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Macronutrients in Health and Disease: Protein

Protein supports the maintenance and growth of body tissues. The amino acids that make up proteins are used for the synthesis of nucleic acids, cell membranes, hormones, neurotransmitters, and plasma proteins that serve transport functions and exert the colloid osmotic pressure needed to maintain fluid in vascular space. Protein is also the second largest energy store, second to adipose tissue because of the large amount of muscle tissue that is a labile source of amino acids for gluconeogenesis, although carbohydrate (in the form of glycogen) is used between meals as a primary source.

The Food and Nutrition Board of the National Academy of Sciences has determined that 9 amino acids are indispensable for all age groups.15 They must be obtained from the diet to provide amounts required to maintain health, although the body synthesizes both essential and nonessential amino acids to varying degrees. The essential amino acids are:

  • Isoleucine.
  • Leucine.
  • Lysine.
  • Methionine.
  • Phenylalanine.
  • Threonine.
  • Tryptophan.
  • Valine.
  • Histidine.

During growth and in various disease states, several other amino acids (arginine, cysteine, glutamine, glycine, proline, tyrosine) are regarded as conditionally indispensable.16 The term “conditionally indispensable” applies when endogenous synthesis cannot meet metabolic need (e.g., under special pathophysiological circumstances, including prematurity in infants, and severe catabolic stress in adults.15

The effects of certain conditionally indispensable amino acids may be of interest to clinicians involved in the care of critically ill patients. One of these is glutamine, a precursor of both adenosine triphosphase (ATP) and nucleic acids.17 Depletion of glutamine through hypercatabolic/hypermetabolic illness may result in enterocyte and immunocyte starvation,18 and glutamine enrichment of enteral or parenteral feedings limits nitrogen loss and improves outcome (significantly reducing bacteremia, sepsis, and hospital stay) in critically ill patients who are post surgery or in the intensive care unit (ICU). 19,20 In addition, glutamine significantly increases plasma concentrations of taurine,21 an amino acid with antihypertensive, antiarrhythmic, and positive inotropic effects.18 This may be important in patients with chronic renal failure, for whom low intracellular taurine concentrations are common and who are at high risk for cardiac events.

Cysteine is a conditionally essential amino acid in infants, one that may promote nitrogen retention in immature infants especially.22 As a precursor of glutathione, cysteine also plays important roles in antioxidant defense and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production, and the immune response).23 Patients with liver disease cannot meet their requirements for cysteine due to diminished activity of transsulfuration pathways.18 The importance of cysteine is also underscored by its role in synthesizing N–acetylcysteine (NAC), a glutathione precursor with important clinical and preventative effects. These include reducing the risk of exacerbations and improving symptoms in patients with chronic bronchitis;24 significantly reducing the risk of radiocontrast–induced nephropathy25; and reducing the expression of a number of cancer risk markers in humans.26 Patients with cirrhosis may benefit from supplementation with specific (eg, branched–chain) amino acids (see Cirrhosis).

Although a deficiency of dietary protein is clearly detrimental, many chronic conditions may be caused or exacerbated by an excess of protein, particularly animal protein. These include osteoporosis, kidney stones, chronic kidney disease, and possibly certain cancers. Food from plant sources supplies protein in the amount and quality adequate for all ages.27,28

The major difference between diets providing animal and plant proteins appears to be that, while plant foods contain all essential amino acids, some are limited in lysine or sulfur–containing amino acids. The amino acids provided by various plant foods tend to complement each other, however, and it is not, necessary to intentionally combine foods.31 The natural combinations of foods in typical vegetarian diets provide more than adequate amounts of complete protein. Soy products provide protein with a biological value as high as that of animal protein. Because plant sources of protein are free of cholesterol and low in saturated fat and provide dietary fiber and various phytochemicals, they present advantages in comparison with animal protein sources.

Protein requirements are increased in certain conditions. These include severe acute illness; burn injury, and end–stage renal disease. (See Burns and End–Stage Renal Disease for further information). In some studies of nursing home residents, protein deficiency has emerged as a concern.29

Protein needs are influenced by life stage. Protein requirements are highest in the growing years, with infants 0 to 12 months and children 1 to 3 years of age requiring 1.5 g/kg and 1.1 g/kg, respectively. Requirements for protein remain high relative to adult needs during the period from growth to puberty (ages 4 –13 years), at 0.95 g/kg, and are reduced to near–adult levels (0.85 g/kg) in 14 to 18 years of age. Pregnancy and lactation also increase protein needs, to 1.1 g/kg of maternal pre–pregnancy weight for the former and 1.3 g/kg for the latter.30

For healthy adults, the Estimated Average Requirement (EAR) set by the Institute of Medicine (IOM) is considerably lower (0.66 mg/kg/day, 47 and 38 grams per day for men and women respectively) 31 In addition, the intake of adequate protein–sparing calories (see below) allows for maintenance of lean body mass at roughly this level of intake.28

Most adults in Western countries consume more protein than the recommended EAR and RDA of 0.66 mg/kg and 0.8 g/kg, respectively, In fact, the Continuing Survey of Food Intakes indicated protein intakes at 1.5g/kg, roughly double the requirement,31 while others have found that less than 30% to 50% of U.S. adults consume dietary protein in amounts that could be considered moderate (ie, at or near recommended levels of intake).32 Excessive intakes may contribute to risk for certain chronic diseases (see below).

Energy adequacy spares protein. When considering protein requirements, it is important to consider the number of calories available for nitrogen sparing (i.e., calories from both carbohydrate and protein). A ratio of 150 nonprotein calories per each gram of nitrogen (provided by 6.25 g of protein) is considered sufficient for protein sparing. Thus, a healthy, 60–kg woman consuming 0.8 g protein per kg body weight would consume approximately 7.7 grams of nitrogen, and would require approximately 1,152 calories to remain in nitrogen equilibrium. Without these energy sources, proteins will be deaminated and used to meet energy needs. In illness, protein sparing does not occur to any appreciable extent33 (see below).

Illness causes protein catabolism and affects interpretation of serum protein values. In well–nourished individuals experiencing mild–to–moderate illness, negative nitrogen balance can occur over the short term, mainly in skeletal muscle. Protein storage will be restored once appetite, intake, and activity resume pre–illness levels. In this context, additional dietary protein is not required.

In critically ill patients and those with chronic illnesses involving infection and inflammation, protein requirements exceed the norm and significant losses of protein occur.34,35 Serum proteins commonly used to assess protein status are often influenced by the presence of illness. These include albumin, prealbumin, transthyretin, and retinol binding protein. In otherwise healthy individuals, reduced protein and calorie intake does not cause hypoalbuminemia. However, in the presence of infection, liver and kidney diseases, surgery, and other conditions involving elevated metabolic rate, immune activation, and inflammation, cytokines direct protein synthesis toward that of acute–phase proteins, with subsequent reduction in serum proteins.36 Alternately, cytokines will direct amino acids toward energy production rather than protein synthesis.33 In terms of measuring the effectiveness of nutrition intervention, transthyretin and retinol–binding protein have the greatest clinical utility, because these are the earliest to rise when acute–phase protein levels decrease.36

In metabolically stressed patients, both inadequate and excessive protein can cause problems. Even brief periods of protein–calorie deprivation can tip the balance from anabolism to catabolism in critically ill patients. Protein requirements in the range of 1.25 to 2.0 g/kg have been recommended for the critically ill by the American Society for Enteral and Parenteral Nutrition,37 and intakes in the range of 1.2 to 1.5 g/kg have been found helpful for promoting the healing of pressure ulcers. However, others have noted no additional reduction in body protein losses at levels above 1.2 g/kg protein.34 Clinical judgment regarding protein needs may therefore be essential for treating patients on an individualized basis.

Overfeeding of protein can also cause problems, including acidosis and azotemia. In patients not given adequate water, hypertonic dehydration (tube feeding syndrome) may result from obligate water losses that occur due to higher urea production.33 Acute toxic effects of excess protein intake are rare, but are seen in cases of inborn errors of amino acid metabolism and in patients with hemorhagic esophageal varices, which precipitates encephalopathy in patients with liver disease.19 In certain conditions (eg, chronic kidney disease), diets that provide lower amounts of protein than the Dietary Reference Intakes (DRI) have been useful for improving clinical status (see Chronic Kidney Disease).

Additional dangers of excess protein intake include idiopathic hypercalciuria38; greater risk for type 2 diabetes;39 and, when protein constitutes >35% of total energy intake, hyperaminoacidemia, hyperammonemia, hyperinsulinemia nausea, and diarrhea.40 Other dangers associated with excess protein intake are related mainly to animal protein and include gout, osteoporosis, and certain cancers (see individual disorders for further information).


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