Hepatopulmonary Syndrome Portopulmonary Hypertension. M. Verhaegen Ochtendkrans

Transcription

1 Hepatopulmonary Syndrome Portopulmonary Hypertension M. Verhaegen Ochtendkrans

2 End Stage Liver Disease (ESLD) and Arterial Hypoxemia Cardiopulmonary causes irrespective of ESLD E.g. heart failure, COPD Causes associated with liver disease Hepatopulmonary syndrome (HPS) Portopulmonary hypertension (POPH) Hepatic hydrothorax Multifactorial

3 End Stage Liver Disease (ESLD) and Arterial Hypoxemia Cardiopulmonary causes irrespective of ESLD E.g. heart failure, COPD Causes associated with liver disease Hepatopulmonary syndrome (HPS) Portopulmonary hypertension (POPH) Hepatic hydrothorax Multifactorial

4 Outline Hepatopulmonary syndrome Portopulmonary hypertension Definition Epidemiology Clinical signs and symptoms Pathogenesis Diagnosis Treatment Conclusion Summary

5 HEPATOPULMONARY SYNDROME

6 HPS: Definition Definition: triad Liver disease +/- portal hypertension +/- cirrhosis Acute liver failure and ischemic hepatitis have been associated with HPS Impaired oxygenation Age-corrected alveolar-arterial O 2 gradient 15 mmhg while breathing room air Or: PaO 2 < 80 mmhg while breathing room air Intrapulmonary vascular dilatation Exclusion of intrinsic cardiopulmonary pathology

7 HPS: Definition Definition: triad Liver disease +/- portal hypertension +/- cirrhosis Acute liver failure and ischemic hepatitis have been associated with HPS Impaired oxygenation Age-corrected alveolar-arterial O 2 gradient 15 mmhg while breathing room air PaO 2 < 80 mmhg while breathing room air Intrapulmonary vascular dilatation Exclusion of intrinsic cardiopulmonary pathology

8 HPS: Pulmonary Vessels Arteriovenous malformations in the lungs Vasodilation of pulmonary (pre)capillary vessels µm (normal: 7 15 µm) An absolute increase in the number of dilated vessels Pleural and pulmonary arteriovenous shunts and portopulmonary venous anastomoses

9 HPS: Hypoxemia Gas exchange abnormalities leading to hypoxemia 1. Ventilation-perfusion mismatch 2. Intrapulmonary shunting: large right-left shunt 3. Limitation of O 2 diffusion O 2 therapy may improve oxygenation Impaired hypoxic pulmonary vasoconstriction 30% of patients

10 Severity of HPS There is no universally consistent classification of HPS according to severity Possible classification according to PaO 2 (in patients breathing room air and with A-a O 2 gradient 15 mmhg) Mild: PaO 2 80 mmhg Moderate: PaO 2 60 and < 80 mmhg Severe: PaO 2 50 and < 60 mmhg Very severe: PaO 2 < 50 mmhg (<300 mmhg while breathing 100% oxygen) There is discussion about a relationship between the severity of liver disease the presence or severity of HPS

11 HPS: Prevalence A very wide range of prevalence has been reported in patients with chronic liver disease: 4 - ~ 30% Heterogenous diagnostic criteria: various cutoffs for gas exchange abnormalities Diagnostic methods

12 HPS: Symptoms Patients may be asymptomatic Dyspnea Insidious onset: initially dyspnea at exertion Platypnea Increasing dyspnea from supine to upright position Orthodeoxia PaO 2 decreases > 4 mmhg or O 2 saturation decreases > 5% when the patients moves from a supine to an upright position Pulmonary arteriovenous malformations occur predominantly at the base of the lungs increased perfusion of the lower lobes with more ventilation/perfusion mismatching and increased shunting in the upright position

13 HPS: Clinical Signs Spider naevi: cutaneous marker for intrapulmonary vascular dilatation? More systemic and pulmonary vasodilatation More impaired hypoxic pulmonary vasoconstriction Higher grades of hypoxemia Cyanosis Digital clubbing

14 HPS: Pathogenesis of Pulmonary Vasodilatation Nitric oxide appears to play a key role in the of pulmonary vascular changes of HPS, but several other mediators and mechanisms have been proposed Increased NO production in the lungs? NO theory: incomplete explanation Possible mechanisms Failure of the damaged liver to clear circulating pulmonary vasodilators Production of pulmonary vasodilators by the damaged liver Inhibition of circulating vasoconstrictive substances by the damaged liver

