Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis.
ABSTRACT Sitosterolaemia is an extremely rare autosomal recessive disease, the key feature of which is the impairment of pathways that normally prevent absorption and retention of non-cholesterol sterols, for example plant sterols and shellfish sterols. The clinical manifestations are akin to familial hypercholesterolaemia (such as presence of tendon xanthomas and premature atherosclerosis), but with "normal to moderately elevated" cholesterol levels. The gene(s) causing sitosterolaemia was mapped to the STSL locus on human chromosome 2p21, and mutations in either of the two genes that comprise this locus, ABCG5 or ABCG8, cause this disease. Exact prevalence is unknown, but there are estimated to be 80-100 cases around the world. This rare disease has shed light into the molecular mechanisms that control sterol trafficking in the enterocyte and hepatocyte; ABCG5 and ABCG8 heterodimerise to form a sterol efflux transporter in the liver and intestine. In this review the pathophysiology, clinical manifestations and approach to clinical and laboratory diagnosis of this disease are described.
- SourceAvailable from: Raul D. Santos[Show abstract] [Hide abstract]
ABSTRACT: Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH.European heart journal. 07/2014;
- [Show abstract] [Hide abstract]
ABSTRACT: Although homozygous familial hypercholesterolaemia (HoFH) is rare, patients with this disease have a poor prognosis, even when they receive the best available treatment, including pharmacotherapy and apheresis. The current therapeutic gap emphasizes the potential impact of new and developmental treatment options, which include lomitapide, mipomersen, anti-PCSK9 monoclonal antibodies and CETP inhibitors. It is imperative that patients with HoFH receive the most appropriate treatment as early as possible and clinical guidance is needed to provide clinicians with the information they require to expedite diagnosis and initiate effective treatment. Until now, however, guidance on the management of (HoFH) has generally been included as part of broader guidelines on dyslipidemia, FH or low-density lipoprotein (LDL)-apheresis and even in guidelines specifically on FH, HoFH has been under-represented. A consensus statement on recommendations for the management of HoFH has recently been published by a working group of the European Atherosclerosis Society. An outline of the content of the statement is presented in the current paper.Atherosclerosis Supplements 09/2014; 15(2):26–32. · 9.67 Impact Factor
- Clinical Lipidology 12/2013; 8(6):649-658. · 0.86 Impact Factor
2008;61;588-594 J. Clin. Pathol.
S Kidambi and S B Patel
presentation and laboratory diagnosis
Sitosterolaemia: pathophysiology, clinical
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on 27 June 2008
Sitosterolaemia: pathophysiology, clinical
presentation and laboratory diagnosis
S Kidambi,1S B Patel1,2
1Division of Endocrinology
(Department of Medicine),
Medical College of Wisconsin,
Milwaukee, Wisconsin, USA;
2Department of Veterans
Affairs, Clement J. Zablockiva
VA Medical Center, Milwaukee,
Dr S Kidambi, Division of
Endocrinology (Department of
Medicine), 9200 West
Wisconsin Avenue, Milwaukee,
WI 53226, USA; skidambi@
Accepted 7 December 2007
Sitosterolaemia is an extremely rare autosomal recessive
disease, the key feature of which is the impairment of
pathways that normally prevent absorption and retention
of non-cholesterol sterols, for example plant sterols and
shellfish sterols. The clinical manifestations are akin to
familial hypercholesterolaemia (such as presence of
tendon xanthomas and premature atherosclerosis), but
with ‘‘normal to moderately elevated’’ cholesterol levels.
The gene(s) causing sitosterolaemia was mapped to the
STSL locus on human chromosome 2p21, and mutations
in either of the two genes that comprise this locus,
ABCG5 or ABCG8, cause this disease. Exact prevalence is
unknown, but there are estimated to be 80–100 cases
around the world. This rare disease has shed light into the
molecular mechanisms that control sterol trafficking in the
enterocyte and hepatocyte; ABCG5 and ABCG8 hetero-
dimerise to form a sterol efflux transporter in the liver and
intestine. In this review the pathophysiology, clinical
manifestations and approach to clinical and laboratory
diagnosis of this disease are described.
