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Title: Aetiology of an unknown liver disease in northern Ethiopia
Author: Robinson, Oliver James Kaldor
ISNI:       0000 0004 2735 479X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Cases of a novel form of liver disease, localised to a cluster of villages in the Tigray region of Northern Ethiopia, were first reported in 2001. Up to January 2010, 591 cases were recorded, including 228 deaths. Symptoms include epigastric and abdominal swelling. Children are particularly susceptible, with some children having died within three months of the onset of symptoms, whereas some adults report living with the disease for many years. The pattern of spread suggested an environmental toxin was the causative agent, with investigations implicating the plant toxins, pyrrolizidine alkaloids. The ultimate aim of the research presented in this thesis was to determine the aetiology of the disease and a multi-disciplinary approach, involving clinical research, ethnography, biochemical and metabonomic analysis and toxicology, has been employed to achieve this. The disease was first characterised clinically: The disease presents with epigastric pain, initial bloody diarrhoea and progressive ascites with either hepatomegaly or splenomegaly or both. Histology of liver biopsy specimens revealed centrilobular necrosis in acute cases and bile ductular proliferation and fibrosis in chronic cases. Biochemical analysis identified γ-glutamyl transferase as a sensitive indicator of the disease. Ethnographic investigation of the lifestyle of the residents of the affected villages revealed a monotonous diet, the presence of a similar disease among livestock and suggested millet and animal products as potential sources of exposure to the aetiological agent(s). The pesticide DDT was identified as a further potential risk factor for the disease. A global metabonomic analysis of patient urine samples using 1H NMR spectroscopy was conducted and several metabolites associated with the disease were identified. Targeted LC-MS assays were then developed to detect pyrrolizidine alkaloid exposure among patients, either through detection of the parent alkaloid, acetyllycopsamine (AL), in urine samples or extraction and detection of pyrrolic metabolite adducts from whole blood. Relative AL urinary concentrations were found to be significantly higher among cases. AL was shown to be hepatotoxic in the mouse model, and at high doses induced centrilobular hepatic necrosis and metabolic changes similar to that observed in the human disease. Finally, DDT was detected at high levels in patient urine and serum samples. DDT was shown to substantially enhance the toxic effects of AL in the mouse model, through induction of the CYP3A11 enzyme, and in combination with AL induced liver pathology closely resembling the human disease. In conclusion, the available evidence suggests that the disease arises from co-exposure to DDT and pyrrolizidine alkaloids, including AL.
Supervisor: Toledano, Mireille ; Thursz, Mark Sponsor: Economic and Social Research Council ; Schistosomiasis Control Initiative
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral