Azathioprine-induced pancytopenia in a patient with pompholyx and defi
http://www.100md.com
《英国医生杂志》
1 Ysbyty Gwynedd, Bangor, Gwynedd LL57 2PW
Correspondence to: M Konstantopoulou maria. konstantopoulou@nww-tr.wales.nhs.uk
Introduction
Azathioprine is rapidly and probably nonenzymatically converted to 6-mercaptopurine (figure).8 In turn, 6-mercaptopurine is converted to thiopurine nucleotide analogues, initially by the enzyme hypoxanthine guanine phosphoribosyl transferase and then by multienzyme steps. These analogues are subsequently incorporated into DNA, and this is believed to be the mechanism for the drug's cytotoxic action.
Azathioprine metabolism
A second enzyme, xanthine oxidase, catalyses the conversion of 6-mercaptopurine to 6-thiouric acid. This enzyme is competitively inhibited by allopurinol, and concurrent administration of both allopurinol and azathioprine can lead to azathioprine toxicity. Xanthine oxidase is not present in haemopoietic tissue, nor does it show genetic variability.8
It is the TPMT pathway, however, that is mainly responsible for the inactivation of azathioprine. In contrast with the other enzymes, the catabolic activity of TPMT is governed by a genetic polymorphism involving several variant alleles. This explains the differential susceptibility to myelosuppression.3 8 Individuals who are homozygous for the low activity TPMT allele are extremely susceptible to acute myelotoxicity with azathioprine and other thiopurine drugs such as mercaptopurine. In their original study, Weinshilboum and Sladek found that 0.3% of subjects (1:300 of the population) were in this category, with very low or undetectable erythrocyte TPMT activity.3 They found that 88.6% were homozygous for a high TMPT activity allele and 11.1% were heterozygous, with reduced but still measurable TPMT activity. Holme et al found similar populations in a larger retrospective study of 3291 individuals with a wide range of medical conditions, but they suggested that the proportion with negligible TPMT might be slightly higher (0.45%, 1:220); this study also identified a subpopulation (9% of subjects) with TPMT activity above the normal range.7
Dosage in azathioprine treatment is often empirical and has been estimated as ranging from 0.5 to 2.6 mg/kg/day.6 The British National Formulary recommends 1-3 mg/kg/day. However, in one survey, only 13% of dermatologists prescribed the drug according to body weight (usually 2.0-2.5 mg/kg/day); for the rest the usual starting dose was 100 mg/day.13 In our patient the dose was 1 mg/kg/day.
Monitoring the full blood count during the early stages of treatment with azathioprine is not a satisfactory method for detecting toxicity. The reserve of cells in the bone marrow will sustain cell counts for some time before marrow toxicity is reflected in the peripheral blood. In our case the peripheral blood count was still normal five weeks after starting treatment.
Prior measurement of erythrocyte TPMT activity will not only identify individuals at risk of myelosuppression, it will also identify patients with high enzyme activity. This is important because such patients may show a suboptimal response to conventional doses of azathioprine. The table shows recommended doses of azathioprine based on thiopurine methyltransferase activity.8 It is not clear what dosage should be recommended for patients with very high TPMT activity, but it may be as much as 3 mg/kg/day.11
Suggested treatment doses according to erythrocyte thiopurine methyltransferase (TPMT) activity. Adapted from El-Azhary8
Azathioprine myelotoxicity is not idiosyncratic and unpredictable. It can be anticipated in individuals with low, and particularly very low or undetectable, TPMT activity. Assays for TPMT measurement are readily available and should be considered when starting treatment, particularly bearing in mind the life threatening complications of neutropenia and the cost of drugs to treat it.14 We wish to draw attention to this because awareness of the significance of TPMT activity has been reported as "patchy" across specialties.7 In this case, profound pancytopenia could have been prevented if TPMT been measured before treatment.
Measure erythrocyte thiopurine methyltransferase (TPMT) activity before treating with azathioprine
Contributors: MK, AWM, and JRCS looked after the patient whose case is reported; MK, AB, and AWM drafted the report and did the bulk of the literature search; KDG organised the measurement of thiopurine methyltransferase and gave advice on biochemical details; JRCS helped to write up the case. The guarantor is AWM.
Funding: None.
Competing interests: None declared.
References
Scerri L. Azathioprine in dermatological practice. An overview with special emphasis on its use in non-bullous inflammatory dermatoses. Adv Exp Med Biol 1999;455: 343-8.
Weinshilboum RM, Raymond FA, Pazmino PA. Human erythrocyte thiopurine methyltransferase: radiochemical microassay and biochemical properties. Clin Chim Acta 1978:85: 323-33.
Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980:32: 651-62.
Anstey A, Lennard L, Mayou SC, Kirby JD. Pancytopenia related to azathioprine—an enzyme deficiency caused by a common genetic polymorphism: a review. J R Soc Med 1992;85: 752-6.
Anstey A. Azathioprine in dermatology: a review in the light of advances in understanding methylation pharmacogenetics. J R Soc Med 1995:88: 155-60P.
Snow JL, Gibson LE. The role of genetic variation in thiopurine methyltransferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients. Arch Dermatol 1995;131: 193-7.
Holme SA, Duley JA, Sanderson J, Routledge PA, Anstey A. Erythrocyte thiopurine methyltransferase assessment prior to azathioprine use in the UK. Q J Med 2002;95: 439-44.
El-Azhary RA. Azathioprine: current status and future considerations. Int J Dermatol 2003;42: 335-41.
Wojnarowska F, Kirtschig G, Highet AS, Venning VA, Khumalo NP. Guidelines for the management of bullous pemphigoid. Br J Dermatol 2002;147: 214-21.
Harman KE, Albert S, Black MM. Guidelines for the management of pemphigus vulgaris. Br J Dermatol 2003;149: 926-37.
Anstey AV, Wakelin S, Reynolds NJ. Guidelines for prescribing azathioprine in dermatology. Br J Dermatol 2004;151: 1123-32.
Ford LT, Berg JD. Determination of thiopurine S-methyltransferase activity in erythrocytes using 6-thioguanine as substrate and a non-extraction liquid chromatographic technique. J Chrom B 2003;798; 111-5.
Tan BB, Lear JT, Gawkrodger DJ, English JSC. Azathioprine in dermatology: a survey of current practice in the UK. Br J Dermatol 1996:136: 351-5.
Jackson AP, Hall AG, McLelland J. Thiopurine methyltransferase levels should be measured before commencing patients on azathioprine. Br J Dermatol 1997:136: 133-4.(M Konstantopoulou, locum consultant derm)
Correspondence to: M Konstantopoulou maria. konstantopoulou@nww-tr.wales.nhs.uk
Introduction
Azathioprine is rapidly and probably nonenzymatically converted to 6-mercaptopurine (figure).8 In turn, 6-mercaptopurine is converted to thiopurine nucleotide analogues, initially by the enzyme hypoxanthine guanine phosphoribosyl transferase and then by multienzyme steps. These analogues are subsequently incorporated into DNA, and this is believed to be the mechanism for the drug's cytotoxic action.
Azathioprine metabolism
A second enzyme, xanthine oxidase, catalyses the conversion of 6-mercaptopurine to 6-thiouric acid. This enzyme is competitively inhibited by allopurinol, and concurrent administration of both allopurinol and azathioprine can lead to azathioprine toxicity. Xanthine oxidase is not present in haemopoietic tissue, nor does it show genetic variability.8
It is the TPMT pathway, however, that is mainly responsible for the inactivation of azathioprine. In contrast with the other enzymes, the catabolic activity of TPMT is governed by a genetic polymorphism involving several variant alleles. This explains the differential susceptibility to myelosuppression.3 8 Individuals who are homozygous for the low activity TPMT allele are extremely susceptible to acute myelotoxicity with azathioprine and other thiopurine drugs such as mercaptopurine. In their original study, Weinshilboum and Sladek found that 0.3% of subjects (1:300 of the population) were in this category, with very low or undetectable erythrocyte TPMT activity.3 They found that 88.6% were homozygous for a high TMPT activity allele and 11.1% were heterozygous, with reduced but still measurable TPMT activity. Holme et al found similar populations in a larger retrospective study of 3291 individuals with a wide range of medical conditions, but they suggested that the proportion with negligible TPMT might be slightly higher (0.45%, 1:220); this study also identified a subpopulation (9% of subjects) with TPMT activity above the normal range.7
Dosage in azathioprine treatment is often empirical and has been estimated as ranging from 0.5 to 2.6 mg/kg/day.6 The British National Formulary recommends 1-3 mg/kg/day. However, in one survey, only 13% of dermatologists prescribed the drug according to body weight (usually 2.0-2.5 mg/kg/day); for the rest the usual starting dose was 100 mg/day.13 In our patient the dose was 1 mg/kg/day.
