Materiały źródłowe

• #1 Hepatopulmonary syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9403489/

  Hepatopulmonary syndrome (HPS) is a pulmonary vascular complication of liver disease, which adversely affects prognosis. The disease is characterised by intrapulmonary vascular dilatations and shunts, resulting in impaired gas exchange. A complex interaction between the liver, the gut and the lungs, predominately impacting pulmonary endothelial cells, immune cells and respiratory epithelial cells, is responsible for the development of typical pulmonary alterations seen in HPS. […] The development of impaired gas exchange in HPS has been attributed to 3 mechanisms resulting from alterations in the alveolar microcirculation: V/Q mismatch, diffusion limitation and the presence of direct AV communications. V/Q mismatch results from increased pulmonary blood flow due to microvascular alterations, while ventilation remains unchanged. Diffusion limitation occurs because oxygen must travel a greater distance to bind haemoglobin due to vascular dilation. Direct AV communications bypass the alveolar microcirculation, resulting in direct mixing of venous and arterial blood.

• #2 Review article: Update on current and emergent data on hepatopulmonary syndrome

  https://www.wjgnet.com/1007-9327/full/v24/i12/1285.htm

  Hepatopulmonary syndrome (HPS) is a frequent pulmonary complication of end-stage liver disease, characterized by impaired arterial oxygenation induced by intrapulmonary vascular dilatation. […] Nitric oxide overproduction and angiogenesis seem to be the hallmarks of a complicated pathogenetic mechanism, leading to intrapulmonary shunting and ventilation-perfusion mismatch. […] Intrapulmonary capillary vasodilatations constitute the main anatomic disturbance of HPS leading to impaired arterial oxygenation through ventilation-perfusion mismatch. […] The diameter of the dilated vessels may vary from 15-100 m and in some cases to 500 m when HPS is present, whereas normally it ranges between 8 m and 15 m. […] Dilatation of pre-capillary and capillary vessels in combination with reduced or absent tone of pulmonary vasculature result in increased pulmonary blood flow, which is also boosted by hyperdynamic circulation in liver disease.

• #3 Hepatopulmonary syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9403489/

  Hepatopulmonary syndrome (HPS) is a pulmonary vascular complication of liver disease, which adversely affects prognosis. The disease is characterised by intrapulmonary vascular dilatations and shunts, resulting in impaired gas exchange. A complex interaction between the liver, the gut and the lungs, predominately impacting pulmonary endothelial cells, immune cells and respiratory epithelial cells, is responsible for the development of typical pulmonary alterations seen in HPS. […] The development of impaired gas exchange in HPS has been attributed to 3 mechanisms resulting from alterations in the alveolar microcirculation: V/Q mismatch, diffusion limitation and the presence of direct AV communications. V/Q mismatch results from increased pulmonary blood flow due to microvascular alterations, while ventilation remains unchanged. Diffusion limitation occurs because oxygen must travel a greater distance to bind haemoglobin due to vascular dilation. Direct AV communications bypass the alveolar microcirculation, resulting in direct mixing of venous and arterial blood.

• #4 Review article: Update on current and emergent data on hepatopulmonary syndrome

  https://www.wjgnet.com/1007-9327/full/v24/i12/1285.htm

  As a result, an excessive amount of blood passes through the pulmonary circulation without completing gas exchange, leading to increased alveolar arterial gradient and arterial hypoxemia, particularly during muscular activity. […] Intrapulmonary arteriovenous shunting constitutes another mechanism causing arterial hypoxia in HPS. […] The presence of more pronounced vascular dilatations and arteriovenous communications in lower lung zones may interpret the mechanism of orthodeoxia, i.e. reduction of PaO2 from supine to upright patient position. […] It seems that the severity of arterial hypoxemia is related to the extent of ventilation-perfusion mismatch, intrapulmonary shunting and diffusion impairment. […] Intrapulmonary vascular dilatations seem to be the result of an imbalance between several vasodilators and vasoconstrictors.

• #5 Hepatopulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562169/

  Vasodilation and angiogenesis lead to arteriovenous (AV) shunt formation within pulmonary vasculature, leading to a mismatch of ventilation-perfusion. The pulmonary capillaries are dilated to 15 to 500 mm in HPS compared to a normal diameter between 8 and 15 mm. […] This pulmonary vasodilation, AV shunts, and impaired diffusion lead to ventilation-perfusion mismatch, creating increased alveolar-arterial gradient and hypoxemia. […] Pulmonary vasodilation is most distinct in the lung bases, elucidating the symptoms like platypnoea and orthodeoxia associated with HPS. […] Two types of HPS have been identified based on the location of dilated pulmonary vessels: Type I: Dilatation of vessels at the precapillary levels near gas exchange units of the lungs; supplemental O2 increases PaO2 in this type of HPS. Type II: Larger dilatation of vessels causing arteriovenous shunts away from gas exchange units of lungs; supplemental O2 is not helpful.

• #6 Review article: Update on current and emergent data on hepatopulmonary syndrome

  https://www.wjgnet.com/1007-9327/full/v24/i12/1285.htm

  Hepatopulmonary syndrome (HPS) is a frequent pulmonary complication of end-stage liver disease, characterized by impaired arterial oxygenation induced by intrapulmonary vascular dilatation. […] Nitric oxide overproduction and angiogenesis seem to be the hallmarks of a complicated pathogenetic mechanism, leading to intrapulmonary shunting and ventilation-perfusion mismatch. […] Intrapulmonary capillary vasodilatations constitute the main anatomic disturbance of HPS leading to impaired arterial oxygenation through ventilation-perfusion mismatch. […] The diameter of the dilated vessels may vary from 15-100 m and in some cases to 500 m when HPS is present, whereas normally it ranges between 8 m and 15 m. […] Dilatation of pre-capillary and capillary vessels in combination with reduced or absent tone of pulmonary vasculature result in increased pulmonary blood flow, which is also boosted by hyperdynamic circulation in liver disease.

• #7 Hepatopulmonary syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9403489/

  Hepatopulmonary syndrome (HPS) is a pulmonary vascular complication of liver disease, which adversely affects prognosis. The disease is characterised by intrapulmonary vascular dilatations and shunts, resulting in impaired gas exchange. A complex interaction between the liver, the gut and the lungs, predominately impacting pulmonary endothelial cells, immune cells and respiratory epithelial cells, is responsible for the development of typical pulmonary alterations seen in HPS. […] The development of impaired gas exchange in HPS has been attributed to 3 mechanisms resulting from alterations in the alveolar microcirculation: V/Q mismatch, diffusion limitation and the presence of direct AV communications. V/Q mismatch results from increased pulmonary blood flow due to microvascular alterations, while ventilation remains unchanged. Diffusion limitation occurs because oxygen must travel a greater distance to bind haemoglobin due to vascular dilation. Direct AV communications bypass the alveolar microcirculation, resulting in direct mixing of venous and arterial blood.

• #8 Hepatopulmonary syndrome: update on pathogenesis and clinical features | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/nrgastro.2012.123

  Hepatopulmonary syndrome (HPS) is a serious vascular complication of liver disease that occurs in 532% of patients with cirrhosis. […] The presence of HPS markedly increases mortality. […] 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. […] Defining the mechanisms involved in the microvascular alterations of HPS has the potential to lead to effective medical therapies. […] Excess lung production of gaseous vasodilators, nitric oxide and carbon monoxide contributes to vasodilatation in human and experimental HPS. […] Pulmonary angiogenesis has an additive role in the development of experimental HPS.

• #9 Medical treatment for hepatopulmonary syndrome: a systematic review

  https://rcm.mums.ac.ir/article_3255.html

  Hepatopulmonary syndrome (HPS) is known as a chronic liver disease associated with severe pulmonary deoxygenation due to intrapulmonary vascular vasodilation. […] The exact pathogenesis of HPS is still unclear. […] Nitric oxide synthesis, pulmonary angiogenesis, and endothelin-1 are the main factors responsible for pulmonary vascular bed alternations in HPS patients and also the target of various treatment strategies. […] The major underlying molecular mechanism responsible for the further alternations during the HPS might be the overexpression of TNF-alpha due to endotoxin shock and overexpression of endothelial and inducible nitric oxide synthase which leads to over production of nitric oxide as a major vasodilator factor in HPS. […] Based on clinical and experimental studies, overproduction of NO is proposed as a responsible mechanism of HPS development.

• #10 Hepatopulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562169/

  Hepatopulmonary syndrome (HPS) was first proposed in 1977 based on autopsy and clinical findings. Autopsies showed dilated pulmonary vasculature in patients with liver cirrhosis and were thought to cause some of the pulmonary manifestations seen in patients with chronic liver disease. HPS is defined as reduced arterial oxygen saturation due to dilated pulmonary vasculature in the presence of advanced liver disease or portal hypertension. […] Pulmonary vascular dilatation resulting from an imbalance between vasodilators and vasoconstrictors is thought to be the main cause of HPS. The exact mechanism of vasodilation is not precise, and multiple studies are ongoing to elucidate the exact mechanism. Pulmonary endothelial nitric oxide synthetase (eNOS) stimulation occurs in the lungs as a result of increased hepatic production of endothelin 1 (ET1) and pulmonary endothelin B (ETB) due to stress. eNOS stimulation causes increased nitric oxide (NO) production, a potent vasodilator.

• #11 Review article: Update on current and emergent data on hepatopulmonary syndrome

  https://www.wjgnet.com/1007-9327/full/v24/i12/1285.htm

  The increased production of nitric oxide (NO) and carbon monoxide (CO), two pulmonary vasodilators, constitutes the key process for the development of pulmonary vasodilatation. […] The binding of endothelin-1 to its pulmonary receptor ET-1B triggers the activation of endothelial and inducible nitric oxide synthase (eNOS and iNOS) resulting in elevated NO production and NO-induced pulmonary vasodilatation. […] In patients with liver dysfunction, activation and massive accumulation of intravascular macrophages is observed as a result of intestinal bacterial translocation and endotoxemia. […] These macrophages in the pulmonary vasculature produce proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-), contributing in the NO-mediated vasodilatation through iNOS activation.

• #12 Hepatopulmonary Syndrome: Recent Advances in Treatment

  https://www.medscape.com/viewarticle/778720

  Hepatopulmonary syndrome (HPS) is an important cause of dyspnea and hypoxia in the setting of liver disease, occurring in 10-30% of patients with cirrhosis. It is due to vasodilation and angiogenesis in the pulmonary vascular bed, which leads to ventilation-perfusion mismatching, diffusion limitation to oxygen exchange, and arteriovenous shunting. There is evidence, primarily from animal studies, that vasodilation is mediated by a number of endogenous vasoactive molecules, including endothelin-1 and nitric oxide (NO). In experimental HPS, liver injury stimulates release of endothelin-1 and results in increased expression of ETB receptors on pulmonary endothelial cells, leading to upregulation of endothelial NO synthase (eNOS) and subsequent increased production of NO, which causes vasodilation.

