Cell Injury And Death Flashcards
Etiology
Cause of disease
Pathogenesis
Mechanism of development of disease
Molecular/morphological changes
Biochemical and structural alterations seen in disease
Clinical manifestations
Functional consequences of disease
Adaptation of a cell in response to stress is associated with adjustments in _______ and _______ of the cell.
Structure and function
When does cell unjustly occur?
when limits of adaptation are surpassed or when
undergo adaptation and/or injury function adaptive responses are not available.
What are the limitations of survival of an injured cell?
nature and
duration of the injury and concurrent exposure to other cell stressors.
Necrosis is characterized by:
structural changes that result from cell death
Is there inflammation associated with post-Mortem change (autolysis)?
No
What are the five morphologic patterns of adaptation for cells under stress?
- atrophy
- hypertrophy
- hyperplasia
- metaplasia
- dysplasia
Morphologic adaptation pattern that results in shrinkage of cells or organs due to loss of cell substance.
Atrophy
This is associated with reduced function of cell but not necessarily death
Postpartum involution of uterus and age-related changes of thymus are examples of what kind of cell adaptation?
Physiologic atrophy
What are causes of pathological atrophy?
- disuse
- hypoxia
- pressure
- denervation
- endocrine deficiency
- idiopathic
Osteoporosis is an example of what cell adaptation?
Pathological atrophy from disuse
tissue and organ atrophy associated with
diminished blood or oxygen supply
Pathological atrophy associated with hypoxia
neoplasms, aneurysms or other conditions that compress adjacent structures can cause what kind of cell adaptation?
Pathological atrophy due to pressure
atrophy of skeletal muscle following interruption of nerve supply is an example of what kind of cell adaptation?
Pathologic atrophy due to denervation
atrophy of target organs associated with hormone inadequacy can cause what kind of cell adaptation?
Pathologic atrophy due to endocrine deficiency
Cell adaptation seen in Alzheimer’s is an example of:
Idiopathic atrophy (unknown origin)
Cell adaptation resulting in enlargement of existing, non-dividing cells?
Hypertrophy
As seen in skeletal and cardiac muscle cells
If myocardial hypertrophy occurs with athletic conditioning, when does it become pathologic?
when caused by hypertension, valve lesions, etc.
Cell adaptation resulting in enlargement of tissue due to proliferation of cells capable of mitosis
Hyperplasia
What regulates proliferation as seen in hyperplasia?
growth factors, cytokines and growth inhibitors
Wound repair and tissue regeneration is an example of what kind of cell adaptation?
Hyperplasia
Compensatory responses, as in partial organ loss or physical stress is an example of what kind of cell adaptation?
Hyperplasia
Enlargement of a uterus during pregnancy or breasts during lactation, due to hormones are examples of what kind of cell adaptation?
Hyperplasia
Abnormal hormonal stimulation of growth factors on target cells due to chronic irritation or viruses can cause what kind of cell adaptation?
Pathologic hyperplasia
Cancer is an example of what cell adaptation?
Pathological hyperplasia after exposure of carcinogen
Cell adaptation where there is substitution of one type of “mature” cell with another “mature” cell type that may be better suited to cope with an altered environment
Metaplasia
Reprogramming of stem (reserve) cells of epithelium or of undifferentiated mesenchymal cells in connective tissue is an example of what kind of cell adaptation?
Metaplasia
What kind of cell adaptation occurs in Barrett’s esophagus?
Columnar cell metaplasia of lower esophagus
Ossification of fibrous scars is an example of what cell adaptation?
Metaplasia
Atypical substitution of one type of “mature” cell with another “mature” cell type resulting in lack of cellular uniformity and increased mitosis resembling cancer
Dysplasia
Are dysplasic cell adaptations reversible?
Mild to moderate are, but if entire layer of epithelium is involved, it will likely lead to cancer
The HPV virus will cause what kind of cell adaptation in the uterine cervix?
