Lecture 29

Question 1

four main mechanisms leading to abnormal intracellular accumulations

Answer 1

1. Inadequate removal of a normal substance secondary to defects in packaging and transport, as in fatty change (steatosis) in the liver
2. 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
3. Failure to degrade a metabolite due to inherited enzyme deficiencies, typically lysosomal enzymes. The resulting disorders are called lysosomal storage diseases
4. 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

Question 2

pigments

Answer 2

• 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

Question 3

exogenous pigments

Answer 3

• 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

Question 4

endogenous pigments

Answer 4

• 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

Question 5

lipofuscin granules

Answer 5

small brown granules in the cytoplasm, but clustered close to the nucleus
(“free points”)

pg 713

Question 6

melanin

Answer 6

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

Question 7

hemosiderin

Answer 7

• 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

Question 8

pathologic calcification

Answer 8

• 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

Question 9

dystrophic calcification

Answer 9

• 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

Question 10

metastatic calcification

Answer 10

• 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

Question 11

histology of calcium salts

Answer 11

• 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

Question 12

psammoma bodies

Answer 12

• 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

Question 13

abnormal metabolism

Answer 13

• 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

Question 14

cholesterol and cholesterol esters

Answer 14

• 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

Question 15

atherosclerosis

Answer 15

• 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

Question 16

cholesterolosis vs xanthomas

Answer 16

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

Question 17

protein accumulations

Answer 17

• 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

Question 18

α1-antitrypsin deficiency

Answer 18

• 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

Question 19

lysosomal storage diseases

Answer 19

• 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

Question 20

Niemann-Pick Disease

Answer 20

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

Question 21

Tay-Sachs Disease (G M2 Gangliosidosis)

Answer 21

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

Question 22

Gaucher Disease

Answer 22

• 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

Question 23

Gaucher Disease Type I

Answer 23

• 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

Question 24

Gaucher Disease Type II

Answer 24

• 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

Question 25

Gaucher Disease Type III

Answer 25

• 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

Question 26

glycogen storage diseases (glycogenoses)

Answer 26

• 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

Question 27

Pompe disease

Answer 27

• 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

Question 28

cellular aging

Answer 28

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

Question 29

mechanisms that cause and counteract cellular aging

Answer 29

• 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