Chapter 10. Nutritional Diseases

Essential Nutrients

An adequate diet must provide sufficient total proteins, sufficient total calories, essential amino acids, essential fatty acids, vitamins, and minerals. A deficiency of any of these dietary factors leads to disordered cellular metabolism and cellular injury with recognizable symptoms and signs of nutritional deficiency. Nutritional diseases arising from total protein-energy deficiency and various vitamin and mineral deficiencies are well-recognized (Table 10-1).

Nutritional Deficiency

Deficiency of an essential nutrient may arise in a variety of ways.

Primary Nutritional Deficiency

Nutritional deficiency resulting from inadequate food intake (primary malnutrition) is common in developing nations but also occurs in developed countries among poor individuals, among the elderly, among individuals consuming fad diets, and in some mentally retarded and alcoholic individuals.

Secondary Nutritional Deficiency

Malnutrition occurring in the presence of adequate food consumption is termed secondary malnutrition.

Failure of Intestinal Absorption

Nutritional deficiency may result from a general malabsorptive state or a defect of absorption of a specific substance, eg, failure of vitamin B12 absorption in pernicious anemia.

Increased Metabolic Demand

Increased demand for specific dietary substances—eg, the increased folic acid requirement in pregnancy—may cause relative insufficiency and evidence of disease.

Antagonists

The presence of antagonists to essential dietary substances—eg, folic acid antagonists such as methotrexate used in cancer chemotherapy—may induce symptoms of nutritional deficiency.

Nutritional Excess

At the other extreme of nutritional disease, excessive intake of food results in obesity. Obesity is an important problem in many developed countries and is responsible for considerable clinical illness. Excessive intake of particular food groups may also contribute to the development of certain diseases; eg, cholesterol and saturated fats predispose to athero-sclerosis. More rarely, clinical disease occurs with excessive intake of specific food substances, eg, vitamins A and D and iron (Table 10-1).

Protein-Energy Malnutrition (Marasmus; Kwashiorkor)

Causes

The general malnutrition occurring in developing countries is commonly a deficiency both of total calorie and total protein intake. Young children tend to be most affected because they have increased metabolic demands for nutrients during the rapid early growth phase and because they often do not fare well in the competition for limited food resources.

Marasmus and kwashiorkor are part of a clinical spectrum of protein-energy malnutrition, with kwashiorkor the more extreme disorder. Early concepts of marasmus as a purely caloric deficiency and kwashiorkor as a purely protein deficiency are now questioned. In most cases, elements of both conditions are present, leading to an increasing preference for the term protein-energy malnutrition (PEM).

Protein-energy malnutrition affects about 400 million children in the world, making it a major health problem.

Clinical Features

Developmental Effects

Growth Retardation

Comparison of the weight and height of a child with the norms for age provides the most accurate estimate of protein-energy malnutrition. However, establishment of such normal values in itself poses a problem. If weight and height norms for the United States are used for nonindustrialized societies, about 80% of children will be deemed to be growth-retarded. Earlier hypotheses proposing that genetic factors might account for some of the observed differences have been brought into question by the observation that first-generation descendants of immigrants to the United States attain heights and weights comparable to those of their American age-mates if they consume a similar diet. Such data suggest that a subtle but pervasive form of malnutrition may actually cause entire populations to suffer from mild growth retardation. Conversely, of course, populations in developed countries suffer the disease of overnutrition (see Obesity).

Intellectual Impairment

Whether protein-energy malnutrition causes impaired intellectual development is controversial, although evidence is increasing that malnutrition in the first 2 years of life does cause permanent deficits.

Immunologic Deficiency

Severe protein-energy malnutrition is associated with defects in both humoral and cellular immunity that result in a high incidence of serious infections. It is probable that less severe immunodeficiency occurs with milder degrees of malnutrition; it may be responsible in part for the high incidence of respiratory and gastrointestinal infections—and the high associated mortality rates—in severely malnourished children in developing societies.

