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Summary. The topic of this monograph is liver cancer associated with chronic HCV infection. We start with some background information on chronic HCV infection and its long-term sequelae, one of which is liver cancer. The rest of the article is concerned with liver cancer or hepatocellular carcinoma (HCC). Epidemiology, risk factors, treatment and outcomes are discussed. We focus on those aspects that are of specific interest in people with haemophilia: studies performed in haemophilia populations, the use of invasive diagnostic and therapeutic tools and the outcome of liver transplantation. Throughout the paper, recommendations are given on surveillance for and diagnosis of HCC and on the practical aspects of invasive procedures. These recommendations are based on professional guidelines, other published evidence and the authors’ experience. In general, diagnostic and therapeutic options are the same in persons with and without haemophilia.

Background: The role of the immune system in the pathogenesis of nonanastomotic biliary strictures (NAS) after orthotopic liver transplantation (OLT) is unclear. A loss-of-function mutation in the CC chemokine receptor 5 (CCR5-Delta 32) leads to changes in the immune system, including impaired chemotaxis of regulatory T cells. Aim: To investigate the impact of the CCR5-Delta 32 mutation on the development of NAS. Methods: In 384 OLTs, we assessed the CCR5 genotype in donors and recipients and correlated this with the occurrence of NAS. Results: The CCR5-Delta 32 allele was found in 65 (16.9%) recipients. The cumulative incidence of NAS at 5 years was 6.5% in wild-type (Wt) recipients vs 17.2% for carriers of the CCR5-Delta 32 allele (P 2 years after OLT, compared with 10% in the Wt group. In multivariate regression analysis, the adjusted risk of developing NAS was four-fold higher in recipients with CCR5-Delta 32 (P

Hepatitis E virus (HEV) infections are known to run a self-limiting course. Recently, chronic hepatitis E has been described in immunosuppressed patients after solid-organ transplantation. Besides the general recommendation to lower the immunosuppressive medication in these patients, there is currently no specific treatment. We here describe the successful use of pegylated interferon alpha-2b in the treatment of 2 liver transplant recipients who suffered a chronic HEV infection for 9 years (case A) or 9 months (case B). After 4 weeks of therapy, a 2-log decrease (case A) and a 3-log decrease (case B) in the viral load were observed. In case A, who received treatment for 1 year, serum viral RNA became undetectable from week 20 onward, and serum liver enzymes normalized completely. In case B, interferon was discontinued at week 16 because of a lack of a further decline in the viral load. However, 4 weeks after the cessation of therapy, viral RNA was no longer detectable in the serum, and this was probably related to a further decline in the immunosuppressive medication. Liver tests normalized completely. In both cases, no relapse has been noted so far. We conclude that pegylated interferon alpha-2b may be useful in the treatment of chronic HEV infections in patients in whom the reduction of the immunosuppressive medication alone is not sufficient. Liver Transpl 16:474-477, 2010. (C) 2010 AASLD.

Objective. The severity of systemic amyloidosis is thought to be related to the extent of amyloid deposition. We studied whether amyloid load in fat tissue reflects disease severity and predicts survival.Methods. We studied all consecutive patients with systemic amyloidosis seen between January 1994 and January 2007 in our tertiary referral center. Congo red-stained abdominal fat smears were graded by 2 observers using a validated semiquantitative scoring system. Disease severity was measured by the total number of major organs involved and the extravascular retention of the serum amyloid P component (EVR(24)). The association of amyloid load in fat tissue with disease severity and overall survival was studied using multiple regression analysis.Results. Two hundred twenty patients were included in the study (120 with AL amyloidosis, 66 with AA amyloidosis, and 34 with ATTR amyloidosis). Amyloid grade in fat tissue was associated with the number of major organs involved and EVR(24). Female sex turned out to be associated with a higher grade of amyloid in fat tissue than male sex. Amyloid grade in fat tissue was an independent predictor of decreased survival, as were heart involvement, the number of organs involved, AA or AL type of amyloid, and age.Conclusion. The amount of amyloid in subcutaneous fat tissue in systemic amyloidosis reflects disease severity, as measured by the number of organs involved and EVR(24), and predicts decreased survival independent of other well-known factors.

Hepatitis E virus (HEV) infection is known to run a self-limited course. Recently, chronic hepatitis E has been described in several immunosuppressed patients after solid organ transplantation. The prevalence of HEV infection after transplantation, however, is unknown. We studied HEV parameters [HEV RNA, HEV immunoglobulin M (IgM), and HEV immunoglobulin G (IgG) by enzyme-linked immunosorbent assay and confirmatory immunoblotting] in a cohort of 285 adult liver transplant recipients. The most recent freeze-stored sera were investigated, and if they were positive, a retrospective analysis was performed. Samples from 274 patients (96.1%) tested negative for all HEV parameters. This included a patient described earlier as having experienced an episode of chronic HEV hepatitis in the past. One patient was found positive for HEV RNA without HEV antibodies. She presently suffers from chronic HEV hepatitis and has also been described before. Sera from 9 patients tested positive for HEV IgG without HEV IgM or HEV RNA. Six of these 9 patients (2.1% of the total) were found to have HEV IgG antibodies in retrospect related to an HEV infection at some time pre-transplant as they also tested positive in a pretransplant serum sample. One of these 9 patients suffered in retrospect from a chronic HEV infection with mild hepatitis between 2 and 5 years after liver transplantation on the basis of the course of HEV RNA, IgM, and IgG, aminotransferases, and liver histology. Overall, the prevalence of acquired HEV hepatitis after liver transplantation was 1% in this cohort. We conclude that liver transplant recipients have a risk for chronic HEV infection, but the prevalence is low.

Biliary reconstruction using Roux-en-Y choledochojejunostomy has been suggested as a risk factor for the development of nonanastomotic biliary strictures (NAS) after liver transplantation. Roux-en-Y reconstruction, however, is preferentially used in patients transplanted for primary sclerosing cholangitis (PSC), and the disease itself is also associated with a higher incidence of NAS. The aim of this study was to determine whether Roux-en-Y reconstruction is really an independent risk factor for NAS. A series of 486 consecutive adult liver transplants were studied. Biliary reconstruction in patients transplanted for PSC was either by Roux-en-Y choledochojejunostomy or by duct-to-duct anastomosis, depending on the quality of the recipient's extrahepatic bile duct. Univariate and multivariate statistical analyses were used to identify risk factors for the development of NAS. The overall incidence of NAS was 16.5% (80/486). In univariate analyses, the following variables were significantly associated with NAS: PSC as the indication for transplantation, type of biliary reconstruction (Roux-en-Y versus duct-to-duct), and postoperative cytomegalovirus infection. After multivariate logistic regression analysis, PSC as the indication for transplantation (odds ratio, 2.813; 95% confidence interval, 1.624-4.875; P < 0.001) and postoperative cytomegalovirus infection (odds ratio, 2.098; 95% confidence interval, 1.266-3.477; P = 0.004) remained as independent risk factors for NAS. Biliary reconstruction using Roux-en-Y choledochojejunostomy was not identified as an independent risk factor for NAS. In conclusion, the association between Roux-en-Y choledochojejunostomy and NAS observed in previous studies can be explained by the more frequent use of Roux-en-Y reconstruction in patients with PSC. Roux-en-Y reconstruction itself is not an independent risk factor for NAS. Liver Transpl 15:924-930, 2009. (c) 2009 AASLD.

