Abstract
HLA association with drug-induced liver injury has recently been pointed out about multiple medicines. The aim of this study was to evaluate relationship between HLA gene and liver injury related to Baikal skullcap-containing Kampo medicines (BSCK). We previously examined HLA genes in 3 cases of BSCK-induced liver injury. Recently we could encounter 2 cases diagnosed as “definitely-related case” of BSCK-induced liver injury. HLA genes of the 2 cases were analyzed by Sequencing Based Typing method with Next Generation Sequencer at HLA Laboratory in Kyoto. HLA-DPA1*02:02:02 and DPB1*05:01:01 were observed in the 2 cases: concordance was not observed in HLA-A, B, C, DRB1, DRB4, DQA1, or DQB1. The previous 3 cases of BSCK-induced liver injury had the same allele type to the 2 cases only in HLA-DPA1. Putting all these together, HLA-DPA1*02:02:02 was observed in common among 5 cases of BSCK-induced liver injury. HLA-DPA1*02:02:02 is possibly associated with BSCK-induced liver injury.
Keywords: Baikal skullcap, Drug-induced liver injury, HLA, Kampo medicine
Introduction
Baikal Skullcap (Scutellaria baicalensis) is a flowering perennial plant native to East Asia used as a component herb in Kampo medicine (Japanese herbal medicine). Baikal Skullcap contains large amounts of flavonoids, including baicalin, baicalein and wogonin, which are the active components accounting for its sedative and anti-inflammatory activity.
We previously reported that the incidence of liver injury related to Baikal skullcap is by far higher than that related to other herbs contained in Kampo medicines [1, 2]; however, the mechanism of skullcap hepatotoxicity is not known.
Several species of skullcap are used in many countries as herbal medicines or supplements. Prior case reports described hepatotoxicity related to herbal supplements that contained skullcap [3, 4]. Liver injury related to skullcap has been found worldwide.
Recently, HLA association with drug-induced liver injury or with drug eruption has been pointed out about multiple medicines [5]. We previously reported on possible relationship between HLA gene and liver injury related to Baikal skullcap-containing Kampo medicines (BSCK) [6].
The HLA haplotype in the previous-reported cases are shown in Table 1 (case1–3). In the 3 cases, same allele type was observed in HLA-DRB1, DRB4, DQA1, DQB1, and DPA1. We aimed to explore HLA association with BSCK hepatotoxicity in other cases.
Table 1.
HLA haplotype of previous 3 cases [6]
| HLA | DRB1 | DRB3/4/5 | DQA1 | |||
|---|---|---|---|---|---|---|
| Case 1 | 04:06:01a | 15:02:01 | 4*01:03:01a | 5*01:02 | 01:03:01 | 03:01:01a |
| Case 2 | 04:06:01a | 09:01:02 | 4*01:03:01a | 4*01:03:02 | 03:01:01a | 03:02 |
| Case 3 | 04:06:01a | 08:02:01 | 4*01:03:01a | 03:01:01a | ||
| HLA | DQB1 | DPA1 | DPB1 | |||
|---|---|---|---|---|---|---|
| Case 1 | 03:02:01a | 06:01:01 | 02:01:01 | 02:02:02a | 05:01:01 | 09:01:01 |
| Case 2 | 03:02:01a | 03:03:02 | 02:02:02a | 05:01:01 | ||
| Case 3 | 03:02:01a | 01:03:01 | 02:02:02a | 02:01:02 | 02:02:01 | |
aConcordant HLA in 3 cases
Subject and Methods
Recently we could examine HLA genes in two other cases of BSCK-induced liver injury. The liver injuries of them were diagnosed as “definitely-related case” because accidental re-administration of BSCK to them caused recurrence of liver injury.
In the 2 cases, HLA-A, B, C, DRB1, DRB3/4/5, DQA1, DQB1, DPA1 and DPB1 were analyzed by Sequencing Based Typing method with Next Generation Sequencer at HLA Laboratory, public interest incorporated foundation in Kyoto. In the previous study, HLA genes of the 3 cases had been analyzed by the same method at HLA Laboratory. This study was performed after approval by ethics committee in our clinic.
