Nutritional Principles and Assessment of the Gastroenterology Patient

Diligent attention to patients’ nutritional needs can have a major positive impact on medical outcomes. This is particularly true in GI and liver disease because many of these conditions, in addition to altering nutrient metabolism and requirements, are prone to interfere with ingestion and assimilation of nutrients. Nutritional 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 part, to failure to distinguish patients who stand to benefit from nutritional care from those whose outcomes will not respond to nutritional intervention. The fact that many clinical trials have failed to demonstrate a benefit of nutritional support in hospitalized patients is often because such a distinction has not been made. The major aim of this chapter is to provide the scientific principles and practical tools necessary to recognize patients who will benefit from focused attention to their nutritional needs, and to provide the guidance necessary to develop a suitable nutritional plan for these individuals.

Over- or under-feeding a patient can be detrimental to clinical outcomes, so developing a nutritional plan most appropriately begins by determining the patient’s estimated caloric and protein needs.

Basic Nutritional Concepts

Energy Stores

Endogenous energy stores are oxidized continuously for fuel. Triglyceride (TG) present in adipose tissue is the body’s major fuel reserve and is critical for survival during periods of starvation ( Table 5.1 ). The high energy density and hydrophobic nature of TGs make them a five-fold better fuel per unit mass than glycogen. 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 kcal/g on oxidation and is stored intracellularly as a gel, containing approximately 2 g of water per gram of glycogen. Adipose tissue cannot provide fuel for certain tissues like bone marrow, erythrocytes, leukocytes, renal medulla, eye tissues, and peripheral nerves, which cannot oxidize lipids and require glucose for their energy supply. During endurance exercise, glycogen and TGs in muscle tissue provide an important source of fuel for working muscles.

TABLE 5.1

Endogenous Fuel Stores in a 70-kg Man

Tissue	Fuel source	Mass
Tissue	Fuel source	Grams	Kilocalories
Adipose	Triglyceride	13,000	121,000
Liver	Protein	300	1,200
	Glycogen	100	400
	Triglyceride	50	450
Muscle	Protein	6,000	24,000
	Glycogen	400	1,600
	Triglyceride	250	2,250
Blood	Glucose	3	12
	Triglyceride	4	37
	Free fatty acids	0.5	5

Energy Metabolism

Energy is required continuously for normal organ function, maintenance of metabolic homeostasis, heat production, and performance of mechanical work. Daily total energy expenditure (TEE) has three components: resting energy expenditure (REE) (≈70% of 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 latter two components of TEE should be considered when estimating caloric needs for ambulatory individuals, in acutely ill, hospitalized patients, the energy expended in physical activity is typically ignored and the energy expended in the thermic effect of feeding is built into the predictive equations that follow.

Resting Energy Expenditure

REE represents energy expenditure while a person lies quietly awake in an interprandial state; under these conditions, about 1 kcal/kg body weight is consumed per hour in healthy adults. Energy requirements of specific tissues differ dramatically ( Table 5.2 ). The liver, intestine, brain, kidneys, and heart constitute roughly 10% of total body weight but account for about 75% of REE. In contrast, skeletal muscle at rest consumes some 20% of REE, but represents approximately 40% of body weight. Adipose tissue consumes less than 5% of REE but usually accounts for greater than 20% of body weight.

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.

An accurate assessment of REE is best obtained by indirect calorimetry, in which in vivo energy expenditure is estimated by measuring carbon dioxide production and oxygen consumption while the subject is at rest. Although indirect calorimetry is considered a gold standard for determining REE, obtaining such 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 ). The Harris-Benedict and Mifflin equations are designed for use in adults, whereas the WHO formulas includes equations for both children and adults. These equations are generally accurate in healthy subjects but are inaccurate, for example, in persons who are at extremes in weight because of anomalous body composition, and it is in these settings where determination by indirect calorimetry is useful. In the setting of acute illness, the predictive equations are usually adequate although it is necessary to insert correction factors of one type or another since inflammation and metabolic stress greatly influence energy expenditure. Protein-energy malnutrition (PEM) and hypocaloric feeding without superimposed illness each decrease REE to values 10% to 15% below those expected for actual body size, whereas acute illness or trauma predictably increases energy expenditure (see later).

TABLE 5.3

Commonly Used Formulas for Calculating Resting Energy Expenditure

Harris-Benedict Equation
Men	66 + (13.7 × W) + (5 × H) − (6.8 × A)
Women	665 + (9.6 × W) + (1.8 × H) − (4.7 × A)
Mifflin Equation
Men	(10 × W) + (6.25 × H) − (5 × A) + 5
Women	(10 × W) + (6.25 × H) − (5 × A) − 161
World Health Organization Formula

Age (yr)	Male	Female
0-3	(60.9 × W) − 54	(60.1 × W) − 51
3-10	(22.7 × W) − 495	(22.5 × W) + 499
10-18	(17.5 × W) + 651	(12.2 × W) + 746
18-30	(15.3 × W) + 679	(14.7 × W) + 996
30-60	(11.2 × W) + 879	(8.7 × W) + 829
>60	(13.5 × W) + 987	(10.5 × W) + 596

Calculated as kilocalories per day.

A , Age in years; H , height in centimeters; W , weight in kilograms.

Energy Expenditure of Physical Activity

The effect of physical activity on energy expenditure depends on the intensity and duration of daily activities. Highly trained athletes can increase their TEE 10- to 20-fold during athletic events. The activity factors shown in Table 5.4 , each expressed as a multiple of REE, can be used to estimate TEE in active patients. The energy expended during a particular physical activity is equal to (REE per hour) × (activity factor) × (duration of activity in hours). TEE represents the summation of energy expended during all daily activities, including rest periods.

TABLE 5.4

Relative Thermic Effect of Various Levels of Physical Activity

Adapted from Alpers DA, Stenson WF, Bier DM. Manual of nutritional therapeutics. Boston: Little, Brown; 1995.

Activity Level	Examples	Activity Factor
Resting		1.0
Very light	Standing, driving, typing	1.1-2.0
Light	Walking 2-3 miles/hr, shopping, light housekeeping	2.1-4.0
Moderate	Walking 3-4 miles/hr, biking, gardening, scrubbing floors	4.1-6.0
Heavy	Running, swimming, climbing, basketball	6.1-10.0

Thermic Effect of Feeding

Eating or infusing nutrients increases metabolic rate. Dietary protein causes the greatest stimulation of metabolic rate, followed by carbohydrate and then fat. A meal containing all these nutrients usually increases metabolic rate by 5% to 10% of ingested or infused calories.

Recommended Energy Intake in Hospitalized Patients

In arriving at a nutritional plan for hospitalized patients, it is usually not necessary to obtain actual measurements of energy expenditure with a bedside indirect calorimeter. A number of simple formulas can be used instead and make up in practical value what they lack in accuracy. A few examples follow.

Methods Incorporating Metabolic Stress Factors

Metabolic stress (i.e., any injury or illness that incites some degree of systemic inflammation) will increase the metabolic rate through a variety of mechanisms (see later). The increase in energy expenditure is roughly proportional to the magnitude of the stress. Thus, the total daily energy requirement of an acutely ill patient can be estimated by multiplying the predicted REE (as determined by the Harris-Benedict or WHO equations) by a stress factor:

TEE = REE \times Stress factor

$TEE = REE \times Stress factor$

Table 5.5 delineates metabolic stress factors that accompany some common conditions and clinical scenarios in inpatients. Because the Mifflin equation was not designed to be used to estimate TEE with stress factors, it is not recommended in this context. In acutely ill hospitalized patients, it is not usually necessary to include an activity factor.

TABLE 5.5

Metabolic Stress Factors for Estimating Total Energy Expenditure in Hospitalized Patients

From Psota T, Chen KY. Measuring energy expenditure in clinical populations: rewards and challenges. Eur J Clin Nutr 2013; 67:436–42.

Injury or Illness	Relative Stress Factor ∗
Second- or third-degree burns, >40% BSA	1.6-2.0
Multiple trauma	1.5-1.7
Second- or third-degree burns, 20%-40% BSA	1.4-1.5
Severe infections	1.3-1.4
Acute pancreatitis	1.1-1.2
Second- or third-degree burns, 10%-20% BSA	1.2-1.4
Long bone fracture	1.2
Peritonitis	1.2
Uncomplicated postoperative state	1.1

BSA , Body surface area.

