2531Vitamin and Trace Mineral Deficiency and Excess CHAPTER 333

High doses of supplemental carotenoids do not result in toxic symptoms but should be avoided in smokers due to an increased risk of lung

cancer. Very high doses of β-carotene (~200 mg/d) have been used to

treat or prevent the skin rashes of erythropoietic protoporphyria. Carotenemia, which is characterized by a yellowing of the skin (in creases

of the palms and soles) but not the sclerae, may follow ingestion of

>30 mg of β-carotene daily. Hypothyroid patients are particularly

susceptible to the development of carotenemia due to impaired breakdown of carotene to vitamin A. Reduction of carotenes in the diet

results in the disappearance of skin yellowing and carotenemia over a

period of 30–60 days.

■ VITAMIN D

The metabolism of the fat-soluble vitamin D is described in detail in

Chap. 409. The biologic effects of this vitamin are mediated by vitamin D receptors, which are found in most tissues; binding with these

receptors potentially expands vitamin D actions to many different

cell systems and organs (e.g., immune cells, brain, breast, colon, and

prostate) in addition to the classic endocrine effects on calcium and

phosphate metabolism and bone health. Vitamin D is thought to be

important for maintaining normal function of many nonskeletal tissues such as muscle (including heart muscle), for immune function,

and for inflammation as well as for cell proliferation and differentiation. Older studies have shown that vitamin D may be useful as

adjunctive treatment for tuberculosis, psoriasis, and multiple sclerosis

or for the prevention of certain cancers. Vitamin D insufficiency may

increase the risk of type 1 diabetes mellitus, cardiovascular disease

(insulin resistance, hypertension, or low-grade inflammation), or brain

dysfunction (e.g., depression). However, the exact physiologic roles of

vitamin D in these nonskeletal diseases and the importance of these

roles have so far not been clarified. Recent placebo-controlled studies

did not show a therapeutic benefit of vitamin D for cancer prevention,

control of cardiovascular disease, or risk of type 2 diabetes, depression,

tuberculosis infection, or other respiratory infections. Presently, it is

not known whether these effects of vitamin D supplements (with or

without calcium) might be different according to the baseline status

(normal vs severely deficient) of patients.

The skin is a major source of vitamin D, which is synthesized upon

skin exposure to ultraviolet B radiation (UV-B; wavelength, 290–320 nm).

Except for fish, food (unless fortified) contains only limited amounts of

vitamin D. Vitamin D2

 (ergocalciferol) is obtained from plant sources

and is the chemical form found in some supplements.

Deficiency Vitamin D status has been assessed by measuring

serum levels of 25-dihydroxyvitamin D (25[OH] vitamin D); however,

there is no consensus on a uniform assay, on optimal serum levels, or

on the real benefit of biochemical screening. The optimal level might,

in fact, differ according to the targeted disease entity. Epidemiologic

and experimental data indicate that a 25(OH) vitamin D level of

>20 ng/mL (≥50 nmol/L; to convert ng/mL to nmol/L, multiply by

2.496) is sufficient for good bone health. The latter 25(OH) vitamin D

plasma concentration would cover the requirements of 97.5% of the

population. Some experts, however, advocate higher serum levels (e.g.,

>30 ng/mL) for other desirable endpoints of vitamin D action. There

is insufficient evidence to recommend combined vitamin D and calcium supplementation as a primary preventive strategy (as opposed

to secondary prevention) for reduction of the incidence of fractures in

healthy men and premenopausal women.

Risk factors for vitamin D deficiency are old age, lack of sun exposure, dark skin (especially among residents of northern latitudes), fat

malabsorption, and obesity; deficiency can also occur after gastric

bypass surgery. In addition, in African populations, the prevalence of

vitamin D deficiency might be high (especially in women, newborn

babies, urban populations, and those living in northern African countries). Rickets represents the classic disease of vitamin D deficiency.

Signs of deficiency are muscle soreness, weakness, and bone pain.

Some of these effects are independent of calcium intake. To prevent

glucocorticoid-induced osteoporosis, treatment with calcium (1000–

1200 mg/d) and vitamin D (600–800 IU/d) through diet and/or supplements in combination with weight-bearing exercise is recommended.

The U.S. National Academy of Sciences recently advised that the

majority of adult North Americans should receive 600 IU/d of vitamin

D (RDA = 15 μg/d or 600 IU/d; Chap. 332). However, for people aged

>70 years, the RDA is set at 20 μg/d (800 IU/d). The consumption

of fortified or enriched foods as well as suberythemal sun exposure

should be encouraged for people at risk for vitamin D deficiency.

If adequate intake is impossible, vitamin D supplements should be

taken, especially during the winter months. Vitamin D deficiency can

be treated by oral administration of 50,000 IU/week for 6–8 weeks

followed by a maintenance dose of 800 IU/d (20 μg/d) from food and

supplements once normal plasma levels have been attained. There is

still uncertainty regarding the optimal therapeutic dosage (high vs low)

for elderly at risk of falls. The physiologic effects of vitamin D2

 and

vitamin D3

 are similar when these vitamins are ingested over long

periods.

Toxicity The upper limit of intake has been set at 4000 IU/d. Contrary to earlier beliefs, acute vitamin D intoxication is rare and usually

is caused by the uncontrolled and excessive ingestion of supplements or

by faulty food fortification practices. High plasma levels of 1,25(OH)2

vitamin D and calcium are central features of toxicity and mandate

discontinuation of vitamin D and calcium supplements; in addition,

treatment of hypercalcemia may be required.

■ VITAMIN E

Vitamin E is the collective designation for all stereoisomers of tocopherols and tocotrienols, although only the α-tocopherols meet human

requirements. Vitamin E acts as a chain-breaking antioxidant and

is an efficient peroxyl radical scavenger that protects low-density

lipoproteins and polyunsaturated fats in membranes from oxidation.

A network of other antioxidants (e.g., vitamin C, glutathione) and

enzymes maintains vitamin E in a reduced state. Vitamin E also inhibits prostaglandin synthesis and the activities of protein kinase C and

phospholipase A2

.

Absorption and Metabolism After absorption, vitamin E is

taken up from chylomicrons by the liver, and a hepatic α-tocopherol

transport protein mediates intracellular vitamin E transport and incorporation into very-low-density lipoprotein. The transport protein has

a particular affinity for the RRR isomeric form of α-tocopherol; thus,

this natural isomer has the most biologic activity.

Requirement Vitamin E is widely distributed in the food supply,

with particularly high levels in sunflower oil, safflower oil, and wheat

germ oil; γ-tocotrienols are notably present in soybean and corn oils.

Vitamin E is also found in meats, nuts, and cereal grains, and small

amounts are present in fruits and vegetables. Vitamin E pills containing

doses of 50–1000 mg are ingested by ~10% of the U.S. population. The

RDA for vitamin E is 15 mg/d (34.9 μmol or 22.5 IU) for all adults.

Diets high in polyunsaturated fats may necessitate a slightly higher

intake of vitamin E.

Dietary deficiency of vitamin E does not exist in developed countries but can occur in developing countries due to inadequate intake.

Vitamin E deficiency is seen only in severe and prolonged malabsorptive diseases, such as celiac disease, chronic cholestatic liver disease,

or after small-intestinal resection or bariatric surgery. Children with

cystic fibrosis or prolonged cholestasis may develop vitamin E deficiency characterized by areflexia and hemolytic anemia. Children

with abetalipoproteinemia cannot absorb or transport vitamin E and

become deficient quite rapidly. A familial form of isolated vitamin E

deficiency also exists; it is due to a defect in the α-tocopherol transport

protein. Vitamin E deficiency causes axonal degeneration of the large

myelinated axons and results in posterior column and spinocerebellar

symptoms. Peripheral neuropathy is initially characterized by areflexia,

with progression to an ataxic gait, and by decreased vibration and position sensations. Ophthalmoplegia, skeletal myopathy, and pigmented

retinopathy may also be features of vitamin E deficiency. A deficiency

of either vitamin E or selenium in the host has been shown to increase

certain viral mutations and, therefore, virulence. The laboratory diagnosis of vitamin E deficiency is based on low blood levels of α-tocopherol (<5 μg/mL, or <0.8 mg of α-tocopherol per gram of total lipids).

2532 PART 10 Disorders of the Gastrointestinal System

TREATMENT

Vitamin E Deficiency

Symptomatic vitamin E deficiency should be treated with 800–1200

mg of α-tocopherol per day. Patients with abetalipoproteinemia

may need as much as 5000–7000 mg/d. Children with symptomatic

vitamin E deficiency should be treated orally with water-miscible

esters (400 mg/d); alternatively, 2 mg/kg per d may be administered

intramuscularly. Vitamin E in high doses may protect against oxygen-induced retrolental fibroplasia and bronchopulmonary dysplasia as well as intraventricular hemorrhage of prematurity. Vitamin

E has been suggested to increase sexual performance, treat intermittent claudication, and slow the aging process, but convincing

evidence for these properties is lacking. When given in combination with other antioxidants, vitamin E may help prevent macular

degeneration. Vitamin E may have favorable therapeutic effects in

noncirrhotic nondiabetic patients with nonalcoholic steatohepatitis. High doses (60–800 mg/d) of vitamin E have been shown in

controlled trials to improve parameters of immune function and

reduce colds in nursing home residents, but intervention studies

using vitamin E to prevent cardiovascular disease or cancer have

not shown efficacy, and at doses >400 mg/d, vitamin E may even

increase all-cause mortality rates and prostate cancer risk (especially in combination with selenium supplements).

Toxicity All forms of vitamin E are absorbed and could contribute

to toxicity; however, the toxicity risk seems to be rather low as long as

liver function is normal. High doses of vitamin E (>800 mg/d) may

reduce platelet aggregation and interfere with vitamin K metabolism

and are therefore contraindicated in patients taking warfarin and antiplatelet agents (such as aspirin or clopidogrel). Nausea, flatulence, and

diarrhea have been reported at doses >1 g/d.

■ VITAMIN K

There are two natural forms of vitamin K: vitamin K1

, also known as

phylloquinone, from vegetable sources, and vitamin K2

, or menaquinones, which are synthesized by bacterial flora and found in hepatic tissue. Phylloquinone can be converted to menaquinone in some organs.

Vitamin K is required for the posttranslational carboxylation of glutamic acid, which is necessary for calcium binding to γ-carboxylated

proteins such as prothrombin (factor II); factors VII, IX, and X; protein

C; protein S; and proteins found in bone (osteocalcin) and vascular

smooth muscle (e.g., matrix Gla protein). However, the importance of

vitamin K for bone mineralization and prevention of vascular calcification is not known. Warfarin-type drugs inhibit γ-carboxylation by preventing the conversion of vitamin K to its active hydroquinone form.

Dietary Sources Vitamin K is found in green leafy vegetables such

as kale and spinach, and appreciable amounts are also present in margarine and liver. Vitamin K is present in vegetable oils; olive, canola,

and soybean oils are particularly rich sources. The average daily intake

by Americans is estimated to be ~100 μg/d.

Deficiency The symptoms of vitamin K deficiency are due to hemorrhage; newborns are particularly susceptible because of low fat stores,

low breast milk levels of vitamin K, relative sterility of the infantile

intestinal tract, liver immaturity, and poor placental transport. Intracranial bleeding as well as gastrointestinal and skin bleeding can occur

in vitamin K–deficient infants 1–7 days after birth. Thus, vitamin K

(0.5–1 mg IM) is given prophylactically at delivery.

Vitamin K deficiency in adults may be seen in patients with

chronic small-intestinal disease (e.g., celiac disease, Crohn’s disease),

in those with obstructed biliary tracts, or after small-bowel resection. Broad-spectrum antibiotic treatment can precipitate vitamin

K deficiency by reducing numbers of gut bacteria, which synthesize

menaquinones, and by inhibiting the metabolism of vitamin K.

In patients with warfarin therapy, the antiobesity drug orlistat can

lead to changes in international normalized ratio due to vitamin K

malabsorption. The assessment of the vitamin K status can be done by

measurement of phylloquinone (vitamin K1

) concentration in serum

(deficiency <0.15 μg/L); the cellular utilization of vitamin K can be

assessed by the serum or plasma concentration of undercarboxylated

prothrombin (protein induced by vitamin K absence/antagonism

[PIVKA-II]). An elevated prothrombin time or activated partial

thromboplastin time or reduced clotting factors are useful markers in

severe deficiency but are otherwise nonspecific and lack sensitivity.

Vitamin K deficiency is treated with a parenteral dose of 10 mg. For

patients with chronic malabsorption, 1–2 mg/d should be given orally

or 1–2 mg per week can be taken parenterally. Patients with liver

disease may have an elevated prothrombin time because of liver cell

destruction as well as vitamin K deficiency. If an elevated prothrombin

time does not improve during vitamin K therapy, it can be deduced that

this abnormality is not the result of vitamin K deficiency.

Toxicity Toxicity from dietary phylloquinones and menaquinones

has not been described. High doses of vitamin K can impair the actions

of oral vitamin K antagonist anticoagulants.

MINERALS

See also Table 333-2.

■ CALCIUM

See Chap. 409.

■ ZINC

Zinc is an integral component of many metalloenzymes in the body;

it is involved in the synthesis and stabilization of proteins, DNA, and

RNA and plays a structural role in ribosomes and membranes. Zinc

is necessary for the binding of steroid hormone receptors and several

other transcription factors to DNA. Zinc is essential for normal spermatogenesis, fetal growth, and embryonic development.

Absorption The absorption of zinc from the diet is inhibited by

dietary phytate, fiber, oxalate, iron, and copper as well as by certain

drugs, including penicillamine, sodium valproate, and ethambutol.

Protein-containing foods, i.e., meat, shellfish, nuts, and legumes, are

good sources of bioavailable zinc, whereas zinc in grains and legumes

is less available for absorption. Grains and legumes contain phytate that

binds zinc in the intestine and reduces its availability for absorption.

Deficiency Mild zinc deficiency has been described in many diseases, including diabetes mellitus, HIV/AIDS, cirrhosis, alcoholism,

inflammatory bowel disease, malabsorption syndromes, and sickle

cell disease. In these diseases, mild chronic zinc deficiency can cause

stunted growth in children, decreased taste sensation (hypogeusia), and

impaired immune function. Severe chronic zinc deficiency has been

described as a cause of hypogonadism and dwarfism in several Middle

Eastern countries. In these children, hypopigmented hair is also part

of the syndrome. Acrodermatitis enteropathica is a rare autosomal

recessive disorder characterized by abnormalities in zinc absorption.

Clinical manifestations include diarrhea, alopecia, muscle wasting,

depression, irritability, and a rash involving the extremities, face, and

perineum. The rash is characterized by vesicular and pustular crusting

with scaling and erythema. Occasional patients with Wilson’s disease

have developed zinc deficiency as a consequence of penicillamine

therapy (Chap. 415).

Zinc deficiency is prevalent in many developing countries and usually coexists with other micronutrient deficiencies (especially iron deficiency). Zinc (20 mg/d until recovery) may be an effective adjunctive

therapeutic strategy for diarrheal disease and pneumonia in children

≥6 months of age.

The diagnosis of zinc deficiency is usually based on a serum zinc

level <12 μmol/L (<70 μg/dL). Pregnancy and birth control pills may

cause a slight depression in serum zinc levels, and hypoalbuminemia

from any cause can result in hypozincemia. In acute stress situations

(illness, but also postexercise recovery), zinc may be redistributed

from serum into tissues. Zinc deficiency may be treated with 60 mg

of elemental zinc taken by mouth twice a day. Zinc gluconate lozenges

(13 mg of elemental zinc every 2 h while awake) have been reported to

2533Vitamin and Trace Mineral Deficiency and Excess CHAPTER 333

reduce the duration and symptoms of the common cold in adults, but

study results are conflicting.

Toxicity Acute zinc toxicity after oral ingestion causes nausea,

vomiting, and fever. Zinc fumes from welding may also be toxic and

cause fever, respiratory distress, excessive salivation, sweating, and

headache. Chronic large doses of zinc (ranging from 150 to 450 mg/d)

may depress immune function and cause hypochromic anemia as a

result of a secondary copper deficiency. Intranasal zinc preparations

should be avoided because they may lead to irreversible damage of the

nasal mucosa and anosmia.

■ COPPER

Copper is an integral part of numerous enzyme systems, including

amine oxidases, ferroxidase (ceruloplasmin), cytochrome c oxidase,

superoxide dismutase, and dopamine hydroxylase. Copper is also a

component of ferroprotein, a transport protein involved in the basolateral transfer of iron during absorption from the enterocyte. As such,

copper plays a role in iron metabolism, melanin synthesis, energy

production, neurotransmitter synthesis, and CNS function; the synthesis and cross-linking of elastin and collagen; and the scavenging of

superoxide radicals. Dietary sources of copper include shellfish, liver,

nuts, legumes, bran, and organ meats.

Deficiency Dietary copper deficiency is relatively rare, although

it has been described in premature infants who are fed milk diets

and in infants with malabsorption (Table 333-2). Copper-deficiency

anemia (refractory to therapeutic iron) has been reported in patients

with malabsorptive diseases and nephrotic syndrome and in patients

treated for Wilson’s disease with chronic high doses of oral zinc, which

can interfere with copper absorption. Menkes kinky hair syndrome is an

X-linked metabolic disturbance of copper metabolism characterized

by intellectual disability, hypocupremia, and decreased circulating

ceruloplasmin (Chap. 413). This syndrome is caused by mutations in

the copper-transporting ATP7A gene. Children with this disease often

die within 5 years because of dissecting aneurysms or cardiac rupture.

Aceruloplasminemia is a rare autosomal recessive disease characterized by tissue iron overload, mental deterioration, microcytic anemia,

and low serum iron and copper concentrations.

The diagnosis of copper deficiency is usually based on low serum

levels of copper (<65 μg/dL) and low ceruloplasmin levels (<20 mg/

dL). Serum levels of copper may be elevated in pregnancy or stress conditions since ceruloplasmin is an acute-phase reactant and 90% of circulating copper is bound to ceruloplasmin. It has been suggested that

mild or subclinical copper deficiency is more common than expected;

at-risk individuals include patients with cholestasis or chronic diarrheal diseases, dialysis patients, and people on long-term zinc supplements. The role of copper in cardiovascular disease, immune function,

bone health, or neurodegenerative diseases is still unclear.

Toxicity Copper toxicity is usually accidental (Table 333-2). In severe

cases, kidney failure, liver failure, and coma may ensue. In Wilson’s

disease, mutations in the copper-transporting ATP7B gene lead to

accumulation of copper in the liver and brain, with low blood levels

due to decreased ceruloplasmin (Chap. 415). A potential negative role

of copper in the pathogenesis of Alzheimer’s disease has been reported.

■ SELENIUM

Selenium, in the form of selenocysteine, is a component of the enzyme

glutathione peroxidase, which serves to protect proteins, cell membranes, lipids, and nucleic acids from oxidant molecules. As such,

selenium is being actively studied as a chemopreventive agent against

TABLE 333-2 Deficiencies and Toxicities of Metals

ELEMENT DEFICIENCY TOXICITY

TOLERABLE UPPER (DIETARY) INTAKE

LEVEL

Boron No biologic function determined Developmental defects, male sterility, testicular atrophy 20 mg/d (extrapolated from animal data)

Calcium Reduced bone mass, osteoporosis Renal insufficiency (milk-alkali syndrome),

nephrolithiasis, impaired iron absorption,

thiazide diuretics

2500 mg/d (milk-alkali)

Copper Anemia, growth retardation, defective

keratinization and pigmentation of hair,

hypothermia, degenerative changes in aortic

elastin, osteopenia, intellectual disability

Nausea, vomiting, diarrhea, hepatic failure, tremor,

psychiatric disturbances, hemolytic anemia, renal

dysfunction

10 mg/d (liver toxicity)

Chromium Impaired glucose tolerance Occupational: Renal failure, dermatitis, pulmonary

cancer

Not determined

Fluoride ↑ Dental caries Dental and skeletal fluorosis, osteosclerosis 10 mg/d (fluorosis)

Iodine Thyroid enlargement, ↓ T4

, cretinism Thyroid dysfunction, acne-like eruptions 1100 μg/d (thyroid dysfunction)

Iron Muscle abnormalities, koilonychia, pica,

anemia, ↓ work performance, impaired

cognitive development, premature labor,

↑ perinatal maternal death

Gastrointestinal effects (nausea, vomiting, diarrhea,

constipation), iron overload with organ damage, acute

and chronic systemic toxicity, increased susceptibility to

malaria, increased risk association with certain chronic

diseases (e.g., diabetes)

45 mg/d of elemental iron

(gastrointestinal side effects)

Manganese Impaired growth and skeletal development,

reproduction, lipid and carbohydrate

metabolism; upper body rash

General: Neurotoxicity, Parkinson-like symptoms

Occupational: Encephalitis-like syndrome, Parkinsonlike syndrome, psychosis, pneumoconiosis

11 mg/d (neurotoxicity)

Molybdenum Severe neurologic abnormalities Reproductive and fetal abnormalities 2 mg/d (extrapolated from animal data)

Selenium Cardiomyopathy, heart failure, striated muscle

degeneration

General: Alopecia, nausea, vomiting, abnormal nails,

emotional lability, peripheral neuropathy, lassitude,

garlic odor to breath, dermatitis

Occupational: Lung and nasal carcinomas, liver

necrosis, pulmonary inflammation

400 μg/d (hair, nail changes)

Phosphorus Rickets (osteomalacia), proximal muscle

weakness, rhabdomyolysis, paresthesia,

ataxia, seizure, confusion, heart failure,

hemolysis, acidosis

Hyperphosphatemia 4000 mg/d

Zinc Growth retardation, ↓ taste and smell,

alopecia, dermatitis, diarrhea, immune

dysfunction, failure to thrive, gonadal atrophy,

congenital malformations

General: Reduced copper absorption, gastritis,

sweating, fever, nausea, vomiting

Occupational: Respiratory distress, pulmonary fibrosis

40 mg/d (impaired copper metabolism)

2534 PART 10 Disorders of the Gastrointestinal System

certain cancers, such as prostate cancer. However, it remains unclear

whether selenium is effective as a chemopreventive agent or whether

it increases cancer risk (e.g., prostate cancer). Convincing evidence for

a protective effect of selenium on cognitive decline or cardiovascular

disease risk is presently lacking. Selenocysteine is also found in the

deiodinase enzymes, which mediate the deiodination of thyroxine to

triiodothyronine (Chap. 382). Rich dietary sources of selenium include

seafood, muscle meat, and cereals, although the selenium content of

cereal is determined by the soil concentration. Countries with low soil

concentrations include parts of Scandinavia, China, and New Zealand.

Keshan disease is an endemic cardiomyopathy found in children and

young women residing in regions of China where dietary intake of

selenium is low (<20 μg/d). Concomitant deficiencies of iodine and

selenium may worsen the clinical manifestations of cretinism. Chronic

ingestion of large amounts of selenium leads to selenosis, characterized by hair and nail brittleness and loss, garlic breath odor, skin rash,

myopathy, irritability, and other abnormalities of the nervous system.

■ CHROMIUM

Chromium potentiates the action of insulin in patients with impaired

glucose tolerance, presumably by increasing insulin receptor–mediated signaling, although its usefulness in treating type 2 diabetes is

uncertain. In addition, improvement in blood lipid profiles has been

reported in some patients. The usefulness of chromium supplements

in muscle building has not been substantiated. Rich food sources of

chromium include yeast, meat, and grain products. Chromium in the

trivalent state is found in supplements and is largely nontoxic; however,

chromium-6 is a product of stainless steel welding and is a known pulmonary carcinogen as well as a cause of liver, kidney, and CNS damage.

■ MAGNESIUM

See Chap. 409.

■ FLUORIDE, MANGANESE, AND

ULTRATRACE ELEMENTS

An essential function for fluoride in humans has not been described,

although it is useful for the maintenance of structure in teeth and

bones. Adult fluorosis results in mottled and pitted defects in tooth

enamel as well as brittle bone (skeletal fluorosis).

Manganese and molybdenum deficiencies have been reported in

patients with rare genetic abnormalities and in a few patients receiving prolonged total parenteral nutrition. Several manganese-specific

enzymes have been identified (e.g., manganese superoxide dismutase).

Deficiencies of manganese have been reported to result in bone demineralization, poor growth, ataxia, disturbances in carbohydrate and lipid

metabolism, and convulsions.

Ultratrace elements are defined as those needed in amounts

<1 mg/d. Essentiality has not been established for most ultratrace elements, although selenium, chromium, and iodine are clearly essential

(Chap. 382). Molybdenum is necessary for the activity of sulfite and

xanthine oxidase, and molybdenum deficiency may result in skeletal

and brain lesions.

■ FURTHER READING

Combs GF Jr, Mcclung JP: The Vitamins: Fundamental Aspects in

Nutrition and Health. 5th ed. London, Academic Press, 2017, p 612.

Imdad A et al: Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age.

Cochrane Database Syst Rev 3:CD008524, 2017.

Lassi ZS et al: Zinc supplementation for the promotion of growth

and prevention of infections in infants less than six months of age.

Cochrane Database Syst Rev 4:CD010205, 2020.

Mechanick JI et al: Clinical practice guidelines for the perioperative

nutrition, metabolic, and nonsurgical support of patients undergoing

bariatric procedures–2019 update. Surg Obes Relat Dis 16:175, 2020.

Namaste SM et al: Methodologic approach for the Biomarkers

Reflecting Inflammation and Nutritional Determinants of Anemia

(BRINDA) project. Am J Clin Nutr 106(Suppl 1):333S, 2017.

Ngo B et al: Targeting cancer vulnerabilities with high-dose vitamin C.

Nat Rev Cancer 19:271, 2020.

Ota Y et al: Comprehensive review of Wernicke encephalopathy:

Pathophysiology, clinical symptoms and imaging findings. Jpn J

Radiol 38:809, 2020.

Stevens GA et al: Trends and mortality effects of vitamin A deficiency

in children in 138 low-income and middle-income countries between

1991 and 2013: A pooled analysis of population-based surveys.

Lancet Glob Health 3:e528, 2015.

Tanumihardjo SA et al: Biomarkers of nutrition for development

(BOND): Vitamin A review. J Nutr 146:1816S, 2016.

Vinceti M, Rothman KJ: More results but no clear conclusion on

selenium and cancer. Am J Clin Nutr 104:245, 2016.

World Health Organization: Guideline: Vitamin A supplementation in pregnant women. Geneva, World Health Organization, 2011.

Malnutrition occurs in 30–50% of hospitalized patients depending on

the setting and criteria that are used. Poor wound healing, compromised immune status, impaired organ function, increased length of

hospital stay, and increased mortality are among the notable adverse

outcomes associated with malnutrition. It is now widely appreciated

that acute or chronic inflammation contribute to the pathophysiology

of disease-related or injury-related malnutrition. The presence of

inflammation can also render historic nutrition assessment indicators,

like albumin and prealbumin, unreliable, and inflammation diminishes

favorable responses to nutrition therapies. In order to guide appropriate care, it is necessary to properly assess and diagnose malnutrition.

Nutrition assessment is a comprehensive evaluation to diagnose a malnutrition syndrome and to guide intervention and expected outcomes.

Patients are often targeted for assessment after being identified at nutritional risk based on screening procedures conducted by nursing or

nutrition personnel within 24 h of hospital admission. Screening tends

to focus explicitly on a few risk variables like weight loss, compromised

dietary intake, and high-risk medical/surgical diagnoses. Preferably,

health professionals complement this screening with a systematic

approach to comprehensive nutrition assessment that incorporates an

appreciation for the contributions of inflammation that serve as the

basis for new approaches to the diagnosis and management of malnutrition syndromes.

■ MALNUTRITION SYNDROMES

Famine and starvation have long been leading causes of malnutrition

and remain so in developing countries. However, with improvements

in agriculture, education, public health, health care, and living standards, malnutrition in the settings of disease, surgery, and injury has

become a prevalent concern throughout the world. Malnutrition now

encompasses the full continuum of undernutrition and overnutrition

(obesity). For the objectives of this chapter, we will focus upon the former. Historic definitions for malnutrition syndromes are problematic

in their use of diagnostic criteria that suffer poor sensitivity, sensitivity,

and interobserver reliability. Definitions overlap, and confusion and

misdiagnosis are frequent. In addition, some approaches do not recognize undernutrition in obese persons. While the historic syndromes

of marasmus, kwashiorkor, and protein-calorie malnutrition remain in

use, this chapter will instead highlight evolving insights to the diagnosis of malnutrition syndromes.

