Editing Cholesterol (section)

===Hypercholesterolemia===
{{Main|Hypercholesterolemia|Lipid hypothesis}}
[[File:ColesterolemiaMortalitaE.png|thumb|Cholesterolemia and mortality for men and women <50 years and >60 years]]
According to the [[lipid hypothesis]], elevated levels of cholesterol in the blood lead to [[atherosclerosis]] which may increase the risk of [[myocardial infarction|heart attack]], [[stroke]], and [[peripheral artery disease]]. Since higher blood LDL – especially higher LDL concentrations and smaller LDL particle size – contributes to this process more than the cholesterol content of the HDL particles,<ref name="Brunzell_2008">{{cite journal | vauthors = Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum JL | title = Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation | journal = Diabetes Care | volume = 31 | issue = 4 | pages = 811–822 | date = April 2008 | pmid = 18375431 | doi = 10.2337/dc08-9018 | doi-access = free }}</ref> LDL particles are often termed "bad cholesterol". High concentrations of functional HDL, which can remove cholesterol from cells and atheromas, offer protection and are commonly referred to as "good cholesterol". These balances are mostly genetically determined, but can be changed by body composition, [[medication]]s, diet,<ref>{{cite web | url = https://www.heartuk.org.uk/healthy-diets/healthy-diets | archive-url = https://web.archive.org/web/20201029150758/https://www.heartuk.org.uk/healthy-diets/healthy-diets | archive-date = 29 October 2020 | work = Department of Health (UK), NHS Choices | title = More evidence for Mediterranean diet | date = 8 March 2011 | access-date = 11 November 2015 }}</ref> and other factors.<ref name="Durrington_2007">{{cite journal | vauthors = Durrington P | title = Dyslipidaemia | journal = Lancet | volume = 362 | issue = 9385 | pages = 717–731 | date = August 2003 | pmid = 12957096 | doi = 10.1016/S0140-6736(03)14234-1 | s2cid = 208792416 }}</ref> A 2007 study demonstrated that blood total cholesterol levels have an exponential effect on cardiovascular and total mortality, with the association more pronounced in younger subjects. Because cardiovascular disease is relatively rare in the younger population, the impact of high cholesterol on health is larger in older people.<ref name="Lewington_2007">{{cite journal | vauthors = Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, Qizilbash N, Peto R, Collins R | title = Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths | journal = Lancet | volume = 370 | issue = 9602 | pages = 1829–1839 | date = December 2007 | pmid = 18061058 | doi = 10.1016/S0140-6736(07)61778-4 | s2cid = 54293528 }}</ref>

Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis.<ref name=NCEPIII>{{cite web | title = Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report | publisher = National Institutes of Health. National Heart, Lung and Blood Institute | url = https://www.nhlbi.nih.gov/files/docs/resources/heart/atp-3-cholesterol-full-report.pdf|date=1 September 2002 | access-date = 2008-10-27}}</ref> Conversely, the total cholesterol can be within normal limits, yet be made up primarily of small LDL and small HDL particles, under which conditions atheroma growth rates are high. A ''post hoc'' analysis of the IDEAL and the EPIC prospective studies found an association between high levels of HDL cholesterol (adjusted for apolipoprotein A-I and apolipoprotein B) and increased risk of cardiovascular disease, casting doubt on the cardioprotective role of "good cholesterol".<ref name="van_der_Steeg_2008">{{cite journal | vauthors = van der Steeg WA, Holme I, Boekholdt SM, Larsen ML, Lindahl C, Stroes ES, Tikkanen MJ, Wareham NJ, Faergeman O, Olsson AG, Pedersen TR, Khaw KT, Kastelein JJ | title = High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies | journal = Journal of the American College of Cardiology | volume = 51 | issue = 6 | pages = 634–642 | date = February 2008 | pmid = 18261682 | doi = 10.1016/j.jacc.2007.09.060 | doi-access =}}</ref><ref name="Robinson_2012">{{cite journal | vauthors = Robinson JG, Wang S, Jacobson TA | title = Meta-analysis of comparison of effectiveness of lowering apolipoprotein B versus low-density lipoprotein cholesterol and nonhigh-density lipoprotein cholesterol for cardiovascular risk reduction in randomized trials | journal = The American Journal of Cardiology | volume = 110 | issue = 10 | pages = 1468–1476 | date = November 2012 | pmid = 22906895 | doi = 10.1016/j.amjcard.2012.07.007 }}</ref>

