- Email: [email protected]
Hepatitis related to cytomegalovirus infection in two patients with Crohn's disease treated with azathioprine
BRIEFCLINICALOBSERVATION
DIGEST LIVER DIS 4000;32:G2G-9
Hepatitis related to cytomegalovirus infection in two patients with Crohn’s disease treated with azathioprine F. Castiglione G. Del Vecchio A. Rispo A. Cozzolino E. Di Girolamo D. Cappuccio G. Mazzacca
Blanc0
Azathioprine-related side-effects occur in about 15% of treated patients. Liver toxicity is a rare complication of this drug, but is considered, in most cases, a contraindication to the continuation of treatment. However: abnormal liver tests may occur in patients under azathioprine treatment also due to infections. The distinction between toxic and infective causes of abnormal liver tests is important in order to identify patients that can be rechallenged with the drug. Cytomegalovirus infection is common in immunosuppressed transplant recipients, while the incidence is lower in patients with inflammatory bowel disease treated with immunosuppressive drugs. To our knowledge, only 2 cases of cytomegalovirus hepatitis occurring during azathioprine treatment for Crohns disease had been reported so far Here, we describe two patients who experienced mild hepatitis associated with the onset of cytomegalovirus infection during azathioprine treatment. The infection was documented by the appearance of IgM anti cytomegalovirus. Both cases were self-limiting. In one of the 2 patients, azathioprine was given again after resolution of the hepatitis with good control of Crohns disease and without other complications. We also retrospectively evaluated the incidence of liver abnormalities assessed by blood tests in 58 consecutive patients with Crohns disease treated with azathioprine at our institution. Abnormal results were obtained in B out of these 58 patients, requiring discontinuation of the drug in 3 patients, two of whom were the cytomegalovirus cases described above.
Digest FlVR#:
Liver
Key words:
Dis 2000;32:626-9 azathioprine;
Chron’s
disease;
cytomegalovirus
infection;
hepatitis
Division of Gastroantarology, Medical School, University “Federico II’, Naples.
Introduction AI/~IWSS
for cmuqmn&lm:
Dr. F. Castiglione. Cattadre di Gastroenterologia, Facolta di Medicina e Chirurgie, UniversitB Federico II, via S. Pensini 5, 80131 Naples, Itely. Fax: +39-08 I-5465649. E-mail: [email protected] Subrnitted May 15, 2000. Revised July 26, 2000. Accepted July 29, 2000.
626
The use of azathioprine (AZA) and its derivative 6-mercaptopurine for inflammatory bowel disease (IBD) has increased in recent years 1*. Indications for use include refractory, fistulizing, and steroid-dependent Crohn’s disease (CD) ’ 2. In these patients, AZA and 6-mercaptopurine can induce long-lasting remission and often therapy is continued for 3-5 years 3 4. Due to the long-term treatment, side effects occur in about 15% of the patients 2 5. The most frequent forms of toxicity include skin rash, pancreatitis, and dose-related neutropenia * 35. Liver toxicity is a rare, but important complication of this drug and falls into one of two categories: early onset allergic-type reactions and non-allergic dose-dependent reactions 2. In a large group of pa-
L Castiglione et al.
tients with IBD treated with 6-mercaptopurine, Present et al. 5 observed hepatitis in only 0.3 % of the cases. However, in other groups the incidence of hepatitis was greater 6-x.Although rare, the observation of significant abnormalities in aminotransferase levels has been considered a possible contraindication to the continuation of treatment. However, abnormalities in liver tests may also derive from the occurrence of infections that have been described in about 7% of the patients treated with AZA, being life-threatening in only 2% of the cases * 5 ‘. Cytomegalovirus (CMV) infection is common in immunosuppressed transplant recipients receiving cyclosporine 9 lo, while it has seldom been described in patients with IBD treated with immunosuppressive drugs. Only 1 case of disseminated CMV infection has been described in a large series of 396 cases treated with 6-mercaptopurine for IBD 5. In this report, we describe 2 cases of mild hepatitis associated with CMV infection which occurred during AZA treatment in patients with CD. We also retrospectively evaluated our patients treated with AZA and monitored for liver toxicity.
