JPGN Journal of Pediatric Gastroenterology and Nutrition Publish Ahead of Print DOI : 10.1097/MPG.0000000000000566
Topiramate-Induced Acute Liver Failure in a Pediatric Patient - A Case Report and Review of Literature
Authors: Margaret Z. Tsien1,3, MD; Jonathan Cordova, DO2; Asad Qadir5; Lei Zhao4, MD, PhD; John Hart, MD4; and Ruba Azzam, MD1, 2
Affiliations: Departments of Pediatrics1, Section of Gastroenterology, Hepatology, and Nutrition2 at Comer Children’s Hospital; Department of Internal Medicine3 and Department of Pathology4 at University of Chicago Medical Center; University of Chicago Pritzker School of Medicine5
Address correspondence to: Margaret Z. Tsien, MD 5841 S Maryland Ave, MC 7082 Chicago, IL 60637 Office phone: 773-702-6840, Office fax: 773-834-3950 E-Mail: [email protected]
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Abbreviations: Drug-induced liver injury (DILI) Acute liver failure (ALF)
Word Count: 999 Figures: 1
Disclosure Statements 1. The authors have no financial relationships relevant to this article. No funding was secured for this study. 2. No honorarium, grant, or other form of payment was given to anyone to produce the manuscript. 3. The authors have no conflict of interest to disclose. 4. The manuscript will not be submitted to any other journal while it is under consideration by Journal of Pediatric Gastroenterology and Nutrition 5. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and take full responsibility for the manuscript.
Abstract: This is the case of a pediatric patient presenting in acute liver failure (ALF) likely related to topiramate toxicity. The unique presentation of fulminant liver failure and severe hyperammonemia while on long term topiramate therapy not combined with valproate, demonstrates the need for more awareness of this adverse event.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Introduction: Drug-induced liver injury (DILI) represents a special type of adverse drug reaction. More than 600 drugs and chemicals have been associated with significant liver injury. Hepatotoxicity is a well-known adverse effect of first generation antiepileptics. Second generation antiepileptics generally have a milder side effect profile; however, hepatotoxicity and hyperammonemic encephalopathy have been reported in patients on topiramate, in conjunction with other antiepileptics.
We report a case of a pediatric patient presenting in acute liver failure (ALF) with remarkable coagulopathy and hyperammonemia that likely resulted from topiramate toxicity, compounded by hypovolemic shock.
Case Description: The patient is an 11-year-old male with history of cerebral palsy, intellectual disability, and epilepsy who presented with somnolence and diarrhea. Initial evaluation revealed AST 5666U/L, ALT 7890U/L, GGT 243U/L, bilirubin 5.9mg/dL, INR 10.8 and ammonia 1350mcg/dL; consistent with ALF. His home medications, since infancy, included topiramate, phenobarbital, diazepam and baclofen. Both serum antiepileptic blood levels were within their therapeutic ranges, although the trough topiramate level of 21.2ug/ml (normal range 2-25ug/ml) was significantly elevated from his previous levels of 5-7ug/ml.
In addition, he had acidosis (pH 7.1, lactate 18mmol/L); AKI (creatinine 2.2mg/dL) and hypovolemic shock. At baseline he was nonverbal but able to communicate with
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
crying/moaning. On admission, he was unresponsive with grade IV hepatic encephalopathy. A CT head showed no intracranial hemorrhage or edema. An electroencephalogram was normal. Topiramate was held given his ALF and hyperammonemia, but phenobarbital, baclofen, and diazepam were continued.
Work up for ALF included: negative serum viral studies (including EBV/CMV serology and PCR, Hep A,B,C, Coxsackie A & B ab panels, Echovirus Ab, HSV 1/ HSV 2 serology and PCR, Parvovirus B19 ab, HHV6, Enterovirus PCR from nares); negative urine toxicology screen; undetectable acetaminophen; negative autoimmune workup (ANA, smooth muscle antibody, LKM), normal ceruloplasmin, and elevated ferritin but negative iron stains on biopsy. A nasal respiratory viral panel was positive for enterovirus/rhinovirus, and adenovirus. Serum adenovirus PCR and liver biopsy adenoviral stain were negative. A liver ultrasound/doppler showed good hepatic flow and minimal fatty infiltration.
Aminotransferases, ammonia, and coagulopathy rapidly improved with resuscitation, fresh frozen plasma, and discontinuation of topiramate. On day 4 of admission, a transjugular liver biopsy revealed severe acute hepatitis and microvesicular steatosis involving 50% of the liver parenchyma consistent with DILI (Figure 1). Given the pathology and the clinical improvement after discontinuation of topiramate, the patient’s ALF and hyperammonemia were deemed a consequence of topiramate toxicity.
The patient continued to improve over the following weeks with normalization of laboratory values. However, he remains ventilator-dependent and his mental status is further impaired.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Discussion Acute liver failure in pediatric patients is rare. Around 50% of pediatric ALF cases remain without etiology. According to the Pediatric ALF registry between 1999 and 2004, DILI accounted for 19% of cases of ALF of which 5% were idiosyncratic (non-acetaminophen induced) [1]. In adults in the United States, idiosyncratic reactions make up 13% of all ALF cases. Regardless of age, idiosyncratic DILI from any single medication is uncommon [2].
Topiramate is an antiepileptic medication also used in migraine prevention. It is metabolized by the cytochrome P450 system and induces CYP3A4 activity which can alter the levels of other anticonvulsants. Topiramate as a cause of ALF has only rarely been suggested, and the mechanism of DILI is not well understood.
Using RUCAM causality assessment of a drug in acute liver injury, topiramate as a causal agent for acute liver failure is probable [3]. The timing of the elevated topiramate level, the rapid decrease in ALT after discontinuation, and the lack of a concomitant drug trigger adds to the argument. The case scores a total of 8 RUCAM points which puts him on the border of “probably” and “high probably” of topiramate as a cause of hepatotoxicity.
The elevated ammonia level also supports topiramate-induced hepatic toxicity. The proposed mechanism for topiramate-induced hyperammonemia is via an inhibition of type V mitochondrial carbonic anhydrase. This inhibition decreases bicarbonate synthesis, which is needed for the synthesis of carbamyl phosphate from free ammonia. This is an essential step in
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
the urea cycle for detoxification of ammonia [4]. An ammonia level of >1300, as in our patient, is rare. Both ALF and topiramate can cause hyperammonemia independently.
No well-established characteristic pathology for topiramate hepatotoxicity exists. Our patient’s pathology showed a hepatocellular and cholestatic pattern of damage with microvesicular steatosis, consistent with DILI. Histology of idiosyncratic DILI in children tends to be diverse, often with inflammatory activity and cholestasis [5].
There have been 3 previous case reports of DILI attributed primarily to topiramate. Unlike our case, these incidents occurred after initiating topiramate whereas our patient was on topiramate for the past 10 years. However, our patient’s topiramate level was >4-fold higher than it had ever been before, with no changes in his medications and no supplements, which we hypothesize mimics a “new drug” effect. Bjoro et al. described an adult with ALF requiring a liver allograft 4 months after topiramate was added to a stable regimen of carbamazepine and days after a dose increase [6]. Similarly, Doan et al. reported a case of ALF in a young adult for whom topiramate was added to a long-standing valproate regimen[7]. Her liver function tests corrected after discontinuing topiramate. Finally, del Val Antonana et al. reported a case of hepatotoxicity in a 16-year-old male who received topiramate as monotherapy, initiated 10 weeks prior to presentation[8]. He had elevated transaminases and coagulopathy but no hyperammonemia. His findings resolved 2 weeks after discontinuing topiramate.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Conclusion We report a rare case of ALF likely caused by topiramate toxicity in a pediatric patient, whose hypovlemia could have potentiated the liver toxicity.
