Surgery (St Vincent's) - Theses
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ItemPrediction of chemotherapy-induced hepatic injuries on clinical, imaging and genetic parameters following treatment of colorectal carcinoma( 2012)Chemotherapy-induced hepatic injuries (CIHI) are an increasingly common and serious problem facing clinicians. Peri-operative outcomes following hepatic resection are inferior in patients with severely injured livers. Development of injury however remains unpredictable. Similar injury phenotypes are associated with other disease states such as diabetes and obesity. It may be possible to predict risk of CIHI by combining an analysis of clinical features with genetic factors known to be involved in the metabolism of chemotherapeutics. Similarly, functional imaging such as hepatic iminodiacetic acid (HIDA) scanning may provide early warning of deteriorating liver function secondary to hepatic injury. A combined model incorporating clinical, imaging and genetic parameters may be able to be developed to provide a risk level for individual patients based on these features. Firstly, 233 samples of non-cancerous hepatic tissue stored in a tissue bank and pathology archive were retrieved and scored for histological hepatic injury (steatosis, steatohepatitis and sinusoidal injury [SI]) using previously validated methods. Clinical features regarding these patients were extracted and correlated with degree of injury. Next, applying a candidate gene approach employing genes known to be relevant regarding tumour response or host toxicity, genetic features were correlated with hepatic injury and peri-operative outcomes. mRNA expression data, genetic sequencing for known polymorphisms and probing for presence of absence of other relevant isoforms of relevant genes was undertaken. A pilot study was then developed to prospectively assess hepatic injury comparing pre-chemotherapy samples of non-cancerous hepatic tissue with tissue collected at hepatic resection following treatment. HIDA scanning was performed pre- and post-chemotherapy, and genetic features were analyzed using microarray mRNA expression techniques. Injury rates were 18%, 4% and 19% for steatosis, steatohepatitis and SI, respectively. On multivariate analysis, high-grade steatosis was more common in diabetics [odds ratio (OR)=3.24, p=0.01] and patients with higher weight (OR/kg=1.04, p=0.02) and steatohepatitis was increased with metabolic syndrome (OR=5.54, p=0.02). Chemotherapy overall demonstrated a trend towards approximately doubled risk of high-grade steatosis and steatohepatitis while not affecting SI. Pre-operative chemotherapy was however associated with increased SI on multivariate analysis (OR=3.39, p<0.001). Operative morbidity was not increased with chemotherapy, but was increased with steatosis (OR=2.38, p<0.001). Low-level DPD mRNA expression was associated with steatosis on multivariate analysis (OR=1.53 p=0.03). Presence of GSTT1 was associated with sinusoidal injury (regardless of chemotherapy administration status) OR=5.31 (p=0.01). Preliminary results suggest changes in HIDA clearance rate and excretion half-life may herald hepatic injury. It appears there is a specific microarray expression signature in non-cancerous liver tissue indicative of severe hepatic injury following treatment with chemotherapy. Predisposition to development of CIHI may be predictable based upon individual patient characteristics, such as diabetes and higher weight (for steatosis), metabolic syndrome (for steatohepatitis) or pre-operative chemotherapy use (SI). Into this equation, low expression of DPD mRNA needs to be considered regarding steatosis, and GSTT1 presence for SI. HIDA parameters may contribute baseline characteristics predictive of injury, but this requires further validation. Similarly, microarray expression analyses also appear promising regarding identifying an injury-prone subgroup pre-treatment. It is the presence of high-grade injury (particularly steatosis) that increases peri-operative morbidity and not administration of chemotherapy as such.