Liver Injury Induced by the Japanese Herbal Drug Kamishoyosan

Traditional Japanese herbal medicines (kampo medicines) are currently used for various purposes, and they have even shown effectiveness in some cases that were resistant to conventional treatments. Most general practitioners in Japan consider kampo medicine to be safe and less harmful than many conventional medications. As described in this case report, however, kamishoyosan given to a 48-year-old woman for menopausal disturbance appeared to induce liver injury.

Case Report

A 48-year-old woman was admitted to our hospital with acute liver injury. Two years earlier, she had taken the herbal medicine kamishoyosan for 1 month to treat symptoms of postmenopausal syndrome. Two months before admission, she had started taking kamishoyosan again due to a recurrence of hot flashes and night sweats. Two weeks after restarting treatment with kamishoyosan, she underwent a routine checkup that revealed abnormal liver function test results; her serum aspartate aminotransferase (AST) level was 64 IU/L, and her alanine aminotransferase (ALT) level was 102 IU/L. She was advised to go to the hospital for a detailed evaluation of her condition.

No contributory family history was identified. The patient did not drink alcohol or smoke cigarettes, and she had not used illicit drugs. She did not have any risk factors for HIV infection, had not traveled abroad, and did not have a habit of eating raw meat. She was afebrile but reported general fatigue. On physical examination, she was conscious and alert. Her conjunctivae were icteric but not anemic. Her abdomen was soft and flat with no tenderness. Her spleen and liver were not palpable, and superficial lymph nodes were not swollen. No skin rash was apparent, and neurologic examination showed no abnormalities. Her blood pressure was 106/58 mmHg, and her body temperature was 36.5° C. Laboratory tests revealed a white blood cell count of 4.7 × 10³ cells/μL, hemoglobin level of 13.4 g/dL, platelet count of 29.8 × 10⁴/μL, total protein level of 6.3 g/dL, albumin level of 3.9 g/dL, total bilirubin level of 12.8 mg/dL, direct bilirubin level of 8.9 mg/dL, AST level of 900 IU/L, ALT level of 972 IU/L, alkaline phosphatase level of 420 IU/L, and prothrombin time of 99%. Tests for markers of hepatitis A, B, and C virus infection; cytomegalovirus infection; herpes simplex virus infection; Epstein-Barr virus infection; and HIV infection yielded negative results. Test results for antinuclear antibody, anti-mitochondrial-M2 antibody, anti-smooth muscle antibody, and anti—liver/kidney/ microsome-1 antibody were all negative. Levels of immunoglobulin (Ig)A, IgG, and IgM were 265 mg/dL, 969 mg/dL, and 174 mg/dL, respectively. Abdominal ultrasonography did not detect dilatation of the bile duct, swelling of the gallbladder, or abnormal liver size. Computed tomography with contrast medium showed an almost homogeneous liver. These results were compatible with acute liver injury.

Drug-induced liver injury due to kamishoyosan was suspected, and the medication was stopped. One week after admission, a liver biopsy was performed (Figure 1). Pathologic examination of the liver revealed necrosis and acidophilic degeneration of hepatocytes in the parenchyma. The portal tract was enlarged, with infiltration of lymphocytes and eosinophils, but few plasma cells were observed.

Figure 1.

Histopathologic examination revealed expansion of the portal triad due to infiltration of many inflammatory cells and dropout of many hepatocytes (hematoxylin and eosin stain, 40× magnification; A). Acidophilic degeneration of hepatocytes and bile-stained hepatocytes are shown in the parenchyma, but no cholestasis was apparent in the small bile duct (hematoxylin and eosin stain, 200× magnification; B).

In addition to bed rest, treatment with intravenous glycyrrhizin (80 mL/day) was started following the liver biopsy. Aminotransferase and bilirubin levels gradually normalized. Changes in bilirubin, AST, and ALT levels are shown in Figure 2. The patient was discharged on Day 26 after admission; at this time, she was instructed to begin taking ursodeoxycholic acid (600 mg/day). Liver function test results had almost returned to normal by 42 days after discharge.

