| Why is this test done? | This test is done to help diagnose certain types of anemia [pernicious anemia]. It can also detect a problem with vitamin B12 [cyanocobalamin] absorption in the intestine. |
| How to prepare: |
|
| Target Values: |
|
| Associated Tests: | Other tests can be performed at the same time, such as a complete blood count , blood vitamin B12, folate , anti-intrinsic factor antibodies and intrinsic factor. |
General Information
Vitamin B12 is an important vitamin for the body. It plays several roles, especially with hemoglobin and red blood cell production. This vitamin is found in certain foods such as offals, seafood, fish, eggs, dairy products and enriched cereals. For the body to be able to absorb this vitamin a factor must however be present in the intestine. This factor is called intrinsic factor and is produced in the stomach. Certain people do not produce this factor and consequently suffer from vitamin B12 deficiency.
To perform this test, a certain amount of vitamin B12 is injected in the patient. The patient also takes lightly radioactive vitamin B12 by the mouth. Urine produced over the next 24 hours is then collected and analyzed to detect the presence of vitamin B12, making it possible to know if the patient is able to absorb vitamin B12 or not.
What you need to know before the test
Before going for blood tests, a procedure or other exam, it is best to always bring a list of all the drugs you take [prescription, OTC and natural health products]. Unless told otherwise, you should take your medication as usual on the day of the test. When in doubt, ask your pharmacist for more information.
© Copyright Vigilance Santé
The patient information leaflets are provided by Vigilance Santé Inc. This content is for information purposes only and does not in any manner whatsoever replace the opinion or advice of your health care professional. Always consult a health care professional before making a decision about your medication or treatment.
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Journal Article
Ralph Carmel
2Department of Medicine, New York Methodist Hospital, Brooklyn, NY 11215, and Weill Medical College of Cornell University, New York, NY 10021
Author disclosures: R. Carmel, no conflicts of interest.
Search for other works by this author on:
Revision received:
06 August 2007
Published:
01 November 2007
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An appreciation of the physiological peculiarities of cobalamin [vitamin B-12] is indispensable to understanding cobalamin deficiency. Almost alone among B vitamins, cobalamin deficiency is very often linked to failures of absorption [1,2]. Adults rarely become symptomatic or anemic just because of poor dietary intake.
One peculiarity is how tightly the complicated, high-affinity binding protein- and receptor-dependent absorptive process built around gastric intrinsic factor [IF], and around other binding proteins throughout the body, controls every aspect of cobalamin transport and transfer [2]. The IF system assures both delivery from limited animal-derived dietary sources and reabsorption of biliary cobalamin, partially explaining the often muted clinical impact of poor intake. Yet the saturable system's own somewhat limited capacity and subtly restrictive, even exclusionary features [perhaps meant to exclude nonfunctional cobalamin analogs] also create inefficiencies that are not always obvious. Barely >1 μg of cobalamin is made available from most meals no matter their cobalamin content, and then only if the IF-mediated process functions properly [2,3].
The greatest weakness, however, also lies in the heavy dependence of absorption, and thus cobalamin status, on the IF-based system, whose sole back-up, a nonsaturable but dismally inefficient carrier-free diffusion, can transport only 1% of presented cobalamin. Should IF secretion be lost [“pernicious anemia”] or its delivery of cobalamin to IF receptors fail [intestinal malabsorption], it cannot be compensated dietarily except with cobalamin intake so massive as to be unavailable in nature. As much as 1000 μg would need to be ingested daily to compensate for the failure of both absorption and enterohepatic reabsorption by the IF system, but very few food items contain >1–2 μg/100 gm portion [3]. The carrier-mediated and carrier-free absorption processes of most other B vitamins, such as folate, are more effective.
An important saving grace derives from another peculiarity of cobalamin, its slow turnover. Except for rare defects of cellular utilization, whatever causes cobalamin deficiency in adults must persist for several years to deplete body stores [which exceed daily intake 1000-fold] to the point of clinical consequences. Many potential disturbances, whether malabsorptive or not, are too transitory to produce clinical cobalamin deficiency or often even subclinical deficiency, which consists of biochemical changes without apparent clinical consequences [2,4].
Absorption testing
Because a clinical diagnosis of cobalamin deficiency, with hematologic or neurologic changes, implies the presence of long-standing gastrointestinal disease until proven otherwise [1], absorption testing has always been an essential task for clinicians and investigators. The traditional Schilling test, designed in 1953, identifies malabsorption by the poor urinary excretion of an orally administered cobalamin dose. When repeated along with a dose of IF, the test also distinguishes between gastric and intestinal defects. If malabsorptive processes stay undiagnosed, management decisions and vitamin replacement strategies tend to be haphazard and incomplete [Table 1].
TABLE 1
Questions that cannot be answered reliably without determining cobalamin absorption status
| 1. Must cobalamin replacement be lifelong, long term, or short term?1 |
| 2. Is relapse of the deficiency likely? |
| 3. Should cobalamin replacement be conducted with periodic injection or large daily oral doses, or will small oral doses suffice? |
| 4. Are all sources of oral cobalamin or only food-bound cobalamin absorbed poorly? |
| 5. Are other, coexisting nutrient deficiencies likely?2 |
| 6. Does the underlying disorder responsible for cobalamin deficiency require direct treatment itself? Can it be reversed? |
| 7. Which cobalamin-unrelated complications of the underlying disorder itself need monitoring or intervention?3 Are there linked comorbidities or risks? |
| 8. If cobalamin absorption is normal, is the cause of the cobalamin deficiency dietary,4 metabolic [hereditary or acquired], drug-related, or unknown? |
| 9. If the cobalamin deficiency is only subclinical at the time of diagnosis, is it likely to be stationary or to progress?5 |
| 1. Must cobalamin replacement be lifelong, long term, or short term?1 |
| 2. Is relapse of the deficiency likely? |
| 3. Should cobalamin replacement be conducted with periodic injection or large daily oral doses, or will small oral doses suffice? |
| 4. Are all sources of oral cobalamin or only food-bound cobalamin absorbed poorly? |
| 5. Are other, coexisting nutrient deficiencies likely?2 |
| 6. Does the underlying disorder responsible for cobalamin deficiency require direct treatment itself? Can it be reversed? |
| 7. Which cobalamin-unrelated complications of the underlying disorder itself need monitoring or intervention?3 Are there linked comorbidities or risks? |
| 8. If cobalamin absorption is normal, is the cause of the cobalamin deficiency dietary,4 metabolic [hereditary or acquired], drug-related, or unknown? |
| 9. If the cobalamin deficiency is only subclinical at the time of diagnosis, is it likely to be stationary or to progress?5 |
1
Disorders of free-cobalamin malabsorption, especially pernicious anemia, are likely to be permanent and require lifelong treatment, but FCM may not be [nor may dietary inadequacy or acquired disorders of cobalamin metabolism].
2
For example, malabsorption of additional nutrients is likely if intestinal disease is the cause and is less likely if the malabsorption is gastric in origin.
3
Examples of such higher risks include gastric malignancy and thyroid dysfunction in patients with pernicious anemia but not in those with other malabsorptive disorders.
4
Dietary cause is often assumed without evidence or with weak evidence; this is especially frequently done in patients with general malnutrition [even though the duration of malnutrition is often too short to induce cobalamin deficiency] and in population surveys.
5
If asymptomatic subclinical deficiency arises from causes that are irreversible, such as pernicious anemia or some intestinal diseases, it cannot be deemed clinically innocuous and it requires long-term cobalamin treatment. However, to date, cobalamin treatment has not been proven necessary or helpful for subclinical deficiency without underlying malabsorption, and the duration of treatment, if chosen, is unknown [7]. Finally, proof that malabsorption exists also strengthens the likelihood that a suspected mild deficiency is not spurious.
TABLE 1
Questions that cannot be answered reliably without determining cobalamin absorption status
| 1. Must cobalamin replacement be lifelong, long term, or short term?1 |
| 2. Is relapse of the deficiency likely? |
| 3. Should cobalamin replacement be conducted with periodic injection or large daily oral doses, or will small oral doses suffice? |
| 4. Are all sources of oral cobalamin or only food-bound cobalamin absorbed poorly? |
| 5. Are other, coexisting nutrient deficiencies likely?2 |
| 6. Does the underlying disorder responsible for cobalamin deficiency require direct treatment itself? Can it be reversed? |
| 7. Which cobalamin-unrelated complications of the underlying disorder itself need monitoring or intervention?3 Are there linked comorbidities or risks? |
| 8. If cobalamin absorption is normal, is the cause of the cobalamin deficiency dietary,4 metabolic [hereditary or acquired], drug-related, or unknown? |
| 9. If the cobalamin deficiency is only subclinical at the time of diagnosis, is it likely to be stationary or to progress?5 |
| 1. Must cobalamin replacement be lifelong, long term, or short term?1 |
| 2. Is relapse of the deficiency likely? |
| 3. Should cobalamin replacement be conducted with periodic injection or large daily oral doses, or will small oral doses suffice? |
| 4. Are all sources of oral cobalamin or only food-bound cobalamin absorbed poorly? |
| 5. Are other, coexisting nutrient deficiencies likely?2 |
| 6. Does the underlying disorder responsible for cobalamin deficiency require direct treatment itself? Can it be reversed? |
| 7. Which cobalamin-unrelated complications of the underlying disorder itself need monitoring or intervention?3 Are there linked comorbidities or risks? |
| 8. If cobalamin absorption is normal, is the cause of the cobalamin deficiency dietary,4 metabolic [hereditary or acquired], drug-related, or unknown? |
| 9. If the cobalamin deficiency is only subclinical at the time of diagnosis, is it likely to be stationary or to progress?5 |
1
Disorders of free-cobalamin malabsorption, especially pernicious anemia, are likely to be permanent and require lifelong treatment, but FCM may not be [nor may dietary inadequacy or acquired disorders of cobalamin metabolism].
2
For example, malabsorption of additional nutrients is likely if intestinal disease is the cause and is less likely if the malabsorption is gastric in origin.
3
Examples of such higher risks include gastric malignancy and thyroid dysfunction in patients with pernicious anemia but not in those with other malabsorptive disorders.
4
Dietary cause is often assumed without evidence or with weak evidence; this is especially frequently done in patients with general malnutrition [even though the duration of malnutrition is often too short to induce cobalamin deficiency] and in population surveys.
5
If asymptomatic subclinical deficiency arises from causes that are irreversible, such as pernicious anemia or some intestinal diseases, it cannot be deemed clinically innocuous and it requires long-term cobalamin treatment. However, to date, cobalamin treatment has not been proven necessary or helpful for subclinical deficiency without underlying malabsorption, and the duration of treatment, if chosen, is unknown [7]. Finally, proof that malabsorption exists also strengthens the likelihood that a suspected mild deficiency is not spurious.
In 1973, Doscherholmen and Swaim [5] expanded the scope of malabsorption to include food-cobalamin malabsorption [FCM], an inability to release food-bound cobalamin and make it available to gastric IF. FCM cannot be diagnosed with the Schilling test, whose radiolabeled test dose of free cobalamin bypasses the need to release food-bound cobalamin.
Work from many laboratories in the 1980s and early 1990s established that FCM was associated with 30–50% of all low cobalamin levels, a frequency at least 10-fold that of the more clinically ominous malabsorption of free cobalamin that occurs when gastric IF secretion or its uptake by intestinal IF receptors fails [6]. However, the individual impact of FCM on cobalamin status is typically milder and more delayed. That is because FCM affects only a preparatory step and thus compromises rather than abrogates the final IF-mediated steps of absorption [and presumably does not impair reabsorption of biliary cobalamin]. Pernicious anemia, the absence of IF, was originally lethal and even now carries the risk of neurologic deterioration if not properly diagnosed and treated [2,3], whereas most persons with FCM have asymptomatic, subclinical cobalamin deficiency or sometimes no deficiency at all [6,7].
Numerous studies explored absorption testing methods and the mechanisms of FCM, as reviewed elsewhere [6]. It became evident that the mechanisms were more diverse than initially suspected, that FCM does not always require atrophic gastritis and achlorhydria, and that our understanding of FCM and its implications was incomplete [5–7]. As one poorly understood example, the intriguing reversal of FCM after antibiotic treatment has been attributed separately to Helicobacter pylori and facultative anaerobes, although neither organism's role was identified or directly proven [4,7–10]. FCM testing never became clinically available and much work remains to be done [6,7].
The problems today
Despite scientific advances and the reawakened general interest when mild and often subclinical cobalamin deficiency was found to affect much wider swaths of the population than the disruptions of IF function responsible for severe deficiency [e.g. 10–20% vs. 1–2%, respectively, of elderly persons] [2,4,11,12], the diagnosis and study of cobalamin malabsorption have not fared well in the past decade. How diagnosis and study reached their lowest point since the pre-1953 days merits review.