Monitoring the full blood count during the early stages of treatment with azathioprine is not a satisfactory method for detecting toxicity. The reserve of cells in the bone marrow will sustain cell counts for some time before marrow toxicity is reflected in the peripheral blood. In our case the peripheral blood count was still normal five weeks after starting treatment.
Prior measurement of erythrocyte TPMT activity will not only identify individuals at risk of myelosuppression, it will also identify patients with high enzyme activity. This is important because such patients may show a suboptimal response to conventional doses of azathioprine. The table shows recommended doses of azathioprine based on thiopurine methyltransferase activity.8 It is not clear what dosage should be recommended for patients with very high TPMT activity, but it may be as much as 3 mg/kg/day.11
Suggested treatment doses according to erythrocyte thiopurine methyltransferase (TPMT) activity. Adapted from El-Azhary8
Azathioprine myelotoxicity is not idiosyncratic and unpredictable. It can be anticipated in individuals with low, and particularly very low or undetectable, TPMT activity. Assays for TPMT measurement are readily available and should be considered when starting treatment, particularly bearing in mind the life threatening complications of neutropenia and the cost of drugs to treat it.14 We wish to draw attention to this because awareness of the significance of TPMT activity has been reported as "patchy" across specialties.7 In this case, profound pancytopenia could have been prevented if TPMT been measured before treatment.
Measure erythrocyte thiopurine methyltransferase (TPMT) activity before treating with azathioprine
Contributors: MK, AWM, and JRCS looked after the patient whose case is reported; MK, AB, and AWM drafted the report and did the bulk of the literature search; KDG organised the measurement of thiopurine methyltransferase and gave advice on biochemical details; JRCS helped to write up the case. The guarantor is AWM.
Funding: None.
Competing interests: None declared.
References
Scerri L. Azathioprine in dermatological practice. An overview with special emphasis on its use in non-bullous inflammatory dermatoses. Adv Exp Med Biol 1999;455: 343-8.
Weinshilboum RM, Raymond FA, Pazmino PA. Human erythrocyte thiopurine methyltransferase: radiochemical microassay and biochemical properties. Clin Chim Acta 1978:85: 323-33.
Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980:32: 651-62.
Anstey A, Lennard L, Mayou SC, Kirby JD. Pancytopenia related to azathioprine—an enzyme deficiency caused by a common genetic polymorphism: a review. J R Soc Med 1992;85: 752-6.
Anstey A. Azathioprine in dermatology: a review in the light of advances in understanding methylation pharmacogenetics. J R Soc Med 1995:88: 155-60P.
Snow JL, Gibson LE. The role of genetic variation in thiopurine methyltransferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients. Arch Dermatol 1995;131: 193-7.
Holme SA, Duley JA, Sanderson J, Routledge PA, Anstey A. Erythrocyte thiopurine methyltransferase assessment prior to azathioprine use in the UK. Q J Med 2002;95: 439-44.
El-Azhary RA. Azathioprine: current status and future considerations. Int J Dermatol 2003;42: 335-41.
Wojnarowska F, Kirtschig G, Highet AS, Venning VA, Khumalo NP. Guidelines for the management of bullous pemphigoid. Br J Dermatol 2002;147: 214-21.
Harman KE, Albert S, Black MM. Guidelines for the management of pemphigus vulgaris. Br J Dermatol 2003;149: 926-37.
Anstey AV, Wakelin S, Reynolds NJ. Guidelines for prescribing azathioprine in dermatology. Br J Dermatol 2004;151: 1123-32.
Ford LT, Berg JD. Determination of thiopurine S-methyltransferase activity in erythrocytes using 6-thioguanine as substrate and a non-extraction liquid chromatographic technique. J Chrom B 2003;798; 111-5.
Tan BB, Lear JT, Gawkrodger DJ, English JSC. Azathioprine in dermatology: a survey of current practice in the UK. Br J Dermatol 1996:136: 351-5.
Jackson AP, Hall AG, McLelland J. Thiopurine methyltransferase levels should be measured before commencing patients on azathioprine. Br J Dermatol 1997:136: 133-4.(M Konstantopoulou, locum consultant derm)