Learn — General pathology: cell injury, inflammation, healing & haemodynamics

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Introduction to pathology — cell injury, necrosis and apoptosis

Pathology is the study of disease — its cause (aetiology), the mechanism by which the cause produces the disease (pathogenesis), the structural changes in cells and tissues (morphology) and their functional consequences — and it begins with the cell, because every disease starts as injury to cells. Cell injury is reversible while the cell can adapt or recover and becomes irreversible at the point of death, which takes one of two forms: necrosis, the messy death of groups of cells that provokes inflammation, and apoptosis, the tidy programmed death of single cells that does not.

Causes of cell injury in rough order of frequency: hypoxia and ischaemia (the commonest — reduced blood flow, low oxygen, anaemia, poisoning of respiration), physical agents (trauma, heat, cold, radiation, electricity), chemicals and drugs (alcohol, paracetamol, carbon tetrachloride), infections, immune reactions, genetic defects and nutritional imbalance; the cell's most vulnerable systems are its ATP supply, membranes, protein synthesis and DNA.
Cells adapt before they die: atrophy (shrinkage — a limb in a cast, the brain in old age), hypertrophy (bigger cells — the left ventricle in hypertension, the muscle of the athlete), hyperplasia (more cells — the prostate of the old man, the endometrium under oestrogen), metaplasia (one adult cell type replaced by another better suited to the insult — the squamous lining of a smoker's bronchus, Barrett's oesophagus) and dysplasia, the disordered growth that is the step before cancer.
Reversible injury shows as cellular swelling (hydropic change, from failure of the sodium pump) and fatty change (triglyceride droplets, above all in the liver of the alcoholic, the diabetic and the malnourished); the point of no return is marked by severe membrane damage, the leak of enzymes into the blood (the troponin of the infarct, the transaminases of hepatitis) and the nuclear changes of pyknosis, karyorrhexis and karyolysis.
Necrosis by pattern: coagulative (the architecture is preserved as a ghost — ischaemic infarcts of heart, kidney and spleen), liquefactive (the tissue turns to fluid — the brain after a stroke, an abscess), caseous (cheesy — the granuloma of tuberculosis), fat necrosis (chalky white deposits from lipase — acute pancreatitis, trauma to the breast), fibrinoid (immune deposits in vessel walls — vasculitis, malignant hypertension) and gangrene, which is coagulative necrosis of a limb or bowel with putrefaction added.
Gangrene is dry (a mummified, black, shrivelled toe from slow arterial occlusion in atherosclerosis and diabetes, with a clear line of demarcation), wet (swollen, foul, spreading, from venous obstruction or infection — the diabetic foot, strangulated bowel) or gas gangrene (Clostridium perfringens in a contaminated wound, with crepitus and toxaemia, a surgical emergency).
Apoptosis is programmed cell death by a caspase cascade: single cells shrink, the chromatin condenses, the cell fragments into membrane-bound apoptotic bodies that are eaten by neighbours, and there is no inflammation; it is physiological in embryogenesis, the shedding of the endometrium, the involution of the lactating breast and the culling of immune cells, and pathological in viral hepatitis (councilman bodies), radiation and the tumour cell that escapes it — which is why cancers grow.
The leftovers of injury are read on slides and in the clinic: intracellular accumulations (lipofuscin, the wear-and-tear pigment of ageing; haemosiderin after bleeding or transfusion; melanin), and calcification — dystrophic in dead or damaged tissue with a normal serum calcium (tuberculous nodes, atheroma, damaged heart valves) and metastatic in normal tissue when the serum calcium is high (hyperparathyroidism, vitamin D excess, bone destruction).

Inflammation — acute and chronic, cardinal signs and mediators

Inflammation is the protective response of vascularised living tissue to injury — infection, trauma, heat, chemicals, immune reaction, necrosis — that brings fluid, proteins and leucocytes to the site to destroy the cause and clear the debris so that healing can begin. It is acute when it is rapid, short and dominated by neutrophils and fluid, and chronic when it is prolonged and dominated by macrophages, lymphocytes and fibrosis, and it is the pathology behind almost every -itis the nurse treats and every fever she charts.