• #13 Hepatopulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562169/

  Translocation of intestinal bacteria and endotoxemia in liver disease patients leads to massive accumulation of macrophages and monocytes in the lungs. These macrophages release tumor necrosis factor-alpha (TNF-alpha) in pulmonary vessels, leading to inducible nitric oxide synthetase (iNOS) activation. iNOS stimulation also causes increased nitric oxide (NO) production. Bacterial accumulation and increased NO cause increased levels of heme oxygenase. Heme oxygenase causes the degradation of heme and leads to increased carbon monoxide (CO) production. Being potent vasodilators, this increased production of NO and CO plays a crucial role in pulmonary vasodilatation. Also, macrophages, monocytes, and TNF alpha activate vascular endothelial growth factor (VEGF), leading to increased angiogenesis in the pulmonary vasculature.

• #14 Review article: Update on current and emergent data on hepatopulmonary syndrome

  https://www.wjgnet.com/1007-9327/full/v24/i12/1285.htm

  The increased production of nitric oxide (NO) and carbon monoxide (CO), two pulmonary vasodilators, constitutes the key process for the development of pulmonary vasodilatation. […] The binding of endothelin-1 to its pulmonary receptor ET-1B triggers the activation of endothelial and inducible nitric oxide synthase (eNOS and iNOS) resulting in elevated NO production and NO-induced pulmonary vasodilatation. […] In patients with liver dysfunction, activation and massive accumulation of intravascular macrophages is observed as a result of intestinal bacterial translocation and endotoxemia. […] These macrophages in the pulmonary vasculature produce proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-), contributing in the NO-mediated vasodilatation through iNOS activation.

• #15

  https://gastro.zaslavsky.com.ua/index.php/journal/article/view/590

  Circulatory changes with increased blood flow and vasodilatation/vasoconstriction imbalance are an integral consequence of liver cirrhosis and portal hypertension and can affect the pulmonary circulation with the development of vascular disorders, with hepatopulmonary syndrome (HPS) being the most common. […] HPS is a serious pulmonary complication of progressive liver disease, resulting in a poor clinical prognosis. […] Vascular tone decrease, monocytic infiltration of pulmonary vessels, formation of intrapulmonary arteriovenous shunts, dysfunction of alveolar type II cells, destruction of the endothelial glycocalyx are important in the pathogenesis of HPS. […] Infiltration of the pulmonary vessels by monocytes is one of the key factors of HPS. […] This migration is facilitated by the intestinal microbiota translocation into the portal bloodstream with increased expression of proinflammatory cytokines (tumor necrosis factor , interleukins 1, 6), leading to the activation of monocytes.

• #16 Hepatopulmonary syndrome: update on pathogenesis and clinical features | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/nrgastro.2012.123

  Hepatopulmonary syndrome (HPS) is a serious vascular complication of liver disease that occurs in 532% of patients with cirrhosis. […] The presence of HPS markedly increases mortality. […] 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. […] Defining the mechanisms involved in the microvascular alterations of HPS has the potential to lead to effective medical therapies. […] Excess lung production of gaseous vasodilators, nitric oxide and carbon monoxide contributes to vasodilatation in human and experimental HPS. […] Pulmonary angiogenesis has an additive role in the development of experimental HPS.

• #17 Review article: Update on current and emergent data on hepatopulmonary syndrome

  https://www.wjgnet.com/1007-9327/full/v24/i12/1285.htm

  The increased production of nitric oxide (NO) and carbon monoxide (CO), two pulmonary vasodilators, constitutes the key process for the development of pulmonary vasodilatation. […] The binding of endothelin-1 to its pulmonary receptor ET-1B triggers the activation of endothelial and inducible nitric oxide synthase (eNOS and iNOS) resulting in elevated NO production and NO-induced pulmonary vasodilatation. […] In patients with liver dysfunction, activation and massive accumulation of intravascular macrophages is observed as a result of intestinal bacterial translocation and endotoxemia. […] These macrophages in the pulmonary vasculature produce proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-), contributing in the NO-mediated vasodilatation through iNOS activation.

• #18 Hepatopulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562169/

  Translocation of intestinal bacteria and endotoxemia in liver disease patients leads to massive accumulation of macrophages and monocytes in the lungs. These macrophages release tumor necrosis factor-alpha (TNF-alpha) in pulmonary vessels, leading to inducible nitric oxide synthetase (iNOS) activation. iNOS stimulation also causes increased nitric oxide (NO) production. Bacterial accumulation and increased NO cause increased levels of heme oxygenase. Heme oxygenase causes the degradation of heme and leads to increased carbon monoxide (CO) production. Being potent vasodilators, this increased production of NO and CO plays a crucial role in pulmonary vasodilatation. Also, macrophages, monocytes, and TNF alpha activate vascular endothelial growth factor (VEGF), leading to increased angiogenesis in the pulmonary vasculature.

• #19 SciELO Brazil – Hepatopulmonary syndrome: an update Hepatopulmonary syndrome: an update

  https://www.scielo.br/j/spmj/a/VXYTNbsCXRD6VFCpVhFcccP/

  Emphasis has been given to the roles that endothelin (ET-1) may play in the pulmonary microcirculation and in the genesis of IPVD. […] Following liver damage, ET-1 produced in the liver arrives in the pulmonary circulation and appears to preferentially interact with the ETB receptor, thereby promoting pulmonary vasodilatation. […] In cases of liver cirrhosis, the levels of tumor necrosis factor-alpha (TNF-) also rise, and this contributes towards the accumulation of macrophages in the lumen of the pulmonary vessels. […] Analysis on a model for liver cirrhosis and hyperdynamic circulation following common bile duct ligation (CBDL) has revealed greater hepatic production and plasma circulation of ET-1, which is associated with the development of HPS. […] Experimental studies have demonstrated consistent results regarding the high production of carbon monoxide (CO) that is associated with IPVD.

• #20 Hepatopulmonary syndrome: update on pathogenesis and clinical features | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/nrgastro.2012.123

  Hepatopulmonary syndrome (HPS) is a serious vascular complication of liver disease that occurs in 532% of patients with cirrhosis. […] The presence of HPS markedly increases mortality. […] 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. […] Defining the mechanisms involved in the microvascular alterations of HPS has the potential to lead to effective medical therapies. […] Excess lung production of gaseous vasodilators, nitric oxide and carbon monoxide contributes to vasodilatation in human and experimental HPS. […] Pulmonary angiogenesis has an additive role in the development of experimental HPS.

• #21 Review article: Update on current and emergent data on hepatopulmonary syndrome

  https://www.wjgnet.com/1007-9327/full/v24/i12/1285.htm

  Angiogenesis is considered another crucial mechanism interpreting HPS pathogenesis. […] Intestinal bacterial translocation and the consequent endotoxemia due to liver dysfunction lead to the recruitment of monocytes and activated macrophages to the lung. […] These inflammatory cells together with circulating TNF- stimulate the activation of vascular endothelial growth factor (VEGF) signaling pathways, which are related to angiogenesis. […] The accumulation of CD68+ macrophages in the lungs of common bile duct ligation rats, expressing iNOS and VEGF, has been correlated to the presence of HPS. […] Although it can be postulated that VEGF constitutes a regulator of angiogenesis with a possible role in the development of HPS, further studies with measurements of VEGF are needed to unravel the exact pathogenetic pathways.

• #22 Review article: Update on current and emergent data on hepatopulmonary syndrome

  https://www.wjgnet.com/1007-9327/full/v24/i12/1285.htm

  Angiogenesis is considered another crucial mechanism interpreting HPS pathogenesis. […] Intestinal bacterial translocation and the consequent endotoxemia due to liver dysfunction lead to the recruitment of monocytes and activated macrophages to the lung. […] These inflammatory cells together with circulating TNF- stimulate the activation of vascular endothelial growth factor (VEGF) signaling pathways, which are related to angiogenesis. […] The accumulation of CD68+ macrophages in the lungs of common bile duct ligation rats, expressing iNOS and VEGF, has been correlated to the presence of HPS. […] Although it can be postulated that VEGF constitutes a regulator of angiogenesis with a possible role in the development of HPS, further studies with measurements of VEGF are needed to unravel the exact pathogenetic pathways.

• #23 Hepatopulmonary Syndrome: Recent Advances in Treatment

  https://www.medscape.com/viewarticle/778720

  In addition, increased phagocytosis of bacterial endotoxin in the lung not only promotes stimulation of inducible NO synthase, which increases NO production, but also contributes to intrapulmonary accumulation of monocytes, which may stimulate angiogenesis via vascular endothelial growth factor pathway. […] Thus, HPS represents a relatively common and important cause of pulmonary disease in patients with cirrhosis.

• #24

  https://gastro.zaslavsky.com.ua/index.php/journal/article/view/590

  Monocytes located in the pulmonary circulation promote the vasodilation through the activation of inducible nitric oxide (NO) synthase and thus NO production. […] This is also associated with endothelial dysfunction due to a decreased hepatic secretion of bone morphogenetic protein 9 and increased endothelin 1, endothelial overexpression of endothelin B receptors, and increased endothelial NO production. […] Proangiogenic factors such as vascular endothelial growth factor, platelet-derived growth factor, and placental growth factor play an important role in the proliferation of pulmonary capillaries. […] Chronic inflammation in HPS disrupts the continuity of the endothelial glycocalyx layer. […] This article provides an overview of the current knowledge on the pathogenesis of HPS, summarizes many features of the disease based on the literature research in MEDLINE database on the PubMed platform.

• #25 The Hepatopulmonary Syndrome | Abdominal Key

  https://abdominalkey.com/the-hepatopulmonary-syndrome/

  HPS develops when pulmonary microvascular dilatation and/or angiogenesis develops in the setting of liver disease. The mechanisms that trigger these microvascular changes are incompletely characterized. In experimental HPS induced by common bile duct ligation (CBDL), both pulmonary microvascular dilatation and angiogenesis contribute to altered gas exchange. Similar changes are not observed in other rodent models of cirrhosis and portal hypertension, suggesting that CBDL triggers unique molecular events that influence the pulmonary microvasculature. The two most well-recognized events include increased microvascular endothelin signaling and accumulation of monocytes in the microvascular lumen. Upregulated endothelin-1 (ET-1) signaling occurs via increased circulating ET-1 levels, in part derived from cholangiocytes, and by increased lung endothelial endothelin B (ETB) receptor expression in response to increased shear stress due to systemic vascular changes. The result is enhanced ETB receptor mediated endothelial-derived nitric oxide (NO) production. Monocyte accumulation within the microvasculature is enhanced by ET-1 alterations and also by tumor necrosis factor (TNF-) production from bacterial translocation of intestinal micro-organisms and possibly specific overexpression of monocyte chemotactic and angiogenic chemokines (i.e., fractalkine). Intravascular monocytes are an important source for local pulmonary production of NO, carbon monoxide (CO), and vascular endothelial growth factor (VEGF) which contribute to vascular and gas exchange abnormalities. Recently, in vitro studies have demonstrated that upregulation of the ERK signaling pathway and cholangiocyte VEGF overexpression may be associated with cholangiocyte ET-1 production. Accordingly, in CBDL animals, inhibition of TNF-, ETB receptor signaling, CO production, tyroxine kinase receptor, or angiogenesis ameliorate HPS.

• #26 Hepatopulmonary syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9403489/

  Work in the CBDL model has identified underlying pathophysiologic triggers for 3 mechanisms that contribute to the development of hypoxemia in the disease: relaxation of blood vessels leading to vasodilation, angiogenesis leading to shunt formation, and alveolar dysfunction. […] Studies in experimental HPS directly targeting classic pro-angiogenic pathways including VEGF, PDGF and Raf kinases, using the receptor tyrosine kinase inhibitor sorafenib have shown beneficial effects in the pulmonary microvasculature and improvement in gas exchange.

• #27 Hepatopulmonary syndrome – Past to present | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-hepatopulmonary-syndrome-past-present-S1665268119319180

  In human models, the vasodilatation is assumed to result from excessive vascular production of vasodilators, particularly nitric oxide (NO). […] Intestinal endotoxemia accompanying cirrhosis may be an important factor in the development of hepatopulmonary syndrome. […] Overproduction of TNF-alpha due to endotoxin stimulation of Kupffer cells via mitogen-activated protein kinase (MAPK) signal transduction pathway may be a major mechanism mediating the pathologic alterations of hepatopulmonary syndrome. […] Hypoxemia is postulated to be due to decreased oxygen diffusion across the dilated vessels along with a decrease in intrapulmonary blood transit time. […] The blood transit time is decreased due to the low vascular resistance in the intrapulmonary dilatations and the associated hyperdynamic circulation characteristic of liver disease.

• #28 Hepatopulmonary Syndrome – OpenAnesthesia

  https://www.openanesthesia.org/keywords/hepatopulmonary-syndrome/

  Hepatopulmonary syndrome (HPS) is characterized by intrapulmonary vascular dilatations in the setting of portal hypertension, leading to right-to-left shunts and hypoxia. […] Patients with portal hypertension have a hyperdynamic circulation, with high cardiac output resulting in splanchnic volume overload and bowel wall edema, which leads to bacterial translocation and the subsequent release of cytokines and endotoxins into the systemic circulation. […] Endotoxemia and bacterial translocation leads to the activation of macrophages and monocytes in the lungs, causing the accumulation and/or activation of cytotoxic and vasodilatory mediators such as nitric oxide, tumor necrosis factor-alpha, carbon monoxide, and endothelin which contribute to the development of abnormal pulmonary vascular dilatation.

• #29 Hepatopulmonary Syndrome: Oxidative Stress and Physical Exercise – European Medical Journal

  https://www.emjreviews.com/hepatology/article/hepatopulmonary-syndrome-oxidative-stress-and-physical-exercise/

  Hepatopulmonary syndrome (HPS) may be defined by hepatic disease, gas exchange abnormalities that may lead to hypoxaemia, and the presence of pulmonary vascular dilations. […] The pulmonary tissue may be damaged by reactive oxygen species or nitric oxide. […] Liver disease can contribute to HPS oxidative stress and is one of the main factors responsible for the reduction of gas exchange. […] Liver damage makes it more difficult for the organ to filter blood from the portal vein, which leads to the appearance of portosystemic shunts and a decrease in the hepatic phagocytic capacity. […] As a result, the lung filtrates systemic blood to compensate for the decrease in hepatic phagocytosis, and the increase in the lung phagocytic activity results in macrophage accumulation in the pulmonary endothelium and increases cytokine and NO levels in the extracellular environment.

• #30 Hepatopulmonary Syndrome: Oxidative Stress and Physical Exercise – European Medical Journal

  https://www.emjreviews.com/hepatology/article/hepatopulmonary-syndrome-oxidative-stress-and-physical-exercise/

  Hepatopulmonary syndrome (HPS) may be defined by hepatic disease, gas exchange abnormalities that may lead to hypoxaemia, and the presence of pulmonary vascular dilations. […] The pulmonary tissue may be damaged by reactive oxygen species or nitric oxide. […] Liver disease can contribute to HPS oxidative stress and is one of the main factors responsible for the reduction of gas exchange. […] Liver damage makes it more difficult for the organ to filter blood from the portal vein, which leads to the appearance of portosystemic shunts and a decrease in the hepatic phagocytic capacity. […] As a result, the lung filtrates systemic blood to compensate for the decrease in hepatic phagocytosis, and the increase in the lung phagocytic activity results in macrophage accumulation in the pulmonary endothelium and increases cytokine and NO levels in the extracellular environment.

• #31 Hepatopulmonary syndrome – Past to present | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-hepatopulmonary-syndrome-past-present-S1665268119319180

  In human models, the vasodilatation is assumed to result from excessive vascular production of vasodilators, particularly nitric oxide (NO). […] Intestinal endotoxemia accompanying cirrhosis may be an important factor in the development of hepatopulmonary syndrome. […] Overproduction of TNF-alpha due to endotoxin stimulation of Kupffer cells via mitogen-activated protein kinase (MAPK) signal transduction pathway may be a major mechanism mediating the pathologic alterations of hepatopulmonary syndrome. […] Hypoxemia is postulated to be due to decreased oxygen diffusion across the dilated vessels along with a decrease in intrapulmonary blood transit time. […] The blood transit time is decreased due to the low vascular resistance in the intrapulmonary dilatations and the associated hyperdynamic circulation characteristic of liver disease.

• #32 The Hepatopulmonary Syndrome | Abdominal Key

  https://abdominalkey.com/the-hepatopulmonary-syndrome/

  The pathogenesis of altered oxygenation in HPS derives from the changes in the pulmonary microvascular bed. In humans, capillary dilatation and pleural arteriovenous malformations have been described in a limited number of cases. In experimental HPS, both pulmonary vascular dilatation and angiogenesis occur. Three mechanisms of hypoxemia have been described in human HPS: anatomic arteriovenous shunting, ventilation-perfusion mismatch (increased capillary blood flow), and diffusion-perfusion mismatching (impaired passage of oxygen from the alveolus into the vasculature). The relative contribution of these mechanisms to gas exchange abnormalities appear to vary based on the severity of HPS.

• #33 Hepatopulmonary syndrome: What we know and what we would like to know

  https://www.wjgnet.com/1007-9327/full/v22/i25/5728.htm

  Hepatopulmonary syndrome (HPS) is characterized by abnormalities in blood oxygenation caused by the presence of intrapulmonary vascular dilations (IPVD) in the context of liver disease, generally at a cirrhotic stage. […] The majority of the information about the etiopathogenesis of HPS has been obtained through experiments on animals. […] The main mediators involved in the onset of IPVD, which are fundamental to the pathogenesis of HPS, are nitric oxide (NO) and carbon monoxide (CO). […] The principal abnormality which defines HPS is the dilatation of pre and post-capillary pulmonary vessels in the alveolar regions. […] With HPS there is an increase in the alveolar-arterial gradient of O2 (AaO2) and hypoxemia which is caused by three mechanisms. […] The vasodilatation of alveolar capillaries results in an excessive amount of blood flowing into the normally ventilated alveoli, which causes a decline in the ventilation perfusion quotient, resulting in increased AaO2 and/or arterial hypoxemia.

• #34 Hepatopulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562169/

  Vasodilation and angiogenesis lead to arteriovenous (AV) shunt formation within pulmonary vasculature, leading to a mismatch of ventilation-perfusion. The pulmonary capillaries are dilated to 15 to 500 mm in HPS compared to a normal diameter between 8 and 15 mm. […] This pulmonary vasodilation, AV shunts, and impaired diffusion lead to ventilation-perfusion mismatch, creating increased alveolar-arterial gradient and hypoxemia. […] Pulmonary vasodilation is most distinct in the lung bases, elucidating the symptoms like platypnoea and orthodeoxia associated with HPS. […] Two types of HPS have been identified based on the location of dilated pulmonary vessels: Type I: Dilatation of vessels at the precapillary levels near gas exchange units of the lungs; supplemental O2 increases PaO2 in this type of HPS. Type II: Larger dilatation of vessels causing arteriovenous shunts away from gas exchange units of lungs; supplemental O2 is not helpful.

• #35 Hepatopulmonary syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Hepatopulmonary_syndrome

  In medicine, hepatopulmonary syndrome is a syndrome of shortness of breath and hypoxemia (low oxygen levels in the blood of the arteries) caused by vasodilation (broadening of the blood vessels) in the lungs of patients with liver disease. […] The hepatopulmonary syndrome results from the formation of microscopic intrapulmonary arteriovenous dilatations in patients with both chronic, and far less commonly acute liver failure. The mechanism is unknown but is thought to be due to increased liver production or decreased liver clearance of vasodilators, possibly involving nitric oxide. […] The dilation of these blood vessels causes overperfusion relative to ventilation, leading to ventilation-perfusion mismatch and hypoxemia. […] 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.

• #36 Hepatopulmonary Syndrome By Dr.Tinku Joseph | PPT

  https://www.slideshare.net/slideshow/hepatopulmonary-syndrome-by-drtinku-joseph/64366092

  Widespread pulmonary precapillary and capillary vasodilatation leads to hypoxemia. […] These changes lead to ventilation perfusion (V/Q) mismatch: Results from widespread pulmonary vasodilatation and decreased V/Q ratio in alveolar-capillary units leading to low pressure of oxygen in arterial blood (PaO2) and low oxygen (O2) content of the blood leaving these units. […] Right to left shunting of the blood results from direct arterio-venous communications that have no contact with breathed air. […] Excessive vasodilatation causes O2 molecules not to reach the center of dilated capillaries readily. […] The diagnosis of HPS can be made when all of the following abnormalities have been confirmed: A) Portal hypertension (with or without concomitant liver parenchymal disease) B) Impaired oxygenation C) Intrapulmonary vascular abnormalities, referred to as IPVDs. […] The most sensitive measure of impaired oxygenation is an elevated alveolar-arterial (A-a) oxygen gradient, defined as 15 mmHg when breathing room air. […] Liver transplantation can resolve HPS by correcting the underlying liver disease.

