Endovascular closure of a congenital extrahepatic portosystemic shunt for the treatment of hepatopulmonary syndrome in an infant.

Congenital portosystemic shunts may result in the development of hepatopulmonary syndrome, typically presenting with progressive hypoxemia in later childhood. We describe a case of a 5-month-old male with heterotaxy with polysplenia presenting with new onset hypoxemia. Subsequent evaluation identified an extrahepatic portosystemic shunt arising from the confluence of the main portal and superior mesenteric veins draining into the left renal vein. To treat his hypoxemia and prevent future complications of shunting, the patient underwent a successful single-stage endovascular closure.

Cardiac index and hepatopulmonary syndrome in liver transplantation candidates: The pulmonary vascular complications of liver disease study.

BACKGROUND AND AIMS: Hepatopulmonary syndrome (HPS) and a hyperdynamic circulation are common complications of advanced liver disease, but the relationship between HPS and cardiac index (CI) is poorly understood. We sought to compare CI in patients with and without HPS and to assess the relationship between CI and symptoms, quality of life, gas exchange, and exercise capacity among liver transplantation (LT) candidates. We performed a cross-sectional analysis within the Pulmonary Vascular Complications of Liver Disease 2 study, a multicenter prospective cohort study of patients being evaluated for LT. We excluded patients with obstructive or restrictive lung disease, intracardiac shunting, and portopulmonary hypertension. We included 214 patients (81 with HPS and 133 controls without HPS). Compared with controls, patients with HPS had a higher CI (least square mean 3.2 L/min/m 2 , 95% CI 3.1-3.4 vs. 2.8 L/min/m 2 , 95% CI 2.7-3.0, p < 0.001) after adjustment for age, sex, Model for End-stage Liver Disease-Sodium (MELD-Na) score and beta-blocker use, and a lower systemic vascular resistance. Among all LT candidates, CI was correlated with oxygenation (Alveolar-arterial oxygen gradient r =0.27, p < 0.001), intrapulmonary vasodilatation severity ( p < 0.001), and biomarkers of angiogenesis. Higher CI was independently associated with dyspnea and worse functional class and physical quality of life after adjusting for age, sex, MELD-Na, beta-blocker use, and HPS status. HPS was associated with a higher CI among LT candidates. Independent of HPS, higher CI was associated with increased dyspnea and worse functional class, quality of life, and arterial oxygenation.

Imaging in hepatopulmonary syndrome-case report. A multicenter approach during the coronavirus pandemic.

A 60-year-old lady with alcoholic liver disease developed central cyanosis and orthodeoxia. A technetium-99m macro-aggregated albumin lung perfusion scan and contrast echocardiogram were performed. A 13% right to left shunt was calculated from the macro-aggregated albumin scan. There were more bubbles in the left heart than the right at the end of the contrast echocardiogram. Hepatopulmonary syndrome was therefore diagnosed. The patient had a liver transplant five days after these investigations. Further discussion about hepatopulmonary syndrome will be provided. Normally, macro-aggregated albumin scans are performed in few centers, however as this was at the height of the coronavirus pandemic, the scan needed to be performed locally to reduce the chance of the patient getting coronavirus. Local radiographers were remotely instructed on conducting the macro-aggregated albumin scan by a larger center to provide a timely and important investigation in a logistically difficult scenario.

Hypoxemia and if it is the liver? Hepatopulmonary syndrome : about a case.

The hepatopulmonary syndrome is defined as the triad of liver disease, pulmonary gas exchange abnormalities leading to arterial deoxygenation and widespread pulmonary vascular dilatation. It is one of the not infrequently cases of dyspnea within patients with liver disease. We report the case of a 32-year-old woman with cirrohsis and portal hypertention who presented with dyspnea worsning progressively. The blood gas revealed a deep hypoxemia with a PaO2 rate 42mmHg but clinically well tolerated. Pulmonary embolism and pneumonia were rapidly excluded by a CT pulmonary angiography. An echocadiography done in order to find any heart disease suspected a patent foramen ovale. A transthoracic contrast echocardiography showed an important pulmonary vascular dilatation.The association of cirrohsis, pulmonary vascular dilatation and hypoxemia made the diagnos of hepatopulmonary syndrome.