Dysplasia
hypoxic injury due to decreased blood flow
Ischemia
Local causes of ischemia
- arterial occlusion
- venous obstruction
- shunting of blood (steal syndrome)
Systemic causes if ischemia
- congestive heart failure
- shock
Causes of reversible and irreversible cell injury:
- ischemia
- hypoxia
- anoxia
- aging
- nutritional
- endocrine
- genetic
- immune
- infections
- physical agents
- chemical agents
decreased blood oxygen levels
Hypoxemia
What is the difference between hypoxic hypoxia and anemic hypoxia?
The decreased blood oxygen levels in hypoxic hypoxia is cause by decreased availability of oxygen while anemic hypoxia is due to deficiency in oxygen delivery associated with hemoglobin and/or iron
How does cyanide cause cell injury?
disrupts mitochondrial cytochrome oxidases effectively stopping oxidation and ATP production
What are some examples of physical agents that can cause cell injury?
mechanical trauma, temperature extremes, electrical injury, various forms of radiant energy, etc.
What is the mechanism of injury associated with a hypoxic injury?
Compromised oxidative phosphorylation and therefore decreased ATP synthesis. Without ATP to perform work, membrane permeability increases and cells/organelles swell
How can reperfusion of hypoxic tissue with blood cause additional injury to the cell?
- more free radical formation with sudden onset of oxygen and oxidative phosphorylation
- inflammation
- calcium from reestablished blood flood enters and damages injured cells
Most calcium is sequestered in the mitochondria and endoplasmic reticulum of cells and maintained at very low levels. Reperfusion of hypoxic tissue can result in calcium entering injured cells, causing further damage by activating what?
- phospholipases (degrading lipid membranes)
- proteases (degrading enzymes and cell structures)
- ATPases (inhibiting oxidative phosphorylation)
- endonucleases (breaking peptide bonds)
Exposure to free radicals can cause cell injury. What are some ways that we can be exposed?
- radiation
- enzymatic metabolism
- redox reactions
- transition metals (iron, copper)
- products of lipid oxidation
How are free radicals removed or degraded?
by spontaneous decay and/or action of enzymes.
What are common causes of alterations to membrane permeability after cell injury?
- ATP depletion
- activation of phospholipases
- direct damage to the membrane
Irreversible damage to the mitochondria leads to:
Cell death
What is considered to be the indicator for severe cell injury and death?
Increased serum enzyme levels due to altered membrane homeostasis and permeability
Necrosis
Pattern of change as a cell dies after injury
self-digestion by enzymes derived from
lysosomes within the injured cell
Intrinsic (autolysis) denaturation
digestion of cell components by enzymes derived from inflammatory leukocytes
Extrinsic (heterolysis) denaturation
Characteristic features of necrosis include:
- cell swelling
- disruption of organelles
- consumption of glycogen
What is considered the “hallmark” of cell death
Nuclear changes
Shrinking and increased basophilic staining of the nucleus on light microscopy
Pyknosis
fragmentation and breakdown of nuclei
Karyorrhexis
dissolution of nucleus
Karyolysis
What kind of necrosis is characterized by predominantly cytoplasmic proteins being denatured?
Coagulation necrosis
Where is coagulation necrosis commonly seen?
most “solid” organs (heart, kidney, muscle, adrenal, etc.).
In what type of necrosis is the cell outline and the basic tissue architecture preserved for a time before being removed? (Sometimes referred to as “fried egg whites” appearance)
Coagulation
bacterial abscesses and infarcts of soft tissues lead to what type of necrosis?
Liquefaction necrosis
In what type of necrosis is tissue rapidly destroyed by autolysis mechanisms and debris removed? (Often a fluid filled cavity forms at site of destruction)
Liquefaction necrosis
Type of necrosis where damaged tissue becomes “cheesy” in appearance
Caseous necrosis
What are common causes of caseous necrosis?
TB
Leprosy
Caseous necrosis is considered to be a combination of what types of necrosis?
Coagulation and liquefaction
What characterized fat necrosis?
