Pathology Exam 1 Notes

What is Pathology?

• The study of:

  • diseases.

• Investigates:

  • Causes of disease.

  • Associated changes at the levels of:

    • Cell

    • Tissues

    • Organs

• These investigations explain presenting signs and symptoms.

What is Pathophysiology?

• Physiology is the study of:

  • functions of living organisms.

• Pathophysiology is the study of:

  • Study of abnormalities in physiological functions.

• Responses to disruptions

  • in homeostasis.

Etiology

• Origin of:

  • disease

• Underlying causes and modifying factors:

  • Genetic or environmental

Pathogenesis

• Steps in the development of disease.

• How etiological factors trigger:

  • Cellular and molecular changes.

  • Structural and functional abnormalities that characterize the disease.

Pathology Disciplines

• General Pathology

  • Cellular and tissue alterations caused by a pathological stimuli.

  • how all cell reactions when injured

• Systems Pathology

  • Reactions and abnormalities of specialized organs.

  • how the organ reactions/ fails when injured

Etiology: WHY the Disease Arises

• Study of the:

  • causes or reasons for phenomena.

• Identify the causal factor(s):

  • Idiopathic: Unknown cause.

  • Iatrogenic: Resulting from medical treatment.

  • Causative agent: Specific factor causing the disease.

Pathogenesis: HOW the Disease Develops

• How etiological factors:

  • alter physiological function.

• Development of:

  • clinical manifestations.

Clinical Manifestations

• Observed as:

  • signs and symptoms.

• Signs:

  • Objective changes that a clinician can observe and measure

(e.g., fever or rash).

• Symptoms:

  • Subjective changes in body functions that are not apparent to an observer

  • (e.g., headache or nausea).

• Syndrome: When etiology of signs/symptoms are not determined.

Stages and Clinical Course

• Latent or incubation period:

  • No recognition by patient; lab tests may detect.

• Prodromal period/Prodrome:

  • Appearance of first signs/symptoms (non-specific).

• Manifest illness/Acute phase:

  • Signs/symptoms at greatest severity.

• Subclinical phase:

  • Patient functions normally although disease well established.

Acute vs. Chronic Conditions

• Acute Condition:

  • Severe manifestations for a short time (hours to a few weeks).

• Chronic Condition:

  • Lasts for months to years.

  • Acute can become chronic, or chronic can have acute exacerbations.

Course of Disease

• Exacerbations:

  • Sudden increase in severity.

• Remissions:

  • Decline or abatement in severity.

• Convalescence

  • Stage of recovery after disease, injury, or surgery.

• Sequela:

  • A condition or complication that arises after a previous disease

Statistical Normality

• Estimation of diseases in a normal population is based on a bell-shaped curve.

• 95% fall within the normal range

Reliability, Validity, and Predictive Value

• Reliability:

  • Ability of a test to give the same result in repeated measurements.

• Validity:

  • Degree to which a measurement reflects the true value of what it intends to measure.

• Predictive Value:

  • Extent to which the test can differentiate between the presence or absence of a condition.

    • Positive predictive value.

    • Negative predictive value.

Sensitivity and Specificity

• Sensitivity:

  • Probability that a test will be positive when applied to a person with a particular condition.

• Specificity:

  • Probability that a test will be negative when applied to a person without a particular condition.

Individual Factors

• Cultural considerations:

  • Health and illness reflect each culture's experience.

• Age differences:

  • Hair color, skin turgor, organ size.

• Gender differences:

  • Hemoglobin concentrations, serum creatine levels.

• Situational differences:

  • Deviation from normal should be considered abnormal or an adaptation mechanism.

• Time variations:

  • Body's response from day to night, or at varying times.

Concepts of Epidemiology

• Epidemiology study of:

  • patterns of disease.

• Examines:

  • Occurrence (how often the disease happens)

  • Prevalence (how many people currently have the disease at a given time)

  • Transmission (how the disease spreads)

  • Distribution (who is affected)

• Endemic disease:

  • Native to a local region.

  • Always present in a certain population (e.g., malaria).

• Epidemic disease:

  • Outbreak spreading rapidly/extensively through a population.

  • Affecting an atypically large amount of people within a population (e.g., smallpox, typhus).

• Pandemic disease:

  • Worldwide epidemic, spread to large geographic areas (e.g., polio in the 50s, TB after WWI, AIDS, SARS).

Factors Affecting Patterns of Disease

• Age:

  • Developmental, maturity, postmaturity

• Ethnic group:

  • Sickle cell anemia vs. pernicious anemia.

  • Sickle Cell Anemia
    - Genetic blood disorder
    - Red blood cells = sickle-shaped
    - Causes pain, anemia, infections

  • Pernicious Anemia
    - Vitamin B12 deficiency
    - Body can't absorb B12 (lack of intrinsic factor)
    - Causes fatigue, pale skin, numbness

• Gender:

  • Endometriosis (women), hyperplasia of the prostate (men).

• Socioeconomic factors and lifestyle conditions:

  • Obesity vs. malnutrition.

• Geographic location:

  • Malaria, African sleeping sickness.

Levels of Prevention

• Primary prevention:

  • Treatment before they have the disease

  • Reducing risk factors

• Secondary prevention:

  • Early detection, screening, and management

• Tertiary prevention:

  • Medical and surgical.

  • Rehabilitation, supportive care, attempts to alleviate disability and restore function.

Reversible Cell Injury

• Results in cellular swelling.

• Accumulation of excess substances in the cell.

• Inability to perform normal metabolic functions causes:

  • Lack of ATP.

  • Dysfunction of associated enzymes

• Acute stress or injury removed, cell returns to pre-injury state.

Hydropic Swelling

• Due to accumulation of water.

• 1st manifestation of reversible cell injury.

• Malfunction of Na^+/K^+ pumps (lack of ATP).

• large and pale cytoplasm

• dilated/swollen organelles

• Swelling of the organ has suffix -megaly

Intercellular Accumulations

• Toxic and provoke immune response.

• Occupy space needed for cellular functions.

• Can be indicators not the actual cause of injury.

• Types:

  • Excessive amounts of intracellular substances

    • Lipids (Tay Sachs, excess alcohol consumption)

  • Accumulation of abnormal substances produced by the cell due to faulty metabolism

    • Glucose -> sorbitol -> fructose

  • Pigments or inorganic particles unable to degrade

    • Melanin, mineral dusts

Protein Accumulation

• Cellular stress may lead to:

  • accumulation and aggregation of denatured proteins.

• Abnormally folded intracellular proteins may cause:

  • dysfunction or death.

• Chaperones are:

  • heat shock proteins

  • They are responsible for:

    • binding and refolding.

• Ubiquitin targets:

  • abnormally folded proteins.

Accumulation of Inorganic Particles

• Chronic inflammation:

  • in lungs

• Destruction of:

  • pulmonary alveoli

• Formation of:

  • scar tissue

• Calcification of:

  • heart valves and blood vessels.

Cellular Adaptations

• Responses that allow cells to:

  • modulate structure and function.

• May not be beneficial to the cell.

• Common responses:

  • Atrophy: decrease in cell size

  • Hypertrophy: increase in cell size

  • Hyperplasia: increase in cell number

  • Metaplasia: conversion of one cell to another (potentially reversible)

  • Dysplasia: disorderly growth

Atrophy

• Shrinkage in cell size by:

  • the loss of cell substance.

