Link between persistent, unexplained gamma-glutamyltransferase elevation and porto-sinusoidal vascular disorder.

Background & Aims: Porto-sinusoidal vascular disorder (PSVD) is a group of vascular disorders characterized by lesions involving portal venules and sinusoids, irrespective of the presence of portal hypertension. Liver biopsy is essential for diagnosis. In a single-center study, we demonstrated high rates of PSVD in patients with persistently elevated gamma-glutamyltransferase (GGT). This multicenter study aims to establish PSVD prevalence in a larger dataset of individuals with persistent and unexplained GGT elevation, and to identify associated risk factors. Methods: The study included all patients who underwent liver biopsy for persistent and unexplained GGT elevation in five Italian hepatology units between March 2015 and December 2021. Results: A total of 144 patients met the inclusion criteria. The majority were males (76/144, 52.8%) and mean age was 51.9 years (range 19-74). Only 12 (8.3%) had liver stiffness measurements (LSM) >10 kPa, while 7 (4.8%) had ultrasound evidence of portal hypertension. Histological findings were consistent with PSVD in 96 patients (67%). Alternative diagnoses were steatohepatitis in 13 (9%), sarcoidosis in 3 (2%) and congenital hepatic fibrosis in 3 (2%) patients. Histological findings were non-specific in 29 (20%) patients. PSVD was associated with male sex (odds ratio [OR] 2.60, 95% CI 1.13-5.99), LSM <10 kPa (OR 11.05, 95% CI 2.16-56.66) and GGT <200 U/L (OR 2.69, 95% CI 1.22-5.98). Conclusions: PSVD was the main cause of persistent and unexplained elevation of GGT3. Male sex, LSM <10 kPa and GGT <200 U/L were associated with PSVD. These findings highlight the role of liver biopsy in elucidating the underlying pathology and aiding in the diagnosis of patients with persistent and unexplained GGT elevation. Impact and implications: In outpatient settings, it is common to encounter individuals with persistent and unexplained gamma-glutamyltransferase elevations. This study reveals, for the first time, a non-negligible prevalence of porto-sinusoidal vascular disorder among these individuals when they undergo liver biopsy. Male sex, liver stiffness measurement <10 kPa, and gamma-glutamyltransferase <200 IU/L predict this histological finding. These results may raise awareness of clinically relevant conditions that may be present in patients with persistent liver enzyme changes, even in the absence of signs of advanced chronic liver disease or portal hypertension. Additionally, the data may encourage further studies in the field of porto-sinusoidal vascular disorder, particularly to define its clinical evolution in patients without signs of portal hypertension at diagnosis.