The Netter Collection
OF MEDICAL ILLUSTRATIONS
Digestive System
Part III—Liver, Biliary Tract,
and Pancreas
2nd Edition
A compilation of paintings prepared by
Frank H. Netter, MD
Editor Associate Editors
James C. Reynolds, MD John A. Martin, M.D., FASGE
June F. Klinghoffer Distinguished Associate Professor and Senior Associate
Professor and Chair Consultant
Department of Medicine Division of Gastroenterology and Hepatology
Drexel University College of Medicine Mayo Clinic
Philadelphia, Pennsylvania Rochester, Minnesota;
Adjunct Associate Professor of Medicine
Senior Associate Editor
and Surgery
Peter J. Ward, PhD Northwestern University Feinberg School
Associate Professor of Anatomy of Medicine
Department of Biomedical Sciences Chicago, Illinois
West Virginia School of Osteopathic Medicine
Lewisburg, West Virginia Grace L. Su, MD
Professor of Medicine and Surgery
University of Michigan Medical School
Chief of Gastroenterology and Associate Chief
of Medicine
VA Ann Arbor Healthcare System
Ann Arbor, Michigan
David C. Whitcomb, MD, PhD
Professor of Medicine
Cell Biology & Physiology and Human Genetics
Chief, Division of Gastroenterology, Hepatology
and Nutrition
University of Pittsburgh
Pittsburgh, Pennsylvania
Additional Illustrations by Carlos A.G. Machado, MD
CONTRIBUTING ILLUSTRATORS
John A. Craig, MD
Tiffany S. DaVanzo, MA, CMI
Kristen Wienandt Marzejon, MS, MFA
James A. Perkins, MS, MFA
1600 John F. Kennedy Blvd.
Ste. 1800
Philadelphia, PA 19103-2899
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS ISBN: 978-1-4557-7392-3
DIGESTIVE SYSTEM: PART III—LIVER, BILIARY TRACT,
AND PANCREAS, VOLUME 9, SECOND EDITION
Copyright © 2017 by Elsevier Inc.
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ABOUT THE EDITORS
James C. Reynolds, MD, Editor, is professor of Physicians) and served in this role from 1999 to 2007. Peter J. Ward, PhD, Senior Associate Editor, was
medicine and the June F. Klinghoffer Distinguished From 2006 to 2008 he served as president of the medical born in Denver but grew up primarily in Casper,
Chair of the department of medicine at Drexel Univer- staff at Hahnemann University Hospital and was a Wyoming, graduating from Kelly Walsh High School
sity College of Medicine in Philadelphia. member of the board of directors of the hospital. He in 1992. He attended Carnegie Mellon University in
became interim chair of medicine in 2002. In 2005 he Pittsburgh and graduated with a bachelor of science
Dr. Reynolds, a native of Florida, graduated from was named the June F. Klinghoffer Distinguished Chair degree in biology (genetics, biochemistry, molecular
Florida State University and received his medical of the department of medicine. As Chair he has led the biology) with a minor in chemistry in 1996. He first
degree from the University of Florida, where he was department to a fivefold increase in clinical billing while encountered gross anatomy, histology, embryology, and
president of his class and received several honors, doubling faculty size and extramural research income. neuroanatomy at the College of Veterinary Medicine in
including admission to Alpha Omega Alpha as a junior, The department continues to receive accolades for its 1998. Having found a course of study that engrossed
the John B. Gorrie Award as the student with the best support of exceptional quality and transplantation him, he matriculated through these courses at Purdue
promise for outstanding future performance, as well as outcomes and for the national recognition of several College of Veterinary Medicine, as well as at the branch
research awards. He completed his residency at Cornell divisions. campus of the Indiana University School of Medicine.
University at New York Hospital and Memorial Sloan Dr. Ward completed a master’s degree in Dr. Kevin
Kettering Cancer Center. He then completed a 3-year Dr. Reynolds is a member of the editorial board of Hannon’s muscle research laboratory and then began a
fellowship at the Hospital of the University of Digestive Diseases and Sciences and is a reviewer for many doctorate program in anatomy education under Dr.
Pennsylvania. He joined the faculty at the University of other journals. He has published over 100 manuscripts James Walker. He completed his thesis work in 2005—
Pennsylvania, where he became program director and in peer-reviewed journals and has coedited five books. strategies to improve student achievement and recall of
associate chief of the division. He remained funded by He has received numerous honors including Phi Beta medical anatomy—a qualitative and quantitative study.
the National Institutes of Health (NIH) and other Kappa, AOA, and “Physician of the Year” in 1995 by
national organizations for his research into the effect of the Greater Pittsburgh Chapter of the Crohn’s and In July 2005 Dr. Ward joined the faculty of the West
neuropeptides on gastrointestinal motility. In 1990 he Colitis Foundation of America, and has been recog- Virginia School of Osteopathic Medicine (WVSOM) in
became chief of the division of gastroenterology, hepa- nized as the most outstanding gastroenterologist in Lewisburg, West Virginia. He has taught gross anatomy,
tology, and nutrition at the University of Pittsburgh, Pittsburgh on two separate occasions by Pittsburgh embryology, neuroscience, histology, radiography, and
where he was a tenured associate professor of medicine Magazine. He has also been named among Philadel- the history of medicine. During this time he has also
and cell biology. He was co-director of the Centers for phia’s “Top Docs” 10 times by Philadelphia Magazine. been director of the WVSOM plastination facility,
Digestive Health and an associate professor of medicine He has received teaching awards in both basic and clini- coordinator of the graduate teaching fellows, chair of
and cell biology. In 1996 he became professor of cal sciences from the University of Pennsylvania and the curriculum committee, creator and director of a
medicine with tenure and chief of the division of gas- Drexel. clinical anatomy intensive elective course, host of many
troenterology and hepatology at MCP Hahnemann anatomy-centered events between WVSOM and the
University, now the Drexel University College of Med- Dr. Reynolds is board certified in internal medicine Japan College of Osteopathy and the Atlas College of
icine. He held this position and that of program direc- and gastroenterology and hepatology by the American Osteopathy. Dr. Ward has also served on the council of
tor from 1996 to 2008. In those 12 years he held Boards of Internal Medicine. His primary clinical inter- the American Association of Clinical Anatomists
numerous leadership roles in the hospital and college ests are in the early detection and prevention of cancer, and several of the special interest groups of the same
of medicine. He was elected vice-president of the uni- complications of gastroesophageal reflux, and gastroin- organization. He is also a member of the American
versity physicians practice plan (Drexel University testinal motility disorders. Association of Anatomists, American Association for
the History of Medicine, and the American Association
of Veterinary Anatomists. His research continues to
explore how medical students learn effectively, with
particular emphasis on anatomy. In conjunction with
Bone Clones, Inc., Dr. Ward has been producing a
series of tactile models that mimic the feel of anatomical
structures when intact and when ruptured during the
physical examination. He enjoys exploring the use of
video and other media as a supplementary resource in
medical education. These videos are available to view
at Clinical Anatomy Explained! on YouTube.
vi THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
About the Editors
John A. Martin, MD, Associate Editor, is associate Grace L. Su, MD, Associate Editor, is professor David C. Whitcomb, MD, PhD, Associate
professor, senior associate consultant, and associate of medicine and surgery at the University of Editor, is the Giant Eagle Foundation Professor
chair for endoscopy at Mayo Clinic in Rochester, Michigan. She received her undergraduate degree from of Cancer Genetics, professor of medicine, cell biology
Minnesota. His clinical, research, and medical educa- Yale University and medical degree from the University and physiology, and human genetics, and the chief of
tion efforts and interests are focused on endoscopic of Chicago Pritzker School of Medicine. After complet- the division of gastroenterology, hepatology, and nutri-
retrograde cholangiopancreatography (ERCP), advanced ing her internal medicine residency and gastroenterol- tion at the University of Pittsburgh School of Medicine.
interventional endoscopy, surgical endoscopy, hepatobi- ogy fellowship at the University of Pittsburgh in 1994, A graduate of Manchester College, North Manchester,
liary disorders, pancreaticobiliary diseases, transplanta- she was a member of the faculty until she moved to the Indiana, he completed his graduate training at The
tion surgery, natural orifice transluminal endoscopic University of Michigan in 1995, where she rose through Ohio State University with a doctorate in physiology in
surgery (NOTES), development of novel endoscopic the ranks to become professor both in internal medicine 1983, and a medical degree in 1985. He attended Duke
devices, bariatrics, and interdisciplinary investigation of and surgery, the latter because of her multidisciplinary University for training in internal medicine and a fel-
advanced molecular imaging technologies. He is also research program. Dr. Su has also had a part-time lowship in gastroenterology and hepatology. With
involved in interdisciplinary study of new simulation appointment at the University of Michigan affiliate, VA recruitment to the University of Pittsburgh, UPMC,
models and devices for endoscopic training and educa- Ann Arbor Healthcare System, where she is the associ- and the VA Pittsburgh Medical Center in 1991 as an
tion. While on faculty at Northwestern University ate chief of medicine for subspecialty care and access as assistant professor of medicine, Dr. Whitcomb began
Feinberg School of medicine, he co-founded the North- well as chief of the gastroenterology section. She is in illustrious career focusing on pancreatic disorders.
western Interdisciplinary NOTES Investigation Group also director of the Ann Arbor Specialty Care Access
and initiated the third-tier fellowship program in Network-Extension of Community Healthcare Out- Dr. Whitcomb established a major research labora-
advanced interventional endoscopy at Northwestern comes (SCAN-ECHO) program, a transformational tory with continuous funding from the NIH, VA,
Memorial Hospital, and was the recipient of excellence initiative that leverages technology to improve liver Department of Defense, National Pancreas Founda-
in teaching awards from both the division of gastroen- subspecialty care delivery within the VA healthcare tion, Wayne Fusaro Pancreatic Cancer Research Fund,
terology and hepatology and the department of medi- system, particularly to underserved and rural areas. As and other sources. In addition to research, he remains
cine, as well as the interdisciplinary service award from the director of one of the earliest Liver SCAN-ECHO clinically active, and accepted expanding administrative
the Transplantation Institute. He is the recipient of the programs, she has led the way in applying this novel roles as chief of the nutrition support service, then chief
Distinguished Service Award of the American Society case-based distance learning program to improve access of gastroenterology at the Pittsburgh VA Medical
for Gastrointestinal Endoscopy (ASGE). Co-founder to liver subspecialty care. Center, and finally chief, division of gastroenterology,
and formerly Chair of the ASGE Institute for Training hepatology and nutrition in 2000. His innovative
and Technology (IT&T) Committee, he currently Dr. Su has won many teaching and research awards approach to academic medicine resulted in transforma-
serves as councilor on the governing board of the ASGE. in gastroenterology. She has served on many NIH study tion of the GI division into one of the top academic
Dr. Martin also serves in an editorial capacity for a sections, particularly one devoted to career develop- digestive disease programs in the world.
number of medical publications and applications. ment in gastroenterology. She is a section editor for
the premier gastroenterology journal, Gastroenterology, Dr. Whitcomb serves on many national and interna-
Dr. Martin graduated from the University of Virginia as well as guest editor for multiple other journals tional committees for the major gastroenterology and
College of Arts and Sciences and the University of including Clinical Liver Disease. pancreatic societies. He served as a counselor for the
Virginia School of Medicine and then served his resi- American Gastroenterology Association and the Inter-
dency at University Hospitals of Cleveland, Case Dr. Su has broad research interests. In addition to 25 national Association of Pancreatology and was presi-
Western Reserve University. He received his fellowship years investigating innate immune system interactions dent of the American Pancreas Association. He serves
training in gastroenterology and hepatology at the Uni- with the liver, Dr. Su has also had a long-standing as editor and chief of Nature’s Clinical and Translational
versity of Pittsburgh, where he concentrated in pancre- research interest in noninvasive methods of assessing Gastroenterology journal, pancreas section editor of
aticobiliary disorders and therapeutic endoscopy. He liver fibrosis and disease. She has developed methods of UpToDate, associate editor for Pancreas and Pancreatol-
undertook third-tier fellowship training in advanced quantitative image analysis that have evolved into ogy, and serves on the advisory board for Nature Reviews
interventional endoscopy under Drs. Gregory Haber, analytic morphomics, an innovative high-throughput, Gastroenterology & Hepatology. He serves as a peer
Norman Marcon, and Paul Kortan at The Wellesley highly automated, anatomically indexed methodology reviewer for a number of scientific journals and as a
Hospital–St. Michael’s, University of Toronto, Ontario, for assessing body composition and organ measure- grant reviewer for the NIH, VA, DOD, and other insti-
Canada. Dr. Martin was appointed to the faculty of the ments from CT scans. By linking the morphological tutions. Dr. Whitcomb co-founded the Midwest Mul-
University of Pittsburgh School of Medicine in July data to clinical outcomes, she has developed highly ticenter Pancreatic Study Group, the North American
1997, joined the faculty of Northwestern University accurate noninvasive methods for the diagnosis and Pancreatic Study Group, and the Collaborative Alliance
Feinberg School of Medicine in 2003, and was recruited prognosis of liver disease and other gastrointestinal for Pancreatic Education and Research (CAPER) and
to the Mayo Clinic in Rochester, Minnesota, in 2015. diseases. She is presently the associate director for is the founder and director of the annual international
the Morphomics Analysis Group at the University of clinical-translational pancreas working group meeting,
Dr. Martin and his wife, Angela, have two wonderful Michigan. PancreasFest. He also co-founded and is chairman of the
young sons, Owen and Egan, and live in Rochester, medical advisory board of Ariel Precision Medicine LLC,
Minnesota, where they enjoy running, biking, and all Dr. Su is married with a wonderful husband and has a biotechnology company focusing on complex trait
the outdoors have to offer in the upper Midwest. two grown sons. genetics and precision medicine.
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS vii
About the Editors
Dr. Whitcomb’s research and discoveries resulted in but not altered sweat chloride or lung disease. His work from the International Association of Pancreatology for
a major paradigm shift in understanding inflammatory on pancreatic diseases as a complex gene-environment outstanding contributions to pancreas research.
disease of the pancreas. He has published over 300 disorder also resulted in major advances in a paradigm
manuscripts and has edited eight books on pancreatic for personalized medicine. Currently he is leading the Dr. Whitcomb and his wife, Chris, have four grown
disease. His laboratory group discovered the gene vari- UPMC Precision Medicine Initiative for Complex Dis- children, Jessica Michelle Gibson, David Michael
ants causing hereditary pancreatitis (PRSS1), a familial orders at UPMC. Whitcomb, Laura Edisene Graf, and John Clement
pancreatic cancer gene (PALLD), the primary genetic Whitcomb III, plus three grandchildren—Weston,
risk factor for alcoholic chronic pancreatitis (CLDN2), Dr. Whitcomb has received many honors and awards, Logan, and Holden. He and his wife live in Pittsburgh,
the smoking risk modifier for chronic pancreatitis including the Collaborative Alliance for Pancreatic Pennsylvania, where they continue to actively support
(CTRC) and a new CFTR-associated syndrome causing Education and Research Lifetime Achievement and local philanthropic organizations and international
pancreatic, male reproductive, and sinus dysfunction Mentoring Award and the George E. Palade Medal ministries.
viii THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
PREFACE
The opportunity to continue to promote the extraor- complexity and integrated beauty of this fascinating from Temple University. Dr. Parkman brings a special
dinary educational value of the exquisite art of Dr. organ system. The classic images Dr. Netter drew were new focus on the neurophysiology and electrical physi-
Frank Netter in a state-of- the-art update of this classic preserved whenever possible and altered only as neces- ology of normal gastric function and disease.
series has been an honor for me and my esteemed asso- sary. Dozens of modern radiographic and endoscopic
ciate editors. Netter’s images have brought insightful images have been added to all sections in all volumes. I review common anatomic, physiologic, and clinical
value to students for over 6 decades and have now been The first section in both Parts I and II summarizes aspects of intestinal disorders in Section 1 of Part II. In
updated and enhanced to benefit future generations of shared aspects of the digestive system. Each subsequent Section 2, Dr. Missale Solomon offers a beautifully
students. This updated edition of Digestive System has section is dedicated to a specific organ and reviews written treatment of normal and abnormal disorders of
been rewritten and renewed to include cutting-edge normal anatomy and physiology, pathology, pathophys- the primary digestive organ, the small intestine. In
science and state-of-the-art endoscopic, pathologic, and iology, and disease presentation and treatment. Section 3, one of modern gastroenterology’s eminent
radiographic images, along with Netter’s ageless draw- educators and Dean at the University of Connecticut,
ings and images that provide insights that foster stu- Each section has been written by authors who were Suzi Rose, MD, discusses the colon.
dents’ and practitioners’ understanding of the anatomy, chosen for their dedication to teaching the fascinating
physiology, and pathophysiology of all eight regions aspects of the digestive system. I had the honor of Part III reviews the normal physiology and patho-
that make up the fascinating and complex digestive choosing incredibly distinguished associate editors with physiology of the liver, biliary tract, and pancreas.
system. whom I have had the pleasure of working throughout Grace Su, MD, a distinguished clinician and scientist
my career. In each case they have published expertise from the University of Michigan, has exquisitely
Frank Netter, MD, described by the Saturday Evening in their respective organ system and have demonstrated updated the section on the liver in a way that will bring
Post as the “Michelangelo of Medicine,” continues to be their commitment to and skill in medical education. great insights into this, the largest solid organ in the
an icon in medical education. The insightful imagery Their knowledge and insights bring updated scientific body. John Martin, MD, another premier physician
of his medical illustrations provides value for students understanding of disease mechanisms and current treat- from the Mayo Clinic, provides wonderful modern
at all levels of experience who seek insights into the ments that will convey understanding of the largest and images of the biliary tract in Section 2, as well as
structure and function of digestion in ways that few most complex organ system that is unparalleled by descriptions of its many associated disorders. Section 3,
other texts have in the history of medical education. His other texts. In each section, Dr. Peter Ward updated on pancreatic function and disease, is written by one of
vision for these texts—integrating factual information each of the subsections on normal anatomy and physiol- the world’s premiere scientists and clinicians on pancre-
with visual aids—provides unparalleled insights. While ogy. He has worked hard to preserve the original pic- atology, Dr. David Whitcomb, chief of gastroenterol-
born at the onset of the twentieth century, his back- tures of Dr. Netter while ensuring the accuracy of the ogy and hepatology at the University of Pittsburgh.
ground mimics many modern medical students— text based on current terminology and science.
beginning his education in the arts before becoming a I would like to express my gratitude for the talented
scientist. By following his mother’s wishes to move In Part I of this three-part set I sought to provide and dedicated contributors to this wonderful update.
beyond art and into medicine, Frank Netter used his insights and an overview of the upper digestive tract. First and foremost, thanks must be given to Dr. Netter
passion and brush to communicate the science and the Michele Young, MD, associate chief of gastroenterology posthumously for providing the initial version of this
art of medicine in unparalleled ways. In distinction to at the University of Arizona’s Veterans Administrative text and its wonderful illustrations. I especially want to
anatomy texts that offer images of structure only, Hospital in Phoenix, has written the first organ-focused thank the associate editors and other contributing
Netter’s paintings also brought incredible insights into chapter on the complex anatomy, physiology, and patho- authors. I also want to thank the amazing artists
the pathophysiology of disease. Just as important, in physiology of pharyngeal and upper esophageal func- who work with the publishers, Jim Perkins, Tiffany
ways unsurpassed by any other text, he and his dedi- tions. New insights into imaging and physiologic DaVanzo, Kristen Wienandt Marzejon, and especially
cated disciples have illustrated how patients are affected understanding of the complexities of swallowing are Dr. Machado, for their talents and commitment to
by the suffering caused by disease. In all three of these provided. David A. Katzka, MD, distinguished profes- preserving the magnificent style and imagery of Dr.
revised parts of Digestive System, new artists, committed sor of medicine at the Mayo Clinic, revised the section Netter’s drawing. I want to thank my editors at Elsevier,
to the style and value of Dr. Netter’s illustrations and on the esophagus, and is clearly one of the world’s Marybeth Thiel and Elyse O’Grady, for their expertise,
led by Carlos Machado, MD, have modernized both the authorities on the topic. New insights into diseases that patience , and support. Finally, I want to thank my
science and the art of his illustrations in all aspects of are common today but were not known at the time of loving wife for more than 4 decades of unwavering
the digestive system. the first edition, including Barrett’s esophagus and support of my efforts to make contributions to the field
eosinophilic esophagus, are beautifully illustrated and of gastroenterology, which never ceases to fascinate and
This update of the digestive system’s anatomy and discussed. Part I closes with a section by Henry Parkman, challenge me.
