Thioguanine (also referred to as 6-thioguanine and as tioguanine) is a purine analogue that is used in the therapy of acute and chronic myelogenous leukemias. Thioguanine therapy is associated with minor, usually transient and asymptomatic elevations in serum aminotransferase levels and has also been linked to rare instances of cholestatic acute liver injury and to chronic liver injury, resulting in portal hypertension due to nodular regenerative hyperplasia.
Thioguanine (thye" oh gwa' neen) is a thiopurine, a purine analogue and antimetabolite. It is a derivative of mercaptopurine (2-amino-6-mercaptopurine) and, like its parent molecule, inhibits purine metabolism, thus blocking DNA, RNA and subsequent protein synthesis. Thioguanine also has antiinflammatory activity. Thioguanine was approved for use in the United States in 1966 and is commonly used in the therapy of acute and chronic myelogenous (nonlymphocytic) leukemias. Thioguanine has also been used off-label to treat autoimmune diseases as a steroid sparing agent. Thioguanine is available generically and under the brand name of Tabloid as tablets of 40 mg. The usual dose is 1 to 3 mg per kilogram or 40 to 120 mg daily and it is typically given long term. Common side effects include nausea, abdominal upset, rash, aphthous ulcers and dose related bone marrow suppression.
As with other thiopurines, thioguanine has been associated with several forms of hepatotoxicity, including mild, transient and asymptomatic rises in serum aminotransferase levels, an acute hepatic injury developing during the first year of starting therapy, and a chronic hepatic injury marked by variable degrees of peliosis hepatis, veno-occlusive disease and/or nodular regenerative hyperplasia. Chronic injury typically arises 1 to 5 years after starting thioguanine and can present insidiously with signs and symptoms of portal hypertension.
Mild serum aminotransferase elevations can occur during thioguanine therapy, particularly with high doses during the first 12 weeks of therapy. These elevations are generally asymptomatic, benign and self-limited, resolving rapidly either with stopping therapy, decreasing the dose and often even with continuing treatment without modifications. ALT elevations during thioguanine therapy may be due to a direct toxic effect of the drug; ALT elevations as well as myelotoxicity have been linked to higher levels of methyl-mercaptopurine, a product of one of the metabolic pathways of thioguanine metabolism.
The acute hepatic injury due to thioguanine usually presents with fatigue and jaundice and with a mixed hepatocellular-cholestatic pattern of serum enzyme elevations after 2 to 12 months of starting therapy. Rash, fever and eosinophilia are uncommon and autoantibodies are generally not found. Liver biopsy typically shows intrahepatic cholestasis with focal hepatocellular necrosis and scant inflammation. The liver injury usually resolves rapidly on stopping, but prolonged cholestasis has been reported and some cases have been fatal. This form of hepatotoxicity appears to be idiosyncratic and a class effect of the thiopurines, although more typical of azathioprine than thioguanine or mercaptopurine.
The chronic thioguanine hepatotoxicity typically presents with fatigue and signs and symptoms of portal hypertension with mild liver enzyme abnormalities and minimal jaundice arising 6 months to many years after starting thioguanine. Liver biopsy shows nodular regenerative hyperplasia and varying amounts of sinusoidal dilation and central vein injury. This syndrome can progress to hepatic failure, particularly if thioguanine is continued, but improvement on stopping therapy is typical. The onset of this syndrome may be acute with abdominal pain and ascites, in which situation liver biopsy usually shows sinusoidal dilation, central congestion and injury to sinusoidal endothelial cells suggestive of veno-occlusive disease, which is currently referred to as sinusoidal obstructive syndrome. Typically, serum aminotransferase levels and alkaline phosphatase levels are minimally elevated, even in the presence of hyperbilirubinemia and other manifestations of hepatic dysfunction and portal hypertension. Many cases of nodular regenerative hyperplasia due to the thiopurines present initially with thrombocytopenia of unknown cause, and a gradual decrease in platelet count is probably the most reliable marker for the development of non-cirrhotic portal hypertension. Among the thiopurines, this syndrome is more frequent with thioguanine than azathioprine, and appears to be least frequent with mercaptopurine.
