The hepatopulmonary syndrome: NO way out?: Fig. 1.—

Abstract

"How diseases of the liver affect lung function?" is one of those puzzling questions that can turn obsessive for those who want to understand how two seemingly distinctive organs can interact and eventually lead to severe disorders [1,2]. The most common respiratory consequence of liver disease is hypoxaemia, which is often mild to moderate [3]. Seldom severe hypoxaemia occurs when the arterial pressure of oxygen (Pa,O 2 ) falls below 8 kPa (60 mmHg), heralding the occurrence of a condition known as the "hepatopulmonary syndrome" (HPS). HPS is characterised by a triad of conditions, namely: 1) advanced liver disease (with or without liver cirrhosis); 2) widespread intrapulmonary vasodilatation; and 3) alveolar-arterial oxygen gradient (PA-a,O 2 ) w2.6 kPa (20 mmHg) whilst breathing room air [2,3]. Clinical symptoms typically include shortness of breath, which may either worsen on standing (platypnoea) and/or be accompanied by a 10% fall in Pa,O 2 (orthodeoxia). As with other lung disorders, hypoxaemia results from impaired gas exchange, which, in HPS, is particularly perturbed by excessive and widespread dilatation of intrapulmonary vessels. After decades of careful investigations, the underlying mechanisms linking altered gas exchange and pulmonary vasodilatation are now well delineated [2][3][4]. Reduced tone causing vascular relaxation occurs at both ends of the capillary bed, i.e. affecting pre-capillary and post-capillary vessels. This allows mixed venous blood to speed through, or even bypass, gas exchange units. It is believed that hypoxaemia occurs as a result of one (or the combination of several) of these following mechanisms: 1) ventilation-perfusion mismatching (reflecting excess perfusion for a given ventilation); 2) true intrapulmonary anatomical shunts; and 3) diffusion-perfusion impairment (due to increased oxygen diffusion distance from alveoli to haemoglobin across the dilated vessels) [5][6][7][8][9]. Vascular dilatation can be observed using contrast-enhanced echocardiography or fractional brain uptake after lung perfusion of technetium-99m macroaggregated albumin lung scanning [10].As pulmonary vasodilatation is the main culprit, hunting endogenous vasodilators that reduce pulmonary vascular tone logically became a sound strategy for those whose quest was to unravel the missing "molecular" link between the diseased liver and the affected lung. Nitric oxide (NO), one of the most potent and prominent endogenous pulmonary vasodilators [11], soon appeared as a very likely candidate, not only for the hyperdynamic circulatory syndrome in cirrhosis [12], but also for HPS [13]. This hypothesis has been further consolidated in the light of clinical and experimental results from several recent studies [2]. First, pulmonary endogenous production of NO, which can be assessed by measuring exhaled NO [14], is increased in patients with HPS [15][16][17][18] and returns to normal values 3-12 months after orthotopic liver transplantation [17,18]. Interestingly, normalisation of exhaled NO concentrations was ...

Highlights of the ERS Task Force on pulmonary-hepatic vascular disorders (PHD)☆

“…More recently, the accumulation of intravascular macrophages has also been found to be an important source of NO as well as carbon monoxide generated by haeme oxygenase-1 (HO-1). Both ET-1 and tumour necrosis factor-alpha (TNF-a) appear to contribute and may interact in the development of experimental HPS [4,5].…”

Inhaled iloprost for hepatopulmonary syndrome: improvement of hypoxemia

“…NO antagonists such as methylene blue or NG-nitro-L-arginine-methylester (L-NAME) have been suggested as possible therapies [14][15][16][17]. NO release by endotoxin production secondary to enteral translocation of Gram-negative bacteria due to portal hypertension has been suggested to cause excessive pulmonary vasodilation.…”

Hepatopulmonary syndrome: proposed mediators of pulmonary vasodilation

“…Since nitrogen (II) oxide (NO) is recognized as one of the most powerful endogenous pulmonary vasodilators, it has been suggested as the most likely candidate not only for the hyperdynamic type of circulation in liver cirrhosis but also for HPS 10 . As a lipophilic molecule, NO easily diffuses through cell membranes into the neighbouring cells (e.g.…”