Review article: The association between nodular regenerative hyperplasia, inflammatory bowel disease and thiopurine therapy

Alimentary Pharmacology and Therapeutics

Volumn 38, Issue 9, 2013, Pages 1025-1037

  Musumba, C O ^a  

^a ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AZATHIOPRINE; BLEOMYCIN; BUSULFAN; CARMUSTINE; CHLORAMBUCIL; CYCLOPHOSPHAMIDE; CYTARABINE; DIDANOSINE; DOXORUBICIN; LIVER ENZYME; MERCAPTOPURINE; OXALIPLATIN; TIOGUANINE;

AGE; ARTICLE; AUTOIMMUNE DISEASE; CLINICAL FEATURE; DISEASE ASSOCIATION; DOSE RESPONSE; DRUG DOSE COMPARISON; DRUG MEGADOSE; DRUG SAFETY; ENTERITIS; GENDER; HEMATOLOGIC MALIGNANCY; HISTOPATHOLOGY; HUMAN; HYPERTRANSAMINASEMIA; INCIDENCE; INFECTION; INTESTINE STENOSIS; LIVER BIOPSY; LIVER HYPERPLASIA; LOW DRUG DOSE; NODULAR REGENERATIVE HYPERPLASIA; ORGAN TRANSPLANTATION; PATHOGENESIS; PRIORITY JOURNAL; PROTHROMBOTIC DISORDER; RISK FACTOR; SIDE EFFECT; SMALL INTESTINE RESECTION; THROMBOCYTOPENIA; THROMBOSIS;

6-MERCAPTOPURINE; AZATHIOPRINE; COLITIS, ULCERATIVE; CROHN DISEASE; FEMALE; FOCAL NODULAR HYPERPLASIA; HUMANS; IMMUNOSUPPRESSIVE AGENTS; INCIDENCE; MALE; RISK FACTORS; THIOGUANINE; TIME FACTORS;

EID: 84885167937     PISSN: 02692813     EISSN: 13652036     Source Type: Journal    
DOI: 10.1111/apt.12490     Document Type: Article

References (95)

1. Hartleb M, Gutkowski K, Milkiewicz P,. Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension. World J Gastroenterol 2011; 17: 1400-9.
2. Nakanuma Y, Hoso M, Sasaki M, et al,. Histopathology of the liver in non-cirrhotic portal hypertension of unknown aetiology. Histopathology 1996; 28: 195-204. (Pubitemid 26091910)
3. Reshamwala PA, Kleiner DE, Heller T,. Nodular regenerative hyperplasia: not all nodules are created equal. Hepatology 2006; 44: 7-14. (Pubitemid 44049133)
4. Schouten JN, Garcia-Pagan JC, Valla DC, Janssen HL,. Idiopathic noncirrhotic portal hypertension. Hepatology 2011; 54: 1071-81.
5. Stromeyer FW, Ishak KG,. Nodular transformation (nodular "regenerative" hyperplasia) of the liver. A clinicopathologic study of 30 cases. Hum Pathol 1981; 12: 60-71. (Pubitemid 12239395)
6. Wanless IR,. Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 1990; 11: 787-97. (Pubitemid 20191384)
7. Ferlitsch A, Teml A, Reinisch W, et al,. 6-thioguanine associated nodular regenerative hyperplasia in patients with inflammatory bowel disease may induce portal hypertension. Am J Gastroenterol 2007; 102: 2495-503. (Pubitemid 47631796)
8. Ueno S, Tanabe G, Sueyoshi K, et al,. Hepatic hemodynamics in a patient with nodular regenerative hyperplasia. Am J Gastroenterol 1996; 91: 1012-5. (Pubitemid 26143545)
9. Cazals-Hatem D, Hillaire S, Rudler M, et al,. Obliterative portal venopathy: portal hypertension is not always present at diagnosis. J Hepatol 2011; 54: 455-61.
10. Duseja A, Chawla Y,. Portal hypertension in nodular regenerative hyperplasia: a mixed bag! Gastroenterol Hepatol 2012; 27: 1260-2.
11. Naber AH, van Haelst U, Yap SH,. Nodular regenerative hyperplasia of the liver: an important cause of portal hypertension in non-cirrhotic patients. J Hepatol 1991; 12: 94-9.
12. Plessier A, Rautou PE, Valla DC,. Management of hepatic vascular diseases. J Hepatol 2012; 56 (Suppl. 1): S25-38.
13. Manzia TM, Gravante G, Di Paolo D, et al,. Liver transplantation for the treatment of nodular regenerative hyperplasia. Dig Liver Dis 2011; 43: 929-34.
14. Colina F, Alberti N, Solis JA, Martinez-Tello FJ,. Diffuse nodular regenerative hyperplasia of the liver (DNRH). A clinicopathologic study of 24 cases. Liver 1989; 9: 253-65. (Pubitemid 19249669)
15. Nzeako UC, Goodman ZD, Ishak KG,. Hepatocellular carcinoma and nodular regenerative hyperplasia: possible pathogenetic relationship. Am J Gastroenterol 1996; 91: 879-84. (Pubitemid 26143523)
16. Sood A, Cox GA 2nd, McWilliams JP, Wang HL, Saab S,. Patients with nodular regenerative hyperplasia should be considered for hepatocellular carcinoma screening. Hepatol Res 2013; doi: 10.1111/hepr.12136 [Epub ahead of print].
17. DeLeve LD, Valla DC, Garcia-Tsao G,. Vascular disorders of the liver. Hepatology 2009; 49: 1729-64.
18. Haboubi NY, Ali HH, Whitwell HL, Ackrill P,. Role of endothelial cell injury in the spectrum of azathioprine-induced liver disease after renal transplant: light microscopy and ultrastructural observations. Am J Gastroenterol 1988; 83: 256-61.
19. Wanless IR, Godwin TA, Allen F, Feder A,. Nodular regenerative hyperplasia of the liver in hematologic disorders: a possible response to obliterative portal venopathy. A morphometric study of nine cases with an hypothesis on the pathogenesis. Medicine 1980; 59: 367-79. (Pubitemid 10044733)
20. Jharap B, van Asseldonk DP, de Boer NK, et al,. Low inter-observer agreement on nodular regenerative hyperplasia of the liver: an European inter-observer analysis. Gastroenterology 2010; 138: S456.
21. Hillaire S, Bonte E, Denninger MH, et al,. Idiopathic non-cirrhotic intrahepatic portal hypertension in the west: a re-evaluation in 28 patients. Gut 2002; 51: 275-80. (Pubitemid 34791461)
22. Jha P, Poder L, Wang ZJ, Westphalen AC, Yeh BM, Coakley FV,. Radiologic mimics of cirrhosis. AJR Am J Roentgenol 2010; 194: 993-9.
23. Laharie D, Vergniol J, Bioulac-Sage P, et al,. Usefulness of noninvasive tests in nodular regenerative hyperplasia of the liver. Eur J Gastroenterol Hepatol 2010; 22: 487-93.
24. Seiderer J, Zech CJ, Reinisch W, et al,. A multicenter assessment of liver toxicity by MRI and biopsy in IBD patients on 6-thioguanine. J Hepatol 2005; 43: 303-9. (Pubitemid 40956884)
25. Zech CJ, Seiderer J, Reinisch W, et al,. Thioguanin-induced nodular regenerative hyperplasia of the liver-ROC analysis of different MR techniques. Eur Radiol 2007; 17: 1898-905. (Pubitemid 46909682)
26. Arvanitaki M, Adler M,. Nodular regenerative hyperplasia of the liver. A review of 14 cases. Hepatogastroenterology 2001; 48: 1425-9. (Pubitemid 33010439)
27. Bissonnette J, Genereux A, Cote J, et al,. Hepatic hemodynamics in 24 patients with nodular regenerative hyperplasia and symptomatic portal hypertension. J Gastroenterol Hepatol 2012; 27: 1336-40.
28. de Boer NK, Mulder CJ, van Bodegraven AA,. Nodular regenerative hyperplasia and thiopurines: the case for level-dependent toxicity. Liver Transpl 2005; 11: 1300-1. (Pubitemid 41511949)
29. 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. (Pubitemid 350199222)
30. Gisbert JP, Gonzalez-Lama Y, Mate J,. Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic review. Am J Gastroenterol 2007; 102: 1518-27. (Pubitemid 46976279)
31. Dubinsky MC, Vasiliauskas EA, Singh H, et al,. 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology 2003; 125: 298-303. (Pubitemid 36929408)
32. de Boer NK, Reinisch W, Teml A, et al,. 6-Thioguanine treatment in inflammatory bowel disease: a critical appraisal by a European 6-TG working party. Digestion 2006; 73: 25-31. (Pubitemid 43800658)
33. de Boer NK, Tuynman H, Bloemena E, et al,. Histopathology of liver biopsies from a thiopurine-naive inflammatory bowel disease cohort: prevalence of nodular regenerative hyperplasia. Scand J Gastroenterol 2008; 43: 604-8. (Pubitemid 351536051)
34. Lesna M, Spencer I, Walker W,. Letter: liver nodules and androgens. Lancet 1976; 1: 1124.
35. Sale GE, Lerner KG,. Multiple tumors after androgen therapy. Arch Pathol Lab Med 1977; 101: 600-3. (Pubitemid 8230235)
36. Sweeney EC, Evans DJ,. Hepatic lesions in patients treated with synthetic anabolic steriods. J Clin Pathol 1976; 29: 626-33.
37. Arnott ID, Ghosh S,. Portal hypertension in the presence of minimal liver damage in Crohn's disease on long-term azathioprine: possible endothelial cell injury. Eur J Gastroenterol Hepatol 2000; 12: 569-73. (Pubitemid 30326626)
38. 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.
39. 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; 1313: 74-6.
40. 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.
41. Cohen-Ezra O, Avni Y, Morgenstern S, Ben-Ari Z,. Nodular regenerative hyperplasia as a complication of thiopurine treatment in a patient with inflammatory bowel disease. Harefuah 2012; 151: 675-8.
42. Daniel F, Cadranel JF, Seksik P, et al,. Azathioprine induced nodular regenerative hyperplasia in IBD patients. Gastroenterol Clin Biol 2005; 29: 600-3. (Pubitemid 40825163)
43. de Boer NK, Mulder CJ, van Bodegraven AA,. Myelotoxicity and hepatotoxicity during azathioprine therapy. Neth J Med 2005; 63: 444-6. (Pubitemid 43019744)
44. Duvoux C, Kracht M, Lang P, Vernant JP, Zafrani ES, Dhumeaux D,. Nodular regenerative hyperplasia of the liver associated with azathioprine therapy. Gastroenterol Clin Biol 1991; 15: 968-73.
45. 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. (Pubitemid 351828931)
46. Laish I, Pomeranz I, Kitay-Cohen Y, Konikof F,. Thiopurine-induced hyperammonaemic encephalopathy in a patient with Crohn's disease. Harefuah 2012; 151: 692-5.
47. Leon-Montanes R, Trigo-Salado C, Leo-Carnerero E, De-la-Cruz-Ramirez MD, Herrera-Justiniano JM, Marquez-Galan JL,. Treatment with adalimumab in a patient with regenerative nodular hyperplasia secondary to azathioprine. Rev Esp Enferm Dig 2013; 105: 168-70.
48. Lopez-Martin C, de la Fuente-Fernandez E, Corbaton P, Sanchez MC, Gisbert JP,. Nodular regenerative hyperplasia: azathioprine-induced hepatotoxicity in a patient with Crohn's disease. Gastroenterol Hepatol 2011; 34: 16-9.
49. Russmann S, Zimmermann A, Krahenbuhl S, Kern B, Reichen J,. Veno-occlusive disease, nodular regenerative hyperplasia and hepatocellular carcinoma after azathioprine treatment in a patient with ulcerative colitis. Eur J Gastroenterol Hepatol 2001; 13: 287-90. (Pubitemid 32205420)
50. Schumann M, Preiss JC, Loddenkemper C, et al,. Nodular regenerative hyperplasia as a side effect of azathioprine in a patient with Crohn's disease. Dtsch Med Wochenschr 2008; 133: 1897-900.
