research paper on vitamin b12

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The discovery of vitamin B(12)

Affiliation.

1 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Dublin, Ireland. jscott @ tcd.ie
PMID: 23183296
DOI: 10.1159/000343114

The discovery of vitamin B(12), the elucidation of its role in metabolism, and the effects and treatment of its deficiency occurred in distinct phases over more than 100 years, and it was the subject of two separate Nobel Prizes. The valuable contribution of clinical reports and studies of patients with pernicious anemia throughout the 19th century resulted in enough clinical definition to allow Minot and Murphy to put together the first hallmark study on treatment of the condition, leading them to a Nobel Prize. These researchers were not the first to suggest that an inadequacy of nutrients was the cause of pernicious anemia, but their particular input was a carefully designed intervention in well-characterized pernicious anemia patients, of a special diet containing large amounts of liver. They found consistent improvement in the clinical and blood status of all subjects, most of whom remained on remission indefinitely. After the successful intervention studies, the next advance was made by Castle who discovered that a gastric component, which he called intrinsic factor, was missing in pernicious anemia. Many years later, intrinsic factor was found to be a glycoprotein that formed a complex with vitamin B(12), promoting its absorption through ileal receptors. The vitamin was isolated by two groups simultaneously and was crystallized and characterized in the laboratory of Dorothy Hodgkin, contributing to her Nobel Prize in 1964. Subsequently, the various biochemical roles of vitamin B(12) were elucidated, including its important interaction with folate and their common link with megaloblastic anemia. Many of the early clinical studies recognized that vitamin B(12) deficiency also caused a severe neuropathy leading to paralysis and death, while post mortem analysis demonstrated spinal cord demyelination. Vitamin B(12) is still the subject of intense research and, in particular, its role in preventing these irreversible neurological lesions remains unclear.

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Int J Mol Sci

A Brief Review on Vitamin B 12 Deficiency Looking at Some Case Study Reports in Adults

In the era of evidence-based medicine, the randomized clinical trial corresponds to the top step in the qualitative scale of the evidence available in the literature, while small series of cases or the description of individual cases occupy the last place. However, the latter represent an important part of clinical practice and have significantly influenced the evolution of medicine, contributing significantly to the advancement of scientific knowledge. Vitamin B 12 deficiency shares several common symptoms that affect several tissues and organs with health aliments, so its diagnosis could be unobvious for the broad array of its effects and investigation methods used. In this review, we focused our attention on some case reports related to the vitamin B 12 deficiency associated to anemia, neurologic disorders, and hyperhomocysteinemia. B 12 deficiency reversal is simply achieved by prompt therapy, even though it is not the same for several disorders.

1. Introduction

During the 1940s, an intensive search for the active factor in liver extracts that prevents pernicious anemia showed that both folate and vitamin B 12 prevent megaloblastic anemia, but only vitamin B 12 can prevent neurological complications [ 1 ]. It is now known that the two vitamins act jointly in regenerating methionine from homocysteine (Hcy). Hcy accumulates if conversion to methionine is slowed because of a shortage of folate or vitamin B 12 or both, and a raised plasma Hcy suggests sub-optimal nucleic acid and amino-acid metabolism. It also has direct harmful effects, e.g., it increases the risk of cardiovascular disease through thickening the lining of blood vessels and may also increase the risk of certain cancers and dementia.

As reactions catalyzed by tetrahydrofolate are crucial for cell growth and multi-plication, rapidly dividing cells are particularly vulnerable to a deficiency of either folate or vitamin B 12 . In adults, this affects the bone marrow, causing megaloblastic anemia. In the early embryo, morphogenetic events (particularly those depending on focal rapid cell multiplication) may be affected, increasing the risk of congenital malformation. Single gene disorders caused by rare variants of several enzymes involved in one-carbon transfer cause problems ranging from greatly increased plasma Hcy levels with very early onset cardiovascular disease, to developmental delay and neurological problems, with or without megaloblastic anemia [ 2 ]. As previously reported [ 2 ], methionine synthase, a vitamin-B 12 -dependent enzyme, catalyzes the folic acid’s donation of a methyl group across methylenetetrahydrofolate reductase (MTHFR). Elevated plasma levels of Hcy can be caused by a deficiency of either vitamin B 12 or folate, and in human subjects mild (13–24 µM) and moderate (25–60 µM) hyperhomocysteinemia (HHcy) are also associated with mutations of MTHFR genes.

Vitamin B 12 , also called cobalamin, is synthesized only by micro-organisms [ 3 ]. Dietary sources are meat (particularly liver), shellfish, some cheeses, yeast extracts, and the root nodules of legumes (peas, beans, and so on), mainly due to simultaneous bacteria presence in soil and/or their aerial surfaces. Figure 1 reports the main animal dietary B 12 source and its average content in raw/fresh amounts. Based on the absorption of labeled vitamin B 12 from some food products, such as chicken meat, rainbow trout, or eggs the bioavailability of vitamin B 12 is generally assumed to be 40% or 50% for healthy adults without alteration of gastrointestinal functioning [ 4 ]. Bioavailability also varies by type of food source. For example, dairy products have a bioavailability of vitamin B 12 three times higher than meat or fish [ 5 ]. Moreover, the bioavailability of vitamin B 12 from dairy products is considerable [ 6 ]. This aspect should take into consideration for vitamin B 12 recommendations. However, most of the information on B 12 bioavailability from foods was collected 40–50 years ago, and more recent methods to derive recommendations based on dose–response evidence are still under development [ 4 ]. Currently, to maintain a healthy hematological status and serum vitamin B 12 levels, average daily intakes of vitamin B 12 from food of 5.94 mcg for men and 3.78 mcg for women aged 20 and older have been recommended. For children aged 2–19 years old, mean daily intakes of vitamin B 12 from food range from 3.76 mcg to 4.55 mcg [ 7 ]. The original estimates of dietary folate and vitamin B 12 requirements and recommended dietary allowances (RDAs) were based on the amount needed to avoid manifest deficiency disorders (megaloblastic anemia, with sub-acute combined degeneration of the cord in the case of vitamin B 12 deficiency) and on levels observed in populations. However, these levels do not essentially represent necessary requirements.

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Object name is ijms-22-09694-g001.jpg

The average content of B 12 in animal dietary sources.

As reported by Carmel [ 8 ], average total body stores of vitamin B 12 are 3–5 mg, mostly in the liver. After excretion from bile, it mostly is reabsorbed from the small intestine. It is first bound within the duodenum and jejunum to intrinsic factor produced by gastric parietal cells and is then absorbed in the terminal ileum [ 9 ]. Thus, when there is little or no vitamin B 12 in the diet, stores may last for up to 5–10 years before manifestations of vitamin B 12 are seen clinically. The etiology of vitamin B 12 deficiency usually includes causes related to malabsorption, such as autoimmune gastritis (pernicious anemia), celiac disease, inflammatory bowel disease, surgical gastrectomy, gastric bypass, and ileal resection. Less commonly, vitamin B 12 deficiency can occur due to nutritional habits (strict vegans, breastfed infants born to vegan mothers with decreased dietary intake of animal products), nitrous oxide abuse, Diphyllobothrium latum infection, pancreatic insufficiency, drug interference (metformin, proton pump inhibitors, drug affected purine, and pyrimidine synthesis), inherited disorders affecting intrinsic factor and other inherited disorders including methylmalonic acidemia and transcobalamin II deficiency. Moreover, alcohol abuse could represent a risk for vitamin B 12 deficiency, for its direct connection with the Hcy concentration, besides reflecting the degree of hepatocytes injury [ 10 , 11 ].

The prevalence of vitamin B 12 deficiency is difficult to ascertain because of diverse etiologies, different evaluation methods (i.e., total serum B 12 (sB 12 ), methylmalonic acid (MMA), holotranscobalamin (holoTC), and total homocysteine (Hcy), as well as different assays (i.e., radioassay or chemiluminescence) [ 12 ]. The worldwide prevalence of B 12 deficiency is estimated to be around 6%, and in Europe it is 1.6–10%. Prevalence is higher in adults over 60 years of age, ranging from 10% to 19% across various countries and is generally higher in women than in men [ 13 ]. Pawlak [ 14 ] examined the prevalence of vitamin B 12 deficiency among individuals adhering to vegetarian diets. The reviewed studies show relatively high deficiency prevalence among vegetarians. B 12 deficiency in infants is about 45%, among the children and adolescents ranging from 0% to 33.3%, and among pregnant women ranging from 17% to 39%, dependent on the trimester. Adults and elderly individuals had a deficiency range of 0–86.5%. Higher deficiency prevalence was reported in vegans than in other vegetarians, while deficiency prevalence of 0% was reported among vegans who consumed vitamin B 12 -fortified foods, highlighting that vitamin B 12 supplements to ensure adequate vitamin B 12 intake should be considered in these subjects.

Currently, research suggests that there are disease implications associated with vitamin B 12 deficiency, especially in vegetarian populations [ 15 , 16 , 17 ], in pregnancy [ 18 , 19 ], in the elderly [ 20 ], and in developing countries [ 19 ].

In the era of evidence-based medicine (EBM), the randomized clinical trial corresponds to the top step in the qualitative scale of the evidence available in the literature, while small series of cases or the description of individual cases occupy the last place. However, the latter represent an important part of clinical practice and have significantly influenced the evolution of medicine, contributing significantly to the advancement of scientific knowledge. Several reviews describe the results of different clinical trials on the vitamin B 12 deficiency treatment in different pathological conditions. Here, we focused our attention on some case reports related to the vitamin B 12 deficiency associated with anemia, neurologic disorders, or HHcy to assess if a common therapeutic approach with vitamin B 12 supplementation can reverse pathological and/or symptomatologic status. We performed a search in the MEDLINE database (PubMed database; National Library of Medicine, Bethesda, MD) to review the vitamin B 12 deficiency associated with anaemia, neurologic disorders, or HHcy. All English-language case reports published between 2000 and 2021 in the MEDLINE database were searched using the MeSH search: (cobalamin OR vitamin B 12 ) AND (nutrition* OR diet*); Limits Activated: Case Reports, English. The search was further limited to adults and only more representative cases with clear cause/effect evidence will be considered.

2. Vitamin B 12 and Anemia

The role of red blood cells (RBCs) is to transport oxygen through the body. When the number of RBCs is lower than usual body’s tissues and organs do not get enough oxygen, this blood disorder is known as anemia. Among different types of anemia, megaloblastic anemia is characterized by RBCs that are larger than normal and not able to exit the bone marrow to enter the bloodstream and deliver oxygen. However, the molecular basis of these cytomorphological aberrations remains unclear. This clinical condition indicates an altered synthesis of DNA, commonly due to a deficiency of vitamin B 12 or folic acid, both needed for the production and maturation of RBCs. In particular, the cytoplasm is excessive compared to the nucleus, causing their accumulation in the bone marrow (megaloblastosis) and macrocytosis in the peripheral blood [ 21 ]. In fact, the hallmark of megaloblastic anemia is macrocytic anemia (mean corpuscular volume, MCV > 100 fL), often associated with a reduction in the number of mature blood cells (cytopenia). A gold standard for diagnosing megaloblastic anemia is absent, so appropriate clinical and laboratory evaluation allows to establish the correct diagnosis.

