Novel therapies in chronic liver disease
thesisposted on 01.03.2017 by Hodge, Alexander David
In order to distinguish essays and pre-prints from academic theses, we have a separate category. These are often much longer text based documents than a paper.
This thesis will address the two foremost concerns in clinical hepatology today: finding a treatment for those with cirrhosis and treating the emerging epidemic of non-alcoholic fatty liver disease (NAFLD). These two issues represent the two ends of the chronic liver disease spectrum. End-stage disease is a chronic fibrotic disease, the result of any number of aetiologies. In situations where the underlying cause cannot be treated or the treatment is unsuccessful, there is a need for an anti-fibrotic, liver regenerative treatment to address this cirrhotic end stage. Currently there are no successful therapies and the scarcity of donors and increase in demand means transplantation is not a viable treatment strategy for the majority of people. In Chapters 2 & 3 in my thesis I assessed a novel, readily available, and plentiful cell-based therapy, the amniotic epithelial cell (hAEC). I examined the mechanisms through which hAEC reduce liver scarring by affecting the cell involved in this process, the hepatic stellate cell (HSC). I have shown that hAEC release soluble factors in vitro that have an anti-fibrotic effect on HSC through reduced proliferation, activation, collagen production and increased collagenase activity. In an animal model of chronic liver disease I showed that both hAEC and conditioned media (CM) therapy reduced liver fibrosis. However, only hAEC tempered the expression of liver progenitor cell (LPC) markers in the diseased liver, a marker of disease severity. Furthermore I examined the effects of hAEC on the LPC to assist in the restoration of liver parenchyma in chronic liver disease. I have shown that in vitro, hAEC induce LPC proliferation and differentiation into hepatocytes through soluble factors. These chapters add to the growing body of evidence for the use of hAEC as a therapy in chronic liver disease, which one day may enter human trials. NAFLD is emerging as the most common chronic liver disease in the world. Successful treatment strategies are needed to manage this condition before cirrhosis develops. There are no successful medical therapies for NAFLD, leaving lifestyle modification by diet and exercise the only successful intervention. However, poor adherence to these regimens and poor long-term response necessitates the need for a new approach. In chapter 4 I have explained the results of a 12-week randomised controlled clinical trial (with subsequent 12-week cross over) of a novel lifestyle modification compared to standard care calorie restriction / exercise advice in the treatment of NAFLD and its associated metabolic conditions. I have shown that both intermittent fasting and standard care advice result in weight, total body fat mass and body mass index reduction with improvements in leptin and adiponectin. However, only intermittent fasting resulted in an improvement in transient elastography, waist circumference, visceral fat volume, blood pressure and insulin resistance. Intermittent fasting was also well tolerated and well adhered. When groups crossed over to the alternative arms, those who changed from standard care to intermittent fasting noted continued improvements in weight, waist circumference, total body fat mass and transient elastography. Whereas, those who changed from intermittent fasting to standard care advice gained weight, waist circumference, total body fat mass and developed insulin resistance. Through this pilot study I have shown that counting minutes not calories by adhering to intermittent fasting is a well tolerated, safe and cheap method that in addition to weight and total body fat loss appears to target the liver and visceral adiposity in a way that standard diet and exercise advice do not. I hope that the results of this pilot study can form the basis for further research in larger trials with liver histological endpoints.