Brief Article
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World J Hepatol. Mar 27, 2014; 6(3): 150-154
Published online Mar 27, 2014. doi: 10.4254/wjh.v6.i3.150
Khat (Catha Edulis) as a possible cause of autoimmune hepatitis
Shahzad Riyaz, Mohammad Imran, Dermot Gleeson, Mohammed A Karajeh
Shahzad Riyaz, Mohammad Imran, Dermot Gleeson, Mohammed A Karajeh, Liver Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, S10 2JF, United Kingdom
Author contributions: Riyaz S contributed to data collection and analysis and wrote the manuscript; Imran M helped with data collection; Gleeson D supervised management of patients and contributed to revision of manuscript; Karajeh MA conceived the study, supervised management of patients and revised manuscript
Correspondence to: Dr. Mohammed A Karajeh, Consultant Gastroenterologist, Liver Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Glossop Road, Room P9, Sheffield, S10 2JF, United Kingdom. mohammed.karajeh@sth.nhs.uk
Telephone: +44-114-2268746 Fax: +44-114-2268894
Received: September 12, 2013
Revised: December 20, 2013
Accepted: January 17, 2014
Published online: March 27, 2014

Abstract

AIM: To investigate the potential role of khat in triggering auto immune hepatitis.

METHODS: Patients with a history of khat use and acute hepatitis were identified using the computer database in the hepatology department at the Royal Hallamshire Hospital. They were then assessed for probability of having autoimmune hepatitis using the revised autoimmune hepatitis scoring criteria.

RESULTS: Six patients were identified. All of them had presented with acute hepatitis on a background of khat. All were male and five of these patients were of Somali origin, while one patient was from Yemen. The patients were given points on the modified autoimmune hepatitis score which is based on their liver enzymes, autoimmune screen, exclusion of viral hepatitis alcohol and drugs, immunoglobulin levels and liver histology. The patients were given a score of -4 for khat use due to its potential to cause drug induced liver injury. Five of these patients scored between 10 and 15 points, placing them in the probable group for having autoimmune hepatitis. All of these patients were treated with prednisolone and demonstrated a good response to immunosuppression.

CONCLUSION: One possibile cause of hepatotoxicity with khat could be via triggering of autoimmune hepatitis in a genetically susceptible individual. Further studies are needed for confirmation.

Key Words: Khat, Autoimmune hepatitis, Drug induced liver injury, Acute hepatitis, Herbs

Core tip: Khat causes hepatotoxicity. One possible mechanism could be by inducing autoimmune hepatitis.



INTRODUCTION

Khat (Catha Edulis Celestrasae) is an evergreen shrub native to East Africa and Southern Arabia. It is chewed daily by over 20 million people in these countries. Chewing khat is a popular social habit, particularly in young males, that has spread to Yemeni, Somali and East African communities living in the United Kingdom and United States[1]. The use of khat as a stimulant is increasing primarily due to immigration. The Somali population in the United Kingdom is estimated to be as high as 90000, and concerns over health and social problems associated with chewing khat have grown due to its potential side effects including hypertension, coronary vasospasm, myocardial infarction, delayed intestinal absorption, and mood disorders, which may result from its sympathomimetic action[2].

Various studies and case reports have suggested that khat is also hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration[3-7]. Recent studies in Somali populations have shown that khat can cause acute severe liver injury in humans due to its hepatotoxic effects[8,9]. Certain drugs that are known to be hepatotoxic cause liver damage by inducing an immunological response leading to a clinical presentation similar to autoimmune hepatitis (AIH). D’Souza et al[10] have described atypical presentation of AIH in young Somali men, although any history of khat use was not reported. Our aim was to assess the possible relationship of khat and autoimmune hepatitis in patients presenting with acute hepatitis on a background of khat use.

MATERIALS AND METHODS

The Hepatology database at Sheffield Hospitals was searched for patients referred to the Hepatology department between 2005 and 2010 with liver problems and a history of khat use. All of the patients were tested for hepatitis A, B and C serology, autoimmune profile (including antinuclear antibodies, smooth muscle antibodies and LKM-1 antibodies), ceruloplasmin, alpha-1 antitrypsin, and serum ferritin, and underwent ultrasound scanning of the abdomen, which was normal. This was followed by a percutaneous liver biopsy. Each biopsy was reviewed with particular attention to features of interface hepatitis, lobular necroinflammation and biliary changes. The patients were categorized according to the probability of having autoimmune hepatitis: no evidence (scores < 10), probable (scores of 10-15) or definite (score of more than 15), according to the established international criteria for diagnosis of autoimmune hepatitis[11,12].

All patients were treated with prednisolone (0.5 mg per kilogram per day) initially. Complete response, partial response and no response were defined according to the original and revised international autoimmune hepatitis criteria[11,12].

RESULTS

Acute hepatitis was defined in accordance with the scheme established by the Council for International Organisations of Medical Sciences (CIOMS)[13], and by the USFDA Drug Hepatotoxicities Steering Committee[14]. Eight patients were identified, of which six had presented with acute hepatitis on this basis. All were male and five of these patients were of Somali origin, while one patient was from Yemen. The age range of these patients was 24 to 57 years (mean 42.3 years). All of the patients had been using khat for several years. There was no history of herbal medication (other than khat) or alcohol use in any patient. All other causes of liver injury were excluded via non invasive liver screen. Five of the six patients went on to have a liver biopsy. The patients were scored according to the revised autoimmune hepatitis criteria - (Table 1). They were given -4 for khat use on the scoring system due to its potential hepatotoxicity. Despite this, five out of six patients had a pre treatment score of 10 to 15 which placed them in the probable group for autoimmune hepatitis.

Table 1 Patient scores according to the revised criteria for diagnosing autoimmune hepatitis.
ParametersScorePatient 1Patient 2Patient 3Patient 4Patient 5Patient 6
ALP:ALT (or AST) ratio125/1569170/1223187/1957179/1005298/105259/118
< 1.52222222
1.5-3.00
> 3.0-2
Serum IgG above normal
> 2.033333
1.5-2.022
1.0-1.51
< 1.000
ANA, SMA or LKM-1
> 1:80333
Approximately 1:8022
Approximately 1:401
< 1:400000
AMA positive-4NegativeNegativeNegativeNegativeNegativeNegative
Viral hepatitis markers
Positive-3
Negative3333333
Drug History
Positive-4-4-4-4-4-4-4
Negative1
Average alcohol intake
< 25 g/d2222222
> 60 g/d-2
Liver histology
Interface hepatitis33333N/A3
Lymphoplasmacytic infiltrate1111
Rosetting of liver cells11111
None of the above-5
Biliary changes-3
Other changes-3
Other autoimmune diseases22 (IDDM)00000
Optional additional parameters
Sero positivity-other antibodies22 (ENA+)
HLA DR3 or DR41N/AN/AN/AN/AN/AN/A
Pretreatment score13813111110

The five patients that were in the probable group had at least a partial response to corticosteroids with a greater than 50% reduction in their ALT after one month of treatment. Only two patients had more than 1 year of follow up, with one showing complete response to treatment. The patient that had scored negative for AIH (< 10) showed the least improvement with prednisolone and continued to have raised liver enzymes after 1 year of treatment. Four out of the six patients were maintained on long term low dose prednisolone while the other two patients were lost to follow up after 1 year. Two patients were commenced on azathioprine with complete response at 1 year follow-up. There was no history of re-exposure to khat.

Five out of six patients met the criteria for probable diagnosis of AIH but none of the patients actually met the criteria for confirmed diagnosis (score > 15). It has been reported previously that Somalian patients with AIH present atypically. It is therefore suggested that the AIH in these patients may have been triggered by khat use.

DISCUSSION

Over 40 khat strains are grown and used in Southern Arabia and East Africa. It is consumed in the form of fresh leaves which may often be contaminated with pesticides. The leaves of khat contain the Pyrrolizidine alkaloids, Cathine, Cathidine, and Cathinone. The pleasure derived from khat chewing is attributed to the euphoric action of Cathinone which is a sympathomimetic amine, with properties similar to amphetamine[15]. Although Cathinone is restricted in the United Kingdom under the Misuse of Drugs Act 1971, khat possession and use are not[1].

