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Hepatopulmonary Disorders: Gas Exchange and Vascular Manifestations in Chronic Liver Disease

Robert Rodríguez‐Roisin, Michael J. Krowka, Alvar Agustí

10.1002/cphy.c170020

Source: Volume 8, Issue 2, April 2018

Published online: March 2018

Full Article on Wiley Online Library



ABSTRACT

This review concentrates on the determinants of gas exchange abnormalities in liver‐induced pulmonary vascular disorders, more specifically in the hepatopulmonary syndrome. Increased alveolar‐arterial O2 difference, with or without different levels of arterial hypoxemia, and reduced diffusing capacity represent the most characteristic gas exchange disturbances in the absence of cardiac and pulmonary comorbidities. Pulmonary gas exchange abnormalities in the hepatopulmonary syndrome are unique encompassing all three pulmonary factors determining arterial PO2, that is, ventilation‐perfusion imbalance, increased intrapulmonary shunt and oxygen diffusion limitation that, combined, interplay with two relevant nonpulmonary determinants, that is, increased total ventilation and high cardiac output. Behind the complexity of this lung‐liver association there is an abnormal pulmonary vascular tone that combines inhibition of hypoxic pulmonary vasoconstriction with a reduced (or blunted) hypoxic vascular response. The pathology and pathobiology include the presence of intrapulmonary vascular dilatations with or without pulmonary vascular remodeling, i.e. angiogenesis. Liver transplantation, the only effective therapeutic approach to successfully improve and resolve the vast majority of complications induced by the hepatopulmonary syndrome, along with a large list of frustrating pharmacologic interventions, are also reviewed. Another liver‐induced pulmonary vascular disorder with less gas exchange involvement, such as portopulmonary hypertension, is also considered. © 2018 American Physiological Society. Compr Physiol 8:711‐729, 2018.

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Figure 1. Figure 1. (A) Mechanisms of gas exchange, namely, ventilation‐perfusion matching with absence of intrapulmonary shunt and of oxygen diffusion limitation, under normal conditions. (B) Mechanisms of arterial hypoxemia in the hepatopulmonary syndrome that illustrate intrapulmonary vascular dilatations inducing ventilation‐perfusion imbalance, the main pulmonary determinant, perhaps with mild increased intrapulmonary shunt, with or without diffusion limitation to oxygen [reproduced with permission from Ref. (91)].
Figure 2. Figure 2. Pulmonary vascular resistance (expressed in mmHg/L/min) (top) and ventilation‐perfusion imbalance (as assessed by the dispersion of pulmonary blood flow—dimensionless) (bottom) responses to three inspired oxygen fractions breathing in subjects with liver cirrhosis (94). Compared to ambient air, pulmonary vascular resistance increases significantly as opposed to unchanged ventilation‐perfusion inequalities during hypoxic breathing; by contrast, pulmonary vascular resistance remains unaltered with further ventilation‐perfusion worsening during hyperoxic breathing.
Figure 3. Figure 3. Pulmonary vascular resistance (expressed in mmHg/L/min) (top) and ventilation‐perfusion imbalance (as assessed by the dispersion of pulmonary blood flow—dimensionless) (bottom) responses to the breathing of different inspired oxygen fractions in subjects with liver cirrhosis without and with spiders (94). Compared to ambient air, individuals without spiders (left) increase pulmonary vascular resistance whereas ventilation‐perfusion imbalance remains unchanged during 11% oxygen (hypoxic) breathing (left); by contrast, in subjects with spiders (right) pulmonary vascular resistance remains unaltered while ventilation‐perfusion worsens, that is, the dispersion of pulmonary blood flow, during 100% oxygen (hyperoxic) breathing (right), overall reinforcing the view of a paradoxical behavior of the pulmonary vasculature in those with worse liver dysfunction (i.e., with spiders).
Figure 4. Figure 4. Lineal carbon monoxide diffusing capacity (DLCO) (as % predicted) and inverse (left) intrapulmonary shunt negative associations (right) (y‐axes), respectively, with arterial PO2 (x‐axis) in subjects with hepatopulmonary syndrome, candidates to liver transplantation [reproduced with permission from Ref. (74)].
Figure 5. Figure 5. Both a descriptor of ventilation‐perfusion imbalance (intrapulmonary shunt and areas with low ventilation‐perfusion ratios) (left) and the inert gas diffusion component of arterial hypoxemia, expressed as the difference between the predicted inert and measured (actual) arterial PO2, (right) (y‐axes) correlate inversely with carbon monoxide diffusing capacity (DLCO) (as % predicted) (x‐axis) in subjects with hepatopulmonary syndrome, candidates for liver transplantation [reproduced with permission from Ref. (74)].
Figure 6. Figure 6. Alveolar‐arterial O2 difference (top) and carbon monoxide diffusing capacity (DLCO) (as % predicted) (bottom) values in individuals with hepatopulmonary syndrome, before and after liver transplantation, assessed at mid‐term (median, 15 months) and at long‐term (median, 86 months) (bars indicate mean values). While each value of alveolar‐arterial O2 difference decrease, that reflect individual respective increases in arterial PO2, diffusing capacity values remain unaltered [reproduced with permission from Ref. (72)].
Figure 7. Figure 7. Postural‐induced major differences (bars) on arterial blood gases, ventilation‐perfusion imbalance, cardiac output (Q˙T), and total ventilation in individuals with the hepatopulmonary syndrome with (solid bars) and without (gray bars) orthodeoxia (from top to bottom) (DISP R‐E* represents an overall index of ventilation‐perfusion heterogeneity—dimensionless; ns, not significant) [reproduced with permission from Ref. (47)]. For further explanation, see text.
Figure 8. Figure 8. Arterial PO2, AaPO2 (alveolar‐arterial PO2 difference), intrapulmonary shunt (expressed as percentage of cardiac output), and an overall index of ventilation‐perfusion imbalance (DISP R‐E*) values, before and after acute nebulization of NG‐nitro‐l‐arginine methyl ester (L‐NAME) (arrows), in subjects with hepatopulmonary syndrome (bars indicate mean values) [reproduced with permission from Ref. (46)].


