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1、CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 NUMBER 1 JANUARY 200657CHRISTOPHER SIBLEY, MD Department of Cardiology, Johns Hopkins University, Baltimore, MDNEIL J. STONE, MD* Professor of Clinical Medicine, Feinberg School of Medicine, Northwestern University, Chicago, ILFamilial hypercholesterole
2、mia: A challenge of diagnosis and therapyREVIEW ABSTRACTPeople with familial hypercholesterolemia (FH) have dramatically high levels of low-density lipoprotein cholesterol (LDL-C), which can lead to accelerated atherosclerosis and, if untreated, early cardiovascular death.Although the heterozygous f
3、orm of FH is often unrecognized, detecting it early can enable risk reduction before premature coronary heart disease occurs. KEY POINTSAtherosclerotic vascular disease occurs at much younger ages in FH than in other dyslipidemias, and the incidence is likely related to the duration and severity of
4、the hypercholesterolemia.FH causes characteristic tendon xanthomas, especially in the Achilles tendons, that can be missed unless specifically sought. In young white patients, arcus corneae may be a clue to heterozygous FH.Relatives of patients with FH should have their cholesterol checked.For patie
5、nts with heterozygous FH, statin therapy markedly reduces LDL-C and is the mainstay of a multidrug treatment regimen. Patients with homozygous FH are at high risk of premature aortic valvular stenosis and coronary atherosclerosis and need intensive multidrug therapy at an early age. LDL apheresis ca
6、n be added to a multidrug regimen if such therapy fails to control cholesterol levels.ANY PEOPLEhave high cholesterol, but a distinct minority have extremely high levels due to genetic defects in lipoprotein metabolism. These patients need our special attention because they are at high risk of ather
7、osclerot- ic cardiovascular disease at a young age.1 Moreover, their relatives (including their chil- dren) also need our attention because many of them share the same genetic defects. Unfortunately, appreciation of the chal- lenges in the treatment of those with disorders of lipoprotein metabolism
8、lags significantly behind our knowledge of the evaluation and treatment of mild or moderate hypercholes- terolemia. This article focuses on familial hypercho- lesterolemia (FH), an autosomal-codominant monogenic disorder of low-density lipoprotein cholesterol (LDL-C) metabolism. There are other fami
9、lial forms of high cholesterol, but FH has characteristic clinical features that clinicians should be able to recognize.2,3 FH IS DUE TO MUTATIONS IN THE LDL RECEPTOR GENEFH is primarily due to mutations in the LDL receptor gene on the short arm of chromo- some 19.4These mutations can reduce the abs
10、olute number of LDL-C receptors or pre- vent LDL-C from binding to these receptors. The result is a greatly diminished ability to remove LDL-C from the blood. The homozygous form of FH is rare, with a prevalence of about 1 in 1 million. PatientsM*Dr. Stone has indicated that he serves as a consultan
11、t for and has given educational talks sponsored by the Abbott, Merck, Merck-Schering, Pfizer, Reliant, and Sonosite corporations.CREDITCME58CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 NUMBER 1 JANUARY 2006are considered to have homozygous FH if they have two mutant copies of the gene, regardless
12、of whether both alleles carry the same muta- tion or different mutations (ie, in “double het- erozygotes”). In either case, the clinical pre- sentation is characteristic and dramatic: skin and tendon xanthomas, total cholesterol lev- els between 500 and 1,000 mg/dL, and the onset in childhood of sym
13、ptomatic coronary disease as well as aortic valve and proximal root disease.4 In contrast, the heterozygous form of FH is relatively common, with an estimated preva- lence of 1 in 500 in the United States and United Kingdom. The frequency is much higher among Chinese Canadians, French Canadians, Fin
14、ns, Dutch, Icelanders, Lebanese Christians, Lithuanian Jews, and South African Afrikaners. This “founder effect” occurs in communities founded by a small number of immigrants, some of whom carried specific mutations.5 Total cholesterol levels in heterozygous FH average 325 to 450 mg/dL. The clinical
15、 presentation is not as dramatic or as pro- nounced as in homozygous FH, but many patients remain at markedly elevated risk for coronary heart disease and death in the fourth or fifth decade of life if untreated. In an older but instructive report of the “natural history” of heterozygous FH,6116 aff
16、ected US families were referred to the National Institutes of Health in the late 1960s and early 1970s (before statins were avail- able). The index cases were omitted from the analyses. The risk of coronary heart disease byage 60 was 1 in 2 for male heterozygous patients and 1 in 6 for their female counter- partsstrikingly higher than in their other- wise similar but unaffected relatives. DIAGNOSIS IS CLINICALAlthough markedly elevated LDL-C is the key to the diag
