INTRACELLULAR ACCUMULATIONS

INTRACELLULAR ACCUMULATIONS Dr.Maha Arafah

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

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

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

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

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)

α-1antitrypsin deficiency

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

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)

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

Fatty Change (Steatosis)

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.

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

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

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

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.

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)

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

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%

Cholesterol and Cholesteryl Esters

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

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

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).

Foam cells

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

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

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

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

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

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

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

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.

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

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

Glycogen

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

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

Pigments

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

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.

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

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

INTRACELLULAR ACCUMULATIONS