With increasing reports of hepatotoxicity from herbs like ashwagandha and turmeric, how can we approach threats of restriction and ensure their safe use as medicine?
There have been increasing reports of herb induced liver injuries (HILIs) occurring over the last few years leading to products being recalled or entire species being withdrawn from sale for an indefinite period. This is the case for ashwagandha root (Withania somnifera), that has been banned for sale in some European countries (1). There have also been cases reported in connection with green tea leaf (Camellia sinensis) extracts (2) and also with turmeric rhizome (Curcuma longa) extracts (3) amongst others.
Reports of hepatotoxicity
Over a ten-year period in the Spanish Registry, medicinal herbs were the 10th most common medicines associated with drug-induced liver injury (DILI) (4). In the English, Spanish and Portuguese literature, 936 cases have been reported with 82.8% making complete recovery, however 6.6% of these required liver transplantation. Moreover 1.4% developed chronic liver disease and 10.4% died (5). A further 1979 cases of HILI from Chinese herbs have been reported from the Chinese academic literature (6).
Reports such as these are of major concern to the UK medicines regulators, the Medicines and Healthcare Regulatory Agency (MHRA) and they have documented that,
“Risks associated with poor quality care include failure to refer the patient back to their general practitioner when required, failure to form a correct diagnosis and rationale for treatment, failure to consider the risks of herb-drug interactions, excessive claims to treat disease and failure to explain treatment and label prescriptions adequately, Additionally, quality assurance requirements for herbal medicines and nutraceuticals is patchy, and mainly relies on voluntary schemes, however there is no requirement for practitioners to adhere to these schemes.”(7).
Many of these reports may well have confounding factors, such as concurrent medication, poor quality of herbal products or inappropriate dosage. However, even if these cases are rare, practitioners should have a thorough understanding of:
- The underlying mechanisms for HILIs
- Reasons why these adverse reactions of hepatotoxicity might occur
- How to recognise signs and symptoms
- Preventative strategies to minimise the risk of hepatotoxicity
- What remedial action to take if a HILI is suspected.
Diagnosis of herb-induced liver injury
Herb-induced liver injury (HILI) can be caused by natural products, herbal medicines, and food supplements (nutraceuticals), including Chinese formula nutraceuticals. HILI is often difficult to diagnose in the early stages and requires the insight and knowledge of a skilled and appropriately trained clinician. It is estimated that approximately 10% of cases will prove fatal (8).
HILIs may be intrinsic or idiosyncratic. An intrinsic HILI is often known, mainly predictable, acute and dose dependent, we know that if we take too much paracetamol in a day then there is a risk of liver injury, and above a certain dosage, which can be a little as twice the maximum dose, liver injury will almost certainly occur. This can be the same with herbal medicines, especially the ones that are known to have strong effects, including Schedule 20 herbs (limited to practitioner use with strict dosing guidelines) and the herbs classed as being more ‘toxic’ in the East and South Asian materia medicas. Although, the dosages at which an adverse reaction manifests are likely to be far higher than those expected with the single active ingredients found in pharmaceuticals.
An idiosyncratic reaction, which includes allergic reactions, is often not known, not predictable, may occur over any length of time and are not dose-dependant, although higher dosages may increase the inherent risk. It is mainly this type of reaction that is reported in connection with herbal medicines.
Extracts vs plant-only products
With the majority of cases connected with turmeric or green tea, these have been extracts rather than the dried plant material and there appears to be an ongoing trend to try and increase the potency of extracts, both through standardisation and strengthening of active ingredients, e.g. the catechins for green tea and the curcumins for turmeric, and through developing methods to increase the bioavailability of these products either through adapting the dosage form, e.g. with liposomal extracts or by attempting to inhibit some of the body’s mechanisms by which it removes foreign compounds (xenobiotics) from the body.
This has particularly been seen with the introduction of black pepper or one of its active ingredients, piperine, into products in an attempt to inhibit glucuronic acid conjugation in phase two liver metabolism — one of the body’s ways of removing xenobiotics by making them more water soluble and, therefore, more readily excreted through the urinary system.
Whereas these strategies may well increase the potential therapeutic benefit of these products, this could also increase the risk of adverse reactions. However, practitioners of herbal medicine tend not to use these products, relying more on single herb ingredients supplied by industrial suppliers. Many of these suppliers have some safeguards in place, in that they are voluntarily regulated by professional bodies such at the British Herbal Medicine Association and The Register of Chinese Herbal Medicine who carry out audits on these suppliers to assess their compliance with Good Manufacturing Practice (GMP) and perform some additional spot testing of their products though links with The University of Westminster, London.
The main weakness in these schemes, as highlighted by the MHRA, is that it is not compulsory for practitioners to buy their herbs from these sources and so there can still be potential for poorer quality or adulterated herbs and herbal products being prescribed.
What are the risks, signs and symptoms of hepatotoxicity?
Some of the hepatotoxicity risk factors for patients who take herbal medicines for the first time and that practitioners need to take into account, include people of middle age, concurrent use of other prescription or over the counter medicines, a history of alcohol abuse or other recreational drug use, history of liver disease or history of allergic reaction or autoimmune disease (8).
By taking a thorough case history, a practitioner can be more aware of these risk factors and closely monitor the patient for any HILI warning signs of symptoms. The signs and symptoms of a HILI can include fatigue, malaise, nausea, vomiting, abdominal pain, diarrhoea, anorexia, dark urine, yellowing of eyes or yellowing of skin, rash, itching and flu-like symptoms, although only one or two of these symptoms may be apparent and in rare cases the patient may remain asymptomatic until a late stage (9).
The majority of the most serious cases of HILI, those resulting in a liver transplant or even death, have been those where there has been little or no involvement with a healthcare practitioner. Most often these have been cases where the patient has self-prescribed the herbal medicine and has taken it unsupervised, possibly unaware of potential side effects or adverse reactions.
The good news is that if these signs and symptoms are recognised at an early stage and the treatment is stopped then the prognosis is good and the patient is likely to make a good recovery (10).
Education and guidance
The most efficient way of recognising the symptoms of hepatotoxicity and stopping the medication is through patient education. Patients need to be made aware of any potential adverse reaction at the first consultation, even if they have taken herbal medicines before without any ill effects.
The warning signs of hepatotoxicity should be explained verbally and written down for future reference. It can be explained that these are very rare reactions, much like peanut allergies are very rare, however although rare, side-effects and adverse reactions are still a possibility and one that needs to be dealt with quickly and efficiently. Moreover, without a thorough explanation of these possible adverse reactions it’s impossible for the patient to give informed consent and so could have detrimental consequences in the case of any insurance claim.
Conclusion
Relying on the patient to take charge of monitoring their progress is not enough by itself and regular follow ups should take place where the practitioner can do their own assessment and take appropriate action where required. This is one of the great benefits of treatment by a professional herbalist rather than relying on self-medication. By using this approach it is much less likely that a HILI can cause any serious or long-term damage. This is a model of best care for the patient, best practice and peace of mind for the practitioner and is ultimately good for the wider profession as a whole.
References
- Lubarska M, Hałasiński P, Hryhorowicz S, Mahadea DS, Łykowska-Szuber L, Eder P, Dobrowolska A, Krela-Kaźmierczak I. Liver Dangers of Herbal Products: A Case Report of Ashwagandha-Induced Liver Injury. Int J Environ Res Public Health. 2023; 20(5):3921. https://doi.org/10.3390/ijerph20053921
- Grajecki D, Ogica A, Boenisch O, Hübener P, Kluge S. Green tea extract-associated acute liver injury: Case report and review. Clin Liver Dis (Hoboken). 2022;20(6):181-187. https://doi.org/10.1002/cld.1254
- Lombardi N, Crescioli G, Maggini V, et al. Acute liver injury following turmeric use in Tuscany: An analysis of the Italian Phytovigilance database and systematic review of case reports. Br J Clin Pharmacol. 2021;87:741–753. https://doi.org/10.1111/bcp.14460
- Andrade, Raúl J., M. Isabel Lucena, M. Carmen Fernández, Gloria Pelaez, Ketevan Pachkoria, Elena García-Ruiz et al. Drug-Induced Liver Injury: An Analysis of 461 Incidences Submitted to the Spanish Registry Over a 10-Year Period, Gastroenterology. 2005;129(2):512-521 https://doi.org/10.1016/j.gastro.2005.05.006
- Ballotin VR, Bigarella LG, Brandão ABM, Balbinot RA, Balbinot SS, Soldera J. Herb-induced liver injury: Systematic review and meta-analysis. World J Clin Cases. 2021;9(20):5490-5513. https://doi.org/10.12998/wjcc.v9.i20.5490
- Ma X, Peng JH, Hu YY. Chinese Herbal Medicine-induced Liver Injury. J Clin Transl Hepatol. 2014; 2(3):170-5. https://doi.org/10.14218/JCTH.2014.00009
- HMAC. Safety, Regulation and Herbal Medicines: A review of the evidence. A report prepared by the UK Herbal Medicines Advisory Committee (HMAC) for the Herbal Medicines and Practitioners Working Group (HMPWG), October, 2014
- Nunes DRDCMA, Monteiro CSJ, Dos Santos JL. Herb-Induced Liver Injury-A Challenging Diagnosis. Healthcare (Basel). 2022;10(2):278. https://doi.org/10.3390/healthcare10020278
- Frenzel C., Teschke R. Herbal Hepatotoxicity: Clinical Characteristics and Listing Compilation. Int. J. Mol. Sci. 2016;17:588. https://doi.org/10.3390/ijms17050588
- Peláez D., Fernández H., Regino W. Emerging Concepts: Herb-Induced Liver Injury (HILI) Rev. Colomb. Gastroenterol. 2019;34:56–62. https://doi.org/10.22516/25007440.355
