Cirrhosis after orthotopic liver transplantation in the absence of primary disease recurrence
Liver allograft cirrhosis is a relatively uncommon complication of liver transplantation. Most cases can be attributed to disease recurrence, particularly recurrent hepatitis C. Little is known about the frequency, etiology, and natural history of liver allograft cirrhosis occurring without evidence of recurrent disease. The aim of the present study was to review the clinicopathological features in this group of patients. We retrospectively reviewed data from all adult patients who were transplanted between 1982 and 2002 and survived >12 months after orthotopic liver transplantation (n = 1,287). Cases of histologically proven cirrhosis were identified from histopathological data entered into the Liver Unit Database. A total of 48 patients (3.7%) developed cirrhosis. In 29 of them, cirrhosis could be attributed to recurrent disease (hepatitis C, 11; hepatitis B, 4; autoimmune hepatitis, 4; primary biliary cirrhosis, 2; primary sclerosing cholangitis, 3; nonalcoholic steatohepatitis, 4; alcoholic liver disease, 1). In 9 of the 19 patients without evidence of disease recurrence, another cause of cirrhosis could be identified (de novo autoimmune hepatitis, 4; biliary complications, 4; acquired hepatitis B, 1). In the remaining 10 cases, the cause of cirrhosis remained unknown; their previous biopsies had shown features of chronic hepatitis of uncertain etiology. Three patients in this group died, and the remaining 7 are alive with good graft function 3–12 years after cirrhosis was first diagnosed. The prevalence of “cryptogenic” posttransplant cirrhosis was significantly higher in patients initially transplanted for fulminant seronegative hepatitis (6%) than in those transplanted for other diseases (0.3%). In conclusion, posttransplant cirrhosis without disease recurrence is uncommon, but it is more frequent in patients transplanted for fulminant seronegative hepatitis. Chronic hepatitis is the most frequent underlying pathological process in cases where the cause of cirrhosis remains uncertain. Liver Transpl, 2007. © 2007 AASLD.
With the increasing success of liver transplantation (LT) in overcoming perioperative challenges, the focus of transplant clinicians has moved from considering 1-year survival to assessing the long-term outlook.1, 2 Long-term survival is affected by many factors, including disease recurrence and the consequences of prolonged immunosuppression, including infection, malignancy, and cardiovascular disease. Late complications of liver transplantation may progress to cirrhosis and late graft failure and have therefore become an area of increasing concern.3 Most of the diseases for which transplantation is done in the adult population have the potential to recur,4 and recurrent disease is the most common cause of graft dysfunction in people surviving more than 12 months post-LT. By contrast, other complications such as rejection are much less common during this time than in the early posttransplant period.
Possible causes for cirrhosis in the liver allograft are recurrent or de novo primary liver disease and complications of liver transplantation itself. Recurrent disease is responsible for most cases of cirrhosis after LT.5 The most common cause is recurrent hepatitis C infection: Up to 50% of hepatitis C virus (HCV)-positive patients can be expected to develop cirrhosis within 10 years after transplant,6, 7 making recurrent HCV infection the leading indication for late retransplantation8 Other recurrent diseases less frequently associated with progression to cirrhosis in the liver allograft are hepatitis B virus (HBV) infection,9, 10 autoimmune diseases-primary biliary cirrhosis [PBC],11, 12 primary sclerosing cholangitis PSC,13–15 and autoimmune hepatitis (AIH),16 and fatty liver disease- both alcoholic17 and nonalcoholic.18, 19 Diseases arising de novo that have been associated with progression to cirrhosis include viral infection (both HBV and HCV20–23) de novo autoimmune hepatitis,24, 25 and nonalcoholic steatohepatitis.26 The main complication of liver transplantation itself that may lead to cirrhosis is ischemic cholangiopathy, which in some cases is associated with a biliary type of cirrhosis closely resembling sclerosing cholangitis.27 Although chronic rejection is not typically associated with fibrosis, some cases presenting late may be associated with fibrotic changes related to venous obliteration and/or ductular reaction.28
