Cellular Acummulations

Overview

Intracellular accumulations

• Etiology: 
  • Metabolic derangement
  • Intrinsic abnormality in the cell function (genetic disease)
  • Exogenous source
• Effect: Substances that accumulate may or may not be harmful.

Mechanisms

• Abnormal metabolism:
  • Normal substance produced → defect in packaging and transport → substance build-up
  • Seen in fatty liver (increase in lipid particles)
• Abnormal protein folding and transport:
  • Abnormal substance (misfolded proteins) produced → overwhelms repair → accumulate in the endoplasmic reticulum (ER)
  • Seen in ɑ-1 antitrypsin deficiency
• Lack of enzyme:
  • Substrate → failure to convert to the final product (no enzyme) → increased amount of substrate
  • Seen in lysosomal storage disease
• Deposition of an exogenous material or indigestible substance:
  • Exogenous substance → cell with no capacity to degrade or transport → accumulation
  • Seen in silicosis (silica) and anthracosis (carbon)

Pigments

Exogenous pigments

Pigments coming from outside the body:

• Tattoos: pigments phagocytosed by macrophages, often without inflammatory response
• Carbon or coal dust:
  • Anthracotic or carbon pigment: carbonaceous debris from urban living, coal mining, and cigarette smoking
  • Associated with anthracosis, accumulation of black pigment in the lungs
  • Coal worker’s pneumoconiosis: fibrotic lung disease that develops from the reaction to accumulated carbon dust in the lungs

Endogenous pigments

Endogenous pigments are synthesized within the body.

Lipofuscin or lipochrome:

• Wear and tear or aging pigment
• Derived from lipid peroxidation and accumulates in lysosomes 
• Found most commonly in the heart and liver
• Brown atrophy: Significant amounts of lipofuscin impart a brown discoloration to the affected organ.
• Microscopic morphology: yellow-brown pigment granules often surrounding the nucleus

Hemosiderosis (iron):

• Accumulation of hemosiderin, a storage form of iron, in macrophages without side effects
• Iron physiology:
  • Iron has 2 storage forms: ferritin and hemosiderin
  • ↑ Iron → ferritin forms hemosiderin granules (hemosiderin pigment = aggregates of ferritin micelles)
• Microscopic morphology: hemosiderin stains positive in Prussian blue
• Found in:
  • Local bruise or extravasated blood cells to the site of injury
  • Multiple transfusions (overload of exogenous iron)
  • Hemolytic anemia (red cell lysis releases iron)
  • Genetic defect of iron metabolism (hemochromatosis)

Hemochromatosis (iron):

• Iron accumulates in the parenchyma due to excessive iron absorption.
• Associated with side effects
• Types:
  • Hereditary: due to mutation of genes
  • Secondary: due to parenteral administration of iron (e.g., transfusions)
• Found in:
  • Liver: cirrhosis 
  • Skin: abnormal pigmentation (especially sun-exposed areas) 
  • Pancreas: diabetes mellitus
  • Heart: cardiomyopathy, arrhythmias
  • Joints: synovitis
• Microscopic morphology: yellow-brown granules

Bilirubin:

• Orange-yellow compound produced from the breakdown of heme from RBCs
• Heme → biliverdin (“green bile”) → bilirubin (“red bile”)
• Conjugated in the liver and excreted in bile
• Jaundice: yellow discoloration of mucous membranes and skin due to accumulation of bilirubin
• Found in:
  • Liver or biliary disease (conjugated bilirubin)
  • Hemolysis (unconjugated bilirubin)

Melanin:

• Brown-black pigment formed by melanocytes and transferred to keratinocytes 
• Synthesis: oxidation of tyrosine to dopaquinone, catalyzed by tyrosine kinase
• Main forms of melanin:
  • Eumelanin (brown/black): stronger shielding property against ultraviolet (UV) radiation
  • Pheomelanin (yellow/orange): less UV protection, produces free radicals and contributes to oxidative stress
  • Neuromelanin: found in the brain
• Clinical correlation:
  • Benign accumulations (freckles, moles): nevus
  • Light-skinned individuals or populations living further from the equator: richer pheomelanin, higher risk for carcinogenesis

Calcium Accumulation

Metastatic calcification

• Calcium deposition in normal or abnormal tissues due to hypercalcemia
• Hypercalcemia:
  • Parathyroid hormone (PTH) excess or hyperparathyroidism:
    • Parathyroid tumors
    • Malignant tumors secreting PTH-related protein
  • Secondary hyperparathyroidism from renal disease (due to phosphate retention)
  • Resorption of bone tissue:
    • Immobilization
    • Bone metastasis
    • Increased bone turnover (Paget’s disease)
    • Bone marrow malignancies (multiple myeloma, leukemia)
  • Vitamin D disorders (vitamin D intoxication, sarcoidosis)
• Affects acid-secreting cells (alkali environment predisposes to metastatic calcification):
  • Gastric mucosa
  • Lungs
  • Kidneys (nephrocalcinosis)
  • Systemic arteries
  • Pulmonary veins

