Homocysteine elevated serum levels

Indirect indicators of vitamin B12 deficiency include measurements of the metabolites homocysteine and methylmalonic acid (MMA) in serum and MMA in urine (see the Biochemical Perspectives section). Whereas the serum homocysteine concentration increases during folate or vitamin B12 deficiencies, the serum and urine MMA concentrations increase only in vitamin B12 deficiency. Therefore, MMA determinations can be used to differentiate vitamin B12 deficiency from folate deficiency. The normal concentration of MMA in serum ranges from 0.08 to 0.28 pmol/L. MMA is quantified using gas-liquid chromatography and mass spectrometry. Elevated concentrations of MMA and homocysteine in serum may precede the development of hematological abnormalities and reductions in serum vitamin B12 concentrations. One should be aware that other conditions, including renal in sufficiency and inborn errors of metabolism, can also result in elevated serum levels of MMA. 

In the early stages of reduced vitamin B12 absorption, the amount of vitamin B12 bound to TCII decreases rapidly (10-21 days) without any decrease in the total serum B12 level. The total vitamin B12 concentration begins to decline only when the saturation of TCII falls below 5%. Reduced saturation of TCII is thus one of the earliest indicators of reduced intake of vitamin B12 and is detectable in advance of clinical disease. This makes holo-TCII particularly valuable for use as a screening test in susceptible populations. Elevated serum and urine concentrations of homocysteine and MMA occur somewhat later and represent early evidence of cellular dysfunction that occurs when body (liver) stores have been greatly depleted. 

In the early stages of vitamin B12 deficiency, classic signs and symptoms of megaloblastic anemia may not be evident and serum levels of vitamin B12 may be within normal limits. Therefore measurement of MMA and homocysteine is useful, as these parameters are often the first to change. Increased levels of serum MMA and homocysteine may be evident, as both of these are involved in enzymatic reactions dependent on vitamin Bn, and a deficiency in vitamin Bn allows for accumulation of these precursors. Elevations in MMA are more specific for vitamin Bn deficiency, while elevated homocysteine can be indicative of either vitamin Bn or folic acid deficiency, but offers greater specificity for folate plasma levels. Low levels of vitamin Bn result in hyperhomocysteinemia, which the majority of data suggest is an independent risk factor for cerebrovascular, peripheral vascular, coronary, and venous thromboembolic disease. Hyperhomocysteinemia may also be linked to dementia and Alzheimer s disease. ... 

It is of paramount importance to rule out vitamin B12 deficiency when folate deficiency is detected, as symptoms are similar. Laboratory changes associated with folate deficiency are similar to those seen in vitamin Bn deficiency, except vitamin Bn levels are normal. Decreases occur in the serum folate level (<3 ng/mL) within a few days of dietary folate limitations. The RBC folate level (<150 ng/mL) also declines and may be a better indicator of deficiency, as levels remain constant throughout the life span of the erythrocyte. Serum folate levels are sensitive to short-term changes such as dietary restrictions or alcohol intake, which may result in a short-term decline in serum levels with adequate tissue stores. It should be noted that an estimated 60% of patients with pernicious anemia have falsely low RBC folate levels, in all probability due to the requirement of cobal-amin for the normal transfer of methyltetrahydrofolate from plasma to cells. Additionally, if serum or erythrocyte folate levels are borderline, serum homocysteine is usually increased with a folic acid deficiency. If serum MMA levels are also elevated, vitamin B12 deficiency needs to be ruled out. 

In snmmary, individuals with elevated serum homocysteine are at increased risk of sporadic AD, bnt the mechanisms are controversial. This study shows that high serum homocysteine levels in female mice correlate with higher Ap peptide levels in the brain. Since Ap plays a central role in the pathogenesis of AD, the results advance a plansible mechanism underlying the higher risk for AD in hyperhomo-cysteinemia. On the basis of these results, future epidemiological studies should place emphasis on the gender differences noted. 

Elevated serum MMA and tHcy concentrations can be considered alternative specific metabolic parameters of cobalamin deficiency. Measurement of functional metabolite MMA requires sophisticated equipment and is, therefore, unsuitable for routine use. Total homocysteine is a more sensitive analyte than tfii2 in diagnosing subclinical vitamin B12 deficiency because its plasma levels increase before clinical symptoms appear. However, the lack of specificity of this analyte represents a serious limit to its use. Total homocysteinemia depends on genetic or physiological factors, life style, diseases in progress, and drugs. HHCY is caused by folate or vitamin Bg deficiency and renal failure. 

