Introduction: Antimitochondrial antibodies (AMA) serum positivity represents a major criterion for diagnosing primary biliary cholangitis (PBC). However, AMA positivity may be found in the presence of normal liver enzymes, suggesting that it could predispose to the development of PBC over time. This study aimed to evaluate the incidence and risk factors for PBC development in a cohort of AMA positive patients.Materials and methods: This retrospective-longitudinal study, conducted from January 2014 to December 2023, enrolled all patients tested AMA positive in the central laboratory of the academic hospital in Udine (Italy), that serves a population of 537.943 inhabitants.Results: 392 patients tested positive for AMA and 133(33.9%) of them fulfilled the diagnostic criteria for PBC. The annual incidence of AMA positivity and PBC was 5.31/100000 and 2.09/100000 inhabitants, respectively. At the time of the first AMA detection, 93/133(69.9%) patients had an established PBC. In the remaining 40 patients, PBC developed during the follow-up with a declining annual rate, ranging from 4.7% to 1%, with a cumulative 5- and 10-years incidences of 11.7% and 13.4% respectively. At the univariate and multivariate time-to-event analysis PBC occurrence was associated with baseline AMA titre>225 UI/L(O.R. 2.01, 95% C.I. 1.39-2.91, p<0.001), levels of gamma-glutamyltranspeptidase (GGT)>40 UI/L(O.R. 4.25, 95% C.I. 2.76-6.54, p<0.001) and alanine-aminotransferase (AST)>30 UI/L(O.R 1.69, 95% C.I. 1.16-2.45, p=0.005).Conclusions: In AMA positive patients, baseline AMA titre, GGT and AST serum levels anticipate the PBC development.

BACKGROUND AND AIMS:Long-term albumin (LTA) is effective for treating ascites in decompensated cirrhosis. This study aims to analyse the clinical courses of patients receiving LTA and provide a 3 month stratification to personalise management integrating LTA with other options. METHODS:Patients receiving LTA included in the multicentre, retrospective, observational Real-ANSWER study were stratified into three categories according to the response of ascites after 3 months of treatment: 'responders' (grade 0-1 ascites), 'partial responders' (at least grade 2 ascites not receiving therapeutic paracentesis) and 'non-responders' (at least grade 2 ascites receiving therapeutic paracentesis). Clinical trajectories and outcomes of the different categories were compared. RESULTS:Of the 252 patients included (median Child-Pugh 9, MELDNa 18), 36% were responders, 29% partial responders and 35% non-responders. Responders differed significantly from the other groups, with higher cumulative incidence of LTA discontinuation for clinical improvement (33%) and transplantation (26%), a lower 18 month mortality (13%) and minimal use of TIPS. Partial and non-responders showed similar trajectories with high mortality (35% and 42%) and low incidence of transplantation (12% and 11%). TIPS was performed predominantly among non-responders (15%). Both groups had a few patients (12% and 8%) able to stop LTA for clinical improvement frequently related to an effective etiologic treatment. CONCLUSIONS:Using a 3 month stratification according to the ascites response of LTA, patients can be grouped into three categories with different clinical courses and outcomes. This may help to stratify prognosis and inform clinical discussions on the management of ascites by integrating LTA with other available options.

