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{{Hepatopulmonary syndrome}}
{{Hepatopulmonary syndrome}}
{{CMG}}; {{AE}} {{Soroush}}
{{CMG}}; {{AE}} {{Soroush}}
==Overview==
==Overview==


The exact pathogenesis of hepatopulmonary syndrome is not fully understood. Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental hepatopulmonary syndrome, and thus might underlie hepatopulmonary syndrome in humans. It is thought that hepatopulmonary syndrome is the result of microscopic intrapulmonary arteriovenous dilatations due to either increased liver production or decreased the liver clearance of [[Vasodilator|vasodilators]], possibly involving [[nitric oxide]]. The progression to hepatopulmonary syndrome is believed that involves the  [[Nitric oxide|nitric oxid]]<nowiki/>e [[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 [[Lung|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 [[Capillary|capillaries]] per [[red blood cell]], exacerbating the [[hypoxemia]]. As discussed below a variety of angiogenesis-related genes polymorphism has been linked to hepatopulmonary syndrome. Increased levels of endothelin-1 in cirrhotic patients have been correlated with intrapulmonary molecular and gas exchange abnormalities, hypothesizing a probable contribution to the pathogenesis of hepatopulmonary syndrome.


==Pathophysiology==
===Physiology===




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 [[Vasodilator|vasodilators]], possibly involving [[nitric oxide]]. The progression to hepatopulmonary syndrome is believed that involves the  [[Nitric oxide|nitric oxid]]<nowiki/>e [[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 [[Lung|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 [[Capillary|capillaries]] per [[red blood cell]], exacerbating the [[hypoxemia]].
<br />
==Pathophysiology==
===Physiology===
'''Nitric oxide'''
'''Nitric oxide'''


Line 24: Line 17:
* The [[endothelium]] (inner lining) of [[blood vessel]]s 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.  
* The [[endothelium]] (inner lining) of [[blood vessel]]s 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 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).    [http://jpet.aspetjournals.org/cgi/content/abstract/317/1/341].
* 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).    [http://jpet.aspetjournals.org/cgi/content/abstract/317/1/341].
Line 36: Line 29:
*The vascular smooth muscle cells detaching and loosening signaled by Ang2 enables the migration and sprouting of endothelial cells.  
*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.
*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.
*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.  
*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.  
*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.
*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.
* 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.
*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.  
*In pathologic conditions such as ischemic myocardium, arteriogenesis can allow for as much as a 20-fold enlargement of collateral network vessels.  
Line 105: Line 98:


===Pathogenesis===
===Pathogenesis===
Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental hepatopulmonary syndrome, and thus might underlie hepatopulmonary syndrome in humans.<ref name="pmid18509123">Rodríguez-Roisin R, Krowka MJ (2008) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18509123 Hepatopulmonary syndrome--a liver-induced lung vascular disorder.] ''N Engl J Med'' 358 (22):2378-87. [http://dx.doi.org/10.1056/NEJMra0707185 DOI:10.1056/NEJMra0707185] PMID: [https://pubmed.gov/18509123 18509123]</ref>
<ref name="pmid11003635">Fallon MB, Abrams GA (2000) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11003635 Pulmonary dysfunction in chronic liver disease.] ''Hepatology'' 32 (4 Pt 1):859-65. [http://dx.doi.org/10.1053/jhep.2000.7519 DOI:10.1053/jhep.2000.7519] PMID: [https://pubmed.gov/11003635 11003635]</ref>
<ref name="pmid14762853">Krowka MJ, Mandell MS, Ramsay MA, Kawut SM, Fallon MB, Manzarbeitia C et al. (2004) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=14762853 Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database.] ''Liver Transpl'' 10 (2):174-82. [http://dx.doi.org/10.1002/lt.20016 DOI:10.1002/lt.20016] PMID: [https://pubmed.gov/14762853 14762853]</ref>
<ref name="pmid891282">Kennedy TC, Knudson RJ (1977) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=891282 Exercise-aggravated hypoxemia and orthodeoxia in cirrhosis.] ''Chest'' 72 (3):305-9. [http://dx.doi.org/10.1378/chest.72.3.305 DOI:10.1378/chest.72.3.305] PMID: [https://pubmed.gov/891282 891282]</ref>
'''Vasodilators'''
'''Vasodilators'''


