Abstract
Portopulmonary hypertension (POPH) is a condition defined by the development of pulmonary arterial hypertension (PAH) that is associated with liver disease or portal hypertension. Untreated POPH has a poor prognosis. POPH can be treated with PAH-targeted therapy and can sometimes resolve with liver transplantation (LT); however, poorly controlled POPH can preclude LT owing to an increased peri-operative risk. We report a case of POPH that was diagnosed as an unknown atrial septal defect during PAH-targeted therapy. As observed in our case, the same patient may have several causes of PAH. It is important to confirm an unknown shunt disease using echocardiography during PAH-targeted therapy.
Learning objective
It is difficult to detect unknown shunt disease in patients who are diagnosed with pulmonary arterial hypertension (PAH) owing to other causes. We report a case of portopulmonary hypertension that was diagnosed as an unknown atrial septal defect during PAH-targeted therapy. This report highlights the same patient may have several causes of PAH. It is important to confirm an unknown shunt disease using echocardiography during PAH-targeted therapy.
Keywords: Portopulmonary hypertension, Liver transplantation, Atrial septal defect
Introduction
Pulmonary arterial hypertension (PAH) is a chronic progressive disease characterized by elevated pulmonary artery pressure and pulmonary vascular resistance (PVR). According to the new definition, PAH is characterized by a combination of mean pulmonary arterial pressure (PAP) >20 mmHg at rest, pulmonary capillary wedge pressure (PAWP) <15 mmHg, and PVR >3 Wood units [1].
Portopulmonary hypertension (POPH) is defined as PAH complicated by portal hypertension, with or without advanced hepatic disease. POPH is increasingly recognized, with recent evidence suggesting it to be one of the leading causes of PAH. Approximately 2 %–6 % of the patients diagnosed with portal hypertension develop POPH [2]. The prognosis in patients with liver disease who also suffer from significant POPH is considered to be poor [3]. Although liver transplantation (LT) may resolve POPH, advanced stages of this disease may jeopardize safety and the success of LT [4]. We herein report a case of POPH that was diagnosed as an unknown shunt disease during PAH-targeted therapy.
Case report
A 51-year-old-woman was diagnosed with hepatitis B virus-related decompensated cirrhosis in 2014. In May 2016, the patient developed dyspnea with WHO functional Class II limitations, and transthoracic echocardiography revealed pulmonary hypertension. She was referred to our hospital in June 2016. Echocardiography revealed a dilated right ventricle with an estimated systolic pressure of 68 mmHg. Results of the blood analysis did not suggest any collagen disease that led to pulmonary hypertension. The patient was previously diagnosed with esophageal varices. Abdominal computed tomography (CT) revealed splenomegaly and mesenteric venous dilation. Lung perfusion scintigraphy did not detect pulmonary thromboembolism and showed no substantial accumulation in the brain or kidneys. Right heart catheterization (RHC) revealed a PAP of 68/23 (41) mmHg and a cardiac index of 5.49 L/min/m2. Further, a significant increase in the oxygen saturation level was not observed. Accordingly, the patient was diagnosed with POPH. Administration of macitentan (10 mg/day) was initiated, followed by tadalafil (40 mg/day), within 2 months.
Echocardiography was performed 4 months after initiating medications and a previously unseen shunt flow was observed in the atrial septum (Fig. 1). RHC revealed a decrease in PAP to 43/16 (26) mmHg. A significant increase in the right atrial (RA) oxygen saturation level was observed (superior vena cava, 73.6 % vs. RA, 87.1 %), and the ratio of pulmonary to systemic flow was 2.25. The patient was confirmed to have a secundum atrial septal defect (ASD). Therefore, transvenous closure using the Amplatzer septal occluder was attempted in November 2016 (defect hole size, 18 mm; device size, 19 mm).
Fig. 1.
Findings of transthoracic echocardiography performed before and 4 months after pulmonary artery hypertension-targeted therapy. Two-dimensional echocardiography (Panel a) and color Doppler echocardiography (Panel b) using the right sternal border approach at first admission did not show shunt flow. Two-dimensional echocardiography (Panel c) and color Doppler echocardiography (Panel d) after 4 months demonstrated unknown secundum atrial septal defect shunt flow.
