This article has Open Peer Review reports available.
Severe cholestatic jaundice after a single administration of ajmaline; a case report and review of the literature
© Mullish et al.; licensee BioMed Central Ltd. 2014
Received: 10 November 2013
Accepted: 27 March 2014
Published: 2 April 2014
Ajmaline is a pharmaceutical agent now administered globally for a variety of indications, particularly investigation of suspected Brugada syndrome. There have been previous reports suggesting that repetitive use of this agent may cause severe liver injury, but little evidence exists demonstrating the same effect after only a single administration.
A 33-year-old man of Libyan origin with no significant past medical history underwent an ajmaline provocation test for investigation of suspected Brugada syndrome. Three weeks later, he presented with painless cholestatic jaundice which peaked in severity at eleven weeks after the test. Blood tests confirmed no evidence of autoimmune or viral liver disease, whilst imaging confirmed the absence of biliary tract obstruction. A liver biopsy demonstrated centrilobular cholestasis and focal rosetting of hepatocytes, consistent with a cholestatic drug reaction. Over the course of the next few months, he began to improve clinically and biochemically, with complete resolution by one year post-exposure.
Whilst ajmaline-related hepatotoxicity was well-recognised in the era in which the drug was administered as a regular medication, clinicians should be aware that ajmaline may induce severe cholestatic jaundice even after a single dose administration.
Ajmaline is an alkaloid agent that was first isolated from the roots of Rauwolfia serpentine, and is classified as a class Ia antiarrhythmic. It has a number of different clinical indications for its use, with the major one at present being to elicit the characteristic ST segment changes on electrocardiogram (ECG) in patients suspected of having type 1 Brugada syndrome . It has been used previously as maintenance treatment for different arrhythmias including atrial fibrillation in patients with Wolff-Parkinson-White syndrome and also in patients with ventricular tachycardia . These, however, are now relatively rare indications for its use.
Although ajmaline administration appears to be generally safe, there have been previous reports of apparent drug-induced liver injury (DILI) related to its use. Some of these reports, however, were hampered by methodological flaws, and many of them were described in the era prior to easily-accessible serological confirmation/ exclusion of other liver insults, e.g. chronic viral hepatitis. Furthermore, there is to date only very scant evidence of ajmaline causing liver injury after only a single administration, the predominant means in which the drug is delivered at present. We here present an unusual case of severe cholestatic jaundice occurring after only a single administration of ajmaline.
A 33-year-old man of Libyan origin was seen in cardiology clinic for investigation of pre-syncope. He had a strong family history of premature sudden death of unclear aetiology. As part of his assessment, he underwent an ajmaline provocation test, during which he had continuous ECG monitoring. After administration of 80 mg (equivalent to 1 mg/kg) of ajmaline, his monitoring demonstrated 2:1 atrioventicular block before reversion back to normal sinus rhythm. There had been no electrophysiological evidence of a type 1 Brugada syndrome prior to the assessment being stopped. The man was asymptomatic and had no evidence of arrhythmia during three hours of subsequent observation, and was discharged home.
Three weeks later, the man presented with painless jaundice, pruritus, nausea, dark urine and pale-coloured stools to his family physician. He had no personal or family history of liver disease and had not been jaundiced previously. He took no regular medications, and denied the use of alcohol, recreational drugs or herbal/ traditional therapies. Examination revealed jaundice and excoriation, but neither hepatomegaly nor features of chronic liver disease. An ultrasound of his abdomen demonstrated a normal appearance to the liver parenchyma, with no biliary dilatation. The common bile duct (CBD) measured 5 mm in maximal diameter, and no gallstones were seen. There was normal portal and hepatic venous flow. Sonographic appearances of the pancreas, spleen and kidneys were normal. He was kept under review.
By nine days into his admission, his symptoms had begun to improve and his biochemistry stabilised, and he was discharged back to community care. When reviewed three weeks later, his pruritus had completely resolved. By one year after the initial exposure to ajmaline, his serum bilirubin and liver enzymes had near normalised (Figure 1).
There is strong evidence that this man’s illness represented the unusual syndrome of ajmaline-related cholestatic jaundice. On the CIOS/RUCAM scale, a validated scoring system for suspected drug-induced liver injury, this patient scores 8, which is interpreted as ‘probable’ DILI [4, 5]. This in conjunction with his histological findings indicates that it is very likely this patient’s liver injury was entirely ajmaline-induced, especially given the thorough exclusion of other possible aetiologies.
Ajmaline-related liver injury, at the time of writing this article, is not listed on the LiverTox website (http://www.livertox.nih.gov) that has been recently founded by the Liver Disease Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in collaboration with the National Library of Medicine (NLM) . Case studies have described an association between repetitive ajmaline administration and liver injury, with the typical pattern identified being that of an initial acute hepatitis followed by a prolonged period of cholestasis [7–9]. However, no previous histologically confirmed cases of DILI following a single dose administration of ajmaline have been described in the literature. A single case report of cholestatic jaundice after a single administration of the medication has been described , but in this report biliary obstruction was not formally excluded via magnetic resonance imaging and the histological nature of the underlying injury was not delineated and hence not definitively confirmed to be secondary to this agent. This case describes a 54-year-old woman who presented with cholestatic jaundice three weeks after an ajmaline challenge, with a complete clinical and biochemical recovery at four months post-exposure. The time course and pattern of liver enzymes between the administration of the drug, the onset of jaundice and the recovery between our patient and the patient in the prior case report are similar.
Research into possible mechanisms of ajmaline-related cholestasis is limited, although immune precipitates within bile canaliculi have been found on liver biopsy samples taken from a patient with cholestasis after repetitive ajmaline exposure . This may be consistent with ajmaline acting as a hapten when bound to proteins within the bile canaliculi. There is now evidence that an individual’s susceptibility to an idiosyncratic drug-induced liver injury may relate to a number of factors, including single nucleotide polymorphisms within particular HLA subtypes [11–13]. Ajmaline is metabolised by the cytochrome P450 enzyme 2D6. It is recognised that 71% of European Caucasians have functional alleles of this enzyme, whilst this is only the case in approximately 50% of Asians and Africans . It may be the case in this patient that exposure to ajmaline in the context of a non-functional CYP2D6 allele, plus inheritance of a vulnerable HLA subtype, increased this patient’s propensity to drug-related liver injury.
In conclusion, hepatologists, pathologists, toxicologists and cardiologists should recognise the association between even a single administration of ajmaline and prolonged cholestatic jaundice with the presence of centrilobular cholestasis histologically. This case also highlights the importance of taking an accurate and thorough medication history from both the patient and his primary physician, including single-dose agents that patients may have been administered. It may be that patients from Africa and Asia have an increased propensity to this form of liver injury. Further research is needed to try and elucidate the mechanistic pathway by which ajmaline results in cholestasis.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
The authors thank Professor Mark Thursz for his help in preparing this manuscript for publication.
- Siddiqui S, Siddiqui RH: Chemical examination of the roots of Rauwolfia serpintina. J Indian Chem Soc. 1931, 8: 667-680.Google Scholar
- Brugada R, Brugada J, Antzelevitch C, Kirsch GE, Potenza D, Towbin JA, Brugada P: Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation. 2000, 101: 510-515. 10.1161/01.CIR.101.5.510.View ArticlePubMedGoogle Scholar
- Brugada J, Brugada P, Brugada R: The ajmaline challenge in Brugada syndrome – a useful tool or misleading information?. Eur Heart J. 2003, 24 (12): 1085-1086. 10.1016/S0195-668X(03)00232-X.View ArticlePubMedGoogle Scholar
- 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. 10.1016/0895-4356(93)90101-6.View ArticlePubMedGoogle Scholar
- 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. 10.1016/0895-4356(93)90102-7.View ArticlePubMedGoogle Scholar
- LiverTox website. http://www.livertox.nih.gov, accessed 11th March 2014
- Pariente EA, Pessayre D, Bentata-Pessayre M, Capron J-P, Marti R, Delcenserie R, Callard P, Benhamou JP: Hépatite a l’ajmaline. Description de 4 observations et revue de la littérature. Gastroentérologie Clinique et Biologique. 1980, 4: 240-245.PubMedGoogle Scholar
- Rotmensch HH, Liron M, Yust I, Klejman A, Livni E, Moalem T, Gefel A: Cholestatic jaundice: an immune response to prajmalium bitartrate. Postgrad Med J. 1980, 56 (660): 738-741. 10.1136/pgmj.56.660.738.View ArticlePubMedPubMed CentralGoogle Scholar
- Larrey D, Pessayre D, Duhamel G, Casier A, Degott C, Feldmann G, Erlinger S, Benhamou JP: Prolonged cholestasis after ajmaline-induced acute hepatitis. J Hepatol. 1986, 2 (1): 81-87. 10.1016/S0168-8278(86)80011-3.View ArticlePubMedGoogle Scholar
- Mellor G, Fellows I, Williams I: Intrahepatic cholestatic hepatitis following diagnostic ajmaline challenge. Europace. 2013, 15 (3): 314-10.1093/europace/eus206.View ArticlePubMedGoogle Scholar
- Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, Day CP, Ruiz-Cabello F, Donaldson PT, Stephens C, Pirmohamed M, Romero-Gomez M, Navarro JM, Fontana RJ, Miller M, Groome M, Bondon-Guitton E, Conforti A, Stricker BH, Carvajal A, Ibanez L, Yue QY, Eichelbaum M, Floratos A, Pe'er I, Daly MJ, Goldstein DB, Dillon JF, Nelson MR, Watkins PB: Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology. 2011, 141 (1): 338-347. 10.1053/j.gastro.2011.04.001.View ArticlePubMedPubMed CentralGoogle Scholar
- Donaldson PT, Daly AK, Henderson J, Graham J, Pirmohamed M, Bernal W, Day CP, Aithal GP: Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury. J Hepatol. 2010, 53 (6): 1049-1053. 10.1016/j.jhep.2010.05.033.View ArticlePubMedGoogle Scholar
- Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe'er I, Floratos A, Daly MJ, Goldstein DB, John S, Nelson MR, Graham J, Park BK, Dillon JF, Bernal W, Cordell HJ, Pirmohamed M, Aithal GP, Day CP, DILIGEN Study, International SAE Consortium: HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009, 41 (7): 816-819. 10.1038/ng.379.View ArticlePubMedGoogle Scholar
- Bradford LD: CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendents. Pharmacogenomics. 2002, 3 (2): 229-243. 10.1517/146224184.108.40.206.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/14/60/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.