low-dose cyclophosphamide-induced hepatotoxicity in a...
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Chakkor et al. Int J Gastroenterol Hepatol Transpl Nutr 2017;2(iii):14-16 ISSN 2455–9393
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Case Report
Low-dose Cyclophosphamide-induced hepatotoxicity in a multiple
sclerosis patient: A case report and literature review Chakkor A1, Salihoune M1, Znati K2, Mahassini N2, Kabbaj N1
ABSTRACT Cyclophosphamide (CTX) is an alkylating agent commonly used to treat malignancies
and immune-mediated inflammatory nonmalignant processes. It is used off-label for
multiple sclerosis (MS) treatment as a disease-modifying therapy (DMT). Acute
adverse effects include bone marrow suppression, hemorrhagic cystitis, nausea,
vomiting, and hair loss. Hepatotoxicity with high dose CTX is well recognized but low
dose CTX induced hepatitis has rarely been described.
We report a case of a 28-year-old woman with MS who developed acute icteric
hepatitis within 8 weeks of receiving low dose intravenous CTX and
methylprednisolone (MP). Liver biopsy showed liver cell necrosis. CTX and steroid
treatment were discontinued, and her symptoms and laboratory tests improved.
Steroids were reintroduced without relapse; the evolution was favorable with liver
enzymes normalization.
To the best of our knowledge, this is the first report of acute cholestatic hepatitis
developing after administration of low-dose CTX in MS patient. We may suggest that
baseline liver function tests and periodic assessment should be monitored during CTX
treatment.
INTRODUCTION
Cyclophosphamide is a synthetic nitrogen mustard-like
alkylating agent indicated for the treatment of malignancies1 and
nephritic syndrome.2 It is used off-label for the treatment of
many diseases, including MS and lupus nephritis.3 Reported
side effects include bone marrow suppression with opportunistic
infections, hemorrhagic cystitis, temporary infertility, nausea,
vomiting and hair loss.4 In fact, hepatotoxicity with high-dose
CTX is well recognized, but hepatitis due to low dose CTX has
rarely been described.5,6
We hereby report a case of acute icteric hepatitis following a
short course of low-dose CTX in a young woman with MS. To
the best of our knowledge, this is the first reported case of low-
dose CTX-Induced hepatotoxicity in a MS patient.
CASE REPORT
A 28-year-old African female was referred to our unit in
November 2016 for a recent onset of acute jaundice. Eight
weeks prior to this presentation, she was diagnosed with
remitting MS on the basis of clinical and radiological findings
(Fig. 1). The patient received IV CPM (1g) and IV MP (1g)
every four weeks for 3 months. She had no history of liver
disease, alcohol intake or risk factors for viral hepatitis. She
wasn’t taking any other medications or herbal preparations. She
was icteric with dark urine and pale stools. Body temperature
was 37.2°. There was no abdominal tenderness or any sign of
chronic liver disease in the physical examination.
Laboratory findings showed hyperbilirubinemia 159 mg/dl,
normal indirect bilirubinemia 4.9 mg/dl, liver cytolysis with
markedly elevated alanine aminotransferase 475 UI/l (Nx10.3)
and aspartate aminotransferase 350 UI/l (Nx10) with mild
increase in alkaline phosphatase 177U/L (Normal 105) and
gammaglutamyl-transpeptidase GGT 45 U/L (Normal 38). Total
protein, albumin, gammaglobulines, coagulation times, serum
creatinine and C-reactive protein were unremarkable. Blood and
platelet counts were normal. An abdomen ultrasound showed no
biliary obstruction or signs of cirrhosis or portal hypertension.
Viral hepatitis (A, B, C) were ruled out by appropriate virologic
tests. Autoimmune screening (Anti-mitochondrial M2-
antibodies, anti-liver-kidney microsome antibodies, anti-smooth
International Journal of Gastroenterology, Hepatology,
Transplant & Nutrition
1 EFD - Gastroenterology Unit, Ibn Sina Hospital, Mohamed V University, Rabat –
Morocco 2 Anatomopathology Department, Ibn Sina Hospital, Mohamed V University, Rabat -
Morocco
Address for Correspondence:
Amal Chakkor
E-mail: [email protected]
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Key words: Cyclophosphamide, Hepatotoxicity, Multiple Sclerosis
Chakkor et al. Int J Gastroenterol Hepatol Transpl Nutr 2017;2(iii):14-16 ISSN 2455–9393
15
muscle antibodies) was negative. The patient underwent liver
biopsy which showed features of acute hepatitis with liver cell
necrosis (Fig. 2).
At this stage, the decision was to discontinue CTX and steroids
and to follow up the patient. Within 2 weeks, jaundice
disappeared; bilirubine and transaminases levels decreased more
than half. At 4-month follow-up, steroids were reintroduced
without relapse of hepatitis. A diagnosis of CTX-induced
hepatitis was made. CTX was stopped and the patient was
considered for immunotherapy.
DISCUSSION
Herein we report the first case of acute icteric hepatitis after
low-dose IV CTX for MS. CTX is a synthetic, nitrogen
mustard-like alkylating agent that requires hepatic metabolism
for activity.7 The major safety issues that have been associated
in MS patients include bladder cancer and gonadal toxicity.8
Portaccio et al evaluated 112 patients with MS who received
pulse CTX of 700 mg/m2 monthly for 12 months then
bimonthly for 12 months. Serious side effects happened in
21.4% of patients and included: amenorrhea,
hypogammaglobulinemia, hemorrhagic cystitis and
malignancies.9 Perini et al. concluded that using the usual MS
protocol, the most common side effects were mild alopecia,
nausea, vomiting and cystitis.10
Figure 1: Spinal cord and Brain MRI showing multiple
inflammatory lesions consistent with active MS
CTX is an uncommon hepatic toxin. Mild and transient
elevations in serum aminotransferase levels are found in up to
43% of patients with cancer who undergo CTX.11 The liver
abnormalities are generally asymptomatic and transient and
don’t require dose modification. Hepatotoxicity related to low-
dose IV CTX administration has rarely been reported. Enzyme
elevations are more common with higher doses. The onset is
within 2 to 8 weeks of starting CTX. The injury in most cases
resolves within 1 to 3 months after stopping.12 Only few reports
of elevated hepatic enzymes are attributed to the drug and none
of them was addressed in MS patient;13-17 Akay et al. reported a
patient with scleroderma who developed acute hepatitis after 6
weeks of low-dose oral CTX 100 mg daily.13 Synder et al
reported a case of CTX-induced hepatotoxicity after 5 weeks of
oral CTX 100 mg/day in a patient with granulomatosis with
polyangiitis.14 Subranamian et al. reported a case of acute
hepatic failure within 24 hours of receiving low dose IV CTX in
a patient with progressive glomerulonephritis secondary to
granulomatosis with polyangiitis.15 Martinez-Gabarron reported
a case that developed acute hepatitis with cholestasis after the
first dose of CTX (500 mg) and then resolved within a few days.
Fifteen days later, the second CTX bolus was given (750 mg),
and the patient developed acute hepatitis with cholestasis, which
normalized a few days after withdrawing CTX.16 Cleland BD et
al reported a case of a 67-year-old woman who developed acute
liver injury with jaundice 8 weeks after starting oral CTX (100
mg daily) for nephrotic syndrome thought to be due to lupus
erythematosus, CTX was discontinued and her liver test
abnormalities improved rapidly.17
Figure 2: Cyclophosphamide-induced acute hepatitis:
Polymorphous infiltration with numerous neutrophilic
polynuclear (a), hepatic lobular (b) and parcellar necrosis
(c) (HEx 40)
In this present case, cholestatic hepatitis occurred within 8
weeks after administration of a total cumulative dose of 3 g MP
and 3g CTX. The prompt improvement in liver tests upon
stopping CTX was supportive of CTX immutability especially
since CTX induced idiosyncratic liver disease typically arises
within 2 to 8 weeks of starting therapy and usually has a
hepatocellular pattern of serum enzyme elevations.
Nevertheless, the relationship to CTX is still not proven,
particularly because of the possibility of rare acute hepatitis due
to viral hepatitis E, cytomegalovirus, Epstein-Barr virus, or
herpes simplex virus infection.
The mechanism of CTX-induced hepatitis is not clearly
understood. It is extensively metabolized by the hepatic
cytochrome P450 system. This probably induces sinusoidal
obstruction syndrome, leading to a direct toxic effect on
sinusoidal cells in the liver, thereby causing necrosis,
obstruction, and obliteration of hepatic veins.18,19
CONCLUSION
Hepatotoxicity may occur even after low-dose IV CTX
treatment. Physicians should be aware of this potentially serious
Chakkor et al. Int J Gastroenterol Hepatol Transpl Nutr 2017;2(iii):14-16 ISSN 2455–9393
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adverse reaction and should not reintroduce CTX after
hepatotoxicity caused by the first dose. We may suggest that
initial and follow-up liver function tests should be done and
monitored in all patients receiving this chemotherapy.
DISCLOSURE
The authors report no conflicts of interest in this study.
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