2018 liver anesthesiology and critical care medicine 2nd ed

Elnaggar, MD Department of Surgery, Columbia University Medical Center, New York, NY, USA Emmanuel Weiss, MD, PhD Department of Anesthesiology and Critical Care Medecine, Beaujon, HUPN

Liver Anesthesiology and Critical Care Medicine

Gebhard Wagener

Editor

Liver Anesthesiology and Critical Care

Medicine

Second Edition

ISBN 978-3-319-64297-0 ISBN 978-3-319-64298-7 (eBook)

https://doi.org/10.1007/978-3-319-64298-7

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work, and to my parents, who contributed so much to who I am.

Liver transplantation has made remarkable progress in the 48 years since the first human liver transplant, and especially in the last 30 years, since the intro-duction of cyclosporine made long-term survival after liver transplantation feasible

A procedure that was initially untested and experimental became routine and is now the accepted treatment for end-stage liver disease in many parts of the world About 6000 liver transplants are done in the United States every year, and graft and patient survival is excellent We are able to administer transplants to children, do living related and split liver transplants, and only the shortage of organs limits the expansion of our field

This progress is not only due to advances in immunosuppression, surgical techniques, or organ preservation but also due to improvements in anesthetic techniques Anesthesia care initially provided by few experts in a small num-ber of centers proliferated and is now often standardized and protocolized Advances in anesthesiology enabled the development of surgical techniques such as caval cross-clamp or partial liver transplantation There are few pro-cedures in which the close cooperation of surgeon and anesthesiologist is as essential for the success of the surgery and liver (transplant) surgery would have never flourished as it did without the teamwork and partnership between anesthesiologists and surgeons

Within the last 20 years there has been tremendous progress in clinical research of liver transplant anesthesia that aims to reduce blood transfusions, augment organ preservation, and improve overall outcome Anesthesia for liver surgery has made a similar astounding progress and now extensive resections are conceivable that would have been impossible before Postoperative critical care medicine as a continuation of the intraoperative care is now frequently in the hands of anesthesiologists and intensivists spe-cialized in hepatic intensive care, reflecting the increasing knowledge in this field

This book aims to summarize the progress in liver anesthesiology and critical care medicine of the last 20 years and serves as a guide to those who care for patients undergoing liver transplantation and liver resections The authors are the leaders in the field of liver anesthesiology and critical care in Europe, Asia, and the United States The foundation of this book is the increasing fund of knowledge gained through clinical research as well as through the extensive clinical experience of the authors that they share with the readers

Foreword to the First Edition

This textbook provides the necessary background to understand the

com-plexity of the liver and its pathophysiology It summarizes the elaborate

logis-tics involved in donor and recipient matching in Europe and the United States

and then describes the routine intraoperative management of liver transplant

recipients and patients undergoing hepatic resections It addresses common

comorbidities and complications and how they may affect the preoperative

work-up and intraoperative management The postoperative critical care

sec-tion describes the routine care after liver transplantasec-tion and resecsec-tion as well

as diagnosis and management of possible complications including pain

management

This book aims to summarize our current knowledge of liver

anesthesiol-ogy and critical care It will serve as a reference for those who routinely care

for patients with liver disease Those new to our exciting field will gain

suf-ficient knowledge to successfully address many of the complex issues that

may arise during liver anesthesiology and critical care medicine To those

who have extensive experience in the care of patients undergoing liver

(trans-plant) surgery this book will serve as an authoritative reference and enable an

in-depth immersion into the exciting field of hepatic anesthesiology and

criti-cal care medicine

Pittsburgh, PA, USA Thomas E Starzl, MD, PhD (1926–2017)

Liver transplantation and liver surgery have made enormous strides in the last

20 years It has been transformed from an often heroic operation requiring massive amounts of blood transfusions to almost routine surgery with little blood loss in spite of increasing recipient morbidity This advancement is reflected in improved long-term mortality rates in the face of preferentially allocating more marginal organs to sicker recipients

Many little steps and advances are responsible for this achievement, not least improvements of anesthetic techniques and postoperative care These little steps may not be immediately obvious but were necessary to accomplish such a progress Clinical and preclinical research in liver anesthesiology and critical care medicine in the last 10 years has thrived, and a new generation of anesthesiologists and intensive care physicians is willing to scrutinize their clinical practice using clinical research tools instead of relying only on expe-rience This has created a fascinating and productive interaction within the small group of anesthesiologists and intensivists who care for these severely sick patients

This book summarizes their current knowledge by bringing together the leading experts of our subspecialty It not only condenses a large amount of clinical research but also includes opinions and experiences when evidence is insufficient

It is an in-depth review of the field and presents the current best edge It aims to be the definitive resource of liver anesthesiology and critical care medicine Experienced and busy practitioners will find essential infor-mation to manage complex conditions of liver disease The novice anesthesi-ologist or resident will be able to use this book as a thorough and comprehensive introduction to our field and rapidly gain extensive knowledge as well as obtain practical advice for those complex and scary situations that can occur

knowl-so frequently during liver transplantation

This book provides a comprehensive review of the pathophysiology of liver disease, pharmacology, immunology, and its implications for the anes-thesiologist and intensivist Anesthesiologic and postoperative care of liver transplant recipients requires a thorough appreciation of the intricacies of liver disease and its complications Extrahepatic manifestations of liver dis-ease are addressed in chapters separated by organ systems Routine manage-ment as well as common intra- and postoperative complications are described

in detail to provide the knowledge required to care for these patients

Preface to the First Edition

Liver transplantation is expanding internationally and a large body of

work and experience originates from centers in Europe and Asia Experts

from the United States, Europe, and Asia have contributed to this book to give

a global perspective of liver transplant anesthesiology

A separate section reviews the anesthetic and postoperative management

of patients undergoing liver resection New surgical approaches have allowed

us to perform more extensive and intricate resections that pose new

chal-lenges to the anesthesiologist and intensivists Surgical techniques and their

physiologic repercussions are described in detail, and management strategies

for routine as well as complex cases and their possible complications are

offered

We hope this book will alleviate the apprehension often associated with

caring for these sick patients and encourage many readers to engage in liver

anesthesiology and critical care medicine

New York, NY, USA Gebhard Wagener, MD

The first edition of this book was published six years ago Since then liver anesthesiology and critical care medicine has rapidly evolved in pace with new developments in surgery and transplantation Laparoscopic and laparoscopic- assisted liver surgery that was rarely used before is now routine

in many centers and its use for living donor hepatectomies will greatly increase acceptance of liver graft donation Anesthetic management is very different for this type of surgery, and anesthesiologists need to understand the risks and benefits of these new technologies Left lobe living liver donation for adult recipients is now frequently used and will expand the potential donor pool and reduce the risk for morbidities for the donor This would not have been possible without a better understanding of the regulation of liver blood flow and improved treatment for early graft dysfunction in the ICU Pain procedures have evolved and the use of novel, ultrasound-guided regional analgesic techniques improved patient comfort and recovery

The advent of highly successful treatment of hepatitis C with new antiviral drugs may one day reduce the number of liver transplants However in the last six years the need for organs kept rising, resulting in lower quality grafts assigned to sicker recipients This greatly complicates the anesthetic and critical care management of these patients

Liver anesthesiology and critical care medicine has matured into a specialty in its own right with national and international societies and meet-ings The anesthesiology section of the International Liver Transplant Society continues to thrive with an annual educational meeting and an extraordinarily instructive and useful educational website (https://ilts.org/education/) Independent subspecialty societies such at the Liver Intensive Care Group of Europe (LICAGE) and the newer Society for the Advancement

sub-of Transplant Anesthesia (SATA) in the United States meet regularly to share advances in the field, develop guidelines, and facilitate scientific prog-ress Many centers now offer fellowships in liver transplant anesthesiology and societies are currently developing fellowship guidelines to potentially gain approval by the Accreditation Council for Graduate Medical Education (ACGME) in the United States

To reflect these remarkable changes in our field, all chapters in this book have been revised for this edition We also added multiple new chapters, for example, about chronic liver disease, regulation of liver blood flow, evalua-tion of liver function, and evidence in liver anesthesiology Among others the

Preface to the Second Edition

chapter on pain underwent a major revision and now includes detailed

description of regional analgesic techniques

We hope that this book remains a useful companion for those who start in

this exciting field as well for the experienced liver anesthesiologist and

intensivist

New York, NY, USA Gebhard Wagener, MD

I sincerely thank the authors of this book for their excellent contributions They have spent many hours of diligent and hard work creating delightful, intelligent, and insightful chapters that were a pleasure to read and edit

