thioguanine-anhydrous and Focal-Nodular-Hyperplasia

Conventional thiopurines are effective for the maintenance of remission of Crohn's disease and ulcerative colitis, however, up to half of patients are intolerant or unresponsive to these medications. Thioguanine is an alternative thiopurine that has shown efficacy in inflammatory bowel disease, and is particularly useful to circumvent certain side effects associated with conventional thiopurines, for example, pancreatitis. Its association with nodular regenerative hyperplasia of the liver has hindered its widespread use. Areas covered: We aim to outline the rational use of thioguanine, including safety monitoring, with particular regard to hepatotoxicity. A literature search was performed: PubMed was searched for full papers and abstracts published in English since January 2000 using the following terms, alone and in combination: 'azathioprine', 'thiopurine', 'Crohn's disease', 'inflammatory bowel disease', 'nodular regenerative hyperplasia', 'mercaptopurine', 'thioguanine', 'ulcerative colitis'. Further relevant papers were identified from the reference lists of selected papers. Expert commentary: Despite optimisation strategies such as metabolite measurements and the use of allopurinol, a significant proportion of patients will remain intolerant to thiopurines, especially those with allergic reactions, including pancreatitis. For this subgroup of patients we suggest that low dose thioguanine is an alternative to other therapies that are either parenteral or expensive.

Topics: Animals; Antimetabolites; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Crohn Disease; Drug Monitoring; Focal Nodular Hyperplasia; Gastrointestinal Agents; Humans; Pancreatitis; Risk Factors; Thioguanine; Treatment Outcome

Nodular regenerative hyperplasia (NRH) is increasingly being recognised in patients with inflammatory bowel disease (IBD). However, the pathogenesis and incidence of NRH in IBD, and the putative roles played by azathioprine (AZA), mercaptopurine (MP), or tioguanine (TG) remain unclear.. To summarise the data on the association between NRH and thiopurine therapy in patients with IBD.. A literature search was performed in PubMed and MEDLINE databases using the keywords 'nodular regenerative hyperplasia AND (inflammatory bowel disease OR Crohn's disease OR ulcerative colitis) AND (azathioprine OR mercaptopurine OR tioguanine OR thioguanine).' No time limit was placed on studies included.. Inflammatory bowel disease patients treated with AZA have a cumulative incidence of NRH of approximately 0.6% and 1.28% at 5 and 10 years, respectively, whereas those treated with high-dose TG (>40 mg/day) have a frequency of NRH of up to 62%, which is higher in patients with elevated liver enzymes and/or thrombocytopaenia than those without these abnormalities (frequency 76% vs. 33%). Conversely, low-dose TG therapy (<20 mg/day) is relatively safe, with no cases of NRH observed. NRH has also been found in 6% of operated thiopurine-naïve IBD patients. Male gender, older age, and stricturing disease/small bowel resection have been consistently identified as high-risk factors for NRH.. The pathogenesis of nodular regenerative hyperplasia in patients with IBD is complex and multifactorial involving disease-specific, genetic and iatrogenic risk factors. Clinicians should maintain a high index of suspicion for diagnosing nodular regenerative hyperplasia, especially in IBD patients with high-risk factors on thiopurine therapy, regardless of the presence of laboratory abnormalities.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Focal Nodular Hyperplasia; Humans; Immunosuppressive Agents; Incidence; Male; Mercaptopurine; Risk Factors; Thioguanine; Time Factors

Topics: Adult; Biopsy; Chemical and Drug Induced Liver Injury; Cohort Studies; Disease Progression; Female; Focal Nodular Hyperplasia; Humans; Hypertension, Portal; Inflammatory Bowel Diseases; Liver; Male; Middle Aged; Netherlands; Thioguanine