Studies of late posttransplant liver biopsies have shown that the majority (up to 70–90%) develop histological abnormalities.11, 23, 29–37 These abnormalities are commonly seen in protocol biopsies obtained from recipients who are clinically well with good graft function. The most common histological pattern of damage in late posttransplant biopsies is chronic hepatitis. The majority of cases of chronic hepatitis that are seen following liver transplantation can be attributed to viral or autoimmune disease, usually recurrent, sometimes acquired, with recurrent hepatitis C being the single most important cause. However, there remain a number of cases for which no obvious cause can be identified.2, 16, 38, 39 The incidence varies, but in our center, “idiopathic” chronic hepatitis is observed in approximately 40% of patients biopsied as part of routine annual review and is the most common histological diagnosis in this setting.2, 38 By a process of exclusion, it has been suggested that some of these cases may represent a form of late cellular rejection.40, 41 This suggestion is supported by the observation that that late cellular rejection may have features different from those typically seen in early acute rejection and may more closely resemble chronic viral or autoimmune hepatitis.30, 42–44 A recent study showed that chronic hepatitis, unrelated to disease recurrence, is a common finding in protocol biopsies from pediatric liver allograft recipients.40 More than 60% of the children studied had developed chronic hepatitis 10 years posttransplant, and 50% of those with chronic hepatitis had progressed to bridging fibrosis or cirrhosis by 10 years. However, the extent to which “idiopathic” chronic hepatitis causes progressive liver damage in the adult population is uncertain.
We have observed progressive liver damage resulting in cirrhosis in adult liver transplant recipients who do not have recurrence of their primary disease in their grafts. The clinicopathological features of this group of patients have been further investigated and form the basis for the study presented here.
PATIENTS AND METHODS
Between January 1982 and December 2002, 1,647 adult patients underwent orthotopic liver transplantation at the Liver Unit, Queen Elizabeth Hospital, Birmingham, UK. A total of 1,287 had survived more than 12 months posttransplantation. Until 1996, protocol biopsies were obtained annually for the first 5 years and at year 10. Thereafter, with the exception of those grafted for HCV infection who still underwent annual biopsy, protocol biopsies were carried out at year 1 and then at 3-year intervals. Biopsies were also taken when clinically indicated.
Cases of histologically proven cirrhosis after LT were identified from the Liver Unit database. Those who developed liver allograft cirrhosis were assessed with regard to their pretransplant diagnosis and clinical and other laboratory findings during follow-up to identify possible causes of cirrhosis and its clinical impact. The evaluation included clinical and demographic features of recipients, indication for LT, age, gender, race, body mass index, cytomegalovirus status, cold ischemia time, warm ischemia time, and immunosuppressive regimen. Laboratory investigations included biochemical, serological, immunological, and histological studies.
Histological assessment of those who developed graft cirrhosis included a review of all other biopsies obtained more than 12 months posttransplant. Biopsies were assessed using a standard protocol in which a range of histological features are evaluated and graded semiquantitatively.40, 45 In biopsies showing features of chronic hepatitis, the severity of necroinflammatory activity in portal/periportal regions and the liver parenchyma was graded semiquantitatively and combined to produce an overall inflammation grade of 1 (mild), 2 (moderate), and 3 (severe). Fibrosis was assessed separately and defined as mild (stage 1) when periportal fibrosis was present without bridging, moderate (stage 2) if there was bridging fibrosis (portal-portal or portal-central) without nodule formation, and severe (stage 3) if cirrhosis was present.
Disease recurrence was diagnosed on the basis of an appropriate pretransplant diagnosis in conjunction with compatible posttransplant biochemical, virological, serological, radiological, and histological findings as follows:
Exhibits histological features characterized by portal tract lesions (mononuclear inflammatory cell infiltrate, lymphoid aggregates, epithelioid granulomas, and bile duct damage/loss)11, 46 and positive antimitochondrial antibodies, with or without a cholestatic liver profile.
