Phenytoin-induced toxic cholestatic hepatitis in a patient with skin lesions: case report. (Case Report).Abstract
Phenytoin phenytoin /phen·y·to·in/ (fen´i-toin?) an anticonvulsant used in the control of various kinds of epilepsy and of seizures associated with neurosurgery.
n. is a highly effective and widely prescribed anticonvulsant anticonvulsant /an·ti·con·vul·sant/ (-kon-vul´sant) inhibiting convulsions, or an agent that does this.
A drug that prevents or relieves convulsions. agent, but it can be associated with dose-related side effects and hypersensitivity reactions. We present a case of phenytoin-induced cholestatic hepatotoxicity hepatotoxicity (hepˑ··tō·t in a 47-year-old woman who had exfoliative dermatitis, an increase in liver enzymes with a cholestatic pattern, and eosinophilia eosinophilia /eo·sin·o·phil·ia/ (e?o-sin?o-fil´e-ah) abnormally increased eosinophils in the blood.
An increase in the number of eosinophils in the blood. 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 Liver Function Tests Definition
Liver function tests, or LFTs, include tests for bilirubin, a breakdown product of hemoglobin, and ammonia, a protein byproduct that is normally converted into urea by the liver before being excreted by the kidneys. returned to normal values.
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by more than twofold increases in liver function test values, which return to normal when the offending agent is withdrawn.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)
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 lymphadenopathy /lym·phad·e·nop·a·thy/ (-op´ah-the) disease of the lymph nodes.
angioimmunoblastic lymphadenopathy , angioimmunoblastic lymphadenopathy with dysproteinemia (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 Leukocytosis Definition
Leukocytosis is a condition characterized by an elevated number of white cells in the blood.
Leukocytosis is a condition that affects all types of white blood cells. , atypical lymphocytosis lymphocytosis /lym·pho·cy·to·sis/ (-si-to´sis) an excess of normal lymphocytes in the blood or an effusion.
n. , 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 hepatomegaly /hep·a·to·meg·a·ly/ (hep?ah-to-meg´ah-le) enlargement of the liver.
The abnormal enlargement of the liver. Also called megalohepatia. 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 epoxide /epox·ide/ (e-pok´sid) an organic compound containing a reactive group resulting from the union of an oxygen atom with two other atoms, usually carbon, that are themselves joined together. 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 idiosyncrasy /id·io·syn·cra·sy/ (-sing´krah-se)
1. a habit peculiar to an individual.
2. an abnormal susceptibility to an agent (e.g., a drug) peculiar to an individual. as possible explanations for hepatic injury observed in patients with phenytoin hypersensitivity. (14) A few studies in the literature describe beneficial effects of steroid
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.
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Dilantin-125, Dilantin Infatabs
Pharmacologic class: Hydantoin derivative
Therapeutic class: Anticonvulsant
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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.
A 47-year-old woman was admitted to our dermatology clinic because of disseminated exfoliative ex·fo·li·a·tive
Marked by exfoliation, desquamation, or profuse scaling. 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 hemiparesis /hemi·pa·re·sis/ (-pah-re´sis) paresis affecting one side of the body.
Slight paralysis or weakness affecting one side of the body. on the left side. Her white blood cell count white blood cell count,
n a diagnostic clinical laboratory test to determine the number and types of leukocytes present in a measured sample of blood. Overall the normal number of leukocytes ranges from 5000 to 10,000/mm3. 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 Erythrocyte Sedimentation Rate Definition
The erythrocyte sedimentation rate (ESR), or sedimentation rate (sed rate), is a measure of the settling of red blood cells in a tube of blood during one hour. 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 Herpes simplex virus
A virus that can cause fever and blistering on the skin, mucous membranes, or genitalia.
Mentioned in: Conjunctivitis
herpes simplex virus , coxsackie virus cox·sack·ie·vi·rus also Cox·sack·ie virus
Any of a group of enteroviruses that are associated with a variety of diseases, including meningitis, myocarditis, and pericarditis, and primarily affect children during the summer months. , 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 lob·ule
1. A small lobe.
2. A section or subdivision of a lobe.
lob inflammatory infiltrates with excess of eosinophils Eosinophils
A leukocyte with coarse, round granules present.
Mentioned in: Histiocytosis X
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.
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