Editorial
Hepatopulmonary Syndrome: A Forgotten Liver-induced Lung Vascular Disorder
Robert Rodríguez-Roisin
Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain
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Reslizumab and mepolizumab target soluble IL-5, benralizumab is directed against the α subunit of the IL-5 receptor, dupilumab is an antagonist of the IL-4α receptor and the target of omalizumab is IgE.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Mattia Nigro, Edoardo Simonetta, Miguel Ángel Martínez-García, Stefano Aliberti" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Mattia" "apellidos" => "Nigro" ] 1 => array:2 [ "nombre" => "Edoardo" "apellidos" => "Simonetta" ] 2 => array:2 [ "nombre" => "Miguel Ángel" "apellidos" => "Martínez-García" ] 3 => array:2 [ "nombre" => "Stefano" "apellidos" => "Aliberti" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0300289622006718?idApp=UINPBA00003Z" "url" => "/03002896/0000005900000003/v4_202401230711/S0300289622006718/v4_202401230711/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S0300289622006639" "issn" => "03002896" "doi" => "10.1016/j.arbres.2022.12.001" "estado" => "S300" "fechaPublicacion" => "2023-03-01" "aid" => "3225" "copyright" => "SEPAR" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "edi" "cita" => "Arch Bronconeumol. 2023;59:134-6" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Primary Ciliary Dyskinesia and Bronchiectasis: New Data and Future Challenges" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "134" "paginaFinal" => "136" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1795 "Ancho" => 2925 "Tamanyo" => 591353 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clinical features, diagnostic tools and mangament of primary ciliary dyskinesia.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Charlotte O. Pioch, David W. Connell, Amelia Shoemark" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Charlotte O." "apellidos" => "Pioch" ] 1 => array:2 [ "nombre" => "David W." "apellidos" => "Connell" ] 2 => array:2 [ "nombre" => "Amelia" "apellidos" => "Shoemark" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0300289622006639?idApp=UINPBA00003Z" "url" => "/03002896/0000005900000003/v4_202401230711/S0300289622006639/v4_202401230711/en/main.assets" ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Hepatopulmonary Syndrome: A Forgotten Liver-induced Lung Vascular Disorder" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "137" "paginaFinal" => "138" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Robert Rodríguez-Roisin" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Robert" "apellidos" => "Rodríguez-Roisin" "email" => array:1 [ 0 => "robrodroi@gmail.com" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain" "identificador" => "aff0005" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1099 "Ancho" => 1675 "Tamanyo" => 129086 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Sketch illustrating the three key criteria to establish the diagnosis of HPS: an arterial oxygenation defect (<span class="elsevierStyleItalic">i.e.</span>, AaPO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>15<span class="elsevierStyleHsp" style=""></span>mmHg with or without a PaO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>80<span class="elsevierStyleHsp" style=""></span>mmHg, while breathing ambient air); a chronic hepatic disorder; and the presence of intrapulmonary vascular dilatations (IPVD), as assessed by either positive findings on contrast-enhanced echocardiography with air bubbles or abnormal uptake in the brain [>6%] with radioactive lung-perfusion scanning.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">This editorial, commissioned by the Board of <span class="elsevierStyleItalic">Arch Bronconeumol</span>, focuses on some of the most prominent clinical and pathophysiological concepts related to the hepatopulmonary syndrome (HPS), an enthralling liver-induced lung vascular disorder prevailing in liver cirrhosis (LC). This seems to be timely in the context of an overwhelming period of research focused to all fields of pulmonary vascular disorders.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Year 1966 represents a quantum leap in the understanding of the structural basis of what ultimately would be named HPS 25 years later.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> In that year, Berthelot et al.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a> showed that the post-mortem lung findings in patients with LC consisted of pronounced pulmonary vessel dilatations at both the pre-capillary and capillary levels, with or without associated pleural spider <span class="elsevierStyleItalic">naevi</span> in an otherwise intact pulmonary architecture. That study further dug into the intriguing nature of the link between oxygen desaturation and intrapulmonary arterial shunt in the lungs of LC, a problem that remained unsettled until that time. During the 60's and 70's, arterial hypoxaemia (PaO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>80<span class="elsevierStyleHsp" style=""></span>mmHg, at rest while breathing ambient air) in patients with LC had been variously attributed to several mechanisms, such as shifts in the oxyhaemoglobin dissociation curve, intrapulmonary and porto-pulmonary shunts, alveolar-capillary diffusion limitation, and/or ventilation–perfusion (V<span class="elsevierStyleInf">A</span>/Q) imbalance, none to them sufficiently convincing, in the apparent absence of cardiac or pulmonary disease.</p><p id="par0015" class="elsevierStylePara elsevierViewall">This enticing dilemma was eventually unraveled by a series of investigations using the multiple inert gas elimination technique (MIGET)<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a> in patients with LC to elucidate the essences of arterial hypoxaemia.