Exacerbation of Myopathy in Glycogen Debrancher Deficiency After Liver Transplantation: Case Report and Review of the Literature.

BACKGROUND: Glycogen storage disorder (GSD) type IIIa is a rare inherited genetic disorder affecting liver and muscle tissue. Liver transplantation (LT) improves metabolic control, but muscle involvement persists. CASE: We report the case of a 31-year-old man who underwent orthotopic LT for end-stage liver disease caused by GSD type IIIa. After LT, he developed worsening clinical signs of myopathy, along with exponentially increasing levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and creatine kinase. Liver-related elevations of AST and ALT were excluded through liver biopsy and endoscopic cholangiography; consequently, AST and ALT elevations were attributed to the underlying muscle involvement. Exacerbation of muscle disease after LT could be attributed to restoration of liver glycogen metabolism after LT, leading to increased glucose accumulation in muscle cells, where the gene defect persists. A dietary intervention with a high-protein, ketogenic diet was initiated but did not lead to significant improvement of myalgia. CONCLUSION: LT exacerbated muscle disease in a patient with GSD type IIIa. Patients should be counseled about this possible side effect of LT in GSD type IIIa.

Durvalumab Plus Gemcitabine and Cisplatin in Patients with Advanced Biliary Tract Cancer: An Exploratory Analysis of Real-World Data.

BACKGROUND: The combination of gemcitabine and cisplatin (gem/cis) with the anti-PD-L1-antibody durvalumab was recently approved as first line therapy for biliary tract cancer (BTC) based on the results of the TOPAZ-1 trial. OBJECTIVE: We aim to analyse the feasibility and efficacy of the triple combination therapy in patients with BTC in a real-world setting and in correspondence with the genetic alterations of the cancer. METHODS: In this single-centre retrospective analysis, all patients with BTC and treated with durvalumab plus gem/cis from April 2022 to September 2023 were included. Survival and treatment response were investigated, within the context of the inclusion and exclusion criteria of TOPAZ-1 and in correspondence with genetic alterations of the cancer. RESULTS: In total, 35 patients, of which 51% met the inclusion criteria of the TOPAZ-1 trial, were analysed. Patients treated within TOPAZ-1 criteria did not have a significantly different median overall survival and progression free survival than the rest of the patients (10.3 versus 9.7 months and 5.3 versus 5 months, respectively). The disease control rate of patients within the TOPAZ-1 criteria was 61.1%, in comparison to 58.8% in the rest of patients. A total of 51 grade 3 and 4 adverse events were observed without significant differences in the subgroups. No specific correlating patterns of genetic alterations with survival and response were observed. CONCLUSIONS: The treatment of advanced patients with BTC with durvalumab and gem/cis, even beyond the inclusion criteria of the TOPAZ-1 trial, shows promising safety.

Neurological worsening in Wilson disease - clinical classification and outcome.

BACKGROUND & AIMS: Prevention of neurological worsening (NW) under therapy is an unmet need in the management of Wilson disease (WD). In this study, we aimed to characterize the occurrence, associated outcomes and potential reversibility of NW in WD. METHODS: From a total cohort of 457 patients with WD, 128 patients with WD and neurological features at any time point (all Caucasian, 63 females, median age at diagnosis 22 years) were identified by chart review at University Hospital Heidelberg and grouped according to initial presentation. The timing and occurrence of NW was assessed following a structured clinical examination during clinical visits. RESULTS: Early NW (within the first 3 months of therapy) was observed in 30 out of 115 (26.1%) patients with neurological or mixed presentation and never in patients with a purely hepatic or asymptomatic presentation (0%). Late NW (after >12 months) was seen in a further 23 (20%) with neurological or mixed presentation and in 13 out of 294 (4.4%) patients with a hepatic or asymptomatic presentation. The median time from start of treatment to late NW was 20 months. Only three patients experienced NW between 3 and 12 months. NW was observed with D-penicillamine, trientine and zinc therapy and was reversible in 15/30 (50%) with early NW and in 29/36 (81%) with late NW. CONCLUSIONS: In this study, we identified two peaks in NW: an early (≤3 months) treatment-associated peak and a late (>12 months of treatment) adherence-associated peak. Early paradoxical NW was attributed to treatment initiation and pre-existing neurological damage, and was not observed in those with a hepatic or asymptomatic presentation. Late NW is likely to be associated with non-adherence. IMPACT AND IMPLICATIONS: In patients with Wilson disease, defined as an excess accumulation of copper which can damage the liver, brain and other vital organs, neurological worsening can occur despite chelation therapy. The study identifies different patterns of 'early' (<3 months) vs. 'late' (>12 months) neurological worsening in relation to initiation of chelation therapy and establishes possible causes and the potential for reversibility. These data should be useful for counseling patients and for guiding the optimal management of chelation therapy.

Generating evidence for diagnosis and therapy of RarE LIVEr disease: the RELIVE Initiative for systematic reviews and meta-analyses.

BACKGROUND: Rare liver lesions and diseases have seldomly aroused major interest of researchers. For most guidelines, presumably similar clinical conditions are pooled without detailed investigations of singularities that they present. MAIN TEXT: A multidisciplinary project aiming to establish evidence-based therapies for rare liver diseases has been founded. A series of systematic reviews and meta-analyses will be the starting point for a structured development of guidelines for rare conditions of the liver affecting pediatric and adult populations. The novel approach will be focusing on case reports and small patient series with distinct rare liver diseases without pooling several presumably acceptably similar conditions. Thus, a vital resource of information will be utilized, which has been largely neglected hitherto. CONCLUSION: Highly specific recommendations based on highest available evidence will therefore be developed for specific conditions, advancing the individualized medicine approach for the afflicted patients.

Spleen transient elastography predicts actuarial survival after liver transplantation.

Background: Splenic transient elastography (TE) correlates with increased portal pressure. Little data are available in the post liver transplantation (LTx) setting. Methods: Three months after LTx, we performed splenic TE in 125 LTx recipients. Results: Mean splenic TE values were 29.4 (±6.3; range, 21.6-49.2) kPa. Splenic TE correlated with reduced time to development until persistent ascites (30 events, OR =1.082, 95% CI: 1.034-1.133; P=0.001), hepatorenal syndrome (8 events, OR =1.109, 95% CI: 1.015-1.211; P=0.022) and hepatic encephalopathy (16 events, OR =1.136, 95% CI: 1.066-1.211; P=0.000). In Cox univariate analysis, splenic TE served as a predictor of actuarial survival free of liver (OR =1.114, 95% CI: 1.050-1.182; P<0.001) and remained an independent risk factor associated with reduced actuarial survival free of LTx in multivariate analysis (OR =1.103, 95% CI: 1.026-1.186; P=0.008). Conclusions: Splenic TE measurement at 3 months after LTx serves as a robust predictor of survival in LTx recipients.

Clinical effects and safety of different transarterial chemoembolization methods for bridging and palliative treatments in hepatocellular carcinoma.

PURPOSE: We assessed and compared clinical effects and safety endpoints of three methods of transarterial chemoembolization (TACE), conventional (cTACE), with drug-eluting beads (DEB-TACE), and with degradable starch microspheres (DSM-TACE), used in patients with hepatocellular carcinoma (HCC) in the bridging to liver transplant (LT) and the palliative setting. METHODS: In our center, 148 patients with HCC underwent 492 completed TACE procedures between 2008 and 2017 (158 for bridging to LT; 334 for palliative treatment) which we analyzed retrospectively. Of these procedures, 348 were DEB-TACE, 60 cTACE, and 84 DSM-TACE. RESULTS: The cTACE procedure revealed a significantly longer period of hospitalization (p = 0.02), increased occurrence of nausea (p = 0.025), and rise in alanine transaminase (ALT) levels (p = 0.001), especially in the palliative setting. In the bridging to LT cohort, these clinical endpoints did not reach statistical significance. CONCLUSIONS: The clinical safety of different TACE methods for HCC in both the palliative and the bridging to LT setting was equivalent. In the palliative setting, the cTACE procedure revealed an increased risk for adverse clinical effects such as nausea, elevation of ALT, and a prolonged period of hospitalization what might either be related to the systemic effects of the chemotherapeutic agent or to the differences in both collectives. Thus, further studies must be conducted on a larger number of TACE procedures to effectively explore the clinical side effects of the various TACE variants.

