the effect of curcumin and placebo on human gall-bladder function: an ultrasound study
TRANSCRIPT
The effect of curcumin and placebo on human gall-bladder function:an ultrasound study
A. RASYID & A. LELO*
Department of Radiology and *Pharmacology, School of Medicine, Universitas Sumatera Utara, Medan, Indonesia
Accepted for publication 13 October 1998
INTRODUCTION
Medicinal plants containing curcumin as an active
compound, i.e. Curcuma longa and Curcuma xanthorrhiza
known as `jamu', are traditionally consumed for their
health bene®ts by Indonesian people, including by
pregnant women.1 The crude Curcuma species is
believed to give bene®cial effects in the treatment of
jaundice (as cholagogum) and hepatic diseases.2 Ani-
mal studies con®rmed that curcumin has a hepatopro-
tective effect in addition to effect on bile secretion
stimulation.2, 3 Ammon & Wahl claimed that the doses
(25 mg/kg body weight) administered intravenously in
experimental animals were, however, too large to be
used in humans and were therefore of no clinical
relevance.3
At the present time, various studies have been
conducted to de®ne a suitable cholecystokinetic agent
for the prevention of gall-bladder stone formation in
patients who are at high risk, e.g. those in sepsis, long
standing fasting periods, or receiving total parenteral
nutrition. Erythromycin,4, 5 fatty meals6, 7 and amino-
acids8 are able to stimulate gall-bladder contraction by
different mechanisms. It is not known whether the
traditional cholagog curcumin has a similar effect on
the human gall-bladder.
However, several clinical studies have demonstrated
that 20 mg curcumin, administered three times daily,
gave positive clinical effects in cases of acute and
chronic hepatitis.9, 10 The present study was therefore
carried out in order to de®ne whether a small dose of
curcumin still has a clinical bene®t in stimulating the
contraction of human gall-bladder, by comparing the
SUMMARY
Background: The extract of medicinal plants containing
curcumin is traditionally believed to have a positive
contraction effect on the human gall-bladder.
Aims: To compare the effect of 20 mg curcumin or
placebo on the gall-bladder volume of healthy volun-
teers.
Methods: A randomized, double blind and crossover
design study was carried out in 12 healthy volunteers
(seven males and ®ve females). Ultrasonography exam-
ination was carried out serially to measure the gall-
bladder volume. The data obtained was analysed by
paired Student's t-test.
Results: The fasting gall-bladder volumes of
15.74 � 4.29 mL on curcumin and 15.98 � 4.08 mL
on placebo were similar (P > 0.20). The gall-bladder
volume was reduced within the period after curcumin
administration. The percentage of gall-bladder volume
reduction at 0.5, 1.0, 1.5 and 2.0 h after 20 mg
curcumin administration were 11.8 � 6.9, 16.8 � 7.4,
22.0 � 8.5 and 29.3 � 8.3%, respectively, which was
statistically signi®cant compared to placebo.
Conclusion: On the basis of the present ®ndings, it
appears that curcumin induces contraction of the
human gall-bladder.
Correspondence to: Dr A. Lelo, Bagian Farmakologi, Fakultas Kedokteran,
Universitas Sumatera Utara. Jl. Dr Mansur 5, Kampus Universitas
Sumatera Utara, Medan, Indonesia.E-mail: [email protected]
Aliment Pharmacol Ther 1999; 13: 245±249.
Ó 1999 Blackwell Science Ltd 245
gall-bladder volume after the administration of 20 mg
curcumin or placebo.
MATERIALS AND METHODS
This study was conducted as randomized, double blind
and crossover design with a wash-out period of 1 week,
on 12 healthy volunteers (seven males and ®ve females)
whose ages ranged from 24 to 48 years. (Mean � s.d.;
34.58 � 6.36 years.), weight ranging from 45 to 65 kg
(54.58 � 7.66 kg) and height ranging from 150 to
168 cm (60.67 � 6.32 cm). All the subjects gave
informed written consent to participate in the study.
