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
Histopathology of pulmonary anthracosis, showing interstitial black material
Image: “Histopathology of pulmonary anthracosis” by Mikael Häggström, M.D. License: CC0 1.0
Section of a lung showing changes consistent with chronic exposure to coal dust (anthracosis): Areas appear black due to the build-up of coal-dust particles.
Image: “Black Lung in Appalachia” by US National Library of Medicine. License: Public Domain
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
Brownish deposits from hemosiderin in the kidney
Image: “Hemosiderin” by National Institutes of Health. License: Public Domain
Histopathology of a liver with homozygous genetic hemochromatosis. The blue coloration of iron is seen after its histochemical reaction with Prussian blue dye.
Image: “Hemochromatosis acini” by BioMed Central Dermatology, Mathew, J. et al. License: CC BY 3.0
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)
Scleral icterus: the first clinical sign of bilirubin deposition in the body
Image: “Jaundice eye new” by CDC/Dr. Thomas F. Sellers/Emory University. License: Public Domain
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
Image shows a nevus, a benign, uniformly pigmented brown papule with dark color due to high concentration of melanin
Image: “Nevus NCI” by National Cancer Institute. License: Public Domain
Micrograph of epidermis showing the melanocytes, keratinocytes, and melanin
Image: “Micrograph of keratinocytes, basal cells and melanocytes in the epidermis” by Setijanti H.B. et al. License: CC BY 4.0
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)
- Parathyroid hormone (PTH) excess or hyperparathyroidism:
- 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)
Images of excised aortic valves:
Image: “Macroscopic appearance” by Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan. License: CC BY 4.0
First picture (left): tricuspid aortic valve stenosis (TAV-AS) illustrating calcifications (white-yellow deposits) with fused commissures.
Second picture: congenital bicuspid aortic valve stenosis (CBAV-AS) with 2 calcified cusps with raphe (black arrow) and severe fibrous thickening.
Third picture (right): congenital bicuspid aortic valve regurgitation (CBAV-AR); R (right coronary cusp) and L (left coronary cusp) are fused, with coaptation sites thicker than the other portions (white arrow).
Histopathology illustrates psammoma bodies (green arrows) in meningioma
Image: “Histopathology Reveals Psammoma Bodies” by Department of Radiodiagnosis, Government Medical College, Nagpur Maharashtra, India. License: CC BY 2.5
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)
- Cytoskeleton proteins:
- 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.
Photomicrograph of bone biopsy (multiple myeloma): sheet of plasma cells with a prominent large Russell body (homogeneous eosinophilic inclusion)
Image: “Russell body” by Department of Pathology, Dr, Ram Manohar Lohia Hospital, New Delhi, India. License: CC BY 2.0Photomicrographs of chronic traumatic encephalopathy that show tau-immunostained section of the frontal cortex with neurofibrillary tangles and neuritic threads (A and B). Higher magnification (C and D) shows band- and flame-shaped neurofibrillary tangles.
Image: “Index case of military CTE” by Departments of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA. License: CC BY 2.0
Amyloid deposits in the kidney under hematoxylin and eosin stain:
Image: “Amyloid deposits in the three major compartments of the kidney” by Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. License: CC BY 4.0
A. Glomerular amyloid deposits in mesangial spaces (red arrow).
B. Interstitial amyloidosis (red arrow).
C. Vascular amyloidosis (red arrow).
D. Congo red stain of vascular amyloid deposits (red arrow).
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
- Atherosclerosis
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
- Arteriolar hyalinosis:
- 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
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 4.0References
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