Recurrent primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis after transplantation

Viral hepatitis and malignancy frequently recur after transplantation, but recurrence of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis is controversial. Differences in study design, number of patients, immunosuppressive treatment, length of follow-up, and criteria for recurrence account for discrepant results. Most patients with suspected recurrent disease are asymptomatic after transplantation. In patients transplanted for PBC, antimitochondrial antibodies frequently persist and do not correlate with disease recurrence; liver biopsy remains the gold standard for diagnosis. Exclusion of other disorders that can mimic PBC is paramount prior to making a diagnosis of recurrent disease. The effects of immunosuppression may modify or delay disease expression within the graft. If PBC recurs, intermediate-term patient and graft survival is excellent, but long-term studies will be necessary to address the impact of disease recurrence on the allograft. Due to lack of a diagnostic gold standard, a diagnosis of recurrent PSC after transplantation is difficult to make. An accurate diagnosis of PSC recurrence requires well-defined cholangiographic and histologic criteria. Other disorders that can produce biliary strictures after transplantation should be excluded. As with PBC, the effects of immunosuppression may modify or delay disease expression within the graft; medium-term patient and graft survival is excellent. Recurrence of autoimmune hepatitis is based on clinical, biochemical, serologic, and histologic criteria. As in patients transplanted for PBC and PSC, other conditions that can mimic autoimmune hepatitis require exclusion prior to making a diagnosis of recurrence. Most adult recipients respond to an increase in immunosuppression, whereas pediatric recipients do not respond as well. A cautious approach to withdrawal of immunosuppression is warranted in all patients transplanted for autoimmune hepatitis and the consequences of recurrent disease within the graft will require prolonged follow-up. Future studies should focus on preventive and therapeutic strategies for recurrent autoimmune diseases after transplantation.     

Immunosuppression in hepatitis B virus and hepatitis C virus transplants: special considerations

The management of the immunosuppression treatment must take account its consequences on viral replication. Such treatment operates on the emerging balance between the recurrence of the virus on the graft and the immune response of the host. Randomized and prospective trials are currently ongoing with the purpose of determining the opportunity and relevance of each immunosuppressive agent in the treatment. In HBV patients, good control of HBV reinfection by prophylactic strategies using HBIG, lamivudine, or both have decreased the impact of immunosuppression on HBV recurrence. In contrast, HCV recurrence is now a major problem. The mechanisms of viral recurrence need to be deepened thus requiring new studies. The absence of in vitro and in vivo systems to study HCV reinfection is a lack in the comprehension of the relation between HCV and immunosuppression. It will allow adapting the effectiveness of the immunosuppression treatment. The treatment's primary target is to avoid graft rejection, and its secondary objective is to limit the risk of viral recurrence.     

Renal transplantation in lupus nephritis

Most patients with systemic lupus erythematosus (SLE) are suitable candidates for renal transplantation. However, a number of them may present some disease-related problems. As cardiovascular disease is a leading cause of morbidity and mortality in SLE patients, a careful pretransplant cardiovascular screening is recommended. A search for antiphospholipid antibodies is also useful as the presence of these antibodies can cause an early graft thrombosis. The risk of recurrence of SLE nephritis after transplantation may range between 2 and 30%. In most cases recurrence is characterized by mild histologic lesions. Only rarely does it lead to graft failure. Postransplant immunosuppression does not differ from that used routinely. Whenever possible, a steroid-free immunosuppression should be scheduled to prevent iatrogenic toxicity in patients who have already received long-term steroid treatment. The results of kidney transplantation largely depend on the clinical conditions at transplantation. In patients with poor clinical status or receiving an aggressive immunosuppression it is advisable to postpone the transplant. When some selection criteria are respected, the results of renal trasplantation in SLE patients are at least as good as in other transplant recipients.     

Recurrence of primary biliary cirrhosis after transplantation. The pathologist's view.