Bhattacharyya and Connor reported a new disease
in two Caucasian sisters who were referred to
them for tendon xanthomas dating back to their
childhood. Surprisingly, plasma cholesterol in these
individuals was in the normal range, unlike in
familial hypercholesterolaemia—the most com-
mon cause of tendon xanthomas. Astuteness of
these physicians led to the discovery of high levels
of plant sterols (specifically b-sitosterol) in these
sisters, and to the description of a new disease
Familiarity with the normal metabolism of plant
sterols is essential before understanding the disease
Chemistry of plant sterols
The term plant sterol constitutes both phytosterols
and phytostanols. Phytosterols are closely related
in structure to cholesterol (which is not found in
any abundance in plants), differing mainly in the
side-chain configuration (fig 1). The most common
plant sterols include sitosterol, campesterol and
stigmasterol, but more than 20 other non-choles-
terol sterols occur naturally.7
cannot synthesise plant sterols; hence the only
source of plant sterols present in them comes from
the diet. Phytostanols have a saturated B ring (the
mammalian body can convert sterols to stanols,
but usually can not metabolise these plant sterols
any further). To produce a wide variety of sterols,
plants have evolved a biosynthetic pathway
different from that of the vertebrates. In plants,
two separate pathways can be used to synthesise
the C5 isoprenes (isopentenyl diphosphate and
dimethylallyl diphosphate) that are used for sterol
(MVA) pathway or the plastidal 2-C-methy-D-
erthritol-4-phosphate (MEP) pathway (vertebrates
use only the MVA pathway). It appears that there
are multiple genes encoding each enzyme; the
significance of this is not clear.8Post-lanosterol
(with the characteristic A, B, C and D rings), the
sterol synthesis pathway differs from vertebrates in
that the ‘‘R’’ tail contains more than 8 carbon
atoms, resulting in sterols that have more than 27
carbon atoms, with varying levels of reduced and
oxidised C–H bonds. This results in a panoply of
sterols species (.20) in plants. Each species of plant
may have varying levels of each of these different
species. Invertebrates, cholesterol is themajor sterol
Plant sterol metabolism
A typical western diet contains 150–400 mg of
plant sterols per day, which is in the same range as
dietary cholesterol intake.9–11
absorption of plant sterols is ,5%, compared to
an average of 55% for cholesterol.10 12–15Each sterol
species has its own rate of absorption; in general,
the closer the structural similarity to the choles-
terol, the higher the absorption and the greater the
desaturation of the structure (the ring or the R
tail), the poorer the absorption. In addition to the
‘‘first-pass’’ poor absorption in the intestine, the
liver rapidly and preferentially excretes these
sterols into the bile. Both these processes ensure a
very low level of net retention of non-cholesterol
sterols,16resulting in total plasma plant sterol levels
of ,1 mg/dl17 18compared to 200 mg/dl for cho-
lesterol. It should also be pointed out that non-
cholesterol sterols can come from non-plant
sources, such as from shellfish etc, and these are
also excluded in a similar manner.3
It was unclear until recently how the vertebrate
gastrointestinal tract and liver differentiated struc-
turally similar compounds such as cholesterol and
plant sterols, although it was known that plant
sterols were poorly absorbed and their presence
decreased intestinal cholesterol uptake, suggesting
that their pathways did intersect.19–21
proposed mechanisms focused on understanding
how plant sterols interfered with cholesterol
uptake. Plant sterols, being more hydrophobic than
cholesterol, were thought to compete with choles-
terol for micelle formation, thus resulting in
reduced cholesterol solubilisation and intestinal
uptake.22–25In addition, the small amounts of plant
Usually the net
588J Clin Pathol 2008;61:588–594. doi:10.1136/jcp.2007.049775
sterols that were absorbed did not seem to be subjected to the
same metabolism as cholesterol (esterification, storage, or
metabolised to bile salts or steroid hormones), but were
preferentially excreted into bile by the liver.26They are
transported via the same lipoproteins and there is no evidence
at this time if the presence of higher amounts of plant sterols in
these lipoproteins alters their function in any fashion. Non-
cholesterol sterols can be hydroxylated at the 5a position
(leading to the formation of 5a stanols). The majority of the
absorbed non-cholesterol sterols are largely excreted unchanged
in the bile.7 27
One of the early mechanisms attributed to this poor
absorption of plant sterols was the high specificity of the
esterification enzyme, ACAT-2, in the enterocyte for choles-
terol, thus leaving phytosterols unesterified and barring their
entry into the chylomicrons.28
The observation that patients with sitosterolaemia had higher
absorption and circulating levels of non-cholesterol sterols
suggested that these individuals lack the natural ability to
diminish the uptake of non-cholesterol sterols in the gut and fail
