Nagata et al. BMC Complementary and Alternative Medicine (2016) 16:207
DOI 10.1186/s12906-016-1182-1

RESEARCH ARTICLE

Open AccessTotal dosage of gardenia fruit used bypatients with mesenteric phlebosclerosis
Yutaka Nagata1,2*, Tetsuo Watanabe3, Kazuhiko Nagasaka1,2, Masaaki Yamada4, Masafumi Murai5,6, Sunao Takeuchi7,
Mai Murase7, Toshinori Yazaki7, Takayuki Murase7, Kenichi Komatsu8, Machiko Kaizuka8, Mika Sano9, Koji Asano10,
Chikao Ando2 and Norihide Taniuchi7

Abstract
Background: Mesenteric phlebosclerosis (MP) is a disease characterized by fibrotic change or calcification of themesenteric vein. Recently, there has been an increase in case reports of MP related to herbal medicine usage.
Long-term intake of gardenia fruit (GF) is suspected as a possible cause. However, many GF users do not develop
this disease and the association between GF and MP remains unclear. In this study, we investigated for the firsttime the dosage of GF used by patients with and without MP.
Methods: We used a medical chart review study design to assess the association between GF and MP. We
reviewed patients with a history of intake of herbal medicines containing GF. Among these patients, we selectedpatients who were examined by colonoscopy and abdominal plain computed tomography (CT). We investigated
the findings of colonoscopy, CT scan and histological examination. We assessed the total dosages of GF alongside
the duration of ambulatory visit, the administration period of herbal medicine containing GF and pre-existing
disease in order to compare MP cases and non-MP patients.
Results: Ten MP cases and 42 non-MP patients were analyzed. We summarized clinical findings of MP cases. All
MP cases used more GF than non-MP patients and were administered more than approximately 5,000 grams of
GF in cumulative dosage.
Conclusions: This study indicated that excessive intake of GF contributes to and/or accelerates the developmentof MP suggesting that long-term usage of GF in excessive amounts increases the risk of MP.
Keywords: Gardenia fruit, Herbal medicine, Kampo, Mesenteric phlebosclerosis, Sanshishi

Background
Mesenteric phlebosclerosis (MP) is a relatively new
disease entity [1] and is also known as phlebosclerotic
colitis [2–15]. Recently, it has been termed ‘idiopathic’mesenteric phlebosclerosis [16–22], because its etiology
remains unclear. In typical MP cases, abdominal X-rays
and computed tomography (CT) scans demonstratespotted or linear calcification around the right hemicolon [2, 8]. The bronze coloration of colonic membrane
is characteristic findings of this disease. In advanced
MP cases, edema, ulceration, rigidity and stenosis on* Correspondence: ynagata@suwachuo.jp
1
Department of Oriental Traditional Medical Center, Suwa Central Hospital,
4300 Tamagawa, Chino, Nagano 391-8503, Japan
2
River Side Clinic, Chino, Nagano, Japan
Full list of author information is available at the end of the article

endoscopic examination are also observed [1]. Several
cases have been reported as chronic ischemic colitis[23, 24] and chronic ischemic lesions [25–28].
Previously published cases indicated an association
with several conditions such as portal hypertension as aresult of liver dysfunction [3, 4, 13], blood coagulation
disorders [24], CREST syndrome [29], dialysis [15],vasculitis [6], diabetes mellitus [30, 31], hyperlipidemia[30] and hypertension [31] related to MP. Recently, thenumber of case reports of MP with a history of intake ofherbal medicine has increased [9, 16–18, 32–34]. In
particular, gardenia fruit (GF), ‘Sanshishi’ in Japanese, isattracting attention as a possible cause [33, 34]. Almost
all of the reported herbal medicine-related MP cases
took GF over a long period of time [33, 34]. As such,© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Nagata et al. BMC Complementary and Alternative Medicine (2016) 16:207

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some are of the opinion that it is desirable to avoid
long-term usage of medicines containing GF [9, 33].
It is also the case, however, that there were several patients that had taken GF for a longer period of time thanMP cases in our experience [34]. There has not been
sufficient data to assess this discrepancy. In this study,
we first reviewed the dosages of GF in patients with orwithout MP.
The aim of this study was to review the dosage of GF
used by patients with and without MP, and to resolve
above-mentioned discrepant issue.

Table 1 Medical-grade extract preparations of Kampo formulas
containing gardenia fruit
Kampo formula GF (g/day) Corporations manufacturing and marketing
Bofutsushosan

1.2 gHon, JPS, Kot, Kra, Mat, Osu,
San, Tai, Toy, Tsu

Gorinsan2.0 gToy, Tsu

Inchinkoto

3.0 g

Kot, Kra, Osu, Toy, Tsu

2.0 g

Tei

Kamikihito

2.0 g

Kra, Osu, Tai, Toy, Tsu.

Kamisyoyosan

2.0 g

Hon, Jun, JPS, Kot, Kra, Mat, Osu,
San, Tai, Tei, Toy, Tsu

Methods

Keigairengyoto

1.5 gOsu, Tai, Tei, Tsu

Patients

Orengedokuto

2.0 g

Hon, Jun, JPS, Kot, Kra, Osu, Sak,
San, Tai, Tei, Toa, Toy, Tsu

Ryutansyakanto

1.5 gKot, Tai

1.0 g

San, Tsu

1.5 g

Kot, Tei, Tsu

We reviewed ambulatory patients with a history of Kampo
treatment from December 1, 2013 to May 25, 2015.
Among the patients that reported usage of herbal
medicines containing GF, we selected patients who were
examined by colonoscopy and abdominal plain CT. We
reviewed the findings of these clinical examinations
performed from June 4, 2010 to May 25, 2015. A series of
examinations were performed at the following facilities:
Suwa Central Hospital, River Side Clinic and Shinsapporo
Keiaikai Hospital.
Herbal medicines containing gardenia fruit

We used two dosage forms of Kampo preparations,
namely extract preparations and traditional decocted
herbal medicines. Medical-grade extract preparations of
Kampo formulas containing GF as one of the ingredientsused in Japan are listed in Table 1.
Colonoscopy and CT scan

Upon receipt of patient consent, colonoscopy and CT
scan were performed to screen for MP and otherdiseases. We considered the diagnosis of MP from thefindings of these clinical examinations and histologicalinspection [34]. Thickening of the affected colonic wallwith calcification and associated calcification of themesenteric vein and its tributaries on CT scan confirmed
the presence of MP [2, 7]. We regarded the following
findings as valuable changes at the early stage: slight
calcification of the right hemicolon, increase in CT
values in surrounding adipose tissue [4] and mild dilatation of the ileocecal vein.
Histological inspection

A diagnosis of MP was confirmed with histologicalinspection. Fibrotic deposition observed in the pericapillary region of the lamina propria [1] was the diagnostic
criteria used in our hospital in this study. The specimens
for examination were collected by colonoscopic biopsy.
We used an excision sample of a colectomy in a patientundergoing an emergency operation. The biopsy was

Saikoseikanto
Seihaito

2.0 g

Tsu

Seijobofuto

2.5 gTsu, Osu

Shin’iseihaito

3.0 g

Kot, Tsu, Osu

1.5 g

Kra

Shishihakuhito

3.0 g

Kot

Unseiin

1.5 gKra, Osu, Tei

2.0 gToy, Tsu, Hon, Jun, Kot

GF gardenia fruit, Hon Honzo, Jun Junko, Kot Kotaro, Kra Kracie, Mat Matsuura,
Osu Osugi, Sak Sakamoto, San Sanwa, Tai Taikodo, Tei Teikoku, Toa Toayakuhin,
Toy Toyoyakko, Tsu Tsumura

performed in a case in which the color change of thecolonic membrane was suspected. The biopsy specimens were collected from a location with a mild blue
coloration or a characteristic bronze color change. We
evaluated the degree of fibrillization and associatedreduction of ductal cell density in the lamina propria(Additional file 1: Table S1) [34].
Medication history and total dosages of gardenia fruit

We reviewed the medication history of various kinds ofherbal medicine containing GF. Moreover, we investigated the administration period of these medicines andthe duration of ambulatory visit from clinical records.
We excluded patients from this study who obtained
GF-containing drugs from other facility. All patients
started taking of GF at our facilities.
This allowed for investigation of duration from the
beginning to the end of use for herbal medicines containing GF. We reviewed clinical records that recorded
from January 23, 1997 to May 25, 2015.
We also calculated cumulative GF dosage, which ispresented in Table 1. Various dosages of GF are consumed depending on the manufacturing of each drug.
Mixtures of GF and other crude drugs are extracted with

Nagata et al. BMC Complementary and Alternative Medicine (2016) 16:207

water for manufacturing a freeze-dried extract preparation. Concretely, only with the Bofutsushosan extract
does, the dosage of GF vary from 0.4 g in a single
administration (2.5 g/one packet) to 1.2 g in a daily dose
(7.5 g/3 packets). In addition, we used traditional medicines, decocted with a mixture of crude drugs and water.
The quantities of one-time dosages of GF in decocted
traditional medicines were 1–3 g. We calculated thecumulative dosage of GF administered to each patientfrom such data.
Pre-existing diseases

We also investigated pre-existing diseases. The diagnostic criteria for pre-existing diseases were as follows:[elevated triglyceride (TG)]: TG ≥ 150 mg/dL or taking
therapeutic drug for a hypertriglyceridemia, [elevatedlow-density lipoprotein cholesterol (LDL-c)]: LDL-c ≥140 mg/dL or taking a therapeutic drug for hypercholesterolemia, [hypertension (HT)]: systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥ 85 mmHg
or taking an antihypertensive drug, and [diabetes mellitus (DM)]: fasting plasma glucose ≥ 110 mg/dL or HbA1c(NGSP) ≥ 6.5 % [35] or taking an oral hypoglycemic
agent. These criteria were in agreement with criteria
proposed by the Examination Committee for Metabolic
Syndrome in Japan [36].
Comparison between MP cases and non-MP patients

We assessed the duration of ambulatory visit, the administration period of herbal medicine containing GF,
cumulative GF dosage and pre-existing disease in order
to compare MP cases and non-MP patients.
Statistical analysis

Statistical analysis was performed with JMP 9 (SAS Institute Japan, Tokyo). Data were expressed as mean ±S.D.. Either a Student t test, Fisher’s exact test or
Mann–Whitney U test were used for statistical analysis
of patient characteristics. A value of P < 0.05 was considered statistically significant.

Results
Reviewed patients

We reviewed 1,927 patients with a history of Kampo
treatment from December 1, 2013 to May 25, 2015.
Two-hundred and forty-nine patients took herbal
medicines containing GF.
MP cases of enrolled patients

This study enrolled 52 patients that had used GFcontaining herbal medicines and received colonoscopy
and/or CT scan. We found 10 MP cases in total at three
institutions (Table 2); 5 were male, and 5 were female.
The mean age at the time of diagnosis of MP cases wasPage 3 of 11

66.1 years (range: 49 to 76 years old). All MP cases werediagnosed by histological inspection with colonic biopsy
specimen or excision sample from an operation. One
case (No. 3) developed into acute abdomen and wasgiven a diagnosis of MP during emergency surgery. Twocases (No. 1, 10) were accidently found in CT. The othertwo cases were accidentally (No. 6, 8) pointed out incolonoscopy. The other five cases were diagnosed by ascreening examination for MP as we actively searched
for undiagnosed cases of MP actively with colonoscopy
and CT scan.
We scrutinized the endoscopic findings of 9 MP cases
receiving colonoscopy. Typical bronze coloration wasobserved in 5 of 9 MP cases. Four cases remained a mildor dark blue coloration on colonoscopy.
Concerning the findings of CT scan, thickening of
the affected colonic wall with calcification was observed in
5 of 9 MP cases who had a CT scan. Linear calcification of
the mesenteric vein and its tributaries on CT scan wasobserved in 7 of 9 cases. Typical CT images were observedwith a MP case (No. 2 of Table 2) (Fig. 1). Two cases
continued to have slight calcification. Mild vasodilation of
the ileocecal vein was observed in 1 of 9 cases.
The maximum dose of the MP cases was 15,792 g(No. 1 of Table 2). Colonoscopy showed typical bronze
mucosa extending from the cecum to the transverse
colon. Moreover, redness and erosion of the colonicmembrane were observed in the cecum and the ascending colon (Fig. 2a, b). There was no color change in thedescending colon (Fig. 2c). Severe wall thickening andtypical linear calcification were observed on CT scan(Fig. 2d). The histological findings of moderate fibrotic
lesions in pericapillary region of the lamina propria wereobserved (Fig. 3). Fibrillization was associated with areduction of ductal cell density in part of the specimen.
Pre-existing disease

All MP cases had pre-existing disease (Table 2). Six MP
cases had hypertension, and LDL-c was elevated in sevenMP cases. There was no significant difference in eachfactor between MP cases and non-MP patients in thisstudy (Table 3). Of 10 cases with MP, only one femalecase had liver disease. Although her dosage of GF was
minimal in MP cases, typical linear calcification and wall
thickening was observed.
GF administration period

