Drug‐induced liver injury in the United States: A review of multi‐ingredient supplements

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Abbreviations

ALP

alkaline phosphatase

ALT

alanine aminotransferase

AST

aspartate aminotransferase

CT

computed tomography

DILI

drug‐induced liver injury

DILIN

drug‐induced liver injury network

ERCP

endoscopic retrograde cholangiopancreatography

HDS

herbal and dietary supplement

MRCP

magnetic resonance cholangiopancreatography

MRI

magnetic resonance imaging

RUCAM

Roussel Uclaf Causality Assessment Model

ULN

upper limit of normal

Herbal and dietary supplement (HDS) usage in the United States has become increasingly prominent over the past few decades, with approximately 50% of all Americans and 70% of adults older than 71 years reporting HDS use.1 The array of supplements consumed is expansive, ranging from multivitamins to bodybuilding supplements to performance and weight‐loss enhancers. Albeit rare, drug‐induced liver injury (DILI) caused by HDSs has been observed more frequently by the drug‐induced liver injury network (DILIN) and has been reported as the second most common cause of DILI.2 Therefore, it is important for clinicians to be able to make the appropriate diagnosis of DILI and be attentive to the potentially hepatotoxic effects of HDS, particularly those that are seemingly healthful.

Defining Liver Injury and Recognizing Patterns of Injury

Historically, as established by an international consensus meeting in 1990, liver injury was proposed as: (1) an increase of more than twice the upper limit of normal (ULN) in the serum levels of alanine aminotransferase (ALT) or conjugated bilirubin; or (2) a combined increase in the levels of aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin, with one of these being more than twice the ULN.3 Recently, revisions to the definition of liver injury suggested significantly higher liver enzyme levels with the AST or ALT three to five times the ULN.2, 4

Patterns of liver injury have also been described using the R ratio, calculated from the ratio of serum ALT to the serum ALP, both expressed as multiples of the ULN.3 An R ratio ≥5 is consistent with a hepatocellular pattern (predominant elevation of the ALT), whereas an R ratio ≤2 indicates a cholestatic pattern (predominant elevation of the ALP), and a mixed pattern can be observed when the R ratio is between 2 and 5.

Diagnosing Liver Injury

DILI is a diagnosis of exclusion and relies on a detailed history of ingested agents; it is not uncommon for patients to withhold information on supplement use. Patients may only exhibit subtle symptoms such as fatigue or nausea at the time of presentation. Therefore, a high level of clinical suspicion is required. More specific signs of liver injury include jaundice, abdominal pain, rash, and pruritus.

In addition to a thorough history, all other causes of liver injury such as viral and alcoholic hepatitis, autoimmune causative factors, anatomic abnormalities, metabolic derangements, and biliary diseases must be excluded (Fig. 1). It is also important to rule out hepatitis E, because it may present similarly to DILI.5

Figure 1.

Diagnosis of drug‐induced liver injury. Abbreviations: CT, computed tomography; DILI, drug‐induced liver injury; ERCP, endoscopic retrograde cholangiopancreatography; HDS, herbal and dietary supplement; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging.

Assessing Causality

Without one particular test to diagnose DILI, efforts have been made to objectively assess the likelihood that liver injury is due to a drug or HDS. The Roussel Uclaf Causality Assessment Model (RUCAM) was developed to address such issues of causality.6 A modified RUCAM, the Maria and Victorino scale, included additional parameters in the scoring system such as fever and rash, but also excluded other risk factors such as age, alcohol, and pregnancy.7 As a validated causality algorithm and found in one series to be superior to the Maria and Victorino scale, the RUCAM is more commonly used.8, 9

In the United States, consensus expert opinion has been widely regarded as the gold standard for assessing causality (Table 1). This method has been adopted by the DILIN, with the probability of a causal relationship between an agent and liver injury being conveyed as a likelihood score. A study comparing the DILIN causality assessment approach with the RUCAM revealed that the former was more likely to generate a score supportive of DILI.10

Table 1.

