Lecture 29 Flashcards
Cell Stress - Aging, Injury, Adaptation, Death: Intracellular Accumulations
four main mechanisms leading to abnormal intracellular accumulations
- Inadequate removal of a normal substance secondary to defects in packaging and transport, as in fatty change (steatosis) in the liver
- Accumulation of an endogenous substance as a result of genetic or acquired defects in its folding, packing, transport, or secretion, as with certain mutated forms of α1-antitrypsin
- Failure to degrade a metabolite due to inherited enzyme deficiencies, typically lysosomal enzymes. The resulting disorders are called lysosomal storage diseases
- Deposition and accumulation of an abnormal exogenous substance when the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Accumulation of carbon or silica particles is an example of this type of alteration
pg 710
pigments
- colored substances, some of which are normal constituents of cells (ex: melanin)
- others are abnormal and originating outside the body
- exogenous pigments: originating outside the body
- endogenous pigments: synthesized within the body
pg 711
exogenous pigments
- most common: carbon (coal dust) -> air pollutant in urban areas
- when carbon is inhaled, it is picked up by macrophages within the alveoli and transported through lymphatic channels to lymph nodes
- accumulations of carbon blacken the tissues of the lungs (anthracosis) and the involved lymph nodes
- if severe enough, could cause a fibroblastic reaction or even emphysema -> coal worker’s pneumoconiosis
tattooing: localized, exogenous pigmentation of the skin; phagocytosed by dermal macrophages and remain for the rest of life; pigments do not usually evoke inflammatory response
pg 711
endogenous pigments
- lipofuscin is an insoluble pigment known as lipochrome or wear-and-tear pigment
- composed of polymers of lipids and phospholipids in complex with protein, suggesting that it is derived through lipid peroxidation of polyunsaturated lipids of intracellular membranes
- NOT injurious to cell or its functions; IS a sign of free radical injury and lipid peroxidation
- appears as a yellow-brown, finely granular cytoplasmic, often perinuclear, pigment
- seen in cells undergoing slow, regressive changes, especially in the liver and heart of aging patients or patients with severe malnutrition and cancer cachexia
pg 712
lipofuscin granules
small brown granules in the cytoplasm, but clustered close to the nucleus
(“free points”)
pg 713
melanin
the ONLY endogenous brown-black pigment -> formed when the enzyme tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes
homogenistic acid is a black pigment that occurs in patients with alkaptonuria (a rare metabolic disease) and is deposited in the skin, CT, and cartilage -> pigmentation known as ochronosis
pg 714
hemosiderin
- hemoglobin-derived, golden yellow-brown, granular, or crystalline pigment -> major storage form of iron
- stored in association with a protein (apoferritin) to form ferritin micelles
- ferritin forms hemosiderin granules when there is local or systemic excess of iron
- hemosiderin pigment represents aggregates of ferritin molecules
- under normal conditions, small amounts of hemosiderin can be seen in the mononuclear phagocytes of the bone marrow, spleen, and liver as breakdown products of RBCs
- local or systemic excesses of iron cause hemosidering to accumulate within cells -> local excesses result from hemorrhages in tissues (such as bruises)
pg 715
pathologic calcification
- abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts
- calcification almost always present in the atheromas of advanced atherosclerosis, also commonly develops in aging or damaged heart valves
- calcium salts appear macroscopically as fine, white granules or clumps, often felt as gritty deposits
pg 716
dystrophic calcification
- when the deposition occurs locally in dying tissues
- occurs despite normal serum levels of calcium and in the absence of derangements in calcium metabolism
- occurs in areas of necrosis and in foci of enzymatic necrosis of fat
- happens in the heart valves
pg 716
metastatic calcification
- the deposition of calcium salts in otherwise normal tissues
- almost always results from hypercalcemia secondary to a disturbance in calcium metabolism
- may occur widely throughout the body but principally affects the interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins (all of which excrete acid and have an internal alkaline compartment predisposing them to calcification)
pg 716, 718
histology of calcium salts
- have a basophilic, amorphous granular, sometimes clumped appearance
- can be intracellular, extracellular, or both
- heterotropic bone may form in the foci of calcifcatoin (formation of bone where it shouldn’t be)
- single necrotic cells may act as seed crystals that become encrusted by the mineral deposits
- progressive acquisition of outer layers may create lamellated configurations called psammoma bodies
pg 719
psammoma bodies
- represent a characteristic feature seen in association with papillary thyroid carcinomas
- appear as round, calcified concretions with concentric laminations
- resemble grains of sand
pg 720
abnormal metabolism
- inadequate removal of a normal substance secondary to defects in packaging and transport
- common causes of fatty change in the liver are toxins (alcohol, haolgenated hydrocarbons (chloroform), etc), chronic hypoxia, diabetes mellitus, and obesity
- histologically: well-preserved nucleus is squeezed into the displaced rim of cytoplasm about the fat vacuole
pg 721
cholesterol and cholesterol esters
- cholesterol accumulations are manifested histologically by intracellular vacuoles in several pathologic processes
- some fat-laden cells may rupture, releasing cholesterol and cholesterol esters into the extracellular space where they may form crystals
- some form long needles that produce distinct clefts in tissue sections, while other small crystals are phagocytosed by macrophages and activate inflammatory processes
pg 722-723
atherosclerosis
- in atherosclerotic plaques, smooth muscle cells and macrophages within the initial layer of the aorta and large arteries are filled with lipid vacuoles, most of which contain cholesterol and cholesterol esters
- cells have a foamy appearance (foam cells) and aggregates of them in the vascular intima produce the characteristic yellow cholesterol-laden atheromas
pg 722
cholesterolosis vs xanthomas
intracellular accumulation of cholesterol within macrophages is characteristic of acquired and hereditary hyperlipidemic states
cholesterolosis: focal accumulations of cholesterol-laden macrophages (foam cells) in the lamina propria of the gallbladder
xanthomas: clusters of foamy cells in the subepithelial CT of the skin and in tendons forming tumorous masses
pg 723
protein accumulations
- usually appear intracellularly as rounded, eosinophilic (bright red) droplets, vacuoles, or aggregates in the cytoplasm
- on EM: amorphous, fibrillar, or crystalline in appearance
- reabsorption droplets in proximal renal tubules are seen in renal diseases associated with protein loss in the urine (proteinuria)
- in the kidney, small amounts of protein filtered through the glomerulus are normally reabsorbed by pinocytosis in the proximal tubule
- in disorders with heavy leakage across the glomerular filter, there is increased reabsorption of protein into vesicles and the protein appears as pink hyaline droplets within the cytoplasm of the tubular cell
- process is reversible -> if proteinuria diminishes, protein droplets are metabolized and disappear
- histologically: look like a ton of small dark pink dots
pg 724
α1-antitrypsin deficiency
- patients with genetic deficiency of the antiprotease α1-antitrypsin have a markedly enhanced tendency to develop emphysema that is compounded by smoking
- α1-antitrypsin is a major inhibitor of proteases (particularly elastase) secreted by neurophils during inflammation
- in α1-antitrypsin deficiency, mutations in the protein significantly slow folding, resulting in the buildup of partially folded intermediates, which aggregate in the ER of hepatocytes and are not secreted (buildup of protein in liver)
- histologically: scattered pink round inclusions within the cytoplasm of hepatocytes
- liver is damaged first and eventually the lungs are too due to the lack of elastase inhibition
pg 726-727
lysosomal storage diseases
- a complex substrate is normally degraded by a series of lysosomal enzymes (A,B,C) forming soluble end products
- with a deficiency or malfunction of one of the enzymes, there is incomplete catabolism resulting in accumulation in the lysosomes
- can eventually lead to cell death
pg 728
Niemann-Pick Disease
two related disease characterized by lysosomal accumulation of sphingomyelin due to an inherited deficiency of sphingomyelinase
Type A: severe infantile form with extensive neurologic involvement, marked visceral accumulations of sphingomyelin, and progressive wasting and early death within the first 3 years of life
Type B: organomegaly but generally no CNS involvement, usually survive into adulthood
