VITAMIN B12 AND DEVELOPMENT

Many research studies emphasize the health complications of nutritional cobalamine

deficiency and a necessity of clinical, biochemical and metabolic monitoring in infants born

to mothers suffering from vitamin B12 deficiency. Dietary deficiencies of vitamin B12 during

pregnancy and lactation may result in health problems in exclusively breastfed infants.

Physical examination of these children have revealed psychomotoric retardation, apathy,

muscular hypotonia, irritability, anorexia, abnormal movements and failure to thrive.

Laboratory analysis show haematological abnormalities, such as a megaloblastic anaemia, a

low level of vitamin B12, high level of homocystein and methylmalonic acid and

methylmalonic aciduria. MRI of the brain reveals diffuse frontotemporoparietal atrophy and

retardation of myelination [4]. Some studies have shown a relationship between maternal

vitamin B12 status and birth weight. One of them extends those findings directly in terms of

neonatal vitamin B12 status and birth weight. Vitamin B12 status in the mother was related to

neonatal vitamin B12 status as measured by cord serum vitamin B12 concentration. In

addition, low neonatal vitamin B12 concentrations were adversely associated with low birth

weights [5]. A marginal maternal vitamin B12 status increases the risk of an offspring with

spina bifida [6].

There are different vegetarian dietary patterns, some of which are nutritionally adequate

for children. However, others may lack essential nutrients. Lack of animal products in the

diet decreases the intake of essential nutrients which may influence bone metabolism. This is

a very serious problem, especially in childhood and adolescence when growth and bone

turnover are the most intensive. Bone metabolism is regulated by variety factors, which are

involved in the bone formation and bone re-absorption processes. Osteocalcin is one of the

markers of bone formation (produced by osteoblast) which plays an important role in the

regulation of bone growth. Recent data support the concept that other modulators, such as

leptin (a hormone from adipose tissue), play an important role in the control of body fat

storage and energy expenditure. Higher leptin levels were observed in obese subjects and

lower levels in anorectic patients. Lower levels of osteocalcin and leptin are accompanied by

lower vitamin B12 concentration may retard relevant bone growth and development in

childhood [7].

Children have specific and increased nutritional requirements in comparison with adults.

Rapid growth and enhanced energy expenditure explain these differences. Any diet deviation

178 Ilia Volkov, Inna Rudoy and Yan Press

will increase exposure to the risk of nutritional deficiency along with corresponding health

consequences. Whenever a diet restriction for children is required for medical reasons,

particular attention must be paid to the food regimen in order to avoid any health problem,

especially growth retardation [8].

COBALAMIN-RESPONSIVE

NEUROPSYCHOLOGICAL CONDITIONS

The only function that has been indicated as unique for vitamin B 12 is the synthesis of

myelin, a component of the sheaths that protect nerve fibers. Vitamin B12 deficiency can

cause peripheral neuropathy and combined system diseases involving demyelination of the

dorsal columns and the corticospinal tract. In most episodes neurological complaints,

commonly paresthesias or ataxia, is the first symptom of cobalamin deficiency. The median

duration of symptoms between diagnosis and treatment with vitamin B12 is a few months,

although in some patients there are longer delays in diagnosis. Diminished vibratory

sensation and proprioception in the lower extremities are the most common objective

findings. A wide variety of neuropsychological symptoms and signs have been encountered,

such as ataxia, loss of cutaneous sensation, muscle weakness, diminished or hyperactive

reflexes, spasticity, urinary or fecal incontinence, orthostatic hypotension, loss of vision,

dementia, psychoses, and disturbances of mood. Multiple neurological syndromes were often

seen in a single patient. Severity of neurological dysfunction before treatment is clearly

related to the duration of symptoms prior to diagnosis [9].

Recurrent seizures, extrapyramidal system involvement in the form of involuntary

movements (myoclonus-like involuntary movements, chorea and focal dystonia) or acute

onset parkinsonism have been reported as a rare manifestations of vitamin B12 deficiency

[10,11,12,13].

Optic nerve involvement is a rare but recognized appearance of vitamin B12 deficiency,

which may proceed to visual failure if not diagnosed early enough.

