Water-soluble Vitamins and their Deficiencies

Water-soluble vitamins are soluble in the blood and minimally stored in the body, unlike fat-soluble vitamins. The most clinically important water-soluble vitamins include vitamin B1 (thiamin), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folate), vitamin B12 (cobalamin) (the last 2 being some of the most clinically important vitamins and discussed separately), and vitamin C (ascorbic acid). Many of these vitamins are critical components of different metabolic pathways and play important roles in normal cell function. Most are found in our daily diet, but some people with restrictive diets, malabsorptive conditions, or alcohol use disorder may present clinically with vitamin deficiencies and their consequences. Since they are water-soluble and excreted by the kidneys, most of these vitamins do not reach toxic levels.

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Overview

Definition

Vitamins are important organic substances that are required for normal metabolic functions These substances cannot be synthesized by the body; they must be ingested in the diet. The vitamins are divided into water-soluble and fat-soluble vitamins. 

  • The most clinically important water-soluble vitamins are the B vitamins and vitamin C. 
  • Deficiencies of these vitamins can lead to clinical manifestations.
  • In some cases, overuse can result in toxicity, but for most of the water-soluble vitamins, excess is simply excreted by the kidneys.
  • Intake recommendations are listed as a U.S. Recommended Dietary Allowance (RDA), which is the average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals. 

Summary of clinically important water-soluble vitamin deficiencies

Table: Summary of clinically important water-soluble vitamin deficiencies
VitaminClinical condition caused by deficiency
B1 (thiamin)
  • Beriberi:
    • Infantile beriberi
    • Dry beriberi
    • Wet beriberi
  • Wernicke-Korsakoff syndrome
B3 (niacin)Pellagra
Vitamin CScurvy
Folate and vitamin B12
  • Megaloblastic anemia
  • Neural tube defects (folate)
  • Peripheral neuropathy (especially B12)

Vitamin B1: Thiamin

Vitamin B1 is also known as thiamin. Thiamin deficiency causes the clinical syndromes of beriberi and Wernicke-Korsakoff syndrome.

Functions

  • Critical in energy metabolism:
    • An important cofactor for several key enzymes in the Krebs cycle, including:
      • Pyruvate dehydrogenase
      • α-Ketoglutarate dehydrogenase 
    • Important for growth, development, and normal cell function
  • Nerve functions:
    • Required for the propagation of cholinergic and serotonergic nerve impulses
    • Involved in myelin sheath maintenance
    • Deficiency produces neuropathy and other neurologic symptoms.

Absorption, metabolism, transport, and storage

  • Absorption:
    • Primarily in the jejunum and ileum
    • Absorbed through both active transport and passive diffusion
  • Thiamin diphosphate (TDP) (also known as thiamin pyrophosphate):
    • Metabolically active form of thiamin
    • Thiamin is transported in the blood in a dephosphorylated state.
    • Enters cells through active transport with an ATPase
    • Thiamin is activated to TDP via intracellular phosphorylation.
  • Half-life and storage:
    • Highest concentrations of thiamin are found in:
      • Skeletal muscles
      • Liver
      • Heart
      • Kidneys
      • Brain
    • Half-life: 10–20 days
    • Storage capacity is limited → continuous intake is required to maintain normal levels.
  • Excretion: urine

Daily requirement

Typical RDAs for thiamin:

  • Infants: 0.2–0.3 mg/day 
  • Children: increases from 0.5 mg at age 1 to 0.9 mg at ages 9–13
  • Males ≥ 14 years: 1.2 mg
  • Females ≥ 14 years: 1.0–1.4 mg depending on age and pregnancy/lactation status

Dietary sources

Thiamin is found in:

  • Whole grains and brown rice
  • Meat: pork and beef
  • Fish and seafood
  • Legumes
  • Yeast
  • Fortified breads, cereals, rice, and infant formula

Deficiency: beriberi and Wernicke-Korsakoff syndrome

Thiamin deficiency manifests as 2 types of clinical syndromes: beriberi and Wernicke-Korsakoff syndrome.

Beriberi:

  • Rare in developed countries
  • Infantile beriberi:
    • Occurs in infants breastfed by thiamine-deficient mothers
    • Presents clinically with:
      • Fulminant cardiac syndrome: cardiomegaly, tachycardia, cyanosis, dyspnea
      • Aphonic (soundless) crying
      • Vomiting
      • Agitation, purposeless movement, altered consciousness, and seizures
  • Dry beriberi:
    • Symmetrical peripheral neuropathy, including both sensory and motor defects, primarily in the distal extremities
    • Confusion
    • Difficulty speaking
    • Involuntary eye movements
  • Wet beriberi:
    • Signs and symptoms of cardiac involvement similar to infantile beriberi: cardiomegaly, tachycardia, cardiomyopathy, heart failure, and peripheral edema
    • Neuropathy

Wernicke-Korsakoff syndrome: 2 different syndromes that are different stages of the same disease.