LA, left atrium; RA, right atrium.
One year later, LT was performed for advanced hepatic encephalopathy. The Model for End-Stage Liver Disease score of the patient was 16. RHC was performed prior to transplantation; PAP was reduced to 30/16 (23) mmHg and PVR was reduced to 0.9 WU. She benefited from LT in August 2018. RHC was performed 3 years after LT. The patient's PAP was 23/10 (15) mmHg and cardiac index was 3.24 L/min/m2. Further, tapering of PAH-targeted therapy was initiated. Hemodynamic changes in the patient are shown in Table 1. The patient provided informed consent for publication of this report and all accompanying images; patient identity was protected.
Table 1.
Patient hemodynamic changes.
| Hemodynamic data | Pre PAH-targeted therapy | Post PAH-targeted therapy | Post transcatheter closure | Post LT |
|---|---|---|---|---|
| Systolic PAP (mmHg) | 68 | 43 | 30 | 23 |
| Diastolic PAP (mmHg) | 23 | 16 | 16 | 10 |
| Mean PAP (mmHg) | 41 | 26 | 23 | 15 |
| PAWP (mmHg) | 8 | 10 | 11 | 8 |
| RA (mmHg) | 8 | 6 | 7 | 4 |
| CI (L/min/m2) | 5.49 | 5.93 | 6.66 | 3.24 |
| PVR (WU) | 3.0 | 1.2 | 0.9 | 1.2 |
| Qp/Qs | 1.39 | 2.25 | – | – |
PAH, pulmonary artery hypertension; LT, liver transplantation; PAP, pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; RA, right atrial; CI, cardiac index; PVR, pulmonary vascular resistance; Qp/Qs, pulmonary blood flow/systemic blood flow ratio.
Discussion
POPH is a severe complication of portal hypertension. In this case report, the patient with POPH was diagnosed with ASD post PAP improvement. It is difficult to detect unknown ASD in patients who are diagnosed with pulmonary hypertension owing to other causes. When the patient was first admitted, her PVR increased and the left-to-right shunt flow decreased. Therefore, echocardiography or catheterization could not diagnose ASD. After PAH-targeted therapy, PVR decreased and RA pressure decreased slightly. Furthermore, the cardiac output increased and PAWP increased slightly. We believe that these hemodynamic changes increased the left-to-right shunt flow in this case. Although echocardiography is the first-line technique for diagnosing this disease, it can remain undiagnosed until adulthood [5]. In previous studies, echocardiography of the atrial septum using the subcostal and right sternal border approach was the preferred method for non-invasive diagnosis [6], [7]. Transesophageal echocardiography and contrast echocardiography are useful when shunt disease is difficult to diagnose with two-dimensional echocardiography or color-Doppler echocardiography [8]. Furthermore, cardiac computed tomography is useful for assessing the anatomy and visualizing additional congenital abnormalities in adult patients with ASD [9]. It is important to detect shunt flow at the time of initial diagnosis and also during the treatment.
The treatment for patients with POPH should be carefully selected. Historical data indicate that untreated POPH has a very poor prognosis [3]. Krowka et al. reported a retrospective analysis of patients with POPH. Peri-operative cardiopulmonary mortality after LT was 50 % in patients with a mean PAP of <35–50 mmHg [4]. In general, PAH-targeted therapy leads to a significant hemodynamic improvement in the conditions of patients with POPH. A recent meta-analysis summarized that PAH-targeted therapy followed by LT improved pulmonary hemodynamics and prognosis in these patients [10]. In cases wherein the PAH-targeted therapy adequately reduces pulmonary pressure and LT is considered safe and feasible, their combination confers a better prognosis than medical treatment alone. The primary goal of therapy for patients with POPH, who are candidates for LT, is to reduce the mean PAP before proceeding to LT. Three years after LT, our patient had normal hemodynamic parameters. According to Deroo et al. [10], 50 % of all patients discontinued PAH-targeted therapy after LT. In this case report, the patient was diagnosed with two PAH-related disorders, and we believe that caution should be exercised when discontinuing PAH-targeted therapy. Further prospective studies are needed to identify predictive factors for late postoperative outcomes.
