EP CASE REPORT .............................................................................................................................................................................
Intrahepatic cholestatic hepatitis following diagnostic ajmaline challenge Greg Mellor1*, Ian Fellows2, and Ian Williams1 1 Department of Cardiology, Norfolk & Norwich University Hospital, Norwich, UK and 2Department of Gastroenterology, Norfolk & Norwich University Hospital, Norwich, UK
5
* Corresponding author. 43 Stonehill Road, Great Shelford, Cambridge CB22 5JL, UK. Tel: +44 79677 713345, Email:
[email protected]
We present a case of a 54-year-old woman who developed an intrahepatic cholestatic hepatitis following a diagnostic ajmaline challenge. Hepatic side effects have been described with ajmaline in the era of chronic use, but no reports exist of such complications from diagnostic use to the best of our knowledge. Polymorphisms in the metabolizing enzyme, CYP2D6, may be significant. A 54-year-old woman underwent diagnostic ajmaline challenge as screening for Brugada syndrome. She was given a dose of 1 mg/kg of ajmaline in 10 mg aliquots at 2 min intervals. She underwent continuous 12-lead electrocardiogram (ECG) monitoring. The test was negative with no change from her normal resting ECG. There were no immediate complications, and she was discharged home after a 4 h period of observation. Three weeks later she presented to her general practitioner with a 1 week history of pruritis, jaundice, and dark urine. She was pyrexial and felt systemically unwell. Her appetite was poor and she had lost 3 kg. Clinical examination confirmed jaundice, but revealed no stigmata of chronic liver disease and no hepatomegaly. Biochemistry demonstrated raised serum bilirubin and liver enzymes, predominantly alanine transaminase. Hepatic synthetic function was normal. There was a mild peripheral blood eosinophilia. Ultrasound showed normal liver parenchyma, with normal calibre bile ducts and a stone-free gallbladder. Further investigations for underlying liver disease including viral serology, autoantibodies, and serum ferritin were all unremarkable. The patient was managed conservatively with oral ursodeoxycholic acid and clinically improved over a period of 4 months. Serum bilirubin peaked at 266 mmol/L and remained .100 mmol/L for 2 months. Sub-clinical raised bilirubin persisted for several months after correction of liver enzymes. As the patient’s symptoms were improving she did not undergo a liver biopsy. Pre-test liver functions tests are not known. The patient did not have any history of, risk factors for, or family history of liver disease. She took no medication and minimal alcohol.
10
15
20
25
30
35
40
45
Figure 1 Liver function post-ajmaline challenge.
Ajmaline is an alkaloid found in the root of Rauwolfia serpentina. It is a class Ia antiarrhythmic agent currently recommended as a diagnostic tool in cases of suspected Brugada syndrome without typical ECG features. It has previously been used as an antiarrhythmic drug. There is a small number of reports of ajmaline-induced hepatitis or cholestasis associated with chronic use of the drug in this era. Larrey et al.1 describe three cases of cholestatic jaundice precipitated by regular ajmaline use. These patients had a similar clinical picture to our patient and all recovered with conservative management. Patients had hypereosinopilia, and liver biopsies in these
50
55
& The Author 2012.
patients showed centrilobular cholestasis and portal inflammatory infiltration. Therefore, an autoimmune aetiology was suspected, although the precise mechanism was unclear. Ajmaline is metabolized via the cytochrome p450 enzyme CYP2D6. Polymorphisms in the CYP2D6 gene are common and up to 26% of European Caucasians have non-functioning alleles2, perhaps explaining the susceptibility of certain individuals. Ajmaline has been used as a diagnostic tool in patients with suspected Brugada syndrome without typical ECG changes since reported by Brugada et al. 3 in 2000. Despite this, there are no reports to our knowledge of similar problems occurring with the low doses used in diagnostic ‘challenges’. The mechanism of this reaction remains unclear but may relate to polymorphisms of CYP2D6. We recommend routine liver function testing before undertaking an ajmaline challenge. Conflict of interest: none declared.
60
65
References 1. Larrey D, Pessayre D, Duhemal G et al. Prolonged cholestasis after ajmaline-induced acute hepatitis. J Hepatol 1986;2:81– 7. 2. Bradford L. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 2002;3:229 –43. 3. Brugada R, Brugada J, Antzelevitch C et al. 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 –5.
70
75
80
85
90
95
100
105
110
