The official journal of the Japan Atherosclerosis Society andthe Asian Pacific Society of Atherosclerosis and Vascular Diseases

Review

J Atheroscler Thromb, 2021; 28: 665-678. http://doi.org/10.5551/jat.RV17050

Homozygous Familial Hypercholesterolemia
Atsushi Nohara 1, Hayato Tada 2, Masatsune Ogura 3, Sachiko Okazaki 4, Koh Ono 5, Hitoshi Shimano 6,
Hiroyuki Daida 7, Kazushige Dobashi 8, Toshio Hayashi 9, Mika Hori 10, Kota Matsuki 11, Tetsuo Minamino 12,
Shinji Yokoyama 13, and Mariko Harada-Shiba 14 on behalf of the Committee on Primary Dyslipidemia under
the Research Program on Rare and Intractable Disease of the Ministry of Health, Labour and Welfare of Japan†
1

Department of Clinical Genetics, Ishikawa Prefectural Central Hospital, Kanazawa, Japan
Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan3
Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
4
Division for Health Service Promotion, The University of Tokyo, Tokyo, Japan
5
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
6
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine University of Tsukuba, Tsukuba, Japan
7
Faculty of Health Science, Juntendo University, Juntendo University Graduate School of Medicine, Tokyo, Japan
8
Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
9
School of Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan10
Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
11
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
12
Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
13
Institute for Biological Functions, Chubu University, Aichi, Japan
14
Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
2†

The Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of
Health, Labour and Welfare of Japan: Mariko Harada-Shiba (Department of Molecular Pathogenesis, National Cerebral andCardiovascular Center Research Institute, Osaka, Japan), Shun Ishibashi (Division of Endocrinology and Metabolism, Department
of Internal Medicine, School of Medicine, Jichi Medical University, Tochigi, Japan), Shinji Yokoyama (Institute for Biological
Functions, Chubu University, Aichi, Japan), Hitoshi Shimano (Department of Internal Medicine (Endocrinology and Metabolism),
Faculty of Medicine University of Tsukuba, Tsukuba, Japan), Koutaro Yokote (Department of Endocrinology, Hematology andGerontology, Chiba University Graduate School of Medicine, Chiba, Japan), Hideaki Bujo (Department of Clinical-Laboratory andExperimental-Research Medicine, Toho University Sakura Medical Center, Chiba, Japan), Shizuya Yamashita (Rinku General
Medical Center, Osaka, Japan), Kazuhisa Tsukamoto (Department of Internal Medicine, Teikyo University, Tokyo, Japan), Toshio
Hayashi (School of Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan), Katsunori Ikewaki (Divisionof Neurology, Anti-Aging, and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Saitama,
Japan), Takanari Gotoda (Department of Metabolic Biochemistry, Faculty of Medicine, Kyorin University, Tokyo, Japan), Kazushige
Dobashi (Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan), Yoshihiro Miyamoto (Open
Innovation Center, National Cerebral and Cardiovascular Center, Osaka, Japan), Misa Takegami (Department of Preventive
Medicine and Epidemiology, National Cerebral and Cardiovascular Center, Osaka, Japan), Yoshiki Sekijima (Department ofMedicine (Neurology & Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan), Yasushi Ishigaki (Division of
Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan), Hiroaki
Okazaki (Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan),Atsushi Nohara (Ishikawa Prefectural Central Hospital, Kanazawa, Japan), Shingo Koyama (Division of Neurology and Clinical
Neuroscience, Department of Internal Medicine III, Yamagata University Faculty of Medicine, Yamagata, Japan), Kyoko Inagaki(Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Nippon Medical School, Tokyo, Japan), Koh
Ono (Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan), Masahiro Koseki(Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of Medicine, Osaka, Japan),
Hiroyuki Daida (Faculty of Health Science, Juntendo University, Juntendo University Graduate School of Medicine, Tokyo, Japan),
Manabu Takahashi (Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University,
Tochigi, Japan), Kimitoshi Nakamura (Department of Pediatrics, Kumamoto University Graduate School of Medical Sciences,
Kumamoto, Japan), Takashi Miida (Department of Clinical Laboratory Medicine, Juntendo University Graduate School of
Medicine, Tokyo, Japan), Masa-aki Kawashiri (Department of Cardiovascular Medicine, Graduate School of Medical Sciences,
Kanazawa University, Kanazawa, Japan), Tetsuo Minamino (Department of Cardiorenal and Cerebrovascular Medicine, Faculty of
Medicine, Kagawa University, Kagawa, Japan), Sachiko Okazaki (Division for Health Service Promotion, The University of Tokyo,
Tokyo, Japan), Hayato Tada (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences,
Kanazawa, Japan), Jun Wada (Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University

665

Nohara et al .

Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan), Masatsune Ogura (Division of Lipid
Metabolism, Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute,
Osaka, Japan), Hirotoshi Ohmura (Department of Cardiovascular Medicine, School of Medicine, Juntendo University, Tokyo,
Japan), Mika Hori (Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya,Japan), Kota Matsuki (Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki,
Japan), Masashi Yamamoto (Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of
Medicine, Chiba, Japan), Yasuo Takeuchi (Division of Nephrology, Kitasato University School of Medicine, Kanagawa, Japan),
Atsuko Nakatsuka (Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate
School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan), Daisaku Masuda (Department of Cardiology,
Health Care Center, Rinku Innovation Center for Wellness Care and Activities (RICWA), Rinku General Medical Center, Osaka,
Japan), Satoshi Hirayama (Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo,
Japan), Masayuki Kuroda (Center for Advanced Medicine, Chiba University Hospital, Chiba University, Chiba, Japan), Takashi
Yamaguchi (Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan), Takeyoshi
Murano (Clinical Laboratory Program, Faculty of Science, Toho University, Chiba, Japan).

Familial hypercholesterolemia (FH) is an inherited disorder with retarded clearance of plasma LDL caused
by mutations of the genes involved in the LDL receptor-mediated pathway and most of them exhibit autosomal
dominant inheritance. Homozygotes of FH (HoFH) may have plasma LDL-C levels, which are at least twice ashigh as those of heterozygous FH (HeFH) and therefore four times higher than normal levels. Prevalence of
HoFH had been estimated as 1 in 1,000,000 before but more recent genetic analysis surveys predict 1 in 170,000
to 300,000. Since LDL receptor activity is severely impaired, HoFH patients do not or very poorly respond to
medications to enhance activity, such as statins, and have a poorer prognosis compared to HeFH. HoFH should
therefore be clinically distinguished from HeFH. Thorough family studies and genetic analysis are recommended
for their accurate diagnosis.
Fatal cardiovascular complications could develop even in the first decade of life for HoFH, so aggressive
lipid-lowering therapy should be initiated as early as possible. Direct removal of plasma LDL by lipoprotein
apheresis has been the principal measure for these patients. However, this treatment alone may not achieve stable
LDL-C target levels and combination with drugs should be considered. The lipid-lowering effects of statins and
PCSK9 inhibitors substantially vary depending on the remaining LDL receptor activity of individual patients.
On the other hand, the action an MTP inhibitor is independent of LDL receptor activity, and it is effective inmost HoFH cases.
This review summarizes the key clinical issues of HoFH as well as insurance coverage available under theJapanese public healthcare system.
Key words: Homozygous familial hypercholesterolemia, Family study, Genetic diagnosis, Lipoprotein apheresis,
MTP inhibitor, PCSK9 inhibitor, Cutaneous and Tendon Xanthoma, Aortic Supra-valvular stenosis

Introduction
Familial hypercholesterolemia (FH) is an
inherited disorder of lipoprotein metabolism caused
by mutations of the genes involved in the LDL
receptor-mediated pathway for cellular uptake of
LDL. Most FH patients show an autosomal dominant
trait. Hyper-LDL-cholesterolemia remains throughout
their lives and causes premature coronary heart disease
unless properly treated 1-3).

Early diagnosis and initiation of lipid-lowering
therapy is essential for preventing development ofcardiovascular complications, even in Japan wherecardiovascular disease is not the leading cause of deathand its prevalence among FH patients seems to be
somewhat lower than in Western countries.
Heterozygous FH (HeFH) patients who carry themutated gene in a single allele have plasma LDLcholesterol (LDL-C) levels double normal or higher
and may experience the first cardiovascular event as

Address for correspondence: Atsushi Nohara, Department of Clinical Genetics, Ishikawa Prefectural Central Hospital, 2-1 Kuratsuki-Higashi, Kanazawa, Ishikawa
920-8530, Japan
E-mail: atsushinohara@mac.com
Received: March 15, 2021
Accepted for publication: March 16, 2021
Copyright©2021 Japan Atherosclerosis Society
This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

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Homozygous Familial Hypercholesterolemia

A 3ͲyearͲold patient:
wrists, knees, ankles

Adult cases:
fingers, buttocks, Achilles tendon

Fig. 1. Cutaneous and Tendon Xanthomas in HoFH
Presence of cutaneous xanthomas from childhood is strongly suggestive of HoFH, and tendon xanthomas are generally prominent in adults
with HoFH.

early as their thirties. With mutations in both alleles,
homozygous FH (HoFH) exhibits LDL-C levels twice
those of HeFH, or even higher, and patients develop
cardiovascular complications even in the first decadeof their lives. Most HoFH is refractory to statins andother standard lipid-lowering drugs as most of them
depend on remaining LDL receptor activity. Thus,
HoFH has a poor prognosis compared to HeFH andtherefore, earlier diagnosis and more aggressive
treatments are required to prevent premature death.
1. Clinical Manifestations of HoFH
Familial hypercholesterolemia (FH) is a disease
with a triad of clinical characteristics: elevated LDLC, cutaneous and/or tendon xanthomas, andpremature atherosclerotic cardiovascular disease(ASCVD). A genetic defect in LDL receptor functionis the cause of FH, and activity of the LDL receptor iscompletely or almost completely absent in HoFH
patients. HoFH includes homozygotes or compound/
double heterozygotes of autosomal-dominant disease-causing mutations in the related genes, and theirparents are HeFH, but there are rare exceptions thatexhibit autosomal recessive inheritance 4, 5).
1) Elevated LDL-C Levels
HoFH patients have very high LDL-C levels
from birth, which puts them at very high-risk ofcoronary heart disease. Plasma LDL-C levels are morethan 500 mg/dL in many cases of geneticallyconfirmed HoFH, but there is considerable variationin lipid levels among patients. Those with LDL-C
levels over 370 mg/dL (or total cholesterol levels over
450 mg/dL) in the fasting steady state should consult
with specialists as they are probably cases of HoFH.
2) Cutaneous and Tendinous Xanthomas (Fig. 1)
Characteristic cutaneous xanthomas that havedeveloped since infancy are physical findings
suggestive of HoFH. They are commonly found on
the extensor surfaces of the elbows/knees and wrist/
gluteal regions and parents often take a child to a667

Nohara et al .

doctor for the first visit because of them 6). Tendon
xanthomas are pathognomonic for both HeFH and
HoFH, but not apparent during childhood andgradually appear around puberty. Xanthomas can be
repressed or made to regress with continuous
aggressive lipid-lowering treatment.
3) ASCVD
The prognosis for untreated HoFH is extremely
poor. It is difficult for patients to live beyond 30 years
without treatment. The LDL-C accumulationthreshold hypothesis, which uses a calculation of[LDL-C x years of life], has been proposed as arational explanation for the coronary risk of FH, andaccording to it, the coronary threshold of HoFH
would be around 11 years old even for individuals
with lower LDL-C levels 7). Angina or myocardial
infarction from infancy, as well as aortic supravalvular
and/or valvular stenosis are often noted in HoFH
(Fig. 2), and may become the main cause of death inpatients. Even with substantially effective treatment,
systemic atherosclerosis, with such manifestations asaortic aneurysms, peripheral artery disease, andcerebrovascular disease, develops along with aging.
Aggressive LDL-lowering treatments should be started
as young as possible to prevent these atherosclerotic
complications.
2. Prevalence
In the 1970s, prevalence of HeFH was estimatedas 1 in 500 in the general population, and accordingly,that of HoFH as 1 in 1,000,000 8). However, more
recent molecular genetic studies have revealed that FH
is more common than previously expected. HeFH is
now estimated as 1 in 200 to 300 and HoFH as 1 in
170,000 to 300,000 in many countries including
Japan 9-13).
3. Genetics
LDL receptor-related disease-causing mutations
are identified only in 60 to 80% of clinicallydiagnosed HeFH 14-16). Most of them are in the LDL
receptor gene (LDLR), and those in apolipoprotein
B-100 (coded as APOB gene), the main ligand for the
LDL receptor, have also been reported mainly in
Caucasian populations 17). In 2003, gain-of-function
mutations in PCSK9, the gene coding proprotein
convertase subtilistin/kexin-type 9 and enhancer of
LDL receptor degradation, were found. This wasconsidered to be the second major FH-related gene,
explaining 5% of HeFH in Japan 18).
Families with FH caused by mutations in LDLR,APOB, and PCSK9 all show autosomal dominant
inheritance. Since LDLR accounts for the majority of
668

Fig. 2. Aortic Supra-valvular stenosis in HoFH
Supra-valvular stenosis is a pathognomonic finding of HoFH, andone of the causes of premature cardiac death in this disease.

the FH mutations, most individuals with HoFH are“true homozygotes” or “compound heterozygotes” fortwo different mutations in LDLR. Some patients are“double heterozygotes”, having combined mutationsin LDLR and PCSK9 4), for example. The parents of
HoFH children who are “true or compound
heterozygotes” mostly show the HeFH phenotype. On
the other hand, the family traits of HoFH “double
heterozygotes” may not apparently exhibit simple
Mendelian inheritance since the heterozygotes for
PCSK9 show a variety of phenotypes.
It should be noted that HeFH is underdiagnosed
and undertreated in the general population 3). In the
background of one suspected case of HoFH, there aremany family members with HeFH , and they must be
properly cared for in time to prevent their premature
death.
Besides the mutations discussed above, thosecausing, autosomal recessive hypercholesterolemia(ARH), a rare unique type of FH have been reported
in Japan 4, 5). ARH is caused by mutations in a genecoding low-density lipoprotein receptor adaptor
protein 1 (LDLRAP1). LDLRAP1 is an adaptor
protein making a complex with clathrin and LDL
receptors for efficient endocytosis of LDL receptors.
Heterozygous carriers of this mutation do not exhibit
the HeFH phenotype so it apparently shows
autosomal recessive inheritance. If the parents in aprobable case of HoFH have normolipidemia, ARH
may be considered.
Disease-causing mutations cannot be identified
in 20% to 40% of clinically diagnosed HeFH 19). Thismay be due to still-unknown FH-related genes orlimitations of analytic technologies. A clinicalHomozygous Familial Hypercholesterolemia

Table 1. Diagnostic criteria for FH in children
1. Elevated serum LDL cholesterol levels: untreated LDL-C level of ≥ 140 mg/dL (If total cholesterol level is ≥ 220 mg/dL, measure LDL-C level)
2. Family history of FH or premature CAD (within second-degree relatives)• Secondary hyperlipidemia should be ruled out.
• If a patient meets both of the above-mentioned criteria, FH is diagnosed.
• As LDL-C levels fluctuate during growth due to dietary and hormonal influences, careful examination is required.
• Clinical symptoms and findings including angina, xanthomas, and corneal arcus are rare in heterozygous FH children. Therefore, family
history of FH is important in making diagnosis• Premature CAD is defined as occurrence of CAD in men ＜ 55 years old or in women ＜ 65 years old.
• Homozygous FH should be suspected if patient has xanthomas.

Table 2. Diagnostic criteria for heterozygous FH in adults (15 years of age or older)
1. Hyper-LDL-cholesterolemia (an untreated LDL-C level of ＞= 180 mg/dL)
2. Tendon xanthoma (tendon xanthoma on the backs of the hands, elbows, knees, etc. or Achilles tendon hypertrophy) or xanthoma tuberosum
3. Family history of FH or premature CAD (within the patient's second-degree relatives)• The diagnosis should be made after excluding secondary hyperlipidemia.
• If a patient meets two or more of the above-mentioned criteria, the condition should be diagnosed as FH. In cases of suspected FH,
obtaining a diagnosis using genetic testing is desirable.
• Xanthoma palpebrarum is not included in xanthoma tuberosum.
• Achilles tendon hypertrophy is diagnosed if the Achilles tendon thickness is ＞= 9 mm on X- ray imaging.
• An LDL-C level of ＞= 250 mg/dL strongly suggests FH.
• If a patient is already receiving drug therapy, the lipid level that led to treatment should be used as the reference for diagnosis.
• Premature CAD is defined as the occurrence of CAD in men ＜ 55 years of age or women ＜ 65 years of age, respectively.
• If FH is diagnosed, it is preferable to also examine the patient’s family members.

diagnosis of typical HoFH cannot be excluded even if
two pathogenic FH gene variants are not identified. A
substantial portion of HeFH cases without “known”
F H - g e n e m u t a t i o n s c o u l d b e “p o l y g e n i c
hypercholesterolemia” 20) or “oligogenic FH” 21-23),
though these concepts of FH have not become
established. Although genetic analysis provides adefinitive diagnosis of HoFH, the possibility of suchcases cannot be excluded. Therefore, clinicalassessment including thorough physical examinationand familial studies is essential. For information,
Japanese public healthcare insurance does not cover
the expenses for HoFH genetic testing as of February
2021.
4. Pathophysiology
LDL receptor activity is completely or nearly all
lost in HoFH. Severely elevated LDL-C levels frombirth (more exactly, from fetal period 24)) often cause
fatal cardiovascular disease even in infancy. As an
example of cholesterol deposition in tissues,
pathognomonic skin xanthomas develop from infancy
in HoFH and tendon xanthomas become apparent
later, and they are more prominent than those in
HeFH.

5. Diagnostic Criteria in Japan
1) Clinical Diagnosis
A clinical diagnosis of HoFH can be made on
the basis of skin or tendon xanthomas since infancy,
and untreated LDL-C levels of twice those of HeFH
or higher. Diagnostic criteria for FH in Japaneseguidelines apply not only HeFH but also HoFH 1, 4)(Table 1, Table 2). In cases with very high LDL-C
and/or prominent xanthomas, HoFH should besuspected 25, 26).
Skin xanthomas since infancy arepathognomonic for HoFH, and sometimes the chiefcomplaint for the first consultation with doctors 4)(Fig. 1). Skin xanthomas in pediatric HoFH are
frequently found in flexures of the wrist and ankles,
and also in other regions having mechanical stress.
Tendon xanthomas are more prominent than in
HeFH 27), but become apparent later than skinxanthomas.
Typical HoFH exhibits total cholesterol levels of
more than 600 mg/dL in total 1), but there isconsiderable overlapping of levels between HoFH andsevere HeFH 28). LDL-C levels over 370 mg/dL (ortotal cholesterol levels over 450 mg/dL) in the fasting
steady state would be sufficient for a diagnosis ofprobable HoFH and the patient should be referred to669

Nohara et al .

specialists. In pediatric patients, plasma LDL-C levels
may fluctuate and should be measured multiple times.
Measurement of LDL receptor activity in the
fibroblasts of patients provides useful information indiagnosing HoFH, but is currently not routinely
available at the laboratories of commercial or researchfacilities in Japan. Assaying LDL receptor activity inlymphocytes is feasible 29) but less reliable thanfibroblast measurements.
2) Genetic Diagnosis
Genetic testing is recommended for suspected
HoFH cases, but is not covered by Japanese publichealthcare insurance as of February 2021. Genetic
diagnosis indicates the potential efficacy of drug
treatment and thereby therapeutic strategies 30, 31).
Conversely, drug ineffectiveness (for example,
refractory to PCSK9 inhibitors) may suggest the
HoFH genotype so genetic tests should be consideredin such cases 32).
The possibility of detecting an FH-causative
mutation in HeFH is 60 to 80%. Therefore, diagnosis
should be carefully made together with clinicalexaminations and detailed familial studies even incases of suspected HoFH where the mutations
detected are apparently in 0 alleles or only 1 allele,because a genetic test does not exclude the possibilityof HoFH due to unknown gene mutations.
Consultation with experienced specialists is requiredin such cases.
6. Screening/Follow-Up for ASCVD
Most HoFH patients may die of ASCVD before
30 years old if untreated 33, 34). Once HoFH issuspected, extensive examination for ASCVD should
be carried out. In HoFH, the potentially fatal
disorders of angina pectoris, myocardial infarction,
and aortic supra-valvular and valvular stenosis could
occur even in childhood (Fig. 2). Aortic supra-valvular
and valvular stenosis in HoFH is sometimes difficult
to treat and lethal 35). If patients are left untreated until
around 20 years old, ASCVD risk is extremely high.
Heart and aortic disease proceeds and systemic
atherosclerosis develops later in life.
Non-invasive tests such as cardiac ultrasonography,
carotid ultrasonography, and electrocardiograms
should be conducted first, and enhanced CT for the
aorta and coronary artery and coronary angiography
should be considered when necessary 36). Exercise stresstests should be carefully performed with consideration
for patient safety.
7. Differential Diagnosis
A differential diagnosis should be made using
670

high LDL-C levels and prominent xanthomas. LDL-C
may be elevated to HoFH levels by secondary
hypercholesterolemia such as hypothyroidism or
nephrotic syndrome. Xanthomas may develop due tohypercholesterolemia in primary biliary cholangitis.
Sitosterolemia, caused by the ATP-binding cassettetransporter ABCG5/ABCG8 gene (ABCG5/ABCG8)
mutations 37), sometimes exhibits elevation of LDL-C
and skin xanthomas comparable to HoFH during thesuckling stage 38). Although LDL-C elevation and skinxanthomas subside after weaning from breastfeeding,elevated levels of plasma plant-sterols (including
sitosterol) persist in these patients. There is also
cerebrotendinous xanthomatosis (CTX), an autosomal
recessive disease caused by sterol 27-hydroxylase gene
(CYP27A) mutations, which is characterized byprominent xanthomatosis in the tendon and brain andsometimes accompanied by central nervous symptoms(mental retardation, cognitive impairment, or motor
ataxia) 39). CTX is clinically diagnosed by elevatedplasma cholestanol levels. A differential diagnosis
should be carefully made because these diseases require
specific therapeutic approaches.
8. Treatment of HoFH
HoFH patients may suffer fatal ASCVD from
infancy so initiation of aggressive LDL-C lowering as
early as possible is essential for preventing theirpremature deaths 1, 4) (Fig. 3, Fig. 4). Specific therapeuticstrategies for preventing ASCVD development inindividual cases should be planned in addition to LDL
lowering.
Patients as well as their families will be burdenedby various sources of stress such as anxiety aboutprognosis, concern about heredity, and costs oftreatments. Supportive information should be
provided, including that on possible financial aid, thetherapeutic options available, and genetic counseling.
Financial aid is available under The Program for
Designated Intractable Diseases of the Japanese publichealthcare system. Pediatric FH patients can receive
support separately under The Program of Medical Aid
for Chronic Pediatric Diseases of Specified Categories,
which covers both HeFH and HoFH. In practice,consultation with specialists should strongly beadvised.
1) Adult HoFH (15 years of age or older)
The LDL-C management goal is less than 100
mg/dL in primary prevention, and less than 70 mg/dL
in secondary prevention 1) in the Japanese guideline(Fig. 3). Medication should start with statins atappropriate doses 40), followed by increasing them tomaximal tolerated doses and combination with otherHomozygous Familial Hypercholesterolemia

Diagnosis of FH homozygote(consultation with specialists)

Commence guidance on lifestyle habit improvement and appropriate body weight,
and lipid-lowering therapy at same timeLDL-C management targets: Primary prevention: <100 mg/dL
Secondary prevention: <70 mg/dL

Statin at maximal tolerated dose

,QLWLDWH/'/DSKHUHVLVUse statins and consider ezetimibe, PCSK9 inhibitor,
MTP inhibitor, resin, probucol in combination

