Portopulmonary hypertension

Other names| Pulmonary arterial hypertension associated with portal hypertension
Specialty| Pulmonology, Hepatology

Portopulmonary hypertension (PPH)[1] is defined by the coexistence of portal and pulmonary hypertension. PPH is a serious complication of liver disease, present in 0.25 to 4% of all patients with cirrhosis. Once an absolute contraindication to liver transplantation, it is no longer, thanks to rapid advances in the treatment of this condition.[2] Today, PPH is comorbid in 4-6% of those referred for a liver transplant.[3][4]

## Contents

* 1 Presentation
* 2 Pathophysiology
* 3 Diagnosis
* 4 Treatment
* 5 Prognosis
* 6 References
* 7 External links

## Presentation

PPH presents roughly equally in male and female cirrhotics; 71% female in an American series and 57% male in a larger French series.[5][6] Typically, patients present in their fifth decade, aged 49 +/- 11 years on average.[5][7]

In general, PPH is diagnosed 4–7 years after the patient is diagnosed with portal hypertension[8] and in roughly 65% of cases, the diagnosis is actually made at the time of invasive hemodynamic monitoring following anesthesia induction prior to liver transplantation.[8]

Once patients are symptomatic, they present with right heart dysfunction secondary to pulmonary hypertension and its consequent dyspnea, fatigue, chest pain and syncope.[9] Patients tend to have a poor cardiac status, with 60% having stage III-IV NYHA heart failure.[5]

PPH is actually independent of the severity of cirrhosis but may be more common in specific types of cirrhosis, in one series more so in Autoimmune Hepatitis and less in Hepatitis C cirrhosis,[6] while in another it was equally distributed throughout the diagnoses.[4]

## Pathophysiology

PPH pathology arises both from the humoral consequences of cirrhosis and the mechanical obstruction of the portal vein.[10] A central paradigm holds responsible an excess local pulmonary production of vasoconstrictors that occurs while vasodilatation predominates systemically.[11] Key here are imbalances between vasodilatory and vasoconstricting molecules; endogenous prostacyclin and thromboxane (from Kupffer Cells)[12][13] or nitric oxide (NO) and endothelin-1 (ET-1).[7] ET-1 is the most potent vasoconstrictor under investigation[14] and it has been found to be increased in both cirrhosis[15] and pulmonary hypertension.[16] Endothelin-1 has two receptors in the pulmonary arterial tree, ET-A which mediates vasoconstriction and ET-B which mediates vasodilation. Rat models have shown decreased ET-B receptor expression in pulmonary arteries of cirrhotic and portal hypertensive animals, leading to a predominant vasoconstricting response to endothelin-1.[17]

In portal hypertension, blood will shunt from portal to systemic circulation, bypassing the liver. This leaves unmetabolized potentially toxic or vasoconstricting substances to reach and attack the pulmonary circulation. Serotonin, normally metabolized by the liver, is returned to the lung instead where it mediates smooth muscle hyperplasia and hypertrophy.[18] Moreover, a key pathogenic factor in the decline in status of PPH patients related to this shunting is the cirrhotic cardiomyopathy with myocardial thickening and diastolic dysfunction.[citation needed]

Finally, the pulmonary pathology of PPH is very similar to that of primary pulmonary hypertension.[19] The muscular pulmonary arteries become fibrotic and hypertrophy while the smaller arteries lose smooth muscle cells and their elastic intima. One study found at autopsy significant thickening of pulmonary arteries in cirrhotic patients.[20] This thickening and remodeling forms a positive feedback loop that serves to increase PAP and induce right heart hypertrophy and dysfunction.[citation needed]

## Diagnosis

The diagnosis of portopulmonary hypertension is based on hemodynamic criteria:[citation needed]

1. . Portal hypertension and/or liver disease (clinical diagnosis—ascites/varices/splenomegaly)
2. . Mean pulmonary artery pressure—MPAP > 20 mmHg at rest (revised from 25 to 20 according to 6th World Pulmonary Hypertension Symposium)
3. . Pulmonary vascular resistance—PVR > 240 dynes s cm−5
4. . Pulmonary artery occlusion pressure— PAOP < 15mmHg or transpulmonary gradient—TPG > 12 mmHg where TPG = MPAP − PAOP.[21]

The diagnosis is usually first suggested by a transthoracic echocardiogram, part of the standard pre-transplantation work-up. Echocardiogram estimated pulmonary artery systolic pressures of 40 to 50 mm Hg are used as a screening cutoff for PPH diagnosis,[3] with a sensitivity of 100% and a specificity as high as 96%.[22] The negative predictive value of this method is 100% but the positive predictive value is 60%.[23] Thereafter, these patients are referred for pulmonary artery catheterization.[citation needed]

The limitations of echocardiography are related to the derivative nature of non-invasive PAP estimation. The measurement of PAP by echocardiogram is made using a simplified Bernoulli equation. High cardiac index and pulmonary capillary wedge pressures, however, may lead to false positives by this standard. By one institution's evaluation, the correlation between estimated systolic PAP and directly measured PAP was poor, 0.49.[24] For these reasons, right heart catheterization is needed to confirm the diagnosis.[citation needed]

## Treatment

In general, the treatment of PPH is derived from the treatment of pulmonary hypertension. The best treatment available is the combination of medical therapy and liver transplantation.[25][citation needed]

The ideal treatment for PPH management is that which can achieve pulmonary vasodilatation and smooth muscle relaxation without exacerbating systemic hypotension. Most of the therapies for PPH have been adapted from the primary pulmonary hypertension literature. Calcium channel blockers, b-blockers and nitrates have all been used – but the most potent and widely used aids are prostaglandin (and prostacyclin) analogs, phosphodiesterase inhibitors, nitric oxide and, most recently, endothelin receptor antagonists and agents capable of reversing the remodeling of pulmonary vasculature.[citation needed]

Inhaled nitric oxide vasodilates, decreasing pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) without affecting systemic artery pressure because it is rapidly inactivated by hemoglobin,[26] and improves oxygenation by redistributing pulmonary blood flow to ventilated areas of lung.[27] Inhaled nitric oxide has been used successfully to bridge patients through liver transplantation and the immediate perioperative period, but there are two significant drawbacks: it requires intubation and cannot be used for long periods of time due to methemoglobinemia.[28]

Prostaglandin PGE1 (Alprostadil) binds G-protein linked cell surface receptors that activate adenylate cyclase to relax vascular smooth muscle.[29] Prostacyclin – PGI2, an arachidonic acid derived lipid mediator (Epoprostenol, Flolan, Treprostenil) – is a vasodilator and, at the same time, the most potent inhibitor of platelet aggregation.[30] More importantly, PGI2 (and not nitrous oxide) is also associated with an improvement in splanchnic perfusion and oxygenation.[31] Epoprostenol and ilioprost (a more stable, longer acting variation[32]) can and does successfully bridge for patients to transplant.[33] Epoprostenol therapy can lower PAP by 29-46% and PVR by 21-71%.,[34] Ilioprost shows no evidence of generating tolerance, increases cardiac output and improves gas exchange while lowering PAP and PVR.[35] A subset of patients does not respond to any therapy, likely having fixed vascular anatomic changes.[citation needed]

Phosphodiesterase inhibitors (PDE-i) have been employed with excellent results. It has been shown to reduce mean PAP by as much as 50%,[36] though it prolongs bleeding time by inhibiting collagen-induced platelet aggregation.[37] Another drug, Milrinone, a Type 3 PDE-i increases vascular smooth muscle adenosine-3,5-cyclic monophosphate concentrations to cause selective pulmonary vasodilation.[38] Also, by causing the buildup of cAMP in the myocardium, Milrinone increases contractile force, heart rate and the extent of relaxation.

The newest generation in PPH pharmacy shows great promise. Bosentan is a nonspecific endothelin-receptor antagonist capable of neutralizing the most identifiable cirrhosis associated vasoconstrictor,[39] safely and efficaciously improving oxygenation and PVR,[40][41] especially in conjunction with sildenafil.[42] Finally, where the high pressures and pulmonary tree irritations of PPH cause a medial thickening of the vessels (smooth muscle migration and hyperplasia), one can remove the cause –control the pressure, transplant the liver – yet those morphological changes persist, sometimes necessitating lung transplantation. Imatinib, designed to treat chronic myeloid leukemia, has been shown to reverse the pulmonary remodeling associated with PPH.[4][43][44]

## Prognosis

Following diagnosis, mean survival of patients with PPH is 15 months.[45] The survival of those with cirrhosis is sharply curtailed by PPH but can be significantly extended by both medical therapy and liver transplantation, provided the patient remains eligible.[citation needed]

Eligibility for transplantation is generally related to mean pulmonary artery pressure (PAP). Given the fear that those PPH patients with high PAP will have right heart failure following the stress of post-transplant reperfusion or in the immediate perioperative period, patients are typically risk-stratified based on mean PAP. Indeed, the operation-related mortality rate is greater than 50% when pre-operative mean PAP values lie between 35 and 50 mm Hg; if mean PAP exceeds 40–45, transplantation is associated with a perioperative mortality of 70-80% (in those cases without preoperative medical therapy)[46][22] Patients, then, are considered to have a high risk of perioperative death once their mean PAP exceeds 35 mmHg.[47]

Survival is best inferred from published institutional experiences. At one institution, without treatment, 1-year survival was 46% and 5-year survival was 14%. With medical therapy, 1-year survival was 88% and 5-year survival was 55%. Survival at 5 years with medical therapy followed by liver transplantation was 67%.[21] At another institution, of the 67 patients with PPH from 1652 total cirrhotics evaluated for transplant, half (34) were placed on the waiting list. Of these, 16 (48%) were transplanted at a time when 25% of all patients who underwent full evaluation received new livers, meaning the diagnosis of PPH made a patient twice as likely to be transplanted, once on the waiting list. Of those listed for transplant with PPH, 11 (33%) were eventually removed because of PPH, and 5 (15%) died on the waitlist. Of the 16 transplanted patients with PPH, 11 (69%) survived for more than a year after transplant, at a time when overall one-year survival in that center was 86.4%. The three-year post-transplant survival for patients with PPH was 62.5% when it was 81.02% overall at this institution.[4]

## References

1. ↑ Adapted from: Tapper EB: http://wikidoc.org/index.php/Portopulmonary_hypertension
2. ↑ Kuo, PC; Plotkin, JS; Gaine, S; Schroeder, RA; Rustgi, VK; Rubin, LJ; Johnson, LB (27 April 1999). "Portopulmonary hypertension and the liver transplant candidate.". Transplantation 67 (8): 1087–93. doi:10.1097/00007890-199904270-00001. PMID 10232556.
3. ↑ 3.0 3.1 Torregrosa, M; Genesca, J; Gonzalez, A; Evangelista, A; Mora, A; Margarit, C; Esteban, R; Guardia, J (27 February 2001). "Role of Doppler echocardiography in the assessment of portopulmonary hypertension in liver transplantation candidates.". Transplantation 71 (4): 572–4. doi:10.1097/00007890-200102270-00015. PMID 11258439.
4. ↑ 4.0 4.1 4.2 4.3 Tapper, EB; Knowles, D; Heffron, T; Lawrence, EC; Csete, M (June 2009). "Portopulmonary hypertension: imatinib as a novel treatment and the Emory experience with this condition.". Transplantation Proceedings 41 (5): 1969–71. doi:10.1016/j.transproceed.2009.02.100. PMID 19545770.
5. ↑ 5.0 5.1 5.2 Le Pavec et al. Portopulmonary Hypertension: Survival and Prognostic Factors. Am J Respir Crit Care Med Vol 178. pp 637–643, 2008
6. ↑ 6.0 6.1 Kawut, SM; Krowka, MJ; Trotter, JF; Roberts, KE; Benza, RL; Badesch, DB; Taichman, DB; Horn, EM et al. (July 2008). "Clinical risk factors for portopulmonary hypertension.". Hepatology 48 (1): 196–203. doi:10.1002/hep.22275. PMID 18537192.
7. ↑ 7.0 7.1 Benjaminov, FS; Prentice, M; Sniderman, KW; Siu, S; Liu, P; Wong, F (September 2003). "Portopulmonary hypertension in decompensated cirrhosis with refractory ascites.". Gut 52 (9): 1355–62. doi:10.1136/gut.52.9.1355. PMID 12912870.
8. ↑ 8.0 8.1 Hadengue, A; Benhayoun, MK; Lebrec, D; Benhamou, JP (February 1991). "Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics.". Gastroenterology 100 (2): 520–8. doi:10.1016/0016-5085(91)90225-a. PMID 1985048.
9. ↑ Martínez-Palli, G; Taurà, P; Balust, J; Beltrán, J; Zavala, E; Garcia-Valdecasas, JC (November 2005). "Liver transplantation in high-risk patients: hepatopulmonary syndrome and portopulmonary hypertension.". Transplantation Proceedings 37 (9): 3861–4. doi:10.1016/j.transproceed.2005.09.119. PMID 16386564.
10. ↑ Budhiraja, R; Hassoun, PM (February 2003). "Portopulmonary hypertension: a tale of two circulations.". Chest 123 (2): 562–76. doi:10.1378/chest.123.2.562. PMID 12576381.
11. ↑ Moller, S; Henriksen, JH (28 January 2006). "Cardiopulmonary complications in chronic liver disease.". World Journal of Gastroenterology 12 (4): 526–38. doi:10.3748/wjg.v12.i4.526. PMID 16489664.
12. ↑ Christman, BW; McPherson, CD; Newman, JH; King, GA; Bernard, GR; Groves, BM; Loyd, JE (9 July 1992). "An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension.". The New England Journal of Medicine 327 (2): 70–5. doi:10.1056/NEJM199207093270202. PMID 1603138.
13. ↑ Maruyama, T; Ohsaki, K; Shimoda, S; Kaji, Y; Harada, M (January 2005). "Thromboxane-dependent portopulmonary hypertension.". The American Journal of Medicine 118 (1): 93–4. doi:10.1016/j.amjmed.2004.11.007. PMID 15639216.
14. ↑ Giaid, A (September 1998). "Nitric oxide and endothelin-1 in pulmonary hypertension.". Chest 114 (3 Suppl): 208S–212S. doi:10.1378/chest.114.3_supplement.208s. PMID 9741571.
15. ↑ Gerbes, AL; Møller, S; Gülberg, V; Henriksen, JH (March 1995). "Endothelin-1 and -3 plasma concentrations in patients with cirrhosis: role of splanchnic and renal passage and liver function.". Hepatology 21 (3): 735–9. PMID 7875671.
16. ↑ Stewart, DJ; Levy, RD; Cernacek, P; Langleben, D (15 March 1991). "Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease?". Annals of Internal Medicine 114 (6): 464–9. doi:10.7326/0003-4819-114-6-464. PMID 1994793.
17. ↑ Luo, B; Liu, L; Tang, L; Zhang, J; Stockard, CR; Grizzle, WE; Fallon, MB (May 2003). "Increased pulmonary vascular endothelin B receptor expression and responsiveness to endothelin-1 in cirrhotic and portal hypertensive rats: a potential mechanism in experimental hepatopulmonary syndrome.". Journal of Hepatology 38 (5): 556–63. doi:10.1016/s0168-8278(03)00012-6. PMID 12713865.
18. ↑ Egermayer, P; Town, GI; Peacock, AJ (February 1999). "Role of serotonin in the pathogenesis of acute and chronic pulmonary hypertension.". Thorax 54 (2): 161–8. doi:10.1136/thx.54.2.161. PMID 10325923.
19. ↑ Schraufnagel DE, Kay JM. Structural and pathologic changes in lung vasculature in chronic liver disease. Clin Chest Med 1996; 17: 1
20. ↑ Matsubara, O; Nakamura, T; Uehara, T; Kasuga, T (May 1984). "Histometrical investigation of the pulmonary artery in severe hepatic disease.". The Journal of Pathology 143 (1): 31–7. doi:10.1002/path.1711430106. PMID 6737114.
21. ↑ 21.0 21.1 Swanson, KL; Wiesner, RH; Nyberg, SL; Rosen, CB; Krowka, MJ (November 2008). "Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups.". American Journal of Transplantation 8 (11): 2445–53. doi:10.1111/j.1600-6143.2008.02384.x. PMID 18782292.
22. ↑ 22.0 22.1 Kim et al. Accuracy of Doppler Echos in the assessment of PTHN in liver transplant candidates. Liver Transplant. 6:453, 2000
23. ↑ Colle, IO; Moreau, R; Godinho, E; Belghiti, J; Ettori, F; Cohen-Solal, A; Mal, H; Bernuau, J et al. (February 2003). "Diagnosis of portopulmonary hypertension in candidates for liver transplantation: a prospective study.". Hepatology 37 (2): 401–9. doi:10.1053/jhep.2003.50060. PMID 12540791.
24. ↑ Tapper EB, unpublished data
25. ↑ "Chapter 9 - Portopulmonary Hypertension". Pulmonary Vascular Disease: 132–142. 2006. doi:10.1016/B978-1-4160-2246-6.50015-8. ISBN 9781416022466. https://www.sciencedirect.com/science/article/pii/B9781416022466500158. Retrieved 11 August 2021.
26. ↑ Steudel, W; Hurford, WE; Zapol, WM (October 1999). "Inhaled nitric oxide: basic biology and clinical applications.". Anesthesiology 91 (4): 1090–121. doi:10.1097/00000542-199910000-00030. PMID 10519513.
27. ↑ Lowson. Inhaled alternative to nitric oxide. Anesthesiology 2002;96:1504-13
28. ↑ "Methemoglobinemia". https://www.lecturio.com/concepts/methemoglobinemia/.
29. ↑ Kerins et al. Prostacyclin and Prostaglandin E1: Molecular mechanisms and therapeutic utility. Prog Hemostasis Thrombosis 1991;10:307-37
30. ↑ Vane et al. Pharmacodynamic profile of prostacyclin. Am J Cardiol 1995;75:3A-10A
31. ↑ Eichelbrönner, O; Reinelt, H; Wiedeck, H; Mezödy, M; Rossaint, R; Georgieff, M; Radermacher, P (September 1996). "Aerosolized prostacyclin and inhaled nitric oxide in septic shock--different effects on splanchnic oxygenation?". Intensive Care Medicine 22 (9): 880–7. doi:10.1007/BF02044111. PMID 8905421.
32. ↑ Minder, S; Fischler, M; Muellhaupt, B; Zalunardo, MP; Jenni, R; Clavien, PA; Speich, R (October 2004). "Intravenous iloprost bridging to orthotopic liver transplantation in portopulmonary hypertension.". The European Respiratory Journal 24 (4): 703–7. doi:10.1183/09031936.04.00133203. PMID 15459152.
33. ↑ et al. Successful use of chronic epoprostenol as a bridge to liver transplant in severe PPHTN. Transplant 1998 4:457
