H EPATOPULMONARY SYNDROME AND CIRRHOTIC CARDIOMYOPATHY Perceptor: Dr Shalimar.
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Transcript of H EPATOPULMONARY SYNDROME AND CIRRHOTIC CARDIOMYOPATHY Perceptor: Dr Shalimar.
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 fraction
Highly specific but less sensitive -ve in most
patients with positive bubble contrast echo
Cannot 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 hypoxemia
Chest x-ray Normal Hilar enlargement
Contrast 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 cirrhosisSystemic Increase in plasma volume, non-central blood volume
and heart rate Decrease in central arterial blood volume and
systemic vascular resistance
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
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 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
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 CC
OLT-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 CCFCorrect 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 - SPECIFIC
Liver transplantNormalisation 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