Hepatotoxicity after low-dose cyclophosphamide therapy.

To the Editor: Hepatotoxicity during high-dose cyclophosphamide (CYC) therapy has been reported, (1,2) but hepatitis due to low-dose CYC treatment has rarely been described. (3) We report a 40-year-old male patient diagnosed with primary scleroderma, treated with D-penicillamine (D-PEN) followed by cyclophosphamide. The patient was treated with D-PEN for 1.5 years and responded well to treatment. He did not take any other medications for the following 2.5 years. When the patient developed polyarthralgia and sinusitis, he was treated and responded well to low-dose steroids and oral CYC (100 mg/d). The same dose of CYC was continued for 45 days and the total cumulative dose of CYC was estimated to be 4.5 g. Because of progressive jaundice lasting for one week, the patient was readmitted. Laboratory findings revealed an albumin of 3.3 mg/dL, globulin 2.9 mg/dL, alkaline phosphatase 206 U/L, aspartate aminotransferase 1806 U/L, alanine aminotransferase 2407 U/L, gamma glutamyl transferase 202 U/L, lactate dehydrogenase 818 U/L, direct bilirubin 6.3 mg/dL, indirect bilirubin 4.2 mg/dL, partial thromboplastin time 14.2 seconds, Cu 134 U/L (70-153 U/L) and ceruloplasmin 409 U/L (280-570 U/L). Ultrasonography of the hepatobiliary system did not reveal any obstructive lesions. Serology for hepatitis A, B and C, toxoplasma IgM, cytomegalovirus IgG and IgM, herpes simplex virus Type 1 and Type 2 IgM, Brucella IgM and IgG, antimitochondrial antibody M2, anti-Sp100, anti-LKM-1, and anti-SLA were all found to be negative. Hepatitis C virus RNA was performed with real time PCR and was found to be negative. Liver function tests returned to normal levels 11 weeks following discontinuation of CYC. No other reason was found for the hepatic injury, and the patient's cyclophosphamide therapy was determined to be the cause.

In the practice of oncology, cyclophosphamide is given by either intermittent pulse or continued low-dose regimen. Two well-known dose-related side effects of CYC are bone marrow suppression and hepatic injury. (4) High-dose bolus CYC may cause transient hepatitis (5); however, hepatotoxicity related to low-dose CYC administration has rarely been reported. In these studies, liver injury occurred within 2 to 8 weeks after initiation of CYC treatment. Our patient developed hepatitis soon after CYC treatment.

Since hepatitis is not a common adverse reaction of D-PEN and the D-PEN treatment occurred long before the patient's hepatitis symptoms, D-PEN does not appear to be responsible for the acute hepatitis.

Our patient was also given steroids. But rather than causing hepatitis, corticosteroids may have overwhelmed the symptoms of drug-induced liver injury. Therefore, the only possible cause for the hepatitis seems to be the CYC therapy in our patient. Hepatotoxicity may occur with CYC treatment even after very small doses. Physicians should be aware of this potentially serious reaction and initial and follow-up liver function tests should be performed in patients undergoing CYC treatment.

Hakan Akay, MD

Department of Internal Medicine

Tuba Akay, MD

Family Physician

Sema Secilmis, MD

Department of Internal Medicine

Zeliha Kocak, MD

Infectious Diseases Department

Omer Donderici, MD

Department of Internal Medicine

Ministry of Health Ankara Research & Training Hospital

Ankara, Turkey

References

1. McDonald GB, Slattery JT, Bouvier ME, et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood 2003;101:2043-2048.

2. Cleland BD, Pokorny CS. Cyclophosphamide related hepatotoxicity. Aust N Z J Med 1993;23:408.

3. Mok CC, Wong WM. Shek TW, et al. Cumulative hepatotoxicity induced by continuous low-dose cyclophosphamide therapy. Am J Gastroenterol 2000;95:845-846.

4. Fraiser LH, Kanekal S, Kehrer JP. Cyclophosphamide toxicity. Characterising and avoiding the problem. Drugs 1991;42:781-795.

5. Spitzer TR, Cirenza E, McAfee S, et al. Phase I-II trial of high-dose cyclophosphamide, carboplatin and autologous bone marrow or peripheral blood stem cell rescue. Bone Marrow Transplant 1995;15:537-542.