Introduction to Pathophysiology
PART ONE: CENTRAL CONCEPTS OF PATHOPHYSIOLOGY: CELLS AND TISSUES UNIT
I: THE CELL 1 Cellular Biology, 1 2 Altered Cellular and Tissue Biology, 49 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases, 103 UNIT
II: GENES AND GENE-ENVIRONMENT INTERACTION 4 Genes and Genetic Diseases, 135 5 Genes, Environment-Lifestyle, and Common Diseases, 164 6 Epigenetics and Disease, 183 UNIT
III: MECHANISMS OF SELF-DEFENSE 7 Innate
Immunity: Inflammation, 191 8 Adaptive Immunity, 224 9 Alterations in Immunity and Inflammation, 262 10 Infection, 298 11 Stress and Disease, 338 UNIT
IV: CELLULAR PROLIFERATION: CANCER 12
Cancer Biology, 363 13 Cancer Epidemiology, 402 14 Cancer in Children, 442 PART TWO: PATHOPHYSIOLOGIC ALTERATIONS: ORGANS AND SYSTEMS UNIT V: THE NEUROLOGIC SYSTEM 15 Structure and Function of the Neurologic System, 447 16 Pain, Temperature Regulation, Sleep, and Sensory Function, 484 17 Alterations in Cognitive Systems, Cerebral Hemodynamics, and Motor Function, 527 18 Disorders of the Central and Peripheral Nervous Systems and the Neuromuscular Junction, 581 19 Neurobiology of Schizophrenia, Mood Disorders, and Anxiety Disorders, 641 20 Alterations of Neurologic Function in Children, 660 UNIT VI: THE ENDOCRINE SYSTEM 21 Mechanisms of Hormonal Regulation, 689 22 Alterations of Hormonal Regulation, 717 UNIT VII: THE REPRODUCTIVE SYSTEMS 23 Structure and Function of the Reproductive Systems, 768 24 Alterations of the Female Reproductive System, 800 25 Alterations of the Male Reproductive System, 885 26 Sexually Transmitted Infections, 918 UNIT VIII: THE HEMATOLOGIC SYSTEM 27 Structure and Function of the Hematologic System, 945 28
Alterations of Erythrocyte Function, 982 29
Alterations of Leukocyte, Lymphoid, and Hemostatic Function, 1008 30 Alterations of Hematologic Function in Children, 1055 UNIT IX: THE CARDIOVASCULAR AND LYMPHATIC SYSTEMS
31 Structure and Function of the Cardiovascular and Lymphatic Systems, 1083 32 Alterations of Cardiovascular Function, 1129 33 Alterations of Cardiovascular Function in Children, 1194 UNIT X: THE PULMONARY SYSTEM 34 Structure and Function of the Pulmonary System, 1225 35
Alterations of Pulmonary Function, 1248 36
Alterations of Pulmonary Function in Children, 1290
UNIT XI: THE RENAL AND UROLOGIC SYSTEMS
37 Structure and Function of the Renal and Urologic Systems, 1319 38 Alterations of Renal and Urinary Tract Function, 1340 39 Alterations of Renal and Urinary Tract Function in Children, 1376 UNIT XII: THE DIGESTIVE SYSTEM 40 Structure and Function of the Digestive System, 1393 41
Alterations of Digestive Function, 1423 42
Alterations of Digestive Function in Children, 1486
UNIT XIII: THE MUSCULOSKELETAL SYSTEM 43
Structure and Function of the Musculoskeletal
System, 1510 44 Alterations of Musculoskeletal Function, 1540 45 Alterations of Musculoskeletal Function in Children, 1591 UNIT
XIV: THE
INTEGUMENTARY SYSTEM 46 Structure, Function, and Disorders of the Integument, 1616 47 Alterations of the Integument in Children, 1653 UNIT
XV: MULTIPLE INTERACTING SYSTEMS 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults, 1668 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children, 1699 Glossary, 172
INTRODUCTION TO PATHOPHYSIOLOGY
The word root “patho” is derived from the Greek word pathos, which means suffering. The Greek word root “logos” means discourse or, more commonly, system of formal study, and “physio” pertains to functions of organisms. Generally, pathophysiology is the systematic study of the functional changes in cells, tissues, and organs altered by disease and/or injury. Important, however, is the inextricable component of suffering. Knowledge of cellular biology as well as anatomy and physiology and the various organ systems of the body is an essential foundation for the study of pathophysiology. To understand pathophysiology the student must also use principles, concepts, and basic knowledge from other fields of study, including biology, genetics, immunology, pathology, and epidemiology. A number of terms are used to focus the discussion of pathophysiology; they may be used interchangeably at times, but that does not necessarily indicate that they have the same meaning. These terms are reviewed in Table I-1.
