2523Vitamin and Trace Mineral Deficiency and Excess CHAPTER 333

nutritional needs, encouraging increased intake of fruits and vegetables, whole grains, and low-fat milk in conjunction with reduced

intake of sodium and high-calorie sugary drinks. The Web version

of the guide provides a calculator that tailors the number of servings

suggested for healthy patients of different weights, sexes, ages, and

life-cycle stages to help them to meet their needs while avoiding excess

(https://www.myplate.gov/myplate-plan and www.ChooseMyPlate.gov).

Patients who follow ethnic or unusual dietary patterns may need extra

instruction on how foods should be categorized and on the appropriate

portion sizes that constitute a serving. The process of reviewing the

guide with patients helps them transition to healthier dietary patterns

and identifies food groups eaten in excess of recommendations or in

insufficient quantities. For persons on therapeutic diets, assessment

against food-exchange lists may be useful. These include, for example,

American Diabetes Association food-exchange lists for diabetes and

the Academy of Nutrition and Dietetics food-exchange lists for renal

disease.

■ NUTRITIONAL STATUS ASSESSMENT

Full nutritional status assessment is reserved for seriously ill patients

and those at very high nutritional risk when the cause of malnutrition is still uncertain after the initial clinical evaluation and dietary

assessment. It involves multiple dimensions, including documentation

of dietary intake, anthropometric measurements, biochemical measurements of blood and urine, clinical examination, health history

elicitation, and functional status evaluation. Therapeutic dietary prescriptions and menu plans for most diseases are available from most

hospitals and from the Academy of Nutrition and Dietetics. For further discussion of nutritional assessment, see Chap. 334.

■ GLOBAL CONSIDERATIONS

The DRIs (e.g., the EAR, the UL, and energy needs) are estimates of

physiologic requirements based on experimental evidence. Assuming that appropriate adjustments are made for age, sex, body size,

and physical activity level, these estimates should be applicable to

individuals in most parts of the world. However, other values are not

transportable. The AIs are based on customary and adequate intakes

in U.S. and Canadian populations, which appear to be compatible

with good health, rather than on a large body of direct experimental

evidence. Similarly, the AMDRs represent expert opinion regarding the approximate intakes of energy-providing nutrients that are

healthful in these North American populations, and the CDRR may

also vary in other populations. Thus, these measures should be used

with caution in other settings. Nutrient-based standards like the DRIs

have also been developed by the World Health Organization/Food and

Agricultural Organization of the United Nations and are available on

the Web (https://www.who.int/activities/establishing-global-nutrientrequirements). The European Food Safety Authority (EFSA) Panel on

Dietetic Products, Nutrition, and Allergies periodically publishes its

recommendations in the online EFSA Journal (https://efsa.onlinelibrary.

wiley.com/journal/18314732). Other countries have promulgated similar recommendations. The different standards have many similarities

in their basic concepts, definitions, and nutrient recommendation

levels, but there are some differences from the DRIs as a result of the

functional criteria chosen, environmental differences, the timeliness of

the evidence reviewed, and expert judgment. There is a growing trend

toward global harmonization of these recommendations.

■ FURTHER READING

Brannon PM et al: Scanning for new evidence to prioritize updates to

the Dietary Reference Intakes: Case studies for thiamin and phosphorus. Am J Clin Nur 104:1366, 2016.

Forster H et al: Personalized nutrition: The role of new dietary assessment methods. Proc Nutr Soc 75:96, 2016.

Gibson RS: Principles of Nutritional Assessment, 2nd ed. Oxford,

Oxford University Press, 2005.

Lewis JL, Dwyer JT: Establishing nutrient intake values, in Present

Knowledge in Nutrition, Vol 2. BP Marriott, DF Birt, VA Stallings, AA

Yates, eds. London, Academic Press, 2020, pp 267–289.

Marriott BP et al: Present knowledge, in Nutrition Vol 1: Basic Nutrition and Metabolism, Vol 2: Clinical and Applied Topics in Nutrition.

London, Academic Press, 2020.

National Academy of Sciences, Engineering, and Medicine:

Guiding Principles for Developing Dietary Reference Intakes Based

on Chronic Disease. Washington DC, National Academies Press,

2017.

National Academy of Sciences, Engineering, and Medicine:

Global Harmonization of Methodological Approaches to Nutrient

Intake Recommendations: Proceedings of a Workshop. Washington

DC, National Academies Press, 2018.

National Academy of Sciences, Engineering, and Medicine:

Dietary Reference Intakes for Sodium and Potassium. Washington

DC, National Academies Press, 2019.

National Academy of Sciences, Engineering, and Medicine:

Advancing Nutrition and Food Science: 80th Anniversary of the

Food and Nutrition Board: Proceedings of a Symposium. Washington

DC, National Academics Press, 2020.

National Academy of Sciences, Engineering, and Medicine:

Harmonizing the Process for Establishing Nutrient Reference Values:

A Tool Kit. Washington DC, National Academies Press, 2020.

Report of the Subcommittee on Interpretation and Uses of

Dietary Reference Intakes and Upper Reference Levels of

Nutrients, and the Steering Committee on the Scientific

Evaluation of Dietary Reference Intakes, Food and Nutrition Board: Dietary Reference Intakes: Applications in Dietary

Assessment. Washington, DC, National Academies Press, 2008.

Stover PJ, King JC: More nutrition precision, better decisions for the

health of our nation J Nutr 150:3058, 2020.

Yaktine A et al: Why the derivation of nutrient reference values

should be harmonized and how it can be accomplished. Adv Nutr

11:1112, 2020.

Yetley EA et al: Options for basing Dietary Reference Intakes (DRIs)

on chronic disease endpoints report from a joint US-/Canadiansponsored working group. Am J Clin Nutr 105:249S, 2017.

333 Vitamin and Trace

Mineral Deficiency and

Excess

Paolo M. Suter

Vitamins are required constituents of the human diet because they are

synthesized inadequately or not at all in the human body. Only small

amounts of these substances are needed to carry out essential biochemical reactions (e.g., by acting as coenzymes or prosthetic groups).

Overt vitamin or trace mineral deficiencies are rare in Western countries because of a plentiful, varied, and inexpensive food supply; food

fortification; and use of supplements. However, multiple nutrient

deficiencies may appear together in persons who are chronically ill,

alcoholic, or living in poverty. After bariatric surgery, patients are

at high risk for multiple nutrient deficiencies. Moreover, subclinical

vitamin and trace mineral deficiencies (often designated as “hidden

hunger”), as diagnosed by laboratory testing, are quite common in the

normal population, especially in the geriatric age group and socioeconomically deprived individuals due to the lack of nutrient-dense foods.

