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Hepatopulmonary Syndrome and Portopulmonary Hypertension: Pulmonary Vascular Complications of Liver Disease

Kathryn del Valle, Hilary M. DuBrock

10.1002/cphy.c210009

Source: Volume 12, Issue 2, April 2022

Published online: October 2021

Full Article on Wiley Online Library



Abstract

Pulmonary vascular disease is a frequent complication of chronic liver disease and portal hypertension, affecting up to 30% of patients. There are two distinct pulmonary vascular complications of liver disease: hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH). HPS affects 25% of patients with chronic liver disease and is characterized by intrapulmonary vasodilatation and abnormal arterial oxygenation. HPS negatively impacts quality of life and is associated with a 2‐fold increased risk of death compared to controls with liver disease without HPS. Angiogenesis, endothelin‐1 mediated endothelial dysfunction, monocyte influx, and alveolar type 2 cell dysfunction seem to play important roles in disease pathogenesis but there are currently no effective medical therapies. Fortunately, HPS resolves following liver transplant (LT) with improvements in hypoxemia. POPH is a subtype of pulmonary arterial hypertension (PAH) characterized by an elevated mean pulmonary arterial pressure and pulmonary vascular resistance in the setting of normal left‐sided filling pressures. POPH affects 5% to 6% of patients with chronic liver disease. Although the pathogenesis has not been fully elucidated, endothelial dysfunction, inflammation, and estrogen signaling have been identified as key pathways involved in disease pathogenesis. POPH is typically treated with PAH targeted therapy and may also improve with liver transplantation in selected patients. This article highlights what is currently known regarding the diagnosis, management, pathobiology, and outcomes of HPS and POPH. Ongoing research is needed to improve understanding of the pathophysiology and outcomes of these distinct and often misunderstood pulmonary vascular complications of liver disease. © 2021 American Physiological Society. Compr Physiol 12:3281‐3302, 2022.

Figure 1. Figure 1. This figure illustrates the mechanisms of hypoxemia in hepatopulmonary syndrome. In a normal healthy lung with uniform alveolar ventilation and perfusion (Panel A), pulmonary capillary diameter is 8 to 15 μm. Oxygen diffuses into the capillaries and ventilation‐perfusion is matched. In patients with hepatopulmonary syndrome (Panel B), capillaries are dilated and perfusion is not uniform leading to ventilation‐perfusion mismatch. Intrapulmonary shunt and reduced oxygen diffusion into the capillaries may also occur (bold arrows). Reprinted, with permission, from Rodriguez‐Roisin R and Krowka MJ, 2008 119.
Figure 2. Figure 2. This figure illustrates the finding of delayed opacification of the left atrium in hepatopulmonary syndrome. The contrast‐enhanced echocardiograms in Panels (A) and (B) show opacification of the right atrium (RA) and right ventricle (RV) with microbubbles and delayed opacification of the left atrium (LA) and left ventricle (LV). Reprinted, with permission, from Rodriguez‐Roisin R and Krowka MJ, 2008 119.
Figure 3. Figure 3. This figure demonstrates increased uptake of technetium‐labeled MAA in the brain, consistent with intrapulmonary or intracardiac shunting. Panel (A) shows radioactivity of technetium‐labeled MAA in the anterior lungs, and Panel (B) shows radioactivity in the posterior lungs, as well as the kidneys. Panels (C) and (D) show radioactivity in the right and left side of the cerebrum, respectively (uptake in the brain, 62%; normal uptake, <6%). Reprinted, with permission, from Rodriguez‐Roisin R and Krowka MJ, 2008 119.
Figure 4. Figure 4. This figure illustrates the approach to the diagnosis of hepatopulmonary syndrome.
Figure 5. Figure 5. This figure illustrates the current knowledge regarding disease pathophysiology and potential therapeutic targets in hepatopulmonary syndrome. Important features include pulmonary Endothelin‐1 induced endothelial dysfunction, monocyte influx, angiogenesis, and Alveolar type 2 cell dysfunction. Abbreviations: HO‐1, heme oxygenase‐1; PDGFR, PDGF receptor; PlGF, placental growth factor; VEGF‐A, vascular endothelial growth factor‐A; VEGFR1, vascular endothelial growth factor receptor‐1; VEGFR2, vascular endothelial growth factor receptor‐2. Reprinted, with permission, from Raevens S and Fallon MB, 2018 111.
Figure 6. Figure 6. This figure illustrates a general approach to the diagnosis of portopulmonary hypertension. *A diagnosis of portopulmonary hypertension (POPH) can be made in this setting after ruling out alternative causes of pulmonary hypertension.
Figure 7. Figure 7. This figure illustrates the pathologic changes associated with portopulmonary hypertension. Similar to idiopathic pulmonary arterial hypertension, plexogenic lesions, medial hypertrophy, and in‐situ thrombosis are characteristic findings. (A) Plexogenic type. Lung explant from a 37‐year‐old women with stage IV primary biliary cirrhosis who underwent combined heart‐lung‐liver transplantation. Parent pulmonary artery (left) shows medial hypertrophy, as well as intimal fibroelastosis at the origin of the arterial branch. The branch (right) is involved by two microaneurysms (arrows) that contain plexiform lesions (Verhoeff‐van Gieson). (B) Plexogenic type. Autopsy specimen from a 55‐year‐old woman with cryptogenic cirrhosis. This highly obstructive plexiform lesion is acutely occluded by platelet‐fibrin thrombi (pink homogeneous material, arrows) (Hemotoxylin‐eosin). (C) Thrombotic type. Post‐liver transplantation autopsy specimen of the lung (day 7) from a 46‐year‐old man with hepatitis C liver disease and cirrhosis. The muscular pulmonary arteriole is obstructed by a recanalized thrombus, showing two small residual lumens (arrows) (Verhoeff‐van Gieson). (D) Fibrotic type. Post‐liver transplantation autopsy specimen of the lung (day 9) from a 54‐year‐old man with alcoholic cirrhosis and alpha1‐antitrypsin deficiency. (ZZ phenotype). The muscular pulmonary arteriole is completely occluded by an old dense fibrous plug (arrow), presumably of thrombotic origin (Verhoeff‐van Gieson). Reprinted, with permission, from Krowka MJ and Edwards WD, 2000 73.


Figure 1. This figure illustrates the mechanisms of hypoxemia in hepatopulmonary syndrome. In a normal healthy lung with uniform alveolar ventilation and perfusion (Panel A), pulmonary capillary diameter is 8 to 15 μm. Oxygen diffuses into the capillaries and ventilation‐perfusion is matched. In patients with hepatopulmonary syndrome (Panel B), capillaries are dilated and perfusion is not uniform leading to ventilation‐perfusion mismatch. Intrapulmonary shunt and reduced oxygen diffusion into the capillaries may also occur (bold arrows). Reprinted, with permission, from Rodriguez‐Roisin R and Krowka MJ, 2008 119.


Figure 2. This figure illustrates the finding of delayed opacification of the left atrium in hepatopulmonary syndrome. The contrast‐enhanced echocardiograms in Panels (A) and (B) show opacification of the right atrium (RA) and right ventricle (RV) with microbubbles and delayed opacification of the left atrium (LA) and left ventricle (LV). Reprinted, with permission, from Rodriguez‐Roisin R and Krowka MJ, 2008 119.


Figure 3. This figure demonstrates increased uptake of technetium‐labeled MAA in the brain, consistent with intrapulmonary or intracardiac shunting. Panel (A) shows radioactivity of technetium‐labeled MAA in the anterior lungs, and Panel (B) shows radioactivity in the posterior lungs, as well as the kidneys. Panels (C) and (D) show radioactivity in the right and left side of the cerebrum, respectively (uptake in the brain, 62%; normal uptake, <6%). Reprinted, with permission, from Rodriguez‐Roisin R and Krowka MJ, 2008 119.


Figure 4. This figure illustrates the approach to the diagnosis of hepatopulmonary syndrome.


Figure 5. This figure illustrates the current knowledge regarding disease pathophysiology and potential therapeutic targets in hepatopulmonary syndrome. Important features include pulmonary Endothelin‐1 induced endothelial dysfunction, monocyte influx, angiogenesis, and Alveolar type 2 cell dysfunction. Abbreviations: HO‐1, heme oxygenase‐1; PDGFR, PDGF receptor; PlGF, placental growth factor; VEGF‐A, vascular endothelial growth factor‐A; VEGFR1, vascular endothelial growth factor receptor‐1; VEGFR2, vascular endothelial growth factor receptor‐2. Reprinted, with permission, from Raevens S and Fallon MB, 2018 111.


Figure 6. This figure illustrates a general approach to the diagnosis of portopulmonary hypertension. *A diagnosis of portopulmonary hypertension (POPH) can be made in this setting after ruling out alternative causes of pulmonary hypertension.


Figure 7. This figure illustrates the pathologic changes associated with portopulmonary hypertension. Similar to idiopathic pulmonary arterial hypertension, plexogenic lesions, medial hypertrophy, and in‐situ thrombosis are characteristic findings. (A) Plexogenic type. Lung explant from a 37‐year‐old women with stage IV primary biliary cirrhosis who underwent combined heart‐lung‐liver transplantation. Parent pulmonary artery (left) shows medial hypertrophy, as well as intimal fibroelastosis at the origin of the arterial branch. The branch (right) is involved by two microaneurysms (arrows) that contain plexiform lesions (Verhoeff‐van Gieson). (B) Plexogenic type. Autopsy specimen from a 55‐year‐old woman with cryptogenic cirrhosis. This highly obstructive plexiform lesion is acutely occluded by platelet‐fibrin thrombi (pink homogeneous material, arrows) (Hemotoxylin‐eosin). (C) Thrombotic type. Post‐liver transplantation autopsy specimen of the lung (day 7) from a 46‐year‐old man with hepatitis C liver disease and cirrhosis. The muscular pulmonary arteriole is obstructed by a recanalized thrombus, showing two small residual lumens (arrows) (Verhoeff‐van Gieson). (D) Fibrotic type. Post‐liver transplantation autopsy specimen of the lung (day 9) from a 54‐year‐old man with alcoholic cirrhosis and alpha1‐antitrypsin deficiency. (ZZ phenotype). The muscular pulmonary arteriole is completely occluded by an old dense fibrous plug (arrow), presumably of thrombotic origin (Verhoeff‐van Gieson). Reprinted, with permission, from Krowka MJ and Edwards WD, 2000 73.
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Article Title: Hepatopulmonary Syndrome and Portopulmonary Hypertension: Pulmonary Vascular Complications of Liver Disease
 

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Kathryn del Valle, Hilary M. DuBrock. Hepatopulmonary Syndrome and Portopulmonary Hypertension: Pulmonary Vascular Complications of Liver Disease. Compr Physiol 2021, 12: 3281-3302. doi: 10.1002/cphy.c210009