Review article

http://dx.doi.org/10.6065/apem.2016.21.1.7
Ann Pediatr Endocrinol Metab 2016;21:7-14

Sitosterolemia: a review and update of pathophysiology,

clinical spectrum, diagnosis, and management
Eun-Gyong Yoo, MD, PhD Sitosterolemia is an autosomal recessive disorder characterized by increased plant
sterol levels, xanthomas, and accelerated atherosclerosis. Although it was originally
Department of Pediatrics, reported in patients with normolipemic xanthomas, severe hypercholesterolemia
CHA Bundang Medical Center, have been reported in patients with sitosterolemia, especially in children.
CHA University, Seongnam, Korea Sitosterolemia is caused by increased intestinal absorption and decreased
biliary excretion of sterols resulting from biallelic mutations in either ABCG5 or
ABCG8, which encode the sterol efflux transporter ABCG5 and ABCG8. Patients
with sitosterolemia show extreme phenotypic heterogeneity, ranging from
almost asymptomatic individuals to those with severe hypercholesterolemia
leading to accelerated atherosclerosis and premature cardiac death.
Hematologic manifestations include hemolytic anemia with stomatocytosis,
macrothrombocytopenia, splenomegaly, and abnormal bleeding. The mainstay
of therapy includes dietary restriction of both cholesterol and plant sterols and
the sterol absorption inhibitor, ezetimibe. Foods rich in plant sterols include
vegetable oils, wheat germs, nuts, seeds, avocado, shortening, margarine and
chocolate. Hypercholesterolemia in patients with sitosterolemia is dramatically
responsive to low cholesterol diet and bile acid sequestrants. Plant sterol assay
should be performed in patients with normocholesterolemic xanthomas,
hypercholesterolemia with unexpectedly good response to dietary modifications or
to cholesterol absorption inhibitors, or hypercholesterolemia with poor response to
statins, or those with unexplained hemolytic anemia and macrothrombocytopenia.
Because prognosis can be improved by proper management, it is important to find
these patients out and diagnose correctly. This review article aimed to summarize
recent publications on sitosterolemia, and to suggest clinical indications for plant
sterol assay.

Keywords: Sitosterolemia, Phytosterolemia, Hypercholesterolemia, Plant sterol

Introduction

Sitosterolemia, also known as phytosterolemia, is an autosomal recessive disorder characte­

Received: 14 March, 2016 rized by increased plant sterol levels, xanthomas, and accelerated atherosclerosis1,2). It is caused
Accepted: 15 March, 2016 by increased intestinal absorption and decreased biliary excretion of plant sterols resulting
from homozygous or compound heterozygous mutations in either ABCG5 or ABCG8, which
Address for correspondence: encode the sterol efflux transporter ABCG5 (sterolin-1) and ABCG8 (sterolin-2) that pumps
Eun-Gyong Yoo, MD, PhD
sterols out to intestinal lumen or into bile3,4). Although it is a rare disease, it is an important
Department of Pediatrics, CHA
Bundang Medical Center, CHA
disease that led to understanding of the physiologic pathway about sterol influx and efflux5,6).
University, 59 Yatap-ro, Bundang-gu, Mediterranean stomatocytosis/macrothrombocytopenia has been identified as the hemato­
Seongnam 13496, Korea logical presentation of sitosterolemia7). Stomatocytic hemolysis, large platelets, splenomegaly,
Tel: +82-31-780-1999 and abnormal bleeding can be associated, and hematologic manifestations can be the only
Fax: +82-31-780-5239 clinical sign of sitosterolemia8). The true prevalence of sitosterolemia is unknown due to
E-mail: [email protected]

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// ISSN: 2287-1012(Print)
creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any ISSN: 2287-1292(Online)
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©2016 Annals of Pediatric Endocrinology & Metabolism

