Cellular Accumulations

Substances can accumulate in the cytoplasm, nucleus, or organelles as a result of an intrinsic cellular dysfunction or metabolic abnormalities. Commonly seen substances are pigments, calcium, iron, fat, cholesterol, and glycogen. These substances are produced by the cell and can increase in amount when there is inadequate removal of the substance or failure of metabolite degradation. Defective protein folding, packaging, and transport, both genetic and acquired, also produce substance accumulation. In some instances, deposition is from an external source, such as coal dust. The cell does not have an inherent mechanism of elimination, so material builds up in the exposed site.

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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.


  • 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)


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


  • 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)


  • 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


  • 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


  • 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.


  • 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


  • 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
Glycogen Accumulation

Liver biopsy:
(a) Periodic Acid-Schiff stain-positive for glycogen accumulation (rose-violet color)
(b) Glycogen abolishes after pretreatment with diastase.

Image: “Liver Biopsy” by US National Library of Medicine. License: CC BY 4.0

Hyaline Change


  • 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
Castleman's Disease

Lymph node biopsy (hematoxylin and eosin stain): 2 follicles with hyaline-vascular changes (yellow arrow), regressed germinal centers (black arrows) surrounded by concentric layers of small lymphocytes (white arrows)

Image: “Castleman’s Disease” by 1st Department of Internal Medicine and Diabetes Center, Tzaneio General Hospital of Piraeus, 18536 Piraeus, Greece. License: CC BY 4.0


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