of Medicine, Section of Internal Medicine, University of Verona,
EuroBloodNet Referral Center for Iron Metabolism Disorders, Azienda
Ospedaliera Universitaria Integrata Verona, 37138, Verona, Italy.
* Giacomo Marchi and Fabiana Busti equally contributed to the work.
Received: May 30, 2020
Accepted: May 5, 2020
Mediterr J Hematol Infect Dis 2020, 12(1): e2020043 DOI 10.4084/MJHID.2020.043
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
people are at risk for cobalamin (vitamin B12) deficiency because of a
number of common disorders (e.g., autoimmune gastritis) and drugs
(e.g., antacids) that may alter its absorption and utilization. The
prevalence of cobalamin deficiency increases with age, resulting,
particularly elevated, in frail and institutionalized subjects. At
variance with common sense, the diagnosis is far from simple. It
requires a high degree of suspicion, due to heterogeneity and
non-specificity of the signs and symptoms, ranging from macrocytosis
(with or without anemia) to neuropsychiatric manifestations, that
characterize several other aging-related disorders, like hematological
malignancies, diabetes, hypothyroidism or vasculopathy. Furthermore,
the detection of low levels of serum vitamin B12 appears poorly
sensitive and specific. Other biomarkers, like serum homocysteine or
methylmalonic acid, have improved the diagnostic possibilities but are
expensive, not widely available, and may be influenced by some
confounders (e.g., folate deficiency, or chronic renal failure). Early
recognition and treatment are crucial since a proportion of patients
develop severe complications, such as bone marrow failure and
irreversible neurological impairment. High-dose oral treatment has
proven to be as effective as the parenteral route, even in subjects
with malabsorption, ensuring the complete resolution in the majority of
cases. In this review, we trace the essential role of cobalamin in
humans, the possible causes and impact of deficiency, the diagnostic
challenges and the therapeutic options, between old and emerging
concepts, with a particular focus on the elderly.
Role of Cobalamin in Metabolic Processes
Cbl is crucial for several metabolic functions, including cell proliferation and survival, energy production, and nervous system integrity, as it represents a pivotal cofactor for two ubiquitously expressed enzymes, the cytosolic methionine-synthase, and the mitochondrial methylmalonyl coenzyme A mutase (Figure 1).
The methionine-synthase catalyzes the conversion of methyl-tetrahydrofolate (methyl-THF) and homocysteine (Hcy) into THF and methionine, a basilar step toward DNA synthesis. The enzyme dysfunction is responsible for the nucleus-cytoplasm maturation asynchrony affecting cells with an elevated regenerative rate, predominantly the hematopoietic precursors (leading to megaloblastic anemia), but also epithelial and mucous cells (causing glossitis). Moreover, it causes a reduction of the methionine-derived metabolite S-adenosylmethionine (SAM), required for neurotransmitters and phospholipids synthesis, eventually compromising cell membrane structure and fluidity, myelin formation, and neurotransmission.
The methylmalonyl coenzyme A mutase (MUT) catalyzes the isomerization of L-methyl-malonyl-CoA in succinyl-CoA, a key molecule in the tricarboxylic acid cycle, essential for ATP generation, ketone bodies metabolism, myelinization, and heme biosynthesis.
Prevalence of Cbl Deficiency (CblD) in the Elderly
Further uncertainties derive from the absence of "gold standard" tests and cut-offs. Many studies, in fact, considered serum Cbl levels alone (with different standard intervals), others utilized Cbl reduction in combination with additional serum biomarkers, like homocysteine (Hcy) and/or methylmalonic acid (MMA).
Currently, the estimated prevalence of CblD ranges from 4-5% in community-living elderly[5,6] to about 30-40% in institutionalized subjects with multiple comorbidities. Among the latter, CblD was responsible for anemia in 4% of cases. Since the presence of anemia or macrocytosis does not accurately predict CblD, some Authors have advocated generalized biochemical screening for CblD in the aged population.[9,10]
Diagnosis of CblD
The measurement of circulating Cbl is often the first-line test to be performed. The reference intervals vary among laboratories, but, in general, levels below 150 pmol/l (200 pg/ml) are consistent with deficiency, while levels above 300 pmol/l (400 pg/ml) are considered normal. However, this test has reduced sensitivity and specificity. Diagnosis may be missed in the presence of falsely normal circulating Cbl levels, as it has been observed in ordinary conditions, such as chronic liver diseases, myeloproliferative neoplasms, or in the presence of anti-intrinsic factor antibodies.[1,12] Moreover, the assay measures the two endogenous forms of Cbl, holohaptocorrin, and the only biologically active holotranscobalamin (HoloTC). A reduction in total Cbl levels may actually reflect a mere impairment of holohaptocorrin synthesis (e.g., during cancer, pregnancy, liver disease, and autoimmune disorders), with little (if any) clinical significance.
Over the past 30 years, it has become evident that serum Hcy and MMA levels represent more sensitive and early indicators of CblD.[1,12] Despite this, their use in clinical practice is hampered by scarce availability, the lack of validated methods and thresholds, and relatively higher costs. In addition, their levels tend to rise per se with aging.
In the absence of impaired renal function, an elevation of MMA (>350 nmol/l) is the most specific biomarker. The Hcy increase (>15 µmol/l) is sensitive but less specific, also rising in the case of folate deficiency, B6 vitamin deficiency, hypothyroidism, and decreased GFR. MMA and Hcy play a role in subjects with borderline Cbl values (i.e., 150-300 pmol/l), or whenever there is a discrepancy between a clinical picture suggesting CblD and apparently normal Cbl levels.[13,14] Both can be helpful in confirming a true CblD after replacement therapy, as they usually normalize within a week. MMA elevation has also been associated with poorer functional outcomes in subjects with reduced Cbl levels.
Finally, the HoloTC assay has the best accuracy theoretically, but its clinical usefulness is precluded by the scarce availability and the lack of reference values and standardization among laboratories.
Recently, a combined index of the Cbl status (named 4cB12), based on Cbl, Hcy, MMA, and HoloTc levels, has been suggested to improve the recognition of CblD, particularly in the early subclinical stages.
A possible algorithm for the diagnosis of CblD in the elderly is depicted in Figure 2.
Causes of CblD
Of note, a relatively small fraction of ingested Cbl can be absorbed along the entire intestine by passive diffusion, and that explains why high-dose oral therapy may be effective even in people with malabsorption.
Multiple conditions can interfere with the complicated multi-step journey of Cbl from food to cells. The main etiologies (summarized in Table 1) comprise: 1) pernicious anemia (PA), 2) maldigestion (eventually leading to the so-called "food-bound Cbl malabsorption," FBCM), 3) ileum disorders, 4) insufficient intake, and 5) increased consumption. PA and FBCM represent the primary causes in all age groups and are particularly frequent in the elderly, while an insufficient dietary intake is quite uncommon. In addition to acquired causes, sporadic congenital disorders (e.g., transcobalamin deficiency) can lead to CblD, but they typically manifest in newborns and are not relevant in the elderly. On the other hand, CblD in older people is frequently multi-factorial.
|Table 1. Main causes for Cbl deficiency in the elderly.|
The disorder is a consequence of severe immune-mediated damage of the gastric mucosa, which causes atrophy (atrophic autoimmune gastritis, AAG), especially in the fundus and the body, with a spared antrum. Histological confirmation of gastric atrophy needs for PA diagnosis. In addition, diagnosis is confirmed by the presence of two types of auto-antibodies, targeting the acid-producing H+/K+ ATPase of parietal cells (Parietal Cells Antibody or PCA), or the IF/IF binding site in the small bowel (Intrinsic Factors).
Antibody or IF), respectively. PCA causes hypo- or achlorhydria through the destruction of the parietal cells, also impairing the production of IF. Their presence may precede clinically overt atrophic gastritis by several years. PCA has high sensitivity (80-90%) in the early stage of the disease, but much lower specificity (50%), since they are also present in other autoimmune diseases (e.g., thyroiditis, type 1 diabetes, Addison's disease, and vitiligo), as well as in healthy elderly without AAG. IFA, which hamper the Cbl-IF complex formation or its binding to enterocytes, are considered more specific markers but have lower sensitivity (around 60%).
Fasting hypergastrinemia (present in 75% of subjects) and low Pepsinogen I levels may be useful in the diagnosis of PA, while the Shilling test that specifically investigated IF-mediated malabsorption has been abandoned due to its complexity and the need of using of isotope-labeled Cbl.
The diagnostic workup should also include an evaluation of iron status. Indeed, achlorhydria causes iron malabsorption and may lead to iron deficiency (ID) that typically precede megaloblastic anemia. PCA and endoscopic atrophic gastritis are encountered in about 20-30% of patients with unexplained or refractory ID.
Moreover, screening for autoimmunity is indicated, as a proportion of patients (especially those with genetic susceptibility associated with specific HLA-DR pattern) may develop other organ-specific immune-mediated disorders. Recent studies demonstrated that thyroid disorders (particularly Hashimoto's thyroiditis) affect up to 40% of patients with AAG and may be asymptomatic in the majority, leading to diagnostic and treatment delays. Thyroiditis with AAG (formerly known as "thyrogastric syndrome") is currently considered part of the polyglandular autoimmune syndromes, which include several endocrine and nonendocrine manifestations.
Finally, patients with PA harbor almost 7-fold higher risk of developing gastric neoplasms (adenocarcinomas, lymphomas, and carcinoids) as an end-stage evolution of gastric atrophy, achlorhydria and compensatory hypergastrinemia, which causes cellular metaplasia. For this reason, many experts recommend that adults with PA undergo endoscopic surveillance at baseline and every 3 to 5 years for life, although this practice is not universally accepted.
Food-bound cobalamin malabsorption
H. pylori-related gastritis. The most relevant form of FBCM is caused by chronic H. pylori (HP) infection, a common disorder in aged people. HP is strongly associated with atrophic gastritis. The mechanisms by which HP provokes gastritis are still unclear, but the production of antibodies cross-reacting with parietal cells H+/K+ ATPase may be involved. Interestingly, HP eradication has been reported to improve not only anemia and mean corpuscular volume (MCV), but also Cbl levels. The same was not observed in subjects in whom eradication therapy was unsuccessful. In successful cases, the positive Cbl balance may be related not only to HP eradication per se but also to the eradication of other small intestine bacteria potentially interfering with Cbl uptake. Treating HP is also important to reduce the risk of gastric cancer, which is increased in patients with long-standing infection.[29,30]
Drugs. In the elderly, long-term polypharmacy for comorbidities may favor CblD. PPI and H2-RA suppress both gastric acid secretion and IF production. A study including >200,000 subjects showed that CblD was more common in people assuming PPI or H2-RA for >2-years, especially in those treated with the highest dose. Similarly, a recent systematic review and meta-analysis were consistent with a higher risk of CblD in people chronically using PPI.
Metformin interferes with the Cbl absorption via a dose-dependent reduction of intestinal free calcium ions required for uptake of the Cbl¬-IF complex by ileal enterocyte receptors.
Although PPI, H2-RA, and metformin appear to reduce Cbl bioavailability, the clinical significance of such an effect is still controversial. In clinical practice, it is crucial to keep in mind this as an additional cofactor in subjects with other predisposing factors (e.g., in those with high Cbl need due to chronic hemolysis), as well as in those with anemia and neurologic/cognitive impairments. Anyway, a regular reassessment of actual benefits and risks associated with these drugs is recommended, especially in the elderly.
Gastric surgery. Total or partial gastrectomy are relatively common causes of CblD. Achlorhydria and the absence of pepsin lead to impaired Cbl dissociation from food, and the reduced IF production impairs Cbl absorption. In patients with total gastrectomy, CblD occurs relatively early (after about 15 months), while in partial distal resections presentation is delayed by several years, mainly in patients with low pre-operative Cbl stores. Cbl supplementation is always required after gastric surgery.
Malabsorption Due to Small Intestine Disorders
Dietary Poor Intake
Increased Cbl Consumption
|Table 2. Differential diagnosis of macrocytosis (with or without anemia) in the elderly.|
In addition to ineffective erythropoiesis, the erythrocytes released into the circulation have increased rigidity, which may be responsible for peripheral hemolysis, leading to haptoglobin consumption and elevation of both serum bilirubin and lactate dehydrogenase (LDH). The peripheral blood smear may show anisocytosis, poikilocytosis, stomatocytes, dacriocytes, red cell fragments, and target cells (Figure 3A). Thrombocytopenia and leukopenia may also occur. Neutrophils typically present hypersegmentation of their nuclei (Figure 3B). Detection of at least 3 neutrophils with at least 5 lobes, or one containing at least 6, is considered specific for CblD. Hypersegmented neutrophils are an early sign of megaloblastosis, but they have scarce sensitivity and may persist for days after Cbl levels correction. In severe cases, the initial differential diagnosis can include myelodysplastic syndromes, hemolytic anemias, or even acute leukemia. Severe CblD could lead to a picture that mimics thrombotic microangiopathy (TMA), also known as pseudo-TMA. Both conditions are characterized by red cell fragmentation coupled with thrombocytopenia. An evaluation of reticulocytes count (reduced in severe CblD, elevated in TMA) is generally useful for differentiating the disorders and is critical to avoid unnecessary/complex treatment for TMA.
Recognizing CblD as the etiology of neuropsychiatric signs in the elderly requires a high degree of suspicion, since they may develop before or even in the absence of anemia or macrocytosis in around 20% of patients.[36,47] Neurological impairment is usually heralded by proprioception and vibration loss due to peripheral sensory neuropathy. Other common neurological findings include paresthesia, gait ataxia, abnormal reflexes, bowel/bladder incontinence, optic atrophy, altered smell and taste, lethargy, and extrapyramidal signs. Autonomic dysfunction can also occur, leading to orthostatic hypotension and syncope. CblD in the elderly can be associated with poor coordination, walking difficulties, falls, and loss of function.
Subacute combined degeneration (SCD) of the spinal cord due to demyelination is a rare complication of CblD, which, if untreated, may cause irreversible spastic ataxia. SCD can be detected by MRI in T2-weighted images, showing symmetrical hyperintensity of posterior and lateral columns in the cervical and thoracic spinal cord, although imaging sensitivity appears quite low.
In advanced stages, cognitive decline, psychosis with hallucinations, and depression may be observed. Severe CblD in the elderly may predispose to delirium,[45,50,51] although this association has been confuted by a recent report.
Of note, recent trials do not support Cbl supplementation in the elderly with normal to low Cbl levels for preventing cognitive deterioration.[53,54]
Low Cbl levels, with or without hyperhomocysteinemia, has been associated with high markers of bone turnover and increased fracture risk. However, the clinical relevance of such association is debated, and, at present, supplementation cannot be recommended for preventing fracture in the elderly.[57,58]
Finally, hyperhomocysteinemia resulting from CblD has been associated with endothelial dysfunction, and accelerated atherosclerosis.[60,61] However, studies evaluating Hcy-lowering treatment by B-vitamins supplementation have failed to demonstrate an improvement in cardiovascular outcomes.[62,63]
Cbl can be administered orally and parenterally (intramuscularly, IM). Subcutaneous, transdermal, sublingual, and nasal formulations are also available, but their role in clinical practice appears marginal, because of their variable effectiveness and higher costs. Two formulations are currently available, cyanocobalamin and hydroxocobalamin.
Initial parenteral administration is appropriated in the subjects with (e.g., PA, or gastric resections) and in those with symptoms, requiring a prompt correction.[45,64] The typical schedule consists of 1 injection (1,000 mg, of which about 10% is retained) three times a week for 1 to 2 weeks, followed by weekly injections for a month. Maintenance therapy is based on monthly administration for cyanocobalamin, once every other month, for hydroxocobalamin.
