16.2 — Cell Injury and Cell Death

Every disease is, at some level, cells behaving abnormally. And there are only a small number of ways a cell can be injured, and only a small number of ways it can respond — which is why apparently unrelated diseases produce such similar tissue changes.

The most important idea in this chapter is that there is a point of no return. Up to it, injury is reversible and the cell recovers completely. Past it, the cell dies whatever is done. Identifying where that point is, and what determines it, is the whole basis of emergency medicine.

The causes of cell injury

Six categories, and they cover everything.

Oxygen deprivation — the commonest and most important.

Three varieties, and they are not interchangeable. Hypoxia — low oxygen in the blood. Ischaemia — reduced blood flow. And ischaemia is worse than hypoxia, because it removes the glucose supply and the waste removal as well as the oxygen.

A tissue with hypoxic blood can still run glycolysis; a tissue with no blood flow cannot (Chapter 1.6).

Physical agents — trauma, temperature extremes, radiation, electricity, pressure changes.

Chemical agents and drugs — including oxygen at high concentration, which is toxic.

Infectious agents.

Immunological reactions — including autoimmunity, and including the immune response to an infection, which frequently causes more damage than the organism.

Genetic defects and nutritional imbalances.

Reversible injury

Two changes, both of which follow from the same failure.

Cellular swelling. ATP falls, so the sodium–potassium pump slows (Chapter 1.4). Sodium accumulates inside, water follows osmotically, and the cell swells.

This is the first structural change in almost any injury, and it is entirely reversible.

Fatty change. Lipid accumulating in the cytoplasm, particularly in liver, heart and kidney. Common in alcohol, obesity and toxin exposure, and also reversible.

And that reversibility is the point of the whole chapter. A fatty liver from alcohol or obesity is not damage in the permanent sense; it resolves entirely if the cause is removed (Chapter 9.4). Which is why identifying it early matters so much.

The point of no return

Two events mark it, and neither can be undone.

Severe membrane damage — the cell can no longer maintain any gradient.

Massive calcium influx — and this is the crucial one.

Cells hold their internal calcium about ten thousand times lower than the outside (Chapter 10.3), and it costs energy to do so. When ATP fails, calcium floods in.

And calcium activates a set of destructive enzymes simultaneously: proteases that digest the cytoskeleton, phospholipases that destroy membranes, ATPases that consume what little energy remains, and endonucleases that fragment DNA.

So the cell's own machinery, released from restraint, destroys it.

The other irreversible event is mitochondrial permeability transition — pores opening in the inner mitochondrial membrane, collapsing the proton gradient (Chapter 1.6). Once that happens, no ATP can be made and recovery is impossible.

Which is why the timings in emergency medicine are what they are. Brain: 4 to 6 minutes. Heart muscle: 20 to 30 minutes. Kidney: 30 minutes to an hour. Skeletal muscle: 2 to 4 hours.

The differences track energy demand, glycolytic capacity and stored substrate — which is exactly why the brain, with the highest demand and no reserve, goes first (Chapter 1.1).

Reperfusion injury

And here is a result that is genuinely counter-intuitive: restoring the blood supply causes additional damage.

Three mechanisms.

Oxygen returning to tissue with disrupted mitochondria produces a burst of reactive oxygen species, which damage membranes, proteins and DNA.

Calcium overload worsens as the blood supply delivers more.

And inflammation. Neutrophils arrive, activate, and release their contents into tissue that is already injured (Chapter 13.1).

Complement is activated by proteins exposed on damaged cells.

So a proportion of the final damage in a heart attack or stroke is caused by the treatment that saved the tissue.

And this is not an argument against reperfusion — the net effect is overwhelmingly beneficial, and every minute of delay costs more than reperfusion injury adds. It is an argument for the research effort into limiting it, which has so far produced very little that works in humans despite a great deal that works in animals — a recurring pattern worth noting.

Therapeutic hypothermia after cardiac arrest (Chapter 14.2) is one intervention that does appear to help, by reducing metabolic demand during the vulnerable period.

The two ways cells die

Chapter 1.8 established the distinction. Here is why it matters clinically.

Necrosis — death by injury. The cell swells and bursts, spilling its contents. Always affects groups of cells. Always causes inflammation, because the released contents are danger signals (Chapter 13.1).

Apoptosis — death by instruction. The cell shrinks, fragments, and is neatly removed. Affects single cells. No inflammation.

And the practical distinction is visible in the patient. Necrosis produces pain, swelling, fever and a raised white cell count. Apoptosis produces none of those — which is why the loss of neurons in a neurodegenerative disease is silent while a stroke is not.

And enzymes leak from necrotic cells into the blood, which is the basis of a large part of diagnostic medicine (Chapter 1.3): troponin from heart muscle, ALT and AST from liver, creatine kinase from skeletal muscle, amylase and lipase from pancreas.

Apoptosis releases nothing measurable, which is exactly why it is harder to detect and harder to treat.

Patterns of necrosis

And the pattern tells a pathologist the cause, which is why they are named.

Coagulative necrosis — the tissue architecture is preserved for days, looking like a pale shadow of itself. The enzymes that would digest it are themselves denatured by the acidosis. The pattern of ischaemic death in every organ except the brain.

Liquefactive necrosis — the tissue dissolves into liquid. Occurs in bacterial infection, where neutrophil enzymes digest everything — this is what pus is — and, uniquely among organs, in the brain.

The brain is the exception because it has little supporting connective tissue and abundant lysosomal enzymes, so an infarct liquefies and leaves a fluid-filled cavity rather than a scar. Which is why brain tissue is not replaced.

