Cellular Adaptation

In order to cope with their environment, cells undergo structural and functional changes. These cellular adaptations are reversible responses that allow cells to survive and continue to adequately function. Adaptive processes consist of increased cellular size and function (hypertrophy), increase in cell number (hyperplasia), decrease in cell size and metabolic activity (atrophy), or a change in the phenotype of the cells (metaplasia). If the stress or stimulus is removed, the cell can return to its original state. However, when the limits of the adaptive responses are exceeded, cellular function is adversely affected, leading to cellular injury.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Definition

Adaptation:

  • Reversible changes in number, size, phenotype, or cell function in response to physiologic and pathologic changes in the environment
  • Allows cell survival and continued cellular function in an altered steady state
  • Results from:
    • Increased demand 
    • Changes in vascular supply, nutrients, or stimulation
    • Chronic irritation
Cellular response to stress and stimuli

Cellular response to stress and stimuli

Image by Lecturio.

Hypertrophy

Overview

  • Cells increase in size 
  • No additional new cells
  • ↑ In cellular size → ↑ in size of affected organ
  • Can occur along with hyperplasia
  • Triggered by:
    • Hormonal signaling
    • Functional demand
  • Types:
    • Physiologic hypertrophy
    • Pathologic hypertrophy

Physiologic hypertrophy

  • Due to:
    • Increased functional demand
    • Hormonal stimulation and effect of growth factors
  • Clinical correlation: 
    • Uterine growth in pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
    • Skeletal muscle growth after exercise

Pathologic hypertrophy

  • Due to increased workload 
  • Clinical correlation: left ventricular hypertrophy
    • Hypertrophy of the wall of the left ventricle 
    • Occurs in hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
    • Persistently increased burden → degradation and death of myocytes → cardiac failure
Heart left ventricular hypertrophy

Cross-section of a heart with left ventricular hypertrophy: Note the thickened ventricular walls and associated reduced ventricular cavity.

Image: “Heart left ventricular hypertrophy short axis view” by Patrick J. Lynch, medical illustrator. License: CC BY 2.5

Mechanism

  • Increase in cellular protein production resulting from:
    • Action of growth factors
    • Switch in gene expression
  • Enlargement of cells or organs has a limit.
  • Regressive changes or cellular death occur when this limit is reached and/or stress is not relieved.

Hyperplasia

Overview

  • Cells increase in number in response to a stimulus.
  • Can occur simultaneously with hypertrophy 
  • Occurs only if cells are capable of dividing (cardiac myocytes and neurons in the brain do not undergo hyperplasia)
  • ↑ In cellular number → ↑ in size of affected organ 
  • Types: 
    • Physiologic hyperplasia
    • Pathologic hyperplasia
Adaptive cell changes

Illustration of the difference between hypertrophy (increase in size of cells) and hyperplasia (increase in number of cells)

Image by Lecturio.

Physiologic hyperplasia

  • Results from a normal stressor
  • Brought on by an increase in hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview and growth factors to enhance functional capacity of the organ
  • Hormonal hyperplasia: 
    • Clinical correlation: glandular epithelium Glandular epithelium Glandular epithelia, composed of epithelial tissue, are specialized structures that play a role in the production and release of enzymes, hormones, sweat, oil, and mucus in organisms. The secretion and release of these substances are prompted by either external or internal stimuli. Glandular Epithelium of mammary glands in puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty and pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
  • Compensatory hyperplasia
    • Results from damage or resection 
    • Clinical correlation: 
      • Restoration of a part of the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver after it has been resected
      • Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow hyperplasia in response to acute bleeding
      • Partial nephrectomy leads to hyperplasia of the remaining kidney.

Pathologic hyperplasia

  • Results from excessive or inappropriate stimulation of hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview or growth factors
  • Clinical correlation: 
    • Prolonged estrogen exposure → endometrial hyperplasia Endometrial Hyperplasia Endometrial hyperplasia (EH) is the abnormal growth of the uterine endometrium. This abnormal growth may be due to estrogen stimulation or genetic mutations leading to uncontrolled proliferation. Endometrial Hyperplasia and Endometrial Cancer → leading to endometrial bleeding
    • Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens benign prostatic hyperplasia Benign prostatic hyperplasia Benign prostatic hyperplasia (BPH) is a condition indicating an increase in the number of stromal and epithelial cells within the prostate gland (transition zone). Benign prostatic hyperplasia is common in men > 50 years of age and may greatly affect their quality of life. Benign Prostatic Hyperplasia → bladder outlet obstruction
    • Papillomavirus → epithelial hyperplasia → warts and mucosal lesions

Mechanism

  • Results from stimulation by growth factors → mature cells proliferate or new cells form from tissue stem cells
  • Hyperplasia can stop once the stimulus is removed.
  • Unrestricted stimulation → persistent proliferation and increased likelihood of genetic aberrations → increased risk of cancer

Atrophy

Overview

  • Decrease in size and number of cells, resulting in reduced metabolic activity
  • If a sufficient number of cells undergo this process, the whole organ becomes atrophic.
  • 2 types of atrophy:
    • Physiologic
    • Pathologic

Physiologic atrophy

  • Results from a normal stimulus 
  • Clinical correlation:
    • Uterine involution: reduction of the size of the uterus after giving birth
    • Thyroglossal duct and notochord atrophy during embryonic development

Pathologic atrophy

  • Can be localized or generalized
  • Causes and clinical correlation:
    • Loss of workload or disuse atrophy: bedridden patients → prolonged disuse → skeletal muscle fibers decrease in number and size
    • Loss of innervation or denervation atrophy:  spinal muscular atrophy Spinal Muscular Atrophy Spinal muscular atrophy (SMA) is a spectrum of autosomal recessive syndromes characterized by progressive proximal muscle weakness and atrophy, possibly due to degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem. Spinal Muscular Atrophy (SMA) ( SMA SMA Spinal muscular atrophy (SMA) is a spectrum of autosomal recessive syndromes characterized by progressive proximal muscle weakness and atrophy, possibly due to degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem. Spinal Muscular Atrophy (SMA)), degeneration of the anterior horn of the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord from a defect in the survival motor neuron gene → damaged nerve → skeletal muscle atrophy
    • Decrease in blood supply:  atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis → chronic ischemia → aging brain or senile atrophy → cognitive decline
    • Lack of nutrition: protein-calorie malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries → skeletal muscle proteins are utilized as a source of energy → muscle wasting 
    • Loss of endocrine stimulation:  menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause → loss of estrogen → vaginal atrophy 
    • Pressure: tumor compresses adjacent tissue → pressure disrupts cells and compromises the blood supply → atrophy of the surrounding tissues 
  • Note: Hypoplasia is a condition of smaller-than-normal organ or tissue resulting from an abnormal or incomplete development. The tissue involved was never normal in size.
Mpv17 mutation

Photos showing the hands and legs of patients with axonal sensorimotor polyneuropathy Polyneuropathy Polyneuropathy is any disease process affecting the function of or causing damage to multiple nerves of the peripheral nervous system. There are numerous etiologies of polyneuropathy, most of which are systemic and the most common of which is diabetic neuropathy. Polyneuropathy:
Hands, patient 1 (a) and 2 (b). Right hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand shows severe, atrophied, intrinsic muscle and flexion deformities of interphalangeal joints.
Lower extremities, patient 1 (c) and 2 (d). Severe bilateral distal muscle atrophies with ankle joint deformities are observed in both patients.

Image: “Hand and leg Leg The lower leg, or just "leg" in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg pictures of patients” by Department of Biochemistry, Ewha Womans University School of Medicine, Seoul, Korea. License: CC BY 4.0

Mechanism

  • Characterized by a decrease in protein synthesis and an increase in protein degradation
  • Ubiquitin-proteasome pathway:
    • Ubiquitin ligases are activated, resulting in attachment of ubiquitin to cellular proteins.
    • These proteins become targets for degradation.
  • Atrophy is also accompanied by autophagy:
    • Self-degradative process in which a cell eats its contents
    • Marked by the presence of autophagic vacuoles: contain lysosome-degraded proteins, pathogens, and cellular organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles 
    • Some cell debris resists autophagy, persisting as residual bodies
    • Lipofuscin granules:
      • An example of residual bodies, seen in cells as yellow-brown pigment (“wear-and-tear” pigment)
      • When increased in a tissue, causes brownish discoloration (brown atrophy)
  • If atrophy persistently reduces vascular supply:
    • Irreversible cell injury Cell injury The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death occurs.
    • Cells die by apoptosis, a regulated mechanism of cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death, eliminating irreparably damaged cells.

