General
Pathology
Cellular Growth and Differentiation:
Normal Regulation and Adaptations
Dr. Eric P. Lasala, DPSP
Definition of Terms
l Pathology- is the study of disease and its processes
l Pathogenesis- is the process of disease formation
l Etiology- is the cause of the disease, it maybe biological, chemical or mechanical
l Morphologic Change- structural alterations to the tissues involved in the disease, that is a characteristic of the disease process
l Functional derangements-the clinical significance of the structural changes that alters the functions of the diseased tissues, organ or system
l Rudolf Virchow- father of modern pathology, lived during the 19th century
l Normal homeostasis-normal physiologic demands; refers to the normal cellular environment and its surrounding cells
l Cellular adaptations- where when a cell is subjected to a certain stimuli, the environment reaches a new altered but steady state
l Cell injury- when the cell which has been subjected to a harmful stimuli, and has adapted to the said stimuli, upon continuous stimulation is further altered and reaches a destructive state that is no longer reversible
l Cell injury- is reversible up to a certain point
l Cell death-the point of no return, where the cell injury is no longer reversible; there are two morphologic patterns of cell death
Ψ Necrosis- the more common form of cell death manifested with severe swelling and destruction of the organelles
Ψ Apoptosis is a regulated cell death, designed for the elimination of unwanted cell population
Causes of Cell Injury
l Hypoxia
l Physical agents
l Chemicals and drugs
l Infectious agents
l Immunologic reactions
l Genetic derangements
l Nutritional imbalances
Hypoxia
l Extremely important and common cause of cell injury and death
l It impinges on aerobic oxidative respiration
l Loss of blood supply ( ischemia) which occurs when arterial blood flow is impeded is the most common cause of hypoxia
l Another cause of hypoxia is inadequate oxygenation due to:
Ψ Cardiorespiratory failure
Ψ Loss of the oxygen carrying capacity of the blood
Ψ Oxygen deprivation
Physical
Agents
l Mechanical trauma
l Extremes of temperatures (burns and deep cold)
l Sudden changes in atmospheric pressure
l Radiation
l Electric shock
Chemical
Agents and Drugs
l Simple chemicals like glucose and salt may cause injury by directly or deranging electrolytes homeostasis of cells
l Oxygen in high concentrations is toxic
l Arsenic, cyanide, mercuric salts
l Environmental and air pollutants
l Insecticides, herbicides
l Industrial and occupational hazards
l Alcohol and narcotic drugs
Infectious
Agents
l Ranges from submicroscopic viruses to large tapeworms
l Rickettsiae
l Bacteria
l Fungi
Immunologic
Reactions
l Maybe life saving or lethal
l Although the immune system serves as a defense mechanism, immune responses may in fact cause cell injury, examples are:
Anaphylactic shock
Autoimmune diseases
Rheumatic heart disease
Genetic
Derangements
l May result to gross defects such as in Downs Syndrome
l Or maybe subtle as is seen in Sickle cell disease
l Inborn errors of metabolism
Nutritional
Imbalances
l Protein calorie deficiencies
l Vitamin deficiencies
l Nutritional excess
l Excess of lipids predisposes one to stherosclerosis (or is it atherosclerosis?)
Types of Cellular Population According
to Ability to Manufacture DNA
l Labile Cells
l Stable Cells
l Permanent Cells
Labile
Cells
l Cells that continuously proliferate
l They do not stop to reproduce themselves from time of birth
l They are cells that are capable of producing DNA
l They regularly replace old and defective cells with fresh new cells
l Examples of labile cells:
Ψ Mucosal cells of the intestines, urinary tract, hematopoeitic system
Stable
Cells
l Cells that do not routinely reproduce themselves but are capable of doing so if proper stimulation is applied
l They are also capable of DNA production but are at the G0 pahse or resting phase when not stimulated
l Cells that are stable include:
Ψ Liver cells
Ψ Other solid organs but only to a lesser extent
Permanent
Cells
l These are type of cells that are not capable of DNA production and are therefore not capable of reproducing itself
l Examples:
Brain tissue
Nerves
Muscles tissues
Cellular Adaptations
l Hyperplasia- increase in the number of cells in an organ or tissue which may then have an increased volume
l Takes place when the cellular population is capable of synthesizing DNA
l Maybe:
Physiologic
Pathologic
Hyperplasia
l Physiologic hyperplasia
Hormonal hyperplasia- best seen in the proliferation of the glandular epithelium of the female breast at puberty and pregnancy
l Compensatory Hyperplasia-maybe seen in the case of partial hepatectomy
Mechanisms of Hyperplasia
l In a normal liver only 0.5-1% of the cells undergo DNA replication
l As early as 12 hours after partial hepatectomy, the cells increase their DNA synthesis
l Peaks at 1-2 days after, where as much as 10% of the cell population maybe involved
l DNA synthesis declines 1-2 weeks after, and the cells become quiescent again
l Factors involved in physiologic hyperplasia:
Ψ Growth factors (HGF,EGF)
Ψ Cytokines (IL-6, TNF alpha)
Ψ Growth inhibitors (TGF-beta)
Pathologic
Hyperplasia
l Most forms involve instances of excessive hormonal stimulation or as effects of growth factors on target cells
l Examples:
Endometrial hyperplasia
l This type of hyperplasia is a fertile soil where cancerous proliferation may eventually arise
l Hyperplasia of connective tissue cells maybe seen in healing and repair, this type of hyperplasia is not pathologic
l Hyperplasia of viral infections HPV (Human Papiloma Virus) , which causes skin warts and other mucosal epitheliums causes masses of hyperplastic cells
Hypertrophy
l Refers to an increase in the size of the cells and with such change an increase in the size of the organ
l A hypertrophied organ has no new cells, only larger cells
l The increase in the size of the cells is due to the production of more structural components
l There are two forms:
Ψ Pathologic Hypertrophy
Ψ Physiologic Hypertrophy
Physiologic
Hypertrophy
l Does not involve cell division
l Example:
Massive physiologic growth of the uterus during pregnancy is an example of hormonal hypertrophy
Hypertrophy of the breasts during lactation
Muscular enlargements-seen in increased workloads (skeletal m., cardiac m.)
l The synthesis of more proteins and filaments occur thus achieving a balance between the demand and the cells functional capacity
l Factors involved in physiologic hypertrophy:
Mechanical triggers
Trophic triggers ( polypeptide GF and vasoactive agents)
l Whatever the exact mechanism of the hypertrophy, it will eventually reach a limit beyond which enlargement of the muscle mass is no longer able to compensate for the increased burden and the cells start to fail
l Degenerative Changes that follow after the cells start to fail:
Lysis of the cells
Loss of the myofibrillar contractile elements
Death
v Necrosis
v Apoptosis
Limiting factors for Hypertrophy
l Limitation of the vascular supply to the enlarged fiber
l Diminished oxidative capabilities of the mitochondria
l Alterations in protein synthesis and degradation
l Cytoskeletal alterations
Atrophy
l Shrinkage in the size of the cell by the loss of cell substance
l Still represents another form of adaptation
l When sufficient number of cells are involved, the entire tissue or organ diminishes in size and becomes atrophic
Types
of Atrophy
Physiologic
Atrophy:
l Common during the early stages of development
l Seen in the atrophy of the notochord and the thyroglossal duct
l Also seen in adults:
seen in the decrease in the size of the uterus after parturition and menopause
Pathologic
Atrophy
l Depends on the basic cause
l It can be localized or generalized
Common Causes of Pathologic Atrophy
