Sandbox:Prince

Pathophysiology

Familial hypercholesterolemia is a common autosomal dominant disorder caused by mutations involving three genes.

These mutations include the following:

• The LDL receptor
• The apolipoprotein B gene, which impairs binding of LDL particles to the LDL receptor
• Proprotein convertase subtilisin/kexin type 9 gene, which leads to decreased LDL metabolism

Familial hypercholesterolemia has one known ApoB defect (R3500Q) and a multitude of LDL receptor defects, the frequency of which is different for each population. The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It comprises 18 exons and spans 45kb, and the gene product contains 839 amino acids in mature form.

Familial disorders of cholesterol metabolism may result from one of the following:

• Overproduction of lipoproteins
• Impaired removal of lipoproteins (this may result from primary defect with the lipoprotein or its receptor)

LDL cholesterol normally circulates in the body for 2.5 days, after which it is cleared by the liver. In FH, the half-life of an LDL particle is almost doubled to 4.5 days. This leads to markedly elevated LDL levels, with the other forms of cholesterol remaining normal, most notably HDL. The classic form of familial hypercholesterolemia results from defects in the cell surface receptor that normally removes LDL particles from the blood plasma.

The excess circulating LDL is taken up by cells all over the body—most notably, by macrophages, and particularly the ones in a primary streak (the earliest stage of atherosclerosis). Oxidation of LDL increases its uptake by foam cells.

Although atherosclerosis can occur in all people, many FH patients develop accelerated atherosclerosis due to the presence of excess LDL. Some studies of FH cohorts suggest that additional risk factors are generally present when an FH patient develops atherosclerosis.

The degree of atherosclerosis roughly depends of the amount of LDL receptors still expressed by the cells in the body, as well as the functionality of these receptors. In the heterozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In more serious form (i.e., the homozygous form), the "broken" receptor is not expressed at all.

In heterozygous FH, only one of the two DNA copies (alleles) is damaged, and there will be at least 50% of the normal LDL receptor activity (i.e., the "healthy" copy and whatever the "broken" copy can still contribute).

In homozygous FH, however, both alleles are damaged to some degree, which can lead to extremely high levels of LDL. Children with this form of FH may develop extremely premature heart disease. A further complication is the ineffectiveness of statins.

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Familial hypercholesterolemia from other Diseases

Epidemiology and Demographics Familial hypercholesterolaemia-causing mutations are estimated to occur in 1:217 in the general population

Risk Factors smoking cesation weight/lack of exercise t2dm high fat diet

Screening

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

hgghg

The original 1992 National

Cholesterol Education Program (NCEP) report National Cholesterol Education Program: Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents (NCEP Pediatric Guidelines) recommended screening for elevated cholesterol levels only among children with either a family history of early CVD or elevated TC levels.8

The Expert Panel recommends two complementary strategies to reduce future risk for clinical CVD. Primordial prevention seeks to prevent the acquisition of risk factors by optimizing CV health for all, beginning in infancy. Primary prevention requires screening to identify children at increased risk for CVD. This section focused on screening and reviewed the limitations of current knowledge within the requirements for a useful screening program. Taking these factors into account, the Expert Panel recommends routine measurement of length/height and weight beginning in infancy, with calculation of BMI annually beginning at age 2 years to identify growth trends; yearly assessment of BP from age 3 years; and universal screening for lipid abnormalities by a nonfasting non-HDL–C level at age 10 years. These screening strategies, described in detail in the respective risk factor sections of these Guidelines, will identify a relatively large number of children for whom the Expert Panel recommends intensified lifestyle intervention. Only a small number of children will require pharmacologic therapy. While they await the results of future research, the Expert Panel members conclude that recommending these assessments, followed by interventions as part of routine pediatric care, represents the best current primary prevention strategy to lower lifetime risk of atherosclerotic vascular disease.

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

Laboratory Findings

http://www.nhlbi.nih.gov/files/docs/guidelines/peds_guidelines_full.pdf

Primary Lipid Disorders Lipid/Lipoprotein Abnormality Familial hypercholesterolemia Homozygous: hhLDL–C Heterozygous: hLDL–C* Familial defective apolipoprotein B hLDL–C Familial combined hyperlipidemia* Type IIa: hLDL–C Type IV: h VLDL–C, hTG Type IIb: hLDL–C, hVLDL–C, hTG Types IIb and IV often with iHDL–C Polygenic hypercholesterolemia hLDL–C Familial hypertriglyceridemia (200–1,000 mg/dL) hVLDL-C, hTG Severe hypertriglyceridemia (≥1,000 mg/dL) hChylomicrons, hVLDL–C, hhTG Familial hypoalphalipoproteinemia iHDL–C Dysbetalipoproteinemia (TC: 250–500 mg/dL; hIDL–C, hchylomicron remnants

In FH, a genetic diagnosis is important for family screening, to establish the diagnosis in patients with borderline LDL-C and to improve patient adherence to therapy.

