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Biomedical subjects

Jürgen Geisel

Publications and source records attributed to Jürgen Geisel.

At least 19 recordsLinked to original sources
PubMed2006

Biventricular versus conventional right ventricular stimulation for patients with standard pacing indication and left ventricular dysfunction: the Homburg Biventricular Pacing Evaluation (HOBIPACE).

OBJECTIVES: The Homburg Biventricular Pacing Evaluation (HOBIPACE) is the first randomized controlled study that compares the biventricular (BV) pacing approach with conventional right ventricular (RV) pacing in patients with left ventricular (LV) dysfunction and a standard indication for antibradycardia pacing in the ventricle. BACKGROUND: In patients with LV dysfunction and atrioventricular block, conventional RV pacing may yield a detrimental effect on LV function. METHODS: Thirty patients with standard indication for permanent ventricular pacing and LV dysfunction defined by an LV end-diastolic diameter > or =60 mm and an ejection fraction < or =40% were included. Using a prospective, randomized crossover design, three months of RV pacing were compared with three months of BV pacing with regard to LV function, N-terminal pro-B-type natriuretic peptide (NT-proBNP) serum concentration, exercise capacity, and quality of life. RESULTS: When compared with RV pacing, BV stimulation reduced LV end-diastolic (-9.0%, p = 0.022) and end-systolic volumes (-16.9%, p < 0.001), NT-proBNP level (-31.0%, p < 0.002), and the Minnesota Living with Heart Failure score (-18.9%, p = 0.01). Left ventricular ejection fraction (+22.1%), peak oxygen consumption (+12.0%), oxygen uptake at the ventilatory threshold (+12.5%), and peak circulatory power (+21.0%) were higher (p < 0.0002) with BV pacing. The benefit of BV over RV pacing was similar for patients with (n = 9) and without (n = 21) atrial fibrillation. Right ventricular function was not affected by BV pacing. CONCLUSIONS: In patients with LV dysfunction who need permanent ventricular pacing support, BV stimulation is superior to conventional RV pacing with regard to LV function, quality of life, and maximal as well as submaximal exercise capacity.

Aged↗
PubMed2005

25-hydroxyvitamin D deficiency in renal transplant recipients.

CONTEXT: Bone disease after kidney transplantation is a common problem. The serum levels of the active vitamin D metabolite 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D] have been studied extensively. In contrast, there has not been much concern about the serum levels of 25-hydroxyvitamin D(3) [25(OH)D]. However, it is well recognized that serum levels of 1,25(OH)(2)D are often normal in vitamin D-deficient patients. Moreover, inadequate serum 25(OH)D may limit the extrarenal production of 1,25(OH)(2)D that could lead to increased risk of many chronic diseases. OBJECTIVE: We analyzed whether renal transplant patients were at a higher risk of 25(OH)D deficiency because of the consequence of their need to protect themselves from sun exposure. DESIGN, SETTING, AND PATIENTS: We hypothesized that renal transplant recipients are at high risk to develop 25(OH)D deficiency. Serum 25(OH)D levels were analyzed in renal transplant patients with adequate renal function and in an age- and gender-matched control group (n = 31) at the end of winter. All renal transplant patients practiced solar UV-protection after transplantation. 25(OH)D levels were compared using a nonparametrical test (Wilcoxon rank sum test). RESULTS: Serum 25(OH)D levels were significantly lower in renal transplant patients compared with controls (P = 0.007). Geometric mean (with 95% confidence interval) in renal transplant patients was 10.9 ng/ml (8.2-14.3) compared with 20.0 ng/ml (15.7-25.5) in the control group. CONCLUSIONS: Renal transplant recipients are at high risk to develop 25(OH)D deficiency. Treatment with vitamin D is recommended to correct their vitamin D deficiency, which may help protect them from serious vitamin D deficiency-related health problems that include an increased risk for internal malignancies.

Adult↗
PubMed2005

The vegetarian lifestyle and DNA methylation.

Vegetarians have a lower intake of vitamin B12 than omnivores do. Vitamin B12 deficiency (holotranscobalamin II <35 pmol/L or methylmalonic acid >271 nmol/L) was found in 58% of 71 vegetarians studied. Higher homocysteine levels (>12 micromol/L) found in 45% indicate disturbed remethylation of homocysteine to methionine. The methylation of DNA is strongly linked to homocysteine metabolism. Since DNA methylation is an important epigenetic factor in the regulation of gene expression, alteration of the methylation pattern has been associated with aging, cancer, atherosclerosis and other diseases. Three observations indicate that DNA methylation could be diminished by a vegetarian lifestyle. The vegetarian diet has a low content of methionine, remethylation of homocysteine is reduced by vitamin B12 deficiency and elevated homocysteine levels can induce the generation of S-adenosylhomocysteine (SAH), a potent inhibitor of methyltransferases. In our study we observed a significant correlation between SAH and whole-genome methylation (r=-0.36, p<0.01). This observation underlines the role of SAH as a potent inhibitor of methyltransferases. The methylation status was not correlated with homocysteine or S-adenosylemethionine (SAM). These results indicate that the degree of methylation does not depend on the supply of methyl groups and that the reverse generation of SAH has no influence. In addition to whole-genome methylation, the specific promoter methylation of the p66Shc gene was studied. However, the latter did not correlate with SAH, SAM or homocysteine. Obviously, the promoter methylation of the p66Shc gene is controlled in a specific way, without following the general regulating influence of SAH. In conclusion, an inhibitory effect of SAH on whole-genome methylation was found, but from our data no interaction between vegetarian lifestyle and DNA methylation could be determined.

Adaptor Proteins, Signal Transducing↗
PubMed2005

The usefulness of holotranscobalamin in predicting vitamin B12 status in different clinical settings.

Serum concentrations of homocysteine (Hcy) and methylmalonic acid (MMA) become increased in B12-deficient subjects and are therefore, considered specific markers of B12 deficiency. Serum level of holotranscobalamin (holoTC) becomes decreased before the development of the metabolic dysfunction. We investigated the usefulness of holoTC in diagnosing B12 deficiency in some clinical settings. We measured serum concentrations of holoTC, MMA, Hcy and total B12 in omnivores, vegetarians, elderly people and haemodialysis patients. Our results indicated that the incidence of holoTC <35 pmol/L was highest in the vegans (76%). Low holoTC and elevated MMA were detected in 64% of the vegans and 43% of the lacto- and lacto-ovovegetarians. An elevated MMA and a low holoTC were found in subjects with total serum B12 as high as 300 pmol/L. The distribution of holoTC in elderly people was similar to that in younger adults (median holoTC 55 pmol/L in both groups). A low holoTC and an elevated MMA were found in 16% of the elderly group. An elevated MMA and a normal holoTC were found in 20% of the elderly group who had a relatively high median serum concentration of creatinine (106.1 micromol/L). Serum concentrations of holoTC in dialysis patients were considerably higher than all other groups (median 100 pmol/L). This was also associated with severely increased serum levels of MMA (median 987 nmol/L). From these results it can be concluded that serum concentration of holoTC is a much better predictor of B12 status than total B12. This was particularly evident in case of dietary B12 deficiency. Serum concentrations of holoTC as well as MMA can be affected by renal dysfunction. Elevated MMA and normal holoTC in patients with renal insufficiency may not exclude vitamin B12 deficiency. HoloTC seems not to be a promising marker in predicting B12 status in renal patients.

Adult↗
PubMed2005

Evaluation of alkaline phosphatase activity assay for the Reflotron system after substitution of the comparison method.

The alkaline phosphatase (ALP) assay for the Reflotron system is a dry chemistry method applicable for decentralized testing. The ALP diethanolamine method has been applied as the comparison method, which is now replaced by the more widely distributed aminomethylpropanol method. The new comparison method measures ALP activities by approximately 59% lower compared to the former method. The analytical performance of the newly calibrated ALP Reflotron method was evaluated at three clinical laboratories. The study of the imprecision showed coefficients of variation ranging from 1.6-3.0% (intraassay) and 2.7-5.7% (interassay). Blood samples from liver disease patients (n=192), adolescents (n=40) and pregnant women in the third trimester (n=34) were collected in order to evaluate the impact of different ALP isoenzymes. The comparison between ALP Reflotron and the new comparison method revealed an excellent agreement in Passing-Bablok regression analysis (slope: 1.004; intercept: 0.14 U/l; median difference: 0.5%) for samples with prevailing liver ALP. However, in plasma samples with predominantly elevated bone or placental isoenzyme the Reflotron method measured lower or higher activities, respectively (slope: 0.912, 1.394; intercept: -4.16, -17.26 U/l; median difference: -10.58, 26.33%). The ALP Reflotron assay is an adequate method for decentralized testing. It shows a good precision and agreement with the comparison method, although the systematic differences for placental and bone ALP isoenzymes have to be considered.

Adolescent↗
PubMed2004

Screening for functional sequence variations and mutations in ABCA1.

Mutations in the ATP-binding cassette 1 transporter gene (ABCA1) are responsible for the genetic HDL-deficiency syndromes, which are characterized by severely diminished plasma HDL-C levels and a predisposition to cardiovascular disease and splenomegaly. The ABCA1 gene contains 50 exons and codes for a 2261-amino acid long membrane protein that facilitates phospholipid and cholesterol transport. Several mutations have been identified so far as responsible either for Tangier disease or for reduced HDL levels. We have selectively looked for additional polymorphisms in functionally relevant regions of the gene in cohorts constituted of individuals with altered HDL levels as well as healthy blood donors and octogenarians, and screened for mutations in the complete coding region of selected individuals with extremely aberrant HDL levels. In the promoter region, which is important for regulation of gene expression, we have identified several polymorphisms including one VNTR polymorphism, located at a putative ZNF202 binding site, which displayed different binding of ZNF202 in an electromobility shift assay. Three novel SNPs were discovered in the promoter region (G1047C, C1152T and C1440T). The prevalence of exchange G1047C (G-395C) was found significantly increased in probands with low HDL compared to probands with high HDL. Exchanges C1152T (C-290T) and C1440T (C-7T) were significantly more frequent in the cohort with low HDL compared to healthy blood donors and octogenarians. In the C-terminal part of ABCA1, known to interact with other proteins, two novel sequence variations (F2163S and V2244I) have been found in one phenotype related to cardiovascular disease, but none in the aforementioned cohorts. In one individual with extremely high HDL levels, the V771M polymorphism was found in a homozygous state. In patients with HDL deficiency, three novel mutations have been identified (W590L, W840R and R1068C). To facilitate further research in ABCA1 sequence variations and expand our understanding of their effects, we are introducing a webpage archive (http://www.abca1-mutants.all.at) containing all sequence variations reported in ABCA1 so far. This webpage provides a more recent and detailed summary of sequence variations and mutations in ABCA1 than existing databases and should also be of interest for molecular diagnosis of ABCA1-related HDL deficiency.

ATP Binding Cassette Transporter 1↗
PubMed2004

The measurement of complexed prostate-specific antigen has a better performance than total prostate-specific antigen.

The aim of this study was to compare the diagnostic utility of complexed prostate-specific antigen (cPSA) with total PSA (tPSA) in screening for prostate cancer. Serum concentrations of tPSA and cPSA were measured in 4479 adult men during the prostate cancer screening program in the Saarland region (Germany). The percentage of men with c/tPSA ratio above the cut-off value of 0.75 increased with increasing tPSA intervals: tPSA 0-0.9 microg/l, 4.4%; 1.0-1.9 microg/l, 24.3%; 2.0-2.9 microg/l, 43.9%; 3.0-3.9 microg/l, 50.4%; and 4.0-20 microg/l, 60.2%. The commonly accepted tPSA cut-off value of 3.9 microg/l matched to the 93rd percentile of the overall population (corresponding cPSA value, 2.9 microg/l). A total of 202 men out of 313 with increased cPSA had increased c/tPSA ratio (cut-off > or = 0.75) vs. 186 out of 312 men with increased tPSA. Thus, an additional 16 men at high risk for prostate cancer were selected only if cPSA was utilised as a first line parameter. Our data show that, compared to tPSA, cPSA measurement will always detect more high-risk patients, independent of the cut-off levels utilised for cPSA, tPSA and c/tPSA ratio. cPSA is more effective than tPSA in selecting subjects with an elevated c/tPSA ratio who are at high risk of prostate cancer. Thus, cPSA might be seen as the superior first-line parameter in screening for prostate cancer. Using lower cut-off values for tPSA or cPSA than the commonly accepted values seems reasonable for screening purposes.

Adult↗
PubMed2004

Alteration of homocysteine catabolism in pre-eclampsia, HELLP syndrome and placental insufficiency.

Hyperhomocysteinemia is a risk factor in obstetrical complications such as pre-eclampsia, 'hemolysis, elevated liver enzymes, low platelet' (HELLP)-syndrome and placental insufficiency. The aim of our study was to investigate the alterations of homocysteine catabolism in these patients in relation to serum B-vitamins and renal function. Maternal fasting serum from pre-eclampsia (n=24), HELLP (n=20) and placental insufficiency (n=25) patients at the time of diagnosis and pregnant controls (n=34) was analyzed for homocysteine and its metabolites cystathionine and methylmalonic acid, the vitamins B6, B12 and folate, renal and additional parameters. Cystathionine, a parameter of homocysteine catabolism, was significantly increased in pre-eclampsia and HELLP compared with controls and placental insufficiency patients (mean concentrations: 343, 324, 248, 227 nmol/l; p=0.001). Homocysteine, folic acid, vitamin B6 and methylmalonic acid, however, did not differ significantly between groups. The main determinants of cystathionine are cystatin C and vitamin B6, whereas the main determinants of homocysteine are folate and uric acid. The strongest dependency of cystathionine on vitamin B6 was observed in pre-eclampsia and HELLP patients. The results suggest that the vitamin B6-dependent trans-sulfuration pathway is activated in pre-eclampsia and HELLP syndrome, probably by oxidative stress. Therefore, the demand for vitamin B6 is increased in these patients. Furthermore, renal dysfunction and low vitamin B6 levels contribute to the increase of cystathionine in pre-eclampsia and HELLP patients.

Cystathionine↗
PubMed2003

Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians.

BACKGROUND: Vegetarians have a lower intake of vitamin B-12 than do omnivores. Early and reliable diagnosis of vitamin B-12 deficiency is very important. OBJECTIVE: The objective was to investigate vitamin B-12 status in vegetarians and nonvegetarians. DESIGN: The study cohort included 66 lactovegetarians or lactoovovegetarians (LV-LOV group), 29 vegans, and 79 omnivores. Total vitamin B-12, methylmalonic acid, holotranscobalamin II, and total homocysteine concentrations were assayed in serum. RESULTS: Of the 3 groups, the vegans had the lowest vitamin B-12 status. In subjects who did not consume vitamins, low holotranscobalamin II (< 35 pmol/L) was found in 11% of the omnivores, 77% of the LV-LOV group, and 92% of the vegans. Elevated methylmalonic acid (> 271 nmol/L) was found in 5% of the omnivores, 68% of the LV-LOV group, and 83% of the vegans. Hyperhomocysteinemia (> 12 micromol/L) was present in 16% of the omnivores, 38% of the LV-LOV group, and 67% of the vegans. The correlation between holotranscobalamin II and vitamin B-12 was weak in the low serum vitamin B-12 range (r = 0.403) and strong in the high serum vitamin B-12 range (r = 0.769). Holotranscobalamin II concentration was the main determinant of total homocysteine concentration in the vegetarians (beta = -0.237, P < 0.001). Vitamin B-12 deficiency led to hyperhomocysteinemia that was not probable in the upper folate range (> 42.0 nmol/L). CONCLUSIONS: Vegan subjects and, to a lesser degree, subjects in the LV-LOV group had metabolic features indicating vitamin B-12 deficiency that led to a substantial increase in total homocysteine concentrations. Vitamin B-12 status should be monitored in vegetarians. Health aspects of vegetarianism should be considered in the light of possible damaging effects arising from vitamin B-12 deficiency and hyperhomocysteinemia.