The average administration period was 11.1 years (range:
4.0 to 15.9 years) in MP cases (Table 3). We also investigated the relation of the administration period of GF
for MP cases and non-MP patients. Regarding this point,
GF was administered in several non-MP patients longer
than the shortest administration period of MP cases(Fig. 4). However, there were significant differences inNagata et al. BMC Complementary and Alternative Medicine (2016) 16:207

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Table 2 Characteristics and clinical findings of 10 MP cases
No. Age Sex

Chief complaint/
MP symptom

Kampo formulas containing
GF/Clinical findings

GF intake cumulative dosage
Administration period

Pre-existing
disease

1. 76 M

Chief complaint Hypertension

Orengedokuto

15,792 g
14.1 years

DM, HT, LDL-c

MP symptom none

Clinical findings (location)
Colonoscopy: Bronze coloration (C to T) Redness and Erosion (C to A)
Histology: Moderate fibrillization
CT scan: Linear calcification (C to T) Wall thickening (C to A)

Chief complaint Hypertension

Orengedokuto,
Orengedokuto,
Ryutansyakanto

MP symptom none

Clinical findings (location)
Colonoscopy: Bronze coloration (C to T)
Histology: Severe fibrillization
CT scan: Linear calcification (C to T) Wall thickening (C to A)

Chief complaint Hypertension

Orengedokuto, Kamisyoyosan,
Ryutansyakanto, Seihaito

MP symptom Ileus(Colectomy)

Clinical findings (location)
Histology: Fibrillization of the colonic mucosa and the mesentericvein in excision sample
CT scan: Linear calcification (C to T) Wall thickening (C to A)

Chief complaint
Skin itching

Unseiin, Kamisyoyosan,
Keigairengyoto, Orengedokuto

MP symptom none

Clinical findings (location)
Colonoscopy: Mild blue coloration (C to A)
Decreased transparency of blood vessels (C to A)
Histology: Mild fibrillization
CT scan: Slight calcification, CT value increase, Mild vasodilation (the ileocecal vein)

Chief complaint
Cutaneous pruritus

UnseiinMP symptom Constipation
Abdominal pain

Clinical findings (location)
Colonoscopy: Dark blue coloration (C to T) Redness and Erosion (C to A)
Histology: Severe fibrillization
CT scan: Linear calcification (C to T) Wall thickening (C to T)

Chief complaint Dermatitis
and Obesity

Bofutsusyosan, Unseiin,
Keigairengyoto, Orengedokuto

MP symptom none

Clinical findings (location)
Colonoscopy: Edematous membrane and Bronze coloration (C to A)
Histology: Concentric fibrillization surrounding capillary vessel

Chief complaint
Cutaneous pruritus

UnseiinMP symptom none

Clinical findings (location)
Colonoscopy: Bronze coloration (C to T)
Histology: Severe fibrillization
CT scan: Linear calcification (the ileocolic vein)

Chief complaint
Hot flush

Kamisyoyosan, Kamikihito,
Orengedokuto, Shin’iseihaito

MP symptom none

Clinical findings (location)
Colonoscopy: Bronze coloration (C to T)
Histology: Mild - Moderate fibrillization
CT scan: Slight calcification and CT value increase (C to A)

Chief complaint
Flushed face,
Feeling of cold

Kamisyoyosan

MP symptom none

Clinical findings (location)
Colonoscopy: Mild blue coloration (C to T)
Histology: Mild - Moderate fibrillization
CT scan: Linear calcification (C to A)

2. 76 M

3. 70 M

4. 49 F5. 75 M

6. 58 F7. 68 M

8. 58 F9. 64 F

14,683 g
15.9 years

8,119 g11.9 years

7,972 g12.2 years

6,579 g
6.8 years

6,499 g13.5 years

6,372 g12.2 years

5,588 g
4.0 years

5,408 g11.4 years

HT, LDL-c

DM, HT, TG

LDL-c

HT

LDL-c

DM, HT, LDL-c, TG

LDL-c, TG

HT, LDL-c, TG

Nagata et al. BMC Complementary and Alternative Medicine (2016) 16:207

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Table 2 Characteristics and clinical findings of 10 MP cases (Continued)
10. 67 F