The Subjective Global Assessment, a comprehensive nutrition

assessment that included a metabolic stress of disease component,

was described and validated in the 1980s. In 2010, an International

Consensus Guideline Committee incorporated a new appreciation for

334 Malnutrition and

Nutritional Assessment

Gordon L. Jensen

2535 Malnutrition and Nutritional Assessment CHAPTER 334

the role of inflammatory response into their proposed nomenclature

for nutrition diagnosis in adults in the clinical practice setting. Starvation-associated malnutrition is when there is chronic starvation without

inflammation, chronic disease–associated malnutrition is when inflammation is chronic and of mild to moderate degree, and acute disease– or

injury-associated malnutrition is when inflammation is acute and of

severe degree (see Table 334-1 for examples). In 2012, the Academy

of Nutrition and Dietetics and the American Society for Parenteral

and Enteral Nutrition (ASPEN) extended this approach using clinical

characteristics to support diagnosis, including the presence of illness

or injury, poor food intake, weight loss, and physical findings of fat

loss, muscle loss, edema, or reduced grip strength. In 2016, the European Society for Parenteral and Enteral Nutrition (ESPEN) formally

adopted a disease/inflammation-based construct similar to these

earlier approaches. Also in 2016, the Global Leadership Initiative on

Malnutrition (GLIM), a collaborative effort of ASPEN, ESPEN, the

TABLE 334-1 History and Physical Examination Elements

ELEMENT NOTES

Historical Data

Body weight Ask about usual weight, peak weight, and deliberate weight loss. A 4.5-kg (10-lb) weight loss over 6 months is noteworthy, and a weight loss

of >10% of usual body weight is prognostic of clinical outcomes. Use medical records, family, and caregivers as information resources.

Medical and surgical

conditions; chronic

disease

Look for medical or surgical conditions or chronic disease that can place one at nutritional risk secondary to increased requirements or

compromised intake or assimilation such as: critical illness, severe burns, major abdominal surgery, multitrauma, closed head injury, previous

gastrointestinal surgery, severe gastrointestinal hemorrhage, enterocutaneous fistula, gastrointestinal obstruction, mesenteric ischemia,

severe acute pancreatitis, chronic pancreatitis, inflammatory bowel disease, celiac disease, bacterial overgrowth, solid or hematologic

malignancy, bone marrow transplant, acquired immune deficiency syndrome, and organ failure/transplant—kidney, liver, heart, lung, or gut.

A number of conditions or diseases are characterized by severe acute inflammatory response including critical illness, major infection/sepsis,

adult respiratory distress syndrome, systemic inflammatory response syndrome, severe burns, major abdominal surgery, multitrauma, and

closed head injury.

Many conditions or diseases are more typically associated with mild to moderate chronic inflammatory response. Examples include

cardiovascular disease, congestive heart failure, cystic fibrosis, inflammatory bowel disease, celiac disease, chronic pancreatitis,

rheumatoid arthritis, solid tumors, hematologic malignancies, sarcopenic obesity, diabetes mellitus, metabolic syndrome, cerebrovascular

accident, neuromuscular disease, dementia, organ failure/transplant (kidney, liver, heart, lung, or gut), periodontal disease, pressure wounds,

and chronic obstructive pulmonary disease. Note that acute exacerbations, infections, or other complications may superimpose acute

inflammatory response on such conditions or diseases.

Examples of starvation-associated conditions that generally have little or no discernable inflammatory component include anorexia nervosa

or compromised intake in the setting of major depression.

Constitutional signs/

symptoms

Fever or hypothermia can indicate active inflammatory response. Tachycardia is also common. Anorexia is another manifestation of

inflammatory response and is also often a side effect of treatments and medications.

Eating difficulties/

gastrointestinal

complaints

Poor dentition or problems swallowing can compromise oral intake. Vomiting, nausea, abdominal pain, abdominal distension, diarrhea,

constipation, and gastrointestinal bleeding can be signs of gastrointestinal pathology that may place one at nutritional risk.

Eating disorders Look for distorted body image, compulsive exercise, amenorrhea, vomiting, tooth loss, dental caries, and use of laxatives, diuretics, or Ipecac.

Medication use Many medications can adversely affect nutrient intake or assimilation. Review potential drug–drug and drug–nutrient interactions.

A pharmacist consultant can be helpful.

Dietary practices and

supplement use

Look for dietary practices including therapeutic, weight reduction, vegetarian, macrobiotic, and fad diets. Also record use of dietary

supplements, including vitamins, minerals, and herbals. Ask about dietary intake. Recall, record, and food frequency tools are available.

It is estimated that 50% or more of adults take dietary supplements.

Influences on

nutritional status

Ask about factors such as living environment, functional status (activities of daily living and instrumental activities of daily living),

dependency, caregiver status, resources, dentition, alcohol or substance abuse, mental health (depression or dementia), and lifestyle.

Physical Examination Data

Body mass index (BMI) BMI = weight in kg/(height in meters)2

BMI <18.5 kg/m2

 proposed screen for malnutrition per National Institutes of Health guidelines. BMI ≤15 kg/m2

 or less is associated with

increased mortality.

Comparison with ideal body weight for stature can also be determined from reference tables. Note hydration status and edema at the time

body weight is determined.

Weight loss Look for loss of muscle mass and subcutaneous fat.

Temporal and neck muscle wasting may be readily observed. Anthropometrics including skinfolds and circumferences can be useful but

require training to achieve reliability.

Weakness/loss of

strength

Decreased handgrip and leg extensor strength have been related to loss of muscle mass in malnourished states. Lower extremity weakness

may be observed in thiamine deficiency.

Peripheral edema Peripheral edema may confound weight measurements and is often observed with reduced visceral proteins as well as inflammatory states.

Edema may also be observed with thiamine deficiency.

Hair examination Hair findings are indicative of certain nutrient deficiencies.

Loss: protein, vitamin B12, folate

Brittle: biotin

Color change: zinc

Dry: vitamins A and E

Easy pluckability: protein, biotin, zinc

Coiled, corkscrew: vitamins A and C

Alopecia is common in severely malnourished persons.

Ask about excessive hair loss on pillow or when combing hair.

(Continued)

2536 PART 10 Disorders of the Gastrointestinal System

TABLE 334-1 History and Physical Examination Elements

ELEMENT NOTES

Skin examination Skin findings are indicative of certain nutrient deficiencies.

Desquamation: riboflavin

Petechiae: vitamins A and C

Perifollicular hemorrhage: vitamin C

Ecchymosis: vitamins C and K

Xerosis, bran-like desquamation: essential fatty acid

Pigmentation, cracking, crusting: niacin

Acneiform lesions, follicular keratosis, xerosis: vitamin A

Acro-orificial dermatitis, erythematous, vesiculobullous, and pustular: zinc

Characteristic nutritional dermatitis and skin findings may be observed with a number of nutrient deficiencies. Wounds and pressure sores

should also be noted as indicators of compromised nutritional status.

Eye examination Ocular findings are indicative of certain nutrient deficiencies.

Bitot’s spots: vitamin A

Xerosis: vitamin A

Angular palpebritis: riboflavin

Also ask about difficulties with night vision/night blindness; indicates vitamin A deficiency.

Perioral examination Perioral findings are indicative of certain nutrient deficiencies.

Angular stomatitis and cheilosis: B complex, iron, protein

Glossitis: niacin, folate, vitamin B12

Magenta tongue: riboflavin

Bleeding gums, gingivitis, tooth loss: vitamin C

Angular stomatitis, cheilosis, and glossitis are associated with vitamin and mineral deficiencies. Note poor dentition, caries, and tooth loss.

Difficulty swallowing and impairment of gag should also be recognized.

Extremity examination Extremity findings indicate certain nutrient deficiencies

Arthralgia: vitamin C

Calf pain: thiamine

Extremities may also exhibit loss of muscle mass and/or peripheral edema. Neurologic findings in the extremities may also result from

deficiencies described below.

Mental status/nervous

system examination

Mental and nervous system findings indicate certain nutrient deficiencies.

Ophthalmoplegia and foot drop: thiamine

Paresthesia: thiamine, vitamin B12, biotin

Depressed vibratory and position senses: vitamin B12

Anxiety, depression, and hallucinations: niacin

Memory disturbance: vitamin B12

Hyporeflexia, loss of lower extremity deep tendon reflexes: thiamine, vitamin B12

Conduct formal cognitive and depression assessments as appropriate. Dementia and depression are common causes of malnutrition among

older persons. Wernicke-Korsakoff syndrome may be observed with severe thiamine deficiency.

Functional assessment Observe and test physical performance as indicated: gait, chair stands, stair steps, and balance. These provide complex measures of

integrated neurologic status, coordination, and strength.

Source: Reproduced with permission from GL Jensen: Nutritional Syndromes, In: Korenstein, D (Ed). ACP Smart Medicine [publisher archive]. Philadelphia (PA): American

College of Physicians, 2013.

(Continued)

Latin American Federation of Parenteral and Enteral Nutrition, the

Parenteral and Enteral Society of Asia, and other nutrition societies,

embarked on an effort to build global consensus around commonly

used evidence-based criteria for diagnosis of malnutrition in adults in

clinical settings. Weight loss, low body mass index, and reduced muscle

mass were selected as phenotypic criteria, whereas reduced food intake

and disease burden/inflammation were selected as etiologic criteria.

One phenotypic criterion and one etiologic criterion were deemed necessary for the preliminary diagnosis of malnutrition. Where available,

this diagnosis should trigger comprehensive nutrition assessment by

a skilled nutrition professional. However, the primary objective is to

offer a simple approach that can be readily used in global settings with

limited clinical nutrition resources. Recent studies suggest that these

newer approaches to diagnosis of malnutrition have similar utility in

predicting adverse outcomes. This is not surprising since they share

a number of common criteria including a metabolic stress of disease

component that is a proxy indicator of inflammation. Irrespective of

the approach that is selected, assessment of patients can be facilitated

using the indicators of malnutrition and inflammation described

below.

■ NUTRITION ASSESSMENT

There is unfortunately no single clinical or laboratory indicator of comprehensive nutritional status. Assessment therefore requires systematic

integration of data from a variety of sources. Micronutrient deficiencies

of clinical relevance may be detected in association with any of the

malnutrition syndromes, but a detailed discussion of their assessment

is beyond the scope of this chapter (see Chap. 333). Physical findings

characteristic of micronutrient deficiencies are, however, summarized

in Table 334-1.

Medical/Surgical History and Clinical Diagnosis Knowledge

of a patient’s medical/surgical history and associated clinical diagnoses

is especially helpful in discerning the likelihood of malnutrition and

inflammation. Nonvolitional weight loss is a well-validated nutrition

assessment indicator and is often also associated with underlying disease or inflammatory condition. The degree and duration of weight

loss determine its clinical significance. A 10% loss of body weight over

6 months is of clinical relevance, whereas a 30% loss of body weight

over the same duration is severe and life-threatening. Since weight loss

history is often unavailable or unreliable, one should query the patient

2537 Malnutrition and Nutritional Assessment CHAPTER 334

as well as the medical records, family, and caregivers as appropriate to

secure a valid weight trajectory.

A number of conditions or diseases are characterized by severe acute

inflammatory response, whereas others are more typically associated

with a chronic inflammatory response that is mild to moderate in

severity and may be relapsing and remitting (Table 334-1). It is also

common for acute inflammatory events to be superimposed on those

with chronic conditions; for example, a patient with chronic renal disease is admitted to the hospital with sepsis. The inflammatory milieu,

especially when severe, may modify nutrient requirements by elevating

resting energy expenditure and promoting muscle catabolism and

nitrogen losses. Inflammation also promotes anorexia, decreasing food

intake and further compromising nutritional status. A deteriorating

course may result because the presence of inflammation may reduce

the benefit of nutritional interventions and the associated malnutrition

may in turn diminish the effectiveness of medical therapies. It is also

imperative to recognize medical/surgical conditions or diseases that

place patients at increased risk to become malnourished because they

have increased nutritional requirements or compromised intake or

assimilation (Table 334-1).