  • Wernicke’s encephalopathy:
    • An acute encephalopathy requiring emergent treatment (20% mortality without treatment)
    • Symptoms include: peripheral neuropathy, ocular abnormalities (e.g., nystagmus, ophthalmoplegia), ataxia, aphasia, and confusion
  • Korsakoff psychosis:
    • A chronic thiamin deficiency, often occurring as a consequence of Wernicke’s encephalopathy
    • Symptoms include short-term memory deficits and confabulation with otherwise grossly normal cognition
  • Wernicke-Korsakoff syndrome is seen in patients with alcohol use disorder 8–10 times more than in the general population. 

Therapeutic uses and clinical relevance

  • Thiamin deficiency can occur in:
    • Patients with alcoholism, due to poor dietary intake
    • Patients on total parenteral nutrition (TPN) without adequate supplementation
    • Patients who have undergone bariatric surgery, due to malabsorption
    • Patients with AIDS, possibly due to malnutrition in a catabolic state
    • Patients with rapidly progressing hematologic malignancies
  • Treatment is with IV then oral thiamine supplementation depending on the severity of disease.
  • Symptoms of toxicity: none identified (the kidney can rapidly clear most excess thiamin, and thiamin is not stored in large amounts in the body)

Vitamin B2: Riboflavin

Vitamin B2 is known as riboflavin, and deficiency is rarely seen in the United States.

Functions

  • Involved in many metabolic pathways as an essential component of coenzymes
  • Involved in energy production in the Krebs cycle
  • Catalyzes multiple oxidation-reduction reactions
  • Important for normal growth, development, and cell function

Absorption, metabolism, transport, and storage

  • Hydrolysis of dietary riboflavin into free riboflavin in the stomach via gastric acid and proteolytic enzymes
  • Passive absorption via a transport system in the small intestine (this system can become saturated)
  • Free riboflavin is bound to albumin and some immunoglobulins in the blood.
  • Transported to the liver via the bloodstream
  • Free riboflavin is metabolized to its active form, flavin adenine dinucleotide (FAD), via intracellular ATP-dependent phosphorylation.
  • Stored as flavoproteins (flavin complexed with proteins) in limited amounts, primarily in the liver

Daily requirement

  • Infants: 0.3–0.4 mg/day 
  • Children 1–13 years: 0.5–0.9 mg/day
  • Adults: 1.0–1.6 mg/day depending on exact age, sex, and pregnancy/lactation status

Dietary sources

  • Milk
  • Eggs
  • Organ meats (e.g., liver and kidneys), lean meat, and fish
  • Green vegetables (e.g., asparagus, broccoli, spinach)
  • Yeasts
  • Fortified cereals and breads

Deficiency

  • Symptoms:
    • Stomatitis, cheilitis, and/or glossitis (inflammation of the mouth, lips, and/or tongue)
    • Pharyngitis (“sore throat”)
    • Seborrheic dermatitis 
    • Cataracts
    • Normochromic normocytic anemia
  • Due to inadequate intake in:
    • Vegan diets, especially in athletes
    • Heavy alcohol use
    • Pregnancy
    • Patients with anorexia nervosa
    • Malabsorption in celiac and other intestinal diseases
    • Long-term use of barbiturates
  • Rarely can be seen in patients with a condition known as Brown-Vialetto-Van Laere syndrome, which results from a congenital defect in riboflavin-dependent enzymes.

Therapeutic uses and clinical relevance

  • Therapeutic replacement in cases of deficiency due to inadequate intake
  • HIV patients with lactic acidosis due to certain antiretroviral medications (lactic acidosis can be reversed by riboflavin therapy)
  • Limited evidence suggests a role for its use in migraine prevention
  • Symptoms of toxicity: none identified (saturation of the absorption mechanisms and rapid excretion by the kidneys prevents toxic accumulation)

Vitamin B3: Niacin

Niacin is the generic name for a group of compounds including nicotinic acid, nicotinamide, and related derivatives. It is widely distributed in plant and animal foods. Niacin deficiency causes the clinical condition known as pellagra.

