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Methodological Preference in Causality Assessment of Herbal Hepatotoxicity

Reviewed: Teschke R, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: challenges and pitfalls of causality assessment methods. World J Gastroenterol. 2013;19(19):2864-2882.

According to the authors, “A total of 60 herbs, herbal drugs, and herbal dietary supplements have been reported to cause herb induced liver injury (HILI), though convincing causality assessment rarely was provided.” The purpose of this article was to review the diagnostic causality assessment algorithms that have been used in HILI cases.

The authors first describe the data required for a proper HILI causality assessment. Herbal product quality is a primary concern for determining causality. Therefore, the following information is required: brand name with details of ingredients, plant parts, batch number, and expiration date; manufacturer; and herbal product quality certifications (i.e., good agricultural and manufacturing practices). The authors provide an example of why this information is important: “Several hundred kava [Piper methysticum, Piperaceae] varieties exist, but specific information on kava variety identification was missing in all spontaneous reports and case report publications of suspected hepatotoxicity. This leaves open which kava variety had to be incriminated.”

In various kava-related HILI cases, it was unclear if unpeeled rhizomes, peeled or unpeeled roots, and/or stem peelings also were used, which hampers the evaluation of causation. Beginning on the day that HILI is suspected, the authors state that detailed information should be gathered, including: daily dose; exact start and end date of administration of the herb; date of increased liver values; demographics; medical history; liver enzyme levels on days eight, 30, 180, and later; alcohol and drug use; details to exclude alternate diagnoses; liver and biliary track imaging; etc. (cf. Tables 1 and 2 in the article for a complete list). The authors include a checklist to assist the physician in meeting all of these requirements.

There has been debate regarding the best method for causality assessment in hepatotoxicity cases. There are two main categories of methodology — prospective and retrospective analyses. Prospective assessments occur when the physician is actively assessing the patient. The methods for prospective assessments include the Council for International Organizations of Medical Sciences (CIOMS) scale (also called the Roussel Uclaf Causality Assessment Method scale), the Maria and Victorino (MV) scale, the Naranjo scale, the Karch and Lasagna (KL) method, and the ad hoc approach. Retrospective analyses are based on an expert panel evaluation of a reported or published case. Retrospective analyses include the Drug-Induced Liver Injury Network (DILIN) method, the World Health Organization global introspection method (WHO method) as defined by the WHO Collaborating Centre for International Drug Monitoring, and expert opinion. The following represents the order of frequency of use: CIOMS scale > WHO method > Naranjo scale > ad hoc > KL method > DILIN. However, many reports do not list the method used, so the authors assume that the ad hoc approach was used in those reports; therefore, the ad hoc approach may be used more frequently than actually reported. The National Institutes of Health (NIH) LiverTox method prefers the CIOMS scale. The authors describe the specific details of each method.

“CIOMS was developed by an international expert panel,” the authors state, “and validated by cases with positive reexposure tests serving as a gold standard.” The CIOMS scale takes into account all core elements of hepatotoxicity and thereby has advantages over other algorithms. One does not need to be an expert to use the CIOMS method. Using the CIOMS scale at the start of the suspected HILI ensures prospectively the collection of highly qualified case data and enables a complete case evaluation.

The MV scale was developed in an attempt to improve the CIOMS scale by adding other clinical elements and by simplifying and changing the relative weight of assessment parameters. A comparison of the CIOMS and MV demonstrated poor agreement between the scales. According to the authors, “…the CIOMS scale showed better discriminative power and produced assessments closer to those of specialists. These limitations restrict the general use of the MV scale in hepatotoxicity cases.”

“The Naranjo scale,” wrote the authors, “includes all of the general features important in assessing causality; however, the most critical elements are not weighed in judging the likelihood of liver injury, for example specific time to onset, criteria for recovery time, and list of critical diagnoses to exclude, limiting the use of this scale for assessing hepatotoxicity.” They continued “…the Naranjo scale is easier to apply [than the CIOMS scale], but has less sensitivity and specificity in assigning causality to cases of liver injury.” The authors state that the Naranjo scale is unacceptable in suspected HILI cases because it is not specific for liver toxicity.

The KL method is not liver specific or validated for hepatotoxicity. The authors state that the KL method should not be used for suspected HILI cases.

In the ad hoc approach, the article describes that the physician “notes the coincidence of herbal product and chemical drug use, and will estimate the likelihood of a hepatotoxic reaction. After ruling out alternative causes, the ad hoc approach is often used to distinguish a probable, possible, or unlikely causality.” An important limitation of the approach is that no universally accepted description exists for either the method or its application. The authors recommend against using the ad hoc approach because it is not liver specific or validated.

The DILIN method, the authors write, “is based on a narrative summary and a compilation of clinical findings and sequential biochemical abnormalities” culled from clinical records. The method requires experts and is used when time to conclusion is not critical.

“[T]he WHO method was not developed for hepatotoxicity cases,” the authors state. As such, this method does not take hepatotoxicity characteristics into consideration. It is not based on a gold standard, it is not quantitative, and has not been validated for hepatotoxicity. Causality assessment by the WHO method is used retrospectively and requires a panel of experts rarely available at a hospital or physician’s office. The authors state that the method is not acceptable for suspected HILI.

The expert opinion method is poorly defined, other than requiring a panel of experts for causality assessment. Individual opinion may result in judgement bias. The authors state that the method is not acceptable for suspected HILI.

The authors conclude that on the day HILI is suspected, causality assessment should be initiated in all cases using the CIOMS scale preferably in its updated form. The physician is responsible for making available all necessary data for a high-quality judgement; otherwise, causality evaluation will be problematic. Future issues for HILI cases with established causality are to define genetic, environmental, and immunological determinants of HILI susceptibility.

—Heather S. Oliff, PhD