Saponification caused by hydrolysis of lipid deposits in adipose tissue combining with calcium to form soaps which appear as chalky white deposits
Enzymatic fat necrosis is characteristic of:
Acute pancreatitis
inflammation and the formation of dense fibrous tissue deposits in subcutaneous adipose tissue (especially breast)
Traumatic fat necrosis
Type of necrosis where vascular or perivascular tissues are injured and blood vessels become more permeable to plasma proteins producing characteristic deposits
Fibrinoid necrosis
What are some causes of fibrinoid necrosis?
- malignant HTN
- vasculitis
- immune complex disease
Type of necrosis characterized by chronic, nodular and potentially deforming fibrotic scars
Gummatous necrosis
When does gummatous necrosis occur?
During tertiary stage of syphillis
coagulation necrosis that is modified by bacterial activity
Gangrene
Where is gangrene most common?
in an extremity that has lost its blood supply
Type of gangrene where coagulation predominates and affected tissues dry out before significant bacterial infections are established
Dry gangrene (mummification)
What causes dry gangrene?
Frostbite
Infarctions
Type of gangrene where liquefaction predominates and affected tissues become soft
Wet (moist) gangrene
Wet (moist) gangrene can be caused by:
- arterial occlusion with deep infarcts of an extremity
- intestinal infarcts
- acute appendicitis
- cholecystitis
Type of gangrene that occurs in deep, blood-deprived wounds (aerobic conditions) contaminated with anaerobic bacteria that produce gas
Gas (infectious) gangrene
Gas (infectious) gangrene is caused by:
- compound fracture
- contamination of surgical site or other deep wound
Programmed cell death is called
Apoptosis
How is programmed cell death different from cell death due to injury?
Cell membranes do not rupture and no inflammation
What are the steps of apoptosis?
- Chromatin condenses
- This aggregation leads to karyorrhexis of nucleus
- cell continue to shrink into apoptosis bodies
- these are consumed by phagocytes
Apoptosis is a regulated process to eliminate cells that are no longer required. What can cause it?
- diminished growth factors or hormones
- activated genetic mechanisms that identify abnormal cells
Examples of apoptosis
- Involution of hormone-dependent tissues (e.g.
endometrium, post-lactating breast) - tissue remodeling
- destruction of neutrophils and eosinophils
It has been reported that cyclic overload of tendons
activates stress-activated protein kinases in tendon fibroblasts causing some of these cells to ________. Consequently, collagen synthesis and repair responses are diminished which lead to weakening of the collagenous matrix and increased risk for tearing.
undergo apoptosis
ATP is depleted in muscle causing actin-myosin bonds to lock up in what post-Mortem change
Rigor mortis
What is algor mortis
Cooling of body core temperature
The post-Mortem change where the color of skin changes due to pooling of blood causing staining with hemoglobin derivatives
Livor mortis
A group of disorders characterized by alterations of organelles and the cytoskeleton
Subcellular alterations
a type of subcellular alteration where damaged cell components are taken up by autophagosomes and lipid products accumulate in residual bodies
Autophagocytosis
What is lipofuscin?
The lipid accumulations in residual bodies during autophagocytosis that is common during aging and chronic degenerative disease
A type of subcellular alteration where there is expansion of the smooth endoplasmic reticulum (SER) of hepatocytes
Induction
prolonged exposure to chemicals and
drugs metabolized by the P-450 centered mixed function oxidase of the SER will cause what kind of subcellular alteration? Why?
Induction (expansion), because it increases the capacity of the liver to metabolize a variety of agents including barbiturates, steroids, certain carcinogens, alcohol, CCl4, bilirubin, and bile acids.
Abnormalities of the cytoskeleton affect functions that include:
phagocytosis, locomotion, movement of organelles and ciliary activity
hereditary spherocytosis, Kartagener’s syndrome and leukocyte defects all have abnormalities of what?
Cytoskeleton
Substances that cannot otherwise be mobilized or excreted from the cell are stores in ________ or other sytoplasmic structures.
