Commonly available dietary supplements, herbs and medicines – do they pose a risk for liver health? Literature review in the context of the Polish population

Introduction

The concept of drug-induced liver injury also encompasses damage of the liver as a result of using dietary supplements and herbs [1, 2]. According to the Act of 25^th August 2006 on food and nutrition safety, a dietary supplement is a foodstuff intended to complement the standard diet [3]. This group does not include products with proven therapeutic effects recognized by pharmaceutical law [3]. Liver damage is most commonly caused by multi-ingredient products [4]. According to statistics, the issue of drug-induced liver injury affects 14-19 out of 100,000 residents of Europe, although these data may be significantly underestimated due to the difficulties in unequivocally identifying the cause of liver dysfunction [5, 6]. During medical interviews, patients often mention only prescription drugs, so conversing with the patient requires special care on the part of the physician and active inquiry about other consumed substances. Fully reliable data on liver damage caused solely by dietary supplements are not available, although there is an expected upward trend in such damage due to the constant increase in popularity and consumption of these products [4]. There are three fundamental mechanisms of liver damage: direct, indirect, and secondary. The first depends on the amount of the damaging substance consumed. Damage occurs after exceeding the toxic dose threshold [7]. In the second, rarer case, the damage occurs suddenly, most likely depending on the individual’s immune response [5]. The risk of this damage is gender-dependent and increases in the presence of specific gene polymorphisms, a history of liver disease, obesity, or diabetes [7, 8]. The third mechanism results from individual metabolism and/or immune reaction [7] (Table 1). Due to the difficulties in identifying the causes of liver damage, often associated with the use of multi-ingredient preparations and combining supplements with prescription medications, using available information gathered in national and European registries of drug-induced liver injury can be helpful.

The diagnosis of liver damage due to the use of dietary supplements or herbs is problematic due to difficulties in unequivocally identifying the hepatotoxic substance. Characteristic of this type of organ damage is acute hepatitis, with a significant increase in serum aminotransferase activity and simultaneous absence or slight increase in alkaline phosphatase activity. Typically, autoimmune processes are not observed, and mortality is not precisely known [4]. This damage most commonly occurs within 4 months of initial exposure and resolves within 2 months of eliminating the toxic component and initiating treatment [4]. Establishing a diagnosis requires gathering a detailed history of nutrition, alcohol consumption, use of supplements, medicinal preparations, and any recent illnesses or new symptoms experienced in recent months. This makes it possible to determine the likelihood of exposure to substances with hepatotoxic potential and plan any necessary differential diagnosis.

This publication summarizes information on the hepatotoxicity of dietary supplements, herbs, and commonly available medications based on the guidelines of the American Association for the Study of Liver Diseases (AASLD) from 2022 and the latest available medical literature, in the context of the Polish population.

Methods

The literature review was conducted in 2023. In addition to presenting the guidelines of the AASLD from 2022, publications available in PubMed and Google Scholar databases were used and legal regulations were cited. The findings of the Supreme Audit Office’s inspections and data published by the Chief Sanitary Inspectorate were presented. The literature review was created in the context of the Polish population.

Dietary supplements and legal regulations

Dietary supplements are food products intended to supplement the diet with nutritional components [9]. This category includes products containing vitamins, minerals, or substances exhibiting physiological or nutritional effects. Legally permitted are the production and sale of single- and multi-ingredient preparations in various dosage forms: capsules, tablets, coated tablets, ampoules, liquids, or powders [3]. It is estimated that 72% of Poles use dietary supplements. According to available data, 50% of people over 20 years of age used dietary supplements in the last month [10].

In line with legal regulations of the European Union, the approval of a supplement for commercial circulation requires documenting its history of safe use and verifying the chemical composition of individual ingredients [7]. In Poland, it is mandatory to notify the Chief Sanitary Inspectorate when introducing a product to the market [11]. To ensure the safety of dietary supplements, the manufacturer is obligated to include various information on the packaging, such as a clear designation of “dietary supplement”, indication of the nature of the substances in the product, presentation of the recommended daily intake, and a warning against exceeding the recommended portion. Additionally, it is necessary to state that dietary supplements cannot be used as a substitute for a varied diet [12].

Liver injury caused by dietary supplementation

The risk of liver damage from supplement use arises from the complexity of the products (whose individual components may interact), the concealment of certain ingredients, or the presence of contaminants such as pesticides and heavy metals [7]. Most adverse health effects of dietary supplement use may result from insufficient oversight of the market for such products [9]. As indicated by the Supreme Audit Office report from 2016, the safety of dietary supplements in the country has not been ensured [9, 13]. Intentional non-disclosure of supplement ingredients is often associated with the presence of pharmaceutical substances that give the supplement its declared effect. For example, in supplements claiming to enhance sexual performance, sildenafil may be present [7]. AASLD directly lists products whose use has led to liver damage, such as advertised “fat burners” – Hydroxycut, Oxy-Elite Pro, and numerous Herbalife products [7].

Special attention should be paid to dietary supplements intended for improving body shape, increasing metabolism, reducing fat tissue, and increasing muscle mass. Products containing green tea extract, such as the aforementioned multi-ingredient supplement Oxy-Elite Pro, or products containing anabolic-androgenic steroids, have proven to be dangerous. Green tea extract is obtained from the leaves of the Camellia sinensis plant, attributed with antioxidant, lipogenesis inhibiting, and metabolism-enhancing effects in vitro studies, although its unequivocal effect on weight loss in humans has not been proven [4, 14]. Nevertheless, dietary supplement manufacturers have popularized green tea extract. Symptoms of acute liver inflammation occurring 1-3 months after starting to consume this product have been described [4]. However, the chemical component directly responsible for organ damage has not been identified, the damage being classified as idiosyncratic [4]. Despite this, the European Food Safety Authority questions the safety of one of the catechins present in green tea extract: (–)-3-gallate epigallocatechin. Based on this, the European Commission legally requires information on the presence of this component in the product, its maximum total daily intake (800 mg), and the need for medical consultation before use [15]. Oxy-Elite Pro was introduced to the market as a product enabling weight loss and muscle tissue development. The use of the supplement caused jaundice, with a significant increase in serum aminotransferase activity in some consumers [16]. The most likely cause of complications after using this supplement was the use of synthetic, impure aegeline [4]. Despite warnings from the Chief Sanitary Inspectorate and subsequent withdrawal of the supplement from circulation, it is still available for sale online, posing a potential threat to the health of consumers. Anabolic-androgenic steroids, approved as medicines, are sometimes improperly used to induce muscle mass gain and improve physical condition by athletes, bodybuilders, and recreational trainers, most often in young and middle-aged individuals [4]. The consequences of improper and non-compliant use of these preparations are widely described: liver cell damage, cholestasis, liver steatosis, chronic vascular and tumor damage, as well as complications in the form of kidney failure [4, 17, 18]. Physicians should also pay attention to substances included in many broad-spectrum dietary supplements, the improper or unaware intake of which may lead to liver damage. These include niacin (used to support the therapy of cardiovascular and nervous system diseases), vitamin A (used in skin diseases), or iron (high intake of which in young children is dangerous) [19].

Liver injury caused by herbs and commonly available medicines

In the case of herbal usage, liver damage primarily results from the possibility of contamination of herbal raw materials with mycotoxins, residues of herbicides, and pesticides, which mainly contaminate the product during its production and storage [20]. Additionally, in many cases, the doses of herbal substances contributing to liver injury are not known [20]. The AASLD identifies selected herbs that can act destructively on the organ, causing hepatocellular (H) or mixed (H/M) liver damage: popular green tea leaves (H), used in insulin resistance and inflammatory gastrointestinal conditions, Malabar tamarind (H), used to boost immunity, butterbur (H/M), widely used Baikal skullcap (H), exhibiting psychoactive effects, kratom (M), used for anti-inflammatory purposes, and turmeric (H). Also potentially dangerous are: improperly used comfrey taken orally, black cohosh root used to relieve menopausal symptoms or stress-relieving cannabidiol (CBD) [19].

Polypharmacy is widespread in Poland. It is estimated to affect 56% of elderly individuals [9, 21]. A particular risk arises from the frequent use of over-the-counter medications observed among a high percentage of the population. This tendency is exacerbated by advertisements presented in the media [22]. Consequently, as of January 1, 2023, a prohibition of advertising medical products through the portrayal of a doctor or other medical professional has been enforced in Poland. This measure aims to minimize the risk associated with the unsupervised use of medications [23]. Liver damage due to medication is typically diagnosed approximately 6 months after the commencement of use [7]. The highest risk is associated with the ingestion of commonly available nonsteroidal anti-inflammatory drugs (NSAIDs). It is estimated that in the United States, paracetamol overdose causes over 500 deaths annually, and in developed countries, it accounts for > 50% of cases of drug-induced liver damage [24]. In recent years, Poland has witnessed an upward trend in paracetamol poisonings [25]. Similar but broader observations were made in Ireland [26]. The large number of over-the-counter medications containing this active ingredient contributes to this phenomenon.

The hepatotoxicity of paracetamol is caused by the presence of the metabolite NAPQI, which is formed with the involvement of cytochrome P450 enzymes. This metabolite is not efficiently detoxified by glutathione, leading to its accumulation and subsequent binding to proteins at certain amino acid residues. Ultimately, increased oxidative stress leads to the activation of c-Jun N-terminal kinases, which increases the permeability of mitochondria, resulting in their destruction. As a result, ATP production in hepatocytes is hindered, leading to cell death and impairment of metabolic functions [27]. Basic biochemical tests in individuals with paracetamol poisoning show an international normalized ratio (INR) > 1.5, elevated levels of aminotransferases to the milliunit levels, increased bilirubin levels, and electrolyte disturbances [28]. In cases of suspected poisoning, it is necessary to measure the serum concentration of paracetamol [28]. The treatment of paracetamol poisoning involves the administration of N-acetylcysteine (NAC), which supports the formation of glutathione to eliminate NAPQI. Intravenous administration of NAC according to the modified Prescott protocol is 300 mg/kg of body weight on the first day, followed by oral administration of 1130 mg/kg of body weight within 72 hours [29].

In Poland, paracetamol is present in popular preparations under dozens of trade names. Due to the promotion of the aforementioned products in the media as mild remedies for cold symptoms and pain relief, it is highly probable that patients unknowingly exceed safe doses.

Summary and conclusions

The risk of liver damage due to the use of dietary supplements, herbs, and commonly available medications is real and may potentially increase with the growing number of such products available for sale. Conducting a thorough interview with the patient is essential for accurately determining the cause of liver damage and subsequently initiating appropriate treatment. With the increasing popularity of dietary supplements, herbs, and commonly available medications in Poland, preventive actions appear to play a significant role. Minimizing the risk of liver injury may involve:

Disclosures

This research received no external funding.

Institutional review board statement: Not applicable.

The authors declare no conflict of interest.