Joseph Tucker, MD
SUNY-Downstate Medical Center
Robert Karp, MD
SUNY-Downstate Medical Center
Steven Bachrach, MD
Nemours/A. I. duPont Hospital for Children
Thomas Jefferson University
Pre-Test
Q1. Vitamin D in infants is chiefly:
A. Synthesized by bacterial flora in the GI tract.
B. Derived from the mother's breast milk.
C. Synthesized in the skin in a series of UV-dependent reactions.
D. Synthesized in the parathyroid glands.
Q2. In humans, the highest concentration of Vitamin D is found in:
A. Blood
B. Liver
C. Adipose Tissue
D. Muscle
Q3. True or False. The function of Vitamin D most important in preventing nutritional rickets is the enhancement of calcium absorption
Q4. Vitamin D is best described as:
A. A fat-soluble steroid
B. A water-soluble polypeptide
C. A water-soluble amino acid
D. A fat-soluble lipid
Q5. An example of a food rich in Vitamin D is:
A. Spinach
B. Yogurt
C. Beef
D. Salmon
Q6. Vitamin D achieves its biologic effects chiefly by:
A. Binding to membrane receptors on the surfaces of target cells.
B. Binding to receptors within the nuclei of target cells.
C. Binding to allosteric enzymes within the cytosol of target cells.
D. Binding to calcium in the cytosol of target cells.
Q7. The AAP recommends which of the following regarding vitamin D supplementation for infants?
A. Vitamin D is contraindicated in infants who are breast-fed.
B. Infants do not need supplementation for the first 6 months of life.
C. Infants don't need Vitamin D supplementation if they are drinking at least ½ liter of fortified formula every day.
D. Only for darker pigmented infants during winter months.
Objectives
At the conclusion of this section, residents will able to:
1. Appreciate that the term "Vitamin D" refers to a family of steroid hormones and precursors derived from both nutritional and metabolic sources.
2. Identify the role of Vitamin D in the regulation of calcium and phosphorous homeostasis in humans.
3. Recommend foods rich in vitamin D.
4. Insure an intake of Vitamin D in solely breast fed infants.
5. Diagnose Vitamin D deficiency rickets in children.
6. Recognize hereditary as opposed to nutritional or disease related rickets.
7. Appreciate potential toxicity of Vitamin D
Facilitator Preparation
For this section, the facilitator should
1. Review the several sections in Pediatric Nutrition Notes on calcium metabolism and Vitamin D.
2. Bachrach S, Fisher J, Parks JS. An outbreak of vitamin D deficiency rickets in a susceptible population. Pediatrics. 1979 Dec;64(6):871-7. This was the first report of rickets in recent years, though there have been many more since then.
3. Holick MF. Vitamin D (in) Modern Nutrition in Health and Disease, 9th edition. Shils M (ed) Lippincott Williams and Wilkins 1999.
4. Gordon CM, DePeter KC, Feldman HA, et al Prevalence of Vitamin D Deficiency Among Healthy Adolescents Arch Pediatr Adolesc Med. 2004;158:531-537.
5. Loud KJ, Gordon CM Adolescent bone health Arch Pediatr Adolesc Med. 2006;160:1026-1032.
6. Hollis BW. Vitamin D (in in) Shils,ME, Shike M. AC Ross, B Caballero, RJ Cousins. (eds) Modern Nutrition in Health and Disease, 10th edition. Lippincott Williams Wilkins, Baltimore, MD. Pp 376-395.
A remarkable chapter on this topic is in Passmore and Davidson's classic Human Nutrition and Dietetics, 8th edition Churchill Livingstone. London Find one, buy one! They describe the evolutionary origins of skin color and its relation to calcium metabolism.
7. Read also similar sections in the Pediatric Nutrition Handbook, 5th edition. Robert Kleinman, MD editor.
Introduction:
Calcium and Vitamin D
Vitamin D plays a vital role in humans in the maintenance of physiologic serum concentrations of calcium and phosphorus. Vitamin D is synthesized in the skin when exposed to bright sunlight, and can also be derived from dietary sources. The chief action of vitamin D occurs in the brush border of the small intestine, where it enhances the absorption of dietary calcium and phosphorus. Vitamin D also mobilizes calcium and phosphorus from bone stores. Vitamin D is especially important in children, who require adequate calcium and phosphorus to mineralize growing bones.