I would also like to thank their families for the time the authors missed with them while writing these chapters Dr Jean Mantz, one of the authors and a true leader in our field, died last year; I feel privileged to have known such an outstanding doctor

This book would not have been possible without the encouragement, port, and advice of Dr Margaret Wood who has unwaveringly supported me throughout my career and all my colleagues and friends at Columbia University Medical Center I am immensely grateful to all of you

sup-I would further like to thank my editors from Springer Science + Business Media, Asja Parrish, Rebekah Collins, and Saanthi Shankhararaman, who have been indefatigable and immensely patient with me Thank you

Thank you, Taryn Lai and Nina Yoh for your help, insights and advice with so many aspects of this book (and life!) Also thank you to Tara Richter-Smith and Erin Hittesdorf who have reviewed and corrected syntax, style and references of many of these chapters and were essential in finishing this book

I am sincerely grateful to my colleagues, residents, students, and nurses that I have had the pleasure to work with for many years and, most importantly,

to my patients, who taught me so much about disease, life, and death

Acknowledgments

Part I Physiology, Pathophysiology and Pharmacology

of Liver Disease

1 Physiology and Anatomy of the Liver 3

Teresa Anita Mulaikal and Jean C Emond

2 Chronic Liver Failure and Hepatic Cirrhosis 21

Lauren Tal Grinspan and Elizabeth C Verna

Andrew Slack, Brian J Hogan, and Julia Wendon

4 The Splanchnic and Systemic Circulation in Liver Disease 63

Nina T Yoh and Gebhard Wagener

5 Drug Metabolism in Liver Failure 69

Simon W Lam

6 Evaluation of Liver Function 79

Vanessa Cowan

Part II Anesthesiology for Liver Transplantation

7 History of Liver Transplantation 89

John R Klinck and Ernesto A Pretto

8 Recipient and Donor Selection and Transplant Logistics:

The European Perspective 101

Gabriela A Berlakovich and Gerd R Silberhumer

9 Recipient and Donor Selection and Transplant

Logistics: The US Perspective 109

Ingo Klein, Johanna Wagner, and Claus U Niemann

10 Surgical Techniques in Liver Transplantation 121

Holden Groves and Juan V del Rio Martin

11 Intraoperative Monitoring 135

Claus G Krenn and Marko Nicolic

Contents

David Hovord, Ruairi Moulding, and Paul Picton

14 Hemodynamic Changes, Cardiac Output Monitoring

and Inotropic Support 163

Anand D Padmakumar and Mark C Bellamy

15 Coagulopathy: Pathophysiology, Evaluation,

and Treatment 173

Bubu A Banini and Arun J Sanyal

16 Physiology, Prevention, and Treatment

of Blood Loss During Liver Transplantation 195

Simone F Kleiss, Ton Lisman, and Robert J Porte

17 The Marginal Liver Donor and Organ

Preservation Strategies 207

Abdulrhman S Elnaggar and James V Guarrera

18 Pediatric Liver Transplantation 221

Philipp J Houck

19 Combined Solid Organ Transplantation

Involving the Liver 233

Geraldine C Diaz, Jarva Chow, and John F Renz

20 Liver Transplantation for the Patient

with High MELD 247

Cynthia Wang and Randolph Steadman

21 Perioperative Considerations for Transplantation

in Acute Liver Failure 257

C P Snowden, D M Cressey, and J Prentis

22 The Patient with Severe Co-morbidities: Renal Failure 269

Andrew Disque and Joseph Meltzer

23 The Patient with Severe Co-morbidities:

Cardiac Disease 281

Shahriar Shayan and Andre M De Wolf

24 Pulmonary Complications of Liver Disease 293

Mercedes Susan Mandell and Masahiko Taniguchi

25 The Patient with Severe Co-morbidities: CNS Disease

and Increased Intracranial Pressure 307

Prashanth Nandhabalan, Chris Willars, and Georg Auzinger

Contents

Part III Anesthesiology for Liver Surgery

26 Hepatobiliary Surgery: Indications, Evaluation and Outcomes 333

Jay A Graham and Milan Kinkhabwala

27 Liver Resection Surgery: Anesthetic Management, Monitoring, Fluids and Electrolytes 349

Emmanuel Weiss, Jean Mantz, and Catherine Paugam-Burtz

28 Anesthetic Aspects of Living Donor Hepatectomy 367

Paul D Weyker and Tricia E Brentjens

29 Complications of Liver Surgery 377

Oliver P F Panzer

30 The Patient with Liver Disease Undergoing Non-hepatic Surgery 389

Katherine Palmieri and Robert N Sladen

Part IV Critical Care Medicine for Liver Transplantation

31 Routine Postoperative Care After Liver Transplantation 415

Jonathan Hastie and Vivek K Moitra

32 Immunosuppression 431

Enoka Gonsalkorala, Daphne Hotho, and Kosh Agarwal

33 Acute Kidney Injury After Liver Transplantation 445

Raymond M Planinsic, Tetsuro Sakai, and Ibtesam A Hilmi

34 Early Graft Failure 451

Avery L Smith, Srinath Chinnakotla, and James F Trotter

35 Sepsis and Infection 455

Fuat Hakan Saner

36 Respiratory Failure and ARDS 469

James Y Findlay and Mark T Keegan

Part V Critical Care Medicine for Liver Surgery

37 Postoperative Care of Living Donor for Liver Transplant 485

Sean Ewing, Tadahiro Uemura, and Sathish Kumar

38 Liver Surgery: Early Complications—Liver Failure, Bile Leak and Sepsis 497

Albert C Y Chan and Sheung Tat Fan

39 Pain Management in Liver Transplantation 507

Paul Weyker, Christopher Webb, and Leena Mathew

Index 525

Kosh Agarwal, MD Institute of Liver Studies, Kings College Hospital,

London, UK

Georg Auzinger, EDIC, AFICM Department of Critical Care/Institute of

Liver Studies, King’s College Hospital, London, UK

Bubu A Banini, MD, PhD Division of Gastroenterology and Hepatology,

Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA

Mark C Bellamy, MA, MB, BS, FRCP(Edin), FRCA, FFICM St James’s

University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, West Yorkshire, UK

