Elevated circulating BMP9 aggravates pulmonary angiogenesis in hepatopulmonary syndrome rats through ALK1-Endoglin-Smad1/5/9 signalling.

BACKGROUND: Bone morphogenetic protein 9 (BMP9) is a hepatokine that plays a pivotal role in the progression of liver diseases. Moreover, an increasing number of studies have shown that BMP9 is associated with hepatopulmonary syndrome (HPS), but its role in HPS is unclear. Here, we evaluated the influence of CBDL on BMP9 expression and investigated potential mechanisms of BMP9 signalling in HPS. METHODS: We profiled the circulating BMP9 levels in common bile duct ligation-induced HPS rat model, and then investigated the effects and mechanisms of HPS rat serum on pulmonary vascular endothelial dysfunction in rat model, as well as in primarily cultured rat pulmonary microvascular endothelial cells. RESULTS: Our data revealed that circulating BMP9 levels were significantly increased in the HPS rats compared to control group. Besides, the elevated BMP9 in HPS rat serum was not only crucial for promoting endothelial cell proliferation and tube formation through the activin receptor-like kinase1 (ALK1)-Endoglin-Smad1/5/9 pathway, but also important for accumulation of monocytes. Treatments with ALK1-Fc or silencing ALK1 expression to inhibit the BMP9 signalling pathway effectively eliminated these effects. In agreement with these observations, increased circulating BMP9 was associated with an increase in lung vessel density and accumulation of pro-angiogenic monocytes in the microvasculature in HPS rats. CONCLUSIONS: This study provided evidence that elevated circulating BMP9, secreted from the liver, promote pulmonary angiogenesis in HPS rats via ALK1-Endoglin-Smad1/5/9 pathway. In addition, BMP9-regulated pathways are also involved in accumulation of pro-angiogenic monocytes in the pulmonary microvasculature in HPS rats.

Disrupted BMP-9 Signaling Impairs Pulmonary Vascular Integrity in Hepatopulmonary Syndrome.

RATIONALE: Hepatopulmonary syndrome (HPS) is a severe complication of liver diseases characterized by abnormal dilatation of pulmonary vessels, resulting in impaired oxygenation. Recent research highlights the pivotal role of liver-produced bone morphogenetic protein (BMP)-9 in maintaining pulmonary vascular integrity. OBJECTIVES: This study aimed to investigate the involvement of BMP-9 in human and experimental HPS. METHODS: Circulating BMP-9 levels were measured in 63 healthy controls and 203 cirrhotic patients, with or without HPS. Two animal models of portal hypertension were employed: common bile duct ligation (CBDL) with cirrhosis and long-term partial portal vein ligation (PPVL) without cirrhosis. Additionally, the therapeutic effect of low-dose BMP activator FK506 was investigated, and the pulmonary vascular phenotype of BMP-9 knockout rats was analyzed. MEASUREMENTS AND MAIN RESULTS: Patients with HPS related to compensated cirrhosis demonstrated lower levels of circulating BMP-9 compared to patients without HPS. Severe cirrhosis patients exhibited consistently low levels of BMP-9. In animal models, HPS characteristics, including intrapulmonary vascular dilations (IPVDs) and alveolo-arterial gradient enlargement, were observed. HPS development in both rat models correlated with reduced intrahepatic BMP-9 expression, decreased circulating BMP-9 level and activity, and impaired pulmonary BMP-9 endothelial pathway. Daily treatment with FK506 for 2-weeks restored BMP pathway in the lungs, alleviating IPVDs, and improving gas exchange impairment. Furthermore, BMP-9 knockout rats displayed a pulmonary HPS phenotype, supporting its role in disease progression. CONCLUSION: The study findings suggest that portal hypertension-induced loss of BMP-9 signaling contributes to HPS development.

New therapeutic strategy with extracorporeal membrane oxygenation for refractory hepatopulmonary syndrome after liver transplant: A case report.

