Pulmonary complications of liver disease

Hepatopulmonary syndrome and porto-pulmonary hypertension had appeared in the exam at least once, as Question 28 from the second paper of 2022. In this case the candidates were instructed to compare these conditions with hepatorenal syndrome in a table presenting their definitions pathophysiology and specific treatment.

So:

Hepato-pulmonary syndrome Porto-pulmonary hypertension Hepatorenal syndrome
Definitions
  • "An arterial oxygenation defect induced by intrapulmonary vascular dilatations associated with hepatic disease"
  • "Pulmonary arterial hypertension associated with portal hypertension, with or without hepatic disease" 
  • "Kidney injury resulting from renal vasoconstriction in the setting of systemic and splanchnic arterial vasodilatation in patients with advanced cirrhosis"
Pathophysiology
  • Increased vasodilator molecule release due to liver disease (NO, CO, endothelin-1)
  • Thus, impaired hypoxic pulmonary vasoconstriction and  enhanced angiogenesis,  producing V/Q mismatch and arteriovenous shunts
  • Decreased hepatic metabolism of vasoconstrictor substances
  • Hyperdynamic pulmonary circulation (thus, shear stress in the pulmonary vessels)
  • Increased inflammatory cytokines 
  • Thromboembolic phenomena originating in the portal circulation
  • Splanchnic arterial and venous vasodilation due to increase NO, CO, endothelin-1
  • Blood volume sequestration in  the splanchnic circulation
  • Compensatory renin-angiotensin-aldosterone overactivity and sympathetic overactivity
  • Thus,  renal arterial vasoconstriction
Specific treatment
  • Long term home oxygen
  • Cavoplasty
  • Angioembolisation of shunting AVMs
  • TIPS
  • Transplant
  • Oral and inhaled pulmonary vasodilators:
  • Prostacyclin
  • Phosphodiesterase inhibitors
  • Endothelin receptor antagonists
  • Noradrenaline
  • Albumin
  • Terlipressin
  • Octreotide
  • TIPS
  • Transplant

Unless otherwise stated, the information summarised here mainly comes from the excellent paper by Benz et al (2020).

Hepato-pulmonary syndrome

The definition for this entity, given by the ERS task force in 2005, is 

"An arterial oxygenation defect induced by intrapulmonary vascular dilatations associated with hepatic disease"

The usual association is with chronic liver disease where such dilatations are more likely to form, but in all fairness even acute liver failure can produce this sort of thing, because there is nothing in the pathophysiology that might insist on a slow onset. Observe:

  • In liver disease (acute or chronic), there is an increase in the amount of circulating vasodilatory mediators, specifically nitric oxide, endothelin-1 and carbon monoxide
  • This is due to an increased hepatic production of endothelin-1 and the increased expression of endothelial nitric oxide synthase seen in portal hypertension (as it produces systemic endotoxemia by permitting an increase in bacterial gut translocation)
  • The result is the delivery of vasodilatory mediators to the pulmonary circulation
  • The excess vasodilation affects oxygenation by:
    • Impairing hypoxic pulmonary vasoconstriction
    • Increasing intrapulmonary shunting
    • With chronic exposure, enhanced angiogenesis occurs, producing chronic arteriovenous shunts
  • The result is V/Q mismatch, specifically shunt.

This is apparently seen in a large number of cirrhosis patients (up to 30%). Platypnoea (where the patients experience an improvement in respiratory distress when they are laying flat) is often found, together with orthodeoxia (where oxygenation improves with lying down and deteriorates with upright position).

Portopulmonary hypertension

The definition for this entity, given by the ERS task force in 2005, is 

"Pulmonary arterial hypertension associated with portal hypertension, with or without hepatic disease"

Though the college examiners ask about the pathophysiology - there is no established scientific consensus with regards to how this thing happens. "A remodeling process of the pulmonary vasculature leads to increased pulmonary vascular resistance" is the best they can do, it seems. If one had to fill an SAQ answer with unscientific conjecture about the pathogenesis of this condition, it would consist of:

  • Decreased hepatic metabolism of vasoconstrictor substances
  • Hyperdynamic pulmonary circulation (thus, shear stress in the pulmonary vessels)
  • Increased inflammatory cytokines 
  • Thromboembolic phenomena originating in the portal circulation

The net effect is pulmonary hypertension. Interestingly, there does not seem to be a correlation between the severity of the pulmonary hypertension and the severity of the liver disease; in other words this is not necessarily seen with just the severe end stage versions.

Hepatic hydrothorax

Pleural effusions are ubiquitous in ICU patients anyway, and so one might reasonably ask what hoops an effusion must jump through in order to be declared a "hydrothorax". The reader is reminded that pleural effusions do not form spontaneously for no specific reason, and that there is usually an explanation for them, such as heart failure, pneumonia, subdiaphragmatic collection, et cetera. A hepatic hydrothorax is therefore a pleural effusion where there is no such explanation, and where there is ascites. Specific features therefore include:

  • Transudative biochemistry
  • Low cell count
  • No other explanatory condition (eg. heart failure)
  • The presence of ascites and/or portal hypertension (ascites is 

These are also usually seen on the right side (80%), more so than the left. The prevailing hypothesis for how these form involves fluid from the abdomen sloshing up into the pleural cavity along diaphragmatic defects, hitherto hidden. This also accounts for the right-sided preference of such effusions, as the diaphragm on the right is thinner and less muscular (Huang et al, 2005). As intraabdominal pressure becomes increased, the negative pressure in the pleural cavity sucks the ascites up into the chest. It does not help that these patients also concurrently experience several other "effusiogenic" influences, sich as hypoalbuminaemia and RAAS-mediated fluid accumulation.

Spontaneous bacterial empyema

A collection of proteinaceous fluid in the chest is an inviting culture medium for any passing organisms. It is therefore not even remotely surprising that, once a hepatic hydrothorax has formed, an empyema is not far behind. The identification of this collection would therefore rely on the finding of clinical sepsis, intrapleural organisms, and/or polymorphonuclear leukocytes on thoracocentesis (>250/μL with bugs, or >500/μL without). 

References

Benz, Fabian, et al. "Pulmonary complications in patients with liver cirrhosis." Journal of translational internal medicine 8.3 (2020): 150-158.

Huang, Pei-Ming, et al. "The morphology of diaphragmatic defects in hepatic hydrothorax: thoracoscopic finding." The Journal of thoracic and cardiovascular surgery 130.1 (2005): 141-145.

Rodriguez-Roisin, R., et al. "Pulmonary–hepatic vascular disorders (PHD)." European Respiratory Journal 24.5 (2004): 861-880.

Krowka, Michael J. "Hepatopulmonary syndrome and portopulmonary hypertension: the pulmonary vascular enigmas of liver disease." Clinical Liver Disease 15.Suppl 1 (2020): S13.