KETOCONAZOLE-INDUCED LIVER DAMAGE
JORGE A. FINDOR1, JUAN A.
SORDA1, ESTELA BRUCH IGARTUA1, ALEJANDRA AVAGNINA2
1 División de
Gastroenterología, 2 Departamento de Patología, Hospital de
Clínicas José de San Martín, Facultad de Medicina, Universidad de
Key words: ketoconazole, liver damage, hepatic failure,
hepatic massive necrosis, hepatic submassive necrosis
cases (four females, one male) of ketoconazole-related liver damage
are presented, two of whom died. All patients received ketoconazole
(400 mg/day) for various mycoses. In the four women the first signs of
hepatotoxicity appeared after four weeks of therapy. One fatal case
developed massive necrosis with fulminant liver failure and the other,
submassive necrosis. In four cases cholestasis was a prominent
finding. Biochemical evidence of biliary stasis may persist for
several months, as occurred in the three surviving patients of our
series. The two fatal cases continued receiving the drug in spite of
its adverse effects. Consequently, repeated evaluation is recommended
to detect early signs of liver involvement.
hepática inducida por ketoconazol. Se presentan 5 pacientes, 4
mujeres y 1 hombre, con toxicidad hepática por ketoconazol (Ke) 2 de
los cuales tuvieron una evolución fatal. Todos los pacientes
recibieron una dosis de 400 mg/día de Ke por diversos tipos de
micosis superficiales. En las 4 mujeres los primeros signos de
hepatotoxicidad aparecieron dentro del mes de iniciada la terapia. Los
2 casos fatales fueron del sexo femenino. Una de ellas presentó una
necrosis hepática masiva con falla hepática fulminante mientras que
la otra una necrosis submasiva. En 4 casos la colestasis constituyó
la marca bioquímica e histológica más sobresaliente. Las evidencias
bioquímicas de colestasis pueden persistir por tiempo prolongado a
pesar de la suspensión de la droga como ha sido observado en los 3
pacientes que sobrevivieron. La continuidad de la ingesta de Ke
después de la aparición de signos de hepatotoxicidad se asociaría
con un peor pronóstico y por tal motivo sería recomendable evaluar a
todos los pacientes en forma periódica durante la fase inicial del
Postal address: Dr. Jorge A. Findor, Paraguay 2068,1425
Buenos Aires, Argentina.
Received: 30-I-1998 Accepted: 23-IV-1998
Ketoconazole, an azole compound, is a widely used and highly
effective antifungal agent1, 2. Side effects are uncommon, but can be
significant and on rare occasions lethal drug-induced liver failure
ensues3, 4, as well as non-fatal liver injury5, 7. Fulminant liver
failure is extremely infrequent and until 1997 we only found in the
literature seven well documented cases3, 5, 8, 9. On the other hand,
reports on pathology findings are scanty8, 10. This paper describes
five cases of ketokonazole-related hepatotox-icity, two of whom died.
In all patients liver biopsy was available.
Case 1 was a 61-year-old female with no history of disease or
alcohol abuse, treated with ketoconazole (400 mg/day) since November
1989 for onychomycosis. A previous check-up (October 1989) found no
abnormality. After 20 days of therapy she noted intense fatigue and on
January 1990, also jaundice and choluria. However, she continued
taking the drug for another 10 days, until she visited her physician.
On January 23, 1990, jaundice, hypocholia, choluria, fatigue and
flapping were observed. Laboratory studies revealed: bilirubin 8.5
mg%; AST, 168 IU/L, ALT, 132 IU/L, and prothrombin time (PT), 16 sec.
On February 2, 1990, the encephalopathy worsened and the patient was
admitted into a critical care unit with fetor hepaticus and severe
jaundice. The liver border was not palpable and percussive dullness
was absent. No splenomegaly, collateral circulation or skin signs of
chronic liver disease were detected. Laboratory studies showed:
bilirubin 28.5 mg% (conjugate 23.6 mg%), alkaline phosphatase, 59 IU/L
(N = 50 IU/L); PT 30 sec; glycemia 78 mg% and creatinine 1.1 mg%.