Deficiency of vitamin D causes hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and can ultimately lead to rickets and osteomalacia. While rickets is now considered rare in the United States, the incidence of rickets has risen over the last decade, and vitamin D deficiency is common, even in healthy young adults. Vitamin D deficiency is especially common during the winter months and in patients who are homebound, unable to go outside, or otherwise chronically shielded from the sun. Excess vitamin D can lead to vitamin D intoxication (Hypervitaminosis D), manifested by hypercalcemia and its sequelae.
The major cause of vitamin D deficiency in infants is prolonged breast-feeding without dietary supplementation combined with inadequate sun exposure. While healthy adults usually receive enough sun exposure to synthesize adequate vitamin D in the skin, infants are less likely to get adequate sun exposure. Darker skinned infants and those living at higher latitudes or in inner cities are at higher risk for vitamin D deficiency. Strict vegans are also at increased risk. Since the only foods naturally high in vitamin D are fatty fish and fish oils, most dietary vitamin D is found in foods fortified with synthetic vitamin D. In North America and many other parts of the world, infant formula and cow's milk are fortified with 400 IU of vitamin D per liter.
Prolonged vitamin D deficiency in infants and children can (and does) lead to hypocalcemic rickets. The principle function of Vitamin D, enhanced calcium absorption, is lost.. Other causes of hypocalcemia include enzymatic deficiencies in vitamin D metabolism, defects in the vitamin D receptor, hypoparathyroidism, and dietary calcium deficiency. Rickets refers to bone changes due to deficient mineralization at the growth plate. Thus, rickets can only develop in children before the growth plates are fused.
Rickets often occurs concomitantly with osteomalacia, a disorder characterized by impaired mineralization of the bone matrix. Osteomalacia, since it is a disorder of the bone matrix, and not the growth plate, can develop independently in adults. The initial presentation of rickets is that of hypocalcemia, due to impaired calcium absorption in the gut. Later, skeletal manifestations occur at the areas of fastest bone growth, namely the distal forearm, the knee, and the costochondral junctions. The presentation of advanced rickets is striking because of skeletal deformities. These include:
TEACHING CAPTION: These finding do not occur until calcium is depleted from bone, late in the clinical course. Both prevention and treatment of rickets are with Vitamin D and Calcium.
A case study - part 1
Michaela R. is a 2-week-old infant brought by her mother for a first complete evaluation. You had met her mother, Rachel, as a medical student during her third year rotation in pediatrics when she was pregnant. She asked if you would be willing to be her infant's pediatrician and you said, "sure."
During the informal interactions in late pregnancy you asked about breast-feeding and Rachel said that she never even considered formulae. When she returned to work she would use her breast milk. When you met Michaela as a newborn, you suggested to Rachel that she begin using a Vitamin D supplement for her infant. Rachel raised several arguments against vitamin supplementation including: "The baby has 4 months supply stored in her liver," and "I won't give vitamins manufactured in a factory." You suggested cod liver oil "No," Rachel says, "it's an animal product." [Hyperlink your sections on alternative medicine for more discussion.] "Besides, I'm white so I don't have to worry about Vitamin D deficiency."
Q1. What is vitamin D?
A1. The term vitamin D is often used to describe a family of vital compounds involved in calcium and phosphorus homeostasis.
"Vitamin D1" is an antiquated term referring to a mixture of Vitamin D2 and D3. Vitamin D without the subscript can refer to either vitamin D2 or vitamin D3.
The foundation for construction of Vitamin D compounds is the configuration of cholesterol precursors as follows:
CAPTION: Under the influence of UV light humans convert 7-dehydrocholesterol to cholecalciferol (D3). Both vitamin D2 (diet) and vitamin D3 (diet or UV) enter the human body's vitamin D metabolic pathway. The first step occurs in the liver, where vitamin D is hydroxylated to form 25-hydroxyvitamin D (25-OH-D, or calcidiol).
Vitamin D3 (cholecalciferol (A) is hydroxylated in the liver ([25(OH)] and then in the kidney (1,25(OH)2) to form the most biologically active form of Vitamin D -- 1,25(OH)2 cholecalciferol, also known as calcitriol.
