Primary hypertriglyceridemia: Difference between revisions

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__NOTOC__
__NOTOC__
{{SI}}
{{SI}}
{{CMG}}; {{AE}} {{USAMA}}
{{CMG}}; {{AE}} {{USAMA}}; {{TarekNafee}}
 
'''To view Lipoprotein disorders main page [[ Lipoprotein disorders | Click here]]'''<br>
'''To view Hyperlipoproteinemia main page [[ Hyperlipoproteinemia | Click here]]''' <br>
 
{{SK}}: ''Primary hypertriglyceridemia; Familial hypertriglyceridemia; Type IV hyperlipoproteinemia; Type 4 hyperlipoproteinemia; Hyperlipoproteinemia type IV; Type 4 Hyperlipidemia''


{{SK}} [[Primary hypertriglyceridemia|Familial hypertriglyceridemia]]; [[Primary hypertriglyceridemia|Type IV hyperlipoproteinemia]]; [[Primary hypertriglyceridemia|Type-IV hyperlipoproteinemia]]; [[Primary hypertriglyceridemia|Type 4 hyperlipoproteinemia]]
==Overview==
==Overview==
Primary hypertriglyceridemia, or type 4 hyperlipidemia, develops from high concentration of [[triglyceride]]s in the blood. It is also known as [[hypertriglyceridemia]] (or ''pure hypertriglyceridemia''). [[Hypertriglyceridemia]] denotes high (''hyper-'') blood levels (''-emia'') of [[triglyceride]]s, the most abundant [[fat]]ty molecule in most organisms. [[Triglyceride]] levels are usually not extremely elevated in cases of primary hypertriglyceridemia. Elevated levels of [[triglycerides]] can be detrimental to normal cardiac functioning.<ref name="pmid22962670">{{cite journal| author=Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH et al.| title=Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 9 | pages= 2969-89 | pmid=22962670 | doi=10.1210/jc.2011-3213 | pmc=3431581 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22962670  }} </ref> It has been associated with [[atherosclerosis]], even in the absence of [[hypercholesterolemia]] (high [[cholesterol]] levels). Very high triglyceride levels may also interfere with [[blood tests]]; [[hyponatremia]] may be reported spuriously (''[[pseudohyponatremia]]''). A related term is "[[hyperglyceridemia]]," or "[[hyperglyceridaemia]]," which refers to a high level of all [[glycerides]], including [[monoglycerides]], [[diglycerides]], and [[Triglycerides|triglycerides.]]
Primary hypertriglyceridemia, or type 4 hyperlipidemia has high concentration of [[triglyceride]]s in the blood. It is also known as [[hypertriglyceridemia]] (or ''pure hypertriglyceridemia''). [[Hypertriglyceridemia]] denotes high (''hyper-'') blood levels (''-emia'') of [[triglyceride]]s, the most abundant [[fat]]ty molecule in most organisms. [[Triglyceride]] levels are usually not extremely elevated in cases of primary hypertriglyceridemia. Elevated levels of [[triglycerides]] can be detrimental to normal cardiac functioning.<ref name="pmid22962670">{{cite journal| author=Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH et al.| title=Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 9 | pages= 2969-89 | pmid=22962670 | doi=10.1210/jc.2011-3213 | pmc=3431581 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22962670  }} </ref> It has been associated with [[atherosclerosis]], even in the absence of [[hypercholesterolemia]] (high [[cholesterol]] levels). Very high triglyceride levels may also interfere with [[blood tests]], [[hyponatremia]] may be reported spuriously (''[[pseudohyponatremia]]''). A related term is "[[hyperglyceridemia]]," or "[[hyperglyceridaemia]]," which refers to a high level of all [[glycerides]], including [[monoglycerides]], [[diglycerides]], and [[Triglycerides|triglycerides.]]


==Historical Perspective==
==Historical Perspective==
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===Classification by Gene Mutation===
===Classification by Gene Mutation===
Primary hypertriglyceridemia may be classified according to the following gene mutations:<ref name="pmid27578109">{{cite journal| author=De Castro-Orós I, Civeira F, Pueyo MJ, Mateo-Gallego R, Bolado-Carrancio A, Lamíquiz-Moneo I et al.| title=Rare genetic variants with large effect on triglycerides in subjects with a clinical diagnosis of familial vs nonfamilial hypertriglyceridemia. | journal=J Clin Lipidol | year= 2016 | volume= 10 | issue= 4 | pages= 790-7 | pmid=27578109 | doi=10.1016/j.jacl.2016.02.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27578109  }} </ref><ref name="pmid26614228">{{cite journal| author=Hruz PW| title=Commentary. | journal=Clin Chem | year= 2015 | volume= 61 | issue= 12 | pages= 1444 | pmid=26614228 | doi=10.1373/clinchem.2015.243964 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26614228  }} </ref>
Primary hypertriglyceridemia may be classified according to the following gene mutations:<ref name="pmid27578109">{{cite journal| author=De Castro-Orós I, Civeira F, Pueyo MJ, Mateo-Gallego R, Bolado-Carrancio A, Lamíquiz-Moneo I et al.| title=Rare genetic variants with large effect on triglycerides in subjects with a clinical diagnosis of familial vs nonfamilial hypertriglyceridemia. | journal=J Clin Lipidol | year= 2016 | volume= 10 | issue= 4 | pages= 790-7 | pmid=27578109 | doi=10.1016/j.jacl.2016.02.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27578109  }} </ref><ref name="pmid26614228">{{cite journal| author=Hruz PW| title=Commentary. | journal=Clin Chem | year= 2015 | volume= 61 | issue= 12 | pages= 1444 | pmid=26614228 | doi=10.1373/clinchem.2015.243964 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26614228  }} </ref>
*[[LPL]] gene: [[LPL]] is the primary enzyme used in the catabolism of [[lipids]] rich in [[triglycerides]]. The mutations in [[LPL]] can be further classified on the basis of their specific substitutions such as:<ref name="pmid26104879">{{cite journal| author=Bouabdellah M, Iraqi H, Benlian P, Berqia I, Benchekroun L, Chraïbi A et al.| title=[Familial hypertriglyceridemia: biochemical, clinical and molecular study in a Moroccan family]. | journal=Ann Biol Clin (Paris) | year= 2015 | volume= 73 | issue= 4 | pages= 474-84 | pmid=26104879 | doi=10.1684/abc.2015.1058 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26104879  }} </ref>
*[[LPL]] gene: [[LPL]] is the primary enzyme involved in the catabolism of [[lipids]] rich in [[triglycerides]]. The mutations in [[LPL]] can be further classified on the basis of their specific substitutions such as:<ref name="pmid26104879">{{cite journal| author=Bouabdellah M, Iraqi H, Benlian P, Berqia I, Benchekroun L, Chraïbi A et al.| title=[Familial hypertriglyceridemia: biochemical, clinical and molecular study in a Moroccan family]. | journal=Ann Biol Clin (Paris) | year= 2015 | volume= 73 | issue= 4 | pages= 474-84 | pmid=26104879 | doi=10.1684/abc.2015.1058 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26104879  }} </ref>
**Gly188Glu  
**Gly188Glu  
**Asp9Asn
**Asp9Asn
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*High [[triglycerides]]: 200-499 mg/dL
*High [[triglycerides]]: 200-499 mg/dL
*Very high [[triglycerides]]: >500 mg/dL
*Very high [[triglycerides]]: >500 mg/dL
'''To view the ATPIII guidelines for classification of triglyceride levels, [[Adult Treatment Panel guidelines (ATP III)|click here.]]'''
'''For a detailed classification of [[hyperlipoproteinemia]], [[Hyperlipoproteinemia#Classification|click here]].'''


==Pathophisiology==
==Pathophisiology==
===Pathogenesis===
===Pathogenesis===
The regulation of [[lipids]] in the body can be affected at any of the following three stages:<ref name="pmid17100406">{{cite journal| author=Hachem SB, Mooradian AD| title=Familial dyslipidaemias: an overview of genetics, pathophysiology and management. | journal=Drugs | year= 2006 | volume= 66 | issue= 15 | pages= 1949-69 | pmid=17100406 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17100406  }} </ref>
The regulation of [[lipids]] in the body can be affected at any of the following three stages:<ref name="pmid17100406">{{cite journal| author=Hachem SB, Mooradian AD| title=Familial dyslipidaemias: an overview of genetics, pathophysiology and management. | journal=Drugs | year= 2006 | volume= 66 | issue= 15 | pages= 1949-69 | pmid=17100406 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17100406  }} </ref>
*Exogenous pathway that involves synthesis of [[chylomicrons]] in the intestines to transport [[triglycerides]] and [[cholesterol]] to be utilized by the body
*Exogenous pathway that involves synthesis of [[chylomicrons]] in the intestines to transport [[triglycerides]] and [[cholesterol]] to be utilized by the body.
*Endogenous pathway that involves production of [[VLDL]] cholesterol and [[TG]] within the body and transportation to various tissues
*Endogenous pathway that involves production of [[VLDL]] cholesterol and [[TG]] within the body and transportation to various tissues.
*The reverse cholesterol transport involves exchange of [[TG]]<nowiki/>s (from [[LDL]] and [[VLDL]]) and [[HDL]] [[cholesteryl ester]] using [[cholesteryl ester transfer protein]] to remove peripheral [[cholesterol]] and supply it to the [[liver]] and other organs
*The reverse cholesterol transport involves exchange of [[TG]]<nowiki/>s (from [[LDL]] and [[VLDL]]) and [[HDL]] [[cholesteryl ester]] using [[cholesteryl ester transfer protein]] to remove peripheral [[cholesterol]] and supply it to the [[liver]] and other organs.


Primary hypertriglyceridemia can occur through various mechanisms involving abnormal mutations in the LPL gene, which can increase triglyceride levels up to 80%.<ref name="pmid22179026">{{cite journal| author=Hassing HC, Surendran RP, Mooij HL, Stroes ES, Nieuwdorp M, Dallinga-Thie GM| title=Pathophysiology of hypertriglyceridemia. | journal=Biochim Biophys Acta | year= 2012 | volume= 1821 | issue= 5 | pages= 826-32 | pmid=22179026 | doi=10.1016/j.bbalip.2011.11.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22179026  }} </ref><ref name="pmid10359734">{{cite journal| author=Wittrup HH, Tybjaerg-Hansen A, Nordestgaard BG| title=Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis. | journal=Circulation | year= 1999 | volume= 99 | issue= 22 | pages= 2901-7 | pmid=10359734 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10359734  }} </ref><ref name="pmid9323055">{{cite journal| author=Nordestgaard BG, Abildgaard S, Wittrup HH, Steffensen R, Jensen G, Tybjaerg-Hansen A| title=Heterozygous lipoprotein lipase deficiency: frequency in the general population, effect on plasma lipid levels, and risk of ischemic heart disease. | journal=Circulation | year= 1997 | volume= 96 | issue= 6 | pages= 1737-44 | pmid=9323055 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9323055  }} </ref>
Primary hypertriglyceridemia can occur through various mechanisms involving abnormal mutations in the LPL gene, which can increase triglyceride levels up to 80%.<ref name="pmid22179026">{{cite journal| author=Hassing HC, Surendran RP, Mooij HL, Stroes ES, Nieuwdorp M, Dallinga-Thie GM| title=Pathophysiology of hypertriglyceridemia. | journal=Biochim Biophys Acta | year= 2012 | volume= 1821 | issue= 5 | pages= 826-32 | pmid=22179026 | doi=10.1016/j.bbalip.2011.11.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22179026  }} </ref><ref name="pmid10359734">{{cite journal| author=Wittrup HH, Tybjaerg-Hansen A, Nordestgaard BG| title=Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis. | journal=Circulation | year= 1999 | volume= 99 | issue= 22 | pages= 2901-7 | pmid=10359734 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10359734  }} </ref><ref name="pmid9323055">{{cite journal| author=Nordestgaard BG, Abildgaard S, Wittrup HH, Steffensen R, Jensen G, Tybjaerg-Hansen A| title=Heterozygous lipoprotein lipase deficiency: frequency in the general population, effect on plasma lipid levels, and risk of ischemic heart disease. | journal=Circulation | year= 1997 | volume= 96 | issue= 6 | pages= 1737-44 | pmid=9323055 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9323055  }} </ref>
* Abnormal [[very low density lipoprotein|very low density lipoprotein (VLDL]]) production in [[liver]] (internal pathway) and synthesis of [[chylomicrons]] in the [[intestines]] (external pathway)
* Abnormal [[very low density lipoprotein|very low density lipoprotein (VLDL]]) production in [[liver]] (internal pathway) and synthesis of [[chylomicrons]] in the [[intestines]] (external pathway).
*Abnormal [[Lipoprotein lipase|lipoprotein lipase (LPL)-mediated]] [[lipolysis]]
*Abnormal [[Lipoprotein lipase|lipoprotein lipase (LPL)-mediated]] [[lipolysis]].
*Abnornal remanant clearance
*Abnornal remanant clearance
*Reduction of [[HDL-C]] levels ([[hypoalphalipoproteinemia]]), which predisposes patients to [[ischemic heart disease]]
*Reduction of [[HDL-C]] levels ([[hypoalphalipoproteinemia]]), which predisposes patients to [[ischemic heart disease]].
[[Primary hypertriglyceridemia]] causes an increase in the [[ABCA1|ABCA]]-1 dependent efflux of [[cholesterol]] from macrophage to serum due to an increased amount of prebeta-HDL in serum, which leads to an increased risk of cardiac complications.<ref name="pmid17980882">{{cite journal| author=Attia N, Ramaharo A, Paul JL, Cambillau M, Beaune P, Grynberg A et al.| title=Enhanced removal of cholesterol from macrophage foam cells to serum from type IV hypertriglyceridemic subjects. | journal=Atherosclerosis | year= 2008 | volume= 198 | issue= 1 | pages= 49-56 | pmid=17980882 | doi=10.1016/j.atherosclerosis.2007.09.023 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17980882  }} </ref>
*Primary hypertriglyceridemia causes an increase in the [[ABCA1|ABCA]]-1 dependent efflux of [[cholesterol]] from macrophage to serum due to an increased amount of prebeta-HDL in serum, which leads to an increased risk of cardiac complications.<ref name="pmid17980882">{{cite journal| author=Attia N, Ramaharo A, Paul JL, Cambillau M, Beaune P, Grynberg A et al.| title=Enhanced removal of cholesterol from macrophage foam cells to serum from type IV hypertriglyceridemic subjects. | journal=Atherosclerosis | year= 2008 | volume= 198 | issue= 1 | pages= 49-56 | pmid=17980882 | doi=10.1016/j.atherosclerosis.2007.09.023 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17980882  }} </ref>


