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

Pleura / Diaphragm • Hepatic hydrothorax• Chylothorax• Effect of massive

ascites

Pulmonary vasculature• HPS• PPH

HPS

1884 Fluckiger, described a patient with cirrhosis, marked cyanosis and clubbing

1966 Berthelot- dilatation of pulmonary vessels in an autopsy series

‘Hepatopulmonary syndrome’ coined in 1977 Kennedy et al. Exercise aggravated hypoxemia and orthodeoxia in cirrhosis. Chest 1977;72:305-9

HPS Triad

Arterial oxygenation defect Intrapulmonary vasodilation Presence of liver disease

Prevalence among liver 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 Chronic hepatitis 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

HPS

PATHOGENESIS OF HPS

Grace et al, journal of gastroenterology and hepatology 28 (2013) 213-219

Liver injury TGF/VEGF Angiogenesis

HEPATOPULMONARY SYNDROME

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

CLINICAL PRESENTATION

Dyspnea, platypnea and orthodeoxiaClubbing

• 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

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 Respir Dis 1989;140(6):1631–5.

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

INVESTIGATIONS• Determination of IPVD

• Contrast ECHO• Lung perfusion scan using

macroaggregated albumin

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

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.

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

Lung perfusion scan using 99m Tc MAA

Measures shunt fractionHighly specific but less sensitive -ve in most

patients with positive bubble contrast echoCannot differentiate between intracardiac shunts

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

DIAGNOSTIC CRITERIA

Rodríguez-Roisin et al. Eur Respir J 2004; 24: 861-880

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.

TREATMENT OF HPS

Treatment

MedicalInterventiona

lradiology

Liver transplant

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

MEDICAL - POTENTIAL TARGETS OF THERAPY

PTX: pentoxifylline, MB: methylene blue, MMF: mycophenolate mofetil, and CAPE: caffeic acid phenethyl ester Eshraghian et al. Biomed Res Int. 2013;2013:670139

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.

INTERVENTIONAL RADIOLOGYTIPS- Few case reports, some showed benefit But majority- no benefitTIPS 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

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

‘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.

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

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

HPS PPHTNClinical Exam Cyanosis, clubbing No cyanosis

Clubbing less commonECG findings None RBBB, RAD, RV

hypertrophyABG Mod/severe hypoxemia Mild hypoxemiaChest x-ray Normal Hilar enlargementContrast ECHO

Always + 3-6 cardiac cycles

-ve

99mTcMAA index

6% <6%

Pulmonary angiography

Normal/”spongy” (type I)Discrete AV Commns (II)

Large main PA, distal arterial pruning

OLT Always indicated in severe

Only indicated in mild stages

Medical Mx Ineffective Prostacyclin I2- Epoprostenol

CIRRHOTIC CARDIOMYOPATHY(CC)

‘A sound heart is the life of the flesh…’ Proverbs 14:30

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

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

INTRODUCTIONHeart 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

PATHOGENESIS

MANIFESTATIONS Diastolic dysfunction

Increased collagen contentIncreased ventricular stiffnessInadequate ventricular

relaxation

Pozzi et al Hepatology 1997Coutu et al Circ Res 2004Torregosa et al J Hepatol 2005

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 1974Zambruni et al J Hepatol 2006Pozzi et al Hepatol 1997

EVIDENCE OF FUNCTIONAL AND STRUCTURAL CARDIAC ABNORMALITIES IN CIRRHOTIC PATIENTS WITH AND WITHOUT ASCITES

Pozzi et al. Hepatology1997;26:1131–7.

PAPILLARY MUSCLE CONTRACTILITY IN CIRRHOTIC AND NON CIRRHOTIC RATS

N= 29

Gastroenterology 1996

MANIFESTATIONS Electrophysiological changes

QT prolongation (>0.44 sec) Multiple extra-systoles BBB ST depression Electromechanical dyssynergia

Bernardi et al hepatology 1998Henriksen et al J hepatol 2002

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, interventricular septal 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.

‘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)

o 26% of cirrhotic had NT-proBNP levels > 2000 pg/ml- consistent with CHF

o 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

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 cardiomyopathy criteriaCardiovascular complications of cirrhosis. Gut 57, 268–278. 2008

CLINICAL IMPLICATIONS

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 HRSRuiz del Arbol et al Hepatology 2003

HRS AND CCIn 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

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 2007Huonker et al Gut 1999

‘TIPS VERSUS PARACENTESIS PLUS ALBUMIN FOR REFRACTORY ASCITES IN CIRRHOSIS...’

Gines et alRCT N= 70CHF 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

LIVER TRANSPLANT AND CCOLT-severe stress on CVSIntra & 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 2006Torregosa et al J Hepatol 2005Moller et al Post Grad Med 2009

LIVER TRANSPLANT AND CC Prospective study N=190 patients with ESLD 71 - OLT During the hospitalization period after

transplantationChest 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

‘CARDIAC ALTERATIONS IN CIRRHOSIS: REVERSIBILITY AFTER LIVER TRANSPLANTATION’ N=40 Echocardiography and radionuclide angiography Complete reversal of all abnormal

cardiovascular parameters CV function reverted to normal when studied an

average of 9 months after OLT Improved cardiac workload and exercise

capacity

Torregrosa , et al. Cardiac alterations in cirrhosis: reversibility after liver transplantation. J

Hepatol 2005; 42: 68–74.

MANAGEMENT

TREATMENT - GENERAL Overt CHF is an uncommon – low

afterload Basic principles in Mx of CCF

Correct dyselectrolytemiaMaintain volume statusAvoid toxins like alcohol and cardio-depressant

drugsCareful use of diuretics

TREATMENT - SPECIFIC Beta agonist- Dopamine: Probably ineffective Amrinone which inhibits cAMP degradation might be

useful Ouabain, a short acting cardiac glycoside- ineffective Propranolol improved the prolonged

electrocardiographic QT interval in cirrhotic patients

24 weeks of treatment using an aldosterone receptor antagonist: Impvt in left ventricular wall thickness, peripheral sympathetic activation, and showed a nonsignificant tendency to improve the diastolic dysfunction

Ma et al Hepatol 1997Wong et al Hepatol 2002

TREATMENT - SPECIFICLiver transplant

Normalisation of QTcImprovement in cardiac

functionsDisappearance of LVHNormalisation of exercise

capacityRipoll et al Transplantation 2008

CONCLUSIONS HPS and CCM both are under recognised

conditions HPS: progressive hypoxemia even in the absence of

deteriorating hepatic function Tx CCM & HPS: Affect outcome after TIPS &

liver transplant Both are reversible after OLT Knowledge in pathogenesis- hope of effective

medical treatment

THANK YOU