∗ A stress factor of 1.0 is assumed for healthy controls.

An alternative and simple formula for adult inpatients, although accompanied by some further loss in accuracy, is:

20 to 25 kcal/kg of actual body weight (ABW)/day for unstressed or mildly stressed patients
25 to 30 kcal/ABW/day for moderately stressed patients
30 to 35 kcal/ABW/day for severely stressed patients

In using this formula, adjustments are necessary when the ABW is a misleading reflection of lean body mass. An adjusted ideal body weight (IBW) should be substituted for ABW in obese individuals who are more than 30% heavier than their IBW (desirable body weights appear in Table 5.6 ). Using an adjusted IBW helps prevent an overestimation of energy requirements and is calculated as:

Adjusted IBW = IBW + 0.5 (ABW - IBW)

$Adjusted IBW = IBW + 0.5 (ABW - IBW)$

TABLE 5.6

Desirable Weight in Relation to Height for Men and Women 25 Years or Older

Data from Metropolitan Life Insurance Company. New height standards for men and women. Statistical Bulletin 1959; 40:1-4.

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.

In patients with large artifactual increases in weight due to extracellular fluid retention (e.g., ascites), the IBW should be used to estimate energy requirements rather than the ABW.

Method Without a Stress Factor

The most accurate and extensively validated equation for predicting daily energy expenditure in ill patients is one that does not incorporate a stress factor; it does, however, require knowledge of the minute ventilation, so its use is restricted to patients on mechanical ventilation. This formula (often referred to as the “Penn State Equation”) is:

\begin{matrix} TEE = (REE calculated by Mifflin equation \times 0.96) + \\ (T_{\max} \times 167) + (V_{e} \times 31) - 6212 \end{matrix}

$\begin{matrix} TEE = (REE calculated by Mifflin equation \times 0.96) + \\ (T_{\max} \times 167) + (V_{e} \times 31) - 6212 \end{matrix}$

T _max is the maximum temperature in Celsius over the past 24 hours; V _e is expired minute ventilation in liters.

Table 5.7 describes a simple alternative method for estimating total daily energy requirements in hospitalized patients; it is based on BMI. It lacks the extensive validation of the prior algorithm as well as some of its accuracy, but it does not require knowledge of minute ventilation, is straightforward, and consequently has some genuine utilitarian value. Common sense has to be applied when using an inexact means such as this to estimate energy expenditure in hospitalized individuals, because illness commonly interjects artifacts into these calculations (e.g., ascites, anasarca).

TABLE 5.7

Estimated Energy Requirements for Hospitalized Patients Based on Body Mass Index

Body Mass Index (kg/m ² )	Energy Requirements (kcal/kg/day) ∗
<15	35-40
15-19	30-35
20-29	20-25
≥30	15-20

The lower range within each body mass index (BMI) category should be considered in calculating energy requirements for insulin-resistant or critically ill patients to decrease the risk of hyperglycemia and infection associated with overfeeding.

∗ These values are recommended for critically ill patients and all obese patients; add 20% of the total calories when estimating energy requirements in non–critically ill patients.

Caloric Delivery and Avoidance of Hyperglycemia

Over the past 2 decades, the trend has generally been toward a more conservative approach to caloric delivery in acutely ill patients. One reason for this conservatism is that acute illness and its management often exacerbate preexisting diabetes or produce de novo glucose intolerance. As a result, hyperglycemia is a frequent consequence of enteral, and especially parenteral, nutrition. The issue seems to be particularly germane for ICU patients, in whom even modest hyperglycemia results in worse clinical outcomes, usually of an infectious nature. High-quality clinical trials in surgical ICU (SICU) and medical ICU (MICU) patients have found that morbidity is substantially and significantly reduced in those randomized to intensive insulin therapy who maintained serum glucose levels below 111 mg/dL, compared with those whose glucose values were maintained below 215 mg/dL. Mortality was also significantly lower among SICU 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 MICU greater than 3 days. Similarly, in a clinical trial of pediatric ICU patients, secondary infections, length of PICU stay, and mortality were all reduced by intensive age-specific glucose control. These observations are almost certainly the clinical expression of the numerous mechanistic impairments that acute hyperglycemia produces in the innate immune system.

The clinical benefits of tight glucose control in the ICU, however, have not always been reproducible and come at the cost of more frequent hypoglycemic episodes, so the issue of how tight glucose control should be remains controversial. Extremely tight control, with a target range of 81 to 108 mg/dL, produced a 13-fold greater risk of hypoglycemia and a significantly greater mortality in a large multicenter trial of ICU patients, and is, therefore, excessive. A panel of experts recently recommended instituting protocols to keep blood sugar levels at 150 mg/dL or lower in ICU patients, preferably by use of a continuous infusion of insulin, with monitoring every 1 to 2 hours so that appropriate adjustments can be made and blood sugar values less than 70 mg/dL are avoided. The results of a meta-analysis of 29 trials in critically ill patients recapitulate the previously observed discrepancies between SICU and MICU patients. Overall, the relative risk of septicemia was reduced approximately 25% in those randomized to tight glucose control, although this salutary effect was largely attributable to the SICU patients, in whom reduction in septicemia was almost 50%; no benefit was observed in MICU patients, nor were differences in overall mortality evident in any of the categories of critically ill patients.

The question of appropriate caloric delivery to critically ill overweight and obese patients who account for a burgeoning proportion of patients cared for in ICUs is a controversial issue at present. A popular nutritional approach to such patients is so-called hypocaloric feeding, in which only 60% to 70% of the estimated energy requirement (or 11 to 14 kcal/kg of ABW) is delivered in conjunction with 2 to 2.5 grams of protein/kg of IBW per day, the latter minimizing the risk of producing net protein catabolism and loss of lean body mass. The purported advantages of hypocaloric feeding include improved glycemic control and prevention of metabolic complications like hypercapnia and hypertriglyceridemia. Reduction in fat mass and weight is another consequence of hypocaloric feeding, but should never be a primary objective in feeding obese ICU patients. Systematic reviews that have examined the use of hypocaloric feeding in obese ICU patients, and which have examined important endpoints such as mortality, length of stay, duration of mechanical ventilation, and infectious complications have not yet been able to arrive at a consistent consensus either supporting net benefits or risks of hypocaloric, compared to normocaloric, nutrition support. Thus, the matter remains an unsettled one.

Proteins

Twenty different amino acids (AAs) are commonly found in human proteins. Some AAs (histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, and possibly arginine) are considered essential because their carbon skeletons cannot be synthesized by the body. Other AAs (glycine, alanine, serine, cysteine, tyrosine, glutamine, glutamic acid, asparagine, and aspartic acid) are nonessential in most circumstances because they can be made from endogenous precursors or essential AAs. In disease states and in pre-term infants, intracellular and/or plasma concentrations of certain nonessential AAs are often very low and thought of as “conditionally essential” AAs. For many years, supplemental glutamine was included in TPN to compensate for cellular depletion of this AA during critical illness. However, rigorously conducted clinical trials have shown no benefit associated with administration of supplemental IV glutamine. In a randomized placebo controlled multi-center, multi-national trial of critically ill adults with multiorgan failure, glutamine supplementation was associated with an increase in mortality. Evidently, repletion of a conditionally essential AA during acute illness does not necessarily convey a benefit. However, there continues to be interest in defining clinical scenarios in critical illness (e.g., premature infants), in which supplementation with conditionally essential AAs might improve clinical outcomes. Arginine, cysteine, glycine, glutamine, proline, and tyrosine are AAs that fall into this category.

The body of an average 75-kg man contains about 12 kg of protein. In contrast to fat and carbohydrate, there is no storage depot for protein, so excess intake is catabolized and the nitrogen component is excreted. Inadequate protein intake causes net nitrogen losses, and because no depot form of protein exists, there is an obligatory net loss of functioning protein. The U.S. Recommended Daily Allowance (RDA) of protein has been established at 0.8 g/kg/day, which reflects a mean calculated requirement of 0.6 g/kg/day plus an added factor to take into account the biological variance in requirement observed in a healthy population. Intravenously administered AAs are as effective in maintaining nitrogen balance as oral protein of the same AA composition.

