Acute liver injury following turmeric use in Tuscany: An analysis of the Italian Phytovigilance database and systematic review of case reports

Abstract

Aims Several cases of acute non‐infectious cholestatic hepatitis recently appeared in Italy following consumption of Curcuma longa‐containing dietary supplements. The aim of this research was to describe the Tuscan (Italy) cases of acute hepatitis and to compare them with similar cases of hepatotoxicity published in the literature by performing a systematic review. Methods Records of Tuscan cases of acute hepatitis were obtained from the Italian Phytovigilance system. Each spontaneous report was analysed in order to collect all relevant clinical information of patients and information concerning the Curcuma longa‐containing dietary supplement. Moreover, both the RUCAM and WHO‐UMC systems were used to evaluate the causal relationship between the use of dietary supplement and acute hepatitis. A systematic literature review was performed in MEDLINE and Embase and all case‐reports and case‐series published in English were included. Results Seven cases of acute hepatitis occurring in Tuscany up to September 2019 are described. In all cases, hepatotoxicity was associated with Curcuma longa formulations with high bioavailability and high dosage of curcumin/curcuminoids. The causal relationship was also supported by the positive dechallenge observed in most cases. In the 23 cases identified through the systematic review, the majority of patients were concomitantly exposed to at least one other medication and 16 of them experienced a positive dechallenge. Conclusions Within the frame of poorly controlled and regulated products, such as dietary supplements, the evaluation of Italian cases of Curcuma longa‐induced acute hepatitis and the systematic review of literature confirmed the association between Curcuma longa and liver injury.

Safety assessment of a highly bioavailable curcumin-galactomannoside complex (CurQfen) in healthy volunteers, with a special reference to the recent hepatotoxic reports of curcumin supplements: A 90-days prospective study

“…However, she had the medical history of hospitalization for diclofenac induced liver injury before this incident [ 41 ]. Apart from these four major cases, a few more suspected instances were also reported by health authorities condemning curcumin supplement as the cause for hepatotoxicity, mainly in Italian and US populations [ 15 , 16 , 18 ]. In most of these reported hepatotoxicity cases, the use of one or more concomitant medications or products was identified [ 18 ].…”

“…The extreme safety profile of curcumin has also been established by numerous pre-clinical and clinical studies at 8000–12000 mg/day dosage [ 13 , 14 ]. However, recently there is a mounting interest on the hepatotoxicity of enhanced bioavailable curcumin formulations, owing to a few cases of acute cholestatic hepatitis among some of the long term users and subsequently one of the supplement (Nutrimea's Curcuma Liposomal & black pepper) was recalled by Belgium’s Federal Agency for Food Chain Safety [ [15] , [16] , [17] , [18] , [19] ]. Though no clear evidence were elucidated, various plausible reasons including the use of adjuvants that inhibit body’s essential detoxification pathways with piperine, enhanced bioavailability, adulteration with synthetic curcumin and other toxic food contaminants were suggested for reported toxicity [ [20] , [21] , [22] , [23] , [24] ].…”

Suspected adverse reactions to performance enhancing dietary supplements: Spontaneous reports from the Italian phytovigilance system

“…The biological plausibility of the association between hepatitis and high concentrations of curcumin and piperine is under study (Bi et al, 2019;Lee, Ju-Hee, & Young-Joo, 2012). However, it should be outlined that recent literature supports the association between food supplements containing curcumin and cholestatic hepatitis (Burgos-Morón, Calderón-Montaño, Salvador, Robles, & López-Lázaro, 2010;Chand, Hair, & Beswick, 2020;Lombardi et al, 2020;Menniti-Ippolito et al, 2020;Suhail, Masood, Sharma, John, & Dhamoon, 2020).…”

Complementary and alternative medicine

“…Lombardi ( Lombardi et al, 2020 ) [A] reports seven cases from Italy of turmeric associated acute hepatotoxicity, diagnosed from over threefold transaminase increases with symptoms including jaundice, abdominal pain, itching, and changes in stool and urine colour, and provides a systematic review of available literature. Six of the cases were in middle-aged women (45–68 years of age) with doses of turmeric ranged from 250 to 1800 mg per day taken over 2 weeks to 8 months.…”

“…Also, synthetic curcumin use in some products may contribute to the risk of hepatotoxicity. Since 2019, the Italian Ministry of Health has required cautionary labelling regarding liver function alterations on curcumin containing dietary supplements ( Lombardi et al, 2020 ) [A].…”