Dystrophic calcification

• Deposition of calcium in abnormal (necrotic) tissues with normal calcium levels
• Gross morphology: hard, yellowish granules or deposits
• Microscopic morphology: 
  • Calcium salts: basophilic, amorphous granular appearance
  • Psammoma bodies: concentric lamellated structures from calcium build-up (in papillary thyroid cancer, meningioma, ovarian papillary serous cystadenocarcinoma)
• Found in:
  • Blood vessels (atheromas of atherosclerosis)
  • Damaged heart valves
  • Aging
  • Infections (e.g., tuberculosis, toxoplasmosis)

Protein Accumulation

Microscopic morphology

• Eosinophilic
• Intracellular aggregates, vacuoles, or droplets

Causes

• Increased protein reabsorption in the proximal renal tubule:
  • Affects kidneys (proteinuria in nephrotic syndrome)
  • More protein leakage across the glomerular filter, more protein reabsorbed into vesicles
  • Microscopic morphology: pink hyaline droplets in the tubule cytoplasm 
• Increased protein production:
  • Abundant immunoglobulin synthesis in plasma cells → protein accumulation in the ER → Russell bodies
• Increased cytoskeletal proteins:
  • Cytoskeleton proteins:
    • Support the plasma membrane and the organization of organelles
    • Microtubules, actin filaments, myosin filaments, or intermediate filaments
  • Found in:
    • Alzheimer’s disease: One of the hallmarks is neurofibrillary tangle (microtubule-associated tau proteins).
    • Alcoholic liver disease: has alcoholic hyaline or Mallory hyaline, a cytoplasmic inclusion (made of keratin intermediate filaments)
• Defect in intracellular transport and protein secretion:
  • ɑ-1 antitrypsin deficiency: Genetic mutation leads to misfolding of ɑ-1antitrypsin. 
  • Abnormal ɑ-1antitrypsin accumulates in the ER of the liver → cirrhosis
  • Lack of functional ɑ-1antitrypsin → alveolar damage in the lungs
• Abnormal proteins (protein aggregation diseases):
  • Deposition of misfolded proteins disrupting tissue functions
  • Can be intracellular and/or extracellular
  • Amyloidosis: 
    • Extracellular deposition of amyloid, an insoluble fibrillar protein 
    • Amyloid stains pink or red in Congo red stain and apple-green birefringence under polarized light.

Lipid Accumulation

Triglycerides

• Fatty change or steatosis
  • Represents reversible injury or an abnormality in fat metabolism
  • Organs affected: 
    • Liver (major organ for fat metabolism)
    • Kidney
    • Heart 
    • Skeletal muscle
  • Found in:
    • Fatty liver: associated with alcohol abuse and non-alcoholic steatotic liver disease
    • Others: toxin injury, diabetes mellitus, anoxia, obesity
• Gross morphology: yellow discoloration of the organ
• Microscopic morphology: 
  • Vacuoles of lipidic content within the cells
  • Vacuoles have well-defined edges.

Cholesterol

• Accumulates in phagocytic cells due to lipid overload
• Microscopic morphology: intracellular vacuoles
• Found in:
  • Atherosclerosis
    • Atherosclerotic plaque: accumulation of cholesterol, seen as vacuoles, in the intimal smooth muscle cells and macrophages
  • Xanthomas
    • Plaques or nodules from intracellular cholesterol in the subepithelial connective tissue of skin and tendons
    • Found in altered lipid metabolism
  • Cholesterolosis
    • Cholesterol-laden macrophages or foam cells in the lamina propria of the gallbladder
    • Frequently coexists with cholesterol gallstones
  • Niemann-Pick disease, type C
    • Autosomal recessive lysosomal storage disease due to mutations in either NPC1 or NPC2 
    • Impaired cholesterol transport out of the lysosome
    • Associated with progressive central nervous system disease

Phospholipids

• Released from damaged cell membranes in cell injury
• Myelin figures (whorled phospholipids):
  • Accumulate in the cytosol 
  • Degraded into fatty acids or phagocytosed when the cell dies

Glycogen Accumulation

• Glycogen: normally stored in the liver and skeletal muscles
• Excessive glycogen deposits within cells found in:
  • Glucose metabolism abnormalities (diabetes mellitus)
  • Glycogen storage disease
• Microscopic morphology: 
  • Glycogen: clear vacuoles in the cytoplasm
  • Rose-to-violet color when stained with Best’s carmine or PAS (periodic acid-Schiff) reaction
  • Diastase removes glycogen from the histologic section. 
• Affected organs: liver, heart, skeletal muscle, kidneys, and pancreas

Hyaline Change

Description

• Not a pattern of accumulation but a histologic finding also seen in various retained substances 
• Can be intra- or extracellular
• Microscopic morphology: glassy, homogeneous pink appearance in the cell (hematoxylin and eosin stain)

Cellular findings

• Extracellular
  • Arteriolar hyalinosis: 
    • Thickened arteriolar walls demonstrate homogeneous pink hyaline material.
    • Due to leakage of plasma proteins and deposition of concentric extracellular material
    • Seen in hypertension and diabetes
  • Amyloid
• Intracellular
  • Protein reabsorption droplets in proteinuria
  • Russell bodies 
  • Alcoholic hyaline (Mallory body or hyaline)
  • Councilman bodies or acidophil bodies:
    • From hepatocyte apoptosis (cell shrinkage, pyknosis, karyorrhexis, and cellular fragmentation)
    • Seen in yellow fever, hepatitis