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Case Report OGH Reports 2017; 6(2): 51-55 Peer Reviewed Journal in Oncology, Gastroenterology and Hepatology www.oghreports.org | www.journalonweb.com/ogh Uncommon cause for a common disease-Severe steatohepatitis secondary to Ayurvedic ‘Man-Lion Tonic’ Cyriac Abby Philips1, Praveen Kumar2, Philip Augustine3, Pushpa Mahadevan4 ABSTRACT Narasimha Rasayana (Sanskrit for ‘Man-Lion Tonic’) is a frequently prescribed Ayurvedic herbal medicinal preparation in South India for treatment of fatigue, hair loss, rejuvenation and weight gain in young men and women. The preparation is also considered, as per Vedic medical literature known as Ashtanga Hridayam Uttara to improve fertility by acting as an aphrodisiac. We present the interesting case of a young male, who consumed 2 tablespoons (~15 grams) of the ‘Man-Lion Tonic’ daily for 2 years, presenting with loss of appetite and well-being and elevated transaminases with liver histology showing overlapping features unique to spectrum of acute alcohol liver injury not described with CAM before. Key words: Steatohepatitis, Fatty liver disease, Complementary and alternative medicine, Ayurveda, Drug induced liver injury, Hepatotoxicity. Cyriac Abby Philips1, Praveen Kumar2, Philip Augustine3, Pushpa Mahadevan4 Department of Hepatology and Transplant Medicine, PVS Institute of Digestive Diseases, PVS Memorial Hospital, Cochin, Kerala, INDIA. 2 Deparment of Gastroenterology, Government Medical College, Thrissur, Kerala, INDIA. 3 Department of Gastroenterology, PVS Institute of Digestive Diseases, PVS Memorial Hospital, Cochin, Kerala, INDIA. 4 Deparment of Pathology, VPS Lakeshore Hospital, Cochin, Kerala, INDIA. 1 Correspondence Cyriac Abby Philips Philip Augustine Associates, PVS Memorial Hospital Campus, Kaloor, Cochin 682017, INDIA. Phone: +919207745776 Email: [email protected] History • Submission Date: 23-11-2016; • Review completed: 20-12-2016 • Accepted Date: 12-02-2017. DOI : 10.5530/ogh.2017.6.2.15 Article Available online http://www.oghreports.org Copyright © 2017 Phcog.Net. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license. OGH Reports, Vol 6, Issue 2, Jul-Dec, 2017 INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is the commonest cause of asymptomatic abnormal transaminases world-wide and of chronic liver disease in the developing world, found in 17-30% of the population in Western countries. The well-known primary causes of NAFLD are obesity, type II diabetes, dyslipidemia, and insulin resistance.[1] However, secondary conditions that cause similar clinical and histologic picture, should be considered in patients who present with NAFLD without traditional risk factors. These include disorders of lipid peroxidation such as, abetalipoproteinemia, hypobetalipoproteinemia, familial combined hyperlipidemia; glycogen storage diseases, lipodystrophy syndromes, hepatitis C infection, Wilson’s disease, total parenteral nutrition, severe weight loss secondary to bariatric procedures, celiac disease, drugs such as amiodarone, tamoxifen and anti-retroviral therapy.[2] Here we present the case of severe drug induced steatohepatitis in a young man, who consumed a commonly used complementary and alternative medication, Narasimha Rasayanam or ‘Man-Lion’ Tonic for weight gain for 2 years, presenting with loss of appetite and well-being and elevated transaminases for a period of 2 months’ duration and in whom unique histology of liver injury not previously described with CAM was noted. CASE REPORT A 23-year-old non-alcoholic male without known metabolic syndrome, was referred to our Liver Clinic with a 2-month history of fatigue, loss of appetite and well-being without nausea, diarrhoea, and abdominal pain. The patient reported no smoking, previous liver disease, family history of liver diseases, blood transfusion