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Recurrent Hepatitis C After Transplantation
Complications of chronic hepatitis C, including cirrhosis and hepatocellular carcinoma, remain the most common indication for liver transplantation, accounting for nearly half of all liver transplants in the United States. However, this large group of transplant recipients faces a lower chance of long-term posttransplant survival than those transplanted for other indications. Recurrent hepatitis C is the most common cause of graft loss, which results in death or retransplantation. Although antiviral therapy has become increasingly effective in treating hepatitis C virus (HCV) infection in those with chronic hepatitis, its impact on posttransplant recurrence of infection is currently less than optimal.
Viral Recurrence
Recurrence of HCV infection is nearly universal in patients who are viremic at the time of liver transplantation. The apparent half-life of HCV during the anhepatic and reperfusion phases is shorter than observed in nontransplant patients with chronic hepatitis (half-life of approximately 2 hours). HCV RNA levels drop precipitously (1 log per hour) during the anhepatic phase of liver transplantation with an estimated half-life of 0.8 hours. This rapid rate of HCV decline is not surprising given the robust production and rapid clearance of 10 12 virions per day during normal viral steady-state replication and would predict loss of detectable viremia within 24 hours. Indeed, in one patient who remained anhepatic for 20 hours, virus became undetectable in the blood, although it subsequently reappeared after transplantation. HCV RNA levels continue to decline at a slower rate (half-life of 3.4 hours) for 12 to 24 hours after implantation of the allograft, presumably representing a combination of factors, including normal senescence and clearance of circulating virus, binding of virions to the hepatocytes (reinfection), and the initiation of replication in the allograft. The allograft is probably infected at reperfusion or within a few hours of implantation. The likely source is residual circulating virus, but some have proposed that an extrahepatic compartment may also play a role; this remains controversial and unproven. Viral levels begin to rise as early as 12 hours after implantation with a doubling time of approximately 2 days. In many recipients the HCV RNA level reaches the pretransplant level within just a few days, indicating the capacity of the virus to rapidly adapt to its environment. The adaptability of HCV to a new host liver is not surprising given the baseline diversity of quasispecies in the recipient at the time of transplantation and may result from selection of the viral variant(s) most compatible with the environment. Support for this theory comes from the observation of “bottlenecking,” or decrease in quasispecies diversity, seen shortly after liver transplantation. This bottlenecking may also explain the wide variability in the rate of virus replication (replicative efficiency) after transplant in different patients. Once infection is established, HCV RNA levels increase at an extremely rapid rate with a doubling time of 18 hours and reaching peak levels at or as much as 2 logs greater than pretransplant levels within just a few weeks. These early events are shown graphically in Figure 79-1 .
It is not clear why HCV replication increases so rapidly and to such high levels following liver transplantation. Possible explanations include exogenous immunosuppression, inability of the preexisting host immune response to the virus to respond to infection in the environment of a human leukocyte antigen (HLA) nonidentical allograft, or selection of highly replication competent viral quasispecies. Immunosuppression is typically most intense in the early days and weeks following transplantation. Impaired host innate immune response may blunt barriers to infection of the allograft and allow rapid infection of hepatocytes. Suppression of the adaptive host CD4 + and CD8 + T-cell responses to HCV, particularly with T-cell depleting therapy, might facilitate replication, if indeed these cells can even address infection in nonself hepatocytes. The variability in replication rates between patients is likely explained by these factors, as well as the affinity for the virus to the allograft hepatocyte receptors and the ability of the graft to support replication; these may be explained by both viral and host factors. Indeed, increased expression of occludin and claudin, both components of the hepatitis C virus receptor complex on hepatocytes, correlate with the rapid rise in HCV RNA following reanastomosis of the graft. The HCV RNA level in blood is only a surrogate of total viral load because the intrahepatic HCV levels are typically higher. It is not clear whether these early reinfection kinetics are predictive of the subsequent development of significant liver disease.
Recurrent Liver Disease
Clinical Presentation
HCV recurrence (viremia) is almost universal in patients who were viremic at the time of liver transplantation. Although many studies often report recurrence based upon biochemical evidence of liver injury, it is important to recognize that even histologically advanced recurrent liver disease can occur in the absence of elevated liver enzyme levels. Nonetheless, clinical evidence of recurrent hepatitis (abnormal liver enzyme levels) occurs in the majority of patients with recurrent HCV infection. Acute flares of the alanine aminotransferase (ALT) levels representing acute hepatitis C occur 4 to 12 weeks postoperatively in more than half of patients. Jaundice may be present in some cases. Recurrence should be confirmed histologically to eliminate other causes of liver injury such as rejection, cytomegalovirus infection, and hepatotoxicity from consideration. Distinguishing recurrent hepatitis C from acute cellular rejection or hepatotoxicity may be a challenge for the pathologist because many histological features of these can coexist. Patients with acute hepatitis C should be observed closely. The ALT level will decrease in most as they evolve into a more classic picture of chronic hepatitis. Antiviral treatment is usually not necessary at this point (see later).