Pathophysiology is one of the most important bridging sciences between preclinical and clinical courses for students in the health sciences and it
requires in-depth study at an early stage in the curriculum. The definitions or conceptual models of pathophysiology that we carry in our minds influence what we do with our observations and the rationale that we provide for our actions. Therefore, the clinician must understand that although pathophysiology is a science, it also designates suffering in people; the clinician should never lose sight of this aspect of its definition. As students study clinically-related sciences, they learn to recognize and categorize disease. From the formulation of a differential diagnosis one understands the different clinical manifestations, the signs, and the symptoms of certain pathologies. These understandings structure further investigations, treatment plans, and evaluation. The interaction of these activities determines clinical outcomes and treatment success. Still, the concept of disease can be inherently ambiguous and elusive; many pathologies remain hidden and resist easy classification. One should appreciate that the naming and diagnosing of diseases involve evaluative judgments as well as scientific fact, and that the process is as much a social endeavor as it
is a scientific one. Some diseases, such as tuberculosis, identify a highly specific causative or etiologic agent or process. Others, such as Alzheimer disease or arthritis, indicate pathologic changes of unclear cause. There is considerable need for more research to validate mental health diagnoses. In addition, syndromes and functional disorders simply describe multiple symptoms and signs that frequently occur together. Does commonality exist in all of these labels? The answer is “yes” and “no” and depends on our conception of health and disease. In the strictest sense, objective scientific facts help us know if an individual is healthy or suffering from disease. Critical to attaining health in the United States are nine domains particularly worrisome and include adverse birth outcomes, injuries and homicides, adolescent pregnancy and sexually transmitted infections, HIV and AIDS, drug-related mortality, obesity and diabetes, heart disease, chronic lung disease, and disability.1 An individual’s conception of disease is based on personal beliefs and histories, professional and lay healers who interact with that individual, and society at large. Each idea or construct has the
power to influence other ideas and constructs, and each relationship has the ability to shape the way disease is understood and experienced.2 In short, defining and understanding disease are tremendously ambiguous. Although a discerning mind is key, perhaps an important trait for the new student of pathophysiology is an open and tolerant mind. To believe that science alone can overcome ignorance and that clinical training and technology can overcome ineptitude only encourages arrogance and undermines the scientific purpose. Pathophysiology has had great success in explaining the mechanisms and clinical manifestations associated with infectious diseases. Syndromes of unclear etiology, such as headache and fibromyalgia, have proven to be troublesome. Even more difficult are multifactorial conditions, such as atherosclerosis or type 2 diabetes mellitus, in which several interacting factors contribute to the etiology. Learning how interacting factors relate to one another to increase morbidity or actually cause disease contributes to an appreciation of how emerging concepts revolutionize current understandings. One revolution in thought that has
driven intensive research is that low levels of chronic inflammation cause or contribute to many diseases. The language that clinicians use to discuss diseases and their manifestations is powerful. Lives are altered by a few words uttered by a clinician in a white coat or uniform. “AIDS,” “cancer,” and “heart attack” have become culturally ingrained symbols that portend an individual’s future. Although some futures are determined by scientific evidence, others are determined by subjective experience.3 For example, a person diagnosed with a familial disease may ask, “Will I suffer like my mother did?” This questioning influences individuals’ suffering. In conclusion, pathophysiology the understanding of disease—requires descriptive evidence as well as an evaluative component regarding suffering and the language we use to describe it. Combining objective and subjective perspectives requires new conceptual models that take into account the complex interactions among the body, mind, environment, and spirit.
All body functions depend on the integrity of cells. Therefore, an understanding of cellular biology is intrinsically necessary for an understanding of
disease. An overwhelming amount of information is revealing how cells behave as a multicellular “social” organism. At the heart of cellular biology is cellular communication (“cellular crosstalk”)—how messages originate and are transmitted, received, interpreted, and used by the cell. Fossil records suggest that unicellular organisms resembling bacteria were present on earth 3.5 billion years ago, yet it took another 2.5 billion years for the first multicellular organisms to appear. This delay was seemingly slow because elaborate signaling mechanisms had to evolve that would allow cells to crosstalk. This streamlined conversation between, among, and within cells maintains cellular function and specialization. Intercellular signals allow each cell to determine its position and specialized role. Cells must demonstrate a “chemical fondness” for other cells and their surrounding environment to maintain the integrity of the entire organism. When they no longer tolerate this fondness, the conversation breaks down and cells either adapt (sometimes altering function) or become vulnerable to isolation, injury, or disease. PROKARYOTES AND EUKARYOTES Living cells generally are divided into
two major classes eukaryotes and prokaryotes. The cells of higher animals and plants are eukaryotes, as are the single-celled organisms fungi, protozoa, and most algae. Prokaryotes include cyanobacteria (blue-green algae), bacteria, and rickettsiae. Prokaryotes traditionally were studied as core subjects of molecular biology. Current emphasis is on the eukaryotic cell; much of its structure and function has no counterpart in bacterial cells. Eukaryotes (eu = good; karyon = nucleus) are larger and have more extensive intracellular anatomy and organization than do prokaryotes. Eukaryotic cells have a characteristic set of membrane-bound intracellular compartments, called organelles, that includes a well-defined nucleus. Prokaryotes contain no organelles, and their nuclear material is not encased by a nuclear membrane. Prokaryotic cells are characterized by lack of a distinct nucleus. Besides having structural differences, prokaryotic and eukaryotic cells differ in chemical composition and biochemical activity. The nuclei of prokaryotic cells carry genetic information in a single circular chromosome, and they lack a class of proteins called histones, which in eukaryotic
cells bind with deoxyribonucleic acid (DNA) and are involved in the supercoiling of DNA (see Figure 1-2, p. 4). We now understand that the loops and coiling of DNA are important for many diseases (see Chapter 6). Eukaryotic cells have several chromosomes. Protein production, or synthesis, in the two classes of cells also differs because of major structural differences in ribonucleic acid (RNA)–protein complexes. Other distinctions include differences in mechanisms of transport across the outer cellular membrane and differences in enzyme content. CELLULAR FUNCTIONS Cells become specialized through the process of differentiation, or maturation, so that some cells eventually perform one kind of function and other cells perform other functions. Cells with a highly developed function, such as movement, often lack some other property, such as hormone production, which is more highly developed in some other type of specialized cell. The eight chief cellular functions follow: 1. Movement. Muscle cells can generate forces that produce motion. Muscles that are attached to bones produce limb movements, whereas those that enclose hollow tubes or cavities move or empty
contents when they contract. For example, the contraction of smooth muscle cells surrounding blood vessels changes the diameter of the vessels; the contraction of muscles in walls of the urinary bladder expels urine. 2. Conductivity. Conduction as a response to a stimulus is manifested by a wave of excitation, an electrical potential that passes along the surface of the cell to reach its other parts. Conductivity is the chief function of nerve cells. 3. Metabolic absorption. All cells take in and use nutrients and other substances from their surroundings. Cells of the intestine and the kidney are specialized to carry out absorption. Cells of the kidney tubules reabsorb fluids and synthesize proteins. Intestinal epithelial cells reabsorb fluids and synthesize protein enzymes. 4. Secretion. Certain cells, such as mucous gland cells, can synthesize new substances from substances they absorb and then secrete the new substances to serve as needed elsewhere. Cells of the adrenal gland, testis, and ovary can secrete hormonal steroids. 5. Excretion. All cells can rid themselves of waste products resulting from the metabolic breakdown of nutrients. Membrane-bound sacs
(lysosomes) within cells contain enzymes that break down, or digest, large molecules, turning them into waste products that are released from the cell. 6. Respiration. Cells absorb oxygen, which is used to transform nutrients into energy in the form of adenosine triphosphate (ATP). Cellular respiration, or oxidation, occurs in organelles called mitochondria. 7. Reproduction. Tissue growth occurs as cells enlarge and reproduce themselves. Even without growth, tissue maintenance requires that new cells be produced to replace cells that are lost normally through cellular death. Not all cells are capable of continuous division (see Chapter 2). 8. Communication. Communication is vital for cells to survive as a society of cells. Pancreatic cells, for instance, secrete and release insulin necessary to signal muscle cells to absorb sugar from the blood for energy. Constant communication allows the maintenance of a dynamic steady state.
