5. DISCUSSION
Dapsone is completely absorbed from the gut after its oral
administration and then undergoes extensive biotransformation in the
liver mainly by N-acetylation and N-hydroxylation. During
biotransformation in liver microsomes, dapsone gets converted into
DDS-hydroxylamine (DDS-NOH). The highly reactive hepatotoxic metabolite
of DDS which is DDS-NOH intermediate reportedly induces in oxidative
stress in the liver causing several side effects, including hemolytic
anemia, agranulocytosis, and methemoglobinemia including liver injury
which includes hepatic necrosis, cholestasis, hepatitis, granulomatous
cholestatic hepatitis etc. The liver was the most common extra
dermatologic organ involved in DHS. Mixed hepatitis is the most common
pattern of liver injury.4-6 It has been reported that
hepatic involvement is seen in the early stages of leprosy itself. The
presence of hepatotoxic drugs like rifampicin and other anti-tubercular
drugs may aggravate dapsone-induced liver toxicity in these
patients.1 Dapsone induced hepatitis (DIH) is
typically classified as either direct or idiosyncratic. Idiosyncratic
hepatotoxicity is caused by agents that have little intrinsic toxicity
which causes liver injury only in rare cases. DHS is a severe
idiosyncratic adverse reaction with multi-organ
involvement.3 Direct hepatotoxicity is caused by the
agents that are intrinsically toxic to the liver. The injury caused by
the agent that induces direct hepatotoxicity is common, predictable,
dose-dependent, and reproducible.1 Blood sulfone
levels >2 mg/dl correlate with greater probability of liver
damage, suggesting an intrinsic hepatotoxic effect. Both cholestatic and
hepato-cellular reactions occur, but cholestasisis is the commonest form
of injury.2 The hyperbilirubinemia present in dapsone
syndrome may partly be due to hemolysis in addition to hepatotoxicity.
DIH occurs mostly within the first 4 to 6 weeks of therapy and shows 2
distinctive subtypes: the vast majority (90%) are associated with DHS,
and a minority (10%) that lack DHS. DIH can vary from mild (which
resolves with discontinuation of drug alone) to severe liver injury
including acute liver failure and death. Features that characterize DHS
such as skin reactions, fever, lymphadenopathy, and eosinophilia tend to
overshadow features of liver injury and probably have contributed to
under-recognition of hepatitis and an underestimation of its
severity.5 The temporal relationship between dapsone
therapy and onset of clinical symptoms and objective data led us to
believe that dapsone induced hepatitis in our patient. Mucosal
involvement, hepatitis, higher age, and disease occurrence in resource
poor settings were associated with a higher risk for a fatal outcome,
with an overall fatality of 9.9%.3 Liver failure was
the most frequent cause of death. Other reasons for death were mostly
due to drug reactions such as shock, lung failure and bone marrow
failure.3-4 The best approach to DHS is immediate
discontinuation of the drug and prompt administration of oral or
intravenous glucocorticoid pulse therapy. Some studies showed steroids
leading to faster recovery and lower mortality than those not receiving
steroids. Glucocorticoids are recommended with or without internal organ
involvement. If used, glucocorticoids should be tapered gradually over
one month, as dapsone avidly binds to proteins up to 35 days. Complete
resolution of symptoms and laboratory abnormalities usually occurs with
cessation of dapsone therapy.4,5,7 Laboratory
monitoring should be frequently performed during treatment, including
complete blood counts and liver function tests. Continuation with
dapsone should not be undertaken in these patients and patients must be
informed that they are allergic to sulfa drugs.3