Finally, long term therapy with thiopurines has been
implicated in leading to the development of malignancies, including
hepatocellular carcinoma (HCC) and hepatosplenic T cell lymphoma (HSTCL). Both
of these complications are rare, but have been reported in several dozen case
reports and small case series, most frequently with azathioprine. In neither instance, has the role of thiopurine
therapy in causing the malignacies been proven, and similar cases have been
described in patients with autoimmune conditions or after solid organ
transplantation who have not received thiopurines. Hepatocellular carcinoma
typically arises after years of thiopurine therapy and in
the absence of accompanying liver disease (although sometimes with focal hepatic
glycogenosis). The HCC is most frequently found on an imaging study done of an
unrelated condition. The prognosis is more favorable than that of HCC associated
with cirrhosis. Hepatosplenic T cell lymphoma has been reported largely among
young men with inflammatory bowel disease and long term immunosuppression with a
thiopurine with or without anti-tumor necrosis factor therapy. The typical
presentation is with fatigue, fever, hepatosplenomegaly and pancytopenia. The
diagnosis is made by bone marrow or liver biopsy showing marked infiltration
with malignant T cells. HSTCL is poorly responsive to antineoplastic therapy
and has a high mortality rate.
Likelihood score: A (well known cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism by which thioguanine causes idiosyncratic acute liver injury is not known, but is likely due to an immunological response to a metabolic byproduct of its metabolism. Thioguanine undergoes extensive hepatic metabolism to 6-mercaptopurine and thereafter to other thiopurines via three different pathways. Patients with deficiency in thiopurine methyltransferase which mediates one of these metabolic pathways have a higher rate of complications of thioguanine use, particularly bone marrow suppression. but do not appear to be at higher rise of acute cholestasis or nodular regeneration. The cause of the nodular regenerative hyperplasia that develops after long term thioguanine therapy is not well defined, but it appears to be due to injury to endothelial cells that causes variable degrees of venous outflow obstruction or vascular damage that promotes the nodular transformation. This form of injury is more likely to be a direct toxic effect of the antimetabolite.
Outcome and Management
The serum aminotransferase elevations that occur during thioguanine therapy may improve spontaneously or with dose reduction and generally resolve rapidly with discontinuation. In patients who have aberrant metabolism of thiopurines to 6-methylmercaptopurine (6-MMP) as shown by elevated plasma levels, lowering the dose of thiopurine and adding allopurinol (100 mg daily) may lower 6-MMP levels, reverse aminotransferase elevations while maintaining 6-thioguanine (6-TGN) levels and clinical response. Both the acute cholestasis and the chronic nodular regeneration caused by thioguanine improve upon stopping the medication, but instances of progression to hepatic failure despite discontinuation of thioguanine have been reported with both syndromes. Rechallenge with thioguanine usually results in recurrence of the injury (within days to weeks) and should be avoided. Some patients have tolerated switching therapy to mercaptopurine or azathioprine, but substitution with a structurally unrelated antimetabolite may be more appropriate.
Other Drugs in the Subclass, Purine Analogues/Thiopurines: Azathioprine, Mercaptopurine
REPRESENTATIVE TRADE NAMES
Thioguanine – Generic, Tabloid®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 17 August 2017
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Dubinsky MC, Vasiliauskas EA, Singh H, Abreu MT, Papadakis KA, Tran T, Martin P, et al. 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology 2003; 125: 298-303. PubMed Citation (Among 111 patients with inflammatory bowel disease treated with thioguanine at one institution, 27 [25%] developed abnormal liver tests [ALT 18-139 U/L; Alk P 35-221 U/L], correlating with higher methyl-metabolites of mercaptopurine and fall in platelet count [from 300,000 to 166,000/μL], nodular regeneration found in 76% of 17 patients biopsied with abnormal liver tests and 33% of nine with normal tests).
Rulyak SJ, Saunders MD, Lee SD. Hepatotoxicity associated with 6-thioguanine therapy for Crohn's disease. J Clin Gastroenterol 2003; 36: 234-7. PubMed Citation (27 year old with Crohn's disease developed asymptomatic rise in ALT to 191 U/L 2 weeks after starting thioguanine, ALT then rising to 803 U/L at 4 weeks with normal Alk P and minimal increase in bilirubin [1.5 mg/dL], resolving within 1 month of stopping).
Stoneham S, Lennard L, Coen P, Lilleyman J, Saha V. Veno-occlusive disease in patients receiving thiopurines during maintenance therapy for childhood acute lymphoblastic leukaemia. Br J Haematol 2003; 123: 100-2. PubMed Citation (Retrospective analysis of veno-occlusive disease among 99 children who received thioguanine or mercaptopurine for acute leukemia; 12 developed veno-occlusive disease all of whom received thioguanine and were male; no correlation with dose or thiopurine methyltransferase levels).
Piel B, Vaidya S, Lancaster D, Taj M, Pritchard-Jones K. Chronic hepatotoxicity following 6-thioguanine therapy for childhood acute lymphoblastic leukaemia. Br J Haematol 2004; 125: 410-1; author reply 412. PubMed Citation (Letter in response to Stoneham  reporting veno-occlusive disease in 7 of 59 children receiving thioguanine [12%] with chronic liver injury in 7 [suspected to be nodular regenerative hyperplasia]; patients tolerated being switched to mercaptopurine).
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Broxson EH, Dole M, Wong R, Laya BF, Stork L. Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy. Pediatr Blood Cancer 2005; 44: 226-31. PubMed Citation (Among 12 children treated with thioguanine long term, 4 developed portal hypertension and another had transient veno-occlusive disease, usually presenting with normal liver tests, but persistent thrombocytopenia and splenomegaly with varices on imaging or endoscopy).
Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E,
García-Muñoz B, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish Registry over a 10-year period. Gastroenterology 2005; 129: 512-21. PubMed Citation (Among 446 cases of drug induced liver injury collected in Spain between 1984-2004, azathioprine accounted for 6 cases, ranking 14th; injury usually cholestatic, no fatalities; thioguanine not listed).
De Bruyne R, Portmann B, Samyn M, Bansal S, Knisely A, Mieli-Vergani G, Dhawan A. Chronic liver disease related to 6-thoguanine in children with acute lymphoblastic leukaemia. J Hepatol 2006; 44: 407-10. PubMed Citation (Evaluation of 6 children with acute leukemia who developed sinusoidal obstructive syndrome during thioguanine therapy; disease progressed despite switching to mercaptopurine, biopsies showing nodular regeneration; platelet counts 74-181,000/ μL).
Derijks LJ, Gilissen LP, de Boer NK, Mulder CJ. 6-Thioguanine-related hepatotoxicity in patients with inflammatory bowel disease: dose or level dependent? J Hepatol 2006; 44: 821-2. PubMed Citation (Letter in response to De Bruyne  suggesting that use of lower doses and monitoring for metabolites may help avoid hepatotoxicity).
Ravikumara M, Hill FG, Wilson DC, Gillett PM, Thomas A, Brown R, Darbyshire PJ, et al. 6-Thioguanine-related chronic hepatotoxicity and variceal haemorrhage in children treated for acute lymphoblastic leukaemia - a dual-centre experience. J Pediatr Gastroenterol Nutr 2006; 42: 535-8. PubMed Citation (Retrospective analysis of 75 children treated with maintenance thioguanine after chemotherapy for leukemia identified 10 [13%] with portal hypertension [2 with variceal hemorrhage], biopsy in 5 showed nodular regenerative hyperplasia, persistent splenomegaly and thrombocytopenia in most).
Seiderer J, Zech CJ, Diebold J, Schoenberg SO, Brand S, Tillack C, Göke B,
Ochsenkühn T. Nodular regenerative hyperplasia: a reversible entity associated with azathioprine therapy. Eur J Gastroenterol Hepatol 2006; 18: 553-5. PubMed Citation (54 year old developed jaundice 5 months after starting azathioprine for Crohn disease [bilirubin 7.5 mg/dL, but normal serum enzymes]; biopsy showing nodular regenerative hyperplasia, improvement on stopping).
Heneghan MA, Allan ML, Bornstein JD, Muir AJ, Tendler DA. Utility of thiopurine methyltransferase genotyping and phenotyping, and measurement of azathioprine metabolites in the management of patients with autoimmune hepatitis. J Hepatol 2006; 45: 584-91. PubMed Citation (Among 86 patients with autoimmune hepatitis treated with azathioprine, TPMT mutations did not predict toxicities, one patient developed hepatotoxicity with rise in ALT to 3 times ULN that improved with dose reduction).
Teml A, Schwab M, Hommes DW, Almer S, Lukas M, Feichtenschlager T, Florin T,
et al. A systematic survey evaluating
6-thioguanine-related hepatotoxicity in patients with inflammatory bowel disease.
Wien Klin Wochenschr 2007; 119: 519-26. PubMed Citation (Among 296 patients with inflammatory bowel disease treated with thioguanine for 1 month to 4 years at 15 medical centers, liver enzyme elevations occurred in 43 [15%] and nodular regenerative hyperplasia was found in 16 of 60 patients undergoing liver biopsy; older age was the only risk factor identified).
Shaye OA, Yadegari M, Abreu MT, Poordad F, Simon K, Martin P, Papadakis KA, et al. Hepatotoxicity of 6-mercaptopurine (6-MP) and azathioprine (AZA) in adult IBD patients. Am J Gastroenterol 2007; 102: 2488-94. PubMed Citation (Among 173 adult patients with inflammatory bowel disease treated with azathioprine or mercaptopurine, 8 developed ALT elevations greater than twice ULN [bilirubin 0.3-2.4 mg/dL, ALT 58-434 U/L, Alk P 54-130 U/L], resolving with stopping or lowering dose; toxicity had weak association with higher methyl metabolites in serum).
Gisbert JP, Luna M, González-Lama Y, Pousa ID, Velasco M, Moreno-Otero R, Maté
J. Liver injury in inflammatory bowel disease: long-term follow-up study of 786 patients. Inflamm Bowel Dis 2007; 13: 1106-14. PubMed Citation (Long term follow up of 138 patients treated with azathioprine or mercaptopurine; incidence of any abnormal liver test was 7.1% per year, values >twice ULN occurred in only 2.6% and often resolved spontaneously; 5 of 49 required discontinuation).
Gisbert JP, González-Lama Y, Maté J. Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic review. Am J Gastroenterol 2007; 102: 1518-27. PubMed Citation (Systematic review of the literature on hepatotoxicity of thiopurines in patients with inflammatory bowel disease; rates of hepatotoxicity have ranged from 0-13% [averaging 1.4% per year] depending upon definition of injury and degree of monitoring; these agents can also cause syndromes of acute hypersensitivity reactions, acute cholestasis and chronic injury of endothelial cell injury and nodular regenerative hyperplasia).
Gilissen LP, Derijks LJ, Driessen A, Bos LP, Hooymans PM, Stockbrügger RW,
Engels LG. 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? Dig Liver Dis 2007; 39: 156-9. PubMed Citation (Among 13 patients with inflammatory bowel disease treated with thioguanine for at least 2 years, none had evidence of nodular regeneration by either liver biopsy [n=11] or imaging studies [n=11]).
de Boer NK, van Bodegraven AA, Jharap B, de Graaf P, Mulder CJ. Drug Insight: pharmacology and toxicity of thiopurine therapy in patients with IBD. Nat Clin Pract Gastroenterol Hepatol 2007; 4: 686-94. PubMed Citation (Review of pharmacokinetics and metabolism of thiopurine and management of intolerance using genetic tests for TPMT and measurements of metabolites).
Gardiner SJ, Gearry RB, Burt MJ, Ding SL, Barclay ML. Severe hepatotoxicity with high 6-methylmercaptopurine nucleotide concentrations after thiopurine dose escalation due to low 6-thioguanine nucleotides. Eur J Gastroenterol Hepatol 2008; 20: 1238-42. PubMed Citation (3 patients with autoimmune disorders who developed hepatotoxicity 1-4 months after dose of mercaptopurine or azathioprine was increased [bilirubin 6.9, 37 and 21.2 mg/dL, ALT 195, 200 and 79 U/L, Alk P 123, 109 and 194 U/L]; two progressed to hepatic failure and died; methyl-metabolites of mercaptopurine were elevated in all 3).
Leong RW, Gearry RB, Sparrow MP. Thiopurine hepatotoxicity in inflammatory bowel disease: the role for adding allopurinol. Expert Opin Drug Saf 2008; 7: 607-16. PubMed Citation (Allopurinol can increase levels of mercaptopurine and allow for dose reductions as well as shift its metabolism towards the active [6-thioguanine nucleotides] and away from toxic metabolites [methyl-mercaptopurine ribonucleotide], but requires monitoring).
Lees CW, Maan AK, Hansoti B, Satsangi J, Arnott DR. Tolerability and safety of mercaptopurine in azathioprine-intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther 2008; 27: 220-7. PubMed Citation (Retrospective analysis of 61 patients with inflammatory bowel disease who were intolerant to azathioprine; 36 [59%] were able to tolerate mercaptopurine, including 3 of 9 with hepatotoxicity).
Ehmsen L, Marko C, Breidert M. [Portal vein hypertension during azathioprine therapy in patients with Crohn's disease - a frequent phenomenon?]. Dtsch Med Wochenschr 2008; 133: 950-3. German. PubMed Citation (45 year old man with Crohn's disease on azathioprine for 4 years developed variceal hemorrhage [bilirubin 4.1 mg/dL, normal ALT, platelets 84,000/μL] and was found to have nodular regenerative hyperplasia on liver biopsy, and subsequently improved on stopping azathioprine).
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, 3 were attributed to mercaptopurine, but none to azathioprine or thioguanine).
Rahhal RM, Bishop WP. Initial clinical experience with allopurinol-thiopurine combination therapy in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2008; 14: 1678-82. PubMed Citation (13 patients were treated with allopurinol and dose reduction of azathioprine [by ~60%] with overall increase in 6-thioguanine and decrease in methyl-metabolites; ALT elevations improved in all).
