B12 deficiency: A look beyond pernicious anemia

If an image of an elderly patient with pernicious anemia is the first thing that comes to mind when you think of B₁₂ deficiency, take note: That image could obfuscate a more common case of B₁₂ deficiency—one caused by food-B₁₂ malabsorption.

Food-B₁₂ malabsorption, characterized by the inability to release B₁₂ from food or its binding proteins, is actually the leading cause of B₁₂ malabsorption, especially in elderly patients.^1-4 And unlike pernicious anemia, it’s more likely to be associated with mild, preclinical B₁₂ deficiency.^1,5

Spotting this form of B₁₂ deficiency requires that you focus on its nuances, such as its link to Helicobacter pylori infection and long-term antacid and biguanide use. It also requires that you consider not only a patient’s serum B₁₂ levels, but his homocysteine and methylmalonic acid levels, since they are considered more sensitive indicators of cobalamin deficiency.⁶ Keying in on these indicators early will ensure prompt treatment, which typically includes intramuscular injections of the vitamin, but which could revolve around a more convenient option: oral B₁₂.

A common problem that comes in many shades

B₁₂ deficiency is common in elderly patients⁷ and its incidence increases with age.^7,8 The Framingham study revealed a prevalence of 12% among elderly people living in the community.⁸ Other studies focusing on those who are in institutions or who are sick and malnourished, have suggested a higher prevalence of 30% to 40%.^3,9

The clinical manifestations of B₁₂ deficiency are highly polymorphic and of varying severity ranging from milder conditions such as the common sensory neuropathy and isolated anomalies of macrocytosis and hypersegmentation of neutrophils, to severe disorders, including combined sclerosis of the spinal cord, hemolytic anemia and even pancytopenia (TABLE 1).^1,5,6,10-13

B₁₂ deficiency is often unrecognized or not investigated because the clinical manifestations can be very subtle. In fact, one of its manifestations—mild memory loss—can mimic the early stages of dementia.¹⁴

Further muddying the waters is the fact that B₁₂ deficiency appears to be more common among patients who have a variety of chronic neurologic conditions such as stroke, Parkinson’s disease, dementia, Alzheimer’s disease, and depression—although it is unclear if these are causal relationships.^1,15 In our own studies in which we administered B₁₂ to patients with dementia, we did not observe any improvement.^2,5 Other studies have had similar results.^16,17

B₁₂ deficiency is typically defined in terms of the serum concentration of B₁₂, as well as the concentration of homocysteine and methyl malonic acid—2 components of the cobalamin metabolic pathway. A deficiency exists if the patient’s blood work reveals the following:^2,18

• Serum B₁₂ levels <150 pmol/L and either total serum homocysteine levels >13 μmol/L or methylmalonic acid levels >0.4 μmol/L (in the absence of renal failure and folate and vitamin B₆ deficiencies).
• Low serum holotranscobalamin levels <35 pmol/L.

TABLE 1
Clinical features of B₁₂ deficiency^1,5,6,10-13

The “classic” cause is not the most common

The principal causes of B₁₂ deficiency include pernicious anemia, dietary deficiency, postsurgical malabsorption, and food-B₁₂ malabsorption. Of note is the fact that there is typically a 5- to 10-year delay between the onset of B₁₂ deficiency and the development of clinical illness, in part because of hepatic stores of cobalamin (>1.5 mg).^1,19

In elderly patients, B₁₂ deficiency is classically caused by pernicious anemia,^3,7 the principal characteristics of which have been reported in detail in several reviews.^20-22 The one thing, of course, that bears repeating is that this form of anemia is associated with a lack of intrinsic factor, which facilitates the absorption of B₁₂.

B₁₂ deficiency caused by dietary deficiency is more rare. Dietary causes of deficiency are limited to elderly people who are already malnourished, such as those living in institutions (they may consume inadequate amounts of foods containing vitamin B₁₂) and strict vegetarians.^1,19 (A typical Western diet contributes 3–30 mcg of B₁₂ per day towards the recommended dietary allowance set by the Food and Nutrition Board of the Institute of Medicine (US) of 2.4 mcg/day for adults and 2.6 to 2.8 mcg/day during pregnancy.²³)

