Hemochromatosis-Associated Mortality in the United States (1999-2024): A Nationwide Joinpoint Analysis of Trends and Disparities.

introductionHemochromatosis is a treatable disorder of iron metabolism in which iron progressively accumulates in the liver, heart, pancreas, and endocrine organs, leading to cirrhosis, hepatocellular carcinoma, cardiomyopathy, diabetes, and other end-organ injury. Prior nationwide U.S. mortality analyses predate the ICD-10 era, and contemporary trend data are limited. We assessed trends and disparities in hemochromatosis-associated mortality in the United States (1999-2024).

methodsWe conducted a retrospective serial cross-sectional analysis of national death-certificate data (STROBE- and RECORD-compliant) using the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) Multiple Cause of Death (MCD) database (1999-2020 bridged-race file; 2021-2024 single-race file). Hemochromatosis-associated deaths were identified by ICD-10 code E83.1 (underlying or any contributing cause). Age-adjusted mortality rates (AAMRs) per 100,000 (2000 U.S. standard population) were stratified by sex, race and Hispanic origin, U.S. Census region, age group, state, and urbanization. Temporal trends were assessed with the Joinpoint Regression Program version 6.0.1 (grid search; 0-4 joinpoints; Monte Carlo permutation test, 4,499 permutations; log-linear model), reporting annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals (CIs). Segment 1 refers to the period before any identified joinpoint; segment 2 refers to the period after.

resultsBetween 1999 and 2024, 16,113 hemochromatosis-associated deaths were recorded; annual counts rose from 562 to 841 (+49.6%). The overall AAMR was 0.21 per 100,000 in 1999, 0.14 in 2015 (nadir), and 0.19 in 2024. Joinpoint regression identified one inflection at 2015 (95% CI, 2011-2018): a 16-year decline (APC -1.75%, p < 0.001) and a nine-year rebound (APC +3.07%, p = 0.002); AAPC -0.04% (p = 0.917) masked this two-segment trajectory. Burden was demographically concentrated: men 10,665 (66.2%), non-Hispanic White (NHW) decedents 13,883 (86.2%), and adults aged ≥65 years 9,706 (61.8% of age-classified deaths) - and the male-to-female AAMR ratio widened from 2.23 to 2.55. The post-joinpoint rebound was confined to NHW decedents (joinpoint 2013; segment-2 APC +3.16%, p < 0.001); non-Hispanic Black and Hispanic rates declined monotonically (AAPCs -1.77% and -2.57%, both p < 0.001). The South and West reproduced the two-segment pattern (joinpoints 2014, 2015); no inflection was detected in the Northeast or Midwest. Crude mortality in the 85-and-older stratum rose from 0.96 to 1.76 per 100,000 (+82.4%), with annual deaths rising from 40 to 113. Chronic liver disease was co-listed on 7,412 (46.0%) certificates, followed by diabetes with 2,408 (14.9%), primary liver cancer 1,739 (10.8%), heart failure 1,715 (10.6%), sepsis 1,193 (7.4%), hepatitis C 745 (4.6%), and cardiomyopathy 674 (4.2%).

conclusionThis 26-year nationwide analysis identified a statistically significant reversal in U.S. hemochromatosis-associated mortality in 2015, with a 16-year decline followed by a nine-year rebound concentrated in older NHW men. Non-Hispanic Black and Hispanic mortality declined monotonically, widening race and ethnic disparities, and the end-organ comorbidity profile remained stable. Distinguishing coding, cohort, and penetrance contributions will require individual-level data linking HFE genotype, treatment exposure, and clinical outcomes.