Background/Aims: Nonanastomotic biliary strictures are troublesome complications after liver transplantation. The pathogenesis of NAS is not completely clear, but experimental studies suggest that bile salt toxicity is involved.Methods: In one hundred and eleven adult liver transplants, bile samples were collected daily posttransplantation for determination of bile composition. Expression of bile transporters was studied perioperatively.Results: Nonanastomotic biliary strictures were detected in 14 patients (13%) within one year after transplantation. Patient and donor characteristics and postoperative serum liver enzymes were similar between patients who developed nonanastomotic biliary strictures and those who (lid not. Secretions of bile salts, phospholipids and cholesterol were significantly lower in patients who developed strictures. In parallel, biliary phospholipids/bile salt ratio was lower in patients developing strictures, suggestive for increased bile cytotoxicity. There were no differences in bile salt pool composition or in hepatobiliary transporter expression.Conclusions: Although patients who develop nonanastomotic biliary strictures are initially clinically indiscernible from patients who do not develop nonanastomotic biliary strictures, the biliary bile salts and phospholipids secretion, as well as biliary phospholipids/bile salt ratio in the first week after transplantation, was significantly lower if] the former group. This supports the concept that bile cytotoxicity is involved in the pathogenesis of nonanastomotic biliary strictures. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Liver transplantation aims to halt the progression of the disease in patients with familial amyloidotic polyneuropathy (FAP) caused by hereditary transthyretin-related (ATTR) amyloidosis. Insight in health-related quality of life of these transplanted FAP-patients can be of help to optimize health care delivery. The aim of this cross-sectional study was to assess the health-related quality of life of patients with FAP long-term after transplantation.Nine patients with a post-transplant follow-up of 4 years or more were included in the study. During the annual checks, health-related quality of life was measured with the Short Form-36 (SF-36). Data were compared with non-FAP transplanted patients with the same duration of follow-up and with the normal Dutch population. Pre-transplant, all patients had signs of mild to moderate peripheral polyneuropathy.The results showed that in patients with FAP health-related quality of life was stable in the first 4 years after transplantation. The domain of physical well-being at 4 years after transplantation was significantly lower compared to non-FAP transplanted patients and control Dutch population. The domain of emotional well-being was comparable with non-FAP controls. However, on most health areas patients with FAP scored lower than the non-FAP transplanted patients and the Dutch controls. After four years, the three patients with FAP with longest follow-up (9-12 years) deteriorated in all health domains, except in self-perceived mental health.This study, including only a small number of patients with FAP, shows a relatively low health-related quality of life after liver transplantation, which may deteriorate further with longer follow-up.

Purpose: Liver transplant recepients (LTRs) have an increased risk of colorectal neoplasia. The mechanism responsible for this is unknown. JCV encodes for TAg and has been implicated in colorectal carcinogenesis. We hypothesized that the use of immunosuppression in LTRs facilitates activation of JCV and is responsible for the increased risk of neoplasia. Experimental Design: JCV TAg DNA and protein expression were determined in normal colonic epithelium (n = 15) and adenomatous polyps (n = 26) from LTRs and compared with tissue samples from control patients (normal colon, n = 21; adenomas, n = 40). Apoptosis and proliferation were determined by M30 and Ki-67 immunoreactivity, respectively. Results: JCV TAg DNA was found in 10 of 15 (67%) of normal colonic mucosa from LTRs compared with 5 of 21 (24%) of control normal mucosa (P = 0.025). JCV TAg DNA was detected in 16 of 26 (62%) of the adenomas from LTRs and in 20 of 40 (50%) of control adenomas. JCV TAg protein was expressed in 13 of 26 (50%) adenomas from LTRs versus 2 of 40 (5%) of adenomas from controls (P < 0.001). In adenomas from LTRs, the mean proliferative activity was higher compared with controls (60.3 ± 3.2% versus 42.7 ± 2.8%, P < 0.001), whereas mean apoptotic indices were lower in LTRs (0.29 ± 0.08% versus 0.39 ± 0.06%, P = 0.05). Conclusions: The presence of JCV in the colorectal mucosa and adenomas from LTRs, in concert with the use of immunosuppressive agents, suggests that JCV may undergo reactivation, and the subsequent TAg protein expression might explain the increased risk of colorectal neoplasia in LTRs.

Symptom experience (occurrence and perceived distress) associated with side effects of immunosuppressive medications in organ transplant patients may well be associated with poorer quality of life and medication non-compliance. The aims of this study were: first, to assess symptom experience in clinically stable adult patients during long-term follow-up after liver transplantation; and second, to study the relationship between symptom experience and medication non-compliance. This cross-sectional study included 123 liver transplant patients. Symptom experience was assessed using the "Modified Transplant Symptom Occurrence and Symptom Distress Scale" (29-item version) at the annual evaluation. According to the duration of follow-up, patients were divided into a short-term (1-4 yr) and a long-term (5-18 yr) cohort. Medication non-compliance was measured using electronic monitoring. Results showed that increased hair growth was the most frequent symptom in both sexes. Symptom distress was more serious in women than in men. The most distressing symptom in women was excessive and/or painful periods, while in men this was impotence. Clear differences were revealed at item level between symptom occurrence and symptom distress in relationship with the two time cohorts and between sexes. No relationship was found between symptom experience and prednisolone non-compliance.

BACKGROUND: The model of end-stage liver disease (MELD) score is nowadays widely used to prioritize patients for liver transplantation. AIMS: To assess the contribution of the individual components of the MELD score in interlaboratory variability. METHODS: We sent 15 samples from patients listed for liver transplantation to seven different European laboratories who were asked to measure all three variables. In addition, 10 samples from patients on oral anticoagulant treatment were sent to the same labs for the international normalised ratio (INR) measurement. RESULTS AND CONCLUSIONS: In all 15 samples, a substantial and clinically relevant variation in the calculated MELD score was observed between laboratories. The mean difference in the MELD score between the highest- and the lowest-scoring laboratory was 4.8. The variation in creatinine measurements resulted in differences of up to three MELD points in a single patient when comparing the highest and the lowest scoring lab. The variation in bilirubin measurements only accounted for a difference of one point between the highest- and the lowest-scoring laboratory, but the variation in INRs resulted in differences of 2 to 12 MELD points. MELD scores or INR values were not substantially different in laboratories that used the Owren instead of the more widely used Quick methodology for INR measurements. The variability in the INR in patients on oral anticoagulants was substantially less as compared with the variability in patients with liver disease. In conclusion, we observed a large interlaboratory variation in the MELD score. This variation in the MELD score is primarily caused by the INR.

To estimate the evolution of amyloid in tissue, we studied abdominal fat aspirates of cases with familial amyloidotic polyneuropathy (FAP) longitudinally at regular intervals between 1994 and 2006. In 22 cases (13 carriers and nine patients) not yet transplanted median follow-up was 3.3 years (range 0.4-11.3). We found a significant increase in the amyloid grade of fat tissue from 2+ to 4+ and from 0 to 4+ in two of three subjects with follow-ups of > 7 years, after 7 and 11 years, respectively. All other subjects remained negative or did not show a significant change. In I I liver transplant patients, followup with fat aspirate was available with a median duration of 3.1 years (range 1.0-10. 1). A comparison was made with cardiac amyloid as judged by the cardiac septum diameter and the serum NT-ProBNP (N-terminal pro-B-type natriuretic peptide) level. No stable increase of amyloid in fat was seen in any patient. A stable decrease of amyloid grade was seen in one patient 5 years after transplantation. In contrast, the cardiac septum diameter increased >= 4 min in six of the 11 transplant patients. Our study shows the diagnostic utility of a regularly repeated fat aspirate in carriers at risk for the development of ATTR amyloidosis. Evolution of amyloid deposition in fat tissue is very gradual. After liver transplantation, amyloid deposition in fat tissue seems to stabilize and may even decrease in the long term, whereas amyloid deposition in cardiac tissue appears to be progressive.

SummarySplanchnic vein thrombosis (SVT) has been associated with a hypercoagulable state. Thrombin-activatable fibrinolysis inhibitor (TAFI) may contribute to a hypercoagulable state, and therefore we were interested in the role of TAFI in SVT. Since the disease is frequently associated with liver insufficiency, which affects plasma levels ofTAFI, we studied the role of variation in theTAFI gene in SVT. In a multicenter case-control study on 118 patients with SVT (39 Budd-Chiari syndrome and 85 portal vein thrombosis) and 118 population-based controls, the relationship of SVT with single nucleotide polymorphisms (SNPs) and haplotypes in the TAFI gene (- 438G/A, Ala147Thr, Thr325Ile and 1583A/T) was determined. The risk for SVT was decreased (OR 0.2,95% CI 0.1–0.7) in 147Thr/Thr homozygotes and slightly,but not significantly,increased in carriers of the 325Ile allele (OR 1.6, 95%CI 0.9–2.7). Haplotype analysis confirmed that the Ala147Thr SNP has the strongest association with risk of SVT. In conclusion, genetic variation in the TAFI gene is associated with risk of SVT, suggesting a role for TAFI in the pathogenetic mechanism of SVT.

OBJECTIVE: Despite the use of immunosuppressive drugs, recurrent and de novo inflammatory bowel disease (IBD) can develop after orthotopic liver transplantation (OLT). Cytomegalovirus (CMV) infection has been suggested to play a role in the pathogenesis of IBD. The aim of this study was to investigate the role of CMV infection in the development of IBD after OLT.MATERIAL AND METHODS: All 84 patients who underwent transplantation for primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) in our center between May 1987 and June 2002 and who survived the first year after transplantation were included in the study. Diagnosis of active CMV infection was made using the pp65-antigenemia assay.RESULTS: Thirty-one of the 84 patients (37%) had IBD prior to OLT. Eighteen patients (21%) experienced IBD after OLT, either as flare-up (n=12) or de novo (n=6), at a median of 1.4 years (range 0.3 to 6.3) after OLT. Forty-eight percent of all patients experienced CMV infection after OLT, at a median of 27 days (range 8 to 193). CMV infection was primary in half the patients. At 1, 3, and 5 years after OLT, active IBD-free survival without CMV infection was 91, 88, and 88%, respectively. With CMV infection these figures were 93, 82, and 67%. De novo IBD was seen only in those who had experienced a CMV infection (p=0.02).CONCLUSIONS: In patients transplanted for end-stage PSC or AIH, active IBD, especially de novo IBD, occurred more often in patients who experienced CMV infection in the postoperative period. This finding supports a pathogenic role for CMV in the development of IBD.

After liver transplantation, the prevalence of complications related to the biliary system is 6-35%. In recent years, the diagnosis and treatment of biliary problems has changed markedly. The two standard methods of biliary reconstruction in liver transplant recipients are the duct-to-duct choledochocholedochostomy and the Roux-en-Y-hepaticojejunostomy. Biliary leakage occurs in approximately 5-7% of transplant cases. Leakage from the site of anastomosis, the T-tube exit site and donor or recipient remnant cystic duct is well described. Symptomatic bile leakage should be treated by stenting of the duct by endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTCD). Biliary strictures can occur at the site of the anastomosis (anastomotic stricture; AS) or at other locations in the biliary tree (non-anastomotic strictures; NAS). AS occur in 5-10% of cases and are due to fibrotic healing. Treatment by ERCP or PTCD with dilatation and progressive stenting is successful in the majority of cases. NAS can occur in the context of a hepatic artery thrombosis, or with an open hepatic artery (ischaemic type biliary lesions or ITBL). The incidence is 5-10%. NAS has been associated with various types of injury, e.g. macrovascular, microvascular, immunological and cytotoxic injury by bile salts. Treatment can be attempted with multiple sessions of dilatation and stenting of stenotic areas by ERCP or PTCD. In cases of localized diseased and good graft function, biliary reconstructive surgery is useful. However, a significant number of patients will need a re-transplant. When biliary strictures or ischaemia of the graft are present, stones, casts and sludge can develop.

OBJECTIVES: Combined Budd-Chiari syndrome and Portal Vein Thrombosis (BCS-PVT) is a challenging clinical condition with as yet unknown outcome. The aim of the present study was to investigate etiology, treatment options, and prognosis of patients with BCS-PVT.METHODS: Patients diagnosed with nonmalignant BCS between 1984 and 2001 were identified in a large international study and classified into isolated BCS (n = 204), BCS-PVT without spleno-mesenteric vein thrombosis (SMVT; n = 15), and BCS-PVT with SMVT (n = 18).RESULTS: Multifactorial etiology was present in 58% of patients with combined BCS-PVT. Number of etiological factors increased significantly with the extent of thrombosis (p= 0.002). Main treatment options included anticoagulation and portosystemic shunting, of which extended TIPS showed the most beneficial results. Five-year survival was 59% (95% CI 39-80%) in BCS-PVT versus 85% (95% CI 76-88%) in isolated BCS (p= 0.11). Survival tended to be worse in BCS-PVT patients with SMVT as compared to patients without SMVT (RR = 3.47, p= 0.11).CONCLUSIONS: In BCS, extension of thrombosis into the splanchnic venous bed was significantly related to the number of etiological factors, and was associated with poor outcome. These results strongly support a liberal use of anticoagulants, which so far had been widely debated. Alternatively, derivative shunt procedures appear difficult, yet not impossible.

We present a patient with no medical history admitted for jaundice and dark coloured urine. Further investigations revealed hepatitis A related acute liver failure while the patient had no travel history, nor contact with infected individuals. After admission, the patient deteriorated fulfilling the King's College criteria for acute liver failure. Two days after admission, he underwent liver transplantation and recovered. Careful investigation identified imported semi-dried tomatoes as the source of the hepatitis A infection. This patient was part of a foodborne hepatitis A outbreak in the Netherlands in 2010 affecting 13 patients. Virus sequence analysis of our patient's virus showed a strain commonly found in Turkey. Hepatitis A related acute liver failure is rare, but is associated with a poor prognosis. In developed countries, the incidence of hepatitis A is low, but foodborne outbreaks are emerging. Further, we review the literature on recent foodborne hepatitis A outbreaks in developed countries, hepatitis A related acute liver failure, and hepatitis A vaccine. (C) 2014 Elsevier B.V. All rights reserved.

Limited evidence is available concerning (non)compliance with the immunosuppressive regimen in adult liver transplant recipients. In our study we prospectively assessed prednisolone (non)compliance in 108 adult liver transplant recipients using electronic event monitoring (EEM) in an outpatient setting. The EEM is a pill bottle fitted with a cap containing a microelectronic circuit that registers date and time of bottle openings and closings. Median taking compliance was 100% (range 60-105%), median dosing compliance was 99% (range 58-100%); median timing compliance (TIC) was 94% (42-100%). A drug holiday (DH) of >= 48 h was found in 39% of the patients of >= 72 h in 16% of the patients. Using EEM in liver transplant recipients, we found an overall high level of compliance for prednisolone, except that TIC was low in about one third of the patients. Age below 40 years was found a significant risk factor for decreased TIC and for DHs of >= 48 h.

