Relationship Between the Development of Impaired Glucose Tolerance, the Phenotype of CFLD, and the Risk of Liver Fibrosis

CF - Cystic Fibrosis, Cystic Fibrosis Liver Disease, Cystic Fibrosis-related Diabetes

This study proposes to examine the relationship between the development of impaired glucose tolerance, the phenotype of CFLD, and risk of liver fibrosis.

Pancreas insufficiency is a well-established risk factor for development of CF related diabetes (CFRD), but increased insulin resistance has also been demonstrated in this population. Cystic fibrosis liver disease (CFLD) is a well-established risk factor for the development CFRD. In addition, patients with CFLD and CFRD at high risk of development of severe CFLD and cirrhosis. Recent work has shown that male CF patients with abnormal oral glucose tolerance tests were noted to have elevations in ALT but the significance of this finding has yet to be fully explored. Specifically, an unresolved question remains on whether the elevation in ALT reflects a steatohepatitis as would be observed in a non-CF population or if the increased insulin resistance contributes to fibrosis progression in the classic biliary type cirrhosis seen in cystic fibrosis (CF). Metabolic dysfunction with increasing insulin resistance has been shown to be a key component to the development of non-alcoholic steatosis hepatitis in a non-CF population. The presence of hepatic steatosis has been demonstrated in the CF population, but thus far not been linked to the development of significant steatohepatitis or cirrhosis. One potential explanation for this discordance between effects of hepatic steatosis in the CF and non-CF population, is in the non-CF population it requires multiple decades for hepatic steatosis to result in steatohepatitis and progression to cirrhosis, therefore the progressive fibrosis may not be seen in the CF population due to limited life expectancy. However, as the life expectancy in of patients with CF is increasing with new therapy, the longer-term consequences of hepatic steatosis maybe apparent Alternatively, the presence of increased insulin resistance has been correlated to increase fibrosis progression in other forms of liver disease such as hepatitis C. Therefore, another potential mechanism is the insulin resistance seen in patients with CFRD results in increased fibrosis and development of cirrhosis in patients with classic CFLD. Thus, further characterizing the underlying liver disease phenotype and fibrosis risk in this population is of interest. We propose to examine the relationship between the development of impaired glucose tolerance, the phenotype of CFLD, and risk of liver fibrosis.

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