Gabriela A Berlakovich, MD, FEBS Division of Transplantation,

Department of Surgery, Medical University of Vienna, Vienna, Austria

Tricia E Brentjens, MD Department of Anesthesiology, Columbia

University Medical Center, New York, NY, USA

Catherine Paugam-Burtz, MD, PhD Department of Anesthesiology and

Critical Care Medecine, Beaujon, HUPNVS, Assistance Publique-Hôpitaux

de Paris (AP-HP), Paris, France

University Paris VII, Paris Diderot, Paris, France

Ryan M Chadha, MD Anesthesiology and Perioperative Medicine, Mayo

Clinic Florida, Jacksonville, FL, USA

Albert C Y Chan, MBBS, FRCS Department of Surgery, The University

of Hong Kong, Queen Mary Hospital, Hong Kong, People’s Republic of China

Srinath Chinnakotla, MD Department of Surgery, University of Minnesota,

Minneapolis, MN, USA

Jarva Chow, MD Department of Anesthesiology, Loyola University,

Chicago, IL, USA

Vanessa Cowan, MD Transplant Institute, Beth Israel Deaconess Medical

Center, Boston, MA, USA

Contributors

D M Cressey, BSc (Hons), MBBS, FRCA Department of Perioperative

Medicine and Critical Care, Freeman Hospital, Newcastle Upon Tyne, UK

Geraldine C Diaz, DO Department of Anesthesiology, University of

Illinois at Chicago, Chicago, IL, USA

Andrew Disque, MD Department of Anesthesiology and Perioperative

Medicine, David Geffen School of Medicine, University of California at Los

Angeles, Los Angeles, CA, USA

Abdulrhman S Elnaggar, MD Department of Surgery, Columbia

University Medical Center, New York, NY, USA

Emmanuel Weiss, MD, PhD Department of Anesthesiology and Critical

Care Medecine, Beaujon, HUPNVS, Assistance Publique-Hôpitaux de Paris

(AP-HP), Paris, France

University Paris VII, Paris Diderot, Paris, France

Jean C Emond, MD Department of Surgery, Columbia University Medical

Center, New York, NY, USA

Sean Ewing, MD Department of Anesthesiology, University of Michigan

Health System, Ann Arbor, MI, USA

Sheung Tat Fan, MD, PhD, DSc Liver Surgery Centre, Hong Kong

Sanatorium and Hospital, Hong Kong, People’s Republic of China

James Y Findlay, MB, ChB, FRCA Department of Anesthesiology and

Critical Care Medicine, Mayo Clinic, Rochester, MN, USA

Enoka Gonsalkorala, MD Institute of Liver Studies, Kings College

Hospital, London, UK

Jay A Graham, MD Department of Surgery, Albert Einstein College of

Medicine, Bronx, NY, USA

Lauren Tal Grinspan, MD, PhD Department of Medicine, Columbia

University Medical Center, New York, NY, USA

Holden Groves, MD, MS Columbia University Medical Center, New York,

NY, USA

Department of Anesthesiology, Columbia University Medical Center, New

York, NY, USA

James V Guarrera, MD, FACS Division of Liver Transplant and

Hepatobiliary Surgery, Rutgers New Jersey Medical School, University

Hospital, New York, NJ, USA

Jonathan Hastie, MD Department of Anesthesiology, Cardiothoracic

Intensive Care Unit, Columbia University Medical Center, New York, NY,

USA

Ibtesam A Hilmi, MB, ChB Department of Anesthesiology, University of

Pittsburgh Medical Center, Pittsburgh, PA, USA

Brian J Hogan, BSc, MBBS, MRCP, FEBTM, FFICM Institute of Liver

Studies, Kings College London, Kings College Hospital, London, UK

Daphne Hotho, MD Institute of Liver Studies, Kings College Hospital,

London, UK

Philipp J Houck, MD Department of Anesthesiology, Columbia University

Medical Center, New York, NY, USA

David Hovord, BA, MB, BChir, FRCA Department of Anesthesiology,

University of Michigan Medical School, Ann Arbor, MI, USA

Jean Mantz, MD, PhD Department of Anesthesiology and Critical Care

Medicine, HEGP, APHP, Paris, France

Mark T Keegan, MB, MRCPI, MSc, D ABA Department of Anesthesiology

and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA

Milan Kinkhabwala, MD Department of Surgery, Albert Einstein College

of Medicine, Bronx, NY, USA

Ingo Klein Department of General- and Visceral-, Vascular and Pediatric

Surgery, University of Wuerzburg, Medical Center, Wuerzburg, Germany

Simone F Kleiss, MD Section of Hepato-Pancreato-Biliary Surgery and

Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

John R Klinck, MD, FRCA, FRCPC Division of Perioperative Care,

Cambridge University Hospitals, Cambridge, UK

Claus G Krenn, MD Department of Anaesthesia, General Intensive Care

and Pain Medicine, Medical University of Vienna, General Hospital Vienna, Vienna, Austria

Simon W Lam, PharmD, FCCM Cleveland Clinic, Cleveland, OH, USA Ton Lisman, PhD Section of Hepato-Pancreato-Biliary Surgery and Liver

Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

Mercedes Susan Mandell, MD, PhD Department of Anesthesiology,

University of Colorado, Aurora, CO, USA

Leena Mathew, MD Department of Anesthesiology, Columbia University

Medical Center, New York, NY, USA

Joseph Meltzer, MD Division of Critical Care, Department of Anesthesiology

and Perioperative Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

Contributors

Vivek K Moitra, MD Department of Anesthesiology, Surgical Intensive

Care Unit and Cardiothoracic Intensive Care Unit, Columbia University,

College of Physicians and Surgeons, New York, NY, USA

Ruairi Moulding, BSc, MBBS, FRCA Department of Anaesthesia,

Musgrove Park Hospital, Taunton, UK

Teresa Anita Mulaikal, MD Division of Cardiothoracic and Critical Care

Medicine, Columbia University Medical Center, New York, NY, USA

Prashanth Nandhabalan, MRCP, FRCA, FFICM, EDIC Department of

Critical Care/Institute of Liver Studies, King’s College Hospital, London, UK

Marko Nicolic, MD Department of Anaesthesia, General Intensive Care

and Pain Medicine, Medical University of Vienna, General Hospital Vienna,

Vienna, Austria

Claus U Niemann, MD Anesthesia and Perioperative Care, University of

California San Francisco, San Francisco, CA, USA

Anand D Padmakumar, MBBS, FRCA, EDIC, FFICM St James’s

University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, West

Yorkshire, UK

Katherine Palmieri, MD, MBA Department of Anesthesiology, The

University of Kansas Health System, Kansas City, KS, USA

Oliver P F Panzer, MD Department of Anesthesiology, Columbia

University Medical Center, New York, NY, USA

Paul Picton, MB, ChB, MRCP, FRCA Department of Anesthesiology,

University of Michigan Medical School, Ann Arbor, MI, USA

Raymond M Planinsic, MD Department of Anesthesiology, University of

Pittsburgh Medical Center, Pittsburgh, PA, USA

Robert J Porte, MD, PhD Section of Hepato-Pancreato-Biliary Surgery

and Liver Transplantation, Department of Surgery, University of Groningen,

University Medical Center Groningen, Groningen, The Netherlands

J Prentis, MBBS, FRCA Department of Perioperative Medicine and

Critical Care, Freeman Hospital, Newcastle Upon Tyne, UK

Ernesto A Pretto, MD, MPH Division of Transplant and Vascular

Anesthesia, University of Miami Leonard M Miller School of Medicine,

Jackson Memorial Hospital, Miami, FL, USA

John F Renz, MD, PhD Section of Transplantation, Department of Surgery,

University of Chicago, Chicago, IL, USA

Juan V del Rio Martin, MD, FASTS Hospital Auxilio Mutuo, San Juan,

PR, USA

Tetsuro Sakai, MD, PhD, MHA Department of Anesthesiology, University

of Pittsburgh Medical Center, Pittsburgh, PA, USA

Fuat Hakan Saner, MD Department of General-, Visceral- and Transplant

Surgery, Medical Center University Essen, Essen, Germany

Arun J Sanyal, MD, MBBS Division of Gastroenterology and Hepatology,

Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA

Sathish Kumar, MBBS Department of Anesthesiology, University of

Michigan, Ann Arbor, MI, USA

Shahriar Shayan, MD Department of Anesthesiology, Northwestern

Memorial Hospital, Chicago, IL, USA

Gerd R Silberhumer, MD Division of Transplantation, Department of

Surgery, Medical University of Vienna, Vienna, Austria

Andrew Slack, MBBS, MRCP, EDIC, MD(Res) Department of Critical

Care, Guy’s and St Thomas’s NHS Foundation Trust, London, UK

Robert N Sladen, MBChB, MRCP(UK), FRCPC, FCCM Allen Hyman

Professor Emeritus of Critical Care Anesthesiology at Columbia University Medical Center, College of Physicians and Surgeons of Columbia University, New York, NY, USA

Avery L Smith, MD Baylor University Medical Center, Dallas, TX, USA

C P Snowden, B Med Sci (Hons), FRCA, MD Department of Perioperative

Medicine and Critical Care, Freeman Hospital, Newcastle Upon Tyne, UK

Randolph Steadman, MD, MS Department of Anesthesiology and

Perioperative Medicine, UCLA Health, Los Angeles, CA, USA

Masahiko Taniguchi, MD, FACS Department of Surgery, Hokkaido

University, Sappora, Japan

James F Trotter, MD Baylor University Medical Center, Dallas, TX, USA Tadahiro Uemura, MD, PhD Abdominal Transplantation and Hepatobiliary

Surgery, Allegheny General Hospital, Pittsburgh, PA, USA

Elizabeth C Verna, MD, MS Transplant Initiative, Division of Digestive

and Liver Diseases, Center for Liver Disease and Transplantation, Columbia University Medical Center, New York, NY, USA

