Should transcobalamin deficiency be treated aggressively?

Transcobalamin (transcobalamin II, TC) transports plasma vitamin B₁₂ (cobalamin, Cbl) into cells. TC deficiency is a rare autosomal recessive disorder causing intracellular Cbl depletion, which in turn causes megaloblastic bone marrow failure, accumulation of homocysteine and methylmalonic acid, and methionine depletion. The clinical presentation reflects intracellular Cbl defects, with early-onset failure to thrive with gastrointestinal symptoms, pancytopenia, and megaloblastic anemia, sometimes followed by neurological complications. We report the clinical, biological, and molecular findings and the outcome in five TC-deficient patients. The three treated early had an initial favorable outcome, whereas the two treated inadequately had late-onset severe neuro-ophthalmological impairment. Even if the natural course of the disease over time might also result in late-onset symptoms in the aggressively treated patients, these data emphasize that TC deficiency is a severe disorder requiring early detection and probably long-term aggressive therapy. Mutation analysis revealed six unreported mutations in the TCN2 gene. In silico structural analysis showed that these mutations disrupt the Cbl-TC interaction domain and/or the putative transcobalamin–transcobalamin receptor interaction domain.     

Uptake and metabolism of free cyanocobalamin by cultured human fibroblasts from controls and a patient with transcobalamin II deficiency

We have investigated the uptake and metabolism of free cyanocobalamin (CN-Cbl; vitamin B₁₂) by intact cultured human skin fibroblasts. Monolayers of control fibroblasts take up free CN-[⁵⁷Co]Cbl via a saturable, calcium-independent process that is inhibited by sulfhydryl reagents, inhibitors of protein synthesis, and inhibitors of electron transport, but not by inhibitors of glycolysis. CN-Cbl taken up in this manner is converted to active cobalamin (Cbl) coenzymes (adenosylcobalamin and methylcobalamin) and becomes associated with intracellular Cbl-dependent apoenzymes (methylmalonyl CoA mutase and homocysteine:methyltetrahydrofolate methyltransferase). Since fibroblasts from controls were also found to synthesize transcobalamin II (TC II), a plasma protein shown previously to facilitate the cellular uptake of Cbl, it seemed possible that the observed uptake of free CN-Cbl was TC II-mediated. This thesis was rejected by demonstrating that cells from a patient with complete TC II deficiency took up free CN-Cbl as well as control cells did. Finally, we propose a mechanism by which an uptake process for free Cbl might serve a function in intracellular metabolism of Cbl.     

Hydroxocobalamin for Initial and Long-term Therapy for Vitamin B12 Deficiency

ABSTRACT. Skouby AP (Medical Department II, Municipal Hospital, Copenhagen, Denmark). Hydroxocobalamin for initial and long-term therapy for vitamin B₁₂ deficiency. Seventeen patients were treated for vitamin B₁₂ deficiency with i.m. injection of 1 mg hydroxocobalamin every three months as maintenance therapy for eight to 20 years after an initial depot treatment of one or two series of five i.m. injections on alternate days. In three of four patients given two depot series ≤3 months apart, and with no antibody to transcobalamin II (TC II) detected previously, abnormally high values of serum cobalamins were measured at the end of injection intervals after seven to 12 years. No increase in unsaturated B₁₂ binding capacity (UB₁₂BC) was found in contrast to findings in patients given identical therapy, in whom an early increase above the normal level occurred associated with antibody to TC II. One depot series followed by i.m. injection of 1 mg hydroxocobalamin every third month secured values within the normal range for serum cobalamin, UB₁₂BC and total B₁₂ binding capacity (TB₁₂BC).     

Infantile megaloblastosis secondary to maternal vitamin B12 deficiency

We reviewed six cases of infantile megaloblastosis secondary to maternal vitamin B₁₂ deficiency, the most common cause of infantile megaloblastosis in our institution. Two patients had long-term neurological sequelae, with a further patient remaining abnormal but at short follow-up. In 50% of cases the mother was asymptomatic, with subtle or no peripheral blood abnormalities, having early pernicious anaemia. Any infant which fails to thrive, with progressive neurological deterioration and haematological cytopenias should have their vitamin B₁₂ and folate status rapidly assessed. This is one of the few potentially reversible causes of failure to thrive and neurological deterioration. Early diagnosis and treatment may prevent significant long-term sequelae.     

