Cập nhật về chẩn đoán và điều trị rối loạn lipid máu thể gia đình

Diagnosis of heterozygous FH ❖ Clinical diagnosis if LDL cholesterol >330 mg/dL ❖ Or tendon xanthomas and LDL >95th percentile ❖ Before adulthood, suspect if LDL >200 mg/dL ❖ TG leve

❖ Early onset and symptoms of

coronary heart disease

❖ Autosomal disorder affecting

1:300-500 (heterozygotes) and

1:1,000,000 (homozygotes)

persons in populations

Diagnosis of heterozygous

FH

❖ Clinical diagnosis if LDL cholesterol >330 mg/dL

❖ Or tendon xanthomas and LDL >95th percentile

❖ Before adulthood, suspect if LDL >200 mg/dL

❖ TG levels usually normal or mildly elevated

❖ Likely homozygous FH if LDL >600 mg/dL

❖ Confirmation using LDL receptor analysis

❖ Prevalence of heterozygotes is about 1:300-500 persons

❖ Prevalence of homozygotes is about 1:1,000,000 persons

Main causes of secondary

Xanthoma and

xanthelasma

If identification of a cutaneous lesion is unclear, a biopsy can

be performed Both xanthelasmas and the xanthomas of FH

contain accumulations of cholesterol By contrast, eruptive

xanthomas in patients with severe hypertriglyceridemia

(levels >1000 mg/dL) contain triglycerides

Differential diagnosis of familial

hypercholesterolemia

❖ Dysbetahyperlipoproteinemia (type III hyperlipidemia)

❖ Familial ligand defective apoB-100, familial defective apoB-100

❖ Homozygous autosomal recessive hypercholesterolemia

❖ Sitosterolemia (phytosterolemia)

Specialised tests for familial

hypercholesterolemia

❖ Lipoprotein electrophoresis is expensive and is unnecessary for the diagnosis of FH If fasting lipid analysis reveals elevated

triglyceride levels and the diagnosis of FH is in doubt, beta

quantification (ultracentrifugation and electrophoresis) may be

performed at a major lipid center

❖ LDL receptor analysis can be used to identify the specific LDL

receptor defect This can only be performed at certain research

laboratories and is expensive; and the results have no impact on

management LDL receptor or apoB-100 studies can help

distinguish heterozygous FH from the similar syndrome of familial defective apoB-100, but this finding would not alter treatment

Imaging studies in familial

hypercholesterolemia

❖ Annual echocardiogram and carotid ultrasonography

❖ MSCT coronary angiography every 3-5 years

❖ Stress myocardial perfusion imaging if indicated

Others - aorta and arterial imaging

Natural history of homozygous familial

hypercholesterolemia

❖ Female, born 13 October 1990, marked hypercholesterolemia

❖ Typical angina pectoris, at age 10, large multisite xanthomas

❖ CT coronary angiography, double vessel disease, at age 13

❖ Class 3-4 angina pectoris, severe diffuse triple vessel disease, at age 16

❖ Severe carotid disease (RICA 100%, LICA 90%, basilar 75-90% at age 17

❖ Successful LCCA-LICA stenting at age 17

❖ Plasmapheresis discussed but declined at age 18

❖ Non-Q anterior myocardial infarction at age 19

❖ Death two weeks before 20th birthday, following CABG

❖ Two siblings had earlier died from fatal MI before 18th birthday

Homozygous familial hypercholesterolemia Cholesterol mg/dL LDL mg/dL

in June 2015

Born Feb 1996

Atorvastatin &

Ezetimibe

Medications for homozygous

Alirocumab

The proprotein convertase subtilisin/kexin type 9 (PCSK9)

inhibitor, alirocumab is indicated as adjunct to diet and

maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical

atherosclerotic cardiovascular disease, who require additional lowering of LDLc In one of several efficacy trials it reduces

LDLc by 58% compared with placebo by 24 weeks

Evolocumab

Evolocumab is indicated as an adjunct to diet and other

LDL-lowering therapies (eg, statins, ezetimibe, LDL apheresis) for

the treatment of adolescent and adult patients with homozygous familial hypercholesterolemia who require additional lowering of LDLc It is also indicated for heterozygous FH in adults

Evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDLc levels, and the rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group

(hazard ratio 0.47; 95% confidence interval, 0.28 to 0.78;

P=0.003)

Mipomersen

Mipomersen is approved in the USA to treat homozygous

familial hypercholesterolemia It reduces LDLc, non HDLc, and apolipoprotein B Mipomersen decreases hepatic and plasma apoB as well as apoC-III The compound is a second-

generation antisense oligonucleotide, and can be administered weekly Mipomersen is not approved in Europe for the

treatment of homozygous and severe heterozygous FH

because of its risk profile, which includes cardiovascular risks, malignancies, immune-mediated reactions, and hepatic

abnormalities

Lomitapide

Lomitapide inhibits the microsomal triglyceride transfer

protein (MTP or MTTP) which is necessary for very

low-density lipoprotein (VLDL) assembly and secretion in the

liver It is approved as an adjunct to a low-fat diet and other lipid-lowering treatments in patients with homozygous

familial hypercholesterolemia

Bile acid sequestrants

❖ Anion-exchange compounds work by preventing reabsorption

of bile in the intestine, and modestly lower LDLc, and increase HDLc and TG Not absorbed systemically and, therefore, are safer than most medications

❖ Examples are cholestyramine, colestipol, and colesevelam

❖ Useful in patients who cannot tolerate statins, who have

contraindications for statin therapy, or who request

non-systemic therapy

Procedures for homozygous

Liver transplantation

Liver transplantation is rarely performed because of the

considerable risks associated with the surgery itself and term immunosuppression But a new liver provides functional LDL receptors and causes dramatic decreases in LDLc levels

long-Portacaval anastomosis

Portacaval anastomosis is less hazardous than liver

transplantation and requires no immunosuppression Reduction of LDLc by up to 50% can be achieved, often associated with

regression of coronary, aortic, vascular and cutaneous lesions

LDL apheresis

LDL apheresis for homozygous FH involves selective removal of lipoproteins that contain apo-B by heparin precipitation, dextran sulfate cellulose columns, or immunoadsorption columns All

methods reduce LDLc levels more than 50% and also lower

lipoprotein (a), VLDL, and triglyceride levels HDL is spared The procedure takes 3 or more hours and is performed at 1- to 2-

week intervals Few adverse events are experienced, most of

which are noncritical episodes of hypotension LDL apheresis is

an extremely expensive procedure and is not readily available

Lifestyle interventions for FH

❖ Reduce saturated fats, trans fats, and cholesterol

❖ Weight management

❖ Aerobic and other exercises