• #37 Hepatopulmonary Syndrome – OpenAnesthesia

  https://www.openanesthesia.org/keywords/hepatopulmonary-syndrome/

  Pulmonary vascular dilatation occurs due to increased shear stress on a normally low resistance system, a compensatory mechanism to maintain normal pulmonary vascular resistance. This is the hallmark of HPS, which must be differentiated from PPH (a vasoconstrictive phenomenon) in patients with cirrhosis and pulmonary symptoms. […] HPS is a state of ventilation-perfusion mismatch. Increased perfusion secondary to vascular dilatation and collateralization in the setting of preserved ventilation results in the right-to-left shunting of blood. […] Hypoxia in HPS is worsened by partial impairment of the normal compensatory mechanism hypoxic pulmonary vasoconstriction (HPV). The abnormally dilated pulmonary vasculature has reduced tone and does not respond normally to hypoxic states, worsening the right-to-left shunt.

• #38 Hepatopulmonary Syndrome: A Forgotten Liver-induced Lung Vascular Disorder | Archivos de Bronconeumología

  https://archbronconeumol.org/es-hepatopulmonary-syndrome-a-forgotten-liver-induced-articulo-S0300289622006706

  One of the most outstanding findings however was that patients with cutaneous spider naevi, considered to be a relevant sign of angiogenesis, showed greater liver dysfunction and lower systemic and pulmonary vascular resistance, less hypoxic vascular response, more hypoxaemia, and worse VA/Q imbalance than those without spider naevi. […] Accordingly, the presence of three of the four well-known intrapulmonary factors governing abnormal oxygenation (VA/Q mismatch, increased intrapulmonary shunt, diffusion impairment to oxygen, and hypoventilation) but hypoventilation was compelling in patients with LC, with the predominance of VA/Q inequality induced by an increased pulmonary blood flow enhanced by the absence or impairment of HPV. […] The presence of oxygen diffusion limitation, essentially reflecting a diffusion-perfusion defect, predominates in advanced stages of the HPS, aggravated by a high cardiac output resulting in a shorter transit time of red cells, which are akin to a low diffusing capacity for carbon monoxide (CO) (DLCO) associated with hepatic dysfunction in general and with the HPS in particular.

• #39 Hepatopulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562169/

  Vasodilation and angiogenesis lead to arteriovenous (AV) shunt formation within pulmonary vasculature, leading to a mismatch of ventilation-perfusion. The pulmonary capillaries are dilated to 15 to 500 mm in HPS compared to a normal diameter between 8 and 15 mm. […] This pulmonary vasodilation, AV shunts, and impaired diffusion lead to ventilation-perfusion mismatch, creating increased alveolar-arterial gradient and hypoxemia. […] Pulmonary vasodilation is most distinct in the lung bases, elucidating the symptoms like platypnoea and orthodeoxia associated with HPS. […] Two types of HPS have been identified based on the location of dilated pulmonary vessels: Type I: Dilatation of vessels at the precapillary levels near gas exchange units of the lungs; supplemental O2 increases PaO2 in this type of HPS. Type II: Larger dilatation of vessels causing arteriovenous shunts away from gas exchange units of lungs; supplemental O2 is not helpful.

• #40 Review article: Update on current and emergent data on hepatopulmonary syndrome

  https://www.wjgnet.com/1007-9327/full/v24/i12/1285.htm

  As a result, an excessive amount of blood passes through the pulmonary circulation without completing gas exchange, leading to increased alveolar arterial gradient and arterial hypoxemia, particularly during muscular activity. […] Intrapulmonary arteriovenous shunting constitutes another mechanism causing arterial hypoxia in HPS. […] The presence of more pronounced vascular dilatations and arteriovenous communications in lower lung zones may interpret the mechanism of orthodeoxia, i.e. reduction of PaO2 from supine to upright patient position. […] It seems that the severity of arterial hypoxemia is related to the extent of ventilation-perfusion mismatch, intrapulmonary shunting and diffusion impairment. […] Intrapulmonary vascular dilatations seem to be the result of an imbalance between several vasodilators and vasoconstrictors.

• #41 Hepatopulmonary syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9403489/

  Hepatopulmonary syndrome (HPS) is a pulmonary vascular complication of liver disease, which adversely affects prognosis. The disease is characterised by intrapulmonary vascular dilatations and shunts, resulting in impaired gas exchange. A complex interaction between the liver, the gut and the lungs, predominately impacting pulmonary endothelial cells, immune cells and respiratory epithelial cells, is responsible for the development of typical pulmonary alterations seen in HPS. […] The development of impaired gas exchange in HPS has been attributed to 3 mechanisms resulting from alterations in the alveolar microcirculation: V/Q mismatch, diffusion limitation and the presence of direct AV communications. V/Q mismatch results from increased pulmonary blood flow due to microvascular alterations, while ventilation remains unchanged. Diffusion limitation occurs because oxygen must travel a greater distance to bind haemoglobin due to vascular dilation. Direct AV communications bypass the alveolar microcirculation, resulting in direct mixing of venous and arterial blood.

• #42 Hepatopulmonary Syndrome By Dr.Tinku Joseph | PPT

  https://www.slideshare.net/slideshow/hepatopulmonary-syndrome-by-drtinku-joseph/64366092

  Widespread pulmonary precapillary and capillary vasodilatation leads to hypoxemia. […] These changes lead to ventilation perfusion (V/Q) mismatch: Results from widespread pulmonary vasodilatation and decreased V/Q ratio in alveolar-capillary units leading to low pressure of oxygen in arterial blood (PaO2) and low oxygen (O2) content of the blood leaving these units. […] Right to left shunting of the blood results from direct arterio-venous communications that have no contact with breathed air. […] Excessive vasodilatation causes O2 molecules not to reach the center of dilated capillaries readily. […] The diagnosis of HPS can be made when all of the following abnormalities have been confirmed: A) Portal hypertension (with or without concomitant liver parenchymal disease) B) Impaired oxygenation C) Intrapulmonary vascular abnormalities, referred to as IPVDs. […] The most sensitive measure of impaired oxygenation is an elevated alveolar-arterial (A-a) oxygen gradient, defined as 15 mmHg when breathing room air. […] Liver transplantation can resolve HPS by correcting the underlying liver disease.

• #43 Hepatopulmonary syndrome – Past to present | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-hepatopulmonary-syndrome-past-present-S1665268119319180

  In human models, the vasodilatation is assumed to result from excessive vascular production of vasodilators, particularly nitric oxide (NO). […] Intestinal endotoxemia accompanying cirrhosis may be an important factor in the development of hepatopulmonary syndrome. […] Overproduction of TNF-alpha due to endotoxin stimulation of Kupffer cells via mitogen-activated protein kinase (MAPK) signal transduction pathway may be a major mechanism mediating the pathologic alterations of hepatopulmonary syndrome. […] Hypoxemia is postulated to be due to decreased oxygen diffusion across the dilated vessels along with a decrease in intrapulmonary blood transit time. […] The blood transit time is decreased due to the low vascular resistance in the intrapulmonary dilatations and the associated hyperdynamic circulation characteristic of liver disease.

• #44 Supine vs upright exercise in patients with hepatopulmonary syndrome and orthodeoxia: study protocol for a randomized controlled crossover trial | Trials | Full Text

  https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-021-05633-7

  This is a combination of an increased distance between the alveolar membrane and the red blood cells in the center of dilated capillaries, causing an effective diffusion abnormality, along with a reduced resistance to flow causing increased perfusion through the dilated capillaries which reduces available time for equilibration between the alveolar gas and the blood. […] Accordingly, due to the gravitational redistribution of blood flow to the lung bases in the upright position, there is an increase in blood volume passing through IPVDs, resulting in a worsening diffusion-perfusion defect when moving from the supine to the upright position.

• #45 Hepatopulmonary Syndrome: A Forgotten Liver-induced Lung Vascular Disorder | Archivos de Bronconeumología

  https://archbronconeumol.org/es-hepatopulmonary-syndrome-a-forgotten-liver-induced-articulo-S0300289622006706

  One of the most outstanding findings however was that patients with cutaneous spider naevi, considered to be a relevant sign of angiogenesis, showed greater liver dysfunction and lower systemic and pulmonary vascular resistance, less hypoxic vascular response, more hypoxaemia, and worse VA/Q imbalance than those without spider naevi. […] Accordingly, the presence of three of the four well-known intrapulmonary factors governing abnormal oxygenation (VA/Q mismatch, increased intrapulmonary shunt, diffusion impairment to oxygen, and hypoventilation) but hypoventilation was compelling in patients with LC, with the predominance of VA/Q inequality induced by an increased pulmonary blood flow enhanced by the absence or impairment of HPV. […] The presence of oxygen diffusion limitation, essentially reflecting a diffusion-perfusion defect, predominates in advanced stages of the HPS, aggravated by a high cardiac output resulting in a shorter transit time of red cells, which are akin to a low diffusing capacity for carbon monoxide (CO) (DLCO) associated with hepatic dysfunction in general and with the HPS in particular.

• #46 Supine vs upright exercise in patients with hepatopulmonary syndrome and orthodeoxia: study protocol for a randomized controlled crossover trial | Trials | Full Text

  https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-021-05633-7

  This is a combination of an increased distance between the alveolar membrane and the red blood cells in the center of dilated capillaries, causing an effective diffusion abnormality, along with a reduced resistance to flow causing increased perfusion through the dilated capillaries which reduces available time for equilibration between the alveolar gas and the blood. […] Accordingly, due to the gravitational redistribution of blood flow to the lung bases in the upright position, there is an increase in blood volume passing through IPVDs, resulting in a worsening diffusion-perfusion defect when moving from the supine to the upright position.

• #47 Hepatopulmonary Syndrome By Dr.Tinku Joseph | PPT

  https://www.slideshare.net/slideshow/hepatopulmonary-syndrome-by-drtinku-joseph/64366092

  Widespread pulmonary precapillary and capillary vasodilatation leads to hypoxemia. […] These changes lead to ventilation perfusion (V/Q) mismatch: Results from widespread pulmonary vasodilatation and decreased V/Q ratio in alveolar-capillary units leading to low pressure of oxygen in arterial blood (PaO2) and low oxygen (O2) content of the blood leaving these units. […] Right to left shunting of the blood results from direct arterio-venous communications that have no contact with breathed air. […] Excessive vasodilatation causes O2 molecules not to reach the center of dilated capillaries readily. […] The diagnosis of HPS can be made when all of the following abnormalities have been confirmed: A) Portal hypertension (with or without concomitant liver parenchymal disease) B) Impaired oxygenation C) Intrapulmonary vascular abnormalities, referred to as IPVDs. […] The most sensitive measure of impaired oxygenation is an elevated alveolar-arterial (A-a) oxygen gradient, defined as 15 mmHg when breathing room air. […] Liver transplantation can resolve HPS by correcting the underlying liver disease.

• #48 Hepatopulmonary syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9403489/

  Hepatopulmonary syndrome (HPS) is a pulmonary vascular complication of liver disease, which adversely affects prognosis. The disease is characterised by intrapulmonary vascular dilatations and shunts, resulting in impaired gas exchange. A complex interaction between the liver, the gut and the lungs, predominately impacting pulmonary endothelial cells, immune cells and respiratory epithelial cells, is responsible for the development of typical pulmonary alterations seen in HPS. […] The development of impaired gas exchange in HPS has been attributed to 3 mechanisms resulting from alterations in the alveolar microcirculation: V/Q mismatch, diffusion limitation and the presence of direct AV communications. V/Q mismatch results from increased pulmonary blood flow due to microvascular alterations, while ventilation remains unchanged. Diffusion limitation occurs because oxygen must travel a greater distance to bind haemoglobin due to vascular dilation. Direct AV communications bypass the alveolar microcirculation, resulting in direct mixing of venous and arterial blood.

• #49 Review article: Update on current and emergent data on hepatopulmonary syndrome

  https://www.wjgnet.com/1007-9327/full/v24/i12/1285.htm

  As a result, an excessive amount of blood passes through the pulmonary circulation without completing gas exchange, leading to increased alveolar arterial gradient and arterial hypoxemia, particularly during muscular activity. […] Intrapulmonary arteriovenous shunting constitutes another mechanism causing arterial hypoxia in HPS. […] The presence of more pronounced vascular dilatations and arteriovenous communications in lower lung zones may interpret the mechanism of orthodeoxia, i.e. reduction of PaO2 from supine to upright patient position. […] It seems that the severity of arterial hypoxemia is related to the extent of ventilation-perfusion mismatch, intrapulmonary shunting and diffusion impairment. […] Intrapulmonary vascular dilatations seem to be the result of an imbalance between several vasodilators and vasoconstrictors.

• #50 Hepatopulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562169/

  Vasodilation and angiogenesis lead to arteriovenous (AV) shunt formation within pulmonary vasculature, leading to a mismatch of ventilation-perfusion. The pulmonary capillaries are dilated to 15 to 500 mm in HPS compared to a normal diameter between 8 and 15 mm. […] This pulmonary vasodilation, AV shunts, and impaired diffusion lead to ventilation-perfusion mismatch, creating increased alveolar-arterial gradient and hypoxemia. […] Pulmonary vasodilation is most distinct in the lung bases, elucidating the symptoms like platypnoea and orthodeoxia associated with HPS. […] Two types of HPS have been identified based on the location of dilated pulmonary vessels: Type I: Dilatation of vessels at the precapillary levels near gas exchange units of the lungs; supplemental O2 increases PaO2 in this type of HPS. Type II: Larger dilatation of vessels causing arteriovenous shunts away from gas exchange units of lungs; supplemental O2 is not helpful.

• #51 Hepatopulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562169/

  Vasodilation and angiogenesis lead to arteriovenous (AV) shunt formation within pulmonary vasculature, leading to a mismatch of ventilation-perfusion. The pulmonary capillaries are dilated to 15 to 500 mm in HPS compared to a normal diameter between 8 and 15 mm. […] This pulmonary vasodilation, AV shunts, and impaired diffusion lead to ventilation-perfusion mismatch, creating increased alveolar-arterial gradient and hypoxemia. […] Pulmonary vasodilation is most distinct in the lung bases, elucidating the symptoms like platypnoea and orthodeoxia associated with HPS. […] Two types of HPS have been identified based on the location of dilated pulmonary vessels: Type I: Dilatation of vessels at the precapillary levels near gas exchange units of the lungs; supplemental O2 increases PaO2 in this type of HPS. Type II: Larger dilatation of vessels causing arteriovenous shunts away from gas exchange units of lungs; supplemental O2 is not helpful.

• #52 SciELO Brazil – Hepatopulmonary syndrome: an update Hepatopulmonary syndrome: an update

  https://www.scielo.br/j/spmj/a/VXYTNbsCXRD6VFCpVhFcccP/

  Emphasis has been given to the roles that endothelin (ET-1) may play in the pulmonary microcirculation and in the genesis of IPVD. […] Following liver damage, ET-1 produced in the liver arrives in the pulmonary circulation and appears to preferentially interact with the ETB receptor, thereby promoting pulmonary vasodilatation. […] In cases of liver cirrhosis, the levels of tumor necrosis factor-alpha (TNF-) also rise, and this contributes towards the accumulation of macrophages in the lumen of the pulmonary vessels. […] Analysis on a model for liver cirrhosis and hyperdynamic circulation following common bile duct ligation (CBDL) has revealed greater hepatic production and plasma circulation of ET-1, which is associated with the development of HPS. […] Experimental studies have demonstrated consistent results regarding the high production of carbon monoxide (CO) that is associated with IPVD.

• #53 Medical treatment for hepatopulmonary syndrome: a systematic review

  https://rcm.mums.ac.ir/article_3255.html

  Intrapulmonary vasculature angiogenesis is another vasculature alternation of vasculature bed due to cirrhosis and HPS. […] Increased level of plasma endothelin-1 and over expression of endothelin-B receptor are involved in vasodilation and pathogenesis of HPS. […] According to the experimental and clinical studies endothelin-1 can induce the nitric oxide synthase activity and eventually the nitric oxide production which leads to the development of HPS.

• #54 SciELO Brazil – Hepatopulmonary syndrome: an update Hepatopulmonary syndrome: an update

  https://www.scielo.br/j/spmj/a/VXYTNbsCXRD6VFCpVhFcccP/

  Emphasis has been given to the roles that endothelin (ET-1) may play in the pulmonary microcirculation and in the genesis of IPVD. […] Following liver damage, ET-1 produced in the liver arrives in the pulmonary circulation and appears to preferentially interact with the ETB receptor, thereby promoting pulmonary vasodilatation. […] In cases of liver cirrhosis, the levels of tumor necrosis factor-alpha (TNF-) also rise, and this contributes towards the accumulation of macrophages in the lumen of the pulmonary vessels. […] Analysis on a model for liver cirrhosis and hyperdynamic circulation following common bile duct ligation (CBDL) has revealed greater hepatic production and plasma circulation of ET-1, which is associated with the development of HPS. […] Experimental studies have demonstrated consistent results regarding the high production of carbon monoxide (CO) that is associated with IPVD.

• #55 The Hepatopulmonary Syndrome | Abdominal Key

  https://abdominalkey.com/the-hepatopulmonary-syndrome/

  HPS develops when pulmonary microvascular dilatation and/or angiogenesis develops in the setting of liver disease. The mechanisms that trigger these microvascular changes are incompletely characterized. In experimental HPS induced by common bile duct ligation (CBDL), both pulmonary microvascular dilatation and angiogenesis contribute to altered gas exchange. Similar changes are not observed in other rodent models of cirrhosis and portal hypertension, suggesting that CBDL triggers unique molecular events that influence the pulmonary microvasculature. The two most well-recognized events include increased microvascular endothelin signaling and accumulation of monocytes in the microvascular lumen. Upregulated endothelin-1 (ET-1) signaling occurs via increased circulating ET-1 levels, in part derived from cholangiocytes, and by increased lung endothelial endothelin B (ETB) receptor expression in response to increased shear stress due to systemic vascular changes. The result is enhanced ETB receptor mediated endothelial-derived nitric oxide (NO) production. Monocyte accumulation within the microvasculature is enhanced by ET-1 alterations and also by tumor necrosis factor (TNF-) production from bacterial translocation of intestinal micro-organisms and possibly specific overexpression of monocyte chemotactic and angiogenic chemokines (i.e., fractalkine). Intravascular monocytes are an important source for local pulmonary production of NO, carbon monoxide (CO), and vascular endothelial growth factor (VEGF) which contribute to vascular and gas exchange abnormalities. Recently, in vitro studies have demonstrated that upregulation of the ERK signaling pathway and cholangiocyte VEGF overexpression may be associated with cholangiocyte ET-1 production. Accordingly, in CBDL animals, inhibition of TNF-, ETB receptor signaling, CO production, tyroxine kinase receptor, or angiogenesis ameliorate HPS.

• #56 :: KCJ :: Korean Circulation Journal

  https://e-kcj.org/DOIx.php?id=10.4070/kcj.2015.45.1.77

  A high dose of sildenafil resulted in a dose-dependent fall in PVR associated with a marked increase in ventilation-perfusion heterogeneity in a porcine model. […] The mechanism by which sildenafil but not iloprost, aggravated IPS in this case, might be related to differential expression of the endothelin-1 (ET-1) receptor between HPS and PPHTN, as well as different mechanisms of the two drugs. […] Therefore, different mechanisms of the two drugs may have resulted in a different clinical course in this patient. […] In conclusion, HPS and PPHTN can occur in the same patient and sildenafil may be associated with aggravation of HPS in patients with coexisting HPS and PPHTN. In such cases, SC-TTE may be helpful to demonstrate IPS.

• #57 SciELO Brazil – Hepatopulmonary syndrome: an update Hepatopulmonary syndrome: an update

  https://www.scielo.br/j/spmj/a/VXYTNbsCXRD6VFCpVhFcccP/

  Emphasis has been given to the roles that endothelin (ET-1) may play in the pulmonary microcirculation and in the genesis of IPVD. […] Following liver damage, ET-1 produced in the liver arrives in the pulmonary circulation and appears to preferentially interact with the ETB receptor, thereby promoting pulmonary vasodilatation. […] In cases of liver cirrhosis, the levels of tumor necrosis factor-alpha (TNF-) also rise, and this contributes towards the accumulation of macrophages in the lumen of the pulmonary vessels. […] Analysis on a model for liver cirrhosis and hyperdynamic circulation following common bile duct ligation (CBDL) has revealed greater hepatic production and plasma circulation of ET-1, which is associated with the development of HPS. […] Experimental studies have demonstrated consistent results regarding the high production of carbon monoxide (CO) that is associated with IPVD.

