OGH Reports 2017; 6(2): 51-55Peer Reviewed Journal in Oncology, Gastroenterology and Hepatologywww.oghreports.org | www.journalonweb.com/ogh

OGH Reports, Vol 6, Issue 2, Jul-Dec, 2017 51

Case Report

INTRODUCTIONNon-alcoholic fatty liver disease (NAFLD) is the commonest cause of asymptomatic abnormal trans-aminases world-wide and of chronic liver disease in the developing world, found in 17-30% of the popu-lation in Western countries. The well-known primary causes of NAFLD are obesity, type II diabetes, dyslip-idemia, 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, abet-alipoproteinemia, hypobetalipoproteinemia, familial combined hyperlipidemia; glycogen storage diseases, lipodystrophy syndromes, hepatitis C infection, Wil-son’s disease, total parenteral nutrition, severe weight loss secondary to bariatric procedures, celiac disease, drugs such as amiodarone, tamoxifen and anti-ret-roviral 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, present-ing 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 previ-ously described with CAM was noted.

CASE REPORTA 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 abdomi-nal pain. The patient reported no smoking, previous liver disease, family history of liver diseases, blood

Uncommon cause for a common disease-Severe steatohepatitis secondary to Ayurvedic ‘Man-Lion Tonic’

ABSTRACTNarasimha 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

Cyriac Abby Philips1, Praveen Kumar2, Philip Augustine3, Pushpa Ma-hadevan4

1Department of Hepatology and Trans-plant Medicine, PVS Institute of Diges-tive Diseases, PVS Memorial Hospital, Cochin, Kerala, INDIA.2Deparment of Gastroenterology, Government Medical College, Thrissur, Kerala, INDIA.3Department of Gastroenterology, PVS Institute of Digestive Diseases, PVS Me-morial Hospital, Cochin, Kerala, INDIA.4Deparment of Pathology, VPS Lake-shore Hospital, Cochin, Kerala, INDIA.

Correspondence

Cyriac Abby Philips

Philip Augustine Associates, PVS Memorial Hospital Campus, Kaloor, Cochin 682017, INDIA.

Phone: +919207745776

Email: abbyphilips@gmail.com

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 open- access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Cite this article: Philips CA, Kumar P, Augustine P, Mahadevan P. Uncommon cause for a com-

mon disease-Severe steatohepatitis secondary to Ayurvedic ‘Man-Lion Tonic’. OGH Reports. 2017;6(2):51-5.

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 lymph-adenopathy 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 evalu-ation revealed normal hemogram, total bilirubin 1.2 mg/dL with direct fraction 0.4 mg/dL, alanine transaminase (ALT) 514 IU/L, aspartate transami-nase (AST) 338 IU/L, normal serum protein, albu-min 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 fer-ritin and ceruloplasmin levels were also normal. An ultrasound and a computerized tomography (CT) scan of the abdomen revealed only steatotic hepa-tomegaly and Shearwave elastography showed liver stiffness of 9.2 kPa suggestive of F3 fibrosis. A per-cutaneous ultrasound guided plugged liver biopsy revealed features suggestive of severe mixed macro and micro-vescicular-steatosis (Figure 1A) with lob-ular inflammation, ballooned hepatocytes (Figure

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1B, thin black arrow), Mallory Denk bodies (Figure 1B, thick black ar-row), 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 offend-ing CAM, advised vitamin E and antioxidants, put on a low-fat diet and advised daily activities in the form of brisk walking and treadmill exer-cises. 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.

DISCUSSIONNarasimha 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 rea-soning. The product is available over the counter and for purchase on-line. 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, hon-ey and butter, heated till boiling and then cooled down to a semi-solid consistency. Dosage is usually 1-2 tablespoons once or twice daily with-out 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 sta-bilizer and marking inks.

Excess alcohol consumption, glucocorticoids, total parenteral nutri-tion, amiodarone and methotrexate, chemotherapy associated steatosis related to 5-fluorouracil, tamoxifen, irinotecan, cisplatin, and asparagi-nase 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 steatohepa-titis 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 hepato-cytes 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 macrove-sicular steatosis is noted in the presence of cholestasis. The histological diagnosis of AFLJ requires exclusion of alcoholic hepatitis (AH; the ab-sence of chicken wire fibrosis, neutrophilic inflammation, or Mallory-Denk 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 hepati-

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.

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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 netsViscosity regulator for oil drilling

Leaves of Plumbago zeylanica Ceeylon leadwort or Doctorbush Plumbagin Organic hexane compoundsMethanols

Plumbagin is genotxic and mutagenicUsed for treating canine distemper

Mosquito larvicide

Leaves of Dalbergia sissoo Indian Rosewood Rich in polyphenols Molluscicide against eggs of freshwater snailsJuiced 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 agentCauses weight loss and diarrhea when used

for longer periodsGlaxoSmithKline 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 usesPaste mixed with cattle urine used for

treatment of skin and genital infections and ingested for respiratory infections in some

parts of India

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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.

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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 pres-ence 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 alco-holic 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 pre-dominant 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, major-ity of patients used products that contained vitamins, minerals and bo-tanical extracts. Majority of the patients took non-body building supple-ments 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 func-tional 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 in-vestigations relevant to treatment of NAFLD, such as wolfberry polysac-charides, 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. How-ever, none of these studies are well designed and lacks scientific clini-cal assessment and proper study methodology.[14] Traditional medici-nal 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 ‘po-tential safety’ because of natural ingredients invites acceptance without scientific reasoning.[15] None of the phytochemical agents (except? Res-veratrol) noted in the CAM used by our patient are validated in clinical trials for safety and efficacy in treatment of NAFLD. Severe steatohepati-tis 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/al-ternative 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.

CONCLUSIONComplementary 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 tra-ditional risk factors, drug history taking is of utmost importance.

ACKNOWLEDGEMENTNo Acknowledgement are declared.

CONFLICT OF INTERESTNo conflict of interest are declared.

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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.