Cellular Pathology

What is Cellular Adaptation?

Reversible changes to the size, number, phenotype, metabolic activity or function of cells in response to changes in their environment.

What are examples of Cellular Adaptation?

Hyperplasia

Hypertrophy

Atrophy

Metaplasia

How does Cellular response to stimulus?

Via Physiological and Pathological response

Physiological: in response to normal stimulus

Pathological: in response to abnormal stimulus

An increase in the number of cells in an organ or tissue that may then have increased volume:

Hyperplasia.

What is the Physiological cause of Hyperplasia?

Cause by normal Stressors such as:

Hormonal: Increased number of glandular epithelial breast cells during pregnancy

 enlargement of breasts

 preparation for lactation

Increases functional demand: living at high altitude leads to hyperplasia of erythrocyte precursors in the bone marrow.

Compensatory:

Regeneration of liver following partial hepatectomy

 Regeneration of epidermis after abrasion

What is the Pathological cause of Hyperplasia?

Occurs due to an abnormal stressor (e.g., excessive stimulation of hormones or growth factors)

 Endometrial hyperplasia (increased estrogen)

 Benign prostatic hyperplasia (androgens)

 Epidermal hyperplasia in psoriasis

What Is Hypertrophy and its Physiological and Pathological cause?

Hypertrophy is an increase in the size of cells, which leads to an increase in the size of an organ or tissue.

Physiological causes include increased workload (e.g., muscle growth from exercise)

Pathological causes include stress or damage, such as cardiac hypertrophy due to hypertension or aortic stenosis

Hyperplasia vs Hypertrophy

They both frequently occur together

both can result win increase organ size

A decrease in size of a cell:

Atrophy-

May be due to loss of blood supply, loss of endocrine stimulus, disuse, decreased workload, aging.

What is Physiological cause of Atrophy?

Physiologic:

 Atrophy of brain with aging

 Atrophy of gonads after menopause

(decreased hormones)

 Decrease in the size of the uterus after

pregnancy

What is pathological cause of Atrophy?

Immobilization of a limb after fracture

(disuse)

 Cachexia (starvation, insufficient nutrients)

 Ischemic process (inadequate supply of

oxygen)

A change in epithelium at a site, or location form one type to another: (change in cell)

Mataplasia

Mechanism: epithelium normally present at a site cannot handle the new environment so it converts to a type of epithelium that can adapt.

What is the Physiological and Pathological cause of Metaplasia?

Physiologic:

 Cervical changes

 Pathologic:

 Cigarette smoke

 Barrett’s esophagus

Occurs when the cells cannot adapt to their new environment:

Cell Injury.

Can be reversible or irreversible

What are the Vulnerable systems in cellular injury:

DNA, Cell membrane, Protein generation, Adenosine triphosphate (ATP) production.

What are the causes of cell injury?

Hypoxia, ischemia, Physical agents, Chemical agents, Infectious agents, radiation and toxins, metabolic abnormalities, Immune dysfunction, Nutritional imbalances, Aging.

4 mechanism of cellular injury:

Hypoxia, Free radicals, chemical injury, Increased mitochondrial cytosolic calcium (mitochondria injury)

What is Hypoxia?

Hypoxia is a lack of oxygen in tissues, leading to decreased ATP production, cellular dysfunction, and potentially cell death if prolonged.

Hypoxia (↓ O₂)

↓

↓ Oxidative phosphorylation in mitochondria

↓

↓ ATP production

↓

Failure of ATP-dependent pumps

↓

Cell swelling + ↑ intracellular Ca²⁺

↓

↑ Anaerobic glycolysis

↓

↑ Lactic acid

↓

↓ Intracellular pH

↓

Cell dysfunction

↓

Reversible injury

↓ (if prolonged/severe)

Irreversible injury

↓

Necrosis

What are free radicals in cellular injury?

Free radicals are chemically unstable and react with other molecules —>damage

 Produced by physiologic oxidation-reduction reactions, UV light, ionizing radiation, metals, chemicals (smoking, pollution), inflammation, stress

What are free radicals in Cellular Injury?

Chemical injury = toxins damage cells either directly or through toxic metabolites, causing membrane damage, mitochondrial dysfunction, free radical formation, ATP depletion, and ultimately cell death.

what happens in increased mitochondrial calcium:

Results in:

 Lipid peroxidation

 Mitochondrial injury

 Loss of calcium homeostasis

 ↓ ATP production

 Apoptosis

Increased cytosolic and mitochondrial calcium is a key mechanism of cellular injury because it activates destructive enzymes, damages mitochondria, decreases ATP production, and triggers apoptosis or necrosis.