Shortness of breath due to portopulmonary hypertension and hepatopulmonary syndrome: diagnostic challenges and complex management approach in frail patients.

A 60-year-old woman with a background of frailty, non-alcoholic fatty liver disease (NAFLD), cirrhosis and type 2 diabetes mellitus (T2DM), presented with worsening shortness of breath and a drop in oxygen saturation on sitting and standing up. Her chest X-ray demonstrated evidence of upper lobe venous diversion. Given the hypoxia, she had a computed tomography pulmonary angiography (CTPA) to rule out a pulmonary embolism. The only finding from the CTPA was pulmonary hypertension in the absence of any clots in the lungs. An ultrasound of the abdomen confirmed portal hypertension with splenomegaly and a cirrhotic liver, therefore, an initial diagnosis of portopulmonary hypertension and hepatopulmonary syndrome was made.The patient declined an agitated saline contrast echocardiography. Based on frailty she was not deemed to be a suitable candidate for a liver transplant and was discharged with a package of care alongside home oxygen therapy with periodic review in the gastroenterology clinic. She was assessed as stable with no new concerns while on home oxygen and diuretics.This case highlights challenges in diagnosing and managing patients with cirrhosis, portopulmonary hypertension and hepatopulmonary syndrome with a background of complex comorbidities and frailty.

[Improve the understanding of hepatic disease related pulmonary vascular disease].

Hepatic disease-related pulmonary vascular disease refers to the changes in the structure or function of pulmonary circulation caused by liver parenchymal or hepatic vascular diseases, mainly including hepatopulmonary syndrome characterized by hypoxemia, portopulmonary hypertension characterized by pulmonary hypertension, and hepatic vascular shunt characterized by increased cardiac output and pulmonary hypertension. Early diagnosis and treatment of liver disease and early evaluation of liver transplantation may significantly improve the prognosis for patients with hepatic disease-related pulmonary vascular disease. Moreover, it is necessary to improve clinicians' understanding of this disease and strengthen multidisciplinary cooperation, improve the level of diagnosis and treatment.

Pulmonary vascular disease and exercise hemodynamics in chronic liver disease.

BACKGROUND & AIMS: Portopulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS) are severe pulmonary vascular complications of chronic liver disease and strongly associated with morbidity and mortality. The prevalence of these complications is relatively high in patients evaluated for liver transplantation, however it is virtually unknown in patients with stable chronic liver disease. METHODS: We assessed the pulmonary hypertension (PH) and HPS prevalence in a prospective registry study of our liver out-patient clinic in a tertiary center. Between 2011 and 2016, consecutive patients with cirrhosis or non-cirrhotic portal hypertension were prospectively enrolled after written informed consent. We excluded patients with acute decompensation of liver disease and other causes of PH like severe chronic heart or lung diseases and chronic thromboembolic PH. HPS was diagnosed using contrast enhanced echocardiography and blood gas analysis. Patients were screened for PH using an algorithm implementing severity of dyspnea, echocardiography, cardiopulmonary exercise testing and exercise echocardiography employing a threshold of systolic pulmonary arterial pressure (SPAP) = 50 mmHg at peak exercise. If the algorithm indicated an increased PH risk, patients were invited for invasive investigations by means of right heart and hepatic vein catheter. We defined POPH as resting mPAP≥21 mmHg and PVR>3WU and PAWP<15 mmHg, mild PH as resting mPAP = 21-24 mmHg, and exercise PH as mPAP>30 mmHg and TPR >3 WU at peak exercise. RESULTS: Two-hundred-five patients were enrolled (male 75%; cirrhosis 96%; median age 57 yrs). Sixty-seven patients (33%) fulfilled HPS criteria but only two (1.0%) for severe (PaO2:50-60 mmHg) or very severe HPS (PaO2<50 mmHg). In 18/77 patients (23%) undergoing exercise echocardiography, SPAP at peak exercise exceeded 50 mmHg. Finally, n = 3 (1.5%) patients were invasively diagnosed with POPH, n = 4 (2.9%) with mild PH and n = 2 with exercise PH. CONCLUSION: In chronic liver disease, excluding acute decompensation and other causes of PH, POPH and severe HPS are rare findings while mild to moderate HPS and mild PH or exercise PH are more frequent.

Extracorporeal membrane oxygenation in patients with hepatopulmonary syndrome undergoing liver transplantation: A systematic review of the literature.

