Complementary and alternative medicines and liver disease.

Complementary and alternative medicines (CAM) include conventional medical treatments. Patients worldwide use CAM at alarming rates; thus, reports of CAM-related DILI have been on the rise. The clinical presentations include asymptomatic liver test abnormalities, acute hepatitis with or without jaundice, acute cholestatic liver disease (bland or with hepatitis), acute liver failure, severe hepatitis with features of portal hypertension, and acute decompensation of known or unknown cirrhosis that can lead to acute-on-chronic liver failure. Acute hepatitis with or without necrosis, hepatocellular and canalicular cholestasis, herb-induced or CAM-triggered autoimmune hepatitis, granulomatous hepatitis, severe steatohepatitis, and vanishing bile duct syndrome are common liver biopsy findings in CAM-DILI. The presence of preexisting liver disease predicts severe liver injury, risk of progression to liver failure, and decreased transplant-free survival in patients with CAM-DILI. This review discusses global epidemiology and trends in CAM-DILI, clinical presentation, assessment and outcomes, commonly emerging threats in the context of hepatotoxic herbs, pragmatic assessment of "liver beneficial" herbs and health care myths, patient communication, regulatory framework, and future directions on research in CAM.

Clinical outcomes associated with complementary and alternative medicine-related "immunity-boosting" practices in patients with cirrhosis during the COVID-19 pandemic - an observational study.

During the coronavirus disease 2019 pandemic, Ayurvedic herbal supplements and homeopathic immune boosters (IBs) were promoted as disease-preventive agents. The present study examined the clinical outcomes among patients with chronic liver disease who presented with complications of portal hypertension or liver dysfunction temporally associated with the use of IBs in the absence of other competing causes. This single-center retrospective observational cohort study included patients with chronic liver disease admitted for the evaluation and management of jaundice, ascites, or hepatic encephalopathy temporally associated with the consumption of IBs and followed up for 180 days. Chemical analysis was performed on the retrieved IBs. From April 2020 to May 2021, 1022 patients with cirrhosis were screened, and 178 (19.8%) were found to have consumed complementary and alternative medicines. Nineteen patients with cirrhosis (10.7%), jaundice, ascites, hepatic encephalopathy, or their combination related to IBs use were included. The patients were predominantly male (89.5%). At admission, 14 (73.75%) patients had jaundice, 9 (47.4%) had ascites, 2 (10.5%) presented with acute kidney injury, and 1 (5.3%) had overt encephalopathy. Eight patients (42.1%) died at the end of the follow up period. Hepatic necrosis and portal-based neutrophilic inflammation were the predominant features of liver biopsies. IB analysis revealed detectable levels of (heavy metals) As (40%), Pb (60%), Hg (60%), and various hepatotoxic phytochemicals. Ayurvedic and Homeopathic supplements sold as IBs potentially cause the worsening of preexisting liver disease. Responsible dissemination of scientifically validated, evidence-based medical health information from regulatory bodies and media may help ameliorate this modifiable liver health burden.

A series of homeopathic remedies-related severe drug-induced liver injury from South India.

INTRODUCTION: Homeopathic remedies are highly diluted formulations without proven clinical benefits, traditionally believed not to cause adverse events. Nonetheless, published literature reveals severe local and non-liver-related systemic side effects. We present the first series on homeopathy-related severe drug-induced liver injury (DILI) from a single center. METHODS: A retrospective review of records from January 2019 to February 2022 identified 9 patients with liver injury attributed to homeopathic formulations. Competing causes were comprehensively excluded. Chemical analysis was performed on retrieved formulations using triple quadrupole gas chromatography-mass spectrometry and inductively coupled plasma atomic emission spectroscopy. RESULTS: Males predominated with a median age of 54 years. The most typical clinical presentation was acute hepatitis, followed by acute on chronic liver failure. All patients developed jaundice, and ascites were notable in one-third of the patients. Five patients had underlying chronic liver disease. COVID-19 prevention was the most common indication for homeopathic use. Probable DILI was seen in 77.8%, and hepatocellular injury predominated (66.7%). Four (44.4%) patients died (3 with chronic liver disease) at a median follow-up of 194 days. Liver histopathology showed necrosis, portal and lobular neutrophilic inflammation, and eosinophilic infiltration with cholestasis. A total of 29 remedies were consumed between 9 patients, and 15 formulations were analyzed. Toxicology revealed industrial solvents, corticosteroids, antibiotics, sedatives, synthetic opioids, heavy metals, and toxic phyto-compounds, even in 'supposed' ultra-dilute formulations. CONCLUSION: Homeopathic remedies potentially result in severe liver injury, leading to death in those with underlying liver disease. The use of mother tinctures, insufficient dilution, poor manufacturing practices, adulteration and contamination, and the presence of direct hepatotoxic herbals were the reasons for toxicity. Physicians, the public, and patients must realize that Homeopathic drugs are not 'gentle placebos.'

Spectrum of drug-induced liver injury in a tertiary hospital in southern India.

Background Anti-tuberculosis drugs are thought to account for about 50% of drugs that cause liver injury in India. We show that the spectrum of drugs is much wider than previously reported. Methods We evaluated all patients with unexplained acute liver injury presenting during 2006-2016 using a structured proforma for drug-induced liver injury (DILI). The Roussel Uclaf Causality Assessment Method was used to assess causality. Results DILI was found in 143 of 2534 patients with acute liver injury. Nineteen patients had probable ayurvedic DILI. The other common causes of DILI were statins (16 patients) and anti-tuberculosis drugs (11 patients). Eight patients had DILI post-liver transplant. Fluconazole was the most common cause of post-liver transplant DILI. Chronic DILI (abnormal liver function test after 12 months of stopping the suspected drug) was found in 2 patients. Conclusion In otherwise unexplained acute liver injury, DILI due to ayurvedic drugs should be sought. DILI should be considered in post-liver transplant patients. Patients with DILI should be monitored for at least 12 months to exclude progression to chronic DILI.

Ayurvedic treatment induced severe alcoholic hepatitis and non-cirrhotic portal hypertension in a 14-year-old girl.

We report a novel and as yet undescribed clinical scenario in a young girl with liver failure, in whom, the liver histopathology was suggestive of alcoholic hepatitis in the background of hepatoportal sclerosis and incomplete septal cirrhosis. An extensive clinical and investigational evaluation revealed chronic consumption of multiple Ayurvedic herbal medications for seizure disease. Six months after stopping herbal medicines, the repeat liver biopsy demonstrated resolution of alcohol-related changes but persistence of classical features of non-cirrhotic portal hypertension. Analysis of the retrieved agents, including state of the art chemical and toxicology analysis, using gas chromatography and mass spectroscopy methods demonstrated multiple organic and inorganic toxins associated with acute alcohol and arsenic poisoning related hepatoportal sclerosis/incomplete septal cirrhosis in the young girl.

Comprehensive review of hepatotoxicity associated with traditional Indian Ayurvedic herbs.

With growing antipathy toward conventional prescription drugs due to the fear of adverse events, the general and patient populations have been increasingly using complementary and alternative medications (CAMs) for managing acute and chronic diseases. The general misconception is that natural herbal-based preparations are devoid of toxicity, and hence short- and long-term use remain justified among people as well as the CAM practitioners who prescribe these medicines. In this regard, Ayurvedic herbal medications have become one of the most utilized in the East, specifically the Indian sub-continent, with increasing use in the West. Recent well-performed observational studies have confirmed the hepatotoxic potential of Ayurvedic drugs. Toxicity stems from direct effects or from indirect effects through herbal metabolites, unknown herb-herb and herb-drug interactions, adulteration of Ayurvedic drugs with other prescription medicines, and contamination due to poor manufacturing practices. In this exhaustive review, we present details on their hepatotoxic potential, discuss the mechanisms, clinical presentation, liver histology and patient outcomes of certain commonly used Ayurvedic herbs which will serve as a knowledge bank for physicians caring for liver disease patients, to support early identification and treatment of those who present with CAM-induced liver injury.

Erratum: Removal Notice to "Slimming to the Death: Herbalife® Associated Fatal Acute Liver Failure - Heavy Metals, Toxic Compounds, Bacterial Contaminants and Psychotropic Agents in Products Sold in India", [J Clin Exp Hepatol 9 (2019) 268-272].

[This corrects the article DOI: 10.1016/j.jceh.2018.08.002.].

Complementary and Alternative Medicine-related Drug-induced Liver Injury in Asia.

The use of complementary and alternative medicines (CAMs) for treatment of acute and chronic diseases is on the rise world over, especially in Asian countries, and mostly in China and India. Drug-induced liver injury (DILI) due to CAM is increasingly reported in the literature from multiple centers all around the world and with large-number patient series published from the West, mostly based on nation-wide DILI networks and multicenter collaboration. Comprehensive DILI networks are lacking among major Asian countries with high incidence of CAM practices. Chinese medical societies dealing with drug toxicity, CAM practice and hepatobiliary disease have adopted an integrated approach to establishing identification, diagnosis and treatment of CAM-related DILI, representing a systematic approach that could be iterated by other countries for improving patient outcomes. In this exhaustive review, we provide published data on CAM-related DILI in Asia, with detail on incidences along with analysis of patient population and their clinical outcomes. Concise and clear discussion on commonly implicated CAM agents in major Asian countries and associated chemical and toxicology analyses as well as descriptions of liver biopsy findings are discussed with future directions.