Acute posttransplant hepatitis C should not be confused with fibrosing cholestatic hepatitis (FCH), which is uncommon, typically occurs later (mean, 7.6 months after transplant), and has distinct histological features, including cholestasis, ballooning, thin pericellular/sinusoidal fibrosis, and mild inflammation. FCH presents clinically with marked hyperbilirubinemia and elevated alkaline phosphatase level. In the absence of effective antiviral therapy, it almost inevitably leads to rapidly progressive hepatic failure, graft loss, and death. The incidence of FCH is 2% to 4%, though some small case series have suggested rates as high as 15%, which is clearly an overestimation of the risk. FCH may occur earlier after transplant in patients who receive livers from marginal donors or are more heavily immune suppressed, including recipients of multiorgan transplants. This may be consistent with the independent observation that FCH is more likely in those with very high viral loads in the initial weeks after transplant. Retransplantation is an option that may be considered, but it appears that most centers are reluctant to do so for fear of more rapid recurrence. There does not appear to be more than anecdotal experience to support this reluctance. Prompt initiation of antiviral therapy should be attempted regardless of how ill the patient is. Viral suppression is often associated with clinical improvement and survival. Rejection is common during treatment of FCH with interferon, occurring in as many as 60% of patients. Thus worsening liver test results despite a decline in viral load should suggest this possibility and prompt liver biopsy confirmation.
The most common presentation of recurrent hepatitis C is straightforward chronic hepatitis. Histological changes of chronic hepatitis are present in up to 84% of the grafts on which biopsy was performed 90 days after liver transplantation and in more than 90% by 1 year, though the majority of these have mild inflammation. Grade 3 inflammation is present in approximately 8% at 6 months, 18% at 1 year, and 35% after 2 years ( Fig. 79-2 ).
Natural History
The natural history of chronic hepatitis C in the transplanted liver is highly variable. However, overall the rate of progression of fibrosis is three to six times faster in transplant recipients. The chance of having bridging fibrosis (METAVIR stage F3) or cirrhosis (METAVIR stage F4) is 1%, 11%, 25%, and 41% after 1, 3, 5, and greater than 5 years, respectively (see Fig. 79-2 ). The median time to develop bridging fibrosis or cirrhosis is just 6 to 10 years compared to more than 30 years in immune competent persons. In one series 18% developed cirrhosis after a mean period of just 3.7 years. The mean rate of progression has been reported to be as high as 0.7 to 0.8 METAVIR units per year but is not necessarily linear over time. The rate of progression is related to the amount of inflammation present in the 1-year posttransplant liver biopsy specimen. If the liver biopsy results are normal (no inflammation), show mild inflammation, or show moderate-to-severe inflammation, the risk for cirrhosis at 5 years is 0, 7%, and 39%, respectively. Similarly, Klintmalm et al found that grade 2 or greater inflammation in the liver biopsy specimen 90 days after transplant was an independent predictor of stage 3 or 4 fibrosis by year 2. Progression is far more rapid in patients with persistently abnormal aminotransferase levels.
Patient and Graft Survival
Recurrence of hepatitis C after transplant decreases graft and patient survival ( Fig. 79-3 ). Only recipients transplanted for malignancy have a lower 5-year survival. Overall survival at 3 years is similar in HCV-positive and HCV-negative recipients (78% compared to 82%) but diverges thereafter and may be 10% to 15% lower after 7 to 10 years. Contrary to past reports, it now appears that survival has begun to improve in this cohort, perhaps because of better selection of HCV patients with hepatocellular carcinoma and the increasing use of antiviral therapy.
Survival at 1, 3, and 5 years after transplant among those who eventually progress to cirrhosis is 92%, 74%, and 62% compared to 96%, 96%, and 89% in patients without cirrhosis. This reflects the more rapid loss of hepatic function in patients with cirrhosis after transplantation as compared to nontransplant patients with chronic hepatitis C and cirrhosis. Hepatic decompensation occurs in 30% to 42% of transplant recipients within 1 year of developing cirrhosis as compared to a 3% to 4% annual risk in nontransplant patients. Furthermore, transplant recipients with decompensated cirrhosis do very poorly, with only half surviving the first year and only 20% surviving 2 years. In contrast, half of nontransplant patients with cirrhosis survive 5 years after their first manifestation of hepatic decompensation. Although graft failure represents less than 10% of deaths in all patients with HCV recurrence (sepsis is the most common cause of death), it accounts for about 45% of deaths in patients with advanced fibrosis.
The progression of recurrent disease appears to be more aggressive in the case of HCV and human immunodeficiency virus coinfection. As a result, 2- and 5-year patient survival rates are dramatically lower (73% and 51% versus 91% and 81% in monoinfected recipients).
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