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
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].
Pathogenesis
- 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 HPS 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.
Genetics
- Polymorphisms in genes involved in the regulation of angiogenesis are associated with the risk of HPS.
- According to a study by Roberts et al. After adjustments for race and smoking, 42 SNPs in 21 genes were significantly associated with HPS. [1]
- 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.
References
- ↑ Roberts KE, Kawut SM, Krowka MJ, Brown RS, Trotter JF, Shah V et al. (2010) Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease. Gastroenterology 139 (1):130-9.e24. DOI:10.1053/j.gastro.2010.03.044 PMID: 20346360