• Diminished in function, but not dead.

• Causes:

  • Decreased work load

  • Loss of innervation or endocrine stimulation

  • Diminished blood supply (ischemia)

  • Inadequate nutrition

  • Persistent cell injury

  • Aging

Hypertrophy

• Increase in cell size resulting:

  • in increase in size of organ.

• Increase in cellular content.

• No new cells, just bigger cells.

• Can be physiological

  • Response to growth factor or hormonal stimulation

• or pathological

  • Enlarged heart due to:

    • high blood pressure or aortic valve disease

Hyperplasia

• Takes place IF the tissue is capable of replication.

• Results from increased physiological demands or hormonal stimulation.

  • Demand-induced hyperplasia:

    • Increase in RBC due to high altitude.

  • Hormonal hyperplasia:

    • Increase estrogen -> increase in endometrial cells.

  • Compensatory hyperplasia:

    • Residual tissue grows after removal or loss of part of an organ.

Metaplasia

• Reversible change in which one adult cell type replaces another.

• Usually, the second cell type can tolerate injury better.

• Reprogramming of stem cells.

• Example: Metaplasia of normal columnar to squamous epithelium in a bronchus.

Dysplasia

• Disorganized appearance of cells.

• Adaptive effort gone astray.

• Abnormal variations in size, arrangement, and shape.

• Regarded as pre-neoplastic lesions.

• Significant potential to transform into cancer cells.

Irreversible Cell Injury

• Pathologic cellular death when injury is too severe or prolonged.

• Leads to cell death.

• Two processes:

  1. Necrosis

  2. Apoptosis

Cell Death: Necrosis vs. Apoptosis

• Necrosis:

  • Cell death by external injury.

  • Characterized by cell rupture.

  • Contents spill into extracellular fluid.

  • Inflammation.

  • Pathological process associated with significant tissue damage.

• Apoptosis:

  • programmed cell deaths (Cell suicide)

  • Triggered by intracellular signaling

  • Can be a normal physiological process or pathological in some cases.

  • noninflammation

  • Does not directly kill the cell.

  • Does not rupture.

  • Ingested by neighboring cells.

  • No inflammation.

Necrosis

• Intracellular content is released.

• Enter bloodstream.

• Elevated levels of certain proteins/enzymes can indicate the location of damage.

  • Elevated creatine kinase (MB isoenzyme) or cardiac troponin levels indicate myocardial damage.

Four Types of Tissue Necrosis

1. Coagulative necrosis

2. Liquefactive necrosis

3. Fat necrosis

4. Caseous necrosis

Coagulative Necrosis

• Most common.

• Manifestations are the same regardless of cause.

• Area composed of denatured proteins.

• Generally solid.

• General architecture is preserved for up to weeks.

• Example: Wedged-shaped kidney infarct.

Liquefactive Necrosis

• Dissolution of dead cells occurs quickly.

• Lysosomal enzymes dissolve tissues.

• Brain:

  • Rich in degradative enzymes, little supportive connective tissue.

• Bacterial or fungal infections:

  • Trigger accumulation of localized WBC -> pus.

• Example: Infarct of the brain showing dissolution of tissue.

Fat Necrosis

• Death of adipose tissue.

• Results from trauma or pancreatitis

  • Liquefy fat cells in peritoneum.

• Visible white chalky areas.

• Example: Fat necrosis in acute pancreatitis in mesentery.

Caseous Necrosis

• "Cheesy."

• Area is white, soft, and fragile.

• Dead cells are walled off by inflammatory WBCs.

• In the center, dead cells lose their structure.

• Example: Tuberculosis of the lung.

Gangrene

• Cell death of a large area of tissue.

• Results from disruption of major blood supply.

• Affects toes, legs, bowels.

• Depending on appearance and subsequent infection:

  • Dry

  • Wet

  • Gas

• May be fatal.

Apoptosis

• The rate of cell division and cell death are controlled in cells.

• If cells are not needed, cell suicide will occur.

• Activates a cell death pathway.

• Enzymes degrade the cell’s own DNA and proteins.

• Can be physiologic or pathogenic.

• Can be triggered by extrinsic or intrinsic signals.

Mechanisms of Apoptosis: Extrinsic Signals

1. Withdrawal of survival signals that normally suppress pathway

   • Normal cells rely on environmental signals to stay alive.

   • Remove these signals, cell suicide cascade is activated.

2. Extracellular signals, such as Fas ligand (FasL)

   • Bind to cell -> triggers death cascade through activation of “death receptors”.

   • Leads to DNA degradation and fragmentation of cell.

Mechanisms of Apoptosis: Intrinsic Signals

• Cellular damage causes cells to stall growth and division.

• If damage is too great -> cell suicide.

• Mitochondrial damage

  • Leakage of cytochrome c into cytoplasm

  • Activates intrinsic pathway

  • p53 governs this pathway

Etiology of Cellular Injury

• Variety of cellular assaults

  • Lack of oxygen and nutrients

  • Infection and immune responses

  • Chemical, physical, and mechanical factors

• Extent depends on the duration and severity of the assault and prior condition of cells.

Ischemic and Hypoxic Injury

• Ischemia

  • Interruption of blood flow

• Hypoxia

  • Lack of oxygen, resulting in power failure.

• Most common cause of cell injury.

• Allows metabolic wastes to accumulate.

• Deprives cells of nutrients for glycolysis.

• Reperfusion injury.

Nutritional Injury

• Deficiencies or excess amounts of nutrients

• Nutritional imbalances

  • Deficiencies

    • Iron deficiency affects RBC.

    • Vitamin D deficiency affects bones.

  • Excess

    • Delivery to some cell types and not other cell types.

    • Neurons uptake excess glucose.

Infectious and Immunologic Injury

• Bacteria and viruses

• Either directly or indirectly triggering an immune response.

Chemical Injury

• Toxic chemicals cause cell injury directly OR.

• Injurious only when metabolized into reactive chemicals in the body.

• Some toxins have an affinity for particular cell types

  • Carbon monoxide to hemoglobin.

• Some toxins exert a widespread effect

  • Lead poisoning.

Physical and Mechanical Injury Factors

1. Extremes in temperature

2. Abrupt changes in atmospheric pressure

3. Mechanical deformation

4. Electricity

5. Ionizing radiation

Cellular Aging

• Aging and disease are two different processes.

• Progressive decline in proliferative and reparative capacity of cells.

• Exposure to environmental factors.

Causes of Cellular Aging

• U.V. radiation

• Oxidative stress

• Errors in replication

• Mutations

• Cell loss

• Accumulated metabolic cell damage

Somatic Death

• Death of the entire organism.

• No inflammation or immunologic response occurs prior to death.

• General features include cessation of respirations and heartbeat.

• Rigor mortis

  • ATP depletion leads to actin-myosin cross-bridging.

• Postmortem autolysis

  • Putrefaction.

Congenital Disorders

• Present at birth.

• Grouped according to genetic or environmental causes.

• Congenital malformations

  • Errors in fetal development are associated with structural defects.

• Teratogens

  • Environmental influences.