FH are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria or an LDL-cholesterol above 4.4 mmol/L. Electrocardiogram

Chest X Ray

CT

MRI

Echocardiography or Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Lomitapide is a microsomal triglyceride transfer protein inhibitor currently approved for treatment of homozygous familial hypercholesterolemia that may be useful in the management of severe hypertriglyceridemia.

Surgery

Prevention

References

WikiDoc Resources for Sandbox:Prince
Articles
Most recent articles on Sandbox:Prince Most cited articles on Sandbox:Prince Review articles on Sandbox:Prince Articles on Sandbox:Prince in N Eng J Med, Lancet, BMJ
Media
Powerpoint slides on Sandbox:Prince Images of Sandbox:Prince Photos of Sandbox:Prince Podcasts & MP3s on Sandbox:Prince Videos on Sandbox:Prince
Evidence Based Medicine
Cochrane Collaboration on Sandbox:Prince Bandolier on Sandbox:Prince TRIP on Sandbox:Prince
Clinical Trials
Ongoing Trials on Sandbox:Prince at Clinical Trials.gov Trial results on Sandbox:Prince Clinical Trials on Sandbox:Prince at Google
Guidelines / Policies / Govt
US National Guidelines Clearinghouse on Sandbox:Prince NICE Guidance on Sandbox:Prince NHS PRODIGY Guidance FDA on Sandbox:Prince CDC on Sandbox:Prince
Books
Books on Sandbox:Prince
News
Sandbox:Prince in the news Be alerted to news on Sandbox:Prince News trends on Sandbox:Prince
Commentary
Blogs on Sandbox:Prince
Definitions
Definitions of Sandbox:Prince
Patient Resources / Community
Patient resources on Sandbox:Prince Discussion groups on Sandbox:Prince Patient Handouts on Sandbox:Prince Directions to Hospitals Treating Sandbox:Prince Risk calculators and risk factors for Sandbox:Prince
Healthcare Provider Resources
Symptoms of Sandbox:Prince Causes & Risk Factors for Sandbox:Prince Diagnostic studies for Sandbox:Prince Treatment of Sandbox:Prince
Continuing Medical Education (CME)
CME Programs on Sandbox:Prince
International
Sandbox:Prince en Espanol Sandbox:Prince en Francais
Business
Sandbox:Prince in the Marketplace Patents on Sandbox:Prince
Experimental / Informatics
List of terms related to Sandbox:Prince

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]

Synonyms and keywords: FHC; FH; type IIA hyperlipoproteinemia; hyper-low-density-lipoproteinemia; familial hypercholesterolemic xanthomatosis; LDL receptor disorder

Overview

Familial hypercholesterolemia (also spelled familial hypercholesterolaemia) is a rare genetic disorder characterized by very high LDL cholesterol and early cardiovascular disease running in families.

Classification

Familial hypercholesterolemia may be classified according to the severity of the mutation involving the LDL-cholesterol (LDL-C) receptor or depending on the mode of inheritance as follows:

• Heterozygous vs homozygous
  • This is particularly important because, phenotypically, familial hypercholesterolemia (FH) is characterized by increased plasma levels of total cholesterol and low-density lipoprotein cholesterol, tendinous xanthomata, and premature symptoms of coronary heart disease. These are more pronounced in homozygous than heterozygous individuals.

• Polygenic vs monogenic
  • Polygenic hypercholesterolemia is a major source of atherosclerotic cardiovascular disease. Xanthelasma, premature CHD, tendon xanthomata, and childhood obesity are common in monogenic hypercholesterolemia. Tendon xanthomata and childhood obesity are not observed in polygenic hypercholesterolemia.

Pathophysiology

Both forms of FH are caused by the same problem: a mutation in either the LDL receptor or the ApoB protein. There is one known ApoB defect (R3500Q) and a multitude of LDL receptor defects, the frequency of which is different for each population. The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It comprises 18 exons and spans 45kb, and the gene product contains 839 amino acids in mature form.

Familial disorders of cholesterol metabolism may result from one of the following:

• Overproduction of lipoproteins
• Impaired removal of lipoproteins (this may result from primary defect with the lipoprotein or its receptor).

LDL cholesterol normally circulates in the body for 2.5 days, after which it is cleared by the liver. In FH, the half-life of an LDL particle is almost doubled to 4.5 days. This leads to markedly elevated LDL levels, with the other forms of cholesterol remaining normal, most notably HDL. Goldstein and Brown (1974) showed that the classic form of familial hypercholesterolemia results from defects in the cell surface receptor that normally removes LDL particles from the blood plasma.

The excess circulating LDL is taken up by cells all over the body but most notably by macrophages and especially the ones in a primary streak (the earliest stage of atherosclerosis). Oxidation of LDL increases its uptake by foam cells.

Although atherosclerosis can occur in all people, many FH patients develop accelerated atherosclerosis due to the excess LDL. Some studies of FH cohorts suggest that additional risk factors are generally at play when an FH patient develops atherosclerosis.

The degree of atherosclerosis roughly depends of the amount of LDL receptors still expressed by the cells in the body and the functionality of these receptors. In the hetrozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In more serious forms, the homozygouse form, the "broken" receptor is not expressed at all.

In heterozygous FH, only one of the two DNA copies (alleles) is damaged, and there will be at least 50% of the normal LDL receptor activity (the "healthy" copy and whatever the "broken" copy can still contribute).

In homozygous FH, however, both alleles are damaged in some degree, which can lead to extremely high levels of LDL, and to children with extremely premature heart disease. A further complication is the lack of effect of statins (see below).

Epidemiology

Prevalence

• The prevalence of FH is 1 in 300 to 500 in many populations, making FH among the most common of serious genetic disorders

Ethnicity

• In a few populations (such as French Canadians and Dutch Afrikaners), the prevalence of FH may be as high as 1 in 100

United States

• There are approximately 620,000 FH patients currently living in the United States

Screening

Universal screening for elevated serum cholesterol is recommended.

General population screening

Familial hypercholesterolemia (FH) should be suspected when untreated fasting LDL cholesterol or non HDL cholesterol levels are at or above the following:

• Adults (≥ 20 years):
  • LDL cholesterol ≥ 190 mg/dL or non-HDL cholesterol ≥ 220 mg/dL
• Children, adolescents and young adults (< 20 years):
  • LDL cholesterol ≥160 mg/dL or non- HDL cholesterol ≥ 190 mg/dL

Cholesterol screening should be considered beginning at age 2 for children with a family history of premature cardiovascular disease or elevated cholesterol. All individuals should be screened by age 20.

Although not present in many individuals with familial hypercholesterolemia (FH), the following physical findings should prompt the clinician to strongly suspect FH and obtain necessary lipid measurements if not already available:

• Tendon xanthomas at any age (most common in Achilles tendon and finger extensor tendons, but can also occur in patellar and triceps tendons). B Arcus corneae in a patient under age 45)
• Tuberous xanthomas or xanthelasma in a patient under age 20 to 25

At the LDL cholesterol levels listed below the probability of FH is approximately 80% in the setting of general population screening.

• These LDL cholesterol levels should prompt the clinician to strongly consider a diagnosis of FH and obtain further family information:
  • LDL cholesterol ≥ 250 mg/dL in a patient aged 30 or more
  • LDL cholesterol ≥ 220 mg/dL for patients aged 20 to 29
  • LDL cholesterol ≥ 190 mg/dL in patients under age 20

Screening in children

Lipid screening recommnedations for familial hypercholesterolemia in children are varies by age and their risk factors.

Child-parent familial hypercholesterolemia screening in primary care

• Recent study shows the feasibility and efficacy of child-parent familial hypercholesterolemia screening in primary care setting.
• The conclusion remains that child–parent familial hypercholesterolemia screening is a simple, practical, and effective way of screening the population to identify and prevent a common inherited cause of premature cardiovascular disease.

Prognosis

• Approximately 1 in one million persons is homozygous (or compound heterozygous) for LDLR mutations and has extreme hypercholesterolemia with rapidly accelerated atherosclerosis when left untreated.

Signs and symptoms

• Elevated serum cholesterol, most notably the LDL fraction (VLDL and triglycerides are typically normal)
  • on lipoprotein electrophoresis (rarely done), a hyperlipoproteinemia type II pattern is recognised
• Premature cardiovascular disease, such as:
  • Angina pectoris, leading to PTCA or CABG
  • Myocardial infarction
  • Transient ischemic attacks (TIA's)
  • Cerebrovascular accidents/Strokes
  • Peripheral artery disease (PAOD)
• A family history of premature atherosclerosis

Physical Examination

The following signs are not always present:

Eyes

• Xanthelasma palpabrum (yellowish patches above the eyelids)
• Arcus senilis corneae, whitish discoloration of the iris

Extremities

• Tendon xanthomas (thickening of tendons due to accumulation of macrophages filled with cholesterol).