Usually, adult patients come to medical attention because of symptoms related to anemia, such as fatigability, lethargy, and exertional breathlessness, pale conjunctiva, paleness and dry lips, and a disturbance of taste. We identify eight case reports all describing vitamin B 12 deficiency symptoms with etiological causes that appear to be different. A strict vegan 44-year-old woman with a history of anemia on admission presented lethargy, resulting in an inability to continue her job. Without regular medication assumption, except for the contraceptive pill. The biochemical investigations showed levels of haemoglobin (Hb) 110 g/L (reference range 115–160) and MCV 102 fL (range 80–100), and the cause of macrocytic anemia was highlighted by the slightly low levels of vitamin B 12 138 pmol/L (reference range 148–600). Test for antibodies to intrinsic factor was negative and oral contraceptive assumption could give a false lower vitamin B 12 level. Her lethargy and anemia were improved upon three months of treatment with intramuscular hydroxycobalamin 1000 μg three times a week for two weeks. Serum B 12 increases up to 400 pmol/L, Hb to 133 g/L at three months, as well as an improvement in her lethargy were observed. She was then advised to take oral cyanocobalamin supplements indefinitely as maintenance to prevent further deficiency [ 22 ].

Socha et al. [ 23 ] reported a case of a 68 years-old man with levels of Hb 6.2 g/dL, MCV 121.5 fL. Bone marrow biopsy presented megaloblastic changes as well as multilineage dysplasia suggestive of myelodysplastic syndrome. Further evaluations confirmed severe vitamin B 12 deficiency, including a normal serum folate level 18.1 ng/mL (>4.7), a serum vitamin B 12 level <150 pg/mL (reference range 232–1245); a positive test result for anti-parietal cell antibodies; a normal male karyotype by conventional cytogenetics, a negative hematologic neoplasm next-generation-sequencing panel (62 genes) for disease-associated mutations; in conjunction with normal cytogenetic and next-generation-sequencing panel results, without detectable vitamin B 12 levels The presence of fatigability, shortness of breath, weight loss, and numbness and tingling of both hands as well as complete blood cell count and neurologic symptoms were improved upon treatment of intramuscular cyanocobalamin (1000 μg) followed by high-dose oral cyanocobalamin (1000 μg/day).

Although glossitis rarely represents another symptom of cobalamin deficiency in addition to those related to anemia, the diagnosis of pernicious anemia with recurrent aphthous stomatitis was the clinical diagnosis of a 71-year-old woman case described by Garcia et al. [ 24 ]. Due to the vitamin B 12 malabsorption, the laboratory investigation showed a MCV of 104.1 fL and low serum vitamin B 12 (133 pg/mL). Clinical resolution was observed after two months after a treatment of 1.0 mL of hydroxocolabamin intramuscularly twice weekly over four weeks followed by 1.0 mL once weekly for four weeks. Pontes et al. [ 25 ] reported an oral manifestation of Vitamin B 12 deficiency in a 41-year-old strict vegetarian woman for 2.5 years that had not consumed milk, cheese, fish, meat, or eggs during that time. As suggested by the authors, a wide range of oral signs and symptoms may appear in anemic patients because of basic changes in the metabolism of oral epithelial cells. In fact, with regard to the clinical signs of weakness, fatigue, shortness of breath, and neurologic abnormalities, this woman had burning sensation, pale oral mucosa, glossitis with papillary atrophy, and multiple areas of painful erythema on the dorsal surface and lateral borders of the tongue and buccal mucosa were recorded. The hematologic test results showed low levels of Hb (7.2 g/dL), MCV (fL 144), and serum cobalamin (71.8 pmol/L). After 14 days of treatment, comprising a parenteral dose of cobalamin (1000 mg/week hydroxocobalamin administered intramuscularly over 30 days) and 1 mg of folic acid daily for 30 days, the lesions had completely disappeared, as had all other symptoms. A rare presentation of dietary Vitamin B 12 deficiency anemia was reported by Pahadiya et al. [ 26 ]. A 40-year-old male presented a generalized weakness, fatigability, and hyperpigmentation with ecchymosis. His hemogram showed Hb of 9.7 g/dL, MCV 87.8 fL, and normal levels of Vitamin B 12 equal to 272 pg/mL. Higher levels of lactate dehydrogenase (1250 IU/L) and serum bilirubin 2.43 mg/dL were observed. The authors assumed that these ecchymosed lesions might be due to chronic microhemorrhages in the superficial layer of skin because of thrombocytopenia. The ineffective erythropoiesis and the abnormal red cell membrane are the two pathophysiologic processes featuring in B 12 deficiency anemia. The resulting reduction in red cell lifespan and the associated hemolysis cause a rising in plasma bilirubin and lactic dehydrogenase (LDH). The cutaneous manifestations of Vitamin B 12 deficiency including skin hyperpigmentation was reversible after the Vitamin B 12 supplementation. Treatment with intramuscular hydroxocobalamin 1000 μg daily for five days, subsequently on alternate days for a week, and thereafter weekly for one month restored his hematological parameters to within normal limits and ecchymosis disappeared.

Surani and Sharma [ 27 ] presented a case of pancytopenia caused by an unusual habit of eating pasta. On admission, a 40-year-old female with gradual worsening weakness, intermittent blurry vision, and intermittent paresthesia over three weeks showed the following hematological values: Hb 3.7 g/dL, MCV 105.7 fL, vitamin B 12 level 16.3 ng/mL (range: 200–900 ng/mL). After transfusion of four units of packed red blood cells, the patient was treated with cyanocobalamin intramuscular injection 1000 mcg daily for one week, then weekly for one month, followed by a monthly injection of 1000 mcg. Four days after admission, the patient improved her Hb to 10.3 g/deciliter (post-transfusion), MCV to 100.2 fL, and after two months, on discharge, Vitamin B 12 to >2000 ng/mL.

A case of suspected metformin induced cobalamin deficiency (MICD) causing pseudo thrombotic thrombocytopenic purpura was identified as cause of cobalamin deficiency in a 36-year-old female with type 2 diabetes mellitus on metformin for eight years who presented with hemolytic anemia, thrombocytopenia, schistocytes, and mild acute renal failure was studied by Hussain et al. [ 28 ]. On admission, laboratory investigations revealed very low serum Vitamin B 12 levels 91 pg/mL, Hb 3.7 g/dl, and MCV 95.6 fL. As the initial therapy, the authors prescribed intramuscular (IM) cobalamin 1000 μg daily for one week followed by the same dose IM cobalamin weekly for one month. On discharge, Vitamin B 12 levels increased up to >2000 pg/mL, Hb 8.0 g/dL, MCV 92 fL. Therefore, the authors later prescribed IM cobalamin 1000 μg monthly life long, and at six-month follow-up both Hb 11.9 g/dL and MCV 77 fL improved their values.

Even if a delay could not impair the diagnostic assurance with neurologic symptoms, their treatment would be started promptly to avoid the risk of irreversibility including extensive sensory defects, gait disturbances, and mental changes. The presence of dizziness and generalized weakness for three days, presence of fever, scleral icterus, conjunctival pallor, and hyperpigmentation of the knuckles of both hands presented in a 48-year-old male case reported by Sasi and Yassin [ 29 ]. On admission, the patient’s values were: Hb 6.5 g/dL, MCV 102.6 fL. Hemolysis workup showed indirect hyperbilirubinemia, high lactate dehydrogenase (LDH), low haptoglobin, normal reticulocyte count, and positive direct antiglobulin (DAT). Serum iron studies and thyroid functions were normal, but vitamin B 12 level was remarkably low <37 pmol/L (reference range 133–675 pmol/L). The intramuscular vitamin B 12 injection of 1000 μg once weekly improved blood cell counts, which started an upward trend on day 4 after starting the treatment. On discharge, after 10 days, he was asymptomatic with improved levels of Hb 9.8 g/dL, MCV 95.7 fL, and Vitamin B 12 369 pmol/L and outpatient appointments for weekly B 12 injections.

Below, Table 1 summarizes the corresponding laboratory and clinical investigations of the reported cases in this section on anemia and vitamin B 12 deficiency.

Laboratory and clinical investigations of the reported cases in the section on vitamin B 12 deficiency and anemia, with main changes after treatment.

References	Laboratory and Clinical Investigation	Main Changes after Treatment
Socha et al. [ ]	Full blood profile, Folate levels, Vitamin B levels Parietal cell antibody, Conventional cytogenetics, Hematologic neoplasm next-generation-sequencing panel (62 genes) for disease-associated mutations.	Case 1: Abnormal complete blood cell count findings improved, as did neurologic symptoms. Case 2: rapid improvement of hematologic symptoms and slower but complete resolution of neurologic symptoms.
Garcia et al. [ ]	Hb, MCV, Folate levels, iron, ferritin, vitamins B , B , and B levels, gastroduodenoscopy and gastric biopsy, Antibodies against intrinsic factor and Helicobacter pylori detection	At 12 months the patient was free of the Recurrent aphthous stomatitis with normal levels of hemoglobin, MCV, and vitamin B .
Pontes et al. [ ]	Full blood count, Folate levels and vitamin B levels	After 14 days of treatment complete remission of all symptoms.
Pahadiya et al. [ ]	Full blood profile, vitamin B levels, LDH, bilirubin Bone marrow aspiration, antinuclear antibody and Coomb’s test, Coagulation profile, iron profile Renal function tests, urinalysis and electrolytes Gastroscopy, electrocardiograph, ultrasonography of abdomen, and chest X-ray	At the follow-up of 1 month, hematological parameters were within normal limits and ecchymosis disappeared.
Surani and Sharma [ ]	Full blood profile, Folate levels, vitamin B levels	Hemoglobin improved to 10.3 gm/dL after four days. Complete blood count showed a complete resolution of pancytopenia at two months follow up. Vitamin B and folate level normalized.
Hussain et al. [ ].	Full blood profile, Vitamin B , Folate, Haptoglobin, MMA, Intrinsic factor antibody	At six-month follow-up clinical and laboratory analysis improvement (e.g., hemoglobin improved to 11.9 gm/d).
Sasi and Yassin [ ].	Full blood profile, B level, Bilirubin, LDH Haptoglobin, direct antiglobulin (DAT) Serum iron, thyroid functions	Blood cell counts started showing an upward trend on day 4 after starting the treatment. On discharge, after 10 days of hospital stay, improvement of blood profile and vitamin B (from values <37 pmol/L to 369 pmol/L), remission of all symptoms.