Reversible Dementia and Neuropathy Associated with Folate Deficiency 16 Years After Partial Gastrectomy

A 57-year-old woman developed dementia and peripheral neuropathy 16 years after a partial gastrectomy (Billroth II). Serum cobalamin was 198 pmol/l (reference interval 150–550), and the vitamin B₁₂ absorption test (Schilling) showed decreased absorption (1.7% without and 2.2% with intrinsic factor). In spite of 20 months' therapy with vitamin B₁₂, the neurological symptoms progressed. Folate deficiency was suggested by a very low erythrocyte folate and a slightly abnormal FIGLU test. There were no other signs of general malabsorption. A few months' treatment with folic acid significantly improved the massive neurological manifestations which were verified neurophysiologically as well as histologically. A common role of vitamin B₁₂ and folate in the development of neuropathy is suggested.     

Measuring holotranscobalamin II, an early indicator of negative vitamin B12 balance, by radioimmunoassay in patients with ischemic cerebrovascular disease

Circulating homocysteine is a risk factor of cardiovascular and cerebrovascular events. Hyperhomocysteinemia may be an early indicator for vitamin B₁₂ disorders because cobalamin is a cofactor in the remethylation process of homocysteine. Serum holotranscobalamin (holoTC II) becomes decreased before the development of metabolic dysfunction. In this study, we assessed circulating holoTC II to estimate the diagnosis of vitamin B₁₂ deficiency in the first ischemic cerebrovascular attack. We also compared the efficacy of the measurement of plasma holoTC II with the other standard biochemical and hematological markers used to reach the diagnosis of cobalamin deficiency. Forty-five patients (age 71 years (range 35–90), 16 men/29 women) within the first ischemic cerebrovascular event were included in this prospective study. All the enrolled patients have been administered vitamin B₁₂ 1 mg intramuscular injection once a day for 10 days. At the baseline and on the tenth day of treatment, plasma levels of holoTC II and the proper biochemical and hematological markers in diagnosing cobalamin deficiency were measured. After admission, anemia and diminished serum vitamin B₁₂ levels were determined to be only 20% (9/45) and 44% (20/45), respectively; 78% (35/45) of the patients had low serum holoTC II (<37 pmol/l). Serum homocysteine was higher in patients (49% of them) who had previously suffered a stroke. Thrombocytopenia, hypersegmentated neutrophils, and indirect hyperbilirubinemia were observed in 20% of the patients. Leukopenia and macrocytosis were not evident in any of them. In 18 of 27 patients (67%) that had low holoTC II levels after joining the study and who remained in the study until the end of cobalamin treatment, serum holoTC II levels returned to normal values. Cobalamin deficiency should be considered in patients with cerebrovascular diseases, even if anemia, elevated mean cell volume, depression of the serum cobalamin, or other classic hematological and/or biochemical abnormalities are lacking. Furthermore, measurement of serum holoTC II looks promising as a first-line of tests for diagnosing early vitamin B₁₂ deficiency.     

Turnover of 57Co-labelled Vitamin B12-Transcobalamin II and Autologous 131I-labelled IgG in a Patient with Antibody to Transcobalamin II

In a pernicious anaemia patient with a circulating antibody to transcobalamin II (TC II), the plasma clearance of radioactive vitamin B₁₂ bound to TC II has been shown to be much slower (plasma half-life 8.2 days) than in control subjects (plasma half-life 0.7 days). Thus, the patient's high serum vitamin B₁₂ binding capacity and elevated serum vitamin B₁₂ are the result of decreased catabolism of TC II due to the presence of antibody. The turnover of the B₁₂-TC II-antibody complex was shorter than that observed for autologous ¹³¹I-labelled IgG (plasma half-life 16.8 days). This difference is most likely due to dissociation of the complex.     