Nodular regenerative hyperplasia (NRH) of the liver is associated with inflammatory-mediated diseases and certain drugs. There is conflicting data on the prevalence of NRH and its clinical implications in inflammatory bowel disease (IBD) patients treated with thioguanine.. A retrospective cohort study involving 7 Dutch centers comprised all IBD patients who were being treated with thioguanine and underwent a liver biopsy as part of the standard toxicity screening. Liver biopsy specimens were reviewed by 2 experienced liver pathologists. Clinical data as well as liver chemistry, blood counts, and abdominal imaging were collected.. One hundred eleven IBD patients who submitted to liver biopsy were treated with thioguanine in a daily dose of 0.3 mg/kg for a median duration of 20 (4-64) months. NRH was detected in 6% of patients (7; 95% confidence interval, 3-14 patients). Older age (P = 0.02), elevated gamma-glutamyl transferase (P = 0.01) and alkaline phosphatase (P = 0.01) levels, a higher mean corpuscular volume (P = 0.02), and a lower platelet or leukocyte count (P < 0.01 and P = 0.02, respectively) were associated with NRH. Three of the 7 patients with NRH did not have any associated clinical symptoms or signs. The other 4 had minor biochemical abnormalities only. Ultrasonography revealed splenomegaly in 3 of the 78 patients (4%; 95% confidence interval, 0%-9%), only one of whom had NRH. There was no clinically overt portal hypertension.. The prevalence of NRH was 6% in liver biopsies obtained from IBD patients treated with thioguanine. Histopathological irregularities including NRH were not associated with clinically significant findings over the period of observation.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Chemical and Drug Induced Liver Injury; Female; Focal Nodular Hyperplasia; Humans; Inflammatory Bowel Diseases; Liver; Logistic Models; Male; Middle Aged; Multivariate Analysis; Netherlands; Retrospective Studies; Splenomegaly; Thioguanine; Ultrasonography; Young Adult

The aim of this study was to evaluate the diagnostic value of different magnetic resonance (MR) techniques for the diagnosis of nodular regenerative hyperplasia (NRH). Thirty-one patients with inflammatory bowel disease, who received 6-thioguanin, underwent liver biopsy and liver MRI on a 1.5-T MR system, with gadolinium and superparamagnetic iron oxide particles (SPIO). MR imaging (MRI) was evaluated independently as well as in consensus by two blinded readers, who received the following image sets: pre-contrast; pre-contrast and gadolinium-enhanced; pre-contrast and SPIO-enhanced and all images. The results were correlated with histopathology and diagnostic efficacy parameters were calculated. NRH was found in 13/31 patients. The set "all images" showed the highest sensitivity (84.6%), accuracy (77.4%) and negative predictive value (86.7%). However, results for gadolinium were only slightly inferior. The highest specificity (76.5%) was found for SPIO. The A(z) values of both readers were highest for gadolinium (mean A(z) = 0.824). It can be concluded that gadolinium-enhanced and SPIO-enhanced MRI enable an accurate diagnosis of NRH. Since gadolinium-enhanced MRI is very sensitive, it should be used for screening high-risk patients. SPIO-enhanced MRI is less sensitive, but more specific. The combination of both guarantees a high sensitivity and specificity and, therefore, is the diagnostic procedure of choice.

Topics: Adult; Biopsy, Needle; Contrast Media; Dextrans; Female; Ferrosoferric Oxide; Focal Nodular Hyperplasia; Gadolinium DTPA; Humans; Image Enhancement; Image Processing, Computer-Assisted; Inflammatory Bowel Diseases; Iron; Liver; Liver Regeneration; Magnetic Resonance Imaging; Magnetite Nanoparticles; Male; Meglumine; Middle Aged; Organometallic Compounds; Oxides; Thioguanine

Recent studies suggest an association between 6-thioguanine (6-TG) therapy and hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD). An influence of 6-TG on portal pressure remains to be determined. The aim of the study was to examine the functional relevance of long-term 6-TG treatment on hepatic hemodynamics in IBD patients and its association with NRH.. Patients treated with 6-TG for IBD underwent measurement of the hepatic venous pressure gradient (HVPG) and liver biopsy. 6-TG therapy was stopped when NRH was diagnosed. If elevated, HVPG measurement was repeated after 1 yr.. Twenty-six patients (15 women, 11 men; median age 41 yr, range 23-76) treated with 6-TG for 38 months (median; range 12-45) were included. Among 24 patients with sufficient liver biopsy, 6 patients (25%) were diagnosed with NRH. In these 6 patients, the HVPG was higher (median HVPG 7 mmHg, range 3-14) than in the 18 patients without NRH (median 3 mmHg, range 2-5; P < 0.001). In the patients with NRH, two had clinically significant portal hypertension (CSPH) (13 and 14 mmHg, respectively); in one patient the HVPG was slightly elevated (7 mmHg). No overt clinical signs of portal hypertension were observed. One year after stopping 6-TG therapy, HVPG decreased in all 3 patients with initially elevated HVPG levels.. We demonstrate that IBD patients under long-term 6-TG therapy are at a substantial risk for developing NRH. NRH results in elevation of HVPG and may cause CSPH. Discontinuation of 6-TG therapy extenuates portal hypertension and may thus reduce the risk of complications.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Biopsy; Female; Focal Nodular Hyperplasia; Humans; Hypertension, Portal; Inflammatory Bowel Diseases; Male; Middle Aged; Statistics, Nonparametric; Thioguanine