Functions

Niacin is required for most metabolic processes in the body:

  • Plays a critical role in oxidative and reduction reactions through its active forms:
    • NAD: 
      • Generally involved in catabolic reactions
      • Transfers energy from carbohydrates, fats, and proteins to ATP
    • NAD phosphate (NADP): 
      • Generally involved in anabolic reactions
      • Enables the synthesis of cholesterol and fatty acids
  • Catalyzes over 400 enzymatic reactions, more than any other vitamin-derived coenzyme
  • Participates in antioxidant function
  • Maintains genome integrity, affects gene expression, and is involved in cellular communication
  • Nerve function
  • Cholesterol production

Absorption, metabolism, transport, and storage

  • Most dietary niacin is in the form of NAD and NADP.
  • Dietary NAD and NADP are hydrolyzed 1st to nicotinamide and then some is converted to nicotinic acid by intestinal microbes.
  • Nicotinamide and nicotinic acid are absorbed in the small intestine via passive and facilitated diffusion.
  • Taken up by most cells in the body, where they are converted back to NAD and NADP.
  • NAD and NADP are most concentrated in the muscles and liver.
  • Excess niacin:
    • Some is taken up by RBCs (small storage form).
    • The rest is methylated and excreted in the urine.
  • Tryptophan can also be converted to nicotinamide in the liver using vitamin B6 as a cofactor.

Daily requirement

  • Infants and children: 2 mg/day starting at birth and increasing to 12 mg/day as the child grows 
  • Males ≥ 14 years of age: 16 mg/day
  • Females ≥ 14 years of age: 14 mg/day; 17–18 mg/day while pregnant/ lactating

Dietary sources

  • Meat, especially liver
  • Fish (e.g., salmon, tuna)
  • Poultry
  • Legumes, nuts, and seeds
  • Grains (e.g., brown rice)
  • Fortified cereals, breads, and infant formulas
  • Also synthesized from tryptophan (ability varies significantly between individuals)

Deficiency: pellagra

The clinical syndrome associated with niacin deficiency is called pellagra.

  • Symptoms of pellagra (“the 4 Ds”):
    • Dermatitis: photosensitivity leading to a symmetric, rough pigmented rash in sun-exposed areas
    • Diarrhea
    • Dementia: may include depression progressing to psychosis with memory loss
    • Death (rare)
  • Pellagra is rare in the United States except in certain at-risk populations:
    • Alcohol use disorder
    • Complication of bariatric surgery
    • Anorexia nervosa 
    • Malabsorptive conditions
    • Carcinoid syndrome
    • Hartnup disease: an autosomal recessive disorder resulting in defective absorption of tryptophan
Characteristic skin rash associated with pellagra Malabsorption

Characteristic skin rash associated with pellagra

Image: “This child has the skin rash associated with pellagra” by CDC. License: Public Domain

Therapeutic uses and clinical relevance

  • Used to treat pellagra (along with a B-complex vitamins or yeast product)
  • Niacin has lipid-lowering properties, especially total and LDL cholesterol:
    • Provides no significant protection against cardiovascular disease
    • Rarely used because more modern medications that are more effective at reducing cardiovascular events are available.

Toxicity

  • Not seen with foods containing niacin
  • At pharmacologic doses (1000–3000 mg/day), side effects include:
    • Flushing
    • Hypotension
    • GI effects:
      • Nausea
      • Vomiting
      • Constipation
    • Pruritus and hives 
    • Blurred vision and macular edema
    • Impaired glucose tolerance and insulin resistance
    • Hepatotoxicity and liver failure

Vitamin B5: Pantothenic Acid

Vitamin B5 is also known as pantothenic acid.

Functions

The biologically active form of vitamin B5 is coenzyme A (CoA):

  • Involved in many acetylation reactions in the body:
    • Krebs cycle
    • Histone modification
  • Involved in the synthesis and/or degradation of:
    • Carbohydrates, proteins, amino acids, and fatty acids
    • Cholesterol and steroids
    • Heme A
    • Vitamins A and D
  • Involved in the activation and inactivation of many peptide hormones, including adrenocorticotropic hormone (ACTH)

Absorption, metabolism, transport, and storage

  • About 85% of dietary pantothenic acid is in CoA or phosphopantetheine form → converted to pantothenic acid by digestive enzymes in the intestines
  • Intestinal flora can also produce pantothenic acid in unknown amounts.
  • Absorbed in the intestine and delivered to the blood by active transport
  • Transported by RBCs throughout the body
  • Stored in tissues in the form of CoA and other carrier proteins

Daily requirement

  • Infants: 1.7–1.8 mg/day 
  • Children: increases from 2 mg/day at age 1 to 4 mg/day at age 13
  • Adults: 5 mg, slightly higher during pregnancy and lactation

