Liver International ISSN 1478-3223
CIRRHOSIS AND LIVER FAILURE
Prevalence and impact on survival of hepatopulmonary syndrome and cirrhotic cardiomyopathy in a cohort of cirrhotic patients Andrei M. Voiosu1,2, Ioana C. Daha2,3, Theodor A. Voiosu1,2, Bogdan R. Mateescu1,2, Gheorghe A. Dan2,3, icusß2,4, Mihail R. Voiosu1,2 and Mircea M. Diculescu2,5 Cristian R. Ba 1 2 3 4 5
Department of Gastroenterology, Colentina Clinical Hospital, Bucharest, Romania “Carol Davila” University of Medicine, Bucharest, Romania Department of Cardiology, Colentina Clinical Hospital, Bucharest, Romania Department of Internal Medicine, Colentina Clinical Hospital, Bucharest, Romania Department of Gastroenterology and Hepatology, Fundeni Clinical Institute, Bucharest, Romania
Liver Int. 2015; 35: 2547–2555. DOI: 10.1111/liv.12866
Abstract Background & Aims: Extrahepatic complications of cirrhosis increase the risk for decompensation of the liver disease and death. Previous studies show common pathogenetic mechanisms involved in the development of hepatopulmonary syndrome and cirrhotic cardiomyopathy. We aimed to assess the link between these entities and their effect on disease-related patient morbidity and mortality. Methods: Seventy-four consecutive cirrhotic patients without prior history of cardiovascular and pulmonary disease were included in a prospective observational study. Routine blood work, arterial blood gas analysis, pulse oximetry measurements, N-terminal pro-brain natriuretic peptide levels and contrast enhanced echocardiography examination with tissue Doppler imaging were performed in all patients. Patients were followed up for a median of 6 months and disease-related adverse events and death were the main outcomes tested. Statistical analysis was conducted according to the presence of hepatopulmonary syndrome or cirrhotic cardiomyopathy. Results: Hepatopulmonary syndrome was diagnosed in 17 patients (23%) and cirrhotic cardiomyopathy in 30 patients (40.5%). There was no association between the presence of cirrhotic cardiomyopathy and the existence of mild or moderate hepatopulmonary syndrome. No echocardiographic parameters were useful in predicting the presence of hepatopulmonary syndrome. N-terminal pro-brain natriuretic peptide levels and length of QT interval did not aid in diagnosis of cirrhotic cardiomyopathy. Neither entity had significant influence on disease-related outcomes in the follow-up period. Conclusions: Hepatopulmonary syndrome and cirrhotic cardiomyopathy are independent complications arising in cirrhosis and have a limited influence on morbidity and mortality on a pre-liver transplantation population. Keywords cirrhosis – cirrhotic cardiomyopathy – echocardiography – follow-up studies – hepatopulmonary syndrome
The extrahepatic complications of cirrhosis affect short and long-term patient survival. Entities such as cirrhotic cardiomyopathy (CCM) and the hepatopulmonary syn-
drome (HPS) have been found to share some of the same pathogenetic mechanisms in experimental studies but the clinical implications of this link are unknown (1–8).
Abbreviations A’, late diastolic mitral annular velocity; AaPO2, age-adjusted alveolar-arterial oxygen gradient; CCM, cirrhotic cardiomyopathy; DT, deceleration time of E wave; E/A, peak early (E) to late (A) mitral filling velocity ratio; E’, early diastolic mitral annular velocity; HPS, hepatopulmonary syndrome; IPVDs, intrapulmonary vascular dilatations; IVRT, isovolumetric relaxation time; LAV, left atrial volume indexed to body surface area; LVEF, left ventricular ejection fraction; MELD, model for end-stage liver disease; NT-proBNP, N-terminal pro-brain natriuretic peptide; PASP, estimated pulmonary artery systolic pressure; pCO2, partial pressure of carbon dioxide in arterial blood; pO2, partial pressures of oxygen in arterial blood; QTc, rate corrected QT interval; RVW, right ventricle wall thickness; SpO2, peripheral capillary oxygen saturation approximated by pulse oximetry. Correspondence Andrei M. Voiosu, MD, Colentina Clinical Hospital, sos Stefan cel Mare no. 19-21, Bucharest, Romania Tel/Fax: +40213180604 e-mail: [email protected] Handling Editor: Christophe Bureau Received 4 March 2015; Accepted 4 May 2015
Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
2547
Voiosu et al.