Patients and methods During the period under survey (1995-1999), 58 patients with CD (median age 37 years) attending the Inflammatory Bowel Disease Clinic in our department were treated with AZA. The main indications for AZA treatment were fistula (n. 17), steroid dependency (n. 26), steroid refractoriness (n. 15). AZA was given at the dose of 2 mg/kg body weight/day and the median duration of treatment was-22 months.-
Assay for the hepatitis B antigen (HBsAg) and antibodies against hepatitis C (HCV) and B (HBV) viruses, and CMV were carried out in all patients at baseline. Clinical examinations were carried out monthly with monitoring of serological parameters in order to assess treatment toxicity. Alkaline phosphatase and aminotransferases were recorded in all patients. Patients with abnormal liver parameters underwent a complete virological evaluation (HCV, HBV, CMV) and abdominal ultrasonography. Anti CMV antibodies (IgM and IgG) were assayed by a standard immunoenzymatic method (ETI-CYTOKG plus; ETI-CYTOK-M -reverse-plus; DIA Sorin srl) Results
All 58 patients were assessed at baseline for HBsAg and antibodies against HCV, HBV, and CMV. No patient resulted HCV-Ab positive, while 3 cases were HBsAg positive. All cases were negative for IgM anti-CMV while in 44 patients IgG anti CMV were detected. During follow-up, we observed an increase in aminotransferases in 8 cases. The clinical and biochemical features of these patients are summarised in Table I. In 6 cases, aminotransferase abnormalities were observed after l-24 months of AZA treatment and no viral infection was detected. In 5 of these patients aminotransferases (less than 3-fold the normal values) returned to normal in a few days without withdrawal of treatment or modification in the dose, while in 1 case there was a 5-fold increase in aminotransferases which returned to normal only after discontinuation of AZA treatment. In two of these patients abnormal aminotransferase levels were associated with mild upper-abdominal pain and fever <37.5”C.
Table I. Clinical and biochemical features of the 6 patients with Crohn’s disease with abnormal aminotrensferase levels during azathioprine treatment. ATincrww Ixnovamlvalad
Symptometic
C/W-r&ted
Case 1 Case 2 Other-s Case
:
3
1.5
Case 4 Case 5 Case 6 Case 7 Case 6 AT: aminotransfarasee;
yes yes
: z 1.5 AZ’A: azathioprine;
* fever,
abdominal
YE* no yes” no no
pain.
627
Cytomegslouirus
In the which tected These
hepatitis in Croho’s disease
other 2 cases of abnormal liver blood tests, were negative at baseline for CMV IgG, we dethe appearance of IgM antibodies against CMV. cases are briefly described below.
Case 1 A 27-year-old male with ileo-caecal CD received AZA treatment (2 mg/kg/day) due to lack of response to steroids. After 18 months of AZA, the patient came to the clinic with fever (38.5”C), fatigue, arthralgia, and nightly perspiration, which had lasted for 7 days. Physical examination was negative. The patient was not under corticosteroid treatment. No alcohol or drug exposure was documented other than mesalamine treatment which was continued during hepatitis. Serum blood analysis showed a 2-fold increase both in aminotransferases and gamma-glutamyltranspeptidase, and a slight increase in lactic dehydrogenase. His leukocyte count was 4000/mm3 with 52% polymorphonuclear cells. CMV IgM antibodies were found while IgG antibodies were absent. AZA was interrupted and the patient was monitored weekly. After one week, symptoms disappeared. After 60 days, all liver tests were normal and CMV IgG antibodies were recorded. The patient was in remission for CD and AZA was not given again. Case 2 A 22-year-old male with ileo-caecal CD received AZA treatment (2 mg/kg/day) due to lack of response to steroids. He went into remission and continued treatment for 14 months when he came to the clinic with fever (39”C), hepatomegaly, and arthralgia. Serum blood analysis showed a 3-fold increase in aminotransferases, gamma-glutamyltranspeptidase, and lactic dehydrogenase. His leukocyte count was 4190/mm3 with 54 % polymorphonuclear cells. Both CMV IgM and IgG were found. The patient was not under corticosteroid treatment. No alcohol or drug exposure was documented other than mesalamine treatment which was continued during hepatitis. AZA was interrupted and after only 20 days all liver blood tests were normal. In this patient, a relapse of CD resistant to steroids occurred after 6 months. AZA was given again with good control of CD and no further changes in aminotransferase levels or other complications.