disease has taken a new approach to communicate the MD, a renowned gastric physiologist and physician
James C. Reynolds, MD
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS ix
ADVISORY BOARD
Julio C. Bai, MD Juan Andrés de Paula, MD David Rubin, MD
Chair of Gastroenterology Chief of the Intestinal Diseases Section Joseph B. Kirsner Professor of Medicine
University of El Salvador Gastrointestinal Division Section Chief, Gastroenterology, Hepatology,
Hospital de Gastroenterología Dr. Carlos Bonorino Hospital Italiano de Buenos Aires
Associate Professor of Medicine and Physiology and Nutrition
Udaondo University Institute Hospital Italiano de Buenos Aires Co-Director, Digestive Diseases Center
Buenos Aires, Argentina Buenos Aires, Argentina University of Chicago Medicine and Duchossois
Brian P. Bosworth, MD Janusz A. Jankowski, MD, PhD
Associate Professor of Medicine Consultant Physician Center
Director, Gastroenterology Fellowship Program University Hospitals of Coventry and Warwickshire for Advanced Medicine
Weill Cornell Medical College Honorary Professor Chicago, Illinois
New York Presbyterian Hospital Warwick Medical School, University of Warwick Peter D. Siersema, MD, PhD
New York, New York Coventry, United Kingdom Professor of Gastroenterology
Marcia Cruz-Correa, MD, PhD Head, Department of Gastroenterology
Associate Professor of Medicine and Biochemistry
University of Puerto Rico and Hepatology
Director, Gastrointestinal Oncology Program University Medical Center Utrecht
University of Puerto Rico Cancer Center Utrecht, The Netherlands
San Juan, Puerto Rico
xii THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
CONTRIBUTORS
EDITOR David C. Whitcomb, MD, PhD Lisa M. Glass, MD
James C. Reynolds, MD Professor of Medicine Clinical Lecturer
June F. Klinghoffer Distinguished Professor Cell Biology & Physiology and Human Genetics, University of Michigan Health System
Chief, Division of Gastroenterology, Hepatology Staff Physician
and Chair Department of Internal Medicine
Department of Medicine and Nutrition, Gastroenterology Section
Drexel University College of Medicine University of Pittsburgh VA Ann Arbor Healthcare System
Philadelphia, Pennsylvania Pittsburgh, Pennsylvania Ann Arbor, Michigan
Plates 3-9–3-20 Plates 1-30, 1-53–1-57, 1-73–1-76, 1-85–1-90
SENIOR ASSOCIATE EDITOR Hellan K. Kwon, MD
Peter J. Ward, PhD CONTRIBUTORS Assistant Professor of Medicine
Associate Professor of Anatomy Henry D. Appelman, MD Division of Gastroenterology
Department of Biomedical Sciences M.R. Abell Professor of Surgical Pathology Department of Internal Medicine
West Virginia School of Osteopathic Medicine Department of Pathology University of Michigan Health System
Lewisburg, West Virginia University of Michigan Ann Arbor, Michigan
Plates 1-1–1-18, Plates 2-1–2-4, Plates 3-1–3-8 Ann Arbor, Michigan Plates 1-24, 1-25, 1-29, 1-42–1-52, 1-61–1-66
Plate 1-75 (imaging) Aatur Singhi, MD, PhD
ASSOCIATE EDITORS Darwin L. Conwell, MD, MS Assistant Professor
John A. Martin, M.D., FASGE Division Director The University of Pittsburgh Medical Center
Associate Professor and Senior Associate Consultant Division of Gastroenterology, Hepatology, Department of Pathology
Division of Gastroenterology and Hepatology Pittsburgh, Pennsylvania
Mayo Clinic and Nutrition Plate 3-17–3-20
Rochester, Minnesota; The Ohio State University Jonathon Willatt, MBChB
Adjunct Associate Professor of Medicine and Surgery Wexner Medical Center Assistant Professor
Northwestern University Feinberg School of Columbus, Ohio Body Imaging and Interventional Radiology
Plate 3-12 University of Michigan
Medicine Timothy L. Frankel, MD Ann Arbor, Michigan
Chicago, Illinois Assistant Professor Plates 1-85, 1-86, 1-87(imaging)
Plates 2-5–2-29 Department of Surgery
Grace L. Su, MD University of Michigan
Professor of Medicine and Surgery Staff Physician
University of Michigan Medical School VA Ann Arbor Healthcare System
Chief of Gastroenterology and Associate Chief Ann Arbor, Michigan
Plates 1-91–1-100
of Medicine
VA Ann Arbor Healthcare System
Ann Arbor, Michigan
Plates 1-19–1-23, 1-25–1-29, 1-31–1-41, 1-58–1-60,
1-67–1-72, 1-77–1-84
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS xiii
SECTION 1
LIVER
Plate 1-1 Liver: PART III
Heart Respiratory
Septum diverticulum
transversum Aorta
Vitelline Stomach
duct Liver bud
Duodenum
Midgut
Allantois Hindgut
Septum
3 mm embryo transversum Esophagus
Liver Stomach
Vitelline
duct Midgut
Allantois loop
Cloaca
Development of Liver Pericardial Lungs 5 mm embryo
cavity Esophagus
The foregut is the first segment of the gut tube within Septum Lesser
the abdomen. It is attached to the anterior body wall by transversum Stomach omentum
a ventral/anterior mesentery and to the posterior wall by Vitelline Liver Dorsal
a dorsal/posterior mesentery, the latter supplying blood duct Pancreas mesentary
from the dorsal aorta via the celiac arterial trunk. Two Allantois Dorsal
diverticula extend from the foregut, one dorsally and Gallbladder pancreatic
the other ventrally. The dorsal pancreatic bud extends Cloaca Hindgut bud
into the dorsal mesentery while the liver develops from Gallbladder
the endodermal cells that line the foregut and extend 9 mm embryo Bare area
into the ventral mesentery to create the hepatic diverticu- of liver
lum during the third week. The cells of the hepatic Diaphragm
diverticulum proliferate and extend superiorly into the Liver
septum transversum, which separates the pericardial Falciform
cavity from the developing peritoneal cavity. The cells ligament
of the mature liver will include cells that originated in
both the hepatic diverticulum (hepatocytes) and the in direct contact with the septum transversum, and the body wall; during embryonic and fetal life, it contains
septum transversum (Kupffer cells and fibroblasts). As mesothelial cells (also called the visceral peritoneum of the umbilical vein, which brings oxygenated blood from
the hepatic diverticulum expands within the septum the liver) reflect off of the liver and onto the inferior the placenta through the liver and to the developing
transversum, its connection to the foregut narrows to surface of the diaphragm. This leaves a bare area of the heart. The lesser omentum connects the liver to the
become the bile duct, which will carry bile from the liver liver on its superior surface, “bare” because it is not developing stomach and duodenum; it can be subdi-
to the duodenum. covered by mesothelial cells. vided into the hepatogastric and hepatoduodenal ligaments.
The hepatoduodenal ligament contains the common
At approximately 30 days of development, another As the stomach rotates and shifts to the left, the liver bile duct, as well as the hepatic portal vein and proper
extension of endoderm projects inferiorly from the bile enlarges and fills the superior right side of the abdomen. hepatic artery.
duct. This diverticulum will develop into the gallbladder, The falciform ligament tethers the liver to the anterior
and the connection between it and the bile duct will
become the cystic duct. Just proximal to the developing
gallbladder is yet another diverticulum extending from
the bile duct, the ventral pancreatic bud. The two pan-
creatic buds will fuse to form the mature pancreas, and
the gallbladder will become associated with the inferior
side of the liver.
The ventral mesentery, including connective tissue
from the septum transversum, connects the anterior
abdominal wall to the liver and the liver to the stomach.
These portions of the ventral mesentery thin out to
become the membranous falciform ligament and lesser
omentum, respectively. As the septum transversum
thins to become the central area of the diaphragm, it
leaves a layer of mesothelial cells on the surface of the
liver. The superior surface of the liver, however, remains
2 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-2 Liver
Foregut Hepatic v v
Common cardinal diverticulum vv v
vein in embryo of
Heart (atrium) about 4 mm
Umbilical vein
v
Vitelline vein
Endodermal cells penetrating
Hepatic diverticulum septum transversum to
surround vitelline veins (v)
Gallbladder Liver cells
Septum transversum from diverticulum
Vitelline vein Cells from
septum
Hepatic Gut
diverticulum
Yolk sac
Gallbladder tranSsevpetrusumm
Umbilical vein Vitelline
Hindgut vein
Sinus Schematic sagittal section
venosus of septum in 5-mm embryo
Common
cardinal 1 Gut Development of liver veins
veins 4.5 mm
Development of Liver and Its Umbilical Right 2 Left umbilical
Venous System veins umbilical vein anasto-
Liver 5 mm mosing with
The hepatic diverticulum buds off of the gut tube in Vitelline vein 4 left vitelline
close relation to the vitelline veins, located on the ventral veins anastomosing vein via liver
floor of the foregut at a site corresponding to the future Gut 9 mm sinusoids
duodenum. A vascular plexus branching out from the with liver
vitelline veins becomes surrounded by the endodermal Atrophy of 3 sinusoids, Diaphragm
cells that are developing into the liver. At an early stage, entire Bare area
the right and left vitellines feed blood to a plexus within right then Coronary
the liver, the hepatic sinusoids. Blood from this plexus umbilical atrophies ligament
leaves the developing liver through a pair of veins that and proximal Proximal, Ductus
enter the sinus venosus of the heart alongside the right part of middle (dorsal), venosus
and left umbilical veins coming from the placenta and left and distal (atrophies
the common cardinal veins. Subsequently, the right and umbilical anastomoses after birth)
left vitelline veins form anastomoses between each veins of vitelline veins Left umbilical
other: the first within the liver and then two more Ductus vein in
outside of the liver, lying dorsally and ventrally around venosus Hepatic falciform
the duodenum, so that a vascular ring is formed. Part veins ligament
of this ring will disappear as the distal portion of the (proximal Splenic and
vitelline veins and yolk sac dwindle. The remaining vitellines) superior
portion of the venous trunk that is posterior to the Portal vein mesenteric
duodenum becomes the portal vein; the portion that formed from veins
remains anterior to the duodenum develops into the portions of joining portal
superior mesenteric vein, joined by the splenic vein. The right and left vein
veins leading from the liver to the sinus venosus become
the hepatic veins, the left of which atrophies, so that vitellines
blood from the left half of the liver drains into the right and middle
vitelline vein. The umbilical veins initially drain exclu- anastomosis
sively to the sinus venosus by way of the common
cardinal veins, but they form anastomoses with the 6 mm
sinusoids bilaterally.
the placenta to the developing embryo. For a time the As the liver protrudes into the abdominal cavity, it
As development proceeds, the umbilical veins lose venous blood from the placenta passes through the liver remains in contact with the diaphragm in the bare area,
their connection to the common cardinal veins and to the right vitelline vein. Eventually, a large venous and the attachment to the septum transversum becomes
eventually the rest of the right umbilical vein atrophies, trunk, the ductus venosus, develops and separates from the coronary ligament. At the same time the umbilical
leaving only the left umbilical vein to carry blood from the hepatic sinusoids to carry oxygenated blood to the vein becomes incorporated within the falciform liga-
right atrium of the heart, bypassing most of the liver ment, running from the umbilicus to the liver. After the
parenchyma. At this stage, approximately half of the postnatal circulation is established, no more blood flows
blood from the umbilical vein goes through the ductus through the umbilical vein, and it becomes the fibrous
and the rest passes through the liver. ligamentum teres, still within the falciform ligament.
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 3
Plate 1-3 Liver: PART III
Prenatal circulation
Prenatal and Postnatal Pulmonary trunk Aorta
Circulation Superior vena cava Ductus arteriosus
Right pulmonary artery Left pulmonary artery
Right pulmonary vein Left pulmonary vein
In intrauterine life, fetal blood receives oxygen and Foramen ovale Inferior vena cava
nutrients from maternal blood in the placenta. Except Hepatic vein
during the very early stages when the yolk sac and vitel- Ductus venosus Aorta
line veins are still functioning, the umbilical cord sup-
plies blood to the fetus. While the vitelline veins are Liver Celiac trunk
transformed, the umbilical vein anastomoses with the Hepatic
hepatic sinusoids, so that at one stage (when the fetus portal vein Superior mesenteric artery
is 6 mm long), all of the blood of the umbilical vein Umbilical vein
passes through the primitive hepatic sinusoids. At the Kidney
same time, the right umbilical vein and the proximal Umbilical arteries
portion of the left undergo atrophy, and subsequently, Intestine
the enlarged distal part of the left umbilical vein courses
diagonally through the liver in a channel, the ductus Ligamentum
venosus, which has formed by rearrangement of early arteriosum
hepatic sinusoids. As the lobes of the liver grow, the (obliterated
ductus venosus comes to lie outside the liver and joins ductus
the inferior vena cava, in which the small amount of arteriosus)
deoxygenated venous blood from the caudal portions of
the fetus is mixed with the oxygen-rich blood coming Fossa ovalis
through the ductus venosus. The mixed blood entering (obliterated
the right atrium hits the interatrial membrane (septum foramen ovale)
secundum) and is directed through the foramen ovale Ligamentum venosum
into the left atrium, keeping the foramen open. In the (obliterated ductus venosus)
left atrium the blood mixes with a small amount of Ligamentum teres
nonoxygenated blood from the pulmonary veins, passes (round ligament) of liver
into the left ventricle, and then passes into the ascend- (obliterated umbilical vein)
ing aorta, where this mixed blood perfuses the coronary, Medial umbilical ligaments
common carotid, and subclavian arteries. A small (occluded part of umbilical arteries)
amount of blood within the right atrium from the infe-
rior and superior venae cavae is diverted into the right Postnatal circulation
ventricle and thereafter into the pulmonary trunk, which
supplies the lungs. Because the amniotic fluid is filling and the liver from birth on is provided with oxygen-rich ovalis is an indentation marking the location of the
the air passageways, the lungs have a high resistance, blood only via the hepatic arteries. With the first foramen. In the remaining infants, an oblique commu-
and very little blood from the pulmonary trunk actually respiration, the resistance in the pulmonary vascular nication may persist between the right and left atria,
enters the pulmonary arteries and lungs. Most of the tree diminishes, and this pressure drop leads immedi- which may be demonstrated anatomically but only in
blood in the pulmonary trunk is shunted into the ately to increased blood flow through the pulmonary rare cases is patent enough to allow mixing of oxygen-
descending aorta by way of the ductus arteriosus, where it arteries and veins and into the left atrium. This closes ated and deoxygenated blood. Within 3 months after
joins the blood ejected from the left ventricle. In this the valve of the foramen ovale, so that blood is no birth, the ligamentum arteriosum is no longer patent,
way, the viscera and lower limbs receive mixed- longer shunted from right to left. The foramen ovale is although it may also sometimes persist, allowing the
oxygenation blood, and the heart and brain, organs that closed within 1 year in 75% of newborns. The fossa mixing of blood.
are most sensitive to hypoxia, receive blood with higher
oxygen content directly from the left ventricle.
After birth, the placental blood flow ceases, the
newborn begins breathing, and the oxygen level in the
blood rises significantly. These changes induce closure
of both the ductus venosus and ductus arteriosus. These
channels are obliterated and become fibrous cords,
the ligamentum teres and ligamentum arteriosum, respec-
tively. The ligamentum teres terminates at the superior
margin of the umbilicus, near the two lateral umbilical
ligaments, containing the remnants of the umbilical
arteries, spread in the interior abdominal wall toward
the internal iliac arteries. During embryonic and fetal
life, the two umbilical arteries carried deoxygenated
blood from the body through the umbilical cord to the
placenta. With the closure of the ductus venosus, oxy-
genated blood no longer reaches the inferior vena cava,
4 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-4 Liver
Lateral rectus Transpyloric
(semilunar) plane plane
Diaphragm
11
22
33
44
5 5 Diaphragm
Topography of Liver Liver 6 L1 6 T3 Liver
covered by L3 7 4 covered by
The liver is located in the upper right part of the diaphragm, 7 L5 diaphragm,
abdomen. In the scheme of dividing the abdomen into pleura and 8 8 5 pleura and
nine regions, the liver occupies the right hypochondriac lung 9 9 T5 lung
region and the greater part of the epigastric regions. (percussion 10 (percussion
The left lobe of the liver extends, to a variable degree, dullness) 10 6 dullness)
into the left hypochondriac region. The liver is the Liver
largest organ of the body, weighing 1400 to 1600 g in T7 7 covered by
adult males and 1200 to 1400 g in adult females. In 8 diaphragm
normal, healthy individuals, the liver margin extending Liver and pleura
below the thoracic cage is smooth and offers little resis- covered by T9 9 (percussion
tance to the palpating finger. Downward displacement, diaphragm T 11 10 flatness)
enlargement, hardening, and nodular formation or and pleura 11 Gallbladder
cysts produce definite palpatory findings. Using percus- (percussion Inferior border of liver
sion, one must consider that the lungs overlie the upper flatness) 12
portion of the liver and that the liver, in turn, overlaps L1
the intestines and stomach. Liver
covered by L3
The projections of the liver on the body surface have diaphragm
added significance when one is performing a liver (percussion L5
biopsy. The projections vary, depending upon the posi- flatness or
tion of the individual as well as the body build, espe- intestinal
cially the configuration of the thorax. The liver lies resonance)
close to the diaphragm, and the superior pole of the
right lobe projects as far as the level of the fourth inter- Gallbladder
costal space or the fifth rib, the highest point being
1 cm below the nipple near the lateral body line. The Liver Liver covered Liver covered
superior limit of the left lobe projects to the upper by diaphragm, by diaphragm
border of the sixth rib. Here, the left tip of the liver is Diaphragm pleura and pleura
close to the diaphragm. and lung (percussion
(percussion flatness)
The ribs cover the greater part of the liver’s right dullness)
lobe, and a small part of its anterior surface is in contact
with the anterior abdominal wall. When a person is 1 23 4 5 678
standing erect, the liver extends downward to the 10th 9
or 11th rib in the right midaxillary line. Here, the 10
pleura projects downward to rib 10, and the more
superficial right lung projects to rib 8. The inferior 11
margin of the liver crosses the costal arch in the right
lateral body line approximately at the level of the 12
pylorus (transpyloric line). In the epigastrium the liver is
not covered by the thoracic cage and extends approxi- possible pathologic conditions within the thoracic cage hepar lobatum, and are changed by displacements of the
mately three fingers’ breadth below the base of the which may change the percussion qualities of the tho- organ or more often by thoracic conditions pushing the
xyphoid process in the midline. Part of the left lobe is racic organs. liver inferiorly. Subphrenic abscesses, depending upon
covered again by the rib cage. location and size, also displace the liver inferiorly.
In the horizontal position the projection of the liver Ascites, excessive dilatation of the colon, or abdominal
Over the upper third of the right half of the liver, moves slightly superiorly, and the percussive area of tumors may push the liver superiorly, and retroperito-
percussion gives a dull zone, because here the dia- flatness appears slightly enlarged. The extent of the flat neal tumors may move it anteriorly. Kyphoscoliosis or
phragm, pleura, and lung overlie the liver. Over the sound, best percussed in the horizontal position, pro- a barrel shape of the chest alters the position of the liver.
middle portion, flat percussion is obtained due to the vides information about the size of the organ. Sometimes the liver is abnormally movable (hepatopto-
presence of the liver. Similarly, over the lowest third of sis), causing peculiar palpatory findings.
the liver, a flat percussion tone is usually heard, except The projections of the liver are altered in some dis-
that sometimes intestinal resonance is produced by gas- eases, such as tumor infiltration, cirrhosis, or syphilitic
filled intestinal loops. The border between dullness and
flatness moves during respiration and is altered by
enlargement or displacement of the liver, and also by
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 5
Plate 1-5 Liver: PART III
Diaphragm (pulled up) Coronary ligament Left triangular ligament
Fibrous appendix of liver
Right Left lobe of liver
triangular
ligament Falciform ligament
Right lobe
of liver
Costal Round ligament (ligamentum teres) of liver
impressions (obliterated left umbilical vein) forming free
Gallbladder border of falciform ligament
(fundus) Anterior view
Surfaces and Bed of Liver
The liver is a large, wedge-shaped organ molded to the Colic impression Porta hepatis
underside of the diaphragm and resting upon the Fissure for ligamentum teres
abdominal viscera. Its diaphragmatic surface is divided Round ligament of liver Hepatic portal vein
into a superior part (which includes the cardiac impres- Hepatic artery proper
sion), an anterior part (which extends beyond the dia- Gallbladder Caudate process
phragm onto the anterior abdominal wall), a right part, Quadrate lobe Caudate lobe
and a posterior part (attached to the diaphragm by the Duodenal impression Fissure for
coronary ligament). The border between the anterior Renal impression ligamentum
aspect and visceral surface is the inferior margin. Its con- venosum
sistency, sharpness of edge, smoothness of surface, and Cystic duct Esophageal
movement upon respiration provide clinical informa- impression
tion. On laparotomy, the inferior margin and the ante- Common hepatic duct
rior aspect are first exposed. Otherwise, the hepatic (Common) bile duct Gastric
surfaces are not separated by distinct margins. impression
Right triangular ligament
The liver is covered by peritoneum, except for the Hepatorenal portion of Left triangular
gallbladder bed, the porta hepatis (entry point of the coronary ligament ligament
common hepatic duct, hepatic artery, portal vein, lymphat- Suprarenal impression
ics, and nerves), adjacent parts surrounding the inferior Bare area Hepatic veins Coronary
vena cava, and a space to the right of the inferior vena Inferior vena cava ligament
cava called the bare area, which is in contact with the
right suprarenal gland (suprarenal impression) and the Falciform ligament Visceral surface Left triangular
right kidney (renal impression). The peritoneal duplica- ligament
tions, which extend from the anterior abdominal wall Left Coronary ligament
and from the diaphragm to the organ, form the liga- triangular
ments of the liver, which, along with intraabdominal ligament Bare area
pressure, help fix the liver in its position. The diaphrag- Fissure for Inferior vena cava
matic peritoneal duplication is the coronary ligament, the ligamentum Suprarenal gland
upper layer of which is exposed if the liver is pulled venosum
away from the diaphragm. The right free lateral margin Groove for (inferior) vena cava Right kidney
of the coronary ligament forms the right triangular liga- Right triangular
ment, whereas the left triangular ligament surrounds and Posterior view ligament
merges with the left tip of the liver, the fibrous appendix Superior recess
of the liver. The space between the upper and lower of omental bursa
layers of the coronary ligament is filled with areolar
connective tissue. Below the insertion of the lower layer Duodenum
of the right coronary ligament, the hepatorenal space
extends posterior to the liver and anterior to the right Stomach
kidney. Bed of liver
The falciform ligament extends from the liver to the two fissures may be regarded as the left limb of an The caudate lobe lies superior to the porta hepatis,
anterior abdominal wall, originating from the middle H-shaped pattern characteristic of the visceral surface between the fissure for the ligamentum venosum and
portion of the coronary ligament. This double layer of of the liver. The right limb is formed by the gallbladder the inferior vena cava; the inferior projection of the
peritoneum contains the ligamentum teres (obliterated fossa and the groove for the inferior vena cava. The hori- lobe is the papillary process. The visceral surface of the
left umbilical vein), and its insertion on the liver divides zontal limb is marked by the porta hepatis, where vessels liver reveals further impressions of the organs with
the organ into a right lobe and a left lobe. As the falciform and bile ducts enter and exit the liver. The quadrate lobe, which it is in contact: the impressions for the colon and the
ligament crosses the inferior margin of the liver it between the gallbladder and the fissure for the umbili- right kidney, and on the left lobe the impressions for the
releases the ligamentum teres, which then enters a cal vein, is in contact with the pylorus and the superior esophagus and the stomach. The superior surface is related
fissure on the visceral surface of the liver. Inferiorly, this (first) portion of the duodenum (duodenal impression). to the diaphragm and forms the domes of the liver.