Hepatopulmonary syndrome and cirrhotic cardiomyopathy
Key points
• Both hepatopulmonary syndrome and cirrhotic cardiomyopathy are frequent in this prospective cohort but they arise independently of each other. • The diagnostic and prognostic values of a wide variety of debated and established echocardiographic parameters as well as biomarkers are tested. • While most studies focus on liver transplant recipients and the immediate post-operative period, this study describes the natural history of the complications with up to a year of follow-up. • The lack of influence on mortality of these complications of cirrhosis argues for re-evaluation of the MELD exception policy for hepatopulmonary syndrome. Cirrhotic cardiomyopathy is commonly defined by a blunted cardiac contractile response to stress and/or diastolic dysfunction in the context of electromechanical abnormalities but validated diagnostic criteria are still lacking (9). On the other hand, hepatopulmonary syndrome is reliably detected by identifying altered blood oxygenation in the presence of intrapulmonary vascular dilations (IPVDs) in patients suffering from portal hypertension (10). Recently, patients with hepatopulmonary syndrome were granted exception points to increase their transplant waiting list priority thus making diagnosis and early management of this complication of cirrhosis mandatory (11). But while HPS is a known risk factor for decreased survival in cirrhosis (12–14), comparatively less data regarding the relevance of cirrhotic cardiomyopathy are available (15–17). The proven major implication of CCM is its influence on post-procedural evolution in the setting of transjugular intrahepatic portosystemic shunt or liver transplantation (18–21). Contrast enhanced echocardiography is the method of choice for diagnosing IPVDs in the HPS work-up and this technique has allowed clinicians to describe associated abnormalities in cardiac structure and function in this population. Some of the validated parameters predicting HPS include not only markers of hyperdynamic circulation but also of systolic and diastolic dysfunction consistent with cirrhotic cardiomyopathy (22, 23). This makes a detailed investigation into the effects of HPS on the prevalence of CCM an attractive perspective. The purpose of this study was to identify a possible connection between the presence of the hepatopulmonary syndrome and cirrhotic cardiomyopathy as well as their combined effect on morbidity and mortality in a prospective cohort of cirrhotic patients. Patients and methods
Seventy-four consecutive patients with cirrhosis were included in a prospective observational study at our
2548
tertiary referral centre between November 2013 and January 2015. A detailed history including tobacco and alcohol use was obtained from all patients. Use of nonselective betablockers and diuretics was recorded in this study file but drugs were not suspended during measurements. Prior history of cardiovascular or pulmonary conditions, severe anaemia, diagnosed malignancy or active infection, hepatorenal syndrome, diabetes, a history of or treatment for arterial hypertension, cachexia or obesity, stage II or higher hepatic encephalopathy and refusal to sign the informed consent were considered exclusion criteria. Full physical examination was performed and the presence of more than five telangiectasia on the face or torso as well as digital clubbing was noted. Blood work included complete blood count, INR, albumin, creatinine and total bilirubin levels. Child–Pugh–Turcotte and model for end-stage liver disease (MELD) severity staging scores were determined. Peripheral capillary oxygen saturation (SpO2) was approximated by pulse oximetry measurements taken at rest in both the supine and standing positions to reveal orthodeoxia. Arterial blood samples were drawn in the supine position and the partial pressures of oxygen (pO2) and carbon dioxide (pCO2) were used to calculate the age-adjusted alveolar-arterial oxygen gradient (AaPO2). The presence of an oxygenation defect was defined as an AaPO2 value >15 mmHg in patients less than 65 years of age and >20 mmHg in those over 65 (10). N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were determined by use of a standardized commercially available assay (Elecsysâ proBNP II, Roche Diagnostics GmbH, Mannheim) from venous blood drawn before echocardiography. Standard 12-lead electrocardiographies were obtained and interpreted by a cardiologist to exclude ischaemic or conduction abnormalities. The corrected QT interval (QTc) was calculated according to Fridericia’s formula (QTc = QT/RR0.33) and a value of over 440 ms signified a prolonged repolarization interval. Echocardiography protocol