Principles of Inheritance: Mendel

• Mendel’s Discoveries (Pea Plant Experiments)

  • Showed how traits are inherited

  • Genes have *different versions** → alleles

  • Organism gets *two alleles** (one from each parent)

• Dominant vs. Recessive

  • Dominant allele (R): shows in appearance (phenotype)

  • Recessive allele (r): hidden if dominant is present

• Principle of Segregation

  • Two alleles *separate** during gamete (egg/sperm) formation

  • Each gamete gets *only one** allele

Meiosis

• Meiosis reduces the number of chromosome sets from diploid to haploid.

• Meiosis is preceded by replication of chromosomes.

• Meiosis takes place in two sets of cell divisions, called meiosis I and meiosis II, resulting in four daughter cells.

Genetic Variation: Crossing Over

• Exchange of regions of non-sister chromatids.

• Important source of genetic variation.

Human Life Cycle

• Ovaries/testes make haploid gametes (1 set of chromosomes) by meiosis

• Fertilization: egg + sperm fuse → diploid zygote (2 sets of chromosomes)

• Zygote develops into an adult

Karyotype

• A karyotype is a pictorial arrangement of all of an organism’s chromosomes.

• 22 pairs are called autosomes.

• 23rd pair are the sex chromosomes.

Sex Determination

• Human gender is determined by sex chromosomes

  • Females: XX, homologous chromosomes.

  • Males: XY, not homologous chromosomes, but they behave so during meiosis.

• The presence of a Y chromosome confers male gender.

Punnett Squares

• Shows predictable patterns in transmission of single-gene traits from parents to offspring.

Codominance

• A and B alleles both display normal dominant-recessive relationships with the O allele

• Neither A nor B is dominant over the other

  • A and B are Codominant

Polygenic Inheritance

• Additive effect of two or more genes on a single phenotype.

• Often affected by environmental factors.

• Difficult to predict their occurrence.

• Ex. Human skin color

DNA Mutation and Repair

• Mutation: permanent change in DNA structure

  • Rare

  • Potential mutagens:

    • Radiation

    • Chemicals

    • Viruses

• Single-stranded breaks are easily repaired

• Double-stranded breaks may result in permanent loss of genetic information at the break point.

Two Types of Mutation

• Point mutation

  • Single base substitution

• Frame shift mutation

  • Changes the genetic code dramatically.

  • Addition or removal of a base changes the reading frame.

Genetic Disorders

• Apparent at birth or in later life.

• The majority inherited from parents; some from fetal development mutations

• Divided into three groups:

  1. Chromosomal aberrations

  2. Mendelian single-gene disorders

  3. Multifactorial or polygenetic disorders.

• Fourth group: single gene but doesn’t follow Mendelian pattern

  • Triplet-repeat mutations

  • Mitochondrial mutations

  • Mutations affected by genomic imprinting

Chromosomal Abnormalities

• Errors in chromosome distribution during meiosis

• Alterations of chromosome number can cause genetic disorders

• Large-scale chromosomal alterations often lead to miscarriages or cause a variety of developmental disorders

Aberrant Number of Chromosomes: Nondisjunction

• Failure of chromosomes to divide properly during anaphase

• Anaphase lag:

  • 1 chromosome left out of newly formed cell nucleus

Results of Nondisjunction

• Aneuploidy- abnormal number of a particular chromosome, resulting from the fertilization of gametes in which nondisjunction occurred

  • Trisomy- 3 copies of a particular chromosome

  • Monosomy- only 1 copy of a particular chromosome

  • Polyploidy- an organism has more than two complete sets of chromosomes

Abnormal Chromosome Structure

• Due to breakage

• Loss or rearrangement of pieces of the chromosomes

Autosomal Chromosome Disorders: Trisomy

• Characterization

  • Trisomy 21

    • Extra chromosome 21

    • Most common

    • Associated with advanced maternal age

    • Rare form: 4% is translocation of the long arm of 21 to another chromosome

  • Trisomy 18 and 13

    • Less common and more severe

    • Average life expectancy of a few weeks

Autosomal Chromosome Disorders: Cri du Chat Syndrome

• Characterization:

  • Deletion of short arm of chromosome 5

• Clinical Features

  • Severe mental retardation, round face, congenital heart anomalies

  • Cry resembles a cat crying

  • Some live to adulthood and thrive better than those with trisomies

Sex Chromosome Disorders

• Klinefelter Syndrome

  • 1:500-1:1000 live births

  • Extra X chromosome

    • XXY, XXXY, XXXXY

  • Clinical Features

    • Infertility

    • Tall, long arms and legs

    • Breasts enlargements

    • High pitched voice

  • Treatment: Testosterone therapy

• Turner Syndrome

  • 1:3000 live births

  • Monosomy X

    • X0 or Xx

  • Clinical Features

    • Sterile

    • Short stature

    • Webbed neck

    • Ammenorrhea

  • Treatment: growth hormone, estrogen replacement therapy

  • ~3% survive to birth

Mendelian Single-Gene Disorders

• Result from alterations or mutations of single genes

• Affected genes may code for abnormal enzymes, structural or regulatory proteins

• Classified according to:

  1. Location of defective gene

     • Autosomal or sex chromosome

  2. Mode of transmission

     • Dominant or recessive

  • Pedigree Analysis

Autosomal Dominant Disorders

• Due to a mutation of an autosomal dominant gene

• Males/females are equally affected

• Usually one affected parent

• Unaffected individuals do not transmit disease

Autosomal Dominant Disorders: Marfan Syndrome

• Characterization

  • Connective tissue disorder

  • FBN1 gene mutations (Fibrillin 1), chromosome 15

  • Dominant negative preventing assembly of normal microfibrils

  • 1:5000 persons affected

  • 70-85% familial

• Clinical Features

  • Tall stature

  • Arachnodactyly

  • Cardiovascular lesions

    • Mitral valve prolapse

  • Bilateral dislocation of the lens

• Treatment

  • TGFβ inhibitors

  • Beta blockers

Autosomal Dominant Disorders: Huntington Disease

• Characteristics

  • Neurodegeneration

  • Localized to chromosome 4

  • Triplet repeats (CAG)

    • Glutamine

• Morphology

  • Aggregates in the brain tissue

• Clinical Features

  • Involuntary movements of arms and legs

• Treatment

  • Tetrabenazine (suppresses jerking)

Autosomal Recessive Disorders

• Mutation of an autosomal recessive gene

• Males/females are equally affected

• Both parents are carriers of mutant recessive gene

• Unaffected individuals may transmit to offspring

Autosomal Recessive Disorders: Cystic Fibrosis

• Characterization

  • Abnormal ep. chloride channel protein

  • CFTR gene

  • Chromosome 7

  • Deletion of nucleotides that code of Phenylalanine

  • 5% Caucasian Americans

  • 1:3200 live births

• Clinical Features

  • Thick secretions in glandular tissues

  • Bronchioles and pancreatic ducts are primary affected

Autosomal Recessive Disorders

• Albinism

  • Unable to synthesize tyrosinase

  • Risk for skin cancer, sun burn

• Phenylketonuria

  • Inborn error of metabolism

  • Excess phenylalanine

  • Mental retardation, seizures, severe irritability

Sex-Linked Disorders

• Alleles found on X or Y chromosome

• Recessive X-linked diseases usually occur in males

  • Why?