Gebhard Wagener, MD Department of Anesthesiology, Columbia

University Medical Center, New York, NY, USA

Johanna Wagner Department of General- and Visceral-, Vascular and

Pediatric Surgery, University of Wuerzburg, Medical Center, Wuerzburg, Germany

Cynthia Wang, MD Department of Anesthesiology and Pain Management,

VA North Texas Healthcare System, Dallas, TX, USA

Christopher Webb, MD Department of Anesthesiology, Columbia

University Medical Center, New York, NY, USA

Contributors

Julia Wendon, MbChB, FRCP Institute of Liver Studies, Kings College

London, Kings College Hospital, London, UK

Paul D Weyker, MD Department of Anesthesiology, Columbia University

Medical Center, New York, NY, USA

Chris Willars, MBBS, BSc, FRCA, FFICM Department of Critical Care/

Institute of Liver Studies, King’s College Hospital, London, UK

Andre M De Wolf, MD Department of Anesthesiology, Northwestern

Memorial Hospital, Chicago, IL, USA

Nina T Yoh Columbia University Medical Center, New York, NY, USA

Part I Physiology, Pathophysiology and Pharmacology of Liver Disease

© Springer International Publishing AG, part of Springer Nature 2018

G Wagener (ed.), Liver Anesthesiology and Critical Care Medicine,

Liver anatomy · Liver segments · External

anatomy · Embryology · Hepatocytes · Liver

function

Introduction

This chapter will review the anatomy and

physi-ology of the liver as it pertains to the anesthetic

management during liver surgery and

transplan-tation Anesthetic management of the patient

with chronic liver disease requires a thorough

understanding of the alterations induced in

cir-rhosis that affect many organ systems For

exam-ple liver surgery for ablation of tumors may

reduce the functional mass of the liver resulting

in systemic changes that alter hemodynamics and

renal function In liver transplantation, the body

is deprived of all liver function during the

implan-tation phase and may receive a new liver with

impaired initial function All types of liver

sur-gery may cause hepatic ischemia and reperfusion

injury that may induce both acute and chronic

systemic alterations Thus, an understanding of the structure and function of the liver, is critical for managing the changes in the liver induced during surgery This knowledge, applied through-out the peri-operative period by anesthesiologists with interest and training in liver disease, has been a major factor in the markedly improved outcomes of liver surgery during the past

50 years, and especially since the era of liver transplantation

The liver is the largest gland in the human body and the only organ capable of regeneration [1] This unique ability has been both the subject

of ancient Greek mythology and modern cine best illustrated by the myth in which the injured liver is restored daily as Zeus’ eternal punishment to Prometheus While advances in science allow for the temporary support of renal function in the form of dialysis, and of cardiovas-cular and pulmonary function in the form of extracorporeal membrane oxygenation (ECMO), there is currently no effective substitute for the immune, metabolic, and synthetic functions of the liver other than transplantation (Table 1.1) The absence of artificial liver support makes a thorough understanding of hepatic physiology and pathophysiology imperative to the care of critically ill patients with liver injury as their management requires careful protection of rem-nant function while regeneration occurs

medi-This chapter will review normal liver anatomy, histology, and physiology The first section

T A Mulaikal, MD (*)

Division of Cardiothoracic and Critical Care

Medicine, Columbia University Medical Center,

New York, NY, USA

e-mail: tam36@cumc.columbia.edu

J C Emond, MD

Department of Surgery, Columbia University Medical

Center, New York, NY, USA

1

covers basic liver anatomy and describes

Couinaud’s classification, which divides the liver

into eight segments as a function of its portal

venous and hepatic arterial supply These

seg-ments serve as boundaries for the modern day

hepatectomy The knowledge of each segment’s

vascular supply, proximity to the vena cava, and

spatial orientation is useful in judging the

diffi-culty of resection and use of surgical techniques

such as total vascular isolation to minimize blood

loss For example lesions located posteriorly and

adjacent to the vena cava may necessitate total

vascular isolation with broad implications for the

anesthetic management

The next section will comprise basic liver

his-tology, including a discussion of microanatomy

and cellular function, which have implications

for the regulation of portal blood flow and the

pathophysiology of cirrhosis and portal

hyperten-sion The last section focuses on basic liver

phys-iology, including the immunological role of the

liver, and its metabolic and synthetic functions

Embryology

The liver derives from the ventral foregut

endo-derm during the fourth week of gestation,

responding to signals from the cardiac

meso-derm for hepatic differentiation [2 4] The

ven-tral foregut also gives rise to the lung, thyroid,

and ventral pancreas while the dorsal foregut gives rise to the dorsal pancreas, stomach, and intestines [5] The ventral endoderm responds

to signals from the cardiac mesoderm to ate the hepatic diverticulum that transforms into the liver bud and hepatic vasculature [6] The portal vein derives from the vitelline veins [4] The ductus venosus shunts blood from the umbilical vein, which carries oxygenated blood from the placenta to the fetus, to the vena cava thereby supplying oxygenated blood to the brain The ligamentum venosum is the remnant

gener-of the ductus venosus, and the ligamentum teres

is the remnant of the umbilical vein

The extrahepatic and intrahepatic biliary tracts have different origins The extrahepatic biliary tract, which includes the hepatic ducts, cystic duct, common bile duct, and gallbladder, devel-ops from the endoderm The intrahepatic biliary tract, however, develops from hepatoblasts [2]

Macroscopic Anatomy of the Liver and the Visceral Circulation

Anatomy relevant to surgical management and liver anesthesia includes the blood supply and the intrahepatic architecture of the liver A much more specific knowledge of liver anatomy is required to plan and execute surgical resections and is beyond the scope of this chapter The

Table 1.1 Functions of the liver

Procoagulants Anticoagulants Fibrinolytics Antifibrinolytics Plasma protein synthesis Albumin

Steroid hormone synthesis Cholesterol

Thrombopoietin Angiotensionogen IGF-1

Innate immunity Adaptive immunity Oral and allograft tolerance

Restoration after hepatectomy or trauma

Regulation of intravascular volume Renin-angiogensin- aldosterone

Glucose homeostasis Regulation of portal inflow

Hepatic arterial buffer hypothesis

F.A Fatty acids

T A Mulaikal and J C Emond

afferent blood to the liver is composed of both

arterial and portal blood and accounts for 20–25%

of the cardiac output, and all the blood exits the

liver through the hepatic veins (Fig 1.1) The

hepatic artery is derived from the celiac artery

in most cases but may receive some or all of its

supply from the superior mesenteric artery The

artery divides in order to supply the right and left

lobes and the intraheaptic segments, and the

anat-omy includes several variants that are relevant in

hepatic resections and biliary surgery These

vari-ants do not affect anesthetic management other

than the recognition that surgical errors may

result in ischemic injury to segments of the liver

Furthermore, since the biliary tree is primarily

supplied by the arterial system, bile duct

isch-emia may result in postoperative complications

The portal blood accounts for the majority of

the hepatic blood flow and unites the venous

return from the entire gastrointestinal (GI) tract

with the exception of the rectum that drains into

the iliac vessels The foregut, including the

stom-ach, spleen, pancreas and duodenum drain

directly into the portal vein and the splenic vein,

while the small intestine and the right colon drain

into the superior mesenteric vein This means

that the splenic vein contribution to the portal blood is rich in pancreatic hormones and cyto-kines while the superior mesenteric vein brings nutrients, toxins, and bacteria that are absorbed

by the GI tract In situations of increased portal vein pressure such as cirrhosis and portal vein thrombosis, collateral veins known as varices can develop These connections between the portal vein and the systemic circulation become enlarged and shunt blood away from the liver (Fig 1.2) Shunting results in impaired liver function, most pronounced in alteration of brain function discussed later in the chapter Clinically significant varices may result in GI bleeding in the esophagus, stomach and duodenum, as well

as the rectum Other collateral shunts occur in the retroperitoneum and the abdominal wall, and may result in a large amount of porto-systemic shunting without bleeding but other conse-quences of impaired portal blood flow In addi-tion to the loss of metabolic transformation, the reticulo-endothelial protective function of the liver is also bypassed when large shunts are pres-ent and may result in bacteremia and sepsis and contribute to the hemodynamic alterations of cir-rhosis discussed below

