3 s2.0 B9780323609623000059 PDF

PART
II Nutrition in Gastroenterology
5 Nutritional Principles and Assessment of the

Gastroenterology Patient
Joel B. Mason
CHAPTER OUTLINE intervention. The fact that many clinical trials have failed to demon-
strate a benefit of nutritional support in hospitalized patients is often
BASIC NUTRITIONAL CONCEPTS��52 because such a distinction has not been made. The major aim of this
Energy Stores��52 chapter is to provide the scientific principles and practical tools nec-
Energy Metabolism��52 essary to recognize patients who will benefit from focused attention
Proteins��55 to their nutritional needs, and to provide the guidance necessary to
Carbohydrates��56 develop a suitable nutritional plan for these individuals.
Lipids��56 Over- or under-feeding a patient can be detrimental to clinical
Major Minerals��57 outcomes, so developing a nutritional plan most appropriately begins
by determining the patient’s estimated caloric and protein needs.
MICRONUTRIENTS��57
Vitamins��57
Trace Minerals��57 BASIC NUTRITIONAL CONCEPTS
Physiologic and Pathophysiologic Factors Affecting Energy Stores
Micronutrient Requirements��62
Endogenous energy stores are oxidized continuously for fuel.
STARVATION��63 Triglyceride (TG) present in adipose tissue is the body’s major
MALNUTRITION��64 fuel reserve and is critical for survival during periods of starvation
Protein-Energy Malnutrition (PEM)��65 (Table 5.1). The high energy density and hydrophobic nature of
Physiologic Impairments Caused by Protein-Energy TGs make them a five-fold better fuel per unit mass than glycogen.
Malnutrition��67 TGs liberate 9.3 kcal/g when oxidized and are stored compactly as
oil inside the fat cell. In comparison, glycogen produces only 4.1
NUTRITIONAL ASSESSMENT TECHNIQUES��68 kcal/g on oxidation and is stored intracellularly as a gel, containing
History��68 approximately 2 g of water per gram of glycogen. Adipose tissue
Physical Examination��69 cannot provide fuel for certain tissues like bone marrow, erythro-
Anthropometry��69 cytes, leukocytes, renal medulla, eye tissues, and peripheral nerves,
Functional Measures of Protein-Calorie Status��70 which cannot oxidize lipids and require glucose for their energy
Biochemical Measures of Protein-Calorie Status��71 supply. During endurance exercise, glycogen and TGs in muscle
Rapid Screening Tools for Assessment of Targeted tissue provide an important source of fuel for working muscles.
Populations��72
AGGRESSIVE NUTRITIONAL SUPPORT IN THE Energy Metabolism
HOSPITALIZED PATIENT��73 Energy is required continuously for normal organ function, main-
Malnourished Patients Undergoing Major Surgery��73 tenance of metabolic homeostasis, heat production, and perfor-
Patients Hospitalized with Decompensated Alcohol- mance of mechanical work. Daily total energy expenditure (TEE)
Associated Liver Disease��73 has three components: resting energy expenditure (REE) (≈70% of
Patients Undergoing Radiation Therapy��73 TEE); the energy expenditure of physical activity (≈20% of TEE);
and the thermic effect of feeding (≈10% of TEE), which is the
temporary increase in energy expenditure that accompanies enteral
ingestion or parenteral administration of nutrients. Although the
Diligent attention to patients’ nutritional needs can have a major latter two components of TEE should be considered when esti-
positive impact on medical outcomes. This is particularly true in mating caloric needs for ambulatory individuals, in acutely ill,
GI and liver disease because many of these conditions, in addition hospitalized patients, the energy expended in physical activity is
to altering nutrient metabolism and requirements, are prone to typically ignored and the energy expended in the thermic effect of
interfere with ingestion and assimilation of nutrients. Nutritional feeding is built into the predictive equations that follow.
management, however, often continues to be an inadequately or
incorrectly addressed component of patient care.
Inadequate or misdirected attention to nutritional issues is due, in
Resting Energy Expenditure
part, to failure to distinguish patients who stand to benefit from nutri- REE represents energy expenditure while a person lies quietly awake
tional care from those whose outcomes will not respond to nutritional in an interprandial state; under these conditions, about 1 kcal/kg body
52
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CHAPTER 5 Nutritional Principles and Assessment of the Gastroenterology Patient 53
weight is consumed per hour in healthy adults. Energy requirements multiple of REE, can be used to estimate TEE in active patients.
of specific tissues differ dramatically (Table 5.2). The liver, intestine, The energy expended during a particular physical activity is equal 5
brain, kidneys, and heart constitute roughly 10% of total body weight to (REE per hour) × (activity factor) × (duration of activity in
but account for about 75% of REE. In contrast, skeletal muscle at rest hours). TEE represents the summation of energy expended dur-
consumes some 20% of REE, but represents approximately 40% of ing all daily activities, including rest periods.
body weight. Adipose tissue consumes less than 5% of REE but usu-
ally accounts for greater than 20% of body weight.
An accurate assessment of REE is best obtained by indirect
Thermic Effect of Feeding
calorimetry, in which in vivo energy expenditure is estimated Eating or infusing nutrients increases metabolic rate. Dietary protein
by measuring carbon dioxide production and oxygen consump- causes the greatest stimulation of metabolic rate, followed by carbo-
tion while the subject is at rest. Although indirect calorimetry is hydrate and then fat. A meal containing all these nutrients usually
considered a gold standard for determining REE, obtaining such increases metabolic rate by 5% to 10% of ingested or infused calories.
a measurement is not always practical and, in most instances, is
unnecessary. Instead, one of several empiric equations can be
used to estimate resting energy requirements (Table 5.3).1-4 The
Recommended Energy Intake in Hospitalized Patients
Harris-Benedict and Mifflin equations are designed for use in In arriving at a nutritional plan for hospitalized patients, it is
adults, whereas the WHO formulas includes equations for both usually not necessary to obtain actual measurements of energy
children and adults. These equations are generally accurate in expenditure with a bedside indirect calorimeter. A number of
healthy subjects but are inaccurate, for example, in persons who simple formulas can be used instead and make up in practical
are at extremes in weight because of anomalous body composi- value what they lack in accuracy. A few examples follow.
tion, and it is in these settings where determination by indirect
calorimetry is useful.5 In the setting of acute illness, the predictive Methods Incorporating Metabolic Stress Factors
equations are usually adequate although it is necessary to insert Metabolic stress (i.e., any injury or illness that incites some degree
correction factors of one type or another since inflammation and of systemic inflammation) will increase the metabolic rate through
metabolic stress greatly influence energy expenditure. Protein- a variety of mechanisms (see later). The increase in energy expen-
energy malnutrition (PEM) and hypocaloric feeding without diture is roughly proportional to the magnitude of the stress.6
superimposed illness each decrease REE to values 10% to 15% Thus, the total daily energy requirement of an acutely ill patient
below those expected for actual body size, whereas acute illness or can be estimated by multiplying the predicted REE (as determined
trauma predictably increases energy expenditure (see later). by the Harris-Benedict or WHO equations) by a stress factor:
TEE = REE × Stress factor
Energy Expenditure of Physical Activity Table 5.5 delineates metabolic stress factors that accompany
The effect of physical activity on energy expenditure depends on some common conditions and clinical scenarios in inpatients.
the intensity and duration of daily activities. Highly trained ath- Because the Mifflin equation was not designed to be used to esti-
letes can increase their TEE 10- to 20-fold during athletic events. mate TEE with stress factors, it is not recommended in this con-
The activity factors shown in Table 5.4, each expressed as a text. In acutely ill hospitalized patients, it is not usually necessary
to include an activity factor.
An alternative and simple formula for adult inpatients,
TABLE 5.1 Endogenous Fuel Stores in a 70-kg Man although accompanied by some further loss in accuracy, is:

Mass
• 20 to 25 kcal/kg of actual body weight (ABW)/day for un-
Tissue Fuel source Grams Kilocalories stressed or mildly stressed patients
Adipose Triglyceride 13,000 121,000 • 25 to 30 kcal/ABW/day for moderately stressed patients
• 30 to 35 kcal/ABW/day for severely stressed patients
Liver Protein 300 1,200
Glycogen 100 400 In using this formula, adjustments are necessary when the
Triglyceride 50 450 ABW is a misleading reflection of lean body mass. An adjusted
Muscle Protein 6,000 24,000
ideal body weight (IBW) should be substituted for ABW in obese
Glycogen 400 1,600 individuals who are more than 30% heavier than their IBW
Triglyceride 250 2,250 (desirable body weights appear in Table 5.6). Using an adjusted
IBW helps prevent an overestimation of energy requirements6
Blood Glucose 3 12
Triglyceride 4 37
and is calculated as:
Free fatty acids 0.5 5 Adjusted IBW = IBW + 0.5 (ABW − IBW)
TABLE 5.2 Resting Energy Requirements of Various Tissues in a 70-kg Man

Tissue Mass Energy Consumed
Tissue Grams Percentage Body Weight Kcal/Day Kcal/g Tissue/Day Percentage REE
Liver 1,550 2.2 445 0.28 19
GI tract 2,000 3.0 300 0.15 13
Brain 1,400 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

REE, Resting energy expenditure.

54 PART II Nutrition in Gastroenterology
TABLE 5.3 Commonly Used Formulas for Calculating Resting Energy TABLE 5.5 Metabolic Stress Factors for Estimating Total Energy
Expenditure Expenditure in Hospitalized Patients
Harris-Benedict Equation Injury or Illness Relative Stress Factor*

Men 66 + (13.7 × W) + (5 × H) − (6.8 × A) Second- or third-degree burns, 1.6-2.0
Women 665 + (9.6 × W) + (1.8 × H) − (4.7 × A) >40% BSA
Mifflin Equation Multiple trauma 1.5-1.7

Men (10 × W) + (6.25 × H) − (5 × A) + 5 Second- or third-degree burns, 1.4-1.5
20%-40% BSA
Women (10 × W) + (6.25 × H) − (5 × A) − 161
Severe infections 1.3-1.4
World Health Organization Formula
Age (yr) Male Female Acute pancreatitis 1.1-1.2
0-3 (60.9 × W) − 54 (60.1 × W) − 51 Second- or third-degree burns, 1.2-1.4

10%-20% BSA
3-10 (22.7 × W) − 495 (22.5 × W) + 499
Long bone fracture 1.2
10-18 (17.5 × W) + 651 (12.2 × W) + 746
Peritonitis 1.2
18-30 (15.3 × W) + 679 (14.7 × W) + 996
Uncomplicated postoperative state 1.1
30-60 (11.2 × W) + 879 (8.7 × W) + 829
*A stress factor of 1.0 is assumed for healthy controls.
>60 (13.5 × W) + 987 (10.5 × W) + 596 BSA, Body surface area.

Calculated as kilocalories per day. From Psota T, Chen KY. Measuring energy expenditure in clinical popula-
A, Age in years; H, height in centimeters; W, weight in kilograms. tions: rewards and challenges. Eur J Clin Nutr 2013; 67:436–42.

TABLE 5.4 Relative Thermic Effect of Various Levels of Physical Activity patients. One reason for this conservatism is that acute illness
and its management often exacerbate preexisting diabetes or
Activity Level Examples Activity Factor produce de novo glucose intolerance. As a result, hyperglycemia
Resting 1.0 is a frequent consequence of enteral, and especially parenteral,
Very light Standing, driving, typing 1.1-2.0
nutrition. The issue seems to be particularly germane for ICU
patients, in whom even modest hyperglycemia results in worse
Light Walking 2-3 miles/hr, shopping, 2.1-4.0 clinical outcomes, usually of an infectious nature. High-quality
light housekeeping
clinical trials in surgical ICU (SICU)8 and medical ICU (MICU)9
Moderate Walking 3-4 miles/hr, biking, 4.1-6.0 patients have found that morbidity is substantially and signifi-
gardening, scrubbing floors cantly reduced in those randomized to intensive insulin therapy
Heavy Running, swimming, climbing, 6.1-10.0 who maintained serum glucose levels below 111 mg/dL, com-
basketball pared with those whose glucose values were maintained below

Adapted from Alpers DA, Stenson WF, Bier DM. Manual of nutritional
215 mg/dL. Mortality was also significantly lower among SICU
therapeutics. Boston: Little, Brown; 1995. patients randomized to receive tight glucose control, although in
the MICU study, such reductions in mortality caused by tight
glucose control were only realized in those who resided in the
In patients with large artifactual increases in weight due to MICU greater than 3 days. Similarly, in a clinical trial of pedi-
extracellular fluid retention (e.g., ascites), the IBW should be atric ICU patients, secondary infections, length of PICU stay,
used to estimate energy requirements rather than the ABW. and mortality were all reduced by intensive age-specific glucose
control.10 These observations are almost certainly the clinical
Method Without a Stress Factor expression of the numerous mechanistic impairments that acute
The most accurate and extensively validated equation for predict- hyperglycemia produces in the innate immune system.11
ing daily energy expenditure in ill patients is one that does not The clinical benefits of tight glucose control in the ICU, how-
incorporate a stress factor; it does, however, require knowledge ever, have not always been reproducible12 and come at the cost of
of the minute ventilation, so its use is restricted to patients on more frequent hypoglycemic episodes,8-10, 12 so the issue of how
mechanical ventilation.4 This formula (often referred to as the tight glucose control should be remains controversial. Extremely
“Penn State Equation”) is: tight control, with a target range of 81 to 108 mg/dL, produced
TEE = (REE calculated by Mifflin equation × 0.96) a 13-fold greater risk of hypoglycemia and a significantly greater
+ (Tmax × 167) + (Ve × 31) − 6212 mortality in a large multicenter trial of ICU patients,13 and is,
therefore, excessive. A panel of experts recently recommended
Tmax is the maximum temperature in Celsius over the past 24 instituting protocols to keep blood sugar levels at 150 mg/dL or
hours; Ve is expired minute ventilation in liters. lower in ICU patients, preferably by use of a continuous infusion
Table 5.7 describes a simple alternative method for estimating of insulin, with monitoring every 1 to 2 hours so that appropriate
total daily energy requirements in hospitalized patients; it is based adjustments can be made and blood sugar values less than 70 mg/
on BMI.7 It lacks the extensive validation of the prior algorithm as dL are avoided.14 The results of a meta-analysis of 29 trials in
well as some of its accuracy, but it does not require knowledge of critically ill patients recapitulate the previously observed discrep-
minute ventilation, is straightforward, and consequently has some ancies between SICU and MICU patients.15 Overall, the rela-
genuine utilitarian value. Common sense has to be applied when tive risk of septicemia was reduced approximately 25% in those
using an inexact means such as this to estimate energy expenditure randomized to tight glucose control, although this salutary effect
in hospitalized individuals, because illness commonly interjects was largely attributable to the SICU patients, in whom reduction
artifacts into these calculations (e.g., ascites, anasarca). in septicemia was almost 50%; no benefit was observed in MICU
patients, nor were differences in overall mortality evident in any
Caloric Delivery and Avoidance of Hyperglycemia of the categories of critically ill patients.
Over the past 2 decades, the trend has generally been toward The question of appropriate caloric delivery to critically ill
a more conservative approach to caloric delivery in acutely ill overweight and obese patients who account for a burgeoning
TABLE 5.6 Desirable Weight in Relation to Height for Men and Women 25 Years or Older
5
Men, Medium Frame Women, Medium Frame
Weight (lb) Weight (lb)
Height (ft/inches) Range Midpoint Height (ft/inches) Range Midpoint
5′1″ 113-124 118.5 4′8″ 93-104 98.5
5′2″ 116-128 122 4′9″ 95-107 101
5′3″ 119-131 125 4′10″ 98-110 104
5′4″ 122-134 128 4′11″ 101-113 107
5′5″ 125-138 131.5 5′0″ 104-116 110
5′6″ 129-142 135.5 5′1″ 107-119 113
5′7″ 133-147 140 5′2″ 110-123 116.5
5′8″ 137-151 144 5′3″ 113-127 120
5′9″ 141-155 148 5′4″ 117-132 124.5
5′10″ 145-160 153 5′5″ 121-136 128.5
5′11″ 149-165 157 5′6″ 125-140 132.5
6′0″ 153-170 161.5 5′7″ 129-144 136.5
6′1″ 157-175 166 5′8″ 133-148 140.5
6′2″ 162-180 171 5′9″ 137-152 144.5
6′3″ 167-185 176 5′10″ 141-156 148.5

