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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: January 16, 2014.



Phenytoin, formerly known as diphenylhydantoin, is perhaps the most commonly used major anticonvulsant agent, and is a rare but well known cause of acute idiosyncratic drug induced liver disease that can be severe and even fatal.


Phenytoin (fen' i toyn) is a hydantoin derivative that has potent anti-seizure activity that is believed to be based upon stablization of neuronal membranes caused by an increase in the efflux and decrease in the influx of sodium ions across GABA regulated sodium channels. A similar action in cardiac muscle may account for its activity against ventricular arrhythmias. Phenytoin was first approved for use in the United States in 1946, and currently more than 3 million prescriptions are filled yearly. Current indications for phenytoin are treatment and prevention of generalized tonic-clonic (grand mal) seizures and complex partial seizures and management of status epilepticus. It is now rarely used to suppress ventricular arrhythmias in patients unresponsive to lidocaine. Phenytoin is available generically in oral and parenteral formulations. Oral forms include tablets and capsules of 100 to 300 mg, including extended release formations for once daily dosing. Commercial names include Dilantin. Chewable tablets and oral suspensions are available for pediatric use. The recommended dose of phenytoin for chronic use is 100 mg three times daily. Common side effects include dizziness, ataxia, nausea, gum hyperplasia and rash (which can occur in 10% of patients). Phenytoin has major effects on metabolism of other medications, and patients should be provided specific advice about other medications that can be used during long term phenytoin therapy.


Prospective studies indicate that a fairly high proportion of patients taking phenytoin have transient serum aminotransferase elevations. These elevations are usually benign, not associated with liver histological abnormalities and usually resolve even with drug continuation. In addition, a higher proportion of patients have mild to moderate elevations in gammaglutamyl transpeptidase (GGT) levels, which is indicative of hepatic enzyme induction rather than liver injury. Marked aminotransferase elevations (>3 fold elevated) occur rarely.

Importantly, however, phenytoin is one of the most common causes of clinically apparent drug induced liver disease and acute liver failure. More than 100 cases of liver injury due to phenytoin (diphenylhydantoin) have been published and a characteristic clinical pattern (signature) of injury has been described. The estimated frequency ranges from 1 per 1000 to 1 per 10,000 and probably varies by race and ethnicity. The typical case arises after 2 to 8 weeks of therapy with initial onset of fever, rash, facial edema and lymphadenopathy, followed in a few days by jaundice and dark urine. The serum enzyme elevations can be hepatocellular, although mixed patterns are probably more common and rare cases are cholestatic. Eosinophilia, increased white counts and atypical lymphocytosis are also common. Autoantibody formation is rare. The clinical symptoms and signs can mimic acute mononucleosis or even lymphoma (pseudo-lymphoma syndrome). Almost all cases of phenytoin hepatotoxicity occur in the context of a systemic hypersensitivity syndrome and it is referred to often as the anticonvulsant hypersensitivity syndrome (HDS) or drug rash with eosinophilia and systemic symptoms syndrome (DRESS). Other manifestations can be Stevens-Johnson syndrome, toxic epidermal necrolysis, aplastic anemia, thrombocytopenia, neutropenia, nephritis, and pneumonitis. Most cases of liver injury are self-limiting and resolve within 1 to 2 months of stopping phenytoin. However, the liver injury can be severe and many fatal instances have been reported, phenytoin usually appearing in the top 10 causes of drug induced acute liver failure. In the typical case, however, recovery is usually complete.

Mechanism of Injury

The liver injury caused by phenytoin appears to be due to a hypersensitivity reaction and resembles typical cases of immunoallergic hepatotoxicity. This syndrome is more common in blacks than whites, but few other risk factors have been established. In some populations, the risk of injury correlates with the presence of HLA-B*1502. Phenytoin is metabolized by CYP 450 system to arene oxide, which may represent the toxic or immunogenic intermediate.