Introduction: Liver transplantation (LT) is the recommended curative treatment for cirrhosis with hepatocellular carcinoma (HCC). The radiological evaluation of tumor burden and of tumor response to treatments remains a cornestone in the selection process of candidates for LT. However, detection of HCC can be incidental at the liver explant, demonstrating that the correlation between pre-LT radiology and post-LT pathology in patients with HCC can be inaccurate. Aim. To compare the radiological presence and size of HCC evaluated pre-LT with histological findings observed in the explanted liver in a cohort of liver transplant recipients.Materials and Methods: Pre-LT diagnosis of HCC was performed by means of computed tomography (CT) or magnetic resonance imaging (MRI). The Liver Imaging Reporting and Data System (LI-RADS) and LI-RADS Treatment Response (LR-TR) categories were used to assess the size and number as well as the response to treatment of detected HCC. In transverse sections of the explanted livers the vital HCC lesions were detected. If multifocal tumor was detected, the sum of diameters of focal liver lesions was computed. Statistical analysis was performed using T-test MedCalc version 23.4.0.Results: From January 2015 to November 2025, explanted livers of 50 patients (88% male, median age 60 years) transplanted were evaluated. The most prevalent (58%) etiology of liver cirrhosis was alcohol-related. CT and MRI were performed as pretransplant radiologic diagnosis in 42 and 8 patients respectively, within a median time of 44 days (min 1-max 120 days) from LT. Mean histologic size of HCC was 20.9 mm compared to 14.3 mm detected at the radiologic evaluation (p = 0.0333) (95% CI: 0.53 to 12.66, Pooled Standard Deviation 15.2). In 3 (6%) patients, HCC was incidentally found at explant. Of these 3 cases, focal liver lesions were not detected on the pre-LT radiology imaging in 2 patients while in one patient, hepatic lesion was classified as LI-RADS 3.Conclusions: Although with a small sample size, our study seem to confirm the the potential radiological underestimation of the presence of HCC in the context of LT. These features, if confirmed in larger cohorts, could be relevant in revising the selection of HCC patients for LT within extended criteria.

Background: Liver transplantation (LT) is the best therapeutic strategy in patients with early-stage hepatocellular carcinoma (HCC) and end-stage liver disease. However, cancer recurrence may occur in 15-20% of cases, often configuring a poor prognosis condition. In few cases recurrence arises with a limited pattern, allowing local ablative treatments, including surgical resection, with a potentially curative effect. This is the first report of an extrahepatic nodule resection employing intraoperative ultrasonography through minimally invasive thoracoscopic surgery. Case Description: We here describe the case of a patient with a subdiaphragmatic retrohepatic HCC recurrence following LT treated with percutaneous microwave (MW) ablation and subsequent surgical resection. MW ablation of the nodule resulted in partial response and subsequent computed tomography (CT) demonstrated persistence of the nodule without further metastases development. Surgery was performed through a minimally invasive thoracoscopic approach employing intraoperative ultrasonography with partial success. Follow-up CT scan revealed an additional local recurrence. A further MW ablation procedure led to disease control with no evidence of disease at 2 years follow-up. Conclusions: Local ablative treatments may play a curative role in HCC oligorecurrence following LT. In this context, minimally invasive treatments should be preferred for their safety and lower impact on patients' general conditions. Intraoperative transdiaphragmatic ultrasonography may be useful to correctly localize the target lesions during minimally invasive surgery.

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2Is) have significantly improved the management of diabetes mellitus (DM). In the general population, these drugs have additional benefits, such as weight loss, improvement of liver steatosis, and a cardiorenal protective effect. However, data regarding the effects of GLP-1RAs or SGLT-2Is in the treatment of posttransplant diabetes mellitus (PTDM), obesity, and their potential cardiorenal protective effects in liver transplant (LT) recipients remain limited. PTDM increases the risk of developing graft steatosis, experiencing major cardiovascular events (MACEs), and developing chronic kidney disease and reduces long-term survival in LT recipients. The aim of this systematic review was to evaluate the efficacy and safety of GLP-1RAs and SGLT-2Is in the treatment of PTDM in LT recipients. Methods: Twelve retrospective studies (five specifically conducted in LT recipients and seven in mixed solid organ transplant cohorts, including LT recipients) that collectively enrolled 402 LT recipients treated with GLP-1RAs and/or SGLT-2Is for PTDM were selected. Results: GLP-1Ras and SGLT-2Is reduced serum glycated hemoglobin levels, body weight, and insulin requirements in LT recipients. Some studies reported benefits in reducing graft steatosis, improving renal function, and in reducing the occurrence of MACEs. Common adverse events included gastrointestinal symptoms, which rarely required treatment discontinuation. Conclusions: GLP-1RAs and SGLT-2Is represent promising treatment options for PTDM in LT recipients, offering metabolic benefits with manageable side effects. However, further prospective studies are needed to establish the long-term safety and efficacy, as well as the favorable impact on patient survival, of these drugs in LT recipients.

