Phenytoin-induced toxic cholestatic hepatitis in a patient with skin lesions: case report. (Case Report).

Abstract

Phenytoin is a highly effective and widely prescribed anticonvulsant agent, but it can be associated with dose-related side effects and hypersensitivity reactions. We present a case of phenytoin-induced cholestatic hepatotoxicity in a 47-year-old woman who had exfoliative dermatitis, an increase in liver enzymes with a cholestatic pattern, and eosinophilia after 25 days of phenytoin therapy. The diagnostic workup showed no other possible causes, and the results of a percutaneous liver biopsy were consistent with drug-induced toxic hepatitis. Within 3 weeks after discontinuing phenytoin therapy, her liver function tests returned to normal values.

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Toxic hepatitis is a liver injury that is associated with a chemical toxic agent. It is characterized by more than twofold increases in liver function test values, which return to normal when the offending agent is withdrawn. Phenytoin is widely used as an anticonvulsant agent and is associated with both dose-related side effects and hypersensitivity reactions. The coexistence of hepatic and dermatologic signs is called phenytoin hypersensitivity syndrome. (1)

Discussion

In our case, elevation of liver enzymes and appearance of skin lesions after phenytoin administration strongly suggested a drug-induced hypersensitivity reaction. Clinical recovery after phenytoin therapy was discontinued, the exclusion of other probable causes on the basis of the serologic and radiologic workup, and liver biopsy results provided additional clinical evidence for the diagnosis of phenytoin hypersensitivity.

Phenytoin hypersensitivity can develop within 1 to 4 weeks of phenytoin administration. (2-5) Elevated body temperature (82% of cases), skin lesions (94%), lymphadenopathy (94%), hepatitis (94%), and eosinophilia (76%) have been described as components of this syndrome. (2-9)

The exact incidence of phenytoin hypersensitivity syndrome is not known. There is no age or sex discrepancy. (3,5,6) Skin lesions can range from maculopapular rash to erythema multiforme majus. (2-5) Leukocytosis, atypical lymphocytosis, and eosinophilia can accompany the dermatologic manifestations of the syndrome. (5,7) In our case, leukocytosis and eosinophilia were present concomitantly with exfoliative dermatitis.

In most of the cases, mild hepatomegaly and highly elevated liver enzyme levels are the only clinical findings. (5) Liver injury leading to fulminant hepatitis is rare. (8,10,11) The mechanism responsible for hepatitis is obscure. Phenytoin is metabolized to arene oxide in cytochrome P-450 in the liver, which is normally metabolized by epoxide hydrolyzes. It has been hypothesized that if the patient has a genetic or acquired defect in epoxide hydrolase activity, the metabolism of arene oxides will be impaired, and the resulting accumulation of the oxide can lead to hepatic injury. (3,2,13) Some investigators also have suggested immunologic hypersensitivity and metabolic idiosyncrasy as possible explanations for hepatic injury observed in patients with phenytoin hypersensitivity. (14) A few studies in the literature describe beneficial effects of steroid

Conclusion

Phenytoin is an effective and widely prescribed anticonvulsant drug that can produce dose-related side effects and hypersensitivity reactions. Phenytoin hypersensitivity syndrome is manifested by mild to severe skin lesions coexisting with mild to fulminant toxic hepatitis. The possibility of phenytoin hypersensitivity reactions should be considered in patients who present with elevated liver enzyme values, skin lesions, and fever while being treated with phenytoin therapy. We suggest that sodium valproate and barbexaclone can be used as alternative anticonvulsant therapy in these patients.

Accepted January 23, 2002.

References

(1.) Gungor E, Alli N, Comoglu S, Comcuoglu C. Phenytoin hypersensitivity syndrome. Neurol Sci 2001;22:261-265.

(2.) de la Serna Higuera C, Gil Grande LA, Barcena Marugan R. Toxic cholestatic hepatitis due to phenytoin [in Spanish]. Gastroenterol Hepatol 1995;18:471-473.

(3.) Prosser TR, Lander RD. Phenytoin-induced hypersensitivity reactions. Clin Pharm 1987;6:728-734.

(4.) Mullick FG, Ishak KG. Hepatic injury associated with diphenylhydantoin therapy: A clinicopathologic study of 20 cases. Am J Clin Pathol 1980;74:442-452.

(5.) Roberts EA, Spielberg SP, Goldbach M, Phillips MJ. Phenobarbital hepatotoxicity in an 8-month-old infant. J Hepatol 1990;10:235-239.

(6.) Kahn HD, Faguet GB, Agee JF, Middleton HM III. Drug-induced liver injury: In vitro demonstration of hypersensitivity to both phenytoin and phenobarbital. Arch Intern Med 1984;144:1677-1679.

(7.) Fonseca JC, Azulay DR, Rozembau I, Azulay RD. Hypersensitivity syndrome caused by phenytoin and phenobarbital [in Portuguese]. Med Cutan Ibero Lat Am 1984;12:187-192.

(8.) Lee TJ, Carney CN, Lapis JL, Higgins T, Fallon HJ. Diphenylhydantoin-induced hepatic necrosis: A case study. Gastroenterology 1976;70:422-424.

(9.) Conger LA Jr, Grabski WJ. Dilantin hypersensitivity reaction. Cutis 1996;57:223-226.

(10.) Carro JA, Senior J, Rubio CE, Torres EA. Phenytoin induced fatal hepatic injury. Bol Asoc Med P R 1989;81:359-360.

(11.) Campbell CB, McGuffie C, Weedon AP, Powell LW. Cholestatic liver disease associated with diphenyihydantoin therapy: Possible pathogenic importance of altered bile salt metabolism. Am J Dig Dis 1977;22:255-262.

(12.) Spielberg SP, Gordon GB, Blake DA, Goldstein DA, Herlong HF. Predisposition to phenytoin hepatotoxicity assessed in vitro. N Engl J Med 1981;305:722-727.

(13.) Larrey D, Pageaux GP. Genetic predisposition to drug-induced hepatotoxicity. J Hepatol 1997;26(Suppl 2):12-21.

(14.) Gram L, Bentsen KD. Hepatic toxicity of antiepileptic drugs: A review. Acta Neurol Scand Suppl 1983;97:81-90.

(15.) Sherertz EF, Jegasothy BV, Lazarus GS. Phenytoin hypersensitivity reaction presenting with toxic epidermal necrolysis and severe hepatitis: Report of a patient treated with corticosteroid "pulse therapy." J Am Acad Dermatol 1985;12:178-181.

RELATED ARTICLE: Key Points

* Phenytoin is used widely as an anticonvulsant agent and is associated with both dose-related side effects and hypersensitivity reactions.

* The coexistence of hepatic and dermatologic signs is called phenytoin hypersensitivity syndrome.

* Liver function monitoring is necessary during phenytoin therapy.

Case Report

A 47-year-old woman was admitted to our dermatology clinic because of disseminated exfoliative skin lesions and fever (Figs. 1 and 2). She bad undergone surgery for glioblastoma multiforme 25 days earlier, and phenytoin therapy had been started as prophylaxis against seizures postoperatively. Routine laboratory examinations revealed elevated liver enzyme and bilirubin levels (with a predominance of direct bilirubin), and she was referred to the gastroenterology clinic.

Her physical examination revealed blood pressure to be 150/90 mm Hg, a pulse rate of 96 beats/min, and body temperature at 38.8[degrees]C. The patient's skin showed widely disseminated exfoliative and squamous lesions. The enlarged liver was palpable 3 cm below the costal margin. The patient's neurologic examination revealed hypoactive deep tendon reflexes with hemiparesis on the left side. Her white blood cell count was 19,100/[mm.sup.3], hemoglobin value was 9.2 mg/dl, hematocrit was 27.6%, platelet count was 185,000/[mm.sup.3], and erythrocyte sedimentation rate was 28 mm/h. Eosinophilia was detected on peripheral smear (7%). Other admission laboratory values were as follows: aspartate aminotransferase (AST), 2,453 U/L (normal, <37 U/L); alanine aminotransferase (ALT), 441 U/L (normal, <41 U/L); [gamma]-glutamyltransferase (GGT), 79 IU/L (normal, <49 IU/L); lactate dehydrogenase, 806 U/L (normal, 240-480 U/L); alkaline phosphatase (ALP), 1,431 U/L (normal, 9 1-258 U/L); total bilirubin, 6.4 mg/dl (normal, <1.0 mg/dl); direct bilirubin, 6.1 mg/dl (normal, <0.3 mg/dl); and indirect bilirubin, 0.3 mg/dl (normal, 0.1-1.0 mg/dl). All other routine laboratory findings were within the normal range. Studies for serologic markers of viral hepatitis revealed no acute or chronic infection with cytomegalovirus, Epstein-Barr virus, herpes simplex virus, coxsackie virus, or hepatitis A, B, or C viruses. Abdominal ultrasonograms showed no signs of obstruction in either the intrahepatic or extrahepatic biliary tree. The findings of percutaneous liver biopsy were consistent with drug-induced cholestatic hepatitis, revealing portal and lobular inflammatory infiltrates with excess of eosinophils, mild portal fibrosis, central and focal necrosis, and macrovesicular fatty infiltration (30%).

A diagnosis of phenytoin-induced hypersensitivity reaction and acute toxic cholestatic hepatitis due to phenytoin was made. Topical treatment was applied for skin lesions, and phenytoin was replaced with barbexaclone and valproate sodium. During the course of the patient's hospital stay, all elevated parameters gradually decreased and returned to near-normal levels. After 5 days without phenytoin, her laboratory values were as follows: AST, 160 U/L; ALT, 441 U/L; ALP, 1,380 UIL; and GGT, 791 U/L. The laboratory values on Day 15 were AST, 35 U/L; ALT, 37 U/L; ALP, 580 UIL; and GOT, 162 U/L.

From the Internal Medicine and Gastroenterology Clinic, Sisli Etfal Education and Research Hospital, Istanbul, Turkey.

Reprint requests to Yuksel Altuntas, MD, Haznedar mah, Ilkyuva cad, Meric sokak 26/5, Gungoren, Istanbul, Turkey. Email: [e-mail]

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