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Title: The metabolic profiling of hepatocellular carcinoma
Author: Shariff, Mohamed Idroos Fahmy
ISNI:       0000 0004 2732 0856
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Hepatocellular carcinoma (HCC), the commonest primary liver tumour, is curable if detected early. It is often diagnosed late, carrying a devastating prognosis. In part, this is due to lack of accurate diagnostic markers. Using proton nuclear magnetic resonance (1H NMR) spectroscopy and ultra performance liquid chromatography mass spectrometry (UPLC-MS), metabolic profiles of plasma, serum and urine were generated from an animal model of HCC and three cohorts of patients with HCC from Nigeria, Egypt and the UK. Plasma 1H NMR spectra from an animal model of HCC displayed decreases in lipoproteins, acetyl-glycoprotein, acetoacetate and glucose (p≤0.001). Blood 1H NMR studies of Nigerian and Egyptian patients with HCC compared to healthy controls and those with cirrhosis revealed alterations in levels of LDL (p=0.002, 0.12), VLDL (p=<0.001, 0.77), lactate (p=0.03, 0.12), N-acetylglycoproteins (p=<0.001, 0.001) and acetoacetate (p=0.52, 0.06). Using UPLC-MS blood profiling, lysophosphatidylcholine (24, 0, 0) (LPC), a major cell membrane component, was identified as altered between groups. Urine 1H NMR spectral profiles were distinguished in a Nigerian, mostly HBV-infected HCC cohort, with a sensitivity/specificity of 100%/93% and 89.5%/88.9% from healthy subjects and patients with cirrhosis. Urinary creatinine (p<0.001, 0.06), carnitine (p=0.04, <0.001) and creatine (p=0.05, 0.29) were contributory. In an Egyptian, mostly HCV-infected HCC cohort, sensitivity/specificity was 100%/94% and 81%/71%, displaying reduced creatinine (p=0.003, <0.001), glycine (p=<0.001, 0.88), trimethylamine-N-oxide (p=<0.001, 0.18), hippurate (p=<0.001, 0.66), citrate (p=<0.001, 0.12) and increased carnitine (p=0.29, 0.30) and creatine (p=0.12, 0.33) levels. In the UK cohort, sensitivity/specificity was 53.6%/96%. UPLC-MS of urine from the Nigerian HCC cohort identified elevated acetylcarnitine levels (p=0.07, <0.001). Both in blood and urine, HCC induces a metabolic profile change that can distinguish patients from healthy or cirrhotic controls. Furthermore, there exists some similarity between distinct populations. Underlying pathways may include heightened cellular proliferation, altered cellular, aberrant lipid metabolism and cancer cachexia.
Supervisor: Taylor-Robinson, Simon ; Khan, Shahid ; Cox, Jane Sponsor: London Clinic Fellowship Scheme ; Alan Morement Memorial Fund
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral