3 s2.0 B9781455746927000053

CHAPTER
5
Nutritional Principles and Assessment of

the Gastroenterology Patient
JOEL B. MASON
CHAPTER OUTLINE
Basic Nutritional Concepts...........................................................57 Starvation....................................................................................71
Energy Stores............................................................................. 57 Malnutrition.................................................................................72
Energy Metabolism...................................................................... 57 Protein-Energy Malnutrition.......................................................... 72
Protein........................................................................................ 61 Physiologic Impairments Caused by Protein-Energy
Carbohydrate.............................................................................. 62 Malnutrition............................................................................ 75
Lipids......................................................................................... 62 Nutritional Assessment Techniques.............................................76
Major Minerals............................................................................ 62 Aggressive Nutritional Support in the Hospitalized Patient...........81
Micronutrients.............................................................................62 Malnourished Patients Undergoing Major Surgery......................... 81
Vitamins..................................................................................... 63 Patients Hospitalized with Decompensated Alcoholic
Trace Minerals............................................................................ 63 Liver Disease.......................................................................... 82
Physiologic and Pathophysiologic Factors Affecting Patients Undergoing Radiation Therapy........................................ 82
Micronutrient Requirements..................................................... 70
Diligent attention to patients’ nutritional needs can have a glycogen produces only 4.1 kcal/g on oxidation and is stored
major positive impact on medical outcomes. This is particu- intracellularly as a gel, containing approximately 2 g of water
larly true in GI and liver disease because many of these for every gram of glycogen. Adipose tissue cannot provide
conditions, in addition to altering nutrient metabolism and fuel for certain tissues like bone marrow, erythrocytes, leuko-
requirements, are prone to interfere with ingestion and assimi- cytes, renal medulla, eye tissues, and peripheral nerves, which
lation of nutrients. Nutritional management, however, often cannot oxidize lipids and require glucose for their energy
continues to be an inadequately or incorrectly addressed com- supply. During endurance exercise, glycogen and triglycerides
ponent of patient care. in muscle tissue provide an important source of fuel for
In part, inadequate or misdirected attention to nutritional working muscles.
issues is due to failure to distinguish patients who stand to
benefit from nutritional care from those whose outcomes will
not respond to nutritional intervention. The fact that many
Energy Metabolism
clinical trials have failed to demonstrate a benefit of nutri- Energy is required continuously for normal organ function,
tional support in hospitalized patients is often because such a maintenance of metabolic homeostasis, heat production, and
distinction has not been made. The major aim of this chapter performance of mechanical work. Daily total energy expendi-
is to provide the scientific principles and practical tools neces- ture (TEE) has 3 components: resting energy expenditure
sary to recognize patients who will benefit from focused atten- (≈70% of TEE), the energy expenditure of physical activity
tion to nutritional needs, and to provide the guidance necessary (≈20% of TEE), and the thermic effect of feeding (≈10% of TEE),
to develop a suitable nutritional plan for those individuals. which is the temporary increase in energy expenditure that
accompanies enteral ingestion or parenteral administration of
nutrients.
BASIC NUTRITIONAL CONCEPTS Resting Energy Expenditure

Resting energy expenditure (REE) represents energy expendi-
Energy Stores ture while a person lies quietly awake in an interprandial
Endogenous energy stores are oxidized continuously for fuel. state; under these conditions, about 1 kcal/kg body weight is
Triglyceride present in adipose tissue is the body’s major fuel consumed per hour in healthy adults. Energy requirements of
reserve and is critical for survival during periods of starvation specific tissues differ dramatically (Table 5-2). The liver, intes-
(Table 5-1). The high energy density and hydrophobic nature tine, brain, kidneys, and heart constitute roughly 10% of total
of triglycerides make it a 5-fold better fuel per unit mass than body weight but account for about 75% of REE. In contrast,
glycogen. Triglycerides liberate 9.3 kcal/g when oxidized and skeletal muscle at rest consumes some 20% of REE but repre-
are stored compactly as oil inside the fat cell. In comparison, sents approximately 40% of body weight, and adipose tissue
57
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58 Section II Nutrition in Gastroenterology
consumes less than 5% of REE but usually accounts for more events. The activity factors shown in Table 5-4, each expressed
than 20% of body weight. as a multiple of REE, can be used to estimate TEE in active
An accurate assessment of REE is best obtained by indirect patients. The energy expended during a particular physical
calorimetry, but obtaining such a measurement is not always activity is equal to REE × activity factor × duration of activity
practical and in most instances, unnecessary. Instead, one of in hours. TEE represents the summation of energy expended
several empirical equations can be used to estimate resting during all daily activities, including rest periods.
energy requirements (Table 5-3).1-4 The Harris-Benedict and
Mifflin equations are designed for use in adults, whereas the
WHO formulation includes equations for both children Thermic Effect of Feeding
and adults. These equations are generally accurate in healthy Eating or infusing nutrients increases metabolic rate. Dietary
subjects but are inaccurate in persons who are at extremes protein causes the greatest stimulation of metabolic rate, fol-
in weight or who are ill, because anomalous body composition lowed by carbohydrate and then fat. A meal containing all
and metabolic stress influence energy expenditure. Protein- these nutrients usually increases metabolic rate by 5% to 10%
energy malnutrition and hypocaloric feeding without super- of ingested or infused calories.
imposed illness each decrease REE to values 10% to 15%
below those expected for actual body size, whereas acute
illness or trauma predictably increases energy expenditure Recommended Energy Intake in Hospitalized Patients
(see later). In arriving at a nutritional plan for hospitalized patients, it is
usually unnecessary to obtain actual measurements with a
bedside indirect calorimeter. A number of simple formulas can
Energy Expenditure of Physical Activity be used instead and make up in practical value what they lack
The effect of physical activity on energy expenditure depends in accuracy. A few examples follow.
on the intensity and duration of daily activities. Highly trained
athletes can increase their TEE 10- to 20-fold during athletic
TABLE 5-3 Commonly Used Formulas for Calculating
Resting Energy Expenditure*
TABLE 5-1 Endogenous Fuel Stores in a 70-kg Man Harris-Benedict Equation

Men 66 + (13.7 × W) + (5 × H) − (6.8 × A)
Mass Women 665 + (9.6 × W) + (1.8 × H) − (4.7 × A)
Tissue Fuel Source Grams Kilocalories Mifflin Equation
Adipose Triglyceride 13,000 121,000 Men (10 × W) + (6.25 × H) − (5 × A) + 5

Women (10 × W) + (6.25 × H) − (5 × A) − 161
Liver Protein 300 1200
World Health Organization Formula
Glycogen 100 400
Triglyceride 50 450 Age (yr) Male Female
0-3 (60.9 × W) − 54 (60.1 × W) − 51
Muscle Protein 6000 24,000 3-10 (22.7 × W) − 495 (22.5 × W) + 499
Glycogen 400 1600 10-18 (17.5 × W) + 651 (12.2 × W) + 746
Triglyceride 250 2250 18-30 (15.3 × W) + 679 (14.7 × W) + 996
30-60 (11.2 × W) + 879 (8.7 × W) + 829
Blood Glucose 3 12 >60 (13.5 × W) + 987 (10.5 × W) + 596
Triglyceride 4 37
Free fatty acids 0.5 5 *Calculated as kilocalories per day.
A, age in years; H, height in centimeters; W, weight in kilograms.
TABLE 5-2 Resting Energy Requirements of Various Tissues in a 70-kg Man
Tissue Mass Energy Consumed
Percentage Kcal/g Percentage

Tissue Grams Body Weight Kcal/Day Tissue/Day REE
Liver 1550 2.2 445 0.28 19
GI tract 2000 3.0 300 0.15 13
Brain 1400 2.0 420 0.30 18
Kidneys 300 0.4 360 1.27 15
Heart 300 0.4 235 0.80 10
Skeletal muscle 28,000 40.0 400 0.014 18
Adipose 15,000 21.0 80 0.005 4

GI, gastrointestinal; REE, resting energy expenditure.
Chapter 5 Nutritional Principles and Assessment of the Gastroenterology Patient 59
context. In acutely ill hospitalized patients, it is not usually

TABLE 5-4 Relative Thermic Effect of Various Levels of necessary to include an activity factor.
Physical Activity An alternative and simple formula for adult inpatients,
although accompanied by some further loss in accuracy, is:
Activity Level Examples Activity Factor
• 20 to 25 kcal/kg of actual body weight (ABW)/day for
Resting 1.0 unstressed or mildly stressed patients
• 25 to 30 kcal/ABW/day for moderately stressed patients
Very light Standing, driving, typing 1.1-2.0 • 30 to 35 kcal/ABW/day for severely stressed patients
In using this formula, adjustments are necessary when the
Light Walking 2-3 miles/hr, 2.1-4.0 ABW is a misleading reflection of lean body mass. An adjusted
shopping, light ideal body weight (IBW) should be substituted for ABW in
housekeeping obese individuals who are more than 30% heavier than their
IBW (desirable body weights appear in Table 5-6). Using an
Moderate Walking 3-4 miles/hr, 4.1-6.0 adjusted IBW helps prevent an overestimation of energy
biking, gardening, requirements and is calculated as:
scrubbing floors
Adjusted IBW = IBW + 0.33(ABW − IBW )
Heavy Running, swimming, 6.1-10.0
climbing, basketball In patients with large artifactual increases in weight due to
Adapted from Alpers DA, Stenson WF, Bier DM. Manual of nutritional therapeutics.
extracellular fluid retention (e.g., ascites), the IBW should be
Boston: Little, Brown; 1995. used to estimate energy requirements rather than the ABW.
Method without a Stress Factor

TABLE 5-5 Metabolic Stress Factors for Estimating Total
The most accurate and extensively validated equation for pre-
Energy Expenditure in Hospitalized Patients
dicting daily energy expenditure in ill patients is one that does
Relative Stress
not incorporate a stress factor; it does, however, require
Injury or Illness Factor*
knowledge of the minute ventilation, so its use is restricted to
patients on mechanical ventilation.4 This formula is:
Second- or third-degree burns, >40% BSA 1.6-1.8
TEE = (REE calculated by Mifflin equation × 0.96) +
Multiple trauma 1.5-1.7 (Tmax × 167 ) + ( Ve × 31) − 6212
Second- or third-degree burns, 1.4-1.5 Tmax is the maximum temperature in Celsius over the past 24
20%-40% BSA hours; Ve is expired minute ventilation in liters.
Table 5-7 describes a simple alternative method for esti-
Severe infections 1.3-1.4 mating total daily energy requirements in hospitalized
patients; it is based on BMI.6 It lacks the extensive validation
Acute pancreatitis 1.2-1.4 of the prior algorithm as well as some of its accuracy, but it
does not require knowledge of minute ventilation, is straight-
Second- or third-degree burns, 1.2-1.4 forward, and consequently has some genuine utilitarian value.
10%-20% BSA Common sense has to be applied when using an inexact means
such as this to estimate energy expenditure in hospitalized
Long bone fracture 1.2
individuals, because illness commonly interjects artifacts into
Peritonitis 1.2 these calculations (e.g., ascites, anasarca).
Uncomplicated postoperative state 1.1 Caloric Delivery and Avoidance of Hyperglycemia

*A stress factor of 1.0 is assumed for healthy controls. Over the past 2 decades, the trend has generally been toward
BSA, body surface area. a more conservative approach to caloric delivery in acutely ill
patients. One reason for this conservatism is that acute illness
and its management often exacerbate preexisting diabetes or
Methods Incorporating Metabolic Stress Factors produce de novo glucose intolerance. As a result, hyperglyce-
Metabolic stress (i.e., any injury or illness that incites some mia is a frequent consequence of enteral, and especially par-
degree of systemic inflammation) will increase the metabolic enteral, nutrition. The issue seems to be particularly germane
rate through a variety of mechanisms (see later). The increase for ICU patients, in whom even modest hyperglycemia results
in energy expenditure is roughly proportional to the magni- in worse clinical outcomes, usually of an infectious nature.
tude of the stress.5 Thus, the total daily energy requirement of High-quality clinical trials in surgical ICU (SICU)7 and medical
an acutely ill patient can be estimated by multiplying the ICU (MICU)8 patients have found that morbidity is substan-
predicted REE (as determined by the Harris-Benedict or WHO tially and significantly reduced in those randomized to inten-
equations) by a stress factor: sive insulin therapy who maintained serum glucose levels
below 111 mg/dL, compared with those whose glucose values
TEE = REE × Stress factor were maintained below 215 mg/dL. Mortality was also sig-
nificantly lower among SICU patients randomized to receive
Table 5-5 delineates metabolic stress factors that accompany tight glucose control, although in the MICU study, such reduc-
some common conditions and clinical scenarios in inpatients. tions in mortality caused by tight glucose control were only
Because the Mifflin equation was not designed to be used to realized in those who resided in the MICU longer than 3 days.
estimate TEE with stress factors, it is not recommended in this These clinical observations substantiate years of animal studies
TABLE 5-6 Desirable Weight in Relation to Height for Men and Women 25 Years or Older*
Men, Medium Frame Women, Medium Frame
Weight (lb) Weight (lb)
Height (ft/inches) Range Midpoint Height (ft/inches) Range Midpoint
4′8″ 93-104 98.5
4′9″ 95-107 101
4′10″ 98-110 104
4′11″ 101-113 107
5′0″ 104-116 110
5′1″ 113-124 118.5 5′1″ 107-119 113
5′2″ 116-128 122 5′2″ 110-123 116.5
5′3″ 119-131 125 5′3″ 113-127 120
5′4″ 122-134 128 5′4″ 117-132 124.5
5′5″ 125-138 131.5 5′5″ 121-136 128.5
5′6″ 129-142 135.5 5′6″ 125-140 132.5
5′7″ 133-147 140 5′7″ 129-144 136.5
5′8″ 137-151 144 5′8″ 133-148 140.5
5′9″ 141-155 148 5′9″ 137-152 144.5
5′10″ 145-160 153 5′10″ 141-156 148.5
5′11″ 149-165 157
6′0″ 153-170 161.5
6′1″ 157-175 166
6′2″ 162-180 171
6′3″ 167-185 176

*Corrected to nude weights and heights by assuming 1-inch heel for men, 2-inch heel for women, and indoor clothing weight of 5 and 3 lb for men and women, respectively.
Data from Metropolitan Life Insurance Company. New height standards for men and women. Statistical Bulletin 1959; 40:1-4.
TABLE 5-7 Estimated Energy Requirements for showing that even modest hyperglycemia impairs immune
Hospitalized Patients Based on Body Mass Index (BMI)* function in a variety of tissues.9 The clinical benefits of tight
glucose control in the ICU, however, have not always been
Energy Requirements reproducible10 and come at the cost of more frequent hypogly-
Body Mass Index (kg/m2) (kcal/kg/day)† cemic episodes,7-8,10 so the issue of how tight glucose control
should be remains controversial. A panel of experts recently
<15 35-40 recommended instituting protocols to keep blood sugar
150 mg/dL or lower among ICU patients, preferably by use
15-19 30-35 of a continuous infusion of insulin, with monitoring every 1
to 2 hours so that appropriate adjustments can be made and
20-29 20-25
blood sugar values below 70 are avoided.11 The results of a
≥30 15-20 meta-analysis of 29 trials in critically ill patients recapitulate
the previously observed discrepancies between SICU and
*The lower range within each BMI category should be considered in calculating MICU patients.12 Overall, the relative risk of septicemia was
energy requirements for insulin-resistant or critically ill patients to decrease the risk reduced approximately 25% in those randomized to tight
of hyperglycemia and infection associated with overfeeding.
†
These values are recommended for critically ill patients and all obese patients;
glucose control, although this salutary effect was largely
add 20% of the total calories when estimating energy requirements in non–critically attributable to the SICU patients, in whom reduction in septi-
ill patients. cemia was almost 50%; no benefit was observed in MICU
patients, nor were differences in overall mortality evident in

any of the categories of critically ill patients. TABLE 5-8 Recommended Daily Protein Intake*
The question of appropriate caloric delivery to critically ill
Daily Protein Requirement
overweight and obese patients, who account for a burgeoning
Clinical Condition (g/kg IBW)
proportion of patients cared for in ICUs, is a controversial
issue at present.13 A popular nutritional approach to such Normal 0.75
patients is so-called hypocaloric feeding, in which only 60%
to 70% of the estimated energy requirement (or 11 to 14 kcal/ Metabolic stress 1.0-1.6
kg of ABW) is delivered in conjunction with 2 to 2.5 grams of
protein/kg of IBW per day, the latter minimizing the risk of Hemodialysis 1.2-1.4
producing net protein catabolism and loss of lean body mass.
The advantage of hypocaloric feeding is improved glycemic Peritoneal dialysis 1.3-1.5
control and perhaps prevention of metabolic complications
*Additional protein requirements are needed to compensate for excess protein loss
like hypercapnia and hypertriglyceridemia. Reduction in fat in specific patient populations (e.g., patients with burn injuries, open wounds,
mass and weight is another consequence of hypocaloric protein-losing enteropathy, or nephropathy). Lower protein intake may be
feeding but should never be a primary objective in feeding necessary for patients with renal insufficiency not treated by dialysis and certain
obese ICU patients. Although some observations have shown patients with liver disease and hepatic encephalopathy.
IBW, ideal body weight.
that hypocaloric feeding improves outcomes for obese ICU
patients14—and although it is generally safe except in those
circumstances where high protein intake is contraindicated—
this strategy remains one that must be tested more rigorously
in future clinical trials. balance can sometimes be achieved merely by increasing
caloric delivery if the total amount of calories has been
inadequate.
Protein As metabolic stress (and with it, metabolic rate) increases,
Twenty different amino acids are commonly found in human nitrogen excretion increases proportionately; quantitatively,
proteins. Some amino acids (histidine, isoleucine, leucine, the relationship is approximately 2 mg nitrogen (N)/kcal of
lysine, methionine, phenylalanine, threonine, tryptophan, REE. In part, this increase is explained by the fact that in meta-
valine, and possibly arginine) are considered essential because bolic stress, a larger proportion of the total substrate oxidized
their carbon skeletons cannot be synthesized by the body. for energy is from protein. This has 2 important implications
Other amino acids (glycine, alanine, serine, cysteine, tyrosine, for managing the nutritional needs of ill patients. The first is
glutamine, glutamic acid, asparagine, and aspartic acid) are that illness, by increasing catabolism and metabolic rate,
nonessential in most circumstances because they can be made increases the absolute requirement for protein (see Table 5-8)
from endogenous precursors or essential amino acids. In and does so in a manner that is roughly proportional to the
disease states, intracellular concentrations of certain nones- degree of stress. Second, because a greater proportion of
sential amino acids often drop to very low levels and have energy substrate in acute illness comes from protein, nitrogen
therefore been thought to become essential—so-called condi- balance is more readily achieved if a larger proportion of the
tionally essential amino acids. For many years, supplemental total calories are from protein. In healthy adults, as little as
glutamine was included in TPN to compensate for cellular 10% of total calories have to come from protein to maintain
depletion of this amino acid during critical illness. However, health, whereas in the ill patient, nitrogen balance is achieved
2 rigorously conducted clinical trials that have only recently more easily if 15% to 25% of total calories are delivered as
been reported have shown no benefit—or significant harm— protein.
associated with administration of supplemental glutamine.15 Protein requirements are also determined by the adequacy
The concept of conditionally essential amino acids is not of essential amino acids in the protein source. Inadequate
entirely defunct, however; there are observations to suggest amounts of an essential amino acid result in inefficient uptake,
that cysteine and tyrosine are essential in some patients with so proteins of low biological quality increase the protein
cirrhosis16 because of impaired hepatic synthesis. requirement. In normal adults, approximately 15% to 20% of
The body of an average 75-kg man contains about 12 kg of total protein requirements should be in the form of essential
protein. In contrast to fat and carbohydrate, there is no storage amino acids.
depot for protein, so excess intake is catabolized and the nitro- Additional proteins are needed to compensate for excess
gen component is excreted. Inadequate protein intake causes loss in specific patient populations (e.g., patients with burn
net nitrogen losses, and because no depot form of protein injuries, open wounds, and protein-losing enteropathy or
exists, there is an obligatory net loss of functioning protein. The nephropathy). Delivering less protein than is needed is often
U.S. Recommended Daily Allowance (RDA) of protein has a necessary compromise in patients with acute kidney failure
been established at 0.8 g/kg/day, which reflects a mean calcu- who are not adequately dialyzed; in this situation the rise in
lated requirement of 0.6 g/kg/day plus an added factor to take azotemia is directly proportional to protein delivery. Once
into account the biological variance in requirement observed adequate dialysis is available, protein delivery should be
in a healthy population. Intravenously administered amino increased to the actual projected need, including additional
acids are as effective in maintaining nitrogen balance as oral protein to compensate for losses resulting from dialysis (see
protein of the same amino acid composition.17 Table 5-8). Most patients with hepatic encephalopathy respond
Individual protein requirements are affected by several to simple pharmacologic measures and therefore do not
factors, such as the amount of non-protein calories provided, require a protein restriction; those who do not respond may
overall energy requirements, protein quality, and the patient’s benefit from a modest protein restriction (≈0.6 g/kg/day).
nutritional status (Table 5-8). Protein requirements increase
when calorie intake does not meet energy needs. The magni-
tude of this increase is directly proportional to the deficit in Nitrogen Balance
energy supply. Therefore, nitrogen balance reflects protein Nitrogen (N) balance is commonly used as a proxy measure
intake and energy balance. Correcting a negative nitrogen of protein balance (i.e., whether the quantity of protein [or
amino acids] taken in is sufficient to prevent any net loss of inside the mitochondria, FAs are degraded by beta oxidation
protein). N balance is calculated as the difference between N to acetyl coenzyme A (CoA), which then enters the TCA cycle.
intake and N losses in urine, stool, skin, and body fluids. In Therefore, the ability to use fat as a fuel depends on normally
the clinical setting, it is calculated as follows for adults: functioning mitochondria. A decrease in the number of mito-
chondria or oxidative enzymes associated with aging23 or
N balance = Grams of N administered as nutrition − deconditioning favors the use of carbohydrate as fuel.24
(Urinary urea N[g] + 4)
Every 6.25 g of administered protein (or amino acids) contains Essential Fatty Acids
approximately 1 g of N. The additional 4 g of N loss incorpo- Humans lack the desaturase enzyme needed to produce the
rated into the equation is intended to account for the insen- n-3 (double bond between carbons 3 and 4) and n-6 (double
sible losses from the other sources listed and because urinary bond between carbons 6 and 7) FA series. Linoleic acid (C18:2,
urea N only accounts for about 80% of total urinary nitrogen. n-6) and linolenic acid (C18:3, n-3) should therefore constitute
N balance is a suitable surrogate for protein balance, because at least 2% and 0.5%, respectively, of the daily caloric intake
roughly 98% of total body N is in protein, regardless of the to prevent essential FA deficiency (EFAD). Before the advent
individual’s health. of parenteral nutrition, EFAD was recognized only in infants
A positive N balance (i.e., intake > loss) represents anabo- and manifested as a scaly rash with a specific alteration in the
lism and a net increase in total body protein, whereas a nega- plasma FA profile (see later). Adults were thought not to be
tive N balance represents net protein catabolism. For example, susceptible to EFAD because of sufficient essential FA stores
a negative N balance of 1 g/day represents a 6.25-g/day loss in adipose tissue, but an abnormal FA profile in conjunction
of body protein, which is equivalent to a 30-g/day loss of with a clinical syndrome of EFAD is now known to sometimes
hydrated lean tissue. In practice, N balance studies tend to be occur in adults with severe short bowel syndrome who are on
artificially positive because of overestimation of dietary N long-term TPN that lacks parenteral lipids.25 Adults who have
intake and underestimation of losses due to incomplete urine moderate to severe fat malabsorption (fractional fat excretion
collections and unmeasured outputs. It is best to wait at least >20%) from other causes and who are not TPN dependent also
4 days after a substantial change in protein delivery before N frequently display a biochemical profile of EFAD,26 although
balance is examined, because a labile N pool exists. This tends whether such a biochemical state carries adverse clinical con-
to dampen and retard changes that otherwise would be sequences with it is unclear. Moreover, TPN lacking any
observed as a result of altered protein intake. source of fat may lead to EFAD in adults if no exogenous
source of EFAs is available. The plasma pattern of EFAD may
be observed as early as 10 days after glucose-based TPN is
Carbohydrate started and before the onset of any clinical features.27 In this
Complete digestion of the principal dietary digestible situation, EFAD is probably due to the increase in plasma
carbohydrates—starch, sucrose, and lactose—generate mono- insulin concentrations caused by TPN, because insulin inhibits
saccharides (glucose, fructose, and galactose). In addition, 5 to lipolysis and therefore the release of endogenous essential
20 g of indigestible carbohydrate (soluble and insoluble fibers) FAs. The biochemical diagnosis of EFAD is defined as an abso-
are typically consumed daily. All cells can generate energy lute and relative deficiency in the 2 EFAs in the plasma FA
(adenosine triphosphate [ATP]) by metabolizing glucose to profile. The full clinical EFAD syndrome includes alopecia,
3-carbon compounds via glycolysis, or to carbon dioxide and scaly dermatitis, capillary fragility, poor wound healing,
water via glycolysis and the tricarboxylic acid (TCA) cycle. increased susceptibility to infection, fatty liver, and growth
There is no absolute dietary requirement for carbohydrate; retardation in infants and children.
glucose can be synthesized from endogenous amino acids as
well as glycerol. Nevertheless, carbohydrate is an important
fuel because of the interactions between carbohydrate and
Major Minerals
protein metabolism. Carbohydrate intake stimulates insulin Major minerals are inorganic nutrients that are required in
secretion, which inhibits muscle protein breakdown,18 stimu- large (>100 mg/day) quantities and are important for ionic
lates muscle protein synthesis,19 and decreases endogenous equilibrium, water balance, and normal cell function. Malnu-
glucose production from amino acids.20 In addition, glucose is trition and nutritional repletion can have dramatic effects
the required or preferred fuel for red and white blood cells, on major mineral balance. Evaluation of macromineral defi-
the renal medulla, eye tissues, peripheral nerves, and the ciency and RDA of minerals for healthy adults are shown
brain. However, once glucose requirements for these tissues in Table 5-9.
are met (≈150 g/day), the protein-sparing effects of carbohy-
drate and fat are similar.21
MICRONUTRIENTS
Lipids Micronutrients (the vitamins and trace minerals) are a diverse
Lipids consist of TGs, sterols, and phospholipids. These com- array of dietary components that are necessary to sustain
pounds serve as sources of energy; precursors for steroid health. The physiologic roles of micronutrients are as varied
hormone, prostaglandin, thromboxane, and leukotriene syn- as their composition. Some are used in enzymes as coenzymes
thesis; structural components of cell membranes; and carriers or prosthetic groups, others as biochemical substrates or
of essential nutrients. Dietary lipids are composed mainly of hormones; in some cases, their functions are not well defined.
TGs, which contain saturated and unsaturated long-chain The average daily dietary intake for each micronutrient
fatty acids (FAs) of 16 to 18 carbons. Use of fat as a fuel required to sustain normal physiologic operations is measured
requires hydrolysis of endogenous or exogenous TGs and cel- in milligrams or smaller quantities. In this way, micronutrients
lular uptake of released FAs (see Chapter 102). Long-chain FAs are distinguished from macronutrients (carbohydrates, fats,
are delivered across the outer and inner mitochondrial mem- and proteins) and macrominerals (calcium, magnesium, and
branes by a carnitine-dependent transport system.22 Once phosphorus).
TABLE 5-9 Major Mineral Requirements and Assessment of Deficiency
Laboratory Evaluation
Parenteral Symptoms or Signs of
Mineral Enteral (mmol) Deficiency Test Comment
Sodium 0.5-5 g 60-150 Hypovolemia, weakness Urinary sodium May not reflect body stores;
clinical evaluation is best
Potassium 2-5 g 60-100 Weakness, paresthesias, Serum potassium May not reflect body stores
arrhythmias
Magnesium 300-400 mg 5-15 Weakness, twitching, tetany, Serum magnesium May not reflect body stores
arrhythmias, hypocalcemia Urinary magnesium May not reflect body stores
Calcium 1000-1200 mg 5-15 Osteomalacia, tetany, 24-hr urinary calcium Reflects recent intake
arrhythmias Dual energy radiation Reflects bone calcium
absorptiometry content
Phosphorus 800-1200 mg 20-60 Weakness, fatigue, leukocyte Plasma phosphorus May not reflect body stores
and platelet dysfunction,
hemolytic anemia, cardiac
failure, decreased
oxygenation
An individual’s dietary requirement for any given micro- Trace Minerals

