Vitamin B6 (Pyridoxine) Deficiency

What Is Vitamin B6 (Pyridoxine)?

[dropcap]P[/dropcap]yridoxine is an essential vitamin that is required for the health of nerves, bones, blood, arteries, blood sugar, the immune system and metabolism of proteins.

Two important functions of pyridoxine involve coenzymes that are involved in regulating the metabolism of proteins like methionine and tryptophan and their intermediate amino acid building blocks.

In total, the coenzymic form of vitamin B-6, pyridoxal phosphate (PLP), serves as a coenzyme for over 140 enzymes in human metabolism.¹  Functions are more fully described below.

Magnesium is required for pyridoxine to actually attach to enzymes dependent on it.

Because pyridoxine is excreted from the body by the kidneys, urinary excretion of it cannot be detected when vitamin intake is below the required levels. On the other hand, when intake exceeds saturation in the body, the vitamin and/or its metabolites are actively excreted into urine to prevent excessive toxicity of the vitamins.²

Smoking blocks use of pyridoxine.

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

• Relationship between pyridoxine deficiency and celiac disease. Pyridoxine 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 vitamin which is caused by malabsorption. Plasma PLP (pyridoxal phosphate) level of less than 20 nmol/L reflects vitamin B-6 deficiency.³
• Relationship between pyridoxine deficiency and features. Metabolic analysis shows that marginal vitamin B6 deficiency has widespread metabolic perturbations.¹ Features include:

• • • Impaired ability of blood vessels to relax causing elevated blood pressure,
    • Impaired blood sugar regulation resulting in low levels,
    • Impaired metabolism of amino acids,
    • Impaired production of neurotransmitters,
    • Impaired stomach acid production resulting in poor digestion,
    • Impaired white blood cell production,
    • Impaired antibody production and cell mediated immunity resulting in susceptibility to infection,
    • Impaired production of fatty sheaths of nerve cells, and
    • Impaired production of the porphyrin precursor of heme in hemoglobin resulting in hypochromic small cell anemia with normal iron stores. (Note: If iron deficiency were the cause of this anemia, iron stores would be low.)

• Relationship between pyridoxine deficiency and tryptophan. Patients with adult celiac disease excrete abnormal amounts of tryptophan metabolites after loading with this amino acid, suggesting vitamin B6 deficiency in these patients. The excretion of tryptophan metabolites returns to normal after administration of vitamin B6.⁴
• Relationship between pyridoxine deficiency and niacin deficiency. Pyridoxine deficiency commonly accompanies and can cause vitamin B3 (niacin) deficiency.
• Relationship between pyridoxine deficiency and inflammation. Many inflammatory conditions occurring with celiac disease such as atherosclerosis, rheumatoid arthritis and inflammatory bowel disease are also associated with a lower vitamin B6 status in the body.⁵,⁶ These responses may be due to oxidative stress associated with vitamin B6 deficiency.⁷
• Relationship between pyridoxine deficiency and intestinal damage from celiac disease. Vitamin/mineral deficiencies are 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 celiac disease treatment.⁸

• Relationship between pyridoxine 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.⁹

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

Pyridoxine deficiency is common in people with untreated celiac disease.

A Dutch study in 80 newly diagnosed adult patients with celiac disease found the prevalence for vitamin B6 deficiency was 14.5%.⁸

What Are The Symptoms Of Pyridoxine Deficiency?

Pyridoxine deficiency is marked by these symptoms:

• Abnormal increased blood levels of homocysteine (leading to hardening of the arteries, heart disease and stroke).
• Anemia (causing fatigue, weakness, and breathlessness).
• Antibody production decreased.
• Apathy.
• Cheilosis (cracking at corners of mouth).
• Confusion.
• Convulsions (seizures) may occur in infancy.
• Depression.
• Elevated blood pressure due to impaired ability of blood vessels to relax.
• Frequent infections.
• Impaired cell immunity such as that which initially occurs when gluten contacts the intestinal mucosa.
• Irritability.
• Low white blood cell production.
• Paleness.
• Peripheral neuropathies (numbness, tingling or burning in feet).
• Sleeplessness.
• Seborrhea dermatitis.
• Status epilepticus (repetitive seizures) may occur.¹⁰
• Swollen, sore tongue with indentation marks from teeth along the sides and fissures.
• Weakness.

