Portopulmonary Hypertension(PAH in the setting of liver disease)

George T. Kondos, MD

Associate Professor of Medicine

Department of Medicine

Section of Cardiology

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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

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Clinical Classification of Pulmonary HypertensionVenice 2003Evian 1998

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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

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Risk Factors Associated with PAH

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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

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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 µm 100 µm

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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

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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 PaO2 50-60 mmHg– Individualize Rx if PaO2 <50mmHg– Garlic, Nitric Oxide, portosystemic shuynts, intrapulmonary embolization

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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

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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)

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Survival in PAH (Krowka, Clin Chest Med 2005)

Multicenter study: 10 OLT transplant centersDespite strong slection criteria 36% in-hospital mortality

- 13 deaths due to right heart failure

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Survival in IPAH(McGlaughlin, Chest 2004)

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Portopulmonary Hypertension Pathology

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Portopulmonary Hypertension(Clinical Presentation)

• Subtle

• Exertional dyspnia (most common, nonspecific)

• Fatigue

• Leg edema

• Chest pain or pressure

• syncope

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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

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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

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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

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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: 0.79-1 and 0.6-0.98

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Differential Diagnosis of RHC Findings

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PVR in Portopulmonary HTN

• Debate regarding PVR >120, or > 240 dynes.s.cm-5

• Subgroup of Liver Dx pts with– PVR between 120-240 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

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Screening Algorithm for Portopulmonary HTN

Transthoracic DopplerEcho

Rvsys >50mmHG and/or

Abn RV size/function

Observe; repeat echo12 months if Liver Tx

candidate

Right Heart Cathfor hemodynamic data

MeasureRAmPAPPCWPCOPVR

Characterize PulmonaryHemodynamics

PortopulmonaryHTN diagnosis established

mPAP <25mmHgmPAP >25 mmHg

and PVR >240 dynes.s.cm5mPAP >25 mmHgAnd PVR<240 dynes.s.cm5

Probable highflow state

Portopulmonary HTNDoes not exist

Other Patterns

Institute Treatment

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Acute Vasodilator Testing

• IV epoprostenol

• Inhaled NO

• IV adenosine

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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

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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

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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

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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

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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

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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

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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

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Vasodilator Agonists:

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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

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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

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Portopulmonary Hypertension(Summary)

• Classification– mPAP 25-30 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

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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 35-50 with PVR 240-400, 50% perioperative mortality

– mPAP >50 exclude OLT at most centers

– Repeat doppler echos annually

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High Risk Pulmonary Hemodynamic Profile

Krowka, Liver Tranplantation2000

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Mayo Clinic Intra-op Guidelines(Guidelines for Canceling Surgery)

Krowka, Liver Tranplantation2000