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Calcineurin inhibitors (CNIs) frequently induce neurological complications early after orthotopic liver transplantation (OLT). We hypothesize that longterm CNI therapy after OLT causes dose-dependent cognitive dysfunction and alteration of brain structure. In this study, 85 OLT patients (20 with CNI-free, 35 with CNI low-dose, and 30 with standard-dose CNI immunosuppression) underwent psychometric testing and cerebral magnetic resonance imaging approximately 10 years after OLT to assess brain function and structural brain alterations. A total of 33 healthy patients adjusted for age, sex, and education served as controls. Patients receiving CNI showed a significantly worse visuospatial/constructional ability compared with controls (P ≤ 0.04). Furthermore, patients on low-dose CNI therapy had an overall impaired cognitive function compared with controls (P = 0.01). The tacrolimus total dose and mean trough level were negatively correlated to cognitive function. CNI doses had been adjusted in 91% of the patients in the low-dose and CNI-free groups in the past due to CNI-induced kidney damage. Patients treated with CNI showed significantly more white matter hyperintensities (WMH) than patients on CNI-free immunosuppression and controls (P < 0.05). Both the mean cyclosporine A and tacrolimus trough levels correlated significantly with WMH. In conclusion, longterm CNI therapy carries a risk of cognitive dysfunction especially in patients who already showed nephrotoxic side effects indicating an increased susceptibility of these patients against toxic CNI effects. This subgroup of patients might benefit from a change to CNI-free immunosuppression. Liver Transplantation 24 56-66 2018 AASLD.

Cognitive dysfunction caused by hepatic encephalopathy (HE) improves within the first year after liver transplantation (LT). However, cognitive restitution seems to be incomplete in a subset of patients and after LT a new-onset cognitive decline was described. Data about the longterm development of cognitive function after liver transplantation (LT) are sparse. This prospective study analyzed whether a history of hepatic encephalopathy (HE) before LT had an impact on the longterm outcome of cognitive function after LT and if patients who underwent LT 5 years earlier showed worse cognitive function than healthy controls. The cognitive function of 34 patients was assessed before LT and at 1 year and 5 years after LT by psychometric tests, including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the portosystemic encephalopathy syndrome test, which provides the psychometric hepatic encephalopathy score (PHES). Furthermore, patients completed surveys to assess health-related quality of life (HRQOL). An 22 additional patients were included after LT. Patients were subdivided by having a history of HE before LT. The control group consisted of 55 healthy patients adjusted for age and education. Before LT, patients performed significantly worse than controls in the psychometric tests: RBANS Total Scale (TS), mean ± standard deviation (SD), 92.6 ± 13.3 versus 99.9 ± 12.0, P = 0.01; and PHES, median (interquartile range [IQR]), 0 (-3 to 1) versus 1 (0-2), P

BackgroundIn the first weeks after liver transplantation about 30% of the patients develop a posttransplant encephalopathy. A posttransplant encephalopathy comprises metabolic-toxic caused symptoms such as disorientation, confusion, hallucinations, cognitive dysfunction and seizures. We hypothesize that alterations of cerebral metabolites before liver transplantation predispose posttransplant encephalopathy development after liver transplantation.Methods31 patients with chronic liver disease underwent magnetic resonance spectroscopy (MRS) before liver transplantation to assess glutamine/glutamate (Glx), myo-Inositol (mI), choline (Cho), creatine/phosphocreatine- and N-acetyl-aspartate/N-acetyl-aspartate-glutamate concentrations in the thalamus, lentiform nucleus and white matter. Of these, 14 patients underwent MRS additionally after liver transplantation. Furthermore, 15 patients received MRS only after liver transplantation. Patients' data were compared to 20 healthy age adjusted controls.ResultsPatients showed significantly increased Glx and decreased mI and Cho concentrations compared to controls before liver transplantation (p≤0.01). The MRS values before liver transplantation of patients with posttransplant encephalopathy showed no significant difference compared to patients without posttransplant encephalopathy. Patients after liver transplantation showed increased Glx concentrations (p≤0.01) compared to controls, however, patients with and without posttransplant encephalopathy did not differ. Patients with posttransplant encephalopathy who underwent MRS before and after liver transplantation showed a significant mI increase in all three brain regions (pConclusionPatients with and without posttransplant encephalopathy showed no significant difference in cerebral metabolites before liver transplantation. However, the paired sub-analysis indicates that the extent of cerebral metabolite alterations in patients with liver cirrhosis might be critical for the development of posttransplant encephalopathy after liver transplantation.

PurposeTo investigate cerebral microstructural alterations in patients treated with calcineurin inhibitors (CNI) after orthotopic liver transplantation (OLT) using quantitative magnetic resonance imaging (qMRI) and a cross-sectional study design.MethodsCerebral qMRI was performed in 85 patients in a median 10 years after OLT compared to 31 healthy controls. Patients were treated with different dosages of CNI or with a CNI-free immunosuppression (CNI-free: n = 19; CNI-low: n = 36; CNI-standard: n = 30). T2-, T2*- and T2'- relaxation times, as well as apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in brain gray and white matter by using the regions of interest method.ResultsIn comparison to controls, patients revealed significantly increased T2, T2*, T2', ADC and reduced FA, predominantly in the frontal white matter, indicating microstructural brain alterations represented by increased free water (increased T2), reduced neuronal metabolism (increased T2') and a lower degree of spatial organization of the nervous fibers (reduced FA). CNI-low and CNI-free patients showed more alterations than CNI-standard patients. Analysis of their history revealed impairment of kidney function while under standard CNI dose suggesting that these patients may be more vulnerable to toxic CNI side-effects.ConclusionOur findings suggest that the individual sensitivity to toxic side effects should be considered when choosing an appropriate immunosuppressive regimen in patients after liver transplantation.

