5. MICRONUTRIENT VITAMINS
Try these questions (detailed answers at the bottom):
Q1. The most common clinical presentation at birth of a relative folic acid deficiency is:
A. A megalobastic anemia
B. Subacute combined degeneration of the dorsal columns ("Vegans' back")
C. Neural tube defects
D. All of these occur regularly in clinical practice.
Q2. Vitamin C is not found in which of the following foods:
A. Freshly made sour kraut
B. Freshly squeezed orange juice
C. The needles of the white pine tree
D. A double cheese burger with bacon, fries and a big gulp soda.
E. They all contain ample Vitamin C
Q3. True or False. One does not have to worry about nutrient toxicities with water soluble vitamins.
And these techniques:
1. You already have data from the market place. Try out folate on the Thrifty Food Plan!
2. Form student pairs. Take diet histories from the experience of trying to; purchase foods at $17 a day. Explore how one's own or created personae might react to doubling of income. Calculate folate intake
3. Here's a chance to try out megavitamin theory. Students will go to a health food or a botanica where possible in a field survey of what is recommended. Give lists of common conditions: asthma, kidney stones, hypertension, sinusitis, and dry skin. Check out home remedies from your own culture.
5a. Micronutrient Vitamins -- Vitamin A and analogues
Though Vitamin A was discovered in the early 20th century, the major consequence of dietary deficiency (night blindness) and its cure were recognized in antiquity. Juice from uncooked liver was squeezed into the eye and liver was ingested to provide Vitamin A.
Terms
Retinal, retinol, carotenoid, xerosis, and xerophthalmia
Requirements
Vitamin A can be consumed as "all trans" retinol, the active form, or as one of the 50 or more carotenoids that have Vitamin A activity. The prevention of disease can be achieved with 400 ugm of retinol equivalent a day in infancy to 1,000 ugm/day in adults. A retinol equivalent is defined as 1 ug of retinol, 6 ugm of beta carotene or 12 ugm of other carotenoids. Retinol and carotenoids have anti-oxidant effects and are thought to be anti-carcinogenic and anti-atherogenic. These claims, however, remain unproved with their potential side effects undetermined. High doses of anti-oxidants may function as super-oxidants. The higher intake under DRI theory has been associated with toxicities including increased fractures in older adults. The RDA or Adequate Intake of Vitamin A may be reduced in the near future.
Consequences of deficiency
Vitamin A deficiency affects vision in two ways. The first is the light activated isomerization of the 11-cis bond of retinal in rhodopsin in the dark-adapted retina to the all trans form. All trans rhodopsin is unstable and dissociates into all trans retinal and opsin. We sense what follows as "vision." Second, Vitamin A deficiency results in the replacement of mucous-secreting cells by keratin-producing ones throughout the body. In the skin, there is a follicular hyperkeratosis. In the eye, there is a progressive drying known as xerosis.
At first, a dry (or "Bitot") spot forms on the bulbar conjunctiva adjacent to the cornea. The loss of mucous producing cells undermines the supporting tissues in the cornea. Early xerophthalmia is reversible, but with corneal involvement, it is not. Permanent blindness follows. [See module on Vitamin A].
There are significant effects of Vitamin A deficiency in cell mediated immunity and the complement system. Thus, Vitamin A deficiency has been implemented in the phenomenon seen throughout the developing world: malnutrition --> susceptibility to infection --> increased mortality. The presence of mild Vitamin A deficiency (Bitot spots) with mild protein energy malnutrition (poor growth) has been associated with an increased mortality. In a recent measles epidemic in the United States, children hospitalized with measles had lower circulating Vitamin A levels than children not requiring hospitalization.
Vitamin A excess is a concern as many people experiment with hypothetical preventive and therapeutic usage of retinols in pharmacological doses. Both acute and chronic effects have been noted including photosensitivity, malaise, hyperostosis, and most importantly, increased intracranial pressure - the syndrome of pseudo-tumor cerebrii. A warning known to all older pediatrician comes from a comic strip called "Mark Trail": Hypervitaminosis A has been reported in Arctic explorers who consume polar bear liver.
5b. Micronutrient Vitamins--Vitamin C (Ascorbic Acid)
Ascorbic acid is a water-soluble micronutrient needed for the formation of connective tissue throughout the body. The disease scurvy is a consequence of Vitamin C deficiency. It is expressed by capillary breakage, pinpoint hemorrhages, first bleeding then receding gums with loss of teeth. In children, cartilage, teeth and bones form improperly. In addition, Vitamin C is required to convert tyrosine to norepinephrine and tryptophan to serotonin. The lethargy and fatigue of scurvy are thought to be consequences of the failure to provide these neuro-active chemicals.
Other functions of Vitamin C reflect its anti-oxidant properties and include the maintenance of iron in the reduced (ferrous) state thus promoting absorption and preventing the oxidation of low-density lipoprotein (LDL) -- a critical step in atherogenesis. The role of Vitamin C in the prevention of colds, cancer and coronary artery disease are speculative and beyond the range of ascorbic acid intake available from food in the human diet. Once again, the DRI concept must include an awareness of potential toxicities.
Recommended intake
In the United States, the RDA for Vitamin C ranges from 45mg for infants and growing children to 100mg for lactating women. Far less is required to prevent scurvy.
Foods providing Vitamin C are primarily of vegetable origin. Though found in organ meats, it is degraded as a consequence of cooking. Raw seal and penguin meat kept polar explorers alive. They are a part of the diet in the Arctic. Citrus fruits, raw cabbage family vegetables, and peppers (seed bearing vegetables) are fine sources of vitamin C. This introduces the experiment conducted by Dr. James Lind, a British Navy physician, in 1747. It was the first controlled experiment recorded in the medical literature. Lind took 12 sailors with scurvy directly from a ship and in groups of two observed their responses to various suggested therapies.
With scurvy directly from a ship and in groups of two observed their responses to various suggested therapies.
Those sailors taking oranges or lemons recovered fully in one week! Of note, it took the British Navy 50 years to implement the nutritional policies to prevent scurvy by putting barrels of lemons and limes on board ships taking long voyages. The German Navy used barrels of sauerkraut to the same effect.
Treatment/Prevention
Vitamin C deficiency is exceedingly rare in children on a mixed diet. Evaporated milk formula fed infants need a source of vitamin C. A positive tourniquet (Rumple-Leeds) test may reflect consumption of a fruit free processed foods diet.
5c. Micronutrient Vitamins--Vitamin D (Cholecalciferol)
During the 18th century in European countries and their colonies as the industrial revolution began, Vitamin D deficiency rickets became common occurrence among the urban poor. Rickets was a disease of children living in "poverty and darkness".
Ninety percent of available Vitamin D comes from UV light triggered conversion of 7-dehydrocholesterol based precursors to cholecalciferol. Twenty-five hydroxylation (25 (OH)) to calcidiol occurs in the liver, and under the influence of parathyroid hormone (PTH), di-hydroxylation occurs in the kidney to form 1,25 (OH) 2-cholecalciferol (calcitriol). This is the most active form of Vitamin D.
Vitamin D2, taken orally, is a fat-soluble vitamin derived from plants which requires hydroxylation in liver and then again in the kidney as noted above. Vitamin D2 is "activated ergosterol" while animal derived Vitamin D3 is cholecalciferol. They are biologically equal.
Vitamin D enhances the absorption of calcium from the gut, removal of calcium from bone, and phosphate reabsorption in the kidney. All of these activities are essential to the body to provide sufficient calcium for the production of a strong bony matrix and the maintenance of a consistent serum calcium level. (See Section 4b; see also modules on handicapped children and on Calcium needs)
Four hundred IU of vitamin D is sufficient to prevent "chemical rickets" - only a rise in serum alkaline phosphatase (AlkP). Below 100 IU, bone softening and tibial bowing (rickets derives from the Saxon word wrikken, "twisted") will occur.
