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Portopulmonary Hypertension (PAH in the setting of liver disease)

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)

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Portopulmonary Hypertension (PAH in the setting of liver disease)

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  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 8 µm 100 µm • 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. 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 Differential Diagnosis of Hypoxemia

  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 PaO2 50-60 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: 0.79-1 and 0.6-0.98

  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 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

  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

  23. Acute Vasodilator Testing • IV epoprostenol • Inhaled NO • IV adenosine

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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

  30. 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:

  31. 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

  32. 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

  33. 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

  34. 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

  35. High Risk Pulmonary Hemodynamic Profile Krowka, Liver Tranplantation2000

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

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