Hepatitis Induced by Noni Juice from Morinda citrifolia: A Rare Cause of Hepatotoxicity or the Tip of the Iceberg?

Article (PDF Available)inDigestion 73(2-3):167-70 · February 2006with159 Reads
DOI: 10.1159/000094524 · Source: PubMed
Abstract
A 24-year-old female patient presented to her community hospital with mild elevations of serum transaminase and bilirubin levels. Because of multiple sclerosis, she was treated with interferon beta-1a for 6 weeks. After exclusion of viral hepatitis due to hepatitis A-E, interferon beta-1a was withdrawn under the suspicion of drug-induced hepatitis. One week later, she was admitted again to her community hospital with severe icterus. The transaminase and bilirubin levels were highly elevated, and a beginning impairment of the liver synthesis was expressed by a reduced prothrombin time. The confinement to our department occurred with a fulminant hepatitis and the suspicion of beginning acute liver failure. There was no evidence for hepatitis due to potentially hepatotoxic viruses, alcoholic hepatitis, Budd-Chiari syndrome, hemochromatosis, and Wilson's disease. In her serum there were high titers of liver-kidney microsomal type 1 autoantibody; the serum gamma globulin levels were in the normal range. Fine-needle aspiration biopsy of the liver ruled out an autoimmune hepatitis but showed signs of drug-induced toxicity. During the interview, she admitted that for 'general immune system stimulation' she had been drinking Noni juice, a Polynesian herbal remedy made from a tropical fruit (Morinda citrifolia), during the past 4 weeks. After cessation of the Noni juice ingestion, her transaminase levels normalized quickly and were in the normal range within 1 month.
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Case Report
Digestion 2006;73:167170
DOI: 10.1159/000094524
Hepatitis Induced by Noni Juice from
Morinda citrifolia : A Rare Cause of
Hepatotoxicity or the Tip of the Iceberg?
B. Yüce
a
V. Gülberg
a
J. Diebold
b
A.L. Gerbes
a
a
Department of Internal Medicine II and
b
Institute of Pathology, Ludwig Maximilians University of Munich,
Munich , Germany
that for ‘general immune system stimulation’ she had been
drinking Noni juice, a Polynesian herbal remedy made from
a tropical fruit (Morinda citrifolia) , during the past 4 weeks.
After cessation of the Noni juice ingestion, her transaminase
levels normalized quickly and were in the normal range
within 1 month. Copyright © 2006 S. Karger AG, Basel
Introduction
The use of complementary and alternative medicine,
in particular herbal products and dietary supplements, is
rapidly growing in Europe and in the United States [1]
.
Since such products are usually labeled as dietary supple-
ments, only minor requirements for consumer’s safety
are required before entering the market.
Noni juice, a dietary supplement, is an increasingly
popular herbal drink which is currently distributed by
several companies worldwide. One of those companies
has been noted as ‘one of the fastest-growing private com-
panies in America and less than ten private companies in
the history of the world were able to equal this company’s
first six years of growth’ [http://www.tahitiannoni.com/
united_states/english/public/company]. This suggests in-
creasing consumption of Noni juice in the near future.
Key Words
Herbal toxicity Acute hepatitis Complementary
medicine Dietary supplement
Abstract
A 24-year-old female patient presented to her community
hospital with mild elevations of serum transaminase and bil-
irubin levels. Because of multiple sclerosis, she was treated
with interferon beta-1a for 6 weeks. After exclusion of viral
hepatitis due to hepatitis A–E, interferon beta-1a was with-
drawn under the suspicion of drug-induced hepatitis. One
week later, she was admitted again to her community hospi-
tal with severe icterus. The transaminase and bilirubin levels
were highly elevated, and a beginning impairment of the
liver synthesis was expressed by a reduced prothrombin
time. The confinement to our department occurred with a
fulminant hepatitis and the suspicion of beginning acute liv-
er failure. There was no evidence for hepatitis due to poten-
tially hepatotoxic viruses, alcoholic hepatitis, Budd-Chiari
syndrome, hemochromatosis, and Wilson’s disease. In her
serum there were high titers of liver-kidney microsomal type
1 autoantibody; the serum gamma globulin levels were in
the normal range. Fine-needle aspiration biopsy of the liver
ruled out an autoimmune hepatitis but showed signs of
drug-induced toxicity. During the interview, she admitted
Published online: July 11, 2006
Veit Gülberg, MD
Department of Internal Medicine II, Ludwig Maximilians University of Munich
Marchioninistrasse 15
DE–81377 nchen (Germany)
Tel. +49 89 7095 0, Fax +49 89 7095 5284, E-Mail veit.guelberg@med.uni-muenchen.de
© 2006 S. Karger AG, Basel
00122823/06/0733–0167$23.50/0
Accessible online at:
www.karger.com/dig
ce /Gülberg /Diebold /Gerbes
Digestion 2006;73:167–170
168
The Noni fruit was introduced in the Pacific area near-
ly 2,000 years ago and is one of the most commonly used
and appreciated remedies in local traditional medicine
for a variety of disorders [2] . Apart from scanty preclini-
cal data, efficacy and safety of Noni juice were not vali-
dated in controlled clinical trials. Here, we report a pa-
tient presenting with subacute liver failure most likely
related to the ingestion of high amounts of Noni juice.
