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VITAMINS AND IRON IN HEALTH AND DISEASE

 

GENERAL CONCEPT

The early discoveries of vitamins followed observations on naturally occurring diseases such as scurvy and beriberi. The improvement noted in these diseases when modifications were made in the diet suggested that a deficiency of some sort was the cause of the pathological process. Discoveries came much more rapidly when feeding experiments were performed on experimental animals, and soon the essential nature of many vitamins was recognized.

Many of the water-soluble vitamins are coenzymes or essential parts of a coenzyme and thus have an essential function in the enzymatic machinery of cells.

WATER SOLUBLE VITAMINS

Thiamine (B1)

Thiamine (B1) in the form of thiamine pyrophosphate or cocarboxylase has been shown to play an important role in the decarboxylation of -keto acids such as pyruvate.

Severe deficiency results in the disease beriberi, characterized by high-output heart failure and peripheral polyneuritis. Other symptoms include anorexia, nausea, intestinal atony, disturbances of peripheral nerves, and mental disorders.

Thiamine is present in sufficient quantities in yeast, wheat germ, and pork. One international or USP unit is equal to 3 g of thiamine hydrochloride.

Nicotinic Acid

Nicotinic acid (niacin) is an integral part of at least two important coenzymes, nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP).

NAD and NADP can exist in an oxidized or reduced state and can thus act as hydrogen acceptors or donors in many enzymatic reactions of intermediary metabolism. Microsomal enzymes requiring NADP play an important role also in the metabolism of many drugs.

Pellagra is the disease caused by niacin deficiency. It is characterized by skin lesions, gastrointestinal mucosal changes, with diarrhea, and neurological symptoms including mental disorders.

Nicotinic acid is found in significant amounts in yeast, rice, bran, and liver and other meats. Mammals can synthesize nicotinic acid from tryptophan. Pellagra can occur in patients having carcinoid tumor as a consequence of utilization of tryptophan for serotonin (5-hydroxytryptamine) synthesis.

Nicotinic acid, not nicotinamide, produces marked dilation of small vessels, an effect that is transient but that may be severe on parenteral administration. On a purely empiric basis, nicotinic acid is used experimentally for lowering serum cholesterol and as a vasodilator, but it is not definitely useful.

Riboflavin (B2)

Riboflavin is present in flavin adenine dinucleotide (FAD), which is a coenzyme of flavoprotein enzymes. There is also a flavin mononucleotide (FMN).

A deficiency of riboflavin will cause cheilosis, stomatitis (irritation of mouth), and keratitis (dry skin).

Riboflavin is present in significant quantities in yeast, green vegetable, liver and other meats, eggs, and milk.

Pyridoxine (B6)

Pyridoxine and also pyridoxal and pyridoxamine are various forms of vitamin B6. Pyridoxal phosphate functions as a coenzyme in many reactions such as the decarboxylation of amino acids and transamination reactions between amino acids and keto acids.

A deficiency of pyridoxine results in dermatitis (skin inflammation) and convulsions (seizures). Thiosemicarbazide may act as a convulsant by this mechanism. Isoniazid (used in tuberculosis therapy) may also cause pyridoxine deficiency.

Pyridoxine is present is significant amounts in yeast, liver, rice, bran, and wheat germ.

Pantothenic Acid

Pantothenic acid is a part of a very important coenzyme known as coenzyme A.

Coenzyme A in the form of acetylcoenzyme A is essential for a variety of acetylaction reactions such as the formation of acetylcholine from choline and the acetylation of p-amino compounds. The coenzyme plays an important role in the Krebs cycle sine citric acid is formed from the oxaloacetic acid, acetyl coenzyme A, and water, the reaction regenerating coenzyme A. The coenzyme also plays an important role in fatty acid metabolism.

Pantothenic acid deficiency is not well recognized in humans. In animals it may cause dermatitis, adrenal degeneration, and central nervous system (CNS) symptoms.

Pantothenic acid is found particularly in yeast, bran, egg yolk, and liver.

Ascorbic Acid (Vitamin C)

Ascorbic acid is a reducing agent whose exact biological function is not understood. It may be a cofactor for the transformation of folic to folinic acid and may be necessary for adrenal cortical function and maintenance of normal connective tissue. The recent claim for ascorbic acid in the prevention of the common cold is not based on convincing evidence, although large-scale, controlled clinical trials are not available for proving or disproving its efficacy.

The classical disease of scurvy is characterized by abnormalities in the connective tissue with capillaries and bone being severely affected.

Ascorbic acid is present in large quantities in citrus fruits, green peppers, tomatoes, and fruits and vegetables in general.

Other water-soluble vitamins

There are several other water-soluble factors essential for experimental animals and presumably for humans. These include biotin, folic acid, choline, and inositol.

