Characteristics, classification and incidence of disease

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Chapter 2 Characteristics, classification and incidence of disease

What is disease? 12
Nomenclature of disease 19
Principles of disease classification 20


A disease is a condition in which the presence of an abnormality of the body causes a loss of normal health (dis-ease). The mere presence of an abnormality is insufficient to imply the presence of disease unless it is accompanied by ill health, although it may denote an early stage in the development of a disease. The word disease is, therefore, synonymous with ill health and illness.

Each separately named disease is characterised by a distinct set of features (cause, signs and symptoms, morphological and functional changes, etc.). Many diseases share common features and thereby are grouped together in disease classification systems.

The abnormalities causing diseases may be structural or functional, or both. In many instances the abnormalities are obvious and well characterised (e.g. a tumour); in other instances the patient may be profoundly unwell but the nature of the abnormality is less well defined (e.g. depressive illness).

Limits of normality

Normal is impossible to define as a single discrete state for any biological characteristic. In addition to differences between individuals, the human body changes naturally during fetal development, childhood, puberty, pregnancy (gender permitting), ageing, etc. Therefore, ‘normal’ means the most frequent state in a population defined by age distribution, gender, etc.

Most quantifiable biological characteristics are normally distributed, in statistical terms, about an average value. There are no constant numbers that can be used to define a normal height, weight, serum sodium concentration, etc. Normality, when quantifiable, is expressed as a normal range, usually encompassed by two standard deviations (for a ‘normally’ distributed feature) either side of the mean (Ch. 4). The probability that a measurable characteristic is abnormal increases the nearer it is to the limits of the normal range, but a value lying outside the normal range is not necessarily indicative of abnormality—it is just very probably abnormal.

A distinction must also be drawn between what is usual and what is normal. It is usual to find atheroma (Ch. 13) in an elderly individual—but is it normal? In contrast, atheroma in a teenager is so unusual that it would be regarded as abnormal and worthy of further investigation.

Responses to the environment

The natural environment of any species contains potentially injurious agents to which the individual or species must either adapt or succumb.


Adaptation of the individual to an adverse environment is well illustrated by the following examples. Healthy mountaineers ascending rapidly to the rarefied atmosphere at high altitudes often develop ‘mountain sickness’; they recover by a process of adaptation (increased haemoglobin, etc.), but failure to do so can result in death from heart failure. Fair-skinned people get sunburnt from excessive exposure to ultraviolet light from the sun; some adapt by developing a protective tan, but untanned individuals run a higher risk of skin cancer if they persist in unprotected exposure to the sun for long periods. Environmental micro-organisms are a common cause of disease; those individuals who develop specific defences against them (e.g. antibodies) can resist the infection, but those who fail to adapt may succumb.

Disease: failure of adaptation

Susceptibility of a species to injurious environmental factors results in either its extinction or, over a long period, the favoured selection of a new strain of the species better adapted to withstand such factors. However, this holds true only if the injury manifests itself in the early years of life, thus thwarting propagation of the disease susceptibility by reproduction. If the injury manifests only in later life, or if a lifetime of exposure to the injurious agent is necessary to produce the pathological changes, then the agent produces no evolutionary pressure for change.

An arguable interpretation of disease is that it represents a set of abnormal bodily responses to agents for which, as yet, the human species has little or no tolerance.

Darwinian medicine

The relatively new science of Darwinian medicine is based on the belief that diseases not only have proximate causes and mechanisms (e.g. viruses, bacteria, mutations) but also have evolutionary causes. Darwinian medicine focuses on the latter aspect and, while it may not yield cures for many serious diseases, it can help us to understand their current prevalence. Darwinian medicine is also rooted in the belief that natural selection favours reproductive success rather than health or life-span.

In Why we get sick: the new science of Darwinian medicine, Randolph Nesse, an evolutionary biologist, and George Williams, a psychiatrist, explain the application of evolutionary ideas to medicine with these examples:

Pyrexia and malaise in patients with infections, while unpleasant, have evolved as a way of compromising the metabolism of pathogenic organisms. Thus, antipyretic treatments (e.g. paracetamol) that make the patient more comfortable can prolong the illness.
Microbes evolve more rapidly than humans, thus explaining the perpetual struggle against infection and its worsening by the inappropriate use of antibiotics to which resistance soon develops.
Some modern health problems are due to the evolutionary legacy of thrifty ‘stone age’ bodies living in a plentiful modern environment, thus explaining the rising prevalence of obesity.
Allergic reactions are due to an immune system that is biased towards hypersensitivity to innocent agents rather than insufficient reactivity to genuine threats.