Dietary sources

  • Shiitake mushrooms
  • Sunflower seeds
  • Egg yolks
  • Organ meats (liver and kidney)
  • Beef and chicken
  • Broccoli
  • Dairy
  • Whole grains
  • Fortified cereals, breads, and formula

Clinical relevance

  • Deficiency:
    • Rarely seen because of wide distribution in food and synthesis by the gut flora, but can be seen in people with severe malnutrition (e.g., during war, famine)
    • Presents with paresthesias and dysesthesias of the hands and feet, known as burning feet syndrome
  • Not currently recommended in the treatment of any specific condition other than as part of a generally healthy diet
  • Symptoms of toxicity: none known 

Vitamin B6: Pyridoxine

Vitamin B6 is the generic name for 6 compounds, including pyridoxine, pyridoxal, pyridoxamine, and their phosphate esters.

Functions

Pyridoxal 5´-phosphate (PLP) and pyridoxamine 5´-phosphate (PMP) are the active forms of vitamin B6 and have the following functions:

  • Involved in many metabolic processes, mostly related to protein metabolism
  • Required for the production of RBCs
  • Used in glycogenolysis and gluconeogenesis
  • Used in the transamination process (converting essential amino acids to nonessential amino acids)
  • Take part in neurotransmitter production
  • Cofactor for the production of vitamin B3 (niacin)

Absorption, metabolism, transport, and storage

  • Phosphorylated forms of the vitamin are metabolized to free vitamin B6 before they absorbed.
  • Absorbed by passive diffusion in the jejunum
  • Phosphorylated to active forms in the liver
  • No significant storage in the body

Daily requirement

  • Infants: 0.1–0.3 mg/day 
  • Children 1–8 years of age: 0.5–0.6 mg/day
  • Children 9–13 years of age: 1.0 mg/day
  •  Adults: 1.3–2.0 mg/day for adults, based on sex, age, and pregnancy/lactation status

Dietary sources

Found in a wide variety of foods:

  • Garbanzo beans
  • Poultry
  • Fish
  • Organ meats (e.g., beef liver)
  • Fortified cereals
  • Potatoes and other starchy vegetables
  • Bananas

Deficiency

  • Patients with certain conditions are at risk for vitamin B6 deficiency:
    • Undergoing isoniazid treatment for tuberculosis
    • Impaired renal function and/or diabetes
    • Autoimmune disease, particularly rheumatoid arthritis
    • Malabsorption conditions: inflammatory bowel disease, celiac disease
    • Alcohol abuse
    • Pregnancy
    • Breast cancer and Hodgkin lymphoma
  • Symptoms of pyridoxine deficiency:
    • Stomatitis, cheilitis, and/or glossitis
    • Dermatitis
    • Confusion, irritability, and/or depression
    • Decreased immunity
    • Microcytic anemia

Therapeutic uses and clinical relevance

  • Vitamin B6 is recommended as 1st-line therapy in the treatment of nausea and vomiting in pregnancy.
  • Vitamin B6 supplements have been studied in (but are not currently recommended for) the treatment of:
    • Cancer
    • Cardiovascular disease
    • Cognitive decline

Toxicity

Vitamin B6 is among the only water-soluble vitamins that can cause significant toxicity if taken in high doses.

  • Not found due to regular dietary intake
  • High-dose supplements can cause:
    • Severe and progressive sensory neuropathy 
    • Ataxia
    • Painful skin lesions
    • Photosensitivity
    • Nausea and heartburn

Vitamin B7: Biotin

Functions

Cofactor for several carboxylases that catalyze critical steps in the metabolism of fatty acids, glucose, and amino acids. Biotin is involved in:

  • Histone modification
  • Gene regulation
  • Cell signaling
  • Cell replication
  • Protein synthesis 

Absorption, synthesis, and storage

  • In foods, biotin is bound to proteins.
  • Released from proteins and converted into its free form by GI enzymes
  • Also synthesized by gut microbes
  • Absorbed in the small intestine
  • Stored in the liver
  • Excretion:
    • Excess production in the gut is excreted in the feces.
    • Excess biotin in the serum is excreted in the urine.

Daily requirement

  • Infants: 5–6 µg/day 
  • Children: 6–12 µg/day
  • Teens: 20–25 µg/day 
  • Adults: 30 µg/day (35 µg/day during lactation)

Dietary sources

  • Egg yolk
  • Molasses/yeast
  • Soybean products/legumes
  • Beef liver

Deficiency

Dietary deficiency is extremely rare.