The known relevance of malabsorption to the clinical management and prognosis of deficiency notwithstanding [Table 1], the Schilling test was never popular with patients or some clinicians. It is unwieldy and requires an overnight fast, ingestion of [modestly] radioactive cobalamin, a 24-h collection of urine, a cobalamin injection, 2 trips to the laboratory, and, if the result is abnormal, repetition of the entire procedure with a dose of IF. Like all tests, it has its limitations; it requires normal renal function and complete urine collection and occasionally produces uninterpretable results [13].
To the longstanding frivolous image of cobalamin as the universal placebo, the past decade has added often premature advocacy of diverse preventive benefits of cobalamin [for thrombosis, osteoporosis, memory loss, etc.]. A by-product has been to reduce cobalamin deficiency in many minds from a serious medical disorder to a nonmedical issue satisfied by a random “B-12 shot” or a few pills. A 1983 study reported that 11% of patients with documented pernicious anemia, despite its permanence and serious implications, discontinue treatment or are treated inadequately and suffer relapses [14]; the rate today is unknown. To a receding appreciation of the role of malabsorption, the past decade has added an epidemiological focus on largely subclinical [and often nonmalabsorptive] cobalamin deficiency of uncertain importance within healthy populations, with sometimes incautious extension of its findings and interpretations to medical [and usually malabsorptive] deficiency [4]. Clinicians increasingly faced with asymptomatic patients with purely biochemical abnormalities, and finding normal Schilling test results to far outnumber abnormal ones in them, have grown discouraged or complacent about absorption testing as a whole [my personal observation].
When the manufacturer of the most popular Schilling test kit [Dicopac, Amersham Health] discontinued its licensing in 2003, mainly because of concerns of potential transmission of bovine spongiform encephalopathy via its animal-derived IF dose, much of the medical community's reaction was muted. In fact, requests for the test, whose costs exceeded reimbursement by health insurers, were already in decline. I know of no American manufacturers who provide radioactive cobalamin test doses or IF today.
Given our current ability to recognize a wider range of cobalamin deficiency than ever before [12], the new inability to test absorption has removed a commensurate capacity to differentiate among its many causes and identify the more serious among them. One can hardly distinguish between malabsorptive and nonmalabsorptive origins today, let alone between gastric and intestinal disorders. Testing is attempted infrequently in clinical practice or research and then only with indirect markers for pernicious anemia that lack sensitivity [e.g. serum antibody to IF] or specificity [e.g. serum gastrin, antibody to parietal cells]. Surrogate indicators do not even exist for intestinal causes of malabsorption. The severe diagnostic limitations are ironic in the face of remarkable scientific discoveries, such as the receptor roles of cubilin and amnionless in IF-mediated absorption.
The abandonment of absorption testing has been very harmful for FCM by foreclosing progress in understanding this common entity. Direct testing for FCM, used investigationally more than clinically, largely ceased after 1998. FCM began to be equated routinely with atrophic gastritis. Some investigators then substituted surrogate markers, such as serum pepsinogen, for gastritis and, by extension, FCM [15], even when they had themselves previously reported a poor association between pepsinogen levels and FCM [16]. Serum marker reflections of gastritis often accompany FCM but have such poor sensitivity and specificity as to be diagnostically useless [6,10,16,17]. A study in 1997 [18], faced with discrepancies between results from a mixture of Schilling and food-cobalamin absorption tests and histological evidence of gastric atrophy, went still further. The authors discounted many normal absorption test results, the gold standard, and advocated basing diagnosis of FCM on histological abnormality instead [including duodenal atrophy, which has no known relation to FCM]. Their rationale that normal absorption test results accompanying abnormal histological findings can only mean the test's insensitivity for FCM seems unlikely. Gastric histology is diverse in FCM and overlaps with normal absorption [6–8], whose progression to FCM cannot be assumed.
