Total dosage of gardenia fruit used by patients with mesenteric phlebosclerosis

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 demonstrate spotted 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 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 a result 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, the number of case reports of MP with a history of intake of herbal medicine has increased [9, 16‐18, 32‐34]. In particular, gardenia fruit (GF), ‘Sanshishi’ in Japanese, is attracting 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, 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 than MP 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 or without 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.

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.

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 a possible 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 right hemicolon 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 ingredient used in MP cases with a history of herbal treatment [33]. Similarly, all MP cases at our facilities had used GF and there was no other common ingredient apart from GF in these cases. The long period, spanning several years or 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, the average length of GF administration period was 11.1 years in MP cases (Table 3). We paid particular attention to initial 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 characteristic that 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] and China 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 used in the treatment of several pathological conditions [42‐50]. In fact, symptoms of our MP cases were ameliorated by administration of Kampo formulas containing GF. Therefore, patients wanted to receive these drugs. As such, Asian people 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 by intestinal 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 with a suitable dose of GF could form a MP lesion. The constituents of herbal medicine are orally administered and brought into contact with enteric bacterium. They are metabolized to be bioactive, ineffective, or toxic compounds before they are absorbed from the gastrointestinal tract [51]. It is reported that intestinal bacteria play an important role in the intestinal metabolism of GF-components [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 right side 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 hepatotoxicity has been reported previously [58, 59]. The hepatotoxicity of high doses of geniposide has also been reported to be linked to oxidative stress [59]. Geniposide, a main iridoid glucoside component of GF, is converted to aglycone, genipin [55, 56]. When cross-linked with amino acid, 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 seem to 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 the potential to be harmful. It is now important, however, to consider 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 the literature, 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 had taken 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 or development is likely to be avoided.

MP is sometimes missed or misdiagnosed due to a lack 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 this way 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 with excessive 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 and non-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 the small sample size, particularly in the MP group (n = 10). The correlation between pre-existing disease and onset of MP can be validated in additional investigation with larger patient population. Further verification of the relationship with other risk factors is needed. Although our study suggested an association between MP development and cumulative GF dose, we did not reach an identification of 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 to have taken GF. Specifically, the cumulative dosage of GF seems to be responsible for developing MP rather than the duration of its administration.

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 of MP, suggesting that long-term usage of GF in excessive amounts increases the risk of MP.

CT, computed tomography; DM, diabetes mellitus; GF, gardenia fruit; HT, hypertension; LDL-c, low-density lipoprotein cholesterol; MP, Mesenteric phlebosclerosis; TG, triglyceride