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Interview: Cyriac Abby Philips, MBBS, MD, DM (Hepatology)

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Dr. Cyriac Abby Philips is currently working as Consultant and Physician-Scientist, in The Liver Unit and Monarch Liver Laboratory of the Cochin Gastroenterology Group, based in Kochi, under Philip Augustine Associates. He is also the Clinical Advisor and Doctoral Advisory Committee Member, Department of Cell and Tissue Culture at Sree Chitra Tirunal Institute for Medical Sciences and Technology, a Central Institute under the Government of India, at Trivandrum, Kerala.

Dr. Philips is a two-time American Association for the Study of Liver Diseases (AASLD) clinical hepatology plenary awardee (2015, 2017) and three-time AASLD Young Investigator Award winner (2015, 2016, 2017) and the 2017 winner of the Young Investigator Award of the European Association for the Study of Liver (EASL) for his works on fecal microbiota transplantation in liver disease, Ayurveda and herbal induced liver injury and gut microbiome in alcohol related liver disease. He was conferred the President of India Gold in Hepatology at the Institute of Liver and Biliary Sciences, New Delhi in 2016.

He has published over 160+ peer reviewed articles in high impact journals such as the New England Journal of Medicine, Journal of Hepatology, Hepatology and American Journal of Gastroenterology. He has authored over 12+ chapters on topics in cirrhosis, portal hypertension, alcohol-associated liver disease and drug induced liver injury. He is currently editorial member, academic and guest editor of the Indian Journal of Gastroenterology, Journal of Clinical and Translational Hepatology, BMC Gastroenterology and Biomed Research International. His pioneering work in the field of liver diseases has been the introduction of healthy donor fecal transplant for severe alcoholic hepatitis and novel data on toxicology and chemical analysis of complementary and alternative medicine (specifically AYUSH related) induced liver injury.

You can find him on Twitter at: @drabbyphilips.

Q. Can you provide us with some background on Ayurveda? What is its history and how is it used today? Can it be classified as a subset of "herbal supplements," or is it in a class of its own?

Ayurveda is a traditional system of medicine that originated in India. Principles of Ayurvedic practice are based on accounts of disease and management embodied in classical texts written by ancient ‘sages’, such as Charaka (medicine) and Susruta (medicine and surgery), who ‘received’ such direct knowledge from other sages and through the Hindu god of medicine, Dhanvantari. This, in principle, makes Ayurveda an ancient, traditional, faith-based system of complementary and alternative medicine with historical roots entrenched in primeval beliefs that is still taught and propagated in its naïve form globally.

Ayurveda forms part of the larger unified traditional system of medicine called AYUSH (Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy) that is operational in India and which is overseen and promoted by an independent central-union ministry of AYUSH. Currently, Ayurveda is heavily promoted and utilized as a system with ‘safer’ options and ‘time-tested’ treatments. However, these two terms are inaccurate, since the promotion of ‘safety’ of Ayurvedic medicines has been heavily criticized, with emerging evidence showing severe organ toxicity, such as liver and kidney damage associated with short, intermediate, and long-term use of Ayurvedic drugs.

Similarly, the term ‘time-tested,’ according to valid scientific methodology, does not mean efficacious. This makes Ayurveda a pseudoscience, with the majority of its current practice lacking supporting evidence for efficacy and safety. None of the Ayurvedic drugs or treatment protocols are approved or used as standard of care.

In general, Ayurveda treatments involve the use of probably safe external applications or consumption of simple or complex combinations of herbs, metals, and minerals. These are classified into those which are prepared according to ‘classical ancient texts’ called classical Ayurvedic drug formulations (for example, chyawanprash) or proprietary herbal drugs that are defined as compound formulations that are developed by individuals or pharmaceutical companies with a proprietary right to the drug formulation and its marketing (for example, Liv.52 by Himalaya®). In this regard, current Ayurveda practice involves the use of herbal components in drugs, dietary supplements, and nutraceuticals. It is a much larger industry than just the supplements industry, because of its advertised use in ‘therapeutics.’

Q. You've published quite a bit of research focused on the health concerns of Ayurveda/herbal supplements, particularly with respect to liver toxicity. When and why did you first become interested in this topic?