The five cardinal signs: rubor (redness), calor (heat), tumor (swelling) and dolor (pain) described by Celsus, with functio laesa (loss of function) added by Virchow; redness and heat come from vasodilation, swelling from the exudate, pain from bradykinin and prostaglandins on nerve endings and from the pressure of the swelling.
The vascular events of acute inflammation: a momentary vasoconstriction, then vasodilation (histamine) that slows flow, increased permeability of the venules so that a protein-rich exudate leaks out, and stasis; an exudate has a protein above 3 g/dL, a specific gravity above 1.020 and cells, whereas a transudate — the fluid of heart failure or hypoalbuminaemia, not of inflammation — is protein-poor, clear and acellular.
The cellular events: leucocytes marginate and roll along the endothelium (selectins), adhere firmly (integrins), squeeze through the wall (emigration or diapedesis), follow chemical gradients to the injury (chemotaxis — complement C5a, leukotriene B4, bacterial products) and phagocytose it; neutrophils dominate the first 6 to 24 hours and monocytes-macrophages replace them by 24 to 48 hours, which is why a pus cell is a neutrophil.
The mediators the paper asks: histamine from mast cells (vasodilation and permeability — the first mediator), serotonin, prostaglandins (pain, fever, vasodilation — blocked by NSAIDs), leukotrienes (permeability, bronchospasm), bradykinin (pain), the complement fragments C3a and C5a, nitric oxide, and the cytokines interleukin-1 and tumour necrosis factor, which produce the fever, the acute-phase response and, in excess, septic shock.
Morphological types: serous (blister, pleural effusion), fibrinous (the bread-and-butter pericarditis of uraemia and rheumatic fever), suppurative or purulent (pus — an abscess is a localised collection of pus, a cellulitis a diffuse spread), haemorrhagic, catarrhal (mucous membranes — the common cold), membranous (the pseudomembrane of diphtheria) and ulcerative; the outcomes are resolution, healing by fibrosis, abscess formation and progression to chronic inflammation.
Chronic inflammation follows a persistent cause — tuberculosis, leprosy, a foreign body, an autoimmune disease, an unresolved acute inflammation — and is a mixture of macrophages, lymphocytes and plasma cells with tissue destruction and repair going on together; granulomatous inflammation is its special form, a granuloma being a collection of epithelioid macrophages, often with Langhans giant cells and a rim of lymphocytes, with central caseation in tuberculosis and none in sarcoidosis, leprosy, fungal infection and around sutures.
The systemic signs are the acute-phase response: fever (interleukin-1 and tumour necrosis factor act on the hypothalamus through prostaglandin E2), leucocytosis (neutrophilia in bacterial infection, lymphocytosis in viral, eosinophilia in parasites and allergy, leucopenia in typhoid and overwhelming sepsis), raised C-reactive protein, ESR and fibrinogen, anorexia, malaise and, when the response escapes control, sepsis and septic shock.

Healing and repair — wound healing, factors and complications

Healing is the body's replacement of dead or damaged tissue by living tissue, either by regeneration — the same cell type grows back — or by repair, in which connective tissue fills the gap and leaves a scar; which of the two happens depends on the tissue's capacity to divide and on how much of its framework the injury destroyed. Wound healing is the visible version of this process, examined for its two intentions, its phases and timing, and the local and systemic factors that delay it — the daily concern of every dressing round.

Tissues by regenerative capacity: labile cells divide throughout life and regenerate fully (skin, mucosa of the gut and airways, bone marrow, lymphoid tissue); stable cells are quiescent but can divide when injured (liver, kidney tubules, pancreas, fibroblasts, smooth muscle — the liver regrows after a resection); permanent cells cannot divide and heal only by scar (neurons, cardiac muscle, skeletal muscle) — which is why an infarct of the heart becomes fibrous tissue and a stroke leaves a cyst.
Repair by connective tissue passes through granulation tissue — new capillaries (angiogenesis), fibroblasts and macrophages in a loose, pink, granular, bleeding-on-touch bed that is the sign of a healthy wound — then collagen deposition, contraction by myofibroblasts, and remodelling into a pale scar; the scar reaches about 70 to 80 per cent of the original tensile strength by three months and never the full strength.
Healing by first (primary) intention is the healing of a clean incised wound whose edges are apposed by sutures: a thin clot, neutrophils within 24 hours, epithelium bridging the surface by 24 to 48 hours, macrophages and granulation by day 3, collagen bridging the incision by day 5, and a scar with sutures out at 7 to 10 days; healing by second intention is the healing of a large open or infected wound from the base up, with more granulation, more contraction, longer time and a bigger scar; third intention or delayed primary closure is a contaminated wound left open a few days and then sutured.
The phases overlap: haemostasis and inflammation (day 0 to 3 — platelets, fibrin, neutrophils, then macrophages, the wound warm and swollen), proliferation (day 3 to about three weeks — granulation, epithelialisation, collagen, contraction) and maturation or remodelling (three weeks to a year or more — collagen reorganised, the scar flattens and pales); a wound that is still inflamed at day 5 or has no granulation by day 7 is behind schedule.
Local factors that delay healing: infection (the commonest cause), a foreign body or necrotic tissue, poor blood supply (arterial disease, pressure, tension on the suture line, oedema), movement, a large or deep defect, a haematoma, radiation and repeated trauma; systemic factors: age, diabetes (glucose, neuropathy, ischaemia), malnutrition (protein, vitamin C for collagen, zinc, vitamin A), anaemia and hypoxia, obesity, smoking, uraemia, jaundice, and drugs — corticosteroids, cytotoxics and anti-inflammatories.
Complications: infection; wound dehiscence — the suture line gives way, typically at day 5 to 8 when the tissue is weakest, heralded by a gush of serosanguinous fluid, and evisceration when abdominal contents come through; hypertrophic scar (raised but within the wound's boundary, regresses) versus keloid (grows beyond the boundary, does not regress, commoner in dark skin and over the sternum, shoulder and earlobe, recurs after excision); contracture across a joint (burns), incisional hernia, a persistent sinus over a suture or foreign body, chronic non-healing ulcer, and malignant change in a chronic ulcer (Marjolin's).
Nursing that heals: aseptic technique and a dressing that keeps the wound bed moist and the surrounding skin dry, debridement of slough and necrotic tissue, offloading of pressure and oedema, glycaemic control, protein and calorie intake with vitamin C and zinc, stopping smoking, control of infection on culture rather than by guess, and the record — size, depth, bed, edge, exudate, surrounding skin — that shows whether the wound is on schedule; fracture healing follows the same logic through haematoma, soft and hard callus and remodelling.

