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Half a Century Tales of Familial Hypercholesterolemia (FH) in Japan

View Article: PubMed Central - PubMed

ABSTRACT

Familial hypercholesterolemia (FH) is a disease characterized by a triad: elevated low-density lipoprotein (LDL) cholesterol, tendon xanthomas, and premature coronary heart disease. Thus, it can be considered as a model disease for hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD). For the diagnosis of hetero-FH, the detection of Achilles tendon xanthomas by palpation or on X-ray is an indispensable diagnostic skill in clinical lipidology. To prevent the under-diagnosis and under-treatment of FH, the diagnostic criteria should be more convenient and user-friendly. For a patient with cutaneous or tendon xanthomas, the probability of FH is very high; however, an absence of xanthoma does not rule out FH.

Brown and Goldstein elucidated the pathogenesis of FH by their work on LDL-receptor (LDL-R), for which they were awarded the Nobel Prize in 1985. In the 1950s, FH patients were divided into heterozygous (hetero-) and homozygous (homo-) FH, and diagnosing homo- and hetero-FH based on the phenotypic features of ASCVD or xanthomas frequently became difficult without the DNA analysis of FH genes. It is estimated that heterozygous mutations in the LDL-R or the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene will be found at a combined frequency of 0.005, which corresponds to 1/199 people in the general population in Japan.

Statins and anti-PCSK9 monoclonal antibodies are highly specific and efficient drugs for treating hetero- or homo-FH patients. Most clinical studies have reported an amelioration of ASCVD using long-term statin therapy. Clinical results using anti-PCSK9 monoclonal antibodies will emerge in a few years. In homo-FH patients, mipomersen and lomitapide are expected to yield good results. It is important to sequentially unravel the unrecognized pathogenetic mechanisms of FH to reduce its under-recognition and develop new management strategies for it.

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Related in: MedlinePlus

Distributions of (a) plasma total cholesterol and (b) LDL-cholesterol in FH and non-FH patients. Receiver operating characteristic (ROC) curves discriminating between FH and non-FH subjects by (c) total cholesterol and (d) LDL-cholesterol are shown. Areas under ROC curves (AUC) are shown as mean ± SD.
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Figure 11: Distributions of (a) plasma total cholesterol and (b) LDL-cholesterol in FH and non-FH patients. Receiver operating characteristic (ROC) curves discriminating between FH and non-FH subjects by (c) total cholesterol and (d) LDL-cholesterol are shown. Areas under ROC curves (AUC) are shown as mean ± SD.

Mentions: The distribution of serum total cholesterol (TC) levels of unaffected subjects and hetero- and homo-FH patients are presented in Fig. 1017). Three peaks are observed in the serum cholesterol distribution among members of families affected by FH. These three peaks represent healthy individuals and hetero- and homo-FH patients. For the differential diagnosis of unaffected subjects and hetero-FH patients, establishing a threshold between these groups is essential. For such a threshold, we adapted the TC level for FH diagnosis and set the LDL-C reference value (Fig. 11). For the diagnosis of FH, the reference value of serum TC was 225 mg/dL and that of LDL-C was 162 mg/dL (Fig. 11)18, 19). Thus, the clinical diagnostic criteria of hetero-FH is defined as hyper-LDL cholesterolemia with tendon xanthomas (Table 2).


Half a Century Tales of Familial Hypercholesterolemia (FH) in Japan
Distributions of (a) plasma total cholesterol and (b) LDL-cholesterol in FH and non-FH patients. Receiver operating characteristic (ROC) curves discriminating between FH and non-FH subjects by (c) total cholesterol and (d) LDL-cholesterol are shown. Areas under ROC curves (AUC) are shown as mean ± SD.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383536&req=5

Figure 11: Distributions of (a) plasma total cholesterol and (b) LDL-cholesterol in FH and non-FH patients. Receiver operating characteristic (ROC) curves discriminating between FH and non-FH subjects by (c) total cholesterol and (d) LDL-cholesterol are shown. Areas under ROC curves (AUC) are shown as mean ± SD.
Mentions: The distribution of serum total cholesterol (TC) levels of unaffected subjects and hetero- and homo-FH patients are presented in Fig. 1017). Three peaks are observed in the serum cholesterol distribution among members of families affected by FH. These three peaks represent healthy individuals and hetero- and homo-FH patients. For the differential diagnosis of unaffected subjects and hetero-FH patients, establishing a threshold between these groups is essential. For such a threshold, we adapted the TC level for FH diagnosis and set the LDL-C reference value (Fig. 11). For the diagnosis of FH, the reference value of serum TC was 225 mg/dL and that of LDL-C was 162 mg/dL (Fig. 11)18, 19). Thus, the clinical diagnostic criteria of hetero-FH is defined as hyper-LDL cholesterolemia with tendon xanthomas (Table 2).

View Article: PubMed Central - PubMed

ABSTRACT

Familial hypercholesterolemia (FH) is a disease characterized by a triad: elevated low-density lipoprotein (LDL) cholesterol, tendon xanthomas, and premature coronary heart disease. Thus, it can be considered as a model disease for hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD). For the diagnosis of hetero-FH, the detection of Achilles tendon xanthomas by palpation or on X-ray is an indispensable diagnostic skill in clinical lipidology. To prevent the under-diagnosis and under-treatment of FH, the diagnostic criteria should be more convenient and user-friendly. For a patient with cutaneous or tendon xanthomas, the probability of FH is very high; however, an absence of xanthoma does not rule out FH.

Brown and Goldstein elucidated the pathogenesis of FH by their work on LDL-receptor (LDL-R), for which they were awarded the Nobel Prize in 1985. In the 1950s, FH patients were divided into heterozygous (hetero-) and homozygous (homo-) FH, and diagnosing homo- and hetero-FH based on the phenotypic features of ASCVD or xanthomas frequently became difficult without the DNA analysis of FH genes. It is estimated that heterozygous mutations in the LDL-R or the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene will be found at a combined frequency of 0.005, which corresponds to 1/199 people in the general population in Japan.

Statins and anti-PCSK9 monoclonal antibodies are highly specific and efficient drugs for treating hetero- or homo-FH patients. Most clinical studies have reported an amelioration of ASCVD using long-term statin therapy. Clinical results using anti-PCSK9 monoclonal antibodies will emerge in a few years. In homo-FH patients, mipomersen and lomitapide are expected to yield good results. It is important to sequentially unravel the unrecognized pathogenetic mechanisms of FH to reduce its under-recognition and develop new management strategies for it.

No MeSH data available.


Related in: MedlinePlus