Over the past 20 years, postsurgical malabsorption of B₁₂ has been on the decline, due in large part to the decreasing frequency of gastrectomy and surgical resection of the terminal small intestine.^1,2,5 There are, however, several disorders commonly seen in gastroenterology practice that may be associated with cobalamin malabsorption. These include deficiency in the exocrine function of the pancreas after chronic pancreatitis (usually alcoholic), lymphomas or tuberculosis (of the intestine), Crohn’s disease, Whipple’s disease, and occasionally celiac disease.^3,13

Rounding out the list of causes of B₁₂ deficiency is food-B₁₂ malabsorption, which is the leading cause of B₁₂ malabsorption—especially in elderly patients.^1-4 In our own studies in which we have followed more than 300 patients with a documented B₁₂ deficiency, food-B₁₂ malabsorption accounts for about 60% to 70% of the cases of B₁₂ deficiency in elderly patients, whereas pernicious anemia accounts for only 15% to 25%.^5,24 In our study of 172 hospitalized patients with B₁₂ deficiency (median age, 70), 53% had food-B₁₂ malabsorption.⁵

A form of malabsorption that’s tough to spot

Food-B₁₂ malabsorption is a syndrome characterized by the inability to release B₁₂ from food or intestinal transport proteins, particularly in the presence of hypochlorhydria, in which the absorption of “unbound” B₁₂ is normal. As various studies have shown,^4,5,24 this syndrome is defined by B₁₂ deficiency in the presence of sufficient food-B₁₂ intake and normal Schilling test results, which rules out pernicious anemia. In theory, indisputable evidence of food-B₁₂ malabsorption comes from using a modified Schilling test, which uses radioactive B₁₂ bound to animal proteins (eg, salmon, trout) and reveals malabsorption when the results of a standard Schilling test are normal.^1,5,24

Some authors have speculated about the significance of B₁₂ deficiency related to food-cobalamin malabsorption,¹ because many patients have only mild clinical or hematological features. Several of our patients, however, have had significant features classically associated with pernicious anemia, including polyneuropathy, confusion, dementia, medullar-combined sclerosis, anemia, and pancytopenia.⁵ Nevertheless, the partial nature of this form of malabsorption might produce a more slowly progressive depletion of B₁₂ than does the more complete malabsorption engendered by disruption of intrinsic factor–mediated absorption. The slower progression of depletion probably explains why mild, preclinical deficiency is associated with food-B₁₂ malabsorption more often than with pernicious anemia.^1,5

H pylori, antacid use should raise suspicions

Food-B₁₂ malabsorption is caused primarily by atrophic gastritis.⁵ More than 40% of patients older than 80 years have gastric atrophy that might (or might not) be related to H pylori infection.^3,25 Other factors that contribute to food-B₁₂ malabsorption in elderly people include:

• Chronic carriage of H pylori and intestinal microbial proliferation (in which case B₁₂ deficiency can be corrected by antibiotic treatment)^25,26
• Long-term ingestion of antacids, including H₂-receptor antagonists and proton-pump inhibitors,^27,28 particularly among patients with Zollinger-Ellison syndrome^29,30
• Long-term ingestion of biguanides (metformin)^31-33
• Chronic alcoholism
• Surgery or gastric reconstruction (eg, bypass surgery for obesity)
• Partial pancreatic exocrine failure^1,5
• Sjögren’s syndrome or systemic sclerosis³⁴

In our research involving 92 elderly patients (mean age: 76 years) with food-B₁₂ malabsorption,⁵ we found at least one of the associated conditions or agents listed at left in 60% of the patients. These conditions mainly included atrophic gastritis (H pylori infection) in 30% of the patients and long-term metformin or antacid intake in 20% of the elderly patients.

TABLE 2
French hospital findings support use of oral B₁₂ treatment^38-41,45

IM injection is customary, though dosages vary

The classic treatment for B₁₂ deficiency, particularly when the cause is not a dietary deficiency, is parenteral administration—usually by intramuscular injection—of cyanocobalamin (and in rare occasions, hydroxocobalamin).^7,11,16,35 In the US and UK, dosages range from 100 to 1000 mcg per month (or every 2–3 months when hydroxocobalamin is given). The patient will receive this treatment for the rest of his life.^1,35

In France, the recommended practice is to build up the tissue stores of the vitamin quickly and correct serum B₁₂ hypovitaminosis, particularly in the case of pernicious anemia. The treatment involves administering 1000 mcg of cyanocobalamin per day for 1 week, followed by 1000 mcg per week for 1 month, followed by 1000 mcg per month, normally for the rest of the patient’s life.^2,3,20

Oral therapy is a well-kept secret

In cases of B₁₂ deficiency that don’t involve nutritional deficiency, alternative routes of cobalamin administration, including the oral^16,35-42 and nasal^43,44 routes have been used. These alternative routes offer patients a way to avoid the discomfort, inconvenience, and cost of an office visit for monthly injections.

Our research team has developed an effective oral treatment of food-B₁₂ malabsorption^38-41 and for pernicious anemia⁴⁵ using crystalline cobalamin (cyanocobalamin). Our principal studies of oral B₁₂ treatment (open, not randomized studies) are described in TABLE 2.^38-41,45 Our data confirm the previously reported efficacy of oral crystalline cyanocobalamin, especially in food-B₁₂ therapy.^6,16,36 All of our patients who received oral therapy corrected their B₁₂ levels and at least two thirds corrected their hematological abnormalities.^38-41,45 Moreover, one third of patients experienced a clinical improvement on oral treatment. In most cases of food-B₁₂ malabsorption, a “low” B₁₂ dose (ie, 125–1000 mcg of oral crystalline cyanocobalamin per day) was used.

These data are in line with the results of the 2 prospective randomized controlled studies comparing oral B₁₂ with intramuscular B₁₂ therapy.^35,37 An evidence-based analysis by the Vitamin B₁₂ Cochrane Group supports the efficacy of oral B₁₂ therapy, with doses between 1000 and 2000 mcg given daily in the beginning, and then weekly.⁴⁶ In this analysis, serum B₁₂ levels increased significantly in patients receiving oral vitamin B₁₂ and both groups of patients (receiving oral and intramuscular treatment) had neurological improvement.

In a randomized, parallel-group, double-blind, dose-finding trial, Eussen et al showed that the lowest dose of oral cyanocobalamin required to normalize mild B₁₂ deficiency is more than 200 times the recommended dietary allowance of approximately 3 mcg daily (ie, >500 mcg/day).⁴⁷ The procedure for oral B₁₂ treatment has, however, not been completely validated yet in “real life,” particularly as it relates to long-term efficacy.⁴⁸ Nonetheless, several authors suggest that oral B₁₂ therapy remains one of medicine’s “best-kept secrets.”⁴⁹

Acknowledgements

We are indebted to Professor Marc Imler and Jean-Louis Schlienger who initiated this work and to Helen Fothergill who kindly edited the text for publication in this English-language journal.

Correspondence
Prof. E. Andrès, Service de Médecine Interne, Diabète et Maladies Métaboliques, Clinique Médicale B, Hôpital Civil–Hôpitaux Universitaires de Strasbourg, 1 porte de l’Hôpital, 67091 Strasbourg Cedex, France; emmanuel. [email protected]

If an image of an elderly patient with pernicious anemia is the first thing that comes to mind when you think of B₁₂ deficiency, take note: That image could obfuscate a more common case of B₁₂ deficiency—one caused by food-B₁₂ malabsorption.

Food-B₁₂ malabsorption, characterized by the inability to release B₁₂ from food or its binding proteins, is actually the leading cause of B₁₂ malabsorption, especially in elderly patients.^1-4 And unlike pernicious anemia, it’s more likely to be associated with mild, preclinical B₁₂ deficiency.^1,5

Spotting this form of B₁₂ deficiency requires that you focus on its nuances, such as its link to Helicobacter pylori infection and long-term antacid and biguanide use. It also requires that you consider not only a patient’s serum B₁₂ levels, but his homocysteine and methylmalonic acid levels, since they are considered more sensitive indicators of cobalamin deficiency.⁶ Keying in on these indicators early will ensure prompt treatment, which typically includes intramuscular injections of the vitamin, but which could revolve around a more convenient option: oral B₁₂.

A common problem that comes in many shades

B₁₂ deficiency is common in elderly patients⁷ and its incidence increases with age.^7,8 The Framingham study revealed a prevalence of 12% among elderly people living in the community.⁸ Other studies focusing on those who are in institutions or who are sick and malnourished, have suggested a higher prevalence of 30% to 40%.^3,9

The clinical manifestations of B₁₂ deficiency are highly polymorphic and of varying severity ranging from milder conditions such as the common sensory neuropathy and isolated anomalies of macrocytosis and hypersegmentation of neutrophils, to severe disorders, including combined sclerosis of the spinal cord, hemolytic anemia and even pancytopenia (TABLE 1).^1,5,6,10-13

B₁₂ deficiency is often unrecognized or not investigated because the clinical manifestations can be very subtle. In fact, one of its manifestations—mild memory loss—can mimic the early stages of dementia.¹⁴

Further muddying the waters is the fact that B₁₂ deficiency appears to be more common among patients who have a variety of chronic neurologic conditions such as stroke, Parkinson’s disease, dementia, Alzheimer’s disease, and depression—although it is unclear if these are causal relationships.^1,15 In our own studies in which we administered B₁₂ to patients with dementia, we did not observe any improvement.^2,5 Other studies have had similar results.^16,17

B₁₂ deficiency is typically defined in terms of the serum concentration of B₁₂, as well as the concentration of homocysteine and methyl malonic acid—2 components of the cobalamin metabolic pathway. A deficiency exists if the patient’s blood work reveals the following:^2,18

• Serum B₁₂ levels <150 pmol/L and either total serum homocysteine levels >13 μmol/L or methylmalonic acid levels >0.4 μmol/L (in the absence of renal failure and folate and vitamin B₆ deficiencies).
• Low serum holotranscobalamin levels <35 pmol/L.

TABLE 1
Clinical features of B₁₂ deficiency^1,5,6,10-13

The “classic” cause is not the most common

The principal causes of B₁₂ deficiency include pernicious anemia, dietary deficiency, postsurgical malabsorption, and food-B₁₂ malabsorption. Of note is the fact that there is typically a 5- to 10-year delay between the onset of B₁₂ deficiency and the development of clinical illness, in part because of hepatic stores of cobalamin (>1.5 mg).^1,19

In elderly patients, B₁₂ deficiency is classically caused by pernicious anemia,^3,7 the principal characteristics of which have been reported in detail in several reviews.^20-22 The one thing, of course, that bears repeating is that this form of anemia is associated with a lack of intrinsic factor, which facilitates the absorption of B₁₂.

B₁₂ deficiency caused by dietary deficiency is more rare. Dietary causes of deficiency are limited to elderly people who are already malnourished, such as those living in institutions (they may consume inadequate amounts of foods containing vitamin B₁₂) and strict vegetarians.^1,19 (A typical Western diet contributes 3–30 mcg of B₁₂ per day towards the recommended dietary allowance set by the Food and Nutrition Board of the Institute of Medicine (US) of 2.4 mcg/day for adults and 2.6 to 2.8 mcg/day during pregnancy.²³)

Over the past 20 years, postsurgical malabsorption of B₁₂ has been on the decline, due in large part to the decreasing frequency of gastrectomy and surgical resection of the terminal small intestine.^1,2,5 There are, however, several disorders commonly seen in gastroenterology practice that may be associated with cobalamin malabsorption. These include deficiency in the exocrine function of the pancreas after chronic pancreatitis (usually alcoholic), lymphomas or tuberculosis (of the intestine), Crohn’s disease, Whipple’s disease, and occasionally celiac disease.^3,13

Rounding out the list of causes of B₁₂ deficiency is food-B₁₂ malabsorption, which is the leading cause of B₁₂ malabsorption—especially in elderly patients.^1-4 In our own studies in which we have followed more than 300 patients with a documented B₁₂ deficiency, food-B₁₂ malabsorption accounts for about 60% to 70% of the cases of B₁₂ deficiency in elderly patients, whereas pernicious anemia accounts for only 15% to 25%.^5,24 In our study of 172 hospitalized patients with B₁₂ deficiency (median age, 70), 53% had food-B₁₂ malabsorption.⁵

A form of malabsorption that’s tough to spot

Food-B₁₂ malabsorption is a syndrome characterized by the inability to release B₁₂ from food or intestinal transport proteins, particularly in the presence of hypochlorhydria, in which the absorption of “unbound” B₁₂ is normal. As various studies have shown,^4,5,24 this syndrome is defined by B₁₂ deficiency in the presence of sufficient food-B₁₂ intake and normal Schilling test results, which rules out pernicious anemia. In theory, indisputable evidence of food-B₁₂ malabsorption comes from using a modified Schilling test, which uses radioactive B₁₂ bound to animal proteins (eg, salmon, trout) and reveals malabsorption when the results of a standard Schilling test are normal.^1,5,24

Some authors have speculated about the significance of B₁₂ deficiency related to food-cobalamin malabsorption,¹ because many patients have only mild clinical or hematological features. Several of our patients, however, have had significant features classically associated with pernicious anemia, including polyneuropathy, confusion, dementia, medullar-combined sclerosis, anemia, and pancytopenia.⁵ Nevertheless, the partial nature of this form of malabsorption might produce a more slowly progressive depletion of B₁₂ than does the more complete malabsorption engendered by disruption of intrinsic factor–mediated absorption. The slower progression of depletion probably explains why mild, preclinical deficiency is associated with food-B₁₂ malabsorption more often than with pernicious anemia.^1,5

H pylori, antacid use should raise suspicions

Food-B₁₂ malabsorption is caused primarily by atrophic gastritis.⁵ More than 40% of patients older than 80 years have gastric atrophy that might (or might not) be related to H pylori infection.^3,25 Other factors that contribute to food-B₁₂ malabsorption in elderly people include:

• Chronic carriage of H pylori and intestinal microbial proliferation (in which case B₁₂ deficiency can be corrected by antibiotic treatment)^25,26
• Long-term ingestion of antacids, including H₂-receptor antagonists and proton-pump inhibitors,^27,28 particularly among patients with Zollinger-Ellison syndrome^29,30
• Long-term ingestion of biguanides (metformin)^31-33
• Chronic alcoholism
• Surgery or gastric reconstruction (eg, bypass surgery for obesity)
• Partial pancreatic exocrine failure^1,5
• Sjögren’s syndrome or systemic sclerosis³⁴

In our research involving 92 elderly patients (mean age: 76 years) with food-B₁₂ malabsorption,⁵ we found at least one of the associated conditions or agents listed at left in 60% of the patients. These conditions mainly included atrophic gastritis (H pylori infection) in 30% of the patients and long-term metformin or antacid intake in 20% of the elderly patients.

TABLE 2
French hospital findings support use of oral B₁₂ treatment^38-41,45

IM injection is customary, though dosages vary

The classic treatment for B₁₂ deficiency, particularly when the cause is not a dietary deficiency, is parenteral administration—usually by intramuscular injection—of cyanocobalamin (and in rare occasions, hydroxocobalamin).^7,11,16,35 In the US and UK, dosages range from 100 to 1000 mcg per month (or every 2–3 months when hydroxocobalamin is given). The patient will receive this treatment for the rest of his life.^1,35

In France, the recommended practice is to build up the tissue stores of the vitamin quickly and correct serum B₁₂ hypovitaminosis, particularly in the case of pernicious anemia. The treatment involves administering 1000 mcg of cyanocobalamin per day for 1 week, followed by 1000 mcg per week for 1 month, followed by 1000 mcg per month, normally for the rest of the patient’s life.^2,3,20

Oral therapy is a well-kept secret

In cases of B₁₂ deficiency that don’t involve nutritional deficiency, alternative routes of cobalamin administration, including the oral^16,35-42 and nasal^43,44 routes have been used. These alternative routes offer patients a way to avoid the discomfort, inconvenience, and cost of an office visit for monthly injections.

Our research team has developed an effective oral treatment of food-B₁₂ malabsorption^38-41 and for pernicious anemia⁴⁵ using crystalline cobalamin (cyanocobalamin). Our principal studies of oral B₁₂ treatment (open, not randomized studies) are described in TABLE 2.^38-41,45 Our data confirm the previously reported efficacy of oral crystalline cyanocobalamin, especially in food-B₁₂ therapy.^6,16,36 All of our patients who received oral therapy corrected their B₁₂ levels and at least two thirds corrected their hematological abnormalities.^38-41,45 Moreover, one third of patients experienced a clinical improvement on oral treatment. In most cases of food-B₁₂ malabsorption, a “low” B₁₂ dose (ie, 125–1000 mcg of oral crystalline cyanocobalamin per day) was used.