Objective: Treatment with recombinant interferon is associated with high rates of psychiatric comorbidity. We investigated the relation between catabolism of the essential amino acid tryptophan, being rate-limiting of peripheral and cerebral serotonin formation, and psychiatric symptoms in patients undergoing combination treatment with interferon-a and ribavirin. Patients and Methods: Eighteen patients with viral hepatitis C who received interferon were included. A psychiatrist screened patients before and while on interferon-a treatment for 2 months, using a structured diagnostic interview. Fasting plasma tryptophan and platelet serotonin levels were measured at each visit. Results: At baseline no evident psychopathology was observed. After 2 months of interferon treatment, 10 patients experienced increased irritability. No other structural psychopathology was observed. Decreased plasma tryptophan level correlated with the presence of irritability (p = .047). Platelet serotonin levels were found to be decreased during treatment (p = .002). Conclusions: Aggressive impulse dysregulation is highly prevalent in patients receiving interferon treatment. This is associated with decreased plasma tryptophan levels which may lead to attenuated peripheral and central serotonergic neurotransmission. Key words: interferon, tryptophan, inflammation, serotonin, irritability.

Objective., To determine the efficacy of selective decontamination of the digestive tract (SDD) in patients undergoing elective transplantation of the liver. Design: Randomized, double-blind, placebo-controlled study. Setting. Two academic teaching hospitals. Patients. Adult patients undergoing elective liver transplantation: 26 patients receiving SDD and 29 patients receiving a placebo. Interventions: Patients undergoing SDD were administered 400 mg of norfloxacin once daily as soon as they were accepted for transplantation, Postoperative treatment for this group consisted of 2 mg of colistin, 1.8 mg of tobramycin, and 10 mg of amphotericin B, four times daily, combined with an oral paste containing a 2% solution of the same drugs until postoperative day 30. Prophylactic Intravenous administration of antibiotics was not part of the SDD regimen in this study. Control patients were given a similar regimen with placebo drugs. Measurements: The mean number of postoperative bacterial and fungal infections in the first 30 days after transplantation was the primary efficacy end point. Days on a ventilator, days spent in the intensive care unit, and medical costs were registered as secondary outcome variables. Main Results. Of the 26 patients undergoing SOD, 22 (84.5%) developed an infection in the postoperative study period; In the placebo group (n = 29), these numbers were not significantly different (25 patients, 86%). The mean number of postoperative infectious episodes per patient was also not significantly different: 1.77 (SDD) vs. 1.93 (placebo), Infections Involving Gram-negative aerobic bacteria and Candida species were significantly less frequent in patients receiving SOD (p Conclusions. Selective decontamination of the digestive tract does not prevent Infection in patients undergoing elective liver transplantation and increases the cost of their care. It does, however, affect the type of infection. Infections with Gram-negative bacilli and with Candida species are replaced by infections with Gram-positive cocci.

Plasma levels of coagulation factors differ profoundly between adults and children, but are remarkably stable throughout adulthood. It is unknown which factors determine plasma levels of coagulation factors in a given individual. We hypothesized that the liver, which synthesizes coagulation factors, also controls plasma levels. We measured a panel of coagulation factors in samples taken from either adults or young children who underwent a liver transplantation with adult donor livers. Samples were taken 1-3 months after transplantation, when the patients were clinically stable with adequate graft function. After liver transplantation, the hemostatic profile of the pediatric group was remarkably different from that of the adult group, and resembled the hemostatic profile of normal children. Thus, children transplanted with an adult liver graft maintain a pediatric hemostatic profile after transplantation despite receiving an adult liver graft. These findings suggest that plasma levels of hemostatic proteins are not controlled by the liver.

Background/Aims: Development of de novo malignancies emerges as a serious long term complication after liver transplantation. Methods: We reviewed the medical records of 174 adult one-year survivors for de novo malignancies, The observed cancer rates were compared with the expected cancer rates in the Dutch population. Results: Twenty-one of the 174 patients developed 23 malignancies (12%). Skin and lip cancer accounted for 12 of the 23 malignancies (52%). Only one patient had a B-cell lymphoma. The cumulative risk for de novo malignancy was 6, 20, and 55% at 5, 10, and 15 years after transplantation, respectively, The overall relative risk (RR) as compared with the general population was 4.3 (95% confidence interval 2.4-7.1), Significantly increased RRs were observed for nonmelanoma skin cancer (RR 70.0), non-skin solid cancer (RR 2.7), renal cell cancer (RR 30.0), and colon cancer (RR 12.5), Multivariate analysis showed that an age > 40 years and pretransplant use of immunosoppression were significant risk factors. Conclusions: An increased risk of cancer exists after liver transplantation, for both for skin/lip cancer, and other solid tumors. Older age and the use of immunosuppression are risk factors. (C) 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.

Review of the literature shows that recurrence of primary biliary cirrhosis occurs in about 10% of patients in the first few years after liver transplantation. The cumulative risk is expected to increase in time. The rate of recurrent disease may be affected by the immunosuppression used. Weaning from immunosuppression may initiate recurrence. Disease progression is slow and no reason for graft loss.

Background: Cirrhosis and portal hypertension affect the flow profile of the liver vasculature. In these conditions Doppler ultrasound can provide important information on the hemodynamics of the portal venous system, the hepatic artery and the hepatic veins. Methods: The value of Doppler ultrasound in the assessment of the patient with cirrhosis and portal hypertension was determined by reviewing the Literature. Results: Portal venous blood how becomes reversed with advanced portal hypertension. Reversed flow is also demonstrated in patients with veno-occlusive disease and portosystemic shunts. Despite general agreement that portal flow velocity is decreased in cirrhotic patients, the absolute values of portal flow velocity in both healthy subjects and cirrhotic patients Vary considerably. Errors in Doppler measurements, observer variability and collateral pathways contribute to these variations. Furthermore, portal blood flow is influenced by numerous factors such as changes in the body position, phase of respiration, timing of meals, exercise and cardiac output. Finally, portal flow may be unaltered due to a combination of high inflow from the splanchnic organs and increased resistance within the liver. High resistive index of the hepatic artery is seen in patients with end-stage liver disease, particularly in children with severe cirrhosis secondary to biliary atresia. However, hepatic artery dow remains normal in mast patients. Abnormal hepatic vein flow profiles are seen in patients with cirrhosis, but dampening or flattening of the flow profile has a multifactorial origin (Budd-Chiari, metastases, ascites) and can be observed in healthy subjects. Conclusions: Although many factors may affect the accuracy of volume flow and velocity measurements and the flow profile of the liver vasculature may change in different situations, Doppler ultrasound is useful in the assessment of the patient with cirrhosis and portal hypertension.

Background. The development of immunological donor-specific hyporeactivity may account for the low incidence of chronic rejection after clinical liver transplantation. We investigated whether hyporeactivity commonly develops after liver transplantation by analyzing precursor frequencies of donor-reactive cytotoxic (CTLp) and helper (HTLp) T lymphocytes and mixed lymphocyte culture (MLC) reactivity in liver allograft recipients. We further studied whether CTLp hyporeactivity correlated with changes in donor-specific HTLp frequencies or suppressor cell activity. Methods. CTLp and HTLp frequencies and MLC reactivity against donor and third-party spleen cells were determined in pre- and posttransplantation peripheral blood samples from 18 recipients with good graft function 2 years after transplantation. By mixing posttransplantation samples (with "putative" suppressor cell activity) with pretransplantation samples tin which normal CTL activity with no suppressor cell activity is expected), the presence of suppressor cell activity in peripheral blood was analyzed. Results. Two years after transplantation, all but one (94%) of the recipients had developed CTLp hyporeactivity as evidenced by reduced donor-specific CTLp frequencies. The development of hyporeactivity was not specific for any particular underlying disease. The occurrence of HTL hyporeactivity, however, was less frequent: 38% and 20% of recipients were HTLp and MLC hyporeactive, respectively. Decreases in CTLp frequencies did not correlate with decreased donor-specific HTL function or suppressor cell activity in peripheral blood samples. Conclusions. Donor-specific CTLp hyporeactivity can develop in the majority of liver allograft recipients, irrespective of underlying disease. Donor-specific HTL hyporeactivity, however, occurs infrequently. A reduction in donor-specific CTLp frequencies was found to be independent of changes in donor-specific HTLp or suppressor cell activity, suggesting that other mechanisms (e.g., clonal deletion) are operative in the reduction of donor-specific CTLp after liver transplantation.

Background/Aims: The purpose of the study was to investigate the incidence of and risk factors for splenic artery aneurysms in liver transplant patients. Methods: Medical records and the pre- and 1-year postoperative angiograms of 337 liver transplant patients were reviewed to assess the presence and characteristics of these aneurysms. Results: Forty-five patients with aneurysms were identified (13%): 41 cases in 242 adult patients (17%) and four (4%) in 95 children ( p p p Conclusions: The incidence of splenic artery aneurysms in liver transplant patients is 13%. They are generally multiple and located in the distal third of the splenic artery. The incidence is higher in women and in patients with parenchymal liver disease and portal hypertension. The incidence of rupture was 4%.

Gilbert's syndrome is genetically characterized by an extra TA element in the TATAA-box of the promotor region upstream of the bilirubin UDP-glucuronosyltransferase (UGT1A) coding region (Bosma et al. N Engl J Med 1995; 333: 1171-5). Persistent unconjugated hyperbilirubinemia is occasionally observed in liver transplant recipients with an otherwise normal liver function. We postulate that these patients could have received a liver from a donor with the Gilbert's syndrome genotype. Therefore, we investigated the UGT1A-gene TATAA-box in DNA from liver graft donors of jaundiced and non-jaundiced recipients. DNA was obtained from stored donor lymphocytes and the number of TA elements in the TATAA-box of the UGT1A-gene promotor region was analyzed by polymerase chain-reaction. We observed two liver transplant recipients with persistent unconjugated hyperbilirubinemia. They received liver grafts from donors who were homozygous for an abnormal A(TA)7TAA-box in the UGT1A-gene. Four of 10 non-jaundiced recipients received livers from donors who were homozygous for the normal A(TA)6TAA-box and six received livers from donors who were heterozygous with a normal A(TA)6TAA-box on one allele and a prolonged A(TA)7TAA-box on the other allele. This study shows that liver graft recipients with persistent unconjugated hyperbilirubinemia may have received a liver from a donor with an abnormal TATAA-box in the bilirubin UGT1A-gene promotor region

We retrospectively analyzed the incidence and outcome of steroid-resistant rejection (SRR) during the first 6 months after OLT in 126 patients receiving triple immunosuppression. A total of 95 patients either did not experience acute rejection at all or had acute rejection that subsided without additional treatment. A total of 31 patients had biopsy-proven acute rejection that required therapy: 18 patients had acute rejection that responded to steroid therapy (steroid-sensitive rejection, SSR); the remaining 13 patients had SRR and received ATG. At the onset of acute rejection, no differences in clinical, biochemical, or immunological parameters were present between patients with SSR and SRR. However, the histological grade of acute rejection in the initial biopsy was higher in patients with SRR (P = 0.05). ATG treatment was effective in 10 of the 13 patients and was not associated with an increased incidence of opportunistic infections. Patient and graft survival rates at 2 years were comparable in the three groups. These data show that the incidence of SRR during the first 6 months after OLT is low, and that its treatment with ATG is both effective and well tolerated.

After orthotopic liver transplantation (OLT) bone mass rapidly declines and vertebral fracture rate increases. We studied bone loss and parameters of bone turnover in 53 consecutive patients. In an attempt to reduce bone loss the patients were prophylactically treated with cyclical etidronate in addition to daily 1 alpha-hydroxyvitamin D3 and calcium. During the first 3 months after transplantation median lumbar spinal bone mineral density (BMD) decreased 4.5%; subsequently no significant changes occurred. Median hip BMD continued to fall during the first post-transplantation year and deteriorated 7% over the whole study period. New vertebral fractures were seen in 25% of the patients, which is not lower than previously reported rates in patients not receiving cyclical etidronate. Parathyroid hormone levels increased after OLT (p = 0.01), but remained within normal ranges. Urinary hydroxyproline levels were increased and normalized in the second half-year after OLT. Elevated fasting calciuria increased further after OLT. 1,25-Dihydroxy-vitamin D3 levels were lowered pre-OLT (25 vs 66 pmol/ 1, p < 0.001) and normalized at 3 months after OLT. Serum osteocalcin concentrations remained unchanged and were reduced compared with levels in healthy controls. In summary, increased bone resorption occurs after OLT with persistent decreased bone formation, leading to vertebral fracture in 25% of patients. Etidronate, 1 alpha-calcidol and calcium treatment did not prevent bone loss.

The ability of ultrasound to detect biliary obstruction, bile leakage and generalized ductal changes after orthotopic liver transplantation (OLT) was compared to cholangiography. Cholangiography was considered to be the gold standard. Adequate opacification of the biliary tree was achieved in 139 cholangiograms. Biliary obstruction, intermediate or large bile leakage, and generalized ductal changes were diagnosed with cholangiography in 15% (21/139), 14% (20/139), and 16% (22/139), respectively. Normal ultrasound findings could not exclude biliary stricture, generalized ductal changes, or bile leakage, and fluid collections were not correlated with bile leakage. Abnormal ultrasound findings were highly predictive of the cholangiographic diagnosis of biliary obstruction or generalized ductal changes (specificity of 98% and 100%, respectively). An irregular appearance of the bile ducts and increased periductal echogenicity proved to be characteristic features for generalized ductal changes. (C) 1996 John Wiley & Sons, Inc.

BACKGROUND: Hepatitis E virus (HEV) genotype 3 has been identified in patients with autochthonous HEV infections in developed countries and is currently being recognized as an emerging zoonotic pathogen. HEV infection may lead to a chronic hepatitis in immune-compromised patients.METHODS: We studied the incidence of REV in adult lung transplant recipients at the Medical University Vienna and the University Medical Center Groningen. These recipients presented with elevated liver test results during the post-transplant follow-up period. The time of infection was investigated using stored specimens, and the REV genotype was determined by sequence analysis of the open reading frame (ORF)1 and ORF2 region.RESULTS: The study included 468 adult lung transplant recipients. Ten patients (2.1%) tested positive for HEV RNA. At the time of REV detection, all patients had elevated liver test results, with median alanine aminotransferase levels of 77 U/liter and showed a mild hepatitis. A chronic REV infection was diagnosed in the 8 lung transplant recipients who survived longer than 6 months after transplantation. Viral genotyping revealed only genotype 3 strains. In 2 of the lung transplant recipients treated with oral ribavirin monotherapy, REV RNA was cleared from the plasma within 2 months with simultaneous normalization of alanine aminotransferase levels.CONCLUSIONS: Chronic REV is an important cause of liver test abnormalities after lung transplantation; therefore, routine screening for HEY RNA is strongly recommended in lung transplant recipients. Oral ribavirin appears to be a safe and effective treatment for chronic REV infection in lung transplant recipients. J Heart Lung Transplant 2013;32:341-346 (C) 2013 International Society for Heart and Lung Transplantation. All rights reserved.

