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CARDIO-HEPATOLOGY
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CARDIO-HEPATOLOGY
Connections Between Hepatic and
Cardiovascular Disease
Edited by
TATSUNORI TANIGUCHI
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
SAMUEL S. LEE
Liver Unit, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted
herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes
in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods,
compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the
safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or
damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods,
products, instructions, or ideas contained in the material herein.
ISBN: 978-0-12-817394-7
For Information on all Academic Press publications
visit our website at
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Editorial Project Manager: Franchezca A. Cabural
Production Project Manager: Punithavathy Govindaradjane
Cover Designer: Miles Hitchen
Typeset by MPS Limited, Chennai, India
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Dedication
To my parents, wife, and children.
Tatsunori Taniguchi
To my proudest legacy, my sons Simon, Jack, and Eric.
Samuel S. Lee
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Contents
List of contributors xiii
Preface xv
I
Liver and heart
1. The liverheart relationship: a history 3
HONGQUN LIU AND SAMUEL S. LEE
Introduction 3
The ancient world: east and west 3
The medieval era 5
The modern era 8
The liver in heart failure 8
The heart in liver failure 8
References 8
2. Nonalcoholic fatty liver disease and
cardiovascular disease 11
MASAHIRO KOSEK I
Introduction 11
The definition of nonalcoholic fatty liver disease/nonalcoholic
steatohepatitis 11
Association between nonalcoholic fatty liver disease/
nonalcoholic steatohepatitis and cardiovascular disease 12
Dyslipidemia as causative factors for nonalcoholic fatty liver
disease/nonalcoholic steatohepatitis and cardiovascular
disease 13
Possible underlining molecular mechanisms between
nonalcoholic steatohepatitis and atherosclerosis 13
Association between NAFLD/hepatic fibrosis and cardiac
dysfunction 14
Conclusion 15
References 15
3. Pathophysiologic changes in chronic
heart failure affecting drug pharmacokinetics 17
ROGER K. VERBEECK AND BONIFASIUS S. SINGU
Introduction 17
Fundamental clinical pharmacokinetic principles 18
Clearance concepts 18
Hepatic clearance and oral bioavailability 19
Renal clearance 21
Volume of distribution 22
Half-life 22
Pathophysiological changes affecting pharmacokinetics in
patients with chronic heart failure 23
Intestinal permeability 23
Hepatic clearance 23
Intravenous administration of high hepatic extraction
ratio drugs 24
Oral administration 25
Renal clearance 26
Volume of distribution 26
Pharmacotherapeutic implications: general
recommendations 27
Conclusion 28
References 28
4. Drugs at the crossroads of heart and liver 31
P. TIMOTHY POLLAK AND JUAN GONZALEZ ABRALDES
Introduction 31
Part 1: amiodarone 32
Historical perspective 32
Why amiodarone has not been replaced 32
Pharmacokinetics: the secret to understanding
amiodarone 34
Pharmacokinetics: the determinant of drug exposure 34
Pharmacokinetics: the untenable concept of total
cumulative dose of amiodarone 35
Amiodarone: separating direct and indirect toxicity 36
Amiodarone: lessons from pulmonary toxicity when
considering hepatotoxicity 37
Timelines for amiodarone hepatotoxicity 39
Amiodarone: a drug outside the comfort zone of
mainstream therapeutics 39
Amiodarone hepatotoxicity: plausible pathogenesis 40
Amiodarone hepatotoxicity: clinical picture and
histological findings 41
Amiodarone hepatotoxicity: diagnosis 42
How toxic is amiodarone to the liver? 43
Amiodarone: effects on hepatic metabolism and
other drugs 44
Amiodarone hepatotoxicity: the challenge of attribution 45
Monitoring hepatic function in patients receiving
amiodarone 46
Therapy for hepatotoxicity 47
Amiodarone: principles of clinical pharmacology 47
Conclusions 48
Part 2: beta-blockers 49
Introduction 49
Pathophysiology of portal hypertension and cirrhosis stages 49
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Clinical pharmacology of nonselective beta-blockers in
portal hypertension related to cirrhosis 49
Clinical contexts for the use of nonselective beta-blockers 52
The concept of a therapeutic window of nonselective
beta-blockers in decompensated cirrhosis 55
Summary and current recommendations 57
References 58
5. Obstruction of the liver circulation 65
XUEFENG LUO, OANA NICOAR
˘
A-FARC
˘
AU, MARTA MAGAZ,
FABIAN BETANCOURT, GUILLEM SOY, ANNA BAIGES, FANNY TURON,
VIRGINIA HERNA
´
NDEZ-GEA AND JUAN CARLOS GARCI
´
A-PAGA
´
N
Introduction 65
BuddChiari syndrome 65
Risk factors 65
Natural history 67
Staging and prognosis 68
Treatment and management of complications 68
Stepwise treatment strategy 68
Anticoagulation 68
Thrombolysis 69
Recanalization 69
Transjugular intrahepatic portosystemic shunt 70
Liver transplantation 71
Noncirrhotic nontumoral portal vein thrombosis 71
Risk factors 71
Systemic risk factors 71
Local factors 71
Diagnosis and staging 72
Natural history 72
Treatment of recent nontumoral portal vein thrombosis 73
Anticoagulation 73
Interventional treatment 74
Surgery 74
Treatment of underlying causes 74
Treatment of chronic nontumoral portal vein thrombosis 74
Management of complications of portal hypertension 74
Anticoagulation 75
Transjugular intrahepatic portosystemic shunt 75
Management of portal biliopathy 75
Sinusoidal obstruction syndrome 76
Incidence 76
Pathology 76
Risk factors 76
Diagnosis 76
Imaging studies 77
Biopsy 78
Hepatic venous pressure gradient 78
Baltimore and Seattle criteria 78
Nanjing criteria 79
European society for blood and marrow transplantation 79
Assessing severity 80
Preventive measures 80
Nonpharmacologic prevention 80
Pharmacologic prevention 81
Treatment 82
Supportive therapy 82
General 82
Defibrotide 82
Transjugular intrahepatic portosystemic shunt 82
Hepatic artery thrombosis 83
Etiology and risk factors 83
Surgical cause 83
Portal vein thrombosis 83
Infections 83
Intra-arterial liver-directed therapy 83
Coagulation abnormalities 84
Splenic artery steal syndrome 84
Pediatric liver transplant 84
Clinical presentation 84
Treatment 84
Acknowledgment 85
Conflict of interest statement 85
Financial support 85
References 85
II
Hepatobiliary system in heart failure
6. Epidemiology of liver diseases in heart failure 95
YASSER FOUAD, ROFIDA KHALIFA AND DINA ATTIA
Introduction 95
The liver diseases in patients with heart failure 95
Etiological factors of heart failure associated with hepatic
disorders 96
Hepatic consequences in cardiac patients 96
Liver diseases causing heart failure 99
Diseases leading to heart failure and affecting the liver 100
Infections 100
Congenital causes 101
References 101
7. Cardio-hepatology: liver function tests in
heart failure 105
ATSUSHI OKADA
Liver function tests 105
Blood supply of the liver and its anatomy 105
Pathophysiology of abnormal liver function tests in heart
failure 106
Bilirubin metabolism in the liver 107
Association between abnormal liver function tests and
impaired hemodynamics 107
Liver function tests and prognosis in heart failure 108
Total and direct bilirubin 110
Transaminases (aspartate aminotransferase and alanine
aminotransferase) 110
Gamma-glutamyltranspeptidase and alkaline
phosphatase 110
Prothrombin time international normalized ratio 110
Albumin, cholinesterase, and total protein 111
Hepatic fibrotic markers in heart failure 111
References 111
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8. Prognostic value of liver assessment
(including liver stiffness measurement) in
cardiovascular diseases 115
YUKI SAITO AND TATSUNORI TANIGUCHI
Introduction 115
Heart failure and liver impairment 115
Liver disease is associated with poor outcome of heart failure 116
Liver disease is associated with poor outcomes of
cardiovascular diseases 116
Liver function tests and prognosis of HF 117
Liver function tests in HF 117
Prevalence and prognostic value of abnormal liver
function in chronic heart failure 117
Prevalence and prognostic relevance of abnormal
liver chemistry in acute decompensated heart failure 117
Abnormal liver synthetic function and heart failure 118
Prognostic relevance of markers of hepatic and renal
dysfunction in heart failure 118
Markers of hepatic fibrosis and prognosis of HF 118
Serologic markers of hepatic fibrosis in HF 118
Liver specific micro-RNAs in heart failure 119
Imaging markers of hepatic fibrosis in HF 119
Summary 121
References 121
9. Passive liver congestion and hypoxic
hepatitis 123
SHAZ IQBAL AND PO-HUNG CHEN
Introduction 123
Passive liver congestion 123
Hepatic circulation 123
Mechanism of injury 124
Clinical manifestations 124
Imaging findings 124
Pathologic findings 125
Management 125
Prognosis 126
Summary 126
Mechanism of injury 127
Clinical manifestations 127
Imaging findings 128
Pathologic findings 128
Management 129
Prognosis 129
Summary 130
Conclusion 130
References 130
10. Histopathology of the liver in heart failure 133
PARADIS VALE
´
RIE
Introduction 133
Natural history 133
Pathological analysis 133
Pathogenesis 136
Conclusion 137
References 137
11. The Fontan procedure and liver disease 139
MASANARI KUWABARA AND KOICHIRO NIWA
Introduction 139
Fontan procedure 139
Physiology and prevalence of Fontan-associated liver disease 140
Examination to detect Fontan-associated liver disease 141
Recommendation 141
References 141
III
Cardiovascular system in liver failure
12. Sepsis and the liver 145
RICHARD MOREAU, JAVIER FERNANDEZ, MARIO ALTIERI AND
VICENTE ARROYO
Introduction 145
Sepsis in the general population 145
Pathophysiology of organ dysfunction during the early
phase of sepsis 145
The liver as a victim of deregulated host response to
infection 146
Infection-induced protective responses originating in the
liver 149
Sepsis in patients with cirrhosis 154
Inflammatory phenotype of sepsis in acute-on-chronic liver
failure 154
Clinical features and management of sepsis syndromes
in patients with cirrhosis 157
Spontaneous bacterial peritonitis 157
Bacterial infections unrelated to SBP 161
Management of septic shock 162
Prevention of bacterial infections 162
Fungal infections 162
Conclusions 162
Acknowledgments 162
References 162
13. Bleeding and thrombosis in cirrhosis 165
TON LISMAN
Introduction to hemostasis 165
Platelets 165
Coagulation 166
Fibrinolysis 167
Hemostatic changes in liver diseases 167
Pitfalls of routine diagnostic tests of hemostasis 168
The concept of rebalanced hemostasis 171
Are liver patients really bleeders? 171
Laboratory changes in hemostasis 172
Development of the concept of rebalanced hemostasis 174
Hemostatic balance in different types and severities of liver
diseases 175
Compensated cirrhosis 175
Decompensated cirrhosis and acute-on-chronic liver
failure 176
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