Kava extracts: Safety and risks including rare hepatotoxicity

Causality assessment in hepatotoxicity by drugs and dietary supplements

“…These include misdiagnosis through inappropriate causality assessment by the practising and hospital physicians [2,48] and the regulatory agencies [6] with insufficient documented cases in databases [1,6], differences in causality assessment of identical cases between various national drug regulatory agencies [6], the installation of expert groups that may differ in their causality assessments [22,55], problems of interest between manufacturers and regulatory agencies [25], and insufficient causality assessment by case reports published in scientific journals [6,56]. The main test and post test as frameworks for causality assessment in DDS hepatotoxicity are therefore of benefit for patients, the health communities, manufacturers and drug regulatory agencies, recognizing early and minimizing consecutively the risks of hepatotoxicity and ALF by DDS.…”

“…DDS co-medication is not uncommon [6,57] and increases substantially the risk of hepatotoxicity [4], partly due to common metabolic pathways and interactions at the cytochrome P450 isoenzyme level [34,58].…”

“…At present, practising and hospital physicians, expert groups, manufacturers and healthcare agencies each use their own individual causality approach, open to discussion and not free of conflicts of interest [24]. These difficulties are perpetuated and also evident in the databases of the World Health Organization (WHO) and various national health agencies, showing causality assessments being either hardly practicable or highly debatable [1,6]. Consequently, there is an urgent need for a universally accepted stepwise causality assessment comprehensively established by the physicians and reviewed by the manufacturers and health agencies to achieve a grading of causality accepted by all parties.…”

“…Concomitant genotyping of cytochrome P450 and other enzymes may also be useful in future to minimize the risk of unwanted side-effects, including toxic liver disease elicited by DDS. Hepatotoxicity is a rare, unpredictable and inherent risk associated with the use of various drugs and dietary supplements (DDS) at recommended doses [1][2][3][4][5][6][7][8][9], and several excellent reviews have covered the broad spectrum of DDS hepatotoxicity [10][11][12][13][14][15][16][17][18][19][20][21][22][23]. Potentially hepatotoxic drugs include prescribed and over-the-counter medications, which are intensively studied before marketing both experimentally and in several thousands of healthy persons and patients regarding unwanted sideeffects, including hepatotoxicity [24,25].…”

Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment

“…Among various causality assessment methods, the original and updated CIOMS scales were the preferred tools in cases of DILI [28] and HILI (Table 8) [5] , seen for 573 cases from 23 HILI reports evaluating alternative causes [12,32,34,[36][37][38][39]42,43,47,48,54,[57][58][59][60][61][62][63][64][65][66][67] . Transparency CIOMS based assessments should be reported or published as an original data set suitable for subsequent and independent assessments, rather than as final scores and corresponding causality levels, to improve data transparency.…”