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Hepatopulmonary syndrome and cirrhotic cardiomyopathy

Hepatopulmonary syndrome and cirrhotic cardiomyopathy. Perceptor : Dr Shalimar. PULMONARY COMPLICATIONS IN LIVER DISEASE. Parenchyma Pneumonia Lymphocytic/ organising pneumonia - PBC Panacinar emphysema – alpha1 anti trypsin deficiency Aspiration pneumonia – Hepatic encephalopathy.

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Hepatopulmonary syndrome and cirrhotic cardiomyopathy

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  1. Hepatopulmonary syndrome and cirrhotic cardiomyopathy Perceptor: Dr Shalimar

  2. PULMONARY COMPLICATIONS IN LIVER DISEASE • Parenchyma • Pneumonia • Lymphocytic/organising pneumonia - PBC • Panacinar emphysema – alpha1 anti trypsin deficiency • Aspiration pneumonia – Hepatic encephalopathy • Pleura / Diaphragm • Hepatic hydrothorax • Chylothorax • Effect of massive ascites • Pulmonary vasculature • HPS • PPH

  3. HPS • 1884 Fluckiger, described a patient withcirrhosis, markedcyanosis and clubbing • 1966 Berthelot- dilatation of pulmonaryvessels in an autopsyseries • ‘Hepatopulmonary syndrome’ coined in 1977 • Kennedy et al. Exercise aggravated hypoxemia and orthodeoxia in cirrhosis. Chest 1977;72:305-9

  4. HPS • Triad • Arterialoxygenationdefect • Intrapulmonaryvasodilation • Presence of liverdisease • Prevalenceamongliver transplant patients 4% to 47% • Variability in prevalence- Nonspecificity of clinical criteria & lack of a confirmatory test • For eg: 91% of healthy subjects: varying degrees of intrapulmonary shunting during submaximal aerobic exercise! • Can occur in Chronichepatitis and in NCPF • Mortality rate of 41% ( 9 of 22 adult patients ) at a mean of 2.5 years ( range, 1 to 5 years ) after the diagnosis Grace et al, journal of gastroenterology and hepatology 28 (2013) 213-219

  5. HPS

  6. PATHOGENESIS OF HPS Liver injury TGF/VEGF Angiogenesis Grace et al, journal of gastroenterology and hepatology 28 (2013) 213-219

  7. HEPATOPULMONARY SYNDROME Roberto et al. N Engl J Med 2008;358:2378-87

  8. Clinical Presentation • Dyspnea, platypnea and orthodeoxia • Clubbing • CLD + PHTN (82% of patients). • Dyspnea (18%); may be accompanied by platypnea and orthodeoxia. Khan et al : Pulmonary vascular complications of CLD , Annals of thoracic medicine – vol 6,issue 2, April –June 2011 • Spider angioma - may represent cutaneous markers of intrapulmonary vascular dilatations Lima et al , Frequency , clinical characteristics resp parameters of HPS. Mayo Clin Proc 2004;79:42-8

  9. Orthodeoxia • 3 - definitions for orthodeoxia : a decline in PaO2 of > 4% , of > 5% , or of > 10% • 4 & 5% decline - derived from studies that correlated a PaO2 with a measurable increase in shunt fraction • A decrease of > 10 mmHg in PaO2 commonly considered • 20% to 80% in patients with HPS • Gomez FP, Martinez-Pali G, Barbera JA, et al. Gas exchange mechanism of orthodeoxia in hepatopulmonary syndrome. Hepatology 2004;40(3):660–6 • Edell ES, Cortese DA, Krowka MJ, et al. Severe hypoxemia and liver disease. Am Rev RespirDis 1989;140(6):1631–5.

