A new study has found significant sex differences in bleeding events in patients with Alagille syndrome (ALGS), with females having more spontaneous bleeds than males.

The study, published in EMBO Molecular Medicine, also found retinography to be a reliable, noninvasive analytical method in mice and human patients with ALGS.

“Spontaneous bleeds are a significant cause of death in the rare genetic disease Alagille syndrome, but little is known about the risk factors contributing to the bleeding events, or about vascular development and maintenance in the course of the disease,” the authors wrote. “This study provides evidence for multiple risk factors modulating vascular health in ALGS, including hypertension, frail bones, and sex, and demonstrates that retinography could be further investigated as a clinical tool for monitoring patient vascular health.”

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The research team conducted a systematic review of the literature on vascular events among patients with ALGS based on sex, and they assessed vascular events in ALGS mice. Retinography was used in both patients and mice to assess the usefulness of the method in identifying and confirming vascular changes in ALGS.

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The results revealed that female sex, hypertension, premature vascular aging, reduced skull thickness, and increased tortuosity of retinal vessels were all associated with increased bleeding in ALGS. Females had significantly more spontaneous intracranial bleeds than males, and most bleeds were subarachnoid hemorrhages.

The authors noted that retinography was able to accurately identify vascular anomalies in mice and patients. They speculate that premature vascular aging in the context of ALGS could underlie the early onset of bleeding in these patients. The team found retinal vascular health in the ALGS mice to be severely impaired, with decreased vascular coverage and degenerated ganglion cells.


Hankeova S, Van Hul N, Laznovsky J, et al. Sex differences and risk factors for bleeding in Alagille syndrome. EMBO Mol Med. Published online November 8, 2022. doi:10.15252/emmm.202215809