in liver: hepatocytes and Kupffer cells have a foamy, vacuolated appearance due to deposition of lipids; cells become enlarged; cytoplasm looks foamy due to innumerable, uniform sized vacuoles; foam cells widely distributed in the spleen, liver, lymph nodes, bone marrow, tonsils, GI tract, and lungs -> spleen may become massively enlarged
pg 729
Tay-Sachs Disease (G M2 Gangliosidosis)
hexosaminidase α-subunit deficiency; G M2 gangliosidoses are a group of lysosomal storage diseases caused by deficiency of β-hexosaminidase resulting in an inability to catabolize G M2 gangliosides
- Tay-Sachs results from mutations in the α-subunit locus on chromosome 15 that cause a severe deficiency of hexosaminidase A
- hexosaminidase A is absent from virtually all tissues causing ganglioside accumulation; involvement of neurons and retina
- histologically: neurons ballooned with cytoplasmic vacuoles, each representing a markedly distended lysosome filled with gangliosides
- in EM: several types of cytoplasmic inclusions, most prominent -> whorled configurations within lysosomes composed of onion-skin layers of membranes (different from psammoma bodies as these are seen in light microscopy)
- progressive destruction of neurons, accumulation of complex lipids -> cherry-red spot appears in the macula
pg 730-731
Gaucher Disease
- a cluster of autosomal recessive disorders resulting from mutations in the gene encoding glucocerebrosidase
- MOST common lysosomal storage disorder
- glucocerebrosidase: enzyme that normally cleaves the glucose reside from ceramide (a waxy lipid)
- glucocerebrosides accumulate in phagocytes (but also in CNS in some types)
Histology
- glucocerebrosides accumulate in massive amounts within phagocytic cells throughout the body
- distended phagocytic cells found: spleen, liver, bone marrow, lymph nodes, tonsils, thymus, Peyer patches
- rarely appear vacuolated, but have a fibrillary type of cytoplasm that resembles crumbled tissue paper
- greatly enlarged cells with one or more dark, eccentrically placed nuclei
pg 732-734
Gaucher Disease Type I
- chronic nonneuronopathic form
- storage of glucocerebrosides is limited to the mononuclear phagocytes throughout the body without involving the brain
- splenic and skeletal involvements
- reduced, but detectable, levels of glucocerebrosidase activity
- longevity is slightly shortened
pg 732-734
Gaucher Disease Type II
- acute neuronopathic Gaucher disease
- infantile acute cerebral pattern
- no detectable glucocerebrosidase activity in the tissue
- hepatosplenomegaly seen
- progressive CNS involvement leading to death at an early age
pg 732-734
Gaucher Disease Type III
- intermediate between types I and II
- patients have the systemic involvement characteristic of type I, but have progressive CNS disease that usually begins in adolescence or early adulthood
pg 732-734
glycogen storage diseases (glycogenoses)
- result from a hereditary deficiency of one of the enzymes involved in the synthesis or sequential degradation of glycogen
- may be limited to a few tissues, may be more widespread but not affecting all tissues, OR may be systemic
- if the enzymes that fuel the glycolytic pathway are deficient, glycogen storage occurs in the muscles and is associated with muscular weakness due to impaired energy production
- individuals with myopathic forms of GSD present with muscle cramps after exercise and lactate levels in the blood fail to rise after exercise due to block in glycolysis
- von Gierke disease: most common hepatic form, liver cells store glycogen because of a lack of hepatic glucose-6-phosphatase, liver is enlarged and patients have hypoglycemia
pg 735-736
Pompe disease
- type of glycogen storage disease in which there is a lack of lysosomal acid alpha-glucosidase and all organs are affected
- heart involvement is predominant
- myocardial fibers are fileld with glycogen which is seen histologically as cleared out spaces
- most prominent gross feature is cardiomegaly
pg 736-737
cellular aging
result of a progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences
model systems: have clearly established that aging is influenced by a limited number of genes, genetic anomalies underlie syndromes resembling premature aging, aging is associated with definable mechanistic alterations
pg 738
mechanisms that cause and counteract cellular aging
- DNA damage, replicative senescence, and decreased and misfolded proteins are among the best described mechanisms
- nutrient sensing, exemplified by caloric restriction, counteracts aging by activating various signaling pathways and transcription factors (alter transcription -> increased DNA repair, increased protein homeostasis -> counteraction of cell aging)
pg 739