After completing my training in Hepatology and Liver Transplant Medicine at the Institute of Liver and Biliary Sciences, New Delhi, I returned to my home city of Kochi, situated in the South Indian state of Kerala in the year 2016 to start my clinical practice. My interest was originally alcohol-associated liver diseases (AALD) as Kerala, my home-state, has among the highest-burden of alcohol use and AALD.

However, during the initial few months of my clinical practice, I started to notice many patients with acute liver injury (acute hepatitis with jaundice) and acute liver failure (jaundice with cerebral failure or encephalopathy) without any standard identifiable causes, such as viral infections, prescription drugs with known liver toxicity (for example, old-world painkillers and antibiotics like anti-tuberculosis drugs), autoimmune liver disease, etc. I then proceeded to perform liver biopsies on these patients after receiving informed consent and found that the liver pathology was suggestive of severe, but varied, injury patterns. These findings prompted me to deep dive into the clinical history of the patients to determine the onset of liver injury events in retrospect. What I found was that all of these patients, who did not have identifiable causes for their liver injury, were consuming at times single, most times multiple, classical and proprietary Ayurvedic herbal products for various symptoms and illnesses, ranging from ‘gas formation’ to diabetes and fatty liver, for a few days to a few months, presuming they were “natural and safe” and hence they did not feel the need to disclose this to the treating physician.

I proceeded to document this with attentiveness in the many cases that followed. I went one novel step further to retrieve the suspected offending Ayurvedic herbal drug(s) from the patients’ home (some almost nine hours journey by road) and subjected these medicines to chemical and toxicology analysis (the analyses funding was borne by me from my salary, which I continue to do so, for public health and education). What we discovered from these analyses was interesting and novel, yet concerning. Thereafter, I published my findings as a large single series on Ayurvedic herbal drugs and liver injury with complete chemical/toxicology analysis, in the peer-reviewed Indian Journal of Gastroenterology (official publication of the Indian Society of Gastroenterology) in 2018[1], on which an editorial was written, titled Ayurvedic and herbal medicine-induced liver injury: It is time to wake up and take notice[2]. This study and its findings—that “herbal” does not mean “natural and safe”—changed the course of my work interest toward drug-induced liver injury specifically due to the AYUSH group of drugs. I continue to work on this aspect of untested Ayurvedic herbals, since this was a ‘hidden’ danger to public health on which there is the need to strongly voice, through science-based evidence generation, realistic health education.

Q. Do you believe there is a place in modern medicine for Ayurveda and herbal supplements?

Yes, I do believe that, but not in the current form. Ayurveda is not scientific, some of its aspects are ‘half-baked’, and principles of diagnosis and management are ‘thoughts that border on science’, with current practical applications that are not evidence-based. The first step is to consider Ayurveda a “stepping stone,” rather than the final word in disease prevention and management.

This would mean promoting Ayurveda as a pure branch of ‘translational medicine,’ in which the application of rigorous clinical research protocols and tools, new cutting-edge technologies, and analytics will help us identify and generate data on novel bioactive molecules or compounds that can be then put to use in phased quality trials to promote better clinical outcomes in specific diseases or groups of patients. The current form of Ayurveda is still ‘faith/belief’-based, running on ‘business mode,’ mostly powered by general public sentiments, and patient gullibility, both of which are promoted through unregulated false advertisement-based selling. Use of Ayurveda should be only for bench-to-bedside clinical-translational purposes and not as a therapy.

Q. Can Ayurveda and herbal supplements increase the risk of (or even cause) liver injury? If so, is it the supplements themselves or contaminants in the supplements?

Contrary to popular belief, Ayurvedic herbals and herbal drugs, including those in traditional Chinese medicine, are not safe. They can cause tremendous toxicity to human organs, and in the process produce significant health burdens and resource utilization. Speaking strictly from Ayurvedic herbals point of view, it is well known that contamination and adulteration have caused[3] significant[4] heavy metal poisoning, even in large population clusters.

