Biochemical indices of vitamin B12 nutrition in pregnant patients with subnormal serum vitamin B12 levels

To determine the significance of the commonly observed fall in serum vitamin B₁₂ levels during pregnancy, serum levels of the B₁₂ metabolites methylmalonic acid (MMA) and homocysteine (Hcy) were measured in a group of 50 pregnant patients with subnormal serum B₁₂ (range 45-199 pg/ml) and the results compared with those of 25 pregnant controls (serum B₁₂208-580 pg/ml). Mean values for serum MMA and total Hcy in the subnormal B₁₂ group were 445.4 nmol/L and 7.03 μmol/L, respectively, which were not significantly different from the mean MMA of 440.5 nmol/L and Hcy of 6.88 nmol/L in the controls. For the total group of patients, neither serum MMA nor serum Hcy levels correlated with serum B₁₂. One-third of pregnant patients showed elevated serum MMA values, independent of B₁₂ status. Significant elevation of serum Hcy was detected in only two patients, both with subnormal serum B₁₂ and hematological evidence of B₁₂ deficiency. We conclude that the usual fall in serum B₁₂ concentration in pregnancy does not reflect B₁₂ deficiency at the biochemical level. In establishing true B₁₂ deficiency in pregnancy, the serum Hcy level (in the absence of folate deficiency) but not serum MMA, is of value. © 1995 Wiley-Liss, Inc.     

High prevalences of vitamin B12 and folic acid deficiency in elderly subjects in Israel

The prevalences of vitamin B12 and folic acid deficiency in the general Israeli population of elders has not been assessed. We measured plasma cobalamin and folic acid concentrations in 418 subjects from four institutions for the aged, 749 subjects attending 19 geriatric day centres and 104 healthy controls. Methylmalonic acid (MMA) and/or homocysteine concentrations were determined in subjects who had a cobalamin concentration <221 pmol/l or folic acid concentration <11 nmol/l respectively. The prevalences of vitamin B12 deficiency (cobalamin <147 pmol/l and MMA > or =0.24 micromol/l), and folic acid deficiency (folic acid <11 nmol/l and homocysteine of >15 micromol/l) in subjects from day centres were 12.6% and 16.4% respectively, and in subjects from institutions 1.2% and 2.2% respectively (P < 0.001). Multiple logistic regression analysis indicated that the relative risk of living at home versus institutions for the aged was highly significant, with odds ratios (OR) of 6.8 [95% confidence interval (CI) 2.6-18.0] for vitamin B12 deficiency and 6.6 (95% CI 2.9-13.1) for folic acid deficiency. Analysis of data for day centre patients showed that folic acid deficiency was a significant risk factor of vitamin B12 deficiency (adjusted OR 3.68, 95% CI 2.27-5.98), and vitamin B12 deficiency was a significant risk of folic acid deficiency (adjusted OR 3.69, 95% CI 2.27-6.01). These data suggest that malnutrition is a major cause of the highly prevalent deficiencies of vitamin B12 and/or folic acid in elderly Israeli subjects dwelling at home.     

Serum cobalamin, folate, methylmalonic acid and total homocysteine as vitamin B12 and folate tissue deficiency markers amongst elderly Swedes--a population-based study