Characterized by biochemical changes (increased aminotransferase levels), positive autoantibodies, hypergammaglobulinemia, response to corticosteroids, and histological features (including portal inflammation with plasma cells and interface activity).16, 47
Features cholangiographic changes of nonanastomotic biliary strictures and dilatation in the absence of other causes, and histological criteria (features of chronic biliary disease including fibrous cholangitis).13, 48
Hepatitis C infection.
Biochemical (increased aminotransferase levels) and histological (portal and lobular infiltrate) hepatitis, with positive HCV RNA in serum and/or liver.49
Hepatitis B infection.
Biochemical (increased aminotransferase levels) and histological (portal and lobular infiltrate) hepatitis, with immunohistochemical evidence of hepatitis B surface antigen and hepatitis B core antigen in liver biopsy specimens and HBV DNA in serum.50
Alcoholic and nonalcoholic steatohepatitis.
Exhibits histological features of steatosis or steatohepatitis (hepatocyte ballooning, Mallory bodies, mixed inflammatory cell infiltrate with or without pericellular fibrosis)51 with a clinical history of excess alcohol consumption post-LT or risk factors for nonalcoholic fatty liver disease.
Standard immunosuppression was based on triple therapy with a calcineurin inhibitor, azathioprine, and corticosteroids. Until 1995, cyclosporin A was used (Novartis Pharmaceuticals UK Ltd., Frimley, Surrey, England) and was administered intravenously until the patient was able to take the drug by mouth. The dose was adjusted to maintain trough whole blood levels between 150 and 200 ng/mL in the first 3 months and 100 to 150 ng/mL thereafter. In addition, all patients received prednisolone (20 mg/day) for 3 months and azathioprine (1–2 mg/kg/d, with the dose adjusted according to white cell count). Corticosteroids were gradually withdrawn over 3 months, except in patients grafted for autoimmune hepatitis where steroids were maintained for at least 1 year at a dose of prednisolone 5–7.5 mg/day. Tacrolimus (Prograf, Fujisawa Ltd., London, England) was instituted in the early 1990s for patients unable to tolerate cyclosporin or with late acute allograft rejection, and since 2000 it has been the primary immunosuppressive drug. In the study group, all patients but 1 (on tacrolimus) were started on a cyclosporin-based regimen.
Data were analyzed using SPSS ver. 10 (SPSSUK, Woking, Surrey, UK). Medians and ranges were calculated for continuous variables. Categorical data were compared using the Fisher exact test.
The indications for liver transplantation in 1,287 adult patients who survived more than 12 months during the study period are listed in Table 1. Autoimmune liver diseases (PBC, PSC, AIH; n = 624, or 48%) were the major indications. The diagnosis of seronegative fulminant hepatic failure (FHF), was based on the absence of clinical or pathological features of chronic liver disease, negative serological testing for viruses and autoantibodies, and the exclusion of other causes of liver damage at time of LT.45
Table 1. Indications for Liver Transplantation in 1,287 Patients Who Survived >12 Months Following Liver Transplantation
|Primary biliary cirrhosis||398|
|Primary sclerosing cholangitis||145|
|Hepatitis C virus||129|
|Alcoholic liver disease||122|
|Seronegative fulminant hepatic failure||99|
A total of 48 patients (3.7%) were found to have graft cirrhosis. In 29 of them, cirrhosis could be attributed to recurrence of the original disease in the allograft (Table 2). In the remaining 19 patients, there was no evidence of primary disease recurrence. In 9 of these patients, another cause of cirrhosis could be identified. For the remaining 10 cases, the cause of cirrhosis was unknown. The distribution of causes of cirrhosis unrelated to disease recurrence in relation to the original disease for which transplantation was carried out is summarized in Table 3. Further details relating to these 19 patients are as follows:
Table 2. Causes of Liver Allograft Cirrhosis in Patients Who Survived >12 Months Following Liver Transplantation
| Hepatitis C||11|
| Hepatitis B||4|
| Autoimmune hepatitis||4|
| Primary biliary cirrhosis||2|
| Primary sclerosing cholangitis||3|
| Nonalcoholic steatohepatitis||4|
| Alcoholic liver disease||1|
|Acquired (de novo) disease/other transplant complications||9|
| Autoimmune hepatitis||4|
| Biliary complications||4|
| Hepatitis B||1|
Table 3. Causes of Cirrhosis Compared With Original Indication for Liver Transplantation in 19 Patients Who Developed Liver Allograft Cirrhosis Not Obviously Related to Primary Disease Recurrence
|Seronegative fulminant hepatic failure n = 10 (9.5%)||3||1||–||6|
|Primary biliary cirrhosis n = 5 (1.3%)||–||2||–||3|
|Primary sclerosing cholangitis n = 1 (1.5%)||–||–||–||1|
|A1pha-1 antitrypsin deficiency n = 1 (1.3%)||–||1||–||–|
|Cryptogenic cirrhosis n = 1 (1.4%)||1||–||–||–|
|Autoimmune hepatitis n = 1 (1.2%)||–||–||1||–|
De novo AIH.