Yoo EG • Sitosterolemia: a review and update

underdiagnosis, and sitosterolemia may be more frequent than chylomicrons21). Unesterified cholesterol or plant sterols are
previously thought. One Asian individual with sitosterolemia pumped back to intestinal lumen by ABCG5/ABCG8, the
was identified incidentally out of 2,542 persons from a study in sterol efflux transporters6). The SOAT2 also have low affinity
which plasma plant sterols were analyzed9). with plant sterols, allowing preferential plant sterol efflux by
Because delayed diagnosis can lead to poor clinical outcome the ABCG5/ABCG822). Plant sterols not pumped back to the
due to advanced atherosclerotic cardiovascular disease and intestinal lumen become part of the chylomicrons, transported
prognosis can be improved by proper management including to the liver, and eventually pumped out into the bile by the
plant sterol restriction and cholesterol absorption inhibitor hepatic ABCG5/ABCG8 transporters6,11).
in sitosterolemia, it is important to find these patients out and
diagnose correctly2,8,10). This review article aimed to summarize Disrupted sterol homeostasis in sitosterolemia
recent publications on the pathophysiology, clinical spectrum,
diagnosis and management of sitosterolemia, and to suggest Biallelic defects in either ABCG5 or ABCG8 result in increa­
clinical indications for plant sterol assay. sed intestinal absorption and decreased biliary excretion of
plant sterols, leading to extremely high plasma levels of plant
The plant sterols sterols3,4). Patients with sitosterolemia absorb 15% to 60% of
ingested sitosterol, which lead to a 50- to 200-fold increase in
Plant sterols are rich in vegetable oils, wheat germs, nuts, seeds, their plasma sitosterol levels1,3). Plant sterols comprise 15% to
avocados, chocolate, and margarine2,6). They are structurally 20% of total plasma sterols in patients with sitosterolemia and
very similar to cholesterol, but they differ by the presence of an are carried in low-density lipoprotein (LDL) and very-LDL
ethyl or methyl group (sitosterol and campesterol, respectively) particles3,23).
or a double bond (stigmasterol)1). Sitosterol is usually the most In a patient with liver failure and sitosterolemia that under­
abundant plant sterol in the diet and the predominant form went liver transplantation, the elevated plant sterol levels
found in patients with sitosterolemia8,11). decreased to values less than 1/10 of pretransplantation level,
Average Western diet contains similar amount of cholesterol suggesting that the liver functions as the predominant organ for
and plant sterols. Although approximately 50% of dietary chole­ maintaining sterol balance24). ABCG5/ABCG8 expression either
sterol is absorbed, less than 5% of plant sterols are absorbed in in liver or intestine protected animals from sterol accumulation
normal individuals6,11). High plant sterol diet was extremely in a recent study25).
toxic in animal models of sitosterolemia, and it was suggested Although sterol absorption was moderately increased in
that the mammalian body defends itself against plant sterols heterozygotes, they are asymptomatic with normal cholesterol
because they are toxic when accumulated, although similar levels and normal to slightly increased plant sterol levels1,26).
toxicity have not been documented in human yet12,13).
It is clear that plant sterols are toxic to those with sitos­ Clinical spectrum of sitosterolemia
terolemia, but plant sterol intake seems to be safe to nonsito­
sterolemic individuals. Instead, plant sterols can competitively Patients with sitosterolemia show extreme phenotypic
inhibit cholesterol absorption, and the cholesterol lowering heterogeneity. Whereas some patients with homozygous
effect of plant sterols have been documented11). Although mutations are almost totally asymptomatic, others show severe
they have not been shown to reduce clinical outcomes, many hypercholesterolemia leading to accelerated atherosclerosis
cholesterol lowering functional foods are enriched with plant and premature cardiac death 1,27-30). A 10-year-old girl from
sterols14,15). On the other hand, studies have raised the possibility Iran, who had received almost vegetable-free diet in Iran
of association between plant sterol levels and atherosclerosis16,17). and started to intake much more vegetables and olive oil
The cholesterol lowering effect may compensate the potential after her family moved to Europe, developed xanthomas
risk of increased plant sterol intake9,11), and the debate whether and hypercholesterolemia in a short period of time and was
plant sterol is beneficial or harmful is still ongoing15,18). finally diagnosed for sitosterolemia31). Although the amount
of dietary plant sterol intake should be at least partially
Sterol absorption in normal subjects related with the severity of clinical disease, the mechanism of
phenotypic heterogeneity, even between the family members
Dietary cholesterol and noncholesterol sterols, mainly plant that shares same gene and environment, is not fully understood
sterols and stanols (saturated sterols), are absorbed form the yet. A recent report in a Chinese family with sitosterolemia
intestinal lumen via the sterol influx transporter, Nieman suggested potential effects of NPC1L1 polymorphisms in
Pick C1 Like 1 (NPC1L1)6). The NPC1L1, the gatekeeper of protecting against clinical disease29). Major clinical features of
sterol absorption, have lower affinity to plant sterols than sitosterolemia, especially in young patients with sitosterolemia
cholesterol 19,20). After absorption to the enterocytes, about are summarized in Table 1.
50%–60% of cholesterol is esterified by the acetyl-sterol O-acyl­
transferase 2 (SOAT2) and transported to liver packed in the