Vitamin D requirements are higher using the DRI concept. Calcium absorbed and stored in childhood is required for bone stability. Intakes up to, but not higher, than 800 IU may be necessary to prevent disease later in life. Vitamin D excess results in calcium deposition in arteries, heart, lung and renal tubules leading to a renal tubular acidosis.
TABLE -- Preclinical and Clinical Rickets:
* including bow-legs, frontal bossing, nodules at the costochondral junction, "spade-like" wrists, and Marfan's sign (double malleolus)
Vitamin D is available in some foods, though only the oil extracted from cold-water ocean fish (cod, halibut or percomorph (shark) liver) has levels of sufficient quantity to be recommend for the prevention of rickets. Unfortified milk does not contain Vitamin D. Breast milk contains variable amounts of Vitamin D depending on maternal consumption and exposure to sun. Even when maternal Vitamin D nutrition is most adequate, breast milk will be inadequate as a source for the infant.
Prevention
It is clear what circumstance causes rickets (softening bones in a growing child) and osteomalacia (the disease in an adult) to occur:
** Almost all rickets in healthy children could be attributed to inadequate exposure to sunlight. Perhaps the lighter pigmentation among peoples who live in the far north is an evolutionary response to lack of sunlight in the winter and a decrease in UV light penetrating the atmosphere.
** We live, however, in a world where migration is a common occurrence. Thus, we must provide nutritional supplements rather than allow migrants to the north (people from the Indian sub-continent in Scotland or people of African origin in the United States or Europe) develop chemical if not clinical rickets.
** Unsupplemented breast-fed infants are likely to develop rickets. Mother's milk is not a source of Vitamin D. Pediatric texts from the early 20th century warn against choosing a wet nurse who is either "colored or Italian". Not withstanding this advice, all babies, including those whose mothers and themselves have the lightest possible complexions must have a dietary source of Vitamin D.
** Home bound and institutionalized older children who do not consume commercially produced (and thus Vitamin D fortified) milk must receive a supplement. The consumption of calcium rich food, such as cheese, ice cream or yogurt, does not suffice.
** Children with gastrointestinal, hepatic or renal diseases affecting mineral absorption or hydroxylation of Vitamin D are vulnerable to hypocalcemia and rickets. Dilantin and other anticonvulsant medications increase requirements by stimulating the p450 system's removal of active Vitamin D.
Nutrition rather than heredity as the basis for adaptation
Rickets was endemic in Scandinavia through the 19th century until they discovered the anti-rachitic effect of cod liver oil. By contrast, the darkly pigmented Inuit of the far north (Eskimos) did not have rickets because fish oils were a staple in their diet.
The children shown below illustrate two important points.
** dietary practices are an important part of adaptation to life in the northern hemisphere.
** food habits formed in childhood last a lifetime. Inuit children enjoy a substance (Castor Oil) that to an American child (receiving Cod Liver Oil) is "medicine" -- ugh!
Figure: Response to Castor oil by an Inuit child from Hudson's Bay and by a child in Philadelphia.
The Inuit child responded very favorably to an oily food. Early exposure to fish oils allows these children to accept what American children find repulsive -- cod liver oil.
It's acceptance that led Inuit in the far north to be more resistant to Vitamin D deficiency rickets than their fair-skinned Scandinavian-ancestry neighbors. In early 20th century, the Scandinavians discovered the anti-rachitic effect of fish oils, which had not been a natural part of their diet.
Sources: The film, "Nanook of the North" by Robert Flannery (1923) and a reproduction of the experience in Philadelphia (1982)
Treatment of rickets
We suggest the use of a single-day large dose of Vitamin D2 -- "stosstherapy" -- to children with rickets. This includes the provision of 100,000 I.U. orally every two hours for six doses -- a total of 600,000 I.U. (15,000ugm total). One gram of elemental calcium (via supplements and diet) is provided daily through the treatment phase and beyond. A failure to respond with healing suggests the possibility of non-nutritional rickets. Solutions of Vitamin D2 containing propylene glycol should not be used for stosstherapy.
