1. Portopulmonary Hypertension (PAH in the setting of liver disease)
George T. Kondos, MD
Associate Professor of Medicine
Department of Medicine
Section of Cardiology

2. Classification of Pulmonary Hypertension
1975 WHO Classification
Primary pulmonary hypertension (PPH)
Diagnosis of exclusion
Secondary pulmonary hypertension
Presence of identifiable risk factors
1998 Evian Classification
Clinical classification system
Different categories sharing similarities in pathophysiological mechanisms, clinical presentations, therapeutic options
2003 Revised Clinical Classification of Pulmonary Hypertension
Other classification systems
Pathological
Functional based on the severity of symptoms

3. Clinical Classification of Pulmonary Hypertension
Evian 1998
Venice 2003

4. Evolution of PAH Classification from 1998-2003
The need for a genetic classification system
BMPR2 (50% of cases of FPAH)
<70 mutations
Discontinuing the term PPH
Reclassification of PVOD and PCH
Update on new RFs for PAH
Reassessment of the classification of congenital systemic-to-pulmonary shunts

5. Risk Factors Associated with PAH

6. Associate Liver and Lung Disease
Advanced Liver Disease/Dysfunction
Hepatopulmonary syndrome
Portopulmonary Hypertension
Pulmonary vascular dilatation
Severe arterial hypoxemia
May totally resolve after Tx
Pulmonary vasoconstrictive and proliferative
Leading to pulmonary hypertension
Right heart failure
Frequently not reversible by liver Tx

7. Hepatopulmonary Syndrome
Liver disease
Hypoxemia (A-a >20mmHg or PAO2< 70mmHG
Intrapulmonary vascular dilatations (dilated capillaries)
Diffusion-perfusion impairment
Anatomic R->L shunt
Admin of 02 - partial improvement
Admin 02 in pure R->L - no improvement
Admin 02 in pure diffusion - may normalize PO2 at rest

8. Differential Diagnosis of Hypoxemia
Normal A-a 02 gradient
Hypoventilation
Inhalation of gas with decreased FIO2
Elevated A-a 02 gradient
Ventilation-perfusion mismatch
Anatomic R->L shunt
Diffusion impairment
Diffusion perfusion impairment

9. Hepatopulmonary Syndrome
Worsened by
Inc. C.O. in chronic liver disease
Inc. pulmonary capillary dilatations
Associated clinically with
Orthodeoxia (dec in P02 4mmHg, or dec in P02 5%)
Diagnostic studies
Contrast-enhanced echocardiography
Tc 99m pyrophosphate lung scan with detection over brain or abdominal organs
ABG after breathing 100% 02 (shunt study)
Treatment
Liver Tx if PaO mmHg
Individualize Rx if PaO2 <50mmHg
Garlic, Nitric Oxide, portosystemic shuynts, intrapulmonary embolization

10. Portopulmonary Hypertension (The Challenge)
Difficult to make precise comparative evaluations between Tx candidates
Limited amount accurate data available
Conclusions often conflicting
Failure of development of evidenced based strategies
Different pathological presentations
Various comorbidities
Lack of complete hemodynamic and echocardiographic data

11. Portopulmonary Hypertension
Definition
Presence of portal hyhpertension (ascites, varices, splenomegaly)
Resting mPAP >25mmHg
Exercise mPAP>30mmHg
PCWP <15mmHG
>240 dynes.s.cm-5
Incidence
2-20% of cirrhotic patients
Prevalence may be greater (pts asymptomatic early in the disease)

12. Survival in PAH (Krowka, Clin Chest Med 2005)
Multicenter study: 10 OLT transplant centers
Despite strong slection criteria 36% in-hospital mortality
- 13 deaths due to right heart failure

13. Survival in IPAH (McGlaughlin, Chest 2004)

14. Portopulmonary Hypertension Pathology

15. Portopulmonary Hypertension (Clinical Presentation)
Subtle
Exertional dyspnia (most common, nonspecific)
Fatigue
Leg edema
Chest pain or pressure
syncope

16. Portopulmonary Hypertension (Physical Examination)
Carotid - decreased volume
JVP - elevated, a >> v, possible a<v if TR is present +/- HJR if JVP normal
Chest - unremarkable
CVS - +RVI, S1 nl, S2 increased murmur of TR common, PI uncommon
Extremities - edema

17. Risks of Liver Tx in Portopulmonary HTN
High risk surgery
43 pts with portopulmonary HTN 35% perioperative mortality (Krowka, Liver Transpl 2004)
Right heart failure
Cardiopulmonary collapse
Intrapoperative death 5 pts

18. Portopulmonary HTN (Screening)
CxR and EKG insufficient
Enlarged pulmonary arteries, cardiomegaly pulmonary hemodynamics are markdely abnormal
RAD, RBBB, Twv inversions in the precordial leads - late findings
Transthoracic doppler does not differentiate causes of elevated PAP
Hyperdynamic circulatory state
Increased central volume
Pulmonary vasculopathy of portopulmonary HTN
RHC mandatory for definitive diagnosis
Inc. Rvsys (30-50mmHg) no elevated PVR via RHC

19. Reliability of TTD in Detecting and Quantifying PAH
TR jets analyzable in 39-86% of pts
10 studies have reported correlation coefficients between RVSP estimated from TR jets and RHC
1 study - 51 pts poor correlation (r=0.31)
9 studies - >500 pts, significant correlations (0.83, 0.57, 0.95, 0.78, 0.85, 0.76, 0.93, 0.90, 0.89)
Sensitivity and specificity estimating sPAP ranges: and

20. Differential Diagnosis of RHC Findings

21. PVR in Portopulmonary HTN
Debate regarding PVR >120, or > 240 dynes.s.cm-5
Subgroup of Liver Dx pts with
PVR between dynes.s.cm-5 and inc. PCWP
Pts have increased TPG (mPAP-PCWP) >15mmHg
Consider as having mild portopulmonary HTN
Follow very carefully - natural history unclear
Report CO and PVR as indices
Administration of 1L NS over 10 minutes to identify individuals susceptible of liver ventricular failure during liver allograft reperfusion

22. Screening Algorithm for Portopulmonary HTN
Transthoracic Doppler
Echo
Rvsys >50mmHG and/or
Abn RV size/function
Measure RA
mPAP
PCWP CO
PVR
Observe; repeat echo
12 months if Liver Tx
candidate
Right Heart Cath
for hemodynamic data
Characterize Pulmonary
Hemodynamics
mPAP >25 mmHg
and PVR >240 dynes.s.cm5
mPAP >25 mmHg
And PVR<240 dynes.s.cm5
mPAP <25mmHg
Other Patterns
Portopulmonary
HTN diagnosis established
Probable high
flow state
Portopulmonary HTN
Does not exist
Institute Treatment

24. Acute Vasodilator Testing
IV epoprostenol
Inhaled NO
IV adenosine

25. Acute Vasodilator Testing
Continue until one of the following criteria is met
Drop in SBP by 30% or >, or < 85mmHg
Increased in HR by 40% or >100 bpm
Intolerable side effects: HA, nausea, lightheadedness
Target response achieved
Maximum dose of vasodilator
Responsiveness
Decrease of mPAP at least 10mmHG AND mPAP decreasing to 40mmHG or less AND normal or high CO
ALL THREE CRITERIA NEED TO BE SATISFIED
When should left heart catheterization be done?
Validation of abn PCWP
Evaluation of LV diastolic dysfunction
Syspected left-sided valvular dz (aortic, mitral)
Suspected CAD

26. Medical Treatment for Portopulmonary HTN
Prostacycline - (Epoprostenol) - IV, inhaled
Prostacycline Analogs
Treprostinil (SQ)
Iloprost (inhaled)
Beraprost
Inhaled Nitric Oxide
Phosphodiesterase inhibitors
Sildenafil
Endothelian Receptor Antagonists (ET1 potent vasoconstrictor)
Bosentan (ET-A&B)
Sitaxsentan (ET-A)
Ambrisentan (ET-A)
L-arginine
Combination therapy

27. Prostacycline
Potent vasodilator produced in endothelial and smooth-muscle cells
Antiproliferative and antiplatelet effects
Improvement in survival well documented compared to historical controls
Efficacy in Rx of portopulmonary HTN
Therapeutic bridge to liver Tx
Central venous catheter administration
Side-effects: flushing, HA, jaw pain, leg pain, diarrhea, nausea

28. Inhaled NO Endogenous endothelium derived vasodilator
Directly relaxes vascular smooth muscle by inc. cGMP
Variable response in pts with liver dz
Inc. levels of endogenous NO in liver dz
Utility in predicting acute hemodynamic responsiveness
Continuous inhalation device

29. Phosphodiesterasse Inhibitors
Improve pulmonary hemodynamics by enhancing endogenous NO effects by inhibiting the breakdown of cGMP
Sildenafil: PDE type-5 inhibitor
Dosage adjustments necessary in cirrhotics because of extensive hepatic metabolism

30. Entothelin Receptor Antagonists
Increased conc of ET-1 found in the plasma and lung tissue of pts with PAH
Bosentan competitive inhibitor of ET A and B receptors
Sitaxsentan selective ET-A
Ambrisentan selective ET-A
Limited use: hepatotoxicity

31. L-arginine
Endothelial derived vasodilation predominates over direct smooth muscle cell constriction
EDRF produced by intact endothelium
EDRF mediates Ach vasodilation
EDRF is the NO radical derived from L-arginine
Vasodilator Agonists:

32. PAH out of proportion of Left Heart Disease
Definition:
Severely elevated PAP >35-40mmHG
PCWP or LVEDP <22 mmHG and
TPG >18-20
Treatment
Main concern in treating with pts with elevated LVEDP/CPWP with pulmonary vasodilators is an inc. in CO and venous return to the LV -> pulmonary edema
Few studies looking and pulmonary vasodilators in DD
Optimize diuretics, nitrates, HR control
DO NOT use pulmonary vasodilators if PCWP or LVEDP >16mmHG

33. Postoperative Acute Right Heart Failure
Inc CO seen in 5-18% after reperfusion of the new graft
If there is resistance of PBF then pressure must increase
This leads to systemic increases in PAPs
Leading to acute right ventricular failure
Increase in CO is unpredicatable therefore reduce mPAP to a MILD level
Mechanism:
Removal of the obstruction to portal flow, systemic vasodilation via washout of acid metabolites and other vasodilator substances from the new graft

34. Portopulmonary Hypertension (Summary)
Classification
mPAP MILD
mPAP >35-40 MODERATE
MPAP >45 SEVERE
PVR >240 dynes.sec.cm-5 (>120)
Management mPAP >35
Determine cause
Volume overload -> Rx (effective with normal LV function) -> Tx
Poor cardiac function and elevated filling pressures -> ionotropic agents if no improvement -> no Tx
PVR low, LV function hyperdynamic -> Tx
If mPAP and PVR remain elevated - survial depends on RV function and the stressors applied during the perioperative period

35. Pretransplantation issues with Portopulmonary Hypertension
Does the degree of PAH warrant therapy before OLT is attempted?
mPAP <35 mmHG
What therapy should be selected?
No studies address which agent is efficacious and safe
IV epoprostenol (concerns with thrombycytopenia and splenomegaly), other prostacyclin analogues, silfandil
MD experience, drug availability and safety concerns
What pulmonary hemodynamic goals will facilitate a safe OLT
mPAP with PVR , 50% perioperative mortality
mPAP >50 exclude OLT at most centers
Repeat doppler echos annually

36. High Risk Pulmonary Hemodynamic Profile
Krowka, Liver Tranplantation2000

37. Mayo Clinic Intra-op Guidelines (Guidelines for Canceling Surgery)
Krowka, Liver Tranplantation2000