Ageing and adaptation

One of the main features of ageing is progressive inability of the individual to deal with new or worsening environmental threats (Ch. 12). This is exemplified by the gradual impairment of immune responses, resulting in:

re-emergence of dormant infections such as tuberculosis and herpes zoster
failure to mount an effective immune response to newly encountered pathogens.

Disease predisposition as an adaptive advantage

Paradoxically, a disease or disease predisposition can have beneficial effects on the individual. A few diseases or susceptibilities to diseases, in addition to their deleterious effects, confer adaptive protection against specific environmental pathogens. This advantage may explain the high prevalence of a disease in areas where the specific pathogen for another disease is endemic.

The best examples are:

the sickle cell gene (HbS) and the glucose-6-phosphate dehydrogenase (G6PD) deficiency gene which confer protection against malaria by creating a hostile environment for the plasmodium parasite within red cells
heterozygosity for the most common mutation (deletion of phenylalanine at position 508) in the cystic fibrosis conductance regulator which renders the individual less susceptible to Salmonella typhi infection.


image Aetiology:the cause of a disease
image Pathogenesis: the mechanism causing the disease
image Pathological and clinical manifestations: the structural and functional features of the disease
image Complications and sequelae: the secondary, systemic or remote consequences of a disease
image Prognosis: the anticipated course of the disease in terms of cure, remission, or fate of the patient
image Epidemiology: the incidence, prevalence and population distribution of a disease

All diseases have a set of characteristic features enabling them to be better understood, categorised and diagnosed. For many diseases, however, our knowledge is still incomplete or subject to controversy. The characteristics of any disease are (Fig. 2.1):

aetiology (or cause)
pathogenesis (or mechanism)
morphological, functional and clinical changes (or manifestations)
complications and sequelae (or secondary effects)
prognosis (or outcome)
epidemiology (or incidence).

Fig. 2.1 Characteristics of disease. The relationship between aetiology, pathogenesis, morphological and functional manifestations, and complications and sequelae is exemplified by four diseases. image Skin abscess. image Lung cancer. image Cirrhosis. image Primary hypertension.

The aetiology and pathogenesis of a disease may be combined as aetiopathogenesis.


The aetiology of a disease is its cause: the initiator of the subsequent events resulting in the patient’s illness. Diseases are caused by a variable interaction between host (e.g. genetic) and environmental factors. Environmental causes of diseases are called pathogens, although this term is used commonly only when referring to microbes; bacteria capable of causing disease are pathogenic bacteria and those that are harmless are non-pathogenic.

General categories of aetiological agents include:

genetic abnormalities
infective agents, e.g. bacteria, viruses, fungi, parasites
mechanical trauma.

Some diseases are due to a combination of causes, such as genetic factors and infective agents, and are said to have a multifactorial aetiology.

Sometimes the aetiology of a disease is unknown, but the disease is observed to occur more commonly in people with certain constitutional traits, occupations, habits or habitats; these are regarded as risk factors. These factors may provide a clue to an as yet unidentified aetiological agent. Other risk factors may simply have a permissive effect, facilitating the development of a disease in that individual; examples include malnutrition, which favours infections.

Some agents can cause more than one disease depending on the circumstances; for example, ionising radiation can cause rapid deterioration leading to death, scarring of tissues, or tumours.

Identification of the causes of disease

In terms of causation, diseases may be:

entirely genetic
multifactorial (genetic and environmental interplay)
entirely environmental.

Most common diseases have an entirely environmental cause, but genetic influences in disease susceptibility are being increasingly discovered, and many diseases with no previously known cause are being shown to be due to genetic abnormalities (Ch. 3). This is the reward of applying the principles of clinical genetics and the new techniques of molecular biology to the study of human disease. The extent to which a disease is due to genetic or environmental causes can often be deduced from some of its main features or its association with host factors.

Features pointing to a significant genetic contribution to the occurrence of a disease include a high incidence in particular families or races, or an association with an inherited characteristic (e.g. gender, blood groups, histocompatibility alleles). Diseases associated with particular occupations or geographic regions tend to have an environmental basis; the most abundant environmental causes of disease are microbes (bacteria, viruses, fungi, etc.).