Fig. 3. Algorithm for treatment of adult (15 years of age or older) FH homozygotes
In HoFH, powerful LDL-C lowering therapy is required from a young age to prevent the onset and progression of CAD. Combination oflipid-lowering drugs, including MTP inhibitor, and lipoprotein apheresis is required in many patients with HoFH.
(Adapted from Guidelines for Diagnosis and Treatment of Familial Hypercholesterolemia 20171) “LDL apheresis” means “lipoprotein
apheresis” in this review)'LDJQRVLVRI)+KRPR]\JRWH&RQVXOWVSHFLDOLVW
3URYLGHLQVWUXFWLRQUHJDUGLQJIRRGDQGOLIHVW\OH
DQGVWDUWVWDWLQ  䠄LQFUHDVHWRPD[LPDO WROHUDWHGGRVH䠅DQGGHWHUPLQH
HIIHFWDIWHUDOPRVWDPRQWK 
1RHIIHFW(IIHFWLYH'UXJWKHUDS\
8VHVWDWLQVDQGRWKHUGUXJVLQFRPELQDWLRQ&RQVLGHUDSKHUHVLVGHSHQGLQJRQ/'/& OHYHO,QLWLDWH/'/DSKHUHVLV&RQVLGHUGUXJVRWKHUWKDQVWDWLQVVLPXOWDQHRXVO\,I/'/DSKHUHVLVLVQRWSRVVLEOH'UXJWKHUDS\ZLWKGUXJVVXFKDVH]HWLPLEHUHVLQSUREXFRORU3&6.LQKLELWRUV  6WURQJVWDWLQUHFRPPHQGHGDVWKHUDS\ ,I/'/&OHYHOGHFUHDVHVE\DSSUR[LPDWHO\LWGUXJWKHUDS\KDVEHHQHIIHFWLYHLWZLOOQHHGWREHVWDELOL]HG 3&6.LQKLELWRUVKDYHQRWEHHQXVHGPXFKLQFKLOGUHQDJHG\HDUV'LVFRQWLQXHLI/'/&OHYHOVGRQRW
GHFUHDVH 073LQKLELWRUVKDYHQRWKDGWKHLUVDIHW\DQGHIILFDF\FRQILUPHGLQSHGLDWULFFDVHVFig. 4. Algorithm for treatment of pediatric FH homozygotes
Lifestyle interventions and maximally tolerated statin therapy should be started at the initial diagnosis. Since LDL-C targets are rarely
achieved, lipoprotein apheresis therapy is recommended, and should be commenced by age 5 ideally.

671

Nohara et al .

drugs 41-43). Achievement of these goals with drug
treatment only is, however, not easy in HoFH.
Statins, ezetimibe and PCSK9 inhibitors all act
by enhancing LDL receptor activity 44, 45), so theireffectiveness depends on residual LDL receptor
activity in the individual HoFH patient. Many HoFH
patients are refractory to these drugs. However, if anyof them are effective in lowering LDL-C, they should
be continued together with the additional treatments
described below.
MTP inhibitors (lomitapide) are a class of oral
drug that is independent of LDL receptor activity.
Clinically, they are indicated only for HoFH, and adecrease in LDL-C to approximately half of the
pretreatment level can be achieved in many HoFH
cases, if tolerated 46-49). The main adverse effects are
gastrointestinal symptoms and liver enzyme elevationaccompanied by fat accumulation, similar to thesymptoms observed in patients with MTP
deficiency 50). The MTP inhibitor should be started
with the lowest dose, taking adequate measures inaccordance with nutritional guidance (restricted fat
and alcohol intake), and then the dose should be
carefully increased gradually.
Lipoprotein apheresis directly removes LDL fromplasma through selective absorption or filtration of
LDL using an extra-corporal circulation system, andthis has been the core therapy for HoFH to date 51-53).
LDL-C levels can be precisely decreased by thisprocedure, depending upon the treated plasma
volume, when properly performed. Lipoprotein
apheresis not only removes LDL but also has potential
pleiotropic effects in preventing atherosclerosis
through removal of cell adhesion molecules 54),
coagulation factors 55), and inflammatory cytokines 56).
Lipoprotein apheresis for HoFH once every 1 to 2
weeks is covered by Japanese public healthcare
insurance. The use of ACE inhibitors is contraindicated for patients treated by lipoprotein apheresis
with the Liposorber system and selective absorption of
LDL by dextran sulfate-cellulose because shock may
occur due to an increase in bradykinin activation.
Another option is liver transplantation. While
this is highly invasive, it has been shown be a feasible
therapeutic option for reversing atheroscleroticchanges in HoFH patients that are uncontrollable
with conservative therapy 57, 58).
2) Pediatric HoFH
Even in the suckling stage, children with HoFH
must be referred to specialists for initiation of lipidlowering therapy, as this is the key to a better
prognosis 4). The target LDL-C level should be thesame as for adult HoFH in secondary prevention
672(though not clearly stated in the current pediatricguideline 4)). In pediatric HeFH, it is set at less than
140 mg/dL for primary prevention.
Statins and life-style interventions must be
started at the time of diagnosis. Statins must be
up-titrated and efficacy should be evaluated within a
1-month interval in order to titrate up to the maximal
tolerated doses. Combination therapy with ezetimibe,
bile sequestering resins, and PCSK9 inhibitors should
be considered. These strategies may be effective incases where there is a response in residual LDL
receptor activity. Probucol should also be consideredas it could reduce LDL in HoFH due to an unknown
mechanism. Administration of an MTP inhibitor
could be considered but only with extreme caution
because no results of clinical trials in children havebeen reported. Drug therapy should be conducteduntil it becomes possible to commence lipoprotein
apheresis.
In any case, lipoprotein apheresis must be
considered since LDL-C targets are seldom achievedin HoFH only with drug treatment. This
extracorporeal circulation therapy is generallycommenced at the age of 5 or older, though it hasreportedly been started in a patient who was 3.5 years
old. In Japan, the main method is selective LDL
absorption by dextran sulfate cellulose. However, withthe aim of reducing extracorporeal volume, simple
plasma exchange can be selected for children with abodyweight under 30 kg.
3) Treatment during Pregnancy in HoFH
Female HoFH patients could be treated in thesame way as for secondary prevention on reaching
childbearing age. During pregnancy, LDL and VLDL
are generally increased, and continuation of LDLlowering therapy would be important. Statins andmany other drugs are contraindicated during
pregnancy and breastfeeding, and only bile
sequestering resins can be used, taking proper care,but their LDL-lowering effects are limited 59). It has
been reported that lipoprotein apheresis is effective
and feasible during pregnancy, and a case of
cardiovascular death caused by suspension of apheresis
during pregnancy 60) has been reported. Consultation
with experienced specialists is recommended for
pregnancy in HoFH.
Future Perspectives
Therapeutic options are still limited for HoFH,
and all-out efforts should be made to achieve the best
combination of feasible therapies in many cases.
However, each therapeutic strategy has its advantages