15 HPS: Natural History (1) Spontaneous resolution is unlikely Hypoxemia is generally progressive Mean PaO 2 decline: 5.2 ( ) mmhg/year HPS worsens the prognosis of patients with ESLD HPS patients and no liver TX * (n = 37) Matched controls** (no HPS, no liver TX) (n = 47) Median survival 24 months 87 months p 5-year survival rate 23 % 63 % * No livertx because of age or co-existing conditions ** Matched for cause and severity of liver disease Swanson et al., Hepatology 2005; 41:

16 HPS: Natural History (2) Cause of death: multifactorial Progressive hypoxemic failure: seldom the primary cause of death Related to complications of liver disease Hepatic failure, multisystem organ failure due to sepsis, hepatocellular carcinoma, gastrointestinal bleeding Development of concomitant portopulmonary hypertension is unlikely

17 HPS: Screening Patients with ESLD planned for liver transplantation should be screened for HPS: screening for hypoxemia Pulse oximetry Useful indicator, but insensitive Normal value is possible with mild HPS and increased A-a O 2 gradient Arterial PO 2 The combination of spider naevi, digital clubbing, cyanosis, and severe hypoxemia (PaO 2 < 60 mmhg) in the absence of cardiopulmonary disease strongly suggests HPS In patients with liver disease and hypoxemia further investigations for intrapulmonary vascular dilatation are indicated

18 HPS: Diagnosis (1) Presence of triad 1. Liver disease 2. Impaired oxygenation 3. Intrapulmonary vascular dilatations 2. Impaired oxygenation: arterial PO 2 PaO 2 < 80 mmhg indicates impaired oxygenation Patients > 65 y: PaO 2 < 70 mmhg Patient in upright position if possible More accurate: calculation of alveolar-arterial O 2 gradient (compensates for hyperventilation) A-a O 2 gradient 15 mmhg (> 65 y of age: 20 mmhg) Problem: calculation assumes normal cardiac output

19 HPS: Diagnosis (2) 3. Detection of intrapulmonary vascular dilatations Pulmonary angiography Technetium-99m-labeled macroaggregated albumin scanning Chest computed tomography Contrast-enhanced echocardiography Agitated saline Bubbles in left atrium within 3-6 heart cycles after iv injection when shunts typical of HPS are present Sensitive Less invasive Detection of other problems (e.g. pulmonary hypertension)

20 HPS: Treatment (1) There is no good medical therapy to improve gas exchange and hypoxemia Supplemental O 2 as symptomatic therapy Various medications have been tried (mostly anecdotically or in uncontrolled case series): no (sustained) improvement in oxygenation Several medical interventions have been tried TIPSS: variable response with a few case reports indicating improvement, but there may be a risk of worsening HPS due to an increased hyperkinetic state Other interventions (embolization, plasma exchange): unsuccessful Liver transplantation

21 Treatment Physically occlude IPVDs Spring coil embolization Oppose circulating vasodilators Octreotide (somatostatin analog) Nitric oxide synthase inhibitors Indomethacin Improve V/Q matching Almitrine bismesylate Treat underlying liver disease Chemotherapy and corticosteroids Liver transplantation Treat portal hypertension TIPSS (transjugular intrahepatic portosystemic shunt) Other (miscellaneous) Methylene blue Allium sativum (garlic) Propranolol Plasma exchange Sympathomimetics Efficacy for improving gas exchange in the HPS Modest if technically possible Variable Variable Poor Slight Helpful in one patient Moderately good but variable response Variable Variable in the few patients described Variable None None None Lange and Stoller, UpToDate 2012; adapted from Lange PA, Stoller JK, Ann Int Med 1995; 122: 521

22 HPS: Treatment (2) Liver transplantation Liver transplantation appears to improve survival in patients with HPS HPS patients and no liver TX * (n = 37) HPS patients and liver TX (n = 24) p 5-year survival rate 23 % 76 % Swanson et al., Hepatology 2005; 41:

23 HPS: Treatment (2) Liver transplantation Liver transplantation appears to improve survival in patients with HPS Figure 1. (A) Survival curves from the time of HPS diagnosis for HPS patients and controls (from time of PaO 2 determination) undergoing OLT (P =.69); and HPS patients and controls not undergoing OLT (P =.0003); (B) Survival from the time of OLT for HPS patients with severe hypoxemia and controls (P =.67). Swanson et al., Hepatology 2005; 41:

