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Acute cellular rejection (ACR) after liver transplantation (LT) goes along with allograft dysfunction, which is diagnosed by liver biopsy and concomitant histological analysis, representing the gold standard in clinical practice. Yet, liver biopsies are invasive, costly, time-intensive and require expert knowledge. Herein we present substantial evidence that blood plasma residing peripheral liver-derived extracellular particles (EP) could be employed to diagnose ACR non-invasively. In vitro experiments showed organ-specific EP release from primary human hepatocytes under immunological stress. Secondly, analysis of consecutive LT patients (n=11) revealed significant heightened EP concentrations days before ACR. By conducting a diagnostic accuracy study (n = 69, DRKS00011631), we explored the viability of using EP as a liquid biopsy for diagnosing ACR following LT. Consequently, novel EP populations in samples were identified using visualization of t-distributed stochastic neighbor embedding (viSNE) and self-organizing maps (FlowSOM) algorithms. As a result, the ASGR1 + CD130 + Annexin V + EP subpopulation exhibited the highest accuracy for predicting ACR (area under the curve: 0.80, 95% confidence interval [CI], 0.70-0.90), with diagnostic sensitivity and specificity of 100% (95% CI, 81.67-100.0%) and 68.5% (95% CI, 55.3-79.3%), respectively. In summary, this new EP subpopulation presented the highest diagnostic accuracy for detecting ACR in LT patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kamali, Schmelzle, Kamali, Brunnbauer, Splith, Leder, Berndt, Hillebrandt, Raschzok, Feldbrügge, Felsenstein, Gaßner, Ritschl, Lurje, Schöning, Benzing, Pratschke and Krenzien.)

Background: Increasing evidence suggests that coffee consumption might protect against hepatocellular carcinoma (HCC) and liver cirrhosis-associated death risk. Caffeine is a natural antagonist to extracellular adenosine and exhibits experimental tumoricidal activity., Aim: To evaluate if coffee consumption has beneficial effects on HCC recurrence after orthotopic liver transplantation (OLT)., Methods: Coffee consumption of patients before and after OLT for HCC was assessed and correlated with HCC recurrence. HepG2 cells were analysed for proliferation and metastasis potential after treatment with adenosine, in the presence or absence of adenosine receptor antagonists. Expression of adenosine receptors was determined, and known adenosine-mediated cancer pathways inclusive of MAPK and NF-kappa B were tested., Results: Ninety patients underwent OLT for HCC. Sixteen (17.8%) patients experienced HCC recurrence after median time of 11.5 months (range 1-40.5). For overall survival postoperative coffee intake emerged as major factor of hazard reduction in a multivariate analysis (HR = 0.2936, 95% CI = 0.12-0.71, P = 0.006). Those with such postoperative coffee intake (≥3 cups per day) had a longer overall survival than those who consumed less or no coffee: M = 11.0 years, SD = 0.52 years vs. M = 7.48 years, SD = 0.76 years = 4.7, P = 0.029)., Conclusions: Coffee consumption is associated with a decreased risk of HCC recurrence and provides for increased survival following OLT. We suggest that these results might be, at least in part, associated with the antagonist activity of caffeine on adenosine-A2AR mediated growth-promoting effects on HCC cells., (© 2019 John Wiley & Sons Ltd.)

Objectives: Living-donor liver transplant represents an established alternative to deceased-donor liver transplant. The procedure is considered safe for donors; however, concerns about the donors' health-related quality of life and health status have not been fully addressed. Here, we aimed to assess the health-related quality of life and postoperative and 1-year clinical outcomes in living liver transplant donors., Materials and Methods: All patients undergoing liver resection for adult-to-adult living-donor liver transplant at our center between December 1999 and March 2013 were evaluated retrospectively. Health-related quality of life was evaluated in a second assessment through written health-related quality of life questionnaires (the Short Form 36 assessment tool) sent to all patients who underwent liver resection for living-donor liver transplant between 1989 and 2012., Results: We identified 104 patients who underwent liver resection for living-donor liver donation between December 1999 and March 2013. Postoperative morbidity was 35.9%, with 56.8% of patients having minor complications. No postoperative, 30-day, or 90-day mortality was evident. At year 1 after transplant, 30 patients (28.8%) had (ongoing) complications, of which 80% were considered minor according to Clavien-Dindo classification. Regarding health-related quality of life, liver donors were characterized as having significantly higher scores in the general health perception component in the Short Form 36 assessment tool (P < .001). We found no significant results in other assessment components (all P > .05)., Conclusions: Liver donors are characterized by an excellent health-related quality of life that is comparable to the general population. Because some donors tend to have concerns regarding their employment status after the procedure, a comprehensive and critical evaluation of potential donors is needed.