Vitamin B12 in Plasma in Patients with Continent Ileostomy and Long Observation Time

Plasma cobalamins (vitamin B₁₂) were determined by a microbiological method in 235 patients with continent ileostomies and postoperative observation times of 3–13 years (mean. 6 years). The influence of the reservoir on the vitamin B₁₂ values could not be evaluated in 22 patients (9%)—because of prophylactic treatment in 6%, subnormal B₁₂ values before the operation in 1%, and ‘treatment’ of various neurological symptoms not caused by vitamin B₁₂ deficiency in 2%. Fourteen (7%) of the remaining 213 patients had developed subnormal plasma levels of vitamin B₁₂ and another 14 patients (7%) had ‘borderline’ values (130–200 pmol/l). The median time interval between reservoir operation and the development of subnormal values was 7.5 years (range, 3–11 years). A small-bowel resection had been added to the proctocolectomy in 11 out of 14 patients with subnormal values and in 8 out of 14 patients with borderline values. Subnormal or borderline values were seen in 27% of patients with Crohn's disease and in 12% of patients with ulcerative colitis. No patient had anaemia or neurological symptoms caused by B₁₂ deficiency. The study shows that most patients with continent ileostomies do not develop B₁₂ deficiency, and there is therefore no need for general prophylaxis. Since at least 7% developed subnormal values, the plasma levels of vitamin B₁₂ should, however, be followed up regularly in all patients with continent ileostomies.     

A patient with the inability to maintain in vivo levels of bound cobalamin (Cbl) and manifestations of tissue deficiency of Cbl

A 39-year-old woman presented with mild anemia, glossitis, an increased MCV, a low serum cobalamin (Cbl) (vitamin B12), mild tissue deficiency of Cbl, but with neither malabsorption of Cbl, impaired intake, nor deficiency of or inactivity of transcobalamin II (TC II). Because of a persistently low holo-TC II (TC II carrying Cbl as the circulating complex of TC II-Cbl), much of the evaluation was focused on the patient's TC II. Her TC II promoted the uptake of Cbl, reacted with anti-TC II, and bound Cbl in vitro. A test dose of 200 micrograms of cyanocobalamin (CN-Cbl) i.m. increased her holo TC II to levels higher than those in healthy persons, but with a much more abrupt fall to a subnormal level. Two milligrams of CN-Cbl i.m. followed by 100 micrograms i.m. monthly failed to maintain normal amounts of circulating TC II-Cbl or to overcome the tissue deficiency of Cbl. One milligram i.m. weekly or daily p.o. corrected both. The low holo TC II was considered to be responsible for the clinical expression and may have been primary to the reduced amounts of total and holo R binder of Cbl in the circulation. This study of a newly recognized defect points out the need for circulating holo TC II, a rational use of pharmacologic amounts of Cbl, and a possible interrelationship between TC II and the R binder of Cbl.     

Growth Retardation,General Hypotonia,and Loss of Acquired Neuromotor Skills in the Infants of Mothers With Cobalamin Deficiency and the Possible Role of Succinyl-CoA and Glycine in the Pathogenesis

Vitamin B₁₂ (cobalamin, Cbl) deficiency can cause metabolic, hematological, and neurological abnormalities. Adequate levels of succinyl-coenzyme A (CoA) cannot be synthesized from methylmalonyl-CoA because of the decreased activity of the methylmalonyl-CoA mutase enzyme that uses Cbl as the cofactor. Succinyl-CoA synthesis deficiency leads to decreased heme synthesis and gluconeogenesis. The reason of growth retardation can be gluconeogenesis deficiency together with heme synthesis deficiency whereas the reason of the neurological abnormalities can be glycine increase in the tissue due to decreased heme synthesis. We present 7 infants diagnosed with severe nutritional Cbl deficiency and discuss the role of succinyl-CoA and glycine in the possible pathogenesis in this article. Patients brought to our clinic with a complaint of growth retardation and diagnosed with nutritional Cbl deficiency were included in the study. There were 5 females and 2 males. The mean age was 11 ± 2.30 (range 6–13) months. All patients had general muscular hypotonia and 4 had growth retardation. Neuromotor growth retardation was found in 4 of the children who had previously shown normal neuromotor development for age. The mean Cbl level was 83.8 ± 27.6 (45.6–114) pg/mL. The mean Cbl level of the mothers was 155 ± 56.6 (88–258) pg/mL. Six of the patients had anemia and 1 had thrombocytopenia. Mean corpuscular volume value was 91.5 ± 12.2 fL. Following treatment, the muscle tonus of the patients improved, the anemia and growth retardation decreased, and the lost neuromotor abilities were recovered. Severe nutritional Cbl deficiency is an important nutritional disease where complications can be prevented with early treatment. When evaluating the pathogenesis, it should be noted that nutritional Cbl deficiency is a succinyl-CoA synthesis deficiency.     