How Does The Body Get Pyridoxine?

• The various forms of pyridoxine appear to be absorbed in the small intestine by passive diffusion primarily in the jejunum and ileum.¹¹
• Because of the mucosal damage in the upper small intestine in celiac disease, absorption of pyridoxine in the distal parts of intestine seems to play an important role. Moreover, the site of absorption becomes progressively more distal (toward the colon) with increase in the amount of gluten that is consumed. The mechanism of pyridoxine absorption consists of two separate steps. The first is the entrance into the enterocyte by passive diffusion, the second is the metabolic conversion of pyridoxine into the phosphate forms. In acute celiac disease, activity of pyridoxal kinase is increased whereas concentration of pyridoxal phosphate is decreased in duodenal mucosa.¹²

What Does Pyridoxine Do In The Body?

1. Required for the production of more than 100 enzymes involved in protein metabolism.
2. Required for the release of glucose (sugar needed for energy) from glycogen (compacted glucose) stores in the liver to maintain blood glucose within a normal range.
3. Required for the conversion of the amino acid tryptophan to niacin (vitamin B3).
4. Required for the formation of the neurotransmitters (chemicals needed for nerve communication) serotonin, epinephrine, norepinephrine, and γ-aminobutyeric acid.
5. Required for the formation of histamine (dilates blood vessels and stimulates gastric secretions).
6. Required for the formation of hemoglobin (an oxygen carrying protein in blood cells).
7. Required for maintaining normal blood levels of homocysteine (a transitory amino acid).
8. Required for production of sphingolipids (fats) in the myelin sheaths sheaths (insulators) of nerve cells.
9. Required for maintaining the health of lymphoid organs (thymus, spleen, and lymph nodes) that make white blood cells and antibodies.

How Does Pyridoxine Deficiency Develop In Celiac Disease and/or Gluten Sensitivity?

• Pyridoxine deficiency in celiac disease results from malabsorption due to gluten enteropathy.
• Inflammation has been shown to deplete vitamin B6 in the body.¹³,¹⁴

Does Pyridoxine Deficiency Respond To Gluten-Free Diet?

Yes. Celiac disease-related pyridoxine deficiency responds to a gluten free diet containing adequate pyridoxine and supporting B vitamins.

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.¹⁵

6 Steps To Correct Pyridoxine Deficiency:

• [dropcap]1[/dropcap]Meet, or Exceed the RDA (Recommended Dietary Allowances) for Pyridoxine in milligrams (mg) per day:

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0.1 mg for infants birth-6 months; 0.3 mg for infants 7-12 months;

0.5 mg for children 1-3 years;

0.6 mg for children 4-8 years;

1.0 mg for children 9-13 years;

1.3 mg for male teens 14-18 years; 1.2 mg for female teens 14-18 years;

1.3 mg for males and non-pregnant females age 19-50 years;

1.7 mg for males 51 years and older; 1.5 mg for females 51 years and older;

1.9 mg for pregnancy; 2 mg for breastfeeding women.

High doses of vitamin B6 (200 mg or more per day)  can cause rash from sun exposure, headache, loss of appetite, loss of balance and feeling in the legs. These problems should resolve within 6 months of stopping.

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• [dropcap]2[/dropcap]Diet – Include Food Sources Richest in Pyridoxine in 100 grams:

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Plant sources:

• Peanut butter.
• Seeds – sunflower seeds, sesame seeds.
• Brown rice.
• Nuts – almonds, cashew, Brazil, walnuts.
• Avocado.
• Collard greens.
• Fruits – banana, orange, prunes.
• Potato.
• Beans.
• Brussels sprouts.