Liver transplantation has been accepted as a successful therapeutic tool for irreversible liver diseases such as primary biliary cirrhosis. However, removal of the diseased liver may not eliminate this autoimmune disease, and recurrence of primary biliary cirrhosis in the liver graft has been reported as early as within the first posttransplant year. We studied whether or not primary biliary cirrhosis recurs after liver transplantation in follow-up biopsies of 19 primary biliary cirrhosis patients. Biopsies of 14 non-primary biliary cirrhosis patients served as controls. The median follow-up period was 5 years (range 1–11 years). Both groups of patients were selected according to strict criteria which excluded pre- and posttransplant diseases which could mimic primary biliary cirrhosis. The follow-up biopsies were taken according to a protocol at yearly intervals. Established histologic criteria for primary biliary cirrhosis were assessed semi-quantitatively in 119 biopsies in a coded fashion. A longitudinal study was performed after decoding the biopsies, to document the course of morphological changes in time per patient. In addition to data on liver tests and immunosuppression, antimitochondrial antibodies including the primary biliary cirrhosis specific subtypes (anti-PDH-E2 and BCKD-E2) were determined in freeze-stored serum samples. The biopsies showed a striking concordance between the primary biliary cirrhosis and non-primary biliary cirrhosis groups and few overt histologic abnormalities. There was no significant difference in liver-test results and immunosuppression. Overall anti-mitochondrial antibodies remained present in decreased titers. We found portal granulomas as well as mild bile-duct damage in the 3rd year biopsies of two primary biliary cirrhosis patients, but no abnormal liver tests or clinical symptoms. These findings were not conclusive for primary biliary cirrhosis and subsequent biopsies did not show diagnostic features of primary biliary cirrhosis. Based on these results, we conclude that there were no distinctive histologic nor serologic findings for recurrent primary biliary cirrhosis. In the liver transplant patient population of this study, with a posttransplantation follow-up period of 11 years, no cases of recurrent primary biliary cirrhosis were diagnosed.

International audience; BACKGROUND & AIMS: Hepatitis E virus (HEV) infection can cause chronic hepatitis in recipients of solid organ transplants. However, the factors that contribute to chronic infection and the outcomes of these patients are incompletely understood. We performed a retrospective analysis of data from 17 centers from Europe and the United States that described the progression, outcomes, and factors associated with development of chronic HEV infection in recipients of transplanted solid organs. METHODS: We studied data from 85 recipients of solid organ transplants who were infected with HEV. Chronic HEV infection was defined by the persistent increases in levels of liver enzymes and polymerase chain reaction evidence of HEV in the serum and/or stool for at least 6 months. RESULTS: Fifty-six patients (65.9%) developed chronic hepatitis. Univariate analysis associated liver transplant, shorter times since transplant, lower levels of liver enzymes and serum creatinine, lower platelet counts, and tacrolimus-based immunosuppressive therapy (rather than cyclosporin A) with chronic hepatitis. On multivariate analysis, the independent predictive factors associated with chronic HEV infection were the use of tacrolimus rather than cyclosporin A (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.49-1.97; P = .004) and a low platelet count at the time of diagnosis with HEV infection (OR, 1.02; 95% CI, 1.001-1.1; P = .04). Of patients with chronic hepatitis, 18 (32.1%) achieved viral clearance after the dose of immunosuppressive therapy was reduced. No HEV reactivation was observed after HEV clearance. CONCLUSIONS: HEV infection causes chronic hepatitis in more than 60% of recipients of solid organ transplants. Tacrolimus therapy is the main predictive factor for chronic hepatitis. Dose reductions of immunosuppressive therapy resulted in viral clearance in more than 30% of patients.

To evaluate the diagnostic significance of neutrophil cytoplasmic antibodies in chronic liver diseases, we assessed the prevalence of neutrophil cytoplasmic antibodies in autoimmune liver diseases, in particular in primary sclerosing cholangitis, autoimmune chronic active hepatitis and primary biliary cirrhosis, and we also determined the specificity of perinuclear-pattern neutrophil cytoplasmic antibodies for these autoimmune liver diseases by testing sera from patients with nonautoimmune chronic liver diseases. Neutrophil cytoplasmic antibodies were detected in 79% of sera from patients with primary sclerosing cholangitis (n = 24), in 88% of sera from patients with autoimmune chronic active hepatitis (n = 24) and in 28% of sera from patients with primary biliary cirrhosis (n = 25). The presence of neutrophil cytoplasmic antibodies in these diseases correlated significantly (p < 0.008) with the presence of cirrhosis. Neutrophil cytoplasmic antibodies were not detected in nonautoimmune liver diseases. All neutrophil cytoplasmic antibody-positive sera produced a perinuclear fluorescence pattern on ethanol-fixed granulocytes. On neutrophils fixed with paraformaldehyde, a granular cytoplasmic immunofluorescence pattern was observed, demonstrating the cytoplasmic nature of the antigen or antigens involved. Further characterization studies showed that neutrophil cytoplasmic antibodies in autoimmune liver diseases are not directed against myeloperoxidase, proteinase 3 or elastase, the neutrophil cytoplasmic antibody specificities associated with necrotizing vasculitis, glomerulonephritis or both. On Western blots neutrophil cytoplasmic antibodies in autoimmune liver diseases showed reactivity with either lactoferrin, a 67/66-kD protein combination or a 40-kD polypeptide. Reactivity with either of these proteins was observed in sera from patients with primary sclerosing cholangitis (38%), autoimmune chronic active hepatitis (17%) and primary biliary cirrhosis (20%).(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Primary sclerosing cholangitis is a chronic cholestatic liver disease. An immune aetiology is suggested by associations between PSC and inflammatory bowel disease. Data on concomitant prevalence of other immune-mediated diseases is limited.Aim: To assess the prevalence of concomitant immune-mediated diseases and the impact on disease outcome in PSC.Methods: We included 241 patients and retrospectively reviewed medical charts.Results: Altogether 172(71.4%) patients had concomitant immune-mediated disease, including IBD (149, 61.8%), autoimmune hepatitis (15, 6.2%) and other immune-mediated diseases (47, 19.5%). Thirty nine patients (22.7%) had more than one immune-mediated disease other than PSC. Most frequent extrahepatic non-IBD immune-mediated diseases were sarcoidosis, thyroid disease, and type 1 diabetes mellitus.Age at PSC diagnosis was lower in patients with IBD. In patients with other immune-mediated diseases than autoimmune hepatitis or IBD, age at PSC diagnosis was higher. Younger age at diagnosis and concomitant IBD related to longer survival till death or liver transplantation.Conclusions: In a large PSC population, a high prevalence of concomitant immune-mediated diseases was found. IBD occurred more often in early-acquired PSC, and the other immune-mediated diseases more often in later-acquired PSC. No effect on outcome was found for non-IBD immune mediated disease. (C) 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

This letter discusses the paper by Onyeagocha et al published in the November 2009 issue of the AJP.