Homozygous Familial Hypercholesterolemia

and disadvantages so new therapies are awaited.
Inclisiran, a new siRNA drug that inhibitstranslation of PCSK9, is being developed 61). As theeffect of one injection lasts 6 months to 1 year, thisdrug may be a good option for HoFH patients who
respond to PCSK9 inhibitors. Inclisiran was approvedin the European Union in December 2020.
Evinacumab, an anti-ANGPTL3 antibody, is a
new class of drug that is reportedly effective even in
HoFH 62), and clinical trials are ongoing in Japan andother countries 63). The LDL-C lowering effect of
evinacumab is independent of LDL receptor activity.
Mipomersen (Kynamro), an antisense drug for
the APOB gene, has moderate LDL-lowering effects
but has the adverse effects of liver damage andinjection site reactions. It was approved by the FDA
for HoFH in 2013 64) but rejected by the European
Medicines Agency, and FDA approval was eventually
withdrawn in 2019.
Gene therapy for HoFH has been investigated,
but is still in the experimental stage. Since HoFH is arelatively rare disease, even if approved, demand fortherapies would not be very high anywhere in theworld. Lomitapide had been approved only for thetreatment of HoFH in just 38 countries as of March
2021, including those in North and South America,
the European Economic Area, and only Japan in East
Asia. Lipoprotein-apheresis, which requires specificequipment, is available in a limited number ofcountries. Wider availability of therapeutic measuresfor HoFH should encourage its more active diagnosis
worldwide.
Early diagnosis of FH is essential for preventing
premature death in patients, whether they are heteroor homozygotes 65-67). Universal screening of plasma
lipid levels during childhood has been trialed in someparts of Japan and we expect that such trials on local
universal screening will lead to a nationwide system.
In addition, reverse cascade screening, in which family
members are screened on the basis of child probands,
and continued worldwide registry research should
improve the effectiveness of finding FH 68-76).
Acknowledgments andNotice of Grant Support
This work has been supported by Health, Labourand Welfare Sciences Research Grant for Research on
Rare and Intractable Diseases (H30-nanji-ippan-003).
Conflicts of Interest
Atsushi Nohara has nothing to disclose. Hayato
Tada has nothing to disclose. Masatsune Ogura hasreceived honoraria from Amgen Inc., Astellas Pharma
Inc. Sachiko Okazaki has received scholarship grants
from Minophagen Pharmaceutical Co., Ltd., Kowa
Company, Ltd. Koh Ono has nothing to disclose.
Hitoshi Shimano has nothing to disclose. Hiroyuki
Daida has received honoraria from Amgen Inc.,
Daiichi-Sankyo Co., Ltd., Kowa Co., Ltd., and MSD
K.K., Novartis Pharma K.K., Bayer Yakuhin, Ltd. andreceived clinical research funding from Canon Medical
Systems Corporation, Philips Japan, Ltd., Toho
Holdings Co., Ltd., Asahi Kasei Corporation, andInter Reha Co., Ltd. HD has also received scholarshipgrants from Nippon Boehringer Ingelheim Co., Ltd.,
Otsuka Pharmaceutical Co., Ltd., Sanofi K.K., MSD
K.K., Daiichi-Sankyo Co., Ltd., Pfizer Co., Ltd.,
Mitsubishi Tanabe Pharma Corp., Astellas PharmaInc., Takeda Pharmaceutical Co., Ltd., Teijin Pharma,
Ltd., Shionogi & Co., Ltd., Actelion Pharmaceuticals,Ltd., Actelion Ltd., Kowa Co., Ltd., Bayer Yakuhin,Ltd. HD has also courses endowed by companies,
including Philips Japan, Ltd., ResMed, Fukuda
Denshi Co., Ltd., and Paramount Bed Co., Ltd.
Kazushige Dobashi has nothing to disclose. Toshio
Hayashi has nothing to disclose. Mika Hori has
nothing to disclose. Kota Matsuki has nothing todisclose. Tetsuo Minamino has nothing to disclose.
Shinji Yokoyama has nothing to disclose. Mariko
Harada-Shiba has received stock holdings or options
from Liid Pharma, honoraria from Amgen Inc.,
Astellas Pharma Inc., Sanofi, and scholarship grants
from Aegerion Pharmaceuticals, Inc., Recordati Rare
Diseases Japan, and Kaneka Corporation. Katsunori
Ikewaki has nothing to disclose. Yasushi Ishigaki has
nothing to disclose. Shun Ishibashi has received
honoraria from Kowa Co., Ltd., and a scholarshipgrant from Ono Pharmaceutical Co., Ltd. Kyoko
Inagaki has nothing to disclose. Hirotoshi Ohmura
has nothing to disclose. Hiroaki Okazaki has received
scholarship grants from Minophagen PharmaceuticalCo., Ltd., Kowa Company, Ltd. Masa-aki Kawashiri
has nothing to disclose. Masayuki Kuroda has nothing
to disclose. Masahiro Koseki has received clinicalresearch funding from Kowa Company, Ltd., Rohto
Pharmaceutical Co., Ltd. Takanari Gotoda has
nothing to disclose. Shingo Koyama has nothing todisclose. Yoshiki Sekijima has nothing to disclose.
Manabu Takahashi has nothing to disclose. Yasuo
Takeuchi has nothing to disclose. Misa Takegami has
nothing to disclose. Kazuhisa Tsukamoto has received
honoraria from Bayer Yakuhin, Ltd., MSD Ltd.,
Takeda Pharmaceutical Company Ltd., andscholarship grants from Mitsubishi Tanabe Pharma
Corporation., Bayer Yakuhin, Ltd., Sanofi K.K.
Atsuko Nakatsuka has nothing to disclose. Kimitoshi
673

Nohara et al .

Nakamura has nothing to disclose. Satoshi Hirayama
has nothing to disclose. Hideaki Bujo has nothing todisclose. Daisaku Masuda has received clinical researchfunding from MSD K.K., Ono Pharmaceutical Co.,
Ltd., Takeda Pharmaceutical Co., Ltd., Kowa Co.,
Ltd. Takashi Miida has nothing to disclose. Yoshihiro
Miyamoto has nothing to disclose. Takeyoshi Murano
has nothing to disclose. Takashi Yamaguchi has
nothing to disclose. Shizuya Yamashita has received
honoraria from Kowa Company, Ltd., MSD K.K.
Masashi Yamamoto has nothing to disclose. Koutaro
Yokote has received honoraria from Kowa Company,
Ltd., MSD K.K., Astellas Pharma Inc., Mitsubishi
Tanabe Pharma Corp., Amgen K.K., Takeda
Pharmaceutical Company Limited, Sanofi K.K., Ono
Pharmaceutical Co., Ltd., AstraZeneca K.K., DaiichiSankyo Co., Ltd., Novartis Pharma K.K., Sumitomo
Dainippon Pharma Co., Ltd., Kyowa Kirin Co., Ltd.,
Pfizer Japan Inc., Novo Nordisk Pharma Ltd., Nippon
Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K.,
Taisho Pharmaceutical Co., Ltd., Janssen
Pharmaceutical K.K., and received clinical researchfunding from Taisho Pharmaceutical Co., Ltd. KY has
also received scholarship grants from Mitsubishi
Tanabe Pharma Corp., Takeda Pharmaceutical Co.,
Ltd., MSD K.K., Pfizer Japan Inc., Novo Nordisk
Pharma Ltd., Taisho Pharmaceutical Co., Ltd., Kao
Corporation, Ono Pharmaceutical Co., Ltd., Eli Lilly
Japan K.K., Sumitomo Dainippon Pharma Co., Ltd.,
Nippon Boehringer Ingelheim Co., Ltd., DaiichiSankyo Co., Ltd., Teijin Pharma, Ltd., Shionogi Co.,
Ltd., Bayer Yakuhin, Ltd. Jun Wada has nothing todisclose.
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