Herold J. Metselaar

Systematic Review and Meta‐Analysis of the Impact of Computed Tomography–Assessed Skeletal Muscle Mass on Outcome in Patients Awaiting or Undergoing Liver Transplantation

Liver transplant outcome has improved considerably as a direct result of optimized surgical and anesthesiological techniques and organ allocation programs. Because there remains a shortage of human organs, strict selection of transplant candidates remains of paramount importance. Recently, computed tomography (CT)‐assessed low skeletal muscle mass (i.e. sarcopenia) was identified as a novel prognostic parameter to predict outcome in liver transplant candidates. A systematic review and meta‐analysis on the impact of CT‐assessed skeletal muscle mass on outcome in liver transplant candidates were performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines. Nineteen studies, including 3803 patients in partly overlapping cohorts, fulfilled the inclusion criteria. The prevalence of sarcopenia ranged from 22.2% to 70%. An independent association between low muscle mass and posttransplantation and waiting list mortality was described in 4 of the 6 and 6 of the 11 studies, respectively. The pooled hazard ratios of sarcopenia were 1.84 (95% confidence interval 1.11–3.05, p = 0.02) and 1.72 (95% confidence interval 0.99–3.00, p = 0.05) for posttransplantation and waiting list mortality, respectively, independent of Model for End‐stage Liver Disease score. Less‐consistent evidence suggested a higher complication rate, particularly infections, in sarcopenic patients. In conclusion, sarcopenia is an independent predictor for outcome in liver transplantation patients and could be used for risk assessment.

The transplanted liver graft is capable of clearing asymmetric dimethylarginine

Asymmetric dimethylarginine (ADMA) has been recognized as an endogenous inhibitor of the arginine–nitric oxide (NO) pathway. Its concentration is tightly regulated by urinary excretion and degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which is highly expressed in the liver. Considering the liver as a crucial organ in the clearing of ADMA, we hypothesized increased ADMA levels during hepatic failure and, consequently, a decline of ADMA concentrations after successful liver transplantation. The aim of the present study was to investigate the role of the liver in the metabolism of ADMA in patients undergoing liver transplantation. In this prospective study, we investigated the course of ADMA concentrations in 42 patients undergoing liver transplantation and results showed that preoperative ADMA concentrations were higher in patients with acute (1.26 μmol/L, P < .001) and in patients with chronic (.69 μmol/L, P < .001) hepatic failure compared with healthy volunteers (.41 μmol/L). In addition, ADMA concentrations decreased from the preoperative day to the first postoperative day in both the acute (ΔADMA: −.63 μmol/L, P = .005) and the chronic hepatic failure group (ΔADMA: −0.15 μmol/L, P < .001). Furthermore, in patients who experienced acute rejection, ADMA concentrations were higher during the whole first postoperative month compared with nonrejectors (P = .012). Moreover, in 11 of 13 rejectors (85%) a clear increase in ADMA concentration preceded the onset of the first episode of rejection, which was confirmed by liver biopsy. In conclusion, our results indicate that the transplanted liver graft is quickly capable of clearing ADMA, suggesting preservation of DDAH. In addition, increased ADMA concentrations in the posttransplantation period reflect serious dysfunction of the liver graft during acute rejection. (Liver Transpl 2004;10:1524–1530.)

Epidemiology and management of chronic hepatitis E infection in solid organ transplantation: a comprehensive literature review

Hepatitis E virus (HEV) infection has emerged as a global public health issue. Although it often causes an acute and self‐limiting infection with low mortality rates in the western world, it bears a high risk of developing chronic hepatitis in immunocompromised patients with substantial mortality rates. Organ transplant recipients who receive immunosuppressive medication to prevent rejection are thought to be the main population at risk for chronic hepatitis E. Therefore, there is an urgent need to properly evaluate the clinical impact of HEV in these patients. This article aims to review the prevalence, infection course, and management of HEV infection after solid organ transplantation by performing a comprehensive literature review. In addition, an in‐depth emphasis of this clinical issue and a discussion of future development are also presented. Copyright

