Macronutrients in Health and Disease

Carbohydrate, protein, and fat are essential for health maintenance, growth, reproduction, immunity, and healing. Deficits or excesses of any of these nutrients may compromise these processes, resulting in poor health outcomes, which vary depending on the macronutrient in question and the life stage of the affected person.

In decades past, research on nutrition and disease frequently focused on the problems caused by diets that provided inadequate intakes of protein, calories, or micronutrients. Concerns that such deficient diets could lead to poor growth and development or might result in weight loss in elderly hospitalized individuals are sometimes appropriate. However, an excess of macronutrients is a far greater threat to health and well-being in developed countries and in many developing nations as well. Changing dietary habits have become a driving force behind common chronic diseases.

This chapter focuses on the basics of macronutrients—their roles, sources, and requirements. All macronutrients provide energy. Carbohydrate and protein provide 4 kcal/g, and fat provides 9 kcal/g. The only other nutrient that supplies energy is alcohol, contributing 7 kcal/g.


Carbohydrate, in the form of starches and sugars, is the main energy source in the human diet, typically providing 50% or more of total calories. Carbohydrate-containing foods can be classified in several clinically relevant ways:

Simple vs. Complex Carbohydrate

The term simple carbohydrate refers to monosaccharides and disaccharides. Common monosaccharides include glucose and fructose, while common disaccharides include sucrose and lactose. Figure 1, Figure 2, and Figure 3 represent the chemical structures of glucose, fructose, and sucrose. Foods high in simple carbohydrate include fruit, table sugar, and milk.

Figure 1: Glucose (monosaccharide)


007a Figure 1--Glucose
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Figure 2: Fructose (monosaccharide)


007b Figure 2--Fructose
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Figure 3: Sucrose (disaccharide)


007c Figure 3--Sucrose
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Complex carbohydrate refers to polysaccharides and includes starch, glycogen, and fiber. Starch and fiber are found in plant-based foods, and trace amounts of glycogen are found in animal-based foods including muscle and liver tissue. Cellulose and amylose (Figures 4 and 5) are examples of fiber and starch, respectively. Foods high in starch and fiber include grains, legumes, and starchy vegetables (note that whole fruits are also high in fiber, though not starch).

Figure 4: Cellulose

007d Figure 4--Cellulose
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Figure 5: Partial Structure of Amylose

007e Figure 5--Amylose
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Refined vs. Unrefined Carbohydrates

Refining is a process by which the fibrous outer bran coating and the nutrient-rich germ of grains are removed. By this process, brown rice is converted to white rice, for example, or whole wheat is converted to white flour, greatly reducing the fiber and nutrient content. Note that a food can be rich in complex carbohydrate but also be refined. White rice and white bread, for example, are refined grain products, but they retain their complex carbohydrate.


Dietary fiber refers to carbohydrates that resist digestion in the human small intestine. Fiber is found exclusively in plant foods including fruits, vegetables, legumes, nuts, seeds, and whole grains, and it occurs in two types: Soluble fiber swells in contact with liquids while insoluble fiber does not.

Diets that are high in carbohydrate and fiber and low in fat and cholesterol have clinical utility in prevention and management of several diseases, including obesity, diabetes, heart disease, and hypertension. Dietary fiber promotes satiety, and its intake is inversely associated with body weight and body fat.[1] Higher fiber intakes also appear to have beneficial effects on the gut microbiota.[2],[3] Most Americans underconsume fiber.[4]

Glycemic index.The glycemic index (GI) was first presented in 1981 as a means of quantifying the effects of carbohydrate-rich foods on blood glucose concentrations.[5] The GI of a food is determined by feeding a portion containing 50 g of carbohydrate to 10 healthy people after an overnight fast. Blood glucose is tested at 15- to 30-minute intervals over the next 2 hours, and the results are compared with those obtained by feeding the same amount of glucose or white bread. A GI below 100 means the food has less effect on blood sugar, compared with glucose. A higher number means the test food has a greater effect.[5]