While acute neurotoxic side effects of calcineurin inhibitors (CNI) are well-known, data upon long-term effects on brain structure and function are sparse. We hypothesize that long-term CNI therapy affects the neuroimmune system, thereby, increasing the risk of neurodegeneration. Here, we measured the impact of CNI therapy on plasma levels of brain- and T cell-derived cytokines in a cohort of patients after liver transplantation (LT).Levels of T cell-mediated cytokines (e.g. Interferon-γ (IFN-γ)) and brain-derived cytokines (e.g. brain derived neurotrophic factor (BDNF), platelet derived growth factor (PDGF)) were measured by multiplex assays in plasma of 82 patients about 10 years after LT (17 with CNI free, 35 with CNI low dose, 30 with standard dose CNI immunosuppression) and 33 healthy controls. Data were related to psychometric test results and parameters of cerebral magnetic resonance imaging.IFN-γ levels were significantly higher in the CNI free LT patient group (p=0.027) compared to healthy controls. BDNF levels were significantly lower in LT patients treated with CNI (CNI low: p0.001; CNI standard: p=0.016) compared to controls. PDGF levels were significantly lower in the CNI low dose group (p=0.004) and for PDGF-AB/BB also in the CNI standard dose group (p=0.029) compared to controls. BDNF and PDGF negatively correlated with cognitive function and brain volume (p0.05) in the CNI low dose group.Our results imply that long-term treatment with CNI suppresses BDNF and PDGF expression, both crucial for neuronal signaling, cell survival and synaptic plasticity and thereby may lead to cognitive dysfunction and neurodegeneration.

BACKGROUND Calcineurin inhibitor (CNI) neurotoxicity after liver transplantation might be due to impairment of the cerebral metabolism. AIMS To investigate CNI-related alterations of brain metabolite distributions and associations between cognitive function and brain metabolism in patients with long-term CNI treatment after liver transplantation. METHODS Eighty-two patients (19 CNI free, 34 CNI low-dose and 29 standard-dose CNI immunosuppression) 10 years after liver transplantation and 32 adjusted healthy controls underwent nonlocalised brain phosphorus magnetic resonance spectroscopy (MRS) and single voxel proton MRS in the parietal white matter to estimate brain metabolite contents. The MRS results were correlated with psychometric data assessing cognitive function. RESULTS Phosphorus metabolite concentrations with the exception of phosphocreatine (PCr) were reduced in patients compared to controls. Particularly, patients with low-dose CNI therapy showed a significant decrease in adenosine triphosphate (0.209 ± 0.012 vs 0.222 ± 0.010; P

Liver transplantation (LT) is the only definitive treatment for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC), but a high rate of biliary strictures (BSs) and of recurrent primary sclerosing cholangitis (recPSC) has been reported. In this multicenter study, we analyzed a large patient cohort with a long follow-up in order to evaluate the incidence of BS and recPSC, to assess the impact on survival after LT, and to identify risk factors. We collected clinical, surgical, and laboratory data and records on inflammatory bowel disease (IBD), immunosuppression, recipient and graft outcome, and biliary complications (based on cholangiography and histology) of all patients who underwent LT for PSC in 10 German transplant centers between January 1990 and December 2006; 335 patients (68.4% men; mean age, 38.9 years; 73.5% with IBD) underwent transplantation 8.8 years after PSC diagnosis with follow-up for 98.8 months. The 1-, 5-, and 10-year recipient and graft survival was 90.7%, 84.8%, 79.4% and 79.1%, 69.0%, 62.4%, respectively. BS was diagnosed in 36.1% after a mean time of 3.9 years, and recPSC was diagnosed in 20.3% after 4.6 years. Both entities had a significant impact on longterm graft and recipient survival. Independent risk factors for BS were donor age, ulcerative colitis, chronic ductopenic rejection, bilirubin, and international normalized ratio (INR) at LT. Independent risk factors for recPSC were donor age, IBD, and INR at LT. These variables were able to categorize patients into risk groups for BS and recPSC. In conclusion, BS and recPSC affect longterm graft and patient survival after LT for PSC. Donor age, IBD, and INR at LT are independent risk factors for BS and recPSC and allow for risk estimation depending on the recipient-donor constellation.

Background Hepatitis C is the leading indication for liver transplantation. Differentiation between recurrent graft hepatitis C (RGH-C) and graft rejection (GR) is challenging. Liver biopsy is standard to diagnose both conditions; however, little information is available regarding this procedure in hepatitis C virus (HCV)-infected liver transplant recipients. Methods Liver biopsies (n = 211) from all consecutive patients (n = 138) transplanted for hepatitis C at Hannover Medical School between January 2000 and October 2011 were screened, and a final cohort of 96 patients with 196 biopsies was included. Indications, histopathological findings, and biopsy-related complications were documented. Modifications in the treatment based on the biopsy result and the biochemical outcome were analyzed. Results Most biopsies (196/211, 93%) were representative. Five patients (2.5%) developed non-fatal biopsy-related complications. Biopsy results were GR (35%), RGH-C (31%), and other diagnoses (34%). GR was independently associated with lower albumin (P = 0.025) and higher bilirubin levels (P = 0.011). Treatment was modified based on the biopsy result in 25% of cases. Alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and bilirubin levels improved in 41%, 25%, and 31% of cases 4 weeks post biopsy respectively. ALT improvements were more significant in patients with GR than in those with RGH-C. Conclusion Liver biopsy in HCV-infected liver transplant recipients is safe and representative in >90% of cases. GR is independently associated with lower albumin and higher bilirubin levels.

Patients after orthotopic liver transplantation (OLT) may show cognitive dysfunction. To date, it has not been clear whether this dysfunction is due to residual hepatic encephalopathy (HE) or new-onset cognitive disturbances. Just as little is known about the course and clinical significance. In this prospective, observational study, 50 patients on the waiting list for OLT were examined in an outpatient setting before OLT and 6 and 12 months after OLT with the Psychometric Hepatic Encephalopathy Score, the Inhibitory Control Test, and the critical flicker frequency for the diagnosis of HE; in addition, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used as a tool for the measurement of global cognitive function. The Short Form 36 health survey was used to assess health-related quality of life. Twelve months after OLT, cognitive dysfunction characteristic of HE had resolved, but a secondary cognitive decline became apparent and had features different from those known with HE. Approximately 70% of the patients deteriorated in at least 1 cognitive domain of RBANS. This cognitive decline was related to neither a history of HE nor a history of alcohol abuse, but it was accompanied by a decline in the quality of life. In conclusion, OLT improves HE but is frequently followed by new-onset cognitive dysfunction, which can interfere with the quality of life.

Background Human T-cell lymphotropic virus type 1 (HTLV-1) screening of blood and organ donors is not mandatory in Germany because of its low prevalence (about 7/100 000). An HTLV-1 transmission event caused by a multiple organ donor was investigated. Validity of diagnostic procedures and HTLV-1 disease association in immunosuppressed organ recipients were analyzed. Methods Two screening immunoassays and an immunoblot (confirmatory assay) were used for detection of HLTV-1/2 antibodies. Proviral DNA was quantified in blood and biopsies of organ recipients by HTLV-1 real-time polymerase chain reaction (PCR). Results Proviral HTLV-1-DNA was detected in all blood samples of 3 organ recipients (1-100 copies/10(2) cells), but seroconversion was delayed for up to 2 years in screening assays and >6 years in the confirmatory assay. In 2 of 3 organ recipients, a cutaneous T-cell lymphoma was diagnosed 2 and 3 years after infection, respectively. Proviral HTLV-1 DNA concentration was almost 100 copies/10(2) cells in cutaneous lymphoma biopsies whereas in biopsies of other tissues ≤3.0 copies/10(2) cells were found. The third organ recipient did not suffer from lymphoma, but detailed clinical data on this patient were not available to us. Conclusions Biopsy results support an etiological role for HTLV-1 in these cases of primary cutaneous T-cell lymphoma after solid organ transplant. HTLV-1-associated lymphoma can arise quickly in immunocompromised transplant recipients. The diagnosis of potentially HTLV-1-associated disease in organ recipients may require PCR because of delayed seroconversion.

Background & Aims Extrapyramidal and cerebellar symptoms belong to the most prominent features of episodic hepatic encephalopathy, and usually decrease upon ammonia-lowering therapy. Rapidly progressing parkinsonian symptoms, which are unresponsive to treatment of hepatic encephalopathy, indicate cirrhosis-related Parkinsonism. This study aims at analyzing the prevalence of cirrhosis-related Parkinsonism in patients with liver cirrhosis, and to study the functional status of the striatal dopaminergic system in these patients. Methods 214 patients with liver cirrhosis who were consecutively seen at the out-patient clinic for liver transplant candidates and/or at the transplantation wards at Hannover Medical School, between August 1, 2008 and March 31, 2011, underwent a standardized neurological examination while on the waiting list or immediately after liver transplantation. Single photon emission computer tomography (SPECT) using 123 I-beta-CIT, for the evaluation of the striatal dopamine transporter function, and 123 I-IBZM for the evaluation of the striatal dopamine D2 receptor availability, was performed in 6 patients with cirrhosis-related Parkinsonism. Results Cirrhosis-related Parkinsonism was diagnosed in 9 of 214 patients (4.2%). SPECT revealed significantly decreased dopamine receptor availability in 5 of 6 patients studied, and significantly decreased dopamine transporter availability in 3. Levodopa improved motor dysfunction in two of four patients treated, although only temporarily. Incomplete recovery was observed in two patients after liver transplantation. Conclusions Cirrhosis-related Parkinsonism is more frequent than presumed. The presented data suggest pre- and postsynaptic alteration of striatal dopaminergic neurotransmission as a possible cause of cirrhosis-related Parkinsonism and reveal the limited effects of dopaminergic therapy.

Objective Hepatic encephalopathy (HE) is a common complication of liver insufficiency. While there is widespread acceptance of its importance, there is no consensus on how best to diagnose and monitor HE. Objective To compare the four most favoured methods for the diagnosis of HE. Design 170 patients who were on the waiting list for liver transplantation as well as 86 healthy controls were included in the study. All patients and controls underwent the portosystemic encephalopathy syndrome test yielding the psychometric hepatic encephalopathy score (PHES), the repeatable battery for the assessment of neuropsychological status (RBANS), the inhibitory control test (ICT) and critical flicker frequency (CFF) measurement. Results PHES and ICT targets had the best sensitivity (85.7% vs 85.7%) and specificity (96.5% vs 97.6%) for the diagnosis of overt HE. CFF showed inferior sensitivity (40.9%) for the diagnosis of HE and dependency from previous alcohol abuse (p=0.015). Multiple regression analysis showed that all test results apart from PHES were influenced by secondary diagnoses such as diabetes mellitus and renal insufficiency. Conclusions In the German population of patients awaiting liver transplantation, PHES is the most robust method for the diagnosis and follow-up of HE.

AIM To investigate the impact of hepatic encephalopathy before orthotopic liver transplantation (OLT) and neurological complications after OLT on employment after OLT. METHODS One hundred and fourteen patients with chronic liver disease aged 18-60 years underwent neurological examination to identify neurological complications, neuropsychological tests comprising the PSE-Syndrome-Test yielding the psychometric hepatic encephalopathy score, the critical flicker frequency and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), completed a questionnaire concerning their occupation and filled in the short form 36 (SF-36) to assess health-related quality of life before OLT and 12 mo after OLT, if possible. Sixty-eight (59.6%) patients were recruited before OLT, while on the waiting list for OLT at Hannover Medical School [age: 48.7 ± 10.2 years, 45 (66.2%) male], and 46 (40.4%) patients were included directly after OLT. RESULTS Before OLT 43.0% of the patients were employed. The patients not employed before OLT were more often non-academics (employed: Academic/non-academic 16 (34.0%)/31 vs not employed 10 (17.6%)/52, P = 0.04), had more frequently a history of hepatic encephalopathy (HE) (yes/no; employed 15 (30.6%)/34 vs not employed 32 (49.2%)/33, P = 0.05) and achieved worse results in psychometric tests (RBANS sum score mean ± SD employed 472.1 ± 44.5 vs not employed 443.1 ± 56.7, P = 0.04) than those employed. Ten patients (18.2%), who were not employed before OLT, resumed work afterwards. The patients employed after OLT were younger [age median (range, min-max) employed 47 (42, 18-60) vs not employed 50 (31, 29-60), P = 0.01], achieved better results in the psychometric tests (RBANS sum score mean ± SD employed 490.7 ± 48.2 vs not employed 461.0 ± 54.5, P = 0.02) and had a higher health-related quality of life (SF 36 sum score mean ± SD employed 627.0 ± 138.1 vs not employed 433.7 ± 160.8; P < 0.001) compared to patients not employed after OLT. Employment before OLT (P < 0.001), age (P < 0.01) and SF-36 sum score 12 mo after OLT (P < 0.01) but not HE before OLT or neurological complications after OLT were independent predictors of the employment status after OLT. CONCLUSION HE before and neurological complications after OLT have no impact on the employment status 12 mo after OLT. Instead younger age and employment before OLT predict employment one year after OLT.

