Severe pancytopenia and aspergillosis caused by thioguanine in a thiopurine S-methyltransferase deficient patient: a case report.

Azathioprine and mercaptopurine are widely used in the treatment of inflammatory bowel disease. However, its use is limited by adverse drug event related to the relatively narrow therapeutic index of the active metabolites. Several patients discontinue treatment because of intolerable adverse events or toxicity such as leucopenia and hepatotoxicity. High 6-thioguanine nucleotides and 6-methylmercaptopurine ribonucleotides levels are associated with toxicity. Variations in the thiopurine S-methyltransferase (TPMT) gene can lead to diminished TPMT enzyme activity and to an increased incidence of myelotoxicity due to high 6-methylmercaptopurine ribonucleotides levels after treatment with azathioprine and mercaptopurine. Unlike azathioprine and mercaptopurine, thioguanine is more directly metabolized to the active metabolites without formation of the toxic 6-methylmercaptopurine ribonucleotides. Taking this into account, it seems likely that thioguanine is less associated with myelotoxicity due to TPMT deficiency. However, we report the case of a Crohn's disease patient with life-threatening complications on 6TG treatment due to TPMT deficiency. Our patient developed a severe pancytopenia on thioguanine therapy, with 6-thioguanine nucleotides levels more than 10 times higher than the upper limit of the therapeutic window and was found to be a TPMT poor metabolizer (TPMT *3A/*3A). This case strongly illustrates that knowledge of TPMT enzyme activity is very important in the use of all thiopurines, including thioguanine. In conclusion, clinicians should be aware of the impact of TPMT deficiency on the metabolism of thioguanine and should consider performing preemptive TPMT genotyping in combination with frequent blood test monitoring when using thiopurines in general.

In gastroesophageal reflux disease, differential gene expression in the duodenum points towards enhanced chylomicron production and secretion.

BACKGROUND: Duodenal signaling affects esophageal motility and perception, both pathophysiological factors in gastroesophageal reflux disease (GERD). Duodenal gene expression abnormalities, contributing to altered esophageal sensorimotor function, have not been reported to date. AIM: To identify differentially expressed genes in GERD patients' duodenum. METHODS: Twenty GERD patients (total 24-h acid exposure 6-12%, SAP ≥95%) and ten healthy controls (HC) were included. Two weeks prior to duodenal biopsy collection, ten patients discontinued proton pump inhibitor (PPI) treatment and ten took maximum dose PPI. RNA was profiled on an Affymetrix Human Genome U133 Plus 2.0 array (Affymetrix, Santa Clara, CA, USA). Genes exhibiting a fold change ≥ 1.4 (t test p value <1E-4) were considered differentially expressed. A subset of 21 differentially expressed genes was selected for confirmatory TaqMan low-density array RT-PCR. Mucosal apolipoprotein A-IV (apoA-IV) and cholecystokinin (CCK) concentrations were determined by ELISA and RIA, respectively. RESULTS: In GERD patients off PPI, 23 up- and 23 down-regulated genes relative to HC were found. In GERD patients on PPI, 33 and five genes were higher, respectively, lower expressed. The majority of up-regulated genes were associated with lipid absorption, particularly triglyceride resynthesis and intracellular vesicular transport, rate-limiting processes for chylomicron production and secretion. Differential expression of 11 genes was confirmed by RT-PCR. Mucosal apoA-IV and CCK concentrations (signaling proteins released upon chylomicron secretion) were similar in GERD patients and HC. CONCLUSIONS: The identified mRNA expression differences suggest that in GERD patients' duodenum, the chylomicron production and secretion potential is elevated, and may underlie a mechanism by which postprandial duodenal signaling contributes to GERD symptom generation.

The preoperative reflux pattern as prognostic indicator for long-term outcome after Nissen fundoplication.