STRUCTURE AND FUNCTION OF CELLULAR
COMPONENTS Figure 1-1 shows a “typical” eukaryotic cell. It consists of three components: an outer membrane called the plasma membrane, or plasmalemma; a fluid filling called cytoplasm; and
the intracellular “organs,” or organelles, which are membrane bound and include the nucleus. Nucleus The nucleus, which is surrounded by the cytoplasm and generally is located in the center of the cell, is the largest membrane-bound organelle. Two membranes comprise the nuclear envelope (Figure 1-2, A). The outer membrane is continuous with membranes of the endoplasmic reticulum. The inner membrane encloses the neoplasm. The nucleus contains the nucleolus, a small dense structure composed largely of RNA; most of the cellular DNA; and the DNAbinding proteins, the histones, that regulate its activity. The DNA chain in eukaryotic cells is so extensive that the risk of breakage is high. Therefore, the histones that bind to DNA cause DNA to fold into chromosomes (Figure 1-2, C). The wrapping of DNA into tight packages of chromosomes is essential for cell division in eukaryotes. The primary functions of the nucleus are cell division and control of genetic information. Other functions include the replication and repair of DNA and the transcription of the information stored in DNA. Genetic information is transcribed into RNA, which can be processed into messenger, transport,
and ribosomal RNA and introduced into the cytoplasm, where it directs cellular activities. Most of the processing of RNA occurs in the nucleolus. (The role of DNA and RNA in protein synthesis is discussed in Chapter 4.)
Cytoplasmic Organelles
Cytoplasm is an aqueous solution (cytosol) that fills the cytoplasmic matrix—the space between the nuclear envelope and the plasma membrane. The cytosol represents about half the volume of a eukaryotic cell. It contains thousands of enzymes involved in intermediate metabolism and is crowded with ribosomes making proteins. Newly synthesized proteins remain in the cytosol if they lack a signal for transport to a cell organelle.1 The organelles suspended in the cytoplasm are enclosed in biologic membranes, which enables them to simultaneously carry out functions that require different biochemical environments. These functions, many of which are directed by coded messages carried from the nucleus by RNA, include synthesis of proteins and hormones and their transport out of the cell, isolation and elimination of waste products from the cell, metabolic processes, breakdown and disposal of cellular debris and foreign proteins (antigens), and
maintenance of cellular structure and motility. Also the cytosol functions as a storage unit for fat, carbohydrate, and secretory vesicles. Ribosomes Ribosomes are RNA-protein complexes (nucleoproteins) that are synthesized in the nucleolus and secreted into the cytoplasm through pores in the nuclear envelope called nuclear pore complexes (NPCs).2 These tiny ribosomes may float free in the cytoplasm or attach themselves to the outer membranes of the endoplasmic reticulum (see Figure 1-1, A). Their chief function is to provide sites for cellular protein synthesis. Newly formed ribosomes synthesize a “recognition sequence,” or signal, like an address on a letter. Signal recognition particles (SRPs) in the cytosol bind to the ribosome after recognizing the SRP. Ribophorins, receiver proteins found on the rough sections of the endoplasmic reticulum (ER), act as the “address” site or binding site. The developing protein threads its way through the ER membrane into the lumen. The SRP is removed and the new protein chain is folded into its final conformation. Endoplasmic Reticulum The endoplasmic reticulum (ER) (endo = within; plasma = cytoplasm; reticulum = network) is a