In addition to our original work on investigating Ayurvedic herbal drugs causing severe liver injury and acute liver failure, we have also shown that use of Ayurvedic herbals in patients with chronic liver disease (meaning they have an increased risk for injury) can lead to acute or chronic liver failure, with a very low chance of surviving without a liver transplant. We published this finding in the peer-reviewed journal, Hepatology Communications[5]. Also, traditional use of Ayurvedic systems for management of jaundice (symptom-based management rather than disease- or syndrome-based treatment) among patients with severe alcohol-associated hepatitis led to a high death rate[6].

That complementary and alternative medicine use—such as Ayurvedic herbal and traditional Chinese medicines—can cause severe liver injury and even death has also been shown in multinational studies conducted by the Asia-Pacific Association for Study of the Liver[7]. The cause for such adverse events can be summarized into three categories: 1) Adulteration with known hepatotoxic agents (for example: painkillers in herbal drugs for arthritis); 2) Contamination during manufacturing (example: heavy metals, industrial solvents from equipment), and; 3) Direct toxicity from single or multiple herbs in Ayurvedic medicine. In the latter, toxicity can happen with known toxic herbal components, such as pyrrolizidine alkaloids (the herb Crotalaria) due to ignorance and poor sourcing, causing severe injury to blood vessels in the liver; or epigallocatechin gallate (green tea extracts) that is liver toxic in high doses (unregulated herbal dietary supplements). Direct toxicity can also happen with unknown and unidentified plant-based chemicals such as saponins, terpenes, and anthraquinones.

Q. One of your publications, a case study on a woman who experienced acute liver failure while taking Herbalife products, was recently retracted. Can you run us through what happened?

Herbal and dietary supplements causing liver failure is well documented in the literature. This is also true of Herbalife products, on which multiple studies and publications are already available in peer reviewed journals.

In August 2018, we published the first account of Herbalife-associated liver failure and death in a young woman from the Asia-Pacific region, entitled: “Slimming to the Death: Herbalife®-Associated Fatal Acute Liver Failure-Heavy Metals, Toxic Compounds, Bacterial Contaminants and Psychotropic Agents in Products Sold in India,” published by Elsevier in the Journal of Clinical and Experimental Hepatology (JCEH), the official journal of the Indian Association for the Study of the Liver (INASL). After this was published, Herbalife employees reached out to me to show proof of evidence. I replied saying that all the proof was present in the peer-reviewed published study. Thereafter, Elsevier forwarded me an email from Prof. Steven McMaster of the University of Guelph (whose activities are funded by Herbalife), who wrote a long list of issues with respect to the article, asking Elsevier to retract my paper. Elsevier advised me to reply to the letter in a point-by-point manner. My co-authors and I complied with a strong evidence-based rebuttal. I did not hear from Prof. McMaster again.

Afterward, another letter, this time to the editor in chief of JCEH, was submitted by Dr. Zambrone and colleagues who work at Planitox, a company funded by Herbalife. The editor in chief suggested that I write a point-by-point rebuttal. I did that and both the letter and the reply were published by the journal. Soon after, I received legal notice from DSK Legal in Delhi on behalf of Herbalife stating that I produce more evidence. I replied to the legal notice with all proof of evidence that built our scientifically valid study, specifying that it has undergone peer review before being published. My report, its contents, and the patient’s family ordeal (an interview with the deceased patient’s husband) were thereafter reported by a health journalist, who published it in the online paper The Lede. (Other media were not willing to run the story due to fear of litigation, as Herbalife is well known to litigate.) But little did I know that Herbalife was sending multiple legal letters to the journal’s editor in chief, editorial assistants, the society, and its president, behind our backs.

This led to panic in the editor in chief and the INASL president. The editor in chief called me and said they were going to re-review the paper as per COPE guidelines to look for scientific integrity. I agreed. He asked me to furnish original patient data, including the liver biopsy report, which meant unmasking patient detail. I did that, too, and after completion of the repeat review, I was not notified of any integrity issues. It was a clean, valid paper. If it was not, this would have been communicated.

