Vitamins are complex organic substances required as coenzymes for many metabolic processes necessary to sustain life. With few exceptions, vitamins are not synthesized in the body and must be provided in the diet. Vitamins are classified as (1) fat-soluble: A, D, E, and K; and (2) water-soluble: B vitamins and vitamin C. The B group of vitamins includes thiamin, riboflavin, nicotinamide, pyridoxine, folic acid, and cyanocobalamin.
Vitamin A is a group of compounds that includes vitamin A alcohol (retinol) and the provitamin β-carotene. Dietary vitamin A is absorbed along with fat and is transported to the liver for storage. Retinol in liver stores enters the blood and is complexed with plasma proteins for transport to tissues.
Vitamin A Deficiency (Hypovitaminosis A)
Dietary sources of vitamin A are liver and dairy products (which contain stored or secreted retinol). Beta-carotene is present in leafy green and yellow vegetables. Dietary deficiency of vitamin A is still prevalent among children in underdeveloped areas, mainly in Southeast Asia and India. Sporadic cases are seen in the United States as a result of chronic fat malabsorptive states.
The earliest effect of vitamin A deficiency is failure of night vision (nyctalopia). Night vision is a function of retinal rods and rhodopsin, a light-sensitive pigment. On exposure to light, rhodopsin dissociates, generating a nerve impulse. In vitamin A deficiency, regeneration of rhodopsin in rods fails. In severe deficiency, vision in bright light, which is dependent on retinal cones (which contain iodopsin, a pigment containing vitamin A), also fails.
Abnormal Maturation of Epithelium
Squamous epithelium undergoes thickening owing to hyperplasia and excessive keratinization, with a number of clinical consequences: (1) The conjunctiva becomes muddy, dry (xerophthalmia), and wrinkled. Bitot's spots (elevated white plaques composed of keratinaceous debris) develop. (2) The cornea opacifies, and erosions develop (keratomalacia). These lesions commonly become infected or perforated, causing blindness (Figure 10-5). Vitamin A deficiency is one of the most common causes of blindness in Asia. (3) The skin becomes hyperkeratotic. Hair follicles become elevated and cause a fine papular rash (follicular hyperkeratosis). Glandular epithelium in the body, such as in the bronchial mucosa, undergoes squamous metaplasia (Chapter 16: Disorders of Cellular Growth, Differentiation, & Maturation). Increased susceptibility to respiratory tract and enteric infections may be partly attributable to these epithelial changes.
Keratomalacia caused by vitamin A deficiency in a 5-month-old child.
The effect of vitamin A on squamous epithelial maturation and proliferation led to research into the possible role of vitamin A deficiency in squamous carcinomas. There are no convincing data for a role for vitamin A in causing cancer, but an unexpected side effect of this research was the development of retinoids (vitamin A analogues), which are effective in the treatment of many skin diseases.
Vitamin A Toxicity (Hypervitaminosis A)
Excessive intake of vitamin A produces cerebral dysfunction, raised intracranial pressure, liver enlargement, and bone changes. Chronic toxicity results in mental changes that simulate psychiatric diseases such as depression and schizophrenia. Note that retinoic acid, used in the treatment of skin disease, may be absorbed. It should not be used in pregnancy because it is a potent teratogen.
Vitamin D (cholecalciferol) is derived in 2 ways, from the diet and from the skin. In the diet, vitamin D is absorbed in the small intestine with other fats and transported to the liver for storage. In the skin, 7-dehydrocholesterol (an endogenous steroid) is converted to cholecalciferol by the action of ultraviolet rays in sunlight.
The active form of vitamin D is 1,25 dihydrocholecalciferol, which is produced from cholecalciferol by two sequential hydroxylation steps (Figure 10-6).
Dietary deficiency of vitamin D usually occurs when malnutrition coexists with minimal exposure to sunlight. In most industrialized countries, vitamin D fortification of milk has eradicated dietary deficiency, but deficiency may still occur in elderly people taking restricted diets who live indoors and are not exposed to sunlight and in strict vegetarians who eat no dairy products.
Secondary vitamin deficiency may occur in intestinal malabsorption, chronic renal disease (failure of α-hydroxylation of 25-cholecalciferol at the 1 position), or, very rarely, in liver failure (failure of α-hydroxylation at the 25 position).
The main effect of vitamin D deficiency is reduced intestinal absorption of calcium. Normally, vitamin D stimulates a calcium carrier protein at the brush border of the intestinal cell that transfers calcium from the intestinal lumen across the cell into the blood. Hypovitaminosis D results in a negative calcium balance with failure of normal calcification of osteoid in bone. Deficient mineralization of bone causes rickets (in children with growing bones) or osteomalacia (in adults after epiphysial closure).
Rickets is a disease of children characterized by failure of mineralization of osteoid in bone with abnormalities of bone growth. Failure of mineralization occurs when the plasma level of either calcium or phosphate is decreased over a prolonged period.
Causes and Principal Clinical Types
Table 10–2. Causes of Rickets. ||Download (.pdf)
Table 10–2. Causes of Rickets.
Phosphate deficiencyOther rickets-osteomalacia syndromes (rare)
Dietary deficiency of calcium
Dietary deficiency of vitamin D
Fat malabsorption syndromes (failure of vitamin D absorption)
Failure of 25α-hydroxylation in liver
Failure of 1α-hydroxylation in kidney
Hypophosphatasia (deficient alkaline phosphatase in bone)
Tumor osteomalacia (interference with vitamin D metabolism)
Defects in bone matrix formation
Nutritional deficiency–Most cases of rickets in developing countries are caused by dietary deficiency of vitamin D. In developed countries, other causes—notably chronic renal disease, malabsorption syndromes, and X-linked dominant vitamin D-resistant rickets—are more common than nutritional deficiency.
Vitamin D-resistant rickets–This form of rickets is refractory to treatment with vitamin D. It is inherited as an X-linked dominant trait and is characterized by increased phosphate loss in the renal tubules, leading to phosphaturia and hypophosphatemia (hypophosphatemic rickets). Plasma levels of 1,25-dihydrocholecalciferol are normal.
End-organ insensitivity to vitamin D–This is a very rare inherited disease in which the target cell receptors are insensitive to the action of 1,25-dihydrocholecalciferol. Failure of calcium absorption occurs, causing rickets. This condition is also known as type II vitamin D-dependent rickets.
Vitamin D-sensitive rickets–All conditions in which rickets is caused by deficiency of 1,25-dihydrocholecalciferol (Table 10-2) will respond to treatment with exogenous 1,25-dihydrocholecalciferol (calcitriol). Type I vitamin D-dependent rickets is an inherited (autosomal recessive) form caused by partial deficiency of the renal hydroxylase enzyme required for 1,25-dihydrocholecalciferol synthesis.
Rickets occurs in children, in whom failure of mineralization disrupts new bone formation at the epiphyses (growing regions of bone), causing growth retardation. The epiphysial region of bones affected by rickets shows a mass of disorganized cartilage, uncalcified osteoid, and abnormal calcification (Figure 10-7).
Changes in the growing end of bone (epiphysis) in normal compared with rachitic bone. The normal regular linear arrangement of cartilage cells is replaced in rickets by masses of abnormal, proliferating, disorganized cartilage at the epiphyseal line. Bone growth is retarded, and failure of calcification results in soft trabeculae with increased amounts of uncalcified osteoid.
Clinically, rickets is characterized by widening of the epiphyses of bones of the wrists and knees; masses of osteoid that develop at the costochondral junctions produce a row of small bumps on either side of the sternum (rachitic rosary).
The poorly mineralized bones of rickets are much softer than normal bones, so that bending of weight-bearing bones occurs, eg, bowing of the tibias and abnormal curvatures in vertebrae and the pelvis. Protuberances appear on bones at points of muscle action, and the pull of the contracting diaphragm produces a transverse line across the lower rib cage (Harrison's sulcus). The inward pulling of ribs by the intercostal muscles and forward protrusion of the sternum (pigeon breast) are characteristic of rickets. Softening of the cranial bones (craniotabes) also occurs.
Osteomalacia is the disorder resulting from failure of bone mineralization in adults. Most cases are due to either dietary deficiency or abnormal metabolism of vitamin D. Because bone growth is complete, growth retardation does not occur. Normal adult bone continually turns over by a process of osteoclastic resorption of the trabeculae balanced by osteoblastic bone formation. Normally, bone trabeculae have only a thin seam (12–15 μm thick) of uncalcified osteoid on the osteoblastic side of the trabecula. In osteomalacia, because of defective mineralization, the uncalcified osteoid seams widen (usually > 20 μm thick), producing a characteristic appearance on histologic sections. Furthermore, the surface area of bony trabeculae that is covered by uncalcified osteoid increases from the normal 1–3% to over 20%.
Osteomalacia causes bone pain, but gross skeletal deformities are rare. Subtle radiologic changes such as alteration in bony contours and fine fractures help to establish the diagnosis.