Outcome and Management

Acute phenytoin hepatitis with jaundice has a fatality rate of greater than 10%. For this reason, phenytoin should be stopped promptly if symptoms of liver disease or jaundice arise early during therapy. Monitoring of ALT levels during introduction of phenytoin is recommended by some expert groups, but minor ALT elevations are common and it is unclear at what level of elevation that therapy should be suspended. Chronic injury due to phenytoin hepatotoxicity is rare or nonexistent, but cases of prolonged jaundice resembling vanishing bile duct syndrome have been reported. Rechallenge leads to rapid and usually more severe recurrence which can be fatal and should be avoided. Cross sensitivity with other aromatic anticonvulsants (phenobarbital, carbamazepine, lamotrigine and ethosuximide) can occur but is not invariable. Nevertheless, it is prudent to avoid use of these other aromatic anticonvulsants and to switch to agents such as valproate, gabapentin, levetiracetam or a benzodiazepine, which do not appear to induce the same hypersensitivity syndrome. Corticosteroid therapy is often used in patients with severe phenytoin hepatotoxicity and anecdotal reports suggest that responses are rapid and beneficial. If used, corticosteroid therapy should be limited in dose and duration.

Drug Class: Anticonvulsants


Case 1. Acute immunoallergic hepatitis 3 weeks after starting phenytoin.

[Modified from: Gloria L, Serejo F, Cruz E, Freitas J, Costa A, Ramalho F, Batista A, de Moura MC. Diphenylhydantoin-induced hepatitis: a case report. Hepatogastroenterol 1998; 45: 411-4. PubMed Citation]

A 25 year old man was started on phenytoin (100 mg thrice daily) for new onset seizures and developed fever, mobilliform pruritic rash and fatigue 3 weeks later. He was treated symptomatically and maintained on anticonvulsant therapy until 2 weeks later when he was admitted for worsening rash and jaundice. He had no other medical illnesses, no history of liver disease, drank little alcohol and was taking no other medications except salicylates for fever. On examination, he had a generalized erythematous rash and facial edema. His temperature was 39.5 oC and he had mild cervical, axillary and inguinal adenopathy. He was jaundiced, but had no hepatomegaly or peripheral signs of liver disease. Laboratory tests showed elevations in serum enzymes and bilirubin (Table). The total white count was 18,200/μL with 13% eosinophils and 13% atypical lymphocytes. An abdominal ultrasound was normal without splenomegaly or biliary abnormalities. He tested negative for markers of hepatitis A, B and C as well as cytomegalovirus, Epstein-Barr and herpes simplex viruses. Serological tests for syphilis were negative. Phenytoin was stopped. Initially, the prothromin time was prolonged (20.4 sec, control 11 sec), but it corrected in the following week (and after vitamin K injections). The skin rash became desquamative. A liver biopsy showed changes of acute hepatitis with some granulomata and moderate cholestasis. In follow up six weeks after onset, the rash had resolved, he was asymptomatic and all laboratory tests (white counts and liver tests) were normal.

Key Points

Medication:Phenytoin (100 mg three times daily)
Pattern:Mixed (R=4.9)
Severity:4+ (hospitalization for jaundice, abnormal prothrombin time)
Latency:3 weeks to symptoms, 5 weeks to jaundice
Recovery:Complete within 6 weeks
Other medications:Salicylates for fever

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
Protime (sec)
5 weeks08885704.820.4
4 days10704826.917.0
6 weeks7 days6734743.213.1
10 days2473162.911.0
7 weeks13 days1022131.612.0
11 weeks6 weeksNormalNormalNormal
Normal Values<29<90<1.2


The patient developed a typical acute anticonvulsant hypersensitivity syndrome with fever, rash, facial edema and lymphadenopathy within 3 weeks of starting phenytoin. Signs and symptoms of hepatitis arose thereafter and phenytoin was stopped once jaundice appeared. This pattern of onset and association with immunoallergic manifestations is typical of phenytoin hepatic injury. The enzyme pattern was “mixed” hepatocellular-cholestatic pattern and the liver biopsy showed a similar pattern. The hepatic injury was severe but rapidly reversible once phenytoin was stopped, the reversal beginning ~7 days after stopping, which is typical of phenytoin hepatic injury.



