Abstract
BackgroundHereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease with a varying range of phenotypes involving abnormal vasculature primarily manifested as arteriovenous malformations in various organs, including the nose, brain, liver, and lungs. The varied presentation and involvement of different organ systems makes the choice of potential treatment medications difficult.ResultsA patient with a mixed-clinical presentation and presumed diagnosis of HHT, severe exertional dyspnea, and diffuse pulmonary shunting at the microscopic level presented for treatment. We sought to analyze her metabolomic plasma profile to assist with pharmacologic treatment selection. Fasting serum samples from 5 individuals (4 healthy and 1 with HHT) were metabolomically profiled.A global metabolic network reconstruction, Recon 1, was used to help guide the choice of medication via analysis of the differential metabolism between the patient and healthy controls using metabolomic data. Flux Balance Analysis highlighted changes in metabolic pathway activity, notably in nitric oxide synthase (NOS), which suggested a potential link between changes in vascular endothelial function and metabolism. This finding supported the use of an already approved medication, bevacizumab (Avastin). Following 2 months of treatment, the patient's metabolic profile shifted, becoming more similar to the control subject profiles, suggesting that the treatment was addressing at least part of the pathophysiological state.ConclusionsIn this 'individualized case study' of personalized medicine, we carry out untargeted metabolomic profiling of a patient and healthy controls. Rather than filtering the data down to a single value, these data are analyzed in the context of a network model of metabolism, in order to simulate the biochemical phenotypic differences between healthy and disease states; the results then guide the therapy. This presents one approach to achieving the goals of individualized medicine through Systems Biology and causal models analysis.
Highlights
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease with a varying range of phenotypes involving abnormal vasculature primarily manifested as arteriovenous malformations in various organs, including the nose, brain, liver, and lungs
We considered the treatment of an individual patient and through comparative analysis of her metabolomic profile with non-HHT individuals, differences were identified using constraint-based analysis of a global human metabolic network reconstruction, Recon 1 [17]
The atrial septal defect (ASD) repair resolved the syncopal episodes, her dyspnea continued unabated to the point where she could not walk her dog without getting chest pain and expectorating small amounts of blood streaked sputum
Summary
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease with a varying range of phenotypes involving abnormal vasculature primarily manifested as arteriovenous malformations in various organs, including the nose, brain, liver, and lungs. Further investigation with contrast echocardiography showed she had a large right to left shunt at the pulmonary capillary level but had no treatable AVMs on computed tomography (CT) scan of the chest Her resting oxygen saturations were 97-99% but with effort could decrease to the high 80’s. Because of a strong family history cancer of the colon and some occasional blood streaks in her stool, a colonic endoscopy was done revealing several small polyps in her small intestine and telengiectasias in her large intestine that were ablated with laser therapy Her Endoglin and ALK-1 gene analysis were negative including SMAD-4. Based upon these findings as well as a family history of familial adenomatous polyposis and a sibling with similar diffuse AVMs, a presumed diagnosis of HHT was given based on the Curacao Criteria [18]
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