Cited by 62Drug-Induced Hepatotoxicity and ProtectionComplementary and Alternative Medicine StudiesPlant Toxicity and Pharmacological Properties

The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index; 31 of the 67 sources its claims cite were checked for support.

Ashwagandha-induced liver injury—A case series from India and literature review

Open access
Philips, Cyriac A., Valsan, Arun, Theruvath, Arif H., Ravindran, Resmi, Oommen, Tharun T., Rajesh, Sasidharan, Bishnu, Saptarshi, Augustine, Philip, on behalf of The Liver Research Club India·2023·Hepatology Communications

Abstract

Background: Ashwagandha herb is commonly used in Ayurveda and a “fad” dietary supplement for a host of indications based on low levels of evidence. Recently, ashwagandha was implicated in multiple reports of herb-induced liver injury (HILI), mainly from the United States. We present the first, and currently largest, series of ashwagandha-HILI from multiple centers in India. Methods: We retrospectively analyzed the respective institutional electronic medical records for ashwagandha-HILI. Patients consuming ashwagandha as part of multiherbal formulations or along with other known hepatotoxic supplements or medicines were excluded. All patients underwent a detailed diagnostic workup to exclude competing causes reasonably. Where possible, the implicated herbal formulation was retrieved and subjected to chemical analysis. Results: Out of 23 patients with liver injury from ashwagandha (January 2019 to December 2022), we report 8 patients with single-ingredient formulation-related HILI. Study cohort was male predominant, and cholestatic hepatitis was the commonest presentation. Five patients had underlying chronic liver disease; 3 presented with acute-on-chronic liver failure, and all 3 died on follow-up. In others, the liver injury was prolonged, nonetheless self-limiting. Liver biopsy revealed cholestatic features predominantly with hepatocellular necrosis and lymphocyte/eosinophil predominant portal-based inflammation. One patient progressed to chronic HILI. Chemical analysis revealed only natural phytochemicals without adulteration or contamination. Conclusions: Ashwagandha-HILI presents with cholestatic hepatitis and can lead to the syndrome of acute-on-chronic liver failure with high mortality in those with pre-existing liver disease. Educating the public on avoiding the use of potentially toxic and unrecommended herbal supplements can help mitigate the avoidable liver disease burden in the community.

Overview

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TL;DR

In a retrospective multicenter Indian case series, 8 patients with liver injury attributed to single-ingredient ashwagandha formulations most commonly presented with cholestatic hepatitis; those with pre-existing chronic liver disease who developed acute-on-chronic liver failure all died. Chemical analysis of retrieved products found natural phytochemicals without hepatotoxic adulterants or contaminants.

Key findings

  • Among 8 included patients (6 male, 2 female; median age 49 years), liver injury type by R-ratio was cholestatic in 4, hepatocellular in 3, and mixed in 1; jaundice occurred in 7/8 (87.5%) and pruritus in 5/8 (62.5%).
  • Five patients had underlying chronic liver disease; 3 presented with acute-on-chronic liver failure (ACLF), and all 3 died (overall mortality 37.5%, with deaths at 30, 242, and 288 days). HILI was severe in 6/8 (75%).
  • RUCAM classified 6 cases as probable and 2 as possible. Liver biopsy in 6 patients showed predominantly cholestatic features, lymphocytic/eosinophilic portal-based inflammation, and hepatocellular necrosis in 50%; one patient progressed to chronic HILI.
  • Chemical/toxicology analysis of 5 retrieved formulations found no hepatotoxic contaminants, adulterants, or synthetic agents; identified compounds included glycosides, lactones, terpenes, saponins, and alkaloids, with one product containing trace lead (0.21 mg/kg), cadmium (0.038 mg/kg), and arsenic (0.089 mg/kg).

Methods

  • Retrospective review of institutional electronic medical records from 3 tertiary centers in India, January 2019 to December 2022; from 23 patients with liver injury from ashwagandha-containing supplements, 8 using ashwagandha-only formulations were included.
  • Exclusions included multiherbal ashwagandha products, concomitant potentially toxic herbal supplements or prescription drugs, active alcohol use, and other competing causes of acute liver injury.
  • Evaluation included laboratory tests, viral serologies, autoimmune biomarkers, cross-sectional imaging, R-ratio classification, RUCAM causality assessment, liver biopsy where consented, and chemical/toxicology analysis of retrieved formulations.

