Gemcitabine-Induced Liver Fibrosis

Muhammad Wasif Saif
1
, Armin Shahrokni
2
, Daniel Cornfeld
1
1Yale University School of Medicine. New Haven, CT, USA. 2Griffin Hospital. Derby, CT, USA
Summary
Gemcitabine is the only cytotoxic agent
approved by FDA for the treatment of
pancreatic carcinoma. Gemcitabine has a
relatively safe profile. Major side effects
include bone marrow suppression and flu-like
syndrome. Transient abnormalities of liver
transaminase enzymes are seen in two third of
patients: elevations of alkaline phosphatase
and bilirubin are less common, but severe
hepatic toxicity is uncommon. Four case
reports regarding severe hepatic toxicity of
gemcitabine leading to rapid deterioration in
patients’ health status and death have been
reported. We report the fifth case in which
liver functions were within normal limits but
liver toxicity was preceded by radiological
findings on the MRI.
We describe a 61-year-old male with stage
T4N1M0 who initially received gemcitabine-
oxaliplatin (GemOx) regimen was switched to
gemcitabine-capecitabine (every two weeks
schedule) after four months of therapy due to
lack of response. Restaging CT scan after
eight-weeks showed new multiple foci of low
attenuation resembling simple cysts. MRI of
the abdomen was performed which revealed
early and active fibrosis. Hepatitis panel were
negative. Subsequently the patient developed
nausea, vomiting, abdominal pain and weight
loss and was referred for palliative
radiotherapy. Gemcitabine was discontinued
and follow-up CT scan two months later
showed stable lesions in the liver.
In conclusions, four cases of gemcitabine-
induced liver toxicity has been reported in the
literature. Such toxicity is manifested by
elevated liver transaminases and more
common in the presence of liver metastasis.
However, our case showed that gemcitabine-
induced liver toxicity can be detected by
MRI, before liver enzymes start to rise and
discontinuation of gemcitabine can prevent
further liver toxicity and fibrosis. Report of
such cases is encouraged as it will bring
awareness among clinicians caring for such
patients receiving gemcitabine.
Gemcitabine (difluorodeoxycytidine; dFdC) is
the only cytotoxic agent approved by FDA for
the treatment of advanced pancreatic
carcinoma. It is also useful in non small cell
lung carcinoma, breast, urothelial and ovarian
cancer [1]. Major toxicities of gemcitabine
include marrow suppression, and flu-like
symptoms. Less common toxicities include
(but not limited to): radiation recall [2],
erysipeloid skin toxicity [3], acute myocardial
infarction [4], atrial fibrillation [5], interstitial
pneumonitis [6], respiratory failure [7],
hemolytic uremic syndrome [8], severe
neurotoxicity [9], vasculitis [10] and
reactivation of hepatitis B [11].
Four cases of gemcitabine-induced liver
failure have been reported. [12, 13, 14, 15].
Patients’ characteristics, cumulative dose of
gemcitabine, liver function status at baseline,
laboratory data, imaging findings, biopsy

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Table 1. Published case reports of gemcitabine-induced liver failure.
Case #
Reference
Age
(years)
Sex
Diagnosis
Cumulative dose
Other medications
#1
Dobbie et al. [12]
48
Female Metastatic non-
small cell cancer
Gemcitabine 56,100 mg
Morphine, Naproxen
#2
Coeman et al. [13]
75
Male Localized non-
small cell cancer
Gemcitabine 30,600 mg
Coumadin, Enoxaprine
#3
Robinson et al. [14]
45
Female Metastatic breast
carcinoma
Gemcitabine 5,200 mg
Carboplatin 1,800 mg
Methylprednisolone, Vitamin K,
Promethazine, Esomeprazole,
Oxycodone, Levofloxacin
#4
Kagohashi et al. [15]
57
Male Metastatic non-
small cell cancer
Gemcitabine 1,600 mg
Vinorelbine 40 mg
N/A
N/A: not available
Continues .....
Table 1. Continued.