MRI examination typically demonstrates involvement of the cervical cord in majority of

the patients, although the pathology sometimes begins in the thoracic cord. MRI also has

demonstrated contiguous involvement of multiple segments of the cord. The cord

abnormality can resolve without evidence of cord atrophy on MRI, if treated early.

Multiple Sclerosis (MS) and vitamin B12 deficiency share common inflammatory and

neurodegenerative pathophysiological characteristics. Due to similarities in the clinical

presentations and MRI findings, the differential diagnosis between vitamin B12 deficiency

and MS may be difficult. Additionally, low or decreased levels of vitamin B12 have been

demonstrated in MS patients. Moreover, recent studies suggest that vitamin B12, in addition

to its known role as a co-factor in myelin formation, has important immunomodulatory and

neurotrophic effects. These observations raise the questions of possible causal relationship

between the two disorders, and suggest further studies of the need to monitor closely vitamin

B12 levels in MS patients, as well as potentially requiring supplementation of vitamin B12

alone or in combination with the immunotherapies [14]. Interferon-beta is a mainstay therapy

of demyelinating diseases, but it has only a partial effect on multiple sclerosis in humans and

The Role and Status of Vitamin B12: Need for Clinical Reevaluation and Change 179

in several animal models of the disease. In a recent report the authors demonstrated a

dramatic improvement in the clinical, histological, and laboratory parameters of disease in in

vivo mouse models of demyelinating disease. This was seen following combination therapy

with IFN-beta and vitamin B12 cyanocobalamin [B(12)CN] in non-autoimmune primary

demyelinating ND4 (DM20) transgenic mice, and in acute and chronic experimental

autoimmune encephalomyelitis in mice. Clinical improvement, manifested as near normal

motor function, was associated with reduced astrocytosis and demyelination. IFN-betaB12CN combination therapy may be promising for the treatment of multiple sclerosis [15].

The association of cobalamin deficiency with psychiatric illness has been studied and

debated since this vitamin was first discovered in the 1940s. The clinical relevance of this

deficiency remains the subject of investigation and academic discussion. Vitamin B12 has

fundamental roles in brain function. Intracellular cobalamin is converted to

adenosylcobalamin, coenzyme for methylmalonyl-CoA mutase and to methylcobalamin,

coenzyme for methionine synthase which mediates conversion of homocysteine to

methionine. This leads to an increase in the level of homocysteine (Hcy). Homocysteine has

been implicated as a risk factor for vascular disease, as well as brain atrophy. There is

evidence to implicate Hcy in increased oxidative stress, DNA damage, the triggering of

apoptosis and excitotoxicity, all of which are important mechanisms in neurodegeneration.

Hcy is also prothrombotic and proatherogenic, and causes damage to the vessel wall and is

related to brain atrophy, and possibly to white matter hyperintensities in the brain.

Epidemiological evidence and longitudinal data support the finding that Hcy is a risk factor

for cognitive impairment and Alzheimer's Disease [16,17,18]. This may be due to

cerebrovascular as well as direct neurotoxic mechanisms.

As well as cognitive impairment, the common psychiatric symptoms of vitamin B12

deficiency are continuous depression [19], psychotic symptoms [20], mania, and obsessive

compulsive disorder. The neuropsychiatric severity of vitamin B12 deficiency and the

therapeutic efficacy depends on the duration of signs and symptoms. Therefore, the

consideration of B12 deficiency and testing for serum B12 levels is recommended in all the

patients with organic brain syndrome, atypical psychiatric symptoms and fluctuation of

symptomatology.

RELATIONSHIP OF VITAMIN B12 AND HOMOCYSTEINE IS

THEIR FUNCTION IN CARDIOVASCULAR EVENTS OBVIOUS?

