• Crohn's disease
• Nodular regenerative hyperplasia
• Thiopurine
• Tioguanine
• Ulcerative colitis

• Humans
• Thioguanine/adverse effects
• Hyperplasia
• Retrospective Studies
• Prospective Studies
• Inflammatory Bowel Diseases/drug therapy

• Autoimmune pancreatitis
• Extra-hepatic cholangiocarcinoma
• Immunoglobulin G4 sclerosing cholangitis

• Thioguanine
• dermatology
• drug Rediscovery
• drug-induced liver injury
• gastroenterology
• hematology
• inflammatory Bowel Disease
• rheumatology
• thiopurines

• Antimetabolites, Antineoplastic/administration & dosage
• Antimetabolites, Antineoplastic/adverse effects
• Antimetabolites, Antineoplastic/pharmacokinetics
• Dose-Response Relationship, Drug
• Humans
• Leukemia/drug therapy
• Thioguanine/administration & dosage
• Thioguanine/adverse effects
• Thioguanine/pharmacokinetics

• Cholelithiasis
• Drug induced liver injury
• Hepatitis viruses
• Inflammatory bowel diseases
• Primary sclerosing cholangitis

The recently established association between higher levels of DNA-incorporated thioguanine nucleotides and lower relapse risk in childhood acute lymphoblastic leukaemia (ALL) calls for reassessment of prolonged 6-thioguanine (6TG) treatment, while avoiding the risk of hepatotoxicity.

To assess the incidence of hepatotoxicity in patients treated with 6TG, and to explore if a safe dose of continuous 6TG can be established.

Databases, conference proceedings, and reference lists of included studies were systematically searched for 6TG and synonyms from 1998–2018.

We included studies of patients with ALL or inflammatory bowel disorder (IBD) treated with 6TG, excluding studies with 6TG as part of an intensive chemotherapy regimen. We uploaded a protocol to PROSPERO (registration number CRD42018089424). Database and manual searches yielded 1823 unique records. Of these, 395 full-texts were screened for eligibility. Finally, 134 reports representing 42 studies were included.

We included data from 42 studies of ALL and IBD patients; four randomised controlled trials (RCTs) including 3,993 patients, 20 observational studies including 796 patients, and 18 case reports including 60 patients. Hepatotoxicity in the form of sinusoidal obstruction syndrome (SOS) occurred in 9–25% of the ALL patients in two of the four included RCTs using 6TG doses of 40–60 mg/m²/day, and long-term hepatotoxicity in the form of nodular regenerative hyperplasia (NRH) was reported in 2.5%. In IBD patients treated with 6TG doses of approximately 23 mg/m²/day, NRH occurred in 14% of patients. At a 6TG dose of approximately 12 mg/m²/day, NRH was reported in 6% of IBD patients, which is similar to the background incidence. According to this review, doses at or below 12 mg/m²/day are rarely associated with notable hepatotoxicity and can probably be considered safe.

• Antimetabolites, Antineoplastic/adverse effects
• Antimetabolites, Antineoplastic/therapeutic use
• Chemical and Drug Induced Liver Injury/diagnosis
• Chemical and Drug Induced Liver Injury/etiology
• Chemical and Drug Induced Liver Injury/therapy
• Humans
• Inflammatory Bowel Diseases/complications
• Inflammatory Bowel Diseases/drug therapy
• Liver/drug effects
• Liver/pathology
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
• Publication Bias
• Thioguanine/adverse effects
• Thioguanine/therapeutic use

• Harnessing microbial strategies for treatment of human disease
• Role of commensal flora in GI diseases
• Role of gut microbiome in GI disease
• colitis
• microbiome
• phagocytosis
• purine salvage
• thioguanine

• clinical trial
• inflammatory bowel diseases
• remission
• thioguanine
• treatment

• drug-induced liver injury
• hepatotoxicity
• inflammatory bowel disease
• liver disease
• primary sclerosing cholangitis

Thiopurines are essential drugs to maintain remission in patients with inflammatory bowel disease (IBD). Thiopurines used in IBD are azathioprine (2.0-2.5 mg/kg), mercaptopurine (1.0-1.5 mg/kg) and thioguanine (0.2-0.3 mg/kg). However, mainly due to numerous adverse events associated with thiopurine use, almost 50% of the patients have to discontinue conventional thiopurine treatment. Extensive monitoring and the application of several treatment strategies, such as split-dose administration, co-administration with allopurinol or dose reduction/increase, may increase the chance of successful therapy. With this review, we provide practical information on how thiopurines are initiated and maintained in two thiopurine research centers in The Netherlands. We provide clinical information concerning safety issues, indications and management of therapy that may serve as a guide for the administration of thiopurines in IBD patients in daily practice.

• Thiopurines
• Azathioprine
• Mercaptopurine
• Thioguanine
• Inflammatory bowel disease
• Therapeutic drug monitoring
• Pregnancy
• Metabolites

• Crohn’s disease
• Inflammatory bowel disease
• Thioguanine
• Thiopurines
• Ulcerative colitis

• Antimetabolites, Antineoplastic/therapeutic use
• Humans
• Inflammatory Bowel Diseases/drug therapy
• Thioguanine/therapeutic use

Nodular regenerative hyperplasia (NRH) of the liver is associated with several diseases and drugs. Clinical symptoms of NRH may vary from absence of symptoms to full-blown (non-cirrhotic) portal hypertension. However, diagnosing NRH is challenging. The objective of this study was to determine inter- and intraobserver agreement on the histopathologic diagnosis of NRH.