  • Symptoms:
    • Thinning and loss of hair (all over the body)
    • Dermatitis
    • Conjunctivitis
    • Brittle nails
    • Neurologic symptoms:
      • Lethargy
      • Paresthesias
      • Altered mental status
      • Hallucinations
  • Biotin deficiency may occur in:
    • Chronic alcoholism
    • Pregnant and breastfeeding women 
    • Rare genetic conditions related to biotin processing

Clinical relevance

  • Symptoms of toxicity: none known
  • High doses of biotin supplements can interfere with lab testing assays for:
    • Thyroid function tests
    • Ferritin
    • Troponin
    • Digoxin levels
    • Testosterone
    • Progesterone
    • BNP
  • Patients should abstain from taking high-dose biotin supplements (promoted as vitamins for hair, skin, and nails) for 3–4 days before lab testing.

Vitamin C: Ascorbic Acid

Vitamin C is an important antioxidant and is critical in wound healing and in the synthesis of collagen, among its many functions. Vitamin C deficiency causes the clinical condition scurvy.

Functions

  • Required for the synthesis of:
    • Collagen → essential for wound healing and connective tissue
    • Neurotransmitters
    • Carnitine
  • Has antioxidant properties, along with vitamins A and E
  • Improves absorption of iron from diet
  • Is a cofactor in the reduction of folate to dihydrofolate and tetrahydrofolate
  • Involved in many additional physiologic processes:
    • Protein metabolism
    • Fatty acid transport
    • Immune function

Absorption, transport, and storage

  • Absorbed in the distal small intestine via an active transporter
  • Blood levels are regulated by renal excretion of excess vitamin C in the urine.
  • Some storage in the adrenal glands, brain, and eyes

Daily requirement

  • Infants: 45–50 mg/day 
  • Children 1–13 years of age: 15–45 mg/day
  • People ≥ 14 years of age: 65–90 mg/day based on age, sex, and pregnancy status
  • Lactating females: 115–120 mg/day 

Dietary sources

  • Citrus fruits
  • Other fruits:
    • Kiwifruit
    • Strawberries
    • Cantaloupe
  • Vegetables:
    • Red and green peppers
    • Cabbage
    • Brussels sprouts
    • Broccoli
    • Cauliflower
    • Potatoes
    • Tomatoes

Deficiency: scurvy

Vitamin C deficiency leads to the clinical condition called scurvy and can be seen as soon as 1–3 months with little to no intake. 

  • Symptoms:
    • Delayed wound healing
    • Petechiae, purpura, and ecchymoses
    • Gingivitis with bleeding and loose teeth
    • Arthralgias
    • Follicular hyperkeratosis
    • Iron deficiency anemia due to ↓ iron absorption
  • Populations at risk:
    • Insufficient intake of fruits and vegetables:
      • Drug or alcohol abuse disorders
      • Poverty
      • Institutionalized people
      • Chronically ill patients
    • Cigarette smokers have lower levels of vitamin C (due to ↑ oxidative stress) → require increased intake
Child with vitamin C deficiency

Child with vitamin C deficiency:
A: Contractures and ecchymoses
B: Hyperkeratosis and follicular purpura with corkscrew hairs (arrow)
C: Hemorrhagic gingivitis and neurotic excoriations (arrow)

Image: “Childhood scurvy: an unusual cause of refusal to walk in a child” by Alqanatish JT, Alqahtani F, Alsewairi WM, Al-kenaizan S. License: CC BY 4.0

Therapeutic uses and clinical relevance

  • The only therapeutic use of vitamin C is to treat scurvy.
  • Symptoms of toxicity (due to excess supplementation, not dietary intake):
    • Kidney stones
    • Abdominal pain and diarrhea

References

  1. Pazirandeh, S., Burns, D.L. (2020). Overview of water-soluble vitamins. UpToDate. Retrieved May 7, 2021, from https://www.uptodate.com/contents/overview-of-water-soluble-vitamins
  2. National Institutes of Health Office of Dietary Supplements. (2021). Fact sheets for health professionals: thiamin, riboflavin, niacin, pantothenic acid, vitamin B6, biotin, and vitamin C. Retrieved May 12, 2021, from https://ods.od.nih.gov/factsheets/list-all/
  3. Goetzl, L.M. (2020). Folic acid supplementation in pregnancy. UpToDate. Retrieved May 12, 2021, from https://www.uptodate.com/contents/folic-acid-supplementation-in-pregnancy
  4. Fairfield, K.M. (2019). Vitamin supplementation in disease prevention. UpToDate. Retrieved May 12, 2021, from https://www.uptodate.com/contents/vitamin-supplementation-in-disease-prevention

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