Hepatic Urea Nitrogen Handling in Patients With NASH

Overview

The aim of the project is to investigate the metabolic regulation of the hepatic urea nitrogen handling and various cognitive functions measured by psychometric and neurophysiological tests before and after bariatric surgery in patients with non-alcoholic fatty liver disease (NAFLD).

NAFLD is the most common cause of chronic liver disease in the western world affecting 10-30% of the general population. It is strongly associated with the metabolic syndrome caused by overweight and obesity. NAFLD is a spectrum of liver disease ranging from steatosis (hepatocytic fat accumulation occurs without hepatocellular injury), to non-alcoholic steatohepatitis (NASH) (steatosis is accompanied by inflammation and hepatocyte injury with or without fibrosis) and to cirrhosis in patients that are not consuming excessive alcohol. The prognosis of patients with simple steatosis appears benign whereas NASH often has a progressive course with increased liver-related morbidity and mortality. Patients with liver disease often have impairment of metabolic liver functions. The liver has numerous functions, which are essential for maintenance of life e.g. urea synthesis. This function is central in whole body nitrogen (N) homeostasis and removes ammonia, which is produced during N conversion and is extremely toxic especially for brain functions. Impairment of urea synthesis causes increased ammonia concentrations in the blood, which is taken up by the brain and contributes to development of hepatic encephalopathy in patients with liver disease. This condition is one of the most debilitating complications of liver disease as it affects cognitive functions and with increasing severity also behaviour and motor function. The mild stage (termed minimal hepatic encephalopathy) causes subtle cognitive dysfunction, which can only be detected by means of special tests. The more severe stages (manifest hepatic encephalopathy) are accompanied by manifest dysfunction of sleep pattern and orientation eventually leading to liver coma. The condition is reversible and no structural brain damage occurs. We seek to investigate the consequences of bariatric surgery on liver and brain function with a special focus on NASH patients. The investigations will comprise examination of the capacity for urea synthesis and various psychometric and neurophysiological tests to evaluate the patient's cognitive functions before and 18 months after surgery. A liver biopsy will be availed at the time of surgical intervention and genetic and functional characterization of urea cycle enzymes will be performed to correlate with histological scores, clinical disease staging and ammonia/capacity for urea synthesis. A further liver biopsy will be performed after 18 months to determine if there has been any change in NAFLD disease stage and urea cycle enzymes after intervention.

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