Background and AimsLong-term albumin (LTA) has become standard of care for patients with decompensated cirrhosis in many Italian hepatological centres. This study aimed to address several issues related to patients and treatment still undefined in real-life practice.MethodsThis multicenter retrospective observational study included patients with cirrhosis and ascites receiving LTA (at least one month) between 01/2016 and 02/2022. Data on patient characteristics, albumin treatment, clinical courses and outcomes were collected.Results312 patients, the majority with alcoholic cirrhosis, were included in 5 Italian centers. At baseline, median Child-Pugh was 8, MELD 15 and MELD-Na 18. In 55% of patients, ascites was grade 2, in 36% grade 3 and in 28% refractory, while 47% had paracentesis in the previous 6 months. Median LTA was about 10 months with a median dose of 40 g/week. Albumin was infused in territorial services in 44% of cases and only 1% discontinued due to logistic reasons. Ascites resolved to grade 0-1 in 34% of patients within the first 3 months and 61% at the end of treatment. Among patients receiving paracenteses prior LTA, about 40% had no paracentesis at 6 months. Factors independently associated with ascites resolution were grade 2 ascites and INR at baseline, albumin dose, serum albumin of 38 g/l at 1 month and no paracentesis in the previous 6 months. Interestingly, 75 patients, including some with refractory ascites, discontinued LTA due to clinical improvement. No adverse events were reported.ConclusionsLTA is feasible, safe and very effective in treating ascites, with almost 25% of patients being able to stop treatment for ascites resolution. Patients with uncomplicated ascites appear the best candidates to LTA, although those with refractory ascites may also benefit of treatment. Confirming previous data, on-treatment serum albumin concentration close to 40 g/l predicts a better response.

Background & Aims: Long-term albumin (LTA) is currently standard of care for patients with decompensated cirrhosis in many Italian hepatology centres. In this real-life study, we aimed to describe patient, logistical and treatment-related characteristics in daily clinical practice and to identify predictors of response. Methods: We performed a multicentre, retrospective, observational study in patients with cirrhosis and ascites receiving LTA between 01/2016 and 02/2022 and followed until death, TIPS (transjugular intrahepatic portosystemic shunt) placement, transplantation or 02/2023. Results: A total of 312 patients, the majority with alcohol-related cirrhosis, were included. At baseline, median Child-Pugh, MELD, and MELD-Na were 8, 15, and 18, respectively. Ascites was grade 2 in 55% of patients, grade 3 in 35% and refractory in 27%, while 47% had received large volume paracentesis in the previous 6 months. Median LTA was 10 months with a median dose of 40 g/week. Ascites resolved to grade 0-1 in 34% of patients within the first 3 months and 56% by the end of treatment. Predictors of ascites resolution were age (p = 0.007), baseline grade of ascites (p = 0.007), no paracentesis in the previous 6 months (p = 0.001), aetiological treatment in the past 12 months or during LTA (p = 0.005), weekly albumin dose (p = 0.014) and serum albumin concentration of 40 g/L after 1 month of treatment (p = 0.017). Of the 83 patients with refractory ascites at inclusion, 26% had grade 0/1 ascites at the last observation. No severe albumin-related side-effects were reported and only 1% discontinued for logistical reasons. Conclusions: LTA is feasible as an outpatient treatment for the management of ascites. In the current study, ascites resolved in more than half of patients receiving LTA on top of diuretics, including in some with refractory ascites. Predictors of response to LTA provide useful information for tailoring treatment. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

In liver transplantation (LT), inferior vena cava (IVC) outflow obstruction has been reported in 3% of cases.1 The main determinants are technical errors, extensive fibrosis, and ab extrinsic compression.2 The clinical presentation ranges from lower limb edema to ascites to even allograft failure. Diagnosis is confirmed by contrast computed tomography (CT) scan and by cavography.1 We present a case of a 60-y-old woman who underwent deceased-donor LT for alcohol-related cirrhosis. Piggyback technique, using all hepatic vein orifices, was adopted. Five months after LT, she developed imprinted lower limb edema and diuretic-responsive mild ascites. A contrast CT scan showed a “twisting” of the IVC at the caudal portion of the piggyback anastomosis because of graft rotation (Figure 1). Cavography showed patent suprahepatic veins without transanastomotic pressure gradient. Thus, an endovascular stent (Sinus-XL 30 × 60 mm, Optimed Medizinische Instrumente GmbH, Ettlingen, Germany) was placed in the IVC. Three weeks later, lower limb edema and ascites persisted. A new cavography demonstrated further twisting of the IVC at the caudal extremity of the stent. Considering the high risk of a retransplant, we decided to place another endovascular stent (Sinus-XL 22 × 100 mm) to extend the existing stent inside the IVC. Postprocedure cavography demonstrated that twisting of the IVC was still present at the extreme caudal site of the second stent. Thus, a third endovascular stent (Sinus-XL 22 × 80 mm) was placed, extending the previous 2 stents, reaching the outlet of the renal veins. Four weeks later, both the limb edema and ascites partially improved. The new cavography showed, during each inspiration, nearly complete collapse of the IVC at the extreme caudal site of the third stent. Four additional stents (12 × 60 mm and 14 × 60 mm in IVC; BARD Luminexx, NJ), extending the third stent into the left and right iliac veins (12 × 40 and 14 × 40 mm), were placed. Two weeks later, a contrast CT scan demonstrated complete resolution of IVC twisting (Figure 2). The full sequence of endovascular procedures is documented in Video 1. Limb edema and ascites disappeared in 2 wk, and after a follow-up of 12 mo, the patient remained asymptomatic with preserved graft function, and IVC remained patent at the Doppler ultrasound performed every 2 mo.FIGURE 1.: Contrast CT scan key images obtained at a clinical presentation of limb edema and mild diuretic responsive ascites. A, The horizontal plane CT scan image, demonstrating stenosis of the IVC closed to the piggyback anastomosis (arrow), with patency of the 3 hepatic veins. The caudal portion of the IVC is dilated. B, The sagittal CT scan image that illustrates in more detail a significant IVC stenosis, starting 4 mm caudally to the piggyback anastomosis (arrow). The lumen of the IVC between the piggyback anastomosis and the right heart atrium is uneven. This suggests the presence of a slowing of the flow inside the IVC that, in the absence of thrombosis, can be compatible with a twisting of the vein. CT, computed tomography; IVC, inferior vena cava.FIGURE 2.: Contrast CT scan key image obtained after the successful placement of the seventh endovascular stent. The image shows the entire inferior vena cava and both iliac veins underwent endovascular stenting, which allowed complete resolution of the vein twist. CT, computed tomography.To our knowledge, this is the first reported case of repeated twisting of the IVC after LT treated with insertion of 7 endovascular stents. When ballooning of the IVC is insufficient to restore the durable patency of the vein,3 IVC stenosis after LT is treated with endovascular techniques.3-5 Likewise, endovascular stents may sometimes migrate distally or become thrombosed.1 In our case, although the first endovascular stent did not migrate, it was insufficient to restore IVC patency. We hypothesized that the increased abdominal pressure exerted by ascites precluded the maintenance of IVC patency. Otherwise, a pericaval fibrosis could be developed following the dissection of the caudate lobe from IVC during hepatectomy. In summary, complete stenting of the IVC and iliac veins was successfully performed, avoiding the need to surgically remake the anastomosis.

