Toxicity of 6-thioguanine: no hepatotoxicity in a series of IBD patients treated with long-term, low dose 6-thioguanine. Some evidence for dose or metabolite level dependent effects?

BACKGROUND: 6-Thioguanine is used in inflammatory bowel disease since 2001, with promising short-term results. In 2003, liver histology of some 6-thioguanine treated patients showed nodular regenerative hyperplasia. Recently, magnetic resonance imaging revealed nodular regenerative hyperplasia in patients with normal histology. AIMS: Investigating the presence of nodular regenerative hyperplasia in long-term 6-thioguanine treated patients. PATIENTS AND METHODS: Inflammatory bowel disease patients, using 6-thioguanine minimally 24 months, were asked to undergo liver biopsy and magnetic resonance imaging. RESULTS: Fourteen patients used 6-thioguanine minimally 24 months, 13 participated. Mean 6-thioguanine therapy duration, daily dose and 6-thioguanine nucleotide levels were: 36 months, 18.8 mg (0.28 mg/kg) and 705 pmol/8x10(8) erythrocytes, respectively. Liver histology and magnetic resonance imaging showed no nodular regenerative hyperplasia. DISCUSSION: Liver biopsy and magnetic resonance imaging showed no nodular regenerative hyperplasia in these long-term 6-thioguanine treated inflammatory bowel disease patients. 6-thioguanine dose and metabolite levels were lower compared with previous nodular regenerative hyperplasia reports, suggesting dose or metabolite level-dependent effects. Otherwise, nodular regenerative hyperplasia is related with inflammatory bowel disease itself and immunosuppressives, including azathioprine and 6-mercaptopurine. CONCLUSION: 6-Thioguanine is debated due to nodular regenerative hyperplasia. We found no nodular regenerative hyperplasia in inflammatory bowel disease patients with long-term, low dosed 6-thioguanine, suggesting metabolite level-dependent effects. Therefore, 6-thioguanine still seems useful, but in selected patients, intolerant for other immunosuppressives, low dosed and under close surveillance of metabolite levels and hepatotoxity.

The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients.

BACKGROUND: In vitro studies suggest interactions between mesalazine (mesalamine) and thiopurines by thiopurine S-methyltransferase (TPMT) inhibition, influencing the balance of hepatotoxic 6-methylmercaptopurine ribonucleotide and immunosuppressive tioguanine (thioguanine) metabolites. AIM: To examine the in vivo pharmacokinetic interaction between mesalazine and mercaptopurine. METHODS: A prospective study was performed in quiescent inflammatory bowel disease patients using the combination of mercaptopurine and mesalazine. Laboratory parameters, 6-methylmercaptopurine ribonucleotide and tioguanine levels and thiopurine S-methyltransferase activity in erythrocytes were measured at stable medication, after mesalazine discontinuation and mesalazine reintroduction, further mercaptopurine was continued. RESULTS: Seventeen patients were participated. Mean mercaptopurine dose was 0.78 mg/kg/day and median of mesalazine dose was 3000 mg/day. After mesalazine discontinuation, mean tioguanine levels changed significantly from 262 to 209 pmol/8 x 10(8) red blood cell, increasing to 270 after reintroduction. Mean 6-methylmercaptopurine ribonucleotide levels were 1422, 2149 and 1503 pmol/8 x 10(8) red blood cell respectively. Mean 6-methylmercaptopurine ribonucleotide/tioguanine ratio increased significantly from 6.3 at baseline to 11.2. Mean baseline thiopurine S-methyltransferase activity was 0.58 pmol/10(6) red blood cell/h and stable. All patients had wild-type thiopurine S-methyltransferase genotypes however, leucocyte counts were stable. DISCUSSION: A significantly higher tioguanine levels and improving 6-methylmercaptopurine ribonucleotide/tioguanine ratio were found during mesalazine/mercaptopurine combination. Theoretically, mesalazine inhibits thiopurine S-methyltransferase activity. In vivo thiopurine S-methyltransferase activity did not change, however. CONCLUSION: Mesalazine has synergistic effects on mercaptopurine therapy, but the mechanism is unclear. Combining these drugs may be further indication for mesalazine in inflammatory bowel disease treatment.