Case
Imaging Findings
Abdominal US • Thickening of gallbladder
#1
Autopsy
• Veno-occlusive disease
• Occlusion of terminal hepatic venules
• Sinusoidal congestion and zone 3 hepatic necrosis
Abdominal US • Slight liver steatosis
#2
Autopsy
• Extensive centrolobular parenchymal necrosis
• Extensive intracellular and intra canalicular cholestasis
#3 Liver biopsy
• Hepatocellular degeneration with ballooning and hydropic changes
• The portal triads were irregularly expanded by fibrosis, with scattered eosinophils,
mononuclear cells, polymorphonuclear cells
• Patchy lobular hepatocellular necrosis, fatty metamorphosis and marked cholestasis with
dilated and proliferated cholangioles were noted
#4 Abdominal US • Non obstructive jaundice
Continues .....
Table 1. Continued.
Case
Liver function at baseline
Clinical findings
Laboratory findings
Outcome
#1
Within normal limits
Nausea, vomiting,
jaundice, right upper
quadrant pain, confusion
AST, ALT: 10-fold increase
Total bilirubin: 5-fold increase
Hepatic coma
Death
#2
Within normal limits
Progressive jaundice
Alk.P: 532 IU/L (30-130)
Total bilirubin: 2.1 mg/dL (0-1.2)
Hepatitis panel: negative
Multiple organ
failure
Death
#3
Alk.P: 202 IU/L,(30-130)
AST: 320 IU/L (0-35)
ALT: 222 IU/L (0-35)
Total bilirubin: 0.8 mg/dL (0-1.2)
Tender hepatomegaly
Alk.P: 312 IU/L (30-130)
AST: 294 IU/L (0-35)
ALT: 75 IU/L (0-35)
Total bilirubin: 14.7 mg/dL,(0-1.2)
Ammonia: 49 µmol/L (11-35)
INR: 1.4
Hepatic coma
Death
#4
Within normal limits
N/A
AST, ALT: >1,000 IU/L (0-35)
Total bilirubin: 14.5 mg/dL (0-1.2)
Hepatitis panel: negative
Hepatic failure
Death
Alk.P: alkaline phosphatase
Reference ranges of laboratory findings are reported within parentheses
N/A: not available

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findings (if performed) and outcome are
described in Table 1. None of these patients
have been diagnosed with pancreatic cancer.
We, here, present the first patient with
pancreatic adenocarcinoma who developed
liver fibrosis during treatment with
gemcitabine and capecitabine.
A 61-year-old Caucasian male with past
medical history significant for coronary artery
disease (stent in right coronary artery and left
anterior descending artery) presented in
January 2006 with severe heart burn that
failed medical management. This eventually
led to a CT scan, which discovered the lesion
in the head of pancreas encasing the superior
mesenteric artery and the posterior aspect of
the superior mesenteric vein with no distant
metastases. Subsequent a EUS with FNA
biopsy was performed which confirmed
adenocarcinoma of pancreas in the head
region staged as T4N1M0. The patient was
started on GemOx regimen (gemcitabine
1,000 mg/mover 100 minutes i.v. on day 1
and oxaliplatin 100 mg/mover 2 hours i.v.
on day 2). After four months of treatment
administered every two weeks, no response
was seen on the radiological staging.
Therefore, the regimen was replaced by
gemcitabine-capecitabine. Gemcitabine was
administered a dose of 2,200 mg/m2
intravenously over 30 minutes every two-
weeks with capecitabine given as 2,000 mg
twice daily for seven out of fourteen days.
Restaging CT scan after eight weeks showed
new multiple foci of low attenuation
resembling simple cysts. To further evaluate
these findings on the abdominal CT scan, an
MRI of the abdomen with and without
gadolinium was performed, which showed
multiple simple cysts within liver
parenchyma, largest being within lateral
segment of the left lobe, and might represent
peliosis. On arterial phase post contrast
sequence, there was enhancement seen along
the periphery within the liver most
prominently within the posterior segment of
right lobe which persisted on delayed
sequences. These findings were most
suggestive of early and active fibrosis
(Figures 1, 2, 3, and 4). Liver function tests
were within the normal limits at the baseline
and remained normal throughout the whole
course of chemotherapy cycles (Table 2).
They were normal also at the time of MRI
findings. Hepatitis panel was negative.
History and examination did not suggest any
rheumatologic or infectious etiology. A
Figure 1. Axial CT scan through the liver in the portal
venous phase of enhancement (approximately 60
seconds following the injection of contrast) obtained
one week prior to the MRI is essentially unremarkable
except for scattered tiny hypodensities.
Figure 2. Axial fast response fast spin echo, fat
saturated, T2 weighted image (Flip/TR/TE 90/2000/73,
slice 8 mm, field of view (FOV) 40, matrix 384x192)
through the liver. Linear areas of increased signal
intensity are present along the liver periphery (black
arrows). This is a finding indicative of early or mild
fibrosis. There is also increased signal along the course
of several intrahepatic bile ducts (white arrows). While
this could represent fluid within the ducts, there is also
increased signal within the walls of the ducts (white
arrowhead) which is indicative of inflammation or
fibrosis.

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463
biopsy was suggested but was not denied.
Clinically, he also started deteriorating with
worsening abdominal pain, nausea, vomiting
and weight loss. Therefore, it was decided to
stop gemcitabine-based chemotherapy. Due to
persistent pain, the patient was subsequently
referred for palliative radiotherapy. Follow-up
CT scan in two months showed stable lesions
in the liver and no definitive matastatic lesions.
Gemcitabine (2',2'-difluorodeoxycytidine, dFdC)
is a pyrimidine analog of deoxycytidine. Liver
toxicity associated with gemcitabine has been
reported mostly as a transient rise in
transaminases which rapidly reverses and
usually patients remain asymptomatic [16,
17]. Previously, there have been four case
Figure 3. Axial 3D spoiled gradient echo, fat saturated,
T1 weighted image (Flip/TR/TE 12/4.25/1.9, slice 4
mm, field of view (FOV) 40, matrix 320x192) through
the liver in the arterial phase (approximately 20
seconds after contrast injection) at the same level as
Figure 2 above. There are linear areas of enhancement
around the liver periphery (black arrows) which
correspond to the linear areas of increased T2 signal in
Figure 2. This indicates active inflammation. There is
also arterial enhancement of the intrahepatic bile ducts
(white arrows). The early enhancement indicates active
inflammation.
Figure 4. Axial 3D spoiled gradient echo, fat saturated,
T1 weighted image (Flip/TR/TE 12/4.25/1.9, slice 4
mm, field of view (FOV) 40, matrix 320x192) through
the liver in the equilibrium phase (approximately 120
seconds after contrast injection) at the same level as in
Figures 2 and 3. There is persistent enhancement of the
linear areas of active liver fibrosis (black arrows) and
within the walls of the intrahepatic bile ducts (white
arrows). The biliary enhancement has become more
prominent with time. The delayed enhancement is
typical of fibrosis. The early enhancement seen in
Figure 3 indicates that the process causing fibrosis is
active. Of note, the proximal left portal vein (black
arrowhead) is seen in this more delayed image. It was
not opacified on the arterial phase image (Figure 3).
Table 2. Patient’s laboratory workup.
