Hyperlipidemia in Childhood

1
Hyperlipidemia in Childhood

• Radha R. Cohen, M.D., F.A.A.P
• Pediatric Grand Rounds
• April 1, 2004

2
Hyperlipidemia in ChildhoodOverview

• Basic lipoprotein structure and metabolism
• Role of childhood hyperlipidemia in
  atherosclerosis
• Classification of hyperlipidemias
• Pediatric cholesterol screening guidelines
• Management of hyperlipidemia in children

3
Hyperlipidemia in ChildhoodDefinition

• Hyperlipidemias group of metabolic disorders
  characterized by an abnormal accumulation of
  various lipids in plasma. This may be due to
  genetics, diet or other acquired factors.
• Cholesterol and trigylceride are the primary
  lipids in plasma. Because they are insoluble in
  plasma, they are transported within the vascular
  space as lipoproteins.

4
Hyperlipidemia in ChildhoodLipoprotein structure
Lipoprotein structure

• hydrophobic core
• triglyceride and/or
• cholesterol ester
• surface coat
• phospholipid monolayer
• interspersed free cholesterol and apolipoproteins

5
Hyperlipidemia in Childhood4 Major Classes of
Lipoproteins

• Lipoproteins are divided into several classes
  based on their density.
• Each class appears to have distinct functions and
  atherogenic risk.

6
Hyperlipidemia in Childhood Classes of
Lipoproteins

• Total Cholesterol measured in the blood or serum
  can be viewed as the sum of cholesterol carried
  in the different major lipoproteins
• LDL-cholesterol
• HDL-cholesterol
• VLDL-cholesterol

7
Hyperlipidemia in Childhood LDL

• LDL-cholesterol makes up the majority (60-70) of
  cholesterol in the blood.
• It has B-100 as its major apolipoprotein
  lipoproteins that contain B-100 accumulate in
  arteries and within atherosclerotic plaques.
• It is viewed as the atherogenic lipid high
  levels in adults have been correlated with
  coronary artery disease.

8
Hyperlipidemia in Childhood LDL

• LDL-cholesterol receptors are present throughout
  the body and their metabolism is highly regulated
  by intracellular cholesterol levels.
• Brown and Goldstein received the Noble prize in
  1985 for their work elucidating the control and
  metabolism of LDL-receptors.

9
Hyperlipidemia in Childhood HDL

• HDL-cholesterol typically makes up 20-25 of the
  total cholesterol.
• It is involved with transport of surplus
  cholesterol out of the tissue this reverse
  transport may be responsible for its protective
  action against atherosclerosis.
• In populations with elevated LDL, HDL-levels are
  inversely correlated with coronary
  atherosclerosis.

10
Hyperlipidemia in Childhood VLDL and Chylomicrons

• These are the largest of the lipoproteins and are
  major carriers of triglycerides (TG).
• TG are the main storage form of fatty acids. Long
  chain fatty acids are absorbed in the intestine
  and combine to form triglycerides and are
  transported through the thoracic duct to enter
  the blood stream as chylomicrons.
• Chylomicrons are cleared from the blood stream
  after fasting by lipoprotein lipase.

11
Hyperlipidemia in ChildhoodAtherosclerosis

• Clear evidence linking abnormalities in lipid and
  lipoprotein levels to premature atherosclerosis.
• Studies in adults show an unequivocal
  relationship of elevated levels of total
  cholesterol and LDL-C to premature
  atherosclerosis.

12
Atherosclerosis and Coronary Artery Disease

• Atherosclerosis is a disease of large arteries
  that causes deposits of yellowish plaques
  containing lipoid material and cholesterol in the
  intima of vessel walls.
• This is the pathogenic mechanism for coronary and
  peripheral vascular disease in adults.

13
Atherosclerosis and Coronary Artery Disease

• Advanced lesion results from
• proliferation of smooth muscle cells and
  macrophages
• formation of collagen matrix by smooth muscle
• accumulation of lipid within the cells and
  surrounding tissue
• FATTY STREAKgtFIBROUS PLAQUE

14
Atherosclerosis Begins in Childhood

• In 1962, Strong and McGill reported the autopsy
  findings of gt500 subjects ages 1-69 yrs
• Fatty streaks rare in 1st decade of life but
  almost universal by age 20 yrs

15
Progression of Atherosclerosis

• In Strong McGills study, fibrous plaques were
  1st observed in the second decade but increased
  in frequency and extent during the 3rd 4th
  decades.

16
Atherosclerosis and CAD

• Later in life, fibrous plaques may occlude the
  vessel lumen and potentiate thrombus formation.
• THIS IS WHAT WE WANT TO PREVENT!!!

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Hyperlipidemia in ChildhoodCAD Begins in
Childhood

• Clinical sequelae of atherosclerosis do not
  generally occur until later in life.
• However, there is significant evidence that the
  pathologic changes begin years prior and are
  linked to childhood cholesterol levels.

18
Cholesterol Levels in Childhood and
Atherosclerosis

• Bogalusa Heart Study
• children who had their coronary risk factors
  measured sequentially as participants in this
  study and then died accidentally were studied at
  autopsy
• extent of fatty streaks was related to total and
  LDL cholesterol
• fatty streaks in coronaries related best to VLDL
• inverse relationship of fatty streaks to HDL

19
Cholesterol Levels in Adolescence Linked to
Atherosclerosis

• PDAY (Pathological Determinants of
  Atherosclerosis in Youth) Study- ongoing autopsy
  study of progression of atherosclerosis in
  subjects 15-34yrs
• VLDL and LDL positively and HDL negatively
  associated with fatty streaks and fibrous plaques
• Raised lesions were found in those as young as
  25yrs

20
Cholesterol Levels in Childhood and CAD in
Adulthood

• Epidemiological investigations provide further
  evidence of the importance of cholesterol levels
  in pediatrics
• Cross-population studies show children from
  countries with high incidence of CAD in adulthood
  have higher cholesterol levels than their
  counterparts in countries with low incidence of
  CAD
• Within a population, elevated levels of total and
  LDL cholesterol in children have been associated
  with CAD in adult relatives

21
Hyperlipidemia in Childhood Summary of Data

• Evidence demonstrates that
• fatty streaks occur in young people and then
  progress to atherosclerotic plaques
• extent of arterial lesions is related to serum
  lipid (cholesterol) levels
• manipulation of cholesterol levels can affect
  development of atherosclerosis
• therefore...
• Efforts to prevent the development and
  progression of atherosclerosis should begin in
  childhood and adolescence.

22
Hyperlipidemia in ChildhoodGoal of the
Pediatrician

• Goal of detection / treatment...
• prevention of premature coronary artery disease
• Foundation of this goal depends on...
• coronary artery disease begins in childhood
• coronary artery disease is related to blood
  cholesterol levels
• lowering cholesterol in children will be
  effective in ? CAD

23
National Cholesterol Education Program (NCEP)

• The NCEP was created by the National Heart, Lung,
  and Blood Institute of the NIH in 1985.
• Its charge was to reduce the prevalence of
  hypercholesterolemia in the US population and
  thereby reduce the morbidity and mortality
  associated with CAD.

24
Hyperlipidemia in ChildhoodDefinitions

• Hypercholesterolemia
• total-C or LDL-C ? 95th for age
• Hypertriglyceridemia
• TG ? 95th for age
• These are working definitions of hyperlipidemia
• Levels associated with the least risk of
  developing CAD in adulthood have not been
  determined

25
Hyperlipidemia in ChildhoodNormal Values
National Cholesterol Education Program (NCEP)
Expert Panel on Blood Cholesterol Levels in
Children and Adolescents
26
Hyperlipidemia in ChildhoodNormal Values
National Cholesterol Education Program (NCEP)
Expert Panel on Blood Cholesterol Levels in
Children and Adolescents
27
Hyperlipidemia in ChildhoodClassification

• Primary versus Secondary
• first consideration - whether the hyperlipidemia
  is primary (genetic dyslipidemias) or secondary
  to a metabolic disease or exogenous cause
• common secondary causes during infancy
• glycogen storage disease and biliary atresia
• common secondary causes in childhood
• hypothyroidism, diabetes, nephrotic syndrome
• common exogenous causes
• oral contraceptives, alcohol, steroids

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HyperlipidemiasSecondary Causes
Exogenous Alcohol Contraceptives
Steroid therapy Endocrine and Metabolic
Acute intermittent prophyria Diabetes
mellitus Hypopituitarism Hypothyroidism
Lipodystrophy Pregnancy Storage disease
Cystine storage disease Gaucher disease
Glycogen storage disease Juvenile
Tay-Sachs disease Niemann-Pick disease
Tay-Sachs disease
Renal Chronic renal failure
Hemolytic-uremic syndrome Nephrotic
syndrome Hepatic Benign recuurent
intrahepatic cholestasis Congenital biliary
atresia Acute and transient Burns
Hepatitis Others Anorexia nervosa
Idiopathic hypercalcemia Klinefelter
syndrome Progeria Systemic lupus
erythematosus Werner syndrome
KwiterovichPDisorders of lipid metabolism, in
Rudolph AM (ed) Pediatrics, ed 17.
29
Hyperlipidemia in ChildhoodFrederickson
Classification

• In Circulation 1965, Frederickson and Lees
  published a description of 5 phenotypes to
  categorize people with familial hyperlipidemia
  according to their pattern of elevation of plasma
  lipoproteins.
• As knowledge progressed, it has become apparent
  that there may be several different genetic and
  secondary causes of the same Frederickson
  phenotype.
• This classification system has now fallen out of
  use.

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HyperlipidemiasFredrickson Classification
31
Clinically Important Genetic Dyslipidemias

• For clinical purposes, the following categories
  are more useful in determining risk of
  atherosclerosis, and planning treatment
• Hypercholesterolemia
• Combined hyperlipidemia
• Hypoalphalipoproteinemia

32
Hypercholesterolemia

• Defined as total cholesterol gt170mg/dL for
  children ages 2-19 yrs
• An isolated elevation of cholesterol is nearly
  always due to increase in LDL-C
• 2 genetic disorders are assoc. with
• Total-C LDL-C 2-5Xnormal
• -familial hypercholesterolemia
• -familial defective apoB-100

33
Hypercholesterolemia

• Familial hypercholesterolemia is caused by a
  mutation in LDL receptor gene on short arm of
  chromosome 19.
• Familial defective apoB-100 is due to rare
  mutations of the apoB gene.
• In both cases, LDL receptors are unable to
  interact with apo-B, the protein ligand on LDL
  particles.
• Both have autosomal dominant pattern of
  inheritance.

34
Familial Hypercholesterolemia

• Most commonly recognized form of familial
  hyperlipidemia in childhood
• Incidence of heterozygotes is 1500 and
  homozygotes 1 1 million
• Homozygotes present in childhood with serum
  cholesterol between 400-800mg/dL and cutaneous
  and tendon xanthomas. Angina and MI before
  adolescence are common, and most have severe CAD
  by age 30. Aortic stenosis is also seen.

35
Tendon Xanthomas
tendon xanthomas of the achilles and elbow
36
Tendon Xanthomas
tendon xanthomas of the hand
37
Cutaneous Xanthomas
38
Familial Hypercholesterolemia Findings in
Homozygotes
left coronary artery narrowing
supravalvar lipid deposition
39
Eye Findings in Familial Hypercholesterolemia
Early corneal arcus
Cholesterol deposits in retinal fundus
40
Familial HypercholesterolemiaHeterozygous Form

• LDL-C is gt 95 at birth.
• Lipid levels remain markedly elevated throughout
  childhood and adulthood with total cholesterol
  300-400mg/dL and LDL-C 200-300mg/dL.
• Clinical manifestations include tendon xanthomas
  after age 20, early corneal arcus, and CAD after
  age 30.
• This diagnosis should strongly be suspected in
  anyone with high LDL-C and tendon xanthomas in
  the patient or 1st degree relatives.

41
Familial Hypercholesterolemiaand CAD

• In heterozygous males, the risk for development
  of CAD is estimated to be 20 at age 40yrs, 45
  at age 50yrs, and 75 at age 60yrs.
• FH is thought to account for 3 of premature CAD
  in the US.

42
Familial Hypercholesterolemia

• Family history and screening of family members
  should reveal 1/2 of 1st degree relatives with FH
• Diagnosis can be confirmed by measuring LDL
  receptor activity in cultured skin fibroblasts or
  identifying the gene mutation.
• Prenatal diagnosis is possible by assessing LDL
  receptor activity in cultured amniotic cells.
• Genetic counseling is important, especially if
  partners cholesterol is elevated or not known.

43
Combined Hyperlipidemia

• Familial combined hyperlipidemia was 1st
  described by Goldstein et al. as dominantly
  inherited hyperlipidemia and CAD.
• Affected individuals have either TG or LDL-C gt90
  or both TG LDL-C gt90.
• Phenotype may vary among family members or even
  from time to time in same individual.
  Presentation usually delayed until 3rd decade of
  life. No cutaneous or ocular findings.
• Thought to affect 1 of population and account
  for 10 of premature CAD.

44
Hypoalphalipoproteinemia

• Defined as HDL-C lt 10 for age and sex associated
  with normal LDL-C and TG levels.
• Appears to have autosomal dominant pattern of
  inheritance in that 1/2 of family members have
  low HDL-C and premature atherosclerosis.
• No clinical manifestations other than premature
  atherosclerosis with CAD common as early as 4th
  decade.

45
Cholesterol Screening in Children

• The NCEP recommended selective screening of
  children and adolescents, targeting those who
  were likely to become adults with high blood
  cholesterol and who would thus be at an increased
  risk for the development of cardiovascular
  disease.

46
Cholesterol Screening

• Reasoning for selective screening
• children and adolescents with elevated blood
  cholesterol (particularly LDL) frequently come
  from families in which there is a high incidence
  of CAD among adult members
• high blood cholesterol aggregates in families as
  a result of both shared environments and genetic
  factors
• major risk factor for hypercholesterolemia in a
  child is a family history of premature CAD or
  hypercholesterolemia

47
Cholesterol Screening

• NCEP did not recommend universal screening
  (controversial)
• Reasons against universal screening
• quite a few children with high cholesterol will
  not have high enough levels as adults to require
  treatment
• leads to many young people inappropriately
  labeled as having disease
• could lead to overuse of cholesterol-lowering
  drugs in children

48
Cholesterol Screening

• Reasons for recommending universal screening
• 50 of children with elevated cholesterol levels
  would be missed
• universal screening may benefit young parents as
  well
• children are more likely to receive regular
  health care than young adults

49
Cholesterol Screening

• Selective screening approach
• based on detailed family history and assessment
  of concomitant risk factors
• makes it possible to identify a high risk subset
  while providing a reasonable balance between the
  number to be tested and the number to be detected

50
Selective Cholesterol Screening

• Who should be screened?

• Children and adolescents with
• -family history of premature atherosclerosis
  (parents or grandparents with MI, angina
  pectoris, peripheral vascular disease,
  cerebrovascular disease, or sudden cardiac death
  at or before age 55yrs)
• -parent with high cholesterol (gt240mg/dL)
• -unknown family history, especially those with
  other risk factors (hypertension, diabetes,
  obesity, smoking)

51
Age for Cholesterol Screening

• When do you screen?
• Anytime after 2 years of age
• cholesterol levels relatively stable by this time
• no treatment recommendations for children less
  than 2 years old
• If levels acceptable, repeat after 5 years

52
Cholesterol Screening

• What do you order?
• Total Blood Cholesterol
• less expensive, random/nonfasting
• Fasting Lipid Profile
• 12 hour fast
• measure total cholesterol, HDL, TG
• LDL estimated by formula from Lipid Research
  Clinics
• LDL total cholesterol - (TG/5 HDL)
• inaccurate if TG gt 400 mg/dl or if not fasting

53
Cholesterol Screening

• What to measure also depends on reason for
  screening
• parental high cholesterol ? total cholesterol
• family history of CAD ? fasting lipid profile
• LDL level determines risk and need for treatment

54
Cholesterol Screening
55
Cholesterol Screening

• If LDL-C lt110 mg/dL, no further testing.
• If LDL-C 110-129 mg/dL,educate family, prescribe
  Step One diet, and recheck in 1 year.
• If LDL-C gt130 mg/dL, evaluate for causes (r/o
  secondary causes like hypothyroidism, diabetes
  if familial suspected, measure lipid profiles of
  family) and begin treatment.

