FIDSSA

Case of the Month

December 2016

FIDSSA case of the month- November 2016

Dr Max Peter Winkler, Hout Bay Family Medical Centre, Cape Town (SASTM)

Acute drug induced hepatoxicity in a patient recently returned from Fiji.

In July 2015 a 20-year old woman presented to general practice with a 3 week history of worsening nausea, loss of appetite and jaundice. She had recently returned from 3 month trip to Fiji where she had been working as volunteer teacher on one of the rural outer islands of the Fijian archipelago. Prior to travel she was seen at a local travel clinic and was immunised for hepatitis A and typhoid fever.

She gave no history of any recent febrile illness but was bitten by mosquitoes while away. She was currently taking a combined oral contraceptive pill that she had started before leaving South Africa, and she was not on any other medication. She admitted to occasional alcohol use and smoking while away. She denied any illicit drug use but does admit to frequently drinking a traditionally prepared Kava drink with the local inhabitants in Fiji “on more days than not”.

On examination the patient was stable and apyrexial, she was jaundiced with some abdominal tenderness in the RUQ and 1-2 cm hepatomegaly. She had a normal CNS examination, and no other signs of acute liver failure were noted.

Answer to Q1

In this case, after referral to a local tertiary institution and specialised liver unit, the next most appropriate investigation was a formal liver biopsy and histological examination to determine aetiology. The division of anatomical pathology at the University of Cape Town (UCT) reviewd the liver biopsy:

There was extensive eosinophilic infiltrates surrounding the portal tractsas well as apoptosis in the surrounding hepatocytes. Sirius red staining showed fibrotic changes in the portal tracts suggestive of chronic inflammation and damage; the canniculi of the liver were obstructed with multiple bile plugs. These histological features are all commonly found in cases of drug induced hepatoxicity, and supported a likely diagnosis of drug induced hepatotoxicity.

Answer to Q2

The patient denied any illicit drug use and was only taking the combined oral contraceptive while abroad; she had started the contraceptive before leaving home and had showed no signs of hepatoxicity while on the medication prior to leaving.

She did however admit to drinking a traditionally prepared Kava root extract with local Fijians“ more days than not” while in Fiji.

The first confirmed case of hepatoxicity secondary to ingestion of Kava extracts was described in Germany in 1998; there have since been over 100 suspected cases attributed to its consumption in both commercial and traditional forms. Some of these patients developed fulminant hepatic failure and needed liver transplantation. In 2002 Kava products were withdrawn from public use in the USA, Europe and Australia after the FDA issued a “black box” warning with regards to its potential for possible hepatotoxicity. The South African MCC issued a similar warning with regards to its use in 2003, and its sale has since been banned in South Africa. In 2015 following a court case in Germany the ban on its use there was overturned by a judge due a perceived lack of evidence

In this case the prolonged and frequent consumption of a traditionally prepared Kava drink is the most likely cause of the patient’s symptoms and deranged hepatic biochemistry. This diagnosis is supported by histological features suggestive of acute on chronic drug induced hepatoxicity in the biopsy specimens that were analysed. Other investigations for infectious or autoimmune causes of acute hepatoxicity came back negative hence ruling them out as possible alternative diagnoses.

Q3: What is Kava, and where is it commonly grown and consumed?

Answer to Q3
Kava (Piper Methysticum) is grown throughout Polynesia, Micronesia, and Melanesia. It is thought to have originated on the island of Vanuatu where wild varieties (piper wichmanni ) are still found. From there it spread along trade routes into the other pacific islands where it is now widely cultivated. There are over 200 varieties, with the so called noble varieties the most commonly prepared and consumed.

The drink is prepared almost exclusively from the roots of the kava plant. These are ground up into a paste either by pounding the root with a coral mortar and pestle or through chewing the roots into a paste. This is then mixed with water and strained through a cloth to create a water based emulsion. Historically its use was confined to certain social classes such as chiefs and priests, and consumption often involved elaborate customs and ceremony with its use.

The emulsion contains kavalactones which cause a sedative and mildly anxiolytic effect on users. These kavalactones are thought to work via the GABA neurotransmitter pathway in the brain. In most western countries outside of the pacific region it is commonly sold as a commercial product that is produced by using either ethanol or acetone to extract the active kavalactones from the crushed roots, before being manufactured into a pill or powder. It is marketed as a natural treatment for anxiety disorders amongst many complimentary healthcare providers in the west.