fissure for the ligamentum teres separates the quadrate lobe
from the left lobe of the liver. Beyond the porta hepatis it
is continued superiorly as the fissure for the ligamentum
venosum (the obliterated ductus venosus of the fetus). The
6 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-6 Liver
Omental Round ligament (ligamentum teres) of liver Window cut in lesser omentum
(epiploic) (obliterated umbilical vein) (hepatoduodenal ligament)
foramen
(Winslow) Quadrate lobe Caudate lobe seen through lesser
omentum (hepatogastric ligament)
Gallbladder Left lobe of liver
Right lobe (Common) bile duct
of liver Hepatic artery proper
Kidney Hepatic portal vein
(retro- Lesser
perito- omentum
neal) (hepatogastric
ligament)
Lesser Omentum, Variations Spleen
in Form of Liver Stomach
If the inferior margin of the liver is lifted, the lesser Right colic Duodenum Greater omentum Greater Left colic
omentum is exposed. It is a peritoneal fold extending (hepatic) Variations in form of liver omentum (splenic)
from the first portion of the duodenum and the lesser flexure flexure
curvature of the stomach to the liver, where it is inserted
into the fissure of the ligamentum venosum and con- Very small left Complete atrophy Transverse, “saddlelike” liver,
tinues to the porta hepatis. Here, the layers are sepa- lobe, deep costal of left lobe relatively large left lobe
rated to accommodate the structures running to and impressions (left portal vein
from the liver. On the free right edge of the lesser compression)
omentum is the thick hepatoduodenal ligament. It forms
the anterior boundary of the omental (epiploic) foramen “Tonguelike” Very deep renal Diaphragmatic
(of Winslow), which is the entrance to the omental bursa. process of impression and grooves
The posterior wall of this cavity is formed by the inferior right lobe “corset constriction”
vena cava and the caudate lobe of the liver. Near the right
margin of the lesser omentum is found the common bile Such physical forces may flatten and elongate the liver clinical manifestations other than peculiar findings on
duct, which divides into the cystic duct and common hepatic downward with reduction of the superior diaphrag- palpation. Indentations on the liver are normally pro-
duct. To its left lies the hepatic artery and posterior to matic surface and sometimes with a peculiar tonguelike duced by the ribs, by diaphragmatic insertions, and by
both, the portal vein. The nerves and lymph vessels of extension of the right lobe. In other instances, the corset the costal arch. In kyphoscoliosis, the rib insertions may
the liver accompany these structures. The porta hepatis liver is displaced, and the renal impression is exagger- become very prominent. Parallel sagittal furrows on the
is limited anteroinferiorly by the quadrate lobe and pos- ated. Clinical symptoms (dyspepsia, cholelithiasis, chlo- hepatic convexity have been designated as “diaphrag-
terosuperiorly by the caudate lobe. On the right side of rosis) were ascribed to the corset liver, but it is matic” grooves. None of the described variations are
the porta hepatis, the main hepatic duct branches into questionable whether this condition actually led to considered functionally significant today.
the right and left hepatic ducts and they enter the liver.
On the left side of the porta hepatis the hepatic artery
enters the liver posterior to the branching of the ducts.
The forking portal vein enters posterior to the ductal
and arterial ramifications.
The shape of the liver varies. Its great regenerative
ability, as well as the plasticity of the liver tissue, permits
a wide variety of forms, which depend in part upon
pressure exerted by neighboring organs and in part
upon disease processes or vascular alteration. A greatly
reduced left lobe is compensated for by enlargement of
the right lobe, which reveals very conspicuous and deep
costal impressions. Occasionally, the left lobe is com-
pletely atrophic, with a wrinkled and thickened capsule
and, microscopically, an impressive approximation of
the portal triads, with hardly any lobular parenchyma
between them. In the majority of such cases, vascular
aberrations have been demonstrated, such as partial
obstruction of the lumen of the left branch of the portal
vein by a dilated left hepatic duct or obstruction of the
bile ducts. This lesion is therefore thought to be the
result of a local nutritional deficiency, especially because
the nutritional condition of the left lobe is poor to begin
with. In other instances, associated with a transverse
position of the organ, the left lobe is unduly large.
Historically, deformation of the liver sometimes
resulted from laced corsets or from tight belts or straps.
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 7
Plate 1-7 Liver: PART III
Liver cells with various degrees of fat accumulation,
ranging from fine droplets (A) to large fatty cysts (B)
Cellular Elements of Liver Glycogen in liver
cells (above),
Hepatocytes are the cells that make up the parenchyma stained with Best
of the liver. The cytoplasm of the hepatocytes normally caymine. (right)
contains various defined particles that can be visualized Simple
by histochemical methods. Neutral fat is found in the hematoxylin–
form of droplets, which are stainable in frozen sections eosin stain
by fat stains but appear as vacuoles after dissolution of
fat with the routine use of organic solvents in histologic Variform mitochondria in liver cells A C
techniques. The fat droplets or vacuoles in normal liver reflecting differences in functional activity B
cells do not exceed 4 microns in diameter. They usually (Janus green stain)
line up on the free margin of the cells, like pearls on a
string. Enlargement of the fat droplets is the result of E
an imbalance between the transport of fat to the liver D
from either the intestine or the peripheral tissue, or of
its formation or catabolism within the liver. The imbal- Kupffer cells in various stages. (A) Testing stage; (B) containing
ance in fat metabolism may be focal, mainly due to bacteria; (C) containing pigment; (D) containing red blood cells;
disturbances of the blood flow and local anoxia, or may (E) containing fat droplets
be diffuse. The fat droplets become gradually larger
until the liver cell cytoplasm is studded with droplets of inclusions are bacteria, pigments, red cells, and fat droplets. liver metabolism. They store vitamin A within lipid
different size; the nucleus, however, still remains in the In various abnormal conditions, the phagocytosis inclusions and release it as needed. When the liver is
center. Subsequently, the droplets merge, and one large becomes exaggerated, and resting endothelial-like stel- damaged, these cells cease playing a role in vitamin A
drop pushes the nucleus to the side. Eventually, large late sinusoidal macrophages can rapidly change into the metabolism and differentiate into cells that are similar
drops of neighboring liver cells coalesce to form fatty large phagocytic type. These cells typically line the or identical to myofibroblasts. They then release types I
cysts, in which the fat is actually extracellular and the hepatic sinusoids, where they can interact with incom- and III collagen to repair damage to the stroma
remnants of several cells line the cyst. ing pathogens or fragments. and parenchyma of the liver, thus becoming involved in
the development of cirrhosis by changing the stroma of
Glycogen, if previously precipitated by alcohol fixa- The hepatic stellate cells (Ito cells) are also found within the liver.
tion, appears as fine red particles in the cytoplasm after the sinusoidal space but play a distinct role in normal
staining with Best’s carmine or periodic acid–Schiff
reagent. In routinely fixed and stained sections or
biopsy specimens of normal liver, the dissolved glyco-
gen produces a fine, granulated and vacuolated appear-
ance of the cytoplasm. In severe disease of any kind,
particularly in the agonal period, the glycogen content
becomes markedly reduced, so that, as a rule, in autopsy
specimens little glycogen is found. The glycogen
content of the liver cells is an index of its functional
status. The mitochondria of hepatocytes are stainable
with preparations such as Janus green, appearing as
globular elements in the center and rod-shaped ele-
ments in the periphery of the lobule. They contain, as
do all cells of the body, phospholipids and a great
number of enzyme systems.
The stellate sinusoidal macrophages (Kupffer cells)
assume a wide variety of shapes in the normal liver as
an expression of different activity stages, primarily
phagocytosis. Some of them are flat, similar to endo-
thelial cells in other organs. Others have a large amount
of cytoplasm, which contains various inclusions, not
necessarily an expression of disease. Some of these
8 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-8 Liver
LIVER STRUCTURE: SCHEMA
Lymph vessel
Central vein Connective tissue Central vein
Sublobular vein (tributary to hepatic vein)
Perisinusoidal spaces
Sinusoids
Intrahepatic Structures
LIVER CELL ARRANGEMENT Limiting plate Central vein
The liver is an incredibly complex organ that has mul- of portal space
tiple functions. It receives blood from the hepatic portal Periportal space
vein carrying nutrients and other substances that it Periportal bile ductule
metabolically modifies. The liver releases serum pro-
teins into the bloodstream to maintain bodily homeo- Bile duct
stasis. It stores vitamins A, D, and K, as well as iron. It
also uses bilirubin from the spleen to create bile, which Branch of
it conjugates and excretes into the descending (second) portal vein
part of the duodenum through the bile ducts. The Portal arteriole
microscopic appearance of the liver gives us some
insight into how these processes are accomplished. The Branch of Inlet venule Intralobular bile ductule Central vein
liver is covered by a connective tissue capsule (of Glisson) hepatic artery Periportal bile ductule
that is itself covered by a layer of visceral peritoneum, Distributing vein
except over the bare area of the liver. The capsule sends Periportal arteriole
connective tissue septae into the parenchyma of the Intralobular arteriole
liver, separating it into distinct segments; these will be
discussed in relation to the blood supply to the organ. Lobule Central vein (systemic)
The parenchyma of the liver is constituted almost Hepatocyte cords
entirely of hepatocytes, although other cells will play Sinusoids
important roles that allow the hepatocytes to operate
properly. Portal triad Portal vein branch
Hepatic artery branch
The portal triad refers to three structures that travel Interlobular bile duct
together grossly and microscopically. They are the
hepatic portal vein, hepatic artery, and bile duct; these three Liver arranged as series of hexagonal lobules, each composed of
structures pass into the liver at the porta hepatis and series of hepatocyte cords (plates) interspersed with sinusoids. Each lobule
then subdivide into smaller vessels and ducts, but always surrounds central vein and is bounded by 6 peripheral portal triads (low magnification)
remain close to each other. Subsequent studies have
demonstrated the existence of lymphatic vessels that Portal triad Hepatic artery branch Intercellular network Canaliculi formed
travel along with the portal triad. The portal vein and Portal vein branch of bile canaliculi between tight
hepatic artery deposit blood into large vessels within junctions of
the liver, the hepatic sinusoids. The epithelium and basal Interlobular bile duct adjacent
lamina of these sinusoids are discontinuous, allowing hepatocytes
the blood plasma to exit the confines of these sinusoidal
capillaries. Sinusoids
(fenestrated
The classic description of the liver’s microscopic capillaries)
arrangement is that hepatocytes form cords composed of border cords
cells facing each other across the sinusoids. These cords of hepatocytes
extend in an irregular, crooked, and angular fashion
throughout the liver. The sinusoids are lined by a dis- Hepatocyte cord
continuous epithelium, which not only has large open- Parts of hepatic lobule at portal triad (high magnification)
ings (fenestrae) in the cells themselves, but also large
gaps between adjacent cells. The endothelial lining of space that separates the sinusoidal wall from the hepa- Oxygenated blood enters each sinusoid via the
the sinusoids is made up of simple squamous epithelial tocytes. This space is the beginning of the lymphatics hepatic artery and mixes with deoxygenated blood
cells along with many stellate sinusoidal macrophages of the liver. Fluid in this space drains toward the portal brought to the liver through the hepatic portal vein.
(Kupffer cells) and the occasional hepatic stellate cell triad, entering the space of Mall in the area between Thus, even hepatocytes that are exposed to blood
(Ito cell). Just deep to this layer is a discrete space the hepatocytes and the connective tissue surrounding shortly after it enters a sinusoid do not receive very well
between the sinusoid and the hepatocytes. This is the the portal triad. It thereafter travels in the lymphatic oxygenated blood. Red blood cells and plasma travel
perisinusoidal space (of Disse), and it is filled by microvilli vessels that accompany the portal triad, draining toward through each sinusoid toward a single central vein. The
that extend from the hepatocytes, expanding their the celiac lymph nodes. hepatocytes closest to the central vein invariably receive
surface area and giving them access to the contents of
the blood plasma.
The sinusoids differ from capillaries elsewhere in the
body owing to the specific functions of the Kupffer
cells, which may increase in size, as well as to the
greater permeability of their membrane for macromo-
lecular substances, especially proteins. The large open-
ings in the sinusoids permit a better exchange of
large-sized compounds between liver cell and sinusoid.
The exchange of nutrients and waste products of large
or small size takes place through the perisinusoidal
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 9
Plate 1-9 Liver: PART III
Intrahepatic Structures VASCULAR DUCTAL RELATIONS AND LIVER LOBULES Sublobular veins
Hepatic vein
(Continued) Portal
Sublobular vein triad
the most poorly oxygenated blood. Unlike the portal Central vein Sinusoids
triad, the central veins have no companion structures. Sinusoids Central
vein
LIVER LOBULES Portal
Between the ramifications of portal triads and central triad Portal triads
veins, the hepatic parenchyma is surrounded by a fine
framework of reticular fibers (type III collagen), which, Perivascular fibrous (Glisson) Hepatic artery proper
in turn, are anchored at the portal triads. This network capsule extending into porta Hepatic portal vein
of fibers appears to be arranged in a concentric manner hepatis along vessels and bile duct Common hepatic duct
toward the central vein. This characteristic pattern has
led to the description of the classic liver lobule. This Hepatic artery branch
description of the liver’s microscopic appearance posits
a roughly quadrangular or hexagonal structure, with the Portal vein branch Portal triad
portal triad at each corner and a central vein in the
center. This construct makes it easy to conceptualize Bile ductules
the flow of blood from each triad through the sinusoids,
traveling toward the central vein. The portal triads exist Sinusoids
along the periphery of each liver lobule and therefore
feed blood into several lobules. The periphery of the Liver cell “plates”
human liver lobule between adjacent liver lobules is not
sharply defined. Under abnormal circumstances (e.g., Central veins (tributary to hepatic vein
perilobular fibrosis), a sharper lobular delineation may via sublobular veins)
be found in humans. Pigs typically have stout connec-
tive tissue septae running between adjacent portal
triads, making the liver lobule very easy to visualize.
Sadly, although the same structures exist in humans, the
lobule is not so neatly demarcated. However, the liver
lobule is only one way of organizing the microstructure
of the liver.
One may also start with three (or more) central veins
on the periphery of a triangle (or quadrangle) with a
portal triad in the center. This construct is known as a
portal lobule and is particularly useful for conceptualiz-
ing the flow of bile from the hepatocytes toward the
bile ducts found within each portal triad. This empha-
sizes the glandular activity of the liver and is particularly
useful when looking for pathologic changes occurring
as a result of blockage of the biliary duct system.
Yet another method of viewing the live parenchyma
is the liver acinus, shaped like an American football or
a lentil, with a central vein at each end of the long axis
and a portal triad at each end of the short axis. This
construct is particularly useful when examining the
effect of ischemia and other pathologic processes on the
hepatocytes. The hepatocytes closest to the portal triad
receive the best-oxygenated blood, whereas those
closest to the central veins receive more poorly oxygen-
ated blood. The cells closest to the central vein corre-
spond to the cells at the center of the liver lobule and
the periphery of the portal lobule.
INTRAHEPATIC BILIARY SYSTEM Normal lobular pattern of liver Under these circumstances the arrangement of the
Bile is produced by the hepatocytes but is not released is now realized that they represent artefacts brought distended bile canaliculi is readily visualized without
into the perisinusoidal space. Instead the biliary pas- about by anoxia or other alterations of the animals special stains. With injuries to the liver cells, therefore,
sages start as fine bile canaliculi found on the surface of observed under such conditions. It is, therefore, now the continuity of the walls of bile canaliculi is also
the hepatocytes, opposite their sinusoidal surface. The assumed that the bile canaliculi have a fairly straight destroyed, which explains the backflow of bile from the
bile canaliculi can be demonstrated by injection of dyes lining with only small extensions between neighboring bile capillaries into the tissue spaces in jaundice caused
that are excreted into the bile. The use of fluorescent liver cells, a theory that agrees with the picture seen in by hepatocellular damage.
dyes has greatly enhanced the visualization of the bile tissue sections if the bile capillaries are stained with
capillaries, which fluoresce bright yellow-green under proper techniques, such as mordant hematoxylin. In The bile canaliculi form an intercommunicating
ultraviolet light shortly after injection of fluorescein, in jaundice the bile canaliculi become dilated and filled network between adjacent hepatocytes. They are sur-
vital microscopic studies or tissue sections. In such with bile, sometimes precipitating bile casts or plugs. rounded by the liver cells, and although they appear to
preparations, diverticula, sometimes having a vacuo-
lated appearance, have been observed frequently, but it
10 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-10 Liver
Intrahepatic Structures INTRAHEPATIC VASCULAR SYSTEM
(Continued) Limiting plate of portal space Bile canaliculi
lie within grooves on the outside of the hepatocytes, Branch of portal vein
they are actually part of the cell. Nowhere in the normal Bile ducts
liver are the bile capillaries close to the perisinusoidal
space. The network of bile canaliculi is drained by the Periportal bile ductules
smallest intralobular bile ductules, which in turn drain to
larger periportal bile ductules (canals of Hering), found in Sinusoid
the connective tissue near the portal triads within the
liver. These ductules form communicating loops, which Intralobular bile ductules Central vein
eventually either unite with the periportal bile ductules Portal vein ramification (after Hans Elias)
or independently perforate the limiting plate to reach Outlet sphincters
larger bile ducts running along the portal triad. The Outlet Central vein
intralobular bile ductules are surrounded by a connec- sphincters Peripheral sinusoid
tive tissue sheet that also envelops the arterioles and, Radial sinusoid
possibly, the very small lymphatic vessels. The epithelial Inlet Central vein
cells that line these bile ductules, cholangiocytes, are sphincters Outlet sphincters
cuboidal with a central nucleus, a less-basophilic cyto- Distributing veins
plasm than the surrounding hepatocytes, and a single Inlet venules with inlet sphincters
long cilium extending into the duct’s lumen. The sepa-
ration can be made much more easily when the base- Limiting plate
ment membrane is made visible by connective tissue
stains. As the ducts become wider, owing to the conflu- Small distributing veins
ence of the smaller ducts, their epithelium becomes the
high columnar type and, occasionally, the mucus- Conducting veins
producing type. Mucus is also added to the duct’s
content by small adnexal secretory glands. Distribution of hepatic artery and regulators of blood flow
INTRAHEPATIC VASCULAR SYSTEM Distributing vein Sublobular vein
After the portal vein has forked into main branches and Bile duct
has divided consecutively into smaller branches, the Hepatic artery 4
conducting veins, which eventually reach small portal Intralobular arterioles
tracts in which a central distributing vein, less than Periportal arteriole 4 42 3
0.3 mm in diameter, discharges short inlet venules at Portal arteriole 1
right angles. Finally, the smallest portal vein branches (peribiliary plexus) 4 4
into two terminal twigs entering the parenchyma. The 1. Inlet venule sphincter 2
inlet venules extend through the connective tissue sur- 2. Outlet venule sphincters
rounding the portal triad into the sinusoids within the 3. Central–sublobular vein throttle 4 Central vein
liver lobules, supplying the bulk of the portal vein blood 4. Arteriolar sphincters
to the parenchyma. From the sinusoids, blood flows to 5. Arterial constriction 5
the central vein.
