Drug-Induced Liver Injury Associated with Turmeric and Piperine: A Case and Review

Abstract

Introduction

Turmeric is a common spice used in traditional Chinese and Ayurvedic medicine for a variety of purported health benefits. Recent concerns have arisen regarding turmeric-induced liver injury linked to formulations with enhanced bioavailability, often including piperine found in black pepper.

Case Presentation

We explore a case of a 40-year-old female with increasing fatigue, pruritus, and dark urine following consumption of turmeric and black pepper “wellness shots” leading to a significant drug-induced liver injury.

Conclusion

This case underscores the critical need to recognise herbal remedies, such as turmeric, as potential sources of hepatotoxicity. Despite a reputation of safety, limited regulation and testing of turmeric may mean potential adverse effects are under-recognised. Understanding the mechanisms behind turmeric and black pepper’s hepatotoxicity, including the role of potential genetic predispositions, requires further investigation for its safe use.

Introduction

Turmeric has been valued for centuries in Chinese herbalism and Ayurvedic medicine for its claimed anti-inflammatory, antioxidant, antineoplastic, neuroprotective, and cardioprotective properties and its use is increasingly entering the Western complementary medicine market [1, 2]. Its long history of use has conferred a reputation of safety. Turmeric’s traditionally low rate of adverse effects is principally linked to poor oral absorption, thereby limiting any adequate systemic exposure with the potential for toxicity. However, emerging data suggests a potential link between turmeric and drug-induced liver injury (DILI). Notably, turmeric supplements are increasingly combined with compounds like piperine, the active ingredient in black pepper, to boost its bioavailability. This enhanced bioavailability is being increasingly implicated and thought to possibly potentiate DILI.

Case Presentation

A 40-year-old female was referred to an Australian tertiary hospital by her general practitioner with abnormal liver function tests (LFT). She had a 2-week history of increasing fatigue and loss of appetite, followed by 2 days of pruritus, nausea, and dark-coloured urine. She did not report a history of abdominal pain, weight loss, or fevers. Her only medication was the combined oral contraceptive pill (COCP).

The patient had no other identifiable risk factors for liver disease including the absence of injecting drug use, alcohol intake and unprotected sexual intercourse. She reported a 5 month history of taking daily self-made “wellness shots” by mixing ground turmeric, black pepper, fresh orange juice, apple cider vinegar, and water, though she was unable to quantify specific amounts.

On examination, the patient was jaundiced and vital signs were all within normal parameters. Her abdominal examination was unremarkable, without peripheral stigmata of chronic liver disease. The patient’s full blood count, kidney function, electrolytes, and lipase were unremarkable. Her LFTs revealed an elevated bilirubin 99 (0–20 μmol/L), alanine transaminase (ALT) 2,519 (5–35 U/L), aspartate transaminase 1,296 (5–30 U/L), and gamma-glutamyl transferase 68 (5–35 U/L). Her alkaline phosphatase 107 (30–110 U/L) and albumin 41 (32–47 g/L) were within normal limits. Her liver synthetic function was normal with an internationalised normalised ratio of 1.2 (0.8–1.2). Her platelets were within normal parameters 325 (150–450 × 10⁹/L).

Viral serology, most notably hepatitis A, B, C, cytomegalovirus and Epstein-Barr virus were negative. Her antinuclear antibody (ANA) titre was 1:320 (<1:160); however, the remainder of her autoimmune screen was unremarkable. She had an elevated ferritin 1,156 (30–310 μg/L) and iron saturation 58 (15–46%). No other causes for abnormal LFTs including metabolic and hereditary aetiologies were identified.

An abdominal ultrasound revealed mild periportal oedema without evidence of liver cirrhosis. A percutaneous ultrasound-guided liver biopsy demonstrated widespread necrosis and bridging with apoptotic cells, ceroid-laden macrophages, and hepatocyte rosettes. Plasma cells, eosinophils, granulomatous change, or abnormal staining of copper and iron were not observed. These findings were in keeping with a drug-induced liver process (Fig. 1a, b).

Fig. 1.

