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Thursday, May 4, 2017

Omega-3 fatty acid

From Wikipedia, the free encyclopedia

Omega-3 fatty acids—also called ω-3 fatty acids or n-3 fatty acids[1]—are polyunsaturated fatty acids (PUFAs) with a double bond (C=C) at the third carbon atom from the end of the carbon chain.[2] The fatty acids have two ends, the carboxylic acid (-COOH) end, which is considered the beginning of the chain, thus "alpha", and the methyl (-CH3) end, which is considered the "tail" of the chain, thus "omega"; the double bond is at omega minus 3 (not dash 3). One way in which a fatty acid is named is determined by the location of the first double bond, counted from the methyl end, that is, the omega (ω-) or the n- end. However, the standard (IUPAC) chemical nomenclature system starts from the carbonyl end.

The three types of omega-3 fatty acids involved in human physiology are α-linolenic acid (ALA) (found in plant oils), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) (both commonly found in marine oils). Marine algae and phytoplankton are primary sources of omega-3 fatty acids. Common sources of plant oils containing the omega-3 ALA fatty acid include walnut, edible seeds, clary sage seed oil, algal oil, flaxseed oil, Sacha Inchi oil, Echium oil, and hemp oil, while sources of animal omega-3 EPA and DHA fatty acids include fish, fish oils, eggs from chickens fed EPA and DHA, squid oils, and krill oil. Dietary supplementation with omega-3 fatty acids does not appear to affect the risk of death, cancer or heart disease.[3][4] Furthermore, fish oil supplement studies have failed to support claims of preventing heart attacks or strokes.[5]

Omega-3 fatty acids are important for normal metabolism.[6] Mammals are unable to synthesize omega-3 fatty acids, but can obtain the shorter-chain omega-3 fatty acid ALA (18 carbons and 3 double bonds) through diet and use it to form the more important long-chain omega-3 fatty acids, EPA (20 carbons and 5 double bonds) and then from EPA, the most crucial, DHA (22 carbons and 6 double bonds).[6] The ability to make the longer-chain omega-3 fatty acids from ALA may be impaired in aging.[7][8] In foods exposed to air, unsaturated fatty acids are vulnerable to oxidation and rancidity.[9]

Health effects

Supplementation does not appear to be associated with a lower risk of all-cause mortality.[3]

Cancer

The evidence linking the consumption of fish to the risk of cancer is poor.[10] Supplementation with omega-3 fatty acids does not appear to affect this either.[4]

A 2006 review concluded that there was no link between omega-3 fatty acids consumption and
cancer.[4] This is similar to the findings of a review of studies up to February 2002 that failed to find clear effects of long and shorter chain omega-3 fats on total risk of death, combined cardiovascular events and cancer.[11][12] In those with advanced cancer and cachexia, omega-3 fatty acids supplements may be of benefit, improving appetite, weight, and quality of life.[13] There is tentative evidence that marine omega-3 polyunsaturated fatty acids reduce the risk of breast cancer but this is not conclusive.[14][15]

The effect of consumption on prostate cancer is not conclusive.[15] There is a decreased risk with higher blood levels of DPA, but an increased risk of more aggressive prostate cancer with higher blood levels of combined EPA and DHA (found in fatty fish oil).[16]

Cardiovascular disease

Evidence, in the population generally, does not support a beneficial role for omega-3 fatty acid supplementation in preventing cardiovascular disease (including myocardial infarction and sudden cardiac death) or stroke.[3][17][18] However, omega-3 fatty acid supplementation greater than one gram daily for at least a year may be protective against cardiac death, sudden death, and myocardial infarction in people who have a history of cardiovascular disease.[19] No protective effect against the development of stroke or all-cause mortality was seen in this population.[19] Eating a diet high in fish that contain long chain omega-3 fatty acids does appear to decrease the risk of stroke.[20] Fish oil supplementation has not been shown to benefit revascularization or abnormal heart rhythms and has no effect on heart failure hospital admission rates.[21] Furthermore, fish oil supplement studies have failed to support claims of preventing heart attacks or strokes.[5]

Evidence suggests that omega-3 fatty acids modestly lower blood pressure (systolic and diastolic) in people with hypertension and in people with normal blood pressure.[22] Some evidence suggests that people with certain circulatory problems, such as varicose veins, may benefit from the consumption of EPA and DHA, which may stimulate blood circulation and increase the breakdown of fibrin, a protein involved in blood clotting and scar formation.[23][24] Omega-3 fatty acids reduce blood triglyceride levels but do not significantly change the level of LDL cholesterol or HDL cholesterol in the blood.[25][26] The American Heart Association position (2011) is that borderline elevated triglycerides, defined as 150–199 mg/dL, can be lowered by 0.5-1.0 grams of EPA and DHA per day; high triglycerides 200–499 mg/dL benefit from 1-2 g/day; and >500 mg/dL be treated under a physician's supervision with 2-4 g/day using a prescription product.[27]

ALA does not confer the cardiovascular health benefits of EPA and DHAs.[28]

The effect of omega-3 polyunsaturated fatty acids on stroke is unclear, with a possible benefit in women.[29]

Inflammation

Some research suggests that the anti-inflammatory activity of long-chain omega-3 fatty acids may translate into clinical effects.[30] A 2013 systematic review found tentative evidence of benefit.[31] Consumption of omega-3 fatty acids from marine sources lowers markers of inflammation in the blood such as C-reactive protein, interleukin 6, and TNF alpha.[32]

For rheumatoid arthritis (RA), one systematic review found consistent, but modest, evidence for the effect of marine n-3 PUFAs on symptoms such as "joint swelling and pain, duration of morning stiffness, global assessments of pain and disease activity" as well as the use of non-steroidal anti-inflammatory drugs.[33] The American College of Rheumatology (ACR) has stated that there may be modest benefit from the use of fish oils, but that it may take months for effects to be seen, and cautions for possible gastrointestinal side effects and the possibility of the supplements containing mercury or vitamin A at toxic levels. The National Center for Complementary and Integrative Health has concluded that "[n]o dietary supplement has shown clear benefits for RA", but that there is preliminary evidence that fish oil may be beneficial, and called for further study.[34]

Developmental disabilities

Although not supported by current scientific evidence as a primary treatment for ADHD, autism, and other developmental disabilities,[35][36] omega-3 fatty acid supplements are being given to children with these conditions.[35]

One meta-analysis concluded that omega-3 fatty acid supplementation demonstrated a modest effect for improving ADHD symptoms.[37] A Cochrane review of PUFA (not necessarily omega-3) supplementation found "there is little evidence that PUFA supplementation provides any benefit for the symptoms of ADHD in children and adolescents",[38] while a different review found "insufficient evidence to draw any conclusion about the use of PUFAs for children with specific learning disorders".[39] Another review concluded that the evidence is inconclusive for the use of omega-3 fatty acids in behavior and non-neurodegenerative neuropsychiatric disorders such ADHD and depression.[40]

Fish oil has only a small benefit on the risk of early birth.[41][42] A 2015 meta-analysis of the effect of omega-3 supplementation during pregnancy did not demonstrate a decrease in the rate of preterm birth or improve outcomes in women with singleton pregnancies with no prior preterm births.[43] A systematic review and meta-analysis published the same year reached the opposite conclusion, specifically, that omega-3 fatty acids were effective in "preventing early and any preterm delivery".[44]

Mental health

There is some evidence that omega-3 fatty acids are related to mental health,[45] including that they may tentatively be useful as an add-on for the treatment of depression associated with bipolar disorder.[46] Significant benefits due to EPA supplementation were only seen, however, when treating depressive symptoms and not manic symptoms suggesting a link between omega-3 and depressive mood.[46] There is also preliminary evidence that EPA supplementation is helpful in cases of depression.[47] The link between omega-3 and depression has been attributed to the fact that many of the products of the omega-3 synthesis pathway play key roles in regulating inflammation such as prostaglandin E3 which have been linked to depression.[48] This link to inflammation regulation has been supported in both in vitro [49] and in vivo studies as well as in meta-analysis studies.[31] The exact mechanism in which omega-3 acts upon the inflammatory system is still controversial as it was commonly believed to have anti-inflammatory effects.[50]

There is, however, significant difficulty in interpreting the literature due to participant recall and systematic differences in diets.[51] There is also controversy as to the efficacy of omega-3, with many meta-analysis papers finding heterogeneity among results which can be explained mostly by publication bias.[52][53] A significant correlation between shorter treatment trials was associated with increased omega-3 efficacy for treating depressed symptoms further implicating bias in publication.[53]

Very low quality evidence finds that omega-3 fatty acids might prevent psychosis.[54]

Cognitive aging

Epidemiological studies are inconclusive about an effect of omega-3 fatty acids on the mechanisms of Alzheimer's disease.[55] There is preliminary evidence of effect on mild cognitive problems, but none supporting an effect in healthy people or those with dementia.[56][57][58]

Brain and visual functions

Brain function and vision rely on dietary intake of DHA to support a broad range of cell membrane properties, particularly in grey matter, which is rich in membranes.[59][60] A major structural component of the mammalian brain, DHA is the most abundant omega-3 fatty acid in the brain.[61] It is under study as a candidate essential nutrient with roles in neurodevelopment, cognition and neurodegenerative disorders.[59]

Atopic diseases

Results of studies investigating the role of LCPUFA supplementation and LCPUFA status in the prevention and therapy of atopic diseases (allergic rhinoconjunctivitis, atopic dermatitis and allergic asthma) are controversial; therefore, at the present stage of our knowledge we cannot state either that the nutritional intake of n-3 fatty acids has a clear preventive or therapeutic role, or that the intake of n-6 fatty acids has a promoting role in context of atopic diseases.[62]

Risk of deficiency

People with PKU often have low intake of omega-3 fatty acids, because nutrients rich in omega-3 fatty acids are excluded from their diet due to high protein content.[63]

Chemistry

Chemical structure of alpha-linolenic acid (ALA), an essential omega-3 fatty acid, (18:3Δ9c,12c,15c, which means a chain of 18 carbons with 3 double bonds on carbons numbered 9, 12, and 15). Although chemists count from the carbonyl carbon (blue numbering), biologists count from the n (ω) carbon (red numbering). Note that, from the n end (diagram right), the first double bond appears as the third carbon-carbon bond (line segment), hence the name "n-3". This is explained by the fact that the n end is almost never changed during physiological transformations in the human body, as it is more energy-stable, and other compounds can be synthesized from the other carbonyl end, for example in glycerides, or from double bonds in the middle of the chain.
Chemical structure of eicosapentaenoic acid (EPA)
Chemical structure of docosahexaenoic acid (DHA)

Omega-3 fatty acids that are important in human physiology[64] are α-linolenic acid (18:3, n-3; ALA), eicosapentaenoic acid (20:5, n-3; EPA), and docosahexaenoic acid (22:6, n-3; DHA). These three polyunsaturates have either 3, 5, or 6 double bonds in a carbon chain of 18, 20, or 22 carbon atoms, respectively. As with most naturally-produced fatty acids, all double bonds are in the cis-configuration, in other words, the two hydrogen atoms are on the same side of the double bond; and the double bonds are interrupted by methylene bridges (-CH
2
-), so that there are two single bonds between each pair of adjacent double bonds.

List of omega-3 fatty acids

This table lists several different names for the most common omega-3 fatty acids found in nature.

Common name Lipid name Chemical name
Hexadecatrienoic acid (HTA) 16:3 (n-3) all-cis-7,10,13-hexadecatrienoic acid
α-Linolenic acid (ALA) 18:3 (n-3) all-cis-9,12,15-octadecatrienoic acid
Stearidonic acid (SDA) 18:4 (n-3) all-cis-6,9,12,15-octadecatetraenoic acid
Eicosatrienoic acid (ETE) 20:3 (n-3) all-cis-11,14,17-eicosatrienoic acid
Eicosatetraenoic acid (ETA) 20:4 (n-3) all-cis-8,11,14,17-eicosatetraenoic acid
Eicosapentaenoic acid (EPA) 20:5 (n-3) all-cis-5,8,11,14,17-eicosapentaenoic acid
Heneicosapentaenoic acid (HPA) 21:5 (n-3) all-cis-6,9,12,15,18-heneicosapentaenoic acid
Docosapentaenoic acid (DPA),
Clupanodonic acid
22:5 (n-3) all-cis-7,10,13,16,19-docosapentaenoic acid
Docosahexaenoic acid (DHA) 22:6 (n-3) all-cis-4,7,10,13,16,19-docosahexaenoic acid
Tetracosapentaenoic acid 24:5 (n-3) all-cis-9,12,15,18,21-tetracosapentaenoic acid
Tetracosahexaenoic acid (Nisinic acid) 24:6 (n-3) all-cis-6,9,12,15,18,21-tetracosahexaenoic acid

Forms

Triglycerides

Marine fish oils naturally contain triglycerides with omega-3 fatty acids. There are processes by which the fatty acids can be separated from glycerol, concentrated to a higher EPA and DHA content and reassembled into high omega-3 triglycerides. There are no prescription products of this nature, only dietary supplements. There are disputed claims for superiority - absorption and function - of natural marine oil triglycerides, omega-3 enriched triglycerides, ethyl ester products and free fatty acid products.[citation needed]

Ethyl esters

Omega-3 acid ethyl esters are created by starting with a marine oil, converting the triglycerides to free fatty acids, concentrating the omega-3 fatty acids, and attaching an ethanol molecule to each FA. Available in U.S. as prescription product and dietary supplement. Prescription product brand names Lovaza (had been Omacor),[65] OMTRYG,[66] four generic versions [67] and Ethyl eicosapentaenoic acid (Vascepa)[68] A review compares the prescription products.[69]

Free fatty acids

Omega-3 carboxylic acids are created by starting with a marine oil, disassociating the triglycerides into free fatty acids and concentrating the omega-3 fatty acids. The product is free fatty acids.Prescribed use at 2 or 4 grams per day.[70] The prescription product is named Epanova.[71]

Phospholipids

Phospholipid omega-3 is composed of two fatty acids attached to a phosphate and choline, versus the three fatty acids attached to glycerol in triglycerides. There are no prescription products of this nature, only dietary supplements. One source of phospholipid omega-3 is krill oil.