• #58

  https://gastro.zaslavsky.com.ua/index.php/journal/article/view/590

  Circulatory changes with increased blood flow and vasodilatation/vasoconstriction imbalance are an integral consequence of liver cirrhosis and portal hypertension and can affect the pulmonary circulation with the development of vascular disorders, with hepatopulmonary syndrome (HPS) being the most common. […] HPS is a serious pulmonary complication of progressive liver disease, resulting in a poor clinical prognosis. […] Vascular tone decrease, monocytic infiltration of pulmonary vessels, formation of intrapulmonary arteriovenous shunts, dysfunction of alveolar type II cells, destruction of the endothelial glycocalyx are important in the pathogenesis of HPS. […] Infiltration of the pulmonary vessels by monocytes is one of the key factors of HPS. […] This migration is facilitated by the intestinal microbiota translocation into the portal bloodstream with increased expression of proinflammatory cytokines (tumor necrosis factor , interleukins 1, 6), leading to the activation of monocytes.

• #59

  https://gastro.zaslavsky.com.ua/index.php/journal/article/view/590

  Circulatory changes with increased blood flow and vasodilatation/vasoconstriction imbalance are an integral consequence of liver cirrhosis and portal hypertension and can affect the pulmonary circulation with the development of vascular disorders, with hepatopulmonary syndrome (HPS) being the most common. […] HPS is a serious pulmonary complication of progressive liver disease, resulting in a poor clinical prognosis. […] Vascular tone decrease, monocytic infiltration of pulmonary vessels, formation of intrapulmonary arteriovenous shunts, dysfunction of alveolar type II cells, destruction of the endothelial glycocalyx are important in the pathogenesis of HPS. […] Infiltration of the pulmonary vessels by monocytes is one of the key factors of HPS. […] This migration is facilitated by the intestinal microbiota translocation into the portal bloodstream with increased expression of proinflammatory cytokines (tumor necrosis factor , interleukins 1, 6), leading to the activation of monocytes.

• #60

  https://gastro.zaslavsky.com.ua/index.php/journal/article/view/590

  Circulatory changes with increased blood flow and vasodilatation/vasoconstriction imbalance are an integral consequence of liver cirrhosis and portal hypertension and can affect the pulmonary circulation with the development of vascular disorders, with hepatopulmonary syndrome (HPS) being the most common. […] HPS is a serious pulmonary complication of progressive liver disease, resulting in a poor clinical prognosis. […] Vascular tone decrease, monocytic infiltration of pulmonary vessels, formation of intrapulmonary arteriovenous shunts, dysfunction of alveolar type II cells, destruction of the endothelial glycocalyx are important in the pathogenesis of HPS. […] Infiltration of the pulmonary vessels by monocytes is one of the key factors of HPS. […] This migration is facilitated by the intestinal microbiota translocation into the portal bloodstream with increased expression of proinflammatory cytokines (tumor necrosis factor , interleukins 1, 6), leading to the activation of monocytes.

• #61

  https://gastro.zaslavsky.com.ua/index.php/journal/article/view/590

  Monocytes located in the pulmonary circulation promote the vasodilation through the activation of inducible nitric oxide (NO) synthase and thus NO production. […] This is also associated with endothelial dysfunction due to a decreased hepatic secretion of bone morphogenetic protein 9 and increased endothelin 1, endothelial overexpression of endothelin B receptors, and increased endothelial NO production. […] Proangiogenic factors such as vascular endothelial growth factor, platelet-derived growth factor, and placental growth factor play an important role in the proliferation of pulmonary capillaries. […] Chronic inflammation in HPS disrupts the continuity of the endothelial glycocalyx layer. […] This article provides an overview of the current knowledge on the pathogenesis of HPS, summarizes many features of the disease based on the literature research in MEDLINE database on the PubMed platform.

• #62 SciELO Brazil – Hepatopulmonary syndrome: an update Hepatopulmonary syndrome: an update

  https://www.scielo.br/j/spmj/a/VXYTNbsCXRD6VFCpVhFcccP/

  Hepatopulmonary syndrome (HPS) is a clinical threesome composed of liver disease, intrapulmonary vascular dilatation (IPVD) and arterial gas abnormalities. […] Its pathogenesis is not well defined, but an association of factors such as imbalance in the endothelin receptor response, pulmonary microvascular remodeling and genetic predisposition is thought to lead to IPVD. […] Although not yet completely elucidated, the pathogenesis of HPS is believed to involve a number of factors. Together, these factors lead to IPVD and oxygenation abnormalities in patients with liver disease. […] There have been reports of genetic predisposition associated with possible imbalance in the receptors that regulate pulmonary vascular tonus. […] More recently, there have been reports on the role of bacterial translocation and probable remodeling in the pulmonary vascular bed.

• #63 The Hepatopulmonary Syndrome | Abdominal Key

  https://abdominalkey.com/the-hepatopulmonary-syndrome/

  Less is known about the pathogenesis of human HPS and how the mechanisms identified in the development of experimental HPS contribute to human disease. The fact that HPS occurs across a spectrum of etiologies and disease and portal hypertension severity and develops in less than 50% of cirrhotic patients, suggest that HPS develops in patients with an underlying predisposition. The recent finding that genetic variation in genes associated with vascular growth and development is associated with the risk of HPS raises the possibility that genetic susceptibility to angiogenesis might be a predisposing factor. Systemic and pulmonary production of NO is increased in HPS, but is also increased in cirrhotic patients without HPS. Inhibition of NO production does not reliably improve HPS despite improving systemic hemodynamics. Therefore, the precise role of NO in human HPS is unknown. CO production does appear to be selectively increased in human HPS, although whether this derives from lung production or influences the vasculature is not known. Finally, whether monocytes adhere in the lung vasculature in human HPS, via increased circulating levels of adhesion molecules, and whether inhibition of TNF- or bacterial translocation across the gastrointestinal tract alter the severity of HPS are not well defined.

• #64 Hepatopulmonary Syndrome – Pulmonary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pulmonary-disorders/pulmonary-hypertension/hepatopulmonary-syndrome

  Hepatopulmonary syndrome is hypoxemia caused by pulmonary microvascular vasodilation in patients with portal hypertension; dyspnea and hypoxemia are worse when the patient is upright. […] Hepatopulmonary syndrome results from the formation of microscopic intrapulmonary arteriovenous dilations in patients with chronic liver disease typically when complicated by portal hypertension. The mechanism is unknown but is thought to be due to increased hepatic production or decreased hepatic clearance of vasodilators. The vascular dilations cause overperfusion relative to ventilation, leading to hypoxemia, particularly because patients have an increased cardiac output resulting from systemic vasodilation. […] Hepatopulmonary syndrome is associated with reduced levels of bone morphogenetic protein 9 (BMP9) and BMP10 when compared to control patients with advanced liver disease without hepatopulmonary syndrome. Lower BMP9 levels were further associated with more severe hepatopulmonary syndrome. […] Hepatopulmonary syndrome may regress after liver transplantation or if the underlying liver disease subsides. Prognosis is poor in patients with hepatopulmonary syndrome, ranging from 40 to 60% at 2.5 years.

• #65 Hepatopulmonary Syndrome – Pulmonary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pulmonary-disorders/pulmonary-hypertension/hepatopulmonary-syndrome

  Hepatopulmonary syndrome is hypoxemia caused by pulmonary microvascular vasodilation in patients with portal hypertension; dyspnea and hypoxemia are worse when the patient is upright. […] Hepatopulmonary syndrome results from the formation of microscopic intrapulmonary arteriovenous dilations in patients with chronic liver disease typically when complicated by portal hypertension. The mechanism is unknown but is thought to be due to increased hepatic production or decreased hepatic clearance of vasodilators. The vascular dilations cause overperfusion relative to ventilation, leading to hypoxemia, particularly because patients have an increased cardiac output resulting from systemic vasodilation. […] Hepatopulmonary syndrome is associated with reduced levels of bone morphogenetic protein 9 (BMP9) and BMP10 when compared to control patients with advanced liver disease without hepatopulmonary syndrome. Lower BMP9 levels were further associated with more severe hepatopulmonary syndrome. […] Hepatopulmonary syndrome may regress after liver transplantation or if the underlying liver disease subsides. Prognosis is poor in patients with hepatopulmonary syndrome, ranging from 40 to 60% at 2.5 years.

• #66 SciELO Brazil – Hepatopulmonary syndrome: an update Hepatopulmonary syndrome: an update

  https://www.scielo.br/j/spmj/a/VXYTNbsCXRD6VFCpVhFcccP/

  Hepatopulmonary syndrome (HPS) is a clinical threesome composed of liver disease, intrapulmonary vascular dilatation (IPVD) and arterial gas abnormalities. […] Its pathogenesis is not well defined, but an association of factors such as imbalance in the endothelin receptor response, pulmonary microvascular remodeling and genetic predisposition is thought to lead to IPVD. […] Although not yet completely elucidated, the pathogenesis of HPS is believed to involve a number of factors. Together, these factors lead to IPVD and oxygenation abnormalities in patients with liver disease. […] There have been reports of genetic predisposition associated with possible imbalance in the receptors that regulate pulmonary vascular tonus. […] More recently, there have been reports on the role of bacterial translocation and probable remodeling in the pulmonary vascular bed.

• #67 The Hepatopulmonary Syndrome | Abdominal Key

  https://abdominalkey.com/the-hepatopulmonary-syndrome/

  Less is known about the pathogenesis of human HPS and how the mechanisms identified in the development of experimental HPS contribute to human disease. The fact that HPS occurs across a spectrum of etiologies and disease and portal hypertension severity and develops in less than 50% of cirrhotic patients, suggest that HPS develops in patients with an underlying predisposition. The recent finding that genetic variation in genes associated with vascular growth and development is associated with the risk of HPS raises the possibility that genetic susceptibility to angiogenesis might be a predisposing factor. Systemic and pulmonary production of NO is increased in HPS, but is also increased in cirrhotic patients without HPS. Inhibition of NO production does not reliably improve HPS despite improving systemic hemodynamics. Therefore, the precise role of NO in human HPS is unknown. CO production does appear to be selectively increased in human HPS, although whether this derives from lung production or influences the vasculature is not known. Finally, whether monocytes adhere in the lung vasculature in human HPS, via increased circulating levels of adhesion molecules, and whether inhibition of TNF- or bacterial translocation across the gastrointestinal tract alter the severity of HPS are not well defined.

