Patients with portal hypertension are at increased risk of pulmonary hypertension (termed portopulmonary hypertension). Patients with portopulmonary hypertension suffer from increased morbidity and mortality. In addition, pulmonary hypertension may delay or prevent liver transplantation. The etiology of portopulmonary hypertension is unknown. Endothelin-1 and serotonin are potent pulmonary vasoconstrictors which have been implicated in other forms of pulmonary arterial hypertension. Endothelin-1 binds to endothelin A receptors, causing vasoconstriction and vascular smooth muscle mitogenesis. Single nucleotide polymorphisms in both the preproendothelin gene (Lys198Asn) and the endothelin A receptor gene (-231A/G) have been described. Serotonin is transported into cells by a transporter protein. The promoter region of this gene has an insertion/deletion polymorphism which directly affects the level of serotonin transporter expression and has been associated with the presence of pulmonary hypertension. Investigators have recently found a mutation in a TGF-beta superfamily receptor which accounts for certain forms of pulmonary hypertension. The presence of these genetic variations could explain the occurrence of PPHTN in only certain patients with portal hypertension. We propose a case-control study of patients with portopulmonary hypertension to assess the risk associated with genetic alterations in the endothelin, serotonin, and TGF-beta signalling pathways. This proposal would forge a six-center collaboration of personnel with the skills needed to study this life-threatening pulmonary vascular complication of portal hypertension. The investigators would collect and store pertinent clinical data and a bank of plasma and genetic samples for this and future analyses. The results of this protocol would lead to a larger prospective cohort study of risk factors for portopulmonary hypertension. In addition, this pilot study could suggest targeted preventative or therapeutic modalities, leading to clinical trials for an """"""""orphan"""""""" disease routinely excluded from other research programs and trials of therapy.
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