Of the dozen or more publications studying FCM since 1998, only 3 included absorption testing [8,10,17]. The progression and consequences of lowered standards of evidence are best illustrated by a recent report of responsiveness to low doses of oral cobalamin by patients with FCM in this journal [19]. In it, Blacher et al. [19] diagnosed FCM solely by so-called “Carmel's criteria.” These criteria, a long list of largely unproven, irrelevant, or mistaken assumptions, are not mine, are nowhere to be found or implied in the review paper [6] that was cited as their source, and are dissonant with the existing literature and my work. One such criterion, for example, is simply old age, a category that includes many more persons without FCM than with it and ignores younger adults, in whom FCM is nearly as common [6,7,10]. Among other doubtful criteria, H. pylori infection is very often unaccompanied by FCM [10]; metformin, alcohol abuse, and Ogilvie syndrome have never been proven to cause FCM; and pancreatic insufficiency, bacterial overgrowth, and tropical sprue are associated with abnormal Schilling tests, not with FCM [2,20]. Both the eponym and the criteria were invented by Andrès without subjection to validation or testing for FCM [21–23]. Selective adherence has further compromised them: one of the few valid criteria, the critical requirement that absorption of free cobalamin be proven normal by Schilling test, was applied inconsistently [22] or not at all [19] and is now unavailable. Blacher's [19] and Andrès's [21–23] conclusions that low doses of oral cobalamin suffice in persons with FCM or that patients with FCM often have macrocytic anemia and symptoms contradict most of the literature derived from direct diagnosis. The substantial overdiagnosis of FCM inherent in the “criteria” renders all data and interpretations derived from their application suspect.
Solutions
The conclusion to be drawn from the events of the past decade is that resurrecting cobalamin absorption testing must become a high priority. The restoration of methodologic, scientific, and clinical credibility to the diagnosis and management of cobalamin deficiency will require educational remedies as well as technical ones, because the erosion of confidence by clinicians in the relevance of absorption testing that contributed to the test's disappearance and became ingrained in the years since then must be acknowledged and addressed.
Technical restoration of tests of free cobalamin absorption [e.g. the Schilling test] is the most urgent of the tasks. It could also be the least difficult to achieve. The pressing need for a safe source of IF seems likely to be met with the newly reported recombinant IF [24], which needs careful but expeditious confirmation. Manufacturers will probably be able to restore production of 57Co-labeled cobalamin once the IF source is available, but commercial viability may lag until demand revives. Introduction of 14C-labeled cobalamin [25] may ultimately add the advantage of less exposure to radioactivity once its technical issues are resolved. Suggested alternatives to the Schilling test, such as serum sampling for holo-transcobalamin II after oral cobalamin, await more documentation.
A different challenge is posed by the lack of tests for FCM. The regulatory and technical issues in reintroducing isotopic food-based testing for FCM, as well as optimizing its methodology, seem more daunting than those for the Schilling test but are not insoluble. However, its role in clinical practice is not as clear yet as that of the Schilling test because of the still poorly understood nature and mechanisms of FCM, its slow and often static clinical course, the frequent innocuousness of the subclinical cobalamin deficiency it usually produces, and the potentially massive caseload [6,7].
Nonetheless, scientific precision, represented by direct testing, is all the more, not less, essential in our currently incomplete state of knowledge. No other means exist to better understand FCM and facilitate informed judgments of its clinical application. We know too little of the course and progression of FCM, and much of what we know is anecdotal. Other important unknowns include its geographic distribution [deficiency in poor countries is commonly presumed to be dietary in origin]; the details of the diverse mechanisms that cause or influence it [e.g. the gastric variability, drug effects, and the contributions of H. pylori and other microbes]; and the extent of its impact on cobalamin deficiency. Potentially important clinical and public health implications cannot be addressed adequately without reliable data. Such issues include the value of antibiotics, whether reversing FCM is desirable [and, if so, in whom], who needs high oral doses of cobalamin and who does not, and a nascent discussion of fortification of the diet with cobalamin that must grapple with the paradox that those with the greatest need for cobalamin may be the least able to benefit because of their limited absorptive capacities. The last chapters in the venerable history of this peculiar and fascinating vitamin have not yet been written, but they must be written with scientific rigor.
Restoring confidence among clinicians, investigators, and patients in the benefits of testing absorption when cobalamin deficiency is diagnosed, and sometimes even when it is only suspected, is the most challenging task. Appreciation that malabsorption foretells progression of even mild deficiency lends absorption testing at least as much clinical relevance as the current emphasis on identifying the earliest possible biochemical changes of cobalamin deficiency, which are often evanescent [4,26]. Subclinical deficiency, the most common form of cobalamin deficiency but one whose management has been least studied [2,12], is less likely to be a stationary or fluctuating phenomenon in persons with malabsorption; those with malabsorbtion may be the only subclinically deficient persons who unquestionably require cobalamin treatment. Rational treatment decisions and assessments of prognosis, expectations, and comorbidities are most likely when we know, rather than assume, what caused the cobalamin deficiency [Table 1].
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© 2007 American Society for Nutrition
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