Essential fatty acid

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Essential fatty acids, or EFAs, are fatty acids that humans and other animals must ingest because the body requires them for good health,[ clarification needed ] but cannot synthesize them. [1] [2]

Contents

Only two fatty acids are known to be essential for humans: alpha-linolenic acid (an omega-3 fatty acid) and linoleic acid (an omega-6 fatty acid). These are supplied to the body either as the free fatty acid, or more commonly as some glyceride derivative. [3] Deficiency in these fatty acids is rare. These fatty acids are essential because they are precursors to vitamins, cofactors, and derivatives, including prostaglandins, leukotrienes, thromboxanes, lipoxins, and others. [4]

When the two EFAs were discovered in 1923, they were designated "vitamin F", but in 1929, research on rats showed that the two EFAs are better classified as fats rather than vitamins. [5]

Functions

In the body, essential fatty acids serve multiple functions. In each of these, the balance between dietary ω-3 and ω-6 strongly affects function.

Nomenclature and terminology

Fatty acids comprise an aliphatic hydrocarbon chain plus a carboxyl group (–COOH) at one end, and terminated by a methyl group (–CH3) at the other end. They are almost always straight-chained. The carbon next to the carboxylate is known as α, the next carbon β, and so forth. Since biological fatty acids can be of diverse lengths, the last position is often labelled as a "ω", the last letter in the Greek alphabet. Thus, the ω-3 indicates that the first unsaturated carbon-carbon bond from the terminal end (ω) of the chain is the third one. Typically, the number of carbons and the number of double bonds are also listed in short descriptions of unsaturated fatty acids. For instance, ω-3 18:4, or 18:4 ω-3, or 18:4 n−3 indicates stearidonic acid, an 18-carbon chain with 4 double bonds, and with a double bond between the third and fourth carbon atoms from the CH3 end. Double bonds are cis and separated by a single methylene (CH2) group unless otherwise noted. In free fatty acid form, the chemical structure of stearidonic acid is:

Fatty acid carbon numbering.svg

Examples

Polyunsaturated fatty acids with 16- and 18-carbon chains are sometimes classified as short chain polyunsaturated fatty acids (SC-PUFA), as opposed to long-chain polyunsaturated fatty acids (LC-PUFA), which have more than 18 carbon atoms. [8]

Both the essential fatty acids are SC-PUFA with an 18-carbon chain:

These two fatty acids cannot be synthesized by humans because humans lack the desaturase enzymes required for their production.

They form the starting point for the creation of more desaturated fatty acids, most of which also have a longer carbon chain:

Except for GLA, which has a short 18-carbon chain, these fatty acids have more than 18 carbon atoms and are typically classified as LC-PUFA. [8]

ω-9 fatty acids are not essential in humans because they can be synthesized from carbohydrates or other fatty acids.

Essentiality in human diet

Mammals lack the ability to introduce double bonds in fatty acids beyond carbon 9 and 10, hence the omega-6 linoleic acid (18:2n-6; LA) and the omega-3 alpha-linolenic acid (18:3n-3; ALA) are essential for humans in the diet. However, humans can convert both LA and ALA to fatty acids with longer carbon chains and a larger number of double bonds, by alternative desaturation and chain elongation. [9] [4]

In humans, arachidonic acid (20:4n-6; AA) can be synthesized from LA. In turn, AA can be converted to an even longer fatty acid, the docosapentaenoic acid (22:5n-6; DPA). Similarly, ALA can be converted to docosahexaenoic acid (22:6n-3; DHA), although the latter conversion is limited, resulting in lower blood levels of DHA than through direct ingestion. This is illustrated by studies in vegans and vegetarians. [10] If there is relatively more LA than ALA in the diet it favors the formation of DPA from LA rather than DHA from ALA. This effect can be altered by changing the relative ratio of LA:ALA, but is more effective when total intake of polyunsaturated fatty acids is low.