The study protocol was approved by the Dean of the
School of Medicine, and the University Research
Committee of Universitas Sumatera Utara, Medan,
Indonesia. All subjects were evaluated for their general
good health, i.e. on the basis of a medical history,
physical examination, laboratory test and ultrasonog-
raphy of the upper abdomen. None of them had a
history of, or clinical evidence of hepatobiliary and
gastrointestinal disease or operation. None of the
subjects was taking any regular medication, including
`jamu' and oral contraceptive pills at least 7 days before
the study. All subjects were forbidden from eating fatty
meals before the study. They had no jaundice, and the
livers and spleens were unpalpable. The bilirubin, SGOT,
SGPT, alkaline phosphates, cholesterol, albumin and
globulin tests were all normal. An ultrasonography of
the upper abdomen showed a normal liver, gall-bladder
and biliary tract. Only subjects who had a gall-bladder
of ellipsoid form could participate in this study.
The curcumin (C21H20O6) used for this study was
purchased from Merck Schudchardt, Munchen, Germa-
ny. The single oral dose of curcumin or placebo
(amylum) employed in this study was swallowed with
100 mL water.
Three dimensions of the gall-bladder (its length, width
and depth) were measured by ultrasonography to
calculate its volume. The ultrasound machine used
was a real time system, model SSH 140 A (Toshiba
Japan) with a 3.75 MHz convex and sector transducer
similar to that used by other investigators.11, 12
The transducer was placed in a saggital plane in the
right upper quadrant of the supine subject with left
lateral decubitus 45° position. Each subject was re-
quired to hold a maximum deep thoracic inspiration in
order to obtain a maximal visualization of the gall-
bladder and to enable standardization of the gall-bladder
measurement. The photograph of the gall-bladder was
taken when it reached its greatest size.
The image was frozen on the oscilloscope screen, and
the greatest length of gall-bladder was measured on the
screen using a previously standardized electronic calli-
per. The transducer was then rotated 90° to obtain an
image of the short axis of the gall-bladder with the
greatest transverse (width) and anteroposterior (depth)
dimensions.
After an overnight fast, the length, width and depth of
gall-bladder were serially measured at 08.00 hours (as
the zero time, t � 0) and then at 0.5, 1.0, 1.5 and
2.0 h after taking curcumin or placebo. The gall-
bladder volume (GV, mL) was estimated using an
ellipsoid approximation:12, 13
GV � 0:52� length�width� depth
To express the gall-bladder contraction, we recorded
the percentage reduction in gall-bladder volume (%GV)
compared to the fasting gall-bladder volume (GV0.0).
%GV � ��GV0:0 ÿ GVt�=GV0:0� � 100%;
Where GV0.0 � fasting gall-bladder volume and
GVt � gall-bladder volume at the time measured. If a
reduction in gall-bladder size was observed, it was noted
as a positive contraction and vice versa.
Data obtained was expressed as mean � standard
deviation, and statistically analysed by paired Student's
t-test with P-values < 0.05 regarded as the level of
statistical signi®cance.
RESULTS
The fasting gall-bladder volumes before taking 20 mg
curcumin (15.74 � 4.29 mL) or placebo
(15.98 � 4.08 mL) were not statistically different
(P > 0.20) (Table 1).
Gall-bladder volume was reduced within the period
immediately following curcumin administration, and
the opposite effect took place in the placebo group
(Figure 1). However, a signi®cant difference (P < 0.05)
in gall-bladder volume between the curcumin and
placebo groups appeared after 0.5 h drug administra-
tion (Table 1).
Correspondingly, 0.5, 1.0, 1.5 and 2.0 h after 20 mg
curcumin administration there was marked increase in
246 A. RASYID & A. LELO
Ó 1999 Blackwell Science Ltd, Aliment Pharmacol Ther 13, 245±249
gall-bladder contraction. This was indicated by the
percentage of gall-bladder volume reduction, i.e.
