Table 5. Selection of HILI reports lacking causality assessment using RUCAM.
| Country | Author | Year | Products | Comments |
|---|---|---|---|---|
| Argentina | Jorge (114) | 2005 | Centella asiatica, syn. Ji Xue Cao | RUCAM was quoted for discussion on reexposure but not used for causality assessment. Thus, causality gradings were not published |
| Austria | Sperl (115) | 1995 | Adenostyles alliariae | No RUCAM was used nor another CAM, which could have promoted the data of the important HILI case described in an infant following use of this special herbal tea |
| Belgium | Vanderperren (116) | 2005 | Senna angustifolia | RUCAM was not applied that could have helped assess and establish causality |
| Canada | Abdualmjid (117) | 2013 | Multiple herbs | RUCAM of 1993 was not applied for individual causality assessment and defining causality grading, but would have strongly been supportive for the excellent list of herbs assumed to cause HILI |
| Bergeron (118) | 2019 | Traditional herbal medicines | No RUCAM was applied, which could have assisted to establish causality of HILI for the three products that were manufactured in China, India, and Japan but sold in Canada | |
| China | Zhou (107) | 2013 | Various herbs | No RUCAM was used; RUCAM was neither discussed nor quoted, herbs were listed among complementary and alternative medicines. Lack of RUCAM use invalidates published conclusions |
| He (119) | 2019 | Various herbs | No CAM including no RUCAM was surprisingly used for this otherwise promising report, conditions that invalidate the published conclusions | |
| Lin (120) | 2019 | Various herbs | No RUCAM was used although the updated RUCAM was discussed and quoted. With regret and as HILI cases remained without a causality grading, conclusions remain vague of this otherwise promising study | |
| France | Gloro (121) | 2005 | Camellia sinensis, syn. Green tea | No RUCAM was used for this early otherwise excellent case report of HILI by green tea extract, while this important and frequently quoted publication would have strongly benefitted if causality would have been established by using RUCAM |
| Kamsu-Foguem (122) | 2014 | Various herbs | RUCAM was not used but merely quoted and discussed, application of RUCAM could have given more strength to the listed potentially hepatotoxic herbs in Africa | |
| Germany | BfArM, previously online but then removed, now quoted by Teschke 2008 (108), Teschke 2009 (123), Teschke 2010 (124), Teschke 2010 (125), Teschke 2010 (126), Teschke 2011 (127) | 2002 | Piper methysticum, syn. Kava | No RUCAM was used by the Germany regulatory agency BfArM but claims of fragile causality for kava were publicized online by BfArM, which subsequently removed the respective link in the course of scientific fire and due to upcoming legal issues. BfArM’s initial removal notice and its statements on the cases can be requested from the first author RT via his email address |
| Teschke (128) | 2012 | Various herbs | No RUCAM was available in listed HILI cases | |
| Teschke (129) | 2013 | Various herbs | No RUCAM mentioned in listed HILI cases | |
| Teschke (130) | 2014 | Various herbs | No RUCAM available in listed cases of HILI caused by herbal TCMs | |
| Teschke (131) | 2015 | Various herbs | No RUCAM mentioned in listed cases of HILI due to traditional and modern herbal medicines | |
| Italy | Pantano (132) | 2016 | Kava, Kratom, and Khat | No RUCAM was used for this excellent and stimulating report on partially new HILI by few herbs potentially causing HILI. This report would have benefitted from a strong causality assessment by RUCAM, as also already stated under the limitations section of the study |
| Cappelleri (133) | 2017 | Various herbs | No RUCAM was applied for this interesting report, whereby RUCAM could have assisted identify the herbal culprit | |
| Japan | Adachi (134) | 2003 | Chaso, Onshido, Green tea extract | No RUCAM was used to establish causality. Discussion arose whether n-nitroso-fenfluramine was the culprit, but green tea extract remained unconsidered, respective reports of HILI by these extracts were not available at time of publication in 2003 |
| The Netherlands | Van Hunsel (135) | 2019 | Multiple herbs | No RUCAM was applied to 2,483 cases of suspected HILI by herbal medicines, but none of the cases was assessed for causality by any robust CAM. Indeed, the updated RUCAM was discussed and quoted but not used. Problematic is that HILI cases were recruited from the section of hepatobiliary disorders rather than from more specific liver sections |
| New Zealand | Savage (136) | 2019 | Artemisia annua | No RUCAM was primarily used in any of the cases; instead, alternative evaluation was attempted using the WHO method that is based on global introspection, heavily disputed among experts because this method is by no means not suitable for cases of liver injury. Besides and in 5 cases, the updated RUCAM was used. Overall evaluation is confounded by poor quality of the cases derived from the national database, the mix of two differently qualified CAMs, and the resulting contradictory causality gradings |
| South Africa | Calitz (137) | 2015 | Multiple herbs | No RUCAM was used which would have largely improved this otherwise excellent compilation of HILI cases |
| Thailand | Kanjanahattakij (138) | 2019 | Multiple herbs | No RUCAM was used, although this report on potentially hepatotoxic plants originating from Thailand could have received more strength by using RUCAM for causality assessment |
| United States | Mahady (139) from USP | 2008 | Actacea racemosa, formerly Cimicifuga racemosa, syn. Black cohosh | No RUCAM was applied by the United States Pharmacopeia (USP); instead, the expert committee used the Naranjo scale, which is not liver specific, lacks validation for liver injury cases and provided a uniform possible causality grading for all 30 cases. This USP report would have benefitted from using the RUCAM of 1993 and avoiding thereby major scientific discussions on methodology issues and highly questionable published conclusions |
| Sarma (140) from USP | 2009 | Camellia sinensis syn. Green tea | No RUCAM was used by the United States Pharmacopeia (USP); instead, the Naranjo scale was applied, not validated and not applicable for liver injury cases. Use of RUCAM would have provided robust causality data, which was finally done in a report published 2020 | |
| Engels (141) | 2013 | Rooibos tea, prepared from Aspalathus linearis | No RUCAM was applied, which could have helped provide a valid causality grading in this otherwise interesting case | |
| Yarnell (142) | 2014 | Various herbs | No RUCAM was used for this large listing of potentially herbs, RUCAM use would have enforced valid causality for many of the herbs | |
| Zheng (143) | 2015 | Various herbal products | No RUCAM was used or any other CAM allowing individual element scoring, although RUCAM was discussed and quoted. Instead, the DILIN method lacking worldwide use and any individual element scoring was praised as gold standard in the US. | |
| Hillman (144) | 2016 | Various herbal products | No RUCAM was applied for causality assessment nor any other CAM allowing individual element scoring, leading to a vague, disputable report | |
| Lunsford (145) | 2016 | Garcinia combogia | No RUCAM was used for assessing causality but it was required and used only for the R value. Study would have substantially benefitted from RUCAM use and by replacing thereby the global introspection method known as subjective, non-transparent non-element scoring method allowing for vague, percentage causality grading based causality grading only | |
| Brown (146) | 2017 | Various herbs | No RUCAM was used for this otherwise excellent, comprehensive online listing of many worldwide used herbs or herbal products that would have substantially benefitted from causality assessment using RUCAM, thereby providing more power on this clinically relevant issue | |
| Navarro (147) | 2017 | Various herbal products | No RUCAM was used to validate causality, which could have been provided by RUCAM | |
| Vega (148) | 2017 | Various herbal products | No RUCAM was applied that could have facilitated comparison with incidence data obtained from European registries, which included prospective data of RUCAM based cases of liver injury. Instead, the current study used the global introspection method that presents subjective opinions not comparable with the scoring algorithms of the transparent objective RUCAM | |
| Mousa (149) | 2018 | Mitragynia speciosa, syn. Kratom | No RUCAM was applied, leading to invalid causality assumptions and disputable conclusions, poor scientific conditions for an otherwise important and rare HILI | |
| Walter (150) | 2018 | Various herbal products | No RUCAM was used, providing controversial conclusions but RUCAM could have helped establish a valid causality for each of the suspected herbal products and avoid major discussions | |
| Alyab (151) | 2019 | Kratom | No RUCAM was used that could have reinforced conclusions presented in this otherwise rare HILI case | |
| Fernandes (152) | 2019 | Kratom | No RUCAM was applied for this otherwise important contribution. Use of RUCAM could have helped establish valid causality and foster published conclusions | |
| Zhu (153) | 2019 | Various herbal products | An own but not validated CAM was used instead of merely RUCAM that was marginally applied for causality assessment because many other CAMs were simultaneously used, some of these were not specific for liver injury or based on global introspection. This invalidates most of the published conclusions, RUCAM could have helped | |
| Quinonez (154) | 2020 | Kratom | No RUCAM was used, providing therefore fragile data and vague conclusions. The use of RUCAM could have assisted enforce robust causality and valid conclusions |
BfArM, Bundesinstitut für Arzneimittel und Medizinprodukte, German regulatory agency; CAM, causality assessment method; DILIN, drug-induced liver injury network; HILI, herb-induced liver injury; RUCAM, Roussel Uclaf Causality Assessment Method.