Chapter 30. Clinical Manifestations of Human Vitamin and Mineral Disorders: A Resumé

Figure 30.1. A. Vitamin A deficiency. Bitot's spot in temporal interpalpebral fissure. B. Vitamin A deficiency. Conjunctival and corneal xerosis. C. Vitamin A deficiency.

Keratomalacia. D. Riboflavin deficiency. Cheilosis and angular stomatitis. E. Riboflavin deficiency. Magenta tongue. F. Niacin deficiency. Symmetric dermatosis of

pellagra. G. Fluorosis. Early stage with brown mottling that is most marked on upper central incisors. H. Zinc deficiency. Typical dermatosis associated with alcoholic

cirrhosis in this patient. (From Ilchyshyn A, Mendelsohn Z. Br Med J 1982;284:1676.)



Extraocular manifestations include perifollicular hyperkeratosis, a heaping up of hyperkeratinized skin epithelium around hair follicles. This condition is most

commonly seen on the outer aspects of the upper arms and the thighs. It is also seen in starvation and has been attributed to B complex vitamin or essential fatty acid

deficiency. Other changes, which include impaired taste, anorexia, vestibular disturbance, bone changes with pressure on cranial nerves, increased intracranial

pressure, congenital malformations and infertility, have been best demonstrated in animals ( 6) (see also Chapter 17).

In recent years, clinical and community trials of vitamin A supplementation of young children have demonstrated a significant decrease in all-cause mortality and

morbidity (6a) (see also Chapter 97).

Toxicity (Hypervitaminosis A)

Acute toxicity is more common in children. Most of the features relate to a rise in intracranial pressure: nausea, vomiting, headache, vertigo, irritability, stupor, fontanel

bulging (in infants), papilledema and pseudotumor cerebri (mimicking brain tumor) ( 7). There is also pyrexia and peeling of the skin.

Chronic poisoning produces a bizarre clinical picture that is often misdiagnosed because of failure to consider excessive vitamin A intake ( 7). It is characterized by

anorexia, weight loss, headache, blurred vision, diplopia, dry and scaling pruritic skin, alopecia, coarsening of the hair, hepatomegaly, splenomegaly, anemia,

subperiosteal new bone growth, cortical thickening (especially bones of hands and feet and long bones of the legs), and gingival discoloration.

X-ray appearance may assist in making a correct diagnosis ( Fig. 30.3, Fig. 30.4). Cranial sutures are widened in the young child. Dense lines that appear at the

metaphyses of all long bones represent cortical hyperostoses. These cortical thickenings usually stop short of the ends of the shafts. Premature fusion of

hypertrophied epiphyseal ossification centers with their shafts is most often seen at the distal ends of the femurs. There may also be metaphyseal cupping and

splaying of the affected end of the shaft. Cortical hyperostosis of the ribs may also occur.



Figure 30.3. A. and B. Frontal and lateral projections of skull of a 2-year-old girl with hypervitaminosis A showing wide sagittal and coronal sutures. (From Watson

RC, Grossman H, Meyers MA. Radiologic findings in nutritional disturbances. In: Shils ME, Olson JA, Shike M. Modern nutrition in health and disease. 8th ed.

Philadelphia: Lea & Febiger, 1994, with permission.)



Figure 30.4. Same patient as in Figure 30.3. A. Dense line occurs at the distal end of radius and ulna. No subperiosteal new bone is present. B. Three weeks later,

periosteal new bone is seen on the lateral aspect of the ulna. (From Watson RC, Grossman H, Meyers MA. Radiologic findings in nutritional disturbances. In: Shils

ME, Olson JA, Shike M. Modern nutrition in health and disease. 8th ed. Philadelphia: Lea & Febiger, 1994, with permission.)



Vitamin A and other retinoids are powerful teratogens in both pregnant experimental animals and women ( 7). Birth defects have been reported in the offspring of

women receiving 13-cis-retinoic acid (isotretinoin) during pregnancy ( 8). An increased risk of birth defects is present in infants of women taking more than 10,000 IU

of supplementary preformed vitamin A per day before the 7th week of gestation ( 9); other reports indicate that birth defects are likely to occur at levels several times

higher.

Hypercarotenosis

Excessive intake of carotenoids can cause hypercarotenosis. Yellow or orange discoloration of the skin (xanthosis cutis, carotenoderma) affects areas where sebum

secretion is greatest—nasolabial folds, forehead, axillae, and groin—and keratinized surfaces such as the palms and soles. The sclerae and buccal membranes are

not affected, which distinguishes it from jaundice, in which they are stained (see Chapter 33).

Vitamin D (Calciferol)

Deficiency

Vitamin D deficiency is manifested as rickets in children and osteomalacia in adults. Those forms not due to primary nutrient deficiency—previously termed metabolic

rickets—also exhibit signs and symptoms of the underlying disease and hypocalcemia.

Rickets. The rachitic infant is restless and sleeps poorly. Consequently, the occipital hair is denuded. Craniotabes, softening of the bones of the skull and their ready

depression on palpation, is often the earliest sign, but it must be present away from the suture lines to be diagnostic of rickets. Frontal bossing occurs and the

fontanels close late. Sitting, crawling, and walking are all delayed. If the disease is active when these activities occur, weight bearing results in bowing of the arms



(Fig. 30.2A), knock-knees (genu valgum), or outward bowing (genu varum).



Figure 30.2. A. Rickets. An infant with nutritional rickets at the crawling stage, demonstrating the role of pressure in causing bowing of the bones, in this case of the

arms. B. Vitamin K deficiency. Hemorrhagic disease of the newborn secondary to vitamin K deficiency. Hemorrhage around the genitalia is a common site. C.

Pellagra. Casal's necklace, a broad band or collar of dermatosis, induced by exposure to sunlight, is a classic sign of pellagra. The patient was an elderly female in

Tanzania. D. Biotin deficiency. Adult on prolonged parenteral nutrition devoid of biotin with alopecia, dermatitis, and conjunctivitis (left). Slit lamp examination

revealed corneal lesions. All were corrected by inclusion of 60 µg of biotin daily (right). (From McClain et al. JAMA, 1982:247:3116, with permission.) E. Scurvy. “Swan

neck” or “corkscrew” deformities of the hairs characteristic of the early stages of adult scurvy. F. Scurvy. In adult scurvy, petechiae are characteristically perifollicular

and usually precede larger extravasations, termed ecchymoses. The thighs and shins are common sites. G. Hypocalcemia. The characteristic contraction of the

hands (tetany) in this marasmic infant is associated with the presence of marked hypocalcemia often secondary to magnesium depletion. H. Zinc deficiency. Lesions

on pressure areas on the back of the hands in a child on prolonged parenteral nutrition who had rapidly depleted zinc stores through loss of large volumes of

intestinal contents following an intestinal fistula. Similar lesions occurred on the elbows and knees. Sterile pustules were present on the palms, and lesions were

present about the mouth. All responded to increased zinc administration. (Courtesy of M. E. Shils.)



