9. Intracellular Accumulations And Pathologic Calcification

Question 1

List and define causes of intracellular accumulation and pathologic calcification (objective)

Answer 1

Answer later

Question 2

Describe how intracellular accumulation can be associated with disease states (objective)

Answer 2

Answer later

Question 3

Intracellular accumulations

Answer 3

Abnormal cellular metabolism result
Can be bad for cell
Can be in cytoplasm, nucleus, in lysosomes
Can be produced by cell or taken up in cell
4 main pathways

Question 4

Abnormal metabolism (pathway 1/4)

Answer 4

Excess synthesis
Decreased removal

Example: steatosis/fatty liver

Question 5

Defect in protein folding/transport (pathway 2/4)

Answer 5

Accumulation of abnormal endogenous substance due to genetic or acquired defects in folding/packaging/transport

Example: mutated forms of alpha 1 anti-trypsin

Question 6

Lack of enzyme (pathway 3/4)

Answer 6

Failure to degrade a metabolite due to inherited enzyme deficiency

Example: storage disorder (lysosomal- Tay Sach, Hunter Syndrome)

Question 7

Ingestion of indigestible materials (pathway 4/4)

Answer 7

• Deposition and accumulation of abnormal exogenous substance.
• When cell does not have enzymatic machinery to degrade the substance or ability to transport to other sites.

Example: carbon or silica accumulation (in lung)

Question 8

Reversibility

Answer 8

Accumulation reversible if overload stopped or controlled (early atherosclerosis, steatosis/fatty change)
In inherited storage disorders, can have cellular injury and lead to death of tissue or patient.

Question 9

Lipids

Answer 9

1. Triglycerides (steatosis/fatty change)
2. Cholesterol/cholesterol esters (atherosclerosis)
3. Phospholipids (myelin figures in necrotic cells)

Question 10

Steatosis/Fatty Change

Answer 10

• TG accumulation in parenchymal cells
• Mostly in liver, but also heart, muscle, kidneys
• Causes: toxins, protein malnutrition, diabetes, obesity, anoxia
• Liver steatosis causes: alcoholic liver disease, non-alcoholic fatty liver disease (diabetes/obesity)

Question 11

Mechanism of fatty change

Answer 11

Hepatocellular steatosis caused by:
1. Shunting of normal substates away from breakdown and towards lipid synthesis
2. Impaired assembly and secretion of lipoproteins
3. Increased peripheral catabolism of fat, releasing free fatty acids into blood
Irreversible: leads to cirrhosis

Question 12

Steatosis/Fatty Change (histology)

Answer 12

Macrovesicular steatosis: cytoplasmic large clear droplets, look like adipocytes
Microvesicular steatosis: fine vacuoles, foamy cytoplasm

Fat washed out of tissue in slide preparation

Question 13

Cholesterol and cholesterol esters

Answer 13

Cell metabolism is tightly regulated
Used for synthesis of cell membranes
In histology accumulation, see intracytoplasmic vacuolese

Question 14

Atherosclerosis (in blood vessels and aorta)

Answer 14

Atherosclerotic plagues:

• Smooth muscle cells and macrophages in surface/wall of arteries filled with lipid vacuoles
• Mostly cholesterol and esters
• Foam cell (foamy macrophages) aggregates in surface/wall of vessel give yellow appearance
• Some can rupture releasing lipids into extracellular space
• Extracellular cholesterol esters may crystallize as long needles (“cholesterol clefts”)

Question 15

Early atherosclerotic lesion: foam cells

Answer 15

Accumulating in subendothelial layer (white spots)

Question 16

Xanthomas (in connective tissue)

Answer 16

Macrophage intracellular accumulation of cholesterol is characteristic of acquired and hereditary hyperlipidemic states

• Groups of foamy macrophages found in connective tissue of skin and in tendons forming masses
• Can be seen in non-hyperlipidemic states

Question 17

Gastric xanthoma (histology)

Answer 17

Foamy macrophages in the lamina propria just beneath epithelial surface of gastric biopsy
(White spots)

Question 18

Cholesterolosis (in gallbladder)

Answer 18

Focal accumulation of cholesterol containing macrophages in lamina propria of gallbladder

Question 19

Niemann-Pick disease, Type C

Answer 19

Lysosomal storage disease

• Enzyme mutation for cholesterol trafficking
• Cholesterol bunches up in many organs

