Intracellular Accumulations

• Intracellular accumulations refer to abnormal quantities of various substances within cells.
• These substances can accumulate in either the cytoplasm or the nucleus.
• Cells may either produce the abnormal substance or store products from pathologic processes elsewhere in the body.

Common Causes of Intracellular Accumulation

• A normal endogenous substance accumulates due to inadequate metabolism.
• Example: Fatty change in the liver.
• A normal or abnormal endogenous substance accumulates because of genetic or acquired defects in metabolism, packaging, transport, or secretion.
• Example: Lysosomal storage diseases.
• An abnormal exogenous substance accumulates because the cell lacks the machinery to degrade or transport it.
• Example: Accumulation of carbon particles.

Lipids

• Major classes of lipids that can accumulate in cells include triglycerides, cholesterol/cholesterol esters, and phospholipids.
• Abnormal lipid-carbohydrate complexes can accumulate in lysosomal storage diseases.

Steatosis (Fatty Change)

• Steatosis, or fatty change, is the abnormal accumulation of triglycerides within parenchymal cells.
• It is commonly seen in the liver but can also occur in the heart, muscle, and kidney.
• Causes include toxins, protein malnutrition, diabetes mellitus, obesity, anoxia, and alcohol abuse.
• Free fatty acids are transported into hepatocytes, where they are esterified to triglycerides, converted into cholesterol or phospholipids, or oxidized to ketone bodies.
• Release of triglycerides requires apoproteins to form lipoproteins.
• Excess triglyceride accumulation results from defects in fatty acid entry to lipoprotein exit.
• Morphology includes clear vacuoles within parenchymal cells.
• Staining with Sudan IV or Oil Red-O imparts an orange-red color to the lipids within these vacuoles.
• In mild cases of fatty change, the liver may appear normal, but with progressive accumulation, it enlarges and becomes yellow and greasy.
• Light microscopy reveals vacuoles displacing the nucleus to the periphery of the cell.
• Occasionally, cells rupture and fat globules coalesce, forming fatty cysts.

Cholesterol and Cholesterol Esters

• Cells use cholesterol for cell membrane synthesis.
• Accumulations of cholesterol esters are seen as intracellular vacuoles in pathologic processes like atherosclerosis.
• In atherosclerotic plaques, smooth muscle cells and macrophages in the artery's intima are filled with lipid vacuoles, mainly cholesterol and cholesterol esters.
• Rupture of fat-laden cells releases lipids into the extracellular space.
• Extracellular cholesterol esters may crystallize into long needles, forming clefts in tissue sections.
• Xanthomas feature intracellular cholesterol accumulation within macrophages in connective tissue of the skin and tendons, seen in hyperlipidemic states.
• Foamy macrophages are often found at sites of cell injury and inflammation due to phagocytosis of cholesterol, Cholesterolosis involves cholesterol-laden macrophages in the gallbladder's lamina propria.
• Niemann-Pick disease, type C, results in cholesterol accumulation in multiple organs due to a mutated enzyme involved in cholesterol trafficking.

Glycogen

• Glycogen is a readily available energy store in the cytoplasm.
• Excessive intracellular glycogen deposits occur in patients with abnormalities in glucose or glycogen metabolism.
• These deposits appear as clear vacuoles within the cytoplasm.
• Staining with mucicarmine or the periodic acid Schiff (PAS) reaction gives glycogen a rose-to-violet color.
• Diabetes mellitus is a prime example of a disorder of glucose metabolism.
• In diabetes, glycogen is found in epithelial cells of the distal portions of the proximal convoluted tubules, as well as within liver cells, β cells of the islets of Langerhans, and heart muscle cells.
• Glycogen storage diseases (glycogenoses) are genetic disorders causing massive glycogen accumulation and cell death due to enzymatic defects in glycogen synthesis or breakdown.

Pigments

• Pigments are colored substances that can be normal constituents of cells (e.g., melanin) or abnormal, collecting in cells under special circumstances.
• They can be exogenous (from outside the body) or endogenous (synthesized within the body).

Exogenous Pigments

• Carbon or coal dust is the most common exogenous pigment, and is considered an air pollutant.
• When inhaled, macrophages pick it up within the alveoli and transport it through lymphatic channels to regional lymph nodes.
• Accumulations of carbon blacken the tissues of the lungs (anthracosis) and involved lymph nodes.
• In coal miners, carbon dust aggregates may induce a fibroblastic reaction or emphysema, causing coal worker's pneumoconiosis.
• Tattooing involves localized, exogenous pigmentation of the skin, where pigments are phagocytosed by dermal macrophages.

Endogenous Pigments

• Lipofuscin is an insoluble pigment, also known as wear-and-tear or aging pigment.
• It is a sign of free radical injury and lipid peroxidation, but not injurious to the cell.
• It appears as a yellow-brown, finely granular intracytoplasmic pigment, often perinuclear, in tissue sections.
• Prominent in the liver and heart of aging patients or those with severe malnutrition and cancer cachexia.
• Melanin is a non-hemoglobin-derived, brown-black pigment formed when tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes.
• Homogentisic acid is a black pigment that occurs in patients with alkaptonuria, a rare metabolic disease.
• This pigment is deposited in the skin, connective tissue, and cartilage, and the pigmentation is known as ochronosis.
• Hemosiderin is a hemoglobin-derived, golden yellow-to-brown, iron-containing pigment in cells.
• Iron is normally stored in ferritin micelles.
• Excess iron causes ferritin to form visible hemosiderin granules as a localized or systemic derangement.
• Local excesses of iron and hemosiderin result from hemorrhages or vascular congestion, such as in a common bruise (hemosiderosis).
• Lysis of erythrocytes causes hemoglobin to transform into hemosiderin.
• Systemic overload of iron causes hemosiderin to deposit in many organs and tissues, which is also called hemosiderosis.
• It is seen with increased absorption of dietary iron, impaired use of iron, hemolytic anemias, and transfusions.
• Iron pigment appears as a coarse, golden, granular pigment within the cytoplasm of cells, usually macrophages.
• In severe systemic hemosiderosis, the pigment may accumulate in parenchymal cells throughout the body (liver, pancreas, heart, and endocrine organs).
• Iron can be visualized in tissues by the Prussian blue histochemical reaction, in which it appears blue-black.
• In most cases of systemic hemosiderosis, the pigment does not damage parenchymal cells or impair organ function.
• In severe cases resulting in hemochromatosis, it can result in liver fibrosis, heart failure, and diabetes mellitus.

Pathologic Calcification

• Pathologic calcification is the abnormal tissue deposition of calcium salts.
• Dystrophic calcification occurs locally in dying tissues, despite normal serum calcium levels and without derangements in calcium metabolism.
• Metastatic calcification occurs in normal tissues due to hypercalcemia secondary to disturbances in calcium metabolism.
• Dystrophic calcification is seen in areas of necrosis and/or damage, such as in the atheromas of advanced atherosclerosis or in aging/damaged heart valves.
• Calcium salts appear as fine, white granules or clumps and often feel like gritty deposits.
• Histologically, calcium salts are basophilic, amorphous granular.
• They can be intracellular, extracellular, or both.
• Heterotopic bone may form in the focus of calcification.
• Progressive deposition on outer layers may create lamellated configurations, called psammoma bodies (papillary cancers).
• Metastatic calcification occurs in normal tissues due to hypercalcemia.
• Principal causes of hypercalcemia include increased secretion of parathyroid hormone (PTH) with subsequent bone resorption, destruction of bone tissue, vitamin D-related disorders, and renal failure.

Jaundice (Icterus)

• Deposition of bile pigments in skin and mucous membranes.
• Indicates high levels of bile pigments (hemobilirubin and cholebilirubin), or hyperbilirubinemia.

Types of Jaundice

• Hemolytic or prehepatic jaundice
• Toxic or intrahepatic jaundice
• Obstructive or post-hepatic jaundice

Ketabolism of Hemoglobin

• Hemolytic (Prehepatic) Jaundice is a state of hemobilirubinemia where the tissues are yellowish in color, often caused by excessive hemolysis of erythrocytes.
• Toxic (Intrahepatic) Jaundice involves accumulation of both hemobilirubin and cholebilirubin in the blood due to degeneration and necrosis of hepatic cells.
• Obstructive (Post Hepatic) Jaundice is caused by the accumulation of cholebilirubin in the blood due to obstruction of bile flow through the biliary ducts.

Jaundice Types and Characteristics

• Hemolytic jaundice involves hemobilirubin and is caused by excessive hemolysis.
• In hemolytic jaundice, the liver cannot convert all hemobilirubin into cholebilirubin, thus hemobilirubin level rises in the blood.
• Toxic jaundice involves hemobilirubin and cholebilirubin and is caused by degenerated and necrotic hepatic cells.
• In toxic jaundice, degenerated and necrotic hepatic cells cannot conjugate all hemobilirubin, so it accumulates in the blood.
• Obstructive jaundice involves cholebilirubin and is caused by obstruction to the flow of bile through the biliary ducts
• In obstructive jaundice, the cholebilirubin and bile produced by the hepatic cells cannot pass to the intestine.

Intracellular accumulations refer to the buildup of abnormal substances within cells, either in the cytoplasm or nucleus. This occurs when cells produce abnormal substances or store products from other parts of the body due to pathologic processes. Common causes include inadequate metabolism, genetic defects, or lack of machinery to degrade substances.