  10. INVESTIGATIONS • Determination of hypoxemia • Pulse oximetry useful screening tool cut off ≤ 97% has high sensitivity • Specificity - PaO2 ≤ 70 mm Hg less sensitive in mild HPS • Arterial blood gas analysis reveal high alveolar-arterial differences, more sensitive • Abrams GA, Jaffe CC, Hoffer PB, Binder HJ, Fallon MB. Diagnostic utility of contrast echocardiography and lung perfusion scan in patients with hepatopulmonary syndrome. Gastroenterology 1995;109:1283-1288

  11. INVESTIGATIONS • Determination of IPVD • Contrast ECHO • Lung perfusion scan using macroaggregated albumin

  12. Contrast echocardiography • Agitated normal saline injected into peripheral vein and cardiac chambers visualised through thoracic echocardiography • Bubbles 25 mcm, vessels 5-8 mcm • Normally trapped in alveolar capillary bed • In presence of intracardiac right to left shunt bubbles seen in left heart within 3 cycles • In case of intrapulmonary shunting seen after 3 cycles

  13. Transthoracic Echocardiography Opacification of the RA and RV with microbubbles and delayed opacification of the LA and LV approximately five cardiac cycles later. Roberto et al. N Engl J Med 2008;358:2378-87.

  14. Lung perfusion scan using 99m Tc MAA • Peripheral venous injection of MAA labelled with Tc 99m • Diameter of 10-90µm, removed in normal pulmonary circulation • Detection of radioactivity in fraction >6% in brain

  15. Lung perfusion scan using 99m Tc MAA • Measures shunt fraction • Highly specific but less sensitive -ve in most patients with positive bubble contrast echo • Cannot differentiate between intracardiac shunts

  16. Other investigations • CXR /HRCT- usually normal/ increased vascular markings in lower zone • PFT - reduced DLCO • Pulmonary angiography • Type 1 or minimal pattern • Finely diffuse, spidery abnormalities • Severe hypoxemia and a response to 100% O2 • The type 2 or discrete pattern • Localized arteriovenous communications • Poor response to supplemental oxygen

  17. DIAGNOSTIC CRITERIA Rodríguez-Roisin et al.EurRespir J 2004; 24: 861-880

  18. Screening algorithm Abrams GA, Sanders MK, Fallon MB: Utility of pulse oximetry in the detection of arterial hypoxemia in liver transplant candidates.  Liver Transpl  2002; 8:391-6.

  19. TREATMENT OF HPS

  20. Treatment • PaO2 response to 100% O2 (> 550 mmHg) •  ventilation-perfusion mismatch or diffusion-perfusion defect •  benefit clinically with this treatment • Poor response (PaO2 < 150 mmHg •  direct AV communications or extensive and extremely vascular channels •  pulmonary angiography  type 2 pattern  therapeutic embolization. Liver Transplantation, Vol 6, No 4, Suppl 1 (July), 2000:pp S31-35

  21. Medical - Potential targets of therapy PTX: pentoxifylline, MB: methylene blue, MMF: mycophenolatemofetil, and CAPE: caffeic acid phenethyl ester Eshraghian et al. Biomed Res Int. 2013;2013:670139

  22. MEDICAL MANAGEMENT- Human trials • Small human trials of medical therapies- disappointing results • Pentoxifylline - small number of patients: failed to improve arterial oxygenation • Norfloxacin- failed to produce any improvement in gas exchange • Tried medications- aspirin, IV Methylene blue • Sani MN, Kianifar HR, Kianee A, Khatami G. Effect of oral garlic on arterial oxygen pressure in children with hepatopulmonary syndrome. World J. Gastroenterol.2006; 12: 2427–31.

  23. Interventional Radiology • TIPS- Few case reports, some showed benefit But majority- no benefit • TIPS may worsen HPS by increasing the hyperkinetic state more pulmonary vasodilatation, shunting, and hypoxemia • Intra-arterial coil embolization of pulmonary AV communications in patients with large shunts- Moderate improvement in hypoxemia • Krowka MJ. Hepatopulmonary syndrome: what are we learning from interventional radiology, liver transplantation, and other disorders? Gastroenterology1995; 109: 1009–13

