Research

The Neurological Complications of Acute Liver Failure

Brain swelling is an important complication from acute liver failure (ALF), and it is a frequent cause of death in patients who suffer this complication. Some cases of acute liver failure spontaneously recover and some are so destructive that a liver transplant would be required to achieve survival. In either scenario, deterring brain swelling and optimizing brain perfusion when brain swelling does occur is a critical element in creating the option of good survivorship in patients with ALF.Since the conventional approaches to limiting brain swelling and lowering intracranial pressure (ICP) are not reliable in patients with ALF, we have been involved with several projects focused on this important treatable but life-threatening neurological complication. While monitoring ICP is an important step toward properly treating these patients, the ALF causes a coagulopathy that often creates hesitance for inserting an invasive device into the skull. Our extensive experience with this disease led to adopting a standardized approach to ICP monitor placement in ALF patients with coagulopathy. We have since systematically studied this approach and presented and published our results demonstrating the safe insertion of ICP monitors in ALF patients without causing significant hemorrhagic complications. This study has been an important step toward changing the clinical approach to optimizing brain perfusion and neurological outcome in ALF patients.

We have developed a strong interest in the role of continuous hemodialysis techniques to facilitate ammonia clearance, and we have a project dedicated to correlate dialysis flow rates to the quality of ammonia clearance.The mechanism of brain swelling from ALF relates, in part, to hyperammonemia. The liver usually creates urea from the ammonia produced as a byproduct of protein metabolism. When the liver acutely fails, ammonia accumulates and is an important contributing factor to the development of brain swelling. The elevated level of ammonia enhances the conversion of glutamic acid to glutamine within astrocytes (the supporting cells of the brain), and this (through several hypothesized mechanisms) leads to cellular swelling and, in aggregate, brain swelling. While it has been long hypothesized that ammonia is not toxic to neurons, we have recently demonstrated (and formally presented) the unique impact of hyperammonemia on specific brain cortical regions in human survivors. This has recently raised questions on whether high ammonia concentrations may have some toxic effects on neurons in addition to its role in astrocytic swelling.In order to more formally study the role of ammonia in causing brain swelling, we have teamed up with our departmental scientists, and colleagues at other institutions to establish an experimental model using fetal mouse brain organotypic cultures (FMBOTC). This method allows the architectural and physiological preservation of intact slices of brain in culture (absent blood flow) to study the impact of variable environmental conditions. We have employed FMBOTC to explore the dose-response relationship of ammonia concentrations to astrocytic swelling and the potential effect of other systemic mediators that may effect the potency of this relationship. Initial success in establishing this model has led to our formal presentation and publication of our work. It is our hope that in the future we will be able to use this model to discover important modifiable factors that have a critical but yet un-described role in the brain swelling associated with ALF. This, in turn, can potentially lead to new treatments for this deadly problem