The treatment response criteria in autoimmune hepatitis (AIH) have been recently updated. This study aimed to assess treatment responses in 39 (16 males) patients with AIH confirmed by histology. Prednisone added to azathioprine or mycophenolate was the most frequent first-line treatment. Serum alanine aminotransferase (ALT) levels were periodically checked for a median of 45 months. Eight (20.5%) patients presented 4 weeks non-response (NR). Baseline lower multiples of ALT above the upper normal limit (UNL) (p = 0.005), Ishak liver fibrosis score > 3 (p = 0.029), and less frequent confluent necrosis > 2 (p < 0.001) were independent predictors of NR. 24 (61.5%) patients achieved complete biochemical response (CBR) at six months. Ishak liver fibrosis score ≤ 3 (p < 0.001), lobular eosinophilic infiltrate (p < 0.001), and ≥50% decrease in serum ALT levels at week 4 (p < 0.001) were independent predictors of CBR. In addition, the GLUCRE score, derived from the multiplication of serum creatinine (mg/dL) and glucose (mg/dL) levels, were identified. A baseline GLUCRE value > 100 strongly predicted CBR failure (p = 0.003) at a follow-up greater than 12 months. In conclusion, the absence of cirrhosis and a ≥50% UNL decrease in serum ALT levels were independent predictors for CBR. A baseline GLUCRE score may help identify patients maintaining longer CBR.

Background & aims: The fourth dose of anti-SARS-CoV-2 vaccine slightly improved the humoral response among previously seronegative liver transplant (LT) recipients. Mycophenolate (MMF) treatment worsens the vaccination response. This study aimed to evaluate whether temporary MMF interruption might improve the immunogenicity of the fourth anti-SARS-CoV-2 BNT16b2 vaccine dose in nonresponsive LT recipients. Methods: LT recipients negative for anti-spike glycoprotein-specific immunoglobulin G receptor-binding domain (s-RBD) antibodies after the third vaccine dose were enrolled. Anti-SARS-CoV-2 spike-specific T-cell responses were measured before and 2 months following the fourth vaccine dose, and anti-SARS-CoV-2 s-RBD antibodies also 6 months thereafter. MMF was suspended two weeks before and after vaccination. Results: Five LT recipients were enrolled. After a mean of 78 days after vaccination, all patients tested positive for anti-SARS-CoV-2 s-RBD antibodies. The mean antibody titer was 8944 UI/mL. The positive antibody response was maintained during a mean of 193 days of follow-up. Three patients developed a positive T-cell response. Two patients (one positive for T-cell response) developed a self-limited SARS-CoV-2 infection. Conclusions: Suspending MMF prior to the fourth dose of the anti-SARS-CoV-2 mRNA vaccine seems feasible and safe. This procedure could restore vaccine-induced immunogenicity in a large portion of previously nonresponsive LT recipients.

With long-term survival after liver transplantation becoming the rule, care for medical problems arising over time in liver-transplanted patients gained increasing importance. The most common causes of death occurring more than 1 year after liver transplantation are unrelated to liver diseases and facilitated by immunosuppressive treatments; examples are malignancies, renal failure, and cardiovascular, metabolic, and infectious diseases. Recipients receive life-long follow-up care at transplant centers, however, the increasing number of liver-transplanted patients is saturating the health care supply that transplant centers have to offer. Primary care physicians are increasingly exposed to liver-transplanted patients, even in the early periods after transplant, and an understanding of the most common risks and complications faced by these patients would enhance their care. This article reviews the long-term care of liver transplant recipients, emphasizing the key internal medicine-related issues that should be known by primary care physicians. A specific section is devoted to implementing strategies to involve these physicians in the long-term follow-up of liver-transplanted patients in close collaboration with transplant hepatologists.