This case is unique with regards to age, degree of hepatic failure, level of hyperammonemic encephalopathy, and onset of toxicity with a chronic medication. Patients with baseline impairment on antiepileptic drugs need close monitoring for subtle changes in mental status. If a patient presents with liver dysfunction on topiramate, caution should be taken with its continuation and further investigation should be undertaken to rule out drug-associated hepatotoxicity.
Figure Legends:
Figure 1: The liver biopsy demonstrates severe lobular disarray and florid portal and lobular inflammatory cell infiltrates. The inflammatory infiltrates consist mostly of lymphocytes and neutrophils. Microvesicular steatosis is present and involves 50% of liver parenchyma. Intrahepatocellular cholestasis and bile plugs are also present.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
References: 1.
Squires, R.H., Jr., et al., Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr, 2006. 148(5): p. 652-658.
2.
Ostapowicz, G., et al., Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med, 2002. 137(12): p. 947-54.
3.
Fontana RJ et al. Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design, and conduct. Drug Safety 2009; 32:55-68.
4.
Latour, P., et al., Drug induced encephalopathy in six epileptic patients: topiramate? valproate? or both? Hum Psychopharmacol, 2004. 19(3): p. 193-203.
5.
Molleston JP et al. Characteristics of idiosyncratic drug-induced liver injury in children: Results from the DILIN prospective study. Journal of Pediatric Gastroenterology and Nutrition. 2011 Aug: 53(2): 182-189.
6.
Bjoro, K., et al., Topiramate and fulminant liver failure. Lancet, 1998. 352(9134): p. 1119.
7.
Doan, R.J. and M. Clendenning, Topiramate and hepatotoxicity. Can J Psychiatry, 2000. 45(10): p. 937-8.
8.
Del Val Antonana, A., I. Ortiz Polo, and R.J. Andrade Bellido, [Topiramate-induced acute hepatitis]. Gastroenterol Hepatol. 33(2): p. 148-9.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Topiramate-Induced Acute Liver Failure in a Pediatric Patient - A Case Report and Review of Literature
Authors: Margaret Z. Tsien1,3, MD; Jonathan Cordova, DO2; Asad Qadir5; Lei Zhao4, MD, PhD; John Hart, MD4; and Ruba Azzam, MD1, 2
Affiliations: Departments of Pediatrics1, Section of Gastroenterology, Hepatology, and Nutrition2 at Comer Children’s Hospital; Department of Internal Medicine3 and Department of Pathology4 at University of Chicago Medical Center; University of Chicago Pritzker School of Medicine5
Address correspondence to: Margaret Z. Tsien, MD 5841 S Maryland Ave, MC 7082 Chicago, IL 60637 Office phone: 773-702-6840, Office fax: 773-834-3950 E-Mail: [email protected]
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Abbreviations: Drug-induced liver injury (DILI) Acute liver failure (ALF)
Word Count: 999 Figures: 1
Disclosure Statements 1. The authors have no financial relationships relevant to this article. No funding was secured for this study. 2. No honorarium, grant, or other form of payment was given to anyone to produce the manuscript. 3. The authors have no conflict of interest to disclose. 4. The manuscript will not be submitted to any other journal while it is under consideration by Journal of Pediatric Gastroenterology and Nutrition 5. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and take full responsibility for the manuscript.
Abstract: This is the case of a pediatric patient presenting in acute liver failure (ALF) likely related to topiramate toxicity. The unique presentation of fulminant liver failure and severe hyperammonemia while on long term topiramate therapy not combined with valproate, demonstrates the need for more awareness of this adverse event.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Introduction: Drug-induced liver injury (DILI) represents a special type of adverse drug reaction. More than 600 drugs and chemicals have been associated with significant liver injury. Hepatotoxicity is a well-known adverse effect of first generation antiepileptics. Second generation antiepileptics generally have a milder side effect profile; however, hepatotoxicity and hyperammonemic encephalopathy have been reported in patients on topiramate, in conjunction with other antiepileptics.
