Familial combined hyperlipidemia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2], Prince Tano Djan, BSc, MBChB [3], Vishal Devarkonda, M.B.B.S[4]
To view Lipoprotein disorders main page Click here
To view Hyperlipoproteinemia main page Click here
Synonyms and keywords: Type IIB hyperlipoproteinemia, Multiple phenotype familial hyperlipidemia, Familial combined hyperlipoproteinemia, and Familial combined hypercholesterolemia-hypertriglyceridemia.
Overview
Familial combined hyperlipidemia is a common metabolic disorder charaterized by increase in cholesterol and/or triglycerides in at least two members of the family, variable intra-individual and intrafamilial lipid phenotype, and increased risk of premature coronary heart disease. Several theories have been postulated about the development of familial combined hyperlipidemia. Its prevalence is estimated to be 0.5-2% in general population annually.[1]
Historical perspective
- In 1967, Fredrickson using paper electrophosresis, classified lipoprotein disorders.[2]
- In 1973, familial combined hyperlipidemia (FCHL) for the first time in medical literature was described by Goldstein.
Classification
- There is no established classification for familial combined hyperlipidemia.
For a detailed classification of hyperlipoproteinemia click here.
Pathophysiology
Pathogenesis
The exact pathogenesis of familial combined hyperlipidemia remains (FCHL) is unknown. Several theories have been postulated about the development of familial combined hyperlipidemia. The underlying mechanisms of the disease involves the following:[1]
VLDL abnormalities
- In many cases, FCHL is caused by overproduction of VLDL-apo B.
- Overproduction of VLDL-apo B could be do to the following:[3][4][5][6]
- Alterations to incorporations of fatty acids in the triglyceride(TG).
- Alterations in postprandial metabolism of VLDLs.
- Defects in activity of lipoprotein lipase, lecithin:cholesterol acyltransferase, and/or hepatic lipase.
- Decreased fatty acid oxidation in liver, results in overproduction of triacylglycerol(TAG), with fatty acids directed to triglyceride(TG) synthesis.
- Imparied postprandial C3 response, would result in impaired peripheral postprandial FFA uptake, which leads to increased hepatic free fatty acids(FFA) flux and VLDL overproduction.
LDL abnormalities
- In many cases, FCHL is caused by predominance of atherogenic LDL "B"(atherogenic) pattern
- LDL "B" pattern could be due to following:[7][8]
- Overproduction of apo B.
- Relative deficit of hepatic lipoprotein lipase can reduce the liver uptake of apo B, leading to increase synthesis of apolipoproteins.
- An increase LDL susceptibility oxidation.
HDLs abnormalities
- In many cases, FCHL is associated with reduced levels of HDL-C.
- Low HDL-C, could be due to the following:[9][10]
- TG-enrichment of HDL particles
- Enhanced hepatic lipase (HL)
- Very high concentration of VLDL-1
Genetics
- The following genes were found to be associated with familial combined hyperlipidemia:[11][12][13][14]
- Locus 1q21-q23, is linked to be associated with familial combined hyperlipidemia and diabetes.
- Newly discovered apo AV gene with APOAI/CIII/AIV cluster was to be associated with FCH transmission.
- Few studies found FCH trait is influenced by multiple loci located to 9p, 16q, and 11.
- Gene encoding upstream transcription factor 1 (USF1) has appeared to be linked to FCH.
Causes
- The cause of familial combined hyperlipidemia is genetic, with complex inheritance to explain the variability in the phenotype.
- Gene-envirnoment interaction strongly influence the laboratory and clinical features of familial combined hyperlipidemia.
Differential diagnosis
Familial combined hyperlipidemia must be differentiated from all other kinds of hyperlipidemias. On the basis of high triglyceride levels it can be differentiated from:
- Familial hyperchylomicronemia
- Familial hypercholesterolemia
- Dysbetalipoprotenemia
- Primary hypertriglyceridemia/ Primary hypertriglyceridemia
- Drugs causing high triglyceride levels:[15]
- Atypical antipsychotic drugs (fluperlapine, clozapine, olanzapine), beta-blockers (especially non-beta 1-selective), bile acid sequestrants, cyclophosphamide, glucocorticoids, Immunosuppressive drugs (cyclosporine, sirolimus), interferon, L-asparaginase, oral estrogens, protease inhibitors, raloxifene, retinoids, rosiglitazone, tamoxifen, thiazide diuretics.
For a detailed differential diagnosis of hyperlipoproteinemia click here.