In preterm infants, the capacity to convert LA to AA and ALA to DHA is limited, and preformed AA and DHA may be required to meet the needs of the developing brain. Both AA and DHA are present in breastmilk and contribute along with the parent fatty acids LA and ALA to meeting the requirements of the newborn infant. Many infant formulas have AA and DHA added to them with an aim to make them more equivalent to human milk.

Essential nutrients are defined as those that cannot be synthesized de novo in sufficient quantities for normal physiological function. This definition is met for LA and ALA but not the longer chain derivatives in adults. [11] The longer chain derivatives particularly, however, have pharmacological properties that can modulate disease processes, but this should not be confused with dietary essentiality.

One study demonstrated linoleic acid deficiency in adults. They found that patients undergoing intravenous nutrition with glucose became isolated from their fat supplies and rapidly developed biochemical signs of essential fatty acid deficiency (an increase in 20:3n-9/20:4n-6 ratio in plasma) and skin symptoms. [12] This could be treated by infusing lipids, and later studies showed that topical application of sunflower oil would also resolve the dermal symptoms. [13] Linoleic acid has a specific role in maintaining the skin water-permeability barrier, probably as constituents of acylglycosylceramides. This role cannot be met by any ω-3 fatty acids or by arachidonic acid.

The main physiological requirement for ω-6 fatty acids is attributed to arachidonic acid, which is the major precursor of prostaglandins, leukotrienes that play a vital role in cell signaling, and an endogenous cannabinoid anandamide. [14] Metabolites from the ω-3 pathway, mainly from eicosapentaenoic acid, are mostly inactive. [15]

Reviews by the European Food Safety Authority [16] made recommendations for minimal intakes of LA and ALA and have also recommended intakes of longer chain ω-3 fatty acids based on the association of oily fish consumption with a lower risk of cardiovascular disease. [17] [18] [19]

Food sources

Some of the food sources of Ω-3 and Ω-6 fatty acids are fish and shellfish, seaweed oil, flaxseed (linseed) and flaxseed oil, hemp seed, olive oil, soya oil, canola (rapeseed) oil, chia seeds, pumpkin seeds, sunflower seeds, leafy vegetables, and walnuts.

Essential fatty acids play a part in many metabolic processes, and there is evidence to suggest that low levels of essential fatty acids, or the wrong balance of types among the essential fatty acids, may be a factor in a number of illnesses, including osteoporosis. [20]

Fish is the main source of the longer omega-3 fats; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), though they initially acquire these fats through the consumption of algae and seaweed. Some plant-based foods contain omega-3 in the form of alpha-linolenic acid (ALA), which appears to have a modest benefit for cardiovascular health. [21] The human body can (and in case of a purely vegetarian diet often must unless certain algae or supplements derived from them are consumed) convert ALA to EPA and subsequently DHA. This elongation of ALA is inefficient. Conversion to DHA is higher in women than in men; this is thought to reflect the need to provide DHA to the fetus and infant during pregnancy and breast feeding. [22]

The IUPAC Lipid Handbook provides a very large and detailed listing of fat contents of animal and vegetable fats, including ω-3 and -6 oils. [23] The National Institutes of Health's EFA Education group publishes Essential Fats in Food Oils. [24] This lists 40 common oils, more tightly focused on EFAs and sorted by n-6:3 ratio. Vegetable Lipids as Components of Functional Food lists notable vegetable sources of EFAs as well as commentary and an overview of the biosynthetic pathways involved. [25] However, these sources are not in perfect agreement. EFA content of vegetable sources varies with cultivation conditions. Animal sources vary widely, both with the animal's feed and that the EFA makeup varies markedly with fats from different body parts.