Conversely, because of the widespread use of nutrient supplements and

food fortification, nutrient toxicities are gaining pathophysiologic and

clinical importance.

Victims of famine, emergency-affected and displaced populations,

refugees, and camp populations are at increased risk for protein-energy

malnutrition and classic micronutrient deficiencies (vitamin A, iron,

2524 PART 10 Disorders of the Gastrointestinal System

heat-labile thiaminases (raw fish, shellfish), which destroy the vitamin,

or heat-stable polyhydroxyphenols (tannins; in coffee, tea, Brussels

sprouts, or betel nuts), which inactivate the vitamin. Thus, drinking

large amounts of tea or coffee could theoretically lower thiamine body

stores.

Deficiency Most dietary deficiency of thiamine worldwide is the

result of poor dietary intake due to the lack of food or disproportionate reliance on highly processed staple crops. Food processing

removes thiamine, and high-heat or long-duration cooking destroys

it. In Western countries, the primary causes of thiamine deficiency

are alcoholism and chronic illnesses such as cancer. Alcohol interferes

directly with the absorption of thiamine and with the synthesis of

thiamine pyrophosphate, and it increases urinary excretion. Thiamine

should always be replenished when a patient with alcoholism is being

refed, as carbohydrate repletion without adequate thiamine can precipitate acute thiamine deficiency with lactic acidosis. Other at-risk

populations are women with prolonged hyperemesis gravidarum and

anorexia, patients with overall poor nutritional status who are receiving

parenteral glucose, patients who have had bariatric/metabolic surgery

(bariatric Wernicke), and patients receiving chronic diuretic therapy

(e.g., in hypertension or systolic heart failure) due to increased urinary

thiamine losses. Different drugs (e.g., metformin, verapamil) could

inhibit intestinal thiamine transporters (ThTR-2), thereby increasing

the risk of deficiency for this vitamin. Maternal thiamine deficiency

can lead to infantile beriberi in breast-fed children. Thiamine deficiency could be an underlying factor in motor vehicle accidents and

could be overlooked in the setting of head injury.

Thiamine deficiency in its early stage induces anorexia and nonspecific symptoms (e.g., irritability, decrease in short-term memory).

Prolonged thiamine deficiency causes beriberi, which is classically

categorized as wet or dry, although there is considerable overlap

between the two categories. In either form of beriberi, patients may

complain of pain and paresthesia. Wet beriberi presents primarily

with cardiovascular symptoms that are due to impaired myocardial

energy metabolism and dysautonomia; it can occur after 3 months of a

thiamine-deficient diet. Patients present with an enlarged heart, tachycardia, high-output congestive heart failure, peripheral edema, and

peripheral neuritis. Patients with dry beriberi present with a symmetric

TABLE 333-1 Principal Clinical Findings of Vitamin Malnutrition

NUTRIENT CLINICAL FINDING

DIETARY LEVEL PER DAY ASSOCIATED

WITH OVERT DEFICIENCY IN ADULTS CONTRIBUTING FACTORS TO DEFICIENCY

Thiamine Beriberi: neuropathy, muscle weakness and wasting,

cardiomegaly, edema, ophthalmoplegia, confabulation

<0.3 mg/1000 kcal Alcoholism, chronic diuretic use, bariatric

surgery, hyperemesis, thiaminases in food

Riboflavin Magenta tongue, angular stomatitis, seborrhea, cheilosis,

ocular symptoms, corneal vascularization

<0.4 mg Alcoholism, individuals with poor diets and

low intake of milk products

Niacin Pellagra: pigmented rash of sun-exposed areas, bright red

tongue, diarrhea, apathy, memory loss, disorientation

<9.0 niacin equivalents Alcoholism, vitamin B6

 deficiency,

riboflavin deficiency, tryptophan deficiency

Vitamin B6 Seborrhea, glossitis, convulsions, neuropathy, depression,

confusion, microcytic anemia

<0.2 mg Alcoholism, isoniazid

Folate Megaloblastic anemia, atrophic glossitis, depression,

↑ homocysteine

<100 μg/d Alcoholism, sulfasalazine, pyrimethamine,

triamterene

Vitamin B12 Megaloblastic anemia, loss of vibratory and position sense,

abnormal gait, dementia, impotence, loss of bladder and

bowel control, ↑ homocysteine, ↑ methylmalonic acid

<1.0 μg/d Gastric atrophy (pernicious anemia),

terminal ileal disease, strict vegetarianism,

acid-reducing drugs (e.g., H2

 blockers),

metformin

Vitamin C Scurvy: petechiae, ecchymosis, coiled hairs, inflamed and

bleeding gums, joint effusion, poor wound healing, fatigue

<10 mg/d Smoking, alcoholism

Vitamin A Xerophthalmia, night blindness, Bitot’s spots, follicular

hyperkeratosis, impaired embryonic development, immune

dysfunction

<300 μg/d Fat malabsorption, infection, measles,

alcoholism, protein-energy malnutrition

Vitamin D Rickets: skeletal deformation, rachitic rosary, bowed legs;

osteomalacia

<2.0 μg/d Aging, lack of sunlight exposure, fat

malabsorption, deeply pigmented skin

Vitamin E Peripheral neuropathy, spinocerebellar ataxia, skeletal

muscle atrophy, retinopathy

Not described unless underlying

contributing factor is present

Occurs only with fat malabsorption

or genetic abnormalities of vitamin E

metabolism/transport

Vitamin K Elevated prothrombin time, bleeding <10 μg/d Fat malabsorption, liver disease,

antibiotic use

zinc, iodine) as well as for overt deficiencies in thiamine (beriberi),

riboflavin, vitamin C (scurvy), and niacin (pellagra).

Body stores of vitamins and minerals vary tremendously. For example, stores of vitamins B12 and A are large, and an adult may not become

deficient until ≥1 year after beginning to eat a deficient diet. However,

folate and thiamine may become depleted within weeks among those

eating a deficient diet. Therapeutic modalities can deplete essential

nutrients from the body; for example, hemodialysis or diuretics remove

water-soluble vitamins, which must be replaced by supplementation.

Vitamins and trace minerals play several roles in diseases: (1) deficiencies of vitamins and minerals may be caused by disease states such

as malabsorption; (2) either deficiency or excess of vitamins and minerals can cause disease in and of itself (e.g., vitamin A intoxication and

liver disease); and (3) vitamins and minerals in high doses may be used

as drugs (e.g., niacin for hypercholesterolemia). Since they are covered

elsewhere, the hematologic-related vitamins and minerals (Chaps. 97

and 99) either are not considered or are considered only briefly in this

chapter, as are the bone-related vitamins and minerals (vitamin D,

calcium, phosphorus, magnesium; Chap. 409).

VITAMINS

See also Table 333-1 and Fig. 333-1.

