Cellular Pathology
§ Pathology
includes study of etiology (what initiates a process), pathogenesis
(mechanism), morphology (how it’s recognized) and functional consequences (how
it produces disease).
§ The
three fundamental processes of cellular pathology are cell injury, cell death
and cellular adaptation. In response to
stressors, cells may adapt or die/be injured.
§ The
etiology of cell injury may be extrinsic or intrinsic, including hypoxia,
physical/chemical agents, drugs, infection, immunologic reactions, genetic, or
nutritional problems.
§ Hypoxia
is the reduction or absence of normal oxygen supply. It may be a result of ischemia, which is the
reduction or absence of blood supply.
They most often go together, but ischemia alone can be damaging from a
lack of trophic substances or accumulation of toxins, and hypoxia alone can
still be damaging (ex: anemia, pulmonary disease, cyanide poisoning).
§ Infarction
is the process in which a portion of a tissue dies as a result of ischemia. An
infarct is the end result of this process.
They may be white or red (still some blood supply to the dead tissue),
but both result from the same underlying mechanism.
§ The
mechanisms by which ischemia causes cell death are inter-dependent and
synergistic. Toxins often influence one
of these mechanisms. They include:
o Decreases
in ATP – oxidative phosphorylation shuts down first in ischemia. Pumps stop running and cells/organelles swell
and have blebs, glycolysis lowers pH and chromatin clumps, protein synthesis
decreases and lipids accumulate since proteins aren’t available to export
lipids as lipoproteins. These early
changes are reversible.
o Increased
intracellular Ca, which is critical to homeostasis. Many enzymes only function within a very
narrow range of [Ca]. Ischemia
inactivates calcium pumps, resulting in calcium activation of enzymes and
increased membrane breakdown along with decreased membrane synthesis.
o Membrane
damage (considered the point of no return)
o Reactive
oxygen species – endogenous or exogenous free radicals. Reperfusion of an ischemic area can add to
ischemic damage, likely by sudden calcium influx or exposure to free radicals
from an influx of inflammatory cells. We
have some level of antioxidant defense from vitamins C and E, glutathione
peroxidase, catalase and superoxide dismutase.
But oxidative stress can result from imbalance between ROS and
antioxidants. Oxidative stress is
associated with aging, diabetes, atherosclerosis, Alzheimer, etc.
§ Cell
injury becomes irreversible most quickly in neurons, followed by myocardium and
hepatocytes, and most slowly in skeletal muscle.
§ Reversible
cell injury is characterized by cell swelling, vacuolar degeneration, and lipid
deposition (especially in the myocardium and liver).
§ Irreversible
injury: necrosis – the morphological
changes in the nucleus and cytoplasm occurring after death in a living tissue,
regardless of the cause of injury. By
the time necrosis is observed, the cell is dead. This need not occur at the tissue level.
o Features
of necrosis include: eosinophilia due to
loss of RNA/ribosomes and denatured protein, nuclear changes (small-pyknosis,
broken apart-karyorrhexis, or dissolved-karyolysis), INFLAMMATION. The inflammation is the big distinguishing
feature, and it usually occurs about 8 hours after cell death. Thus, it won’t occur if the cell dies and
organism also dies at the same time.
§ Types
of Necrosis:
o Coagulative: Results from ischemic cell death, and is seen
in most tissues except for the brain. In
this type of necrosis, the tissue architecture is retained. You typically see ‘tombstones’ of
hyper-eosinophilic cells. It typically
resolves by scar formation.
o Liquefactive: Characterized by complete hydrolysis of dead
cells, resulting in a loss of tissue architecture and usually resulting in a
cyst or cavity. This is the usual
response to infarction in the brain.
o Abscess: Liquefactive necrosis resulting from
localized bacterial/fungal/parasitic infections. It usually has lots of neutrophils within the
abscess (pus=dead neutrophils and debris) which are the source of hydrolytic
enzymes. It often requires surgical
drainage, since vasculature is commonly damaged and antibiotics won’t be
delivered effectively.
o Caseous
(cheese-like): Characteristic of TB and fungal infections. It has a center of cheese-like necrosis
surrounded by a rim of inflammatory cells (all together called a granuloma).
o Fat: Common in the pancreas (from release of
pancreatic enzymes) and breast (from minor trauma). Membrane lipids are digested into FFAs, and
combine with calcium (saponification) to form chalky white deposits. May mimic a carcinoma clinically.