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 Yoo EG • Sitosterolemia: a review and update

Table 1. Clinical spectrum of sitosterolemia Xanthomatosis is rarely observed in young children, and
Clinical spectrum of sitosterolemia References when present, homozygous familial hypercholesterolemia (FH)
Asymptomatic (with or without hypercholesterolemia) 28-30 or autosomal recessive hypercholesterolemia is most often
Xanthomas (with or without hypercholesterolemia) suspected37,38). Xanthomas may begin to appear at very young
Tendinous or tuberous xanthomas on extensor sites 1,10,23,27,28 age in sitosterolemia, sometimes during the first year of life33,35).
Planar xanthomas in the creases of Achilles region 33 Intertriginous xanthomas are a very rare type of planar
Intertriginous xanthomas 35 xanthomas and have been reported to be pathognomonic
Hypercholesterolemia for homozygous FH 39). However, intertriginous xanthomas
Mild to moderate hypercholesterolemia 10,28,31,44 (first noticed at the age of 3 months when the patient was
Severe hypercholesterolemia (≥500 mg/dL) 32,33,35,47 being exclusively breastfed) were observed in a 15-month-old
Premature cardiovascular disease Korean girl with sitosterolemia, suggesting that intertriginous
Premature coronary heart disease (at age 16–29) 10,29 xanthomas may develop in young children with extremely
Sudden cardiac death (at age 5–18) 22,47,48 high cholesterol levels of any etiology35). Friction between the
Hematologic manifestations skins in intertriginous areas may contribute to the development
Hemolytic anemia with stomatocytosis 7,8,52,54 of xanthomas in a chubby infant in whom extensor areas are
Macrothrombocytopenia 7,8,52,54 relatively spared because movement is not active yet.
Splenomegaly 8,53 Most sitosterolemic patients with severe atherosclerotic
Abnormal bleeding 55 cardiovascular disease also showed xanthomas1,10,23,28). Xan­
Arthritis, arthralgia 2 thomas evolve as clusters of foam cells in the skin, and the
Hepatic failure* 24 mechanisms involved in the development of xanthoma seem to
*Not confirmed whether hepatic failure was due to sitosterolemia be similar to those in early stages of atherosclerotic plaques40).
or not. According to a meta-analysis on patients with genetic diagnosis
of FH, the presence of tendon xanthomas was associated with a
3.2 times higher risk of cardiovascular disease41). Xanthelasma
1. Hypercholesterolemia of the eyelids was considered to be only a cosmetic lesion
until recently, however recent prospective studies showed
Although it was originally reported in patients with normo­ that it is connected with an increased cardiovascular risk and
lipemic xanthomas27), cholesterol absorption is also increased reduced average lifespan42). In contrast to the initial case with
in patients with sitosterolemia, and serum cholesterol levels are normolipemic xanthomas27), xanthomas regress and sometimes
usually elevated1,10). Very high levels of cholesterol (up to 1,000 completely disappear in some patients with sitosterolemia,
mg/dL) have been reported in patients with sitosterolemia, usually associated with dramatically decreased plasma choles­
especially in children32,33). Immature intestine may absorb higher terol levels, although plant sterol levels were still relatively
amounts of cholesterol compared with that of adults34). high32,35,43-46).
Breastfed infants with sitosterolemia show unique clinical
features 32,33,35). The plant sterol intake of a breastfed infant 3. Atherosclerotic cardiovascular disease
should be minimal because the plasma sitosterol levels of the
heterozygote mother should be only slightly increased. However Some patients with sitosterolemia develop premature
their cholesterol intake can be high due to high cholesterol atherosclerosis leading to sudden cardiac death at as early as
content of human milk (90–150 mg/L vs. 0–4 mg/L in human 547),1348),1822) years of age, whereas others, even in the same
milk and infant formula, respectively)36). Breastfed infants with family of symptomatic patients, do not show any classic sign of
sitosterolemia can present with extremely high cholesterol levels sitosterolemia24,28,35).
with xanthomatosis, but with normal sitosterol:cholesterol ratio Both elevated plasma cholesterol and plant sterol levels
due to only mildly elevated plant sterol levels33). The plant sterol can contribute to the premature vascular disease in patients
level increase and the cholesterol level somewhat decrease as the with sitosterolemia. Accumulation of plant sterol in plasma
infant start taking fruits and vegetables33,35). lipoproteins influences the stability of both cholesterol and plant
sterol in lipoproteins, favoring the accumulation of these sterols
2. Xanthomas within tissues, initiating inflammatory reactions, and may cause
premature atherosclerosis6).
Tendinous or tuberous xanthomas on extensor areas, such as Coronary plaque disruption and superimposed thrombosis
Achilles tendon, extensor tendons of the hand, elbows and knees is the major cause of acute myocardial infarction and sudden
are the major clinical manifestations of sitosterolemia1,23,27). cardiac death49). The composition and vulnerability of plaque
Minor trauma plays an important role in the development of rather than its volume or the severity of stenosis are more
xanthomas, and this is why they appear on extensor surfaces in important for the development of the thrombus-mediated
most patients37). acute coronary syndromes49). Plant sterols are relatively poorly