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 lbs 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 Hospitalized Patients Proteins

Based on Body Mass Index
Twenty different amino acids (AAs) are commonly found in human
Energy Requirements (kcal/kg/ proteins. Some AAs (histidine, isoleucine, leucine, lysine, methio-
Body Mass Index (kg/m2) day)* nine, phenylalanine, threonine, tryptophan, valine, and possibly
<15 35-40 arginine) are considered essential because their carbon skeletons
15-19 30-35 cannot be synthesized by the body. Other AAs (glycine, alanine,
serine, cysteine, tyrosine, glutamine, glutamic acid, asparagine,
20-29 20-25 and aspartic acid) are nonessential in most circumstances because
≥30 15-20 they can be made from endogenous precursors or essential AAs. In

The lower range within each body mass index (BMI) category should be disease states and in pre-term infants, intracellular and/or plasma
considered in calculating energy requirements for insulin-resistant or concentrations of certain nonessential AAs are often very low and
critically ill patients to decrease the risk of hyperglycemia and infection thought of as “conditionally essential” AAs. For many years, sup-
associated with overfeeding. plemental glutamine was included in TPN to compensate for cellu-
*These values are recommended for critically ill patients and all obese lar depletion of this AA during critical illness. However, rigorously
patients; add 20% of the total calories when estimating energy conducted clinical trials have shown no benefit associated with
requirements in non–critically ill patients. administration of supplemental IV glutamine.17-19 In a randomized

placebo controlled multi-center, multi-national trial of critically
ill adults with multiorgan failure, glutamine supplementation was
proportion of patients cared for in ICUs is a controversial issue associated with an increase in mortality.18 Evidently, repletion of a
at present. A popular nutritional approach to such patients is conditionally essential AA during acute illness does not necessarily
so-called hypocaloric feeding, in which only 60% to 70% of the convey a benefit. However, there continues to be interest in defin-
estimated energy requirement (or 11 to 14 kcal/kg of ABW) is ing clinical scenarios in critical illness (e.g., premature infants),
delivered in conjunction with 2 to 2.5 grams of protein/kg of in which supplementation with conditionally essential AAs might
IBW per day, the latter minimizing the risk of producing net improve clinical outcomes.20 Arginine, cysteine, glycine, gluta-
protein catabolism and loss of lean body mass. The purported mine, proline, and tyrosine are AAs that fall into this category.
advantages of hypocaloric feeding include improved glycemic The body of an average 75-kg man contains about 12 kg of
control and prevention of metabolic complications like hypercap- protein. In contrast to fat and carbohydrate, there is no storage
nia and hypertriglyceridemia. Reduction in fat mass and weight depot for protein, so excess intake is catabolized and the nitro-
is another consequence of hypocaloric feeding, but should never gen component is excreted. Inadequate protein intake causes net
be a primary objective in feeding obese ICU patients. System- nitrogen losses, and because no depot form of protein exists, there
atic reviews that have examined the use of hypocaloric feeding is an obligatory net loss of functioning protein. The U.S. Recom-
in obese ICU patients, and which have examined important end- mended Daily Allowance (RDA) of protein has been established
points such as mortality, length of stay, duration of mechanical at 0.8 g/kg/day, which reflects a mean calculated requirement of
ventilation, and infectious complications have not yet been able 0.6 g/kg/day plus an added factor to take into account the bio-
to arrive at a consistent consensus either supporting net benefits logical variance in requirement observed in a healthy population.
or risks of hypocaloric, compared to normocaloric, nutrition sup- Intravenously administered AAs are as effective in maintaining
port.16 Thus, the matter remains an unsettled one. nitrogen balance as oral protein of the same AA composition.
TABLE 5.8 Recommended Daily Protein Intake is calculated as the difference between N intake and N losses in
urine, stool, skin, and body fluids. In the clinical setting, it can be
Clinical Condition Daily Protein Requirement (g/kg IBW)
conveniently calculated as follows for adults:
Normal 0.80
Metabolic stress 1.0-1.6
N balance = (Grams of N administered as nutrition)
− (Urinary urea N [g] + 4)
Hemodialysis 1.2-1.4
Peritoneal dialysis

1.3-1.5 Every 6.25 g of administered protein (or AAs) contains approx-
Additional protein requirements are needed to compensate for excess imately 1 g of N. The additional 4 g of N loss incorporated into
protein loss in specific patient populations (e.g., patients with burn the equation is intended to account for the insensible losses from
injuries, open wounds, protein-losing enteropathy, or nephropathy). the other sources listed and because urinary urea N only accounts
Lower protein intake may be necessary for patients with renal for approximately 80% of total urinary nitrogen. N balance is a
insufficiency not treated by dialysis and certain patients with liver suitable surrogate for protein balance, because roughly 98% of
disease and hepatic encephalopathy. total body N is in protein, regardless of one’s health.
IBW, Ideal body weight. A positive N balance (i.e., intake > loss) represents anabolism

and a net increase in total body protein, whereas a negative N bal-
ance represents net protein catabolism. For example, a negative
An individual’s protein requirement is affected by several N balance of 1 g/day represents a 6.25 g/day loss of body protein,
factors, such as the amount of non-protein calories provided, which is equivalent to a 30 g/day loss of hydrated lean tissue. In
overall energy requirements, protein quality, and the patient’s practice, N balance studies tend to be artificially positive because
nutritional status (Table 5.8). Protein requirements increase of overestimation of dietary N intake and underestimation of
when calorie intake does not meet energy needs. The magnitude losses due to incomplete urine collections and unmeasured out-
of this increase is directly proportional to the deficit in energy puts. It is best to wait at least 4 days after a substantial change in
supply. Therefore, nitrogen balance reflects both protein intake protein delivery before N balance is determined, because a labile
and energy balance. Correcting a negative nitrogen balance can N pool exists and this tends to dampen and retard changes that
sometimes be achieved merely by increasing caloric delivery if the otherwise would be observed as a result of altered protein intake.
total amount of calories has been inadequate.
As metabolic stress (and with it, metabolic rate) increases,
nitrogen excretion increases proportionately; quantitatively, the
Carbohydrates
relationship is approximately 2 mg nitrogen (N)/kcal of REE. In Complete digestion of the principal dietary digestible carbohy-
part, this increase is explained by the fact that in metabolic stress, a drates—starch, sucrose, and lactose—generate monosaccharides
larger proportion of the total substrate oxidized for energy is from (glucose, fructose, and galactose). In addition, 5 to 20 g of indi-
protein. This has two important implications for managing the gestible carbohydrates (soluble and insoluble fibers) are typically
nutritional needs of ill patients. The first is that illness, by increas- consumed daily. All cells can generate energy (adenosine triphos-
ing catabolism and metabolic rate, increases the absolute require- phate [ATP]) by metabolizing glucose to 3-carbon compounds
ment for protein (see Table 5.8), and does so in a manner that is via glycolysis, or to carbon dioxide and water via glycolysis and
roughly proportional to the degree of stress. Second, because a the tricarboxylic acid (TCA) cycle.
greater proportion of energy substrate in acute illness comes from There is no absolute dietary requirement for carbohydrate; glu-
protein, nitrogen balance is more readily achieved if a larger pro- cose can be synthesized endogenously from either AAs or glycerol.
portion of the total calories are from protein. In healthy adults, as Regardless, carbohydrate is an important fuel because of the interac-
little as 10% of total calories have to come from protein to main- tions between carbohydrate and protein metabolism. Carbohydrate
tain health, whereas in the ill patient, nitrogen balance is achieved intake stimulates insulin secretion, which inhibits muscle protein
more easily if 15% to 25% of total calories are delivered as protein. breakdown, stimulates muscle protein synthesis, and decreases
Protein requirements are also determined by the adequacy of endogenous glucose production from AAs. In addition, glucose is
essential AAs in the protein source. Inadequate amounts of an the required or preferred fuel for red and white blood cells, the renal
essential AA result in inefficient uptake, so proteins of low bio- medulla, eye tissues, peripheral nerves, and the brain. However,
logic quality increase the protein requirement. In normal adults, once glucose requirements for these tissues are met (≈150 g/day),
approximately 15% to 20% of total protein requirements should the protein-sparing effects of carbohydrate and fat are similar.21
be in the form of essential AAs.
Additional proteins are needed to compensate for excess loss in
specific patient populations (e.g., patients with burn injuries, open
Lipids
wounds, and protein-losing enteropathy or nephropathy). Deliver- Lipids consist of TGs, sterols, and phospholipids. These com-
ing less protein than is needed is often a necessary compromise in pounds serve as sources of energy; precursors for steroid hor-
patients with acute kidney failure who are not adequately dialyzed; mone, prostaglandin, thromboxane, and leukotriene synthesis;
in this situation the rise in azotemia is directly proportional to pro- structural components of cell membranes; and carriers of
tein delivery. Once adequate dialysis is available, protein delivery essential nutrients. Dietary lipids are composed mainly of TGs,
should be increased to the actual projected need, including addi- which contain saturated and unsaturated long-chain fatty acids
tional protein to compensate for losses resulting from dialysis (see (FAs) of 16 to 18 carbons. Use of fat as a fuel requires hydro-
Table 5.8). Most patients with hepatic encephalopathy respond lysis of endogenous or exogenous TGs and cellular uptake of
to simple pharmacologic measures and, therefore, do not require released FAs (see Chapter 102). Long-chain FAs are delivered
protein restriction; those who do not respond may benefit from a across the outer and inner mitochondrial membranes by a car-
modest protein restriction (≈0.6 g/kg/day). nitine-dependent transport system. Once inside the mitochon-
dria, FAs are degraded by beta oxidation to acetyl coenzyme A
(CoA), which then enters the TCA cycle. Therefore, the ability
Nitrogen Balance to use fat as a fuel depends on normally functioning mitochon-
Nitrogen (N) balance is commonly used as a proxy measure of dria. A decrease in the abundance or function of mitochondria
protein balance (i.e., whether the quantity of protein [or AAs] associated with aging22 or deconditioning favors the use of car-
taken in is sufficient to prevent any net loss of protein). N balance bohydrate as fuel.23
or prosthetic groups, others as biochemical substrates or hor-

Essential Fatty Acids mones; in some cases, their functions are not well defined. The 5
Humans lack the desaturase enzyme needed to produce the n-3 average daily dietary intake for each micronutrient required
(double bond between carbons 3 and 4) and n-6 (double bond to sustain normal physiologic operations is measured in mil-
between carbons 6 and 7) FA series. Linoleic acid (C18:2, n-6) ligrams or smaller quantities. In this way, micronutrients are
and linolenic acid (C18:3, n-3) are essential FAs and, therefore, distinguished from macronutrients (carbohydrates, fats, and
should constitute at least 2% and 0.5%, respectively, of the daily proteins) and macrominerals (calcium, magnesium, and phos-
caloric intake to prevent a deficiency state. Before the advent of phorus).
parenteral nutrition, essential fatty acid deficiency (EFAD) was An individual’s dietary requirement for any given micronutri-
only recognized in infants and manifested as a scaly rash with ent is determined by many factors, including its bioavailability,
a specific alteration in the plasma FA profile (see later). Adults the amount needed to sustain its normal physiologic functions, a
were thought not to be susceptible to EFAD because of suf- person’s sex and age, any diseases or drugs that affect the nutri-
ficient essential FA stores in adipose tissue. However, an abnor- ent’s metabolism, and certain lifestyle habits like smoking and
mal FA profile in conjunction with a clinical syndrome of EFAD alcohol use. The U.S. National Academy of Sciences Food and
is now known to sometimes occur in adults with severe short Nutrition Board regularly updates dietary guidelines that define
bowel syndrome who are on long-term TPN that lacks paren- the quantity of each micronutrient that is “adequate to meet the
teral lipids.24 Adults who have moderate-to-severe fat malab- known nutrient needs of practically all healthy persons.” These
sorption (fractional fat excretion >20%) from other causes and RDAs underwent revision between 1998 and 2001, and the values
who are not TPN-dependent also frequently display a biochem- for adults appear in Tables 5.10 and 5.11. Formulating an RDA
ical profile of EFAD,25 although whether such a biochemical takes into account the biologic variability in the population, so
state carries adverse clinical consequences is unclear. Moreover, RDAs are set two SDs above the mean requirement; this allows
TPN lacking any source of fat may lead to EFAD in adults if no the requirements of 97% of the population to be met. Thus,
exogenous source of EFAs is available. The plasma pattern of ingestion of quantities that are somewhat less than the RDA are
EFAD may be observed as early as 10 days after glucose-based often sufficient to meet the needs of a particular individual. A
TPN is started and before the onset of any clinical features. In “tolerable upper limit (TUL),” which is “the maximal daily level
this situation, EFAD is probably due to the increase in plasma of oral intake that is likely to pose no adverse health risks,” has
insulin concentrations caused by TPN, because insulin inhibits been established for most micronutrients (see Tables 5.10 and
lipolysis and, therefore, the release of endogenous essential FAs. 5.11). Present recommendations for how much of each micronu-
The biochemical diagnosis of EFAD is defined as an absolute trient is needed in individuals on TPN are based on far less data
and relative deficiency in the 2 EFAs in the plasma FA pro- than were available for development of the RDAs. Nevertheless,
file. The full clinical EFAD syndrome includes alopecia, scaly it is important to have guidelines, and Table 5.12 provides such
dermatitis, capillary fragility, poor wound healing, increased recommendations.
susceptibility to infection, fatty liver, and growth retardation in
infants and children.
Vitamins
Vitamins are categorized as fat soluble (A, D, E, K) or water
Major Minerals soluble (all others) (see Table 5.10). This categorization remains
Major minerals are inorganic nutrients that are required in large physiologically meaningful; none of the fat-soluble vitamins
(>100 mg/day) quantities and are important for ionic equilib- appear to serve as coenzymes, whereas almost all of the water-
rium, water balance, and normal cell function. Malnutrition and soluble vitamins appear to function in that role. Also, the absorp-
nutritional repletion can have dramatic effects on major mineral tion of fat-soluble vitamins is primarily through a micellar route,
balance. Evaluation of macromineral deficiency and the RDA of whereas the water-soluble vitamins are not absorbed in a lipo-
minerals for healthy adults are shown in Table 5.9. philic phase in the intestine (see Chapter 103).
MICRONUTRIENTS Trace Minerals