Limitations

  • Stated: retrospective design and reliance on patient recall for duration/dates of herb consumption may introduce recall bias; data needed for Revised Electronic Causality Assessment Method could not be gathered; RUCAM may underestimate causality for herbal supplements; not all implicated products were retrieved for chemical analysis; HLA testing was not performed due to lack of resources; PCR for HCV and HEV was not performed, though viral hepatitis was considered unlikely.
  • Stated: the authors note the lack of an organized national DILI network and centralized expert-driven data assessment system.
  • Evident from the text: this is a small case series (8 patients) without a control group, and findings may not be generalizable beyond the participating Indian tertiary centers.

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Integrity signals

Registry

Crossref · 10.1097/hc9.0000000000000270

Cites

29 of 29 references verified0 citation errors · 0 not checkable

Statistics

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Figures

Graphical abstract
Graphical abstract CC BY-NC-ND · PubMed Central
FIGURE 1 The various types of ashwagandha formulations that were retrieved from patients. The products marked with a green tick are single-ingredient ashwagandha products, the use of which was one of the inclusion criteria. This study did not include patients using multiherbal products containing ashwagandha as a predominant or additional ingredient. The products which are marked with a “blue beaker icon” were considered adequate and unspoiled for further chemical analysis.
FIGURE 1 The various types of ashwagandha formulations that were retrieved from patients. The products marked with a green tick are single-ingredient ashwagandha products, the use of which was one of the inclusion criteria. This study did not include patients using multiherbal products containing ashwagandha as a predominant or additional ingredient. The products which are marked with a “blue beaker icon” were considered adequate and unspoiled for further chemical analysis.CC BY-NC-ND · PubMed Central
FIGURE 2 Representative liver histology of patients with ashwagandha-induced liver injury. Severe hepatocellular cholestasis (hematoxylin and eosin stain, ×40) (A); lymphocyte and eosinophil predominant portal inflammation (hematoxylin and eosin stain, ×20) (B); bridging necrosis and canalicular cholestasis in the presence of mild to moderate mixed inflammation consisting of lymphocytes, eosinophils, few plasma cells, and neutrophils (hematoxylin and eosin stain, ×20) (C); centrizonal and focal necrosis with minimal inflammation (hematoxylin and eosin stain, ×20) (D); mild to moderate interface hepatitis with lymphocyte predominant and few macrophage-based portal inflammation (E) and in the patient (shown in C) with bridging necrosis and cholestasis, repeat liver biopsy revealed progression to chronic herb-induced liver injury with the formation of vague/incomplete hepatocyte nodules and thick bridging fibrosis (Masson-trichrome stain, ×10) (F).
FIGURE 2 Representative liver histology of patients with ashwagandha-induced liver injury. Severe hepatocellular cholestasis (hematoxylin and eosin stain, ×40) (A); lymphocyte and eosinophil predominant portal inflammation (hematoxylin and eosin stain, ×20) (B); bridging necrosis and canalicular cholestasis in the presence of mild to moderate mixed inflammation consisting of lymphocytes, eosinophils, few plasma cells, and neutrophils (hematoxylin and eosin stain, ×20) (C); centrizonal and focal necrosis with minimal inflammation (hematoxylin and eosin stain, ×20) (D); mild to moderate interface hepatitis with lymphocyte predominant and few macrophage-based portal inflammation (E) and in the patient (shown in C) with bridging necrosis and cholestasis, repeat liver biopsy revealed progression to chronic herb-induced liver injury with the formation of vague/incomplete hepatocyte nodules and thick bridging fibrosis (Masson-trichrome stain, ×10) (F).CC BY-NC-ND · PubMed Central

Verification

Claims the paper makes

99 Own result · 16 Own interpretation · 15 Own method · 11 Partly supported · 11 Sources not found · 5 No basis given · 2 Supported · 2 Couldn’t confirm · 2 Not checked yet · 1 Supported so far · 1 No full text of the sources · accuracy not yet measured

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Show all 89 claims

  • Probably not a substantial claim. 56
  • It may state two separate claims as one. 31
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  • The paper relies on this without support.

    There are no reports of ashwagandha-related liver toxicity published from the Asian continent.

    “There are no reports of ashwagandha-related liver toxicity published from the Asian continent.”
  • The paper relies on this without support.

    Herbal and dietary supplements are not considered drugs/medications, responsibility for their safety lies with manufacturers, and good manufacturing practices approval from health regulatory bodies is required before marketing.

    “The HDS is not considered drugs/medications, and the responsibility for the safety of such products lies with the respective manufacturers, while good manufacturing practices approval from concerned health regulatory bodies is required before marketing.”
  • The paper relies on this without support.

    The doses and durations of ashwagandha intake reported by patients are accurate.