Background: Both liver transplantation (LT) and liver resection (LR) represent curative treatment options for hepatocellular carcinoma (HCC) in patients with liver cirrhosis. In this study, we have compared outcomes between historical and more recent patient cohorts scheduled either for LT or LR, respectively., Methods: Clinicopathological data of all patients with HCC and cirrhosis who underwent LT or LR between 1989 and 2011 were evaluated. Overall survival of patients with HCC within the Milan criteria (MC) was analyzed focusing on changes between different time periods., Results: In total, 364 and 141 patients underwent LT and LR for HCC in cirrhosis, respectively. Among patients with HCC within MC, 214 and 59 underwent LT and LR, respectively. Postoperative morbidity (37 vs. 11%, P < .0001), but not mortality (3 vs. 1%, P = .165), was higher after LR than after LT for HCC within MC. In the period 1989-2004, overall survival (OS) was significantly higher in patients who underwent LT compared to LR for HCC within MC (5-year OS: 77 vs. 36%, P < .0001). Interestingly, in the more recent period 2005-2011, OS was comparable between LT and LR for HCC within MC (5-year OS: 73 vs. 61%, P = .07)., Conclusion: We have noted an improvement of outcomes among patients selected for partial hepatectomy in recent years that were comparable to stable results after LT in cirrhotic patients with HCC. Whether those improvements are due to advances in liver surgery, optimized perioperative managament for patients with liver cirrhosis, and the development of modern multimodal treatment strategies for the recurrent lesions appears plausible.

Context: Non-invasive markers for diagnosis of acute rejection (AR) following liver transplantation have not been developed, yet., Objective: We analyzed the correlation of plasma microparticle levels (MP) with AR., Materials and Methods: MP (CD4, CD8, CD25, CD31, MHC) of 11 AR patients and 11 controls were analyzed within the first week after transplantation., Results: CD4, CD8 and CD31 positive MP were higher in the AR, whereas overall MP count, CD25 and MHCI positive MP proportions did not differ between both groups., Discussion and Conclusion: MP dynamics within the first period of transplantation could help to clarify on-going mechanisms of immunomodulation.

Objectives: To date, fatigue is still poorly understood in recipients of orthotopic liver transplant and simultaneous/sequential liver and kidney transplant procedures. The present study examined the appearance of fatigue in patients who received orthotopic liver and sequential liver and kidney transplant procedures compared with the general population and the influence of various clinical and socioeconomic factors on fatigue levels., Materials and Methods: The Multidimensional Fatigue Inventory survey was sent to all patients with a history of orthotopic liver and simultaneous/sequential liver and kidney transplant. The results were compared to data from a reference population., Results: Our survey included 276 eligible patients: 256 recipients (92.7%) of orthotopic liver transplant and 20 recipients (7.3%) of simultaneous/sequential liver and kidney transplant. Significantly lower fatigue scores were found in the general population compared with both transplant groups (P < .001). There were also no significant differences between the transplant groups. Among the clinical and socioeconomic factors, history of hepatocellular carcinoma, chronic kidney disease, age, family status, and education had a significant impact on fatigue levels., Conclusions: This is the first study to compare fatigue in recipients of orthotopic liver and simultaneous/sequential liver and kidney transplant. We found that fatigue is an important but still poorly understood outcome after transplant.

Background: Liver Retransplantation (Re-LT) procedures are associated with an increased risk of morbidity and mortality. Up to date, there is no knowledge on the health-related quality of life and the mental status of these patients., Methods: Health-Related Quality of Life (HRQoL) was assessed by using the Short Form 36 (SF-36) Health Survey and Mental Status was assessed by using the Hospital Anxiety and Depression Scale (HADS). The patients were examined in different assessments: During regular check-up examinations in the LT outpatient department in 2011 (Survey 1) and in a postal survey in 2013 (Survey 2). Their medical data was collected by using an established database., Results: We received eligible surveys of 383 patients (55.6%) with a history of LT, of which 15 (3.9%) had undergone Re-LT (Re-LT group). These patients were compared to a group of 60 patients who had undergone only one LT. With regard to their HRQoL, the Re-LT group had significantly lower scores on the scales of physical function (PF, p = 0.026), their role-physical (RP, p = 0.008), their vitality (VIT, p = 0.040), and their role-emotional (RE, p = 0.005). The scores for anxiety and depression did not differ significantly between the groups. In a multiple regression analysis, chronic kidney disease was found to be an independent risk factor for decreased scores of PF (p = 0.023)., Conclusions: Patients who have to undergo Re-LT procedures are faceing impairments in physical aspects of a HRQoL. Together with clinical results from other studies, the findings of the present examination underline the need for an optimized organ distribution strategy since not all patients listed for Re-LT appear to benefit from it.

