Contents
Introduction
Injury to cells, tissues and organs is the initiating step in many diseases. Although injury typically conjures up images of some form of trauma, it covers a far more diverse set of processes that damage cells when used as a pathological term.
Infection
Infectious diseases are an important cause of morbidity and mortality, particularly on a planetary scale. Approximately one-third of the global population reside in countries where malaria is endemic; around one-third of the global population have been infected by the hepatitis B virus; schistosomiasis affects around two hundred million people; new cases of tuberculosis are in the region of ten million per year.
Infections can cause disease by a variety of mechanisms and are discussed in their own section.
Autoimmune Disease
Autoimmune diseases arise when the immune system launches an attack against the body's own tissues. They account for a diverse array of conditions and are a significant cause of morbidity and mortality. They are discussed in a separate section.
Hypoxia
Along with infection and autoimmune disease hypoxic injury produces a major burden of morbidity and mortality.
Hypoxia is the term used to describe inadequate oxygen supply to the tissues.
Infarction is necrosis of a tissue or organ due to a disruption of its blood supply that produces complete hypoxia. The related term
ischaemia denotes inadequate blood flow to an organ which prevents that organ from functioning normally. Ischaemia may not necessarily progress to full blown infarction but the ice on which an ischaemic organ is skating is thin. Myocardial infarction and cerebrovascular accidents are very common diseases that are caused by infarction-mediated hypoxia. A less well known entity is intermittent claudication.
Hypoxia is classified into several subtypes.
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Hypoxic
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The rather insistently named hypoxic hypoxia applies to conditions in which the partial pressure of oxygen in the blood is reduced. It occurs either in marked lung dysfunction or in exposure to atmospheres that have a low partial pressure of oxygen.
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Ischaemia
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Ischaemic hypoxia is also known as stagnant hypoxia. The blood is adequately oxygenated and can carry and release oxygen normally but is unable to reach the ischaemic organ or organs.
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Anaemic
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The partial pressure of oxygen in the blood can be adequate but if the number of erythrocytes is insufficient and/or the erythrocytes contain insufficient haemoglobin and/or the haemoglobin is defective the ability of the blood to carry oxygen is impaired. Carbon monoxide poisoning is an example of anaemic hypoxia. The carbon monoxide binds to haemoglobin with around 200 times the affinity of oxygen and therefore prevents the haemoblogin from carrying oxygen. Anaemia due to a loss of red cells has to be severe to produce hypoxia.
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Histotoxic
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In histotoxic hypoxia the blood is adequately oxygenated and its oxygen carrying capacity is normal but the tissues are unable to utilise the oxygen when it is delivered to them. This form of hypoxia is rare. The typically quoted example is cyanide poisoning.
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Disordered Metabolism
In relation to a category of injury the term metabolism is employed in a broad sense to cover nutritional disorders and disturbances of electrolytes as well as damage that arises due to defective metabolic pathways.
Deficiencies of certain essential nutrients cause disease because the body cannot function properly in the absence of the necessary raw materials for energy conversion and construction of new and replacement components. The clinical features that develop may be very specific for nutrients that have a particular function, or can be generalised in the case of inadequate intake of calories. For example, vitamin C deficiency results in scurvy, in which the cross-linking of collagen cannot occur.
Electrolyte disturbances are usually detected in the blood and may be in the form of raised or reduced levels. They typically impact on electrically excitable tissues (heart, skeletal muscle, brain). Direct injury is unusual but the organ dysfunction that results can cause secondary damage. Disorders of acid-base metabolism are technically electrolyte disturbances but are usually referred to separately.
Many disorders of metabolic pathways are due to inherited genetic defects. They can cause disease by producing blockages in metabolic pathways, leading to an accumulation of substrates and a deficiency of products, either or both of which can be harmful. Genetic disease may also affect structural proteins.
In some instances, disordered metabolism is itself the result of an underlying injury (such as coeliac disease which is an autoimmune disorder that targets the epithelial cells of the small intestine; the autoimmune damage to the small intestine produces malabsorption and many of the symptoms of coeliac disease relate to the effects of malabsorption even though the primary mechanism of injury is autoimmune).
Radiation
Radiation-related injury can be the consequence of exposure to electromagnetic radiation or radioactive decay (gamma rays fall into both categories).
Radiation is harmful due to its ability to ionise molecules and generate oxygen free radicals that can react with proteins, lipids and DNA. High levels of radiation produce widespread, fatal damage in cells due to the sheer number of proteins and DNA sites that are harmed. Lower levels exert their effect by mutating DNA.
Alpha, beta and ultraviolet radiation have poor penetrating power and tend only to affect the skin. By constrast, X-rays and gamma rays can penetrate through the entire body and therefore are associated with disease in deeper organs.
The most important form of harmful electromagnetic radiation, in terms of the number of people affected, is ultraviolet light. UV light is a key factor in the development of cutaneous basal cell carcinoma, squamous cell carcinoma and melanoma.
The harmful effects of X-rays need to be borne in mind within radiology departments, both in terms of avoiding subjecting patients to unnecessary radiation-employing investigations and in relation to ensuring that staff do not receive harmful exposure.
Microwave and gamma ray radiation are typically risks only for workers in specialised industries.
Infra-red radiation is a cause of cataracts in glass blowers.
Radioactive decay (alpha, beta and gamma radiation) is primarily a problem for workers in the nuclear industry or in people affected by radioactive fallout from the Hiroshima and Nagasaki bombs or nuclear reactor catastrophes. However, radon gas is a more widespread source of radiation. Its radioactive decay pathway generates alpha, beta and gamma radiation. Radon is particularly common in regions that have granite bedrock and it can accumulate in buildings.
Thermal Injury
Human physiology expends considerable effort in maintaining core body temperature within a narrow range. While the mechanisms that preserve body temperature in a cold environment and increase heat loss in a warm environment allow effective function within a good range of climates, especially when supplemented with clothes, extremes of temperature can impair body function and cause damage.
Cold
Hypothermia occurs if core body temperate drops below 35C. A low temperature reduces the efficacy of enzymes and generally slows metabolism. Pulse and the respiratory rate decrease, out of proportion to the reduction in metabolic activity, so tissues are hypoperfused with hypoxic blood. Furthermore, the viscosity of blood increases when the temperature falls, partly because the endothelium becomes more leaky and therefore plasma is lost into the tissues thereby reducing the fluid component of the blood. The sludgy blood flows less well, exacerbating the problems of hypoperfusion. Thrombosis and infarction can result. Cerebral function is particularly susceptible to impaired blood flow.
Frostbite is a specific form of cold-induced injury in which rapid freezing results in ice crystals forming in tissues and inside cells. The cells rupture. The water in the blood in the extremeties can also freeze, inducing infarction and vascular damage secondary to the expansion of the water when it transforms into ice. The result is necrosis. The extremeties are most likely to be affected because they are typically the coldest parts of the body.
Heat
An extreme elevation of core body temperature (hyperthermia) also disrupts essential physiology, in part due to interference with enzyme function. However, most instances of heat-related injury are produced by hyperthemic states of core body temperate but by the more sudden and localised application of heat in the form of burns.
Burns are the pattern of injury that occurs when the temperature of part of the body, usually the skin, is rapidly and markedly raised by contact with a substance that is much hotter. The common causative agents are hot water or hot metal. In a literal sense the damage that is caused by the heat can be described as melting of the heated tissue: lipid membranes melt, proteins are denatured and cells are killed. Beyond the local loss of dermal tissue there are secondary complications that reflect the basic functions of the skin. Burnt areas of the skin lose fluid and heat. They also represent breaches in the physical barrier component of the innate immune system. If the burns are extensive the disturbance to normal heat and fluid balance can be severe.
Electrical Injury
Many of the aspects of electrical injury, particularly those inflicted by high currents, are similar to burns. The passage of the electric current through the body generates heat because of the resistance to conduction provided by tissues. However, electrocution poses specific risks to excitable tissue. Nerves, cardiac muscle and skeletal muscle are conduits of relatively low resistance and may be preferential routes for the passage of electric current. The current can disrupt the normal electrical activity of the heart and precipitate a fatal arrhythmia.
Chemical Injury
Chemical injury may induce damage by assorted mechanisms. Corrosive and caustic agents operate by crude destruction through oxidation and reduction based reactions. However, other chemicals will give rise to disease by more selective or subtle mechanisms, while a futher cohort, such as some carcinogens, fall in the centre of the spectrum. Poisons would be included in the category of chemical injury. Drugs are another important causes of chemical injury.
Mechanical Trauma
Mechanical trauma encompasses the typical concept of injury, some form of blunt or penetrating trauma or rapid acceleration/deceleration that is produced by macroscopically visible, often everyday, objects or processes. Mechanical trauma is usually associated with damage to blood vessels, either partial or complete transection or rupture; the injury to the adjacent tissue is normally of the same pattern. There can also be tearing, fracture, perforation or rupture of organs, rupture of ligaments and fractures of bones.
Trophic Factor Deprivation
This is a rare form of injury that is mentioned for completeness. Rather than being the primary cause of cell damage of death it may be an intermediary mechanism that is itself caused by one of the other types of injury.
Some tissues require a steady supply of a trophic (or nourishing) factor to maintain health. If this trophic factor is withdrawn, the tissue may undergo atrophy (this is not necessarily injury as such although its consequences for the organism as a whole can be harmful) or apoptosis. The trophic agent is often in the form of a growth factor or stimulating hormone. For example, the adrenal cortex requires stimulation by adrenocorticotrophic hormone (ACTH). If the supply of ACTH is deficient the adrenal cortex will atrophy. Skeletal muscle bulk is preserved by use and basal stimulation from lower motor neurones. If the lower motor neurone supply to a muscle is lost, the muscle will suffer disuse atrophy.
Tolerance of Injury
How a tissue or organ responds to an injury will depend not just on the nature of the insult or its severity but will also be affected by the properties of the tissue.
Labile tissues are constantly turning over and replacing their cells. Examples include the skin and the mucosa of the gastrointestinal tract. These tissues can respond to injury by cranking up their rate of cell production. However, their high mitotic activity makes them susceptible to insults that interfere with cell division, such as chemotherapy.
Stable tissues include the liver. They do not normally manifest much proliferative activity but if disaster strikes they can activate their proliferative capacity and regenerate. In the case of the liver this regeneration can be remarkably effective.
Permanent tissues have little to no regenerative ability. Examples include neurones and cardiac myocytes. Any cells that are lost through injury cannot be replaced. However, they are not vulnerable to many chemotherapy strategies that target rapidly dividing cells (unfortunately, drugs that damage the mitotic spindle, such as vinca alkaloids, are not popular with neurones because they work by interfering with the function of microtubules and neurones are dependent on good microtubule function to preserve their axons).
Beyond these categories there are other nuances that affect how a tissue copes with injury. In particular neurones and cardiac myocytes tolerate ischaemia very poorly due to their high metabolic activity and lack of ability to make effective use of anaerobic metabolism.
At a cellular level, any cell can absorb a certain amount of damage and recover. However, once a critical level of injury has been reached, the cell damage becomes irreversible and incompatible with continued function, so the death of the cell is inevitable.