BACKGROUND: Isolated cases of extracorporeal membrane oxygenation (ECMO) in patients with hepatopulmonary syndrome (HPS) undergoing liver transplantation (LT) have been reported with increasing frequency. We aimed to systemically review and synthesize the available literature on ECMO use in this population. METHODS: A systematic literature review of the PubMed, Web of Science, Cochrane Library, and Embase databases (end-of-search date: November 14, 2021) was conducted in accordance with the PRISMA statement. Eligible studies presented clinical parameters and outcomes of adult or pediatric patients with HPS receiving ECMO support at the time of, or following, LT. RESULTS: Sixteen studies from 4 continents reporting on 17 patients who were initiated on ECMO prior to (n = 2), during (n = 1) or after LT (n = 14) were included. Nine of the 16 studies were published between 2019 and 2021. The median pre-LT PaO2 was 38.0 mmHg (IQR 35.0-52.0). The median time from LT to ECMO initiation was 7 days (IQR, 3-12). Six patients (50%, n = 6 of 12) were extubated post-LT, before deterioration, development of refractory hypoxemia, and initiation of ECMO. Most patients were cannulated with a venovenous configuration (75%, n = 12 of 16). Most patients cannulated with a venoarterial or veno-arterial-venous strategy (75%, n = 3 of 4) had concurrent hemodynamic instability. The median total time on ECMO was 13 days (IQR 10-29). Using linear regression, for patients cannulated postoperatively, each day between LT and ECMO initiation was associated with a 3.5-day increase in total ECMO duration (95%CI: 2.23-4.73, p < 0.001, R2 = 73.7%). The median postoperative intensive care unit length of stay was 40 days (IQR, 37-61) and hospital length of stay was 59.5 days (IQR 42-77). 82.4% of patients (14 of 17) survived to discharge. CONCLUSIONS: ECMO is feasible in patients with HPS undergoing LT and appears to be associated with better outcomes compared to other causes of cardiopulmonary failure in LT patients. As the volume of experience grows, ECMO may become a central part of perioperative support in LT patients with severe HPS.

[Hepatopulmonary syndrome: Prevalence, pathophysiology and clinical implications]. / Syndrome hépatopulmonaire : prévalence, physiopathologie et implications cliniques.

Hepatopulmonary syndrome (HPS) is a pulmonary vascular disease induced by portal hypertension that is characterized by dilation of the pulmonary capillaries and right-to-left shunting, leading to gas exchange abnormalities. While dysregulation of several endothelial cell (EC)-derived angiocrine factors and the development of HPS have been associated, the field is currently lacking in mechanistic understanding on how they contribute to disease initiation, perpetuation, and worsening. Although substantial progress has been made in the description of clinical characteristics and outcomes, no specific targeting therapy has been shown to have a long-term effect on the evolution of HPS; only liver transplantation can lead full or partial reversibility of the syndrome. This article aims to provide a comprehensive review of the clinical and epidemiological definitions of HPS and to describe its experimental models as well as recent advances in understanding the pathophysiology of the disease, with specific focus on BMP-9 and its signaling pathway.

ICU and Hospital Outcomes in Patients with Hepatopulmonary Syndrome Undergoing Liver Transplantation.

PURPOSE: There are limited data regarding hospital and intensive care unit (ICU) outcomes in patients with hepatopulmonary syndrome (HPS) following liver transplantation (LT). METHODS: Data were retrospectively collected from consecutive HPS adult patients who underwent LT and were immediately admitted to the ICU at three transplant centers with shared management protocols, from 2002 to 2018. Demographic, clinical, surgical, laboratory, and outcome data were extracted. RESULTS: We identified 137 patients (74 male, 54%), with a median age at LT of 58 years (IQR: 52-63). One hundred and 31 (95.6%) patients were admitted to the ICU on invasive mechanical ventilation (MV). The median time on invasive MV in the ICU was 12 hours (IQR: 5-28) and 97 patients (74%) were extubated within 24 hours of ICU admission. The median highest positive end expiratory pressure and fraction of inspired oxygen (FiO2) were 7 (IQR: 5-8) and 0.6 (IQR: 0.5-0.7), respectively. 7 patients (5%) developed severe post-transplant hypoxemia. Of all patients, 42 (30.4%) required vasopressors and the median ICU and hospital length of stay (LOS) were 3 (IQR: 1-5) and 10 (IQR: 7-20) days, respectively. The in-hospital mortality rate was 3.6% (5/137). HPS severity was not associated with hospital mortality. CONCLUSION: Most HPS patients have short durations of MV, ICU, and hospital LOS post-LT. HPS severity does not impact hospital mortality.