§ Cellular
adaptations include hyperplasis, hypertrophy, atrophy, and metaplasia.
§ Hyperplasia
is an increase in the number of cells in a tissue/organ. In hyperplasia, you see dividing, mitotic
cells. Hyperplasia may be physiologic,
such as in lactating breasts. But is can
also be pathologic, as in endometrial hyperplasia with unopposed estrogen
stimulation that results in prolonged cycles with menorrhagia (heavy
bleeding). Another example of
hyperplasia is in BPH.
§ Hypertrophy
is an increase in individual cell mass, and is usually reversible. In benign prostatic hyperplasia, bladder
muscle hypertrophies as a results of needing to push the urine out with more
force. Other examples of pathologic
hypertrophy may be hypertrophy of the heart in someone with aortic valve
stenosis or chronic hypertension.
Hypertrophy may results from greater workload, as above, but also from
increased levels of hormones (anabolic or in pregnancy, etc). Genetic mutation in the myostatin gene has
been shown to cause muscle hypertrophy in animals.
§ Atrophy
is cellular shrinkage due to a loss of substance, and may result from disuse,
denervation (polio), ischemia, starvation (protein-calorie malnutrition, or
marasmus), or absence of endocrine stimulation.
Ex: menopause can result in
atrophy of cells making up endometrial glands.
Ex: cachexia, a wasting
associated with cancer, AIDS and other chronic inflammatory diseases.
o Cellular
atrophy may culminate or be accompanied by progressive cell loss, and if enough
occurs an organ or tissue may shrink. In
these cases, atrophy describes both cell shrinkage and cell loss.
§ Metaplasia
is the reversible replacement of one differentiated cell type by another
differentiated cell type. It can be
considered an adaptive substitution by cells that can better withstand an
adverse environment. In smokers, you see
squamous metaplasia where respiratory epithelium is replaced by stratified
squamous cells. Stem cells at the
basement layer differentiate into squamous cells. Metaplastic epithelium may undergo neoplastic
progression to dysplasia (not yet cancer, but cells lose normal architecture on
the way there), and ultimately to neoplasia (cancer w/ clonal cells having a
genetic mutation). Not all metplasias
become cancers, but if the stimulus persists, they may.
§ Cells
may accumulate endogenous or exogenous substances (lipids, protein, glycogen,
carbs, minerals, pigments, etc).
o Pigment
accumulations: anthracosis (accumulation
of dark carbon pigment in city dwellers) or lipofuscin (wear and tear pigment
where you have lots of cell turnover) are examples of benign pigment
accumulations.
o Intracellular
lipid accumulation: Fatty change
(steatosis) is potentially reversible.
It most commonly occurs in the liver, and is caused most commonly by
obesity or alcoholic liver disease. The
liver is typically enlarged and rather than red, it appears yellow/white.
§ Cell
death is not always pathologic; apoptosis is normal in embryogenesis, immune
cell differentiation, menstruation, etc.
Apoptosis may be pathologic too, resulting from DNA damage (w/ p53 as a
principal mediator), viral infection or CD8 T cell mediated injury.
o Apoptosis
is mediated by caspases, cysteine protesases that require activation. Bcl-2 is an anti-apoptotic protein, and its
family contains both pro and anti apoptotic factors. P53 stops cell division in response to DNA
damage in order to facilitate recovery, and if recover fails it initiates
apoptosis.
o Morphologically,
apoptosis is characterized by nuclei breaking into apoptotic bodies. This occurs in single cells with apoptosis,
whereas necrosis tends to occur in large regions of an organ. In apoptosis, DNA is systematically
fragmented and shows as a ladder on a gel, whereas necrotic cell death breaks
it down at random, resulting in a smear.
o Basically,
apoptosis is usually physiologic, occurs in single cells, fragments DNA between
nucleosomes, and produces apoptotic bodies WITHOUT inflammation. Necrosis is usually pathologic, occurs in
groups of cells, randomly fragments DNA and shows swelling, degeneration, and
inflammation.
o Inhibition
of apoptosis facilitates tumorigenesis.
HPV blocks p53 and apoptosis, and can result in squamous cell carcinoma
of the cervix. Constitutive activation
of Bcl-2 blocks apoptosis and facilitates follicular lymphomas.
