of dropped-out patients were correctly reclassified using the Sarco-Model2 . As for the futility threshold, transplanted patients with TPA < 6.0 cm2 /m2 and MELDNa 35-40 (n = 16/833, 1.9%) had the worse results (6-month graft loss = 25.5%). CONCLUSIONS: In sarcopenic patients with MELDNa < 20, the 'urgency' Sarco-Model2 should be used to prioritize the list, while MELDNa value should be preferred in patients with MELDNa ≥ 20. The Sarco-Model2 played a role in more than 30% of the cases in the investigated allocation scenario. In sarcopenic patients with a MELDNa value of 35-40, 'futile' transplantation should be considered.

Liver transplantation for sickle cell disease: a systematic review.

BACKGROUND: Sickle cell disease is a group of autosomal recessive disorders characterised by haemolytic anaemia. Liver is one of the most affected organs, ranging from liver tests alterations to acute liver failure for which liver transplantation is the only life-saving treatment. METHODS: This study aims to make a systematic review of the current literature to evaluate indications, timing, and results of liver transplantation for patients affected by SCD. RESULTS: Twenty-nine patients in total were reported worldwide until 2018, the average patient age is 28.7 (0.42-56), all patients have a pre-transplant diagnosis of SCD. Cirrhosis at transplantation was present in six-teen (n = 16, 55.1%) patients. In ten patients (n = 10, 34.5%), acute liver failure arises from healthy liver and presented sickle cell intrahepatic cholestasis. Eleven patients (n = 11, 39.2%) died, three (n = 3, 10.7%) in the first postoperative month, and seven (n = 7, 25%) in the first year. Mean follow-up was 27 months (range: 7-96), one-year overall survival was 48.7%. DISCUSSION: Liver transplantation for SCD has been increasingly reported with encouraging results. Indications are presently reserved for acute liver failure arising both in healthy liver and end-stage liver disease.

Similar performance of liver stiffness measurement and liver surface nodularity for the detection of portal hypertension in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: We compare the performance of liver surface nodularity (LSN) and liver stiffness measurements (LSM) using transient elastography (TE) for the detection of clinically significant portal hypertension (CSPH) in patients with cirrhosis and hepatocellular carcinoma (HCC). METHODS: All patients with cirrhosis and HCC who underwent computed tomography, LSM and hepatic venous pressure gradient (HVPG) measurements within 30 days between 2015 and 2018 were included. The estimation of CSPH by LSN and LSM, and the LSM-spleen-size-to-platelet ratio score (LSPS) were evaluated and compared. RESULTS: In total, 140 patients were included (109 men [78%], mean age 63 ± 9 years old), including 39 (28%) with CSPH. LSN measurements were valid in 130 patients (93%) and significantly correlated with HVPG (r = 0.68; p <0.001). Patients with CSPH had higher LSN measurements compared with those without [3.1 ± 0.4 vs. 2.5 ± 0.3, p <0.001; area under the receiver operating characteristic (AUROC): 0.87 ± 0.31]. LSM and LSPS were valid in 132 patients (94%) and significantly correlated with HVPG (r = 0.75, p <0.001; AUROC 0.87 ± 0.04 and r = 0.68, p <0.001; AUROC 0.851 ± 0.04, respectively). There was no significant difference in the diagnostic performance between LSN and LSM-LSPS (DeLong, p = 0.28, 0.37, and 0.65, respectively) in patients with both valid tests (n = 122). LSN <2.50 had a 100% negative predictive value for CSPH. A 2-step algorithm combining LSN and LSPS for the diagnosis of CSPH classified 108/140 patients (77%) with an 8% error. CONCLUSIONS: The diagnostic performance and feasibility of LSN measurements were similar to those of LSM for the detection of CSPH in patients with compensated cirrhosis and HCC. Combining LSN and LSPS accurately detected CSPH in >75% of patients. Such a combination could be useful in centres where the HVPG measurement is unavailable. LAY SUMMARY: The diagnostic performance and feasibility of liver surface nodularity was similar to that of liver stiffness measurement (LSM) for the detection of clinically significant portal hypertension in patients with compensated cirrhosis. Thus, liver surface nodularity could be an option for the preoperative detection of clinically significant portal hypertension in patients with hepatocellular carcinoma. Combining liver surface nodularity with LSM-spleen-size-to-platelet ratio score resulted in the accurate detection of clinically significant portal hypertension in >75% of patients, thus limiting the need for HVPG measurements.