Systemic Inflammatory Response: Thiamine and Magnesium Status (Sir TaM Study)

We wish to determine to what extent magnesium, thiamine and transketolase activity are affected by the Systemic Inflammatory Response (SIR). The knee arthroplasty model affords the ideal study design, as surgery generates an inflammatory response.

Blood samples are drawn preoperatively and for up to four days post operatively, and again at three months post-operation.

Thiamine and magnesium play a critical role in glucose metabolism and deficiency results in the accumulation of anaerobic metabolites including lactate (1-3).

Thiamine requires magnesium to be converted to its active form, thiamine pyrophosphate (TPP) (4). TPP also requires magnesium to achieve activation of TPP dependent enzymes during metabolism of glucose (5, 6). The 'gold standard' for the measurement of thiamine status is the measurement of Erythrocyte Transketolase Activity (ETKA)(4, 7-9), and this enzyme's activity is dependent on the presence both thiamine pyrophosphate and magnesium (8, 10). ETKA may therefore represent a 'functional marker' of magnesium status (7, 9, 11, 12).

Studies indicate that low plasma thiamine and magnesium are associated with a range of disease processes, many of which are inflammatory (13-17). Other lipid-soluble vitamins and minerals are known to decrease during the systemic inflammatory response (18, 19), however this relationship is not proven for magnesium. The systemic inflammatory response may therefore confound the interpretation of plasma thiamine and magnesium in the context of sepsis, surgery or autoimmune disease. Elective knee arthroplasty, provokes an inflammatory response and therefore provides an excellent controlled model for understanding the body's response to a systemic insult (19).

Obesity is reported to be associated with magnesium deficiency (17, 20). Intracellular magnesium plays a key role in regulating insulin action, insulin-mediated-glucose-uptake and vascular tone (21-23). Several epidemiologic studies have shown that adults and children consuming a western type diet are consuming 30 - 50% of the RDA for magnesium (24, 25). This deficiency appears to be predominantly subclinical and therefore not routinely investigated.

Obesity is also associated with thiamine and magnesium depletion (17, 20, 26, 27). Magnesium deficiency is also associated with a CRP rise (28-30). Thiamine status is proven to affect lactate concentrations in the blood (2, 3). Lactate accumulation is known to precede the onset of insulin resistance and be characteristically found in patients with obesity related diabetes (31-37).

It is therefore possible that an underlying quiescent magnesium and / or thiamine deficiency may mediate insulin resistance. Thiamine, and its more lipid soluble derivative, benfothiamine, have already shown some promise in the treatment of diabetic complications. The therapeutic potential is intriguing, however the relation between acute changes in the systemic inflammatory response and thiamine and magnesium concentrations, require clarification. Failure to prove the reliability of the thiamine and magnesium measurements in the context of the systemic inflammatory response may lead to patients receiving treatment for a measured deficiency of red cell thiamine and serum magnesium concentrations, which is unreliable. If the therapeutic potential of combined treatment with thiamine and magnesium for the optimization of ETKA function is to be realized (8), it is essential that the erythrocyte and plasma values used to determine thiamine status are definitively established in the context of the systemic inflammatory response. The knee arthroplasty model affords the ideal study design for this as there is a strong association between obesity and knee osteoarthritis (38, 39).

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Eligibility Criteria:
Inclusion Criteria:

* undergoing elective total knee replacement

Exclusion Criteria:

* taking multivitamin