Dataset Information

Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease.

ABSTRACT:

Background & aims

Hepatopulmonary syndrome (HPS) affects 10%-30% of patients with cirrhosis and portal hypertension and significantly increases mortality. Studies in experimental models indicate that pulmonary angiogenesis contributes to the development of HPS, but pathogenesis in humans is poorly understood. We investigated genetic risk factors for HPS in patients with advanced liver disease.

Methods

We performed a multicenter case-control study of patients with cirrhosis being evaluated for liver transplantation. Cases had an alveolar-arterial oxygen gradient > or = 15 mm Hg (or > or =20 mm Hg if age > 64 years) and contrast echocardiography with late appearance of microbubbles after venous injection of agitated saline (intrapulmonary vasodilatation); controls did not meet both criteria for case status. The study sample included 59 cases and 126 controls. We genotyped 1086 common single nucleotide polymorphisms (SNPs) in 94 candidate genes.

Results

Forty-two SNPs in 21 genes were significantly associated with HPS after adjustments for race and smoking. Eight genes had at least 2 SNPs associated with disease: CAV3, ENG, NOX4, ESR2, VWF, RUNX1, COL18A1, and TIE1. For example, rs237872 in CAV3 showed an odds ratio of 2.75 (95% confidence interval: 1.65-4.60, P = .0001) and rs4837192 in ENG showed an odds ratio of 0.35 (95% confidence interval: 0.14-0.89, P = .027). Furthermore, variation in CAV3 and RUNX1 was associated with HPS in gene-based analyses.

Conclusions

Polymorphisms in genes involved in the regulation of angiogenesis are associated with the risk of HPS. Further investigation of these biologic pathways might elucidate the mechanisms that mediate the development of HPS in certain patients with severe liver disease.

SUBMITTER: Roberts KE

PROVIDER: S-EPMC2908261 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHepatopulmonary syndrome (HPS) is defined by liver dysfunction, intrapulmonary vascular dilatations, and impaired oxygenation. The gold standard for detection of intrapulmonary vascular dilatations in HPS is contrast echocardiography. However, two small studies have suggested that patients with HPS have larger segmental pulmonary arterial diameters than both normal subjects and normoxemic subjects with cirrhosis, when measured by CT. We sought to compare CT imaging-based pulmonary vasodilatation in patients with HPS, patients with liver dysfunction without HPS, and matching controls on CT imaging.MethodsWe performed a retrospective cohort study at two quaternary care Canadian HPS centers. We analyzed CT thorax scans in 23 patients with HPS, 29 patients with liver dysfunction without HPS, and 52 gender- and age-matched controls. We measured the artery-bronchus ratios (ABRs) in upper and lower lung zones, calculated the "delta ABR" by subtracting the upper from the lower ABR, compared these measurements between groups, and correlated them with clinically relevant parameters (partial pressure of arterial oxygen, alveolar-arterial oxygen gradient, macroaggregated albumin shunt fraction, and diffusion capacity). We repeated measurements in patients with post-transplant CTs.ResultsPatients had significantly larger lower zone ABRs and delta ABRs than controls (1.20 +/- 0.19 versus 0.98 +/- 0.10, p<0.01; and 0.12 +/- 0.17 versus -0.06 +/- 0.10, p<0.01, respectively). However, there were no significant differences between liver disease patients with and without HPS, nor any significant correlations between CT measurements and clinically relevant parameters. There were no significant changes in ABRs after liver transplantation (14 patients).ConclusionsBasilar segmental artery-bronchus ratios are larger in patients with liver disease than in normal controls, but this vasodilatation is no more severe in patients with HPS. CT does not distinguish patients with HPS from those with uncomplicated liver disease.