Neurologic sequelae from vitamin B 12 deficiency include paresthesias, peripheral neuropathy, and demyelination of the corticospinal tract and dorsal columns subacute combined systems disease. Vitamin B 12 deficiency also has been linked to psychiatric disorders, including impaired memory, irritability, depression, dementia and, rarely, psychosis. Combined systems disease demyelination of dorsal columns and corticospinal tract. In addition to hematologic and neuropsychiatric manifestations, vitamin B 12 deficiency may exert indirect cardiovascular effects.
Similar to folic acid deficiency, vitamin B 12 deficiency produces hyperhomocys-teinemia, which is an independent risk factor for atherosclerotic disease. This possibility becomes especially important when considering vitamin replacement therapy. Folic acid supplementation may mask an occult vitamin B 12 deficiency and further exacerbate or initiate neurologic disease. Therefore, clinicians should consider ruling out vitamin B 12 deficiency before initiating folic acid therapy.
In humans, only two enzymatic reactions are known to be dependent on vitamin B In the first reaction, methylmalonic acid is converted to succinyl-CoA using vitamin B 12 as a cofactor Figure 1.
Vitamin B 12 deficiency, therefore, can lead to increased levels of serum methylmalonic acid. In the second reaction, homocysteine is converted to methionine by using vitamin B 12 and folic acid as cofactors. In this reaction, a deficiency of vitamin B 12 or folic acid may lead to increased homocysteine levels.
Vitamin B 12 deficiency leads to a serum build-up of methylmalonic acid. Deficiency of vitamin B 12 or folic acid can lead to increased homocysteine levels.
Information from Stabler SP. Screening the older population for cobalamin vitamin B 12 deficiency. J Am Geriatr Soc ; An understanding of the vitamin B 12 absorption cycle helps illuminate the potential causes of deficiency.
The acidic environment of the stomach facilitates the breakdown of vitamin B 12 that is bound to food. Intrinsic factor, which is released by parietal cells in the stomach, binds to vitamin B 12 in the duodenum. This vitamin B 12 —intrinsic factor complex subsequently aids in the absorption of vitamin B 12 in the terminal ileum.
In addition to this method of absorption, evidence supports the existence of an alternate system that is independent of intrinsic factor or even an intact terminal ileum. Approximately 1 percent of a large oral dose of vitamin B 12 is absorbed by this second mechanism.
Once absorbed, vitamin B 12 binds to transcobalamin II and is transported throughout the body. The interruption of one or any combination of these steps places a person at risk of developing deficiency Figure 2.
The diagnosis of vitamin B 12 deficiency has traditionally been based on low serum vitamin B 12 levels, usually less than pg per mL pmol per L , along with clinical evidence of disease. However, studies indicate that older patients tend to present with neuropsychiatric disease in the absence of hematologic findings. In a large study 10 of patients with known vitamin B 12 deficiency, Only one patient out of had normal levels of both metabolites, resulting in a sensitivity of Interestingly, 28 percent of the patients in this study had normal hematocrit levels, and 17 percent had normal mean corpuscular volumes.
In another study 13 of patients with known pernicious anemia who had not received maintenance vitamin B 12 injections for months to years, the rise of methylmalonic acid and homocysteine levels was found to precede the decrease in serum vitamin B 12 and the decline in hematocrit. This finding suggests that methylmalonic acid and homocysteine levels can be early markers for tissue vitamin B 12 deficiency, even before hematologic manifestations occur.
Use of methylmalonic acid and homocysteine levels in the diagnosis of vitamin B 12 deficiency has led to some surprising findings.
If increased homocysteine or methylmalonic acid levels and a normalization of these metabolites in response to replacement therapy are used as diagnostic criteria for vitamin B 12 deficiency, approximately 50 percent of these patients have serum vitamin B 12 levels above pg per mL. Other studies have shown similar findings, with the rate of missed diagnosis ranging from 10 to 26 percent when diagnosis is based on low serum vitamin B 12 levels alone. There are, however, a few caveats to keep in mind.
Looking at the reactions that use vitamin B 12 Figure 1 , 3 an elevated methylmalonic acid level is clearly more specific for vitamin B 12 deficiency than an elevated homocysteine level. Vitamin B 12 or folic acid deficiency can cause the homocysteine level to rise, so folic acid levels also should be checked in patients with isolated hyperhomocysteinemia. In addition, folic acid deficiency can cause falsely low serum vitamin B 12 levels.
One study 14 revealed that approximately one third of patients with folic acid deficiency had low serum vitamin B 12 levels—less than pg per mL 74 pmol per L in some patients. Also, methylmalonic acid levels can be elevated in patients with renal disease the result of decreased urinary excretion ; thus, elevated levels must be interpreted with caution. An algorithm for the diagnosis of vitamin B 12 deficiency is provided in Figure 3.
Suggested approach to the patient with suspected vitamin B 12 deficiency. Laboratory diagnosis of vitamin B 12 and folate deficiency. Arch Intern Med ; Once vitamin B 12 deficiency is confirmed, a search for the etiology should be initiated. Causes of vitamin B 12 deficiency can be divided into three classes: nutritional deficiency, malabsorption syndromes, and other gastrointestinal causes Table 2. First, folate deficiency is an unlikely cause of neurologic disease.