  24. Role of Liver transplantation • Only effective treatment, complete resolution in gas exchange abnormalities in 80% of patients • Exception of MELD points • HPS with PaO2 < 60 mm Hg liver Tx indication • Preoperative PaO2 ≤ 50 mm Hg & 99m Tc MAA fraction > 20% - increased mortality immediate post OLT (OR 2.21) UNOS, United Network for Organ Sharing; Liver Transplantation, Vol 6, No 4, Suppl 1 (July), 2000:pp S31-35. Arguedas et al. Hepatology 2003;37:192-7

  25. ‘Natural history of hepatopulmonary syndrome: Impact of liver transplantation. ‘ • Observational study N= 57 • 29/37 (78 % ) with HPS who did not undergo OLT & 5/24 patients (21 %) with HPS who underwent OLT died over a period of 2 years • After OLT HPS had a five-year survival rate of 76 % • Not significantly different to those without HPS Swanson KL et al. Natural history of hepatopulmonary syndrome: Impact of liver transplantation. Hepatology 2005; 41:1122.

  26. Recovery after LT • Recovery from HPS after Tx varies from days to 14 months • Post-OLT nonresolution of HPS uncommon (2%) • Higher baseline macroaggregated albumin shunt fraction - lower rate of postoperative improvement in oxygenation • Patients whose hypoxemia fails to improve- PPH • Aucejo, F, Miller, C, Vogt, D, et al. Pulmonary hypertension after liver transplantation in patients with antecedent hepatopulmonary syndrome: a report of 2 cases and review of the literature. Liver Transpl 2006; 12:1278

  27. PPH • PPH is defined as the development of PAH with m PAP > 25 mm Hg at rest or 30 mm Hg with exercise, in presence of PHTN • Moderate PPH (mPAP > 35  Hg) is associated with an increased operative risk for liver transplantation

  28. Cirrhotic Cardiomyopathy(CC) ‘A sound heart is the life of the flesh…’ Proverbs 14:30

  29. Definition • Clinical syndrome in cirrhosis • Abnormal and blunted CV response • Physiological stress • Pathological sress • Pharmacologic stress • Normal / increased cardiac output and contractility at rest Zardi et al JACC 2010

  30. Introduction • Gould - 1969 - cardiac contractile response to stimuli was depressed in alcoholic cirrhosis • Lee Et al- 1990- down Beta-adrenergic receptor density in cardiac cells in BDL rats • Multiple HD changes in cirrhosis Systemic • Increase in plasma volume, non-central blood volume and heart rate • Decrease in central arterial blood volume and systemic vascular resistance

  31. Introduction Heart • Increase in LAV, LVV and pulmonary blood flow • 30-50% advanced cirrhosis show CC • Up to 21% deaths post transplant attributable to cardiac failure Ripoll et al Transplantation 2008 Tiukinhoy- Laing et al AmJCardiol 2006

  32. Pathogenesis

  33. Manifestations • Diastolic dysfunction • Increased collagen content • Increased ventricular stiffness • Inadequate ventricular relaxation Pozzi et al Hepatology 1997 Coutu et al Circ Res 2004 Torregosa et al J Hepatol 2005

  34. Manifestations • Systolic dysfunction • Normal or increased function at rest • Deteriorates on stress • Prolonged total electromechanical systole • Inotropic and chronotropic incompetence • On maximal exercise, cardiac output increases by 97% in cirrhosis: 300% increase in healthy controls Limas et al Circulation 1974 Zambruni et al J Hepatol 2006 Pozzi et al Hepatol 1997

  35. Evidence of functional and structural cardiac abnormalities in cirrhotic patients with and without ascites Pozzi et al. Hepatology1997;26:1131–7.

  36. Papillary muscle contractility in cirrhotic and non cirrhotic rats • N= 29 Gastroenterology 1996

  37. Manifestations • Electrophysiological changes • QT prolongation (>0.44 sec) • Multiple extra-systoles • BBB • ST depression • Electromechanical dyssynergia Bernardi et al hepatology 1998 Henriksen et al J hepatol 2002

  38. Serum markers • Cardiac troponin I and ANP/BNP elevated • Troponin I level elevated in about 1/3 of cirrhotic patients • BNP levels correlate with QT interval prolongation, interventricularseptal thickness, and impairment of diastolic function • Pateron D et al. Elevated circulating cardiac troponin I in patients with cirrhosis. Hepatology1999; 29: 640-3. • Wong F, Siu S, Liu P, Blendis LM. BNP : is it a predictor of cardiomyopathy in cirrhosis? Clin Sci2001; 101: 621-628.