56
Management of Elevated Cholesterol

• LDL-Cgt130 mg/dL
• Start Step One Diet
• Recheck level in 6 wks.
• If LDL not lt110 mg/dL, intensify Step One Diet
  and recheck in 3 months.
• If goal still not met, prescribe Step Two diet
  for next 3 months.
• If goal still not met after 1 yr with diet alone,
  consider pharmacotherapy.

57
Hyperlipidemia in ChildhoodDetection and
Treatment
long term monitoring recheck lipoprotein
analysis 2x / year
58
Diet Therapy

• Primary approach to treating children and
  adolescents with elevated cholesterol levels
• Aim of diet therapy is to reduce elevated blood
  cholesterol levels while maintaining a
  nutritionally adequate eating pattern
• It is prescribed in two steps that progressively
  reduce the saturated fatty acid (SFA) and
  cholesterol intake

59
Diet Therapy

• Step One diet
• lt 30 total calories from fat
• lt 10 total calories from SFA
• lt 300 mg/day cholesterol
• adequate calories for growth and development

• Requires detailed assessment of current eating
  patterns and instruction by a physician, RD, or
  other professional

60
Diet Therapy

• Step Two diet
• prescribed if careful adherence to Step One diet
  for at least 3 months fails to achieve the
  minimal goals of therapy
• further reduction of SFAs and cholesterol
• lt 30 calories from fat (SAME as Step One)
• lt 7 total calories from SFA
• lt 200 mg/day cholesterol

61
Diet Therapy
National Cholesterol Education Program (NCEP)
Expert Panel on Blood Cholesterol Levels in
Children and Adolescents
62
Mg of Cholesterol in Foods
cholesterol (? 300 mg/day)

• bacon, 3 slices 16 mg
• chicken (3.5 oz), lt meat, no skin75 mg
• shrimp (3.5 oz) 195 mg
• egg, yolk 213 mg
• cheddar cheese (1 oz) 30 mg
• bread, one slice 0 mg
• butter (one TBS) 31 mg
• margarine (one TBS) 0 mg

• McDonalds Big Mac 100 mg
• McDonalds Egg McMuffin 235 mg
• Pizza Hut Pan Pizza (1 slice) 25 mg
• potato chips (1 oz) 0 mg
• cola, regular 0 mg
• chocolate chip cookies(4) 18mg
• peanuts (1 oz) 0 mg

63
Diet Therapy

• General food guidelines
• meat, poultry, and fish
• major sources of high quality protein
• but also major contributors of SFA, total fat,
  and cholesterol
• use LEAN meat, remove skin from poultry
• eggs
• good source of high quality protein, iron, vits
• yolks very high in cholesterol (whitesnone)
• 2 egg whites substituted for 1 egg in recipes

64
Diet Therapy

• Fats and oils
• SATURATED FATTY ACIDS are BAD
• ?intake of saturated oils coconut, palm kernel,
  palm
• ?intake of unsaturated oils sunflower, corn,
  canola, olive, peanut
• margarine instead of butter (with unsaturated oil
  listed as first ingredient)

65
Diet Therapy

• Plant stanol esters
• Are available in low-fat margarine spreads
• Also available in salad dressings and snack bars
• Structurally stanol esters are similar to
  cholesterol and inhibit cholesterol absorption in
  the gut by competitive mechanisms

66
Plant Sterol Esters

• Studies have demonstrated that consumption of
  low-fat margarine containing stanol esters can
  lower total and LDL cholesterol by 10-15 in
  hypercholesterolemic subjects
• Have been studied in children with no adverse
  clinical effects noted
• Does not affect HDL-C or TG levels
• Effects on Total and LDL-C seen in 4-8 weeks with
  a daily dose of 2-3 g (3 Tbsp of the
  commercially available products)
• Examples Benecol and Take Control

67
Exercise

• In addition to diet prescription, dont forget to
  recommend regular aerobic exercise
• 30-45 minutes, at least 4-5 times a week
• Can increase HDL-C
• Can help with regards to other risk factors for
  CAD, such as obesity and hypertension

68
Drug Therapy

• Only a small proportion of children should be
  considered for drug treatment because of the
• potential side effects
• relative expense of medications
• lack of definitive, prospective data on the
  effect of such treatment on children

