Deficitul de vitamina B12 si acid

folic

Paunescu Ruxandra Madalina

Medic rezident an II neurologie
• In afara de deficitul de fier, o alta cauza majora
pentru aparitia anemiei o reprezinta deficitul de
vitamina B12 si acid folic.

• Frecventa de aparitie depinde foarte mult de

populatia studiata, astfel:
- din cauza faptului ca deficitul de vitamina B12 se
dezvolta de a lungul mai multor ani, este mai frecvent
la varstnici;
- iar deficitul de folat aparand cel mai frecvent
datorita unei diete inadecvate, este mai frecvent in
cadrul populatiilor care sunt la risc pentru dezvolatrea
malnutritiei sau in zonele unde mancarea nu este
fortificata*.
• Bacteriile din intestinul animalelor erbivore
sintetizeaza vitamina B12 care apoi este preluata de
organismul gazda, ajungang ulterior la oameni sub
forma de carne (produse lactate, peste...).
• Plantele nu sintetizeaza vitamina B12, dar pot o
contine prin contaminare bacteriana.
• Plantele sintetizeaza acid folic si il furnizeaza oamenilor
direct sub forma de fructe si legume (nuci, legume
verzi, drojdie) si indirect prin carnea erbivorelor.
• Absorbtie si transport: vitamina B12 (factorul
extrinsec) odata ajunsa in stomac se leaga de
FACTORUL INTRINSEC (secretat in paralel cu
acidul clorhidric de catre celulele parietale
gastrice), care transporta cobalamina la nivelul
ileonului si de aici in sistemul venos portal
legata de transcobalamina.

• Absorbtie si transport: acidul folic este o

substanta solubila in apa si se absoarbe rapid in
portiunea superioara a intestinului subtire,
ulterior ajungand in plasma.
Rolurile metabolice ale vitaminei B12 si acidului
folic sunt foarte interconectate.
• Vitamina B12 este un cofactor important in
procesul de metilare -> necesar in reactiile de
formare ADN si metabolism celular.
• Intracelular vitamina B12 se transforma in 2
enzime: adenozil-cobalamina (in mitocondrie)
si metil-cobalamin (in cotiplasma), necesare
pentru homeostaza acidului metil-malonic si
respectiv homocisteina.
 La oameni doar 2 reactii enzimatice sunt
cunoscute a fi dependente de vitamina B12:
1. (intramitocondrial) adenozil-cobalamina ->acidului
metil-malonic -> succinil CoA (vitamina b12 fiind cofactor
al reactiei).
Aceasta reactie permite utilizarea acidului propionic si
este importanta pentru sinteza acizilor grasi,
indispensabili pentru structura normala a membranelor
neuronale si a tecilor de mielina din sistemul nervos
central.
Astfel, deficitul de vit B12 duce la acumularea
metilmalonil-CoA si respectiv propionil-CoA. Conform
acestui mecanism propionil-CoA inlocuieste succinil-CoA,
care este in mod normal amorsa pentru sinteza lanturilor
de acizi grasi =>rezultand lanturi anormale de acizi grasi
gresit inserate la nivelul membranelor lipidice/tecilor de
mielina.
2. (intracitoplasmatic) metil-cobalamina -> homocisteina -
-> metionina.
Afectarea acestei reactii, cauzata de deficitul de
cobalamina ar putea cauza un esec in sinteza ADN ului,
fiind afectata in special productia de megaloblaste
(deoarece neuronii nu se divid, aceasta cascada de
evenimente nu explica leziunile de la nivelul SNC).
metil-cobalamina -> rol in reactia de transformare a
metiltetrahidrofolatului in tetrahidrofolat.
5MTHF->DHF->THF
Tetrahidrofolatul interactioneaza cu 5-10
metilentetrahidrofolatul si dihidrofolatul, contribuind la
sinteza timidilatului din dezoxiuridilat, reactie majora in
sinteza ADN.
• The metabolic roles of folate and B12 are closely interrelated (Fig.
2.1). Folate derivatives are essential cofactors in thymidylate
synthesis, which is a rate-limiting step in the synthesis of DNA. RNA
synthesis, however, is not dependent on folate. Therefore,
deficiency of folate limits gene transcription but not RNA
translation, retarding cell division but not cytoplasmic protein
synthesis. This leads to the typical cytonuclear dissociation of
maturation characteristic of megaloblastic hematopoiesis. Because
cobalamin supports the recycling of folate, vitamin B12 deficiency
causes megaloblastic changes by restricting the folate supply. This
restriction can be at least partially overcome by increasing dietary
folate, allowing the hematopoietic effects of cobalamin deficiency to
be ameliorated by high doses of folic acid. In contrast, the
hematopoietic effects of folate deficiency cannot be overcome by
treatment with vitamin B12.
• COBALAMIN-FOLATE RELATIONS
Folate is required for many reactions in mammalian tissues. Only two
reactions in the body are known to require cobalamin. MethylmalonylCoA
isomerization requires adocobalamin, and the methylation of
homocysteine to methionine requires both methylcobalamin and
5-MTHF (Fig. 95-1). This reaction is the first step in the pathway
by which 5-MTHF, which enters bone marrow and other cells from
plasma, is converted into all the intracellular folate coenzymes. The
coenzymes are all polyglutamated (the larger size aiding retention in
the cell), but the enzyme folate polyglutamate synthase can use only
THF, not MTHF, as substrate. In cobalamin deficiency, MTHF accumulates in
plasma, and intracellular folate concentrations fall due to failure of formation of
THF, the substrate on which folate polyglutamates
are built. This has been termed THF starvation, or the methylfolate trap.
This theory explains the abnormalities of folate metabolism that
occur in cobalamin deficiency (high serum folate, low cell folate, positive purine
precursor aminoimidazole carboxamide ribonucleotide
[AICAR] excretion; Table 95-2) and also why the anemia of cobalamin
deficiency responds to folic acid in large doses.
• vitamin B12 deficiency may exert indirect cardiovascular effects.
Similar to folic acid deficiency, vitamin B12 deficiency produces
hyperhomocys-teinemia, which is an independent risk factor for
atherosclerotic disease.7 Although the role of folic acid
supplementation in reducing homocysteine levels as a method for
preventing coronary artery disease and stroke continues to be a
subject of great interest, there has been little emphasis on the
potential role of vitamin B12 deficiency as a contributing factor in
the development of cardiovascular disease. This possibility
becomes especially important when considering vitamin
replacement therapy. Folic acid supplementation may mask an
occult vitamin B12 deficiency and further exacerbate or initiate
neurologic disease. Therefore, clinicians should consider ruling out
vitamin B12 deficiency before initiating folic acid therapy.8
• CLINICAL PRESENTATION
• The clinical presentation of vitamin B12 and folic acid
deficiency covers a wide range from asymptomatic, to life-
threatening pancytopenia or myelopathy (Table 2.4). The
investigation of any new neuropsychiatric changes should
include an evaluation of vitamin B12 (and folate status) even
in the absence of hematologic signs of a deficiency.7 B12
deficiency is commonly associated with neurologic
changes, and only rarely with folate deficiency; hereditary
folate malabsorption and/ or metabolism are the exception
and associates with progressive neurologic deterioration in
childhood.25 Classically, changes in the tongue mucosa and
mouth angle stomatitis are the earliest signs of folate
deficiency on physical examination.26
CLINIC
Manifestari neuro-psihiatrice:

• Deficitul de vitamina B12 (cobalamina) afecteaza

maduva spinarii, creierul, nervii optici si nervii
periferici, dand nastere unui sindrom neurologic clasic.
• Maduva spinarii este de obicei prima si de multe ori si
singura afectata.
• Termenul de DEGENERESCENTA COMBINATA
SUBACUTA (DCS) este in mod obisnuit rezervat
leziunilor medulare provocate de deficitul de vitamina
B12 si ne ajuta sa distingem aceasta afectiune de alte
boli ale maduvei spinarii care includ modificari la
nivelul cordoanelor posterioare si laterale.
CLINIC:
 Neuro-psihiatric:
• Semnele si simptomele sunt simetrice, predominant distale, iar cele
senzitive le preceda pe cele motorii.

Astfel, initial pacientul acuza slabiciune generalizata si parestezii (furnicaturi,

intepaturi) ce implica mainile > picioarele.

Pierderea simtului vibrator (sensibilitate tactila fina /epicritica si vibratorie)

este cel mai consistent semn. In paralele apare si afectarea sensibilitatii
proprioceptive. (afectare cordoane posterioare)
Afcetarea sensibilitatii termoalgice prin afectarea nervilor periferici (distal,
simetric) sau rar a tracturilor spinotalamice laterale.
Fenomenul Lhermitte

Semnele motorii, apar prin afectarea tracturilor spinocorticale, de obicei sunt

limitate la nivelul mb inf: deficit motor (moderat mm proximali, simtric,
spasticitate), ROT exagerate si clonus (ROT pot fi diminuate sau absente in
afectarea periferica), RCP in extensie.
La inceput mers ataxic ulterior ataxic si spastic.
• Cognitiv:
Frecvente, de la apatie, iritabilitate, somnolenta, neincredere,
instabilitate emotionala, psihoza confuziva sau depresiva,
dementa (megaloblastic madness).
• Vedere:
Este secundara neuropatiei optice; Scotom centrocecal, atrofie
optica.
• Disfunctie autonoma:
Disfunctie sfincter vezical, impotenta.

• Afectarea tesuturilor (stratul epitelial) de la nivelul cavitatii

bucale (GLOSITA), stomac, intestin subtire, tract respirator,
urinar si genital. (macrocitoza, moarte celulara...)
• Gonadele sunte afectate de asemenea, pana la infertilitate.
• Avort, prematuritate, defecte de tub neural.
Hematologic – sangele periferic:

• Celule rosii macrocitare, ovale sau macroovalocite, variate

forme celulare fragmentate, celule rosii nucleate, neutrofile
hipersegmentate (1% cu 6lobi sau 5% cu 5lobi);
• Anemie, de obicei macrocitara, dar poate fi si normo sau
microcitara daca se insoteste de talasemie sau de deficitul
de fier;
• Leucopenie, trombocitopenie, pancitopenie;
• Nivel crescut de LDH, bilirubina indirecta, nivel scazut de
haptoglobina;
• Maduva hipercelulara, eritropoieza megaloblastica cu
diferite grade de displazie si cromatina nucleara imatura;
Cauze:
Gastrointestinal • Gastric atrophy: achlorhydria, achlorhydria + intrinsic
factor deficiency
• Bariatric surgery
• Gastrectomy
• Gastric bypass
• Terminal ileal resection
• Extensive celiac disease
• Crohn’s disease of the stomach
• Bacterial overgrowth in the small bowel (achlorhydria,
anatomical defects, impaired motility)
• Zollinger–Ellison syndrome
• Pancreatic insufficiency
• HIV
• Intestinal parasites

Medications Megadoses of vitamin C, metformin, proton pump inhibitors

Increased utilization Pregnancy

Cauze:
• Cobalamin deficiency is rarely caused by inadequate intake or increased use of the
vitamin (Table 2.2). This is in part due to the pronounced enterohepatic circulation of
cobalamin. Although strict vegetarians become depleted of vitamin B12, vegetables
often contain sufficient bacteria to provide a marginally adequate supply. A developing
fetus shunts cobalamin from its mother, placing her at risk of deficiency, particularly if
her baseline stores are low. Rarely, intestinal parasites can induce deficiency; for
example the fish tapeworm, Diphyllobothrium latum, competesas well, although this is
rare.8

• DEVELOPMENT OF VITAMIN B12 DEFICIENCY

• Cobalamin deficiency is rarely caused by inadequate intake or increased use of the
vitamin (Table 2.2). This is in part due to the pronounced enterohepatic circulation of
cobalamin. Although strict vegetarians become depleted of vitamin B12, vegetables
often contain sufficient bacteria to provide a marginally adequate supply. A developing
fetus shunts cobalamin from its mother, placing her at risk of deficiency, particularly if
her baseline stores are low. Rarely, intestinal parasites can induce deficiency; for
example the fish tapeworm, Diphyllobothrium latum, competes with the host for
cobalamin.9 Acutely, cobalamin metabolism can be disrupted by nitrous oxide
anesthesia and induce a rapid, usually transient, megaloblastic anemia.10 However,
fatalities and severe neuropsychiatric damage have been associated with chronic
administration in patients and recreational use of nitrous oxide.11
• Far more commonly, defects in any of the three levels of the gastrointestinal tract can
lead to vitamin B12 malabsorption: the fundus of the stomach, the pancreas, or the
small bowel.12 Obviously, surgical removal or bypass of any of these regions leads to
B12 malabsorption.13 Bariatric surgery is becoming more prevalent and subsequently
an important risk factor for developing B12 deficiency. Otherwise the etiology is
inflammatory.
• Stomach: In the stomach, food (protein)-bound vitamin B12 must be freed by digestion
with pepsin and bound to “R-proteins,” which is a generic term for proteins that bind
B12.1 The parietal cells in the fundus secrete both the acid necessary for this digestion
and intrinsic factor, the protein to which cobalamin is later transferred in the alkaline
duodenum. Therefore, any process that damages the parietal cells can lead to vitamin B12
malabsorption and eventually deficiency. The most common cause is autoimmune
atrophic gastritis, which increases in prevalence with age and is sometimes associated
with other autoimmune diseases, such as thyroiditis. Helicobacter pylori, however, which
typically causes antral gastritis, can occasionally also infect the fundus.14,15 Proton pump
inhibitors induce chronic hypochlorhydria but rarely cause clinically significant B12
malabsorption. Parodoxically, the hypersecretion of acid in theZollinger–Ellison syndrome
leads to B12 malabsorption by acidifying the small bowel, which must remain alkaline for
the transfer of B12 from the R-binders to intrinsic factor. Antibodies to intrinsic factor, as
in the case of pernicious anemia, also lead to a reduction of vitamin B12-intrinsic factor
complexes necessary for absorption in the small bowel.
• Pancreas: Deficiency of pancreatic enzymes impairs the digestion of R-binders in the small
bowel and therefore the release of B12 to intrinsic factor. Although pancreatic
insufficiency causes cobalamin malabsorption, it rarely is significant enough to become
clinically apparent.
• Small bowel: Vitamin B12–intrinsic factor complexes are endocytosed by the mucosa of
the terminal ileum. Inflammatory bowel disease or particularly extensive celiac or tropical
sprue interfere with this process.16 Bacterial overgrowth in the small bowel, especially
common in the elderly, competes for B12 and makes it less available for absorption.17
Calcium dependent ileal membrane antagonism of metformin leads to diminished B12
absorption in up to one-third of diabetic patients, but rarely leads to anemia, and is
reversed with supplemental calcium.12,18,19 HIV infection is sometimes also associated
with B12 malabsorption, especially in the presence of chronic diarrhea.
Tratament:

• Pacienti la risc