24 HPS: Treatment (2) Liver transplantation Liver transplantation appears to improve survival in patients with HPS Usually there is resolution of dyspnea and hypoxemia (80% of patients) Highly variable time course (2 14 months) Delayed recovery is common DLCO may not improve after transplantation, suggesting persistent subclinical pulmonary vascular changes Most problems occur in the early postoperative period Early postoperative mortality is higher in patients with HPS Risk factors: preoperative PaO 2 (room air) 50 mmhg and preoperative shunt fraction 20% Case reports: prolonged postoperative mechanical ventilation HPS is not considered in MELD score

25 Schiffer et al., Am J Transplant 2006;6:

26 HPS: Conclusion (1) HPS = liver disease + hypoxemia + pulmonary vascular dilatation Screening for HPS (PaO 2 ) is indicated in patients with chronic liver disease and dyspnea, platypnea or orthodeoxia, or in patients considered for liver transplantation In patients with liver disease and severe hypoxemia the diagnosis of HPS is confirmed by the documentation of intrapulmonary vascular dilatation (contrast enchanced echocardiography) Hypoxemia due to HPS is usually progressive with a high risk of morbidity and mortality There is no effective medical therapy or intervention for HPS O 2 therapy generally improves oxygenation in HPS HPS without liver transplantation: higher mortality than in patients with liver dysfunction without HPS

27 HPS: Conclusion (2) Liver transplantation is the only therapeutic option Morbidity and mortality following liver transplantation is (initially) probably higher in patients with HPS than in patients without HPS PaO 2 50 mmhg and significant intrapulmonary shunting Resolution of symptoms due to HPS in 80% of patients

28 PORTOPULMONARY HYPERTENSION

29 Portopulmonary Hypertension (POHP): Definition Combination of Portal hypertension +/- ESLD 10% of patients with POPH do not have liver cirrhosis Causes of portal hypertension associated with POPH: cirrhosis, portal vein thrombosis, hepatic vein sclerosis, congenital portal circulation abnormalities, periportal fibrosis without cirrhosis Pulmonary arterial hypertension (PAH) Mean PAP > 25 mmhg at rest (> 30 mmhg during exercise) Increased PVR > 240 dynes.s.cm -5 PCWP < 15 mmhg Exclusion of alternative causes of PAH

30 POPH: Epidemiology (1) POPH represents ~ 10% of the PAH population Portal hypertension is a risk factor for developing PAH Autopsy studies: the prevalence of PAH is higher in patients with portal hypertension than in the general population McDonnell et al, Am Rev Respir Dis 1983;127: PAH in unselected patients = 0.13% PAH in patients with cirrhosis and portal hypertension = 0.73% The risk of developing PAH is independent of the cause of portal hypertension A relationship between the severity of portal hypertension and the severity of PAH has not been demonstrated

31 POPH: Epidemiology (2) Prevalence: data vary greatly Diagnostic methods Prospective hemodynamic studies: 2-6% of patients with portal hypertension develop PAH Patients undergoing liver transplantation: prevalence of up to 10% There appears to be no association between the severity of liver dysfunction and the risk of PAH

32 POPH: Pathogenesis (1) Numerous theories have been proposed, but no definitive mechanism has been detected Histology: analogous to PAH at the level of the distal pulmonary arteries Vasoconstriction Intimal proliferation Medial hypertrophy Fibrotic changes Plexiform lesions In situ thrombosis

33 POPH: Pathogenesis (2) Possible mechanisms Humoral: imbalance of vasoconstrictor and vasodilatator factors at the pulmonary vasculature Portosystemic shunts allows vascular mediators to bypass the liver metabolism Decreased synthesis of vasoactive factors Serotonin, endothelin-1, thromboxane A2, vasoactive intestinal peptide, interleukin-6, nitric oxide, prostacyclin,.. Endothelial damage with vascular remodeling due to excessive pulmonary blood flow Smooth muscle proliferation Microvascular thrombosis Genetic predisposition Likely multifactorial

34 POPH: Symptoms 1. Clinical manifestations of portal hypertension Time interval between first manifestations of portal hypertension and documentation of PAH: 2 15 years (average 4 7 y) 2. Clinical manifestations of pulmonary arterial hypertension Early stages of POPH: asymptomatic Initially dyspnea on exertion Possibly fatigue, chest pain, syncope, peripheral edema, orthopnea, hemoptysis

35 POPH: Clinical Signs Severe POPH: physical findings of right heart dysfunction and eventually right heart failure Elevated jugular pressure Tricuspid systolic murmur (tricuspid regurgitation) Pulmonary diastolic murmur (pulmonary insufficiency) Dependent pitting edema Ascites

36 POPH: Screening and Diagnosis (1) There is no good screening method for POPH Arterial blood gasses Possibly hypoxemia (mild to moderate) and an increased A-a gradient Pulmonary function tests Normal or decreased diffusion General cardiology screening tests: low sensitivity ECG: right ventricular hypertrophy, right atrial hypertrophy, right axis deviation, right bundle branch block Chest X-ray: enlargement of right heart chambers, dilatation of the pulmonary arteries Suggestive of right heart strain Further investigations for POPH are indicated

37 POPH: Screening and Diagnosis (2) Transthoracic echocardiography Echocardiographic screening: in symptomatic patients with portal hypertension and in candidates for liver transplantation There are at present no data demonstrating that screening with TTE in asymptomatic patients with portal hypertension and liver cirrhosis not severe enough to require tranplantation is beneficial PAPs > 40 mmhg right heart catheterization TTE has a low positive predictive value for POPH TTE and estimated RVSP > 50 mmhg only 65% of patients have an increased PVR (Krowka, Liver Transplant 2003; 9: )

38 POPH: Screening and Diagnosis (3) Right heart catheterization: gold standard for definitive diagnosis of POPH Confirmation of diagnosis of POPH Pulmonary artery pressure: increased Pulmonary capillary wedge pressure: normal Pulmonary vascular resistance: increased Differentiation from ESLD with increased PAP due to high cardiac output, but with a normal PVR (30-50 % of ESLD patients) Hepatic venous wedge pressure: increased Exclusion of other causes of PAH Severity of POPH: prognostic and therapeutic implications

39 Porres-Aguilar et al, Annals of Hepatology, 2008; 7:

40 Distinguishing cardiopulmonary features of portopulmonary hypertension, chronic liver disease, and pulmonary arterial hypertension Kuo et al., Chest 1997; 112:

41 Distinguishing cardiopulmonary features of portopulmonary hypertension, chronic liver disease, and pulmonary arterial hypertension Kuo et al., Chest 1997; 112:

42 POPH: Prognosis Untreated POPH: outcome depends on the severity of PAH and on the severity of liver disease Data indicate that survival is worse in patients with POPH (without liver transplantation) than in patients with PAH of other causes Delayed treatment of POPH? Outcome in patients with POPH depends not only on PAH but also on underlying liver disease Survival is significantly higher in patients with POPH receiving specific therapy for PAH compared to POPH patients not receiving specific therapy for PAH

43 5 y survival = 45 % 5 y survival = 14 % Swanson et al, Am J Transplant 2008; 8:

44 5 y survival = 67 % 5 y survival = 45 % 5 y survival = 14 % Swanson et al, Am J Transplant 2008; 8:

45 POPH: Treatment Insufficient data from studies in patients with POPH: most treatments are copied from studies in patients with PAH of other causes General management Specific therapy for PAH Liver transplantation

46 POPH: General Management (1) Oxygen supplementation Diuretics Treatment of pulmonary hypertension Treatment of ascites and/or peripheral edema Concerns: too rapid fluid removal (hypovolemia) and electrolyte disturbances (hypokalemia intracellular acidosis hyperammonemia hepatic coma) Anticoagulation No good data on efficacy and safety in patients with POPH Contraindications related to liver disease Not recommended in POPH patients Decision on individual basis

47 POPH: General Management (2) Calcium channel blockers: contraindicated in patients with POPH? Mesenteric dilatation worsening of portal hypertension Stop β-blockade In patients with portal hypertension β-blockade is often started to prevent bleeding from esophageal varices Patients with POPH: stopping β-blockade has a beneficial effect on pulmonary hypertension No data on effect on esophageal variceal hemorrhage Avoid TIPSS? Risk of acute increase in cardiac output and mpap

48 POPH: Specific Therapy for PAH Prostanoids Endothelin receptor antagonists Phosphodiesterase type-5 inhibitors No data from RCTs in patients with POPH Case series, small observational studies Risk of hepatotoxicity Some data indicate improved survival with specific therapy for PAH (epoprostenol, bosentan, sildenafil), but other data do not support this Greater survival benefit for patients with milder liver disease? Combined therapy: case reports only Treatment to enable liver transplantation? Target: mpap < 35 mmhg and PVR < 400 dynes.s.cm -5?

49 Swanson et al, Am J Transplant 2008; 8:

50 POPH: Prostanoids (1) Epoprostenol (Flolan ) Data (no RCTs) indicate improved hemodynamics (mpap, PVR, CO) and exercise capacity No documented long-term survival benefit Increased incidence of splenomegaly and thrombocytopenia Adverse effects on hepatic function or portal hypertension? Iloprost (Ventavis )

51 Figure 2. Changes in pulmonary hemodynamic measurements in patients treated with epoprostenol (epoprostenol group) from baseline to most recent right heart catheterization. (A) Mean MPAP significantly improved from 48.4 to 36.1 mm Hg (*P <.0001). TPG improved from 38.5 to 23.2 mm Hg (*P <.0001). There was no significant change in PCWP. (B) Mean CO improved from 5.7 to 7.7 L/min (**P =.0009). There was no significant change in CI. (C) Mean PVR improved from 632 to 282 dynes s cm 5 (*P <.0001). Abbreviations: MPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; TPG, transpulmonary gradient; CO, cardiac output; CI, cardiac index; PVR, pulmonary vascular resistance. Fix et al, Liver Transplant 2007; 13:

52 p= 0.77 Fix et al, Liver Transplant 2007; 13:

53 POPH: Prostanoids (2) Epoprostenol (Flolan ) Iloprost (Ventavis ) Inhaled iloprost: acute hemodynamic and functional improvement over a period of 12 months, but this effect was not sustained over a period of 3 years Hoeper et al, Eur Resp J 2007; 30:

54 POPH: Endothelin Receptor Antagonists (1) Bosentan (Tracleer ) 10 % of patients: (reversible) liver function abnormalities (TA increase) Case reports in POPH Improved symptoms, increased exercise capacity, significant drop in pulmonary vascular resistance No elevation in transaminase levels Retrospective analysis: hemodynamic and functional improvement over a period of 3 years Hoeper et al, Eur Resp J 2007; 30: Ambrisentan (Volibris )

55 Hoeper et al, Eur Resp J 2007; 30:

56 Fig. 2 Individual haemodynamic response to treatment with inhaled iloprost ( ) or bosentan ( ), expressed as change from baseline to first followup measurement of a) mean pulmonary arterial pressure ( P pa ) and b) pulmonary vascular resistance (PVR). a, b) n = 11 in iloprost group and n = 13 in bosentan group. Hoeper et al, Eur Resp J 2007; 30:

57 Fig. 1 a) Overall survival and b) event-free survival of patients with portopulmonary hypertension treated with bosentan ( ) or inhaled iloprost ( ) are shown. Events were deaths, transplantation or clinical worsening requiring the introduction of a new treatment for pulmonary hypertension. The number of subjects at risk were as follows. a) Bosentan group: n = 18, 18, 17, 16, 14, 14 and 11 at 0, 6, 12, 18, 24, 30 and 36 months, respectively. Iloprost group: n = 13, 13, 10, 8, 8, 7 and 6 at 0, 6, 12, 18, 24, 30 and 36 months, respectively. b) Bosentan group: n = 18, 18, 17, 16, 14, 14 and 9 at 0, 6, 12, 18, 24, 30 and 36 months, respectively. Iloprost group: n = 13, 12, 10, 6, 6, 6 and 2 at 0, 6, 12, 18, 24, 30 and 36 months, respectively. a) p = 0.029; b) p = Hoeper et al, Eur Resp J 2007; 30:

58 POPH: Endothelin Receptor Antagonists (2) Ambrisentan (Volibris ) Observational study of 13 patients with POPH Cartin-Ceba et al, Chest 2011; 139: Moderate to severe pulmonary hypertension Results following 12 months of therapy Improved hemodynamic parameters (mpap, PVR, CO) Improved biomarker (B-type natriuretic peptide) Improved symptoms (WHO functional class) No change in level of liver enzymes

