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Neopterin and homocysteine correlations correlate closely in various diseases. Data imply that immune activation is responsible for depletion of B-vitamins and subsequent increase of homocysteine.


Homocysteine-lowering therapy does not affect inflammatory markers of atherosclerosis in patients with stable coronary artery disease

Bleie O, et al. Department of Heart Disease, Haukeland University Hospital, Bergen, Norway, and Institute of Medicine, University of Bergen, Bergen, Norway
(J Intern Med 2007;262:244-53)

Objectives. A high level of total homocysteine (tHcy) is a risk marker for cardiovascular disease (CVD), and is related to inflammation. We wanted to test the effect of homocysteine-lowering B-vitamin therapy, as used in the Western Norway B-vitamin Intervention Trial (WENBIT), on inflammatory markers associated with atherosclerosis. Design. Single centre, prospective double-blind clinical interventional study, randomised in a 2 x 2 factorial design. Subjects and methods. Ninety patients (21 female) with suspected coronary artery disease (CAD), aged 38-80 years, were blindly randomised into one of four groups of daily oral treatment with (A) folic acid (0.8 mg)/vitamin B12 (0.4 mg)/vitamin B6 (40 mg), (B) folic acid/vitamin B12, (C) vitamin B6 alone or (D) placebo. Blood samples were collected before and after 6 months of treatment. Results. Before intervention, median levels of the analytes were: tHcy 11.0 mumol/L, neopterin 8.1 nmol/L, soluble CD40 ligand (sCD40L) 3.9 ng/mL, interleukin (IL)-6 1.9 pg/mL, C-reactive protein (CRP) 1.9 mg/L and low-density lipoprotein (LDL) cholesterol 3.3 mmol/L. tHcy was significantly associated with neopterin (r = 0.49, P < 0.001) and with IL-6 (r = 0.29, P = 0.01), but not with CRP or sCD40L. Neither treatment with folic acid/B12 nor with B6 induced significant changes in any of these inflammatory biomarkers (P >/= 0.14). In patients receiving folic acid/B12 (groups A and B), tHcy was reduced with 33% (P < 0.001). Conclusions. In patients with stable CAD, homocysteine-lowering therapy with B-vitamins does not affect levels of inflammatory markers associated with atherogenesis. Failure to reverse inflammatory processes, may partly explain the negative results in clinical secondary B-vitamin intervention trials.

Homocysteine but not neopterin declines in demented patients on B vitamins

Frick B, et al. Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Innsbruck, Austria
(J Neural Transm 2006;113:1815-9)

Inflammation and immune system activation seem to play an important role in the development and progression of dementia. Hyperhomocysteinemia is common in various forms of dementia, and a significant relationship was found between concentrations of homocysteine and immune activation marker neopterin. B vitamin supplementation is able to slow-down homocysteine formation in patients. In an open-label study, effects of B vitamin supplementation (Beneuran compositum ) on concentrations of homocysteine and neopterin were investigated in 58 patients with Alzheimer's disease (n=30), vascular dementia (n=12) and mild cognitive impairment (n=16). In all groups of patients, a significant percentage of patients presented with homocysteine concentrations >15 micromol/L and with elevated concentrations of immune activation marker neopterin. Decline of homocysteine concentrations was observed after one month of B vitamin supplementation (all p<0.01; paired Kruskal-Wallisn-test). By contrast, neopterin concentrations remained unchanged (all p>0.05). B vitamin supplementation in patients with various forms of dementia did not influence neopterin concentrations, which indicates that the degree of immune activation and inflammation remained unchanged. The question remains, if lowering of homocysteine by folate supplementation alone could have any beneficial effect to modulate the course of dementia development and if longer period of supplementation would also ameliorate immune system activation status.

Hyperhomocysteinemia and immune activation

Schroecksnadel K, et al. Institute of Medical Chemistry and Biochemistry,
University of Innsbruck, Innsbruck, Austria
(Clin Chem Lab Med 2003; 41: 1438-43)

Hyperhomocysteinemia is an established risk factor for atherosclerosis, thrombosis and other vascular diseases. Homocysteine auto-oxidation is considered to be crucially involved in the pathogenesis of these diseases. However, the question remains to be elucidated whether vitamin deficiency and homocysteine accumulation are causal for disease development or rather comprise a secondary phenomenon. Most diseases accompanied by hyperhomocysteinemia are also associated with ongoing activation of the immune system. In vitro experiments show homocysteine to accumulate in stimulated peripheral blood mononuclear cells. In patients with coronary heart disease, with rheumatoid arthritis and in patients with dementia, an association between cellular immune activation and homocysteine metabolism is found. Homocysteine concentrations not only correlate inversely with folate concentrations, they also show a positive relationship with concentrations of immune activation markers like neopterin. Moreover, in patients with various kinds of dementia, increased concentrations of serum peroxides, homocysteine and neopterin correlate with each other. Studies support a role of immune system activation in the development of hyperhomocysteinemia. Stimulation and proliferation of immune cells may lead to the production of reactive oxygen species that may oxidize antioxidants and oxidation-sensitive B-vitamins. An enhanced demand for antioxidants as well as folate and vitamin B12 may develop, together with hyperhomocysteinemia, despite sufficient dietary intake.

Association of hyperhomocysteinemia in Alzheimer disease with elevated neopterin levels

Schroecksnadel K, et al. Institute of Medical Chemistry and Biochemistry, Medical University of Innsbruck, Innsbruck, Austria
(Alzheimer Dis Assoc Disord 2004; 18: 129-33)

In patients with dementias including Alzheimer disease (AD), elevated blood concentrations of homocysteine are common, often going along with low normal folate and vitamin B12. Immune activation leading to oxidative stress also seems to play an important role in the pathogenesis of AD. To find out a possible relationship between immune activation and the development of moderate hyperhomocysteinemia, we determined serum concentrations of homocysteine, folate, vitamin B12 and immune activation markers 75 kD soluble TNF receptor (sTNF-R75) and neopterin in 38 patients with clinically diagnosed AD. A subgroup of patients (45%) presented with increased homocysteine concentrations in comparison to reference ranges in healthy controls of similar age. Also, concentrations of immune activation markers were elevated in a significant proportion of patients. In 17 patients with moderate hyperhomocysteinemia, concentrations of neopterin were higher than in those with lower homocysteine (p < 0.001). Homocysteine correlated with folate (rs= -0.43; p < 0.01) and neopterin (rs= 0.506; p < 0.001). The data suggest that immune activation and concomitant production of reactive oxygen species in patients with AD could be involved in the development of hyperhomocysteinemia via an enhanced decomposition of folate.