These data are in line with the results of the 2 prospective randomized controlled studies comparing oral B₁₂ with intramuscular B₁₂ therapy.^35,37 An evidence-based analysis by the Vitamin B₁₂ Cochrane Group supports the efficacy of oral B₁₂ therapy, with doses between 1000 and 2000 mcg given daily in the beginning, and then weekly.⁴⁶ In this analysis, serum B₁₂ levels increased significantly in patients receiving oral vitamin B₁₂ and both groups of patients (receiving oral and intramuscular treatment) had neurological improvement.

In a randomized, parallel-group, double-blind, dose-finding trial, Eussen et al showed that the lowest dose of oral cyanocobalamin required to normalize mild B₁₂ deficiency is more than 200 times the recommended dietary allowance of approximately 3 mcg daily (ie, >500 mcg/day).⁴⁷ The procedure for oral B₁₂ treatment has, however, not been completely validated yet in “real life,” particularly as it relates to long-term efficacy.⁴⁸ Nonetheless, several authors suggest that oral B₁₂ therapy remains one of medicine’s “best-kept secrets.”⁴⁹

Acknowledgements

We are indebted to Professor Marc Imler and Jean-Louis Schlienger who initiated this work and to Helen Fothergill who kindly edited the text for publication in this English-language journal.

Correspondence
Prof. E. Andrès, Service de Médecine Interne, Diabète et Maladies Métaboliques, Clinique Médicale B, Hôpital Civil–Hôpitaux Universitaires de Strasbourg, 1 porte de l’Hôpital, 67091 Strasbourg Cedex, France; emmanuel. [email protected]

If an image of an elderly patient with pernicious anemia is the first thing that comes to mind when you think of B₁₂ deficiency, take note: That image could obfuscate a more common case of B₁₂ deficiency—one caused by food-B₁₂ malabsorption.

Food-B₁₂ malabsorption, characterized by the inability to release B₁₂ from food or its binding proteins, is actually the leading cause of B₁₂ malabsorption, especially in elderly patients.^1-4 And unlike pernicious anemia, it’s more likely to be associated with mild, preclinical B₁₂ deficiency.^1,5

Spotting this form of B₁₂ deficiency requires that you focus on its nuances, such as its link to Helicobacter pylori infection and long-term antacid and biguanide use. It also requires that you consider not only a patient’s serum B₁₂ levels, but his homocysteine and methylmalonic acid levels, since they are considered more sensitive indicators of cobalamin deficiency.⁶ Keying in on these indicators early will ensure prompt treatment, which typically includes intramuscular injections of the vitamin, but which could revolve around a more convenient option: oral B₁₂.

A common problem that comes in many shades

B₁₂ deficiency is common in elderly patients⁷ and its incidence increases with age.^7,8 The Framingham study revealed a prevalence of 12% among elderly people living in the community.⁸ Other studies focusing on those who are in institutions or who are sick and malnourished, have suggested a higher prevalence of 30% to 40%.^3,9

The clinical manifestations of B₁₂ deficiency are highly polymorphic and of varying severity ranging from milder conditions such as the common sensory neuropathy and isolated anomalies of macrocytosis and hypersegmentation of neutrophils, to severe disorders, including combined sclerosis of the spinal cord, hemolytic anemia and even pancytopenia (TABLE 1).^1,5,6,10-13

B₁₂ deficiency is often unrecognized or not investigated because the clinical manifestations can be very subtle. In fact, one of its manifestations—mild memory loss—can mimic the early stages of dementia.¹⁴

Further muddying the waters is the fact that B₁₂ deficiency appears to be more common among patients who have a variety of chronic neurologic conditions such as stroke, Parkinson’s disease, dementia, Alzheimer’s disease, and depression—although it is unclear if these are causal relationships.^1,15 In our own studies in which we administered B₁₂ to patients with dementia, we did not observe any improvement.^2,5 Other studies have had similar results.^16,17

B₁₂ deficiency is typically defined in terms of the serum concentration of B₁₂, as well as the concentration of homocysteine and methyl malonic acid—2 components of the cobalamin metabolic pathway. A deficiency exists if the patient’s blood work reveals the following:^2,18

• Serum B₁₂ levels <150 pmol/L and either total serum homocysteine levels >13 μmol/L or methylmalonic acid levels >0.4 μmol/L (in the absence of renal failure and folate and vitamin B₆ deficiencies).
• Low serum holotranscobalamin levels <35 pmol/L.