membrane factory that specializes in the synthesis and transport of the protein and lipid components of most of the cell’s organelles. It consists of a network of tubular or saclike channels (cisternae) that extend throughout the cytoplasm and are continuous with the outer nuclear membrane (Figure 1-3). The folded membranes that form the cisternae of the endoplasmic reticulum may be rough (granular) or smooth (agranular). The rough endoplasmic reticulum (rER) is rough because ribosomes and ribonucleoprotein particles are attached to it (see Figure 1-3). Some of the proteins synthesized by these ribosomes remain in the ER, and others are used to construct membranes of other organelles (the Golgi complex, lysosomes, peroxisomes, and nucleus) and of the cell itself. Importantly, the ER is responsible for much of a cell’s protein synthesis and folding, and a new role is sensing cellular stress (see What’s New? Endoplasmic Reticulum, Protein Folding, and ER Stress). Understanding mechanisms of cellular stress will aid diagnosis and treatment of disease. Smooth endoplasmic reticulum (sER) does not contain ribosomes or ribonucleoprotein particles (see Figure 1-1). Rather,
membranous surfaces of the smooth endoplasmic reticulum contain enzymes involved in the synthesis of steroid hormones and are responsible for a variety of reactions required to remove toxic substances from the cell. The endoplasmic reticulum communicates with the Golgi complex and interacts with other organelles, particularly lysosomes and peroxisomes. Golgi Complex The Golgi complex (or Golgi apparatus) is a network of flattened, smooth membranes and vesicles frequently located near the nucleus of the cell (Figure 1-4). Proteins from the endoplasmic reticulum are processed and packaged into small membrane-bound sacs or vesicles called secretory vesicles, which collect at the end of the membranous folds of the Golgi bodies—called cisternae. The secretory vesicles then break off from the Golgi complex and migrate to a variety of intracellular and extracellular destinations, including the plasma membrane. The vesicles fuse with the plasma membrane, and their contents are released from the cell. The best known vesicles are those that have coats made largely of the protein clathrin and are called clathrin-coated vesicles. They bud from the Golgi complex on the outward secretory pathway
and from the plasma membrane on the inward endocytotic pathway (see p. 33). Many molecules, including lipids, proteins, glycoproteins, and enzymes of lysosomes, pass through the Golgi complex at some stage in their maturation. The Golgi complex is a refining plant and directs traffic (e.g., protein, polynucleotide, polysaccharide molecules) in the cell1 (Figure 1-5). Lysosomes
Lysosomes (lyso = dissolution; soma = body) are saclike structures that originate from the Golgi complex (see Figure 1-1, A). They contain more than 40 digestive enzymes called hydrolases, which catalyze bonds in proteins, lipids, nucleic acids, and carbohydrates. Lysosomes function as the intracellular digestive system (Figure 1-6).
Lysosomal enzymes are capable of digesting most cellular constituents completely to their basic components, such as amino acids, fatty acids, and carbohydrates. The lysosomal membrane acts as a protective shield between the powerful digestive enzymes within the lysosome and the cytoplasm, preventing their leakage into the cytoplasmic matrix.
Disruption of the membrane by various treatments or cellular injury leads to a release of the lysosomal
enzymes, which can then react with their specific substrates, causing cellular selfdigestion. Lysosomal abnormalities are involved in a number of conditions that involve cellular injury and death. Lysosomal storage diseases may be the result of a genetic defect or lack of one or more lysosomal enzymes. For example, the lack of lysosomal α-1,4glucosidase leads to an accumulation of glycogen in lysosomes known as Pompe disease. Tay-Sachs disease is characterized by an accumulation of GM2 ganglioside (a lipid) in lysosomes as a result of the deficiency or absence of lysosomal hexosaminidase
A. In gout, undigested uric acid accumulates within lysosomes, damaging the lysosomal membrane. Subsequent enzyme leakage results in cell death and tissue injury.