Transthoracic echocardiography was performed using an iE33 ultrasonographer (Philips Medical Systems, Best, the Netherlands) by a single experienced ultrasonographer according to current guidelines and protocols (24, 25). All patients were on stable doses of diuretics or nonselective betablockers for at least 1 week before examination. In the case of ascitic patients, large-volume paracentesis had been performed at least 48 h prior to ultrasonography to achieve a steady-state (26). At the beginning of the ultrasonographic examination 9 ml of agitated saline mixed with 1 ml of air were injected into the cubital vein to reveal right-to-left shunting. IPVDs were diagnosed by the delayed appearance after at least three cardiac cycles of microbubbles Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Voiosu et al.
in the left heart chambers. A difference of less than three cardiac cycles between right and left heart chambers opacification was diagnostic of patent septum defect and represented an exclusion criterion. Two patients of the original cohort were excluded because of atrial septal defect. The diagnosis of HPS was made in patients who had an altered AaPO2 in the presence of echocardiographically proven IPVDs (10). Heart chamber volumes and thickness of ventricular walls including interventricular septum, right ventricle wall and posterior wall thickness were measured according to current recommendations (24). End-diastolic and end-systolic volumes of the left ventricle and ejection fraction of the LV (LVEF) as well as left atrial volume (LAV) indexed to the body surface area were determined by the area-length rule from the apical four chamber view. Longitudinal ventricular function was assessed in the M-mode in apical four-chamber view by measuring the tricuspid and mitral annular plane systolic excursions. Pulmonary artery systolic pressure (PASP) was determined by applying the modified Bernoulli equation to convert the maximal tricuspid regurgitation velocity into its pressure equivalent and then adding this value to the estimated right atrial pressure (midrange values obtained after assessing the size and inspiratory collapse of the inferior vena cava). In the case of seven patients PASP was not quantifiable because of lack of a tricuspid regurgitation jet. Pulmonary artery acceleration time and right ventricular ejection time were measured by pulsed-wave Doppler as described elsewhere (27). Early (E) and late (A) peak diastolic inflow velocities at the mitral valve were measured by pulsed-wave Doppler in the apical four-chamber view with the sample at the tip of the mitral leaflets. The deceleration time (DT) of the E wave as well as the isovolumetric relaxation time of the left ventricle (IVRT) was determined from the same measurement. Tissue Doppler imaging was used to assess early (E’) and late (A’) peak diastolic myocardial velocity at the lateral mitral annulus as well as the mitral annulus systolic velocity. Further variables such as the ratios of E to A wave peak velocities (E/A), lateral E to E’ (E/E’) as well as the ratio of E’ to A’ velocities (E’/A’) were calculated from the initial measurements. According to the diagnostic criteria for cirrhotic cardiomyopathy proposed by the World Congress of Gastroenterology in Toronto in 2005 (9), the presence of either systolic or diastolic dysfunction was considered sufficient for diagnosis. A left ventricle ejection fraction of less than 55% was indicative of systolic dysfunction while diastolic dysfunction was diagnosed in the presence of at least two of three of the following: age-corrected E/A < 1, IVRT > 80 ms and DT > 200 ms. The current recommendations (25) for echocardiographic diagnosis of diastolic dysfunction based on structural and tissue Doppler-derived measurements (LAV ≥ 34 ml/m2 and lateral E’
