Protocol Liver Biopsies Research Articles

Recurrence of primary sclerosing cholangitis: What do we learn from several transplant centers?

Recurrence of primary sclerosing cholangitis: What do we learn from several transplant centers?

Potential immunological advantage of intravenous mycophenolate mofetil with tacrolimus and steroids in primary deceased donor liver transplantation and live donor liver transplantation without antibody induction

With the current immunosuppressive regimens, graft loss secondary to immunological reasons after successful liver transplantation is a rarity; acute rejections, however, do occur, with the majority of them being steroid-responsive. The aim of the present study is to examine the rate of acute rejection with tacrolimus, intravenous (IV) mycophenolate mofetil (MMF), and steroids in primary deceased donor liver transplant (DDLT) and live donor liver transplant (LDLT) recipients. During the year 2005, 130 patients (mean age: 54.9 +/- 10.8, males: 84, females: 46, 112 DDLT and 18 LDLT) received primary liver transplantation. They were followed up for the incidence of acute rejection in the first 12 months. Liver biopsies were performed as clinically indicated; protocol liver biopsies were never performed. A total of 127 liver biopsies were performed. Thirty-two had a rejection activity index (RAI) score of > or =3, of which 24 biopsies in 20 patients were not treated with a steroid bolus. Eight (6.1%) patients (mean RAI score: 5.1 +/- 1.4) received 750 to 1500 mg of methylprednisolone over 3 days. Out of these, 2 were noncompliant, 4 were off MMF, and 1 was on cyclosporine. All patients responded to steroid therapy. None of the patients required any antibody preparation. In conclusion, IV MMF with tacrolimus and steroids is useful and required antirejection therapy in 6.1% of liver transplant recipients.

Role of AST to platelet ratio index in the detection of liver fibrosis in patients with recurrent hepatitis C after liver transplantation

Per protocol annual liver biopsy represents the gold standard in the assessment of graft fibrosis progression due to recurrent hepatitis C after liver transplantation. Non-invasive liver fibrosis tests have been proposed as surrogate markers of liver fibrosis in hepatitis C virus (HCV)-positive immune-competent patients. No data are available in the literature on the usefulness of non-invasive liver fibrosis tests in liver transplanted patients with recurrent HCV infection. A total of 102 annual per protocol liver biopsies performed in 51 consecutive HCV-positive recipients (31 men), with a follow-up period lasting up to 5 years, were included and evaluated in this study. At each time point, the following non-invasive liver fibrosis tests were calculated: aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, age-platelet index, AST to platelet ratio index (APRI), Forns' fibrosis index and Bonacini's discriminant score. In discriminating patients with histological fibrosis score >2, APRI provided the best area under the receiver operating characteristic curves (AUROC) (0.801), in comparison to the other four non-invasive liver fibrosis tests. The AUROC of APRI was better in female (0.871) than in male (0.753) recipients. Among female recipients, an APRI value >1.4 was 91% sensitive and 75% specific in detecting a staging score >2. The corresponding values among male recipients were 60% and 77%, respectively. Among non-invasive liver fibrosis tests, APRI has the highest diagnostic value in discriminating liver transplanted patients with progression to significant liver fibrosis, although its accuracy is influenced by recipient sex.

Utilización de los donantes añosos en pacientes trasplantados por cirrosis por virus C

the natural history of recurrent hepatitis C after liver transplantation (LT) is extremely variable, with progression to allograft failure in a substantial proportion of patients. The identification of factors associated with this poorer outcome may improve results. While donor age has been identified as one of the most important factors, the actual options to modify this variable are limited. a) to describe the natural history of HCV(+) liver transplant recipients depending on donor age ( < or = 50 years), including clinical, biochemical, and histological outcomes; and b) to identify in the subgroup of organ recipients from aged donors (= 50 years) factors associated with an aggressive course. a retrospective study of clinical and histological data including protocol liver biopsies for 162 HCV (+) liver transplant patients between 1997 and 2001 with at least one year of follow-up. Aggressive recurrent hepatitis C was defined as a progression to fibrosis > 1 during the first year post-LT, development of a cholestatic form of recurrent hepatitis C, and /or graft failure due to HCV during the first five years post-LT. Factors analyzed as potentially associated with recurrent hepatitis C included: a) recipient-related: demographics (age, sex), pre-transplantation (hepatocellular carcinoma, Child-Pugh classification, history of alcohol, HBV serological markers, antiviral treatment, nutritional status, biochemical variables); b) donor-related: demographics (age, sex), cause of death, grade of steatosis defined as minimal vs. moderate-severe > 10%); c) surgery-related: cold preservation and rewarming time, duration of procedure, blood transfusion; and d) post-LT management-related: immunosuppression, liver enzymes in the first 14 days post-LT, acute hepatitis post-LT, surgical complications (vascular and/or biliary). patients were divided into two groups according to donor age group 1 ( < 50 years), n = 83, 51%, and group 2 (= 50 years), n = 79, 49%). Median follow-up was 5 years (range: 3 months-8.5 years). Aggressive recurrent hepatitis C occurred significantly more frequently in the older donor group (64 vs. 20.5%, p < 0.0001). In this group, potent immunosuppression -triple and quadruple regimens- (p = 0.04) and acute hepatitis post-LT (p = 0.03) were the only variables associated with aggressive recurrence. Degree of donor steatosis was not associated with the prognosis of recurrent hepatitis C. the use of aged donors is partly responsible for the accelerated progression of hepatitis C after LT. When old donors are used we should avoid over-immunosuppression, and probably evaluate antiviral therapy in those with acute recurrent hepatitis C.

Diabetes and Hepatic Oxidative Damage Are Associated With Hepatitis C Progression After Liver Transplantation

Posttransplant diabetes mellitus (PTDM) is common after liver transplantation and was recently identified as a risk factor for hepatitis C progression. Increased levels of oxidative stress have been identified in diabetes and hepatitis C. The aim of this study was to evaluate the relationship among PTDM, oxidative damage in liver biopsy specimens, and fibrosis progression posttransplant. Subjects consisted of 27 hepatitis C-infected liver transplant recipients who had liver biopsy specimens available from 49 protocol liver biopsies. Paraffin embedded liver tissue sections were stained for 8-hydroxy-2' deoxyguanosine (8-OHdG), an indicator of hydroxyl radical mediated tissue damage. The percentage of cells staining for 8-OHdG in a histologic section was categorized as high (>66%) versus low score (< or =66%). Fibrosis index was calculated as fibrosis score (0-4)/ years posttransplant. Time to bridging fibrosis or cirrhosis (F3-4) was compared as a function of PTDM and 8-OHdG score. Considering all 49 biopsies, fibrosis index was higher in cases with PTDM (P<0.001) and high 8-OHdG score (P=0.004). High 8-OHdG score was associated with PTDM (P=0.012). In time to event analyses, time to F3-4 was more rapid in patients with PTDM (P=0.02) and in those with high 8-OHdG scores (P<0.001). This study confirmed a relationship between PTDM and hepatitis C fibrosis progression and found that oxidative damage in liver biopsy specimens was associated with PTDM and more rapid development of advanced fibrosis.

Transient elastography (TE) is an accurate tool in monitoring liver-transplanted (LT) patients with recurrent hepatitis C

Background/aims. We previously demonstrated that TE reliably predicts severity of graft damage in LT patients. However, to what extent TE helps monitoring patients with recurrent hepatitis C under protocol liver biopsies (LB) needs to be assessed.

Chronic Ductopenic Rejection in Patients With Recurrent Hepatitis C Virus Treated With Pegylated Interferon Alfa-2a and Ribavirin

Interferon use for post liver transplantation (LT) recurrent hepatitis C (HCV) has not consistently been associated with acute cellular rejection (ACR). We examined the incidence of chronic ductopenic rejection (CR) in patients receiving pegylated interferon alfa-2a and ribavirin (PEG) to treat recurrent HCV. A chart review of 12 patients developing CR while receiving an escalating dose regimen of PEG with protocol liver biopsies every 6 months was conducted. Values are shown as median (range). Twelve of the 70 patients treated with PEG developed CR. Median age at LT was 53 (37-63) years; immunosuppression consisted of tacrolimus or cyclosporine with prednisone. PEG was started at 3.6 (0.2-13.5) years after LT. Two patients had one episode of ACR before PEG. Four patients had first ACR while receiving PEG. CR was diagnosed after 12 (4-17) months of PEG; by then 8 patients had undetectable HCV-RNA. Tacrolimus and cyclosporine levels (ng/mL) were 7.9 (3.2-18.9) and 76 (71-93) before PEG, and 6.9 (3.7-9.7) and 130 (81-153) at CR. Six patients were treated more than 1 year with PEG; three had undetectable HCV-RNA when CR was diagnosed. Five patients are being treated for CR; one has been listed for LT; two patients were retransplanted. Five patients died as a result of sepsis partially related to CR. Treatment with pegylated-interferon alpha-2a and ribavirin may trigger rapidly progressive CR in patients with therapeutic immunosuppressive trough levels, with or without first inducing ACR.

Recurrence of autoimmune hepatitis after liver transplantation without elevation of alanine aminotransferase

It is controversial whether steroid therapy should be continued to prevent the recurrence of autoimmune hepatitis (AIH) in patients who have undergone liver transplantation (LTx) due to AIH. We report a case of recurrent autoimmune hepatitis after LTx despite a persistently normal range of alanine aminotransferase (ALT). A 50-year-old woman was admitted to our hospital because of jaundice and severe liver dysfunction, where she was diagnosed with liver failure due to AIH. Steroid therapy was not effective enough and the patient received living-donor LTx in 1999. Following the operation, the level of ALT was maintained within a normal range and anti-nuclear antibody (ANA) became negative, however, the serum level of IgG gradually elevated and ANA became positive, while platelets decreased. A liver biopsy performed 6 years after LTx showed histological findings of AIH and she was diagnosed with recurrent AIH. A recurrence of AIH may occur after LTx even if the level of ALT remains within a normal range. We consider that a protocol liver biopsy should be performed in patients who undergo LTx due to AIH to decide the indication for steroid therapy.

Liver transplantation for HCV cirrhosis: Improved survival in recent years and increased severity of recurrent disease in female recipients: Results of a long term retrospective study

In recent years, a worsening outcome of hepatitis C virus (HCV)-positive recipients and a faster progression of recurrent disease to overt cirrhosis has been reported. Our aims were to 1) assess patient survival and development of severe recurrent disease (Ishak fibrosis score > 3) in different transplant years; and 2) model the effects of pre- and post-liver transplantation (LT) variables on the severity of recurrent disease. A multicenter retrospective analysis was conducted on 502 consecutive HCV-positive transplant recipients between January 1990 and December 2002. Protocol liver biopsies were obtained at 1, 3, 5, 7, and 10 yr post-LT in almost 90% of the patients. All 502 patients were included in the overall survival analysis, while only the 354 patients with a follow-up longer than 1 yr were considered for the analysis of predictors of disease progression. The overall Kaplan-Meier survival rates were 78.7%, 66.3%, and 58.6%, at 12, 60, and 120 months, respectively, and a trend for a better patient survival over the years emerged from all 3 centers. The cumulative probability of developing HCV-related recurrent severe fibrosis (Ishak score 4-6) in the cohort of 354 patients who survived at least 1 yr remained unchanged over the years. Multivariate analysis indicated that older donors (P = 0.0001) and female gender of recipient (P = 0.02) were the 2 major risk factors for the development of severe recurrent disease, while the adoption of antilymphocytic preparations was associated with a less aggressive course (P = 0.03). Two of these prognostic factors, donor age and recipient gender, are easily available before LT and their combination showed an important synergy, such that a female recipient not only had a much higher probability of severe recurrent disease than a male recipient but her risk increased with the increasing age of the donor, reaching almost 100% when the age of the donor was 60 or older. In conclusion, a trend for a better patient survival was observed in more recent years but the cumulative probability of developing severe recurrent disease remained unchanged. The combination of a female recipient receiving an older graft emerged as a strong risk factor for a severe recurrence.

