Primary hypertriglyceridemia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2]
Synonyms and keywords: Familial hypertriglyceridemia; Type IV hyperlipoproteinemia; Type-IV hyperlipoproteinemia; Type 4 hyperlipoproteinemia
Overview
Primary hypertriglyceridemia, or type 4 hyperlipidemia, develops from 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
- In 1967, Dr. Fredrickson classified lipoprotein disorders using paper electrophoresis.[2]
- In 1964, Dr. Leverton explained the post-carbohydrate rise in triglycerides and the difference in the levels in patients with cirrhosis and metastasis.[3]
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 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:[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]
- Normal triglycerides: <150 mg/dL
- Borderline-high triglycerides: 150-199 mg/dL
- High triglycerides: 200-499 mg/dL
- Very high triglycerides: >500 mg/dL
Pathophisiology
Pathogenesis
The regulation of lipids in the body can be affected at any of the following three stages:[8]
- 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
- The reverse cholesterol transport involves exchange of TGs (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%.[9][10][11]
- Abnormal very low density lipoprotein (VLDL) production in liver (internal pathway) and synthesis of chylomicrons in the intestines (external pathway)
- Abnormal lipoprotein lipase (LPL)-mediated lipolysis
- Abnornal remanant clearance
- Reduction of HDL-C levels (hypoalphalipoproteinemia), which predisposes patients to ischemic heart disease
Primary hypertriglyceridemia causes an increase in the 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.[12]
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 lipomics in the blood, including:
- Familial hypercholesterolemia/Familial combined hyperlipidemia
- Dysbetalipoprotenemia
- Mixed hyperlipoprotenemia
Different features some times must also be differentiated from similar conditions, e.g xanthomas[17] should be differentiated from
- Sitosterolemia
- Cerebrotendinous Xanthomatosis (CTX) - CYP27A1 recesive gene mutation
Epidemiology and Demographics
- 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]
- Obesity
- Diabetes melitis type 2 or Insulin resistance
- Hypertension
- Use of certain medications
Screening
There are no recommendation 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 damage 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]
- Cardiovascular diseases, particularly atherosclerosis of the coronary vessels[24]
- The prevalence of primary hypertriglyceridemia with hypoalphalipoproteinemia in patients less than 55 years of age undergoing coronary arteriography was found to be 15 percent,[25] while an increased risk of ischemic heart disease was found in heterozygous carriers for Gly188Glu mutations in the LPL gene.[10]
- 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[26][27]
- Non-insulin-dependent diabetes mellitus
- Primary hypertriglyceridemia predisposes patients to the development of NIDDM.[28]
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 seen on the elbows and buttocks
Musculoskeletal
- Lipid deposits on tendons
- Joint pain
ENT
- Throat pain
-
Eruptive Xanthomas on an elbow.
Physical Examination
Common physical examination findings of primary hypertriglyceridemia include:[32][33]
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
-
Eruptive xanthoma.
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, | 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.
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.
- A moderate increase (i.e., >500 but <1000) can be treated by statins, while severe increases (>1000) or isolated hypertriglyceridemia needs to be treated by using a fibrate as the primary treatment.[8]
- Extended release niacin (Nicotinic acid) can be used in patients with low HDL and elevated triglyceride levels. [23][33]
- Lomitapide is used to treat genetic hypertriglyceridemia and recurrent refractory acute pancreatitis[41]
Emerging treatment options
- Gene therapy has been recently introduced for patients with LPL deficiency and recurrent or severe pancreatitis. [42]
- Rimonabant a cannabinoid-1 (CB1) receptor antagonist works by decreasing appetite and consumption of food.[43] [44]
- Glitazar drugs have dual agonists on peroxisome proliferator-activated receptor-α (like fibrates) and -γ (like thiozolidinidiones).[45]
- LPL Gene therapy may be helpful by treating monogenic LPL (lipoprotein lipase) deficiency.[46]
Surgery
- Surgical intervention is not recommended for the management of primary hypertriglyceridemia.
- Xanthomas may be surgically removed for cosmetic purposes.
