High prevalence of polymorphism and low activity of thiopurine methyltransferase in patients with inflammatory bowel disease

Larussa, Tiziana; Suraci, Evelina; Lentini, Margherita; Nazionale, Immacolata; Gallo, Luigia; Abenavoli, Ludovico; Imeneo, Maria; Costanzo, Francesco; Cuda, Giovanni; Luzza, Francesco

doi:10.1016/j.ejim.2011.12.002

Cited by 12 publications

(9 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Methods such as denaturing HPLC (DHPLC) [62,64], multiplex amplification refractory mutation (ARMS) [27,28], pyrosequencing [16,30] and TaqMan SNP genotyping [14,33] were reported. Direct sequencing (n = 3) [11,24,67] and RFLP (n = 17) [10,13,23,26,29,[31][32][33][34][35][36][37][38][39]59,60,66] were also reported. Only one study did not specify a genotyping method [65].…”

Section: Laboratory Test Methodsmentioning

confidence: 99%

“…One study specified pediatric patients as an inclusion criterion [25]. Common exclusion criteria were a history of blood transfusions [26,31,32], concurrent medications such as methotrexate [14,26,58], insufficient functioning of major organs [26] and concurrent or history of a variety of acute, chronic or genetic diseases [14,35,37,58]. One study specified that blood samples >8 days old were excluded [27].…”

Section: Design Characteristics Of High-quality Studiesmentioning

confidence: 99%

“…The remaining studies reported either adult or a mix of adult and pediatric samples. Race was not always specified [10,14,[27][28][29][30]36,37,59], but several high-quality studies identified their sample as, for example, Caucasian, Scandinavian or from the United Kingdom [16,23,31,32,58,60,62,[64][65][66].…”

Section: Design Characteristics Of High-quality Studiesmentioning

confidence: 99%

“…Fifteen studies provided data sufficient to calculate sensitivity for detection of a homozygous mutation [10,13,24,25,27,[29][30][31]35,58,59,62,64,66,67]. Due to the absence of homozygous deficient patients (cell count of zero), it was not possible to calculate sensitivity and specificity in all studies.…”

Section: Diagnostic Test Performance Characteristicsmentioning

confidence: 99%

See 3 more Smart Citations

Thiopurine S -Methyltransferase Testing for Averting Drug Toxicity in Patients Receiving Thiopurines: a Systematic Review

et al. 2016

View full text Add to dashboard Cite

show abstract

Section: Laboratory Test Methodsmentioning

confidence: 99%

Section: Design Characteristics Of High-quality Studiesmentioning

confidence: 99%

Section: Design Characteristics Of High-quality Studiesmentioning

confidence: 99%

Section: Diagnostic Test Performance Characteristicsmentioning

confidence: 99%

See 2 more Smart Citations

Thiopurine S -Methyltransferase Testing for Averting Drug Toxicity in Patients Receiving Thiopurines: a Systematic Review

et al. 2016

View full text Add to dashboard Cite

show abstract

“…This resulted in two strata for the test of deficient TPMT enzyme activity/homozygous TPMT mutation versus the rest of the population: (1) studies where the genotype test only considered TPMT*2 and *3, [33][34][35][36][37][38][39][40][41][42] and (2) studies where the genotype test considered TPMT*2, TPMT*3 and additional polymorphisms. [43][44][45] There were three strata for the test of low or intermediate TPMT enzyme activity/ homozygous or heterozygous TPMT mutation versus the rest of the population: (1) studies where the genotype test only considered TPMT*3, 46,47 (2) studies where the genotype test considered TPMT*2 and TPMT*3, 6,[33][34][35][36][37][38][39][40][41][42][48][49][50][51][52][53][54][55][56] and (3) studies where the genotype test considered TPMT*2, TPMT*3 and additional polymorphisms. [42][43][44][45]57,58 The meta-analysis used a Bayesian model.…”