Middle hepatic vein Left hepatic vein Ligamentum venosum Falciform ligmament

Lateral segmental branches

of left lobe Medial segmental branches

of left lobe Left hepatic duct and artery Round ligament of liver (ligamentum teres hepatis) Common hepatic duct Bile duct, hepatic portal vein, and proper hepatic artery Right hepatic

artery and duct

Cystic duct and artery

Right hepatic veinInferior vena cava

Fig 1.1 Arterial and venous circulation of the liver

The hepatic veins join at the level of the

dia-phragm and enter the right chest and are therefore

exposed to alterations of intrathroacic pressure

unlike the remainder of the abdominal

circula-tion The liver is very sensitive to increases of

outflow pressure and obstruction of the hepatic

veins, for example with Budd-Chiari syndrome

or right heart failure Increased hepatic venous

pressure can cause hepatic engorgement and

severe functional impairment of the liver During

liver surgery or transplantation obstruction of the

hepatic outflow for example by clamping or

twisting of the vena cava may result in acute

hemodynamic instability To avoid hemodynamic

collapse as the liver is being manipulated, close

communication between the surgeon and

anes-thesiologist is critical

Although the external anatomy of the liver has

been long recognized (Fig 1.3) [7], the study of

corrosion casts of the intrahepatic vessels and

biliary tree has permitted our current

understand-ing of the intrahepatic anatomy (Fig 1.4) The

external anatomy is described from gross

land-marks including the gallbladder, the vena cava,

and the hepatic ligaments The internal anatomy

is defined by the vascular structures and eight

functionally independent segments Each

seg-ment has an afferent pedicle that includes artery,

portal vein and bile duct, and efferent hepatic

vein From the exterior, the apparent right lobe of

the liver is defined by the vena cava and the bladder fossa The right lobe (segments V–VIII) typically comprises 55–70% of the hepatic tissue and is supplied by the right hepatic artery and the right portal vein, and is drained by the right hepatic vein The central plane between the right and left lobes of the liver is defined by the middle hepatic vein The anatomy of the left lobe is more complex An external left lobe is defined by the falciform ligament (and is termed by some sur-geons as the “left lateral segment”, but consists anatomically of two segments, II and III) The medial portion of the left lobe is morphologically described as the quadrate lobe and is actually segment IV The left lobe segments are supplied

gall-by the left hepatic artery and portal vein, and drained by the left and middle hepatic veins The caudate lobe (segment I) is central and supply and drainage of segment I is fully independent of the right and left liver lobes

Histology Cellular Classification

The liver is composed of a rich population of specialized cells that allow it to carry out com-plex functions They can be grossly character-ized as “parenchymal” cells (hepatocytes) and

Diaphragm

Paraumbilical vein of Sappey Umbilicus Umbilical vein

Retroperitoneal veins of Retzius

Epigastric vein

Interior mesenteric vein Gonadal vein Collateral veins Abdominal wall Omentum Coronary vein Spleen Esophageal varices

Splenophreric collateral veins

“nonparenchymal cells” The nonparenchymal cells include stellate cells, sinusoidal endothelial cells, Kupffer cells, dendritic cells, and lympho-cytes (Fig 1.5 and Table 1.2) The hepatocytes

or parenchymal cells, make up 60–80% of liver cells [8] and carry out the metabolic, detoxifi-cation, and synthetic functions of the liver The hepatocytes have a unique relationship with the sinusoidal endothelium that carefully regulates the exposure of hepatocytes to the metabolic substrate that arrives in the portal blood through fenestrations The baso-lateral membrane of the hepatocyte absorbs nutrients from the sinusoids, which are then processed with excretion of the metabolic products through the apical cell mem-brane into the bile duct Hepatocytes divide under

falciform ligament

teres ligamentum

umbilical fissure

hilus quadrate lobe

caudate lobe gallbladder fossa

left lobe right lobe

Fig 1.3 External

anatomy of the liver

Bismuth H Surgical

anatomy and anatomical

surgery of the liver

World J Surg Jan 1982;

6 (1): 3–9

II

III

IV V

I

VI

VII

VIII

Fig 1.4 Internal anatomy of the liver Bismuth H

Surgical anatomy and anatomical surgery of the liver

World J Surg Jan 1982; 6 (1): 3–9

stress and cytokine stimulation and are the

princi-pal components of mass restoration during

regen-eration (Table 1.1) [1] In vitro, hepatic mitotic

activity is stimulated by hepatocyte growth factor

(HGF), cytokines, and tumor necrosis factor alpha

(TNF) and can be clinically seen after

hepatec-tomy, toxic cell necrosis or trauma [9]

Hepatic stellate or Ito cells are vitamin A and

fat storing cells located in the perisinusoidal

space of Disse, described by Toshio Ito in 1951

[10, 11] These cells are of tremendous

impor-tance and scientific interest as critical regulators

of hepatic function and prime suspects in the

pathogenesis of cirrhosis In the normal liver,

stellate cells are quiescent but can become

acti-vated by injury and then transform into collagen

secreting myofibroblasts with contractile

proper-ties This fibroblast-like cellular activity of

hepatic stellate cells has a protective function in

the generation of scar tissue, promotion of wound

healing, and remodeling of the extracellular

matrix [12] Excessive collagen deposition is the

underlying mechanism of fibrosis and cirrhosis [13] Hepatic stellate cell secretion of collagen into the perisinusoidal space of Disse narrows the sinusoidal lumen, thereby increasing hepatic vas-cular resistance and contributing to portal hyper-tension [10] The impact of this disturbance on sinusoidal perfusion creates a secondary isch-emic injury, potentially accelerating the destruc-tive impact of an initially limited injury [12] Stellate cells also have intrinsic contractile function important in the regulation of blood flow and the pathogenesis of portal hypertension Vasopressin, endothelin-1, and angiotensin II bind to receptors on stellate cells, activating a rho mediated signal transduction pathway and myo-sin II contraction [10, 13] Endothelin-1, angio-tensin II, vasopressin, and their receptors have been studied as therapeutic targets for the treat-ment of portal hypertension and the management

of variceal bleeding [14–18]

Hepatic endothelial cells are fenestrated cells that line the sinusoids and also play an important

Fig 1.5 Hepatic microanatomy Transmission electron

micrographs of (a) sinusoidal endothelium (Ec) with

attached Kupffer cell (KC) encasing the sinusoid lumen

(L), and perisinusoidal stel-late cell (SC) containing fat

droplets in space of Disse (SD); and (b) Pit cell with

typi-cal dense granules This Pit cell is in close contact with the

endothelial lining and is seen to contact microvilli of the

parenchymal cells (arrow-heads) Ec endothelial cell, f fenestrae, L sinusoidal lumen, N nucleus, SD space of

Disse (with kind permission from McCuskey [ 20 ], Fig 1.5a, Fig 6b)

T A Mulaikal and J C Emond

role in the regulation of intrahepatic resistance to

blood flow through expression endothelial nitric

oxide synthase (eNOS) and release of nitric oxide

(NO), a potent vasodilator [19] (Fig 1.6) [20]

Disruption of sinusoidal endothelial cells in

cir-rhosis results in a concomitant decrease in the

pro-duction of NO [21] This is in contrast to the

mesenteric vascular bed that has an increased NO

production in portal hypertension [21] NO ated increase of splanchnic flow is consistent with

medi-the forward flow medi-theory of portal hypertension that

states that portal hypertension is not only due to an increase in hepatic vascular resistance but also due

to splanchnic hyperemia [22] Neoangiogenesis mediated by vascular endothelial derived growth factor (VEGF) also contributes to splanchnic

Table 1.2 Cellular microanatomy

Percentage of liver cells

Xenobiotic metabolism

Protein synthesis and metabolism

Lipid synthesis and metabolism

cellsv Vitamin A and fat storageCollagen secreting myofibroblasts

Scar tissue and wound healing

Fibrosis and cirrhosis

Fenestrated endothelial cells

Release of nitric oxide (NO)

Regulate vascular resistance

APCs

Innate immunity

Angiogenesis of existing vessels from septum transversum mesenchyme

15–20%

APCs

Innate immunity

NO, TNF alpha, cytokines

Ischemia reperfusion injury

Downregulation of APC and T cell activation

Target lipid antigens

Innate and adaptive immunity

5–10%

biliary tree Ventral endoderm → extrahepatic biliary tree

<1%

Table created from the following publications [ 8 10 , 12 ]

APCs (antigen presenting cells), NO (nitric oxide)

hyperemia and the hyperdynamic state of end

stage liver disease [23, 24]

The Kupffer cells are macrophages that reside

in the hepatic sinusoids and constitute 80–90% of

the macrophages in the human body [25] These

cells are specialized due to their exposure to high

concentrations of endotoxin and oxidative stress

in the sinusoids and are critical protectors of the

systemic circulation from exposure to toxins

They are part of the innate immune system,

which is the intrinsic host defense system that

allows nonspecific targeting of foreign antigens,

in contrast to the adaptive immune system that

allows specific targeting of foreign antigens

There is a close relationship between the

regula-tion of blood flow and Kupffer cell macrophage

function based on the NO pathway [26] resulting

in a consistent overlap between ischemic and

inflammatory injury to the liver

Hepatic dendritic cells are antigen presenting

cells synthesized in the bone marrow that can

migrate from the liver to lymphoid tissue, though

they are often localized near the central vein [27]

They serve a critical role in antigen presentation

and activation of T lymphocytes when

encounter-ing an antigen A sub-population of dendritic

cells become resident in the liver and function in this unique environment as key initiators of innate immunity modulating, or in other cases, activating acute inflammatory responses [28].Though small in number relative to other cell populations in the liver, hepatic lymphocytes play in important role in regulating immune defenses within the liver and include natural killer cells, NKT cells, T lymphocytes, and B lymphocytes Natural killer (NK) cells are part of the innate immune system and are known for their nonspecific targeting of tumor cells and viruses NKT cells link the innate and adaptive immune systems They are a subpopulation of lymphocytes with T cell markers and NK cell surface receptors Conventional T and B lympho-cytes are part of the adaptive immune system and play a role in epitope specific cell and antibody mediated destruction of foreign antigens

Anatomic Lobules and Metabolic Zones

The microscopic anatomy of the liver can be ceptualized either as morphologically anatomic

Fig 1.6 Electron micrographs of sinusoidal endothelial

cell, hepatic stellate cell, and Kupffer cell (a) Scanning

electron micrographs of sinusoid illustrating fenestrae

organized in clusters as “sieve” plates (arrowheads) SD

space of Disse, H hepatic parenchymal cell (b) Kupffer

cell (KC) attached to luminal surface of sinusoidal thelium by processes that penetrate fenestrae (with kind permission from McCuskey [ 20 ], Fig 5a, Fig 6b)

endo-T A Mulaikal and J C Emond

hepatic lobules, or functionally, as precise

meta-bolic zones The hexagonal hepatic lobule is

cen-tered around the central vein with the portal triad

(hepatic artery, portal vein, and common bile

duct) at each corner of the hexagon The central

vein is the terminal branch of the hepatic vein

[29] These microscopic ordered aggregrations of

liver cells are complete and independent units of

metabolic capacity that recapitulate on a tiny

scale the entire liver The hepatic artery and

por-tal vein travel together and transport blood

con-taining oxygen and splanchnic metabolites to the

liver that the functional hepatocytes in the hepatic

lobule then process and drain into a common

cen-tral vein Bile from each hepatocyte drains into

canaliculi These canaliculi join to form the

duct-ules that aggregate to form the inter-lobular bile

ducts and eventually the macroscopic segmental

ducts Segmental ducts bring bile to the common

bile duct that drains into the gallbladder and

duo-denum A more functional histologic

classifica-tion of the liver defines metabolic zones that form

the hepatic acinus [30, 31] Zone I is known as

the periportal zone and is centered around the

portal triad, making it oxygen rich given its

prox-imity to the hepatic artery This periportal zone is

the most resilient to hemodynamic stressors, least

susceptible to necrosis, and the first to regenerate

The cells in zone I also have distinct metabolic

capacity and focus on aerobic functions of the

liver such as gluconeogenesis and

glycogenoly-sis, generating a fuel source for the body’s

extra-hepatic work [31–33] Zone I also is the site of

cholesterol synthesis and beta oxidation of fatty

acids It is active in the degradation of amino

acids in the urea cycle, which is responsible for

the majority of ammonia metabolism in the body

[31, 32] While enzymes involved in this

peripor-tal zone are expressed throughout the acinus,

they are metabolically most active in zone I Zone

II is the intermediate zone between zones I and

III Zone III is the pericentral or perivenous zone

and is in close proximity to the central vein This

zone has the lowest oxygen tension (PaO2), is

most susceptible to hemodynmamic stressors,

and the last to regenerate Zone III is involved in

ketogenesis, which generates ketone bodies for

extrahepatic tissues during fasting states Zone

III is also the site of drug detoxification, or phase

I and II metabolism [32]

Immunological Function

of the Liver Innate and Adaptive Immunity

The liver is an integral part of both the innate and adaptive immune systems The innate immune system is the intrinsic host defense system that allows nonspecific targeting of foreign antigens

Of the nonparenchymal cells in the liver, there are four types of antigen presenting cells (APCs) that function as immunologic gatekeepers, engulfing bacteria that enter the portal system from the splanchnic circulation, presenting anti-genic epitopes to effector T and B lymphocytes and preventing bacterial entry into the systemic circulation These four APCs are Kupffer cells, dendritic cells, stellate cells, and sinusoidal endo-thelial cells and are all part of the innate immune system

The innate immune system also includes ral killer (NK) cells and natural killer T (NKT) cells NK cells are considered lymphocytes because they derive from the bone marrow NK cells play a role in the destruction of tumors, bac-teriae, viruses and parasites by killing cells that lack ‘self’ major histocompatibility complex I (MHC I) markers [25] They secrete cytokines that inhibit viral replication and do not require antigen presenting cells to identify their targets [34] They release granules with perforin that puncture cell membranes and granzymes that lyse internal cellular contents, thereby inducing apoptosis of the infected cell NK cells typically constitute up to 30–50% of liver lymphocytes, but may comprise up to 90% of total lympho-cytes in patients with hepatocellular carcinoma Diminished function of NK cells has been associ-ated with increased tumor burden [25, 34] NKT cells link the innate and adaptive immune sys-tems They are a subpopulation of lymphocytes with NK cell surface receptors and T cell markers [25] NKT cells target lipid antigens such as gly-colipids of mycobacterial cell walls [35, 36]

The adaptive immune system is the acquired

host defense system that allows epitope specific

cell and antibody mediated destruction of foreign

antigens, utilizing memory for fighting

subse-quent infections Adaptive immunity comprises

both cellular and humoral immunity Members of

the liver’s adaptive immune system include

con-ventional T and B lymphocytes involved in cell

mediated and antibody mediated immunity

respectively T lymphoctyes such as CD8 T cells

can recognize tumor-associated antigens (TAA)

and eradicate cells of hepatocellular carcinomas

(HCC) [37] The liver is exposed to antigens from

the enteric system that enter the portal circulation

and its adaptive immune system is critical in

pro-tecting the body from exposure of these antigens

to the systemic circulation In contrast to the

cel-lular composition in the peripheral circulation,

the hepatic circulation has a predominance of

nonspecific innate immune cells I as it functions

as an immunologic gatekeeper, regulating the

passage of antigens from the splanchnic to the

portal and finally to the systemic circulation [38]

Oral and Allograft Tolerance

The liver strikes a balance between immunity to

infection and tolerance of commensal bacteria

and orally consumed antigens, a concept known

as oral or systemic tolerance [39] This

immuno-logic adaptation may underlie the physioimmuno-logic

mechanism of allograft tolerance, the

transplan-tation of organs between the same species of

varying genotypes In 1960 Peter Medawar won

the Nobel Prize in Physiology or Medicine for

describing the tolerance of skin grafts between

dizygotic twin cattle [40, 41] This observation

was thought to be due to the in utero exposure of

each twin to erythrocytes of the other [42]

Animal models of porcine allogenic

transplanta-tion illustrate the ability to transplant livers

though not kidneys, between unrelated pigs

with-out rejection [43] Pigs, mice, and rats will accept

unrelated livers without immunosuppressive

therapy and some human liver transplant

recipi-ents can wean their immunosuppressive regimen

over time [28]

This concept of tolerance describes the liver’s ability to downregulate T cell activation or ‘toler-ate’ antigens that present no harm Tolerance is mediated by cytokines such as TNF alpha and interleukin 10 (IL-10) Kupffer cells release these cytokines, which in turn downregulate the activ-ity of antigen presenting dendritic and sinusoidal epithelial cells, thereby decreasing T cell activa-tion [8] Tolerogenicity is important in liver transplantation and may explain why donor leu-kocytes can improve hepatic allograft survival [44]

The mechanism underlying enteric tolerance associated with the liver may be mediated by lipopolysaccharide (LPS) endotoxin, a cell wall component of gram negative bacteria [45] The portal vein delivers antigens to the liver often in the form of lipopolysaccharide (LPS), which complexes with toll-like receptor 4 (TLR 4) and its coreceptors MD 2 and CD 14 on antigen pre-senting cells The constituitive exposure of LPS

to these antigen presenting cells is thought to result in a dampening of the immune response or tolerance [45, 46]

Hepatic Drug Metabolism First Pass Metabolism

Drugs administered intravenously have 100% bioavailability because the original form of the drug reaches the systemic circulation unchanged Drugs ingested orally, however, undergo first pass metabolism The intestines and liver absorb and process drugs thereby decreasing the effec-tive dose that enters systemic circulation Drugs with a high bio-availability are minimally metab-olized by enzymes of the entero-hepatic system