Liver biopsy in keeping with a drug-induced liver process. a Very extensive zone 3 and perivenular confluent hepatocellular necrosis with apoptotic cells, ceroid-laden macrophages, and hepatocyte rosettes. b Period Acid-Schiff Diastase (PASD) stain highlighting very extensive ceroid deposition in phagocytic macrophages.

The patient was commenced on prednisolone 50 mg daily on the eighth day of her admission, prior to biopsy results, due to concerns about a significant ongoing inflammatory component. However, on the same day prior to the first dose of prednisolone administration, there was a noticeable improvement in her LFTs. In particular, her ALT had improved (1,570 U/L) compared to the previous 3 days during which it remained static between 2,000 and 2,200 U/L (Fig. 2a, b). She was discharged on an accelerated taper of prednisolone, decreasing by 5 mg every 3 days until cessation due to high suspicion for DILI, diverging from the typical gradual wean employed for autoimmune hepatitis (AIH).

Fig. 2.

Liver function trend over 9-day hospital admission, red arrow indicative of commencement of steroids. a Trend of ALT and AST. b Trend of ALP, GGT, and total bilirubin. ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; ALT, alanine transaminase; AST, aspartate transaminase.

Outcome and Follow-Up

The patient was followed up in the liver clinic. She tolerated prednisolone well without any major side effects. Her LFTs gradually improved in the first 3 weeks post-discharge, and her bilirubin normalised. However, an ALT flare occurred around the time of prednisolone cessation 4 weeks post-discharge. At her next clinic visit 7 weeks post-discharge, prednisolone was restarted at 15 mg daily, tapering by 5 mg every 2 weeks. By week 15, her ALT had normalised (35 U/L) (Fig. 3). She was advised to avoid turmeric in the future.

Fig. 3.

Trend of liver function post discharge demonstrating ALT flare, blue arrow indicative of time of initial prednisolone cessation, whilst green arrow indicative of time of prednisolone recommencement.

Discussion

DILI encompasses a spectrum of liver dysfunction caused by prescription medications, herbal remedies, and dietary supplements, ranging from mild, asymptomatic enzyme elevations to rare but clinically significant conditions, such as acute hepatic failure. Its incidence and underlying aetiology vary geographically, with antibiotics implicated as the leading cause in Western countries [3]. However, the proportion of cases causing hospital admissions appears to be increasingly linked to herbal and dietary supplements (HDS). An Australian retrospective analysis demonstrated a 32% increase in HDS-related DILI when comparing data between 2009–2011 and 2018–2020 [4]. While DILI typically occurs within 6 months of commencing a medication, the latency period can vary from days to years, making diagnosis challenging [5].

In our case, the patient had consumed daily “wellness shots” containing both turmeric and black pepper in unspecified amounts for a period of 5 months. The temporal correlation between the commencement of this regimen, the onset of abnormal LFTs and histology findings raised a strong clinical suspicion of DILI.

Infrequent reports of turmeric-associated liver injury are likely attributed to its minimal bioavailability (1%) resulting from poor intestinal absorption, rapid hepatic metabolism, and systemic elimination from the body [6]. Inadequate systemic absorption when ingested alone likely limits its ability to cause DILI. However, when combined with piperine, turmeric’s bioavailability has been shown to increase by 20-fold, potentially enabling hepatotoxic effects [7]. While no identifiable studies compare hepatotoxicity in turmeric alone to turmeric combined with black pepper, a recent US Drug-Induced Liver Injury Network (DILIN) case series highlights that piperine was implicated in several cases of turmeric-associated DILI [8].

Most DILI’s are via an idiosyncratic, non-dose dependent process, likely underpinned by genetic risk factors [9]. Susceptibility to liver injury may arise from genetic polymorphisms in the PTPN22 or HLA alleles, with HLA-B*35:01 notably linked to turmeric-induced liver injury [8, 10]. Our patient did not undergo genetic testing, which is not routinely performed in accordance with our health service guidelines, but the presence of genetic susceptibility may explain DILI in this case.