There is now good evidence that primary biliary cirrhosis can recur after transplantation. The diagnosis rests on the liver histology which may be difficult to interpret in the setting of a grafted liver where specific markers are lacking. The triggering factor(s), rate of recurrence and the precise role of immunosuppression remain to be determined.     

Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after orthotopic liver transplantation

Recurrent hepatitis C causes significant morbidity after liver transplantation. Because immunosuppression is associated with enhanced viral replication, we postulated that clinical recurrence of the disease may be associated with augmented immunosuppression for rejection. In 96 patients with hepatitis C who received liver transplants, we recorded the interval from transplantation to recurrence, the episodes of steroid-resistant rejection (SRR) requiring OKT3, the number of rejection episodes, and the use of OKT3 induction. Recurrence was diagnosed based on elevated transaminases and characteristic histology. Hepatitis C recurred in 43 of 96 patients. Fifteen of 21 patients (71.4%) who previously had SRR had recurrence, versus 28 of 75 patients (37.3%) who either had no SRR (72 patients) or had it after recurrence was diagnosed (3 patients) (P <.01). Mean time to recurrence was 127 ± 31 days in the 15 patients who had had SRR versus 246 ± 42 days in the other 28 patients (P = .02). Recurrence and number of rejection episodes were clearly associated: 6 of 33 patients (18.2%) with no rejection had recurrence (P < .05), versus 11 of 26 patients (42.3%) with one rejection episode (P < .05) and 26 of 37 (70.2%) with more than 1 episode (P < .05). OKT3 induction was used in 15 patients; 9 of 15 patients had recurrence (ns) at 337 ± 95 days. Of 72 patients who initially received triple immunosuppression, 30 patients had recurrence at 186 ± 25 days (P = .05). Nine patients received primary FK506; 4 had recurrence at 68 ± 14 days. SRR requiring OKT3 is associated with a higher incidence and earlier presentation of recurrent hepatitis C. Multiple rejection episodes are also associated with a higher recurrence rate. Induction immunotherapy, by reducing the rate of early rejection, may delay the clinical recurrence of hepatitis C.     

The impact of sirolimus on hepatitis C recurrence after liver transplantation

BACKGROUND

While some immunosuppression strategies may accelerate hepatitis C virus (HCV) recurrence after liver transplantation (LT), the impact of sirolimus (SRL) is not known.

OBJECTIVE

To assess the risk of biopsy-proven HCV recurrence and patient survival using known and suspected risk factors for HCV recurrence as covariates.

METHODS

A retrospective analysis of 141 consecutive patients, including 88 who received de novo SRL therapy, who had undergone a first LT for HCV cirrhosis was conducted. Known and suspected risk factor covariates including transplant era, donor and recipient age, Model for End-stage Liver Disease score, cold ischemia time, immunosuppressive drugs and steroid treatment rejection rates were used in the assessment.

RESULTS

Overall, 72.3% of the cohort developed biopsy-proven HCV recurrence. The incidence of HCV recurrence was not significantly different for patients treated with SRL (75% versus 69.8%; P=0.5). There was no difference found for time to recurrence, nor did mean activity or fibrosis scores differ at the time of initial recurrence. However, on follow-up using serial biopsies in patients with recurrence, the mean activity and fibrosis scores were significantly lower in the SRL group. Donor age and acute rejection episodes were the only factors affecting the HCV recurrence rate (expB 1.02 [95% CI 1.01 to 1.03]); P=0.03; and expB 2.8 [95% CI 1.8 to 4.3]; P<0.01], respectively). SRL treatment did not alter patient survival rates. Among patients treated with SRL-based immunosuppression, higher drug area under the curve levels were associated with a trend to lower disease activity and fibrosis at diagnosis; however, higher SRL levels were associated with shorter recurrence-free survival (P=0.038).

CONCLUSION

Results of the present analysis suggest that de novo SRL-based immunosuppression can be safely used in patients undergoing LT for HCV-associated liver disease; however, SRL-based immunosuppression did not significantly affect the timing or severity of post-transplant HCV recurrence. HCV recurrence in SRL-treated patients had lower progressive activity and fibrosis levels on serial biopsy.     

Therapeutic management of recurrent hepatitis C after liver transplantation.

Recurrent hepatitis C ranges from minimal damage to cirrhosis developing in a few months or years in a substantial proportion of transplant recipients. Different virus, host and donor factors are involved in the pathogenesis of recurrence, but many are poorly understood. Therapeutic strategies can be utilized in the pre-, peri- or posttransplantation setting. Antiviral therapy using interferon and ribavirin and modifying immunosuppression are the main strategies to prevent progression disease. The efficacy of interferon and ribavirin is limited and side effects, reduction/withdrawal are frequent. Current sustained virological response rates are approximately 28%. An optimal immunosuppression regimen has not been established. The choice of calcineurin inhibitors has not clearly been shown to affect histological hepatitis C virus (HCV) but higher cumulative exposure to corticosteroids to treat acute rejection is associated with more severe recurrence. The manner in which the doses of immunosuppression are modified has more influence on HCV recurrence than the use of a specific drug per se. Debate about the influence of immunosuppressive regimens on HCV recurrence is ongoing. Potential antifibrotic therapy and new agents targeting HCV infection and replication are emerging and are anticipated to be added to our armentarium in battling recurrent HCV post-LT.     

Extranodal Ki-1 lymphoma in a renal transplant patient

The Ki-1 (CD 30) antigen has been identified as a marker of a subset of large cell anaplastic non-Hodgkin's lymphoma that may have a more favourable prognosis. We describe an immunosuppressed renal transplant patient who developed primary extranodal large cell anaplastic Ki-1 lymphoma of T-cell phenotype confined to the sigmoid colon. The patient was treated with local resection of the sigmoid colon and reduction of immunosuppression and at two year follow-up remains free of recurrence. It is recognised that long term immunosuppression in post transplant patients increases the risk of certain malignancies. Localised gut lymphoma may be amenable to local resection as a curative procedure. (Aust NZ J Med 1992; 22: 51–53.)     

Neoplastic disease after liver transplantation: focus on de novo neoplasms

De novo neoplasms account for almost 30% of deaths 10 years after liver transplantation and are the most common cause of mortality in patients surviving at least 1 year after transplant. The risk of malignancy is two to four times higher in transplant recipients than in an age- and sex-matched population, and cancer is expected to surpass cardiovascular complications as the primary cause of death in transplanted patients within the next 2 decades. Since exposure to immunosuppression is associated with an increased frequency of developing neoplasm, long-term immunosuppression should be therefore minimized. Promising results in the prevention of hepatocellular carcinoma(HCC) recurrence have been reported with the use of m TOR inhibitors including everolimus and sirolimus and the ongoing open-label prospective randomized controlled SILVER. Study will provide more information on whether sirolimus-containing vs m TOR-inhibitorfree immunosuppression is more efficacious in reducing HCC recurrence.     

Therapeutic strategies for post-transplant recurrence of hepatocellular carcinoma

Despite stringent selection criteria, hepatocellular carcinoma recurrence after liver transplantation (LT) still occurs in up to 20% of cases, mostly within the first 2–3 years. No adjuvant treatments to prevent such an occurrence have been developed so far. However, a balanced use of immunosuppression with minimal dose of calcineurin inhibitors and possible addition of mammalian target of rapamycin inhibitors is strongly advisable. Moreover, several pre- and post-transplant predictors of recurrence have been identified and may help determine the frequency and duration of post-transplant follow-up. When recurrence occurs, the outcomes are poor with a median survival of 12 mo according to most retrospective studies. The factor that most impacts survival after recurrence is timing (within 1–2 years from LT according to different authors). Several therapeutic options may be chosen in case of recurrence, according to timing and disease presentation. Surgical treatment seems to provide a survival benefit, especially in case of late recurrence, while the benefit of locoregional treatments has been suggested only in small retrospective studies. When systemic treatment is indicated, sorafenib has been proved safe and effective, while only few data are available for lenvatinib and regorafenib in second line. The use of immune checkpoint inhibitors is controversial in this setting, given the safety warnings for the risk of acute rejection.     

Management of recurrent hepatitis C after liver transplantation

Hepatitis C virus (HCV) reinfection is almost universal in patients transplanted for HCV-related cirrhosis. The medium-term survival after orthotopic liver transplantation (OLT) is similar to other transplanted patients, but the long-term survival remains uncertain. The prevention and an effective treatment of progressive liver disease are the primary aims in HCV recurrence. Interferon and ribavirin, as monotherapy or in combination, have been tried to treat or prevent HCV recurrence. Preliminary studies suggest a better chance of initial HCV clearance and better results in preventing HCV recurrence with combination therapy. IFN or ribavirin, as monotherapy, may normalize liver enzymes, but only gives rise to a transient virological response, without histological improvement. Combination IFN and ribavirin may be able to prevent progression of HCV-related graft disease, but indications and duration of treatment need further evaluation.
No clear association between type and dose of immunosuppressive and outcome of post-transplant HCV recurrence has been found. Strategies to minimize the effects of immunosuppressive drugs include dose reduction of all agents and the selective discontinuation of individual agents. Initial immunosuppression with a single drug may inhibit or delay the severe fibrosis, and further investigation with a single immunosuppressive regimen to evaluate the outcome of recurrent hepatitis C should be performed. The recent evidence that mycophenolate may have an antiviral effect needs a clinical confirmation.
Retransplantation survival is better with early retransplantation, and for indications not directly related to viral recurrence.     

Recurrent primary biliary cirrhosis.

Transplantation has become the accepted form of therapy for patients with end-stage liver disease. The diagnosis of recurrent disease in the allograft has been a matter of controversy, partly because of the difficulties in making the diagnosis in the allograft situation. The conventional criteria for diagnosing PBC may be inappropriate and there are many causes of bile duct damage in the graft. That the PBC-specific autoantibodies [such as antimitochondrial antibody (AMA) and gp-210] persist after transplantation is universally found, and some have reported the aberrant distribution of E2 in the allograft that is typical of PBC in the native liver, whether or not there is histological evidence of PBC recurrence. Most studies now accept that histological features of PBC, such as granulomatous bile duct damage, ductopenia and biliary-type fibrosis, may be found in the allograft; the histological features of PBC are variable and do not mirror the liver tests. The rate of recurrence increases with time, so that by 10 years, recurrence may be found in 30-50% of biopsies. There are no clear factors which identify those at risk of recurrence, but the pattern and degree of immunosuppression may be implicated. Cirrhosis has only rarely been reported. In the medium term, recurrence of PBC has little clinical impact. Ursodeoxycholic acid is used in some centres but there is no clear evidence for benefit.     

Risk factors for hepatitis C recurrence after liver transplantation

Summary.  Hepatitis C virus (HCV)-related end-stage liver disease is the main indication for liver transplantation performed in Europe and the United States. Recurrence of hepatitis C in the graft is universal and may lead to chronic hepatitis in most patients and to cirrhosis in 20–30% of patients within 5–10 years of transplantation. The natural history of HCV recurrence is highly variable but leads to a lower survival rate than other recurrent liver diseases. The immunosuppressed status and several other factors have been linked with the pattern and severity of recurrence. What remains controversial are those factors associated with fibrosis progression and how these could be modified to improve outcome of recurrent hepatitis C. No single factor but a combination of several factors is associated with fibrosis progression on the graft. The major factors associated with accelerated disease recurrence include: high viral load pre- (>10⁶ IU / mL) and / or early post-transplantation (>10⁷ IU / mL at 4 months), donor older than 40–50 years, prolonged ischaemic time, cytomegalovirus coinfection, over immunosuppression and / or abrupt changes in immunosuppression, HIV coinfection, infection by genotype 1b. Cautious follow-up of the pathology of the graft is mandatory including routine biopsies and / or noninvasive monitoring of fibrosis.     

Recurrence of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis after liver transplantation

Liver transplantation (LT) is the standard therapeutic approach for the treatment of end-stage acute and chronic autoimmune liver disease as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Results of liver transplantation in these indications are good with a patient survival after LT at 5 years of 85%. However several series have reported a possible recurrence of primary autoimmune liver disease after liver transplantation. Concerning all these three autoimmune liver diseases, recurrence of the disease on the graft may have multiple clinical, biochemical, histological and radiological expression influenced by different factors as the diagnostic methods used, the degree of immunosuppression and the genetic background of the recipient. We would like with this overview to describe the different pattern of recurrence of these autoimmune liver disease, their potential influence on the liver graft and their therapeutic management.     

Cure of cryptococcemia and preservation of graft function in a renal transplant recipient

Disseminated cryptococcosis with cryptococcemia occurred in a renal transplant patient in whom immunosuppression was continued throughout antifungal therapy in an effort to ensure graft viability. Despite the initial presence of positive fungal cultures of blood, urine, and CSF, infection cleared rapidly, and there has been no evidence of recurrence. Throughout this period, renal function remained unaltered. This favorable outcome suggests that the prognosis for the renal transplant recipient with disseminated cryptococcosis may be improved.     

Sirolimus plus sorafenib in treating HCC recurrence after liver transplantation: a case report

A case of hepatocellular carcinoma (HCC) with pulmonary recurrence after liver transplantation for HCC is presented in this report. The patient showed disease progression on sorafenib therapy demonstrated by computed tomography scans as well as serial serum α-fetoprotein (AFP) elevation. After his immunosuppression therapy was successfully transitioned to sirolimus and a continuation of sorafenib, he achieved partial remission based on RECIST criteria and normalization of AFP. Mammalian target of rapamycin inhibitors including sirolimus alone or in conjunction with sorafenib may be useful in the treatment of post transplant HCC.     

Efficacy of immunosuppression monotherapy after liver transplantation: A meta-analysis

AIM: To assess the advantages and disadvantages of immunosuppression monotherapy after transplantation and the impact of monotherapy on hepatitis C virus (HCV) recurrence.METHODS: Articles from Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded, including non-English literature identified in these databases, were searched up to January 2013. We included randomized clinical trials comparing various immunosuppression monotherapy and prednisone-based immunosuppression combinations for liver transplantation. The modified Jadad scale score or the Oxford quality scoring system was used. Meta-analyses were performed with weighted random-effects models.RESULTS: A total of 14 randomized articles including 1814 patients were identified. Eight trials including 1214 patients compared tacrolimus monotherapy (n = 610) vs tacrolimus plus steroids or triple therapy regarding acute rejection and adverse events (n = 604). Five trials, including 285 patients, compared tacrolimus monotherapy (n = 143) vs tacrolimus plus steroids or triple therapy regarding hepatitis C recurrence (n = 142). Four trials including 273 patients compared cyclosporine monotherapy (n = 148) vs cyclosporine and steroids regarding acute rejection and adverse events (n = 125). Two trials including 170 patients compared mycophenolate mofetil monotherapy (n = 86) vs combinations regarding acute rejection (n = 84). There were no significant differences in the acute rejection rates between tacrolimus monotherapy (RR = 1.04, P = 0.620), and cyclosporine monotherapy (RR = 0.89, P = 0.770). Mycophenolate mofetil monotherapy had a significant increase in the acute rejection rate (RR = 4.50, P = 0.027). Tacrolimus monotherapy had no significant effects on the recurrence of hepatitis C (RR = 1.03, P = 0.752). More cytomegalovirus infection (RR = 0.48, P = 0.000) and drug-related diabetes mellitus (RR = 0.54, P = 0.000) were observed in the immunosuppression combination therapy groups.CONCLUSION: Tacrolimus and cyclosporine monotherapy may be as effective as immunosuppression combination therapy. Mycophenolate mofetil monotherapy was not considerable. Tacrolimus monotherapy does not increase recurrence of HCV.     

