• Clinical science

Cellular changes and adaptive responses


Cellular adaptation is the ability of cells to respond to various types of stimuli and adverse environmental changes. These adaptations include hypertrophy (enlargement of individual cells), hyperplasia (increase in cell number), atrophy (reduction in size and cell number), metaplasia (transformation from one type of epithelium to another), and dysplasia (disordered growth of cells). Tissues adapt differently depending on the replicative characteristics of the cells that make up the tissue. For example, labile tissue such as the skin can rapidly replicate, and therefore can also regenerate after injury, whereas permanent tissue such as neural and cardiac tissue cannot regenerate after injury. If cells are not able to adapt to the adverse environmental changes, cell death occurs physiologically in the form of apoptosis, or pathologically, in the form of necrosis. This learning card provides an overview of the main cellular adaptive mechanisms and their different consequences in the human body.

Cellular adaptation

Definition: Changes experienced by cells in response to physiological or pathological stimuli. These changes usually make cells more tolerable an adverse environment to which they are exposed.

Definition Forms and examples
  • Increased tissue size via enlargement of cells caused by an increase in organelles, and structural proteins.
  • Increased tissue size via an increase in cell numbers
  • Loss of mature cellular differentiation (no longer have morphological features of mature cells)
  • Malignant transformation
  • Disordered growth of epithelium (abnormally frequent mitotic figures, loss of cell orientation, size, and shape)
  • Precancerous: can progress to carcinoma in situ


  • Rapid division and increase in the number of cells


Cell injury


  • Definition: cellular damage due to internal and external environmental changes
    • Early stage (reversible) → results in cellular swelling (e.g., hydropic degeneration)
      • Tissue hypoxia → decreased ATP production:
        • Decreased Na+/K+ ATPasediffusion of Na+ and water into the cell↓ passive Ca2+ efflux and cellular/mitochondrial swelling
        • Disrupted Ca2+ ATPase pump activity → ↓ active Ca2+ removal from the cytoplasm into the extracellular space → Ca2+ accumulates inside the cell and activates degradative enzymes.
      • Low oxygen and ATP result in anaerobic respiration → lactate and ↓ intracellular pH → denatures proteins and causes clumping of nuclear chromatin
      • Detachment of ribosomes and polysomes → decreased protein synthesis
    • Late stage (irreversible) → results in membrane damage and cell death


  • Ischemic cell injury: see details below
    • Atherosclerosis
    • Decreased venous drainage (see ischemia for details)
    • Variable vulnerability: organs have different oxygen demand, oxygen expenditure, and susceptibility to hypoxic damage.
  • Reperfusion injury: see details below
  • Metabolic and nutritional causes
  • Physical causes
  • Autoimmune diseases: immune responses against the body's own cells (e.g., SLE, RA)
  • Genetic defects: misdirect cell metabolism (e.g., cystic fibrosis (CFTR gene), hemophilia A (Xq28 gene), α1-antitrypsin deficiency)
  • Damage induced by medical therapy and chemicals
  • Biological causes


Organs most susceptible to ischemia
Organ Specific structure Clinical significance
  • Proximal tubule (straight segment in the medulla)
  • Thick ascending limb (in the medulla)
  • Region around the central vein (zone III)
  • Centrilobular necrosis (e.g., Budd-Chiari syndrome, shock liver in trauma)
  • Watershed areas
    • Splenic flexure → confluence of blood supply between the SMA and IMA
    • Rectum → confluence of blood supply between the superior rectal artery (branch of the IMA) and the middle and inferior rectal artery
  • Ischemic tolerance time, after which irreversible tissue damage begins to take place
    • Skin: 12 h
    • Musculature: 6–8 h
    • Neural tissue: 2–4 h


Reperfusion injury

Reperfusion injury is tissue damage that occurs when blood flow is restored to a previously ischemic environment (typically > 6 h for most tissues).

Overview of cell death

Cell death is the irreversible damage that renders cells unable to carry their function. It results in either apoptosis or necrosis.

Apoptosis vs. necrosis

Characteristics Apoptosis Necrosis
  • Programmed cell death (ATP-dependent process)
  • Nonphysiologic cell death
  • Membrane damage → influx of calcium
  • Organelle swelling (e.g., mitochondria, endoplasmic reticulum) → inability of cells to produce ATP, release of ribosomes into the cytoplasm (release digestive enzymes), loss of RNA → nuclear shrinkage (pyknosis), fragmentation (karyorrhexis), disintegration (karyolysis) of the nucleus → autolysis
  • Results in an inflammatory response
  • Single cell or small group of cells
  • Cell shrinkage
  • Eosinophilic cytoplasm
  • Nuclear changes
  • Cytoplasmic blebs
  • Apoptotic bodies → phagocytized by macrophages
  • Large group of cells, tissues, or organs
  • Cell swelling, cell blebbing, cell organelle destruction, nuclear changes → cell bursts → inflammation → degradation of the necrotic tissue by leukocytes → organization of granulation tissue



  • Description: programmed cell death (physiological cell turnover)
  • Causes
  • Characteristics
    • ATP-dependent physiological process
    • Usually affects individual cells and not groups of cells (in contrast to necrosis)
    • No inflammatory response or cellular swelling (in contrast to necrosis)

Signaling cascade

Apoptosis can be initiated via two different pathways: the extrinsic pathway (through external stimuli) or the intrinsic pathway (through internal stimuli).