In the past, small daily doses of Vitamin D were provided without assuring adequate calcium intake. One risk of gradual therapy has been that giving small doses of Vitamin D in spurts to the calcium-depleted child may cause a rapid precipitation of calcium and phosphorous in bone and lower the serum calcium even further. Tetany may occur.
Furthermore, giving therapeutic doses of Vitamin D at home may result in hypervitaminosis D when there is under-supervision of an overly enthusiastic parent.
5d. Micronutrient Vitamins--Niacin
Pellagra is among the most important nutritional disorders today, but not because of its occurrence in the United States. Rather, it is the history of the disease that calls for our attention.
In 1913, Joseph Goldberger, M.D., a physician trained in infectious disease, was sent by the United States Public Health Service to find the infectious agent "causing" pellagra in the American South. Dr. Goldberger, known as "the father of American nutrition," was able to discard the specifics of his own training, and instead, use principles of scientific investigation to identify the true cause, a dietary deficiency of the nutrient niacin. He observed that employees of hospitals or prisons in which pellagra was common never contracted the disease. "[T]he peculiar exemptions or immunity," wrote Goldberger, "is inexplicable on the assumption that pellagra is communicable.... the difference is in the diet of the two groups of residents."
His studies alerted researchers to the importance of yet unidentified micronutrients present in the diet. This began the "biologic age" in nutrition research during which the connection was made between "a lack in the diet of `special substances .... which we will call vitamines'" (e.g., cholecalciferol (Vitamin D) and rickets, ascorbic acid (C) and scurvy, thiamin (B-1) and beri-beri (Schneider, 1983)).
More important is Goldberger’s recognition of pellagra’s nutritional origins. “[He] was well aware that pellagra was a problem of poverty and that only improvement in economic conditions would eradicate the disease....[and] could see the great economic and social advantages to be gained if the cycle could be broken and the disease prevented long enough for the stronger, healthier people to help themselves by improving their own food supply." (WH Sebrell, 1955)
Requirement
Niacin is an energy dependent vitamin with 0.7mgm for each 100 calories consumed being adequate at all ages. Since tryptophan is degraded to niacin, 60mgm of tryptophan generates 1mg of niacin. Diets with adequate content of high biologic value (BV) proteins will provide sufficient niacin, also. Thus pellagra is a disease of protein deficiency (too little) or inadequacy (low BV).
Pellagra was seen in the rural south long after Goldberger and his co-workers determined the cause and the cure. The prevalence increased through the great American Depression of the 1930s. A diet based on corn meal and fat-back (fatty pork) is deficient in both niacin and tryptophan. Pellagra is characterized by the "4-Ds" -- Dermatitis, Diarrhea, Dementia, and Death. The 4-Ds occur in that order with prolonged niacin deficiency.
Treatment
It is not sufficient just to provide vitamins or even food. The occurrence of pellagra in an individual, family, or community suggests that there are failings in the social system along with personal or familial dysfunction.
The photograph is of a Central
American child with the
accentuated sun-sensitivity of
pellagra. His parents are
alcoholics. He lived almost
totally on corn-tortillas.
5e. Micronutrient Vitamins -- Folate and B12
Folate and B12 are discussed together because there are two enzymatic reactions needed to provide the methyl group required to convert deoxy- uridine to thymidine. These reactions use folate as a precursor and B12 as an enzyme affecting production of methyl groups. B12 regulated reactions also affect the supply of folate. The major consequence of both folate and B12 deficiency is megaloblastic anemia. Folate sufficiency with B12 deficiency has been associated with subacute combined degeneration of the dorsal and lateral columns of the spinal cord. Since B12 is found only in animal products and folate is plentiful in vegetables, this syndrome, in its fullest expression and without anemia, has been seen in strict vegans -- no animal products of any kind. It can be produced iatrogenically if folate is given to treat the megaloblastic (pernicious) anemia of B12 deficiency. Pernicious anemia results from the absence of an "intrinsic factor" secreted in the stomach which binds B12 for absorption in the ileum.
Of great interest in recent years has been the recognition that a subclinical folate deficiency at conception and during early pregnancy is associated with neural tube defects. While this association was recognized over 20 years ago, difficulties in developing properly controlled studies held efforts back. Current recommendations are to ensure that women of child bearing age receive at least 400 ugm of folate each day to prevent neural tube defects (See module on folate needs).
Women who have given birth to a child with NTD or those with a family history are provided 4mg daily pre-pregnancy. Supplementation prior to conception requires provision of total nutritional adequacy. Teen-agers require broad social support and supplementation of other nutrients.
Requirements
For B12, 0.5 ugm per day is required in infancy, with 3 ugm required in later childhood and adult life. B12 deficiency does not occur unless there is loss of the stomach or ileum, or with the strictest of vegetarian diets. By contrast, folate requirements, ranging from 30ugm/day in infancy to 400 ugm (20 ugm/100cal/day) in later life and an additional 400 ugm/day in pregnancy, are high and deficiencies are likely without supplementation. Women who have given birth to a child with an NTD are given 4 mg of folate each day with additional B12 and choline (See folate module).
Foods
B12 is found in abundance in animal products only. Folate is found in liver as well as dark green vegetables (broccoli and spinach),and beans. The requirement in pregnancy is higher than the amount found in the diet of most people, and it is unlikely that people will be able to consume the 20 ugm/100 calories required in every day life (preconceptionally). Thus, supplementation may be needed for all adolescents. Children with malabsorption, leukemia (except when being treated with anti-metabolites such as methotrexate) and on anti-oxidant drugs may require extra folate, but children on anti-metabolites should not receive folate since the effect may depend on interference with folate metabolism.
5f. Micronutrient Vitamins -- Vitamins B1 (Thiamin), B6 (Pyridoxine) and Biotin
Thiamin
Thiamin is an energy dependent nutrient with a requirement of 0.05mg for each 100 calories consumed. Pregnant and lactating women require an additional allowance of .04mg/100cal. Whole grain cereals have about 0.12 mg/100 cal while polished rice has about 0.005mg/100cal.
Beri-beri, the disease associated with thiamin deficiency, is more likely to occur when polished rice is the staple of the diet since the shell of the rice is the principal source of the vitamin while the rice kernel provides energy. Beri-beri and other consequences of thiamin deficiency such as ophthalmoplegia is most often seen in the United States among alcoholics who have an excellent though thiamin deficient source of energy - alcohol. There are several inborn errors of metabolism which are thiamin responsive – branched chain amino acidemia (“maple syrup urine” disease) being the most common.
Pyridoxine
Children on a mixed diet are unlikely to be pyridoxine deficient. The anti- tuberculous drug, isoniazid (INH), increases pyridoxine needs and seizures are possible. Adults and adolescents taking an adult dose of INH (300mg) should be placed on at least 10mg of B6 each day. The commercially available 50mg tablets are suitable without toxicity.
Pyridoxine dependant seizures are uncommon, but must be considered as a part of the differential diagnosis of any child with a seizure disorder.
Biotin
Deficiency of this micronutrient is rare except among food faddists who eat raw eggs, which have anti-biotin activity. The breast milk of moderately malnourished mothers may lack sufficient biotin. Deficiency in infancy and childhood is exceedingly rare. Five micrograms of biotin for each 100 calories consumed will certainly meet RDA. Milk and nuts are good sources, and fruits and cereal grains contain biotin, too.
Biotin deficient children will show a dry scaly dermatitis with glossitis and anorexia. It is seen with parenteral alimentation without supplementation and with an inborn error of metabolism.
