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PubMed1989

Investigations of bone marrow dyscrasia in a poodle with macrocytosis.

A poodle-type dog with bone marrow dyscrasia and macrocytosis was investigated by clinicopathological, cytological and ultrastructural means. Peripheral blood analysis revealed macrocytosis and the presence of nucleated erythroid cells, some with nuclear/cytoplasmic asynchrony. Tendencies towards neutropenia and granulocytic hypersegmentation were observed. Bone marrow examination revealed low normal myeloid to erythroid ratio, the presence of megaloblasts and some giant metamyelocytes. In addition, there were abnormal mitoses, binuclearity and multinuclearity, incomplete nuclear membranes and nuclear clefts, intracytoplasmic parallel-sided membranes and apparent degenerate erythroid cells. Blood biochemical tests indicated normal to high concentrations of serum vitamin B12, serum folate and red cell folate. Transcobalamin I/IIIB12-binding capacity was similar to values for normal dogs, but transcobalamin II-binding capacity appeared high. It was concluded that the condition had similarities to both congenital dyserythropoietic disorders and true megaloblastic conditions, but until further investigations are reported it might be wise to refer to it as "bone marrow dyscrasia" in poodles.

Animals↗
PubMed1982

The uptake of R-type cobalamin-binding protein by isolated rat liver cells.

The uptake of R-type cobalamin-binding protein from human granulocytes and plasma by isolated parenchymal rat liver cells has been studied. When [57Co] cyanocobalamin-saturated granulocyte-binding protein or transcobalamin III was incubated with the liver cells in a concentration of 500 pM, more than 80% of the vitamin was taken up in 1 h. Vitamin B-12 bound to plasma transcobalamin I, however, was not taken up unless the protein was desialylated by neuraminidase from Vibrio cholerae. The uptake of iodinated pure granulocyte-binding protein, saturated with cobalamin, reached 100% and was accompanied by increasing intracellular proteolytic degradation of the binding protein. EGTA and asialo-orosomucoid completely inhibited this process of uptake and degradation, whereas partial inhibition was caused by chloroquine and colchicine. These observations provide evidence that these (asialo)-R-type cobalamin-binding proteins are taken up by the cell through the plasma membrane receptor for asialoglycoproteins by means of endocytosis followed by proteolysis of the binding protein in the lysosomes.

Animals↗
PubMed1995

The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism.

The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of [57Co]cyanocobalamin (CN-Cbl) bound to transcobalamin II (transcobalamin, TC). The intracellular pool of free [57Co]Cbl increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound [57Co]Cbl fractionated with methionine synthase (MS) and methylmalonyl-CoA mutase (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in MS activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1996

Holotranscobalamins in B12 and non B12 requiring prokaryotes and eukaryotes.

Transcobalamins, vitamin B12 binding proteins, deliver B12 to cell surface receptors which then permit B12 to cross cell membranes for metabolic use. There is little documentation concerning B12 binding proteins in bacteria and protists. We found that prokaryotes and eukaryotes requiring B12, as well as those protists synthesizing B12, also produce several transcobalamins for functionally transporting B12 similar to humans.

Animals↗
PubMed2006

Diagnosis of megaloblastic anaemias.

There are a large number of causes of megaloblastic anaemia. The most frequent are disorders resulting in vitamin B(12) or folate deficiency. The diagnostic process often consists first of establishing the presence of B(12) or folate deficiency and then of determining the cause of deficiency. The blood count, blood film, serum B(12) assay, and red cell and serum folate assays are the primary investigations. Other useful investigations include serum/plasma methylmalonic acid (MMA), plasma total homocysteine (tHCYS) and serum holo-transcobalamin II assays. All currently used tests have limitations regarding specificity or sensitivity or both and the metabolite assays are not widely available. An understanding of these limitations is essential in formulating any diagnostic strategy. The wide use of serum B(12) and metabolite assays has resulted in the increasingly early diagnosis of B(12) deficiency, often in patients without B(12)-related symptoms (subclinical deficiency). Food cobalamin malabsorption is the most frequent cause of a low serum B(12). At least 25% of low serum B(12) levels are not associated with elevated metabolite levels and may not indicate B(12) deficiency. Some of these are caused by partial deficiency of transcobalamine I.

Anemia, Megaloblastic↗
PubMed1980

Problems with the serum vitamin B12 assay.

Quality control trials have shown that, in routine practice, serum vitamin B12 estimations vary so much from laboratory to laboratory that serious confusion can result irrespective of whether microbiological or radioassay methods are used. Even experienced centres find the assay too insensitive and non-specific for a low level to be used as the sole criterion of vitamin B12 deficiency; the haemopoietic and biochemical sequelae of vitamin B12 deficiency also correlate poorly with the serum level. These basic difficulties with the assay seem to stem from the pattern of vitamin B12 (or cobalamin) binding in serum. Human beings are unique in having virtually all of their cobalamin attached to an apparently functionless binder, transcobalamin I. It is therefore not surprising that the serum cobalamin is such a poor predictor of cobalamin deficiency. The metabolically important serum binder is transcobalamin II and deficiency of this protein causes a potentially lethal megaloblastic anaemia even though the serum cobalamin level is normal. Tissue cobalamin depletion with normal serum levels also occurs after nitrous oxide inhalation and in certain inborn errors of metabolism.

Anemia, Megaloblastic↗
PubMed1999

Holotranscobalamin - a sensitive marker of cobalamin malabsorption.

BACKGROUND: No simple and reliable method of identifying patients with cobalamin malabsorption is available at present. The measurement of plasma holotranscobalamin, i.e. the metabolically active cobalamins bound to the transport protein transcobalamin, has been suggested as a means of fulfilling such criteria. DESIGN: We describe a method that directly quantifies cobalamins attached to transcobalamin. The method is evaluated in patients referred for gastrointestinal examination because of suspected cobalamin malabsorption. RESULTS: Of the 101 patients referred, all 48 with gastrointestinal conditions compatible with cobalamin malabsorption had plasma holotranscobalamin below 35 pmol L-1 (interval of 35-160pmol L-1). None of the patients with plasma holotranscobalamin above the lower reference limit had conditions compatible with cobalamin malabsorption. CONCLUSION: The values obtained for plasma holotranscobalamin showed a better correlation with possible malabsorption than the values obtained for plasma cobalamins. The specificity of the test, however, needs to be elucidated further.

Adolescent↗
PubMed2005

Novel and established markers of cobalamin deficiency: complementary or exclusive diagnostic strategies.

New developments in diagnostic markers and a better understanding of the limitations of traditional diagnostic strategies have allowed diagnosis of earlier stages and atypical forms of cobalamin deficiency. Still, there are no generally accepted guidelines for the definition, diagnosis, treatment, and follow-up of cobalamin deficiency. The new trend toward defining cobalamin deficiency purely on the basis of biochemical test outcomes in the absence of overt clinical signs and symptoms could, however, be problematic and may result in overdiagnosis and overtreatment. Use of metabolic markers for the assessment of cobalamin deficiency allows the demonstration of tissue deficiency, but the establishment of the cause of deficiency should also be part of the diagnostic approach. Four groups of diagnostic tests are currently available and these include total cobalamin and cobalamin fractions (such as holo-transcobalamin), tests of gastrointestinal dysfunction, tests of metabolic function, and different gene tests. Among the available tests, only homocysteine, methylmalonic acid, holo-transcobalamin, and possibly methylcitric acid are considered to be useful in clinical practice to add to cobalamin. Gastrointestinal function tests may identify the cause of cobalamin deficiency, whereas the diagnostic usefulness of genetic testing needs to be evaluated. This article provides an overview of recent developments and a reappraisal of novel and established diagnostic markers for cobalamin deficiency.

Biomarkers↗
PubMed1981

The content, binding, and forms of vitamin B12 in milk.

The vitamin B12 (cobalamin, Cbl) content of 19 human milks ranged from 0.33 to 3.20 ng/ml, mean 0.97 ng/ml. The milk content of 10 mothers taking 5 to 100 micrograms of supplemental cyanocobalamin daily was not significantly different from that of unsupplemented mothers. The Cbl native to milk was bound to an R type binder. The R binder was also the dominant, by far, unsaturated Cbl binder, but transcobalamin II was found in every milk. The amounts of transcobalamin II were of the same order of magnitude as in serum and seemed to increase with the interval postpartum. Methylcobalamin was the most abundant Cbl of milk. Human milk from well fed mothers contains adequate amounts of Cbl, but the Cbl may become available only if there are sufficient proteolytic enzymes to release it from binding to R binder.

Chromatography, Gel↗
PubMed1983

Separation of cobalamin analogues in human sera binding to intrinsic factor and to R-type vitamin B12 binders.

Intrinsic factor (IF) and cobalamin-R-binding protein (R-binder) linked to polyacrylamide beads were used to absorb cobalamins from solutions and serum extracts. Both binding agents were equally effective in removing [57Co]B12 from aqueous solution. IF was more effective than R-binder in removing [57Co]B12 added to a serum extract. All endogenous cobalamins detectable in serum by saturation analysis assay were removed by absorption onto R-binder. Absorption with IF removed microbiologically-active cobalamins but left behind analogues assayable with an R-binder. However, when absorption with IF was continued the concentration of R-binding cobalamins steadily declined indicating that IF bound both types of cobalamins through the binding was less avid for the microbiologically-inactive analogues than for microbiologically-active cobalamins. Finally, the R-binding analogues in serum were carried on transcobalamin I and none was detectable on transcobalamin II. The absorption studies establish the presence of two types of cobalamins one binding preferentially to IF and the other preferentially to R-binder. Only the former is detected by microbiological assay.

Absorption↗
PubMed1993

The sources and biochemical characteristics of cobalamin-binders in human amniotic fluid.

The sources and biochemical characteristics of cobalamin-binders in amniotic fluid were investigated. Using gel-permeation chromatography, cobalamin-binder, extracted from amniotic fluid at term, was recovered in a single peak with the molecular size of haptocorrin. Neonatal saliva also contained only haptocorrin. However, neonatal gastric juice contained two types of cobalamin-binders: haptocorrin and intrinsic factor. Amniotic fluid in midtrimester contained three types of cobalamin-binders: haptocorrin, intrinsic factor, and transcobalamin II. The cultured amnion cells secreted mainly apo-transcobalamin II. Concentrations of both apo-haptocorrin and salivary amylase in amniotic fluid increased as gestation advanced. These results suggest that cobalamin-binder in amniotic fluid in midtrimester originates from the fetal salivary gland, fetal gastric mucosa, and amnion cells, and that the contribution by the fetal salivary gland increases at term, when almost all cobalamin-binders in amniotic fluid are haptocorrin.

Amniotic Fluid↗
PubMed1983

Limitations of protein-coated charcoal in the separation of free from bound vitamin B12 in serum.

The effect of haemoglobin and albumin-coated charcoal on the concentration of vitamin B12 binding proteins in serum has been investigated. As commonly employed, coated charcoal removes a significant amount of transcobalamin II (TCII) from serum, but does not affect transcobalamin I and III (TCI and III). Increasing the protein coat up to about 10 mg of protein per 25 mg of charcoal reduces the adsorption of TCII, but increasing the protein concentration beyond this has little added effect. The amount of adsorption is proportional to the amount of coated charcoal employed, but even small amounts adsorb some TCII. These results indicate that protein-coated charcoal is not the ideal way of separating free from bound vitamin B12 in serum; it cannot reliably be used for the measurement of the concentration of apo-TCII but can be employed for the measurement of apo-TCI and III.

Albumins↗
PubMed1988

Distribution of vitamin B12 R-binder in carcinomas of the digestive tract.

To evaluate whether the increase in serum transcobalamin I, seen in patients with carcinoma, is caused by synthesis of R-binder to tumour cells, the distribution of vitamin B12 R-binder in 125 malignant growths of the digestive tract was studied. Positive staining for R-binder with immunoperoxidase was observed in 85 (70%) carcinomas. Positive staining for R-binder was observed in all four cholangiocarcinomas studied, but was absent in nine hepatocellular carcinomas. These findings suggest that determination of R-binder in liver tumours may be of some value in differentiating hepatocellular carcinomas and cholangiocarcinoma, and that synthesis of R-binder by tumour cells causes an increase in serum transcobalamin I.

Adenocarcinoma↗
PubMed2005

Homocysteine and related genetic polymorphisms in Down's syndrome IQ.

OBJECTIVE: Down's syndrome (DS) is the most frequent genetic cause of Alzheimer-type dementia. Its metabolic phenotype involves an increased trans-sulphuration of homocysteine. The aim of the present study was to investigate the influence of homocysteinaemia (t-Hcys), folate, vitamin B(12), and related polymorphisms on intelligence quotient (IQ) in DS. METHODS: The IQ of 131 patients with trisomy 21 from a specialist centre in Sicily was determined and classified according to DMS-IV. The effects of age, folate, vitamin B(12), t-Hcys, and genetic polymorphisms on IQ were evaluated separately and in combination using regression analyses. RESULTS: IQ was significantly lower in DS patients with t-Hcys >7.5 micromol/l (median) and in those who were carriers of methylenetetrahydrofolate reductase (MTHFR) 677 T allele and of methylenetetrahydrofolate reductase 677 T and transcobalamin 776 G combined alleles (p = 0.0013, p = 0.0165, and p = 0.0074, respectively). The IQ correlated significantly with t-Hcys and folate in single and multiple regression analyses, independently of age. In addition, t-Hcys >9.6 micromol/l (upper quartile) was found to be associated with low IQ (<40, median of study group) with an odds ratio of 2.61 (p = 0.0203). The odds ratio was increased by threefold in carriers of MTHFR 677T allele. The MTHFR 677T allele/transcobalamin 776 G allele combination was associated with the risk of DS patients to have an IQ less that the median with an odds ratio of 2.68 (95% CI 1.26 to 5.70, p = 0.0104). CONCLUSION: This study found evidence of an association between t-Hcys and MTHFR 677 T and transcobalamin 776 G alleles with IQ in patients with DS. The association may be related to a defective remethylation of homocysteine, affecting IQ.