To investigate the influence of the type of liver graft donation on donor mortality and morbidity. The clinical course of 87 living liver donors operated on at our center between 2002 and 2009 was retrospectively analysed and data pertaining to all complications were retrieved. No donor mortality was observed and no donor suffered any life-threatening complication. Four donors (4.6%) developed biliary leakage, nine (10.3%) had to be readmitted to hospital and six (6.9%) required some or other type of reoperation related to the previous liver donation. Reoperations included incisional or diaphragmatic hernia repair (n = 4), biliary leakage repair (n = 1) and segmental colon resection combined with diaphragmatic hernia repair (n = 1). There was a statistically significant difference in hospital stay (P < 0.001), autologous blood transfusions (P < 0.001) and operating time (P < 0.005) when right lobe donations (Segments V-VIII) were compared with left lobe (Segments II-IV) and left lateral lobe (Segments II-III) donations, whereas no difference was found between these groups regarding hospital readmission, operative revisions and the incidence or severity of complications. Right lobe donation was associated with prolonged hospital stay, increased blood transfusions and prolonged operating time when compared with left and left lateral lobe donation, whereas donor mortality and morbidity did not differ between these groups.

Intestinal intussusception in the adult is often idiopathic but also known to be associated with chronic inflammatory bowel disease, coeliac disease, tumours or previous abdominal operations. A 22-year-old women after liver transplantation due to Crigler Najar Syndrome suffered from repeated episodes of abdominal pain. The diagnosis of repeated self-limited intestinal intussusceptions was made by computed tomography and ultrasonography. A laparoscopy revealed no cause for the intussusceptions. During a new episode of abdominal pain caused again by an intussusception a colonoscopy was performed that showed aspects of a discreet colitis. In the biopsies CMV was detected by qualitative PCR, while blood tests for CMV pp65 antigen were negative. A therapy with gancyclovir was initiated which lead to remission of the patient's symptoms. A colonoscopy six weeks later showed a completely normal colon, while in the biopsies CMV was not detectable. After a follow-up of one year the patient has not suffered from any further episodes. This case demonstrates the role of chronic intestinal CMV infection as a possible causative factor for repeated intussusceptions in immunosuppressed patients. Whenever possible a PCR for CMV in colon biopsies should be carried out to detect an intestinal CMV infection because as shown in our case results for immunohistopathology and CMV pp65 can be negative despite a chronic infection.

Hepatitis E virus (HEV) infection induces self-limiting liver disease in immunocompetent individuals. Cases of chronic hepatitis E have recently been identified in organ transplant recipients. We questioned if chronic hepatitis E plays a role in graft hepatitis after liver transplantation in a low endemic area. Two hundred twenty-six liver transplant recipients, 129 nontransplanted patients with chronic liver disease, and 108 healthy controls were tested for HEV antibodies. HEV RNA was investigated in all sera from transplanted patients. HEV antibodies were detected in 1 healthy control (1%), 4 patients with chronic liver disease (3%), and 10 liver transplant recipients (4%). Three liver transplant patients also tested positive for HEV RNA. Two of them developed persistent viremia with HEV genotype 3. The patients were anti-HEV immunoglobulin G-negative and HEV RNA-negative before transplantation and had an episode of acute hepatitis 5 or 7 months after transplantation, which led to advanced liver fibrosis after 22 months in 1 patient. Seroconversion to anti-HEV occurred not before 4 months after the first detection of HEV RNA. The possibility of reverse zoonotic transmission was experimentally confirmed by the infection of 5 pigs with a patient's serum. The pigs showed histological inflammation in the liver, and HEV RNA was detectable in different organs, including muscle. In conclusion, the prevalence of HEV infection in Central European liver transplant recipients is low; however, chronic hepatitis E may occur and needs to be considered in the differential diagnosis of graft hepatitis. The diagnosis of HEV infection should be based on HEV RNA determination in immunosuppressed patients. We suggest that immunocompromised individuals should avoid eating uncooked meat and contact with possibly HEV-infected animals.

Introduction of the model of end-stage liver disease (MELD) for organ allocation has changed the waiting-list management. Despite reports of unaffected survival after orthotopic liver transplantation (OLT) in the MELD era, survival rates have decreased in our center. The aim of this study was to identify factors contributing to reduced survival. Three-month survival, recipient and graft parameters of all 323 OLT between 2004 and 2008, which fall into a pre- (N = 220) and a post-MELD (n = 103) era, were analysed by Kaplan-Meier-, Mann-Whitney- and Fisher tests. After the introduction of MELD, mean scores at OLT increased (14.8 vs. 18.6, P = 0.002). The main indications for OLT were not statistically different between eras. Post-MELD recipients were older (47.9 vs. 50.9 years, P = 0.025), donors younger (NS), cold ischemia time shorter (696 vs. 635 min., P = 0.001), and duration of surgery longer (218 vs. 245 min., P = 0.001). Procedure time significantly correlated with MELD and international normalized ratio (INR). Three-month survival dropped (from 88.6% to 79.6%, P = 0.03). Independent variables of survival were creatinine, urea and duration of surgery. Reduced 3-month survival was associated with longer surgery duration, higher creatinine and urea likely reflecting higher recipient morbidity. Survival probability should be incorporated into MELD-based graft allocation.

