Fat-Soluble Vitamins: Deficiency and Excess

General and subspecialty pediatricians commonly encounter fat-soluble vitamin deficiencies and toxicities in clinical practice. Understanding the role of fat-soluble vitamins is crucial for recognizing deficiencies and toxicities in pediatric patients, particularly those with dietary restrictions or medical conditions that affect absorption. Appropriate supplementation, targeted screening, and patient education are essential strategies for optimizing pediatric health outcomes.1After completing this article, readers should be able to: Explain the biological functions of fat-soluble vitamins (A, D, E, and K) and their roles in maintaining health and preventing disease.Discuss the risk factors and clinical manifestations associated with deficiencies and toxicities of fat-soluble vitamins.Describe evidence-based strategies for the diagnosis, treatment, and prevention of fat-soluble vitamin deficiencies, including the appropriate use of laboratory testing.Fat-soluble vitamins (A, D, E, K) are crucial for immune function, cellular signaling, and growth. Unlike water-soluble vitamins, fat-soluble vitamins are stored in the liver and adipose tissue, allowing for longer availability.1 In the United States, deficiencies have become less common with better nutrition and supplements, but 9% of children are still deficient, and 61% are insufficient in vitamin D as measured by serum levels. This vitamin D deficiency/insufficiency is in conjunction with evidence of widespread inadequate dietary vitamin D intake affecting an estimated 87% of young children.2 Although vitamin E deficiency is rare, 69% of children consume below the recommended amount.3 Supplement use improves fat-soluble vitamin levels, with 1% to −23% of infants and toddlers and 35% to 45% of preschoolers taking supplements to address deficiencies.4According to the Institute of Medicine (IOM), the nutrient-based reference values used to assess and plan the diet of healthy individuals are:Recommended dietary allowance (RDA): This is the average daily nutrient intake level sufficient to meet the nutrient requirements of nearly all (97%-98%) healthy individuals in a specific life stage and gender group.Adequate Intake (AI): This is a recommended intake level based on observed or experimentally determined approximations of nutrient intake by a group of healthy people. AI is used when there is insufficient evidence to establish an RDA.Tolerable upper intake level (UL): This is the highest average daily nutrient intake level that is unlikely to pose a risk of adverse health effects to almost all individuals in the general population.5Vitamin A is vital for vision, immune function, and cellular integrity. In children, vitamin A deficiency can lead to vision loss and higher infection risk.6 Although rare in well-resourced countries, vitamin A deficiency is rising in at-risk populations, such as those with restrictive diets or gastrointestinal issues. Early diagnosis and treatment are key to preventing irreversible complications of vision loss and blindness due to structural damage to the eye, particularly the cornea and retina.7Vitamin A comes from 2 sources: preformed vitamin A (retinyl esters) in animal products like liver, dairy, and fish, and provitamin A carotenoids (eg, beta-carotene) in plant foods like carrots and leafy greens.8 Retinyl esters are converted to retinol in the intestine, absorbed, and stored in the liver. Carotenoids are converted to retinal, then retinol. Retinol is transported in the blood by retinol-binding protein and transthyretin, and in target tissues, retinol is oxidized to retinoic acid, which regulates gene expression. Vitamin A forms 11-cis-retinal, essential for phototransduction in the retina. Its active metabolite, all-trans-retinoic acid, regulates gene expression by binding to nuclear receptors.9The RDA for vitamin A varies by age and sex. For children aged 1 to 3 years, the RDA is 300 μg/d, and for those aged 4 to 8 years, it is 400 μg/d. For older children and adolescents, the RDA ranges from 600 to 900 μg/d.9Vitamin A deficiency is often overlooked because of low prevalence and vague symptoms. Contributing factors include restrictive diets, malabsorptive conditions, and chronic illnesses that affect absorption and metabolism. Pediatricians now recognize selective eating in children with autism spectrum disorder (ASD) as a leading cause.10 Untreated gastrointestinal conditions like celiac disease, Crohn disease, and cystic fibrosis also impair fat-soluble vitamin absorption.11Vitamin A deficiency can lead to ophthalmic signs and symptoms ranging from night blindness to severe conditions like xerophthalmia, which includes conjunctival xerosis, Bitot’s spots (foamy, whitish lesions on the temporal bulbar conjunctiva caused by squamous metaplasia, keratinization, and xerosis indicating both local epithelial damage and systemic effects on retinal function and phototransduction), and keratomalacia. Untreated, it can lead to corneal ulceration and blindness.12Vitamin A is essential for epithelial tissue integrity. When deficient, the epithelial barriers are compromised, leading to increased susceptibility to infections and impaired mucosal immunity.13,14 In premature infants, supplementation