Marasmus

Marasmus represents the compensated phase of protein-energy malnutrition, in which the caloric deficiencies are compensated for by catabolism of the body's expendable tissues, adipose tissue and skeletal muscle. The calories and amino acids derived from tissue catabolism are used to maintain normal cellular metabolism.

The catabolism of adipose tissue and muscle leads to extreme wasting, which is the hallmark of marasmus. Because of muscle wasting and loss of subcutaneous fat, the marasmic child has only skin and bone in the extremities, and wasting of facial muscles and fat causes the typical drawn and wizened facial appearance (Figure 10-1).

Normal serum albumin levels are maintained, and there is no edema. Adequate synthesis of structural proteins and enzymes also continues. Sufficient glucose is available from gluconeogenesis of protein to maintain cellular metabolism. Marasmic children are alert and will eat ravenously when given food. Because gastrointestinal tract digestive enzymes are secreted in the normal way, any food that is eaten is digested and absorbed normally. Marasmus is therefore relatively easy to treat—simply providing food while ensuring adequate fluid and electrolyte balance is sufficient.

Kwashiorkor

Kwashiorkor represents the decompensated phase of protein-energy malnutrition. While total caloric intake may be adequate (barely), protein intake is not, to the extent that catabolism of endogenous protein cannot compensate. Decreased synthesis of enzymes and structural proteins occurs, and serum albumin levels fall. Failure of cellular metabolism occurs and is manifested in the brain, where it causes lethargy and somnolence. Children with kwashiorkor are difficult to feed because of extreme apathy and anorexia. Deficient digestive enzyme production in the intestine and atrophy of small intestinal villi result in failure to absorb ingested food. For these reasons, kwashiorkor is much more difficult to treat than marasmus, and hospitalization is usually required.

Decreased serum albumin levels result in generalized edema. Ascites produces the protuberant abdomen that is characteristic of kwashiorkor. Abnormal fat metabolism causes fatty liver with hepatomegaly, which is reversible. Changes also occur in the hair, which becomes fine and brittle, with abnormal pigmentation—reddish in color, with alternating light bands (flag sign). The skin shows abnormal pigmentation and increased desquamation (flaky paint dermatosis). Kwashiorkor is also associated with nutritional anemia due to deficient intake of iron and folic acid and deficient erythropoietin production.

“Kwashiorkor” is a Ghanaian word meaning “displaced child,” with the connotation of “the illness the older child suffers when the next is born”—coincident with weaning of the child from breast milk to a protein-deficient diet.

Eating Disorders

Eating disorders resulting from psychiatric disorders are a common cause of nutritional disturbance. Anorexia nervosa and bulimia are the 2 most common eating disorders.

Anorexia Nervosa

Anorexia nervosa occurs chiefly in teenage girls and results from a distorted perception of body image and size that makes the patient believe she is much fatter than she is. This causes severe restriction of food intake, leading to protein-energy malnutrition, similar in many ways to marasmus (Figure 10-2).

In addition to marked weight loss and muscle wasting, these patients show abnormal hypothalamic-pituitary function that is believed to be an adaptive mechanism to chronic starvation. Gonadotropin (follicle-stimulating hormone and luteinizing hormone) secretion is decreased, leading to failure of ovulation and amenorrhea. Decreased corticotropin and thyrotropin secretion leads to decreased plasma levels of cortisol and thyroxine. Thermoregulation and secretion of antidiuretic hormone are also frequently abnormal. Death may ensue in extreme cases.

Bulimia Nervosa

Bulimia occurs chiefly in young women. Fifteen to 20 percent of women under 30 years of age in the United States are believed to suffer from bulimia.