Drug‐induced Liver Injury Network Causality Scale

Score	Likelihood	Description
Definite (1)	>95%	The evidence for the drug causing injury is beyond a reasonable doubt.
Highly likely (2)	75%‐95%	The evidence for the drug causing injury is clear and convincing, but not definite.
Probable (3)	50%‐74%	The preponderance of the evidence supports the link between the drug and the liver injury.
Possible (4)	25%‐49%	The evidence for the drug causing injury is equivocal but present.
Unlikely (5)	<25%	There is evidence than a causative factor other than a drug caused the injury.

Hepatotoxic Herbal and Dietary Supplement

In Table 2, we list several supplements that have been implicated in liver injury. These particular supplements are composed of more than one ingredient, as is typical of HDS in the United States. A review of single ingredients reported to be potential hepatotoxins is presented in a complementary article featured within this publication. Additional information on previously implicated hepatotoxic agents can be obtained from LiverTox, an online database produced by the National Institutes of Diabetes and Digestive and Kidney Diseases and the National Library of Medicine. The Web site provides up‐to‐date clinical information for patients, physicians, and researchers on prescription and nonprescription medications such as HDSs that have been attributed to liver injury.

Table 2.

Summary of Hepatotoxic Preparations

Multi‐ingredient Supplement	Common Uses	Injury Pattern	Suspected Hepatotoxic Ingredient	Comments
Bodybuilding and performance‐enhancing supplements	Treatment of malignancy, body building, performance enhancement	Cholestatic	Stanozolol Danazol Methyltestosterone	Injury can be acute or chronic, ranging from transient elevation in transaminases to chronic vascular injury to adenomas and hepatocellular cancer.
Chinese herbs	Performance enhancement, weight loss, well‐being, management of blood pressure, diabetes, memory improvement	Unknown	Unknown, wide range of ingredients	Reports of adulteration and contamination may attribute to liver injury.
Herbalife nutritional supplements	Weight loss and well‐being	Hepatocellular	Unknown, ingredients are variable	Repeated exposure has caused reinjury after initial normalization of liver enzymes.
Weight‐loss supplements (Hydroxycut, OxyELITE Pro, SlimQuick)	Weight loss, performance enhancement	Hepatocellular	Green tea Garcinia cambogia

It should be emphasized that there is no standard nomenclature for the classification of HDSs. Therefore, it is difficult to identify products by their intended uses because they may be marketed for different purposes.

Bodybuilding and Performance‐Enhancing Supplements

Given their androgenic properties, anabolic steroids are commonly used for male sex hormone replacement and treatment of certain diseases, as well as for bodybuilding and improving athletic performance. Steroids have been implicated in liver injury with manifestations ranging from transient serum elevations to an acute cholestatic syndrome, to chronic vascular injury and hepatic tumors such as adenomas and hepatocellular carcinoma.11 Case reports of liver injury resulting from bodybuilding and performance‐enhancing supplements have described with remarkable consistency, a distinct pattern of intrahepatic cholestasis.12, 13

Chinese Herbs

Used commonly for medicinal and healing purposes, Chinese herbal remedies have been used for centuries. With a large variety of herbs available, it is difficult to determine which particular ingredient is implicated in liver injury. Factors such as contamination and adulteration of preparations may be the cause of hepatotoxicity.14, 15

Herbalife Nutritional Supplements

Marketed for weight loss and well‐being, the Herbalife catalog features products that range from shakes to multivitamin tablets to protein bars. The product composition of Herbalife is variable particularly among different countries. Liver injury has ranged from transient elevation of serum transaminases to fulminant hepatic failure requiring transplantation.16, 17

Weight‐Loss Supplements

Many weight‐loss supplement products such as Hydroxycut, OxyELITE Pro, and SlimQuick have been reported to cause a hepatocellular pattern of injury.18, 19 This may be attributed to specific ingredients within these supplements such as green tea or Garcinia cambogia. However, direct toxicity has not been proved, and injury may be secondary to idiosyncratic reactions.

Conclusion

HDSs are commonly used and can cause liver injury; however, establishing causality of DILI from HDSs presents a unique challenge. That is, whether liver injury is due to a combination of multiple ingredients or a single toxic component warrants further investigation. Although several unanswered questions surround the investigation of DILI, it is imperative that the clinician remains vigilant to HDS as a potential cause of liver injury.