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

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

Clinical Classification of Pulmonary Hypertension Evian 1998 Venice 2003

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

Risk Factors Associated with PAH

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

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

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

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

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

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)

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

Survival in IPAH (McGlaughlin, Chest 2004)

Portopulmonary Hypertension Pathology

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

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

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

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

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

Differential Diagnosis of RHC Findings

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

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

Acute Vasodilator Testing IV epoprostenol Inhaled NO IV adenosine

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

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

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

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

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

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

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:

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

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

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

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

High Risk Pulmonary Hemodynamic Profile Krowka, Liver Tranplantation2000

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