Biliary Rhabdomyosarcoma in Pediatric Patients: A Systematic Review and Meta-Analysis of Individual Patient Data.

BACKGROUND: The biliary tree is a rare location of pediatric rhabdomyosarcoma. Due to the low incidence, there is a lack of evidence concerning therapeutic guidelines for this tumor location. In particular, the impact of surgery is discussed controversially. PURPOSE: Objective is to generate evidence-based treatment guidelines for pediatric biliary rhabdomyosarcoma (BRMS). All available published data on therapeutic regimens and important prognostic factors are investigated with a focus on the role of surgery. METHODS: A systematic literature search of MEDLINE, Web of Science, and CENTRAL was performed. Patient data were entered individually. Data was pooled and qualitative and quantitative analyses of demographic data, therapy, postoperative/interventional outcomes, relapse, and survival were conducted. In an individual patient data analysis, cox regression was applied to identify key factors predicting the outcome of patients with BRMS. RESULTS: 65 studies met the inclusion criteria, providing data on 176 patients with BRMS. Individual patient data analysis showed a 5-year overall survival and progression-free survival of 51% and 50% for the total study population. For patients treated after 2000, 5-year OS and PFS was 65% and 59%, respectively. Absence of surgical tumor resection was an independent risk factor for death (Hazard ratio 8.9, 95%-CI 1.8-43.6, p = 0.007) and significantly associated with recurrent disease and disease-related death. CONCLUSION: This analysis provides comprehensive information on the largest number of patients hitherto reported in the literature. BRMS is still associated with high morbidity and mortality. Surgical tumor resection is essential for appropriate oncological treatment of BRMS. International cooperation studies are needed to enhance evidence and improve the outcome of this orphan disease. PROTOCOL REGISTRATION: PROSPERO (CRD42021228911) https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021228911.

Scirrhous Hepatocellular Carcinoma: Systematic Review and Pooled Data Analysis of Clinical, Radiological, and Histopathological Features.

BACKGROUND: Aberrant subtypes of hepatocellular carcinoma (HCC) account for 20-30% of all HCCs and habitually present a challenge in diagnosis and treatment. Scirrhous hepatocellular carcinoma (s-HCC) is often misdiagnosed as cholangiocarcinoma, fibrolamellar hepatocellular carcinoma, or metastasis. METHODS: Electronic databases (PubMed, Web of Knowledge, Google Scholar, Cochrane Library, and WHO International Clinical Trials Registry Platform) were searched for publications on scirrhous hepatocellular carcinoma without date or language restrictions. Quality assessment was performed using a tool proposed by Murad et al for case reports and series. For observational studies, MINORS quality assessment tool was used. This study was registered at PROSPERO (CRD42020212323). RESULTS: S-HCC arises in patients with chronic hepatitis (hepatitis B in 60% and hepatitis C in 21%). S-HCC primarily affects men with a mean age of 55.8 years. Serum AFP is elevated above 20IU/mL in 66.7% of the patients. On ultrasound, s-HCC presents as hypoechoic or mosaic pattern lesions (47.6% each) and causes a retraction of the liver surface (70%) when near the capsule. Delayed enhancement of the tumor is evident in 87.0%. On MRI, 65.0% of s-HCCs show a target appearance. Histopathologic pattern is mostly irregular (97.6%). Lesions show a bulging appearance (100%), septae (85.6%) and a central scar (63.5%), and usually lack central necrosis (75%). Immunohistochemistry shows HepPar 1 positivity in 64.6%, CK7 in 40.7%, and EMA in 41.9%. The 5-year overall survival rate estimates 45.2% and 45.5% of the patients experience a recurrence after hepatectomy. CONCLUSION: S-HCC is a rare subtype of HCC primarily arising in hepatitis- or cirrhosis-afflicted livers and incorporates atypical radiological and histopathological HCC features. Despite lower recurrence rates, overall survival of patients with s-HCC is poorer than generally for HCC, underlining the need for individualized treatment. Patients with atypical lesions of the liver should be referred to tertiary hospitals for interdisciplinary assessment and treatment.

Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study).

BACKGROUND & AIMS: Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF. METHODS: In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 µg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary efficacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period. RESULTS: Patients treated with G-CSF had a 90-day transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p = 0.992 and HR 1.058; 95% CI 0.727-1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the G-CSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. CONCLUSIONS: In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. CLINICALTRIALS. GOV NUMBER: NCT02669680 LAY SUMMARY: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies.

Treatment stage migration and treatment sequences in patients with hepatocellular carcinoma: drawbacks and opportunities.

PURPOSE: This retrospective analysis focuses on treatment stage migration in patients with hepatocellular carcinoma (HCC) to identify successful treatment sequences in a large cohort of real-world patients. METHODS: 1369 HCC patients referred from January 1993 to January 2020 to the tertiary center of the Heidelberg University Hospital, Germany were analyzed for initial and subsequent treatment patterns, and overall survival. RESULTS: The most common initial treatment was transarterial chemoembolization (TACE, n = 455, 39.3%) followed by hepatic resection (n = 303, 26.1%) and systemic therapy (n = 200, 17.3%), whereas the most common 2nd treatment modality was liver transplantation (n = 215, 33.2%) followed by systemic therapy (n = 177, 27.3%) and TACE (n = 85, 13.1%). Kaplan-Meier analysis revealed by far the best prognosis for liver transplantation recipients (median overall survival not reached), followed by patients with hepatic resection (11.1 years). Patients receiving systemic therapy as their first treatment had the shortest median overall survival (1.7 years; P < 0.0001). When three or more treatment sequences preceded liver transplantation, patients had a significant shorter median overall survival (1st seq.: not reached; 2nd seq.: 12.4 years; 3rd seq.: 11.1 years; beyond 3 sequences: 5.5 years; P = 0.01). CONCLUSION: TACE was the most common initial intervention, whereas liver transplantation was the most frequent 2nd treatment. While liver transplantation and hepatic resection were associated with the best median overall survival, the timing of liver transplantation within the treatment sequence strongly affected median survival.

SARS-CoV-2 Seroprevalence and Clinical Features of COVID-19 in a German Liver Transplant Recipient Cohort: A Prospective Serosurvey Study.

BACKGROUND: In liver transplant (LT) recipients with severe coronavirus disease 2019 (COVID-19), fatal outcome has been reported in a substantial subset of patients. Whether LT recipients are at increased risk for severe COVID-19 compared with the general population is controversial. Here we report the results of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurvey in a large LT recipient cohort. METHODS: A total of 219 LT recipients were enrolled between May 5, 2020, and August 6, 2020, at the University Hospital Heidelberg. Serum blood samples were collected and tested for anti-SARS-CoV-2 IgG. SARS-CoV-2 RNA was detected in nasopharyngeal swabs using reverse transcription-polymerase chain reaction assays. RESULTS: Taking into account known risk factors of arterial hypertension, obesity, diabetes, or leukopenia, LT recipients a priori represented a high-risk cohort for severe COVID-19 with 101 of 219 (46.1%) presenting with more than 2 risk factors for severe COVID-19. Out of 219 LT recipients, 8 (3.7%) either had a positive test result for nasopharyngeal SARS-CoV-2 RNA or anti-SARS-CoV-2 serum IgG. Five of eight (62.5%) did not show any clinical signs of infection, three of eight (37.5%) had self-limited disease, and none required hospitalization for COVID-19. Two of eight (25%) had known exposure to infected health care staff as the probable source of infection. CONCLUSIONS: In summary, LT recipients showed a SARS-CoV-2 seroconversion rate similar to that of the general population with a substantial percentage of unrecognized infections.

Optimized Trientine-dihydrochloride Therapy in Pediatric Patients With Wilson Disease: Is Weight-based Dosing Justified?

OBJECTIVES: The aim of the study was to investigate the efficacy and safety of trientine-dihydrochloride (TD) in pediatric patients with Wilson disease (WD) and the effect of different weight-based dosages on their clinical and biochemical outcome. METHODS: We retrospectively reviewed the clinical data of 31 children with WD receiving TD therapy ages under 18 years at the time of diagnosis. Outcome measures included parameters of copper metabolism and liver function tests. To examine the impact of different weight-based dosages, 2 dosage subgroups were analyzed. Group 1 received less than 20 mg/kg TD per day, group 2 more than 20 mg ·â€Škg-1 ·â€Šday-1. RESULTS: Median follow-up was 60 (5-60) months in the total study group. During TD therapy, nonceruloplasmin-bound copper was reduced from mean 1.53 (0.01-6.95) at baseline to 0.62 (0.01-4.57) µmol/l. 24h-urinary copper excretion diminished to 1.85 (0.8-9.6) µmol/day approximating the therapeutic goal of 1.6 µmol/day. Seven of 31 patients (22.6%) required discontinuation of TD treatment, in 4 cases it was because of adverse events (ulcerative colitis, gingival and breast hypertrophy, hirsutism, elevation of transaminases).Investigations about weight-based dosage showed no significant difference of any laboratory parameter between the 2 cohorts. But in terms of clinical safety, adverse effects because of TD were only found in 6.7% of children in group 1 (<20 mg ·â€Škg-1 ·â€Šday-1, median follow-up 60 [9-60] months), whereas in group 2 (>20 mg ·â€Škg-1 ·â€Šday-1, median follow-up 60 [14-60] months), it was 63.6%. CONCLUSIONS: TD proves to be an efficacious alternative chelating agent for children with WD. Weight-based dosages above the recommended 20 mg ·â€Škg-1 ·â€Šday-1 may increase the rate of adverse effects in pediatric patients.

The macrophage activation marker soluble CD163 is elevated and associated with liver disease phenotype in patients with Wilson's disease.

BACKGROUND: Macrophages play a significant role in liver disease development and progression. The macrophage activation marker soluble (s)CD163 is associated with severity and prognosis in a number of different acute and chronic liver diseases but has been only sparsely examined in Wilson's disease (WD). We investigated sCD163 levels in patients with acute and chronic WD and hypothesized associations with liver disease phenotype and biochemical markers of liver injury. METHODS: We investigated sCD163 in two independent cohorts of WD patients: 28 patients with fulminant WD from the US Acute Liver Failure (ALF) Study Group registry and 147 patients with chronic disease from a German WD registry. We included a control group of 19 healthy individuals. Serum sCD163 levels were measured by ELISA. Liver CD163 expression was determined by immunohistochemistry. RESULTS: In the ALF cohort, median sCD163 was 10-fold higher than in healthy controls (14.6(2.5-30.9) vs. 1.5(1.0-2.7) mg/L, p < 0.001). In the chronic cohort, median sCD163 was 2.6(0.9-24.9) mg/L. There was no difference in sCD163 according to subgroups based on initial clinical presentation, i.e. asymptomatic, neurologic, hepatic, or mixed. Patients with cirrhosis at the time of diagnosis had higher sCD163 compared with those without cirrhosis (3.0(1.2-24.9) vs. 2.3(0.9-8.0) mg/L, p < 0.001); and both cohorts significantly lower than the ALF patients. Further, sCD163 correlated positively with ALT, AST, GGT and INR (rho = 0.27-0.53); and negatively with albumin (rho = - 0.37), (p ≤ 0.001, all). We observed immunohistochemical CD163 expression in liver tissue from ALF patients. CONCLUSIONS: Although sCD163 is not specific for WD, it was elevated in WD patients, especially in those with ALF. Further, sCD163 was higher in patients with cirrhosis compared to patients without cirrhosis and associated with biochemical markers of liver injury and hepatocellular function. Thus, macrophage activation is evident in WD and associates with liver disease phenotype and biochemical parameters of liver disease. Our findings suggest that sCD163 may be used as a marker of liver disease severity in WD patients.

Applicability of scoring systems predicting outcome of transarterial chemoembolization for hepatocellular carcinoma.

PURPOSE: Several scoring systems have been proposed to predict the outcome of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). However, the application of these scores to a bridging to transplant setting is poorly validated. Evaluation of the applicability of prognostic scores for patients undergoing TACE in palliative intention vs. bridging therapy to liver transplantation (LT) is necessary. METHODS: Between 2008 and 2017, 148 patients with HCC received 492 completed TACE procedures (158 for bridging to transplant; 334 TACE procedures in palliative treatment intention at our center and were analyzed retrospectively. Scores (ART, CLIP, ALBI, APRI, SNACOR, HAP, STATE score, Child-Pugh, MELD, Okuda and BCLC) were calculated and evaluated for prediction of overall survival. ROC analysis was performed to assess prediction of 3-year survival and treatment discontinuation. RESULTS: In patients receiving TACE in palliative intention most scores predicted OS in univariate analysis but only mSNACOR score (p = 0.006), State score (p < 0.001) and Child-Pugh score (p < 0.001) revealed statistical significance in the multivariate analysis. In the bridging to LT cohort only the BCLC score revealed statistical significance (p = 0.002). CONCLUSIONS: Clinical usability of suggested scoring systems for TACE might be limited depending on the individual patient cohorts and the indication. Especially in patients receiving TACE as bridging to LT none of the scores showed sufficiently applicability. In our study Child-Pugh score, STATE score and mSNACOR score showed the best performance assessing OS in patients with TACE as palliative therapy.

Non-invasive diagnosis of cirrhosis and long-term disease monitoring by transient elastography in patients with Wilson disease.

BACKGROUND & AIMS: The value of liver stiffness measurement (LSM) by transient elastography (TE) for non-invasive fibrosis staging and disease monitoring has not been established in patients with Wilson disease (WD). METHODS: Liver stiffness measurement by TE and non-invasive fibrosis scores (APRI, FIB-4) were analysed from 188 WD patients with liver biopsy (LBX). Longitudinal LSM was performed in 128 (68.1%) patients. RESULTS: One hundred and eighty-eight patients (mean age: 35 ± 14 years, 54.8% women; 27.1% with histological cirrhosis) were studied. Forty-four[23.4%] patients were recently diagnosed with WD, while 144[76.6%] were previously diagnosed (>1 year between LBX and LSM). Overall, LSM (11.3 vs 6.1 kPa, P < .001), APRI (0.72 vs 0.38, P < .001) and FIB-4 (1.54 vs 0.89, P < .001) were higher in cirrhotic than in non-cirrhotic patients. This was even more pronounced in recently diagnosed patients (35.2 kPa vs 6.4 kPa, P < .001). Accuracy for diagnosing cirrhosis at an LSM cut-off ≥9.9 kPa was better in recently diagnosed (PPV: 74%, NPV: 100%) vs previously diagnosed (PPV: 53%, NPV: 82%) patients. Recently diagnosed patients had higher Area Under the Curve (AUC) for APRI (0.79 vs 0.61) and FIB-4 (0.84 vs 0.65) than previously diagnosed patients. At APRI <1.5 and FIB-4 <3.25 cirrhosis was ruled out with a specificity of 93% and 95% respectively. During a median follow-up of 46 (24-66) months, only 5.9% (5/85) of non-cirrhotic WD patients showed progression to cirrhotic LSM values, while 30.8% (4/13) of cirrhotic WD patients showed LSM suggestive of cirrhosis regression. CONCLUSION: TE-based LSM ≥9.9 kPa accurately identifies cirrhosis in WD patients. Next to TE-LSM <9.9 kPa, APRI <1.5 and FIB-4 <3.25 values assist to non-invasively rule out cirrhosis. LSM remains stable in most non-cirrhotic patients on WD therapy, while one-third of cirrhotic patients present clinically relevant decreases in LSM.

Liver Grafts with Major Extended Donor Criteria May Expand the Organ Pool for Patients with Hepatocellular Carcinoma.

The major extended donor criteria (maEDC; steatosis >40%, age >65 years, and cold ischemia time >14 h) influence graft and patient outcomes after liver transplantation. Despite organ shortages, maEDC organs are often considered unsuitable for transplantation. We investigated the outcomes of maEDC organ liver transplantation in patients with hepatocellular carcinoma (HCC). Two hundred and sixty-four HCC liver transplant patients were eligible for analysis. Risk factor analysis was performed for early allograft dysfunction; primary nonfunction; 30-day and 90-day graft failure; and 30-day, 90-day, and 1-year patient mortality. One-year graft survival was higher in recipients of no-maEDC grafts. One-year patient survival did not differ between the recipients of no-maEDC and maEDC organs. The univariate and multivariate analyses revealed no association between maEDC grafts and one-year patient mortality. Graft survival differed between the recipients of no-maEDC and maEDC organs after correcting for a laboratory model of end-stage liver disease (labMELD) score with a cut-off value of 20, but patient survival did not. Patient survival did not differ between recipients who did and did not meet the Milan criteria and who received grafts with and without maEDC. Instead of being discarded, maEDC grafts may expand the organ pool for patients with HCC without impairing patient survival or recurrence-free survival.

Routine Liver Elastography Could Predict Actuarial Survival after Liver Transplantation.

BACKGROUND AND AIMS: Transient elastography (TE) has routinely been implemented in the diagnosis and assessment of chronic liver disease. Little data are available in the post liver transplant (LTx) setting. METHODS: Three months after LTx, we performed TE in 137 liver transplant recipients and investigated its predictive value upon further clinical outcome. The mean follow-up time for clinical outcome was 24 months. RESULTS: Mean TE value was 10.6 kPa (± 6.3 kPa; range 2.8 - 29.9 kPa). There was a significant correlation between TE and aspartate aminotransferase (AST) (p=0.004), gamma-glutamyl transferase (GGT) (p=0.031) and bilirubin (p<0.001) serum levels. In Cox univariate analysis, TE served as a predictor of actuarial survival free of liver transplantation (OR=1.111, 95%CI: 1.051-1.174; p<0.001). In multivariate analysis, TE remained an independent risk factor associated with reduced actuarial survival free of liver transplantation (OR=1.080, 95%CI: 1.001-1.166; p=0.047), along with thrombocytes (OR=0.992, 95%CI: 0.986-0.999; p=0.020) and metabolic co-disease (OR = 0.250, 95%CI: 0.070-0.895; p=0.033). CONCLUSION: Transient elastography measurement at three months after LTx seems a robust predictor of survival in liver transplant recipients.

Multidrug-Resistant Bacteria and Disease Progression in Patients with End-Stage Liver Disease and after Liver Transplantation.

BACKGROUND: Multidrug-resistant (MDR) pathogens represent an emerging challenge in end-stage liver disease and in liver transplant recipients. METHODS: We evaluated the impact of MDR bacteria upon clinical outcomes in patients with end-stage liver disease (n = 777) at the time of enrollment on the liver transplant (LTx) waiting list, after first LTx (n = 645), and after second LTx (n = 128). RESULTS: Colonization/infection with MDR bacteria was present in 72/777 patients on the waiting list, in 98/645 patients at first LTx, and in 46/128 patients at second LTx. While on the LTx waiting list, the time until first hydropic decompensation (p = 0.021), hepatic encephalopathy (p < 0.001) and hepatorenal syndrome (p < 0.001) was reduced in the presence of MDR bacteria, which remained an independent risk factor of poor survival in multivariate analysis (p < 0.001). Following first and second liver transplant, MDR bacteria were associated with an increased risk of infection-related deaths (first LTx: p < 0.001; second LTx: p = 0.037) and reduced actuarial survival (first LTx: p < 0.001; second LTx: p = 0.046). CONCLUSIONS: We showed that MDR pathogens are associated with poor outcomes before, after first and after recurrent LTx.

Asprosin response in hypoglycemia is not related to hypoglycemia unawareness but rather to insulin resistance in type 1 diabetes.

Asprosin is a counter-regulatory hormone to insulin which plays a role in fasting. It may therefore also play a role in hypoglycaemia unawareness, which has been subsequently examined in this pilot study. Intravenous glucose tolerance test was used to induce controlled hyperglycemia whereas a hyperinsulinemic clamp test was used to induce a controlled hypoglycaemia in 15 patients with diabetes type 1, with and without hypoglycaemia unawareness. Changes in asprosin plasma levels did not differ between patients with and without hypoglycaemia unawareness. However, nine patients with insulin resistance as well as higher liver stiffness values and low-density lipoprotein but lower high-density lipoprotein levels did not show the expected increase in asprosin plasma levels during hypoglycemia. Therefore, insulin resistance and alterations in liver structure, most likely early stages of non-alcoholic fatty liver disease, seem to be relevant in type 1 diabetes and do not only lead to elevated plasma levels of asprosin, but also to a blunted asprosin response in hypoglycemia.