The characteristic x-ray appearance usually precedes clinical signs ( Fig. 30.5). The diaphyseal ends of the bones, most characteristically the lower ends of the radius

and ulna, lose their sharp, clear outline, become cup shaped, and show a spotty or fringelike rarefaction. Due to failure of calcification the distance between the radius

and ulna and the metacarpals appears increased. Shadows cast by the shaft decrease in density, and the network formed by laminae becomes coarse. As healing

begins, a thin white line of calcification appears in the epiphysis, becoming thicker and denser as calcification proceeds. Lime salts are deposited beneath the

periosteum, the shaft casts a denser shadow, and the lamellae disappear. Bone morphology is also discussed in Chapter 83.



Figure 30.5. A 10-month-old boy during various stages of rickets. A. Noncalcified provisional zone and fraying of the distal humerus are evident. Strands of calcified

osteoid project from the sides of the bone. B. Cupping, spread metaphysis, fraying, and cortical spurs occur. Transverse linear recalcified density develops in rachitic

metaphysis. A fracture is present in the midshaft of the radius. Greenstick fractures are common in the long bones. C. Metaphyseal spongiosum recalcifies and fuses

with that of the provisional zone of calcification. Diffuse layer of racalcified cortex is present. (From Watson RC, Grossman H, Meyers MA. Radiologic findings in

nutritional disturbances. In: Shils ME, Olson JA, Shike M. Modern nutrition in health and disease. 8th ed. Philadelphia: Lea & Febiger, 1994, with permission.)



The rachitic rosary, caused by enlargement of the costochondral junctions of the ribs, is said to be smoother than that due to scurvy (see discussion of vitamin C). The

chest may be deformed to give Harrison's sulcus or groove, which consists of a bilateral indentation of the lateral parts of the lower ribs (see also Chapter 18). Other

deformities of the chest, such as depression (funnel chest or pectus excavatum) of the sternum, are now considered to be congenital and not rachitic in origin.

Occasionally, stridor and intermittent sudden airway obstruction due to laryngospasm may present in infancy as a result of hypocalcemia accompanying biochemical

and x-ray evidence of rickets but without the classical bony physical signs. A few instances of congenital cataract appear to be due to vitamin D deficiency in the

mother (10).

Osteomalacia. The main features of osteomalacia are bone pains and tenderness, skeletal deformity, and weakness of the proximal muscles. In severe cases, all the

bones are painful and tender, often enough to disturb sleep. Tenderness may be particularly marked over Looser's zones (Milkman lines), usually occurring in the

long bones, pelvis, ribs, and around the scapulae in a bilaterally symmetric pattern. These radiotranslucent zones are sometimes termed “pseudofractures.” True

fractures of the softened bones are common. The proximal muscle weakness, the cause of which is uncertain, is more marked in some forms of osteomalacia than in

others. Osteomalacia usually results in a waddling gait and difficulty going up and down stairs. In the elderly it may simulate paraplegia; in younger persons it may

simulate muscular dystrophy. Immigrant women to Europe and North America from Asia and the Middle East are especially susceptible.

Toxicity (Hypervitaminosis D)

Some of the symptoms and signs are related to hypercalcemia and are common to all causes of that condition. Anorexia, nausea, vomiting, and constipation are

usually present. Weakness, hypotonia, stupor, and hypertension are less common. Polyuria and polydipsia are caused by hypercalciuria. Renal colic due to stone

formation may result.

X-ray of the skeleton may assist diagnosis. There is increased epiphyseal bone density due to excessive calcium deposition.

Vitamin D excess has been reported to take two forms: mild and severe. In the mild form the patient is usually 3 to 6 months of age, and the symptoms and signs are

those already described. In the severe form, also seen in infants, in addition to the manifestations of hypercalcemia, there is mental retardation, stenosis of the aorta

and the pulmonary arteries, and a characteristic facial appearance termed elfin facies (11).

Vitamin E (Tocopherol)

Deficiency

In recent years clinical disease responsive to vitamin E has attracted considerable attention. Low-birth-weight infants are particularly susceptible, especially if fed

formulas high in polyunsaturated fatty acids after occurrence of hemolytic anemia; the condition is made worse by iron supplements ( 12, 13). Defective vitamin E

status of premature infants may also contribute to their greater susceptibility to platelet dysfunction, intraventricular hemorrhage, retinopathy of prematurity, and



bronchopulmonary dysplasia. Lipofuscin deposition within muscle cells has been reported to account for the brown bowel syndrome ( 14).

Recently, the molecular basis has been discovered of two conditions in which vitamin E deficiency has long been known to figure prominently ( 15). In spinocerebellar

ataxias of the Friedreich's ataxia type there is a defect in the a-tocopherol-transfer protein (a-TTP), and in abeta lipoproteinemia (Bassen-Kornzweig syndrome,

acanthocytosis) there are mutations in the gene coding for one subunit of the microsomal triglyceride-transfer protein. Friedreich's ataxia presents in childhood with

progressive ataxia of gait, dysarthria, areflexia, extensor plantar signs, and impaired vibratory and positional sense. In abeta-lipoproteinemia there is steatorrhea,

acanthocytes (erythrocytes with spiny projections of the membrane), retinitis pigmentosa–like changes in the retina, ataxia, and mental retardation. (See also Chapter

19.)

Toxicity

In the early 1980s, use of an intravenous vitamin E product (E-Ferol), a drug that had not been approved by the United States Food and Drug Administration (FDA),

led to pulmonary deterioration, thrombocytopenia, liver and renal failure, and a high mortality in newborn premature infants ( 16). Its toxicity may have been related to

non–vitamin E constituents of the formulation ( 16a). Reports that low-birth-weight infants receiving pharmacologic doses of vitamin E had a high incidence of sepsis

and necrotizing enterocolitis ( 17) have not been confirmed (see also Chapter 19 concerning safety).

Vitamin K

Deficiency (Hypoprothrombinemia)

Understanding of the pathogenesis of vitamin K deficiency in the neonate has increased considerably. Hemorrhagic disease of the newborn (HDN) is usually

classified into three syndromes: early, classic, and late ( 18). The early form presents within 0 to 24 hours of birth and the most common bleeding sites are

cephalohematoma, within the gut (producing melena neonatorum), and around the genitalia ( Fig. 30.2B). Classical HDN presents on day 1 to 7, and the bleeding is

usually gastrointestinal, dermal, nasal, or from circumcision. The peak incidence of late HDN is from the 3rd to 6th week, and intracranial hemorrhage (rare in

classical HDN) accounts for about 50% of the bleeding episodes at presentation. Late HDN may occur over weeks 2 to 12 and also commonly affects the skin and

gastrointestinal tract.

In the adult, bleeding from this cause is most common in chronic liver disease, obstructive jaundice, and in patients receiving anticoagulants, prolonged antibiotic

therapy, or certain cephalosporin antibiotics, such as moxalactam disodium.