Haemodynamic disorders — oedema, thrombosis, embolism, infarction and shock

The haemodynamic disorders are the disturbances of fluid and blood in the tissues and vessels — oedema and its opposite, dehydration; hyperaemia and congestion; haemorrhage; thrombosis; embolism; infarction; and shock — that follow from the physics of the circulation rather than from any one organ's disease. They are asked in every paper for Virchow's triad, the kinds of embolism and the classification of shock, and they are the pathology behind the swollen leg, the sudden breathlessness and the falling blood pressure the nurse must act on within minutes.

Oedema is excess fluid in the interstitial space, from increased hydrostatic pressure (heart failure, venous obstruction, a deep vein thrombosis), reduced plasma oncotic pressure (nephrotic syndrome, cirrhosis, protein-energy malnutrition), lymphatic obstruction (filariasis, after mastectomy — non-pitting), sodium retention (renal failure) or inflammation (an exudate); it pits over the tibia and sacrum, collects first where hydrostatic pressure is highest (the ankles, the sacrum in bed) and, when generalised, is anasarca.
Hyperaemia is active — arterial dilation, red and warm (exercise, inflammation, blushing) — and congestion is passive, venous, blue and cool (the nutmeg liver of right heart failure, the heart-failure cells and brown induration of the lung in left heart failure); haemorrhage is graded by size as petechiae (1 to 2 mm — platelet disorders, meningococcaemia), purpura (up to a centimetre), ecchymosis (a bruise) and haematoma, and by site (haemothorax, haemoperitoneum, haemarthrosis).
Thrombosis is clotting inside a living vessel, and Virchow's triad names its causes — endothelial injury (atheroma, catheters, vasculitis), abnormal flow (stasis in an immobile calf or a fibrillating atrium, turbulence at a bifurcation) and hypercoagulability (surgery, cancer, pregnancy and the pill, dehydration, factor V Leiden); arterial thrombi are pale, platelet-rich and form on atheroma, venous thrombi are red, fibrin-rich and form in the deep veins of the calf.
A thrombus is propagated, dissolved, organised and recanalised, or embolised; deep vein thrombosis is the great preventable one — the risks are immobility, surgery, pregnancy and the puerperium, oral contraceptives, malignancy, obesity and a previous clot — and its prevention is early ambulation, calf exercises, graduated compression stockings or pneumatic compression, hydration and prophylactic low-molecular-weight heparin in the at-risk.
An embolus is a detached mass carried in the blood to a site remote from its origin: a thromboembolus from a deep vein to the lung (pulmonary embolism, more than 95 per cent of emboli — sudden dyspnoea, pleuritic pain, tachycardia, collapse), fat from a fractured long bone (24 to 72 hours later — dyspnoea, petechiae over the chest and axillae, confusion), air from an open vein or central line (more than about 100 mL kills — nurse the patient in the left lateral head-down position), amniotic fluid in labour (collapse and disseminated intravascular coagulation), septic, tumour and paradoxical emboli through a patent foramen ovale.
An infarct is necrosis from loss of blood supply: white or pale in solid organs with a single arterial supply (heart, kidney, spleen), red or haemorrhagic in loose or doubly supplied tissue or after venous occlusion (lung, intestine, testicular torsion); the outcome depends on the collateral supply, the speed of occlusion, the tissue's oxygen tolerance (the brain dies in minutes, skeletal muscle survives hours) and the oxygen content of the blood.
Shock is systemic hypoperfusion of the tissues: hypovolaemic (haemorrhage, burns, diarrhoea, dehydration), cardiogenic (infarction, arrhythmia, tamponade), distributive (septic, anaphylactic, neurogenic — the vessels dilate, so septic shock is warm at first) and obstructive (massive pulmonary embolism, tension pneumothorax); it moves through a compensated stage (tachycardia, cool skin, normal pressure — the stage to catch), a progressive stage (hypotension, oliguria under 0.5 mL/kg/h, acidosis, confusion) and an irreversible stage of multi-organ failure.

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