    • Females have two X chromosomes, so they usually have at least one normal allele

    • Only one X chromosome, so a single recessive allele will cause disease

Sex-Linked Disorders: Hemophilia A

• Characterization

  • Deficiency in factor VIII

  • Inability to form fibrin clot

• Clinical Features

  • Bleed easily and profusely from minor injuries

  • Hematoma

  • First massive HIV-infected patients

Nonmendelian Single-Gene Disorders

• Does not follow classic Mendelian principles

• Categories

  1. Caused by long triplet repeat mutations, such as fragile X syndrome

  2. Due to mitochondrial DNA mutations

  3. Associated with genomic imprinting

Triple Repeat Mutations: Fragile X

• Characterization

  • 2nd most common

  • 200-4000 repeats of sequence of CGG

  • Loss of function (silencing) of FMR I gene

• Familial Mental Retardation Protein

• Clinical Features

  • Mental retardation

  • Abnormal facial features

Diagnosis, Counseling, and Gene Therapy: Prenatal Diagnosis and Counseling

• Maternal age >34 years

• Chromosomal disorder in a previous pregnancy

• Known family history of x-linked disorders

• Known family history of inborn errors of metabolism

• Neural tube anomalies in a previous pregnancy

• Known carrier for recessive genetic disorder

Diagnosis, Counseling, and Gene Therapy: Fetal Testing

• In amniocentesis, the liquid that bathtes the fetus is removed and tested

• In chorionic villus sampling (CVS), a sample of the placenta is removed and tested

• Ultrasound and fetoscopy allow fetal health to be assessed visually in utero

Diagnosis, Counseling, and Gene Therapy: Genetic Analysis and Therapy

• Treat genetic disease by replacing defective gene with healthy gene

• Recombinant DNA Technology

  • PCR

  • Restriction enzymes

  • Electrophoresis

  • Sequencing

  • Nucleic acid hybridization

  • Genetic engineering

Neoplasia

• Means "new growth"

• Implies abnormality of cellular growth/tumor

  • Malignant neoplasm is cancer

    • may not be survivable

  • Benign growth is generally easily cured

• Cancer is associated with altered expression of cellular genes

Types of Tumors

• Benign

  • Grow more slowly

  • Little vascularity

  • Rarely necrotic

  • Retains function of origin tissue

  • Many encapsulated

• Malignant

  • Rapid growth

  • Initiate blood vessel growth

  • Frequently necrotic areas

  • Dysfunctional

Tumor Terminology

• Benign

  • -oma (e.g., adenoma)

• Malignant

  • -carcinoma (epithelial origin)

  • -sarcoma (mesenchymal origin)

  • (e.g., adenocarcinoma)

Malignant Phenotype

• Normal

  • Constant reassurance from the environment

  • Proliferate only when space is available

  • Appropriate mitogen-stimulating signals needed

  • Responds to apoptotic signals

• Malignant

  • Disregard cell and tissue boundaries

  • Proliferate despite initiation

  • Escape signals to die

  • Contribute poorly to the function of tissue

Epidemiology and Cancer Risk Factors

• Cancer is the 2nd leading cause of death in the U.S.

• Most cancer deaths occur in individuals over age 55

• Men have 1:2 risk of developing cancer; women

Blood Cells

• Myeloid progenitor cell

  • Red blood cells (erythrocytes): Transport oxygen and carbon dioxide.

  • Platelets: Initiate blood clotting.

  • White blood cells (leukocytes):

    • Phagocytes

      • Basophils: Release histamine, may promote T cell development.

      • Eosinophils: Kill antibody-coated parasites.

      • Neutrophils: Phagocytose antibody-coated pathogens.

      • Mast cells: Release histamine when damaged.

      • Monocytes: Develop into macrophages.

      • Macrophages: Engulf and digest microorganisms; activate T cells.

      • Dendritic cells: Present antigens to T cells.

• Lymphoid progenitor cell

  • Lymphocytes

    • B cells: Differentiate to form antibody-producing cells and memory cells.

    • Plasma cells: Secrete antibodies.

    • T cells: Kill virus-infected cells; regulate activities of other white blood cells.

    • Natural killer (NK) cells: Attack and lyse virus-infected or cancerous body cells without previous exposure.

General Scheme of Cellular Events

• APCs (Macrophages, Dendritic Cells)

• T-Cells: Control Everything

  • CD4: "REGULATORS" (Helper)

  • CD8: "EFFECTORS"

• B-Cells: Plasma Cells, which produce Antibodies

• NK Cells: kill tumor cells and virally infected cells without previous exposure

Cellular Interactions

• B lymphocyte (B)

  • Activated by microbial antigen to become a plasma cell, leading to antibody secretion.

• CD4+ helper T lymphocyte (TH)

  • Activated by microbial antigen in phagocyte to release cytokines.

    • Cytokines lead to: Activation of macrophages, stimulation of B lymphocytes, inflammation

• CD8+ cytotoxic T lymphocyte (CTL)

  • Activated by infected cell containing microbial antigen to kill the infected cell.

MHC: Major Histocompatibility Complex

• A genetic "LOCUS" on Chromosome 6, which codes for cell surface compatibility.

• Also called HLA (Human Leukocyte Antigens) in humans

• Ensures self-cell antigens are recognized and tolerated. Unrecognized cells are NOT tolerated.

General Types of Immunity

• Innate (natural)

  • Present before birth, "NATURAL"

  • First line of defense

  • No previous exposure to agent required

  • Nonspecific

  • Physical and chemical mechanical barriers

• Adaptive (acquired)

  • Developed by exposure to pathogens or antigens

  • Specific response to infectious agent

  • Immunological memory for invader

Summary of Differences between Innate and Adaptive Immunity

Principal Mechanisms of Innate and Adaptive Immunity

• Innate Immunity

  • Epithelial barriers

  • Phagocytes

  • Complement

  • NK cells

• Adaptive Immunity

  • B lymphocytes

    • Antibodies

  • T lymphocytes

    • Effector T cells

Innate Immunity: Physical and Chemical Barriers

• Intact skin: effective physical barrier

  • Low pH: bactericidal for many organisms

  • Normal skin flora: helps prevent colonization by pathogens

    • Loss of normal flora allows resistant organisms or fungi to proliferate

Innate Immunity: Physical and Chemical Barriers to Infections

Innate Immunity: Mucous Membranes

• Ciliated epithelial cells trap and sweep away airborne particles and organisms.

• Goblet cells produce mucus to make the epithelial surface sticky.

• Enzymes in secretions inhibit invasion by organisms.

Innate Immunity: Natural Secretions

• Chemical barriers

  • Tears

  • Saliva

  • Mucus

  • Fatty acids

  • Bile acids

Innate Immunity: Plasma Proteins

• Antimicrobial and antiviral effects

• Acute phase reactants

• Complement cascades and components

• Tumor necrosis factor alpha (TNF)

• Interferons (IFN)

Inflammation: Purposes

• Neutralize and destroy invading and harmful agents.

• Limit the spread of harmful agents to other tissue.

• Prepare damaged tissue for repair.