Micronutrients (vitamins and trace minerals) are a diverse Compelling evidence exists for the essential nature of 10 trace
array of dietary components that are necessary to sustain elements in humans: iron, zinc, copper, chromium, selenium,
health. The physiologic roles of micronutrients are as varied iodine, fluorine, manganese, molybdenum, and cobalt (see Table
as their composition. Some are used in enzymes as coenzymes 5.11). The biochemical functions of trace elements have not been
TABLE 5.9 Major Mineral Requirements and Assessment of Deficiency

Laboratory Evaluation
Parenteral
Mineral Enteral (mmol) Symptoms or Signs of Deficiency Test Comment
Calcium 1000-1200 mg 5-15 Metabolic bone disease, tetany, 24-hr urinary calcium Reflects recent intake
arrhythmias Dual energy radiation Reflects bone calcium
absorptiometry content
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
Phosphorus 800-1200 mg 20-60 Weakness, fatigue, leukocyte and platelet Plasma phosphorus May not reflect body stores
dysfunction, hemolytic anemia, cardiac
failure, decreased oxygenation
Potassium 2-5 g 60-100 Weakness, paresthesias, arrhythmias Serum potassium May not reflect body stores
Sodium 0.5-5 g 60-150 Hypovolemia, weakness Urinary sodium May not reflect body stores;
clinical evaluation is best
TABLE 5.10 Salient Features of Vitamins

Vitamin Deficiency (RDA)* Toxicity (TUL)† Assessment of Status
A Follicular hyperkeratosis and night blindness In adults, >150,000 μg may cause Retinol concentration in the
are early indicators. Conjunctival xerosis, acute toxicity: fatal intracranial plasma, as well as vitamin A
degeneration of the cornea (keratomalacia), hypertension, skin exfoliation, and concentrations in milk and tears,
and dedifferentiation of rapidly proliferating hepatocellular injury. Chronic toxicity are reasonably accurate measures
epithelia are later indications of deficiency. may occur with habitual daily intake of status. Toxicity is best assessed
Bitot spots (focal areas of the conjunctiva or of >10,000 μg: alopecia, ataxia, bone by elevated levels of retinyl esters
cornea with foamy appearance) are an and muscle pain, dermatitis, cheilitis, in plasma. A quantitative measure
indication of xerosis. Blindness caused by conjunctivitis, pseudotumor cerebri, of dark adaptation for night vision
corneal destruction and retinal dysfunction hepatic fibrosis, hyperlipidemia, and and electroretinography are useful
may ensue. Increased susceptibility to hyperostosis are common. Single functional tests.
infection is also a consequence (1 μg large doses of vitamin A (30,000
of retinol is equivalent to 3.33 IU of μg) or habitual intake of >4500 μg/
vitamin A; F, 700 μg; M, 900 μg). day during early pregnancy can
be teratogenic. Excessive intake
of carotenoids causes a benign
condition characterized by yellowish
discoloration of the skin (3000 μg).
D Deficiency results in decreased mineralization of Excess amounts result in abnormally Serum concentration of the
newly formed bone, a condition called rickets in high concentrations of calcium and major circulating metabolite,
childhood and osteomalacia in adults. Deficiency phosphate in the serum; metastatic 25-hydroxyvitamin D, is an
also contributes to osteoporosis in later life and calcifications, renal damage, and excellent indicator of systemic
is common following gastric bypass procedures. altered mentation may occur (100 μg status except in advanced kidney
Expansion of epiphyseal growth plates and for ages >9). disease (stages 4-5), in which
replacement of normal bone with unmineralized impairment of renal 1-hydroxylation
bone matrix are the cardinal features of rickets; results in dissociation of the
the latter feature also characterizes osteomalacia. mono- and dihydroxy vitamin
Deformity of bone and pathologic fractures result. concentrations; measuring
Decreased serum concentrations of calcium and the serum concentration of
phosphate may occur (1 μg is equivalent to 40 IU; 1,25-dihydroxyvitamin D is then
15 μg, ages 19-70; 20 μg, ages > 70). necessary.
E Deficiency caused by dietary inadequacy is rare in Depressed levels of vitamin Plasma or serum concentration of
developed countries. Usually seen in premature K-dependent procoagulants, alpha-tocopherol is used most
infants, individuals with fat malabsorption, and potentiation of oral anticoagulants, commonly. Additional accuracy is
individuals with abetalipoproteinemia. RBC and impaired leukocyte function obtained by expressing this value
fragility occurs and can produce hemolytic have been reported. Doses of 800 per mg of total plasma lipid. The
anemia. Neuronal degeneration produces mg/day have been reported to RBC peroxide hemolysis test is
peripheral neuropathies, ophthalmoplegia, and increase slightly the incidence of not entirely specific but is a useful
destruction of the posterior columns of the hemorrhagic stroke (1000 mg). measure of the susceptibility of cell
spinal cord. Neurologic disease is frequently membranes to oxidation.
irreversible if deficiency is not corrected early
enough. May contribute to hemolytic anemia
and retrolental fibroplasia in premature infants.
Has been reported to suppress cell-mediated
immunity (15 mg).
K Deficiency syndrome is uncommon except in Rapid IV infusion of vitamin K1 has Prothrombin time is typically used as
breast-fed newborns (in whom it may cause been associated with dyspnea, a measure of functional vitamin K
“hemorrhagic disease of the newborn”), adults flushing, and cardiovascular status; it is neither sensitive nor
who have fat malabsorption or are taking drugs collapse; this is likely related to the specific for vitamin K deficiency.
that interfere with vitamin K metabolism (e.g., dispersing agents in the dissolution Determination of fasting plasma
warfarin, phenytoin, broad-spectrum antibiotics), solvent. Supplementation may vitamin K is an accurate indicator.
and individuals taking large doses of vitamin E interfere with warfarin-based Undercarboxylated plasma
and anticoagulant drugs. Excessive hemorrhage anticoagulation. Pregnant women prothrombin is also an accurate
is the usual manifestation (F, 90 μg; M, 120 μg). taking large amounts of the metric, but only for detecting the
provitamin menadione may deliver deficient state, and is less widely
infants with hemolytic anemia, available.
hyperbilirubinemia, and kernicterus
(TUL not established).
TABLE 5.10 Salient Features of Vitamins—cont’d

5
Thiamine (vitamin Classic deficiency syndrome (beriberi) remains Excess intake is largely excreted in the The most effective measure of vitamin
B1) endemic in Asian populations consuming polished urine, although parenteral doses of B1 status is the RBC transketolase
rice diet. Globally, alcoholism, chronic renal >400 mg/day are reported to cause activity coefficient, which
dialysis, and persistent nausea and vomiting after lethargy, ataxia, and reduced tone of measures enzyme activity before
bariatric surgery are common precipitants. High the GI tract (TUL not established). and after addition of exogenous
carbohydrate intake increases the need for B1. Mild TPP; RBCs from a deficient
deficiency commonly produces irritability, fatigue, individual express a substantial
and headaches. More pronounced deficiency can increase in enzyme activity
produce peripheral neuropathy, cardiovascular with addition of TPP. Thiamine
and cerebral dysfunction. Cardiovascular concentrations in the blood or
involvement (wet beriberi) includes heart failure urine are also measured.
and low peripheral vascular resistance. Cerebral
disease includes nystagmus, ophthalmoplegia,
and ataxia (Wernicke encephalopathy), as well as
hallucinations, impaired short-term memory, and
confabulation (Korsakoff psychosis). Deficiency
syndrome responds within 24 hr 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 with Toxicity has not been reported in Most common method of
(vitamin B2) deficiencies of other B vitamins. Isolated humans (TUL not established). assessment is determining the
deficiency of riboflavin produces hyperemia activity coefficient of glutathione
and edema of nasopharyngeal mucosa, reductase in RBCs (the test is
cheilosis, angular stomatitis, glossitis, seborrheic invalid for individuals with glucose-
dermatitis, and normochromic, normocytic 6-phosphate dehydrogenase
anemia (F, 1.1 mg; M, 1.3 mg). deficiency). Measurements of blood
and urine concentrations are less
desirable methods.
Niacin (vitamin B3) Pellagra is the classic deficiency syndrome and is Human toxicity is known largely through Assessment of status is problematic;
often seen in populations in which corn is the major studies examining hypolipidemic blood levels of the vitamin are
source of energy. Still endemic in parts of China, effects; includes flushing, not reliable. Measurement of
Africa, and India. Diarrhea, dementia (or associated hyperglycemia, hepatocellular injury, urinary excretion of the niacin
symptoms of anxiety or insomnia), and a and hyperuricemia (35 mg). metabolites N-methylnicotinamide
pigmented dermatitis that develops in sun-exposed and 2-pyridone are thought to
areas are typical features. Glossitis, stomatitis, be the most effective means of
vaginitis, vertigo, and burning dysesthesias are assessment.
early signs. Occasionally occurs in carcinoid
syndrome, because tryptophan is diverted to other
synthetic pathways (F, 14 mg; M, 16 mg).
Pantothenic acid Deficiency is rare; reported only as a result of Diarrhea is reported to occur with Whole blood and urine
(vitamin B5) feeding semisynthetic diets or consumption doses exceeding 10 g/day (TUL concentrations of pantothenic
of an antagonist such as calcium not established). acid are indicators of status;
homopantothenate, which has been used to serum levels are not thought to be
treat Alzheimer disease. Experimental isolated accurate.
deficiency in humans produces fatigue,
abdominal pain and vomiting, insomnia, and
paresthesias of the extremities (5 mg).
Pyridoxine Deficiency is usually seen in conjunction with other Chronic use with doses exceeding Many useful laboratory methods
(vitamin B6) water-soluble vitamin deficiencies. Stomatitis, 200 mg/day (in adults) may cause of assessment exist. Plasma or
angular cheilosis, glossitis, irritability, depression, peripheral neuropathies and erythrocyte PLP levels are most
and confusion occur in moderate to severe photosensitivity (100 mg). common. Urinary excretion of
depletion; normochromic, normocytic anemia xanthurenic acid after an oral
has been reported in severe deficiency. Abnormal tryptophan load or activity indices
EEGs and, in infants, convulsions also have been of RBC aminotransferases
reported. Isoniazid, cycloserine, penicillamine, (ALT and AST) all are functional
ethanol, and theophylline are drugs that can measures of B6-dependent
inhibit B6 metabolism (ages 19-50, 1.3 mg; enzyme activity.
>50 yr, 1.5 mg for women, 1.7 mg for men).
Biotin (vitamin B7) Isolated deficiency is rare. Deficiency in humans Toxicity has not been reported in Plasma and urine concentrations
has been produced experimentally by dietary humans, with doses as high as of biotin are diminished in the
inadequacy, prolonged administration of TPN that 60 mg/day in children (TUL not deficient state. Elevated urine
lacks the vitamin, and ingestion of large quantities established). concentrations of methyl citrate,
of raw egg white, which contains avidin, a protein 3-methylcrotonylglycine, and
that binds biotin with such high affinity that it 3-hydroxyisovalerate are also
renders it bio-unavailable. Alterations in mental observed in deficiency.
status, myalgias, hyperesthesias, and anorexia
occur. Later, seborrheic dermatitis and alopecia
develop. Biotin deficiency is usually accompanied
by lactic acidosis and organic aciduria (30 μg).
Continued
TABLE 5.10 Salient Features of Vitamins—cont’d

Folate (Vitamin B9) Women of childbearing age are the most likely Daily dosage >1000 μg may partially Serum folate levels reflect short-term
to develop deficiency. The classic deficiency correct the anemia of B12 folate balance, whereas RBC
syndrome is a megaloblastic anemia. deficiency and therefore mask folate is a better reflection of tissue
Hematopoietic cells in the bone marrow become (and perhaps exacerbate) the status. Serum homocysteine
enlarged and have immature nuclei, reflecting associated neuropathy. Large levels rise early in deficiency but
ineffective DNA synthesis. The peripheral blood doses are reported to lower seizure are nonspecific because B12 or
smear demonstrates macro-ovalocytes and threshold in individuals prone to B6 deficiency, renal insufficiency,
polymorphonuclear leukocytes with an average seizures. Parenteral administration and older age may also cause
of more than 3.5 nuclear lobes. Megaloblastic is rarely reported to cause allergic elevations.
changes in other rapidly proliferating epithelia phenomena from dispersion agents
(e.g., oral mucosa, GI tract) produce glossitis (1000 μg).
and diarrhea, respectively. Sulfasalazine and
diphenytoin inhibit absorption, predisposing to
deficiency. Habitually low intake may increase
the risk of colorectal cancer. (400 μg of dietary
folate equivalent [DFE]; 1 μg folic acid = 1 μg
DFE; 1 μg food folate = 0.6 μg DFE).
Cobalamin (vitamin Dietary inadequacy is a rare cause of deficiency, A few allergic reactions have been Serum or plasma concentrations
B12) except in strict vegetarians. The vast majority of reported from crystalline B12 are generally accurate. Subtle
cases of deficiency arise from loss of intestinal preparations and are probably due deficiency with neurologic
absorption—a result of pernicious anemia, to impurities, not the vitamin (TUL complications is increasingly
pancreatic insufficiency, atrophic gastritis, SIBO, not established). recognized among those ≥ 60 yr of
or ileal disease. Megaloblastic anemia and age, and can best be established
megaloblastic changes in other epithelia (see by concurrently measuring the
“Folate”) are the result of sustained depletion. concentration of plasma B12 and
Demyelination of peripheral nerves, the posterior (1) serum methylmalonic acid
and lateral columns of the spinal cord, and (MMA) or (2) holotranscobalamin
nerves within the brain may occur. Altered II (holoTCII) because the latter
mentation, depression, and psychoses occur. are sensitive indicators of cellular
Hematologic and neurologic complications may deficiency. A low-normal plasma
occur independently. Folate supplementation B12 of 200-350 pg/mL (=148-258
in doses exceeding 1000 μg/day may partly pmol/L) with an elevated MMA
correct the anemia, thereby masking (or perhaps or decreased holoTCII should be
exacerbating) the neuropathic complications considered a state of deficiency.
(2.4 μg).
Ascorbic and Overt deficiency is uncommonly observed in Quantities exceeding 500 mg/day (in Plasma ascorbic acid concentration
dehydroascorbic developed countries. The classic deficiency adults) sometimes cause nausea and reflects recent dietary intake,
acid (vitamin C) syndrome is scurvy, characterized by fatigue, diarrhea. Acidification of the urine whereas leukocyte levels more
depression, and widespread abnormalities in with vitamin C supplementation, closely reflect tissue stores.
connective tissues (e.g., inflamed gingivae, and the potential for enhanced Plasma levels in women are ≈20%
petechiae, perifollicular hemorrhages, impaired oxalate synthesis, have raised higher than in men for any given
wound healing, coiled hairs, hyperkeratosis, and concerns regarding nephrolithiasis, dietary intake.
bleeding into body cavities). In infants, defects but this has yet to be demonstrated.
in ossification and bone growth may occur. Supplementation with vitamin C may
Tobacco smoking lowers plasma and leukocyte interfere with laboratory tests based
vitamin C levels (F, 75 mg; M, 90 mg; the on redox potential (e.g., fecal occult
requirement for cigarette smokers is increased blood testing, serum cholesterol,
by 35 mg/day). 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).