Cell Injury diagram:

Reversible injury is characterized by cellular swelling and recovery after removal of the stress, whereas irreversible injury involves severe mitochondrial and membrane damage leading to necrosis or apoptosis.

Two types of cell death:

Apoptosis: controlled (programmed) cell death/breakdown of cells occurring in response to irreversible cellular damage or as part of normal growth and development.

Necrosis: uncontrolled breakdown of cells/cell death in response to irreversible cellular injury

Phases of Apoptosis:

Initiation: caspases (enzyme) become catalytically active.

Execution: action of caspases causes cell death.

PATTERNS OF OCCURRENCE OF APOPTOSIS

During growth and development, some cells serve a function in the growth phase but then need to be removed after their purpose is fulfilled.

 In neonates, a rapid cell growth rate is necessary.

 In adults, unrestrained cell growth can cause cancer.

 When DNA sustains irreparable damage, the cell must be destroyed so any mutations that may have developed will not be propagated.

 Apoptosis removes damaged cells from the body = safety step

What is Intrinsic pathway in apoptosis?

The intrinsic pathway is a form of apoptosis initiated by internal cellular signals, often due to stress or damage, activating caspases and leading to programmed cell death.

What is extrinsic pathway in apoptosis?

The extrinsic pathway is a form of apoptosis initiated by external signals, such as ligands binding to death receptors on the cell surface, which activates caspases and leads to programmed cell death.

What does cell death look like microscopically?

Chromatin condensation and fragmentation

Uncontrolled (randomized) breakdown of cells/cell death in response to irreversible cellular injury; triggers inflammatory response:

Necrosis

Gross morphology of necrosis:

softening and discoloration

Different types of microscopic morphology of necrosis:

• Coagulative necrosis- firm

• Liquefactive necrosis- liquid

• Fat necrosis- chalk

• Caseous necrosis- cheese

Apoptosis vs necrosis

Apoptosis- blebbing

Necrosis- swelling

The most common type of necrosis, usually caused by ischemia (loss of blood supply) or infarction in solid organs.

Coagulative necrosis

protein denaturation (loos of blood)

Infarction = tissue death (necrosis) caused by a loss of blood supply (ischemia)

Organs affected: any organ (except brain- liquefactive)

Gross morphology of necrosis

dry, hard, yellow- white appearance to tissue

What organ is affected by liquefactive necrosis?

Brain

abscess formation (bacterial infection in lungs etc.)

Enzymatic breakdown in lipid-rich organs

Liquefactive necrosis

occurs when tissue becomes transformed into a liquid mass due to enzymatic breakdown, often seen in lipid-rich organs like the brain. (Loss of cellular architecture)

Gross morphology of liquefactive necrosis?

Tissue transformed into a liquid, viscous mass.

LIQUEFACTIVE NECROSIS – MICROSCOPIC MORPHOLOGY

loss of organ cellular architecture

 lipid-laden

macrophages replace the dead tissue

change in adipose tissue due to trauma or the release of enzymes from adjacent organs:

Fat necrosis

Breakdown of lipid + release of fatty acids + calcium  chalky deposits.

Due to infections, trauma, ischemia, toxins

what are the common organ affected by fat necrosis?

Organs affected: commonly breast and pancreas

What is Gross morphology of fat necrosis?

Gross morphology: yellow, white/chalky deposits

Microscopic morphology of fat necrosis?

large, lipid filled vacuoles

Occurs when the immune system cannot successfully remove a foreign stimuli (e.g., tuberculosis).

Caseous Necrosis:

Immune system seals off the foreign matter by forming a granuloma.

A type of necrosis characterized by the appearance of cheese-like (caseous) material, often seen in tuberculosis infections.

organs affected of Caseous necrosis?

any organs

Gross morphology of caseous necrosis

Gross morphology: yellow-white, soft, “cheesy” appearance

Microscopic morphology of caseous necrosis

granuloma with central necrosis, eosinophilia

Cellular Accumulations

Cellular accumulations occur when substances build up inside cells because they are produced too much, not metabolized properly, or cannot be removed.

Substances can accumulate in cells due to cellular damage or intrinsic abnormality in metabolic function (e.g. genetic disease)

Substances that can accumulate:

 Lipofuscin

 Calcium

 Protein

 Iron

 Fat

 Cholesterol

 Glycogen

 Pigments

Lipofuscin

“wear-and-tear” pigment, endogenous production

 Mechanism of formation: product of lipid peroxidation which accumulates in lysosomes as cells ages; cells cannot get rid of it.

 Organs affected: commonly in the heart, liver, skin.

Gross morphology of lipofuscin

brown discoloration to organs

Microscopic morphology of lipofuscin:

finely granular, yellow-brown pigment, which often surrounds the nucleus

What are the causes of hypercalcemia

 Causes of hypercalcemia:

 Increased parathyroid hormone (PTH)

 Destruction of bone by tumors

 Vitamin D intoxication

 Renal failure

 Sarcoidosis

Organs affected: vasculature, kidneys, lungs

deposition of calcium salts in normal tissues due to high blood calcium levels (hypercalcemia).

Metastatic calcification.

Dystrophic calcification.

deposition of calcium salts in damaged, dying, or necrotic tissues despite normal blood calcium levels.

 Tuberculosis

 Atheroma, infarct

 Fat necrosis (pancreatitis)

Gross morphology of calcium accumulation

Hard, yellow nodules

Microscopic morphology of calcium accumulation

chunky, smooth, purple granules

CELLULAR ACCUMULATIONS - PROTEIN

Gross and microscopic morphology of protein accumulation

Gross morphology: blue-black foci on tissue once stained.

Microscopic morphology:

 Amyloidosis: amyloid deposits

stain eosinophilic/pink-pale; pink

or red on Congo red stain

 Alzheimer’s disease:

neurofibrillary tangles

 Fatty liver: Mallory hyaline-

eosinophilic, pink, rope-like

deposits

Two type of calcium accumulation

dystrophic and metastatic

patients who have hypercalcemia have deposition of calcium within normal or abnormal tissue

Mechanism of metastatic calcification- form of calcium accumulation.

patients who have normal levels of calcium have deposition of calcium only within abnormal tissue (necrosis or damage)

Mechanism of dystrophic calcification:

Sites of abnormal tissue:

 Tuberculosis

 Atheroma, infarct

 Fat necrosis (pancreatitis)

Sites of accumulation of calcium

Organs affected: vasculature, kidneys, lung

Mechanism of formation of protein?

Increased protein absorption in proximal renal tubule (renal disease)

 Increased cytoskeletal proteins

 Neurofibrillary tangles (Alzheimer’s disease)

 Intermediate filaments (Mallory hyaline) in the liver due to alcoholism, fatty liver

 Increased protein production

 Defect in intracellular transport and protein secretion

 Abnormal proteins (protein aggregation diseases)- amyloidosis

Mechanism of iron accumulation:

accumulation of hemosiderin due to ↑ iron

Sites of accumulation of Iron

liver, skin, pancreas, heart

accumulation of iron in organs without resultant side effects

Hemosiderosis

Accumulation of iron in parenchymal cells resulting in side

effects (e.g. DM, cirrhosis)

Hemochromatosis

Organs affected by hemochromatosis: liver, skin, pancreas, heart

Gross morphology of Iron accumulations

Gross morphology: dark brown color

Microscopic morphology of Iron accumulation

chunky, yellow-brown granules on H & E stain; blue on Prussian blue stain.

mechanism of of formation of fat accumulation (steatosis)

Intrinsic abnormality in fat metabolism.

Can indicate reversible damage.

Sites of accumulation of Fat (steatosis)

Organs affected: liver, kidney, heart, skeletal muscle

Gross and Microscopic morphology of Steatosis

 Gross morphology: yellow discoloration of an organ.

 Microscopic morphology: one or several clear vacuoles within the cell.

Mechanism of cholesterol accumulation

Hypercholesterolemia: elevated blood cholesterol levels lead to disruption in cellular function, oxidative stress, inflammation.

Sites of Cholesterol Accumulation

Organs affected: blood vessels (atherosclerosis)

CHOLESTEROL- GROSS & MICROSCOPIC MORPHOLOGY

 Gross morphology: yellow discoloration of an organ

 Microscopic morphology: foam cells (lipid-laden macrophages)

mechanism of accumulation- Glycogen

accumulates due to glycogen storage disorders or disease of glucose metabolism.

Sites of accumulation of glycogen

Organs affected: liver and skeletal muscle

Microscopic morphology of Glycogen accumulation

clear vacuoles in the cytoplasm

Gross morphology of glycogen accumulation

Gross morphology: Usually no obvious changes visible to the naked eye.

Mechanism of accumulation of pigments

Pigments are colored substances that accumulate in cells. They can be endogenous (made by the body) or exogenous (from outside the body).

Sites of Pigment accumulation

skin, eyes

Necessary for chromosomal integrity and genomic stability

Telomere

Telomeres get progressively shorter with each cell division until cells become senescent or die.

Cellular aging occurs partly because telomeres shorten with each cell division, eventually causing cells to stop dividing (senescence) or die.

Telomere biology disorders

(dyskeratosis congenita, progeria)