Answer to Q4

There are numerous theories as to why kava seems to cause hepatotoxicity in some individuals, and include the following:\

Direct cytotoxic effect of the kavalactones and their metabolites on hepatocytes. There have been numerous studies on the effects of kavalactones on hepatocytes and the evidence of direct toxic effects have been mixed; however some researchers have demonstrated cytotoxic effects in vitro.
Inhibition of the P450 enzyme pathway in the liver leading to increased levels of potentially toxic drug metabolites in the liver, notably when there has been consumption of other over-the-counter and prescription medications that also share the same pathway in the liver (e.g. paracetamol).
Contamination with fungal or other toxins during storage of the raw ingredients, the most commonly implicated contaminant is mould (aflatoxin) whose growth is facilitated by the warm humid pacific climate. However pesticides, fertilisers, oils and bacteria have also been implicated.
Commercial preparations can contain root peelings, stems and even leaves of the Kava plant. These, especially the leaves, are thought to possibly contain more toxic alkaloid compounds that increase the risk of hepatotoxicity.
The method of preparation of commercial preparations uses acetone and ethanol to extract the active ingredients before preparation; this leads to much higher concentrations of kavalactones (70% vs 30%) than the traditionally prepared drink. However, as we have seen in this case hepatotoxicity can occur even with traditional water based emulsions.
As previously mentioned there are more than 200 different cultivars of Kava. It is thought that certain cultivars seem to be associated with more adverse events. In 2002 Vanuatu passed a law classifying kava into i) noble varieties ii) medicinal varieties iii) “tu dei” varieties and vi) wild varieties. The last two classes are banned from export due to the high risk of potential adverse events associated with their use. The concern is that these varieties might have found their way into commercial preparations due to poor regulation and export control.
Possible genetic variations amongst populations seem to predispose certain populations to hepatoxicity, the gene CYP26D has been thought to play a role but this needs to be investigated further (1% of pacific islanders vs 12% of Europeans carry this genetic variation).

Lessons learned

Fortunately in this case the patient made a full recovery after conservative treatment in hospital and did not require any further interventions or treatment. Her liver enzymes have since returned to normal and she has since returned to Fiji to continue teaching.

Even though the incidence (0.3/1,000,000 daily doses) of developing hepatoxicity is low, hopefully this case report will alert clinicians to the potential hepatotoxic effects of this substance amongst at risk individuals. When faced with a traveller to the pacific one should warn them about the possible risks involved with Kava consumption and advise them to be aware of its quality and origins if they do decide to consume it. The same and potentially even greater risk applies to the use of commercially prepared products that might be available in certain countries where its sale has not been banned.

Acknowledgements

Dr G Skead and Prof H Wainwright, UCT division of anatomical pathology for access to and copies of the Histology Slides

Prof W Spearman, GSH department of hepatology for the clinical notes and the management of the patient in the liver unit.

References

Hepatitis induced by Kava (Piper methysticum rhizoma).Stickel F1, Baumüller HM, Seitz K, Vasilakis D, Seitz G, Seitz HK, Schuppan D. J Toxicol Clin Toxicol. 2003;41(2):109-13.

Acute hepatitis induced by kava kava.Humberston CL1, Akhtar J, Krenzelok EP.

Planta Med. 2015 Dec;81(18):1647-53. doi: 10.1055/s-0035-1558295. Epub 2015 Dec 22.

Contaminant hepatotoxins as culprits for kava hepatotoxicity--fact or fiction? Teschke R, Sarris J, Lebot V, MMWR Morb Mortal Wkly Rep. 2002 Nov 29;51(47):1065-7.

Hepatic toxicity possibly associated with kava-containing products--United States, Germany, and Switzerland, 1999-2002. Centers for Disease Control and Prevention (CDC).

Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

Flaminia Pantano,Roberta Tittarelli,Giulio Mannocchi,Simona Zaami,Serafino Ricci,Raffaele Giorgetti,Daniela Terranova, Francesco P. Busardò,and Enrico Marinelli, Rolf Teschke, Academic Editor,Phytother Res. 2013 Mar;27(3):472-4. doi: 10.1002/ptr.4729. Epub 2012 May 14, Liver Int. 2010 Oct;30(9):1270-9. doi: 10.1111/j.1478-3231.2010.02308.x.

Kava hepatotoxicity: pathogenetic aspects and prospective considerations.

Teschke R1. Liver Int. 2010 Oct;30(9):1270-9. doi: 10.1111/j.1478-3231.2010.02308.x.

Toxic Hepatitis After Consumption of Traditional Kava Preparation
Stefan U . Christl , MD , Axel Seifert , MD , and Dirk Seeler , MD

Department of Gastroenterology, Asklepios Klinik Harburg, Hamburg, Germany
J Travel Med. 2009 Jan-Feb;16(1):55-6. doi: 10.1111/j.1708-8305.2008.00259.x. http://www.news24.com/SouthAfrica/News/Kava-products-get-MCC-chop-20030822

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