Discussion Several studies have clearly shown the efficacy of immunosuppressive treatment in refractory, fistulizing, and steroid-dependent CD 3 4 l1 **. Thus, immunosuppressive drugs are being increasingly used world-wide for IBD. Susceptibility to infection and toxicity due to prolonged 628
treatments are of great concern both to physicians and the patients taking immunosuppressive agents. Liver toxicity is a rare complication of these drugs. However, abnormal results of liver tests may occur in patients under AZA treatment also due to infections. The distinction between toxic and infective causes of abnormal liver tests is important in order to identify those patients that can be rechallenged with the drug. Here we describe 2 cases of mild hepatitis unrelated to AZA toxicity, but associated with CMV infection. The hepatitis occurred in both these young patients treated with azathioprine for more than 12 months. The hepatitis was self-limiting and was resolved completely after discontinuation of AZA treatment. The diagnosis of acute CMV hepatitis was supported by the presence of IgM anti-CMV that returned to normal after appearance of IgG. Furthermore, in neither patient, was there any exposure to alcohol or other hepatotoxic drugs. In one of the patients described here, AZA had induced a stable remission of the disease and, therefore, we did not reintroduce immunosuppressive treatment after resolution of hepatitis. In the other case, relapse of the disease not responding to steroids was evident 6 months after resolution of hepatitis. AZA was prescribed again and no modification in liver blood tests was recorded during a 1Zmonth period of further AZA treatment. To our knowledge, only 2 cases of CMV hepatitis occurring during AZA treatment for CD have been described so far 5 13. On the contrary, CMV infection is common in immunosuppressed transplant recipients receiving cyclosporine 9 lo. Furthermore, CMV hepatitis has been described in one patient with rheumatoid arthritis chronically treated with methotrexate 14. The low incidence of CMV infection in patients with IBD being treated with AZA or 6-mercaptopurine may be related to their effect of CMV replication inhibition demonstrated in vitro 15. We also retrospectively evaluated the incidence of abnormal liver tests in consecutive patients with CD treated with AZA at our institution. In our series, 8 out of 58 patients showed abnormalities in aminotransferases during AZA treatment, although only in 3 cases was drug withdrawal necessary. In 2 of these 3 patients, hepatitis was related to CMV infection. Liver toxicity, being potentially serious, is considered one of the complications that may require withdrawal of AZA treatment in patients with IBD under immunosuppressive therapy. Hepatic dysfunction was documented in 0.3-21% of the patients with IBD treated with AZA, requiring drug withdrawal or, more frequently, dose reduction in the majority of cases 5-8. In patients showing a partial response to immunosuppression and with chronically active disease, the withdrawal of AZA therapy due to intolerance may represent an undesirable event that can significantly affect patient
L Crstiglione et al.
outcome. In our opinion, correct diagnosis of the abnormalities of liver tests occurring during AZA therapy may help to distinguish real toxic events from viral infections. This is particularly important considering that the majority of cases of CMV hepatitis are selflimiting and that, in the more severe cases, ganciclovir may represent a useful therapeutic option since it has been shown to be effective in the treatment of CMV infection in immunosuppressed transplant recipients lo. We suggest that CMV-specific antibody determination and other diagnostic procedures aimed at identifying the causes of hepatitis, other than toxic, should be routinely performed in patients with CD who experience liver impairment during AZA treatment. In cases with CMV infection requiring continuation of immunosuppression a challenge with AZA could be made after resolution of the hepatitis.
References ’ Sandbom WJ. Azathioprine: state of the art in inflammatory bowel disease. Stand J Gastroenterol 1998;33(Suppl 225):92-9. 2 Su CG, Stein RB, Lewis JD, Lichtenstein GR. Azathioprine or 6mercaptopmine for inflammatory bowel disease: do risks outweigh benefits? Digest Liver Dis 2000;32:5 18-3 1. 3 Korelitz BI, Adler DJ, Mendelsohn RA, Sacknoff AL. Long-term experience with 6-mercaptopurine in the treatment of Crohn’s disease. Am J Gastroenterol 1993;88: 1198-205. 4 Present DH. Cyclosporine and other immunosuppressive agents: current and future role in the treatment of inflammatory bowel disease. Am J Gastroenterol 1993;88:627-30. 5 Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI.