Three days later the encephalopathy improved but the severe
coagulation disorder persisted. Hepatitis A and B virus markers, and
antinuclear, smooth muscle, and mitochondria antibodies were negative.
An anti-HCV test done retrospectively using bank serum was also
negative. The ultrasonogram revealed reduced liver size and normal
bile bladder and bile ducts.
Renal function deteriorated and a gastrointestinal tract bleeding due
to congestive gastropathy supervened; the endoscopy showed grade I
On March 1, the patient died. The post-mortem liver examination
revealed hepatocyte necrosis with collapse of multiple acinary 3
zones. The necrotic areas were confluent, with portal-central and
portal-portal necrotic bridges. Severe cholestasis with bile thrombi
in ducts peripheral to portal bands and necrotic areas was seen, in
addition to groups of periportal hepatocytes that displayed feathery
degeneration (Fig. 1 and 2) and macrophages with cytoplasmic fat-laden
vacuoles. Hepatocyte regeneration signs were focal and a mild portal
and sinusoid inflammatory infiltrate with lymphocytes and
polymor-phonuclear leukocytes, many of them eosinophils, was
obser-ved. When reticulin and trichromic techniques were used, the
architectural distortion produced by the confluent necrotic zones
collapse and incipient cirrhosis due to collagen fiber deposition, was
evident. The picture was then one of submassive liver necrosis with
severe cholestasis and signs of progression to cirrhosis (Fig. 3).
Case 2 was a 43-year-old female admitted on September 26, 1987 in
stupor. The physical examination revealed good nutrition status, no
fever, intense jaundice, ecchymosis on arms and legs, and hematomas.
Reflexes were normal and a certain degree of muscular rigidity with
cogged wheel sign was observed. Flapping was obvious. The liver size
was reduced. The patient had a history of 10 years of adult celiac
disease, controlled with diet. She also had a onychomycosis and
vaginal fungal infection for the last 3 months, treated with
ketoconazole (400 mg/day). The patient then presented with fatigue,
increasing gastric intolerance, jaundice, choluria, and hipocholia and
therefore, on August 6, 1987, the drug was discontinued. Laboratory
studies showed: bilirubin 16.5 mg% (conjugate, 12.8 mg%); ALT, 1.600
IU/L; AST 740 IU/L; cholesterol 139 mg%, PT 15 sec; serum protein 6.8
mg%; albumin 3.9 g% and globulin 2.9 g%. Blood counts were normal. IgM
anti-HAV and HBsAg were negative. Since then, the deterioration was
On September 26, 1987, encephalopathy with renal failure developed.
Laboratory studies showed: AST 300 IU/L; ALT 410 IU/L; glycemia 140
mg%; PT 48 sec and ammonium 230 mg/dl. Screening for HBsAg, IgM
anti-HAV, anti-CMV and anti-EB was negative. An anti-HCV done
retrospectively using second generation ELISA with stored serum was
negative. One day before death the liver was not palpable and
percussion was difficult; the patient had severe jaundice and was in
coma. She developed epistaxis, gum bleeding and oligoanuria and on
September 28, 1987, died. The post-mortem examination revealed massive
liver necrosis, bile ducts proliferation and an inflammatory
infiltrate composed of lymphocytes and polymor-phonuclear leukocytes.
The residual liver parenchyma showed hepatocyte regeneration (Fig. 4).
The picture was consistent with fulminant hepatitis of several week’s
Case 3 was a 65-year-old female admitted on June 1992 with
jaundice, choluria and acholia, treated with ketoconazole (400 mg/day)
for 3 months, for onychomycosis. She had lost almost 6 kg of weight in
one month. She had no history of surgery, blood transfusions or
alcohol abuse. Ten days before hospitalization laboratory examinations
showed: bilirubin 4 mg%; AST 480 IU/L; ALT 560 IU/L; alkaline
phosphatase 180 IU/L (N = 50 IU/L); gamma-glutamyl transpeptidase
(G-GTP); 156 IU/L (N = 33 IU/L) and PT, 14 sec. Jaundice with flapping
was obvious. Auditory and visual evoked potentials were consistent
with hepatic encephalopathy. The ultrasonogram was normal. HAV, HBV
and HCV markers were negative. A HCV RNA test using PCR excluded
viremia. One week after admission the clinical and laboratory features
improved. On day 15 a liver biopsy revealed perivenular cholestasis
with canalicular bile plugs, isolated necrotic hepatocytes, and
lipofuscin-laden macrophages in acinary zone 3. Portal inflammation
was minimal. One month after ketoconazole was withdrawn, elevated
levels of alkaline phosphatase (97 IU/L) and G-GTP (112 IU/L)
persisted. Two months later HAV, HBV, and HCV markers were negative.