Adult↗
PubMed2003

Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism and the B-vitamins: a facet of nature-nurture interplay.

BACKGROUND: Methylenetetrahydrofolate reductase 677 (MTHFR 677) polymorphism may provoke hyperhomocysteinemia when folate status is low. The influence of MTHFR 677 mutation on homocysteine (HCY) levels in relation to vitamin B12 and folate status was investigated in the current study. SUBJECTS AND METHODS: 113 vegetarians, 123 omnivorous Germans, and 117 omnivorous Syrians were recruited. MTHFR 677 genotype, HCY, methylmalonic acid (MMA), total serum vitamin B12, serum folate, and vitamin B6 were determined using conventional methods. RESULTS: Omnivorous Germans displayed the lowest HCY levels compared with vegetarians and Syrians (median 8.0, 10.4, and 11.3 micromol/l, respectively). The highest serum folate and the highest MMA levels were found in vegetarians (median folate = 30.0; MMA = 355 nmol/l). Among vegetarians and Syrians, TT subjects had higher HCY levels than other genotypes which were, however, no longer significant in the highest folate tertiles. When the data were pooled, the odds ratio (OR, 95% CI) for HCY > 12 micromol/l was 3.81 (1.55-9.34) in TT compared with CC subjects. The OR increased to 28.85 (4.63-179.62) in TT subjects who had folate in the lowest tertile, and to 21.84 (4.81-99.1) in TT subjects who had MMA in the highest MMA tertile. CONCLUSION: MTHFR 677 TT individuals are more liable to hyperhomocysteinemia under vitamin B12 deficiency than the other two genotypes. In such a case, relative folate shortage may progressively increase HCY levels. TT individuals may have increased folate and vitamin B12 requirements compared to the other CC and CT genotypes.

Adolescent↗
PubMed2003

Stimulatory effect of homocysteine on interleukin-8 expression in human endothelial cells.

Elevated plasma homocysteine is an independent risk factor for atherosclerosis. An important initial step of atherosclerosis is the adhesion and infiltration of monocytes to the lesion site. It has been shown that the pro-inflammatory cytokine interleukin-8 can rapidly cause rolling monocytes to adhere firmly onto monolayers expressing E-selectin. The objective of the present study was to investigate the effect of homocysteine on interleukin-8 production in human endothelial cells. Cells were incubated with various concentrations of homocysteine for 20 h. The gene expression was determined by real-time PCR and the interleukin-8 protein was measured by immunoassay analysis. Homocysteine enhanced the expression of interleukin-8 in a dose-dependent manner (181% of controls at 2.5 mmol/l homocysteine). Stimulation of gene expression was associated with a parallel increase in interleukin-8 protein synthesis (160% of controls at 5.0 mmol/l homocysteine). By co-incubation of endothelial cells with homocysteine and copper sulfate, a further elevation of interleukin-8 expression (251% of controls) was observed, whereas copper sulfate alone had no stimulatory effect. In conclusion, the present study demonstrated that homocysteine altered endothelial cell function by stimulating interleukin-8 expression, suggesting a contribution of homocysteine to the initiation and progression of atherosclerosis. The formation of homocysteine-induced oxidation products might serve as one of the underlying mechanisms of this effect.

Catalase↗
PubMed2003

DACH-LIGA homocystein (german, austrian and swiss homocysteine society): consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations.

About half of all deaths are due to cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and getting larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases, homocysteine, a "new" risk factor, is being viewed with mounting interest. Homocysteine is a sulfur-containing intermediate product in the normal metabolism of methionine, an essential amino acid. Folic acid, vitamin B12, and vitamin B6 deficiencies and reduced enzyme activities inhibit the breakdown of homocysteine, thus increasing the intracellular homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild hyperhomocysteinemia and cardiovascular disease or all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10 micromol/l, the risk increase follows a linear dose-response relationship with no specific threshold level. Hyperhomocysteinemia as an independent risk factor for cardiovascular disease is thought to be responsible for about 10% of total risk. Elevated plasma homocysteine levels (>12 micromol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10% of the general population and in up to 40% of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence over-proportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial anti-thrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteine-mediated oxidative stress. Especially when acting as direct or indirect antagonists of cofactors and enzyme activities, numerous agents, drugs, diseases, and lifestyle factors have an impact on homocysteine metabolism. Folic acid deficiency is considered the most common cause of hyperhomocysteinemia. An adequate intake of at least 400 microg of folate per day is difficult to maintain even with a balanced diet, and high-risk groups often find it impossible to meet these folate requirements. Based on the available evidence, there is an increasing call for the diagnosis and treatment of elevated homocysteine levels in high-risk individuals in general and patients with manifest vascular disease in particular. Subjects of both populations should first have a baseline homocysteine assay. Except where manifestations are already present, intervention, if any, should be guided by the severity of hyperhomocysteinemia. Consistent with other working parties and consensus groups, we recommend a target plasma homocysteine level of <10 micromol/l. Based on various calculation models, reduction of elevated plasma homocysteine concentrations may theoretically prevent up to 25% of cardiovascular events. Supplementation is inexpensive, potentially effective, and devoid of adverse effects and, therefore, has an exceptionally favorable benefit/risk ratio. The results of ongoing randomized controlled intervention trials must be available before screening for, and treatment of, hyperhomocysteinemia can be recommended for the apparently healthy general population.

Austria↗
PubMed2003

The role of genetic factors in the development of hyperhomocysteinemia.

Moderate hyperhomocysteinemia has been identified as a new independent risk factor for cardiovascular and neurodegenerative diseases. This fact has produced interest in the study of genetic variants involved in homocysteine metabolism and its relationship to pathogenesis. Recently, more than 15 different genes were studied for their relationship to plasma homocysteine levels. We determined the influence of genetic variants in five genes (5,10-methylenetetrahydrofolate reductase (MTHFR) 677C --> T, serine hydroxymethyltransferase (SHMT) 1420C --> T, thymidylate synthase (TS) 2R --> 3R, catechol-O-methyltransferase (COMT) 1947G --> A and transcobalamin (TC) 776C --> G) on plasma homocysteine, folic acid and parameters of vitamin B12 metabolism in 111 vegetarians (mean age: 46 +/- 15 years) and 118 healthy seniors (mean age: 82 +/- 6.5 years). Median homocysteine concentration in plasma was significantly influenced by the MTHFR genotypes in both populations. In the vegetarians the median homocysteine level was increased by 8 micromol/l in individuals homozygous for the mutation as compared to wild-type or heterozygous genotypes (20.4 micromol/l vs. 12.9 and 12.7 micromol/l, respectively). This unexpected increase was observed although the folate levels were in medium to elevated ranges. Our results suggest that vegetarians have a higher demand for folate to neutralize the genotype effect. Preclinical vitamin B12 deficiency in vegetarians may be the cause for disturbed remethylation and folate trap. Plasma homocysteine was not significantly influenced by the SHMT, TS, COMT and TC mutations. In addition, for the TC mutation a trend toward cellular vitamin B12 deficiency was observed. The methylmalonic acid (MMA) levels were slightly elevated and the holotranscobalamin-II (holoTC-II) levels decreased. In the vegetarian group a significant relationship between the COMT genotype and holoTC-II concentration in plasma was determined, whereas the high activity COMT genotype (G/G) resulted in increased levels (35 micromol/l vs. 21 micromol/l for heterozygous and low activity genotypes). The MMA levels were inversely correlated to holoTC-II concentrations. In conclusion, the study on vegetarians and seniors documents interesting lifestyle-genotype interactions. Although the TC and COMT mutations influence cellular vitamin B12 metabolism, this effect did not result in overt homocysteine elevation.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed2003

Functional vitamin B12 deficiency and determination of holotranscobalamin in populations at risk.

BACKGROUND: The prevalence of a sub-clinical functional vitamin B12 deficiency in the general population is higher than previously expected. Total serum vitamin B12 may not reliably indicate vitamin B12 status. To get more specificity and sensitivity in diagnosing vitamin B12 deficiency, the concept of measuring holotranscobalamin II (holoTC), a sub-fraction of vitamin B12, has aroused great interest. HoloTC as a biologically active vitamin B12 fraction promotes a specific uptake of its vitamin B12 by all cells. In this study we investigated the diagnostic value of storage (holoTC) of vitamin B12 and functional markers (methylmalonic acid (MMA)) of vitamin B12 metabolism in populations who are at risk of vitamin B12 deficiency. SUBJECTS AND METHODS: Our study included 93 omnivorous German controls, 111 German and Dutch vegetarian subjects, 122 Syrian apparently healthy subjects, 127 elderly Germans and finally 92 German pre-dialysis renal patients. Serum concentrations of homocysteine (Hcy) and MMA were measured by gas chromatography-mass spectrometry, folate and vitamin B12 by chemiluminescence immunoassay, and holoTC by utilizing a RIA test. RESULTS: High Hcy (>12 micromol/l), high MMA (>271 nmol/l) resp. low holoTC (vitamin B12) in serum were detected in 15%, 8% resp. 13% (1%) of German controls, 36%, 60%, resp. 72% (30%) of vegetarians, 42%, 48% resp. 50% (6%) of Syrians, 75%, 42%, resp. 21% (7%) of elderly subjects and 75%, 67% resp. 4% (2%) of renal patients. The lowest median levels of holoTC were observed in vegetarians, followed by the Syrian subjects (23 and 35 pmol/l, respectively). Renal patients had significantly higher levels of holoTC compared to the German controls (74 vs. 54 pmol/l). In the vitamin B12 range between 156 pmol/l (conventional cut-off level) and 241 pmol/l, both mean concentrations of holoTC and MMA were in the pathological range. HoloTC was the earliest marker for vitamin B12 deficiency followed by MMA. Vitamin B12 deficiency causes folate trapping. A higher folate level is required to keep Hcy normal. The relationship between MMA and holoTC seemed dependent on renal function. In renal patients with a glomerular filtration rate below 36 ml/min, a significantly lower mean level of MMA was detected within the highest tertile of holoTC concentration, compared to the lowest tertile. Thus, in renal patients, a higher serum concentration of circulating holoTC is required to deliver sufficient amounts of holoTC into the cells. CONCLUSION: Our data support the concept that the measurement of holoTC and MMA provides a better index of cobalamin status than the measurement of total vitamin B12. HoloTC is the most sensitive marker, followed by MMA. The use of holoTC and MMA enables us to differentiate between storage depletion and functional vitamin B12 deficiency. Renal patients have a higher requirement of circulating holoTC. In renal dysfunction, holoTC cannot be used as a marker of vitamin B12 status.

Adult↗
PubMed2003

The impact of hyperhomocysteinemia as a cardiovascular risk factor in the prediction of coronary heart disease.

Coronary heart disease often occurs in the absence of traditional risk factors. Consequently, epidemiological studies exploring novel risk factors are necessary to improve the prediction of coronary heart disease. This study evaluated five promising markers of cardiovascular risk: homocysteine, C-reactive protein, fibrinogen, lipoprotein(a) (Lp(a)), free apolipoprotein(a) (apo(a)) and Lp(a) phenotypes. The study included 135 patients with angiographically confirmed atherosclerosis. The control group consisted of 93 sex- and age-matched individuals. The Mann-Whitney U-test was used for group comparison. New risk factors were evaluated by binary logistic regression. The odds ratios were calculated continuously for homocysteine in dependence on C-reactive protein. Low density lipoprotein (LDL)-cholesterol was nearly identical in controls and patients. Homocysteine, C-reactive protein, fibrinogen, high density lipoprotein (HDL)-cholesterol and Lp(a) discriminated highly significantly between both groups. The continuously calculated odds ratio for homocysteine demonstrated a distinct influence of C-reactive protein. In the group with high C-reactive protein levels, homocysteine levels above 9.6 micromol/l resulted in a markedly elevated risk (odds ratio 12), in the group with C-reactive protein levels below 5 mg/dl, a comparable risk increase was observed at a homocysteine level of 16.6 micromol/l. This data strongly suggests that plasma homocysteine helps identify individuals at risk, especially among those with elevated C-reactive protein levels.

Aged↗
PubMed2002

Vegetarian lifestyle and monitoring of vitamin B-12 status.

Vegetarians are at risk to develop deficiencies of some essential nutrients, especially vitamin B-12 (cobalamin). Cobalamin occurs in substantial amounts only in foods derived from animals and is essential for one-carbon metabolism and cell division. Low nutritional intake of vitamin B-12 may lead to negative balance and, finally, to functional deficiency when tissue stores of vitamin B-12 are depleted. Early diagnosis of vitamin B-12 deficiency seems to be useful because irreversible neurological damages may be prevented by cobalamin substitution. The search for a specific and sensitive test to diagnose vitamin B-12 deficiency is ongoing. Serum vitamin B-12 measurement is a widely applied standard method. However, the test has poor predictive value. Optimal monitoring of cobalamin status in vegetarians should include the measurement of homocysteine (HCY), methylmalonic acid (MMA), and holotranscobalamin II. Vitamin B-12 deficiency can be divided into four stages. In stages I and II, indicated by a low plasma level of holotranscobalamin II, the plasma and cell stores become depleted. Stage III is characterized by increased levels of HCY and MMA in addition to lowered holotranscobalamin II. In stage IV, clinical signs become recognizable like macroovalocytosis, elevated MCV of erythrocytes or lowered haemoglobin. In our investigations, we have found stage III of vitamin B-12 deficiency in over 60% of vegetarians, thus underlining the importance of cobalamin monitoring in this dietary group.

Analysis of Variance↗
PubMed2002

Apolipoprotein E2/E2 genotype in combination with mutations in the LDL receptor gene causes type III hyperlipoproteinemia.

The primary genetic cause of type III hyperlipoproteinemia is the homozygous presence of the apolipoprotein E2 allele. However, only approximately 1% of subjects with the apolipoprotein E2/E2 genotype develop type III hyperlipoproteinemia. Other factors are therefore necessary to express type III hyperlipoproteinemia. Two individuals were identified as having type III hyperlipoproteinemia (triglyceride to very low-density lipoprotein (VLDL) cholesterol ratio >0.3). However, in contrast to unchanged or slightly decreased low-density lipoprotein (LDL)-cholesterol levels typically observed in type III patients, elevated LDL-cholesterol levels were observed. The expected apolipoprotein E2/E2 isoform was confirmed by genetic analysis. To explain the elevated LDL-cholesterol level, single strand conformation polymorphism analysis was performed to screen for mutations in the LDL receptor gene. In both individuals, mutations causing an impaired LDL receptor function (2 bp insertion in exon 3 and Glu119 --> Gly mutation in exon 4) were identified. In six more unrelated individuals, these mutations combined with the common apolipoprotein E3/E3 genotype, resulted in an isolated, severe LDL-cholesterol elevation. Our results indicate that the level of LDL receptors plays an important role in remnant clearance, and that the combination of the binding-defective apolipoprotein E2 with a defective LDL receptor precipitate type III hyperlipoproteinemia.

Adult↗