Lysozyme
What are common causes of storage disorders?
- metabolism inadequate to remove
- abnormal endogenous (internal origin) substances
- congenital enzyme abnormality
- abnormal exogenous (external origin) substance
Accumulation of lipids in parenchymal cells of organs associated with lipid metabolism.
Fatty metamorphosis (steatosis, fatty “change”)
Fatty metamorphosis is common in where?
Liver due to alcohol abuse, diabetes, obesity
Fatty metamorphosis is less common where?
Heart, muscle and kidney
Lipid accumulation in hepatocytes can be caused by:
- obesity
- alcohol abuse
- diabetes
- kwashiorkor (protein deficiency due to malnourishment)
- toxic injury
- liver infection
What are the gross changes associated with fatty liver?
- enlargement, softening and yellowing of liver
- blunting of liver margins
What are the pathogenic mechanisms of fatty change in the liver?
- hyperlipidemia
- excess FA synthesis
- impaired FA oxidation
- excess esterification of FA to TG
- apoprotein insufficiency
- failure to secrete lipoproteins
What is adiposity?
Stromal infiltration of fat
What are common locations of adiposity?
- lymph nodes
- pancreas
- right ventricle and atria
Chronic hypoxia (anemia) to the heart causes fatty deposits in what kind of pattern?
Triggered effect - alternating yellow (fat) and red (muscle) bands of tissue
Profound hypoxia and myocardial infections (such as diphtheria) cause what kind of pattern of fat deposits?
Uniform
Clusters of lipid-containing macrophages- common in dermis and tendons and associated with hyperlipidemia.
Xanthoma
Intimal plaques consisting of lipid deposits (chiefly
cholesterol and its esters) in large-medium arteries
Atherosclerosis
Atherosclerosis causes luminal narrowing and promotes ______.
Thrombosis
What is associated with cherry red spots of the macula and neurological deterioration and eventual death of infants?
Tay Sachs disease, a lysosomal storage disease
What lysosomal storage disease is associated with a deficiency in hexosaminidase A with causes accumulation of ganglioside (the brain is affected since gangliosides are metabolized in nerve tissue)?
Tay Sachs disease
What lysosomal storage disease is associated with a deficiency in sphingomyelinase casusing sphingomyelin and cholesterol to accumulate in macrophages and in neurons?
Niemann - Pick disease
What is associated with cherry red spots of the macula, hepatospelnomegaly and infant death?
Niemann-pick disease
What lysosomal storage disease is associated with a deficiency in glucocerebrosidase and causes accumulation of glucocerebroside
(typically in macrophages)?
Gaucher’s disease
Synthesis of excessive quantities of immunoglobulins (Ig) by
plasma cells may give rise to large proteinaceous deposits known as Russell bodies that accumulate in the endoplasmic reticulum in what condition?
Multiple myeloma (plasma cell neoplasms)
What condition is characterized by swelling, homogenous appearance, and increased fragility of affected segments of skeletal muscle due to hyaline accumulation?
“Zenker’s hyaline degeneration” (a segmental necrosis of skeletal muscle)
Accumulated cytoplasmic fibrils (intermediate filaments) and ubiquitin in injured hepatocytes, often associated with alcohol abuse
Mallory bodies
Lewy bodies are associated with what neurodegenerative disease?
Parkinson’s
Neurofibrillary tangles are associated with what neurodegenerative diseases?
Alzheimer’s and Huntington’s
CDJ and mad cow disease are associated with accumulation of what?
Abnormally folded prion proteins
α1 antitrypsin deficiency, cystic fibrosis, familial hypercholesterolemia are all associated with what?
Defective transport and secretion of critical proteins (enzymes, receptors, etc.)
Crooke’s hyaline are accumulated intermediate filaments in pituitary basophils in what disease?
Cushing’s
What are the proteins that participate in activities of normal cells, including protein folding, disaggregation and intracellular transport? May minimize lethal injury during ischemia and reperfusion.