TABLE 1
Clinical features of B₁₂ deficiency^1,5,6,10-13

The “classic” cause is not the most common

The principal causes of B₁₂ deficiency include pernicious anemia, dietary deficiency, postsurgical malabsorption, and food-B₁₂ malabsorption. Of note is the fact that there is typically a 5- to 10-year delay between the onset of B₁₂ deficiency and the development of clinical illness, in part because of hepatic stores of cobalamin (>1.5 mg).^1,19

In elderly patients, B₁₂ deficiency is classically caused by pernicious anemia,^3,7 the principal characteristics of which have been reported in detail in several reviews.^20-22 The one thing, of course, that bears repeating is that this form of anemia is associated with a lack of intrinsic factor, which facilitates the absorption of B₁₂.

B₁₂ deficiency caused by dietary deficiency is more rare. Dietary causes of deficiency are limited to elderly people who are already malnourished, such as those living in institutions (they may consume inadequate amounts of foods containing vitamin B₁₂) and strict vegetarians.^1,19 (A typical Western diet contributes 3–30 mcg of B₁₂ per day towards the recommended dietary allowance set by the Food and Nutrition Board of the Institute of Medicine (US) of 2.4 mcg/day for adults and 2.6 to 2.8 mcg/day during pregnancy.²³)

Over the past 20 years, postsurgical malabsorption of B₁₂ has been on the decline, due in large part to the decreasing frequency of gastrectomy and surgical resection of the terminal small intestine.^1,2,5 There are, however, several disorders commonly seen in gastroenterology practice that may be associated with cobalamin malabsorption. These include deficiency in the exocrine function of the pancreas after chronic pancreatitis (usually alcoholic), lymphomas or tuberculosis (of the intestine), Crohn’s disease, Whipple’s disease, and occasionally celiac disease.^3,13

Rounding out the list of causes of B₁₂ deficiency is food-B₁₂ malabsorption, which is the leading cause of B₁₂ malabsorption—especially in elderly patients.^1-4 In our own studies in which we have followed more than 300 patients with a documented B₁₂ deficiency, food-B₁₂ malabsorption accounts for about 60% to 70% of the cases of B₁₂ deficiency in elderly patients, whereas pernicious anemia accounts for only 15% to 25%.^5,24 In our study of 172 hospitalized patients with B₁₂ deficiency (median age, 70), 53% had food-B₁₂ malabsorption.⁵

A form of malabsorption that’s tough to spot

Food-B₁₂ malabsorption is a syndrome characterized by the inability to release B₁₂ from food or intestinal transport proteins, particularly in the presence of hypochlorhydria, in which the absorption of “unbound” B₁₂ is normal. As various studies have shown,^4,5,24 this syndrome is defined by B₁₂ deficiency in the presence of sufficient food-B₁₂ intake and normal Schilling test results, which rules out pernicious anemia. In theory, indisputable evidence of food-B₁₂ malabsorption comes from using a modified Schilling test, which uses radioactive B₁₂ bound to animal proteins (eg, salmon, trout) and reveals malabsorption when the results of a standard Schilling test are normal.^1,5,24

Some authors have speculated about the significance of B₁₂ deficiency related to food-cobalamin malabsorption,¹ because many patients have only mild clinical or hematological features. Several of our patients, however, have had significant features classically associated with pernicious anemia, including polyneuropathy, confusion, dementia, medullar-combined sclerosis, anemia, and pancytopenia.⁵ Nevertheless, the partial nature of this form of malabsorption might produce a more slowly progressive depletion of B₁₂ than does the more complete malabsorption engendered by disruption of intrinsic factor–mediated absorption. The slower progression of depletion probably explains why mild, preclinical deficiency is associated with food-B₁₂ malabsorption more often than with pernicious anemia.^1,5

H pylori, antacid use should raise suspicions

Food-B₁₂ malabsorption is caused primarily by atrophic gastritis.⁵ More than 40% of patients older than 80 years have gastric atrophy that might (or might not) be related to H pylori infection.^3,25 Other factors that contribute to food-B₁₂ malabsorption in elderly people include:

• Chronic carriage of H pylori and intestinal microbial proliferation (in which case B₁₂ deficiency can be corrected by antibiotic treatment)^25,26
• Long-term ingestion of antacids, including H₂-receptor antagonists and proton-pump inhibitors,^27,28 particularly among patients with Zollinger-Ellison syndrome^29,30
• Long-term ingestion of biguanides (metformin)^31-33
• Chronic alcoholism
• Surgery or gastric reconstruction (eg, bypass surgery for obesity)
• Partial pancreatic exocrine failure^1,5
• Sjögren’s syndrome or systemic sclerosis³⁴

In our research involving 92 elderly patients (mean age: 76 years) with food-B₁₂ malabsorption,⁵ we found at least one of the associated conditions or agents listed at left in 60% of the patients. These conditions mainly included atrophic gastritis (H pylori infection) in 30% of the patients and long-term metformin or antacid intake in 20% of the elderly patients.

TABLE 2
French hospital findings support use of oral B₁₂ treatment^38-41,45

IM injection is customary, though dosages vary

The classic treatment for B₁₂ deficiency, particularly when the cause is not a dietary deficiency, is parenteral administration—usually by intramuscular injection—of cyanocobalamin (and in rare occasions, hydroxocobalamin).^7,11,16,35 In the US and UK, dosages range from 100 to 1000 mcg per month (or every 2–3 months when hydroxocobalamin is given). The patient will receive this treatment for the rest of his life.^1,35

In France, the recommended practice is to build up the tissue stores of the vitamin quickly and correct serum B₁₂ hypovitaminosis, particularly in the case of pernicious anemia. The treatment involves administering 1000 mcg of cyanocobalamin per day for 1 week, followed by 1000 mcg per week for 1 month, followed by 1000 mcg per month, normally for the rest of the patient’s life.^2,3,20

Oral therapy is a well-kept secret

In cases of B₁₂ deficiency that don’t involve nutritional deficiency, alternative routes of cobalamin administration, including the oral^16,35-42 and nasal^43,44 routes have been used. These alternative routes offer patients a way to avoid the discomfort, inconvenience, and cost of an office visit for monthly injections.

Our research team has developed an effective oral treatment of food-B₁₂ malabsorption^38-41 and for pernicious anemia⁴⁵ using crystalline cobalamin (cyanocobalamin). Our principal studies of oral B₁₂ treatment (open, not randomized studies) are described in TABLE 2.^38-41,45 Our data confirm the previously reported efficacy of oral crystalline cyanocobalamin, especially in food-B₁₂ therapy.^6,16,36 All of our patients who received oral therapy corrected their B₁₂ levels and at least two thirds corrected their hematological abnormalities.^38-41,45 Moreover, one third of patients experienced a clinical improvement on oral treatment. In most cases of food-B₁₂ malabsorption, a “low” B₁₂ dose (ie, 125–1000 mcg of oral crystalline cyanocobalamin per day) was used.

These data are in line with the results of the 2 prospective randomized controlled studies comparing oral B₁₂ with intramuscular B₁₂ therapy.^35,37 An evidence-based analysis by the Vitamin B₁₂ Cochrane Group supports the efficacy of oral B₁₂ therapy, with doses between 1000 and 2000 mcg given daily in the beginning, and then weekly.⁴⁶ In this analysis, serum B₁₂ levels increased significantly in patients receiving oral vitamin B₁₂ and both groups of patients (receiving oral and intramuscular treatment) had neurological improvement.

In a randomized, parallel-group, double-blind, dose-finding trial, Eussen et al showed that the lowest dose of oral cyanocobalamin required to normalize mild B₁₂ deficiency is more than 200 times the recommended dietary allowance of approximately 3 mcg daily (ie, >500 mcg/day).⁴⁷ The procedure for oral B₁₂ treatment has, however, not been completely validated yet in “real life,” particularly as it relates to long-term efficacy.⁴⁸ Nonetheless, several authors suggest that oral B₁₂ therapy remains one of medicine’s “best-kept secrets.”⁴⁹

Acknowledgements

We are indebted to Professor Marc Imler and Jean-Louis Schlienger who initiated this work and to Helen Fothergill who kindly edited the text for publication in this English-language journal.

Correspondence
Prof. E. Andrès, Service de Médecine Interne, Diabète et Maladies Métaboliques, Clinique Médicale B, Hôpital Civil–Hôpitaux Universitaires de Strasbourg, 1 porte de l’Hôpital, 67091 Strasbourg Cedex, France; emmanuel. [email protected]