reduces chronic lung disease. More specifically, retinoic acid influences the homing, differentiation, and function of leukocytes. It promotes the differentiation of regulatory T cells, which help maintain immune tolerance and prevent excessive inflammatory responses.15 Retinoic acid also enhances the production of immunoglobulins and cytokines, which are vital for effective immune responses.16 This is particularly evident in the case of measles, where vitamin A deficiency can exacerbate the severity of the disease and increase the risk of complications and death. The World Health Organization (WHO) recommends vitamin A supplementation for all children with acute measles regardless of their country of residence to reduce the risk for complications, whereas the Centers for Disease Control (CDC) recommends that vitamin A may be supplemented by a licensed provider in infants and children in the United States with measles. Children with severe measles, including hospitalized patients, should be managed with vitamin A supplementation.17Severe vitamin A deficiency is treated with high-dose supplementation, with oral supplementation being the first choice. Parenteral (intravenous and intramuscular) vitamin A palmitate is used when oral intake is not possible or in cases of severe malabsorption. The oral supplementation doses are:Aged 1 to 8 years: 17 500 to 35 000 units daily for 10 days.Infants: 7500 to 15 000 units daily for 10 days.Follow up therapy, aged 1 to 8 years: 5000 to 10 000 units daily for 2 months.Follow up therapy, aged over 8 years: 10 000 to 20 000 units daily for 2 months.18A toxic dose of vitamin A is 25 000 IU/kg body weight in a single dose or 4000 IU/kg daily for 6 to 15 months.19 In children and adolescents, toxicity may cause irritability and vomiting, whereas bulging fontanelles may be seen in infants. Chronic toxicity can lead to poor weight gain, anorexia, and signs of increased intracranial pressure, with physical findings such as hepatosplenomegaly, dry skin, and peeling. Acute toxicity may present as headache, dizziness, bone pain, and nausea.20,21The main cause of vitamin A toxicity in children is excessive intake of supplements, especially water-miscible, emulsified, and solid forms, which are more toxic than oil-based forms.22 Over-consumption of chewable vitamin supplements, often in the form of multivitamins, is common in young children and presents with varied symptoms.23 From a dietary perspective, consumption of large amounts of liver or beta-carotene-rich vegetables can also contribute to chronic toxicity.24Vitamin D is crucial for bone health, calcium, and phosphate metabolism, and may help reduce the risk of respiratory tract infections. Ensuring adequate levels through diet, supplementation, and sun exposure is key to preventing deficiencies and promoting children’s overall health.Vitamin D is obtained from 2 sources: cholecalciferol (D3), synthesized in the skin through ultraviolet B (UVB) exposure, and ergocalciferol (D2) from plant sources and fungi. In the liver, D3 and D2 are hydroxylated to form 25-hydroxyvitamin D (calcidiol), the main circulating form used to assess vitamin D status. Calcidiol is then converted in the kidneys to 1,25-dihydroxyvitamin D (calcitriol), the active form that regulates calcium and phosphate by increasing their absorption, reabsorption, and mobilization.25Dietary sources of vitamin D include fatty fish (such as salmon, mackerel, and tuna), fish liver oils, and fortified foods like milk, orange juice, and cereals. Egg yolks and certain mushrooms also provide smaller amounts of vitamin D.26 Sensible sunlight exposure also helps prevent vitamin D deficiency. The Endocrine Society recommends 5 to 10 minutes of sun on arms, legs, or face, 2 to 3 times per week, without sunscreen, to maintain adequate levels. Skin pigmentation, location, and season can affect vitamin D synthesis. It is important to balance sun exposure with skin protection, using sunscreen after initial exposure to prevent sunburn.27The American Academy of Pediatrics (AAP) recommends 400 IU of vitamin D daily for infants, children, and adolescents to prevent rickets and maintain adequate vitamin D levels. The IOM suggests 400 IU for infants (aged 0–12 months) and 600 IU for children (aged 1–18 years). The Endocrine Society recommends 400 to 1000 IU/d for infants and 600 to 1000 IU/d for children and adolescents for optimal vitamin D status.28Because of the challenge of determining true vitamin D requirements through growth and development, multiple definitions of vitamin D deficiency have been proposed. Institution-specific thresholds may vary depending on local practice.IOM: The IOM defines vitamin D deficiency as a serum 25-hydroxyvitamin D level of less than 12 ng/mL (30 nmol/L). Levels between 12 and 20 ng/mL (30 to 50 nmol/L) are considered inadequate.29Endocrine Society: The Endocrine Society defines vitamin D deficiency as a serum 25-hydroxyvitamin D level of less than 20 ng/mL (50 nmol/L) and insufficiency as a level of 21 to 29 ng/mL (52.5 to 72.5 nmol/L).30European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN): ESPGHAN defines severe vitamin D deficiency as a serum 25-hydroxyvitamin D level of less than 25 nmol/L (10 ng/mL) and sufficiency as