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Medical > Therapy > Special indications

Portopulmonary Hypertension and Hepatopulmonary Syndrome

Introduction
In association with advanced liver disease two distinct pulmonary circulatory syndromes have been described (1, 2) a) hepatopulmonary syndrome (HPS) and b) portopulmonary hypertension (PPHTN). The common determinant of HPS and PPHTN is portal hypertension (+/- liver cirrhosis) and portosystemic shunting. Hepatopulmonary syndrome is characterised by hypoxaemia from pulmonary vascular dilatation and direct arteriovenous shunts. PPHTN is a specific condition characterised by an elevated pulmonary artery pressure (MPAP), increased pulmonary vascular resistance (PVR) a normal pulmonary artery occlusion pressure (PAOP) in the presence of portal hypertension and the absence of other potential causes of pulmonary hypertension. In the WHO classification PPHTN represents a subset of pulmonary arterial hypertension (3, 4).

Definition
Most patients with chronic liver disease have hyperdynamic circulatory states and an increase in blood volume, which can result in increased pulmonary artery pressure and low pulmonary vascular resistance. Therefore specific hemodynamic, oxygen and imaging criteria have evolved to define HPS and PPHTN. PPTHN is a subtype of PAH defined by an elevated pulmonary artery pressure and increased pulmonary vascular resistance in association with portosystemic shunts, whereas HPS is characterized by arterial hypoxemia due to intrapulmonary vascular dilatation. Diagnostic criteria are summarized in Table 1 according to the Respiratory Society-European Association for Study of the liver (ERS-EASL). Consensus regarding “normal” pulmonary vascular resistance in the setting of advanced liver disease varies but values greater than 240 dynes x sec x cm-5 is generally considered pathological (5, 6), although some authorities have defined pulmonary hypertension by a value > 120 dynes * sec * cm-5 (6). PPHTP is graded hemodynamically into mild (MPAP 25-35 mmHg), moderate (MPAP 35-45 mmHg) and severe (MPAP >45 mmHg).

Portopulmonary hypertension	Hepatopulmonary syndrome
Portal hypertension > 10 mmHg	Chronic liver disease
MPAP >25 mmHg at rest ( > 30 mmHg during exercise)	Pa02 <70 mmHg or
PAOP < 15 mmHg	Alveolar-arterial 02 gradient >20 mmHg
PVR > 240 dynes * sec * cm-5 (a)	Intrapulmonary vascular dilatations (b)

(a) PVR = (MPAP-PAOP) x 80/Cardiac Output : This criterion helps to distinguish between increased PAP due to high-flow and hyperdynamic circulatory states (normal or low PVR) and PPHTN.
(b) Detected by contrast echocardiography, lung perfusion scanning, or pulmonary angiography.

Hepatopulmonary Syndrome
The HPS has been defined as a triad of portal hypertension, pulmonary vasodilatation an hypoxemia. Clinical signs can be dyspnoea, cyanosis, clubbing of the fingers and fatigue. Orthodeoxia (arterial desaturation in the upright position with improvement in the supine position) and platypnea (dyspnea in the upright position with improvement in the supine position) may occur. These symptoms are caused by the effects of gravity do to predominantly in the lung bases localised pulmonary arteriovenous shunts. The incidence of HPS is about 10 % in patients hospitalised for liver cirrhosis 2 and 10-20 % in patients who are candidates for liver transplantation 7. The prognosis of HPS is poor with one year survival rates between 16 % and 38% once Pa02 is < 6.7 kPa (8, 9). No drug therapy has proved efficacious. Nevertheless there are case reports of Pa02 improvement with the use of Aspirin, indomethacin, and oral Allium (Garlic) or intravenous methylene blue. The goal of these drugs is to improve ventilation-perfusion relationship (perhaps by inducing vasoconstriction), which could subsequently increase Pa02.

Supplemental oxygen consistently has provided improvement in Pa02. Interventional radiology with coil embolotherapy is a limited but significant option in selected patients. Transjugular intrahepatic portosystemic shunt (TIPS) has been developed to reduce the degree of portal hypertension. HPS is now considered by most centers to be an indication for orthotopic liver transplantation (OLT). HPS resolves in 62 % to 82 % of patients with successful OLT, but resolution of hypoxemia may take up to 15 months (10).

Portopulmonary Hypertension
PPHTN is a well recognised and difficult to treat complication of advanced liver disease and it is the most important cause of increased mean pulmonary artery pressure in this setting. Vasoconstriction, endothelial and smooth muscle proliferation, plexiform lesions and in situ thrombosis characterize this entity which share the same vascular pathology from that seen in idiopathic pulmonary hypertension. The lack of prostacyclin synthase within the pulmonary endothelium suggest a lack of vasodilator capability. The development of structural pulmonary vascular changes are not well understood, but shear stress due to increased blood flow in a hyperdynamic circulatory state, volume overload and vasoconstriction caused by substances from the vascular bed of the hepatosplenic circulation are responsible factors (11). Poor correlations with Childs-Turcotte-Pugh severity, levels of liver enzyme and splanchnic hemodynamics have been reported (12). Exertional dyspnoea is the most common non-specific symptom (11) and other signs like fatigue and leg edema can be easily confused with those of underlying liver disease. Patients with PPTHN are clinically similar to those with idiopathic pulmonary hypertension, except for being 5-10 years older with an equal sex ratio. Pulmonary hypertension is an uncommon complication of portal hypertension, afflicting between 2 % and 5 % of these patients (13, 14, 15) However, the prevalence in liver transplant candidates is higher and ranges from 4 % to 26 % (16, 17, 18, 19). But, most of these patients have a) high-flow states (normal or low PVR) and bearing in mind that the pulmonary artery pressure-flow relationship normally shows a slope of 2-2.5 mmHg/L/min 2 it is evident that a cirrhotic patient with high cardiac output is likely to be wrongly diagnosed as having PPHTN and/or b) increased central blood volume (increased PAOP). Thus, the incidence of "true" PPHTN (increased PVR) is about 4 % to 9 % (16, 17, 19). The prognosis is poor with a 6-months mortality rate of 50 % after diagnosis (12). No survival greater than 36 months has been reported in severe PPHTN (MPAP >50 mmHg) (16, 20). Unlike liver transplantation for HPS, PPHTN is a relative contraindication to liver transplantation due to the significant cardiopulmonary mortality associated with OLT when pulmonary hypertension exists. Mortality seems to correlate with the degree of the MPAP. The development of portopulmonary hypertension is uncertain and varies from 3 weeks to 5 years (21).

Whereas patients with mild to moderate PPHTN (MPAP <35 mmHg) can be safely transplanted without an increased risk of mortality (16, 17, 19, 20), the perioperative mortality rate is about 50 % in patients with a MPAP between 35 and 49 mmHg 20 and a pulmonary vascular resistance more than 240 dynes * sec * cm-5 and it reaches 80 to 100 % if the mean pressure were > 50 mmHg (20, 22). The high perioperative mortality results primarily from the sudden increase in cardiac output after reperfusion of the new graft (in the range of 5-10 %, but up to 300 %) and lead, with a fixed PVR, to acute right ventricular failure. Severe PPHTN has therefore been considered to be a contraindication to OLT. Nevertheless, if the MPAP is lowered to 35 mmHg or less, the PVR is < 240 dynes * sec * cm-5 as well as an improvement in right ventricular function is noted, there is no reported increased risk to proceeding with transplantation (23). If acute vasodilator therapy is not effective, then surgery is postponed and long-term vasodilator therapy such as intravenous epoprostenol is started and may facilitate successful OLT 24 25 26 27 28. McLaughlin et al reported a 33 % decrease in MPAP and a 68 % decrease in PVR after an average of 12.7 months treatment with continuous epoprostenol infusion (29). The disadvantage of epoprostenol is its very short half-life, a rapid development of tolerance and the administration can be compromised in patients with fluctuating mental status from hepatic encephalopathy. Thus, the more stable prostacyclin analogues iloprost or trepostinil might be an alternative treatment option.

Advantages of trepostinil over epoprostenol include easier administration and avoidance of line sepsis and a rebound pulmonary hypertension in cases of abrupt drug discontinuation. Control of pain and reactions at the infusion site related to trepostinil remains a problem. Although various local measures are employed, some patients require systemic pain management. Benza et al reported a mean PVR decrease by 18 %, an improved or unchanged NYHA functional class in 19 of 21 patients and an impressive survival of 71 % at 19 months in PPTHN patients with long-term subcutaneous trepostinil infusion (30).

The use of an endothelin receptor antagonist (e. g. bosentan) might be a treatment option because plasma levels of ET-1 are elevated in patients with PPTHN. But it bears the potential for hepatic toxicity (31). Treatment with bosentan in patients with PAH (Patients with PPTHN were excluded) showed an increase in hepatic enzymes in about 10 % (32). There are some case reports and retrospective case series in patients with advanced liver disease (Child A-C) and PPTHN treated with bosentan that demonstrate clinical and hemodynamic improvement without elevation of hepatic enzymes (33, 34). To date the use of bosentan in patients with PPTHN should be restricted to experienced centres, but if the above mentioned observations can be confirmed by controlled trials it would offer several advantages over yet available therapies.

Sildenafil has been used in managing PPHTN, but no trials have been done. There is concern about this drug because patients with liver disease have already increased nitric oxide effect (sildenafil is exactly working on this mechanism) and sildenafil plasma levels and duration of action are altered in these patients and the optimal dose is not known.

The ACCP suggests calcium-channel blockers to be considered in vasodilator responders (acute vasodilator study with MPAP decrease >10 mmHg to reach a MPAP < 40 mmHg with a normal or high cardiac output).

Diuretics are used to avoid fluid overload states and oxygen supplementation is given to keep the arterial oxygen saturation > 90 %. Long term oxygen therapy should be considered in patients with pa02 < 8 kPa (6).

The role of anticoagulation in PPTHN is unknown but potentially dangerous given the already present increased risk of bleeding. It is not recommended in PPHTN.

Patients with PPHTN are managed with vasodilator therapy for several months before transplantation, continuing the medication through the procedure. After transplantation it’s a clinical judgment as to how quickly patients can be weaned off, but pulmonary vascular abnormalities may even progress. Post transplant patients can be switched from intravenous epoprostenol or subcutaneous trepostinil to calcium channel blocker or to bosentan.

In conclusion the therapeutic agents available for the treatment of PPHTN have been primarily used in the treatment of PAH. Only few of the drugs have been systematically evaluated in PPHTN patients and information regarding the treatment options comes from case series and case reports. Clinical experience is most extensive with intravenous epoprostenol for this patient population.

Transthoracic echocardiography is the screening procedure of choice if portopulmonary hypertension is suspected, but right heart catheterization is mandatory for the definitive diagnosis (many screened patients have increased RVs but they do not have increased PVR). Right heart catheterization is indicated if right ventricular systolic pressure is greater than 50 mmHg and should delineate the hyperdynamic circulatory state from volume overload, cardiac failure and vasoconstriction with vasoproliferation (e. g. PPHTN). It also allows an evaluation of acute vasoreactivity and can be used to monitor the effectiveness of therapeutic interventions. For details in screening and diagnostic algorithm see http://www.phassociation.org/Medical/Advances_in_PH/Summer_2004/screening.pdf and for management of PH diagnosed at introduction of anaesthesia for liver TPL http://www.phassociation.org/Medical/Advances_in_PH/Summer_2004/management.pdf.
Once PPHTN has been diagnosed, follow-up with echocardiography is performed every 6 months to assess effectiveness of therapy, right ventricular function and in patients on the liver transplant waiting list to assure maintenance of hemodynamic eligibility.


References:

1. Krowka MJ. Hepatopulmonary Syndrome and Portopulmonary Hypertension. Curr Treat Options Cardiovasc Med 2002;4(3):267-273.

2. Naeije R. Hepatopulmonary syndrome and portopulmonary hypertension. Swiss Med Wkly 2003;133(11-12):163-9.

3. Nicod LP. Pulmonary hypertension. Swiss Med Wkly 2003;133(7-8):103-10.

4. Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet 2003;361(9368):1533-44.

5. Kuo PC, Schroeder RA, Vagelos RH, et al. Volume-mediated pulmonary responses in liver transplant candidates. Clin Transplant. 1996;10(6 Pt 1):521-7.

6. Rodriguez-Roisin R, Krowka MJ, Herve P, Fallon MB. Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J. 2004;24(5):861-80.

7. Martinez GP, Barbera JA, Visa J, et al. Hepatopulmonary syndrome in candidates for liver transplantation. J Hepatol. 2001;34(5):651-7.

8. Lange PA, Stoller JK. The hepatopulmonary syndrome. Ann Intern Med. 1995;122(7):521-9.

9. Herve P, Lebrec D, Brenot F, et al. Pulmonary vascular disorders in portal hypertension. Eur Respir J. 1998;11(5):1153-66.

10. Krowka MJ, Porayko MK, Plevak DJ, et al. Hepatopulmonary syndrome with progressive hypoxemia as an indication for liver transplantation: case reports and literature review. Mayo Clin Proc. 1997;72(1):44-53.