69
Drug Therapy

• Consider drug therapy
• following adequate trial of diet therapy
  for 6 months to 1 year if
• LDL remains gt 190 mg/dl
• LDL remains gt 160 mg/dl and
• family history of premature CAD or
• 2 other risk factors still exist (HDLlt45 mg/dl,
  obesity, diabetes, hypertension)
• LDL gt 130 mg/dl but lt160 mg/dl, no specific
  recommendations for drug therapy

70
Drug Therapy

• Only approved for children older than 10 years of
  age
• Diet exercise therapy must continue
• Follow up
• 6 weeks after starting medication
• every 3 months thereafter until goal is met
• then every 6 months

71
Drug Therapy

• Bile-acid binding resins
• Ezetimibe
• HMG-CoA reductase inhibitors (statins)
• Niacin (nicotinic acid)
• Fibric acid derivatives

72
Bile Acid Sequestrants

• Primary therapy recommended in children
• Cholestyramine (Questran) and colestipol
  (Cholestid)
• Reduce LDL levels by 20
• Long-term compliance limited, presumably due to
  unpalatability and GI side effects (nausea,
  bloating, constipation, flatulence)

73
Bile Acid Sequestrants

• Mechanism of action
• anion exchange resins
• bind (-) bile acids in SI
• resin/bile complex out via feces
• prevents enterohepatic circulation of bile acids
• ? bile acid concentration in hepatocytes causes
  an ? conversion of cholesterol to bile acids
• causes ? in intracellular cholesterol
• activates an increased uptake of LDL cholesterol
  particles
• outcome ? plasma cholesterol

74
Bile Acid Sequestrants

• Overall safe because not absorbed and lack
  systemic toxicity
• However, they can cause malabsorption of
  fat-soluble vitamins and folic acid so a daily
  MVI containing folic acid and iron is recommended
• Their use is limited in patients who also have
  elevated TG since they can increase TG levels
• Check CBC and LFTs annually in patients

75
Bile Acid Sequestrants

• cholestyramine and colestipol
• both are powders that are mixed with water or
  juice before ingestion cholestyramine is also
  available as flavored bars
• choice of one over the other depends on
  individual taste preference and side effects
• dose is not related to body weight but to levels
  of total and LDL cholesterol
• start on lowest dose possible, then ? one dose at
  a time until goal achieved

76
Bile Acid Sequestrants

• cholestyramine and colestipol
• dosing regimen
• one dose 9 g packet of cholestryramine, one bar
  of cholestyramine, or 5 g colestipol
• daily doses TC LDL
• 1 lt245 lt195
• 2 245-300 195-235
• 3 301-345 236-280
• 4 345
• take immediately before, during, or after meals
  (largest amount of bile acids in intestine)

77
Ezetimibe (Zetia)

• Relatively new agent
• Inhibits intestinal absorption of cholesterol
• Limited study in children 10-18 yrs
• Lowers LDL-C by up to 15-20
• May decrease TG and increase HDL-C
• Given as a single 10mg dose tablet
• No major side effects noted
• In adults has been used in conjunction with
  statins

78
Statins

• HMG-CoA reductase inhibitors work by inhibiting
  the rate-limiting step in cholesterol
  biosynthesis
• Have been used in adults gt10-15 years with good
  success and safety
• Can decrease Total and LDL-C by 20-60
• Limited studies in children show efficacy and no
  significant side effects, but studies were
  underpowered for safety

79
Statins

• Must monitor LFTs every 3-6 months as there is a
  potential for hepatocellular toxicity
• Also, statins are potentially teratogenic so they
  should be used with caution in female
  adolescents.

80
Hyperlipidemia in ChildhoodSummary

• CAD is a major cause of significant mortality,
  morbiditity, and expense
• It begins in childhood and progresses in severity
  as we age
• It results from a combination of inter-related
  factors such as genetics, hypercholesterolemia,
  hypertension, obesity, diabetes, and smoking
• Many of these risk factors are largely
  preventable and/or modifiable

81
Hyperlipidemia in ChildhoodSummary

• Efforts to prevent the development and
  progression of atherosclerosis should begin in
  childhood and adolescence
• Selective cholesterol screening can identify
  those children at highest risk for
  hypercholesterolemia
• For those children with hypercholesterolemia, a
  diet low in SFAs and cholesterol is the mainstay
  of therapy

82
Hyperlipidemia in Childhood