Probability of disease

The relationship between the quantity of causal agent and the probability that disease will result is not always simply linear (Fig. 2.2). For example, many infections occur only on exposure to a sufficient dose of micro-organisms; the body’s defence mechanisms have to be overcome before disease results. Some agents capable of causing disease, such as alcohol, are actually beneficial in small doses; those who abstain from alcohol have a slightly higher risk of premature death from ischaemic heart disease.


Fig. 2.2 Relationships between the amount of a causal agent and the probability of disease. image Physical agents. For example, the risk of traumatic injury to a pedestrian increases in proportion to the kinetic energy of the motor vehicle. image Infectious agents. Many infectious diseases result only if sufficient numbers of the micro-organism (e.g. bacterium, virus) are transmitted; smaller numbers are capable of being eliminated by the non-immune and immune defences. image Allergens. In sensitised (i.e. allergic) individuals, minute amounts of an allergen will provoke a severe anaphylactic reaction. image J-shaped curve. Best exemplified by alcohol, of which small doses (c. 1–2 units per day) reduce the risk of premature death from ischaemic heart disease, but larger doses progressively increase the risk of cirrhosis.

Host predisposition to disease

Many diseases are the predictable consequence of exposure to the initiating cause; host factors make relatively little contribution. This is particularly true of physical injury: the immediate results of mechanical trauma or radiation injury are dose-related; the outcome can be predicted from the strength of the injurious agent.

Other diseases are the probable consequence of exposure to causative factors, but they are not inevitable. This is exemplified by infections with potentially harmful bacteria: the outcome can be influenced by various host factors such as nutritional status, genetic influences and pre-existing immunity.

Some diseases occur more commonly in individuals with a congenital predisposition. For example, ankylosing spondylitis (Ch. 25), a disabling inflammatory disease of the spinal joints of unknown aetiology, occurs more commonly in individuals with the HLA-B27 allele.

Some diseases predispose patients to the risk of developing other diseases. Diseases associated with an increased risk of cancer are designated premalignant conditions; for example, hepatic cirrhosis predisposes to hepatocellular carcinoma, and ulcerative colitis predisposes to carcinoma of the large intestine. The histologically identifiable antecedent lesion from which the cancers directly develop is designated the premalignant lesion.

Some diseases predispose to others because they have a permissive effect, allowing environmental agents that are not normally pathogenic to cause disease. This is exemplified by opportunistic infections in patients with impaired defence mechanisms resulting in infection by organisms not normally harmful (i.e. non-pathogenic) to humans (Ch. 9). Patients with leukaemia or the acquired immune deficiency syndrome (AIDS), organ transplant recipients, or other patients treated with cytotoxic drugs or steroids, are susceptible to infections such as pneumonia due to Aspergillus fungi, cytomegalovirus or Pneumocystis jiroveci.

Causes and agents of disease

It is argued that a distinction should be made between the cause and the agent of a disease. For example, tuberculosis is caused, arguably, not by the tubercle bacillus (Mycobacterium tuberculosis) but by poverty, social deprivation and malnutrition—the tubercle bacillus is ‘merely’ the agent of the disease; the underlying cause is adverse socio-economic factors. There is, in fact, incontrovertible evidence that the decline in incidence of many serious infectious diseases is attributable substantially to improvements in hygiene, sanitation and general nutrition rather than to immunisation programmes or specific antimicrobial therapy. Such arguments are of relevance here only to emphasise that the socio-economic status of a country or individual may influence the prevalence of the environmental factor or the host susceptibility to it. In practice, causes and agents are conveniently embraced by the term aetiology.

Causal associations

A causal association is a marker for the risk of developing a disease, but it is not necessarily the actual cause of the disease. The stronger the causal association, the more likely it is to be the aetiology of the disease. Causal associations become more powerful if:

they are plausible, supported by experimental evidence
the presence of the disease is associated with prior exposure to the putative cause
the risk of the disease is proportional to the level of exposure to the putative cause
removal of the putative cause lessens the risk of the disease.

The utility of these statements is exemplified by reference to the association between lung cancer and cigarette smoking. Lung cancer is more common in smokers than in non-smokers; tobacco yields carcinogenic chemicals; the risk of lung cancer is proportional to cigarette consumption; population groups that have reduced their cigarette consumption (e.g. doctors) show a commensurate reduction in their risk of lung cancer.