OBJECTIVES: The possibilities of detecting tissue cobalamin and folate deficiency are under debate. In this report the levels of serum cobalamin, folate, methylmalonic acid (MMA) and total homocysteine (tHcy) and their interrelations in a representative random population sample are presented. DESIGN: Cohort study. SETTING: A general mid-Swedish population. SUBJECTS: A 20% random sample of persons 70 years or older in a defined geographical area were invited to a survey. A total of 235 (85%) persons responded, out of whom 224 had no interfering diseases. MAIN OUTCOME MEASURES: Serum cobalamin, folate, MMA and tHcy. RESULTS: The serum levels of cobalamin, folate, MMA and tHcy were all correlated to cobalamin and folic acid treatment. They were also correlated to the intake of multivitamin preparations. In addition, serum cobalamin was higher in untreated women than in men but not correlated to age. Serum folate was correlated neither to sex nor age. Serum tHcy and MMA were both directly correlated to age but MMA not to sex. MMA was inversely correlated to serum cobalamin but not to serum folate, whereas serum tHcy was inversely correlated to serum cobalamin, folate and creatinine. Neither serum cobalamin, folate, MMA nor tHcy had any significant correlation to haemoglobin, erythrocyte volume fraction (EVF) or mean red cell volume. Half of the study population had abnormal MMA or tHcy levels, suggesting a latent or overt tissue deficiency of cobalamin or folate. CONCLUSIONS: A substantial proportion of the elderly general population had signs of low tissue levels of cobalamin or folate. Amongst those who took multivitamin preparations this proportion was much lower.     

Function of vitamin B12 in the central nervous system as revealed by congenital defects

The 13 cases of methylcobalamin (MeCbl) deficiency presenting in early infancy have all been developmentally delayed, and the majority have had seizures, hypotonia, lethargy, and microcephaly. The CNS injury appears to occur during the first 6 months of postnatal life. The same symptoms are seen in acquired cobalamin (Cbl) deficiency in the same age group. MRI performed at age 18–19 months and after 13–14 months of large amounts of Cbl, in two cases showed delayed myelination, most pronounced in the cerebrum. Isolated MeCbl deficiency is the consequence of cblE and G mutations where the lesion is of a single Cbl-dependent enzyme, the methyltransferase. One effect of a deficiency of MeCbl, and of the associated failure of the methionine synthase reaction, is, therefore, an impairment of myelination of the brain of the newborn. The slow, but usually incomplete, improvement in psychomotor status after years of treatment with Cbl may be related to the eventual myelination. However, the hypotonia, lethargy, and impaired responsiveness react to treatment with Cbl within 24–48 hours, which suggests an expression of MeCbl deficiency on the CNS distinct from the delayed myelination. Although there is much to be learned, it is now clear that a normally functioning Cbl-dependent methyl transferase is required for development and function of the human brain.     

Crohn's disease and vitamin B12 metabolism

The concentrations of vitamin B₁₂, its analogs, and the haptocorrin and transcobalamin carriers in 21 patients suffering from Crohn's disease and a group of controls (20 adults) were measured. There were no significant differences in the mean values for vitamin B₁₂, total corrinoids (vitamin B₁₂ + analogs), or vitamin B₁₂ or total corrinoids bound to haptocorrin or transcobalamin of the Crohn's and control patients. There was a significant increase in the binding capacity of transcobalamin in the Crohn's patients compared to the controls (P<0.001), but there was no difference in the binding capacities of haptocorrin. The serum concentrations of the markers of vitamin B₁₂ status, homocysteine and methylmalonic acid, showed an increase (P<0.01) in homocysteine in the Crohn's disease patients, but no change in methylmalonic acid. As the hyperhomocysteinemia was associated with normal folate concentrations, there may have been a defect in the activation of the enzyme due to altered intracellular vitamin B₁₂ status.     

Dietary deficiency of vitamin B12 is associated with low serum cobalamin levels in non-vegetarians

A prospective study of 106 patients with low serum cobalamin (vitamin B12) levels showed that, in 37, it was unexplained. The dietary intake of the vitamin was assessed in these patients by questionnaire and was found to be low in 10 (37%). None of these patients was vegetarian and they were of varying age and social circumstance. Dietary deficiency may be the sole cause of a low serum cobalamin in a significant proportion of non-vegetarians. An assessment of dietary intake should be part of the investigation of cobalamin deficiency.     

Measurement of red blood cell-vitamin B12: A study of the correlation between intracellular B12 content and concentrations of plasma holotranscobalamin II

We have recently reported a new and rapid assay to measure plasma holotranscobalamin II (holo TC II) as a means of exploring vitamin B12 status. In order to further evaluate the significance of plasma holo TC II in determining tissue cobalamin, we have chosen the red blood cell-vitamin B12 (RBC-B12) assay as a measure of tissue vitamin B12 content and studied the relationship between RBC-B12 and plasma holo TC II levels. Plasma holo TC II and RBC-B12 concentrations were concomitantly assayed in 20 hematologically normal controls and cancer patients. In our groups of controls, the mean value of RBC-B12 was determined as 241 ± 51 pg/ml of packed erythrocytes (PE) with a range varying from 180 to 355 pg/ml PE. Preliminary results obtained in 32 cancer patients revealed lower holo TC II and RBC-B12 levels than the control group and a required threshold value of 70 pg/ml of holo TC II in order to maintain a normal RBC-B12 greater than 180 pg/ml PE.     

Anaerobic biosynthesis of the lower ligand of vitamin B12

Vitamin B₁₂ (cobalamin) is required by humans and other organisms for diverse metabolic processes, although only a subset of prokaryotes is capable of synthesizing B₁₂ and other cobamide cofactors. The complete aerobic and anaerobic pathways for the de novo biosynthesis of B₁₂ are known, with the exception of the steps leading to the anaerobic biosynthesis of the lower ligand, 5,6-dimethylbenzimidazole (DMB). Here, we report the identification and characterization of the complete pathway for anaerobic DMB biosynthesis. This pathway, identified in the obligate anaerobic bacterium Eubacterium limosum, is composed of five previously uncharacterized genes, bzaABCDE, that together direct DMB production when expressed in anaerobically cultured Escherichia coli. Expression of different combinations of the bza genes revealed that 5-hydroxybenzimidazole, 5-methoxybenzimidazole, and 5-methoxy-6-methylbenzimidazole, all of which are lower ligands of cobamides produced by other organisms, are intermediates in the pathway. The bza gene content of several bacterial and archaeal genomes is consistent with experimentally determined structures of the benzimidazoles produced by these organisms, indicating that these genes can be used to predict cobamide structure. The identification of the bza genes thus represents the last remaining unknown component of the biosynthetic pathway for not only B₁₂ itself, but also for three other cobamide lower ligands whose biosynthesis was previously unknown. Given the importance of cobamides in environmental, industrial, and human-associated microbial metabolism, the ability to predict cobamide structure may lead to an improved ability to understand and manipulate microbial metabolism.Vitamin B₁₂ (cobalamin) is required by the majority of animals, protists, and prokaryotes, although B₁₂ and other cobamide cofactors are synthesized exclusively by a subset of prokaryotes (1). Cobalamin is a member of the cobamide family of cofactors that are composed of a central cobalt ion coordinated by a tetrapyrrolic corrin ring, an upper ligand, and a lower ligand covalently tethered to the corrin ring by a nucleotide loop (Fig. 1A) (1). The lower ligand of cobalamin is 5,6-dimethylbenzimidazole (DMB). Purines, phenolic compounds, and other substituted benzimidazoles have also been found as cobamide lower ligands (2).Open in a separate windowFig. 1.Vitamin B₁₂ structure and the labeling pattern of DMB. (A) Structure of cyanocobalamin (vitamin B₁₂). Cbi and the lower ligand DMB are indicated. (B) AIR is a branch point in the biosynthesis of thiamin (8), purines (27), and benzimidazoles (as shown in this study). The symbols represent the origins of atoms in each product: ●, formyltetrahydrofolate; #, glutamine; *, glycine; shaded circle, erythrose 4-phosphate or threose; ▪, methionine.Distinct oxygen-requiring (aerobic) and oxygen-sensitive (anaerobic) cobamide biosynthesis pathways have been characterized, and each contains ∼30 genes (1). The biosynthetic pathway for DMB remained elusive until the discovery of the bluB gene, the product of which fragments reduced flavin mononucleotide (FMNH₂) to produce DMB in an oxygen-dependent reaction (3–6). Currently, the only unidentified genes in the cobamide biosynthesis pathway are those required for the anaerobic biosynthesis of DMB and other benzimidazoles (7). Based on previous isotope-labeling studies, performed mainly in the anaerobic bacterium Eubacterium limosum, the biosynthesis of DMB was proposed to branch from the purine biosynthetic pathway, similar to the pyrimidine ring of the cofactor thiamin pyrophosphate (Fig. 1B) (2, 8–15). Here, we sought to identify the genes in Eubacterium limosum required for the biosynthesis of DMB.     

Oral cobalamin (vitamin B12) treatment. An update

The objective of this review was to evaluate oral cobalamin (vitamin B₁₂) therapy in adult and elderly patients, from the perspective of a hematologist. PubMed was systematically searched for English and French articles published from January 1990 to January 2007. Data from our working group, the ‘Groupe d’étude des carences en vitamine B₁₂des Hôpitaux Universitaires de Strasbourg’, have also been included. Several prospective studies in well‐determined population (n = 4), prospective randomized studies (n = 3) and a systematic review by the Cochrane group (n = 1) provide evidence that oral cobalamin therapy may adequately treat cobalamin deficiency, particularly hematological abnormalities or manifestations. These studies suggest that at least 1000 μg/day of oral cyanocobalmin are needed for pernicious anemia and a mean daily dose of 250 μg for food‐cobalamin malabsorption. This present review confirms the previously reported efficacy of oral cobalamin treatment in adult and elderly patients.     

Interrelationships between Vitamin B12 and Folic Acid in Myelomatosis: Cobalamin Coenzyme and Tetrahydrofolic Acid Function

Cobalamin and folate metabolism was investigated in 43 patients with myelomatosis, in 8 control subjects of similar age and 22 younger controls. Plasma total cobalamin was lower in myeloma patients than in either of the control groups and methylcobalamin (Me-Cbl) was disproportionately reduced. Erythrocyte levels of total cobalamin were very similar in patients and elderly controls but were half the levels in younger controls. Erythrocyte levels of Me-Cbl were slightly higher in patients than in the elderly controls. FIGLU excretion after L-histidine was elevated in 53 % of the patients but values did not correlate with serum or erythrocyte folate or with plasma total cobalamin. FIGLU excretion decreased after DL-methionine or Me-Cbl only in patients whose FIGLU excretion was initially high. The results are discussed in the light of the ‘methylfolate trap hypothesis’ and suggest that some patients with myelomatosis have insufficient activity of methionine synthetase to meet the additional metabolic demand for one carbon compounds.     

In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations

In a recent study of older participants (age >/=60 years) in the 1999-2002 National Health and Nutrition Examination Survey (NHANES), we showed that a combination of high serum folate and low vitamin B(12) status was associated with higher prevalence of cognitive impairment and anemia than other combinations of vitamin B(12) and folate status. In the present study, we sought to determine the joint influence of serum folate and vitamin B(12) concentrations on two functional indicators of vitamin B(12) status, total homocysteine (tHcy) and methylmalonic acid (MMA), among adult participants in phase 2 of the NHANES III (1991-1994) and the NHANES 1999-2002. Exclusion of subjects who were <20 years old, were pregnant, had evidence of kidney or liver dysfunction, or reported a history of alcohol abuse or recent anemia therapy left 4,940 NHANES III participants and 5,473 NHANES 1999-2002 participants for the study. Multivariate analyses controlled for demographic factors, smoking, alcohol use, body mass index, self-reported diabetes diagnosis, and serum concentrations of creatinine and alanine aminotransferase revealed significant interactions between serum folate and serum vitamin B(12) in relation to circulating concentrations of both metabolites. In subjects with serum vitamin B(12) >148 pmol/liter (L), concentrations of both metabolites decreased significantly as serum folate increased. In subjects with lower serum vitamin B(12), however, metabolite concentrations increased as serum folate increased starting at approximately 20 nmol/L. These results suggest a worsening of vitamin B(12)'s enzymatic functions as folate status increases in people who are vitamin B(12)-deficient.     

Spouses of demented patients with low cobalamin levels: a new risk group for cobalamin deficiency

Abstract: Low serum cobalamin levels are common in conditions such as dementia and often represent mild deficiency. We surveyed serum cobalamin levels prospectively in spouses and blood relatives of demented patients to determine if any familial predisposition exists for the low levels. Cobalamin status in most of the relatives found to have low levels was assessed further by means of blood counts, metabolic tests, neurologic evaluation, absorption studies and response to cobalamin therapy. Serum cobalamin levels in 36 spouses correlated with those of the 36 demented patients related to them (r = 0.46, p = 0.004). A significant association was not seen in 34 blood relatives of 34 demented patients (r = 0.27). Most importantly, 67% of the spouses of demented patients with low serum cobalamin had low values themselves, compared with only 3% of the spouses of patients with normal levels (p = 0.001). Detailed study of 4 of the 5 spouses (and 3 blood relatives) with low cobalamin levels showed no anemia in any case. Nevertheless, 4 of the subjects had metabolic evidence of deficiency and one had electrophysiological abnormalities; all these defects improved with cobalamin therapy. These observations identify a hitherto unsuspected group of people at high risk for cobalamin deficiency and suggest that spouses of demented patients with low cobalamin levels should also have their cobalamin levels measured. The increased frequency of low serum cobalamin levels in spouses of demented patients with low levels represents in most cases a true, mild cobalamin deficiency that responds to treatment.     

Prospective evaluation of protein bound vitamin B12 (cobalamin) malabsorption in the elderly using trout flesh labelled in vivo with 57Co-cobalamin

Background—The frequency of dietary proteinbound vitamin B₁₂ malabsorption in elderly patients remains controversial.
Aims—To evaluate this malabsorption inelderly hospitalised patients using a modified Schilling test.
Patients—Fourteen elderly patients with lowB₁₂ blood levels were prospectively selected from 394 hospitalised patients.
Methods—The modified Schilling test was performedwith trout labelled in vivo.
Results—The test was normal in five healthyelderly subjects, in 7/8 patients with pancreatic insufficiency, and innine non-elderly patients with antral gastritis. The low decision limitwas established at 3.3% (median 4.8%). From the 14 elderly patientswith low B₁₂ prospectively selected from 394 hospitalisedpatients, seven had a real deficiency with anaemia and an increasedhomocysteine and/or methylmalonate serum level. The modified Schillingtest showed malabsorption in five of these patients, including two inwhich the standard Schilling test was normal, and three in which the standard Schilling test was partially corrected by an intrinsic factor.
Conclusions—Protein bound vitamin B₁₂malabsorption was detected in at least 0.5% of elderly hospitalisedpatients, using the labelled trout flesh absorption test.

Keywords:cobalamin deficiency; malabsorption; gastritis; Schilling test

     

Visualization of a radical B12 enzyme with its G-protein chaperone

G-protein metallochaperones ensure fidelity during cofactor assembly for a variety of metalloproteins, including adenosylcobalamin (AdoCbl)-dependent methylmalonyl-CoA mutase and hydrogenase, and thus have both medical and biofuel development applications. Here, we present crystal structures of IcmF, a natural fusion protein of AdoCbl-dependent isobutyryl-CoA mutase and its corresponding G-protein chaperone, which reveal the molecular architecture of a G-protein metallochaperone in complex with its target protein. These structures show that conserved G-protein elements become ordered upon target protein association, creating the molecular pathways that both sense and report on the cofactor loading state. Structures determined of both apo- and holo-forms of IcmF depict both open and closed enzyme states, in which the cofactor-binding domain is alternatively positioned for cofactor loading and for catalysis. Notably, the G protein moves as a unit with the cofactor-binding domain, providing a visualization of how a chaperone assists in the sequestering of a precious cofactor inside an enzyme active site.Metallocofactors are ubiquitous in biology and essential for many cellular processes. Their use comes at a price, however, because metallocofactors are expensive to biosynthesize and transport, can have associated toxicity, and must be correctly assembled into their target enzyme for activity. To address these challenges, nature often employs protein metallochaperones. Chaperone-assisted cofactor delivery limits cellular dilution, minimizes inadvertent reactivity associated with the free cofactor, and ensures proper enzyme assembly (1–3). The importance of metallocofactor trafficking is underscored by the manifestation of diseases when mutations affect trafficking proteins. One important group of metallochaperones comprises the small guanine nucleotide-binding proteins (G proteins) belonging to the SIMIBI class (after signal recognition particle, MinD, and BioD) of P-loop NTPases (4). The human G-protein chaperone, MMAA (methylmalonic aciduria type A protein, mitochondrial; gene product of cblA), is involved in the assembly of adenosylcobalamin (AdoCbl, coenzyme B₁₂)-dependent methylmalonyl-CoA mutase (MCM) (5, 6). Mutations in MMAA and MCM result in methylmalonic aciduria, a genetically inherited metabolic disease that is devastating in newborns and infants (7). Bacterial homologs of MMAA are involved in assembly of other metalloproteins and include HypB for hydrogenase (8) and UreG for urease (9). These G-protein chaperones bind to their target proteins and then use their GTP hydrolase (GTPase) activity to assist maturation of the target with high specificity (10–12). The mechanisms by which these essential chaperones perform their functions, however, are not well established, in large part because of the absence of structural information on their complexes with target proteins.An extensively studied member of the G-protein chaperones is MeaB^12–14, a bacterial ortholog of MMAA. Its target MCM requires AdoCbl to catalyze the radical-mediated 1,2-rearrangement of methylmalonyl-CoA (CoA) to succinyl-CoA (Fig. S1A) (13), an essential step in the degradation of odd-chain fatty acids, cholesterol, and branched amino acids. In this reaction and those of related isomerases, AdoCbl serves as a radical reservoir, reversibly generating the working 5′-deoxyadenosyl radical via homolytic cleavage of its cobalt–carbon bond (13–15). It is critically important for these isomerases to be loaded with AdoCbl and not any other cofactor derivative, which would yield inactive enzyme. MeaB performs this gating function for MCM and uses its GTPase activity to enable cofactor delivery (12) from the adenosyltransferase that synthesizes AdoCbl (16, 17). MeaB additionally remains associated with MCM during turnover and reduces the rate of oxidative inactivation (18). Notably, MeaB is structurally and mechanistically distinct from the ATP-dependent chaperones for AdoCbl-dependent eliminating enzymes, such as diol dehydratase: these chaperones, also termed reactivases, bind to inactivated enzymes and use their ATPase activity to eject damaged cofactor but do not affect AdoCbl delivery (19). An ortholog of MeaB, MeaI, is found fused to isobutyryl-CoA mutase. Termed IcmF (20), the fusion protein exhibits both GTPase activity and AdoCbl-dependent carbon skeleton isomerase activity, interconverting isobutyryl-CoA and n-butyryl-CoA, as well as pivalyl-CoA and isovaleryl-CoA (Fig. S1 B and C) (20, 21). The latter activity is newly discovered and may have relevance to the biodegradation of branched compounds (22).Herein, we present the crystal structure of IcmF from Cupriavidus metallidurans containing bound AdoCbl and GDP•Mg²⁺, providing what is, to our knowledge, the first visualization of the juxtaposition of a G-protein chaperone and its target AdoCbl-dependent mutase. In addition, the crystal structure of IcmF in the absence of cofactors reveals the conformational changes required for cofactor loading.     

Quantitation of urinary methylmalonic acid by gas chromatography mass spectrometry and its clinical applications

Urine methylmalonic acid (MMA) concentrations were detected in 79 Chinese patients by gas chromatography mass spectrometry (GC/MS), using a selected ion monitoring program. 10 of the 79 patients were found to have cobalamin deficiency. Their urine MMA amounts were all elevated with a mean value 1376 ng/microliter (11.66 mmol/l), ranging from 40.46 to 3900 ng/microliter (0.34-33.05 mmol/l). The remaining 69 cases were found to be unrelated to cobalamin deficiency. Their mean urine MMA was 3.62 ng/microliter (30.0 mumol/l), ranging from 0-17.47 ng/microliter (0-148.0 mumol/l). In this study, we found that urine MMA detected by GC/MS was a simple, rapid, convenient, specific and sensitive method for the diagnosis of cobalamin deficiency. The urine MMA concentrations in cases not due to cobalamin deficiency would not exceed 20 ng/microliter (169.5 mumol/l), whereas in cobalamin deficiency the urine MMA levels always exceeded 20 ng/microliter, or were even much higher. No overlapping of the results of urine MMA between these 2 groups of patients could be seen in our study. Detection of urine MMA is useful in the demonstration or exclusion of cobalamin deficiency in any suspect patients.     

High prevalence of low serum vitamin B12 in a multi-ethnic Israeli population

This study ascertained serum vitamin B12 levels among patients with Gaucher disease and among healthy Israelis. Serum B12 and metabolites' levels were studied in consecutive adult patients with Gaucher disease not treated with enzyme plus Ashkenazi Jewish neighbour-controls, together with healthy blood-donor volunteers of various ethnicities. Each group showed a high incidence of low serum B12 concentrations, with a 22.3% incidence among Ashkenazi Jews and 40% among patients with Gaucher disease. These findings raise questions on the individual and community levels of serum B12. We recommend evaluation of B12 levels among geographically contingent peoples.     

Advantages of serum pepsinogen A combined with gastrin or pepsinogen C as first-line analytes in the evaluation of suspected cobalamin deficiency: a study in patients previously not subjected to gastrointestinal surgery

Lindgren A, Lindstedt G, Kilander AF (Borås Central Hospital and Sahlgrenska University Hospital, Göteborg, Sweden). Advantages of serum pepsinogen A combined with gastrin or pepsinogen C as first-line analytes in the evaluation of suspected cobalamin deficiency: a study in patients previously not subjected to gastrointestinal surgery. J Intern Med 1998; 244 : 341–349.

Objectives

Since there is a significant overlap in serum cobalamin concentrations between healthy and cobalamin-deficient individuals, we wanted to compare two different principles for use as supplementary tests to serum cobalamin concentration in patients with suspected cobalamin malabsorption and deficiency.

Design

Clinical study of consecutive patients.

Setting

The catchment area of Sahlgrenska University Hospital, Göteborg.

Subjects

A total of 112 patients with suspected cobalamin deficiency who had not previously undergone gastrointestinal surgery.

Interventions

Gastroduodenoscopy with biopsies taken from the gastric body and the duodenum, Schilling test, and measurement of serum methylmalonic acid (MMA), total homocysteine (Hcy), pepsinogens A and C, and gastrin.

Main outcome measures

Number of patients with gastric body atrophy identified with the combination of MMA and Hcy, and pepsinogen A combined with pepsinogen C or gastrin.

Results

About 95% of the patients with severe gastric body atrophy had abnormal concentrations of serum pepsinogen A and/or gastrin or pepsinogen A/C ratio, whereas 65% had abnormal metabolite concentrations. Serum pepsinogen A combined with pepsinogen C identified 100%, and combined with gastrin 88%, of the patients with gastric body atrophy and elevated metabolite tests, and 67 and 75%, respectively, of those who had not yet developed elevated metabolite tests.

Conclusions

Pepsinogen A, combined with pepsinogen C or gastrin, should be the first option in evaluating patients with suspected cobalamin deficiency who have not previously undergone gastrointestinal surgery.