Many symptomless patients are detected through the finding of a raised mean corpuscular volume (MCV) on a routine blood count. The main clinical features in more severe cases are those of anemia. Anorexia is usually marked, and there may be weight loss, diarrhea, or constipation. Glossitis, angular cheilosis, a mild fever in more severely anemic patients, jaundice (unconjugated), and reversible melanin skin hyperpigmentation also may occur with a deficiency of either folate or cobalamin. Thrombocytopenia sometimes leads to bruising, and this may be aggravated by vitamin C deficiency or alcohol in malnourished patients. The anemia and low leukocyte count may predispose to infections, particularly of the respiratory and urinary tracts. Cobalamin deficiency has also been associated with impaired bactericidal function of phagocytes.
General Tissue Effects of Cobalamin and Folate Deficiencies
After the marrow, the next most frequently affected tissues are the epithelial cell surfaces of the mouth, stomach, and small intestine and the respiratory, urinary, and female genital tracts. The cells show macrocytosis, with increased numbers of multinucleate and dying cells. The deficiencies may cause cervical smear abnormalities.
Complications of Pregnancy
The gonads are also affected, and infertility is common in both men and women with either deficiency. Maternal folate deficiency has been implicated as a cause of prematurity, and both folate deficiency and cobalamin deficiency have been implicated in recurrent fetal loss and neural tube defects, as discussed below.
Folic acid supplements at the time of conception and in the first 12 weeks of pregnancy reduce by ∼70% the incidence of neural tube defects (NTDs) (anencephaly, meningomyelocele, encephalocele, and spina bifida) in the fetus. Most of this protective effect can be achieved by taking folic acid, 0.4 mg daily at the time of conception.
The incidence of cleft palate and harelip also can be reduced by prophylactic folic acid. There is no clear simple relationship between maternal folate status and these fetal abnormalities, although overall the lower the maternal folate, the greater the risk to the fetus. NTDs also can be caused by antifolate and antiepileptic drugs.
An underlying maternal folate metabolic abnormality has also been postulated. One abnormality has been identified: reduced activity of the enzyme 5,10-methylene-THF reductase (MTHFR) (Fig. 105-1) caused by a common C677T polymorphism in the MTHFR gene. In one study, the prevalence of this polymorphism was found to be higher in the parents of NTD fetuses and in the fetuses themselves: Homozygosity for the TT mutation was found in 13% compared with 5% in control subjects. The polymorphism codes for a thermolabile form of MTHFR. The homozygous state results in a lower mean serum and red cell folate level compared with control subjects, as well as significantly higher serum homocysteine levels. Tests for mutations in other enzymes possibly associated with NTDs, e.g., methionine synthase and serine–glycine hydroxymethylase, have been negative. Autoantibodies to folate receptors were suggested to be more common in mothers of NTD babies, but this has been disproved.
Children with severe homocystinuria (blood levels ≥100 μmol/L) due to deficiency of one of three enzymes, methionine synthase, MTHFR, or cystathionine synthase (Fig. 105-1), have vascular disease, e.g., ischemic heart disease, cerebrovascular disease, or pulmonary embolus as teenagers or in young adulthood. Lesser degrees of raised serum homocysteine and low levels of serum folate and homozygous inherited mutations of MTHFR have been found to be associated with cerebrovascular, peripheral vascular, and coronary heart disease and with deep vein thrombosis. Prospective randomized trials of lowering homocysteine levels with supplements of folic acid, vitamin B12, and vitamin B6 against placebo over a 5-year period in patients with vascular disease or diabetes have not, however, shown a reduction of major cardiovascular events, nor have these supplements reduced the risk of recurrent cardiovascular disease after an acute myocardial infarct. It is possible that these trials were not sufficiently powered to detect a small (e.g., 10%) benefit or that another underlying factor is responsible for both the vascular damage and the raised homocysteine. Alternatively, the beneficial effects of lowering homocysteine were offset in these trials by the vitamins stimulating endothelial cell proliferation. Meta-analysis has suggested that folic acid supplementation reduces the risk of stroke by 18%. The results of longer and larger trials are needed to resolve these uncertainties.
Prophylactic folic acid in pregnancy has been found in some but not all studies to reduce the subsequent incidence of acute lymphoblastic leukemia (ALL) in childhood. A significant negative association has also been found with the MTHFR C677T polymorphism and leukemias with mixed lineage leukemia (MLL) translocations, but a positive association with hyperdiploidy in infants with ALL or acute myeloid leukemia or with childhood ALL. A second polymorphism in the MTHFR gene, A1298C, is also strongly associated with hyperdiploid leukemia. There are various positive and negative associations between polymorphisms in folate-dependent enzymes and the incidence of adult ALL. The C677T polymorphism is thought to lead to increased thymidine pools and “better quality” of DNA synthesis by shunting 1-carbon groups toward thymidine and purine synthesis. This may explain its reported association with a lower risk for colorectal cancer. Most but not all studies suggest that prophylactic folic acid also protects against colon adenomas. Other tumors that have been associated with folate polymorphisms or status include follicular lymphoma, breast cancer, and gastric cancer. Because folic acid may “feed” tumors, it probably should be avoided in those with established tumors unless there is severe megaloblastic anemia due to folate deficiency.
Cobalamin deficiency may cause a bilateral peripheral neuropathy or degeneration (demyelination) of the posterior and pyramidal tracts of the spinal cord and, less frequently, optic atrophy or cerebral symptoms.
The patient, more frequently male, presents with paresthesias, muscle weakness, or difficulty in walking and sometimes dementia, psychotic disturbances, or visual impairment. Long-term nutritional cobalamin deficiency in infancy leads to poor brain development and impaired intellectual development. Folate deficiency has been suggested to cause organic nervous disease, but this is uncertain, although methotrexate injected into the cerebrospinal fluid may cause brain or spinal cord damage.
An important clinical problem is the nonanemic patient with neurologic or psychiatric abnormalities and a low or borderline serum cobalamin level. In such patients, it is necessary to try to establish whether there is significant cobalamin deficiency, e.g., by careful examination of the blood film, tests for serum gastrin level and for antibodies to IF or parietal cells, along with serum methylmalonic acid (MMA) measurement if available. A trial of cobalamin therapy for at least 3 months will usually also be needed to determine whether the symptoms improve.
The biochemical basis for cobalamin neuropathy remains obscure. Its occurrence in the absence of methylmalonic aciduria in TC II deficiency suggests that the neuropathy is related to the defect in homocysteine-methionine conversion. Accumulation of S-adenosylhomocysteine in the brain, resulting in inhibition of transmethylation reactions, has been suggested.
Psychiatric disturbance is common in both folate and cobalamin deficiencies. This, like the neuropathy, has been attributed to a failure of the synthesis of SAM, which is needed in methylation of biogenic amines (e.g., dopamine) as well as that of proteins, phospholipids, and neurotransmitters in the brain (Fig. 105-1). Associations between lower serum folate or cobalamin levels and higher homocysteine levels and the development of decreased cognitive function and dementia in Alzheimer's disease have been reported. A 2-year double-blind placebo-controlled randomized clinical trial involving healthy subjects >65 years old given folate, cobalamin, and vitamin B6 supplements showed no benefit for cognitive performance, whereas a 3-year (FACIT) study did show benefit.