FAT-SOLUBLE VITAMINS

Vitamin A

Vitamin A performs an important function in connection with dark adaptation, being part of the visual purple of the retina, It also maintains the integrity of various epithelial structures.

Deficiency of vitamin A produces night blindness, keratinization of the conjunctiva (xerophthalmia), and ulcerations of the cornea (keratomalacia). The skin becomes rough because of hyperkeratosis, Respiratory infections occur in animals deficient in vitamin A, perhaps due to changes in the bronchial epithelium, but there is no good evidence to indicate any connection between vitamin A deficiency and respiratory infection in human beings.

Vitamin A occurs particularly in eggs, milk, vegetables, and fish liver oils.

Vitamin A is stored in the liver, In large quantities the vitamin may cause toxic effects such as anorexia, hepatomegaly, loss of hair, and periosteal thickening of long bones.

Cod liver oil contains 850 IU of vitamin A per gram, a unit being equal to 0.6 g of -carotene. The administration of more than 25,000 IU/day is seldom justified.

Vitamin D

Vitamin D refers to one of several sterols. Vitamin D2 (calciferol) is obtained by irradiation of ergosterol.

Vitamin D3 is present in fish liver oils and is produced in the skin by the action of sunlight on 7-dehydrocholesterol. Dihydrotachysterol has actions resembling those of the parathyroid hormone and was discussed in connection with that subject.

Deficiency of vitamin D brings forth the various manifestations of rickets in growing children and animals. There is a disturbance in calcification of bones and teeth. The bones may become soft. Swollen epiphyses and lack of normal calcification are demonstrable by radiological examination.

The main function of vitamin D appears to be exerted on the intestinal absorption of calcium and phosphate. In large quantities the vitamin may exert an effect on bone dissolution similar to the action of the parathyroid hormone.

The daily requirement of vitamin D depends on the calcium needs of the individual. Growing children and pregnant or lactating women require more of the vitamin because their daily calcium absorption must be greater.

Vitamin D preparations are standardized by determining their effect of calcification in rats maintained on a diet deficient in vitamin D. The international unit is 0.025 g of vitamin D3.

Adults require 400 units of vitamin D in 24 hours. Infants, children, and also pregnant or lactating women may require as much as twice this amount. It may be administered in the form of fish liver oils, as calciferol, or as synthetic oleo-vitamin D. Dihydrotachysterol (Hydracalciferol) is used in hypoparathyroidism to raise the serum calcium level.

Excessive doses of the D vitamins cause hypercalcemia, with anorexia and metastatic calcifications in the kidney.

Vitamin E

Vitamin E is present in wheat-germ oil and in many foods. Its role in animal reproduction has been well established, and the term tocopherol implies its importance in childbearing. There are several tocopherols, but -tocopherol has the highest activity.

Deficiency of vitamin E produces abortion in the female animal and degeneration of the germinal epithelium in the male animal. Muscular dystrophy also develops in animals on a vitamin E-deficient diet. Many other functions have been claimed for -tocopherol, and many of its therapeutic applications have been suggested largely on the basis of uncritical clinical observations. The exact daily requirement of vitamin E in humans are not known, but quantities of 5 to 30 mg or more have been used in many clinical series.

The feeding of large amount s of unsaturated fats may increase the tocopherol requirements. It has been suggested that tocopherol functions as a biological antioxidant whose function becomes particularly important when tissues contain peroxidizable lipids.

There is some evidence that vitamin E could decrease the incidence of prostate cancer in men, however the incidence of strokes is increased.

Vitamin K

Vitamin K is essential for production of Prothrombin by the liver, and in its absence hemorrhagic manifestations occur.

Vitamin K preparations are useful in bleeding caused by hypoprothrombinemia. Causes of hypoprothrombinemia are severe liver disease, biliary obstruction, malabsorption syndromes, coumarin and indandione drugs, Salicylates in large doses, reduction of intestinal flora by chemotherapeutic agents, and hypoprothrombinemia of small infants.

Commonly used preparations are vitamin K1 (phytonadione; Mephyton) and various forms of vitamin K3 (menadione).

The daily requirement for vitamin K cannot be stated because considerable quantities are synthesized by the bacterial flora of the intestine. The dosage varies greatly, depending on the nature and severity of Prothrombin deficiency. Doses of 1 to 2 mg by mouth or injection may suffice. On the other hand, very large doses may have to be administered in emergency situations when Prothrombin levels have been depressed by the anticoagulant drugs. As much as 100 mg or more of vitamin K1 emulsion has been used in this situation by the intravenous route.

Individuals who are subject to primaquine-sensitive anemia may react with hemolysis to large doses of vitamin K. Such doses can also aggravate liver disease and produce jaundice, particularly in infants.