Inheritance of transcobalamin II (TC II) in two families with TC II deficiency and related immunodeficiency

Transcobalamin II (TC II) is an essential transport protein for vitamin B₁₂ in blood. TC II can be separated into isoproteins by polyacrylamide gel electrophoresis. This method was used in combination with a specific radioimmunosorbent technique to evaluate genetic variants and inheritance of TC II-deficient genes in relatives of two children with congenital TC II deficiency. Both patients presented with impairment of haematopoietic and immunological functions. Seven heterozygous individuals for TC II deficiency, who are clinically normal, were detected in the two families. Two out of seven could be identified unambiguously by TC II isoprotein analysis, as carriers of a deficient gene, which does not express functional TC II. Application of this new method to detect heterozygous carriers of the deficient gene provides a valuable addition to genetic counselling.     

Vitamin B12 and vitamin B6 supplementation is needed among adults with phenylketonuria (PKU)

Summary Phenylketonuria (PKU) is caused by an autosomal recessive deficiency of the enzyme phelnylalanine hydroxylase leading to a failure to convert phenylalanine to tyrosine. To avoid irreversible neurological damage because of increased phenylalanine, treatment is instituted rapidly after birth. We examined 31 adult PKU patients living on a less protein-restricted diet. Theoretically, these PKU patients had an increased risk of developing vitamin B₁₂ and B₆ deficiency because of a limited intake of animal products. Besides laboratory tests (n = 31) we obtained clinical information (n = 30) and detailed information on food consumption (n = 28). Three-quarters of the patients had early biochemical signs of vitamin B₁₂ deficiency. In spite of a normal folate status, 9 (29%) had a plasma homocysteine above 12 μmol/L. In accord with these findings, the food questionnaires indicated that 11 (39%) patients received less than the recommended daily vitamin B₁₂, and 20 (71%) received less vitamin B₆ than recommended. A significant association was found between reduced vitamin B₁₂ intake and both reduced serum cobalamins (p = 0.04) and reduced serum transcobalamin saturation (p = 0.03). Eleven patients took a vitamin pill daily, and these patients had a significantly lower plasma homocysteine compared to the rest. The present study suggests that adult PKU patients were at increased risk of developing vitamin B₁₂ deficiency, and their intake of vitamin B₆ was below the recommended daily intake. In conclusion PKU patients need continuing dietary guidance throughout adult life, and considering the risks, costs and potential benefits, daily vitamin supplementation seems justified in these patients.     

The lymphocyte as a marker of past nutritional status: persistence of abnormal lymphocyte deoxyuridine (dU) suppression test and chromosomes in patients with past deficiency of folate and vitamin B12

In short-term suspension cultures of bone marrow cells or PHA-stimulated lymphocytes from normal subjects, non-radioactive deoxyuridine (dU) suppresses the incorporation of radioactive thymidine ([³H]TdR) or its analogue, [¹²⁵I]deoxyuridine ([¹²⁵I]Udr), into DNA. This normal suppression by deoxyuridine (dU) is impaired in both of these cell systems from patients with deficiency of folate or vitamin B₁₂, and corrected by the appropriate vitamin. Patients with megaloblastic anaemia due to deficiency of vitamin B₁₂ or folate were studied before and after treatment. When treatment had returned to normal the bone marrow morphology and the serum and red cell vitamin levels, then the dU suppression test and chromosomal changes in the bone marrow were also corrected. However, the dU suppression test and chromosomal changes remained abnormal in lymphocytes as long as 84 d after therapy. These abnormal lymphocyte dU suppression tests were corrected by the appropriate in vitro additions of folic acid, methylfolate and vitamin B₁₂, depending on the vitamin deficiency present before therapy. These studies suggest that an abnormal lymphocyte dU suppression test corrected by the appropriate vitamin in vitro, and characteristic chromosome abnormalities in lymphocytes, when these are absent in the bone marrow, indicate past deficiency of vitamin B₁₂ or folate. These changes can be used for retrospective diagnosis of these deficiencies in patients treated by ‘shotgun’ therapy. They further support the concepts that circulating unstimulated lymphocytes: (1) do not incorporate appreciable amounts of vitamin B₁₂ or folic acid; (2) reflect the vitamin status of the patient at the time the lymphocytes were generated; and (3) cannot replace bone marrow in dU suppression tests aimed at diagnosis of current marrow and other non-lymphocyte cell line nutrient status. These studies add to the evidence that selective nutrient deficiency may occur in one but not another cell line in the same person, and point to the need for more studies on factors affecting nutrient delivery, uptake, and utilization by various human cell lines. These studies also provide a new approach to evaluation of circulating lymphocyte age.     