We report a case of a pediatric patient presenting in acute liver failure (ALF) with remarkable coagulopathy and hyperammonemia that likely resulted from topiramate toxicity, compounded by hypovolemic shock.
Case Description: The patient is an 11-year-old male with history of cerebral palsy, intellectual disability, and epilepsy who presented with somnolence and diarrhea. Initial evaluation revealed AST 5666U/L, ALT 7890U/L, GGT 243U/L, bilirubin 5.9mg/dL, INR 10.8 and ammonia 1350mcg/dL; consistent with ALF. His home medications, since infancy, included topiramate, phenobarbital, diazepam and baclofen. Both serum antiepileptic blood levels were within their therapeutic ranges, although the trough topiramate level of 21.2ug/ml (normal range 2-25ug/ml) was significantly elevated from his previous levels of 5-7ug/ml.
In addition, he had acidosis (pH 7.1, lactate 18mmol/L); AKI (creatinine 2.2mg/dL) and hypovolemic shock. At baseline he was nonverbal but able to communicate with
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
crying/moaning. On admission, he was unresponsive with grade IV hepatic encephalopathy. A CT head showed no intracranial hemorrhage or edema. An electroencephalogram was normal. Topiramate was held given his ALF and hyperammonemia, but phenobarbital, baclofen, and diazepam were continued.
Work up for ALF included: negative serum viral studies (including EBV/CMV serology and PCR, Hep A,B,C, Coxsackie A & B ab panels, Echovirus Ab, HSV 1/ HSV 2 serology and PCR, Parvovirus B19 ab, HHV6, Enterovirus PCR from nares); negative urine toxicology screen; undetectable acetaminophen; negative autoimmune workup (ANA, smooth muscle antibody, LKM), normal ceruloplasmin, and elevated ferritin but negative iron stains on biopsy. A nasal respiratory viral panel was positive for enterovirus/rhinovirus, and adenovirus. Serum adenovirus PCR and liver biopsy adenoviral stain were negative. A liver ultrasound/doppler showed good hepatic flow and minimal fatty infiltration.
Aminotransferases, ammonia, and coagulopathy rapidly improved with resuscitation, fresh frozen plasma, and discontinuation of topiramate. On day 4 of admission, a transjugular liver biopsy revealed severe acute hepatitis and microvesicular steatosis involving 50% of the liver parenchyma consistent with DILI (Figure 1). Given the pathology and the clinical improvement after discontinuation of topiramate, the patient’s ALF and hyperammonemia were deemed a consequence of topiramate toxicity.
The patient continued to improve over the following weeks with normalization of laboratory values. However, he remains ventilator-dependent and his mental status is further impaired.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Discussion Acute liver failure in pediatric patients is rare. Around 50% of pediatric ALF cases remain without etiology. According to the Pediatric ALF registry between 1999 and 2004, DILI accounted for 19% of cases of ALF of which 5% were idiosyncratic (non-acetaminophen induced) [1]. In adults in the United States, idiosyncratic reactions make up 13% of all ALF cases. Regardless of age, idiosyncratic DILI from any single medication is uncommon [2].
Topiramate is an antiepileptic medication also used in migraine prevention. It is metabolized by the cytochrome P450 system and induces CYP3A4 activity which can alter the levels of other anticonvulsants. Topiramate as a cause of ALF has only rarely been suggested, and the mechanism of DILI is not well understood.
Using RUCAM causality assessment of a drug in acute liver injury, topiramate as a causal agent for acute liver failure is probable [3]. The timing of the elevated topiramate level, the rapid decrease in ALT after discontinuation, and the lack of a concomitant drug trigger adds to the argument. The case scores a total of 8 RUCAM points which puts him on the border of “probably” and “high probably” of topiramate as a cause of hepatotoxicity.