Animal sources: Animal sources are more available than plant sources.

• Liver.
• Fish – halibut, rainbow trout, canned sockeye salmon, and canned tuna.
• Poultry.
• Pork.
• Beef.
• Egg.
• Milk.[/box]

• dropcap]3[/dropcap] Diet – Avoid, Limit, or Eat Separately These Foods That Deplete or Interfere With Absorption:

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• Tobacco smoke blocks use of vitamin B6.[/box]

 

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

Certain prescription drugs deplete vitamin B6. Ask your doctor or pharmacist about possible interactions between pyridoxine supplements and medications you’re taking. For example, vitamin B6 may diminish the effectiveness of the medication L-DOPA in persons with Parkinson’s disease.

On the other side – Vitamin B6 makes these drugs less effective: Dilantin® (phenytoin)  used to treat seizures and levodopa used to treat Parkinson disease. Taking Vitamin B6 with Amiodarone (Cordarone®) used to treat irregular heartbeat with known sun sensitivity side effects may increase sunburn and blistering.

Here are common medications that deplete vitamin B6 thereby increasing risk for vitamin B6 deficiency and should to be monitored:

ANTI-HYPERTENSIVES (Catapres®, Aldomet®). ANTI-INFLAMMATORIES – Disrupt Intestinal permeability. Corticosteroids (Prednisone, Medrol®, Aristocort®, Decadron). ANTIBIOTICS – Disrupt Intestinal permeability. Tetracyclines. ANTI-TUBERCULOSIS Isoniazid®. Seromycin®.

FEMALE HORMONES – Disrupt Intestinal permeability. Oral Contraceptives (Norinyl®, Ortho-Novum®, Triphasil®, and others). Oral Estrogen/Hormone Replacement (Evista®, Prempro®, Premarin®, Estratab® and others). LOOP DIURETICS (Lasix®, Bumex®, Edecrin®). ASTHMA Theophylline. BLOOD ANEMIA Erythropoietin®.

 

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

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• A blood level concentration  should be obtained to determine status before supplementing.
• Pyridoxine is available without prescription in regular and extended-release (long-acting) tablets and as part of multivitamin supplements to be taken by mouth.
• The upper tolerable limit is 100 mg per day for adults.
• Natural preparations made from food are superior to synthetic ones which are manufactured from petroleum.
• 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, in eye drops it damages the eye surface), propylparaben, paraben, polyethylene glycol, propylene glycol (propanediol), polysorbate 60.

Caution: Supplementation with pyridoxine at doses greater than 50 mg/d for extended duration may be harmful and should be discouraged.¹⁶

Doses between 200 mg and 1,000 mg for long periods have been associated with peripheral neuropathy and progressive sensory ataxia. Although, persons with drug induced neuritis may tolerate doses higher than 100 mg.

 Storage Note: Store container tightly sealed, away from heat, moisture and direct light to avoid loss of potency. That is, in a safe kitchen cabinet  – not in the bathroom or on the kitchen table.[/box]

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

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• None reported. Check with your pharmacist.[/box]

Medical Research Findings On Pyridoxine Deficiency In Celiac Disease and/or Gluten Sensitivity:

RESEARCH STUDY SUMMARIES

“Inadequate nutrient intake in patients with celiac disease: results from a German dietary survey.” This study investigating the nutritional composition of a gluten free diet and to compare it with non-gluten free diet in a representative German non-celiac disease population found that male and female celiac patients in Germany have inadequate nutrient intakes. Data from 88 patients aged 14-80 years who filled out a prospective 7-day food diary and a questionnaire were analyzed and compared to the DACH reference values and to data from the German National Diet and Nutrition Survey (NVS II).

Results: The average daily micronutrient intake of male and female patients, specifically of vitamin B1, B2, B6, folic acid, magnesium and iron, was significantly lower in celiac patients compared to the NVS II. Based on these findings, regular (laboratory) monitoring of celiac patients should be recommended.¹⁷.