Chaperonins
What proteins have a role in refolding denatured proteins or they may participate in the removal or sequestration of damaged components in certain cells undergoing chronic stress?
Ubiquitin
A meshwork of fibrils comprised of peptides arranged in a beta-pleated sheet pattern that are deposited in organs and tissues?
Amyloid
Amyloid light chain is associated with what amyloidosis?
Multiple myeloma
Amyloid associated protein is associated with what kinds of amyloidoses?
- Chronic inflammatory conditions such as RA, Crohn’s
- Infectious conditions such as TB, leprosy, osteomyelitis, etc.
What condition consists of deposits of a modified prealbumin (transthyretin) in peripheral nerves?
Familial amyloid polyneuropathy
Cardiac amyloid are associated with what kind of symptoms?
Irregular heartbeat, ventricular dysfunction and cardiomegaly
Beta2-microglobulin amyloidosis what cause what?
Chronic renal failure needing long term dialysis
Amyloid deposits in the pancreatic islets will result in?
Type 2 diabetes
What is the treatment for amyloidosis?
amyloidosis is incurable but procedures that decrease the proteins that make up amyloid and control underlying contributing diseases may be useful. Conservative therapies might employ anti- inflammatory agents, dietary choices and supplements.
What glycogen storage disorder is caused by a deficiency of glucose-6-phosphatase?
Von Gierke’s disease
How do children with von Gierke’s disease present?
Enlarged liver with a protruding abdomen and failure to thrive
What glycogen storage disorder is caused by a defect in alpha1-glucosidase (a lysosomal enzyme) that affects the striated muscle?
Pompe’s disease
In persistent hyperglycemia (severe diabetes mellitus), it is
common to see glycogen deposits where?
adjacent to the nuclei of hepatocytes, ß-cells, renal tubular cells and myocardial cells
Tumors of melanocytes?
Pigmented nevi or moles
The principal pigment of skin consisting largely of
tyrosine derivatives, that is synthesized in melanocytes by tyrosinase-dependent pathways. =
Melanin
Congenital lack of melanin in variable patterns that affect skin, hair, and in some, the eyes
Albinism
Acquired patchy areas of skin depigmentation
Vitiligo
Condition with increased ACTH due to primary
insufficiency of the adrenal cortex that causes hyperpigmentation of the skin
Addison’s disease
Melanin in the urine indicates what?
Extensive malignant melanoma
tissue discoloration secondary to accumulated homogentisic acid.
Ochronosis
Increased homogentistic acid in urine, giving it a black color?
Alkaptonuria
The stainable form of iron is a complex of protein and ferric ions called?
Hemosiderin
Ferrous iron in heme groups (hemoglobin, myoglobin, cytochromes) does not stain. Neither does ferritin
iron accumulates in macrophages with little effect on parenchymal cells
Hemosiderosis
Iron accumulation that eventually causes parenchymal (organ) damage
Hemochromatosis
The type of hemochromatosis that is associated with congenital gene defects that regulate intestinal absorption of iron; consequently iron is absorbed excessively.
Primary hemochromatosis
Type of hemochromatosis that results from chronic hemolytic disorders and/or multiple transfusions?
Secondary hemochromatosis
What is the classic “triad” manifestations of hemochromatosis?
- cirrhosis
- pancreatic fibrosis
- bronzed skin
tissue discoloration due to bilirubin excess
Jaundice
brown-colored undigestible lipid derivatives that accumulate during aging or during atrophy/chronic injury (AKA aging or wear and tear pigment)
Lipofuscin
Ingestion of lead produces a lead-sulfide line where?
Gingival margin
What effects are most concerning with lead pigment deposits?
Can cause issues with CNS development
What is the most common exogenous pigmentation?
Carbon, which is picked up by and stored by macrophages
excess deposits of copper that affects the liver, basal ganglia and eyes (Kayser-Fleischer ring) is called what?
Wilson’s disease
Two main patterns of tissue calcification?
- amorphous calcium salts
- organized bone (pathologic ossification)
The pathogenesis of tissue calcification involves two steps?
