Vitamin B12 Deficiency - References for Diagnosis and Treatment

Symptoms of Vitamin B12 Deficiency

The Gluten File


Malabsorption is common in gluten sensitivity and/or celiac disease causing a variety of nutritional deficiencies and related symptoms, including B12 deficiency. B12 deficiency can cause many neurological and other symptoms, and left untreated it can cause irreversible brain and nerve damage. If diagnosed and treated early, most of the symptoms are reversible.

Vitamin B12 deficiency is most often associated with another autoimmune disease, Pernicious Anemia (actual anemia is absent in 25-30%). If one has Pernicious Anemia they must supplement life long with 1000-2000mcg oral B12, because they lack the intrinsic factor needed to utilize B12.

Theoretically, in celiac disease, a B12 deficiency will eventually self correct once the intestinal damage is healed. However, because it is very possible to have co-existing Pernicious Anemia, one should never risk stopping B12 supplements without careful monitoring of B12 levels...for the rest of your life.

B12 deficiency is also on the increase because of the overuse of antacids, that can block absorption of many important nutrients. Other drugs, including Metformin and birth control pills, are associated with vitamin B12 depletion.  It is also seen in those who have had gastric surgery. B12 deficiency is common in the elderly patient, but can occur at any age. The articles below outline the many possible causes of B12 deficiency, diagnostics, etc.

Symptoms of B12 deficiency can mimic those of MS, Lupus, Lyme Disease, Alzheimer's Disease, and more.

Please visit  Rose's site about B12 deficiencyShe suffered extensive damage from a B12 deficiency that went undiagnosed for much too long, and she has devoted much of her life since educating patients and practitioners about B12 deficieny. She taught me everything I know, and much of what is on this page is thanks to her. Thank you, Rose.

The following tests may be used to diagnose B12 deficiency. A B12 serum level in isolation is not the most useful measure.

  B12 serum level

  holotranscobalamin+ (holoTC)

  methylmalonic acid* (MMA)

  homocysteine*  (HCY)

+ holotranscobalamin (holoTC) is a newer test that measures "metabolically active B12", now available commercially.

* an elevation in MMA or Hcy can indicate a functional B12 deficiency even with normal B12 levels.  High MCV (cell volume) can also indicate B12 deficiency.

Active B12: a rapid, automated assay for holotranscobalamin on the Abbott AxSYM analyzer.
PMID: 18178666  Mar 2008

CONCLUSION: Our data support the concept that the measurement of holoTC and MMA provides a better index of cobalamin status than the measurement of total vitamin B12. HoloTC is the most sensitive marker, followed by MMA. The use of holoTC and MMA enables us to differentiate between storage depletion and functional vitamin B12 deficiency. Renal patients have a higher requirement of circulating holoTC. In renal dysfunction, holoTC cannot be used as a marker of vitamin B12 status.
Functional vitamin B12 deficiency and determination of holotranscobalamin in populations at risk.

PMID: 14656029 Nov 2003

Lab Tests Online - B12 Deficiency
: B12 level, methylmalonic acid, homocysteine, intrinsic factor antibody, parietal cell antibody, MCV

Related Articles:

eMedicine link on vitamin B12 associated neurological diseases:

eMedicine on Nutritional Neuropathy

AAFP on Vitamin B12 Deficiency

PDRHealth on Vitamin B12

Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings JNNP

Emedicine on Pernicious Anemia

Metformin Linked to Vitamin B12 deficiency

Sjögren's syndrome: a potential new aetiology of mild cobalamin deficiency


Life Extensions magazine article on B12

Just a good story!

The experts speak 

On Diagnosis......