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Yoo EG • Sitosterolemia: a review and update

esterified by the sterol-esterifying enzyme acyl-CoA-cholesterol reduced αIIbβ3 surface expression, loss of the GPIba-
acyl transferase. Macrophages incubated with sitosterol- FlnA linkage, microparticle formation, and ultimately poor
containing lipoproteins accumulated free sterols and underwent hemostatic functions.
necrotic cell death, which may contribute to the formation of
rupture-prone plaque50). Diagnosis of sitosterolemia
Premature coronary heart disease can develop in sitostero­
lemic patients with normal cholesterol levels. A 16-year-old Routine laboratory methods do not distinguish plant sterols
sitosterolemic girl with normal cholesterol level was reported from cholesterol, and a more accurate method such as gas
to have premature coronary heart disease requiring coronary chromatography-mass spectrometry (GC-MS) is required.
bypass grafts 51), and a normocholesterolemic patient who Measurement of serum plant sterol by GC-MS or liquid
underwent a 3 vessel coronary bypass surgery at the age of 29 chromatography-mass spectrometry is regarded as a reliable test
was diagnosed with sitosterolemia after that10). for screening sitosterolemia, in which unequivocally increased
On the other hand, Hansel et al.30) could not find signifi­ plant sterol levels and sitosterol: cholesterol levels are almost
cant signs of premature atherosclerosis in 5 patients with invariably observed1).
sitosterolemia aged 11 to 21 years, in spite of severe hypercho­ Genetic confirmation can be given by direct sequencing of
lesterolemia as well as extremely high plant sterol levels. They exons and intron-exon boundaries of the ABCG5 and ABCG8
suggested that the premature atherosclerosis in some patients genes, each comprised of 13 exons and located in a head-to-
with sitosterolemia may be due at least in part to mechanisms head organization on chromosome 2p21, and documenting the
independent of elevated circulating plant sterol levels30). homozygous or compound heterozygous mutations in either
ABCG5 or ABCG83,4). Asian patients usually have mutations
4. Hematologic manifestations in ABCG5, while Caucasian patients usually have ABCG8
mutations 3,32) . However, mutations in ABCG8 have been
Rees et al.7) revealed that stomatocytic hemolysis and macro­ reported in 3 of 8 families with hematologic manifestations of
thrombocytopenia (previously known as the Mediterranean sitosterolemia according to a recent Chinese study, suggesting
stomatocytosis or Mediterranean macrothrom­b ocytopenia, that ABCG8 mutations are not exclusive to Caucasians53). DNA
which had been a poorly understood hematological condition) sequencing of ABCG5/ABCG8 is should be performed to rule
is the hematological presentation of sitosterolemia. out sitosterolemia in breastfed infants, because they can exhibit
Stomatocysis, hemolytic anemia, thrombocytopenia with only mild elevation of plasma sitosterol level and normal
very large platelets, splenomegaly, and abnormal bleeding can sitosterol:cholesterol ratio33).