51. Seiderer J, Zech CJ, Diebold J, et al,. Nodular regenerative hyperplasia: a reversible entity associated with azathioprine therapy. Eur J Gastroenterol Hepatol 2006; 18: 553-5. (Pubitemid 43832759)
52. Tuyama AC, Krakauer M, Alzaabi M, Fiel MI, Legnani P, Schiano TD,. Mercaptopurine-induced hepatoportal sclerosis in a patient with Crohn's disease. J Crohns Colitis 2012; 7: 590-3.
53. Holtmann M, Schreiner O, Kohler H, et al,. Veno-occlusive disease (VOD) in Crohn's disease (CD) treated with azathioprine. Dig Dis Sci 2003; 48: 1503-5. (Pubitemid 36936684)
54. Vernier-Massouille G, Cosnes J, Lemann M, et al,. Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine. Gut 2007; 56: 1404-9. (Pubitemid 47517834)
55. Seksik P, Mary JY, Beaugerie L, et al,. Incidence of nodular regenerative hyperplasia in inflammatory bowel disease patients treated with azathioprine. Inflamm Bowel Dis 2011; 17: 565-72.
56. Mesonero F, Martinez-Gonzalez J, Parejo S, et al,. Nodular regenerative hyperplasia due to thiopurines in patients with inflammatory bowel disease; retroespective review in hospital series. ECCO Abstracts 2013, 2013. Poster presentations: Clinical: Therapy and observation.
57. Chaparro M, Ordas I, Cabre E, et al,. Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients. Inflamm Bowel Dis 2013; 19: 1404-10.
58. Gisbert JP, Luna M, Gonzalez-Lama Y, et al,. Liver injury in inflammatory bowel disease: long-term follow-up study of 786 patients. Inflamm Bowel Dis 2007; 13: 1106-14. (Pubitemid 47402594)
59. Shaye OA, Yadegari M, Abreu MT, et al,. Hepatotoxicity of 6-mercaptopurine (6-MP) and azathioprine (AZA) in adult IBD patients. Am J Gastroenterol 2007; 102: 2488-94. (Pubitemid 47631795)
60. Bouhnik Y, Lemann M, Mary JY, et al,. Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Lancet 1996; 8996: 215-9. (Pubitemid 26035245)
61. Lopez-Martin C, Chaparro M, Espinosa L, Bejerano A, Mate J, Gisbert JP,. Adverse events of thiopurine immunomodulators in patients with inflammatory bowel disease. Gastroenterol Hepatol 2011; 34: 385-92.
62. Jharap B, Seinen ML, de Boer NK, et al,. Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts. Inflamm Bowel Dis 2010; 16: 1541-9.
63. Derijks LJ, de Jong DJ, Gilissen LP, et al,. 6-Thioguanine seems promising in azathioprine- or 6-mercaptopurine-intolerant inflammatory bowel disease patients: a short-term safety assessment. Eur J Gastroenterol Hepatol 2003; 15: 63-7. (Pubitemid 36135664)
64. Dubinsky MC, Hassard PV, Seidman EG, et al,. An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy. Inflamm Bowel Dis 2001; 7: 181-9. (Pubitemid 32776509)
65. Shastri S, Dubinski MC, Poordad FF, Vasiliauskas EA, Geller SA,. Nodular hyperplasia of the liver (Sabourin lesion) occuring with inflammatory bowel diseases in combination with 6-thioguanine therapy (abstr). Am J Clin Pathol 2002; 118: 631.
66. Shastri S, Dubinsky MC, Fred Poordad F, Vasiliauskas EA, Geller SA,. Early nodular hyperplasia of the liver occurring with inflammatory bowel diseases in association with thioguanine therapy. Arch Pathol Lab Med 2004; 128: 49-53. (Pubitemid 38049566)
67. Geller SA, Dubinsky MC, Poordad FF, et al,. Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease. Am J Surg Pathol 2004; 28: 1204-11. (Pubitemid 39121614)
68. Herrlinger KR, Deibert P, Schwab M, et al,. Remission maintenance by tioguanine in chronic active Crohn's disease. Aliment Pharmacol Ther 2003; 17: 1459-64. (Pubitemid 36831436)
69. Teml A, Schwab M, Hommes DW, et al,. A systematic survey evaluating 6-thioguanine-related hepatotoxicity in patients with inflammatory bowel disease. Wien Klin Wochenschr 2007; 18: 519-26. (Pubitemid 350012389)
70. de Boer NK, Derijks LJ, Gilissen LP, et al,. On tolerability and safety of a maintenance treatment with 6-thioguanine in azathioprine or 6-mercaptopurine intolerant IBD patients. World J Gastroenterol 2005; 11: 5540-4.
71. Gilissen LP, Derijks LJ, Driessen A, et al,. 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. (Pubitemid 46117931)
72. Ansari A, Elliott T, Fong F, et al,. Further experience with the use of 6-thioguanine in patients with Crohn's disease. Inflamm Bowel Dis 2008; 14: 1399-405.