Venous drainage of the liver itself begins with the explain the relatively strong tendency for centrilobular
The blood supply and drainage of the structures in central veins that are located at the terminus of each congestion and necrosis to occur in humans. Compara-
the portal tract, especially of the bile ducts, differ from hepatic sinusoid. The central veins unite to form sublobu- tively small veins frequently enter larger hepatic vein
those of the hepatic parenchyma in that the portal vein lar veins, which, in turn, form larger intrahepatic veins and tributaries at right angles, a design that provides a pos-
branches act as vessels that drain blood rather than finally join the inferior vena cava as hepatic veins. In con- sibility for reduced drainage by contraction of the larger
supply it. Small venules collecting blood from the capil- trast to some animals such as the rat, no sinusoids enter vessel. Such a throttle mechanism, in the absence of true
lary plexus in the portal tracts, and especially around sublobular and larger hepatic vein tributaries in the muscular sphincters, is recognized in a morphologic
the bile ducts, transport it into the lobular parenchyma human. That situation represents a potential difficulty sense by a dilatation of the smaller vessel just before it
by uniting with inlet venules acting as “internal roots” for the drainage of the hepatic parenchyma and might pierces the wall of the larger one.
of the portal vein. Malignant hepatic tumors frequently
have a blood supply more similar to that of the struc-
tures of the portal tract than to that of the parenchyma,
and the efferent portal vein branches corresponding to
the “internal roots” may become large trunks; these
facts might suggest that these tumors are derived from
structures in or near the portal tracts.
The hepatic artery ramifies parallel with the portal
vein branches. Arterioles are released into the lobular
parenchyma and terminate at different levels of the
lobule, providing fresh arterial blood to all of its parts.
The bulk seems to be released close to the portal triad
by periportal arterioles, although longer intralobular arte-
rioles carry arterial blood to sinusoids further from the
triad. The arterial branches within the connective tissue
surrounding the portal triad supply its constituents with
blood via portal arterioles; the blood is drained by “inter-
nal roots” of the portal vein or distributing veins.
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 11
Plate 1-11 Liver: PART III
Anatomic Right lobe Left lobe Division into segments is
lobes Right (part of) liver Left (part of) liver based upon ramifications
of bile ducts and hepatic
Functional vessels. It does not entirely
surgical Lateral Medial correspond with division
segments division Medial division division Lateral division into anatomic lobes.
Posterior Lateral segment (II)
lateral Posterior medial (Medial (Lateral superior area)
Vessel and Duct segment segment (VIII) superior Left anterior
Distribution, Liver Segments (VII) (Anterior area) lateral segment
(Posterior superior area) (III)
The intrahepatic distribution of vessels and bile ducts superior Medial (Lateral Parietal
was successfully studied on casts prepared by injecting area) segment (IV) inferior surface
a chemically impregnable plastic into the vascular and Right
biliary conduits before removing tissue by corrosive anterior Anterior (Medial area)
agents. The knowledge thus obtained proved to be a lateral
valuable asset for the cholangiographic demonstration segment medial inferior
of the vascular apparatus in vivo but was also of more (VI) segment (V) area)
than theoretical interest in view of the recognition of (Posterior (Anterior
segmental divisions, similar to those in the lungs, which inferior inferior area) Right lobe Left lobe
opened up the possibility of partial hepatectomy or the area)
excision of single metastatic nodules and surgical exci- (Anterior Anterior medial segment (V)
sion of specific segments. Although the human liver, in
contrast to the liver of some animals, fails to display Right inferior (Medial Medial
surface lobulation, the parallel course of the branches anterior area) inferior segment (IV)
of the hepatic artery, portal vein, and bile ducts and the area)
appearance of clefts in these preparations of vessels and lateral Quadrate Left
ducts pointed to a distinct lobular composition. A major segment (VI) lobe anterior
lobar fissure extends obliquely inferior from the fossa (Posterior Posesgtemrieonrt(c(Ia)udal) lateral
for the inferior vena cava to the gallbladder fossa, which Visceral inferior area) segment (III)
does not coincide with the surface separation between surface (Lateral
the right and left lobes running along the insertion of inferior area)
the falciform ligament and the fossa for the ductus Posterior lateral Lateral
venosus. Through this fissure extends one of the main segment (VII) segment (II)
trunks of the hepatic vein, the tributaries of which never (Posterior superior (Lateral superior
follow the distribution of the other vessels but cross the area)
portal vein branches in an interdigitated fashion. area)
Each lobe is partitioned by a segmental division and (Medial
is drained by a lobar bile duct of the first order. The Right Left superior
right division extends obliquely from the junction of 7 Caudate area)
the anterior and posterior surfaces inferiorly toward the process
lower border of the liver and continues on the inferior 8 Caudate lobe
surface toward the porta hepatis, dividing the right lobe
into an anterior and a posterior segment, each of which is 11 Distribution of vessels
drained by a bile duct of the second order. The left and ducts
segmental cleft runs on the anterior surface along the 5 3 4 6 12 1 Right branch
attachments of the falciform ligament and on the vis- 1 2 2 Left branch
ceral surface through the fissure of the ligamentum 3 Anterior segment
teres and ligamentum venosum. This fissure divides the 4 Medial segment
left lobe into a medial and a lateral segment, but in a sig- 5 Posterior segment
nificant number of cases it is crossed by bile ducts and 13 6 Lateral segment
vessels. The lateral segment corresponds to the classic 9 16 7 Anterior inferior area
descriptions of the left lobe, whereas the aspect of the
medial segment on the visceral liver surface corre- 8 Medial inferior area
sponds to the quadrate lobe. The four bile ducts of the 9 Anterior superior area
second order fork into those of the third order, which 15 15 14 10 Medial superior area
drain either the superior or the inferior area of the cor-
responding segments. Thus, the bile ducts and the 11 Posterior inferior area
accompanying vessels can be designated according to 10 12 Lateral inferior area
the lobes, segments, and areas to which they belong. 13 Posterior superior area
The anatomically distinct caudate lobe has a vascular 14 Lateral superior area
arrangement that divides it into a left portion drained by Phantom division Inferior vena cava Common hepatic duct, hepatic 15 Caudate lobe
the left lobar duct and a right portion drained by the between anterior and portal vein, and proper hepatic
right lobar duct. The caudate process, connecting the posterior superior areas artery (right and left)
caudate lobe with the right lobe of the liver, has a sepa- 16 Caudate process
rate net of vessels, which, in the majority of cases, com-
municates with branches of the right lobar duct. Neither lobar duct systems. Intrahepatic anastomoses between individual variations are met in abundance. They
the caudate lobe nor other parts of the liver provide an intraparenchymal branches of the arteries also have not concern, especially, the lateral superior vessels and
effective communication between the right and left been found, but in one fourth of the cases interconnec- ducts for the appendix fibrosa. Rudimentary bile ducts
tions between the right and left systems exist through are frequent in this region. The incidence of segmental
small extrahepatic or subcapsular anastomosing vessels. bile duct variation is greater on the right, whereas that
of segmental arteries is greater on the left side. Further-
The distribution of draining bile ducts and afferent more, the observations of several investigating groups
blood vessels, as described and pictorialized in a sche- are, in some respects, still at variance.
matic fashion, is valid in the majority of instances, but
12 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-12 Liver
Right gastric artery (cut) Intermediate hepatic artery Right and left inferior phrenic
Common hepatic duct Hepatic artery proper arteries (shown here from
Right hepatic artery Left hepatic artery common stem)
Cystic artery Hepatic portal vein Celiac trunk
Abdominal aorta
Gallbladder Common hepatic Short
artery gastric
arteries
Left
gastric
artery
Cystic
duct
(Common)
bile duct
Supraduodenal Left gastro-omental
artery (gastro-epiploic)
Gastroduodenal artery (cut)
artery Artery to tail of
pancreas
Greater pancreatic artery
Splenic artery
Dorsal pancreatic artery
Arterial Blood Supply Posterior superior Inferior pancreatic artery
of Liver, Biliary System, pancreaticoduodenal Anastomotic branch
and Pancreas artery (phantom) Middle colic artery (cut)
Anterior superior Superior mesenteric artery
As is the case in the gastrointestinal system in general, pancreaticoduodenal artery Inferior pancreaticoduodenal artery
the arterial supply of the liver, biliary system, and pan- Posterior inferior
creas is incredibly variable. This plate will cover the Right gastro-omental pancreaticoduodenal artery
typical branching pattern, and we will thereafter review (gastro-epiploic) artery (cut) Anterior inferior
the most common variations of the vasculature related pancreaticoduodenal artery
to the liver. The celiac trunk is usually a short, thick
artery originating from the aorta just below the aortic omentum) alongside the common bile duct and hepatic duct, and the liver. In a minority of cases, however, the
hiatus in the diaphragm. It extends horizontally and portal vein. The proper hepatic artery ascends anterior right hepatic artery crosses anterior to the bile duct. All
forward above the pancreas, and splits into left gastric, to the hepatic portal vein and to the left of the common terminal branches of the hepatic artery enter the liver
common hepatic, and splenic arteries. bile duct. As it nears the liver, it divides into several at the porta hepatis, alongside the hepatic portal vein and
branches, most commonly into a right hepatic and a left hepatic bile ducts. The left hepatic artery passes ante-
From the celiac trunk, the common hepatic artery hepatic artery. The right hepatic artery generally passes rior to the left hepatic bile duct and also frequently
passes anteriorly and to the right to enter the right posterior to the common hepatic duct to enter the cystic gives off a large branch, the intermediate hepatic artery,
margin of the lesser omentum, in which it ascends. As triangle (of Calot), formed by the cystic duct, the hepatic which also passes anterior to the left hepatic bile duct.
the common hepatic artery turns superiorly, it gives
origin first to the gastroduodenal artery, which supplies
arteries to the stomach, duodenum, and pancreas, then
usually to the supraduodenal artery, and finally to the
right gastric artery. The continuation of the common
hepatic artery, after the gastroduodenal artery departs,
is thereafter known as the proper hepatic artery. It ascends
within the hepatoduodenal ligament (part of the lesser
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 13
Plate 1-13 Liver: PART III
12
Intermediate hepatic artery
Left hepatic artery
Right hepatic artery
Replaced Proximal
common bifurcation of
hepatic artery Left gastric hepatic artery or
taking origin artery right and left
from superior
mesenteric Splenic artery hepatic arteries
artery originating
Gastroduodenal separately
artery from celiac trunk
3 4
Hepatic Artery Variations Replaced right Replaced left
hepatic artery hepatic artery
It is important to know the textbook branching pattern taking origin taking origin
of the hepatic arteries, but it is equally important to from superior from left
realize that many variations on this pattern exist and mesenteric gastric artery
one cannot anticipate the branching that may be found artery
in any one individual. These variations occur with equal
incidence in the right and left hepatic arteries and are 5 6
of more than passing surgical significance, mostly
because of the liver necrosis that follows their unin- Accessory Accessory
tended ligation. A replaced artery originates from a right hepatic left hepatic
source different from that in the standard description artery from artery from
and substitutes for the typical vessel. An accessory artery superior left gastric
is an extra vessel present in addition to those originating mesenteric artery
according to standard descriptions. An example of a artery
replacement artery is the origin of the common hepatic
artery from the superior mesenteric artery (1). It passes 7 8
through, or posterior to, the head of the pancreas, and
its ligation during a pancreaticoduodenal resection Accessory Right hepatic
deprives the liver of its arterial blood supply. Under left hepatic artery crossing
these circumstances, only the left gastric and splenic artery from anterior to
arteries arise from the celiac trunk. Sometimes, right or right hepatic common
left hepatic arteries originate independently from the celiac artery hepatic duct
trunk or fork off from a very short common hepatic instead of
artery (2). Under these conditions, the gastroduodenal posterior
artery originates from the right hepatic artery. Some-
what frequently, the right hepatic artery, giving off the accessory (6). If it is replaced, only the right hepatic right hepatic artery, originating at its typical site of
gastroduodenal artery, originates from the superior mes- artery comes from the celiac trunk, whereas in the pres- departure, crosses anterior to the common hepatic duct
enteric artery, whereas the left hepatic artery, in turn ence of an accessory vessel, the common and proper instead of posterior to it (8), a variation worthy of
giving off the intermediate hepatic artery, is derived hepatic arteries take their usual course. Ligation of a being remembered in the exploration of the duct. The
from the celiac trunk (3). Ligation of the replaced right replaced left hepatic artery (for instance, during gas- described variations are also significant in the formation
hepatic artery, especially where it crosses the junction trectomy) endangers the blood supply to the left lobe of collaterals after obstruction or ligation of an artery.
of the cystic and common ducts (for instance, during of the liver. Other variations not described here are less frequent,
cholecystectomy) deprives the right lobe of the liver of but their potential existence should not be ignored or
its blood supply. In contrast, ligation of an accessory right An accessory left hepatic artery may also come from discounted when operating in this field.
hepatic artery, coming from the superior mesenteric artery the right hepatic artery (7). In about 12% of cases the
(5), is far less significant, because another right hepatic
artery runs its typical course. Under these circum-
stances, two right hepatic arteries may be found in the
cystic (Calot) triangle. A replaced right hepatic artery
is far more frequent than an accessory one. An aberrant
left hepatic artery, originating from the left gastric artery,
is, in half of cases, replaced (4) and, in the other half,
14 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-14 Liver
1. Originating 2. Originating 3. Originating 4. Originating
from normal from intermediate from proper from
right hepatic hepatic artery hepatic gastroduodenal
outside cystic (may also
triangle come from
left hepatic)
Inter-
mediate
hepatic
artery
Cystic artery Left (Crossing (Crossing
hepatic anterior to anterior to
Right artery Left gastric hepatic duct) common
hepatic artery bile duct)
Proper artery
hepatic artery Celiac trunk
Right
Splenic
artery
gastric artery Gastroduodenal artery
Supraduodenal artery
5. Originating 6. Originating in 7. Originating outside
from celiac cystic triangle from cystic triangle
(may also come aberrant right hepatic from aberrant
from aorta) (from superior mesenteric) right hepatic
Aorta
Cystic Artery and (Crossing
Its Variations anterior to
hepatic duct)
Superior
mesenteric artery
The cystic artery most frequently originates from the 8. Double cystic artery: 9. Double cystic artery:
right hepatic artery within the cystic triangle of Calot, both from normal both from normal right hepatic;
to the right of the common hepatic duct. However, its right hepatic in one inside and one outside
frequent variations are of great significance in cholecys- cystic triangle cystic triangle
tectomy and are best recognized by careful dissection 11. Double cystic artery:
of the structures in the triangle. Typically, the artery 10. Double cystic artery: both from aberrant
divides into an anterior branch, going to the free peri- posterior from right right hepatic; one
toneal surface of the gallbladder, and a posterior branch, hepatic, anterior inside and one
going to the nonperitoneal surface and the gallbladder from gastroduodenal outside cystic
bed. The branches communicate with each other by triangle
means of numerous twigs. In about 20% of cases, the
cystic artery does not originate in the triangle but arises frequently, one or both of the cystic arteries originate cystic duct, in case the entire cystic artery or its super-
from the right hepatic artery (1) outside the triangle, from outside the triangle. In these cases, the most frequent ficial branch starts from the gastroduodenal artery or
the intermediate (2) or left hepatic artery, or, even less pattern is an origin of the anterior cystic artery outside other intestinal arteries. Double cystic arteries may also
frequently, from the proper hepatic artery (3) before it the triangle from the right hepatic artery with crossing arise within or outside of the triangle from an aberrant
forks into its branches. In all these instances it crosses in front of the bile duct, and origin of the posterior right hepatic artery (11). The number of possible varia-
the anterior and sometimes the posterior aspect of the branch to the deeper structures of the gallbladder high tions is great, and their incidence is not negligible. It
common hepatic duct. Rare replacements include an within the triangle (9). Rarely, the anterior cystic artery should be emphasized that an artery resembling the
origin from the gastroduodenal artery (4), and even from may originate from the gastroduodenal artery (10). For cystic artery in its course and paralleling the cystic duct
the celiac trunk (5) or independently from the aorta. In the surgeon it is well to remember that an important is not necessarily the cystic artery but may be a branch
these instances the cystic artery originates inferior to vessel may have an inferior origin and accompany the of the proper or right hepatic artery.
the origin of the cystic duct and crosses anterior to the
common bile duct. The cystic artery may also be
derived from an aberrant right hepatic artery coming from
the superior mesenteric artery, the origin being either
within the cystic triangle (6) or outside of it (7). In the
latter instance it again crosses anterior to the common
hepatic duct.
Double cystic arteries are also frequently encountered,
occurring in approximately 25% of cases. Under these
circumstances both the superficial, or anterior, branch
and the deeper posterior branch may arise within the
triangle from the right hepatic artery (8). As a rule, the
origin of the posterior branch is much higher in the
triangle, whereas the anterior branch may swing cau-
dally around the proximal part of the cystic duct. Less
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 15
Plate 1-15 Liver: PART III
Umbilicus Esophageal veins Blood from superior
Left gastric vein mesenteric vein
Falciform ligament and round ligament of liver Blood from splenic, gastric,
Splenic vein and inferior mesenteric veins
Para-umbilical veins Mixture of above two
Posterior, Right gastric vein Caval tributaries
Anterior Hepatic portal vein
superior
pancreatico- 1
duodenal 2
veins
Portal Vein Tributaries, 1 Short
Portacaval Anastomoses 24 gastric
veins
The portal vein forms posterior to the head of the 4 Left
pancreas at the height of the second lumbar vertebra by gastro-
confluence of the superior mesenteric and splenic veins. Superior mesenteric vein omental
It runs posterior to the first portion of the duodenum Posterior, (gastro-
and then in the right border of the lesser omentum to Anterior epiploic)
enter the liver at the porta hepatis, where it splits into inferior vein
its hepatic branches. The portal vein receives the left pancre-
gastric vein, which communicates with the esophageal aticodu- 4 Right gastro-
venous plexus. The latter, in turn, connects with the short odenal omental (gastro-
gastric veins and the azygos and hemiazygos veins in the veins 4 4 epiploic) vein
lower and middle parts and with various branches of the Middle4
superior vena cava, such as the brachiocephalic and infe- colic Inferior
rior thyroid veins in the upper part of the esophageal vein mesenteric
region. The portal vein further accepts the right gastric vein
vein, which with the left gastric vein forms a loop. The 4
left main branch of the portal vein admits the paraum- 4 Left colic
bilical veins and, occasionally, a persisting umbilical vein. 4 vein
Anterior,
The superior mesenteric vein originates at the root of Posterior 4
the mesentery as it receives venous blood from midgut cecal veins Sigmoid veins
veins such as the middle colic, right colic, ileocolic, jejunal, Appendicular
ileal, and inferior pancreaticoduodenal veins, receiving in vein 4
addition many small veins. It runs anterior to the third
portion of the duodenum and the uncinate process Ileocolic vein Right colic vein Left and right
of the pancreas. A foregut vein, the right gastroepiploic Portacaval anastomoses superior
vein, coming from the right aspects of the greater rectal veins
curvature of the stomach, also enters the superior 1 Esophageal 3 Rectal
mesenteric vein. 2 Para-umbilical 4 Retroperitoneal Middle rectal veins
which supposedly does not receive nutrient-rich pro- 3 Levator ani muscle
The splenic vein usually receives the inferior mesenteric tective blood from the small intestine.
vein just posterior to the body of the pancreas. The Inferior rectal veins
inferior mesenteric vein drains hindgut structures; it The portacaval anastomoses have great clinical sig-
begins with the superior rectal veins and continues in the nificance. They dilate when the blood flow in the portal hemorrhoids, with the attendant danger of hemor-
posterior abdominal wall, receiving many tributaries, vein and/or through the liver is restrained; they relieve rhage, thrombosis, and inflammation. The varicosities
particularly the sigmoid and left colic veins. The splenic portal hypertension and may be lifesaving in acute of the esophageal veins (and less so of the gastric veins
vein itself begins at the hilus of the spleen and admits portal hypertension but, as in chronic obstruction, may of the stomach) may lead to esophageal hemorrhage,
the left gastroomental vein, short gastric veins (both of shunt blood from the liver, compromising the liver’s the most dangerous complication of portal hyperten-
which communicate with esophageal veins), and pan- vital functions and, therewith, contributing to hepatic sion. The various retroperitoneal portacaval anastomoses
creatic veins which anastomose with retroperitoneal insufficiency. Dilatation of the rectal veins results in have less clinical significance. The paraumbilical anasto-
veins, and therefore with the caval system. moses lead to a marked dilatation of the veins in the
anterior abdominal wall. If these veins converge toward
The shortness of the hepatic portal vein discourages the umbilicus, they form what is called caput medusae.
mixing of the blood coming from its constituents, so
that the right extremity of the liver may chiefly receive
blood coming from the superior mesenteric vein. The
left lobe may receive blood from the left gastric, inferior
mesenteric, and splenic veins, whereas the left part of
the right lobe, including the caudate and quadrate
lobes, receives mixed blood. These streamlines, dem-
onstrated in experimental animals, are not seen during
portal venography and are not certain to occur in the
human being. Their existence has been assumed,
however, to explain the localization of tumor metastases
and abscesses and also the predominance of massive
necrosis in acute fatal viral hepatitis in the left lobe,
16 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-16 Liver
Variations Right gastric vein Left gastric vein often
Esophageal vein Short gastric veins enters junction of splenic
Cystic vein and superior mesenteric
Portal vein Left gastric vein Spleen veins
1.09 cm. Splenic 0.45 cm. Portal Left gastric vein
vein vein
Sup. pancreatico- Superior Splenic vein
duodenal vein mesenteric
Superior vein Left gastric vein may enter
mesenteric vein splenic vein (24% of cases)
R. gastro-omental vein Pancreatic veins Right gastric vein
Inferior pancreatico-
duodenal vein Inferior Left gastric vein
Right colic vein mesenteric Left gastro-
Ileocolic vein Middle vein omental vein
colic
vein Left colic vein
Intestinal veins
Portal vein
Typical arrangement Splenic vein
Inferior mesenteric vein may Inferior mesenteric vein may
enter junction of splenic enter superior mesenteric vein
and superior mesenteric
High intestinal veins
Portal Vein: Variations Portal vein Splenic vein Portal vein Splenic vein
and Anomalies Superior Inferior Superior
mesenteric vein mesenteric vein mesenteric vein Inferior
mesenteric vein
The anatomy of the portal vein system is less variable Anomalies Portal vein
than that of the hepatic arteries. However, the varia- entering inferior
tions that do occur in this series of vessels are of para- Portal vein anterior vena cava
mount importance during shunt operations for portal to head of pancreas and (hepatic artery
hypertension. The length of the portal vein varies from first part of duodenum enlarged)
5.5 to 8 cm, with an average of approximately 6.5 cm,
the mean diameter being normally 1.09 cm. In cirrho- Pulmonary vein Congenital
sis, however, the diameter becomes considerably wider. entering portal stricture of
It is of practical importance that in only slightly over less embedded into the head of the pancreas, the many portal vein
10% of the studied cases no vessel enters the main stem pancreatic venous tributaries are so short that they may normal in a morphologic sense can function without
of the portal vein, but in the vast majority, several veins be easily torn during a shunt operation, and their liga- receiving blood from the portal vein. With this anomaly,
are admitted that may be torn during the dissection for tion creates technical problems. the hepatic artery is considerably enlarged. A great
portacaval anastomosis. Dangerous hemorrhage may Of the rare congenital anomalies of the portal vein, rarity is an entrance of the pulmonary vein into the portal
result, and ligation of these vessels may interfere with the one of surgical significance concerns an abnormal vein; this is probably the consequence of some distur-
the size of the portal vein and the performance of the position anterior to the head of the pancreas and the duode- bance in the development of the venous systems at an
anastomosis. In more than two thirds of cases, the left num. Another rare but physiologically interesting early fetal stage. Another extremely rare variation is the
gastric vein, which is of major significance as portal anomaly is the entrance of the portal vein into the inferior presence of congenital strictures of the portal vein at the
drainage from esophageal varices, enters into the left vena cava. It would indicate that a liver that appears porta hepatis, producing severe portal hypertension
aspect of the portal vein. Otherwise it enters at the that may not be relieved by surgical anastomoses.
junction of the splenic and superior mesenteric veins, and
in almost one fourth of cases, it joins the splenic vein.
