Casini Rebecca, Vyhlidal Carrie A, Bracken Julia M, Sherman Ashley K, Ahmed Atif, Singh Vivekanand, Williams Veronica, Shakhnovich Valentina
Department of Pediatrics, North Shore University Health System, Skokie, IL 60201, USA.
KCAS Bioanalytical & Biomarker Services, Shawnee, KS 66061, USA.
Pharmaceuticals (Basel). 2023 Feb 28;16(3):373. doi: 10.3390/ph16030373.
Crohn's disease with upper gastrointestinal tract involvement occurs more often in children than adults and has the potential to interfere with oral drug absorption. We aimed to compare disease outcomes in children receiving oral azathioprine for the treatment of Crohn's disease with (DP) and without (NDP) duodenal pathology at diagnosis.
Duodenal villous length, body mass index (BMI), and laboratory studies were compared in DP vs. NDP during the first year post-diagnosis, using parametric/nonparametric tests and regression analysis (SAS v9.4); the data are reported as the median (interquartile range) or the mean ± standard deviation. Thiopurine metabolite concentration (pmol/8 × 10 erythrocytes) 230-400 was considered therapeutic for 6-thioguanine nucleotides (6-TGN), and >5700 was considered hepatotoxic for 6-methylmercaptopurine (6-MMPN).
Twenty-six of the fifty-eight children enrolled (29 DP, 29 NDP) started azathioprine for standard medical care, including nine DP and ten NDP who had normal thiopurine methyltransferase activity. Duodenal villous length was significantly shorter in DP vs. NDP (342 ± 153 vs. 460 ± 85 μm; < 0.001) at diagnosis; age, sex, hemoglobin, and BMI were comparable between groups. A trend toward lower 6-TGN was observed in the DP vs. NDP subset receiving azathioprine (164 (117, 271) vs. 272 (187, 331); = 0.15). Compared to NDP, DP received significantly higher azathioprine doses (2.5 (2.3, 2.6) vs. 2.2 (2.0, 2.2) mg/kg/day; = 0.01) and had an increased relative risk of sub-therapeutic 6-TGN. At 9 months post-diagnosis, children with DP had significantly lower hemoglobin (12.5 (11.7, 12.6) vs. 13.1 (12.7, 13.3) g/dL; = 0.01) and BMI z-scores (-0.29 (-0.93, -0.11) vs. 0.88 (0.53, 0.99); = 0.02) than children with NDP.
For children with Crohn's disease, duodenal pathology, marked by villous blunting, increased the risk of sub-therapeutic 6-TGN levels, despite higher azathioprine dosing during the first year post-diagnosis. Lower hemoglobin and BMI z-scores at 9 months post-diagnosis suggest the impaired absorption/bioavailability of nutrients, as well as oral drugs, in children with duodenal disease.
克罗恩病累及上消化道在儿童中比成人更常见，并且有可能干扰口服药物的吸收。我们旨在比较诊断时患有十二指肠病变（DP）和未患有十二指肠病变（NDP）的接受口服硫唑嘌呤治疗克罗恩病的儿童的疾病结局。
在诊断后的第一年，使用参数/非参数检验和回归分析（SAS v9.4）比较DP组和NDP组的十二指肠绒毛长度、体重指数（BMI）和实验室检查结果；数据以中位数（四分位间距）或均值±标准差表示。硫嘌呤代谢物浓度（每8×10⁶个红细胞中pmol数）230 - 400被认为对6 - 硫鸟嘌呤核苷酸（6 - TGN）具有治疗作用，>5700被认为对6 - 甲基巯基嘌呤（6 - MMPN）具有肝毒性。
纳入的58名儿童中有26名（29名DP，29名NDP）开始使用硫唑嘌呤进行标准医疗护理，其中9名DP和10名NDP的硫嘌呤甲基转移酶活性正常。诊断时，DP组的十二指肠绒毛长度明显短于NDP组（342±153 vs. 460±85μm；P<0.001）；两组之间的年龄、性别、血红蛋白和BMI相当。在接受硫唑嘌呤治疗的DP组与NDP组亚组中观察到6 - TGN有降低趋势（164（117, 271）vs. 272（187, 331）；P = 0.15）。与NDP组相比，DP组接受的硫唑嘌呤剂量明显更高（2.5（2.3, 2.6）vs. 2.2（2.0, 2.2）mg/kg/天；P = 0.01），且6 - TGN治疗不足的相对风险增加。诊断后9个月，DP组儿童的血红蛋白（12.5（11.7, 12.6）vs. 13.1（12.7, 13.3）g/dL；P = 0.01）和BMI z评分（-0.29（-0.93, -0.11）vs. 0.88（0.53, 0.99）；P = 0.02）明显低于NDP组儿童。
对于患有克罗恩病的儿童，以绒毛变钝为特征的十二指肠病变增加了6 - TGN水平治疗不足的风险，尽管在诊断后的第一年硫唑嘌呤剂量较高。诊断后9个月较低的血红蛋白和BMI z评分表明十二指肠疾病儿童的营养物质以及口服药物的吸收/生物利用度受损。