===Genetics===
===Genetics===
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==Differentiating {{PAGENAME}} from Other Diseases==
==Differentiating {{PAGENAME}} from Other Diseases==
Primary hypertriglyceridemia must be differentiated from other diseases that cause abnormal increases in lipomics in the blood, including:
Primary hypertriglyceridemia must be differentiated from other diseases that cause abnormal increases in serum triglycerides, including:
*[[Familial hypercholesterolemia]]/[[Familial combined hyperlipidemia]]
*[[Familial hypercholesterolemia]]/[[Familial combined hyperlipidemia]]
*[[Dysbetalipoproteinemia|Dysbetalipoprotenemia]]
*[[Dysbetalipoproteinemia|Dysbetalipoprotenemia]]
*[[Mixed hyperlipoproteinemia|Mixed hyperlipoprotenemia]]
*[[Mixed hyperlipoproteinemia|Mixed hyperlipoprotenemia]]


Different features some times must also be differentiated from similar conditions, e.g xanthomas<ref name="pmid27678445">{{cite journal| author=Koopal C, Visseren FL, Marais AD, Westerink J, Spiering W| title=Tendon xanthomas: Not always familial hypercholesterolemia. | journal=J Clin Lipidol | year= 2016 | volume= 10 | issue= 5 | pages= 1262-5 | pmid=27678445 | doi=10.1016/j.jacl.2016.05.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27678445  }} </ref> should be differentiated from
Primary hypertriglyceridemia must also be differentiated from other diseases that may cause xanthomas such as:<ref name="pmid27678445">{{cite journal| author=Koopal C, Visseren FL, Marais AD, Westerink J, Spiering W| title=Tendon xanthomas: Not always familial hypercholesterolemia. | journal=J Clin Lipidol | year= 2016 | volume= 10 | issue= 5 | pages= 1262-5 | pmid=27678445 | doi=10.1016/j.jacl.2016.05.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27678445  }} </ref>  
*[[Sitosterolemia]]
*[[Sitosterolemia]]
*Cerebrotendinous Xanthomatosis (CTX) - [[CYP27A1]] recesive  gene mutation
*Cerebrotendinous Xanthomatosis (CTX) - [[CYP27A1]] recesive  gene mutation
For a detailed differential diagnosis of [[hyperlipoproteinemia]] click '''[[Hyperlipoproteinemia#Differential Diagnosis|here]]'''.


==Epidemiology and Demographics==
==Epidemiology and Demographics==


*The prevalence of type 4 hyperlipidemia (i.e., primary hypertriglyceridemia) is 5%–10% in the general population.<ref name="pmid17420495">{{cite journal| author=Yuan G, Al-Shali KZ, Hegele RA| title=Hypertriglyceridemia: its etiology, effects and treatment. | journal=CMAJ | year= 2007 | volume= 176 | issue= 8 | pages= 1113-20 | pmid=17420495 | doi=10.1503/cmaj.060963 | pmc=1839776 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17420495  }} </ref>
=== Prevalence ===
*According to the NCEP-ATPIII definition of high [[triglycerides]] (>200 mg/dl), the prevalence of [[hypertriglyceridemia]] due to any cause (including the secondary causes) is about 16% of the adult population.<ref>Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report.  ''Circulation'' 2002; 106; page 3240</ref>  
* The prevalence of type 4 hyperlipidemia (i.e., primary hypertriglyceridemia) is 5%–10% in the general population.<ref name="pmid17420495">{{cite journal| author=Yuan G, Al-Shali KZ, Hegele RA| title=Hypertriglyceridemia: its etiology, effects and treatment. | journal=CMAJ | year= 2007 | volume= 176 | issue= 8 | pages= 1113-20 | pmid=17420495 | doi=10.1503/cmaj.060963 | pmc=1839776 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17420495  }} </ref>
* According to the [[Adult Treatment Panel guidelines (ATP III)|NCEP-ATPIII]] definition of high [[triglycerides]] (>200 mg/dl), the prevalence of [[hypertriglyceridemia]] due to any cause (including the secondary causes) is about 16% of the adult population.<ref>Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report.  ''Circulation'' 2002; 106; page 3240</ref>  


===Age===
===Age===
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==Risk Factors==
==Risk Factors==
'''Positive family history''' is the most potent risk factor for primary hypertriglyceridemia. Other factors that can contribute to the manifestation and severity of the disease are:<ref name="pmid26343209">{{cite journal| author=Shah AS, Wilson DP| title=Primary hypertriglyceridemia in children and adolescents. | journal=J Clin Lipidol | year= 2015 | volume= 9 | issue= 5 Suppl | pages= S20-8 | pmid=26343209 | doi=10.1016/j.jacl.2015.04.004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26343209  }} </ref><ref name="pmid17420495">{{cite journal| author=Yuan G, Al-Shali KZ, Hegele RA| title=Hypertriglyceridemia: its etiology, effects and treatment. | journal=CMAJ | year= 2007 | volume= 176 | issue= 8 | pages= 1113-20 | pmid=17420495 | doi=10.1503/cmaj.060963 | pmc=1839776 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17420495  }} </ref>  
Positive family history is the most potent risk factor for primary hypertriglyceridemia. Other factors that can contribute to the manifestation and severity of the disease are:<ref name="pmid26343209">{{cite journal| author=Shah AS, Wilson DP| title=Primary hypertriglyceridemia in children and adolescents. | journal=J Clin Lipidol | year= 2015 | volume= 9 | issue= 5 Suppl | pages= S20-8 | pmid=26343209 | doi=10.1016/j.jacl.2015.04.004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26343209  }} </ref><ref name="pmid17420495">{{cite journal| author=Yuan G, Al-Shali KZ, Hegele RA| title=Hypertriglyceridemia: its etiology, effects and treatment. | journal=CMAJ | year= 2007 | volume= 176 | issue= 8 | pages= 1113-20 | pmid=17420495 | doi=10.1503/cmaj.060963 | pmc=1839776 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17420495  }} </ref>  
*[[Obesity]]
*[[Obesity]]
*[[Diabetes mellitus type 2|Diabetes melitis type 2]] or [[Insulin resistance]]
*[[Diabetes mellitus type 2|Diabetes melitis type 2]] or [[Insulin resistance]]
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==Screening==
==Screening==
There are no recommendation for screening the young adult population for primary hypertriglyceridemia.<ref name="pmid27538032">{{cite journal| author=Chou R, Dana T, Blazina I, Daeges M, Bougatsos C, Jeanne TL| title=Screening for Dyslipidemia in Younger Adults: A Systematic Review for the U.S. Preventive Services Task Force. | journal=Ann Intern Med | year= 2016 | volume= 165 | issue= 8 | pages= 560-564 | pmid=27538032 | doi=10.7326/M16-0946 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27538032  }} </ref> [[USPSTF guidelines]] for 2016 show insufficient evidence to assess possible benefits of screening children and adolescents under 20 years old.<ref name="pmid27532917">{{cite journal| author=US Preventive Services Task Force. Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW et al.| title=Screening for Lipid Disorders in Children and Adolescents: US Preventive Services Task Force Recommendation Statement. | journal=JAMA | year= 2016 | volume= 316 | issue= 6 | pages= 625-33 | pmid=27532917 | doi=10.1001/jama.2016.9852 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27532917  }} </ref>
There are no recommendations for screening the young adult population for primary hypertriglyceridemia.<ref name="pmid27538032">{{cite journal| author=Chou R, Dana T, Blazina I, Daeges M, Bougatsos C, Jeanne TL| title=Screening for Dyslipidemia in Younger Adults: A Systematic Review for the U.S. Preventive Services Task Force. | journal=Ann Intern Med | year= 2016 | volume= 165 | issue= 8 | pages= 560-564 | pmid=27538032 | doi=10.7326/M16-0946 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27538032  }} </ref> [[USPSTF guidelines]] for 2016 show insufficient evidence to assess possible benefits of screening children and adolescents under 20 years old.<ref name="pmid27532917">{{cite journal| author=US Preventive Services Task Force. Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW et al.| title=Screening for Lipid Disorders in Children and Adolescents: US Preventive Services Task Force Recommendation Statement. | journal=JAMA | year= 2016 | volume= 316 | issue= 6 | pages= 625-33 | pmid=27532917 | doi=10.1001/jama.2016.9852 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27532917  }} </ref>


==Natural History, Complications, and Prognosis==
==Natural History, Complications, and Prognosis==
===Natural History===
===Natural History===
If left untreated, primary hypertriglyceridemia may result in [[pancreatitis]], which can become chronic and damage the pancreas. Rarely, [[pancreatitis]] can be life-threatening.<ref name="medline plus"><nowiki>{{</nowiki>https://medlineplus.gov/ency/article/000408htm<nowiki>}} Accessed on 7 November,2016</nowiki></ref>
If left untreated, primary hypertriglyceridemia may result in [[pancreatitis]], which can become chronic and result in irreversible damage of the pancreas. Rarely, [[pancreatitis]] can be life-threatening.<ref name="medline plus"><nowiki>{{</nowiki>https://medlineplus.gov/ency/article/000408htm<nowiki>}} Accessed on 7 November,2016</nowiki></ref>


===Complications===
===Complications===
Line 97: Line 107:


*Non-alcoholic fatty liver disease ([[NAFLD]])
*Non-alcoholic fatty liver disease ([[NAFLD]])
*[[Pancreatitis]] caused by [[TG]] breakdown by [[pancreatic lipase]] and the release of [[free fatty acids]], leading to production of [[free radicals]]<ref name="pmid19293788">{{cite journal| author=Tsuang W, Navaneethan U, Ruiz L, Palascak JB, Gelrud A| title=Hypertriglyceridemic pancreatitis: presentation and management. | journal=Am J Gastroenterol | year= 2009 | volume= 104 | issue= 4 | pages= 984-91 | pmid=19293788 | doi=10.1038/ajg.2009.27 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19293788  }} </ref><ref name="pmid8288962">{{cite journal| author=Glueck CJ, Lang J, Hamer T, Tracy T| title=Severe hypertriglyceridemia and pancreatitis when estrogen replacement therapy is given to hypertriglyceridemic women. | journal=J Lab Clin Med | year= 1994 | volume= 123 | issue= 1 | pages= 59-64 | pmid=8288962 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8288962  }} </ref>
*[[Pancreatitis]] caused by [[TG]] breakdown by [[pancreatic lipase]] and the release of [[free fatty acids]], leading to production of [[free radicals]].<ref name="pmid19293788">{{cite journal| author=Tsuang W, Navaneethan U, Ruiz L, Palascak JB, Gelrud A| title=Hypertriglyceridemic pancreatitis: presentation and management. | journal=Am J Gastroenterol | year= 2009 | volume= 104 | issue= 4 | pages= 984-91 | pmid=19293788 | doi=10.1038/ajg.2009.27 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19293788  }} </ref><ref name="pmid8288962">{{cite journal| author=Glueck CJ, Lang J, Hamer T, Tracy T| title=Severe hypertriglyceridemia and pancreatitis when estrogen replacement therapy is given to hypertriglyceridemic women. | journal=J Lab Clin Med | year= 1994 | volume= 123 | issue= 1 | pages= 59-64 | pmid=8288962 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8288962  }} </ref>
*[[Non-insulin-dependent diabetes mellitus]]
*[[Non-insulin-dependent diabetes mellitus]]
**Primary hypertriglyceridemia predisposes patients to the development of NIDDM.<ref name="pmid8299439">{{cite journal| author=Sane T, Taskinen MR| title=Does familial hypertriglyceridemia predispose to NIDDM? | journal=Diabetes Care | year= 1993 | volume= 16 | issue= 11 | pages= 1494-501 | pmid=8299439 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8299439  }} </ref>
**Primary hypertriglyceridemia predisposes patients to the development of NIDDM.<ref name="pmid8299439">{{cite journal| author=Sane T, Taskinen MR| title=Does familial hypertriglyceridemia predispose to NIDDM? | journal=Diabetes Care | year= 1993 | volume= 16 | issue= 11 | pages= 1494-501 | pmid=8299439 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8299439  }} </ref>
Line 105: Line 115:


==Diagnosis==
==Diagnosis==
The diagnosis of primary hypertriglyceridemia is based on the triglyceride levels in blood obtained by a lipid profile. It is preferable to estimate fasting triglyceride levels rather than non-fasting levels.<ref name="pmid22962670">{{cite journal| author=Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH et al.| title=Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 9 | pages= 2969-89 | pmid=22962670 | doi=10.1210/jc.2011-3213 | pmc=3431581 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22962670  }} </ref> Genetic studies can be done for confirmatory purposes after a proposed diagnosis of primary hypertriglyceridemia has been established in the presence of a positive family history.
The diagnosis of primary hypertriglyceridemia is based on the [[triglyceride]] levels in blood obtained by a [[lipid profile]]. It is preferable to estimate fasting [[triglyceride]] levels rather than non-fasting levels.<ref name="pmid22962670">{{cite journal| author=Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH et al.| title=Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 9 | pages= 2969-89 | pmid=22962670 | doi=10.1210/jc.2011-3213 | pmc=3431581 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22962670  }} </ref> Genetic studies can be done for confirmatory purposes after a proposed diagnosis of primary hypertriglyceridemia has been established in the presence of a positive family history.


===History and Symptoms===
===History and Symptoms===
Line 117: Line 127:
====Dermatological====
====Dermatological====
*Eruptive [[xanthomas]]: yellow papules with erythemtous base, demonstrating deposition of triglycerides in the cutaneous histiocytes
*Eruptive [[xanthomas]]: yellow papules with erythemtous base, demonstrating deposition of triglycerides in the cutaneous histiocytes
**Primarily seen on the elbows and buttocks
**Primarily on the elbows and buttocks


====Musculoskeletal====
====Musculoskeletal====
Line 124: Line 134:


====ENT====
====ENT====
*Throat pain  
*Throat pain


<gallery>
===Physical Examination===
File:Eruptive xanthoma 2.jpeg| Eruptive Xanthomas on an elbow.
Common physical examination findings of primary hypertriglyceridemia include:<ref name="pmid19064332">{{cite journal| author=Soubrier M, Dubost JJ, Thiéblot P, Ristori JM| title=Oligo-arthritis and type IV hyperlipoproteinemia. | journal=Joint Bone Spine | year= 2009 | volume= 76 | issue= 1 | pages= 95-7 | pmid=19064332 | doi=10.1016/j.jbspin.2008.03.009 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19064332  }} </ref><ref name="pmid16672684">{{cite journal| author=Pejic RN, Lee DT| title=Hypertriglyceridemia. | journal=J Am Board Fam Med | year= 2006 | volume= 19 | issue= 3 | pages= 310-6 | pmid=16672684 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16672684  }} </ref>
</gallery>


===Physical Examination===
'''General Appearance'''
Common physical examination findings of primary hypertriglyceridemia include:<ref name="pmid19064332">{{cite journal| author=Soubrier M, Dubost JJ, Thiéblot P, Ristori JM| title=Oligo-arthritis and type IV hyperlipoproteinemia. | journal=Joint Bone Spine | year= 2009 | volume= 76 | issue= 1 | pages= 95-7 | pmid=19064332 | doi=10.1016/j.jbspin.2008.03.009 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19064332  }} </ref><ref name="pmid16672684">{{cite journal| author=Pejic RN, Lee DT| title=Hypertriglyceridemia. | journal=J Am Board Fam Med | year= 2006 | volume= 19 | issue= 3 | pages= 310-6 | pmid=16672684 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16672684  }} </ref> 
*Increased body mass index ([[obesity]])
*[[Lymphadenopathy]]
====Dermatological====
====Dermatological====
*Eruptive [[xanthomas]]
*Eruptive [[xanthomas]]
Line 143: Line 153:
*Arthritis
*Arthritis
*Tendon xanthomas
*Tendon xanthomas
<gallery>
File:Eruptive xanthoma 2.jpeg| Eruptive Xanthomas on an elbow.
</gallery>
====Gastrointestinal====
====Gastrointestinal====
*Hepatosplenomegaly
*Hepatosplenomegaly
Line 152: Line 166:
File:Eruptive xanthoma.jpeg| Eruptive xanthoma.  
File:Eruptive xanthoma.jpeg| Eruptive xanthoma.  
</gallery>
</gallery>
====Central nervous system====
*[[Peripheral neuropathy]]


===Laboratory Findings===
===Laboratory Findings===
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==Treatment==
==Treatment==
The mainstay of treatment of primary hypertriglyceridemia is lifestyle modification (e.g., diet and exercise). Medical therapy shows benefits in patients in whom lifestyle modifications fail to control [[triglyceride]] levels. [[Gene therapy]] is an emerging treatment option.
The mainstay of treatment of primary hypertriglyceridemia is lifestyle modification (e.g., diet and exercise). Medical therapy shows benefits in patients in whom lifestyle modifications fail to control [[triglyceride]] levels. [[Gene therapy]] is an emerging treatment option. Supportive clinical trial data for pharmacological therapies for treatment of hypertriglyceridemia includes:
* [[Hypertriglyceridemia niacin|Niacin data]]
* [[Niacin AIM HIGH study|Niacin AIM HIGH trial]]
* [[Hypertriglyceridemia omega-3 fatty acids|Omega 3 data]]


===Non-Pharmacological===
===Non-Pharmacological===
Line 233: Line 252:
* [[Niacin extended release|Extended release niacin]] (Nicotinic acid) can be used in patients with low [[HDL]] and elevated [[triglyceride]] levels. <ref name="pmid27710158">{{cite journal| author=Kushner PA, Cobble ME| title=Hypertriglyceridemia: the importance of identifying patients at risk. | journal=Postgrad Med | year= 2016 | volume=  | issue=  | pages=  | pmid=27710158 | doi=10.1080/00325481.2016.1243005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27710158  }} </ref><ref name="pmid16672684">{{cite journal| author=Pejic RN, Lee DT| title=Hypertriglyceridemia. | journal=J Am Board Fam Med | year= 2006 | volume= 19 | issue= 3 | pages= 310-6 | pmid=16672684 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16672684  }} </ref>
* [[Niacin extended release|Extended release niacin]] (Nicotinic acid) can be used in patients with low [[HDL]] and elevated [[triglyceride]] levels. <ref name="pmid27710158">{{cite journal| author=Kushner PA, Cobble ME| title=Hypertriglyceridemia: the importance of identifying patients at risk. | journal=Postgrad Med | year= 2016 | volume=  | issue=  | pages=  | pmid=27710158 | doi=10.1080/00325481.2016.1243005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27710158  }} </ref><ref name="pmid16672684">{{cite journal| author=Pejic RN, Lee DT| title=Hypertriglyceridemia. | journal=J Am Board Fam Med | year= 2006 | volume= 19 | issue= 3 | pages= 310-6 | pmid=16672684 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16672684  }} </ref>
*[[Lomitapide]] is used to treat genetic hypertriglyceridemia and recurrent refractory [[acute pancreatitis]].<ref name="pmid27785928">{{cite journal| author=Brahm AJ, Hegele RA| title=Lomitapide for the treatment of hypertriglyceridemia. | journal=Expert Opin Investig Drugs | year= 2016 | volume=  | issue=  | pages=  | pmid=27785928 | doi=10.1080/13543784.2016.1254187 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27785928  }} </ref>
*[[Lomitapide]] is used to treat genetic hypertriglyceridemia and recurrent refractory [[acute pancreatitis]].<ref name="pmid27785928">{{cite journal| author=Brahm AJ, Hegele RA| title=Lomitapide for the treatment of hypertriglyceridemia. | journal=Expert Opin Investig Drugs | year= 2016 | volume=  | issue=  | pages=  | pmid=27785928 | doi=10.1080/13543784.2016.1254187 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27785928  }} </ref>
The following table demonstrates features of various pharmacological therapies aimed at decreasing serum triglyceride levels:
{| width="70%" class="wikitable" border="1"
|- style="height:50px"
| bgcolor="Gray" |''' Drug '''
| bgcolor="Gray" |''' Mechanism of benefit '''
| bgcolor="Gray" |''' Dosage '''
| bgcolor="Gray" |''' Advantages '''
| bgcolor="Gray" |''' Side-effects '''
| bgcolor="Gray" |''' Contraindication '''
|-
| '''[[Niacin]]/[[Nicotinic acid]]'''
|
* ↓ [[LDL]] (17-26%)<ref name="pmid17804845">{{cite journal| author=Brunzell JD| title=Clinical practice. Hypertriglyceridemia. | journal=N Engl J Med | year= 2007 | volume= 357 | issue= 10 | pages= 1009-17 | pmid=17804845 | doi=10.1056/NEJMcp070061 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17804845  }} </ref>
* ↑ [[HDL]]
| 1.5 - 2 gm once daily
|
* [[Statin]] alone or combination therapy of niacin with statin are usually the first options in [[premature coronary artery disease]].
* ↓ [[atherosclerosis]] in [[hypertriglyceridemia]] patients.
|
* Flushing
* Pruritus
* Nausea
* Hepatitis (higher doses)
|
* [[Hypersensitivity]]
* Hepatic disease
|-
|-
| '''[[Omega-3 fatty acids]]'''
|
* ↓ hepatic [[lipogenesis]]
* ↓ plasma [[lipoprotein lipase]] activity.
* ↑ hepatic mitochondrial and peroxisomal [[beta-oxidation]]
* Inhibition of acyl CoA:1,2-[[diacylglycerol acyltransferase]] enzyme
* [[EPA]]and [[DHA]] are poor enzyme substrates for [[triglyceride]] synthesis in [[liver]] & inhibits [[esterification]] of other [[fatty acids]].
|
* 3 g/day of EPA and DHA is under FDA's "[[Generally Recognized As Safe]]" category. <ref name="pmid16825676">{{cite journal| author=Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B et al.| title=n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. | journal=Am J Clin Nutr | year= 2006 | volume= 84 | issue= 1 | pages= 5-17 | pmid=16825676 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16825676  }} </ref>
* Higher doses increases risk of bleeding
|
* ↓ [[VLDL]] <ref name="pmid6736254">{{cite journal| author=Nestel PJ, Connor WE, Reardon MF, Connor S, Wong S, Boston R| title=Suppression by diets rich in fish oil of very low density lipoprotein production in man. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 1 | pages= 82-9 | pmid=6736254 | doi=10.1172/JCI111422 | pmc=PMC425187 | url= }} </ref>, <ref name="pmid11303007">{{cite journal| author=Durrington PN, Bhatnagar D, Mackness MI, Morgan J, Julier K, Khan MA et al.| title=An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. | journal=Heart | year= 2001 | volume= 85 | issue= 5 | pages= 544-8 | pmid=11303007 | doi= | pmc=PMC1729738 | url= }} </ref>
* ↓ serum triglyceride by ≥ 50%
|
* [[Bleeding]] at high doses
* Fishy smell, can be reduced by
** Freezing of medication
** Trying different formulation
** Taking medication with food
* [[Nausea]]
(approximately 4 % of individuals at < 3 gm/d, and 20% at > 4gm/d experiences git side-effects)<ref name="pmid16825676">{{cite journal| author=Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B et al.| title=n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. | journal=Am J Clin Nutr | year= 2006 | volume= 84 | issue= 1 | pages= 5-17 | pmid=16825676 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16825676  }} </ref>
|
* Hypersensitivity
|-
| '''[[Fibrate]]'''
|
* ↓ [[triglyceride]] (20-45%)
* ↓ [[LDL]]
|
* [[Gemfibrozil]] 600mg BD
* [[Fenofibrate]] 145 mg OD
|
* ↓ non-fatal [[myocardial infarction]]
* No benefit on [[HDL]] levels, fatal coronary events or total mortality
|
* [[Myositis]]
* [[Gallbladder stone]]
|
* [[Hypersensitivity]]
* Hepatic disease
* [[End stage renal disease]]
|-
|}
* ↑ - Increase
* ↓ - Decrease


===Emerging treatment options===
===Emerging treatment options===
* [[Gene therapy]] has been recently introduced for patients with [[LPL]] deficiency and recurrent or severe [[pancreatitis]].<ref name="pmid25585702">{{cite journal| author=Kassner U, Salewsky B, Wühle-Demuth M, Szijarto IA, Grenkowitz T, Binner P et al.| title=Severe hypertriglyceridemia in a patient heterozygous for a lipoprotein lipase gene allele with two novel missense variants. | journal=Eur J Hum Genet | year= 2015 | volume= 23 | issue= 9 | pages= 1259-61 | pmid=25585702 | doi=10.1038/ejhg.2014.295 | pmc=4538214 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25585702  }} </ref>
* [[Gene therapy]] has been recently introduced for patients with [[LPL]] deficiency and recurrent or severe [[pancreatitis]].<ref name="pmid25585702">{{cite journal| author=Kassner U, Salewsky B, Wühle-Demuth M, Szijarto IA, Grenkowitz T, Binner P et al.| title=Severe hypertriglyceridemia in a patient heterozygous for a lipoprotein lipase gene allele with two novel missense variants. | journal=Eur J Hum Genet | year= 2015 | volume= 23 | issue= 9 | pages= 1259-61 | pmid=25585702 | doi=10.1038/ejhg.2014.295 | pmc=4538214 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25585702  }} </ref>
*[[Rimonabant]] a [[cannabinoid]]-1 (CB1) receptor antagonist works by decreasing appetite and consumption of food.<ref name="pmid15755787">{{cite journal| author=Boyd ST, Fremming BA| title=Rimonabant--a selective CB1 antagonist. | journal=Ann Pharmacother | year= 2005 | volume= 39 | issue= 4 | pages= 684-90 | pmid=15755787 | doi=10.1345/aph.1E499 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15755787  }} </ref> <ref name="pmid16697306">{{cite journal| author=Gelfand EV, Cannon CP| title=Rimonabant: a cannabinoid receptor type 1 blocker for management of multiple cardiometabolic risk factors. | journal=J Am Coll Cardiol | year= 2006 | volume= 47 | issue= 10 | pages= 1919-26 | pmid=16697306 | doi=10.1016/j.jacc.2005.12.067 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16697306  }} </ref>
*[[Rimonabant]] a [[cannabinoid]]-1 (CB1) receptor antagonist works by decreasing appetite and consumption of food.<ref name="pmid15755787">{{cite journal| author=Boyd ST, Fremming BA| title=Rimonabant--a selective CB1 antagonist. | journal=Ann Pharmacother | year= 2005 | volume= 39 | issue= 4 | pages= 684-90 | pmid=15755787 | doi=10.1345/aph.1E499 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15755787  }} </ref><ref name="pmid16697306">{{cite journal| author=Gelfand EV, Cannon CP| title=Rimonabant: a cannabinoid receptor type 1 blocker for management of multiple cardiometabolic risk factors. | journal=J Am Coll Cardiol | year= 2006 | volume= 47 | issue= 10 | pages= 1919-26 | pmid=16697306 | doi=10.1016/j.jacc.2005.12.067 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16697306  }} </ref>


*Glitazar drugs have dual [[agonists]] on [[peroxisome]] proliferator-activated receptor-α (like fibrates) and -γ (like thiozolidinidiones).<ref name="pmid16239637">{{cite journal| author=Nissen SE, Wolski K, Topol EJ| title=Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. | journal=JAMA | year= 2005 | volume= 294 | issue= 20 | pages= 2581-6 | pmid=16239637 | doi=10.1001/jama.294.20.joc50147 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16239637  }} </ref>
*Glitazar drugs have dual [[agonists]] on [[peroxisome]] proliferator-activated receptor-α (like [[fibrates]]) and -γ (like thiozolidinidiones).<ref name="pmid16239637">{{cite journal| author=Nissen SE, Wolski K, Topol EJ| title=Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. | journal=JAMA | year= 2005 | volume= 294 | issue= 20 | pages= 2581-6 | pmid=16239637 | doi=10.1001/jama.294.20.joc50147 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16239637  }} </ref>


*LPL Gene therapy may  be helpful by treating monogenic LPL (lipoprotein lipase) deficiency.<ref name="pmid16259561">{{cite journal| author=Rip J, Nierman MC, Sierts JA, Petersen W, Van den Oever K, Van Raalte D et al.| title=Gene therapy for lipoprotein lipase deficiency: working toward clinical application. | journal=Hum Gene Ther | year= 2005 | volume= 16 | issue= 11 | pages= 1276-86 | pmid=16259561 | doi=10.1089/hum.2005.16.1276 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16259561  }} </ref>
*[[LPL]] [[gene therapy]] may  be helpful by treating monogenic LPL ([[lipoprotein lipase]]) deficiency.<ref name="pmid16259561">{{cite journal| author=Rip J, Nierman MC, Sierts JA, Petersen W, Van den Oever K, Van Raalte D et al.| title=Gene therapy for lipoprotein lipase deficiency: working toward clinical application. | journal=Hum Gene Ther | year= 2005 | volume= 16 | issue= 11 | pages= 1276-86 | pmid=16259561 | doi=10.1089/hum.2005.16.1276 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16259561  }} </ref>


===Surgery===
===Surgery===
*Surgical intervention is not recommended for the management of primary hypertriglyceridemia.
*Surgical intervention is not recommended for the management of primary hypertriglyceridemia.
* Xanthomas may be surgically removed for cosmetic purposes.
*[[Xanthomas]] may be surgically removed for cosmetic purposes.


===Prevention===
===Prevention===
====Primary Prevention====
====Primary Prevention====
Primary hypertriglyceridemia is a genetic disease and there are no recommendations proposed so far for the primary prevention.
As primary hypertriglyceridemia is a genetic disease, no recommendations have been established proposed for its primary prevention.
 
====Secondary Prevention====
====Secondary Prevention====
Secondary prevention of primary hypertriglyceridemia may be achieved with
Measures for the secondary prevention of primary hypertriglyceridemia include:
 
*[[Genetic counseling]]
*Genetic counselling
*The NCEP proposes dietary and behavioral measures to reduce the burden of [[atherosclerosis]].<ref name="pmid12485966">{{cite journal| author=National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)| title=Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. | journal=Circulation | year= 2002 | volume= 106 | issue= 25 | pages= 3143-421 | pmid=12485966 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12485966  }} </ref><ref name="pmid8501844">{{cite journal| author=| title=Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II) | journal=JAMA | year= 1993 | volume= 269 | issue= 23 | pages= 3015-23 | pmid=8501844 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8501844  }} </ref><ref name="pmid2040066">{{cite journal| author=Carleton RA, Dwyer J, Finberg L, Flora J, Goodman DS, Grundy SM et al.| title=Report of the Expert Panel on Population Strategies for Blood Cholesterol Reduction. A statement from the National Cholesterol Education Program, National Heart, Lung, and Blood Institute, National Institutes of Health. | journal=Circulation | year= 1991 | volume= 83 | issue= 6 | pages= 2154-232 | pmid=2040066 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2040066  }} </ref>
*The NCEP proposes dietary and behavioral measures to reduce the burden of atherosclerosis.<ref name="pmid12485966">{{cite journal| author=National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)| title=Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. | journal=Circulation | year= 2002 | volume= 106 | issue= 25 | pages= 3143-421 | pmid=12485966 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12485966  }} </ref><ref name="pmid8501844">{{cite journal| author=| title=Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II) | journal=JAMA | year= 1993 | volume= 269 | issue= 23 | pages= 3015-23 | pmid=8501844 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8501844  }} </ref><ref name="pmid2040066">{{cite journal| author=Carleton RA, Dwyer J, Finberg L, Flora J, Goodman DS, Grundy SM et al.| title=Report of the Expert Panel on Population Strategies for Blood Cholesterol Reduction. A statement from the National Cholesterol Education Program, National Heart, Lung, and Blood Institute, National Institutes of Health. | journal=Circulation | year= 1991 | volume= 83 | issue= 6 | pages= 2154-232 | pmid=2040066 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2040066  }} </ref>
**Clinical approach includes lifestyle modifications.
#Clinical approach includes lifestyle modifications
**Population-based approach includes the reduction of individual risk of the patient.
#Population based approach includes reduction of individual risk of the patint


==References==
==References==

Latest revision as of 19:34, 5 April 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2]; Tarek Nafee, M.D. [3]

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To view Hyperlipoproteinemia main page Click here

Synonyms and keywords:: Primary hypertriglyceridemia; Familial hypertriglyceridemia; Type IV hyperlipoproteinemia; Type 4 hyperlipoproteinemia; Hyperlipoproteinemia type IV; Type 4 Hyperlipidemia

Overview

Primary hypertriglyceridemia, or type 4 hyperlipidemia has high concentration of triglycerides in the blood. It is also known as hypertriglyceridemia (or pure hypertriglyceridemia). Hypertriglyceridemia denotes high (hyper-) blood levels (-emia) of triglycerides, the most abundant fatty molecule in most organisms. Triglyceride levels are usually not extremely elevated in cases of primary hypertriglyceridemia. Elevated levels of triglycerides can be detrimental to normal cardiac functioning.[1] It has been associated with atherosclerosis, even in the absence of hypercholesterolemia (high cholesterol levels). Very high triglyceride levels may also interfere with blood tests, hyponatremia may be reported spuriously (pseudohyponatremia). A related term is "hyperglyceridemia," or "hyperglyceridaemia," which refers to a high level of all glycerides, including monoglycerides, diglycerides, and triglycerides.

Historical Perspective

Classification

There is no single established classification system for primary hypertriglyceridemia. However, primary hypertriglyceridemia may be classified according to gene mutation or severity of triglyceridemia.

Classification by Gene Mutation

Primary hypertriglyceridemia may be classified according to the following gene mutations:[4][5]

  • LPL gene: LPL is the primary enzyme involved in the catabolism of lipids rich in triglycerides. The mutations in LPL can be further classified on the basis of their specific substitutions such as:[6]
    • Gly188Glu
    • Asp9Asn
    • Asn291Ser
    • Ser447Ter
  • APOA5
  • LMF1
  • GPIHBP1

Classification by Severity of Triglyceridemia

Hypertriglyceridemia may be classified according to the concentration of triglycerides on the lipid profile. More marked elevations are usually seen in cases of hypertriglyceridemia resulting from secondary causes.[7]

To view the ATPIII guidelines for classification of triglyceride levels, click here.

For a detailed classification of hyperlipoproteinemia, click here.

Pathophisiology

Pathogenesis

The regulation of lipids in the body can be affected at any of the following three stages:[8]

Primary hypertriglyceridemia can occur through various mechanisms involving abnormal mutations in the LPL gene, which can increase triglyceride levels up to 80%.[9][10][11]

Genetics

  • The development of primary hypertriglyceridemia can follow either an autosomal dominant (AD) or autosomal recessive (AR) mode of inheritance.[6][13]
  • The LPL gene can have various mutations. Gly188Glu, Asp9Asn, Asn291Ser, and Ser447Ter substitutions can affect lipid metabolism and one's risk of developing ischemic heart disease (IHD). Heterozygous Gly188Glu carriers have an increased risk of IHD, while Ser447Ter carriers enjoy a protective effect.[10]

Causes

The primary cause of primary hypertriglyceridemia is a genetic mutation in the LPL gene, leading to abnormal metabolism of triglycerides in the body.[14][15][16]

Differentiating Primary hypertriglyceridemia from Other Diseases

Primary hypertriglyceridemia must be differentiated from other diseases that cause abnormal increases in serum triglycerides, including:

Primary hypertriglyceridemia must also be differentiated from other diseases that may cause xanthomas such as:[17]

For a detailed differential diagnosis of hyperlipoproteinemia click here.

Epidemiology and Demographics

Prevalence

  • The prevalence of type 4 hyperlipidemia (i.e., primary hypertriglyceridemia) is 5%–10% in the general population.[15]
  • According to the NCEP-ATPIII definition of high triglycerides (>200 mg/dl), the prevalence of hypertriglyceridemia due to any cause (including the secondary causes) is about 16% of the adult population.[18]

Age

  • Primary hypertriglyceridemia rarely presents in childhood.[19]

Gender

  • Primary hypertriglyceridemia appears to affect men and women equally.

Race

  • Primary hypertriglyceridemia does not appear to have a racial predilection.

Risk Factors

Positive family history is the most potent risk factor for primary hypertriglyceridemia. Other factors that can contribute to the manifestation and severity of the disease are:[14][15]

Screening

There are no recommendations for screening the young adult population for primary hypertriglyceridemia.[20] USPSTF guidelines for 2016 show insufficient evidence to assess possible benefits of screening children and adolescents under 20 years old.[21]

Natural History, Complications, and Prognosis

Natural History

If left untreated, primary hypertriglyceridemia may result in pancreatitis, which can become chronic and result in irreversible damage of the pancreas. Rarely, pancreatitis can be life-threatening.[22]

Complications

Approximately one in four citizens of the United States has a high level of triglycerides (>150mg/dl) that can predispose them to and directly lead to numerous complications, including:[23]

Prognosis

Baseline triglyceride levels can predict mortality due to cardiovascular cause in first-degree relatives of affected patients, without being influenced by total serum cholesterol concentration. [29]

Diagnosis

The diagnosis of primary hypertriglyceridemia is based on the triglyceride levels in blood obtained by a lipid profile. It is preferable to estimate fasting triglyceride levels rather than non-fasting levels.[1] Genetic studies can be done for confirmatory purposes after a proposed diagnosis of primary hypertriglyceridemia has been established in the presence of a positive family history.

History and Symptoms

The hallmark of primary hypertriglyceridemia is elevated triglyceride levels. A positive family history of diagnosed primary hypertriglyceridemia and elevated triglyecride levels on a lipid profile are suggestive of familial hypertriglyceridemia. The symptoms of hypertriglyceridemia can vary in accordance with the severity of the condition. The most common symptoms include:[17][30][31][32]

Gastrointestinal

Ophthalmological

  • Creamy appearance of the retina

Dermatological

  • Eruptive xanthomas: yellow papules with erythemtous base, demonstrating deposition of triglycerides in the cutaneous histiocytes
    • Primarily on the elbows and buttocks

Musculoskeletal

ENT

  • Throat pain

Physical Examination

Common physical examination findings of primary hypertriglyceridemia include:[32][33]

General Appearance

Dermatological

  • Eruptive xanthomas
  • Tuberous xanthomas
  • Palmar xanthomas

Ophthalmology

  • Lipemia retinalis
  • Xanthelasmas (yellow plaques near the inner part of the eyelids)
  • Corneal arcus (clouding of the cornea)

Musculoskeletal

  • Arthritis
  • Tendon xanthomas

Gastrointestinal

  • Hepatosplenomegaly
  • Pancreatitis

ENT

  • Enlarged (cholesterol deposited) tonsils

Central nervous system

Laboratory Findings

An elevated concentration of triglycerides on fasting lipid profile in patient with a positive family history is diagnostic of primary hypertriglyceridemia. The laboratory findings consistent with primary hypertriglyceridemia include:[33][34][35][36]

Lab Tests Biomarker Result
Lipid Profile VLDL Elevated
Serum Triglycerides Elevated
HDL Prebeta HDL Elevated
HDL-C Decreased
LDL
Total Cholesterol Normal or Elevated
Plasma appearance Clear to cloudy
CMP Fasting Insulin levels May be elevated

(Metabolic Syndrome)

LFTs usually abnormal
CBC Cell indices,

Peripheral smear

Pancytopenia

Pseudo-Niemann pick cells

Other Glucose Tolerance usually abnormal
Carbohydrate Inducibility usually abnormal
Fat Intolerance Normal

Imaging Findings

There are no specific findings associated with primary hypertriglyceridemia.

Other Diagnostic Studies

There are no other diagnostic studies associated with the diagnosis of primary hypertriglyceridemia.

Treatment

The mainstay of treatment of primary hypertriglyceridemia is lifestyle modification (e.g., diet and exercise). Medical therapy shows benefits in patients in whom lifestyle modifications fail to control triglyceride levels. Gene therapy is an emerging treatment option. Supportive clinical trial data for pharmacological therapies for treatment of hypertriglyceridemia includes:

Non-Pharmacological

  • The mainstay of therapy for hypertriglyceridemia includes lifestyle modifications to lower the triglyceride levels to below 150 mg/dl.
    • A reduction of weight by 5-10% can help decrease the triglyceride levels by 20%.[23]
  • Other measures include steps to reduce dietary fat and limit the consumption of high glycemic index foods.[37]
    • Appropriate dietary changes, coupled with an increase in aerobic activity, can substantially decrease triglyceride content in the body.
    • Diet adjustment and weight loss can cut triglyceride levels by up to 25%.[38]
    • In conjunction with other lifestyle modifications, the daily consumption of 4 grams of omega 3 fatty acids can also be helpful in reducing plasma levels by up to 20%.[39][40]
  • Other factors that may be secondarily increasing triglyceride levels, including diabetes and/or hypothyroidism, should be treated; alcohol consumption should be minimized; and medications like beta blockers, isotretinoin, glucocorticoids may have to be held to help with decreasing excessively increased triglyceride levels.

Medical Therapy

The means of treating elevated triglyceride levels varies according to the severity of the condition.

The following table demonstrates features of various pharmacological therapies aimed at decreasing serum triglyceride levels:

Drug Mechanism of benefit Dosage Advantages Side-effects Contraindication
Niacin/Nicotinic acid 1.5 - 2 gm once daily
  • Flushing
  • Pruritus
  • Nausea
  • Hepatitis (higher doses)
Omega-3 fatty acids
  • Bleeding at high doses
  • Fishy smell, can be reduced by
    • Freezing of medication
    • Trying different formulation
    • Taking medication with food
  • Nausea

(approximately 4 % of individuals at < 3 gm/d, and 20% at > 4gm/d experiences git side-effects)[43]

  • Hypersensitivity
Fibrate
  • ↑ - Increase
  • ↓ - Decrease

Emerging treatment options

Surgery

  • Surgical intervention is not recommended for the management of primary hypertriglyceridemia.
  • Xanthomas may be surgically removed for cosmetic purposes.

Prevention

Primary Prevention

As primary hypertriglyceridemia is a genetic disease, no recommendations have been established proposed for its primary prevention.

Secondary Prevention

Measures for the secondary prevention of primary hypertriglyceridemia include:

  • Genetic counseling
  • The NCEP proposes dietary and behavioral measures to reduce the burden of atherosclerosis.[7][51][52]
    • Clinical approach includes lifestyle modifications.
    • Population-based approach includes the reduction of individual risk of the patient.

References

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