Causal associations may be neither exclusive nor absolute. For example, because some heavy cigarette smokers never develop lung cancer, smoking cannot alone be regarded as a sufficient cause; other factors are required. Conversely, because some non-smokers develop lung cancer, smoking cannot be regarded as a necessary cause; other causative factors must exist.

Causal associations tend to be strongest with infections. For example syphilis, a venereal disease, is always due to infection by the spirochaete Treponema pallidum; there is no other possible cause for syphilis; syphilis is the only disease caused by Treponema pallidum.

Koch’s postulates

An infective (e.g. bacterial, viral) cause for a disease is not usually regarded as proven until it satisfies the criteria enunciated by Robert Koch (1843–1910), a German bacteriologist and Nobel prizewinner in 1905:

The organism must be sufficiently abundant in every case to account for the disease.
The organism associated with the disease can be cultivated artificially in pure culture.
The cultivated organism produces the disease upon inoculation into another member of the same species.
Antibodies to the organism appear during the course of the disease.

The last was added subsequently to Koch’s list. Although Koch’s postulates have lost their novelty, their relevance is undiminished. However, each postulate merits further comment because there are notable exceptions:

In some diseases the causative organism is very sparse. A good example is tuberculosis, where the destructive lung lesions contain very few mycobacteria; in this instance, the destruction is caused by an immunological reaction triggered by the presence of the organism.
Cultivation of some organisms is remarkably difficult, yet their role in the aetiology of disease is undisputed.
Ethics prohibit wilful transmission of a disease from one person to another, but animals have been used successfully as surrogates for human transmission.
Immunosuppression may lessen the antibody response and also render the host extremely susceptible to the disease. In addition, if an antibody is detected it should be further classified to confirm that it is an IgM class antibody, denoting recent infection, rather than an IgG antibody, denoting long-lasting immunity due to previous exposure to the organism.


The pathogenesis of a disease is the mechanism through which the aetiology (cause) operates to produce the pathological and clinical manifestations. Groups of aetiological agents often cause disease by acting through the same common pathway of events.

Examples of pathogeneses of disease include:

inflammation: a response to many micro-organisms and other harmful agents causing tissue injury
degeneration: a deterioration of cells or tissues in response to, or failure of adaptation to, a variety of agents
carcinogenesis: the mechanism by which cancer-causing agents result in the development of tumours
immune reactions: undesirable effects of the body’s immune system.

These pathways of disease development constitute our knowledge of general pathology, and their description forms Part 2 of this textbook.

Latent intervals and incubation periods

Few aetiological agents cause signs and symptoms immediately after exposure. Usually, some time elapses. In the context of carcinogenesis, this time period is referred to as the latent interval; it is often two or three decades. In infectious disorders (due to bacteria, viruses, etc.), the period between exposure and the development of disease is called the incubation period; it is often measured in days or weeks, and each infectious agent is usually associated with a characteristic incubation period.

The reason for discussing these time intervals here is that it is during these periods that the pathogenesis of the disease is being enacted, culminating in the development of symptomatic pathological and clinical manifestations that cause the patient to seek medical help.

Structural and functional manifestations

The aetiological agent (cause) acts through a pathogenetic pathway (mechanism) to produce the manifestations of disease, giving rise to clinical signs and symptoms (e.g. weight loss, shortness of breath) and the abnormal features or lesions (e.g. carcinoma of the lung) to which the clinical signs and symptoms can be attributed. The pathological manifestations may require biochemical methods for their detection and, therefore, should not be thought of as only those visible to the unaided eye or by microscopy. The biochemical changes in the tissues and the blood are, in some instances, more important than the structural changes, many of which may appear relatively late in the course of the disease.

Although each separately named disease has its own distinctive and diagnostic features, it is possible to generalise about the range of structural and functional abnormalities, alone or combined, resulting in ill health.

Structural abnormalities

Common structural abnormalities causing ill health are:

space-occupying lesions (e.g. tumours) destroying, displacing or compressing adjacent healthy tissues
deposition of an excessive or abnormal material in an organ (e.g. amyloid)
abnormally sited tissue (e.g. tumours, heterotopias) as a result of invasion, metastasis or developmental abnormality
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