Phenytoin – Generic, Dilantin®




Product labeling at DailyMed, National Library of Medicine, NIH


Phenytoin chemical structure


References updated: 16 January 2014

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    (3 siblings, ages 23 to 32 years, developed fever, rash, facial edema, lymphadenopathy, eosinophilia and anicteric hepatitis 2-21 days after starting phenytoin, resolving rapidly; index case had in vitro evidence of toxicity of carbamazepine and phenytoin, but not phenobarbital and similar findings in siblings).
  • Roy AK, Mahoney HC, Levine RA. Phenytoin-induced chronic hepatitis. Dig Dis Sci 1993; 38: 740-3. [PubMed: 8462373]
    (52 year old woman had chronic, mild ALT elevations on long term phenytoin [bilirubin and Alk P normal], biopsy showing mild inflammation without fibrosis, ALT elevations resolved rapidly with stopping and recurred within 5 days of rechallenge).
  • Handfield-Jones SE, Jenkins RE, Whittaker SJ, Besse CP, McGibbon DH. The anticonvulsant hypersensitivity syndrome. Br J Dermatol 1993; 129: 175-7. [PubMed: 7654579]
    (2 women and 1 man, ages 20, 46 and 61 years developed fever and rash 3, 4 and 10 weeks after starting phenytoin or carbamazepine; two required corticosteroids; only 1 had hepatitis; one died of multiorgan failure, others switched to valproate or clobazam without recurrence).
  • Garcia-Samaniego J, Soriano V, Soto J, Munoz F. [Phenytoin hypersensitivity syndrome]. An Med Interna 1994; 11: 541-2. [PubMed: 7654902]
    (15 year old developed fever and oral ulcers 2 months after starting phenytoin, followed by rash, pruritus and adenopathy [bilirubin 8 mg/dL, ALT 780 U/L, Alk P 836 U/L and eosinophilia]; given corticosteroids and switched to valproate and recovered).
  • Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern Med 1995; 155: 2285-90. 7487252. (One 24 year old woman and a 38 year old man developed anticonvulsant hypersensitivity syndrome, 4 and 6 weeks after starting carbamazepine [bilirubin 0.6 and 4.1 mg/dL, ALT 402 and 1890 U/L, Alk P 184 and 487 U/L] both recovered but required corticosteroid therapy).
  • Mauri-Hellweg D, Bettens F, Mauri D, Brander C, Hunziker T, Pichler WJ. Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. J Immunol 1995; 155: 462-72. [PubMed: 7602118]
    (In vitro lymphocyte studies on patients with drug allergy, found proliferation in response to specific drugs, including phenytoin, with proliferation of both CD4 and CD8 T cells and increase in CD-25 and HLA-DR expression and production of IL5 and IFNγ).
  • de la Serna Higuera C, Gil Grande LA, Barcena Marugan R. [Toxic cholestatic hepatitis due to phenytoin]. Gastroenterol Hepatol 1995; 18: 471-3. [PubMed: 8521225]
    (51 year old woman developed rash, fever and then jaundice 3 weeks after starting phenytoin [bilirubin 8.2 mg/dL, ALT 847 U/L, Alk P 1782 U/L, 15% eosinophilia], and slow biochemical recovery).
  • Schneider S, Charles F, Chichmanian RM, Montoya ML, Rampal P. [Acute hepatitis associated with microvesicular steatosis induced by Atrium] Gastroenterol Clin Biol 1995; 19: 1064-5. [PubMed: 8729422]
    (37 year old woman developed right upper quadrant pain after 6 months of Atrium therapy [bilirubin rising to 2.0 mg/dL, ALT 9 times ULN, Alk P normal, ANA 1:1000], biopsy showed microvesicular fat; also on carbimazole and phenytoin).
  • Wallace SJ. A comparative review of the adverse effects of anticonvulsants in children with epilepsy. Drug Saf. 1996; 15: 378-93. [PubMed: 8968693]
    (Systematic review; ALT elevations occur in 4% of children on phenytoin, 6% on valproate, 1% on carbamazepine, but not with gabapentin or phenobarbital; skin rash and Stevens-Johnson syndrome discussed related to phenobarbital).
  • Chopra S, Levell NJ, Cowley G, Gilkes JJH. Systemic corticosteroids in the phenytoin hypersensitivity syndrome. Br J Dermatol 1996; 134: 1109-12. [PubMed: 8763435]