l Decreased workload
-also known as atrophy of disease
Seen in a limb in a plaster cast
Initial decrease in size is reversible after the activity is resumed
After prolonged disuse, the skeletal m. fibers decrease in size and number and may also result to increase bone resorption ( osteoporosis of disuse)
l Loss of innervation
Also known as denervation atrophy
The normal function of any skeletal muscle is dependent on its nerve supply
l Diminished blood supply
Decrease blood supply (ischemia) to the tissue as a result of arterial occlusive disease
In late adulthood, the brain undergoes progressive atrophy presumably as atherosclerosis narrows the blood supply
l Inadequate nutrition
Profound protein calorie malnutrition (marasmus) is associated with the use of muscle fibers as a source of energy after all other reserves such as adipose tissue have been depleted resulting to marked muscle wasting
l Loss of endocrine stimulation
Breasts and other reproductive organs are mostly involved
Loss of estrogen stimulation after menopause results in physiologic atrophy of the endometrium, vagina and breast
l Aging (Senile Atrophy)
Aging process is associated with cell loss
Morphologically seen in tissues containing permanent cells ( brain and heart)
l Pressure
Tissue compression for any length of time
Although atrophic cells have diminished functions, they are not dead
Apoptosis or programmed cell death maybe induced by the same signals that cause atrophy that may contribute to the loss of organ mass
l A balance in protein synthesis and degradation plays a key role in atrophy
l Atrophic cells maybe replaced by fatty in-growth
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Metaplasia
l Reversible change in which one adult cell type is replaced by another adult cell type
l Represents an adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment
l Columnar to squamous metaplasia
Ψ Most common type
Ψ Seen in chronic smoker, where the normal columnar ciliated epithelium of the respiratory tree are replaced by the more robust squamous epithelium
Ψ Stones in the excretory ducts may cause the normal mucosa to be eroded and replaced by squamous epithelium ( salivary glands )
l Deficiency of Vitamin A
Ψ Vitamin A is at the forefront of epithelial repair, if deficient, it may result to a defect in the repair of destroyed epithelium, and therefore results to the development of metaplasia to replace the more delicate epithelial cells with something tougher such as squamous epithelium
l Although the more rugged squamous epithelium replaces the more delicate columnar cells, it cannot replace the capability of the columnar cells to produce mucous which is important in the function of mucosal cells
l Cancer formation in metaplastic tissues may ensue if the influences that predispose to metaplasia persists
Other
Metaplasias
l Squamous to columnar metaplasia
Seen in Barrett esophagitis, wherein the normal squamous epithelium of the esophagus is replaced by columnar mucus secreting cells as a result of repeated wretching or vomitting of acidic gastric contents
l Connective Tissue Metaplaisia
Formation of cartilage, bone or adipose tissues (mesenchymal cells) in tissues that normally do not contain this elements
Seen in myositis ossificans, wherein bone tissue forms in the muscle tissue after a fracture
Metaplasia - Arise from a reprogramming of stem cells that are known to exist in most epithelia or of undifferentiated mesenchymal cells present in connective tissues
Intracellular Accumulations
l A manifestation of metabolic derangements
l A type of cellular adaptation
l Maybe normal or abnormal accumulations
l Categories of abnormal intracellular accumulations:
Normal constituents of cells
Abnormal substances
Pigments
l Normal Cellular constituents
Water
Lipid
Protein
Carbohydrates
Lipids as Abnormal Intracellular
Accumulations
l Maybe any of the following
Triglycerides
Cholesterol
Cholesterol esters
Phospholipids
l Steatosis
Fatty change of the liver
Abnormal accumulations of triglycerides within hepatic parenchymal cells
Often seen in the liver because it is a major organ of fat metabolism
May also be found in the heart, skeletal muscles and kidneys
l Causes of steatosis:
Toxins
Protein malnutrition
Diabetes mellitus
Obesity
Anoxia
l In industrialized nations, the most common cause of significant fatty change in the liver is alcohol abuse
l Alcohol is a hepatotoxin that alters mitochondrial and ribosomal function
l Fatty change is reversible
l The significance of fatty change depends on the cause and severity of the accumulations