11. Krowka MJ. Hepatopulmonary syndrome versus portopulmonary hypertension: distinctions and dilemmas. Hepatology. 1997;25(5):1282-4.

12. Robalino BD, Moodie DS. Association between primary pulmonary hypertension and portal hypertension: analysis of its pathophysiology and clinical, laboratory and hemodynamic manifestations. J Am Coll Cardiol 1991;17(2):492-8.

13. McDonnell PJ, Toye PA, Hutchins GM. Primary pulmonary hypertension and cirrhosis: are they related? Am Rev Respir Dis 1983;127(4):437-41.

14. Hadengue A, Benhayoun MK, Lebrec D, Benhamou JP. Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991;100(2):520-8.

15. Yang YY, Lin HC, Lee WC, et al. Portopulmonary hypertension: distinctive hemodynamic and clinical manifestations. J Gastroenterol 2001;36(3):181-6.

16. Ramsay MA, Simpson BR, Nguyen AT, Ramsay KJ, East C, Klintmalm GB. Severe pulmonary hypertension in liver transplant candidates. Liver Transpl Surg 1997;3(5):494-500.

17. Castro M, Krowka MJ, Schroeder DR, et al. Frequency and clinical implications of increased pulmonary artery pressures in liver transplant patients. Mayo Clin Proc 1996;71(6):543-51.

18. Taura P, Garcia-Valdecasas JC, Beltran J, et al. Moderate primary pulmonary hypertension in patients undergoing liver transplantation. Anesth Analg 1996;83(4):675-80.

19. Starkel P, Vera A, Gunson B, Mutimer D. Outcome of liver transplantation for patients with pulmonary hypertension. Liver Transpl 2002;8(4):382-8.

20. Krowka MJ, Plevak DJ, Findlay JY, Rosen CB, Wiesner RH, Krom RA. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl 2000;6(4):443-50.

21. Ramsay MA. Perioperative mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl. 2000;6(4):451-2.

22. De Wolf AM, Scott VL, Gasior T, Kang Y. Pulmonary hypertension and liver transplantation. Anesthesiology 1993;78(1):213-4.

23. Krowka MJ, Mandell MS, Ramsay MA, et al. Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database. Liver Transpl. 2004;10(2):174-82.

24. Plotkin JS, Kuo PC, Rubin LJ, et al. Successful use of chronic epoprostenol as a bridge to liver transplantation in severe portopulmonary hypertension. Transplantation 1998;65(4):457-9.

25. Krowka MJ, Frantz RP, McGoon MD, Severson C, Plevak DJ, Wiesner RH. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): A study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology 1999;30(3):641-8.

26. Tan HP, Markowitz JS, Montgomery RA, et al. Liver transplantation in patients with severe portopulmonary hypertension treated with preoperative chronic intravenous epoprostenol. Liver Transpl 2001;7(8):745-9.

27. Ramsay MA, Spikes C, East CA, et al. The perioperative management of portopulmonary hypertension with nitric oxide and epoprostenol. Anesthesiology 1999;90(1):299-301.

28. Mair P, Kaehler CH, Pomaroli A, Schwarz B, Vogel W, Margreiter R. Orthotopic liver transplantation in a patient with severe portopulmonary hypertension. Acta Anaesthesiol Scand 2001;45(4):513-8.

29. McLaughlin VV, Genthner DE, Panella MM, Hess DM, Rich S. Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series. Ann Intern Med. 1999;130(9):740-3.

30. Benza RL, Thallaj JA, Rayburn BK, Foley BA, Bourge RC, Roscigno R. Safety and efficacy of trepostinil in cirrhosis-related pulmonary arterial hypertension. Presented at the 54th Annual meeting of the American Association for the Study of Liver Diseases. Boston 2003.

31. Ramsay MA. Liver Transplant Considerations and Outcome for Portopulmonary Hypertension Patient. Advances in Pulmonary Hypertension 2004 Summer.

32. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346(12):896-903.

33. Barth F, Gerber PJ, Reichen J, Dufour JF, Nicod LP. Efficiency and safety of bosentan in child C cirrhosis with portopulmonary hypertension and renal insufficiency. Eur J Gastroenterol Hepatol 2006;18(10):1117-9.

34. Hoeper MM, Halank M, Marx C, et al. Bosentan therapy for portopulmonary hypertension. Eur Respir J 2005;25(3):502-8.

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