or exposure to toxins. His past medical history was significant for consumption of herbal complementary and alternative (CAM), known as Narasimha Rasayana (Man-Lion Tonic, daily once, approximately 15 g for 2 years) taken for weight gain and ‘rejuvenation’. On physical examination, the patient was alert, and oriented to time, place and person without pallor, icterus, peripheral lymphadenopathy or stigmata of chronic liver disease. His weight was 56 kg and height 168 cm, with body mass index of 19.8 kg/m2. Liver span was 18 cm in the right mid clavicular line. The laboratory evaluation revealed normal hemogram, total bilirubin 1.2 mg/dL with direct fraction 0.4 mg/dL, alanine transaminase (ALT) 514 IU/L, aspartate transaminase (AST) 338 IU/L, normal serum protein, albumin and globulin, international normalized ratio 1.1 with normal renal function tests. C-reactive protein level was mildly raised 12.3 mg/L (normal 0–5 mg/L). Results of serologic tests were negative for hepatitis B surface antigen; anti-hepatitis B-core Immunoglobulin (IgM and core total); anti-hepatitis A and E virus IgM; anti-hepatitis C virus antibody; anti-Cytomegalovirus IgM; anti-Epstein–Barr virus IgM; anti-nuclear antibodies; anti-smooth-muscle antibodies; anti-mitochondrial antibodies; and anti-neutrophil cytoplasmic antibodies. Serum ferritin and ceruloplasmin levels were also normal. An ultrasound and a computerized tomography (CT) scan of the abdomen revealed only steatotic hepatomegaly and Shearwave elastography showed liver stiffness of 9.2 kPa suggestive of F3 fibrosis. A percutaneous ultrasound guided plugged liver biopsy revealed features suggestive of severe mixed macro and micro-vescicular-steatosis (Figure 1A) with lobular inflammation, ballooned hepatocytes (Figure Cite this article: Philips CA, Kumar P, Augustine P, Mahadevan P. Uncommon cause for a common disease-Severe steatohepatitis secondary to Ayurvedic ‘Man-Lion Tonic’. OGH Reports. 2017;6(2):51-5. 51 Philips et al.: Severe steatohepatitis secondary to Man-Lion Tonic Figure 1: Liver histopathology revealing features suggestive of severe mixed macro and micro-vescicular-steatosis (A, H&E 10x) with lobular inflammation, ballooned hepatocytes (B, thin black arrow; H&E 40x), Mallory Denk bodies (B, thick black arrow; H&E 40x), micro-vescicular steatosis related foamy degeneration (C, black arrow, H&E 40x) and periportal and preisinusoidal (or chicken wire fibrosis, D; Masson Trichrome, 20x) fibrosis suggestive of severe steatohepatitis. 1B, thin black arrow), Mallory Denk bodies (Figure 1B, thick black arrow), micro-vescicular steatosis related foamy degeneration (Figure 1D, black arrow) and periportal and preisinusoidal (chicken wire) fibrosis suggestive of severe steatohepatitis (NASH CRN activity grade 6/8 and NASH CRN fibrosis stage 2). The patient was advised to stop the offending CAM, advised vitamin E and antioxidants, put on a low-fat diet and advised daily activities in the form of brisk walking and treadmill exercises. On follow up after 4 weeks, his ALT and AST had decreased to 101 IU/L and 68 IU/L with improvement in well-being and appetite. DISCUSSION Narasimha Rasayanam or ‘Man-Lion Tonic’ is a commonly utilized Ayurvedic herbal medicine in South India for treatment of a variety of symptoms ranging from fatigue to loss of libido without scientific reasoning. The product is available over the counter and for purchase online. Advertisements and publicity about this product is rampant among lower class and lower middle class population who opt for cheaper and easy symptomatic treatment options without the need for investigational expenditure. The ‘Man-Lion Tonic’ has 10 herbal ingredients (Table 1), mixed in special proportions along with powdered iron alloy, water, honey and butter, heated till boiling and then cooled down to a semi-solid consistency. Dosage is usually 1-2 tablespoons once or twice daily without a specified duration limit. The herbal components of this concoction have a plethora of other non-medicinal uses such as being part of dyeing agents, drill oil viscosity regulators, construction grade wall plaster stabilizer and marking inks. 52 Excess alcohol consumption, glucocorticoids, total parenteral nutrition, amiodarone and methotrexate, chemotherapy associated steatosis related to 5-fluorouracil, tamoxifen, irinotecan, cisplatin, and asparaginase are also causes of macrovesicular steatosis.