Prevention
Primary Prevention
Primary hypertriglyceridemia is a genetic disease and there are no recommendations proposed so far for the primary prevention.
Secondary Prevention
Secondary prevention of primary hypertriglyceridemia may be achieved with
- Genetic counselling
- The NCEP proposes dietary and behavioral measures to reduce the burden of atherosclerosis.[7][47][48]
- Clinical approach includes lifestyle modifications
- Population based approach includes reduction of individual risk of the patint
References
- ↑ 1.0 1.1 Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH; et al. (2012). "Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline". J Clin Endocrinol Metab. 97 (9): 2969–89. doi:10.1210/jc.2011-3213. PMC 3431581. PMID 22962670.
- ↑ Culliton BJ (1987). "Fredrickson's bitter end at Hughes". Science. 236 (4807): 1417–8. PMID 3296193.
- ↑ LEVERTON RM (1964). "CARBOHYDRATE INDUCED HYPERTRIGLYCERIDEMIA". Nutr Rev. 22: 328–30. PMID 14223171.
- ↑ De Castro-Orós I, Civeira F, Pueyo MJ, Mateo-Gallego R, Bolado-Carrancio A, Lamíquiz-Moneo I; et al. (2016). "Rare genetic variants with large effect on triglycerides in subjects with a clinical diagnosis of familial vs nonfamilial hypertriglyceridemia". J Clin Lipidol. 10 (4): 790–7. doi:10.1016/j.jacl.2016.02.010. PMID 27578109.
- ↑ Hruz PW (2015). "Commentary". Clin Chem. 61 (12): 1444. doi:10.1373/clinchem.2015.243964. PMID 26614228.
- ↑ 6.0 6.1 Bouabdellah M, Iraqi H, Benlian P, Berqia I, Benchekroun L, Chraïbi A; et al. (2015). "[Familial hypertriglyceridemia: biochemical, clinical and molecular study in a Moroccan family]". Ann Biol Clin (Paris). 73 (4): 474–84. doi:10.1684/abc.2015.1058. PMID 26104879.
- ↑ 7.0 7.1 National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2002). "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. 106 (25): 3143–421. PMID 12485966.
- ↑ 8.0 8.1 Hachem SB, Mooradian AD (2006). "Familial dyslipidaemias: an overview of genetics, pathophysiology and management". Drugs. 66 (15): 1949–69. PMID 17100406.
- ↑ Hassing HC, Surendran RP, Mooij HL, Stroes ES, Nieuwdorp M, Dallinga-Thie GM (2012). "Pathophysiology of hypertriglyceridemia". Biochim Biophys Acta. 1821 (5): 826–32. doi:10.1016/j.bbalip.2011.11.010. PMID 22179026.
- ↑ 10.0 10.1 10.2 Wittrup HH, Tybjaerg-Hansen A, Nordestgaard BG (1999). "Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis". Circulation. 99 (22): 2901–7. PMID 10359734.
- ↑ Nordestgaard BG, Abildgaard S, Wittrup HH, Steffensen R, Jensen G, Tybjaerg-Hansen A (1997). "Heterozygous lipoprotein lipase deficiency: frequency in the general population, effect on plasma lipid levels, and risk of ischemic heart disease". Circulation. 96 (6): 1737–44. PMID 9323055.
- ↑ Attia N, Ramaharo A, Paul JL, Cambillau M, Beaune P, Grynberg A; et al. (2008). "Enhanced removal of cholesterol from macrophage foam cells to serum from type IV hypertriglyceridemic subjects". Atherosclerosis. 198 (1): 49–56. doi:10.1016/j.atherosclerosis.2007.09.023. PMID 17980882.
- ↑ Johansen CT, Hegele RA (2011). "Genetic bases of hypertriglyceridemic phenotypes". Curr Opin Lipidol. 22 (4): 247–53. doi:10.1097/MOL.0b013e3283471972. PMID 21519249.
- ↑ 14.0 14.1 Shah AS, Wilson DP (2015). "Primary hypertriglyceridemia in children and adolescents". J Clin Lipidol. 9 (5 Suppl): S20–8. doi:10.1016/j.jacl.2015.04.004. PMID 26343209.