About one in 250 individuals can have a genetic mutation for the LDL cholesterol receptor that causes them to have familial hypercholesterolemia.<ref name="pmid28864697">{{cite journal | vauthors = Akioyamen LE, Genest J, Shan SD, Reel RL, Albaum JM, Chu A, Tu JV | title = Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis | journal = BMJ Open | volume = 7 | issue = 9 | page = e016461 | date = September 2017 | pmid = 28864697 | pmc = 5588988 | doi = 10.1136/bmjopen-2017-016461 }}</ref> Inherited high cholesterol can also include genetic mutations in the PCSK9 gene and the gene for apolipoprotein B.<ref>{{Cite web|url=https://www.heart.org/en/health-topics/cholesterol/causes-of-high-cholesterol/familial-hypercholesterolemia-fh|title=Familial Hypercholesterolemia (FH)|website=www.heart.org|language=en|access-date=2019-08-02}}</ref>

Elevated cholesterol levels are treatable by a diet that reduces or eliminates saturated fat, and trans fats,<ref name="aha-prev">{{cite web |url=https://www.heart.org/en/health-topics/cholesterol/prevention-and-treatment-of-high-cholesterol-hyperlipidemia |title=Prevention and Treatment of High Cholesterol (Hyperlipidemia) |publisher=American Heart Association |access-date=23 August 2023 |date=2023}}</ref><ref name="mayo food" /> often followed by one of various [[Lipid-lowering agent|hypolipidemic agents]], such as [[statin]]s, [[fibrate]]s, cholesterol absorption inhibitors, [[monoclonal antibody therapy]] ([[PCSK9]] inhibitors), nicotinic acid derivatives or bile acid sequestrants.<ref name=NICE67>{{NICE|67|Lipid modification|2008}}</ref> There are several international guidelines on the treatment of hypercholesterolemia.<ref name="Mannu_2012">{{cite journal | vauthors = Mannu GS, Zaman MJ, Gupta A, Rehman HU, Myint PK | title = Update on guidelines for management of hypercholesterolemia | journal = Expert Review of Cardiovascular Therapy | volume = 10 | issue = 10 | pages = 1239–1249 | date = October 2012 | pmid = 23190064 | doi = 10.1586/erc.12.94 | s2cid = 5451203}}</ref>

Human trials using [[HMG-CoA reductase]] inhibitors, known as [[statin]]s, have repeatedly confirmed that changing lipoprotein transport patterns from unhealthy to healthier patterns significantly lowers cardiovascular disease event rates, even for people with cholesterol values currently considered low for adults.<ref>{{cite journal | vauthors = Kizer JR, Madias C, Wilner B, Vaughan CJ, Mushlin AI, Trushin P, Gotto AM, Pasternak RC | title = Relation of different measures of low-density lipoprotein cholesterol to risk of coronary artery disease and death in a meta-regression analysis of large-scale trials of statin therapy | journal = The American Journal of Cardiology | volume = 105 | issue = 9 | pages = 1289–1296 | date = May 2010 | pmid = 20403481 | pmc = 2917836 | doi = 10.1016/j.amjcard.2009.12.051 }}</ref> Studies have shown that reducing LDL cholesterol levels by about 38.7&nbsp;mg/dL with the use of statins can reduce cardiovascular disease and stroke risk by about 21%.<ref>{{cite journal | vauthors = Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC, Sperling L, Virani SS, Yeboah J | title = 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines | journal = Circulation | volume = 139 | issue = 25 | pages = e1082–e1143 | date = June 2019 | pmid = 30586774 | pmc = 7403606 | doi = 10.1161/CIR.0000000000000625 }}</ref> Studies have also found that statins reduce atheroma progression.<ref name="Nicholls_2008">{{cite journal | vauthors = Nicholls SJ | title = Rosuvastatin and progression of atherosclerosis | journal = Expert Review of Cardiovascular Therapy | volume = 6 | issue = 7 | pages = 925–933 | date = August 2008 | pmid = 18666843 | doi = 10.1586/14779072.6.7.925 | s2cid = 46419583 }}</ref> As a result, people with a history of cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels (total cholesterol below 5.0&nbsp;mmol/L [193&nbsp;mg/dL]),<ref name="pmid12114036">{{cite journal | title = MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial | journal = Lancet | volume = 360 | issue = 9326 | pages = 7–22 | date = July 2002 | pmid = 12114036 | doi = 10.1016/S0140-6736(02)09327-3 | s2cid = 35836642 | author1 = Heart Protection Study Collaborative Group }}</ref> and in men without cardiovascular disease, there is benefit from lowering abnormally high cholesterol levels ("primary prevention").<ref name="Shepherd_1995">{{cite journal | vauthors = Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ | title = Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group | journal = The New England Journal of Medicine | volume = 333 | issue = 20 | pages = 1301–1307 | date = November 1995 | pmid = 7566020 | doi = 10.1056/NEJM199511163332001 | doi-access = free }}</ref> Primary prevention in women was originally practiced only by extension of the findings in studies on men,<ref name="Grundy_2007">{{cite journal | vauthors = Grundy SM | title = Should women be offered cholesterol lowering drugs to prevent cardiovascular disease? Yes | journal = BMJ | volume = 334 | issue = 7601 | page = 982 | date = May 2007 | pmid = 17494017 | pmc = 1867899 | doi = 10.1136/bmj.39202.399942.AD }}</ref> since, in women, none of the large statin trials conducted prior to 2007 demonstrated a significant reduction in overall mortality or in cardiovascular endpoints.<ref name="Kendrick_2007">{{cite journal | vauthors = Kendrick M | title = Should women be offered cholesterol lowering drugs to prevent cardiovascular disease? No | journal = BMJ | volume = 334 | issue = 7601 | page = 983 | date = May 2007 | pmid = 17494018 | pmc = 1867901 | doi = 10.1136/bmj.39202.397488.AD }}</ref> Meta-analyses have demonstrated significant reductions in all-cause and cardiovascular mortality, without significant heterogeneity by sex.<ref>{{cite journal | vauthors = Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, de Craen AJ, Knopp RH, Nakamura H, Ridker P, van Domburg R, Deckers JW | title = The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials | journal = BMJ | volume = 338 | page = b2376 | date = June 2009 | pmid = 19567909 | pmc = 2714690 | doi = 10.1136/bmj.b2376 }}</ref>

{| class="wikitable" style="float:right"
|+Risk for heart disease
|-
! bgcolor ="#cccccc" colspan=2| Level
! bgcolor ="#cccccc" rowspan=2| Interpretation
|-
! bgcolor ="#cccccc"| [[Milligram|mg]]/[[Decilitre|dL]]
! bgcolor ="#cccccc"| [[Mole (unit)|mmol]]/[[Litre|L]]
|-
| < 200
| < 5.2
| Desirable level<br />(lower risk)
|-
| 200–240
| 5.2–6.2
| Borderline high risk
|-
| > 240
| > 6.2
| High risk
|}

The 1987 report of [[National Cholesterol Education Program]], Adult Treatment Panels suggests the total blood cholesterol level should be: < 200&nbsp;mg/dL normal blood cholesterol, 200–239&nbsp;mg/dL borderline-high, > 240&nbsp;mg/dL high cholesterol.<ref name="pmid3422148">{{cite journal | title = Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. The Expert Panel | journal = Archives of Internal Medicine | volume = 148 | issue = 1 | pages = 36–69 | date = January 1988 | pmid = 3422148 | doi = 10.1001/archinte.148.1.36 }}</ref> The [[American Heart Association]] provides a similar set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease:<ref name=aha-prev/> Statins are effective in lowering LDL cholesterol and widely used for [[primary prevention]] in people at high risk of cardiovascular disease, as well as in [[secondary prevention]] for those who have developed cardiovascular disease.<ref name="AlenghatDavis2019">{{cite journal | vauthors = Alenghat FJ, Davis AM | title = Management of Blood Cholesterol | journal = JAMA | volume = 321 | issue = 8 | pages = 800–801 | date = February 2019 | pmid = 30715135 | pmc = 6679800 | doi = 10.1001/jama.2019.0015 }}</ref> The average global mean total Cholesterol for humans has remained at about 4.6&nbsp;mmol/L (178&nbsp;mg/dL) for men and women, both crude and age standardized, for nearly 40 years from 1980 to 2018, with some regional variations and reduction of total Cholesterol in Western nations.<ref>{{cite web |title=Mean total cholesterol trends Global estimates |url=https://apps.who.int/gho/data/view.main.MEANTOTALCHOLESTEROLGLOBALv|website=World Health Organization |access-date=27 April 2024}}</ref>