BACKGROUND: Due to the lack of published literature about treatment of refractory hepatopulmonary syndrome (HPS) after liver transplant (LT), this case adds information and experience on this issue along with a treatment with positive outcomes. HPS is a complication of end-stage liver disease, with a 10%-30% incidence in cirrhotic patients. LT can reverse the physiopathology of this process and restore normal oxygenation. However, in some cases, refractory hypoxemia persists, and extracorporeal membrane oxygenation (ECMO) can be used as a rescue therapy with good results. CASE SUMMARY: A 59-year-old patient with alcohol-related liver cirrhosis and portal hypertension was included in the LT waiting list for HPS. He had good liver function (Model for End-Stage Liver Disease score 12, Child-Pugh class B7). He had pulmonary fibrosis and a mild restrictive respiratory pattern with a basal oxygen saturation of 82%. The macroaggregated albumin test result was > 30. Spirometry demon strated a forced expiratory volume in one second (FEV1) of 78%, forced vital capacity (FVC) of 74%, FEV1/FVC ratio of 81%, diffusion capacity for carbon monoxide of 42%, and carbon monoxide transfer coefficient of 57%. He required domiciliary oxygen at 2 L/min (16 h/d). The patient was admitted to the intensive care unit (ICU) and extubated in the first 24 h, needing high-flow therapy and non-invasive ventilation and inhaled nitric oxide afterwards. Reintubation was needed after 72 h. Due to the non-response to supportive therapies, installation of ECMO was decided with progressive recovery after 9 d. Extubation was possible on the tenth day, maintaining a high-flow nasal cannula and de-escalating to conventional oxygen therapy after 48 h. He was discharged from ICU on postoperative day (POD) 20 with a 90%-92% oxygen saturation. Steroid recycling was needed twice for acute rejection. The patient was discharged from hospital on POD 27 with no symptoms, with an 89%-90% oxygen saturation. CONCLUSION: Due to the favorable results observed, ECMO could become the central axis of treatment of HPS and refractory hypoxemia after LT.

Pulmonary Dysfunction in Patients with Cirrhosis of the Liver: A Study of Pulmonary Function Tests and Arterial Blood Gases.

Background and Aim: Respiratory complications in liver cirrhosis can occur due to various mechanisms, such as ascites causing restricted lung expansion and opening of intrapulmonary vascular shunts due to high portal pressures. We aimed to study the effects of the liver dysfunction on the lungs by evaluating arterial blood gas (ABG) and pulmonary function test (PFT) of all study subjects. Subjects and Methods: A cross-sectional study was done between August 2020 and September 2022. Diagnosed cases of the liver cirrhosis were enrolled in the study after informed consent and were subjected to the following investigations: chest X-ray, oximetry, spirometry, diffusing capacity of the lung for carbon monoxide (DLCO), two-dimensional echocardiography, and ABG analysis (ABGA). The cases were divided into three groups based on their Child-Pugh staging, and statistical analysis was done on the collected data. Results: A total of 64 (53 males and 11 females) patients with an average age of 49.82 ± 9.89 years were studied. Alcoholism was the most common cause of cirrhosis in males. Breathlessness (65.6%) and pleural effusion (26.6%) were the most common respiratory symptoms and signs, respectively. Seventeen patients had hepatic hydrothorax, eight patients had hepatopulmonary syndrome (HPS), and six patients had portopulmonary hypertension. Low pH (17.2%) and oxygen partial pressure (PaO2) (20.3%) were the most common ABGA findings. The pH, PaO2, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), and DLCO were significantly low in Child Pugh Stage C (P < 0.05). The pH, pO2, HCO3, FEV1, FVC, FEV1/FVC, and DLCO were significantly lower in patients with HPS (P < 0.05). Conclusion: Metabolic acidosis and low FEV1/FVC and DLCO were the common findings in study subjects. Pulmonary dysfunction was common in advanced liver cirrhosis. Patients with HPS had worse ABG and PFT parameters than those without HPS.