-Lysosomes are the waste disposal system of the cell

Question 20

Protein accumulations

Answer 20

Usually rounded eosinophillic droplets, vacuoles, or aggregates in cytoplasm (PINK)
Amorphous, fibrillar, crystalline
Some diseases (amyloidosis): deposits mainly extracellular

Diverse causes

Question 21

Renal tubule reabsorption droplets

Answer 21

• In kidney conditions that have protein loss in urine (proteinuria)
• Normal: protein that filter through glomerulus are reabsorbed by proximal tubular cells
• Heavy proteinuria: increased reabsorption of protein into vesicles (reversible)
• Protein appears like pink hyaline droplets in cytoplasm of proximal tubular cells

Question 22

Normal secreted proteins that are produced in excess

Answer 22

• Certain plasma cells actively synthesizing immunoglobulins (in areas of chronic inflammation, plasma cell neoplasms) may show Russell Bodies
• ER becomes hugely distended: large eosinophillic cytoplasmic inclusions

Question 23

Russel bodies (histology)

Answer 23

Large pink droplets (example in a plasma cell tumor, myeloma)

Question 24

Defective intracellular transport and secretion of protiens

Answer 24

-Alpha 1 anti-trypsin deficiency: mutation in protein slows its folding leading to build up of partially folded intermediates which aggregate in the ER of liver cells and are not secreted
(Resulting deficiency in circulating enzyme caused lung emphysema)
-May also be damage from ER stress due to misfolded proteins

Question 25

Alpha 1 anti-trypsin deficiency: liver (histology)

Answer 25

Liver parenchyma stained with PAS stain after diastase treatment: Magenta-colored cytoplasmic inclusions Represents aggregates of misfolded A1AT protein

Question 26

Accumulation of cytoskeletal proteins

Answer 26

Certain forms of cell injury cause aggregation of keratin filaments and neurofilaments 1. Alcoholic hyaline (Mallory Denk body) 2. Neurofibrillary tangle

Question 27

Alcoholic hyaline (Mallory Denk body)

Answer 27

-Eosinophilic cytoplasmic inclusion in liver cells -Characteristic of alcoholic liver disease (but not specific) -Composed of keratin intermediate filaments Histology: clumped amorphous pink body, tangled keratin fibrils, cytoplasmic location

Question 28

Neurofibrillary tangle

Answer 28

- Alzheimer disease - Contains neurofilaments and other proteins like TAU, tau is a component of tangles Histology: eosinophilic clumped, can be in cytoplasm or extracellular

Question 29

Protein aggregation may lead to ER stress

Answer 29

Excess misfolded proteins leads to ER stress: 1. Failure to adapt- apoptosis 2. Adapt- unfolded protein response (decreased protein synthesis, increased production of chaperones)

Question 30

'Hyaline"

Answer 30

Morphological term, descriptive term - alteration in cellular or extracellular space that gives homogenous glassy pink appearance on H+E sections 1. Intracellular: reabsorption droplets, alcoholic hyaline, Russell bodies 2. Extracellular: arterioles in hypertension/diabetes, collagenous fibrous tissue in scar

Question 31

Arteriolar hyaline (histology)

Answer 31

Extracellular hyaline; amorphous eosinophilic material in arteriolar wall

Question 32

Glycogen (1/2)

Answer 32

Energy source stored in cytoplasm - excessive with abnormal glucose or glycogen metabolism - glycogen dissolves in aqueous fixatives so glycogen accumulations appear CLEAR - positive stain on PAS stain (PAS +) - Diabetes- glycogen found in kidney, liver, heart cells

Question 33

Glycogen (2/2)

Answer 33

Glycogen storage diseases (glycogenoses) - enzyme problem in synthesis/breakdown of glycogen - massive accumulation of glycogen - causes cell injury or death - Pompe and von Gierke disease

Question 34

Pigments

Answer 34

``` Colored substances Normal: melanin Abnormal: -Exogenous (carbon) -Endogenous (hemosiderin-iron accumulates) ```

Question 35

Exogenous pigment: Carbon

Answer 35

- Coal dust, black lungs - Inhaled, picked up by alveolar macrophages, transported through lymphatic channels to regional (tracheo-bronchial) lymph nodes - Anthracosis (black lungs)

Question 36

Exogenous pigment: Tattoo

Answer 36

- Localized pigmentation of skin or bowel - In skin, pigment phagocytosed by dermal macrophages - Generally inert, not associated with inflammation - Reside locally long term * Surgeons use this to aid later surgery

Question 37

Endogenous pigment: Lipofuscin

Answer 37

"Wear-and-tear" - cells undergoing slow regressive change - liver and heart of aging people or patients with severe malnutrition cancer cachexia (wasting) - Insoluble polymers of lipids and phospholipids in complex with proteins (from membranes) - Not harmful - May indicate exposure to free radical injury

Question 38

Lipofuscin pigment (histology)

Answer 38

Yellow brown pigment, finely granular, cytoplasmic often perinuclear Granules often around nucleus

Question 39

Endogenous pigment: Melanin

Answer 39

Exogenous brown-black pigment | -formed when enzyme tyrosinase catalyzes tyrosine to dopa in melanocytes

Question 40

Endogenous pigment: Hemosiderin

Answer 40

Hemoglobin-derived - Storage of iron - Golden yellow-brown granular or crystalline

Question 41

Iron metabolism

Answer 41

1. In circulation, iron normally carried by transferrin 2. In cells, iron stored with apoferritin to form ferritin micelles (in most cells) 3. Local or systemic excess of iron, ferratin forms hemosiderin granules (bunches of ferritin micelles)

Question 42

Normal iron breakdown

Answer 42

In sites where there is red blood cell breakdown (bone marrow, spleen, liver)

Question 43

Local excess of iron breakdown

Answer 43

- Hemorrhage into tissue (skin bruise) - Macrophages breakdown blood - Removal of iron to ferritin to hemosiderin - Parallel breakdown of heme moiety: biliverdin (green bile) to bilirubin (red bile) - Gives rise to multicolors of reabsorbing bruise (red blue, green blue, golden yellow)

Question 44

Hemosiderosis

Answer 44

Systemic overload of iron Causes: 1. Increased absorption of dietary iron (hemochromatosis) 2. Hemolytic anemias (premature lysis of rbc's, releases abnormal amounts of iron 3. Repeated blood transfusions (like exogenous administration of iron)

Question 45

Hemosiderosis in Liver (histology)

Answer 45

Liver parenchyma: special stain for iron (Prussian blue stain) Iron stained blue

Question 46

Pathologic Calcification

Answer 46

Abnormal deposits of calcium salts 1. Dystrophic: deposits of calcium locally in dying/abnormal tissue, typical serum calcium levels, calcium metabolism normal. 2. Metastatic: deposits in otherwise normal tissue, hypercalcemia and some abnormality in calcium metabolism

Question 47

Dystrophic Calcification

Answer 47

- may be seen in tissue necrosis - usually in atheromas of advanced atherosclerosis - may be seen in ageing/damaged heart valves - "Psammoma bodies" - "Asbestos bodies"

Question 48

Cardiac valves with calcification

Answer 48

Fine white granules, may be clumped, gritty to touch or to cut

Question 49

Calcification: microscopic appearance

Answer 49

Basophilic (purple), amorphous granular, may be clumped Can be extracellular or intracellular or both -Heterotopic bone may form in long-standing areas of calcification (bone forming where it shouldn't)

Question 50

Psammoma Bodies

Answer 50

- Necrotic cells can seed calcium deposition - Subsequent deposition of additional layers of calcium gives a lamellate appearance Example: papillary serous ovarian tumor In tumors with papillary morphology

Question 51

Asbestos Bodies

Answer 51

- Deposition of calcium and iron salts on asbestos fibers | - Beaded, dumbbell appearance

Question 52

Metastatic Calcification

Answer 52

In normal tissues whenever hypercalcemia. Causes: 1. Increased PTH with subsequent bone resorption (due to parathyroid tumors) 2. Resorption of bone (tumors: myeloma, leukemia, extensive skeletal metastases; accelerated turnover: Paget's disease; immobilization) 3. Vitamin D disorders (Vit D intoxication, sarcoidosis)+William's syndrome (hypercalcemia in infancy, sensitivity to Vitamin D) 4. Renal failure (renal failure to retention of phosphate to hyperparathyroidism) Other: milk-alkali syndrome (excessive ingestion of calcium and absorbable antacids (mild or calcium phosphate)

Question 53

Metastatic Calcification (general)

Answer 53

Particular sites include gastric mucosa, kidneys, lungs (all of these secrete acid and have an internal alkaline compartment that is predisposed to calcification) - microscopically similar to dystrophic - usually does not cause clinical dysfunction (unless massive deposition in lungs or kidney)