MEDICAL USES OF VITAMINS

Vitamins should be used as a medicine in :

  1. Individuals with a poor dietary history.
  2. Deficiency diseases.
  3. Special disease states.
  4. Hereditary vitamin dependency states.

Individuals with a poor dietary history include vegetarians who do not consume dairy products, individuals who do not consume fruits and green vegetables, pregnant or lactating women, and infants. Vegetarians develop vitamin B12 deficiency and require supplementation with 10 g daily doses.

Ascorbic acid, 50 mg daily, should be given to persons who do not eat fruits and green vegetables.

Folate supplementation (0.5 mg) and pyridoxine should be given to pregnant women. Lactating women should probably take at least 80 mg of ascorbic acid daily, and their increased thiamine requirements should be met by proper food intake. Infants fed cow's milk should receive about 35 mg ascorbic acid daily, and the newborn should receive a single intramuscular injection of 0.5 to 1 mg of vitamin K, since vitamin K deficiency develops until the intestinal flora is established.

Deficiency diseases include alcoholism, pernicious anemia, total or partial gastrectomy, chronic pancreatitis (fibrocystic disease), celiac disease (nontropical sprue), tropical sprue, short bowel syndrome, and dietary deficiencies. Detailed discussion of the supplementation required in each of these conditions is beyond the scope of this review.

Additional special disease states include injection with Diphyllobothrium latum, hypoparathyroidism, and the carcinoid syndrome. The corresponding supplementation's are vitamin B12, vitamin D2, and niacin.

Hereditary vitamin dependency states have been recognized in which the apoenzyme fails to react normally with the coenzyme, the condition being partially overcome by large doses of the corresponding vitamins. For example, an inborn error in the apoenzyme pyruvate carboxylase can produce lactic acidosis and is treated with 20 mg of thiamine daily. There are several rare diseases of this type, which provide some justification for the search for conditions that might be benefited by the megavitamin concept. It should be remembered that the effectiveness of levodopa in parkinsonism would not have been discovered without someone trying unusually large doses of the drug. This, however, should not be considered an endorsement of the megavitamin therapy, which in most cases is ineffective and is not based on sound theory or controlled clinical trials.

ADVERSE EFFECTS OF VITAMINS

Although slight excesses of vitamin intake are more wasteful than dangerous, large doses of several of the vitamins can produce adverse effects.

The water-soluble vitamins are generally harmless except in special circumstances.

Thiamine injected intravenously has produced a shock like state, and an anaphylactic-type sensitization to it has been suspected.

Nicotinic acid is a fairly potent vasodilator, and for that reason nicotinamide, which does not affect the blood vessels, is preferred.

Folic acid may be dangerous in persons who have pernicious anemia, since it may aggravate the neurological manifestations of the disease. For this reason the modern tendency is to eliminate folic acid from multiple vitamin preparations.

Ascorbic acid is remarkably nontoxic. When given in large quantities, the vitamin is rapidly cleared by the kidney, however could increase the risk for oxalate kidney stones. Also, in multiple myeloma high dosages could acidify the urine which would precipitate the myeloma protein and damage the kidneys.

Pyridoxine promotes the peripheral decarboxylation of levodopa and thus decreases its effectiveness in the treatment of parkinsonism.

The fat-soluble vitamins are more likely to produce distinct pathological changes when given in excessive quantities.

Hypervitaminosis A has been described as occurring in children when doses of the order of 100,000 units or more are administered for many days. Changes in skeletal (bone) development, hepatomegaly (enlarged liver), anemia, loss of hair, and other symptoms have been described in these patients.

When used in large quantities, vitamin D can produce hypercalcemia with metastatic calcification in the kidney and blood vessels. This is not likely to happen in the treatment of rickets, but occasionally large amounts of vitamin D2 are used in other diseases such as lupus vulgaris in which there is no reason to suspect a deficiency.

Hemolytic anemia (break down of red cells), and jaundice have been reported following parenteral use of large doses of the various vitamin K preparations.

The occurrence of these adverse reactions is an additional reason for maintaining a rational attitude toward the use of vitamins in cases in which their indications are not clear.

Recommended daily dietary allowances and therapeutic doses of vitamins


Vitamin

Average

daily adult requirement


Therapeutic dose

Thiamine 1.5 mg 2-10 mg
Nicotinamide 20 mg 100-300 mg
Riboflavin 2 mg 2-10 mg
Pyridoxine 2 mg 10 mg
Ascorbic acid 60 mg 100-150 mg
Vitamin A 4000 units 25,000 units
Vitamin D 400 units 5000 units or more
Vitamin E Unknown 30 units

 

 
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