This case discusses a 46-year-old female with autoimmune hepatitis, liver cirrhosis, and portal hypertension who developed portopulmonary hypertension. She was initially treated with supplemental oxygen which improved her symptoms and exercise capacity. Later, she was started on the endothelin receptor antagonist ambrisentan which further improved her hemodynamics and functional status based on repeat right heart catheterization and six-minute walk tests over six months. The document discusses the management of portopulmonary hypertension and the role of targeted pulmonary hypertension therapies such as endothelin receptor antagonists in its treatment.

1. George Giannakoulas
AHEPA University Hospital
Thessaloniki, Greece
Case # 1 – Porto-
pulmonary
hypertension

2. Disclosures
Honoraria for lectures
– Actelion
– GSK
– Bayer
Participated in advisory boards
– Actelion
– Bayer
– United Thepapeutics

3. Cardiologist swimming in attractive waters of
gastroenterology and respiratory medicine

4. Female
DoB: 17/11/1968, 46y

5. Background
• 2008
– Autoimmune hepatitis
– Liver cirrhosis
– Smoker, history of mild asthma
• 2009
– episode of acute PE, anticoagulation for 6 months

6. Background
• 2010
– Portal hypertension (splenomegaly, thrombocytopenia, mild
oesophageal varices)
– Portal thrombosis
• Hepatology assessment
– Child-Pugh class B cirrhosis
– MELD score 12

7. MELD score
• MELD =(0.957 x LN(creatinine) + 0.378 x
LN(bilirubin) +1.12 x LN(INR) +0.643) x 10
Capped at 40

8. Medications
• Azathioprine 2mg/kg
• Propranolol 40 mg tid
• LMWH

9. Background
• 2010:
– shortness of breath on exertion, fatigue
– no syncope
– no chest pain

10. Echo
• No signs of significant LV systolic or diastolic
dysfunction
• No RV dilatation
• RVSP = 39 mmHg

11. Diagnostic tests
• ABG on room air
– pH 7.41, PO2 56mmHg, PCO2 37mmHg, A-a gradient 35mmHg
• PFTs
– DLCO 70% predicted, mild obstruction and restriction
• HRCT and CT pulmonary angio
– mild enlargement of some distal pulmonary arterioles and areas
of nontapering pulmonary vessels. No pulmonary thrombosis

12. 6MWT
Pre Post
SpO2 (%) 96 81
HR (bpm) 55 105
Borg score 1 6
Total walked distance 471m

13. Bubble echo – hepatopulmonary syndrome
Cycle 0 Cycle 6

14. Management - Supplemental oxygen
• 1 liter of supplemental oxygen per minute at rest and 3
liters per minute (L/min) with exertion

15. Hepatopulmonary syndrome (HPS):
Definition
1. room air pO2 <80mmHg or A-a gradient
>15mmHg
2. evidence of intrapulmonary shunting (typically
on contrast-enhanced echocardiography or a
lung perfusion scan)
3. portal hypertension with or without cirrhosis

16. Hepatopulmonary syndrome: Characteristics
• 10–30% of patients referred for LTx evaluation and only
1% of patients with chronic liver disease in the non-
transplant setting (Deibert 2006)
• Dilatation at both the pre- and capillary level of the
pulmonary circulation, especially in the lower lobes

17. Clinical course
• Improved gradually with oxygen therapy
• Patient was placed on the liver transplant list with a
MELD exception for HPS

18. 1/2013
Current condition
• Dyspnoea in mild exertion since 6months
• NYHA 3
• BMI: 28kg/cm2
• SAT 96%, no clubbing
• HR 65/min,
• BP 120/80mmHg
• Loud P2
• No ascites/ mild peripheral edema
• Palpable liver/spleen
6MWT (without oxygen)
Pre Post
SpO2 96 87
HF 63 111
Borg 0 6
Total walked distance 452 m

19. Echo
– Mild RV dilatation
– TAPSE 2.3cm
– RVSP 85mmHg
– Mild pericardial effusion

21. • ECG: SR, no RVH
• LFTs: DLCO 55% predicted
• HRCT: No lung disease
• Lung perfusion scan: Negative for proximal CTEPH,
can’t rule out distal subsegmental disease
• Normal immunologic tests
• Normal thyroid function
Diagnostic tests

22. Hepatology workup
• Child-Pugh class B
• MELD score 15

23. Hb: 13 g/dl,
HR: 69/min
BSA: 1.85m2
Baseline
Pressure (mmHg) SAT (%)
RA 7
RV 78/7
PA 77/31/46 75.5
PAWP 10
Ao 120/70 96.8
PVR (Wood) 6.7
PVRi (Woodxm2) 12.4
CI (L/min/m2) 2.91
Pulmonary angiography: No signs of CTEPH
RHC - indirect Fick

24. Pulmonary angiogram
Negative for CTEPH

25. ERS Task Force Pulmonary-Hepatic Vascular Disorders Scientific
Committee Guidelines for PoPH candidates for OLT
Rodriguez-Roisin R et al. Eur Respir J 2004

26. Therapy
• Patient was taken off the liver transplant list
• Patient was put on ambrisentan 5 mg od with close LFT
monitoring.
• Propranolol (primary prevention) discontinued

27. 6 months later – clinical assessment
• Clinical improvement
• NYHA 2
• 6MWT 536m
• Does not need supplemental oxygen therapy
• Echo: borderline RV size and normal systolic function
• BNP: normal

28. Hb: 11.5 g/dl,
HR: 77/min
BSA: 1.8m2
Baseline
Pressure (mmHg) SAT (%)
RA 9
RV 67/19
PA 67/36/49 78
PAWP 10
Ao 120/70 98
PVR (Wood) 3.98
PVRi (Woodxm2) 7.2
CI (L/min/m2) 5.5
At 6 months
repeat RHC - thermodilution

29. Baseline (Fick) after 6 months (TD)
6MWT (m) 452 536
PA (mmHg)
PVR (W)
CI (L/min/m2)
77/31/m46
6.7
2.9
67/36/m49
3.9
5.5

30. Significant CI increase could be
attributed to
1. targeted therapy with ERA
2. b-blocker cessation
3. 1 and 2

31. β-blocker cessation in PoPH
• All patients (n=10) were free of PAH targeted therapies
• 28% increase in cardiac output with no change in mean pulmonary
artery pressure, resulting in a 19% decrease in pulmonary vascular
resistance
Provencher et al. Gastroenterology 2006

32. β-blocker cessation in PoPH
Provencher et al. Gastroenterology 2006

33. Targeted PAH therapy with bosentan
n=34 consecutive patients with PoPH treated with first-line bosentan
Short-term evaluation was performed after 5±2 months after bosentan
initiation
Savale et al. ERJ 2013

34. Targeted PAH therapy with ambrisentan
Cartin-Ceba et al. Chest 2011
n=17 patients with PoPH treated with ambrisenten monotherapy

35. Anemia can also increase cardiac output
baseline after 6 months
6MWT (m) 452 536
PA (mmHg)
PVR (W)
CI (L/min/m2)
77/31/m46
6.7
2.9
67/36/m49
3.9
5.5
Hb (g/dl) 13 11.5

36. How would you proceed with this
patient?
1. Add a PDE-5 inhibitor
2. Do nothing
3. Repeat the RHC using the indirect Fick method

38. Treatment goals

39. Hemodynamic improve is not related to the
severity of the liver disease
The short-term haemodynamic response was significantly
better in patients with C-P class B cirrhosis compared with
those with C-P class A cirrhosis or with noncirrhotic portal
hypertension
Savale et al. ERJ 2013

40. Incidence of PoPH
1-3 per million population
(Humbert 2006)
Cirrhosis <1%
(Mc Donnell 1983)
Portal Hypertension 2-3%
(Hadengue 1991, Yang 2000)
Liver transplant candidates 6-8.5%
(Colle 2003, Ramsay 1997)
Liver transplant recipients 2.5-4%
(Galie 2001, Taura 1996, Castro 1996)

41. Portopulmonary Hypertension
• Identification of POPH is usually made at an average of
4–7 yrs after the diagnosis of portal hypertension
• Risk factors: Autoimmune etiology and female sex
• Independent of the severity of the liver disease
• Prognosis is related to the severity of cirrhosis and to
cardiac function

42. Portopulmonary Hypertension and liver
transplantation
• Untreated or treated, if mean PAP>50mmHg peri-
transplant mortality is well over 50%
• If mean PAP is 35-50mmHg and PVR greater than
250dynes, mortality 50%
• Consensus goals of PAH therapy in PoPH:
– Mean PAP less than 35mmHg
– Mean PAP 35-50mmHg with PVR less than 250 dynes and
normal RV function

43. RCTs on medical therapy
• PoPH patients are usually excluded from RCTs with
PAH-specific therapies

45. Take home messages
• HPS should be suspected in symptomatic patients with portal
hypertension who present with desaturation at rest or during
exercise
• HPS and PoPH are clinically distinct entities with seemingly distinct
pathophysiologies, but they can very rarely occur simultaneously or
sequentially in the same patient
• The effect of PAH targeted therapies in PoPH seem to be similar to
those observed in other forms of PAH
• Β-blockers should be discontinued when possible in patients with
PoPH

46. Thanks

47. Back up slides

48. Child-Pugh score

49. 44% had >20% difference
between thermodilution and Fick
Using PVR >3 Wood units as a
diagnostic criteria for PAH, 27
patients (13±2%) would have
inconsistency in PAH diagnosis
between TD and Fick
n=213 RHCs, 79 (40%) of whom had PAH

50. PAH determinants of prognosis
ESC guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009

51. Hemodynamics in portal hypertension
mPAP CI PCWP PVR TPG
Hyperdynamic < 35 NL NL
Volume overload < 35 NL NL <10
PoPH > 25 NL NL >10

52. REVEAL 2-year survival patterns for POPH and IPAH categorized
by previous versus newly diagnosed (Dx) at the time of entry into
the registry

53. Current POPH screening evaluation and
treatment algorithm used at the Mayo Clinic