CIRRHOSIS AND LIVER FAILURE
Prevalence and impact on survival of hepatopulmonary syndrome and cirrhotic cardiomyopathy in a cohort of cirrhotic patients Andrei M. Voiosu1,2, Ioana C. Daha2,3, Theodor A. Voiosu1,2, Bogdan R. Mateescu1,2, Gheorghe A. Dan2,3, icusß2,4, Mihail R. Voiosu1,2 and Mircea M. Diculescu2,5 Cristian R. Ba 1 2 3 4 5
Department of Gastroenterology, Colentina Clinical Hospital, Bucharest, Romania “Carol Davila” University of Medicine, Bucharest, Romania Department of Cardiology, Colentina Clinical Hospital, Bucharest, Romania Department of Internal Medicine, Colentina Clinical Hospital, Bucharest, Romania Department of Gastroenterology and Hepatology, Fundeni Clinical Institute, Bucharest, Romania
Liver Int. 2015; 35: 2547–2555. DOI: 10.1111/liv.12866
Abstract Background & Aims: Extrahepatic complications of cirrhosis increase the risk for decompensation of the liver disease and death. Previous studies show common pathogenetic mechanisms involved in the development of hepatopulmonary syndrome and cirrhotic cardiomyopathy. We aimed to assess the link between these entities and their effect on disease-related patient morbidity and mortality. Methods: Seventy-four consecutive cirrhotic patients without prior history of cardiovascular and pulmonary disease were included in a prospective observational study. Routine blood work, arterial blood gas analysis, pulse oximetry measurements, N-terminal pro-brain natriuretic peptide levels and contrast enhanced echocardiography examination with tissue Doppler imaging were performed in all patients. Patients were followed up for a median of 6 months and disease-related adverse events and death were the main outcomes tested. Statistical analysis was conducted according to the presence of hepatopulmonary syndrome or cirrhotic cardiomyopathy. Results: Hepatopulmonary syndrome was diagnosed in 17 patients (23%) and cirrhotic cardiomyopathy in 30 patients (40.5%). There was no association between the presence of cirrhotic cardiomyopathy and the existence of mild or moderate hepatopulmonary syndrome. No echocardiographic parameters were useful in predicting the presence of hepatopulmonary syndrome. N-terminal pro-brain natriuretic peptide levels and length of QT interval did not aid in diagnosis of cirrhotic cardiomyopathy. Neither entity had significant influence on disease-related outcomes in the follow-up period. Conclusions: Hepatopulmonary syndrome and cirrhotic cardiomyopathy are independent complications arising in cirrhosis and have a limited influence on morbidity and mortality on a pre-liver transplantation population. Keywords cirrhosis – cirrhotic cardiomyopathy – echocardiography – follow-up studies – hepatopulmonary syndrome
The extrahepatic complications of cirrhosis affect short and long-term patient survival. Entities such as cirrhotic cardiomyopathy (CCM) and the hepatopulmonary syn-
drome (HPS) have been found to share some of the same pathogenetic mechanisms in experimental studies but the clinical implications of this link are unknown (1–8).
Abbreviations A’, late diastolic mitral annular velocity; AaPO2, age-adjusted alveolar-arterial oxygen gradient; CCM, cirrhotic cardiomyopathy; DT, deceleration time of E wave; E/A, peak early (E) to late (A) mitral filling velocity ratio; E’, early diastolic mitral annular velocity; HPS, hepatopulmonary syndrome; IPVDs, intrapulmonary vascular dilatations; IVRT, isovolumetric relaxation time; LAV, left atrial volume indexed to body surface area; LVEF, left ventricular ejection fraction; MELD, model for end-stage liver disease; NT-proBNP, N-terminal pro-brain natriuretic peptide; PASP, estimated pulmonary artery systolic pressure; pCO2, partial pressure of carbon dioxide in arterial blood; pO2, partial pressures of oxygen in arterial blood; QTc, rate corrected QT interval; RVW, right ventricle wall thickness; SpO2, peripheral capillary oxygen saturation approximated by pulse oximetry. Correspondence Andrei M. Voiosu, MD, Colentina Clinical Hospital, sos Stefan cel Mare no. 19-21, Bucharest, Romania Tel/Fax: +40213180604 e-mail: [email protected] Handling Editor: Christophe Bureau Received 4 March 2015; Accepted 4 May 2015
Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
2547
Voiosu et al.