nutrient is determined by many factors, including its bioavail-
ability, the amount needed to sustain its normal physiologic Compelling evidence exists for the essential nature of 10
functions, a person’s gender and age, any diseases or drugs trace elements in humans: iron, zinc, copper, chromium,
that affect the nutrient’s metabolism, and certain lifestyle selenium, iodine, fluorine, manganese, molybdenum, and
habits like smoking and alcohol use. The U.S. National cobalt (see Table 5-11). The biochemical functions of trace ele-
Academy of Sciences Food and Nutrition Board regularly ments have not been as well characterized as those of the
updates dietary guidelines that define the quantity of each vitamins, but most of their functions appear to be as compo-
micronutrient that is “adequate to meet the known nutrient nents of prosthetic groups or as cofactors for a number of
needs of practically all healthy persons.” These RDAs under- enzymes.
went revision between 1998 and 2001, and the values for Aside from iron, the trace mineral depletion clinicians are
adults appear in Tables 5-10 and 5-11. Formulating an RDA most likely to encounter is zinc deficiency. Zinc depletion is a
takes into account the biological variability in the population, particularly germane issue to the gastroenterologist, because
so RDAs are set 2 SDs above the mean requirement; this allows the GI tract is a major site for zinc excretion. Chronically exces-
the requirements of 97% of the population to be met. Ingestion sive losses of GI secretions, such as chronic diarrhea in inflam-
of quantities that are somewhat less than the RDA are usually matory bowel disease, is a known precipitant for zinc
sufficient to meet the needs of a particular individual. A “toler- deficiency, and in this setting zinc requirements often increase
able upper limit (TUL),” which is “the maximal daily level of several-fold.28 Nevertheless, a biochemical diagnosis of zinc
oral intake that is likely to pose no adverse health risks,” has deficiency is problematic, as is true for many of the other
been established for most micronutrients (see Tables 5-10 and essential trace minerals. Accurate laboratory assessment of
5-11). Present recommendations for how much of each micro- zinc status is complicated by the very low concentrations of
nutrient is needed in individuals on TPN are based on far less zinc in bodily fluids and tissues, a lack of correlation between
data than what were available for development of the RDAs. serum and red blood cell levels of zinc with levels in the target
Nevertheless, it is important to have guidelines, and Table 5-12 tissues, and the reality that functional tests have yet to be
provides such recommendations. devised. Furthermore, it is well recognized that in acute illness
a shift in zinc occurs from the serum compartment into the
liver, further obscuring the diagnostic value of serum zinc
Vitamins levels.29,30 It is often best to simply proceed with empirical zinc
Vitamins are categorized as fat soluble (A, D, E, K) or water supplementation in patients whose clinical scenario puts them
soluble (all others) (see Table 5-10). This categorization at high risk of zinc deficiency.
remains physiologically meaningful; none of the fat-soluble Some reports have indicated that TPN solutions that
vitamins appear to serve as coenzymes, whereas almost all of deliver several-fold more manganese than what is recom-
the water-soluble vitamins appear to function in that role. mended in Table 5-12 may lead to deposition of the mineral
Also, the absorption of fat-soluble vitamins is primarily in the basal ganglia, with extrapyramidal symptoms, seizures,
through a micellar route, whereas the water-soluble vitamins or both.31 Because the content of manganese varies widely in
are not absorbed in a lipophilic phase in the intestine (see the different trace element mixtures available for TPN
Chapter 103). Text continued on p. 70
TABLE 5-10 Salient Features of Vitamins
Vitamin Deficiency (RDA)* Toxicity (TUL)† Assessment of Status
A Follicular hyperkeratosis and night In adults, >150,000 µg may cause Retinol concentration in the
blindness are early indicators. Conjunctival acute toxicity—fatal intracranial plasma, as well as vitamin
xerosis, degeneration of the cornea hypertension, skin exfoliation, and A concentrations in milk
(keratomalacia), and dedifferentiation of hepatocellular injury. Chronic and tears, are reasonably
rapidly proliferating epithelia are later toxicity may occur with habitual accurate measures of
indications of deficiency. Bitot spots (focal daily intake of >10,000 µg— status. Toxicity is best
areas of the conjunctiva or cornea with alopecia, ataxia, bone and muscle assessed by elevated levels
foamy appearance) are an indication of pain, dermatitis, cheilitis, of retinyl esters in plasma.
xerosis. Blindness caused by corneal conjunctivitis, pseudotumor A quantitative measure
destruction and retinal dysfunction may cerebri, hepatic fibrosis, of dark adaptation for
ensue. Increased susceptibility to infection hyperlipidemia, and hyperostosis night vision and
is also a consequence (1 µg of retinol are common. Single large doses electroretinography are
equivalent to 3.33 IU of vitamin A; F, of vitamin A (30,000 µg) or useful functional tests
700 µg; M, 900 µg) habitual intake of >4500 µg/day
during early pregnancy can be
teratogenic. Excessive intake of
carotenoids causes a benign
condition characterized by
yellowish discoloration of the skin.
Habitually large doses of
canthaxanthin, a carotenoid, have
the additional capability of
inducing a retinopathy (3000 µg)
D Deficiency results in decreased Excess amounts result in Serum concentration

mineralization of newly-formed bone called abnormally high concentrations of of the major circulating
rickets in childhood and osteomalacia in calcium and phosphate in the metabolite, 25-
adults. Expansion of epiphyseal growth serum; metastatic calcifications, hydroxyvitamin D, is an
plates and replacement of normal bone renal damage, and altered excellent indicator of
with unmineralized bone matrix are the mentation may occur (100 µg for systemic status except in
cardinal features of rickets; the latter ages >9) advanced kidney disease
feature also characterizes osteomalacia. (stages 4-5), in which
Deformity of bone and pathologic fractures impairment of renal
occur. Decreased serum concentrations of 1-hydroxylation results in
calcium and phosphate may occur (1 µg is dissociation of the
equivalent to 40 IU; 15 µg, ages 19-70; mono- and dihydroxy
20 µg, ages >70) vitamin concentrations;
measuring the serum
concentration of 1,25-
dihydroxyvitamin D is then
necessary
E Deficiency caused by dietary inadequacy is Depressed levels of vitamin K– Plasma or serum

rare in developed countries. Usually seen in dependent procoagulants and concentration of alpha-
premature infants, individuals with fat potentiation of oral anticoagulants tocopherol is used most
malabsorption, and individuals with have been reported, as has commonly. Additional
abetalipoproteinemia. Red blood cell impaired leukocyte function. accuracy is obtained by
fragility occurs and can produce hemolytic Doses of 800 mg/day have been expressing this value per
anemia. Neuronal degeneration produces reported to increase slightly the mg of total plasma lipid.
peripheral neuropathies, ophthalmoplegia, incidence of hemorrhagic stroke Red blood cell peroxide
and destruction of the posterior columns of (1000 mg) hemolysis test is not
the spinal cord. Neurologic disease is entirely specific but is a
frequently irreversible if deficiency is not useful measure of the
corrected early enough. May contribute to susceptibility of cell
hemolytic anemia and retrolental fibroplasia membranes to oxidation
in premature infants. Has been reported to
suppress cell-mediated immunity (15 mg)
TABLE 5-10 Salient Features of Vitamins—cont’d
K Deficiency syndrome is uncommon except Rapid intravenous infusion of Prothrombin time is

in breast-fed newborns (in whom it may vitamin K1 has been associated typically used as a measure
cause “hemorrhagic disease of the with dyspnea, flushing, and of functional vitamin K
newborn”), adults who have fat cardiovascular collapse; this is status; it is neither sensitive
malabsorption or are taking drugs that likely related to the dispersing nor specific for vitamin K
interfere with vitamin K metabolism (e.g., agents in the dissolution solvent. deficiency. Determination
warfarin, phenytoin, broad-spectrum Supplementation may interfere of fasting plasma vitamin K
antibiotics), and individuals taking large with warfarin-based is an accurate indicator.
doses of vitamin E and anticoagulant anticoagulation. Pregnant women Undercarboxylated plasma
drugs. Excessive hemorrhage is the usual taking large amounts of the prothrombin is also an
manifestation (F, 90 µg; M, 120 µg) provitamin menadione may deliver accurate metric, but only
infants with hemolytic anemia, for detecting the deficient
hyperbilirubinemia, and state, and is less widely
kernicterus (TUL not established) available
Thiamine Classic deficiency syndrome (beriberi) is Excess intake is largely excreted The most effective measure
(vitamin B1) described in Asian populations consuming in the urine, although parenteral of vitamin B1 status is the
polished rice diet. Alcoholism, chronic renal doses of >400 mg/day are erythrocyte transketolase
dialysis, and persistent nausea and reported to cause lethargy, ataxia, activity coefficient, which
vomiting after bariatric surgery are common and reduced tone of the GI tract measures enzyme activity
precipitants. High carbohydrate intake (TUL not established) before and after addition of
increases need for B1. Mild deficiency exogenous TPP; red blood
commonly produces irritability, fatigue, and cells from a deficient
headaches. More pronounced deficiency individual express a
can produce peripheral neuropathy and substantial increase in
cardiovascular and cerebral dysfunction. enzyme activity with
Cardiovascular involvement (wet beriberi) addition of TPP. Thiamine
includes heart failure and low peripheral concentrations in the blood
vascular resistance. Cerebral disease or urine are also measured
includes nystagmus, ophthalmoplegia, and
ataxia (Wernicke’s encephalopathy), as well
as hallucinations, impaired short-term
memory, and confabulation (Korsakoff’s
psychosis). Deficiency syndrome responds
within 24 hours to parenteral thiamine but
is partially or wholly irreversible after a
certain stage (F, 1.1 mg; M, 1.2 mg)
Riboflavin Deficiency is usually seen in conjunction Toxicity has not been reported in Most common method of
(vitamin B2) with deficiencies of other B vitamins. humans (TUL not established) assessment is determining
Isolated deficiency of riboflavin produces the activity coefficient of
hyperemia and edema of nasopharyngeal glutathione reductase in
mucosa, cheilosis, angular stomatitis, red blood cells (the test is
glossitis, seborrheic dermatitis, and invalid for individuals with
normochromic, normocytic anemia glucose-6-phosphate
(F, 1.1 mg; M, 1.3 mg) dehydrogenase deficiency).
Measurements of blood
and urine concentrations
are less desirable methods
Niacin Pellagra is the classic deficiency syndrome Human toxicity is known largely Assessment of status is
(vitamin B3) and is often seen in populations in which through studies examining problematic; blood levels
corn is the major source of energy. Still hypolipidemic effects; includes of the vitamin are not
endemic in parts of China, Africa, and flushing, hyperglycemia, reliable. Measurement of
India. Diarrhea, dementia (or associated hepatocellular injury, and urinary excretion of the
symptoms of anxiety or insomnia), and a hyperuricemia (35 mg) niacin metabolites
pigmented dermatitis that develops in N-methylnicotinamide and
sun-exposed areas are typical features. 2-pyridone are thought to
Glossitis, stomatitis, vaginitis, vertigo, and be the most effective
burning dysesthesias are early signs. means of assessment
Occasionally occurs in carcinoid syndrome,
because tryptophan is diverted to other
synthetic pathways (F, 14 mg; M, 16 mg)
Continued
Pyridoxine Deficiency is usually seen in conjunction Chronic use with doses exceeding Many useful laboratory
(vitamin B6) with other water-soluble vitamin 200 mg/day (in adults) may cause methods of assessment
deficiencies. Stomatitis, angular cheilosis, peripheral neuropathies and exist. Plasma or erythrocyte
glossitis, irritability, depression, and photosensitivity (100 mg) PLP levels are most
confusion occur in moderate to severe common. Urinary excretion
depletion; normochromic, normocytic of xanthurenic acid after an
anemia has been reported in severe oral tryptophan load or
deficiency. Abnormal EEGs and, in infants, activity indices of RBC
convulsions also have been reported. aminotransferases (ALT and
Sideroblastic anemias are responsive to AST) all are functional
B6 administration. Isoniazid, cycloserine, measures of B6-dependent
penicillamine, ethanol, and theophylline are enzyme activity
drugs that can inhibit B6 metabolism (Ages
19-50, 1.3 mg; >50 yr, 1.5 mg for women,
1.7 mg for men)
B12 Dietary inadequacy is a rare cause of A few allergic reactions have been Serum or plasma
deficiency, except in strict vegetarians. The reported from crystalline B12 concentrations are
vast majority of cases of deficiency arise preparations and are probably generally accurate. Subtle
from loss of intestinal absorption—a result due to impurities, not the vitamin deficiency with neurologic
of pernicious anemia, pancreatic (TUL not established) complications, as
insufficiency, atrophic gastritis, SIBO, or described in the
ileal disease. Megaloblastic anemia and “Deficiency” column, can
megaloblastic changes in other epithelia best be established by
(see “Folate”) are the result of sustained concurrently measuring the
depletion. Demyelination of peripheral concentration of plasma
nerves, the posterior and lateral columns of B12 and serum
the spinal cord, and nerves within the brain methylmalonic acid,
may occur. Altered mentation, depression, because the latter is a
and psychoses occur. Hematologic and sensitive indicator of
neurologic complications may occur cellular deficiency
independently. Folate supplementation in
doses exceeding 1000 µg/day may partly
correct the anemia, thereby masking (or
perhaps exacerbating) the neuropathic
complications (2.4 µg)
Folate Women of childbearing age are the most Daily dosage >1000 µg may Serum folate levels reflect
likely to develop deficiency. The classic partially correct the anemia of B12 short-term folate balance,
deficiency syndrome is megaloblastic deficiency and therefore mask whereas RBC folate is
anemia. Hematopoietic cells in the bone (and perhaps exacerbate) the a better reflection of
marrow become enlarged and have associated neuropathy. Large tissue status. Serum
immature nuclei, which reflect ineffective doses are reported to lower homocysteine levels rise
DNA synthesis. The peripheral blood smear seizure threshold in individuals early in deficiency but are
demonstrates macro-ovalocytes and prone to seizures. Parenteral nonspecific because B12
polymorphonuclear leukocytes with an administration is rarely reported to or B6 deficiency, renal
average of more than 3.5 nuclear lobes. cause allergic phenomena from insufficiency, and older age
Megaloblastic changes also occur in other dispersion agents (1000 µg) may also cause elevations
epithelia that proliferate rapidly (e.g., oral
mucosa, GI tract), producing glossitis and
diarrhea, respectively. Sulfasalazine and
diphenytoin inhibit absorption and
predispose to deficiency (400 µg of dietary
folate equivalent [DFE]; 1 µg folic acid =
1 µg DFE; 1 µg food folate = 0.6 µg DFE)
C (ascorbic and Overt deficiency is uncommonly observed Quantities exceeding 500 mg/day Plasma ascorbic acid
dehydroascorbic in developed countries. The classic (in adults) sometimes cause concentration reflects
acid) deficiency syndrome is scurvy, nausea and diarrhea. Acidification recent dietary intake,
characterized by fatigue, depression, and of the urine with vitamin C whereas leukocyte levels
widespread abnormalities in connective supplementation, and the more closely reflect tissue
tissues (e.g., inflamed gingivae, petechiae, potential for enhanced oxalate stores. Plasma levels in
perifollicular hemorrhages, impaired wound synthesis, have raised concerns women are ≈20% higher
healing, coiled hairs, hyperkeratosis, and regarding nephrolithiasis, but this than in men for any given
bleeding into body cavities). In infants, has yet to be demonstrated. dietary intake
defects in ossification and bone growth Supplementation with vitamin C
may occur. Tobacco smoking lowers may interfere with laboratory tests
plasma and leukocyte vitamin C levels (F, based on redox potential (e.g.,
75 mg; M, 90 mg; requirement for cigarette fecal occult blood testing, serum
smokers increased by 35 mg/day) cholesterol, serum glucose).
Withdrawal from chronic ingestion
of high doses of vitamin C
supplements should occur
gradually over 1 month because
accommodation does seem to
occur, raising a concern for
rebound scurvy (2000 mg)
Biotin Isolated deficiency is rare. Deficiency in Toxicity has not been reported in Plasma and urine
humans has been produced experimentally humans, with doses as high as concentrations of biotin
by dietary inadequacy, prolonged 60 mg/day in children (TUL not are diminished in the
administration of TPN that lacks the established) deficient state. Elevated
vitamin, and ingestion of large quantities urine concentrations
of raw egg white, which contains avidin, a of methyl citrate,
protein that binds biotin with such high 3-methylcrotonylglycine,
affinity that it renders it bio-unavailable. and 3-hydroxyisovalerate
Alterations in mental status, myalgias, are also observed in
hyperesthesias, and anorexia occur. Later, deficiency
seborrheic dermatitis and alopecia develop.
Biotin deficiency is usually accompanied by
lactic acidosis and organic aciduria (30 µg)
Pantothenic acid Deficiency rare; reported only as a result of Diarrhea is reported to occur with Whole blood and urine
feeding semisynthetic diets or as an doses exceeding 10 g/day (TUL concentrations of
antagonist to the vitamin. Experimental not established) pantothenic acid are
isolated deficiency in humans produces indicators of status; serum
fatigue, abdominal pain and vomiting, levels are not thought to be
insomnia, and paresthesias of the accurate
extremities (5 mg)
*RDA, recommended daily allowance; established for female (F) and male (M) adults by the U.S. Food and Nutrition Board, 1999-2001. In some cases, data are insufficient
to establish an RDA, in which case the adequate intake (AI) established by the board is listed.
†
TUL, tolerable upper level; established for adults by the U.S. Food and Nutrition Board, 1999-2001.
EEG, electroencephalogram; PLP, pyridoxyl 5-phosphate; RBC, red blood cell; SIBO, small intestinal bacterial overgrowth; TPN, total parenteral nutrition; TPP, thiamine
pyrophosphate.
Adapted from Goldman L, Ausiello D, Arend W, et al, editors. Cecil textbook of medicine. 23rd ed. Philadelphia: WB Saunders; 2014. With permission.
TABLE 5-11 Salient Features of Trace Minerals
Mineral Deficiency (RDA)* Toxicity (TUL)† Assessment of Status
Chromium Deficiency in humans is only described Toxicity after oral ingestion is Plasma or serum
for patients on long-term TPN whose uncommon and seems confined to concentration of chromium
TPN contained inadequate chromium. gastric irritation. Airborne exposure is a crude indicator of
Hyperglycemia or impaired glucose may cause contact dermatitis, chromium status; it appears
tolerance is uniformly observed. Elevated eczema, skin ulcers, and to be meaningful when the
plasma free fatty acid concentrations, bronchogenic carcinoma (No TUL value is markedly above or
neuropathy, encephalopathy, and established) below the normal range
abnormalities in nitrogen metabolism are
also reported. Whether supplemental
chromium may improve glucose
tolerance in mildly glucose intolerant but
otherwise healthy individuals remains
controversial (F, 25 µg; M, 35 µg)
Copper Dietary deficiency is rare; it has been Acute copper toxicity has been Practical methods for
observed in premature and low-birth- described after excessive oral detecting marginal deficiency
weight infants exclusively fed a cow’s intake and with absorption of are not available. Marked
milk diet and in individuals on long-term copper salts applied to burned skin. deficiency is reliably
TPN without copper. Clinical Milder manifestations include detected by diminished
manifestations include depigmentation of nausea, vomiting, epigastric pain, serum copper and
skin and hair, neurologic disturbances, and diarrhea; coma and ceruloplasmin
leukopenia and hypochromic, microcytic hepatocellular injury may ensue in concentrations, as well as
anemia, skeletal abnormalities, and poor severe cases. Toxicity may be seen low erythrocyte superoxide
wound healing. The anemia arises from with doses as low as 70 µg/kg/day. dismutase activity
impaired uptake of iron and is therefore a Chronic toxicity is also described.
secondary form of iron deficiency Wilson disease is a rare inherited
anemia. The deficiency syndrome, except disease associated with abnormally
the anemia and leukopenia, is also low ceruloplasmin levels and
observed in Menkes disease, a rare accumulation of copper particularly
inherited condition associated with in the liver and brain, eventually
impaired copper uptake (900 µg) leading to damage of these 2
organs (10 mg)
Fluoride Intake of <0.1 mg/day in infants and Acute ingestion of >30 mg/kg body Estimates of intake or clinical
0.5 mg/day in children is associated with weight of fluoride is likely to cause assessment are used
an increased incidence of dental caries. death. Excessive chronic intake because no reliable
Optimal intake in adults is between 1.5 (0.1 mg/kg/day) leads to mottling laboratory test exists
and 4.0 mg/day (F, 3 mg; M, 4.0 mg) of the teeth (dental fluorosis),
calcification of tendons and
ligaments, and exostoses and may
increase brittleness of bones
(10 mg)
Iodine In the absence of supplementation, Large doses (>2 mg/day in adults) Urinary excretion of iodine is
populations relying primarily on food may induce hypothyroidism by an effective laboratory means
from soils with low iodine content have blocking thyroid hormone synthesis. of assessment. The thyroid-
endemic iodine deficiency. Maternal Supplementation with >100 µg/day stimulating hormone (TSH)
iodine deficiency leads to fetal to an individual who was formerly level in the blood is an
deficiency, which produces spontaneous deficient occasionally induces indirect, not entirely specific
abortions, stillbirths, hypothyroidism, hyperthyroidism (1.1 mg) means of assessment. Iodine
cretinism, and dwarfism. Rapid brain status of a population can be
development continues through the estimated by the prevalence
second year, and permanent cognitive of goiter
deficits may be induced by iodine
deficiency during that period. In adults,
compensatory hypertrophy of the thyroid
(goiter) occurs, along with varying
degrees of hypothyroidism (150 µg)
TABLE 5-11 Salient Features of Trace Minerals—cont’d
Iron Most common micronutrient deficiency in Iron overload typically occurs when Negative iron balance initially
the world. Women of childbearing age habitual dietary intake is extremely leads to depletion of iron
constitute the highest risk group because high, intestinal absorption is stores in the bone marrow;
of menstrual blood losses, pregnancy, excessive, repeated parenteral bone marrow biopsy and the
and lactation. Hookworm infection is the administration of iron occurs, or a concentration of serum
most common cause worldwide. The combination of these factors exists. ferritin are accurate and early
classic deficiency syndrome is Excessive iron stores usually indicators of such depletion.
hypochromic microcytic anemia. Glossitis accumulate in reticuloendothelial As deficiency becomes more
and koilonychia (spoon nails) are also tissues and cause little damage severe, serum iron (SI)
observed. Easy fatigability often develops (hemosiderosis). If overload decreases and total iron
as an early symptom before appearance continues, iron will eventually begin binding capacity (TIBC)
of anemia. In children, mild deficiency of to accumulate in tissues such as increases; an iron saturation
insufficient severity to cause anemia is hepatic parenchyma, pancreas, (= SI/TIBC) of <16%
associated with behavioral disturbances heart, and synovium, damaging suggests iron deficiency.
and poor school performance these tissues (hemochromatosis). Microcytosis, hypochromia,
(postmenopausal F, 8 mg; M, 8 mg; Hereditary hemochromatosis arises and anemia ensue in latter
premenopausal F, 18 mg) as a result of homozygosity of a stages of the deficient state.
common recessive trait. Excessive Elevated levels of serum
intestinal absorption of iron is ferritin or an iron saturation
observed in homozygotes (45 mg) >60% raises suspicion of
iron overload, although
systemic inflammation
elevates serum ferritin level
regardless of iron status
Manganese Manganese deficiency has not been Toxicity by oral ingestion is Until the deficiency
conclusively demonstrated in humans. unknown in humans. Toxic syndrome is better defined,
It is said to cause hypocholesterolemia, inhalation causes hallucinations, an appropriate measure of
weight loss, hair and nail changes, other alterations in mentation, and status will be difficult to
dermatitis, and impaired synthesis extrapyramidal movement disorders develop
of vitamin K–dependent proteins (11 mg)
(F, 1.8 mg; M, 2.3 mg)
Molybdenum Cases of human deficiency are extremely Molybdenum has low toxicity; No effective clinically
rare; caused by TPN lacking the element occupational exposures and high available assessment exists.
or by parenteral administration of sulfite. dietary intake are linked to Rare cases of deficiency
Reported to result in hyperoxypurinemia, hyperuricemia and gout in are associated with
hypouricemia, low urinary sulfate epidemiologic studies (2 mg) hypouricemia,
excretion, and CNS disturbances (45 µg) hypermethionemia, and low
levels of urinary sulfate with
elevated excretion of sulfite,
xanthine, and hypoxanthine
Selenium Deficiency is rare in North America but Toxicity is associated with nausea, Erythrocyte glutathione
has been observed in individuals on diarrhea, alterations in mental peroxidase activity and
long-term TPN lacking selenium. Such status, peripheral neuropathy, plasma, or whole blood,
individuals have myalgias and/or and loss of hair and nails; such selenium concentrations are
cardiomyopathy. Populations in some symptoms were observed in adults the most commonly used
regions of the world, most notably some who inadvertently consumed methods of assessment.
parts of China, have marginal intake of between 27 and 2400 mg (400 µg) They are moderately
selenium. It is in these regions of China accurate indicators of status
that Keshan’s disease is endemic,
a condition characterized by
cardiomyopathy. Keshan’s disease can
be prevented (but not treated) by
selenium supplementation (55 µg)
Continued
TABLE 5-11 Salient Features of Trace Minerals—cont’d
Zinc Deficiency of zinc has its most profound Acute zinc toxicity can usually be There are no accurate
effect on rapidly proliferating tissues. induced by ingestion of >200 mg of indicators of zinc status
Mild deficiency causes growth zinc in a single day (in adults). It is available for routine clinical
retardation in children. More severe manifested by epigastric pain, use. Plasma, erythrocyte,
deficiency is associated with growth nausea, vomiting, and diarrhea. and hair zinc concentrations
arrest, teratogenicity, hypogonadism and Hyperpnea, diaphoresis, and are frequently misleading.
infertility, dysgeusia, poor wound healing, weakness may follow inhalation of Acute illness, in particular, is
diarrhea, dermatitis on the extremities zinc fumes. Copper and zinc known to diminish plasma
and around orifices, glossitis, alopecia, compete for intestinal absorption: zinc levels, in part by
corneal clouding, loss of dark adaptation, chronic ingestion of >25 mg zinc/ inducing a shift of zinc out
and behavioral changes. Impaired cellular day may lead to copper deficiency. of the plasma compartment
immunity also is observed. Excessive Chronic ingestion of >150 mg/day and into the liver. Functional
loss of GI secretions (e.g., through has been reported to cause gastric tests that determine dark
chronic diarrhea or fistulas) may erosions, low high-density adaptation, taste acuity, and
precipitate deficiency. Acrodermatitis lipoprotein cholesterol levels, and rate of wound healing lack
enteropathica is a rare recessively impaired cellular immunity (40 mg) specificity
inherited disease in which intestinal
absorption of zinc is impaired (F, 8 mg;
M, 11 mg)
*Recommended Daily Allowance (RDA) established for female (F) and male (M) adults by the U.S. Food and Nutrition Board, 1999-2001. In some cases, insufficient data
exist to establish an RDA, in which case the adequate intake (AI) established by the Board is listed.
†
Tolerable upper level (TUL) established for adults by the U.S. Food and Nutrition Board, 1999-2001.
Adapted from Goldman L, Ausiello D, Arend W, et al, editors. Cecil textbook of medicine. 22nd ed. Philadelphia: WB Saunders; 2004. With permission.
compounding, the health professional needs to be mindful of proximal portion of the GI tract are therefore likely to result
this issue as protocols for TPN admixtures are developed. in multiple deficiencies. Even in the absence of proximal small
intestinal disease, however, extensive ileal disease, small intes-
Physiologic and Pathophysiologic Factors tinal bacterial overgrowth (SIBO), and chronic cholestasis may
interfere with the maintenance of adequate intraluminal con-
Affecting Micronutrient Requirements jugated bile acid concentrations and thereby may impair
absorption of fat-soluble vitamins.
Age Conditions that produce fat malabsorption are frequently
An evolution of physiology continues throughout the life associated with selective deficiencies of the fat-soluble vita-
cycle, with an impact on the requirements of certain micronu- mins. The early stages of many vitamin deficiencies are not
trients with aging; specific RDAs for older adults have now apparent clinically and therefore may go undetected until pro-
been developed. The mean vitamin B12 status of most popula- gression of the deficiency has resulted in significant morbidity.
tions, for example, declines significantly with older age, in This can be disastrous in conditions like spinocerebellar
large part because of the high prevalence of atrophic gastritis degeneration due to vitamin E deficiency, which often is irre-
and its resultant impairment of protein-bound vitamin B12 versible.35 Fat-soluble vitamin deficiencies are well-recognized
absorption.32 Some 10% to 15% of the older ambulatory popu- complications of cystic fibrosis and congenital biliary atresia,
lation is thought to have significant vitamin B12 depletion in which fat malabsorption often is overt, but monitoring is
because of this phenomenon, and neuropathic degeneration also necessary in conditions associated with more subtle fat
may occur in older individuals whose plasma vitamin B12 malabsorption, such as the latter stages of chronic cholestatic
levels are in the low-normal range (150 to 300 pg/mL), even liver disease.36,37
in the absence of hematologic manifestations. For this reason, Restitution of vitamin deficiencies can sometimes be dif-
the use of sensitive indicators of cellular depletion of vitamin ficult when severe fat malabsorption is present, and initial
B12 (e.g., serum methylmalonic acid levels in conjunction with correction may require parenteral administration. In severe fat
serum levels of vitamin B12) are now recommended for diag- malabsorption, chemically modified forms of vitamins D and
nosis.33 Some experts also suggest that older adults should E that largely bypass the need for the lipophilic phase of intes-
consume a portion of their vitamin B12 requirement in the tinal absorption are commercially available for oral use and
crystalline form (i.e., as a supplement) rather than relying only can be helpful. The polyethylene glycol succinate form of
on the naturally occurring protein-bound forms found in vitamin E (Nutr-E-Sol) is very effective in patients with severe
food.34 Compared with younger adults, those who are older fat malabsorption who cannot absorb conventional alpha-
require greater quantities of vitamins B6 and D and calcium to tocopherol.38 Similarly, hydroxylated forms of vitamin D
maintain health, and these requirements are reflected in the (1-hydroxyvitamin D [Hectorol] and 1,25-dihydroxyvitamin
new RDAs (see Tables 5-10 and 5-11). D [Rocaltrol]) can be used in patients resistant to the more
conventional forms of vitamin D. Intermittent monitoring of
serum calcium levels is indicated in the first few weeks of
Malabsorption and Maldigestion therapy with hydroxylated forms of vitamin D, because they
Both fat- and water-soluble micronutrients are absorbed pre- are considerably more potent than vitamin D2 or D3, and risk
dominantly in the proximal small intestine, the only exception of vitamin D toxicity exists. In contrast, water-miscible prepa-
being vitamin B12. Diffuse mucosal diseases that affect the rations of fat-soluble vitamins, in which a conventional form
TABLE 5-12 Guidelines for Daily Administration of TABLE 5-13 Interactions of Drugs on Micronutrient Status
Parenteral Micronutrients in Adults and Children
Drug(s) Nutrient Mechanism(s)
Micronutrient Adults Children
Dextroamphetamine, Potentially all Induces anorexia
Vitamin fenfluramine, micronutrients
levodopa
A 1000 µg (= 3300 IU) 700 µg
D 5 µg (= 200 IU) 10 µg
Cholestyramine Vitamin D, Adsorbs nutrient,
E 10 mg (= 10 IU) 7 mg
folate decreases
K 1 mg 200 µg
absorption
C 100 mg 80 mg
Folate 400 µg 140 µg PPIs Vitamin B12 Modest bacterial
Niacin 40 mg 17 mg overgrowth,
Riboflavin 3.6 mg 1.4 mg decreases gastric
Thiamine 3 mg 1.2 mg acid/pepsin,
B6 4 mg 1 mg impairs absorption
B12 5 µg 1 µg
Pantothenic acid 15 mg 5 mg Sulfasalazine Folate Impairs absorption
Biotin 60 µg 20 µg and inhibits
folate-dependent
Trace Elements
enzymes
Copper 0.5-1.5 mg 20 µg/kg/day
Chromium 10-15 µg 0.2 µg/kg/day Isoniazid Pyridoxine Impairs uptake of
Manganese 0.1 mg 1 µg/kg/day vitamin B6
Zinc 2.5-4.0 mg 50 µg/kg/day
Molybdenum 15 µg 0.25 µg/kg/day NSAIDs Iron GI blood loss
Iodine* — —
Selenium 100 µg 2 µg/kg/day Penicillamine Zinc Increases renal
Iron 1-2 mg 1 mg/day excretion
From Goldman L, Ausiello D, Arend W, et al, editors. Cecil textbook of medicine.
*Naturally occurring contamination of parenteral nutrition formulas appears to
22nd ed. Philadelphia: WB Saunders; 2004. With permission.
provide sufficient quantities of iodine.
Adult vitamin guidelines adapted from American Society of Parenteral and Enteral
Nutrition (ASPEN). Board of Directors and the Clinical Guidelines Task Force.
Guidelines for the use of parenteral and enteral nutrition in adult and pediatric
patients. JPEN J Parenter Enteral Nutr 2002; 26:144. Children’s values adapted
STARVATION
from Greene HL, Hambidge KM, Schanler R, Tsang RC. Guidelines for the use of
vitamins, trace elements, calcium, magnesium, and phosphorus in infants and
children receiving total parenteral nutrition: report of the Subcommittee on Pediatric
Parenteral Nutrient Requirements from the Committee on Clinical Practice Issues of During periods of energy and/or protein deficit, an array of
the American Society for Clinical Nutrition. Am J Clin Nutr 1988; 48:1324; Am J
Clin Nutr 1989; 49:1332; and Am J Clin Nutr 1989; 50:560. compensatory mechanisms serves to lessen the pathophysio-
logic impact of these deficits. These responses decrease the
metabolic rate, maintain glucose homeostasis, conserve body
of vitamin A or E is dissolved in polysorbate 80 (e.g., nitrogen, and increase the uptake of adipose tissue TGs to
Aquasol-E, Aquasol-A), have not been proved to improve meet energy needs. To appreciate how acute illness disrupts
overall absorption. this compensatory scheme, it is first necessary to understand
Maldigestion usually results from chronic pancreatic insuf- how the body adapts to starvation in the absence of underly-
ficiency, which if untreated, frequently causes fat malabsorp- ing disease.
tion and deficiencies of fat-soluble vitamins. Vitamin B12 During the first 24 hours of fasting, the most readily avail-
malabsorption can also be demonstrated in this setting, but able energy substrates (i.e., circulating glucose, FAs and TGs,
clinical vitamin B12 deficiency is rare unless other conditions and liver and muscle glycogen) are used as fuel sources. The
known to diminish its absorption are also present (e.g., atro- sum of energy provided by these stores in a 70-kg man,
phic gastritis or chronic administration of proton pump inhibi- however, is only about 5000 kJ (1200 kcal) and therefore is less
tors [PPIs]).39 Whether long-term administration of PPIs alone than a full day’s requirements. Hepatic glucose production
warrants occasional checks of vitamin B12 status is a matter of and oxidation decrease, whereas whole-body lipolysis
debate.40 Regardless, malabsorption of vitamin B12 from atro- increases, and the latter provides additional FAs and ketone
phic gastritis or with PPIs is confined to dietary sources of bodies.43 Oxidation of FAs released from adipose tissue TGs
vitamin B12. Small supplemental doses of crystalline vitamin accounts for about 65% of the energy consumed during the
B12 are absorbed readily in both cases. Histamine H2 receptor first 24 hours of fasting.
antagonists also inhibit protein-bound vitamin B12 absorption, During the first several days of starvation, obligate glucose-
although the effect generally is believed to be less potent than requiring tissues like the brain and blood cells, which collec-
with the PPIs.41 tively account for about 20% of total energy consumption, can
Many medications may adversely affect micronutrient use only glycolytic pathways to obtain energy. Because FAs
status. The manner in which drug-nutrient interaction occurs cannot be converted to carbohydrate by these glycolytic
varies; some of the more common mechanisms are described tissues, they must use glucose or substrates that can be con-
in Table 5-13. A comprehensive discussion of drug-nutrient verted to glucose. Glucogenic amino acids derived from skel-
interactions is beyond the scope of this chapter, and the reader etal muscle (chiefly alanine and glutamine) are a major source
is referred to other references for a detailed discourse on of substrate for this purpose. Approximately 15% of the REE
this topic.42 is provided by oxidation of protein.44 The relative contribution
of gluconeogenesis to hepatic glucose production increases as accelerated. Death commonly occurs when there is a 30% to
the rate of hepatic glycogenolysis declines because the latter 50% loss of skeletal muscle protein.52 In humans, it has been
process becomes redundant; after 24 hours of fasting, only proposed that there are certain thresholds beyond which
15% of liver glycogen stores remain. lethality is inevitable: depletion of total body protein between
During short-term starvation (1 to 14 days), several adap- 30% and 50% and of fat stores between 70% and 95%, or
tive responses appear that lessen the loss of lean mass. A reduction of BMI below 13 kg/m2 for men and 11 kg/m2
decline in levels of plasma insulin, an increase in plasma epi- for women.53,54
nephrine levels, and an increase in lipolytic sensitivity to cat-
echolamines stimulate adipose tissue lipolysis.45,46 The increase
in FA delivery to the liver, in conjunction with an increase in MALNUTRITION
the ratio of plasma glucagon-to-insulin concentrations,
enhances the production of ketone bodies by the liver. A In the broadest sense, malnutrition implies a sustained imbal-
maximal rate of ketogenesis is reached by 3 days of starvation, ance between nutrient availability and nutrient requirements.
and plasma ketone body concentration is increased 75-fold by This imbalance results in a pathophysiologic state in which
7 days. In contrast to FAs, ketone bodies can cross the blood- intermediary metabolism, organ function, and body composi-
brain barrier and provide most of the brain’s energy needs by tion are variously altered. Sustained is an important element
7 days of starvation.47 The use of ketone bodies by the brain of this definition, because homeostatic mechanisms and nutri-
greatly diminishes glucose requirements and thus spares the ent reserves are usually adequate to compensate for any short-
need for muscle protein degradation to provide glucose pre- term imbalance.
cursors. If early protein breakdown rates were to continue Customarily, the term malnutrition is used to describe a
throughout starvation, a potentially lethal amount of muscle state of inadequacy in protein, calories, or both and is more
protein would be catabolized in less than 3 weeks. Similarly, precisely called protein-energy malnutrition (PEM) or protein-
the heart, kidney, and skeletal muscle change their primary calorie malnutrition. Occasionally it is used to describe a state
fuel substrate to FAs and ketone bodies. Other tissues like of excessive availability, such as a sustained excess of calories
bone marrow, renal medulla, and peripheral nerves switch (e.g., obesity) or a vitamin (e.g., vitamin toxicity).
from full oxidation of glucose to anaerobic glycolysis, result-
ing in increased production of pyruvate and lactate. The latter
2 compounds can be converted back to glucose in the liver
Protein-Energy Malnutrition
using energy derived from fat oxidation via the Cori cycle, and There are different pathways whereby PEM may evolve.
the resulting glucose is available for systemic consumption. Primary PEM is caused by inadequate intake of protein and/
This enables energy stored as fat to be used for glucose or calories or, less commonly, when the protein ingested is of
synthesis. such poor quality that 1 or more essential amino acids becomes
Whole-body glucose production decreases by more than a limiting factor in the maintenance of normal metabolism.
50% during the first few days of fasting because of a marked Secondary PEM is caused by illness or injury.
reduction in hepatic glucose output. As fasting continues, con- Acute illnesses and injuries increase bodily requirements
version of glutamine to glucose in the kidney represents for protein and energy substrate and impair digestion, absorp-
almost 50% of total glucose production. Energy is conserved tion, and uptake of these nutrients in various ways. Conse-
by a decrease in physical activity secondary to fatigue and a quently, secondary PEM usually arises from multiple factors.
roughly 10% reduction in REE due to increased conversion of Illness and injury also commonly induce anorexia (see later
active thyroid hormone to its inactive form and suppressed for mechanisms), so primary and secondary factors often act
sympathetic nervous system activity. in concert to create PEM in the setting of illness.
During long-term starvation (14 to 60 days), maximal Illness or injury may directly interfere with nutrient
adaptation is reflected by a plateau in lipid, carbohydrate, and assimilation; for example, extensive ileal disease or resection
protein metabolism. The body relies almost entirely on adipose may directly produce fat malabsorption and a caloric deficit.
tissue for its fuel, providing more than 90% of daily energy The most common causes of secondary PEM, however, are
requirements.48 Muscle protein breakdown decreases to less the remarkable increases in protein catabolism and energy
than 30 g/day, causing a marked decrease in urea nitrogen expenditure that occur as a result of a systemic inflammatory
production and excretion. The decrease in osmotic load dimin- response. REE may increase as much as 80% above basal
ishes urine volume to 200 mL/day, thereby reducing fluid levels in a manner roughly proportional to the magnitude of
requirements. Total glucose production decreases to approxi- the inflammatory response, which in turn is roughly propor-
mately 75 g/day, providing fuel for glycolytic tissues (40 g/ tional to the severity and acuity of the illness. Thus, REE in
day) and the brain (35 g/day) while maintaining a constant patients with extensive second- and third-degree burns (the
plasma glucose concentration. Energy expenditure decreases prototype for maximal physiologic stress) may approach twice
by 20% to 25% at 30 days of fasting and remains relatively normal; with sepsis, REE is about 1.5 times normal, and with
constant thereafter despite continued starvation. a localized infection or fracture of a long bone, REE is 25%
The metabolic response to short- and long-term starvation above normal.5 Such stress factors can be used to construct
differs somewhat between lean and obese persons. Obesity is a formula for predicting the caloric needs of ill individuals
associated with a blunted increase in lipolysis and decrease in (see Table 5-5).
glucose production compared with that in lean persons.49,50 Protein catabolism during illness or injury also increases
In addition, protein breakdown and nitrogen losses are less in in proportion to the severity and acuity of the insult and
obese persons, thereby helping conserve muscle protein.51 therefore parallels the increase in energy consumption. The
Events that mark the terminal phase of starvation have magnitude of increase in protein catabolism, however, is
been studied chiefly in laboratory animals. Body fat mass, proportionately greater than that observed with energy con-
muscle protein, and the sizes of most organs are markedly sumption, such that urinary urea N losses, which reflect the
decreased. The weight and protein content of the brain, degree of protein catabolism in acute illness, are about 2.5
however, remain relatively stable. During this final phase of times the basal level with maximal stress.5 This increase in
starvation, body fat stores reach a critical level, energy derived catabolism results in a net loss of protein because the rate of
from body fat decreases, and muscle protein catabolism is synthesis usually does not rise in concert with the rise in
catabolism.55 No known storage form of protein exists in the produce a proportionately greater loss of muscle mass such
body, so any net loss of protein represents a loss of functionally that it matches or exceeds the loss in fat mass.57,58 Although
active tissue. A healthy adult typically loses about 12 g N/day the lean mass lost in illness is preferentially from the somatic
in urine, and excretion may increase to as much as 30 g/day protein compartment, with sustained stress there also will be
during critical illness. Because 1 g of urinary N represents the a significant contraction of the visceral protein compartment
catabolism of approximately 30 g of lean mass, it follows that (Table 5-14). The metabolic forces associated with acute illness
severe illness may produce a daily loss of up to about 0.5 kg and injury are potent, and restoration of muscle mass is
of lean mass as a result of excess protein catabolism. Most of unlikely with nutritional support unless the underlying
this loss comes from skeletal muscle, where the efflux of amino inflammatory condition is corrected. There is increasing inter-
acids increases 2- to 6-fold in critically ill patients.56 est in attenuating or reversing net catabolism with the use of
Mobilization of amino acids from skeletal muscle appears exogenous anabolic agents in conjunction with nutrition,
to be an adaptive response. Once liberated, these amino acids, although to date it remains unclear whether the clinical ben-
in part, are deaminated and used for gluconeogenesis; they efits of using exogenous growth hormone and other anabolic
are also taken up by the liver and other visceral organs. The agents in acute illness outweigh their potential side effects.59,60
proteolysis of muscle under stress thus enables the body to Another important ramification of the potency of the catabolic
shift amino acids from skeletal muscle (the somatic protein state associated with acute illness is that most of the weight
compartment) to the visceral organs (the visceral protein com- gained with provision of nutritional support is the result of
partment), the functions of which are more critical for immedi- increases in fat mass and body water; only minor increases in
ate survival during illness. Nevertheless, with sustained stress, lean mass are observed until the inflammatory focus is
the limitations of this adaptive response become evident, and resolved.61
even the visceral protein compartment sustains a contraction Cytokines are the most important mediators of alterations
in mass.48 in energy and protein metabolism that accompany illness and
injury. In a wide spectrum of systemic illnesses, increased
Primary versus Secondary Protein-Energy Malnutrition: secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α,
IL-6, and interferon (IFN)-γ has been observed to be associ-
A Body Compartment Perspective ated with increased energy expenditure and protein catabo-
The type of tissue lost as malnutrition evolves is critical in lism, as well as the shift of amino acids into the visceral
determining the pathologic ramifications of weight loss. Over compartments.62-64 Such observations concur with in vitro
95% of energy expenditure resides in the lean body mass, studies in human cells and animal models that have shown
which therefore contains the bulk of metabolism that sustains remarkably potent effects of these cytokines in this regard
homeostasis. It is the maintenance of this body compartment (Table 5-15). In the wasting syndrome associated with cancer,
that is most critical for health. Lean body mass can be subdi- proteolysis-inducing factor and lipid-mobilizing factor are
vided further into somatic and visceral protein compartments, humoral mediators that appear to be unique to cancer
blood and bone cells, and extracellular lean mass, such as cachexia, contributing to protein catabolism and loss of
plasma and bone matrix (Fig. 5-1). In total or semistarvation adipose tissue, respectively.65 Promising data in animal models
in otherwise healthy individuals, adipose tissue predominates of cancer cachexia indicate that specific inhibitors of cancer-
as a primary energy source; thus, fat mass contracts to a mediated protein catabolism can be designed that greatly
much greater degree proportional to the loss of lean mass.48 reduce the morbidity and mortality associated with the
Alterations in metabolism from injury or illness, however, cachexia produced by this disease.66
Extracellular lean mass

Blood cells,
(plasma, bone mineral, etc.)
Protein-Energy Malnutrition in Children
bone cells, etc.
7% 36% Undernutrition in children differs from that in adults, because
Visceral it affects growth and development. Much of our understand-
mass ing of undernutrition in children comes from observations
7% made in underdeveloped nations where poverty, inadequate
food supply, and unsanitary conditions lead to a high preva-
lence of PEM. The Waterlow classification of malnutrition
(Table 5-16) takes into account a child’s weight for height
(wasting) and height for age (stunting).67 The characteristics of
the 3 major clinical PEM syndromes in children—kwashiorkor,
marasmus, and nutritional dwarfism—are outlined in Table
5-17.68 Although these 3 syndromes are classified separately,
overlap syndromes often coexist in the same patient.
Muscle
mass
22% TABLE 5-14 Body Compartment Losses in Simple
Fat Starvation versus Metabolic Stress
mass
28% Skeletal Muscle Visceral Loss of
Parameter Wasting Wasting Fat Mass
FIGURE 5-1. Body composition analysis by weight in a healthy
adult. Speckled segments and gray segment collectively repre- Starvation + +/−* +++
sent lean body mass. Speckled segments alone represent body
cell mass. (Adapted from Mason JB. Gastrointestinal cancer; Metabolic +++ ++/−* +++
nutritional support. In: Kelsen D, Daly J, Kern S, et al, editors. stress
Principles and practice of gastrointestinal oncology. Philadelphia: *Relatively spared early in the process; can become pronounced with extended
Lippincott Williams & Wilkins; 2002.) starvation or metabolic stress.
with kwashiorkor are typically lethargic and apathetic but

Kwashiorkor become very irritable when held. Kwashiorkor is not caused
The word kwashiorkor, from the Ga language of West Africa, by a relative deficiency in protein intake; rather, it most often
means “disease of the displaced child” because it was com- occurs when there is physiologic stress (e.g., infection) in an
monly seen after weaning. The presence of peripheral edema already malnourished child. Because infection or other acute
distinguishes children with kwashiorkor from those with stress is usually present in kwashiorkor, the metabolic aberra-
marasmus and nutritional dwarfism. Children with kwashior- tions associated with secondary PEM are in play, and contrac-
kor also have characteristic skin and hair changes (see later). tions of the visceral protein compartment are evident. A
The abdomen is protuberant because of weakened abdominal decrease in serum proteins like albumin is common, distin-
muscles, intestinal distention, and hepatomegaly, but ascites guishing it from pure marasmus. Kwashiorkor is character-
is rare. The presence of ascites, therefore, should prompt the ized by leaky cell membranes that permit movement of
clinician to search for liver disease or peritonitis. Children potassium and other intracellular ions into the extracellular
space, causing water movement and edema.
TABLE 5-15 Major Cytokines That Mediate Marasmus

Hypercatabolism and Hypermetabolism Associated with Weight loss and marked depletion of subcutaneous fat and
Metabolic Stress muscle mass are characteristic features of children with maras-
mus. Ribs, joints, and facial bones are prominent, and the skin
Cytokine Cell Sources Metabolic Effects is thin, loose, and lies in folds. In contrast, the visceral protein
compartment is relatively spared, a fact that often is reflected
TNF-α Monocytes/macrophages, Decreased FFA by a normal serum albumin level, which in turn sustains
lymphocytes, Kupffer synthesis normal oncotic pressure in the vascular compartment, thus
cells, glial cells, Increased lipolysis minimizing edema and helping to distinguish these children
endothelial cells, natural Increased amino from those with kwashiorkor.
killer cells, mast cells acid release from
muscles
Increased hepatic Nutritional Dwarfism
amino acid uptake The child with failure to thrive may be of normal weight
Fever for height but have short stature and delayed sexual
IL-1β Monocytes/macrophages, Increased ACTH and
neutrophils, cortisol levels
lymphocytes, Increased acute- TABLE 5-17 Features of Protein-Energy Malnutrition
keratinocytes, Kupffer phase protein Syndromes in Children
cells synthesis
Increased amino Syndrome
acid release from
muscles Nutritional
Decreased insulin Parameter Kwashiorkor Marasmus Dwarfism
secretion
Weight for age 60-80 <60 <60
Fever
(% expected)
IL-6 Monocytes/macrophages, Increased acute-
Weight for Normal or Markedly Normal
keratinocytes, phase protein
height decreased decreased
endothelial cells, synthesis
fibroblasts, T cells, Fever Edema Present Absent Absent
epithelial cells Decreased appetite
Mood Irritable when Alert Alert
IFN-γ Lymphocytes, pulmonary Increased monocyte
picked up,
macrophages respiratory burst
apathetic
FFA, free fatty acid; IFN, interferon; IL, interleukin. when alone
Adapted from Smith M, Lowry S. The hypercatabolic state. In: Shils M, Olson J,
Shike M, Ross AC, editors. Modern nutrition in health and disease. Baltimore: Appetite Poor Good Good
Williams & Wilkins; 1999. p 1555.
TABLE 5-16 Waterlow Classification of Protein-Energy Malnutrition in Children
Parameter Normal Mild Moderate Severe
Weight for Height (Wasting)

Percentage of median NCHS standard 90 to 100 80 to 89 70 to 79 <70
Standard deviation from the NCHS median +Z to −Z −1.1 Z to −2 Z −2.1 Z to −3 Z <−3 Z
Height for Age (Stunting)

Percentage of median NCHS standard 95 to 105 90 to 94 85 to 89 <85
Standard deviation from NCHS median +Z to −Z −1.1 Z to −2 Z −2.1 Z to −3 Z <−3 Z
NCHS, National Center for Health Statistics; Z, Standard Score.
development. Providing appropriate feeding can stimulate sometimes accompanied by bradycardia and, in conjunction
catch-up growth and sexual maturation. with the factors noted, can lead to low blood pressure.
The diagnosis of PEM is different in adults than in chil-
dren, because adults do not grow in height. Therefore, under-
nutrition in adults causes wasting rather than stunting. In Immune System
addition, although pure forms of kwashiorkor and marasmus The immune system is the most vulnerable to PEM, which
can occur in adults, contemporary studies of adult PEM in explains why several functions of immunity are used diagnos-
industrialized societies typically focus on hospitalized patients tically as indicators of malnutrition (e.g., total lymphocyte
with secondary PEM, coexisting illness or injury, and overlap- count and delayed skin hypersensitivity). The functional
ping features of kwashiorkor and marasmus. integrity of T lymphocytes, polymorphonuclear leukocytes,
and complement is uniformly blunted, whereas impaired B
lymphocyte production of antibodies is variably affected. A
Physiologic Impairments Caused by moderately to severely malnourished patient is an immuno-
compromised individual. Malnutrition leads to increased sus-
Protein-Energy Malnutrition ceptibility to infection, which in turn promotes development
PEM adversely affects almost every organ system, although of PEM, so a vicious cycle is created.
the brain usually is spared. Almost all adverse effects are
reversible with nutritional restitution. The following discus-
sion is not exhaustive; rather, it emphasizes impairments that Respiratory System
commonly translate into overt morbidity or that are important The diaphragm and other respiratory muscles undergo struc-
in the diagnosis of PEM. The effects described reflect what tural and functional atrophy, diminishing inspiratory and
occurs in primary PEM; superimposition of acute illness and expiratory pressures and vital capacity. These changes in mus-
secondary PEM often imposes more complexity. cular performance, in conjunction with blunted ventilatory
drive, impair the ability to sustain ventilation in the severely
malnourished individual. In patients with a tracheostomy,
adherence of bacteria to the tracheal epithelium correlates
System Effects with the severity of PEM, exacerbating other compromises in
the immune system described earlier.
Gastrointestinal Tract
Although PEM alone produces adverse effects on GI structure
and function, diminished stimulation of the GI tract by a lack Endocrine System
of ingested nutrients has an independent effect. Thus, sus- Although alterations in hormones are common in PEM, many
tained absence of nutrients passing through the intestine of of the changes can be perceived as serving adaptive functions.
healthy, nutritionally replete, parenterally fed individuals The inadequate intake of food leads to a decrease in the avail-
alone results in functional atrophy of the small intestinal ability of circulating glucose and amino acids, low circulating
mucosa, as evidenced by a loss of brush border enzymes and levels of insulin, and increased levels of growth hormone.
diminished integrity of the epithelial barrier. Villus atrophy These alterations, in conjunction with the decreased levels of
may also be observed with lack of intestinal stimulation, but in somatomedins and increased levels of cortisol in PEM,
the absence of PEM the degree of structural atrophy is minor.69 promote skeletal muscle catabolism and at the same time
The structural and functional deterioration of the intestinal enhance incorporation of the liberated amino acids into vis-
tract, pancreas, and liver as a result of PEM is described best ceral organs. Urea synthesis is inhibited, decreasing nitrogen
in children. Marked blunting of the intestinal villi is seen and loss and enhancing reutilization of amino acids. Enhancement
is usually associated with loss of some or all of the brush of lipolysis and gluconeogenesis provides a substrate for
border hydrolases. Gastric and pancreatic secretions are energy needs.
reduced in volume and contain decreased concentrations of Serum levels of triiodothyronine (T3) and thyroxine (T4) are
acid and digestive enzymes, respectively. The volume of bile commonly decreased in conjunction with increased concentra-
and the concentrations of conjugated bile acids in bile are tions of reverse T3, resembling the pattern observed in the
reduced. Increased numbers of facultative and anaerobic bac- euthyroid sick syndrome. The decreased concentration of T3
teria are found in the upper small intestine, probably explain- may play a role in decreasing REE and the protein catabolic
ing the increased proportion of free bile acids in the intestinal rate observed in primary PEM.
lumen. Malabsorption of carbohydrates, fats, and fat- and Primary gonadal dysfunction is common in adults with
water-soluble vitamins may occur, and the degree of steator- moderate to severe PEM and results in impaired reproductive
rhea is proportional to the severity of the PEM, creating a potential. Decreased circulating levels of testosterone in men
vicious cycle of further malnutrition. The abdominal protuber- and estrogen in women is evident, and amenorrhea is common.
ance sometimes seen in advanced malnutrition is thought to Delayed puberty or loss of menstrual periods most often
arise in part from intestinal hypomotility and gas distention. occurs when lean body mass drops below a critical threshold.
These changes can also be considered physiologic adaptations
because ensuring immediate survival is more critical than
Cardiovascular System the need for sexual maturation in the child or reproduction in
Moderate to severe PEM produces quantitative and qualita- the adult.
tive declines in the cardiac muscle. Myocardial mass is dimin-
ished, although proportionately less than the loss in body
weight. Myofibrillar atrophy, edema, and (less commonly)
patchy necrosis and infiltration with chronic inflammatory Other Effects
cells are seen in the myocardium. These structural changes are
associated with impaired myocardial performance. A decrease Wound Healing
in stroke volume, cardiac output, and maximal work capacity Well-nourished individuals lay down more collagen at the site
may be observed and are most evident under conditions of a surgical wound than those with even mild malnutrition.
of increased demand. Such functional impairments are Nutritional repletion of the malnourished patient before
surgery leads to better wound healing than if nutritional needs malnutrition-related morbidity. Thus, the presence of PEM
are only addressed postoperatively. has a predictive value. Even more importantly, identifying
malnourished patients and appropriate nutritional interven-
tion is likely to improve clinical outcome.71-75 Meta-analyses
Skin have underscored the importance of performing objective
Undernutrition often causes dry, thin, and wrinkled skin, nutritional assessments to categorize inpatients, because indi-
with atrophy of the basal layers of the epidermis and viduals who are well-nourished or mildly malnourished seem
hyperkeratosis. Severe malnutrition may cause considerable to realize little benefit from intensive nutritional support.76-78
depletion of skin protein and collagen. Patients with kwashi- A comprehensive nutritional assessment requires a history,
orkor experience sequential skin changes in different areas. physical examination, evaluation of anthropometrics or func-
Hyperpigmentation occurs first, followed by cracking and tional measures of nutritional status, and a panel of laboratory
stripping of superficial layers, leaving behind hypopigmented, blood tests. Some of the more commonly used assessment
thin, and atrophic epidermis that is friable and easily tools are weight, height, and other anthropometric measures
macerated. (e.g., skinfold thickness and midarm measurements), func-
tional measures (e.g., hand grip strength or skin testing for
evidence of anergy); serum protein concentrations (e.g.,
Hair albumin or prealbumin); complete blood count, including
Scalp hair becomes thin and sparse and is easily pulled out. absolute lymphocyte count; and 24-hour urinary creatinine
In contrast, the eyelashes become long and luxuriant, and and blood urea nitrogen levels. Less readily available mea-
there may be excessive lanugo in children. The hair of children sures of body composition, such as bioelectrical impedance
with kwashiorkor develops hypopigmentation, with reddish- and total body potassium, can be helpful in the appropriate
brown, gray, or blond discoloration. Adults may lose axillary setting. Some of these measures lack a high degree of specific-
and pubic hair. ity but continue to be useful in clinical care because of their
prognostic significance. Because no single parameter is suffi-
ciently sensitive or specific to assess PEM, these tools are most
Kidneys effective when used in combination. If the clinician is under-
Renal mass and function are often well preserved during taking a nutritional assessment solely to determine whether a
undernutrition. When malnutrition is severe, however, there patient falls into a category of moderate to severe PEM, far
are decreases in kidney weight, glomerular filtration rate, less than comprehensive assessment will usually suffice; such
ability to excrete acid and sodium, and ability to concentrate simple means of categorization are provided in the following
urine. Mild proteinuria also may occur. sections.
Bone Marrow History

Severe undernutrition suppresses bone marrow red blood cell
and white blood cell production, leading to anemia, leukope- Weight Loss
nia, and lymphocytopenia. Unintentional weight loss associated with illness is the single
most practical predictor of a clinically significant degree of
PEM. It is useful to quantify such loss by determining whether
NUTRITIONAL ASSESSMENT the patient has sustained a mild (<5%), moderate (5% to 10%),
or severe (>10%) degree of loss over the preceding 6 months.
TECHNIQUES Because acute illness incites a disproportionately large loss of
lean mass, it is not surprising that a more than 10% uninten-
The purpose of nutritional assessment is to identify PEM and tional loss in body weight usually correlates with a 15% to 20%
other nutritional deficits even when they are not readily dis- decrease in total body protein.58 This degree of unintentional
cernible. PEM can be subtle, but most cases are detected when loss is an important threshold because it is associated with
a systematic nutritional assessment is performed. An example impaired physiology, a poor clinical outcome, and extended
of subtle but clinically significant PEM is found in Child- hospitalization79-81; it also defines those individuals who will
Turcotte-Pugh class A alcoholic cirrhotics. These individuals likely benefit from intensive nutritional support. The clinician
usually appear well nourished. Indeed, one criterion to deter- should nevertheless be mindful that determining the magni-
mine class A status is a normal serum albumin level, but tude of weight loss by history has limited accuracy. One study
studies of whole-body nitrogen by in vivo neutron activation found that one third of patients with true weight loss go unde-
analysis have demonstrated that more than half of these class tected by history, and one quarter of those who had been
A individuals have less than 80% of expected total body weight-stable are miscategorized as having undergone weight
protein,70 the threshold level below which patients have loss.82 Furthermore, the nutritional significance of changes in
increased morbidity associated with malnutrition.58 body weight can be confounded by changes in hydration
In otherwise healthy people and in those who are chroni- status and extracellular fluid accumulation. Because weight
cally ill, PEM is usually defined by comparing an anthropo- loss is an imperfect indicator of PEM, it is useful to obtain
metric measurement (e.g., weight for height) to established other historical clues that can contribute to the identification
normative standards (see Table 5-6). In contrast, there is no of these patients (see later).
gold standard to define and measure PEM in the acutely ill
patient, because most parameters used to assess PEM in
otherwise healthy persons are altered by illness; weight and Food Intake
the concentration of serum proteins are prime examples. Has there been a change in habitual diet pattern (number,
Despite the inaccuracies inherent in assessing PEM in size, and contents of meals)? What is the reason for altered
acutely ill individuals, the usefulness of nutritional assess- food intake (e.g., change in appetite, mental status or mood,
ment in this setting has been repeatedly demonstrated. Acutely ability to prepare meals, ability to chew or swallow, GI
ill patients who are malnourished sustain higher rates of symptoms)?
Evidence of Malabsorption TABLE 5-18 Classification of Nutritional Status by Body

Are there symptoms consistent with malabsorption (e.g., Mass Index in Adults
greasy, fatty stools, osteopenia, easy bruisability)?
Body Mass Index (kg/m2) Nutritional Status
Evidence of Specific Nutrient Deficiencies <16.0 Severely malnourished
Are there symptoms of specific nutrient deficiencies, including 16.0-16.9 Moderately malnourished
macrominerals, micronutrients, and water? (See Tables 5-9
to 5-11.) 17.0-18.4 Mildly malnourished
18.5-24.9 Normal
Influence of Disease on Nutrient Requirements
Is the nature of the patient’s underlying illness one that is 25.0-29.9 Overweight
likely to increase nutrient needs or nutrient losses?
30.0-34.9 Obese (class I)
Functional Status 35.0-39.9 Obese (class II)

Has the patient’s ability to perform daily activities that deter- ≥40 Obese (class III)
mine consumption of wholesome meals changed? Can the
patient still shop and prepare meals? Have finances interfered
with the ability of the patient to purchase food?
large control population, and inter-individual variability in

Physical Examination the population limits this method’s accuracy for correctly
predicting PEM in one individual. Table 5-6 displays the
Hydration Status 1959 Metropolitan Life Insurance Company “desirable body
The patient should be evaluated for signs of dehydration (e.g., weights” that were established with prospective mortality
hypotension, tachycardia, postural changes, mucosal xerosis, data. The 1959 tables remain preferable to the 1983 tables
decreased axillary sweat, dry skin), and excess body fluid (e.g., because of certain assumptions made in the construction of
edema or ascites). the latter. In the context of the Metropolitan tables, desirable
weight for height is defined as that figure associated with
maximal longevity. In general, individuals whose weight is
Tissue Depletion less than 85% of the standard can be considered to have a
A general loss of adipose tissue can be assumed if there are clinically significant degree of PEM. Of note is that desirable
well-defined bony, muscular, and venous outlines and loose weights in this table are substantially less than average weights
skin folds. A fold of skin pinched between the forefinger and in North America.
thumb can reveal the adequacy of subcutaneous fat. Presence Body mass index (Table 5-18), defined as weight (in kilo-
of hollowness in the cheeks, buttocks, and perianal area sug- grams) divided by height (in meters squared), has been sup-
gests body fat loss. Examination of the temporalis, interosse- planting the use of weight for height, in part because it
ous, and quadriceps muscles should be done to judge muscle precludes the need to use normative data tables. BMIs outside
wasting. the desirable range (18.5 to 24.9 kg/m2) help identify patients
at increased risk of adverse clinical outcomes. A BMI modestly
above the desirable range has been shown to be predictive of
Muscle Function adverse outcomes in the surgical management of many
Strength testing of individual muscle groups can be performed diseases83-85 and in the medical management of conditions
to determine if there is generalized or localized muscle weak- like alcoholic liver disease.86 Similarly, a low BMI has been
ness. Myocardial function can be evaluated, and respiratory shown to be a robust independent risk factor in surgical and
muscle function can be assessed with spirometry. medical patients.87 Extremely underweight adult patients
(BMI < 14 kg/m2) are at high risk of death and should be
strongly considered for admission to the hospital to initiate
Specific Nutrient Deficiencies intensive nutritional support.
Rapidly proliferating tissues (e.g., oral mucosa, hair, skin, GI The BMI, like weight for height, is a surrogate and imper-
epithelium, bone marrow) are often more sensitive to nutrient fect measure of body composition. A low BMI (<18.5 kg/m2)
deficiencies than tissues that turn over more slowly (e.g., is interpreted as an indication of PEM, and a high BMI
heart, skeletal muscle, brain [see Tables 5-9 to 5-11]). (>24.9 kg/m2) is interpreted as excessive fat mass (overweight
or obesity). Although BMI is accurate in this regard for the
vast majority of adults, it can be just as misleading as any other
Anthropometry measure that relies on body weight without a direct evaluation
Anthropometric techniques are those in which a quantitative of body composition.88 For example, the individual with exces-
measure of the size, weight, or volume of a body part is used sive fluid accumulation, where actual fat and body cell mass
to assess protein and calorie status. Historically, one of the are less than that implied by the BMI, and the muscle-bound
most commonly used anthropometric parameters has been athlete, where a high BMI is indicative of an extraordinarily
weight for height. This is a useful parameter when neither the large lean mass, are 2 examples of how the underlying assump-
patient nor family can provide reliable historical information, tions inherent in the BMI are false. Gender and race are also
but it is less desirable than a history of unintentional weight confounding variables, although the differences are clinically
loss, because it requires the patient’s weight to be judged irrelevant. More important are the remarkable changes in
against a normative standard that has been established in a body composition that accompany development, making the
TABLE 5-19 Advanced Techniques for Measurement of TABLE 5-20 Normative Standards for Upper Arm Muscle
Body Compartments Area and Sum of Triceps and Subscapular Skinfolds
Primary Use in Body Percentile

Technique Compartment Analysis
Parameter Age 5th 50th 85th
Underwater (hydrostatic) Proportion of body
weighing89 composed of FM, proportion Upper Arm Muscle Area (cm2)*
of body composed of LM Men 25-29 38 53 65
45-49 37 55 66
Air displacement Proportion of body
65-69 33 48 63
plethysmography91 composed of FM, proportion
Women 25-29 20 30 38
of body composed of LM
45-49 21 32 45
65-69 22 35 46
Dual energy x-ray Absolute FM and LM; bone
absorptiometry92 density Sum of Triceps and Subscapular Skinfolds (mm)
Total body potassium93 Body cell mass Men 25-29 12 24 41

45-49 13 29 43
Isotopically labeled water and TBW, ICW, ECW 65-69 12 27 42
NaBr dilution94 Women 25-29 18 37 58
45-49 21 46 68
In vivo neutron activation Total body protein, absolute 65-69 22 45 65
analysis95 FM, absolute LM
*Mid–upper arm muscle area (cm2) is calculated as follows:
90
CT Regional FM/LM For men:
[ arm circumference − {π × triceps skinfold}]2
MRI 96
Regional FM/LM Area = − 10
4π
ECW, extracellular water; FM, fat mass; ICW, intracellular water; LM, lean mass; For women:
NaBr, sodium bromide; TBW, total body water. [ arm circumference − {π × triceps skinfold}]2
Area = − 6 .5
4π
Adapted with permission from Frisancho AR. Anthropometric standards for the
interpretation of BMI in childhood and adolescence very assessment of growth and nutritional status. Ann Arbor, Mich: University of
complex.89 Michigan Press; 1990.
It should be apparent from this discussion that measure-
ments of relevant body compartments (e.g., fat mass or fat-free
mass) can reveal important information about nutritional tables, there is considerable inter-individual variation in
status that is often obscured by measurement of weight alone. values, so these measurements are more useful in population
Underwater (hydrostatic) weighing, dual energy x-ray absorp- studies than in an individual. Moreover, these measures are
tiometry (DEXA), air impedance plethysmography, total body highly operator dependent.98 Also, although the updated data-
potassium, isotopically labeled water dilution, in vivo neutron bases defining normative values no longer contain the race
activation analysis, CT, and MRI are accurate noninvasive and age biases of older versions, correction factors for hydra-
(or minimally invasive) techniques of measuring body tion and physical activity are still unavailable.
compartments.89-96 All are highly effective, but because of their In practice, we have found the most useful clinical role
expense, lack of accessibility, and impracticality, their use is for the measurement of skinfolds and muscle area is in track-
largely relegated to the sphere of clinical research. A detailed ing patients with serial measurements over time as a means
understanding of these tools is beyond the scope of this of monitoring their recovery from disease or response to a
chapter, but the primary use of each, with reference to detailed clinical intervention. In this manner, the patient is being com-
reviews, is outlined in Table 5-19. pared with himself or herself rather than with some normative
In the clinical setting, simple but less accurate techniques value. In gastroenterology, the use of skinfolds and muscle
are used to assess body compartments. An approximate area has been of particular value in the assessment and man-
measure of whole-body fat mass can be derived from assess- agement of cirrhotic patients, because cirrhosis corrupts
ing the thickness of subcutaneous fat, which in a normally almost all the other common measures of nutritional status.
proportioned adult contains roughly half of the body’s adipose Abnormally low values for triceps skinfold (TSF) and MAMC
stores. The triceps and subscapular sites are used most com- are independent predictors of mortality in cirrhotics, and
monly for this purpose, and it is best to use the sum of the their incorporation into a Cox regression model improves the
triceps and subscapular folds because sizable inter-individual prognostic value of the Child-Turcotte Score.99 Also, when
differences exist in fat distribution. Furthermore, as total body patients with severe alcoholic hepatitis are treated with ana-
fat changes, the subcutaneous fat at each site responds in a bolic steroids, improvements in MAMC and other measures
different manner. Similarly, mid-arm muscle circumference of the fat-free mass (FFM) correlate with a positive response
(MAMC) provides a measure of skeletal muscle mass. Table to treatment.100
5-20 contains guidelines for interpretation of skinfold and Interest continues in bioimpedance analysis (BIA) as an
mid-arm muscle area based on data from the first 2 National inexpensive, relatively easy, noninvasive, and safe means of
Health and Nutrition Examination Surveys (NHANES I assessing FFM, body cell mass (BCM), and total body water
and II).97 (TBW). BCM is sometimes perceived as a more important
Clinical use of skinfolds and appendicular muscle area has measure of lean mass than FFM because it does not include
distinct weaknesses. As was true for the weight-for-height non-living lean mass (e.g., blood plasma and bone minerals
[see Fig. 5-1]). Resistance to electrical flow through the body

is measured, which is proportional to fat and bone mineral Biochemical Measures of Protein-Calorie Status
content, because these body components have poor conduc-
tivity. Because all other components of the body are suffused Serum Proteins
with electrolyte-laden water that readily conducts an electric The serum concentrations of several proteins synthesized in
current, calculations of TBW, FFM, and BCM can be made if the liver are used as indicators of protein-calorie status:
one abides by some general assumptions that define the water albumin, prealbumin (transthyretin), transferrin, and retinol-
content of each compartment. Those with expertise in its use binding protein (RBP [Table 5-21]). A low concentration of any
have found it useful for monitoring the FFM in outpatient of these proteins strongly suggests the presence of PEM in an
studies of renal dialysis and HIV-infected patients.101,102 Acute individual without a concurrent illness or injury. Because the
illness, however, produces shifts in the total amount of body half-lives of prealbumin, transferrin, and RBP are considerably
water and its distribution in the different compartments, shorter than albumin’s, it follows that changes in nutritional
rendering the technique largely worthless in the inpatient status will be reflected more promptly in levels of these 3
setting.103 Furthermore, the algorithms used to calculate body proteins than in albumin.
composition contain assumptions about body water that can A variety of factors alters the serum concentration of each
change with age, obesity, and disease, so BIA must be revali- of these proteins. Prealbumin levels are often elevated in
dated within any population in which it is used. chronic kidney disease or by glucocorticoid or oral contracep-
tive administration. The degree to which serum levels of all
these proteins are decreased in cirrhosis increases incremen-
Functional Measures of Protein-Calorie Status tally with worsening grades of the Child classification,
Several techniques have been developed that exploit the fact although even patients who are Child class A have a small
that skeletal muscle function is impaired in PEM, although decrease in albumin compared with healthy individuals.111
only 1 has acquired wide acceptance: fist-grip dynamometry All these proteins behave as negative acute-phase reactants
(FGD). Respiratory muscle strength evaluation has been used (i.e., their serum concentrations drop in response to systemic
in the past but, as outlined below, is prone to several con- inflammation, roughly proportional to the magnitude of the
founding factors that corrupt its results. FGD uses a hand- inflammatory response). This effect diminishes their reliability
held dynamometer to measure the maximal fist-grip force as indicators of PEM in the acutely ill patient, particularly
that can be elicited. When examined as a surrogate measure when used as a sole metric of nutritional status.112 Nonethe-
of total body protein in patients awaiting GI surgery, FGD less, with proper respect for their limited accuracy, they can
correlated strongly with in vivo neutron activation analysis still be useful. For example, prealbumin has been shown to be
and with MAMC.104 Similarly, FGD is excellent for detecting an efficient rapid means of screening inpatients for PEM on
depleted body cell mass in cirrhotic patients,105 a group in hospital admission.113
which it is notoriously difficult to perform nutritional assess-
ment. As noted, valid indicators of moderate to severe PEM
are strong predictors of clinical outcome in acutely ill patients, Creatinine-Height Index
and FGD is effective in this regard. Preoperative patients The amount of creatinine excreted in the urine over a 24-hour
whose fist-grip strength is less than 85% of age- and gender- period, corrected for the patient’s height, is an excellent means
corrected standards have a 2-fold increased risk of periopera- of assessing total skeletal muscle mass. The relationship holds
tive complications compared with those whose FGD is because a relatively constant percentage (≈2%) of muscle cre-
normal.106 In patients undergoing surgery for GI cancers, FGD atine is converted to creatinine each day. Values that are more
had superior sensitivity and specificity in predicting periop- than 20% below gender- and height-adjusted normative values
erative morbidity and mortality than a widely used discrimi- are indicative of moderate to severe PEM (Table 5-22). Updated
nant analysis called the prognostic nutritional index.107 FGD normative creatine-height index (CHI) values for children of
holds considerable promise for rapid and convenient assess- ages 3 to 18 years are available.114 In sick persons, the CHI
ment of protein-calorie status in both inpatients and outpa- tends to correlate with simple measures like unintentional
tients, but the technique is limited by its requirement for an weight loss, as well as with highly accurate measures of skel-
alert and cooperative patient. etal muscle like DEXA.115 However, incomplete urine collec-
Respiratory muscle strength, typically measured with a tion, abnormal or unstable renal function, excessive meat or
bedside spirometer as maximal sustained inspiratory force milk ingestion immediately preceding or during the collec-
and/or maximal sustained expiratory force, has also been tion, and glucocorticoid administration can alter creatinine
used as a measure of protein-calorie status108 but is generally excretion independently of changes in muscle mass.
considered unreliable because too many non-nutritional
factors may alter its measurement.
Although PEM adversely affects the physiology of almost Discriminant Analyses of Protein-Calorie Status
all organ systems, the immune system is in the most sensitive. As noted, many of the parameters used to measure PEM can
Delayed hypersensitivity skin testing, which assesses the also predict important clinical outcomes, but each parameter
integrity of cell-mediated immunity, has been used most often has its own limitations. Multifactorial indices that incorporate
in this regard. In critically ill patients, skin testing has value various combinations of these parameters have been devel-
in predicting mortality,109 but its interpretation is fraught with oped through the use of discriminant analyses. By combining
confounding variables, such as older age, systemic infection, the strengths of several parameters, the goal is to arrive at a
and major surgery, each of which will independently depress more accurate prognostic index to determine whether patients
reactivity. Furthermore, reactivity improves in an unpredict- have a substantial degree of PEM and to optimize the ability
able manner with nutritional restitution, so it is not useful for to predict which patients will have adverse clinical outcomes
monitoring patient progress.110 The value of skin testing to because of PEM. Thus, one may identify who might benefit
assess nutritional status is used best as part of an array of from intensive attention to their nutritional needs. Table 5-23
parameters that collectively assess nutritional status (see later, lists the prognostic indices that have been most widely studied,
“Discriminant Analyses of Protein-Calorie Status”). along with the outcomes each has been shown to predict.
TABLE 5-21 Proteins Synthesized in the Liver and Used to Assess Nutritional Status
Normal Value Mean

