Systematic Reviews
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Jul 16, 2021; 9(20): 5490-5513
Published online Jul 16, 2021. doi: 10.12998/wjcc.v9.i20.5490
Herb-induced liver injury: Systematic review and meta-analysis
Vinícius Remus Ballotin, Lucas Goldmann Bigarella, Ajacio Bandeira de Mello Brandão, Raul Angelo Balbinot, Silvana Sartori Balbinot, Jonathan Soldera
Vinícius Remus Ballotin, Lucas Goldmann Bigarella, School of Medicine, Universidade de Caxias do Sul, Caxias do Sul 95070-560, RS, Brazil
Ajacio Bandeira de Mello Brandão, Post-Graduate Program in Medicine, Division of Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050-110, RS, Brazil
Raul Angelo Balbinot, Silvana Sartori Balbinot, Jonathan Soldera, Department of Clinical Gastroenterology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, RS, Brazil
Author contributions: All authors contributed to study concept and design and drafting of the manuscript; all authors contributed to acquisition of data, analysis, and interpretation of data; Ballotin VR contributed to statistical analysis; Soldera J contributed to study supervision; all authors contributed to critical revision of the manuscript for important intellectual content.
Conflict-of-interest statement: All authors have nothing to disclose.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jonathan Soldera, MD, MSc, Associate Professor, Staff Physician, Department of Clinical Gastroenterology, Universidade de Caxias do Sul, Rua Francisco Getúlio Vargas, 1130, Caxias do Sul 95070-560, RS, Brazil. jonathansoldera@gmail.com
Received: February 23, 2021
Peer-review started: February 23, 2021
First decision: March 28, 2021
Revised: April 3, 2021
Accepted: May 25, 2021
Article in press: May 25, 2021
Published online: July 16, 2021
ARTICLE HIGHLIGHTS
Research background

In the last decades, the use of herbal supplements in the East and in the West, natural products, and alternative medicines has risen considerably, which is consistently underreported by patients. Despite popular belief that the consumption of natural products is harmless, herbs might cause injury to various organs. Herb-induced liver injury (HILI) is a term currently used to describe liver injury related to herbal medicines. The manifestations can vary depending on the causing product, ranging from asymptomatic cases with increased transaminases to fulminant liver failure, resulting in liver transplantation or death.

Research motivation

Our motivation was to gather data from case reports and case series in the literature to provide an overview for physicians suspecting HILI and to raise awareness for the risk associated with self-prescribed use of herbal products.

Research objectives

We aimed to review systematically the literature to identify herbal products associated with liver injury and describe the type of lesion associated with each product.

Research methods

This study was carried out in accordance with the recommendations contained in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Studies were retrieved using comprehensive search terms on nine electronic databases with no date of publication restrictions. Clinical case reports or case series involving herbal drug use and hepatotoxicity were included in the study. Studies were excluded if they were not case reports or case series or if they were not related to the topic. The variables collected were demographic data, herbs used, clinical presentation, liver function tests, biopsy results, comorbidities, comedications, and treatment, and the outcome measured was recovery, chronic liver disease, or death. Causality was assessed using the Maria and Victorino System of Causality Assessment in Drug Induced Liver Injury. Simple descriptive statistics, such as the mean ± standard deviation, frequency, and median were used to characterize the data. Data were summarized using RStudio (version 4.0.2), and the patterns of liver injury were classified using R value.

Research results

A total of 446 references corresponding to 936 cases were included. Case reports from the United States were the most common, and 65.2% of patients were females. The most prevalent herbs and herbal products were He-Shou-Wu, green tea extract, Herbalife, kava kava, and greater celandine, and a previous report of liver injury by the implied herb was described in 855 cases (98.1%). The most common clinical presentation of the reviewed cases was jaundice (46.3%), followed by abdominal pain and nausea (22.4% and 17.2%, respectively). The most common pattern of HILI was hepatocellular, in 660 (70%) cases, followed by sinusoidal obstruction syndrome in 92 (9.7%) cases and cholestatic in 80 (8.5%) cases. The mean Maria and Victorino System of Causality Assessment score was 8.69 (3.93, standard deviation) and median. The most prevalent treatments consisted of supportive care (66.1%), such as herbal withdrawal and intravenous fluid replacement. Complete recovery occurred in 782 (82.8%) of patients. Chronic liver disease and death were observed in 1.5% and 10.4% of the cases, respectively.

Research conclusions

This systematic review comprehensively gathers data from case reports and case series in the literature to provide an overview for physicians suspecting HILI and their patients. Further research should evaluate the potential HILI risk (incidence and prevalence) and clinical characteristics and identify hepatotoxic compounds of herbs and their pharmacokinetic and pharmacodynamic properties. It is necessary to improve our knowledge on possible risk factors for the development of liver injury, to validate causality assessment tools, and to improve treatment efficacy for HILI. The discussion of the risk of herbal use with the patients is paramount. The authors hope that these findings can offer direction for health professionals and scientific research and thus help to avoid liver failure associated with HILI in the future.

Research perspectives

Herbs and herbal products are a growing cause of liver damage that patients and physicians should be aware. Patients should be specifically asked about the use of herbs and herbal products because patients often do not consider them to be harmful. Further research should evaluate the potential HILI risk (incidence and prevalence) and clinical characteristics and identify hepatotoxic compounds on herbs and their pharmacokinetic and pharmacodynamic properties.