Intracellular accumulations Flashcards
1
Q
Pathology of intracellular inclusions
A
- pathology: structural, biochemical, functional basis of disease
- core aspects: etiology, pathogenesis, morphologic changes, clinical manifestation
- cellular adaptations, reversible and irreversible cell injury, cell death
- stresses of different types mat induce changes in cells and tissues other than those typical changes
- metabolic derangements and sublethal chronic injury of cells may be associated with intracellular accumulation of various substances
- calcium is often deposited at sites of cell death
2
Q
intracellular accumulations
A
- accumulation of abnormal amounts of various substances in the cell: manifestation of abnormal cellular metabolism
- may be innocuous or injurious to the cell
- may be in cytoplasm, nucleus, within subcellular organelles (lysosomes)
- substances may be produced by the cell or produced elsewhere and taken up by the cell
- coneptually four main pathways leading to intracellular accumulations
3
Q
Abnormal metabolism
A
- Excess synthesis
- Decreased removal
- Examples: Steatosis/Fatty liver
4
Q
Defect in protein folding/ transport
A
Accumulation of abnormal endogenous substance due to genetic or acquired defects in
- Folding
- Packaging
- Transport
Example: mutated forms of alpha 1 anti-trypsin
5
Q
Lack of enzyme
A
- Failure to degrade a metabolite due to inherited enzyme deficiency
- Accumulation of endogenous material
- Example: storage disease
6
Q
Ingestion of indigestible materials
A
- Deposition and accumulation of abnormal exogenous substance
- When cell does not have enzymatic machinery to degrade the substance or ability to transport it elsewhere
- Example: carbon or silica
7
Q
Lipids
A
All major classes of lipids accumulate in cells
- Triglycerides (steatosis/fatty change)
- cholesterols/cholesterol esters (atherosclerosis)
- Phospholipids (myelin figures in necrotic cells)
8
Q
Steatosis/ Fatty Change
A
- Abnormal accumulation of TGs within parenchymal cells
- Liver is main organ involved in fat metabolism but can happen in heart, muscle, and kidneys
Causes:
-Toxins, protein malnutrition, diabetes, obesity, anoxia
- Most common causes in developed world is alcoholic or non alcoholic fatty liver disease
- Irreversible damage is cirrhosis
9
Q
Steatosis/fatty change morphology
A
- Macrovesicular steatosis: cytoplasmic large clear droplet that looks like adipocyte
- Microvesicular steatosis: fine vacuoles with foamy cytoplasm
- Fat is washed out in process of slide preparation
10
Q
Cholesterol and cholesterol esters
A
- Cell metabolism of cholesterol is highly regulated
- Used in synthesis of membranes
- Generally without intracellular accumulation
- Histologic morphology of cholesterol: intracytoplasmic vacuoles
11
Q
Atherosclerosis
A
Atheroclerotic plaques
- Smooth muscle cells and macrophages in surface/wall of arteries filled with lipid vacuoles
- Mostly cholesterol and cholesterol esters
- Aggregates give yellow appearance of atheromas
- Some may rupture and release lipids into extracellular space
- Extracellular cholesterol esters may crystallize into long needles called cholesterol clefts
12
Q
Xanthomas
A
- Macrophage intracellular accumulation of cholesterol due to acquired and hereditary hyperlipidemic states
- Groups of foamy macrophages found in connective tissue of skin and in tendons forming masses called xanthomas
- May also be seen in non-hyperlipidemic states
- -sporadic
13
Q
Gastric xanthoma
A
- Foamy macrophages and histiocytes in lamina propria
- Massive intracellular accumulation of cholesterol
14
Q
Cholesterolosis of gallbladder
A
- Focal accumulation of cholesterol containing macrophages in lamina propria of gall bladder
- Makes the cytoplasm look lighter than the normal pink that is seen
15
Q
Niemann-Pick disease Type C
A
- Lysosomal storage disease
- Mutations affecting enzyme involved in cholesterol trafficking
- Cholesterol accumulates in multiple organs
16
Q
Protein accumulations
A
- Usually rounded eosinophilic droplets (pink), vacuoles or aggregates in the cytoplasm
- Electron microscopy: amorphous, fibrillar, crystalline
- Some diseases (some amyloidoses): deposits mainly extracellular
- Diverse causes
17
Q
Renal Tubule resorption droplets
A
- Seen in kidney conditions that have protein loss in the urine (proteinuria)
- Normally small amounts of protein that filter through glomerulus are reabsorbed by the proximal tubular cells
- Heavy proteinuria → increased reabsorption of proteins into vesicles
- Protein has appearance of pink hyaline droplets within cytoplasm of proximal tubular cells
- Reversible process
18
Q
Normal secreted proteins that are produced in excess
A
- Certain plasm cells actively synthesizing immunoglobulins (areas in chronic inflammation, plasma cell neoplasms) may show Russell bodies
- ER becomes hugely distending: large eosinophilic cytoplasmic inclusions
19
Q
Russell Bodies
A
Large cytoplasmic protein droplets (in a plasma cell tumor)
20
Q
Alpha 1 anti-trypsin deficiency
A
- Defective intracellular transport and secretion of proteins
- Mutation in protein slows its folding → build up of partially folded intermediates which aggregate in ER of liver cells