An individual’s protein requirement is affected by several factors, such as the amount of non-protein calories provided, overall energy requirements, protein quality, and the patient’s nutritional status ( Table 5.8 ). Protein requirements increase when calorie intake does not meet energy needs. The magnitude of this increase is directly proportional to the deficit in energy supply. Therefore, nitrogen balance reflects both protein intake and energy balance. Correcting a negative nitrogen balance can sometimes be achieved merely by increasing caloric delivery if the total amount of calories has been inadequate.

TABLE 5.8

Recommended Daily Protein Intake

Clinical Condition	Daily Protein Requirement (g/kg IBW)
Normal	0.80
Metabolic stress	1.0-1.6
Hemodialysis	1.2-1.4
Peritoneal dialysis	1.3-1.5

Additional protein requirements are needed to compensate for excess protein loss in specific patient populations (e.g., patients with burn injuries, open wounds, protein-losing enteropathy, or nephropathy). Lower protein intake may be necessary for patients with renal insufficiency not treated by dialysis and certain patients with liver disease and hepatic encephalopathy.

IBW , Ideal body weight.

As metabolic stress (and with it, metabolic rate) increases, nitrogen excretion increases proportionately; quantitatively, the relationship is approximately 2 mg nitrogen (N)/kcal of REE. In part, this increase is explained by the fact that in metabolic stress, a larger proportion of the total substrate oxidized for energy is from protein. This has two important implications for managing the nutritional needs of ill patients. The first is that illness, by increasing catabolism and metabolic rate, increases the absolute requirement for protein (see Table 5.8 ), and does so in a manner that is roughly proportional to the degree of stress. Second, because a greater proportion of energy substrate in acute illness comes from protein, nitrogen balance is more readily achieved if a larger proportion of the total calories are from protein. In healthy adults, as little as 10% of total calories have to come from protein to maintain health, whereas in the ill patient, nitrogen balance is achieved more easily if 15% to 25% of total calories are delivered as protein.

Protein requirements are also determined by the adequacy of essential AAs in the protein source. Inadequate amounts of an essential AA result in inefficient uptake, so proteins of low biologic quality increase the protein requirement. In normal adults, approximately 15% to 20% of total protein requirements should 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 wounds, and protein-losing enteropathy or nephropathy). Delivering less protein than is needed is often a necessary compromise in patients with acute kidney failure who are not adequately dialyzed; in this situation the rise in azotemia is directly proportional to protein delivery. Once adequate dialysis is available, protein delivery should be increased to the actual projected need, including additional protein to compensate for losses resulting from dialysis (see Table 5.8 ). Most patients with hepatic encephalopathy respond to simple pharmacologic measures and, therefore, do not require protein restriction; those who do not respond may benefit from a modest protein restriction (≈0.6 g/kg/day).

Nitrogen Balance

Nitrogen (N) balance is commonly used as a proxy measure of protein balance (i.e., whether the quantity of protein [or AAs] taken in is sufficient to prevent any net loss of protein). N balance 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 conveniently calculated as follows for adults:

\begin{matrix} N balance = (Grams of N administered as nutrition) - \\ (Urinary urea N [g] + 4) \end{matrix}

$\begin{matrix} N balance = (Grams of N administered as nutrition) - \\ (Urinary urea N [g] + 4) \end{matrix}$

Every 6.25 g of administered protein (or AAs) contains approximately 1 g of N. The additional 4 g of N loss incorporated into the equation is intended to account for the insensible losses from the other sources listed and because urinary urea N only accounts for approximately 80% of total urinary nitrogen. N balance is a suitable surrogate for protein balance, because roughly 98% of total body N is in protein, regardless of one’s health.

A positive N balance (i.e., intake > loss) represents anabolism and a net increase in total body protein, whereas a negative N balance represents net protein catabolism. For example, a negative N balance of 1 g/day represents a 6.25 g/day loss of body protein, which is equivalent to a 30 g/day loss of hydrated lean tissue. In practice, N balance studies tend to be artificially positive because of overestimation of dietary N intake and underestimation of losses due to incomplete urine collections and unmeasured outputs. It is best to wait at least 4 days after a substantial change in protein delivery before N balance is determined, because a labile N pool exists and this tends to dampen and retard changes that otherwise would be observed as a result of altered protein intake.

Carbohydrates

Complete digestion of the principal dietary digestible carbohydrates—starch, sucrose, and lactose—generate monosaccharides (glucose, fructose, and galactose). In addition, 5 to 20 g of indigestible carbohydrates (soluble and insoluble fibers) are typically consumed daily. All cells can generate energy (adenosine triphosphate [ATP]) by metabolizing glucose to 3-carbon compounds via glycolysis, or to carbon dioxide and water via glycolysis and the tricarboxylic acid (TCA) cycle.

There is no absolute dietary requirement for carbohydrate; glucose can be synthesized endogenously from either AAs or glycerol. Regardless, carbohydrate is an important fuel because of the interactions between carbohydrate and protein metabolism. Carbohydrate intake stimulates insulin secretion, which inhibits muscle protein breakdown, stimulates muscle protein synthesis, and decreases endogenous glucose production from AAs. In addition, glucose is the required or preferred fuel for red and white blood cells, the renal medulla, eye tissues, peripheral nerves, and the brain. However, once glucose requirements for these tissues are met (≈150 g/day), the protein-sparing effects of carbohydrate and fat are similar.

Lipids

Lipids consist of TGs, sterols, and phospholipids. These compounds serve as sources of energy; precursors for steroid hormone, prostaglandin, thromboxane, and leukotriene synthesis; structural components of cell membranes; and carriers of essential nutrients. Dietary lipids are composed mainly of TGs, which contain saturated and unsaturated long-chain fatty acids (FAs) of 16 to 18 carbons. Use of fat as a fuel requires hydrolysis of endogenous or exogenous TGs and cellular uptake of released FAs (see Chapter 102 ). Long-chain FAs are delivered across the outer and inner mitochondrial membranes by a carnitine-dependent transport system. Once inside the mitochondria, FAs are degraded by beta oxidation to acetyl coenzyme A (CoA), which then enters the TCA cycle. Therefore, the ability to use fat as a fuel depends on normally functioning mitochondria. A decrease in the abundance or function of mitochondria associated with aging or deconditioning favors the use of carbohydrate as fuel.

Essential Fatty Acids

Humans lack the desaturase enzyme needed to produce the n-3 (double bond between carbons 3 and 4) and n-6 (double bond between carbons 6 and 7) FA series. Linoleic acid (C18:2, n-6) and linolenic acid (C18:3, n-3) are essential FAs and, therefore, should constitute at least 2% and 0.5%, respectively, of the daily caloric intake to prevent a deficiency state. Before the advent of parenteral nutrition, essential fatty acid deficiency (EFAD) was only recognized in infants and manifested as a scaly rash with a specific alteration in the plasma FA profile (see later). Adults were thought not to be susceptible to EFAD because of sufficient essential FA stores in adipose tissue. However, an abnormal FA profile in conjunction with a clinical syndrome of EFAD is now known to sometimes occur in adults with severe short bowel syndrome who are on long-term TPN that lacks parenteral lipids. Adults who have moderate-to-severe fat malabsorption (fractional fat excretion >20%) from other causes and who are not TPN-dependent also frequently display a biochemical profile of EFAD, although whether such a biochemical state carries adverse clinical consequences is unclear. Moreover, TPN lacking any source of fat may lead to EFAD in adults if no exogenous source of EFAs is available. The plasma pattern of EFAD may be observed as early as 10 days after glucose-based TPN is started and before the onset of any clinical features. In this situation, EFAD is probably due to the increase in plasma insulin concentrations caused by TPN, because insulin inhibits lipolysis and, therefore, the release of endogenous essential FAs. The biochemical diagnosis of EFAD is defined as an absolute and relative deficiency in the 2 EFAs in the plasma FA profile. The full clinical EFAD syndrome includes alopecia, scaly dermatitis, capillary fragility, poor wound healing, increased susceptibility to infection, fatty liver, and growth retardation in infants and children.