A Retransplant Case for Hepatopulmonary Syndrome Without Liver Cirrhosis or Portosystemic Shunt After Living-Donor Liver Transplantation: A Case Report.

Hepatopulmonary syndrome (HPS) is a disease of gas exchange caused by intrapulmonary shunting secondary to liver disease-associated intrapulmonary vascular dilation. HPS is characterized by the triad of cirrhosis, chronic liver disease, or portosystemic shunting (PSS); arterial hypoxemia; and intrapulmonary arteriovenous shunting in the absence of a primary cardiopulmonary anomaly. We encountered a rare case of HPS without liver disease or PSS. The patient was an 8-year-old girl who underwent living donor liver transplantation (LDLT) shortly after developing fulminant hepatitis at 11 months of her age. Eight years after LDLT, hypoxemia and shortness of breath developed. The shunt ratio on 99mTc-macroaggregated albumin (MAA) lung perfusion scintigraphy (99mTc-MAA lung scan) was 32%. The patient had no cardiopulmonary disease, so we diagnosed her illness as HPS. We did not find cirrhosis, chronic liver disease, or PSS as a cause of HPS. We thought the graft was the cause of HPS. A second transplantation was planned. One year after the diagnosis of HPS, the shunt ratio on 99mTc-MAA lung scan worsened to 42%, digital clubbing appeared, and hypoxemia was worsening. Thus, we performed a second LDLT. After LDLT the shunt ratio on 99mTc-MAA lung scan normalized (6%) and cyanosis resolved. We determined that the graft was the cause of HPS; the typical causes of HPS were not clearly revealed in the histologic examination of the second liver explant. Acute rejection occurred twice after LDLT, so we speculated that HPS occurred because the graft became stressed over the long term.

Endothelial glycocalyx in hepatopulmonary syndrome: An indispensable player mediating vascular changes.

Hepatopulmonary syndrome (HPS) is a serious pulmonary vascular complication that causes respiratory insufficiency in patients with chronic liver diseases. HPS is characterized by two central pathogenic features-intrapulmonary vascular dilatation (IPVD) and angiogenesis. Endothelial glycocalyx (eGCX) is a gel-like layer covering the luminal surface of blood vessels which is involved in a variety of physiological and pathophysiological processes including controlling vascular tone and angiogenesis. In terms of lung disorders, it has been well established that eGCX contributes to dysregulated vascular contraction and impaired blood-gas barrier and fluid clearance, and thus might underlie the pathogenesis of HPS. Additionally, pharmacological interventions targeting eGCX are dramatically on the rise. In this review, we aim to elucidate the potential role of eGCX in IPVD and angiogenesis and describe the possible degradation-reconstitution equilibrium of eGCX during HPS through a highlight of recent literature. These studies strongly underscore the therapeutic rationale in targeting eGCX for the treatment of HPS.

Management of Decompensated Cirrhosis and Associated Syndromes.

Patients with cirrhosis account for 3% of intensive care unit admissions with hospital mortality exceeding 50%; however, improvements in survival among patients with acutely decompensated cirrhosis and organ failure have been described when treated in specialized liver transplant centers. Acute-on-chronic liver failure is a distinct clinical syndrome characterized by decompensated cirrhosis associated with one or more organ failures resulting in a significantly higher short-term mortality. In this review, we will discuss the management of common life-threatening complications in the patient with cirrhosis that require intensive care management including neurologic, cardiovascular, gastrointestinal, pulmonary, and renal complications.

Severe hepatopulmonary syndrome with hypoxemia refractory to liver transplant: Recovery after 67 days of ECMO support.