Upper
reference
limit
Baseline
(Jan 2006)
Jun 2006
Sep 2006
(At the time of
MRI finding)
Nov 2006
Dec 2006
(Referral to
radiotherapist)
BUN (mg/dL)
18
15
12
15
11
11
Creatinine (mg/dL)
1.2
1.1
0.7
1.0
0.9
0.8
AST (IU/L)
35
24
47
18
20
17
ALT (IU/L)
35
35
46
16
17
9
Alk.P (IU/L)
130
88
79
47
52
58
Total bilirubin (mg/dL) 1.20
0.39
0.28
0.43
0.36
0.43
Albumin (g/dL)
5.0
4.0
3.7
3.7
3.6
N/A
LDH (IU/L)
242
N/A
N/A
198
202
N/A
Ammonia (µmol/L)
35
N/A
N/A
N/A
N/A
18
Alk.P: alkaline phosphatase
ALT: alanine aminotransferase
AST: aspartate aminotransferase
BUN: blood urea nitrogen
LDH: lactate dehydrogenase
N/A: not available

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reports reporting serious liver toxicity
secondary to gemcitabine. As described in
Table 1, all these four cases have been
reported on patients with non-pancreatic
carcinoma [12, 13, 14, 15]. Three patients had
either localized or metastatic non small cell
carcinoma of lung and the fourth patient had
matastatic breast carcinoma [14]. Liver
function tests were within normal limit at
baseline in three cases and abnormal in the
fourth case patient (elevated alkaline
phosphatase, aspartate aminotransferase and
alanine aminotransferase [14]. In two cases,
patients received more than total of 30,000
mg of gemcitabine [12, 13] and in the other
two cases patients received less than 6,000
mg of gemcitabine [14, 15]. In all four cases,
patients presented with significant liver
toxicity as manifested by significant increase
in alkaline phosphatase, aspartate amino-
transferase, alanine aminotransferase and total
bilirubin. In two cases, hepatitis panel has
been checked and those were negative [13,
15]. Three patients have undergone either
biopsy or autopsy [12, 13, 14]. In a case
reported by Dobbie et al., [12] autopsy
showed occlusion of terminal hepatic venules,
sinusoidal congestion and zone-three
hepatocyte necrosis which was consistent
with veno-occlusive disease. Authors
attributed the veno-occlusive disease to
gemcitabine and considered the chronic HCV
as a potential risk factor. Autopsy in a case
that has been reported by Coeman et al., [13]
showed intracellular and intra canalicular
cholestasis without evidence of obstruction.
Interestingly, autopsy showed preservation of
liver architecture and extensive centrilobular
parenchymal necrosis was acute because there
was no collapse or approximation of portal
fields. Authors have emphasized on
considering gemcitabine as one of the causes
of cholestasis in patients who are receiving
gemcitabine either as a single therapy or in
combination with other medication and
chemotherapy medications. Biopsy that has
been performed on a case being reported by
Robinson et al., [14] showed irregular
expansion of portal triads by fibrosis and
marked cholestasis with dilated and
proliferated cholangioles Autopsy revealed
patchy lobular hepatocellular necrosis. The
biopsy was compatible with cholestatic liver
disease and it was consistent with drug-
induced hepatocellular injury. Subsequently
autopsy has been performed and showed
capsular metastasis and intrahepatic
metastasis involving 10-15% of hepatic
parenchyma. On the other hand, our patient
was receiving lower dose than the patient
described in this paper due to expected poor
tolerance in US patients, a fact well-known to
oncologists now. Our patient is the first
patient with pancreatic carcinoma who
developed radiological findings of liver
fibrosis following treatment with gemcitabine.
The current patient had received a total of
14,350 mg of gemcitabine and 1,435 mg of
oxaliplatin. Additionally, he received another
12,452 mg of gemcitabine with 12,000 mg of
capecitabine. A biopsy was suggested but was
not performed. The dose was picked from a
randomized phase II study published in 2003
[18]. This schedule was selected due to
patient’s request as he lived distant and
biweekly regimen was convenient. Similar
biweekly regimen of gemcitabine has been
safely tested in other studies and tumor types.
Our patient received gemcitabine-
capecitabine after GemOx combination failed
to show response. In a randomized phase II
clinical trial by Scheithauer et al., [18] that
investigated the efficacy of gemcitabine-
capecitabine in treatment of metastatic
pancreatic adenocarcinoma, investigators
found no grade III or IV hepatic toxicity in
the combination arm. So it is very unlikely
that combination of gemcitabine and
capecitabine is responsible for liver fibrosis.
Moreover, literature review and our extensive
personal experience suggest that capecitabine
can be safely administered to patients with
cancer and liver dysfunction [16, 19, 20].