But then, suddenly, one day I received an email from Mr. Sameer Gupta of Elsevier, notifying me that my article will be removed due to legal reasons. No choice given; they were going to remove it. And they did. Initially, the reasons for removal were 'legal.' Later on, they modified this statement to “This article, which was published in the March-April 2019 issue of the journal, has been removed at the request of the JCEH’s Editor-in-Chief and the Indian National Association for the Study of the Liver (INASL). INASL and JCEH no longer support the content of and conclusions drawn in the article because the scientific methodology, analysis and interpretation of data underlying the article were insufficient for the conclusions drawn, and, with its removal, the article can no longer be relied upon.” This statement modification was completely false, immoral, unscientific and it was an insult to the authors and to the spirit of science. Also note that INASL has absolutely no role in decision-making from this article’s point of view and, at the time, the president of INASL advised the editor in chief to remove the article and provide selfish reasons to save the journal and the society, leaving the authors (us) to fend for ourselves. The proof to support these statements were never declared or shared with us, since the two rounds of peer review came back clean.

So, we sent a legal notice to the journal, editor in chief and the INASL, stating they remove the modified versions of the statement and restore the original version. To top this, the published letter (by Zambrone et al.) and our reply to it was also removed and then retracted without notifying me or the co-authors, and without any substantiating reasons provided by the journal or the publisher. This, again, was handwashing from the journal and INASL to save themselves and not because of any issues with the science we published. The statements were changed on PubMed, but remain the same on the journal website to protect the interest of the journal and the INASL—against the science and reasoning.

Q. Are you disputing this retraction, and if so, how and why?

My article was removed, the removal reasons were unjustly modified without notification, and thereafter two letters were retracted without reasons or notification, only to satisfy Herbalife’s threats and to save the journal’s face. The publisher and the journal have been ignoring the commotion this industry-driven unscientific practice has caused. I emailed Elsevier regarding the issue and have not heard back from them. INASL and the journal JCEH remain ignorant to this issue still—they like to play dead, wishing that the trouble will go away after a while. But I have raised this issue with the Committee on Publication Ethics (COPE) for an arbitration because it was COPE’s guidelines that were fully broken in this dirty deal. This investigation is ongoing.

Meanwhile, I have prepared an updated version of the manuscript, including raw metadata on sample analysis, product raw metagenomic results, and a blinded patient biopsy report to be uploaded to Zenodo (CERN research repository). Going against the journal and the publisher on legal terms is our last resort, since we are only salaried physicians from a low-income country who will need to struggle from both a time and financial point of view, to take the fight uphill.

Q. What changes do you think are needed to help keep valid scientific findings available while also providing room for healthy scientific debate and dispute?

Thank you for this question. The onus lies mostly on the journal and its editorial board. If a journal has decided to publish scientifically valid findings, but one that could potentially attract conflicts and debate, without doubt, the decision to persevere and defend such allegations must be made on the basis of scientific credibility only, and not peer pressure and legal threats which foster escapism at the cost of credible science. If there is solid science and evidence backing up the claims made in a paper, the scientific community and the journal/publisher need not fret.

This is exemplified by similar publications on Herbalife in the Journal of Hepatology, which still remain in the scientific databases, without coercion to remove or such allegations, even though the journal is published by the same Elsevier who retracted our paper unreasonably as per advice from the journal (JCEH) and society that owns the journal. Healthy scientific debates about concerns should be made through letters to the editor, wherein both the parties receive the chance and the right to defend each other’s statements. Such deliberations will nurture rational and realistic discussions that ensure debates happen within the scientific domain—and not throw it open for stakeholders to steer its outcome or demean science.

Q. Is there anything else you’d like our readers or other members of the scientific community to know?

For the reader, I would like to stress that one must not be blinded by the terms ‘natural,’ ‘herbal,’ and ‘safe’—they must question it, like they question the adverse events associated with a procedure or the side effects associated with a conventional prescription drug. Always be curious when it comes to one’s own health. Do not blindly follow or fall for what is always advertised in the ‘positive’. If possible, have an open discussion with your primary care physician or a specialist—who must also be ready to rationalize and be well-informed regarding alternative medicines.

For the members of the scientific community, I would urge them to provide detailed questions on the history of complementary and alternative medicine use to every patient they come in contact with, mandatorily. This would help us understand health-seeking behavior to identify interventional strategies for primary prevention and provide insights on clinical outcomes to prepare management protocols better. If there is an observation which is novel or reportable from a public health perspective, follow it up with validated scientific methods and generate solid evidence to bring it to the table. Science and patient outcomes can improve this way only.

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