DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

 

Overview of Product(s)

Azathioprine is an immunosuppressive medication that is often used alongside other treatments, such as corticosteroids, to improve the survival of organ transplants.¹ In Malaysia, azathioprine is also indicated for the treatment of various autoimmune conditions, including severe rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, polymyositis, autoimmune chronic active hepatitis, pemphigus vulgaris, polyarteritis nodosa, autoimmune hemolytic anemia, and chronic refractory idiopathic thrombocytopenic purpura. Currently, three products containing azathioprine, all in oral form, are registered with the Drug Control Authority (DCA).² 

 

Overview of Safety Concern

Non-cirrhotic portal hypertension (NCPH) is a rare condition defined by elevated blood pressure in the portal venous system in the absence of cirrhosis or other known liver diseases.³ It is typically accompanied by splenomegaly, hypersplenism, and pancytopenia. NCPH encompasses a heterogeneous group of liver disorders affecting the vascular system, classified based on the location of resistance to blood flow. Historically, cases without identifiable risk factors were referred to as idiopathic non-cirrhotic portal hypertension (INCPH).⁴

Portosinusoidal vascular disease (PSVD) is a modified clinical concept based on INCPH, introduced by the European Association’s Vascular Liver Disease Group (VALDIG) to provide a more comprehensive definition and facilitate early diagnosis.^4-5 Compared to traditional INCPH, PSVD includes patients with common liver diseases, portal vein thrombosis, or specific histological features even in the absence of clinical signs of portal hypertension.

  

Source of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA), through its global safety signal monitoring, noted that the European Medicines Agency (EMA) had issued updates concerning the risk of NCPH/PSVD associated with azathioprine use.⁶

The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) recommended that NCPH/PSVD be included in the warnings section and listed as adverse reactions of unknown frequency under the System Organ Class (SOC) hepatobiliary disorders category for all azathioprine-containing medicinal products.⁶ Additionally, the PRAC advised removing statements that indicate hepatic damage is primarily described in transplant patients. These recommendations were based on PRAC’s review of available evidence from EudraVigilance (the European pharmacovigilance database), literature, and cumulative reviews submitted by the contacted marketing authorisation holders.

 

Background of Safety Issue

Cases of NCPH/PSVD have been reported in association with azathioprine therapy.^6-13 In addition to cases treated with azathioprine following renal transplantation, several literature reports predominantly involved male patients with inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis.^7-11 While NCPH/PSVD may remain asymptomatic for extended periods, the condition is typically slowly progressive.^7-8 Commonly reported features include gradual and persistent thrombocytopenia, splenomegaly, and oesophageal varices.^7-12 Laboratory abnormalities such as low platelet counts or elevated liver enzymes may also occur, sometimes in the absence of clinical symptoms.

The observed time to onset ranged from 3 months to 20 years following azathioprine initiation, with the largest reported series reporting a median of 4 years.^7-12 In some cases, azathioprine withdrawal resulted in temporary or permanent improvement in liver histology and symptoms.^6,13 However, some reports suggest that NCPH/PSVD is probably not reversible and may show severe clinical progression despite azathioprine discontinuation, including cases where INCPH persisted beyond 6 years or oesophageal varices recurred 2 years after drug cessation.^7,8,11,12

While the precise mechanism behind azathioprine-induced NCPH/PSVD is not fully understood, it is believed to involve endothelial damage to the hepatic sinusoids and veins caused by azathioprine-induced glutathione depletion.^7,8,10,12 Some researchers have proposed that intrinsic immunologic factors related to Crohn's disease may also play a role.¹² The resulting vascular injury may impair hepatic blood flow and increase portal pressure, leading to portal hypertension.^3,7,10 The condition can progress to serious complications, including life-threatening bleeding from oesophageal varices, ascites, liver failure, portal vein thrombosis, and the potential need for invasive interventions or liver transplantation.^3,7,8,10,12

Early identification and close monitoring of NCPH/PSVD are crucial to preventing and managing potentially irreversible or fatal complications.^7,10,12 However, diagnosing NCPH/PSVD can be challenging due to the absence of definitive diagnostic tests and typically requires a high-quality liver biopsy, detailed clinical evaluation, and expert pathological review.³ Given the variable onset and often delayed presentation, clinicians are advised to remain vigilant for the possibility of azathioprine-induced NCPH/PSVD, especially when a drop in platelet count and splenomegaly occur following azathioprine treatment.^7,11,12 Close monitoring for signs of NCPH/PSVD is advised throughout the course of azathioprine therapy and even after it is discontinued.

 

Local Adverse Drug Reaction (ADR) Reports¹⁴

To date, the NPRA has received a total of 294 ADR reports with 590 adverse events suspected to be related to azathioprine-containing products. The most frequently reported adverse events include pancytopenia (32 reports), alanine aminotransferase increased (23), and vomiting (22). No reports of non-cirrhotic portal hypertension or portosinusoidal vascular disease have been received locally.