Generally, the pharmacokinetics of
capecitabine are not affected in patients with
mild to moderate hepatic dysfunction, but
there are no data available for patients with
severe hyperbilirubinemia. This was also
found to be true in the UK-based study which
actually concluded that no dose adjustment of

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capecitabine was necessary in patient with
mild to moderate hepatic dysfunction
secondary to liver metastases [21]. Therefore,
capecitabine was not believed to be
responsible. The main toxicity of oxaliplatin,
a major drug in the treatment of metastatic
colorectal carcinoma, is neurologic. Severe
sinusoidal lesions of the liver have been
recently described in patients receiving pre-
operative oxaliplatin-containing chemo-
therapy, but their clinical relevance is
unknown [22]. Oxaliplatin was stopped more
than two months and no such findings were
seen on CT scan both during and after
oxaliplatin therapy. The clinical significance
of this case really lies in the fact that
sometimes, radiological findings may come
before any clinical or laboratory
abnormalities. Above all, stopping
gemcitabine can reverse such changes.
Radiological changes with normal liver
function tests have been reported with other
chemotherapeutic agents, e.g. methotrexate
[23]. Causes of liver fibrosis are vast. Chronic
hepatitis B and C can cause liver fibrosis.
Cheong et al., [11] have reported a case of
reactivation of hepatitis B after administration
of gemcitabine. Hepatitis panel was negative
in our case. Veno-occlusive disease of liver
can be ruled out based on the setting of
normal liver function tests through the whole
course. Hepatotoxic drugs are generally
categorized to be dose-dependent or
predictable
vs. dose-independent or
unpredictable (idiosyncratic). Idiosyncratic
reactions may be immunoallergic or
metabolic, and the two mechanisms may be
interrelated. In view of the absence of rash,
eosinophilia, and other features of drug-
induced hypersensitivity, the frequently noted
transient elevated liver function tests with
gemcitabine therapy in previously published
case reports, metabolic idiosyncratic reaction
to gemcitabine seems the most compatible
mechanistic route of hepatic injury.
Classification based on clinical, laboratory,
and histological findings are more commonly
used, and other patient’s liver disease can be
categorized as a cholestatic hepatitis. In our
case, radiological findings preceded the liver
enzyme abnormality. Sessa et al. [24] showed
that gemcitabine induced hepatic toxicity can
be increased in the presence of liver
metastasis. In a case, reported by Robinson et
al., [14], biopsy showed liver fibrosis but
autopsy showed capsular and intrahepatic
metastasis. It is still not clear why metastasis
in liver can increase the risk of gemcitabine
toxicity and in a study done by Venook et al.
[25], investigating the toxicity of gemcitabine
in liver and renal failure, investigators found
that gemcitabine toxicity is increased when
bilirubin is above 2 mg/dL, however our case
shows that gemcitabine induced liver toxicity
and fibrosis can be detected by MRI and
discontinuation of gemcitabine can prevent
further fibrosis and more toxicity. However,
without a confirmatory biopsy these changes
should be considered as suggestive rather than
definitive of the diagnosis of liver fibrosis.
In summary, although gemcitabine has a
relatively safe profile but case reports have
shown that it can cause serious liver damage.
By exclusion, gemcitabine is the probable
causative agent in this case, although it can
never be completely excluded that a
combined effect of gemcitabine together with
other medications or factors could be
responsible. Gemcitabine should be included
in the differential diagnosis of cholestasis
during chemotherapy with this agent. MRI
can be a noninvasive imaging technique of
choice for early detection of gemcitabine
induced liver fibrosis and discontinuation of
gemcitabine can lead to stabilization of liver
fibrosis.
Received March 29th, 2007 - Accepted May
21st, 2007
Keywords gemcitabine; Liver Cirrhosis;
Magnetic Resonance Imaging; Pancreatic
Neoplasms; Transaminases
Conflict of interest The authors have no
potential conflicts of interest
Correspondence
Muhammad Wasif Saif
Section of Medical Oncology

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Yale University School of Medicine
333 Cedar Street; FMP:116
New Haven, CT 06520
USA
 
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