BMJ Clinical Review: General Medicine, Haematology andRheumatology
BMJ Clinical Review: General Medicine, Haematology andRheumatology
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| ISBN-13: | 9781472744180 |
|---|---|
| Publisher: | BPP Learning Media Ltd |
| Publication date: | 09/30/2015 |
| Series: | BMJ Clincial Review Series |
| Sold by: | Barnes & Noble |
| Format: | eBook |
| File size: | 10 MB |
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BMJ Clinical Review General Medicine, Heamatology and Rheumatology
By Babita Jyoti, Ahmed Hamad
BPP Learning Media Ltd
Copyright © 2015 BPP Learning Media LtdAll rights reserved.
ISBN: 978-1-4727-4418-0
CHAPTER 1
Vitamin B12 deficiency
Alesia Hunt, haematology specialist registrar, Dominic Harrington, consultant clinical scientist, and scientific director of Viapath LLP, Susan Robinson, haematology consultant
Vitamin B12 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. Intracellular conversion of vitamin B12 to two active coenzymes, adenosylcobalamin in mitochondria and methylcobalamin in the cytoplasm, is necessary for the homeostasis of methylmalonic acid and homocysteine, respectively. Methylmalonic acid is converted into succinyl-CoA, of which vitamin B12 is a cofactor for the reaction. Homocysteine is biosynthesised from methionine then resynthesised into methionine or converted into amino acid cysteine.
Vitamin B12 (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 B12 deficiency.
What causes vitamin B12 deficiency?
Foods containing vitamin B12 are derived only from animals: meat, fish, and dairy. The daily Western diet contains around 5-30 µg of vitamin B12 daily, of which 1-5 µg is absorbed. The UK government recommends a daily intake of 1.5 µg of vitamin B12, with the European Union recommending 1 µg and the United States recommending 2.4 µg. Body storage is relatively high, about 1-5 mg. Therefore deficiency from diminished intake or absorption may not manifest for several years after the depletion of stores. Box 1 outlines the common causes of vitamin B12 deficiency.
Who gets vitamin B12 deficiency and how common is it?
Deficiency can manifest in different groups as a result of periods when requirements are increased, such as during growth in children and adolescence or in pregnancy. Certain groups may have reduced intake, such as those with poor nutrition, older people, or people who adhere to a vegan or vegetarian diet.
In the United Kingdom and United States the prevalence of vitamin B12 deficiency is around 6% in people aged less than 60 years, and closer to 20% in those aged more than 60 years. Across Latin America approximately 40% of children and adults have clinical or subclinical deficiency. The prevalence of deficiency is much higher in African and Asian countries — for example, 70% in Kenyan schoolchildren, 80% in Indian preschool children, and 70% in Indian adults. In vegan and vegetarian groups the rates vary — in the United Kingdom, 11% of vegans are deficient in vitamin B12 and in Ethiopia 62% of vegetarian pregnant women are deficient.
What is the pathophysiology of vitamin B12 deficiency?
In serum, vitamin B12 is bound to haptocorrin as holohaptocorrin (formally transcobalamin III) and to transcobalamin as holotranscobalamin. Holohaptocorrin accounts for 80-94% of endogenous plasma vitamin B12. Holotranscobalamin on the other hand accounts for 6-20% of bound vitamin B12. It is synthesised in enterocytes and, through receptor mediated endocytosis, is responsible for uptake of vitamin B12 from the ileum into the blood as well as into other cells. Only vitamin B12 bound as holotranscobalamin is presented for cellular uptake. The malabsorption of this holotranscobalamin protein-bound vitamin B12 results in vitamin B12 deficiency in several cases.
Intrinsic factor is a protein, produced by the parietal cells of the cardiac and fundic mucosa of the stomach. It binds vitamin B12 to allow its absorption through the gastrointestinal tract, by way of a receptor on the intrinsic factor that is specific to cells at the terminal ileum. If there is resection or disease of the gastric mucosa or terminal ileum this leads to vitamin B12 deficiency as a result of malabsorption.
Pernicious anaemia is an autoimmune disease with atrophy of the gastric mucosa of the body and fundus of the stomach. This reduces the number of parietal cells that produce the intrinsic factor necessary for absorption of vitamin B12. Secretion of intrinsic factor parallels gastric acid; thus there will be reduced secretion in an alkaline environment created by the long term use of high dose proton pump inhibitors and similar drugs. Figure 1 illustrates the normal mechanism of vitamin B12 absorption.