Rare instances of deficiency have been attributed to dietary restriction ( 19) or inadequate TPN (20). Large doses of vitamin E may induce deficiency of vitamin K ( 21).

Toxicity

Kernicterus (bilirubin encephalopathy) has occurred in low-birth-weight infants receiving large doses of menadione (75 mg) or its water-soluble derivatives; it has not

occurred when vitamin K itself has been given. Lethargy, hypotonia, and loss of sucking reflex are followed by opisthotonos, generalized spasticity, and frequently

death from pulmonary complications. Survivors may develop the postkernicterus syndrome: high-frequency nerve deafness, athetoid cerebral palsy, and dental

enamel dysplasia.

Thiamin (Vitamin B 1, Aneurin)

Deficiency

Beriberi in the adult occurs in two distinct forms, wet and dry beriberi, in which the cardiovascular and the nervous systems, respectively, are affected. Both may be

involved in the same patient, but one or the other tends to predominate. Infantile beriberi is described separately (see also Chapter 21).

Cardiovascular beriberi usually manifests as chronic high-output right- and left-sided heart failure with tachycardia, rapid circulation time, elevated peripheral venous

pressure, sodium retention, and edema (22). A much less common acute fulminating form of heart failure (sometimes called “shoshin”) is characterized by severe

metabolic lactic acidosis, intense dyspnea, thirst, anxiety, and cardiovascular collapse. Signs also include stocking-glove cyanosis, extreme tachycardia,

cardiomegaly, hepatomegaly, and neck vein distension. Edema is usually absent ( 23). This highly fatal form is not uncommon as a cause of sudden death in young

migrant laborers in the Orient subsisting on rice.

Beriberi of the Nervous System (24). Cerebral Beriberi (Wernicke-Korsakoff Syndrome). Cerebral beriberi in its most severe form, mental confusion, accompanied

by ophthalmoplegia due to paralysis of the 6th cranial nerve, leads to coma. Korsakoff's psychosis consists of loss of memory for distant events, inability to form new

ones, and loss of insight and initiative. The patient is alert and can converse, think, and solve problems. Response to thiamin is complete in only 25% of cases and

partial in 50%. Ethanol is thought to have a direct part in neurotoxicity ( 25, 26). Wernicke encephalopathy is most likely to occur in chronic alcoholics given

carbohydrates without adequate thiamin replacement or in nonalcoholic depleted patients given infusions high in glucose without adequate thiamin. It is reported as a

complication of vertical-banded gastroplasty for morbid obesity ( 27). (See Chapter 95.)

Peripheral Neuropathy The most characteristic features of peripheral neuropathy are symmetric footdrop, associated with marked tenderness of the calf muscles, and

a mild disturbance of sensation over the outer aspects of the legs and thighs and in patches over the abdomen, chest, and forearms. Ataxia with loss of position and

vibration sense, burning paresthesias in the feet, and amblyopia are less common.

Infantile Beriberi. Early manifestations of infantile beriberi are anorexia, vomiting, pallor, restlessness, and insomnia. The disease progresses typically to (a) an

acute cardiac form in infants 2 to 4 months of age, (b) a subacute aphonic form in those 5 to 7 months old, and (c) a chronic, pseudomeningeal form in those between

8 and 10 months of age. The acute form presents with dyspnea, cyanosis, a rapid thready pulse, and other signs of acute heart failure. In the subacute form, aphonia

or a characteristic hoarse cry, dysphagia, vomiting, and convulsions predominate. The chronic form is characterized by neck retraction, opisthotonos, edema, oliguria,

constipation, and meteorism (28).

Subacute Necrotizing Encephalomyopathy (SNE, Leigh's Disease). SNE may be related to a defect in thiamin metabolism. About 100 cases have been reported

(29). Onset is usually before 1 year of age. Hypoventilation and apnea, cranial neuropathies, and hypotonia are the most common features.

Possible Toxicity

Large doses of thiamin have been given to alcoholics as a part of their therapy. A survey of the U.S. literature revealed a significant number of reports of adverse

effects in the late 1930s to early 1940s. From 1943 to 1973 there were six reports of sensitization of an anaphylactic nature, with nothing similar until 1992. At that

time a case was reported of an alcoholic with a high blood alcohol level given 100 mg of thiamin-HCl intravenously, which was associated with onset of nausea,

anxiety, arrhythmia, moderate hypotension, and wheezing; improvement occurred with epinephrine, antihistamines, and steroids ( 30). In contrast, 9 deaths were

reported in the European literature between 1965 and 1985. Of note is the absence of reports of anaphylactic reactions with multivitamins containing thiamin used in

TPN solutions.

Riboflavin

Deficiency

The skin and mucous membranes are affected in what is known as the orooculogenital syndrome. Areas of skin involved are usually those containing many

sebaceous glands: mainly the nasolabial folds, alae nasi, external ears, eyelids, scrotum in the male, and labia majora in the female. They become reddened, scaly,

greasy, painful, and pruritic. Plugs of inspissated sebum may accumulate in the hair follicles and give the appearance known as dyssebacia, or sharkskin ( Fig. 30.6).



Figure 30.6. Dyssebacea associated with riboflavin deficiency.



At the angles of the mouth there are painful fissures known as angular stomatitis when active (see Fig. 30.1B and Fig. 30.1D). When chronic, these fissures give rise

to one form of rhagades. Vertical fissures of the vermilion surfaces of the lips constitute cheilosis. These and the angular lesions may become infected with Candida

albicans, giving rise to the appearance known as perleche. The tongue may be painful, swollen, and magenta colored ( Fig. 30.1E). These mucocutaneous changes

may also be seen in other nutrient deficiencies or in elderly edentulous individuals with chronically moist angles. Because deficiency is often multiple, it is rarely

possible in clinical practice to demonstrate the precise cause.

Other signs that have been described include photophobia, lacrimation, and conjunctival injection. Corneal neovascularization, so common in experimental animals, is

rarely seen in man. The hemopoietic and nervous systems are occasionally affected. A normocytic normochromic anemia, reticulocytopenia, leukopenia,

thrombocytopenia from marrow hypoplasia, and peripheral neuropathies with hyperesthesia, altered temperature sensation, and pain have been reported ( 31).

Niacin

Deficiency

Pellagra affects primarily the skin, gastrointestinal tract, and nervous system. Dermatosis is usually the earliest and most prominent manifestation. It is symmetric and

appears on parts exposed to sunlight or trauma. Erythema progresses to keratosis and scaling with pigmentation. The back of the hands, wrists, forearms, face, and

neck (Casal's necklace) are typically affected ( Fig. 30.1F and Fig. 30.2C). The skin and mucous membrane changes of riboflavin deficiency are also commonly

present (see above).

The tongue often has a “raw beef” appearance, is bright red, swollen, and painful. Symptoms of gastritis, bouts of diarrhea, and signs of malabsorption suggest similar

changes in the gastrointestinal tract.

Nervous system involvement is suggested in the early stages by periods of depression with insomnia, headaches, and dizziness. Later, tremulous movement or

rigidity of the limbs occurs with loss of tendon reflexes, numbness, and paresis of the extremities, ultimately incapacitating the patient. In profound deficiency, an

encephalopathy has been described that resembles that of acute cerebral beriberi (see section on thiamin) but responds to some extent to niacin. Mental disturbance

is so prominent in some patients that there is a real danger that the true diagnosis might be missed and the patient be incarcerated in a mental institution.

Toxicity

Side effects of megadoses (e.g., 3 g/day) include vasodilatation, flushing, pruritus, blistering of the skin with brown pigmentation, nausea, vomiting, and headache

(32).

Pyridoxine (Vitamin B6)

Deficiency

Pyridoxine deficiency is rarely severe enough to produce signs or symptoms. Volunteers receiving a deficient diet and a pyridoxine antagonist became irritable and

depressed. Seborrheic dermatosis affected the nasolabial folds, cheeks, neck, and perineum. Several subjects also developed glossitis, angular stomatitis,

blepharitis, and a peripheral neuropathy.

An uncommon form of sideroblastic anemia, often severe, has been reported to respond in some instances to pyridoxine, but most cases appear to be due to

dependency rather than deficiency ( 33). Some years ago convulsions occurred in infants fed a milk formula in which the pyridoxine had been destroyed during

processing (34).

Toxicity

A sensory neuropathy has been attributed to the abuse of pyridoxine in megadoses ( 35). Seven adults developed gradually progressive sensory ataxia and profound

lower limb impairment of position and vibration sense. Touch, temperature, and pain perception were less affected. The motor and central nervous systems were

unaffected. One review suggested that an impurity in the pharmacologic product might have been responsible ( 36).

Two patients with encephalitis suffered intensification of symptoms after dosing with pyridoxine and improved after its discontinuation ( 37).

Biotin

Deficiency

Biotin deficiency has occasionally been induced in patients who consumed large amounts of raw egg white over a prolonged period. Egg white contains avidin, which

antagonizes the action of biotin. The skin of the face and hands becomes dry, shining, and scaling. The oral mucosa and tongue are swollen, magenta, and painful.

The most clear-cut cases of biotin deficiency occurred in children and adults maintained on long-term TPN in the early days before biotin was included in commercial

vitamin formulations. An infant with short gut syndrome received TPN from 5 months of age. Five months later the infant lost all body hair and developed a waxy

pallor, irritability, lethargy, mild hypotonia, and an erythematous rash. Biotin deficiency was confirmed biochemically, and all signs were reversed by supplementation

(38). Two adult patients receiving home parenteral nutrition after extensive gut resection developed hair loss that was reversed by 200 µg biotin given intravenously

daily (39). Another adult with alopecia, rash, and metabolic acidosis responded to 60 µg of biotin added to parenteral fluids (30.2 D) (see also Chapter 28).

Vitamin B12 (Cobalamin)

Deficiency

Deficiency may be primary or secondary, as in pernicious anemia.

Pernicious Anemia. Pernicious anemia usually manifests after middle age. There is a slight female preponderance. It may be associated with signs of other

autoimmune diseases. The most common complaints—those associated with anemia—ordinarily do not arise until the anemia is well advanced. Neurologic changes



may long precede the hematologic changes. The tongue may be red, smooth, shining, and painful. Anorexia, weight loss, indigestion, and episodic diarrhea are all

usually present (see Chapter 27 and Chapter 88).

The typical patient has prematurely gray hair and blue eyes. A few patients have widespread brownish pigmentation affecting nail beds and skin creases but sparing

the mucous membranes (in contrast to Addison's disease). In advanced cases there is usually pyrexia, enlargement of the liver and spleen, and occasionally bruising

due to thrombocytopenia. Older patients may present with congestive cardiac failure.

A distal sensory neuropathy with “glove and stocking” sensory loss, paresthesias, and areflexia may occur in isolation or more commonly together with a myelopathy

known as subacute combined degeneration of the cord. In this condition the initial symptom is symmetric paresthesias of the feet or, occasionally, of the hands. A

combination of weakness and loss of postural sense makes walking increasingly difficult. Psychiatric disturbances, especially mild dementia, may be the presenting or

only feature. Visual loss from optic atrophy is not uncommon.

Congenital lack of intrinsic factor presents before the age of 2 years with irritability, vomiting, diarrhea, weight loss, and anemia. It was reported that an infant

exclusively breast fed by a mother with latent pernicious anemia developed megaloblastic anemia and neurologic abnormalities ( 40).

Primary Dietary Deficiency. When dietary lack or malabsorption is the cause of deficiency, anemia is usually the most prominent feature, but glossitis, optic atrophy,

and subacute combined degeneration of the cord have also been described. Hyperpigmentation of the skin of the forearms has been reported. Megaloblastic anemia

developed in an infant exclusively breast fed by a vegan mother ( 41).

Folic Acid

Deficiency

The anemia of folic acid deficiency has morphologic features similar to those of vitamin B 12 deficiency (see Chapter 26 and Chapter 88), but it develops much more

rapidly. Subacute combined degeneration of the cord does not occur, but about 20% of patients may have peripheral neuropathy. The tongue may be red and painful

in the acute stage. In chronic deficiency, the tongue papillae atrophy, leaving a shiny, smooth surface. Hyperpigmentation of the skin similar to that occasionally seen

in vitamin B12 deficiency has been noted.

Folic acid therapy before conception is now accepted as protective against neural tube defects in infants of families in which these abnormalities have previously

arisen (42). Inadequate one-carbon metabolism in conditions associated with genetic mutations and hyperhomocysteinemia is described in Chapter 26, Chapter 27

and Chapter 34).

Folate deficiency has been described in TPN with certain amino acid mixtures in the absence of supplementary folic acid ( 43). There is a single report of an infant,

exclusively breast fed by a mother taking estrogen-progestogen contraceptive pills, who developed megaloblastic anemia responsive to folic acid ( 44).

Pantothenic Acid

Deficiency

Researchers reported “burning feet syndrome” in adult volunteers on a deficient diet and claimed that this condition responded to pantothenic acid. In clinical practice

this distressing condition has rarely responded to this treatment, and there is at present no certain clinical manifestation of pantothenic acid deficiency.

Vitamin C (Ascorbic Acid)

Deficiency

Scurvy tends to affect either the very young or the elderly. The clinical picture differs in these two groups.

Infantile Scurvy (Barlow's Disease). The onset of infantile scurvy, usually in the second half of the 1st year of life, is preceded by a period of fretfulness, pallor, and

loss of appetite. Localizing signs are tenderness and swelling, most marked at the knees or ankles. These signs result from characteristic bone changes demonstrable

by radiograph (Fig. 30.7, Fig. 30.8 and Fig. 30.9).



Figure 30.7. A 27-month-old boy with scurvy. Frontal (A) and lateral (B) chest roentgenograms demonstrate bony swelling at the costochondral junctions of the ribs.

(From Watson RC, Grossman H, Meyers MA. Radiologic findings in nutritional disturbances. In: Shils ME, Olson JA, Shike M. Modern nutrition in health and disease.

8th ed. Philadelphia: Lea & Febiger, 1994, with permission.)



Figure 30.8. A 10-month-old boy with scurvy. A thick white line occurs at the metaphyses of the long bones of the knees. Linear breaks are present in the bones

proximal and parallel to the white lines of the distal femur. Spurs are present and best seen at the ends of the femurs and medial aspect of the right tibia. The

ossification centers have central rarefaction with heavy ring shadows on the margins. Periosteal new bone is along the medial aspects of the tibias. (From Watson

RC, Grossman H, Meyers MA. Radiologic findings in nutritional disturbances. In: Shils ME, Olson JA, Shike M. Modern nutrition in health and disease. 8th ed.

Philadelphia: Lea & Febiger, 1994, with permission.)



Figure 30.9. A 12-month-old boy with healing scurvy. A. Fracture of the provisional zone of the calcification of the distal femur with early calcification is apparent.

Displacement of the soft tissues is due to hematoma that has not begun to calcify. B. Extensive calcification of elevated periosteum occurs after 2 weeks of vitamin C

therapy. (From Watson RC, Grossman H, Meyers MA. Radiologic findings in nutritional disturbances. In: Shils ME, Olson JA, Shike M. Modern nutrition in health and

disease. 8th ed. Philadelphia: Lea & Febiger, 1994, with permission.)



The earliest x-ray changes appear at the sites of most active growth; the sternal end of the ribs, distal end of the femur, proximal end of the humerus, both ends of the

tibia and fibula, and distal ends of the radius and ulna. A zone of rarefaction immediately shaftward of the zone of provisional calcification gives rise to the “corner

fracture” sign. Atrophy of trabecular structure and blurring of trabecular markings cause a “ground glass” appearance. Widening of the zone of provisional calcification

causes a dense shadow at the end of the shaft which is also seen at the periphery of the centers of ossification. This ringlike appearance is seen best at the knee and

is very characteristic of scurvy. As the deficiency proceeds, fractures may occur in areas of extending rarefaction. The overlying zone of provisional calcification may

be comminuted with the shaft, and spur formation may occur. Epiphyses may separate and be displaced. Temporary healing often modifies the radiologic appearance.

With treatment, even the grossest deformities resolve, although radiologic evidence may persist for several years.

Enlargement of the costochondral junctions produces the scorbutic rosary, which has a sharper feel than that due to rickets (see section on vitamin D). The infant

often adopts the “pithed frog” position of maximum comfort, with the legs flexed at the knees and the hips partially flexed and externally rotated. The arms are less

commonly involved. Hemorrhage and spongy changes in the gums are confined to the sites of teeth that have recently erupted or are about to do so. Bleeding may

occur anywhere in the skin (the orbit is a frequent site) or from mucous membranes, including the renal tract. In infancy, intracranial hemorrhages are rapidly

progressive if treatment is delayed, and death may occur. Petechiae and ecchymoses, usually found in the region of the bone lesions, are less common than in the

adult. Microcytic hypochromic anemia is common, a normochromic normocytic picture less so. Older children may develop characteristic perifollicular hemorrhages

and hair changes seen in the adult.

Adult Scurvy. Early symptoms of adult scurvy are weakness, easy fatigue, and listlessness, followed by shortness of breath and aching bones, joints, and muscles,

especially at night. These symptoms are followed by characteristic changes in the skin ( 45). Acne, indistinguishable from that of adolescence, precedes defects in the

hairs of the body. These defects consist of broken and coiled hairs and a “swan-neck” deformity resulting from their being flat instead of round in cross section ( Fig.

30.2E). A salient feature of scurvy in the adult is perifollicular hemorrhages and perifollicular hyperkeratosis, most commonly affecting the anterior aspects of the

thorax, forearms, thighs, and legs and the anterior abdominal wall ( Fig. 30.2F).

Frank bleeding is a late feature of scurvy. The classic gum changes are only associated with natural teeth or buried roots and are enhanced by poor dental hygiene

and advanced caries. The interdental papillae become swollen and purple and bleed with trauma. In advanced scurvy, the gums are spongy and friable, bleeding

freely. Secondary infection leads to loosening of the teeth and to gangrene. Patients who are edentulous or whose teeth are in good repair have little or no evidence

of scorbutic gingivitis. Hemorrhage commonly occurs deep in muscles and into joints as well as over large areas of the skin in the form of ecchymoses ( Fig. 30.10).

Multiple splinter hemorrhages may form a crescent near the distal ends of the nails. Old scars break down, and new wounds fail to heal. Bleeding into viscera or the

brain leads to convulsions and shock; death may occur abruptly.



Figure 30.10. Perifollicular hemorrhages of the legs in adult scurvy.



ESSENTIAL FATTY ACIDS (EFAS)

Although EFAs are not vitamins in the ordinary sense, it is convenient to consider symptoms of deficiency of these fatty acids here.

w-6 EFA Deficiency

Growth retardation, sparse hair growth, branlike desquamation of the skin of the trunk, poor wound healing, and increased susceptibility to infection have been

observed in infants receiving a formula deficient in essential fat or in children and adults receiving long-term, lipid-free parenteral nutrition ( 46).

Sometimes there is only dry, flaky skin, but more advanced deficiency results in scaling, eczematoid dermatosis, usually starting on the nasolabial folds and eyebrows

and spreading across the face and neck ( Fig. 30.11). Anemia and enlarged fatty liver have also been reported.



Figure 30.11. Dermatosis of essential fatty acid deficiency associated with total parenteral nutrition. (Courtesy of Dr. R. E. Hodges.)



w-3 EFA Deficiency

The first human report of w-3 EFA deficiency was of a 7-year-old girl with extensive gut resection who received TPN rich in w-6 but very low in w-3 fatty acids.

Neurologic changes included paresthesias, weakness, inability to walk, pain in the legs, and blurred vision ( 47). These are reported to have responded to change of

treatment, but it is possible that other deficiencies, including that of vitamin E, might have been responsible. Other possible cases have since been reported, and the

subject has been reviewed (48). It now appears that the symptoms of the two kinds of fatty acid deficiency are quite distinct.



