Porto-sinusoidal vascular disorder and sinusoidal obstructive syndrome in patients treated with thiopurines: a systematic review.
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BACKGROUND: Thiopurines (azathioprine [AZA], 6-mercaptopurine [6-MP], 6-thioguanine [6-TG]) can cause hepatic microvascular injury, presenting chronically as porto sinusoidal vascular disorder (PSVD) or related vascular lesions, or acutely as sinusoidal obstruction syndrome (SOS/veno-occlusive disease). We reviewed evidence across indications. METHODS: We searched MEDLINE, EMBASE, Web of Science, SCOPUS, and the Cochrane Library from inception to 12 January 2026. We included studies reporting PSVD, SOS, or hepatic vascular lesions in thiopurine exposed patients, capturing historical terminology and distinguishing clinicopathological PSVD from isolated histopathological lesions. RESULTS: Of 980 records, 97 studies were included across inflammatory bowel disease, haematological disorders, transplantation, and rheumatological diseases. The strongest causal signal emerged in paediatric acute lymphoblastic leukaemia maintenance, where randomised comparisons showed excess hepatic vascular injury, predominantly SOS and portal hypertension phenotypes, with 6-TG versus 6-MP, prompting protocol amendments and limiting prolonged 6-TG use. Outside haematology, evidence for AZA/6-MP associated PSVD and related vascular lesions came mainly from observational cohorts and case reports. PSVD presented insidiously with preserved synthetic function; early clues included unexplained thrombocytopenia or splenomegaly, with progression to varices, ascites, portal vein thrombosis, and portal-hypertension complications. Dose/exposure intensity and host susceptibility modified risk, supporting a plausible continuum between acute and chronic phenotypes, although direct evidence of progression from SOS to PSVD remains limited. CONCLUSIONS: Thiopurines cause a spectrum of hepatic microvascular injury. Evidence most strongly implicates 6-TG, whereas evidence for AZA/6-MP-associated PSVD and related vascular lesions is less consistent but relevant. New thrombocytopenia or splenomegaly should prompt evaluation for portal hypertension; thiopurine withdrawal is recommended when PSVD/SOS is suspected. INTRODUCTION AND OBJECTIVES: Thiopurines (azathioprine [AZA], 6-mercaptopurine [6-MP], 6-thioguanine [6-TG]) can cause hepatic microvascular injury, which may present chronically as porto-sinusoidal vascular disorder (PSVD) or related vascular lesions, or acutely as sinusoidal obstruction syndrome (SOS/veno-occlusive disease). We systematically reviewed evidence across all clinical indications. MATERIALS AND METHODS: We searched MEDLINE (PubMed), EMBASE, Web of Science Core Collection, SCOPUS, and the Cochrane Library from inception to 12 January 2026. We included original studies (case reports/series, observational studies, clinical trials) reporting PSVD or SOS or relevant hepatic vascular lesions historically associated with these entities in thiopurine-exposed patients, capturing historical terminology and distinguishing a clinicopathological diagnosis of PSVD from reports limited to individual histopathological vascular lesions. RESULTS: From 980 records, 97 studies were included across inflammatory bowel disease, haematological disorders, transplant recipients, rheumatological diseases and other indications. The strongest causal signal emerged in paediatric acute lymphoblastic leukaemia maintenance therapy: randomised comparisons consistently showed a marked excess of hepatic vascular injury, predominantly SOS and portal-hypertension phenotype, with 6-TG versus 6-MP, prompting protocol amendments and limiting prolonged 6-TG use in that setting. Outside haematology, evidence for AZA/6-MP-associated PSVD and related vascular lesions came mainly from observational cohorts and case-based evidence. Clinically overt PSVD typically presented insidiously with preserved liver synthetic function. Early clues included unexplained thrombocytopenia or splenomegaly, with potential progression to varices, ascites, portal vein thrombosis (PVT) and other portal-hypertension complications. Overall, dose/exposure intensity and host susceptibility appeared to modify risk, consistent with a plausible pathophysiological continuum between distinct acute and chronic phenotypes; however direct evidence of progression from SOS to PSVD remains limited. CONCLUSIONS: Thiopurines can precipitate a spectrum of hepatic microvascular injury. Evidence most strongly implicates 6-TG (dose/exposure dependent), whereas AZA/6-MP-associated PSVD and related vascular lesions is less consistent but remains clinically relevant. In exposed patients, new thrombocytopenia or splenomegaly should trigger evaluation for portal hypertension; thiopurine withdrawal is recommended when PSVD/SOS is suspected.