After four months, all laboratory tests were normal.
Case 4 was a 26-year-old male first seen on April 1993, who after
one week on ketoconazole (400 mg/day) developed jaundice, choluria,
and pruritus. Hepatomegaly, jaundice, and scratch lesions were noted.
The spleen was not palpable. Laboratory studies revealed: bilirubin 8
mg% (conjugate 5 mg%); ALT 168 IU/L; AST 86 IU/L; cholesterol 200 mg%;
PT 12 sec; serum protein 7.2 g%; albumin 4.1 g%, and gammaglobulin 1.2
g%. HAV, HBV, and HCV markers and PCR for HCV RNA were negative.
Twenty days after ketoconazole was discontinued, a liver biopsy showed
cholestasis with capillary thrombi in acinar zone 3. Hepatocyte
ballooning with isolated cell necrosis and regeneration were seen.
Portal Inflammatory infiltration was scanty and mixed, with
lymphocytes and polymorphonuclear leukocytes (Fig. 5).
As increased levels of alkaline phosphatase and G-GTP persisted after
two months without ketoconazole, and endoscopic retrograde
cholangiography was performed, but no abnormality was detected. Viral
markers and antinuclear, antimitochondria, and anti smooth muscle
antibodies were negative. Ursodeoxycholic acid (600 mg/day) was
prescribed and one year later, all laboratory tests were normal.
Case 5 was a 52-year-old female first seen on May 1994, who after
three months on ketoconazole (400 mg/day) developed epigastric
discomfort, asthenia, jaundice, and pruritus. Laboratory studies
revealed: bilirubin 15 mg%; PT 11 sec; ALT 700 IU/L, and AST 468 IU/L.
Ketoconazole was withdrawn; antiHAV IgM, HBsAg, anti-HBc IgM, and PCR
for HCV RNA were negative. The clinical status improved and on July 7,
1994, a bilirubin of 2.2/1.6 mg%, ALT of 23 IU/L, AST of 17 IU/L,
alkaline phosphatase of 183 IU/L, and G-GTP of 23 IU/L were noted.
A liver biopsy showed little portal infiltration with lymphocytes and
eosinophils with no invasion of the borderline plate. In acinar zones
3 disorganization of hepatocyte plates with prominent waxy
pigment-laden macrophages was seen. Some hepatocytes had biliary
pigment within their cytoplasm, but no canalicular bile plugs.No
fibrosis was present. Those findings suggested resolving hepatitis
with biliary stasis. All viral markers were negative. Eight months
later the patients was asymp-tomatic and laboratory tests were normal.
The first report on ketoconazole-induced liver damage was
documented as early as 198111, 12. On occasion, the cause-effect
relationship was confirmed by rechallenge6, 12, 13. The incidence of
ketoconazole hepatotoxicity is low and estimations ranged between
1/10.000 and 1/15.0009, 14, but more recently it was shown that it may
be as high as 1/2.00015. Although a review of 2.671 liver biopsies
found 26 cases of drug-induced liver injury, only one of this serie
was associated with ketoconazole16.
Most patients are asymptomatic and only a minority has jaundice.
