Ketoconazole-induced fulminant hepatitis necessitating liver transplantation Timothy E. Knight, MD, Craig Y. Shikuma, MD, * and Judith Knight, RN, BSN** Honolulu, Hilo, and Kailua-Kana, Hawaii The most serious side effect of ketoconazo1e is hepatitis, which has proved fatal in seven reported cases. We present a case offulminant hepatic failure in a 45-year-old Oriental woman that probably would have been fatal except for a successful liver transplant. A review of the literature of fatalities associated with ketoconazole is presented. (J AM ACAD DERMATOL 1991;25:398-400.) Ketoconazole is effective in the treatment of a variety of deep and superficial fungal infections.1, 2 Side effects are uncommon but can be significant. The most serious is drug-induced hepatitis that has proved fatal in seven reported cases. 3.8 This is a: report of fulminant hepatic failure that necessitated a liver transplant in a 45-year-old Oriental woman who had taken ketoconazole for 58 days. CASE REPORT
A45-year-old Japanese-American woman complained of a separating thumbnail for which she had had no treatment. Shehad been treatedfor hyperthyroidism with 1evothyroxine (Synthroid) replacement. She gave no history of liver disease or of excessive alcohol intake. Physical examination showed onycholysis and subungual hyperkeratosis of the thumbnail. A diagnosis of candidal onychomycosis was established and she was treated with ketoconazo1e, 200 mg daily. One month later, the nail had improved. The patient appeared well and had no complaints. She was told to continue ketoconazole for another month. No liver function tests were performed. After 58 days of therapy, the patient suddenly became ill with anorexia, nausea, malaise, and dark-colored urine. She discontinued the medication when her symptoms began. Physical examination revealed tenderness to palpation in the right upper quadrant, without hepatomegaly. No jaundice was noted. Initial laboratory values included bilirubin, 4:2 mgjdl (normal up to 1.0 mg/dl); alkaline
From the Department of Medicine, Division of Dermato!ogy, The John A. Burns School of Medicine, Honolulu. Hawaii. Reprint requests: Timothy E. Knight, MD, 75-184 Hualalai Rd. #203, Kailua-Kona, HI 96740. *Private practice, Hilo. "Private practice, Kailu-Kona.
]6/4/2S603
398
phosphatase, 102 U jL (normal 50 to 136 U jL); lactate dehydrogenase (LDH),401 UjL (normal 100 to 190Uj L); SGOT 1328 UjL (normal 5 to 43 UjL). Tests for IgM antibody to hepatitis A, hepatitis B core antibody, hepatitis B surface antigen, and ANA were negative. During the second week of illness, worsening symptoms and onset of jaundice prompted hospitalization. Peak laboratory values were alkaline phosphatase, 157 U /L; LDH, 709 UjL; SGOT, 2561 UjL; and SGPT, 3811 U/L. Despite supportive care, the patient experienced in~ creasing nausea, vomiting, anorexia, and icterus. Liver failure ensued during the third week ofillness. The patient underwent liver transplantation 3weeks after onset ofher symptoms. DISCUSSION
Symptomatic hepatitis from ketoconazole use was documented as early as 1981, soon after introduction of the drug. 9, 10 In several cases a cause-effect relationship has been established by rechallenge. 5, 9, 11 The reaction appears to be idiosyncratic rather than illlmunoallergic or toxic; it is unrelated to daily dosage, cumulative total dose, or duration of therapy.5, 12, 13 The incidence has been determined by the manufacturer to be 1 in 10,0004 and, in a later report, 1 in 15,000 exposures. 5 These estimates, however, have not been corrected for re~ porting rate, so the actual incidence is probably greater. One Dutch review estimated that the true incidence of symptomatic hepatic injury from ketoconazole was closer to 1 in 2000. 13 Symptoms may develop as soon as 2 days after initiation oftherapy14 or as long as 365 days15, with a mean of approximately 2 months. 3, 4, 8, 13 Jaundice, the most frequent sign, occurs in 63% to 100% of cases. 3, 5,8, 13 Anorexia, nausea, vomiting, and malaise follow as the next most-frequent complaints. 3, 4, 8 Statistical
Volume 25 Number 2, Part 2 August 1991
Ketoconazole-induced hepatitis 399
Table I. Hepatic failure reactions from ketoconazole Time from Duration Time to onset to of onset of death/liver therapy symptoms transplant Age Dose (days) (yr) Sex (mg/day) (days) (days)
52
F
200
N.S.
63
67
F
200
60
60
38 F 59 M
200 200
103 17
103 16
63
F
400
N.s.
N.S.
70 M
200
N.S.
N.S.
57
F
400
28
88
45
F
200
58
58
35
Status of Rxat onset of symptoms
Other concurrent medications
DiagnoSes
Reference
N.S,
Onychomycosis 4 History of hepatitis 26 Discontinued Hydrochlorothiazide Onychomycosis 6 Isosorbide Hypertension Nitroglycerin Angina Bactrim DTIs, recurrent Discontinued N.S. Onychomycosis 7 30 Discontinued Colistin Intestinal 7 7 Amikacin candidiasis Amphotericin B Acute myeloblastic leukemia 8 N.S. Candidal N.S. , Continued onychomycosis "Fungal toe N.S. 8 N.S. Continued infection" Mitral valve disease Discontinued N.S. Candidal 8 35 vaginitis Discontinued Synthroid Candldal Present 22 onychomycosis report Treated hyperthyroidism Continued
N.s" Not stated; Rx. prescription of ketoconazole.
analysis reveals that females are affected more frequently, even when calculations are controlled for the fact that they receive the drug more often. The reactions have occurred in all age groilps, but the elderly seem more predisposed. 4, 5, 13 Our patient's laboratory studies indicated a hepatic reaction of the hepatocellular type (transaminases >8 times normal, alkaline phosphatase
A45-year-old Japanese-American woman complained of a separating thumbnail for which she had had no treatment. Shehad been treatedfor hyperthyroidism with 1evothyroxine (Synthroid) replacement. She gave no history of liver disease or of excessive alcohol intake. Physical examination showed onycholysis and subungual hyperkeratosis of the thumbnail. A diagnosis of candidal onychomycosis was established and she was treated with ketoconazo1e, 200 mg daily. One month later, the nail had improved. The patient appeared well and had no complaints. She was told to continue ketoconazole for another month. No liver function tests were performed. After 58 days of therapy, the patient suddenly became ill with anorexia, nausea, malaise, and dark-colored urine. She discontinued the medication when her symptoms began. Physical examination revealed tenderness to palpation in the right upper quadrant, without hepatomegaly. No jaundice was noted. Initial laboratory values included bilirubin, 4:2 mgjdl (normal up to 1.0 mg/dl); alkaline
From the Department of Medicine, Division of Dermato!ogy, The John A. Burns School of Medicine, Honolulu. Hawaii. Reprint requests: Timothy E. Knight, MD, 75-184 Hualalai Rd. #203, Kailua-Kona, HI 96740. *Private practice, Hilo. "Private practice, Kailu-Kona.
]6/4/2S603
398
phosphatase, 102 U jL (normal 50 to 136 U jL); lactate dehydrogenase (LDH),401 UjL (normal 100 to 190Uj L); SGOT 1328 UjL (normal 5 to 43 UjL). Tests for IgM antibody to hepatitis A, hepatitis B core antibody, hepatitis B surface antigen, and ANA were negative. During the second week of illness, worsening symptoms and onset of jaundice prompted hospitalization. Peak laboratory values were alkaline phosphatase, 157 U /L; LDH, 709 UjL; SGOT, 2561 UjL; and SGPT, 3811 U/L. Despite supportive care, the patient experienced in~ creasing nausea, vomiting, anorexia, and icterus. Liver failure ensued during the third week ofillness. The patient underwent liver transplantation 3weeks after onset ofher symptoms. DISCUSSION
Symptomatic hepatitis from ketoconazole use was documented as early as 1981, soon after introduction of the drug. 9, 10 In several cases a cause-effect relationship has been established by rechallenge. 5, 9, 11 The reaction appears to be idiosyncratic rather than illlmunoallergic or toxic; it is unrelated to daily dosage, cumulative total dose, or duration of therapy.5, 12, 13 The incidence has been determined by the manufacturer to be 1 in 10,0004 and, in a later report, 1 in 15,000 exposures. 5 These estimates, however, have not been corrected for re~ porting rate, so the actual incidence is probably greater. One Dutch review estimated that the true incidence of symptomatic hepatic injury from ketoconazole was closer to 1 in 2000. 13 Symptoms may develop as soon as 2 days after initiation oftherapy14 or as long as 365 days15, with a mean of approximately 2 months. 3, 4, 8, 13 Jaundice, the most frequent sign, occurs in 63% to 100% of cases. 3, 5,8, 13 Anorexia, nausea, vomiting, and malaise follow as the next most-frequent complaints. 3, 4, 8 Statistical
Volume 25 Number 2, Part 2 August 1991
Ketoconazole-induced hepatitis 399
Table I. Hepatic failure reactions from ketoconazole Time from Duration Time to onset to of onset of death/liver therapy symptoms transplant Age Dose (days) (yr) Sex (mg/day) (days) (days)
52
F
200
N.S.
63
67
F
200
60
60
38 F 59 M
200 200
103 17
103 16
63
F
400
N.s.
N.S.
70 M
200
N.S.
N.S.
57
F
400
28
88
45
F
200
58
58
35
Status of Rxat onset of symptoms
Other concurrent medications
DiagnoSes
Reference
N.S,
Onychomycosis 4 History of hepatitis 26 Discontinued Hydrochlorothiazide Onychomycosis 6 Isosorbide Hypertension Nitroglycerin Angina Bactrim DTIs, recurrent Discontinued N.S. Onychomycosis 7 30 Discontinued Colistin Intestinal 7 7 Amikacin candidiasis Amphotericin B Acute myeloblastic leukemia 8 N.S. Candidal N.S. , Continued onychomycosis "Fungal toe N.S. 8 N.S. Continued infection" Mitral valve disease Discontinued N.S. Candidal 8 35 vaginitis Discontinued Synthroid Candldal Present 22 onychomycosis report Treated hyperthyroidism Continued
N.s" Not stated; Rx. prescription of ketoconazole.
analysis reveals that females are affected more frequently, even when calculations are controlled for the fact that they receive the drug more often. The reactions have occurred in all age groilps, but the elderly seem more predisposed. 4, 5, 13 Our patient's laboratory studies indicated a hepatic reaction of the hepatocellular type (transaminases >8 times normal, alkaline phosphatase