l Fatty change is a harbinger of cell death, but hepatocytes may occur without undergoing fatty change
l Grossly, the liver is enlarged and increasingly yellow, weighing 3-6 kg and transformed into a bright yellow, soft greasy organ
l Other forms of intracellular lipid accumulations:
Atherosclerosis- smooth m. cells and macrophages within the intimal layer of the large arteries and aorta are filled with lipid vacuoles which are made up of cholesterol and cholesterol esters
l Other forms of intracellular lipid accumulations:
Xanthomas- intracellular accumulations of cholesterol within macrophages characteristic of acquired and hereditary hyperlipidemic states; maybe seen as clusters of foamy macrophages subepithelial connective tissue of the skin producing tumorous masses
Proteins as Abnormal Intracellular
Accumulations
l Reabsorption droplets- seen in the proximal renal tubules in renal diseases associated with protein loss; a reversible process
l Russel Bodies- synthesis of excessive amounts of normal secretory proteins, seen in plasma cells
Glycogen as Abnormal Intracellular
Accumulations
l Glycogen is a rapidly available energy store present in the cytoplasm
l Seen in patients with abnormal glucose or glycogen metabolism, e.g., diabetes mellitus
l May also be seen in the following cells:
Liver cells
Beta cells in the islets of Langerhans
Heart muscles
Pigments as Abnormal Intracellular
Accumulations
l Colored substances, some of which are normal constituents of cells, others are abnormal and collect in special circumstances
l Maybe:
Endogenous
Exogenous
l Exogenous
carbon or coal dust is the most common form
Anthracosis is the accumulation of carbon within macrophages which blacken the tissue of the lungs or lymph nodes
Tattooing is a form of exogenous pigmentation of the skin
l Endogenous
Lipofuscin, also known as the wear and tear pigment is not injurious to the cell
It is a tell tale sign of free radical injury and lipid peroxidation
Appears as a yellow brown finely granular intra cytoplasmic pigment in the liver and heart of aging patients and in severe malnutrition and cancer
l Melanin is a non hemoglobin derived brown-black pigment
l It is the only endogenous brown black pigment
l Homogentisic acid is an abnormal brown black endogenous pigment seen in alkaptunuria leading to onchronosis
l Hemosiderin is a hemoglobin derived yellow to brown pigment in which form iron is stored in the cells
l The best example is the common bruise
l A condition caused by a systemic overload of iron where hemosiderin is deposited in many organs and tissues
l Causes of increases hemosiderin in tissues:
Increased absorption of dietary iron
Impaired use of iron
Hemolytic anemia
Excessive or multiple transfusion
l Hemochromatosis is the extreme, severe accumulation of iron, associated with liver or pancreatic damage resulting to:
Liver fibrosis
Heart failure
Diabetes mellitus
Pathologic Calcification
l Implies the abnormal accumulation of calcium salts together with smaller amounts of iron, magnesium and mineral salts
l There are two forms:
Dystrophic calcification
Metastatic calcification
l Dystrophic calcification is a calcification that occurs locally in non-viable or dying tissues
l Encountered in areas of necrosis
Coagulative necrosis
Caseous necrosis
Liquefactive necrosis
Enzymatic fat necrosis
l Metastatic calcification may occur in normal tissues whenever there is hypercalcemia
l Calcium is deposited in vital tissues
l Almost always reflects a disturbance in calcium metabolism
l Hypercalcemia can accentuate metastatic calcification
l Principles in the cause of hypercalcemia:
Increased secretion of PTH
Destruction of bone tissues
Vitamin D related disorders
Renal Failure
l Less common causes of hypercalcemia:
Aluminum intoxication in chronic renal dialysis
Milk alkali syndrome due to the excessive intake of milk or calcium carbonate (calcium and absorbable antacids)
l Sites affected by metastatic calcification
Gastric mucosa
Kidneys
Lungs
Systemic arteries
Pulmonary veins
Hyaline Change
l A descriptive histologic term rather than a marker of cell injury
l Refers to an alteration within cells or in the extracellular space, which gives a homogenous, glassy, pink appearance in routine histologic secretions ( H and E)
l Examples of hyaline change:
Ψ Reabsorption droplets
Ψ Mallory bodies
Ψ Russel bodies
l Extracellular hyaline
Ψ Examples:
v Collagenous tissues in scar
v Long standing hypertension and diabetes mellitus causes hyalinized walls of the arteries