Laboratory Studies

LDL-receptor gene defects can be identified with genetic testing. Testing is generally undertaken when:

• A family member has been shown to have a mutation;
• High cholesterol is found in a young patient with atherosclerotic disease;
• Tendon xanthomas are found in a patient with high cholesterol.

Treatment

Heterozygous FH

Heterozygous FH can be treated effectively with statins. These are drugs that inhibit the body's ability to produce cholesterol by blocking the enzyme hydroxymethylglutaryl CoA reductase (HMG-CoA-reductase). Maximum doses are often necessary. Statins work by forcing the liver to produce more LDL receptor to maintain the amount of cholesterol in the cell. This requires at least one functioning copy of the gene (see below).

In case statins are not effective, either a drug from the fibrate or bile acid sequestrant class can be added, as well as niacin/acipimox. As the combination of fibrates and statins is associated with a markedly increased risk of myopathy and rhabdomyolysis (breakdown of muscle tissue, leading to acute renal failure), these patients are monitored closely.

Homozygous FH

Homozygous FH is a different story. As previously mentioned, the LDL levels are much higher and the most effective treatments (statins) require at least one copy of the functional LDL receptor gene. In this case, high amounts of bile acid sequestrants are often given; occasionally high-dosed statins can help express a dysfunctional (but some times working) LDL receptor. Other treatments used are LDL apheresis (clearing LDL by blood filtration, similar to dialysis) and - as a last resort - a liver transplant. The last option will introduce liver cells with working LDL receptors, effectively curing the condition.

History

The Norwegian physician Dr C Müller first associated the physical signs, high cholesterol levels and autosomal dominant inheritance in 1938. In the early 1970s and 1980s, the genetic cause for FH was described by Dr Joseph L. Goldstein and Dr Michael S. Brown of Dallas, Texas [3].

Differential Diagnosis

	Diseases	Mode of Inheritance	Laboratory Findings								Other Findings	Management	Complications	Prognosis
			Lipid Profile					Other Laboratory Findings
			Total Cholesterol	LDL	HDL	Triglycerides	Plasma Appearance	Chylomicrons	VLDL	Genetic mutations
Primary Hyperlipoprotenemia	Type I	Autosomal Recessive & Autosomal Dominant(Rare)	Normal or ↑	↓	↓↓↓	↑↑↑↑	Milky	↑↑↑↑	↓	-LPL gene mutation	-Fat tolerance markedly abnormal -Carbohydrate inducibility may be abnormal	Treatment for hyperlipoproteinemia type 1 is intended to control blood triglyceride levels with a very low-fat diet	-Recurrent Pancreatitis -Rarely life threatening	Good
	Type IIA
	Type IIB
	Type III
	Type IV	Autosomal Recessive & Autosomal Dominant	Normal or ↑		Prebeta-HDL ↑ & HDL-C ↓	↑↑	Clear or Cloudy	Normal	↑	-LPL genes (Gly188Glu,Asp9Asn, Asn291Ser,Ser447Ter) -APOA5 -LMF1 -GPIHBP1	Hyperglycemia, Pancytopneia and pseudo-Niemann pick cells	-Weight reduction -Niacin or Fibrates -Gene therapy	-Ischemic Heart Disea -Recurrent Pancreatitis -NIDDM -NAFLD
	Type V	Variable	↑ to ↑↑	↓	↓↓↓	↑↑↑↑	Creamy supernatant and turbid infranatant	↑	↑↑↑	❑ Apo E, Apo A5 mutations ❑ LPL gene mutation in 10% of western population patients	❑ Restriction of dietary fat eliminates Chylomicrons and reverts to type IV HLP ❑ When triglyceride levels are >1000mg/dl given the rarity of type I it is almost always type V HLP	❑ Weight reduction ❑ Niacin or Fibrates or Strong statins ❑ Low fat diet	❑ Recurrent Pancreatitis	❑ Good

External links

• MEDPED (Make Early Diagnosis to Prevent Early Deaths)
• NCBI (Familial Hypercholesterolemia Page at National Center for Biotechnology Information)
• H·E·A·R·T UK (H·E·A·R·T UK, Familial Hypercholesterolemia charity based in the United Kingdom)

Template:WikiDoc Sources