■ THIAMINE (VITAMIN B1

)

Thiamine was the first B vitamin to be identified and therefore is

referred to as vitamin B1

. Thiamine functions in the decarboxylation of

α-ketoacids (e.g., pyruvate α-ketoglutarate) and branched-chain amino

acids and thus is essential for energy generation. In addition, thiamine

pyrophosphate acts as a coenzyme for a transketolase reaction that mediates the conversion of hexose and pentose phosphates. It has been postulated that thiamine plays a role in peripheral nerve conduction, although

the exact chemical reactions underlying this function are not known.

Food Sources The median intake of thiamine in the United States

from food alone is ~2 mg/d. Primary food sources for thiamine include

yeast, organ meat, pork, legumes, beef, whole grains, and nuts. Milled

rice and grains contain little thiamine. Thiamine deficiency is therefore more common in cultures that rely heavily on a milled polished

rice-based diet. Certain foods contain antithiamine factors such as

2525Vitamin and Trace Mineral Deficiency and Excess CHAPTER 333

FIGURE 333-1 Structures and principal functions of vitamins associated with human disorders.

Vitamin

Thiamine (B1)

Riboflavin (B2) Flavin mononucleotide

 (FMN) and flavin

 adenine dinucleotide

 (FAD)

Cofactor for

 oxidation,

 reduction

 reactions,

 and covalently

 attached

 prosthetic groups

 for some

 enzymes

Niacin Nicotinamide adenine

 dinucleotide phosphate

 (NADP) and nicotinamide

 adenine dinucleotide

 (NAD)

Coenzymes for

 oxidation and

 reduction

 reactions

Vitamin B6 Pyridoxal phosphate Cofactor for

 enzymes of amino

 acid metabolism

Folate Polyglutamate forms of

 (5, 6, 7, 8)

 tetrahydrofolate with

 carbon unit

 attachments

Coenzyme for one

 carbon transfer in

 nucleic acid and

 amino acid

 metabolism

Active derivative or

 cofactor form

Principal

function

CH2OH

HO CH2OH

N

N N

NH

Ribityl

N

O

O

NH2

CH3

CH2CH2OH

N N

N S

N

H

O

C O

Vitamin B12 Methylcobalamine

Adenosylcobalamin

Coenzyme for

 methionine

 synthase

 and

 L-methylmalonyl-

 CoA mutase

H2N

CH2

N N

N

N C CH

CH2

CH2

COOH

H

N

H

N

H

O

O

O

C CH

CH2

CH2

COOH

O

C OH

n

CH3

CH3

CH3

CH3

CH3

CH3

CH3

H3C

H3C

H3C

CH2

CH2CH2CONH2

NHCOCH2CH2

CH2CH2CONH2

CH2CH2CONH2

CH2CH2CONH2

CONH2

CH2

CH2 CHCH3

CONH2

HOCH2

HO

Co+

NN

NN

N

N

O

O O

P

O–

O

OH Cbl

Thiamine pyrophosphate Coenzyme for

 cleavage of

 carbon-carbon

 bonds; amino

 acid and

 carbohydrate

 metabolism

+

peripheral neuropathy of the motor and sensory systems, with diminished reflexes. The neuropathy affects the legs most markedly, and

patients have difficulty rising from a squatting position.

Alcoholic patients with chronic thiamine deficiency also may have

central nervous system (CNS) manifestations known as Wernicke’s

encephalopathy, which consists of horizontal nystagmus, ophthalmoplegia (due to weakness of one or more extraocular muscles),

cerebellar ataxia, and mental impairment (Chap. 453). When there

is an additional loss of memory and a confabulatory psychosis, the

syndrome is known as Wernicke-Korsakoff syndrome. Despite the

typical clinical picture and history, Wernicke-Korsakoff syndrome is

underdiagnosed.

The laboratory diagnosis of thiamine deficiency usually is made by

a functional enzymatic assay of transketolase activity measured before

and after the addition of thiamine pyrophosphate. A >25% stimulation

in response to the addition of thiamine pyrophosphate (i.e., an activity

2526 PART 10 Disorders of the Gastrointestinal System

Vitamin

Vitamin C

Vitamin A Retinol, retinaldehyde,

 and retinoic acid

Formation of

 rhodopsin (vision)

 and glycoproteins

 (epithelial cell

 function); also

 regulates gene

 transcription

Vitamin D 1,25-Dihydroxyvitamin D Maintenance of

 blood calcium

 and phosphorus

 levels;

 antiproliferative

 hormone

Vitamin E Tocopherols and

 tocotrienols

Antioxidants

Active derivative or

 cofactor form

Principal

function

Vitamin K Vitamin K hydroquinone Cofactor for

 posttranslation

 carboxylation of

 many proteins

 including essential

 clotting factors

Ascorbic acid and

 dehydroascorbic acid

Participation as a

 redox ion in many

 biologic

 oxidation and

 hydrogen transfer

 reactions

O

O

C C

OH OH OH

CC C CH2OH

O

O

R

CH2OH

(β-Carotene)

(Retinol)

OH

CH2

HO OH

CH2[CH2 CH CH2]3H

HO

O

CH2

CH3

FIGURE 333-1 (Continued)

coefficient of 1.25) is interpreted as abnormal. Thiamine or the phosphorylated esters of thiamine in serum or blood also can be measured

by high-performance liquid chromatography to detect deficiency.

TREATMENT

Thiamine Deficiency

In acute thiamine deficiency with either cardiovascular or neurologic signs, 200 mg of thiamine three times daily should be

given intravenously until there is no further improvement in acute

symptoms; oral thiamine (10 mg/d) should subsequently be given

until recovery is complete. Cardiovascular and ophthalmoplegic

improvement occurs within 24 h. Other manifestations gradually

clear, although psychosis in Wernicke-Korsakoff syndrome may

be permanent or may persist for several months. Other nutrient

deficiencies should be corrected concomitantly. In view of the

widespread, often unrecognized (subclinical) deficiency, a more

generous supplementation of this vitamin in the emergency care

setting is warranted.

Toxicity Although hypersensitivity/anaphylaxis has been reported

after high intravenous doses of thiamine, no adverse effects have been

recorded from either food or supplements at high doses.

■ RIBOFLAVIN (VITAMIN B2

)

Riboflavin is important for the metabolism of fat, carbohydrate, and

protein, acting as a respiratory coenzyme and an electron donor.

Enzymes that contain flavin adenine dinucleotide (FAD) or flavin

mononucleotide (FMN) as prosthetic groups are known as flavoenzymes (e.g., succinic acid dehydrogenase, monoamine oxidase,

glutathione reductase). FAD is a cofactor for methyltetrahydrofolate

reductase and therefore modulates homocysteine metabolism. The

vitamin also plays a role in drug and steroid metabolism, including

detoxification reactions.