5g. Micronutrient Vitamins--Vitamin K
This fat-soluble vitamin is actively involved in the clotting mechanisms of humans. Prothrombin and three clotting factors (VII, IX, and X) are regulated by Vitamin K . These are all engaged in the extrinsic system that results in clotting with injury. A common cattle poisoning from the active agent in spoiled clover, Dicoumerol, has resulted in the production of an anticoagulant used therapeutically and a rodent poison (Warfarin). Both substances are, at times, ingested by children. The antidote is Vitamin K.
Requirement
Most Vitamin K is produced in the gastrointestinal tract, and deficiency is unlikely if there is a normal gut flora and normal absorption of fat. When there is interference with the normal flora or malabsorption, 300 to 500 ugm of Vitamin K , given as an IM injection, will be more than adequate.
Foods
Vitamin K is found in leafy green vegetables and in fishmeal. A primary deficiency in this vitamin is highly unlikely.
Newborns
Neonatal deficiency in Vitamin K occurs because 1) the placenta does not permit easy transfer of lipids and 2) the newborn's gut is sterile. For that reason, in the United States, infants are given IM injections of 0.5 or 1mg of Vitamin K immediately after birth.
Potential toxicity of water soluble viatmins
A common teaching is that fat soluble vitamins have an inherant potential for toxicity while water soluble ones, because they are eliminated quickly in the urine, do not. Alhadeff et al. lists the following five ways that water soluble viamins can be toxic.
Table: Five ways water soluble vitamins can be toxic
1. Direct toxic effects,
Example: Vitamin C causes gastroenteritis; Niacin leads to flushing
2. Lead to dependency/withdrawal states upon discontinuation,
Example: Rebound scurvy following C withdrawal
3. Mask signs of underlying disease,
Example: Vitamin C permits iron absorbtion in GI bleed
4 Interferes with laboratory tests,
Example: Vitamin C inactivates tests for GI bleeding
5. Interact with other drugs/vitamins,
Example: Excessive folate intake hides need for B12
TEACHING CAPTION: An aditional consequence is that one might consume excess fat soluble vitamins in the process of increasing water soluble vitamin intake (e.g., taking several once a day multi-vitamin preparations each day). Use of DRI to determine intake requires an appreciation of these potential toxicities.
[Material derived from Alhadeff L, Gualtieri T, Lipton M. Toxic effects of water-soluble vitamins. Nutrition Reviews, 1984;42(2):33-40. See also Part IV Section 8-D, "Nutritional concerns for vitamin and hormone supplementation."]
The answers :
A1. The answer is C. Megaloblastic anemias from folate deficiency are possible but unlikely. Excess folate relative to B12 is the cause for vegan's back (and see below); it is an uncommon condition in adults and not seen in children. It can be seen in pernicious anemia and is why B12 is always given with folate. The occurrence of Neural Tube Defects (NTDs), prematurity and intrauterine growth retardation (IUGR) correlate closely with levels of folate in the diet. The pathophysiology is shown in the module on folic acid needs.
A2. Do you believe that the answer is E?. We hope not. The answer is D, but you knew that. The other sources, pickled cabbage, citrus fruits, and pine needles, were all recognized in the folk ways of various peoples.
A3. The answer is false. All nutrients interact with one another; some are directly toxic while others affect metabolism of drugs adversely. Excess Vitamin C, for example, will increase iron absorption to toxic levels with hemochromatosis. It can cause renal stone formation, and prevent a stool guiac test from being positive in bleeding due to colon cancer. Folate in the absence of B12 will mask pernicious anemia or trigger neurologic disease (See module on Sports Medicine).
And techniques:
1. You are likely to find that folate is a very expensive nutrient
2. The interview could show how an increase in income increases adaptability. It's also possible that people become used to the diets of the poor and don't change.
3. One may find some really effective techniques in the health food stores and bodegas.