Nutrition assessment should also include a review of medications

with attention to undesirable side effects including anorexia, xerostomia, nausea, diarrhea, and constipation. Potential drug–nutrient

interactions should also be identified.

Clinical Signs and Physical Examination Nonspecific clinical

indicators of inflammation include fever, hypothermia, and tachycardia. The nutrition-focused physical examination should identify edema

as well as signs of weight gain/loss and specific nutrient deficiencies.

Thorough examination should be particularly directed to those parts

of the body where high cell turnover occurs (e.g., hair, skin, mouth,

tongue) as they are most likely to exhibit observable signs of nutritional

deficiencies (Table 334-1). Physical findings of weight loss associated

with decreased muscle and subcutaneous fat mass should not be overlooked, but when appreciable edema is present, these changes may not

be readily appreciated.

Anthropometric Data Body weight measurements are recommended with each clinic visit or hospitalization so that a reliable weight

change trajectory may be monitored. Patients should be weighed in a

consistent manner without overgarments or shoes. In order to secure

valid measurements, calibration of scales and appropriate staff training

are essential. Chair or bed scales may be used for those who cannot

stand. For those who are able, height should be measured in a standing

position, without shoes, using a stadiometer. If an adult cannot safely

stand, height can be estimated by doubling the arm span measurement

(from the patient’s sternal notch to the end of the longest finger). Stature of frail older persons can also be estimated from measurement of

knee height using a caliper device.

Body weight is often standardized for height to obtain an ideal

weight for comparison, but available reference tables require subjective

assessment of frame size and offer limited reference data for many relevant population groups, including older persons. A simple measure of

body size and an indirect measure of body fatness is provided by body

mass index (BMI), defined as weight (kg)/height (m2

). The National

Institutes of Health BMI categories for adults are as follows: BMI

<18.5 = underweight, BMI 18.5–24.9 = desirable, BMI 25.0–29.9 =

overweight, and BMI ≥30 = obese. Note that being overweight or

obese does not mean that one cannot be severely malnourished due

to inadequate nutrition intake or assimilation. Underweight status

is not required for the diagnosis of malnutrition. While classical

anthropometric measurements including skinfolds and circumferences

can be helpful, their utility in routine patient care has been limited

because practitioner training is required to achieve suitable reliability.

Body composition assessment methodologies include bioelectrical

impedance analysis (BIA), dual-energy x-ray absorptiometry (DEXA),

computed tomography (CT), and magnetic resonance imaging (MRI).

The imaging modalities have become the state of the art for precise

measurements of muscle mass. It is possible to take advantage of CT or

MRI studies that are being done for other clinical purposes to evaluate

musculature.

Laboratory Indicators Laboratory findings (Table 334-2) are but

one part of the comprehensive nutrition assessment and must be used

in combination with other domains of assessment to appropriately

diagnose a malnutrition syndrome. Although serum albumin and prealbumin are often measured in patients with suspected malnutrition,

their utility is limited due to their poor sensitivity and specificity as

indicators of nutritional status. Patients with low albumin or prealbumin may or may not prove to be malnourished when evaluated by

comprehensive nutrition assessment because these proteins are readily

reduced by the systemic response to injury, disease, or inflammation.

C-reactive protein is a positive acute-phase reactant that may be measured to help discern whether active inflammation is manifest. If Creactive protein is increased and albumin or prealbumin decreased,

inflammation is likely to be a contributing factor. Since it is recognized

that C-reactive protein suffers limitations as a point-in-time measure,

trends in levels over the clinical course may be helpful. Research suggests that interleukin 6, and perhaps other cytokines, may also offer

promise as indicators of inflammatory status. Nonspecific laboratory

indicators that are often associated with inflammatory response

include leukocytosis and hyperglycemia. Additional tests that may

be obtained to help confirm the presence of inflammatory response

include 24-h urine urea nitrogen and indirect calorimetry. In the setting of severe acute systemic inflammatory response, negative nitrogen

balance and elevated resting energy expenditure are anticipated.

Dietary Assessment Dietary assessment can be used to detect

inadequate or imbalanced food or nutrient intakes. While dietary

assessment in patient care settings can be quite challenging, 24-h recall

and modified diet history approaches are sometimes used. A modified

diet history is targeted to query types and frequencies of intake of specific foods of interest. It is often necessary to access diverse resources

for diet history information including the patient, medical records,

family, and caregivers. Consultation of a registered dietitian nutritionist is highly recommended. Dietary practices and supplements should

be carefully reviewed for potential inadequacies and toxicities. Since

patients will often present to health care practitioners with acute medical events superimposed upon chronic health conditions, it is common

for patients to have had decreased food intakes and malnutrition for

extended periods prior to assessment. It is therefore imperative that

compromised dietary intake should not be overlooked so that appropriate intervention may be undertaken.

Ongoing assessment is indicated when parenteral or enteral feedings

are initiated, because it is necessary to discern what amount of formula

is actually being administered to and received by the patient. Enteral

feedings, in particular, are often interrupted or held for procedures,

tolerance issues, and feeding tube displacements. It is therefore not

unusual for such patients to be appreciably underfed for extended

periods. When a patient is beginning to transition to oral feedings, it

is imperative to monitor quantities of food and/or supplements that

are actually consumed as well as patient tolerance to feeding. Meals are

often delayed or missed for tests or procedures. If possible, the patient

should be queried about intake since tray inspection is notoriously

unreliable as an indicator of consumption.

Functional Outcomes Advanced malnutrition is accompanied by

declines in muscle mass and function that can be detected by strength

and physical performance measures. Handgrip strength measured with

a simple handgrip dynamometer is the most practical routine clinical

assessment. Physical performance tests such as timed gait, chair stands,

and stair steps are used in the comprehensive assessment of integrated

functions in frail older persons.

The decline in overall functional status observed in advanced

malnutrition is associated with nutrient deficiencies and impairment

of organ system functions. Poor wound healing and immune compromise are examples of such impairments. Improved wound healing

parameters and restored responsiveness to recall antigens by delayed