Section: Meta-analysis Statistical Methodsmentioning

confidence: 99%

Thiopurine S-methyltransferase testing for averting drug toxicity: a meta-analysis of diagnostic test accuracy

et al. 2016

View full text Add to dashboard Cite

Thiopurine S-methyltransferase (TPMT) deficiency increases the risk of serious adverse events in persons receiving thiopurines. The objective was to synthesize reported sensitivity and specificity of TPMT phenotyping and genotyping using a latent class hierarchical summary receiver operating characteristic meta-analysis. In 27 studies, pooled sensitivity and specificity of phenotyping for deficient individuals was 75.9% (95% credible interval (CrI), 58.3-87.0%) and 98.9% (96.3-100%), respectively. For genotype tests evaluating TPMT*2 and TPMT*3, sensitivity and specificity was 90.4% (79.1-99.4%) and 100.0% (99.9-100%), respectively. For individuals with deficient or intermediate activity, phenotype sensitivity and specificity was 91.3% (86.4-95.5%) and 92.6% (86.5-96.6%), respectively. For genotype tests evaluating TPMT*2 and TPMT*3, sensitivity and specificity was 88.9% (81.6-97.5%) and 99.2% (98.4-99.9%), respectively. Genotyping has higher sensitivity as long as TPMT*2 and TPMT*3 are tested. Both approaches display high specificity. Latent class meta-analysis is a useful method for synthesizing diagnostic test performance data for clinical practice guidelines.

show abstract

Association of thiopurine methyltransferase status with azathioprine side effects in Chinese patients with systemic lupus erythematosus

et al. 2013

View full text Add to dashboard Cite

Azathioprine (AZA) is indicated for the treatment of systemic lupus erythematosus (SLE). Thiopurine methyltransferase (TPMT) is the rate-limiting enzyme in the steps of AZA metabolization. Heritable deficiency of TPMT enzyme activity and polymorphisms may lead to leukopenia. This study aims to detect TPMT polymorphisms and TPMT enzyme activity in Chinese SLE patients and to describe the association between TPMT genotypes and adverse effects of AZA. One hundred and twenty-six SLE patients with present or previous thiopurine therapy were identified from a local database. Adverse effects were documented. No TPMT*2, TPMT*3A, or TPMT*3B mutant alleles were detected. TPMT*3C was detected in four patients (3.17 %). The heterozygotes had significantly lower mean TPMT activity as compared to the homozygotes (2.38 ± 1.24 vs. 12.56 ± 7.02 U/mL, P < 0.001). Twenty-seven cases (21.42 %) exhibited adverse effects. All of the heterozygotes (4/4, 100 %) developed severe leukopenia, and three cases (3/4, 75 %) of whom exhibited alopecia simultaneously. The specificity of TPMT*3C for predicting leukopenia and alopecia was 100 and 99.17 %, respectively, and the sensitivity was 28.57 and 60.00 %, respectively. The mean value of TPMT activity with leukopenia (4.67 ± 3.01 vs. 13.2 ± 6.94 U/mL RBC, P < 0.001) or alopecia (2.31 ± 1.16 vs. 12.65 ± 6.98 U/mL RBC, P < 0.001) was significantly lower than those without. TPMT*3C was the most common mutant polymorphism found in the study group. TPMT activity is reduced in TPMT*3C mutant. AZA-induced leukopenia and alopecia were partly correlated to TPMT*3C heterozygotes and low TPMT activity. The results of this study suggest that the value of TPMT genotyping before AZA therapy was limited in Chinese SLE patients, considering the low sensitivity. Routine monitoring of TPMT activity before prescribing and continuous hematological monitoring dose were recommended.

show abstract

High prevalence of polymorphism and low activity of thiopurine methyltransferase in patients with inflammatory bowel disease

Cited by 12 publications

References 30 publications

Thiopurine S -Methyltransferase Testing for Averting Drug Toxicity in Patients Receiving Thiopurines: a Systematic Review

Thiopurine S -Methyltransferase Testing for Averting Drug Toxicity in Patients Receiving Thiopurines: a Systematic Review

Thiopurine S-methyltransferase testing for averting drug toxicity: a meta-analysis of diagnostic test accuracy

Association of thiopurine methyltransferase status with azathioprine side effects in Chinese patients with systemic lupus erythematosus

Contact Info

Product

Resources

About