6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Int Med 1989;111:641-9. 6 Kirschner BS. Safety of Azathioprine and 6-Mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology 1998;115:813-21. ’ Verhave M, Winter HS, Grand RJ. Azathioprine in the treatment of children with inflammatory bowel disease. J Pediatr 1990;117:809-14. * Markowitz J, Grancher K, Mandel F, Daum F. Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for Pediatric Gastroenterology and Nutrition. Am J Gastroenterol 1993;88:44-8. 9 Gomez E, de Ona M, Melon S, Alvarez R, Laures A, Rodriguez M, et al. Control of cytomegalovirus disease in renal transplant patients treated with prednisone, azathioprine and cyclosporine using intensive monitoring and decreased immunosuppression. Nephron 1999;82:238-45. lo Paya CV, Hermans PE, Wiesner RH, Ludwig J, Smith TF, Rakela J, et al. Cytomegalovirus hepatitis in liver transplantation: prospective analysis of 93 consecutive orthotopic liver transplantations. J Infect Dis 1989;160:752-8. ii George J, Present DH, Pou R, Bodian C, Rubin PH. The longterm outcome of ulcerative colitis treated with 6-mercaptopurine. Am J Gastroenterol 1996; 9 1: 17 1 l-4. I2 Biancone L, Pallone F. Current treatment modalities in active Crohn’s disease. Ital J Gastroenterol Hepatol 1999;31:508-14. I3 Topiel MS, Kutscher JJ, Pilipshen SJ, Quinton KJ. Cytomegalovims infection, 9-( 1,3dihydroxy-2-propoxymethyl)guanine, and Crohn’s disease. Ann Int Med 1986;105:302-3. I4 Montilla Morales C, Lopez Long0 FJ, Moreno Garcia AC, Carreno Perez L. Hypertransaminasemia and methotrexate: not always a toxic effect? Rev Clin Esp 1998;198:822-4. l5 Shin&i K, Ishibashi M, Okuno T, Namazue J, Yamanishi K, Sonoda T, et al. Immunosuppressive dose of azathioprine inhibits replication of human cytomegalovims in vitro. Arch Virol 1991;117:165-71.
629
DIGEST LIVER DIS 4000;32:G2G-9
Hepatitis related to cytomegalovirus infection in two patients with Crohn’s disease treated with azathioprine F. Castiglione G. Del Vecchio A. Rispo A. Cozzolino E. Di Girolamo D. Cappuccio G. Mazzacca
Blanc0
Azathioprine-related side-effects occur in about 15% of treated patients. Liver toxicity is a rare complication of this drug, but is considered, in most cases, a contraindication to the continuation of treatment. However: abnormal liver tests may occur in patients under azathioprine treatment also due to infections. The distinction between toxic and infective causes of abnormal liver tests is important in order to identify patients that can be rechallenged with the drug. Cytomegalovirus infection is common in immunosuppressed transplant recipients, while the incidence is lower in patients with inflammatory bowel disease treated with immunosuppressive drugs. To our knowledge, only 2 cases of cytomegalovirus hepatitis occurring during azathioprine treatment for Crohns disease had been reported so far Here, we describe two patients who experienced mild hepatitis associated with the onset of cytomegalovirus infection during azathioprine treatment. The infection was documented by the appearance of IgM anti cytomegalovirus. Both cases were self-limiting. In one of the 2 patients, azathioprine was given again after resolution of the hepatitis with good control of Crohns disease and without other complications. We also retrospectively evaluated the incidence of liver abnormalities assessed by blood tests in 58 consecutive patients with Crohns disease treated with azathioprine at our institution. Abnormal results were obtained in B out of these 58 patients, requiring discontinuation of the drug in 3 patients, two of whom were the cytomegalovirus cases described above.
Digest FlVR#:
Liver
Key words:
Dis 2000;32:626-9 azathioprine;
Chron’s
disease;
cytomegalovirus
infection;
hepatitis
Division of Gastroantarology, Medical School, University “Federico II’, Naples.
