In Latin America, 16 million-18 million people are thought to be infected with Trypanosoma cruzi, the parasite that causes American trypanosomiasis. The pathophysiology of this disease, particularly that of its chronic phase, has yet to be fully elucidated. The major function of haptoglobin, an acute-phase plasma protein found in three different phenotypes (Hp1-1, Hp2-1 and Hp2-2), is to bind to free haemoglobin and so prevent the accumulation of reactive hydroxyl radicals and renal damage. The haptoglobin phenotype present can influence the severity and progression of many diseases, including infectious ones. The aim of the present study was to see if any haptoglobin phenotype could be associated with any of the various clinical forms of American trypanosomiasis, and so explore the possibility that haptoglobin and iron metabolism have a role in the pathophysiology of this disease. The Brazilian subjects investigated were either suffering from the 'indeterminate' (N=16), chronic cardiac (N=34), chronic digestive (N=13) or chronic 'combined' (i.e. cardiac plus digestive; N=29) forms of the disease or were apparently healthy blood donors from the same region as the patients (N=197). Haptoglobin phenotypes were determined by polyacrylamide-gel electrophoresis. Among the iron-related parameters investigated in the patients, only total iron-binding capacity and the serum concentration of haptoglobin differed significantly with haptoglobin phenotype. Compared with its frequency in the healthy controls, the Hp2-2 phenotype was much more frequent in the patients with any form of American trypanosomiasis, in the patients with the indeterminate form of the disease, and in the patients with the chronic combined form (P<or=0.0001 for each). It therefore appears that, in terms of the pathogenesis in those exposed to T. cruzi, possession of the 2-2 phenotype of haptoglobin may be detrimental.100213-21