MINERALS

Calcium

Hypocalcemia

Symptoms and signs of underlying disorders are present in hypocalcemia. True hypocalcemia (i.e., subnormal ionized calcium) in clinical conditions is rarely caused

by inadequate calcium ingestion but rather by disorders of calcium metabolism or use. It affects the nervous system with depression and psychosis, progressing to

dementia or encephalopathy. The most characteristic syndrome is tetany, consisting of (a) paresthesias about the lips, tongue, fingers, and feet; (b) carpopedal

spasm, resulting in “obstetrician's hand,” or Trousseau's sign, a deformity that may be painful and prolonged ( Fig. 30.2G); (c) generalized muscle aching; and (d)

spasm of the facial muscles. At the earlier stage of latent tetany, neuromuscular irritability may be elicited by provocative tests. Chvostek's sign is contraction of the

facial muscles on light tapping of the facial nerve. Trousseau's sign is carpopedal spasm induced by restriction of the blood supply to a limb by a tourniquet or

elevation above systolic pressure with a blood pressure cuff applied for 3 minutes or less. Rarely, cataract is the earliest feature.

In about 80% of very low birth weight infants, osteopenia can be diagnosed radiologically, and rickets is much less common ( 49). In the neonate and older infant,

tetany may manifest as rhythmic, focal myoclonic jerks, sometimes followed by convulsions, cyanosis, and heart failure. Muscular spasms and laryngismus stridulus

may occur in young children.

Osteoporosis

Calcium insufficiency plays an ill-defined role in this condition of loss of bone mass (see Chapter 83 and Chapter 85). It is common in the elderly, especially in

postmenopausal white women. There is bone deformity, localized pain, and fractures. Osteomalacia may coexist. The most common deformity is loss of height caused

by vertebral collapse, which accounts for most of the pain. Fractures of the neck of the femur and Colles' fracture above the wrist are most commonly precipitated by

trauma, which may be trivial, in elderly persons with osteoporosis.

Calcium-Deficiency Rickets

Reports from South Africa suggested that true rickets can be produced by dietary calcium deficiency in the presence of normal vitamin D status ( 50). The histologic

changes of rickets were confirmed by biopsy and responded to calcium therapy alone ( 51).

Hypercalcemia

Hypercalcemia has a variety of causes and produces a symptom complex that is, to some extent, characteristic. Gastrointestinal symptoms include anorexia, nausea,

vomiting, constipation, abdominal pain, and ileus. Renal system involvement produces polyuria, nocturia, polydipsia, stone formation, and sometimes hypertension

and signs and symptoms of uremia. Muscle weakness and myopathy occur. More advanced disease, which causes psychosis, delirium, stupor, and coma, may be

fatal.

Phosphorus

Hypophosphatemia

Hypophosphatemia is defined as lowered inorganic phosphate level (<0.71 mmol/L, or 2.2 mg/dL) with or without a significant decrease in the total body phosphate in

relation to total body nitrogen. The latter situation usually occurs in any situation stimulating anaerobic glycolysis, such as infusion of hypertonic glucose continuously

without adequate phosphate replacement; this results in a shift of serum inorganic phosphate into cells and a fall in serum phosphate levels. The markedly depressed

serum phosphate (usually <0.30 mmol/L, or 0.93 mg/dL) is associated in 3 to 4 days with circumoral and extremity paresthesias and red cell fragility and hemolysis.

Total Body Phosphate Depletion

Total body phosphate depletion occurs with total body nitrogen loss as the result of various diseases that lead to excessive loss of both in the stool (e.g.,

malabsorption, vitamin D deficiency) or in the urine (e.g., hyperparathyroidism, congenital or drug-induced renal tubular acidosis, severe potassium depletion). In the

management of advanced renal disease, administration of phosphate-binding gels intended to reduce phosphate absorption in association with restricted phosphate

in the diet may lead to symptomatic phosphate deficiency ( 52, 53) (Table 30.1) (see also Chapter 8).



Table 30.1 Manifestations of Phosphate Depletion and/or Hypophosphatemia



Potassium

Deficiency

Potassium deficiency is usually due to excessive losses in urine or stool, less commonly to decreased intake, as in starvation or failure to give potassium in



intravenous solutions, and losses in sweat as in cystic fibrosis.

Severe hypokalemia (serum K <3 mmol/L, or <3 mEq/L) may cause muscle weakness leading to respiratory failure, paralytic ileus, hypotension, and tetany. Potassium

nephropathy results in polyuria with secondary polydipsia. Cardiac effects are particularly likely in patients receiving digitalis. The electrocardiogram (ECG) is

characteristic with S-T segment depression, increased U wave amplitude, and T wave amplitude less than that of U wave in the same lead. Premature ventricular and

atrial contractions and ventricular and atrial tachyarrhythmias occur.

Toxicity (Hyperkalemia)

Acute oliguric states are often responsible for hyperkalemia, but excessive ingestion or infusion may produce symptoms even in the presence of normal renal function.

Cardiac toxicity, of serious import, starts with shortening of the Q-T interval of the ECG and tall, peaked T waves. Progressive toxicity with serum K levels above 6.5

mmol/L (>6.5 mEq/L) causes nodal and ventricular arrhythmias, widening of the QRS complex, PR interval prolongation and disappearance of the P wave, and finally

degeneration of the QRS complex with ventricular asystole or fibrillation and death.

Magnesium

Deficiency

In depletion studies in humans as well as in clinical practice, when hypomagnesemia (defined as serum Mg <1.5 mEq/L, <1.9 mg/dL) progresses below 1.0 mEq/L, it

is often accompanied by hypocalcemia and hypokalemia.

The symptoms and signs of both experimental and clinical deficiency are primarily neuromuscular: Trousseau and Chvostek signs, muscle fasciculations, tremor,

muscle spasm, personality changes, anorexia, nausea, and vomiting. Recently, low dietary intake of magnesium was associated with impaired lung function and

wheezing (54). Convulsions or coma in infancy is not infrequently associated with magnesium deficiency.

Magnesium depletion has been associated with malabsorption syndromes, renal tubular abnormalities, endocrine dysfunction, and genetic and familial conditions

(55). In some clinical situations, serum magnesium may be within normal limits despite evidence of cellular or tissue depletion (see also Chapter 9).

Toxicity (Hypermagnesemia)

Elevated serum magnesium levels (>2.1 mEq/L, >2.5 mg/dL) are not uncommon in patients with renal failure who are receiving magnesium-containing drugs and in

children with chronic constipation treated with magnesium sulfate enemas. With higher levels, deep tendon reflexes disappear and ECG abnormalities (prolonged PR

interval, widening of QRS complex, and increased T wave amplitude) occur. Hypertension, respiratory depression, narcosis, and ultimately cardiac arrest may occur

with very high blood magnesium levels (see Chapter 9).

Iodide (Iodine)

Deficiency

Enlargement of the thyroid gland is the most common clinical sign of iodide deficiency. When it is due to iodine lack, this condition is termed simple, colloid, endemic,

or euthyroid goiter. It is more common in women and is often noted at the onset of puberty, during pregnancy, or at the menopause. Early on, the enlargement is soft,

symmetric, and smooth; later, multiple nodules and cysts may appear. Most patients are euthyroid, a few have hyperthyroidism, and rarely hypothyroidism occurs.

