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• W2015044897 abstract "Lamotrigine (LTG) has been associated with serious idiosyncratic reactions, including fulminant hepatic failure in children and adults (1-4). Recently Sen et al. (5) proposed treating hepatotoxicity induced by phenytoin (PHT), a drug that is 90% protein bound, by detoxification with the molecular adsorbents recirculating system (MARS). Because this blood-purification system is based on the principle of albumin dialysis, it is especially useful in cases of toxicity induced by highly protein bound drugs. LTG is eliminated primarily by glucuronide conjugation, and its plasma protein binding is 55% (6). We describe a woman with LTG-induced fulminant liver failure who recovered rapidly after MARS treatment. A 30-year-old woman was admitted to the Liver Disease Unit with symptoms typical of fulminant hepatic failure. Her medical history revealed a diagnosis of epilepsy with complex partial seizures (several times a year) since age 15 years. In the past, standard and ambulatory EEGs were normal; brain computed tomography and magnetic resonance imaging disclosed only slight ventricular asymmetry (left > right). At age 25 years, when seizures increased in frequency to several per month, the patient was started on antiepileptic therapy with carbamazepine (CBZ), 800 mg/day. About one month later, an episode of severe liver intoxication necessitated hospital admittance. On that occasion, after ceftriaxone was also given, disseminated intravascular coagulation (DIC) developed. CBZ and ceftriaxone were immediately discontinued, liver function returned to normal, and the patient was discharged after 4 weeks. Because seizures persisted, valproate (VPA), topiramate (TPM), and levetiracetam (LEV) were tried sequentially in monotherapy, without achieving seizure control. Twenty days before admission to our hospital, LEV (1,500 mg/day) had been switched to LTG, started at 25 mg/day and increased by 25 mg every week. At the time of admission, she was receiving LTG, 75 mg/day, no other potentially hepatotoxic drugs or herbal medications, and LEV had been discontinued for 7 days. At examination, she appeared drowsy; she complained of headache, vomiting, and diarrhea; her temperature was 39.5°C; and she had a diffuse maculopapular rash and jaundice, which had worsened gradually during the previous 2 days. Laboratory findings included aspartate aminotransferase, 4,960 IU/L; alanine aminotransferase, 7,268 IU/L; total bilirubin, 14 mg/dl; prothrombin time, 33%; international normalized ratio (INR), 2.44; creatinine, 2 mg/dl; white cells, 8.3 × 103/L (82.2% neutrophils, 0.1% eosinophils); platelets, 84 × 103/L; hemoglobin, 10 g/dl; hematocrit, 28%; protein, 5.5 g/dl; albumin, 3.2 g/dl; and blood urea nitrogen, 35 mg/dl. Serum tests for hepatitis A, B, and C, cytomegalovirus, and Epstein–Barr virus were negative. The EEG was typical of hepatic encephalopathy with diffuse slow activity and bi–triphasic sharp waves (Fig. 1A). LTG was immediately discontinued, and therapy was started with corticosteroids, diuretics, and vitamin K. The patient was scheduled for liver transplantation. On hospital day 3, while awaiting transplantation, she underwent two MARS sessions, one lasting 6 h, and the other, 3 h, separated by an interval of 12 h, by using the procedure described by Sen et al. (5). The MARS extracorporeal support system (Teraklin AG, Rostock, Germany) uses albumin-enriched dialysate to facilitate the removal of albumin-bound toxins. The dialysate-stored human serum albumin was passed through a column with uncoated charcoal and a second column with an anion-exchanger resin. After the second MARS session, her conditions and laboratory findings started to improve progressively, and the EEG showed a gradual return to baseline (Fig. 1B). A: EEG abnormalities during the acute phase of hepatic failure. B: Seven days after the patient received treatment with the molecular adsorbents recirculating system (MARS), the EEG returned to normal. C: Histologic appearance of liver biopsy specimen, showing inflammatory infiltrates within the lobules and clusters of necrotic hepatocytes. Bile thrombi also are evident (arrows) [H&E; ×150]. D: Liver cell necrosis was maximal in zone 3 of the lobules (arrow: centrilobular vein) [Sirius red; ×200]. A liver biopsy 10 days after the MARS session showed a mixed portal infiltrate (lymphocytes, neutrophils, and scattered eosinophils), with diffuse interface hepatitis (Fig. 1C and D). The lobules displayed moderate necrotic–inflammatory lesions, particularly in centrilobular areas. Extensive intracytoplasmic ceroid pigment accumulation also was evident in scattered areas, as well as intracytoplasmic cholestasis. These features were compatible with moderate-to-severe drug-induced hepatitis. Twenty days after admission, aspartate aminotransferase was 181; alanine aminotransferase, 60; total bilirubin, 3 mg/dl; prothrombin time, 88%; INR, 1.11; creatinine, 0.73 mg/dl; white cells, 3.91 103/L (59.2% neutrophils, 1.1% eosinophils); platelets, 150 × 103/L; hemoglobin, 11.2 g/dl; hematocrit, 30.7%; protein, 7 g/dl; albumin, 3 g/dl; and blood urea nitrogen, 19.1 mg/dl. The patient was discharged after 24 days. During her hospital stay, she had no seizures, and, at her request, she was referred to her neurologist without antiepileptic medication. At least 12 cases (four children and eight adults) of serious LTG-induced liver toxicity have been reported, of whom five died and seven recovered (1-4).The histopathologic findings suggest that in our patient, as also proposed for some previously reported cases (2-4), the disorder reflected an immune-mediated allergic reaction. A possible mechanism could be formation of antibodies against modified drug metabolite–protein aggregates, possibly owing to an inheritable deficiency in cellular detoxification mechanisms (7). In other cases, however, other mechanisms for LTG-induced liver failure cannot be excluded. In previous reports, comedication with other anticonvulsants (especially VPA) or other drugs, a rapid titration schedule, and coexisting medical conditions have been listed as risk factors for LTG-induced liver toxicity. In our patient, LTG was used in monotherapy, was slowly titrated, and no concomitant medical conditions existed. Unlike other reported cases, our patient also had a history of hypersensitivity to CBZ, suggesting a cross-sensitivity with LTG despite the different chemical structure of the two drugs. Patients with known hypersensitivity to a drug may develop cross-sensitivity to other agents through lymphocyte sensitization (8, 9). Our most interesting finding is the rapid recovery after institution of MARS treatment. None of the previously reported cases had been managed with this procedure. Although it cannot be excluded that prompt discontinuation of the offending agent, coupled with conventional supportive therapy, led by itself to recovery, the rapid and striking improvement after MARS in a patient whose condition was so serious as to indicate liver transplantation is consistent with a potential usefulness of such treatment. We conclude that MARS should be regarded as a promising option for the management of immune-mediated hepatotoxicity induced by LTG. The earlier MARS is applied, the more it would be likely to be of value." @default.
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• W2015044897 date "2005-09-28" @default.
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• W2015044897 title "Acute Hepatitis Associated with Lamotrigine and Managed with the Molecular Adsorbents Recirculating System (MARS)" @default.
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• W2015044897 doi "https://doi.org/10.1111/j.1528-1167.2005.00269.x" @default.
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