Serum Protein ± SD (Range)* Half-Life (Days) Function Comment†
Albumin 4.5 (3.5-5.0) 14-20 Maintains plasma oncotic Serum levels are determined by
pressure; carrier for small many different processes
molecules
Transferrin 2.3 (2.0-3.2) 8-9 Binds Fe2+ in plasma and Iron nutriture influences plasma
transports it to bone level; increased during pregnancy,
marrow estrogen therapy, and acute
hepatitis; reduced in protein-
losing enteropathy and
nephropathy, chronic infections,
uremia, and acute catabolic
states; often is measured
indirectly as total iron-binding
capacity
Transthyretin 0.30 (0.2-0.5) 2-3 Binds T3 and to a lesser Increased in patients with chronic
(prealbumin) extent T4; is a carrier for kidney disease on dialysis;
RBP reduced in acute catabolic states,
after surgery, in hyperthyroidism;
serum level is determined by
overall energy and nitrogen
balance
Retinol-binding 0.0372 ± 0.0073‡ 0.5 Transports vitamin A in Catabolized in the renal proximal
protein (RBP) plasma; binds tubular cell; with renal disease,
noncovalently to RBP increases and its half-life is
prealbumin prolonged; low plasma levels in
vitamin A deficiency, acute
catabolic states, after surgery,
and in hyperthyroidism
*Units are g/L. Normal range varies among centers; check local values.
†
All the listed proteins are influenced by hydration and presence of hepatocellular dysfunction.
‡
Normal values are age- and gender-dependent. Table value is for pooled subjects.
SD, standard deviation; T3, triiodothyronine; T4, thyroxine.
Adapted from Heymsfield S, Tighe A, Wang Z-M. Nutritional assessment by anthropometric and biochemical means. In: Shils M, Olson J, Shike M, editors. Modern nutrition
in health and disease. 8th ed. Philadelphia: Lea & Febiger; 1994. p 812.
Because many of the parameters incorporated into these severe malnutrition (category C). Despite the subjective nature
indices are influenced by disease severity and nutritional of some of its components, there is excellent agreement among
status, such indices are more properly thought of as assessing independent observers.117 The SGA has been shown to be reli-
an integration of illness severity and the likelihood of able, even in the hands of first-year medical and surgical resi-
malnutrition. dents,118 and has been validated as a predictor of clinical
outcomes in chronically institutionalized older adults and
Rapid Screening Tools for Assessment of patients with a variety of medical conditions.119-121
Targeted Populations
Assessing nutritional status with inexpensive, rapid, and con- Mini-Nutritional Assessment
venient means that are accurate in identifying patients with The MNA was developed as a rapidly administered screen to
PEM are of great value, particularly when large numbers of detect PEM in geriatric populations. A combination of history,
people need to be evaluated. Two such tools have been devel- limited physical examination, and simple anthropometrics
oped and extensively validated: the subjective global assess- (BMI, arm and calf circumference) can be obtained in a few
ment (SGA) and the Mini-Nutritional Assessment (MNA). minutes. Subjects receive a score that classifies them as being
nourished, malnourished, or at risk of malnutrition. The MNA
is a valid means of detecting PEM in older adults who are
Subjective Global Assessment generally healthy and ambulatory, as well as those who are
SGA (Box 5-1) was initially intended for use in surgical inpa- frail and institutionalized122,123; in the chronically institutional-
tients as a means of assessing nutritional status and predicting ized, it possesses considerable predictive value in projecting
postoperative infections; for the latter, it was found to be a future morbidity.124 One disadvantage of the MNA is that it
better predictor than serum albumin concentration, delayed does not screen for overweight or obesity. Other screening
skin hypersensitivity, MAMC, CHI, and the prognostic nutri- tools designed for geriatric populations, such as the Nutrition
tional index.116 A focused history and physical examination are Screening Initiative, have the ability to screen for under- and
used to categorize patients as well nourished (category A), overnutrition but have not been as extensively validated as
having mild or moderate malnutrition (category B), or having the MNA.125
TABLE 5-22 Normative Values for Daily Creatinine TABLE 5-23 Prognostic Indices in Hospitalized Patients
Excretion Based on Height
Incorporated
Men* Women† Index Parameters Correlates With
Ideal Ideal Likelihood of Serum folate, serum Duration of

Height Creatinine Height Creatinine malnutrition vitamin C, serum hospitalization
(cm) (mg) (cm) (mg) albumin, lymphocyte
count, hematocrit,
157.5 1288 147.3 830 triceps skinfold, arm
muscle circumference,
160.0 1325 149.9 851 weight
162.6 1359 152.4 875 Prognostic Serum albumin, serum Frequency of

nutritional transferrin, delayed postoperative
165.1 1386 154.9 900 index hypersensitivity, complications
triceps skinfold and mortality
167.6 1426 157.5 925
Instant Serum albumin, Frequency of
170.2 1467 160.0 949
nutritional lymphocyte count postoperative
index infection
172.7 1513 162.6 977
Hospital Serum albumin, Hospital mortality
175.3 1555 165.1 1006
prognostic delayed
177.8 1596 167.6 1044 index hypersensitivity,
presence of sepsis or
180.3 1642 170.2 1076 cancer
Adapted from Mason J, Rosenberg I. Protein-energy malnutrition. In: Isselbacher K,
182.9 1691 172.7 1109 Braunwald E, Wilson J, et al, editors. Harrison’s principles of internal medicine.
13th ed. New York: McGraw-Hill; 1994. p 440.
185.4 1739 175.3 1141
188.0 1785 177.8 1174 of sustained metabolic stress, nutritional support generally
will not lead to an increase in the protein compartment of the
190.5 1831 180.3 1206
body. Moreover, a gain in weight may not occur, and when it
does, much of the initial gain is from water and an expanded
193.0 1891 182.9 1240
fat mass.126 Despite these limitations, even in the absence of
*Creatinine coefficient (men) = 23 mg/kg of ideal body weight. weight gain or increases in serum protein levels, a course of
†
Creatinine coefficient (women) = 18 mg/kg of ideal body weight. nutritional support for an appropriate patient can improve
From Blackburn GL, Bistrian BR, Maini BS, et al. Nutritional and metabolic
physiologic functions and clinical outcome.127
assessment of the hospitalized patient. JPEN J Parenter Enteral Nutr 1977; 1:11-22.
The following sections cite some clinical scenarios particu-
larly relevant to gastroenterology for which compelling
clinical research upholds that aggressive nutritional support
AGGRESSIVE NUTRITIONAL SUPPORT IN provides benefit to the inpatient.
THE HOSPITALIZED PATIENT Malnourished Patients Undergoing Major Surgery

The chapter that follows provides detailed descriptions of the Nutritional support can be beneficial for moderately to
approaches to nutritional management that are presently severely malnourished patients who are scheduled to undergo
accepted as appropriate in the setting of specific GI and hepatic major surgery. Aggressive nutritional support for 7 or more
diseases. As a means of introduction, however, it is first worth days before surgery reduces perioperative complications and
considering under what circumstances compelling clinical sometimes mortality in malnourished patients.71-78,128-130 In the
observations indicate that “aggressive nutritional support” Veterans Association Cooperative Trial,71 which encompassed
(defined as using whatever means necessary and practical to almost 500 subjects about to undergo major abdominal or
meet the patient’s nutritional needs) truly benefits the acutely thoracic surgery, patients who were categorized as severely
ill patient. In practice, any acutely ill patient who has moder- malnourished and randomized to receive preoperative TPN
ate to severe malnutrition and is unlikely to be able to meet realized an almost 90% decrease in noninfectious periopera-
his or her own nutritional needs within 48 hours is a strong tive complications. No benefits were observed in mildly
candidate for aggressive nutritional support. Another common malnourished or well-nourished individuals. In trials of
indication for aggressive nutritional support is when a well- moderately to severely malnourished patients, preoperative
nourished or mildly malnourished inpatient is judged to be nutrition support generally conveys sizeable benefits: a trial
unlikely to meet at least 80% of his or her projected calorie that enrolled 90 patients with gastric or colorectal cancers
or protein goals for the coming 10 days. To date, there is undergoing surgery demonstrated a 35% decline in overall
insufficient evidence-based science to prove efficacy of this complications and a significant reduction in mortality.130 The
latter indication, although common sense would suggest it to observation that the benefits of preoperative nutritional
be true. support are confined to those with a substantial degree of
Catabolic forces that accompany acute illness make it dif- malnutrition is the same conclusion reached by meta-
ficult to correct nutritional deficits. In those with a high degree analyses.76,77 Deferring aggressive nutritional support until
trials have demonstrated that the rates of morbidity, mortality,

BOX 5-1 Subjective Global Assessment (SGA) of and the speed of recovery are improved with prompt institu-
Nutritional Status tion of enteral or parenteral nutrition in these patients.72-74,135
History
Weight change: Patients Undergoing Radiation Therapy
Loss in past 6 months: amount = __________ kg;
% loss = __________ The usefulness of aggressive nutrition support in patients
Change in past 2 weeks: __________ Increase undergoing radiation therapy has been studied most exten-
__________ No change __________ Decrease sively in those who have head and neck and esophageal
Dietary intake change: cancers. There is now reasonable evidence in these patients
No change ________ Change ________ Duration = ________ weeks that placement of a PEG tube and administration of supple-
Dietary status: mental tube feedings during and after the course of radiation
__________ Suboptimal solid diet therapy prevents further deterioration of nutritional status.136,137
__________ Hypocaloric liquids In patients with head and neck cancers, supplemental PEG
__________ Starvation feedings have also been shown to improve quality of life.
Gastrointestinal symptoms (that have persisted for >2 weeks): Although improvements in survival or decreased morbidity
________ None ________ Nausea ________ Vomiting have not yet been demonstrated, improved quality of life
________ Diarrhea ________ Anorexia alone may warrant its use in this setting.
Functional capacity:
__________ No dysfunction __________ Dysfunction
Duration = __________ Weeks
Type:
KEY REFERENCES
__________ Working suboptimally
__________ Ambulatory but not working Full references for this chapter can be found on
__________ Bedridden www.expertconsult.com.
Effect of disease on nutritional requirements:
Primary diagnosis: __________ 3. Mifflin M, St. Jeor S, Hill L, et al. A new predictive equation
Metabolic demand: _________ Low stress _________ Moderate for resting energy expenditure in healthy individuals. Am J
stress _________ High stress Clin Nutr 1990; 51:241-7.
7. van den Berghe G, Wouters P, Weekers F, et al. Intensive
Physical Examination (Normal, Moderate, or Severe) insulin therapy in the critically ill patients. N Engl J Med
__________ Loss of subcutaneous fat (triceps, chest) 2001; 345:1359-67.
__________ Muscle wasting (quadriceps, deltoids)
8. van den Berghe G, Wilmer A, Hermans G, et al. Intensive
__________ Ankle or sacral edema
insulin therapy in the medical ICU. N Engl J Med 2006;
__________ Ascites
354:449-61.
SGA Rating* 12. Wiener R, Wiener D, Larson R. Benefits and risks of tight
A = Well nourished glucose control in critically ill adults: A meta-analysis.
B = Mild or moderate malnutrition JAMA 2008; 300:933-44.
C = Severe malnutrition 13. Port A, Apovian C. Metabolic support of the obese
intensive care unit patient: A current perspective. Curr
*The ranks of A, B, and C in the SGA are assigned on the basis of subjective
weighting. A patient with weight loss and muscle wasting who is currently Opin Clin Nutr Metab Support 2010; 13:184-91.
eating well and gaining weight is classified as well nourished. A patient with 15. Van den Berghe G. Low glutamine levels during critical
moderate weight loss (between 5% and 10%), continued compromise in food illness—adaptive or maladaptive? N Engl J Med 2013;
intake, continued weight loss, progressive functional impairment, and moderate 368:1549-50.
stress due to illness is classified as moderately malnourished. A patient with
severe weight loss (>10%), poor nutrient intake, progressive functional 28. Wolman SL, Anderson GH, Marliss EB, et al. Zinc in total
impairment, and muscle wasting is usually classified as having severe parenteral nutrition: Requirements and metabolic effects.
malnutrition. Gastroenterology 1979; 76:458-67.
33. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J
Med 2013; 368:149-60.
48. Hoffer LJ. Metabolic consequences of starvation. In: Shils
after surgery does not appear to have the same ability to M, Shike M, Ross AC, et al, editors. Modern nutrition in
diminish perioperative complications.131 health and disease. 10th ed. Baltimore: Lippincott Williams
Provision of nutrients via an enteral approach is also ben- & Wilkins; 2006. p 730.
eficial. There have been fewer trials done of preoperative 55. Wolfe RR. Regulation of skeletal muscle protein metabolism
enteral support than of preoperative TPN, but it appears that in catabolic states. Curr Opin Clin Nutr Metab Care 2005;
preoperative enteral support conveys the same nutritional132 8:61-5.
and clinical133 benefits as TPN. As with TPN, postoperative 58. Hill G. Body composition research: Implications for the
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support is less likely to convey benefit to the patient.134 1992; 16:197-218.
70. Prijatmoko D, Strauss B, Lambert J, et al. Early detection of
Patients Hospitalized with Decompensated protein depletion in alcoholic cirrhosis: Role of body
composition analysis. Gastroenterology 1993; 105:1839-45.
Alcoholic Liver Disease 77. Heyland D, MacDonald S, Keefe L, et al. TPN in the
The prevalence of moderate to severe PEM is so high in critically ill patient: a meta-analysis. JAMA 1998;
patients admitted for acute alcoholic hepatitis and other forms 16:2013-19.
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assume all such patients are malnourished. Furthermore, nutritional status. Gastroenterology 1990; 99:1845-6.
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CHAPTER

Nutritional Principles and Assessment of

BASIC NUTRITIONAL CONCEPTS Resting Energy Expenditure

TABLE 5-1 Endogenous Fuel Stores in a 70-kg Man Harris-Benedict Equation

Tissue Fuel Source Grams Kilocalories Mifflin Equation

Adipose Triglyceride 13,000 121,000 Men (10 × W) + (6.25 × H) − (5 × A) + 5

TABLE 5-2 Resting Energy Requirements of Various Tissues in a 70-kg Man

Tissue Mass Energy Consumed

Percentage Kcal/g Percentage

Liver 1550 2.2 445 0.28 19

GI tract 2000 3.0 300 0.15 13

Brain 1400 2.0 420 0.30 18

Kidneys 300 0.4 360 1.27 15

Heart 300 0.4 235 0.80 10

Skeletal muscle 28,000 40.0 400 0.014 18

Adipose 15,000 21.0 80 0.005 4

context. In acutely ill hospitalized patients, it is not usually

Method without a Stress Factor

Uncomplicated postoperative state 1.1 Caloric Delivery and Avoidance of Hyperglycemia

Men, Medium Frame Women, Medium Frame

Weight (lb) Weight (lb)

Height (ft/inches) Range Midpoint Height (ft/inches) Range Midpoint

4′8″ 93-104 98.5

4′9″ 95-107 101

4′10″ 98-110 104

4′11″ 101-113 107

5′0″ 104-116 110

5′1″ 113-124 118.5 5′1″ 107-119 113

5′2″ 116-128 122 5′2″ 110-123 116.5

5′3″ 119-131 125 5′3″ 113-127 120

5′4″ 122-134 128 5′4″ 117-132 124.5

5′5″ 125-138 131.5 5′5″ 121-136 128.5

5′6″ 129-142 135.5 5′6″ 125-140 132.5

5′7″ 133-147 140 5′7″ 129-144 136.5

5′8″ 137-151 144 5′8″ 133-148 140.5

5′9″ 141-155 148 5′9″ 137-152 144.5

5′10″ 145-160 153 5′10″ 141-156 148.5

5′11″ 149-165 157

6′0″ 153-170 161.5

6′1″ 157-175 166

6′2″ 162-180 171

6′3″ 167-185 176

patients, nor were differences in overall mortality evident in

TABLE 5-9 Major Mineral Requirements and Assessment of Deficiency

An individual’s dietary requirement for any given micro- Trace Minerals

TABLE 5-10 Salient Features of Vitamins

Vitamin Deficiency (RDA)* Toxicity (TUL)† Assessment of Status

D Deficiency results in decreased Excess amounts result in Serum concentration

E Deficiency caused by dietary inadequacy is Depressed levels of vitamin K– Plasma or serum

TABLE 5-10 Salient Features of Vitamins—cont’d

Vitamin Deficiency (RDA)* Toxicity (TUL)† Assessment of Status

K Deficiency syndrome is uncommon except Rapid intravenous infusion of Prothrombin time is

TABLE 5-10 Salient Features of Vitamins—cont’d

Vitamin Deficiency (RDA)* Toxicity (TUL)† Assessment of Status

TABLE 5-10 Salient Features of Vitamins—cont’d

Vitamin Deficiency (RDA)* Toxicity (TUL)† Assessment of Status

TABLE 5-11 Salient Features of Trace Minerals

Mineral Deficiency (RDA)* Toxicity (TUL)† Assessment of Status