Although much is known about the chemical and enzymatic reactions of riboflavin, the clinical manifestations of riboflavin deficiency

are nonspecific and are similar to those of other deficiencies of B vitamins. Riboflavin deficiency is manifested principally by lesions of the

mucocutaneous surfaces of the mouth and skin. In addition, corneal

vascularization, anemia, and personality changes have been described

with riboflavin deficiency.

Deficiency and Excess Riboflavin deficiency almost always is due

to dietary deficiency. Milk, other dairy products, and enriched breads

and cereals are the most important dietary sources of riboflavin in the

United States, although lean meat, fish, eggs, broccoli, and legumes are

also good sources. Riboflavin is extremely sensitive to light, and milk

should be stored in containers that protect against photodegradation.

Laboratory diagnosis of riboflavin deficiency can be made by determination of red blood cell or urinary riboflavin concentrations or by

measurement of erythrocyte glutathione reductase activity, with and

without added FAD. Because of the limited capacity of the gastrointestinal tract to absorb riboflavin (~27 mg after one oral dose) as well as

the instantaneous urinary excretion, riboflavin toxicity has not been

described.

2527Vitamin and Trace Mineral Deficiency and Excess CHAPTER 333

■ NIACIN (VITAMIN B3

)

The term niacin refers to nicotinic acid and nicotinamide and their

biologically active derivatives. Nicotinic acid and nicotinamide serve

as precursors of two coenzymes, nicotinamide adenine dinucleotide

(NAD) and NAD phosphate (NADP), which are important in numerous oxidation and reduction reactions in the body. In addition, NAD

and NADP are active in adenine diphosphate–ribose transfer reactions

involved in DNA repair and calcium mobilization.

Metabolism and Requirements Nicotinic acid and nicotinamide

are absorbed well from the stomach and small intestine. The bioavailability of niacin from beans, milk, meat, and eggs is high; bioavailability

from cereal grains is lower. Since flour is enriched with “free” niacin

(i.e., the non-coenzyme form), bioavailability is excellent. Median

intakes of niacin in the United States considerably exceed the recommended dietary allowance (RDA).

The amino acid tryptophan can be converted to niacin with an

efficiency of 60:1 by weight. Thus, the RDA for niacin is expressed in

niacin equivalents. A lower-level conversion of tryptophan to niacin

occurs in vitamin B6

 and/or riboflavin deficiencies and in the presence

of isoniazid. The urinary excretion products of niacin include 2-

pyridone and 2-methyl nicotinamide, measurements of which are used

in the diagnosis of niacin deficiency.

Deficiency Niacin deficiency causes pellagra, which is found

mostly among people eating corn-based diets in parts of China,

Africa, and India. Pellagra in North America is found mainly among

alcoholics; among patients with congenital defects of intestinal and

kidney absorption of tryptophan (Hartnup disease; Chap. 420); and

among patients with carcinoid syndrome (Chap. 84), in which there is

increased conversion of tryptophan to serotonin. The antituberculosis

drug isoniazid is a structural analogue of niacin and can precipitate

pellagra. In the setting of famine or population displacement, pellagra

results from the absolute lack of niacin but also from the deficiency

of micronutrients required for the conversion of tryptophan to niacin

(e.g., iron, riboflavin, and pyridoxine). The early symptoms of pellagra

include loss of appetite, generalized weakness and irritability, abdominal pain, and vomiting. Bright red glossitis then ensues and is followed

by a characteristic skin rash that is pigmented and scaling, particularly

in skin areas exposed to sunlight. This rash is known as Casal’s necklace

because it forms a ring around the neck; it is seen in advanced cases.

Vaginitis and esophagitis also may occur. Diarrhea (due in part to proctitis and in part to malabsorption), depression, seizures, and dementia

are also part of the pellagra syndrome. The primary manifestations of

this syndrome are sometimes referred to as “the four Ds”: dermatitis,

diarrhea, and dementia leading to death. Aging is characterized by a

decline in cellular NAD+, and it seems plausible that maintaining and/

or reestablishing cellular NAD+, might favorably modulate the risk of

chronic diseases of aging (e.g., metabolic disorders).

TREATMENT

Pellagra

Treatment of pellagra consists of oral supplementation with 100–

200 mg of nicotinamide or nicotinic acid three times daily for

5 days. High doses of nicotinic acid (2 g/d in a time-release form)

are used for the treatment of elevated cholesterol and triglyceride

levels and/or low high-density lipoprotein cholesterol levels, but

without proven evidence to prevent cardiovascular disease. Nevertheless, nicotinic acid may be useful in patients with statin intolerance or severe hypertriglyceridemia (Chap. 407).

Toxicity Prostaglandin-mediated flushing due to binding of the

vitamin to a G protein–coupled receptor has been observed at daily

nicotinic acid doses as low as 30 mg taken as a supplement or as

therapy for dyslipidemia. There is no evidence of toxicity from niacin

that is derived from food sources. Flushing always starts in the face

and may be accompanied by skin dryness, itching, paresthesia, and

headache. Flushing is subject to tachyphylaxis and often improves

with time; premedication with aspirin may alleviate these symptoms.

Nausea, vomiting, and abdominal pain also occur at similar doses of

niacin. Hepatic toxicity is the most serious toxic reaction caused by

sustained-release niacin and may present as jaundice with elevated

aspartate aminotransferase (AST) and alanine aminotransferase (ALT)

levels. A few cases of fulminant hepatitis requiring liver transplantation

have been reported at doses of 3–9 g/d. Other toxic reactions include

glucose intolerance, hyperuricemia, macular edema, and macular

cysts. The combination of nicotinic acid preparations for dyslipidemia

plus 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase

inhibitors may increase the risk of rhabdomyolysis. The upper limit for

daily (nontherapeutic) niacin intake has been set at 35 mg.

■ PYRIDOXINE (VITAMIN B6

)

Vitamin B6

 refers to a family of compounds that includes pyridoxine,

pyridoxal, pyridoxamine, and their 5′-phosphate derivatives. 5′-Pyridoxal phosphate (PLP) is a cofactor for >100 enzymes involved in

amino acid metabolism. Vitamin B6

 also is involved in heme and

neurotransmitter synthesis and in the metabolism of glycogen, lipids,

steroids, sphingoid bases, and several vitamins, including the conversion of tryptophan to niacin.

Dietary Sources Plants contain vitamin B6

 in the form of pyridoxine, whereas animal tissues contain PLP and pyridoxamine phosphate.

The vitamin B6

 contained in plants is less bioavailable than that in

animal tissues. Rich food sources of vitamin B6

 include legumes, nuts,

wheat bran, and meat, although it is present in all food groups.

