Discussion
Reactivation of hepatitis B virus can cause serious liver damage. Therefore, it is recommended to check the HBV infection status before starting anticancer chemotherapy or immunotherapy and to continue monitoring for the presence or absence of reactivation thereafter1, 2. On the other hand, there are few reports of the reactivation of hepatitis C virus, and there are many unclear points about the pathophysiology. In this case, it is possible that chronic hepatitis C was acutely exacerbated due to endogenous cortisol secretion in Cushing’s syndrome. Although the definition of HCV reactivation has not been defined, several studies3, 4, 5 have defined an increase of HCVRNA of 1.0 log IU/ml or more as HCV reactivation. In addition, the definition of acute exacerbation of chronic hepatitis C is that ALT increases to more than three times the upper limit of the reference range3, 4, 6. Mahale et al. reported a retrospective study in which acute exacerbation of chronic hepatitis C due to cancer medication was seen in 11% of 308 patients3. Torres et al. also reported that, in a prospective study of 100 patients with cancer medication, HCV reactivation was found in 23%4. Given these reports, HCV reactivation potentially could occur quite frequently. However, Torres et al. reported that only 10% of all patients had acute exacerbations, none of which led to liver failure4. Such data suggest that HCV reactivation may often be overlooked in actual cases without aggravation. Thus, the frequency of aggravation due to hepatitis virus reactivation is thought to be lower for HCV than for HBV. However, there are some reports of deaths from acute exacerbation of chronic hepatitis C7-10. In addition, if severe hepatitis develops following viral reactivation, mortality rates have been reported to be similar for HBV and HCV8,11. Thus, reactivation of HCV is considered to be a pathological condition that requires caution, similar to HBV. Torres et al. reported that administration of rituximab or corticosteroids is a significant independent risk factor4. In addition, there are reports of acute exacerbation of chronic hepatitis C due to corticosteroids administered as antiemetics and as immunosuppressive therapy12, 13, 14. Therefore, excess cortisol can reactivate not only HBV but also HCV. The mechanism by which HCV is reactivated with cortisol is assumed to be decreased cell-mediated immunity due to rapid apoptosis of circulating T cells caused by steroids4, enhancement of HCV infectivity by upregulation of viral receptor expression on the hepatocyte surface15, and enhanced viral replication16. In addition, there is a report that genotype 2 is more common in cases with acute exacerbation of chronic hepatitis C4, 13, which is consistent with this case.
Regarding HBV reactivation due to Cushing’s syndrome, three cases of acute exacerbation of chronic hepatitis B have been reported17, 18, 19. It is believed that Cushing’s syndrome caused a decrease in cell-mediated immunity and humoral immunity due to an endogenous excess of cortisol, resulting in an acute exacerbation of chronic hepatitis B13. As described above, because an excess of cortisol can cause reactivation of HCV, it is considered that a decrease in immunocompetence due to Cushing’s syndrome, which is an excess of endogenous cortisol, can also cause reactivation of HCV and acute exacerbation of chronic hepatitis. However, as far as we can determine, no cases of Cushing’s syndrome causing HCV reactivation or acute exacerbation of chronic hepatitis C have been reported, and this is the first report. In addition, this case, in which good results were obtained by treatment with DAAs, is considered to be very helpful in deciding treatment policy. In the future, when liver damage appears in HCV-infected patients with Cushing’s syndrome, it will be necessary to distinguish the acute exacerbation and reactivation of chronic hepatitis C. Then, treatment with DAAs may be considered to be effective for reactivation of HCV and acute exacerbation of chronic hepatitis.