The overlap syndrome raises several questions. First could these patients have two coincident autoimmune diseases? Such possibility cannot be discarded in particular in the setting of consecutive occurrence of the two conditions (eg, PBC followed by AIH) and this is consistent with the fact that autoimmune diseases are associated with one another in about 5% to 10% of cases. Furthermore, it is presumed that they share similar genetic susceptibility. A second possibility could be that overlap syndrome represents the middle of a continuous spectrum of two autoimmune liver diseases. The systematic study of the relationships between elementary histologic lesions and biochemistries in "pure" PBC patients pleads strongly for such a hypothesis. Pure PBC is characterized by 2 different groups of elementary lesions that are not interrelated: first, florid bile duct lesions and bile duct paucity and second, lymphocytic piecemeal necrosis and lobular necro-inflammatory changes. Furthermore, the first set of lesions is selectively associated with biochemical cholestasis and IgM levels, whereas the second set of lesions is selectively associated with serum transaminase activities and IgG levels. These observations are consistent with the assumption that two main mechanisms are involved in the progression of liver injury in PBC. The first is bile duct destruction leading to chronic cholestasis and fibrosis of biliary pattern. The second is lymphocytic piecemeal necrosis of hepatocytes, which tends to lead to cirrhosis, the pattern of which resembles cirrhosis following various forms of chronic active hepatitis. The author has therefore speculated that the picture of pure PBC results always forms the clinical and biochemical expression of the two main histologic lesions, and combination of these processes might explain why the spectrum of PBC varies from typical PBC to AIH or PBC overlap. A third hypothesis is that an exaggerated hepatitic response in PBC is associated with the HLA haplotype commonly seen in AIH, eg, B8, DR3, DR4. Further studies are obviously needed to confirm such an attractive hypothesis. Other possible explanation for the concurrent occurrence of features of both conditions in the same individual includes the selective modulation of HLA class 1, class 2 expression and Rantes by cholestasis itself and in particular bile acids. It is conceivable that the degree of interface and lobular inflammation in PBC and PSC may be modulated by chemokines, their receptors, and the parenchymal concentrations of individual bile acids that are all, at least in part, genetically determined.