59 POPH: Phosphodiesterase Type-5 Inhibitors Sildenafil (Revatio ) Insufficient data in POPH Retrospective case series of 14 patients (Reichenberger et al;. Eur Respir J 2006:; 28:563-67) Moderate to severe POPH +/- prostanoid (6/8) Sustained improvement of 6-minute walk test and B-type natriuretic peptide levels (up to 12 months) Hemodynamic benefit (mpap and PVR decrease) at 3 months was not sustained at 12 months

60 POPH and Liver Transplantation (1) Severity of PAH and liver transplantation in POPH patients Mild to moderate PAH: no major influence on outcome Severe PAH: high perioperative risk and poor clinical outcome Pulmonary problems Liver congestion and primary graft dysfunction Contraindication? In the past: a mpap 35 mmhg was considered a contraindication Level of mpap is a strong predictor of survival mpap 35 mmhg: very high perioperative mortality rate (35-60%) Case series: succesful liver transplantation with mpap 35 mmhg At present: mpap 45 mmhg?

61 POPH and Liver Transplantation (2) Reversibility of POPH after liver transplantation? If PAH resolves, it may take months to years AASLD guidelines: consider liver transplantation in patients with severe POPH only if PAH can be effectively controlled with medical therapy Careful selection of patients Well-defined protocols Role of medical treatment before liver transplantation? MELD score underestimates mortality risk of POPH patients on waiting list for liver transplantation Regular echocardiographic follow-up while on waiting list (biannual?) Combined liver-(heart)-lung transplantation: insufficient outcome data

62 POPH: Conclusion (1) POPH = portal hypertension + pulmonary arterial hypertension Screening for POPH (contrast enhanced echocardiography) is indicated in symptomatic (dyspnea) patients with portal hypertension or in patients with portal hypertension considered for liver transplantation In patients with a systolic pulmonary artery pressure > 40 mmhg a right heart catheterization is indicated Diagnosis/differential diagnosis Severity classification and therapeutic implications Severe POPH has a high risk of mortality Prognosis is worse in patients with PAH caused by POPH than in patients with other causes of PAH

63 POPH: Conclusion (2) Specific treatment for PAH is not well documented in POPH patients Patients with POPH treated with advanced pharmacological therapy for PAH appear to have a better prognosis than untreated POPH patients Treatment as a bridge to liver transplantation? Liver transplantation is a therapeutic option in selected patients Mild POPH (mpap mmhg): generally good outcome following transplantation and reversibility of PAH Moderate POPH (mpap mmhg): generally favorable outcome following transplantation, but reversibility of PAH is questionable Severe POPH (mpap 45 mmhg): generally poor outcome following transplantation and no reversibility of PAH After liver transplantation, it may take months to years for PAH to resolve in POPH patients

64 HPS POPH Definition Common symptoms Clinical signs 1. Liver disease 2. Impaired oxygenation PaO 2 <80mmHg, A-a O 2 15 mmhg 3. Intrapulmonary vascular dilation Dyspnea Platypnea Orthodeoxia Cyanosis and finger clubbing Spider naevi 1. Portal hypertension 2. Pulmonary arterial hypertension Mean PAP > 25 mmhg PVR > 240 dynes.s. cm -5 PCWP < 15 mmhg Exclusion other causes of PAH Dyspnea on exertion Orthopnea Signs of right heart failure ECG No specific abnormalitiies RBTB, right axis, RV strain and hypertrophy Chest X-ray No specific abnormalitiies Cardiomegaly Large main pulmonary arteries

65 HPS POPH Arterial blood gasses Moderate to severe hypoxemia Normal or mild hypoxemia Contrast-enhanced echocardiography Pulmonary hemodynamics and angiographic findings Liver transplantation Positive (LA opacification for > 3-6 cardiac cycles after RA opacification) Normal Discrete AV communications Always indicated, even in severe cases Negative Mean PAP at rest > 25 mmhg Mean PCWP < 15 mmhg PVR > 240 dynes.s. cm -5 Dilated main pulmonary arterial tree Distal arterial pruning Mild to moderate POPH: indicated Severe POPH: generally not indicated

66 Referenties Hepatopulmonary Syndrome A Liver-Induced Lung Vascular Disorder. Giusca et al.: Eur J Int Med 2011; 22: Portopulmonary hypertension: From diagnosis to treatment. Rodriguez-Roisin and Krowka: N Engl J Med 2008; 358: Portopulmonary hypertension and hepatopulmonary syndrome. Hoeper et al.: Lancet 2004; 363: