Rapidly progressive recurrent hepatitis C virus infection starting 9 days after liver transplantation.

Early histological recurrence of hepatitis C after liver transplantation (LT) has a negative impact on patient and graft survival. We report a case of histological recurrence of HCV occurring in the second week after LT. A 75-year-old woman with chronic HCV and hepatocellular carcinoma underwent LT with an organ from a 75-year-old HCV-negative deceased donor. After an uneventful early postoperative period, an increase in the transaminases was observed, and on postoperative day 9 day, the alanine aminotransferase (ALT) was 673 IU/mL and aspartate aminotransferase (AST) 300 IU/mL, with normal alkaline phosphatase and bilirubin. Analysis of liver biopsy samples showed diffuse necroinflammatory changes with acidophilic bodies and concomitant mild acute cellular rejection. Subsequently there was a further increase in the transaminases, and on postoperative day 13, the AST rose to 445 IU/mL and ALT to 992 IU/mL. Repeat biopsy was performed, and analysis of the samples revealed lymphocytic portal inflammation with lymphoid aggregates and mild interface hepatitis, parenchymal necrosis, activation of sinusoidal lining cells, and mild steatosis. The biopsy sample was characteristic for HCV recurrence. The HCV RNA level was 84,000,000 copies/mL, and markers for other viral causes were not present. The patient became jaundiced and her course progressively worsened. She died on day 87 after transplantation. To our knowledge, this is the earliest reported case of histological recurrence of HCV after LT. It illustrates the importance of older donor and recipient age in the same patient as cofactors for early HCV recurrence and poor outcome.     

Tacrolimus and cyclosporin doses and blood levels in hepatitis C and alcoholic liver disease patients after liver transplantation.

Hepatitis C virus (HCV)-induced cirrhosis is the most common indication for liver transplantation (LT). However, graft reinfection is nearly universal. The choice of immunosuppression, including the calcineurin inhibitor (CNI), may have some effect on severity of recurrence and graft survival. In addition, HCV recurrence may have some impact on metabolism of immunosuppressive drugs. In this retrospective study, we examined the dose and blood levels of tacrolimus (TAC) and cyclosporin A (CYA) in HCV patients consecutively undergoing transplantation (TAC, n = 44; CYA, n = 60) and surviving 12 months post-LT. In addition, we examined the CNI dose and blood levels in an age- and gender-matched comparison group of patients who were transplanted for alcoholic liver disease (ALD) (TAC, n = 44; CYA, n = 47). During the 12-month period of observation, TAC levels were significantly higher for HCV than for ALD patients (P = 0.002). The dose of TAC decreased over time for both HCV and ALD patients (P < 0.001), but the reduction was greater for HCV patients (P = 0.03). CYA dose decreased over time for both groups (P < 0.001) but a greater reduction was observed for the HCV group (P = 0.007). For both HCV and ALD patients, CYA levels decreased over time (P < 0.001) but there was no significant difference between HCV and ALD patients. Thus, to maintain comparable blood levels, a greater reduction of dose was required for HCV than for ALD patients. In conclusion, our observations demonstrate a likely effect of HCV infection on CNI metabolism, an effect that is not clearly due to graft damage. Physicians need to be alert to this interaction and to the need to respond quickly to changes in CNI levels that may be associated with HCV infection and with HCV clearance during antiviral therapy.     

The impact of acute alcoholic hepatitis in the explanted recipient liver on outcome after liver transplantation.

Patients with clinical acute alcoholic hepatitis (AAH) are not considered suitable candidates for orthotopic liver transplantation (OLT). The histological correlates of AAH are often seen in the explanted liver at the time of transplantation. The importance of these findings remains inconclusive regarding their role as a prognostic marker for patient or allograft health. Our aim was to examine the explanted liver of patients with purely alcoholic liver disease (ALD) for findings of histologic AAH and to correlate these to patient and graft outcomes. We compared patients with and without histological AAH with patients transplanted for non-ALD. Of 1,097 liver transplant recipients, 148 had ALD and 125 were non-ALD control patients with similar demographics. Thirty-two of 148 ALD patients had histologic AAH, and 116 had bland alcoholic cirrhosis (BAC). Twenty-eight percent of the ALD patients reported <6 months abstinence, and 54% reported <12 months abstinence. There was a statistically significant relationship between the presence of histologic AAH and abstinence durations<12 months (P=0.009), but not <6 months. Overall, posttransplantation patient and graft survival between the ALD and non-ALD groups was not significantly different (P=0.53). Furthermore, patient and graft survival between ALD patients with histologic AAH and BAC were similar (P=0.13 and P=0.11, respectively). The rate of posttransplantation relapse among ALD patients was 16%; however, there was no increase in graft loss, nor was there decreased survival compared with controls. The patients with histologic AAH and those with BAC had no differences in posttransplantation relapse (P=0.13). In multivariate analysis, patient and graft survival was not influenced by pretransplantation abstinence or posttransplantation relapse. In conclusion, histological alcoholic hepatitis in the explant did not predict worse outcome regarding relapse, and allograft or patient survival for liver transplant recipients. Caution should be exercised when liver histology is used to discriminate among suitable candidates for OLT concerning alcoholic patients.     

Rapid progressive hepatitis C after liver transplantation: a case report

A 56-year-old man on hemodialysis for 3 years because of chronic renal failure underwent living related donor liver transplantation (LRDLT) and splenectomy using the right hepatic lobe for liver cirrhosis type C (genotype 1b) with hepatocellular carcinoma. At 69 postoperative days (POD), he displayed a high fever and his blood transaminase and total bilirubin were increased. Based on finding in his liver biopsy, we diagnosed rapid recurrence of progressive hepatitis C after LRDLT, so we administered IFNβ. Thereafter his liver function returned to normal and his HCV-mRNA decreased to 1200 kcopy/mL. We inferred that hemodialysis and splenectomy decreased his immunity, allowing rapidly progressive hepatitis C recurrence after LRDLT.     

Use of somatostatin for complications occurring after liver transplantation.

Somatostatin can be helpful after liver transplantation in some well-defined indications. In uncontrolled digestive haemorrhage, a short course of somatostatin therapy can be of great help in controlling the acute bleeding and to avoid emergency laparotomy. Somatostatin could also be helpful in bilio-pancreato-intestinal fistula, but in this case its advantage over elective surgical treatment remains to be confirmed.     

Recurrence of autoimmune hepatitis after liver transplantation.

BACKGROUND: The literature data on the recurrence of autoimmune hepatitis (AIH) after orthotopic liver transplantation (OLTX) is scanty. METHODS: We analyzed the frequency of recurrent AIH in 47 patients who had been transplanted for AIH and survived at least 1 year after surgery. The following criteria were applied to diagnose recurrence: (1) positive autoantibodies in the titer> or =1:40; (2) hypertransaminasemia; (3) histological features of chronic hepatitis; (4) need of reintroduction or significant increase of steroids; and (5) lack of serum markers of viral hepatitis. RESULTS: A total of 13 patients (1 male/12 females) developed recurrent AIH after an interval of 6-63 months after OLTX (mean 29 months). Mean AST level at recurrence was 542+/-129 U/L. Three patients from this group needed regrafting. Mismatch of DR3+ recipient and DR3- donor was not more common in the recurrent disease group (37%) compared to the nonrecurrence group (31%) (P=NS). CONCLUSIONS: Recurrence of AIH after OLTX was diagnosed in a high proportion of patients and some of them required regrafting. DR3+ patients are not particularly prone to develop recurrence.     

General compliance after liver transplantation for alcoholic cirrhosis

In recent years, alcoholic cirrhosis has been accepted as an indication for OLT, compliance of patients suffering from alcoholic cirrhosis is still under discussion, however. 118 patients who had undergone OLT for alcoholic cirrhosis were considered for analysis. The mean follow-up time of the study population was 53.7 ± 38.9 months. Compliance was defined by 3 parameters: 1. Sobriety. Fifteen (13 %) out of 118 recipients suffered an alcohol relapse during the observation period. There was no difference between the groups with or without alcohol relapse concerning compliance with medication, incidence of rejection, or adherence to check-ups. 2. Drug-compliance. Nineteen recipients (16 %) were not within the target range with the immunosuppressive medication. Comparison of the compliant- and non-compliant groups produced a significant difference for late acute rejection, the other parameters being similar in the subgroups. 3. Adherence to appointments. Nearly all patients in the study population ( > 95 %) were compliant with both transplant and psychological appointments in the outpatient clinic. In conclusion, analysis of our data indicates that patients with OLT for alcoholic cirrhosis are compliant, although alcohol relapse occurs in 13 % of recipients. Received: 4 June 1999/Revised: 23 November 1999/Accepted: 15 December 1999     

Long-term follow-up after liver transplantation for alcoholic liver disease under tacrolimus

BACKGROUND: Liver transplantation (LTx) for alcohol-related liver disease (ALD) is an accepted modality of treatment and is one of the most common indications for LTx in the United States. The present report examines the long-term patient survival, graft survival, rates of recidivism, and development of de novo cancers in this group, and compares these results with a contemporaneous group of patients who were transplanted for non-ALD indications. METHODS: Between August 1989 and December 1992, 185 adults received LTx for ALD (group I). During the same time interval, 649 adults received LTx for non-ALD (group II). The mean follow-up time was 94+/-10.7 months for group I vs. 92+/-11 months for group II. Kaplan-Meier survival estimates and the incidence of cancers using Surveillance Epidemiologic End Result data were compared in both groups. RESULTS: At 5 years after orthotopic LTx, the overall patient survival and graft survival for group I were 72.0% and 66.5% vs. 66.5% and 60.3% for group II, respectively. After 5 years, the patient survival and graft survival for the alcoholic group were significantly lower (P=0.001) compared to the non-alcoholic group. The rate of de novo oropharyngeal cancer and lung cancer was 25.5 times and 3.7 times higher, respectively, in ALD group compared with the general population matched for age, sex, and length of follow-up (P=0.001), whereas this was not higher in the non-ALD group. Prior pretransplant length of sobriety and alcohol rehabilitation was not associated with the rate of post-LTx rate of recidivism, which was 20%. Out of 79 deaths in group I, only 1 was attributed to recidivism and 3 to noncompliance with recidivism. The other deaths occurred from de novo cancer (n=13), posttransplant lymphoproliferative disorder (n=5), age-related complications (n=23), and other infection or miscellaneous causes (n=34). CONCLUSIONS: Patient and graft survival past 5 years after orthotopic LTx is significantly lower for ALD for a variety of reasons (P=0.001). The rate of upper airway malignances was significantly higher in ALD patients than for non-ALD post-LTx patients and the general public. Graft loss/death related to recidivism or chronic rejection was extremely low. More attention is needed for early diagnosis of de novo cancer and prevention of cardiorespiratory and cerebrovascular complications.     

Liver transplantation for alcoholic liver disease.

BACKGROUND. Alcoholism is the leading cause of end-stage liver failure in the United States, but the application of liver transplantation to the treatment of alcoholic liver disease remains controversial because of medical and ethical concerns. Information about the outcome of patients who undergo transplantation for alcoholic cirrhosis would help to resolve these concerns. METHODS. The results of 41 patients (Group 1) with alcoholic liver disease were compared with those of patients who underwent liver transplantation for other medical problems (group 2) at this center. Thirty of the 32 survivors from group 1 and 30 matched subjects from group 2 were interviewed to assess substance dependence, recidivism, and activity level. RESULTS. Compared with control subjects, patients with alcoholic liver disease had equivalent patient and graft survival rates and achieved an equal level of postoperative health. These results were achieved even though patients with alcoholic liver disease had significantly worse liver failure and more morbidity before surgery, and one third of the patients in this group were not abstinent before transplantation. CONCLUSIONS. We conclude that patients with alcoholic liver disease merit equal consideration for liver transplantation compared with other causes of liver failure. Treatment of the addictive disorder should be included before and after surgery.     

Progression of liver fibrosis in patients with chronic hepatitis C after orthotopic liver transplantation

BACKGROUND: Hepatitis C virus (HCV)-related cirrhosis is the leading indication for orthotopic liver transplantation (OLTx). HCV recurrence is universal after OLTx, with a highly variable course. This study aimed to find factors that affect progression of fibrosis in recurrent HCV. METHODS: Fifty-eight HCV patients underwent OLTx at our center who were selected on the basis of available preOLTx serum or explanted liver sample and liver biopsy obtained at least 6 months postOLTx. All liver biopsies were performed when clinically indicated and were scored using the modified Hepatitis Activity Index (HAI). Primary immunosuppression consisted of tacrolimus and prednisone. RESULTS: The group included 41 males (mean age 49.6 years). HCV genotype distribution was 1a, 31 (53%); 1b, 16 (28%), and others 11 (19%). The mean follow-up was 53.1 months. Patients with genotype 1a (n=31; mean 46.3 months) had significantly lower fibrosis-free survival analyzed by the presence of fibrosis stages 5 and 6 when compared with other genotypes (n=27; mean 60.1 months; P=0.0088, log rank test). Mean HAI scores were significantly higher in HCV genotype 1a, although there were no differences in survival between genotypes. Similarly, patients with cytomegalovirus (CMV) infection postOLTx (n=4) had a higher fibrosis progression rate compared with those without CMV (n=54) (mean fibrosis-free survival 29.0 vs. 53.0 months P=0.0004, log-rank test). Human leukocyte antigen matching and rate of acute rejection did not influence progression of fibrosis. CONCLUSION: Patients with HCV genotype 1a and those developing CMV postOLTx have a higher rate of hepatic fibrosis progression after OLTx for HCV-related chronic liver disease.     

