We previously discussed the certificate of analysis myth and economically motivated adulteration in the dietary supplement industry. This article focuses on the basics of how the supply chain of dietary ingredients works and why it is critical for clinicians always to consider the possibility of supplement-induced adverse side effects such as herb-induced liver injury (HILI).

The surging interest in dietary supplements over the past few decades reflects a positive shift toward proactive health literacy and preventative wellness. Many of these products provide legitimate benefits when formulated responsibly. Yet, as consumption grows, so does the clinical burden of unverified sourcing. Let’s look at the following clinical case study:

A 45-year-old woman presents to the emergency department with acute epigastric pain, severe fatigue, and alarming transaminase spikes (AST > 1,400 IU/L, ALT > 900 IU/L). She has no history of heavy alcohol use, viral hepatitis, or metabolic liver disease. Her only daily routine is a “100 percent Organic, Premium Immune-boosting Tea” carrying a prestigious-looking “Made in Japan” label on the box. One of the clinicians suspects that the patient suffers from acute HILI/drug-induced liver injury (DILI). Others think that the probability of HILI is quite low based on the highly reputable country-of-origin label of the supplement.

This illustrates the “shadow” supply chain: Unverified botanicals grown in polluted soils are legally routed through high-prestige transit hubs to mask their true origin.

Substantial transformation

This is a legal term in international customs law and indicates that a product’s origin (shown on the supplement label) becomes the country where “the good underwent a fundamental change in form, appearance, nature, or character.” This creates the “geographic halo” trap in supplement manufacturing. In the above scenario, clinicians rightfully assumed that the herbal ingredients were grown in pristine Japanese soil by Japanese farmers. However, this country-of-origin label tells nothing about the legal loophole. The loophole works like this:

• Country A (unverified/polluted origin): A farm harvests raw, impure botanical powder containing heavy metals and pesticides.
• Country B (high-prestige hub): The raw powder is shipped to a supplement manufacturing facility. The facility mixes the powder with processing aids/preservatives/flavors, encapsulates the blend into soft gel, and packages it into plastic bottles.
• The legal shift: The raw botanical powder has now undergone substantial transformation. Manufacturers frequently use this step to claim that Country B is where the product was “manufactured,” thereby printing a prestigious “Made in Japan” or “Formulated in Korea” stamp on the label.

Furthermore, to navigate the customs law, supplement brands use qualified phrasing such as “Produced/Formulated in Japan” and “Packaged in South Korea.” A “Made in [Country]” stamp tells you where the manufacturing happened, not where the plant grew or got harvested/processed. In other words, what an average consumer and clinician sees on the package never tells you about the origin of raw materials in the supplement. This is why clinicians must consider the possibility of supplement-induced adverse side effects regardless of what the packaging says.

Prevalence of DILI/HILI

Interest in traditional/alternative medicine and dietary/herbal supplements has been skyrocketing. The data from the National Health and Nutrition Examination Survey reveals that 60.2 percent of adults aged >20 and 35.7 percent of youth aged 0 to 19 used any dietary supplement in the past 30 days during August 2021 to August 2023. Concurrently, incidents of supplement-induced adverse effects have been on the rise. Approximately 23,000 emergency department visits in the U.S. every year are attributed to adverse events related to dietary/herbal supplements. Herbal or dietary supplements (HDS)-induced liver injury accounts for 20 percent of hepatotoxicity cases in the U.S. Moreover, HDS-related liver failure necessitating waitlisting for liver transplantation in the U.S. has increased eightfold over the last quarter century. It is critical for health care providers to consider the possibility of supplement-induced adverse effects and obtain as much information as possible about patients’ supplements during history-taking. The solution is not to abandon supplementation altogether, but to elevate our standards as clinicians and consumers. In the next article, we will identify some common dietary ingredients associated with HDS-related liver injury and a history-taking checklist on supplement usage.

Alisa Sano is a public health auditor.