Hepatopulmonary syndrome and cirrhotic cardiomyopathy
Key points
• Both hepatopulmonary syndrome and cirrhotic cardiomyopathy are frequent in this prospective cohort but they arise independently of each other. • The diagnostic and prognostic values of a wide variety of debated and established echocardiographic parameters as well as biomarkers are tested. • While most studies focus on liver transplant recipients and the immediate post-operative period, this study describes the natural history of the complications with up to a year of follow-up. • The lack of influence on mortality of these complications of cirrhosis argues for re-evaluation of the MELD exception policy for hepatopulmonary syndrome. Cirrhotic cardiomyopathy is commonly defined by a blunted cardiac contractile response to stress and/or diastolic dysfunction in the context of electromechanical abnormalities but validated diagnostic criteria are still lacking (9). On the other hand, hepatopulmonary syndrome is reliably detected by identifying altered blood oxygenation in the presence of intrapulmonary vascular dilations (IPVDs) in patients suffering from portal hypertension (10). Recently, patients with hepatopulmonary syndrome were granted exception points to increase their transplant waiting list priority thus making diagnosis and early management of this complication of cirrhosis mandatory (11). But while HPS is a known risk factor for decreased survival in cirrhosis (12–14), comparatively less data regarding the relevance of cirrhotic cardiomyopathy are available (15–17). The proven major implication of CCM is its influence on post-procedural evolution in the setting of transjugular intrahepatic portosystemic shunt or liver transplantation (18–21). Contrast enhanced echocardiography is the method of choice for diagnosing IPVDs in the HPS work-up and this technique has allowed clinicians to describe associated abnormalities in cardiac structure and function in this population. Some of the validated parameters predicting HPS include not only markers of hyperdynamic circulation but also of systolic and diastolic dysfunction consistent with cirrhotic cardiomyopathy (22, 23). This makes a detailed investigation into the effects of HPS on the prevalence of CCM an attractive perspective. The purpose of this study was to identify a possible connection between the presence of the hepatopulmonary syndrome and cirrhotic cardiomyopathy as well as their combined effect on morbidity and mortality in a prospective cohort of cirrhotic patients. Patients and methods
Seventy-four consecutive patients with cirrhosis were included in a prospective observational study at our
2548
tertiary referral centre between November 2013 and January 2015. A detailed history including tobacco and alcohol use was obtained from all patients. Use of nonselective betablockers and diuretics was recorded in this study file but drugs were not suspended during measurements. Prior history of cardiovascular or pulmonary conditions, severe anaemia, diagnosed malignancy or active infection, hepatorenal syndrome, diabetes, a history of or treatment for arterial hypertension, cachexia or obesity, stage II or higher hepatic encephalopathy and refusal to sign the informed consent were considered exclusion criteria. Full physical examination was performed and the presence of more than five telangiectasia on the face or torso as well as digital clubbing was noted. Blood work included complete blood count, INR, albumin, creatinine and total bilirubin levels. Child–Pugh–Turcotte and model for end-stage liver disease (MELD) severity staging scores were determined. Peripheral capillary oxygen saturation (SpO2) was approximated by pulse oximetry measurements taken at rest in both the supine and standing positions to reveal orthodeoxia. Arterial blood samples were drawn in the supine position and the partial pressures of oxygen (pO2) and carbon dioxide (pCO2) were used to calculate the age-adjusted alveolar-arterial oxygen gradient (AaPO2). The presence of an oxygenation defect was defined as an AaPO2 value >15 mmHg in patients less than 65 years of age and >20 mmHg in those over 65 (10). N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were determined by use of a standardized commercially available assay (Elecsysâ proBNP II, Roche Diagnostics GmbH, Mannheim) from venous blood drawn before echocardiography. Standard 12-lead electrocardiographies were obtained and interpreted by a cardiologist to exclude ischaemic or conduction abnormalities. The corrected QT interval (QTc) was calculated according to Fridericia’s formula (QTc = QT/RR0.33) and a value of over 440 ms signified a prolonged repolarization interval. Echocardiography protocol
Transthoracic echocardiography was performed using an iE33 ultrasonographer (Philips Medical Systems, Best, the Netherlands) by a single experienced ultrasonographer according to current guidelines and protocols (24, 25). All patients were on stable doses of diuretics or nonselective betablockers for at least 1 week before examination. In the case of ascitic patients, large-volume paracentesis had been performed at least 48 h prior to ultrasonography to achieve a steady-state (26). At the beginning of the ultrasonographic examination 9 ml of agitated saline mixed with 1 ml of air were injected into the cubital vein to reveal right-to-left shunting. IPVDs were diagnosed by the delayed appearance after at least three cardiac cycles of microbubbles Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Voiosu et al.
in the left heart chambers. A difference of less than three cardiac cycles between right and left heart chambers opacification was diagnostic of patent septum defect and represented an exclusion criterion. Two patients of the original cohort were excluded because of atrial septal defect. The diagnosis of HPS was made in patients who had an altered AaPO2 in the presence of echocardiographically proven IPVDs (10). Heart chamber volumes and thickness of ventricular walls including interventricular septum, right ventricle wall and posterior wall thickness were measured according to current recommendations (24). End-diastolic and end-systolic volumes of the left ventricle and ejection fraction of the LV (LVEF) as well as left atrial volume (LAV) indexed to the body surface area were determined by the area-length rule from the apical four chamber view. Longitudinal ventricular function was assessed in the M-mode in apical four-chamber view by measuring the tricuspid and mitral annular plane systolic excursions. Pulmonary artery systolic pressure (PASP) was determined by applying the modified Bernoulli equation to convert the maximal tricuspid regurgitation velocity into its pressure equivalent and then adding this value to the estimated right atrial pressure (midrange values obtained after assessing the size and inspiratory collapse of the inferior vena cava). In the case of seven patients PASP was not quantifiable because of lack of a tricuspid regurgitation jet. Pulmonary artery acceleration time and right ventricular ejection time were measured by pulsed-wave Doppler as described elsewhere (27). Early (E) and late (A) peak diastolic inflow velocities at the mitral valve were measured by pulsed-wave Doppler in the apical four-chamber view with the sample at the tip of the mitral leaflets. The deceleration time (DT) of the E wave as well as the isovolumetric relaxation time of the left ventricle (IVRT) was determined from the same measurement. Tissue Doppler imaging was used to assess early (E’) and late (A’) peak diastolic myocardial velocity at the lateral mitral annulus as well as the mitral annulus systolic velocity. Further variables such as the ratios of E to A wave peak velocities (E/A), lateral E to E’ (E/E’) as well as the ratio of E’ to A’ velocities (E’/A’) were calculated from the initial measurements. According to the diagnostic criteria for cirrhotic cardiomyopathy proposed by the World Congress of Gastroenterology in Toronto in 2005 (9), the presence of either systolic or diastolic dysfunction was considered sufficient for diagnosis. A left ventricle ejection fraction of less than 55% was indicative of systolic dysfunction while diastolic dysfunction was diagnosed in the presence of at least two of three of the following: age-corrected E/A < 1, IVRT > 80 ms and DT > 200 ms. The current recommendations (25) for echocardiographic diagnosis of diastolic dysfunction based on structural and tissue Doppler-derived measurements (LAV ≥ 34 ml/m2 and lateral E’