Major Minerals

Major minerals are inorganic nutrients that are required in large (>100 mg/day) quantities and are important for ionic equilibrium, water balance, and normal cell function. Malnutrition and nutritional repletion can have dramatic effects on major mineral balance. Evaluation of macromineral deficiency and the RDA of minerals for healthy adults are shown in Table 5.9

TABLE 5.9

Major Mineral Requirements and Assessment of Deficiency

Mineral	Enteral	Parenteral (mmol)	Symptoms or Signs of Deficiency	Laboratory Evaluation
Mineral	Enteral	Parenteral (mmol)	Symptoms or Signs of Deficiency	Test	Comment
Calcium	1000-1200 mg	5-15	Metabolic bone disease, tetany, arrhythmias	24-hr urinary calcium Dual energy radiation absorptiometry	Reflects recent intake Reflects bone calcium content
Magnesium	300-400 mg	5-15	Weakness, twitching, tetany, arrhythmias, hypocalcemia	Serum magnesium Urinary magnesium	May not reflect body stores May not reflect body stores
Phosphorus	800-1200 mg	20-60	Weakness, fatigue, leukocyte and platelet dysfunction, hemolytic anemia, cardiac failure, decreased oxygenation	Plasma phosphorus	May not reflect body stores
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

Micronutrients

Micronutrients (vitamins and trace minerals) are a diverse array of dietary components that are necessary to sustain health. The physiologic roles of micronutrients are as varied as their composition. Some are used in enzymes as coenzymes or prosthetic groups, others as biochemical substrates or hormones; in some cases, their functions are not well defined. The average daily dietary intake for each micronutrient required to sustain normal physiologic operations is measured in milligrams or smaller quantities. In this way, micronutrients are distinguished from macronutrients (carbohydrates, fats, and proteins) and macrominerals (calcium, magnesium, and phosphorus).

An individual’s dietary requirement for any given micronutrient is determined by many factors, including its bioavailability, the amount needed to sustain its normal physiologic functions, a person’s sex and age, any diseases or drugs that affect the nutrient’s metabolism, and certain lifestyle habits like smoking and alcohol use. The U.S. National Academy of Sciences Food and Nutrition Board regularly updates dietary guidelines that define the quantity of each micronutrient that is “adequate to meet the known nutrient needs of practically all healthy persons.” These RDAs underwent revision between 1998 and 2001, and the values for adults appear in Tables 5.10 and 5.11 . Formulating an RDA takes into account the biologic variability in the population, so RDAs are set two SDs above the mean requirement; this allows the requirements of 97% of the population to be met. Thus, ingestion of quantities that are somewhat less than the RDA are often sufficient to meet the needs of a particular individual. A “tolerable upper limit (TUL),” which is “the maximal daily level of oral intake that is likely to pose no adverse health risks,” has been established for most micronutrients (see Tables 5.10 and 5.11 ). Present recommendations for how much of each micronutrient is needed in individuals on TPN are based on far less data than were available for development of the RDAs. Nevertheless, it is important to have guidelines, and Table 5.12 provides such recommendations.

TABLE 5.10

Salient Features of Vitamins

Adapted from Goldman L, Ausiello D, Arend W, et al, editors. Cecil textbook of medicine. 23rd ed. Philadelphia: WB Saunders; 2014. With permission.