The elevated ammonia level also supports topiramate-induced hepatic toxicity. The proposed mechanism for topiramate-induced hyperammonemia is via an inhibition of type V mitochondrial carbonic anhydrase. This inhibition decreases bicarbonate synthesis, which is needed for the synthesis of carbamyl phosphate from free ammonia. This is an essential step in
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
the urea cycle for detoxification of ammonia [4]. An ammonia level of >1300, as in our patient, is rare. Both ALF and topiramate can cause hyperammonemia independently.
No well-established characteristic pathology for topiramate hepatotoxicity exists. Our patient’s pathology showed a hepatocellular and cholestatic pattern of damage with microvesicular steatosis, consistent with DILI. Histology of idiosyncratic DILI in children tends to be diverse, often with inflammatory activity and cholestasis [5].
There have been 3 previous case reports of DILI attributed primarily to topiramate. Unlike our case, these incidents occurred after initiating topiramate whereas our patient was on topiramate for the past 10 years. However, our patient’s topiramate level was >4-fold higher than it had ever been before, with no changes in his medications and no supplements, which we hypothesize mimics a “new drug” effect. Bjoro et al. described an adult with ALF requiring a liver allograft 4 months after topiramate was added to a stable regimen of carbamazepine and days after a dose increase [6]. Similarly, Doan et al. reported a case of ALF in a young adult for whom topiramate was added to a long-standing valproate regimen[7]. Her liver function tests corrected after discontinuing topiramate. Finally, del Val Antonana et al. reported a case of hepatotoxicity in a 16-year-old male who received topiramate as monotherapy, initiated 10 weeks prior to presentation[8]. He had elevated transaminases and coagulopathy but no hyperammonemia. His findings resolved 2 weeks after discontinuing topiramate.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Conclusion We report a rare case of ALF likely caused by topiramate toxicity in a pediatric patient, whose hypovlemia could have potentiated the liver toxicity.
This case is unique with regards to age, degree of hepatic failure, level of hyperammonemic encephalopathy, and onset of toxicity with a chronic medication. Patients with baseline impairment on antiepileptic drugs need close monitoring for subtle changes in mental status. If a patient presents with liver dysfunction on topiramate, caution should be taken with its continuation and further investigation should be undertaken to rule out drug-associated hepatotoxicity.
Figure Legends:
Figure 1: The liver biopsy demonstrates severe lobular disarray and florid portal and lobular inflammatory cell infiltrates. The inflammatory infiltrates consist mostly of lymphocytes and neutrophils. Microvesicular steatosis is present and involves 50% of liver parenchyma. Intrahepatocellular cholestasis and bile plugs are also present.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
References: 1.
Squires, R.H., Jr., et al., Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr, 2006. 148(5): p. 652-658.
2.
Ostapowicz, G., et al., Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med, 2002. 137(12): p. 947-54.
3.
Fontana RJ et al. Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design, and conduct. Drug Safety 2009; 32:55-68.
4.
Latour, P., et al., Drug induced encephalopathy in six epileptic patients: topiramate? valproate? or both? Hum Psychopharmacol, 2004. 19(3): p. 193-203.
5.
Molleston JP et al. Characteristics of idiosyncratic drug-induced liver injury in children: Results from the DILIN prospective study. Journal of Pediatric Gastroenterology and Nutrition. 2011 Aug: 53(2): 182-189.
6.
Bjoro, K., et al., Topiramate and fulminant liver failure. Lancet, 1998. 352(9134): p. 1119.
7.
Doan, R.J. and M. Clendenning, Topiramate and hepatotoxicity. Can J Psychiatry, 2000. 45(10): p. 937-8.
8.
Del Val Antonana, A., I. Ortiz Polo, and R.J. Andrade Bellido, [Topiramate-induced acute hepatitis]. Gastroenterol Hepatol. 33(2): p. 148-9.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