Beta-glucan reflects liver injury after preservation and transplantation in dogs.

Graft failure and extrahepatic organ complications, which frequently develop after transplantation, may be related to inflammatory mediators stimulated by endotoxin (ET). The role of endotoxemia after liver transplantation is controversial and may depend upon differences in the ET assay method used in the various contradicting studies. While the standard Limulus amebocyte lysate (LAL) is reactive for ET and beta-glucan, a novel turbidimetric assay method enables separate determinations of ET and beta-glucan. Beagle dogs undergoing orthotopic liver transplantation were divided into two groups. In Group I (n = 6) the grafts were transplanted immediately and in Group II (n = 6) grafts were preserved for 48 h in University of Wisconsin (UW) solution. Animals received cyclosporine immunosuppression and were followed for 14 days. Daily measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) were performed. Samples for ET and beta-glucan measurement were collected serially and processed using the turbidimetric assay method. While no graft failure was seen in Group I, three of six Group II animals died from graft failure within 1 day after transplantation. Preservation and reperfusion injury was much more severe in the Group II grafts than in Group I grafts. While endotoxemia could not be detected, postoperative beta-glucan levels (undetectable pretransplant) were seen in both groups. Beta-glucan levels were much higher in Group II grafts than in Group I grafts, and correlated with the severity of liver damage. In conclusion, this study shows that beta-glucan, instead of ET, appears during the early posttransplant period. We believe that posttransplant elevation of beta-glucan is related to liver damage, especially endothelial damage by preservation and reperfusion.     

Diffuse biliary tract injury after orthotopic liver transplantation.

An unusual type of diffuse biliary tract injury after liver transplantation that is characterized by multiple intrahepatic biliary strictures, ductal dilatations, fluid collections, or intrahepatic abscesses has been identified. Over a 5-year period, a total of 10 patients (2%) developed diffuse intrahepatic biliary injury with established vascular patency and no obvious source for their biliary tract pathology. All patients received livers preserved in University of Wisconsin solution with a mean preservation time of 16 hours. This biliary tract injury was associated with the presence of severe preservation injury and Roux limb biliary reconstruction. Of the 10 patients, 5 were treated nonoperatively with multiple stricture dilations and stent placements, 3 underwent retransplantation, 1 was treated operatively with hepaticojejunostomy, and 1 died of sepsis. This study suggests that this complication appears to be related to preservation injury and that the etiology may be ischemic in origin.     

Alcohol recidivism impairs long-term patient survival after orthotopic liver transplantation for alcoholic liver disease.

The aim of this study was to evaluate the rate of alcohol recidivism after orthotopic liver transplantation (OLT) for alcoholic liver disease (ALD) and its influence on the allograft and patient survival, as well as the development of comorbidities and de novo cancers. The study was performed on 54 subjects previously analyzed and transplanted in our center for ALD, whose follow-up was prolonged to a mean of 99.2 (SD 31.7) months (range, 14-155). Medical records were reviewed, and data on alcohol consumption, therapeutic compliance, graft evolution, rejection, infections, comorbidities, rates of de novo malignancies and other clinical events, and survival were collected. Comparisons between groups were performed by the Fisher's exact test, and survival was assessed by the Kaplan-Meier method. Survival curves were compared using the Mantel-Cox statistic. The risk of death resulting from alcohol recidivism was analyzed with a Cox proportional hazards model. Fourteen patients who underwent transplantation for ALD (25.9%) returned to alcohol use between 5.0 and 86.9 months after OLT (median, 47.5). There was no significant association between the presence or absence of alcohol recidivism and the occurrence of graft rejection, infections, associated comorbidities after OLT, or compliance. The 5- and 10-year survival rates for patients with alcohol recidivism were 92.9% and 45.1%, respectively, compared with 92.4% and 85.5%, respectively, for patients without alcohol recidivism. These figures show significantly lower survival rates in recidivistic patients after 10 years (P < 0.01, Mantel-Cox). The fact that patients who resumed alcohol consumption have a worse 10-year survival rate might be attributed to a higher frequency of deaths, primarily from cancer and cardiovascular events.     

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.