- ↑ 15.0 15.1 15.2 Yuan G, Al-Shali KZ, Hegele RA (2007). "Hypertriglyceridemia: its etiology, effects and treatment". CMAJ. 176 (8): 1113–20. doi:10.1503/cmaj.060963. PMC 1839776. PMID 17420495.
- ↑ Ford ES, Giles WH, Dietz WH (2002). "Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey". JAMA. 287 (3): 356–9. PMID 11790215.
- ↑ 17.0 17.1 Koopal C, Visseren FL, Marais AD, Westerink J, Spiering W (2016). "Tendon xanthomas: Not always familial hypercholesterolemia". J Clin Lipidol. 10 (5): 1262–5. doi:10.1016/j.jacl.2016.05.005. PMID 27678445.
- ↑ 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
- ↑ Tullu MS, Advirkar AV, Ghildiyal RG, Tambe S (2008). "Familial hypertriglyceridemia". Indian J Pediatr. 75 (12): 1257–8. doi:10.1007/s12098-008-0219-y. PMID 19057857.
- ↑ Chou R, Dana T, Blazina I, Daeges M, Bougatsos C, Jeanne TL (2016). "Screening for Dyslipidemia in Younger Adults: A Systematic Review for the U.S. Preventive Services Task Force". Ann Intern Med. 165 (8): 560–564. doi:10.7326/M16-0946. PMID 27538032.
- ↑ US Preventive Services Task Force. Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW; et al. (2016). "Screening for Lipid Disorders in Children and Adolescents: US Preventive Services Task Force Recommendation Statement". JAMA. 316 (6): 625–33. doi:10.1001/jama.2016.9852. PMID 27532917.
- ↑ {{https://medlineplus.gov/ency/article/000408htm}} Accessed on 7 November,2016
- ↑ 23.0 23.1 23.2 Kushner PA, Cobble ME (2016). "Hypertriglyceridemia: the importance of identifying patients at risk". Postgrad Med. doi:10.1080/00325481.2016.1243005. PMID 27710158.
- ↑ Thompson WG, Gau GT (2009). "Hypertriglyceridemia and its pharmacologic treatment among US adults--invited commentary". Arch Intern Med. 169 (6): 578–9. doi:10.1001/archinternmed.2008.594. PMID 19307520.
- ↑ Genest JJ, Martin-Munley SS, McNamara JR, Ordovas JM, Jenner J, Myers RH; et al. (1992). "Familial lipoprotein disorders in patients with premature coronary artery disease". Circulation. 85 (6): 2025–33. PMID 1534286.
- ↑ Tsuang W, Navaneethan U, Ruiz L, Palascak JB, Gelrud A (2009). "Hypertriglyceridemic pancreatitis: presentation and management". Am J Gastroenterol. 104 (4): 984–91. doi:10.1038/ajg.2009.27. PMID 19293788.
- ↑ Glueck CJ, Lang J, Hamer T, Tracy T (1994). "Severe hypertriglyceridemia and pancreatitis when estrogen replacement therapy is given to hypertriglyceridemic women". J Lab Clin Med. 123 (1): 59–64. PMID 8288962.
- ↑ Sane T, Taskinen MR (1993). "Does familial hypertriglyceridemia predispose to NIDDM?". Diabetes Care. 16 (11): 1494–501. PMID 8299439.
- ↑ Austin MA, McKnight B, Edwards KL, Bradley CM, McNeely MJ, Psaty BM; et al. (2000). "Cardiovascular disease mortality in familial forms of hypertriglyceridemia: A 20-year prospective study". Circulation. 101 (24): 2777–82. PMID 10859281.
- ↑ Leaf DA (2008). "Chylomicronemia and the chylomicronemia syndrome: a practical approach to management". Am J Med. 121 (1): 10–2. doi:10.1016/j.amjmed.2007.10.004. PMID 18187065.
- ↑ Rachadi H, Ramli I, Touzani A, Hassam B, Ismaili N (2016). "[Spectacular presentation of tuberous xanthomas revealing a homozygous familial hypercholesterolemia]". Presse Med. 45 (2): 269–71. doi:10.1016/j.lpm.2015.09.027. PMID 26796480.
- ↑ 32.0 32.1 Soubrier M, Dubost JJ, Thiéblot P, Ristori JM (2009). "Oligo-arthritis and type IV hyperlipoproteinemia". Joint Bone Spine. 76 (1): 95–7. doi:10.1016/j.jbspin.2008.03.009. PMID 19064332.
- ↑ 33.0 33.1 33.2 Pejic RN, Lee DT (2006). "Hypertriglyceridemia". J Am Board Fam Med. 19 (3): 310–6. PMID 16672684.
- ↑ Sandoval-Sus JD, Zhang L (2016). "Familial hypertriglyceridemia manifests with pancytopenia and bone marrow pseudo–Niemann-Pick cells". Blood. 127 (6): 787. PMID 27453965.
- ↑ Bordugo A, Carlin E, Demarini S, Faletra F, Colonna F (2014). "A neonate with a 'milky' blood. What can it be?". Arch Dis Child Fetal Neonatal Ed. 99 (6): F514. doi:10.1136/archdischild-2014-305940. PMID 24747307.
- ↑ Braunwald, Eugene. Heart Disease- Fourth Edition. Harvard Medical School: W. B. SAUNDERS COMPANY. p. 1137. ISBN 0-7216-3097-9.
- ↑ Jenkins DJ, Kendall CW, Augustin LS, Franceschi S, Hamidi M, Marchie A; et al. (2002). "Glycemic index: overview of implications in health and disease". Am J Clin Nutr. 76 (1): 266S–73S. PMID 12081850.
- ↑ Gerhard GT, Ahmann A, Meeuws K, McMurry MP, Duell PB, Connor WE (2004). "Effects of a low-fat diet compared with those of a high-monounsaturated fat diet on body weight, plasma lipids and lipoproteins, and glycemic control in type 2 diabetes". Am J Clin Nutr. 80 (3): 668–73. PMID 15321807.
- ↑ Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ; et al. (2006). "Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review". BMJ. 332 (7544): 752–60. doi:10.1136/bmj.38755.366331.2F. PMC 1420708. PMID 16565093.
- ↑ Stefanutti C, Julius U (2015). "Treatment of primary hypertriglyceridemia states--General approach and the role of extracorporeal methods". Atheroscler Suppl. 18: 85–94. doi:10.1016/j.atherosclerosissup.2015.02.017. PMID 25936310.
- ↑ Brahm AJ, Hegele RA (2016). "Lomitapide for the treatment of hypertriglyceridemia". Expert Opin Investig Drugs. doi:10.1080/13543784.2016.1254187. PMID 27785928.
- ↑ Kassner U, Salewsky B, Wühle-Demuth M, Szijarto IA, Grenkowitz T, Binner P; et al. (2015). "Severe hypertriglyceridemia in a patient heterozygous for a lipoprotein lipase gene allele with two novel missense variants". Eur J Hum Genet. 23 (9): 1259–61. doi:10.1038/ejhg.2014.295. PMC 4538214. PMID 25585702.
- ↑ Boyd ST, Fremming BA (2005). "Rimonabant--a selective CB1 antagonist". Ann Pharmacother. 39 (4): 684–90. doi:10.1345/aph.1E499. PMID 15755787.
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- ↑ Nissen SE, Wolski K, Topol EJ (2005). "Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus". JAMA. 294 (20): 2581–6. doi:10.1001/jama.294.20.joc50147. PMID 16239637.
- ↑ Rip J, Nierman MC, Sierts JA, Petersen W, Van den Oever K, Van Raalte D; et al. (2005). "Gene therapy for lipoprotein lipase deficiency: working toward clinical application". Hum Gene Ther. 16 (11): 1276–86. doi:10.1089/hum.2005.16.1276. PMID 16259561.
- ↑ "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)". JAMA. 269 (23): 3015–23. 1993. PMID 8501844.
- ↑ Carleton RA, Dwyer J, Finberg L, Flora J, Goodman DS, Grundy SM; et al. (1991). "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". Circulation. 83 (6): 2154–232. PMID 2040066.