- initiation/nucleation: critical step where deposits for crystallized nuclei
- growth/accretion: the deposition of calcium continues one initiated
What type of calcification occurs locally in diseased, injured or necrotic tissue where serum calcium and phosphorus levels are normal.
Dystrophic calcification
Within cells, ________ are usually the first to calcify
mitochondria
When calcium salts are complexed with coagulation factors. Include hematomas, blood clots (“phleboliths”), atherosclerotic plaques and valvular lesions, old scars, TB lesions, necrotic tissues, etc.
Extracellular calcification
What often calcifies during menopause?
Uterine fibroids
What is a lithopedion?
A calcified fetus
What kind of calcification occurs in normal tissues in association with hypercalcemia?
Metastatic calcification
Where do metastatic calcification predictably occur?
pulmonary alveoli, gastric
hypercalcemia. mucosa (near parietal cells), small blood vessels and basement membranes of certain renal tubules.
What can cause hypercalcemia?
- Increased secretion of parathyroid hormone (tumor)
- Destruction of bone tissue (multiple myeloma/metastasis)
- Increased bony remodeling (Paget’s disease)
- Increased Vitamin-D
- Renal failure
a condition marked by deposition of calcium salts in the skin
Calcinosis cutis
A condition marked by deposition of calcium deposits in connective tissue
Calcinosis interstitialis
Intraparenchymal cell triglycerides are deposited in hepatocytes in what condition?
Fatty metamorphosis of liver
Intraparenchymal cell triglycerides are deposited in myocardia in what condition?
“Thrush breast”
Focal deposits of lipid- containing macrophages in subcutaneous tissues, etc.
Xanthoma
Cholesterol and other lipid deposits in intima of arteries?
Atherosclerosis
Deposits of sphingomyelin in neurons and systemic macrophages occurs in what condition?
Niemann-Pick disease
Gangliosides deposit in neurons in what condition?
Tay Sachs
Ig is found in plasma cells form______.
Russell bodies
Protein inclusions formed in pituitary basophils are called ______ and are seen in what disease?
Crooke’s hyaline
Cushing’s disease
Protein inclusions in injured hepatocytes are called _______.
Mallory bodies
Deposits of complex insoluble protein materials that appear under a number of circumstances
Amyloidosis
Accumulated glycogen deposits in liver and kidney
Von Gierke’s disease
Accumulations of glycogen in
myocardium (lethal at early age)
Pompe’s disease
Hyperglycemia with glycogen deposits in hepatocytes and renal tubular epithelium
Diabetes mellitus
Diffuse deposits of melanin in skin and mucous membranes can be secondary to what conditions?
- Addison’s
- pregnancy
- functional basophilic adenoma of pituitary
Focal aggregates of pigmented melanocytes
Pigmented nevi
Ochronosis (tissue discoloration) cartilage deposits, discoloration of urine cause by deposits of homogentisic acid is called what?
Alkaptonuria
Accumulation of lipofuscin in cells of several tissues including heart, liver and brain are associated with ______
Ageing, chronic injury (“wear and tear”, “brown atrophy”)
Iron deposits in systemic macrophages
Hemosiderosis
Iron deposits in liver, pancreas and skin, joints and heart, etc.
Hemochromatosis (“bronze diabetes”)- severe iron storage disorder
Bilirubin accumulates in blood and tissue fluids, skin, sclera, etc.
Jaundice
Discolored lead deposits at gingival line, organ and neurological damage
Plumbism (exposure to lead)
Copper deposits in liver, basal ganglia and eye
Wilson’s disease
Somatic (fibroblasts) cells undergo a predetermined number of divisions (doublings) and this number is species specific. How many doublings of fibroblasts is normal for human adults?
50 doublings
Limitations in doubling capacity of a cell is known as:
Hayflick phenomenon
The Hayflick phenomenon implies that biological organisms are programmed to “wear out”. What are the proposed mechanisms of this:
- loss of chromosome telomeres
- “clock genes”
