Clinical spectrum and burden of extrahepatic manifestations in chronic hepatitis B: A multinational study from 2000 to 2025.

Chronic hepatitis B virus (HBV) infection is associated with both hepatic and extrahepatic complications. While liver-related outcomes are well characterized, the burden, demographic patterns, and survival associated with extrahepatic manifestations (EHMs) remain incompletely defined. This study aimed to evaluate the spectrum, incidence, and survival impact of EHMs in a large, geographically diverse cohort of patients with chronic HBV infection. We conducted a retrospective cohort study using the TriNetX Global Research Network, including 2,32,820 patients aged 0 to 90 years with chronic HBV infection. Demographic variables included age, sex, race, ethnicity, and geographic region. EHMs assessed comprised renal (glomerulonephritis), vasculitic (polyarteritis nodosa), musculoskeletal (arthralgia), hematologic (aplastic anemia), immunologic (cryoglobulinemia), and neurologic (polyneuropathy) conditions. Incidence proportions and incidence rates per person-day were calculated and stratified by demographic characteristics. Survival probabilities were estimated for each manifestation. The mean age of the cohort was 60 ± 14 years, and 56.9% were male. Racial distribution included Asian (34.4%), White (15.4%), Black or African American (12.1%), and unknown race (34.4%). Most patients were non-Hispanic (53.6%), with 44.1% reporting unknown ethnicity. Patients were represented across all US regions and internationally. Glomerulonephritis occurred in 1.26% of patients, with higher incidence in older adults, males, and Native Hawaiian/Other Pacific Islander and Hispanic/Latino populations. Polyarteritis nodosa was rare (0.04%) and predominated in older individuals, American Indian/Alaska Native, and Hispanic/Latino patients. Arthralgia was the most frequent EHM (13.76%), increasing with age and more common among females and Black or African American individuals. Cryoglobulinemia (0.10%) and aplastic anemia (0.12%) were uncommon. Polyneuropathy affected 3.27% of patients, with higher prevalence among older adults and males. Chronic HBV infection is associated with a wide spectrum of extrahepatic manifestations, with substantial variation by demographic factors. These findings underscore the need for comprehensive multisystem surveillance and targeted risk stratification in patients with chronic HBV infection.