Human health

Essential fatty acids play an important role in the life and death of cardiac cells. [26] [27] [28] [29] Additionally, essential fatty acids are crucial for the development of several endocannabinoids with a multitude of functions in the body, such as Docosahexaenoyl ethanolamide (DHA-EA/synaptamide). Many omega-3 and omega-6 derived essential fatty acids act similarly to endocannabinoids such as anandamide and 2-AG, possessing activity at the CB1 and CB2 receptors, among others. 29

Reference intake values

Reference intake values for as published by the Panel on Dietetic Products, Nutrition and Allergies of the European Food Safety Authority (EFSA). [30]

Common nameTypeReference intake values
alpha-Linolenic acid (ALA)Omega-32 g
Linoleic acid (LA)Omega-610 g

In the United States, the Adequate Intake (AI) for omega-3 fatty acids is for ALA. It is based on the median intake, and for adults the values are 1.6 g/day for men and 1.1 g/day for women. EPA and DHA contribute about 10 percent of total omega-3 intake. The AI for omega-6 fatty acids is for linoleic acid and is also based on the median intake: 17 g/day for younger men, dropping to 14 g/day for men over 50 years old; for younger women 12 g/d, and 11 g/day for women over 50. Studies have shown that smaller intakes reverse the symptoms of deficiency, but there is inadequate information to set an Estimated Average Requirement (EAR) for either. [31]

Essential fatty acid deficiency

Essential fatty acid deficiency results in a dermatitis similar to that seen in zinc or biotin deficiency. [32]

See also

Related Research Articles

<span class="mw-page-title-main">Fatty acid</span> Carboxylic acid

In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, from 4 to 28. Fatty acids are a major component of the lipids in some species such as microalgae but in some other organisms are not found in their standalone form, but instead exist as three main classes of esters: triglycerides, phospholipids, and cholesteryl esters. In any of these forms, fatty acids are both important dietary sources of fuel for animals and important structural components for cells.

Omega−3 fatty acids, also called Omega−3 oils, ω−3 fatty acids or n−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chemical structure. They are widely distributed in nature, being important constituents of animal lipid metabolism, and they play an important role in the human diet and in human physiology. The three types of omega−3 fatty acids involved in human physiology are α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). ALA can be found in plants, while DHA and EPA are found in algae and fish. Marine algae and phytoplankton are primary sources of omega−3 fatty acids. DHA and EPA accumulate in fish that eat these algae. Common sources of plant oils containing ALA include walnuts, edible seeds, and flaxseeds as well as hempseed oil, while sources of EPA and DHA include fish and fish oils, and algae oil.

α-Linolenic acid Chemical compound

α-Linolenic acid, also known as alpha-Linolenic acid (ALA), is an n−3, or omega-3, essential fatty acid. ALA is found in many seeds and oils, including flaxseed, walnuts, chia, hemp, and many common vegetable oils.

An unsaturated fat is a fat or fatty acid in which there is at least one double bond within the fatty acid chain. A fatty acid chain is monounsaturated if it contains one double bond, and polyunsaturated if it contains more than one double bond.

<span class="mw-page-title-main">Arachidonic acid</span> Fatty acid used metabolically in many organisms

Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the Neo-Latin word arachis (peanut), but peanut oil does not contain any arachidonic acid.

<span class="mw-page-title-main">Omega-6 fatty acid</span> Fatty acids where the sixth bond is double

Omega-6 fatty acids are a family of polyunsaturated fatty acids that have in common a final carbon-carbon double bond in the n-6 position, that is, the sixth bond, counting from the methyl end.

gamma-Linolenic acid or GLA is an n−6, or omega-6, fatty acid found primarily in seed oils. When acting on GLA, arachidonate 5-lipoxygenase produces no leukotrienes and the conversion by the enzyme of arachidonic acid to leukotrienes is inhibited.

Linoleic acid (LA) is an organic compound with the formula HOOC(CH2)7CH=CHCH2CH=CH(CH2)4CH3. Both alkene groups are cis. It is a fatty acid sometimes denoted 18:2 (n-6) or 18:2 cis-9,12. A linoleate is a salt or ester of this acid.

<span class="mw-page-title-main">Eicosapentaenoic acid</span> Chemical compound

Eicosapentaenoic acid is an omega-3 fatty acid. In physiological literature, it is given the name 20:5(n-3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid with a 20-carbon chain and five cis double bonds; the first double bond is located at the third carbon from the omega end.

<span class="mw-page-title-main">Docosahexaenoic acid</span> Chemical compound

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-linolenic acid or obtained directly from maternal milk, fatty fish, fish oil, or algae oil.