Ansari A, Elliott T, Baburajan B, Mayhead P, O'Donohue J, Chocair P, Sanderson J, et al. Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease. Aliment Pharmacol Ther 2008; 28: 734-41. PubMed Citation (11 patients with inflammatory bowel disease who developed hepatotoxicity within 1-8 weeks of starting azathioprine [n=10] or mercaptopurine [n=1] were treated with allopurinol and low doses of the thiopurine; 9 tolerated long term therapy without recurrence).
Xin HW, Xiong H, Wu XC, Li Q, Xiong L, Yu AR. Relationships between thiopurine S-methyltransferase polymorphism and azathioprine-related adverse drug reactions in Chinese renal transplant recipients. Eur J Clin Pharmacol 2009; 65: 249-55. PubMed Citation (Association found between TPMP activity and hemato- but not hepatotoxicity; only 2 of 16 patients with hepatotoxicity were heterozygous for TPMT mutations, none were homozygous).
Hindorf U, Johansson M, Eriksson A, Kvifors E, Almer SH. Mercaptopurine treatment should be considered in azathioprine intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther 2009; 29: 654-61. PubMed Citation (Analysis of usefulness of measuring thiopurine metabolites in management of 238 patients with autoimmune hepatitis on azathioprine, finding it useful only in managing patients with a poor response; patients with hepatotoxicity were not able to tolerate switch to mercaptopurine).
Murakami A, Tanaka Y, Ueda M, Nagano Y, Kunisaki R, Morimoto M, Enaka M, et al. Hepatocellular carcinoma occurring in a young Crohn's disease patient. Pathol Int 2009; 59: 492-6. PubMed Citation (25 year old man with 12 year history of Crohn disease presented with hepatocellular carcinoma approximately one year after starting infliximab; no other risk factors identified; review of literature identified 7 cases in patients with Crohn's, mean age 20 years, all had received azathioprine and two infliximab).
Moran G, Dillon J, Green J. Crohn's disease, hepatosplenic T-cell lymphoma
and no biological therapy: are we barking up the wrong tree? Inflamm Bowel Dis.
2009; 15 (9): 1281-2. PubMed Citation (Although fewer than 200 cases of
hepatospenic T cell lymphoma [HSTCL] have been described in the literature, 23
have occurred in patients with inflammatory bowel disease, all of whom were on
thiopurines and 16 also on anti-tumor necrosis factor antagonists [anti-TNF];
the authors describe a 23 year old man with ulcerative colitis treated with
azathioprine for 7 years without anti-TNF who developed HSTCL).
Beigel F, Jürgens M, Tillack C, Subklewe M, Mayr D, Göke B, Brand S, et al.
Hepatosplenic T-cell lymphoma in a patient with Crohn's disease. Nat Rev
Gastroenterol Hepatol 2009; 6: 433-6. PubMed Citation (58 year old man
with 35 year history of Crohn disease on azathioprine for 5 years developed
Miura H, Kawaguchi T, Takazoe M, Kitamura S, Yamada H. Hepatocellular
carcinoma and Crohn's disease: a case report and review. Intern Med 2009; 48:
815-9. PubMed Citation (52 year old Japanese man with 36 year history of
Crohn disease, but never treated with thiopurines presented with hepatic mass,
found to be HCC with chronic hepatitis in non-tumorous liver tissue).
Ochenrider MG, Patterson DJ, Aboulafia DM. Hepatosplenic T-cell lymphoma in
a young man with Crohn's disease: case report and literature review. Clin
Lymphoma Myeloma Leuk 2010; 10: 144-8. PubMed Citation (18 year old man
with 5 year history of Crohn disease treated with mercaptopurine developed HSTCL
[bilirubin and ALT levels normal]).
Bermejo F, López-Sanromán A, Algaba A, Van-Domselaar M, Gisbert JP,
García-Garzón S, Garrido E, et al. Mercaptopurine rescue after azathioprine-induced liver injury in inflammatory bowel disease. Aliment Pharmacol Ther 2010; 31: 120-4. PubMed Citation (Retrospective analysis of 31 patients with inflammatory bowel disease who were switched from azathioprine to mercaptopurine because of liver toxicity; in 87% mercaptopurine was tolerated without evidence of further toxicity).
Leung Y, Sparrow MP, Schwartz M, Hanauer SB. Long term efficacy and safety of allopurinol and azathioprine or 6-mercaptopurine in patients with inflammatory bowel disease. J Crohns Colitis 2009; 3: 162-7. PubMed Citation (Among 25 patients with inflammatory bowel disease switched from thiopurines to thioguanine and allopurinol for up to 2 years, none developed abnormal liver tests or thrombocytopenia).
Takatsu N, Matsui T, Murakami Y, Ishihara H, Hisabe T, Nagahama T, Maki S, et al. Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol 2009; 24: 1258-64. PubMed Citation (TPMT deficiency variants were rare [~2%] in Japanese and were not increased among those with azathioprine intolerance due to toxicity; 2 cases had hepatotoxicity).
Andrejic J, Rojas-Balcazar J, Dennis M, Berkelhammer C. Azathioprine-induced
hypersensitivity hepatitis: tolerance to 6-mercaptopurine. Inflamm Bowel Dis.
2010; 16: 1828-9. PubMed Citation (50 year old man with ulcerative colitis developed jaundice 4 weeks after starting azathioprine [bilirubin 4.6 mg/dL, ALT 1077 U/L, Alk P 361 U/L], resolving upon stopping and not recurring when treated with mercaptopurine [for up to 6 years]).
Ishida M, Naka S, Shiomi H, Tsujikawa T, Andoh A, Nakahara T, Saito Y, et al. Hepatocellular carcinoma occurring in a Crohn's disease patient. World J Gastroenterol 2010; 16: 3215-8. PubMed Citation (37 year old Japanese man treated with azathioprine for 8 years developed liver cancer without cirrhosis but with glycogenosis present; review of 10 reported cases, all without cirrhosis).
Bryant DL, Miles CJ, Gearry RB. Nodular regenerative hyperplasia of the liver secondary to azathioprine in a patient with inflammatory bowel disease. N Z Med J 2010; 123: 74-6. PubMed Citation (54 year old man developed ascites and splenomegaly 18 months after starting azathioprine for Crohn disease, biopsy showing nodular regenerative hyperplasia, improving upon stopping).
Wang HS, Gao YJ, Li J, Lu FJ, Miao H, Qian XW, Zhu XF. [Clinical characteristics of hepatic veno-occlusive disease in 6 children with hematologic neoplasm treated with 6-thioguanine]. Zhonghua Er Ke Za Zhi 2010; 48: 708-10. Chinese. PubMed Citation (Abstract only: 6 children ages 3 to 5 years developed sinusoidal obstruction syndrome during therapy of leukemia with thioguanine in combination with other agents; diagnosis made clinically).
Leal-Valdivieso C, Naves JE, Mañosa M, Zabana Y, Cabré E, Domènech E. [Portal hypertension in patients with inflammatory bowel disease]. Gastroenterol Hepatol 2010; 33: 297-302. Spanish. PubMed Citation (Two patients, man and woman, ages 29 and 34 years, developed portal hypertension after thiopurine therapy for 6 and 10 years).
López-Martín C, de la Fuente-Fernández E, Corbatón P, Sánchez MC, Gisbert JP. [Nodular regenerative hyperplasia: azathioprine-induced hepatotoxicity in a patient with Crohn's disease]. Gastroenterol Hepatol 2011; 34: 16-9. Spanish. PubMed Citation (53 year old man developed abnormal liver tests after 5 years of azathioprine therapy [7 months after dose increase] for Crohn disease [bilirubin 2.2 mg/dL, ALT 61 U/L, Alk P 284 U/L], with esophageal varices and biopsy showing nodular regenerative hyperplasia; slow improvement upon stopping).
Blogowski W, Marlicz W, Smereczynski A, Lawniczak M, Lewosiuk A, Starzynska T. Nodular regenerative liver hyperplasia as a complication of azathioprine-containing immunosuppressive treatment for Crohn's disease. Immunopharmacol Immunotoxicol 2011; 33: 398-402. PubMed Citation (40 year old woman with Crohn disease developed nodular regenerative hyperplasia [splenomegaly and varices] 3 years after starting azathioprine).
van Asseldonk DP, Jharap B, Kuik DJ, de Boer NK, Westerveld BD, Russel MG, Kubben FJ, et al. Prolonged thioguanine therapy is well tolerated and safe in the treatment of ulcerative colitis. Dig Liver Dis 2011; 43: 110-5. PubMed Citation (Among 46 patients switched from other thiopurines to thioguanine and treated for an average of 2 years, none developed hepatotoxicity and liver biopsies done in 12 showed no evidence of nodular regeneration).
Seksik P, Mary JY, Beaugerie L, Lémann M, Colombel JF, Vernier-Massouille G,
Cosnes J. Incidence of nodular regenerative hyperplasia in inflammatory bowel disease patients treated with azathioprine. Inflamm Bowel Dis 2011; 17: 565-72. PubMed Citation (Among 1888 patients with inflammatory bowel disease treated with azathioprine for median of 2.5 years, 15 developed nodular regenerative hyperplasia, 0.6% at 5 and 1.3% at 10 years; predictive factors were male gender and history of small bowel resection).