11.8 � 6.9, 16.8 � 7.4, 22.0 � 8.5 and 29.3 � 8.3%,
respectively (P < 0.01). On the other hand, after
placebo administration the percentage reduction in
gall-bladder volume was only notable 0.5 h after
administration, by 10.9 � 22.8% and then after 1.0 h
placebo administration there was a negative gall-
bladder contraction, i.e. by ) 10.1 � 16.0% at 1.5 h
and ) 18.2 � 17.2% at 2.0 h (Table 2).
During the study period and on the following day no
side-effects were reported by the subjects.
DISCUSSION
The fasting gall-bladder volume (�15 mL) demonstrat-
ed in the present study falls within the range of values
reported by Donald et al. (0.98±27.18 mL).13
This double-blind, placebo-controlled crossover study
showed that a single oral dose of 20 mg curcumin
stimulates the contraction of the human gall-bladder.
Gall-bladder volume was reduced in the period following
curcumin administration, and the opposite took place in
the placebo group (Figure 1). With the exception of two
cases, half an hour after the placebo and curcumin
administrations, after every meals ingestion,14 there
was a reduction in gall-bladder volume. Due to the
physiological effect of re®lling, 1 h after placebo admin-
istration there was a tendency for the gall-bladder
volume to increase which was larger than the fasting
gall-bladder volume (baseline). On the other hand there
was a steady decrease in gall-bladder volume over time
following the administration of curcumin. There was
therefore a signi®cant difference (P < 0.05) in gall-
bladder volume between the curcumin and placebo
groups from 0.5 h after drug administration (Table 1).
Correspondingly, 0.5, 1.0, 1.5 and 2.0 h after 20 mg
curcumin administration there was marked increase in
gall-bladder contraction. This was seen in the percent-
age gall-bladder volume reduction: 11.77 � 6.93%,
16.75 � 7.42%, 22.04 � 8.54% and 29.32 � 8.26%,
respectively (P < 0.01). On the other hand, after placebo
administration, the percentage reduction in gall-bladder
volume was only notable at 0.5 h administration.
Table 1. Gall-bladder volume after placebo and 20 mg curcumin administration
Gall-bladder volume (ml) at the time (h) point
Group 0.0 0.5 1.0 1.5 2.0
Placebo 15.98 � 4.08 14.25 � 5.87 15.68 � 3.89 17.41 � 3.96 19.02 � 5.78
Curcumin 15.74 � 4.92 13.76 � 3.27 12.93 � 2.99 12.08 � 2.70 10.93 � 2.34
P 0.4012 0.4429 0.0321 < 0.001 < 0.001
Figure 1. Individual gall-bladder volumes
(n � 12) in response to placebo and 20 mg
curcumin administered as a single oral
dose.
CURCUMIN AND GALL-BLADDER FUNCTION 247
Ó 1999 Blackwell Science Ltd, Aliment Pharmacol Ther 13, 245±249
At 1.0 h after placebo administration there was a
negative gall-bladder contraction (Table 2).
In order to con®rm the bene®t of the substance in
diminishing the risk of developing gall-bladder stones,
Kakkos et al. found that erythromycin (7 mg/kg body
weight, i.v.) induced a biphasic gall-bladder contraction,
with maximum contractility at 15 min (10.2%) and
between 120 and 180 min (22.6%).4 While after oral
administration, erythromycin also induces the contrac-
tion of gall-bladder by 21%, but there is no further
signi®cant increase after prolonged oral administra-
tion.5 The maximal contraction effect from high risk
intravenous erythromycin (22.6%) at 2.0 h after ad-
ministration does not seem much different from that of
20 mg curcumin (29.32%), as was demonstrated in this
study (Table 2). This result indicates that curcumin
might be useful in preventing gall-bladder stone forma-
tion.