Hepatopulmonary syndrome (HPS) is a complication of end stage liver disease (ESLD) and is manifested by severe hypoxemia, which usually responds to liver transplantation (LT). As compared to patients undergoing LT for other etiologies, patients with HPS present an increased risk of postoperative morbidity and mortality. There is no effective treatment for patients whose hypoxemia does not respond to LT. This subset of patients is at a highly increased risk of death. There are very few reports on the use of extracorporeal membrane oxygenation (ECMO) in this setting with rapid response. However, there is no prior report of ECMO utilization for longer than 4 weeks. We present the case of a 17 year-old male patient who underwent LT for ESLD secondary to chronic portal vein thrombosis and HPS. He received a liver from a deceased donor and presented with severe HPS after LT, requiring ECMO support for 67 days. The patient was discharged home and is breathing in ambient air. He is currently asymptomatic and has a normal liver function.

Hepatopulmonary Syndrome and Portopulmonary Hypertension: Pulmonary Vascular Complications of Liver Disease.

Pulmonary vascular disease is a frequent complication of chronic liver disease and portal hypertension, affecting up to 30% of patients. There are two distinct pulmonary vascular complications of liver disease: hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH). HPS affects 25% of patients with chronic liver disease and is characterized by intrapulmonary vasodilatation and abnormal arterial oxygenation. HPS negatively impacts quality of life and is associated with a 2-fold increased risk of death compared to controls with liver disease without HPS. Angiogenesis, endothelin-1 mediated endothelial dysfunction, monocyte influx, and alveolar type 2 cell dysfunction seem to play important roles in disease pathogenesis but there are currently no effective medical therapies. Fortunately, HPS resolves following liver transplant (LT) with improvements in hypoxemia. POPH is a subtype of pulmonary arterial hypertension (PAH) characterized by an elevated mean pulmonary arterial pressure and pulmonary vascular resistance in the setting of normal left-sided filling pressures. POPH affects 5% to 6% of patients with chronic liver disease. Although the pathogenesis has not been fully elucidated, endothelial dysfunction, inflammation, and estrogen signaling have been identified as key pathways involved in disease pathogenesis. POPH is typically treated with PAH targeted therapy and may also improve with liver transplantation in selected patients. This article highlights what is currently known regarding the diagnosis, management, pathobiology, and outcomes of HPS and POPH. Ongoing research is needed to improve understanding of the pathophysiology and outcomes of these distinct and often misunderstood pulmonary vascular complications of liver disease. © 2021 American Physiological Society. Compr Physiol 11:1-22, 2021.

[Liver transplantation for hepatopulmonary syndrome complicating cirrhosis]. / Transplantation hépatique pour syndrome hépatopulmonaire compliquant une cirrhose.

Hepato-pulmonary syndrome (HPS) is a pulmonary vascular complication of cirrhosis quite frequent but often under-diagnosed, and characterized by intra-pulmonary capillary and pre-capillary vascular dilatations that may lead to severe hypoxemia. HPS is often asymptomatic but may induce a progressive dyspnea. HPS diagnosis is based on arterial gasometry that proves the hypoxemia and contrast-enhanced echo-cardiography revealing the vascular dilatations. Screening of HPS is recommended in every cirrhotic patient complaining of dyspnea or in every liver transplantation candidate. Indeed, the only effective treatment of HPS is liver transplantation; HPS patients receive exception-points in the MELD (Model for End-Stage Liver Disease) liver allocation score. The authors report herein the case of a 39-year-old male patient with a cirrhosis of unknown origin complicated by HPS which appeared as a disabling dyspnea. This patient underwent liver transplantation a year after HPS diagnosis and recovered completely.

Le syndrome hépatopulmonaire est une complication vasculaire pulmonaire de la cirrhose relativement fréquente et sous-diagnostiquée, caractérisée par des vasodilatations capillaires et pré-capillaires intrapulmonaires pouvant entraîner une hypoxémie sévère. Souvent asymptomatique, ce syndrome se révèle le plus souvent par une dyspnée d'apparition progressive. Le diagnostic est réalisé par une gazométrie artérielle prouvant l'hypoxémie et une échographie cardiaque de contraste démontrant l'existence de vasodilatations intrapulmonaires. Le dépistage du syndrome hépatopulmonaire est préconisé chez tout patient atteint de cirrhose présentant de la dyspnée et chez tout patient candidat à une greffe hépatique. En effet, le seul traitement efficace est la transplantation hépatique, et ces patients bénéficient d'ailleurs de points d'exception dans le calcul du score de MELD («Model for End-Stage Liver Disease¼). Nous rapportons ici le cas d'un patient de 39 ans atteint d'une cirrhose d'origine indéterminée compliquée d'un syndrome hépatopulmonaire qui s'est révélé par une dyspnée devenue rapidement invalidante. Ce patient a pu bénéficier d'une transplantation hépatique un an après le diagnostic de syndrome hépatopulmonaire, permettant ainsi une guérison complète tant sur plan hépatique que pulmonaire.