Distinctions between various kinds of carbohydrate are clinically important. Diets high in sugars and refined carbohydrate may increase plasma triglyceride concentrations. Some studies have shown reductions in triglycerides with low-GI diets,[6] while other studies have reported reductions in total and HDL cholesterol, with no effect on triglycerides.[7]

In studies of individuals with diabetes, a meta-analysis of 11 prior studies showed that diets emphasizing low-GI foods reduce hemoglobin A1c (the principal clinical measure of long-term blood glucose control) by about 0.5 percentage points. Studies showed a similar benefit for both type 1 and type 2 diabetes.[8]

Although dietary carbohydrate provides glucose, available evidence indicates that people who consume approximately 3 servings per day of whole-grain foods have a 20-30% lower risk of developing type 2 diabetes than individuals consuming < 3 servings per week.[9] Greater whole grain consumption is also associated with a decreased risk of cardiovascular disease and weight gain.[10] Whole grain intake also improves markers of metabolic health according to a 2018 network meta-analysis of randomized intervention trials.[11] Of all the food groups investigated using data from 16 European countries, inadequate intake of whole grains had the greatest impact on years lost to disability or early death from coronary heart disease, stroke, type 2 diabetes, and colorectal cancer.[12]

Low-fat, high-carbohydrate, high-fiber diets also significantly reduce the need for insulin and oral hypoglycemic agents in patients with type 2 diabetes.[13] Such diets are also associated with significant improvements in blood lipid concentrations, blood pressure, and indices of atherosclerosis (see Hyperlipidemia chapter) and appear to be useful for preventing and treating some intestinal disorders (see Constipation, Inflammatory Bowel Disease, Peptic Ulcer Disease, and Gastroesophageal Reflux Disease chapters).

Clinicians should be aware that patients may mistakenly blame carbohydrate for weight or health problems, based on the tenets of popular low-carbohydrate weight-loss diets. Patients may need to be reminded that carbohydrate is essential to human health. Complex carbohydrates, in unprocessed or minimally processed forms, are staple foods in the diets of countries where chronic diseases are rarely seen. In areas of changing dietary patterns, where carbohydrate-rich foods become displaced by animal-derived products and highly processed foods, several chronic diseases become much more common. In Japan, for example, the Westernization of the diet occurring in the latter half of the 20th century meant a sharp decrease in rice consumption and an increase in meat and total fat intake, with corresponding increases in obesity, diabetes, cardiovascular disease, and other health problems.[14] In studies of Japanese adults over the age of 40, diabetes prevalence was between 1-5% prior to 1980. By 1990, prevalence of the disease had increased to 10-12%.[14]

Carbohydrate Intolerance

Lactose intolerance. Intolerance of certain kinds of carbohydrate is common and may mimic medical disorders. Lactase, the enzyme in the jejunum that cleaves the milk sugar lactose, normally disappears sometime after the age of weaning. Its disappearance is gradual and extremely variable in age of onset. For some, the enzyme disappears in early childhood; in others, it wanes in late adulthood. The nonpersistence of lactase was once regarded as an abnormal condition, referred to as lactose intolerance. It is now known to be the biological norm, occurring in the vast majority of individuals. For most whites, however, lactase persists throughout life, a condition referred to as lactase persistence.

After lactase disappearance, the consumption of milk or other lactose-containing products can cause bloating, cramping, diarrhea, and flatulence, which may be mistaken for a number of gastrointestinal diseases.[15] Some authorities advise individuals with these symptoms to limit their consumption of lactose-containing products to small amounts consumed throughout the day, or to use plant-based nondairy beverages or lactase-treated dairy products. However, after the age of weaning, there is no nutritional requirement for either milk or milk substitutes, and their inclusion in the diet is based on preference rather than nutritional needs.

Sucrase deficiency. This condition is rare in the general public. It has been reported in adults with renal calculi,[16] and one study found sucrase deficiency in 31% of a population of individuals with HIV.[17]

Fructose malabsorption. Fructose malabsorption can also cause significant gastrointestinal symptoms (e.g., bloating, cramps, osmotic diarrhea) that may not respond to medications or surgical interventions.[18] However, fructose malabsorption is only likely to be problematic for individuals consuming concentrated amounts of this sugar (e.g., beverages with high-fructose corn syrup), as opposed to those eating reasonable quantities of fruit.[19] Malabsorption appears to be a problem mainly with fructose intakes exceeding 25 g per meal, although in patients with functional bowel disease, malabsorption may occur with amounts < 15 g.[20]

Congenital carbohydrate intolerances. Congenital carbohydrate intolerances are rare but life-threatening. These conditions include sucrase-maltase deficiency, glucose-galactose malabsorption, and alactasia (a total absence of lactase).[21]


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 Institute of Medicine has determined that 9 amino acids are indispensable for all age groups.[22] 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.[23] This term applies when endogenous synthesis cannot meet metabolic need (e.g., under special pathophysiologic circumstances, including prematurity in infants and severe catabolic stress in adults).[23]

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 triphosphate (ATP) and nucleic acids.[24] Depletion of glutamine through hypercatabolic/hypermetabolic illness may result in enterocyte and immunocyte starvation,[25] 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 postsurgery or in the intensive care unit.[26],[27] In addition, glutamine significantly increases plasma concentrations of taurine,[28] an amino acid with antihypertensive, antiarrhythmic, and positive inotropic effects.[26] This may be important for patients with chronic kidney disease, in whom low intracellular taurine concentrations are common and who are at high risk for cardiac events.

Cysteine is a conditionally indispensable amino acid in infants, one that may promote nitrogen retention in immature infants especially.[29] 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).[30] Patients with liver disease cannot meet their requirements for cysteine due to diminished activity of transsulfuration pathways.[22] The importance of cysteine is also underscored by its role in synthesizing N-acetylcysteine, a glutathione precursor with important clinical and preventive effects. These include reducing the risk of exacerbations and improving symptoms in patients with chronic bronchitis,[31] significantly reducing the risk of radiocontrast-induced nephropathy,[32] and reducing the expression of a number of cancer risk markers in humans.[33] Patients with cirrhosis may benefit from supplementation with specific (e.g., branched-chain) amino acids (see Cirrhosis chapter).

Certain 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 can supply protein in the amount and quality adequate for all ages.[34],[35]

The major difference between diets providing animal protein and those providing 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, however, tend to complement each other, and it is not necessary to intentionally combine foods.[36] 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 over 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 chapters). In some studies of nursing home residents, protein deficiency has emerged as a concern in those who are not eating normal amounts of food.[37] Protein requirements for strength and endurance athletes can range from 1.2 – 1.7 g/kg/day.[38] Even at these levels of protein intake, plant sources of protein are sufficient. Because many patients have questions about getting adequate protein and some may seek out high-protein foods or products that have harmful consequences, it is important to provide reassurance that there is no requirement for animal protein.

Protein needs are influenced by life stage. Protein requirements are highest in the growing years, with infants up 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 to 13 years), at 0.95 g/kg, and are reduced to near-adult levels (0.85 g/kg) from 14 to 18 years of age. Pregnancy and lactation also increase protein needs to 1.1 g/kg of maternal prepregnancy weight for the former and 1.3 g/kg for the latter.[39]

For healthy adults, the Estimated Average Requirement (EAR) set by the Institute of Medicine (IOM) is considerably lower (0.66 g/kg/d), 47 and 38 g per day for men and women, respectively.[36] In addition, the intake of adequate protein-sparing calories (see below) allows for maintenance of lean body mass at roughly this level of intake.[34] Most adults in Western countries consume more protein than the recommended EAR and Recommended Daily Allowance (RDA) of 0.66 g/kg/d and 0.8 g/kg/d, respectively. In the 2011/2012 What We Eat in America survey, adult men and women consumed a mean of 98.8 and 68.1 g of protein per day, respectively.[40] These amounts are approximately double the EAR. 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 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 kilogram body weight would consume approximately 7.7 g 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 extent (see below).[41]

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.[42],[43] 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 acute-phase proteins, with subsequent reduction in serum proteins.[44] Alternatively, cytokines will direct amino acids toward energy production rather than protein synthesis.[41] Thus prealbumin and albumin are not reliable indicators of malnutrition. Malnutrition should be diagnosed only when at least two specific characteristics are present according to the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition consensus statement. Low prealbumin and albumin levels seem to be more indicative of inflammation than nutrition status.[45] 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.[44]

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 1.2 to 2.0 g/kg have been recommended for critically ill patients with a body mass index < 30 by the American Society for Enteral and Parenteral Nutrition, and intakes in the range of 1.2 to 1.5 g/kg have been found helpful for promoting the healing of pressure ulcers.[46] However, others have noted no additional reduction in body protein losses at levels above 1.2 g/kg protein.[42] 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.[41] Acute toxic effects of excess protein intake are rare, but they are seen in cases of inborn errors of amino acid metabolism and in patients with hemorrhagic esophageal varices, which precipitates encephalopathy in patients with liver disease.[26] In certain conditions (e.g., chronic kidney disease), diets that provide lower amounts of protein than the Dietary Reference Intakes have been useful for improving clinical status (see Chronic Kidney Disease chapter).

Additional dangers of excess protein intake include idiopathic hypercalciuria,[47] greater risk for type 2 diabetes,[48][49] cancer, and overall mortality.[50] When protein constitutes > 35% of total energy intake, dangers include hyperaminoacidemia, hyperammonemia, hyperinsulinemia, nausea, and diarrhea.[51] Other dangers associated with excess protein intake are related mainly to animal protein. These include gout and certain cancers (see individual chapters in this book for further information).


Dietary fats are the least-required macronutrient, with only a few grams per day needed for the absorption of fat-soluble vitamins A, D, E, and K, among other functions. Foods contain combinations of saturated and unsaturated fats. Substantial quantities of saturated fat are found in dairy products, eggs, meats, and tropical oils (palm and coconut), while unsaturated fats predominate in liquid fats (e.g., vegetable oils). The latter are subdivided into monounsaturated fats (predominant in avocado and olive and canola oils) and polyunsaturated fats (found in nuts, seeds, seed oils, and, to a lesser extent, in meats).

Only the polyunsaturated fatty acids (PUFA) are essential to human nutrition, since the body does not synthesize these. PUFA have roles as structural components of cell membranes and as signaling molecules (e.g., eicosanoids).[52] The essential fatty acids (EFA) include linoleic acid (an omega-6 fatty acid) and alpha-linolenic acid (an omega-3 fatty acid). Some examples of food sources of omega-6 fatty acids are vegetable oils, avocados, and walnuts, while omega-3 fatty acids can be found in nuts, seeds, oils, and fish. Although people following vegan and vegetarian diets generally have lower intakes of omega-3 fatty acids than omnivores, a 2014 review reported that there is no evidence that they experience any adverse effects as a result.[53]

The IOM recommends a ratio of dietary linoleic (omega-6) to alpha-linolenic (omega-3) acid intake of 10:1; however, this figure is controversial (some suggest a higher intake of omega-3). The suggested adequate intakes for each EFA for different age groups is listed in Table 1, EFA Requirements (g/d).[39]

Table 1:

Recommended Ratio of Linoleic Acid to Alpha-Linolenic Fatty Acid,

Table 1: Recommended Ratio of Linoleic Acid to Alpha-Linolenic Fatty Acid, by Age Group, EFA Requirements (g/d)




Infants (0-6 months)
Infants (7-12 months)
Children (1-3 years)
Children (4-8 years)



Males (9-13)
Females (9-13)
Males (14-18)
Females (14-18)



Males (19-50)
Females (19-50)
Males (51- > 70)
Females (51- > 70)






The IOM Food and Nutrition Board currently recommends a range of fat intake of 20% to 35% of total energy intake.[39] This, too, is controversial, given that good health outcomes have been achieved with considerably lower levels of fat intake.[54][55][56] Most individuals can meet their EFA needs by consuming very small amounts of fat per day (~14 g or 0.5 oz), although many people are eating far more than this (~85 g or 3 oz, on average).[57]

This level of excess consumption of fats is problematic because EFA derivatives are raw materials for eicosanoids (i.e., prostaglandins, leukotrienes, and thromboxanes), hormone-like chemicals with short-lived but powerful effects. Eicosanoids play significant roles in immune function, inflammation, thrombosis, proliferation, reproduction, gastroprotection, and hemostasis, in addition to other functions.[58] The omega-6 polyunsaturated fatty acid linoleic acid and the omega-3 polyunsaturated fatty acid alpha-linolenic acid are metabolized to long-chain fatty acids (arachidonic and eicosapentanoic acids, respectively), which are the precursors for the eicosanoids. These long-chain derivatives are also found in some food products, with arachidonic acid being present in meat, eggs, and dairy products, and eicosapentanoic acid found in fish. These food sources are not required, however, as eicosanoids are produced in the body.

The type and amount of PUFA consumed (omega-6 vs. omega-3) are important considerations. Certain kinds of eicosanoids will predominate when omega-6 fats, found in vegetable oils and animal fats, are in plentiful supply, as is the case with Western diets.[59] These include prothrombotic thromboxanes (e.g., thromboxane A2); immunosuppressive prostaglandins (e.g., prostaglandin E2); and proinflammatory leukotrienes (e.g., leukotriene B4). Reducing the intake of omega-6 fatty acids (particularly arachidonic acid from animal products) while proportionately increasing the intake of omega-3 fatty acids results in the production of eicosanoids with reduced potential to do harm (e.g., thromboxane A3, prostaglandin E3, and leukotriene B5).[59]

The benefit of limiting fat. Saturated fats tend to raise cholesterol and triglyceride concentrations (see Obesity and Hyperlipidemia chapters); reducing saturated fat intake tends to improve blood lipid concentrations. Reducing total fat (not just replacing saturated with unsaturated fatty acids) is helpful for reducing body weight. As noted above, fat provides 9 calories per gram, more than twice that of protein or carbohydrate. A 2014 systematic review of 67 studies reported that, although successful long-term weight loss involves energy deficit, a reduction in fat intake can lead to an energy deficit even when individuals eat to satiety.[60] These findings agree with earlier reports that individuals who are successfully maintaining significant weight loss typically consume less than 25% of their total daily calories from fat.[61]

Intake of polyunsaturated and monounsaturated fatty acids should also be limited. PUFA are particularly sensitive to lipid peroxidation, resulting in generation of reactive oxygen species (superoxide and hydroxyl radicals, hydrogen peroxide, singlet oxygen, hypochlorous acid). Diets that are both low in antioxidants (e.g., Western diets) and high in PUFA may result in a condition termed oxidative stress,[62] which damages DNA, proteins, and carbohydrates, thereby contributing to a spectrum of common chronic diseases.[63],[64]Peroxidation of PUFA in low-density lipoprotein (LDL) increases the amount of oxidized LDL, a key stimulus for atherosclerosis progression.

In general, fatty foods provide very few nutrients. Other than essential fatty acids, vegetable oils provide only vitamins E and K, which can be obtained from other sources. Ideally, fats should not be added to meals. Rather, they should be consumed in modest amounts from foods that are a vehicle for other essential nutrients. For example, nuts provide essential fatty acids, magnesium, copper, folic acid, potassium, fiber, and vitamin E.[65]


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Last updated: November 6, 2020