• #68 Hepatopulmonary Syndrome: Oxidative Stress and Physical Exercise – European Medical Journal

  https://www.emjreviews.com/hepatology/article/hepatopulmonary-syndrome-oxidative-stress-and-physical-exercise/

  Hepatopulmonary syndrome (HPS) may be defined by hepatic disease, gas exchange abnormalities that may lead to hypoxaemia, and the presence of pulmonary vascular dilations. […] The pulmonary tissue may be damaged by reactive oxygen species or nitric oxide. […] Liver disease can contribute to HPS oxidative stress and is one of the main factors responsible for the reduction of gas exchange. […] Liver damage makes it more difficult for the organ to filter blood from the portal vein, which leads to the appearance of portosystemic shunts and a decrease in the hepatic phagocytic capacity. […] As a result, the lung filtrates systemic blood to compensate for the decrease in hepatic phagocytosis, and the increase in the lung phagocytic activity results in macrophage accumulation in the pulmonary endothelium and increases cytokine and NO levels in the extracellular environment.

• #69 Hepatopulmonary Syndrome: Oxidative Stress and Physical Exercise – European Medical Journal

  https://www.emjreviews.com/hepatology/article/hepatopulmonary-syndrome-oxidative-stress-and-physical-exercise/

  Hepatopulmonary syndrome (HPS) may be defined by hepatic disease, gas exchange abnormalities that may lead to hypoxaemia, and the presence of pulmonary vascular dilations. […] The pulmonary tissue may be damaged by reactive oxygen species or nitric oxide. […] Liver disease can contribute to HPS oxidative stress and is one of the main factors responsible for the reduction of gas exchange. […] Liver damage makes it more difficult for the organ to filter blood from the portal vein, which leads to the appearance of portosystemic shunts and a decrease in the hepatic phagocytic capacity. […] As a result, the lung filtrates systemic blood to compensate for the decrease in hepatic phagocytosis, and the increase in the lung phagocytic activity results in macrophage accumulation in the pulmonary endothelium and increases cytokine and NO levels in the extracellular environment.

• #70 Hepatopulmonary Syndrome: Oxidative Stress and Physical Exercise – European Medical Journal

  https://www.emjreviews.com/hepatology/article/hepatopulmonary-syndrome-oxidative-stress-and-physical-exercise/

  NO acts as a molecular signal that mediates the vasodilation of pulmonary capillaries when it is produced in low concentrations by vascular endothelial cells. […] Experimental studies that used the BDL surgical model have indicated an increase in oxidative stress of hepatic and pulmonary tissues, as well as other lung alterations typical of HPS. […] The researchers concluded that the experimental model of common BDL simulates the main symptoms of HPS, which suggests it is a good model to investigate oxidative stress, hepatic changes, and the respiratory system. […] The experimental models more commonly used to investigate the abnormalities caused by HPS are the BDL and partial portal vein ligation in rats. […] In both models, NO develops an important rule regarding the pathogenesis of the experimental HPS, which causes vascular dilation and leads to hypoxaemia, similar to the findings of cirrhotic patients.

• #71 Hepatopulmonary syndrome: What we know and what we would like to know

  https://www.wjgnet.com/1007-9327/full/v22/i25/5728.htm

  Hepatopulmonary syndrome (HPS) is characterized by abnormalities in blood oxygenation caused by the presence of intrapulmonary vascular dilations (IPVD) in the context of liver disease, generally at a cirrhotic stage. […] The majority of the information about the etiopathogenesis of HPS has been obtained through experiments on animals. […] The main mediators involved in the onset of IPVD, which are fundamental to the pathogenesis of HPS, are nitric oxide (NO) and carbon monoxide (CO). […] The principal abnormality which defines HPS is the dilatation of pre and post-capillary pulmonary vessels in the alveolar regions. […] With HPS there is an increase in the alveolar-arterial gradient of O2 (AaO2) and hypoxemia which is caused by three mechanisms. […] The vasodilatation of alveolar capillaries results in an excessive amount of blood flowing into the normally ventilated alveoli, which causes a decline in the ventilation perfusion quotient, resulting in increased AaO2 and/or arterial hypoxemia.

• #72 Hepatopulmonary syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9403489/

  A complex interaction between the liver, the gut and the lungs, predominately impacting pulmonary endothelial cells, immune cells and respiratory epithelial cells, is responsible for the development of IPVDs and intrapulmonary shunting in HPS. These phenomena result in V/Q mismatch, diffusion restriction and right-to-left shunting, responsible for impaired gas exchange and hypoxemia. Bacterial translocation with pulmonary intravascular recruitment of immune cells, pulmonary endothelial dysfunction, angiogenesis, and AT2 cell dysfunction represent the most important underlying mechanisms and are considered potential therapeutic targets. […] The pathogenesis of alterations in the microcirculation in HPS has been the focus of study over the last 20 years. This work has been facilitated by the recognition that experimental common bile duct ligation (CBDL) recapitulates many features of human HPS.

• #73 Hepatopulmonary Syndrome: Oxidative Stress and Physical Exercise – European Medical Journal

  https://www.emjreviews.com/hepatology/article/hepatopulmonary-syndrome-oxidative-stress-and-physical-exercise/

  NO acts as a molecular signal that mediates the vasodilation of pulmonary capillaries when it is produced in low concentrations by vascular endothelial cells. […] Experimental studies that used the BDL surgical model have indicated an increase in oxidative stress of hepatic and pulmonary tissues, as well as other lung alterations typical of HPS. […] The researchers concluded that the experimental model of common BDL simulates the main symptoms of HPS, which suggests it is a good model to investigate oxidative stress, hepatic changes, and the respiratory system. […] The experimental models more commonly used to investigate the abnormalities caused by HPS are the BDL and partial portal vein ligation in rats. […] In both models, NO develops an important rule regarding the pathogenesis of the experimental HPS, which causes vascular dilation and leads to hypoxaemia, similar to the findings of cirrhotic patients.

• #74 The Hepatopulmonary Syndrome | Abdominal Key

  https://abdominalkey.com/the-hepatopulmonary-syndrome/

  HPS develops when pulmonary microvascular dilatation and/or angiogenesis develops in the setting of liver disease. The mechanisms that trigger these microvascular changes are incompletely characterized. In experimental HPS induced by common bile duct ligation (CBDL), both pulmonary microvascular dilatation and angiogenesis contribute to altered gas exchange. Similar changes are not observed in other rodent models of cirrhosis and portal hypertension, suggesting that CBDL triggers unique molecular events that influence the pulmonary microvasculature. The two most well-recognized events include increased microvascular endothelin signaling and accumulation of monocytes in the microvascular lumen. Upregulated endothelin-1 (ET-1) signaling occurs via increased circulating ET-1 levels, in part derived from cholangiocytes, and by increased lung endothelial endothelin B (ETB) receptor expression in response to increased shear stress due to systemic vascular changes. The result is enhanced ETB receptor mediated endothelial-derived nitric oxide (NO) production. Monocyte accumulation within the microvasculature is enhanced by ET-1 alterations and also by tumor necrosis factor (TNF-) production from bacterial translocation of intestinal micro-organisms and possibly specific overexpression of monocyte chemotactic and angiogenic chemokines (i.e., fractalkine). Intravascular monocytes are an important source for local pulmonary production of NO, carbon monoxide (CO), and vascular endothelial growth factor (VEGF) which contribute to vascular and gas exchange abnormalities. Recently, in vitro studies have demonstrated that upregulation of the ERK signaling pathway and cholangiocyte VEGF overexpression may be associated with cholangiocyte ET-1 production. Accordingly, in CBDL animals, inhibition of TNF-, ETB receptor signaling, CO production, tyroxine kinase receptor, or angiogenesis ameliorate HPS.

• #75 Hepatopulmonary Syndrome: Oxidative Stress and Physical Exercise – European Medical Journal

  https://www.emjreviews.com/hepatology/article/hepatopulmonary-syndrome-oxidative-stress-and-physical-exercise/

  NO acts as a molecular signal that mediates the vasodilation of pulmonary capillaries when it is produced in low concentrations by vascular endothelial cells. […] Experimental studies that used the BDL surgical model have indicated an increase in oxidative stress of hepatic and pulmonary tissues, as well as other lung alterations typical of HPS. […] The researchers concluded that the experimental model of common BDL simulates the main symptoms of HPS, which suggests it is a good model to investigate oxidative stress, hepatic changes, and the respiratory system. […] The experimental models more commonly used to investigate the abnormalities caused by HPS are the BDL and partial portal vein ligation in rats. […] In both models, NO develops an important rule regarding the pathogenesis of the experimental HPS, which causes vascular dilation and leads to hypoxaemia, similar to the findings of cirrhotic patients.

• #76 Hepatopulmonary Syndrome: A Forgotten Liver-induced Lung Vascular Disorder | Archivos de Bronconeumología

  https://archbronconeumol.org/es-hepatopulmonary-syndrome-a-forgotten-liver-induced-articulo-S0300289622006706

  The use of the more sensitive oxygen gradient (AaPO2) to make the diagnosis of HPS becomes important because it can increase abnormally before the PaO2 itself becomes abnormally low as the oxygen gradient compensates for the reduced levels of arterial carbon dioxide (CO2) and hyperventilation, both common in LC. […] Importantly, the severity of HPS is classified according to the levels of PaO2 breathing ambient air. […] Fallon et al. have made substantial experimental contributions using the chronic bile duct ligation model in rats and mice and have identified key pathophysiological triggers for the mechanisms that contribute to gas exchange abnormalities in HPS. Relaxation of blood vessels leading to pulmonary vasodilation, angiogenesis, leading to the development of VA/Q mismatching and increased intrapulmonary shunt, and alveolar dysfunction emerge as the principal mechanisms. […] Regrettably, no effective pharmacological therapies are available as yet so liver transplant has become the only effective therapeutic approach that results in complete resolution of the HPS.

• #77 Hepatopulmonary syndrome: update on pathogenesis and clinical features | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/nrgastro.2012.123

  Hepatopulmonary syndrome (HPS) is a serious vascular complication of liver disease that occurs in 532% of patients with cirrhosis. […] The presence of HPS markedly increases mortality. […] 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. […] Defining the mechanisms involved in the microvascular alterations of HPS has the potential to lead to effective medical therapies. […] Excess lung production of gaseous vasodilators, nitric oxide and carbon monoxide contributes to vasodilatation in human and experimental HPS. […] Pulmonary angiogenesis has an additive role in the development of experimental HPS.