73. de Boer NK, Zondervan PE, Gilissen LP, et al,. Absence of nodular regenerative hyperplasia after low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients. Dig Liver Dis 2008; 40: 108-13.
74. Almer SH, Hjortswang H, Hindorf U,. 6-Thioguanine therapy in Crohn's disease-observational data in Swedish patients. Dig Liver Dis 2009; 41: 194-200.
75. van Asseldonk DP, Jharap B, Kuik DJ, et al,. Prolonged thioguanine therapy is well tolerated and safe in the treatment of ulcerative colitis. Dig Liver Dis 2011; 43: 110-5.
76. de Bruyne R, Portmann B, Samyn M, et al,. Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia. J Hepatol 2006; 44: 407-10. (Pubitemid 43069224)
77. 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 2.
78. Kane S, Cohen SM, Hart J,. Acute sinusoidal obstruction syndrome after 6-thioguanine therapy for Crohn's disease. Inflamm Bowel Dis 2004; 10: 652-4. (Pubitemid 39276476)
79. Danese S, Colombel J-F, Reinisch W, Rutgeerts PJ,. Review article: infliximab for Crohn's disease treatment-shifting therapeutic strategies after 10 years of clinical experience. Aliment Pharmacol Ther 2011; 33: 857-69.
80. Buster EH, van Vuuren HJ, Zondervan PE, Metselaar HJ, Tilanus HW, de Man RA,. Thiopurine-methyltransferase and inosine triphosphate pyrophosphatase polymorphism in a liver transplant recipient developing nodular regenerative hyperplasia on low-dose azathioprine. Eur J Gastroenterol Hepatol 2008; 20: 68-72. (Pubitemid 350307492)
81. Lennard L, Richards S, Cartwright CS, Mitchell C, Lilleyman JS, Vora A,. The thiopurine methyltransferase genetic polymorphism is associated with thioguanine-related veno-occlusive disease of the liver in children with acute lymphoblastic leukemia. Clin Pharmacol Ther 2006; 80: 375-83. (Pubitemid 44479753)
82. Jacobs SS, Stork LC, Bostrom BC, et al,. Substitution of oral and intravenous thioguanine for mercaptopurine in a treatment regimen for children with standard risk acute lymphoblastic leukemia: a collaborative Children's Oncology Group/National Cancer Institute pilot trial (CCG-1942). Pediatr Blood Cancer 2007; 49: 250-5. (Pubitemid 47236212)
83. 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. (Pubitemid 37222763)
84. Bernstein CN, Blanchard JF, Houston DS, Wajda A,. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study. Thromb Haemost 2001; 85: 430-4. (Pubitemid 32233013)
85. Di Fabio F, Lykoudis P, Gordon PH,. Thromboembolism in inflammatory bowel disease: an insidious association requiring a high degree of vigilance. Semin Thromb Hemost 2011; 37: 220-5.
86. Esmon CT,. Inflammation and thrombosis. J Thromb Haemost 2003; 1: 1343-8.
87. Irving PM, Pasi KJ, Rampton DS,. Thrombosis and inflammatory bowel disease. Clin Gastroenterol Hepatol 2005; 3: 617-28. (Pubitemid 40984719)
88. Sventoraityte J, Zvirbliene A, Kiudelis G, et al,. Immune system alterations in patients with inflammatory bowel disease during remission. Medicina (Kaunas) 2008; 44: 27-33.
89. Bataille F, Rohrmeier C, Bates R, et al,. Evidence for a role of epithelial mesenchymal transition during pathogenesis of fistulae in Crohn's disease. Inflamm Bowel Dis 2008; 14: 1514-27.
90. Arnott ID, Kingstone K, Ghosh S,. Abnormal intestinal permeability predicts relapse in inactive Crohn disease. Scand J Gastroenterol 2000; 35: 1163-9.
91. DeLeve LD, Wang X, Kuhlenkamp JF, Kaplowitz N,. Toxicity of azathioprine and monocrotaline in murine sinusoidal endothelial cells and hepatocytes: the role of glutathione and relevance to hepatic venoocclusive disease. Hepatology 1996; 23: 589-99. (Pubitemid 26087175)
92. Stork LC, Matloub Y, Broxson E, et al,. Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial. Blood 2010; 14: 2740-8.
93. Oancea I, Png CW, Das I, et al,. A novel mouse model of veno-occlusive disease provides strategies to prevent thioguanine-induced hepatic toxicity. Gut 2012; 62: 594-605.
94. Al Hadithy AF, de Boer NK, Derijks LJ, Escher JC, Mulder CJ, Brouwers JR,. Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations. Dig Liver Dis 2005; 37: 282-97. (Pubitemid 41070528)
95. Duley JA, Florin TH,. Thiopurine therapies: problems, complexities, and progress with monitoring thioguanine nucleotides. Ther Drug Monit 2005; 27: 647-54. (Pubitemid 41437645)