Under all these circumstances, the right gastric vein may
enter into the portal vein stem. On its right aspect, the
portal vein may admit the superior pancreaticoduodenal
vein, and close to the liver the cystic vein, which fre-
quently joins the right side of the portal vein. The usual
anatomic description of the formation of the portal vein
is found in only about half of cases. In the remainder,
the inferior mesenteric vein enters the junction of the
splenic and superior mesenteric veins or joins the supe-
rior mesenteric vein.
The size of the splenic vein, of major importance in
a splenorenal shunt, is said to average less than 0.5 cm
between the splenic hilus and the junction with the
inferior mesenteric vein. As a rule, the splenic vein is
widened to a lesser degree in portal hypertension than
is the portal vein. Because the splenic vein is more or
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 17
Plate 1-17 Liver: PART III
Low-power sections
of liver
Perisinusoidal
spaces (Disse)
very narrow
or obliterated
Connective tissue
of portal triad
Perisinusoidal
space (Disse)
Perisinusoidal Sinusoid Terminal
spaces (Disse) Periportal space (Mall) lymphatic
markedly widened vessel
Lymphatic Drainage of Liver
and Bile Tract
The perisinusoidal space (of Disse) separates the sinusoidal Phrenic lymph nodes
wall from the hepatocytes. The spaces are filled by Caval opening
extensions of the hepatocyte cytoplasm and are tra-
versed by fine arcuate reticular fibers, extending from Left gastric
the basement membrane of the capillaries to the hepa- nodes
tocytes, which themselves do not rest on a basement
membrane. Through these spaces the exchange of fluid, Cystic
and especially solids from the liver cells to the sinusoi- node
dal lumen and vice versa, takes place. Under normal (Calot)
circumstances the perisinusoidal spaces are almost com-
pletely invisible and the arcuate reticular fibers can Hepatic nodes some from the right side of the posterior surface drain
hardly be separated from the sinusoidal basement mem- Celiac nodes directly to the celiac nodes. The lymph vessels from the
branes. However, in the agonal period, and especially Right gastric nodes gallbladder and from most of the extrahepatic bile ducts
in passive congestion, in anoxia, or in various toxic drain to the hepatic nodes, but a few vessels from the
conditions, hepatic edema sets in, with widening of the thoracic duct. Lymphatic vessels near the bare area of common bile duct also run to the right gastric lymph
sinusoidal spaces, which are filled by a protein-rich the liver, on the posterior and superior aspects of the nodes. Anastomoses of the hepatic lymphatics with duo-
fluid. This widening may develop very rapidly, probably organ, drain toward the inferior vena cava as it passes denal and pancreatic lymphatics are typically noted only
as a result of an abnormally increased permeability for through the diaphragmatic hiatus of the diaphragm. in the presence of adhesions.
serum protein brought about, for instance, by hypoxia. There, lymphatic fluid encounters the phrenic lymph
Therefore, in autopsy specimens (even when the liver nodes in the vicinity of the thoracic duct.
is normal), as a rule, the perisinusoidal spaces are
expanded, whereas in biopsy specimens they are usually In addition, a few vessels from the left side of the
invisible. In toxic conditions or congestion, this widen- posterior surface drain to the left gastric lymph nodes and
ing may be markedly exaggerated. The fluid in the
perisinusoidal space is the beginning of lymph from deep
lymphatic vessels from the liver. This fluid travels in a
direction similar to that of the bile, toward nearby
portal triads, to join larger lymph vessels that parallel
the bile duct, hepatic artery, and hepatic portal vein.
Few lymphatics are present in the central canals around
the tributaries of the hepatic vein; lymph tends to travel
toward the portal triad. Lymph from the more superfi-
cial regions of the liver and its capsule drain to superficial
lymphatic vessels. The capsule of the liver (Glisson
capsule) contains a dense network of lymphatics that
communicates with a lymphatic network in the gall-
bladder bed. These widespread intercommunications
make the hepatic lymphatic system a functional unit.
The lymphatic drainage of the liver follows several
routes. Superficial lymphatic vessels as well as deep
lymphatic vessels from the inferior and anterior region
of the liver drain to hepatic lymph nodes, found running
alongside the hepatic arteries at the porta hepatis. Addi-
tional lymph nodes are found along the proper and
common hepatic arteries. Lymphatic fluid drains along
these nodes to reach the celiac lymph nodes at the base of
the celiac trunk and inferior vena cava. From there,
lymphatic vessels proceed to the cisterna chyli, and a
few extend directly from the porta hepatis to the
18 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-18 Liver
Sympathetic fibers Parasympathetic fibers
Preganglionic Preganglionic
Postganglionic Postganglionic
Afferent fibers
Innervation of Liver and Common areas of referred pain in T7 T7 Sympathetic trunk
Bile Tract biliary disease T7 T8
T9 Dorsal root
The liver, gallbladder, and biliary tract receive their Right greater splanchnic nerve T8 T10 (spinal) ganglion
nerve supply from the sympathetic and parasympathetic Posterior vagal trunk T8 Thoracic part of spinal
systems as well as the right phrenic nerve. The sympa- cord
thetic innervation comes chiefly from the intermediolat- Right phrenic nerve to diaphragmatic T9 Left greater
eral cell column of the 7th to the 10th spinal segments. part of parietal peritoneum T9 splanchnic nerve
Axons from these levels exit via the anterior roots, Anterior vagal trunk
spinal nerves, and white rami communicans to reach T10
and pass through the sympathetic ganglia of the sympa-
thetic trunk. Preganglionic sympathetic axons reach the T10
prevertebral ganglia by way of the thoracic splanchnic
nerves and synapse with the nerve cells within the Hepatic branch of
ganglia. Most of the postganglionic sympathetic fibers anterior vagal trunk
to the liver probably originate in the celiac ganglia; some Diaphragm
of them may start in small ganglia present at the porta Phrenic ganglion
hepatis. The parasympathetic innervation is provided by Celiac ganglia
both vagal trunks, the posterior trunk of which tra- Common hepatic artery
verses, with some branches, the right portion of the Splenic artery
celiac plexus but does not form synapses within it. The
anterior vagal trunk reaches the liver through the hepa- Anterior hepatic plexus
togastric ligament from the anterior surface of the Posterior hepatic plexus
esophagus and stomach.
Aorta
The preganglionic parasympathetic and postgangli- Gastroduodenal
onic sympathetic nerves form the anterior and posterior artery and plexus
hepatic plexuses. The anterior plexus lies near the
hepatic artery; it is composed mostly of fibers from the Sphincter of
left portion of the celiac plexus and from the right hepatopancreatic ampulla
abdominal branch of the anterior vagal trunk. The pos-
terior plexus, behind the portal veins and the bile ducts, Ramification of nerve
receives fibers from the right celiac ganglion and the fibers around fine branch
posterior vagal trunk. Within the liver, nerves follow of hepatic artery
the branches of the blood vessels and bile ducts to reach
their targets. The innervation of the intrahepatic blood white rami, and then the posterior roots to reach the painful (because of stretching of the capsule and trac-
vessels is analogous to that of other blood vessels. In spinal cord. The phrenic nerve also enters the liver, tion on the hepatic ligaments); this condition and the
the wall of the bile ducts a nerve fiber network extends sometimes joined by sympathetic fibers, with branches shoulder pain on the right side reflect innervation by the
close to the epithelium. Apparently the branches of the distributed to the coronary and falciform ligaments and phrenic nerve. Biliary tract pains are felt either as cir-
common hepatic artery are supplied entirely by sympa- to the capsule of the liver. Pain elicited in the liver is cumscribed tenderness in the gallbladder region or as
thetic fibers, whereas the muscles of the bile ducts and usually of the dull type, associated with diffuse tender- colicky pain. Pain radiates to the back just below the tip
the gallbladder are innervated by both autonomic ness over the right upper quadrant of the abdomen and of the right scapula, to the right shoulder, to the sub-
nerves. The extrahepatic bile ducts and the gallbladder pain in the right shoulder. A beltlike area of skin hyper- sternal area, and sometimes also to the anterior left
receive branches from the anterior and posterior hepatic sensitivity, corresponding to the ninth thoracic and first chest. Involvement of the subserosa produces sharply
plexuses. Preganglionic parasympathetic axons synapse lumbar vertebrae, is generally found on the right side defined knifelike pain associated with hyperesthesia of
with postganglionic parasympathetic nerve cells near of the body. Acute enlargement of the liver is frequently the skin.
their target, such as the muscularis of the gallbladder
and the smooth muscle of the bile ducts.
Nonpainful, reflexive afferent inputs from the liver,
gallbladder, and extrahepatic bile ducts travel to the
medulla oblongata by running in a retrograde fashion
along the parasympathetic inputs to each organ. They
are therefore found within the anterior and posterior
vagal trunks and vagus nerves. Afferent nerves that
carry visceral pain signals from the liver and extrahe-
patic biliary system travel along sympathetic fibers to
each organ. Therefore they pass along the hepatic
arteries, through the thoracic splanchnic nerves and
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 19
Plate 1-19 Circulating blood Liver: PART III
Unconjugated
Congenital and Familial Biliary Conjugated bilirubin
Hyperbilirubinemias substances bilirubin
Congenital and familial hyperbilirubinemias can be Conjugated Unconjugated Block (1)
divided into conjugated and unconjugated hyperbiliru- (direct) (indirect)
binemias. Unconjugated hyperbilirubinemia results bilirubin bilirubin
from blockages at the level of uptake of unconjugated in blood increased
bilirubin by the hepatocyte (1) and prior to conjugation Chole- in blood
(2). Conjugated hyperbilirubinemia occurs from block- stasis
age at the point of excretion of bilirubin into the cana-
liculus (3) or downstream from the point of excretion. Block (4)
Unconjugated bilirubin passes through the liver cell Block (3)
membrane facing the sinusoid, probably without the Block (2)
participation of the Kupffer cell, and is conjugated by Bilirubin Glucuronyl Unconjugated
the enzyme glucuronyl transferase, with glucuronic glucuronide transferase bilirubin
acid. This acid is derived from glucose, linked to uridine
phosphate, and oxidized to uridine diphosphate +
glucuronic acid. The promptly reacting bilirubin UDPGA
glucuronide is excreted into the bile.
Bile
Bilirubin transport through the liver cell may be par- canaliculus
tially or completely blocked at any of four sites. Uptake
of unconjugated bilirubin by the liver cell may be Defective bilirubin excretion Deficiency of Impaired
blocked at the sinusoidal surface by multiple causes, glucuronyl transferase bilirubin
including conditions with reduced hepatic blood flow, Dubin-Johnson Rotor Transient: immaturity of uptake by
such as congestive heart failure and portosystemic syndrome disease glucuronide conjugating liver cell
shunting. Whether inherited disorders such as Gilbert system of liver cell:
syndrome do this is less clear. unidentified liver section inhibition of transferase
pigment deposits normal by steroids of serum
Gilbert syndrome, the most common disorder of bili- in liver
rubin glucuronidation, results from a defect in the Permanent:
promoter of the gene that encodes the enzyme incomplete Gilbert disease
uridine diphosphoglucuronate-glucuronosyltransferase posthepatitis syndrome
1A1 (UGT1A1), resulting in reduced hepatic bilirubin-
UGT activity. The disease is benign but presents as complete; Crigler-Najjar
episodes of mild jaundice, which are typically triggered syndrome (kernicterus)
by fasting, hemolysis, intercurrent febrile illness, stress, Liver section normal
physical exertion, and other situations that may increase
bilirubin production. Despite the episodes of mild jaun- multidrug- resistance–associated protein-2 component of bile acid and other components of bile. With the
dice, there is no liver injury and liver enzymes are not of the bile transporter. The defect in Rotor syndrome exception of benign recurrent cholestasis, these disorders,
increased. The prognosis for patients with Gilbert syn- has not been molecularly identified but is thought to which present in childhood or infancy, are associated
drome is similar to that of the general population. be related to a defect in hepatic storage of conjugated with growth failure and progressive liver disease.
bilirubin rather than of excretion into the canaliculi.
By contrast, patients who have absence or deficiency Dubin-Johnson syndrome is associated with accumula- The fourth block occurs downstream at the point of
of glucuronyl transferase, as found in Crigler-Najjar tion of a golden-brown pigment in the liver cells which secretion of bile into the canaliculi. Two well-described
syndrome, have significant rates of morbidity and mor- causes the liver to appear black. Progressive familial disorders, Alagille syndrome and abnormalities of villin
tality. As opposed to Gilbert syndrome, in which the intrahepatic cholestasis is a heterogeneous group of dis- gene expression, result in structural defects in the bile
defect is in the promoter region, the defects in Crigler- orders, characterized by various defects in the secretion canalicular structure and are associated with chronic
Najjar syndrome are caused by a variety of alterations cholestasis.
to the coding sequences of the UGT1A1 gene. This
results in abnormal protein production and absent (type
1 Crigler-Najjar syndrome) or very low (type II Crigler-
Najjar syndrome) hepatic UGT1A1 activity. In type I
disease, in which levels can reach more than 20 to
50 mg/dL, kernicterus can develop if intervention
is not rapid. Short-term treatments, such as photo-
therapy and plasmapheresis, and long-term treatments,
such as liver transplantation, are necessary for afflicted
individuals.
Inherited disorders that cause conjugated hyperbili-
rubinemia involve blocks at the level of the biliary
excretion of conjugated bilirubin (3) or downstream of
the point of excretion (4). There is an increase in serum
conjugated and unconjugated bilirubin. These disor-
ders, including Dubin-Johnson syndrome, Rotor syn-
drome, progressive familial intrahepatic cholestasis, and
benign recurrent intrahepatic cholestasis, are caused by
multiple different defects, some which have been iden-
tified and others not. Dubin-Johnson syndrome and Rotor
syndrome have similar phenotypes characterized by mild
fluctuating conjugated and unconjugated hyperbilirubi-
nemia associated with an excellent prognosis. The
genetic defect in Dubin-Johnson syndrome is in the
20 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-20 Liver
Cystic disease
involving the liver,
kidneys, and
pancreas
Congenital Anomalies
The development of ductules and bile ducts depends Riedel’s lobe
upon organizing influences. Disturbances of develop-
ment lead to an irregular arrangement of the ducts, commonly, caused by accumulation of blood, lymph, the lobe itself is mostly normal, but it may exhibit
resulting in solid nodules or in cysts. Small irregular and bile. Ciliated cysts are derived from misplaced fibrosis or bile stasis if the blood supply and bile drain-
proliferations of ductules and bile ducts, surrounded intestinal endoderm, or they may be teratoid. age in the pedicle are compromised. The Riedel lobe is
by excessive fibrotic tissue, appearing as small white either a congenital anomaly or of unknown cause, but
nodules, are a frequent incidental finding in biopsy and Riedel lobe is a tonguelike extension of the right lobe, it is benign. The main clinical significance of the Riedel
autopsy specimens. The narrow cavities form an irregu- projecting from the anterior margin around the gall- lobe lies in unusual palpatory findings in the area of the
lar plexus, usually connected with the biliary system and bladder. As a rule, the projection is 1 to 2 inches long, gallbladder, which can be readily mistaken for a dis-
often containing small bile calculi. The significance of irregularly shaped, and narrow at its neck. Exception- tended gallbladder, tumor in the omentum, or pancre-
these hamartomas, also called multiple bile duct adeno- ally, it is very long and extends into the pelvis. Some- atic cyst. A Riedel lobe can be mistaken on imaging for
mas, lies in their differentiation from inflammatory times the neck is thinned to a freely movable pedicle, hepatomegaly.
lesions. consisting mainly of fibrosed tissue. The liver tissue in
The same embryologic disturbance leads to cyst for-
mation when the hamartomatous cavities become large
or communicate with each other. The large ones are
found mostly in adults, indicating that they grow during
life. Occasionally, single large cysts are observed, which
cause pressure symptoms. More frequent is polycystic
disease of the liver, which is, in at least half of cases,
associated with polycystic disease of the kidney and,
though not so regularly, with pancreatic cysts. Some-
times other anomalies, such as aneurysms of the cere-
bral arteries, are encountered simultaneously. The
lesion is often familiar. Exceptionally, this hepatic
involvement may produce upper abdominal pain and a
feeling of fullness, without functional impairment. This
mostly occurs in the fourth and fifth decades. Malignant
degeneration seems to be rare. The health of the patient
is primarily influenced by the renal involvement. The
hepatic cysts are lined by a cuboidal epithelium, which
is often desquamated. Their lumen contains a clear
yellow fluid. Other hepatic cysts are parasitic or, less
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 21
Plate 1-21 Liver: PART III
Epithelial cells Kupffer cells
Phagocytosis
Storage
Metabolic pool
Liver Functions γ-globulin
formation
The liver, ranking first in size as a parenchymal organ, Secretion: Immune
takes also first position in number, variety, and com- glucose, bodies
plexity of functional accomplishments. Only the most proteins,
essential features of the liver’s physiology and those coagulation Liver as a whole
which are of principal interest for the practice of medi- factors,
cine are illustrated and discussed in the following pages enzymes Electrolyte and Blood
of this section. In the accompanying plate an attempt bile water balance pigment
has been made to present a classifying and summarizing breakdown
survey. Detoxification Filter
action
Holding a strategic position between the intestinal
and general circulation and harboring, according to its Sphincteric
dimensions, a large amount of blood and extracellular blood flow
fluid, the liver exercises a major influence on the volume regulation
of circulating blood and its constituents. The liver acts
as a sponge or “flood chamber,” which can be filled or Bile drainage Sinusoidal permeability
congested, as in failure of the right heart. The “filter
action” of the liver also results from its peculiar ana- Bile duct system Vascular system
tomic location, because all nutrients, and also injurious
materials absorbed by the intestines, are brought to the It is excreted into the bile capillaries and leaves the liver scavenger cells that remove by phagocytosis pigments,
organ via the portal system. The effect of the liver on through the intrahepatic bile duct system to reach the bacteria, and other corpuscular or macromolecular
water and electrolyte balance, though it is regulated duodenum via the extrahepatic bile tract. elements.
mainly by the kidneys, lungs, adrenals, and hypophysis,
should not be underestimated, not only because of the The Kupffer cells, besides functioning as endothelial The liver’s vascular system serves the proper intrahe-
large parenchymal mass of the organ but also because cells like others elsewhere in the organism, represent patic blood distribution by sphincter actions. The two
all the ingested water and salts pass through the liver the quantitatively most important part of the reticulo- blood supplies (hepatic artery under high pressure and
before entering other extracellular departments. endothelial system. These cells are concerned with the portal vein under low pressure) are harmonized. The
breakdown of hemoglobin to bilirubin, participate in the hepatic sinusoids differ from other capillaries in that
The hexagonal, epithelial liver cells have multitudinous formation of γ-globulin and immune bodies, and act as they have a greater permeability for proteins.
and very diversified functions. They are the site of the
chemical transformations that make body constituents
from foodstuffs or their digested breakdown products
and that correlate the three main categories of organic
body material, so that the totality of the liver cells
becomes a great “metabolic pool” of the organism. The
versatility of this central chemical laboratory of the
organism, together with the liver’s storage capacity for
glycogen, proteins, fats, and vitamins, is of the utmost
significance for the energy economy of the entire body.
The liver stores these organic materials not only for its
own need but to satisfy the needs of distant organs. It
gives glucose to the blood to maintain the sugar level and
to supply energy for all vital phenomena. The liver cells
form many of the serum proteins to provide forces for
the oncotic pressure of the plasma or to be used as a
transport vehicle for water-insoluble compounds or as
coagulating factors or to fulfill enzymatic functions and
other functions.
The epithelial hepatic cells, furthermore, protect the
organism from injurious agents by a variety of detoxifica-
tion processes, which yield substances deprived of detri-
mental properties.
The bile, also manufactured by the epithelial cells,
contains the characteristic bile pigments, salts of bile
acids, cholesterol, and a number of other components.
22 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-22 Liver
Liver with
intestinal
drainage
Hepatic
portal vein
Innate Immune System Common Splenic artery and vein
and Liver hepatic Inferior mesenteric vein
artery
The liver serves a central role in the immune system. Superior Bacteria
As the largest solid organ in the body, the liver has a mesenteric Viruses
dual blood supply. In addition to the conventional arte- artery and toxins
rial blood supply from the hepatic artery (which is fed and vein
by the aorta), the liver is also the main drainage system Inferior LPS
for the gastrointestinal tract, with about 80% of its mesenteric GN
blood supply coming from the portal vein. As a result, artery bacteria
it is exposed to blood that has a rich supply of bacterial
products (including endotoxin), environmental toxins, Kupffer Endothelial
and food antigens. As the gateway to the systemic blood cell cell
system, the liver serves important roles as the first line Dendritic Fenestrae
of defense and as an immune modulator. It is estimated cell Stellate
that approximately 30% of the total blood flows through T cell cell
the liver every minute, and with this blood is carried all NKT cell
the immune cells, such as lymphocytes, that may circu- phagocytosis and antigen processing and presentation. NK cell
late throughout the body. Kupffer cells can also generate various products, includ- Space
ing cytokines, prostanoids, nitric oxide, and reactive of Disse
In its essential role as the immune regulator, the oxygen intermediates. These factors regulate not only
unique anatomic structure of the liver is important. In the phenotypes of the Kupffer cells that produce them Hepatocyte
addition to the parenchymal cells, the hepatocytes but also the phenotypes of other immune cells, such as
(which constitute approximately 80% of all the cells in natural killer cells and natural killer T cells. also has many natural killer T cells and TCRγδ T cells.
the liver) and the remaining nonparenchymal cells In fact, the liver has more natural killer T cells than any
(which include a wide array of cells) are essential to the The liver also has a very large population of T cells, other organ. Natural killer T cells constitute up to 30%
immune system. These include endothelial cells, stel- including nonconventional T cells. In addition to the of all T cells in the liver, a situation very different from
late cells, Kupffer cells, and lymphocytes. The liver conventional CD8- and CD4-positive T cells, the liver other parts of the body. The liver is also one the richest
sinusoidal endothelial cells (LESC) form a monolayer sources of γδδ T cells. The reason for this unique com-
between the hepatocytes and the portal blood supply. position of immune cells is not known, but their pres-
Unlike traditional veins, the sinusoids in the liver have ence likely plays an important role in both the first line
sievelike fenestrations that allow for greater contact of defense against microorganisms and in regulation of
between the cells that come through the sinusoids, such the immune response.
as lymphocytes, as well as other components in the
portal blood. In the space of Disse between the sinusoids
and the hepatocytes, there are many interactions that
may be critical for immune function. LESC, which
make up the bulk of the nonparenchymal cells (≈50%),
express receptors supporting their role in the immune
response, including molecules such as the mannose
receptor and scavenger receptor, which promote
antigen uptake. They even express major histocompat-
ibility class I and II molecules and costimulatory mol-
ecules CD40, CD80, and CD86, which are important
for antigen uptake.
Next to the LESC in the sinusoidal vascular space
are Kupffer cells or hepatic macrophages. Kupffer cells
account for approximately 20% of nonparenchymal
cells in the liver and are the largest group of fixed mac-
rophages in the body. They are localized in the peri-
portal area but can migrate to different areas, including
through the space of Disse to make direct contact with
hepatocytes. Kupffer cells are very heterogeneous and
can perform many specialized functions, including
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 23
Plate 1-23 Liver: PART III
1. Normal Vitamin K in food
prothrombin Prothrombin
formation
Prothrombin
formed in liver
Clot
2. Obstructive Absorption Vitamin K
jaundice of vitamin K in also formed
(ingestion of presence of bile by intestinal
vitamin K) bacteria
Vitamin K in food 3. Obstructive
No prothrombin jaundice
formed (injection of Prothrombin
water-soluble Prothrombin
menadione formed
derivative,
“synthetic
vitamin K”)
Bleeding Clot
continues
(no clot)
Little absorption
of vitamin K due
to absence of bile
5. Liver cell
4. Liver cell damage
damage (injection of Damaged liver
(ingestion of Vitamin K in food water-soluble still fails to form
vitamin K) prothrombin
Prothrombin Formation menadione despite presence
Little derivative, of viamin K
Several plasma proteins involved in the complex process formation “synthetic
of blood coagulation, such as factors I (fibrinogen), II of prothrombin vitamin K”) Bleeding
(prothrombin), V, VII, IX, X, XII, and XIII, are manu- continues
factured by the liver. The capacity to make prothrom- Bleeding (no clot)
bin as well as factors VII, IX, and X depends on the continues
availability of vitamin K1, a naphthoquinone derivative, (no clot)
ingested with food or formed by intestinal bacteria.
This naturally occurring vitamin, existing in two chem- Prothrombin formation is impaired in obstructive time; if the liver cells are damaged, however, parenteral
ically different forms (K1 and K2), is water-insoluble due jaundice, because the absence of bile prevents vitamin K administration does not serve these functions, or does
to long carbon side chains and requires bile acids for absorption, as well as in conditions with liver cell so only temporarily. For this reason, parenteral
its absorption. A synthetic water-soluble naphthoquinone damage, because bile acid production is deficient and, administration of menadione can differentiate between
without side chains (menadione) can substitute for the more so, because the liver’s ability to create prothrom- vitamin K deficiency and liver dysfunction as the cause
natural vitamin. bin is fundamentally lost. Accordingly, parenteral for a prolonged prothrombin time, and it will improve
administration of menadione restores prothrombin for- clotting in obstructive jaundice but not when there is
The prothrombin time, which measures the time it mation and therewith normalizes the prothrombin liver dysfunction (liver cell damage).
takes for prothrombin (factor II) to be converted to
thrombin (activated factor II), is a very useful measure
of the body’s coagulation function and liver function.
The liver produces, furthermore, a number of factors
necessary for the conversion of prothrombin into
thrombin (factors V, VII, and X). If these factors are
deficient, the effects in liver disease parallel those of
prothrombin lack.
24 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-24 Liver
Blanching
on pin-point
pressure
Icterus Spider nevi Foetor hepaticus
Physical Diagnosis of Palmar erythema Finger clubbing and nail bed changes Gynecomastia
Liver Disease
Hepatomegaly Splenomegaly Pruritus
The clinical diagnosis of liver disease is not difficult
in advanced hepatic decompensation. A history of deep- Ascites Presacral Edema Ankle
ening jaundice, dark urine, light stools, progressive Testicular atrophy 101
increase in girth of the abdomen, and subjective symp-
toms of weakness, anorexia, and other digestive difficul- Light 99 Fever
ties focus the attention of the clinician upon the liver. stool 70
Icterus (i.e., more or less deep staining of the skin, Dark unrine 50 Bradycardia
sclerae, and mucous membranes) may be present in
extrahepatic obstructive jaundice, as well as in hepato- Caput medusae
cellular injury. The icterus present in prehepatic
(hemolytic) jaundice, however, usually does not stain in mild or chronic forms of liver disease, foetor hepati- posthepatic jaundice. The pruritus is thought to be due
the tissues as deeply as in the other forms. In hepatic cus is mostly to be considered of grave prognostic to an increased concentration of bile salts in the blood-
and posthepatic jaundice, the urine is dark and the feces significance. stream. Elevated alkaline phosphatase and serum cho-
are light, particularly if the jaundice is deep. In prehe- lesterol are frequently seen in association with the
patic jaundice, on the other hand, bilirubin does not Clubbing of the fingers and whitening of the nail beds are pruritus; they are the outstanding features of so-called
appear in the urine, but the urine may be dark due to seen in some patients with cirrhosis of the liver when primary biliary cirrhosis.
increased amounts of urobilin. For the same reason, the there is the development of hepatopulmonary syn-
feces in prehepatic jaundice are also dark. It is impor- drome. These signs are not specific for hepatic disease. Presacral and ankle edema, often notable in patients
tant to remember that in certain advanced cases of liver Severe pruritus, with or without jaundice, may be the with advanced liver disease, is primarily the result of
disease little or no jaundice may be apparent. outstanding symptom in patients with the cholestatic lowered serum albumin and sodium; free water reten-
type of liver disease and is frequently present in tion is considered a contributive factor.
The appearance of spider nevi or telangiectasias, gyne-
comastia, palmar erythema, testicular atrophy, fine skin,
sparsity of body hair, and prostatic atrophy is generally
believed to be due to hyperestrogenism. Despite the
fact that these changes are secondary, their appearance
frequently helps to establish the diagnosis.
The detection of an enlarged or a tender liver is seen
in patients with biliary cirrhosis or alcoholic or nonal-
coholic fatty liver disease. With a primary or secondary
hepatic neoplasm, the liver may be massively enlarged
and nodular. In congestive heart failure or constrictive
pericarditis, the liver may also be enlarged and tender.
In other types of cirrhosis, the organ may be very small
and not palpable.
The presence of splenomegaly, ascites, and caput
medusae raises the suspicion of portal hypertension,
though the spleen may be enlarged in patients with
parenchymal liver disease without portal hypertension
(e.g., in congestive heart failure).
In moderately severe and advanced cases of hepatic
disease, particularly when hepatic coma has supervened,
a foetor hepaticus is often discerned by the trained clini-
cian. This odor is distinctive but difficult to describe. It
is a musty, sweetish odor, not unpleasant, which at times
is more easily detected by the physician upon entering
the sickroom than when he or she is close to the patient.
Although it may disappear following enemas or drastic
bowel movements, and though it is sometimes observed
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 25
Plate 1-25 Liver: PART III
Serum transaminases Pancreas Heart Muscle Intestine Tumor
Liver Damaged Damaged Contracted Damaged
cells cells or damaged
Damaged Dead (postoperative)
cells cells
No
enzymes
Circulation
Transaminases
Serum alaline transaminase (ALT)
Serum aspartate transaminase (AST)
1000 Acute
hepatic
necrosis
Serum transaminases Acute
units per 100 ml hepatitis
400 Chronic hepatitis
Cholestasis; intrahepatic or extrahepatic
100 Normal
40
1 2 3 4 5 6 Da7ys 8 9 10 11 12 13
Alkaline phosphatase test
Normal Bone disease Marked
Alkaline phosphatase Increased flow elevation
from bone from bone of blood
level
Normal
blood
level
Liver Function Tests
Liver function tests are a panel of serum biochemical Alkaline Excretion in bile Liver cell Blood
tests used to diagnose and monitor liver disease. phosphatase Blood damage level
Although generally referred to as liver function tests, from gut wall level moderately
serum aspartate transaminase (AST), alanine transami- high elevated
nase (ALT), and alkaline phosphatase tests should more Common duct
appropriately be named liver injury tests because they obstruction
may represent markers of liver injury. Albumin and (complete)
bilirubin levels and prothrombin time are more appro-
priately known as markers of liver synthetic function. ??
Patterns of liver injury test elevations are useful in the
diagnosis of liver disease. Patients with hepatitis or Normal flow Increased flow to Increased flow to
acute hepatic necrosis will have a pattern of liver injury from bone and gut blood due to block blood due to block
tests that show marked increases in the serum transami- of excretion or to of excretion or to
nases (AST and ALT), and those with cholestasis (either production by liver production by liver
intrahepatic or extrahepatic) will have marked increases
in alkaline phosphatase and bilirubin relative to the cells, or osteoblasts, which can also release the enzyme In many hepatobiliary diseases, alkaline phosphatase
serum transaminases. into the blood. The serum alkaline phosphatase activity is also elevated. Some alkaline phosphatase is normally
is elevated with increased osteoblastic activity. It is very excreted in the bile, and, therefore, interference with
Serum transaminase elevations usually reflect damage high in such bone diseases as rickets, osteomalacia, and bile flow may lead to an increase in the serum activity
to hepatic parenchymal cells which results in increased Paget disease. It is moderately elevated with most car- of alkaline phosphatase. In addition, there may be
cell membrane permeability and leakage of these cinoma metastases to bone, especially so if they are release from damaged hepatocytes and induction of
enzymes into the circulation. Although this finding is osteoblastic. In myeloma, the activity is not elevated. these enzymes by processes that damage the biliary
most likely due to liver injury, it is important to recog- Alkaline phosphatase is also delivered to the blood from epithelia, including biliary obstruction or cholestatic
nize that similar elevations may occur with damage to the intestinal wall. liver disease.
other tissues; production of AST and, to a lesser degree,
ALT may occur in damage to the heart, muscle, intes-
tine, pancreas, and other tissues.
Although alkaline phosphatase can be derived from
injury to cholangiocytes, alkaline phosphatase is also
found in appreciable amounts in the bone-forming
26 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-26 Liver
NORMAL FORMATION AND CIRCULATION OF BILE PIGMENT
Perisinusoidal Bloodstream
space
Bile
canaliculi Liver
cells
Threshold
Liver Liver Kidney
sinusoid Urine
Kupffer urobilinogen Ϯ
cells
Bile Reticulo-
ducts endothelial
(intra-and cell
extrahepatic)
Red
cell
Portal
vein
Bilirubin and Bile Acid Key Bowel Stool
Metabolism Biliverdin globin
Indirect reacting bilirubin but only slightly soluble in water, gives the red diazo
From the quantity of bile pigment excreted, the rate of Prompt reacting bilirubin reaction (with sodium nitrite and sulfanilic acid) of van
hemoglobin turnover has been calculated to be 16 to Urobilinogen den Bergh; however, this is possible only after special
24 g/day under normal conditions. Of the available treatment of the pigment to increase its water solubility
pathways of hemoglobin breakdown, the one via the rings connected by methene (–CH) bridges, forming a (e.g., by the addition of alcohol, caffeine, or urea).
bile pigments is the most important. The site of bile ring, inside of which a bivalent iron atom is bound. For this reason, the pigment has also been called
pigment formation is the reticuloendothelial system, of Hemoglobin is released when red blood cells are indirect-reacting, unconjugated bilirubin (or heme biliru-
which the Kupffer cells are a part. The excretion of bile destroyed. Its breakdown starts by an opening of the bin, bilirubin B, or bilirubin globin). Unconjugated
pigment, however, is the task of the parenchymal liver tetrapyrrole ring structure at one of the methene bilirubin is taken up by liver cells, which conjugate it.
cells. Any defect in this excretion process, either because bridges. The resulting biliverdin-iron-globin (verdohe-
of liver cell damage or because the liver is unable to moglobin) loses its iron and globin and becomes bili-
cope with the quantity of bile pigment, leads to jaun- verdin, which is subsequently reduced to free or
dice. The increase of bilirubin in the blood results in unconjugated bilirubin. This pigment, soluble in lipids
its appearance in the urine.
Most of the hemoglobin molecule (96%) for each
species is globin, a specific protein to which the pigment
radicle, heme, is attached. Heme consists of four pyrrole
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 27
Plate 1-27 Liver: PART III
Amount of bile BILE ACID CIRCULATION AND METABOLISM: ENTEROHEPATIC Elevated
acid return CIRCULATION AND CELLULAR MECHANISMS OF METABOLISM systemic
controls rate serum bile
of synthesis Intrahepatic metabolic acid
disorders
Bile acid Bile acid
synthesis synthesis
1° bile acids Intrahepatic 1° bile acids
2° bile acids obstruction 2° bile acids
Extrahepatic
obstruction
2° Normal 2° Cholestasis
bile bile
acids acids
Fecal loss Decreased fecal loss
Bile acids synthesized by liver secreted Extrahepatic obstruction or intrahepatic disorders that
into gut, reabsorbed, and recycled through affect bile synthesis, transport, absorption, or secretion
liver, with small amount lost in feces result in decreased enterohepatic circulation of bile acids
Cellular mechanisms of metabolism
Sinusoid Bile duct
(portal system)
Epimerization HCO3–
Cholesterol Canaliculus
1° bile acids Hepatocyte
3Na+ Na+ Conjugation
Sodium ATP cotransporter
Bilirubin and Bile Acid pump
Metabolism (Continued) 2K+
Bile acids reabsorbed
A water-soluble bilirubin diglucuronide forms, which from intestine 2° bile acids
shows the van den Bergh reaction without pretreat-
Na+ cHoCtrOan3–sporter
cotransporter
HCO3–
ment. This form has been designated as prompt (direct)- Primary (1°) acids synthesized, conjugated, and sectreted into canaliculi. In gut, portion of bile acid
reacting bilirubin (conjugated bilirubin). is converted to secondary (2°) bile acids. Bile acids (90%) reabsorbed into portal system and returned
Conjugated bilirubin passes from the liver cells into to liver; in hepatocytes, primary forms recycled and secondary acids epimerized and excreted
the bile canaliculi and flows from there into the biliary
passages. If it is retained there for protracted periods, it
can be oxidized to biliverdin. Under normal conditions,
conjugated bilirubin eventually reaches the intestines,
where it is reduced by intestinal bacteria into several reabsorbed and returned by the portal bloodstream to that this type of urobilin formation may lead to errone-
compounds, mainly the colorless mesobilirubinogen the liver. The bulk of the reabsorbed portion is trans- ous diagnostic interpretations.
and stercobilinogen, both being designated collectively formed back into bilirubin, completing an enterohe- Although bilirubin accounts for the color of bile and
as urobilinogen. Only with the suppression of bacterial patic circulation. serves an important function in hemoglobin metabo-
flora by antibiotics or with increased peristalsis in diar- A very small amount of urobilinogen escapes the liver lism and elimination, the biliary pathway also serves
rhea does bilirubin appear in the feces. The main fecal and appears in the urine. Oxidizing bacteria may trans- many other important functions. The predominant
pigment is urobilin, the intestinal oxidation product of form urobilinogen into urobilin either in the bladder components of bile are bile acids, which are synthesized
a part of the urobilinogen compounds. Approximately or, more frequently, in urine that has been left standing by hepatocytes and excreted via specialized receptors
one third of the urobilinogen formed from bilirubin is too long before examination. One should be mindful into the bile canaliculi to the gastrointestinal tract,
28 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-28 Liver
Biliary tree
HEPATIC PROTEIN AND BILE ACID METABOLISM:
NORMAL SERUM PROTEIN AND CLOTTING FACTORS AND CHOLESTASIS
Normal
Normal serum protein and clotting factors
Circulation Hepatocyte
Bile Bile Bile acid Bile
acids acids synthesis acids
Normal fat Toxins
absorption Detoxified Detoxification To
compounds Protein synthesis duodenum
Serum (albumin-clotting
proteins factors)
Clotting
factors
Hepatocytes (with polarity of transport and secretion) synthesize serum proteins
and clotting factors and secrete them into the bloodstream. Bile acids absorbed
from circulation and secreted along with newly synthesized bile acids into
biliary tree. Toxins absorbed from circulation, detoxified, and returned to
circulation
Cholestasis
Serum proteins weight loss
Clotting factors easy bruising
Intrahepatic obstruction
Extrahepatic Bile Bile acid Bile Bile
obstruction acids synthesis acid acids
Alkaline Alkaline reflux
Bile acids phos- phosphatase
Malabsorption phatase synthesis
of fats and
steatorrhea Toxins Detoxification Obstruction
Bilirubin and Bile Acid Serum Protein
Metabolism (Continued) proteins synthesis
Clotting
where they facilitate the formation of the micelles factors
needed for absorption of dietary fat and fat-soluble vita-
mins. Bile acids also have many other functions related Obstructed bile flow and reflux of bile acids into hepatocytes result in
to interactions with the intestinal epithelium. In addi- increased synthesis and secretion of alkaline phosphatase. Resultant hepato-
tion, the biliary pathway is important for the transport cellular damage inhibits synthesis of proteins and clotting factors and limits
of cholesterol to the gastrointestinal tract and elimina- detoxification
tion of lipid-soluble toxins, drugs, metals, and other
substances. Many organic anions and cations are function mutations in the ATPB7 gene, which regulates gastrointestinal bacteria. Both primary and secondary
excreted in the bile, such as drugs and toxins. Other copper excretion from the biliary tract. In addition, bile bile acids are resorbed and recycled through the liver,
components of bile include hormones, vitamins, cyto- contains albumin, lysosomal enzymes, haptoglobin, and and only small amounts are lost in the feces. Extrahe-
kines (such as tumor necrosis factor and leukotrienes), secretory immunoglobulin A, all of which likely serve patic obstruction or intrahepatic disorders result in
and divalent cations such as copper. In fact, as an impor- important immune functions in the gastrointestinal cholestasis, which leads to loss of bile acids in the stool
tant component of body copper regulation, chronic tract. and elevates systemic bile acid levels. With cholestasis,
cholestasis leads to excess copper accumulation in the there are decreased serum proteins and clotting factors,
liver. Thus it is not surprising that Wilson disease (a Primary bile acids are synthesized by bile, and sec- which can lead to weight loss and easy bruising.
copper storage disorder) is caused by the loss of ondary bile acids are the result of bacterial action by
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 29
Plate 1-29 Liver: PART III
PERCUTANEOUS SUCTION AND LAPAROSCOPIC TECHNIQUES
Liver Biopsy Klatskin biopsy needle
Midaxillary line Intercostal space
The microscopic examination of liver tissue, obtained 7
by biopsy, is an important tool in the diagnosis of liver 8
disease. It provides important basic information on 9
potential causes of liver disease, as well as prognostic
information based on the degree of damage and 1. Saline (1 mL) injected to expel 3. Breath held in expiration, while needle
fibrosis. tissue fragments from needle pushed to maximum depth with quick
7th to 9th intercostal rectilinear movement without rotation;
Liver biopsy can be performed in several ways. space in midaxillary line aspiration maintained
Wedge specimens, obtained from the free edge of the
liver during surgery (either laparoscopic or open), may (Biopsy specimen recovered by
be useful but may also be unsatisfactory because sub- expelling saline from syringe)
capsular fibrosis is accentuated on the free edge to the
extent that an almost normal liver may appear to be 2. Maximum aspiration exerted on syringe 4. Needle withdrawn rapidly
cirrhotic. Specimens should be excised from the ante- without rotation; aspiration
rior aspect of the liver, or a needle biopsy of the more maintained
central parts may be obtained. The procedure is best
performed at the beginning of the operation, in order Laparoscopic technique
to minimize the observation of misleading, nonspecific
tissue alterations, particularly focal necrosis with leuko- Laparoscopic needle biopsy Laparoscopic excision biopsy
cytes, which may result from the operation per se.
is indicated in patients with a bleeding tendency such as tumor tissue, and fracture of a liver containing amyloid.
Liver biopsy can be performed percutaneously either coagulopathy, ascites, or other disorders precluding a Additional hazards include laceration of an intercostal
blindly or with ultrasound guidance. The patient is percutaneous approach. The theoretical advantage of a artery, perforation of the gallbladder or bile ducts, and
placed in a supine position with arms above the head transjugular approach is that if bleeding were to occur, pneumothorax. The most common risks are pain and
and legs positioned to increase the intercostal space. it would occur into the vascular space. Contraindica- bleeding, with the risk of a fatal complication at around
The liver is localized with percussion, and a suitable tions to liver biopsy are significant hemorrhagic tenden- 1 in 10,000 patients. Careful consideration of the indica-
area in the intercostal space is identified in the midaxil- cies, infections, and a dilated, aberrant bile duct on the tions for biopsy and vigilant observation of the patient
lary line. Localization can also be made and confirmed surface of the liver. Further risks of lacerating the liver following the procedure will sharply reduce the chance
by ultrasound. occur with intraperitoneal hemorrhage, bleeding from of dangerous complications.
Multiple different needles are available but can be
categorized as two types: an aspiration/suction needle,
such as the Jamshidi, Menghini, or Klatskin needle, or
a cutting needle, such as the Tru-Cut, Vim-Silverman,
or spring-loaded automatic device. With the aspiration
needles, a syringe usually containing saline is attached.
After local anesthesia is placed, the needle is inserted
into the subcutaneous tissue. A small amount of fluid is
injected to remove tissue fragments from the needle
lumen. The plunger is retracted, creating suction in the
syringe, and the needle is advanced into the liver at the
end of an expiration or while the breath is held in expi-
ration. The instrument is withdrawn quickly, aspiration
being maintained. The diameter of the specimen is rela-
tively small, but not distorted, and is sufficient in diffuse
hepatic diseases such as hepatitis. The technique is
readily applied in small children and in other uncoop-
erative persons. Larger specimens, thus obtained, are
particularly advantageous in detecting focal lesions such
as granulomas or carcinomas.
With the cutting needles, a split needle is passed
through a cannula and advanced into the liver, where
the beveled halves punch out a small core. The cannula
is advanced over the needle, so that both halves are
brought together, trapping some tissue. The entire
instrument is then quickly withdrawn.
With any technique, the specimen can be extruded
from the needle into a glass tube in which it can be
inspected with transillumination, frequently permitting
a macroscopic diagnosis. In cirrhosis, nodules can be
seen, and the specimen readily breaks into small pieces.
In severe cholestasis, the specimen appears green, in
hemochromatosis it is brown, and granulomas or tumor
metastases may be recognized as white nodules.
In addition to the percutaneous approach, liver biopsy
can also be performed via a transjugular approach. This
30 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-30 Liver
Noninvasive Assessments for
Hepatic Fibrosis
Accurate staging of hepatic fibrosis is important for the Positioning of
prediction of patient prognosis and response to treat- probe against
ment in liver disease. Liver biopsy is considered the the intercostal
gold standard for the diagnosis of pathologic conditions space
of the liver and the staging of fibrosis, but it has several
drawbacks. It is invasive and expensive and associated 7.7 kPa
with a mortality rate of approximately 0.2% for all
causes. It can be inaccurate owing to sampling error Liver stiffness is computed from the
from the irregular distribution of pathologic changes. shear wave propagation map and is
Several noninvasive tests have been developed, most expressed in kilopascals.
commonly for patients with chronic hepatitis C and
nonalcoholic fatty liver disease (NAFLD); they can be 3 cm
divided into serum markers and imaging modalities.
Testing aims to differentiate between minimal fibrosis Probe generates vibration that
(stage 0 to 1 out of 4) and significant fibrosis (higher creates a shear wave with
than stage 2 out of 4), but up to 50% of tests will fall consistent frequency and energy.
in the indeterminate range. A combination of serologic Low energy ultrasound follows
testing and imaging can improve accuracy. Practice the propagation of the shear
guidelines have now incorporated a few noninvasive wave through the liver tissue.
tests into the recommendations for determining the
presence of advanced fibrosis, but biopsy is still typically 2.5 cm 6.5 cm
recommended for prognosis and treatment decisions.
Depth and volume of tissue measured
SERUM MARKERS
Most scoring systems use a combination of direct space and measured by pulse-echo ultrasound. The approximately 95%. There are limitations with this
markers, which are proteins derived from structural results are expressed in kilopascals (kPa), ranging from technique, including a limited depth of penetration
proteins of the fibrotic matrix or inflammatory media- 2.5 to 75 kPa; values differ according to the cause of (important in obese patients); this problem has led to
tors involved in fibrogenesis or fibrolysis, or indirect liver disease. In general, normal liver stiffness is lower the development of a larger probe. Hepatic steatosis
markers, which are simple biochemical tests that are than 5 kPa and definitive cirrhosis is higher than 15 and inflammation can affect shear wave propagation
thought to correlate with the progression of fibrosis but kPa. A series of 10 pulses is measured to ensure uniform and accuracy.
are not directly involved in the process. Indirect markers results and accurate velocity measurements. This tech-
are attractive given their wide availability and lower nique has been studied most extensively in patients with Other imaging techniques include real-time shear
cost. Examples of these algorithms include APRI (AST/ chronic hepatitis C virus infection; it has shown supe- wave elastography and acoustic radiation force impulse
platelet ratio), FIB-4 (platelet count, AST, ALT, and rior results in diagnosing cirrhosis compared with most imaging; their efficacy seems to be similar to that of
age), and NAFLD fibrosis (age, body mass index, plate- serologic tests, with a sensitivity and specificity of transient elastography, but they provide much less data
let count, AST, ALT, presence of diabetes/glucose intol- and clinical use.
erance, albumin) scores. APRI and FIB-4 scores are
used primarily in chronic hepatitis C, where a score of
1.0 or higher or 3.25 or higher predicts cirrhosis with
72% and 97% specificity, respectively. The NAFLD
fibrosis score is used in patients with the disease, where
a score of higher than 0.675 predicts advanced fibrosis
with 98% specificity. There are also several proprietary
tests in which several indirect markers are used; they
are mainly studied in Europe and the United States in
patients with hepatitis B or C, including the FibroTest/
FibroSure, ActiTest, and Hepascore, which have had
good accuracy in studies.
IMAGING STUDIES
Standard imaging techniques, such as ultrasound,
computed tomography (CT), and magnetic resonance
imaging (MRI), can detect advanced cirrhosis, but
usually only once the complications of portal hyperten-
sion have developed. Specialized ultrasound and mag-
netic resonance elastography techniques can assess liver
stiffness by measuring the velocity of a mechanical pulse
as it travels through the liver tissue. The velocity
increases as the liver stiffness (fibrosis) increases. Mag-
netic resonance elastography is less studied, but its
results seem to be similar to those of ultrasound-based
transient elastography, or FibroScan. FibroScan mea-
sures liver stiffness (and, therefore, fibrosis) and can
predict complications such as large varices and surgical
risk in patients with known cirrhosis. A pulse is deliv-
ered through a transducer placed over an intercostal
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 31
Plate 1-31 Liver: PART III
Intrahepatic
ULTRASOUND disease.
Ultrasonography routinely used Normal
to differentiate extrahepatic caliber
cholestasis from intrahepatic bile ducts
disease
Extrahepatic
obstruction.
Dilated
bile ducts
Imaging Studies of Liver
Over the past few decades, there have been tremendous
advances in medical imaging technology which have
made radiologic imaging a standard for the care of
patients with liver disease. Ultrasound, CT scanning,
and MRI now produce images with high resolution and
are routinely used in clinical practice.
ULTRASOUND STUDIES Normal liver ultrasound not as operator dependent as ultrasound and
Abdominal ultrasound is often the first diagnostic provides a more thorough and detailed evaluation of
imaging technique used to examine liver disease because In addition to its use for diagnostic purposes, ultra- the liver and other abdominal structures. Unlike
of its wide availability, portability, and ease of use. With sound is also used to guide needle placement in the ultrasound, CT scans are not limited by overlying
standard liver ultrasound, intravenous access is not correct anatomic space in interventional procedures gas patterns or ascites. CT images are acquired after
needed, and there is no ionizing radiation. The tech- such as paracentesis and liver biopsy. radiographic beams are transmitted through the patient
nique is based on transmitting targeted sound waves of COMPUTED TOMOGRAPHY and collected by rotating detectors opposite to the
varying frequencies through the tissue and detecting CT scanning is superior to ultrasound in imaging the beams. The amount of radiation detected is attenuated
the reflected waves. The computerized conversion of hepatobiliary system, except for the gallbladder. CT is by the tissue being imaged. With processing, anatomic
these signals results in images on a screen that reflects
differential acoustic properties of the tissue and can be
extrapolated to give anatomic and textural information.
Solid or cystic lesions can be detected by ultrasound.
Ultrasound is usually the preferred study for screening
for hepatocellular carcinoma in patients with cirrhosis.
In patients with fatty liver, ultrasound can be useful in
detecting evidence of fat. Vessel patency can also be
assessed with the Doppler technology; one can detect
important clinical scenarios such as portal vein throm-
bosis or assess patency of a previously placed shunt
such as the transjugular intrahepatic portosystemic
shunt (TIPS).
Ultrasound is particularly useful for evaluating the
gallbladder and gallbladder pathologic conditions. It
also allows for detection of intrahepatic and extrahe-
patic biliary dilatation. It is often the first test used in
a patient with right upper quadrant pathologic condi-
tions. It can rule out gallstones or gallbladder wall
thickening, which may represent inflammation or may
be a sign of common bile duct stones.
32 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-32 Liver
COMPUTED TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING
Computed tomography of normal liver (left) and normal liver with liver cyst on (right)
Imaging Studies of Liver
(Continued)
reconstruction can produce two-dimensional and three- Magnetic resonance imaging of normal liver
dimensional images. Intravenous iodinated contrast
material can be infused into the vessels, and by timed
image acquisition, valuable information can be obtained
from any potential liver lesion. For example, in the case
of hepatocellular carcinoma, arterial enhancement of
lesions timed when the contrast is traversing the hepatic
artery, followed by reimaging of the liver when contrast
is in the portal vein, can show the characteristic
“washout” appearance diagnostic of hepatocellular car-
cinoma. From a clinical standpoint, radiologic diagnosis
has surpassed tissue diagnosis in patients with underly-
ing cirrhosis. Thus, CT scanning is a useful tool for the
evaluation of hepatic lesions. In addition to providing
important information about mass lesions, both benign
and malignant, CT scanning can provide information
about the patency of blood vessels and contours of the
liver. For example, with development of cirrhosis, there
are characteristic structural changes such as nodularity
and caudate lobe enlargement that can be easily detected
on CT. Evidence of portal hypertension can also be
seen in many areas, such as varices, ascites, and spleno-
megaly. These features can be used in the diagnosis of
cirrhosis in the absence of liver biopsy.
MAGNETIC RESONANCE IMAGING for protons to fully align with the external magnetic hepatocellular carcinomas, and metastases. In addition,
MRI is another important technique for hepatobiliary field as opposed to the rate at which protons are out there is an opportunity to characterize evidence of
imaging. Using a strong magnetic field to align rotating of phase with respect to adjacent protons. Water is hemochromatosis and cirrhosis. Contrast-enhanced
protons within tissues, one can release the alignment dark on T1 images and bright on T2 images, but for MRI is similar to CT scanning in its ability to further
and measure the energy release at different time inter- fat, the darkness and brightness are the other way characterize liver tumors. In addition to standard
vals. Characteristic signal intensity from different around. MRI, magnetic resonance cholangiography can
tissues is dependent on the relative water and fat provide valuable images of the biliary tree without
content. Converting the signals to gray-scale cross- Using MRI and T1 and T2 images, one can differenti- contrast dye.
sectional images can provide valuable hepatobiliary ate many liver lesions, including cysts, hemangiomas,
imaging. T1 and T2 signals indicate the time required
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 33
Plate 1-33 Liver: PART III
LIVER DISEASES CAUSED BY PREGNANCY AND INCIDENTAL TO PREGNANCY
Liver Disease in Pregnancy
Normal physiologic changes occurring in pregnancy Caused by pregnancy Fibrin films Pernicious
may result in altered liver function tests but are not Eclampsia vomiting
evidence for intrinsic liver disease. With progression of Incidental to pregnancy
pregnancy, serum albumin levels drop owing to expan- Hemolytic familial jaundice Fatty liver of pregnancy
sion of the total body volume. Serum alkaline phospha- Viral hepatitis
tase levels increase because of a rise in placental alkaline Choledocholithiasis
phosphatase. Serum transaminases, however, are not yellow–brown bile pigment retained in hepatocytes and Viral hepatitis with massive necrosis
anticipated to change with pregnancy. small dilated canaliculi located between pairs of hepa- Pruritus can cause significant distress and morbidity
tocytes. Inflammation and hepatocyte necrosis are gen- in the mother. ICP is not associated with an increased
Diseases of the liver that occur during pregnancy can erally absent, and the intrahepatic bile ducts in the rate of maternal death, but the disorder is associated
be divided into three types: (1) liver disease that occurs portal tracks appear normal. This finding is pathogno- with significant rates of perinatal morbidity and mortal-
only in pregnancy, (2) liver disease that can occur at any monic of intrahepatic cholestasis of any origin and ity, which appear to be correlated with levels of serum
time, including during pregnancy, and (3) chronic differs markedly from the pathologic findings in other bile acids. The fetal complication rate is increased in
underlying liver disease that is detected during preg- unique liver disorders of pregnancy. parallel with maternal serum bile acid levels; most of
nancy. Liver diseases that occur only in pregnancy are the complications occur in women with bile acid levels
hyperemesis gravidarum, intrahepatic cholestasis of
pregnancy, liver diseases associated with preeclampsia/
eclampsia (e.g., the syndrome of hemolytic anemia,
elevated liver enzymes, and low platelets [HELLP syn-
drome]), and acute fatty liver of pregnancy.
Hyperemesis gravidarum is a condition of excessive
nausea and vomiting that develops during pregnancy.
This condition is not an intrinsic liver disease but can
result in abnormalities of liver function. During the first
trimester, liver function tests can be abnormal in some
patients. Abnormalities are generally mild, but trans-
aminase levels may occasionally be 20 to 30 times the
abnormal range. Liver biopsy is usually not necessary
but can show mild fatty change or no abnormality. The
liver abnormalities of hyperemesis gravidarum usually
resolve rapidly when dehydration and nutritional
deficits are controlled.
Intrahepatic cholestasis of pregnancy (ICP) is a choles-
tatic liver disease that usually appears in the third tri-
mester. It disappears abruptly after delivery but may
recur with subsequent pregnancies or with use of oral
contraceptives. It is characterized by the presence of
pruritus (the sine qua non of this condition) and
increased bile acids. Pruritus usually occurs at 28 weeks
but can occur earlier. Mild liver enzyme elevations (par-
ticularly, of serum transaminases) are also noted, with
mild elevations in alkaline phosphatase. Visible jaundice
is unusual but can occasionally occur. Elevated bile acid
levels are very diagnostic; they can vary widely, from
mildly elevated levels up to levels that are 100-fold the
upper limit of normal. In patients with severe pruritus
accompanied by jaundice, fat malabsorption may occur
with vitamin K deficiency. In a few patients, this will
result an abnormal prothrombin time.
The mechanism by which ICP occurs is likely a com-
bination of hormonal and genetic factors. Impairment
of bile formation owing to the cholestatic effects of
estrogen and, possibly, progesterone during pregnancy
is superimposed on genetic variances in one or more
hepatocyte bile transporters. Mutations of the ABCB4
(adenosine triphosphate–binding cassette, subfamily b,
member 4) gene, which encodes the hepatic phospho-
lipid transporter MDR3 (multidrug resistance 3), have
been found in some patients with the disease. Mutations
in other genes that regulate bile acid transport
have also been noted, including ATP8B1, ABCB11
(ATP-dependent canalicular transporter for bile acids),
and NRH1HA encoding the familial intrahepatic cho-
lestasis 1 protein, and in the bile salt export pump or
farnesoid X. The pathologic finding in ICP is golden
34 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-34 Liver
Liver Disease in Pregnancy HELLP SYNDROME AND ECLAMPSIA
HELLP Syndrome (Hemolysis, Abnormal Liver Function Tests, Low Platelets)
(Continued)
greater than 40 µmol. The treatment of choice for Clinical symptoms
IHCP is delivery of the infant; once the infant has been Nausea, vomiting
born, pruritus usually resolves. If the fetus is too imma- Right upper quadrant pain
ture to be delivered, symptomatic therapy is recom- Jaundice
mended. Ursodeoxycholic acid has been shown to
improve liver function and relieve pruritus in the Laboratory findings Complications • Acute kidney injury
mother and may also benefit the fetal outcome. The • Hemolysis (with schistocytes seen on peripheral • Placental abruption • Pulmonary edema
bile acid binder cholestyramine has been tried but does • Hepatic subcapsular • Disseminated
not appear as effective as ursodeoxycholic acid. Because smear)
fetal hemorrhage has been reported in women with • Elevated liver function tests hematoma intravascular
severe disease and vitamin K deficiency, vitamin K • Low platelet count • Retinal detachment coagulation (DIC)
supplementation should be given near term to all
women with jaundice or prolonged cholestasis. Eclampsia
Unlike hyperemesis gravidarum and ICP, HELLP Clinical symptoms
syndrome and acute fatty liver of pregnancy are associated • Generalized, tonic-clonic seizure
with preeclampsia. In fact, HELLP syndrome was first • Early symptoms may include:
described as a distinct entity in a subset of women who
had severe preeclampsia/eclampsia and liver disease. A Blurred vision
rare but devastating disease, HELLP syndrome is diag- Severe frontal or occipital headache
nosed by a constellation of symptoms, including micro- Altered mental status
angiopathic hemolytic anemia, thrombocytopenia, and
elevated liver tests occurring in the third trimester. Complications
Although the pathogenesis is unknown, the relationship • Cerebral hemorrhage
with preeclampsia/eclampsia suggests that this is a
disease of abnormal hepatic endothelial reactivity or pathophysiologic changes that take place during preg- pressure increases with each stage of pregnancy; in
disruption. The initial event may be abnormal tropho- nancy. Some patients may exhibit signs of liver disease patients with preexisting portal hypertension, the risk
blastic implantation leading to reduced tissue perfusion during pregnancy owing to preexisting chronic liver of variceal bleeding is a major cause of morbidity and
and endothelial dysfunction. This endothelial dysfunc- disease. In this latter group, the ability to become preg- mortality. Pregnancy has not been shown to aggravate
tion is accompanied by platelet activation and aggrega- nant depends on the severity of the liver disease; quiescent autoimmune hepatitis or Wilson disease;
tion. The characteristic liver lesion seen on biopsy is patients with more active or progressive liver disease however, it is best to have the disease under control
fibrin thrombi in the periportal sinusoids, hepatocyte may not be able to conceive. before a woman becomes pregnant and not to stop
necrosis, and periportal hemorrhage. therapy prior to or during pregnancy. In patients with
In patients with preexisting liver diseases, several viral hepatitis B, certain precautions need to be taken
Acute fatty liver of pregnancy also has some association issues need to be addressed. First, the risk of pregnancy to decrease the risk of transmission to the fetus.
with preeclampsia, but it is not as strong as in HELLP depends on the level of portal hypertension. Portal
syndrome. There is a strong association of acute
fatty liver of pregnancy with mitochondrial long-
chain 3-hydroxyacyl-CoA dehydrogenase deficiency
(LCHAD) in the fetus. LCHAD deficiency in the fetus
can cause accumulation of long-chain 3-hydroxy-fatty
acyl metabolites, which are toxic to the liver. It is
thought that some interaction of the accumulation in
long-chain 3-hydroxy-fatty acyl metabolite with envi-
ronmental stresses to the mother in the third trimester
may result in sudden onset of liver failure from acute
fatty liver of pregnancy. Patients often present with
nonspecific symptoms, such as nausea, vomiting, and
right upper quadrant or epigastric pain, associated with
malaise, headache, and anorexia. Patients typically
develop progressive jaundice, but pruritus is rare. Acute
liver failure may ensue, with the onset of severe coagu-
lopathy and hypoglycemia. The serum aminotransfer-
ases can be elevated 10-fold to 15-fold but are relatively
unimpressive in view of other laboratory evidence of
fulminant hepatic failure. Liver biopsy shows the diag-
nostic finding of centrilobular microvesicular fatty infil-
tration with little or no inflammation.