[3] Valproate, tetracycline (intravenous administration), aspirin, nucleoside reverse transcriptase inhibitors, glucocorticoids, nonsteroidal anti-inflammatory drugs and cocaine are causative agents. Drugs rarely associated with steatohepatitis are amiodarone, methotrexate tamoxifen, and irinotecan.[4, 5] It was interesting to note that in our patient, histopathology showed foamy degeneration of the hepatocytes. Foamy degeneration (AFD) of hepatocytes is classically seen in severe alcoholic fatty liver disease. It is closely related to alcoholic fatty liver with jaundice (AFLJ). Both are defined by steatosis involving > 75% of hepatocytes. In the latter, diffuse macrovesicular steatosis is noted in the presence of cholestasis. The histological diagnosis of AFLJ requires exclusion of alcoholic hepatitis (AH; the absence of chicken wire fibrosis, neutrophilic inflammation, or MalloryDenk bodies) and is characterized by the presence of significant diffuse microvesicular, foamy-appearing steatosis involving the perivenular and often midzonal hepatocytes, similar to that seen in several non-alcoholic liver injuries with abnormal mitochondrial fatty acid oxidation.[6] The only report of CAM causing severe microvesicular steatohepatitis was secondary to Margosa oil use.[7] Schoepfer and colleagues reported 12 cases of toxic hepatitis implicating Herbalife preparations (1998-2004) with 10 sufficiently documented to permit causality analysis. In their cohort, liver histology showed hepatic necrosis, marked lymphocytic/eosinophilic infiltration and cholestasis patterns. Fulminant liver failure with explant showing giant cell hepatiOGH Reports, Vol 6, Issue 2, Jul-Dec, 2017 Philips et al.: Severe steatohepatitis secondary to Man-Lion Tonic Table 1: Components of Narasimha Rasayanam (Man-Lion Tonic), their contents and non-medicinal uses. * Ingredient Common name/ Description Content Non Ayurvedic Properties Leaves of Acacia catechu Cutch tree or Black Cutch, Arecanut tree Rich in flavanols Red colouring agent in Paan (betel leaf with areca nut and tobacco chewed for its stimulant and psychoactive effects) Agent in dyeing and leather tanning Preservative for fishing nets Viscosity regulator for oil drilling Leaves of Plumbago zeylanica Ceeylon leadwort or Doctorbush Plumbagin Organic hexane compounds Methanols Plumbagin is genotxic and mutagenic Used for treating canine distemper Mosquito larvicide Leaves of Dalbergia sissoo Indian Rosewood Rich in polyphenols Molluscicide against eggs of freshwater snails Juiced leaves and bark used as bonding agent in construction grade wall plaster Leaves of Pterocarpus marsupium Indian Kino Tree or Malabar Kino Stillbenoids, natural phenols, rich in resveratrol Hypoglycemic agent Causes weight loss and diarrhea when used for longer periods GlaxoSmithKline in 2010 suspended a small clinical trial of SRT501, a resveratrol compound due to adverse effects Fruit of Terminalia chebula Black Myrobalan (plum -like fruit bearing tree) Glycosides, triterpenes, gallic acid, coumadins, tannins, phenols No potential uses Paste mixed with cattle urine used for treatment of skin and genital infections and ingested for respiratory infections in some parts of India OGH Reports, Vol 6, Issue 2, Jul-JDec, 2017 53 Philips et al.: Severe steatohepatitis