OBJECTIVES: We set out to investigate the impact of the preoperative reflux pattern on long-term outcome after Nissen fundoplication. Recent studies disagree on whether patients with pathological upright reflux should be discouraged from undergoing surgery. METHODS: A total of 338 patients underwent Nissen fundoplication. Of these, 234 of 289 patients had pathological acid exposure on preoperative 24-h esophageal pH monitoring and their reflux was classified as pathological upright (n=81), supine (n=55), or bipositional (n=98). Clinical outcomes and results of endoscopy, manometry, and 24-h pH monitoring were compared before surgery, and at 3 months and 5 years after surgery. RESULTS: Patients with pathological upright and supine reflux had similar preoperative reflux parameters. In patients with pathological bipositional reflux, however, preoperative total acid exposure was higher than that in patients with upright or supine reflux (18.3% vs. 10.7 and 7.5%; P<0.001 and P<0.001). Prevalence of esophagitis was higher in patients with bipositional reflux than in those with upright reflux, both before (64.0 vs. 45.6%; P=0.035) and 3 months after surgery (16.0 vs. 3.5%; P=0.018). Before surgery, mean lower esophageal sphincter (LES) pressure was lower compared with the upright and supine reflux groups (1.0 vs. 1.5 and 1.6 kPa; P=0.007 and 0.005, respectively). The increase in quality of life, reduction of symptoms, use of acid-suppressing drugs, total acid exposure, and esophagitis were independent of reflux pattern at 3 months and 5 years after surgery (all P<0.05). Prevalence of recurrent pathological acid exposure was higher in the bipositional group than in the upright group (40.9 vs. 10.7%; P=0.013). Surgical reintervention was significantly more common in bipositional reflux patients (20.0 vs. 8.9% for upright and 4.1% for supine). CONCLUSIONS: All three pathological reflux patterns respond favorably to Nissen fundoplication in the long term. Patients with pathological bipositional reflux, however, suffer from more severe disease with higher chance of recurrence and reoperation.

Gastroesophageal pressure gradients in gastroesophageal reflux disease: relations with hiatal hernia, body mass index, and esophageal acid exposure.

OBJECTIVES: The roles of intragastric pressure (IGP), intraesophageal pressure (IEP), gastroesophageal pressure gradient (GEPG), and body mass index (BMI) in the pathophysiology of gastroesophageal reflux disease (GERD) and hiatal hernia (HH) are only partly understood. METHODS: In total, 149 GERD patients underwent stationary esophageal manometry, 24-h pH-metry, and endoscopy. RESULTS: One hundred three patients had HH. Linear regression analysis showed that each kilogram per square meter of BMI caused a 0.047-kPa increase in inspiratory IGP (95% confidence interval [CI] 0.026-0.067) and a 0.031-kPa increase in inspiratory GEPG (95% CI 0.007-0.055). Each kilogram per square meter of BMI caused expiratory IGP to increase with 0.043 kPa (95% CI 0.025-0.060) and expiratory IEP with 0.052 kPa (95% CI 0.027-0.077). Each added year of age caused inspiratory IEP to decrease by 0.008 kPa (95% CI -0.015-0.001) and inspiratory GEPG to increase by 0.008 kPa (95% CI 0.000-0.015). In binary logistic regression analysis, HH was predicted by inspiratory and expiratory IGP (odds ratio [OR] 2.93 and 2.62, respectively), inspiratory and expiratory GEPG (OR 3.19 and 2.68, respectively), and BMI (OR 1.72/5 kg/m(2)). In linear regression analysis, HH caused an average 5.09% increase in supine acid exposure (95% CI 0.96-9.22) and an average 3.46% increase in total acid exposure (95% CI 0.82-6.09). Each added year of age caused an average 0.10% increase in upright acid exposure and a 0.09% increase in total acid exposure (95% CI 0.00-0.20 and 0.00-0.18). CONCLUSIONS: BMI predicts IGP, inspiratory GEPG, and expiratory IEP. Age predicts inspiratory IEP and GEPG. Presence of HH is predicted by IGP, GEPG, and BMI. GEPG is not associated with acid exposure.

Concomitant functional dyspepsia and irritable bowel syndrome decrease health-related quality of life in gastroesophageal reflux disease.

OBJECTIVE: Previous studies have reported an overlap between gastroesophageal reflux symptoms, functional dyspepsia (FD) and irritable bowel syndrome (IBS). The aim of this study was to investigate the prevalence of FD and IBS in gastroesophageal reflux disease (GERD) and the effect on health-related quality of life (HRQoL). MATERIAL AND METHODS: FD and IBS prevalence and HRQoL were assessed by means of questionnaires in 215 referred and 48 non-referred (non-care-seeking) GERD patients, proven with 24-h pH-metry. HRQoL in 131 matched controls was used for comparison. RESULTS: In this group of GERD patients 25% had FD (Dutch general population 13-14%), 35% had IBS (Dutch general population 0.6-6%) and 5% had both FD and IBS. Only 35% had neither FD nor IBS. Among referred GERD patients, the prevalence of FD and IBS was higher (p=0.002 versus non-referred). Compared with controls, GERD patients without FD/IBS had lower HRQoL scores on only one of the nine SF-36 subscales (p