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