secondary to Man-Lion Tonic Fruit of Embelia ribes False Black Pepper Benzoquinones, alkaloids, resins and tannins Cyclodextrin-based polymers for therapeutic delivery As components of hydrogels Leaves and fruit of Terminalia bellirica Bastard myrobalan Beta-sitosterol, gallic acid, ellagic acid, ethyl gallate, galloyl glucose Used in volatile oil preparations Fruit of Semecarpus anacardium Marking – Nut Tree Biflavonoids, phenolic complounds, oxy-acids, non-volatile alcohols Marking inks Fixator agent for color dyes Flowers of Clerodendrum serratum Glory Bower or Bleeding Heart flower Flavanoids, terpenoids and steroids None Flowers of Eclipta prostate False Daisy Coumestans, polyacetylenes, thiophene derivatives, steroids, triterpenes, flavonoids None * Sources: Narasimha – Rasayanam - Retrieved from: http://www.bimbima.com/health/post/2016/02/23/narasimha-rasayanam-ingredients-and-uses-directions. aspx; Baliga et al. Rasayana Drugs From the Ayurvedic System of Medicine as Possible Radioprotective Agents in Cancer Treatment. Integr Cancer Ther. 2013 Nov;12(6):455-63; Parasuraman S et al. Polyherbal formulation: Concept of ayurveda. Pharmacogn Rev. 2014 Jul-Dec; 8(16): 73–80; Dixit VK. Controversial ayurvedic herbs. J Adv Pharm Technol Res. 2011 Apr-Jun; 2(2): 78–80. 54 OGH Reports, Vol 6, Issue 2, Jul-Dec, 2017 Philips et al.: Severe steatohepatitis secondary to Man-Lion Tonic tis (GCH) occurred in one, while sinusoidal obstruction syndrome was observed in another.[8] Very recently, Shetty and colleagues from India, reported herbal medicine use as the cause of giant cell hepatitis in an adult patient.[9] In our patient, we noted a mixed macro and microvesicular pattern of steatohepatitis with foamy degeneration and perisinusoidal fibrosis - a histopathology pattern encompassing AFD, AFLJ and AH – which is not described in literature, especially with CAM. We suspect that the presence of phytochemicals such as phenolic and carbolic compounds along with alkaloids and tannins leading to mitochondriopathy, would have caused a mixed pattern of injury similar to histopathology of acute alcoholic liver disease spectrum. Drug induced steatohepatitis is a rare form of drug induced liver injury (DILI) and is regarded as an uncommon cause of a common disease. The common histological patterns observed in DILI are acute and chronic hepatitis, acute and chronic cholestasis, and mixed cholestatic hepatitis. A Spanish group study on DILI noted that only 2 out of the 110 cases on liver histopathology showed a predominant pattern of steatosis.[10] However, more recent data from the Drug Induced Liver Injury Network (DILIN) concluded that although this is rarely described as the dominant pattern, 26% of cases showed some degree of steatosis and macrovesicular type as the predominant pattern noted in over 70% of the cases.[11] In a study by Navarro et al on liver injury from herbals and dietary supplements in the DILIN, majority of patients used products that contained vitamins, minerals and botanical extracts. Majority of the patients took non-body building supplements and 81% of the total number enrolled had identifiable ingredients. [12] Use of pure Ayurvedic products and related liver injury has not been reported in any drug injury screening networks. In recent years, it has been shown that some monomers and certain functional mixtures of herbs have potential uses in NAFLD treatment. Xiao and colleagues carried out an extensive PubMed review on randomized trials on several herbal derivatives under intense basic and/or clinical investigations relevant to treatment of NAFLD, such as wolfberry polysaccharides, garlic-derived monomers, red grape–derived resveratrol, and milk thistle–derived substances. However, a more detailed mechanistic research methodology and long-term clinical evaluations are needed for their future applications.