Therapeutic drug monitoring in patients with inflammatory bowel disease and established azathioprine therapy.

BACKGROUND AND OBJECTIVE: Azathioprine is widely used in the treatment of corticosteroid-dependent and refractory inflammatory bowel disease (IBD). The efficacy of this treatment is based on the production of 6-thioguanine nucleotides, but extremely elevated levels may cause bone marrow suppression. Other azathioprine metabolites, 6-methylmercaptopurine ribonucleotides, are associated with hepatotoxicity. Therapeutic drug monitoring (TDM) may be of help in optimising azathioprine treatment, but data on TDM in established azathioprine therapy are lacking. We therefore measured metabolite levels in a small cohort of patients established on azathioprine therapy. PATIENTS AND METHODS: 6-Thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP) levels in erythrocytes were measured in 15 IBD outpatients established on azathioprine therapy for at least 3 months at baseline and 1, 4 and 8 weeks after inclusion (mean duration of treatment 28 months; range 7-67 months). Disease activity was evaluated by the Crohn's Disease Activity Index (Crohn's disease) or Truelove-Witts (ulcerative colitis) scores. Metabolite levels were measured by modified high-performance liquid chromatography assay (HPLC). Primary outcome measures were 6-TGN and 6-MMP metabolite levels and 95% confidence intervals (CIs). SECONDARY OUTCOMES were correlations between metabolite levels, drug dose, disease activity and laboratory parameters and compliance. RESULTS: One patient had active disease during the study period. Eleven of 15 patients (73%) completed the 8-week study period. Dropout reasons were noncompliance in three patients (20%) and intolerance in one patient (7%). PRIMARY OUTCOMES: At baseline mean 6-TGN levels were 158 (95% CI 113, 203) pmol/8.10(8) RBC (red blood cells), steadily increasing over the 8-week study period, but not significantly. Two patients had zero levels. Another two had significantly increasing levels also suggesting noncompliance. Mean 6-MMP levels showed almost a similar pattern. At baseline, levels were 2213 (95% CI 722, 3704) pmol/8.10(8) RBC. SECONDARY OUTCOMES: A correlation was found between all RBC 6-MMP levels and azathioprine dose (mg/kg bodyweight) [r = 0.43, p = 0.001] and also between the 6-MMP/6-TGN ratio and azathioprine dose (mg/kg) [r = 0.36, p = 0.010). There was no correlation between RBC 6-TGN or 6-MMP levels and haematological parameters or disease activity scores. No hepatic, pancreatic or myelotoxicity occurred.Thirteen of 15 patients (87%) had baseline steady-state 6-TGN levels below the therapeutic threshold of 235 pmol/8.10(8) RBC. Forty percent (6/15) of our patients were noncompliant; TDM revealed this noncompliance in four of the six patients (27% of all patients). CONCLUSION: Our small study demonstrates that TDM may provide insight into individual pharmacokinetics. However, TDM does not seem to be useful in patients with IBD established on azathioprine therapy and without disease activity, although it may be helpful in cases of worsening IBD activity to elucidate noncompliance or inefficient treatment.

The outcome of esophagogastroduodenoscopy (EGD) in asymptomatic outpatients with iron deficiency anemia after a negative colonoscopy.

Background: Both iron deficiency and iron deficiency anemia require extensive investigation because of their possible association with gastrointestinal malignancy. If no other sources of blood loss are apparent, the gastrointestinal tract is examined to detect sources of occult blood loss. In the absence of gastrointestinal symptoms, the colon is first examined, especially in the elderly. The aim of this study was to determine the outcome of esophagogastroduodenoscopy (EGD) after a prior negative colonoscopy in outpatients without gastrointestinal complaints, referred due to iron deficiency anemia. Methods: Thirty-five patients (22 female and 13 male) with a median age of 71 years were studied over a 2-year period. Anemia was defined as a hemoglobin (Hb) level below 7.4 mmol/l in women or below 8.0 mmol/l in men and iron deficiency if one of the following was present: ferritin level equal to or below 20 µg/l for men and equal to or below 10 µg/l for women, a serum iron concentration equal to or below 45 µg/dl (8.1 µmol/l) with a transferrin saturation of 10% or less, or the absence of iron stores in bone marrow biopsy specimens. Patients with prior gastrointestinal disease or surgery, gastrointestinal symptoms, or other obvious causes of blood loss were excluded. Lesions that were considered to be potential sources of blood loss were clearly defined. Results: The mean Hb level of the 35 patients studied was 5.5 mmol/l (range 1.8-7.8 mmol/l). Abnormalities were found in 10 patients (28.6%), all of which were benign. Erosive and ulcerative lesions in the stomach, in a hiatal hernia, or in the esophagus were diagnosed in eight patients, benign villous adenoma was seen in one patient, and celiac disease in another, although duodenal biopsies were taken in only 15 patients. Erosions and/or ulcerations were found in four of 11 patients (36%) using NSAIDs and/or salicylates (ASA). Seventy percent of the lesions were found in elderly patients (>65 years), 56% of whom were using NSAIDs and/or ASA. Conclusions: EGD should always be performed in patients with iron deficiency anemia after a negative colonoscopy, although upper gastrointestinal malignancy will probably be an infrequent finding. The presence of a significant, treatable lesion is most likely in the elderly and in those with a history of NSAID or ASA use. Routine duodenal biopsies should be performed to further increase the outcome of EGD.

High incidence of inflammatory bowel disease in The Netherlands: results of a prospective study. The South Limburg IBD Study Group.

PURPOSE: To gain recent epidemiologic information about inflammatory bowel disease in The Netherlands, a prospective study over four years (1991-1995) was performed. METHODS: The incidence of inflammatory bowel disease and its subgroups was examined using standardized reports of newly diagnosed patients. A separate study compared the Inflammatory Bowel Disease Registration and computerized diagnostic files of a subgroup of general practitioners with the aim of estimating completeness of case ascertainment. RESULTS: The following mean incidence rates (per 100,000 inhabitants and year) were found: 6.9 (95 percent confidence interval, 5.9-7.9) for Crohn's disease, 10 (95 percent confidence interval, 8.7-11.2) for ulcerative colitis (23 percent of these with ulcerative proctitis), and 1.1 (95 percent confidence interval, 0.7-1.5) for indeterminate colitis. In the age category 20 to 29 years, the incidence rate of Crohn's disease with small-bowel involvement was higher in females than in males. In extended ulcerative colitis, a male preponderance was observed in the older age groups. Estimated case ascertainment was 78 percent. CONCLUSIONS: Compared with recent studies in neighboring countries, the observed age and gender standardized incidence rates are high in the south of The Netherlands. Completeness of case ascertainment might have contributed to this observation; however, case ascertainment was low in ulcerative proctitis. In the study area, differences in age and gender standardized incidence rates and in disease localizations could be compatible with an influence of environmental risk factors.

An uncommon cause of anaemia in ulcerative colitis.

A 56-year-old woman is reported with severe ulcerative colitis who developed a corticosteroid-resistant haemolytic anaemia. The pathogenesis and treatment options in ulcerative-colitis-related haemolytic anaemia are discussed.

Crohn's disease of the appendix.

Two patients with Crohn's disease confined to the appendix are described. The condition may present as acute appendicitis or appendiceal infiltrate. Therapy of either manifestation includes appendectomy. Concurrent Crohn's disease elsewhere in the gastrointestinal tract may be found in 25 per cent of the patients. A recurrence rate of 10 to 15 per cent in the remaining patients justifies a follow-up of some three years.

Ursodeoxycholic acid treatment in a patient with primary biliary cirrhosis.

A women with stage I-II primary biliary cirrhosis was treated with ursodeoxycholic acid (UDCA). During UDCA treatment a notable improvement in biochemical liver profile was achieved. Liver histology did not deteriorate after one year UDCA. UDCA offers a promising non-toxic alternative in the treatment of PBC.

Efficacy of diltiazem in the treatment of diffuse oesophageal spasm.

Calcium antagonist relax smooth muscle, a possible useful concept in treatment of diffuse oesophageal spasm. Therefore the effects of oral diltiazem (60 mg t.d.s.) and placebo were compared in eight patients with diffuse oesophageal spasm in a 10-week double-blind crossover study. The patients recorded the severity of chest pain and/or dysphagia in daily pain diaries using visual analogue scales. Chest pain index and dysphagia index were calculated by multiplying frequency with daily intensity of each individual symptom. When compared to placebo, diltiazem did not significantly change the overall dysphagia index and chest pain index. An individual sizeable reduction of dysphagia was attained on diltiazem in four out of six patients and in six out of eight patients suffering from chestpain. Side effects were not seen during diltiazem therapy. Diltiazem, in our study, did not yield in a significant improvement of symptoms in diffuse oesophageal spasm. Diltiazem, however, can offer relief in selected individual patients suffering from diffuse oesophageal spasm.

Sucralphate-technetium scintigraphy in inflammatory bowel disease: experience in 23 patients.

Serial abdominal scanning after the oral administration of sucralphate-99mTc was performed in order to determine the extent of active inflammatory bowel disease in 15 patients with Crohn's disease and in 8 patients with ulcerative colitis. Scintigraphic data were compared with those obtained by endoscopy and radiology in all patients. True positive scans were obtained in 6 (40%) patients with Crohn's disease and in 3 (38%) patients with ulcerative colitis. Overall, sensitivity was higher in colonic disease than that in ileal disease. In 4 (17%) patients, false negative scans were obtained and in the remaining 10 (44%) patients, localisation of the inflammatory bowel disease by the isotope was completely inaccurate. Since sensitivity of the sucralphate-99mTc scintigraphy appears to be low, its widespread use in the screening for inflammatory bowel disease or in assessing the extent of disease involvement cannot be advocated at this moment.

Clinical relevance of lysozyme in the faeces.

To elucidate the value of faecal lysozyme determination in the differential diagnosis of patients with atypical abdominal complaints, stool samples of healthy controls, patients with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) were analysed. Faecal lysozyme concentration in healthy controls ranged from 0 to 6 mg/l with a mean of 3 mg/l. Patients with IBS had similar faecal lysozyme levels. In contrast, faecal lysozyme concentrations in patients with IBD were increased (range 6 to 104 mg/l). The difference between patients with IBS and IBD was highly significant (P less than 0.001). The determination of faecal lysozyme concentration may provide a useful test in the work-up of patients with abdominal complaints. In addition, the faeces lysozyme concentration appeared to be an objective parameter of the inflammatory activity of IBD in 11 patients investigated.

Faecal lysozyme: determination, reference intervals and some data in gastro-intestinal disease.

After diluting faecal samples with a solution of Brij and saline and subsequently ultrafiltrating the faecal mixtures, lysozyme concentration can be reproducibly measured in the obtained faecal fluids, using a turbidimetric method. Measuring faecal lysozyme concentration enables discrimination normal individuals and patients with irritable bowel syndrome between patients with inflammatory bowel disease and colonic cancer. Lysozyme distribution in stools appears to be homogeneous. Faecal lysozyme concentration is stable when samples are stored during at least 1 wk at 6 degrees C. It appears that the lysozyme activity is directly correlated with the clinical status and severity of the disease. Faecal lysozyme may thus serve as an important tool both in diagnosis and in follow-up in the out-patients clinic for gastroenterology.

A new method for chemical analysis of faeces.

By using a centriflo membrane cone filter it has become possible to obtain an ultrafiltrate from a 24-h stool specimen. In this faecal fluid several clinical chemical parameters were analysed, such as pH, osmolality, creatinine, sodium, potassium, calcium, magnesium, chloride, bicarbonate, phosphate and lactate. Reference intervals for these substances were obtained in healthy individuals. The data of this control group were compared to those of patients with diarrhoea due to active inflammatory bowel disease, irritable bowel syndrome, lactose intolerance and persons with an ileostomy.

Energy intake and the appearance of 5,8,11-eicosatrienoic acid in serum lipids during parenteral nutrition without fat.

During parenteral nutrition without fat, biochemical changes in fatty acid composition of serum lipids may occur, such as a decrease in the concentration of linoleic and arachidonic acid and an increase of 5,8,11-eicosatrienoic acid. In various reports on essential fatty acid deficiency in parenteral nutrition, the rates and degrees of these changes in fatty acid composition of serum lipids are different. We have tested the hypothesis that a relationship exists between the energy intake and the increase in 5,8,11-eicosatrienoic acid in parenteral nutrition without fat. The hypothesis is based on the assumption that mobilization of lipids from body fat, and thus of stored essential fatty acids, only takes place when energy intake is below requirements. Seventeen patients with gastrointestinal diseases were fed parenterally without fat during 1 to 5 weeks (mean 3.5 week). The energy supply to the patients varied from 88 to 222 kilo Joules per kilogram per day. In all patients, the fatty acid pattern of the serum phospholipid fraction was determined weekly. It appeared that those patients with the highest energy intake per kilogram body weight showed the lowest increase in 5,8,11-eicosatrienoic acid. In ten patients, energy was given as glucose and fructose, in seven patients as sorbitol. The type of carbohydrate investigated did not influence the changes in the fatty acid pattern. Results show further that the individual values of the concentrations of 5,8,11-eicosatrienoic acid and of arachidonic acid provide more information concerning the essential fatty acid status of a patient than the commonly used ratio of these two fatty acids.

Total parenteral nutrition in Crohn's disease.

A personal experience involving use of total parenteral nutrition in 115 patients with Crohn's disease is reported from a medical unit. Remission occurred without surgery in 24 patients. The regimen was considered to have failed in its objectives in 50 patients, and complications were recorded in 57.

Simultaneous and consecutive administration of nutrients in parenteral nutrition.

In seven patients, six with Crohn's disease and one with pancreatitis, two methods of parenteral nutrition were compared: the partial consecutive administration of the components of a parenteral nutrition regimen versus the administration of all nutrients simultaneously. With respect to the consecutive regimen, the simultaneous infusion regimen gave an improvement in the nitrogen balance of 13% and a decrease in urinary lactic acid of about 50%. Urinary excretion of alpha-amino nitrogen, glucose, and fructose was very small in both cases but was slightly lower during the simultaneous infusion regimen. The improvement in the nitrogen balance attained with the simultaneous infusion regimen can be explained by the fact that infused nutrients, especially carbohydrates, cause fewer metabolic disturbances. The simultaneous infusion regimen has three other advantages. The patients rarely complain of headache and nausea, the infusion regimen is markedly simplified and the risk of contamination when nutrients are added to the infusion bottles in the ward is considerably diminished.

Skin lesions in acquired zinc deficiency due to parenteral nutrition.

The skin lesions seen in 10 patients who received parenteral nutrition during treatment of chronic enteropathy are described. All of these patients had a lowered serum zinc concentration. The skin lesions were similar to those seen in acrodermatitis enteropathica. After supplementation with zinc sulphate, the skin lesions disappeared completely. A decrease in the serum alkaline phosphatase level can be regarded as a sign of an impending zinc deficiency. Parenteral nutrition formulae should contain a sufficient amount of zinc.