A Single-Center Experience on Outcomes of Complementary and Alternative Medicine Use Among Patients With Cirrhosis.

Drug-induced liver injury (DILI) due to complementary and alternative medicine (CAM) use is on the rise throughout the world by patients looking for "safer" alternatives. However, data on acute-on-chronic liver failure (ACLF) due to CAM are lacking. In a large cohort of patients with cirrhosis, we retrospectively studied CAM-related health-seeking behavior and attempted to identify those who developed possible CAM-DILI-related ACLF. In this study, we examine the clinical, biochemical, and liver histopathologic characteristics of possible CAM-DILI-related ACLF, describe implicated CAM agents, and discuss predictors of patient outcomes. Out of 1,666 patients with cirrhosis, 68% used CAM at some point. A total of 35.7% (n = 30/84) patients presented with CAM-related DILI leading to ACLF in the whole CAM-DILI-related decompensation cohort. The most common CAM was unlabeled polyherbal Ayurvedic formulations. Of possible patients with ACLF, 63% self-medicated with CAM based on social media sharing. Mean age ± SD was 51.9 ± 9.9 years, 83% were male patients, median follow-up duration was 173 (range, 14-584) days, median Child-Turcotte-Pugh score was 13 (range, 10-14), Model for End-Stage Liver Disease-sodium score was 30.1 ± 4.8, median chronic liver failure-organ failure (CLIF-C-OF) score was 11 (range, 8-14), and median CLIF-C-ACLF score was 98 (range, 87-127). Portal-based neutrophilic predominant mixed inflammation, hepatocyte ballooning, autoimmune-like features, and severe cholestasis were seen on liver biopsy. Overall, 53% of patients died (median survival 194 days). Baseline overt hepatic encephalopathy and CLIF-C-OF score, total bilirubin, hyponatremia and leukocytosis, and grade of ACLF predicted 1-, 3-, 6- and 12-month mortality, respectively. Conclusion: Possible CAM-DILI-related ACLF has a high mortality. Strict monitoring and identification of CAM use among people with cirrhosis and an integrative public health educational practice can help ameliorate this modifiable risk factor that potentiates heavy liver disease burden and resource use.

Homeopathy-medicine induced severe alcoholic hepatitis.

We present a teetotaler with compensated non-alcoholic fatty-liver-disease related cirrhosis who presented with acute worsening of his chronic liver disease. The acute event was not discernible even after extensive work up and finally a transjugular liver biopsy revealed features suggestive of severe alcoholic hepatitis. The patient and the family denied occult alcohol use when questioned over multiple times and finally, the culprit 'alcohol' was found to be the homoeopathy medicines that the patient was consuming over a month for treatment of Gilbert's syndrome. We retrieved and tested the homoeopathy drug for alcohol content and found an alarming 18% ethanol in the same, confirming our diagnosis.

Ayurveda Herbal Medicine-induced Liver Cirrhosis.

We present the rare case of a young male with sinusoidal obstruction syndrome due to Ayurvedic herbal medicine which he took for management of bilateral leg swelling associated with protein-losing enteropathy due to intestinal lymphangiectasia. The patient developed progressive sinusoidal fibrosis leading to cirrhosis on long term follow-up. In a diagnosis that took three years to conclude, we showcase serial liver biopsies that reveal the rare disease progression. Complementary and alternative medicine use among apparently healthy population is a potentially modifiable risk factor for liver diseases, in the presence of adequate public health education from concerned authorities.

Slimming to the Death: Herbalife®-Associated Fatal Acute Liver Failure-Heavy Metals, Toxic Compounds, Bacterial Contaminants and Psychotropic Agents in Products Sold in India.

For legal reasons, the publisher has withdrawn this article from public view. For additional information, please contact the publisher.

Outcomes and Toxicology of Herbal Drugs in Alcoholic Hepatitis - A Single Center Experience from India.