Vitamin	Deficiency (RDA) ∗	Toxicity (TUL) ^†	Assessment of Status
A	Follicular hyperkeratosis and night blindness are early indicators. Conjunctival xerosis, degeneration of the cornea (keratomalacia), and dedifferentiation of rapidly proliferating epithelia are later indications of deficiency. Bitot spots (focal areas of the conjunctiva or cornea with foamy appearance) are an indication of xerosis. Blindness caused by corneal destruction and retinal dysfunction may ensue. Increased susceptibility to infection is also a consequence (1 μg of retinol is equivalent to 3.33 IU of vitamin A; F, 700 μg; M, 900 μg).	In adults, >150,000 μg may cause acute toxicity: fatal intracranial hypertension, skin exfoliation, and hepatocellular injury. Chronic toxicity may occur with habitual daily intake of >10,000 μg: alopecia, ataxia, bone and muscle pain, dermatitis, cheilitis, conjunctivitis, pseudotumor cerebri, hepatic fibrosis, hyperlipidemia, and hyperostosis are common. Single large doses of vitamin A (30,000 μg) or habitual intake of >4500 μg/day during early pregnancy can be teratogenic. Excessive intake of carotenoids causes a benign condition characterized by yellowish discoloration of the skin (3000 μg).	Retinol concentration in the plasma, as well as vitamin A concentrations in milk and tears, are reasonably accurate measures of status. Toxicity is best assessed by elevated levels of retinyl esters in plasma. A quantitative measure of dark adaptation for night vision and electroretinography are useful functional tests.
D	Deficiency results in decreased mineralization of newly formed bone, a condition called rickets in childhood and osteomalacia in adults. Deficiency also contributes to osteoporosis in later life and is common following gastric bypass procedures. Expansion of epiphyseal growth plates and replacement of normal bone with unmineralized bone matrix are the cardinal features of rickets; the latter feature also characterizes osteomalacia. Deformity of bone and pathologic fractures result. Decreased serum concentrations of calcium and phosphate may occur (1 μg is equivalent to 40 IU; 15 μg, ages 19-70; 20 μg, ages > 70).	Excess amounts result in abnormally high concentrations of calcium and phosphate in the serum; metastatic calcifications, renal damage, and altered mentation may occur (100 μg for ages >9).	Serum concentration of the major circulating metabolite, 25-hydroxyvitamin D, is an excellent indicator of systemic status except in advanced kidney disease (stages 4-5), in which impairment of renal 1-hydroxylation results in dissociation of the mono- and dihydroxy vitamin concentrations; measuring the serum concentration of 1,25-dihydroxyvitamin D is then necessary.
E	Deficiency caused by dietary inadequacy is rare in developed countries. Usually seen in premature infants, individuals with fat malabsorption, and individuals with abetalipoproteinemia. RBC fragility occurs and can produce hemolytic anemia. Neuronal degeneration produces peripheral neuropathies, ophthalmoplegia, and destruction of the posterior columns of the spinal cord. Neurologic disease is frequently 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).	Depressed levels of vitamin K-dependent procoagulants, potentiation of oral anticoagulants, and impaired leukocyte function have been reported. Doses of 800 mg/day have been reported to increase slightly the incidence of hemorrhagic stroke (1000 mg).	Plasma or serum concentration of alpha-tocopherol is used most commonly. Additional accuracy is obtained by expressing this value per mg of total plasma lipid. The RBC peroxide hemolysis test is not entirely specific but is a useful measure of the susceptibility of cell membranes to oxidation.
K	Deficiency syndrome is uncommon except in breast-fed newborns (in whom it may cause “hemorrhagic disease of the newborn”), adults who have fat malabsorption or are taking drugs that interfere with vitamin K metabolism (e.g., warfarin, phenytoin, broad-spectrum antibiotics), and individuals taking large doses of vitamin E and anticoagulant drugs. Excessive hemorrhage is the usual manifestation (F, 90 μg; M, 120 μg).	Rapid IV infusion of vitamin K ₁ has been associated with dyspnea, flushing, and cardiovascular collapse; this is likely related to the dispersing agents in the dissolution solvent. Supplementation may interfere with warfarin-based anticoagulation. Pregnant women taking large amounts of the provitamin menadione may deliver infants with hemolytic anemia, hyperbilirubinemia, and kernicterus (TUL not established).	Prothrombin time is typically used as a measure of functional vitamin K status; it is neither sensitive nor specific for vitamin K deficiency. Determination of fasting plasma vitamin K is an accurate indicator. Undercarboxylated plasma prothrombin is also an accurate metric, but only for detecting the deficient state, and is less widely available.
Thiamine (vitamin B ₁ )	Classic deficiency syndrome (beriberi) remains endemic in Asian populations consuming polished rice diet. Globally, alcoholism, chronic renal dialysis, and persistent nausea and vomiting after bariatric surgery are common precipitants. High carbohydrate intake increases the need for B ₁ . Mild deficiency commonly produces irritability, fatigue, and headaches. More pronounced deficiency can produce peripheral neuropathy, cardiovascular and cerebral dysfunction. Cardiovascular involvement (wet beriberi) includes heart failure 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).	Excess intake is largely excreted in the urine, although parenteral doses of >400 mg/day are reported to cause lethargy, ataxia, and reduced tone of the GI tract (TUL not established).	The most effective measure of vitamin B ₁ status is the RBC transketolase activity coefficient, which measures enzyme activity before and after addition of exogenous TPP; RBCs from a deficient individual express a substantial increase in enzyme activity with addition of TPP. Thiamine concentrations in the blood or urine are also measured.
Riboflavin (vitamin B ₂ )	Deficiency is usually seen in conjunction with deficiencies of other B vitamins. Isolated deficiency of riboflavin produces hyperemia and edema of nasopharyngeal mucosa, cheilosis, angular stomatitis, glossitis, seborrheic dermatitis, and normochromic, normocytic anemia (F, 1.1 mg; M, 1.3 mg).	Toxicity has not been reported in humans (TUL not established).	Most common method of assessment is determining the activity coefficient of glutathione reductase in RBCs (the test is invalid for individuals with glucose-6-phosphate dehydrogenase deficiency). Measurements of blood and urine concentrations are less desirable methods.
Niacin (vitamin B ₃ )	Pellagra is the classic deficiency syndrome and is often seen in populations in which corn is the major source of energy. Still endemic in parts of China, Africa, and India. Diarrhea, dementia (or associated symptoms of anxiety or insomnia), and a pigmented dermatitis that develops in sun-exposed areas are typical features. Glossitis, stomatitis, vaginitis, vertigo, and burning dysesthesias are early signs. Occasionally occurs in carcinoid syndrome, because tryptophan is diverted to other synthetic pathways (F, 14 mg; M, 16 mg).	Human toxicity is known largely through studies examining hypolipidemic effects; includes flushing, hyperglycemia, hepatocellular injury, and hyperuricemia (35 mg).	Assessment of status is problematic; blood levels of the vitamin are not reliable. Measurement of urinary excretion of the niacin metabolites N -methylnicotinamide and 2-pyridone are thought to be the most effective means of assessment.
Pantothenic acid (vitamin B ₅ )	Deficiency is rare; reported only as a result of feeding semisynthetic diets or consumption of an antagonist such as calcium homopantothenate, which has been used to treat Alzheimer disease. Experimental isolated deficiency in humans produces fatigue, abdominal pain and vomiting, insomnia, and paresthesias of the extremities (5 mg).	Diarrhea is reported to occur with doses exceeding 10 g/day (TUL not established).	Whole blood and urine concentrations of pantothenic acid are indicators of status; serum levels are not thought to be accurate.
Pyridoxine (vitamin B ₆ )	Deficiency is usually seen in conjunction with other water-soluble vitamin deficiencies. Stomatitis, angular cheilosis, glossitis, irritability, depression, and confusion occur in moderate to severe depletion; normochromic, normocytic anemia has been reported in severe deficiency. Abnormal EEGs and, in infants, convulsions also have been reported. Isoniazid, cycloserine, penicillamine, ethanol, and theophylline are drugs that can inhibit B ₆ metabolism (ages 19-50, 1.3 mg; >50 yr, 1.5 mg for women, 1.7 mg for men).	Chronic use with doses exceeding 200 mg/day (in adults) may cause peripheral neuropathies and photosensitivity (100 mg).	Many useful laboratory methods of assessment exist. Plasma or erythrocyte PLP levels are most common. Urinary excretion of xanthurenic acid after an oral tryptophan load or activity indices of RBC aminotransferases (ALT and AST) all are functional measures of B ₆ -dependent enzyme activity.
Biotin (vitamin B ₇ )	Isolated deficiency is rare. Deficiency in humans has been produced experimentally by dietary inadequacy, prolonged administration of TPN that lacks the vitamin, and ingestion of large quantities of raw egg white, which contains avidin, a protein that binds biotin with such high affinity that it renders it bio-unavailable. Alterations in mental 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).	Toxicity has not been reported in humans, with doses as high as 60 mg/day in children (TUL not established).	Plasma and urine concentrations of biotin are diminished in the deficient state. Elevated urine concentrations of methyl citrate, 3-methylcrotonylglycine, and 3-hydroxyisovalerate are also observed in deficiency.
Folate (Vitamin B ₉ )	Women of childbearing age are the most likely to develop deficiency. The classic deficiency syndrome is a megaloblastic anemia. Hematopoietic cells in the bone marrow become enlarged and have immature nuclei, reflecting ineffective DNA synthesis. The peripheral blood smear demonstrates macro-ovalocytes and polymorphonuclear leukocytes with an average of more than 3.5 nuclear lobes. Megaloblastic changes in other rapidly proliferating epithelia (e.g., oral mucosa, GI tract) produce glossitis 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).	Daily dosage >1000 μg may partially correct the anemia of B ₁₂ deficiency and therefore mask (and perhaps exacerbate) the associated neuropathy. Large doses are reported to lower seizure threshold in individuals prone to seizures. Parenteral administration is rarely reported to cause allergic phenomena from dispersion agents (1000 μg).	Serum folate levels reflect short-term folate balance, whereas RBC folate is a better reflection of tissue status. Serum homocysteine levels rise early in deficiency but are nonspecific because B ₁₂ or B ₆ deficiency, renal insufficiency, and older age may also cause elevations.
Cobalamin (vitamin B ₁₂ )	Dietary inadequacy is a rare cause of deficiency, except in strict vegetarians. The vast majority of cases of deficiency arise from loss of intestinal absorption—a result of pernicious anemia, pancreatic insufficiency, atrophic gastritis, SIBO, or ileal disease. Megaloblastic anemia and megaloblastic changes in other epithelia (see “Folate”) are the result of sustained depletion. Demyelination of peripheral nerves, the posterior and lateral columns of the spinal cord, and nerves within the brain may occur. Altered mentation, depression, and psychoses occur. Hematologic and neurologic complications may occur independently. Folate supplementation in doses exceeding 1000 μg/day may partly correct the anemia, thereby masking (or perhaps exacerbating) the neuropathic complications (2.4 μg).	A few allergic reactions have been reported from crystalline B ₁₂ preparations and are probably due to impurities, not the vitamin (TUL not established).	Serum or plasma concentrations are generally accurate. Subtle deficiency with neurologic complications is increasingly recognized among those ≥ 60 yr of age, and can best be established by concurrently measuring the concentration of plasma B ₁₂ and (1) serum methylmalonic acid (MMA) or (2) holotranscobalamin II (holoTCII) because the latter are sensitive indicators of cellular deficiency. A low-normal plasma B12 of 200-350 pg/mL (=148-258 pmol/L) with an elevated MMA or decreased holoTCII should be considered a state of deficiency.
Ascorbic and dehydroascorbic acid (vitamin C)	Overt deficiency is uncommonly observed in developed countries. The classic deficiency syndrome is scurvy, characterized by fatigue, depression, and widespread abnormalities in connective tissues (e.g., inflamed gingivae, petechiae, perifollicular hemorrhages, impaired wound healing, coiled hairs, hyperkeratosis, and bleeding into body cavities). In infants, defects in ossification and bone growth may occur. Tobacco smoking lowers plasma and leukocyte vitamin C levels (F, 75 mg; M, 90 mg; the requirement for cigarette smokers is increased by 35 mg/day).	Quantities exceeding 500 mg/day (in adults) sometimes cause nausea and diarrhea. Acidification of the urine with vitamin C supplementation, and the potential for enhanced oxalate synthesis, have raised concerns regarding nephrolithiasis, but this has yet to be demonstrated. Supplementation with vitamin C may interfere with laboratory tests based on redox potential (e.g., fecal occult blood testing, serum cholesterol, serum glucose). Withdrawal from chronic ingestion of high doses of vitamin C supplements should occur gradually over 1 month because accommodation does seem to occur, raising a concern for rebound scurvy (2000 mg).	Plasma ascorbic acid concentration reflects recent dietary intake, whereas leukocyte levels more closely reflect tissue stores. Plasma levels in women are ≈20% higher than in men for any given dietary intake.