Inflammation: Host Response

• Host’s response to injury or infection

  • Localizes infection; removes agent; repairs damage; removes debris

• Cardinal signs of inflammatory response

  • Redness, heat, swelling, pain, loss of function

• 3 phases of inflammatory response:

  • \uparrow blood flow to site

  • \uparrow vascular permeability

  • Migration of WBCs to site

Inflammation: Process

• Damaged cell initiates

• Signs of inflammation

  • redness

  • heat

  • swelling

  • Pain

• Function is to trap microbes, toxins or foreign material & begin tissue repair

Inflammation: Causes

• Physical agents: burns, radiation

• Chemical agents: acids, corrosives

• Microbial: most common

  • Gram-negative bacteria produce endotoxins and lipopolysaccharides that can cause strong inflammatory responses.

  • Other bacteria produce exotoxins

• Inflammation can be beneficial or detrimental to the host

Inflammation: Types

• Acute

  • Short in duration, lasting less than 2 weeks

  • Involves a discrete set of events

• Chronic

  • More diffuse

  • Extends over a longer period

  • May result in scar tissue formation or deformity

Adaptive Immunity

• Also known as acquired immunity

• Specifically directed against a particular type of invader

• Involves cell or antibody directed against a particular antigen

  • Antigen can be any substance: microbe, food, pollen, tissue

• Normally self–tolerant

  • (does not attack normal body tissue)

Antigens and Antibodies

• Immunogen: substance capable of eliciting a humoral or cellular immune response

• Antigen: stimulates antibody production and binds to the produced antibody

  • Epitope: specific site on the antigen to which antibody or T cell receptors bind

• One antigen can have many epitopes

Immunoglobulin Classes

• IgG: major immunoglobulin in blood; 80% & crosses placenta

• IgM: largest; effective in microbial killing; 1st AB to be produced after invasion

• IgA: secretory; present in body fluids; found in body secretions (mucous membranes)

• IgE: seen in allergy and parasites

• IgD: regulates activation of B cells

Lymphoid Organs

• Primary lymphoid organs

  • Bone marrow: produces B cells over the lifetime of the host

  • Thymus: produces T lymphocytes until the host reaches puberty

• Secondary lymphoid organs

  • Lymph nodes, spleen, Peyer’s patches

Types of Adaptive Immunity

• Cell-mediated

  • T-cells attack directly

    • Cytotoxic T-cells

• Humoral

  • B cells become plasma cells

    • produce specific antibodies

• Helper T cells (CD4) aid both cell- and antibody-mediated responses

Maturation of T and B Cells

• T cells mature in the thymus (cell-mediated response)

  • killer cells attack antigens

  • helper cells costimulate T and B cells

  • effective against fungi, viruses, parasites, cancer, and tissue transplants

  • Inside the cell

• B cells mature in the bone marrow (antibody-mediated response)

  • plasma cells form antibodies

  • effective against bacteria

  • Outside the cell

Humoral vs. Cellular Immunity

• Humoral Immunity

  • B lymphocytes

    • Secreted antibody

    • Neutralization

    • Lysis (complement)

    • Phagocytosis (PMN, macrophage)

• Cellular Immunity

  • T-cell

    • T-cell receptor

    • Proliferation and activation of effector cells (macrophages, cytotoxic T cells)

    • Destruction of phagocytosed microbes

    • Lysis of infected cell

    • Antigen-presenting cell

      • Processed and presented antigen

Primary Immune Response

• IgM antibody appears first, then IgG on first exposure to antigen

Secondary Immune Response

• Follows re-exposure to the same antigen

• Shorter response time

• Larger quantity of IgG

• Persists longer due to memory cells

Secretion of Antibodies: Primary vs. Secondary Response

• Primary Response

  • IgM appears first, followed by IgG after the primary stimulus

• Secondary Response

  • IgG level is much higher and persists longer compared to the primary response after the secondary stimulus

  • IgM levels are also present but to a lesser extent compared to IgG

Alterations in Immune Function - Chapter 10

Objectives

• Describe and understand Autoimmunity

• Differentiate and give examples of the four (4) different types of hypersensitivity reactions

Immune System Disorders

• What can go wrong?

  • Hypersensitivity Reactions, I-IV

  • "Auto"-Immune Diseases

  • Immune Deficiency Syndromes, IDS:

    • Primary (Genetic)

    • Secondary (Acquired)

Inappropriate Immune Responses

• Excessive immune responses

  • Autoimmunity and hypersensitivity disorders

• Deficient immune responses

  • Ineffective because of disease

Excessive Immune Responses

Autoimmunity: Failure of Self Tolerance

• Failure of the immune system to recognize self

  • Immune response (IR) develops to the self-antigens

  • The IR may produce autoantibody or self- reacting T cells

General Features of Autoimmune Diseases

• > 40 autoimmune diseases identified; affect 5-7% of U.S. population

• Most autoimmune diseases are chronic

  • Significant morbidity and mortality result

• Women more frequently affected

• Most occur in adults aged 20-40 years

• Some diseases cause initial tissue damage; others do not

Predisposing Factors for Autoimmunity

Several factors contribute to the loss of tolerance to self-antigens:

• Genetic

• Hormonal

• Environmental

• Failure of a regulatory sequence in the immune response

Classification of Autoimmune Diseases

• Organ-specific – damage is to a single organ

  • Example: Hashimoto’s thyroiditis

• Systemic – autoantibody can cause damage in multiple organ systems

  • Example: systemic lupus erythematosus (SLE)

Organ-Specific and Systemic Autoimmune Diseases

Classification of Autoimmune Diseases

Underlying Effector Mechanisms for Autoimmune Diseases

Hypersensitivity

• Hypersensitivity – EXAGGERATED immune response against normally harmless antigens

  • Can cause inflammation and/or tissue damage

  • Involves either humoral or cell-mediated immunity

Classification of Hypersensitivity

• Type I – Immediate (anaphylactic)

• Type II – Antibody-Dependent Cytotoxic

• Type III – Immune-Complex-Mediated

• Type IV – Delayed (cell-mediated)

  • Immediate Hypersensitivity

    • B cell mediated

  • Delayed Hypersensitivity

    • T cell mediated

Type I IMMEDIATE HYPERSENSITIVITY

• “Immediate” means seconds to minutes

• “Immediate Allergic Reactions”, which may lead to anaphylaxis, shock, edema, dyspnea death

  • 1) Allergen exposure

  • 2) IMMEDIATE phase: MAST cell Degranulation, vasodilatation, vascular leakage, smooth muscle (broncho)-spasm

Type I Hypersensitivity - (Allergy or Atopy)

• Immediate – occurs rapidly (2-3 min.) after exposure to the allergen

• Antibody involved: IgE

• Cells involved: MAST CELLS, BASOPHILS

  • IgE receptor

  • Histamine etc.

Type I Hypersensitivity - Mechanism

Host exposed to allergen (pollen, food, insect venom, etc.)

1. Allergen-specific IgE produced

2. IgE binds to mast cells or basophils via Fc receptor on the cell surface (These “sensitized” cells can persist for weeks)

3. Re-exposure to same allergen; allergen binds to Fab of IgE

4. Activation/degranulation of mast cell or basophil

5. Mediators released from cells

Clinical Manifestations of Type I Hypersensitivity

Range from mild to life-threatening:

• Allergic rhinitis

• Allergic asthma

• Atopic dermatitis

• Urticaria (Hives)

• Gastrointestinal reactions

• Systemic anaphylaxis

Allergic Rhinitis

• Most common atopic disorder in U.S.

• Common symptoms:

  • Runny nose, sneezing, watery eyes

• Elicited by airborne allergens:

  • Pollens, molds, animal dander, dust mites

• Can be seasonal or year-round

Allergic Asthma

• Often occurs with allergic rhinitis

• Caused by some of the same allergens that cause allergic rhinitis

• Often associated with environmental factors

  • Pollution, cigarette smoke

• Symptoms:

  • Exaggerated bronchial response, cough, wheezing, shortness of breath

Atopic Dermatitis

• Triggered by many factors:

  • Contact with irritants such as soap or detergents, airborne allergens, foods

• Symptoms:

  • Itchy, red skin rash

  • Chronic lesions with thickened skin may develop

• Secondary bacterial infection may occur

Urticaria

• Commonly associated with allergies to latex, foods, drugs

• Symptoms:

  • Widespread, itchy white areas surrounded by redness (erythema)

• May be localized or associated with anaphylaxis

Gastrointestinal Reactions

• Usually associated with food allergy or may cause systemic anaphylaxis

• Symptoms:

  • Nausea

  • Vomiting

  • Abdominal pain

  • Diarrhea

Systemic Anaphylaxis

• Potentially life-threatening; can involve multiple organ systems

• Commonly associated with food (shellfish, peanuts), drugs (penicillin), or venom (bee-sting)

• Symptoms:

  • Hypotension, shock, airway obstruction

• CAN BE FATAL without prompt treatment

  • Injection with epinephrine

Diagnosis of Type I Hypersensitivity

• History and physical exam important

• Allergy testing

  • skin test method of choice

  • Used to determine the degree of sensitization with specific allergens

• In vitro allergy tests

Treatment of Type I Hypersensitivity

• AVOIDANCE of allergen – food, pet, etc.

• Drugs that BLOCK allergic response

  • Antihistamines, theophylline, epinephrine, cromolyn sodium, corticosteroids

• Immunotherapy – desensitization or “allergy shots”

  • Patient is given increasing amounts of allergen(s) over time to induce tolerance and produce blocking (IgG) antibody

Type II Hypersensitivity

• Immediate form of hypersensitivity

• Caused by IgG and IgM antibodies directed against CELL SURFACES OR TISSUE ANTIGENS

  • TISSUE SPECIFIC

  • Damage or destruction of target cells

• Complement activation may or may not be required in these reactions

Type II Hypersensitivity - Antibody Mediated Immunity

Type II Hypersensitivity - Mechanism

IgG or IgM binds to antigens

1. Fc region sticks out away from cell membrane

2. Acts as a bridge for complement or effector cell

3. Leads to lysis

   • Complement mediated lysis

   • Opsonization allows lysis or phagocytosis

Clinical Manifestations of Type II Hypersensitivity

• Transfusion reaction

• Hyperacute graft rejection

• Hemolytic disease of the newborn (HDN)

• Drug-induced hypersensitivity

• Autoimmune diseases

Transfusion Reactions

• Antibodies against red blood cell (RBC) antigens can result in intravascular hemolysis of the transfused RBCs

  • Caused by transfusion with donor blood incompatible for ABO or other blood group

• Treatment

  • immediate termination of transfusion

• Prevented by performing compatibility testing (crossmatch) of donor and recipient prior to transfusion

Hemolytic Disease of the Newborn

• Occurs during pregnancy

• Rh negative mother is sensitized to her fetus’s Rh-positive red cell group antigens

• Mother’s exposure occurs when fetal and maternal blood are mixed

Autoimmune Diseases

• Autoimmune hemolytic anemia

  • IgG or IgM antibodies to patient RBCs spontaneously develop

• Autoimmune thrombocytopenic purpura

  • Antibody to platelets destroys them in the spleen

  • treatment is splenectomy

Autoimmune Diseases (cont.)

• Hashimoto’s thyroiditis

  • Autoantibodies against thyroglobulin damage thyroid gland

  • Treatment – thyroid hormones

• Goodpasture’s syndrome

  • Autoantibodies to kidney and lung basement membrane

  • Treatment – corticosteroids to suppress the immune response and plasmapheresis to remove autoantibodies; kidney dialysis may be required

Autoimmune Diseases (cont.)

• Grave’s disease

  • Autoantibody against receptor for thyroid stimulating hormone (TSH)

  • Thyroid gland is OVERSTIMULATED, resulting in hyperthyroidism

  • Laboratory detection – measure TSH and T4 serum hormones

  • Treatment – thyroidectomy

Autoimmune Diseases (cont.)

• Myasthenia gravis

  • Antibodies against Ach receptors

  • Antibody-antigen complex recruits complement

  • Complement disrupts muscle cell membrane

Hyperacute Graft Rejection

• If recipient has preformed anti-MHC antibodies, graft (i.e., kidney) will be destroyed rapidly

• Prevented by testing to detect antibodies in the recipient prior to selection of the organ donor

Type III Hypersensitivity

Type III Hypersensitivity - Immune Complex Mediated

• Antigen/Antibody “Complexes”

• Where do they go?

  • Kidney (Glomerular Basement Membrane)

  • Blood Vessels

  • Skin

  • Joints

Type III Hypersensitivity- Immune - Complex-Mediated

• IgG or IgM antibody involved

• Antigen: foreign protein, infectious disease organism, self-antigen

• When ag/ab complexes are not cleared by the mononuclear phagocytic system, they are deposited in tissues, causing damage

• Ag/ab complexes bind complement and activate the cascade, yielding biologically active fragments that can damage tissues

Clinical Manifestations of Type III Reactions

• Autoimmune diseases

  • Systemic lupus erythematosus (SLE)

  • Rheumatoid arthritis (RA)

• Drug reactions

  • Penicillin and sulfa drug allergies

• Infectious diseases

  • Viral hepatitis, mononucleosis, malaria, etc.

Lupus (SLE)

• Etiology: Antibodies (ABs) directed against the patient’s own DNA, HISTONES, NON-histone RNA, and NUCLEOLUS

• Pathogenesis: Progressive DEPOSITION and INFLAMMATION to immune deposits, in skin, joints, kidneys, vessels, heart, CNS

• Morphology: “Butterfly” rash, skin deposits, glomerolunephritis

• Clinical expression: Progressive renal and vascular disease

Type IV Hypersensitivity

Type IV Hypersensitivity - Delayed or Cell-Mediated

• No antibody involved

• Sensitized T cells react with antigen

• Reaction takes ~24 hours to develop following contact with antigen

Clinical Manifestations of Type IV Hypersensitivity

• Contact dermatitis

  • Skin reaction caused by contact with a variety of agents

    • detergents, cosmetics, poison ivy or oak, nickel in jewelry

  • Allergens act as haptens and bind skin protein è activate specific memory T cells

  • Skin reaction appears hours to days later:

    • Redness, swelling, itchy and painful blisters

Clinical Diagnosis of Type IV Hypersensitivity Reactions

• Skin tests to measure memory response of TDTH previously sensitized with antigen

  • Intradermal injection

    • i.e., Mantoux TB test

  • Look for induration (hardness) on skin around injection site in 48-72 hours

  • Patch tests

    • used for allergic contact dermatitis

Summary

• I Acute allergic reaction

• II Antibodies directed against cell surfaces

• III Immune complexes

• IV Delayed Hypersensitivity, e.g., Tb skin test

Immunodeficiency Disorders (IDS)

• Primary Immunodeficiency Disorders

• Secondary Immunodeficiency Disorders

Immunodeficiency Disorders

• Primary

  • Congenital: present at birth

    • Genetic:

      • Spontaneous mutation or inherited

      • Most defects are minor or subclinical

      • Subdivided by cell type affected or the point at which cell maturation is blocked

    • Acquired primary disorders of the immune cells, such as HIV/AIDS.

• Secondary

  • Due to an exogenous agent or condition

    • Severe nutritional defects, burns, chemotherapy

  • Not usually present at birth

  • Immunodeficiency not always permanent

Primary Immunodeficiencies

• Severe combined immunodeficiency (SCID)

• T cell activation deficiencies

• Deficient immunoglobulin production

• Disorders of phagocytes

• Complement deficiencies

Secondary Immunodeficiencies- Causes

Not due to genetic mutation

MANY CAUSES:

• Brief period in infants after maternal antibody wanes

• Many viruses briefly affect immune response

• Nutritional defects – malnutrition, mineral deficiency

• Tumor cells may replace hematopoietic cells in marrow

• Splectomized patients – mild immunodeficiency

• Immunosuppressive drugs in allograft recipients

What is HIV?

• HIV is a retrovirus

  • Infects CD4 lymphocytes; gains access to cells, resulting in cell death

HIV-Induced Immunodeficiency

• Etiology: HIV

• Pathogenesis: Infection, Latency, Progressive T- Cell loss

• Morphology: MANY

• Clinical Expressions: Infections, Neoplasms, Progressive Immune Failure, Death

HIV - CD4 T cells/mm3

• Diagnosis of AIDS based on:

  • Antibodies to HIV

  • Presence of virus in blood (viral load)

  • \<200 CD4 cells/mm3 of blood

  • Impaired delayed hypersensitivity

  • Presence of opportunistic infections

• Therapy

  • highly active retroviral therapy

• HIV vaccine development

  • research in progress

Epidemiology of HIV

• HOMOSEXUAL (40%, and declining)

• INTRAVENOUS DRUG USAGE (25%)

• HETEROSEXUAL SEX (now most common mode)

Malignant Disorders of White Blood Cells

Objectives

• Review of normal white blood cells

• Diagnosis of Hematologic Neoplasm

• Myeloid Neoplasm

  • Chronic Myeloid Leukemia

  • Acute Myeloid Leukemia

• Lymphoid Neoplasm

White Blood Cell Features

• Monocyte (MO)

• Eosinophil (E)

Leukocyte Count and Differential (Adult Values)

Erythrocyte and Platelet Count (Adult Values)

Classification of Hematologic Neoplasms

• Lymphoid Neoplasms

  • Arise from Lymphoid stem cells

  • Include:

    • B cell leukemia/lymphoma/myeloma

    • T cell leukemia/lymphoma

    • NK cell leukemia/lymphoma

• Myeloid Neoplasms

  • Arise from Myeloid stem cells

  • Include:

    • Granulocytic leukemia

    • Monocytic leukemia

    • Erythroid leukemia

    • Megakaryocytic leukemia

    • PVI (Polycythemia Vera)

    • Essential thrombocythemia

Leukemias

• Malignant proliferations of white blood cells.

• In lymphocytes, leukemias closely relate to malignant lymphomas.

Lymphomas

• Nodal or Extranodal

• T or B cell origin

• Follicular or Diffuse

• Hodgkin or Non-Hodgkin:

  • Hodgkin lymphoma: Characterized by binucleate Reed-Sternberg cells surrounded by lymphocytes, macrophages, and eosinophils in a lymph node.

Leukemias vs. Lymphomas

• All leukemias of lymphocytes have lymphoma counterparts.

• Primary lymphomas can have “leukemic” phases.

• Myeloid leukemia infiltrating a lymph node (or any other site) is NOT called a lymphoma, but a myeloid infiltrate.

• All lymphomas are malignant proliferations of lymphocytes.

Classification of Hematologic Neoplasms (by Lineage)

• Myeloid Lineage: RBC, platelets, monocytes, granulocytes

  • Myeloproliferative disease

  • Myelodysplastic/proliferative disease and syndromes

  • Acute myeloid leukemia

• Lymphoid Lineage: B cells, T cells, NK cells

  • B cell neoplasm

  • T cell and NK neoplasm

  • Hodgkin disease

• Categories are based on the cell type of the neoplasm, not its location in the body.

Etiology, Diagnosis, Treatment, and Management

Etiology of Myeloid and Lymphoid Neoplasms

• Exact cause is unknown; basic mechanism involves cell mutation disrupting growth control and differentiation pathways.

  • Viruses

  • Radiation exposure

  • Chemical exposure (slight)

Diagnosis of Hematologic Neoplasms

• Most common clinical manifestations:

  • Leukopenia: lymphadenopathy, joint swelling and pain, weight loss, anorexia, hepatomegaly, splenomegaly

  • Anemia: pallor, fatigue, malaise, shortness of breath, decreased activity tolerance

  • Thrombocytopenia: platelet count below 20,000 cells/μl, petechiae, easy bruising, bleeding gums, occult hematuria, retinal hemorrhages

  • Neutropenia: absolute neutrophil count <500 cells/μl

Hematologic Neoplasms Diagnosis

• Evaluation of peripheral blood sample is a key aspect.

• Definitive diagnosis: bone marrow aspiration or lymph node biopsy.

Treatment

• Management relies on combination chemotherapy to remove malignant cells.

• Stem cell transplant to rescue and restore bone marrow function.

Principles of Treatment

• Radiation and tissue-specific drug therapy may be indicated.

• Chemotherapy: induce long-term remission.

• Complete remission (CR): return to normal hematopoiesis with normal red cell, neutrophil, and platelet count; no detectable neoplastic cells.

• CR is NOT A CURE; treatment protocols include chemotherapy cycles; chemotherapeutic agents induce apoptosis.

Prevention and Management of Complications

• Maintaining adequate nutrition status:

  • Addressing anorexia, weight loss, nausea, vomiting, stomatitis

  • Managing growth delay

• Infection (most troublesome):

  • Prevention

  • Early detection

  • Rapid management

  • Growth factors to shorten time if patient is neutropenic

• Bone marrow transplantation (BMT) for certain leukemias:

  • Addressing bone marrow failure due to intense chemotherapy from BMT

  • Stem cells reintroduced into bone marrow

  • Close match necessary or graft-versus-host disease could occur

  • Peripheral stem cell transplantation allows stem cells to be harvested from the circulating bloodstream

• Allogenic transplantation: stem cells from closely matched relative

• Autologous transplantation: stem cells from patient’s own blood to be reinfused

• Anemia: common complication of leukemia and chemotherapy.

  • Normocytic, normochromic anemia: suppressed red blood cell production in bone marrow, but size/shape of RBCs present are normal.

