INTRACELLULAR ACCUMULATIONS HA MWAKYOMA, MD

Objectives To study: Overview of intracellular accumulations Accumulation of Lipids Accumulation of Cholesterol Accumulation of Proteins Accumulation of Glycogen Accumulation of Pigments Pathologic Calcification 2

Overview Under some circumstances cells may accumulate abnormal amounts of various substances,. They may be harmless or associated with varying degrees of injury . 3

Overview May be found: Came to the cell through: in the cytoplasm within organelles (typically lysosomes) in the nucleus Came to the cell through: Synthesis by affected cells Produced elsewhere 4

Pathways Normal or increased rate of production of a normal substance, but metabolic rate is inadequate to remove it (e.g. fatty change in liver) 5

Pathways A normal or an abnormal endogenous substance accumulates because of genetic or acquired defects in its folding, packaging, transport, or secretion. e.g. In α-1antitrypsin deficiency, α1at accumulates in the liver causing cirrhosis) 6

α-1antitrypsin deficiency 7

Pathways 3. An inherited defect in an enzyme may result in failure to degrade a metabolite. The resulting disorders are called storage diseases. 8

Pathways 4. An abnormal exogenous substance is deposited and accumulates because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. (e.g. Accumulations of carbon or silica particles) 9

Accumulation of Lipids Lecture will include Overview of intracellular accumulations Accumulation of Lipids Accumulation of Cholesterol Accumulation of Proteins Accumulation of Glycogen Accumulation of Pigments Pathologic Calcification 10

Fatty Change (Steatosis) 11

Fatty Change Fatty change refers to any abnormal accumulation of triglycerides within parenchymal cells. Site: liver, most common site it may also occur in heart, skeletal muscle, kidney, and other organs. 12

Causes of Fatty Change Toxins (most importantly: Alcohol abuse) diabetes mellitus Protein malnutrition (starvation) Obesity Anoxia 13

Starvation will increase this Hepatotoxins (e.g. alcohol) by disrupting mitochondria and SER ; anoxia Defects in any of the steps of uptake, catabolism, or secretion can lead to lipid accumulation. CCl4 and protein malnutrition 14

The significance of fatty change Depends on the cause and severity of the accumulation. Mild it may have no effect on cellular function. Severe fatty change may transiently impair cellular function In the severe form, fatty change may precede cell death, and may be an early lesion in a serious liver disease called nonalcoholic steatohepatitis 15

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Morphology of fatty change Most common site: the liver and the heart. With increasing accumulation, the organ enlarges and becomes progressively yellow, soft, and greasy. 17

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Light of microscopy fatty change Early: small fat vacuoles in the cytoplasm around the nucleus. Later stages: the vacuoles coalesce to create cleared spaces that displace the nucleus to the cell periphery Occasionally contiguous cells rupture (fatty cysts) 20

Is Fatty liver reversible? Fatty change is reversible except if some vital intracellular process is irreversibly impaired (e.g., in CCl4 poisoning), 22

Prognosis of Fatty liver Mild: benign natural history (approximately 3% will develop cirrhosis Moderate to sever: inflammation, degeneration in hepatocytes, +/- fibrosis (30% develop cirrhosis) 5 to 10 year survival:67% and 59% 23

Accumulation of Cholesterol Lecture will include Overview of intracellular accumulations Accumulation of Lipids Accumulation of Cholesterol Accumulation of Proteins Accumulation of Glycogen Accumulation of Pigments Pathologic Calcification 24

Cholesterol and Cholesteryl Esters 25

Cellular cholesterol metabolism is tightly regulated to ensure normal cell membrane synthesis without significant intracellular accumulation 26

Conditions associated with Cholesterol and Cholesteryl Esters accumulation Several different pathologic processes: 1. Macrophages in contact with the lipid debris of necrotic cells or abnormal (e.g., oxidized) forms of lipoproteins 27

1. Macrophages in contact with the lipid debris These macrophages may be filled with minute, membrane-bound vacuoles of lipid, imparting a foamy appearance to their cytoplasm (foam cells). 28

Foam cells 29

Atherosclerosis: smooth muscle cells and macrophages are filled with lipid vacuoles composed of cholesterol and cholesteryl esters 30

Atherosclerosis: These give atherosclerotic plaques their characteristic yellow color and contribute to the pathogenesis of the lesion 31

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Conditions associated with Cholesterol and Cholesteryl Esters accumulation 3. In hereditary and acquired hyperlipidemic syndromes, macrophages accumulate intracellular cholesterol 4. Xanthomas: clusters of foamy macrophages present in the subepithelial connective tissue of skin or in tendons 33

Accumulation of Proteins Objctives To study: Overview of intracellular accumulations Accumulation of Lipids Accumulation of Cholesterol Accumulation of Proteins Accumulation of Glycogen Accumulation of Pigments Pathologic Calcification 34

Proteins 35

Proteins Morphologically visible protein accumulations are much less common than lipid accumulations They may occur because excesses are presented to the cells or because the cells synthesize excessive amounts 36