Severe endemic goiter is often accompanied by cretinism. Endemic cretinism occurs in two distinct forms, the myxedematous and the neurologic, which may coexist

(56). In most areas of the world, the neurologic form is by far the more common. The clinical manifestations of the two conditions are listed in Table 30.2 (see also

Chapter 13).



Table 30.2 Comparative Clinical Features in Myxoedematous and Neurologic Cretinism



Toxicity

Prolonged excessive intake of iodine leads eventually to iodide goiter and myxedema, especially in patients with preexisting Hashimoto's thyroiditis.

Iron

Deficiency

Iron deficiency has its major impact on many systems via reduction in tissue oxygenation due to decreased hemoglobin concentration. The clinical picture depends on

the rapidity of development of anemia and on its severity (see Chapter 10 and Chapter 88).

The typical microcytic hypochromic anemia of insidious onset manifests as increasing fatigue and slight pallor, best seen in the mucous membranes. Later,

cardiorespiratory signs and symptoms include exertional dyspnea, tachycardia, palpitations, angina, claudication, night cramps, increased arterial and capillary

pulsation, cardiac bruits, reversible cardiac enlargement and, if cardiac failure occurs, basal crepitations, peripheral edema, and ascites. Neuromuscular involvement

is evidenced by headache, tinnitus, vertigo, cramps, faintness, increased cold sensitivity, and retinal hemorrhage. Gastrointestinal symptoms include anorexia,

nausea, constipation, and diarrhea. Low-grade fever, menstrual irregularity, urinary frequency, and loss of libido may occur.

Iron deficiency per se has certain characteristics not usually associated with other forms of anemia. A nonspecific glossitis with almost complete loss of filiform

papillae is common. Angular stomatitis is less frequent. Spoon-shaped nails (koilonychia) are characteristic of longstanding iron deficiency. The Patterson-Kelly

(Plummer-Vinson) syndrome is the association of iron deficiency anemia, glossitis, dysphagia, and achlorhydria, usually seen in middle-aged women, but much less

commonly than was formerly the case. In severe cases, postcricoid webs and malignant change in this region may occur. Signs of deficiency of some B group

vitamins are also often present. Pica (geophagia) is an occasional feature. Even mild iron deficiency is considered important in decreased work efficiency ( 58). In

infants and young children, certain aspects of learning ability are impaired.



Toxicity

Acute poisoning causes vomiting, upper abdominal pain, pallor, cyanosis, diarrhea, drowsiness, and shock. Death may occur in children mistaking iron tablets for

sweets.

Chronic toxicity (hemochromatosis, iron overload) affects many tissues (see Chapter 10). Diabetes, often the presenting feature, eventually develops in about 80% of

patients. The skin is a characteristic slate-gray color. The liver becomes enlarged and then cirrhotic, and hepatoma may develop. Cardiomyopathy leads to heart

failure in about 50% of patients. Pituitary failure may cause testicular atrophy and loss of libido. Focal hemosiderosis damages the lungs and kidneys.

Copper

Deficiency

The principal features of copper deficiency are a hypochromic anemia unresponsive to iron therapy, neutropenia, and osteoporosis. Early radiologic findings are

osteoporosis of the metaphyses and epiphyses and retarded bone age. Typical findings are increased density of the provisional zone of calcification and cupping with

sickle-shaped spurs in the metaphyseal region. Other skeletal abnormalities include periosteal layering and submetaphyseal and rib fractures ( Fig. 30.12).



Figure 30.12. Bone changes due to copper deficiency. (From Bennani-Smires C, Medina J, Young LW. Am J Dis Child 1980;134:1155.)



Premature infants are especially vulnerable and have shown the following signs: pallor, decreased pigmentation of the skin and hair, prominent superficial veins, skin

lesions resembling seborrheic dermatitis, failure to thrive, diarrhea, and hepatosplenomegaly. Some have features suggesting central nervous system damage,

including hypotonia, apathy, psychomotor retardation, apparent lack of visual responses, and apneic episodes.

The most extreme form is seen in Menkes' steely hair disease ( 59), a complex X-linked disease of male infants in which there is both failure to absorb copper and then

failure to form functional cuproproteins. Interference with cross-linking of elastin and collagen can be held responsible for many of the features: premature rupture of

the membranes leading to premature birth, lax skin and joints, elongation and dilatation of major arteries resulting in rupture and hemorrhage, subintimal thickening

with partial occlusion of major arteries, hernias, and diverticula of bladder and ureters causing recurrent infection or rupture. Osteoporosis, flaring of metaphyseal

edges, and Wormian bones in cranial sutures may all be secondary to collagen abnormalities. Lack of pigmentation of the skin and hair and abnormal spiral twisting

(pili torti) and fragility of hair add to the characteristic appearance of affected babies. Neurologic development rarely progresses beyond 6 to 8 weeks, and even these

functions are lost during the ensuing months. Ataxia is striking in mild cases.

Toxicity

In Wilson's disease (hepatolenticular degeneration) accumulation of copper in the liver leads to cirrhosis and signs of liver failure. Deposits in the brain result in

tremors, choreoathetoid movements, rigidity, dysarthria, and eventually dementia. Anemia and signs of renal failure are common. Characteristic changes in the eye

are the Kayser-Fleischer ring, a brown or green ring near the limbus of the cornea, and a “sunflower” cataract. Childhood cirrhosis has been common on the Indian

subcontinent and is reported to occur in Indian children living elsewhere ( 60). It has been attributed to copper accumulation in the liver. The suggestion that the

source of the copper is milk contaminated by boiling and storage in brass and copper pots has not been con-firmed ( 61).

Acute poisoning has resulted from ingestion of solutions of copper salts or contaminated water supplies or dialysis fluid. In severe cases, evidence of hepatic or renal

failure (or both) is found.

Zinc

Deficiency

The first report of human zinc deficiency was from Iran, consisting of a syndrome of dwarfism, hypogonadism, anemia, hepatosplenomegaly, rough dry skin, and

lethargy associated with geophagia (62). In a similar picture in Egypt, parasitism appears to play an important role ( 63). Hypogeusia (impaired taste) and growth

retardation in otherwise healthy children have been found to respond to zinc supplementation in parts of North America ( 64).

Clinical cases of zinc deficiency have been reported with various manifestations, depending on the severity of depletion and other factors. In addition to those

mentioned above they include dermatoses, immune deficiencies, glossitis, photophobia, lack of dark adaptation, and delayed wound healing. Precipitating factors

include short bowel syndrome, alcoholism with pancreatic and liver disease ( Fig. 30.1H), sickle cell anemia, certain chelating medications, the acrodermatitis

enteropathica genotype, intestinal losses via fistula, and inadequate amounts of zinc in parenteral nutrition fluids (see Chapter 11).

