Nearly 38% of Danes Live With Chronic Disease Linked to Flawed Tissue Scaffolding

Researchers have systematically counted how many people live with, and die from, chronic diseases driven by dysregulation of the extracellular matrix — the fibrous scaffold that gives every tissue its shape and chemical cues — and the numbers are far larger than earlier estimates suggested. In a nationwide register-based study of the entire Danish population, the team classified 331 chronic conditions as either fibrotic diseases, in which matrix accumulates excessively, or tissue destruction diseases, in which matrix is degraded faster than it is rebuilt. By 2023, 38% of the Danish population was living with at least one such condition, and in 2024 the group accounted for 540 deaths per 100,000 people when recorded as the underlying cause of death, rising to 647 per 100,000 when contributing causes were included.

The study, which drew on the Danish National Patient Register and the Danish Cause of Death Register, covered everyone with an active civil registration number in Denmark between 1 January 1994 and 31 December 2024 — 8,504,378 unique individuals in total, of whom 5,945,094 were alive and resident at the end of 2024. Unlike sample surveys, registry data of this kind cover the full population, so the prevalence and mortality figures are population measures rather than estimates drawn from a subset, and the researchers report them without confidence intervals. Key mortality findings for 2024 were independently replicated in the UK Biobank cohort of roughly 500,000 participants, although the authors used that cohort only to validate mortality rates, not absolute prevalence, because it is a selected volunteer cohort rather than a complete registry.

The classification work is the technical core of the study. The researchers reviewed all 1,701 Danish ICD-10 level-two disease codes and assigned each to one of four mutually exclusive categories: fibrotic diseases, tissue destruction diseases, non-ECM diseases, or unknown. Two domain experts with relevant clinical expertise independently assessed the codes within each ICD-10 chapter in a double-blinded, Delphi-inspired consensus process. Where uncertainty arose, coders were required to consult at least three peer-reviewed publications describing the disease’s pathophysiology and its relationship to matrix remodelling, and a third expert adjudicated disagreements. After review, 995 unique codes were classified: 194 as fibrotic diseases, 137 as tissue destruction diseases — together forming the ECM-related group of 331 — 635 as non-ECM diseases, and 29 as unknown.

The resulting disease list is strikingly broad. Neoplasms made up the largest share of fibrotic diseases, at 49%, reflecting the fact that most solid tumours contain fibrotic stromal tissue; musculoskeletal diseases dominated the tissue destruction group at 33%, a category that also includes osteoarthritis, osteoporosis, rheumatoid arthritis, inflammatory bowel diseases and atopic dermatitis. Classic fibrotic conditions include idiopathic pulmonary fibrosis, chronic kidney disease, cardiovascular disease, systemic sclerosis and liver cirrhosis. Many conditions show features of both processes, but the classification assigns each code according to the net direction of chronic matrix remodelling — tissue gain through fibrosis or tissue loss through degradation — rather than transient or stage-specific variation.

The prevalence figures are remarkable. In 2023, an estimated 19% of the Danish population lived with one or more fibrotic diseases — 22.6% of women and 15.1% of men — while 30% lived with one or more tissue destruction diseases, and 38% with at least one ECM-related disease overall. Prevalence was consistently higher in women than in men across all categories, and it rose steeply with age: from 17.6% among people under 40 to 80.7% among those aged 85 and over for ECM-related diseases overall, with fibrotic diseases climbing from 4.9% to 52.9% and tissue destruction diseases from 14.4% to 67.7% across the same age range. Since 2013, prevalence has remained relatively stable, with only minor fluctuations.

Mortality, however, showed the opposite sex pattern. Men consistently exhibited slightly higher mortality rates than women across all disease groups, even though women carried a higher prevalence — a dissociation the authors connect to the well-described mortality–morbidity paradox, in which women experience more chronic illness while men die more often. Proposed explanations include hormonal differences, greater health-care utilisation and earlier diagnosis among women, and higher levels of risk behaviours and later presentation among men. The gap is starkest for musculoskeletal diseases, the most prevalent ECM category at roughly 17%, with a female excess of about five percentage points, yet accounting for under 5% of ECM-related deaths. Osteoporosis exemplifies this: highly prevalent, especially in women, but rarely a direct cause of death.

The magnitude of the mortality contribution depends heavily on how deaths are counted. In 2024, fibrotic diseases caused 381 deaths per 100,000 people as the underlying cause and 504 per 100,000 as a contributing cause; the corresponding rates for tissue destruction diseases were 159 and 250 per 100,000. For all ECM-related diseases combined, the rates were 540 and 647 per 100,000 respectively. Within the fibrotic group, neoplasms dominated the death toll, accounting for 68.0% of fibrotic deaths as underlying causes and 62.9% as contributing causes, while respiratory diseases and diseases of the nervous system contributed most to mortality among tissue destruction diseases. The consistently higher figures for contributing causes highlight that matrix pathology frequently modifies disease trajectories rather than acting as the primary killer.

Mortality has also been falling. Between 1994 and 2024, crude mortality for ECM-related diseases as the underlying cause declined from 702.9 to 540.6 deaths per 100,000, and from 853.5 to 647.5 per 100,000 for contributing causes. Fibrotic disease mortality fell from 498.6 to 381.1 per 100,000 as the underlying cause, and tissue destruction disease mortality from 204.2 to 159.6 per 100,000. Poisson regression confirmed significant annual declines across all groups, with a modest but statistically significant faster relative decline among women. The authors caution, however, that a marked discontinuity in 2006 coincided with Denmark’s transition to electronic death certification, suggesting that part of the apparent decline may reflect changes in reporting practice rather than a genuine reduction in disease burden.

The UK Biobank replication broadly supported the Danish mortality estimates. For underlying causes of death, UK Biobank rates were slightly higher for fibrotic diseases (470 versus 381 per 100,000) and overall ECM-related diseases (623 versus 540 per 100,000), while tissue destruction rates were closely matched (153 versus 159 per 100,000), with similar patterns for contributing causes. The authors argue that the combination of high prevalence and declining mortality means more people are now living longer with these conditions — likely reflecting improved diagnosis, national cancer screening programmes and better chronic disease management — yet the persistent burden carries major implications for quality of life and health-care utilisation. They also note that emerging disease-modifying therapies, such as resmetirom and semaglutide, which have shown promising effects on MASH resolution and fibrosis-related outcomes, may alter the future trajectory of an important subset of fibrotic diseases.

The study has clear limitations. The classification reflects diseases in which persistent matrix dysregulation is a defining pathological feature, not a claim that matrix biology is absent from other diseases or that it causes disease onset, and no causal inference about matrix dysregulation is possible within this framework. Hospital-based registers miss conditions managed mainly in primary care — around 80% of Danish type 2 diabetes patients, for example — and restricting prevalence to diagnoses recorded from 1995 onward risks underestimation, which the authors mitigated with a 20-year retrospective look-back window. Misclassification in death records, particularly for contributing causes, may bias mortality estimates. Findings primarily reflect Northern European populations and health systems. Even so, the authors argue that treating extracellular matrix dysregulation as a shared disease framework — spanning 331 conditions across nearly every organ system — could sharpen burden estimation, strengthen the case for therapies targeting common matrix pathways, and inform disease surveillance, prevention and health policy prioritisation.

Subject of Research: Population-level prevalence and mortality of fibrotic and tissue destruction diseases driven by extracellular matrix dysregulation in Denmark

Article Title: Prevalence and mortality of chronic extracellular matrix dysregulated diseases: a nationwide register-based study

Article References: Christiansen, R. C., Bager, C. L., Heinz, A., Bay-Jensen, A. C., Leeming, D. J., Khanna, D., Genovese, F., Rieder, F., Schett, G., Mortensen, J. H., Henriksen, K., Willumsen, N., Conaghan, P. G., Kalluri, R., Friedman, S. L., Nielsen, S. H., Larsen, S., Heymans, S., Maher, T. M., … Karsdal, M. A. (2027). Prevalence and mortality of chronic extracellular matrix dysregulated diseases: a nationwide register-based study. The Lancet Regional Health – Europe, 72, Article 101901. https://doi.org/10.1016/j.lanepe.2026.101901

Image Credits: AI Generated

DOI: 10.1016/j.lanepe.2026.101901

Keywords: extracellular matrix, fibrosis, tissue destruction, register-based study, Denmark, prevalence, mortality, ICD-10, chronic disease, UK Biobank, epidemiology, chronic