Cryoglobulinaemia was diagnosed in three patients. The first was a 61-year-old man with severe skin involvement and polyneuropathy caused by type I cryoglobulinaemia associated with a small B cell clone in the bone marrow. A 73-year-old woman presented with neuropathy and renal and skin involvement due to type II cryoglobulinaemia associated with hepatitis C virus infection. The third patient was a 23-year-old woman with skin and renal involvement caused by type III cryoglobulinaemia. Cryoglobulins are circulating proteins that precipitate below a temperature of 37 degrees Celsius. This precipitation causes several signs and symptoms and, in some cases, severe organ damage. According to the Brouet classification, there are three different types of cryoglobulinaemia. Treatment focuses on their underlying causes and on the prevention of cryoglobulin precipitation. It is important to avoid hypothermia, which was the cause of severe manifestations in two of our patients.

Hepatitis E virus (HEV) infection is known to run a self-limited course. Recently, chronic hepatitis E has been described in several immunosuppressed patients after solid organ transplantation. The prevalence of HEV infection after transplantation, however, is unknown. We studied HEV parameters [HEV RNA, HEV immunoglobulin M (IgM), and HEV immunoglobulin G (IgG) by enzyme-linked immunosorbent assay and confirmatory immunoblotting] in a cohort of 285 adult liver transplant recipients. The most recent freeze-stored sera were investigated, and if they were positive, a retrospective analysis was performed. Samples from 274 patients (96.1%) tested negative for all HEV parameters. This included a patient described earlier as having experienced an episode of chronic HEV hepatitis in the past. One patient was found positive for HEV RNA without HEV antibodies. She presently suffers from chronic HEV hepatitis and has also been described before. Sera from 9 patients tested positive for HEV IgG without HEV IgM or HEV RNA. Six of these 9 patients (2.1% of the total) were found to have HEV IgG antibodies in retrospect related to an HEV infection at some time pre-transplant as they also tested positive in a pretransplant serum sample. One of these 9 patients suffered in retrospect from a chronic HEV infection with mild hepatitis between 2 and 5 years after liver transplantation on the basis of the course of HEV RNA, IgM, and IgG, aminotransferases, and liver histology. Overall, the prevalence of acquired HEV hepatitis after liver transplantation was 1% in this cohort. We conclude that liver transplant recipients have a risk for chronic HEV infection, but the prevalence is low.

Biliary reconstruction using Roux-en-Y choledochojejunostomy has been suggested as a risk factor for the development of nonanastomotic biliary strictures (NAS) after liver transplantation. Roux-en-Y reconstruction, however, is preferentially used in patients transplanted for primary sclerosing cholangitis (PSC), and the disease itself is also associated with a higher incidence of NAS. The aim of this study was to determine whether Roux-en-Y reconstruction is really an independent risk factor for NAS. A series of 486 consecutive adult liver transplants were studied. Biliary reconstruction in patients transplanted for PSC was either by Roux-en-Y choledochojejunostomy or by duct-to-duct anastomosis, depending on the quality of the recipient's extrahepatic bile duct. Univariate and multivariate statistical analyses were used to identify risk factors for the development of NAS. The overall incidence of NAS was 16.5% (80/486). In univariate analyses, the following variables were significantly associated with NAS: PSC as the indication for transplantation, type of biliary reconstruction (Roux-en-Y versus duct-to-duct), and postoperative cytomegalovirus infection. After multivariate logistic regression analysis, PSC as the indication for transplantation (odds ratio, 2.813; 95% confidence interval, 1.624-4.875; P0.001) and postoperative cytomegalovirus infection (odds ratio, 2.098; 95% confidence interval, 1.266-3.477; P = 0.004) remained as independent risk factors for NAS. Biliary reconstruction using Roux-en-Y choledochojejunostomy was not identified as an independent risk factor for NAS. In conclusion, the association between Roux-en-Y choledochojejunostomy and NAS observed in previous studies can be explained by the more frequent use of Roux-en-Y reconstruction in patients with PSC. Roux-en-Y reconstruction itself is not an independent risk factor for NAS. Liver Transpl 15:924-930, 2009. (c) 2009 AASLD.

Long-term morbidity and survival after orthotopic liver transplantation (OLT) are to a large degree determined by cardiovascular disease and cancer. Tobacco use is a well-known risk factor for both. The aim of this study was to examine smoking behavior before and after OLT and to define groups at risk for resuming tobacco use after OLT. In addition, we looked for a relation between smoking and morbidity after OLT. All 401 adult patients with a follow-up of at least 2 years after OLT were included. Data were collected from the charts. A questionnaire about smoking habits at 4 time points before and after OLT was sent to all 326 patients alive, and 301 (92%) patients responded. Both before and after OLT, 53% of patients never used tobacco, and around 17% were active smokers. Of the active smokers during the evaluation for OLT, almost one-third succeeded in cessation, often during the waiting time for OLT. Twelve percent of former smokers restarted smoking, mainly after OLT. Tobacco use was the highest in patients with alcoholic liver disease (52% were active smokers before OLT, and 44% were after OLT) and the lowest in patients with primary sclerosing cholangitis (1.4% were active smokers before OLT). At 10 years, the cumulative rate of malignancies was 12.7% in active smokers versus 2.1% in nonsmokers (P = 0.019). No effect on skin cancer or cardiovascular disease was found. In conclusion, smoking is a serious problem after OLT and increases the risk for malignancy. Prevention programs should focus not only on active smokers but also on former smokers. Liver Transpl 15: 648-655, 2009. (C) 2009 AASLD.

BACKGROUND: Platelet transfusions have been identified as an independent risk factor for survival after orthotopic liver transplantation (OLT). In this study, we analyzed the specific causes of mortality and graft loss in relation to platelet transfusions during OLT.METHODS: In a series of 449 consecutive adult patients undergoing a first OLT, the causes of patient death and graft failure were studied in patients who did or did not receive perioperative platelet transfusions.RESULTS: Patient and graft survival were significantly reduced in patients who received platelet transfusions, compared with those who did not (74% vs 92%, and 69% vs 85%, respectively at 1 yr; P CONCLUSIONS: These findings suggest that platelet transfusions are an important risk factor for mortality after OLT. The current study extends previous observations by identifying acute lung injury as the main determinant of increased mortality. The higher rate of graft loss in patients receiving platelets is related to the higher overall mortality rate and does not result from specific adverse effects of transfused platelets on the grafted liver.

The prospects for patients who survive the first year after liver transplantation are discussed. The 10-year survival for these patients is more than 80%. The quality of life is good, as measured on self-assessment scales. Pregnancy is possible. The main side-effects of drugs concern osteoporosis (corticosteroids), deterioration of renal function (cyclosporine), and de novo malignancies. Recurrence of original disease is at present of clinical importance for Budd-Chiari syndrome and hepatitis B and D. Recurrence of primary biliary cirrhosis is still under discussion.

