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.