What are the clinical features of vitamin B12 deficiency?
The clinical manifestations of vitamin B12 deficiency (fig 2), represent the effects of depletion on multiple systems and vary greatly in severity. The clinical manifestations are heterogeneous but can also be different depending on the degree and duration of deficiency.
Mild deficiency manifests as fatigue and anaemia, with indices suggesting B12 deficiency but an absence of neurological features. Moderate deficiency may include an obvious macrocytic anaemia with, for example, glossitis and some mild or subtle neurological features, such as distal sensory impairment. Severe deficiency shows evidence of bone marrow suppression, clear evidence of neurological features, and risk of cardiomyopathy. However, it is important to recognise that clinical features of deficiency can manifest without anaemia and also without low serum vitamin B12 levels. In these cases treatment should still be given without delay.
Bone marrow
The bone marrow is most commonly affected. Anaemia may range from mild to severe, with symptoms of fatigue on exertion, dyspnoea, palpitations, and pallor. All cell lines can be affected, with macrocytic anaemia, low white cell count or neutropenia, and thrombocytopenia.
Tissues and organ dysfunction
Epithelial changes with vitamin B12 deficiency include skin hyperpigmentation and glossitis. Reproductive tissue can be affected, manifesting as infertility. Deficiency can also result in osteoporosis, with reduced bone derived alkaline phosphatase and plasma osteocalcin. Rarely, cardiomyopathy can occur.
Neurological features
Neurological impairment includes motor disturbances, sensory loss, abnormal balance and reflexes, cognitive impairment, and memory loss. Extreme cases may present with stupor or psychosis. An estimated 20% of patients with neurological signs do not manifest anaemia. Clinical features of anaemia may be minimal and the blood indices may not reflect important anaemia. Neurological symptoms can occur in isolation so it is important to consider a diagnosis of vitamin B12 deficiency in the presence of neurological symptoms of unknown cause, as neurological features may progress and become irreversible.
Subacute combined degeneration of the spinal cord involves demyelination of the posterior and lateral tracts. Initial bilateral peripheral neuropathy can progress to axonal degeneration and neuronal death if left untreated. This is followed by disturbances of proprioception, vibratory sense, and areflexia. Patients may mention clumsiness, poor coordination, and difficulty walking. Without treatment, weakness and stiffness may develop, manifesting as spastic ataxia. Damage to peripheral nerves results in sleepiness, altered taste and smell, and optic atrophy. In severe deficiency or advanced stages, a dementia-like illness may be seen, and frank psychosis with hallucinations, paranoia, and severe depression.
Which investigations should be carried out to determine vitamin B12 deficiency?
Several investigations reflecting physiological, static, and functional B12 status are available (table). Box 2 outlines when testing for vitamin B12 deficiency should be considered.
There is still no ideal test for measuring vitamin B12 deficiency. Measuring the serum cobalamin level remains the preferred choice. Second line tests include measuring plasma methylmalonic acid levels, which can help clarify uncertainties of underlying biochemical and functional deficiencies. Serum holotranscobalamin has an indeterminate "grey area" and therefore should be correlated with testing for methylmalonic acid. Testing for plasma homocysteine may be helpful but is less specific than for methylmalonic acid. Furthermore, given the variety of laboratory techniques and assay, reference ranges are established locally, resulting in an inability of definitive definitions for clinical and subclinical deficiency states.
Physiological investigations
Investigations that may allude to physiological changes reflecting vitamin B12 deficiency include full blood count (mean cell volume and haemoglobin), reticulocyte count, blood film, and lactate dehydrogenase. Macrocytosis is the most common trigger for checking vitamin B12 status. Bone marrow biopsy is rarely required but may be indicated in selective cases where the diagnosis is unclear or blood indices show that the patient is not responding to adequate treatment (fig 3).
Patients with a concomitant iron deficiency may not develop the morphological features of vitamin B12 deficiency until the iron deficiency has resolved. Macrocytosis may also be absent or masked by thalassaemia trait. The diagnostic algorithim in figure 4 can be used to interpret the results of the full blood count and haematinic tests.
Vitamin B12 level
Vitamin B12 level is actually a measurement of serum cobalamin. Measurement of vitamin B12 in serum is the most common assay used to evaluate vitamin B12 levels. The test, however, also measures both serum holohaptocorrin and serum holotranscobalamin, and as such may mask true deficiency or falsely imply a deficient state. The test is widely available at low cost and uses an automated method and competitive-binding immune chemiluminescence.
The clinically normal level for serum cobalamin is not completely clear. It has been suggested that serum cobalamin <148 pmol/L (200 ng/L) would be sensitive enough to diagnose 97% of patients with vitamin B12 deficiency. It is not clear what level of serum cobalamin may represent subclinical deficiency.
Holotranscobalamin
Holotranscobalamin, the metabolically active form of vitamin B12, can be measured by immunoassay. Reference ranges depend on the individual assay, according to the specific laboratory. The theoretical merits of measuring the levels of holotranscobalamin have been known for many years but it is only recently that an assay suited to routine use, known as active B12, has become available. Emerging evidence indicates that a low level of holotranscobalamin is a more reliable marker of impaired vitamin B12 status than is a low level of serum vitamin B12. Holotranscobalamin may be the earliest marker for vitamin B12 depletion. This test is increasingly being adopted; however, discrepancies remain about mode of application and assignment of cut-off values. A second confirmatory test, such as for methylmalonic acid levels, is recommended if the result is in the intermediate range.
Methylmalonic acid
The conversion of methylmalonic acid to succinyl-CoA requires B12 as a cofactor and hence accumulation occurs if B12 is not available. An increase in methylmalonic acid level is an indicator of vitamin B12 deficiency in tissue and this persists for several days even after replacement is started. Measurement of methylmalonic acid may be the most representative marker of metabolic vitamin B12 insufficiency. The interpretation in older patients (>65 years) and those with impaired renal function is, however, potentially challenging because levels can be falsely increased. High levels of plasma methylmalonic acid, however, usually indicate cobalamin deficiency. Methylmalonic acid is measured using gas chromatography mass spectrometry, a high cost test.
Total homocysteine
Plasma total homocysteine levels are increased in B12 deficiency. Plasma total homocysteine can increase early in the course of deficiency. It is a sensitive but non-specific marker and it is also high in folate deficiency, B 6 deficiency, renal failure, and hypothyroidism. Most laboratories regard levels >15 µmol/L as high, although the reference range depends on the individual technique. The sample must be processed within two hours, which may inhibit the usefulness of the test.
Identifying the cause of vitamin B12 deficiency
Once a diagnosis of vitamin B12 deficiency is identified, history taking and examination are important (see fig 3). If there is no obvious dietary lack of vitamin B12 or malabsorption, tests for intrinsic factor and antiparietal cell antibodies should be performed to exclude pernicious anaemia.
How is vitamin B12 deficiency treated?
Timing of treatment
It is usually acceptable to start treatment within a few days of a confirmed diagnosis (box 3 summarises treatment and management). If there are neurological disturbances then treatment should be expedited and started without delay. Specialist input should be sought in the event of neurological features, including impaired cognitive state (box 4). Neurological presentation may occur in the absence of haematological changes, with early treatment essential to avoid permanent neurological disability. Emergency treatment with packed red cell transfusion may be required for major anaemia in the presence of cardiovascular compromise.
Parenteral treatment
Data from randomised controlled trials and observational studies for parenteral treatment are lacking; however, the expert consensus for standard treatment in the United Kingdom is to begin parenteral treatment with intramuscular hydroxocobalamin. This bypasses the possibility of the debate about whether the treatment will be adequately taken, absorbed, and metabolised. Standard initial treatment for patients without neurological involvement is 1000 µg intramuscularly three times a week for two weeks. If there are neurological symptoms then 1000 µg intramuscularly on alternate days should be continued for up to three weeks or until there is no further improvement. In irreversible cases, for example, pernicious anaemia, the treatment should be continued for life. For temporary causes, such as pregnancy, the treatment can be reviewed when the patient is fully replete and the causative agent removed.
Hydroxocobalamin is generally well tolerated. Rarely, side effects include itching, exanthema, chills, fever, hot flushes, nausea, dizziness, and very rarely anaphylaxis. There can be a cross over reaction to cobalamin; if there is concern about this then the drug should be administered in a place where hypersensitivity can be managed, with hydrocortisone and chlorphenamine cover available.
Oral treatment
Cyanocobalamin is an oral preparation that can be given at a dose of 50-150 µg daily, as licensed and outlined in the British National Formulary. The duration is determined by the cause of the deficiency. If the cause is irreversible then parental therapy should be continued for life. This is a drug preparation requiring conversion to metabolically active cobalamins. A Cochrane review of two randomised controlled trials in 108 people with vitamin B12 deficiency found that high oral doses of B12 (1000 µg and 2000 µg daily) were as effective as intramuscular treatment in achieving haematological and neurological responses. However, UK national consensus is that there are arguments against the use of oral cobalamin in severely deficient patients and those with malabsorption. High dose oral cobalamin may be a suitable alternative in selective cases, where intramuscular injections are not tolerated and compliance is not a problem, as previously described.
Oral treatment may be considered in certain situations — for example, in mild or subclinical deficiency with no clinical features and when absorption and compliance are definitely not a problem.
Treatment with vitamin B12 leads to the production of new erythrocytes, which results in an intracellular influx of potassium. This may produce severe hypokalemia, which requires monitoring and appropriate treatment.
(Continues...)
Excerpted from BMJ Clinical Review General Medicine, Heamatology and Rheumatology by Babita Jyoti, Ahmed Hamad. Copyright © 2015 BPP Learning Media Ltd. Excerpted by permission of BPP Learning Media Ltd.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
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Table of Contents
Contents
About the publisher,About The BMJ,
About the editors,
Introduction to General Medicine, Haematology and Rheumatology,
Vitamin B12 deficiency Alesia Hunt, Dominic Harrington, Susan Robinson,
Assessment and management of alcohol use disorders Ed Day, Alex Copello, Martyn Hull,
Acute altitude illnesses Chris Imray, Adam Booth, Alex Wright, Arthur Bradwell,
Non-cardiovascular effects associated with statins Chintan S Desai, Seth S Martin, Roger S Blumenthal,
Management of paracetamol poisoning Robin E Ferner, James W Dear, D Nicholas Bateman,
Viral meningitis Sarah A E Logan, Eithne MacMahon,
Guillain-Barré syndrome John B Winer,
An approach to the evaluation and management of syncope in adults Steve W Parry, Maw Pin Tan,
Nephrotic syndrome in adults Richard P Hull, David J A Goldsmith,
Hyperkalaemia Moffat J Nyirenda, Justin I Tang, Paul L Padfield, Jonathan R Seckl,
Refeeding syndrome: what it is, and how to prevent and treat it Hisham M Mehanna, Jamil Moledina, Jane Travis,
Managing health problems in people with intellectual disabilities Henny M J van Schrojenstein Lantman-de Valk, Patricia Noonan Walsh,
Managing the care of adults with Down's syndrome Kristin M Jensen, Peter D Bulova,
Management of deep vein thrombosis and prevention of post-thrombotic syndrome R H W Strijkers, A J Ten Cate-Hoek, S F F W Bukkems, C H A Wittens,
Heparin induced thrombocytopenia Lori-Ann Linkins,
Diagnosis and management of heritable thrombophilias Peter MacCallum, Louise Bowles, David Keeling,
Management of sickle cell disease Mariane de Montalembert,
Management of sickle cell disease in the community Valentine Brousse, Julie Makani, David C Rees,
The diagnosis and management of erythrocytosis Clodagh Keohane, Mary Frances McMullin, Claire Harrison,
Diagnosis and management of thalassaemia M Peters, H Heijboer, F Smiers, P C Giordano,
Diagnosis and management of haemophilia Karin Fijnvandraat, Marjon H Cnossen, Frank W G Leebeek, Marjolein Peters,
Leukaemia update. Part 1: diagnosis and management Nicholas F Grigoropoulos, Roger Petter, Mars B Van 't Veer, Mike A Scott, George A Follows,
Leukaemia update. Part 2: managing patients with leukaemia in the community Nicholas F Grigoropoulos, Roger Petter, Mars B Van 't Veer, Mike A Scott, George A Follows,
Multiple myeloma Dean Smith, Kwee Yong,
Transfusing blood safely and appropriately Michael F Murphy, Jonathan H Waters, Erica M Wood, Mark H Yazer,