Vitamin B12 Deficiency

What Is Vitamin B12?

[dropcap]V[/dropcap]itamin B12, also called cobalamin, is a highly complex vitamin that functions in two coenzyme forms: adenosylcobalamin and methylcobalamin.

These forms of the vitamin play important roles in the physical and chemical processes by which amino acids become proprionate, proprionate that becomes acetate,  and single carbons.

Q: Why are these steps important?

A: These steps are essential for normal function in the workings of all cells, especially for those of the digestive tract, bone marrow and nervous tissue.

Vitamin B12 is mainly excreted through bile into the duodenum (first part of the small intestine) for excretion in stool.¹ However, if vitamin B12 is needed, it is reabsorbed in the ileum (end of the small intestine) while excess is excreted in stool and very little in urine.²

The blood level of vitamin B12 in healthy people ranges between 140 and 750 pg/ml.

What Is Vitamin B12 Deficiency In Celiac Disease and/or Gluten Sensitivity?

• Relationship between vitamin B12 deficiency and celiac disease. Vitamin B12 deficiency is a classic symptom of celiac disease that results when the level within cells is too low to meet needs of the body for this crucial vitamin that is caused by malabsorption.
• Relationship between vitamin B12 deficiency and signs. Vitamin B12 deficiency is characterized by 1) impaired metabolism of all cells mainly resulting in blood disorders that include megaloblastic anemia, resulting from defective blood cell formation due to poor folate action owing to lack of vitamin B12, and low platelets and low white blood cells due to impaired formation; 2) nervous system disorders that involve balance, behavior and thinking; and 3) gastrointestinal disorders that include poor digestion, poor intestinal function and altered bowel motility (peristalsis).
• Relationship between vitamin B12 deficiency and liver stores. Symptoms of vitamin B12 deficiency appear when liver stores are depleted.
• Relationship between vitamin B12 deficiency and neurological damage. Evidence suggests that mental symptoms of depression and fatigue are detectable before anemia develops and progressive neuropathy with loss of position-sense and balance. If vitamin B12 is not replaced, permanent neurological damage, including degeneration of nerves and spinal cord can result.
• Relationship between vitamin B12 deficiency and loss of brain tissue. Vitamin B12 deficiency causes brain atrophy or shrinkage.³

• Relationship between vitamin B12 deficiency and hypertension due to elevated blood homocysteine level. In metabolism, homocysteine is briefly formed in the breakdown of the amino acid methionine. It is normally converted to cystathione and then to the amino acid cysteine by means of a vitamin B6 (pyridoxine) dependent enzyme.

  In the reverse, conversion of homocysteine to methionine requires an enzyme dependent on adequate folic acid and vitamin B12 levels. Insufficient methionine levels and/or inefficiency in this process results in elevated homocysteine plasma levels that are toxic to blood vessels.⁴

How Prevalent Is Vitamin B12 Deficiency In Celiac Disease and/or Gluten Sensitivity?

• Vitamin B12 deficiency is common in patients with untreated celiac disease.⁵,⁶
• The prevalence for vitamin B12 deficiency was 19% in 80 newly diagnosed adult patients.⁷
• In a retrospective study examining patient data, vitamin B12 deficiency was seen in approximately 5% of 405 patients seen in a hospital setting for celiac disease.⁸
• Out of 22 patients at diagnosis of celiac disease who presented with blood abnormalities, vitamin B12 deficiency was found in two, vitamin B12 deficiency coexisted with iron deficiency and zinc in 3 patients, vitamin B12 deficiency coexisted with copper in two.⁹

What Are The Symptoms Of Vitamin B12 Deficiency?

Vitamin B12 deficiency is marked by these symptoms:

• Anorexia.
• Shortness of breath.
• Fatigue.
• Weakness.
• Irritability.
• Distorted taste.
• Beefy red, smooth tongue with burning.
• Intermittent diarrhea and constipation.
• Poorly localized abdominal pain.
• Hypochlorhydria (low stomach acid).
• Considerable weight loss.
• Muscle stiffness and generalized weakness in legs.
• Numbness with tingling and burning in feet (neuropathy).
• Later, spasticity and loss of balance, depression, confusion and impaired thinking develop.
• Late signs include increase in blood and urinary levels of homocysteine, methylmalonic acid, and aminoisocaproate; megaloblastic anemia which gives a lemon yellow tint to skin; and poor clotting due to thrombocytopenia in half of severe cases.
• In advanced deficiency, paranoia, delirium, hallucinations, and spastic ataxia develop.¹⁰

How Does The Body Get Vitamin B12?

