Faculty Bibliography

Leishmaniasis, a protozoal infection transmitted by sandfly bite, produces a clinical spectrum of disease ranging from asymptomatic infection to ulcerative skin and mucosal lesions to visceral involvement. Leishmaniasis is endemic in regions of Africa, the Middle East, south Asia, southern Europe, northern South America, and Central America. There has been an increase in imported leishmaniasis into developed, non-endemic countries due to increasing global travel. While pentavalent antimonials have been the mainstay of antileishmanial treatment for decades, newer therapeutic options have become available for all forms of infection, including liposomal amphotericin B, miltefosine, fluconazole, and ketoconazole. For the returning traveler with cutaneous leishmaniasis in the USA, treatment approaches are determined based on infecting species, initial presentation, extent and progression of disease, the advantages and drawbacks of available parenteral and oral drugs, and clinician-consultant experience.

LEARNING OBJECTIVE 1: Recognize and distinguish the clinical features of drug-induced hepatitis from other etiologies of hepatitis LEARNING OBJECTIVE 2: Manage acute drug-incuded hepatitis with concomitant hepatitis C infection CASE: A 61 year-old Hispanic female presented with jaundice, dark urine and progressive fatigue of three weeks duration. The patient presented to her primary care physician three weeks prior to admission with bloating and early satiety, and was started on rabeprazole 20 mg daily. After one week, blood tests were drawn which were notable for an AST/ ALT of 1680/1123 u/L, alkaline phosphatase of 283 u/L, and total bilirubin of 1.7 mg/dL. The patient subsequently noted worsening abdominal discomfort, fatigue and jaundice. She was referred for an endoscopy that demonstrated severe gastritis. The patient was then prescribed omeprazole 40 mg daily and ranitidine 20 mg daily, with discontinuation of rabeprazole. Due to progression of her symptoms the patient presented to our hospital where she was found to have an AST/ALT of 3423/1620 u/L, alkaline phosphatase of 269 u/L, total bilirubin 10 mg/dL, and a direct bilirubin 6mg/dL. Physical exam was significant for jaundice, icteric sclera, and mild right upper quadrant pain. A CAT scan of the abdomen and pelvis demonstrated several small hepatic cysts, but was otherwise normal. The patient's medications including omeprazole were held, and her hepatic enzymes subsequently improved, which was suggestive of a diagnosis of drug-induced hepatitis. In addition, workup of the patient's liver function abnormalities revealed a positive hepatitis C antibody and viral load of 7x 10 6 copies/mL. Due to suspicion of acute hepatitis C versus drug-induced hepatitis, a liver biopsy was performed which was significant for acute drug induced hepatitis intermixed with elements of chronic hepatitis C. DISCUSSION: In cases of acute hepatitis of unclear etiology, medications should always be considered as possible culprits and reviewed thoroughly. Alth!

INTRODUCTION: Classical Hodgkin's Lymphoma (cHL) has been frequently associated with Epstein-Barr virus (EBV), which can be found in a latent pattern in Reed-Sternberg (RS) cells. However, the impact of the presence of EBV in RS cells and its prognosis are still controversial. We analysed the presence of EBV in RS cells and its influence in the clinical evolution of patients with cHL treated in two public hospitals in the city of Sao Paulo, Brazil. MATERIALS AND METHODS: We selected 97 patients with cHL from 1994 to 2004. Patients were only included in this study if they had (1) >18 years, (2) negative HIV serology, (3) undergone similar chemotherapy protocols, (4) paraffin blocks available with enough material for systematic review and histological reclassification and for detection of EBV in RS cells by in situ hybridization and immunohistochemistry and (5) clinical, epidemiological and laboratorial parameters available after a thorough chart review. RESULTS: EBV was identified in 52.5% of the cases. Mixed cellularity (MC) subtype was more common in EBV-related tumours (25.5%) (p=0.005). There was no difference on age, gender, stage and the presence of B symptoms between the two groups. The presence of EBV did not influence event free survival (EFS) (p=0.38) or overall survival (OS) (p=0.80) with a median follow-up of 80 months. CONCLUSION: We demonstrate that the prevalence of EBV-related cHL in this Brazilian population is 52.5% and, that, the presence of EBV does not change the clinical evolution and OS of patients treated with similar chemotherapy protocols.

Drug-induced hepatitis remains a challenging problem for drug development and safety because of the lack of animal models. In the current work, we discovered a unique interaction that makes mice deficient in both IL-10 and IL-4 (IL-10/4-/-) highly sensitive to the hepatotoxic effects of acetaminophen (APAP). Male C57Bl/6 wild type (WT) and mice deficient in one or more cytokines were treated with 120 mg/kg APAP. Within 24 h after WT, IL-10-/-, IL-4-/-, or IL-10/4-/- mice were administered APAP, 75% of the IL-10/4-/- mice died of massive hepatic injury while all other genotypes were resistant to liver toxicity at this dose of APAP. The unique susceptibility of IL-10/4-/- mice was associated with reduced levels of liver glutathione and remarkably high serum levels of IL-6 and several proinflammatory factors including TNF-alpha, IFN-gamma, macrophage inflammatory protein-1alpha (MIP-1alpha), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), and osteopontin (OPN) as well as nitric oxide (NO). IL-6 appeared to have a causal role in controlling the unique susceptibility of IL-10/4-/- mice to APAP-induced liver disease (AILD) because IL-6 neutralizing antibody reversed the high sensitivity of these mice to AILD. Moreover, IL-10/4/6-/- mice were also resistant to the enhanced susceptibility to AILD and expressed relatively low levels of most proinflammatory factor genes that were elevated in the IL-10/4-/- mice. In conclusion, liver homeostasis following AILD appears to be highly dependent on the activities of both IL-10 and IL-4, which together help prevent overexpression of IL-6 and other potential hepatotoxic factors.