A prospective evaluation of fibrosis progression in patients with recurrent hepatitis C virus following liver transplantation

Recurrence of hepatitis C virus (HCV) following liver transplantation (LT) is universal. A subset of these patients develop advanced fibrosis and cirrhosis and it is believed that this leads to increased posttransplantation mortality. The specific aims of this study were to determine the incidence of advanced fibrosis and those factors associated with this process, and to evaluate causes for mortality in patients with recurrent HCV. A total of 227 patients who underwent LT with chronic HCV were monitored prospectively. The mean age of this group at LT was 49.5 yr; 76% were male and 85% were Caucasian. Fibrosis progression was monitored by protocol liver biopsy, initially performed 6 months after LT and then at 6- to 24-month intervals. Advanced fibrosis, defined as the bridging fibrosis or cirrhosis, developed in 1%, 11%, 25%, and 41% of patients after 1, 3, 5, and 6-10 yr, respectively. Acute cellular rejection hepatic steatosis, a persistent elevation in serum alanine aminotransferase and donor-race were associated with the development of advanced fibrosis. In contrast, the development of advanced fibrosis was not affected by the use of interferon prior to undergoing LT, cytomegalovirus disease, or donor age. A total of 60 patients (26%) died over 15 yr of follow-up. Although graft failure accounted for 45% of deaths in patients with advanced fibrosis, this represented only 8% of all deaths in patients with recurrent HCV. Sepsis was the most common cause of death and this was observed with similar frequency in patients who developed advanced fibrosis (45%) and in those with less advanced fibrosis (47%). In conclusion, approximately 41% of patients with recurrent HCV developed advanced fibrosis 6-10 yr after LT. However, complications associated with sepsis, not recurrent cirrhosis, was the most common cause of death in patients with recurrent HCV and this was similar in patients with or without advanced fibrosis.

Natural history of unexplained chronic hepatitis after liver transplantation

Unexplained chronic hepatitis (CH) in the adult liver allograft recipient is not uncommon, but its natural history and clinical significance is unknown. A retrospective study was undertaken of adult liver allograft recipients to determine the frequency and natural history of unexplained CH. We evaluated only those patients who had undergone >or=2 liver biopsies after 6 months and were grafted for indications where recurrent disease could be confidently excluded (alcoholic liver disease [ALD] in those who remained abstinent and fulminant hepatic failure [FHF] from drug reactions). Of 288 patients who were transplanted for ALD or FHF, 30 fulfilled the above criteria. CH was first diagnosed at a median of 15.25 months after transplantation. A total of 24 patients showed mild necroinflammatory changes, and 12 had mild or moderate fibrosis. Liver tests did not reflect the presence or degree of inflammation or fibrosis. After a median of 4 years, necroinflammatory scores were increased in 5; new or progressive fibrosis was noted in 13%; 3 had developed cirrhosis; and 5 developed clinical evidence of portal hypertension. Progressive fibrosis was associated with a high titer of anti-nuclear antibodies (>1:1600) and a portal tract plasma cell infiltrate. There was a trend for correlation between necroinflammatory activity and fibrosis stage, but this did not reach statistical significance (P = 0.06). Serum alkaline phosphatase (P = 0.012) and female gender of the donor (P = 0.033) were associated with progressive fibrosis. Unexplained CH is not uncommon in the liver allograft and may progress to established cirrhosis in a subgroup of patients transplanted for ALD or FHF. Standard liver tests do not reflect the extent of these changes, so protocol liver biopsies may be required to detect these changes. We recommend careful history and follow-up in these patients.

Clinical Outcome after Living Donor Liver Transplantation in Patients with Hepatitis C Virus-associated Cirrhosis

Hepatitis C virus (HCV)-associated cirrhosis is an increasingly frequent indication for liver transplantation (LT). However, HCV recurrence is universal and this immediately occurs following LT, which endangers both the graft and patient survival. We investigated the frequency of posttransplant recurrence of HCV infection and the patient-graft survival, and we analyzed the responses to ribavirin and interferon therapy in the patients with recurrent HCV infection after living donor liver transplantation (LDLT). We retrospectively reviewed the clinical outcomes of 39 HCV-associated cirrhosis patients who underwent LDLT at Asan Medical Center between August 1992 and June 2006. In this study, the diagnosis of recurrent HCV was made on the basis of increased transaminases and serum HCV RNA levels greater than 10 million IU/mL because protocol liver biopsy was not performed. HCV recurrence was seen in 26 of the 39 LDLT patients (66.7%). 86.7% of recurrence occurred within the first postoperative year. Antiviral treatment was used for all patients with recurrence of HCV. None of the 10 patients receiving ribavirin alone and 9 of 16 patients who received combination therapy with pegylated interferon alpha-2a plus ribavirin became HCV RNA negative and they remained persistently negative during the median follow-up of 24.9 months. Our data indicates that there is no significant factor influencing HCV recurrence except for the recipient's age. The 2-year patient survival for the HCV patients with HCC and those patients without HCC were 81.2% and 81.3%, respectively (P=0.85) and the 2-year graft survival rates were 81.2% and 68.2%, respectively (P=0.29). No patient died from HCV recurrence during the follow-up period. Combination therapy with ribavirin and interferon appears to improve the outcome of recurrent HCV infected patients after LDLT.

Prediction of significant fibrosis in hepatitis C virus infected liver transplant recipients by artificial neural network analysis of clinical factors

Interest in developing noninvasive markers of liver fibrosis continues to increase, especially in recurrent hepatitis C virus infection after liver transplantation. Recently, a model for predicting significant fibrosis (bridging fibrosis and cirrhosis) on the basis of logistic regression and routine laboratory data has been proposed (logit model). The aim of the present study was to evaluate the accuracy of an artificial neural network, a technique reported to work better than logit models in complex biological situations, built on those same clinical variables and data set of patients, in predicting significant fibrosis. The neural network was constructed on the training set of 414 protocol biopsies, from liver transplant recipients, and then tested on the remaining 96 biopsies, as validation set. Model performances of neural network and logit model were evaluated and compared by means of areas under receiver operating characteristic curves. With a cutoff value of >0.4 to predict significant fibrosis, the neural network provided sensitivity, specificity, positive and negative predictive values, respectively, of 100, 79.5, 60.5 and 100%, in the validation set. The performance of the neural network was significantly better than that of the logit model (in the validation set area under the curve = 0.93 vs. 0.84; P = 0.045). Artificial neural network provides accurate prediction of the presence or absence of significant fibrosis from clinical variables, allowing theoretically protocol liver biopsy to be avoided in several instances, a result of particular interest, given the lack of other types of reliable noninvasive indexes of fibrosis in the setting of transplantation.

HLA-DRB1 Donor-Recipient Mismatch Affects the Outcome of Hepatitis C Disease Recurrence After Liver Transplantation

This study extends our previously reported observations that various immunological factors are associated with the occurrence of histologically proven recurrent hepatitis C. The two specific issues investigated were to confirm the associations of MHC alleles and donor/recipient mismatch with the occurrence of recurrent hepatitis C in an independent cohort of newly transplanted patients and to look for immunologic and nonimmunologic variables affecting the severity of the recurrent disease. Two separate cohorts of consecutive patients were studied: a look-back cohort (LC) of 120 patients and a cohort for studying the disease progression (CSDP) of 190 patients. Protocol liver biopsies were obtained at least 1, 3, 5, 7, and 10 years after liver transplantation (LT). A fully mismatched donor/recipient pair at the DRB1 locus was confirmed to be associated with both the recurrence of histologic hepatitis in the LC (59% vs 23%, P = .0002) and its progression beyond stage 3 in the CSPD (71.4% vs 39.3%, P = .0003). Relevant immunologic and nonimmunologic variables were included into a multivariate Cox proportional model and three variables, namely, donor age, full HLA-DRB1 donor-recipient mismatch, and HLA B14, resulted in independent risk factors for the development of severe fibrosis. This study provides evidence that DRB1 donor-recipient mismatch affects both the occurrence and progression of recurrent hepatitis C disease. This information is clinically relevant as it may help to better allocate organs and to recognize patients at risk for progression so that specific interventions can be implemented.

Long‐term follow‐up after recurrence of primary biliary cirrhosis after liver transplantation in 100 patients

Orthotopic liver transplantation (OLT) is the only effective curative therapy for end-stage primary biliary cirrhosis (PBC). Survival after OLT is excellent, although recent data have shown a recurrence rate of PBC of up to 32% after transplantation. The aim of this study is to investigate the course after disease recurrence, particularly with regard to liver function and survival in a long-term follow-up. Between April 1989 and April 2003, 1,553 liver transplantations were performed in 1,415 patients at the Charité, Virchow Clinic. Protocol liver biopsies were taken after one, three, five, seven, 10 and 13 yr. One hundred (7%) patients suffered from histologically proven PBC. Primary immunosuppression consisted of cyclosporine (n = 54) or tacrolimus (Tac) (n = 46). Immediately after OLT, all patients received ursodeoxycholic acid. Corticosteroids were withdrawn three to six months after OLT. The median age of the 85 women and 15 men was 55 yr (range 25-66 yr). The median follow-up after liver transplantation was 118 months (range 16-187 months) and after recurrence 30 months (range 4-79 months). Actuarial patient survival after five, 10 and 15 yr was 87, 84 and 82% respectively. Ten patients (10%) died after a median survival time of 32 months. Two of these patients developed organ dysfunction owing to recurrence of PBC. Histological recurrence was found in 14 patients (14%) after a median time of 61 months (range 36-122 months). Patients with Tac immunosuppression developed PBC recurrence more often (p < 0.05) and also earlier (p < 0.05). Fifty-seven patients developed an acute rejection and two patients a chronic rejection episode. Liver function did not alter within the first five yr after histologically proven PBC recurrence. Multivariate analysis of the investigated patients showed that the recipient's age and Tac immunosuppression were significant risk factors for PBC recurrence. Long-term follow-up of up to 15 yr after liver transplantation, owing to PBC, in addition to maintenance of liver function, shows excellent organ and patient survival rates. Although protocol liver biopsies revealed histological recurrence in 14 (14%) patients, only two patients developed graft dysfunction. Tac-treated patients showed more frequently and also earlier histologically proven PBC recurrence; however, in our population we could not observe an impact on graft dysfunction and patient's survival.

Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence

HCV-related disease recurrence progresses rapidly after liver transplantation. We hypothesised that withdrawal of immunosuppression might favourably impact on disease progression. Weaning off immunosuppression was attempted in 34 HCV-RNA positive patients (mean age 62+/-6.4 years) transplanted 63.5+/-20.1 months earlier, under cyclosporine A monotherapy. Patients were followed for 3 years including yearly protocol liver biopsies. Primary endpoints were feasibility of weaning off immunosuppression and its impact on disease progression. Secondary endpoint was to identify predictors of an immunosuppression-free state and fibrosis progression. Complete and permanent immunosuppression withdrawal was achieved in 8 patients (23.4%), whereas 14 (41.2%) developed rejection within eight months despite an initial response and 12 (35.2%) rejected during tapering. After a mean follow-up 45.5+/-5.8 months weaned patients showed stabilisation/improvement of histological fibrosis (P<0.01), lower necro-inflammation (P<0.02) and improved liver function (P<0.05) compared to weaning-intolerants. Multiple logistic regression identified low blood cyclosporine A trough levels during the first post-transplant week (P=0.004) and initial steroid-free immunosuppression (P<0.008) as independent predictors of sustained weaning. Achievement of immunosoppression freedom (P=0.02) and baseline staging score (P<0.0001) were independently associated with stabilisation/improvement of histological fibrosis. Reconstitution of immune-competence in the host improves the natural history of HCV recurrence in the graft.

Treatment of HCV recurrence: Do the pretransplantation rules apply?

Treatment of HCV recurrence: Do the pretransplantation rules apply?

Influence of donor/recipient HLA-matching on outcome and recurrence of hepatitis C after liver transplantation

The aim of this study was to analyze the effect of human leukocyte antigen (HLA) matching on outcome, severity of recurrent hepatitis C and risk of rejection in hepatitis C positive patients after liver transplantation (LT). In a retrospective analysis, 165 liver transplants in patients positive for hepatitis C virus (HCV) with complete donor/recipient HLA typing were reviewed for recurrence of HCV and outcome. Follow-up ranged from 1 to 158 months (median, 74.5 months). Immunosuppression consisted of either cyclosporine-A- or tacrolimus-based quadruple induction therapy including or an interleukin 2-receptor antagonist. Protocol liver biopsies were performed after 1, 3, 5, 7, and 10 years and staged according to the Scheuer scoring system. The overall 1-, 5-, and 10-year graft survival figures were 81.8%, 69.11 and 62%, respectively. There was no correlation in the study population between number of HLA mismatches and graft survival. The number of rejection episodes increased significantly in patients with more HLA mismatches (P < 0.05). In contrast to this, the fibrosis progression was significantly faster in patients with 0-5 HLA mismatches compared to patients with a complete HLA mismatch. In conclusion, HLA matching did not influence graft survival in patients after LT for end-stage HCV infection, however, despite less rejection episodes, the fibrosis progression increased in patients with less HLA mismatches within the first year after LT.