Background and Aims: We aimed to study clinical outcomes and liver biopsy features of alcoholic hepatitis (AH) patients on complementary and alternative medicines (CAMs) and to analyze the retrieved drugs for chemical and toxic components linked to drug-induced liver injury. Methods: We retrospectively assessed clinical, biochemical and liver biopsy features of AH patients on CAM with drug-induced liver injury (AH-CAM, n = 27) and compared them to a control group (classical AH, n = 29) on standard of care. Patients without liver biopsy evaluation and other causes for liver disease were excluded. Samples of the CAMs (n = 42) from patients were retrieved and assessed for chemical and toxins. Results: All were males, and significantly worse clinical presentation, biochemical severity, and liver disease scores were notable in patients with AH-CAM. Traditional Ayurvedic-polyherbal formulations were the most commonly used CAM. On liver histology, varying grades of severe-necrosis, severe hepatocellular, canalicular, cholangiolar cholestasis with predominant lymphocytic-portal-inflammation and varying grades of interface-hepatitis were noted in AH-CAM. Analysis of CAMs revealed presence of heavy metals up to 100,000 times above detectable range and adulterants, such as antibiotics, chemotherapy agents, nonsteroidal anti-inflammatory drugs, alcohols, antidepressants, anxiolytics, and recreational drugs. On follow up, a significantly higher number of patients with AH on CAM died at end of 1, 3- and-6-months compared to controls (37% vs. 83%, 29% vs. 62%, 18% vs. 52% respectively; p < 0.001). Conclusions: Patients with AH and CAM-related drug-induced liver injury have extremely poor short-term survival in the absence of liver transplantation compared to those patients with AH on evidence-based management. Early transplant referral and educating on and curbing of CAM use in severe liver disease through strict monitoring of unregulated traditional health practices can help ease the burden of liver-related death.

Chemical Analysis of Weight Loss Herbal Supplement Safe Lean™ Associated With Acute Liver Injury - A Concern for Spurious Drug, Misbranding and Adulteration.

Liver injury due to herbal and dietary supplements are well described in literature and its incidence has been on the rise in the past decade. Labelling an herbal product as non-medicinal and as a supplement precludes protocols needed for testing, trials and marketing criteria. This has led to rampant use of clinically unproven multi-herb-based drugs use for a myriad of lifestyle diseases. In this report, we discuss a new dietary weight loss supplement, Safe Lean™ that was found to be the cause of liver injury in a young obese woman, that resolved after discontinuation, and discuss current literature on component, toxicology and chemical analysis of the offending drug.

Ayurveda metallic-mineral 'Bhasma'-associated severe liver injury.

Ayurveda Bhasma is a metallic-mineral preparation homogenised with herbal juices or decoctions and modified with heat treatment to apparently detoxify the heavy metals. It is widely recommended for the treatment of many disease conditions by practitioners of complementary and alternative medicine in the absence of good quality clinical trial evidence on its safety and efficacy. Heavy metal-induced liver injury is widely reported in the literature, and heavy metal adulteration of non-Bhasma-related Ayurveda and herbal products has been well described. We report a patient who developed severe liver injury requiring listing for liver transplantation for improved survival, after consumption of Bhasma for dyspepsia. This case describes the first documented case and toxicology analysis of Ayurveda Bhasma associated with severe drug-induced liver injury. Physicians must be alert regarding patient's use of supposedly safe Ayurveda Bhasma that may promote acute severe liver injury in the absence of other known aetiologies.

Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis.

INTRODUCTION: Alcohol-induced intestinal dysbiosis is central to the development of the severe alcoholic liver disease. We present the first study to compare outcomes in patients of severe alcoholic hepatitis (SAH) on nutritional therapy, corticosteroids, pentoxifylline, and healthy donor fecal transplantation (FMT) and discuss distinct microbial community and microbiome metabolic functional changes after FMT. METHODS: Out of 1271 liver disease patients, 809 (63.7%) were diagnosed to have the alcoholic liver disease, of which 51 patients (8 treated with corticosteroids, 17 with nutritional support only, 10 with pentoxifylline, 16 receiving FMT) were included. Clinical, biochemical parameters, liver disease, and alcoholic hepatitis severity scores at baseline and mortality at the end of 1 and 3 months were analyzed between groups. Stool microbiota (SM) analysis was performed for healthy controls (HC) and respective recipients after FMT. RESULTS: All the patients were male. The proportions of patients surviving at the end of 1 and 3 months in the steroids, nutrition, pentoxifylline, and FMT group were 63%, 47%, 40% and 75% [p = 0.179] and 38%, 29%, 30%, and 75% [p = 0.036], respectively. When compared with FMT, relative risk and hazard ratios for death were higher in all the other groups. Following FMT, distinct and beneficial modulation of SM and pathways of dysregulated metabolism, infections, inflammation, and oxidative stress in SAH patients were noted in tandem with improved clinical outcomes. CONCLUSIONS: Healthy donor FMT for SAH improves survival beyond what is offered by current therapies and can function as a cost-effective bridge to liver transplant (LT) or for improving transplant-free survival. Larger studies and randomized trials are unmet needs.