Chief complaint
Hepatitis

Orengedokuto

5,379 g
9.4 years

MP symptom none

Clinical findings (location)
Colonoscopy: Mild blue coloration (C to T)
Histology: Mild - Moderate fibrillization
CT scan: Linear calcification (C to T) Wall thickening (C to A)

Liver disease

CT computed tomography, GF gardenia fruit, MP mesenteric phlebosclerosis, DM diabetes mellitus, HT hypertension, LDL-c elevated low-density lipoprotein cholesterol, TG elevated triglyceride, C the caecum, A the ascending colon, T the transverse colon, Oblique type medicines, traditional decocted herbal medicines

the duration of ambulatory visit and GF administration
period between MP cases and non-MP patients (Table 3).

Cumulative dosage of gardenia fruit

We investigated the cumulative dosages of GF in all 52
patients, including the 10 MP cases (Fig. 5). The tencases with a definitive diagnosis of MP had all used
more GF than non-MP patients. There was a remarkably
significant difference between MP cases and non-MP
patients in cumulative GF dose (Table 3).
The minimum dosage of GF was 5,379 g in MP cases.
The maximum dose of GF administered to non-MP
patients was 4,542 g. There was a constant distinction in
GF dosage for MP diagnosed cases and non-diagnosed
patients (Fig. 5).

aRelationship between GF administration period
and GF dose

We presented a relation between GF administration
period and cumulative dosages of GF in each patient inall 52 subjects in Fig. 6. Although there were several
non-MP patients that had taken GF for a longer periodof time than MP cases, all non-MP patients used less GF
than all MP cases.

Discussion
In this study, we reviewed 10 MP cases and 42 non-MP
patients. All MP cases had used more GF than non-MP
patients. Our results suggested that excessive intake of
GF contributes to and/or accelerates the development of
MP.

c

b

Fig. 1 Typical findings of CT scan in MP cases (No. 2 in Table 2). Typical calcification and wall thickening in the transverse colon (a) and theascending colon (b). Linear calcification in the transverse colon in coronal section (c). The blue colored arrows indicate the typical calcification.
The red colored arrows indicate the thickening in the colon. CT, computed tomography; MP, mesenteric phlebosclerosis

Nagata et al. BMC Complementary and Alternative Medicine (2016) 16:207

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a

b

c

d

Fig. 2 Clinical findings of colonoscopy and CT scan in MP cases (No. 1 in Table 2). Bronze coloration and redness in the ascending colon (a),bronze coloration in the hepatic flexure (b) and normal membrane in the descending colon (c) on colonoscopy. Linear calcification and wall
thickening in the ascending colon (d) on CT scan. CT, computed tomography; MP, mesenteric phlebosclerosis

a

b

c

d

Fig. 3 Histological findings in MP Case (No.1 in Table 2). Moderate pericapillary concentric fibrillization was noted in the specimens collected at
the ascending colon. The fibrillization was associated with a reduction of ductal cell density in part of specimen. [Haematoxylin and Eosin stain:
a x10 : c x20]. [Azan stain: b x10, d x20]. MP, mesenteric phlebosclerosis

Nagata et al. BMC Complementary and Alternative Medicine (2016) 16:207

Table 3 Comparison of non-MP patients with MP cases
non-MP(n = 42)MP (n = 10)

P valueAge (year)

58.2 ± 14.8

66.1 ± 9.1.1113a58.5 (16–86)

67.5 (49–77)

Sex (male/female)

11/31

5/5

.2509b

BMI (kg/m2)

22.5 ± 3.8

23.0 ± 2.3.7024a22.5 (16.0–31.4) 22.8 (19.5–27.7)
DM (yes/no)

5/37

3/7

.1710bHT (yes/no)

14/28

6/4

.1562b

LDL-c (yes/no)

19/23

7/3

.2913bTG (yes/no)

8/34

4/6

.2125bLiver disease (yes/no)

0/42

1/9

.1923b

6.8 ± 4.3

13.9 ± 3.0.0001c6.3 (1.5–17.9)

15.1 (6.5–16.3)

Herbal medicine treatment
Ambulatory visit (years)

GF administration period 4.2 ± 3.7(years)3.1 (0.2–14.8)
Cumulative dosage
of GF (g)11.1 ± 3.5
12.1 (1.5–15.9)

1319.7 ± 1077.7 8239.1 ± 3817.4
997.5(54.0–4542.0).0001c< .0001c

6539.0(5379.0–15792.0)

Data are expressed as mean ± S.D. and median (minimum - maximum)
MP mesenteric phlebosclerosis, BMI body mass index, DM diabetes mellitus,
HT hypertension, LDL-c elevated low-density lipoprotein cholesterol,
TG elevated triglyceride, GF gardenia fruitaComparison between non-MP group and MP group by Student’s t testbComparison between non-MP group and MP group by Fisher’s exact testcComparison between non-MP group and MP group by Mann-Whitney U-test

The essential pathology of “phlebosclerosis” has been
described as a fibrous degeneration of the intima and/or
media and adventitia with or without calcification [37].
Some pathogenic and etiological factors such as inflammation, thrombosis, mechanical stress and calcium deposition are mentioned, however, the role of these factors
have not been established.
Although the actual cause and pathogenesis of MP
remains largely unclear, GF has attracted attention as apossible cause of MP [9, 33]. Published reports provided
three viewpoints regarding the suspected association
between GF and MP: (1) most herbal medicine-related
MP cases took GF for a long time, (2) most MP cases
were reported from the Asia region where GF is commonly used, and (3) a favorite site of MP is the righthemicolon where the constituents of GF are largely
metabolized. Our results appear to support and rationalize these suggestions.
Firstly, GF has been reported as a common ingredientused in MP cases with a history of herbal treatment [33].
Similarly, all MP cases at our facilities had used GF andthere was no other common ingredient apart from GF inthese cases. The long period, spanning several years orPage 7 of 11

over a decade, suggested that such a large quantity of
GF can explain the long-term intake of GF in MP cases.
In previous research, the average length of herbal treatment leading to development of MP was reported as
13.6 years in the largest-scale study [38]. In this study, theaverage length of GF administration period was 11.1 years
in MP cases (Table 3). We paid particular attention toinitial changes such as a thickened colon and elevated CT
value on CT scans, and slight color change on colonoscopy. This might have allowed us to detect MP cases
earlier than other facilities.
Secondly, an association between GF and MP can be
explained by regional/cultural factors. It is characteristicthat almost all reported cases of MP were in individuals
from Asian countries such as Japan [1, 2, 4, 5, 7, 8, 16, 17],
Taiwan including Taiwanese residents in Canada [10, 12,
14, 18, 20, 39], Hong Kong [11, 40], Korea [13, 19, 41] andChina including a Chinese resident in the USA [15, 21, 22,32]. GF has long been used in eastern Asia as a crude drug
or coloring agent. GF is a one of the most useful herbal
medicines applied in Kampo treatment. Herbal medicines
containing GF are often necessary to improve a patient's
quality of life. They are useful for the relief of various
symptoms (Additional file 2: Table S2) and have been usedin the treatment of several pathological conditions [42–50].
In fact, symptoms of our MP cases were ameliorated byadministration of Kampo formulas containing GF. Therefore, patients wanted to receive these drugs. As such, Asianpeople have a high chance of taking more GF than residents of other regions.
Finally, a favorite site of MP is common to the section
where the constituents of GF are largely decomposed byintestinal bacteria. Previous reports supposed that certain
toxic biochemical agents or water-soluble irritants
absorbed from the ascending colon cause chronic damage[16, 18]. We also consider that sustained stimulation witha suitable dose of GF could form a MP lesion. The constituents of herbal medicine are orally administered andbrought into contact with enteric bacterium. They aremetabolized to be bioactive, ineffective, or toxic compounds before they are absorbed from the gastrointestinal
tract [51]. It is reported that intestinal bacteria play animportant role in the intestinal metabolism of GFcomponents [52, 53]. Because the distal ileum and colon
have bacteria in large quantities, the main area affected by
the metabolites passing through it might be at the rightside colon [54].
The metabolism of the main constituents of GF has
been previously studied [53, 55–57]. Metabolites from
GF include eight major bioactive constituents, including
geniposidic acid, chlorogenic acid, genipin-1-β-gentiobioside, geniposide, genipin, rutin, crocin-1 and crocin-2[57]. Among these constituents, geniposide has been suggested as a possible cause of MP [33]. Geniposide-inducedNagata et al. BMC Complementary and Alternative Medicine (2016) 16:207(year)

Page 8 of 11

GF administration period (years)