Bulimia is characterized by episodes of overeating (binges) followed by efforts to avoid the threatened weight gain by induced vomiting, laxative abuse, excessive physical activity, and fasting (binge-purge cycles). Bulimics usually have normal body weight. The pathologic effects of bulimia are the consequences of induced vomiting, eg, mucosal tears of the esophagus, with bleeding (Mallory-Weiss syndrome) and aspiration pneumonitis; and laxative abuse—commonly resulting in alkalosis and hypokalemia, the latter sometimes severe enough to precipitate cardiac arrhythmias.

Obesity

Ideal weights are established on the basis of height, sex, and body frame, and obesity is usually defined as a body weight 20% greater than ideal weight. However, in a population in which as many as 25% of middle-aged individuals are obese, normal weights derived from population studies may constitute a falsely high baseline.

Other definitions of obesity include a 20% increase in weight beyond one's weight at age 25 years and an increase in thickness of subcutaneous tissue when measured as skinfold thickness over the triceps. In the latter instance, obesity is present if one can “pinch an inch”—normal skinfold thickness for males is less than 23 mm.

Causes

Conceptually, two types of obesity are recognized, although in practice they are not always distinguishable. The more common adult-onset obesity is associated with hypertrophy of existing fat cells. In childhood-onset obesity, there is hyperplasia of fat cells (ie, an increased number) followed by hypertrophy. In both types, clinical obesity follows long-term caloric intake in excess of what is required for the maintenance of body functions. The excess calories are converted into stored adipose tissue—mainly subcutaneous fat—but fatty tissue is also distributed in internal organs such as the heart, pancreas, and omentum. This does not usually cause any abnormality of cell function or clinical disease unless present to an extreme degree.

In the United States, obesity affects 20% of middle-aged men and 40% of middle-aged women. The incidence of obesity peaks at about age 50 years—an indication that a smaller percentage of obese people survive past this age compared with nonobese individuals.

Clinical Features

A man who is 30% overweight has an increased mortality risk of 40% compared with a man of ideal weight. The increased risk for a similarly overweight woman is 30%. Although a statistical association between obesity and an increased risk of death has been established, the mechanisms are unclear.

Hypoventilation Syndrome

Even extreme (morbid) obesity is rarely an immediate cause of death. Hypoventilation syndrome resulting from obesity (Pickwickian syndrome; Figure 10-3) is due to increased fat in the chest wall, which causes decreased alveolar ventilation and consequent chronic CO2 retention, daytime somnolence, and apneic attacks. If severe, death may result. Although the full-blown syndrome is rare, milder degrees may account for the increased risk associated with surgery and general anesthesia in obese patients.

Diseases Associated with Obesity

The increased mortality rate associated with obesity is mainly attributable to the more frequent occurrence of serious cardiovascular diseases (Figure 10-4).

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

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)

Causes

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.

Clinical Features

Visual Impairment

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.

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

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).

Vitamin D Deficiency

Causes

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).

Clinical Features

Pathophysiology

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

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.)

1. 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.

2. 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.

3. 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.

4. 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.

Clinical Features

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).

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

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

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).

Vitamin K Deficiency

Causes

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.

Clinical Features

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

Vitamin K toxicity is rare. In the few reported cases, acute hemolytic anemia has been the major manifestation.

Vitamin E

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

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.

Vitamin C Deficiency

Causes

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.

*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.

Clinical Features

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.

Vitamin C Toxicity

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 (Vitamin B1)

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.

Thiamin Deficiency

Causes

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.

Clinical Features

Wet Beriberi

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

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.

Riboflavin (Vitamin B2)

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.

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 Deficiency

Causes

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).

Clinical Features

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.

Dermatitis

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.

Diarrhea

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

Dementia results from a progressive degeneration of neurons in the cerebral cortex. There is concurrent spinal cord degeneration.

Niacin Toxicity

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 (Vitamin B6)

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

Causes

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 Features

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 & Vitamin B12

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.

