Fat-soluble Vitamins and their Deficiencies

Fat-soluble vitamins are absorbed and stored in adipose tissue (fat) and the liver. These vitamins can be released from storage and used when necessary. The 4 important fat-soluble vitamins are A, D, E, and K. Each vitamin has its own function, and deficiencies can lead to significant clinical manifestations. Diagnosis of deficiencies is by clinical presentation and lab testing, and management of vitamin deficiency is with supplementation. Because these vitamins are fat-soluble and stored in the body, overuse of supplemental vitamins may lead to toxicity and adverse effects, especially with vitamins A and D.

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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. They are divided into water-soluble and fat-soluble vitamins. 

  • The most clinically important fat-soluble vitamins are the vitamins A, D, E, and K. 
  • Deficiencies and overuse of these vitamins can lead to clinical manifestations.
  • 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. 
  • There may be special circumstances in infants or elderly or pregnant patients.

Absorption and storage

Fat-soluble vitamins are absorbed from the intestines with fat. In general, this process requires:

  • Lingual and gastric lipases
  • Bile salts for solubilization and production of micelles
  • Pancreatic lipases
  • Intestinal mucosal absorption
  • Packaging into chylomicrons within the intestinal mucosal cells
  • Chylomicrons are sent to the liver via the lymphatics for processing.
  • Fat-soluble vitamins are stored in adipose tissue.

Groups at higher risk for deficiency

For all of the fat-soluble vitamins, patients with fat-malabsorption issues are at higher risk for deficiency. These conditions include:

  • Pancreatic insufficiency (results in insufficient lipase) from cystic fibrosis, chronic pancreatitis, or pancreatectomy 
  • Cholestatic liver disease (results in insufficient bile)
  • Celiac disease
  • Crohn disease
  • Short bowel syndrome
  • Patients with a history of some types of bariatric surgery

Mnemonic

To remember the fat-soluble vitamins, use the saying: “The Fat cat is in the ADEK (pronounce it like attic).”

Vitamin A: Retinoids

Forms

Known as retinoids, vitamin A comes in several active forms and several precursor forms:

  • Retinol and retinyl esters: storage form
  • Retinal: part of the rhodopsin complex in rod cells (responsible for light and motion detection)
  • Retinoic acid: important for cell differentiation
  • Beta-carotene: a vitamin A precursor

Functions

  • Vision: 
    • Rhodopsin and retinal play important roles in night vision.
    • Retinal starts in the all-trans configuration → converted to the 11-cis-retinal configuration when a photon is absorbed
    • This conformational change activates transducin, which ultimately results in the closing of calcium channels → decreases neurotransmitter release
    • ↓ Neurotransmitters: signal to the brain that light has been detected
    • To remember that vitamin A is important for vision, think “retina” in the eye.
  • Cell differentiation: 
    • Retinoic acid affects gene expression and cell differentiation.
    • Critical to the development of the eyes, heart, lungs, and kidneys
  • Vitamin A is also involved in:
    • Skin epithelialization
    • Growth
    • Immune function
    • Reproduction
  • Vitamin A is an antioxidant.
Steps in light detection Vitamin A

Steps in light detection in the cone or rods cells mediated by the retinal form of vitamin A, found in rhodopsin
cGMP: cyclic guanosine monophosphate
GDP: guanosine diphosphate
GMP: guanosine monophosphate
GTP: guanosine triphosphate

Image by Kevin Ahern, PhD.

Absorption, metabolism, transport, and storage

  • Different forms of vitamin A are absorbed in the small intestine from dietary sources. 
  • These different forms are hydrolyzed into retinol at the mucosal brush border.
  • Retinols are re-esterified, incorporated into chylomicrons, and then excreted into the lymphatics, where they are moved to the liver.
  • Most of the total body retinol is stored in the liver.

Daily requirements

Typical RDAs for vitamin A are: 

  • Children ≤ 8 years of age (varies based on exact age): 300–500 µg 
  • Children 9–13: 600 µg
  • Females ≥ 14 years: 700 µg (higher if pregnant or lactating)
  • Males ≥ 14 years: 900 µg

Dietary sources

Mostly from yellow and orange foods: 

  • Highest sources: liver and fish oil
  • Other animal sources:
    • Dairy
    • Egg yolks
  • Orange plants:
    • Carrots
    • Sweet potatoes
    • Pumpkin
  • Other red/yellow plants:
    • Cantaloupe
    • Mangos
    • Tomatoes
    • Red bell peppers
  • Green, leafy vegetables:
    • Spinach
    • Broccoli

Symptoms of deficiency

The primary symptoms of clinical concern are related to vision:

  • Visual symptoms:
    • Poor night vision (nyctalopia) 
    • Dry eye (xerophthalmia) 
    • Blindness
  • Hyperkeratosis (scaly skin) and destruction of hair follicles 
  • Poor bone growth due to decreased endochondral bone formation and osteoblastic activity
  • Impaired immune system function due to direct effect on T cells

Groups at higher risk for deficiency

Vitamin A deficiency is uncommon in developed countries, but it may be encountered in the following groups:

  • Preterm infants
  • Children and pregnant and lactating women in developing countries
  • Patients with fat malabsorption

Therapeutic uses

Forms of vitamin A are used in treatments for the following conditions:

  • Acute myeloid leukemia
  • Acne: found in topical and oral medications
  • Measles (for children in developing countries; appears to reduce mortality)

Toxicity

Typically occurs only with chronic ingestion of large amounts of synthetic or animal sources of vitamin A (approximately 10× the RDA). Absorption of beta-carotene (plant sources) is highly regulated and is extremely unlikely to cause toxicity. Symptoms of toxicity include:

  • Nausea
  • Headache
  • Vertigo
  • Blurred vision
  • Teratogenicity if used in pregnant patients (e.g., isotretinoin used in acne treatment)
  • Hepatotoxicity

Vitamin D: Calciferol

Technically, vitamin D is a hormone because it is made in the body, while actual vitamins are not made in the body. Vitamin D3 is made in the skin of all vertebrates when they are exposed to the sun, while D2 is produced by some fungi (e.g., mushrooms) and can be consumed in food or supplement form.

Functions

Vitamin D’s most important impacts are related to calcium and phosphate:

  • Promotes absorption of calcium and phosphate from the intestines
  • Stimulates osteoblasts in bone and enhances bone mineralization
  • Is involved in:
    • Immune function and inflammation
    • Glucose and cholesterol metabolism
    • Cell growth, proliferation, differentiation, and apoptosis

Absorption, synthesis, transport, and storage

Synthesis from sun exposure is very important for conversion into an active form.

  • In the skin, UV light exposure causes a temperature-dependent rearrangement of 7-dehydrocholesterol, converting it into vitamin D3 (cholecalciferol). 
  • Vitamin D3 is hydroxylated in the liver to 25-hydroxyvitamin D3 (25(OH)D3):
    • Also known as calcidiol, calcifediol, and 25-hydroxycholecalciferol
    • 25(OH)D3 is the primary circulating form of vitamin D in the body and is what is measured clinically in lab work.
    • Half-life: 2–3 weeks 
  • 25(OH)D undergoes a second hydroxylation in the kidney and forms the physiologically active 1,25-dihydroxyvitamin D3 (1,25(OH)D3):
    • Also known as calcitriol 
    • Most active form
    • Half-life: 4–6 hours 
  • Vitamin D2 (ergocalciferol) is synthesized by fungi, undergoes two hydroxylations, and has biologic activity similar to 1,25(OH)D3.
  • Both vitamins D2 and D3 can be absorbed from the intestines:
    • Absorbed via simple passive diffusion and membrane carrier proteins
    • Fat enhances absorption
    • Vitamin D is incorporated into micelles, absorbed by enterocytes, and packaged into chylomicrons.
Vitamin D types

Types of vitamin D

Image by Lecturio. License: CC BY-NC-SA 4.0

Daily requirement

Guidelines vary around the world and for some professional societies. The U.S. RDAs are:

  • Infants: 400 IU (10 µg)
  • People 1–70 years of age, including pregnant/lactating women: 600 IU (15 µg)
  • People ≥ 71: 800 IU (20 µg)

Sources of vitamin D

  • The primary source of vitamin D is sunlight exposure:
    • 5–30 minutes of midday sun exposure to the face, arms, hands, and legs
    • Sunscreens block vitamin D–producing UV rays, but many people do not apply sufficient amounts to block all vitamin D synthesis.
  • Vitamin D is not found in breast milk. 
  • Few foods contain vitamin D; some that do include:
    • Fatty fish (trout, salmon, tuna, and mackerel) and fish liver oils 
    • Mushrooms (vitamin D2)
  • Fortified dairy products provide most of the vitamin D in the American diet:
    • Milk and plant milk alternatives (e.g., soy, almond, or oat milk)
    • Orange juice 
    • Cereal 
    • Infant formula

