Acute hepatitis caused by a natural lipid-lowering product: When
‘‘alternative” medicine is no ‘‘alternative” at allq
Antonio Grieco1,*, Luca Miele1,?, Maurizio Pompili1,?, Marco Biolato1,
Fabio M. Vecchio3, Ignazio Grattagliano2, Giovanni Gasbarrini1
1Institute of Internal Medicine, Catholic University of Rome, 8 Largo A. Gemelli, 00168 Rome, Italy
2Section of Internal Medicine, DIMIMP, University of Bari, Bari, Italy
3Institute of Pathology, Catholic University of Rome, Rome, Italy
Background/Aims:The general public’s growing mistrust of the pharmaceutical industry and its perception of the lack of
adverse effects of ‘‘natural” therapy have lead to the increasing use of ‘‘alternative drugs” for hypercholesterolemia.
Methods:A sixty-three year old woman presented with severe hypertransaminasemia that had developed progressively
over a few weeks. For six months she had been taking Equisterol?, an over-the-counter lipid-lowering product containing
guggulsterol and red yeast rice extract. The product had been prescribed for hypercholesterolemia because the patient had
developed hepatotoxicity while on lovastatin.
Results:Liver biopsy revealed severe lobular necroinflammatory changes with an eosinophilic infiltrate. The episode was
regarded as an adverse drug reaction after exclusion of other possible causes of acute liver disease and the prompt nor-
malization of liver function tests after Equisterol?had been discontinued. Red yeast rice extract’s cholesterol-lowering
properties are largely due to fungal metabolites known as monacolins, one of which – monacolin K – is identical to
Conclusions:The choice of an alternative medicine approach in this case subjected the patient to ‘‘re-challenge” with the
official medicine agent that had previously caused mild hepatotoxicity. Physicians should keep in mind that ‘‘alternative”
medicine is not always the safest alternative and sometimes it is not even ‘‘alternative.”
? 2009 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.
Keywords: Alternative medicine; Equisterol; Red yeast rice; Lovastatin; Hepatotoxicity; Drug-induced liver disease
Elevated serum levels of low-density lipoprotein
(LDL) cholesterol are an important independent risk
factor for coronary heart disease (CHD). Their reduc-
tion has been shown to lower the incidence of CHD
among individuals with dyslipidemia and the frequency
of CHD-related death in patients who already have
CHD. The guidelines for management of hypercholes-
terolemia formulated by the National Cholesterol Edu-
cation Program Adult Treatment Panel emphasise the
use of dietary modifications, weight loss, and physical
activity. Drug therapy is reserved for cases that cannot
be managed with therapeutic lifestyle changes alone
0168-8278/$36.00 ? 2009 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.
Received 13 November 2008; received in revised form 29 January 2009;
accepted 3 February 2009
Associate Editor: J.G. McHutchison
qThe authors who have taken part in this study declared that they do
not have a relationship with the manufacturers of the drugs involved
either in the past or present and they did not receive funding from the
manufacturers to carry out their research.
*Corresponding author. Tel.: +39 06 30155451; fax: +39 06
E-mail address: email@example.com (A. Grieco).
?These authors contributed equally to this work.
Abbreviations: CHD, coronary heart disease; LFTs, liver function
tests; DILI, drug-induced liver disease.
Journal of Hepatology 50 (2009) 1273–1277
and/or those characterised by substantial cardiovascular
Statins are the drugs most widely used to achieve
this goal. Based on the results of several meta-analyses
of pooled data from randomised clinical trials and
observational studies, the risk of abnormal liver func-
tion tests (LFTs) in patients on statin therapy has been
estimated around 1% [2–5]. A large retrospective
cohort analysis has recently shown that statin therapy
is also safe for patients with pre-existing liver disease
. However, the public’s growing mistrust of ‘‘Big
Pharma” and its perception of products derived from
plants as ‘‘natural” therapy with no potential for
adverse effects have lead to the increasing use of ‘‘alter-
native drugs” for hypercholesterolemia. The truth is
that use of these products can be quite dangerous, as
recently illustrated by the cases of acute liver failure
associated with certain dietary supplements and ‘‘natu-
ropathic hepatoprotectors” [7–9].
We report the case of a patient who had discontin-
ued statin therapy after developing drug-induced liver
disease with hypertransaminasemia. She later devel-
oped acute hepatotoxicity as a result of treatment with
a natural lipid-lowering product, which turned out to
contain the same statin that had caused her prior liver
2. Case report
In January 2005, a 63-year-old woman with a two-
year history of hypercholesterolemia and family history
of ischemic heart disease was started on lovastatin
(20 mg/day). Six months later (June 2005), she was
found to have mildly elevated serum transaminase levels
(1.5 times higher than the upper normal limits) with a
transient rise in ANA antibody titers (1:40). Investiga-
tion of the LFT alterations revealed no serological evi-
dence of viral infection (hepatitis A, B, or E; Epstein
Barr; Herpes; or Cytomegalovirus), cryoglobulins, or
other auto-antibodies (AMA, LKM, EMA). The renal
and thyroid profiles were normal, and there was no
hepatomegaly on the abdominal sonogram. She refused
to have a liver biopsy.