- Results in deficiency in circulating enzyme causes emphysema of the lung
- May also be damage from the ER stress due to misfolded proteins
21
Q
Accumulation of cytoskeletal proteins
A
Certain forms of cell injury cause aggregation of keratin filaments and neurofilaments
22
Q
Alcoholic hyalin (Mallory Denk body)
A
- Eosinophilic cytoplasmic inclusion in liver cells
- Characteristic of alcoholic liver disease (but not specific)
- Composed of keratin intermediate filaments
Slide
- Arrows are clumped amorphous eosinophilic body in cytoplasm made of tangled keratin fibrils
- Inset is immunostain of keratins and clumped staining in the cytoplasm
23
Q
Neurofibrillary tangle
A
- Found in Alzheimer disease
- Contains neurofilaments and other proteins (tau)
- Eosinophilic clumped material can be in cytoplasm or extracellular
- Silver stain can show tange in neuron
- Immunohistochemistry can show tau tangle
24
Q
Hyaline
A
- Alteration in cellular or extracellular space that gives homogeneous glassy pink appearance on routine H and E
- Variety of pathologies can give rise to this appearance → not a specific pattern of accumulation
Intracellular
-Resorption of droplets, alcoholic, Russell bodies
Extracellular
- Arterioles in hypertension, diabetes
- Collagenous fibrous tissue in a scar
25
Glycogen
- Energy stored in cytoplasm of cell
- Excessive deposits may be seen with abnormal glucose and glycogen metabolism
- Glycogen accumulations appear clear
- Positive staining on PAS stain
- Diabetes
- Glycogen found in renal tubular cells, liver, heart cells
26
Glycogen storage diseases
- Glycogenoses
- Enzymatic defects in synthesis or breakdown in glycogen
- Causes of cell injury and cell death
- Examples: pope disease, von Gierke disease
27
Pigments
- Colored substances
- May be normal constituents (melanin)
- May be abnormal and accumulate in particular circumstances
- Exogenous (carbon)
- Endogenous (hemosiderin)
28
Carbon accumulation
- Most common exogenous pigment
- Air pollutant in urban areas
- Inhaled and picked up by alveolar macrophages → transported through lymphatic channels to regional lymph nodes
- Blackens lung and node tissues: anthracosis
- Heavy exposure may cause serious lung disease
29
Tattoos
- Localization of pigmentation of skin (bowel)
- In skin: pigment is phagocytosed by dermal macrophages
- Generally inert, not associated with inflammation
- May reside locally long term
30
Lipofuscin
- Endogenous pigment
- Wear and tear pigment
- Seen in cells undergoing slow regressive change
- Prominent in liver and heart of aging individuals or patients with severe malnutrition cancer cachexia (wasting)
- Insoluble polymers of lipids and phospholipids in complex proteins derived from breakdown of subcellular membranes
- Not harmful to cells
- May indicate cell exposure to free radical injury
31
Melanin
- Endogenous
- Brown or black
- Formed when enzyme tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes
32
Hemosiderin pigment
- Hemoglobin derived
- Major storage form of iron
- Golden yellow-brown granular or crystalline
- In circulation, iron is carried in transferrin and stored with apoferritin to form ferritin micelles in cells
- Local or systemic excess forms hemosiderin granules that can be seen by microscopy
33
Iron breakdown
Normal
-May be seen in sites where there is blood cell breakdown (bone marrow, spleen, liver)
Excess of iron breakdown
- Hemorrhage into tissues (bruise)
- Macrophages breakdown blood
- Remove iron → ferritin → hemosiderin
- Parallel breakdown of heme moiety: biliverdin (green bile) → bilirubin (red bile)
- Gives rise to multicolors of bruises
34
Hemosiderosis
- Systemic overload of iron
- Hemosiderin may be deposited in many tissues
Causes
- Increases absorption of iron (inborn error: hemochromatosis)
- Hemolytic anemias (premature lysis) → releases abnormal quantities of iron
- Repeated blood transfusion (exogenous administration of iron)
35
Dystrophic calcification
- Deposits of calcium locally in dying/abnormal tissue
- Typically serum calcium levels
- Typically calcium metabolism is normal
- May be seen in areas of tissue necrosis
- Usually present in atheromas of advanced atherosclerosis
- May be seen in ageing/damaged heart valves
- Psammoma and asbestos bodies
36
Psammoma bodies
- Necrotic cells can seed calcium deposition
- Subsequent deposition of additional layers of calcium gives a lamellated appearance
- Seen in tumors with papillary morphology
37
Asbestos bodies
- Deposition of calcium and iron salts on asbestos fibers
| - Beaded, dumbbell appearance
38
Metastatic calcification
Deposits of calcium in otherwise normal tissues
Usually associated with hypercalcemia, some abnormality in calcium metabolism
Four main causes
- Increased secretion of PTH with bone reabsorption
- Reabsorption of bone (tumors, skeletal metastases, accelerated turnover, Paget’s disease, immobilization)
- Vitamin D related disorders (intoxication, sarcoidosis)
- Renal failure (retention of phosphate → hyperparathyroidism)
- Other: mild alkali syndrome (ingestion of calcium and absorbable antacids)
- Particular sites: gastric mucosa, kidneys, lungs
- Usually does not cause clinical dysfunction
- Microscopically morphologically similar to dystrophic calcification