Groups at risk for vitamin D deficiency

  • Diets low in vitamin D; these are more common in people who:
    • Have a milk allergy or lactose intolerance
    • Consume restrictive diets (e.g., vegan)
  • Breastfed infants
  • Older adults: skin does not synthesize vitamin D3 efficiently.
  • People with limited sun exposure 
  • Dark-skinned people: melanin in the epidermal layer of the skin results in a reduced ability to produce vitamin D from sunlight.
  • Conditions that cause fat malabsorption
  • Obesity (BMI ≥ 30): vitamin D is sequestered in the subcutaneous tissues, which ↓ circulating levels.
  • Chronic renal insufficiency: impaired hydroxylation in the kidneys

Symptoms of deficiency

Modest and even severe vitamin D deficiency is widely prevalent around the world and sufficient intake is necessary for bone and general health. With severe deficiency, the following may result:

  • Hypophosphatemia, hypocalcemia, and secondary hyperparathyroidism → bone demineralization
  • Rickets in children; presents with:
    • Weak or soft bones 
    • Stunted growth 
    • Bowed legs and difficulty walking
    • Bone pain
  • Osteomalacia in adults:
    • Presentation similar to that for rickets in children
    • Increased risk of bone fracture

Toxicity

  • Hypervitaminosis D: causes increased absorption of calcium in the GI tract, which may cause hypercalcemia, which can lead to:
    • Nausea and vomiting
    • Muscle weakness
    • Neuropsychiatric disturbances
    • Anorexia
    • Dehydration, polydipsia, polyuria, and kidney stones
  • In extreme cases, vitamin D toxicity causes:
    • Renal failure
    • Calcification of soft tissues throughout the body (including in coronary vessels and heart valves)
    • Cardiac arrhythmias

Vitamin E: Tocopherols

Vitamin E is a group of compounds that includes tocopherols and tocotrienols. Vitamin E is an important antioxidant that is synthesized only in plants.

Forms

There are 8 chemical forms of tocopherol:

  • α-, β-, ɣ-, and Δ-tocopherol 
  • α-, β-, ɣ-, and Δ-tocotrienol
  • Only α-tocopherol has significant activity in humans.

Functions

Vitamin E is the fat-soluble equivalent of vitamin C (which is water-soluble) in that it acts as an antioxidant. Vitamin E is a free radical scavenger and can donate electrons and is involved in:

  • Fatty acid oxidation 
  • Cellular respiration
  • Prolonging the life of RBCs by removing free radicals
  • Protecting membrane lipids from peroxidation
  • Indirectly inhibiting arachidonic acid metabolism → inhibition of platelet aggregation
  • Inhibiting protein kinase C, which is involved in cell proliferation and differentiation

Absorption and transport

  • Ingested in the diet, digested by enzymes, absorbed by intestinal mucosal cells, and packaged into chylomicrons
  • Chylomicrons transport the α-tocopherol form of vitamin E to the liver through the lymphatic system.
  • In hepatocytes, α-tocopherol is packaged in VLDLs and secreted into the bloodstream.

Daily requirement

The RDAs for vitamin E are:

  • Infants and children: requirements increase from 4 mg at birth to 7 mg by age 8
  • Children 9–13: 11 mg
  • People ≥ 14, including pregnant women: 15 mg daily
  • Lactating women: 19 mg

Dietary sources

  • Wheat germ
  • Nuts and seeds (especially almonds, peanuts, and peanut butter)
  • Plant oils:
    • Olive oil
    • Sunflower oil
    • Safflower oil
  • Fortified cereals

Deficiency

  • Very rare in humans
  • May be seen in patients with:
    • Fat malabsorption
    • Rare genetic disorder called “ataxia and vitamin E deficiency” (AVED) 
  • Clinical manifestations:
    • Neuromuscular signs of ataxia and peripheral neuropathy
    • Hemolytic anemia

Therapeutic uses and clinical relevance

  • Supplementation is indicated in patients with vitamin E deficiency.
  • Vitamin E supplements have been studied in many diseases and are not currently recommended as treatment or prevention for any condition other than vitamin E deficiency.

Toxicity

  • Increased risk of hemorrhagic stroke due to vitamin E’s ability to inhibit platelet aggregation and antagonize vitamin K–dependent clotting factors
  • Increased risk of prostate cancer in men
  • Small increased risk of all-cause mortality

Vitamin K: Quinone

Vitamin K is consumed in the diet and synthesized by the normal intestinal flora. Newborns cannot produce vitamin K because they have a sterile gut.

Forms

  • Vitamin K1: phylloquinone, primary dietary form
  • Vitamin K2: menaquinone, primarily from bacteria, including bacteria within the human GI tract

Functions

  • Vitamin K is an active coenzyme for glutamate carboxylase, which carboxylates important factors involved in coagulation:
    • Procoagulants factors II, VII, IX, and X; after carboxylation, these proteins gain an affinity for platelets and promote blood clotting.
    • Anticoagulants: proteins C and S
  • Vitamin K is also important as a cofactor for multiple proteins involved in bone mineralization.

Absorption and transport

  • Ingested in the diet, digested by enzymes, absorbed by intestinal mucosal cells, and packaged into chylomicrons
  • Repackaged in the hepatocytes into VLDLs for secretion into the blood
  • Rapidly metabolized and excreted (very little vitamin K circulates in the blood)

Daily requirements

The RDAs for vitamin K are:

  • Infants: 2–2.5 µg/day 
  • Children 1–3 years old: 30 µg
  • Children 4–13 years old: 55–60 µg 
  • Adolescents 14–18 years old: 75 µg/day
  • Adult women (including during pregnancy and lactation): 90 µg/day
  • Adult men: 120 µg/day

Dietary sources

  • Found mostly in green, leafy vegetables:
    • Collard and turnip greens
    • Spinach
    • Kale
    • Broccoli
  • Other dietary sources with lower amounts include:
    • Soybeans and soybean oil
    • Blueberries
    • Chicken

Deficiency

Vitamin K deficiency is extremely rare, but because it blocks the protein carboxylation essential for blood clotting, a severe deficiency can result in bleeding problems. 

  • Clinical bleeding symptoms due to vitamin K deficiency:
    • Ecchymoses (easy bruising)
    • Melena or hematochezia (GI bleeding)
    • Menorrhagia
    • Hematuria
  • Diagnosis: 
    • Lab testing of the PT and INR is done in suspected deficiency.
    • These same tests are used to monitor anticoagulation status with the anticoagulant medication warfarin.
  • Chronic deficiency can also lead to reduced bone mineralization.
  • Deficiencies are more common in patients:
    • With fat malabsorption
    • On longer courses of antibiotics, which affects the intestinal bacteria

Therapeutic uses and clinical relevance

  • Newborn infants should receive an IM injection of vitamin K at birth to prevent bleeding (vitamin K transport across the placenta is poor).
  • Supplementation of vitamin K is essential in patients on total parenteral nutrition (TPN).
  • Vitamin K in the diet (such as eating greens or in a supplement) interferes with the anticoagulation medication warfarin (Coumadin), which is a vitamin K antagonist. 
    • Patients taking warfarin for anticoagulation need to maintain a stable dietary intake and avoid large daily variations of greens.
    • Vitamin K is the antidote to excess anticoagulation.
  • Used to reverse poisoning by rodenticides, which contain high doses of coumarin

Toxicity

  • The U.S. Food and Nutrition Board (FNB) at the National Academy of Medicine has not established safe upper limits for vitamin K.
  • The FNB states, “No adverse effects associated with vitamin K consumption from food or supplements have been reported in humans or animals.”
  • A synthetic, water-soluble form of vitamin K, known as menadione, was previously used in premature infants and was associated with hemolytic anemia and jaundice. This formulation is no longer available.

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References

  1. Pazirandeh, S., Burns, D.L. (2020). Overview of vitamin A. UpToDate. Retrieved June 3, 2021, from https://www.uptodate.com/contents/overview-of-vitamin-a
  2. National Institutes of Health Office of Dietary Supplements. (2021). Vitamin A Fact Sheet for Health Professionals. Retrieved June 3, 2021, from https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/ 
  3. Pazirandeh, S., Burns, D.L. (2020). Overview of vitamin D. UpToDate. Retrieved June 3, 2021, from https://www.uptodate.com/contents/overview-of-vitamin-d 
  4. National Institutes of Health Office of Dietary Supplements. (2021). Vitamin D Fact Sheet for Health Professionals. Retrieved June 3, 2021, from https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ 
  5. Pazirandeh, S., Burns, D.L. (2020). Overview of vitamin E. UpToDate. Retrieved June 3, 2021, from https://www.uptodate.com/contents/overview-of-vitamin-e
  6. National Institutes of Health Office of Dietary Supplements. (2021). Vitamin E Fact Sheet for Health Professionals. Retrieved June 3, 2021, from https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/ 
  7. Pazirandeh, S., Burns, D.L. (2020). Overview of vitamin K. UpToDate. Retrieved June 3, 2021, from https://www.uptodate.com/contents/overview-of-vitamin-k
  8. National Institutes of Health Office of Dietary Supplements. (2021). Vitamin K Fact Sheet for Health Professionals. Retrieved June 3, 2021, from https://ods.od.nih.gov/factsheets/vitaminK-HealthProfessional/ 

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