Biochemistry

Transporters

DHA in the form of lysophosphatidylcholine is transported into the brain by a membrane transport protein, MFSD2A, which is exclusively expressed in the endothelium of the blood–brain barrier.[72][73]

Mechanism of action

The 'essential' fatty acids were given their name when researchers found that they are essential to normal growth in young children and animals. The omega-3 fatty acid DHA, also known as docosahexaenoic acid, is found in high abundance in the human brain.[74] It is produced by a desaturation process, but humans lack the desaturase enzyme, which acts to insert double bonds at the ω6 and ω3 position.[74] Therefore, the ω6 and ω3 polyunsaturated fatty acids cannot be synthesized and are appropriately called essential fatty acids.[74]

In 1964 it was discovered that enzymes found in sheep tissues convert omega-6 arachidonic acid into the inflammatory agent called prostaglandin E2[75] which both causes the sensation of pain and expedites healing and immune response in traumatized and infected tissues.[76] By 1979 more of what are now known as eicosanoids were discovered: thromboxanes, prostacyclins, and the leukotrienes.[76] The eicosanoids, which have important biological functions, typically have a short active lifetime in the body, starting with synthesis from fatty acids and ending with metabolism by enzymes. If the rate of synthesis exceeds the rate of metabolism, the excess eicosanoids may, however, have deleterious effects.[76] Researchers found that certain omega-3 fatty acids are also converted into eicosanoids, but at a much slower rate. Eicosanoids made from omega-3 fatty acids are often referred to as anti-inflammatory, but in fact they are just less inflammatory than those made from omega-6 fats. If both omega-3 and omega-6 fatty acids are present, they will "compete" to be transformed,[76] so the ratio of long-chain omega-3:omega-6 fatty acids directly affects the type of eicosanoids that are produced.[76]

Interconversion

Conversion efficiency of ALA to EPA and DHA

Humans can convert short-chain omega-3 fatty acids to long-chain forms (EPA, DHA) with an efficiency below 5%.[77][78] The omega-3 conversion efficiency is greater in women than in men, but less-studied.[79] Higher ALA and DHA values found in plasma phospholipids of women may be due to the higher activity of desaturases, especially that of delta-6-desaturase.[80]

These conversions occur competitively with omega-6 fatty acids, which are essential closely related chemical analogues that are derived from linoleic acid. They both utilize the same desaturase and elongase proteins in order to synthesize inflammatory regulatory proteins.[48] The products of both pathways are vital for growth making a balanced diet of omega-3 and omega-6 important to an individual’s health.[81] A balanced intake ratio of 1:1 was believed to be ideal in order for proteins to be able to synthesize both pathways sufficiently, but this has been controversial as of recent research.[82]

The conversion of ALA to EPA and further to DHA in humans has been reported to be limited, but varies with individuals.[83][84] Women have higher ALA conversion efficiency than men, which is presumed[85] to be due to the lower rate of use of dietary ALA for beta-oxidation. This suggests that biological engineering of ALA conversion efficiency is possible. Goyens et al. argue that the absolute amounts of ALA and LA each influence conversion rates separately, rather than simply the ratio between the two.[86]

Omega-6 to omega-3 ratio

Human diet has changed rapidly in recent centuries resulting in a reported increased diet of omega-6 in comparison to omega-3.[87] The rapid evolution of human diet away from a 1:1 omega-3 and omega-6 ratio, such as during the Neolithic Agricultural Revolution, has presumably been too fast for humans to have adapted to biological profiles adept at balancing omega-3 and omega-6 ratios of 1:1.[88] This is commonly believed to be the reason why modern diets are correlated with many inflammatory disorders.[87] While omega-3 polyunsaturated fatty acids may be beneficial in preventing heart disease in humans, the level of omega-6 polyunsaturated fatty acids (and, therefore, the ratio) does not matter.[82][89]
Both omega-6 and omega-3 fatty acids are essential: humans must consume them in their diet. Omega-6 and omega-3 eighteen-carbon polyunsaturated fatty acids compete for the same metabolic enzymes, thus the omega-6:omega-3 ratio of ingested fatty acids has significant influence on the ratio and rate of production of eicosanoids, a group of hormones intimately involved in the body's inflammatory and homeostatic processes, which include the prostaglandins, leukotrienes, and thromboxanes, among others. Altering this ratio can change the body's metabolic and inflammatory state.[11] In general, grass-fed animals accumulate more omega-3 than do grain-fed animals, which accumulate relatively more omega-6.[90] Metabolites of omega-6 are more inflammatory (esp. arachidonic acid) than those of omega-3. This necessitates that omega-6 and omega-3 be consumed in a balanced proportion; healthy ratios of omega-6:omega-3, according to some authors, range from 1:1 to 1:4.[91] Other authors believe that a ratio of 4:1 (4 times as much omega-6 as omega-3) is already healthy.[92][93] Studies suggest the evolutionary human diet, rich in game animals, seafood, and other sources of omega-3, may have provided such a ratio.[94][95]

Typical Western diets provide ratios of between 10:1 and 30:1 (i.e., dramatically higher levels of omega-6 than omega-3).[96] The ratios of omega-6 to omega-3 fatty acids in some common vegetable oils are: canola 2:1, hemp 2-3:1,[97] soybean 7:1, olive 3–13:1, sunflower (no omega-3), flax 1:3,[98] cottonseed (almost no omega-3), peanut (no omega-3), grapeseed oil (almost no omega-3) and corn oil 46:1 ratio of omega-6 to omega-3.[99]

History

Although omega-3 fatty acids have been known as essential to normal growth and health since the 1930s, awareness of their health benefits has dramatically increased since the 1980s.[100][101]

On September 8, 2004, the U.S. Food and Drug Administration gave "qualified health claim" status to EPA and DHA omega-3 fatty acids, stating, "supportive but not conclusive research shows that consumption of EPA and DHA [omega-3] fatty acids may reduce the risk of coronary heart disease".[102] This updated and modified their health risk advice letter of 2001 (see below).

The Canadian Food Inspection Agency has recognized the importance of DHA omega-3 and permits the following claim for DHA: "DHA, an omega-3 fatty acid, supports the normal physical development of the brain, eyes and nerves primarily in children under two years of age."[103]

Dietary sources

Grams of omega-3 per 3oz (85g) serving[104] [105]
Common name grams omega-3
Flax 11.4 [106]
Hemp 11.0
Herring, sardines 1.3–2
Mackerel: Spanish/Atlantic/Pacific 1.1–1.7
Salmon 1.1–1.9
Halibut 0.60–1.12
Tuna 0.21–1.1
Swordfish 0.97
Greenshell/lipped mussels 0.95[106]
Tilefish 0.9
Tuna (canned, light) 0.17–0.24
Pollock 0.45
Cod 0.15–0.24
Catfish 0.22–0.3
Flounder 0.48
Grouper 0.23
Mahi mahi 0.13
Orange roughy 0.028
Red snapper 0.29
Shark 0.83
King mackerel 0.36
Hoki (blue grenadier) 0.41[106]
Gemfish 0.40[106]
Blue eye cod 0.31[106]
Sydney rock oysters 0.30[106]
Tuna, canned 0.23[106]
Snapper 0.22[106]
Mutton 0.12[107]
Eggs, large regular 0.109[106]
Strawberry or Kiwifruit 0.10-0.20
Broccoli 0.10-0.20
Barramundi, saltwater 0.100[106]
Giant tiger prawn 0.100[106]
Lean red meat 0.031[106]
Turkey 0.030[106]
Cereals, rice, pasta, etc. 0.00[106]
Fruit 0.00[106]
Milk, regular 0.00[106]
Bread, regular 0.00[106]
Vegetables 0.00[106]

Daily values

In the United States, the Institute of Medicine publishes a system of Dietary Reference Intakes, which includes Recommended Dietary Allowances (RDAs) for individual nutrients, and Acceptable Macronutrient Distribution Ranges (AMDRs) for certain groups of nutrients, such as fats. When there is insufficient evidence to determine an RDA, the institute may publish an Adequate Intake (AI) instead, which has a similar meaning, but is less certain. The AI for α-linolenic acid is 1.6 grams/day for men and 1.1 grams/day for women, while the AMDR is 0.6% to 1.2% of total energy.Because the physiological potency of EPA and DHA is much greater than that of ALA, it is not possible to estimate one AMDR for all omega-3 fatty acids. Approximately 10 percent of the AMDR can be consumed as EPA and/or DHA.[108] The Institute of Medicine has not established a RDA or AI for EPA, DHA or the combination, so there is no Daily Value (DVs are derived from RDAs), no labeling of foods or supplements as providing a DV percentage of these fatty acids per serving, and no labeling a food or supplement as an excellent source, or "High in..."[citation needed] As for safety, there was insufficient evidence as of 2005 to set an upper tolerable limit for omega-3 fatty acids,[108] although the FDA has advised that adults can safely consume up to a total of 3 grams per day of combined DHA and EPA, with no more than 2 g from dietary supplements.[6]

Recommendations

The American Heart Association (AHA) has made recommendations for EPA and DHA due to their cardiovascular benefits: individuals with no history of coronary heart disease or myocardial infarction should consume oily fish two times per week; and "Treatment is reasonable" for those having been diagnosed with coronary heart disease. For the latter the AHA does not recommend a specific amount of EPA + DHA, although it notes that most trials were at or close to 1000 mg/day. The benefit appears to be on the order of a 9% decrease in relative risk.[109] The European Food Safety Authority (EFSA) approved a claim "EPA and DHA contributes to the normal function of the heart" for products that contain at least 250 mg EPA + DHA. The report did not address the issue of people with pre-existing heart disease. The World Health Organization recommends regular fish consumption (1-2 servings per week, equivalent to 200 to 500 mg/day EPA + DHA) as protective against coronary heart disease and ischaemic stroke.