The diagnosis of drug induced liver injury (DILI) vs AIH triggered by khat is challenging. Various causality methods have been used for herbal induced liver injury and can be broadly divided into retrospective and prospective methods[16-25]. Establishing with any degree of certainty as to whether the liver disease is drug-induced can be very difficult[26]. The issue is further compounded by the relatively rare incidence of DILI, under reporting and potential drug interactions, due to which establishing the identity of the culprit drug may be impossible[27,28]. Furthermore, histology is often unhelpful as it only provides the type and degree of liver injury rather than the aetiology. The key to causality is to assess the temporal relationship between drug initiation and development of abnormal liver tests and to diligently exclude other causes of liver diseases. This includes liver injury induced by alcohol, viral hepatitis (acute hepatitis A, B, C and E), autoimmune causes, metabolic disorders, biliary obstruction and sepsis.

The diagnosis of AIH alone is based on the characteristic clinical and histological features as well as the absence of other potential causes of hepatitis. The revised criteria for diagnosis of autoimmune hepatitis are considered the current gold standard[11,12]. Drugs can occasionally cause a clinical-serological picture similar to autoimmune hepatitis and may trigger autoimmune hepatitis in patients with an underlying genetic pre-disposition to autoimmune hepatitis, or the patients may develop AIH as a squeal of the drug itself. In a Swedish study of 23 patients who developed chronic DILI 23.1% were subsequently diagnosed with autoimmune hepatitis, the suspected drugs being ranitidine, enalapril, oestrogen, carbamazepine, and oestriol[29]. In a recent case series, Peevers et al[9] described seven patients presenting with acute hepatitis who had a history of khat use. Two of those patients met the criteria for the diagnosis of probable AIH. It has been reported previously that Somalian patients with AIH present atypically. In a study of Somalian patients with a history of AIH, it was noted that all of the patients were male and scored in the probable group[10]. History of chewing khat was not mentioned in that particular study. However, in our series, all of the patients who presented with acute hepatitis had a history of khat use with five out of six patient meeting the criteria for probable AIH and demonstrating a good clinical response to immunosuppression. We therefore conclude that, in addition to producing DILI, khat may also trigger AIH in patients with a possible genetic pre-disposition.

Recently, Terschke et al[30] have validated the use of the CIOMS scale to be used with herbal induced liver injury (HILI) cases. Although the diagnosis of AIH is well founded in these patients, the causality assessment by means of CIOMS is not available. Also, the small number of patients in this series means that our hypothesis of AIH being induced by khat can only be tentative and should be interpreted with caution. Whether these patients benefit from long-term immunosuppression after stopping khat remains unclear. Further studies of similar groups of patients are required to increase our understanding of this phenomenon and its management.

COMMENTS
Background

Khat is widely used in Southern arabia and East Africa. It is also known that autoimmune hepatitis presents atypically in these population as it is more common in males and presents at a younger age.

Research frontiers

Khat is well known to cause liver damage but the mechanism of this remains elusive. Patients in the areas where khat is consumed, present with atypical autoimmune hepatitis - the cause of which is not known.

Innovations and breakthroughs

The authors present an interesting observation of development of autoimmune hepatitis in a group of patients consuming Khat.

Applications

People can treat these group of patients more effectively by understanding the possible mechanisms of liver damage caused by Khat use.

Terminology

Khat (Catha Edulis Celestrasae) is an evergreen shrub native to East Africa and Southern Arabia. It is chewed daily by over 20 million people in these countries for its addictive and euphoric properties.

Peer review

This is an important case-report and the manuscript reads well.

Footnotes

P- Reviewers: Agustin C, Ding WX, Grattagliano I, Mehmet C, Neil LJ, Teschke R S- Editor: Song XX L- Editor: A E- Editor: Zhang DN

References
1.  Griffiths P Qat use in London: a study of qat use among a sample of Somalis living in London. Home Office drugs prevention initiative. London: Home Office 1998; .  [PubMed]  [DOI]
2.  Al-Habori M. The potential adverse effects of habitual use of Catha edulis (khat). Expert Opin Drug Saf. 2005;4:1145-1154.  [PubMed]  [DOI]
3.  Al-Mamary M, Al-Habori M, Al-Aghbari AM, Baker MM. Investigation into the toxicological effects of Catha edulis leaves: a short term study in animals. Phytother Res. 2002;16:127-132.  [PubMed]  [DOI]
4.  Douglas H, Boyle M, Lintzeris N. The health impacts of khat: a qualitative study among Somali-Australians. Med J Aust. 2011;195:666-669.  [PubMed]  [DOI]
5.  Brostoff JM, Plymen C, Birns J. Khat--a novel cause of drug-induced hepatitis. Eur J Intern Med. 2006;17:383.  [PubMed]  [DOI]
6.  Stuyt RJ, Willems SM, Wagtmans MJ, van Hoek B. Chewing khat and chronic liver disease. Liver Int. 2011;31:434-436.  [PubMed]  [DOI]
7.  Roelandt P, George C, d’Heygere F, Aerts R, Monbaliu D, Laleman W, Cassiman D, Verslype C, van Steenbergen W, Pirenne J. Acute liver failure secondary to khat (Catha edulis)-induced necrotic hepatitis requiring liver transplantation: case report. Transplant Proc. 2011;43:3493-3495.  [PubMed]  [DOI]
8.  Chapman MH, Kajihara M, Borges G, O’Beirne J, Patch D, Dhillon AP, Crozier A, Morgan MY. Severe, acute liver injury and khat leaves. N Engl J Med. 2010;362:1642-1644.  [PubMed]  [DOI]
9.  Peevers CG, Moorghen M, Collins PL, Gordon FH, McCune CA. Liver disease and cirrhosis because of Khat chewing in UK Somali men: a case series. Liver Int. 2010;30:1242-1243.  [PubMed]  [DOI]
10.  D’Souza R, Sinnott P, Glynn MJ, Sabin CA, Foster GR. An unusual form of autoimmune hepatitis in young Somalian men. Liver Int. 2005;25:325-330.  [PubMed]  [DOI]
11.  Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WG, Czaja AJ, Desmet VJ. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929-938.  [PubMed]  [DOI]
12.  Johnson PJ, McFarlane IG. Meeting report: International Autoimmune Hepatitis Group. Hepatology. 1993;18:998-1005.  [PubMed]  [DOI]
13.  Bénichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990;11:272-276.  [PubMed]  [DOI]
14.  Navarro V; Hepatic adverse event nomenclature document (online). Available from URL: http://www.fda.gov/cder/livertox/presentations2005/Vic_Navarro.ppt.  .  [PubMed]  [DOI]
15.  Kalix P. Cathinone, a natural amphetamine. Pharmacol Toxicol. 1992;70:77-86.  [PubMed]  [DOI]
16.  Danan G, Benichou C. Causality assessment of adverse reactions to drugs--I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46:1323-1330.  [PubMed]  [DOI]
17.  Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs--II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol. 1993;46:1331-1336.  [PubMed]  [DOI]
18.  Teschke R, Schwarzenboeck A, Hennermann KH. Causality assessment in hepatotoxicity by drugs and dietary supplements. Br J Clin Pharmacol. 2008;66:758-766.  [PubMed]  [DOI]
19.  Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology. 1997;26:664-669.  [PubMed]  [DOI]
20.  Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245.  [PubMed]  [DOI]
21.  Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. Clin Pharmacol Ther. 1977;21:247-254.  [PubMed]  [DOI]
22.  Teschke R, Wolff A. Regulatory causality evaluation methods applied in kava hepatotoxicity: are they appropriate? Regul Toxicol Pharmacol. 2011;59:1-7.  [PubMed]  [DOI]
23.  Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, Rochon J. Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct. Drug Saf. 2009;32:55-68.  [PubMed]  [DOI]
24.   Available from: http://whoumc.org/Graphics/24734.pdf.  [PubMed]  [DOI]
25.  Teschke R, Schulze J, Schwarzenboeck A, Eickhoff A, Frenzel C. Herbal hepatotoxicity: suspected cases assessed for alternative causes. Eur J Gastroenterol Hepatol. 2013;25:1093-1098.  [PubMed]  [DOI]
26.  Verma S, Kaplowitz N. Diagnosis, management and prevention of drug-induced liver injury. Gut. 2009;58:1555-1564.  [PubMed]  [DOI]
27.  Fontana RJ. Acute liver failure due to drugs. Semin Liver Dis. 2008;28:175-187.  [PubMed]  [DOI]
28.  Chang CY, Schiano TD. Review article: drug hepatotoxicity. Aliment Pharmacol Ther. 2007;25:1135-1151.  [PubMed]  [DOI]
29.  Björnsson E, Davidsdottir L. The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice. J Hepatol. 2009;50:511-517.  [PubMed]  [DOI]
30.  Teschke R, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: challenges and pitfalls of causality assessment methods. World J Gastroenterol. 2013;19:2864-2882.  [PubMed]  [DOI]