The objective of this review is to highlight the continued exclusion of discussion in the literature regarding alternative causes and proper causality assessment of cases of hepatotoxicity when use of dietary supplements is reported. Though independent experts are working diligently to advance the discussion related to alternative causes of hepatotoxicity resulting in idiosyncratic drug-induced liver injury/herb-induced liver injury (DILI/HILI), the literature continues to recite the same cases, such as those presented here, to reiterate potentially biased positions and ignore current, standardized and valid evaluations utilizing the Roussel Uclaf Causality Assessment Method (RUCAM). Several historical cases purporting hepatotoxicity induced by use of dietary supplements are presented in this review to demonstrate how such cases may be improperly assessed due to bias, inconsistent use of causality assessment methods, as well as use of causality assessment methods deemed obsolete. This in essence, delays any true progress in establishing sound criteria to determine and address the actual cause(s) of DILI/HILI.
Dietary supplements (DS) are an ever growing sector of healthcare, along with lifestyle and wellness trends, particularly when it comes to weight loss. There is an abundance of information available regarding proposed links between the consumption of DS in general and some specific nutraceutical brands in the development of (DILI/HILI) in patients who take these products. Unfortunately, in the majority of published cases determined to have been caused by DS consumption, alternative causes for the hepatotoxic events were not considered. As a result, there is now a growing trend to reevaluate these reported cases for alternative causes using the more consistent and objective RUCAM causality assessment method in order to determine the actual causative risk factor(s) for the development of DILI/HILI [
Many individuals who choose to use DS for weight loss are overweight, some significantly so (Body Mass Index (BMI) > 35). It is important to acknowledge that consumers of DS (particularly weight loss supplementation) include a large number of individuals seeking ways to adopt a healthier lifestyle to reverse or negate issues related to being overweight. It is well-known that metabolic compromise and other chronic conditions are not uncommon to these populations and as a result, may render such individuals more susceptible to liver-related complications especially as they pursue weight loss goals and/or make significant changes to their dietary intake. Pre-existing medical conditions such as obesity, insulin resistance and diabetes can be associated with hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). These are disorders which may return certain types of abnormal serology results. In fact, while weight loss can be a necessary component for disease management [
In addition, it is possible for an individual to have an individualized immune reaction to a product, the same way one might have an allergic reaction to any food product, such as gluten for example [
As noted in the aforementioned recent publication, an observed issue with some of the reported cases of hepatotoxicity determined to be caused by DS consumption entails insufficient information related to: “patients’ history, concomitant use of medication and/or other compounds (including alcohol), observations on discontinuation of use (dechallenge), results found with markers, viral serology and autoantibodies, observations concerning re-exposure to the suspect products, and specifications of product use” [
Some of the current issues plaguing meaningful discussion around DILI/HILI and the use of DS include: lack of discussion of alternative causes of hepatotoxicity including liver injury linked to rapid weight loss; preexisting health conditions such as obesity, insulin resistance, diabetes, hepatic steatosis and non-alcoholic fatty liver disease (NAFLD) [
Observation of the published literature highlights a disconnect between the continued efforts to address the
Obesity (BMI ≥ 30) [ | Hepatic steatosis [ |
---|---|
Insulin resistance/metabolic syndrome [ | Non-alcoholic fatty liver disease (NAFLD) [ |
Diabetes mellitus type II [ | Hepatic viral infection [ |
Cardiovascular disease [ | Use of medication(s) known to be hepatotoxic [ |
aforementioned issues in the literature, resulting in the perpetual discussion of the same retrospective cases implicating DS consumption as causative [
Since in the majority of the published retrospective cases alternative causes were never considered and subsequently not addressed, it stands to chance that exposure to any number of agents, DS or otherwise, may exacerbate an already compromised liver.
In the majority of the cases listed in the table, pertinent information such as liver function test values, viral serology or supportive data for assigning causality to DS use were not reported. In the original reports, factors that are known to contribute to the development of liver injury (e.g. BMI of 25 and greater, pre-existing metabolic, cardiovascular and/or hepatic disease, use of hepatotoxic agents, etc.) were not even considered as causative in the reported events. If these important parameters were taken into consideration at presentation, a more plausible cause for the reported injury would have likely have been determined even in the face of reported positive reexposure tests.
Independent medical experts have questioned the methodology by which these cases were evaluated [
Lack of consideration for alternative causes of hepatic injury is not the only issue with the cases presented in
Patient | Reported vent | Originally determined DS causality | Risk factors for hepatotoxicity not considered in original evaluation | DS causality determined on reevaluation |
---|---|---|---|---|
55 yr female [ | DS consumption of unknown daily dose for 6 months prior to symptom onset | WHO: Certain | BMI of 33, use of aspirin, preexisting hyperlipidemia | RUCAM: Unlikely |
48 yr female [ | DS consumption of unknown daily dose for 9 months prior to symptom onset | WHO: Certain | BMI of 32, use of alpha adrenergic blocker for preexisting hypertension | RUCAM: Unlikely |
78 yr female [ | DS consumption of unknown daily dose for 12 months prior to symptom onset | WHO: Certain | BMI of 27, use of aspirin, bisphosphonates, preexisting diabetes mellitus type II | RUCAM: Unlikely |
30 yr male [ | DS consumption of unknown daily dose for 26 months prior to symptom onset | WHO: Certain | BMI of 33, preexisting Hepatitis E | RUCAM: Excluded |
44 yr female [ | DS consumption of unknown daily dose for 6 months prior to symptom onset | WHO: certain RUCAM: Likely | BMI unknown, use of bupropion for 20 days reported. Case determined to be poorly documented. | RUCAM: Excluded |
39 yr female [ | DS consumption of unknown daily dose for 6 months prior to symptom onset | Karch and Lasagna: Definite | BMI unknown, viral serology and imaging results not reported. Case determined to be poorly documented | RUCAM: Unlikely |
49 yr female [ | DS consumption of unknown daily dose for 2 years prior to symptom onset | Karch and Lasagna: Conditional | BMI unknown, negative virology reported but no details provided, case determined to be poorly documented | RUCAM: Excluded |
to ensure more consistent and standardized evaluation of suspected DILI/HILI it is recommended case reports utilize a structured reporting format like RUCAM. A recent publication reveals: “The [RUCAM] scale is specific and validated for hepatotoxicity, which is not the case for the Naranjo scale, the WHO global introspection method or the ad hoc approach. As these approaches are not specific, and not validated for causality assessment of hepatotoxicity, the author consider them obsolete” [
In conclusion, in order to fully appreciate a clinical presentation of DILI/HILI and determine the actual cause of liver injury when consumption of DS is reported, it is important to consider a multitude of risk factors which may provide a more plausible explanation for the reported event (e.g. viral infection, obesity, NAFLD, diabetes mellitus type II, etc.) and to utilize a more consistent causality assessment method. This point has been emphasized in the literature “to detail the conditions of exposure to [DS] under assessment for a full understanding of the risks associated with consumption” [
Vasilios Frankos,Raushanah Najeeullah,Joel Morgan, (2016) Critical Evaluation for Alternative Causes of Drug Induced and Herbal Induced (DILI/HILI) Hepatotoxicity. Health,08,800-804. doi: 10.4236/health.2016.89084