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In this issue of Liver Transplantation, 2 papers from the liver transplant group at Birmingham, United Kingdom, describe recipients with idiopathic inflammation in liver allografts (idiopathic posttransplantation hepatitis [IPTH]) that, in some cases, resulted in marked fibrosis and cirrhosis. Syn1 performed a retrospective study of liver allograft recipients who survived for at least 6 months, had chronic hepatitis at initial biopsy and underwent at least one other later biopsy, and in whom recurrent disease was excluded. Among 1,968 patients transplanted over a 20-year period, 288 required transplantation for either alcoholic cirrhosis or for fulminant hepatic failure due to drug hepatotoxicity. Liver biopsy samples were obtained when clinically indicated or per protocol at 1- to 3-year intervals. Thirty recipients fulfilled the inclusion criteria and were studied further. Chronic hepatitis was diagnosed at 6-72 months after transplantation, and 22 patients were found to have hepatitis during the first 2 years. Most initial biopsies showed mild inflammatory activity and mild to moderate fibrosis was noted in 12 of the 30 recipients. Two of the patients with increased fibrosis fulfilled criteria for de novo autoimmune hepatitis, and 3 had increased steatosis or steatohepatitis. Five of the 12 recipients developed marked graft dysfunction. Female sex and serum alkaline phosphatase levels correlated with progressive fibrosis.

In a separate study, Seyam2 identified transplant recipients with histologically proven graft cirrhosis from their liver unit database. Biopsy samples obtained from those recipients 12 months after transplantation were reviewed by a semiquantitative protocol. Among 1,287 patients transplanted over a period of 11 years, 48 (3.7%) were found to have graft cirrhosis. In 29 recipients, cirrhosis was attributed to recurrent disease, and in 9, other causes could be identified. The remaining 10 patients, at a median of 7 years after transplantation, had no apparent etiology of graft cirrhosis. In all 10 of those cases, however, biopsy samples obtained before the onset of cirrhosis showed features of chronic hepatitis without an apparent etiology (IPTH). The authors concluded that almost 40% of patients with graft cirrhosis had cirrhosis of an indeterminate etiology. The Birmingham group also recently reported a high incidence (>50%) of idiopathic chronic hepatitis in long-term protocol biopsy samples from pediatric recipients.3

Among the many recipient factors that influence long-term posttransplantation outcome, age, comorbid conditions, and original disease etiology are clearly important. Donor factors such as age, cardiac status, cold ischemia time, degree of steatosis, and severity of preservation injury primarily exert their effects on outcome early after transplantation. However, with the use of extended-criteria organs, donor factors and the early postoperative course are likely to exert increasingly important influences on long-term patient and graft survival. One example is repeat transplants that fare worse compared with first transplants. Between 1997 and 2004, 1-year graft and patient survival rate averaged 83% and 88% for the primary transplantation. However, for repeat transplants, it averaged 66% and 73%, respectively. Five-year graft and patient survival averaged 67% and 74% for primary transplants compared with 46% and 55% for repeat transplants, respectively.4 These results emphasize the importance of applying strategies that would ensure optimal graft and patient survival after transplantation.

Clinically relevant acute graft rejection remains a common but manageable problem that occurs mostly at 5-30 days after transplantation. When indicated by laboratory values, the diagnosis is confirmed by allograft biopsy, the results of which show mixed but predominantly mononuclear portal inflammation, bile duct damage, and portal and central perivenulitis.5 A variety of effective immunosuppressive agents have, however, largely eliminated the negative impact of acute rejection on short-term graft survival, because fibrosis and chronic rejection are relatively uncommon outcomes of acute rejection.6, 7

The standardization of acute and chronic rejection grading by the Banff schema shows that important differences exist at various centers in the incidence and severity of early acute rejection episodes.5, 7, 8 Whether the severity of early acute rejection has an effect on long-term outcome or late biopsy findings has not been studied in any detail. But Birmingham has a documented history of providing immunosuppression with a light hand, with excellent short- and long-term patient and graft survival rates.8–10

The high incidence and high impact of IPTH at Birmingham requires further scrutiny. Before discussing possible explanations, however, it is important to determine whether there is a center-specific effect. Table 1 lists most studies where information about the incidence of IPTH in long-term survivors could be extracted, even though a specific diagnosis of IPTH was not assigned. Most studies share 2 conclusions: recurrence of the original disease (and biliary tract complications) is the most common cause of late dysfunction/abnormalities; and abnormal biopsy findings are common, even in the absence of recurrent disease.

Table 1. Studies of Biopsy Findings in Long-Term Liver Allograft Survivors for Whom Information About IPTH Could Be Extracted
StudyLength of follow-upIncidence of unexplained inflammation in allograftConclusions/recommendations
  1. Abbreviations: IPTH, idiopathic posttransplantation hepatitis; HCV, hepatitis C virus; LFT, liver function test; PBC, primary biliary cirrhosis.