Case Report
A 24-year-old female patient presented to her community hos-
pital with jaundice. On admission the alanine aminotransferase
level was elevated to 1,538 U/l, that of bilirubin to 5.25 mg/100 ml,
and that of -glutamyltransferase to 110 U/l. After ruling out viral
hepatitis A–E by serological testing, there was a suspicion of drug-
induced hepatitis due to interferon beta-1a (IFN). The patient had
been treated with IFN for 10 weeks after the diagnosis of multiple
sclerosis had been established, following an episode of inflamma-
tion of the optic nerve. After 4 weeks of IFN therapy, a routine
laboratory examination revealed normal liver enzyme values.
Nevertheless, IFN was initially suspected of causing her hepatitis
and was, therefore, withdrawn.
One week after IFN withdrawal, the patient was examined
again, with a dramatic increase of her liver enzyme levels (biliru-
bin 43.5 mg/100 ml, aspartate aminotransferase 2,818 U/l, ala-
nine
aminotransferase 3,648 U/l). Thus, she was referred to our
tertiary liver unit with the diagnosis of subacute liver failure.
Physical examination revealed a patient with severe jaundice;
apart from this, the physical examination was inconspicuous. An
ultrasound scan of the liver ruled out intra- or extrahepatic bile
duct obstruction as well as vascular abnormalities or focal le-
sions.
We found no evidence for viral hepatitis A–E or other poten-
tially hepatotoxic viruses, alcoholic hepatitis, Budd-Chiari syn-
drome, hemochromatosis, or Wilson’s disease. The most remark-
able laboratory finding was an increased titer for liver-kidney
microsomal autoantibody type 1 (1:
3,840), with no other autoan-
tibodies detectable. However, liver biopsy did not reveal evidence
for an autoimmune disease. There were confluent necroses of
periportal and intralobular hepatocytes, lymphoplasmacellular
and neutrophil inflammation, canalicular cholestasis, and mod-
erate fibrosis ( fig. 1 ). This pattern was highly suspicious for drug-
induced hepatitis. Furthermore, the autoimmune hepatitis score
[3] including histology summed up to 5 points, rating the diagno-
sis of autoimmune hepatitis as unlikely.
At this point, we took an extended medical history and asked
the patient about any recent changes of her dietary habits in detail.
Now she reported that she had been drinking Noni juice for 4
weeks for ‘general immunostimulation’. We convinced the patient
to immediately stop the consumption of Noni juice. Thereafter,
the transaminase levels fell rapidly and were within the normal
range after 1 month ( fig. 2 ). In summary, we diagnosed a drug-
induced hepatitis due to ingestion of Noni juice.
Discussion
Hepatotoxicity due to herbal remedies is a rare, but
well-known adverse event [4] . Since most of these herbal
remedies are dietary supplements, only few requirements
are necessary to launch such products onto the market.
Scarcely a complete analysis of all ingredients is available,
and a definitive characterization of pharmacologically
active as well as toxic compounds is difficult or even im-
possible. Due to nonstandardized manufacturing proce-
dures and naturally occurring variability, the composi-
tion of compounds varies in most of the preparations.
These issues also apply to Noni juice. A number of com-
pounds was identified, two of them having the potential
for being hepatotoxic [2] , but a complete analysis is lack-
ing. The first group comprises the anthraquinones (like
nordamnacanthal, morindone, rubiadin, rubiadin-1-
methyl ether, anthraquinone glycoside) which are candi-
dates for having a dose-dependent hepatotoxicity. The
second group which was suspected also for having idio-
syncratic hepatotoxic potential are the coumarins, e.g.,
scopoletin [2] . Very recently, 3 cases of severe hepatitis
were reported demonstrating potential hepatotoxicity of
Noni juice [5, 6] ( table 1 ). Since there are millions of Noni
juice consumers, idiosyncratic hepatotoxicity seems more
likely to be the problem. Moreover, the high titers of au-
toantibodies of the liver-kidney microsomal type in our
patient may be a clue to this type of drug reaction, since
F i g . 1 . Representative liver biopsy specimen, revealing periportal
and intralobular hepatocyte necrosis, mixed inflammatory reac-
tion, and prominent canalicular cholestasis. HE. ! 400.
Hepatitis by Noni
Digestion 2006;73:167–170
169
autoantibodies were reported in hepatotoxicity induced
by other drugs [7] . We, therefore, conclude that in our
patient Noni juice induced an idiosyncratic hepatitis.
Interactions between other herbal products and syn-
thetic drugs are well known. For example, St. Johns wort
(Hypericum perforatum) interacts with numerous con-
ventional drugs, including ciclosporin, simvastatin, and
others [8] . Thus, it seems quite possible that Noni juice
worsened a preexisting liver damage due to IFN; hepato-
toxicity of IFN treatment has been reported before in a
patient with multiple sclerosis [9] . In another report [3] ,
a preexisting liver damage, possibly due to Chinese herb-
al mix and acetaminophen, was worsened after the inges-
tion of Noni juice. Thus, in addition to the potential of
damaging a healthy liver, synergistic mechanisms of hep-
atotoxicity due to Noni juice are likely.
40
30
20
10
4,000
3,000
2,000
1,000
U/l mg/100 ml
00
July August September Oktober
Interferon beta-1a
Nonijuice
Diagnosis of
multiple sclerosis
T a b l e 1 . Reports on the hepatotoxicity of Noni juice
Gender Age
years
Concomitant
medication
Amount of Noni Duration of
ingestion
Delay between
ingestion and
onset of symptoms
Laboratory values
(maximum noted)
Refer-
ence
Male 45 none 1 glass/day ‘few weeks’ ‘few weeks’ AST 604 U/l 6
ALT 1,995 U/l
GGT 539 U/l
bilirubin 0.82 mg/dl
Male 29 acetaminophen, 1.5 liters within
3 weeks prior to
admission
not stated not stated AST 1,557 U/l 5
Chinese herbal ALT 626 U/l
mix bilirubin 45.3 mg/dl
Female 62 none 2 liters 4 months 4 weeks AST 1,455 U/l 5
ALT 2,381 U/l
GGT 241 U/l
bilirubin 2.9 mg/dl
Female 24 interferon beta-1a 1–1.5 liters 4 weeks 3 weeks AST 2,818 U/l this
study
ALT 3,648 U/l
bilirubin 43.5 mg/100 ml
AST = Aspartate aminotransferase; ALT = alanine aminotransferase; GGT =
-glutamyltransferase.
F i g . 2 . Serum concentrations of alanine
aminotransferase (U/l; U ) and bilirubin
(mg/100 ml; f ) during and after cessation
of the IFN therapy and ingestion of Noni
juice.
ce /Gülberg /Diebold /Gerbes
Digestion 2006;73:167–170
170
In summary, the increasing popularity of Noni juice
adds another task to gastroenterologists and hepatolo-
gists: patients with unexplained elevation of liver enzyme
levels or liver failure should be questioned carefully about
the ingestion of Noni juice as well as other herbal reme-
dies, and patients with preexisting liver impairment
should be advised not to consume Noni juice. Quite like-
ly with a growing awareness, the number of patients with
diagnosed liver injury due to ingestion of Noni juice will
increase.
References
1 Stickel F, Patsenker E, Schuppan D: Herbal
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2 Wang MY, West BJ, Jensen CJ, Nowicki D, Su
C, Palu AK, Anderson G: Morinda citrifolia
(Noni): a literature review and recent ad-
vances in Noni research. Acta Pharmacol Sin
2002;
23: 1127–1141.
3 Alvarez F, Berg PA, Bianchi FB, et al: In-
ternational Autoimmune Hepatitis Group
Report: review of criteria for diagnosis of
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31:
929–938.
4 Pageaux GP, Larrey D: Alternative medicine,
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Kaplowitz N, DeLeve LD (eds): Drug-In-
duced Liver Disease. New York, Marcel
Dekker, 2003, pp 709–724.
5 Stadlbauer V, Fickert P, Lackner C, Schmer-
laib J, Krisper P, Trauner M, Stauber RE:
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7 Hinrichsen H, Lüttges J, Klöppel G, Fölsch
UR, Schmidt WE: Idiosyncratic drug aller-
gic phenprocoumon-induced hepatitis with
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as autoimmune hepatitis. Scand J Gastroen-
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comes. Mult Scler 2004;
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    • "Phenolic acids are consistently associated with reduced risk of cardiovascular disease, cancer and other chronic diseases by mechanismsrelated to the scavenging of free radicals and as prooxidant metals (antioxidant), although there are reports for toxic effects of compounds isolated from the fruit of M. citrifolia (Ee et al., 2009;Nualsanit et al., 2012;Aziz et al., 2014). Earlier reports indicated that fruits (Millonig et al., 2005;Stadlbauer et al., 2005;Yüceet al., 2006), leaves (West et al., 2006;Lopez-Cepero et al., 2007) and juice (Sivagnanam et al., 2011;Mrzljak et al., 2013) of M. citrifolia are hepatotoxic in humans, since preparations for them are rich inanthraquinones and coumarins (scopoletin) (Ee et al., 2009), they induce generation of free radicals derived from oxygen and trigger oxidative stress. Free radicals cause depletion of intracellular reduced glutathione and mitochondrial membrane potential, thus initiating lipid peroxidation and eventually, cell death (Su et al., 2005;Bussmann et al., 2013). "
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    • "The claimed hepatoprotective properties on noni juice however still remain speculative [6, 7]. Recently, seven cases of Morinda citrifolia-associated liver injury emerged in the literature, emphasizing its possible hepatotoxic effect [8 9 10 11 12 13]. "
    [Show abstract] [Hide abstract] ABSTRACT: Noni juice is a popular herbal dietary supplement globally used for preventive or therapeutic purposes in a variety of ailments, claiming to exhibit hepatoprotective properties as well. Herein we present the case of a 38-year-old woman who developed acute liver injury associated with noni juice consumption on a long-term (9 months) anticonvulsant therapy. Clinical presentation and liver biopsy were consistent with severe, predominantly hepatocellular type of injury. Both agents were stopped and corticosteroids were initiated. Five months later the patient had fully recovered. Although in the literature the hepatotoxicity of noni juice remains speculative, sporadic but emerging cases of noni juice-associated liver injury address the need to clarify and investigate potential harmful effects associated with this supplement.
    Full-text · Article · Jan 2013
    • "The possibility of TNJ-induced toxicity was assessed in aged mice consuming the equivalent of a recommended dose in women for most of their adult life. Serum levels of the hepatic enzymes, aspartate transferase (AST) and alanine transferase (ALT), were examined in the TNJ-treated mice, since these are considered markers of liver damage in humans and both were elevated in the case reports on hepatotoxicity with noni use [19–22, 36, 37]. In addition, serum blood urea nitrogen (BUN), a marker of renal function, was assessed. "
    [Show abstract] [Hide abstract] ABSTRACT: Morinda citrifolia (noni) is reported to have many beneficial properties, including on immune, inflammatory, quality of life, and cancer endpoints, but little is known about its ability to prevent or treat breast cancer. To test its anticancer potential, the effects of Tahitian Noni Juice (TNJ) on mammary carcinogenesis were examined in MMTV- neu transgenic mice. Mammary tumor latency, incidence, multiplicity, and metastatic incidence were unaffected by TNJ treatment, which suggests that it would not increase or decrease breast cancer risk in women taking TNJ for its other benefits. However, noni may be useful to enhance treatment responses in women with existing HER2/ neu breast cancer since TNJ resulted in significant reductions in tumor weight and volume and in longer tumor doubling times in mice. Remarkably, its ability to inhibit the growth of this aggressive form of cancer occurred with the mouse equivalent of a recommended dose for humans (
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