Blackfoot disease and arsenic: a never-ending story.

Blackfoot disease (BFD) is an endemic peripheral vascular disease confined to the southwestern coast of Taiwan. This article reviews the epidemiology, clinical manifestations and diagnosis, pathology, etiology and pathogenesis of this disease. Sporadic cases of BFD occurred as early as in the early 20th century, and peak incidence was noted between 1956 and 1960, with prevalence rates ranging from 6.51 to 18.85 per 1,000 population in different villages. Typical clinical symptoms and signs of progressive arterial occlusion mainly found in the lower extremities, but in rare cases, the upper extremities might also be involved. Ulceration, gangrene and spontaneous or surgical amputation were typical fate. An extensive pathological study concluded that 30% of the BFD patients had histologic lesions compatible with thromboangiitis obliterans and 70% showed changes of arteriosclerosis obliterans. Epidemiologic studies carried out since mid-20th century revealed that BFD was associated with the consumption of inorganic arsenic from the artesian wells. Recent studies confirmed the existence of preclinical peripheral vascular disease, subclinical arterial insufficiency and defects in cutaneous microcirculation in the residents of the endemic villages. A more recent study suggested that the methylation capacity of arsenic can interact with arsenic exposure in the development of peripheral vascular disease among residents of BFD-endemic areas. The incidence of BFD decreased dramatically after the implementation of tap water in these villages over the past 2-3 decades. The atherogenicity of arsenic could be associated with its effects of hypercoagulability, endothelial injury, smooth muscle cell proliferation, somatic mutation, oxidative stress, and apoptosis. However, its interaction with some trace elements and its association with hypertension and diabetes mellitus could also explain part of its higher risk of developing atherosclerosis. Although humic substances have also been suggested as a possible cause of BFD, epidemiologic studies are required to confirm its etiologic role.