Mutations within the low density lipoprotein (LDL)-receptor gene result in familial hypercholesterolemia, an autosomal dominant inherited disease. Clinical homozygous affected subjects die of premature coronary artery disease as early as in early childhood. We identified a girl at the age of five yr with clinical homozygous familial hypercholesterolemia presenting with achilles tendon xanthomas and arcus lipoides. Her total cholesterol reached up to 1050 mg/dL. Molecular characterization of the LDL-receptor gene revealed a homozygous p.W577R mutation. Despite intensive treatment interventions with the combination of diet, statins, colestipol, and LDL-apheresis, the patient developed symptomatic coronary artery disease at the age of 16 yr. Subsequently, orthotopic liver transplantation was performed to cure the defective LDL-receptor gene. Clinical follow-up for almost nine yr post-transplantation revealed excellent liver function, normal liver enzymes, normal LDL-cholesterol, and regression of both tendon xanthomas and symptomatic coronary artery disease. In conclusion, liver transplantation can effectively reduce LDL-cholesterol in a familial hypercholesterolemia recipient with subsequent regression of xanthomas and atherosclerosis. Timing is extremely important in these exceptional cases to exclude the demand for heart transplantation due to severe coronary artery disease. In addition, the identification of the LDL-receptor as etiology of clinical homozygous hypercholesterolemia is a prerequisite once liver transplantation is considered as therapeutic option.

Context Studies of all types of organ transplant recipients have suggested that weight gain, expressed as an increase in body mass index (BMI), after transplant is common. Objectives To describe weight gain during the first year after transplant and to determine risk factors associated with weight gain with particular attention to type of transplant. Design, Setting, and Participants A prospective study of 502 consecutive organ transplant recipients (261 kidney, 73 liver, 29 heart, 139 lung) to identify patterns of BMI change. Measurements were made during regular outpatient clinical visits at 2, 6, and 12 months after transplant. Data were retrieved from patients' charts and correlated with maintenance corticosteroid doses. Results Overall, mean BMI (SD; range) was 23.9 (4.5; 13.6–44.1) at 2 months and increased to 25.4 (4.0; 13.0–42.2) by the end of the first postoperative year. BMI levels organized by World Health Organization categories showed a trend toward overweight/obesity in kidney (53.4%), liver (51.5%), heart (51.7%), and lung (33.1%) patients by 12 months after transplant. BMI changed significantly ( P = .05) for all organ types and between all assessment points, except in kidney recipients. Maintenance corticosteroid doses were not a predictor of BMI at 12 months after transplant for most patients. Conclusions Weight gain was common among patients undergoing kidney, liver, heart, and lung transplant; however, many showed BMI values close to normality at the end of the first year after transplant. In most cases, increased BMI levels were related to obesity before transplant and not to maintenance corticosteroid therapy.

In advanced stages of polycystic liver disease, often associated with polycystic kidney disease, a curative therapy is liver or combined liver-kidney transplantation. However, little is known about long-term outcome and quality of life. Between 1990 and 2003, 36 patients (32 female, 4 male) with polycystic liver or combined liver-kidney disease underwent liver (n = 21) or liver-kidney (n = 15) transplantation at our center. Main indications for liver transplantation were cachexia, muscle atrophy, loss of weight, recurrent cyst infections, portal hypertension, and ascites. Apart from clinical parameters, 2 anonymous questionnaires (standard short form 36 and self-designed) addressing quality of life and social status were evaluated. Five patients (14 %) died due to sepsis or myocardial infarction with pneumonia, all within 61 days after transplantation. The follow-up time of the remaining 31 patients ranged from 5 to 156 months, with a mean of 62 months. Of the 23 (74%) answered the questionnaires, 91% of patients felt "much better" or "better," only 9% felt "worse" than before, and 52% of patients participated in sports regularly. Fatigue, physical fitness, loss of appetite, and vomiting improved significantly after transplantation. Physical attractiveness and interest in sex increased as well. Professional occupation did not change for 71% of patients. Family situation before and after transplantation changed in 1 case only. Finally, 78% of patients said they would opt for transplantation again, while 17% were undecided; 1 patient would not repeat transplantation. In conclusion, patients with advanced polycystic liver or polycystic liver-kidney disease have an excellent survival rate and an improved quality of life after liver or combined liver-kidney transplantation.

Fibrosing cholestatic hepatitis is a deleterious manifestation of hepatitis B virus infection in immunocompromised patients. Without treatment, this condition is usually fatal within weeks of onset. Liver retransplantation has not been successfully performed to date, and treatment intervention was generally unsuccessful before the advent of adefovir dipivoxil. However, concerns have been expressed about the use of this agent in patients who are renally compromised. A 40-year-old liver transplant recipient with hepatitis B virus reinfection, resistance to lamivudine, and fibrosing cholestatic hepatitis complicated by terminal renal impairment and spontaneous bacterial peritonitis was treated with adefovir dipivoxil 10 mg after every dialysis. Since initiating treatment with adefovir dipivoxil 10 mg, a dramatic virologic and clinical improvement was observed in this patient. The patient returned to work full-time within 6 months of starting adefovir dipivoxil without the need for liver retransplantation. Serum HBV DNA (Amplicor HBV; Roche Diagnostics, Basle, Switzerland) decreased by 6 log10 copies/mL and became negative (< 400 copies/mL) within 8 weeks of treatment and remains negative at the last available assessment. The patient continues to require renal dialysis, but is generally well. Creatinine clearance improved from 8 mL/min to 16 mL/min during the course of treatment. No adverse events related to adefovir dipivoxil were observed. Adefovir dipivoxil resulted in significant clinical improvement in this patient with hepatitis B virus–induced fibrosing cholestatic hepatitis, despite the presence of renal impairment and lamivudine resistance. (Liver Transpl 2003;9:191-196.)

Although central nervous system complications (CNSCs) are common after orthotopic liver transplantation (OLT), standardized prospective studies are still lacking. This prospective study was aimed at determining the incidence of CNSCs, describing their clinical presentations, and establishing predicting factors. One hundred thirty-six adult patients who underwent OLT at Hannover Medical School between December 2008 and June 2011 were included. Weekly examinations were performed by a neurologist during the hospital stay after OLT. Patient data, donor data, and operative and postoperative variables were collected. Patients with cerebral dysfunction after OLT underwent a diagnostic work-up, which included brain imaging and, if necessary, cerebrospinal fluid analysis. Patients with central nervous system (CNS) symptoms but negative imaging and cerebrospinal fluid results and patients with pontine myelinolysis or posterior reversible encephalopathy syndrome were placed in a metabolic-toxic CNSC group, and patients with strokes, intracranial hemorrhaging, or CNS infections were placed in a nonmetabolic CNSC group. Multiple regression analysis was used to identify independent risk factors for the development of metabolic-toxic CNSCs. After excluding two patients that died after OLT without regaining consciousness, forty-four (32.8%) patients developed CNSCs: 37 of these patients (27.6%) had metabolic-toxic CNSCs, and 7 (5.2%) had nonmetabolic CNSCs. Acute-on-chronic liver failure, the number of subsequent surgeries, and primary sclerosing cholangitis were identified as independent predictors for the development of metabolic-toxic CNSCs. Metabolic-toxic CNSCs were associated with prolonged hospital stays, and nonmetabolic CNSCs were associated with higher mortality. In conclusion, CNSCs are common and relevant complications after OLT. Patients after OLT, especially with risk factors, should undergo a regular standardized neurological examination that would allow early detection of these complications.