3. Vitamin B 12 and Neurological Disorders

The neurologic manifestations of B 12 deficiency, including myelopathy, neuropathy, dementia [ 30 , 31 ], and rarely cerebellar ataxia and movement disorders, are difficult to diagnose. In fact, the neurological abnormalities caused by cobalamin deficiency could take place without any hematological or gastrointestinal context [ 32 ], and in the absence of anemia or an elevated mean cell volume [ 33 ]. The severity of neurological complications may be reversed only by an early treatment after onset, so a timely diagnosis is important. Despite the rapid correction of vitamin B 12 levels by prompt therapy and early clinical improvement, the recovery of polyneuropathy on nerve conduction could be slow. Deficiency of vitamin B 12 , mostly in vegetarians was found to be associated with depression and adverse neurological function. Berkins [ 15 ] points out that the dietary intake of vitamin B 12 and vitamin B 6 might have an effect on brain structure. Ralapanawa et al. [ 34 ] reported a strict vegetarian 66-year-old female case with demyelinating polyneuropathy without features of anemia (Hb concentration of 12.1 g/dL, RBCs count of 4.39/mm 3 , MCV of 83.3 fL), but very low serum vitamin B 12 levels (84.90 pg/mL reference range 208–963 pg/mL). To reverse neurological manifestations, after three months of therapy with intramuscular hydroxycobalamine 1000 μg for seven days, weekly for six weeks and thereafter three monthly, the patient showed clinical improvement, with repeated B 12 levels being elevated up to 308.6 pg/mL. At one- and three-year follow up for nerve conduction study previously absent, early clinical improvement was demonstrated, with a slow recovery of polyneuropathy on nerve conduction studies. Even though vitamin B 12 deficiency neuropathy is a rare debilitating disease that affects mostly the elderly, young adults with neuropathic symptoms warrant a high index of suspicion. The cause of neurological symptoms resulting from vitamin B 12 deficiency could be due to the role of methylcobalamin in myelin synthesis. The lack of cobalamin could induce the destruction of myelin sheaths or incorporation of abnormal fatty acids in myelin sheaths, thus leading to impaired neural function and/or transmission. The diagnosis of Vitamin B 12 deficiency is challenging in resource limited-settings due to limited access to diagnostic tools and unfamiliarity with the disease, owing to its rarity especially in young people. This is the case reported by Ekabe et al. [ 35 ]. A 28-year-old sub-Saharan female, presenting peripheral neuropathic symptoms, was treated with oral vitamin B 12 tablets at doses of 2 mg per day for three months. A diagnosis of vitamin B 12 deficiency related peripheral neuropathy was made based on her symptoms, ovalo-macrocytosis and hyper-segmented neutrophils on peripheral blood smear. After one month of therapy, an improvement in neurological symptoms was recorded. The authors highlighted the pivotal role of basic investigations like peripheral blood smear for the timely detection and management of vitamin B 12 associated neurological disease in resource-limited settings. A case of sub-acute combined degeneration (SCD), the most common neurological disorder, in a 33-year-old woman without anemia or macrocytosis leading was diagnosed by Maamar et al. [ 36 ] as suspected vitamin B 12 deficiency, subsequently confirmed by a low serum cobalamin. First investigations revealed Hb 12.1 g/100 mL, MCV 91 fL, other biochemical parameters were within normal limits, while magnetic resonance (MR) imaging of the spine revealed intramedullary hyperintensity in the posterior column of the cervico-dorsal spinal cord, highly suggestive of subacute combined degeneration (SCD). In fact, the patient’s vitamin B 12 serum level was low (30 pg/mL; reference range 200–700 pg/mL) while serum folate was within the normal range (26 ng/mL; reference range 18–30 ng/mL). Intramuscular administration of B 12 resulted in correction of the neurological signs (paresthesis and sphincter disorders). At a seven-year follow-up, while still receiving intramuscular vitamin B 12 monthly, the patient was found to be functionally independent with no neurological deficits. Early spinal MR imaging could support the early diagnosis of SCD of the spinal cord due to Vitamin B 12 deficiency as reported in the case of a 57-year-old man by Senol et al. [ 37 ]. Following clinical and laboratory examinations, the patient was evaluated as cervical myelopathy due to Vitamin B 12 deficiency (60 pg/mL (reference range 189–883 pg/mL). The symptoms totally disappeared two months after intramuscular supplementation of vitamin B 12 (1000 µg IM daily for a week and then weekly for six weeks) and the MR imaging abnormalities significantly improved. The same diagnosis of SCD was considered and confirmed by laboratory findings in a 56-year-old man by Srikanth et al. [ 38 ]. The patient presented an acute onset of paresthesia involving both hands and feet of 15 days duration, difficulty in walking, and inability to feel the ground for the same period. Neurological examination revealed impairment of sensation of fine touch, pinprick, joint position, and vibration in both hands and feet bilaterally. All the deep tendon reflexes were exaggerated, more so in the lower limbs, with no evidence of motor weakness. Gastric endoscopy and biopsy revealed changes of atrophic gastritis and folic acid and vitamin B 12 levels in the serum were 7 micrograms and 75 picograms, respectively. Cervical MR image findings were consistent with SCD. MR imaging lesion was completely resolved treating the patient with parenteral administration of vitamin B 12 and oral folic acid. In summary, SCD is clinically characterized by predominant involvement of the dorsal columns and the lateral columns of the spinal cord, resulting in sensory deficits, paresthesia, weakness, ataxia, and gait disturbance. In some patients, MR imaging shows abnormalities of the spinal cord, indicating demyelination of the posterior column. Early diagnosis and treatment play an important role in the reversibility of neurological deficits. Delayed treatment results in irreversible disabling neurological impairment, such as spasticity and paraplegia.

The seizures rarely occur in patients with vitamin B 12 deficiency and the molecular mechanisms involving cobalamin in epileptogenesis are unknown. However, Kumar [ 39 ] reported this unusual symptom of vitamin B 12 deficiency in a 26-year-old man. A diagnosis of vitamin B 12 deficiency with multiple neuropsychiatric manifestations, namely dementia, psychosis, seizures, and myeloneuropathy, was considered. Investigations confirmed the suspicion Hb 13.2 g/dL, and MCV 114 fL. Serum B 12 assay was 26 pg/mL and folate levels were 28 ng/mL. His symptoms responded to parenteral vitamin B 12 therapy started on intramuscular vitamin B 12 injections. At 24 months follow-up, the seizures disappeared and functionality was independent. Regarding this disturbance, the author highlighted the similarities of cobalamin deficiency with multiple sclerosis and supposed that the probable impairment of cerebral neurons was due to destroyed myelin sheaths, which are more susceptible to the excitatory effects of glutamate. Mavromati and Sentissi [ 40 ] report a clinical case of delirium due to vitamin B 12 deficiency in a vegetarian female 62-year-old. Delirium could have multiple causes, so the initial diagnosis presented various difficulties. Details on neurological symptoms are reported. The laboratory and clinical examinations excluded infectious, vascular, neoplastic, metabolic, and endocrine causes. Her serum vitamin B 12 level was low (91 pmol/L) and folic acid was normal (22.2 mg/L). The patient was treated with vitamin B 12 supplementation. The vitamin B 12 level was normalized one week later (330 pmol/L). A psychiatric examination two weeks after the first evaluation revealed an important diminution of cognitive deficiency and a partial remission of the depressive symptoms (MADRS score 22, MMSE 28/30 and DRS-R-98 4; the clock test was normalized). Four weeks after the episode, there was a total remission of the depressive symptoms (MADRS score: 4) and stable mental status. The cause of the vitamin B 12 deficiency was attributed to the patient’s strict vegetarianism and this finding underlines the importance of conducting a complete laboratory test panel for delirium, including the blood levels of vitamin B 12 . Table 2 summarizes the corresponding laboratory and clinical investigations of the reported cases in this section on neurological disorders and vitamin B 12 deficiency.

Laboratory and clinical investigations of the reported cases in the section on vitamin B 12 and neurological disorders, with main changes after treatment.

References	Laboratory and Clinical Investigations	Main Changes after Treatment
Ralapanawa et al. [ ]	Full blood profile, serum creatinine, plasma glucose, thyroid stimulating hormone levels, vitamin B levels, nerve conduction studies	After 3 months, clinical improvement, with repeated B levels being elevated up to 308.6 pg/mL. Follow up at 1 and 3 years showed improvement of nerve conduction.
Ekabe et al. [ ]	Full blood profile, HIV test, Treponema pallidum hematoglutinin assay (TPHA), erythrocyte sedimentation rate and peripheral blood smear analysis, stool exam and urinalysis	At 1 months follow up good clinical recovery, improvement in neurological symptoms and a follow up MCV of 97 fl, red blood cell count of 4.1 million/µL, and reticulocyte count of 0.95%.
Maamar et al. [ ]	Full blood profile, Somatosensorial evoked potential (SEP), MRI, vitamin B levels, Folate levels, bone marrow biopsy	Correction of the neurological signs (paresthesis and sphincter disorders).
Senol et al. [ ]	Blood glucose, AST, ALT, blood urea nitrogen, creatinine, Hb, MCV, white blood cell count, sedimentation rate, Vitamin B levels, HbA1C level, Somatosensorial evoked potential (SEP), Electromyography, Gastric endoscopy and biopsy, Brain MR, Cervical spine MR imaging	At two months follow up complete resolution of symptoms, MR imaging abnormalities significantly improved; impairment of the Somatosensorial evoked potential continued.
Srikanth et al. [ ]	Full blood profile, bone marrow biopsy, Visual evoked potential and brain stem evoked potential studies, Gastric endoscopy and biopsy, workups for infections, para infectious myelitis, multiple sclerosis and connective tissue disorders, Folate levels, vitamin B levels, cervical MR examination	At 10 months follow-up, MRI revealed total resolution of cord abnormality.
Kumar [ ]	Full blood profile, bone marrow biopsy, vitamin B levels, Folate levels, Anti-intrinsic factor antibody Gastric endoscopy and biopsy, Brain CT scan, EEG	At 24 months follow-up resolution of seizure and functional independence.
Mavromati & Sentissi [ ]	Full blood profile, Electrolytes, vitamin B levels, Folate levels, Lyme’s test brain MRI, Neuropsychiatric tests	At 1 week normalization of vitamin B level (330 pmol/L); at 2 weeks important diminution of the cognitive deficiency and a partial remission of the depressive symptoms (MADRS score 22, MMSE 28/30 and DRS-R-98 4; the clock test was normalised). Four weeks after the episode total remission of the depressive symptoms (MADRS score: 4) and stable mental status.

4. Vitamin B 12 Deficiency and Hyperhomocysteinemia

Vitamin B 12 deficiency can also lead to HHcy and may be associated with osteoporosis, depression, cognitive decline, and some forms of dementia in the elderly. More recently, vitamin B 12 deficiency has been reported as common among patients with HHcy and thrombosis [ 41 ], although the presence of a direct effect of vitamin deficiency rather than mediated by HHcy or other factors is to clarify. In fact, lifestyle-related factors, such as smoking status, BMI, and physical activity, could interfere between HHcy and the thromboembolism relationship [ 42 ]. Moreover, the effect of lowering Hcy levels in patients with intermediate (total Hcy 30–100 µmol/L) or severe HHcy (total Hcy > 100 µmol/L) remains unknown [ 43 ]. The cases described below report examples of vitamin B 12 deficiency and HHcy related to different causes.

A case of cerebral venous thrombosis secondary to HHcy caused by vitamin B 12 deficiency in a 32-year-old Indo-Aryan man who followed a strict vegetarian diet is reported by Kapur [ 44 ]. The preliminary blood examination revealed macrocytic anemia with hemoglobin of 11.4 g/dL and mean corpuscular volume (MCV) of 110 fL. Peripheral blood film showed macrocytes and macro-ovalocytes with hypersegmented neutrophils; low serum cobalamin levels 68 pg/mL (200–600) with normal folate levels and total serum Hcy levels of 36 μmol/L (5.0–13.9) were observed. In addition to other treatments, the patient received parenteral cyanocobalamin 1000 μg once daily for seven days. Gradually, he regained sensorium, his power improved, and he was discharged on orally administered sodium valproate, warfarin, and methylcobalamin. Repeated investigations undertaken at six months after stopping anticoagulants showed normal serum cobalamin 364 pg/mL (200–600) and fasting total Hcy levels 8.4 μmol/L (5.0–13.9). The authors conclude that HHcy is an independent risk factor for cerebral venous thrombosis in patients with cobalamin deficiency, especially those who follow a strict vegetarian diet, and that HHcy can be easily reversed with vitamin supplementation, cobalamin, and folic acid.

