No outbreaks selleck chem Brefeldin A of veno-occlusive liver disease associated with pyrrolizidine alkaloids have been reported to our knowledge in East Africa. Pyrrolizidine alkaloids are inert until dehydrogenation by cytochrome P450 3A4 (CYP3A4) in the liver [19], where reactive toxic pyrrolic and N-oxide metabolites directly damage liver sinusoidal endothelial cells and hepatocytes (zone III of the liver acinus) [20]. Pyrroles cause chromosomal damage in a dose-dependent manner, resulting in an inflammatory response that culminates in fibrin deposition [17], [20], [21]. Although plants in both the Asteraceae and Fabaceae families ingested by study participants may contain pyrrolizidine alkaloids, our data shows a strong association between significant liver fibrosis and use of herbs in the Asteraceae family but not the Fabaceae family.

The literature about African traditional herbal medicines is limited and does not explain why this difference might exist. Traditional herbal medicine remedies used in Rakai and throughout Uganda are often mixtures containing multiple herbs [8], [22]. It is possible that herbs in the Asteraceae family are taken at high doses, or potentiate the toxicity of other herbs or hepatotoxins. Two participants with fibrosis reported use of Vernonia amygdalina in the Asteraceae family. This particular herb is commonly used in Africa is thought to have hepatoprotective properties [23]. However, animal studies show that at higher doses, this member of the Asteracaae family may be hepatotoxic.

In an in-vivo rat CCl4 liver injury model, low doses (250�C500 mg/kg) of Vernonia amygdalina were hepatoprotective, but a high dose (750 mg/kg) caused increased hepatoxicity [24]. Herbs from the Lamiaceae family were associated with a 3.4 fold increase in significant liver fibrosis among all participants in our study Dacomitinib (p=0.017). Herbs in the Lamiaceae family have been associated with hepatoxicity in an in-vivo rabbit model [25]. In addition, Aloe, taken by two participants in our study, has been linked in case reports to severe hepatitis [26]. However, data about the potential hepatotoxicity of many herbs used by participants in this study do not exist, or come from animal model studies only that should be interpreted cautiously. The risk of significant fibrosis associated with herb use was similar in the overall and HIV- infected study populations. Data on herb use was limited in the HIV-infected population, and plant family specific analysis was only possible for the Asteraceae family. Only two HIV- infected participants reported using herbs in the Asteraceae family. Despite the small number of HIV-infected participants in this study who reported herb use, it is important to note that ART may alter the toxicity profile of co-administered herbs.