Lovastatin therapy was interrupted, and three months
reason, the statin was definitively discontinued, and
polyunsaturated fatty acid supplementation (1 g/day
b.i.d.) was started. In June 2007, her total cholesterol
remained high (240 mg/dlL), and a metabolic consultant
prescribed complementary therapy with a natural prod-
(Istituto Farmacoterapico Italiano
S.p.A., Rome, Italy), one 30-mg tablet once a day.
According to the manufacturer, Equisterol contains
Fig. 1. (A) Clinical Chronology. Serum transaminases, c-glutamyl transpeptidase levels and ANA titres. After discontinuation of Equisterol, liver
enzymes returned to a near-normal range and ANA titres were undetectable. (B) Enlargement of the portal tracts, mild fibrosis, and bile-duct proliferation
(hematoxylin and eosin, 10?). (C) Lobular disarray with liver-cell necrosis and a severe eosinophilic inflammatory infiltrate (hematoxylin and eosin, 10?).
A. Grieco et al./Journal of Hepatology 50 (2009) 1273–1277
guggulsterol (from the Ayurvedic medicinal plant
Commiphora mukul); sistosterol; chlorogenic acid; poli-
cosanol (a natural substance derived from sugar cane);
vitamins C, E, and B6; niacin; coenzyme Q; and 1–17 g
of red yeast rice (roughly equivalent to 15 mg of
In December 2007 she was admitted to our depart-
ment for markedly elevated transaminase levels and fati-
gue. Her BMI was normal (24.8 Kg/m2), and she denied
all use of alcohol (a claim confirmed by her relatives).
The admission laboratory work-up disclosed severe
liver-cell necrosis (ALT 1760 U/L, AST 1046 U/L, nor-
mal values 7–45) with cholestasis (ALP 722 U/L, normal
values 99–279; GGT 157 U/L, normal values 5–36) and
hyperbilirubinemia (total 1.9 mg/dl, direct 0.9 mg/dl)
(Fig. 1A). Fasting glucose, insulin, ferritin, and total
cholesterol levels were within normal limits.
We excluded hepatotropic viral infections and other
common causes of hypertransaminasemia. The patient
was also screened for Wilson’s disease and alpha-1-anti-
trypsin disease. ANA, AMA, anti-LKM, ASMA, serum
antiendomysial antibodies, pANCA, and cANCA anti-
body titers were negative, but IgG levels were mildly ele-
vated (1600–1630 mg/dL). The HLA haplotype was
negative for DR3 and/or DR4. Abdominal ultrasonog-
raphy showed an enlarged liver (bipolar diameter of
the right lobe: 15.7 cm) with mild steatosis. The gall
bladder and biliary tree were normal with no sign of
lithiasis. A liver biopsy revealed severe lobular necroin-
flammatory changes, the presence of eosinophil granulo-
cytes, and widening of the portal spaces with mild
fibrosis. The bile ductules were characterised by prolifer-
ation and metaplasia (Fig. 1 B and C).
Equisterol was discontinued, and the patient was
treated for one week with glutathione i.v. (600 mg/
day) and ursodeoxycholic acid p.o. (300 mg/day t.i.d).
After ten days we observed a clear reduction of both
transaminases and cholestasis indices. The Doppler
ultrasound scan of the carotid arteries showed no evi-
dence of atherosclerosis. Therefore, she was discharged
with instructions for appropriate lifestyle modifications,
and all drug therapy was deferred because of the low
Serum transaminase levels and cholestasis indices
were monitored monthly. Six months after discharge,
the former were only mildly elevated (ALT 144 U/L,
AST 81 U/L), and gamma-GT and alkaline phosphatase
levels were within normal limits.
We report a case of unequivocal hepatotoxicity
caused by a ‘‘natural” over-the-counter remedy for
hypercholesterolemia in a woman who had already
experienced LFT alterations during statin therapy for
the same condition. The product of concern contains
sterols from the Ayurvedic medicinal plant, C. mukul
(also known as guggul or myrrh), and extract of red
yeast rice. Commiphora mukul contains guggulsterone
band E, mainly in the sterol fraction, which possesses
documented cholesterol-lowering properties related to
its antagonism of the farnesoid X receptor, a nuclear
hormone receptor that is activated by bile acids .
A single case of rhabdomyolysis has been reported in
a patient taking C. mukul extract for high cholesterol
, but to date there have been no unequivocal cases
of liver toxicity associated with the use of guggul.
Therefore, we do not believe that this plant sterol is
responsible for the problems experienced by our
The second lipid-lowering ingredient of Equisterol is
an extract of red yeast rice (cook rice fermented by the
yeast Monascus purpureus). Its ability to reduce total
cholesterol levels has been well documented , and
its safety has been confirmed in a randomised, dou-
ble-blind trial . A single case of severe rhabdomyol-
ysis has been tentatively attributed to the use of red
yeast rice by a renal transplant recipient. However, this
patient was also on chronic therapy with cyclosporine,
and the authors of the report noted that the latter drug
may have interfered with metabolism of the yeast-
related sterols by cytochrome P-450 isoenzyme 3A4
. Red yeast rice contains cholesterol-synthesis-
inhibiting fungal metabolites known as monacolins
. Roughly 75% of the antihyperlipidemic activity
of red yeast rice seems to be attributable to the lactone
and hydroxy-acid forms of monacolin K, a metabolite
of Monascus ruber that inhibits 3-hydroxy-3-methyl-
glutaryl coenzyme A (HMG-CoA) reductase [13,15].
In 1979, monacolin K and lovastatin (then known as
mevinolin) were recognized to be identical compounds
produced, respectively, by M. ruber and Aspergillus ter-
reus . Five milligrams of monacolin K has been
shown to be the equivalent of 20–40 mg of lovastatin
In the case described here, the patient took a daily
dose of monacolin K somewhere between 15 and
30 mg for at least 6 months. This is the equivalent of
60–120 mg of lovastatin, a daily dose 3–4 times higher
than the one she had been taking in 2005 (20 mg/day).
At that dose, the patient experienced mildly elevated
transaminase levels, which spontaneously returned to
normal when the lovastatin was discontinued. There-
fore, the episode that led to her hospitalization in
December 2007 can be regarded as a positive response
to re-challenge, which is currently considered the single
most accurate means for demonstrating direct causal
links between drug use and liver toxicity . Another
case of hepatitis has recently been attributed to red yeast
rice, and the laboratory and histological findings were
very similar to those of our patient. This adds support
A. Grieco et al./Journal of Hepatology 50 (2009) 1273–1277
to our hypothesis that this dietary supplement produces
liver damage via mechanisms similar to those underlying
the hepatotoxicity of any HMG-CoA inhibitor .
Today, the safety of lovastatin is widely recognized.
Hepatotoxic side effects are very infrequent, even in
individuals with elevated liver enzymes before treat-
ment . However, premarketing and postmarketing
studies have both shown that the frequency of these
side effects is dose-related and almost always reversible
[19–21]. It is therefore conceivable that the hepatotoxic
effects we observed were similar to those that would be
(>80 mg/day). In the only reported case of this type
in which a liver biopsy was obtained, the histologic
findings were almost identical to those described in
the present report .
Although cases of statin-induced autoimmune hepati-
tis have been reported [22–24], we do not feel that auto-
immunity played any role in the present case – as an
initial trigger or ‘‘booster.” This conclusion is supported
by the absence of autoantibodies, the spontaneous reso-
lution of all symptoms without any specific therapy, and
by the patient’s HLA profile, which is not compatible
with a diagnosis of autoimmune hepatitis. In fact, the
possibility of autoimmune hepatitis was excluded in
light of the rapid response to withdrawal of lovastatin,
the patient’s HLA haplotype, and the low International
Autoimmune Hepatitis Group score .
Ayurvedic products may also be contaminated by
toxic substances, such as heavy metals and arsenic, as
recently reported . It is impossible to determine
whether the supplement used by our patient contained
similar substances. As in the United States, dietary sup-
plements are not subjected to the same rigorous controls
used for pharmaceuticals. Heavy metal toxicity in par-
ticular seems to target mainly renal  and cognitive
functions , and we have found no reports of hepato-
toxicity caused by these contaminants.
This case highlights one major problem related to the
complementary and alternative medicine market. The
products sold in this market are advertised as – and con-
sidered by most patients to be – ‘‘natural substances” or
‘‘nutritional supplements” that are consequently safer
than conventional drugs. However, these products often
contain multiple active ingredients in poorly specified
amounts, their labelling is often incomplete, and their
chemical composition is only partially known by
patients and physicians alike.
The toxic hepatitis described in this report was caused
by the attempt to control the patient’s hypercholesterol-
emia without resorting to conventional statin therapy,
which had previously caused mild signs of hepatotoxicity.
As a result, the patient was unwittingly treated with an
agent identical to the statin that needed to be avoided. As
this report illustrates, ‘‘alternative” medicine is not always
the best alternative: sometimes, it is no alternative at all.
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