This case report reveals that there may be several causes of PAH in a patient. During the treatment of patients with pulmonary hypertension, it is important to consider the possibility of unknown shunt disease in all cases.
Declaration of competing interest
Kayoko Kubota received honorarium from Nippon Shinyaku and Janssen Pharmaceutical.
References
- 1.Simonneau G., Montani D., Celermajer D.S., Denton C.P., Gatzoulis M.A., Krowka M., Williams P.G., Souza R. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53:1801913. doi: 10.1183/13993003.01913-2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Savale L., Guimas M., Ebstein N., Fertin M., Jevnikar M., Renard S., Horeau-Langlard D., Tromeur C., Chabanne C., Prevot G., Chaouat A., Moceri P., Artaud-Macari É., Degano B., Tresorier R., et al. Portopulmonary hypertension in the current era of pulmonary hypertension management. J Hepatol. 2020;73:130–139. doi: 10.1016/j.jhep.2020.02.021. [DOI] [PubMed] [Google Scholar]
- 3.Swanson K.L., Wiesner R.H., Nyberg S.L., Rosen C.B., Krowka M.J. Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups. Am J Transplant. 2008;8:2445–2453. doi: 10.1111/j.1600-6143.2008.02384.x. [DOI] [PubMed] [Google Scholar]
- 4.Krowka M.J., Plevak D.J., Findlay J.Y., Rosen C.B., Wiesner R.H., Krom R.A. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl. 2000;6:443–450. doi: 10.1053/jlts.2000.6356. [DOI] [PubMed] [Google Scholar]
- 5.Baumgartner H., De Backer J., Babu-Narayan S.V., Budts W., Chessa M., Diller G.P., Lung B., Kluin J., Lang I.M., Meijboom F., Moons P., Mulder B.J.M., Oechslin E., Roos-Hesselink J.W., Schwerzmann M., et al. 2020 ESC guidelines for the management of adult congenital heart disease. Eur Heart J. 2021;42:563–645. doi: 10.1093/eurheartj/ehaa554. [DOI] [PubMed] [Google Scholar]
- 6.Shub C., Dimopoulos I.N., Seward J.B., Callahan J.A., Tancredi R.G., Schattenberg T.T., Reeder G.S., Hagler D.J., Tajik A.J. Sensitivity of two-dimensional echocardiography in the direct visualization of atrial septal defect utilizing the subcostal approach: experience with 154 patients. J Am Coll Cardiol. 1983;2:127–135. doi: 10.1016/s0735-1097(83)80385-4. [DOI] [PubMed] [Google Scholar]
- 7.Iliceto S., Antonelli G., Sorino M., Ricci A. Detection of atrial septal defect by right sternal border echocardiography. Am J Cardiol. 1984;54:376–378. doi: 10.1016/0002-9149(84)90200-5. [DOI] [PubMed] [Google Scholar]
- 8.Soliman O.I., Geleijnse M.L., Meijboom F.J., Nemes A., Kamp O., Nihoyannopoulos P., Masani N., Feinstein S.B., Ten Cate F.J. The use of contrast echocardiography for the detection of cardiac shunts. Eur J Echocardiogr. 2007;8:S2–S12. doi: 10.1016/j.euje.2007.03.006. [DOI] [PubMed] [Google Scholar]
- 9.Osawa K., Miyoshi T., Morimitsu Y., Akagi T., Oe H., Nakagawa K., Takaya Y., Kijima Y., Sato S., Kanazawa S., Ito H. Comprehensive assessment of morphology and severity of atrial septal defects in adults by CT. J Cardiovasc Comput Tomogr. 2015;9:354–361. doi: 10.1016/j.jcct.2015.04.007. [DOI] [PubMed] [Google Scholar]
- 10.Deroo R., Trépo E., Holvoet T., De Pauw M., Geerts A., Verhelst X., Colle I., Van Vlierberghe H., Fallon M.B., Raevens S. Vasomodulators and liver transplantation for portopulmonary hypertension: evidence from a systematic review and meta-analysis. Hepatology. 2020;72:1701–1716. doi: 10.1002/hep.31164. [DOI] [PubMed] [Google Scholar]