No doubt about the association between vitamin B12 and homocysteinemia [21,22], but

their synergistic or separated role in the development of atherosclerosis and influence on

cardiovascular events is nevertheless controversial. In observational studies, elevated plasma

total homocysteine levels have been positively associated with ischemic stroke risk

[23,24,25]. Numerous retrospective and prospective studies have revealed a consistent,

independent relationship between mild hyperhomocysteinemia and cardiovascular disease or

all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10

mol/l, the risk increase follows a linear dose-response relationship with no specific

threshold level. Hyperhomocysteinemia, as an independent risk factor for cardiovascular

180 Ilia Volkov, Inna Rudoy and Yan Press

disease, is thought to be responsible for approximately 10% of the total risk. Elevated plasma

homocysteine levels (>12 mol /l; moderate hyperhomocysteinemia) are considered cytotoxic

and are found in 5-10% of the general population and in up to 40% of patients with vascular

disease. Based on various calculation models, reduction of elevated plasma homocysteine

concentrations may theoretically prevent up to 25% of cardiovascular events. Treatment of

hyperhomocysteinemia is recommended for the apparently healthy general population [26].

Some large studies confirm that a supplementation with group B vitamins did not reduce the

risk of major cardiovascular events or all-cause mortality in patients with vascular disease

[27,28]. We suppose, the outcomes of these and similar trials could be different if the

researches had paid attention to the following points: 1. Using vitamin B12 or B-complex as

secondary prevention of cardiovascular events for patients with irreversible changes of blood

vessels is probably in error. Rather vitamin B12 or B-complex should be used as primary

prevention! 2. Using high doses of vitamin B12 will probably be more effective than using

"group B vitamins". Furthermore, using folic acid alone for prevention of cardiovascular

diseases has been proven to be ineffective [29], while very high doses of vitamin B12 (60 mg

every day for 6 months) has been used effectively without any toxic side effects for the

treatment of other diseases [30].

MYTHS AND REALITY ABOUT

HEMATOLOGICAL ABNORMALITIES

Hemopoesis is the process in which new blood cells are produced, in which Vitamin B12,

folate, and iron have fundamental roles. New erythrocytes replace the oldest erythrocytes

(normally about one percent) that are phagocytosed and destroyed each day. Erythroblasts

require folate and vitamin B12 for proliferation during their differentiation. Deficiency of

folate or vitamin B12 inhibit purine and thymidylate syntheses, impairs DNA synthesis, and

causes erythroblast apoptosis, resulting in megaloblastic anemia from ineffective

erythropoiesis. The presence of macro-ovalocytes having a high MCV, anisocytosis,

poikilocytosis and hypersegmented neutrophils, anemia, leukopenia, and thrombocytopenia

or pancytopenia suggests a megaloblastic disorder associated with a nutritional deficiency,

i.e., vitamin B12.

During last decades, the hematological manifestations related to cobalamin deficiency

have been differed from descriptions reported in textbooks or"old" studies. Dr. Alan L

Diamond made one of a number of attempts to systematize standard knowledge as follows

[31]: "Vitamin B12 deficiency produces the classic picture of macrocytic anemia, with a mean

corpuscular value (MCV) greater than 100 fL. The MCV correlates with estimated vitamin

B12 level: MCV of 80-100 fL indicates less than 25% probability of vitamin B12 deficiency

MCV of 115-129 fL indicates a 50% propability; MCV greater 130 indicates 100%

propability." It's a classic "textbook" picture of vitamin B12 deficiency. But as far as we

know, our patients don't read a textbook… It is well known now vitamin B12 deficiency may

be accompanied by iron deficiency, and this association could have masked the macrocytosis

[32,33].

The Role and Status of Vitamin B12: Need for Clinical Reevaluation and Change 181

Vitamin B12 deficiency has many causes, and pernicious anemia has been described as a

widespread cause of vitamin B12 deficiency. The term "pernicious anemia" applies only to the

condition associated with chronic atrophic gastritis. A some population researches revealed

that 1.9 percent of persons more than 60 years old have undiagnosed pernicious anemia [34].

Although the disease may be silent until the obvious end stage, the underlying gastric lesion

can be predicted many years before anemia develops. The discovery of a serum inhibitor of

intrinsic factor (later found to be an autoantibody to the intrinsic factor) and of autoantibodies

to parietal cells laid the foundation for the immunologic explanation of the underlying

gastritis that causes pernicious anemia. The vitamin B12–intrinsic factor complex is carried to

the terminal ileum, where it is absorbed after binding to intrinsic-factor receptors on the

luminal membranes of ileal cells. Malabsorption of vitamin B12 in patients with pernicious

anemia is due to intrinsic-factor deficiency. Two mechanisms are responsible. First, the

progressive destruction and eventual loss of parietal cells from the gastric mucosa lead to

failure of intrinsic-factor production. Indeed, the severity of the gastric lesion correlates with

the degree of impaired secretion of intrinsic factor and the reduction in vitamin B12

absorption. Second, blocking autoantibodies present in the gastric juice can bind to the

vitamin B12–binding site of intrinsic factor, thereby preventing the formation of the vitamin

B12–intrinsic factor complex. Vitamin B12 is required for DNA synthesis. Therefore, the

major organs affected by vitamin B12 deficiency are those in which cell turnover is rapid,

such as the bone marrow and the gastrointestinal tract [35]. The usual presentation

accompany symptoms of anemia; asymptomatic patients can be identified by routine

hematologic investigations. But hematological abnormalities, such as anemia may be absent

at the time of neurological presentation [3].

Examination of bone marrow reveals megaloblasts and large myeloid precursors.

Current studies on cobalamin deficiency, including more precise definitions and the

description of new etiologies of cobalamin deficiency, such as insufficient dietary intake

[33], food-cobalamin malabsorption syndrome [36,37] (characterized by the inability to

release cobalamin from food or a deficiency of intestinal cobalamin transport proteins or

both) due to chronic carriage of helicobacter pylori [38] and intestinal microbial proliferation,

which can be caused by antibiotic treatment, long-term ingestion of biguanides (metformin)

[39,40] and antacids, including H2-receptor antagonists and proton pump inhibitors [41]

(particularly among patients with Zollinger–Ellison syndrome [42]), chronic alcoholism,

surgery or gastric reconstruction (e.g., bypass surgery for obesity), partial pancreatic exocrine

failure, hereditary cobalamin metabolism diseases as Imerslund-Grasbeck syndrome [43]

(selective vitamin B12 malabsorption with proteinuria) show that hematological abnormalities

are generally incomplete, as compared to historical descriptions.

Vitamin B12 deficiency may also influence the granulocyte and platelet lines and may be

mistaken for leukaemia [44] in all cases the important practical indicator is positive response

to vitamin B12 treatment.

Some European countries have deferred the decision to introduce food fortification with

folic acid for prevention of neural tube defects and other congenital anomalies because of

concerns about potential masking of vitamin B12 deficiency [45].

182 Ilia Volkov, Inna Rudoy and Yan Press

KNOWN CUTANEOUS AND MUCOUS MANIFESTATIONS OF

VITAMIN B12 DEFICIENCY AND THE NOVEL

USE OF VITAMIN B12 IN DERMATOLOGY

The characteristic dermatological sign of vitamin B12 deficiency is cutaneous

pigmentation [46,47,48,49], which can be reversed by administration of vitamin B12 .

Increased cutaneous pigmentation is especially accentuated in palmar creases, on the dorsa of

hands and feet, in intertriginous areas, on oral mucosa and in recent scars. The mechanism of

hyperpigmentation is unexplained. Histology showed an increase of melanin in the basal

layer. In electron microscopic study, many melanosomes were observed in melanocytes and

surrounding keratinocytes. There is supposition that the dominant mechanism of

hyperpigmentation due to vitamin B12 deficiency is not a defect in melanin transport, but is

rather an increase in melanin synthesis.

We investigated and reported a case of the paradoxical disappearance of chronic

erythema nodosum [50], which had persisted for more than half a year in spite of a prolonged

treatment with non-steroidal anti-inflammatory drugs. When the patient complained of

paresthesias, a blood test for vitamin B12 was performed and a prominent vitamin B12

deficiency was discovered. Since treatment was initiated with intramuscular vitamin B12

injections, not only did the paresthesias disappear, but the erythema nodosum, as well. The

patient continued to receive maintenance therapy with vitamin B12 without recurrence of

erythema nodosum.