Deficiency Symptoms of vitamin B6

 deficiency include epithelial

changes, as seen frequently with other B vitamin deficiencies. In

addition, severe vitamin B6

 deficiency can lead to peripheral neuropathy, abnormal electroencephalograms, and personality changes that

include depression and confusion. In infants, diarrhea, seizures, and

anemia have been reported. Microcytic hypochromic anemia is due

to diminished hemoglobin synthesis, since the first enzyme involved

in heme biosynthesis (aminolevulinate synthase) requires PLP as a

cofactor (Chap. 97). In some case reports, platelet dysfunction has

been reported. Since vitamin B6

 is necessary for the conversion of

homocysteine to cystathionine, it is possible that chronic low-grade

vitamin B6

 deficiency may result in hyperhomocysteinemia, which has

been associated with vascular dysfunction and an increased risk of cardiovascular disease; however, so far, there is only limited randomized

controlled trial evidence (Chap. 420). Independent of homocysteine,

low levels of circulating vitamin B6

 have been associated with inflammation and elevated levels of C-reactive protein.

Certain medications, such as isoniazid, l-dopa, penicillamine, and

cycloserine, interact with PLP due to a reaction with carbonyl groups.

Pyridoxine should be given concurrently with isoniazid to avoid

neuropathy. The increased ratio of AST to ALT seen in alcoholic liver

disease reflects the relative vitamin B6

 dependence of ALT. Vitamin B6

dependency syndromes that require pharmacologic doses of vitamin B6

are rare; they include cystathionine β-synthase deficiency, pyridoxine-responsive (primarily sideroblastic) anemias, and gyrate atrophy

with chorioretinal degeneration due to decreased activity of the mitochondrial enzyme ornithine aminotransferase. In these situations,

100–200 mg/d of oral vitamin B6

 is required for treatment.

Severe nausea and vomiting in pregnancy might respond to pyridoxine combined with doxylamine. High doses of vitamin B6

 have

been used to treat carpal tunnel syndrome, premenstrual syndrome,

schizophrenia, autism, and diabetic neuropathy but have not been

found to be effective.

The laboratory diagnosis of vitamin B6

 deficiency is generally based

on low plasma PLP values (<20 nmol/L). Vitamin B6

 deficiency is

treated with 50 mg/d; higher doses of 100–200 mg/d are given if the

deficiency is related to medication use. Vitamin B6

 should not be given

with l-dopa, since the vitamin interferes with the action of this drug.

Toxicity The safe upper limit for vitamin B6

 has been set at 100 mg/d,

although no adverse effects have been associated with high intakes of

2528 PART 10 Disorders of the Gastrointestinal System

vitamin B6

 from food sources only. When toxicity occurs, it causes

severe sensory neuropathy, leaving patients unable to walk; however,

in most cases, this is reversible upon cessation of the high intake. Medication safety monitoring suggests a rather high prevalence of vitamin

B6

–induced neuropathy. Accordingly, long-term high-dose vitamin B6

supplementation should be discouraged. Some cases of photosensitivity and dermatitis have been reported.

■ FOLATE (VITAMIN B12)

See Chap. 99.

■ VITAMIN C

Both ascorbic acid (only the l-isomer) and its oxidized product dehydroascorbic acid are biologically active. Actions of vitamin C include

antioxidant activity, promotion of nonheme iron absorption, carnitine

biosynthesis, conversion of dopamine to norepinephrine, tyrosine

catabolism, histone and DNA demethylation, and synthesis of many

peptide hormones. Vitamin C is also important for connective tissue

metabolism and cross-linking (proline hydroxylation), and it is a component of many drug-metabolizing enzyme systems, particularly the

mixed-function oxidase systems.

Absorption and Dietary Sources Vitamin C is almost completely absorbed if <100 mg is administered in a single dose; however,

only ≤50% is absorbed at doses >1 g. Enhanced degradation and fecal

and urinary excretion of vitamin C occur at higher intake levels.

Good dietary sources of vitamin C include citrus fruits, green vegetables (especially broccoli), tomatoes, and potatoes. Consumption of

five servings of fruits and vegetables a day provides vitamin C in excess

of the RDA of 90 mg/d for men and 75 mg/d for women. In addition,

~40% of the U.S. population consumes vitamin C as a dietary supplement in which “natural forms” of the vitamin are no more bioavailable

than synthetic forms. Smoking (including “passive” smoking), hemodialysis, pregnancy, lactation, and stress (e.g., infection, trauma) appear

to increase vitamin C requirements.

Deficiency Vitamin C deficiency causes scurvy. In the United

States, this condition is seen primarily among the poor and the elderly,

in alcoholics who consume <10 mg/d of vitamin C, and in young

adults who eat severely unbalanced diets. In addition to generalized

fatigue, symptoms of scurvy primarily reflect impaired formation of

mature connective tissue and include bleeding into the skin (petechiae,

ecchymoses, perifollicular hemorrhages); inflamed and bleeding gums;

and manifestations of bleeding into joints, the peritoneal cavity, the

pericardium, and the adrenal glands. In children, vitamin C deficiency

may cause impaired bone growth. Laboratory diagnosis of vitamin C

deficiency is based on low plasma or leukocyte levels.

Administration of vitamin C (200 mg/d) improves the symptoms

of scurvy within several days. High-dose vitamin C supplementation

(e.g., 0.2 g up to several grams per day) may slightly decrease the symptoms and duration of upper respiratory tract infections. Vitamin C supplementation has also been reported to be useful in Chédiak-Higashi

syndrome (Chap. 64) and osteogenesis imperfecta (Chap. 413). Diets

high in vitamin C have been claimed to lower the incidence of certain

cancers, particularly esophageal and gastric cancers. If proven, this

effect may be because vitamin C can prevent the conversion of nitrites

and secondary amines to carcinogenic nitrosamines. Emerging evidence suggests a therapeutic effect of intravenous parenteral (not oral)

pharmacologic doses of up to 1g/kg body weight of ascorbic acid in the

treatment of cancers (e.g., metastatic pancreatic, ovarian, glioblastoma,

and non-small-cell lung cancers). The mechanism of pharmacologic

ascorbate in cancer treatment (as a stand-alone agent or with other

therapeutic agents) appear to be pro-oxidative, either synergistic (e.g.,

gemcitabine, PD-1 inhibitors, radiation) or additive with other agents.

