Hepatopulmonary syndrome
Definition
- Typically defined as a widened alveolar-arterial oxygen gradient (A-a pO2) on room air (>15 mmHg, or >20 mmHg in patients >64 years of age) with or without hypoxemia resulting from intrapulmonary vasodilatation in the presence of hepatic dysfunction or portal hypertension.
- The hallmark of HPS is intrapulmonary vasodilatation of the precapillary and capillary vessels, impairing arterial oxygenation. A few pleural and pulmonary arteriovenous communications (shunts) and portopulmonary venous anastomosis are common findings as well.
Other key points
- Incidence is 15 to 20% in those with cirrhosis
- Can co exist with other cardiopulmonary abnormalities.
- A pO2 <70 mmHg is useful for clinically identifying those with significant HPS.
- There is no relationship between the presence or severity of the HPS and the severity of liver disease.
- Severity of hypoxemia appears to be directly related to the extent of intrapulmonary shunt, diffusion-perfusion impairment, or both.
Pathogenesis: current concepts
- Excessive vascular production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) causing vasodilatation.
- Other mediators may contribute to vascular tone i.e. heme oxygenase 1
- Hepatic endothelin-1 (ET-1) appears to be an important mechanism for triggering the increase in pulmonary eNOS and the onset of vasodilatation.
- Progression of HPS results in accumulation of macrophages in the pulmonary microvasculature, which produce inducible NOS & heme oxygenase 1. They respectively release NO and CO, causing further vasodilatation.
- TNF-a contributes to macrophage accumulation.
Clinical manifestations
- Insidious onset of exertional dyspnoea.
- Platypnea: shortness of breath exacerbated by sitting up and improved by lying supine.
- Orthodeoxia: hypoxemia exacerbated by going from supine to a upright position.
- Pulmonary AVMs are predominantly situated at the lung bases. Hence, dependent blood pooling occurs on sitting/standing with subsequent increased AV shunting.
- Clubbing, cyanosis and spider naevi in the presence of liver disease/portal hypertension should raise the suspicion of HPS.
Diagnosis
- Triad
- Of liver disease or portal hypertension
- Of intrapulmonary vasodilatation
- Elevated age adjusted A-a pO2 gradient: [0.26age -0.43] + 10
Investigations
- ABG
- Performed when SpO2 <97% or if history and exam strongly suggests HPS.
- CXR and pulmonary function tests to assess for other pulmonary disorders i.e. hepatic hydrothorax, COPD, pulmonary fibrosis.
- Transthoracic microbubble contrast ECHO
- The left ventricle opacifies at least three cardiac cycles after the right (delayed shunting). Microbubbles do not pass through normal capillaries. This intrapulmonary shunting is characteristic of HPS.
- Macroaggregated albumin scan
- This is useful to determine the contribution of HPS in patients with both intrapulmonary vasodilatation and intrinsic cardiopulmonary disease. Radiolabelled albumin macroaggregates (20um) are infused into the venous circulation. In significant intrapulmonary shunting, a fraction of the macroaggregates pass from the lungs into the systemic circulation. Normally, these particles would become trapped in the pulmonary microvasculature.
- Pulmonary function tests
- Abnormal findings are of low specificity.
- TLC and expiratory flow rates are generally normal in HPS.
- Diffusion impairment for CO is common in HPS.
- Pulmonary angiography
- Low sensitivity for detecting intrapulmonary vasodilatation. Should only be performed when pO2 <60mmHg which is poorly responsive to oxygen administration and when there is a strong suspicion of direct AV communications that may be amenable to embolisation.
- High resolution CT
- Some evidence that quantitation of intrapulmonary vasodilatation is possible
Natural history/prognosis
- The natural history has yet to be fully established but most patients with HPS appear to have progressive intrapulmonary vasodilatation with worsening gas exchange.
- Reported median survival of 24 months and a 5-year survival rate of 23% in those not suitable for OLT.
- Survival and mortality rates are worse for patients with HPS, even after adjustment for the Child Turcotte Pugh classification of liver disease.
- Death is often due to hepatic complications rather than respiratory.
Treatment
- Orthotopic liver transplant is the only effective treatment for HPS. HPS with a pO2 <60mmHg is considered to be an indication for OLT. However, it may take up to a year post transplant for arterial hypoxaemia to normalise.
- Long term oxygen therapy is mainstay treatment for those with pO2 <60mmHg or exertional induced hypoxaemia.
- The role of TIPSS is uncertain and there are no established medical therapies.
Degree of severity
- Mild: Alveolar–arterial oxygen gradient ?15 mm Hg, partial pressure of oxygen ?80 mm Hg
- Moderate: Alveolar–arterial oxygen gradient ?15 mm Hg, partial pressure of oxygen ?60 to <80 mm Hg
- Severe: Alveolar–arterial oxygen gradient ?15 mm Hg, partial pressure of oxygen ?50 to <60 mm Hg
- Very severe: Alveolar–arterial oxygen gradient ?15 mm Hg, partial pressure of oxygen <50 mm Hg (<300 mm Hg while the patient is breathing 100% oxygen).
2.The hepatopulmonary syndrome. Palma DT, Fallon MB. J Hepatol. 2006 Oct;45(4):617-25.