During pregnancy, acute liver disease may occur
coincidentally or chronic disease may be found that
predated the pregnancy. Common diseases such as viral
hepatitis may occur more commonly given the risk
factors present in a young female population. Some
liver diseases such as gallbladder disease, herpes
hepatitis, and Budd-Chiari syndrome occur more
commonly in the setting of pregnancy because of the
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 35
Plate 1-35 Liver: PART III
Stab wound
Trauma
Because of its size, location, and fixation, the liver is Ruptures
frequently subjected to trauma, which may be either and laceration
penetrating or blunt. Next to the brain, the liver is the
organ most commonly hit by blunt violence. Bullet or Subcapsular hematoma Detached fragments
stab wounds penetrate to various depths and produce an of liver in right
intrahepatic canal with a ragged wall and a lumen filled lateral gutter
with blood. In more than a fourth of penetrating tho-
racoabdominal wounds, the liver is injured. The blunt necrosis; if the patient survives, the area may be sur- later stages, it may be the result of liver abscesses or
injuries lead to ruptures or lacerations varying in size and rounded by a demarcation zone with fibroplasia. Com- traumatic cholangitis. Foreign bodies, such as bullets,
sometimes in number. They are most commonly the pletely detached liver tissue pieces are well tolerated in the liver may eventually migrate into the biliary ducts
result of automobile accidents or of falls. The lacera- within the peritoneal cavity and may even be organi- and produce obstructive jaundice.
tions may be inflicted by broken ribs, or the organ may cally attached in the lateral gutter.
be crushed by the impact of the thoracic cage and the The liver is relatively insensitive to external ionizing
resisting spine. Internal stress or contrecoup effects The laboratory manifestations of hepatic trauma are radiation; even the effects of internal radiation from
during a blunt injury may lead to subcapsular or central surprisingly insignificant. Jaundice is rare and occurs radioactive substances accumulating in the liver (e.g.,
lacerations; if the impact is slight, only a subcapsular mainly if the gallbladder and bile ducts are ruptured. In phosphorus-32) are not severe.
hematoma may develop.
Rupture, as the consequence of blunt injury, is facili-
tated if the liver has become more friable or when the
capsular tension has increased owing to abscesses, cysts,
infectious diseases such as malaria or hepatitis, and fatty
liver. Unlike in the spleen, so-called spontaneous
rupture of a mildly damaged liver is rare. It has been
claimed that postprandial hyperemia may predispose to
rupture of the liver, and rupture during pregnancy has
also been reported.
Except for temporary slight peritoneal irritations
from blood oozing into the peritoneal cavity, subcapsular
hematomas and small lacerations or ruptures usually heal
with few clinical manifestations and leave a pigmented
or white subcapsular scar. If the hematoma becomes
infected, intrahepatic or subphrenic or subhepatic
abscesses may complicate the clinical course. Hepatic
cysts also may develop, as may biliary fistulae after lac-
eration of a small bile duct. Rarer complications are
portal vein thrombosis or arterial aneurysms. From a
forensic point of view, it is interesting that acute hepa-
titis, including the fulminant variety, and even cirrhosis
have been connected causally with a preceding trauma.
Centrilobular necrosis may be a consequence of shock.
A definite association of trauma with other diffuse
hepatic diseases is, however, rather difficult to prove.
Severe laceration or rupture of the liver has a high
mortality rate, more so in military than in civilian prac-
tice. Death early after the trauma is caused by hepatic
hemorrhage, which is severe and does not stop readily
for several reasons: the walls of the valveless hepatic
veins are thin, the liver is extremely vascular, the bile
admixed with the blood interferes with clotting, and the
diaphragm massages the liver. During the past decade,
angiographic embolization has supplanted surgery as
the preferred treatment of hepatic hemorrhage in
hemodynamically stable patients. Later, the effects of
biliary peritonitis, following laceration of bile ducts
or shock or infection, become important causes of
death. Previously, the term hepatorenal syndrome was
coined to describe the complication of renal failure
after trauma that was thought to be a result of the toxic
effect from tissue breakdown products from the liver.
However, traumatized, necrotic, and even completely
separated hepatic tissue has not been convincingly
proved to exert a toxic effect different from that of other
organs, although it must be admitted that interruption
of blood flow to parts of the liver leads to rapid ischemic
36 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-36 Liver
Erythroblastosis
CAUSES OF JAUNDICE IN NEONATES
Bile duct atresia; extrahepatic
(biliary atresia)
Amenable
to surgery
Jaundice in
Neonatal Period
Jaundice in the first days of life is a common phenom- Sequela
enon. In general, the yellowish discoloration of the cirrhosis
skin and sclera results from accumulation of unconju-
gated hyperbilirubinemia and is a normal physiologic Bile inspissation (cystic fibrosis)
event that resolves on its own. This physiologic jaun-
dice has multiple causes, including a higher hematocrit, Bile duct atresia; intrahepatic Infections in utero
shorter life span of fetal blood cells, and relatively low (Alagille’s syndrome) and peripartum
level of conversion of bilirubin to urobilinogen by
intestinal flora, resulting in higher absorption of biliru- Jaundice aggravated
bin back into the circulation. In addition, there is low by prematurity
activity of the enzyme uridine-diphosphoglucuronate Immature
glucuronosyltransferase (UGT1A1), which normally
converts unconjugated bilirubin to conjugated biliru- Physiologic jaundice
bin. UGT1A1 activity in term infants at 7 days of age
is approximately 1% of adults and levels do not reach indirect-reacting bilirubin is kept below 20 mg/dL. If as has the appearance of an abnormal Moro reflex. The
adult levels until 14 weeks of age. Before birth, this untreated, the brain complications of neonatal jaundice majority of children who develop kernicterus die within
enzyme is actively down-regulated because bilirubin may become clinically recognizable within the first a short time, usually in 1 to 10 days after showing the
needs to be unconjugated to cross the placenta. After week of life. The infant becomes drowsy, vomits, and first signs. A minority, perhaps 25% to 30%, survive,
birth, the enzyme gains function over time. These are refuses to take food. Irregularities in respiration, insta- with permanent brain damage. Their mental develop-
slowed in preterm infants, and thus prematurity aggra- bility of circulation, muscular twitchings, spasticity, and ment may be retarded, and their ability to walk is
vates and prolongs the physiologic process of the opisthotonus may be observed. A certain shrillness of delayed or is never acquired. Speech difficulties or inad-
decline of bilirubin. Severe bile stasis has been observed the baby’s cry has been considered a characteristic sign, equate muscle coordination occur, and the children
in the livers of such prematurely born children, as have
many hematopoietic foci, but no hepatocellular degen-
eration has been seen, except, occasionally, in the left
hepatic lobe, which quite suddenly loses its supply of
oxygenated blood after interruption of the placental
circulation.
The physiologic jaundice seen in infants is generally
benign; if serum bilirubin levels rise excessively,
however, bilirubin may accumulate in the brain and
portions of the brain may have a yellowish color. This
brain affliction was named kernicterus by German
pathologists in the latter part of the nineteenth century.
Unconjugated bilirubin is toxic to the brain and can
cause brain damage if the condition is left untreated.
The nuclei (Kerne) in the basal ganglia are extremely
pigmented and degenerated. In some cases, the cells of
the Ammon horn and, rarely, some parts of the cortex
are similarly colored and in the process of disintegra-
tion. The mechanism of these cellular changes in the
central nervous system and the reason for the predilec-
tion for the basal ganglion cannot be explained. Abnor-
mal permeability of the barrier between blood and
spinal fluid in early postnatal life and damage produced
by anoxia, predisposing to the deposition of bile
pigment, have been cited as instrumental factors. The
relationship between the degree of bilirubinemia and
the postmortem finding of kernicterus has been studied,
with the result that the level of the indirect-reacting
or nonconjugated, and therefore lipid-soluble, bilirubin
seems to have a bearing on the cerebral changes,
but other factors, such as immaturity, anoxia, anemia,
and the duration of jaundice, also have an influence.
Kernicterus develops rarely when the level of the
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 37
Plate 1-37 Liver: PART III
MANIFESTATIONS OF KERNICTERUS AND TREATMENT
Jaundice in Neonatal
Period (Continued)
remain physically helpless. Untreated kernicterus is a Spasticity
cause of cerebral palsy. Because of this, the general Kernicterus
recommendation is to initiate phototherapy at a certain
threshold bilirubin level determined by an assessment Jaundiced infant under phototherapy Jaundiced infant receiving exchange transfusion
of the risk for severe hyperbilirubinemia based on level (with eye proctection) (through umbilical lines)
and age. The body temperature and fluid status must
be monitored, and eye patches are required. In cases of are a broad nasal bridge, triangular facies, and deep-set infections. Commonly acquired pathogens include the
severe unconjugated hyperbilirubinemia, exchange eyes). Most cases of the syndrome have been associated TORCH group of agents, Toxoplasma gondii, rubella
transfusion may prevent possible kernicterus. with a JAG-1 gene mutation. virus, cytomegalovirus, herpesvirus, and Treponema pal-
lidum. Bacterial infections can also result in jaundice.
Unconjugated hyperbilirubinemia may occur in Other causes of obstruction include cystic changes of
isoimmune-mediated hemolysis caused by ABO or Rh the bile ducts (choledochal cysts), gallstones, sludge, Metabolic causes include alpha-1 antitrypsin defi-
incompatibility. The most significant type of neonatal and tumors. Bile inspissation has been described in ciency, which can present as neonatal hepatitis. Galac-
jaundice is associated with hemolytic disease of the newborn, infants with cystic fibrosis. tosemia occasionally produces jaundice in the neonatal
also known as erythroblastosis fetalis. The cause of this period. Parenteral nutrition is another important cause
condition is the presence of maternal immunoglobulin Other causes of chronic cholestasis in infants are of neonatal cholestasis that can lead to jaundice.
G (IgG), which crosses the placenta to react with red infections, including bacterial, protozoal, and viral
blood cells in the fetal circulation, resulting in hemoly-
sis. This may occur when a mother who is Rh-negative
is exposed to the erythrocytes of an Rh-positive fetus
who inherited this factor from the paternal side. Fetal
erythrocytes passing through the placenta elicit the for-
mation of maternal antibodies, which, in turn, enter
the fetus and destroy the red blood cells carrying
the Rh blood group. Rh-negative mothers who have
been pregnant before and now are pregnant with an
Rh-positive infant should be given Rh immunoglobulin
during pregnancy and within 48 hours after delivery to
prevent sensitization. This agent works by binding any
fetal red blood cells with the offending antigen before
the mother is able to produce an immune response and
form antibodies.
Cholestasis may be a cause of neonatal jaundice.
Cholestasis in the neonatal period can result from
obstruction, metabolic/genetic abnormalities, infec-
tion, and toxic insults. Obstruction can have multiple
causes, including extrahepatic biliary atresia, Alagille
syndrome, inspissated bile/mucous plugs, and chole-
dochal cysts. Biliary atresia or extensive hypoplasia of
the extrahepatic bile ducts is an idiopathic disease that
affects the extrahepatic bile ducts, resulting in progres-
sive jaundice within 8 weeks of birth. This results from
persistence of the early temporary stage of solid-duct
anlagen prior to the development of hollow channels.
The fibrous cord, which may be found in place of the
bile duct or parts thereof, contains no epithelium and
may be so fine as to suggest complete aplasia. Oblitera-
tion occurs mostly in the lower parts of what should
have developed into the common bile duct. Early rec-
ognition and surgical intervention improve the outcome
in biliary atresia. Even with optimal management, the
sequelae of biliary cirrhosis can occur with time, and
many patients require liver transplantation for long-
term treatment. In addition to extrahepatic biliary
atresia, abnormalities of intrahepatic ducts can occur in
Alagille syndrome. In this disease, there is a paucity of
interlobular ducts associated with systemic features,
such as cardiac abnormalities, butterfly vertebrae, and
dysmorphic facies (the classic features in the syndrome
38 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-38 Liver
Complete situs inversus
Congenital Malpositions
of Liver
Though encountered only on very rare occasions, con- In complete situs inversus, the reversal of right to left Partial situs inversus
genital malpositions of the liver may create diagnostic and left to right must have been determined during the Other congenital malpositions (not illustrated)
problems. Transposition of the liver, in which the large very first phases of structural organization in the include ectopia of the liver, resulting from an inherited
lobe and gallbladder are lying on the left side and, cor- embryo. Alteration of the normal rotation of the intes- defect of the muscles of the abdominal wall, and hepatic
respondingly, the small lobe is on the right side, is usually tine has been offered as an explanation for partial situs hernias at the umbilicus, which produce a peculiar mass
accompanied by transposition of other intraperitoneal inversus, with differences in the width of the vitelline near the navel. Bulging of the thin membranous part of
organs, at least. In such instances, the pylorus lies to the and umbilical veins playing a determining role. Rota- the diaphragm into the cavity of the thorax permits
left of the midline; the fundus of the stomach, descend- tion of the stomach from the primitive median position herniation of part of the liver; this has characteristic
ing colon and sigmoid colon, and spleen are found on the to the right rather than to the left has been considered radiologic findings but, nevertheless, may pose prob-
right side, and the appendix and cecum, of course, are on a causative factor for transposition of the liver. lems of differential diagnosis of intrathoracic or subdia-
the left. This situation, in which the positional anomaly phragmatic masses.
is restricted to the intraabdominal organs, is called
partial situs inversus; in complete situs inversus, which is
more common, the chest organs are transposed in
the same mirror-image fashion. In such cases, the pulsa-
tion of the apex of the heart may be felt on the right
side. The aortic arch and the aorta descend on the right
side; the right lung has two lobes and the left three. In
some cases, only the chest organs are transposed, and the
abdominal organs, including the liver, are in the normal
position. Absence of the normal hepatic dullness on
auscultatory percussion may lead to a wrong diagnosis,
particularly in gallbladder diseases, but these and other
diagnostic difficulties arising from complete or partial
situs inversus are readily resolved by roentgenologic
examination.
The causes of situs inversus have not been estab-
lished, and the explanations offered are all hypothetical.
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 39
Plate 1-39 Liver: PART III
Cloudy swelling
Diffuse
liver cell
damage
Pathologic Features of Central
Liver Injury eosinophilic
degeneration
Liver cell injury may be brought about by nutritional Mallory
deficiencies, chemical agents, lack of oxygen, viral and bodies
bacterial infections, and metabolic disturbances. What- “Councilman
ever the etiologic factors may be, certain similar histo- bodies”
logic features of liver injury may be present. One of the
first signs of injury that can be recognized in a morpho- Ballooning
logic sense occurs most frequently in the centrilobular (hydropic
zone, where cells lose their basophilism and become swelling)
acidophilic or eosinophilic. A more severe degree of
degeneration is characterized by variations in size and Fatty
staining qualities of nuclei and cytoplasm of the neigh- metamor-
boring liver cells. This diffuse change results in a poly- phosis
morphous irregularity of the liver cell plates (disarray
or unrest). nuclei, rarefied cytoplasm, and sharp borders, an indicates some defect in lipid metabolism or lipoprotein
appearance that reminds one of plant cells. This is synthesis or an increased quantity of adipose or dietary
Progression of eosinophilic cytoplasmic degenera- probably the result of defects in membrane and/or lipid brought to the liver. The most common causes of
tion leads to formation of acidophilic clumps around mitochondrial function and is common to many hepatic macrovesicular fat are alcohol consumption or nonal-
the nuclei. They are found in various types of hepatic injuries, including alcoholic liver injury and nonalco- coholic fatty liver disease. Another form of liver cell
injuries, though Mallory, describing these bodies, first holic fatty liver disease. degeneration is feathery degeneration, a form of liver cell
considered them originally characteristic of alcoholic death associated with cholestasis. Cells undergoing this
cirrhosis. Mallory bodies are accumulations of cytokera- Another manifestation of liver injury is fat accumula- form of death have cytoplasm that appears flocculant,
tin intermediate filaments inside liver cells; they are tion in the hepatocytes or steatosis. The presence of and they are larger than normal hepatocytes.
often caused by Wilson disease or cholestasis. Diffuse fat, which can be microvesicular or macrovesicular,
clumping of the cytoplasm may induce a homogeneous
appearance; the nucleus becomes pyknotic and eventu-
ally disappears. The cell remnants are expelled from the
liver plate and lie in the tissue spaces as acidophilic
masses, or so-called Councilman bodies (named for the
person who discovered similar formations in patients
with yellow fever; these dead cells are also known as
acidophil bodies or apoptotic bodies). The cells are
present in the body for only a few hours, before they
are cleaned up by Kupffer cells; their presence, there-
fore, suggests that liver injury is ongoing.
Another histologic expression of cell injury is
hydropic swelling or balloon degeneration. The cells
appear ballooned, with central but relatively small
40 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
Plate 1-40 Liver
Pathologic Features Two-cell-thick plates Regenerative nodule
of Hepatic Regeneration
and Atrophy
Cells of the liver plates constantly disappear and are Multinuclear giant cells Proliferation of bile ductules
replaced by new cells by either mitotic or amitotic divi-
sion. Binucleate cells are, therefore, seen under normal Kupffer cell reaction Pressure atrophy (due to metastatic tumor)
circumstances. This regenerative activity is accentuated The reticuloendothelial system and, consequently, Atrophy of the liver cells may be the result of starva-
if liver cells are lost because of disease or trauma. After the Kupffer cells respond to injury with more extensive tion but it may come forth also as the result of pressure
successive partial hepatectomies, the liver restores itself, regeneration than any other system of the body. Kupffer in the vicinity of space-occupying lesions, such as
and eventually the amount rebuilt exceeds by far the cell reactions may, therefore, be elicited by stimuli that tumors, abscesses, granulomas, or lesions of amyloido-
weight of those portions that the liver has lost. The cause injury, such as bacteria, liver cell breakdown, or sis. The liver cells in such instances become stretched
regeneration takes place not only close to areas of extir- intoxication, or by agents that cause only phagocytosis. and may eventually lose their cytoplasmic basophilia,
pation or spontaneous necrosis but also in parts remote Most endothelial cells of the liver sinusoids exhibit the indicating focal functional insufficiency. Hardly ever is
from the area of lost liver tissue. Local, as well as characteristics of Kupffer cells. Their cytoplasm bulges a focal loss significant enough to be reflected in the
remote, liver regeneration occurs in hepatic diseases into the lumen and contains engulfed material. overall function of the liver.
whenever degeneration and necrosis of hepatic tissue
occur. Regenerated hepatic tissue may make up for, and
therefore mask, the loss of function, and it is for this
reason that hepatic tests sometimes yield normal values
in spite of widespread hepatic disease. The regenerative
processes are also responsible for the often perplexing
variety of morphologic pictures in hepatic diseases.
Regeneration reveals itself in various structural forms
and stages. Lost parts of a liver cell plate are replaced
by liver cells growing into the empty meshes of the
framework. Mitosis of singular cells or binucleate cells
without mitotic figures may appear, or the entire liver
cell plate may increase from a thickness of one cell to
that of two cells, simulating the appearance of the liver
in lower animals or in the embryo. Liver cells or liver
cell groups that become isolated during necrosis of the
surrounding tissue or during the development of cir-
rhosis may transform themselves into independent
regenerative nodules. Active regeneration in these nodules
is usually most marked in the periphery, where several-
cell-thick plates are found, in contrast to one-cell-thick
plates in their center. The plates converge toward the
center, indicating blood drainage from the center,
although a central vein usually is not formed.
Sometimes, especially in infants, the division of liver
cells does not keep pace with the division of the nuclei,
so that multinuclear giant cells form, in which biliary
inclusion may be found.
The so-called proliferations of bile ductules accompany-
ing degenerative and necrotizing processes are mainly,
but not solely, located in the periphery of the lobule.
They have often been interpreted as attempted liver cell
regeneration from bile ducts and ductules. Electron
microscopic and radioautographic evidence indicates
that the proliferated bile ductules are derived from
ductules and not from liver cells, apparently in contrast
to what occurs in the embryo. Regenerated liver cells
might resemble bile ductules, however.
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 41
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