Liver specimens (n=48) previously diagnosed as NRH, were reviewed for the presence of NRH by seven pathologists without prior knowledge of the original diagnosis or clinical background. The majority of the liver specimens were from thiopurine using inflammatory bowel disease patients. Histopathologic features contributing to NRH were also assessed. Criteria for NRH were modified by consensus and subsequently validated. Interobserver agreement was evaluated by using the standard kappa index.

After review, definite NRH, inconclusive NRH and no NRH were found in 35% (23-40%), 21% (13-27%) and 44% (38-56%), respectively (median, IQR). The median interobserver agreement for NRH was poor (κ = 0.20, IQR 0.14-0.28). The intraobserver variability on NRH ranged between 14% and 71%. After modification of the criteria and exclusion of biopsies with technical shortcomings, the interobserver agreement on the diagnosis NRH was fair (κ = 0.45).

The interobserver agreement on the histopathologic diagnosis of NRH was poor, even when assessed by well-experienced liver pathologists. Modification of the criteria of NRH based on consensus effort and exclusion of biopsies of poor quality led to a fairly increased interobserver agreement. The main conclusion of this study is that NRH is a clinicopathologic diagnosis that cannot reliably be based on histopathology alone.

• Biopsy
• Humans
• Hyperplasia
• Hypertension, Portal/pathology
• Liver/pathology
• Liver/physiopathology
• Liver Diseases/diagnosis
• Liver Diseases/pathology
• Liver Diseases/physiopathology
• Observer Variation
• Regeneration

Thiopurines are widely used for maintenance treatment of inflammatory bowel disease. Inter-individual variability in clinical response to thiopurines may be attributed to several factors including genetic polymorphisms, severity and chronicity of disease, comorbidities, duration of administration, compliance issues and use of concomitant medication, environmental factors and clinician and patient preferences. The purpose of this review is to summarise the current evidence on thiopurine safety and toxicity, to describe adverse drug events and emphasise the significance of drug interactions, and to discuss the relative safety of thiopurine use in adults, elderly patients, children and pregnant women. Thiopurines are safe to use and well tolerated, however dose adjustment or discontinuation of treatment must be considered in cases of non-response, poor compliance or toxicity. Drug safety, clinical response to treatment and short to long term risks and benefits must be balanced throughout treatment duration for different categories of patients. Treatment should be individualised and stratified according to patient requirements. Enzymatic testing prior to treatment commencement is advised. Surveillance with regular clinic follow-up and monitoring of laboratory markers is important. Data on long term efficacy, safety of thiopurine use and interaction with other disease modifying drugs are lacking, especially in paediatric inflammatory bowel disease. High quality, collaborative clinical research is required so as to inform clinical practice in the future.

• Thiopurines
• Azathioprine
• Mercaptopurine
• Inflammatory bowel disease
• Adult
• Children
• Therapeutic drug monitoring

• Capillarization
• endotheliopathy
• portal hypertension

The use of thiopurines as immunosuppression for the treatment of refractory or chronic active inflammatory bowel disease is established for both Crohn's disease and ulcerative colitis. Nevertheless, many questions remain concerning the optimal treatment regimens of azathioprine, 6-mercaptopurine and thioguanine. We will briefly summarize dose recommendations, indications for thiopurine therapy and side effects which are relevant in clinical practice. We discuss some currently debated topics, including the combination of azathioprine and allopurinol, switching of thiopurine therapy in case of side effects, the use of azathioprine in pregnancy, the infection risk using thiopurines and the evidence when to stop thiopurines. Excellent reviews have been published on the thiopurine metabolic pathway which will not be discussed here in detail.

• Thiopurines
• Inflammatory bowel disease
• Crohn’s disease
• Ulcerative colitis
• Immunosuppression
• Infection

The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine, are efficacious in the arsenal of inflammatory bowel disease (IBD) therapy. Previous reports indicate that 6-thioguanine nucleotide (6-TGN) levels correlate with therapeutic efficacy, whereas high 6-methylmercaptopurine (6-MMP) levels are associated with hepatotoxicity and myelotoxicity. Due to their complex metabolism, there is wide individual variation in patient response therein, both in achieving therapeutic drug levels as well as in developing adverse reactions. Several strategies to optimize 6-TGN while minimizing 6-MMP levels have been adopted to administer the thiopurine class of drugs to patients who otherwise would not tolerate these drugs due to side-effects. In this report, we will review different approaches to administer the thiopurine medications, including the administration of 6-mercaptopurine in those unsuccessfully treated with azathioprine; co-administration of thiopurine with allopurinol; co-administration of thiopurine with anti-tumor necrosis factor α; 6-TGN administration; desensitization trials; and split dosing of 6-MP.

• Azathioprine
• Drug levels
• Inflammatory bowel disease
• 6-Mercaptopurine
• Thiopurine

Nodular regenerative hyperplasia (NRH) is a rare liver condition characterized by a widespread benign transformation of the hepatic parenchyma into small regenerative nodules. NRH may lead to the development of non-cirrhotic portal hypertension. There are no published systematic population studies on NRH and our current knowledge is limited to case reports and case series. NRH may develop via autoimmune, hematological, infectious, neoplastic, or drug-related causes. The disease is usually asymptomatic, slowly or non-progressive unless complications of portal hypertension develop. Accurate diagnosis is made by histopathology, which demonstrates diffuse micronodular transformation without fibrous septa. Lack of perinuclear collagen tissue distinguishes NRH from typical regenerative nodules in the cirrhotic liver. While the initial treatment is to address the underlying disease, ultimately the therapy is directed to the management of portal hypertension. The prognosis of NRH depends on both the severity of the underlying illness and the prevention of secondary complications of portal hypertension. In this review we detail the epidemiology, pathogenesis, diagnosis, management, and prognosis of NRH.

• Nodular regenerative hyperplasia
• Portal hypertension
• Comorbidities