 

Advice for Healthcare Professionals

• Be aware of the potential risk of non-cirrhotic portal hypertension (NCPH) or portosinusoidal vascular disease (PSVD) in patients receiving azathioprine therapy, especially with long-term use.
• Early identification and close monitoring of NCPH/PSVD are crucial to preventing and managing complications that can be irreversible or fatal. Monitor patients closely throughout the course of azathioprine therapy for signs of NCPH/PSVD, even after it is discontinued.
• Remain vigilant for early signs suggestive of NCPH/PSVD, including liver enzyme abnormalities, mild jaundice, thrombocytopenia, and splenomegaly. Consider further evaluation (e.g. imaging or a liver biopsy) as clinically appropriate.
• Educate patients to inform doctor if they experience symptoms suggestive of liver or blood abnormalities, such as yellowing of the skin or eyes, abdominal discomfort, persistent fatigue, easy bruising, or unusual bleeding.
• Discontinue azathioprine if NCPH/PSVD is confirmed, initiate appropriate management of complications, and consider alternative therapies where indicated.
• Report all suspected adverse events associated with azathioprine-containing products to the NPRA.

 

References:

1. National Pharmaceutical Regulatory Agency (NPRA). Imuran Tablets 50mg [Package Insert]. 2022 May 15 [cited 2025 Feb 3]. The Malaysian Product Registration Database (QUEST). Available from: http://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2025 [cited 2025 Feb 3]. Available from: https://www.npra.gov.my
3. Fiordaliso M, Marincola G, Pala B, Muraro R, Mazzone M, Di Marcantonio MC, Mincione G. A Narrative Review on Non-Cirrohotic Portal Hypertension: Not All Portal Hypertensions Mean Cirrhosis. Diagnostics (Basel). 2023 Oct 20;13(20):3263. Available from: https://doi.org/10.3390/diagnostics13203263
4. Gioia S, Nardelli S, Ridola L, Riggio O. Causes and Management of Non-cirrhotic Portal Hypertension​. Curr Gastroenterol Rep. 2020 Sep 17;22(12):56. Available from: https://doi.org/10.1007/s11894-020-00792-0
5. Liu J, Zhang Q, Liu Y, Ma HX, Han X, Ma Y, Zhao LL, Li J. Porto-Sinusoidal Vascular Disease: A New Nomenclature Different from Idiopathic Non-Cirrhotic Portal Hypertension. Diagnostics (Basel). 2024 Sep 16;14(18):2053. Available from: https://doi.org/10.3390/diagnostics14182053
6. European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee (PRAC) recommendations on signals. Adopted at the 25-28 November 2024 PRAC meeting [Internet]. 2025 Jan 7 [cited 2025 Feb 3]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-25-28-november-2024-prac-meeting_en.pdf
7. Vernier-Massouille G, Cosnes J, Lemann M, Marteau P, Reinisch W, Laharie D, Cadiot G, Bouhnik Y, De Vos M, Boureille A, Duclos B, Seksik P, Mary JY, Colombel JF. Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine. Gut. 2007 Oct;56(10):1404-9. Available from: https://doi.org/10.1136/gut.2006.114363
8. Dooremont D, Decaestecker J, De Wulf D, Ghillebert G, Van Vlierberghe H, Van Dorpe J, Baert F. Azathioprine induced serious portal hypertension: a case series of three IBD patients and review of the literature. Acta Gastroenterol Belg [Internet]. 2013 Sep;76(3):342-6. Available from https://www.ageb.be/ageb-journal/ageb-volume/ageb-article/625/
9. Manfready RA, Husney J, Golfeyz S, Thung S, Weisberg I. Long-Term Azathioprine Use and the Development of Non-Cirrhotic Portal Hypertension: 2250. Am J Gastroenterol [Internet]. 2018 Oct 113():p S1275. Available from: https://journals.lww.com/ajg/fulltext/2018/10001/long_term_azathioprine_use_and_the_development_of.2249.aspx
10. Seo JW, Kim ES, Han MH, Kweon YO. Non-cirrhotic portal hypertension related to azathioprine therapy in a patient with Crohn's disease. Intest Res. 2021 Apr;19(2):247-251. Epub 2020 Jul 2. Available from: https://doi.org/10.5217/ir.2020.00016
11. Yazaki T, Kawashima K, Ishihara S. Azathioprine-Induced Porto-Sinusoidal Vascular Disease Complicated with Oesophageal Varices in a Crohn's Disease Patient - Case Report. J Crohns Colitis. 2023 Oct 20;17(9):1549-1551. Available from: https://doi.org/10.1093/ecco-jcc/jjad066
12. Chabbouh K, Cherif D, Debbabi H, Kchir H, Hassine H, Ben-Hammamia S, Lakhoua G, Jarray A, Frikha W, Chelly B, El-Aidli S, Mizouni H, Haouet S, Maamouri N. Idiopathic non-cirrhotic portal hypertension (INCPH) during azathioprine treatment in patient with Crohn's disease: A case report. Therapie. 2022 Jul-Aug;77(4):489-491. Available from: https://doi.org/10.1016/j.therap.2021.07.001
13. 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 May;18(5):553-5. doi: 10.1097/00042737-200605000-00018. PMID: 16607155.
14. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2025 [cited 2025 Jan 22]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Wang Khee Ing

Reviewed/Edited by: Choo Sim Mei, Dr Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali