Metabolism of Human Diseases

Metabolism of

Human Diseases

Eckhard Lammert

Martin Zeeb Editors

Organ Physiology and Pathophysiology

Metabolism of Human Diseases

Eckhard Lammert • Martin Zeeb

Editors

Metabolism of Human

Diseases

Organ Physiology

and Pathophysiology

ISBN 978-3-7091-0714-0 ISBN 978-3-7091-0715-7 (eBook)

DOI 10.1007/978-3-7091-0715-7

Springer Wien Heidelberg New York Dordrecht London

Library of Congress Control Number: 2014940716

© Springer-Verlag Wien 2014

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Editors

Eckhard Lammert

Department of Biology

Institute of Metabolic Physiology

German Diabetes Center

Heinrich Heine University Düsseldorf

Düsseldorf

Germany

Martin Zeeb

CardioMetabolic Diseases Research

Boehringer Ingelheim Pharma

GmbH & Co KG

Biberach

Germany

v

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Martin Zeeb and Eckhard Lammert

Part I Brain

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Lorraine V. Kalia

Major Depressive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Donatella Marazziti, Grazia Rutigliano, Stefano Baroni,

and Liliana Dell’Osso

Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Peter F. Buckley and Adriana Foster

Epilepsy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Wesley Plinke and Detlev Boison

Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Giulia Ambrosi, Silvia Cerri, and Fabio Blandini

Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Milos D. Ikonomovic and Steven T. DeKosky

Migraine and Cluster Headache. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Massimo Leone and Paola Di Fiore

Multiple Sclerosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

Markus Kipp

Down Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Maria D. Torres and Jorge Busciglio

Part II Eye

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Anja Mataruga and Frank Müller

Age-Related Macular Degeneration. . . . . . . . . . . . . . . . . . . . . . . . . . 67

Monika Fleckenstein and Frank G. Holz

Contents

vi

Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Samuel D. Crish and Christine M. Dengler-Crish

Part III Teeth and Bones

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Kazuhiko Kawasaki and Kenneth M. Weiss

Dental Caries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

Colin Robinson

Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Emmanuel Biver and René Rizzoli

Part IV Joints

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Jessica Bertrand and Jan Hubert

Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

Camille Roubille, Johanne Martel-Pelletier,

and Jean-Pierre Pelletier

Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

Marianna Meroni, Elena Bernero, and Maurizio Cutolo

Part V Gastrointestinal Tract

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Satish Keshav and Philip Allan

Peptic Ulcer Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

Peter C. Konturek and Stanislaw J. Konturek

Gastroenteritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

Christina Quigley and Xi Jiang

Lactose Intolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

Anthony K. Campbell and Stephanie B. Matthews

Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

Kishore Vipperla and Stephen J. O’Keefe

Part VI Pancreas

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

Alexandra E. Folias and Matthias Hebrok

Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

Alena Welters and Eckhard Lammert

Contents

vii

Part VII Liver

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

Dieter Häussinger

Cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

Matteo Rosselli and Massimo Pinzani

Part VIII Fat Tissue

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

Gabriele Schoiswohl, Jules Aljammal, and Erin E. Kershaw

Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

Kana Inoue, Norikazu Maeda, and Tohru Funahashi

Part IX Lung

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

Martin Zeeb, Andreas Schnapp, and Michael-Paul Pieper

Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

Kenji Izuhara, Shoichi Suzuki, Kazuhiko Arima, Shoichiro Ohta,

Masako Inamitsu, and Ken-ichi Yamamoto

Chronic Obstructive Pulmonary Disease (COPD) . . . . . . . . . . . . . . 221

Irena Konstantinova and Andrew C. Pearce

Community-Acquired Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

Salvador Sialer, Leonardo F. Difrancesco, Teresa Foix Fabregas,

and Antoni Torres

Part X Heart

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

Axel Gödecke

Atherosclerotic Heart Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

Massimo Slavich and Juan Carlos Kaski

Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

Roman Pfi ster and Erland Erdmann

Part XI Blood Vessels

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261

Victor W.M. van Hinsbergh, Rick Meijer, and Etto C. Eringa

Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

Dwi Setyowati Karolina and Kandiah Jeyaseelan

Contents

viii

Varicose Veins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273

Rishi Mandavia, Muzaffar A. Anwar, and Alun H. Davies

Part XII Blood

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

Deena Iskander and Barbara J. Bain

Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

Daniel A. Dworkis and Martin H. Steinberg

Hyperlipidemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

Paul Durrington and Handrean Soran

Part XIII Immune System

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305

Christian Münz

Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313

Bruno Conti and Tamas Bartfai

Sepsis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

Jean-Charles Preiser and Jean-Louis Vincent

Allergies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323

Norbert Meyer and James Yun

Part XIV Kidney

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331

Markus M. Rinschen, Linus A. Völker,

and Paul T. Brinkkötter

Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339

Colleen Flynn and George L. Bakris

Chronic Kidney Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345

Golaun Odabaei, George A. Kaysen, and Shubha Ananthakrishnan

Gout. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351

Sonia Nasi and Alexander So

Urinary Tract Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357

Matt S. Conover, Michael E. Hibbing, and Scott J. Hultgren

Kidney Stones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

Andreas Neisius and Glenn M. Preminger

Contents

ix

Part XV Reproductive System

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369

Danny J. Schust and Donald R. Gullicks

Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379

Tanja Fehm and Eugen Ruckhäberle

Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

Rahul Aggarwal and Eric Small

Part XVI Cancer

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

Zachary E. Stine and Chi V. Dang

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401

Contents

E. Lammert, M. Zeeb (eds.), Metabolism of Human Diseases, 1

DOI 10.1007/978-3-7091-0715-7_1, © Springer-Verlag Wien 2014

The scientifi c community has increasingly recog￾nized metabolic alterations as being critical com￾ponents or even drivers of human disease.

Metabolism of Human Diseases discusses the

metabolism and signaling pathways in tissues and

organs known to be relevant for common human

diseases. It thus bridges the existing gap between

biochemistry and physiology textbooks, on the one

hand, and pathology textbooks, on the other hand.

Metabolism of Human Diseases is directed at

advanced students, doctors, and scientists from

all categories of life sciences and medicine (e.g.,

biochemists, biologists, physiologists, pharma￾cologists, pharmacists, toxicologists, and physi￾cians) with an interest in the metabolism and

molecular mechanisms of human diseases, irre￾spective of their specialization.

The book is divided into different parts, each

related to a human organ or tissue. Each part begins

with an overview chapter presenting the anatomic

and physiological properties of the organ or tissue

in question relevant for the subsequent disease

chapters of the section (Fig. 1 ). The overview

introduces organ- or tissue-specifi c metabolism and

signaling pathways as well as intra- and inter-organ

communication (i.e., “inside-in,” “inside-out,” and

“outside-in” signaling). The disease chapters dis￾cuss pathomechanisms of the diseases with empha￾sis on metabolic alterations and affected signaling

pathways. In addition, they briefl y introduce major

treatments currently in use and in clinical trials as

well as their infl uence on the patient’s metabolism.

The diseases have been selected to cover a

wide spectrum of human diseases in the industri￾alized world (as described in the tenth edition of

the International Classifi cation of Diseases, ICD￾10). They include many of the most common

(based on diagnosis), most deadly (based on

numbers of deaths), and most expensive (based

on treatment costs) illnesses.

Each chapter of Metabolism of Human

Diseases contains up to three simplifi ed fi gures

and tables that illustrate important elements of

anatomy, physiology, metabolism, signaling path￾ways, or treatment. All fi gures are presented in a

common layout to facilitate understanding of the

contents of each chapter (Fig. 2 ). Since Yousun

Koh provided the layout and fi nal presentation,

we would like to express our gratitude to her.

Finally, more than a hundred international

experts contributed state-of-the-art chapters to

the book, and we would like to thank all of them

for their work and dedication.

We wish the owner of the book a pleasant read!

Best regards,

Martin Zeeb and Eckhard Lammert

M. Zeeb

CardioMetabolic Diseases Research ,

Boehringer Ingelheim Pharma GmbH & Co KG ,

Birkendorfer Straße 65 ,

88400 Biberach (Riss) , Germany

e-mail: [email protected]

E. Lammert (*)

Department of Biology,

Institute of Metabolic Physiology ,

German Diabetes Center,

Heinrich Heine University Düsseldorf ,

Universitätsstraße 1 , 40225 Düsseldorf , Germany

e-mail: [email protected]

Introduction

Martin Zeeb and Eckhard Lammert

2

Fat tissue

Overview

Metabolic syndrome

Kidney

Overview

Hypertension

Chronic kidney disease

Gout and hyperuricemia

Urinary tract infections

Kidney stones

Lung

Overview

Asthma

COPD

Pneumonia

Brain

Overview

Major depressive disorder

Schizophrenia

Epilepsy

Parkinson’s disease

Alzheimer’s disease

Migraine and cluster headache

Multiple sclerosis

Down syndrome

Joints

Overview

Osteoarthritis

Rheumatoid arthritis

Reproductive system

Overview

Breast cancer

Blood vessels

Overview

Stroke

Varicose Veins

Immune system

Overview

Fever

Sepsis

Allergies

Gastrointestinal

tract

Overview

Peptic ulcer

Gastroenteritis

Lactose intolerance

Colorectal cancer

Pancreas

Overview

Diabetes mellitus

Heart

Overview

Atherosclerotic heart disease

Heart failure

Liver

Overview

Cirrhosis

Cancer

Overview

Reproductive system

Prostate cancer

Eye

Overview

Macular degeneration

Glaucoma Blood

Overview

Sickle Cell Disease

Hyperlipidemia

Teeth and bones

Overview

Dental caries

Osteoporosis

Fig. 1 Summary of overview chapters and disease chapters

Treatment

Brackets indicate enzymes

ABC

[ABC]

Influences, results in

Inhibits, blocks

Is converted or metabolized to

Is transported to, released

Magnification

Is termed / called

Increased / decreased

Increased / decreased

under treatment

Receptors

Receptors that act as ion channels

Open and closed transporters

or channels or pumps

Activation

Fig. 2 Explanation of

symbols ( arrow , dashed

arrow , dotted arrow ,

arrowheads , enzyme brackets ,

receptor symbol , transporter

symbol , activation symbol )

used in this book. Enzymes

are marked in brackets .

Outcomes of treatment are

indicated with light gray

arrowheads

M. Zeeb and E. Lammert

Part I

Brain

E. Lammert, M. Zeeb (eds.), Metabolism of Human Diseases, 5

DOI 10.1007/978-3-7091-0715-7_2, © Springer-Verlag Wien 2014

Anatomy and Physiology

of the Brain

The brain is a remarkably complex organ both in

its structure and function. At the macroscopic

level, it can be divided into three major compo￾nents: (1) brainstem (which includes medulla,

pons, and midbrain), (2) cerebellum (with its cor￾tex and deep nuclei), and (3) cerebral hemispheres

(which are composed of cerebral cortex, subcorti￾cal white matter, basal ganglia and thalamus, lim￾bic system, and hypothalamus and pituitary). The

cerebral cortex itself is divided into frontal, pari￾etal, temporal, and occipital lobes (Fig. 1 ). At the

microscopic level, there are two primary cell

types: (1) neurons (which receive, process, and

transmit information by electrical and biochemical

changes mediated, in part, by neurotransmitters)

and (2) glia (which are a diverse group of cells

with expanding roles in brain function).

The various macroscopic regions of the brain

are responsible for different physiological func￾tions. The brainstem contains nuclei required for

autonomic functions, such as regulation of heart

rate and respiration. Most cranial nerves, which

provide motor and sensory function to structures

of the cranium, are also located within the brain￾stem. These include the trigeminal nerve (cranial

nerve V); its sensory portion supplies touch, tem￾perature, and pain sensation to the face, as well as

innervates the cerebral vessels to form the tri￾geminovascular system (see chapter “Migraine

and cluster headache”). The cerebellum func￾tions to coordinate movements. The cerebral cor￾tex contains areas important for motor and

sensory functions, as well as association areas,

which are required for more complex functions,

such as language and executive function. The

basal ganglia, including the substantia nigra, are

responsible for the control of motor activity (see

chapter “Parkinson’s disease”). The limbic sys￾tem supports a variety of functions including

memory and emotion. It receives inputs from

diverse areas of the brain; for example, the meso￾limbic system, which plays important roles in

reward, motivation, and addiction, is composed

of projections from the midbrain to limbic areas

(see chapter “Major depressive disorder”). The

thalamus plays a critical relay function by medi￾ating all motor output from and nearly all sensory

input to the cortex. The hypothalamus is mainly

involved in the regulation of visceral and endo￾crine activities with the hypothalamus and pitu￾itary being the major hormonal regulators (see

chapters “Major depressive disorder”,

“Rheumatoid arthritis”, and “Overview” under

part “Reproductive system”).

Optimal brain function requires a well￾regulated metabolic environment. Extracerebral

L. V. Kalia

Division of Neurology, Department

of Medicine , University of Toronto ,

Toronto , ON M5T 2S8 , Canada

Movement Disorders Centre , Toronto

Western Hospital, University Health Network ,

Toronto , ON M5T 2S8 , Canada

e-mail: [email protected]

Overview

Lorraine V. Kalia

6

systems remove metabolic products and protect

the brain from sudden metabolic perturbations.

Necessary nutrients are delivered via the circula￾tion and must cross the blood-brain barrier

(BBB), which is formed by endothelial cells lin￾ing cerebral microvessels, their basal lamina, and

the end-feet of specialized glial cells called astro￾cytes. Astrocytes and the entire BBB protect neu￾rons from toxic metabolites by preventing their

transport into the brain via exclusion or effl ux

and by neutralizing harmful compounds via

uptake or enzymatic inactivation [ 1 ]. Neuronal

dysfunction and associated neurological diseases

can occur when the brain’s stable metabolic envi￾ronment is disrupted.

Brain-Specifi c Metabolic/Molecular

Pathways and Processes

Neurons are uniquely designed to receive infor￾mation from the environment or other neurons,

process this information, and send information

to other neurons or effector tissues (i.e., neuro￾transmission). The cell body, or soma, contains

the nucleus and additional organelles required

for protein synthesis and metabolic maintenance.

In most neurons, several dendrites and a single

axon extend from the soma. Information is typi￾cally transported from the dendrites to the soma

to the axon within a neuron by means of elec￾trical events, which are mediated by the opening

and closing of specifi c ion channels. Regulated

transport of Na + and K + through the cell mem￾brane is critical. Depolarization of the cell mem￾brane occurs if positive ions (Na + ) enter the cell,

whereas hyperpolarization results from exiting of

positive ions (K + ) from the cell. When the cell

reaches a threshold of depolarization, an electri￾cal signal called an action potential is generated,

and this signal is propagated along the length of

the axon. At the axon terminal, the neuron com￾municates with another neuron or an effector

tissue within a specialized structure called a syn￾apse. A typical synapse consists of a presynaptic

axonal bouton, a postsynaptic dendritic spine,

and the intervening space called the synaptic

cleft (Fig. 2 ). Arrival of the action potential at the

axonal bouton triggers the release of neurotrans￾mitter from presynaptic vesicles into the synaptic

Frontal lobe Temporal lobe

Cerebral cortex

Parietal lobe Occipital lobe

Thalamus

Pituitary

Medulla

Pons

Midbrain

Hypothalamus

Cerebellum

Brain stem

Fig. 1 Basic macroscopic

anatomy of the human brain

L.V. Kalia