Asymptomatic transaminase elevation occurs between 6 and 12% of the
cases15, 17. This elevation is self limited and of short duration, but
sometimes a biphasic elevation occur and normalization takes more
time18. Liver damage due to ketoconazole does not seem to depend on
the daily or accumulative dose, but generally, patients showing
hepatic side-effects were taking the drug for more than 10 days8, 9,
15. Only one patient of our series was on ketoconazole therapy for a
shorter period. He was not receiving other potentially hepatotoxic
agent; all viral markers, including nested PCR for HBV and HCV were
repeatedly negative during the follow-up and the ERCP showed a normal
extra and intrahepatic biliary tree. As the histopathology was
suggestive of drug-induced hepatotoxicity, a causal relationship
between ketoconazole and liver injury was assumed to be likely. In
fact, some patients develop signs of toxic liver damage as soon as one
or two days after therapy with ketoconazole begins8, 19 but this event
is highly uncommon. Elderly patients are more prone to liver
dysfunction15, but younger cases are also well documented20. Only one
of our patients was under 40. Ketoconazole-induced hepatotoxicity is
more frequent in women15. Our findings confirmed this notion. Men are
also vulnerable to toxic reactions due to this drug, but to a much
The mechanism of ketoconazole-related liver injury is still unknown,
but it seems to be idiosyncratic rather than immunoallergic7, 17. The
absence of eosinophilia, skin rash, or hepatic granulomas in our
patients favors this opinion, but a hypersensitivity component as
contributive factor cannot be excluded. Usually, the hepatic
side-effects of ketoconazole are self-limited, but sometimes, even
when the drug is discontinued, the liver damage progresses15, 21.
In contrast, if the drug is not withdrawn when symptoms of intolerance
develop, the liver injury and the ultimate outcome may worsen9.
Nevertheless, there are also reports describing resolution in patients
who continue on ketoconazole22.
In both of our patients with lethal outcome the drug was not
interrupted until after several days of clear evidence of
hepatotoxicity. In one patient with acute liver failure a orthotopic
liver transplantation was successfully performed23. Cases of
non-lethal ketoconazole-induced fulminant hepatitis are much more
frequent20, 24. In one patient, therapy with corticosteroid seemed to
be beneficial25. However, the subfulminant liver failure observed in
one of our cases was never, to our knowledge, described before.
Cholestasis seems to be an outstanding characteristic of ketoconazole
hepato-toxicity7, 10, but others18 found a prevalence of
necroinflammatory lesions. It was noted in about half of cases in some
studies8. In our series, three patients presented with histological
evidence of cholestasis associated with necroinflammatory lesions.
The biopsy findings in one of our fatal cases (Case 2) were similar to
those already described9. Lakeb-Bakaar et al.8 also described the
marked ductular cholestasis. As they point out, this event is more
common in sepsis, but in their cases it was probably related to the
drug. In some non-fatal cases, Stricker et al.15 found “beginning
fibrosis”. Presumably, patients with severe necrosis who survive may
have residual structural damage-fibrosis or even lesions suggesting
Cholestasis does not seem to represent an unfavo-rable factor. In our
series, only one of the two fatal cases had definite laboratory and
pathology findings of severe cholestasis. Of the three surviving
patients, on the other hand, one had cholestatic jaundice in spite of
the favorable outcome.
In the future it will be necessary to compare in more detail the
prevalence of hepatotoxic reactions to ketoconazole and the new oral
antifungal azole derivatives1, 26. Recently it has been reported that
fluconazole for example is much less hepatotoxic than ketoconazole27,
28. Mycoses, especially in certain immunodeficiencies, may have a very
severe prognosis. Considering that a great number of patients have
been treated with ketoconazole, a very effective drug, it is important
to point out that hepatotoxicity due to this agent remains extremely
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Fig. 1.– Case 1. Area of confluent necrosis in acinar zone 3.
Paraseptal hepatocytes swollen and pale (cholate stasis), and foamy
histiocytes (xanthomatus cells). (H & E stain, 250 x).
Fig. 2.– Case 1. A portal tract with severe ductular cholestasis. A
confluent necrotic zone crosses the right side of the picture. (H
& E stain, 100 x).
Fig. 3.– Case 1. Reticulum stain showing bridging due to the
reticulum framework collapse, and nodular regeneration of the
hepatocyte plates (25 x).
Fig. 4.– Case 2. Extensive necrosis around a centrilobular vein, and
surviving hepatocytes at the periphery of the lobule. (H & E
stain, 25 x).
Fig. 5.– Case 4. Mild portal inflammation, with lymphocytes and
polymorphonuclear leukocytes. There is a mild aggregate of
ceroid-laden macrophages at the center of the tract. (H & E stain,