Toxicity Taking >2 g of vitamin C in a single dose may result

in abdominal pain, diarrhea, and nausea. Since vitamin C may be

metabolized to oxalate, it is feared that chronic high-dose vitamin C

supplementation could result in an increased prevalence of kidney

stones. However, except in patients with preexisting renal disease, this

association has not been borne out in several trials. Nevertheless, it is

reasonable to advise patients with a history of kidney stones (especially

oxalate renal stones) and renal insufficiency not to take large doses of

vitamin C. There is also an unproven but possible risk that chronic high

doses of vitamin C could promote iron overload and iron toxicity (e.g.,

in patients with hemochromatosis or thalassemia major). High doses of

vitamin C can induce hemolysis in patients with glucose-6-phosphate

dehydrogenase deficiency, and doses >1 g/d can cause false-negative

guaiac reactions and interfere with tests for urinary glucose. High

doses may interfere with the activity of certain drugs and diagnostic

tests (e.g., false-negative results of guaiac-based fecal occult blood

tests).

■ BIOTIN

Biotin (also known as vitamin B7

 or vitamin H) is a water-soluble vitamin that plays a role in gene expression, gluconeogenesis, and fatty acid

synthesis and serves as a carbon dioxide (CO2

) carrier on the surface

of both cytosolic and mitochondrial carboxylase enzymes. The vitamin

also functions in the catabolism of specific amino acids (e.g., leucine)

and in gene regulation by histone biotinylation. Excellent food sources

of biotin include organ meat such as liver or kidney, soy and other

beans, yeast, and egg yolks; however, egg white contains the protein

avidin, which strongly binds the vitamin and reduces its bioavailability.

Biotin deficiency due to low dietary intake is rare; rather, deficiency

is due to inborn errors of metabolism. Biotin deficiency has been

induced by experimental feeding of egg white diets and by biotin-free

parenteral nutrition in patients with short bowels. In adults, biotin

deficiency results in mental changes (depression, hallucinations),

paresthesia, anorexia, and nausea. A scaling, seborrheic, and erythematous rash may occur around the eyes, nose, and mouth as well as

on the extremities. In infants, biotin deficiency presents as hypotonia,

lethargy, and apathy. In addition, infants may develop alopecia and a

characteristic rash that includes the ears. At present, evidence does not

support a therapeutic role of high-dose biotin in multiple sclerosis. The

laboratory diagnosis of biotin deficiency can be established on the basis

of a decreased concentration of urinary biotin (or its major metabolites), increased urinary excretion of 3-hydroxyisovaleric acid after a

leucine challenge, or decreased activity of biotin-dependent enzymes

in lymphocytes (e.g., propionyl-CoA carboxylase). Treatment requires

pharmacologic doses of biotin, that is, up to 10 mg/d. No toxicity is

known. High-dose biotin supplements could interfere with different

immunoassay platforms based on streptavidin-biotin technology (e.g.,

biotinylated immunoassays), resulting in false-positive (e.g., free T4

 or

T3

) or false-negative tests (e.g., thyroid-stimulating hormone, troponin,

β-human chorionic gonadotropin pregnancy test).

■ PANTOTHENIC ACID (VITAMIN B5

)

Pantothenic acid is a component of coenzyme A and phosphopantetheine, which are involved in fatty acid metabolism and the synthesis of

cholesterol, steroid hormones, and all compounds formed from isoprenoid units. In addition, pantothenic acid is involved in the acetylation

of proteins. The vitamin is excreted in the urine, and the laboratory

diagnosis of deficiency is based on low urinary vitamin levels.

The vitamin is ubiquitous in the food supply. Liver, yeast, egg yolks,

whole grains, and vegetables are particularly good sources. Human

pantothenic acid deficiency has been demonstrated only by experimental feeding of diets low in pantothenic acid or by administration

of a specific pantothenic acid antagonist. The symptoms of pantothenic acid deficiency are nonspecific and include gastrointestinal

disturbance, depression, muscle cramps, paresthesia, ataxia, and hypoglycemia. Pantothenic acid deficiency is believed to have caused the

“burning feet syndrome” seen in prisoners of war during World War II.

No toxicity of this vitamin has been reported.

■ CHOLINE

Choline is a precursor for acetylcholine, phospholipids, and betaine.

Choline is necessary for the structural integrity of cell membranes,

cholinergic neurotransmission, lipid and cholesterol metabolism,

methyl-group metabolism, and transmembrane signaling. Recently,

a recommended adequate intake was set at 550 mg/d for men and

2529Vitamin and Trace Mineral Deficiency and Excess CHAPTER 333

425 mg/d for women, although certain genetic polymorphisms can

increase an individual’s requirement. Choline is thought to be a “conditionally essential” nutrient in that its de novo synthesis occurs in

the liver and results in lesser-than-used amounts only under certain

stress conditions (e.g., alcoholic liver disease). The dietary requirement for choline depends on the status of other nutrients involved in

methyl-group metabolism (folate, vitamin B12, vitamin B6

, and methionine) and thus varies widely. Choline is widely distributed in food

(e.g., egg yolks, wheat germ, organ meat, milk) in the form of lecithin

(phosphatidylcholine). Choline deficiency has occurred only in experimental conditions or in patients receiving parenteral nutrition devoid

of choline and rarely in specific inborn errors of choline metabolism.

Deficiency results in fatty liver, elevated aminotransferase levels, and

skeletal muscle damage with high creatine phosphokinase values.

The diagnosis of choline deficiency is currently based on low plasma

levels, although nonspecific conditions (e.g., heavy exercise) may also

suppress plasma levels.

Toxicity from choline results in hypotension, cholinergic sweating,

diarrhea, salivation, and a fishy body odor. The upper limit for choline

intake has been set at 3.5 g/d. Because of its ability to lower cholesterol and homocysteine levels, choline treatment has been suggested

for patients with dementia and patients at high risk of cardiovascular

disease. However, the benefits of such treatment have not been firmly

documented; recently, signals for an increased cardiovascular risk have

been reported. Choline- and betaine-restricted diets are of therapeutic

value in trimethylaminuria (“fish odor syndrome”) or in decreasing the

production of the gut microbiome-derived trimethylamine N-oxide

(TMAO) as a potential cardiovascular risk modulator.

■ FLAVONOIDS

Flavonoids constitute a large family of polyphenols that contribute

to the aroma, taste, and color of fruits and vegetables. Major groups

of dietary flavonoids include anthocyanidins in berries; catechins in

green tea and chocolate; flavonols (e.g., quercetin) in broccoli, kale,

leeks, onions, and the skins of grapes and apples; and isoflavones

(e.g., genistein) in legumes. Isoflavones have a low bioavailability and

are partially metabolized by the intestinal flora. The dietary intake of

flavonoids is estimated at 10–100 mg/d; this figure is almost certainly

an underestimate attributable to a lack of information on their concentrations in many foods. Several flavonoids have antioxidant activity

and affect cell signaling. From observational epidemiologic studies

and limited clinical (human and animal) studies, flavonoids have been

postulated to play a role in the prevention of several chronic diseases,

including neurodegenerative disease, diabetes, and osteoporosis. The

ultimate importance and usefulness of these compounds against

human disease have not been consistently demonstrated. Nevertheless,

a dietary pattern with high intake of fruits, vegetables, and legumes

should be encouraged to assure a higher intake of these and others

nonnutritive bioactives.