Protein accumulations Example: Nephrotic syndrome: In the kidney trace amounts of albumin filtered through the glomerulus are normally reabsorbed by pinocytosis in the proximal convoluted tubules After heavy protein leakage, pinocytic vesicles containing this protein fuse with lysosomes, resulting in the histologic appearance of pink, hyaline cytoplasmic droplets 37

The process is reversible; if the proteinuria abates, the protein droplets are metabolized and disappear. 38

Protein accumulations Example: 2. marked accumulation of newly synthesized immunoglobulins that may occur in the RER of some plasma cells, forming rounded, eosinophilic Russell bodies. 39

Protein accumulations Example: 3. Mallory body, or "alcoholic hyalin," is an eosinophilic cytoplasmic inclusion in liver cells that is highly characteristic of alcoholic liver disease These inclusions are composed predominantly of aggregated intermediate filaments 40

Protein accumulations Example: 4. The neurofibrillary tangle found in the brain in Alzheimer disease is an aggregated protein inclusion that contains microtubule-associated proteins 41

Accumulation of Glycogen Lecture will include Overview of intracellular accumulations Accumulation of Lipids Accumulation of Cholesterol Accumulation of Proteins Accumulation of Glycogen Accumulation of Pigments Pathologic Calcification 42

Glycogen 43

Glycogen Associated with abnormalities in the metabolism of either glucose or glycogen. Examples: In poorly controlled diabetes mellitus, glycogen accumulates in renal tubular epithelium, cardiac myocytes, and β cells of the islets of Langerhans. Glycogen accumulates within cells in a group of closely related genetic disorders collectively referred to as glycogen storage diseases, or glycogenoses 44

In these diseases, enzymatic defects in the synthesis or breakdown of glycogen result in massive stockpiling, with secondary injury and cell death. 45

Pigments 46

Pigments Pigments are colored substances that are either: exogenous, coming from outside the body, or endogenous, synthesized within the body itself. 47

Exogenous pigment The most common is carbon When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes. 48

Exogenous pigment Aggregates of the pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis). 49

Heavy accumulations may induce emphysema or a fibroblastic reaction that can result in a serious lung disease ( coal workers' pneumoconiosis) 50

Asbestos bodies Asbestos bodies 51

Accumulation of Pigments Objectives To study: Overview of intracellular accumulations Accumulation of Lipids Accumulation of Cholesterol Accumulation of Proteins Accumulation of Glycogen Accumulation of Pigments Pathologic Calcification 52

Endogenous pigments include lipofuscin, melanin, and certain derivatives of hemoglobin. 53

Lipofuscin "wear-and-tear pigment" is an insoluble brownish-yellow granular intracellular material that seen in a variety of tissues (the heart, liver, and brain) as a function of age or atrophy. Consists of complexes of lipid and protein that derive from the free radical-catalyzed peroxidation of polyunsaturated lipids of subcellular membranes. It is not injurious to the cell but is important as a marker of past free-radical injury. The brown pigment when present in large amounts, imparts an appearance to the tissue that is called brown atrophy. 54

Lipofuscin By electron microscopy, the pigment appears as perinuclear electron-dense granules 55

Melanin is an endogenous, brown-black pigment produced in melanocytes Although melanocytes are the only source of melanin, adjacent basal keratinocytes in the skin can accumulate the pigment (dermal macrophages) 56

Melanin

Hemosiderin is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron. Hemosiderin pigment represents large aggregates of ferritin micelles, can be seen by light and electron microscopy 58

Hemosiderin Although hemosiderin accumulation is usually pathologic, small amounts of this pigment are normal in the mononuclear phagocytes of the bone marrow, spleen, and liver, where there is extensive red cell breakdown 59

Hemosiderin Local excesses of iron, and consequently of hemosiderin, result from hemorrhage. Bruise: The original red-blue color of hemoglobin is transformed to varying shades of green-blue by the local formation of biliverdin (green bile) and bilirubin (red bile) from the heme 60

Hemosiderin The iron ions of hemoglobin accumulate as golden-yellow hemosiderin. The iron can be unambiguously identified by the Prussian blue histochemical reaction 61

Hemosiderosis is systemic overload of iron, hemosiderin is deposited in many organs and tissues It is found at first in the mononuclear phagocytes of the liver, bone marrow, spleen, and lymph nodes and in scattered macrophages throughout other organs. With progressive accumulation, parenchymal cells throughout the body (principally the liver, pancreas, heart, and endocrine organs) will be affected 62

Hemosiderosis Hemosiderosis occurs in the setting of: increased absorption of dietary iron impaired utilization of iron hemolytic anemias transfusions (the transfused red cells constitute an exogenous load of iron). . 63

Effect of hemosiderosis In most instances of systemic hemosiderosis, the iron pigment does not damage the parenchymal cells However, more extensive accumulations of iron are seen in hereditary hemochromatosis with tissue injury including liver fibrosis, heart failure, and diabetes mellitus

Pathologic Calcifications ● dystrophic deposition of calcium and other minerals in injured tissue (e.g.,atherosoma in blood vessels, heart valves in elderly individuals, old tuberculosis lesions)

Pathologic Calcification ●metastatic Calcium deposits in normal tissues in hypercalcemic states