Ranunculaceae

Liver

Cimicifuga racemosa contains diterpenoids that cause liver damage in animals, either via reactive metabolites or by an autoimmune mechanism. In humans Cimicifuga racemosa has been reported to cause hepatitis [ , ]. However, evaluation of reports of acute liver disease is difficult, owing to the use of combination preparations and failure to analyse suspected products for purity and identity. Causality has not therefore been established.

• A 57-year-old woman developed autoimmune hepatitis 3 weeks after taking black cohosh tablets [ ].

The authors believed that a casual relation was likely but no brand or dose or any other characterization of the herbal remedy was obtained. Causality in this case may therefore have been related to something in the tablets but not necessarily to black cohosh itself.

• A 52-year-old woman was hospitalized with acute liver failure [ ]. She had taken a herbal mixture containing Cimicifuga racemosa , ground ivy, and three other medicinal herbs for 3 months. She had no risk factors for hepatitis and had taken no other medicines. Her condition deteriorated and she developed hepatic encephalopathy as well as hepatorenal failure. She underwent liver transplantation with an uneventful postoperative course. Analysis of the herbal mixture revealed no undeclared constituents.

The authors thought that either Cimicifuga racemosa or ground ivy could have caused this adverse event.

Black cohosh has been linked to fulminant hepatic failure that required liver transplantation [ ].

• A 47-year-old woman took an extract of C. racemosa for 1 week to treat menopausal symptoms; she developed jaundice and raised liver enzymes [ ]. No other causes of liver damage were found. She required liver transplantation.

Black cohosh has been associated with two cases of hepatotoxicity in postmenopausal women [ ].

• A 50-year-old woman developed a retro-orbital headache. There were slightly raised aspartate aminotransferase and gamma glutamyl transferase activities, but a full blood count and other biochemical tests were normal. Her symptoms were attributed to an unidentified viral illness, and she was discharged after a few days. However, she was readmitted because of persisting headache 10 days later. Her liver function had deteriorated and serology for hepatitis A, B, and C, Epstein–Barr virus, and cytomegalovirus was negative. On questioning, she revealed that she had been taking black cohosh to relieve menopausal symptoms. She was advised to stop taking it, and 1 week later she became asymptomatic and her liver function normalized.

• A 51-year-old woman developed epigastric pain with abnormal liver function tests (a raised alkaline phosphatase, alanine aminotransferase, and gamma glutamyl transferase; tests for hepatitis A, B, and C and Epstein–Barr virus were negative. Further questioning revealed that she had self-medicated with black cohosh since her hysterectomy 2 months before. The medication was withdrawn and 1 week later her liver function had normalized.

Although these cases were relatively mild because of early detection, liver damage due to black cohosh can be very serious and even life-threatening [ , , ]. The authors concluded that when a patient develops unexplained jaundice or abnormal liver function tests, particularly in the perimenopausal age group, it is important to include consumption of herbal remedies in the history-taking. They might have added that it is always important to ask patients about consumption of non-prescribed medicines.

The Committee on Herbal Medicinal Products of the European Medicines Agency (EMA) has reviewed case reports of hepatotoxicity in patients taking Cimicifuga racemosa root, and considers that there is a potential association between hepatotoxicity and herbal medicines containing Cimicifuga [ ]. The Committee reviewed 16 of the 42 case reports of hepatotoxicity to assess if Cimicifuga is linked to liver damage. Five cases were excluded, seven were thought to be unlikely to be related, and in four cases there was a temporal association between the start of Cimicifuga treatment and the occurrence of the hepatic reaction. The EMA has advised patients to stop using Cimicifuga , to consult their doctor immediately if symptoms of liver injury develop, and to inform their doctor if they are using herbal medicine products. The EMA has also advised health-care professionals to ask their patients about the use of Cimicifuga -containing products and to report suspected hepatic reactions to their national adverse reactions reporting schemes.

Musculoskeletal

Muscle damage has been attributed to black cohosh [ ].

• A 54-year-old woman took a herbal product derived from black cohosh (Remifemin®) for menopausal vasomotor symptoms. She took one tablet bd for 1 year, stopped taking it, and then started taking it again 2 months later. Each tablet contains 20 mg of dried rhizome and root extracts, standardized to contain 1 mg of 27-deoxyactein. After 2 months she started to feel weak. She had increased activities of creatine kinase (247 U/l; reference range 24–170) and lactate dehydrogenase (987 U/l; 230–460). The black cohosh was withdrawn and her symptoms improved within 10 days; the enzyme activities fell and were normal after 20 days.

There may have been very mild muscle damage in this case, but the increases in enzymes were much less than one usually sees in cases of rhabdomyolysis.