Background & Aims: The long-term immunogenicity of anti-SARS-CoV-2 vaccines in liver transplant (LT) recipients is unknown. We aimed to assess the long-term antibody response of the Pfizer-BioNTech (R) BNT162b2 vaccine in LT recipients compared to controls. Methods: LT recipients underwent anti-SARS-CoV-2 anti-receptor-binding domain protein IgG (anti-RBD) and anti-nucleocapsid protein IgG antibody (anti-N) measurements at the first and 1, 4 and 6 months after the second vaccination dose. Results: One hundred forty-three LT recipients and 58 controls were enrolled. At baseline, 131/143 (91.6%) LT recipients tested anti-N negative (COVID-19 naive), and 12/143 (8.4%) tested positive (COVID-19 recovered) compared to negative controls. Among COVID-19 naive, 22.1% were anti-RBD positives 1 month after the first vaccine dose, while 66.4%, 77%, and 78.8% were 1, 4 and 6 months following the second vaccine dose. In contrast, 100% of controls were positive at 4 months (p <0.001). The median anti-RBD titer 4 months after the second vaccine dose was significantly lower (32 U/ml) in COVID-19 naive than in controls (852 U/ml, p <0.0001). A higher daily dose of mycophenolate mofetil (MMF) (p <0.001), higher frequency of ascites (p = 0.012), and lower serum leukocyte count (p = 0.016) were independent predictors of anti-RBD negativity at 6 months. All COVID-19 recovered patients tested positive for anti-RBD at each time point. The median antibody titer was similar in those taking MMF (9,400 U/ml, 11,925 U/ml, 13,305 U/ml, and 10,095 U/ml) or not taking MMF (13,950 U/ml, 9,575 U/ml, 3,500 U/ml, 2,835 U/ml, p = NS) 3 weeks after the first and 1, 4 and 6 months after the second vaccine dose, respectively. Conclusions: In COVID-19-naive LT recipients, the immunogenicity of anti-SARS-CoV-2 vaccination was significantly lower than that in controls. MMF was the main determinant of vaccination failure in SARS-CoV-2-naive patients. Lay summary: The immunogenicity of anti-SARS-CoV-2 vaccination in liver transplant recipients is currently unknown. Herein, we show that liver transplant recipients who have not previously had COVID-19 are less likely to mount effective antibody responses to vaccination than a control population. The main determinant of vaccination failure was the use of the immunosuppressive drug mycophenolate mofetil. (C) 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Background Patients with liver disease may be at increased risk of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection due to immune dysfunction. However, the risk of nosocomial SARS-CoV-2 infection in these patients remains unknown. This study aimed to determine whether patients with liver disease are at an increased risk of nosocomial transmission of SARS-CoV-2 infection upon admission to the hospital for diagnostic or therapeutic procedures. Methods The study prospectively enrolled 143 patients who were admitted at least once to the hepatology unit at our hospital; 95 patients (66%) were admitted at least twice during the study period. History of past symptomatic SARS-CoV-2 exposure was assessed on the day before hospital admission via an interview. Patients were evaluated for active SARS-CoV-2 infection via real-time reverse transcription–polymerase chain reaction (RT-PCR) performed on nasopharyngeal swabs and tests for serum anti-SARS-CoV-2 immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies. Results None of the patients enrolled tested positive for SARS-CoV-2 infection by RT-PCR at the first or the second clinical evaluation. One patient who had previously received a liver transplant and who had a history of symptomatic SARS-CoV-2 infection that occurred 4 months before hospital admission tested positive for anti-SARS-CoV-2 IgG but not IgM antibodies at each of the two hospital admissions. Conclusions The results of our study suggest that patients with liver disease are at no increased risk of nosocomial SARS-CoV-2 infection. These data support the policy of maintaining clinical hospital checks that will be necessary until or possibly even after the completion of the current SARS-CoV-2 vaccination campaign.