Background & Aims Focal white matter lesions mimicking microvascular lesions were connected to the development of hepatic encephalopathy (HE) in patients with cirrhosis. This study aims to assess the relationship between cerebrovascular risk factors and the prevalence and extent of these lesions in patients with cirrhosis, as well as their impact upon cognitive function. Methods 55 cirrhotic patients underwent neurological examination, psychometric testing and magnetic resonance imaging. T2-weighted images were reviewed for white matter lesions by a neuroradiologist and a neurologist, independently. Patients were allocated into three groups: (i) no or

To the Editor: Transplant recipients receiving immunosuppressive therapy have a high risk of developing post-transplant lymphoproliferative disorders. The majority of these are B-cell-derived non-Hodgkin's lymphomas (1). In contrast, primary cutaneous lymphoma after transplantation is rare (1). We report a case of mycosis fungoides (MF) after liver transplantation in an adult.

Patients after orthotopic liver transplantation (OLT) may show cognitive dysfunction. To date, it has not been clear whether this dysfunction is due to residual hepatic encephalopathy (HE) or new-onset cognitive disturbances. Just as little is known about the course and clinical significance. In this prospective, observational study, 50 patients on the waiting list for OLT were examined in an outpatient setting before OLT and 6 and 12 months after OLT with the Psychometric Hepatic Encephalopathy Score, the Inhibitory Control Test, and the critical flicker frequency for the diagnosis of HE; in addition, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used as a tool for the measurement of global cognitive function. The Short Form 36 health survey was used to assess health-related quality of life. Twelve months after OLT, cognitive dysfunction characteristic of HE had resolved, but a secondary cognitive decline became apparent and had features different from those known with HE. Approximately 70% of the patients deteriorated in at least 1 cognitive domain of RBANS. This cognitive decline was related to neither a history of HE nor a history of alcohol abuse, but it was accompanied by a decline in the quality of life. In conclusion, OLT improves HE but is frequently followed by new-onset cognitive dysfunction, which can interfere with the quality of life.

Summary HCV RNA levels correlate with the long-term outcome of hepatitis C in liver transplant recipients. Nucleic acid testing (NAT) is usually used to confirm HCV reinfection and to examine viral loads after liver transplantation. HCV core antigen (HCVcoreAg) testing could be an alternative to NAT with some potential advantages including very low intra- and interassay variabilities and lower costs. The performance of HCVcoreAg testing in organ transplant recipients is unknown. We prospectively studied 1011 sera for HCV RNA and HCVcoreAg in a routine real-world setting including 222 samples obtained from patients after liver or kidney transplantation. HCV RNA and HCVcoreAg test results showed a consistency of 98% with a very good correlation in transplanted patients (r > 0.85). The correlation between HCV RNA and HCVcoreAg was higher in sera with high viral loads and in samples from patients with low biochemical disease. Patients treated with tacrolimus showed a better correlation between both parameters than individuals receiving cyclosporine A. HCV RNA/HCVcoreAg ratios did not differ between transplanted and nontransplanted patients, and HCV RNA and HCVcoreAg kinetics were almost identical during the first days after liver transplantation. HCVcoreAg testing can be used to monitor HCV viral loads in patients after organ transplantation. However, the assay is not recommended to monitor antiviral therapies.

Background Short-term posttransplantation survival and health-related quality of life (HRQoL) is exceptionally high for all patients after organ transplantation; however, predictors of the HRQoL outcome are not well understood. Trajectories of patients' perceived benefit/burden ratio associated with the transplant procedure may differ when taking the organ type for transplantation into account. Methods A prospective, single-center cohort study assessed the trajectories of 354 patients after kidney (n=165), liver (n=53), heart (n=24), and lung (n=112) transplantation at 2, 6, 12, and 24 months with respect to psychosocial outcomes (HRQoL, anxiety, depression, social support, and work performance). Results Mean age was 50±13 years, and 61.6% were male in the overall sample. Demographics differed with respect to organ type. HRQoL measured by the mean SF-36 Physical Component Scale was 36.8 (95% confidence interval, 35.7-37.8) and 48.9 (95% confidence interval, 47.2-49.7) for the Psychosocial Component Scale for the entire sample at 2 months and showed a marginal decrease until 24 months after transplantation. Overall, HRQoL increased for all organ types with differing trajectories. Liver patients reported the lowest HRQoL benefit for the majority of the physical (P≤0.01) and psychosocial (P≤0.01) SF-36 subscales. Anxiety (17.4%) and depression (13.8%) were prevalent in the overall sample. Depression symptoms impaired HRQoL outcomes in both SF-36 components and unemployment impacted the SF-36 psychosocial outcomes. Conclusions HRQoL improved after transplantation for all four types of transplant, but the trajectories were different. Regular screening for depression symptoms may diminish psychologic disorders and distress after transplantation and thus may further improve outcomes.

BACKGROUND Hepatocellular carcinomas (HCC) that originate de novo in liver transplants without preceding HCC in the explanted organ have only rarely been reported. Because recent data demonstrated a mixed hepatocellular chimerism caused by the integration of host-derived stem cells, a study was conducted on the origin of tumor cells in de novo HCC. METHODS From two cases of de novo HCC arising in liver transplants after hepatitis B reinfection, tumor cells and non-neoplastic liver cells from the patient's own liver and donor liver were isolated by laser microdissection, and highly polymorphic short tandem DNA repeats (STR) were investigated. RESULTS Isolated tumor cells revealed donor-specific STR genotypes that could clearly be discriminated from the genotype of the host. CONCLUSIONS Hepatitis B virus-associated de novo HCC in liver transplants is of donor but not of host origin. The new technique described here can also discriminate between true recurrence of the original tumor and new recipient tumors.