*RDA, Recommended daily allowance; established for female (F) and male (M) adults by the U.S. Food and Nutrition Board, 1999-2001 (updated in 2010
for vitamin D and calcium). 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; 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

5
Mineral Deficiency (RDA)* Toxicity (TUL)† Assessment of Status
Chromium Deficiency in humans is only described for patients Toxicity after oral ingestion is uncommon Plasma or serum concentration of
on long-term TPN containing inadequate and seems confined to gastric irritation. chromium is a crude indicator of
chromium. Hyperglycemia or impaired Airborne exposure may cause contact chromium status; it appears to
glucose tolerance is uniformly observed. dermatitis, eczema, skin ulcers, and be meaningful when the value is
Elevated plasma free fatty acid concentrations, bronchogenic carcinoma (No TUL markedly above or below the normal
neuropathy, encephalopathy, and abnormalities established). range.
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 observed Acute copper toxicity has been described Practical methods for detecting marginal
in premature and low-birth-weight infants after excessive oral intake and with deficiency are not available. Marked
exclusively fed a cow’s milk diet and in absorption of copper salts applied to deficiency is reliably detected by
individuals on long-term TPN without copper. burned skin. Milder manifestations diminished serum copper and
Clinical manifestations include depigmentation include nausea, vomiting, epigastric pain, ceruloplasmin concentrations, as
of skin and hair, neurologic disturbances, and diarrhea; coma and hepatocellular well as low erythrocyte superoxide
leukopenia and hypochromic, microcytic injury may ensue in severe cases. dismutase activity.
anemia, skeletal abnormalities, and poor wound Toxicity may be seen with doses as
healing. The anemia arises from impaired low as 70 μg/kg/day. Chronic toxicity
uptake of iron and is, therefore, a secondary is also described. Wilson disease is a
form of iron deficiency anemia. The deficiency rare inherited disease associated with
syndrome, except the anemia and leukopenia, abnormally low ceruloplasmin levels and
is also observed in Menkes disease, a rare accumulation of copper particularly in
inherited condition associated with impaired the liver and brain, eventually leading to
copper uptake (900 μg). damage of these 2 organs (10 mg).
Fluoride Intake of <0.1 mg/day in infants and 0.5 mg/ Acute ingestion of >30 mg/kg body weight Estimates of intake or clinical
day in children is associated with an increased of fluoride is likely to cause death. assessment are used because no
incidence of dental caries. Optimal intake in Excessive chronic intake (0.1 mg/kg/ reliable laboratory test exists.
adults is between 1.5 and 4.0 mg/day (F, 3 mg; day) leads to mottling of the teeth (dental
M, 4.0 mg). fluorosis), calcification of tendons and
ligaments, and exostoses, and may
increase brittleness of bones (10 mg).
Iodine In the absence of supplementation, populations Large doses (>2 mg/day in adults) Urinary excretion of iodine is an effective
relying primarily on food from soils with low may induce hypothyroidism by laboratory means of assessment.
iodine content have endemic iodine deficiency. blocking thyroid hormone synthesis. The thyroid-stimulating hormone
Maternal iodine deficiency leads to fetal Supplementation with >100 μg/day to (TSH) level in the blood is an
deficiency, which produces spontaneous an individual who was formerly deficient indirect, not entirely specific means
abortions, stillbirths, hypothyroidism, cretinism, occasionally induces hyperthyroidism of assessment. Iodine status of a
and dwarfism. Rapid brain development (1.1 mg). population can be estimated by the
continues through the second year, and prevalence of goiter.
permanent cognitive 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).
Iron Most common micronutrient deficiency in the Iron overload typically occurs when habitual Negative iron balance initially leads to
world. Women of childbearing age constitute dietary intake is extremely high, intestinal depletion of iron stores in the bone
the highest risk group because of menstrual absorption is excessive, repeated marrow; bone marrow biopsy and
blood losses, pregnancy, and lactation. parenteral administration of iron occurs, the concentration of serum ferritin
Hookworm infection is the most common or a combination of these factors exists. are accurate and early indicators
cause worldwide. The classic deficiency Excessive iron stores usually accumulate of such depletion. As deficiency
syndrome is hypochromic microcytic anemia. in reticuloendothelial tissues and becomes more severe, serum iron
Glossitis and koilonychia (spoon nails) are also cause little damage (hemosiderosis). If (SI) decreases and total iron binding
observed. Easy fatigability often develops as an overload continues, iron will eventually capacity (TIBC) increases; an iron
early symptom before appearance of anemia. begin to accumulate in tissues such saturation (= SI/TIBC) of <16%
In children, mild deficiency of insufficient as hepatic parenchyma, pancreas, suggests iron deficiency. Microcytosis,
severity to cause anemia is associated with heart, and synovium, damaging these hypochromia, and anemia ensue in
behavioral disturbances and poor school tissues (hemochromatosis). Hereditary latter stages of the deficient state.
performance (postmenopausal F, 8 mg; M, 8 hemochromatosis arises as a result of Elevated levels of serum ferritin or an
mg; premenopausal F, 18 mg). homozygosity of a common recessive iron saturation >60% raises suspicion
trait. Excessive intestinal absorption of of iron overload, although systemic
iron is observed in homozygotes (45 mg). inflammation elevates serum ferritin
level regardless of iron status.
Manganese Manganese deficiency has not been conclusively Toxicity by oral ingestion is unknown Until the deficiency syndrome is better
demonstrated in humans. It is said to cause in humans. Toxic inhalation causes defined, an appropriate measure of
hypocholesterolemia, weight loss, hair and nail hallucinations, other alterations status will be difficult to develop.
changes, dermatitis, and impaired synthesis of in mentation, and extrapyramidal
vitamin K–dependent proteins (F, 1.8 mg; M, movement disorders (11 mg).
2.3 mg).
Continued
TABLE 5.11 Salient Features of Trace Minerals—cont’d

Mineral Deficiency (RDA)* Toxicity (TUL)† Assessment of Status
Molybdenum Cases of human deficiency are extremely rare; Molybdenum has low toxicity; occupational No effective clinically available
caused by TPN lacking the element or by exposures and high dietary intake are assessment exists. Rare cases
parenteral administration of sulfite. Reported to linked to hyperuricemia and gout in of deficiency are associated with
result in hyperoxypurinemia, hypouricemia, low epidemiologic studies (2 mg). hypouricemia, hypermethionemia,
urinary sulfate excretion, and CNS disturbances and low levels of urinary sulfate with
(45 μg). elevated excretion of sulfite, xanthine,
and hypoxanthine.
Selenium Deficiency is rare in North America but has been Toxicity is associated with nausea, diarrhea, Erythrocyte glutathione peroxidase
observed in individuals on long-term TPN alterations in mental status, peripheral activity and plasma, or whole blood,
lacking selenium. Such individuals have myalgias neuropathy, and loss of hair and nails; selenium concentrations are the
and/or cardiomyopathy. Populations in some such symptoms were observed in adults most commonly used methods of
regions of the world, most notably some parts who inadvertently consumed between 27 assessment. They are moderately
of China, have marginal intake of selenium. and 2400 mg (400 μg). accurate indicators of status.
It is in these regions of China that Keshan
disease is endemic, a condition characterized
by cardiomyopathy. Keshan disease can
be prevented (but not treated) by selenium
supplementation (55 μg).
Zinc Deficiency of zinc has its most profound effect Acute zinc toxicity can usually be induced by There are no accurate indicators of zinc
on rapidly proliferating tissues. Mild deficiency ingestion of >200 mg of zinc in a single day status available for routine clinical
causes growth retardation in children. More (in adults). It is manifested by epigastric use. Plasma, erythrocyte, and hair
severe deficiency is associated with growth pain, nausea, vomiting, and diarrhea. zinc concentrations are frequently
arrest, teratogenicity, hypogonadism and infertility, Hyperpnea, diaphoresis, and weakness misleading. Acute illness, in particular,
dysgeusia, poor wound healing, diarrhea, may follow inhalation of zinc fumes. is known to diminish plasma zinc
dermatitis on the extremities and around orifices, Copper and zinc compete for intestinal levels, in part by inducing a shift of
glossitis, alopecia, corneal clouding, loss of dark absorption: chronic ingestion of >25 mg zinc out of the plasma compartment
adaptation, and behavioral changes. Impaired zinc/day may lead to copper deficiency. and into the liver. Functional tests
cellular immunity also is observed. Excessive loss Chronic ingestion of >150 mg/day has that determine dark adaptation, taste
of GI secretions (e.g., through chronic diarrhea or been reported to cause gastric erosions, acuity, and rate of wound healing lack
fistulas) may precipitate deficiency. Acrodermatitis low high-density lipoprotein cholesterol specificity.
enteropathica is a rare recessively inherited levels, and impaired cellular immunity (40
disease in which intestinal absorption of zinc is mg).
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.

