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Elevated Levels of Endothelin-1 in Hepatic Venous Blood Are Associated with Intrapulmonary Vasodilatation in Humans

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Abstract

Background

Hepatopulmonary syndrome is a pulmonary vascular complication of cirrhosis in which intrapulmonary vasodilatation (IPV) results in hypoxemia. Endothelin-1 (ET-1), produced by proliferating cholangiocytes, has been identified as a mediator of IPV in an animal model of HPS, but the pathophysiology of IPV in humans has not been defined.

Aim

The purpose of this study was to assess whether cirrhosis with IPV, which often leads to HPS, is associated with increased hepatic venous ET-1 blood levels.

Methods

We performed a prospective cohort pilot study of 40 patients with liver disease undergoing transjugular liver biopsy from November 1, 2008 to September 1, 2009. Patients were categorized according to absence (−) or presence (+) of IPV as determined by bubble-contrasted echocardiography. Hepatic venous blood was assayed for ET-1 by ELISA. The percent volume of cholangiocytes in the liver biopsy specimen was determined by morphometric analysis, as a measure of bile duct proliferation.

Results

Nine subjects were excluded, due to absence of cirrhosis (6) and patent foramen ovale (3). Of the remaining 31 subjects, IPV was present in 18 (58%). Median hepatic venous ET-1 was higher with IPV+ than IPV− at levels of 9.1 pg/mL (range 7.5–11.7) versus 2.1 pg/mL (1.3–5.6), respectively (P = 0.004). ET-1 levels correlated positively with cholangiocyte percent volume (r = 0.72, P < 0.001) but not with measures of liver dysfunction (bilirubin, INR, MELD score, or hepatic venous pressure gradient).

Conclusion

In human cirrhosis, increased hepatic venous ET-1 is associated with IPV and increased hepatic cholangiocyte volume.

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Abbreviations

BDP:

Bile duct proliferation

BC-TTE:

Bubble-contrasted transthoracic echocardiography

CTP:

Child-Turcotte-Pugh

CSPH:

Clinically significant portal hypertension

CBDL:

Common bile duct ligation

CK7:

Cytokeratin 7

DAB:

Diaminobenzidine

ET-1:

Endothelin-1

HV:

Hepatic venous

HVPG:

Hepatic venous pressure gradient

HPS:

Hepatopulmonary syndrome

IPV:

Intrapulmonary vasodilatation

LT:

Liver transplantation

MELD:

Model of end stage liver disease

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Acknowledgment

This project was funded by the South Carolina Clinical & Translational Research Institute, Medical University of South Carolina’s CTSA, NIH/NCRR Grant Number UL1RR029882 and the American College of Gastroenterology Junior Faculty Development Award. Imaging facilities were supported, in part, by Cancer Center Support Grant P30 CA138313 to the Hollings Cancer Center.

Conflict of interest

None.

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, ART 7100A, 25 Courtenay Dr. MSC 290, Charleston, SC, 29425, USA

    David G. Koch & Adrian Reuben

  2. Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA

    Galina Bogatkevich

  3. Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA

    Venkat Ramshesh & John J. Lemasters

  4. Division of Interventional Radiology, Medical University of South Carolina, Charleston, SC, USA

    Renan Uflacker

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  1. David G. Koch
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Correspondence to David G. Koch.

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Koch, D.G., Bogatkevich, G., Ramshesh, V. et al. Elevated Levels of Endothelin-1 in Hepatic Venous Blood Are Associated with Intrapulmonary Vasodilatation in Humans. Dig Dis Sci 57, 516–523 (2012). https://doi.org/10.1007/s10620-011-1905-6

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  • DOI: https://doi.org/10.1007/s10620-011-1905-6

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