Figure 2.

After infusion of glycyrrhizin, levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (T.bil) improved, but levels of alkaline phosphatase (ALP) and gamma-glutamyltransferase (³-GTP) were unchanged. Ursodeoxycholic acid (UDCA) was started after discharge, and values of ALP and ³-GTP returned to normal ranges. Prothrombin time was maintained above 95% during admission (data not shown).

Discussion

Herbal medicines have been widely used around the world as alternative medicines. Clinicians are often confronted with situations in which conventional medicines are ineffective and patients' symptoms remain unrelieved, in which case herbal medicines may be tried. Despite a lack of evidence, kampo medicine is widely seen in Japan as offering an alternative treatment for various diseases. Kamishoyosan, which reduces levels of cytokines such as interleukin (IL)-6 and IL-8, is effective against hot flashes due to menopausal syndrome.¹ Kamishoyosan also has anxiolytic and antidepressive effects, and widespread use of kamishoyosan for psychiatric and neuropathic disorders can be expected.^2–5 Although kamishoyosan is widely used as an alternative drug, few side effects have been reported.

In this case, the patient was not taking any drugs besides kamishoyosan. Nevertheless, she reported taking vitamins intermittently, so vitamins could not be absolutely excluded as possible etiologic agents. However, her use of vitamins was infrequent, so this possibility seems unlikely. Two years before admission, she had taken kamishoyosan for menopausal syndrome. After treatment for 1 month, her symptoms resolved and the medication was stopped. Several months before admission, kamishoyosan treatment was restarted because of recurrent symptoms. Liver biopsy showed invasion of eosino-phils into the portal tract in the liver. The mechanism of hepatic injury was complicated, but immunoallergic mechanisms were suggested.

Melchart and colleagues investigated the frequency of liver enzyme elevations in 1,507 patients treated with traditional Chinese herbs. A greater-than-2-fold elevation in ALT values was observed in 14 patients (0.9%).⁶ In another study, Nakazawa and coworkers examined 305 outpatients who were given kampo medicine and found that 15 patients showed elevated ALT levels.⁷ The researchers reported that 87% of liver injury in these patients occurred more than 3 months after initiation of therapy. Liver injury was mild in almost all reported cases, but periodic evaluation of liver function is very important.

The same report also noted that Scutellariae radix was the only component common to all kampo medicines that caused liver injury.⁷ Terada and colleagues studied interstitial pneumonia (IP) and liver dysfunction (LD) associated with kampo medicine and found that Scutellariae radix was contained in kampo medicines taken by 94% of IP patients and 89% of LD patients.⁸ However, kamishoyosan is made from Bupleurum radix, Peony radix, Atractyloidis raceae rhizome, Japanese Angelica radix, Hoelen, Gardenia fructus, Moutan cortex, Ginger rhizome, Glycyrrhiza root, and Mentha herb; it does not contain Scutellariae radix. Thus, care must be taken regarding kampo medicine-induced liver injury even if the formulation does not contain Scutellariae radix. Kampo medicine contains several components (and each component contains multiple ingredients), which makes detecting causative ingredients difficult. However, mechanisms of liver damage caused by several herbal medicine ingredients have recently been elucidated.^9,10 Further investigation is necessary.

In this case, the patient was middle-aged, so it was important to differentiate kampo medicine—induced liver injury from autoimmune hepatitis. In the acute phase of autoimmune hepatitis, test results might be negative for antinuclear antibody, and hypergammaglobulinemia may not be detected.¹¹ The possibility of autoimmune hepatitis must, therefore, be taken into account. However, liver biopsy in this case showed scarce infiltration of plasma cells despite the presence of many eosinophils in the portal tract. The results of liver biopsy were thus compatible with drug-induced liver damage. Histologic evaluation, as in this case, is important.¹²

As mentioned above, use of kampo medicine has been increasing. Therefore, further clarification of the mechanisms underlying kampo medicine activity is warranted; as a first step, clinicians need to accumulate case reports such as this one.