    (46 year old woman developed rash and fever, 8 weeks after starting phenytoin [bilirubin 1.0 mg/dL, AST 96 U/L, Alk P 642 U/L, 7% eosinophils], with rapid response to prednisone, relapse when stopped early).
  • Conger LA Jr, Grabski WJ. Dilantin hypersensitivity reaction. Cutis 1996; 57: 223-6. [PubMed: 8727770]
    (41 year old woman developed fever, rash, lymphadenopathy and facial edema 6 weeks after starting phenytoin [no mention of bilirubin, ALT 63 U/L, Alk P 137 U/L, 13% eosinophils, 3% atypical lymphocytes], resolving rapidly upon stopping).
  • Schlienger RG, Shear NH. Antiepileptic drug hypersensitivity syndrome. Epilepsia 1998; 39 Suppl 7: S3-7. [PubMed: 9798755]
    (Review: onset 2-8 weeks after starting therapy with aromatic anticonvulsants presenting with high fever, rash, adenopathy and pharyngitis followed by organ involvement, most commonly the liver [~50%], but also hematologic, renal or pulmonary; eosinophilia, blood dyscrasias, nephritis; sometimes facial edema, oral ulcers, hepatosplenomegaly, myopathy, disseminated intravascular coagulation, atypical lymphocytosis; rash usually exanthema with pruritus, occasional follicular pustules or exfoliative dermatitis and erythroderma, erythema muliforme, Stevens-Johnson syndrome or toxic epidermal necrolysis).
  • Gloria L, Serejo F, Cruz E, freitas J, Costa A, Ramalho F, Batista A, Carneiro de Moura M. Diphenylhydantoin-induced hepatitis: a case report. Hepatogastroenterol 1998; 45: 411-4. [PubMed: 9638415]
    (25 year old man developed fever, rash, facial edema and malaise 3 weeks after starting phenytoin followed by jaundice [bilirubin 6.9 mg/dL, ALT 888 U/L, Alk P 570 U/L, 13% eosinophils], resolving within 6 weeks of stopping).
  • Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf 1999; 21: 489-501. [PubMed: 10612272]
    (Classic review of anticonvulsant hypersensitivity syndrome: triad of fever, rash and internal organ injury occurring 1-8 weeks after exposure to anticonvulsant, liver being most common internal organ involved. Occurs in 1:1000-1:10,000 initial exposures to phenytoin, carbamazepine, phenobarbital or lamotrigine, unrelated to dose, perhaps predisposed by valproate; liver injury arises 1-4 weeks after onset of rash and ranges in severity from asymptomatic ALT elevations to icteric hepatitis to acute liver failure. High mortality rate with jaundice; other organs include muscle, kidney, brain, heart and lung. Pseudolymphoma syndrome and serum sickness like syndrome are separate complications of anticonvulsants. Role of corticosteroids uncertain; cross reactivity among the agents should be assumed).
  • Kakar A, Byotra SP. Phenytoin induced severe agranulocytosis and hepatitis. J Assoc Physicians India 1999; 47: 644. [PubMed: 10999171]
    (45 year old woman developed fever one week after starting phenytoin [bilirubin not given, ALT 106 U/L, Alk P 913 U/L]).
  • Hamer HM, Morris HH. Hypersensitivity syndrome to antiepileptic drugs: a review including new anticonvulsants. Clevel Clin J Med 1999; 66: 239-45. [PubMed: 10199060]
    (Clinical review of anticonvulsant hypersensitivity syndrome; occurs in 1-5/10,000 users, higher risk in African Americans and siblings of affected subjects; liver involvement common, but most cases anicteric; other manifestations are facial edema, lymphadenopathy, bone marrow aplasia, pseudolymphoma, thyroiditis, pneumonitis and interstitial nephritis).
  • Hamer HM, Morris HH. Successful treatment with gabapentin in the presence of hypersensitivity syndrome to phenytoin and carbamazepine: a report of three cases. Seizure 1999; 8: 190-2. [PubMed: 10356381]
    (3 patients with onset of rash, fever, lymphadenopathy and eosinophilia 4-6 weeks after starting either phenytoin or carbamazepine, [bilirubin 0.5-1.8 mg/dL, ALT 866-1402 U/L, Alk P 69-364U/L], all 3 later tolerated gabapentin).
  • Nashed MH, Liao L. Possible atypical cross-sensitivity between phenytoin and carbamazepine in the anticonvulsant hypersensitivity syndrome. Pharmacother 2001; 21: 502-5. [PubMed: 11310525]
    (73 year old black woman developed rash, fever and confusion 3-4 weeks after starting phenytoin and failed to improve when switched to carbamazepine [peak bilirubin 0.7 mg/dL, ALT 77 U/L, Alk P 521, 19% eosinophils], with rapid resolution on stopping both).
  • Gungor E, Alli N, Comoglu S, Comcuoglu C. Phenytoin hypersensitivity syndrome. Neurol Sci 2001; 22: 261-5. [PubMed: 11731881]
    (5 cases from Turkey, with fever, rash, edema, eosinophils and increased white blood cell counts, 2 days to 3 months after starting phenytoin [bilirubin normal, ALT 34-97 U/L, Alk P 498-747 U/L], rapid recovery after stopping).
  • Bessmertny O, Hatton RC, Gonzalez-Peralta RP. Antiepileptic hypersensitivity syndrome in children. Ann Pharmacother 2001; 35: 533-8. (Among 14 children with anticonvulsant hypersensitivity syndrome, 58% were receiving phenytoin, 43% carbamazepine, and 29% phenobarbita; 63% had ALT and 36% bilirubin elevations and 1 died of hepatic failure).
  • Kaur S, Sarkar R, Thami GP, Kanwar AJ. Anticonvulsant hypersensitivity syndrome. Pediatr Dermatol 2002; 19: 142-5. (13 year old boy on phenytoin developed fever, rash and facial edema 1 month after starting carbamazepine [bilirubin 0.4 mg/dL, ALT 72 U/L, Alk P 551 U/L] and did not improve until both agents were stopped, subsequently remaining well on valproate).
  • Galindo PA, Borja J, Gomez E, et al. Anticonvulsant drug hypersensitivity. J Invest Allergol Clin Immunol 2002; 12: 299-304. [PubMed: 12926190]
    (Patch testing on 15 patients with skin reactions to anticonvulsants; 12 were positive, often to several of the aromatic anticonvulsants).
  • Altuntas Y, Ozturk B, Erdem L, Gunes G, Karul S, Ucak S, Senul A. Phenytoin-induced toxic cholestatic hepatitis in a patient with skin lesions: case report. South Med J 2003; 96: 201-3. [PubMed: 12630649]
    (47 year old woman developed exfoliative rash 25 days after starting phenytoin with fever, leukocytosis, eosinophilia and hepatitis [bilirubin 6.4 mg/dL, ALT 441 U/L, Alk P 1431 U/L], rapid improvement on stopping).
  • Choi TS, Doh KS, Kim SH, Jang MS, Suh KS, Kim ST. Clinicopathological and genotypic aspects of anticonvulsant-induced pseudolymphoma syndrome. Brit J Dermatol 2003; 148: 730-6. [PubMed: 12752131]
    (8 patients from Korea with maculopapular rash, fever, lymphadenopathy and facial edema arising 3 to 24 [mean=7] weeks after starting an anticonvulsant, elevated liver tests in 5; largely dermatologic description).
  • Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transplant 2004; 10: 1018-23. [PubMed: 15390328]
    (Among ~50,000 liver transplants done in the United States between 1990 and 2002, 137 [0.2%] were done for idiosyncratic drug induced acute liver failure, of which 10 were attributed to phenytoin, 10 to valproate and 1 to carbamazepine, but none to lamotrigine or other anticonvulsants).
  • Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-101. [PubMed: 16165719]
    (36 years of reporting to Swedish registry identified 103 cases of acute liver failure due to drugs, of which 1 was attributed to phenytoin, 1 to valproate and 1 to carbamazepine, but none to lamotrigine or other anticonvulsants ).
  • Sierra NM, García B, Marco J, Plaza S, Hidalgo F, Bermejo T. Cross hypersensitivity syndrome between phenytoin and carbamazepine. Pharm World Sci 2005; 27: 170-4. (Among 20 patients with anticonvulsant hypersensitivity syndrome due to carbamazepine or phenytoin who were restarted on the other opposite agent, 9 redeveloped hypersensitivity features, but 8 were subsequently able to tolerate valproate [4], viabatrin [2] or phenobarbital [2] without problems). [PubMed: 16096883]
  • Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig Liver Dis 2006; 38: 33-8. [PubMed: 16054882]
    (In WHO database of fatal adverse drug reactions from 1968-2003 including 4690 reports of drug induced liver fatality, phenytoin ranked 12th [57 cases], the only anticonvulsant among the top 19 causes).
  • Korem M, Hiller N, Ackerman Z, Chajek-Shaul T, Abramowitz Y. Spleen rupture secondary to anticonvulsant hypersensitivity syndrome. Eur J Intern Med 2006; 17: 517-9. [PubMed: 17098601]
    (23 year old woman developed rash, fever, edema and eosinophilia [27%] 2 months after starting phenytoin [Alk P 320 U/L, but no bilirubin or ALT values], suffered spontaneous splenic rupture, but was managed medically).
  • Tohyama M, Hashimoto K, Yasukawa M, Kimura H, Horikawa T, Nakajima K, Urano Y, et al. Association of human herpes virus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome. Br J Dermatol 2007; 157: 934-40. [PubMed: 17854362]
    (Anti-HHV-6 testing of 100 patients with drug induced hypersensitivity syndrome [34% with hepatitis] found rise in IgG levels in 62 patients, largely in more severe cases; HHV-6 DNA detected in 18; drugs included carbamazepine, phenobarbital, phenytoin, allopurinol, sulfasalazine and mexiletine).
  • Mansur AT, Pekcan Yaşar S, Göktay F. Anticonvulsant hypersensitivity syndrome: clinical and laboratory features. Int J Dermato 2008; 47: 1184-9. (Among 31 patients seen at a single Turkish medical center with anticonvulsant hypersensitivity syndrome, 48% had received carbamazepine, 36% phenytoin, 10 lamotrigine and 6% lamotrigine and valproate; onset 2 to 86 days after starting with ALT elevations in 71%, eosinophilia in 64%, only one death [TEN]).
  • Björnsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scan 2008; 118: 281-90. [PubMed: 18341684]
    (Review of all anticonvulsants; phenytoin usually causes liver injury as a part of the hypersensitivity syndrome, in 1:10,000 to 1:50,000 persons, 100 published cases, mean onset at 4 weeks, 13% mortality).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, valproate accounted for 6 cases, lamotrigine 5, phenytoin 5, gabapentin and topiramate 1 each).
  • Ito S, Shioda M, Sasaki K, Imai K, Oguni H, Osawa M. Agranulocytosis following phenytoin-induced hypersensitivity syndrome. Brain Develop 2009; 31: 449-51. [PubMed: 18774664]
    (5 year old boy with hypersensitivity syndrome after 12 days of phenytoin with mild ALT elevations [154 U/L] but no jaundice, who suffered from transient neutropenia during recovery).
  • Crespo Pérez L, Moreira Vicente V, Cano Ruiz A, Gobernado Serrano JM, Cobo Ibañez N, Milicua Salamero JM. [Anticonvulsant hypersensitivity syndrome: an entity to be remembered]. Gastroenterol Hepatol 2009; 32: 687-92. [PubMed: 19732994]
    (15 year old girl developed fever, rash and adenopathy 6 weeks after starting carbamazepine and phenytoin [peak bilirubin 16.3 mg/dL, ALT 809 U/L, GGT 809 U/L, eosinophils 5%], resolving within a month of stopping both drugs).
  • Franciotta D, Kwan P, Perucca E. Genetic basis for idiosyncratic reactions to antiepileptic drugs. Curr Opin Neurol 2009; 22: 144-9. [PubMed: 19262378]
    (Review of the genetic associations with hypersensitivity reactions to anticonvulsant medications; closest association has been with HLA-B*1502 and Stevens-Johnson syndrome after aromatic anticonvulsants).
  • Newell BD, Moinfar M, Mancini AJ, Nopper AJ. Retrospective analysis of 32 pediatric patients with anticonvulsant hypersensitivity syndrome (ACHSS). Pediatr Dermatol 2009; 26: 536-46. [PubMed: 19840307]
    (Among 32 children with anticonvulsant hypersensitivity syndrome seen at two medical centers, 12 had been exposed to phenytoin, 13 carbamazepine, 5 phenobarbital, 5 lamotrigine and 1 primidone [who also received lamotrigine]; liver involved in 91%, but jaundice in just 18%, no deaths).
  • Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 2010; 105: 2396-404. [PubMed: 20648003]