De novo AIH was found in 4 patients (2 female, 2 male): median aspartate aminotransferase was 77 IU/L (range, 24–376; upper limit of normal, 43 IU/L); the median serum immunoglobulin G was 38 g/L (range, 30.9–67.2 g/L; upper limit of normal 16 g/L); autoantibodies present were antinuclear antibodies at a titre ≥1:400 in 3 patients; and liver-kidney microsomal-1 (LKM-1) antibodies (titre >1:1,600) were present in the fourth patient. Liver histology showed chronic hepatitis with at least moderate interface hepatitis in all 4 cases. Indications for liver transplantation were PBC (n = 2), seronegative FHF (n = 1), and alpha-1 antitrypsin deficiency (n = 1). The median time to cirrhosis was 72 months (range, 12–168). One patient developed signs of decompensation, but none died or required re-LT.
Four patients (3 female, 1 male) developed graft cirrhosis secondary to biliary complications at a median of 60 months (range, 18–120). Two patients had radiologically confirmed anastomotic strictures, with biochemical and histopathological features consistent with chronic biliary disease. Both of them are clinically well without interventions. The other 2 patients underwent retransplantation, 1 for ischemic cholangiopathy, and the other for chronic intractable cholestasis following acquired hepatitis A, which induced aplastic anaemia complicated with severe transfusion siderosis. Of the 2 patients who underwent retransplantation, 1 subsequently died due to chronic rejection.
Acquired hepatitis B.
One male patient, initially transplanted for AIH, was found to have HBV infection in a liver biopsy obtained 45 months following retransplantation for chronic rejection. This biopsy also showed extensive fibrosis amounting to established cirrhosis. HBV serology was negative prior to transplantation. No HBV antigens were detectable in earlier biopsies obtained during the first 3 months post-LT, and the source of HBV infection was uncertain. This patient is currently alive and well with good graft function.
Cause of cirrhosis unknown.
In the remaining 10 patients (7 females and 3 males), who developed graft cirrhosis at a median of 84 (range, 14–166) months post-LT, no etiological factor was identified. In all 10 cases, previous follow-up biopsies had shown histological features of chronic hepatitis. The histopathological changes seen in biopsies obtained >12 months from these 10 patients are summarized in Table 4. The incidence of cirrhosis evolving from chronic hepatitis was significantly higher in seronegative FHF (6% compared with 0.3% in other diseases) (P < 0.001).
