Pyridoxine deficiency

Pyridoxine deficiency also known as vitamin B6 deficiency is associated with microcytic anemia, electroencephalographic (EEG) abnormalities, dermatitis with cheilosis (scaling on the lips and cracks at the corners of the mouth) and glossitis (swollen tongue), depression and confusion, and weakened immune function ¹. Individuals with borderline vitamin B6 concentrations or mild deficiency might have no deficiency signs or symptoms for months or even years. In infants, vitamin B6 deficiency causes irritability, abnormally acute hearing, and convulsive seizures ¹.

Isolated vitamin B6 deficiency (pyridoxine deficiency) is uncommon; inadequate vitamin B6 status is usually associated with low concentrations of other B-complex vitamins, such as vitamin B12 (cobalamins) and folic acid (vitamin B-9) ¹. Vitamin B6 deficiency causes biochemical changes that become more obvious as the deficiency progresses ¹.

End-stage renal diseases, chronic renal insufficiency, and other kidney diseases can cause vitamin B6 deficiency ². In addition, vitamin B6 deficiency can result from malabsorption syndromes, such as celiac disease, Crohn’s disease, and ulcerative colitis. Certain genetic diseases, such as homocystinuria, can also cause vitamin B6 deficiency ¹. Some medications, such as antiepileptic drugs, can lead to deficiency over time.

Vitamin B6 is a water-soluble vitamin that is naturally present in many foods, added to others and available as a dietary supplement. Vitamin B6 is the generic name for six compounds (vitamers) with vitamin B6 activity: pyridoxine, an alcohol; pyridoxal, an aldehyde; and pyridoxamine, which contains an amino group; and their respective 5’-phosphate esters ³. Pyridoxal 5’ phosphate (PLP) and pyridoxamine 5’ phosphate (PMP) are the active coenzyme forms of vitamin B6 ⁴. Substantial proportions of the naturally occurring pyridoxine in fruits, vegetables, and grains exist in glycosylated forms that exhibit reduced bioavailability ².

Vitamin B-6 or pyridoxine is important for normal brain development and for keeping the nervous system and immune system healthy. Vitamin B6 (pyridoxine) is involved as a cofactor in over 100 enzyme reactions including amino acid metabolism, particularly homocysteine; carbohydrate metabolism, including gluconeogenesis and glycogenolysis; and lipid metabolism. Vitamin B-6 has a role in cognitive development thru neurotransmitter synthesis, immune function with interleukin-2 production, and hemoglobin formation.

Fetal brain development requires adequate vitamin B6 (pyridoxine) and this continues throughout infancy. Vitamin B6 recommendations are made in accordance with age and life stage with pregnancy and breastfeeding involving the highest recommended daily allowance (see Table 1 below) ⁵.

The human body cannot store viaymin B6, and thus a daily source is required. The recommended daily amount of vitamin B-6 for adults is is 1 to 1.7 mg per day. Children ages 1 to 3 are recommended to have 0.5 mg per day, and those 3 to 13 are recommended to have 1 mg per day. During pregnancy and lactation, the recommendations are 1.9 mg and 2 mg per day (see Table 1 below). Food sources of vitamin B-6 include beef liver and other organ meats, poultry, fish, potatoes and other starchy vegetables, chickpeas and bananas (see Table 2 below). There appears to be a bioavailability preference for meat over plant source B6. This may be important to those who favor a plant-based diet exclusively. These individuals may need added supplementation.

The most common vitamin B6 vitamer in supplements is pyridoxine in the form of pyridoxine hydrochloride [HCl], although some supplements contain pyridoxal 5’ phosphate (PLP). Vitamin B6 supplements are available in oral capsules or tablets (including sublingual and chewable tablets) and liquids. Absorption of vitamin B6 from supplements is similar to that from food sources and does not differ substantially among the various forms of supplements ⁶. Although the body absorbs large pharmacological doses of vitamin B6 well, it quickly eliminates most of the vitamin in the urine ⁷.

About 28%–36% of the general population uses supplements containing vitamin B6 ⁸. Adults aged 51 years or older and children younger than 9 are more likely than members of other age groups to take supplements containing vitamin B6.

Table 1: Recommended Dietary Allowances (RDAs) for Vitamin B6 (pyridoxine)

Age	Male	Female	Pregnancy	Lactation
Birth to 6 months	0.1 mg*	0.1 mg*
7–12 months	0.3 mg*	0.3 mg*
1–3 years	0.5 mg	0.5 mg
4–8 years	0.6 mg	0.6 mg
9–13 years	1.0 mg	1.0 mg
14–18 years	1.3 mg	1.2 mg	1.9 mg	2.0 mg
19–50 years	1.3 mg	1.3 mg	1.9 mg	2.0 mg
51+ years	1.7 mg	1.5 mg

Footnotes:

• Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.
• Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.

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The average diet for adults is estimated to include 6 to 10 mg of Pyridoxine vitamers. Excessive amounts exceed 250 mg per day and, on a chronic basis, may result in toxicity leading to untoward effects on skin, gastrointestinal and the neurologic system ⁹. It is rare to develop vitamin B6 toxicity for an individual on ordinary food diets without supplementation. Excessive supplementation for chronic periods (months to greater than a year) has resulted in sensory neuropathies and movement disorders. The severity of symptoms is dose-dependent. Additional clinical findings of toxicity may include photosensitivity, gastrointestinal symptoms such as nausea and heartburn, as well as painful dermatological eruptions. These symptoms resolve for the most part over time with the elimination of the B6 supplement. The vitamin B6 toxicity-induced sensory polyneuropathy causes decreased touch, temperature, and vibration sensation and results in poor coordination ⁹.

Vitamin B6 concentrations can be measured directly by assessing concentrations of pyridoxal 5’ phosphate (PLP); other vitamers (i.e., pyridoxine, pyridoxal and pyridoxamine); or total vitamin B6 in plasma, erythrocytes, or urine ⁶. Vitamin B6 concentrations can also be measured indirectly by assessing either erythrocyte aminotransferase saturation by pyridoxal 5’ phosphate (PLP) or tryptophan metabolites. Plasma pyridoxal 5’ phosphate (PLP) is the most common measure of vitamin B6 status.

Pyridoxal 5’ phosphate (PLP) concentrations of more than 30 nmol/L have been traditional indicators of adequate vitamin B6 status in adults ². However, the Food and Nutrition Board at the Institute of Medicine of the National Academies used a plasma pyridoxal 5’ phosphate (PLP) level of 20 nmol/L as the major indicator of adequacy to calculate the Recommended Dietary Allowances (RDAs) for adults ².

Vitamin B6 pyridoxine functions

The human body absorbs vitamin B6 in the jejunum. Phosphorylated forms of the vitamin are dephosphorylated, and the pool of free vitamin B6 is absorbed by passive diffusion ⁴.

Vitamin B6 in coenzyme forms performs a wide variety of functions in your body and is extremely versatile, with involvement in more than 100 enzyme reactions, mostly concerned with protein metabolism ⁶. Both pyridoxal 5’ phosphate (PLP) and pyridoxamine 5’ phosphate (PMP) are involved in amino acid metabolism, and pyridoxal 5’ phosphate (PLP) is also involved in the metabolism of one-carbon units, carbohydrates, and lipids ². Vitamin B6 also plays a role in cognitive development through the biosynthesis of neurotransmitters and in maintaining normal levels of homocysteine, an amino acid in the blood ². Vitamin B6 is involved in gluconeogenesis and glycogenolysis, immune function (for example, it promotes lymphocyte and interleukin-2 production), and hemoglobin formation ².

Pyridoxine is the emergency antidote for isoniazid (INH) overdose, ethylene glycol, hydralazine, and gyromitrin mushroom poisoning. The two most common uses of vitamin B6 are in the treatment of the toxicological emergencies: isoniazid and ethylene glycol overdoses. In isoniazid overdose-related seizure, the dose is 5 grams in adults and 1 gram in children unless the amount of isoniazid is specifically known. Pyridoxine can be given at a rate of 0.5 to 1 gram/minute until seizures stop or maximum dose given. Patients who are asymptomatic and have not had seizures after a potentially toxic ingestion of isoniazid within 2 hours, should receive the recommended dose of pyridoxine. In ethylene glycol overdose, vitamin B6 is recommended at 50 to 100 mg IV every 6 hours to facilitate shunting the metabolism of ethylene glycol to nontoxic pathways leading to glycine (nontoxic) instead of toxic pathways leading to toxic metabolites such as formate. Additionally, vitamin B6 (pyridoxine) is used preventatively during isoniazid therapy of tuberculosis to prevent isoniazid-induced polyneuropathy.