DILI is a diagnosis of exclusion [11] and can be challenging to differentiate from AIH. The patient’s Roussel Uclaf Causality Assessment Method (RUCAM) score was six, consistent with probable likelihood of causality between turmeric and the liver injury. A Revised Original Score for Autoimmune Hepatitis was 12, suggestive of probable AIH. While this is an interesting observation, AIH was deemed unlikely due to clinical correlation with turmeric exposure and the absence of serological and histological findings typically associated with AIH. However, drug-induced autoimmune-like hepatitis (DI-ALH) was considered as a possible alternative.

DI-ALH is a rare phenotype of DILI exhibiting an immune-mediated response that can clinically, biochemically and histologically be indistinguishable from AIH; however, unlike AIH, it usually resolves within 6 months without long-term immunosuppression and rarely progresses to cirrhosis [12]. In this case, an ALT flare following steroid cessation prompted consideration of DI-ALH. The initial rapid steroid wean may have been too abrupt, preventing adequate resolution of the liver injury. Subsequent normalisation of ALT levels following an extended course of steroids, along with the absence of cirrhosis, further supported the possibility of DI-ALH. A positive ANA titre of 1:320 can also be seen in DI-ALH. A review by García-Cortés et al. [13] reveals that ANA positivity was consistently observed across various drugs implicated in cases of DI-ALH. Although DI-ALH is typically defined by the absence of recurrent injury, cases of relapse following initial steroid cessation have been reported, as observed in our patient. Eosinophils and plasma cells can be seen on liver histology in DI-ALH, similar to AIH; a retrospective cohort study found eosinophilic infiltrates more common in DI-ALH, whilst plasma cells were more frequently seen in AIH [14]. However, both were absent in the biopsy conducted early in this case and a repeat biopsy was not performed as the patient demonstrated biochemical improvement with a second, slower weaning course of steroids. Given the significant overlap in clinical and diagnostic features, distinguishing between DILI and DI-ALH in this case was challenging.

The role of steroids in DILI is contentious, with limited evidence supporting their efficacy for most types of drug-induced hepatotoxicity [15]. However, a systematic review suggested potential benefit in severe cases, with four of eight studies across Europe and Asia reporting statistically significant reductions (at least 50% improvement from peak value) in bilirubin and transaminase levels with steroid use [16]. Nonetheless, the scarcity of literature complicates the ability to draw definitive conclusions on its benefit.

Whilst there are no known interactions between turmeric and COCPs, it is worth noting that oral contraceptives are a known cause of DILI. In our case, the patient had been using COCPs for several years, liver injury occurred after a 5-month consumption of turmeric, and no adverse effects were observed post-recommencement of COCPs. This made the diagnosis of COCP-induced DILI unlikely.

Stati et al. [17] notably highlight the dichotomy between increasing reports of turmeric’s hepatotoxicity and the existing literature on its potential hepatoprotective effects. Curcumin has antioxidant, anti-inflammatory, and anti-apoptotic properties that are thought to help reduce liver toxicity [18]. Various studies have been conducted on animals such as rats, with reports of curcumin improving markers of inflammation and liver transaminases [19]. There has been increasing application to humans, with particular focus on curcumin use for prevention of metabolic dysfunction-associated steatotic liver disease. Meta analyses and randomised control trials have reported improvements either in metabolic dysfunction-associated steatotic liver disease grade, or significant reductions in liver transaminases and inflammatory cytokines. However, these studies have been limited by paucity of data, small sample sizes, short follow-up duration, and large inter-study heterogeneity [20–22]. Positive findings have also been reported around curcumin’s effects on hepatitis, liver cirrhosis, and hepatocellular carcinoma, though these studies share similar constraints [23–26]. Despite this body of evidence, several cases of turmeric-associated DILI have been documented, as summarised in Table 1, which serves as a comparison and provides further context to the complexity between turmeric’s potential hepatoprotective and hepatotoxic effects.

Table 1.

