Familial combined hyperlipidemia

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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], Prince Tano Djan, BSc, MBChB [3], Vishal Devarkonda, M.B.B.S[4]

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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

LDL abnormalities

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]

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:

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:

Physical examination

Ptients with familial combined hyperlipidemia may present with the following:

Eyes

Extremities

Non-specific signs

The following non-specific signs may also be seen in patients with familial combined hyperlipidemia:

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]

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]

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. 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.
  2. Culliton BJ (1987). "Fredrickson's bitter end at Hughes". Science. 236 (4807): 1417–8. PMID 3296193.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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. 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. 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. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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. 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.
  31. Sveger T, Nordborg K (2004). "Apolipoprotein B as a marker of familial hyperlipoproteinemia". J Atheroscler Thromb. 11 (5): 286–92. PMID 15557711.
  32. 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.
  33. 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.


rance of LDL. Prevalence in the population is 10%.


References



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