Introduction  Older patients are neglected in clinical trials and are likely to be excluded from liver transplantation (LT). The aim of this study was to assess fatigue, anxiety, depression, and health-related quality of life (HRQoL) in elderly LT recipients. Methods  Questionnaires were mailed to patients who underwent LT between 1993 and 2013. Three groups were created: patients ≥ 70, 60 - 69, and < 60 years old. Mental-health status, life satisfaction, and fatigue were assessed using, respectively, the Hospital Anxiety and Depression Scale (HADS), Questions on Life Satisfaction (FLZ-M), and the Multidimensional Fatigue Inventory (MFI-20). Results  In total, 276 eligible questionnaires (40.1 %) were received out of 689 patients with a history of LT. No age-related differences were found with regard to anxiety or depression in the study sample. Patients ≥ 70 years old had significantly better life satisfaction in regards to income (p = 0.003) and work (p = 0.005) compared to patients < 60 years. The overall fatigue scores were the highest in patients < 60 years (52.7, SD = 15.8) and ≥ 70 years (52.7, SD = 17.7) compared to patients 60 - 69 years old (48.2, SD = 17.3, p = 0.037). Discussion  Advanced age alone should not be considered a contraindication for LT due to potentially poor quality of life outcomes., Competing Interests: Conflict of interest: Declaration of conflicting interests None of the authors has any personal or institutional financial interest in drugs, materials, or devices described in this manuscript. Funding F.K is a participant in the BIH‐Charité Clinical Scientist Program funded by the Charité –Universitätsmedizin Berlin and the Berlin Institute of Health. Author contributions C.B. conducted and supervised the study. N.K., M.H.M., G.W., G.A, H.H., and M.B. recruited the participants, collected the data, and prepared the figure and tables. F.K. and C.B. interpreted the data and wrote the manuscript. A.H. and M.S. reviewed the manuscript. Details and comments The corresponding author (CB) confirms that the manuscript has not been submitted or published in any other journal. The study was conducted and prepared according to the Declaration of Helsinki. All the co-authors agree with the publication. Sponsor's role None., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: This study seeks to examine the impact of orthotopic liver transplantation (OLT) on Health-Related Quality of Life (HRQoL) and mental health in patients with different MELD scores., Methods: Patients who has undergone orthotopic liver transplant (OLT) or were on the waiting list for OLT were submitted to HRQoL and depression/anxiety assessment by questionnaire: Short-Form 36 (SF-36), Questions on Life Satisfaction (FLZ-M), Patient Health Questionnaire-4 (PHQ-4). Data were analysed following division of patients into three groups: pretransplant patients with a MELD score <10, ≥10, and OLT recipients., Results: The surveys were sent to 940 consecutive patients within one week in June 2013. Of these 940 patients, 869 (92.4%) met the inclusion criteria. In total, 291 (33.5%) eligible questionnaires (OLT group: 235, MELD <10: 25; MELD &#95;10: 31) were suitable for analysis. General health (GH), vitality (VIT), and mental health (MH) were lower in both pretransplant groups compared to the OLT group (all p < 0.05). Anxiety and depression were higher in the MELD <10 group than in the OLT group (anxiety: p < 0.05; depression: p < 0.01)., Discussion: Patients with low MELD scores seem to benefit from OLT with regards to HRQoL and mental health., (Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The influence of immunosuppression on the recipients' quality of life (QoL) is of major importance after OLT and has not yet been evaluated., Methods: The impact of different immunosuppression regimens after OLT was evaluated in 275 patients using the Short Form 36 (SF-36) survey. The following immunosuppressive strategies were compared: (a) CNI, (b) mTOR inhibitors, and (c) mTOR combined with CNI. All regimens were prescribed alone (mono) or in combination (+) with prednisolone and/or mycophenolate mofetil (MMF)., Results: Highest scores were evident in patients in the mTOR+ group. There were significantly higher values for general health perceptions (GH, p = 0.049), vitality (VIT, p = 0.020), and physical component summary (PCS, p = 0.041) when compared to CNImono and for GH (p = 0.042) and VIT (p = 0.043), when compared to mTORmono. Early conversion to mTOR inhibitors (two months after OLT), with a statistically significant improvement for the dimension role-emotional (RE, p = 0.027)., Discussion: mTOR inhibitor-based regimens appear to have beneficial effects on QoL after OLT, especially after an early conversion., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: In contrast to the well-described beneficial organic effects of liver transplantation (OLT) in patients with end-stage liver disease, changes in the mental status of patients after OLT remain poorly understood. The current study seeks to evaluate the influence of OLT on anxiety, depression, and dispositional optimism in patients with end-stage liver disease., Material and Methods: Questionnaires were sent to patients on the OLT waiting list and patients after OLT. Depression/anxiety and dispositional optimism were assessed using the HADS and LOT-R questionnaires, respectively. These findings were compared to results from the general population., Results: The number of returned questionnaires was 292 of 940 (31.1%; 57 patients on the liver transplant waiting list: waiting group, 235 liver transplant recipients: OLT group). Both depression and anxiety scores were significantly higher in the waiting group when compared to the OLT group (p<0.05) and the general population (anxiety: p<0.001, depression: p<0.05), respectively. The OLT group was characterized by significantly higher anxiety scores (p<0.001) compared to the general population. Depression and summation scores did not differ (p>0.05). Dispositional optimism was higher in the OLT group compared to the waiting group (p<0.05) and to the general population (p<0.01). The waiting group had equal values as the general population (p>0.05)., Conclusions: Besides beneficial effects on liver function, OLT appears to be associated with significant improvements in depression and anxiety and a more optimistic view of life.