Hannelore Barg-Hock

Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients

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 patients 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. Liver Transpl 16:74–82, 2010.

Outcome and quality of life in patients with polycystic liver disease after liver or combined liver‐kidney transplantation

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. Liver Transpl 12:1268‐1277, 2006.

The introduction of MELD-based organ allocation impacts 3-month survival after liver transplantation by influencing pretransplant patient characteristics.

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.

Prediction of survival after liver transplantation by pre-transplant parameters

Objective. 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. Material and methods. 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. Results. 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 MELD >16 (71.7%) and <16 (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 µmol/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%; p<0.001) with a specificity of 87.3% and a sensitivity of 68.75%. Conclusion. 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.

Comparison of the most favoured methods for the diagnosis of hepatic encephalopathy in liver transplantation candidates

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.

Health-related quality of life after solid organ transplantation: a prospective, multiorgan cohort study.

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.

Biliary Strictures and Recurrence After Liver Transplantation for Primary Sclerosing Cholangitis: A Retrospective Multicenter Analysis

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. Liver Transpl 22:42‐52, 2016.

Living donor liver transplantation: effect of the type of liver graft donation on donor mortality and morbidity

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.

Cirrhosis-related Parkinsonism: Prevalence, mechanisms and response to treatments

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.

Liver transplantation in a subject with familial hypercholesterolemia carrying the homozygous p.W577R LDL-receptor gene mutation

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.