9. Intracellular Accumulations And Pathologic Calcification Flashcards
List and define causes of intracellular accumulation and pathologic calcification (objective)
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Describe how intracellular accumulation can be associated with disease states (objective)
Answer later
Intracellular accumulations
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
Abnormal metabolism (pathway 1/4)
Excess synthesis
Decreased removal
Example: steatosis/fatty liver
Defect in protein folding/transport (pathway 2/4)
Accumulation of abnormal endogenous substance due to genetic or acquired defects in folding/packaging/transport
Example: mutated forms of alpha 1 anti-trypsin
Lack of enzyme (pathway 3/4)
Failure to degrade a metabolite due to inherited enzyme deficiency
Example: storage disorder (lysosomal- Tay Sach, Hunter Syndrome)
Ingestion of indigestible materials (pathway 4/4)
- 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)
Reversibility
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.
Lipids
- Triglycerides (steatosis/fatty change)
- Cholesterol/cholesterol esters (atherosclerosis)
- Phospholipids (myelin figures in necrotic cells)
Steatosis/Fatty Change
- 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)
Mechanism of fatty change
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
Steatosis/Fatty Change (histology)
Macrovesicular steatosis: cytoplasmic large clear droplets, look like adipocytes
Microvesicular steatosis: fine vacuoles, foamy cytoplasm
Fat washed out of tissue in slide preparation
Cholesterol and cholesterol esters
Cell metabolism is tightly regulated
Used for synthesis of cell membranes
In histology accumulation, see intracytoplasmic vacuolese
Atherosclerosis (in blood vessels and aorta)
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”)
Early atherosclerotic lesion: foam cells
Accumulating in subendothelial layer (white spots)
Xanthomas (in connective tissue)
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
Gastric xanthoma (histology)
Foamy macrophages in the lamina propria just beneath epithelial surface of gastric biopsy
(White spots)
Cholesterolosis (in gallbladder)
Focal accumulation of cholesterol containing macrophages in lamina propria of gallbladder
Niemann-Pick disease, Type C
Lysosomal storage disease
- Enzyme mutation for cholesterol trafficking
- Cholesterol bunches up in many organs
-Lysosomes are the waste disposal system of the cell
Protein accumulations
Usually rounded eosinophillic droplets, vacuoles, or aggregates in cytoplasm (PINK)
Amorphous, fibrillar, crystalline
Some diseases (amyloidosis): deposits mainly extracellular
Diverse causes
Renal tubule reabsorption droplets
- 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
Normal secreted proteins that are produced in excess
- 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
Russel bodies (histology)
Large pink droplets (example in a plasma cell tumor, myeloma)
Defective intracellular transport and secretion of protiens
-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
Alpha 1 anti-trypsin deficiency: liver (histology)
Liver parenchyma stained with PAS stain after diastase treatment:
Magenta-colored cytoplasmic inclusions
Represents aggregates of misfolded A1AT protein
Accumulation of cytoskeletal proteins
Certain forms of cell injury cause aggregation of keratin filaments and neurofilaments
- Alcoholic hyaline (Mallory Denk body)
- Neurofibrillary tangle
Alcoholic hyaline (Mallory Denk body)
-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
Neurofibrillary tangle
- Alzheimer disease
- Contains neurofilaments and other proteins like TAU, tau is a component of tangles
Histology: eosinophilic clumped, can be in cytoplasm or extracellular
Protein aggregation may lead to ER stress
Excess misfolded proteins leads to ER stress:
- Failure to adapt- apoptosis
- Adapt- unfolded protein response (decreased protein synthesis, increased production of chaperones)
‘Hyaline”
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
Arteriolar hyaline (histology)
Extracellular hyaline; amorphous eosinophilic material in arteriolar wall
Glycogen (1/2)
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
Glycogen (2/2)
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
Pigments
Colored substances Normal: melanin Abnormal: -Exogenous (carbon) -Endogenous (hemosiderin-iron accumulates)
Exogenous pigment: Carbon
- Coal dust, black lungs
- Inhaled, picked up by alveolar macrophages, transported through lymphatic channels to regional (tracheo-bronchial) lymph nodes
- Anthracosis (black lungs)
Exogenous pigment: Tattoo
- 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
Endogenous pigment: Lipofuscin
“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
Lipofuscin pigment (histology)
Yellow brown pigment, finely granular, cytoplasmic often perinuclear
Granules often around nucleus
Endogenous pigment: Melanin
Exogenous brown-black pigment
-formed when enzyme tyrosinase catalyzes tyrosine to dopa in melanocytes
Endogenous pigment: Hemosiderin
Hemoglobin-derived
- Storage of iron
- Golden yellow-brown granular or crystalline
Iron metabolism
- In circulation, iron normally carried by transferrin
- In cells, iron stored with apoferritin to form ferritin micelles (in most cells)
- Local or systemic excess of iron, ferratin forms hemosiderin granules (bunches of ferritin micelles)
Normal iron breakdown
In sites where there is red blood cell breakdown (bone marrow, spleen, liver)
Local excess of iron breakdown
- 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)
Hemosiderosis
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)
Hemosiderosis in Liver (histology)
Liver parenchyma: special stain for iron (Prussian blue stain)
Iron stained blue
Pathologic Calcification
Abnormal deposits of calcium salts
- Dystrophic: deposits of calcium locally in dying/abnormal tissue, typical serum calcium levels, calcium metabolism normal.
- Metastatic: deposits in otherwise normal tissue, hypercalcemia and some abnormality in calcium metabolism
Dystrophic Calcification
- may be seen in tissue necrosis
- usually in atheromas of advanced atherosclerosis
- may be seen in ageing/damaged heart valves
- “Psammoma bodies”
- “Asbestos bodies”
Cardiac valves with calcification
Fine white granules, may be clumped, gritty to touch or to cut
Calcification: microscopic appearance
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)
Psammoma Bodies
- 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
Asbestos Bodies
- Deposition of calcium and iron salts on asbestos fibers
- Beaded, dumbbell appearance
Metastatic Calcification
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)
Metastatic Calcification (general)
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)
