Kampo-induced liver injury: A case report and a systematic review

Kampo medicine is the Japanese form of traditional herbal medicine that is still very popular in Japan. The word Kampo means ‘Chinese style’ in Japanese. Kampo developed out of traditional Chinese herbal medicine after it was introduced into Japan in the 7th century. In the early 20th century, Kampo was further influenced by modern Western medicine and science. The Kampo system is a pragmatic and simplified version of Chinese herbal medicine. Kampo medicines are standardised and not individualised as in Chinese herbal medicine. They are based on the current symptoms of the patient, interpreted in the philosophy of Kampo. Kampo diagnostics consider hypofunction and hyperfunction, heat and cold, superficies and interior, and yin and yang.

Today, Kampō is fully integrated into the Japanese national health care system, and numerous Kampo preparations are registered in Japan and reimbursable from public funds. These standardised formulas contain mixtures of herbal ingredients. They are manufactured under proper quality control. The most commonly used plants include liquorice, ginger and Chinese peony root. Most Japanese doctors routinely prescribe Kampo medicines, and most patients combine Kampo with Western medicine. Since 2002, the teaching of Kampo has been included in Japanese curricula of medical and pharmacy education.

The efficacy of Kampo medicines is often less solidly documented than one would hope or expect. There is a remarkable shortage of high-quality clinical trials. One review concluded that “Kampo medicines potentially play some roles in preventing or ameliorating side effects of anticancer agents. Supportive care with Kampo medicines for patients with cancer might lead to physical, mental, and nutritional improvement.” As Kampo medicines contain pharmacologically active ingredients, they can also cause adverse effects and might interact with synthetic drugs. Yet, the risks of Kampo are currently woefully under-investigated.

This case of severe liver injury following the administration of the Kampo medicine ‘Saibokuto‘ attempted to identify the likely causative crude drug inducing liver injury through a systematic literature review.

A 29-year-old woman developed severe liver injury approximately two months after Saibokuto administration, necessitating steroid pulse therapy for recovery. A literature search was conducted. Using PubMed and the “Igaku Chuo Zasshi (ICHUSHI) database,” two individuals independently selected studies published between January 1997 and February 15, 2023. The search focused on studies involving human subjects, published in either English or Japanese, and specifically investigated Kampo medicines categorized as over-the-counter or prescription drugs suspected as causative agents of drug-induced liver injury (DILI). Studies on health supplements, discontinued Kampo medicines, and autoimmune hepatitis, were excluded. As it is ethically impossible to rechallenge drugs that cause liver injury, this review primarily relied on case report literature.

Through the review, 37 cases (men/women: 12/25, including present case) were analyzed, including 32 reports (36 cases) from 3,055 studies that met the inclusion criteria. Notably, 65.9% of cases were associated with Scutellariae radix, with onset occurring within 45 (1-730) days and recovery within 35 (7-184) days.

The authors concluded that their case study and literature review underscore a prevalent association between liver injury and Kampo medicines containing Scutellariae radix. Vigilant liver function monitoring, particularly within the first 2 months of administration, is recommended, especially for formulations containing Scutellariae radix.

Radix Scutellariae (scullcap) is the dried root of the medicinal plant Scutellariae baicalensis Georgi. It has a long history of application in traditional herbalism. Six flavones seem to be its major bioactive constituents. All six flavones are pharmacologically active.

Scullcap has been advocated to treat arthritis, lung problems, hay fever, seizures, HIV or AIDS, and hepatitis. Scullcap applied to the skin has been used to treat psoriasis, sores or swelling, and hemorrhoids. The evidence that it is effective for any condition is far from convincing. Adverse effects of scullcap are equally under-researched.

The paper discussed above is a poignant remeinder of the ‘appeal to tradition‘: not everything that has been used for centuries is safe. Only proper scientific investigations will determine the risk/benefit profile of a therapy.