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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.

No MeSH data available.


Plasma cholesterol levels in different genotypes of homo-FH patients.Plasma cholesterol levels in the homo-FH due to LDL-R mutants are higher than those in the homo-FH due to PCSK9 E32K homo-FH or autosomal recessive homo-FH. Data were obtained from our previous studies by Mabuchi et. al.12) and Tada et. al.14)
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Figure 13: Plasma cholesterol levels in different genotypes of homo-FH patients.Plasma cholesterol levels in the homo-FH due to LDL-R mutants are higher than those in the homo-FH due to PCSK9 E32K homo-FH or autosomal recessive homo-FH. Data were obtained from our previous studies by Mabuchi et. al.12) and Tada et. al.14)

Mentions: Hetero-FH cases diagnosed due to abnormalities in the FH-related genes are highly diverse, and it is clear that the serum cholesterol level varies depending on the particular mutation. The genotypic heterogeneity of LDL-R produces the clinical phenotypic variation (Fig. 12)12, 16). Similar variations with respect to other FH-related genes have also been identified. An apparent difference was found by the genetic investigation of homo-FH while comparing the plasma cholesterol levels in homo-FH patients in whom LDL-R mutations, PCSK9 mutations, and the classical gene mutations are unknown (Fig. 13). In terms of clinical severity, the order of FH is as follows: LDL-R mutation > Apo-B-100 mutation > PCSK9 mutation > ARH mutation. Furthermore, gene mutations should be identified and the associated clinical severity should be investigated. Even in cases with same gene mutation, the diagnosis may be hypolipidemic FH, normolipidemic FH, or hyperlipidemic FH. In this context, although the search for FH-related genes is a desirable endeavor, the precise genotypic diagnosis is unlikely to alter the treatment paradigm (achievement of target LDL-C level) or the choice of pharmacotherapeutic agents.


Half a Century Tales of Familial Hypercholesterolemia (FH) in Japan
Plasma cholesterol levels in different genotypes of homo-FH patients.Plasma cholesterol levels in the homo-FH due to LDL-R mutants are higher than those in the homo-FH due to PCSK9 E32K homo-FH or autosomal recessive homo-FH. Data were obtained from our previous studies by Mabuchi et. al.12) and Tada et. al.14)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 13: Plasma cholesterol levels in different genotypes of homo-FH patients.Plasma cholesterol levels in the homo-FH due to LDL-R mutants are higher than those in the homo-FH due to PCSK9 E32K homo-FH or autosomal recessive homo-FH. Data were obtained from our previous studies by Mabuchi et. al.12) and Tada et. al.14)
Mentions: Hetero-FH cases diagnosed due to abnormalities in the FH-related genes are highly diverse, and it is clear that the serum cholesterol level varies depending on the particular mutation. The genotypic heterogeneity of LDL-R produces the clinical phenotypic variation (Fig. 12)12, 16). Similar variations with respect to other FH-related genes have also been identified. An apparent difference was found by the genetic investigation of homo-FH while comparing the plasma cholesterol levels in homo-FH patients in whom LDL-R mutations, PCSK9 mutations, and the classical gene mutations are unknown (Fig. 13). In terms of clinical severity, the order of FH is as follows: LDL-R mutation > Apo-B-100 mutation > PCSK9 mutation > ARH mutation. Furthermore, gene mutations should be identified and the associated clinical severity should be investigated. Even in cases with same gene mutation, the diagnosis may be hypolipidemic FH, normolipidemic FH, or hyperlipidemic FH. In this context, although the search for FH-related genes is a desirable endeavor, the precise genotypic diagnosis is unlikely to alter the treatment paradigm (achievement of target LDL-C level) or the choice of pharmacotherapeutic agents.

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.