The cases of four Moroccan patients with acute vein thrombosis of different sites are reported by Ammouri [ 45 ]. Three men and one woman of different ages (a 34-year-old man, a 60-year-old man, a 58-year-old man, and a 47-year-old woman) were selected. All patients presented low hemoglobin level (from 8.6 g/dL to 9.5 g/dL), low MCV, low cobalamin plasma level (about 60 pg/mL; normal >120 pg/mL), and high levels of plasma Hcy (50 to 200 μmol/L; normal range <15 µmol/L) with normal folate plasma levels. For all, it pernicious anemia and venous thrombosis secondary to HHcy were evident. First, the authors speculated that normal folate levels may have contributed to the delay in the diagnosis of pernicious anemia, leading to severe HHcy and the consequent development of vascular injury. HHcy could lead to venous thrombosis by several pathways.

For example, the toxic effect of Hcy on the vascular endothelium and on the dotting cascade, as well procoagulant properties of Hcy, including the decrease of antithrombin III binding to endothelial heparan sulfate, an increase of affinity between lipoprotein(a) and fibrin, induction of tissue factor activity in endothelial cells, and inhibition of inactivation of factor V by activated protein. In all patients, clinical and biological abnormalities disappeared upon vitamin B 12 supplementation. The authors concluded that vitamin B 12 supplements can rapidly correct HHcy avoiding and preventing thrombotic events.

Tanaka et al. [ 43 ] reported a case of a 39-year-old man with inferior vena cava (IVC) thrombus. The analysis of risk factors of venous thromboembolism shown HHcy (total Hcy 83.1 µmol/L; normal range 5–15 µmol/L) due to an unbalanced diet with a deficiency of folic acid and vitamin B 12 . The patient was treated with both folic acid and vitamin B 6 /B 12 supplementation in association with warfarin, inducing a significant resolution of thrombus after four weeks and no evidence of recurrent IVC thrombus at six months. The authors concluded that B vitamins and folic acid therapy might be effective in patients with severe HHcy.

An interesting case of a 43-year-old man presenting with a two-week history of painless ascending sensory disturbances, suspected to be suffering from acute inflammatory polyneuropathy, is reported by Ulrich et al. [ 46 ]. On clinical examination, deep tendon reflexes were preserved, muscle strength was 5/5 everywhere, and gait was ataxic. Initial laboratory assessment showed nearly normal holotranscobalamin (43 pmol/L; pmol/L normal >50 pmol/L), suggesting no vitamin B 12 deficiency. Surprisingly, further investigation showed high Hcy (48.5 µmol/L; normal <10 µmol/L), suggesting an impairment of vitamin B12-dependent metabolism leading to the diagnosis of SCD. The patient remembered having taken tablets containing cobalamin for three days before hospitalization. The authors concluded that holotranscobalamin can be rapidly normalized during supplementation and the analysis of methylmalonic acid and Hcy might help to detect B 12 deficiency in patients who recently started supplementation.

A case of a 24-year-old male with unprovoked bilateral submassive pulmonary emboli with a high level of Hcy without anemia is reported by Kovalenko et al. [ 47 ] Complete blood count showed a MCV of 104fL without anemia, and Hcy level was 41.3 μmol/L (normal 4.0–13.7 μmol/L). Workup for macrocytosis was notable for low vitamin B 12 (72 pg/mL) and folate (2.1 ng/mL) levels. After vitamin B 12 supplementation, serum Hcy levels did not decrease to normal values. The authors speculated that a poor absorption of B vitamins due to a small bowel resection two years before and excessive alcohol consumption could have impaired the results. Another case associated with alcoholism was previously described by Goette et al. [ 48 ]. The authors described a rare case of a 32-year-old man with severe HHcy underlying a probable cause of thromboembolic complications. The patient did not have a history of cardiovascular disease, but he had at least a six-month history of alcohol abuse at least six months before hospital admission. Laboratory assays showed abnormalities in liver functions, vitamin B 12 (226 pg/mL; normal range 150–675 pg/mL) and folate (1.6 μg/L; normal range 1.4–11.8 μg/L) were low but within normal range, while serum Hcy was at least 12 times higher than normal (173 μmol/L). The patient was treated with 5 mg oral folic acid and 20 mg oral vitamin B 6 daily. Vitamin supplementation was then adapted and integrated with other drugs, such as weight-adapted low molecular weight heparin and L-arginine. For some patients, the authors suggested the screening for HHcy in association with endothelial dysfunction markers as appropriate.

Ruscin et al. [ 49 ] illustrated the case of a 78-year-old nonvegetarian white woman with gastroesophageal reflux treated for long-term with histamine(2) (H(2))-receptor antagonists and a proton-pump inhibitor (PPI). During treatment, vitamin B 12 dropped from normal values (413 pg/mL) to 256 pg/mL; methylmalonic acid (MMA) and Hcy were elevated at 757 nmol/L and 27.3 micromol/L, respectively, serum folate was within the normal range (4.9 ng/mL), and serum creatinine was slightly elevated at 1.4 mg/dL. In addition, no renal dysfunction was present. After oral treatment with vitamin B 12 (1000 microg/d), MMA and Hcy concentrations decreased dramatically. The authors speculated vitamin B 12 deficiency because of cobalamin malabsorption from food intake due to drug interference, suggesting vitamin B 12 status monitoring in patients taking these medications for an extended time, particularly >4 years.

As known, elevated plasma Hcy is involved in cognitive decline, including Alzheimer’s disease, mild cognitive impairment, and dementia, especially in elderly subjects. McCaddon [ 50 ] reported seven cases of older patients (four women aged 78 years, 84 years, 77 years and 87 years, 84 years old, and two men 71 and 75 years old). They presented with cognitive impairment and/or depression, dementia, etc. Each had different vitamin B 12 status with HHcy. Treatment with N-acetylcysteine, together with B vitamin supplements, improves cognitive status in hyperhomocysteinemic patients. The authors concluded that it could be important to evaluate inadequate vitamin B 12 and folate metabolism in subjects with cognitive diseases, underlining the importance of clinical trials to evaluate the beneficial effects of a synergistic approach to cognitively impaired hyperhomocysteinaemic patients.

Table 3 shows the corresponding laboratory and clinical investigations of the reported cases in this section on HHcy and vitamin B 12 deficiency.

Laboratory and clinical investigations of the reported cases in the section on vitamin B 12 deficiency and HHcy, with main changes after treatment.

References	Laboratory and Clinical Investigation	Main Changes after Treatment
Tanaka et al. [ ]	Full blood profile, prothrombin time, protein C, protein S levels, total homocysteine, folic acid, vitamin B (Antinuclear antibody (fluorescent antibody technique), immunoglobulin G anticardiolipin antibodies (IgG ACA), phospholipid (GPL), Lupus anticoagulant (diluted Russell’s viper venom time rate). Tumor marker, carcinoembryonic antigen (CEA carbohydrate antigen 19-9, and a-fetoprotein (AFP), CT	Serum homocysteine level decreased (total homocysteine: 12.4 mmol/L), and swelling of his leg improved with significant resolution of thrombus by CT.
Kapur [ ]	Full blood profile, Peripheral blood film, serum cobalamin levels, prothrombin time, protein S, antithrombin III, fibrinogen levels, factor V Leiden assay and prothrombin gene mutation, fasting total serum homocysteine levels, neurological examination, Cerebrospinal fluid examination, CT, MRI	Significant improvement of neurological symptoms. At 6 months normal serum cobalamin 364 pg/mL (200–600) and fasting total homocysteine levels 8.4 μmol/L (5.0–13.9). The rest of the thrombophilia profile was within normal limits.
Ammouri [ ]	Full blood profile, prothrombin time, partial thromboplastin time, fibrinogen level, protein C, protein S levels, antithrombin III function, genetic testing for factor V Leiden and factor II mutation, plasma homocysteine level, cobalamin plasma level, folate plasma, antibodies to intrinsic factor, bone marrow biopsy, chest radiographs, ECG, TC, Ultrasonography	Case 1: After a 1-year follow up total remission of psychiatric disorders and thrombotic events. Hemoglobin and homocysteine plasma levels were within normal range. Case 2: At 6-month follow-up period, hemoglobin and homocysteine plasma levels were within normal range. No thrombotic events for 3 years after the follow-up. Case 3: At 6-month follow-up period, hemoglobin and homocysteine plasma levels were within normal range. No thrombotic events during 4 years of follow-up. Case 4: At 3-year follow-up no psychiatric disorders and thrombotic events. Homocysteine plasma level was within normal range.
Ulrich [ ].	Full blood profile, holotranscobalamin plasma levels, total homocysteine, MMA, Folate, zinc and copper, Electroneurography, CT, MRI.	Cyanocobalamin, MMA and homocysteine levels continuously decreased, and were normal again after 1 month; improvement of sensory disturbances and gait ataxia; At 2 months follow-up MRI showed significant regression of the dorsal column hyperintensities.
Kovalenko et al. [ ]	Full blood profile, troponin, blood urea nitrogen, creatinine, serum electrolytes, B-type natriuretic peptide level, Factor V Leiden, prothrombin mutation, cardiolipin antibody, lupus anticoagulant, anti-B glycoprotein, protein C, protein S levels, Homocysteine level, vitamin B , folate levels, chest radiographs, ECG, echocardiogram, Pulmonary angiography	Serum Hcy levels did not decrease to normal values.
Goette et al. [ ].	Full blood profile, lipid profile, Liver function tests (γ-glutamyl transpeptidase, Alanine transaminase and aspartate aminotransferase, bilirubin), activated partial thromboplastin time, international normalized ratio, thrombin time, activated recalcification, fibrinogen, clotting factors II, XII and VIII levels, protein C, protein S, anti-phospholipid antibodies, vitamin B , folate, Hcy, analyses of cofactors and enzymes involved in homocysteine metabolism, serum levels of 8-isoprostaglandin F2α dimethy larginine (ADMA), Plasma concentrations of arginine and symmetric dimethyl arginine (SDMA), serum level of creatinine, urine analysis 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, TC, computed tomography angiography, ultrasound, echocardiogram	At 2 weeks follow-up level of homocysteine had decreased to 57.6 μmol/L. Three weeks later homocysteine level was 18.1 μmol/L, and after 3 months it was 5.5 μmol/L. After completing his the following metabolites had decreased: ADMA, to 0.363 μmol/L; SDMA, to 0.32 μmol/L; arginine, to 62.8 μmol/L; light reflex rheography and oscillography shown normal perfusion; improvement of pain, paraesthesia in right leg and increasing of pain-free walking distance.
Ruscin et al. [ ]	Full blood profile, vitamin B , methylmalonic acid (MMA), total serum homocysteine, serum folate, serum creatinine, renal function test.	At first follow-up vitamin B has increased, MMA and HCYS was reduced at 351 nmol/L and 23.7 µmol/L respectively. At second follow-up vitamin B was normal; MMA and HCYS were further reduced but remain slight elevated.
McCaddon [ ]	Full blood profile, vitamin B , serum and red cell folate, plasma folate, parietal cell antibodies, total serum homocysteine, cognitive tests.	Case 1: improvement in memory and cognitive tests. Case 2: Within one month tHcy fell to 7.5 μmol/L; no significant cognitive deficits. Case 3: No improvement; the patient died from a bronchopneumonia several weeks later. Case 4: At six-months follow up tHcy fell to 6.6 μmol/L; marked improvement in general behaviour observed also three years later. Case 5: improvement in cognitive tests. Case 6: tHcy fell to 9.6 μmol/L; improvement in cognitive tests. Case 7: At one month follow-up tHcy fell to 8.3 μmol/L; improvement in cognitive tests. At one year follow up MRI scan showed no significant progression in the extent or size of the focal areas of abnormality in the deep white matter, and no change in ventricular configuration.

5. Conclusions

Low B 12 status is a risk factor of megaloblastic anemia, various neuropsychiatric symptoms, and other clinical manifestations. The nutritional guideline recommends the nutrient amounts to be consumed as part of a normal diet to ensure health and safety at each stage of life. In the presence of adequate consumption, any factor influencing their absorption or utilization should be considered. Vitamin B 12 can be stored in relatively large quantities and its degradation is slow. So, an inadequate intake corresponds to longstanding vegetarians or vegans without any supplement replacement. When the etiology is dietary deficiency, the mainstay of treatment is vitamin B 12 supplementation. Recently [ 51 ], the British Society for Haematology (BSH) issued an update regarding the guidance on Vitamin B 12 replacement. Where Vitamin B 12 deficiency is not thought to be diet-related, i.e., due to pernicious anemia, prior gastrectomy, bariatric surgery, achlorhydria, pancreatic insufficiency, short bowel syndrome, bacterial overgrowth, or inflammatory bowel disease, the administration of hydroxocobalamin 1 mg IM every 2–3 months for life is recommended, in addition to special advice during the COVID-19 pandemic for patients established on IM hydroxocobalamin. Where B 12 deficiency is thought to be diet-related, people should either take oral cyanocobalamin tablets 50–150 micrograms daily between meals or have a twice-yearly hydroxocobalamin 1 mg injection. In vegans, treatment may need to be life-long, whereas in other people with dietary deficiency, replacement treatment can be stopped once the vitamin B 12 levels have been corrected and the diet has improved. As shown by the case reports above, B 12 deficiency reverse is simply addressed by prompt therapy, even though it is not the same for several disorders. In the presence of adequate intake, vitamin B 12 deficiency shares several common symptoms that affect several tissues and organs with health aliments, so its diagnosis could be unobvious for the broad array of its effects and investigation methods used. Screening for vitamin B12 deficiency is generally not recommended in average risk subjects. Case reports emphasize the importance of conducting a wide range of laboratory tests, including an evaluation of vitamin blood levels. Even though case reports may be considered as approaches to personalized therapy based on clinical practice, they could account for important information regarding uncommon events as well as stimulate new hypotheses, and thus may support the emergence of new research. Moreover, under specific conditions, other diagnostic tests should not be neglected. For example, the spinal MR imaging could represent a differential diagnosis of symmetrical posterior spinal cord lesions, some of which are not well known. Because the degree of resolution of the clinical symptoms in B 12 deficiency depends on early detection, MR findings should not be overlooked. Particularly with respect to neurological damage, several questions remain unanswered concerning B 12 deficiency, and newer genetic analysis and the effects of the microbiome may represent interesting areas of investigation for evaluating the variability of B 12 deficiency.

Below, Figure 2 outlines the main conclusion of this brief review.

An external file that holds a picture, illustration, etc.
Object name is ijms-22-09694-g002.jpg

Main conclusions. * According with reference range provided by the local laboratory.

Abbreviations

ADMA	8-isoprostaglandin F2α dimethy larginine
CT	computed tomography
DRS-R-98	Delirium Rating Scale—Revised-98
Hb	hemoglobin
Hcy	homocysteine
HHcy	hyperhomocysteinemia
MICD	metformin induced cobalamin deficiency
MADRS	Montgomery Asberg Depression rating scale
MCV	mean corpuscular volume
MMA	methylmalonic acid
MR	magnetic resonance
MMSE	Mini-Mental State Examination
MTHFR	5,10-methylenetetrahydrofolate reductase gene
PPI	proton-pump inhibitor
RDAs	recommended dietary allowances
RBCs	red blood cells
SCD	sub-acute combined degeneration
SDMA	arginine and symmetric dimethyl arginine
TPHA	Treponema pallidum hematoglutinin assay

Author Contributions

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Published: 16 November 2023
Reprogramming

Vitamin B 12 emerges as key player during cellular reprogramming

Alba Vílchez-Acosta ORCID: orcid.org/0000-0001-8268-591X 1 ,
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By analysing the effect of disrupting microbiota during in vivo reprogramming, Kovatcheva et al. demonstrated that vitamin B 12 -dependent metabolism is a limiting factor for cellular reprogramming and plasticity, and propose its therapeutic supplementation for the improvement of tissue repair.

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Acknowledgements

We thank Sara Picó, University of Lausanne, for her comments. The authors’ research is supported by the Milky Way Research Foundation (MWRF), the Eccellenza grants from the Swiss National Science Foundation (SNSF), the University of Lausanne, and the Canton Vaud. Gabriela Desdín-Micó was supported by the EMBO postdoctoral fellowship (EMBO ALTF 444-2021).

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Efficacy of different routes of vitamin B12 supplementation for the treatment of patients with vitamin B12 deficiency: A systematic review and network meta-analysis

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Omar Ahmed Abdelwahab ORCID: orcid.org/0000-0001-8266-0245 1 , 2 ,
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This systematic review and network meta-analysis aimed to evaluate the three different administration routes of vitamin B12: oral, intramuscular (IM), and sublingual (SL) routes.

We searched four electronic databases (PubMed, Scopus, Web of Science, and Cochrane CENTRAL Register of Controlled Trials). We included only comparative studies. We performed a frequentist network meta-analysis to measure network estimates for the relative outcomes. Moreover, we conducted a pairwise meta-analysis using a random effect model to obtain direct estimates for outcomes. All outcomes were continuous, and the relative treatment effects were pooled as mean difference (MD) with 95% confidence intervals.

Thirteen studies were included in the meta-analysis, with a total of 4275 patients. Regarding increasing vitamin B12 levels, the IM route ranked first, followed by the SL route (MD = 94.09 and 43.31 pg/mL, respectively) compared to the oral route. However, these differences did not reach statistical significance owing to the limited number of studies. Regarding the hemoglobin level, the pooled effect sizes showed no difference between all routes of administration that could reach statistical significance. However, the top two ranked administration routes were the oral route (78.3) and the IM route (49.6).

All IM, oral, and SL routes of administration of vitamin B12 can effectively increase the level of vitamin B12 without significant differences between them, as thought previously. However, the IM route was the top-ranked statistically but without clinical significance. We found no significant difference among studied administrated routes in all other CBC parameters and homocysteine levels.

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The effect of vitamin B12 and folic acid supplementation on routine haematological parameters in older people: an individual participant data meta-analysis

Efficacy and safety of ferric carboxymaltose and other formulations in iron-deficient patients: a systematic review and network meta-analysis of randomised controlled trials.

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Introduction

Vitamin B12 is a water-soluble vitamin that may be derived from foods, including fish, meat, dairy products, and cereals that have been fortified. It can also be taken in supplement form. After being extracted by gastric acid, it travels to the terminal ileum, where it is co-absorbed along with the intrinsic factor, an enzyme from the stomach’s parietal cells (Fig. 1 ) [ 1 , 2 ]. Vitamin B12 is essential for neurologic function, red blood cell creation, and DNA synthesis and is a coenzyme for three primary biochemical conversions: homocysteine to methionine, 5-methyltetrahydrofolate to tetrahydrofolate, and methylmalonic acid to succinyl coenzyme A [ 1 , 2 ].

Vitamin B12 absorption, transport and metabolism

Reduced serum vitamin B12 levels (< 200 ng per mL [148 pmol per L]) are considered vitamin B12 deficiency [ 1 , 2 ] and are associated with reduced hematopoietic and epithelial cell proliferation, elevated levels of methylmalonic acids, and propionic that impact the myelin sheaths of nerve fibers, and elevated serum homocysteine, a contributing factor for cardiovascular disorders [ 3 ]. Blood manifestations related to the deficiency in vitamin B12 are anemia (megaloblastic macrocytic), leukopenia, and thrombocytopenia; moreover, a paradoxical thrombocytosis may occur [ 4 , 5 ]. In neuropsychiatry, it may cause areflexia, peripheral neuropathy, olfactory impairment, gait irregularities, proprioception, and vibratory sensation loss, cognitive problems (including dementia-like manifestations and psychosis), and irritability. In the gastrointestinal, it may cause glossitis [ 5 , 6 , 7 , 8 ]. So, the treatment of vitamin B12 deficiency is devastating.

There are different routes for the administration of any vitamin. Oral and intramuscular (IM) vitamin B12 are the most common routes for treating vitamin B12 deficiency, and several studies have evaluated their efficacy [ 9 , 10 ]. However, in the case of vitamin B12 malabsorption, irrespective of the cause of malabsorption, the intramuscular route is preferred [ 11 , 12 ]. According to the British Society for Hematology recommendations, for individuals with severe insufficiency and malabsorption syndromes, IM vitamin B12 delivery is preferable; however, oral replacement therapy may be recommended for patients with asymptomatic, moderate illness who have no concerns about absorption or compliance [ 13 ].

The sublingual (SL) route of vitamin B12 administration has been evaluated as an alternative route to oral and IM routes, especially in the case of vitamin B12 malabsorption [ 14 , 15 , 16 ], but there is no sufficient data to consider this route in the guidelines. This systematic review and network meta-analysis aimed to assess the efficacy of those three different routes of administration of vitamin B12.

For this research, we used the same format that the PRISMA statement recommends for systematic reviews and meta-analyses [ 17 ]. Every stage was carried out in a manner entirely consistent with the Cochrane Handbook of Systematic Reviews and Meta-analyses of Interventions [ 18 ].

Eligibility criteria

Studies were included in our review if they satisfied the following criteria:

Population: studies on patients with vitamin B12 deficiency

Intervention and comparator: studies where the experimental and control groups received vitamin B12 through any of these routes of administration: SL, IM, and oral

Outcome: studies reporting at least any of the following serum levels: vitamin B12, folate, hemoglobin, hematocrit, mean corpuscular volume, plasma homocysteine, urine methylmalonic acid, leukocyte, and platelets

Study design: comparative studies whose design was controlled trials with patients allocated to receive SL, IM, or oral vitamin B12 in a random or non-random allocation manner. We considered both blinded and open-label studies. We also included controlled prospective and retrospective observational studies with extreme caution; these studies were separated from randomized controlled trials in subgroups and were only considered in calculating the pooled effect size if their results were consistent with randomized controlled trials. In case of discrepancy between randomized controlled trials and observational studies, the results highlighted this, and the outcomes of randomized controlled trials were prioritized

Studies for which complete full texts were not accessible, studies not published in English, studies whose data were unsuitable for extraction and analysis, and studies that were described as abstracts only or thesis were all excluded.

Information sources and search strategy

We performed a comprehensive search of four electronic databases (PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials) from inception until May 7, 2022, using the following query: (B 12, Vitamin OR Vitamin B12 OR B12, Vitamin OR Cyanocobalamin OR Cobalamins OR Cobalamin OR Eritron OR Vitamin-B12 OR Hydroxocobalamin OR Deltavit B12) AND (Sublingual OR tongue OR Oral OR Intravenous OR IV OR Inhalation OR Buccal OR Cutaneous OR Mucosal OR Parenteral OR Subcutaneous OR SC OR Intramuscular OR IM OR Intranasal). The search was carried out by O.A.A.

Furthermore, the references of the included studies were manually searched for any potentially eligible studies. The detailed search strategy and results for each database are presented in Supplementary 1.

Selection process

Five authors (S.D., A.K., R.A.D., T.E., and T.F.) separately screened the titles and abstracts of all identified articles to determine their relevance to this meta-analysis. The second step involved screening the full-text articles of the included abstracts to determine the final eligibility for meta-analysis. Duplicates were excluded using Endnote (Clarivate Analytics, PA, USA). The discussion was used to settle any disagreements.

Data collection process and data items

Five reviewers (S.D., A.K., R.A.D., T.E., and T.F.) collected data onto a standardized data extraction sheet. Extracted information focused on four primary areas: (1) summary of the included studies (including study ID, title, study design, country, inclusion criteria, exclusion criteria, interventions, dose, sample size, treatment duration, and the main findings); (2) study population characteristics (including age, sex body mass index, serum level of vitamin B12, hematocrit, hemoglobin, and mean corpuscular volume (MCV) levels); (3) risk of bias domains according to the study design; and (4) outcome measures (the primary outcomes were the serum levels of vitamin B12 and hemoglobin and the secondary outcomes includes the levels of MCV, homocysteine, platelets count, and white blood cells count). The discussion was used to settle any disagreements.

Assessing the risk of bias in the individual studies

We independently evaluated the quality of each included study by two authors (S.D. and T.E.). The Cochrane assessment tool was used for randomized clinical trials (ROB2) [ 19 ]. Newcastle Ottawa scale (NOS) was used to assess the risk of bias for observational studies [ 20 ]. For non-randomized controlled trials, we used the Cochrane ROBINS-I tool [ 21 ]. A third author (O.A.A.) solved any disagreements.

Statistical analysis

We measured network estimates for the related outcomes using a frequentist network meta-analysis of aggregate data. The evident heterogeneity in the intervention comparison effects across studies was accommodated using the random effect model as a framework. Moreover, we conducted a pairwise meta-analysis using a random effect model to obtain direct estimates for outcomes. The transitivity assumption was examined to determine if patient and research characteristics were sufficiently comparable across comparisons. Additionally, using a loop-specific methodology, we assessed the consistency assumption locally in a closed loop [ 22 ]. The surface under the cumulative ranking (SUCRA) was used to rank the intervention’s hierarchy in the network model; then, we estimated the mean ranks [ 23 ]. A comparison-adjusted funnel plot was used to explore the potential publication bias [ 23 ].

We used a three-level hierarchical network meta-analysis to incorporate the exchangeability between different study designs to predict an effect estimate for each study design individually [ 24 ]. Thus, this model allows strength to be borrowed within the different classes of study designs, strengthening interference and potentially reducing the uncertainty around each study design and consequently increasing the ability to inform decision-making frameworks. All data of this approach were pooled as Cohen’s d with 95% confidence intervals.

All outcomes of interest were continuous, and the relative treatment effects were pooled as mean difference (MD) with 95% confidence intervals. All analyses were done in STATA version 17 using the network command.

Literature search results

Our literature search process retrieved 22,262 records. Five thousand two hundred ten duplicates were removed using Endnote, and 17,052 were screened for title and abstract. One hundred forty-nine articles were qualified for full-text screening after being subjected to title and abstract screening. The meta-analysis comprised 13 of these investigations. No further papers were included after manually searching the references of the listed studies. Figure 2 illustrates the PRISMA flow diagram of the study recruitment process.

PRISMA flow diagram of studies’ screening and selection

Characteristics of the included studies

Thirteen studies were included in the meta-analysis, with a total of 4275 patients. In all studies, patients were assigned to receive either oral, SL, or IM vitamin B12. A summary of the included studies and the characteristics of the population in each study are provided in Tables 1 and 2 , respectively. According to the Cochrane ROB 2 tool, four studies had some concerns, two had high, and one had a low risk of bias. According to ROBINS-I checklists, one study had a high risk of bias, and one had a moderate risk of bias. Two studies had good quality, and one had fair quality, according to the NOS tool (Supplementary 2).

Primary outcomes

Vitamin B12

The network of treatment comparisons for vitamin B12 included three active individual nodes (Fig. S1; top panel) . Each node represents a different administration route; the oral administration route was the most well-connected intervention with all other interventions directly linked to it; therefore, it has been used as the reference for comparison. Figure 3 A shows network estimates of treatment effect on vitamin B12 levels for different route administrations compared with the oral route. Network meta-analysis showed that either the IM route (MD 94.09 pg/mL, 95% CI [− 93.36 to 281.54]) or the SL route (MD 43.31 pg/mL, 95% CI [− 228.92 to 315.54]) compared to the oral route did not reach a significant difference to increase vitamin B12 levels. According to SUCRA values, the top-ranked intervention for increasing levels of vitamin B12 was the IM route (74.2), followed by the SL route (48.4) (Table 3 (A)).

Network estimates of treatment effect on each outcome

We performed a three-level hierarchical model to investigate the pooled effect sizes according to the study design in which there was no significant difference between the IM and the oral routes compared to the SL route ( P = 0.31, 0.16, respectively). There was a significant difference between the oral and the IM routes (Cohen’s d − 0.74, 95% CI [− 1.06 to − 0.43]; P < 0.001). The pooled effect sizes were not homogenous ( I 2 > 50%); Fig. S2.

Five studies comprising 3730 patients reported Hb. The network diagram included three individual nodes, (Fig. S1; bottom panel). Each node represents a different drug intervention, in which the oral route was the well-connected route of administration with all other routes directly linked to it.

Figure 3 B shows network estimates of treatment effect on Hb levels for different administration routes compared to the oral route. Pooled effect sizes showed no difference between all routes of administration to increase Hb without substantial statistical evidence (Fig. 3 B). According to SUCRA values, the top two ranked administration routes were the oral route (78.3) followed by the IM route (49.6) (Table 3 (B)).

The three-level hierarchical model showed no significant difference among all comparisons of administration routes; Cohen’s d was 0.07 for IM vs SL routes, 0.06 for oral vs IM routes, and 0.22 for oral vs SL routes. The pooled effect size was homogenous ( I 2 = 0%) (Fig. S3).

Secondary outcomes

Five included studies comprising 3605 patients reported change in MCV, four studies comprising 140 patients reported change in homocysteine levels, four studies comprising 3588 patients reported change in platelets count, and only three studies with 3430 patients reported change in WBC count.

Figures S4 and S5 show networks of routes of administration for secondary outcomes. Figure 3 C–F summarize the results for secondary outcomes. Network meta-analysis showed no evidence of differences among all possible comparisons for secondary outcomes (MCV, homocysteine levels, platelet counts, and WBC counts). Supplementary Table 5 presents SUCRA values. However, none of the three-level hierarchical models showed any significance among all possible comparisons of administration routes (Figs. S6-S9).

Significance of the study

To our knowledge, this is the most comprehensive network meta-analysis comparing the efficacy of SL, IM, and oral routes of administration of vitamin B12 in patients with vitamin B12 deficiency. The significance of this paper is not only to compare the three routes of administration but also to evaluate them and determine which route is the best to administrate the drug. The study also opens the door for more future research about the administration routes of vitamin B12 and other vitamins.

Summary of the findings

The current article evaluated 13 studies, of which eight were randomized clinical trials comparing different administration routes of vitamin B12 in patients with vitamin B12 deficiency. A total of 4275 patients with vitamin B12 deficiency were included in the final analysis. We found that irrespective of the route of vitamin B12 administration, serum vitamin B12 levels were increased. When comparing the different routes, the top-ranked route for increasing levels of vitamin B12 was the IM route, followed by the SL route. However, this difference has no clinical significance.

Interestingly, we found no significant difference among studied administrated routes in all other CBC parameters such as Hb, MCV, platelets count, WBC count, and homocysteine level. Given the fact that vitamin B12 levels were increased insignificantly among all routes, the preference of the administrated route should be referenced to the advantages and disadvantages of each route as well as the patient situation, which will be decided according to the physician’s opinion.

We highlighted the summary of the advantages and disadvantages of each route in (Fig. 4 ) [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ], as treatment decision depends on the patient’s condition and the physician’s opinion. The details about the advantages and disadvantages of each route are present in Supplementary 4.

Advantages and disadvantages of each route of administration

Sublingual vs intramuscular and oral routes of administration

A previous systematic review by Cochrane compared the effectiveness of oral versus IM routes of vitamin B12 administration. It showed that both effectively improve serum vitamin B12 levels for people suffering from vitamin B12 deficiency. However, the dosage of oral vitamin B12 might be a clinical factor that affects this outcome [ 9 ]. This contributes to the absorption mechanism of oral vitamin B12, which does not depend only on intrinsic factors, but the absorption can be done through passive diffusion. Passive diffusion accounts for 1.2% of overall absorption, with little effect on bioavailability in patients with pernicious anemia or gastro-duodenal resection [ 49 , 50 ].

As our results showed, there is no difference between them in terms of efficacy, but in terms of patients’ tolerance, advantages, and disadvantages of each route, the sublingual route is preferred over IM and oral routes. SL vitamin B12 is as adequate as IM and oral vitamin B12. However, the SL route of administration has more advantages and fewer disadvantages than IM and oral routes. So, we recommend using SL vitamin B12 rather than oral and IM, especially in patients who do not tolerate IM injection and patients who need prolonged vitamin B12 supplementation, such as patients with long-term metformin use and patients with pernicious anemia or with gastro-duodenal resection [ 51 , 52 , 53 , 54 ]. In terms of cost, the IM route is higher in cost than the SL and oral routes [ 2 , 55 ].

We recommend future research directions to determine when to start with SL, IM, or oral vitamin B12 in different situations.

Implications in practice

As there is no apparent clinical significance, the treatment should depend on the patient’s condition. We advise physicians to examine every patient carefully to exclude every cause that may lead to malabsorption and then choose the most appropriate route. SL route could be used in patients with pernicious anemia or malabsorption causes. However, the oral route cannot be excluded as it did not depend on intrinsic factors only, as the simple diffusion (without the need for intrinsic factors) is now considered another mechanism for the absorption of vitamin B12 [ 49 , 50 ].

Before this meta-analysis, the IM route was generally the preferred route, but our results showed that no route is usually preferred, and SL and oral routes should be considered comparable alternative routes.

Strength points and limitations

Based on our knowledge, this is the most updated meta-analysis on this topic, including all available evidence based on our inclusion criteria of including only controlled studies, either RCTs or controlled observational studies, to reach the highest accessible quality of evidence from the available evidence found in the literature. We are the first meta-analysis comparing the different administration routes of vitamin B12, and the first meta-analysis includes the SL route of administration in the analysis.

The limitations of this work are that we included RCTs, non-RCTs, and observational studies, which may lower the overall quality of evidence of the included studies. We cannot find the full text of one study which seems to be included. The head-by-head comparison between the three interventions was made only in one paper of the included studies. Additionally, there was variability between the included studies in the follow-up duration, which may cause heterogeneity in the results obtained.

All IM, oral, and SL routes of administration of vitamin B12 can effectively increase the level of vitamin B12 without significant differences between them, as thought previously. However, the IM route was the top-ranked statistically, followed by the SL and then the oral routes, but without clinical significance. We found no significant difference among studied administrated routes in all other CBC parameters such as Hb, MCV, platelets count, WBC count, and homocysteine level.

Availability of data and materials

The datasets used and/or analyzed during the current study are available as MS Excel files (.xlsx) and RevMan file (.rm5) from the corresponding author upon reasonable request.

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Omar Ahmed Abdelwahab, Ahmed Abdelaziz, Sherein Diab, Ali khazragy, Toka Elboraay, Taha Fayad, Rehab Adel Diab & Ahmed Negida

Faculty of Medicine, Al-Azhar University, Cairo, Egypt

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Faculty of Medicine, Alexandria University, Alexandria, Egypt

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Faculty of Medicine, Zagazig University, Zagazig, Egypt

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All authors contributed to the study’s conception and design. SD, AK, TE, and TF did the screening, data extraction and quality assessment of the included studies. AA and RAD prepare the analysis plan, apply this plan, and write the results. OAA and AN wrote the whole manuscript. All authors read and approved the final manuscript.

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Abdelwahab, O.A., Abdelaziz, A., Diab, S. et al. Efficacy of different routes of vitamin B12 supplementation for the treatment of patients with vitamin B12 deficiency: A systematic review and network meta-analysis. Ir J Med Sci 193 , 1621–1639 (2024). https://doi.org/10.1007/s11845-023-03602-4

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A brief review on vitamin b 12 deficiency looking at some case study reports in adults.

1. Introduction

2. vitamin b 12 and anemia, 3. vitamin b 12 and neurological disorders, 4. vitamin b 12 deficiency and hyperhomocysteinemia, 5. conclusions, author contributions, conflicts of interest, abbreviations.

ADMA	8-isoprostaglandin F2α dimethy larginine
CT	computed tomography
DRS-R-98	Delirium Rating Scale—Revised-98
Hb	hemoglobin
Hcy	homocysteine
HHcy	hyperhomocysteinemia
MICD	metformin induced cobalamin deficiency
MADRS	Montgomery Asberg Depression rating scale
MCV	mean corpuscular volume
MMA	methylmalonic acid
MR	magnetic resonance
MMSE	Mini-Mental State Examination
MTHFR	5,10-methylenetetrahydrofolate reductase gene
PPI	proton-pump inhibitor
RDAs	recommended dietary allowances
RBCs	red blood cells
SCD	sub-acute combined degeneration
SDMA	arginine and symmetric dimethyl arginine
TPHA	Treponema pallidum hematoglutinin assay

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References	Laboratory and Clinical Investigation	Main Changes after Treatment
Socha et al. [ ]	Full blood profile, Folate levels, Vitamin B levels Parietal cell antibody, Conventional cytogenetics, Hematologic neoplasm next-generation-sequencing panel (62 genes) for disease-associated mutations.	Case 1: Abnormal complete blood cell count findings improved, as did neurologic symptoms. Case 2: rapid improvement of hematologic symptoms and slower but complete resolution of neurologic symptoms.
Garcia et al. [ ]	Hb, MCV, Folate levels, iron, ferritin, vitamins B , B , and B levels, gastroduodenoscopy and gastric biopsy, Antibodies against intrinsic factor and Helicobacter pylori detection	At 12 months the patient was free of the Recurrent aphthous stomatitis with normal levels of hemoglobin, MCV, and vitamin B .
Pontes et al. [ ]	Full blood count, Folate levels and vitamin B levels	After 14 days of treatment complete remission of all symptoms.
Pahadiya et al. [ ]	Full blood profile, vitamin B levels, LDH, bilirubin Bone marrow aspiration, antinuclear antibody and Coomb’s test, Coagulation profile, iron profile Renal function tests, urinalysis and electrolytes Gastroscopy, electrocardiograph, ultrasonography of abdomen, and chest X-ray	At the follow-up of 1 month, hematological parameters were within normal limits and ecchymosis disappeared.
Surani and Sharma [ ]	Full blood profile, Folate levels, vitamin B levels	Hemoglobin improved to 10.3 gm/dL after four days. Complete blood count showed a complete resolution of pancytopenia at two months follow up. Vitamin B and folate level normalized.
Hussain et al. [ ].	Full blood profile, Vitamin B , Folate, Haptoglobin, MMA, Intrinsic factor antibody	At six-month follow-up clinical and laboratory analysis improvement (e.g., hemoglobin improved to 11.9 gm/d).
Sasi and Yassin [ ].	Full blood profile, B level, Bilirubin, LDH Haptoglobin, direct antiglobulin (DAT) Serum iron, thyroid functions	Blood cell counts started showing an upward trend on day 4 after starting the treatment. On discharge, after 10 days of hospital stay, improvement of blood profile and vitamin B (from values <37 pmol/L to 369 pmol/L), remission of all symptoms.

References	Laboratory and Clinical Investigations	Main Changes after Treatment
Ralapanawa et al. [ ]	Full blood profile, serum creatinine, plasma glucose, thyroid stimulating hormone levels, vitamin B levels, nerve conduction studies	After 3 months, clinical improvement, with repeated B levels being elevated up to 308.6 pg/mL. Follow up at 1 and 3 years showed improvement of nerve conduction.
Ekabe et al. [ ]	Full blood profile, HIV test, Treponema pallidum hematoglutinin assay (TPHA), erythrocyte sedimentation rate and peripheral blood smear analysis, stool exam and urinalysis	At 1 months follow up good clinical recovery, improvement in neurological symptoms and a follow up MCV of 97 fl, red blood cell count of 4.1 million/µL, and reticulocyte count of 0.95%.
Maamar et al. [ ]	Full blood profile, Somatosensorial evoked potential (SEP), MRI, vitamin B levels, Folate levels, bone marrow biopsy	Correction of the neurological signs (paresthesis and sphincter disorders).
Senol et al. [ ]	Blood glucose, AST, ALT, blood urea nitrogen, creatinine, Hb, MCV, white blood cell count, sedimentation rate, Vitamin B levels, HbA1C level, Somatosensorial evoked potential (SEP), Electromyography, Gastric endoscopy and biopsy, Brain MR, Cervical spine MR imaging	At two months follow up complete resolution of symptoms, MR imaging abnormalities significantly improved; impairment of the Somatosensorial evoked potential continued.
Srikanth et al. [ ]	Full blood profile, bone marrow biopsy, Visual evoked potential and brain stem evoked potential studies, Gastric endoscopy and biopsy, workups for infections, para infectious myelitis, multiple sclerosis and connective tissue disorders, Folate levels, vitamin B levels, cervical MR examination	At 10 months follow-up, MRI revealed total resolution of cord abnormality.
Kumar [ ]	Full blood profile, bone marrow biopsy, vitamin B levels, Folate levels, Anti-intrinsic factor antibody Gastric endoscopy and biopsy, Brain CT scan, EEG	At 24 months follow-up resolution of seizure and functional independence.
Mavromati & Sentissi [ ]	Full blood profile, Electrolytes, vitamin B levels, Folate levels, Lyme’s test brain MRI, Neuropsychiatric tests	At 1 week normalization of vitamin B level (330 pmol/L); at 2 weeks important diminution of the cognitive deficiency and a partial remission of the depressive symptoms (MADRS score 22, MMSE 28/30 and DRS-R-98 4; the clock test was normalised). Four weeks after the episode total remission of the depressive symptoms (MADRS score: 4) and stable mental status.

References	Laboratory and Clinical Investigation	Main Changes after Treatment
Tanaka et al. [ ]	Full blood profile, prothrombin time, protein C, protein S levels, total homocysteine, folic acid, vitamin B (Antinuclear antibody (fluorescent antibody technique), immunoglobulin G anticardiolipin antibodies (IgG ACA), phospholipid (GPL), Lupus anticoagulant (diluted Russell’s viper venom time rate). Tumor marker, carcinoembryonic antigen (CEA carbohydrate antigen 19-9, and a-fetoprotein (AFP), CT	Serum homocysteine level decreased (total homocysteine: 12.4 mmol/L), and swelling of his leg improved with significant resolution of thrombus by CT.
Kapur [ ]	Full blood profile, Peripheral blood film, serum cobalamin levels, prothrombin time, protein S, antithrombin III, fibrinogen levels, factor V Leiden assay and prothrombin gene mutation, fasting total serum homocysteine levels, neurological examination, Cerebrospinal fluid examination, CT, MRI	Significant improvement of neurological symptoms. At 6 months normal serum cobalamin 364 pg/mL (200–600) and fasting total homocysteine levels 8.4 μmol/L (5.0–13.9). The rest of the thrombophilia profile was within normal limits.
Ammouri [ ]	Full blood profile, prothrombin time, partial thromboplastin time, fibrinogen level, protein C, protein S levels, antithrombin III function, genetic testing for factor V Leiden and factor II mutation, plasma homocysteine level, cobalamin plasma level, folate plasma, antibodies to intrinsic factor, bone marrow biopsy, chest radiographs, ECG, TC, Ultrasonography	Case 1: After a 1-year follow up total remission of psychiatric disorders and thrombotic events. Hemoglobin and homocysteine plasma levels were within normal range. Case 2: At 6-month follow-up period, hemoglobin and homocysteine plasma levels were within normal range. No thrombotic events for 3 years after the follow-up. Case 3: At 6-month follow-up period, hemoglobin and homocysteine plasma levels were within normal range. No thrombotic events during 4 years of follow-up. Case 4: At 3-year follow-up no psychiatric disorders and thrombotic events. Homocysteine plasma level was within normal range.
Ulrich [ ].	Full blood profile, holotranscobalamin plasma levels, total homocysteine, MMA, Folate, zinc and copper, Electroneurography, CT, MRI.	Cyanocobalamin, MMA and homocysteine levels continuously decreased, and were normal again after 1 month; improvement of sensory disturbances and gait ataxia; At 2 months follow-up MRI showed significant regression of the dorsal column hyperintensities.
Kovalenko et al. [ ]	Full blood profile, troponin, blood urea nitrogen, creatinine, serum electrolytes, B-type natriuretic peptide level, Factor V Leiden, prothrombin mutation, cardiolipin antibody, lupus anticoagulant, anti-B glycoprotein, protein C, protein S levels, Homocysteine level, vitamin B , folate levels, chest radiographs, ECG, echocardiogram, Pulmonary angiography	Serum Hcy levels did not decrease to normal values.
Goette et al. [ ].	Full blood profile, lipid profile, Liver function tests (γ-glutamyl transpeptidase, Alanine transaminase and aspartate aminotransferase, bilirubin), activated partial thromboplastin time, international normalized ratio, thrombin time, activated recalcification, fibrinogen, clotting factors II, XII and VIII levels, protein C, protein S, anti-phospholipid antibodies, vitamin B , folate, Hcy, analyses of cofactors and enzymes involved in homocysteine metabolism, serum levels of 8-isoprostaglandin F2α dimethy larginine (ADMA), Plasma concentrations of arginine and symmetric dimethyl arginine (SDMA), serum level of creatinine, urine analysis 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, TC, computed tomography angiography, ultrasound, echocardiogram	At 2 weeks follow-up level of homocysteine had decreased to 57.6 μmol/L. Three weeks later homocysteine level was 18.1 μmol/L, and after 3 months it was 5.5 μmol/L. After completing his the following metabolites had decreased: ADMA, to 0.363 μmol/L; SDMA, to 0.32 μmol/L; arginine, to 62.8 μmol/L; light reflex rheography and oscillography shown normal perfusion; improvement of pain, paraesthesia in right leg and increasing of pain-free walking distance.
Ruscin et al. [ ]	Full blood profile, vitamin B , methylmalonic acid (MMA), total serum homocysteine, serum folate, serum creatinine, renal function test.	At first follow-up vitamin B has increased, MMA and HCYS was reduced at 351 nmol/L and 23.7 µmol/L respectively. At second follow-up vitamin B was normal; MMA and HCYS were further reduced but remain slight elevated.
McCaddon [ ]	Full blood profile, vitamin B , serum and red cell folate, plasma folate, parietal cell antibodies, total serum homocysteine, cognitive tests.	Case 1: improvement in memory and cognitive tests. Case 2: Within one month tHcy fell to 7.5 μmol/L; no significant cognitive deficits. Case 3: No improvement; the patient died from a bronchopneumonia several weeks later. Case 4: At six-months follow up tHcy fell to 6.6 μmol/L; marked improvement in general behaviour observed also three years later. Case 5: improvement in cognitive tests. Case 6: tHcy fell to 9.6 μmol/L; improvement in cognitive tests. Case 7: At one month follow-up tHcy fell to 8.3 μmol/L; improvement in cognitive tests. At one year follow up MRI scan showed no significant progression in the extent or size of the focal areas of abnormality in the deep white matter, and no change in ventricular configuration.