From: Laboratory Diagnosis of Vitamin B12 and Folate Deficiency
A Guide for the Primary Care Physician
Christopher F. Snow, MD

"As discussed above, patients with Cbl deficiency may have overt neurologic disease in the absence of hematologic findings. Patients with neurologic symptoms and signs and a normal complete blood cell count
require a modified diagnostic approach because of several considerations. 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 non-toxic, the risk-benefit ratio favors treatment in questionable cases. "

From: AAFP on Vitamin B12 Deficiency
"Diagnosis of vitamin B12 deficiency is typically based on measurement of serum vitamin B12 levels; however, about 50 percent of patients with subclinical disease have normal B12 levels."

Disorders of cobalamin (Vitamin B12) metabolism:Emerging concepts in pathophysiology, diagnosis and treatment  Lawrence R. Solomon,  2006
"Since cobalamin, methylmalonic acid and homocysteine levels fluctuate and neither predict nor preclude responses to cobalamin, cobalamin therapy is suggested for symptomatic patients regardless of the results of these diagnostic tests."

On Dosage and Form...

On dosage, from:
Vitamin B12 Deficiency
ROBERT C. OH, CPT, MC, USA, U.S. Army Health Clinic, Darmstadt, Germany
DAVID L. BROWN, MAJ, MC, USA,Madigan Army Medical Center, Fort Lewis,Washington

"Contrary to prevailing medical practice, studies show that supplementation with oral vitamin B12 is a safe and effective treatment for the B12 deficiency state. Even when intrinsic factor is not present to aid in the absorption of vitamin B12 (pernicious anemia) or in other diseases that affect the usual absorption sites in the terminal ileum, oral therapy remains effective.

"Although the daily requirement of vitamin B12 is approximately 2 mcg, the initial oral replacement dosage consists of a single daily dose of 1,000 to 2,000 mcg (Table 4). This high dose is required because of the variable absorption of oral vitamin B12 in doses of 500 mcg or less.19 This regimen has been shown to be safe, costeffective, and well tolerated by patients."

Regarding oral B12:
Goldman: Cecil medical textbook --- Saunders 2000
"One option is intramuscular or subcutaneous administration of cyanocobalamin. . . . Oral cobalamin therapy in a dose of 1000 to 2000 mug/day has recently been shown to be as effective and possibly superior to the standard parenteral regimen. Both regimens give prompt and equivalent hematologic and neurologic responses, but post-treatment serum cobalamin levels are significantly higher and post-treatment methylmalonic acid levels are significantly lower with the oral regimen. Oral cobalamin, 1000 to 2000 mug [mcg]/day, is the treatment of choice for most patients."

On Neurological Manifestations...
From: The Neurological Manifestations of Gastrointestinal Disease by Mark Skeen, MD.
Neurologic Clinics
Volume 20 € Number 1 € February 2002
"Neurologic manifestations of cobalamin deficiency are now frequently recognized in the absence of anemia or other significant hematologic manifestations.[51] [61] [88] [151] Cobalamin levels were previously considered 100% sensitive in detecting deficiency. Numerous recent reports demonstrate symptomatic cobalamin deficiency in the presence of normal or borderline cobalamin levels.[89] [106] [151] Subacute combined degeneration has also been reported in a patient with a high serum vitamin B12 level and an abnormal plasma vitamin B12 -binding protein.[130] Serum methylmalonic acid and homocysteine levels rise as a marker of tissue deficiency of cobalamin and decline in response to therapy.[81] [89] [106]"
"The most common manifestations are paresthesias, ataxia, memory loss, and
extremity weakness.[88] Cerebral symptoms are reported frequently and on
occasion they are the only manifestation.[88] Subacute combined degeneration
of the spinal cord occurs, with degeneration of dorsal columns and
corticospinal tracts. In many patients, peripheral neuropathy accompanies
spinal cord manifestations, and paresthesias and loss of vibratory sensation
may result from either or both pathologic processes. Although it is
frequently difficult to distinguish which site of pathology is primarily
responsible for distal sensory changes, some studies have demonstrated the
existence of mixed axonal and demyelinating sensorimotor neuropathies.[41]
[104] "
"Subacute combined degeneration has also been reported in a patient with a
high serum vitamin B12 level and an abnormal plasma vitamin B12 -binding
protein.[130] Serum methylmalonic acid and homocysteine levels rise as a
marker of tissue deficiency of cobalamin and decline in response to
therapy.[81] [89] [106] Although serum methylmalonic acid level appears to
be the most sensitive single test for tissue deficiency, further sensitivity
results from the determination of both metabolites.[81] [89] [106] In
addition, the demonstration of falling metabolite levels after therapy adds
diagnostic certainty in atypical cases.[89]
"Although rare patients may demonstrate an exacerbation of neurologic
manifestations soon after beginning therapy, these patients subsequently
respond to therapy
. Most patients respond dramatically to therapy, with a
decrease in paresthesias beginning within a few days of therapy and maximal
improvement within 1 to 3 months. Other neurologic manifestations begin to
improve in 2 to 4 weeks, with maximal response within 6 months.[61]
et al reported one patient in whom objective functional improvement in signs
of myelopathy occurred beyond the third year of treatment.[61] Recovery is
inversely related to the severity and duration of symptoms prior to