Table 4. Histopathological Findings in Biopsies obtained >12 Months Posttransplant and Final Outcome in 10 Patients Who Developed Cirrhosis of Unknown Cause
|1||PBC||144||3||3|| ||Active cirrhosis (Well with normal LFTs, 24 years post-LT)|
|2||PBC. Retransplant at 3 months for chronic rejection||21||2||2/3||Mild ductopenia, ductular reaction.||CH (moderate) and early cirrhosis.|
|43||2||3||Bile ducts normal, no ductular reaction.||Active cirrhosis (died from fungal sepsis 5 years post-LT).|
|3||PBC||12||2||3||–||CH (moderate) and probable cirrhosis.|
| || ||22||2||3||Mild ductular reaction, scanty CAP deposits.||CH (moderate) and probable cirrhosis.|
| || ||35||2||3||Mild ductular reaction, CAP deposits.||Active cirrhosis (died from septic shock, 8 years post-LT).|
|4||PSC. Retransplant at 1 month for HAT||12||2||1||Zone 3 necroinflammation.||CH (moderate).|
| || ||24||2||1||Zone 3 necroinflammation.||CH (moderate).|
| || ||78||2||1||Mild ductular reaction. No CAP||CH (moderate).|
| || ||114||2||3|| ||CH (moderate) and early cirrhosis.|
| || ||151||2||3|| ||CH (moderate) and cirrhosis (raised alkaline phosphatase,? cause. Otherwise well 14 years post-LT).|
|5||Seronegative FHF||12||0||1||Mild ductular reaction; scanty CAP deposits.||Low-grade biliary features; ?cause.|
| || ||24||1||1||Mild steatosis; biliary features no longer conspicuous.||CH (mild).|
| || ||51||1||2||Mild fatty change; septal fibrosis.||CH (mild).|
| || ||77||1||2||Mild steatosis; scanty CAP deposits.||CH (mild).|
| || ||103||2||3||Mild steatosis; scanty CAP deposits.||CH (moderate) and probable cirrhosis (died from graft failure 12 years post-LT).|
|6||Seronegative FHF||14||0||1||Marginal ductular reaction.||Low-grade biliary features; ?cause.|
| || ||24||1||1||–||CH (mild).|
| || ||49||1||2||–||CH (mild).|
| || ||59||1||1||–||CH (mild).|
| || ||166||1||3|| ||CH (mild) and probable cirrhosis (well with normal LFTs, 17 years post-LT).|
|7||Seronegative FHF||12||0||1||Cholestasis, marginal ductular reaction.||Low-grade biliary obstruction.|
| || ||23||1||1||Biliary features no longer conspicuous.||CH (mild).|
| || ||35||1||1||–||CH (mild).|
| || ||48||3||2||Bridging necrosis.||CH (severe).|
| || ||120||1||3|| ||CH (mild) and probable cirrhosis (raised alkaline phosphatase,?cause. Otherwise well 15 years post-LT)|
|8||Seronegative FHF||16||1||2||–||CH (mild).|
| || ||46||1||3||–||CH (mild) and probable cirrhosis (well with normal LFTs 7.5 years post-LT)|
|9||Seronegative FHF||14||1||0||Mild sinusoidal dilatation and congestion.||CH (mild) and congestion; ?cause.|
| || ||26||1||3||Congestive changes no longer present.||CH (mild) and probable cirrhosis (well with normal LFTs, 6 years post-LT).|
|10||Seronegative FHF||14||2||2||Confluent perivenular necrosis.||CH (moderate).|
| || ||24||3||2/3||Panacinar necrosis with postnecrotic collapse.||CH (severe) with early postnecrotic cirrhosis.|
| || ||46||1||3|| ||CH (mild) and cirrhosis.|
| || ||69||1||2/3||Ductular reaction, small amounts of CAP.||CH (mild) and early cirrhosis, biliary features; ?cause.|
| || ||91||1||3||Bilirubinostasis, ductular reaction.||CH (mild) and cirrhosis, biliary features; ? cause (clinically well 9.5 years post-LT. LFTs abnormal: AST 3× normal, alkaline phosphatase 3× normal, bilirubin 5× normal).|
Histological features of chronic hepatitis were characterized by predominantly portal-based mononuclear inflammation associated with interface hepatitis. Varying degrees of lobular inflammation with hepatocyte necrosis or apoptosis were also frequently present. The diagnosis of chronic hepatitis also required that bile duct lesions or vascular changes characteristic of acute or chronic rejection were minimal or absent.40, 45 Likewise, in the patients transplanted for PBC or PSC, there were no bile duct lesions or other features to suggest disease recurrence. In 7 of the 10 patients who developed cirrhosis of unknown origin, biliary features were also noted. These features were mild, usually transient, and not associated with significant biochemical cholestasis or other features suggesting a biliary problem. The overall features in all 10 cases were thus considered to be predominantly those of a chronic hepatitic process, with progressive periportal fibrosis leading to cirrhosis.