*The exact [[pathogenesis]] of the hepatopulmonary syndrome is not completely understood.
*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 [[Vasodilator|vasodilators]], possibly involving [[nitric oxide]].
*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 [[Vasodilator|vasodilators]], possibly involving [[nitric oxide]].<ref name="pmid8620957">Cremona G, Higenbottam TW, Mayoral V, Alexander G, Demoncheaux E, Borland C et al. (1995) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8620957 Elevated exhaled nitric oxide in patients with hepatopulmonary syndrome.] ''Eur Respir J'' 8 (11):1883-5. PMID: [https://pubmed.gov/8620957 8620957]</ref>
*The progression to hepatopulmonary syndrome is believed that involves the nitric oxide metabolism.
<ref name="pmid9328302">Rolla G, Brussino L, Colagrande P, Dutto L, Polizzi S, Scappaticci E et al. (1997) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=9328302 Exhaled nitric oxide and oxygenation abnormalities in hepatic cirrhosis.] ''Hepatology'' 26 (4):842-7. [http://dx.doi.org/10.1053/jhep.1997.v26.pm0009328302 DOI:10.1053/jhep.1997.v26.pm0009328302] PMID: [https://pubmed.gov/9328302 9328302]</ref>
<ref name="pmid11549549">Nunes H, Lebrec D, Mazmanian M, Capron F, Heller J, Tazi KA et al. (2001) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11549549 Role of nitric oxide in hepatopulmonary syndrome in cirrhotic rats.] ''Am J Respir Crit Care Med'' 164 (5):879-85. [http://dx.doi.org/10.1164/ajrccm.164.5.2009008 DOI:10.1164/ajrccm.164.5.2009008] PMID: [https://pubmed.gov/11549549 11549549]</ref>
<ref name="pmid9824266">Luo B, Abrams GA, Fallon MB (1998) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=9824266 Endothelin-1 in the rat bile duct ligation model of hepatopulmonary syndrome: correlation with pulmonary dysfunction.] ''J Hepatol'' 29 (4):571-8. PMID: [https://pubmed.gov/9824266 9824266]</ref>
<ref name="pmid16628648">Gómez FP, Barberà JA, Roca J, Burgos F, Gistau C, Rodríguez-Roisin R (2006) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16628648 Effects of nebulized N(G)-nitro-L-arginine methyl ester in patients with hepatopulmonary syndrome.] ''Hepatology'' 43 (5):1084-91. [http://dx.doi.org/10.1002/hep.21141 DOI:10.1002/hep.21141] PMID: [https://pubmed.gov/16628648 16628648]</ref>
 
*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|hypoxemi]]<nowiki/>a.
*The dilation of these blood vessels causes overperfusion relative to ventilation, leading to ventilation-perfusion mismatch and [[Hypoxemia|hypoxemi]]<nowiki/>a.
*There is an increased gradient between the partial pressure of [[oxygen]] in the [[Pulmonary alveolus|alveoli of the lung]] and adjacent arteries (alveolar-arterial [A-a] gradient) while breathing room air.
*There is an increased gradient between the partial pressure of [[oxygen]] in the [[Pulmonary alveolus|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|supine positio]]<nowiki/>n improves oxygenation as blood is redistributed from the bases to the apices.
*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|supine positio]]<nowiki/>n 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]].
*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'''
'''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-related genes polymorphism has been linked to hepatopulmonary syndrome.
* As discussed below a variety of angiogenesis realated genes polimorphism has been linked to hepatopulmonary syndrome.
*An increased levels of endothelin-1 in cirrhotic patients have been correlated with intrapulmonary molecular and gas exchange abnormalities, hypothesizing a probable contribution to the pathogenesis of hepatopulmonary syndrome.<ref name="pmid24731444">Zhang J, Yang W, Hu B, Wu W, Fallon MB (2014) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=24731444 Endothelin-1 activation of the endothelin B receptor modulates pulmonary endothelial CX3CL1 and contributes to pulmonary angiogenesis in experimental hepatopulmonary syndrome.] ''Am J Pathol'' 184 (6):1706-14. [http://dx.doi.org/10.1016/j.ajpath.2014.02.027 DOI:10.1016/j.ajpath.2014.02.027] PMID: [https://pubmed.gov/24731444 24731444]</ref>


==Genetics==
==Genetics==
Line 140: Line 144:
Conditions associated with hepatopulmonary syndrome include:
Conditions associated with hepatopulmonary syndrome include:


*[Condition 1]
*'''Chronic liver disease''' of virtually any etiology such as:
*[Condition 2]
 
*[Condition 3]
:*Alcoholic liver disease
:*[[Cirrhosis]] due to viral disease like HBV, HCV
:*[[Non-alcoholic fatty liver disease|None alcoholic fatty liver disease (NASH)]]
:*Toxin and drug-induced liver disease
:*[[Wilson's disease]]
:*[[Hemochromatosis]]
:*[[Autoimmunity|Autoimmune disorders]] such as:
:** Autoimmune hepatitis
:** Primary biliary cholangitis
:** Primary sclerosing cholangitis
:*Alpha-one antitrypsin deficiency
:*Chronic biliary obstruction
:*Cryptogenic (idiopathic) cirrhosis
:*[[Hepatocellular carcinoma]]
*It also, has even been reported in a number of patients with '''acute liver diseases'''


==Gross Pathology==
==Gross Pathology==
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of hepatopulmonary syndrome.
 