Oral Cbl (50-150 μg/day) represents a cheaper and easier route of administration, more comfortable for the patients and effective in the majority of mild-moderate cases. It is also more suitable in patients under anticoagulant therapy, in whom IM injections may be contraindicated. Recently, its role has been re-evaluated even in subjects with malabsorption or FBCM, in which high-dose oral Cbl (1,000 μg daily) has proven as non-inferior to the parenteral route.[67,68] Indeed, small amounts of Cbl (0.5-4%) can be passively absorbed by the entire bowel, via an IF-independent pathway. Therefore, high oral doses of 1,000 μg deliver at least 5 μg of Cbl, which are largely sufficient to satisfy daily requirements. However, in clinical practice, the role of high-dose oral Cbl in PA or malabsorption is still debated, and injectable Cbl remains frontline therapy. Food alters oral Cbl absorption; thus, it should preferably be assumed on an empty stomach.
Monitoring the hematological and clinical response to Cbl replacement therapy is essential, as it is useful to confirm the diagnosis. Typically, the reticulocyte crisis occurs in 1 week, anemia and macrocytosis improve within 3-4 weeks, and normalization of Hb and MCV is generally achieved within sixth-eighth weeks. The neurological response is less predictable and can take from 1 week to 3 months. Neurological irreversible damages have been described in about 6% of cases, and are more frequent in patients with ≥6-months treatment delay.
Monitoring serum Cbl levels is scantly informative since they rapidly rise with supplementation regardless of the actual repletion of Cbl body stores. Serum MMA and Hcy levels tend to decrease or even normalize by the first week (unless renal failure coexists), and this may further support the diagnosis in uncertain cases.
Particular attention has to be paid to other possible causes of anemia, such as folate and iron deficiency. In patients with both Cbl and folate deficiency, Cbl should be given first in order to avoid the risk of precipitating SCD of the spinal cord.
Moreover, some drugs may interfere with Cbl metabolism and absorption. This is particularly true for PPI, which are often inappropriately prescribed in the elderly, and whose cessation should be considered whenever clear indications for their use are not present.
Cbl supplements are generally well-tolerated even when prescribed at high doses. Adverse effects may include hot flushes, acneiform eruptions, and, quite rarely, severe allergic reactions (i.e., anaphylaxis), especially in subjects with cobalt sensitivity.[36,55] Transient hypokalemia can be observed when severe anemias respond to Cbl as a consequence of potassium uptake by growing hematopoietic cells, but its clinical relevance has never been proven.
Concerns have been raised about the safety of generalized Cbl supplementation, especially regarding a possible increased risk of lung cancer.[71,72,73] However, a meta-analysis of randomized controlled trials (RCTs) denied any effects of Cbl supplementation on cancer incidence or mortality, rather showing a lower risk of melanoma. Monitoring circulating Cbl levels in lifelong treated high-risk patients (e.g., male smokers) could be a reasonable approach to avoid overtreatment.
Finally, the use of multivitamin supplements is becoming very popular among older people. Taking these supplements, which often contain low-dose Cbl (3-5 μg/day) in association with vitamin D, iron, or proteins, may be theoretically useful for short periods, for instance, to compensate poor nutrition after a disabling disease. However, there is currently no evidence of their efficacy in preventing CblD, and probably they have little (if any) effects in treating CblD in the elderly.
- Stabler, SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med. 2013; 368(2): 149-60. https://doi.org/10.1056/NEJMcp1113996 PMid:23301732
- Green R. Vitamin B12 deficiency from the perspective of a practicing hematologist. Blood. 2017; 129(19): 2603-11. https://doi.org/10.1182/blood-2016-10-569186 PMid:28360040
- Lu SC. S-Adenosylmethionine. Int J Biochem Cell Biol. 2000; 32(4): 391-95. https://doi.org/10.1016/S1357-2725(99)00139-9
R, Grimley Evans J, Schneede J, Nexo E, Bates C, Fletcher A, Prentice
A, Johnston C, Ueland PM, Refsum H, Sherliker P, Birks J, Whitlock G,
Breeze E, Scott JM. Vitamin B12 and folate deficiency in later life.
Age Ageing. 2004; 33(1): 34-41. https://doi.org/10.1093/ageing/afg109 PMid:14695861
J, Rosenberg IH, Wilson PW, Stabler SP, Allen RH. Prevalence of
cobalamin deficiency in the Framingham elderly population. Am J Clin
Nutr. 1994; 60(1): 2-11. https://doi.org/10.1093/ajcn/60.1.2 PMid:8017332
E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE,
Noblet-Dick M, Maloisel F, Schlienger JL, Blicklé JF. Vitamin B12
(cobalamin) deficiency in elderly patients. CMAJ. 2004; 171(3): 251-59.
https://doi.org/10.1503/cmaj.1031155 PMid:15289425 PMCid:PMC490077
CW, Ip CY, Leung CP, Leung CS, Cheng JN, Siu CY. Vitamin B12 deficiency
in the institutionalized elderly: A regional study. Exp Gerontol. 2015;
69: 221-25. https://doi.org/10.1016/j.exger.2015.06.016 PMid:26122132
E, Federici L, Kaltenbach G. Hematological manifestations related to
cobalamin deficiency in elderly patients. Eur J Intern Med. 2008;
19(2): 149-50. https://doi.org/10.1016/j.ejim.2007.05.006 PMid:18249317
S, Koskinen P, Irjala K, Löppönen M, Isoaho R, Kivelä SL, Pelliniemi
TT. Vitamin B12 deficiency in the aged: a population-based study. Age
Ageing. 2007; 36(2): 177-83. https://doi.org/10.1093/ageing/afl150 PMid:17189285
- Wong CW. Vitamin B12 deficiency in the elderly: is it worth screening? Hong Kong Med J. 2015; 21(2): 155-64. https://doi.org/10.12809/hkmj144383 PMid:25756278
V, Hamilton MS, Molloy AM. Guidelines for the diagnosis and treatment
of cobalamin and folate disorders. Br J Haematol. 2014; 166(4):
496-513. https://doi.org/10.1111/bjh.12959 PMid:24942828
BHR, Wouters HJCM, Heiner-Fokkema MR, van der Klauw MM. The Many Faces
of Cobalamin (Vitamin B12) Deficiency. Mayo Clin Proc Innov Qual
Outcomes. 2019; 3(2): 200-14. https://doi.org/10.1016/j.mayocpiqo.2019.03.002 PMid:31193945 PMCid:PMC6543499
P, Edwin P, Popiel B, Lammersfeld C, Gupta D. Methylmalonic Acid and
Homocysteine as Indicators of Vitamin B-12 Deficiency in Cancer. PLoS
One. 2016; 11(1): e0147843. https://doi.org/10.1371/journal.pone.0147843 PMid:26807790 PMCid:PMC4725715
SM, Oh J, Chun MR, Lee SY. Methylmalonic Acid and Homocysteine as
Indicators of Vitamin B12 Deficiency in Patients with Gastric Cancer
after Gastrectomy. Nutrients. 2019; 11(2). https://doi.org/10.3390/nu11020450 PMid:30795564 PMCid:PMC6412945
BHR, Wouters HJCM, de Jong WHA, Huls G, van der Klauw MM. Association
of vitamin B12, methylmalonic acid, and functional parameters. Neth J
Med. 2020; 78(1): 10-24.
- Jarquin Campos
A, Risch L, Nydegger U, Wiesner J, Vazquez Van Dyck M, Renz H, Stanga
Z, Risch M. Diagnostic Accuracy of Holotranscobalamin, Vitamin B12,
Methylmalonic Acid, and Homocysteine in Detecting B12 Deficiency in a
Large, Mixed Patient Population. Dis Markers. 2020; 2020: 7468506. https://doi.org/10.1155/2020/7468506 PMid:32089757 PMCid:PMC7017578
SN. Biochemical markers of vitamin B12 deficiency combined in one
diagnostic parameter: the age-dependence and association with cognitive
function and blood hemoglobin. Clin Chim Acta. 2013; 422: 47-53. https://doi.org/10.1016/j.cca.2013.04.002 PMid:23583557
- Bizzaro N, Antico A. Diagnosis and classification of pernicious anemia. Autoimmun Rev. 2014; 13(4-5): 565-68. https://doi.org/10.1016/j.autrev.2014.01.042 PMid:24424200
- Annibale B, Lahner E, Fave GD. Diagnosis and management of pernicious anemia. Curr Gastroenterol Rep. 2011; 13(6): 518-24. https://doi.org/10.1007/s11894-011-0225-5 PMid:21947876
- Hershko C, Camaschella C. How I treat unexplained refractory iron deficiency anemia. Blood. 2014; 123(3): 326-33. https://doi.org/10.1182/blood-2013-10-512624 PMid:24215034
- Andres E, Serraj K. Optimal management of pernicious anemia. J Blood Med. 2012; 3: 97-103. https://doi.org/10.2147/JBM.S25620 PMid:23028239 PMCid:PMC3441227
E, Conti L, Cicone F, Capriello S, Cazzato M, Centanni M, Annibale B,
Virili C.Thyro-entero-gastric autoimmunity: Pathophysiology and
implications for patient management. Best Pract Res Clin Endocrinol
Metab. 2019; 101373. https://doi.org/10.1016/j.beem.2019.101373 PMid:31864909
BH, Chan J, Kyaw T, Alderuccio F. Cutting edge issues in autoimmune
gastritis. Clin Rev Allergy Immunol. 2012; 42(3): 269-78. https://doi.org/10.1007/s12016-010-8218-y PMid:21174235
G, Dawsey SM, Engels EA, Ricker W, Parsons R, Etemadi A, Lin SW, Abnet
CC, Freedman ND. Cancer Risk After Pernicious Anemia in the US Elderly
Population. Clin Gastroenterol Hepatol. 2015; 13(13): 2282-89 e1-4. https://doi.org/10.1016/j.cgh.2015.05.040 PMid:26079040 PMCid:PMC4655146
E, Esposito G, AnnibaleD. Pernicious Anemia: Time to Justify Endoscopic
Monitoring? Clin Gastroenterol Hepatol. 2016; 14(2): 322. https://doi.org/10.1016/j.cgh.2015.07.038 PMid:26240006
AH, Pimentel M. Gastrointestinal bacterial overgrowth: pathogenesis and
clinical significance. Ther Adv Chronic Dis. 2013; 4(5): 223-31. https://doi.org/10.1177/2040622313496126 PMid:23997926 PMCid:PMC3752184
A, Roham M. Role of Helicobacter pylori infection in the manifestation
of old age-related diseases. Mol Genet Genomic Med. 2020; e1157. https://doi.org/10.1002/mgg3.1157 PMid:32067423 PMCid:PMC7196471
K, Beyan C, Ural AU, Cetin T, Avcu F, Gülşen M, Finci R, Yalçín A.
