Overview of Pathology

The Cell

disease is the manifestation of cellular dysfunction (pathology—study of this dysfunction)

classification dependent on their capacity to multiply

labile – those that continue to multiply throughout life (e.g. epithelium, skin)
stabile – those that multiply but are normally quiescent (e.g. hepatocytes, resp. mucosa, endothelium)
permanent – those that cannot proliferate (e.g. myocardium)

abnormalities underlying disease

too much death (permanent, e.g. myocardial infarction); or too much growth (labile, e.g. cancer)

Cell Injury

sublethal – abnormal intracellular material from metabolism or extracellular environ.—usually subclinical

hepatocellular steatosis ("fatty liver") and cytokeratin filaments in liver cells (Mallory bodies) – both often associated with consumption of alcohol

lethal – accidents (failure of the blood supply), homicide (via killer cells), or suicide (programmed death)

morphological changes

necrosis – swelling, often by ischemia; cellular rupture with damage to surrounding tissue and consequent inflammation
apoptosis – shrinkage by suicide; equal and opposite force to mitosis

Inflammation and Repair

inflammation evolved due to constant threat of infection associated with injury

inflammation prevents infection—circulate inactively in blood (more efficient)

inflammation without infection occurs for either of two reasons:

(1) rapid doubling time of pathogenic bacteria requires acute inflammatory response prior to infection
(2) inflammation used by the immune response as a non-specific method of destroying selected targets

autoimmune disease or allergy if excessive

return of function (ultimate goal of inflammatory response); possible only for labile and stabile (basement membrane – guidance/growth factors)

permanent cells produce scar tissue instead
stimulated epidermal cells manufacture their own basement membranes as they regenerate

Vascular Disturbances

hemostasis – injury requires clotting in seconds to minutes (order of magnitude shorter than inflam.)

two clotting mechanisms solidify blood upon contact with connective tissue, hair triggered but controlled

"intrinsic" – by coming in contact within collagen
"extrinsic" – by mixing with tissue factors released by injured cells

hemostasis in wrong place = thrombosis (greatest cause of morbidity/mortality in developed countries)

produces ischemic cell death (infarction), most notably of permanent myocardial cells

hemodynamic disturbances – two most common:

(1) redistribution of fluid to the extracellular space (e.g. pulmonary edema in congestive heart failure)
(2) inability to provide adequate O₂ to tissue locally (ischemia) or globally (shock)

Chronic Cell Injury

usually from repeated sublethal acute cellular injury

permanent cells – adapt to stress by modulating size (e.g., myocardial hypertrophy in hypertension)

disproportionate increase in extracellular connective tissue
mild ischemia since too much muscle for blood supply

stabile and labile cells – use hypertrophy and also hyperplasia (more cells)

errors in replication usually produce inferior cells – otherwise, termed neoplasia

metaplasia – genetic alterations in precursor cells eliminate and replace cells of one phenotype with another

e.g., squamous metaplasia of respiratory mucosa as a response to chronic irritation from cigarette smoke
usually subclinical and reversible, but can also produce neoplasias if stimulus not removed
connective tissues may also undergo metaplasia, but do not generally produce neoplasias

other precancerous lesions (with or without metaplasia) – can persist, regress, advance to neoplasia

dysplasia – cellular changes too irregular to be called hyperplasia but not as irregular as carcinoma
carcinoma-in-situ – epithelium replaced by layer of cancer cells without invasion of basement membrane

Tumors – purposeless growths of atypical tissue – autonomous and clinically aggressive

benign vs. malignant

benign – less morphologically atypical, fewer slowly growing mitoses, less invasive, do not metastasize, can progress to carcinoma
malignant – less differentiated, high nucl./cytopl. ratio, vary in size/shape (cell/nucl. polymorphism)

tumor types

epithelial (80% of all tumors) – benign suffix "-oma," malignant "-carcinoma" (through lymph nodes)
mesodermal – benign "-oma," malignant tumors are "-sarcoma" (directly through bloodstream)

exception: hematopoietic lymphomas and leukemias, which do not have a benign counterpart

mixed cell type – from pluripotent cells (many possible developmental paths)

most distinctive mixed tumor: teratoma – more than one germ layer in single mass

Causes of Tumors

nurture

chemical injury – contribute to up to 80-90% of human tumors – tobacco is leading cause of fatal cancers in developed nations
physical injury – especially radiation (ultraviolet rays that cause DNA crosslinking in epithelial cells)
biological injury – oncogenic viruses

nature

oncogenes – involved in regulated cell growth, either as growth factors, receptors, signal transduction
anti-oncogenes (tumor suppressor genes) – two-hit hypothesis (e.g., p53)

p53: stops cell cycle to allow repair of DNA defects; if repair fails à triggers apoptosis; stimulates transcription of genes involved in differentiation; turned on by hypoxia, inducing many cells to commit suicide via apoptosis

Why Do We Get Sick? (A Philosophical Digression)

IT'S A JUNGLE OUT THERE – microorganisms are sophisticated and capable of faster evolution

Design Compromises – no evolutionary pressure to maintain the organism past reproduction

permanent cells cause most elderly diseases because they are less likely to become cancerous younger

Civilization – fatty diets, automobiles, drugs, artificial lights, central heating, etc.

Genes – some of our genes are perpetuated despite the fact that they cause disease, because:

the disease is a result of a combination of genetics and our industrialized environment/longer life span
the genes provide other benefits (e.g., the gene that causes sickle cell anemia also prevents malaria)