• #78 Hepatopulmonary Syndrome – Pulmonary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pulmonary-disorders/pulmonary-hypertension/hepatopulmonary-syndrome

  Hepatopulmonary syndrome is hypoxemia caused by pulmonary microvascular vasodilation in patients with portal hypertension; dyspnea and hypoxemia are worse when the patient is upright. […] Hepatopulmonary syndrome results from the formation of microscopic intrapulmonary arteriovenous dilations in patients with chronic liver disease typically when complicated by portal hypertension. The mechanism is unknown but is thought to be due to increased hepatic production or decreased hepatic clearance of vasodilators. The vascular dilations cause overperfusion relative to ventilation, leading to hypoxemia, particularly because patients have an increased cardiac output resulting from systemic vasodilation. […] Hepatopulmonary syndrome is associated with reduced levels of bone morphogenetic protein 9 (BMP9) and BMP10 when compared to control patients with advanced liver disease without hepatopulmonary syndrome. Lower BMP9 levels were further associated with more severe hepatopulmonary syndrome. […] Hepatopulmonary syndrome may regress after liver transplantation or if the underlying liver disease subsides. Prognosis is poor in patients with hepatopulmonary syndrome, ranging from 40 to 60% at 2.5 years.

• #79

  https://www.pneumon.org/Hepatopulmonary-syndrome,136770,0,2.html

  The hepatopulmonary syndrome is characterized by the combination of hypoxemia and endopulmonary vascular dilatations in patients with liver disease. […] Evidence exists that endopulmonary dilatations correlate with the presence of portal hypertension. The increased production of nitrogen monoxide (NO) and the activation of endothelin receptors are shown to play an important role in the pathogenesis of the syndrome by causing vascular dilatation and by interrupting the normal mechanism of hypoxic vasoconstriction in the lung. […] Prognosis is poor and mortality exceeds 40%.

• #80 Thieme E-Journals – Seminars in Respiratory and Critical Care Medicine / Abstract

  https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0032-1301730

  Hepatopulmonary syndrome (HPS) is characterized by an oxygenation defect induced by pulmonary vascular dilatation in the setting of liver cirrhosis or portal hypertension. […] The key event in its pathogenesis is the development of intrapulmonary vascular dilatation (IPVD), which has been linked to increased pulmonary levels of nitric oxide. […] Liver transplantation is the only available treatment for HPS, resulting in complete resolution or significant improvement in gas exchange in over 85% of patients.

• #81 Successful treatment of severe hepatopulmonary syndrome with a sequential use of TIPS placement and liver transplantation | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-successful-treatment-severe-hepatopulmonary-syndrome-S1665268119318162

  Hepatopulmonary syndrome (HPS) is a complication of portal hypertension (PH) defined by the presence of liver disease, abnormal pulmonary gas exchange and evidence of intrapulmonary vascular dilatations (IPVD) producing a right to left intrapulmonary shunt. […] The hallmark of HPS is the presence of IPVD, probably secondary to portal hypertension and producing a right to left intrapulmonary shunt. […] Currently, liver transplantation is considered the treatment of choice for HPS. However, because of severe hypoxemia, the procedure is contraindicated in many cases. […] The diagnostic procedures currently used to establish the presence of HPS are microbubble contrast echocardiography and technetium-labeled macroaggregated albumin scan (MAA scan). […] At present, there is no effective medical therapy considered useful in the management of HPS.

• #82 Hepatopulmonary syndrome: update on pathogenesis and clinical features | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/nrgastro.2012.123

  Hepatopulmonary syndrome (HPS) is a serious vascular complication of liver disease that occurs in 532% of patients with cirrhosis. […] The presence of HPS markedly increases mortality. […] 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. […] Defining the mechanisms involved in the microvascular alterations of HPS has the potential to lead to effective medical therapies. […] Excess lung production of gaseous vasodilators, nitric oxide and carbon monoxide contributes to vasodilatation in human and experimental HPS. […] Pulmonary angiogenesis has an additive role in the development of experimental HPS.

• #83 Hepatopulmonary syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9403489/

  Work in the CBDL model has identified underlying pathophysiologic triggers for 3 mechanisms that contribute to the development of hypoxemia in the disease: relaxation of blood vessels leading to vasodilation, angiogenesis leading to shunt formation, and alveolar dysfunction. […] Studies in experimental HPS directly targeting classic pro-angiogenic pathways including VEGF, PDGF and Raf kinases, using the receptor tyrosine kinase inhibitor sorafenib have shown beneficial effects in the pulmonary microvasculature and improvement in gas exchange.

• #84 SciELO Brazil – Hepatopulmonary syndrome: an update Hepatopulmonary syndrome: an update

  https://www.scielo.br/j/spmj/a/VXYTNbsCXRD6VFCpVhFcccP/

  Experimental findings regarding the roles of ET-1, TNF- and intestinal endotoxemia in the development of IPVD in the pulmonary microvasculature may contribute towards understanding the physiopathology of HPS in humans and allow the use of new treatments in the future. […] It has recently been suggested that, in addition to the functional changes, structural remodeling of the pulmonary microvasculature may occur in patients with HPS.

• #85 Frontiers | Advances in Diagnostic Imaging of Hepatopulmonary Syndrome

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.817758/full

  There is a clear connection between hypoxemia and liver disease. In presence of liver disease, it appears that pulmonary vasodilatation (PV) leads to a mismatch between ventilation/perfusion and diffusing capacity. […] The severity of HPS can be classified according to the PaO2 into either mild (PaO2 ≥80 mmHg), moderate (PaO2 60–79 mmHg), severe (PaO2 50–59 mmHg), or very severe (PaO2 <50 mmHg). [...] HPS is a serious pulmonary complication of end-stage liver disease. The mortality of patients with HPS is significantly high and the prognosis is poor. Early detection and timely treatment may help improve the prognosis. [...] The focus of clinical diagnosis is to identify evidence of PV in patients with chronic liver disease complicated with hypoxemia. Therefore, clinical assessment must be combined with the results of imaging examination.

• #86 Frontiers | Advances in Diagnostic Imaging of Hepatopulmonary Syndrome

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.817758/full

  There is a clear connection between hypoxemia and liver disease. In presence of liver disease, it appears that pulmonary vasodilatation (PV) leads to a mismatch between ventilation/perfusion and diffusing capacity. […] The severity of HPS can be classified according to the PaO2 into either mild (PaO2 ≥80 mmHg), moderate (PaO2 60–79 mmHg), severe (PaO2 50–59 mmHg), or very severe (PaO2 <50 mmHg). [...] HPS is a serious pulmonary complication of end-stage liver disease. The mortality of patients with HPS is significantly high and the prognosis is poor. Early detection and timely treatment may help improve the prognosis. [...] The focus of clinical diagnosis is to identify evidence of PV in patients with chronic liver disease complicated with hypoxemia. Therefore, clinical assessment must be combined with the results of imaging examination.

• #87 Hepatopulmonary syndrome: update on pathogenesis and clinical features | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/nrgastro.2012.123

  Hepatopulmonary syndrome (HPS) is a serious vascular complication of liver disease that occurs in 532% of patients with cirrhosis. […] The presence of HPS markedly increases mortality. […] 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. […] Defining the mechanisms involved in the microvascular alterations of HPS has the potential to lead to effective medical therapies. […] Excess lung production of gaseous vasodilators, nitric oxide and carbon monoxide contributes to vasodilatation in human and experimental HPS. […] Pulmonary angiogenesis has an additive role in the development of experimental HPS.

• #88 Review article: Update on current and emergent data on hepatopulmonary syndrome

  https://www.wjgnet.com/1007-9327/full/v24/i12/1285.htm

  The increased production of nitric oxide (NO) and carbon monoxide (CO), two pulmonary vasodilators, constitutes the key process for the development of pulmonary vasodilatation. […] The binding of endothelin-1 to its pulmonary receptor ET-1B triggers the activation of endothelial and inducible nitric oxide synthase (eNOS and iNOS) resulting in elevated NO production and NO-induced pulmonary vasodilatation. […] In patients with liver dysfunction, activation and massive accumulation of intravascular macrophages is observed as a result of intestinal bacterial translocation and endotoxemia. […] These macrophages in the pulmonary vasculature produce proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-), contributing in the NO-mediated vasodilatation through iNOS activation.

• #89 Review article: Update on current and emergent data on hepatopulmonary syndrome

  https://www.wjgnet.com/1007-9327/full/v24/i12/1285.htm

  Angiogenesis is considered another crucial mechanism interpreting HPS pathogenesis. […] Intestinal bacterial translocation and the consequent endotoxemia due to liver dysfunction lead to the recruitment of monocytes and activated macrophages to the lung. […] These inflammatory cells together with circulating TNF- stimulate the activation of vascular endothelial growth factor (VEGF) signaling pathways, which are related to angiogenesis. […] The accumulation of CD68+ macrophages in the lungs of common bile duct ligation rats, expressing iNOS and VEGF, has been correlated to the presence of HPS. […] Although it can be postulated that VEGF constitutes a regulator of angiogenesis with a possible role in the development of HPS, further studies with measurements of VEGF are needed to unravel the exact pathogenetic pathways.

• #90 The Hepatopulmonary Syndrome | Abdominal Key

  https://abdominalkey.com/the-hepatopulmonary-syndrome/

  The pathogenesis of altered oxygenation in HPS derives from the changes in the pulmonary microvascular bed. In humans, capillary dilatation and pleural arteriovenous malformations have been described in a limited number of cases. In experimental HPS, both pulmonary vascular dilatation and angiogenesis occur. Three mechanisms of hypoxemia have been described in human HPS: anatomic arteriovenous shunting, ventilation-perfusion mismatch (increased capillary blood flow), and diffusion-perfusion mismatching (impaired passage of oxygen from the alveolus into the vasculature). The relative contribution of these mechanisms to gas exchange abnormalities appear to vary based on the severity of HPS.

• #91 Hepatopulmonary Syndrome: A Forgotten Liver-induced Lung Vascular Disorder | Archivos de Bronconeumología

  https://archbronconeumol.org/es-hepatopulmonary-syndrome-a-forgotten-liver-induced-articulo-S0300289622006706

  The use of the more sensitive oxygen gradient (AaPO2) to make the diagnosis of HPS becomes important because it can increase abnormally before the PaO2 itself becomes abnormally low as the oxygen gradient compensates for the reduced levels of arterial carbon dioxide (CO2) and hyperventilation, both common in LC. […] Importantly, the severity of HPS is classified according to the levels of PaO2 breathing ambient air. […] Fallon et al. have made substantial experimental contributions using the chronic bile duct ligation model in rats and mice and have identified key pathophysiological triggers for the mechanisms that contribute to gas exchange abnormalities in HPS. Relaxation of blood vessels leading to pulmonary vasodilation, angiogenesis, leading to the development of VA/Q mismatching and increased intrapulmonary shunt, and alveolar dysfunction emerge as the principal mechanisms. […] Regrettably, no effective pharmacological therapies are available as yet so liver transplant has become the only effective therapeutic approach that results in complete resolution of the HPS.

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