Hepatopulmonary syndrome is related to the development of acute-on-chronic liver failure and poor prognosis in cirrhotic patients.

BACKGROUND AND AIMS: Long-term prospective data on hepatopulmonary syndrome (HPS) from a large number of patients, especially in Asian patients, are lacking. We evaluated the long-term prognosis of HPS and the development of acute-on-chronic liver failure (ACLF), and related factors. METHODS: A total of 142 patients with cirrhosis who underwent saline-agitated contrast echocardiography for the diagnosis of HPS were enrolled and observed prospectively from 2014 to 2019. RESULTS: A total of 59 patients (41%) were diagnosed with HPS (24 grade 1, 23 grade 2, 12 grade 3). Thirty-eight and 37 patients died in the HPS and non-HPS groups, respectively (p < 0.01). The 5-year survival rate was 47% in the HPS group and 62% in the non-HPS group. In the Cox proportional hazards model, HPS and Model for End-stage Liver Disease (MELD) score ≥ 18, and Child-Turcotte-Pugh (CTP) class B/C were significant risk factors for mortality after adjusting for other risk factors (HPS hazard ratio [HR] = 1.9, p = 0.01; MELD score ≥ 18 HR = 2.3, p < 0.01; CTP class B/C HR = 2.9, p < 0.01). Compared to that in non-HPS group, the HPS group had a significantly higher incidence of ACLF during follow-up (p < 0.01) and more frequently presented with lung involvement of ACLF (p = 0.03). CONCLUSIONS: In the long-term follow-up cohort, patients with HPS showed poorer prognosis than that of patients without HPS. HPS was a risk factor for ACLF development independent of hepatic dysfunction, and lung involvement was significantly common than without ACLF.

M2 macrophage accumulation contributes to pulmonary fibrosis, vascular dilatation, and hypoxemia in rat hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) markedly increases the mortality of patients. However, its pathogenesis remains incompletely understood. Rat HPS develops in common bile duct ligation (CBDL)-induced, but not thioacetamide (TAA)-induced cirrhosis. We investigated the mechanisms of HPS by comparing these two models. Pulmonary histology, blood gas exchange, and the related signals regulating macrophage accumulation were assessed in CBDL and TAA rats. Anti-polymorphonuclear leukocyte (antiPMN) and anti-granulocyte-macrophage colony stimulating factor (antiGM-CSF) antibodies, clodronate liposomes (CL), and monocyte chemoattractant protein 1 (MCP1) inhibitor (bindarit) were administrated in CBDL rats, GM-CSF, and MCP1 were administrated in bone marrow-derived macrophages (BMDMs). Pulmonary inflammatory cell recruitment, vascular dilatation, and hypoxemia were progressively developed by 1 week after CBDL, but only occurred at 4 week after TAA. Neutrophils were the primary inflammatory cells within 3 weeks after CBDL and at 4 week after TAA. M2 macrophages were the primary inflammatory cells, meantime, pulmonary fibrosis, GM-CSFR, and CCR2 were specifically increased from 4 week after CBDL. AntiPMN antibody treatment decreased neutrophil and macrophage accumulation, CL or the combination of antiGM-CSF antibody and bindarit treatment decreased macrophage recruitment, resulting in pulmonary fibrosis, vascular dilatation, and hypoxemia in CBDL rats alleviated. The combination treatment of GM-CSF and MCP1 promoted cell migration, M2 macrophage differentiation, and transforming growth factor-ß1 (TGF-ß1) production in BMDMs. Conclusively, our results highlight neutrophil recruitment mediates pulmonary vascular dilatation and hypoxemia in the early stage of rat HPS. Further, M2 macrophage accumulation induced by GM-CSF/GM-CSFR and MCP1/CCR2 leads to pulmonary fibrosis and promotes vascular dilatation and hypoxemia, as a result, HPS develops.