Caseous necrosis — cheese-like, crumbly. Characteristic of tuberculosis (Chapter 17.8), and the appearance is distinctive enough to be diagnostic.

Fat necrosis — in acute pancreatitis, where released lipase digests surrounding fat and the fatty acids bind calcium (Chapter 9.5).

Fibrinoid necrosis — in blood vessel walls, in vasculitis and malignant hypertension.

Gangrene — a clinical rather than a microscopic term. Dry gangrene is coagulative necrosis from arterial occlusion, and the tissue is black and mummified. Wet gangrene has bacterial infection superimposed, and it spreads. Gas gangrene is clostridial infection producing gas in the tissue — a surgical emergency with a very short timeline.

Adaptation

Before injury, cells adapt. And every adaptation is reversible if the stimulus stops, which is the useful part.

Hypertrophy — cells get bigger. Muscle with exercise; the left ventricle in hypertension (Chapter 7.6); the uterus in pregnancy.

Hyperplasia — more cells. The breast in pregnancy; the endometrium under oestrogen; the prostate with age (Chapter 10.5).

Atrophy — cells shrink. Disuse, denervation, loss of blood supply, loss of hormonal stimulation, ageing.

And disuse atrophy is fast and clinically significant. Complete bed rest costs 1 to 1.5 percent of muscle mass per day in older adults (Chapter 6.7), which is why immobility in hospital is now treated as a harm rather than an inevitability.

Metaplasia — one differentiated cell type replaced by another.

And this is where adaptation shades into risk. In a smoker, the ciliated airway lining is replaced by squamous epithelium — tougher, and unable to clear mucus (Chapter 8.1). In reflux, the oesophageal squamous lining is replaced by intestinal-type lining — Barrett's oesophagus, which tolerates acid better and carries an increased cancer risk (Chapter 9.1).

Metaplasia is a sensible short-term adaptation that removes a protective function and creates a site where dysplasia can develop.

Dysplasia — disordered growth with abnormal cells. Not cancer, and a recognised precursor. Potentially reversible if the stimulus is removed, and the basis of cervical screening (Chapter 15.3).

Accumulations

Cells store what they cannot process, and the deposits are diagnostic.

Lipid — fatty liver; cholesterol in atherosclerotic plaques (Chapter 18.1).

Protein — misfolded proteins in the neurodegenerative diseases (Chapter 1.3).

Glycogen — in the glycogen storage diseases and in poorly controlled diabetes.

Pigments. Lipofuscin — "wear and tear pigment" — accumulates with age in heart, liver and neurons, and is essentially indigestible debris from lipid peroxidation. Haemosiderin from iron overload (Chapter 2.8). Carbon in the lungs of city dwellers and miners.

Calcium. Dystrophic calcification — calcium depositing in dead or damaged tissue with normal blood calcium. Occurs in atherosclerotic plaques, damaged heart valves, old tuberculous lesions, and in breast tissue — where microcalcifications on a mammogram are one of the earliest signs of ductal carcinoma in situ.

Metastatic calcification — deposition in normal tissue because blood calcium is high (Chapter 10.3).

Free radicals and antioxidants

Reactive oxygen species are produced continuously by normal metabolism — the electron transport chain leaks a small percentage of electrons (Chapter 1.6) — and by radiation, drugs, inflammation and reperfusion.

They damage lipids, proteins and DNA.

The body's defences are substantial: superoxide dismutase, catalase (Chapter 1.5), glutathione, and dietary vitamins C and E.

And this is where a widely believed idea deserves correcting.

The free radical theory of ageing — that accumulated oxidative damage causes ageing, and that antioxidant supplements should therefore slow it — has not survived testing.

Large trials of antioxidant supplements have consistently failed to show benefit, and several have shown harm. Beta-carotene supplements increased lung cancer in smokers. High-dose vitamin E increased mortality in meta-analyses. Antioxidant supplementation during exercise blunts some of the training adaptations, apparently because the reactive species are part of the signal.

The current understanding is that reactive oxygen species are signalling molecules as well as damaging ones, and that suppressing them indiscriminately interferes with useful processes.

Fruit and vegetables remain beneficial. Isolated high-dose antioxidant supplements do not, and the difference between those two statements is one of the more useful things in nutrition (Chapter 24.2).

Ageing at the cellular level

Several mechanisms, and they interact.

Telomere shortening and the Hayflick limit (Chapter 1.7).

Cellular senescence — cells that stop dividing permanently but do not die. And they are not inert: senescent cells secrete inflammatory signals — the senescence-associated secretory phenotype — which damages neighbouring tissue.

Which makes them a treatment target. Senolytic drugs, which selectively kill senescent cells, extend healthy lifespan in mice. Human trials are early, and the results so far are promising rather than established, and it is worth being clear that no anti-ageing drug has yet been shown to work in humans.

Accumulated DNA damage, mitochondrial dysfunction, protein misfolding, epigenetic drift, and stem cell exhaustion.

And the frequently repeated claim that "you replace all your cells every seven years" is wrong. Turnover varies from days to never: gut lining 3 to 5 days, skin 4 weeks, red cells 120 days, liver about a year, fat cells about 8 years, and cortical neurons, heart muscle cells and the lens of the eye essentially never (Chapters 1.7, 5.1).

Carbon dating of cells using the atmospheric carbon-14 spike from nuclear testing established this directly — a genuinely clever method, using the fallout of the 1950s and 60s as a global time stamp.

What the next page fixes

Cell death triggers a response, and that response is where most of the visible features of disease come from. Chapter 16.3 covers inflammation and repair as a general process — acute, chronic, and what determines whether tissue is restored or scarred.