Drug-induced liver injury was recently reported as a major complication leading to hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD) and 6-thioguanine (6-TG) therapy. The aim of the study was to evaluate the prevalence of 6-TG-related hepatotoxicity in a large multi-centered IBD population by means of a systematic online survey.. Clinical and laboratory data, imaging techniques (sonography, CT, MRI) and histology of liver biopsies were surveyed in IBD patients treated with 6-TG. The decision on whether liver imaging and/or liver biopsy were performed was exclusively at the discretion of the investigator.. 6-TG use was fully documented in 296 patients (median treatment duration 56 weeks, range < 1-207). Laboratory signs of drug-induced liver injury were found in 43 patients (14.5%). Liver imaging revealed pathologic results in 68/176 patients (38.6%). Liver biopsy was performed in a subset of 60 patients; using silver-reticulin staining (n = 59), NRH was considered in 16 patients (27.1%). Age was the only independent, albeit weak, risk factor for development of NRH.. This large online survey confirms the strong association between 6-TG treatment and the significant risk of development of NRH in patients with IBD. The definitive diagnosis of NRH depends solely upon liver biopsy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biopsy; Child; Data Collection; Data Interpretation, Statistical; Female; Focal Nodular Hyperplasia; Humans; Inflammatory Bowel Diseases; Internet; Liver; Magnetic Resonance Imaging; Male; Middle Aged; Risk Factors; Smoking; Surveys and Questionnaires; Thioguanine; Treatment Outcome; Ultrasonography

6-Thioguanine (6-TG) has been used as an alternative thiopurine for inflammatory bowel disease (IBD) patients not responsive to or intolerant of azathioprine (AZA) and 6-mercaptopurine (6-MP). 6-TG-related hepatotoxicity, including liver biochemistry value elevations, sinusoidal collagen deposition on electron microscopy, and veno-occlusive disease, have been described related to its use as therapy for neoplastic disease.. We studied 38 liver biopsies from patients treated with 6-TG, almost all of whom (n = 125) received 6-TG for 1 to 3 years at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center. All biopsies were fixed in 4% buffered formalin and prepared in the usual manner. Hematoxylin and eosin, Masson's trichrome (trichrome), and reticulin silver impregnation (reticulin) stained slides were studied. In 23 cases, tissue was also prospectively fixed in glutaraldehyde and processed for electron microscopy.. In 20 of the 37 patients studied (53%), nodular regeneration of varying degree was seen with reticulin. In only 4 of these 20 instances (11% of the total) were the changes seen with hematoxylin and eosin and in 3 of the 4, only in retrospect after studying the reticulin preparation. Minimal fibrosis was seen with trichrome in only 13 biopsies (34%), but sinusoidal collagen deposition was observed in 14 of the 23 cases studied with electron microscopy (60%). The biopsy from the 1 patient with nodular hyperplasia obvious with hematoxylin and eosin also demonstrated changes of venous outflow obstruction.. 6-TG-treated IBD patients are at significant risk for nodular hyperplasia, early fibrosis and, less often, venous outflow disease (Budd-Chiari). The natural history of these changes is unknown and follow-up biopsies are needed to determine histologic and clinical sequela. Patients not demonstrating nodular hyperplasia or fibrosis who continue with 6-TG because there are no better therapeutic choices should be periodically rebiopsied.

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Child; Female; Focal Nodular Hyperplasia; Humans; Inflammatory Bowel Diseases; Liver Cirrhosis; Male; Microscopy, Electron; Middle Aged; Thioguanine; Time Factors