Intracellular accumulations

Question 1

Pathology of intracellular inclusions

Answer 1

• 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

Question 2

intracellular accumulations

Answer 2

• 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

Question 3

Abnormal metabolism

Answer 3

• Excess synthesis
• Decreased removal
• Examples: Steatosis/Fatty liver

Question 4

Defect in protein folding/ transport

Answer 4

Accumulation of abnormal endogenous substance due to genetic or acquired defects in

• Folding
• Packaging
• Transport

Example: mutated forms of alpha 1 anti-trypsin

Question 5

Lack of enzyme

Answer 5

• Failure to degrade a metabolite due to inherited enzyme deficiency
• Accumulation of endogenous material
• Example: storage disease

Question 6

Ingestion of indigestible materials

Answer 6

• 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

Question 7

Lipids

Answer 7

All major classes of lipids accumulate in cells

• Triglycerides (steatosis/fatty change)
• cholesterols/cholesterol esters (atherosclerosis)
• Phospholipids (myelin figures in necrotic cells)

Question 8

Steatosis/ Fatty Change

Answer 8

• 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

Question 9

Steatosis/fatty change morphology

Answer 9

• 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

Question 10

Cholesterol and cholesterol esters

Answer 10

• Cell metabolism of cholesterol is highly regulated
• Used in synthesis of membranes
• Generally without intracellular accumulation
• Histologic morphology of cholesterol: intracytoplasmic vacuoles

Question 11

Atherosclerosis

Answer 11

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

Question 12

Xanthomas

Answer 12

• 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

Question 13

Gastric xanthoma

Answer 13

• Foamy macrophages and histiocytes in lamina propria

- Massive intracellular accumulation of cholesterol

Question 14

Cholesterolosis of gallbladder

Answer 14

• Focal accumulation of cholesterol containing macrophages in lamina propria of gall bladder
• Makes the cytoplasm look lighter than the normal pink that is seen

Question 15

Niemann-Pick disease Type C

Answer 15

• Lysosomal storage disease
• Mutations affecting enzyme involved in cholesterol trafficking
• Cholesterol accumulates in multiple organs

Question 16

Protein accumulations

Answer 16

• 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

Question 17

Renal Tubule resorption droplets

Answer 17

• 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

Question 18

Normal secreted proteins that are produced in excess

Answer 18

• 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

Question 19

Russell Bodies

Answer 19

Large cytoplasmic protein droplets (in a plasma cell tumor)

Question 20

Alpha 1 anti-trypsin deficiency

Answer 20

• 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

Question 21

Accumulation of cytoskeletal proteins

Answer 21

Certain forms of cell injury cause aggregation of keratin filaments and neurofilaments

Question 22

Alcoholic hyalin (Mallory Denk body)

Answer 22

• 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

Question 23

Neurofibrillary tangle

Answer 23

• 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

Question 24

Hyaline

Answer 24

• 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

Question 25

Glycogen

Answer 25

• 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

Question 26

Glycogen storage diseases

Answer 26

• Glycogenoses
• Enzymatic defects in synthesis or breakdown in glycogen
• Causes of cell injury and cell death
• Examples: pope disease, von Gierke disease

Question 27

Pigments

Answer 27

• Colored substances
• May be normal constituents (melanin)
• May be abnormal and accumulate in particular circumstances
• Exogenous (carbon)
• Endogenous (hemosiderin)

Question 28

Carbon accumulation

Answer 28

• 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

Question 29

Tattoos

Answer 29

• 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

Question 30

Lipofuscin

Answer 30

• 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

Question 31

Melanin

Answer 31

• Endogenous
• Brown or black
• Formed when enzyme tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes

Question 32

Hemosiderin pigment

Answer 32

• 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

Question 33

Iron breakdown

Answer 33

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

Question 34

Hemosiderosis

Answer 34

• 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)

Question 35

Dystrophic calcification

Answer 35

• 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

Question 36

Psammoma bodies

Answer 36

• Necrotic cells can seed calcium deposition
• Subsequent deposition of additional layers of calcium gives a lamellated appearance
• Seen in tumors with papillary morphology

Question 37

Asbestos bodies

Answer 37

• Deposition of calcium and iron salts on asbestos fibers

- Beaded, dumbbell appearance

Question 38

Metastatic calcification

Answer 38

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