The detrimental effects of iron on the joint: a comparison between haemochromatosis and haemophilia

Abstract

Joint damage due to (recurrent) joint bleeding in haemophilia causes major morbidity. Although the exact pathogenesis has not been fully elucidated, a central role for iron is hypothesised. Likewise, in hereditary haemochromatosis joint destruction is caused by iron overload. A comparison between these types of arthropathy could provide more insight in the influence of iron in inducing joint damage. A literature review was performed to compare both disorders with respect to their clinical and histological characteristics, and preclinical studies on the influence of iron on different joint components were reviewed. Similarities in the features of arthropathy in haemochromatosis and haemophilia are cartilage degeneration, subchondral bone changes with osteophyte and cyst formation, and osteoporosis. In both disorders synovial inflammation and proliferation are seen, although this is much more explicit in haemophilia. Other substantial differences are the age at onset, the occurrence of chondrocalcinosis radiographically and calcium pyrophosphate dihydrate deposition disease in haemochromatosis, and a rapid progression with joint deformity and neovascularisation in haemophilia. Preclinical studies demonstrate detrimental effects of iron to all components of the joint, resulting in synovial inflammation and hyperplasia, chondrocyte death, and impaired osteoblast function. These effects, particularly the synovial changes, are aggravated in the presence of a pro-inflammatory signal, which is prominent in haemophilic arthropathy and minimal in haemochromatosis. Additional research is needed to further specify the role of iron as a specific target in treating these types of arthropathy.

Advanced magnetic resonance imaging of cartilage components in haemophilic joints reveals that cartilage hemosiderin correlates with joint deterioration

“…This has been elucidated by Ghadially et al where iron detection with light microscopy after Prussian Blue/Perls’ staining was compared to electron probe X‐ray analysis of articular cartilage of rabbits after induced chronic hemarthrosis. In keeping with this observation, abundant synovial hemosiderin has been reported in haemophilic joints, whereas cartilage iron deposition has only been described in one case by light microscopy .…”

“…In hemochromatosis, it has been proposed that iron might contribute to the degeneration of cartilage, but a direct relationship between joint iron accumulation and degree of arthritis has not been established …”

Die hereditäre Hämochromatose: Eine interdisziplinäre diagnostische und therapeutische Herausforderung

“…chemischen Eigenschaften als direkten Verursacher der Zell-und Gewebsschädigung auch im Gelenk anzusehen. In mehreren Untersuchungen fanden sich aber keine entzündlichen Veränderungen der Synovialmembran [18]. Diese Befunde könnte die begrenzte Wirksamkeit von anti-inflammatorischen bzw.…”

Joint hemorrhage accelerates cartilage degeneration in a rat immobilized knee model

“…In hemophilic arthropathy, pro-in ammatory cytokines such as interleukin (IL)-1β [6][7][8] and tumor necrosis factor (TNF)-α [6,9] are produced in the hemosiderin-laden synovial tissue, and these cytokines trigger catabolic programs, activating nitric oxide (NO) [1,6] and matrix metalloproteinase (MMP) expression [6], osteoarthritis [10], and rheumatoid arthritis. These cytokines also increase iron uptake into monocytes and synovial broblasts and accelerate the vicious cycle of synovitis [7].…”