Second, the neurologic disease of Cbl deficiency may be irreversible if treatment is withheld or delayed; because Cbl therapy is nontoxic, the risk-benefit ratio favors treatment in questionable cases.
Finally, an apparent response to therapy or lack of response to therapy is less definitive in ruling in or ruling out Cbl deficiency than is the serial measurement of abnormal initial hematologic parameters. Even in patients with a normal complete blood cell count, it may be worthwhile to monitor the MCV after treatment because a significant decline within the normal range provides additional evidence of Cbl deficiency.
An approach to the diagnosis of Cbl deficiency in patients with isolated neurologic findings is outlined in Figure 4. All 12 had elevated levels of serum Hcy and serum MMA. All 5 patients had a clinical neurologic response to Cbl therapy and normalization of metabolite levels.
The accurate diagnosis of Cbl and folate deficiency is a complex task. No easily performed test can reliably serve as a diagnostic gold standard. Consequently, the performance characteristics of the available laboratory tests are difficult to ascertain. In each case, the primary physician must integrate clinical information, laboratory test results, and response to specific treatment and keep in mind the relative risks and benefits of administering or withholding vitamin replacement therapy.
The algorithms in this article should not be considered rigid guides; if diagnostic uncertainty exists, consultation with a hematologist is advisable. Corresponding author: Christopher F. Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy Continue.
Figure 1. View Large Download. Synthesis of methionine from homocysteine. Cbl indicates cobalamin. Table 1. Koop H Review article: metabolic consequences of long-term inhibition of acid secretion by omeprazole. Aliment Pharmacol Ther. Schilling RF The role of the pancreas in vitamin B absorption.
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Diagnosis of cobalamin deficiency, II: relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Norman EJMorrison JA Screening elderly populations for cobalamin vitamin B12 deficiency using the urinary methylmalonic acid assay by gas chromatography mass spectrometry.
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Chanarin I The Megaloblastic Anaemias. This is usually caused by an underlying condition affecting your digestive system, such as coeliac disease.
This can be caused by an underlying condition that affects one of your organs, such as:. Some types of medicines reduce the amount of folate in your body or make the folate harder to absorb. These include some anticonvulsants medicines used to treat epilepsy , colestyramine, sulfasalazine and methotrexate.
Your GP will be aware of medicines that can affect your folate levels and will monitor you if necessary. Your body sometimes requires more folate than normal. This can cause folate deficiency if you cannot meet your body's demands for the vitamin. Premature babies born before the 37th week of pregnancy are also more likely to develop a folate deficiency because their developing bodies require higher amounts of folate than normal.
If you're pregnant or there's a chance you could get pregnant, it's recommended that you take a microgram folic acid tablet every day before pregnancy and until you're 12 weeks pregnant. This will ensure that both you and your baby have enough folate and help your baby grow and develop. Folic acid tablets are available with a prescription from a GP, or you can buy them from pharmacies, large supermarkets and health food stores.
If you're pregnant and have another condition that may increase your body's need for folate, your GP will monitor you closely to prevent you becoming anaemic. In some cases, you may need a higher dose of folic acid. For example, if you have diabetes, you should take a 5 milligrams 5mg supplement of folic acid instead of the standard micrograms.
Find out more about vitamins and nutrition in pregnancy. Page last reviewed: 23 May Next review due: 23 May Causes of vitamin B12 deficiency Pernicious anaemia Pernicious anaemia is the most common cause of vitamin B12 deficiency in the UK.
They are pernicious anaemia, myxoedema and acromegaly. Vitamin B12 is ubiquitous in food and so deficiency is usually due to malabsorption.
Hydroxocobalamin is usually given by parenteral injection in the form of 1 mg in 1 mL. In severe anaemia it may need to be given every week at first but before long this is changed to once every three months and continued for life. There is as yet no evidence-based guidance as to the optimum regime. Serum B12 is not always an accurate reflection of deficiency at a cellular level. Functional vitamin B12 deficiency with normal serum B12 is common in the elderly and is associated with neurocognitive abnormalities, but its cause is unknown [ 6 ].
The use of oral and nasal cobalamin is being researched and may be of value in mild B12 deficiency, particularly in the elderly. Neither preparation is currently available in the UK [ 7 ]. Folic acid is produced in 5 mg tablets. The oral form is usually sufficient, although in severe malabsorption it may be necessary to give it parenterally. The usual dose is 5 mg daily for four months after which a tablet is given between one and seven days a week, depending upon the nature of the malabsorption.
If there is both folate and vitamin B12 deficiency, it is essential to start treating the B12 deficiency before starting folate, or the latter may aggravate the B12 deficiency and precipitate subacute combined degeneration of the cord. As well as treating the deficiency, attention must be paid to the underlying condition. With pernicious anaemia, this usually involves just injections every three months, an annual FBC and a great readiness to investigate any suspicion of gastric malignancy.
Alcoholism diagnosis and management in primary care can be very difficult, not least because of the problem of denial. Am Fam Physician. Guidelines for the diagnosis and treatment of cobalamin and folate disorders ; British Committee for Standards in Haematology
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