Introduction AI/~IWSS
for cmuqmn&lm:
Dr. F. Castiglione. Cattadre di Gastroenterologia, Facolta di Medicina e Chirurgie, UniversitB Federico II, via S. Pensini 5, 80131 Naples, Itely. Fax: +39-08 I-5465649. E-mail: [email protected] Subrnitted May 15, 2000. Revised July 26, 2000. Accepted July 29, 2000.
626
The use of azathioprine (AZA) and its derivative 6-mercaptopurine for inflammatory bowel disease (IBD) has increased in recent years 1*. Indications for use include refractory, fistulizing, and steroid-dependent Crohn’s disease (CD) ’ 2. In these patients, AZA and 6-mercaptopurine can induce long-lasting remission and often therapy is continued for 3-5 years 3 4. Due to the long-term treatment, side effects occur in about 15% of the patients 2 5. The most frequent forms of toxicity include skin rash, pancreatitis, and dose-related neutropenia * 35. Liver toxicity is a rare, but important complication of this drug and falls into one of two categories: early onset allergic-type reactions and non-allergic dose-dependent reactions 2. In a large group of pa-
L Castiglione et al.
tients with IBD treated with 6-mercaptopurine, Present et al. 5 observed hepatitis in only 0.3 % of the cases. However, in other groups the incidence of hepatitis was greater 6-x.Although rare, the observation of significant abnormalities in aminotransferase levels has been considered a possible contraindication to the continuation of treatment. However, abnormalities in liver tests may also derive from the occurrence of infections that have been described in about 7% of the patients treated with AZA, being life-threatening in only 2% of the cases * 5 ‘. Cytomegalovirus (CMV) infection is common in immunosuppressed transplant recipients receiving cyclosporine 9 lo, while it has seldom been described in patients with IBD treated with immunosuppressive drugs. Only 1 case of disseminated CMV infection has been described in a large series of 396 cases treated with 6-mercaptopurine for IBD 5. In this report, we describe 2 cases of mild hepatitis associated with CMV infection which occurred during AZA treatment in patients with CD. We also retrospectively evaluated our patients treated with AZA and monitored for liver toxicity.
Patients and methods During the period under survey (1995-1999), 58 patients with CD (median age 37 years) attending the Inflammatory Bowel Disease Clinic in our department were treated with AZA. The main indications for AZA treatment were fistula (n. 17), steroid dependency (n. 26), steroid refractoriness (n. 15). AZA was given at the dose of 2 mg/kg body weight/day and the median duration of treatment was-22 months.-
Assay for the hepatitis B antigen (HBsAg) and antibodies against hepatitis C (HCV) and B (HBV) viruses, and CMV were carried out in all patients at baseline. Clinical examinations were carried out monthly with monitoring of serological parameters in order to assess treatment toxicity. Alkaline phosphatase and aminotransferases were recorded in all patients. Patients with abnormal liver parameters underwent a complete virological evaluation (HCV, HBV, CMV) and abdominal ultrasonography. Anti CMV antibodies (IgM and IgG) were assayed by a standard immunoenzymatic method (ETI-CYTOKG plus; ETI-CYTOK-M -reverse-plus; DIA Sorin srl) Results
All 58 patients were assessed at baseline for HBsAg and antibodies against HCV, HBV, and CMV. No patient resulted HCV-Ab positive, while 3 cases were HBsAg positive. All cases were negative for IgM anti-CMV while in 44 patients IgG anti CMV were detected. During follow-up, we observed an increase in aminotransferases in 8 cases. The clinical and biochemical features of these patients are summarised in Table I. In 6 cases, aminotransferase abnormalities were observed after l-24 months of AZA treatment and no viral infection was detected. In 5 of these patients aminotransferases (less than 3-fold the normal values) returned to normal in a few days without withdrawal of treatment or modification in the dose, while in 1 case there was a 5-fold increase in aminotransferases which returned to normal only after discontinuation of AZA treatment. In two of these patients abnormal aminotransferase levels were associated with mild upper-abdominal pain and fever <37.5”C.
Table I. Clinical and biochemical features of the 6 patients with Crohn’s disease with abnormal aminotrensferase levels during azathioprine treatment. ATincrww Ixnovamlvalad
Symptometic
C/W-r&ted
Case 1 Case 2 Other-s Case
:
3
1.5
Case 4 Case 5 Case 6 Case 7 Case 6 AT: aminotransfarasee;
yes yes
: z 1.5 AZ’A: azathioprine;
* fever,
abdominal
YE* no yes” no no
pain.