Histopathological findings

  1. Shrunken and irregularly shaped cells with membrane blebbing
  2. The cell detaches from other cells or the extracellular matrix.
  3. Nuclear changes (pyknosis, karyorrhexis, karyolysis)
  4. Degradation of the cell into apoptotic bodies
  5. Phagocytosis by macrophages

Proteins of the Bcl-2 family can have opposite effects, e.g., Bad and Bax have a proapoptotic effect, whereas Bcl-2 and Bcl-xL have an antiapoptotic effect!

Abnormal regulation of apoptosis

Tumor suppressor genes that regulate the cell cycle and cell death can mutate and allow cells to remain alive even if they have abnormal genes that can cause cancer. Some examples include:


  • Short description: collective term for unprogrammed cell death and tissue destruction
  • Characteristics
    • Never physiologically induced
    • Always associated with an inflammatory reaction
  • Process: : cell damage → nuclear changes (pyknosis, karyorrhexis, karyolysis) → cell swelling, cell wall protrusions, cell organelle destruction → cell bursts → inflammation → degradation of the necrotic tissue by leukocytes → organization of granulation tissue

Types of necrosis

Definition Pathophysiology Microscopic appearance Example
Coagulative necrosis
  • A type of necrosis caused by tissue ischemia that occurs in most tissues except the brain
  • Decreased oxygen delivery → decreased ATP
    • anaerobic metabolism → increased lactic acid production → decreased pH → denaturation of proteins (including proteolytic enzymes) → cell death
    • Impaired Na+/K+-ATPase↑ intracellular Na+↑ intracellular H2 → cell swelling
  • Preserved, anuclear, eosinophilic cellular architecture.
  • H&E staining: eosinophilia
  • Myocardial, splenic, hepatic, and renal infarction
  • Gangrene
  • Organ damage caused by acidic solutions
Liquefactive necrosis
  • A type of necrosis with liquefaction/softening of the affected tissue
  • Release of hydrolytic enzymes from neutrophilic lysosomes that digest the affected tissue
  • Macrophages and cellular debris (early) followed by cystic spaces or cavitations (late)
  • In bacterial infections → cellular debris and neutrophils
  • Bacterial abscesses (purulent infection)
  • Stroke
  • Pancreatitis (due to enzymatic damage to the parenchyma)
  • Organ damage caused by alkaline solutions
Fibrinoid necrosis
  • Vessel wall damage with fragments of embedded cellular debris, serum, and fibrin
  • Necrotic areas stain intense red
Caseous necrosis
  • A type of necrosis characterized by granular debris that results from macrophages walling off a pathogen
  • Cellular debris in a granular pattern, epitheloid cells and multinucleated giant cells that form granulomas
Fat necrosis
  • A type of necrosis in which adipose cells die off prematurely
  • Adipocytes with no nuclei
  • Saponification: dark blue appearance on H&E staining
Gangrenous necrosis

Cellular inclusions



Can be metastatic (diffuse) or dystrophic (localized)

Metastatic calcification Dystrophic calcification
  • Diffuse calcification of normal tissue
  • Localized calcification of degenerated inflammatory sites or necrotic tissues
Involved tissues
  • Normal tissues of kidney, lung, gastric mucosa, and blood vessels
  • Abnormal necrotic tissues or degenerated inflammatory sites

Associated conditions/tissue

Serum calcium findings
  • Usually increased
  • Usually normal


  • Finely speckled calcium throughout soft tissues


  • Hyaline: : descriptive term used for proteins that appear homogeneously transparent under light microscopy and are eosinophilic in H&E staining (also stain red in the van Gieson's stain). It can be used to differentiate between intracellular and extracellular hyaline.
  • Hyalinization: replacement of normal tissue by proteins that have an eosinophilic, homogenous, translucent appearance on H&E staining.

Intracellular hyaline



Morphology Occurrence
Mallory bodies Inclusion bodies within the cytoplasm of the hepatocytes that contain intermediate filaments and appear pink on H&E stain. Most common in alcoholic liver disease
Councilman bodies An eosinophilic remnant of apoptotic hepatocytes with pyknosis Particularly in yellow fever and viral hepatitis.
Schaumann bodies Round calcium and protein inclusions in the cytoplasm with laminar stratification Granulomas in sarcoidosis
Russel bodies Accumulation of immunoglobulins Plasma cells in plasmacytoma or chronic inflammation

Extracellular hyaline

  • 1. Barone J, Castro MA. Kaplan USMLE Step 1 Lecture Notes 2016. New York, NY, USA: Kaplan Medical; 2016.
  • 2. Le T, Bhushan V,‎ Sochat M, Chavda Y, Zureick A. First Aid for the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017.
  • 3. Goljan EF. Rapid Review Pathology. Philadelphia, PA: Elsevier Saunders; 2018.
  • Guerini D. The Ca2+ pumps and the Na+/Ca2+ exchangers. Biometals. 1998; 11(4): pp. 319–30. pmid: 10191496.
last updated 10/22/2019
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