Absence of an intracellular cobalamin-binding protein in cultured fibroblasts from patients with defective synthesis of 5'-deoxyadenosylcobalamin and methylcobalamin

Three distinct classes of human mutations (cbl A, cbl B, and cbl C) cause defective synthesis of cobalamin (Cbl; vitamin B₁₂) coenzymes. Cultured fibroblasts from that unique class (cbl C) deficient in the synthesis of both Cbl coenzymes, 5′-deoxyadenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), were used to explore the underlying defect. We compared the uptake of transcobalamin II(TC II)-bound cyano[⁵⁷Co]cobalamin (CN-Cbl) by cbl cells with that of other control and mutant cell lines. Although the cbl C cells initially took up CN-[⁵⁷Co]Cbl normally, they were unable to retain it. To characterize this “leak” further, cell extracts were prepared following incubation and chromatographed on Sephadex G-150. After incubations of 1-2 hr, most of the CN-[⁵⁷Co]Cbl accumulated by control cells was still bound to TC II; the remainder was free. Thereafter, an ever-increasing fraction of the labeled Cbl eluted with an intracellular cobalamin-binding protein (ICB); more than 80% of the total was so bound after 76 hr incubations. ICB had an apparent molecular weight similar to that of several Cbl “R” binders (about 120,000), but was distinguished from them by its failure to react with specific anti-“R”binder antiserum. Significantly, no ICB was detected in extracts of three different cbl C lines even aftr prolonged incubations, whereas its appearance in cbl A, cbl B, and mutase apoenzyme mutants was normal. We propose: that ICB is required for retention of cobalamins by cells; and that cbl C cells “leak” cobalamins and show defective synthesis of Cbl coenzymes because they lack this intracellular binder.     

Reversal of apparent AIDS dementia complex following treatment with vitamin B12

Abstract. The human immunodeficiency virus (HIV)-associated dementia complex is characterized by difficulties in concentration and memory followed by apathy, social withdrawal and motor dysfunction. Decreased serum vitamin B₁₂ levels occur in up to 20% of patients with acquired immune deficiency syndrome (AIDS) and may adversely contribute to the haematologic and neurologic dysfunction which is frequently attributed to the human immunodeficiency virus. We describe a patient with AIDS who presented with an apparent advanced AIDS dementia complex. There was an associated low serum vitamin B₁₂ resulting from malabsorption due to low gastric intrinsic factor secretion. Following treatment with vitamin B₁₂ the symptoms resolved over a 2-month period. We believe that the AIDS dementia complex represented a reversible adverse synergistic interaction between the human immunodeficiency virus and vitamin B₁₂ deficiency.     

In vivo plasma binding capacity for cyanocobalamin

Many investigators have alluded to or described the presence of multiple vitamin B₁₂ binding proteins in human plasma (Mendelsohn, Watkin, Horbett and Fahey, 1958; Miller, 1958; Hall and Finkler, 1962; Rosenthal, Hill and Haessler, 1964; Heller, Epstein, Cunningham, Henderson and Yakulis, 1964). Recently, Hall and Finkler (1963, 1964) separated two cyanocobalamin plasma binders with distinctly different characteristics. One fraction (Transcobalamin II or TC II) is apparently a β-globulin which is involved in the immediate carrier state, while the other (Transcobalamin I or TC I), an α-globulin, is the endogenous B₁₂ binding protein. Gabuzda, Worm-Petersen and Lous (1965) confirmed these findings, demonstrating that cyanocobalamin is bound in vitro by a distinctly separate protein from that to which it is bound endogenously. Methods derived from a study of plasma binding by vitamin B₁₂ analogues have been utilized to determine in vivo plasma binding capacity for cyanocobalamin (Meyer, Schiffer, White and Cronkite, 1965). It is proposed that this in vivo plasma binding capacity represents to a large extent the B₁₂ carrying capacity of TC II.     

