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

Review

J Atheroscler Thromb, 2021; 28: 791-801. http://doi.org/10.5551/jat.RV17052

Diagnosis and Management of Sitosterolemia 2021
Hayato Tada 1, Akihiro Nomura 1, Masatsune Ogura 2, Katsunori Ikewaki 3, Yasushi Ishigaki 4, Kyoko Inagaki 5,
Kazuhisa Tsukamoto 6, Kazushige Dobashi 7, Kimitoshi Nakamura 8, Mika Hori 9, Kota Matsuki 10,
Shizuya Yamashita 11, Shinji Yokoyama 12, Masa-aki Kawashiri 1 and Mariko Harada-Shiba 13 on behalf of theCommittee 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 Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
3
Division of Neurology, Anti-Aging, and Vascular Medicine, Department of Internal Medicine, National Defense Medical College,
Saitama, Japan
4
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
5
Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Nippon Medical School, Tokyo, Japan
6
Department of Internal Medicine, Teikyo University, Tokyo, Japan
7
Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
8
Department of Pediatrics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
9
Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan10
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
11
Rinku General Medical Center, Osaka, Japan
12
Institute for Biological Functions, Chubu University, Aichi, Japan
13
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,

791

Tada et al .

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
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).

Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as
sitosterol. This disease is caused by loss-of-function genetic mutations in ATP-binding cassette (ABC) subfamily
G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in selective
excretion of plant sterols from the liver and intestine, leading to failure to prevent absorption of food plantsterols. This disorder has been considered to be extremely rare. However, accumulated clinical data as well as
genetics suggest the possibility of a much higher prevalence. Its clinical manifestations resemble those observedin patients with familial hypercholesterolemia (FH), including tendon xanthomas, hyper LDL-cholesterolemia,
and premature coronary atherosclerosis. We provide an overview of this recessive genetic disease, diagnostic aswell as therapeutic tips, and the latest diagnostic criteria in Japan.
Key words: Sitosterolemia, ABCG5, ABCG8, Familial hypercholesterolemia

Introduction
Sitosterolemia (OMIM #210250, and #618666)is an autosomal recessive disorder of lipid metabolism
characterized by increased absorption and decreased
biliary excretion of plant sterols and cholesterol,re s u l t i n g i n p r o m i n e n t l y e l e v a t e d s e r u mconcentrations of plant sterols, such as sitosterol,
campesterol, and stigmasterol (Fig. 1) 1, 2). Thiscondition was first described by Bhattacharyya andConnor in 1974 3). Patients with sitosterolemia
primarily exhibit tendinous and tuberous xanthomas
and premature coronary atherosclerosis, resemblingthese characteristics in patients with familial
hypercholesterolemia (FH) 4-9). Severity of thephenotypes of sitosterolemia appears to be morevariable than for FH possibly due to its greater
dependency on dietary sterol intake 10, 11). In addition,
they have a wider variety, which includes hemolysis,
splenomegaly, platelet abnormalities, and arthralgia/
arthritis 12). This disease is caused by biallelic(homozygous/compound heterozygous) loss-offunction (LOF) mutations in either ATP-binding
cassette (ABC) subfamily G member 5 or member 8(ABCG5 and ABCG8, respectively) that play animportant role in excreting sterols from the liver andintestine (Fig. 1) 13, 14). Therefore, increased absorptionof plant sterols from the intestine and their decreased
secretion from the liver are the primary cause ofsitosterolemia 15, 16). Several (adaptive) secondarychanges in lipid metabolism have been found to be
associated with the accelerated sterol absorption; for

Address for correspondence: Masa-aki Kawashiri, Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
E-mail: mk@med.kanazawa-u.ac.jp
Received: March 17, 2021
Accepted for publication: March 20, 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.

792

Sitosterolemia Clinical Guide 2021

6PDOO %LOLDU\LQWHVWLQH WUDFW%ORRG$F\O &R$

9/'/+0*&R$UHGXFWDVH

13&/

/'//'/UHFHSWRU%LOH DFLG&KROHVWHURO$%&**$%&**

13&/
3ODQWVWHURO&KROHVWHURO+HSDWRF\WH&K\ORPLFURQUHPQDQW

0LFHOOH

3ODQWVWHURO&KROHVWHURO&KROHVWHU\OHVWHU

6PDOO LQWHVWLQDO PHPEUDQH&KROHVWHU\O
3ODQWVWHURO
HVWHU&KROHVWHURO
073
$&$7
&KROHVWHURO $SROLSRSURWHLQ % &K\ORPLFURQ
3KRVSKROLSLG/\PSK
7ULJO\FHULGHVFig. 1. Schema of sterol metabolism focusing on ABCG5/8 and NPC1L1
In the intestine, plant sterols and cholesterol are absorbed via NPC1L1, while they are excreted
via ABCG5/8. The same pattern is observed in hepatocytes.

example, altered solubilization of sterols in intestinal
micelles, increased activity of acyl CoA: cholesterolacyltransferase (ACAT), and changes in intracellulartransport processes of sterols.
Sitosterolemia used to be considered an
extremely rare disorder but recent studies indicate thepossibility of a much higher prevalence in the general
population 6-10).
Based on the pathophysiology of this disease,ezetimibe, an inhibitor of Niemann-Pick C1 Like 1(NPC1L1) that mediates absorption of dietarycholesterol in the intestine 17), has been shown to beeffective in reducing serum sitosterol as well as
cholesterol in sitosterolemic patients, together withdietary management to restrict intake of these sterols 18, 19).
In this review article, we discuss the current
understanding of sitosterolemia, its diagnostic criteria,
and future perspectives.

