Can my original disease recur in the new liver?

Liver transplantation was performed because your liver disease caused cirrhosis and later signs of liver failure such as variceal bleeding, ascites, or encephalopathy. In most cases this process takes years to occur. Many liver diseases—particularly inherited diseases such as hemochromatosis, Wilson’s disease, and alpha-1 antitrypsin deficiency—are cured by transplantation and therefore do not recur. Other diseases, such as alcoholic liver disease, do not recur as long as the recipient remains sober. Fatty liver disease, also known as nonalcoholic steatohepatitis, may not recur if the recipient maintains adequate weight and blood sugar control after transplantation.

Many of the common liver diseases are due to autoimmune processes. In other words, the immune system identifies the liver cells or bile ducts as foreign tissue and abnormal. It then tries to attack and eliminate the liver. This process results in slow but steady damage to liver and/or bile duct cells and can lead to cirrhosis. Examples of autoimmune liver diseases include autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and overlap syndrome. The pretransplant treatment of these conditions is difficult and may involve suppression of the immune system.

After transplantation, there is a risk—estimated to be 5% to 25%—that these autoimmune diseases may recur. Of course, there are also several reasons why the disease would not recur. After transplantation the patient takes immunosuppressive drugs, primarily to prevent rejection. Fortunately, these same drugs have a second benefit: They can be effective in controlling autoimmune diseases. A second reason for optimism regarding recurrence relates to the new liver’s genetics. Before transplantation the recipient’s immune system had recognized its own liver as foreign and developed specific antibodies to attack it. These antibodies may have been capable of recognizing only the native (recipient’s own) liver; as a consequence, they may not identify the new liver as foreign. These antibodies are not the same ones that might potentially cause rejection of the transplanted organ.

There are other, equally valid, reasons why the autoimmune disease might recur in the new liver. First, the antibodies developed for the native liver may, in fact, be able to recognize the new liver as foreign, starting the disease process all over again. Second, the immune system may develop new antibodies to attack the transplanted liver. Third, the transplant team and patient are usually motivated to reduce the immunosuppressive medications in an effort to limit the side effects; as a result, the autoimmune disease may become inadequately controlled by the medications. Finally, there may be other factors that we are not aware of that cause autoimmune diseases.

Recurrence of hepatitis C virus (HCV) disease in the transplanted organ occurs in all patients transplanted for HCV-related cirrhosis who still have the virus when they undergo transplantation. This virus is actually detectable in the bloodstream and the new liver as early as during the transplant operation. Typically, HCV-infected patients develop elevated liver enzymes and signs of an inflamed liver about 3 to 6 months after the transplant. Most of these patients have mild to moderate inflammation, minimal to mild scarring of the liver, and acceptable 1- and 5-year survival rates. Most can expect 10 to 20 years of good liver health before significant damage from HCV recurs. A smaller proportion of patients, perhaps 20% to 40%, develop a more rapid progression of HCV liver disease. These patients may develop signs of liver failure 5 to 10 years after the transplant. Even less common (affecting 1% to 5% of HCV-infected patients) is fibrosing cholestatic hepatitis, which can destroy the new liver within 1 year. At the present time we have not identified any pretransplant features that can predict with certainty which pathway any individual liver transplant recipient with HCV disease will follow.

Patients transplanted with known HCV are monitored in the usual posttransplant fashion. Some transplant programs schedule liver biopsies to occur at predetermined time intervals to get an idea of the rate at which inflammation and scarring are progressing. Other programs biopsy only those patients who develop abnormal liver blood tests. If the biopsy shows significant inflammation or scarring due to recurrent HCV, treatment is considered.

There are three approaches to treating hepatitis C recurrence after liver transplantation:

• Prophylaxis against hepatitis C is the administration of medications to protect the new liver from becoming infected with the virus. Unfortunately, no HCV antibody preparations effectively protect the new liver, so this approach is not possible.

• The preemptive approach calls for treatment of everyone with hepatitis C after transplantation, regardless of the timing or severity of the infection.

• Treatment of established recurrent disease is the most commonly applied option.

To date, no published study has compared preemptive therapy to treatment of established disease. In addition, no data suggest that early treatment during the first clinical signs of recurrent HCV disease influences the natural history of the disease. Based on the limited available data, the role for preemptive antiviral therapy remains to be defined.

A number of recent studies have reported that combination therapy with interferon and ribavirin is associated with a sustained virologic response (cure) rate of 20% to 30% in liver recipients with recurrent HCV disease; however, most of these studies were small. One major problem with these studies is the significant variability in the ways that patients were chosen for treatment and immunosuppression, making the interpretation of the results of these studies difficult. Nevertheless, the rate of sustained virologic response seems to be lower than the rate reported for nontransplant HCV patients. In addition, interferon/ribavirin therapy in liver recipients with recurrent HCV disease is associated with toxicity of the medications and side effects, leading to more frequent dose reductions and discontinuation of therapy.

In view of the many unknowns about the natural history of recurrent HCV disease, two approaches to treatment can be suggested. The first approach is to start treatment at the first evidence of acute graft injury (acute recurrent HCV disease), which typically occurs in the first 6 months after transplant. The second approach is to initiate treatment when the patient shows evidence of liver disease based on the results of a liver biopsy. Given that the results of treatment at these two time points, the tolerability of the treatment, and its effectiveness in improving the transplant recipient’s health are unknown, it is important to discuss these issues with your transplant team. Your transplant team may already have a preferred approach.

Many questions remain unanswered with regard to the treatment of post–liver transplant HCV disease, including the timing of treatment, the best treatment regimen, the most effective duration of therapy, and the role of immunosuppression in progressive recurrent HCV disease. Nevertheless, although no firm recommendations can be made, the research conducted to date suggests that a patient with recurrent HCV disease who has stage 2 or higher fibrosis should be considered for a trial of combination pegylated interferon/ribavirin therapy. Several ongoing studies are currently addressing these issues.