The model of end-stage liver disease (MELD) score is nowadays widely used to prioritize patients for liver transplantation.To assess the contribution of the individual components of the MELD score in interlaboratory variability.We sent 15 samples from patients listed for liver transplantation to seven different European laboratories who were asked to measure all three variables. In addition, 10 samples from patients on oral anticoagulant treatment were sent to the same labs for the international normalised ratio (INR) measurement.In all 15 samples, a substantial and clinically relevant variation in the calculated MELD score was observed between laboratories. The mean difference in the MELD score between the highest- and the lowest-scoring laboratory was 4.8. The variation in creatinine measurements resulted in differences of up to three MELD points in a single patient when comparing the highest and the lowest scoring lab. The variation in bilirubin measurements only accounted for a difference of one point between the highest- and the lowest-scoring laboratory, but the variation in INRs resulted in differences of 2 to 12 MELD points. MELD scores or INR values were not substantially different in laboratories that used the Owren instead of the more widely used Quick methodology for INR measurements. The variability in the INR in patients on oral anticoagulants was substantially less as compared with the variability in patients with liver disease. In conclusion, we observed a large interlaboratory variation in the MELD score. This variation in the MELD score is primarily caused by the INR.

Hepatitis E virus (HEV) infection is known to run a self-limiting course. Sporadic cases of acute hepatitis due to infection with HEV genotype 3, present in pig populations, are increasingly recognized. Zoonotic transmission seems infrequent. The entity of unexplained chronic hepatitis after liver transplantation has been recognized. Detection of HEV in 2 liver transplant recipients triggered a review of these cases. Freeze-stored sera were available for retrospective analysis. HEV antibodies were determined. For virus detection and identification, a fragment of the gene encoding the major capsid protein (open reading frame 2) was amplified by reverse-transcription polymerase chain reaction and sequenced to identify the genotype. Two months after liver transplantation, case A developed unexplained chronic hepatitis, which developed into cirrhosis. Retransplantation followed 7 years later, after which chronic hepatitis recurred. In retrospect, HEV RNA was present in serum 3 weeks after the first transplantation and remained present afterwards. HEV RNA was also present in retransplant liver tissue. HEV antibodies appeared late after retransplantation. Case B developed unexplained chronic hepatitis 7 years after transplantation. Retransplantation was needed 5 years later, after which no signs of hepatitis recurred. In retrospect, the period of chronic hepatitis up to the retransplantation coincided with HEV RNA in serum. In case B, antibodies developed, the viral load was much lower than in case A, and the virus seemed to be cleared after retransplantation. Genotyping in both cases revealed 2 unique strains of genotype 3. In conclusion, chronic HEV infection may develop in immunosuppressed patients, who may then serve as long-term carriers of the virus. We hypothesize that HEV may be the cause of chronic hepatitis in liver transplant recipients.

Long-term follow-up studies on the impact of vascular events (VE) and risk factors of liver transplant recipients are scarce. In this study, 311 recipients of a first isolated liver transplant who survived at least 1 year were followed up from 1979 to 2002. The median follow-up duration was 6.2 (range1-22.7) years. Overall median survival was 18.7 [95% confidence interval (CI): 15.5-20.1] years and this was significantly lower compared with age- and sex-matched controls. Eleven (21%) of the patients had a vascular cause of death and VE were the third cause of death. VE occurred later compared with other causes of death (mean 10.3 years vs. 4.5 years, P

Serum amyloid P component (SAP) binds to amyloid.I-123-SAP scintigraphy is used to evaluate the extent and distribution of amyloid in systemic amyloidosis and has great clinical value in the detection of systemic amyloidosis. The aim of the study was to assess during scintigraphy the diagnostic performance and prognostic value of a simple parameter describing extravascular I-123-SAP retention in systemic amyloidosis. Methods: Two hundred megabecquerels of I-123-labeled human SAP was injected intravenously for scintigraphy in 20 controls and in 189 consecutive patients with systemic and localized amyloidosis. Extravascular retention of I-123-SAP was quantified from serum and urine measurements after 24 h (EVR24) and 48 h. Sensitivity and specificity were assessed, and retention was correlated with kidney, heart, liver, and nerve involvement and with survival. Results: The cutoff value representing a desired specificity of 90% of EVR24 was 50%. The associated sensitivity of EVR24 for detecting reactive systemic, immunocyte-derived (AL), and hereditary amyloidosis was 65%,61 %, and 22%, respectively, using a cutoff point of 50%. In AL amyloidosis, the EVR24 increased with the number of organs involved (from a mean of 43% for 1 organ to a mean of 81 % for 4 organs). The EVR24 correlated with serum alkaline phosphatase (r = 0.63) and with creatinine clearance (r = -0.36). In AL amyloidosis, both cardiac involvement (hazard ratio, 3.9; 95% CI, 2.0-7.8) and EVR24 (hazard ratio, 2.0; 95% CI, 1.1-3.9) were independent predictors of survival. Conclusion: In AL amyloidosis, the EVR24 is strongly associated with organ involvement and with prognosis and might serve as an indicator of the body amyloid load. Quantification of SAP retention using the EVR24 has no additional value over I-123-SAP scintigraphy in the detection of systemic amyloidosis.

Background: Regulatory T-cells (Treg) are natural Suppressors of autoimmunity. Previous studies indicate that immunosuppressive drugs, especially calcineurin-inhibitors, may interfere with Treg homeostasis. Inflammatory bowel disease (IBD) can relapse or develop de novo after liver transplantation. IBD is associated with a relative deficiency of Treg. The aim of this study was to determine the effect of long-term immunosuppression on the presence of Treg in the noninflamed colonic mucosa of liver transplant recipients.Methods: Colonic biopsies of normal mucosa of 36 liver transplant recipients on different types of immunosuppression and 11 controls were studied. Treg marker Foxp3 and Treg products transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) were studied by quantitative polymerase chain reaction (Q-PCR) and immunohistochemistry. TGF-beta-induced Smad-protein 3 and 7 were studied by Q-PCR.Results: No significant differences between controls and patients were observed in IL-10, TGF-beta, and Smad expression. Mucosal Foxp3 mRNA levels and Foxp3+CD3+ cells were significantly 4 reduced in transplant recipients using prednisone/azathioprine/tacrolimus compared with controls but no direct relationship between Foxp3 expression and I specific drug was detected.Conclusions: These results challenge the hypothesis that calcineurin-induced reduction of Treg or TGF-beta expression predisposes nontransplanted tissue to inflammation, but indicate that combined immunosuppression hampers Treg development in the intestine.

Nonanastomotic biliary strictures (NAS) after orthotopic liver transplantation (OLT) are associated with high retransplant rates. The aim of the present study was to describe the treatment of and identify risk factors for radiological progression of bile duct abnormalities, recurrent cholangitis, biliary cirrhosis, and retransplantation in patients with NAS. We retrospectively studied 81 cases of NAS. Strictures were classified according to severity and location. Management of strictures was recorded. Possible prognostic factors for bacterial cholangitis, radiological progression of strictures, development of severe fibrosis/cirrhosis, graft survival, and patient survival were evaluated. Median follow-up after OLT was 7.9 years. NAS were most prevalent in the extrahepatic bile duct. Twenty-eight patients (35%) underwent some kind of interventional treatment, leading to a marked improvement in biochemistry. Progression of disease was noted in 68% of cases with radiological follow-up. Radiological progression was more prevalent in patients with early NAS and one or more episodes of bacterial cholangitis. Recurrent bacterial cholangitis (> 3 episodes) was more prevalent in patients with a hepaticojejunostomy. Severe fibrosis or cirrhosis developed in 23 cases, especially in cases with biliary abnormalities in the periphery of the liver. Graft survival, but not patient survival, was influenced by the presence of NAS. Thirteen patients (16%) were retransplanted for NAS. In conclusion, especially patients with a hepaticojejunostomy, those with an early diagnosis of NAS, and those with NAS presenting at the level of the peripheral branches of the biliary tree, are at risk for progressive disease with severe outcome.