Intro to pathology and Cell Injury and Cell Death

Pathology is the study of:

Links between disease and basic science (pathos=disease)

A disease is:

A physical or functional disorder of normal body systems that places an individual as risk for adverse consequences

General disease diagnosis and treatment

Health care providers diagnose disease with a combination of tools, and then treatment is given to improve prognosis

Etiology Definition

Cause of disease

Pathogenesis definition

Mechanism of disease development

Morphologic/Pathogenic change definition

Alteration in cells and organs, they are characteristic of a disease or diagnostic of an etiologic process

Pathophysiology definition

Functional changes associated with or resulting form disease or injury. Can be seen in signs and symptoms

Example of pathological process affecting various tissues differently

Squamous cell carcinoma:

• In skin=indolent (painless)

• In esophagus= life-threatening

Example of pathologic process causing different diseases in different organs

Myocardial infarction (MI)=due to ischemia

Cerebrovascular indecent (CVA)=due to ischemia

2 classes of etiologic factors:

Genetic and acquired

Genetic etiology factor

Inherited mutations and disease-associated gene variants or polymorphisms

Acquired etiology factor

Infectious, nutritional, chemical, physical

Most common disorders are caused by:

Multifactorial effects, arise from effects of various external factors on a genetically susceptible individual

Example of acquired disorders:

Traumatic ulcer, syphilis, coronary atherosclerosis with thrombosis, caries, cataracts

Examples of genetic disorders:

Amelogenesis imperfecta, Marfan syndrome, Crouzon syndrome, APC gene mutation, familial Polyposis

Pathogenesis, the mechanism of development is:

Sequence of events in response of cells/tissues to etiologic event, form initial stimulus to disease expression

Examples of different general pathogenesis:

• cancer needing multiple mutations to be cancerous

• Smoking and alcohol

• radiation exposure

Photo of odontogenic cyst

Odontogenic cyst pathogenesis:

Develops by accumulation of fluid between the reduced enamel epithelium and the tooth crown

Odontogenic cyst functional consequences:

Pericoronal (around tooth crown) radiolucency, loss of bone, failure of teeth to erupt, need for ortho/OS (to restore occlusion)

Retinoblastoma can be caused by:

Inheriting a mutation in the Rb gene

The field of diagnostic pathology has expanded to include what methods?

Molecular biologic and immunologic approaches for analyzing disease states

Morphology of kidney disease:

Granular surface, decreased function, smaller size, high urine protein

(Lung) chronic passive venous congestion

3 Categories that providers use to make diagnoses

• clinical diagnosticians identify diseases through pt history and physical exam

• Pathologists examine cells/tissues that were removed from the body to identify diseases

• Radiologists image the intact body to identify disease

Virtually all forms of diseases start with:

Molecular structural alterations in cells

Tissue with functional abnormalities lead to:

Clinical manifestations (symptoms, signs) of disease and its progress (clinical course and outcome)

What is the most commonly mutated protein in cancer

p53

Etiologic agents (smoking) —> pathogenesis —> pathologic changes —> clinical manifestations (HPV wart)

Many proliferation genes are upregulated in:

HSNCC, Head and neck squamous cell carcinoma

Symptom definition

Experienced, reported by the patient

Sign definition

Discovered by doctor during examination or by in vitro examination

Call injury results when:

• Limits of adaptive responses are exceeded

• Cells are exposed to damaging insults, deprived of critical nutrients

• compromised by mutations effecting cellular function

Increased load of normal myocyte leads to:

Respond to increased load with: hypertrophy

• increased BP, required more mechanical effort of myocardial cells=enlarge

Normal myocyte responds to cell injury with:

A reversibly injured myocyte undergoes functional alterations:

• cytoplasmic changes

• cellular swelling

• fat accumulation

Leads to reduced blood flow and cell death

Causes of cell injury

• oxygen deprivation

• physical agents

• chemical and infectious agents

• tapeworms and fungi

• radiation and extreme cold

Sequential development of biochemical and morphologic changes in cell injury

Range of function and structure depends on:

• genetic program of metabolism (receptors to allow substrates)

• differentiation (stem vs mature)

• specialization of cell

• availability of metabolic substrates (like iron)

What is cellular adaptation

A cell adapting to an altered or new steady state

They’re acceptable changes to the environment by modifying metabolism or growth pattern.

2 Types of physiologic adaption

Metabolic and structural

Metabolic physiologic adaptation

Fine regulation of metabolic function that’s not easily detectable as a structural change

ex: FA mobilization in fasting

Structural physiologic adaptation

• Increase in cellular activity (size and #)

• Decreased cellular activity (size and #)

• Alteration of cell morphology (differentiation)

Atrophy definition

Decrease in size and function

Hypertrophy definition

Increase in size

Hyperplasia definition

Increase in number of cells

Metaplasia definition

Reversible change from one cell type to another (altered differentiation)

Dysplasia definition

Abnormal changes in cellular components (usually a cancer precursor)

Pathologic causes of Atrophy

Atrophy of disease, loss if innervation, less blood supply, aging

Physiologic causes of atrophy

• Uterine atrophy after giving birth

• By puberty the thymus starts to shrink and become replaces by fat

Left=atrophic muscle cell

Right= normal muscle cell

Hypertrophy definition

Increased functional demand on tissue met by increase in cell size (more structural proteins made, no new cells)

Hyperplasia definition

Increased functional demand on tissue met by increase in cell number

Hypertrophy physiologic properties

• Stimulated by hormones (like uterus and breast in pregnancy)

• Increase in workload (exercise)=skeletal muscle hypertrophy

Hypertrophy pathologic properties

Increased workload is associated with changes in gene expression (heart muscle adaptation) atrial/brain natriuretic factors

• Alpha-myosin replaced by beta-myosin heavy chain

• TGF-beta, etc

Photo of hypertrophied uterus (recently pregnant)

Left=regular skeletal muscle

Right= hypertrophy of skeletal muscle in response to exercise

Beyond the limit of compensation, adaptive change can cause:

Congestive heart failure, apoptosis, and/or necrosis

Physiologic cause of hyperplasia examples:

• Hormonal: female breasts during puberty and pregnancy

• Compensatory: Liver after partial hepatectomy (liver regrowth)

Pathologic cause of hyperplasia(may be precancerous):

• excessive hormonal stimulation causes abnormal cell division

  • prostate cells increase in umber=enlarged prostate

  • excess estrogen causes uterus lining to thicken

• excessive growth factors= excessive multiplying of cells

  • injury=growth factors to repair=fibroblast recruitment= new tissue

• Some viruses can cause abnormal cell growth

  • HPV: causes warts and epithelial growths like papillomas

  • some high-risk HPV can contribute to precancerous changes

Benign prostatic hyperplasia (BPH)

Non-cancerous, age-related enlargement of the prostate gland

Metaplasia mechanism

A result of reprogramming stem cells (reserve cells) that are signaled by: cytokines, growth factors, and extracellular factors

(—>induce TF—>cascade of genes—>differentiated metaplastic cell)

Columnar squamous metaplasia example

In uterine cervix inflammation, normal columnar cells are replaced with squamous cells (to better withstand environment and irritation)

Barrett esophagus metaplasia example

Normal squamous intestinal cells convert to columnar cells (esophageal mucosa reacting to chronic acid inflammation, GERD) PRECANCEROUS change

Reversible injury involves(hydropic degeneration):

• membrane blebbing/cell swelling

• mitochondrial swelling

• ribosomal detachment

• loosen attachments

• fatty change in liver

Irreversible injury involves:

• lysosomal rupture/disappearance

• large, bizarre mitochondria

• calcium deposits

• membrane break

Left=normal kidney tubules and epithelial cells

Middle=reversible, early ischemic injury

Right= Necrosis, irreversible injury, of epithelial cells

Reversible cell injury effect on tissues/organs:

Pallor (compression of capillaries), increase weight (from cellular swelling), and increase turgor (from increase in size)

Left=normal mitochondria

Right= Ischemic cell mitochondria (swollen and round), REVERSIBLE

2 causes of sublethal liver cell damage

Hydropic degeneration in paraquat poisoning and fatty change in alcoholism

Cell response to injury depends on:

Type, duration, and severity of injury

Consequences of injury depends on:

Type, state, and adaptability of injured cell

Cellular sites with more vulnerability to injury:

Cell membrane, aerobic respiration, protein synthesis, genetic apparatus

When do morphologic changes become apparent?

Only after derangement of some critical biochemical system

2 Principle types of cell death:

Necrosis and apoptosis

Necrosis morphologic changes

Progressive injury leads to breakdown of plasma membrane, organelles, and nucleus and leakage of contents, and inflammation

Apoptosis morphologic changes

As chromatins condense and membrane blebs, cellular fragmentation occurs and apoptotic bodies are phagocytosed

Morphologic signs suggestive of apoptosis in kidney biopsy:

Cellular shrinkage and nuclear condensation

Signs of lung necrosis:

• bronchiolar lumen containing fibrin, neutrophils, cellular debris, and extravasated RBCs (inflammatory cells)

• bronchiolar epithelial cells contain intracytoplasmic eosinophilic inclusion (suggest viral infection)

2 types of damage that can cause inadequate ATP production:

Hypoxia or mitochondrial damage

Anaerobic ATP production is limited by:

Accumulation of lactate, and is usually quickly exhausted

What causes cloudy swelling?

Lack of ATP—>failure of membrane pumps—> swelling on internal membrane systems

Outcome of ischemia:

Ischema=less blood blow=less O2=Less ATP to tissues=pumps stop working=membrane damage=necrosis

Examples of ischemia cell damage

• damage to cytoskeleton (from swelling)

• free radical injury, lipid breakdown

• entry of extracellular Ca and H2O

• leakage of enzymes/proteins

• lysosomal rupture

Coagulative necrosis

Protein denaturation, from ischemic in most tissue except the brain

Liquefactive necrosis

Hydrolytic enzymatic digestion of tissues, mostly from infections. Ischemic brain infarcts develops from lack of blood flow not from infection.

Caseous necrosis

Typical of Tuberculosis (TB), cheese-like, see in lung

Hemorrhagic necrosis

Dead tissue is replaced by extravasated blood (venous block)

Fat necrosis:

Enzymatic: lipases released in pancreatitis

Traumatic: breast fat is replaced by lipid-laden macrophages

Gangrenous necrosis:

Ischemic most commonly found in skin and soft tissues of feet

Fibrinoid necrosis

Immune deposits common in vessel walls

Gummatous necrosis

Restricted necrosis in spirochetal infection, seen in syphilis

Coagulative vs liquefactive necrosis

• Coagulative: Dead tissue is preserved for a few days, localized area of coagulative necrosis is an infarct (early in process, hold shape)

• Liquefactive: Digestion of dead cells makes a viscous liquid, like from many infections. Creamy yellow necrotic material (leukocyte presence)=pus (dead cells begin digestion)

Caseous necrosis, TB granulomas

Liquefactive necrosis in brain of patient with stroke

Liquefactive necrosis in an abscess

Acute pancreatitis causing enzymatic fat necrosis (in alcoholic pt with elevated serum amylase levels)

Gangrenous necrosis: atherosclerotic—>ischemia

Apoptosis in induced by:

Tightly regulated suicide system where cells destined to die activate intrinsic enzymes that degrade cells’ genomic DNA and nuclear/cytoplasmic proteins (most apoptosis is intrinsic)

Apoptosis cellular mechanism

Breaks up cells into plasma membrane bound fragments. Plasma membrane remains intact, surface components produce signals for phagocytes to find.

Physiologic situations where phagocytosis is important:

• removal of supernumerary cells during development

• involution (shrinkage) of hormone-dependent tissue on hormone withdrawal

• cell turnover in proliferating clel populations

• elimination of potentially harmful self-reactive lymphocytes to prevent immune reactions against self

• death of host cells that have served their purpose