Chakkor et al. Int J Gastroenterol Hepatol Transpl Nutr 2017;2(iii):14-16 ISSN 2455–9393

14

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: amalchakkor@gmail.com

Access this article online

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Website:

www.journal.pghtn.com

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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