as well characterized as those of the vitamins, but most of their Some reports have indicated that TPN solutions that deliver
functions appear to be as components of prosthetic groups or as several-fold more manganese than what is recommended in
cofactors for enzymes. Table 5.12 may lead to deposition of the mineral in the basal gan-
Aside from iron, the trace mineral depletion clinicians are glia, with resulting extrapyramidal symptoms, seizures, or both.28
most likely to encounter is zinc deficiency. Zinc depletion is a Because the content of manganese varies widely in the different
particularly germane issue to the gastroenterologist, because trace element mixtures available for TPN compounding, health
the GI tract is a major site for zinc excretion. Chronically exces- professionals need to be mindful of this issue as protocols for
sive losses of GI secretions, such as chronic diarrhea in IBD, is a TPN mixtures are developed.
known precipitant for zinc deficiency, and, in this setting, zinc
requirements often increase several-fold.26 Nevertheless, a bio- Physiologic and Pathophysiologic Factors Affecting
chemical diagnosis of zinc deficiency is problematic (as is true for
many of the other essential trace minerals) because accurate labo- Micronutrient Requirements
ratory assessment of zinc status is complicated by the very low
concentrations of zinc in bodily fluids and tissues, a lack of corre-
Age
lation between serum and red blood cell levels of zinc with levels An evolution of physiology continues throughout the life cycle,
in the target tissues, and the reality that suitable functional tests with an impact on the requirements of certain micronutri-
have yet to be devised. Furthermore, it is well recognized that in ents with aging; specific RDAs for older adults have now been
acute illness a shift in zinc occurs from the serum compartment developed. The mean vitamin B12 status of most populations,
into the liver, further obscuring the diagnostic value of serum for example, declines significantly with older age, in large part
zinc levels.27 Alkaline phosphatase is a zinc-dependent protein, because of the high prevalence of atrophic gastritis and its
and therefore serum activity of the enzyme has sometimes been resultant impairment of protein-bound vitamin B12 absorp-
proposed as a functional measure of zinc status. However, its pre- tion.29 Some 10% to 15% of the older ambulatory population
dictive value is quite low and therefore is inadequate for assessing is thought to have significant vitamin B12 depletion because of
individuals in a clinical setting. It is often best to simply proceed this phenomenon, and neuropathic degeneration may occur
with empiric zinc supplementation in patients whose clinical sce- in older individuals whose plasma vitamin B12 levels are in the
nario puts them at high risk of zinc deficiency. low-normal range (150 to 300 pg/mL), even in the absence of
TABLE 5.12 Guidelines for Daily Administration of Parenteral ileal disease, SIBO, and chronic cholestasis may interfere with
Micronutrients in Adults and Children the maintenance of adequate intraluminal conjugated bile acid 5
concentrations and thereby may impair absorption of fat-soluble
Micronutrient Adults Children
vitamins.
Fat-Soluble Vitamins Conditions that produce fat malabsorption are frequently
A 1000 μg (= 3300 IU) 700 μg associated with selective deficiencies of the fat-soluble vitamins.
D 5 μg (= 200 IU) 10 μg The early stages of many vitamin deficiencies are not apparent
clinically and therefore may go undetected until progression of
E 10 mg (= 10 IU) 7 mg
the deficiency has resulted in significant morbidity. This can be
K 1 mg 200 μg disastrous in conditions like spinocerebellar degeneration due to
Water-Soluble Vitamins vitamin E deficiency, which often is irreversible.31 Fat-soluble
C 100 mg 80 mg
vitamin deficiencies are well-recognized complications of cystic
fibrosis and congenital biliary atresia, in which fat malabsorp-
B6 4 mg 1 mg tion often is overt, but monitoring is also necessary in conditions
B12 5 μg 1 μg associated with more subtle fat malabsorption, such as the latter
Biotin 60 μg 20 μg stages of chronic cholestatic liver disease.31
Restitution of vitamin deficiencies can sometimes be diffi-
Folate 400 μg 140 μg cult when severe fat malabsorption is present, and initial cor-
Niacin 40 mg 17 mg rection may require parenteral administration. In severe fat
Pantothenic acid 15 mg 5 mg malabsorption, chemically modified forms of vitamins D and E
that largely bypass the need for the lipophilic phase of intestinal
Riboflavin 3.6 mg 1.4 mg
absorption are commercially available for oral use and can be
Thiamine 3 mg 1.2 mg helpful. The polyethylene glycol succinate form of vitamin E
Trace Elements (Nutr-E-Sol) is very effective in patients with severe fat malab-
Chromium 10-15 μg 0.2 μg/kg/day sorption who cannot absorb conventional alpha-tocopherol.32
Similarly, hydroxylated forms of vitamin D (1-hydroxyvitamin
Copper 0.5-1.5 mg 20 μg/kg/day
D [Hectorol] and 1,25-dihydroxyvitamin D [Rocaltrol]) can be
Iodine* — — used in patients resistant to the more conventional forms of
Iron 1-2 mg 1 mg/day vitamin D. Monitoring of serum calcium levels is indicated in
Manganese 0.1 mg 1 μg/kg/day
the first few weeks of therapy with hydroxylated forms of vita-
min D, because they are considerably more potent than vita-
Molybdenum 15 μg 0.25 μg/kg/day min D2 or D3, and risk of vitamin D toxicity exists. In contrast,
Selenium 100 μg 2 μg/kg/day water-miscible preparations of fat-soluble vitamins, in which a
Zinc 2.5-4.0 mg 50 μg/kg/day conventional form of vitamin A or E is dissolved in polysor-
bate 80 (e.g., Aquasol-E, Aquasol-A), have not been proved to
*Naturally occurring contamination of parenteral nutrition formulas improve overall absorption.
appears to provide sufficient quantities of iodine. Maldigestion usually results from chronic pancreatic insuffi-
Adult vitamin guidelines adapted from American Society of Parenteral and
Enteral Nutrition (ASPEN). Board of Directors and the Clinical Guidelines
ciency, which, if untreated, frequently causes fat malabsorption
Task Force. Guidelines for the use of parenteral and enteral nutrition and deficiencies of fat-soluble vitamins. Vitamin B12 malabsorp-
in adult and pediatric patients. J Parenter Enteral Nutr 2002; 26:144. tion also can be demonstrated in this setting, but clinical vitamin
Children’s values adapted from Greene HL, Hambidge KM, Schanler R, B12 deficiency is rare unless other conditions known to diminish
Tsang RC. Guidelines for the use of vitamins, trace elements, calcium, its absorption are also present (e.g., atrophic gastritis or chronic
magnesium, and phosphorus in infants and children receiving total administration of PPIs).33 Whether long-term administration
parenteral nutrition: report of the Subcommittee on Pediatric Parenteral of PPIs alone warrants occasional checks of vitamin B12 status
Nutrient Requirements from the Committee on Clinical Practice Issues of is a matter of debate.34 Regardless, malabsorption of vitamin B12
the American Society for Clinical Nutrition. Am J Clin Nutr 1988; 48:1324; from atrophic gastritis or with PPIs is confined to dietary sources
Am J Clin Nutr 1989; 49:1332; and Am J Clin Nutr 1989; 50:560.
of vitamin B12. Small supplemental doses of crystalline vitamin
B12 are absorbed readily in both cases. Histamine-2 receptor
hematologic manifestations. For this reason, the use of sensi- antagonists also inhibit protein-bound vitamin B12 absorption,
tive indicators of cellular depletion of vitamin B12 (e.g., serum although the effect generally is believed to be less potent than
methylmalonic acid levels in conjunction with serum levels with the PPIs.35
of vitamin B12) are now recommended for diagnosis.30 Some Many medications may adversely affect micronutrient status.
experts also suggest that older adults should consume a portion The manner in which drug-nutrient interaction occurs varies;
of their vitamin B12 requirement in the crystalline form (i.e., as a some of the more common mechanisms are described in Table
supplement) rather than relying only on the naturally occurring 5.13. A comprehensive discussion of drug-nutrient interactions
protein-bound forms found in food. Compared with younger is beyond the scope of this chapter, and the reader is referred to
adults, elders require greater quantities of vitamins B6 and D other references for a detailed discourse on this topic.36
and calcium to maintain health, and these requirements are
reflected in the new RDAs (see Tables 5.10 and 5.11). STARVATION
During periods of energy or protein deficit or both, an array of
Malabsorption and Maldigestion compensatory mechanisms serves to lessen the pathophysiologic
Both fat- and water-soluble micronutrients are absorbed pre- impact of these deficiencies. These responses decrease the meta-
dominantly in the proximal small intestine, the only exception bolic rate, maintain glucose homeostasis, conserve body nitrogen,
being vitamin B12, which is absorbed in the ileum. Diffuse muco- and increase the uptake of adipose tissue TGs to meet energy
sal diseases that affect the proximal portion of the GI tract are, needs. To appreciate how acute illness disrupts this compensa-
therefore, likely to result in multiple deficiencies. Even in the tory scheme, it is first necessary to understand how the body
absence of proximal small intestinal disease, however, extensive adapts to starvation in the absence of underlying disease.
TABLE 5.13 Interactions of Drugs on Micronutrient Status FAs and ketone bodies. Other tissues like bone marrow, renal
medulla, and peripheral nerves switch from full oxidation of
Drug(s) Nutrient Mechanism(s)
glucose to anaerobic glycolysis, resulting in increased produc-
Cholestyramine Vitamin D, folate Adsorbs nutrient, decreases tion of pyruvate and lactate. The latter two compounds can
absorption be converted back to glucose in the liver using energy derived
Dextroamphetamine, Potentially all Induces anorexia from fat oxidation via the Cori cycle, and the resulting glucose
fenfluramine, micronutrients is available for systemic consumption. This enables energy
levodopa stored as fat to be used for glucose synthesis.
Isoniazid Pyridoxine Impairs uptake of vitamin B6 Whole-body glucose production decreases by greater than
50% during the first few days of fasting because of a marked
NSAIDs Iron GI blood loss reduction in hepatic glucose output. As fasting continues, conver-
Penicillamine Zinc Increases renal excretion sion of glutamine to glucose in the kidney represents almost 50%
PPIs Vitamin B12 Modest bacterial overgrowth, of total glucose production. Energy is conserved by a decrease in
decreases gastric acid/ physical activity secondary to fatigue and a roughly 10% reduc-
pepsin, impairs absorption tion in REE resulting from increased conversion of active thyroid
Sulfasalazine Folate Impairs absorption and hormone to its inactive form and suppressed sympathetic nervous
inhibits folate-dependent system activity.
enzymes During long-term starvation (14 to 60 days), maximal adap-

tation is reflected by a plateau in lipid, carbohydrate, and pro-
From Goldman L, Ausiello D, Arend W, et al, editors. Cecil textbook of
tein metabolism. The body relies almost entirely on adipose
medicine. 22nd ed. Philadelphia: WB Saunders; 2004. With permission.
tissue for its fuel, providing greater than 90% of daily energy
requirements.42 Muscle protein breakdown decreases to less
than 30 g/day, causing a marked decrease in urea nitrogen pro-
duction and excretion. The decrease in osmotic load diminishes
During the first 24 hours of fasting, the most readily avail- urine volume to 200 mL/day, thereby reducing fluid require-
able energy substrates (i.e., circulating glucose, FAs and TGs, ments. Total glucose production decreases to approximately 75
and liver and muscle glycogen) are used as fuel sources. The g/day, providing fuel for glycolytic tissues (40 g/day) and the
sum of energy provided by these stores in a 70-kg man, how- brain (35 g/day) while maintaining a constant plasma glucose
ever, is only about 5000 kJ (1200 kcal) and therefore is less concentration. Energy expenditure decreases by 20% to 25%
than a full day’s requirements. Hepatic glucose production and at 30 days of fasting and remains relatively constant thereafter
oxidation decrease, whereas whole-body lipolysis increases, despite continued starvation.
the latter providing additional FAs and ketone bodies.37 Oxi- The metabolic response to short- and long-term starvation
dation of FAs released from adipose tissue TGs accounts for differs somewhat between lean and obese persons. Obesity is
about 65% of the energy consumed during the first 24 hours associated with a blunted increase in lipolysis and decrease in
of fasting. glucose production compared with that in lean persons.43, 44 In
During the first several days of starvation, obligate glucose- addition, protein breakdown and nitrogen losses are less in obese
requiring tissues like the brain and blood cells, which collec- persons, thereby helping conserve muscle protein.45
tively account for about 20% of total energy consumption, can Events that mark the terminal phase of starvation have been
use only glycolytic pathways to obtain energy. Because FAs can- studied chiefly in laboratory animals. Body fat mass, muscle pro-
not be converted to carbohydrate by these glycolytic tissues, tein, and the sizes of most organs are markedly decreased. The
they must use glucose or substrates that can be converted to weight and protein content of the brain, however, remain rela-
glucose. Glucogenic AAs derived from skeletal muscle (chiefly tively stable. During the final phase of starvation, body fat stores
alanine and glutamine) are a major source of substrate for this reach a critical level, energy derived from body fat decreases,
purpose. Approximately 15% of the REE is provided by oxida- and muscle protein catabolism is accelerated. Death commonly
tion of protein.38 The relative contribution of gluconeogenesis occurs when there is a 30% to 50% loss of skeletal muscle pro-
to hepatic glucose production increases as the rate of hepatic tein.46 In humans, it has been proposed that there are certain
glycogenolysis declines because the latter process becomes thresholds beyond which lethality is inevitable: depletion of total
redundant; after 24 hours of fasting, only 15% of liver glycogen body protein between 30% and 50% and of fat stores between
stores remain. 70% and 95%, or reduction of BMI below 13 kg/m2 for men and
During short-term starvation (1 to 14 days), several adap- 11 kg/m2 for women.47, 48
tive responses appear that lessen the loss of lean mass. A decline
in levels of plasma insulin, an increase in plasma epinephrine
levels, and an increase in lipolytic sensitivity to catechol-
amines stimulate adipose tissue lipolysis.39, 40 The increase in
MALNUTRITION
FA delivery to the liver, in conjunction with an increase in the In the broadest sense, malnutrition implies a sustained imbal-
ratio of plasma glucagon-to-insulin concentrations, enhances ance between nutrient availability and nutrient requirements.
the production of ketone bodies by the liver. A maximal rate This imbalance results in a pathophysiologic state in which
of ketogenesis is reached by 3 days of starvation, and plasma intermediary metabolism, organ function, and body composi-
ketone body concentration is increased 75-fold by 7 days. In tion are variously altered. Sustained is an important element of
contrast to FAs, ketone bodies can cross the blood-brain bar- this definition, because homeostatic mechanisms and nutrient
rier and provide most of the brain’s energy needs by 7 days reserves are usually adequate to compensate for any short-term
of starvation.41 The use of ketone bodies by the brain greatly imbalance.
diminishes glucose requirements and thus spares the need for Customarily, the term malnutrition is used to describe a state
muscle protein degradation to provide glucose precursors. If of inadequacy in protein, calories, or both and is more precisely
early protein breakdown rates were to continue throughout called protein-energy malnutrition or protein-calorie malnutrition.
starvation, a potentially lethal amount of muscle protein would Occasionally it is used to describe a state of excessive availability,
be catabolized in less than 3 weeks. Similarly, the heart, kid- such as a sustained excess of calories (e.g., obesity) or a vitamin
ney, and skeletal muscle change their primary fuel substrate to (e.g., vitamin toxicity).
contains the bulk of metabolism that sustains homeostasis. It is

Protein-Energy Malnutrition (PEM) the maintenance of this body compartment that is most critical for 5
There are different pathways whereby PEM may evolve. Primary health. Lean body mass can be subdivided further into somatic and
PEM is caused by inadequate intake of protein, calories, or both, visceral protein compartments, blood and bone cells, and extracel-
or, less commonly, when the protein ingested is of such poor lular lean mass, such as plasma and bone matrix (Fig. 5.1). In total-
quality that one or more essential AAs becomes a limiting fac- or semi-starvation in otherwise healthy individuals, adipose tissue
tor in the maintenance of normal protein metabolism. Secondary predominates as a primary energy source; thus, fat mass contracts
PEM is caused by illness or injury. to a much greater degree proportional to the loss of lean mass.42
Acute illnesses and injuries increase bodily requirements for Alterations in metabolism from injury or illness, however, produce
protein and energy substrate and impair digestion, absorption, a proportionately greater loss of muscle mass such that it matches
and uptake of these nutrients in various ways. Consequently, or exceeds the loss in fat mass.51 Although the lean mass lost in ill-
secondary PEM usually arises from multiple factors. Illness and ness is preferentially from the somatic protein compartment, with
injury also commonly induce anorexia (see later for mechanisms), sustained stress there also will be a significant contraction of the
so primary and secondary factors often act in concert to create visceral protein compartment (Table 5.14). The metabolic forces
PEM in the setting of illness. associated with acute illness and injury are potent, and restora-
Illness or injury may directly interfere with nutrient assimilation of muscle mass is unlikely with nutritional support unless the
tion; for example, extensive ileal disease or resection may directly underlying inflammatory condition is corrected. There is increas-
produce fat malabsorption and a caloric deficit. The most coming interest in attenuating or reversing net catabolism with the
mon causes of secondary PEM, however, are the remarkable use of exogenous anabolic agents in conjunction with nutrition,
increases in protein catabolism and energy expenditure that although, to date, it remains unclear whether administration of
occur as a result of a systemic inflammatory response. REE may β-hydroxymethylbutyrate, growth hormone, oxandrolone, pro-
increase as much as 80% above basal levels in a manner roughly pranolol, or other anabolic agents in acute illness, improve clini-
proportional to the magnitude of the inflammatory response, cal outcomes and outweigh their potential side effects.52 Another
which in turn is roughly proportional to the severity and acuity important ramification of the potency of the catabolic state associ-
of the illness. Thus, REE in patients with extensive second- and ated with acute illness is that most of the weight gained with provi-
third-degree burns (the prototype for maximal physiologic stress) sion of nutritional support is the result of increases in fat mass and
may approach twice normal; with sepsis, REE is about 1.5 times body water; only minor increases in lean mass are observed until
normal, and with a localized infection or fracture of a long bone, the inflammatory focus is resolved.53
REE is 25% above normal.6 Such stress factors can be used to
construct a formula for predicting the caloric needs of ill indi- Blood cells, Extracellular lean mass
viduals (see Table 5.5). bone cells, etc. (plasma, bone mineral, etc.)
Protein catabolism during illness or injury also increases in 7% 36%
proportion to the severity and acuity of the insult and therefore Visceral
parallels the increase in energy consumption. The magnitude mass
of increase in protein catabolism, however, is proportionately 7%
greater than that observed with energy consumption, such that
urinary urea N losses, which reflect the degree of protein catab-
olism in acute illness, are about 2.5 times the basal level with
maximal stress.6 This increase in catabolism results in a net loss
of protein because the rate of synthesis usually does not rise in
concert with the rise in catabolism.49 No known storage form of
protein exists in the body, so any net loss of protein represents a
loss of functionally active tissue. A healthy adult typically loses
about 12 g N/day in urine, and excretion may increase to as much Muscle
as 30 g/day during critical illness. Because 1 g of urinary N repre- mass
sents the catabolism of approximately 30 g of lean mass, it follows 22%
that severe illness may produce a daily loss of up to about 0.5 kg Fat
of lean mass as a result of excess protein catabolism. Most of this mass
loss comes from skeletal muscle, where the efflux of AAs increases 28%
two- to six-fold in critically ill patients.50
Fig. 5.1 Body composition analysis by weight in a healthy adult.
Mobilization of AAs from skeletal muscle appears to be an
Speckled segments and gray segment collectively represent lean body
adaptive response. Once liberated, these AAs, in part, are deami-
mass. Speckled segments alone represent body cell mass. (Adapted
nated and used for gluconeogenesis; they are also taken up by the
from Mason JB. Gastrointestinal cancer: nutritional support. In: Kelsen
liver and other visceral organs. The proteolysis of muscle under
D, Daly J, Kern S, et al., editors. Principles and practice of gastrointesti-
stress thus enables the body to shift AAs from skeletal muscle
nal oncology. Philadelphia: Lippincott Williams & Wilkins; 2002.)
(the somatic protein compartment) to the visceral organs (the
visceral protein compartment), the functions of which are more
critical for immediate survival during illness. Nevertheless, with
sustained stress, the limitations of this adaptive response become TABLE 5.14 Body Compartment Wasting and Losses in Simple
evident, and even the visceral protein compartment sustains a Starvation Versus Metabolic Stress
contraction in mass.42
Skeletal Muscle Visceral Loss of
Parameter Wasting Wasting Fat Mass
Primary Versus Secondary Protein-Energy Malnutrition: A
Starvation + +/−* +++
Body Compartment Perspective
Metabolic stress +++ ++/−* +++

The type of tissue lost as malnutrition evolves is critical in deter-
*Relatively spared early in the process; can become pronounced with
mining the pathologic ramifications of weight loss. Over 95% of extended starvation or metabolic stress.
energy expenditure resides in the lean body mass, which, therefore,
Cytokines are the most important mediators of alterations underdeveloped nations where poverty, inadequate food supply,
in energy and protein metabolism that accompany illness and and unsanitary conditions lead to a high prevalence of PEM. The
injury. In a wide spectrum of systemic illnesses, increased secre- Waterlow classification of malnutrition (Table 5.16) takes into
tion of interleukin (IL)-1β, tumor necrosis factor -α, IL-6, and account a child’s weight for height (the inadequacy of which is
interferon-γ has been observed to be associated with increased termed “wasting”) and height for age (the inadequacy of which is
energy expenditure and protein catabolism, as well as the shift of termed “stunting”).59 The characteristics of the three major clini-
AAs into the visceral compartments.54-56 Such observations con- cal PEM syndromes in children—kwashiorkor, marasmus, and
cur with in vitro studies in human cells and animal models that nutritional dwarfism—are outlined in Table 5.17.60 Although
have shown remarkably potent effects of these cytokines (Table these 3 syndromes are classified separately, in reality, clinical pre-
5.15). In the wasting syndrome associated with cancer, proteoly- sentations in which they overlap often occur.
sis-inducing factor and zinc-α-2-glycoprotein (‘lipid-mobilizing
factor’) are humoral mediators that appear to be unique to cancer Kwashiorkor
cachexia, contributing to protein catabolism and loss of adipose The word kwashiorkor, from the Ga language of West Africa,
tissue, respectively.57 Promising data in animal models of cancer means “disease of the displaced child” because it was commonly
cachexia indicate that specific inhibitors of cancer-mediated pro- seen after weaning. The presence of peripheral edema distin-
tein catabolism can be designed that greatly reduce the morbid- guishes children with kwashiorkor from those with marasmus
ity and mortality associated with the cachexia produced by this and nutritional dwarfism. Children with kwashiorkor also have
disease.58 characteristic skin and hair changes (see later). The abdomen is
protuberant because of weakened abdominal muscles, intesti-
nal distention, and hepatomegaly, but ascites is rare. The pres-
Protein-Energy Malnutrition in Children ence of ascites, therefore, should prompt the clinician to search
Undernutrition in children differs from that in adults because for liver disease or peritonitis. Children with kwashiorkor are
it affects growth and development. Much of our understanding typically lethargic and apathetic, but become very irritable
of undernutrition in children comes from observations made in when held. Kwashiorkor most often occurs when a physiologic
stress (e.g., infection) is superimposed on an already malnour-
ished child. Because infection or other acute stress is usually
TABLE 5.15 Major Cytokines That Mediate Hypercatabolism and present in kwashiorkor, the metabolic aberrations associated
Hypermetabolism Associated with Metabolic Stress with secondary PEM are in play, and contractions of the vis-
ceral protein compartment are evident. A decrease in serum
Cytokine Cell Sources Metabolic Effects
proteins like albumin is common, distinguishing it from pure
IFN-γ Lymphocytes, pulmonary Increased monocyte marasmus. Kwashiorkor is characterized by leaky cell mem-
macrophages respiratory burst branes that permit movement of potassium and other intracel-
IL-1β Monocytes/macrophages, Increased ACTH and cortisol lular ions into the extracellular space, causing water movement
neutrophils, lymphocytes, levels and edema.
keratinocytes, Kupffer cells Increased acute-phase
protein synthesis
Increased AA release from
muscles TABLE 5.17 Features of Protein-Energy Malnutrition Syndromes in
Decreased insulin secretion Children
Fever
Syndrome
IL-6 Monocytes/macrophages, Increased acute-phase
keratinocytes, endothelial protein synthesis Parameter Kwashiorkor Marasmus Nutritional
cells, fibroblasts, T cells, Fever Dwarfism
epithelial cells Decreased appetite Appetite Poor Good Good
TNF-α Monocytes/macrophages, Decreased FFA synthesis Edema Present Absent Absent
lymphocytes, Kupffer Increased lipolysis
cells, glial cells, endothelial Increased AA release from Mood Irritable when Alert Alert
cells, natural killer cells, muscles picked up,
mast cells Increased hepatic AA uptake apathetic
Fever when alone

Weight for age 60-80 <60 <60
AA, Amino acid; FFA, free fatty acid; IFN, interferon; IL, interleukin.
(% expected)
Adapted from Smith M, Lowry S. The hypercatabolic state. In: Shils M,
Olson J, Shike M, Ross AC, editors. Modern nutrition in health and Weight for height Normal or Markedly Normal
disease. Baltimore: Williams & Wilkins; 1999. p 1555. decreased decreased

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 90-100 80-89 70-79 <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 95-105 90-94 85-89 <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.

Marasmus Cardiovascular System

Weight loss and marked depletion of subcutaneous fat and Moderate to severe PEM produces quantitative and qualitative 5
muscle mass are characteristic features of children with maras- declines in the cardiac muscle. Myocardial mass is diminished,
mus. Ribs, joints, and facial bones are prominent, and the skin although proportionately less than the loss in body weight.
is thin, loose, and lies in folds. In contrast, the visceral protein Myofibrillar atrophy, edema, and (less commonly) patchy necro-
compartment is relatively spared, a fact that often is reflected sis and infiltration with chronic inflammatory cells are seen in
by a normal serum albumin level, which in turn sustains normal the myocardium; these structural changes are associated with
oncotic pressure in the vascular compartment, thus minimizing impaired myocardial performance. A decrease in stroke volume,
edema and helping to distinguish these children from those with cardiac output, and maximal work capacity may be observed and
kwashiorkor. are most evident under conditions of increased demand. Such
functional impairments are sometimes accompanied by bradycar-
Nutritional Dwarfism dia and, in conjunction with the factors noted, can lead to low
The child with failure to thrive may be of normal weight for blood pressure.
height but have short stature and delayed sexual development.
Providing appropriate feeding can stimulate catch-up growth and Immune System
sexual maturation. The immune system is the most vulnerable to PEM, which
The diagnosis of PEM is different in adults than in children, explains why several functions of immunity are used diagnosti-
because adults do not grow in height. Therefore, undernutri- cally as indicators of malnutrition (e.g., total lymphocyte count
tion in adults causes wasting rather than stunting. In addition, and delayed skin hypersensitivity). The functional integrity of
although pure forms of kwashiorkor and marasmus can occur T lymphocytes, polymorphonuclear leukocytes, and comple-
in adults, contemporary studies of adult PEM in high-income ment is uniformly blunted, whereas impaired B lymphocyte
societies typically focus on hospitalized patients with secondary production of antibodies is variably affected. A moderately to
PEM, coexisting illness or injury, and overlapping features of severely malnourished patient is an immunocompromised indi-
kwashiorkor and marasmus. vidual. Malnutrition leads to increased susceptibility to infec-
tion, which in turn promotes development of PEM, so a vicious
Physiologic Impairments Caused by Protein-Energy cycle is created.
Malnutrition Respiratory System
PEM adversely affects almost every organ system, although the The diaphragm and other respiratory muscles undergo structural
brain usually is spared. Almost all adverse effects are reversible and functional atrophy, diminishing inspiratory and expiratory
with nutritional restitution. The following discussion is not pressures and vital capacity. These changes in muscular perfor-
exhaustive; rather, it emphasizes impairments that commonly mance, in conjunction with blunted ventilatory drive, impair the
translate into overt morbidity or that are important in the diag- ability to sustain ventilation in the severely malnourished indi-
nosis of PEM. The effects described reflect what occurs in pri- vidual. In patients with a tracheostomy, adherence of bacteria
mary PEM; superimposition of acute illness and secondary PEM to the tracheal epithelium correlates with the severity of PEM,
often imposes more complexity. exacerbating other compromises in the immune system described
earlier.
Endocrine System
System Effects Although alterations in hormones are common in PEM, many
Gastrointestinal Tract of the changes can be perceived as serving adaptive functions.
Although PEM alone produces adverse effects on GI structure The inadequate intake of food leads to a decrease in the avail-
and function, diminished stimulation of the GI tract by a lack ability of circulating glucose and AAs, low circulating levels of
of ingested nutrients has an independent effect. Thus, sustained insulin, and increased levels of growth hormone. These altera-
absence of nutrients passing through the intestine of healthy, tions, in conjunction with the decreased levels of somatome-
nutritionally replete, parenterally fed individuals alone results in dins and increased levels of cortisol in PEM, promote skeletal
functional atrophy of the small intestinal mucosa, as evidenced by muscle catabolism and at the same time enhance incorpora-
a loss of brush border enzymes and diminished integrity of the tion of the liberated AAs into visceral organs. Urea synthesis is
epithelial barrier. Villus atrophy may also be observed with lack inhibited, decreasing nitrogen loss and enhancing reutilization
of intestinal stimulation, but in the absence of PEM, the degree of AAs. Enhancement of lipolysis and gluconeogenesis provides
of structural atrophy is minor.61 a substrate for energy needs.
The structural and functional deterioration of the intestinal Serum levels of triiodothyronine (T3) and thyroxine (T4) are
tract, pancreas, and liver as a result of PEM is described best in commonly decreased in conjunction with increased concentra-
children. Marked blunting of the intestinal villi is seen and is usu- tions of reverse T3, resembling the pattern observed in the euthy-
ally associated with loss of some or all of the brush border hydro- roid sick syndrome. The decreased concentration of T3 may play
lases. Gastric and pancreatic secretions are reduced in volume and a role in decreasing REE and the protein catabolic rate observed
contain decreased concentrations of acid and digestive enzymes, in primary PEM.
respectively. The volume of bile and the concentrations of conju- Primary gonadal dysfunction is common in adults with
gated bile acids in bile are reduced. Increased numbers of faculta- moderate-to-severe PEM and results in impaired reproductive
tive and anaerobic bacteria are found in the upper small intestine, potential. Decreased circulating levels of testosterone in men
probably explaining the increased proportion of free bile acids in and estrogen in women is evident, and amenorrhea is com-
the intestinal lumen. Malabsorption of carbohydrates, fats, and mon. Delayed puberty or loss of menstrual periods most often
fat- and water-soluble vitamins may occur and the degree of ste- occurs when lean body mass drops below a critical threshold.
atorrhea is proportional to the severity of the PEM, creating a These changes can also be considered physiologic adaptations,
vicious cycle of further malnutrition. The abdominal protuber- because ensuring immediate survival is more critical than the
ance sometimes seen in advanced malnutrition is thought to arise need for sexual maturation in the child or reproduction in the
in part from intestinal hypomotility and gas distention. adult.
improve clinical outcome.64-68 Meta-analyses have underscored