Contamination

Heavy metal poisoning by the body's accumulation of traces of heavy metals, in particular mercury, lead, nickel, arsenic, and cadmium, is a possible risk from consuming fish oil supplements.[medical citation needed] Also, other contaminants (PCBs, furans, dioxins, and PBDEs) might be found, especially in less-refined fish oil supplements.[citation needed] However, heavy metal toxicity from consuming fish oil supplements is highly unlikely, because heavy metals selectively bind with protein in the fish flesh rather than accumulate in the oil. An independent test in 2005 of 44 fish oils on the US market found all of the products passed safety standards for potential contaminants.[110][unreliable source?]

Throughout their history, the Council for Responsible Nutrition and the World Health Organization have published acceptability standards regarding contaminants in fish oil. The most stringent current standard is the International Fish Oils Standard.[111][non-primary source needed] Fish oils that are molecularly distilled under vacuum typically make this highest-grade; levels of contaminants are stated in parts per billion per trillion.[citation needed]

Fish

The most widely available dietary source of EPA and DHA is oily fish, such as salmon, herring, mackerel, anchovies, menhaden, and sardines. Oils from these fish have a profile of around seven times as much omega-3 as omega-6. Other oily fish, such as tuna, also contain n-3 in somewhat lesser amounts. Consumers of oily fish should be aware of the potential presence of heavy metals and fat-soluble pollutants like PCBs and dioxins, which are known to accumulate up the food chain. After extensive review, researchers from Harvard's School of Public Health in the Journal of the American Medical Association (2006) reported that the benefits of fish intake generally far outweigh the potential risks. Although fish are a dietary source of omega-3 fatty acids, fish do not synthesize them; they obtain them from the algae (microalgae in particular) or plankton in their diets.[112]

Fish oil

Fish oil capsules

Marine and freshwater fish oil vary in content of arachidonic acid, EPA and DHA.[113] They also differ in their effects on organ lipids.[113] Not all forms of fish oil may be equally digestible. Of four studies that compare bioavailability of the glyceryl ester form of fish oil vs. the ethyl ester form, two have concluded the natural glyceryl ester form is better, and the other two studies did not find a significant difference. No studies have shown the ethyl ester form to be superior, although it is cheaper to manufacture.[114][115]

Krill

Krill oil is a source of omega-3 fatty acids.[116] The effect of krill oil, at a lower dose of EPA + DHA (62.8%), was demonstrated to be similar to that of fish oil on blood lipid levels and markers of inflammation in healthy humans.[117] While not an endangered species, krill are a mainstay of the diets of many ocean-based species including whales, causing environmental and scientific concerns about their sustainability.[118][119][120]

Plant sources

Chia is grown commercially for its seeds rich in ALA.
Flax seeds contain linseed oil which has high ALA content
Table 1. ALA content as the percentage of the seed oil.[121]

Common name Alternative name Linnaean name % ALA
Kiwifruit seed oil Chinese gooseberry Actinidia deliciosa 63[122]
Perilla shiso Perilla frutescens 61
Chia seed chia sage Salvia hispanica 58
Flax linseed Linum usitatissimum 53[87] – 59[123]
Lingonberry Cowberry Vaccinium vitis-idaea 49
Fig seed oil Common Fig Ficus carica 47.7[124]
Camelina Gold-of-pleasure Camelina sativa 36
Purslane Portulaca Portulaca oleracea 35
Black raspberry
Rubus occidentalis 33
Hemp
Cannabis sativa 19
Canola
mostly Brassica napus   9[87] – 11

Table 2. ALA content as the percentage of the whole food.[87][125]
 
Common name Linnaean name % ALA
Flaxseed Linum usitatissimum 18.1
Hempseed Cannabis sativa 8.7
Butternuts Juglans cinerea 8.7
Persian walnuts Juglans regia 6.3
Pecan nuts Carya illinoinensis 0.6
Hazel nuts Corylus avellana 0.1

Flaxseed (or linseed) (Linum usitatissimum) and its oil are perhaps the most widely available botanical source of the omega-3 fatty acid ALA. Flaxseed oil consists of approximately 55% ALA, which makes it six times richer than most fish oils in omega-3 fatty acids.[126] A portion of this is converted by the body to EPA and DHA, though the actual converted percentage may differ between men and women.[127]

In 2013 Rothamsted Research in the UK reported they had developed a genetically modified form of the plant Camelina that produced EPA and DHA. Oil from the seeds of this plant contained on average 11% EPA and 8% DHA in one development and 24% EPA in another.[128][129]

Eggs

Eggs produced by hens fed a diet of greens and insects contain higher levels of omega-3 fatty acids than those produced by chickens fed corn or soybeans.[130] In addition to feeding chickens insects and greens, fish oils may be added to their diets to increase the omega-3 fatty acid concentrations in eggs.[131]

The addition of flax and canola seeds to the diets of chickens, both good sources of alpha-linolenic acid, increases the omega-3 content of the eggs, predominantly DHA.[132]

The addition of green algae or seaweed to the diets boosts the content of DHA and EPA, which are the forms of omega-3 approved by the FDA for medical claims. A common consumer complaint is "Omega-3 eggs can sometimes have a fishy taste if the hens are fed marine oils".[133]

Meat

Omega-3 fatty acids are formed in the chloroplasts of green leaves and algae. While seaweeds and algae are the source of omega-3 fatty acids present in fish, grass is the source of omega-3 fatty acids present in grass fed animals.[134] When cattle are taken off omega-3 fatty acid rich grass and shipped to a feedlot to be fattened on omega-3 fatty acid deficient grain, they begin losing their store of this beneficial fat. Each day that an animal spends in the feedlot, the amount of omega-3 fatty acids in its meat is diminished.[135]

The omega-6:omega-3 ratio of grass-fed beef is about 2:1, making it a more useful source of omega-3 than grain-fed beef, which usually has a ratio of 4:1.[90]

In a 2009 joint study by the USDA and researchers at Clemson University in South Carolina, grass-fed beef was compared with grain-finished beef. The researchers found that grass-finished beef is higher in moisture content, 42.5% lower total lipid content, 54% lower in total fatty acids, 54% higher in beta-carotene, 288% higher in vitamin E (alpha-tocopherol), higher in the B-vitamins thiamin and riboflavin, higher in the minerals calcium, magnesium, and potassium, 193% higher in total omega-3s, 117% higher in CLA (cis-9 trans-11, which is a potential cancer fighter), 90% higher in vaccenic acid (which can be transformed into CLA), lower in the saturated fats linked with heart disease, and has a healthier ratio of omega-6 to omega-3 fatty acids (1.65 vs 4.84). Protein and cholesterol content were equal.[90]

In most countries, commercially available lamb is typically grass-fed, and thus higher in omega-3 than other grain-fed or grain-finished meat sources. In the United States, lamb is often finished (i.e., fattened before slaughter) with grain, resulting in lower omega-3.[136]