EEG , Electroencephalogram; PLP , pyridoxyl 5-phosphate; RBC , red blood cell; TPP , thiamine pyrophosphate.

∗ 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.

TABLE 5.11

Salient Features of Trace Minerals

Adapted from Goldman L, Ausiello D, Arend W, et al, editors. Cecil textbook of medicine. 22nd ed. Philadelphia: WB Saunders; 2004. With permission.

Mineral	Deficiency (RDA) ∗	Toxicity (TUL) ^†	Assessment of Status
Chromium	Deficiency in humans is only described for patients on long-term TPN containing inadequate chromium. Hyperglycemia or impaired glucose tolerance is uniformly observed. Elevated plasma free fatty acid concentrations, neuropathy, encephalopathy, and abnormalities in nitrogen metabolism are also reported. Whether supplemental chromium may improve glucose tolerance in mildly glucose intolerant but otherwise healthy individuals remains controversial (F, 25 μg; M, 35 μg).	Toxicity after oral ingestion is uncommon and seems confined to gastric irritation. Airborne exposure may cause contact dermatitis, eczema, skin ulcers, and bronchogenic carcinoma (No TUL established).	Plasma or serum concentration of chromium is a crude indicator of chromium status; it appears to be meaningful when the value is markedly above or below the normal range.
Copper	Dietary deficiency is rare; it has been observed in premature and low-birth-weight infants exclusively fed a cow’s milk diet and in individuals on long-term TPN without copper. Clinical manifestations include depigmentation of skin and hair, neurologic disturbances, leukopenia and hypochromic, microcytic anemia, skeletal abnormalities, and poor wound healing. The anemia arises from impaired uptake of iron and is, therefore, a secondary form of iron deficiency anemia. The deficiency syndrome, except the anemia and leukopenia, is also observed in Menkes disease, a rare inherited condition associated with impaired copper uptake (900 μg).	Acute copper toxicity has been described after excessive oral intake and with absorption of copper salts applied to burned skin. Milder manifestations include nausea, vomiting, epigastric pain, and diarrhea; coma and hepatocellular injury may ensue in severe cases. Toxicity may be seen with doses as low as 70 μg/kg/day. Chronic toxicity is also described. Wilson disease is a rare inherited disease associated with abnormally low ceruloplasmin levels and accumulation of copper particularly in the liver and brain, eventually leading to damage of these 2 organs (10 mg).	Practical methods for detecting marginal deficiency are not available. Marked deficiency is reliably detected by diminished serum copper and ceruloplasmin concentrations, as well as low erythrocyte superoxide dismutase activity.
Fluoride	Intake of <0.1 mg/day in infants and 0.5 mg/day in children is associated with an increased incidence of dental caries. Optimal intake in adults is between 1.5 and 4.0 mg/day (F, 3 mg; M, 4.0 mg).	Acute ingestion of >30 mg/kg body weight of fluoride is likely to cause death. Excessive chronic intake (0.1 mg/kg/day) leads to mottling of the teeth (dental fluorosis), calcification of tendons and ligaments, and exostoses, and may increase brittleness of bones (10 mg).	Estimates of intake or clinical assessment are used because no reliable laboratory test exists.
Iodine	In the absence of supplementation, populations relying primarily on food from soils with low iodine content have endemic iodine deficiency. Maternal iodine deficiency leads to fetal deficiency, which produces spontaneous abortions, stillbirths, hypothyroidism, cretinism, and dwarfism. Rapid brain development continues through the second year, and 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).	Large doses (>2 mg/day in adults) may induce hypothyroidism by blocking thyroid hormone synthesis. Supplementation with >100 μg/day to an individual who was formerly deficient occasionally induces hyperthyroidism (1.1 mg).	Urinary excretion of iodine is an effective laboratory means of assessment. The thyroid-stimulating hormone (TSH) level in the blood is an indirect, not entirely specific means of assessment. Iodine status of a population can be estimated by the prevalence of goiter.
Iron	Most common micronutrient deficiency in the world. Women of childbearing age constitute the highest risk group because of menstrual blood losses, pregnancy, and lactation. Hookworm infection is the most common cause worldwide. The classic deficiency syndrome is hypochromic microcytic anemia. Glossitis and koilonychia (spoon nails) are also observed. Easy fatigability often develops as an early symptom before appearance of anemia. In children, mild deficiency of insufficient severity to cause anemia is associated with behavioral disturbances and poor school performance (postmenopausal F, 8 mg; M, 8 mg; premenopausal F, 18 mg).	Iron overload typically occurs when habitual dietary intake is extremely high, intestinal absorption is excessive, repeated parenteral administration of iron occurs, or a combination of these factors exists. Excessive iron stores usually accumulate in reticuloendothelial tissues and cause little damage (hemosiderosis). If overload continues, iron will eventually begin to accumulate in tissues such as hepatic parenchyma, pancreas, heart, and synovium, damaging these tissues (hemochromatosis). Hereditary hemochromatosis arises as a result of homozygosity of a common recessive trait. Excessive intestinal absorption of iron is observed in homozygotes (45 mg).	Negative iron balance initially leads to depletion of iron stores in the bone marrow; bone marrow biopsy and the concentration of serum ferritin are accurate and early indicators of such depletion. As deficiency becomes more severe, serum iron (SI) decreases and total iron binding capacity (TIBC) increases; an iron saturation (= SI/TIBC) of <16% suggests iron deficiency. Microcytosis, hypochromia, and anemia ensue in latter stages of the deficient state. Elevated levels of serum ferritin or an iron saturation >60% raises suspicion of iron overload, although systemic inflammation elevates serum ferritin level regardless of iron status.
Manganese	Manganese deficiency has not been conclusively demonstrated in humans. It is said to cause hypocholesterolemia, weight loss, hair and nail changes, dermatitis, and impaired synthesis of vitamin K–dependent proteins (F, 1.8 mg; M, 2.3 mg).	Toxicity by oral ingestion is unknown in humans. Toxic inhalation causes hallucinations, other alterations in mentation, and extrapyramidal movement disorders (11 mg).	Until the deficiency syndrome is better defined, an appropriate measure of status will be difficult to develop.
Molybdenum	Cases of human deficiency are extremely rare; caused by TPN lacking the element or by parenteral administration of sulfite. Reported to result in hyperoxypurinemia, hypouricemia, low urinary sulfate excretion, and CNS disturbances (45 μg).	Molybdenum has low toxicity; occupational exposures and high dietary intake are linked to hyperuricemia and gout in epidemiologic studies (2 mg).	No effective clinically available assessment exists. Rare cases of deficiency are associated with hypouricemia, hypermethionemia, and low levels of urinary sulfate with elevated excretion of sulfite, xanthine, and hypoxanthine.
Selenium	Deficiency is rare in North America but has been observed in individuals on long-term TPN lacking selenium. Such individuals have myalgias and/or cardiomyopathy. Populations in some regions of the world, most notably some parts of China, have marginal intake of selenium. 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).	Toxicity is associated with nausea, diarrhea, alterations in mental status, peripheral neuropathy, and loss of hair and nails; such symptoms were observed in adults who inadvertently consumed between 27 and 2400 mg (400 μg).	Erythrocyte glutathione peroxidase activity and plasma, or whole blood, selenium concentrations are the most commonly used methods of assessment. They are moderately accurate indicators of status.
Zinc	Deficiency of zinc has its most profound effect on rapidly proliferating tissues. Mild deficiency causes growth retardation in children. More severe deficiency is associated with growth arrest, teratogenicity, hypogonadism and infertility, dysgeusia, poor wound healing, diarrhea, dermatitis on the extremities and around orifices, glossitis, alopecia, corneal clouding, loss of dark adaptation, and behavioral changes. Impaired cellular immunity also is observed. Excessive loss of GI secretions (e.g., through chronic diarrhea or fistulas) may precipitate deficiency. Acrodermatitis enteropathica is a rare recessively inherited disease in which intestinal absorption of zinc is impaired (F, 8 mg; M, 11 mg).	Acute zinc toxicity can usually be induced by ingestion of >200 mg of zinc in a single day (in adults). It is manifested by epigastric pain, nausea, vomiting, and diarrhea. Hyperpnea, diaphoresis, and weakness may follow inhalation of zinc fumes. Copper and zinc compete for intestinal absorption: chronic ingestion of >25 mg zinc/day may lead to copper deficiency. Chronic ingestion of >150 mg/day has been reported to cause gastric erosions, low high-density lipoprotein cholesterol levels, and impaired cellular immunity (40 mg).	There are no accurate indicators of zinc status available for routine clinical use. Plasma, erythrocyte, and hair zinc concentrations are frequently misleading. Acute illness, in particular, is known to diminish plasma zinc levels, in part by inducing a shift of zinc out of the plasma compartment and into the liver. Functional tests that determine dark adaptation, taste acuity, and rate of wound healing lack specificity.

∗ 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.

TABLE 5.12

Guidelines for Daily Administration of Parenteral Micronutrients in Adults and Children

Adult vitamin guidelines adapted from American Society of Parenteral and Enteral Nutrition (ASPEN). Board of Directors and the Clinical Guidelines Task Force. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enteral Nutr 2002; 26:144. Children’s values adapted from Greene HL, Hambidge KM, Schanler R, Tsang RC. Guidelines for the use of vitamins, trace elements, calcium, magnesium, and phosphorus in infants and children receiving total parenteral nutrition: report of the Subcommittee on Pediatric Parenteral Nutrient Requirements from the Committee on Clinical Practice Issues of the American Society for Clinical Nutrition. Am J Clin Nutr 1988; 48:1324; Am J Clin Nutr 1989; 49:1332; and Am J Clin Nutr 1989; 50:560.

Micronutrient	Adults	Children
Fat-Soluble Vitamins
A	1000 μg (= 3300 IU)	700 μg
D	5 μg (= 200 IU)	10 μg
E	10 mg (= 10 IU)	7 mg
K	1 mg	200 μg
Water-Soluble Vitamins
C	100 mg	80 mg
B ₆	4 mg	1 mg
B ₁₂	5 μg	1 μg
Biotin	60 μg	20 μg
Folate	400 μg	140 μg
Niacin	40 mg	17 mg
Pantothenic acid	15 mg	5 mg
Riboflavin	3.6 mg	1.4 mg
Thiamine	3 mg	1.2 mg
Trace Elements
Chromium	10-15 μg	0.2 μg/kg/day
Copper	0.5-1.5 mg	20 μg/kg/day
Iodine ∗	—	—
Iron	1-2 mg	1 mg/day
Manganese	0.1 mg	1 μg/kg/day
Molybdenum	15 μg	0.25 μg/kg/day
Selenium	100 μg	2 μg/kg/day
Zinc	2.5-4.0 mg	50 μg/kg/day

∗ Naturally occurring contamination of parenteral nutrition formulas appears to provide sufficient quantities of iodine.

Vitamins

Vitamins are categorized as fat soluble (A, D, E, K) or water soluble (all others) (see Table 5.10 ). This categorization remains physiologically meaningful; none of the fat-soluble vitamins appear to serve as coenzymes, whereas almost all of the water-soluble vitamins appear to function in that role. Also, the absorption of fat-soluble vitamins is primarily through a micellar route, whereas the water-soluble vitamins are not absorbed in a lipophilic phase in the intestine (see Chapter 103 ).

Trace Minerals

Compelling evidence exists for the essential nature of 10 trace elements in humans: iron, zinc, copper, chromium, selenium, iodine, fluorine, manganese, molybdenum, and cobalt (see Table 5.11 ). The biochemical functions of trace elements have not been as well characterized as those of the vitamins, but most of their functions appear to be as components of prosthetic groups or as cofactors for enzymes.

Aside from iron, the trace mineral depletion clinicians are most likely to encounter is zinc deficiency. Zinc depletion is a particularly germane issue to the gastroenterologist, because the GI tract is a major site for zinc excretion. Chronically excessive losses of GI secretions, such as chronic diarrhea in IBD, is a known precipitant for zinc deficiency, and, in this setting, zinc requirements often increase several-fold. Nevertheless, a biochemical diagnosis of zinc deficiency is problematic (as is true for many of the other essential trace minerals) because accurate laboratory assessment of zinc status is complicated by the very low concentrations of zinc in bodily fluids and tissues, a lack of correlation between serum and red blood cell levels of zinc with levels in the target tissues, and the reality that suitable functional tests have yet to be devised. Furthermore, it is well recognized that in acute illness a shift in zinc occurs from the serum compartment into the liver, further obscuring the diagnostic value of serum zinc levels. Alkaline phosphatase is a zinc-dependent protein, and therefore serum activity of the enzyme has sometimes been proposed as a functional measure of zinc status. However, its predictive value is quite low and therefore is inadequate for assessing individuals in a clinical setting. It is often best to simply proceed with empiric zinc supplementation in patients whose clinical scenario puts them at high risk of zinc deficiency.

Some reports have indicated that TPN solutions that deliver several-fold more manganese than what is recommended in Table 5.12 may lead to deposition of the mineral in the basal ganglia, with resulting extrapyramidal symptoms, seizures, or both. Because the content of manganese varies widely in the different trace element mixtures available for TPN compounding, health professionals need to be mindful of this issue as protocols for TPN mixtures are developed.

Physiologic and Pathophysiologic Factors Affecting Micronutrient Requirements

Age

An evolution of physiology continues throughout the life cycle, with an impact on the requirements of certain micronutrients with aging; specific RDAs for older adults have now been developed. The mean vitamin B ₁₂ status of most populations, for example, declines significantly with older age, in large part because of the high prevalence of atrophic gastritis and its resultant impairment of protein-bound vitamin B ₁₂ absorption. Some 10% to 15% of the older ambulatory population is thought to have significant vitamin B ₁₂ depletion because of this phenomenon, and neuropathic degeneration may occur in older individuals whose plasma vitamin B ₁₂ levels are in the low-normal range (150 to 300 pg/mL), even in the absence of hematologic manifestations. For this reason, the use of sensitive indicators of cellular depletion of vitamin B ₁₂ (e.g., serum methylmalonic acid levels in conjunction with serum levels of vitamin B ₁₂ ) are now recommended for diagnosis. Some experts also suggest that older adults should consume a portion of their vitamin B ₁₂ requirement in the crystalline form (i.e., as a supplement) rather than relying only on the naturally occurring protein-bound forms found in food. Compared with younger adults, elders require greater quantities of vitamins B ₆ and D and calcium to maintain health, and these requirements are reflected in the new RDAs (see Tables 5.10 and 5.11 ).

Malabsorption and Maldigestion

Both fat- and water-soluble micronutrients are absorbed predominantly in the proximal small intestine, the only exception being vitamin B ₁₂ , which is absorbed in the ileum. Diffuse mucosal diseases that affect the proximal portion of the GI tract are, therefore, likely to result in multiple deficiencies. Even in the absence of proximal small intestinal disease, however, extensive ileal disease, SIBO, and chronic cholestasis may interfere with the maintenance of adequate intraluminal conjugated bile acid concentrations and thereby may impair absorption of fat-soluble vitamins.

Conditions that produce fat malabsorption are frequently associated with selective deficiencies of the fat-soluble vitamins. The early stages of many vitamin deficiencies are not apparent clinically and therefore may go undetected until progression of the deficiency has resulted in significant morbidity. This can be disastrous in conditions like spinocerebellar degeneration due to vitamin E deficiency, which often is irreversible. Fat-soluble vitamin deficiencies are well-recognized complications of cystic fibrosis and congenital biliary atresia, in which fat malabsorption often is overt, but monitoring is also necessary in conditions associated with more subtle fat malabsorption, such as the latter stages of chronic cholestatic liver disease.

Restitution of vitamin deficiencies can sometimes be difficult when severe fat malabsorption is present, and initial correction may require parenteral administration. In severe fat malabsorption, chemically modified forms of vitamins D and E that largely bypass the need for the lipophilic phase of intestinal absorption are commercially available for oral use and can be helpful. The polyethylene glycol succinate form of vitamin E (Nutr-E-Sol) is very effective in patients with severe fat malabsorption who cannot absorb conventional alpha-tocopherol. Similarly, hydroxylated forms of vitamin D (1-hydroxyvitamin D [Hectorol] and 1,25-dihydroxyvitamin D [Rocaltrol]) can be used in patients resistant to the more conventional forms of vitamin D. Monitoring of serum calcium levels is indicated in the first few weeks of therapy with hydroxylated forms of vitamin D, because they are considerably more potent than vitamin D ₂ or D ₃ , and risk of vitamin D toxicity exists. In contrast, water-miscible preparations of fat-soluble vitamins, in which a conventional form of vitamin A or E is dissolved in polysorbate 80 (e.g., Aquasol-E, Aquasol-A), have not been proved to improve overall absorption.

Maldigestion usually results from chronic pancreatic insufficiency, which, if untreated, frequently causes fat malabsorption and deficiencies of fat-soluble vitamins. Vitamin B ₁₂ malabsorption also can be demonstrated in this setting, but clinical vitamin B ₁₂ deficiency is rare unless other conditions known to diminish its absorption are also present (e.g., atrophic gastritis or chronic administration of PPIs). Whether long-term administration of PPIs alone warrants occasional checks of vitamin B ₁₂ status is a matter of debate. Regardless, malabsorption of vitamin B ₁₂ from atrophic gastritis or with PPIs is confined to dietary sources of vitamin B ₁₂ . Small supplemental doses of crystalline vitamin B ₁₂ are absorbed readily in both cases. Histamine-2 receptor antagonists also inhibit protein-bound vitamin B ₁₂ absorption, although the effect generally is believed to be less potent than with the PPIs.

Many medications may adversely affect micronutrient status. The manner in which drug-nutrient interaction occurs varies; some of the more common mechanisms are described in Table 5.13 . A comprehensive discussion of drug-nutrient interactions is beyond the scope of this chapter, and the reader is referred to other references for a detailed discourse on this topic.

TABLE 5.13

Interactions of Drugs on Micronutrient Status

From Goldman L, Ausiello D, Arend W, et al, editors. Cecil textbook of medicine. 22nd ed. Philadelphia: WB Saunders; 2004. With permission.

Drug(s)	Nutrient	Mechanism(s)
Cholestyramine	Vitamin D, folate	Adsorbs nutrient, decreases absorption
Dextroamphetamine, fenfluramine, levodopa	Potentially all micronutrients	Induces anorexia
Isoniazid	Pyridoxine	Impairs uptake of vitamin B ₆
NSAIDs	Iron	GI blood loss
Penicillamine	Zinc	Increases renal excretion
PPIs	Vitamin B ₁₂	Modest bacterial overgrowth, decreases gastric acid/pepsin, impairs absorption
Sulfasalazine	Folate	Impairs absorption and inhibits folate-dependent enzymes

Starvation

During periods of energy or protein deficit or both, an array of compensatory mechanisms serves to lessen the pathophysiologic impact of these deficiencies. These responses decrease the metabolic rate, maintain glucose homeostasis, conserve body nitrogen, and increase the uptake of adipose tissue TGs to meet energy needs. To appreciate how acute illness disrupts this compensatory scheme, it is first necessary to understand how the body adapts to starvation in the absence of underlying disease.

During the first 24 hours of fasting, the most readily available energy substrates (i.e., circulating glucose, FAs and TGs, and liver and muscle glycogen) are used as fuel sources. The sum of energy provided by these stores in a 70-kg man, however, is only about 5000 kJ (1200 kcal) and therefore is less than a full day’s requirements. Hepatic glucose production and oxidation decrease, whereas whole-body lipolysis increases, the latter providing additional FAs and ketone bodies. Oxidation of FAs released from adipose tissue TGs accounts for about 65% of the energy consumed during the first 24 hours of fasting.

During the first several days of starvation, obligate glucose-requiring tissues like the brain and blood cells, which collectively account for about 20% of total energy consumption, can use only glycolytic pathways to obtain energy. Because FAs cannot be converted to carbohydrate by these glycolytic tissues, they must use glucose or substrates that can be converted to glucose. Glucogenic AAs derived from skeletal muscle (chiefly alanine and glutamine) are a major source of substrate for this purpose. Approximately 15% of the REE is provided by oxidation of protein. The relative contribution of gluconeogenesis to hepatic glucose production increases as the rate of hepatic glycogenolysis declines because the latter process becomes redundant; after 24 hours of fasting, only 15% of liver glycogen stores remain.

During short-term starvation (1 to 14 days), several adaptive 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 catecholamines stimulate adipose tissue lipolysis. The increase in FA delivery to the liver, in conjunction with an increase in the ratio of plasma glucagon-to-insulin concentrations, enhances the production of ketone bodies by the liver. A maximal rate of ketogenesis is reached by 3 days of starvation, and plasma ketone body concentration is increased 75-fold by 7 days. In contrast to FAs, ketone bodies can cross the blood-brain barrier and provide most of the brain’s energy needs by 7 days of starvation. The use of ketone bodies by the brain greatly diminishes glucose requirements and thus spares the need for muscle protein degradation to provide glucose precursors. If early protein breakdown rates were to continue throughout starvation, a potentially lethal amount of muscle protein would be catabolized in less than 3 weeks. Similarly, the heart, kidney, and skeletal muscle change their primary fuel substrate to FAs and ketone bodies. Other tissues like bone marrow, renal medulla, and peripheral nerves switch from full oxidation of glucose to anaerobic glycolysis, resulting in increased production of pyruvate and lactate. The latter two compounds can be converted back to glucose in the liver using energy derived from fat oxidation via the Cori cycle, and the resulting glucose is available for systemic consumption. This enables energy stored as fat to be used for glucose synthesis.

Whole-body glucose production decreases by greater than 50% during the first few days of fasting because of a marked reduction in hepatic glucose output. As fasting continues, conversion of glutamine to glucose in the kidney represents almost 50% of total glucose production. Energy is conserved by a decrease in physical activity secondary to fatigue and a roughly 10% reduction in REE resulting from increased conversion of active thyroid hormone to its inactive form and suppressed sympathetic nervous system activity.

During long-term starvation (14 to 60 days), maximal adaptation is reflected by a plateau in lipid, carbohydrate, and protein metabolism. The body relies almost entirely on adipose tissue for its fuel, providing greater than 90% of daily energy requirements. Muscle protein breakdown decreases to less than 30 g/day, causing a marked decrease in urea nitrogen production and excretion. The decrease in osmotic load diminishes urine volume to 200 mL/day, thereby reducing fluid requirements. Total glucose production decreases to approximately 75 g/day, providing fuel for glycolytic tissues (40 g/day) and the brain (35 g/day) while maintaining a constant plasma glucose concentration. Energy expenditure decreases by 20% to 25% at 30 days of fasting and remains relatively constant thereafter despite continued starvation.

The metabolic response to short- and long-term starvation differs somewhat between lean and obese persons. Obesity is associated with a blunted increase in lipolysis and decrease in glucose production compared with that in lean persons. In addition, protein breakdown and nitrogen losses are less in obese persons, thereby helping conserve muscle protein.

Events that mark the terminal phase of starvation have been studied chiefly in laboratory animals. Body fat mass, muscle protein, and the sizes of most organs are markedly decreased. The weight and protein content of the brain, however, remain relatively stable. During the final phase of starvation, body fat stores reach a critical level, energy derived from body fat decreases, and muscle protein catabolism is accelerated. Death commonly occurs when there is a 30% to 50% loss of skeletal muscle protein. In humans, it has been proposed that there are certain thresholds beyond which lethality is inevitable: depletion of total body protein between 30% and 50% and of fat stores between 70% and 95%, or reduction of BMI below 13 kg/m ² for men and 11 kg/m ² for women.

Malnutrition

In the broadest sense, malnutrition implies a sustained imbalance between nutrient availability and nutrient requirements. This imbalance results in a pathophysiologic state in which intermediary metabolism, organ function, and body composition are variously altered. Sustained is an important element of this definition, because homeostatic mechanisms and nutrient reserves are usually adequate to compensate for any short-term imbalance.

Customarily, the term malnutrition is used to describe a state of inadequacy in protein, calories, or both and is more precisely called protein-energy malnutrition or protein-calorie malnutrition . Occasionally it is used to describe a state of excessive availability, such as a sustained excess of calories (e.g., obesity) or a vitamin (e.g., vitamin toxicity).

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