34. ↑ Kuo PC, Johnson LB, Plotkin JS, Howell CD, Bartlett ST, Rubin LJ. Continuous intravenous infusion of epoprostenol for the treatment of portopulmonary hypertension. Transplantation 1997; 63: 604
35. ↑ Lowson, SM (March 2005). "Inhaled alternatives to nitric oxide.". Critical Care Medicine 33 (3 Suppl): S188-95. doi:10.1097/01.ccm.0000156792.40298.5a. PMID 15753727.
36. ↑ Makisalo, H; Koivusalo, A; Vakkuri, A; Hockerstedt, K (July 2004). "Sildenafil for portopulmonary hypertension in a patient undergoing liver transplantation.". Liver Transplantation 10 (7): 945–50. doi:10.1002/lt.20153. PMID 15237383.
37. ↑ Berkels, R; Klotz, T; Sticht, G; Englemann, U; Klaus, W (April 2001). "Modulation of human platelet aggregation by the phosphodiesterase type 5 inhibitor sildenafil.". Journal of Cardiovascular Pharmacology 37 (4): 413–21. doi:10.1097/00005344-200104000-00008. PMID 11300654.
38. ↑ Haraldsson et al. The additive pulmonary vasodilatory effect of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension. Aesth Analg 2001;93:1439-45
39. ↑ Rubin, LJ; Badesch, DB; Barst, RJ; Galie, N; Black, CM; Keogh, A; Pulido, T; Frost, A et al. (21 March 2002). "Bosentan therapy for pulmonary arterial hypertension.". The New England Journal of Medicine 346 (12): 896–903. doi:10.1056/NEJMoa012212. PMID 11907289.
40. ↑ Hoeper, MM; Halank, M; Marx, C; Hoeffken, G; Seyfarth, HJ; Schauer, J; Niedermeyer, J; Winkler, J (March 2005). "Bosentan therapy for portopulmonary hypertension.". The European Respiratory Journal 25 (3): 502–8. doi:10.1183/09031936.05.00080804. PMID 15738295.
41. ↑ Kuntzen, C; Gülberg, V; Gerbes, AL (January 2005). "Use of a mixed endothelin receptor antagonist in portopulmonary hypertension: a safe and effective therapy?". Gastroenterology 128 (1): 164–8. doi:10.1053/j.gastro.2004.09.005. PMID 15633133.
42. ↑ Wilkins, MR; Paul, GA; Strange, JW; Tunariu, N; Gin-Sing, W; Banya, WA; Westwood, MA; Stefanidis, A et al. (1 June 2005). "Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study.". American Journal of Respiratory and Critical Care Medicine 171 (11): 1292–7. doi:10.1164/rccm.200410-1411OC. PMID 15750042.
43. ↑ Schermuly, RT; Dony, E; Ghofrani, HA; Pullamsetti, S; Savai, R; Roth, M; Sydykov, A; Lai, YJ et al. (October 2005). "Reversal of experimental pulmonary hypertension by PDGF inhibition.". The Journal of Clinical Investigation 115 (10): 2811–21. doi:10.1172/JCI24838. PMID 16200212.
44. ↑ Ghofrani, HA; Seeger, W; Grimminger, F (29 September 2005). "Imatinib for the treatment of pulmonary arterial hypertension.". The New England Journal of Medicine 353 (13): 1412–3. doi:10.1056/NEJMc051946. PMID 16192491.
45. ↑ Ramsay, MA; Simpson, BR; Nguyen, AT; Ramsay, KJ; East, C; Klintmalm, GB (September 1997). "Severe pulmonary hypertension in liver transplant candidates.". Liver Transplantation and Surgery 3 (5): 494–500. doi:10.1002/lt.500030503. PMID 9346791.
46. ↑ Csete, M (July 1997). "Intraoperative management of liver transplant patients with pulmonary hypertension.". Liver Transplantation and Surgery 3 (4): 454–5. doi:10.1002/lt.500030422. PMID 9346782.
47. ↑ Krowka, MJ; Plevak, DJ; Findlay, JY; Rosen, CB; Wiesner, RH; Krom, RA (July 2000). "Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation.". Liver Transplantation 6 (4): 443–50. doi:10.1053/jlts.2000.6356. PMID 10915166.

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