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a> The patients showed mild systemic and pulmonary vasodilation, increased alveolar–arterial oxygen gradient (AaPO<span class="elsevierStyleInf">2</span>) (≥15<span class="elsevierStyleHsp" style=""></span>mm Hg) with or without modest hypoxaemia and mild hypocapnia, and normal lung functions tests. The distributions of V<span class="elsevierStyleInf">A</span>/Q ratios displayed mild abnormalities (<span class="elsevierStyleItalic">i.e.</span>, a small proportion of the cardiac output diverted to areas with a low V<span class="elsevierStyleInf">A</span>/Q ratio), while intrapulmonary shunt was mildly increased or conspicuously absent. Under hypoxic breathing conditions, both pulmonary artery pressure and vascular resistance slightly increased or did not change, whereas V<span class="elsevierStyleInf">A</span>/Q distributions remained essentially unchanged; by contrast, during breathing 100% oxygen, V<span class="elsevierStyleInf">A</span>/Q distributions worsened suggesting release (abolition) of hypoxic pulmonary vasoconstriction (HPV). Of note that diffusion limitation to oxygen, as assessed by the MIGET, was not detected. One of the most outstanding findings however was that patients with cutaneous <span class="elsevierStyleItalic">spider naevi</span>, 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 V<span class="elsevierStyleInf">A</span>/Q imbalance than those without <span class="elsevierStyleItalic">spider naevi</span>. Within the next three years four new studies were published in a row in patients with more severe grades of LC and pronounced gas exchange abnormalities,<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">5–8</span></a> thus confirming and expanding our seminal findings. Accordingly, the presence of three of the four well-known intrapulmonary factors governing abnormal oxygenation (V<span class="elsevierStyleInf">A</span>/Q mismatch, increased intrapulmonary shunt, diffusion impairment to oxygen, and hypoventilation) but hypoventilation was compelling in patients with LC, with the predominance of V<span class="elsevierStyleInf">A</span>/Q inequality induced by an increased pulmonary blood flow enhanced by the absence or impairment of HPV. An increase in the PaO<span class="elsevierStyleInf">2</span> to the breathing of 100% oxygen (≥300<span class="elsevierStyleHsp" style=""></span>mm Hg) often occurs in the HPS, a response that may be increased by an elevated cardiac output in the context of the characteristic hyperkinetic circulation of LC. 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) (DL<span class="elsevierStyleInf">CO</span>) associated with hepatic dysfunction in general and with the HPS in particular. Likewise, DL<span class="elsevierStyleInf">CO</span> may be reduced because the alveolar–capillary interface is too wide to allow for complete equilibration of CO with haemoglobin. Arterial hypoxaemia may also be reduced by hyperventilation, which increases the levels of alveolar PO<span class="elsevierStyleInf">2</span>, and high cardiac output, which raises the mixed venous partial pressure of oxygen, other things being equal. The use of the more sensitive oxygen gradient (AaPO<span class="elsevierStyleInf">2</span>) to make the diagnosis of HPS becomes important because it can increase abnormally before the PaO<span class="elsevierStyleInf">2</span> itself becomes abnormally low as the oxygen gradient compensates for the reduced levels of arterial carbon dioxide (CO<span class="elsevierStyleInf">2</span>) and hyperventilation, both common in LC. Importantly, the severity of HPS is classified according to the levels of PaO<span class="elsevierStyleInf">2</span> breathing ambient air. Likewise, both V<span class="elsevierStyleInf">A</span>/Q and intrapulmonary shunt worsening constitute the principal mechanism of <span class="elsevierStyleItalic">orthodeoxia</span> (<span class="elsevierStyleItalic">i.e.</span>, decreased PaO<span class="elsevierStyleInf">2</span> from supine to upright) observed in 30% of the patients with the HPS,<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a> because of a more rigid and fixed pulmonary vascular tone, less liable to proportionately accommodate gravitational blood flow changes to ventilation in dependent alveolar units.</p><p id="par0020" class="elsevierStylePara elsevierViewall">An international task force<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">9,10</span></a> defined the term as a clinical triad that encompasses an arterial oxygenation defect, a chronic hepatic disorder (portal hypertension with or without cirrhosis), and the presence of intrapulmonary vascular dilatations (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Data from liver-transplant centres indicate that the prevalence of the HPS ranges from 5 to 32%.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a> Advanced liver disease associated with several pulmonary and/or pleural complications is part of the differential diagnosis of the HPS. Clinical judgment may still be necessary, nonetheless, to unravel the severity of arterial hypoxaemia in the HPS and in coexisting commoner pulmonary conditions, such as chronic obstructive airway and interstitial diseases. Patients with HPS are frequently dyspnoeic when not asymptomatic, so the disease can be concealed and its diagnosis delayed. Arterial blood gas measurements and contrast echocardiography are mandatory for the diagnostic work-up.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a> The HPS is associated with a profile of abnormal systemic angiogenesis, worse exercise and functional capacity, and an overall increased risk of death.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">11</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">Rendu–Osler–Weber syndrome</span> (or hereditary haemorrhagic telangiectasia) and post-surgical consequences of cavo-pulmonary anastomoses for various congenital heart conditions can resemble or mimic the HPS.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a> Both can be associated with severe arterial hypoxaemia induced by pulmonary vascular dilatation, which may be diffuse or discrete in nature. Krowka and associates have comprehensively investigated a close condition, namely portopulmonary hypertension, sometimes associated with mild hypoxaemia but rarely with severe hypoxaemia, and frequently confused with the HPS.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Fallon et al.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">12</span></a> 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,<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">13,14</span></a> leading to the development of V<span class="elsevierStyleInf">A</span>/Q mismatching and increased intrapulmonary shunt, and alveolar dysfunction emerge as the principal mechanisms. The differential function of endothelin (ET) 1 in the pulmonary vasculature results from binding with its receptors: the vascular smooth muscle expressed ET A or B (ETB) receptors mediate vasoconstriction, while the endothelial expressed ETB receptor activates endothelial nitric oxide (NO) synthase and increases NO, ultimately leading to vasodilation.</p><p id="par0035" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> To wrap up, the HPS remains an enthralling model in Medicine to further pave the pathophysiology and biopathology of pulmonary gas exchange abnormalities in patients with hepatic diseases, a problem that uniquely illustrates the tantalizing interplay between arterial oxygenation and the liver.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of Interest</span><p id="par0040" class="elsevierStylePara elsevierViewall">RR-R has no conflict of interest to disclose.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of Interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1099 "Ancho" => 1675 "Tamanyo" => 129086 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Sketch illustrating the three key criteria to establish the diagnosis of HPS: an arterial oxygenation defect (<span class="elsevierStyleItalic">i.e.</span>, AaPO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>15<span class="elsevierStyleHsp" style=""></span>mmHg with or without a PaO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>80<span class="elsevierStyleHsp" style=""></span>mmHg, while breathing ambient air); a chronic hepatic disorder; and the presence of intrapulmonary vascular dilatations (IPVD), as assessed by either positive findings on contrast-enhanced echocardiography with air bubbles or abnormal uptake in the brain [>6%] with radioactive lung-perfusion scanning.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0080" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The hepatopulmonary syndrome: new name, old complexities" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R. Rodriguez-Roisin" 1 => "A.G. Agusti" 2 => "J. Roca" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/thx.47.11.897" "Revista" => array:6 [ "tituloSerie" => "Thorax" "fecha" => "1992" "volumen" => "47" "paginaInicial" => "897" "paginaFinal" => "902" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1465744" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0085" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Arterial changes in the lungs in cirrhosis of the liver–lung spider nevi" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "P. Berthelot" 1 => "J.G. Walker" 2 => "S. Sherlock" 3 => "L. 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Bosch" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/arrd.1987.135.5.1085" "Revista" => array:6 [ "tituloSerie" => "Am Rev Respir Dis" "fecha" => "1987" "volumen" => "135" "paginaInicial" => "1085" "paginaFinal" => "1092" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3579008" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0100" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severe hypoxemia and liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "E.S. Edell" 1 => "D.A. Cortese" 2 => "M.J. Krowka" 3 => "K. Rehder" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/ajrccm/140.6.1631" "Revista" => array:6 [ "tituloSerie" => "Am Rev Respir Dis" "fecha" => "1989" "volumen" => "140" "paginaInicial" => "1631" "paginaFinal" => "1635" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2513764" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0105" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pulmonary and extrapulmonary contributors to hypoxemia in liver cirrhosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "C. Melot" 1 => "R. Naeije" 2 => "P. Dechamps" 3 => "R. Hallemans" 4 => "P. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 46 | 23 | 69 |
| 2024 September | 59 | 24 | 83 |
| 2024 August | 73 | 42 | 115 |
| 2024 July | 82 | 22 | 104 |
| 2024 June | 100 | 36 | 136 |
| 2024 May | 85 | 24 | 109 |
| 2024 April | 54 | 22 | 76 |
| 2024 March | 54 | 24 | 78 |
| 2024 February | 57 | 27 | 84 |
| 2024 January | 75 | 40 | 115 |
| 2023 December | 92 | 33 | 125 |
| 2023 November | 47 | 26 | 73 |
| 2023 October | 65 | 51 | 116 |
| 2023 September | 67 | 47 | 114 |
| 2023 August | 53 | 46 | 99 |
| 2023 July | 101 | 39 | 140 |
| 2023 June | 106 | 31 | 137 |
| 2023 May | 217 | 60 | 277 |
| 2023 April | 246 | 121 | 367 |
| 2023 March | 467 | 158 | 625 |
| 2023 February | 4 | 3 | 7 |
| 2023 January | 14 | 8 | 22 |
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