Physical fitness, fatigue, and quality of life after liver transplantation

Fatigue is often experienced after liver transplantation. The aims of this cross-sectional study were to assess physical fitness (cardiorespiratory fitness, neuromuscular fitness, body composition) in liver transplant recipients and to explore whether physical fitness is related to severity of fatigue. In addition, we explored the relationship between physical fitness and health-related quality of life. Included were 18 patients 1–5xa0years after transplantation (aged 48.0xa0±xa011.8xa0years) with varying severity of fatigue. Peak oxygen uptake during cycle ergometry, 6-min walk distance, isokinetic muscle strength of the knee extensors, body mass index, waist circumference, skinfold thickness, severity of fatigue, and health-related quality of life were measured. Cardiorespiratory fitness in the liver transplant recipients was on average 16–34% lower than normative values (Pxa0≤xa00.05). Furthermore, the prevalence of obesity seemed to be higher than in the general population (17 vs. 10%). We found no deficit in neuromuscular fitness. Cardiorespiratory fitness was the only fitness component that was related with severity of fatigue (rsxa0=xa0−0.61 to rsxa0=xa0-0.50, Pxa0≤xa00.05). Particularly cardiorespiratory fitness was related with several aspects of health-related quality of life (rsxa0=xa00.48 to rsxa0=xa00.70, Pxa0≤xa00.05). Results of our study imply that cardiorespiratory fitness and body composition are impaired in liver transplant recipients and that fitness is related with severity of fatigue (only cardiorespiratory fitness) and quality of life (particularly cardiorespiratory fitness) in this group. These findings have implications for the development of rehabilitation programs for liver transplant recipients.

Persistent fatigue in liver transplant recipients: a two-year follow-up study.

van Ginneken BTJ, van den Berg‐Emons RJG, van der Windt A, Tilanus HW, Metselaar HJ, Stam HJ, Kazemier G. Persistent fatigue in liver transplant recipients: a two‐year follow‐up study.u2028Clin Transplant 2010: 24: E10–E16.

Intravenous Immunoglobulin Treatment in Humans Suppresses Dendritic Cell Function via Stimulation of IL-4 and IL-13 Production

High-dose i.v. Ig (IVIg) is a prominent immunomodulatory therapy for various autoimmune and inflammatory diseases. Recent mice studies suggest that IVIg inhibits myeloid cell function by inducing a cascade of IL-33–Th2 cytokine production causing upregulation of the inhibitory FcγRIIb, as well as by modulating IFN-γ signaling. The purpose of our study was to explore whether and how these mechanisms are operational in IVIg-treated patients. We show that IVIg in patients results in increases in plasma levels of IL-33, IL-4, and IL-13 and that increments in IL-33 levels correlate with rises in plasma IL-4 and IL-13 levels. Strikingly, no upregulation of FcγRIIb expression was found, but instead a decreased expression of the activating FcγRIIa on circulating myeloid dendritic cells (mDCs) after high-dose, but not after low-dose, IVIg treatment. In addition, expression of the signaling IFN-γR2 subunit of the IFN-γR on mDCs was downregulated upon high-dose IVIg therapy. In vitro experiments suggest that the modulation of FcγRs and IFN-γR2 on mDCs is mediated by IL-4 and IL-13, which functionally suppress the responsiveness of mDCs to immune complexes or IFN-γ. Human lymph nodes and macrophages were identified as potential sources of IL-33 during IVIg treatment. Interestingly, stimulation of IL-33 production in human macrophages by IVIg was not mediated by dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN). In conclusion, high-dose IVIg treatment inhibits inflammatory responsiveness of mDCs in humans by Th2 cytokine-mediated downregulation of FcγRIIa and IFN-γR2 and not by upregulation of FcγRIIb. Our results suggest that this cascade is initiated by stimulation of IL-33 production that seems DC-SIGN independent.

Trends in liver transplantation for primary biliary cirrhosis in the Netherlands 1988-2008

BackgroundA decrease in the need for liver transplantations (LTX) in Primary Biliary Cirrhosis (PBC), possibly related to treatment with ursodeoxycholic acid (UDCA), has been reported in the USA and UK. The aim of this study was to assess LTX requirements in PBC over the past 20 years in the Netherlands.MethodsAnalysis of PBC transplant data of the Dutch Organ Transplant Registry during the period 1988-2008, including both absolute and proportional numbers. The indication for LTX was categorized as liver failure, hepatocellular carcinoma or poor quality of life (severe fatigue or pruritus). Data were analysed for two decades: 1.1.1988-31.12.1997 (1st) and 1.1.1998-31.12.2007 (2nd). The severity of disease was quantified using MELD scores. To fit lines which show trends over time we applied a linear regression model.ResultsA total of 110 patients (87% women) was placed on the waiting list. 105 patients were transplanted (1st: 61, 2nd: 44), 5 (5%) died while listed. The absolute annual number of LTX for PBC slightly decreased during the 20 year period, the proportional number decreased significantly. At the time of LTX the mean age was 53.6 yrs. (1st: 53.4, 2nd: 53.8), the mean MELD score 13.9 (1st:14.5, 2nd:13.0). The median interval from diagnosis to LTX was 90.5 months (1st:86.5, 2nd: 93.5). 69% of patients was treated with UDCA (1st 38%, 2nd 82%).ConclusionsOver the past 20 years the absolute number of LTX for PBC in the Netherlands showed a tendency to decrease whereas the proportional decrease was significant. There was a trend over time toward earlier transplantation.

Fatigue After Liver Transplantation: Effects of a Rehabilitation Program Including Exercise Training and Physical Activity Counseling

Background It is hypothesized that increasing physical fitness and daily physical activity can lead to a reduction in fatigue. However, standard medical care following liver transplantation seldom includes rehabilitation that focuses on physical fitness and physical activity. Objective The aim of this study was to explore whether a rehabilitation program can reduce fatigue in recipients of liver transplants. Furthermore, effects on physical fitness, physical activity, and cardiovascular risk were studied, and adherence, satisfaction, and adverse events were assessed. Design This was an uncontrolled intervention study. Setting The study took place in an outpatient rehabilitation clinic. Patients Eighteen recipients of a liver transplant who were fatigued participated in a 12-week rehabilitation program including physical exercise training and counseling on physical activity. The primary outcome measure was fatigue. Other outcome measures were: aerobic capacity, muscle strength, body fat, daily physical activity, lipid profile, and glycemic control. All measurements were performed before and after the rehabilitation program. Adherence, satisfaction, and adverse events were registered. Results After the program, participants were significantly less fatigued, and the percentage of individuals with severe fatigue was 22% to 53% lower than before the program. In addition, aerobic capacity and knee flexion strength were significantly higher, and body fat was significantly lower after the program. Participants were able to perform physical exercise at the target training intensity, no adverse events were registered, and attendance (93%) and mean patient satisfaction (8.5 out of 10, range=7–10) were high. Limitations No control group was used in the study. Conclusions A rehabilitation program consisting of exercise training and physical activity counseling is well tolerated and seems promising in reducing fatigue and improving fitness among recipients of liver transplants.

Rotavirus in Organ Transplantation: Drug-Virus-Host Interactions

Although rotavirus is usually recognized as the most common etiology of diarrhea in young children, it can in fact cause severe diseases in organ transplantation recipients irrespective of pediatric or adult patients. This comprehensive literature analysis revealed 200 cases of rotavirus infection with 8 related deaths in the setting of organ transplantation been recorded. Based on published cohort studies, an average incidence of 3% (187 infections out of 6176 organ recipients) was estimated. Rotavirus infection often causes severe gastroenteritis complications and occasionally contributes to acute cellular rejection in these patients. Immunosuppressive agents, universally used after organ transplantation to prevent organ rejection, conceivably play an important role in such a severe pathogenesis. Interestingly, rotavirus can in turn affect the absorption and metabolism of particular immunosuppressive medications via several distinct mechanisms. Even though rotaviral enteritis is self‐limiting in general, infected transplantation patients are usually treated with intensive care, rehydration and replacement of nutrition, as well as applying preventive strategies. This article aims to properly assess the clinical impact of rotavirus infection in the setting of organ transplantation and to disseminate the interactions among the virus, host and immunosuppressive medications.

Can we turn down autonomous wishes to donate anonymously

Imagine a Samaritan living kidney donor, who some time ago has anonymously donated one of his kidneys to a patient on top of the waiting list. He now contacts the transplantation centre once again, to donate part of his liver. The Centre, startled by this idea, refers him to the regular screening procedure for all Samaritan donations. It turns out that his wish is well‐informed, voluntarily made and that he is competent to decide. We acknowledge that a donor’s wish should not be followed in all cases, even though this wish is a clear expression of his own free will. However, a refusal must be based on sound moral reasons and it is less clear what reasons these might be. We outline the most common arguments for refusal, assess these arguments in terms of strengths and weaknesses, and show which arguments, if any at all, are most promising. We conclude, firstly, that we should only assess risks (which include motivations), not judge relationships, and secondly, that it is not a transplant centre’s mission to carry out a donor’s life project.