Helicobacter pylori--is it a novel causative agent in Vitamin B12
deficiency? Arch Intern Med. 2000; 160(9): 1349-53. https://doi.org/10.1001/archinte.160.9.1349 PMid:10809040
SE, Choi KD, Choe J, Kim SO, Na HK, Choi JY, Ahn JY, Jung KW, Lee J,
Kim DH, Chang HS, Song HJ, Lee GH, Jung HY. The effect of eradication
of Helicobacter pylori on gastric cancer prevention in healthy
asymptomatic populations. Helicobacter. 2018; 23(2): e12464. https://doi.org/10.1111/hel.12464 PMid:29345408
IJ, Kook MC, Kim YI, Cho SJ, Lee JY, Kim CG, Park B, Nam BH.
Helicobacter pylori Therapy for the Prevention of Metachronous Gastric
Cancer. N Engl J Med: 2018; 378(12): 1085-95. https://doi.org/10.1056/NEJMoa1708423 PMid:29562147
- Hesdorffer CS, Longo DL. Drug-Induced Megaloblastic Anemia. N Engl J Med. 2015; 373(17): 1649-58. https://doi.org/10.1056/NEJMra1508861 PMid:26488695
JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and
histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA.
2013; 310(22): 2435-42. https://doi.org/10.1001/jama.2013.280490 PMid:24327038
SB, Nagaraja V, Kapur A, Eslick GD. Association between vitamin B12
deficiency and long-term use of acid-lowering agents: a systematic
review and meta-analysis. Intern Med J. 2015; 45(4): 409-16. https://doi.org/10.1111/imj.12697 PMid:25583062
JW. Proton Pump Inhibitors, H2-Receptor Antagonists, Metformin, and
Vitamin B-12 Deficiency: Clinical Implications. Adv Nutr. 2018; 9(4):
511S-518S. https://doi.org/10.1093/advances/nmy023 PMid:30032223 PMCid:PMC6054240
Y, Kim HI, Hyung WJ, Song KJ, Lee JH, Kim YM, Noh SH. Vitamin B(12)
deficiency after gastrectomy for gastric cancer: an analysis of
clinical patterns and risk factors. Ann Surg. 2013; 258(6): 970-75. https://doi.org/10.1097/SLA.0000000000000214 PMid:24096753
- Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ. 2014; 349: g5226. https://doi.org/10.1136/bmj.g5226 PMid:25189324
R, Fusco S, Sganga F, Falcone B, Vetrano DL, Abbatecola A, Corica F,
Maggio M, Ruggiero C, Fabbietti P, Corsonello A, Onder G, Lattanzio F.
Inappropriate Use of Proton Pump Inhibitors in Elderly Patients
Discharged From Acute Care Hospitals. J Nutr Health Aging. 2016; 20(6):
665-70. https://doi.org/10.1007/s12603-015-0642-5 PMid:27273358
R, Kopylov U, Szilagyi A, Saxena A, Rosenblatt DS, Warner M, Bessissow
T, Seidman E, Bitton A. Vitamin B12 deficiency in inflammatory bowel
disease: prevalence, risk factors, evaluation, and management. Inflamm
Bowel Dis. 2014; 20(6): 1120-28. https://doi.org/10.1097/MIB.0000000000000024 PMid:24739632
R, Lester SE, Babatunde T. The prevalence of cobalamin deficiency among
vegetarians assessed by serum vitamin B12: a review of literature. Eur
J Clin Nutr. 2014; 68(5): 541-48. https://doi.org/10.1038/ejcn.2014.46 PMid:24667752
G, Laganà AS, Rapisarda AM, La Ferrera GM, Buscema M, Rossetti P, Nigro
A, Muscia V, Valenti G, Sapia F, Sarpietro G, Zigarelli M, Vitale SG.
Vitamin B12 among Vegetarians: Status, Assessment and Supplementation.
Nutrients. 2016; 8(12). https://doi.org/10.3390/nu8120767 PMid:27916823 PMCid:PMC5188422
- Girelli, D., G. Marchi, and C. Camaschella, Anemia in the Elderly. HemaSphere. 2018; 2(3): e40. https://doi.org/10.1097/HS9.0000000000000040 PMid:31723768 PMCid:PMC6745992
W, Elemary M, Burnouf T, Seghatchian J, Goubran H. Vitamin B12
deficiency and metabolism-mediated thrombotic microangiopathy (MM-TMA).
Transfus Apher Sci. 2019; 102717. https://doi.org/10.1016/j.transci.2019.102717 PMid:31902683
PN, Tran MH. Cobalamin deficiency presenting with thrombotic
microangiopathy (TMA) features: A systematic review. Transfus Apher
Sci. 2018; 57(1): 102-06. https://doi.org/10.1016/j.transci.2018.01.003 PMid:29454538
JA, Mason J, Choi J, Holguin M. B12 deficiency leading to marked
poikilocytosis versus true schistocytosis, a pernicious problem.
Transfus Apher Sci. 2017; 56(4): 576-77. https://doi.org/10.1016/j.transci.2017.06.003 PMid:28711333
C, Steinle NI, Regenold WT. The neuropsychiatry of vitamin B12
deficiency in elderly patients. J Neuropsychiatry Clin Neurosci. 2012;
24(1): 5-15. https://doi.org/10.1176/appi.neuropsych.11020052 PMid:22450609
N, Grover S, Agarwal M. Does B12 deficiency lead to lack of treatment
response to conventional antidepressants? Psychiatry (Edgmont). 2010;
- Lavoie MR, Cohen NC,
Gregory TA, Weber PV. Subacute combined degeneration: a case of
pernicious anaemia without haematological manifestations. BMJ Case Rep.
2020; 13(3). https://doi.org/10.1136/bcr-2020-234276 PMid:32209580
KK, Malhotra HS, Garg RK, Gupta PK, Roy B, Gupta RK. Prevalence of MR
imaging abnormalities in vitamin B12 deficiency patients presenting
with clinical features of subacute combined degeneration of the spinal
cord. J Neurol Sci. 2014; 342(1-2): 162-66. https://doi.org/10.1016/j.jns.2014.05.020 PMid:24857760
BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP. Vitamin
B(12) deficiency and depression in physically disabled older women:
epidemiologic evidence from the Women's Health and Aging Study. Am J
Psychiatry. 2000; 157(5): 715-21. https://doi.org/10.1176/appi.ajp.157.5.715 PMid:10784463
- Sanford AM, Flaherty JH. Do nutrients play a role in delirium? Curr Opin Clin Nutr Metab Care. 2014; 17(1): 45-50. https://doi.org/10.1097/MCO.0000000000000022 PMid:24296414
U, Baysal E, Ay N, Altas Y, Altindag R, Yaylak B, Alp V, Demirtas E.
Relationship between cobalamin deficiency and delirium in elderly
patients undergoing cardiac surgery. Neuropsychiatr Dis Treat. 2015;
11: 2033-39. https://doi.org/10.2147/NDT.S87888 PMid:26300642 PMCid:PMC4535547
Shariatpanahi M, Velayati A, Jamalian SA, Babevaynejad M, Vahdat
Shariatpanahi Z. The relationship between serum cobalamin, folic acid,
and homocysteine and the risk of post-cardiac surgery delirium.
Neuropsychiatr Dis Treat. 2019; 15: 1413-19. https://doi.org/10.2147/NDT.S201620 PMid:31190843 PMCid:PMC6536132
AD, Allen E, Clarke R, Elbourne D, Fletcher AE, Letley L, Richards M,
Whyte K, Uauy R, Mills K. Effects of vitamin B-12 supplementation on
neurologic and cognitive function in older people: a randomized
controlled trial. Am J Clin Nutr. 2015; 102(3): 639-47. https://doi.org/10.3945/ajcn.115.110775 PMid:26135351 PMCid:PMC4548176
AW, Denton DA, Di Nisio M, Chong LY, Abraham RP, Al-Assaf AS, Anderson
JL, Malik MA, Vernooij RW, Martínez G, Tabet N, McCleery J. Vitamin and
mineral supplementation for maintaining cognitive function in
cognitively healthy people in mid and late life. Cochrane Database Syst
Rev. 2018; 12: CD011906. https://doi.org/10.1002/14651858.CD011906.pub2 PMCid:PMC6353240
- Brescoll J, Daveluy S. A review of vitamin B12 in dermatology. Am J Clin Dermatol. 2015; 16(1): 27-33. https://doi.org/10.1007/s40257-014-0107-3 PMid:25559140
RA, Pluijm SM, de Groot LC, Lips P, Smit JH, van Staveren WA.
Homocysteine and vitamin B12 status relate to bone turnover markers,
broadband ultrasound attenuation, and fractures in healthy elderly
people. J Bone Miner Res. 2005; 20(6): 921-29. https://doi.og/10.1359/JBMR.050202 PMid:15883631
AW, Swart KM, van Wijngaarden JP, van Dijk SC, Ham AC, Brouwer-Brolsma
EM, van der Zwaluw NL, Dhonukshe-Rutten RA, van der Cammen TJ, de Groot
LC, van Meurs J, Lips P, Uitterlinden AG, Zillikens MC, van Schoor NM,
van der Velde N. Effect of Vitamin B12 and Folic Acid Supplementation
on Bone Mineral Density and Quantitative Ultrasound Parameters in Older
People with an Elevated Plasma Homocysteine Level: B-PROOF, a
Randomized Controlled Trial. Calcif Tissue Int. 2015; 96(5): 401-09. https://doi.org/10.1007/s00223-015-9968-6 PMid:25712255 PMCid:PMC4415946
Wijngaarden JP, Swart KM, Enneman AW, Dhonukshe-Rutten RA, van Dijk SC,
Ham AC, Brouwer-Brolsma EM, van der Zwaluw NL, Sohl E, van Meurs JB,
Zillikens MC, van Schoor NM, van der Velde N, Brug J, Uitterlinden AG,
Lips P, de Groot LC. Effect of daily vitamin B-12 and folic acid
supplementation on fracture incidence in elderly individuals with an
elevated plasma homocysteine concentration: B-PROOF, a randomized
controlled trial. Am J Clin Nutr. 2014; 100(6): 1578-86. https://doi.org/10.3945/ajcn.114.090043 PMid:25411293
B, Jepchumba VK, Guéant JL, Guéant-Rodriguez RM. Mechanisms of
homocysteine-induced damage to the endothelial, medial and adventitial
layers of the arterial wall. Biochimie. 2020 [Epub ahead of print]. https://doi.org/10.1016/j.biochi.2020.02.012 PMid:32105811
DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence
on causality from a meta-analysis. BMJ. 2002; 325(7374): 1202. https://doi.org/10.1136/bmj.325.7374.1202 PMid:12446535 PMCid:PMC135491
- Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J. 2015; 14: 6. https://doi.org/10.1186/1475-2891-14-6 PMid:25577237 PMCid:PMC4326479
JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, Sides
EG, Wang CH, Stampfer M. Lowering homocysteine in patients with
ischemic stroke to prevent recurrent stroke, myocardial infarction, and
death: the Vitamin Intervention for Stroke Prevention (VISP) randomized
controlled trial. JAMA. 2004; 291(5): 565-75. https://doi.org/10.1001/jama.291.5.565 PMid:14762035
AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions
for preventing cardiovascular events. Cochrane Database Syst Rev. 2017;
8: CD006612. https://doi.org/10.1002/14651858.CD006612.pub5 PMCid:PMC6483699
- Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008; 112(6): 2214-21. https://doi.org/10.1182/blood-2008-03-040253 PMid:18606874 PMCid:PMC2532799
E, Zulfiqar AA, Vogel T. State of the art review: oral and nasal
vitamin B12 therapy in the elderly. QJM. 2020; 113(1): 5-15. https://doi.org/10.1093/qjmed/hcz046 PMid:30796433
E, Zulfiqar AA, Serraj K, Vogel T, Kaltenbach G. Systematic Review and
Pragmatic Clinical Approach to Oral and Nasal Vitamin B12 (Cobalamin)
Treatment in Patients with Vitamin B12 Deficiency Related to
Gastrointestinal Disorders. J Clin Med. 2018; 7(10). https://doi.org/10.3390/jcm7100304 PMid:30261596 PMCid:PMC6210286
H, Li L, Qin LL, Song Y, Vidal-Alaball J, Liu TH. Oral vitamin B12
versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane
Database Syst Rev. 2018; 3: CD004655. https://doi.org/10.1002/14651858.CD004655.pub3 PMCid:PMC6494183
CC, Vidal-Alaball J, Cannings-John R, McCaddon A, Hood K, Papaioannou
A, Mcdowell I, Goringe A. Oral vitamin B12 versus intramuscular vitamin
B12 for vitamin B12 deficiency: a systematic review of randomized
controlled trials. Fam Pract. 2006; 23(3): 279-85. https://doi.org/10.1093/fampra/cml008 PMid:16585128
H, Berlin R, G Brante G. Oral treatment of pernicious anemia with high
doses of vitamin B12 without intrinsic factor. Acta Med Scand. 1968;
184(4): 247-58. https://doi.org/10.1111/j.0954-6820.1968.tb02452.x PMid:5751528
S, Benardon S, Diani M, Barbareschi M. Acneiform eruptions caused by
vitamin B12: A report of five cases and review of the literature. J
Cosmet Dermatol. 2018; 17(1): 112-15. https://doi.org/10.1111/jocd.12360 PMid:28594082
M, Bønaa KH, Nygård O, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen
K, Njølstad I, Refsum H, Nilsen DW, Tverdal A, Meyer K, Vollset SE.
Cancer incidence and mortality after treatment with folic acid and
vitamin B12. JAMA. 2009; 302(19): 2119-26. https://doi.org/10.1001/jama.2009.1622 PMid:19920236
A, Carreras-Torres R, Larose TL, Yuan JM, Stevens VL, Weinstein SJ,
Albanes D, Prentice R, Pettinger M, Cai Q, Blot WJ, Arslan AA,
Zeleniuch-Jacquotte A, McCullough ML, Le Marchand L, Wilkens LR, Haiman
CA, Zhang X, Stampfer MJ, Smith-Warner SA, Giovannucci E, Giles GG,
Hodge AM, Severi G, Johansson M, Grankvist K, Langhammer A, Brumpton
BM, Wang R, Gao YT, Ericson U, Bojesen SE, Arnold SM, Koh WP, Shu XO,
Xiang YB, Li H, Zheng W, Lan Q, Visvanathan K, Hoffman-Bolton J, Ueland
PM, Midttun Ø, Caporaso NE, Purdue M, Freedman ND, Buring JE, Lee IM,
Sesso HD, Michael Gaziano J, Manjer J, Relton CL, Hung RJ, Amos CI,
Johansson M, Brennan P; LC3 consortium and the TRICL consortium. Is
high vitamin B12 status a cause of lung cancer? Int J Cancer. 2019;
145(6): 1499-1503. https://doi.org/10.1002/ijc.32033 PMid:30499135 PMCid:PMC6642017
TM, White E, Chen CL. Long-Term, Supplemental, One-Carbon
Metabolism-Related Vitamin B Use in Relation to Lung Cancer Risk in the
Vitamins and Lifestyle (VITAL) Cohort. J Clin Oncol. 2017; 35(30):
3440-48. https://doi.org/10.1200/JCO.2017.72.7735 PMid:28829668 PMCid:PMC5648175
SL, Chen TS, Ma CY, Meng YB, Zhang YF, Chen YW, Zhou YH. Effect of
vitamin B supplementation on cancer incidence, death due to cancer, and
total mortality: A PRISMA-compliant cumulative meta-analysis of
randomized controlled trials. Medicine (Baltimore). 2016; 95(31):
e3485. https://doi.org/10.1097/MD.0000000000003485 PMid:27495015 PMCid:PMC4979769