a level greater than 50 nmol/L (20 ng/mL).31In the United States, data from the National Health and Nutrition Examination Survey (NHANES) for 2017 to 2018 indicate that 21.3% of children had serum 25-hydroxyvitamin D levels below 50 nmol/L, which is considered deficient by all 4 societies listed earlier.32The causes of decreased circulating vitamin D levels are varied and can depend on region, lifestyle, concurrent medical conditions, and genetics.Limited sunlight exposure affects vitamin D synthesis. UVB radiation converts 7-dehydrocholesterol to pre-vitamin D3, but high skin pigmentation reduces UVB penetration. Sunscreen with sun protection factor 30, widely used in children, can reduce synthesis by up to 95%. Higher latitudes also receive less UVB, especially in winter, reducing vitamin D production.33Limited nutritional intake can lead to vitamin D deficiency. Breastfed infants, especially with low maternal vitamin D, are at risk. The AAP recommends 400 IU/d for breastfeeding infants. Studies suggest 6000 to 6400 IU/d of maternal supplementation ensures adequate levels in breast milk. In childhood and adolescence, inadequate intake of vitamin D-rich foods can also contribute to deficiency.34Obesity reduces vitamin D bioavailability because vitamin D is stored in adipose tissue, leading to lower circulating levels. Obese children may also have a sedentary lifestyle, limited sunlight exposure, and poor diet, all contributing to reduced vitamin D levels.35Anticonvulsant medications (eg, phenytoin, phenobarbital) and glucocorticoids lower vitamin D levels by increasing its breakdown. In the case of phenobarbital, vitamin D bioactivation is also reduced by the drug’s interference with vitamin D3 25-hydroxylase. Orlistat (a lipase inhibitor) and cholestyramine (a bile acid sequestrant) can cause fat malabsorption, impairing vitamin D absorption.36,37Conditions such as celiac disease, cystic fibrosis, and inflammatory bowel disease impair vitamin D absorption. Chronic kidney disease affects the conversion of 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D.38,39Vitamin D deficiency in children leads to significant skeletal consequences, most notably rickets, which is due to impaired calcium and phosphate absorption. Vitamin D deficiency reduces calcium absorption from 30% to 40% to 10% to 15%, causing hypocalcemia and secondary hyperparathyroidism. This increases renal calcium reabsorption and phosphate excretion, leading to hypophosphatemia, which disrupts chondrocyte maturation and growth plate development, causing bone widening in rickets.40 Rickets is classified in 3 stages:Stage 1: Characterized by osteopenia and may be but such as and levels are and become signs include of the or and of the or and of the with more skeletal and complications such as growth and The the due to of the can from to with signs and symptoms like poor bone pain, and signs include and bone especially at the maternal vitamin D deficiency can also cause in rickets, increasing risk at or the of its vitamin D in children is by serum 25-hydroxyvitamin D levels, which both dietary intake and sunlight D is not as its levels can be or in deficiency because of secondary hyperparathyroidism. a level is for specific conditions like calcium or renal function often in the of vitamin rickets, and certain or of vitamin D is not the AAP targeted for specific are without vitamin D supplementation and are signs of with limited sun exposure, including those in higher have skin, use sunscreen or most of their with conditions that impair fat absorption, such as Crohn disease, celiac disease and cystic fibrosis, chronic kidney disease, or liver with or chronic restrictive eating secondary to or taking medications that affect vitamin D such as and with signs or symptoms of rickets such as bone pain, and skeletal of vitamin D deficiency The AAP recommends IU/d of vitamin D2 or D3 for 6 or a dose of 50 000 IU for 6 is 400 to 1000 The Endocrine Society suggests IU/d or 50 000 IU for 6 to serum 25-hydroxyvitamin D by 600 to 1000 IU/d for D toxicity in children is rare but can from excessive or in may lead to doses for conditions like rickets or can cause toxicity not Vitamin D toxicity causes with symptoms like anorexia, vomiting, and symptoms include and leading to or may also have and kidney with and E as an and of 8 4 and 4 is the most active form and is in by the protein in the liver. Vitamin E from damage by preventing and death. It also roles in gene and immune sources of vitamin E for children include (eg, (eg, (eg, and vegetables (eg, and also provide The for vitamin E in children, as by the are as (aged 4 (aged 5 (aged 6 (aged (aged (aged 15 E rare, is to conditions that impair fat absorption, such as cystic fibrosis, liver disease, and like with vitamin E deficiency also affect vitamin E diets can also cause Vitamin E deficiency causes and symptoms. signs include loss of and cases may lead to like symptoms include increased causing E deficiency can have in children, often in that with daily from inadequate vitamin E levels may contribute to complications, including immune and and are essential to such as impaired in vision loss from conditions like and is the treatment of deficiency. 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