Metaplasia

Overview

  • Differentiated cell types are reversibly changed into another cell type.
  • Brought about by chronic irritation 
  • A cell type is replaced by another type that can better withstand or tolerate the adverse environment that triggered the change.
  • Epithelium appears normal but is not in the normal location.
  • Effects:
    • Reduced function
    • Potential malignant transformation of the tissue (when there is a persistence of triggering conditions)
  • Dysplasia: 
    • Generally not a normative cellular adaptive process but can be found with metaplastic epithelia
    • Characterized by a disordered pattern of growth, with varying size and shape of the cell and nucleus
    • Represents a pre-malignant change

Clinical correlation

  • Respiratory tract and smoking: 
    • Normal ciliated columnar epithelial cells replaced by stratified squamous epithelial cells
    • Squamous epithelial cells: Durable but protective mechanisms (ciliary action and mucus secretion) are lost. 
  • Barrett’s esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus: esophageal squamous epithelial cells replaced by intestinal columnar cells due to acid reflux

Mechanism

  • Reprogramming of local tissue stem cells: Affected cells are driven by external stimuli toward a specific differentiation pathway.
  • The affected organ or tissue is colonized by differentiated cell populations from adjacent sites.
Barrets esophagus

Hematoxylin and eosin staining of the histopathology of Barrett’s esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus, dysplasia, and adenocarcinoma
A. Non-dysplastic Barrett’s mucosa (columnar cells) characterized by uniform, bland nuclei arranged in a surface monolayer
B. Low-grade dysplasia (nuclear hyperchromasia, elongation, and stratification extending up to the surface epithelium Surface epithelium Epithelium is classified according to the cells (squamous, cuboidal, columnar), the number of layers, and other unique characteristics either due to function (transitional epithelium allowing distention) or appearance (pseudostratified epithelium giving a false impression of multiple layers). Surface epithelium has multiple functions, which include protection, secretion, filtration, and sensory reception. Surface Epithelium)
C. High-grade dysplasia (increased architectural and cytologic complexity)
D. Intramucosal adenocarcinoma (severe architectural distortion, including angulated glands).

Image: “Hematoxylin & Eosin staining” by Department of Pathology, The Pennsylvania State University College of Medicine, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA, 17033, USA. License: CC BY 4.0

Clinical Relevance

  • Left ventricular hypertrophy and heart failure: characterized by hypertrophy of the wall of the left ventricle. The condition is eventually complicated by a reduction in systolic function and/or diastolic dysfunction, leading to heart failure. Left ventricular hypertrophy regression can be achieved with control of blood pressure, weight loss, and medications.
  • Endometrial hyperplasia and endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer: the abnormal proliferation of endometrial glands relative to the stroma, resulting from prolonged estrogenic stimulation. Patients present with abnormal uterine bleeding Abnormal Uterine Bleeding Abnormal uterine bleeding is the medical term for abnormalities in the frequency, volume, duration, and regularity of the menstrual cycle. Abnormal uterine bleeding is classified using the acronym PALM-COEIN, with PALM representing the structural causes and COEIN indicating the non-structural causes. Abnormal Uterine Bleeding. Atypical hyperplasia, composed of proliferating glands with nuclear atypia, is associated with an increased risk of endometrial carcinoma.
  • Brain atrophy and dementia: Clinical stroke (ischemia or hemorrhage) or cerebral small vessel disease and degenerative processes lead to atrophy of the cerebral structures, from which cognitive and behavioral impairment can develop. Vascular dementia evolves from reduced cerebrovascular supply. Neuroimaging shows infarcts and accelerated brain atrophy. Imaging of Alzheimer’s disease, a neurodegenerative disorder, shows focal or generalized brain atrophy.
  • Barrett’s esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus and esophageal adenocarcinoma: Barrett’s esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus develops when metaplastic changes occur in the esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus in order to protect itself from gastric acid reflux. The condition is one of the major risk factors for esophageal cancer Esophageal cancer Esophageal cancer is 1 of the most common causes of cancer-related deaths worldwide. Nearly all esophageal cancers are either adenocarcinoma (commonly affecting the distal esophagus) or squamous cell carcinoma (affecting the proximal two-thirds of the esophagus). Esophageal Cancer. Chronic gastroesophageal reflux disease Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease ( GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease) predisposes to dysplasia, or disordered growth and architectural disarray of epithelial cells. Dysplastic changes predispose to the development of adenocarcinoma.

References

  1. Glick, D., Barth, S., MacLeod, K. (2010) Autophagy: cellular and molecular mechanisms. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990190/
  2. Kemp W.L., & Burns D.K., & Brown T.G. (Eds.) (2008). Cellular pathology. Pathology: The Big Picture. McGraw-Hill.
  3. McCullough, P., Bakris, G., Forman, J. (2019) Clinical implications and treatment of left ventricular hypertrophy in hypertension. UpToDate. Retrieved 17 Oct 2020, from https://www.uptodate.com/contents/clinical-implications-and-treatment-of-left-ventricular-hypertrophy-in-hypertension
  4. Oakes, S. (2020) Cell injury, cell death and adaptation in Kumar, V., Abbas, A., Aster, J. & Robbins, S. Robbins and Cotran Pathologic Basis of Disease (10th Ed., pp. 33–65). Elsevier, Inc.

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