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Azzini, E.; Raguzzini, A.; Polito, A. A Brief Review on Vitamin B 12 Deficiency Looking at Some Case Study Reports in Adults. Int. J. Mol. Sci. 2021 , 22 , 9694. https://doi.org/10.3390/ijms22189694

Azzini E, Raguzzini A, Polito A. A Brief Review on Vitamin B 12 Deficiency Looking at Some Case Study Reports in Adults. International Journal of Molecular Sciences . 2021; 22(18):9694. https://doi.org/10.3390/ijms22189694

Azzini, Elena, Anna Raguzzini, and Angela Polito. 2021. "A Brief Review on Vitamin B 12 Deficiency Looking at Some Case Study Reports in Adults" International Journal of Molecular Sciences 22, no. 18: 9694. https://doi.org/10.3390/ijms22189694

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Vitamin B12 deficiency

Vitamin B 12 deficiency

Related content
Peer review
Alesia Hunt , haematology specialist registrar ,
Dominic Harrington , consultant clinical scientist, and scientific director of Viapath LLP ,
Susan Robinson , haematology consultant
1 Haematology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
Correspondence to: A Hunt alesiahunt{at}nhs.net

Summary points

Vitamin B 12 deficiency is a common but serious condition

Clinical presentation may not be obvious thus leading to complex issues around diagnosis and treatment

There is no ideal test to define deficiency and therefore the clinical condition of patients is of the utmost importance

There is evidence that new techniques such as the measurement of holotranscobalamin and methylmalonic acid levels seem useful in more accurately defining deficiency

If the clinical features suggest deficiency then it is important to treat patients to avoid neurological impairment even if there may be discordance between the results and clinical features

Vitamin B 12 is an essential cofactor that is integral to methylation processes important in reactions related to DNA and cell metabolism, thus a deficiency may lead to disruption of DNA and cell metabolism and thus have serious clinical consequences. 1 Intracellular conversion of vitamin B 12 to two active coenzymes, adenosylcobalamin in mitochondria and methylcobalamin in the cytoplasm, is necessary for the homeostasis of methylmalonic acid and homocysteine, respectively. 2 3 Methylmalonic acid is converted into succinyl-CoA, of which vitamin B 12 is a cofactor for the reaction. Homocysteine is biosynthesised from methionine then resynthesised into methionine or converted into amino acid cysteine.

Vitamin B 12 (also referred to as cobalamin) deficiency is relatively common, with important and variable clinical consequences. This review presents a concise summary of the most up to date evidence on how to diagnose and manage vitamin B 12 deficiency.

Sources and selection criteria

We searched PubMed and Google Scholar using the terms “vitamin B 12 deficiency” and “cobalamin deficiency”, and hand selected the most relevant and appropriate articles. We also used evidence based guidelines from the British Committee for Standards in Haematology; however, evidence, especially in the form of randomised controlled trials, is lacking. 4

What causes vitamin B 12 deficiency?

Foods containing vitamin B 12 are …

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Vitamin B12 in Health and Disease
Vitamin B 12 is essential for DNA synthesis and for cellular energy production.This review aims to outline the metabolism of vitamin B 12, and to evaluate the causes and consequences of sub-clinical vitamin B 12 deficiency. Vitamin B 12 deficiency is common, mainly due to limited dietary intake of animal foods or malabsorption of the vitamin.
Full article: Vitamin B12 status in health and disease: a critical
Abstract. Vitamin B 12 (cobalamin) is an essential cofactor for two metabolic pathways. It is obtained principally from food of animal origin. Cobalamin becomes bioavailable through a series of steps pertaining to its release from dietary protein, intrinsic factor-mediated absorption, haptocorrin or transcobalamin-mediated transport, cellular uptake, and two enzymatic conversions (via ...
Vitamin B12 Deficiency and the Nervous System: Beyond Metabolic
2.1. The Mechanism of Vitamin B12 Absorption. In humans, the uptake of VitB12 is a multi-step process (Figure 1), starting in the stomach with the release of VitB12 from food thanks to gastric juices.The free VitB12 binds to Haptocorrin (HC) (also named R-protein or Transcobalamin I and encoded by the TCN1), which is secreted by the oral mucosa.
(PDF) A review of vitamin B12
Cobalamin (Cbl), also known as vitamin B12, is an indispensable water-soluble molecule. As far as it is known at present, its function is restricted to cofactorial activity for only two enzymes ...
Effects of Vitamin B12 Supplementation on Cognitive Function
The aim of this systematic review and meta-analysis of randomized controlled trials (RCTs) is to assess the effects of vitamin B12 alone (B12 alone), in addition to vitamin B12 and folic acid with or without vitamin B6 (B complex) on cognitive function, depressive symptoms, and idiopathic fatigue in patients without advanced neurological ...
Vitamin B12
### What you need to know Vitamin B12 (cobalamin) is a water soluble vitamin required for several physiological processes, including normal nervous system functioning, and red blood cell development and maturation. It has antioxidant effects, is a co-factor in mitochondrial energy metabolism, and contributes to DNA synthesis, the methylation cycle, and epigenetic regulation.12 B12 is present ...
The Many Faces of Cobalamin (Vitamin B12) Deficiency
Abstract. Although cobalamin (vitamin B 12) deficiency was described over a century ago, it is still difficult to establish the correct diagnosis and prescribe the right treatment. Symptoms related to vitamin B 12 deficiency may be diverse and vary from neurologic to psychiatric. A number of individuals with vitamin B 12 deficiency may present ...
Vitamin B12 Deficiency
An elevated level of methylmalonic acid is reasonably specific for vitamin B 12 deficiency, and the level always decreases with vitamin B 12 therapy. 24,36 Modest increases (to 300 to 700 nmol per ...
Vitamin B12 status in health and disease: a critical review. Diagnosis
Vitamin B 12 (cobalamin) is an essential cofactor for two metabolic pathways. It is obtained principally from food of animal origin. Cobalamin becomes bioavailable through a series of steps pertaining to its release from dietary protein, intrinsic factor-mediated absorption, haptocorrin or transcobalamin-mediated transport, cellular uptake, and two enzymatic conversions (via methionine ...
Vitamin B12 in health and disease
Vitamin B 12. Vitamin B (12) is essential for DNA synthesis and for cellular energy production.This review aims to outline the metabolism of vitamin B (12), and to evaluate the causes and consequences of sub-clinical vitamin B (12) deficiency. Vitamin B (12) deficiency is common, mainly due to limited dietary intake ….
Vitamin B12 deficiency from the perspective of a practicing
Traditionally, vitamin B 12 deficiency has been considered to lie within the scope and expertise of hematologists. This assignation has deep historical roots, going back to the earliest recognition of the disease that acquired the eponymic title of Addisonian pernicious anemia following the somewhat vague description by the Guy's Hospital physician, Thomas Addison, of "a very remarkable ...
Vitamin B12 deficiency
Vitamin B 12 (B12) and folate are ... Table 2 Research needs relating to vitamin B 12 ... A landmark paper on the clinical and immunological basis of the disease that is the essential paradigm of ...
Vitamin B12 Sources and Bioavailability
The usual dietary sources of vitamin B 12 are animal foods, meat, milk, egg, fish, and shellfish. As the intrinsic factor-mediated intestinal absorption system is estimated to be saturated at about 1.5-2.0 μg per meal under physiologic conditions, vitamin B 12 bioavailability significantly decreases with increasing intake of vitamin B 12 per ...
The discovery of vitamin B(12)
Abstract. The discovery of vitamin B (12), the elucidation of its role in metabolism, and the effects and treatment of its deficiency occurred in distinct phases over more than 100 years, and it was the subject of two separate Nobel Prizes. The valuable contribution of clinical reports and studies of patients with pernicious anemia throughout ...
A Brief Review on Vitamin B12 Deficiency Looking at Some Case Study
The reviewed studies show relatively high deficiency prevalence among vegetarians. B 12 deficiency in infants is about 45%, among the children and adolescents ranging from 0% to 33.3%, and among pregnant women ranging from 17% to 39%, dependent on the trimester.
The importance of vitamin B12 for individuals choosing plant-based
Vitamin B12 is an essential nutrient that is not made by plants; consequently, unfortified plant-based foods are not a reliable supply. Recent estimates suggest high rates of vitamin B12 deficiency among the vegetarian and vegan populations, particularly in pregnant women or women of child-bearing age who, for ethical and health reasons, are shifting towards higher consumption of plant-based ...
PDF Vitamin B12 emerges as key player during cellular reprogramming
Fig. 1 | Vitamin B12 emerges as key player of cellular reprogramming. a, Microbiota depletion with an antibiotic cocktail (ABX) impairs in vivo reprogramming through reduced levels of microbiota ...
Nutrients
Vitamin B12 is essential for DNA synthesis and for cellular energy production. This review aims to outline the metabolism of vitamin B12, and to evaluate the causes and consequences of sub-clinical vitamin B12 deficiency. Vitamin B12 deficiency is common, mainly due to limited dietary intake of animal foods or malabsorption of the vitamin. Vegetarians are at risk of vitamin B12 deficiency as ...
Vitamin B12: Strategies for enhanced production, fortified functional
Vitamin B 12 is an essential micronutrient that controls many biological functions such as the production of red blood cells (RBCs), DNA synthesis, functioning of nervous system and maintaining the structural integrity of chromosomes. Vitamin B 12 deficiency is more prevalent in vegans and being water-soluble, maintaining its adequate levels in the body is a challenging task.
Efficacy of different routes of vitamin B12 supplementation
Background This systematic review and network meta-analysis aimed to evaluate the three different administration routes of vitamin B12: oral, intramuscular (IM), and sublingual (SL) routes. Methods We searched four electronic databases (PubMed, Scopus, Web of Science, and Cochrane CENTRAL Register of Controlled Trials). We included only comparative studies. We performed a frequentist network ...
IJMS
Feature papers represent the most advanced research with significant potential for high impact in the field. A Feature Paper should be a substantial original Article that involves several techniques or approaches, provides an outlook for future research directions and describes possible research applications. ... Where Vitamin B 12 deficiency ...
Vitamin B12 deficiency
Vitamin B 12 is an essential cofactor that is integral to methylation processes important in reactions related to DNA and cell metabolism, thus a deficiency may lead to disruption of DNA and cell metabolism and thus have serious clinical consequences. 1 Intracellular conversion of vitamin B 12 to two active coenzymes, adenosylcobalamin in mitochondria and methylcobalamin in the cytoplasm, is ...
(PDF) Vitamin B12 deficiency
PDF | Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis,... | Find, read and cite all the research you need ...

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A Brief Review on Vitamin B 12 Deficiency Looking at Some Case Study Reports in Adults

1. Introduction

2. Vitamin B 12 and Anemia

3. Vitamin B 12 and Neurological Disorders

4. Vitamin B 12 Deficiency and Hyperhomocysteinemia

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Vitamin B 12 emerges as key player during cellular reprogramming

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Efficacy of different routes of vitamin B12 supplementation for the treatment of patients with vitamin B12 deficiency: A systematic review and network meta-analysis

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The effect of vitamin B12 and folic acid supplementation on routine haematological parameters in older people: an individual participant data meta-analysis

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