Hepatopulmonary syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Overview

The exact pathogenesis of hepatopulmonary syndrome is not fully understood. It is thought that hepatopulmonary syndrome is the result of microscopic intrapulmonary arteriovenous dilatations due to either increased liver production or decreased liver clearance of vasodilators, possibly involving nitric oxide. The progression to hepatopulmonary syndrome is believed that involves the nitric oxide metabolism. The dilation of these blood vessels causes overperfusion relative to ventilation, leading to ventilation-perfusion mismatch and hypoxemia. There is an increased gradient between the partial pressure of oxygen in the alveoli of the lung and adjacent arteries (alveolar-arterial [A-a] gradient) while breathing room air. Patients with hepatopulmonary syndrome have platypnea-orthodeoxia syndrome (POS); that is, because intrapulmonary vascular dilations (IPVDs) predominate in the bases of the lungs, standing worsens hypoxemia (orthodeoxia)/dyspnea (platypnea) and the supine position improves oxygenation as blood is redistributed from the bases to the apices. Additionally, late in cirrhosis, it is common to develop high output failure, which would lead to less time in capillaries per red blood cell, exacerbating the hypoxemia.

Pathophysiology

Physiology

Nitric oxide

The normal physiology of nitric oxide can be understood as follows:

• The endothelium (inner lining) of blood vessels use nitric oxide to signal the surrounding smooth muscle to relax, thus dilating the artery and increasing blood flow. This underlies the action of nitroglycerin, amyl nitrate, "poppers" (isobutyl nitrite or similar) and other nitrate derivatives in the treatment of heart disease: The compounds are converted to nitric oxide (by a process that is not completely understood), which in turn dilates the coronary artery (blood vessels around the heart), thereby increasing its blood supply. Nitric oxide also acts on cardiac muscle to decrease contractility and heart rate. The vasodilatory actions of nitric oxide play a key role in renal control of extracellular fluid homeostasis. Nitric oxide also plays a role in erection of the penis. Nitric oxide is also a second messenger in the nervous system and has been associated with neuronal activity and various functions like avoidance learning.

• Nitric oxide is synthesized by nitric oxide synthase (NOS). There are three isoforms of the NOS enzyme: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) - each with separate functions. The neuronal enzyme (NOS-1) and the endothelial isoform (NOS-3) are calcium-dependent and produce low levels of gas as a cell signaling molecule. The inducible isoform (NOS-2) is calcium independent and produces large amounts of gas which can be cytotoxic.

• Nitric Oxide (NO) is of critical importance as a mediator of vasorelaxation in blood vessels. Platelet-derived factors, shear stress, angiotensin II, acetylcholine, and cytokines stimulate the production of NO by endothelial nitric oxide synthase (eNOS). eNOS synthesizes NO from the terminal guanidine-nitrogen of L-arginine and oxygen and yields citrulline as a byproduct. NO production by eNOS is dependent on calcium-calmodulin and other cofactors. NO, a highly reactive free radical then diffuses into the smooth muscle cells of the blood vessel and interacts with soluble guanylate cyclase. Nitric oxide stimulates the soluble guanylate cyclase to generate the second messenger cyclic GMP (3’,5’ guanosine monophosphate)from guanosine triphosphate (GTP). The soluble cGMP activates cyclic nucleotide-dependent protein kinase G (PKG or cGKI). PKG is a kinase that phosphorylates a number of proteins that regulate calcium concentrations, calcium sensitization, hyperpolarize cell through potassium channels, actin filament and myosin dynamic alterations that result in smooth muscle relaxation.(see smooth muscle article). [3].