• Vitamin B12 is absorbed in the ileum section of the small intestine (end) by active transport and, at low efficiency (about 1%), by simple diffusion. The active process is enabled by intrinsic factor which is present in gastric secretions.¹⁰
• As long as vitamin B12 is adequately ingested in the diet, absorbed from the gut, and utilized in the body, any excess vitamin is kept and stored in the liver for years as a hedge against deficiency.

What Does Vitamin B12 Do In The Body?

1. Essential for the metabolism of all cells, especially for those of the digestive tract, bone marrow and nervous tissue.
2. Essential for the formation of red blood cells, platelets (clotting cells), and immune cells.
3. Essential for maintenance of the central nervous system.
4. Essential for interaction with folate metabolism, preventing folate derivatives from being trapped in unusable states.
5. Essential for preventing accumulation of homocysteine, a toxic metabolic byproduct linked to cardiovascular disease and connective tissue abnormalities.

How Does Vitamin B12 Deficiency Develop?

• The pathophysiology of vitamin B12 deficiency in celiac disease is unknown.¹¹
• Vitamin B12 deficiency in celiac disease results from malabsorption and is not due to autoimmune gastritis which is the usual cause in the general population.⁶ Protein deficiency worsens vitamin B12 deficiency because of lack of sufficient carriers for this vitamin.

Does Vitamin B12 Deficiency Respond To Gluten-Free Diet?

Yes. Celiac disease-related vitamin B12 deficiency responds to a nutritious gluten free diet with adequate vitamin B12. According to blood level response to diet, supplementation may be required.

Adults with longstanding celiac disease taking extra B vitamins for 6 months showed normalized tHcy (plasma total homocysteine) and significant improvement in general well-being, suggesting that B vitamins should be considered in people advised to follow a gluten-free diet.¹²

6 Steps To Correct Vitamin B12 Deficiency:

• [dropcap]1[/dropcap]Meet, or Exceed the RDA (Recommended Dietary Allowances) for Vitamin B12 in (μg) per day:

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0.4 μg for infants up to 6 months;

0.5 μg for infants 7-12 months;

0.9 μg for children 1-3 years;

1.2 μg for children 4-8 years;

1.8 μg for children 9-13 years.

2.4 μg males and females age 14 and older.

Women who are pregnant or breastfeeding need higher amounts of vitamin B12.[/box]

• [dropcap]2[/dropcap]Diet – Include Food Sources Richest in Vitamin B12:

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Plant Food Sources:

• Not found in plant foodstuffs except some sea vegetables.

Animal Food Sources:

• Beef liver is the highest source.
• Sardines.
• Clams.
• Herring.
• Oysters.
• Flounder.
• Tuna.
• Salmon.
• Lamb.
• Halibut.
• Egg.
• Cheese.
• Crab.[/box] 

• [dropcap]3[/dropcap] Diet – Avoid  Eating At The Same Meal or Limit These Foods That Deplete or Interfere With Absorption:

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• Milk because it makes the stomach juices alkaline which is opposite the acid needed for vitamin B12 digestion.
• Food preserved with proprionate, added as a presevative to retard spoilage. [/box] 

• [dropcap]4[/dropcap]Monitor Medications That Deplete or Interfere With Absorption:

Ask your doctor or pharmacist about possible interactions between vitamin B12 and medications you’re taking.

Here are common medications that increase risk of depletion and should to be monitored with blood testing to discover deficiency:

ANTACIDS / ULCER MEDICATIONS Pepcid®, Tagamet®, Zantac®. Magnesium and Aluminum Antacid preparations (Gaviscon®, Maalox®, Mylanta®). Prevacid®, Prilosec®.   ANTI-DEPRESSANTS  Adapin®, Aventyl®, Elavil®, Pamelor®, and others.  ANTI-VIRAL Zidovudine (Retrovir®, AZT and other related drugs). CHOLESTEROL DRUGS Colestid® and Questran® DIABETIC DRUGS Metformin®. ANTIBIOTIC Chloromycetin®).

MAJOR TRANQUILIZERS Thorazine®, Mellaril®, Prolixin®, Serentil® and others. ANTICONVULSANTS – Phenobarbital and Barbituates; Dilantin®, Tegretol®, Mysoline®, Depakane/Depacon®. ANTI-INFLAMMATORIES Corticosteroids (Prednisone,Medrol®, Aristocort®, Decadron). FEMALE HORMONES Oral Contraceptives (Norinyl®, Ortho-Novum®, Triphasil®, and others). Oral Estrogen/Hormone Replacement (Evista®, Prempro®, Premarin®, Estratab® and others).

 

• [dropcap]5[/dropcap]Manage Nutritional Supplements to Obtain Vitamin B12:

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• A blood level concentration should be obtained to determine status before supplementing.
• Vitamin B12 is available without prescription in tablet form and as part of multivitamin supplements to be taken by mouth.
• Some individuals may require more frequent or larger doses than usual before repletion occurs.
• Natural preparations made from food are superior to synthetic ones that are chemically produced.
• Avoid any preparation that contains these harmful chemicals most of which are derived from benzene (a toxic hydrocarbon, C6H6): benzoic acid, methyparaben (found in breast cancer tissue), propylparaben, paraben, polyethylene glycol, propylene glycol (propanediol), polysorbate 60.

Toxicity: No toxic effects of oral vitamin B12 intake have been demonstrated, even in doses over 1,000 μg daily as long as the liver is healthy and can maintain normal blood levels.[/box]

• [dropcap]6[/dropcap]Other Supplements That Deplete or Interfere With Absorption:

[box type=”shadow” ] Check with your pharmacist. [/box]

What Do Medical Research Studies Tell About Vitamin B12 Deficiency In Celiac Disease and/or Gluten Sensitivity?

RESEARCH STUDY SUMMARIES

“Vitamin and mineral deficiencies are highly prevalent in newly diagnosed celiac disease patients.” This study aiming to assess the nutritional and vitamin/mineral status of current “early diagnosed” untreated adult celiac disease (CD)-patients in the Netherlands found that vitamin/mineral deficiencies are still common in newly “early diagnosed” CD-patients. Specifically, the prevalence for vitamin B12 deficiency was 19%.

Eighty newly diagnosed adult CD-patients were included and a comparable sample of 24 healthy Dutch subjects was added to compare vitamin concentrations. Nutritional status and serum concentrations of folic acid, vitamin A, B6, B12, and (25-hydroxy) D, zinc, haemoglobin (Hb) and ferritin were determined (before prescribing gluten free diet). Almost all CD-patients (87%) had at least one value below the lower limit of reference.

Vitamin/mineral deficiencies were counter-intuitively not associated with a (higher) grade of histological intestinal damage or (impaired) nutritional status. Extensive nutritional assessments seem warranted to guide nutritional advices and follow-up in CD treatment.⁷

“Varied presentation of celiac disease in Pakistani adults. “ This retrospective study investigating the presentation of celiac disease in adults found a prevalence of B12 deficiency in 9.1% of 77 patients.

Subjects included 41 (53.2%) males with median age 26 years and median body mass index of 18 (16 – 22) kg/m². Typical presentation with gastrointestinal symptoms was seen in 76.6%. Atypical presentation with extra intestinal complaints in 7.8% and silent presentation in 15.6%. Major symptoms were diarrhea in 64.9%, weight loss 36.4%, abdominal pain 35.1%, vomiting 32.5%, pallor 24.7%, and weakness 13%. Iron deficiency was documented in 20.8%, B12 deficiency in 9.1%, folic acid deficiency in 6.5% and vitamin D deficiency in 10.4%. Half of the patients had hemoglobin less than 11 g/dl. Osteoporosis and osteomalacia, hypothyroidism, diabetes and atrophic gastritis were seen in 2.6% each. Raised alanine aminotransferase was documented in 23.4%.

Duodenal biopsy, done in 39 patients, revealed increased intraepithelial lymphocytes in 11, along with crypt hyperplasia in 3, partial villous atrophy in 15 and sub-total villous atrophy in 10.¹³

“Clinical trial: B vitamins improve health in patients with coeliac disease living on a gluten-free diet.” This study investigating the biochemical and clinical effects of B vitamin supplementation in adults with longstanding celiac disease found that adults with longstanding celiac disease taking extra B vitamins for 6 months showed normalized tHcy (plasma total homocysteine) and significant improvement in general well-being, suggesting that B vitamins should be considered in people advised to follow a gluten-free diet.

In a double blind placebo controlled multicenter trial, 65 celiac patients (61% women) aged 45-64 years on a strict gluten-free diet for several years were randomized to a daily dose of 0.8 mg folic acid,0.5 mg cyanocobalamin and 3 mg pyridoxine or placebo (no vitamin pill) for 6 months. The outcome measures were psychological general well-being and the plasma total homocysteine (tHcy) level, marker of B vitamin status.

Fifty-seven patients (88%) completed the trial. The tHcy level was baseline median 11.7 micromol/L (7.4-23.0), significantly higher than in matched population controls [10.2 micromol/L (6.7-22.6)]. Following vitamin supplementation, tHcy dropped a median of 34%, accompanied by significant improvement in well-being, notably anxiety and depressed mood for patients with poor well-being.¹²

“Anemia in celiac disease is multifactorial in etiology.” This study assessed the characteristics of anemia from patients seen at a hospital based care center for celiac disease. Blood antibodies for celiac disease measured less than 3 months of diagnosis and the degree of villous atrophy from 405 patients diagnosed after 1995 were analyzed.  B12 deficiency was seen in approximately 5% of these patients.  Macrocytic anemia with concurrent B12 or folate deficiency was seen in 3%.¹⁴

“Vitamin B12 deficiency in untreated celiac disease.” This study investigating the prevalence of vitamin B12 deficiency in patients with celiac disease demonstrated that vitamin B12 deficiency is common in patients with untreated celiac disease and concentration should be measured routinely before supplementation.¹⁵

CASE REPORT SUMMARIES

“Carpopedal spasm in an elderly man: an unusual presentation of celiac disease.” This case report describes diagnosis of celiac disease in a 68-year-old single Caucasian man admitted to the hospital with a 24-hour history of carpopedal spasm of both hands. Apart from generalized weakness, he reported no other symptoms. Physical examination revealed carpopedal spasm, clubbing of fingers and cachexia (body mass index 14 kg/m2). This patient was found to have several unusual features of celiac disease, including a low vitamin B12 level causing anemia, severe hypocalcemia and electrolyte disturbances as the initial manifestations, minimal gastrointestinal symptoms, and negative tTG-antibodies.

Blood tests showed severe hypocalcemia, with a total serum calcium of 1.06 mmol/L (normal range [NR] 2.05-2.55 mmol/L). He also had low serum potassium (2.8 mmol/L; NR 3.5-5.5 mmol/L) and magnesium (0.36 mmol/L; NR 0.65-1.05 mmol/L). Other significant results included hemoglobin 10.6 g/dL (NR 13-18 g/dL), mean corpuscular volume 98.1 fl (NR 82-98 fl), vitamin B12 157 ng/L (NR > 165 ng/L), folate 2.8 g/L (NR 3.1-17.5 μg/L), ferritin 252 μg/L (NR 30-250 μg/L), prothrombin time 20 s (NR 11-14 s), thyroid stimulating hormone 0.87 mu/L (NR 0.35-4.5 mu/L), phosphate 0.57 mmol/L (NR 0.8-1.45 mmol/L), albumin 32 g/L (NR 34-48 g/L) and alkaline phosphatase 313 IU/L (NR 47-141 IU/L). Subsequent results revealed vitamin D deficiency with a low serum 25-OH vitamin D of < 7 μg/L (NR 7-40 μg/L), a low 24-hour urinary calcium excretion of 0.9 mmol (NR 2.5-7.5 mmol) and a raised serum parathyroid hormone of 22.7 pmol/L (NR 1.6-6.9 pmol/L). Serology for tissue transglutaminase (tTG) antibodies was negative, and a serum IgA level of 4.95 g/L (NR 0.8-4.0 g/L) excluded selective IgA deficiency. Electrocardiograph at admission showed prolonged QT interval.

In view of cachexia, clubbing and negative tTG-antibodies, he was further investigated for an occult malignancy. Barium meal and follow through showed dilated proximal bowel loops and absence of normal feathery pattern of the jejunum, features suggestive of a malabsorptive state. Upper gastroscopic examination was normal; however, the duodenal biopsy showed partial and subtotal villous atrophy with increased intra-epithelial lymphocyte infiltration, consistent with the diagnosis of celiac disease.¹⁶

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