18.0
15.9

16.0

14.8

13.5

MP case

14.1
12.2

12.2

14.0

11.9

14.3

Non-MP

12.7

11.4

12.0

9.4

8.7
8.4

7.5

7.8

10.0

7.2

6.6
6.5
8.0

6.2

6.8

6.0
4.0
4.0
1.9
0.2

2.0

0.0
1 2 3 4 5 6 7 8 9 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

MP cases (Nos.1-10) and Non-MP patients (Nos.11-52)(n=52)

Fig. 4 GF administration period (years) in examined cases with or without MP (n = 52). There were several non-MP patients who exceeded MP
cases for duration of administration period of GF. They did not develop MP in spite of their long-term GF administration. GF, gardenia fruit;
MP, mesenteric phlebosclerosis(g)

Cumulative dosage of GF (g)18,00015792

16,00014683
8119

14,0007972
6579

12,000MP case6499

Non-MP

6372
5588

10,000
5408
5379

8,000

6,000

4,000

2,000

4542
3644
3532
2905
2605

2286
2162

1528

1376
973
738

590

54

0
1 2 3 4 5 6 7 8 9 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

MP cases (Nos.1-10) and Non-MP patients (Nos.11-52)(n=52)

Fig. 5 Cumulative GF dosage (g) in examined cases with or without MP (n = 52). The total dosages of GF consumed by MP cases were larger
than those in other 42 patients. The total amount of 5,379 - 15,792 g of GF was used in MP cases. The maximum dose of the non-MP patientswas 4,542 g. GF, gardenia fruit; MP, mesenteric phlebosclerosis

Nagata et al. BMC Complementary and Alternative Medicine (2016) 16:207

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Cumulative dosage of GF (g)18,00016,00015792
14683

MP case14,000Non-MP
12,00010,000
8119
7972

8,000

6372

6579

6,000

5588

6499
5379

5408
4542

4,000
2905
2,000
590

973

0
0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

16.0

18.0

GF administration period (years)
Fig. 6 Relation between GF administration period and cumulative dosages of GF (n = 52). There were several patients that had taken GF fora longer period of time than MP cases. All MP cases used more GF than non-MP patients. GF, gardenia fruit; MP, mesenteric phlebosclerosis

hepatotoxicity has been reported previously [58, 59]. The
hepatotoxicity of high doses of geniposide has also beenreported to be linked to oxidative stress [59]. Geniposide,a main iridoid glucoside component of GF, is converted toaglycone, genipin [55, 56]. When cross-linked with aminoacid, genipin can be observed as having a blue coloration[60]. This might relate to the blue-colored mucosa
observed in MP. Collectively, the ingredients of GF seemto have some kind of influence, but it is still unknown
how they specifically act on MP.
Until recently, it was not known that GF had thepotential to be harmful. It is now important, however, toconsider the possible development of MP. When MP
progresses without clinical checkup, mesenteric circulatory failure may induce severe constipation, ileus, bowel
dysfunction and ischemic colitis. Moreover, total or partial
colectomy has often been performed for such severe cases[3, 4, 6, 26, 28]. As such, due to various concerns in theliterature, calls for awareness and caution associated with
GF and MP have been raised. We are also cautious, however, about the possibility that excessive concern keeps
away a patient from effective treatment. Currently, without sufficient data, special attention should be given to
any lengthy period of GF use that spans over years.
Looking more carefully at longer periods of use, we confirmed in this study that several non-MP patients hadtaken GF for a longer period of time than MP cases. These
non-MP patients were administered GF intermittently

and/or at a low daily dose of GF. Therefore, if the cumulative dose of GF is kept to low levels, MP occurrence ordevelopment is likely to be avoided.
MP is sometimes missed or misdiagnosed due to alack of typical findings. However, we were able to detect
early MP with histological inspection in a colonic biopsy
specimen. If there are findings such as a mild blue
coloration of the colonic membrane, a biopsy should be
performed. However, it is difficult to diagnose MP in thisway since most patients do not wish to undergo a colonoscopy. In such cases, the overall cumulative dose of
GF might provide a criterion for determining whether or
not the patient has MP. Even if these examinations are
not performed, it is recommended that any patients withexcessive intake of GF should refrain from further use.
The most notable result of this study is an association
between GF intake and the emergence of MP. Our
results suggest that an excessive intake of GF, approximately 5,000 g in this study, contributes to and/or
accelerates the development of MP. The threshold may
increase or decrease with the contribution of several
other conditions. It is also necessary to consider etiologies of MP other than GF. We confirmed all MP cases
had pre-existing disease, but there was no significant
difference in each lifestyle disease between MP cases andnon-MP patients in this pilot study. However, we had an
impression that they were numerically different. The
non-significant results in this study could be because of