“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 B6 deficiency was 14.5%.

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, vitamin B6, vitamin B12, and (25-hydroxy) vitamin D, zinc, haemoglobin (Hb) and ferritin (iron) 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.⁸

“Metabolomic analysis reveals extended metabolic consequences of marginal vitamin B-6 deficiency in healthy human subjects.” This study investigating the effects of marginal pyridoxine (vitamin B6) deficiency demonstrated that marginal vitamin B-6 deficiency has widespread metabolic perturbations and illustrate the utility of metabolomics in evaluating complex effects of altered vitamin B-6 intake. Pyridoxal 5′-phosphate (PLP) serves as a coenzyme in the metabolism of amino acids, carbohydrates, organic acids, and neurotransmitters, as well as in aspects of one-carbon metabolism, and therefore vitamin B-6 deficiency has many effects.

Twenty-three healthy men and women aged 20 to 40 years old were fed a 2-day controlled, nutritionally adequate diet followed by a 28-day low-vitamin B-6 diet (<0.5 mg/d) to induce marginal deficiency, as reflected by a decline of plasma PLP from 52.6±14.1 to 21.5±4.6 nmol/L and increased cystathionine from 131±65 to 199±56 nmol/L. Fasting plasma samples obtained before and after vitamin B6 restriction were analyzed by (1)H-NMR with and without filtration and by targeted quantitative analysis by mass spectrometry (MS). NMR spectral features of selected metabolites indicated that vitamin B-6 restriction significantly increased the ratios of glutamine (amino acid) to glutamate and 2-oxoglutarate/glutamate and tended to increase concentrations of acetate, pyruvate, and trimethylamine-N-oxide. Tandem MS showed significantly greater plasma proline (amino acid) after vitamin B-6 restriction, but there were no effects on the profile of 14 other amino acids and 45 acylcarnitines.¹⁸

“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.¹⁹

“Vitamin B-6 absorption in children with acute celiac disease and in control subjects.” This study investigating pyridoxine deficiency in children with celiac disease demonstrated both a malabsorption of pyridoxine in childhood celiac disease and a shifting of the site of pyridoxine absorption from the upper part of jejunum into the more distal parts of intestine.

The concentration of serum pyridoxal phosphate was determined before and 15, 30, 60, 90, and 120 minutes following an oral load test with 5 mg pyridoxine hydrochloride/kg body weight in 14 children with acute celiac disease and in 15 control subjects. Children with acute celiac disease suffer from a biochemical vitamin B-6 deficiency. The increase in pyridoxal phosphate of children with acute celiac disease after loading was significantly decreased when compared with that of control subjects. In children with celiac disease maximal concentration of serum pyridoxal phosphate appeared later (after 60 minutes) and was decreased in comparison to control subjects (after 30 minutes). A positive correlation existed between the net increase of pyridoxal phosphate 60 minutes following pyridoxine loading and the net increase of blood xylose 60 minutes after oral loading.²⁰

CASE REPORT SUMMARIES

“Vitamin B Deficiencies in a Critically Ill Autistic Child With a Restricted Diet.” An 11-year-old male with autism became less responsive and was hospitalized with hepatomegaly and liver dysfunction, as well as severe lactic acidosis. His diet for several years was self-limited exclusively to a single “fast food”-a particular type of fried chicken-and was deficient in multiple micronutrients, including the B vitamins thiamine and pyridoxine. Lactic acidosis improved rapidly with thiamine; 2 weeks later, status epilepticus-with low serum pyridoxine-resolved rapidly with pyridoxine. Dietary B vitamin deficiencies complicated the care of this critically ill autistic child and should be considered in this setting.²¹

 

Sources:

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7. Gregory JF 3rd1, Park Y, Lamers Y, Bandyopadhyay N, Chi YY, Lee K, Kim S, da Silva V, Hove N, Ranka S, Kahveci T, Muller KE, Stevens RD, Newgard CB, Stacpoole PW, Jones DP. Metabolomic analysis reveals extended metabolic consequences of marginal vitamin B-6 deficiency in healthy human subjects. PLoS One. 2013 Jun 11;8(6):e63544. doi: 10.1371/journal.pone.0063544. [↩]
8. Wierdsma NJ, van Bokhorst-de van der Schueren MA, Berkenpas M, Mulder CJ, van Bodegraven AA. Vitamin and mineral deficiencies are highly prevalent in newly diagnosed celiac disease patients. Nutrients. 2013 Sep 30;5(10):3975-92. doi: 10.3390/nu5103975. [↩] [↩] [↩]
9. Lim PO, Tzemos N, Farquharson CA, et al. Reversible hypertension following coeliac disease treatment: the role of moderate hyperhomocysteinaemia and vascular endothelial dysfunction. Journal of Human Hypertension. Jun 2002;16(6):411-5. [↩]
10. Baird JS1, Ravindranath TM2. Vitamin B Deficiencies in a Critically Ill Autistic Child With a Restricted Diet. Nutr Clin Pract. 2014 Aug 11. pii: 0884533614541483. [↩]
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12. Reinken L, Zieglauer H. Vitamin B-6 absorption in children with acute celiac disease and in control subjects. J Nutr. 1978 Oct;108(10):1562-5. [↩]
13. Lotto V, Choi SW, Friso S. Vitamin B6: a challenging link between nutrition and inflammation in CVD. Br J Nutr. 2011 Jul;106(2):183-95. doi: 10.1017/S0007114511000407. [↩]
14. Chiang EP1, Smith DE, Selhub J, Dallal G, Wang YC, Roubenoff R. Inflammation causes tissue-specific depletion of vitamin B6. Arthritis Res Ther. 2005;7(6):R1254-62. [↩]
15. Hallert C, Svensson M, Tholstrup J, Hultberg B. Clinical trial: B vitamins improve health in patients with coeliac disease living on a gluten-free diet. Aliment Pharmacol Ther. 2009 Apr 15;29(8):811-6. doi: 10.1111/j.1365-2036.2009.03945.x. [↩]
16. Ghavanini AA1, Kimpinski K. Revisiting the evidence for neuropathy caused by pyridoxine deficiency and excess. J Clin Neuromuscul Dis. 2014 Sep;16(1):25-31. doi: 10.1097/CND.0000000000000049. [↩]
17. Martin J, Geisel T, Maresch C, Krieger K, Stein J. Inadequate nutrient intake in patients with celiac disease: results from a German dietary survey. Digestion. 2013;87(4):240-6. doi: 10.1159/000348850. [↩]
18. Gregory JF 3rd1, Park Y, Lamers Y, Bandyopadhyay N, Chi YY, Lee K, Kim S, da Silva V, Hove N, Ranka S, Kahveci T, Muller KE, Stevens RD, Newgard CB, Stacpoole PW, Jones DP. Metabolomic analysis reveals extended metabolic consequences of marginal vitamin B-6 deficiency in healthy human subjects. PLoS One. 2013 Jun 11;8(6):e63544. doi: 10.1371/journal.pone.0063544. Print 2013. [↩]
19. Hallert C, Svensson M, Tholstrup J, Hultberg B. Clinical trial: B vitamins improve health in patients with coeliac disease living on a gluten-free diet. Aliment Pharmacol Ther. 2009 Apr 15;29(8):811-6. doi: 10.1111/j.1365-2036.2009.03945.x. [↩]
20. Reinken L, Zieglauer H. Vitamin B-6 absorption in children with acute celiac disease and in control subjects. J Nutr. 1978 Oct;108(10):1562-5. [↩]
21. Baird JS1, Ravindranath TM2. Vitamin B Deficiencies in a Critically Ill Autistic Child With a Restricted Diet. Nutr Clin Pract. 2014 Aug 11. pii: 0884533614541483. [↩]