Hepatitis C after liver transplantation

Hepatitis C is the most common cause of end-stage liver disease leading to liver transplant. The disease can recur after transplant, resulting in clinical hepatitis in up to 75% of patients and severe disease in approximately 7%. Treatment of rejection with steroid boluses and treatment of steroid-resistant rejection with OKT3 have both been shown to increase the incidence of recurrent hepatitis C. The use of OKT3 for steroid-resistant rejection is reportedly associated with more severe recurrence. The calcineurin inhibitors tacrolimus and cyclosporine have not been conclusively associated with different rates or severity of recurrence. Viral levels rise 10- to 15-fold after transplant and appear to be associated with the use of immunosuppression. Studies suggest that high viral levels, either pretransplant or early after transplant, may be associated with severe recurrent disease. Although the role of genotype is still unclear, genotype 1b is known to be associated with a poorer prognosis in nontransplanted patients and a lesser response to treatment than other genotypes. Furthermore, some reports suggest that after transplant, recurrent disease may progress more rapidly in patients with genotype 1. Treatment options after recurrence remain poor. Neither interferon nor ribavirin alone provides any true benefit. Combination therapy appears to have a better short-term outcome but may be poorly tolerated, and long-term benefits are unknown. Prophylaxis with combination therapy may be a better option but requires further study. Finally, retransplantation for recurrent hepatitis C is complicated not by rapid recurrence of disease in the new allograft but by high perioperative mortality that may be predicted by the presence of renal failure or sepsis preretransplant.     

Hepatocellular carcinoma recurrence after acute liver allograft rejection treatment: A multicenter European experience

Background: During the last decades, several risk factors for the recurrence of hepatocellular carcinoma(HCC) after liver transplantation(LT) have been investigated. However, the impact of two important drivers of oncogenesis, namely the immunosuppression and the treatment of acute cellular rejection(ACR) have been marginally addressed. This study aimed at investigating the impact of ACR treatment on the incidence of tumor recurrence in a large European HCC-LT population. Methods: Seven hundred and eighty-one adult patients transplanted between February 1, 1985 and June 30, 2016 were retrospectively analyzed. After propensity score match, 116 patients treated for ACR using steroid boluses were compared with 115 patients who did not present any ACR or a histologic but clinical irrelevant ACR. Results: Steroid boluses treated patients had a 18-fold higher overall incidence of HCC recurrence than those non-treated patients(16.4% vs. 0.9%; P 0.0001). At multivariate Cox regression analysis, steroid boluses used to treat ACR were an independent risk factor for HCC recurrence(HR = 14.2; 95% CI: 1.8–110.4; P = 0.010). Conclusions: The decision to treat ACR as well as to reinforce immunosuppression load should be cautiously taken in view of the presented results. Prospective studies are needed to further elucidate the clinical impact of immunosuppression on HCC recurrence after transplantation.     

乙肝病毒相关肝病肝脏移植术后乙肝复发的预防和治疗

在我国施行肝移植的患者中,绝大多数是乙肝病毒相关性终末性肝病患者,术前病毒复制程度、个体免疫状态和病毒类型与移植术后易感复发密切相关。联合应用乙肝免疫球蛋白与核苷类似物可用于肝脏移植术后抗病毒治疗,近年来报道乙肝疫苗也可有效预防移植术后乙肝复发。本文重点介绍肝脏移植术后乙肝复发的机制及影响因素,探讨预防乙肝复发的各种方案的优劣。