[13] Phytochemical such as Curcumin, Lycopene, Resveratrol and Silymarin have been shown in indexed complementary and alternative journal studies to have steatosis reversing effects. However, none of these studies are well designed and lacks scientific clinical assessment and proper study methodology.[14] Traditional medicinal systems such as Indian Ayurveda, Japanese Kampo and Traditional Chinese medicine have reported on the therapeutic role of polyherbal formulations in treating hepatic ailments including NAFLD. Not many Ayurvedic formulations have been put for a scrutiny in the treatment of NAFLD and widespread use of the same, targeting low costs and ‘potential safety’ because of natural ingredients invites acceptance without scientific reasoning.[15] None of the phytochemical agents (except? Resveratrol) noted in the CAM used by our patient are validated in clinical trials for safety and efficacy in treatment of NAFLD. Severe steatohepatitis secondary to Ayurveda medications in countries like India, might be under reported as rampant use remains unchecked and under-evaluated. Histopathological liver injury patterns overlapping multiple aetiologies or and not specific to commonly described ones, should be thought of secondary to drug use, especially CAM. Knowledge regarding local/alternative medical practices and timely liver biopsies can help clinch the diagnosis in the absence of a strong clinical suspicion. Proper and de- tailed declaration of ingredients by and intense role of government and scientific regulatory agencies scrutiny of ‘alternate’ practice is called for. CONCLUSION Complementary and alternate medications produce a plethora of hepatic injuries ranging from asymptomatic elevation of transaminases to severe liver injury. Regulatory norms defining content and organotoxicity of alternative medications need to be implemented through Government participation. In patients of severe steatohepatitis, in the absence of traditional risk factors, drug history taking is of utmost importance. ACKNOWLEDGEMENT No Acknowledgement are declared. CONFLICT OF INTEREST No conflict of interest are declared. REFERENCES 1. Fotbolcu H, Zorlu E. Nonalcoholic fatty liver disease as a multi-systemic disease. World J Gastroenterol. 2016;28;22(16):4079-90. 2. Kneeman JM, Misdraji J, Corey KE. Secondary causes of nonalcoholic fatty liver disease. Therapeutic Advances in Gastroenterology. 2012;5(3):199-207. https:// doi.org/10.1177/1756283X11430859 ; PMid:22570680 PMCid:PMC3342568. 3. Kleiner, D. E. Liver histology in the diagnosis and prognosis of drug-induced liver injury. Clinical Liver Disease. 2014;4:12-6. https://doi.org/10.1002/cld.371. 4. Sarges P, Steinberg JM, Lewis JH. Drug-Induced Liver Injury: Highlights from a Review of the 2015 Literature. Drug Saf. 2016;39:801-21. https://doi.org/10.1007/ s40264-016-0427-8 ; PMid:27142208. 5. Rabinowich L, Shibolet O. Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease. BioMed Res Intern. 2015; vol. 2015, Article ID 168905, 14 pages. 6. Roth, N., Kanel, G. and Kaplowitz, N. Alcoholic foamy degeneration and alcoholic fatty liver with jaundice: Often overlooked causes of jaundice and hepatic decompensation that can mimic alcoholic hepatitis. Clin Liv Dis. 2015;6(6):1458. https://doi.org/10.1002/cld.520. 7. Sinniah D, Baskaran G. 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Fujimoto M, Tsuneyama K, Kainuma M, Sekiya N, Goto H, Takano Y et al. Evidence-based efficacy of Kampo formulas in a model of non alcoholic fatty liver. Exp Biol Med; 2008;233(3):328-37. https://doi.org/10.3181/0707-RM-207 ; PMid:18296738 Cite this article: Philips CA, Kumar P, Augustine P, Mahadevan P. Uncommon cause for a common disease-Severe steatohepatitis secondary to Ayurvedic ‘Man-Lion Tonic’. OGH Reports. 2017;6(2):51-5. OGH Reports, Vol 6, Issue 2, Jul-JDec, 2017 55