The body requires many trace minerals in addition to iron, calcium, magnesium, and phosphate. Trace minerals needed for adequate function include zinc, copper, selenium, iodine, fluoride, manganese, cobalt, molybdenum, vanadium, chromium, and nickel. Although a physiologic role has been identified for most of these elements, specific clinical deficiency states have been documented only for zinc, copper, iodine, and selenium.

Iron

Iron deficiency due to inadequate intake, impaired absorption, or blood loss is one of the most common deficiency states in humans. Iron is required mainly as a constituent of hemoglobin, and iron deficiency causes a decrease in the amount of hemoglobin in erythrocytes (hypochromic anemia) (Chapter 24: Blood: I. Structure & Function; Anemias Due to Decreased Erythropoiesis). The thinning of mucosal epithelium in the mouth, pharynx, and stomach and the occasional formation of mucosal webs in the esophagus associated with iron deficiency remain unexplained.

Iron excess causes increased storage of iron in the body (hemochromatosis) (Chapters 1 and 43).

Trace Elements

Iodine

Iodine forms an integral part of the thyroid hormone molecule. Iodine deficiency causes a decrease in thyroid hormone output, thereby stimulating pituitary thyroid-stimulating hormone (TSH) production and causing thyroid hyperplasia and enlargement (goiter) (Chapter 58: The Thyroid Gland).

Fluoride

Fluoride is incorporated into the structure of teeth and bone and helps to provide strength and hardness. Fluoride deficiency is closely associated with development of dental caries. In areas where natural water is deficient in fluoride, the high incidence of dental caries can be reduced by the use of toothpastes containing fluoride or adding fluoride to the water supply. Excess fluoride intake causes mottling of tooth enamel.

Calcium & Phosphate

Calcium and phosphate are major components of bone. Calcium and phosphate levels in blood and their absorption from the intestine are regulated by parathyroid hormone and vitamin D. Most abnormalities of calcium and phosphate metabolism result from parathyroid disease or vitamin D-related disease (eg, rickets, osteomalacia). Rarely, excessive intake of calcium—milk-alkali syndrome, due to chronic ingestion of milk and antacids (containing alkali in the form of bicarbonate by patients with peptic ulcers in an effort to relieve pain)—causes hypercalcemia, which may lead to acute neurologic dysfunction.

Hypocalcemia in malabsorption syndrome is attributable partly to deficient absorption of vitamin D and partly to formation of insoluble calcium soaps (complex fatty acids) in the gut. The effects of calcium excess and deficiency are discussed in Chapter 2: Abnormalities of Interstitial Tissues.

Magnesium

Magnesium deficiency results in tetany similar to that seen with hypocalcemia. Magnesium deficiency in humans occurs in malabsorption syndromes and kwashiorkor and in patients receiving diuretic therapy or magnesium-deficient parenteral nutrition products.

Zinc

Zinc deficiency has been described in populations whose diets contain a large amount of unrefined cereal. The phytic acid in the outer layers of cereals binds with dietary zinc and prevents absorption. Clinical manifestations of zinc deficiency include anemia, growth retardation, and gonadal atrophy. Diarrhea and skin rashes also occur. Zinc deficiency has also been reported to cause impaired wound healing in trauma victims.

Copper

Copper is necessary for proper function of various enzyme systems in the body. Deficiency of copper is rare and manifested clinically as decreased hematopoiesis (causing anemia and neutropenia), decreased bone production (leading to osteoporosis), and neurologic abnormalities caused by demyelination and faulty synthesis of neurotransmitters.

Elevated levels of copper due to defective excretion lead to a serious disease (hepatolenticular degeneration, or Wilson's disease; Chapter 43: The Liver: II. Toxic & Metabolic Diseases; Neoplasms).

Selenium

Selenium deficiency has been implicated as a cause of congestive cardiomyopathy. This type of cardiomyopathy has been described in China (Keshan disease) and rarely elsewhere in patients with severe malabsorption who have been receiving parenteral nutrition.