Nagata et al. BMC Complementary and Alternative Medicine (2016) 16:207

the small sample size, particularly in the MP group (n =10). The correlation between pre-existing disease andonset of MP can be validated in additional investigation
with larger patient population. Further verification of therelationship with other risk factors is needed. Although ourstudy suggested an association between MP development
and cumulative GF dose, we did not reach an identificationof the causal ingredient in GF. Thus, identifying the actual
toxic agent is our next task.
This study is the first report about the total GF cumulative dose with or without MP in patients confirmed tohave taken GF. Specifically, the cumulative dosage of GF
seems to be responsible for developing MP rather thanthe duration of its administration.
Limitations

We excluded patients who were already taking GF atanother medical facility prior to coming to our facilities
from the study. We also excluded patients who took
over-the-counter herbal preparations containing GF. If
this was not recorded in the medical charts, it could bepossible that some patients had obtained GF containing
medical-grade preparations from another medical facility
or GF-containing over-the-counter preparations from a
pharmacy. If such cases exist, then it is possible that thethreshold for cumulative GF dosage may be higher.

Conclusion
In this study, all MP cases used more GF than non-MP
patients. This result indicated that excessive intake of
GF contributes to and/or accelerates the development ofMP, suggesting that long-term usage of GF in excessive
amounts increases the risk of MP.
Abbreviations
CT, computed tomography; DM, diabetes mellitus; GF, gardenia fruit; HT,
hypertension; LDL-c, low-density lipoprotein cholesterol; MP, Mesentericphlebosclerosis; TG, triglycerideAcknowledgements
The authors thank Dr. Go Suzuki for providing clinical information. Dr.
Nobuko Nakagawa got the consent from patients as attending physician
in clinical practice. Dr. Aritaka Matsuyama and Minoru Saito conducted thecolonoscopy. Dr. Yasuyuki Takamizawa and Makoto Araki supervised theresearch.
Funding source
No fund was provided by any funding agency for this study.
Availability of data and materials
The data and materials supporting the conclusions of this article arepresented in this main paper.
Authors’ contributions
YN designed the research. YN and TW wrote the manuscript. YN and MY
analyzed the data. YN, TW, KN, M.Murai, ST, M.Murase, TY, TM, KK, MK, CA
and NT performed the research. MS evaluated radiological findings. KA
evaluated pathological findings. KN, CA, and NT supervised. YN and TW
contributed equally. All authors approved the submission of the final version.

Page 10 of 11

Competing interests
The authors declare that they have no competing interest.
Consent for publication
All authors consent to this manuscript’s publication.
Ethics approval and consent to participate
This study was approved by the Ethics Committee in Suwa Central Hospital.
Meticulous attention was taken to avoid specifying individual patients. The
study was done in accordance with the ethical standards of the Helsinki
Declaration of 1964 (as revised in 2013). We used a medical chart review
study design and we reviewed the findings of colonoscopy, CT scan andhistological examination. These examinations were performed upon receipt
of patient consent.
Author details
1
Department of Oriental Traditional Medical Center, Suwa Central Hospital,
4300 Tamagawa, Chino, Nagano 391-8503, Japan. 2River Side Clinic, Chino,
Nagano, Japan. 3Department of Japanese Oriental Medicine andRheumatology, Toyama Prefectural Central Hospital, Toyama, Toyama, Japan.
4
Department of Epidemiology and Health Policy, Graduate School of
Medicine and Pharmaceutical Sciences, University of Toyama, Toyama,
Toyama, Japan. 5Hokudaimae Clinic, Hokkaido Kampo Medical Center,
Sapporo, Hokkaido, Japan. 6Shinsapporo Keiaikai Hospital, Sapporo, Hokkaido,
Japan. 7Department of Internal medicine, Suwa Central Hospital, Chino,
Nagano, Japan. 8Department of Surgery, Suwa Central Hospital, Chino,
Nagano, Japan. 9Department of Radiology, Suwa Central Hospital, Chino,
Nagano, Japan. 10Department of Pathology, Suwa Central Hospital, Chino,
Nagano, Japan.
Received: 25 November 2015 Accepted: 29 June 2016

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