Liver transplantation (LT) is the recommended treatment for patients who develop complications of end-stage liver disease (ESLD) and in those with significant decompensation secondary to acute liver injury. Autoimmune liver diseases account for approximately one quarter of all liver transplantations performed in Europe and the United States. Although these patients have an excellent survival rate, autoimmune liver disease can recur after LT. This review focuses on LT in the treatment of autoimmune liver diseases including autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis and the likelihood and treatment of recurrent disease.
There are many potential causes of abnormal liver tests in patients who undergo transplantation for autoimmune diseases of the liver. These causes may more commonly include cell-mediated rejection, drug toxicities, surgical complications including biliary strictures and vascular complications, or viral hepatitis (including cytomegalovirus, Epstein–Barr virus, or hepatitis B or C virus). Any posttransplantation patient demonstrating increased liver tests should complete an evaluation to include discontinuation (if possible) of any drugs likely to cause elevated liver tests and in particular any new medications started around the time of the liver test changes (including antibiotics, which can be a common cause of drug-induced liver injury). Use of over-the-counter medications and vitamins and homeopathic therapies should also be reviewed. It is recommended that viral serologies be repeated. In most instances, a liver biopsy is needed to help differentiate the cause of abnormal liver tests and in particular to exclude the potential of posttransplantation rejection. In rejection, there is typically a mixed inflammatory portal infiltrate with biliary ductal epithelial injury and endothelial inflammation. The inflammation is a more periportal inflammation than a lobular hepatitis, helping to distinguish rejection from other etiologies of liver inflammation, and from recurrence of primary disease. This is particularly important in diseases such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis, which can recur after liver transplantation.
Autoimmune hepatitis (AIH) occurs more commonly in women than in men and is characterized by the presence of circulating autoantibodies (antinuclear antibody, anti–smooth muscle antibody, and/or anti-liver–kidney microsomal antibody) and elevated serum immunoglobulin levels. Histologically, AIH is characterized by interface hepatitis with plasma cell infiltration. AIH accounts for ∼3% of all pediatric liver transplantations and 4%-6% of all adult liver transplantations. These transplantations may result after complications of chronic liver disease, the development of hepatocellular carcinoma (HCC), or as a result of severe acute AIH unresponsive to corticosteroid therapy. Overall outcomes after LT are excellent, with reported 5- and 10-year patient survival rates of 90% and 75%, respectively, and 1- and 5-year graft survival rates of 84% and 75%, respectively.
Although transplantation for AIH is very successful, recurrent disease is reported in 12%-46% of patients. Variability in the recurrence rate is likely related to whether or not protocol biopsies are performed. In these patients transplanted for AIH, their laboratory test results may not always reflect recurrent inflammatory changes, hence the presence of recurrent disease may only be established if protocol biopsies are performed; therefore, the reported incidence of recurrence may change depending on whether protocol biopsies are performed. The mean time to recurrence is 4.6 years. The diagnosis of recurrence of AIH is based on the presence of elevated aminotransferases, elevated immunoglobulin G levels, positive autoantibodies, and—importantly—findings on the histology of interface hepatitis (Fig. 1). There are no consistent predictors of recurrence of AIH; however, the disease is more likely to recur in patients who undergo transplantation for chronic liver disease rather than patients who undergo transplantation for acute fulminant liver disease. In addition, the presence of severe necroinflammatory activity in the native liver at time of LT is also a reported predictor of recurrence, as is the possession of HLA DR3 or DR4 by the recipient.
The treatment of recurrent AIH following LT is increased immunosuppression. This generally involves reintroduction or an increase in dose of corticosteroids. The addition of azathioprine or mycophenolate mofetil should be considered. There have been reports that conversion from tacrolimus to cyclosporin, or replacement of calcineurin inhibitor with sirolimus may be successful in treating more challenging cases. The key to successful management of recurrent AIH occurring following LT is early diagnosis and intervention. Responsiveness to increased immunosuppression, including the introduction or elevation of corticosteroids, and/or reintroduction of azathioprine or mycophenolate mofetil helps in establishing the diagnosis of recurrent AIH.
Primary Biliary Cirrhosis
Like AIH, primary biliary cirrhosis (PBC) most commonly occurs in women and is characterized by a serologic antimitochondrial antibody. PBC is characterized histologically by chronic destructive, nonsuppurative granulomatous, lymphocytic cholangitis of the small and medium-sized bile ducts. The natural history of PBC seems to be determined by the patient's response to ursodeoxycholic acid therapy at a dose of 13–15 mg/kg/day. It has been reported that those patients achieving at least a 40% reduction in alkaline phosphatase on therapy are less likely to develop disease progression. As a result, PBC has gone from being the most common indication for liver transplantation in the 1980s to the sixth most common etiology in 2006. Most patients will undergo LT when they have developed complications of ESLD or complications such as HCC. There is, however, a group of patients who will be considered for LT with well-preserved liver function who develop intractable symptoms, including pruritus and chronic fatigue. This latter group represents a controversial group of patients for consideration of LT, and in fact a published study has shown that the symptoms of fatigue characteristic of patients with PBC may not improve after LT. The outcome of LT in patients with PBC is excellent. In series reported from both the United Kingdom and United States, the patient 1-, 3-, and 5-year survival rates posttransplantation were 93%-94%, 90%-91%, and 82%-86%, respectively; graft survival in these patients at 1, 3, and 5 years was 85%, 83%, and 57%-81%, respectively. The 10-year patient and graft survivals have been reported at 67% and 61%, respectively.
The reported rate of recurrence of PBC posttransplantation is 21%-23% at 10 years and ≥43% at 15 years. The median time to recurrence is 3–5.5 years, although disease recurrence has been reported within 1 year of transplantation. The diagnosis of recurrent disease can be difficult. Many patients will retain autoantibodies (antimitochondrial antibody) even after transplantation. The diagnosis of recurrent disease, therefore, requires a liver biopsy with histologic features of portal inflammatory infiltrates, lymphoid aggregates, epitheliod granulomata, and bile duct damage (Fig. 2). There are no clear predictors of disease recurrence. Reports suggesting that HLA mismatch or choice of immunosuppression may have an impact are inconclusive.
The treatment of recurrent PBC is also controversial. There are reports of biochemical improvement with ursodeoxycholic acid therapy (15 mg/kg/day), but there is no evidence that it improves patient or graft survival or alters the natural history of disease recurrence. Interestingly, the impact of recurrence of disease posttransplantation is modest. The literature reports graft loss due to recurrent disease of only 1%-5.4%.
Primary Sclerosing Cholangitis
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis leading to biliary strictures (Fig. 3). Unlike the aforementioned autoimmune diseases, PSC is more common in men. It is not considered a classic autoimmune disease, though it seems to share many of the features of an immune-related disease. PSC is the fifth most common indication for LT in the United States. Patients with PSC may require LT after they develop complications of ESLD, develop cancer (both HCC and cholangiocarcinoma), or as a result of frequent cholangitis caused by biliary strictures. The 5-year patient and graft survival rates are 87.5% and 79.2%, respectively. Longer 10-year survivals of patients and grafts are 69.8% and 60.5%.
The risk of recurrence of PSC posttransplantation is 20% at 3 years and 37%-59% at 10 years. A diagnosis of recurrent PSC can be suggested on a liver biopsy; however, confirmation of disease is based on the findings of biliary strictures on MRI/MRC imaging, endoscopic biliary examination, or percutaneous biliary assessment. It can be difficult to distinguish biliary strictures from recurrent PSC versus strictures from other causes, such as anastomotic strictures or intrahepatic biliary ischemic changes seen in the setting of hepatic artery complications, or in donors procured after cardiac death (versus donors procured after brain death). The timing of the development of biliary complications can help distinguish recurrent PSC from biliary stricturing from other etiologies. The median time from LT to the development of biliary recurrent disease is ∼3–5 years. Most biliary complications from surgery would occur earlier after liver transplantation. It is not entirely clear why some patients develop recurrent PSC after LT, but some risk factors have been identified. Retrospective data suggest that the presence of steroid-resistant acute cellular rejection and donor or recipient HLA DRB1*08 are predictors of recurrent disease. There is no established therapy for patients with recurrent disease. The need for retransplantation for graft failure resulting from recurrent disease is significantly more common in PSC (12.4%) than in PBC (1%-5%). Retransplantation is a viable option for patients with recurrent disease, though more data are needed to understand the long-term survival rates in these patients.
Overall patient and graft survival is excellent for patients transplanted for complications of autoimmune liver disease, even in the setting of potential recurrent disease following LT.