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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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.

Historical perspective

• In 1967, Fredrickson using paper electrophosresis, classified lipoprotein disorders.
• 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:

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:
  • 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:
  • 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:
  • 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:
  • 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:
  • 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. More than 3.5 million people in EU and 2.7 million in the US suffer from familial combined hyperlipidemia.

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.

Age

Familial combined hyperlipidemia is commonly seen in all ages in myocardial infarction survivors. Dr. Iwata in 2003 explained that many patients with familial combined hyperlipidemia present during their childhood.

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:

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.

Complications

Complications that can develop in patients with familial combined hyperlipidemia include:

• Atherosclerosis
• Coronary artery disease
• Peripheral artery disease
• Gangrene

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.

Diagnosis

History and symptoms

History is usually suggestive of:

• Premature cardiovascular disease, such as:
  • Angina pectoris, leading to PTCA or CABG
  • Myocardial infarction
  • Transient ischemic attacks (TIA)
  • Cerebrovascular accidents/Strokes
  • Peripheral artery disease (PAD)
• 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
• waist-to-hip ratio appears to be the best determinant of hyperlipidemia, particularly hypertriglyceridemia in FCHL patients.

Laboratory findings

Assessment of the lipid profiles of at least three first-degree relatives is necessary.

A high degree of diagnostic uncertainty exists in the categorization as normal or abnormal of members of FCHL. Its manifestations include:

• 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).
• 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.

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:

• 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:

• 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

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