individuals 21-24), resulting in lower levels of plantsterols than cholesterol in the body. In a recent
investigation of plasma concentrations of plant sterols
in 667,718 subjects, they seemed to be dependent onage, gender, and apolipoprotein E genotype 25).
Accumulation of plant sterols in patients withsitosterolemia would contribute to atherogenesis.
However, dietary intake of plant sterols is generally
considered beneficial for normal individuals as they
competitively inhibit cholesterol absorption, which isthen selectively excreted resulting in lower cholesterollevels 26). The European Atherosclerosis Society
Consensus Panel currently recommends taking plantsterols for patients with a relatively high risk for
cardiovascular disease and/or statin intolerance 20). In
addition, the proinflammatory properties of sitosterol
appear to be much weaker than those of cholesterol 27).
Epidemiology

Plant Sterols
Plant sterols (sitosterol, campesterol, andstigmasterol) are sterol molecules naturally contained
at low levels in plant foods such as fruits, vegetables,nuts and cereals 20). Sitosterol is usually the mostabundant plant sterol in the diet 2) and the average
Japanese diet and Western diets contain similar
amounts of cholesterol and plant sterols. Althoughapproximately 50% of dietary cholesterol is absorbed,
less than 5% of plant sterols is absorbed in normal

Sitosterolemia has long been considered an
extremely rare disorder. Indeed, only 45 sitosterolemic
subjects were reported in a review article published in2003 28). Its autosomal recessive inheritance may havecaused us to think it is a rare disease. However, theExome Aggregation Consortium (ExAC) Exome
Browser, a public genetic database, has suggested that
1 in ~220 general individuals have LOF mutations in
the ABCG5 or ABCG8 gene 29). Therefore, a roughestimate of the number of homozygous/compound793

Tada et al .

heterozygous patients with sitosterolemia is 1 in
~200,000 general individuals. Moreover, a recent
study has shown that a certain proportion of patientsclinically diagnosed as FH could in fact havesitosterolemia 30). Accordingly, this disorder appears to
be much more prevalent than previously thought.
Genetic Backgrounds and Pathophysiology
In 2001, the cause of this disease was identified
as double LOF mutations in the ABCG5 or ABCG8
gene 13, 14). So far, most patients with recognizedsitosterolemia have come from consanguineous
marriages, which has lead to homozygous mutationsin the ABCG5 or ABCG8 gene. However, recent
advances in genetic analysis have revealed that there
are also a number of cases with compound
heterozygous mutations in the ABCG5 and ABCG8
genes. Relatively common pathogenic mutations arec.1166G ＞ A/p.Arg389His, and c.1256G ＞ A/p.
Arg419His in ABCG5 gene 31-33).
The ABCG5 and ABCG8 proteins form
heterodimers and act as a complex, which functions as
a transporter of sterols in the bile and intestine.
Accordingly, patients with sitosterolemia exhibit either
homozygous or compound heterozygous mutations in
the ABCG5 or ABCG8 gene. Besides the above
mutations, Tada et al. previously reported a uniquecase of sitosterolemia caused by double heterozygous
mutations in the ABCG5 and ABCG8 genes,suggesting that specific combinations of mutations
and/or quite deleterious heterozygous mutations may
cause sitosterolemia 34).
Recent genome-wide association studies (GWAS)
indicated that the ABCG5 and ABCG8 genes are
significantly associated with LDL cholesterol levels
and increased prevalence of coronary artery disease(CAD) 35, 36), suggesting that these genes contribute tohigh LDL cholesterol and high plant sterol levels inplasma and risk for CAD among the general
population as well. In addition, Tada et al. haverecently shown that deleterious mutations of the
ABCG5 or ABCG8 gene contribute substantially tomimicking and exacerbation of the FH phenotype 30).
Clinical Manifestations
Individuals suffering from sitosterolemia
primarily present with tendinous and tuberous
xanthomas and premature coronary atherosclerosis,
resembling those in FH. Therefore, a certain
proportion of patients with sitosterolemia could be
misdiagnosed as FH due to tendon xanthomas andelevated LDL cholesterol 30). However, the severity of794

LDL cholesterol elevation and xanthomas appears to
be more variable in sitosterolemia than in FH. In acase of myocardial infarction in a 25-year-old woman
previously described by Kawamura et al. 9), Achilles
tendon xanthomas, as well as significantly elevated
LDL cholesterol levels and sitosterol levels were found,and she was initially misdiagnosed as FH. However,consideration of the recessive pattern of inheritance,
great responsiveness to dietary counseling together
with statin plus ezetimibe (LDL cholesterol was
reduced from 220 mg/dl to 55 mg/dl) lead to theaccurate diagnosis of sitosterolemia.
Typical cases in infancy have also been described.
LDL cholesterol levels in FH tend to be constantly high,whereas those in sitosterolemia may vary with thelatest dietary intake of sterols. The most extreme cases
have been infants who are breastfeeding. They havebeen found to have cutaneous xanthomas associatedwith significant elevation in LDL cholesterol levels,
resembling those in homozygous FH, 6, 37, 38). It has
been noted that weaning alone can reduce their LDL
cholesterol levels, causing the cutaneous xanthomas toregress, despite sitosterol levels that remain
significantly elevated. These observations suggest thatthey are quite vulnerable to a sterol-rich diet, and that
dietary management is very important in infants withsitosterolemia. However, we have experienced several
independent infantile cases of transient
hypercholesterolemia associated with breastfeeding
without any signs of cutaneous xanthomas, where thepatients turned out to be carriers of heterozygous
mutations of the ABCG5 gene (data not shown).
Thus, it appears that some infantile cases of “breastfed
hypercholesterolemia” can be explained byheterozygous mutations of the ABCG5 gene.
In addition, a variety of other phenotypes, suchas hemolysis, splenomegaly, platelet abnormalities,
arthralgia/arthritis have been documented among
patients with sitosterolemia, and some of them havebeen shown to be associated with accumulation ofsitosterol in an animal model 39). The underlying
mechanism responsible for the hematologic
abnormalities observed in some patients withsitosterolemia appears to be accumulation of
circulating sterols in blood cell membranes, leading toabnormal morphology and function 40). Regarding
arthralgia/arthritis, the case of a sitosterolemic patient
who also had a history of recurrent arthritis has been
described. Whole exome sequencing analysis revealed
that this patient had another concomitant genetic
disorder that had caused familial Mediterranean feverwhere arthritis is documented as one of the major
manifestations 7).
Since sitosterolemia is a recessive disorder, inSitosterolemia Clinical Guide 2021