Hepatopulmonary Syndrome Diagnosis in the ICU: The Relevance of Bedside Contrast Saline Echocardiography.

Hepatopulmonary syndrome (HPS) is an underdiagnosed complication of chronic liver disease (CLD) characterised by the presence of hypoxaemia due to intrapulmonary vascular dilatations. We present two cases of HPS diagnosed during their stay in the ICU. Both patients had a medical history of alcoholic CLD with portal hypertension (PH). The first patient was transferred to the ICU for acute hypoxic respiratory failure (AHRF) due to decompensated cirrhosis with large-volume hydrothorax and diagnosis of acute-on-chronic liver failure (ACLF) grade 2. The presence of orthodeoxia, an alveolar-arterial oxygen gradient (O2 A-a grad) of 27 mmHg and positive contrast saline echocardiography confirmed the HPS diagnosis. The second patient was transferred to our general ICU from the surgical ward where he was initially admitted with mild AHRF due to polytrauma conditioning left side rib fractures and a small contusion in the left inferior lobe. Upon ICU admission, he was diagnosed with septic shock (nosocomial pneumonia as the primary site of infection) and required invasive mechanical ventilation. During the initial period of his ICU stay, although an improvement in multiple organ dysfunction was observed, severe AHRF persisted. Moreover, O2 A-a grad of 30 mmHg and positive bedside contrast saline echocardiography confirmed the HPS diagnosis. In this study, we discuss the diagnostic approach of HPS and the increasing relevance of contrast saline echocardiography at the bedside, particularly in critically ill patients. The performance of this technique by trained intensivists at the bedside in the ICU minimises critical moments, such as the time required for intra-hospital transport of patients for complementary examinations, considering they have severe ventilatory compromise, thereby allowing HPS diagnosis with high sensitivity.

Outcomes of liver transplantation for hepatopulmonary syndrome in patients with concomitant respiratory disease.

BACKGROUND & AIMS: Concomitant respiratory disease is a common finding in patients with hepatopulmonary syndrome (HPS). Among patients who underwent liver transplantation (LT) for HPS, we compared characteristics and outcome of patients with versus without concomitant respiratory disease. METHODS: This single center retrospective observational study included patients with HPS who underwent LT between 1999 and 2020. RESULTS: During the study period, 32 patients with HPS received a LT; nine (28%) with concomitant respiratory disease of whom one required a combined lung-liver transplantation. Patients with concomitant respiratory disease had higher PaCO2 (38 vs. 33 mm Hg, p = .031). The 30-day postoperative mortality was comparable, but the estimated cumulative probability of resolution of oxygen therapy after LT in HPS patients with versus those without concomitant respiratory disease was lower: 63% versus 91% at 12 months and 63% versus 100% at 18 months (HR 95% CI .140-.995, p = .040). In addition to the presence of concomitant respiratory disease (p = .040), history of smoking (p = .012), and high baseline 99mTcMAA shunt fraction (≥20%) (p = .050) were significantly associated with persistent need of oxygen therapy. The 5-year estimated cumulative probability of mortality in patients with concomitant respiratory disease was worse: 50% versus 23% (HR 95% CI .416-6.867, p = .463). CONCLUSIONS: The presence of a concomitant respiratory disease did not increase the short-term postoperative mortality after LT in patients with HPS. However, it resulted in a longer need for oxygen therapy.

Systemic Complications Secondary to Chronic Liver Disease.