  • Administer erythropoietin growth factors

  • RBC transfusion therapy

  • Prevent bleeding episodes

• Pain: common complication of both disease process and diagnostic/treatment protocols

  • Most commonly involves bones/joints

  • Result of pressure caused by infiltration and accumulation of neoplastic cells in the bone marrow

  • Hemarthrosis (bleeding into joints)

  • Painful procedures

  • Nausea/mouth pain (stomatitis) frequent from chemotherapy

• Damage to epithelial cells from radiation and chemotherapy

  • Sloughing of skin, mucous membranes, hair common

  • Loss of skin, mucous membrane integrity increases infection risk and contributes to pain

• Abnormalities in growth, development, fertility complications concerning children

Myeloid Neoplasms

• Transformation and proliferation of precursor stem cell

• MULTIPOTENT: overproduction of more than one cell type → MYELOPROLIFERATIVE DISEASE

Myeloproliferative Diseases

• Chronic Myeloid Leukemia (CML)

• Polycythemia vera (PV)

• Essential thrombocytopenia (ET)

  • Usually discovered on CBC analysis

  • Common features:

    • involvement of multipotent hematopoietic progenitor cell

    • marrow hypercellularity

    • overproduction of functional blood cells

    • chromosomal abnormalities

    • eventual spontaneous conversion to AML

    • development of marrow fibrosis

  • Also called “chronic” myeloproliferative disorders because they last for years

Chronic Myeloid Leukemia (CML) - Pathogenesis and Clinical Manifestations

• CML represents approximately 15% of all cases of leukemia in the United States

• Average age of onset: 40-50 years (adult, NOT kids)

• Occurs only occasionally in childhood/adolescence

• NOT AT ALL like an “acute” leukemia, but can develop into an acute leukemia, as a condition called a “blast crisis”

• Characterized by malignant granulocytes that carry the Philadelphia chromosome (Ph+)

• Translocation of chromosomes 9 and 22 causes two genes to be juxtaposed and creates a new fusion gene: bcr/abl

• Enzyme spurs cell proliferation and reduces apoptosis

• Single oncogene - unusual

• CML cells have greater degree of segmentation than AML cells

• Usual clinical presentation

  • High granulocyte count on the CBC

  • Splenomegaly

• Symptoms (when present)

  • Fatigue

  • Weight loss

  • Sweats

  • Bleeding

  • Abdominal discomfort (enlarged spleen)

Chronic Myeloid Leukemia (CML) - Prognosis and Treatment

• CML does not respond well to chemotherapy: poor overall survival time.

• Untreated: median survival 2 years

• Allogenic BMT from suitable donor; autogenic BMT less effective.

• Drugs that target the brc/abl fusion (current research)

Myelodysplastic Syndrome and AML

• Neoplastic cells that ARE MORPHOLOGICALLY AND FUNCTIONALLY ABNORMAL

• Prognosis: poor

• Intensive treatment necessary to extend life

• Differentiate: Myeloproliferative vs. Myelodysplastic

Acute Myeloid Leukemia (AML) - Pathogenesis and Clinical Manifestations

• 80% of cases are adults; median age 64 years

• Malignant disorder associated with transformation of myeloid stem cell

• Bone marrow aspirate must have >20% blasts

  • NORMALLY, a marrow should have only about 1-2 % blasts

• Many have various TRANSLOCATIONS

REMEMBER BLASTS?

• 1) HUGE NUCLEUS

• 2) NUCLEOLI (stain LIGHTER not DARKER than the rest of the nucleus on Wright stain)

• 3) NO cytoplasmic differentiation

• Auer rods

Comparison of Acute and Chronic Leukemias

Lymphoid Neoplasms

• Include malignant transformations of B, T, and NK cells

• Leukemia—when present in blood/marrow

• Lymphoma—when localized in lymphoid tissues

• Lymphoid neoplasms—location consequence of disease stage

• WHO classification uses CELL OF ORIGIN, not staging to classify

Chronic Lymphoid Leukemia (CLL) - Pathogenesis and Clinical Manifestations

• CLL accounts for 30% of all cases of leukemia in the United States

• 95% are malignant B-cell precursors

  • SLOW GROWING. Follows an indolent course; asymptomatic

• 5% associated with more aggressive T-cell transformation

• Usually found on accident by routine blood examinations

• Lymphs look normal and are NOT blasts

• Symptomatic CLL

  • Fatigue, weight loss, anorexia

  • Increased susceptibility to infections

• Malignant lymphocytes invade lymphoid tissues and bone marrow; disrupts function

  • Enlarged, painless lymph nodes (lymphadenopathy)

  • Enlarged spleen

• Many cells from CLL have a “smudge” or “basket” appearance.

• If you know what a NORMAL lymphocyte looks like, you can diagnose CLL purely by numbers! No marrow exam needed!

Chronic Lymphoid Leukemia (CLL) - Prognosis

• Certain genetic mutations present better/worse diagnosis

  • Mutation in IgV associates with median survival of 24 years

  • Without mutation median survival is 8 years

  • Short telomeres and p53 dysfunction poor outcomes

Chronic Lymphoid Leukemia (CLL) - Treatment

• Chemotherapy

• Stem cell transplantation

Acute Lymphoblastic Leukemia/Lymphoma (ALL) - Pathogenesis and Clinical Manifestations

• Malignant disorder of lymphoid cell lineage

• 80% result of malignant transformation of B cells; 20 % involve T cells

• A.L.L primarily a children’s disorder: most common malignancy, 2nd leading cause of death for this population

• Peak incidence: between 3 and 7 years; 2nd peak: middle age

• “Lymphoblasts” which can give rise either to T or B cells are the cells of malignant proliferation

• Symptom onset

  • Abrupt

  • Bone pain, bruising, fever, infection

  • Children may refuse to walk

  • Loss of appetite, fatigue, abdominal pain

  • Enlarged spleen, liver, lymph nodes

  • 3% may present with Central Nervous System manifestations

Acute Lymphoblastic Leukemia/Lymphoma (ALL) - Treatment

• Chemotherapy

• SIGNIFICANT response to chemo: 90% remission, 75% CURE!!!

Plasma Cell Myeloma (Multiple Myeloma) - Pathogenesis and Clinical Manifestations

• Also known as multiple myeloma

• Malignant disorder of mature, antibody-secreting B lymphocytes (plasma cells)

• Malignant plasma cells invade bone and form multiple tumor sites; may also target other tissues, including lymph nodes, liver, spleen, and kidneys

• Occurs exclusively in adults; usually >40 years; median age 65 years; men > women

• Large amount of one type of antibody; forms a characteristic spike

• Bence Jones protein: malignant plasma cells produce light- chain antibody fragments that accumulate in blood and urine

  • Helps confirm diagnosis

  • Can accumulate in kidneys and damage them

• Malignant plasma cells tend to accumulate in bone; pathologic fractures common

  • Bone destruction releases calcium into bloodstream—hypercalcemia

• Most clinical manifestation caused by bone/renal damage

Plasma Cell Myeloma (Multiple Myeloma) - Prognosis and Treatment

• Remission rate with antineoplastics about 60%

• Median survival rate 3 years

• Chemotherapy and BMT