Sources of vitamin B6 (pyridoxine)

Vitamin B6 is found in a wide variety of foods ². The richest sources of vitamin B6 include fish, beef liver and other organ meats, potatoes and other starchy vegetables, and fruit (other than citrus). In the United States, adults obtain most of their dietary vitamin B6 from fortified cereals, beef, poultry, starchy vegetables, and some non-citrus fruits ¹⁰. About 75% of vitamin B6 from a mixed diet is bioavailable ⁶.

The table of selected food sources of vitamin B6 suggests many dietary sources of vitamin B6.

Table 2: Selected Food Sources of Vitamin B6 (pyridoxine)

Food	Milligrams (mg) per serving	Percent DV*
Chickpeas, canned, 1 cup	1.1	55
Beef liver, pan fried, 3 ounces	0.9	45
Tuna, yellowfin, fresh, cooked, 3 ounces	0.9	45
Salmon, sockeye, cooked, 3 ounces	0.6	30
Chicken breast, roasted, 3 ounces	0.5	25
Breakfast cereals, fortified with 25% of the DV for vitamin B6	0.5	25
Potatoes, boiled, 1 cup	0.4	20
Turkey, meat only, roasted, 3 ounces	0.4	20
Banana, 1 medium	0.4	20
Marinara (spaghetti) sauce, ready to serve, 1 cup	0.4	20
Ground beef, patty, 85% lean, broiled, 3 ounces	0.3	15
Waffles, plain, ready to heat, toasted, 1 waffle	0.3	15
Bulgur, cooked, 1 cup	0.2	10
Cottage cheese, 1% low-fat, 1 cup	0.2	10
Squash, winter, baked, ½ cup	0.2	10
Rice, white, long-grain, enriched, cooked, 1 cup	0.1	5
Nuts, mixed, dry-roasted, 1 ounce	0.1	5
Raisins, seedless, ½ cup	0.1	5
Onions, chopped, ½ cup	0.1	5
Spinach, frozen, chopped, boiled, ½ cup	0.1	5
Tofu, raw, firm, prepared with calcium sulfate, ½ cup	0.1	5
Watermelon, raw, 1 cup	0.1	5

Footnotes: *DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin B6 used for the values in Table 2 is 2 mg for adults and children age 4 years and older ¹¹. This DV, however, is changing to 1.7 mg as the updated Nutrition and Supplement Facts labels are implemented ¹². The updated labels must appear on food products and dietary supplements beginning in January 2020, but they can be used now ¹³. FDA does not require food labels to list vitamin B6 content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

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Pyridoxine deficiency causes

In the United States and other western cultures, pyridoxine deficiency is rare with adequate diets, including vitamin B6 sources from poultry, fish, organ meats, potatoes, grains, legumes and noncitrus fruits ⁹.

Vitamin B6 deficiency is rare in isolation and usually found in association with other B vitamin deficiencies such as folic acid (vitamin B9) and vitamin B12 (cobalamins).

Low plasma levels of active vitamin B6 (pyridoxine) are found in chronic alcohol dependence, with obese states, pregnancy, preeclampsia and eclampsia, and malabsorptive states such as celiac, inflammatory bowel disease, and bariatric surgery ⁹.

Additional at-risk groups with inadequate intake or increased metabolic requirements may become functionally deficient in vitamin B6 (pyridoxine). Included in this group are those with renal impairment, autoimmune disorders, and chronic alcohol use. Patients with chronic renal failure, especially those receiving hemodialysis or peritoneal dialysis, have low plasma levels of vitamin B6 (pyridoxine). Autoimmune disorders, such as rheumatoid arthritis, have increased catabolism of B6, resulting in higher demand for dietary supplementation of vitamin B6 (pyridoxine).

Of great clinical importance in toxicology is that drug antagonists to vitamin B6 occurs with the tuberculosis medicine isoniazid. Also, penicillamine and levodopa, as well as some anticonvulsant medications, may interfere with B6 metabolism ¹⁴.

Pyridoxine deficiency symptoms

Vitamin B6 deficiency or pyridoxine deficiency may present with seizures in the young. Severely pyridoxine deficient adults commonly present with rashes and mental status changes. Additional clinical findings of pyridoxine deficiency may include normocytic anemia, a nonspecific pruritic rash, cheilitis with scaly lip skin and cracks in the corner of the mouth and glossitis (swelling of the tongue). Depression is associated with a severe vitamin B6 deficiency as well.

