Familial combined hyperlipidemia
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Lipoprotein Disorders Microchapters |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Type IIB hyperlipoproteinemia
Overview
Based on old and recent definitions, Familial combined hyperlipidemia is a common metabolic disorder charaterized by following:-
- An increased cholesterol and/or triglycerides in at least to members of the same family.
- An intra-individual and intrafamilial variability of the lipid phenotype
- An increased risk of premature coronary heart disease.
Historical perspective
- In 1967, Fredrickson using paper electrophosresis , classified lipoprotein disorder.[1]
- 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.
Pathophysiology
Pathogenesis
The exact pathogenesis of Familial combined hyperlipidemia remains(FCHL) unknown. Several theories have been postulated about the development of a familial combined hyperlipidemia. The underlying mechanisms of the disease involves the following:-
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:-[2][3][4][5]
- 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:-[6][7]
- 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:-[8][9]
- TG-enrichment of HDL particles
- Enhanced hepatic lipase (HL)
- Very high concentration of VLDL-1
Causes
- The cause of familial combined hyperlipidemia remains 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.
- Following genes were found to be associated with familial combined hyperlipidemia.
- 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.
Differential diagnosis
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. [10][11] More than 3.5 million people in EU and 2.7 million in the US suffer from familial combined hyperlipidemia.[10]
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.[12]
Age
Familial combined hyperlipidemia is commonly seen in all ages in myocardial infarction survivors.[11] Dr. Iwata in 2003 explained that many patients with familial combined hyperlipidemia present during their childhood.[13]
Gender
Familial combined hyperlipidemia affects men and women equally.
Screening
The USPSTF has no screening guidelines for the detection of familial combined hyperlipidemia.
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.[14]
Complications
Complications that can develop in patients with familial combined hyperlipidemia include[15][16][17]
- Coronary heart disease
- Coronary vasuclar disease
- Peripheral vascular disease
- Gangrene of the extremities
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.[18]
Diagnosis
History and symptoms
Symptoms of
Physical examination
The following non-specific signs are seen in patients with familial combined hyperlipidemia:
- waist-to-hip ratio appears to be the best determinant of hyperlipidemia, particularly hypertriglyceridemia in FCH patients.
Laboratory findings
Molecular Genetic Testing
Treatment
Pregnancy Management
Investigative Therapies
Gene Therapy
Prevention
Secondary prevention
Prevention of complications
References
- ↑ Culliton BJ (1987). "Fredrickson's bitter end at Hughes". Science. 236 (4807): 1417–8. PMID 3296193.
- ↑ 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.
- ↑ 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.
- ↑ 10.0 10.1 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.
- ↑ 11.0 11.1 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
Template:WikiDoc Sources rance of LDL. Prevalence in the population is 10%.