The diagnosis of rickets or osteomalacia is based on a combination of clinical features, radiographic findings, and laboratory findings, including normal or low serum calcium and phosphate, normal or high alkaline phosphatase, and low vitamin D levels by immunoassay (Chapter 67: Diseases of Bones). Urinary calcium is low. Urinary hydroxyproline is elevated as a result of collagen catabolism in bone.
Vitamin D Toxicity (Hypervitaminosis D)
Vitamin D toxicity occurs only with extreme overdose. Increased calcium absorption and bone resorption cause hypercalcemia, which leads to metastatic calcification, nephrocalcinosis, and chronic renal failure.
Vitamin K is a necessary cofactor for a carboxylase that is involved in the synthesis of blood coagulation factors II (prothrombin), VII, IX, and X in the liver. The main source of vitamin K in humans is the intestinal bacterial flora, which synthesizes some but not enough of the vitamin to meet all needs. A small amount must therefore be provided in the diet (leafy green vegetables, dairy products).
Dietary deficiency of vitamin K is rare. Common causes of vitamin K deficiency include intestinal malabsorption of fat; a lack of intestinal bacterial flora, as occurs in newborns before the intestine is colonized by bacteria (hemorrhagic disease of the newborn), or after prolonged broad-spectrum antibiotic therapy; and the presence of vitamin K antagonists, eg, coumarin derivatives, which exert an anticoagulant effect because they antagonize vitamin K. Many rat poisons are also vitamin K antagonists, causing abnormal bleeding if taken by humans.
Vitamin K deficiency is characterized by decreased plasma levels of blood coagulation factors II (hypoprothrombinemia), VII, IX, and X. The resulting bleeding tendency is manifested as bruises in the skin, gastrointestinal tract hemorrhage (usually melena), and hematuria. Blood coagulation studies reveal an increased prothrombin time.
Vitamin K toxicity is rare. In the few reported cases, acute hemolytic anemia has been the major manifestation.
Vitamin E (tocopherol) acts as an antioxidant in cells, protecting organelles from the noxious action of free radicals and peroxides produced in the cell. Vitamin E is present in a wide variety of foods, and dietary deficiency is rare. It is absorbed with fats; low serum vitamin E levels occur in patients with severe chronic fat malabsorption.
Vitamin E produces several deficiency diseases in animals, including brain and skeletal muscle dysfunction, sterility in male rats, and hemolytic anemia. Human volunteers chronically deprived of vitamin E demonstrated decreased serum levels of vitamin E and an increased susceptibility of erythrocytes to lysis by hydrogen peroxide in vitro; there was no evidence of hemolytic anemia in vivo. Recently, acute hemolytic anemia has been reported to occur in vitamin E-deficient premature infants. Neuromuscular degeneration has been described in some patients and attributed to vitamin E deficiency.
Vitamin C (ascorbic acid) is a water-soluble vitamin present in fresh fruit and leafy vegetables. It is required for the synthesis of collagen, ground substance, and osteoid and acts as a cofactor in the hydroxylation of proline and lysine and in the aggregation of polypeptide chains into the triple helix of tropocollagen. In vitamin C deficiency, fibroblasts secrete abnormal tropocollagen molecules that cannot form normal collagen fibers, leading to impaired wound healing and abnormal synthesis of connective tissue and bone matrix protein. Vitamin C also enhances iron absorption and neutrophil function.
Deficiency of vitamin C causes scurvy, almost always the result of dietary inadequacy. Vitamin C deficiency was common in the past when seamen on long voyages subsisted on a diet that included no fresh fruits or vegetables (Table 10-3).* Today, scurvy occurs in infants fed certain powdered milks deficient in vitamin C and in elderly people whose diets lack fresh fruit or vegetables. Scurvy also occurs in developing countries where malnutrition is prevalent.
scurvy—a “controlled clinical trial.”
scurvy—a “controlled clinical trial.”
On the 20th of May 1747, being on board the Salisbury at sea, he [Dr James Lind] took twelve scorbutic patients under his care. They had putrid gums, spots and lassitude with weakness of the knees. These were put on the following regimens, in addition to normal diet.
Number of Patients
1 quart of cider/day
25 drops of elixir of vitriol
6 spoonfuls of vinegar
1 pint of sea water
A purgative of garlic, balsam of Peru and mustard seed
2 oranges and lemon
The oranges and the lemon had the best effect; one of those who had taken them was fit for duty at the end of six days; the other being more recovered than the other patients was appointed to look after them. Next to the oranges the cider had the best effect. .
*Limey is a slang term for Englishman that originated with the British practice of carrying limes on long sea voyages to prevent scurvy after the association was recognized.
Vitamin C is rapidly absorbed in the jejunum, and deficiency due to malabsorption is uncommon.
In vitamin C deficiency, the collagen types with the highest hydroxyproline content (eg, those in blood vessels) are most severely affected. One of the early clinical features of deficiency is therefore an increased tendency to hemorrhage, probably due to increased fragility of capillaries. Skin petechiae and ecchymoses due to vascular rupture, bleeding gums, and hemorrhages into nails, joints, and subperiosteal tissues occur in severe deficiency.
Wound healing is also abnormal. The tensile strength of scar tissue is reduced, and scars have a greater tendency to reopen. The granulation tissue that forms is normal initially but later appears abnormal because of the accumulation of an amorphous mass of abnormal protein in place of fibrillary collagen.
The gums become swollen and bleed easily. The teeth become loose, probably because of loss of collagen support in the tooth socket. There is an increased tendency to gum infections.
Abnormalities in bone formation are the result of abnormal synthesis of osteoid, the bone matrix protein. Bone growth at the epiphysis is impaired, leading to growth retardation. The gross changes may resemble those of rickets, but the two conditions are easily distinguished on microscopic examination. Rickets is characterized by the presence of excess osteoid and lack of calcification, whereas scurvy is associated with deficient osteoid and much calcified cartilage.
Large doses of vitamin C are commonly ingested to treat or prevent the common cold or sometimes as a prophylactic measure against cancer, although the value of these practices is unproved. High doses of vitamin C have been shown to predispose to arsenic toxicity by converting inactive organic arsenicals in food to toxic arsenic compounds. Megadoses of vitamin C may also increase the incidence of urinary calculi.
Thiamin is required as a coenzyme in the decarboxylation of pyruvate and α-ketoglutarate, which produces acetyl-CoA. Because this is an essential step in glucose metabolism in the citric acid cycle, thiamin deficiency results in impaired energy production within the cell. Thiamin is also a cofactor for the enzyme transketolase, and a decrease in erythrocyte ketolase activity is used as a test for thiamin deficiency. In addition, thiamin is required for synthesis of the neurotransmitter acetylcholine, deficiency of which may lead to neurologic abnormalities. Thiamin excess is not toxic.
In industrialized areas, thiamin deficiency is rare and is seen mainly in chronic alcoholics in association with poor nutrition. In developing countries, thiamin deficiency is uncommon because the vitamin is distributed widely in food, particularly cereals. However, deficiencies do occur in Southeast Asia in populations that eat highly polished rice (thiamin is present in the outer part of the rice seed, which is removed in polishing) and in Africa and South America in populations that subsist on cassava, which lacks thiamin.
Wet beriberi is characterized by extensive peripheral vasodilation and high-output cardiac failure, which produces massive edema, from which the term wet is derived. The heart is enlarged and flabby. Histologic changes are nonspecific; the biochemical basis of cardiac dysfunction is uncertain but may represent failure of energy production in the cell.
Dry beriberi is characterized mainly by changes in the nervous system. Segmental demyelination of peripheral nerves is common and causes peripheral neuropathy. Neuronal loss in the cerebral cortex, brain stem, and cerebellum leads to a clinically characteristic psychotic state known as Korsakoff's syndrome, characterized by memory failure and confabulation (fabrication of imaginary experiences). Another important manifestation of thiamin deficiency in the brain is Wernicke's encephalopathy, which involves the mamillary bodies and periventricular region of the brain stem. Petechial hemorrhages in the acute phase are followed by atrophy and brownish pigmentation arising from deposition of hemosiderin (Figure 10-8). Wernicke's encephalopathy frequently coexists with Korsakoff's syndrome, and both disorders in the United States are seen mainly in alcoholics who also are thiamin-deficient.
Medulla oblongata in Wernicke's encephalopathy, showing bilateral hemorrhages in its dorsal aspect in the floor of the fourth ventricle.
Riboflavin is an important constituent of flavoproteins, which participate in electron transfer in the respiratory chain. Riboflavin deficiency may theoretically impair cellular energy production, although this does not explain the clinical features of deficiency.
Riboflavin is widely distributed in both animal and plant foods. Deficiency is usually caused by inadequate dietary intake and is common only in developing countries. Excessive intake of riboflavin causes no ill effects.
Clinical manifestations of riboflavin deficiency include inflammation and fissuring of the lips (cheilosis), which is most marked at the angles of the mouth (angular stomatitis). The tongue is inflamed (glossitis), with atrophy of the mucous membrane, so that it becomes smooth and deep purplish red (magenta) (Figure 10-9). Vascularization of the cornea may be followed by corneal opacities, ulceration, and blindness. A scaly rash affecting the face and genitalia may occur.
Riboflavin deficiency, showing inflamed tongue. Note also early fissuring at the angles of the mouth.
Niacin (Nicotinic Acid; Nicotinamide)
Niacin is an integral part of nicotinamide adenine dinucleotide (NAD) and NAD phosphate nicotinamide adenine dinucleotide phosphate (NADP), which are coenzymes participating in most oxidation-reduction reactions in the cell.
Niacin is present in many foods, including cereals, meat, and vegetables. It is also synthesized in the body from tryptophan. Niacin deficiency occurs when there is a severe combined deficiency of both niacin and protein, as occurs in developing countries; it is rare in industrialized societies, where it occurs mainly in chronic alcoholics. Niacin deficiency may rarely occur in patients with carcinoid tumors because these tumors consume large amounts of tryptophan to synthesize serotonin (5-hydroxytryptamine).
Niacin deficiency causes pellagra, which is characterized clinically by dermatitis, diarrhea, and dementia (the three Ds). These clinical abnormalities cannot be easily explained on the basis of the known physiologic actions of niacin.
The characteristic dermatitis involves mainly sun-exposed skin. Affected skin is reddened because of increased dermal vascularity, darker because of increased melanin pigmentation, and rough because of excessive keratinization (Figure 10-10). Involvement of the neck produces a characteristic necklace-like effect.
Dermatitis in niacin deficiency (pellagra).
The mucosa of the mouth, tongue, and gastrointestinal tract also shows nonspecific inflammatory changes and mucosal atrophy. The mucous membrane changes in the intestine lead to diarrhea.
Dementia results from a progressive degeneration of neurons in the cerebral cortex. There is concurrent spinal cord degeneration.
Excessive dietary intake of niacin causes no ill effects. Administration of large doses intravenously causes vasodilation, which may produce a burning sensation in the face and head. The phenomenon is temporary and produces no persistent abnormality.
Pyridoxine is converted in the body to pyridoxal 5-phosphate, a coenzyme involved in numerous cellular enzyme systems. Pyridoxine is found in virtually all foods, and pure dietary deficiency is rare even in developing countries.
Pyridoxine deficiency is manifested under certain circumstances. Infants who are fed poor-quality processed milk preparations deficient in pyridoxine develop convulsions that respond to the administration of pyridoxine. Deficiency may occur in pregnancy, when there is an increased metabolic demand for pyridoxine. Infants breast-fed by a pyridoxine-deficient mother may in turn show signs of deficiency. By far the most common cause of clinical pyridoxine deficiency is the ingestion of drugs that are pyridoxine antagonists. These include isoniazid (INH, an antituberculosis drug), oral contraceptives containing estrogen, methyldopa (an antihypertensive drug), and levodopa (used in the treatment of Parkinson's disease).
Clinical manifestations of pyridoxine deficiency are difficult to distinguish from the effects of deficiency of other B vitamins. They may include minor changes in skin (seborrheic dermatitis), eyes (blepharitis), and mouth, including inflammation of the lips (cheilosis) and tongue (glossitis) with fissuring of the angles of the mouth (angular stomatitis).
Pyridoxal 5-phosphate plays a role in the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA). Neurologic manifestations of pyridoxine deficiency—eg, convulsions in infants and peripheral neuropathy in adults—may be caused by deficient synthesis of GABA.
Pyridoxal 5-phosphate is an important coenzyme in the synthesis of δ-aminolevulinic acid, which is the precursor of the porphyrin portion of the hemoglobin molecule. Abnormal hemoglobin synthesis in pyridoxine deficiency may lead to hypochromic and sideroblastic anemia. Patients with some forms of idiopathic sideroblastic anemia may demonstrate a clinical response to high doses of pyridoxine.
Folic acid and vitamin B12 (cyanocobalamin) deficiencies are among the most common vitamin deficiencies in industrialized societies. In their active forms, these vitamins are coenzymes in several reactions involving the synthesis of nucleic acids. The main clinical manifestation of folate and vitamin B12 deficiency is megaloblastic anemia. The cause, detailed effects, and diagnosis of folic acid and vitamin B12 deficiency are discussed in Chapter 24: Blood: I. Structure & Function; Anemias Due to Decreased Erythropoiesis.