be associated with sitosterolemia8). Because the ABCG5 and In contrast to patients with homozygous FH that are relatively
ABCG8 are only expressed in intestine and liver, acquired refractory to dietary modification and cholesterol-lowering
accumulation of circulating plant sterols and their incorporation agents, plasma cholesterol levels in sitosterolemic patients are
into red blood cells (RBC) and platelet seems to be resulting in extremely sensitive to dietary cholesterol restriction and bile
abnormal morphology and function7). acid sequestrants32,43,44).
Blood cells can be a main target for the toxic effect of The entire pathway of cholesterol biosynthesis including
plasma plant sterols, and sitosterolemia can be manifested hepatic hydroxymethylglutaryl coenzyme A (HMG CoA)
mainly by hematologic abnormalities52). Three patients from reductase is exceptionally down-regulated in patients with
a Chinese family, all of whom had suffered from severe sitosterolemia10,56). It was also reported that stigmasterol and
hemolytic anemia and macrothrombocytopenia since 3 to campesterol inhibit activation of sterol regulatory binding
4 years of age and underwent splenectomy in their 10's, was protein-2 (SREBP-2), a transcription factor involved in chole­
diagnosed as sitosterolemia in their 20's. All of these patients sterol biosynthesis, in cultured adrenocortical cells57), and that
had increased plasma sitosterol but normal cholesterol stigmasterol, not sitosterol, inhibits processing of SREBP-2
levels 52). Thirteen sitosterolemic patients with hematologic leading to reduced cholesterol synthesis in mice58).
manifestations, including 2 patients without any classical In nonsitosterolemic individuals, cholesterol synthesis
features of sitosterolemia, had been misdiagnosed with immune increases after sterol depletion, limiting the effect of sterol
thrombocytopenia (ITP), Evans syndrome, or secondary absorption inhibitor or bile acid sequestrant57). However, there is
ITP with delay being 15 to 49 years between symptom onset no such compensatory increase in cholesterol synthesis in those
and correct diagnosis 53) . Plasma plant sterols should be with sitosterolemia, resulting in dramatic reduction in plasma
analyzed in patients with unexplained hemolytic anemia with cholesterol levels59). Sitosterolemia should be suspected when
macrothrombocytopenia to avoid unnecessary splenectomy54). the plasma cholesterol falls more than 40% on a low-cholesterol
Recently, Kanaji et al. 55) have identified that the bleeding diet.
abnormalities and macrothrombocytopenia associated with Sitosterolemia seems to be significantly underdiagnosed,
sitosterolemia are due to direct plant sterol incorporation into and many of these patients should be continuing to intake
the platelet membrane, resulting in platelet hyperactivation, large amount of plant sterols, not knowing that the plant
sterols are 'toxic' to them, but believing that those food are

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 Yoo EG • Sitosterolemia: a review and update

good for their health. Sitosterolemia might also be significantly through its binding to NPC1L1, is currently considered the
underdiagnosed in children in whom screening for lipid profiles choice of treatment for sitosterolemia63). It has been widely used
is not universally performed. Recent guidelines recommend for decreasing serum LDL-cholesterol levels in patients with
screening all children at 9–11 years and again at 17–21 years hypercholesterolemia. Ezetimibe also reduces the intestinal
to find those with hypercholesterolemia 60). Some of those absorption of plant sterols, thereby also lowering plasma
screened may in fact have sitosterolemia, and these patients plant sterol levels. Ezetimibe alone or in combination with
may be distinguished by either remarkable response to dietary cholestyramine successfully decreased plasma cholesterol and
modification or poor response to statins35). plant sterol levels (about by 50%; although still much higher
than normal values)63), resulting in regression of xanthomas and
Management of sitosterolemia improvement of carotid bruits and cardiac murmurs in patients
with sitosterolemia45). Long-term treatment with ezetimibe 10
Management of sitosterolemia aims to reduce plasma plant mg/day was safe, tolerable, and effective in reducing plasma
sterol (as low as possible; although perfect control [sitosterol plant sterol concentrations in patients with sitosterolemia 61,64).
level <1 mg/dL] cannot be achieved) and cholesterol concen­ Ezetimibe reduced plasma and RBC plant sterol levels, while
trations and to prevent or reduce xanthomas and atherosclerotic increasing platelet count and decreasing mean platelet volume,
cardiovascular diseases2). and thereby may reduce the risk for bleeding in sitosterolemia65).
Mainstay of therapy is dietary restriction of both cholesterol Although pharmacotherapy is usually not performed for
and plant sterols. Foods rich in plant sterols include vegetable children under age 10, an individual with extremely high
oils, wheat germs, nuts, seeds, avocado, most of which are levels of cholesterol may begin therapy earlier 66) Ezetimibe
known to be heart-healthy foods2,61). Margarine, shortening, therapy seems to be also safe and effective in children
and chocolate should also be avoided. Polished rice should be with sitosterolemia, although an infant did not respond to
taken instead of whole grains. Shellfish and seaweeds contain ezetimibe therapy at 7 months of age possibly due to immature
significant amount of algae-derived plant sterols that are also glucuronidation system, who finally showed improvement when
hyperabsorbed in these patients, and they should also be ezetimibe was restarted at 2 years of age32). Bile acid sequestrants
avoided62). However, plant sterol-free diet is almost impossible such as cholestyramine can be added for those with insufficient
to accomplish because plant sterols are found in almost every response to ezetimibe2,63).
plant-based foods, and low plant sterol diet have resulted in only Arthritis and arthralgia can also be associated with sitostero­
about 30% reduction of plasma plant sterol levels11,44). lemia, and more strict management of sitosterolemia can be
Pharmacotherapy include the sterol absorption inhibitor, helpful2).
ezetimibe, or bile acid sequestrants such as cholestyramine.
Patients with sitosterolemia usually do not respond to statins Conclusions
because HMG CoA reductase activity is already maximally
inhibited60). Plant sterol assay should be performed in patients with
The bile acid sequestrants inhibit the reabsorption of bile normocholesterolemic xanthomas, hypercholesterolemia with
acids in the ileum and disrupt the enterohepatic circulation unexpectedly good response to dietary modifications or to
of bile acids. The bile acid sequestrants was reported to reduce cholesterol absorption inhibitors, or hypercholesterolemia with
plasma plant sterol levels by up to 45%, although they may result poor response to statins, or those with unexplained hemolytic
in more dramatic decrease in plasma cholesterol levels (50%– anemia and macrothrombocytopenia (Table 2).
80%) and regression of xanthomas43,44). Sitosterolemia should The dramatic cholesterol reduction and regression of
be considered in patients with hypercholesterolemia and/or xanthomas by proper treatment including plant sterol restriction
xanthomas who show dramatic reduction of cholesterol levels and cholesterol absorption inhibitor suggest that sitosterolemia
or regression of xanthomas by bile acid sequestrant therapy. can be a controllable condition, and it is important to find these
However, poor compliance and gastrointestinal side effects limit patients out and diagnose correctly because prognosis can be
the use of cholestyramine. improved by early diagnosis and proper management.
Ezetimibe, an inhibitor of intestinal sterol absorption
Conflict of interest
Table 2. Indications for plant sterol assay
Indications for plant sterol assay No potential conflict of interest relevant to this article was
Normocholesterolemic xanthomas reported.
Dramatic decrease of cholesterol levels in response to low cholesterol
diet and/or bile acid sequestrants or cholesterol absorption inhibitors
Regression of xanthomas, especially with dramatically improved References
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