Metabolic signs of vitamin B12 deficiency in humans: computational model and its implications for diagnostics

Early diagnostics of cobalamin (Cbl, vitamin B₁₂) deficiency is primarily based on measurements of the relevant metabolic markers in blood plasma—total B₁₂, specific Cbl-saturated transporter holo-transcobalamin (holoTC), and substrates of Cbl-dependent enzymatic reactions methylmalonic acid (MMA) and homocysteine (Hcy). Concentrations of B₁₂ and holoTC decrease whereas MMA and Hcy increase under deficiency. Yet, the results of individual tests are often contradictory and do not guarantee unambiguous diagnosis. The current work describes the metabolic manifestation of vitamin B₁₂ deficiency in terms of flux equations fitted to data sets from literature. The model mathematically connects all the markers and presents 4 independent measurements as a single point (x, y) in the combined coordinates x = (holoTC·B₁₂)^½ and y = ½log₁₀(MMA·Hcy). Pairwise averaging compensates for the individual fluctuations of the markers caused by (1) irregular spikes of holoTC, (2) delayed change of the total plasma B₁₂ buffered by an internal Cbl depot, and (3) variations in the production/excretion velocities of MMA and Hcy. Bivariate distribution of the marker combinations (x, y) reveals several peaks of frequency in the analyzed mixed population. The peaks seem to represent the reference subgroups with different B₁₂ physiology and characteristic values of “wellness parameter”: w = log₁₀(holoTC_n) + log₁₀(B_12n) − log₁₀(MMA_n) − log₁₀(Hcy_n), where concentrations are normalized (eg, MMA_n = MMA/MMA_normal). Dynamic response of the organism to B₁₂ intake is quantified and described as an additional analytical tool when classifying uncertain cases. The discussed mathematical approaches are of general applicability in diagnostics.     

Malabsorption and deficiency of vitamin B12 in HIV-infected patients with chronic diarrhea

Deficiency of vitamin B₁₂ is commonly reported in HIV-infected patients. We measured vitamin B₁₂ levels in 36 HIV-infected patients with chronic diarrhea (>3 stools/day for six weeks or more). Eight patients had an identifiable cause of diarrhea. Vitamin B₁₂ levels were low in 39%. Sixteen of these patients were selected to undergo further testing, eight patients with low levels of vitamin B₁₂ and eight with normal B₁₂ levels. These 16 patients had both a stage II Schilling test and measurement of multiple serumd-xylose concentrations performed after both oral and intravenous doses ofd-xylose. Integrated areas under the curves (AUC) ford-xylose concentration versus time were calculated for intravenous and oral doses, andd-xylose bioavailability was determined. Stage II Schilling tests were abnormal in 11 patients, (69%).d-Xylose bioavailability correlated closely with vitamin B₁₂ absorption (r=0.648,P<0.01). Comparisons of mean values for CD4 count, serum albumin, Karnovsky score, six-month weight loss, 1-hr serumd-xylose levels and MCV failed to reveal a significant difference between those with and without abnormal serum vitamin B₁₂ levels. These data indicate that below-normal levels of vitamin B₁₂ are highly prevalent in HIV-infected patients with chronic diarrhea. Malabsorption of vitamin B₁₂ occurs in the setting of an enteropathic process effecting both the proximal and distal small bowel. Since no risk factors for vitamin B₁₂ deficiency could be identified, screening for vitamin B₁₂ deficiency in HIV-infected patients with chronic diarrhea is strongly recommended.Supported in part by grant RR00048 National Institutes of Health, National Center for Research Resources.     

Orthostatic Hypotension as a Manifestation of Vitamin B12 Deficiency

A 90-year-old woman with orthostatic hypotension and near-syncope was found to have a low-normal level of vitamin B₁₂ and no other medical findings that could explain her orthostasis. Her symptoms responded to vitamin B₁₂ replacement therapy. This case shows that vitamin B₁₂ deficiency can induce orthostatic hypotension and syncope that are correctable by vitamin B₁₂ replacement.Key words: Hypotension, orthostatic/etiology/therapy; vitamin B 12/therapeutic use; vitamin B 12 deficiency; vitamin B 12 replacementOrthostatic hypotension (OH) is a common disorder, especially among elderly persons. Patients with OH usually undergo neurologic, cardiologic, and endocrine evaluation, because there are several causes for this presentation. One of these causes, vitamin B₁₂ deficiency, is well known among neurologists but is often overlooked by cardiologists. We describe a case of OH in an elderly woman whose condition improved with vitamin B₁₂ replacement therapy. This case brought the attention of our cardiology group to this vitamin deficiency and its importance as a potential diagnosis in cardiology patients.