Epidemiology and Demographics
Epidemiology
Familial combined hyperlipidemia is a a very common genetic hyperlipidemia . The prevalence is estimated to be 0.5-2% in general population annually. Familial combined hyperlipidemia is commonly seen in patients with coronary disease( 10%) , patients less than 60 years of age who have survived an acute infarct (11.3%) and upto 40% in all myocardial infarction survivors. [16][17] More than 3.5 million people in EU and 2.7 million in the US suffer from familial combined hyperlipidemia.[16]
Demographics
Geographical distribution can not be estimated so far as most of the studies conducted on familial combined hyperlipidemia consist of Caucasian population living the United States and Europe.[18]
Age
Familial combined hyperlipidemia is commonly seen in all ages in myocardial infarction survivors.[17] Dr. Iwata in 2003 explained that many patients with familial combined hyperlipidemia present during their childhood.[19]
Gender
Familial combined hyperlipidemia affects men and women equally.
Screening
Screening in children and adolescents
The USPSTF has no screening guidelines for the detection of familial combined hyperlipidemia however, early detection of lipid disorders in childhood has benefit of reducing the risk and severity of cardiovascular disease (CVD) in adulthood. The pediatric dyslipidemia screening guidelines from the 2011 expert panel integrated Guidelines for cardiovascular health and risk reduction in children and adolescents has therefore outlined the following:[20][21] [22]
|
Pediatric dyslipidemia screening guidelines from the 2011 Expert Panel Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents | ||
|---|---|---|
| Age | Screening recommendation | Reommendation level |
| birth- <2years | No lipid screening | C |
| 2-8years ( No routine lipid screening,
however screen if one of the following is present using FLP two times) |
Parent, grandparent, aunt/uncle, or sibling with myocardial infarction (MI), angina, stroke, coronary artery bypass graft Strongly recommend (CABG)/stent/angioplasty at <55 years in males, <65 years in females | B |
| Parent with TC ≥ 240 mg/dL or known dyslipidemia | B | |
| Child has diabetes, hypertension, BMI ≥ 95th percentile or smokes cigarettes | B | |
| Child has a moderate- or high-risk medical condition (eg. Diabetes mellitus type 1 and type 2, chronic renal disease/end-stage renal disease/ postrenal transplant, Postorthotopic heart transplant, Kawasaki disease with current aneurysms) | B | |
| 9-11years (Universal Screening) | Universal screening with a non-FLP screening using non-HDL-C levels ( Non-HDL–C = TC – HDL–C) when Non-HDL ≥ 145 mg/dL, HDL < 40 mg/dL check FLP × 2 | B |
| Do further FLP if LDL–C ≥ 130 mg/dL, non-HDL–C ≥ 145 mg/dL HDL–C < 40 mg/dL, TG ≥ 100 mg/dL if < 10 years; ≥ 130 mg/dL if ≥ 10 years. Repeat FLP after 2 weeks but within 3 months | B | |
| 12-16years (Selective screening using FLP x 2) | Lipid screening is not recommended for those ages 12–16 years because of significantly decreased sensitivity and specificity for predicting adult LDL–C levels and significantly increased false-negative results in this age group. Selective screening ( Interval between FLP measurements: after 2 weeks but within 3 months) is recommended for those with the clinical indications outlined below: | B |
| Parent, grandparent, aunt/uncle or sibling with MI, angina, stroke, CABG/stent/ Strongly recommend angioplasty, sudden death at < 55 years in males, < 65 years in females | B | |
| • Parent with TC ≥ 240 mg/dL or known dyslipidemia | B | |
| Patient has diabetes, hypertension, BMI ≥ 85th pr\ercentile or smokes cigarettes | B | |
| Patient has a moderate- or high-risk medical condition (eg. Diabetes mellitus type 1 and type 2, chronic renal disease/end-stage renal disease/ postrenal transplant, Postorthotopic heart transplant, Kawasaki disease with current aneurysms) | B | |
| 17-19years | Universal screening once during this time period with a nonfasting lipid screening using non-HDL-C levels. If Non-HDL-C ≥ 145 mg/dL, HDL-C < 40 mg/dL do FLP × 2, Further screening with FLP if LDL-C ≥ 130 mg/dL, non-HDL-C ≥ 145 mg/dL HDL-C < 40 mg/dL, TG ≥ 130 mg/dL repeat FLP after 2 weeks but within 3 months | B |
| 17-21years | Universal screening once during this time period with a nonfasting lipid screening using non-HDL-C levels. If Non-HDL-C ≥ 190 mg/dL, HDL-C < 40 mg/dL do FLP × 2, Further screening with FLP when LDL-C ≥ 160 mg/dL, non-HDL-C ≥ 190 mg/dL, HDL-C < 40 mg/dL, TG ≥ 150 mg/dL repeat FLP after 2 weeks but within 3 months | B |
Natural History, Complications, and Prognosis
Natural History
If left untreated, familial combined hyperlipidemia leads to increased carotid artery initima-media thickness and an increased risk of cardiovascular disease.[23]
Complications
Complications that can develop in patients with familial combined hyperlipidemia include:[24][25][26][27]
Prognosis
The presence of hypertriglyceridemia along with hypercholesterolemia is a poor prognostic factor. The coronary flow reserve in young patients is decreased in the presence of this combination.[28]
Diagnosis
History and symptoms
History is usually suggestive of:
- Premature cardiovascular disease, such as:
- Family history of premature atherosclerosis
Physical examination
Ptients with familial combined hyperlipidemia may present with the following:
Eyes
- Xanthelasma palpabrum (yellowish patches above the eyelids)
- Arcus senilis corneae, whitish discoloration of the iris
Extremities
- Tendon xanthomas
Non-specific signs
The following non-specific signs may also be seen in patients with familial combined hyperlipidemia:
- Obesity and insulin resistance[29]
- waist-to-hip ratio appears to be the best determinant of hyperlipidemia, particularly hypertriglyceridemia in FCHL patients.[18]
Laboratory findings
Assessment of the lipid profiles of at least three first-degree relatives is necessary.[30]
A high degree of diagnostic uncertainty exists in the categorization as normal or abnormal of members of FCHL.[18] Its manifestations include:[30][3][9]
- Hypercholesterolemia
- Hypertriglyceridemia
- Combination of above
- Increased circulating very-low-density lipoprotein (VLDL) apolipoprotein (apo) B
- Reduced levels of HDL cholesterol
- Children with apolipoprotein B level exceeding the 95th percentile may be diagnostic of familial combined hyperlipidemia (FCHL).[31]
- Familial combined hyperlipidemia (FCHL) is traditionally diagnosed by total plasma cholesterol and/or triglyceride levels above the 90th percentile adjusted for age and gender. However, recent studies suggest that the diagnosis of FCHL is best predicted by absolute apoB levels combined with triglyceride and total cholesterol levels adjusted for age and gender and may accurately be calculated by a nomogram.[32]
Treatment
Non-pharmacological therapy
- Exercise and dietary therapy with low cholesterol and fat diet have been shown to be effective.
- Avoiding other risk factors responsible for the complications (example smoke cessation).
- Subnormal control with non pharmacological therapies requires pharmacological treatment.
Medical Therapy
Familial combined hyperlipidemia can be treated with the following options:[18]
- Bile acid binding agents are an option if triglyceride levels are <200mg/dL.
- Statins can be used if triglyceride levels are <500mg/dL.
- Fibrates and Nicotinic acid can otherwise be used.
Prevention
Prevention of complications
Disease prevention in familial combined hyperlipidemia is mainly towards prevention of complications as shown below:[33]
- Early screening in childhood in case of family history of premature cardiovascular disease or severe hyperlipidemia in first degree relatives
- Lifestyle modifications
- Control of cardiovascular risk factors
References
- ↑ 1.0 1.1 Gaddi A, Cicero AF, Odoo FO, Poli AA, Paoletti R, Atherosclerosis and Metabolic Diseases Study Group (2007). "Practical guidelines for familial combined hyperlipidemia diagnosis: an up-date". Vasc Health Risk Manag. 3 (6): 877–86. PMC 2350131. PMID 18200807.
- ↑ Culliton BJ (1987). "Fredrickson's bitter end at Hughes". Science. 236 (4807): 1417–8. PMID 3296193.
- ↑ 3.0 3.1 Venkatesan S, Cullen P, Pacy P, Halliday D, Scott J (1993). "Stable isotopes show a direct relation between VLDL apoB overproduction and serum triglyceride levels and indicate a metabolically and biochemically coherent basis for familial combined hyperlipidemia". Arterioscler Thromb. 13 (7): 1110–8. PMID 8318511.
- ↑ Meijssen S, Derksen RJ, Bilecen S, Erkelens DW, Cabezas MC (2002). "In vivo modulation of plasma free fatty acids in patients with familial combined hyperlipidemia using lipid-lowering medication". J Clin Endocrinol Metab. 87 (4): 1576–80. doi:10.1210/jcem.87.4.8408. PMID 11932285.
- ↑ Evans K, Burdge GC, Wootton SA, Collins JM, Clark ML, Tan GD; et al. (2008). "Tissue-specific stable isotope measurements of postprandial lipid metabolism in familial combined hyperlipidaemia". Atherosclerosis. 197 (1): 164–70. doi:10.1016/j.atherosclerosis.2007.03.009. PMID 17466309.