    “The dose of ashwagandha ranged from 10 to 15 g/d to 500 mg per day based on the type of formulation or as labeled on the product.”
  • The paper relies on this without support.

    The retrospective clinical data collected from patients are complete and accurate.

    “the study design and retrospective collection of patient data were approved by the respective institutional ethics and review boards.”
  • The paper relies on this without support.

    The chemical analysis of the retrieved ashwagandha formulations reflects the composition of the formulations actually consumed by the patients.

    “A detailed representation of various ashwagandha formulations retrieved from the patients and the specific formulations that were subjected to chemical analysis and toxicology are shown in Figure 1.”
  • The paper relies on this without support.

    The exclusion of other competing causes was sufficient to attribute the liver injury to ashwagandha.

    “The other 15 patients were excluded because they had consumed concomitant potentially toxic herbal formulations or were on ashwagandha-based multiherbal preparations, or had other competing causes for liver injury”
  • The paper relies on this without support.

    Most herbal supplements implicated in liver injury are frequently mislabeled or have accurate ingredients not evidently disclosed.

    “Most herbal supplements implicated in liver injury are frequently mislabeled or accurate ingredients not evidently disclosed.”
  • The paper relies on this without support.

    Ashwagandha is generally considered safe to consume.

    “Although ashwagandha is generally considered safe to consume”
  • The paper relies on this without support.

    There has been an increase in reports of DILI due to ashwagandha use.

    “there has been an increase in reports of DILI due to its use”
  • The paper relies on this without support.

    The increase in reports of DILI due to ashwagandha use is driven by unscientific and nonevidence-based promotion among general people through print, visual, and social media.

    “driven by unscientific and nonevidence-based promotion among general people through print, visual, and social media.”
  • The paper relies on this without support.

    RUCAM is the standardized, validated tool to measure causality in DILI.

    “RUCAM is the standardized, validated tool to measure causality in DILI”
  • The paper relies on this without support.

    Published studies on single-ingredient herbal supplements have used RUCAM to approximate causality, while others have only depended on an exhaustive diagnosis of exclusion without using any causality tools.

    “published studies on single-ingredient herbal supplements have used RUCAM to approximate the causality, while others have only depended on an exhaustive diagnosis of exclusion without using any causality tools.”
  • The paper relies on this without support.

    The newly developed Revised Electronic Causality Assessment Method and the gold standard DILIN consensus are better tools for causality assessment.

    “We understand that the newly developed Revised Electronic Causality Assessment Method and the gold standard DILIN consensus are better tools for causality assessment.”
  • The paper relies on this without support.

    Multiple prior studies have demonstrated a drug or herb-specific HLA association with DILI.

    “Multiple prior studies have demonstrated a drug or herb-specific HLA association with DILI.”
  • The paper relies on this without support.

    Ashwagandha use as a dietary supplement for unproven indications has been rising in western countries, especially for mental health disorders and as a workout supplement among gym-goers.

    “but lately, its use as a dietary supplement for unproven indications has been on the rise in western countries, especially for mental health disorders and as a workout supplement among gym-goers.”
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Metadata

Authors
Philips, C. A., Valsan, A., Theruvath, A. H., Ravindran, R., Oommen, T. T., Rajesh, S., Bishnu, S., Augustine, P., & India, O. B. O. T. L. R. C.
Affiliations
  • Amrita Institute of Medical Sciences and Research Centre (IN)
  • Rajagiri Hospital (IN)
  • Department of Gastroenterology and Hepatology, Astha Medical Centre, Koshbagan, Burdwan, West Bengal, India
Corresponding author
Philips, Cyriac A.
Venue
Hepatology Communications
Published
2023-09-27
Volume
7
Issue
10
ISSN
2471-254X (ISSN-L)
OpenAlex
W4387078308
Cited by
62
References
29
Citations by year
2026: 26 · 2025: 14 · 2024: 17 · 2023: 4
FWCI
14.58
Type
journal article
Language
en
Open access
Locations
  • Hepatology Communications (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Medicine › Complementary and alternative medicine › Complementary and Alternative Medicine Studies
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Plant Toxicity and Pharmacological Properties
Keywords
Withania somnifera, herb-induced liver injury, hepatotoxicity, cholestatic hepatitis, acute-on-chronic liver failure, herbal supplements, Ayurveda, chronic liver disease, liver necrosis
MeSH terms
Hepatitis, Humans, India, Male, Plant Extracts, Retrospective Studies, Chemical and Drug Induced Liver Injury, Chemical and Drug Induced Liver Injury, Chronic, Acute-On-Chronic Liver Failure

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