Berenguer et al.,12 adult (n = 248)1–5 years<10–30%“Hepatitis” frequently seen in non-HCV recipients, but activity is mild. Therefore, protocol biopsies justified only in HCV-positive patients. Non-HCV-positive recipients with normal LFTs should not undergo protocol biopsies.
Sebagh et al.,11 adult (n = 143)10 years<10%Chronic viral hepatitis and chronic rejection major causes of dysfunction. Protocol biopsies recommended because of frequent abnormalities when LFTs are normal.
Pappo et al.,21 adult (n = 65)Mean survival 9.9 years∼35%Recurrence of original disease and biliary tract complications were major problems. Six of 17 patients had unexplained chronic hepatitis, but several of these had PBC as original disease. Protocol biopsies recommended.
Slapak et al.,22 adult (n = 116)Mean 8.4 years18–48%Thirteen of 27 patients had unexplained chronic hepatitis, but 8 of 13 had PBC as original disease. Protocol biopsies recommended.
Heneghan et al.,23 adult (n = 99)> 1 year∼15%IPTH not mentioned as specific diagnosis or important problem, but “nonspecific inflammation” seen in 15 of 99 patients transplanted for cryptogenic or alcoholic cirrhosis.
Contos et al.24, adult (n = 30)Median follow-up of 3.5 yearsNot mentionedIPTH not mentioned as specific diagnosis or important problem.
Maor-Kendler et al.,25 adult (n = 71)Mean survival of ∼4 years∼15%IPTH not mentioned as specific diagnosis or important problem, but listed as “nonspecific inflammation.”
Burra et al.,26 adult (n = 51)> 1 year∼25%, but difficult to determine timing of biopsyIPTH not mentioned as specific diagnosis or important problem, but alcoholic patients showed “portal lymphocytic inflammation.”
Rosenthal et al.,13 pediatric (n = 54)1 year∼50%IPTH not mentioned as important problem, but “portal mononuclear inflammation” present in nearly half of recipients. Long-term follow-up not included. Argues against long-term protocol biopsies in children.

Immunosuppression is generally monitored and titrated on the basis of laboratory studies that principally include the serum transaminase, alkaline phosphatase, gamma glutamyl transpeptidase, and bilirubin levels, in combination with blood levels of immunosuppressants such as cyclosporine and tacrolimus. Some centers, such as Birmingham, perform protocol liver biopsies, whereas others limit the use of allograft biopsies to establish the diagnosis of graft dysfunction as indicated by abnormal biochemical values. Low-grade rejection activity, and IPTH, could therefore persist and remain untreated at centers where protocol biopsies are not routinely performed.

Few long-term biopsy studies, however, other than Birmingham, discuss IPTH as an important clinical problem (Table 1). This is true even for those centers performing protocol biopsies.11–13 Even so, Rosenthal et al.13 lists “portal and lobular mononuclear inflammation” as being present in up to 50% of the pediatric recipients who undergo protocol liver biopsy obtained at 1 year of follow-up. Whether “portal and lobular mononuclear inflammation” or “nonspecific inflammation” at one center is diagnosed as “IPTH” at another center could certainly account for some of the differences. Nevertheless, it is difficult to conclude whether the Birmingham group is unnecessarily alerting the liver transplant community to the clinical significance of “IPTH,” or that other centers12, 13 that do not advocate long-term protocol biopsies are cavalierly ignoring the potential significance of “portal and lobular or nonspecific mononuclear inflammation.” The truth is probably somewhere in between. Idiopathic posttransplantation hepatitis is likely a more important problem than is currently recognized at many centers, but Birmingham might also be experiencing a center-specific effect. Our experience is that we do see occasional cases of IPTH, but most chronic hepatitis cases in long-term liver allograft recipients have an identifiable cause. We do not, however, routinely obtain protocol biopsies in asymptomatic long-term survivors with normal liver injury tests. Instead, we subject long-term survivors to biopsy if liver function abnormalities arise that are deviations from baseline for that particular patient.

What, then, could be the cause of IPTH, and why does it seem to be a more common and/or more serious issue in Birmingham? Evans et al.3 suggested that IPTH might represent a chronic hepatitic form of rejection, a contention reenforced by a return of long-term survivors to corticosteroid therapy. We would at least partially agree that this is the leading consideration. There are also cases of IPTH that would qualify for a diagnosis of centrilobular-based acute rejection14 or new-onset autoimmune hepatitis1, 3, 15 based on the histopathologic pattern of injury, autoantibodies, and increased serum gamma globulins. Other cases might also be attributable to as yet undiscovered transmissible agents or viruses. Hepatitis C accounted for a large number of cases of non-A, non-B hepatitis. Other proposed hepatotrophic viruses such as hepatitis G, GBV, and F have not stood the rigors of scientific scrutiny. Still, the possibility of other unidentified hepatotrophic viruses remains.

It is also possible that the early posttransplantation course, including the incidence and severity of acute rejection, could affect the long-term biopsy findings. Like all other immune responses, acute and especially chronic rejection reactions evolve over time and diversify by epitope spreading.16–18 Tissue damage during acute rejection can release cryptic antigens and trigger immunity directed against non–major histocompatibility complex (MHC) determinants. For example, donor livers contain many non-MHC proteins that are foreign to the recipient, including drug metabolizing enzymes and their isotypes.19, 20 Because many foreign non-MHC proteins are produced by hepatocytes, a “hepatitic” form of immunologic injury/rejection might then be expected.

Regardless, these studies from Birmingham certainly raise warning signs to the rest of the liver transplant community that should not be ignored. If a high percentage of long-term survivors after liver transplantation, especially children, develop IPTH, then a strong argument is made for closer follow-up, including performing protocol biopsies. However, additional studies should be undertaken before such a broad and potentially controversial recommendation can be made. First, more individual center studies are needed on the incidence, severity, and clinical consequences of IPTH to determine whether center-specific differences exist. Second, more studies are also needed to determine whether early and/or late immunosuppression management policies and early posttransplantation immunologic events influence long-term outcome and biopsy findings.

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