Two patterns of disease progression were seen among the 6 patients initially transplanted for seronegative FHF. The first 3 patients (5,6, and 7 in Table 4) were young (≤21 years old at the time of transplant) and had received at least 1 bolus of high-dose corticosteroids for episodes of acute cellular rejection occurring during the first month, with the subsequent development of cirrhosis at 108, 120, and 166 months post-LT. The other 3 patients (8,9, and 10 in Table 4) were older (age at time of transplant 49–52 years), with no antecedent rejection episodes, and had developed cirrhosis at 26, 46, and 48 months after LT. One patient died from graft failure 12 years following LT. Currently, 4 other patients are well with good graft function at intervals ranging from 38 to 65 months after cirrhosis was first diagnosed. The sixth patient is currently well clinically, 67 months after cirrhosis was first diagnosed, but with abnormal liver biochemistry.
Three female patients transplanted for PBC with unexplained chronic hepatitis in their grafts developed cirrhosis, 12, 21, and 144 months after transplantation. Of the 3 PBC patients, 2 died from infective complications at 5 and 8 years' post-LT. The other is currently alive and well with normal LFTs, 24 years post-transplant. One patient initially transplanted for PSC had cirrhosis 10 years post-retransplantation for hepatic artery thrombosis. This patient is currently alive and well 4 years later.
Measurements of serum autoantibodies and immunoglobulins were carried out on at least 1 occasion for 5 of the 10 patients in this group (patients 1, 5, and 8–10 in Table 4). One patient transplanted for PBC became AMA positive, but tests for all other autoantibodies were negative and serum immunoglobulin G levels were normal.
For 8 of the 10 patients in this group (patients 1–7 and 10 in Table 4), treatment with low-dose corticosteroids was recommenced following a histological diagnosis of chronic hepatitis. In all 8 patients treated with steroids, the liver biopsy obtained prior to treatment showed at least moderate inflammatory activity. In 6 of the 8 pretreatment biopsies, there was early or established cirrhosis.
We report an uncommon form of allograft cirrhosis with no evidence of disease recurrence in 19 (1.5%) of 1,287 adult patients who survived more than 12 months post-LT during a 20-year period. In 9, a potentially treatable or preventable cause could be identified. The etiology of cirrhosis in the remaining 10 cases is uncertain.
De novo AIH is more common in the pediatric population, possibly related to immunosuppressive drugs interfering with normal T-cell maturation,25, 52–55 but it has also been described in adults.24, 56, 57 Early diagnosis is important, since treatment, if initiated promptly, is often successful.25 However, some patients have a more aggressive course leading to cirrhosis or graft failure. We identified 4 patients with de novo AIH, 2 of whom had been transplanted for PBC, which appears to be the most common underlying disease when de novo AIH develops in adults. One patient had type 2 AIH with high titres of LKM-1, noninsulin-dependent diabetes mellitus, and thyrotoxicosis. The immunosuppressive regimen was modified by increasing the dosage or adding corticosteroids. None of these patients died or developed graft failure.
Biliary tract complications after LT are a heterogeneous group with multifactorial etiologies.58, 59 Ischemic biliary strictures due to vascular compromise typically show features of biliary obstruction; however, the histological changes are often patchy in distribution.38 They are more difficult to manage and more frequently require surgical correction or retransplantation.60 We observed graft loss 4 years post-LT necessitating retransplantation in 1 patient. Radiological features of biliary outflow obstruction (anastomotic strictures) caused biliary cirrhosis in 2 patients (1.5 and 10 years post-LT), without adverse effect on patient or graft survival.
In our series, all 10 patients with cirrhosis of unknown etiology had previous biopsies showing unexplained chronic hepatitis. This sequence of events occurred significantly more frequently (6%) in the seronegative FHF group than in the group with other diseases (0.3%). These findings confirm an earlier report from our center in which a higher incidence of chronic hepatitis was observed in patients transplanted for fulminant seronegative hepatitis than in those transplanted for acute liver failure of other causes.45 Three of 41 patients in the earlier study had progressed to cirrhosis, a prevalence similar to that of cirrhosis among patients transplanted for seronegative FHF (9.5%) in the current study. The high frequency of chronic hepatitis and fibrosis post-LT in seronegative FHF raises the possibility of the recurrence of a disease process, the etiology of which remains elusive.45 Previous reports have suggested that an autoimmune-related61 or a viral-related process62 may be the cause.
Some of the cases of unexplained chronic hepatitis with cirrhosis described herein may represent a form of late cellular rejection. Previous studies have suggested that late rejection may be associated with histological changes that are different from those seen in early acute rejection and more closely resemble those occurring in chronic viral or autoimmune hepatitis30, 42–44 A recent study of late protocol post-LT biopsies in children showed a strong association between the presence of unexplained chronic hepatitis and the development of autoantibodies.40 However, only a minority of those with autoantibody-positive chronic hepatitis fulfilled the diagnostic criteria for de novo autoimmune hepatitis. These observations raise questions regarding the relationship between rejection and so-called de novo autoimmune hepatitis and the criteria that should be used to diagnose these 2 conditions. Routine testing for autoantibodies was not carried out as part of the present study. However, among the 10 patients who developed cirrhosis complicating unexplained chronic hepatitis, the 5 patients who had an autoantibody screen were all negative. A larger study is required to determine the prevalence and clinicopathological significance of autoantibodies developing de novo in adults with unexplained posttransplant chronic hepatitis.
A higher frequency of chronic hepatitis (without typical bile duct lesions) has been observed in late posttransplant biopsies from PBC and PSC patients than in those from patients transplanted for diseases not recurring or not associated with chronic hepatitis.38 Four patients reported herein, who were transplanted for PBC and PSC, developed cirrhosis of uncertain etiology on a histological background of chronic hepatitis. None had bile duct lesions or other biliary features to suggest recurrent disease. It is nevertheless possible that the chronic hepatitis seen in these cases may represent an atypical form of recurrent disease in which the classical histological abnormalities or other diagnostic features are lacking.
It is important to establish an etiological diagnosis of unexplained posttransplant histological abnormalities, especially in patients who are clinically asymptomatic with good graft function, to highlight possible therapeutic options. Assuming that most cases of posttransplant chronic hepatitis, excluding viral causes, have an underlying immune basis (recurrent and de-novo AIH, late rejection with atypical features), additional immunosuppression may be justified in those cases where a viral etiology can be clearly excluded. Although corticosteroid therapy was given to 8 of the 10 patients who developed cirrhosis as a complication of unexplained chronic hepatitis, 6 of the patients were already cirrhotic by the time that steroid therapy began. Further prospective studies are required to determine the role of immunosuppression in treatment of chronic hepatitis presenting at an earlier stage.
In conclusion, posttransplant cirrhosis is relatively uncommon, at least in the first decade after transplantation. The majority of cases are increasingly likely to be related to recurrent disease, particularly recurrent HCV infection. However, in our study, approximately 40% of all cases could not be ascribed to recurrent disease, and in half of these cases no other obvious cause could be identified. Chronic hepatitis is the most frequent underlying pathological process in cases where the cause of cirrhosis remains uncertain. The long-term follow-up of unexplained chronic hepatitis remains to be evaluated thoroughly to highlight potentially reversible and treatable processes. Routine histological assessment, especially in centers where viral-related end-stage liver diseases are not the main indications for liver transplantation, should therefore still be recommended.