Summary

Vitamin D deficiency is now increasingly recognized throughout the United States as a problem that may affect numerous patient populations. Even more concerning to general practitioners has been the growing prevalence of this condition in otherwise healthy children. Contributing to widespread vitamin D deficiency are few naturally available dietary sources and insufficient sun exposure that is exacerbated by the need to use sunscreen products to prevent skin cancer. Preventing deficiency has gained considerable attention, especially in light of the emerging evidence that vitamin D has other important functions, in addition to optimizing bone and mineral metabolism. Addressing these evolving issues, the American Academy of Pediatrics (AAP) in recently updated guidelines has doubled the vitamin D intake recommended for infants, children and adolescents.[1] Pediatricians are now faced with a critical role in promoting adequate vitamin D intake in their patients and identifying children at higher risk for deficiency who may require more vitamin D to maintain health.

Educational objectives

At the conclusion of this activity, participants will be able to:

• Explain rationale behind recent AAP guidelines to double vitamin D intake from infancy through adolescence, compared to previous recommendations
• Discuss classical actions of vitamin D and its newly recognized functions
• Describe risk factors for vitamin D deficiency that might call for higher doses of vitamin D to prevent deficiency

CME credit

This is an article from The Child's Doctor, Spring/Summer 2009 issue. You must read all five articles and complete each related quiz before receiving 2 Category 1 credits for the Spring/Summer 2009 issue.

Author disclosures

Dr. Ali has no industry relationships to disclose and does not refer to products that are still investigational or not labeled for the use in discussion.

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Prevalence and definition of vitamin D deficiency

Symptoms of vitamin D deficiency may be vague in infants, and many children and adolescents are asymptomatic. However, severe deficiency of this nutrient in children may lead to rickets and at times can present with seizures related to hypocalcemia.

Vitamin D deficiency is determined by measuring serum 25-hydroxyvitamin D or 25(OH)D levels. While controversy remains over the definition of optimal levels of 25(OH)D, one possible index of normalcy relates to prevention of secondary hyperparathyroidism. Based on this feature, insufficiency may occur at levels of 25(OH)D < 32 ng/mL, since elevation of parathyroid hormone (PTH) was noted in adults once levels fell below this threshold value.[2] This relationship was also demonstrated in healthy adolescents.[3] The AAP recommends on the basis of available evidence, that serum 25(OH)D concentrations in infants and children should be at least 20 ng/mL (50 nmol/L).[1] Previously, vitamin D deficiency was considered to occur at levels < 11 ng/mL.

Although changing definitions of deficiency complicate estimates of prevalence, studies indicate that too many individuals lack enough vitamin D for overall health. One recent publication has described the deficiency of vitamin D as a pandemic.[4] A new meta-analysis of cross-sectional data from 394 studies, including pediatric data, showed widespread global vitamin D deficiency; the mean reported 25(OH)D level in children younger than 15 years of age was 14.8 ng/mL (37 nmol/L).[5]

In a study of more than 1,000 children, our group at Children's Memorial Hospital has uncovered that up to 75% of patients seen in the kidney disease practices were vitamin D deficient during a decade of study, with deficiency defined as 25(OH)D < 15 ng/mL. In addition, we found an increasing prevalence of nutritional vitamin D deficiency during that decade.[6]

AAP guidelines

To improve prevention of vitamin D deficiency given new considerations about the levels needed to maintain health, the AAP has published updated guidelines recommending that a minimal daily intake of 400 IU of vitamin D begin soon after birth and continue throughout adolescence.[1] This means that any exclusively breast-fed infant or any infant drinking less than 1 liter of vitamin D-fortified formula per day will require additional supplementation.

The new minimum daily intake doubles the amount in the AAP's previous recommendations, which advised 200 IU of vitamin D per day beginning in the first 2 months of life, to continue through adolescence. The earlier minimum intake was thought to prevent physical signs of vitamin D deficiency and maintain levels of 25(OH)D greater than or equaling to 11 ng/mL. However, newer information examining biomarkers linked to vitamin D deficiency in adults (eg, PTH, bone mineralization, insulin resistance, calcium absorption) has raised concerns that this minimum intake is not sufficient, even for infants and children, and the safety of 400 IU per day has long been established.