Summary of published case reports and series on drug-induced liver injury related to turmeric: clinical characteristics, investigations, and outcomes

Study	Patients, n	Demographics	Risk factors	Dose/day	Time to onset, months	Autoantibodies	ALT, U/L	Histology	Outcome
Lombardi et al. [27] (2021), Italy	7	55–68	1 case denosumab	Mean 773 mg	Mean 2.6	Negative	Mean 2,176	N/A	Resolved
		6F, 1M		Range 250–1,812.5 mg			Range 257–3,303
Alghzawi et al. [28] (2024), US	1	66, F	None	1/2 teaspoon	6	Negative	1,644	Cirrhotic liver with mixed inflammatory infiltrate, bile ductular reaction and hepatocellular necrosis	Acute liver failure, hepatorenal syndrome, death
				not specified
Smith et al. [29] (2023), US	1	62, F	None	N/A	0.7	Negative	1,889	N/A	Resolved
Sohal et al. [30] (2021), US	2	53, 57	Atorvastatin	2,000 mg	3, one N/A	ANA 1/40 (1 case)	733, 1,335	Hepatocyte ballooning and necrosis, mononuclear portal inflammation	Resolved
		2F		other N/A
Azkue et al. [31] (2024), Spain	1	35, F	None	120 mg	2	Negative	2,230	N/A	Resolved
Chand et al. [32] (2020), Australia	1	62, F	Breast ca hormone therapy not specified	N/A	10	Negative	2,308	Parenchymal inflammation with neutrophils, mononuclear cells, plasma cells, occasional eosinophils, focal parenchymal necrosis, and mild cholestasis	Resolved
Imam et al. [33] (2019), US	1	78, F	None	N/A	1	ANA 1/320	609	N/A	Resolved
						ASMA 1/20
Smati et al. [34] (2023), US	1	36, F	None	2,000 mg	6	Negative	1,077	Chronic portal triaditis, bile duct injury, patchy hepatocellular necrosis	Resolved
Luber et al. [35] (2019), Australia	2	52, 55	Diclofenac	375 mg	1 & 5	ANA 1/60 (1 case)	1,149, 2,591	Florid inflammatory cell infiltrate in portal tracts, interface hepatitis	Resolved
		1F, 1M		Other N/A
Sunagawa et al. [36] (2022), US	1	49, F	None	1,000 mg	1.5	ANA 1/320	3,289	N/A	Resolved
Halegoua-DeMarzio et al. [8] (2023), US	10	Age range: 35–71	None	Not specified	Median: 2.8	ANA positive: 50%, no titres	Median: 1,392	Acute hepatitis – moderate-severe inflammation, eosinophils or plasma cells/bridging necrosis; or cholestatic hepatitis	9 resolved, 1 death due to acute liver failure
		8F, 2M			Range: 1.2–14.1	ASMA positive: 20%, no titres	Range: 470–2,521
Current report	1	40, F	COCP	Not specified	5	ANA 1/320	2,688	Widespread necrosis, bridging with apoptotic cells, ceroid-laden macrophages, hepatocyte rosettes	Resolved

This case underscores the importance of recognising herbal and dietary supplements as potential culprits of liver injury. Loose regulations and testing standards for herbal supplements often mean significant adverse effects such as hepatotoxicity are only recognised in post-marketing surveillance. This highlights the need to re-evaluate the regulatory measures within the complementary industry. Additionally, the scarcity of comprehensive data on turmeric-induced DILI underscores the importance of initiatives like the DILIN in the USA. Such databases compiling DILI cases aim to enhance the safe use of medicines and alternative health therapies. Ultimately, larger scale clinical trials are needed to investigate the mechanisms underlying turmeric and black pepper’s hepatotoxicity.

The CARE Checklist has been completed by the authors for this case report. Additionally, the raw excel data used to generate Figures 2A, 2B, and 3 are provided as supplementary files – Figures S2A, S2B, and S3 – in PDF format and are attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000543679).

Statement of Ethics

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors declare that there are no conflicts of interest in this study. This work has not previously been presented in any form.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

A.S. and J.H.A. were responsible for the draft of the manuscript. A.S., S.E., J.H.A., K.W., T.W., I.S., and A.D. have contributed to the manuscript in terms of concept, writing, and editing. A.S., S.E., J.H.A., K.W., T.W., I.S., and A.D. were responsible for the critical revision of important intellectual content and editing of the manuscript and have given final approval of the article for publication.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All data generated or analysed during this study are included in this article and its online supplementary material files. Further enquiries can be directed to the corresponding author.