* On [[gross pathology]], dilatation of pulmonary precapillary and capillary vessels, as well as an absolute increase in the number of dilated vessels are characteristic findings of hepatopulmonary syndrome.<ref name="pmid24217535">Padma S, Palaniswamy SS, Gandhi S, Babu K S (2014) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=24217535 Hepatorenal cutaneous syndrome demonstrated by 99mTc macro aggregated albumin whole-body scintigraphy.] ''Clin Nucl Med'' 39 (9):813-5. [http://dx.doi.org/10.1097/RLU.0000000000000278 DOI:10.1097/RLU.0000000000000278] PMID: [https://pubmed.gov/24217535 24217535]</ref>
* Nevertheless, pathological examination of lungs play no role in the diagnosis and management of hepatopulmonary syndrome.
* On the other hand, diagnosis and management of the chronic liver disease are essentially based on pathological sampling and analysis.


==Microscopic Pathology==
==Microscopic Pathology==
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of hepatopulmonary syndrome.
 
* Hepatopulmonary syndrome results from the formation of microscopic intrapulmonary arteriovenous dilations.
* Nevertheless, pathological examination of lungs play no role in the diagnosis and management of hepatopulmonary syndrome.
* On the other hand, diagnosis and management of the chronic liver disease are essentially based on pathological sampling and analysis.<ref name="pmid11003635">Fallon MB, Abrams GA (2000) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11003635 Pulmonary dysfunction in chronic liver disease.] ''Hepatology'' 32 (4 Pt 1):859-65. [http://dx.doi.org/10.1053/jhep.2000.7519 DOI:10.1053/jhep.2000.7519] PMID: [https://pubmed.gov/11003635 11003635]</ref><ref name="pmid15516683">Rodríguez-Roisin R, Krowka MJ, Hervé P, Fallon MB, ERS Task Force Pulmonary-Hepatic Vascular Disorders (PHD) Scientific Committee (2004) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15516683 Pulmonary-Hepatic vascular Disorders (PHD).] ''Eur Respir J'' 24 (5):861-80. [http://dx.doi.org/10.1183/09031936.04.00010904 DOI:10.1183/09031936.04.00010904] PMID: [https://pubmed.gov/15516683 15516683]</ref>
 
<br />


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}


[[Category: (name of the system)]]
[[Category:Surgery]]
[[Category:Medicine]]
[[Category:Pulmonology]]
[[Category:Cardiology]]
[[Category:Gastroentrology]]
[[Category:Up-To-Date]]

Latest revision as of 17:54, 6 September 2019

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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. Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental hepatopulmonary syndrome, and thus might underlie hepatopulmonary syndrome in humans. It is thought that hepatopulmonary syndrome is the result of microscopic intrapulmonary arteriovenous dilatations due to either increased liver production or decreased the 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. As discussed below a variety of angiogenesis-related genes polymorphism has been linked to hepatopulmonary syndrome. Increased levels of endothelin-1 in cirrhotic patients have been correlated with intrapulmonary molecular and gas exchange abnormalities, hypothesizing a probable contribution to the pathogenesis of hepatopulmonary syndrome.

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

Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental hepatopulmonary syndrome, and thus might underlie hepatopulmonary syndrome in humans.[1] [2] [3]

[4]


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.[5]

[6] [7] [8] [9]

  • 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

  • As discussed below a variety of angiogenesis-related genes polymorphism has been linked to hepatopulmonary syndrome.
  • An increased levels of endothelin-1 in cirrhotic patients have been correlated with intrapulmonary molecular and gas exchange abnormalities, hypothesizing a probable contribution to the pathogenesis of hepatopulmonary syndrome.[10]

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. [11]
  • The following genes had at least 2 SNPs associated with the disease:

Associated Conditions

Conditions associated with hepatopulmonary syndrome include:

  • Chronic liver disease of virtually any etiology such as:
  • It also, has even been reported in a number of patients with acute liver diseases

Gross Pathology

  • On gross pathology, dilatation of pulmonary precapillary and capillary vessels, as well as an absolute increase in the number of dilated vessels are characteristic findings of hepatopulmonary syndrome.[12]
  • Nevertheless, pathological examination of lungs play no role in the diagnosis and management of hepatopulmonary syndrome.
  • On the other hand, diagnosis and management of the chronic liver disease are essentially based on pathological sampling and analysis.

Microscopic Pathology

  • Hepatopulmonary syndrome results from the formation of microscopic intrapulmonary arteriovenous dilations.
  • Nevertheless, pathological examination of lungs play no role in the diagnosis and management of hepatopulmonary syndrome.
  • On the other hand, diagnosis and management of the chronic liver disease are essentially based on pathological sampling and analysis.[2][13]


References

  1. ↑ Rodríguez-Roisin R, Krowka MJ (2008) Hepatopulmonary syndrome--a liver-induced lung vascular disorder. N Engl J Med 358 (22):2378-87. DOI:10.1056/NEJMra0707185 PMID: 18509123
  2. ↑ 2.0 2.1 Fallon MB, Abrams GA (2000) Pulmonary dysfunction in chronic liver disease. Hepatology 32 (4 Pt 1):859-65. DOI:10.1053/jhep.2000.7519 PMID: 11003635
  3. ↑ Krowka MJ, Mandell MS, Ramsay MA, Kawut SM, Fallon MB, Manzarbeitia C et al. (2004) Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database. Liver Transpl 10 (2):174-82. DOI:10.1002/lt.20016 PMID: 14762853
  4. ↑ Kennedy TC, Knudson RJ (1977) Exercise-aggravated hypoxemia and orthodeoxia in cirrhosis. Chest 72 (3):305-9. DOI:10.1378/chest.72.3.305 PMID: 891282
  5. ↑ Cremona G, Higenbottam TW, Mayoral V, Alexander G, Demoncheaux E, Borland C et al. (1995) Elevated exhaled nitric oxide in patients with hepatopulmonary syndrome. Eur Respir J 8 (11):1883-5. PMID: 8620957
  6. ↑ Rolla G, Brussino L, Colagrande P, Dutto L, Polizzi S, Scappaticci E et al. (1997) Exhaled nitric oxide and oxygenation abnormalities in hepatic cirrhosis. Hepatology 26 (4):842-7. DOI:10.1053/jhep.1997.v26.pm0009328302 PMID: 9328302
  7. ↑ Nunes H, Lebrec D, Mazmanian M, Capron F, Heller J, Tazi KA et al. (2001) Role of nitric oxide in hepatopulmonary syndrome in cirrhotic rats. Am J Respir Crit Care Med 164 (5):879-85. DOI:10.1164/ajrccm.164.5.2009008 PMID: 11549549
  8. ↑ Luo B, Abrams GA, Fallon MB (1998) Endothelin-1 in the rat bile duct ligation model of hepatopulmonary syndrome: correlation with pulmonary dysfunction. J Hepatol 29 (4):571-8. PMID: 9824266
  9. ↑ Gómez FP, Barberà JA, Roca J, Burgos F, Gistau C, Rodríguez-Roisin R (2006) Effects of nebulized N(G)-nitro-L-arginine methyl ester in patients with hepatopulmonary syndrome. Hepatology 43 (5):1084-91. DOI:10.1002/hep.21141 PMID: 16628648
  10. ↑ Zhang J, Yang W, Hu B, Wu W, Fallon MB (2014) Endothelin-1 activation of the endothelin B receptor modulates pulmonary endothelial CX3CL1 and contributes to pulmonary angiogenesis in experimental hepatopulmonary syndrome. Am J Pathol 184 (6):1706-14. DOI:10.1016/j.ajpath.2014.02.027 PMID: 24731444
  11. ↑ 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
  12. ↑ Padma S, Palaniswamy SS, Gandhi S, Babu K S (2014) Hepatorenal cutaneous syndrome demonstrated by 99mTc macro aggregated albumin whole-body scintigraphy. Clin Nucl Med 39 (9):813-5. DOI:10.1097/RLU.0000000000000278 PMID: 24217535
  13. ↑ Rodríguez-Roisin R, Krowka MJ, Hervé P, Fallon MB, ERS Task Force Pulmonary-Hepatic Vascular Disorders (PHD) Scientific Committee (2004) Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J 24 (5):861-80. DOI:10.1183/09031936.04.00010904 PMID: 15516683
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