More current testing methods determine LDL ("bad") and HDL ("good") cholesterol separately, allowing cholesterol analysis to be more nuanced. The desirable LDL level is considered to be less than 100&nbsp;mg/dL (2.6 [[Mole (unit)|mmol]]/L).<ref name=AHA>{{cite web|title= How To Get Your Cholesterol Tested|url=https://www.heart.org/en/health-topics/cholesterol/how-to-get-your-cholesterol-tested |publisher=American Heart Association|date=2023|access-date=23 August 2023 }}</ref><ref name=CDC>{{cite web|url=https://www.cdc.gov/cholesterol/cholesterol_screening.htm |title=About cholesterol |date=20 March 2023 |publisher=US Centers for Disease Control and Prevention|access-date=23 August 2023 }}</ref>

[[File:Blood values sorted by mass and molar concentration.png|thumb|center|600px|[[Reference ranges for blood tests]], showing usual, as well as optimal, levels of HDL, LDL, and total cholesterol in mass and molar concentrations, is found in orange color at right, that is, among the blood constituents with the highest concentration.]]

Total cholesterol is defined as the sum of HDL, LDL, and VLDL. Usually, only the total, HDL, and triglycerides are measured. For cost reasons, the VLDL is usually estimated as one-fifth of the triglycerides and the LDL is estimated using the Friedewald formula (or a [[Low-density lipoprotein#Estimation of LDL particles via cholesterol content|variant]]): estimated LDL = [total cholesterol] − [total HDL] − [estimated VLDL]. Direct LDL measures are used when triglycerides exceed 400&nbsp;mg/dL. The estimated VLDL and LDL have more error when triglycerides are above 400&nbsp;mg/dL.<ref name="Warnick_1990">{{cite journal | vauthors = Warnick GR, Knopp RH, Fitzpatrick V, Branson L | title = Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints | journal = Clinical Chemistry | volume = 36 | issue = 1 | pages = 15–19 | date = January 1990 | pmid = 2297909 | doi = 10.1093/clinchem/36.1.15 | doi-access = free }}</ref>

In the [[Framingham Heart Study]], each 10&nbsp;mg/dL (0.6 [[Mole (unit)|mmol]]/L) increase in total cholesterol levels increased 30-year overall mortality by 5% and CVD mortality by 9%. While subjects over the age of 50 had an 11% increase in overall mortality, and a 14% increase in cardiovascular disease mortality per 1&nbsp;mg/dL (0.06 [[Mole (unit)|mmol]]/L) year drop in total cholesterol levels. The researchers attributed this phenomenon to [[Correlation does not imply causation|a different correlation]], whereby the disease itself increases risk of death, as well as changes a myriad of factors, such as weight loss and the inability to eat, which lower serum cholesterol.<ref name="Anderson_1987">{{cite journal | vauthors = Anderson KM, Castelli WP, Levy D | url=https://jamanetwork.com/journals/jama/article-abstract/365739 | title = Cholesterol and mortality. 30 years of follow-up from the Framingham study | journal = JAMA | volume = 257 | issue = 16 | pages = 2176–2180 | date = 24 April 1987 | pmid = 3560398 | doi = 10.1001/jama.1987.03390160062027 }}</ref> This effect was also shown in men of all ages and women over 50 in the Vorarlberg Health Monitoring and Promotion Programme. These groups were more likely to die of cancer, liver diseases, and mental diseases with very low total cholesterol, of 186&nbsp;mg/dL (10.3 [[Mole (unit)|mmol]]/L) and lower. This result indicates the low-cholesterol effect occurs even among younger respondents, contradicting the previous assessment among cohorts of older people that this is a marker for frailty occurring with age.<ref name="Ulmer_2004">{{cite journal | vauthors = Ulmer H, Kelleher C, Diem G, Concin H | title = Why Eve is not Adam: prospective follow-up in 149650 women and men of cholesterol and other risk factors related to cardiovascular and all-cause mortality | journal = Journal of Women's Health | volume = 13 | issue = 1 | pages = 41–53 | year = 2004 | pmid = 15006277 | doi = 10.1089/154099904322836447 }}</ref>