The systemic sequelae of chronic liver disease (CLD) may be due to portal hypertension and shunting, malnutrition, and/or a low grade inflammatory state. This article will focus on the consequences of chronic liver disease affecting extrahepatic organs. Portal hypertension underlies many systemic complications of CLD. Aside from varices and ascites, portal hypertension may cause both hepatopulmonary syndrome and portopulmonary hypertension leading to respiratory compromise. Cardiomyopathy may also occur secondary to end stage liver disease. Hepatorenal syndrome is also well recognised and hepatic encephalopathy is a consequence of the effect of liver dysfunction on the brain. Compromise of the immune system is well described in end-stage liver disease leading to sepsis and its consequences. Bony disease including osteoporosis and hepatic arthropathy may both be seen in children with CLD. CLD may be asymptomatic initially but then complications may present as the disease progresses. Furthermore, systemic effects of end stage liver disease may complicate liver transplant. These complications often present insidiously or at the time of acute decompensation. Thus, it is important that healthcare providers are vigilant when caring for children with CLD. This article outlines the secondary complications of CLD with an overview of the definition and diagnosis, pathophysiology, management and prognosis of each.

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.

[Pulmonary Complications in Patients with Liver Cirrhosis].

Portal hypertension is a clinical syndrome defined by an increased portal venous pressure. The most frequent cause of portal hypertension is liver cirrhosis, and many of the complications of cirrhosis, such as ascites and gastroesophageal variceal bleeding, are related to portal hypertension. Portal hypertension is a pathological condition caused by the accumulation of blood flow in the portal system. This blood flow retention reduces the effective circulation volume. To compensate for these changes, neurotransmitter hormone changes and metabolic abnormalities occur, which cause complications in organs other than the liver. A hepatic hydrothorax is fluid accumulation in the pleural space resulting from increased portal pressure. Hepatopulmonary syndrome and portopulmonary hypertension are the pulmonary complications in cirrhosis by deforming the vascular structure. Symptoms, such as dyspnea and hypoxia, affect the survival and the quality of life of patients. These lung complications are usually underestimated in the management of cirrhosis. This review briefly introduces the type of lung complications of cirrhosis.

Bilateral Arteriovenous Shunting Through Pial and Perforating Vessels With Multiple Strokes in a Patient With Hepatopulmonary Syndrome.

Hepatopulmonary syndrome (HPS) is a condition characterized by chronic liver disease, intrapulmonary arteriovenous shunting, and increased alveolar-arterial oxygen gradient. This case report presents a 54-year-old male patient with a history of stroke, liver cirrhosis, portal vein thrombosis, hypertension, diabetes, and bladder cancer, who presented with worsening headaches and confusion over the course of five years. Digital subtraction angiogram (DSA) revealed multiple bilateral arteriovenous shunts, suggesting a shunting mechanism similar to that observed in HPS. We propose that this unique case could provide valuable insights into the parallels between the pathophysiology of HPS and diffuse arteriovenous shunting in the brain and the increased risk of ischemic and hemorrhagic events in both cases. Further studies are needed to establish a clearer understanding of this relationship and its implications for patients with chronic liver disease.

Pulmonary Assessment of the Liver Transplant Recipient.

Respiratory symptoms and hypoxemia can complicate chronic liver disease and portal hypertension. Various pulmonary disorders affecting the pleura, lung parenchyma, and pulmonary vasculature are seen in end-stage liver disease, complicating liver transplantation (LT). Approximately 8% of cirrhotic patients in an intensive care unit develop severe pulmonary problems. These disorders affect waiting list mortality and posttransplant outcomes. A thorough history, physical examination, and appropriate laboratory tests help diagnose and assess the severity to risk stratify pulmonary diseases before LT. Hepatopulmonary syndrome (HPS), portopulmonary hypertension (POPH), and hepatic hydrothorax (HH) are respiratory consequences specific to cirrhosis and portal hypertension. HPS is seen in 5-30% of cirrhosis cases and is characterized by impaired oxygenation due to intrapulmonary vascular dilatations and arteriovenous shunts. Severe HPS is an indication of LT. The majority of patients with HPS resolve their hypoxemia after LT. When pulmonary arterial hypertension occurs in patients with portal hypertension, it is called POPH. All other causes of pulmonary arterial hypertension should be ruled out before labeling as POPH. Since severe POPH (mean pulmonary artery pressure [mPAP] >50 mm Hg) is a relative contraindication for LT, it is crucial to screen for POPH before LT. Those with moderate POPH (mPAP >35 mm Hg), who improve with medical therapy, will benefit from LT. A transudative pleural effusion called hepatic hydrothorax (HH) is seen in 5-10% of people with cirrhosis. Refractory cases of HH benefit from LT. In recent years, increasing clinical expertise and advances in the medical field have resulted in better outcomes in patients with moderate to severe pulmonary disorders, who undergo LT.

Serum Soluble Vascular Endothelial Growth Factor Receptor 1 as a Potential Biomarker of Hepatopulmonary Syndrome.

Background and Aims: The results of basic research implicate the vascular endothelial growth factor (VEGF) family as a potential target of hepatopulmonary syndrome (HPS). However, the negative results of anti-angiogenetic therapy in clinical studies have highlighted the need for markers for HPS. Therefore, we aimed to determine whether VEGF family members and their receptors can be potential biomarkers for HPS through clinical and experimental studies. Methods: Clinically, patients with chronic liver disease from two medical centers were enrolled and examined for HPS. Patients were divided into HPS, intrapulmonary vascular dilation [positive contrast-enhanced echocardiography (CEE) and normal oxygenation] and CEE-negative groups. Baseline information and perioperative clinical data were compared between HPS and non-HPS patients. Serum levels of VEGF family members and their receptors were measured. In parallel, HPS rats were established by common bile duct ligation. Liver, lung and serum samples were collected for the evaluation of pathophysiologic changes, as well as the expression levels of the above factors. Results: In HPS rats, all VEGF family members and their receptors underwent significant changes; however, only soluble VEGFR1 (sFlt-1) and the sFlt-1/ placental growth factor (PLGF) ratio were changed in almost the same manner as those in HPS patients. Furthermore, through feature selection and internal and external validation, sFlt-1 and the sFlt-1/PLGF ratio were identified as the most important variables to distinguish HPS from non-HPS patients. Conclusions: Our results from animal and human studies indicate that sFlt-1 and the sFlt-1/PLGF ratio in serum are potential markers for HPS.

Pulmonary function testing in patients with liver cirrhosis (Review).

Liver cirrhosis is a common long-term outcome of chronic hepatic inflammation. Patients with liver cirrhosis may also have pulmonary complications. There are several reasons for pulmonary dysfunction in liver cirrhosis, including intrinsic cardiopulmonary dysfunction unrelated to liver disease and specific disorders related to the presence of liver cirrhosis and/or portal hypertension. The most prevalent and clinically significant pulmonary complications are hepatic hydrothorax, hepatopulmonary syndrome, spontaneous pulmonary empyema and portopulmonary hypertension. Pulmonary function tests (PFTs) have traditionally been used to assess the lung function of patients with liver cirrhosis. To the best of our knowledge, the present review is the first to detail all types of PFTs performed in patients with liver cirrhosis and discuss their clinical significance. Patients with liver cirrhosis have reduced values of spirometric parameters, diffusion capacity for carbon monoxide (DLCO), lung volumes, maximal inspiratory pressure and maximal expiratory pressure. Furthermore, they have a higher closing volume, a greater airway occlusion pressure 0.1 sec after the onset of inspiratory flow and greater exhaled nitric oxide values. In order to improve pulmonary function, patients with ascites may require therapeutic paracentesis. Such findings should be considered when evaluating individuals with liver disease, particularly those who may require surgery. Poor lung function, particularly restrictive lung disease, can have an impact on post-transplant outcomes, such as ventilator time, length of hospital duration and post-operative pulmonary complications; thus, the transplant care team needs to be aware of its prevalence and relevance.

MiR26-5p inhibits pathological pulmonary microvascular angiogenesis via down-regulating WNT5A.

Objectives: Pathological micro angiogenesis is a key pathogenic factor in pulmonary diseases such as pulmonary hypertension and hepatopulmonary syndrome. More and more pieces of evidence show that excessive proliferation of pulmonary microvascular endothelial cells is the key event of pathological micro angiogenesis. The purpose of this research is to reveal the mechanism of miR26-5p regulating pulmonary microvascular hyperproliferation. Materials and Methods: Hepatopulmonary syndrome rat model was made by common bile duct ligation. HE and IHC staining were used for analysis of the pathology of the rat. CCK8, transwell, and wound healing assay were used to assess miR26-5p or target gene WNT5A functioned toward PMVECs. microRNA specific mimics and inhibitors were used for up/down-regulated miR26-5p expression in PMVECs. Recombinant lentivirus was used for overexpression/knockdown WNT5A expression in PMVECs. And the regulation relationship of miR26-5p and WNT5A was analyzed by dual-luciferase reporter assay. Results: qPCR showed that miR26-5p was significantly down-regulated in the course of HPS disease. Bioinformatics data showed that WNT5A was one of the potential key target genes of miR26-5p. Immunohistochemistry and qPCR analysis showed that WNT5A was largely expressed in pulmonary microvascular endothelial cells, in addition, this molecule was significantly up-regulated with the progression of the disease. Furthermore, dual luciferase reporter assay showed that miR26-5p could bind to WNT5A 3 'UTR region to inhibit WNT5A synthesis. Conclusion: The results suggested MiR26-5p negatively regulated PMVECs proliferation and migration by WNT5A expression. Overexpression of miR26-5p may be a potentially beneficial strategy for HPS therapy.

Telomere biology disorder presenting acutely with pulmonary fibrosis and hepatopulmonary syndrome in a young adult male.

A 33-year-old man presented with acute dyspnoea and profound hypoxaemia, and had clubbing, greying of hair, orthodeoxia and fine inspiratory crackles. CT chest showed established pulmonary fibrosis in a usual interstitial pneumonia pattern. Additional investigations revealed a small patent foramen ovale, pancytopenia, and oesophageal varices and portal hypertensive gastropathy from liver cirrhosis. Telomere length testing demonstrated short telomeres (<1st percentile), confirming the diagnosis of a telomere biology disorder. An interstitial lung disease gene panel identified a pathogenic variant in TERT (c.1700C>T, p.(Thr567Met)) and a variant of uncertain significance in PARN (c.1159G>A, p.(Gly387Arg)). Combined lung and liver transplantation was deemed not suitable due to frailty and severe hepatopulmonary syndrome, and he died 56 days after presentation. Early recognition of the short telomere syndrome is important, and its multi-organ involvement poses challenges to management. Genetic screening may be important in younger patients with pulmonary fibrosis or in unexplained liver cirrhosis.

Hepatopulmonary Syndrome in a Patient With Autoimmune Hepatitis and Chronic Hepatitis C: A Case Report Highlighting Typical Echo Findings.

Hepatopulmonary syndrome (HPS) is a rare complication of liver disease characterized by intrapulmonary vascular dilatations leading to arterial hypoxemia. We present the case of a 59-year-old female with a past medical history of bilateral breast cancer status post mastectomy who presented with progressive dyspnea on exertion and fatigue. A comprehensive diagnostic workup was conducted to exclude other cardiac, pulmonary, and systemic etiologies. She was diagnosed with autoimmune hepatitis along with chronic hepatitis C. Echocardiography revealed characteristic findings of intrapulmonary shunting characteristic of HPS. The patient showed improvement in pulmonary symptoms and oxygenation status following the initiation of steroid therapy. Although corticosteroids are not the definitive treatment for HPS, they were considered a supportive measure in this case. However, it is important to note that liver transplantation remains the definitive treatment for HPS. This case underscores the importance of echocardiography and the potential role of supportive measures, like corticosteroids, in managing HPS-related symptoms, particularly in patients with autoimmune hepatitis, as a bridging therapy while awaiting liver transplantation.