    (313 cases of drug induced liver injury were seen over a 12 year period at a large hospital in Bangalore, India; 21 [6.7%] were attributed to phenytoin, one of which was fatal).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury including 8 due to phenytoin, 3 to carbamazepine and 2 to valproate).
  • Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. [PMC free article: PMC2997312] [PubMed: 21039766]
    (Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, phenytoin accounting for 57 cases [0.6%, ranking 20th] for an adjusted relative risk odds ratio of 3.0).
  • Devarbhavi H, Karanth D, Prasanna KS, Adarsh CK, Patil M. Drug-Induced liver injury with hypersensitivity features has a better outcome: a single-center experience of 39 children and adolescents. Hepatology 2011; 54: 1344-50. [PubMed: 21735470]
    (Among 39 children with drug induced liver disease seen at a single referral center in India between 2005 and 2010, 10 cases were due to phenytoin and 6 to carbamazepine, all of whom survived in contrast to deaths of 12 of 23 children with hepatocellular injury without signs of hypersensitivity [largely due antituberculosis medications]).
  • Molleston JP, Fontana RJ, Lopez MJ, Kleiner DE, Gu J, Chalasani N; for the Drug-Induced Liver Injury Network. Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN Prospective Study. J Pediatr Gastroenterol Nutr 2011; 53: 182-9. [PMC free article: PMC3634369] [PubMed: 21788760]
    (Among 30 children with drug induced liver injury enrolled in a prospective US database between 2004 and 2008, 8 were due to anticonvulsants [lamotrigine in 3, valproate in 3, phenytoin in 1 and carbamazepine in 1], none of which were fatal or led to chronic injury).
  • Neuman MG, Cohen L, Nanau RM, Hwang PA. Genetic and immune predictors for hypersensitivity syndrome to antiepileptic drugs. Transl Res 2012; 159: 397-406. [PubMed: 22500513]
    (Study of 20 patients with hypersensitivity reactions to phenytoin or carbamazepine and 40 controls found positive lymphocyte toxicity assays in all patients with hypersensitivity and a correlation of HLA-B*1502 with the allergic reactions in Han Chinese).
  • Knowles SR, Dewhurst N, Shear NH. Anticonvulsant hypersensitivity syndrome: an update. Expert Opin Drug Saf 2012; 11: 767-78. [PubMed: 22794330]
    (Updated review of anticonvulsant hypersensitivity syndrome; associated with phenytoin, phenobarbital, lamotrigine and carbamazepine and rarely with zonisamide, valproate and oxcarbazepine).
  • Drugs for epilepsy. Treat Guidel Med Lett 2013; 11: 9-18. [PubMed: 23348233]
    (Concise review of indications and side effects of anticonvulsants mentions that phenytoin is no longer considered a drug of first choice because of its pharmacokinetics, side effects and drug-drug interactions, and that phenytoin can cause hypersensitivity reactions, Stevens-Johnson syndrome and fatal hepatitis).
  • Gaeti WP, Obreli-Neto PR, Moliterno RA, Schiavon GB, Cuman RK. HLA typing in Brazilian boys with aromatic antiepileptic drug-induced DRESS. Int J Clin Pharm 2013; 35: 319-22. (9 and 11 year old boys developed rash, fever, facial edema and eosinophilia [8-14%] 27 and 19 days after starting an anticonvulsant [carbamazepine and phenytoin], with elevations in ALT [631 and 222 U/L] and Alk P [835 and 439 U/L] without jaundice; HLA testing showed no commonality and absence of B*1502]
  • Ghabril M, Fontana R, Rockey D, Jiezhun G, Chalasani N. Drug-induced liver injury caused by intravenously administered medications: The Drug-induced Liver Injury Network experience. J Clin Gastroenterol 2013; 47: 553-8. [PMC free article: PMC3681898] [PubMed: 23388845]
    (Among 524 cases of drug induced liver injury from the US, 32 were attributed to intravenous medications including 3 to phenytoin).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, including 1 attributed to phenytoin among only 410 persons receiving the drug in Iceland).


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