E-6) Homocysteinurla (defect in cystathionine synthase at this step). This is the most common form of ho-mocysteinuria). The enzyme defect leads to elevated levels of homocysteine, which can be detected in the urine. Serum methionine is also elevated. The clinical problems include dislocation of the lens, mental retardation, and various skeletal and neurologic problems. The mechanisms are unclear. Treatment may include administration of pyridoxine, decreasing dietary methionine and increasing cysteine. Elevated blood homocysteine is a risk factor for heart disease. 

Vitamin B12 and folate are both required for conversion of homocysteine to methionine. Increased serum homocysteine may help define vitamin B12 or folate deficiency. Homocysteine levels can also be elevated in vitamin Bg deficiency, renal failure, hypothyroidism, and in persons with a genetic defect in cystathionine /S-synthase. Additionally, elevated levels have been caused by medications including nicotinic acid, theophylline, methotrexate, and L-dopa. 

A vitamin B12 coenzyme is needed to convert methyknalonyl coenzyme A to succinyl co-enzyme A. Patients with vitamin B12 deficiency almost always have increased urinary excretion of methylmalonic acid (MMA). MMA is amore specific marker for vitamin B12 deficiency compared to homocysteine. MMA levels are not elevated in folate deficiency, as folate does not participate in MMA metabolism. Levels of both MMA and homocysteine are usually elevated prior to the development of hematologic abnormalities and reductions in serum vitamin B12 levels. MMA levels need to be interpreted cau-... 

If the blood levels of methionine and homocysteine are very elevated and cystine is low, cystathionine p-synthase could be defective, but a cystathionase deficiency is also a possibility. With a deficiency of either of these enzymes, cysteine could not be synthesized, and levels of homocysteine would rise. Homocysteine would be converted to methionine by reactions that require B12 and tetrahydrofolate (see Chapter 40). In addition, it would be oxidized to homocystine, which would appear in the urine. The levels of cysteine (measured as its oxidation product cystine) would be low. A measurement of serum cystathionine levels would help to distinguish between a cystathionase or cystathionine p-synthase deficiency. 

In the type of homocystinuria in which the patient is deficient in cystathione 13-synthase, the elevation in serum methionine levels is presumed to be the result of enhanced rates of conversion of homocysteine to methionine, caused by increased availability of homocysteine (see Fig. 39.14). In type II and type HI homocystinuria, in which there is a deficiency in the synthesis of methyl cobalamin and of N -methyltetrahydrofolate, respectively (both required for the methylation of homocysteine to form methionine), serum homocysteine levels are elevated but serum methionine levels are low (see Fig. 39.14). 

A third way in which serum homocysteine levels can be elevated is by a mutated cystathinone-(3-synthase or a deficiency in vitamin B6, the required cofactor for that enzyme. These defects block the ability of homocysteine to be converted to cystathionine, and the homocysteine that does accumulate cannot all be accommodated by conversion to methionine. Thus, an accumulation of homocysteine results. 

Major vitamin Bi2-dependent metabolic processes include the formation of methionine from homocysteine, and the formation of succinyl coenzyme A from methylmalonyl coenzyme A. Thus, apart from directly determining vitamin B12 concentration in serum, elevated levels of both methylmalonic acid and homocysteine may indicate a vitamin B12 deficiency. Serum cobalamine concentration is often determined by automated immunoassays using an intrinsic factor as binding agent. These assays have mainly replaced the microbiological methods. Literature data about vitamin B12 concentration in serum varies. Values <110-150pmoll are considered to reflect deficiency, whereas values >150-200pmoll represents an adequate status. 

Vitamin B12 deficiency is generally assessed based on serum vitamin B12 concentration, plasma homocysteine concentration and serum methylmalonic acid (MMA) concentration (Savage et al. 1994). Serum vitamin B12 concentration has been reported by many researchers, including us, to be similar in patients with CKD and healthy individuals (Koyama et al. 2002). However, plasma total homocysteine level is elevated in an inverse relationship with the reduction in renal function (Bostom and Lathrop 1997). 

High serum homocystein (22,23,172) is an important risk factor for both LEAD and CAD. Elevated levels of homocystein have been successfully dealt with green leafy salads and other foodstuffs rich in folic acid and also with pharmacologic preparations containing folic acid and vitamin B complex. 

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