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

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.

Fig. 1.

Physical findings in a hetero-FH patient. S.N. 43 y.o. Male, Achilles tendon thickness (ATT); 17.0 mm, TC 392 mg/dL, TG; 124 mg/dL Bilateral xanthelasma (+), r-eye; arcus corneae (+), bilateral hands; tendon xanthomas (+), bilateral Achilles tendon xanthomas (+)

Fig. 2.

Physical findings in a homo-FH patient. S.Y. 24 y.o. male, ATT; 42.0 mm, TC 538 mg/dL, TG 80 mg/dL, HDL-C 28 mg/dL, LDL-C 486 mg/dL, LDL-R gene mutations; D280Y/D280Y. Severe xanthomas on the backs of bilateral hands and nose root. Severe bilateral planar xanthomas around knee joints, bilateral periosteal xanthomas below knee joints, severe ATT; 42.0 mm

Fig. 3.

Severe planar and tuberous xanthomatosis in a homo-FH boy. M.K. 3 y.o. TC 599 mg/dL, TG 61 mg/dL, HDL-C 53 mg/dL, LDL-C 534 mg/dL Achilles tendon xanthoma (−), His FH genes were double mutations; LDL-R C183S/PCSK9 E32K. This patient is responsive to statin (pitavastatin) and ezetimibe. The same double mutations in the FH-related genes (LDL-R and PCSK9) were observed in his younger brother (K.K.), but he has no cutaneous and tendon xanthomas.

Fig. 4.

Achilles tendon xanthoma can be easily diagnosed by palpation or on X-ray. (Left; 6.0 mm, Right; 17.0 mm)

Fig. 5.

The first case of homo-FH in Japan was reported by Yamakawa and Kashiwabara in 1922. This 35-year-old man showed prominent generalized cutaneous and tendon xanthomatosis and severe ASCVD symptoms and signs due to hypercholesterolemia of 526 mg/dL.

Fig. 6.

In 1974, Brown and Goldstein succeeded in the elucidation of FH, and they were awarded Nobel Prize in 1985. They visited Kanazawa for giving us memorial lectures in 1992. (Left; M.S. Brown, Right; J.L. Goldstein. They permitted me to use this picture in this article.)

Fig. 7.

Effects of various concentrations of LDL on HMG-CoA reductase activity in cultured skin fibroblasts from unaffected subjects and hetero- and homo-FH patients. Residual LDL-R activity was enough in normal subjects, and in hetero-FH patients residual LDL-R activity is about half of normal activity, and receptor activity in receptor-negative homo-FH patients is null, and the activity in the receptor-defective homo-FH is less than 20% of normal activity.

Fig. 8.

Location of point mutations and small deletions/insertions in LDL-R gene in Japanese FH patients in Hokuriku district.

Fig. 9.

The frequency of FH gene mutations in LDL-receptor and PCSK9 in Japan.

Fig. 10.

Plasma cholesterol distributions in homo-FH patients, hetero-FH patients and unaffected subjects. Clearly three peaks are observed in the serum cholesterol distribution among members of families affected by FH. These three peaks represent healthy individuals and hetero-FH and homo-FH patients.

Fig. 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.

Fig. 12.

Plasma cholesterol distributions in each genotypic hetero-FH patient. Genotypic variations show phenotypic heterogeneity. Size of each boxes show mean ± SD.

Fig. 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⁾

Fig. 14.

Two brothers with the same genotypic double heterozygotes due to LDL-R gene mutant C183S and PCSK9 E32K show quite different phenotypic characteristics. The elder brother shows generalized planar xanthomatosis. His plasma TC was 629 mg/dL, LDL-C 581 mg/dL, and his plasma cholesterol responded very well to statin and ezetimibe, and his xanthomatosis became smaller and softer and almost disappeared without LDL-apheresis. But his younger brother has no xanthomas, and his TC was 291 mg/dL, and his LDL-C was 227 mg/dL and he had never been treated by statin or any other medication.

Fig. 15.

A homo-FH man had been treated by LDL-apheresis for more than 35 years. After 3 years of LDL-apheresis, his xanthomatosis greatly decreased in size and hardness.

Fig. 16.

The male homo-FH patient (S.Y.) due to true homozygote with LDL-R D280Y/D280Y has been treated by LDL-apheresis for more than 35 years. His severe xanthomatosis rapidly decreased in size and number, and his frequent anginal attacks almost disappeared after the long-term treatment.

Fig. 17.

Statin drugs discovered by Endo showed dramatic LDL-C reductions in hetero-FH and non-FH patients, and thus, compactin was called as “Penicillin for hypercholesterolemia”. (Left; A. Endo, Right; H. Mabuchi, A, Endo permitted me to use this picture.)

Fig. 18.

Effects of compactin on plasma total-, IDL-, LDL- and HDL-cholesterol levels in patients with hetero-FH. LDL-C level was reduced by 29%, and HDL-C increased slightly.

Fig. 19.

Cumulative number of myocardial infarction (MI) cases in male and female hetero-FH patients in prestatin era MI was first noted in men in the 3 decade of life and in women in the 4 decade of life. The mean age of first MI attack is 50 years old in the male hetero-FH, and 65 years old in female hetero-FH patients. The MI patients younger than those ages could be called as “premature MI” cases

Fig. 20.

Molecular pathogenesis of FH Genetic mechanism in the pathogenesis of FH is shown here (n = 1,067). Causes of FH are LDL-R mutations (69.7%), PCSK9 gain of function mutations (5.7%), ARH (1.4%) and other unknown mutation (23.2%).