Adam de Beaumais T, Fakhoury M, Medard Y, Azougagh S, Zhang D, Yakouben K,
Jacqz-Aigrain E. Determinants of mercaptopurine toxicity in paediatric acute
lymphoblastic leukemia maintenance therapy. Br J Clin Pharmacol 2011;71: 575-84.
PubMed Citation (66 children with acute leukemia treated with mercaptopurine were tested for thiopurine methyltransferase [TPMT] and inosine pyrophosphatase (ITPA) polymorphisms and for serum levels of mercaptopurine and metabolites; those with higher levels of methyl metabolites [which varied by ITPA genotype] were more likely to have hepatotoxicity, present in 84% of participants).
Calabrese E, Hanauer SB. Assessment of non-cirrhotic portal hypertension associated with thiopurine therapy in inflammatory bowel disease. J Crohns Colitis 2011; 5: 48-53. PubMed Citation (Review of thiopurine toxicity and its management, highlighting a case of nodular regenerative hyperplasia in a patient with Crohn's colitis treated with mercaptopurine).
Srirajaskanthan R, Valliani D. Azathioprine induced hepatitis in patients with
inflammatory bowel disease. Int J Clin Pharm 2011; 33: 724-5. PubMed Citation (Two patients developed symptoms, jaundice and ALT elevations on azathioprine therapy, both having normal TPMT levels; few details given).
Masia R, Pratt DS, Misdraji J. A histopathologic pattern of centrilobular
hepatocyte injury suggests 6-mercaptopurine-induced hepatotoxicity in patients
with inflammatory bowel disease. Arch Pathol Lab Med 2012; 136: 618-22.
PubMed Citation (Review of liver biopsies from 3 patients with mercaptopurine induced liver injury showed a similar pattern centrilobular injury, minimal inflammation, ceroid-laden macrophages and steatosis, without nodular regeneration or sinusoidal dilatation).
Tack GJ, van Asseldonk DP, van Wanrooij RL, van Bodegraven AA, Mulder CJ.
Tioguanine in the treatment of refractory coeliac disease--a single centre
experience. Aliment Pharmacol Ther 2012; 36: 274-81. PubMed Citation (Among 12 patients with refractory celiac disease treated with thioguanine for 3 weeks to 8 years, one developed liver test abnormalities at 9 months, which resolved only when thioguanine was stopped 8 months later).
Costantino G, Furfaro F, Belvedere A, Alibrandi A, Fries W. Thiopurine
treatment in inflammatory bowel disease: response predictors, safety, and
withdrawal in follow-up. J Crohns Colitis 2012; 6: 588-96. PubMed Citation (Retrospective analysis of 266 patients with IBD treated with azathioprine or mercaptopurine of whom 32.5% had at least one adverse event, liver toxicity occurring in 23 patients [9%], 5 within 0-4 weeks, 12 after 2-6 months, and 6 after 6 months; specific details not given).
Smith MA, Blaker P, Marinaki AM, Anderson SH, Irving PM, Sanderson JD.
Optimising outcome on thiopurines in inflammatory bowel disease by
co-prescription of allopurinol. J Crohns Colitis 2012; 6: 905-12. PubMed Citation (Analysis of 110 patients with IBD treated with combination of a thiopurine and allopurinol, including 25 switched from thiopurine monotherapy because of hepatotoxicity, 20 of whom tolerated therapy with normalization of liver test abnormalities).
Hoentjen F, Hanauer SB, de Boer NK, Rubin DT. Two brothers with skewed
thiopurine metabolism in ulcerative colitis treated successfully with allopurinol
and mercaptopurine dose reduction. Dig Dis Sci 2012; 57: 250-3. PubMed Citation (Two brothers with ulcerative colitis had high 6-MMP levels and ALT elevations [114 and 141 U/L] during mercaptopurine therapy, which returned to undetectable [6-MMP] or normal [ALT] when switched to low dose mercaptopurine [25 mg/day] and allopurinol).
Hoentjen F, Seinen ML, Hanauer SB, de Boer NK, Rubin DT, Bouma G, Harrell LE,
et al. Safety and effectiveness of long-term allopurinol-thiopurine
maintenance treatment in inflammatory bowel disease. Inflamm Bowel Dis 2013; 19: 363-9. PubMed Citation (Among 77 patients with IBD and thiopurine resistance or intolerance who were treated with allopurinol and low dose thiopurines, 6-TGN levels increased while 6-MMP levels decreased and serum ALT levels improved in 34 of 42 patients [81%], with elevations on standard dose thiopurines without allopurinol).
Musumba CO. Review article: the association between nodular regenerative
hyperplasia, inflammatory bowel disease and thiopurine therapy. Aliment Pharmacol
Ther 2013; 38: 1025-37.
PubMed Citation (Systematic review of the literature on association of nodular regenerative hyperplasia and thiopurine use in inflammatory bowel disease, suggests the rate is as high as 62% with higher doses [>40 mg daily], but is rare at lower doses [<20 mg daily]).
Selvaraj SA, Chairez E, Wilson LM, Lazarev M, Bass EB, Hutfless S. Use of
case reports and the Adverse Event Reporting System in systematic reviews:
overcoming barriers to assess the link between Crohn's disease medications and
hepatosplenic T-cell lymphoma. Syst Rev 2013; 2: 53. PubMed Citation (Review of the literature and spontaneous reports made to the FDA of HSTCL
and medication use, identified 37 cases, ages 12 to 79 [mean 30] years; 86%
male; disease duration 4 to 35 [mean 10] years; 96% having received thiopurines,
76% biologics; survival poor [8%]).
Bašić Kinda S, Duraković N, Dotlić S, Serventi Seiwerth R, Davidović Mrsić
S, Dubravčić K, Aurer I. Hepatosplenic αβ T-cell lymphoma arising after
long-term azathioprine therapy successfully treated with allogeneic bone marrow
transplant. Leuk Lymphoma 2013; 54: 1334-5. PubMed Citation (Report of a
patient with Crohn disease who developed HSTCL after 7 years of azathioprine
therapy, few details provided).
N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al.
Profile of idiosyncratic drug induced liver injury in Latin America: an analysis
of published reports. Ann Hepatol 2014; 13: 231-9. PubMed Citation (Among
176 reports of drug induced liver injury from Latin America published between
1996 and 2012, none were attributed to thioguanine, azahioprine or mercaptopurine).
N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.;
United States Drug Induced Liver Injury Network. Features and outcomes of 899
patients with drug-induced liver injury: The DILIN Prospective Study.
Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation (Among
899 cases of drug induced liver injury enrolled in a US prospective study
between 2004 and 2013, 10 cases [1.3%] were attributed to azathioprine,
[1.2%] to mercaptopurine but none to thioguanine).
Botros Y, Mathews M, Patel H, Shah N, Baddoura W, de la Torre A. Recurrent
hepatocellular carcinoma in patient with Crohn's disease: incidental or expected
outcome of azathioprine? Case Rep Gastrointest Med 2015; 2015: 939136. PubMed Citation (62 year old man with Crohn disease and azathioprine therapy for
21 years, developed HCC with recurrence after resection; no mention of
Brinkert F, Arrenberg P, Krech T, Grabhorn E, Lohse A, Schramm C. Two cases
of hepatosplenic T-cell lymphoma in adolescents treated for autoimmune
hepatitis. Pediatrics 2016; 138. pii: e20154245. PubMed Citation (Two
patients who developed HSTCL during azathioprine therapy of autoimmune
hepatitis: 21 year old man treated for 5 years and an 18 year old female treated
for 4 years, both presenting with hepatosplenomegaly, fever and
Suárez Ferrer C, Llop Herrera E, Calvo Moya M, Vera Mendoza MI, González
Partida I, González Lama Y, Matallana Royo V, et al. Idiopathic portal
hypertension regarding thiopurine treatment in patients with inflammatory bowel
disease. Rev Esp Enferm Dig 2016; 108: 79-83. PubMed Citation. (Among 1419
patients with inflammatory bowel disease followed at a referral center in Spain,
927 were treated with thiopurines, of whom 63 [7%] developed liver injury,
mostly hepatotoxicity that resolved with dose modification or discontinuation,
but 4 had portal hypetension and probable nodular regenerative hyperplasia [ages
42-72 years, treated for 2.5-10 years, bilirubin 0.4-2.2 mg/dL, ALT 21-65 U/L,
platelet counts 60,000-100,000]).
van de Meeberg MM, Derikx LA, Sinnige HA, Nooijen P, Schipper DL, Nissen LH.
Hepatosplenic T-cell lymphoma in a 47-year-old Crohn's disease patient on
thiopurine monotherapy. World J Gastroenterol 2016; 22: 10465-70. PubMed Citation (47 year old man with Crohn disease on azathioprine therapy
developed HSTCL, few details provided).
Heron V, Fortinsky KJ, Spiegle G, Hilzenrat N, Szilagyi A. Resected
hepatocellular carcinoma in a patient with Crohn's disease on azathioprine. Case
Rep Gastroenterol 2016; 10: 50-6. PubMed Citation (61 year old woman with
30 year history of Crohn disease and 10 years of azathioprine therapy presented
with liver mass with HCC on biopsy without cirrhosis, but no malignancy at time
of resection several months later).
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