Results
HLA haplotype of the additional 2 cases are shown in Table 2 (case4 and 5). The same allele type was observed in HLA-DPA1 and DPB1 in the 2 cases: concordance was not observed in HLA-A, B, C, DRB1, DRB4, DQA1, or DQB1. The same allele type in HLA-DPA1 had also been observed in the previous 3 cases. Putting all these together, HLA-DPA1*02:02:02 was observed in common among 5 cases of BSCK-induced liver injury.
Table 2.
HLA haplotype of recent 2 cases
| HLA | DRB1 | DRB3/4/5 | DQA1 | |||
|---|---|---|---|---|---|---|
| Case 4 | 04:05:01 | 14:05:01 | 3*02:02:01 | 4*01:03:01 | 01:04:01 | 03:03:01 |
| Case 5 | 01:01:01 | 12:01:01 | 3*01:01:02 | 01:01:01 | 04:01:01 | |
| HLA | DQB1 | DPA1 | DPB1 | |||
|---|---|---|---|---|---|---|
| Case 4 | 04:01:01 | 05:03:01 | 02:02:02a | 05:01:01a | ||
| Case 5 | 04:02:01 | 05:01:01 | 01:03:01 | 02:02:02a | 04:02:01 | 05:01:01a |
aConcordant HLA in 2 cases
Discussion
Former literatures reported that one or two specific HLA allele types are occasionally associated with drug hepatotoxicity [5]. For example, DRB1*15:01 -DQB1*06:02 haplotype is associated with liver injury related to amoxicillin-clavulanate [7, 8]. Therefore, in the previous our report [6], we estimated that BSCK hepatotoxicity is possibly associated with a few of the 5 HLA genes: HLA-DRB1, DRB4, DQA1, DQB1, and DPA1 (Table 1).
In this study, HLA-DPA1*02:02:02 was solely observed among the 5 cases in common. The frequency of HLA-DPA1*02:02:02 carriers among our patients was 100%, which was significantly higher than that of the estimated population controls in Japan (approximately 40%, according to HLA Laboratory). Therefore, the association between HLA-DPA1*02:02:02 and BSCK-induced liver injury might be significant.
If this hypothesis suggested in this study is reasonable, HLA typing may be useful in the diagnosis and the prevention of BSCK-induced liver injury. Moreover, it could contribute to elucidation of outbreak mechanism of BSCK hepatotoxicity. HLA-DPA1 is found in the MHC Class II region in the HLA. MHC class II molecules are found only on professional antigen-presenting cells those are important in initiating immune responses. Our previous literature suggested that Skullcap hepatotoxicity is induced by an allergic reaction [9].
Frequencies of each HLA-DPA1 allele were different among the populations from all over the world. Asian people have HLA-DPA1*02:02 as a predominant allele, but Europeans have a low prevalence of HLA-DPA1*02:02 [10]. The incidence of BSCK-induced liver injury could vary depending on the regions of the world.
Conclusion
This preliminary study suggested that HLA-DPA1*02:02:02 is possibly associated with BSCK-induced liver injury. Further studies are needed to examine HLA gene association with BSCK-induced liver injury.
Abbreviations
- BSCK
Baikal skullcap-containing Kampo medicines
- HLA
human leukocyte antigen
- MHC
major histocompatibility complex
Authors’ Contributions
All authors contributed to the study conception and design. Data collection and analysis were performed by Naoki Mantani, Hiroshi Oka. The first draft of the manuscript was written by Naoki Mantani, and all authors commented on previous versions of the manuscript (Review and editing: Takashi Watanabe. Kyohei Miyakawa and Yoko Kimura). All authors read and approved the final manuscript.
Funding
This research did not receive any specific Grant from funding agencies in the public, commercial, or not-for-profit sectors.
Compliance with Ethical Standards
Conflict of interest
Naoki Mantani, Hiroshi Oka, Takashi Watanabe, Kyohei Miyamoto, and Yoko Kimura declare that they have no conflict of interest.
Ethical Approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional committee (Bayside Clinic Ethics Committee 30.10.1) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed Consent
Informed consent was obtained from all individual participants included in the study.
Footnotes
Publisher's Note
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