Protocol liver biopsies in long-term management of patients transplanted for hepatitis B-related liver disease

To evaluate the long-term histological outcome of patients transplanted for HBV-related liver disease and given HBIg prophylaxis indefinitely after LT. Forty-two consecutive patients transplanted for hepatitis B were prospectively studied. HBsAg, HBV-DNA and liver function tests were evaluated in the serum 3, 6 and 12 mo after LT and then yearly. LB was obtained 6 and 12 mo after LT and yearly thereafter. Chronic hepatitis (CH) B after LT was classified as minimal, mild, moderate or severe. HBV recurred in 7/42 (16.6%) patients after 6-96 mo of follow-up. A hundred and eighty-seven LB were evaluated. Four of 7 patients with graft reinfection, all with unknown HBV DNA status before LT, developed cirrhosis at 12-36 mo of follow-up. Of the 122 LB obtained from 28 HBsAg+/HCV- recipients with no HBV recurrence after LT, all biopsies were completely normal in only 2 patients (7.1%), minimal/non-specific changes were observed in 18 (64.2%), and at least 1 biopsy showed CH in the remaining 8 (28.5%). Twenty-nine LB obtained from 7 patients transplanted for HBV-HCV cirrhosis and remaining HBsAg- after LT revealed recurrent CH-C. Actuarial survival was similar in patients with HBsAg+ or HBsAg- liver diseases. Though protocol biopsies may enable the detection of graft dysfunction at an early stage, the risk of progression and the clinical significance of these findings remains to be determined.

Progressive histological damage in liver allografts following pediatric liver transplantation

The long-term histological outcome after pediatric liver transplantation (OLT) is not yet fully understood. De novo autoimmune hepatitis, consisting of histological chronic hepatitis associated with autoantibody formation and allograft dysfunction, is increasingly recognized as an important complication of liver transplantation, particularly in the pediatric population. In this study, 158 asymptomatic children with 5-year graft survival underwent protocol liver biopsies (113, 135, and 64 at 1, 5, and 10 years after OLT, respectively). Histological changes we re correlated with dinical,biochemical, and serological findings. All patients received cydosporine A as primary immunosuppression with withdrawal of corticosteroids at 3 months post OLT. Normal or near-normal histology was reported in 77 of 113 (68%), 61 of 135 (45%), and 20 of 64 (31%) at 1, 5, and 10 years, respectively. The commonest histological abnormality was chronic hepatitis (CH), the incidence of which increased with time [25/113 (22%), 58/135 (43%), and 41/64 (64%) at 1, 5, and 10 years, respectively) (P < .0001)]. The incidence of fibrosis associatedwith CH increasedwith time [13/25 (52%), 47/58 (81%), and 37/41 (91%) at 1, 5, and 10 years, respectively) (P < .0001)]. The severity of fibrosis associated with CH also increased with time, such that by 10 years 15% had progressed to cirrhosis. Aspartate aminotransfemse (AST) levels were slightly elevated in children with CH (median levels 52 IU/L, 63 IU/L, and 48 IU/L at 1, 5, and 10 years, respectively), but this did not reach statistical significance compared with those with normal histology. On multivariate analysis, the only factor predictive of chronic hepatitis was autoantibody positivity (present in 13% and 10% of children with normal biopsies at 5 and 10 years, respectively, and 72% and 80% of those with CH at 5 and 10 years, respectively) (P < .0001). Four children with CH and autoantibodies, who also had raised immunoglobulin G (IgG) levels and AST greater than 1.5 x normal fulfilled the diagnostic criteria for de novo autoimmune hepatitis (AIH). Another two were found to be hepatitis C positive. No definite cause for CH could be identified in the other cases. In condusion, chronic hepatitis is a common finding in children after liver transplantation and is associated with a high risk of developing progressive fibrosis, leading to cirrhosis. Standard liver biochemical tests cannot be relied on either in the diagnosis or in the monitoring of progress of chronic allograft hepatitis. In contrast, the presence ofautoantibodies is strongly associated with the presence of CH. The cause of chronic hepatitis in transplanted allografts is uncertain but may be immune mediated, representing a hepatitic form of chronic rejection.