Figure 1. (A) Mechanisms of gas exchange, namely, ventilation‐perfusion matching with absence of intrapulmonary shunt and of oxygen diffusion limitation, under normal conditions. (B) Mechanisms of arterial hypoxemia in the hepatopulmonary syndrome that illustrate intrapulmonary vascular dilatations inducing ventilation‐perfusion imbalance, the main pulmonary determinant, perhaps with mild increased intrapulmonary shunt, with or without diffusion limitation to oxygen [reproduced with permission from Ref. (91)].


Figure 2. Pulmonary vascular resistance (expressed in mmHg/L/min) (top) and ventilation‐perfusion imbalance (as assessed by the dispersion of pulmonary blood flow—dimensionless) (bottom) responses to three inspired oxygen fractions breathing in subjects with liver cirrhosis (94). Compared to ambient air, pulmonary vascular resistance increases significantly as opposed to unchanged ventilation‐perfusion inequalities during hypoxic breathing; by contrast, pulmonary vascular resistance remains unaltered with further ventilation‐perfusion worsening during hyperoxic breathing.


Figure 3. Pulmonary vascular resistance (expressed in mmHg/L/min) (top) and ventilation‐perfusion imbalance (as assessed by the dispersion of pulmonary blood flow—dimensionless) (bottom) responses to the breathing of different inspired oxygen fractions in subjects with liver cirrhosis without and with spiders (94). Compared to ambient air, individuals without spiders (left) increase pulmonary vascular resistance whereas ventilation‐perfusion imbalance remains unchanged during 11% oxygen (hypoxic) breathing (left); by contrast, in subjects with spiders (right) pulmonary vascular resistance remains unaltered while ventilation‐perfusion worsens, that is, the dispersion of pulmonary blood flow, during 100% oxygen (hyperoxic) breathing (right), overall reinforcing the view of a paradoxical behavior of the pulmonary vasculature in those with worse liver dysfunction (i.e., with spiders).


Figure 4. Lineal carbon monoxide diffusing capacity (DLCO) (as % predicted) and inverse (left) intrapulmonary shunt negative associations (right) (y‐axes), respectively, with arterial PO2 (x‐axis) in subjects with hepatopulmonary syndrome, candidates to liver transplantation [reproduced with permission from Ref. (74)].