Cardiac Syndromes in Liver Disease: A Clinical Conundrum.

Understanding the interaction between the heart and liver is pivotal for managing patients in whom both organs are affected. Studies have shown that cardio-hepatic interactions are bidirectional and that their identification, assessment, and treatment remain challenging. Congestive hepatopathy is a condition that develops in the setting of long-standing systemic venous congestion. If left untreated, congestive hepatopathy may lead to hepatic fibrosis. Acute cardiogenic liver injury develops as a combination of venous stasis and sudden arterial hypoperfusion due to cardiac, circulatory, or pulmonary failure. The treatment of both conditions should be directed toward optimizing the cardiac substrate. Hyperdynamic syndrome may develop in patients with advanced liver disease and lead to multiorgan failure. Cirrhotic cardiomyopathy or abnormalities in pulmonary vasculature, such as hepatopulmonary syndrome and portopulmonary hypertension may also develop. Each complication has unique treatment challenges and implications for liver transplantation. The presence of atrial fibrillation and atherosclerosis in liver disease brings another layer of complexity, particularly in terms of anticoagulation and statin use. This article provides an overview of cardiac syndromes in liver disease, focusing on current treatment options and future perspectives.

Macitentan treatment of portopulmonary hypertension with hepatopulmonary syndrome: a case report and literature review.

Pulmonary arterial hypertension-targeted therapies in portopulmonary hypertension (PoPH) are scarce, let alone for patients with chronic liver failure (CLF) and hepatopulmonary syndrome (HPS). A 48-year male was admitted to the hospital because of cirrhosis for 18 years, systemic oedema, and chest distress after exercise for 1 week. He was diagnosed with CLF, PoPH, and HPS. After 7 weeks of macitentan treatment, the patient's activity tolerance, pulmonary artery systolic pressure, arterial partial pressure of oxygen (PaO2 ), cTNI, and NT-proBNP changes indicated gradual recovery, without hepatic safety concerns. This case indicated that administering macitentan in patients diagnosed as PoPH (with CLF and HPS) may be efficient and safe enough in a clinical setting.

Paediatric porto-sinusoidal vascular disease: Two different clinical phenotypes with subtle histological differences.

BACKGROUND AND AIMS: In paediatrics, porto-sinusoidal vascular disease (PSVD) is relatively unknown and probably underdiagnosed. We aimed to describe clinical phenotypes, histology and outcome of children diagnosed with PSVD. METHODS: Retrospective multicentre study of children diagnosed with PSVD. Diagnosis of PSVD was based on histopathology reports; liver specimens were re-evaluated by two expert liver pathologists. RESULTS: Sixty two children diagnosed with PSVD (M/F = 36/26, median age 6.6 years, range 3.3-10.6), from 7 centres, were included. Thirty-six presented with non-cirrhotic portal hypertension, PH, (PH-PSVD Group = 58%) while 26 had a liver biopsy because of chronic elevation of transaminases without PH (noPH-PSVD Group = 42%). On histology review, the two groups differed for the prevalence of obliterative portal venopathy (more prevalent in PH-PSVD, p = 0.005), and hypervascularised portal tracts (more common in noPH-PSVD, p = 0.039), the other histological changes were equally distributed. At multivariate analysis, platelet count ≤185 000/mm3 was the only independent determinant of PH (p < 0.001). After a median follow-up of 7 years (range 3.0-11.2), in PH-PSVD group 3/36 (8%) required TIPS placement, 5/36 (14%) developed pulmonary vascular complications of PH, and 7/36 (19%) required liver transplantation. In noPH-PSVD none progressed to PH nor had complications. CONCLUSIONS: Paediatric patients with PSVD present with two different clinical phenotypes, one characterised by PH and one by chronic elevation of transaminases without PH. PSVD should be included among the conditions causing isolated hypertransaminasaemia. On histology, the differences between the two groups are subtle. Medium-term outcome is favourable in patients without PH; progression of the disease is observed in those with PH.