■ VITAMIN A

Vitamin A, in the strictest sense, refers to retinol and retinyl esters.

However, the oxidized metabolites retinaldehyde and retinoic acid

are also biologically active compounds. The term retinoids includes

all molecules (including synthetic molecules) that are chemically

related to retinol. Retinaldehyde (11-cis) is the form of vitamin A that

is required for normal vision, whereas retinoic acid is necessary for

normal morphogenesis, growth, and cell differentiation. Retinoic acid

does not function directly in vision and, in contrast to retinol, is not

involved in reproduction. Vitamin A also plays a role in iron utilization, humoral immunity, T cell–mediated immunity, natural killer cell

activity, and phagocytosis.

Vitamin A is found in the human food supply in two forms: preformed as retinyl esters and provitamin A carotenoids. There are >700

carotenoids in nature, ~50 of which can be metabolized to vitamin A.

β-Carotene is the most prevalent carotenoid with provitamin A activity

in the food supply. In humans, significant fractions of carotenoids are

absorbed intact and are stored in liver and fat. It is estimated that in

healthy humans ≥12 μg (range, 4–27 μg) of dietary all-trans β-carotene

is equivalent to 1 μg of retinol activity, whereas the figure is ≥24 μg

for other dietary provitamin A carotenoids (e.g., β-cryptoxanthin, αcarotene). The vitamin A equivalency for a β-carotene supplement in

an oily solution is 2:1.

Metabolism The liver contains ~90% of the vitamin A reserves in

healthy individuals and secretes vitamin A in the form of retinol, which

is bound in the circulation to retinol-binding protein. Once binding

has occurred, the retinol-binding protein complex interacts with a

second protein, transthyretin. This trimolecular complex functions to

prevent vitamin A from being filtered by the kidney glomerulus, thus

protecting the body against the toxicity of retinol and allowing retinol

to be taken up by specific cell-surface receptors that recognize retinolbinding protein. A certain amount of vitamin A enters peripheral cells

even if it is not bound to retinol-binding protein. After retinol is internalized by the cell, it becomes bound to a series of cellular retinol-binding proteins, which function as sequestering and transporting agents

as well as co-ligands for enzymatic reactions. Certain cells also contain

retinoic acid–binding proteins, which have sequestering functions but

also shuttle retinoic acid to the nucleus and enable its metabolism.

Vitamin A metabolites (retinoids) such as retinoic acid are potent

regulators of gene transcription through nuclear receptor signaling, thus

playing a key role in many cellular and metabolic pathways. Two families of receptors (retinoic acid receptors [RARs] and retinoid X receptors

[RXRs]) are active in retinoid-mediated gene transcription. Retinoid

receptors regulate transcription by binding as dimeric complexes to

specific DNA sites—the retinoic acid response elements—in target

genes (Chap. 377). The receptors can either stimulate or repress gene

expression in response to their ligands. RARs bind all-trans retinoic

acid and 9-cis-retinoic acid, whereas RXRs bind only 9-cis-retinoic acid.

The retinoid receptors play an important role in controlling cell

proliferation and differentiation. RXRs dimerize with other nuclear

receptors to function as coregulators of genes responsive to retinoids,

but also to thyroid hormone and calcitriol. RXR agonists induce insulin

sensitivity experimentally, perhaps because RXRs are cofactors for the

peroxisome proliferator-activated receptors, which also mediate fatty

acid and carbohydrate metabolism and are targets for different drugs

including thiazolidinedione drugs (e.g., rosiglitazone and pioglitazone)

(Chap. 404).

Dietary Sources The retinol activity equivalent (RAE) is used to

express the vitamin A value of food: 1 RAE is defined as 1 μg of retinol

(0.003491 mmol), 12 μg of β-carotene, and 24 μg of other provitamin

A carotenoids. In older literature, vitamin A often was expressed in

international units (IUs), with 1 μg of retinol equal to 3.33 IU of retinol

and 20 IU of β-carotene. Although these IUs are no longer in scientific

use, they can still be found in reports of the food industry and in public

health interventions in low-income countries.

Liver, fish, and eggs are excellent food sources for preformed vitamin A; vegetable sources of provitamin A carotenoids include dark

green and deeply colored fruits and vegetables. Moderate cooking of

vegetables enhances carotenoid release for uptake in the gut. Carotenoid absorption is also aided by some fat in a meal. Exclusive breastfeeding can cover the vitamin A needs of infants if the mother has

an adequate vitamin A status and a large enough volume of milk. If

the nursing mother has inadequate vitamin A intake or concomitant

diseases or her infant was a preterm delivery, breast milk probably

will not supply enough vitamin A to prevent deficiency. In developing

countries, chronic dietary deficiency is the main cause of vitamin A

deficiency and is exacerbated by infection. In early childhood, low vitamin A status results from inadequate intakes of animal food sources

and edible oils, both of which are expensive, coupled with seasonal

unavailability of vegetables and fruits and lack of marketed fortified

food products. Factors that interfere with vitamin A metabolism may

also affect status or function. For example, concurrent zinc deficiency

can interfere with the mobilization of vitamin A from liver stores. Alcohol interferes with the conversion of retinol to retinaldehyde in the eye

by competing for alcohol (retinol) dehydrogenase. Drugs that interfere

with the absorption of vitamin A include mineral oil, neomycin, and

bile acid sequestrants (e.g., cholestyramine).

2530 PART 10 Disorders of the Gastrointestinal System

Deficiency Vitamin A deficiency is endemic in areas where diets

are chronically poor, especially in southern Asia, sub-Saharan Africa,

some parts of Latin America, and the western Pacific, including parts

of China. Vitamin A status is usually assessed by measuring serum

retinol (normal range, 1.05–3.50 μmol/L [30–100 μg/dL]) or via

dose-response tests or tests of dark adaptation. To assure a correct

biochemical assessment of vitamin A status, a simultaneous assessment

of the inflammatory status is needed (in analogy to the assessment of

iron status); not doing so may result in an overestimation of vitamin A

deficiency. Correction factors to adjust the measured plasma vitamin

A levels to account for the influence of C-reactive protein and α1

-acid

glycoprotein are available. Stable isotopic or invasive liver biopsy methods are available to estimate total-body stores of vitamin A. As judged

by deficient serum retinol (<0.70 μmol/L [20 μg/dL]), vitamin A

deficiency worldwide is present in 190 million preschool-age children,

among whom >5 million have an ocular manifestation of deficiency

termed xerophthalmia. This condition includes milder stages of night

blindness and conjunctival xerosis (dryness) with Bitot’s spots (white

patches of keratinized epithelium appearing on the sclera) that may

affect 1–5% of children in deficient populations as well as rare, potentially blinding corneal ulceration and necrosis. Keratomalacia (softening of the cornea) leads to corneal scarring that blinds an estimated

quarter of a million children each year and is associated with fatality

rates of 4–25%. However, vitamin A deficiency severe enough to cause

any clinical stage poses an increased risk of death from diarrhea, dysentery, measles, malaria, or respiratory disease. This is because vitamin

