Ixodid Tick-Borne Pathogens as Candidate Triggers for Primary Sclerosing Cholangitis: Ecological Evidence

Background & Aims. Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown etiology whose prevalence varies >30-fold worldwide, peaking in Northern Europe and the U.S. Upper Midwest. This geographic distribution is not fully explained by recognized risk factors. We examine its correlation with Ixodes tick exposure. Approach & Results. PSC incidence across North America, Europe, and Oceania was compared with Lyme incidence, HLA-DRB1*03 frequency, latitude and other environmental factors. Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) were included as controls. A U.S. analysis (MarketScan, 2018-2022; 110.7 million person-years) correlated age and sex-standardized rates against 24 exposures, including Ixodes density and tick-borne infections, using ancestry-adjusted partial correlations. Cross-country PSC incidence tracked Lyme incidence (Spearman rho = 0.71-0.87); HLA-DRB1*03, AIH, and PBC did not. Alaska Native and Greenlandic populations, high-latitude but without established human exposure to Ixodes-borne pathogens, report no PSC despite high autoimmune liver disease and IBD. In the U.S., PSC was clustered and tracked Ixodes-borne pathogen incidence (ancestry-adjusted partial r, log scale: anaplasmosis +0.50, babesiosis +0.56, Powassan virus disease +0.52; in the Northeast-Midwest block, ancestry- and latitude-adjusted r = +0.72, +0.84, and +0.78, respectively). Non-Ixodes infections (Ehrlichia chaffeensis, spotted fever, tularemia), AIH, and PBC were null-to-negative; rural, agricultural, pollution, and healthcare-access also did not correlate. Conclusions. These ecological analyses are consistent with the hypothesis that Ixodes-borne pathogen exposure may trigger PSC. These ecological data cannot establish causation; they are hypothesis-generating, yielding falsifiable predictions for case control, serologic, and animal-model studies.