627
Cytomegslouirus
In the which tected These
hepatitis in Croho’s disease
other 2 cases of abnormal liver blood tests, were negative at baseline for CMV IgG, we dethe appearance of IgM antibodies against CMV. cases are briefly described below.
Case 1 A 27-year-old male with ileo-caecal CD received AZA treatment (2 mg/kg/day) due to lack of response to steroids. After 18 months of AZA, the patient came to the clinic with fever (38.5”C), fatigue, arthralgia, and nightly perspiration, which had lasted for 7 days. Physical examination was negative. The patient was not under corticosteroid treatment. No alcohol or drug exposure was documented other than mesalamine treatment which was continued during hepatitis. Serum blood analysis showed a 2-fold increase both in aminotransferases and gamma-glutamyltranspeptidase, and a slight increase in lactic dehydrogenase. His leukocyte count was 4000/mm3 with 52% polymorphonuclear cells. CMV IgM antibodies were found while IgG antibodies were absent. AZA was interrupted and the patient was monitored weekly. After one week, symptoms disappeared. After 60 days, all liver tests were normal and CMV IgG antibodies were recorded. The patient was in remission for CD and AZA was not given again. Case 2 A 22-year-old male with ileo-caecal CD received AZA treatment (2 mg/kg/day) due to lack of response to steroids. He went into remission and continued treatment for 14 months when he came to the clinic with fever (39”C), hepatomegaly, and arthralgia. Serum blood analysis showed a 3-fold increase in aminotransferases, gamma-glutamyltranspeptidase, and lactic dehydrogenase. His leukocyte count was 4190/mm3 with 54 % polymorphonuclear cells. Both CMV IgM and IgG were found. The patient was not under corticosteroid treatment. No alcohol or drug exposure was documented other than mesalamine treatment which was continued during hepatitis. AZA was interrupted and after only 20 days all liver blood tests were normal. In this patient, a relapse of CD resistant to steroids occurred after 6 months. AZA was given again with good control of CD and no further changes in aminotransferase levels or other complications.
Discussion Several studies have clearly shown the efficacy of immunosuppressive treatment in refractory, fistulizing, and steroid-dependent CD 3 4 l1 **. Thus, immunosuppressive drugs are being increasingly used world-wide for IBD. Susceptibility to infection and toxicity due to prolonged 628
treatments are of great concern both to physicians and the patients taking immunosuppressive agents. Liver toxicity is a rare complication of these drugs. However, abnormal results of liver tests may occur in patients under AZA treatment also due to infections. The distinction between toxic and infective causes of abnormal liver tests is important in order to identify those patients that can be rechallenged with the drug. Here we describe 2 cases of mild hepatitis unrelated to AZA toxicity, but associated with CMV infection. The hepatitis occurred in both these young patients treated with azathioprine for more than 12 months. The hepatitis was self-limiting and was resolved completely after discontinuation of AZA treatment. The diagnosis of acute CMV hepatitis was supported by the presence of IgM anti-CMV that returned to normal after appearance of IgG. Furthermore, in neither patient, was there any exposure to alcohol or other hepatotoxic drugs. In one of the patients described here, AZA had induced a stable remission of the disease and, therefore, we did not reintroduce immunosuppressive treatment after resolution of hepatitis. In the other case, relapse of the disease not responding to steroids was evident 6 months after resolution of hepatitis. AZA was prescribed again and no modification in liver blood tests was recorded during a 1Zmonth period of further AZA treatment. To our knowledge, only 2 cases of CMV hepatitis occurring during AZA treatment for CD have been described so far 5 13. On the contrary, CMV infection is common in immunosuppressed transplant recipients receiving cyclosporine 9 lo. Furthermore, CMV hepatitis has been described in one patient with rheumatoid arthritis chronically treated with methotrexate 14. The low incidence of CMV infection in patients with IBD being treated with AZA or 6-mercaptopurine may be related to their effect of CMV replication inhibition demonstrated in vitro 15. We also retrospectively evaluated the incidence of abnormal liver tests in consecutive patients with CD treated with AZA at our institution. In our series, 8 out of 58 patients showed abnormalities in aminotransferases during AZA treatment, although only in 3 cases was drug withdrawal necessary. In 2 of these 3 patients, hepatitis was related to CMV infection. Liver toxicity, being potentially serious, is considered one of the complications that may require withdrawal of AZA treatment in patients with IBD under immunosuppressive therapy. Hepatic dysfunction was documented in 0.3-21% of the patients with IBD treated with AZA, requiring drug withdrawal or, more frequently, dose reduction in the majority of cases 5-8. In patients showing a partial response to immunosuppression and with chronically active disease, the withdrawal of AZA therapy due to intolerance may represent an undesirable event that can significantly affect patient
L Crstiglione et al.