A deficiency can compromise barrier, innate, and acquired immune

defenses to infection. In areas where deficiency is widely prevalent,

vitamin A supplementation can markedly reduce the risk of childhood

mortality (by 23–34%, on average). About 10% of pregnant women

in undernourished settings also develop night blindness (assessed by

history) during the latter half of pregnancy; this level of moderate

to severe vitamin A deficiency is associated with an increased risk of

maternal infection and death. Maternal vitamin A deficiency may also

exacerbate already low vitamin A nutrition and associated risks for

the newborn. In South Asia, where maternal deficiency is prominent,

giving infants a single oral dose (50,000 IU) of vitamin A shortly after

birth has reduced infant mortality by ≥10%, whereas in African settings less affected by maternal vitamin A deficiency, no effect has been

noted, revealing differences in risk of deficiency and benefit of supplementation across regions. However, the World Health Organization

does not recommend high-dose supplementation to newborns.

TREATMENT

Vitamin A Deficiency

Vitamin A is commercially available for treatment and prevention

in esterified forms (e.g., acetate, palmitate), which are more stable

than other forms. Any stage of xerophthalmia should be treated

with 60 mg (or RAE) or 200,000 IU of vitamin A in oily solution,

usually contained in a soft-gel capsule. The same dose is repeated

1 and 14 days later. Doses should be reduced by half for patients

6–11 months of age. Mothers with night blindness or Bitot’s spots

should be given vitamin A orally 3 mg daily for at least 3 months.

These regimens are efficacious, and they are far less expensive and

more widely available than injectable water-miscible vitamin A.

A common approach to prevention is to provide vitamin A supplementation every 4–6 months to young children 6 months to 5 years

of age (both HIV-positive and HIV-negative) in high-risk areas.

For prevention, infants 6–11 months of age should receive 30 mg of

vitamin A; children 12–59 months of age should receive 60 mg. For

reasons that are not clear, although early neonatal vitamin A may

reduce infant mortality, vitamin A given between 1 and 5 months

of age has not proven effective in improving survival in high-risk

settings.

Uncomplicated vitamin A deficiency is rare in industrialized

countries. One high-risk group—extremely low-birth-weight (<1000-

g) infants—is likely to be vitamin A deficient and should receive a

supplement of 1500 μg (or RAE) three times a week for 4 weeks.

Severe measles in any society can lead to secondary vitamin A

deficiency. Children hospitalized with measles should receive two

60-mg doses of vitamin A on 2 consecutive days. Vitamin A deficiency most often occurs in patients with malabsorptive diseases

(e.g., celiac sprue, short-bowel syndrome) who have abnormal

dark adaptation or symptoms of night blindness without other

ocular changes. Typically, such patients are diagnosed in advanced

care settings where they are treated for 1 month with 15 mg/d of a

water-miscible preparation of vitamin A. This treatment is followed

by a lower maintenance dose, with the exact amount determined

by monitoring serum retinol. Finding application elsewhere in

medicine, retinoic acid is useful in the treatment of promyelocytic

leukemia (Chap. 104) and also is used in the treatment of cystic

acne because it inhibits keratinization, decreases sebum secretion,

and possibly alters the inflammatory reaction (Chap. 57).

No specific signs or symptoms result from carotenoid deficiency.

It was postulated that β-carotene would be an effective chemopreventive agent for cancer because numerous epidemiologic studies

had shown that diets high in β-carotene were associated with lower

incidences of cancers of the respiratory and digestive systems.

However, intervention studies in smokers found that treatment with

high doses of β-carotene actually resulted in more lung cancers than

did treatment with placebo. Non–provitamin A carotenoids such

as lutein and zeaxanthin have been suggested to confer protection

against macular degeneration, and one large-scale intervention

study did not show a beneficial effect except in those with a low

lutein status. The use of the non–provitamin A carotenoid lycopene

to protect against prostate cancer has been proposed. However, the

effectiveness of these agents has not been proved by intervention

studies, and the mechanisms underlying these purported biologic

actions are unknown.

Selective plant-breeding techniques that lead to a higher provitamin A carotenoid content in staple foods may decrease vitamin

A malnutrition in low-income countries. Moreover, a recently

developed genetically modified food (Golden Rice) had a βcarotene–to–vitamin A conversion ratio of ~3:1 in children.

Toxicity The acute toxicity of vitamin A was first noted in Arctic

explorers who ate polar bear liver and has also been seen after administration of 150 mg to adults or 100 mg to children. Acute toxicity

is manifested by increased intracranial pressure, vertigo, diplopia,

bulging fontanels (in children), seizures, and exfoliative dermatitis; it

may result in death. Among children being treated for vitamin A deficiency according to the protocols outlined above, transient bulging of

fontanels occurs in 2% of infants, and transient nausea, vomiting, and

headache occur in 5% of preschoolers. Chronic vitamin A intoxication

is largely a concern in industrialized countries and has been seen in

otherwise healthy adults who ingest 15 mg/d and children who ingest

6 mg/d over a period of several months. Manifestations include dry

skin, cheilosis, glossitis, vomiting, alopecia, bone demineralization

and pain, hypercalcemia, lymph node enlargement, hyperlipidemia,

amenorrhea, and features of pseudotumor cerebri with increased

intracranial pressure and papilledema. Liver fibrosis with portal

hypertension may also result from chronic vitamin A intoxication.

Provision of vitamin A in excess to pregnant women has resulted in

spontaneous abortion and in congenital malformations, including

craniofacial abnormalities and valvular heart disease. In pregnancy,

the daily dose of vitamin A should not exceed 3 mg. Also, topical

retinoids should be avoided during pregnancy. Commercially available

retinoid derivatives are also toxic, including 13-cis-retinoic acid, which

has been associated with birth defects. Thus, contraception should be

continued for at least 1 year and possibly longer in women who have

taken 13-cis-retinoic acid.

In malnourished children, vitamin A supplements (30–60 mg), in

amounts calculated as a function of age and given in several rounds

over 2 years, are considered to amplify nonspecific effects of vaccines.

However, for unclear reasons, in one African setting, there has been a

negative effect on mortality rates in incompletely vaccinated girls.