Other Effects the importance of performing objective nutritional assessments
Wound Healing to categorize inpatients, because individuals who are well-nour-
Well-nourished individuals lay down more collagen at the site ished or mildly malnourished seem to realize little benefit from
of a surgical wound than those with even mild malnutrition. intensive nutritional support.69-71
Nutritional repletion of the malnourished patient before surgery A comprehensive nutritional assessment requires a history,
leads to better wound healing than if nutritional needs are only physical examination, evaluation of anthropometrics or func-
addressed postoperatively. tional measures of nutritional status, and a panel of laboratory
blood tests. Some of the more commonly used assessment tools
Skin are weight, height, and other anthropometric measures (e.g., skin-
Undernutrition often causes dry, thin, and wrinkled skin, with fold thickness and mid-arm measurements); functional measures
atrophy of the basal layers of the epidermis and hyperkerato- (e.g., hand grip strength or skin testing for evidence of anergy);
sis. Severe malnutrition may cause considerable depletion of serum protein concentrations (e.g., albumin or prealbumin);
skin protein and collagen. Patients with kwashiorkor experience complete blood count, including absolute lymphocyte count; and
sequential skin changes in different areas. Hyperpigmentation 24-hour urinary creatinine and blood urea nitrogen levels. Less
occurs first, followed by cracking and stripping of superficial lay- readily available measures of body composition, such as bioelec-
ers, leaving behind hypopigmented, thin, and atrophic epidermis trical impedance and total body potassium, can be helpful in the
that is friable and easily macerated. appropriate setting. Some of these measures lack a high degree
of specificity but continue to be useful in clinical care because of
Hair their prognostic significance. Because no single parameter is suf-
Scalp hair becomes thin and sparse and is easily pulled out. In ficiently sensitive or specific to assess PEM, these tools are most
contrast, the eyelashes become long and luxuriant, and there may effective when used in combination.
be excessive lanugo in children. The hair of children with kwashi- Importantly, if the clinician is undertaking a nutritional assess-
orkor develops hypopigmentation, with reddish-brown, gray, or ment solely to determine whether a patient falls into a category of
blond discoloration. Adults may lose axillary and pubic hair. moderate-to-severe PEM (and thus one who would benefit from
intensive nutritional support), far less than comprehensive assess-
Kidneys ment will usually suffice; such simple means of categorization are
Renal mass and function are often well preserved during under- provided in the following sections.
nutrition. When malnutrition is severe, however, there are
decreases in kidney weight, glomerular filtration rate, ability to
excrete acid and sodium, and ability to concentrate urine. Mild History
proteinuria also may occur.
Weight Loss
Bone Marrow How much weight has been lost and over what time period?
Severe undernutrition suppresses bone marrow red blood cell Unintentional weight loss associated with illness is the single
and white blood cell production, leading to anemia, leukopenia, most practical predictor of a clinically significant degree of
and lymphocytopenia. PEM. It is useful to quantify such loss by determining whether
the patient has sustained a mild (<5%), moderate (5% to 10%),
or severe (>10%) degree of loss over the preceding 6 months.
NUTRITIONAL ASSESSMENT TECHNIQUES Because acute illness incites a disproportionately large loss of
The purpose of nutritional assessment is to identify PEM and lean mass, it is not surprising that a greater than 10% uninten-
other nutritional deficits even when they are not readily discern- tional loss in body weight usually correlates with a 15% to 20%
ible. PEM can be subtle, but most cases are detected when a sys- decrease in total body protein.63 This degree of unintentional loss
tematic nutritional assessment is performed. An example of subtle is an important threshold because it is associated with impaired
but clinically significant PEM is found in Child-Turcotte-Pugh physiology, a poor clinical outcome, and extended hospitaliza-
class A patients with alcoholic cirrhosis. These individuals usually tion72-74; it also defines those individuals who will likely benefit
appear well nourished. Indeed, one criterion to determine class from intensive nutritional support. The clinician should never-
A status is a normal serum albumin level, but studies of whole- theless be mindful that determining the magnitude of weight loss
body nitrogen by in vivo neutron activation analysis have demon- by history has limited accuracy. One study found that one-third
strated that more than half of these class A individuals have less of patients with true weight loss go undetected by history, and
than 80% of expected total body protein,62 the threshold level one-quarter of those who had been weight-stable are miscatego-
below which patients have increased morbidity associated with rized as having undergone weight loss.75 Furthermore, the nutri-
malnutrition.63 tional significance of changes in body weight can be confounded
In otherwise healthy people and in those who are chronically by changes in hydration status and extracellular fluid accumula-
ill, PEM is usually defined by comparing an anthropometric mea- tion. Because weight loss is an imperfect indicator of PEM, it is
surement (e.g., weight for height) to established normative stan- useful to obtain other historical clues that can contribute to the
dards (see Table 5.6). In contrast, there is no gold standard to identification of these patients (see later).
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 the concentration of serum proteins
Food Intake
are prime examples. Has there been a change in habitual diet pattern (number, size,
Despite the inaccuracies inherent in assessing PEM in acutely and contents of meals)? What is the reason for altered food intake
ill individuals, the usefulness of nutritional assessment in this set- (e.g., change in appetite, mental status or mood, ability to prepare
ting has been repeatedly demonstrated. Acutely ill patients who meals, ability to chew or swallow, GI symptoms)?
are malnourished sustain higher rates of malnutrition-related
morbidity. Thus, the presence of PEM has a predictive value.
Even more importantly, identifying malnourished patients and
Evidence of Malabsorption
then providing appropriate nutritional intervention is likely to Are there signs, symptoms, or both consistent with malabsorption?
Evidence of Specific Nutrient Deficiencies TABLE 5.18 Classification of Nutritional Status by Body Mass Index in
Are there signs, symptoms, or both of specific nutrient deficien- Adults 5
cies, including macrominerals, micronutrients, and water? (See
Body Mass Index (kg/m2) Nutritional Status
Tables 5.9 to 5.11.)
<16.0 Severely malnourished
Influence of Disease on Nutrient Requirements 16.0-16.9 Moderately malnourished
Is the nature of the patient’s underlying illness one that is likely
17.0-18.4 Mildly malnourished
to increase nutrient needs or nutrient losses?
18.5-24.9 Normal
Functional Status 25.0-29.9 Overweight
Has the patient’s ability to perform daily activities that determine 30.0-34.9 Obese (class I)
consumption of wholesome meals changed? Can the patient still
shop and prepare meals? Have finances interfered with the ability 35.0-39.9 Obese (class II)
of the patient to purchase food? ≥40 Obese (class III)
Physical Examination longevity. In general, individuals whose weight is less than 85%
of the standard can be considered to have a clinically significant
Hydration Status degree of PEM. Of note is that desirable weights in this table are
The patient should be evaluated for signs of dehydration (e.g., substantially less than average weights in North America.
hypotension, tachycardia, postural changes in blood pressure and Body mass index (Table 5.18), defined as weight (in kilograms)
pulse, mucosal xerosis, decreased axillary sweat, dry skin) and divided by height (in meters squared), has been supplanting the
excess body fluid (e.g., edema or ascites). use of weight for height, in part because it precludes the need to
use normative data tables. BMIs outside the desirable range (18.5
to 24.9 kg/m2) help identify patients at increased risk of adverse
Tissue Depletion clinical outcomes. A BMI modestly above the desirable range has
A general loss of adipose tissue can be assumed if there are well- been shown to be predictive of adverse outcomes in the surgi-
defined bony, muscular, and venous outlines and loose skin folds. cal management of many diseases76-78 and in the medical man-
A fold of skin pinched between the forefinger and thumb can agement of conditions like alcoholic liver disease.79 Similarly, a
reveal the adequacy of subcutaneous fat. The presence of hollow- low BMI has been shown to be a robust independent risk factor
ness in the cheeks, buttocks, and perianal area suggests body fat in surgical and medical patients.80 Extremely underweight adult
loss. Examination of the temporalis, interosseous, and quadriceps patients (BMI <14 kg/m2) are at high risk of death and should
muscles should be done to judge muscle wasting. be strongly considered for admission to the hospital to initiate
intensive nutritional support.
The BMI, like weight for height, is a surrogate and imper-
Muscle Function fect measure of body composition. A low BMI (<18.5 kg/m2) is
Strength testing of individual muscle groups can be performed interpreted as an indication of PEM, and a high BMI (>24.9 kg/
to determine if there is generalized or localized muscle weakness. m2) is interpreted as excessive fat mass (overweight or obesity).
Myocardial function can be evaluated, and respiratory muscle Although BMI is accurate in this regard for the vast majority of
function can be assessed with spirometry. adults, it can be just as misleading as other measures that rely
on body weight without a direct evaluation of body composi-
tion.81 For example, the individual with excessive fluid accumu-
Specific Nutrient Deficiencies lation, where actual fat and body cell mass (BCM) are less than
Rapidly proliferating tissues (e.g., oral mucosa, hair, skin, GI that implied by the BMI, and the muscle-bound athlete, where
epithelium, bone marrow) are often more sensitive to nutrient a high BMI is indicative of an extraordinarily large lean mass,
deficiencies than tissues that turn over more slowly (e.g., heart, are two examples of how the underlying assumptions inherent in
skeletal muscle, brain [see Tables 5.9 to 5.11]). the BMI are false. Sex and race are also confounding variables,
although the differences are clinically irrelevant. More important
are the remarkable changes in body composition that accompany
Anthropometry development, making the interpretation of BMI in childhood and
Anthropometric techniques are those in which a quantitative mea- adolescence very complex.82
sure of the size, weight, or volume of a body part is used to assess It should be apparent from this discussion that measure-
protein and calorie status. Historically, one of the most commonly ments of relevant body compartments (e.g., fat mass or fat-free
used anthropometric parameters has been weight for height. mass [FFM]) can reveal important information about nutritional
This is a useful parameter when neither the patient nor family status that is often obscured by measurement of weight alone.
can provide reliable historical information, but it is less desirable Underwater (hydrostatic) weighing, dual energy x-ray absorpti-
than a history of unintentional weight loss, because it requires the ometry, air impedance plethysmography, total body potassium,
patient’s weight to be judged against a normative standard that isotopically labeled water dilution, in vivo neutron activation
has been established in a large control population, and inter-indi- analysis, computed tomography, and magnetic resonance imag-
vidual variability in the population limits this method’s accuracy ing are accurate noninvasive (or minimally invasive) techniques of
for correctly predicting PEM in one individual. Table 5.6 displays measuring body compartments.82-89 All are highly effective, but
the 1959 Metropolitan Life Insurance Company “desirable body because of their expense, lack of accessibility, and impracticality,
weights” that were established with prospective mortality data. their use is largely relegated to the sphere of clinical research. A
The 1959 table remains preferable to the 1983 tables largely detailed understanding of these tools is beyond the scope of this
because of concerns that the latter did not include an adequate chapter, but the primary use of each, with reference to detailed
sampling of certain segments of the population, and was there- reviews, is outlined in Table 5.19.
fore biased. In the context of the Metropolitan table, desirable In the clinical setting, simple but less accurate techniques are
weight for height is defined as that figure associated with maximal used to assess body compartments. An approximate measure of
TABLE 5.19 Advanced Techniques for Measurement of Body as total body fat changes, the subcutaneous fat at each site responds
Compartments in a different manner. Similarly, mid-arm muscle circumference
(MAMC) provides a measure of skeletal muscle mass. Table 5.20
Primary Use in Body
Technique Compartment Analysis
contains guidelines for interpretation of skinfold and mid-arm
muscle area based on data from the first two National Health and
Air displacement Proportion of body composed Nutrition Examination Surveys (NHANES I and II).90
plethysmography91 of FM, proportion of body Clinical use of skinfolds and appendicular muscle area has dis-
composed of LM
tinct weaknesses. As was true for the weight-for-height tables, there
CT90 Regional FM/LM is considerable inter-individual variation in values, so these mea-
Dual energy x-ray Absolute FM and LM; bone density surements are more useful in population studies than in an indi-
absorptiometry92 vidual. Moreover, these measures are highly operator dependent.91
In vivo neutron activation Total body protein, absolute FM, Also, although the updated databases defining normative values no
analysis95 absolute LM longer contain the race and age biases of older versions, correction
factors for hydration and physical activity are still unavailable.
Isotopically labeled water and TBW, ICW, ECW
In practice, we have found the most useful clinical role for the
NaBr dilution94
measurement of skinfolds and muscle area is in tracking patients
MRI96 Regional FM/LM with serial measurements over time as a means of monitoring their
Total body potassium93 Body cell mass recovery from disease or response to a clinical intervention. In
this manner, the patient is being compared with himself or herself
Underwater (hydrostatic) Proportion of body composed
weighing89 of FM, proportion of body rather than with some normative value. In gastroenterology, the
composed of LM use of skinfolds and muscle area has been of particular value in the
assessment and management of cirrhotic patients, because cirrho-
ECW, Extracellular water; FM, fat mass; ICW, intracellular water; LM, sis corrupts almost all the other common measures of nutritional
lean mass; NaBr, sodium bromide; TBW, total body water.
status. Abnormally low values for triceps skinfold and MAMC
are independent predictors of mortality in patients with cirrho-
sis, and their incorporation into a Cox regression model improves
the prognostic value of the Child-Turcotte Score.92 Also, when
TABLE 5.20 Normative Standards for Upper Arm Muscle Area and Sum patients with severe alcoholic hepatitis are treated with anabolic
of Triceps and Subscapular Skinfolds steroids, improvements in MAMC and other measures of the
Percentile FFM correlate with a positive response to treatment.93
Interest continues in bioimpedance analysis as an inexpensive,
Parameter Age 5th 50th 85th relatively easy, noninvasive, and safe means of assessing FFM,
Upper Arm Muscle Area (cm2)* BCM, and total body water. BCM is sometimes perceived as a
Men 25-29 38 53 65
more important measure of lean mass than FFM because it does
45-49 37 55 66 not include non-living lean mass (e.g., blood plasma and bone
65-69 33 48 63 minerals [see Fig. 5.1]). Resistance to electrical flow through the
body is measured, which is proportional to fat and bone mineral
Women 25-29 20 30 38
45-49 21 32 45
content because these body components have poor conductiv-
65-69 22 35 46 ity. Because all other components of the body are suffused with
electrolyte-laden water that readily conducts an electric current,
Sum of Triceps and Subscapular Skinfolds (mm) calculations of total body water, FFM, and BCM can be made if
Men 25-29 12 24 41 one abides by some general assumptions that define the water
45-49 13 29 43 content of each compartment. Those with expertise in its use
65-69 12 27 42
have found it useful for monitoring the FFM in outpatient stud-
Women 25-29 18 37 58 ies of renal dialysis and HIV-infected patients.94, 95 Acute illness,
45-49 21 46 68 however, produces shifts in the total amount of body water and
65-69 22 45 65 its distribution, rendering the technique largely worthless in the

*Mid-upper arm muscle area (cm2) is calculated as follows: inpatient setting.96 Furthermore, the algorithms used to calculate
For men: body composition contain assumptions about body water that can
[ arm circumference − {π × triceps skinfold}]2 change with age, obesity, and disease, so bioimpedance analysis
Area = − 10 must be revalidated within any population in which it is used.
4π
For women:
[ arm circumference − {π × triceps skinfold }] 2 Functional Measures of Protein-Calorie Status
Area = – 6.5
4π Several techniques have been developed that exploit the fact that
skeletal muscle function is impaired in PEM, although only 1 has
Adapted with permission from Frisancho AR. Anthropometric standards acquired wide acceptance: fist-grip dynamometry (FGD). FGD
for the assessment of growth and nutritional status. Ann Arbor, Mich: uses a hand-held dynamometer to measure the maximal fist-grip
University of Michigan Press; 1990. force that can be elicited. When examined as a surrogate measure