many cases there is a consanguineous marriage in the
background. This could lead to the coincidence ofother recessive genetic disorders, although there is noclear evidence suggesting an association between their
genotypes or inheritance patterns and the severity or
variety of sitosterolemia phenotypes. Comprehensive
genetic analyses in such patients could shed light on
the causal (genetic) backgrounds of their phenotypes.
Sitosterol or Cholesterol?
Sitosterolemia was named for the significant
elevation in serum sitosterol level in this disease. As
sitosterol and other plant sterols have been shown toaccumulate in atherosclerotic lesions of patients withsitosterolemia 4, 41), lowering serum sitosterol has long
been considered to be a target for therapy. However, acausative relationship between marked elevation ofsitosterol in serum and its tissue deposition anddevelopment of atherosclerotic cardiovascular diseases
remains to be demonstrated. The results of studies
regarding an association between serum sitosterollevels and atherosclerosis have been controversial 42-45).
Currently available data as well as the fact that
sitosterolemic patients with premature atherosclerotic
cardiovascular diseases tend to exhibit hyper-LDL
cholesterolemia suggest that LDL cholesterol, rather
than sitosterol is the main causal factor for
atherogenicity. Therefore, further studies assessing therole of sitosterol in the development of atherosclerosis
are needed
Diagnostic Criteria
Diagnostic criteria for sitosterolemia in Japan are
described in Table 1. Serum sitosterol levels could bemeasured using high-sensitive gas chromatography.
Their reference ranges in Japanese individuals havebeen determined as 0.99 - 3.88 µg/mL in males, and1.03 - 4.45 µg/mL in females 46). It is vitally importantto perform differential diagnosis to distinguish it fromFH (Fig. 2A), autosomal recessive hypercholesterolemia(ARH) (Fig. 2B, 2C) and cerebrotendinous
xanthomatosis (CTX) (Fig. 2D, 2E). It is not easy tomake a differential clinical diagnosis of sitosterolemia(Fig. 2F, 2G) just based on physical manifestations 47-50).
Diagnostic Tips for Sitosterolemia
As stated above, patients with sitosterolemia
typically exhibit tendinous and tuberous xanthomas
and premature coronary atherosclerosis, resembling
the manifestations of FH. Therefore, patients withpremature coronary atherosclerosis should be

Table 1. Diagnostic criteria
A. Clinical manifestations
1. Cutaneous or tendon xanthomas
2. Premature coronary artery disease (male ＜45 yr, female ＜55 yr)
B. Laboratory testing
1. Serum sitosterol ≥ 1 mg/dL (10 µg/mL)
C. Differential diagnosis
Exclude familial hypercholesterolemia and cerebrotendinous
xanthomatosis
D. Genetic analysis
Pathogenic mutations in ABCG5 or ABCG8 gene
Definite: fulfills A-1, B-1, C, and D
Probable: fulfills A-1, B-1, and C
Possible: fulfills A-1, A-2, and B-1

examined to see whether they have a special genetic
background including that for sitosterolemia. Absenceof a family history of hypercholesterolemia as well as
premature CAD is likely to indicate sitosterolemia
rather than FH. However, it is of note that somepatients with sitosterolemia have a family history of
hypercholesterolemia and tendon xanthomas despite
its recessive pattern of inheritance. The tendon
xanthomas of sitosterolemia tend to be more severe
than those of heterozygous FH, despite lower levels of
LDL cholesterol. Thus, sitosterolemia should beconsidered in differential diagnosis for heterozygous
FH, which is now considered a relatively frequent
genetic metabolic disease. In addition, LDL
cholesterol levels of sitosterolemic patients tend tovary dramatically depending on their latest dietaryintake of plant sterols, and this would be useful
information in making a clinical diagnosis of thisdisease. ARH and CTX are extremely rare autosomal
recessive diseases, and almost all patients with these
diseases are from consanguineous marriages. It issometimes quite difficult to differentiate sitosterolemia
from ARH based on a single assessment; however,
responsiveness to dietary counseling differs between
sitosterolemia and ARH. On the other hand, patientswith CTX can be differentiated from those withsitosterolemia based on several factors, such as absenceof hypercholesterolemia, chronic diarrhea duringchildhood, juvenile cataracts, and neurologicalsymptoms 49).
Management of Sitosterolemia
Restriction of plant sterols as well as cholesterolshould be the first line strategy. Sitosterolemic patientsshould avoid plant sterol-rich foods, such as corn oil,795

Tada et al .









&

'



Fig. 2. Xanthomas in patients with dyslipidemias(A) Systemic xanthomas in a patient with homozygous FH (3-year-old boy)(B) X-ray of Achilles’ tendon in a patient with ARH (67-year-male)(C) Achilles’ tendon xanthomas in a patient with ARH (67-year-male)(D) X-ray of Achilles’ tendon in a patient with CTX (63-year-male)(E) Achilles’ tendon xanthomas in a patient with CTX (63-year-male)(F) Xanthomas at the ankle in a patient with sitosterolemia (1-year-old girl)(G) Xanthomas at the wrist in a patient with sitosterolemia (1-year-old girl)sesame seeds, peanuts, soybeans, rapeseed oil, sesameoil, rice oil, margarine, avocado, chocolate, andshellfish, whereas, other vegetables and fruits, such as
potato, carrot, and apple contain less plant sterols 51).
In addition to plant sterols, they also need to avoid
cholesterol-rich foods, including animal liver and eggs.
Regarding medication, ezetimibe and bile-acidsequestrant resins have been established as standard
therapies because the primary cause of this disease isincreased absorption of plant sterols from the intestineand their decreased secretion from the liver 15). Bothcould reduce sitosterol (~ 20% by ezetimibe, and ~30% by resins) 18, 52) and LDL cholesterol insitosterolemia. Ezetimibe has also been shown tofavorably increase platelet count 19).
Patients with sitosterolemia usually do notrespond to statins because HMG-CoA reductase
activity is already maximally inhibited 52). However,statins are effective in reducing LDL cholesterol, atleast in some sitosterolemic patients 9, 45), although they
may increase sitosterol levels in others 53). Considering
the lack of a clear association between sitosterol levels
and frequency of atherosclerotic cardiovasculardisease 44), as well as the fact that some patients withsitosterolemia are treated with statins due to being
misdiagnosed with FH 30), statins could at least be used
for patients in a secondary prevention setting. For
796

patients with advanced atherosclerotic lesions andresistance to the standard treatments mentioned
above, LDL apheresis could be considered if
applicable, although it is not officially covered by theJapanese national health insurance 8).
Liver transplantation was performed in a case ofsitosterolemia with liver cirrhosis and reportedly
resulted in a dramatic reduction in serum plant sterollevels 54). Regarding target levels of LDL cholesterol,
there is plenty of clinical evidence suggesting thatlowering LDL cholesterol is associated with reduced
risk for atherosclerotic cardiovascular diseases. In
addition, sitosterolemia has been considered as aphenocopy of FH and therefore, the target LDLcholesterol level should be the same as that of FH.
However, there has been no definite evidence for an
association of sitosterol lowering and prevention ofatherosclerotic cardiovascular diseases so far.
Accordingly, LDL cholesterol, rather than sitosterol,
should be the main biomarker when treating patientswith sitosterolemia. Dietary restriction of plant sterols,ezetimibe, and bile-acid sequestrant resins have beenshown to reduce both LDL cholesterol and sitosterollevels and thus these strategies should be considered as
standard treatment for patients with sitosterolemia.
The plant sterol content of foods and food ingredientsvaries widely from 7 mg/100 g in potatoes andSitosterolemia Clinical Guide 2021

tomatoes to 686-952 mg/100 g in corn oil 55). It istherefore rational to recommend patients withsitosterolemia and reduced function of ABCG5 or
ABCG8 to avoid vegetables rich in plant sterols.
Conclusions and Perspectives
Sitosterolemia is a monogenic disorder that has
been considered rather rare. However, its prevalence
may currently be substantially underestimated 56), so
we should be more careful to identify this disease
among hypercholesterolemic patients with xanthomas.
In particular, to raise awareness of sitosterolemia
among pediatricians and dermatologists, education forthem focusing on its typical manifestations isimportant. Measurement of serum sitosterol is notcovered by Japanese national health insurance but we
firmly believe that it is reasonable for it to be covered
now that we have reference data for serum sitosterollevels among Japanese healthy individuals as well as
patients with sitosterolemia. Ideally, prospective
randomized controlled trials investigating if specificlowering of serum sitosterol leads to reduced risk foratherosclerotic cardiovascular diseases should be
performed. More large-scale observational studies
attempting to demonstrate an independent association
between sitosterol levels and atherosclerotic
cardiovascular diseases are also needed.
To establish the clinical importance of thisdisease for public health, more accurate prevalence
and clinical manifestation data should beaccumulated, supported by the health insurance
system and comprehensive genetic analyses.
Diagnostic criteria of sitosterolemia proposed by theJapanese Ministry of Health, Labor and Welfare
scientific research team for hyperlipidemia would
facilitate the accumulation of such data on this uniquedisorder.
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
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.,
797

Tada et al .

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.
References
1) Escolà-Gil JC, Quesada H, Julve J, Martín-Campos JM,
Cedó L, Blanco-Vaca F. Sitosterolemia: diagnosis,
investigation, and management. Curr Atheroscler Rep,
2014; 16: 424
2) Salen G, Shefer S, Nguyen L, Ness GC, Tint GS, Shore V.
Sitosterolemia. J Lipid Res, 1992; 33: 945-955
3) Bhattacharyya AK, Connor WE. Beta-sitosterolemia andxanthomatosis. A newly described lipid storage disease in
two sisters. J Clin Invest, 1974; 53: 1033-1043
4) Salen G, Horak I, Rothkopf M, Cohen JL, Speck J, Tint
GS, Shore V, Dayal B, Chen T, Shefer S. Lethal
atherosclerosis associated with abnormal plasma and tissue
sterol composition in sitosterolemia with xanthomatosis. J
Lipid Res, 1985; 26: 1126-1133
5) Kolovou G, Voudris V, Drogari E, Palatianos G, Cokkinos
DV. Coronary bypass grafts in a young girl withsitosterolemia. Eur Heart J, 1996; 17: 965-966
6) Tada H, Kawashiri MA, Takata M, Matsunami K,
Imamura A, Matsuyama M, Sawada H, Nunoi H, Konno
T, Hayashi K, Nohara A, Inazu A, Kobayashi J, Mabuchi
H, Yamagishi M. Infantile cases of sitosterolaemia withnovel mutations in the ABCG5 Gene: Extreme
hypercholesterolaemia is exacerbated by breastfeeding.
JIMD Rep, 2015; 21: 115-122
7) Tada H, Kawashiri MA, Okada H, Endo S, Toyoshima Y,
798

Konno T, Nohara A, Inazu A, Takao A, Mabuchi H,
Yamagishi M, Hayashi K. A Rare Coincidence ofSitosterolemia and Familial Mediterranean Fever
Identified by Whole Exome Sequencing. J Atheroscler
Thromb, 2016; 23: 884-890
8) Sakuma N, Tada H, Mabuchi H, Hibino T, Kasuga H.
Lipoprotein apheresis for sitosterolemia. Ann Intern Med,
2017; 167: 896-899
9) Kawamura R, Saiki H, Tada H, Hara A. Acute myocardial
infarction in a 25-year-old woman with sitosterolemia. J
Clin Lipidol, 2018; 12: 246-249
10) Hansel B, Carrié A, Brun-Druc N, Leclert G, Chantepie
S, Coiffard AS, Kahn JF, Chapman MJ, Bruckert E.
Premature atherosclerosis is not systematic in
phytosterolemic patients: severe hypercholesterolemia as aconfounding factor in five subjects. Atherosclerosis, 2014;
234: 162-168
11) Wang J, Joy T, Mymin D, Frohlich J, Hegele RA.
Phenotypic heterogeneity of sitosterolemia. J Lipid Res,
2004; 45: 2361-2367
12) Bastida JM, Benito R, Janusz K, Díez-Campelo M,
Hernández-Sánchez JM, Marcellini S, Girós M, Rivera J,
Lozano ML, Hortal A, Hernández-Rivas JM, GonzálezPorras JR. Two novel variants of the ABCG5 gene cause
xanthelasmas and macrothrombocytopenia: a brief review
of hematologic abnormalities of sitosterolemia. J Thromb
Haemost, 2017; 15: 1859-1866
13) Lee MH, Lu K, Hazard S, Yu H, Shulenin S, Hidaka H,
Kojima H, Allikmets R, Sakuma N, Pegoraro R,
Srivastava AK, Salen G, Dean M, Patel SB. Identificationof a gene, ABCG5, important in the regulation of dietarycholesterol absorption. Nat Genet, 2001; 27: 79-83
14) Lu K, Lee MH, Hazard S, Brooks-Wilson A, Hidaka H,
Kojima H, Ose L, Stalenhoef AF, Mietinnen T, Bjorkhem
I, Bruckert E, Pandya A, Brewer HB Jr, Salen G, Dean M,
Srivastava A, Patel SB. Two genes that map to the STSL
locus cause sitosterolemia: genomic structure andspectrum of mutations involving sterolin-1 and sterolin-2,
encoded by ABCG5 and ABCG8, respectively. Am J
Hum Genet, 2001; 69: 278-290
15) Salen G, Shore V, Tint GS, Forte T, Shefer S, Horak I,
Horak E, Dayal B, Nguyen L, Batta AK, Lindgren FT,
Kwiterovich PO Jr. Increased sitosterol absorption,
decreased removal, and expanded body pools compensate
for reduced cholesterol synthesis in sitosterolemia withxanthomatosis. J Lipid Res, 1989; 30: 1319-1330
16) Lütjohann D, Björkhem I, Beil UF, von Bergmann K.
Sterol absorption and sterol balance in phytosterolemia
evaluated by deuterium-labeled sterols: effect of sitostanol
treatment. J Lipid Res, 1995; 36: 1763-1773
17) Yu L. The structure and function of Niemann-Pick
C1-like 1 protein. Curr Opin Lipidol, 2008; 19: 263-269
18) Salen G, von Bergmann K, Lütjohann D, Kwiterovich P,
Kane J, Patel SB, Musliner T, Stein P, Musser B;
Multicenter Sitosterolemia Study Group. Ezetimibe
effectively reduces plasma plant sterols in patients withsitosterolemia. Circulation, 2004; 109: 966-971
19) Othman RA, Myrie SB, Mymin D, Merkens LS, Roullet
JB, Steiner RD, Jones PJ. Ezetimibe reduces plant sterol
accumulation and favorably increases platelet count insitosterolemia. J Pediatr, 2015; 166: 125-131

Sitosterolemia Clinical Guide 2021

20) Gylling H, Plat J, Turley S, Ginsberg HN, Ellegård L,
Jessup W, Jones PJ, Lütjohann D, Maerz W, Masana L,
Silbernagel G, Staels B, Borén J, Catapano AL, De Backer
G, Deanfield J, Descamps OS, Kovanen PT, Riccardi G,
Tokgözoglu L, Chapman MJ; European Atherosclerosis
Society Consensus Panel on Phytosterols. Plant sterols
and plant stanols in the management of dyslipidaemia
and prevention of cardiovascular disease. Atherosclerosis,
2014; 232: 346-360
21) Othman RA, Myrie SB, Jones PJ. Non-cholesterol sterols
and cholesterol metabolism in sitosterolemia.
Atherosclerosis, 2013; 231: 291-299
22) Bastida JM, Girós ML, Benito R, Janusz K, HernándezRivas JM, González-Porras JR. Sitosterolemia: Diagnosis,
Metabolic and Hematological Abnormalities,
Cardiovascular Disease and Management. Curr Med
Chem, 2019; 26: 6766-6775
23) Hirai K, Shimazu C, Takezoe R, Ozeki Y. Cholesterol,
phytosterol and polyunsaturated fatty acid levels in 1982
and 1957 Japanese diets. J Nutr Sci Vitaminol (Tokyo),
1986; 32: 363-372
24) Ostlund RE Jr, McGill JB, Zeng CM, Covey DF, Stearns
J, Stenson WF, Spilburg CA. Gastrointestinal absorption
and plasma kinetics of soy Delta(5)-phytosterols andphytostanols in humans. Am J Physiol Endocrinol Metab,
2002; 282: E911-916
25) Dayspring TD, Varvel SA, Ghaedi L, Thiselton DL,
Bruton J, McConnell JP. Biomarkers of cholesterol
homeostasis in a clinical laboratory database sample
comprising 667,718 patients. J Clin Lipidol, 2015; 9:807-88126) Izar MC, Tegani DM, Kasmas SH, Fonseca FA.
Phytosterols and phytosterolemia: gene-diet interactions.
Genes Nutr, 2011; 6: 17-26
27) Kurano M, Iso-O N, Hara M, Noiri E, Koike K,
Kadowaki T, Tsukamoto K. Plant sterols increased IL-6
and TNF-α secretion from macrophages, but to a lesser
extent than cholesterol. J Atheroscler Thromb, 2011; 18:
373-38328) Pullinger CR, Kane JP, Malloy MJ. Primary
hypercholesterolemia: genetic causes and treatment of fivemonogenic disorders. Expert Rev Cardiovasc Ther, 2003;
1: 107-119
29) Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks
E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ,
Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA,
Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E,
Berghout J, Cooper DN, Deflaux N, DePristo M, Do R,
Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N,
Howrigan D, Kiezun A, Kurki MI, Moonshine AL,
Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA,
Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K,
Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna
MT, Weisburd B, Won HH, Yu D, Altshuler DM,
Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua
R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman
CM, Kathiresan S, Laakso M, McCarroll S, McCarthy
MI, McGovern D, McPherson R, Neale BM, Palotie A,
Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF,
Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly
MJ, MacArthur DG; Exome Aggregation Consortium.

Analysis of protein-coding genetic variation in 60,706
humans. Nature, 2016; 536: 285-291
30) Tada H, Okada H, Nomura A, Yashiro S, Nohara A,
Ishigaki Y, Takamura M, Kawashiri MA. Rare anddeleterious mutations in ABCG5/ABCG8 genes
contribute to mimicking and worsening of familial
hypercholesterolemia phenotype. Circ J, 2019; 83: 19171924
31) Niu DM, Chong KW, Hsu JH, Wu TJ, Yu HC, Huang
CH, Lo MY, Kwok CF, Kratz LE, Ho LT. Clinicalobservations, molecular genetic analysis, and treatment ofsitosterolemia in infants and children. J Inherit MetabDis, 2010; 33: 437-443
32) Yagasaki H, Nakane T, Toda T, Kobayashi K, Aoyama K,
Ichikawa T, Sugita K. Carotid intima media thickness in agirl with sitosterolemia carrying a homozygous mutationin the ABCG5 gene. J Pediatr Endocrinol Metab, 2017;30: 1007-1011
33) Su X, Shao Y, Lin Y, Zhao X, Zhang W, Jiang M, Huang
Y, Zeng C, Liu L, Li X. Clinical features, molecularcharacteristics, and treatments of a Chinese girl withsitosterolemia: A case report and literature review. J Clin
Lipidol, 2019; 13: 246-250
34) Tada H, Nomura A, Yamagishi M, Kawashiri MA. First
case of sitosterolemia caused by double heterozygous
mutations in ABCG5 and ABCG8 genes. J Clin Lipidol,
2018; 12: 1164-1168
35) Willer CJ, Schmidt EM, Sengupta S, Peloso GM,
Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich
ML, Mora S, Beckmann JS, Bragg-Gresham JL, Chang
HY, Demirkan A, Den Hertog HM, Do R, Donnelly LA,
Ehret GB, Esko T, Feitosa MF, Ferreira T, Fischer K,
Fontanillas P, Fraser RM, Freitag DF, Gurdasani D,
Heikkilä K, Hyppönen E, Isaacs A, Jackson AU,
Johansson Å, Johnson T, Kaakinen M, Kettunen J, Kleber
ME, Li X, Luan J, Lyytikäinen LP, Magnusson PKE,
Mangino M, Mihailov E, Montasser ME, MüllerNurasyid M, Nolte IM, O’Connell JR, Palmer CD,
Perola M, Petersen AK, Sanna S, Saxena R, Service SK,
Shah S, Shungin D, Sidore C, Song C, Strawbridge RJ,
Surakka I, Tanaka T, Teslovich TM, Thorleifsson G, Van
den Herik EG, Voight BF, Volcik KA, Waite LL, Wong A,
Wu Y, Zhang W, Absher D, Asiki G, Barroso I, Been LF,
Bolton JL, Bonnycastle LL, Brambilla P, Burnett MS,
Cesana G, Dimitriou M, Doney ASF, Döring A, Elliott P,
Epstein SE, Ingi Eyjolfsson G, Gigante B, Goodarzi MO,
Grallert H, Gravito ML, Groves CJ, Hallmans G,
Hartikainen AL, Hayward C, Hernandez D, Hicks AA,
Holm H, Hung YJ, Illig T, Jones MR, Kaleebu P,
Kastelein JJP, Khaw KT, Kim E, Klopp N, Komulainen P,
Kumari M, Langenberg C, Lehtimäki T, Lin SY,
Lindström J, Loos RJF, Mach F, McArdle WL, Meisinger
C, Mitchell BD, Müller G, Nagaraja R, Narisu N,
Nieminen TVM, Nsubuga RN, Olafsson I, Ong KK,
Palotie A, Papamarkou T, Pomilla C, Pouta A, Rader DJ,
Reilly MP, Ridker PM, Rivadeneira F, Rudan I, Ruokonen
A, Samani N, Scharnagl H, Seeley J, Silander K,
Stančáková A, Stirrups K, Swift AJ, Tiret L, Uitterlinden
AG, van Pelt LJ, Vedantam S, Wainwright N, Wijmenga
C, Wild SH, Willemsen G, Wilsgaard T, Wilson JF,
Young EH, Zhao JH, Adair LS, Arveiler D, Assimes TL,
799

Tada et al .

Bandinelli S, Bennett F, Bochud M, Boehm BO,
Boomsma DI, Borecki IB, Bornstein SR, Bovet P, Burnier
M, Campbell H, Chakravarti A, Chambers JC, Chen YI,Collins FS, Cooper RS, Danesh J, Dedoussis G, de Faire
U, Feranil AB, Ferrières J, Ferrucci L, Freimer NB, Gieger
C, Groop LC, Gudnason V, Gyllensten U, Hamsten A,
Harris TB, Hingorani A, Hirschhorn JN, Hofman A,
Hovingh GK, Hsiung CA, Humphries SE, Hunt SC,
Hveem K, Iribarren C, Järvelin MR, Jula A, Kähönen M,
Kaprio J, Kesäniemi A, Kivimaki M, Kooner JS,
Koudstaal PJ, Krauss RM, Kuh D, Kuusisto J, Kyvik KO,
Laakso M, Lakka TA, Lind L, Lindgren CM, Martin NG,
März W, McCarthy MI, McKenzie CA, Meneton P,
Metspalu A, Moilanen L, Morris AD, Munroe PB,
Njølstad I, Pedersen NL, Power C, Pramstaller PP, Price
JF, Psaty BM, Quertermous T, Rauramaa R, Saleheen D,
Salomaa V, Sanghera DK, Saramies J, Schwarz PEH, Sheu
WH, Shuldiner AR, Siegbahn A, Spector TD, Stefansson
K, Strachan DP, Tayo BO, Tremoli E, Tuomilehto J,
Uusitupa M, van Duijn CM, Vollenweider P, Wallentin L,
Wareham NJ, Whitfield JB, Wolffenbuttel BHR, Ordovas
JM, Boerwinkle E, Palmer CNA, Thorsteinsdottir U,
Chasman DI, Rotter JI, Franks PW, Ripatti S, Cupples
LA, Sandhu MS, Rich SS, Boehnke M, Deloukas P,
Kathiresan S, Mohlke KL, Ingelsson E, Abecasis GR;
Global Lipids Genetics Consortium. Discovery andrefinement of loci associated with lipid levels. Nat Genet,
2013; 45: 1274-1283
36) Lu X, Peloso GM, Liu DJ, Wu Y, Zhang H, Zhou W, Li J,
Tang CS, Dorajoo R, Li H, Long J, Guo X, Xu M,
Spracklen CN, Chen Y, Liu X, Zhang Y, Khor CC, Liu J,
Sun L, Wang L, Gao YT, Hu Y, Yu K, Wang Y, Cheung
CYY, Wang F, Huang J, Fan Q, Cai Q, Chen S, Shi J,
Yang X, Zhao W, Sheu WH, Cherny SS, He M, Feranil
AB, Adair LS, Gordon-Larsen P, Du S, Varma R, Chen
YI, Shu XO, Lam KSL, Wong TY, Ganesh SK, Mo Z,
Hveem K, Fritsche LG, Nielsen JB, Tse HF, Huo Y,
Cheng CY, Chen YE, Zheng W, Tai ES, Gao W, Lin X,
Huang W, Abecasis G; GLGC Consortium, Kathiresan S,
Mohlke KL, Wu T, Sham PC, Gu D, Willer CJ. Exome
chip meta-analysis identifies novel loci and East Asianspecific coding variants that contribute to lipid levels andcoronary artery disease. Nat Genet, 2017; 49: 1722-1730
37) Park JH, Chung IH, Kim DH, Choi MH, Garg A, Yoo
EG. Sitosterolemia presenting with severe
hypercholesterolemia and intertriginous xanthomas in abreastfed infant: case report and brief review. J Clin
Endocrinol Metab, 2014; 99: 1512-1518
38) Wang W, Jiang L, Chen PP, Wu Y, Su PY, Wang LY. A
case of sitosterolemia misdiagnosed as familial
hypercholesterolemia: A 4-year follow-up. J Clin Lipidol,
2018; 12: 236-239
39) Kanaji T, Kanaji S, Montgomery RR, Patel SB, Newman
PJ. Platelet hyperreactivity explains the bleedingabnormality and macrothrombocytopenia in a murine
model of sitosterolemia. Blood, 2013; 122: 2732-2742
40) Su Y, Wang Z, Yang H, Cao L, Liu F, Bai X, Ruan C.
Clinical and molecular genetic analysis of a family withsitosterolemia and co‐existing erythrocyte and platelet
abnormalities. Haematologica, 2006; 91: 1392-1395
41) Helske S, Miettinen T, Gylling H, Mäyränpää M, Lommi
800

J, Turto H, Werkkala K, Kupari M, Kovanen PT.
Accumulation of cholesterol precursors and plant sterols
in human stenotic aortic valves. J Lipid Res, 2008; 49:
1511-1518
42) Wilund KR, Yu L, Xu F, Vega GL, Grundy SM, Cohen
JC, Hobbs HH. No association between plasma levels ofplant sterols and atherosclerosis in mice and men.
Arterioscler Thromb Vasc Biol, 2004; 24: 2326-2332
43) Assmann G, Cullen P, Erbey J, Ramey DR, Kannenberg F,
Schulte H. Plasma sitosterol elevations are associated withan increased incidence of coronary events in men: resultsof a nested case-control analysis of the Prospective
Cardiovascular Münster (PROCAM) study. Nutr Metab
Cardiovasc Dis, 2006; 16: 13-2144) Genser B, Silbernagel G, De Backer G, Bruckert E,
Carmena R, Chapman MJ, Deanfield J, Descamps OS,
Rietzschel ER, Dias KC, März W. Plant sterols andcardiovascular disease: a systematic review and metaanalysis. Eur Heart J, 2012; 33: 444-451
45) Hansel B, Carrié A, Brun-Druc N, Leclert G, Chantepie
S, Coiffard AS, Kahn JF, Chapman MJ, Bruckert E.
Premature atherosclerosis is not systematic in
phytosterolemic patients: severe hypercholesterolemia as aconfounding factor in five subjects. Atherosclerosis, 2014;
234: 162-168
46) Yoshida H, Tada H, Ito K, Kishimoto Y, Yanai H,
Okamura T, Ikewaki K, Inagaki K, Shoji T, Bujo H,
Miida T, Yoshida M, Kuzuya M, Yamashita S. Reference
intervals of serum non-cholesterol sterols by gender inhealthy Japanese individuals. J Atheroscler Thromb, 2020;
27: 409-417
47) Mabuchi H. Half a Century Tales of Familial
Hypercholesterolemia (FH) in Japan. J Atheroscler
Thromb, 2017; 24: 189-207
48) Tada H, Inaba S, Pozharitckaia D, Kawashiri MA.
Prominent tendon xanthomas and abdominal aortic
aneurysm associated with cerebrotendinous xanthomatosis
identified using whole exome sequencing. Intern Med,
2018; 57: 1119-1122
49) Sekijima Y, Koyama S, Yoshinaga T, Koinuma M, Inaba Y.
Nationwide survey on cerebrotendinous xanthomatosis inJapan. J Hum Genet, 2018; 63: 271-280
50) Tada H, Kawashiri MA, Ikewaki K, Terao Y, Noguchi T,
Nakanishi C, Tsuchida M, Takata M, Miwa K, Konno T,
Hayashi K, Nohara A, Inazu A, Kobayashi J, Mabuchi H,
Yamagishi M. Altered metabolism of low-density
lipoprotein and very-low-density lipoprotein remnant in
autosomal recessive hypercholesterolemia: results fromstable isotope kinetic study in vivo. Circ Cardiovasc
Genet, 2012; 5: 35-41
51) Moreau RA. Composition of Plant Sterols and Stanols in
Supplemented Food Products. J AOAC Int, 2015; 98:
685-69052) Nguyen LB, Cobb M, Shefer S, Salen G, Ness GC, Tint
GS. Regulation of cholesterol biosynthesis insitosterolemia: effects of lovastatin, cholestyramine, anddietary sterol restriction. J Lipid Res, 1991; 32: 19411948
53) Uusitupa MI, Miettinen TA, Happonen P, Ebeling T,
Turtola H, Voutilainen E, Pyörälä K. Lathosterol andother noncholesterol sterols during treatment ofSitosterolemia Clinical Guide 2021

hypercholesterolemia with lovastatin alone and withcholestyramine or guar gum. Arterioscler Thromb, 1992;
12: 807-813
54) Miettinen TA, Klett EL, Gylling H, Isoniemi H, Patel SB.
Liver transplantation in a patient with sitosterolemia andcirrhosis. Gastroenterology, 2006; 130: 542-547
55) Piironrn V, Lampi AM. Occurrence and levels ofphytosterols in foods. In: Dutta PC, editor. Phytosterols
as functional food components and nutraceuticals. New
York: Marcel Dekker, Inc; 2004. Pp. 1-32
56) Tada H, Nohara A, Inazu A, Sakuma N, Mabuchi H,
Kawashiri MA. Sitosterolemia, Hypercholesterolemia, andCoronary Artery Disease. J Atheroscler Thromb, 2018;
25: 783-789

801