(A) Vitamin D3 (cholecalciferol) is shown below as "A;" 1,25(OH)2 cholecalciferol is also shown as "B.":
A B
Of note, when an individual is calcium replete, a feed back mechanism shuts down parathyroid control. Without parathormone, the final product is an inactive form of Vitamin D -- 24, 25(OH)2 cholecalciferol
If Michaela is to get Vitamin D from food, it would be Vitamin D2 provided by activated Ergosterol in commercial fortified milk or Vitamin D3 from cold water fish or fish liver oil.. The endproduct for sunlight exposure is Vitamin D3. The manufactured Vitamin D in vitamin drops is D2 derived from plant sterols. Calcitriol is available for treatment of Vitamin D deficiency. Dosages of Calcitriol must be monitored closely to avoid Hypervitaminosis D.
TEACHING CAPTION: The names are important. One might think that a vitamin preparation has sufficient biologically active Vitamin D when it does not. 1,25(OH)2 -Vitamin D is highly potent an d should not be used in routine care.
Feed back loop:
Calcium levels low:
Cycle described above is maintained. The decrease in Ca++ triggers secretion of parathormone. This causes increased renal phosphorous loss and increased calcium removal from bone. Parathormone also triggers enhanced 1,25 dihhydroxylation of Vitamin D in kidney. With active Vitamin D, increased absorption of Ca++ maintains calcium levels.
Calcium levels high:
The parathyroid stops secreting parathormone. None of the above effects occur. 24,25 Vitamin D is relatively inactive and will remain so as long as this state of affairs continues Calcitriol has many other important functions, including regulation of hematopoietic cell and probably muscle cell function, but this is beyond the scope of this module.
Q2. How can Rachel make sure Michaela has sufficient quantities of Vitamin D?
A2. Given the mother's resistance to use of "artificial" sources for Vitamin D, a possible way to provide her with vitamin D is to take advantage of the natural synthesis pathway in her own skin. Exposure to sunlight, even for brief periods(20 minutes a day of sun exposure to the cheeks of a white child is said to be enough to make the daily requirement of 400 units of vitamin D), will provide Michaela with some Vitamin D and is likely to prevent clinically recognizable rickets in a white child. However, during winter months, Michaela would still require dietary supplementation with Vitamin D as the sun is not sufficiently high in the sky to permit conversion from precursors to cholecalciferol.
Unfortunately, Rachel's reluctance to use animal products or fortified formulae makes it difficult to incorporate vitamin D into Michaela's diet. There are a few foods that are naturally rich in Vitamin D, namely fatty fishes or the oils derived from them. Cod liver oil was the first recognized anti-rachitic factor used by Europeans living in the far north [Hyperlink to Nutrition Notes]
Rachel might be more willing to accept food products that are certified organic, e.g. organic salmon. These dietary complications make it especially important that Michaela receive adequate exposure to sunlight.
Q3. How much vitamin D is recommended for children like Michaela?
A3. The American Academy of Pediatrics recommends that all infants receive 200 IU of vitamin D unless they are drinking at least 500 mL of vitamin D fortified formula per day. The vitamin D supplementation should be started within the first 2 months of life. It is true that the liver stores a 4 to 6 month supply, but one must not wait too long. Perhaps the 4 and 6 month visits will be missed or the practitioner will forget to provide the Vitamin D.
Q4. Are people with relatively different levels of skin pigment more or less "at-risk" for vitamin D deficiency Rickets and why?
A4. As described in Nutrition Notes fair skin people living in the far north have a survival advantage that compensates for the lack of sunlight at sufficient altitude in the sky to promote production of Vitamin D throughout the year. A second survival advantage is to be lactose tolerant. This allows easier digestion of high calcium, high protein dairy products produced by grass eating cows and goats.
TEACHING CAPTION: Peoples in the far north are at highest risk for Vitamin D deficiency Rickets. See Nutrition Notes for an explanation of why the darkly pigmented polar Inuit are exempt from this phenomenon [HYPERLINK] Hint: do you like Cod Liver Oil? They do.
The figure below shows photos of the indigenous living at longitudes 0 to ___ with a line drawn from sub-Sahara Africa, though North Africa, Spain, France, the Holland, and Scandinavia.
TEACHING CAPTION: Having fair skin does have an advantage with respect to production of Vitamin D. The skin of black Africans and their descendants have a sun screen protective factor of approximately 7. Skin color is an evolutionary response to the duration of exposure to UV light rising at > 45 degrees above horizontal - duration each day and number of days. Decreased exposure requires less melanin in the skin.
Q5. Would being exposed to the sun have harmful effects?
A5. Early sun exposure, especially with burning, increases the likelihood of skin cancers. Dermatologists recommend NO sun exposure before 6 months of age and use of sun screen afterwards. Thus, whatever Michaela gains from having less skin pigmentation will be lost if she wears sun screen (An SPF of 8 is enough to stop ~95% of cutaneous vitamin D synthesis) or is not exposed to the sun.
These recommendations for preventing cancer of the skin in adulthood increase need for vitamin D sources in the diet to prevent vitamin D deficiency. These include from formulae, fortified cow milk, goat milk or soy preparation, cod liver oil, or a vitamin supplement
Vitamin D deficiency rickets is more common among African Americans than people of Asian or European descent. Darker skin increases risk of rickets, but other factors affect the [ENVIRONMENT X HEREDITY] antecedents of this disorder including access to health care, prescribing of supplements, actual use as well as dietary differences - e.g., use of vitamin D fortified cow milk.
Q6. How would you conduct your initial dialogue with Rachel?
A6. Your goal is to convince Rachel to use a supplement. To do so, however, you must be a good listener. Go to Introduction for description of effective listening skills. Construct a dialogue between two residents. One is "Rachel" and the other is the pediatrician.
Rachel constructs "her" story [could be a male resident playing the role] The factors include --, "purity," "chemical nature," animal product," and denial "I don't need it all." Review Nutrition Notes for information on breast milk as a poor source of vitamin D.
The pediatrician reviews the sections on effective listening in the Teacher's Guide and those on calcium and Vitamin D in Nutrition Notes.
Note: we do not generally recognize the character created for Rachel in terms of "different culture" as she is "one of us." Think again about how these ideas and behaviors form a structure of support for her within a community of like-minded people. [Roughly, this is Clifford Geertz's definition of culture.]
The case study continues.
You are not successful in your attempts to convince Rachel. Michaela does not receive a supplement for Vitamin D. Rachel breast feeds exclusively for 6 months when she begins feeding solids. Michaela seems to be fine. She comes a bit late for her "9" month visit. At 11 months you find that she is growing well and is developmentally normal. The examination shows some enlargement at the wrist and a "double fibular malleoli on both ankles. There is a slight genu varus - bow legs on standing. She does not have frontal bossing or a rachitic rosary - painless overgrowth of the costochondral junction." Laboratory evaluation shows a Ca++ of 10.1 mg/dL, a Phosphorus of 3.2__, and an Alk Phos of 546 __. The parathormone (PTH) level is _195___; A radiograph of the distal tibia show fraying at the epiphysis and a widened zone of provisional calcification.
Q7. What does the evaluation suggest?
A7. The calcium is normal while the phosphorus is depressed (Ca X Phos is decreased also), and the Alkaline Phosphatase and PTH levels are elevated. The physical findings are classic signs of clinical rickets. The normal calcium level is not unusual, especially in the early stages of rickets.
To be sure of your diagnosis, however, the evaluation of a child with rickets should include a complete medication and dietary history, paying close attention to calcium and vitamin D intake. [see final Question in module.] Serum creatinine should be drawn to exclude renal insufficiency as a cause of vitamin D deficiency. Liver enzymes must also be evaluated to exclude liver disease as a cause for elevated alkaline phosphatase. To classify the form of rickets, serum PTH, vitamin D levels, and phosphorus should be drawn. Elevated PTH usually indicates hypocalcemic rickets. Normal phosphorus and PTH levels would make the diagnosis of rickets unlikely.
Q8. How do you classify the clinical and laboratory findings?
A8. The following table is taken from Pediatric Nutrition Notes.
* including bow-legs, frontal bossing, nodules at the costochondral junction, "spade-like" wrists, and Marfan's sign (double malleolus)
Q9. What interventions are needed.
A9. The treatment of rickets is described in Nutrition Notes. We recommend "Stosstherapy" done in a single day. The long range therapy depends on your ability to change behavior. Let's try! Continue the dialogue with Rachel and provide guidance for low and high risk infants.
What are your goals for diet therapy?
How can you engage Rachel in a way that puts you in the same place as she?
What small steps could you take?
Case conclusion. With stosstherapy, correction of the rickets is certain. What happens later in life is not so clear. Michaela may be at increased risk for calcium depletion syndromes as an adult.
Q10. What are the risk factors predicting Vitamin D deficiency in adolescence.
A10. In a recently published survey of 307 teen-agers in Boston, 14 (4.6%) had severely reduced levels of 25 (OH) Vitamin D, an additional 61 (19.5) were below acceptable limits, and an additional 129 teen-agers (42%) had sub-optimal levels. Levels of 25 (OH) Vit D correlated directly with consumption of milk and cereal (often fortified) and sunlit seasons of the year. There was an inverse correlation between 25(OH) Vit D levels and BMI and consumption of juice, ice tea, and soft drinks, African American ancestry increased risk for deficiency independent of the other factors. These data suggest that all children in the northern part of the United States, but especially children of color, are at increased risk for Vitamin D deficiency and its consequences later in life.
See Gordon CM, DePeter KC, Feldman HA, et al. Prevalence of Vitamin D Deficiency Among Healthy Adolescents Arch Pediatr Adolesc Med. 2004;158:531-537.
See Loomis WF. Skin pigment and regulation of Vitamin D synthesis in man Science NY 1967; 157:501-506.. This reference as found in the Passmore and Davidson text.
Annotated Pre-test Answers:
A1. The answer is C. Vitamin D in humans is synthesized in the skin from 7-dehydrocholesterol in a series of nonenzymatic, ultraviolet light-dependent reactions. Breast milk contains little vitamin D and infants that are exclusively breast-fed are at risk of developing vitamin D deficiency. Intestinal bacteria synthesize Vitamin K, not vitamin D. The parathyroid glands play a role in vitamin D metabolism through the action of parathyroid hormone, but do not directly synthesize vitamin D.
A2. The answer is A. Vitamin D and all its metabolites travel in the blood bound to Vitamin D Binding Protein. The vast majority of Vitamin D found in the body is in the form of 25-hydroxyvitamin D (calcidiol).
A3. This is true. Enhancing absorption is the principle function. Bone molding is a secondary function.
A4. The answer is A. At one level, when taken orally, Vitamin D is a true "vital amine." That is, it is a substance required in the diet because there is no in vivo production. Vitamin D is also a steroid with precursors produced under the skin when UV light strikes the basal layer and forms cholecalciferol, a steroid -like structure. The subsequent metabolic changes produce the active Vitamin D steroid.
A5. The answer is D. Few natural foods are rich in Vitamin D, but fish liver oils and fatty fish are relatively good sources of Vitamin D. 1 tablespoon of cod liver oil contains 1360 international units (IU) of Vitamin D, and 3 ounces of salmon contains 425 IU of Vitamin D. In comparison a typical multivitamin contains 400 IU of Vitamin D, and a glass of fortified milk or orange juice contains about 100 IU of Vitamin D.
Yogurt is rich in calcium, but not vitamin D.
A6. The answer is B. Vitamin D exerts its effects by binding to nuclear receptors in many different locations in the body, chiefly in small intestine and bone.
A7. The answer is C. The AAP recommends that infants receive 200 IU of Vitamin D daily. Since this is the amount present in 500 mL of fortified formula, infants consuming at least 500 mL of fortified formula per day do not require additional supplementation. Breast milk is an inconsistent source of vitamin D, and breast-fed infants need vitamin D supplementation unless they also consume 500 mL of fortified formula per day. Although infants do receive vitamin D from the mother at birth in the form of 25-OH-D (calcidiol), the half-life of calcidiol is 3-4 weeks, and the plasma concentration falls rapidly if additional sources are unavailable, and the AAP recommends supplementation within the first two months of life.
All infants require Vitamin D supplementation without regard to pigmentation. Breast milk is unreliable. The combination of urban life, clothing, and sun screen protection make every infant vulnerable to Vitamin D deficiency rickets.