<span class="mw-page-title-main">Polyunsaturated fat</span> Type of fatty acid defined by molecular bonds

In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid, which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsaturated fatty acids are essentials. Polyunsaturated fatty acids are precursors to and are derived from polyunsaturated fats, which include drying oils.

Fatty acid desaturases are a family of enzymes that convert saturated fatty acids into unsaturated fatty acids and polyunsaturated fatty acids. For the common fatty acids of the C18 variety, desaturases convert stearic acid into oleic acid. Other desaturases convert oleic acid into linolenic acid, which is the precursor to alpha-linolenic acid, gamma-linolenic acid, and eicosatrienoic acid.

Eicosatetraenoic acid (ETA) designates any straight chain 20:4 fatty acid. Eicosatetraenoic acid belongs to the family of eicosanoids, molecules synthesized from oxidized polyunsaturated fatty acids (PUFAs) to mediate cell-cell communication. The eicosanoids, working in tandem, contribute to a lipid signaling complex widely responsible for inducing an inflammatory immune response. Common signs of inflammation are both internal and external, with effects like visible redness, pain in the surrounding area, swelling, and the sensation of heat—many of these an effect of varying eicosanoid species. These effects are associated with and have been observed in patients with cancers and various neurological/metabolic disorders.

<span class="mw-page-title-main">Essential fatty acid interactions</span>

There are many fatty acids found in nature. Two types of fatty acids considered essential for human health are the omega-3 and omega-6 types. These two essential fatty acids are necessary for some cellular signalling pathways and are involved in mediating inflammation, protein synthesis, and metabolic pathways in the human body.

Docosapentaenoic acid (DPA) designates any straight open chain polyunsaturated fatty acid (PUFA) which contains 22 carbons and 5 double bonds. DPA is primarily used to designate two isomers, all-cis-4,7,10,13,16-docosapentaenoic acid and all-cis-7,10,13,16,19-docosapentaenoic acid. They are also commonly termed n-6 DPA and n-3 DPA, respectively; these designations describe the position of the double bond being 6 or 3 carbons closest to the (omega) carbon at the methyl end of the molecule and is based on the biologically important difference that n-6 and n-3 PUFA are separate PUFA classes, i.e. the omega-6 fatty acids and omega-3 fatty acids, respectively. Mammals, including humans, can not interconvert these two classes and therefore must obtain dietary essential PUFA fatty acids from both classes in order to maintain normal health.

<span class="mw-page-title-main">Mead acid</span> Chemical compound

Mead acid is an omega-9 fatty acid, first characterized by James F. Mead. As with some other omega-9 polyunsaturated fatty acids, animals can make Mead acid de novo. Its elevated presence in the blood is an indication of essential fatty acid deficiency. Mead acid is found in large quantities in cartilage.

<span class="mw-page-title-main">Linoleoyl-CoA desaturase</span> Class of enzymes

Linoleoyl-CoA desaturase (also Delta 6 desaturase, EC 1.14.19.3) is an enzyme that converts between types of fatty acids, which are essential nutrients in the human body. The enzyme mainly catalyzes the chemical reaction

<span class="mw-page-title-main">Oxylipin</span> Class of lipids

Oxylipins constitute a family of oxygenated natural products which are formed from fatty acids by pathways involving at least one step of dioxygen-dependent oxidation. Oxylipins are derived from polyunsaturated fatty acids (PUFAs) by COX enzymes (cyclooxygenases), by LOX enzymes (lipoxygenases), or by cytochrome P450 epoxygenase.

Only two essential fatty acids are known to be essential for humans: alpha-linolenic acid and linoleic acid. The biological effects of the ω-3 and ω-6 fatty acids are mediated by their mutual interactions. Closely related, these fatty acids act as competing substrates for the same enzymes. The biological effects of the ω-3 and ω-6 fatty acids are largely mediated by essential fatty acid interactions. The proportion of omega-3 to omega-6 fatty acids in a diet may have metabolic consequences. Unlike omega-3 fatty acids and omega-6 fatty acids, omega-9 fatty acids are not classed as essential fatty acids because they can be created by the human body from monounsaturated and saturated fatty acids, and are therefore not essential in the diet.

References

  1. ↑ Robert S. Goodhart; Maurice E. Shils (1980). Modern Nutrition in Health and Disease (6th ed.). Philadelphia: Lea and Febinger. pp.  134–138. ISBN   978-0-8121-0645-9.
  2. ↑ Essential fatty acids should not be confused with essential oils, which are "essential" in the sense of being a concentrated essence. Some other fatty acids are sometimes classified as "conditionally essential", meaning that they can become essential under some developmental or disease conditions; examples include docosahexaenoic acid (an omega-3 fatty acid) and gamma-linolenic acid (an omega-6 fatty acid).
  3. ↑ Whitney Ellie; Rolfes SR (2008). Understanding Nutrition (11th ed.). California: Thomson Wadsworth. p. 154.
  4. 1 2 Das, Undurti N. (2006). "Essential Fatty Acids: Biochemistry, Physiology and Pathology". Biotechnology Journal. 1 (4): 420–439. doi:10.1002/biot.200600012. PMID   16892270. S2CID   25945627.
  5. ↑ Burr, G.O., Burr, M.M. and Miller, E. (1931). "On the nature and role of the fatty acids essential in nutrition". J. Biol. Chem. 86 (587): 587–621. doi: 10.1016/S0021-9258(20)78929-5 .{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ↑ Stillwell W, Shaikh SR, Zerouga M, Siddiqui R, Wassall SR (2005). "Docosahexaenoic acid affects cell signaling by altering lipid rafts". Reproduction, Nutrition, Development. 45 (5): 559–79. doi: 10.1051/rnd:2005046 . PMID   16188208.
  7. ↑ Calder PC (December 2004). "n-3 fatty acids, inflammation, and immunity--relevance to postsurgical and critically ill patients". Lipids. 39 (12): 1147–61. doi:10.1007/s11745-004-1342-z. PMC   7101959 . PMID   15736910.
  8. 1 2 Buckley MT, et al. (2017). "Selection in Europeans on Fatty Acid Desaturases Associated with Dietary Changes". Mol Biol Evol. 34 (6): 1307–1318. doi:10.1093/molbev/msx103. PMC   5435082 . PMID   28333262.
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  10. ↑ Sanders TA (2009). "DHA Status of vegetarians". Prostaglandins Leukotrienes Essential Fatty Acids. 81 (2–3): 137–41. doi:10.1016/j.plefa.2009.05.013. PMID   19500961.
  11. ↑ FAO/WHO Fats and fatty acids in human nutrition. Report of an expert consultation. FAO Food and Nutrition Paper 91, Rome 2011. ISSN 0254-4725
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  13. ↑ Prottey, C; Hartop, PJ; Press, M (1975). "Correction of the cutaneous manifestations of essential fatty acid deficiency in man by application of sunflower-seed oil to the skin". J Invest Dermatol. 64 (4): 228–34. doi: 10.1111/1523-1747.ep12510667 . PMID   1117180.
  14. ↑ Maccarrone, M; Finazzi-Agró, A (22 August 2003). "The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis". Cell Death & Differentiation. 10 (9): 946–955. doi: 10.1038/sj.cdd.4401284 . PMID   12934069.
  15. ↑ Sanders, Tom; Emery, Peter (2003). Molecular Basis of Human Nutrition. London: Taylor Frances. ISBN   9780367806323.
  16. ↑ Jones, A (2010). "EFSA Scientific Opinion on Dietary Reference Values for fats, including saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans fatty acids and cholesterol". EFSA Journal. 8 (3): 1461. doi: 10.2903/j.efsa.2010.1461 .
  17. ↑ Heather Hutchins, MS, RD (2005-10-19). "Symposium Highlights -- Omega-3 Fatty Acids: Recommendations for Therapeutics and Prevention". Omega-3 fatty acids and their counterparts, n-6 fatty acids, are essential polyunsaturated fatty acids (PUFA) because they cannot be synthesized de novo in the body.{{cite web}}: CS1 maint: multiple names: authors list (link)
  18. ↑ Nugent KP, Spigelman AD, Phillips RK (June 1996). "Tissue prostaglandin levels in familial adenomatous polyposis patients treated with sulindac". Diseases of the Colon and Rectum. 39 (6): 659–62. doi:10.1007/BF02056946. PMID   8646953. S2CID   25642190. Arachidonic acid is an essential fatty acid…
  19. ↑ Carlstedt-Duke J, Brönnegård M, Strandvik B (December 1986). "Pathological regulation of arachidonic acid release in cystic fibrosis: the putative basic defect". Proceedings of the National Academy of Sciences of the United States of America. 83 (23): 9202–6. Bibcode:1986PNAS...83.9202C. doi: 10.1073/pnas.83.23.9202 . PMC   387103 . PMID   3097647. [T]he turnover of essential fatty acids is increased (7). Arachidonic acid is one of the essential fatty acids affected.
  20. ↑ Kruger MC, Horrobin DF (September 1997). "Calcium metabolism, osteoporosis and essential fatty acids: a review". Progress in Lipid Research. 36 (2–3): 131–51. doi:10.1016/S0163-7827(97)00007-6. PMID   9624425.
  21. ↑ Pan A, Chen M, Chowdhury R, et al. (December 2012). "α-Linolenic acid and risk of cardiovascular disease: a systematic review and meta-analysis". Am. J. Clin. Nutr. (Systematic review). 96 (6): 1262–73. doi:10.3945/ajcn.112.044040. PMC   3497923 . PMID   23076616.
  22. ↑ Burdge GC, Calder PC (September 2005). "Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults" (PDF). Reprod. Nutr. Dev. 45 (5): 581–97. doi: 10.1051/rnd:2005047 . PMID   16188209. Archived (PDF) from the original on 2017-08-15.
  23. ↑ "IUPAC Lipid Handbook" (PDF). iupac.org. Archived (PDF) from the original on 2006-02-12.
  24. ↑ "Essential Fats in Food Oils" (PDF). efaeducation.org. Archived (PDF) from the original on 2014-12-10.
  25. ↑ Vegetable Lipids as Components of Functional Food Archived 2006-03-20 at the Wayback Machine , Stuchlik and Zak
  26. ↑ Honoré E, Barhanin J, Attali B, Lesage F, Lazdunski M (March 1994). "External blockade of the major cardiac delayed-rectifier K+ channel (Kv1.5) by polyunsaturated fatty acids". Proceedings of the National Academy of Sciences of the United States of America. 91 (5): 1937–41. Bibcode:1994PNAS...91.1937H. doi: 10.1073/pnas.91.5.1937 . PMC   43279 . PMID   8127910.
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  28. ↑ Landmark K, Alm CS (November 2006). "[Alpha-linolenic acid, cardiovascular disease and sudden death]". Tidsskrift for den Norske Lægeforening (in Norwegian). 126 (21): 2792–4. PMID   17086218.
  29. ↑ Herbaut C (September 2006). "[Omega-3 and health]". Revue Médicale de Bruxelles (in French). 27 (4): S355–60. PMID   17091903.
  30. ↑ European Food Safety Authority (EFSA) (2009-07-01). "Labelling reference intake values for n-3 and n-6 polyunsaturated fatty acids". EFSA Journal. 7 (7): 1176. doi: 10.2903/j.efsa.2009.1176 . ISSN   1831-4732.
  31. ↑ Food and Nutrition Board (2004). "DIETARY REFERENCE INTAKESFOREnergy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids" (PDF). pp. 464, 471. Archived from the original (PDF) on 2022-06-27.
  32. ↑ James, William D.; Elston, Dirk; Treat, James R.; Rosenbach, Misha A.; Neuhaus, Isaac (2019-01-18). Andrews' Diseases of the Skin: Clinical Dermatology. Elsevier Health Sciences. p. 482. ISBN   9780323551885.
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