outcome. In our opinion, correct diagnosis of the abnormalities of liver tests occurring during AZA therapy may help to distinguish real toxic events from viral infections. This is particularly important considering that the majority of cases of CMV hepatitis are selflimiting and that, in the more severe cases, ganciclovir may represent a useful therapeutic option since it has been shown to be effective in the treatment of CMV infection in immunosuppressed transplant recipients lo. We suggest that CMV-specific antibody determination and other diagnostic procedures aimed at identifying the causes of hepatitis, other than toxic, should be routinely performed in patients with CD who experience liver impairment during AZA treatment. In cases with CMV infection requiring continuation of immunosuppression a challenge with AZA could be made after resolution of the hepatitis.
References ’ Sandbom WJ. Azathioprine: state of the art in inflammatory bowel disease. Stand J Gastroenterol 1998;33(Suppl 225):92-9. 2 Su CG, Stein RB, Lewis JD, Lichtenstein GR. Azathioprine or 6mercaptopmine for inflammatory bowel disease: do risks outweigh benefits? Digest Liver Dis 2000;32:5 18-3 1. 3 Korelitz BI, Adler DJ, Mendelsohn RA, Sacknoff AL. Long-term experience with 6-mercaptopurine in the treatment of Crohn’s disease. Am J Gastroenterol 1993;88: 1198-205. 4 Present DH. Cyclosporine and other immunosuppressive agents: current and future role in the treatment of inflammatory bowel disease. Am J Gastroenterol 1993;88:627-30. 5 Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI.
6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Int Med 1989;111:641-9. 6 Kirschner BS. Safety of Azathioprine and 6-Mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology 1998;115:813-21. ’ Verhave M, Winter HS, Grand RJ. Azathioprine in the treatment of children with inflammatory bowel disease. J Pediatr 1990;117:809-14. * Markowitz J, Grancher K, Mandel F, Daum F. Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for Pediatric Gastroenterology and Nutrition. Am J Gastroenterol 1993;88:44-8. 9 Gomez E, de Ona M, Melon S, Alvarez R, Laures A, Rodriguez M, et al. Control of cytomegalovirus disease in renal transplant patients treated with prednisone, azathioprine and cyclosporine using intensive monitoring and decreased immunosuppression. Nephron 1999;82:238-45. lo Paya CV, Hermans PE, Wiesner RH, Ludwig J, Smith TF, Rakela J, et al. Cytomegalovirus hepatitis in liver transplantation: prospective analysis of 93 consecutive orthotopic liver transplantations. J Infect Dis 1989;160:752-8. ii George J, Present DH, Pou R, Bodian C, Rubin PH. The longterm outcome of ulcerative colitis treated with 6-mercaptopurine. Am J Gastroenterol 1996; 9 1: 17 1 l-4. I2 Biancone L, Pallone F. Current treatment modalities in active Crohn’s disease. Ital J Gastroenterol Hepatol 1999;31:508-14. I3 Topiel MS, Kutscher JJ, Pilipshen SJ, Quinton KJ. Cytomegalovims infection, 9-( 1,3dihydroxy-2-propoxymethyl)guanine, and Crohn’s disease. Ann Int Med 1986;105:302-3. I4 Montilla Morales C, Lopez Long0 FJ, Moreno Garcia AC, Carreno Perez L. Hypertransaminasemia and methotrexate: not always a toxic effect? Rev Clin Esp 1998;198:822-4. l5 Shin&i K, Ishibashi M, Okuno T, Namazue J, Yamanishi K, Sonoda T, et al. Immunosuppressive dose of azathioprine inhibits replication of human cytomegalovims in vitro. Arch Virol 1991;117:165-71.
629