Actions of Vitamin D

Vitamin D (cholecalciferol) is synthesized from its precursor, 7-dehydrocholesterol, in the skin via isomerization due to the effects of UVB exposure from the sun. Cholecalciferol then undergoes 2 subsequent hydroxylations: the first takes place in the liver at the carbon-25 position through the actions of 25-hydroxylase and the second occurs in the proximal tubule of the kidney, where 25(OH) vitamin D is further modified by a 1-alpha-hydroxylase, to form 1,25(OH)2 vitamin D.

Vitamin D is most commonly recognized as being important for its traditional role in bone and mineral metabolism. 1,25(OH)2 vitamin D is the major regulator for intestinal calcium and phosphorus absorption and has vital actions in maintaining serum calcium and phosphorus levels. It leads to increased renal reabsorption of calcium and phosphorus and increased osteoclast activation in the bone. Ultimately, it is vitamin D adequacy that guarantees optimal skeletal mineralization, through these classic endocrine actions. In otherwise healthy children, severe deficiency of vitamin D leads to the classical findings of rickets, and under-mineralization of the skeleton; in adults the correlate is osteomalacia.

Aside from these classical aspects of vitamin D metabolism, there is mounting literature documenting numerous non-classical or non-endocrine actions of vitamin D as well. Vitamin D is involved in the regulation of the immune system and autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and type 1 diabetes.[7] It is implicated in control of cancer cell growth. Solar UVB radiation and thus vitamin D has been associated with reduced risk of multiple cancers, including breast, colon, ovary, prostate, and non-Hodgkin lymphoma.[8] Vitamin D is also involved in regulating blood pressure through renin and deficiency may be related to cardiovascular diseases, such as hypertension and coronary heart disease.[4,9,10]

Increased risk for vitamin D deficiency

Impaired synthesis and inadequate intake of vitamin D are major risk factors for vitamin D deficiency. Insufficient dietary intake has now been addressed by the new AAP guidelines. This is extremely important as there are very few naturally occurring dietary sources of vitamin D. The National Institutes of Health report cod liver oil, salmon, mackerel, sardines, beef liver, and egg yolk as providing significant levels of vitamin D. Fortified dietary sources of vitamin D may include milk, margarine, pudding, and dry cereal.

Inadequate sun exposure. Another risk factor for vitamin D deficiency is inadequate sun exposure. UV ray exposure that is necessary for synthesis of cholecalciferol in the skin may be affected by season, latitude, time of day, cloud cover, and smog. For example, in more northern latitude sites such as Chicago, there is significantly lower vitamin D-producing UV radiance than at lower latitude sites; in fact at times the winter solar noon irradiance at lower latitude locations exceeds the summer values recorded in Chicago.[11] North of Atlanta (latitude 33 degrees), the average amount of sunlight is insufficient to produce significant vitamin D synthesis from November through February. In addition, the use of sunscreens to reduce the risk of many skin cancers may be a factor, as sunscreens with SPF 8 or greater will block UV rays that produce vitamin D.

Darker skin pigment. It is also likely that individuals with darker skin pigmentation are at higher risk for vitamin D deficiency than their Caucasian counterparts. This may be due to the fact that an increased content of melanin in the skin may decrease vitamin D production.[12] Studies have confirmed that this is a problem that affects healthy children and adolescents, especially those with darkly pigmented skin.[13-15]

Decreased gastrointestinal absorption. Patients at higher risk for vitamin D deficiency may include children with gastrectomy, celiac disease, malabsorptive states, history of extensive bowel surgery, inflammatory bowel disease, and pancreatic insufficiency, including patients with cystic fibrosis.

Liver disease. Patients with liver disease are also at increased risk for vitamin D deficiency. As 25-hydroxylation normally occurs in the liver, this conversion can be impaired with severe liver disease.

Medications. Drugs that increase cytochrome P-450 enzyme activity, such as phenobarbital, carbamazepine, phenytoin, isoniazid, rifampin, and theophylline, increase 25-hydroxylation, but also increase catabolism of 25(OH)D and 1,25(OH)2D to inactive metabolites. Children using these medications are at higher risk for vitamin D deficiency.

Kidney disease. It is well-documented that patients with kidney disease are at increased risk for vitamin D deficiency as well. The proximal tubule is the site of 1,25(OH)2 vitamin D production. It has been shown that in adults, progressive loss of kidney function defined by loss of estimated glomerular filtration rate leads to lower serum levels of 1,25(OH)2 vitamin D and eventual secondary hyperparathyroidism.[16] This is a multifactorial process involving low 1,25(OH)2 vitamin D production, loss of the enzyme 1-alpha-hydroxylase, and hyperphosphatemia that occurs with reduced kidney function and serves as an additional negative stimulus.

Genetic disorders. A few genetic disorders involve abnormalities in vitamin D metabolism. Vitamin D-dependent rickets is an autosomal recessive disorder with hypocalcemia, hypophosphatemia, high parathyroid hormone and alkaline phosphatase concentrations, in addition to bony abnormalities. It is caused by inability to produce 1,25(OH)2 vitamin D due to inactivation mutations in the 1-hydroxylase gene. Vitamin D-resistant rickets is associated with end-organ resistance to 1,25(OH)2 vitamin D, most often due to mutations in the gene encoding the vitamin D receptor. Clinical findings are similar to those in vitamin D-dependent rickets except that serum 1,25(OH)2 vitamin D concentrations are high, as opposed to the low levels seen in the former condition.

Prevention and treatment

The minimum recommended daily intake to prevent rickets and vitamin D deficiency in otherwise healthy infants, children, and adolescents is now 400 IU. Dietary sources may be included in this daily intake for each child, but this requires careful dietary assessment by the primary pediatrician. Liquid vitamins and vitamin D preparations available in the United States generally supply 400 IU per day.

Children with increased risk for vitamin D deficiency, such as patients with chronic fat malabsorption or receiving anti-seizure medications as outlined above, may require serum 25(OH)D status to be determined to ensure sufficiency. These patients may require larger doses to reach target levels, and repeat testing at 3-month intervals would be indicated to ensure normalization of the 25(OH)D level.

Conclusion

The widespread prevalence of vitamin D deficiency necessitates attention to careful dietary assessment of intake and early initiation of multivitamin supplementation in patients who need it. If additional risk factors are found, it may be prudent to assess vitamin D status biochemically.

References

[1.] Wagner CL, et al. American Academy of Pediatrics. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008 Nov;122(5):1142-1152.

[2.] Chapuy MC, et al. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 1997;7:439-443.

[3.] Gordon CM, et al. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med 2004;158:531-537.

[4.] Holick MF, Chen TC. Vitamin D deficiency: A worldwide problem with health consequences. Am J Clin Nutr 2008 Apr;87(4):1080S-1086S.

[5.] Hagenau T, et al. Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: An ecologic meta-regression analysis. Osteoporos Int 2009 Jan;20(1):133-140.

[6.] Ali FN, Arguelles LM, Langman CB, Price HE. Vitamin D deficiency in children with chronic kidney disease: Uncovering an epidemic. Pediatrics 2009 March;123(3):791-796.

[7.] Holick MF. The vitamin D epidemic and its health consequences. J Nutr 2005;135:2739S-2748S.

[8.] Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 2002;94:1867-1875.

[9.] Krause R, et al. Ultraviolet B and blood pressure. Lancet 1998;352:709-710.

[10.] Li Y, et al. 1,25-dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002;110:229-238.

[11.] Kimlin MG, et al. Estimations of the human vitamin D UV exposure in the USA. Photochem Photobiol Sci 2004;3:1067-1070.

[12.] Clemens TL, et al. Increased skin pigment reduces the capacity of skin to synthesize vitamin D3. Lancet 1982;1:74-76.

[13.] Talwar SA, et al. Vitamin-D nutrition and bone mass in adolescent black girls. J Natl Med Assoc 2007;99:650-657.

[14.] Harkness LS, Cromer BA. Vitamin D deficiency in adolescent females. J Adolesc Health 2005;37:75.

[15.] Saintonge S, et al. Implications of a new definition of vitamin D deficiency in a multiracial US adolescent population: The National Health and Nutrition Examination Survey III. Pediatrics 2009 March;123(3):797-803.

[16.] Levin A, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: Results of the study to evaluate early kidney disease. Kidney Int 2007;71:31-38.