Alleles↗
PubMed1985

Levels of iron, vitamin B12, folic acid and their binding proteins during pregnancy.

One hundred pregnant women, not anemic and not receiving iron or vitamin supplements, were chosen at random among the three trimesters of pregnancy to determine the incidence of unexpected iron, plasma folate and/or cobalamin deficiency, and the significance of fluctuating levels of their respective binding proteins. Pregnant females had a nonsignificant fall in serum iron and a fourfold decline in serum ferritin in the 3rd trimester compared with 1st trimester values. There was a steady decrease in plasma cobalamin and cobalophilin levels in every trimester but no difference in transcobalamin II values. Unsaturated cobalamin (UBBC) and unsaturated transcobalamin binding capacity (UTCBC) were lower in the 1st trimester fully recovering afterwards. Plasma folate levels were not lower, although there was a steady reduction in total and unsaturated folate binding capacity throughout pregnancy.

Adult↗
PubMed1991

Metabolism of 1-13C-propionate in vivo in patients with disorders of propionate metabolism.

Metabolism of propionate in human subjects was studied using bolus administration of 1-13C-propionate i.v. or orally. The study population consisted of five patients with propionic acidemia (PA), eight with methylmalonic acidemia (MMA; four responsive to vitamin B12), one each with multiple carboxylase deficiency and transcobalamin-II deficiency, and five healthy volunteers. Concentrations of 1-13C-propionate were measured in blood in three patients with PA, two with MMA, and two controls. Breath samples were obtained at intervals during 3 h after the dose, isotopic enrichment of 13CO2 was measured, and the cumulative percentage of recovery of 13C was calculated from the individual's predicted resting energy expenditure. Recovery of 13CO2 and half-time of 1-13C-propionate in PA were significantly less than normal. The same parameters in MMA were below normal, but significantly greater than in PA. Recovery of 13CO2 was well correlated with clinical severity in PA, but did not correlate in MMA. Differences between MMA and PA may indicate different distribution of propionate pools, differences in inducibility of residual enzyme activities, or an alternate pathway for decarboxylation of propionate available in MMA but not PA. Only one patient with PA demonstrated increased 13CO2 production during biotin treatment. In a B12-responsive MMA patient, no differences were noted within 2 d of initiating treatment with B12, but there was an increase in 13CO2 production after 4 mo. Recovery of 13CO2 was normal in the patient with transcobalamin-II deficiency before and after treatment with vitamin B12.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1982

Brain content of cobalamin and its binders in elderly subjects.

The biological aspects of cobalamin were studied in autopsy brains of eight elderly subjects who had lacked marked neurologic symptoms. Separation of the gray and white matter of the frontal and temporal lobes, and subsequently, subcellular fractionation of each matter were attempted. The contents of cobalamin and its binders and cobalamin concentrations were measured in each subcellular fraction and whole homogenate. The contents of cobalamin were in the ranges of 50 to 60 ng/g wet tissue. No marked differences in contents were found between the frontal and temporal lobes. The mitochondria-rich fraction contained more cobalamin than did the microsomal fraction. Two binders were found; a large-sized and a small-sized. The molecular weight of the larger binder was ca. 120,000, coinciding with the elution region of transcobalamin I, and the molecular weight of the smaller binder was 40,000, coinciding with the elution region of transcobalamin II, in gel filtration respectively. More of the larger binder than the smaller was found in the mitochondria-rich and microsomal fractions. These data are useful for the study of various aspects of cobalamin in brains with various types of neurologic pathology or aging changes.

Aged↗
PubMed1999

Discovery of vitamin B12 in the liver and its absorption factor in the stomach: a historical review.

This review describes the early chronological events in the pursuit of a treatment for pernicious anaemia, and the subsequent discovery of vitamin B12 and the intrinsic factor. It details Castle's experiments which established the theory of extrinsic and intrinsic factors as hemopoietic principles, and describes the studies on purification of the anti-pernicious anaemia principle from liver tissue that terminated in the crystallization of vitamin B12 and identification of its coenzyme forms. Biochemical purification and characterization of the intrinsic factor secreted by the gastric parietal cells, and two other vitamin B12 proteins, R-binder (transcobalamin I, haptocorrin), and transcobalamin II, are discussed in detail. The biochemical reactions in micro-organisms and humans in which vitamin B12 is involved are then briefly reviewed, and finally and briefly the immunological basis of pernicious anaemia is discussed.

Anemia, Pernicious↗