of total body protein in patients awaiting GI surgery, FGD cor-
related strongly with in vivo neutron activation analysis and with
MAMC.97 Similarly, FGD is excellent for detecting depleted BCM
whole-body fat mass can be derived from assessing the thickness of in cirrhotic patients,98 a group in which it is notoriously difficult
subcutaneous fat, which in a normally proportioned adult contains to perform nutritional assessment. As noted, valid indicators of
roughly half of the body’s adipose stores. The triceps and subscap- moderate to severe PEM are strong predictors of clinical out-
ular sites are used most commonly for this purpose, and it is best come in acutely ill patients, and FGD is effective in this regard.
to use the sum of the triceps and subscapular folds because sizable Preoperative patients whose fist-grip strength is less than 85% of
inter-individual differences exist in fat distribution. Furthermore, age- and sex-corrected standards have a two-fold increased risk of
perioperative complications compared with those whose FGD is A variety of factors alters the serum concentration of each of these
normal.99 In patients undergoing surgery for GI cancers, FGD had proteins. Prealbumin levels are often elevated in chronic kidney dis- 5
superior sensitivity and specificity in predicting perioperative mor- ease or by glucocorticoid or oral contraceptive administration. The
bidity and mortality than a widely used discriminant analysis called degree to which serum levels of all these proteins are decreased in
the prognostic nutritional index.100 FGD holds considerable promise cirrhosis increases incrementally with worsening grades of the Child
for rapid and convenient assessment of protein-calorie status in classification, although even patients who are Child class A have a
both inpatients and outpatients, but the technique is limited by its small decrease in albumin compared with healthy individuals.102
requirement for an alert and cooperative patient. All these proteins behave as negative acute-phase reactants,
Respiratory muscle strength, typically measured with a bedside i.e., their serum concentrations drop in response to systemic
spirometer as maximal sustained inspiratory force, maximal sus- inflammation, roughly proportional to the magnitude of the
tained expiratory force, or both, has also been used as a measure of inflammatory response. This effect diminishes their reliability as
protein-calorie status but is generally considered unreliable because indicators of PEM in the acutely ill patient, particularly when
too many non-nutritional factors may alter its measurement. used as a sole metric of nutritional status. Nonetheless, with
Although PEM adversely affects the physiology of almost all proper respect for their limited accuracy, they can still be useful.
organ systems, the immune system is the most sensitive. Delayed For example, prealbumin has been shown to be an efficient rapid
hypersensitivity skin testing, which assesses the integrity of cell- means of screening inpatients for PEM on hospital admission.103
mediated immunity, has been used most often in this regard. In
critically ill patients, skin testing has value in predicting morbidity
and mortality, but its interpretation is fraught with confounding
Creatinine-Height Index
variables such as older age, systemic infection, and major surgery, The amount of creatinine excreted in the urine over a 24-hour
each of which will independently depress reactivity. Furthermore, period, corrected for the patient’s height, is an excellent means
reactivity improves in an unpredictable manner with nutritional of assessing total skeletal muscle mass. The relationship holds
restitution, so it is not useful for monitoring patient progress.101 because a relatively constant percentage (≈2%) of muscle creatine
The value of skin testing to assess nutritional status is used best as is converted to creatinine each day. Values that are greater than
part of an array of parameters that collectively assess nutritional sta- 20% below sex- and height-adjusted normative values are indica-
tus (see later, “Discriminant Analyses of Protein-Calorie Status”). tive of moderate-to-severe PEM (Table 5.22). Updated norma-
tive creatinine-height index (CHI) values for children of ages 3
to 18 years are available.104 In sick persons, the CHI tends to
Biochemical Measures of Protein-Calorie Status correlate with simple measures like unintentional weight loss,
as well as with highly accurate measures of skeletal muscle like
Serum Proteins dual energy x-ray absorptiometry.105 In patients receiving pro-
The serum concentrations of several proteins synthesized in the longed mechanical ventilation, CHI is a strong independent risk
liver are used as indicators of protein-calorie status: albumin, pre- factor concurring with the likelihood of successful weaning and
albumin (transthyretin), transferrin, and retinol-binding protein survival.106
(RBP) (Table 5.21). In the absence of concurrent illness or injury, To avoid misleading results, potential confounders that must
a low concentration of any of these proteins strongly suggests the be considered include incomplete urine collection, abnormal or
presence of PEM. Because the half-lives of prealbumin, transfer- unstable renal function, excessive meat or milk ingestion imme-
rin, and RBP are considerably shorter than that of albumin, it diately preceding or during the collection, and glucocorticoid
follows that changes in nutritional status will be reflected more administration, all of which can alter creatinine excretion inde-
promptly in levels of these three proteins than in albumin. pendently of changes in muscle mass.
TABLE 5.21 Proteins Synthesized in the Liver and Used to Assess Nutritional Status
Normal Value
Serum Protein mean ± SD (Range)* Half-life (Days) Function Comment†
Albumin 4.5 (3.5-5.0) 14-20 Maintains plasma oncotic Serum levels altered by a variety of non-nutritional factors
pressure; carrier for
small molecules
Transferrin 2.3 (2.0-3.2) 8-9 Binds Fe2+ in plasma and Iron nutriture influences plasma level; increased
transports it to bone during pregnancy, estrogen therapy, and acute
marrow 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 by corticosteroid, glucocorticoid, or oral
(prealbumin) extent T4; is a carrier contraceptive administration, in those with chronic
for RBP kidney disease on dialysis; 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 Catabolized in the renal proximal tubular cell; with renal
protein (RBP) in plasma; binds disease, RBP increases and its half-life is prolonged;
noncovalently to low plasma levels in vitamin A deficiency, acute
prealbumin 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 sex-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.

Discriminant Analyses of Protein-Calorie Status Rapid Screening Tools for Assessment of Targeted
As noted, many parameters used to measure PEM can also pre- Populations
dict important clinical outcomes, although each parameter has its Assessing nutritional status with inexpensive, rapid, and conve-
own limitations. Multifactorial indices that incorporate various nient means that are accurate in identifying patients with PEM
combinations of these parameters have been developed through is of great value, particularly when large numbers of people need
the use of discriminant analyses. By combining the strengths of to be evaluated. Two such tools have been developed and exten-
several parameters, the goal has been to arrive at a more accu- sively validated: the subjective global assessment (SGA) and the
rate determination of whether a patient has a substantial degree Mini-Nutritional Assessment (MNA).
of PEM and to optimize the ability to predict which patients
will have adverse clinical outcomes because of PEM. Over the
past several decades, various indices have been developed for
Subjective Global Assessment
use in acutely hospitalized patients: for instance, the Prognostic SGA was initially intended for use in surgical inpatients as a means
Nutritional Index (which incorporates serum albumin, transfer- of assessing nutritional status and predicting postoperative infec-
rin, delayed skin hypersensitivity, and triceps skinfold) predicts tions (Box 5.1); for the latter, it was found to be a better predictor
the likelihood of postoperative complications and mortality in
patients undergoing GI surgery107; the Geriatric Nutritional Risk
Index (which incorporates serum albumin and % IBW) predicts BOX 5.1 Subjective Global Assessment of Nutritional Status
the likelihood of infectious complications and mortality among
elderly inpatients.108 Since readily available metrics of PEM in HISTORY
the acute care setting are so heavily influenced by disease sever-
Weight change:
ity, these indices should not be considered as accurate measures
Loss in past 6 months: amount = __________ kg;
of the degree of malnutrition; more properly, they are best con-
% loss = __________
sidered predictors of morbid and mortal events that are known
Change in past 2 weeks: __________ Increase __________
complications of PEM.
No change __________ Decrease
Two more recent additions to this list of indices for the acute
Dietary intake change:
care setting are the Nutrition Risk Score-2002 and the NUTRIC
No change ________ Change ________
score.109 As is true of the older indices, their use has been
Duration = ________ weeks
designed and validated for a specific type of patient, namely, ICU
Dietary status:
patients. A significant advance accompanying the introduction of
__________ Suboptimal solid diet
the NRS-2002 and NUTRIC is the studies that have explored
__________ Hypocaloric liquids
whether these indices can discriminate those patients who genu-
__________ Starvation
inely benefit from intensive nutritional support from those who
Gastrointestinal symptoms (that have persisted for >2 weeks):
will not.110-112
________ None ________ Nausea ________ Vomiting ________
Diarrhea ________ Anorexia
TABLE 5.22 Normative Values for Daily Creatinine Excretion Based on Functional capacity:
Height __________ No dysfunction __________
Dysfunction Duration = __________ Weeks
Men* Women†
Type:
Ideal Ideal __________ Working suboptimally
Height Creatinine Height Creatinine __________ Ambulatory but not working
(cm) (mg) (cm) (mg) __________ Bedridden
157.5 1288 147.3 830 Effect of disease on nutritional requirements:
160.0 1325 149.9 851
Primary diagnosis: __________
Metabolic demand: _________ Low stress _________
162.6 1359 152.4 875 Moderate stress _________ High stress
165.1 1386 154.9 900 PHYSICAL EXAMINATION (NORMAL, MODERATE, OR
167.6 1426 157.5 925 SEVERE)
170.2 1467 160.0 949 __________ Loss of subcutaneous fat (triceps, chest)
172.7 1513 162.6 977
__________ Muscle wasting (quadriceps, deltoids)
__________ Ankle or sacral edema
175.3 1555 165.1 1006 __________ Ascites
177.8 1596 167.6 1044 SGA RATING*
180.3 1642 170.2 1076 A = Well nourished
182.9 1691 172.7 1109 B = Mild or moderate malnutrition
185.4 1739 175.3 1141
C = Severe malnutrition

188.0 1785 177.8 1174
*The ranks of A, B, and C in the SGA are assigned on the basis of subjec-
190.5 1831 180.3 1206 tive weighting. A patient with weight loss and muscle wasting who is
193.0 1891 182.9 1240 currently eating well and gaining weight is classified as well nourished.
A patient with moderate weight loss (between 5% and 10%), continued
*Creatinine coefficient (men) = 23 mg/kg of ideal body weight. compromise in food intake, continued weight loss, progressive functional
†Creatinine coefficient (women) = 18 mg/kg of ideal body weight.
impairment, and moderate stress due to illness is classified as moderately
From Blackburn GL, Bistrian BR, Maini BS, et al. Nutritional and metabolic malnourished. A patient with severe weight loss (>10%), poor nutrient
assessment of the hospitalized patient. J Parenter Enteral Nutr 1977; intake, progressive functional impairment, and muscle wasting is usually
1:11-22. classified as having severe malnutrition.

than serum albumin concentration, delayed skin hypersensitivity, clinical research upholds that aggressive nutritional support pro-
MAMC, CHI, and the prognostic nutritional index.113 A focused vides benefit to the hospitalized patient. 5
history and physical examination are used to categorize patients
as well nourished (category A), having mild or moderate malnu-
trition (category B), or having severe malnutrition (category C). Malnourished Patients Undergoing Major Surgery
Despite the subjective nature of some of its components, there is Nutritional support can be beneficial for moderately to severely
excellent agreement among independent observers.114 The SGA malnourished patients who are scheduled to undergo major sur-
has been shown to be reliable, even in the hands of first-year gery. Aggressive nutritional support for 7 or more days before sur-
medical and surgical residents,115 and has been validated as a pre- gery reduces perioperative complications and sometimes mortality
dictor of clinical outcomes in chronically institutionalized older in malnourished patients.64-71, 125-127 In the Veterans Affairs TPN
adults and patients with a variety of medical conditions.116-118 Cooperative Study,64 which encompassed almost 500 subjects about
to undergo major abdominal or thoracic surgery, patients who were
Mini-Nutritional Assessment categorized as severely malnourished and randomized to receive pre-
operative TPN realized an almost 90% decrease in noninfectious
The MNA was developed as a rapidly administered screen to perioperative complications. No benefits were observed in mildly
detect PEM in geriatric populations. A combination of history, malnourished or well-nourished individuals. In trials of moderately to
limited physical examination, and simple anthropometrics (BMI, severely malnourished patients, preoperative nutrition support gen-
arm- and calf-circumference) can be obtained in a few min- erally conveys sizeable benefits: a trial that enrolled 90 patients with
utes. Subjects receive a score that classifies them as being nour- gastric or colorectal cancers undergoing surgery demonstrated a 35%
ished, malnourished, or at risk of malnutrition. The MNA is a decline in overall complications and a significant reduction in mor-
valid means of detecting PEM in older adults who are generally tality.127 The observation that the benefits of preoperative nutritional
healthy and ambulatory, as well as those who are frail and institu- support are confined to those with a substantial degree of malnutri-
tionalized119-120; in the chronically institutionalized, it possesses tion is the same conclusion reached by meta-analyses.69, 70 Deferring
considerable predictive value in projecting future morbidity.121 aggressive nutritional support until after surgery does not appear to
One disadvantage of the MNA is that it does not screen for over- have the same ability to diminish perioperative complications.128
weight or obesity. Other screening tools designed for geriatric Provision of nutrients via an enteral approach is also benefi-
populations, such as the Nutrition Screening Initiative, have the cial. There have been fewer trials done of preoperative enteral
ability to screen for under- and overnutrition but have not been support than of preoperative TPN, but it appears that preopera-
as extensively validated as the MNA.122 tive enteral support confers the same nutritional129 and clinical130
benefits as TPN. As with TPN, postoperative enteral nutrition
AGGRESSIVE NUTRITIONAL SUPPORT IN THE in the absence of aggressive preoperative support is less likely to
HOSPITALIZED PATIENT convey benefit to the patient.131
The chapter that follows provides detailed descriptions of
the approaches to nutritional management that are presently Patients Hospitalized with Decompensated Alcohol-
accepted as appropriate in the setting of specific GI and hepatic Associated Liver Disease
diseases. As a means of introduction, however, it is first worth The prevalence of moderate-to-severe PEM is so high in patients
considering under what circumstances clinical observations admitted for acute alcoholic hepatitis and other forms of decom-
indicate that “aggressive nutritional support” (defined as using pensated alcoholic liver disease62 that it is best to assume all such
whatever means necessary and practical to meet the patient’s patients are malnourished. Furthermore, patients with acute
nutritional needs) truly benefits the acutely ill patient. In prac- alcoholic hepatitis usually fall far short of their nutritional needs
tice, any acutely ill patient who has moderate-to-severe malnutri- when allowed to eat freely. Clinical trials have demonstrated that
tion and is unlikely to be able to meet his or her own nutritional the rates of morbidity, mortality, and the speed of recovery are
needs within 48 hours is a strong candidate for aggressive nutri- improved with prompt institution of enteral or parenteral nutri-
tional support. Another common indication for aggressive nutrition in these patients.65-67, 132
tional support is when a well-nourished or mildly malnourished
inpatient is judged to be unlikely to meet at least 80% of his or
her projected calorie or protein goals for the coming 10 days. Patients Undergoing Radiation Therapy
To date, there is insufficient evidence-based science to prove The usefulness of aggressive nutrition support in patients
efficacy of this latter indication, although common sense would undergoing radiation therapy has been studied most extensively
suggest it to be true. in those who have head and neck and esophageal cancers. There
Catabolic forces that accompany acute illness make it difficult to is now reasonable evidence in these patients that placement of
correct nutritional deficits. In those with a high degree of sustained a PEG tube and administration of supplemental tube feedings
metabolic stress, nutritional support generally will not lead to an during and after the course of radiation therapy prevents fur-
increase in the protein compartment of the body. Moreover, a gain ther deterioration of nutritional status.133-134 In patients with
in weight may not occur, and when it does, much of the initial gain head and neck cancers, supplemental PEG feedings have also
is from water and an expanded fat mass.123 Despite these limitations, been shown to improve quality of life. Although improvements
even in the absence of weight gain or increases in serum protein lev- in survival or decreased morbidity have not yet been demon-
els, a course of nutritional support for an appropriate patient can strated, improved quality of life alone may warrant its use in
improve physiologic functions and clinical outcomes.124 this setting.
The following three sections cite some clinical scenarios
particularly relevant to gastroenterology for which compelling Full references for this chapter can be found on www.expertconsult.com.
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Carnegie Institute of Washington; 1919. p. 223. teral nutrition: requirements and metabolic effects. Gastroenterol-
2. WHO (World Health Organization). Energy and protein require- ogy 1979;76:458–67.
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PART

5 Nutritional Principles and Assessment of the

TABLE 5.2 Resting Energy Requirements of Various Tissues in a 70-kg Man

Harris-Benedict Equation Injury or Illness Relative Stress Factor*

Mifflin Equation Multiple trauma 1.5-1.7

0-3 (60.9 × W) − 54 (60.1 × W) − 51 Second- or third-degree burns, 1.2-1.4

TABLE 5.7 Estimated Energy Requirements for Hospitalized Patients Proteins

or prosthetic groups, others as biochemical substrates or hor-

MICRONUTRIENTS Trace Minerals

TABLE 5.9 Major Mineral Requirements and Assessment of Deficiency

TABLE 5.10 Salient Features of Vitamins

TABLE 5.10 Salient Features of Vitamins—cont’d

TABLE 5.10 Salient Features of Vitamins—cont’d

TABLE 5.11 Salient Features of Trace Minerals

TABLE 5.11 Salient Features of Trace Minerals—cont’d

contains the bulk of metabolism that sustains homeostasis. It is

TABLE 5.16 Waterlow Classification of Protein-Energy Malnutrition in Children

Marasmus Cardiovascular System

improve clinical outcome.64-68 Meta-analyses have underscored

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