Figure 5. Both a descriptor of ventilation‐perfusion imbalance (intrapulmonary shunt and areas with low ventilation‐perfusion ratios) (left) and the inert gas diffusion component of arterial hypoxemia, expressed as the difference between the predicted inert and measured (actual) arterial PO2, (right) (y‐axes) correlate inversely with carbon monoxide diffusing capacity (DLCO) (as % predicted) (x‐axis) in subjects with hepatopulmonary syndrome, candidates for liver transplantation [reproduced with permission from Ref. (74)].


Figure 6. Alveolar‐arterial O2 difference (top) and carbon monoxide diffusing capacity (DLCO) (as % predicted) (bottom) values in individuals with hepatopulmonary syndrome, before and after liver transplantation, assessed at mid‐term (median, 15 months) and at long‐term (median, 86 months) (bars indicate mean values). While each value of alveolar‐arterial O2 difference decrease, that reflect individual respective increases in arterial PO2, diffusing capacity values remain unaltered [reproduced with permission from Ref. (72)].


Figure 7. Postural‐induced major differences (bars) on arterial blood gases, ventilation‐perfusion imbalance, cardiac output (Q˙T), and total ventilation in individuals with the hepatopulmonary syndrome with (solid bars) and without (gray bars) orthodeoxia (from top to bottom) (DISP R‐E* represents an overall index of ventilation‐perfusion heterogeneity—dimensionless; ns, not significant) [reproduced with permission from Ref. (47)]. For further explanation, see text.


Figure 8. Arterial PO2, AaPO2 (alveolar‐arterial PO2 difference), intrapulmonary shunt (expressed as percentage of cardiac output), and an overall index of ventilation‐perfusion imbalance (DISP R‐E*) values, before and after acute nebulization of NG‐nitro‐l‐arginine methyl ester (L‐NAME) (arrows), in subjects with hepatopulmonary syndrome (bars indicate mean values) [reproduced with permission from Ref. (46)].
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Further Reading

Fritz JS, Fallon MB and Kawut SM. Pulmonary Vascular Complications of Liver Disease. American Journal of Respiratory and Critical Care Medicine 187: 133-143, 2013.

Krowka MJ, Fallon MB, Kawut SM, Fuhrmann V, Heimbach JK, Ramsay MA, Sitbon O and Sokol RJ. International Liver Transplant Society Practice Guidelines: Diagnosis and Management of Hepatopulmonary Syndrome and Portopulmonary Hypertension. Transplantation 100: 1440-1452, 2016.

Rodriguez-Roisin R, Krowka MJ, Herve P and Fallon MB. Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J 24: 861-880, 2004.

Rodriguez-Roisin R and Krowka MJ. Hepatopulmonary syndrome--a liver-induced lung vascular disorder. N Engl J Med 358: 2378-2387, 2008.

Wagner PD. The physiological basis of pulmonary gas exchange: implications for clinical interpretation of arterial blood gases. Eur Respir J 45: 227-243, 2015.

Teaching Material

R. Rodríguez-Roisin, M. J. Krowka, A. Agustí. Hepatopulmonary Disorders: Gas Exchange and Vascular Manifestations in Chronic Liver Disease. Compr Physiol. 8: 2018, 711-729.

Didactic Synopsis

Major Teaching Points:

  • The paradigm of liver-induced vascular diseases is the hepatopulmonary syndrome, a triad characterized by arterial deoxygenation, intrapulmonary vascular dilatations and hepatic disorder.
  • The key criterion of arterial deoxygenation encompasses an increased alveolar-arterial O2 difference, with or without arterial hypoxemia, arterial hypocapnia, and reduced diffusing capacity.
  • These gas exchange disturbances are essentially induced by ventilation-perfusion imbalance that can be associated with mild-to-moderate increases in intrapulmonary shunt and some diffusion limitation to oxygen transfer.
  • The gas exchange response to 100% oxygen is characterized by ventilation-perfusion worsening without changes in intrapulmonary shunt suggesting inhibition of hypoxic pulmonary vasoconstriction.
  • The hypoxic vascular response can be reduced or abolished pointing to a paradoxical behavior of the underlying pulmonary vascular bed.
  • Portopulmonary hypertension, the other relevant liver-induced pulmonary vascular disorder, is dominated by the hemodynamic hallmarks of the abnormal pulmonary circulatory state with little gas exchange impairment.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: (A) This figure illustrates the three pulmonary factors governing pulmonary gas exchange, namely ventilation-perfusion matching with absence of intrapulmonary shunt and of oxygen diffusion limitation, under normal, healthy conditions while breathing ambient air using the simile of a two-compartmental lung model. (B) Abnormal mechanisms of arterial hypoxemia in the hepatopulmonary syndrome encompassing ventilation-perfusion imbalance, the main pulmonary determinant, that can associate mild increased intrapulmonary shunt, with or without diffusion limitation to oxygen, in the most advances severe conditions [reproduced with permission from Ref. (91)].

Figure 3. Pulmonary vascular resistance (expressed in mmHg/L/min) (top) and ventilation-perfusion imbalance (as assessed by the dispersion of pulmonary blood flow—dimensionless) (bottom) responses to the breathing of different inspired oxygen fractions in subjects with liver cirrhosis without and with spiders (94). Compared to ambient air, individuals without spiders increase pulmonary vascular resistance whereas ventilation-perfusion imbalance remains unchanged during 11% oxygen (hypoxic) breathing (left); by contrast, in subjects with spiders pulmonary vascular resistance remains unaltered while ventilation-perfusion worsens, that is, the dispersion of pulmonary blood flow, during 100% oxygen (hyperoxic) breathing (right), overall reinforcing the view of a paradoxical behavior of the pulmonary vasculature in those with worse liver dysfunction (i.e., with spiders) (see Figure 2).

Figure 4. Teaching points: The lineal correlation between diffusing capacity for carbon monoxide (DLCO) (as % predicted) (left) combined with the negative association with intrapulmonary shunt (right) in subjects with hepatopulmonary syndrome, candidates to liver transplantation [reproduced with permission from Ref. (74)], indicate the close interaction between the three components of gas exchange abnormalities (physiologic and inert gases and carbon monoxide transfer factor).

Figure 5. Both a descriptor of ventilation-perfusion imbalance (intrapulmonary shunt and areas with low ventilation-perfusion ratios) (left) and the inert gas diffusion component of arterial hypoxemia, expressed as the difference between the predicted inert and measured (actual) arterial PO2, (right) (y-axes) correlate inversely with carbon monoxide diffusing capacity (DLCO) (as % predicted) (x-axis) in subjects with hepatopulmonary syndrome, candidates for liver transplantation.

Figure 6. Alveolar-arterial O2 difference (top) and carbon monoxide diffusing capacity (DLCO) (as % predicted) (bottom) values in individuals with hepatopulmonary syndrome, before and after liver transplantation, assessed at mid-term (median,15 months) and at long-term (median, 86 months). While each value of alveolar-arterial O2 difference decrease, that reflect individual respective increases in arterial PO2, diffusing capacity values remain unaltered.

Figure 7. Teaching points: Bars represent changes that reflect measured differences between upright and supine postures in arterial and mixed venous PO2, and their pulmonary (shunt + low VA/Q [ventilation-perfusion]) and DISP R-E* (an overall index of ventilation-perfusion heterogeneity—dimensionless) and nonpulmonary determinants (minute ventilation and cardiac output) of gas exchange in individuals with hepatopulmonary syndrome with (solid bars) and without orthodeoxia (gray bars). Of note that, in individuals who develop orthodeoxia, there is more arterial deoxygenation (decreases in arterial and mixed venous PO2) induced by higher intrapulmonary shunt and areas with low ventilation-perfusion ratios, without changes in the nonpulmonary determinants (ns, not significant) [reproduced with permission from Ref. (47)]. For further explanation, see text.

Figure 8. Arterial PO2, alveolar-arterial PO2, intrapulmonary shunt and an overall index of ventilation-perfusion imbalance (DISP R-E*) values, before and after acute nebulization of NG-nitro-l-arginine methyl ester (L-NAME) (arrows), in subjects with hepatopulmonary syndrome.


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Article Title: Hepatopulmonary Disorders: Gas Exchange and Vascular Manifestations in Chronic Liver Disease
 

How to Cite

Robert Rodríguez‐Roisin, Michael J. Krowka, Alvar Agustí. Hepatopulmonary Disorders: Gas Exchange and Vascular Manifestations in Chronic Liver Disease. Compr Physiol 2018, 8: 711-729. doi: 10.1002/cphy.c170020