- ↑ Pihlajamäki J, Karjalainen L, Karhapää P, Vauhkonen I, Taskinen MR, Deeb SS; et al. (2000). "G-250A substitution in promoter of hepatic lipase gene is associated with dyslipidemia and insulin resistance in healthy control subjects and in members of families with familial combined hyperlipidemia". Arterioscler Thromb Vasc Biol. 20 (7): 1789–95. PMID 10894818.
- ↑ Vakkilainen J, Pajukanta P, Cantor RM, Nuotio IO, Lahdenperä S, Ylitalo K; et al. (2002). "Genetic influences contributing to LDL particle size in familial combined hyperlipidaemia". Eur J Hum Genet. 10 (9): 547–52. doi:10.1038/sj.ejhg.5200844. PMID 12173032.
- ↑ Corella D, Ordovas JM (2005). "SINGLE NUCLEOTIDE POLYMORPHISMS THAT INFLUENCE LIPID METABOLISM: Interaction with Dietary Factors". Annu Rev Nutr. 25: 341–90. doi:10.1146/annurev.nutr.25.050304.092656. PMID 16011471.
- ↑ 9.0 9.1 Soro A, Jauhiainen M, Ehnholm C, Taskinen MR (2003). "Determinants of low HDL levels in familial combined hyperlipidemia". J Lipid Res. 44 (8): 1536–44. doi:10.1194/jlr.M300069-JLR200. PMID 12777471.
- ↑ Georgieva AM, van Greevenbroek MM, Krauss RM, Brouwers MC, Vermeulen VM, Robertus-Teunissen MG; et al. (2004). "Subclasses of low-density lipoprotein and very low-density lipoprotein in familial combined hyperlipidemia: relationship to multiple lipoprotein phenotype". Arterioscler Thromb Vasc Biol. 24 (4): 744–9. doi:10.1161/01.ATV.0000119681.47218.a4. PMID 14751815.
- ↑ Austin MA, Brunzell JD, Fitch WL, Krauss RM (1990). "Inheritance of low density lipoprotein subclass patterns in familial combined hyperlipidemia". Arteriosclerosis. 10 (4): 520–30. PMID 2369363.
- ↑ Coon H, Myers RH, Borecki IB, Arnett DK, Hunt SC, Province MA; et al. (2000). "Replication of linkage of familial combined hyperlipidemia to chromosome 1q with additional heterogeneous effect of apolipoprotein A-I/C-III/A-IV locus. The NHLBI Family Heart Study". Arterioscler Thromb Vasc Biol. 20 (10): 2275–80. PMID 11031215.
- ↑ Eichenbaum-Voline S, Olivier M, Jones EL, Naoumova RP, Jones B, Gau B; et al. (2004). "Linkage and association between distinct variants of the APOA1/C3/A4/A5 gene cluster and familial combined hyperlipidemia". Arterioscler Thromb Vasc Biol. 24 (1): 167–74. doi:10.1161/01.ATV.0000099881.83261.D4. PMC 2773540. PMID 14551155.
- ↑ Badzioch MD, Igo RP, Gagnon F, Brunzell JD, Krauss RM, Motulsky AG; et al. (2004). "Low-density lipoprotein particle size loci in familial combined hyperlipidemia: evidence for multiple loci from a genome scan". Arterioscler Thromb Vasc Biol. 24 (10): 1942–50. doi:10.1161/01.ATV.0000143499.09575.93. PMID 15331429.
- ↑ Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH et al. (2014) National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive summary. J Clin Lipidol 8 (5):473-88. DOI:10.1016/j.jacl.2014.07.007 PMID: 25234560
- ↑ 16.0 16.1 Gaddi A, Galetti C, Pauciullo P, Arca M (1999). "Familial combined hyperlipoproteinemia: experts panel position on diagnostic criteria for clinical practice. Committee of experts of the Atherosclerosis and Dysmetabolic Disorders Study Group". Nutr Metab Cardiovasc Dis. 9 (6): 304–11. PMID 10765523.
- ↑ 17.0 17.1 de Bruin TW, Mailly F, van Barlingen HH, Fisher R, Castro Cabezas M, Talmud P; et al. (1996). "Lipoprotein lipase gene mutations D9N and N291S in four pedigrees with familial combined hyperlipidaemia". Eur J Clin Invest. 26 (8): 631–9. PMID 8872057.
- ↑ 18.0 18.1 18.2 18.3 Gaddi A, Cicero AF, Odoo FO, Poli AA, Paoletti R, Atherosclerosis and Metabolic Diseases Study Group (2007). "Practical guidelines for familial combined hyperlipidemia diagnosis: an up-date". Vasc Health Risk Manag. 3 (6): 877–86. PMC 2350131. PMID 18200807.
- ↑ Iwata F, Okada T, Kuromori Y, Hara M, Harada K (2003). "Screening for familial combined hyperlipidemia in children using lipid phenotypes". J Atheroscler Thromb. 10 (5): 299–303. PMID 14718747.
- ↑ Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. National Heart, Lung, and Blood Institute (2011). "Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report". Pediatrics. 128 Suppl 5: S213–56. doi:10.1542/peds.2009-2107C. PMC 4536582. PMID 22084329.
- ↑ Gooding HC, Rodday AM, Wong JB, Gillman MW, Lloyd-Jones DM, Leslie LK; et al. (2015). "Application of Pediatric and Adult Guidelines for Treatment of Lipid Levels Among US Adolescents Transitioning to Young Adulthood". JAMA Pediatr. 169 (6): 569–74. doi:10.1001/jamapediatrics.2015.0168. PMID 25845026.
- ↑ Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents http://www.nhlbi.nih.gov/guidelines/cvd_ped/peds_guidelines_full.pdf.
- ↑ Keulen ET, Kruijshoop M, Schaper NC, Hoeks AP, de Bruin TW (2002). "Increased intima-media thickness in familial combined hyperlipidemia associated with apolipoprotein B." Arterioscler Thromb Vasc Biol. 22 (2): 283–8. PMID 11834529.
- ↑ Brouwers MC, Reesink KD, van Greevenbroek MM, Meinders JM, van der Kallen CJ, Schaper N; et al. (2009). "Increased arterial stiffness in familial combined hyperlipidemia". J Hypertens. 27 (5): 1009–16. PMID 19402225.
- ↑ Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG (1973). "Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia". J Clin Invest. 52 (7): 1544–68. doi:10.1172/JCI107332. PMC 302426. PMID 4718953.
- ↑ Sniderman AD, Castro Cabezas M, Ribalta J, Carmena R, de Bruin TW, de Graaf J; et al. (2002). "A proposal to redefine familial combined hyperlipidaemia -- third workshop on FCHL held in Barcelona from 3 to 5 May 2001, during the scientific sessions of the European Society for Clinical Investigation". Eur J Clin Invest. 32 (2): 71–3. PMID 11895451.
- ↑ Ayyobi AF, Brunzell JD (2003). "Lipoprotein distribution in the metabolic syndrome, type 2 diabetes mellitus, and familial combined hyperlipidemia". Am J Cardiol. 92 (4A): 27J–33J. PMID 12957324.
- ↑ Pitkänen OP, Nuutila P, Raitakari OT, Porkka K, Iida H, Nuotio I; et al. (1999). "Coronary flow reserve in young men with familial combined hyperlipidemia". Circulation. 99 (13): 1678–84. PMID 10190876.
- ↑ van der Vleuten GM, Veerkamp MJ, van Tits LJ, Toenhake H, den Heijer M, Stalenhoef AF; et al. (2005). "Elevated leptin levels in subjects with familial combined hyperlipidemia are associated with the increased risk for CVD". Atherosclerosis. 183 (2): 355–60. doi:10.1016/j.atherosclerosis.2005.03.019. PMID 16285998.
- ↑ 30.0 30.1 Aguilar Salinas CA, Zamora M, Gómez-Díaz RA, Mehta R, Gómez Pérez FJ, Rull JA (2004). "Familial combined hyperlipidemia: controversial aspects of its diagnosis and pathogenesis". Semin Vasc Med. 4 (2): 203–9. doi:10.1055/s-2004-835379. PMID 15478042.
- ↑ Sveger T, Nordborg K (2004). "Apolipoprotein B as a marker of familial hyperlipoproteinemia". J Atheroscler Thromb. 11 (5): 286–92. PMID 15557711.
- ↑ Veerkamp MJ, de Graaf J, Bredie SJ, Hendriks JC, Demacker PN, Stalenhoef AF (2002). "Diagnosis of familial combined hyperlipidemia based on lipid phenotype expression in 32 families: results of a 5-year follow-up study". Arterioscler Thromb Vasc Biol. 22 (2): 274–82. PMID 11834528.
- ↑ Brun N, Aubert CE, Nanchen D, Rodondi N (2016). "[New guidelines for screening and management of familial dyslipidemia]". Rev Med Suisse. 12 (508): 435–9. PMID 27089599.
Template:WikiDoc Sources rance of LDL. Prevalence in the population is 10%.