On the basis of limited experimental and clinical studies, increased activity of the vasodilatory
nitric oxide-cyclic
guanosine monophosphate pathway is considered to play a key role in the pathogenesis of
hepatopulmonary syndrome. We report a 46-year-old woman with Child-Pugh class C
cirrhosis and progressive dyspnoea for 12 months. Investigations revealed elevated circulating concentrations of
nitric oxide metabolites and exhaled
nitric oxide levels, an hyperdynamic circulation with low systemic vascular resistance and mean arterial pressure, a large right to left intrapulmonary shunt fraction on radiolabelled macroaggregated
albumin perfusion scanning, positive contrast-enhanced echocardiography, reduced diffusion capacity of
carbon monoxide, hypoxaemia and orthodeoxyia, all in keeping with severe
hepatopulmonary syndrome. Sequential inhibition of the
nitric oxide-cyclic
guanosine monophosphate pathway using
curcumin (
diferuloylmethane),
terlipressin and
methylene blue was associated with substantial improvements in vascular tone and the hyperdynamic circulation. No improvement, however, in the intrapulmonary shunt was demonstrated. Both hypoxaemia and
orthodeoxia were substantially, reproducibly and reversibly worsened with all three treatments. Our findings argue against the contention that intrapulmonary shunting and impairment in arterial oxygenation in
hepatopulmonary syndrome are necessarily the consequence of on-going,
nitric oxide-cyclic
guanosine monophosphate-mediated vasodilatation, at least in the chronic stage, and, given the possibility of substantial worsening of pulmonary
oxygen exchange, suggest that inhibition of the
nitric oxide-cyclic
guanosine monophosphate pathway should be avoided in this setting.