The omega-3 content of chicken meat may be enhanced by increasing the animals' dietary intake of grains high in omega-3, such as flax, chia, and canola.[137]

Kangaroo meat is also a source of omega-3, with fillet and steak containing 74 mg per 100 g of raw meat.[138]

Seal oil

Seal oil is a source of EPA, DPA, and DHA. According to Health Canada, it helps to support the development of the brain, eyes, and nerves in children up to 12 years of age.[139] Like all seal products, it is not allowed to be imported into the European Union.[140]

Other sources

A recent trend has been to fortify food with omega-3 fatty acid supplements. Global food companies have launched omega-3 fatty acid fortified bread, mayonnaise, pizza, yogurt, orange juice, children's pasta, milk, eggs, popcorn, confections, and infant formula.[citation needed]

The microalgae Crypthecodinium cohnii and Schizochytrium are rich sources of DHA but not EPA, and can be produced commercially in bioreactors. Oil from brown algae (kelp) is a source of EPA.[141] The alga Nannochloropsis also has high levels of EPA.[142]

In 2006 the Journal of Dairy Science published a study which found that butter made from the milk of grass-fed cows contains substantially more α-linolenic acid than butter made from the milk of cows that have limited access to pasture.[143]

Hypothyroidism

From Wikipedia, the free encyclopedia
Hypothyroidism
Synonyms hypothyreosis
Molecular structure of the thyroxine molecule
Molecular structure of thyroxine, the deficiency of which causes the symptoms of hypothyroidism
Pronunciation
Specialty Endocrinology
Symptoms Poor ability to tolerate cold, feeling tired, constipation, depression, weight gain[3]
Usual onset > 60 years old[3]
Causes Iodine deficiency, Hashimoto's thyroiditis[3]
Diagnostic method Blood tests (thyroid-stimulating hormone, thyroxine)[3]
Prevention Salt iodization[4]
Treatment Levothyroxine[3]
Frequency 0.3–0.4% (USA)[5]

Hypothyroidism, also called underactive thyroid or low thyroid, is a common disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone.[3] It can cause a number of symptoms, such as poor ability to tolerate cold, a feeling of tiredness, constipation, depression, and weight gain.[3] Occasionally there may be swelling of the front part of the neck due to goitre.[3] Untreated hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby, which is called cretinism.[6]

Worldwide, too little iodine in the diet is the most common cause of hypothyroidism.[5][7] In countries with enough iodine in the diet, the most common cause of hypothyroidism is the autoimmune condition Hashimoto's thyroiditis.[3] Less common causes include: previous treatment with radioactive iodine, injury to the hypothalamus or the anterior pituitary gland, certain medications, a lack of a functioning thyroid at birth, or previous thyroid surgery.[3][8] The diagnosis of hypothyroidism, when suspected, can be confirmed with blood tests measuring thyroid-stimulating hormone (TSH) and thyroxine levels.[3]

Prevention at the population level has been with the universal salt iodization.[4] Hypothyroidism can be treated with levothyroxine. The dose is adjusted according to symptoms and normalization of the thyroxine and TSH levels. Thyroid medication is safe in pregnancy. While a certain amount of dietary iodine is important, excessive amounts can worsen certain types of hypothyroidism.[3]

Worldwide about one billion people are estimated to be iodine deficient; however, it is unknown how often this results in hypothyroidism.[9] In the United States, hypothyroidism occurs in 0.3–0.4% of people.[5] Subclinical hypothyroidism, a milder form of hypothyroidism characterized by normal thyroxine levels and an elevated TSH level, is thought to occur in 4.3–8.5% of people in the United States.[5] Hypothyroidism is more common in women than men.[3] People over the age of 60 are more commonly affected.[3] Dogs are also known to develop hypothyroidism and in rare cases cats and horses can also have the disorder.[10] The word "hypothyroidism" is from Greek hypo- meaning "reduced", thyreos for "shield", and eidos for "form."[11]

Signs and symptoms

People with hypothyroidism often have no or only mild symptoms. Numerous symptoms and signs are associated with hypothyroidism, and can be related to the underlying cause, or a direct effect of having not enough thyroid hormones.[12][13] Hashimoto's thyroiditis may present with the mass effect of a goiter (enlarged thyroid gland).[12]
Symptoms and signs of hypothyroidism[12]
Symptoms[12] Signs[12]
Fatigue Dry, coarse skin
Feeling cold Cool extremities
Poor memory and concentration Myxedema (mucopolysaccharide deposits in the skin)
Constipation, dyspepsia[14] Hair loss
Weight gain with poor appetite Slow pulse rate
Shortness of breath Swelling of the limbs
Hoarse voice Delayed relaxation of tendon reflexes
In females, heavy menstrual periods (and later light periods) Carpal tunnel syndrome
Abnormal sensation Pleural effusion, ascites, pericardial effusion
Poor hearing

Delayed relaxation after testing the ankle jerk reflex is a characteristic sign of hypothyroidism and is associated with the severity of the hormone deficit.[5]

Myxedema coma

Man with myxedema or severe hypothyroidism showing an expressionless face, puffiness around the eyes and pallor
Additional symptoms include swelling of the arms and legs and ascites.
Myxedema coma is a rare but life-threatening state of extreme hypothyroidism. It may occur in those who are known to have hypothyroidism when they develop another illness, but it can be the first presentation of hypothyroidism. The illness is characterized by very low body temperature without shivering, confusion, a slow heart rate and reduced breathing effort. There may be physical signs suggestive of hypothyroidism, such as skin changes or enlargement of the tongue.[15]

Pregnancy

Even mild or subclinical hypothyroidism has been associated with impaired fertility and an increased risk of miscarriage.[16] Hypothyroidism in early pregnancy, even with limited or no symptoms, may increase the risk of pre-eclampsia, offspring with lower intelligence, and the risk of infant death around the time of birth.[16][17] Women are affected by hypothyroidism in 0.3–0.5% of pregnancies.[17] Subclinical hypothyroidism during pregnancy has also been associated with gestational diabetes and birth of the baby before 37 weeks of pregnancy.[18]

Children

Newborn children with hypothyroidism may have normal birth weight and height (although the head may be larger than expected and the posterior fontanelle may be open). Some may have drowsiness, decreased muscle tone, a hoarse-sounding cry, feeding difficulties, constipation, an enlarged tongue, umbilical hernia, dry skin, a decreased body temperature and jaundice.[19] A goiter is rare, although it may develop later in children who have a thyroid gland that does not produce functioning thyroid hormone.[19] A goiter may also develop in children growing up in areas with iodine deficiency.[20] Normal growth and development may be delayed, and not treating infants may lead to an intellectual impairment (IQ 6–15 points lower in severe cases). Other problems include the following: large scale and fine motor skills and coordination, reduced muscle tone, squinting, decreased attention span, and delayed speaking.[19] Tooth eruption may be delayed.[21]

In older children and adolescents, the symptoms of hypothyroidism may include fatigue, cold intolerance, sleepiness, muscle weakness, constipation, a delay in growth, overweight for height, pallor, coarse and thick skin, increased body hair, irregular menstrual cycles in girls, and delayed puberty. Signs may include delayed relaxation of the ankle reflex and a slow heart beat.[19] A goiter may be present with a completely enlarged thyroid gland;[19] sometimes only part of the thyroid is enlarged and it can be knobby in character.[22]

Causes

Hypothyroidism is caused by inadequate function of the gland itself (primary hypothyroidism), inadequate stimulation by thyroid-stimulating hormone from the pituitary gland (secondary hypothyroidism), or inadequate release of thyrotropin-releasing hormone from the brain's hypothalamus (tertiary hypothyroidism).[5][23] Primary hypothyroidism is about a thousandfold more common than central hypothyroidism.[8]

Iodine deficiency is the most common cause of primary hypothyroidism and endemic goiter worldwide.[5][7] In areas of the world with sufficient dietary iodine, hypothyroidism is most commonly caused by the autoimmune disease Hashimoto's thyroiditis (chronic autoimmune thyroiditis).[5][7] Hashimoto's may be associated with a goiter. It is characterized by infiltration of the thyroid gland with T lymphocytes and autoantibodies against specific thyroid antigens such as thyroid peroxidase, thyroglobulin and the TSH receptor.[5]

After women give birth, about 5% develop postpartum thyroiditis which can occur up to nine months afterwards.[24] This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.[24]

Autoimmune thyroiditis is associated with other immune-mediated diseases such as diabetes mellitus type 1, pernicious anemia, myasthenia gravis, celiac disease, rheumatoid arthritis and systemic lupus erythematosus.[5] It may occur as part of autoimmune polyendocrine syndrome (type 1 and type 2).[5]
Group Causes
Primary hypothyroidism[5] Iodine deficiency (developing countries), autoimmune thyroiditis, subacute granulomatous thyroiditis, subacute lymphocytic thyroiditis, postpartum thyroiditis, previous thyroidectomy, previous radioiodine treatment, previous external beam radiotherapy to the neck
Medication: lithium-based mood stabilizers, amiodarone, interferon alpha, tyrosine kinase inhibitors such as sunitinib
Central hypothyroidism[8] Lesions compressing the pituitary (pituitary adenoma, craniopharyngioma, meningioma, glioma, Rathke's cleft cyst, metastasis, empty sella, aneurysm of the internal carotid artery), surgery or radiation to the pituitary, drugs, injury, vascular disorders (pituitary apoplexy, Sheehan syndrome, subarachnoid hemorrhage), autoimmune diseases (lymphocytic hypophysitis, polyglandular disorders), infiltrative diseases (iron overload due to hemochromatosis or thalassemia, neurosarcoidosis, Langerhans cell histiocytosis), particular inherited congenital disorders, and infections (tuberculosis, mycoses, syphilis)
Congenital hypothyroidism[25] Thyroid dysgenesis (75%), thyroid dyshormonogenesis (20%), maternal antibody or radioiodine transfer
Syndromes: mutations (in GNAS complex locus, PAX8, TTF-1/NKX2-1, TTF-2/FOXE1), Pendred's syndrome (associated with sensorineural hearing loss)
Transiently: due to maternal iodine deficiency or excess, anti-TSH receptor antibodies, certain congenital disorders, neonatal illness
Central: pituitary dysfunction (idiopathic, septo-optic dysplasia, deficiency of PIT1, isolated TSH deficiency)

Pathophysiology

Diagram of a person with a large blue arrow representing the actions of thyroxine on the body and a green and red arrow representing actions of TSH and TRH respectively
Diagram of the hypothalamic–pituitary–thyroid axis. The hypothalamus secretes TRH (green), which stimulates the production of TSH (red) by the pituitary gland. This, in turn, stimulates the production of thyroxine by the thyroid (blue). Thyroxine levels decrease TRH and TSH production by a negative feedback process.

Thyroid hormone is required for the normal functioning of numerous tissues in the body. In health, the thyroid gland predominantly secretes thyroxine (T4), which is converted into triiodothyronine (T3) in other organs by the selenium-dependent enzyme iodothyronine deiodinase.[26] Triiodothyronine binds to the thyroid hormone receptor in the nucleus of cells, where it stimulates the turning on of particular genes and the production of specific proteins.[27] Additionally, the hormone binds to integrin αvβ3 on the cell membrane, thereby stimulating the sodium–hydrogen antiporter and processes such as formation of blood vessels and cell growth.[27] In blood, almost all thyroid hormone (99.97%) is bound to plasma proteins such as thyroxine-binding globulin; only the free unbound thyroid hormone is biologically active.[5]

The thyroid gland is the only source of thyroid hormone in the body; the process requires iodine and the amino acid tyrosine. Iodine in the bloodstream is taken up by the gland and incorporated into thyroglobulin molecules. The process is controlled by the thyroid-stimulating hormone (TSH, thyrotropin), which is secreted by the pituitary. Not enough iodine, or not enough TSH, can result in decreased production of thyroid hormones.[23]

The hypothalamic–pituitary–thyroid axis plays a key role in maintaining thyroid hormone levels within normal limits. Production of TSH by the anterior pituitary gland is stimulated in turn by thyrotropin-releasing hormone (TRH), released from the hypothalamus. Production of TSH and TRH is decreased by thyroxine by a negative feedback process. Not enough TRH, which is uncommon, can lead to not enough TSH and thereby to not enough thyroid hormone production.[8]

Pregnancy leads to marked changes in thyroid hormone physiology. The gland is increased in size by 10%, thyroxine production is increased by 50%, and iodine requirements are increased. Many women have normal thyroid function but have immunological evidence of thyroid autoimmunity (as evidenced by autoantibodies) or are iodine deficient, and develop evidence of hypothyroidism before or after giving birth.[28]

Diagnosis

Laboratory testing of thyroid stimulating hormone levels in the blood is considered the best initial test for hypothyroidism; a second TSH level is often obtained several weeks later for confirmation.[29] Levels may be abnormal in the context of other illnesses, and TSH testing in hospitalized people is discouraged unless thyroid dysfunction is strongly suspected.[5] An elevated TSH level indicates that the thyroid gland is not producing enough thyroid hormone, and free T4 levels are then often obtained.[5][22] Measuring T3 is discouraged by the AACE in the assessment for hypothyroidism.[5] There are a number of symptom rating scales for hypothyroidism; they provide a degree of objectivity but have limited use for diagnosis.[5]
TSH T4 Interpretation
Normal Normal Normal thyroid function
Elevated Low Overt hypothyroidism
Normal/low Low Central hypothyroidism
Elevated Normal Subclinical hypothyroidism

Many cases of hypothyroidism are associated with mild elevations in creatine kinase and liver enzymes in the blood. They typically return to normal when hypothyroidism has been fully treated.[5] Levels of cholesterol, low-density lipoprotein and lipoprotein (a) can be elevated;[5] the impact of subclinical hypothyroidism on lipid parameters is less well-defined.[20]

Very severe hypothyroidism and myxedema coma are characteristically associated with low sodium levels in the blood together with elevations in antidiuretic hormone, as well as acute worsening of kidney function due to a number of causes.[15]

A diagnosis of hypothyroidism without any lumps or masses felt within the thyroid gland does not require thyroid imaging; however, if the thyroid feels abnormal, diagnostic imaging is then recommended.[29] The presence of antibodies against thyroid peroxidase (TPO) makes it more likely that thyroid nodules are caused by autoimmune thyroiditis, but if there is any doubt, a needle biopsy may be required.[5]

If the TSH level is normal or low and serum free T4 levels are low, this is suggestive of central hypothyroidism (not enough TSH or TRH secretion by the pituitary gland or hypothalamus). There may be other features of hypopituitarism, such as menstrual cycle abnormalities and adrenal insufficiency. There might also be evidence of a pituitary mass such as headaches and vision changes. Central hypothyroidism should be investigated further to determine the underlying cause.[8][29]

Overt

In overt primary hypothyroidism, TSH levels are high and T4 and T3 levels are low. Overt hypothyroidism may also be diagnosed in those who have a TSH on multiple occasions of greater than 5mIU/L, appropriate symptoms, and only a borderline low T4.[30] It may also be diagnosed in those with a TSH of greater than 10mIU/L.[30]

Subclinical

Subclinical hypothyroidism is a milder form of hypothyroidism characterized by an elevated serum TSH level, but with a normal serum free thyroxine level.[31][32] This milder form of hypothyroidism is most commonly caused by Hashimoto's thyroiditis.[33] In adults it is diagnosed when TSH levels are greater than 5 mIU/L and less than 10mIU/L.[30] The presentation of subclinical hypothyroidism is variable and classic signs and symptoms of hypothyroidism may not be observed.[31] Of people with subclinical hypothyroidism, a proportion will develop overt hypothyroidism each year. In those with detectable antibodies against thyroid peroxidase (TPO), this occurs in 4.3%, while in those with no detectable antibodies, this occurs in 2.6%.[5] Those with subclinical hypothyroidism and detectable anti-TPO antibodies who do not require treatment should have repeat thyroid function tests more frequently (e.g. yearly) compared with those who do not have antibodies.[29]

Pregnancy

During pregnancy, the thyroid gland must produce 50% more thyroid hormone to provide enough thyroid hormone for the developing fetus and the expectant mother.[18] In pregnancy, free thyroxine levels may be lower than anticipated due to increased binding to thyroid binding globulin and decreased binding to albumin. They should either be corrected for the stage of pregnancy,[28] or total thyroxine levels should be used instead for diagnosis.[5] TSH values may also be lower than normal (particularly in the first trimester) and the normal range should be adjusted for the stage of pregnancy.[5][28]

In pregnancy, subclinical hypothyroidism is defined as a TSH between 2.5 and 10 mIU/l with a normal thyroxine level, while those with TSH above 10 mIU/l are considered to be overtly hypothyroid even if the thyroxine level is normal.[28] Antibodies against TPO may be important in making decisions about treatment, and should, therefore, be determined in women with abnormal thyroid function tests.[5]

Determination of TPO antibodies may be considered as part of the assessment of recurrent miscarriage, as subtle thyroid dysfunction can be associated with pregnancy loss,[5] but this recommendation is not universal,[34] and presence of thyroid antibodies may not predict future outcome.[35]

Prevention

A 3-month-old infant with untreated congenital hypothyroidism showing myxedematous facies, a big tongue, and skin mottling

Hypothyroidism may be prevented in a population by adding iodine to commonly used foods. This public health measure has eliminated endemic childhood hypothyroidism in countries where it was once common. In addition to promoting the consumption of iodine-rich foods such as dairy and fish, many countries with moderate iodine deficiency have implemented universal salt iodization (USI).[36] Encouraged by the World Health Organization,[37] 130 countries now have USI, and 70% of the world's population are receiving iodized salt. In some countries, iodized salt is added to bread.[36] Despite this, iodine deficiency has reappeared in some Western countries as a result of attempts to reduce salt intake.[36]

Pregnant and breastfeeding women, who require 66% more daily iodine requirement than non-pregnant women, may still not be getting enough iodine.[36][38] The World Health Organization recommends a daily intake of 250 µg for pregnant and breastfeeding women.[39] As many women will not achieve this from dietary sources alone, the American Thyroid Association recommends a 150 µg daily supplement by mouth.[28][40]

Screening

Screening for hypothyroidism is performed in the newborn period in many countries, generally using TSH. This has led to the early identification of many cases and thus the prevention of developmental delay.[41] It is the most widely used newborn screening test worldwide.[42] While TSH-based screening will identify the most common causes, the addition of T4 testing is required to pick up the rarer central causes of neonatal hypothyroidism.[19] If T4 determination is included in the screening done at birth, this will identify cases of congenital hypothyroidism of central origin in 1:16,000 to 1:160,000 children. Considering that these children usually have other pituitary hormone deficiencies, early identification of these cases may prevent complications.[8]

In adults, widespread screening of the general population is a matter of debate. Some organizations (such as the United States Preventive Services Task Force) state that evidence is insufficient to support routine screening,[43] while others (such as the American Thyroid Association) recommend either intermittent testing above a certain age in both sexes or only in women.[5] Targeted screening may be appropriate in a number of situations where hypothyroidism is common: other autoimmune diseases, a strong family history of thyroid disease, those who have received radioiodine or other radiation therapy to the neck, those who have previously undergone thyroid surgery, those with an abnormal thyroid examination, those with psychiatric disorders, people taking amiodarone or lithium, and those with a number of health conditions (such as certain heart and skin conditions).[5] Yearly thyroid function tests are recommended in people with Down syndrome, as they are at higher risk of thyroid disease.[44]

Management

Hormone replacement

Most people with hypothyroidism symptoms and confirmed thyroxine deficiency are treated with a synthetic long-acting form of thyroxine, known as levothyroxine (L-thyroxine).[5][13] In young and otherwise healthy people with overt hypothyroidism, a full replacement dose (adjusted by weight) can be started immediately; in the elderly and people with heart disease a lower starting dose is recommended to prevent over supplementation and risk of complications.[5][23] Lower doses may be sufficient in those with subclinical hypothyroidism, while people with central hypothyroidism may require a higher than average dose.[5]

Blood free thyroxine and TSH levels are monitored to help determine whether the dose is adequate. This is done 4–8 weeks after the start of treatment or a change in levothyroxine dose. Once the adequate replacement dose has been established, the tests can be repeated after 6 and then 12 months, unless there is a change in symptoms.[5] In people with central/secondary hypothyroidism, TSH is not a reliable marker of hormone replacement and decisions are based mainly on the free T4 level.[5][8] Levothyroxine is best taken 30–60 minutes before breakfast, or four hours after food,[5] as certain substances such as food and calcium can inhibit the absorption of levothyroxine.[45] There is no direct way of increasing thyroid hormone secretion by the thyroid gland.[13]

Liothyronine

Adding liothyronine (synthetic T3) to levothyroxine has been suggested as a measure to provide better symptom control, but this has not been confirmed by studies.[7][13][46] In 2007, the British Thyroid Association stated that combined T4 and T3 therapy carried a higher rate of side effects and no benefit over T4 alone.[13][47] Similarly, American guidelines discourage combination therapy due to a lack of evidence, although they acknowledge that some people feel better when receiving combination treatment.[5] Treatment with liothyronine alone has not received enough study to make a recommendation as to its use; due to its shorter half-life it needs to be taken more often.[5]

People with hypothyroidism who do not feel well despite optimal levothyroxine dosing may request adjunctive treatment with liothyronine. A 2012 guideline from the European Thyroid Association recommends that support should be offered with regards to the chronic nature of the disease and that other causes of the symptoms should be excluded. Addition of liothyronine should be regarded as experimental, initially only for a trial period of 3 months, and in a set ratio to the current dose of levothyroxine.[48] The guideline explicitly aims to enhance the safety of this approach and to counter its indiscriminate use.[48]

Desiccated animal thyroid

Desiccated thyroid extract is an animal-based thyroid gland extract,[13] most commonly from pigs. It is a combination therapy, containing forms of T4 and T3.[13] It also contains calcitonin (a hormone produced in the thyroid gland involved in the regulation of calcium levels), T1 and T2; these are not present in synthetic hormone medication.[49] This extract was once a mainstream hypothyroidism treatment, but its use today is unsupported by evidence;[7][13] British Thyroid Association and American professional guidelines discourage its use.[5][47]

Subclinical hypothyroidism

There is little evidence whether there is a benefit from treating subclinical hypothyroidism, and whether this offsets the risks of overtreatment. Untreated subclinical hypothyroidism may be associated with a modest increase in the risk of coronary artery disease.[50] A 2007 review found no benefit of thyroid hormone replacement except for "some parameters of lipid profiles and left ventricular function".[51] There is no association between subclinical hypothyroidism and an increased risk of bone fractures,[52] nor is there a link with cognitive decline.[53]

Since 2008, consensus American and British opinion has been that in general people with TSH under 10 mIU/l do not require treatment.[5][32][54] American guidelines recommend that treatment should be considered if the TSH is elevated but below 10 mIU/l in people with symptoms of hypothyroidism, detectable antibodies against thyroid peroxidase, a history of heart disease or are at an increased risk for heart disease.[5]

Myxedema coma

Myxedema coma or severe decompensated hypothyroidism usually requires admission to the intensive care, close observation and treatment of abnormalities in breathing, temperature control, blood pressure, and sodium levels. Mechanical ventilation may be required, as well as fluid replacement, vasopressor agents, careful rewarming, and corticosteroids (for possible adrenal insufficiency which can occur together with hypothyroidism). Careful correction of low sodium levels may be achieved with hypertonic saline solutions or vasopressin receptor antagonists.[15] For rapid treatment of the hypothyroidism, levothyroxine or liothyronine may be administered intravenously, particularly if the level of consciousness is too low to be able to safely swallow medication.[15]

Pregnancy

In women with known hypothyroidism who become pregnant, it is recommended that serum TSH levels are closely monitored. Levothyroxine should be used to keep TSH levels within the normal range for that trimester. The first trimester normal range is below 2.5 mIU/L and the second and third trimesters normal range is below 3.0 mIU/L.[13][28] Treatment should be guided by total (rather than free) thyroxine or by the free T4 index. Similarly to TSH, the thyroxine results should be interpreted according to the appropriate reference range for that stage of pregnancy.[5] The levothyroxine dose often needs to be increased after pregnancy is confirmed,[5][23][28] although this is based on limited evidence and some recommend that it is not always required; decisions may need to based on TSH levels.[55]

Women with anti-TPO antibodies who are trying to become pregnant (naturally or by assisted means) may require thyroid hormone supplementation even if the TSH level is normal. This is particularly true if they have had previous miscarriages or have been hypothyroid in the past.[5] Supplementary levothyroxine may reduce the risk of preterm birth and possibly miscarriage.[56] The recommendation is stronger in pregnant women with subclinical hypothyroidism (defined as TSH 2.5–10 mIU/l) who are anti-TPO positive, in view of the risk of overt hypothyroidism. If a decision is made not to treat, close monitoring of the thyroid function (every 4 weeks in the first 20 weeks of pregnancy) is recommended.[5][28] If anti-TPO is not positive, treatment for subclinical hypothyroidism is not currently recommended.[28] It has been suggested that many of the aforementioned recommendations could lead to unnecessary treatment, in the sense that the TSH cutoff levels may be too restrictive in some ethnic groups; there may be little benefit from treatment of subclinical hypothyroidism in certain cases.[55]

Epidemiology

Worldwide about one billion people are estimated to be iodine deficient; however, it is unknown how often this results in hypothyroidism.[9] In large population-based studies in Western countries with sufficient dietary iodine, 0.3–0.4% of the population have overt hypothyroidism. A larger proportion, 4.3–8.5%, have subclinical hypothyroidism.[5] Of people with subclinical hypothyroidism, 80% have a TSH level below the 10 mIU/l mark regarded as the threshold for treatment.[32] Children with subclinical hypothyroidism often return to normal thyroid function, and a small proportion develops overt hypothyroidism (as predicted by evolving antibody and TSH levels, the presence of celiac disease, and the presence of a goiter).[57]

Women are more likely to develop hypothyroidism than men. In population-based studies, women were seven times more likely than men to have TSH levels above 10 mU/l.[5] 2–4% of people with subclinical hypothyroidism will progress to overt hypothyroidism each year. The risk is higher in those with antibodies against thyroid peroxidase.[5][32] Subclinical hypothyroidism is estimated to affect approximately 2% of children; in adults, subclinical hypothyroidism is more common in the elderly, and in Caucasians.[31] There is a much higher rate of thyroid disorders, the most common of which is hypothyroidism, in individuals with Down syndrome[19][44] and Turner syndrome.[19]

Very severe hypothyroidism and myxedema coma are rare, with it estimated to occur in 0.22 per million people a year.[15] The majority of cases occur in women over 60 years of age, although it may happen in all age groups.[15]

Most hypothyroidism is primary in nature. Central/secondary hypothyroidism affects 1:20,000 to 1:80,000 of the population, or about one out of every thousand people with hypothyroidism.[8]

History

In 1811, Bernard Courtois discovered iodine was present in seaweed, and iodine intake was linked with goiter size in 1820 by Jean-Francois Coindet.[58] Gaspard Adolphe Chatin proposed in 1852 that endemic goiter was the result of not enough iodine intake, and Eugen Baumann demonstrated iodine in thyroid tissue in 1896.[58]

The first cases of myxedema were recognized in the mid-19th century (the 1870s), but its connection to the thyroid was not discovered until the 1880s when myxedema was observed in people following the removal of the thyroid gland (thyroidectomy).[59] The link was further confirmed in the late 19th century when people and animals who had had their thyroid removed showed improvement in symptoms with transplantation of animal thyroid tissue.[7] The severity of myxedema, and its associated risk of mortality and complications, created interest in discovering effective treatments for hypothyroidism.[59] Transplantation of thyroid tissue demonstrated some efficacy, but recurrences of hypothyroidism was relatively common, and sometimes required multiple repeat transplantations of thyroid tissue.[59]

In 1891, the English physician George Redmayne Murray introduced subcutaneously injected sheep thyroid extract,[60] followed shortly after by an oral formulation.[7][61] Purified thyroxine was introduced in 1914 and in the 1930s synthetic thyroxine became available, although desiccated animal thyroid extract remained widely used. Liothyronine was identified in 1952.[7]

Early attempts at titrating therapy for hypothyroidism proved difficult. After hypothyroidism was found to cause a lower basal metabolic rate, this was used as a marker to guide adjustments in therapy in the early 20th century (around 1915).[59] However, a low basal metabolic rate was known to be non-specific, also present in malnutrition.[59] The first laboratory test to be helpful in assessing thyroid status was the serum protein-bound iodine, which came into use around the 1950s.

In 1971, the thyroid stimulating hormone (TSH) radioimmunoassay was developed, which was the most specific marker for assessing thyroid status in patients.[59] Many people who were being treated based on basal metabolic rate, minimizing hypothyroid symptoms, or based on serum protein-bound iodine, were found to have excessive thyroid hormone.[59] The following year, in 1972, a T3 radioimmunoassay was developed, and in 1974, a T4 radioimmunoassay was developed.[59]

Other animals

Photograph of a Labrador Retriever dog with sagging facial skin characteristic of hypothyroidism
Characteristic changes in the facial skin of a Labrador Retriever with hypothyroidism

In veterinary practice, dogs are the species most commonly affected by hypothyroidism. The majority of cases occur as a result of primary hypothyroidism, of which two types are recognized: lymphocytic thyroiditis, which is probably immune-driven and leads to destruction and fibrosis of the thyroid gland, and idiopathic atrophy, which leads to the gradual replacement of the gland by fatty tissue.[10][62] There is often lethargy, cold intolerance, exercise intolerance, and weight gain. Furthermore, skin changes and fertility problems are seen in dogs with hypothyroidism, as well as a number of other symptoms.[62] The signs of myxedema can be seen in dogs, with prominence of skin folds on the forehead, and cases of myxedema coma are encountered.[10] The diagnosis can be confirmed by blood test, as the clinical impression alone may lead to overdiagnosis.[10][62] Lymphocytic thyroiditis is associated with detectable antibodies against thyroglobulin, although they typically become undetectable in advanced disease.[62] Treatment is with thyroid hormone replacement.[10]

Other species that are less commonly affected include cats and horses, as well as other large domestic animals. In cats, hypothyroidism is usually the result of other medical treatment such as surgery or radiation. In young horses, congenital hypothyroidism has been reported predominantly in Western Canada and has been linked with the mother's diet.[10]

Gene

From Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Gene Chromosome ...