The origin of increased leg iron stores is extravasation of red blood cells (erythrocytes) in conditions of significant venous stasis. Erythrocytes are degraded by the interstitial macrophages, with the released iron incorporated into ferritin. Over time, with increasing overload of iron, the structure of ferritin changes to haemosiderin.4-9 In 1988, Ackermann found a twenty-fold higher average concentration of iron in lower limbs affected by venous ulcers as compared to the upper arm of the same subjects.8 The phenomenon of leg haemosiderin deposits seems to be significant for the entire body, since this protein has been demonstrated in the urine of patients affected by CVD.9
45 patients affected by other neurological diseases (OND) (table 2); this group was composed of patients affected by neurodegenerative disorders (Parkinson disease and amyotrophic lateral sclerosis-ALS), other neuroimmunological disorders including myasthenia gravis and multifocal motor neuropathy (MMN), and cerebrovascular disease (ischaemic stroke, transient ischaemic attack (TIA)).
Oligodendrocytes are the predominant iron-containing cells in the brain. Iron-containing oligodendrocytes are found near neuronal cell bodies, along blood vessels, and are particularly abundant within white matter tracts. Iron-positive cells in white matter are present from birth and eventually reside in defined patches of cells in the adult. These patches of iron-containing cells typically have a blood vessel in their center. Ferritin, the iron storage protein, is also expressed early in development in oligodendrocytes in a regional and cellular pattern similar to that seen for iron. Recently, the functionally distinct subunits of ferritin have been analyzed; only heavy (H)-chain ferritin is found in oligodendrocytes early in development. H-ferritin is associated with high iron utilization and low iron storage. Consistent with the expression of H-ferritin is the expression of transferrin receptors (for iron acquisition) on immature oligodendrocytes. Transferrin protein accumulation and mRNA expression in the brain are both dependent on a viable population of oligodendrocytes and may have an autocrine function to assist oligodendrocytes in iron acquisition. Although apparently the majority of oligodendrocytes in white matter tracts contain ferritin, transferrin, and iron, not all of them do, indicating that there is a subset of oligodendrocytes in white matter tracts. The only known function of oligodendrocytes is myelin production, and both a direct and indirect relationship exists between iron acquisition and myelin production. Iron is directly involved in myelin production as a required co-factor for cholesterol and lipid biosynthesis and indirectly because of its requirement for oxidative metabolism (which occurs in oligodendrocytes at a higher rate than other brain cells). Factors (such as cytokines) and conditions such as iron deficiency may reduce iron acquisition by oligodendrocytes and the susceptibility of oligodendrocytes to oxidative injury may be a result of their iron-rich cytoplasm. Thus, the many known phenomena that decrease oligodendrocyte survival and/or myelin production may mediate their effect through a final common pathway that involves disruptions in iron availability or intracellular management of iron.
Hypothetical molecular mechanisms by which local
iron overload facilitates the development of
venous leg ulcers and multiple sclerosis lesions
M. Simka a,*, Z. Rybak b
a Department of Angiology, Wodzislawska 78, 43-200 Pszczyna, Poland
b Department of Vascular, General and Transplantation Surgery, Medical University, Wroclaw, Poland
Received 4 December 2007; accepted 23 February 2008
Summary This paper presents a hypothetical model of role for iron in the development of venous leg ulcers and
multiple sclerosis. Elevated concentrations of iron were found in the skin affected by venous hypertension and also in
the areas of brain with multiple sclerosis lesions. Individuals with hemochromatosis gene (HFE) mutations: C282Y and
H63D, which result in a less efficient transport of iron by macrophages, are characterized by an increased risk for
venous leg ulcer and multiple sclerosis. Multiple sclerosis is a T cell-mediated disease, and T cells probably participate
in the development of venous ulcers. This deleterious role of ferric ions could be related to the regulation of T cell
proliferation and apoptosis. Under normal conditions excessive accumulation of T cells cannot take place, because
nitric oxide and interferon-gamma drive these cells toward apoptosis. However, in tissues with a high concentration of
iron, T lymphocytes proliferate instead of undergoing apoptosis. This is possible due to the internalization of the INFcR2
chain of the interferon-gamma receptor, the downregulation of inducible nitric oxide synthase expression in
macrophages and the inactivation of the active site of caspases. Yet, it should be emphasized that this hypothesis does
not claim for the increased concentration of iron as a direct causal factor for the development of venous ulcerations or
multiple sclerosis, but rather, iron is a factor that modulates and exaggerates the autoimmune process. Iron chelators,
administered systemically or locally, should potentially exhibit therapeutic and prophylactic activity against venous leg
ulcers and multiple sclerosis.
J Vasc Surg. 2005 Aug;42(2):309-14.
Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration.
Zamboni P, Tognazzo S, Izzo M, Pancaldi F, Scapoli GL, Liboni A, Gemmati D.
Inter-Departmental Vascular Disease Center, University of Ferrara, Italy. email@example.com
OBJECTIVE: Chronic venous disease (CVD) is the most common vascular disorder, progressing in approximately 10% of cases toward chronic venous leg ulceration, whereas the hemochromatosis gene (HFE) C282Y mutation is the most common recognized genetic defect in iron metabolism. Because CVD leads to local iron overload in the affected legs, we investigated whether two common HFE mutations could increase the risk of chronic venous leg ulceration. METHODS: This was a case-control study at the Vascular Diseases Center, University of Ferrara, Italy. From a cohort of 980 consecutive patients affected by severe CVD (CEAP clinical classes C4 to C6) we selected 238 cases with the exclusion of any other comorbidity factor potentially involved in wound etiology (group A). They were subdivided into group B, including 137 patients with ulcer (classes C5 and C6: 98 primary and 39 postthrombotic cases), and group C, including 101 cases with no skin lesions (class C4). They were completely matched for sex, age, and geographic origin with 280 healthy controls (group D). A total of 518 subjects were polymerase chain reaction genotyped for HFE mutations (C282Y and H63D). We assessed the risk of ulceration by comparing the prevalence of ulcer in homogenous cases with and without the HFE variants. Other main outcome measures were the sensitivity, specificity, and predictive values of the genetic test in CVD cases. RESULTS: C282Y mutation significantly increases the risk of ulcer in primary CVD by almost seven times (odds ratio, 6.69; 95% confidence interval, 1.45-30.8; P = .01). Application of the HFE test in primary CVD demonstrated increased specificity and positive predictive values (98% and 86%, respectively), with negligible sensitivity and negative predictive values. CONCLUSIONS: The overlap of primary CVD and the C282Y mutation consistently increases the risk of developing venous leg ulceration. These data, which have been confirmed in other clinical settings, suggest new strategies for preventing and treating primary CVD. CLINICAL RELEVANCE: The number of patients affected by primary CVD is so great that the vast majority of ulcers are also related to this common problem. On the other hand, there is not a reliable way for identifying in advance, from the broad base of primary CVD patients (20-40% of the general population), the high risk minority (10% of primary CVD cases) who will develop a venous ulcer. In such cases, a simple C282Y blood genetic test demonstrated an elevated specificity in predicting ulcer development (98%, CI 95%, 92.8-99.7). The genetic test could be applied starting from the C2 class, varicose veins, the most common situation observed in clinical practice. In perspective, the presence of the C282Y mutation would strengthen the indications and priorities for surgical correction of superficial venous insufficiency.
PMID: 16102632 [PubMed - indexed for MEDLINE]
Publication Types, MeSH Terms
More than 25 per cent of the 161 people scanned without MS (healthy control participants) also showed signs of CCSVI. This is surprising given that previous studies completed by Dr Zamboni suggested that CCSVI was a condition exclusively associated with MS.
Individuals with hemochromatosis gene (HFE) mutations: C282Y and H63D, which result in a less efficient transport of iron by macrophages, are characterized by an increased risk for venous leg ulcer and multiple sclerosis.
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. Given a possible role for dysregulation of iron metabolism in MS disease pathogenesis, we investigated whether or not mutations in the HFE gene influence the prognosis of the disease. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of HFE on MS disease severity. This approach increases the effective sample size by some 40-fold. Genotyping the two sets of MS patients (112 benign and 51 malignant) provided no evidence to suggest that mutations in HFE have any outcome modifying activity, although small effects cannot be ruled out. The frequency of HFE mutations was not different in MS compared to the general population.
Yet, it should be emphasized that this hypothesis does
not claim for the increased concentration of iron as a direct causal factor for the development of venous ulcerations or multiple sclerosis, but rather, iron is a factor that modulates and exaggerates the autoimmune process.
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