From: Highlights of the 2004 American Neurological Association Meeting
Vitamin B12 Deficiency
"Vitamin B12 (cobalamin) deficiency, whether related to nutritional or gastrointestinal disorders, remains an important cause of neurologic complaints. The deficiency may present with a variety of manifestations, including effects on any aspect of the nervous system. Unfortunately, vitamin B12 deficiency may present a diagnostic challenge in that serum cobalamin levels may be normal. Thus, the detection of elevated methylmalonic acid (MMA) may add sensitivity to the diagnosis."

PubMed Abstracts

On Diagnostics

Serum B(12), homocysteine and methylmalonic acid levels are unreliable predictors of B(12)-responsive neurologic disorders, and should be thoroughly investigated and presumptively treated in patients with unexplained leukoencephalopathy because even long-standing deficits may be reversible.
Vitamin B12-responsive severe leukoencephalopathy and autonomic dysfunction in a patient with "normal" serum B12 levels.
PMID: 20587489  June 2010

CONCLUSION: Homocysteine levels are dependent on Marsh classification and the regular use of B-vitamin supplements is effective in reduction of homocysteine levels in patients with celiac disease and should be considered in disease management.
Effect of B vitamin supplementation on plasma homocysteine levels in celiac disease. 
PMID: 19248194  Feb 2009

Pernicious anemia, caused by a deficiency in intrinsic factor, is a rare cause of vitamin B12 deficiency. The most frequent causes are gastric disorders, pancreatic insufficiency, or chronic drug treatment (proton pump inhibitors or metformin) that interfere with the digestion of vitamin B12 digestion, or disorders of the ileum mucosa reducing the absorption of vitamin B12. Oral treatment of vitamin B12 deficiency is possible whatever the etiology, but it has only been validated in small series. Parenteral treatment remains indicated for severe neurologic deficits or whenever patient adherence with treatment is doubtful.
[Vitamin B12 deficiency: a challenging diagnosis and a secret treatment]
PMID: 19024576  Dec 2008

CONCLUSIONS: B12 status declines during prolonged PPI use in older adults, but not with prolonged H2 blocker use; supplementation with RDA amounts of B12 do not prevent this decline. This report reinforces that B12 deficiency is common in the elderly and suggests that it appears prudent to monitor periodically B12 status while on prolonged PPI use, to enable correction before complications ensue.
Do acid-lowering agents affect vitamin B12 status in older adults?
J Am Med Dir Assoc
. 2008 Mar;9(3):162-7.
PMID: 18294598  Mar 2008

How do we evaluate a marginally low B12 level?
PMID: 17217902  Jan 2007

Two Cases of Subacute Combined Degeneration: Magnetic Resonance Findings.
PMID: 17220583  2006

[Diagnosis of vitamin B12 deficiency revised]
PMID: 16385831  Dec 2005

[Vitamin B12 deficiency. New data on an old theme]
PMID: 16395986 Sep 2005

A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults.
PMID: 15135846  April 2004

Ambulatory care increased vitamin B12 requirement associated with chronic acid suppression therapy. 
PMID: 12659601  April 2003

Vitamin B(12) deficiency associated with histamine(2)-receptor antagonists and a proton-pump inhibitor.
PMID: 11978157  May 2002

Low serum vitamin B12 is common in coeliac disease and is not due to autoimmune gastritis
PMID: 11943958 April 2002

Vitamin B12 deficiency in untreated celiac disease. 
PMID: 11280545  Mar 2001

On Oral Dosing

TAKE HOME MESSAGE: Our experience and the present analysis support the use of oral cobalamin therapy in clinical practice.
Efficacy of oral cobalamin (vitamin B12) therapy.
Andrès E, Fothergill H, Mecili M.
Expert Opin Pharmacother. 2010 Feb;11(2):249-56.PMID: 20088746

High daily doses of oral vitamin B12 with ongoing clinical surveillance appear to be as effective as intramuscular treatment.
Evidence for the use of intramuscular injections in outpatient practice.
PMID: 19235496  Feb 2009

One study used a daily oral dosage of 2,000 mcg,
and the other an oral dosage of 1,000 mcg daily for 10 days, then weekly for four weeks, then monthly for life. In both studies, high-dose oral B12 was as effective as intramuscular injection at achieving neurologic and hematologic response.
Is oral vitamin B12 as effective as intramuscular injection?
PMID: 16417065  Jan 2006

Comparing costs of intramuscular and oral vitamin B12 administration in primary care: A cost-minimization analysis.

Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials.
PMID: 16585128  June 2006

Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. 
PMID: 15911731  May 2005

On Neurologic Manifestations

Leukoencephalopathy and autonomic dysfunction have been described in individuals with very low serum B(12) levels (<200 pg/ml), in addition to psychiatric changes, neuropathy, dementia and subacute combined degeneration. Elevated homocysteine and methylmalonic acid levels are considered more sensitive and specific for evaluating truly functional B(12) deficiency. A previously healthy 62-year-old woman developed depression and cognitive deficits with autonomic dysfunction that progressed over the course of 5 years. The patient had progressive, severe leukoencephalopathy on multiple MRI scans over 5 years. Serum B(12) levels ranged from 267 to 447 pg/ml. Homocysteine and methylmalonic acid levels were normal. Testing for antibody to intrinsic factor was positive, consistent with pernicious anaemia. After treatment with intramuscular B(12) injections (1000 mug daily for 1 week, weekly for 6 weeks, then monthly), she made a remarkable clinical recovery but remained amnesic for major events of the last 5 years. Repeat MRI showed partial resolution of white matter changes. Serum B(12), homocysteine and methylmalonic acid levels are unreliable predictors of B(12)-responsive neurologic disorders, and should be thoroughly investigated and presumptively treated in patients with unexplained leukoencephalopathy because even long-standing deficits may be reversible.
Vitamin B12-responsive severe leukoencephalopathy and autonomic dysfunction in a patient with "normal" serum B12 levels.
PMID: 20587489  June 2010

Metformin-Induced Vitamin B12 Deficiency Presenting as a Peripheral Neuropathy.
PMID: 20134380Feb 2010

Results. Fifty-seven patients (88%) completed the trial. The tHcy level was baseline median 11.7 mumol/L (7.4 -23.0), significantly higher than in matched population controls (10.2 mumol/L (6.7-22.6) (P<0.01). Following vitamin supplementation, tHcy dropped a median of 34% (P<0.001), accompanied by significant improvement in well-being (P<0.01), notably Anxiety (P<0.05) and Depressed Mood (P<0.05) for patients with poor well-being. Conclusions. Adults with longstanding coeliac disease taking extra B vitamins for 6 months showed normalized tHcy and significant improvement in general well-being, suggesting that B vitamins should be considered in people advised to follow a gluten-free diet.
Clinical trial: B Vitamins improve health in coeliac patients living on a gluten-free diet.
PMID: 19154566 Jan 2009

Finally, high-dose cobalamin therapy may have salutary pharmacologic effects on neurologic function in a variety of disorders. Many studies lacked appropriate control groups. However, at this time, therapeutic trials with pharmacologic doses of cobalamin are suggested when findings consistent with cobalamin deficiency are present regardless of the results of diagnostic tests.
Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment.
PMID: 16814909  May 2007

Down beat nystagmus in vitamin B 12 deficiency syndrome.
PMID: 16795999 Apr 2006

[Reversible peripheral neuropathy induced by vitamin B12 deficiency]
PMID: 16530131 Jan 2006

Cobalamine deficiency associated with neuropathy and oral mucosal melanosis in untreated gluten-sensitive enteropathy.
PMID: 16041109 June 2005

Multiple Sclerosis (MS) and vitamin B12 deficiency share common inflammatory and neurodegenerative pathophysiological characteristics. Due to similarities in the clinical presentations and MRI findings, the differential diagnosis between vitamin B12 deficiency and MS may be difficult. Additionally, low or decreased levels of vitamin B12 have been demonstrated in MS patients. Moreover, recent studies suggest that vitamin B12, in addition to its known role as a co-factor in myelin formation, has important immunomodulatory and neurotrophic effects. These observations raise the questions of possible causal relationship between the two disorders, and suggest further studies of the need to close monitoring of vitamin B12 levels as well as the potential requirement for supplementation of vitamin B12 alone or in combination with the immunotherapies for MS patients.
Vitamin B12, demyelination, remyelination and repair in multiple sclerosis.
PMID: 15896807 May 2005

Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the association. On the basis of current data, we suggest that oral doses of both folic acid (800 microg daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression.
Treatment of depression: time to consider folic acid and vitamin B12.
PMID: 15671130 Jan 2005

Psychiatric manifestations are frequently associated with pernicious anemia including depression, mania, psychosis, dementia. We report a case of a patient with vitamin B12 deficiency, who has presented severe depression with delusion and Capgras' syndrome, delusion with lability of mood and hypomania successively, during a period of two Months
[Psychiatric manifestations of vitamin B12 deficiency: a case report]
PMID: 15029091  Dec 2003

Catatonia and other psychiatric symptoms with vitamin B12 deficiency.
PMID: 12823174 Aug 2003

High vitamin B12 level and good treatment outcome may be associated in major depressive disorder.
PMID: 14641930 Dec 2003

Neurologic manifestations of gastrointestinal disease.
PMID: 11754307 Feb 2002

Acute dementia with delirium due to vitamin B12 deficiency: a case report. 
PMID: 12269601 2002

Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study.
PMID: 12450964 Dec 2002

Cognitive and behavioral correlates of low vitamin B12 levels in elderly patients with progressive dementia. 
PMID: 11994220 June 2002

Recurrent seizures: an unusual manifestation of vitamin B12 deficiency.
PMID: 15069260 March 2004

Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study. 
PMID: 16709605 July 2006

The most frequent organ-specific autoimmune diseases associated with type 1 diabetes mellitus in children are hypothyroidism and celiac disease. Among adults, other associations exist, notably with pernicious anemia, which is extremely rare in children.
[Pernicious anemia in an adolescent with type 1 diabetes mellitus.]
PMID: 19211232 Feb 2009

CONCLUSION: The combination of autoimmune gastritis and celiac sprue is most likely a variant of the polyglandular autoimmune syndrome type 2. Early diagnosis, life-long gluten-free diet and vitamin B12 administration as well as appropriate aftercare prevent serious complications.
[A severe anemia in a young woman. Description of a rare coincidence]
PMID: 17628841 July 2007

Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at diagnosis: role of B12, folate, and genetics. 
PMID: 15952099 June 2005