Current studies are evaluating the role of vitamin B6 deficiency in heart disease, cancer, and cognitive decline as medical conditions that may respond to supplementation. To date, there is no clear evidence to support supplement use beyond the normal dietary intake. However, some studies indicate a reduction of symptoms in the premenstrual syndrome with supplementation of vitamin B6, particularly a decrease in moodiness, irritability, and forgetfulness. The American College of Obstetrics and Gynecology recommend vitamin B6 supplementation (1.9 mg per day) for hyperemesis gravidarum ¹⁵.

Research on the use of vitamin B-6 for specific conditions shows:

• Heart and blood vessel disease and stroke. Vitamin B-6 has been shown to work together with folate (vitamin B-9) and vitamin B-12 to control high levels of homocysteine in the blood. Elevated homocysteine levels might increase your risk of diseases of the heart and blood vessels (cardiovascular disease). However, research hasn’t shown that taking this mix of supplements reduces the risk or severity of cardiovascular disease and stroke.
• Morning sickness. Vitamin B-6 might reduce the severity of morning sickness during pregnancy. If you have persistent morning sickness symptoms, your pregnancy care provider might prescribe vitamin B-6 supplements.
• Premenstrual syndrome (PMS). There is some evidence that vitamin B-6 might reduce symptoms of PMS, however these studies are considered to be low quality.
• Sideroblastic anemia. Vitamin B-6 is effective at treating this genetic type of anemia.

Pyridoxine deficiency diagnosis

Early or subclinical vitamin B6 deficiency may have vague or fleeting symptoms; however, new onset sensory polyneuropathy, altered mental status, dermatitis in adults, or seizures in infancy should raise clinical suspicion of a clinically significant B6 deficiency. Testing for vitamin B6 can be difficult in real time in many clinical scenarios. Direct serum measurement of the active vitamin pyridoxal 5′-phosphate (PLP) form is available in some clinical settings, however, the assay is not widely available or timely. A clinical alternative is an indirect measurement technique of vitamin B6, which includes measuring urinary excretion of xanthurenic acid (an amino acid catabolite of tryptophan) following a measured bolus of tryptophan. Increased levels of xanthurenic acid may indicate inadequate active B6 for the formation of the amino acid tryptophan.

History should be targeted, and age focused. In the neonate with seizures, mothers with poor nutritional status may be suggestive of a vitamin B6 deficiency. Also, consideration should be given to inborn error of metabolism that is Vitamin B6-dependent.

The older patient should be questioned on nutritional intake, supplement use, and medication history. Also critically important is eliciting a history of potential malabsorption syndromes which have been strongly associated with Vitamin B6 deficiency such as inflammatory bowel disease, celiac, or surgery of the small intestines including bariatric surgery. On a review of systems, the finding of weakness, mental status change, paresthesias, or other sensory or dermatological symptoms may suggest the diagnosis.

Physical exam findings may include confusion and skin lesions, particularly facial lesions such as stomatitis, glossitis, seborrheic dermatitis, and angular cheilitis. Objective physical findings may include peripheral neuropathies, skin photosensitivity, and movement disorders.

Pyridoxine deficiency treatment

In vitamin B6-deficient states and illnesses, treatment dosage is variable and depends on the severity of symptoms. The vitamin is available therapeutically in both oral and parenteral formulations. Neonates with B6 deficiency seizures may require 10 to 100 mg intravenous (IV) for effective treatment of active seizures. Less serious or less acute presentations can be supplemented with doses ranging from 25 mg to 600 mg per day orally depending on symptom complex.

Importantly, vitamin B6 therapy can be life-saving in refractory isoniazid (INH) overdose-induced seizures. The dose is equal to the known amount of isoniazid ingested or a maximum of 5 gms and is dosed 1 to 4 grams IV as the first dose, then 1 g IM or IV every 30 minutes. In ethylene glycol overdose, vitamin B6 is recommended at 50 to 100 mg IV every 6 hours to facilitate shunting the metabolism of ethylene glycol to nontoxic pathways leading to glycine (nontoxic) instead of toxic pathways leading to toxic metabolites such as formate.

Additional, less common uses are in hydralazine overdose where the recommended dose of vitamin B6 is 25 mg/kg, the first third administered intramuscularly and the remainder as a 3-hour IV infusion. Gyromitra (mushroom) toxicity treatment is at 25 mg/kg infused IV over 30 min.

Hyperemesis gravidarum may respond to vitamin B6 at a dosage of 25 mg orally every 8 hours.

Pyridoxine deficiency prognosis

The outcomes for patients with vitamin B6 deficiency are good if supplementation is undertaken before severe deficits have developed.

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