In contrast, drugs with a low bioavailability are extensively metabolized by entero-hepatic enzymes Drugs that undergo extensive first pass metabolism are particularly susceptible to fluc-tuations in blood levels if their enzymatic metab-olism is altered by co-ingestants [47] Age and sex can affect the metabolism and bioavailability

of drugs as well Alcohol is metabolized by both alcohol dehydrogenase (ADH) in the liver and

T A Mulaikal and J C Emond

gastrointestinal tract, and cytochrome P450 2E1

enzymes Women have higher blood ethanol

con-centrations than men who ingest equal amounts

due to decreased gastric ADH that reduces

first-pass metabolism and increases bioavailability

[48, 49] Increased age decreases overall

cyto-chrome P450 activity, increasing the risk of older

individuals for drug induced liver injury (DILI),

with particular susceptibility to

amoxicillin-cla-vulanate, isoniazid, and nitrofurantoin This

sus-ceptibility has not resulted in an increased rate of

transplantation or death [50]

Phase II and III Metabolism, Phase 0

and III Transport

The enzymes involved in drug metabolism in the

liver are part of the P450 cytochrome family

located in the metabolic zone III Cytochrome

P450s catalyze phase I reactions Phase I

reac-tions are oxidation, reduction, and hydrolysis

reactions that increase the polarity of substances

for excretion or for further metabolism by phase

II enzymes [51] Phase II enzymes, such as

uri-dine diphosphate glucuronosyl transferases

(UGTs), sulfotransferases, and glutathione- S-

transferases, conjugate phase I metabolites to

substances such as glucuronate, sulfate, and

glu-tathione [51] These conjugation reactions

trans-form drugs into hydrophilic substances, thereby

increasing their solublility in bile and blood for

excretion Absence or dysfunction of these phase

I or II enzymes can result in hyperbilirubinemia

and encephalopathy

Gene mutations may affect metabolism and

result in specific syndromes For example in

Gilbert’s syndrome a mutation in the promoter

region of bilirubin-UGT leads to decreased levels

of normally functioning enzyme, thereby reduced

conjugation of bilirubin with glucoronide, and an

unconjugated hyperbilirubinemia In Crigler-

Najjar syndrome a mutation of the coding region

of bilirubin-UGT results in absent or defective

bilirubin-UGT, unconjugated

hyperbilirubine-mia, and in some cases kernicterus [52]

Similarly, depletion of molecules involved in

these conjugation reactions can result in liver

injury Acetaminophen toxicity for example occurs because of the relative depletion of gluta-

thione and the accumulation of N-acetyl-p-

benzoquinone-imine (NAPQI), the unconjugated toxic acetaminophen byproduct The accumula-tion of NAPQI leads to zone III or centrilobular necrosis Chronic alcohol use can increase the risk of acetaminophen toxicity due to induction

of cytochrome P450 2E1 (CYP2E1), which increases the conversion of alcohol to its toxic metabolite NAPQI [48] N-acetylcysteine, a pre-

cursor to glutathione and a free radical scavenger, may be beneficial in the treatment of acetamino-phen toxicity [53] Some studies have also sug-gested its use to ameliorate ischemia reperfusion injury, primary graft dysfunction, and acute kid-ney injury in liver transplantation [54, 55] These findings, however, are controversial and not all studies have proven definitive benefit of

N-acetylcysteine in the perioperative transplant setting [56]

Phase 0 and III transport involve carrier ated uptake and elimination of drugs by trans-porters via the basolateral and canalicular membranes respectively In phase 0 transport, drugs are absorbed from the blood into the hepa-tocytes by solute carrier (SLC) transporters [57]

medi-In phase III transport, the hydrophilic substances derived from Phase II metabolism must travel via the lipid soluble canalicular membranes using ATP binding cassette carriers (ABC) [58] ATP splitting is required to transport these hydrophilic substances through the lipophilic canalicular membrane into the bile [59] No metabolism or drug alteration is involved in this transport mech-anism and therefore the term “Phase III metabo-lism” is a misnomer

Substrates, Inducers and Inhibitors

of P450 System: Implications for Toxicity and Therapeutic Failure

Many commonly used drugs in the clinical ting interact with P450 enzyme substrates either

set-as inhibitors or inducers Inhibitors slow down P450 enzyme activity, thereby increasing the substrate bioavailability This can result in drug

toxicity, which has profound implications for

medications with a narrow therapeutic index For

example warfarin is a P450 substrate and

initiat-ing treatment with inhibitors such as azoles,

mac-rolides, beta blockers, calcium channel blockers,

amiodarone, and proton pump inhibitors may

lead to a supra-therapeutic INR and clinically

significant bleeding

Conversely, initiating treatment with a P450

inducer such as phenobarbital, phenytoin,

fos-phenytoin, carbamazepine, or rifampin, may

cause therapeutic failure Women taking oral

contraceptives and anti-epileptic drugs (AEDs)

that are P450 inducers must be cognizant of

the estrogen and progesterone composition of

their oral contraceptives to avoid therapeutic

failure [60]

Hepatic Glucose, Amino Acid,

and Lipid Metabolism

Glucose Homeostasis

The liver has the ability to produce glucose

dur-ing fastdur-ing states to maintain euglycemia, and

provide energy for brain, muscle and red blood

cells Initial fasting conditions trigger the release

of glucagon from the pancreas, thereby

promot-ing glycogenolysis, the release of glucose from

stored glycogen [61] Epinephrine stimulates

glycogenolysis during states of stress Prolonged

fasting or starvation prompts the de novo

synthe-sis of glucose by gluconeogenesynthe-sis The liver is

the main site of gluconeogenesis, the synthesis of

glucose from pyruvate, lactate, glycerol, and

amino acids (non-carbohydrate precursors) Both

gluconeogenesis and glycogenolysis take part in

the periportal metabolic zone I of the liver, the

zone closest to the portal triad

During nonfasting states the liver is able to

store glucose by glycogenesis or convert glucose

to pyruvic acid and ATP by glycolysis These

processes take place in metabolic zone III, or the

pericentral zone This zonal heterogeneity or

dif-ferential expression of metabolic enzymes

priori-tizes crucial metabolic functions that provide

energy or glucose to the body during fasting

states by placing them in close proximity to the oxygen and nutrient rich environment of the por-tal triad [31] The precise regulation of glucose homeostasis is clinically relevant in that hypogly-cemia is the most dramatic manifestation of liver failure and generally implies a terminal state of hepatic failure

Inherited disorders of glucose and glycogen metabolism are known as glycogen storage dis-eases (GSDs) These are enzymatic defects affecting the liver and muscles, the two main sites for glycogen storage [62] Hepatic manifesta-tions of GSDs are characterized by fasting hypo-glycemia, ketosis, and hepatomegaly [63, 64]

Protein Metabolism and Hepatic Encephalopathy

When the body has sufficient protein stores, the liver transforms additional amino acids to ammo-nia in the urea cycle Ammonia detoxification involves the degradation of proteins to their amino acid components, the breakdown of amino acids to alpha ketoacids and ammonia, and the generation of urea This process occurs in the oxygen rich periportal zone I The enzyme gluta-mine synthetase located in the perivenous zone III, then transforms ammonia and glutamate to glutamine Liver dysfunction of any etiology results in hyperammonemia from both a decreased ability to produce urea and glutamine, and diminished first pass metabolism from porto-systemic shunts [65] Ammonia is neurotoxic, as

is the excitatory neurotransmitter glutamate when present in excess [65] Cerebral astrocytes can convert some ammonia to glutamine but supra-physiologic levels of glutamine result in an osmotic intracellular gradient and subsequent edema, elevated intracranial pressure, and at its worst herniation [65] This is the basis of the ammonia-glutamine hypothesis of intracranial hypertension in fulminant hepatic failure [66] Alternatively, some scientists have advocated the

“Trojan horse” hypothesis to explain the nism of cellular edema Glutamine acts as a car-rier or Trojan horse for the uptake of ammonia from the astrocyte cytoplasm to the

mecha-T A Mulaikal and J C Emond

mitochondria The glutamine-derived ammonia

within the mitochondria of astrocytes then

gener-ates free radicals and causes cellular edema [67]

There are two types of cerebral edema:

cyto-toxic edema that results from cellular swelling

due to an increase in osmotic load and

intracellu-lar water absorption, and vasogenic edema from

the increased permeability of solutes and solvents

through a disrupted blood brain barrier [68] The

cerebral edema of fulminant hepatic failure is

pre-dominantly cytotoxic with a preserved blood

brain barrier, and a therapeutic response to

osmotic diuretics such as mannitol and hypertonic

saline [68, 69] Intracranial hypertension is rare in

chronic liver failure due to a compensatory

intra-cellular increase in solute load

Lipid Metabolism and Nonalcoholic

Fatty Liver Disease

The liver is the principal site of lipid metabolism,

both in absorption of dietary fats and their de novo

synthesis Dietary fats are emulsified by bile salts

and absorbed in the form of micelles by the

intes-tine and delivered to the liver via enterohepatic

circulation Fatty acids can be hydrolyzed by

beta-oxidation to generate energy or ATP for the

body’s extra-hepatic metabolism During fasting

states, starvation, or diabetic keto- acidosis (DKA)

when glucose is not available to the body, the liver

can generate ketone bodies (acetoacetic acid, beta

hydroxybutyric acid, and acetone) from fatty

acids that can be used by organs such as the brain

[70] Conversely, in non-alcoholic fatty liver

dis-ease (NAFLD) when hepatic lipid content or

ste-atosis constitutes 5% of liver weight, there is an

increase in triglyceride synthesis and defective

insulin mediated inhibition of lipolysis [71, 72]

Metabolic syndrome, defined as visceral obesity

associated with hypertension, dyslipidemia, and

hyperglycemia may also be associated with

non-alcoholic fatty liver disease by a similarly

impaired insulin mediated inhibition of lipolysis

[73, 74] This metabolic derangement of lipid

metabolism has striking clinical implications

since NAFLD is the most prevalent liver disease

and can progress to non- alcoholic steatohepatitis

(NASH) [72] Close to half of patients with NASH develop fibrosis and one sixth develop cirrhosis that may eventually lead to liver failure requiring transplantation [75]

Liver Coagulation and Fibrinolysis

The liver is a major organ involved in hemostasis since it is the primary synthetic site of pro- coagulants, anticoagulants, fibrinolytics, and antifibrinolytics [76] While extra-hepatic sites such as the endothelium contribute to synthesis

of some coagulation factors such as factor VIII and von Willebrand factor (vWF), the liver remains the principal synthetic site of coagula-tion cascade components Primary and secondary hemostasis requires the formation of a platelet plug and fibrin clot, triggered by tissue trauma or endothelial damage [77] While platelets are made in the bone marrow, they are often seques-tered in the spleen of patients with portal hyper-tension and splenomegaly [78] This platelet sequestration contributes to thrombocytopenia in patients with end stage liver disease Impaired hepatic synthesis of thrombopoietin, the hormone that stimulates megakaryocyte production, also contributes to thrombocytopenia in liver disease Bone marrow suppression secondary to alcohol, viruses, and medications is also a factor [79].The liver synthesizes fibrinogen (factor I), prothrombin (factor II), factor V, and factors VII–XIII It also synthesizes anticoagulants such as antithrombin III, protein C, protein S, selected fibrinolytics such as plasminogen, and antifibri-nolytics such as alpha 2-anitplasmin and throm-bin activatable fibrinolysis inhibitor (TAFI) [76] The balance between pro-coagulants and antico-agulants in liver failure determines the risk of bleeding or thrombosis In end stage liver dis-ease, the balance may be tipped towards antico-agulant and fibrinolytic factors predisposing patients to bleeding, though cases of venous thrombosis can occur secondary to venous stasis

or hepatocellular carcinoma [80] Traditional laboratory makers of coagulopathy such as pro-thrombin time (PT) and partial thromboplastin time (PTT) do not accurately portray the balance

between procoagulant and anticoagulant factors

in liver disease PT and PTT reflect the degree to

which procoagulants factors are depressed but

not whether anticoagulants such as protein C can

offset this deficiency since reagents used in these

laboratory assays do not contain enough

throm-bomodulin to activate protein C [81]

Hyperfibrinolysis has traditionally been

asso-ciated with chronic liver disease as demonstrated

by elevated levels of tissue plasminogen activator

(tPA) and plasmin, both involved in the

degrada-tion of fibrin clots, as well as decreased levels of

alpha 2 plasminogen inhibitor and thrombin

acti-vatable fibrinolysis inhibitor (TAFI) [77, 82]

Thirty to forty percent of patients with liver

dis-ease have laboratory evidence of

hyperfibrinoly-sis Whether or not these markers of fibrinolysis

correlate with a clinical bleeding risk remains

less clear [83, 84]

Other factors that can contribute to clinically

significant bleeding include renal failure with

platelet dysfunction, portal hypertension,

endo-toxemia with fibrinolysis, and disseminated

intra-vascular coagulation [83, 84] Patients with

isolated hepatic coagulopathy usually have

nor-mal to elevated levels of factor VIII and von

Willebrand factor in contrast to patients with

DIC, though both conditions may coexist [77]

Endotoxemia is associated with both fibrinolysis

and a procoagulant state Sepsis induced

hyper-coagulability occurs by the inhibition of activated

protein C and S, as well as by increased tissue

factor expression [85]

Hepatic Endocrine Function

The liver acts as an endocrine organ, producing

hormones such as insulin like growth factor

(IGF-1), thrombopoietin, angiotensinogen, and

steroid hormones The liver produces 75% of

IGF-1, which is a peptide hormone, mediating

the effects of human growth hormone (GH)

Growth hormone activates the release of IGF-1,

which stimulates tissue growth Levels rise

dur-ing puberty, are abnormally high in conditions

such as acromegaly, and may be low in patients

with short stature

Thrombopoietin is a peptide hormone duced in the liver that stimulates megakaryocytes and platelet production Low levels of thrombo-poietin in liver failure may contribute to throm-bocytopenia since these levels as well as platelet counts are restored with orthotopic liver trans-plantation [87, 88]

pro-Angiotensinogen, the precursor of sin, is produced in the liver as well This precur-sor peptide hormone is activated by renin in the renin-angiotensin-aldosterone pathway This pathway is the target of anti-hypertensives such

angioten-as ACE inhibitors and angiotensin receptor blockers (ARBs) The diuretic spironolactone, which antagonizes the pathway’s endpoint aldo-sterone, is used to manage ascites in liver disease

Lastly, the liver is the site of cholesterol thesis and therefore crucial in the genesis of endogenous steroid hormones such as cortisol, aldosterone, and testosterone While these hor-mones are synthesized in the adrenal gland, their precursors are hepatic in origin Estrogens and androgens have receptors in hepatocytes that reg-ulate lipid and glucose homeostasis [88]

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© Springer International Publishing AG, part of Springer Nature 2018

G Wagener (ed.), Liver Anesthesiology and Critical Care Medicine,

Hepatitis · Chronic liver disease · Hepatic fibrosis

· Liver failure · Cirrhosis · Portal hypertension

Abbreviations

AASLD American Association for the Study of

Liver Diseases

AH Alcoholic hepatitis

ATP Adenosine triphosphate

CDC Center for disease control

HSC Hepatic stellate cell

HVPG Hepatic venous pressure gradient

IL Interleukin

MDF Maddrey discriminant function

MELD Model for end-stage liver diseaseNAFLD Nonalcoholic fatty liver diseaseNASH Nonalcoholic steatohepatitisPOPH Portopulmonary hypertensionPSE Portosystemic encephalopathyPVT Portal venous thrombosisSAAG Serum-ascites albumin gradientSBP Spontaneous bacterial peritonitisTGF Transforming growth factorTIPS Transjugular intrahepatic portosys-

temic shuntTLRs Toll-like receptorsTNF Tumor necrosis factorUSPSTF United States preventative services

of persistent liver injury induces a healing response that results in hepatic fibrosis Cirrhosis

is a late stage of hepatic fibrosis characterized by distortion of normal liver architecture that leads

to hepatocellular dysfunction, increased hepatic resistance and ultimately to hepatic

intra-L T Grinspan, MD, PhD

Department of Medicine, Columbia University

Medical Center, New York, NY, USA

E C Verna, MD, MS (*)

Transplant Initiative, Division of Digestive and Liver

Diseases, Center for Liver Disease and Transplantation,

Columbia University Medical Center,

New York, NY, USA

e-mail: ev77@cumc.columbia.edu

2