R.F. van Golen
- A treatment rationale for surgery-induced liver injury
T.M. van Gulik
- Award date
- 28 June 2017
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
The surgical removal of a benign or malignant liver tumor is often the only treatment option with curative intent. During liver resection, the hepatic blood supply is surgically halted in order to limit excessive blood loss. This temporary shortage of oxygen triggers a sterile inflammatory response once the hepatic blood supply is restored. This phenomenon is called hepatic ischemia/reperfusion (I/R) injury. I/R injury compromises the recovery of operated patients, in part because it suppresses post-resection liver regeneration. These effects are more pronounced in patients with pre-existing parenchymal liver injury caused by for instance chemotherapy, steatosis, or cholestasis. This thesis describes several aspects of the pathophysiology of hepatic I/R injury. It was first investigated in patients which immunogenic molecules known as “DAMPs” are released after liver surgery. It was shown that HMGB1 is the DAMP most pertinent for clinical liver I/R. Using a newly developed method to visualize and quantify oxidative stress in real time in mice, it was demonstrated that HMGB1 release is likely caused by mitochondrial oxidative stress in the early postoperative phase. The release of HMGB1 could be attenuated using the mitochondria-targeted antioxidant MitoQ, which led to a reduction in I/R injury. In addition, it was shown that cholestasis in particular suppresses liver regeneration after a partial liver resection in rats. Obeticholic acid, an agonist of bile salt receptor FXR, triggered liver growth during cholestasis but did not accelerate liver regeneration after a partial hepatectomy.
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