Hepatocellular carcinomas (HCC) that originate de novo in liver transplants without preceding HCC in the explanted organ have only rarely been reported. Because recent data demonstrated a mixed hepatocellular chimerism caused by the integration of host-derived stem cells, a study was conducted on the origin of tumor cells in de novo HCC.From two cases of de novo HCC arising in liver transplants after hepatitis B reinfection, tumor cells and non-neoplastic liver cells from the patient's own liver and donor liver were isolated by laser microdissection, and highly polymorphic short tandem DNA repeats (STR) were investigated.Isolated tumor cells revealed donor-specific STR genotypes that could clearly be discriminated from the genotype of the host.Hepatitis B virus-associated de novo HCC in liver transplants is of donor but not of host origin. The new technique described here can also discriminate between true recurrence of the original tumor and new recipient tumors.

Acute cellular rejection (ACR) occurs frequently after liver transplantation and can usually be controlled. Triggering of allospecific immune responses and lack of immunoregulation are currently suggested as a cause of ACR, but there are no investigations of intrahepatic immune responses during ACR. Therefore we prospectively analyzed the intrahepatic T cell infiltration pattern in correlation to the severity of ACR in a cohort of patients with graft hepatitis (n = 151). While CD4(+) cells dominated the portal infiltrates in mild-moderate ACR, CD8(+) cells prevailed in severe ACR. Furthermore portal CD8(+) and not CD4(+) infiltration correlated with serum transaminases and with the likelihood of subsequent ACRs. Surprisingly, the rise of portal effector T cells density during ACR was surpassed by the increase in portal infiltration of regulatory T cells by a factor of two. Thus ACRs rather showed an increase and not a lack of regulation, as was suggested by analysis of peripheral blood mononuclear cells. Despite the pattern of enhanced immunoregulation, patients with severe ACR had a higher risk for subsequent rejections and showed a trend to a reduced survival. Thus, patients with severe rejections might need a modification of their immunosuppression to improve prognosis.

Background & Aims In liver transplant recipients with graft hepatitis, the relevance of herpesviruses is not well defined. Methods Viral loads of CMV, EBV, and HHV-6 were determined in blood and liver biopsies of 170 liver transplant recipients with graft hepatitis by quantitative PCR. Results HHV-6-, CMV-, and EBV-DNA were detected in 58%, 14%, and 44% of the biopsies, respectively, with coinfections in 34%. High intrahepatic HHV-6 DNA levels (>75th percentile, 11.27copies/1000cells) and detection of HHV-6 DNAemia were significantly associated with decreased graft survival after diagnosis of graft hepatitis ( p =0.014 and p =0.003, respectively, median follow-up was 23.8months). Multivariate analysis confirmed high intrahepatic HHV-6 loads as an independent factor associated with reduced graft survival (adjusted hazard ratio 2.61, 95%confidence interval 1.16–5.87). Low concentrations of HHV6 DNA in the liver, indicating latent infection, did not influence graft survival. Neither CMV nor EBV (qualitative detection and high virus loads) nor acute rejection (according to the BANFF score) affected graft survival. However, patients had been treated for CMV reactivations and acute rejections in this retrospective study. High age and high bilirubin levels were the other independent factors associated with reduced graft survival (adjusted hazard ratio 3.56CI 1.52–8.34 and 3.23CI 1.50–6.96, respectively). Conclusions High intrahepatic HHV-6-DNA levels are associated with decreased graft survival in liver transplant recipients with graft hepatitis. The significance of HHV-6 as potential etiology of graft hepatitis needs further evaluation.

To investigate the influence of the type of liver graft donation on donor mortality and morbidity. The clinical course of 87 living liver donors operated on at our center between 2002 and 2009 was retrospectively analysed and data pertaining to all complications were retrieved. No donor mortality was observed and no donor suffered any life-threatening complication. Four donors (4.6%) developed biliary leakage, nine (10.3%) had to be readmitted to hospital and six (6.9%) required some or other type of reoperation related to the previous liver donation. Reoperations included incisional or diaphragmatic hernia repair (n = 4), biliary leakage repair (n = 1) and segmental colon resection combined with diaphragmatic hernia repair (n = 1). There was a statistically significant difference in hospital stay (P0.001), autologous blood transfusions (P0.001) and operating time (P0.005) when right lobe donations (Segments V-VIII) were compared with left lobe (Segments II-IV) and left lateral lobe (Segments II-III) donations, whereas no difference was found between these groups regarding hospital readmission, operative revisions and the incidence or severity of complications. Right lobe donation was associated with prolonged hospital stay, increased blood transfusions and prolonged operating time when compared with left and left lateral lobe donation, whereas donor mortality and morbidity did not differ between these groups.

Hepatitis B virus reactivation during immunosuppressive therapies can lead to liver failure with very limited treatment options available. We report here on two cases of severe hepatitis B reactivation during chemotherapy including rituximab for B cell lymphoma which were treated with liver or liver-cell transplantation. Liver function was normal and HBV infection was unknown in both patients before chemotherapy was started. Impaired liver function became apparent after 4 and 6 courses of chemotherapy, respectively, and both patients experienced fulminant hepatic failure despite antiviral treatment with lamivudine or entecavir. Patient A underwent liver transplantation after documentation of complete remission of the lymphoma and survived without any evidence for hepatitis B recurrence. Patient B received 4 courses of hepatocyte transplantation but did not survive. These cases underline the importance of anti-HBc screening in patients receiving immunosuppressive treatments in particular when rituximab is given. Pre-emptive antiviral treatments should be administered since delayed antiviral treatment is frequently unable to prevent liver failure.

Hepatitis E virus (HEV) infection induces self-limiting liver disease in immunocompetent individuals. Cases of chronic hepatitis E have recently been identified in organ transplant recipients. We questioned if chronic hepatitis E plays a role in graft hepatitis after liver transplantation in a low endemic area. Two hundred twenty-six liver transplant recipients, 129 nontransplanted patients with chronic liver disease, and 108 healthy controls were tested for HEV antibodies. HEV RNA was investigated in all sera from transplanted patients. HEV antibodies were detected in 1 healthy control (1%), 4 patients with chronic liver disease (3%), and 10 liver transplant recipients (4%). Three liver transplant patients also tested positive for HEV RNA. Two of them developed persistent viremia with HEV genotype 3. The patients were anti-HEV immunoglobulin G-negative and HEV RNA-negative before transplantation and had an episode of acute hepatitis 5 or 7 months after transplantation, which led to advanced liver fibrosis after 22 months in 1 patient. Seroconversion to anti-HEV occurred not before 4 months after the first detection of HEV RNA. The possibility of reverse zoonotic transmission was experimentally confirmed by the infection of 5 pigs with a patient's serum. The pigs showed histological inflammation in the liver, and HEV RNA was detectable in different organs, including muscle. In conclusion, the prevalence of HEV infection in Central European liver transplant recipients is low; however, chronic hepatitis E may occur and needs to be considered in the differential diagnosis of graft hepatitis. The diagnosis of HEV infection should be based on HEV RNA determination in immunosuppressed patients. We suggest that immunocompromised individuals should avoid eating uncooked meat and contact with possibly HEV-infected animals.

SUMMARY Background: The postoperative management following solid organ transplantation requires close cooperation between family doctors, internists, the local hospital, and the transplant center. Methods: Selective analysis of current national and international guidelines and relevant review articles. Results/conclusion: In the early phase post transplantation, aftercare involves inpatient treatment and outpatient or inpatient rehabilitation with the aim of complete social and professional reintegration. Early diagnosis and treatment of typical general complications such as post-transplant diabetes, hyperlipidemia, arterial hypertension, osteoporosis, and kidney failure is essential. Early detection and treatment of malignant disease and opportunistic infections in patients with long-term immunosuppression is desirable. Moreover, organ-specific factors have to be taken into account. In the event of transplant dysfunction, recurrence of the underlying disease in the transplant, chronic or acute rejection, and organ-specific infections and drug toxicity have to be considered.

With continuously rising survival rates following orthotopic liver transplantation (OLT), health-related quality of life (HRQOL) of transplant recipients becomes increasingly important. Recipients more than 15 years after OLT were studied retrospectively. HRQOL in 104 adult liver transplant recipients surviving more than 15 years after OLT was assessed using the German Version of the 36-Item Health Survey (SF-36). Liver transplant recipients surviving more than 15 years after OLT scored lower in all categories of SF-36 revealing a poor HRQOL in comparison to the German reference population. A statistical significance was reached in almost all SF-36 categories with the exceptions of mental health and bodily pain, where our study population scored similarly to the reference population. Job rehabilitation after OLT had a positive effect on HRQOL. Patients who returned to their job during the first year after OLT scored significantly higher in the SF-36 categories of physical functioning and role physical. Marital status and the immunosuppression used didn't affect HRQOL as there was no statistical significance reached in any of the comparisons performed. More than 15 years after OLT, long-term survivors present a poor HRQOL comparable to the reference population. Occupational rehabilitation was the only factor shown to positively influence long-term HRQOL.

Score-based medical urgency criteria are used for necessity-oriented liver transplantation (OLT) but lead to an increasing number of complications in patients with reduced post-OLT survival. A prediction of outcome would improve preoperative patient selection and management.One-hundred-and-thirty-three consecutive adult patients (63.9% men, mean age 47.4+/-11.2 years) given transplants between May 2004 and November 2005 at the Hannover Medical School were analysed retrospectively using univariate and multivariate methods.Indications were: 27.1% viral hepatitis, 19.6% primary sclerosing cholangitis, 15.0% alcoholic liver disease, 7.5% metabolic liver disease, 6.8% primary biliary cirrhosis. Overall, 12-month patient survival was 81.2%. The mean MELD score at OLT was 14.5+/-5.3 and 12-month survival with MELD16 (71.7%) and16 (86.2%) differed significantly (p=0.041). Predictors of 12-month mortality included age (53.2+/-9.4 versus 46.1+/-11.2 years; p=0.004), lower cholinesterase (2.9+/-1.88 versus 3.7+/-2.02 kU/l; p=0.026) and serum creatinine (160.4+/-186.8 versus 77.7+/-31.6 micromol/l; p=0.007), with creatinine and cholinesterase as independent parameters. Based on these parameters, a model for predicting patient survival after liver transplantation was calculated and validated in a second independent cohort of 87 OLT patients. This score identified a high-risk group and a low-risk group (overall survival 47.4 versus 91.2%; p0.001) with a specificity of 87.3% and a sensitivity of 68.75%.Age, pre-OLT creatinine and cholinesterase are predictors of short-term post-OLT survival and may be helpful as a bedside score in pre-OLT clinical management, outcome prediction and decision-making.

Mutations within the low density lipoprotein (LDL)-receptor gene result in familial hypercholesterolemia, an autosomal dominant inherited disease. Clinical homozygous affected subjects die of premature coronary artery disease as early as in early childhood. We identified a girl at the age of five yr with clinical homozygous familial hypercholesterolemia presenting with achilles tendon xanthomas and arcus lipoides. Her total cholesterol reached up to 1050 mg/dL. Molecular characterization of the LDL-receptor gene revealed a homozygous p.W577R mutation. Despite intensive treatment interventions with the combination of diet, statins, colestipol, and LDL-apheresis, the patient developed symptomatic coronary artery disease at the age of 16 yr. Subsequently, orthotopic liver transplantation was performed to cure the defective LDL-receptor gene. Clinical follow-up for almost nine yr post-transplantation revealed excellent liver function, normal liver enzymes, normal LDL-cholesterol, and regression of both tendon xanthomas and symptomatic coronary artery disease. In conclusion, liver transplantation can effectively reduce LDL-cholesterol in a familial hypercholesterolemia recipient with subsequent regression of xanthomas and atherosclerosis. Timing is extremely important in these exceptional cases to exclude the demand for heart transplantation due to severe coronary artery disease. In addition, the identification of the LDL-receptor as etiology of clinical homozygous hypercholesterolemia is a prerequisite once liver transplantation is considered as therapeutic option.