  39. ‘Cirrhotic Cardiomyopathy: An Overall Assessment and Role of NT-PROBNP’ • Aim: To evaluate levels of NTproBNP and its relationship with CC • N= 100 cirrhotic patients & 25 controls Cirrhotics: LV mass, E wave velocity- increased LV diastolic function- decreased NT-proBNP higher (1551 pg/ml vs. 856 pg/ml; p < 0.05) • 26% of cirrhotic had NT-proBNP levels > 2000 pg/ml- consistent with CHF • Regression analysis, NT-proBNP significantly related to CTP score, LV mass and cardiac index (β= 0.299, 0.232, 0.243 respectively,p < 0.05) AASLD Abstracts 2013

  40. Diagnostic criteria • Systolic dysfunction: Blunted increase in CO with exercise, volume challenge OR pharmacological stimuli; resting LVEF <55% • Diastolic dysfunction: prolonged deceleration time (>200 ms), E:A ratio <1 • Supportive criteria • EPS abnormalities- abnormal chronotropic response; prolonged QTc • Enlarged LA ; increased myocardial mass; increased BNP and proBNP, troponin I levels 2005 WGO cirrhotic cardiomyopathycriteria Cardiovascular complications of cirrhosis. Gut 57, 268–278. 2008

  41. Clinical Implications

  42. HRS and CC • Impaired cardiac function may predispose patients to HRS • Especially in stressful conditions In one study • 23 patients with SBP, all cleared infection – 8 developed HRS • Lower CO at admission and decreased with resolution of infection • MAP was low in those who developed renal failure • Inadequate ventricular contractility in the face of the CV-Renal stresses imposed by sepsis may contribute to HRS Ruiz del Arbol et al Hepatology 2003

  43. HRS and CC In another study • 24 patients with cirrhosis and ascites • 8 with low CI <1.5 • GFR was low 39 Vs 63 • Creatinine higher 1.3 vs 0.78 • HRS increased 3/7 Vs 1/16 • Worse survival at 3, 6, 12 months Krag et al Gut 2010

  44. TIPS and Cardiomyopathy • CCF is an absolute contraindication for TIPS • Worsening of the hyperdynamic circulation, manifested by an acute increase in CO and a decrease in the SVR In one study • 32 patients undergoing TIPS • Day 28 E/A ratio independent predictor of death at one year • 6/10 with E/A <1 died • 0/22 with E/A >1 Cazzaniga et al Gut 2007 Huonker et al Gut 1999

  45. ‘TIPS versus paracentesis plus albumin for refractory ascites in cirrhosis...’ • Gines et al • RCT N= 70 • CHF was reported in 12% of the TIPS group • Not seen in the paracentesis group Gines P et al.(2002) TIPS versus paracentesis plus albumin for refractory ascites in cirrhosis. Gastroenterology 123:1839–184

  46. Liver transplant and CC • OLT-severe stress on CVS • Intra & Post OP CO compromised due to reduced preload or to impaired myocardial contractility • Cardiac failure cause of 7-21% deaths after OLT Ripoll et al Transplantation 2008 Tiukinhoy- Laing et al AmJCardiol 2006 Torregosa et al J Hepatol 2005 Moller et al Post Grad Med 2009

  47. Liver transplant and CC • Prospective study N=190 patients with ESLD • 71 - OLT • During the hospitalization period after transplantation • Chest radiographic evidence of pulmonary edema in 39 patients (56%) • Overt LVF in 4 patients (6%) • All the patients had no prior evidence of cardiac illness Donovan CL et al 1996 Transplantation 61:1180–1188

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