to excrete non-cholesterol sterols into their bile.1This genetic
disorder pointed towards the existence of a gene that was critical
for intestinal sterol absorption and discrimination and for biliary
sterol excretion. In 1998, the sitosterolaemia locus, STSL, was
mapped by Patel et al to human chromosome 2p21.29This locus
comprises two adjacent and highly homologous genes, ABCG5
and ABCG8, encoding two intestinal sterol half-transporters,
sterolin-1 and sterolin-2;mutationsin eitherlead tothedisease.4 6
ABCG5 and ABCG8 are thought to act as an obligate hetero-
dimers, based on the fact that complete mutations on either gene
cancause sitosterolaemia;this is supported by in vitrodata.4 6 30 31
Structure and function of ABCG5 and ABCG8
Sterolin-1 (ABCG5) and sterolin-2 (ABCG8) belong to the ATP-
binding cassette (ABC) transporter superfamily and the ‘‘G’’
sub-family. They localise to the apical membrane of the
enterocyte and the canalicular membrane of the biliary
tract.30–32Each ABCG5 and ABCG8 gene is composed of 13
exons; they are arranged in a head-to-head configuration on
chromosome 2p21, with about 140 bases separating their first
exons5 33(fig 2). Their genomic organisation suggests a gene
duplication event during evolution. There is a higher prevalence
of polymorphisms in ABCG8, compared to ABCG5, despite its
close proximity and homology with ABCG5. A number of
studies have implicated this locus in disease or physiological
processes, other than sitosterolaemia, ranging from gallstone
formation, lipoprotein kinetics, cholesterol absorption and
obesity to response to drug therapy.34–45Indeed, the remarkable
conservation of the STSL locus between species as diverse as
fish, amphibians, rodents and humans seems to indicate that
the polymorphic changes may have a more dramatic effect on
function.46Sitosterolaemia as well as other human studies have
confirmed that sterol absorption is genetically regulated.35 39 40 47
ABCG5 and ABCG8 proteins contain six transmembrane
domains and one ATP-binding domain each. Once expressed,
they travel as heterodimers to the apical membrane where they
form full, active transporters and require ATP to function. On
the cell surface, they likely promote flopping of sterols from the
inner to the outer leaflets of the plasma membrane.48
Animal and human studies have demonstrated the role of
ABCG5 and ABCG8 in regulating net plant sterol and
cholesterol absorption and elimination from the body.49In the
enterocyte, they promote efflux of plant sterols back into the
intestine, resulting in very low net absorption (,5%), and to
some extent may play a role in excreting cholesterol.2 50 51In the
liver, they promote the excretion of sterols (cholesterol and
plant sterols) into the bile.52–55In mice deficient in Abcg5 or
Abcg8, biliary sterols are very low and do not increase, despite
forced excretion.52 56 57In man, it appears that the liver may be a
more important organ than the gut for keeping the levels of
plant sterols low; a patient with sitosterolaemia underwent a
liver transplantation, and following this, his plant sterol levels
almost normalised despite his genetic defect in the intestine.58
Thus, ABCG5 and ABCG8 may selectively ‘‘pump’’ non-
cholesterol sterols out of the intestinal cells as a first-line
defence to dietary input, and the sterols that escape the
enterocyte and get absorbed are pumped out by hepatic
canalicular ABCG5 and ABCG8. Moreover, in the fasting state,
the liver can continually pump sterols (cholesterol and
stanols compared to cholesterol. Plant
sterols have the same squalene ring
nucleus as cholesterol, but differ mainly in
the side-chain configuration. All plant
sterols have a side-chain of variable
length at C24. In addition, sitostanol and
campestanol lack a double bond between
C5 and C6 compared to their unsaturated
counterparts; stigmasterol has a double
bond between C22 and C23; avenosterol
has a double bond between C24 and C28;
brassicasterol has a double bond between
C22 and C23; and ergosterol differs by the
presence of a double bond between C7
Structures of plant sterols and
J Clin Pathol 2008;61:588–594. doi:10.1136/jcp.2007.049775589
non-cholesterol sterols) into bile and thus maintain a low non-
cholesterol sterol level in the body.50
Regulation of ABCG5 and ABCG8
Liver X receptor (LXR) is a transcriptional factor that increases
ABCG5 and ABCG8 gene expression on the enterocyte border,
thus decreasing the intestinal cholesterol absorption.59LXR
activation restores sterol secretion in ABCG5 knockout mice
which normally produce a sterol-poor bile,57suggesting again an
important role of LXR. More recently, ABCG5 and ABCG8
expression has been shown to be regulated by HNF-4.60
Shortly after identification of ABCG5 and ABCG8, Nieman
Pick C1-like-1 protein (NPC1L1) was identified to be the sterol
transporter thatis responsibleforuptakeof allsterols(cholesterol
and plant sterols) into the enterocyte in the proximal small
plant sterols predominantly being expelled back into the
enterocyte lumen via sterolin pumps, whereas dietary cholesterol
is esterified and incorporated into chylomicrons for secretion into
the lymph at the basolateral surface.
There remain several gaps in our understanding of these
pumps; for example, the exact mechanism of how these pumps
recognise plant sterols and secrete them back into the lumen is
still not known. One hypothesis argues that ABCG5/ABCG8
may act as ‘‘extruders’’, exposing sterols in the outer leaflet of
the membrane for facilitated extraction into the lumen by sterol
acceptors,63such as bile acid:phospholipid complexes, whereas
others have proposed that sterolins may act as ‘‘flippases’’, akin
to the flipping of phospholipids from the inner to the outer
leaflet of the apical membranes.64It is not known under what
circumstances sterolins start excreting cholesterol and which
transcriptional factors, other than LXR and HNF4a, control this
process. In addition, are sterols the only substrate for sterolins,
and if not, what are the other substrates that interact with
(rectangles) separated by 12 introns. Introns and exons are not shown to exact size. Known mutations are indicated on the top of each gene structure.
(B) Model of how ABCG5 and ABCG8 heterodimer may function at the luminal surface; current evidence indicates that these pumps show a preference
for non-cholesterol sterols, but in their absence they will ‘‘flip’’ cholesterol into the lumen of the intestine or biliary channels for ultimate excretion
through the stools.
Gene structure and putative model for action for ABCG5 and ABCG8. (A) ABCG5 and ABCG8 gene structure. Each comprise 13 exons
590J Clin Pathol 2008;61:588–594. doi:10.1136/jcp.2007.049775
these pumps? Studies in mice deficient in ABCG5 and ABCG8
show that some sterol secretion continues and suggest that
genes other than ABCG5/ABCG8 can control the absorption of
cholesterol and plasma plant sterol levels.65
The genetic disease of sitosterolaemia attests to the role of
ABCG5 and ABCG8 in keeping non-cholesterol sterols (plant
sterols as well as shellfish sterols, etc) out of the human body.
Studies on sitosterolaemic patients reveal a 3–12-fold increase in
plant sterol absorption, a 30–100-fold increase in plasma plant
sterol levels, and a 13–100-fold increase in body plant sterol pool
size due to chronic increase in absorption and decrease in
excretion.66–68In the plasma, these sterols are transported, much
like cholesterol, in all the lipoprotein sub-fractions, including
high density lipoprotein (HDL), low density lipoprotein (LDL),
and very low density lipoprotein (VLDL) cholesterol.1
Clinical presentation may vary from the presence of tendon
xanthomas, atherosclerosis and its complications to a milder
phenotype with very few specific symptoms or signs. In their
original description of the disease, Bhattacharyya and Connor
highlighted the presence of tendon and tuberous xanthomas due
to increased absorption of sitosterol from the diet, resulting in
increased plant sterols in the plasma, lipoproteins, red blood
cells, xanthomas, adipose tissue and skin surface.1Subsequently,
several new clinical features have been described (box 1).68–74
Tendon xanthomatosis is similar to that observed in patients
with homozygous familial hypercholesterolaemia. Xanthomas
in sitosterolaemia have been reported as early as 8 years of age
and usually involve the Achilles tendon, though any tendon can
Premature atherosclerosis, and early onset myocardial infarc-
tion and requirement for coronary revascularisation proce-
dures17 68as early as 16 years of age have been reported.72 75–78
The reason for premature cardiovascular disease is unclear in
patients with sitosterolaemia. It could be because of elevated
cholesterol levels (cholesterol absorption is also high and its
excretion in bile is low, similar to plant sterol levels), or it might
be a direct result of elevated plant sterol concentrations. It is not
clear whether mildly elevated plant sterols, as seen in some
normal subjects, are responsible for cardiovascular disease, with
some studies showing neutral effect, some showing elevated risk
and some even suggesting a protective effect; the jury is still out
on this issue.79–83It seems entirely plausible that plant sterols are
associated with cardiovascular disease. Pathological examina-
tion of the xanthomas and arteries of sitosterolaemia patients
shows that they contain plant sterols.72Plant sterols seem to
form xanthomas, even at lower plasma levels (30–40 mg/dl),
whereas cholesterol levels .400 mg/dl are needed to induce
tendon xanthomas in familial hypercholesterolaemia. Perhaps
some species of non-cholesterol sterols (or their metabolites) are
more effective in formation of foam cells and plaque forma-
tion.82These concepts need more investigation.
The full clinical spectrum of this disease is probably not
known due to under diagnosis of the condition. It is important
to recognise that there may be few or no clinical signs to suggest
a person has sitosterolaemia; sometimes haemolysis may be the
only presenting feature.70In addition, patients may just present
with atherosclerotic disease (a common clinical finding) but no
other clues to suggest one should consider sitosterolaemia as a
diagnosis. Thus alerting the medical community may lead to an
‘‘increase’’ in prevalence.
Moreover, sitosterolaemia may be mistaken for familial
hypercholesterolaemia (FH) or cerebrotendinous xanthomatosis
(CTX). Sitosterolaemia is differentiated from FH merely due to
the presence of normal cholesterol levels. CTX may also present
with tendon xanthomas and premature cardiovascular disease;
however, other clinical features of CTX, such as premature
cataracts and neurological symptoms, will help to differentiate
it from sitosterolaemia. The key test is the analysis of blood by
GC or HPLC for different sterol species.
GENETIC ASPECTS OF SITOSTEROLAEMIA
Since it is an autosomal recessive disease, it is necessary to have
mutations in both the alleles of either ABCG5 or ABCG8.
Parents of sitosterolaemic patients (heterozygotes) have no
However, serum plant sterol concentrations are increased
minimally when a diet enriched in plant sterols is consumed,
indicating that the capacity to prevent accumulation of non-
cholesterol sterols may not be rate-limiting.84Several mutations
have been reported and provide important insights in to the
nature of the inheritance. Founder effects for mutations
underlie many of the cases, suggesting that this disease has
been present for many generations, perhaps more than 4000
years.85 86Caucasians seem to carry mutations in ABCG8,
whereas Chinese, Japanese and Indian (20% of known cases)
patients seem to have mutations in ABCG5.5We do not know
the prevalence of heterozygous mutations in the community,
and whether this would confer any selective advantage.
The plant sterols that are elevated in sitosterolaemia are mainly
sitosterol and campesterol (since these are the most abundant
plant sterols in the diet), but stigmasterol, avenasterol, brassi-
casterol, campestanol, sitostanol, and shellfish sterols can also be
increased, based on dietary intake.1 3 87–90Cholesterol forms only
80% of the total plasma sterols in patients with sitosterolaemia.17
Other notable findings include variable cholesterol levels (normal
or mild to moderately elevated plasma cholesterol levels),
thrombocytopenia, chronic haemolytic anaemia and elevated
liver enzymes in some patients.
Disease is suspected in patients with either tendon or tuberous
xanthomas, premature cardiovascular disease associated with
normal cholesterol levels or in those with unexplained haemo-
lysis. Plant sterol levels in normal or heterozygotes should not be
.1 mg/dl as opposed to .20–30 mg/dl in the patients with
sitosterolaemia. Some heterozygotes were found to have higher
than normal levels of plant sterols; but levels were still
substantially lower than in homozygotes.91
Measurement of phytosterols
Usually enzymatic or colorimetric methods are used to quantify
sterols. The colorimetric assay depends on the double bond
between carbons 5 and 6; the enzymatic method uses
Box 1: Symptoms and signs in sitosterolaemia
c Premature atherosclerosis and cardiovascular disease
J Clin Pathol 2008;61:588–594. doi:10.1136/jcp.2007.049775591
‘‘cholesterol’’ oxidase that detects the 3-b hydroxyl group.
These methods cannot differentiate between cholesterol and
plant sterols17 92(fig 1). To detect plant sterols and their stanols,
gas chromatography (GC) or high performance liquid chroma-
tography (HPLC) are needed. However, to detect normal
physiological concentrations (0.05–0.5 mg/dl range), even more
sensitive analytical methods are necessary. Although gas
remain the mainstay, more rapid throughput technologies are
now available, such as electron-spray liquid chromatography–
mass spectrometry (LC–MS), or atmospheric pressure photo-
ionisation combined with liquid chromatography–tandem mass
spectrometry (LC–MS/MS) which could make it possible to
rapidly screen a much larger population for this condition.93It
should also be pointed out that sterols are very stable and can be
measured from serum stored for a long time.
This condition is active from birth. However, it is not clear
whether early neonatal screening for this disease will be
effective. Plant sterol levels in the plasma are highly dependent
on diet, and if the diet does not contain plant sterols, the levels
in the plasma can be predicted to be low in neonates and
infants. Presumably, plant sterols may only accumulate after
the child has been exposed to a diet containing plant sterols
(either as artificial milk or semi-solid food). Screening is still
possible in a sibling of a patient with sitosterolaemia, but should
be undertaken much later than the neonatal period.
The key element in the diagnosis for this disease is, therefore,
ordering the correct test. To date, no other medical conditions
result in elevation of plant sterols; thus detection of high levels
of plant sterols is pathognomonic for this disease. Genetic
testing can also be attempted after a biochemical diagnosis has
Even though there is impairment of both intestinal and hepatic
elimination pathways in patients with sitosterolaemia, it is
sufficient to interrupt one of the pathways to decrease the plant
sterol levels.58 94Ezetimibe binds to NPC1L1, which is a sterol
transporter in the proximal intestine, and blocks uptake and
reuptake of sterols, resulting in lower concentrations of both
cholesterol and plant sterols. Ezetimibe leads to a marked
improvement in plasma sterol concentrations, regression of
xanthomatosis and resolution of cardiovascular disease in
patients with sitosterolaemia.69Recently, hepatic transplanta-
tion in a sitosterolaemic patient resulted in complete normal-
isation of plant sterol levels. Thus even if intestinal sterol
uptake goes unchecked, the absorbed plant sterols can be
eliminated completely by the restored ABCG5 and ABCG8 in
the liver.58Before the discovery of ezetimibe, sitosterolaemia
was treated with bile-acid binding resins,95with fair results.
Restriction of dietary plant sterols may also lower the plasma
plant sterol levels. However, studies on the efficacy of this
treatment are based on a few patients and not in universal
agreement, in part because it is very difficult to not consume
PLANT STEROLS/STANOLS AS TREATMENT FOR
The hypocholesterolaemic effect of plant sterols have been
known for more than 50 years and they have been used as an
add-on therapy.98–100ATP III guidelines have also recommended
the addition of plant sterols/stanols (2 g/day) as a part of the
initial therapeutic lifestyle change for hypercholesterolaemia.101
As already indicated, plant sterols decrease plasma cholesterol
by interfering with their absorption. However, we need to keep
in mind that this universal recommendation cannot be applied
to patients with sitosterolaemia due to high plant sterol
absorption and their potential pathogenicity. Additionally, in
subjects with heterozygous mutations (such as the obligate
carriers), such diets also led to an increase in plant sterols. Given
the rarity of this condition, the use of plant sterol fortified foods
is unlikely to be harmful to the majority of people.
Even though several questions remain unanswered, sitoster-
olaemia is one of the monogenic diseases, study of which has
not only helped the patients who suffer from it but also
contributed to the greater understanding of sterol metabolism.
Greater awareness among cardiologists, to whom the patients
with premature coronary atherosclerosis present, haematolo-
gists, to whom patients with unexplained haemolysis present,
and general internists and pathologists who help in their initial
evaluation and diagnosis, is essential for prompt diagnosis and
Competing interests: None declared.
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c Sitosterolaemia is a rare genetic disease associated with high
plant sterol levels; it manifests with tendon xanthomas,
premature cardiovascular disease, arthralgias and occasionally
c ABCG5 and ABCG8 encode two half-transporters which
normally expel plant sterols into the gut and biliary lumen;
homozygous mutations in either one of these two genes result
in impairment of normal mechanisms that keep plant sterol
levels low in the human body.
c Elevated plant sterol levels in the range 25–30 mg/dl (normal
,1 mg/dl) is pathognomonic for diagnosis of sitosterolaemia.
c The usual methods employed to estimate cholesterol levels
cannot differentiate between cholesterol and plant sterols.
GC–MS or HPLC are necessary to measure plant sterol levels.
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