TPN with inadequate zinc supplementation has occasionally caused an acute deficiency syndrome consisting of diarrhea, mental depression, alopecia, and

dermatosis, usually around the orbits, nose, and mouth ( 65) (Fig. 30.1H). Loss of zinc through an intestinal fistula was responsible for development of skin lesions

about the mouth, palms (sterile pustules), and pressure points on hands and elbows in a 6-year-old child with non-Hodgkin's lymphoma ( Fig. 30.2H); they responded

rapidly to additional zinc.

Acrodermatitis enteropathica, an autosomal recessive disorder manifested in artificially fed infants, caused by a defect in zinc absorption, is characterized by

extensive dermatitis, growth retardation, diarrhea, hair loss, and paronychia (see Chapter 11). The skin changes somewhat resemble those seen in kwashiorkor ( 66),

but the skin changes of zinc deficiency have a typical appearance: the distribution is often acro-orificial, commonly also involving the flexures and friction areas, and

may become generalized. Eczematoid, psoriaform, vesiculobullous, and pustular lesions may be present. The earliest skin lesions are bright reddish, nonscaly

macules and patches.

Toxicity

Ingestion of large amounts of zinc, usually from an acid food or drink from a galvanized container, has caused vomiting and diarrhea. Excessive zinc intake, as in

large daily doses (30–150 mg) for several weeks, interferes with copper absorption and leads to copper deficiency. Severe lethargy in dialysis patients has been

attributed to excessive zinc in dialysis fluids. Accidental intravenous administration of 1.5 g has proven fatal.

Fluoride



Deficiency

Fluorine has not yet been proved an essential element for man, but it has a role in bone mineralization and hardening of tooth enamel. Areas with a low fluorine

content in the water supply have high rates of dental caries. Fluoridation of the water or use of supplemented tooth paste is associated with a significant fall in dental

caries rates (see also Chapter 16).

Toxicity (Fluorosis)

Fluorosis is associated with high levels (>10 ppm) in the drinking water. It is most evident in permanent teeth that develop during high fluorine intake. Deciduous teeth

are affected only at very high levels. The earliest changes, chalky white, irregularly distributed patches on the surface of the enamel, become infiltrated by yellow or

brown staining, giving rise to the characteristic “mottled” appearance ( Fig. 30.1G). More severe fluorosis also causes pitting of the enamel.

Chronic ingestion of very large amounts of fluoride (>5 mg/day) for years may lead to crippling skeletal fluorosis progressing from occasional stiffness or joint pain to

chronic pain and osteoporosis of long bones. This rare condition in the United States is associated with drinking high-fluoride well water ( 66a).

Selenium

Deficiency

Two syndromes have been described from China in which selenium deficiency is believed important. The first is Keshan disease, named for its place of origin, which

consists of a highly fatal cardiomyopathy affecting mainly young children and women of childbearing age. Good response to selenium supplementation has been

reported (67). The other, known as Kashin-Beck disease, features osteoarthritis during preadolescence or adolescence that results in dwarfing and joint deformities

from cartilage abnormalities ( 68) (see Chapter 14).

In the United States, some patients have been reported to develop selenium deficiency on TPN with no added selenium ( 69). Features have included a severe

cardiomyopathy, muscle pain and tenderness, dyschromotrichia, white fingernail beds, and macrocytosis.

Toxicity

Endemic selenosis, long recognized in animals, has been suspected in some human communities, most convincingly from China ( 70). The most frequently observed

signs were loss of hair and nails. Skin lesions and polyneuritis were less certainly attributed to selenium toxicity.

Alopecia and nail changes occurred in New York City from consumption of a “health store” supplement containing excessive amounts of selenium ( 71). In eight

reported cases of criminal poisoning, four were fatal ( 72). Symptoms and signs were distinctive: metallic taste, odor of garlic caused by methylation of selenium,

mucosal irritation, gastroenteritis, paronychia, and red pigmentation of nails, hair, and teeth.

Chromium

Deficiency

A patient receiving total parenteral nutrition for more than 5 years unexpectedly developed 15% weight loss, peripheral neuropathy, and glucose intolerance after 3.5

years of nutritional support ( 73). These conditions were all reversed with chromium therapy. Two further cases have been reported, both with weight loss and

hyperglycemia that responded to chromium (74, 75). In some parts of the world, protein-energy malnutrition appears to be complicated by chromium deficiency ( 76).

Toxicity

Toxicity usually results from direct contact or inhalation in industry. Chrome ulcers on the hands or perforation of the nasal septum may result. Lung cancer can occur,

but only with hexavalent compounds.

Cobalt

There is little evidence of a role for cobalt in human nutrition other than as part of the vitamin B



12



molecule.



Toxicity

Cobalt at one time was recommended for treatment of anemia of nephritis and infection in addition to the usual hemopoietic agents. In this context, it was reported to

cause goiter, myxedema, and congestive heart failure in five patients ( 77). A cardiomyopathy with a high mortality has been described after industrial exposure, during

maintenance dialysis, and after drinking beer that was contaminated with cobalt during processing ( 78).

Molybdenum

Deficiency

An autosomal recessive molybdenum cofactor deficiency resulting in deficiencies of xanthine oxidase and sulfite oxidase was reported in more than 20 patients in the

past decade (79). There is severe brain damage, convulsions are frequent, and about half the patients failed to survive beyond early infancy.

Only one clear-cut case related to prolonged TPN has been reported to date ( 80), involving tachycardia, tachypnea, headache, night blindness, central scotomas,

nausea, vomiting, lethargy, disorientation, and coma. These signs and symptoms were reversed by 300 µg/day of molybdenum, and the urinary excretion of abnormal

amounts of methionine metabolites was dramatically decreased.

Toxicity

Elevated blood levels of molybdenum were associated with a goutlike syndrome in Armenia in 1961 ( 81). Other symptoms and signs mentioned suggested some

involvement of liver, gastrointestinal tract, and kidney. The pathogenesis was unclear.

Manganese

Deficiency

One unsubstantiated case of human deficiency was reported to have occurred when manganese was inadvertently omitted from an experimental diet fed to a

volunteer. Clinical sings included weight loss, transient dermatitis, nausea and vomiting, changes in hair color, and slow growth of hair ( 82).

Toxicity

Manganese toxicity is usually reported in those who mine or refine ore. Prolonged exposure has caused neurologic changes resembling those of parkinsonism or

Wilson's disease. In an area in Greece, well water with a high manganese content may be responsible for occurrence of a parkinsonian syndrome ( 83). Recently, it

has been reported that manganese accumulates in the basal ganglia of patients with cirrhosis of the liver, and it is suggested that this may be associated with the

occurrence of encephalopathy in these patients ( 84). Toxicity has been reported in children given 0.8 to 1.0 mmol of manganese ion per kilogram body weight in



long-term TPN (85). This level is about 50 times greater than the recommendations in Chapter 101.

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SELECTED READING

McLaren DS. A colour atlas and text of diet-related diseases. New ed. London: Wolfe, 1992.