Angiogenesis

• The underlying mechanisms behind angiogenesis are beginning to be discovered.
• The process may begin with vasodilatation mediated by nitric oxide followed by an increase in permeability mediated by VEGF.
• This increased permeability allows for plasma protein extravasation and scaffold formation.
• Endothelial cell migration is supported by adhesion molecules such as PECAM-1 and cadherins.
• The vascular smooth muscle cells detaching and loosening signaled by Ang2 enables the migration and sprouting of endothelial cells.
• The process of angiogenesis is initiated by VEGF by Ang1 and is required to stabilize the endothelial networks and to increase periendothelial cell interactions.
• Platelet derived growth factor (PDGF) stimulates inflammatory cells and promotes cell-cell interactions by molecules such as integrin.
• VEGF has morphogenic effects which allow endothelial cells cords to acquire and enlarge their lumen.
• Unfortunately, muscularization of the network is poorly understood. The process appears to be tissue specific.
• In the coronary arteries, the epicardial layer appears to be the source of smooth muscle cells which migrate under PDGF-BB and VEGF stimulation.
• TGF-beta and downstream transcription factors Smads promote extracellular matrix production and solidify cell-cell interactions.
• FGF can help further this process resulting in arteriogenesis.
• In pathologic conditions such as ischemic myocardium, arteriogenesis can allow for as much as a 20-fold enlargement of collateral network vessels.
• Chemokines and cytokines are upregulated by increased collateral flow which results in monocyte recruitment.
• Monocytes produce proteinases which cause medial destruction and further remodeling.
• Hypoxia-inducible transcription factors (HIF), and their stabilization by peptide regulator 39 help induce and potentiate the neovascularization process.
• Newer imaging techniques utilize knowledge of molecular mechanisms to help enhance image resolution and improve sensitivity and specificity.

Stimulator	Mechanism
FGF	Promotes proliferation & differentiation of endothelial cells, smooth muscle cells, and fibroblasts
VEGF	Affects permeability
VEGFR and NRP-1	Integrate survival signals
Ang1 and Ang2	Stabilize vessels
PDGF (BB-homodimer) and PDGFR	recruit smooth muscle cells
TGF-β, endoglin and TGF-β receptors	↑extracellular matrix production
CCL2	Recruits lymphocytes to sites of inflammation
Histamine
Integrins αVβ3, αVβ5 (?) and α5β1	Bind matrix macromolecules and proteinases
VE-cadherin and CD31	endothelial junctional molecules
ephrin	Determine formation of arteries or veins
plasminogen activators	remodels extracellular matrix, releases and activates growth factors
plasminogen activator inhibitor-1	stabilizes nearby vessels
eNOS and COX-2
AC133	regulates angioblast differentiation
ID1/ID3	Regulates endothelial transdifferentiation
Class 3 semaphorins	Modulates endothelial cell adhesion, migration, proliferation and apoptosis. Alters vascular permeability

Pathogenesis

Vasodilators

• The exact pathogenesis of the hepatopulmonary syndrome is not completely understood.

• It is thought that hepatopulmonary syndrome is the result of microscopic intrapulmonary arteriovenous dilatations due to either increased liver production or decreased liver clearance of vasodilators, possibly involving nitric oxide.
• The progression to hepatopulmonary syndrome is believed that involves the nitric oxide metabolism.
• The dilation of these blood vessels causes overperfusion relative to ventilation, leading to ventilation-perfusion mismatch and hypoxemia.
• There is an increased gradient between the partial pressure of oxygen in the alveoli of the lung and adjacent arteries (alveolar-arterial [A-a] gradient) while breathing room air.
• Patients with hepatopulmonary syndrome have platypnea-orthodeoxia syndrome (POS); that is, because intrapulmonary vascular dilations (IPVDs) predominate in the bases of the lungs, standing worsens hypoxemia (orthodeoxia)/dyspnea (platypnea) and the supine position improves oxygenation as blood is redistributed from the bases to the apices.
• Additionally, late in cirrhosis, it is common to develop high output failure, which would lead to less time in capillaries per red blood cell, exacerbating the hypoxemia.

Angiogenesis

• Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental HPS, and thus might underlie HPS in humans.
• As discussed below a variety of angiogenesis realated genes polimorphism has been linked to hepatopulmonary syndrome.

Genetics

• Polymorphisms in genes involved in the regulation of angiogenesis are associated with the risk of hepatopulmonary syndrome.
• According to a study by Roberts et al. After adjustments for race and smoking, 42 single nucleotide polymorphism (SNP)s in 21 genes were significantly associated with hepatopulmonary syndrome.
• The following genes had at least 2 SNPs associated with the disease:

• CAV3
• ENG
• NOX4
• ESR2
• VWF
• RUNX1
• COL18A1
• TIE1

• 
  

Associated Conditions

Conditions associated with hepatopulmonary syndrome include:

• [Condition 1]
• [Condition 2]
• [Condition 3]

Gross Pathology

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of hepatopulmonary syndrome.

Microscopic Pathology

On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of hepatopulmonary syndrome.