Froehlich et al. demonstrated that a 25 g pure fat meal
caused maximal (85% of the fasting volume at 75 min)
gall-bladder contraction, which was more pronounced
than after the ingestion of a mixed meal containing 8 g
fat (less than 50% of the fasting volume at 45 min).
This group then suggested that a minimal dietary fat
intake of 10±25 g per meal is necessary to prevent an
under-stimulation of the gall-bladder and thus to
diminish the risk of developing gall-bladder stones.6
Their next study illustrated that isocaloric test meals,
i.e. those of a mixed nature containing fat (8 g fat, 10 g
protein, 32 g dextrose) and those that were fat-free
(25 g albumin, 32 g dextrose), produced a similar effect
on gall-bladder contraction.7 Perreard et al. showed
that a low-fat, low-protein diet decreases gall-bladder
emptying.14
Zoli et al. demonstrated that gall-bladder emptying
depended on both the amount and the rate of amino
acid infusion. They then suggested that the intermittent
rapid infusion of small amounts of amino acids may
prevent gallstones in patients receiving intravenous
nutrition.8 Considering the data presented by Froehlich
et al.6, 7 and Zoli et al.,8 it appears that carbohydrate
does not stimulate gall-bladder contraction as has been
demonstrated in the present study (Figure 1), and it is
therefore quite reasonable to use amylum as a placebo
in this type of study.
Although curcumin (1,7-bis(4-hydroxy-3-methoxy-
phenyl)-1,6-heptadiene-3,5-dione), erythromycin with
a macrolide ring, fatty meals or amino acids could be
used as substances in preventing the development of
gall-bladder stones, it seems that the effect of these
drugs on the gall-bladder have no structure-activity
relationships. However, it is known that consuming a
lot of fat will enhance nausea, and erythromycin in
doses which are of antimicrobial bene®t will produce
gastrointestinal side-effects. In Indonesia, the medicinal
plant which contains curcumin has been traditionally
used as cholagogum.2
In this study we used a dosage of curcumin which was
similar to that employed in the study of Pangestu Adi
et al. (25 mg curcumin extracted from the crude of
Curcuma xanthorriza Roxb.;9) and Hadi (20 mg curcum-
in extracted from the crude of Curcuma domestica
Val.;10). They found that 20 mg curcumin administered
three times a day for 1 week produced a positive clinical
effect on acute and chronic hepatitis as was noted from
the decrease in serum transaminases and improvements
in clinical symptoms. It is known that the curcuminoid
available from Curcuma xanthorriza Roxb. (3%) is
relatively smaller than in the Curcuma domestica Val.
(10%),2 which is commonly consumed in our daily
meals.
It is worth noting that no side-effects from the
curcumin were reported by the subjects. This is in good
agreement with the work of Thamlikitkul et al. This
Thai study group treated dyspeptic patients with two
capsules of 250 mg Curcuma domestica Val. four times a
day for 7 days. The dose used in their study was
therefore �50 mg curcumin four times a day. Further-
more, they also mentioned that acute and subacute
toxicity tests of Curcuma domestica Val. carried out by
Table 2. The gallbladder volume changes (%) after placebo and 20 mg curcumin administration
Time (hours)
Group 0.5 1.0 1.5 2.0
Placebo 10.86 � 22.81 0.49 � 17.15 )10.12 � 16.04 )18.15 � 17.22
Curcumin 11.77 � 6.93 16.75 � 7.42 22.04 � 8.54 29.32 � 8.26
P 0.4480 < 0.001 < 0.001 < 0.001
248 A. RASYID & A. LELO
Ó 1999 Blackwell Science Ltd, Aliment Pharmacol Ther 13, 245±249
the Division of Medical Research, National Institute of
Health, Thailand, showed no toxicity.15
Unfortunately, due to the single oral dose of 20 mg
curcumin we employed, we could only reduce the gall-
bladder volume by � 25%, and we will need to perform
further dose±response studies in order to determine the
optimal dose of curcumin which is able to induce an
approximately 50% contraction of the human gall-
bladder.
REFERENCES
1 Agoes A, Munaf S, Lailani Ghanie A, Aziz S. Kebiasaan mi-
num jamu dan hubungannya dengan berat lahir. Maj Obstet
Ginek Indon 1979; 5(2): 94±104. [Jamu drinking habit and
its relation to birth body weight. Indonesian Journal of Ob-
stetric and Gynecology].
2 Sidik. Tumbuh-tumbuhan yang berkhasiat sebagai he-
patoprotektor. Simposium hepatitis, penanggulangan dan
pemanfaatan tumbuhan obat sebagai hepatoprotektor.
[Plants with hepatoprotective effect. Symposium Hepatitis and
Usage of Medicinal Plant as Hepatoprotector] Bandung, 22
October 1988.
3 Ammon HPT, Wahl MA. Pharmacology of Curcuma longa.
Planta Med 1991; 57: 1±7.
4 Kakkos SK, Yarmenitis SD, Kalfarentzos F. Gallbladder con-
traction induced by intravenous erythromycin administra-
tion. Relation to body mass index. Hepato-Gastroenterology
1996; 43: 1540±3.
5 Catnach SM, Fairclough PD, Trembath RC, et al. Effect of oral
erythromycin on gallbladder motility in normal subjects with
gallstones. Gastroenterology 1992; 102: 2071±6.
6 Froehlich F, Gonvers JJ, Fried M. Role of nutrient fat and
cholecystokinin in regulation of gallbladder emptying in man.
Dig Dis Sci 1995; 40(3): 529±33.
7 Froehlich F, Hartmann D, Guezelhan C, et al. In¯uence of
orlistat on the regulation of gallbladder contraction in man. A
randomized double-blind placebo-controlled crossover study.
Dig Dis Sci 1996; 41: 2404±8.
8 Zoli G, Ballinger A, Healy J, et al. Promotion of gallbladder
emptying by intravenous aminoacids. Lancet 1993; 341:
1240±1.
9 Adi P, Soemarto R, Djatmiko W, et al. Temulawak pada
penyakit hati kronik. Simposium Curcuma. Alternatif pen-
gobatan penyakit hati [Curcuma xanthorriza in chronic liver
diseases. Symposium of Curcuma. An alternative treatment of
liver diseases] Surabaya, 13 January 1996.
10 Hadi S. Khasiat ®tofarmaka pada hepatitis. Simposium hepa-
titis. [The effect of phytopharmacy on hepatitis. Symposium of
Hepatitis] Yogyakarta, 2 March 1996.
11 Schedermaier P, Neubrand M, Hansen S, Sanerboruch T.
Variability of gallbladder emptying after oral stimulation.
Scand J Gastroenterology 1997; 32: 719±24.
12 Sharma MP, Saraya A, Anand AC, Karmakar MG. Gallbladder
dysmotility in diabetes mellitus. An ultrasound study. Trop
Gastroenterol 1995; 16(3): 13±18.
13 Donald JJ, Fache SJ, Buckley RA, Burhenne JH. Gallbladder
contractility: variation in normal subjects. Am J Radiol 1991;
157: 753±6.
14 Perreard M, Iconomidis N, Bernard C, et al. In¯uence of a
hypolipidic diet on gallbaldder emptying. Gastroenterol Clin
Biol 1993; 17: 435±40.
15 Thamlikitkul V, Dechatiwongse T, Chantrakul C, et al. Ran-
domized double blind study of Curcuma domestica Val. for
dyspepsia. J Med Assoc Thai 1989; 72(11): 613±19.
CURCUMIN AND GALL-BLADDER FUNCTION 249
Ó 1999 Blackwell Science Ltd, Aliment Pharmacol Ther 13, 245±249