What is disease?

A disease is a condition in which an abnormality of the body causes a loss of normal health. The mere presence of an abnormality is insufficient to imply the presence of disease unless accompanied by ill health, although it may denote an early stage in the development of a disease. Therefore, the World Health Organization defines health as ‘ a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity ’.

Each disease is characterised by a distinct set of features (cause, signs and symptoms, morphological and functional changes, etc.). Many diseases share common features and therefore are grouped into disease classifications.

The abnormalities causing diseases may be structural or functional, or both. In many diseases, 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 not a single discrete state, because there are differences between individuals and natural changes during fetal development, childhood, puberty, pregnancy, ageing, and so on. Therefore ‘normal’ means the most frequent state in a population defined by age distribution, gender, etc.

Most quantifiable biological characteristics are distributed in a bell-shaped curve about an average value (sometimes approximating to the statistical ‘normal’ distribution). No constant numbers can be used to define a normal height, weight, serum sodium concentration, etc. Normality, when quantifiable, is expressed as a normal range, which may be expressed as the mean and 2 standard deviations above and below the mean if it is ‘normally’ distributed ( Ch. 12 ). 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. Atheroma ( Ch. 13 ) in an elderly individual is usual — 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 will either adapt or succumb.

Adaptation

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 risk developing ‘mountain sickness’; this can be avoided by allowing the body to adapt (increased haemoglobin, etc.); 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; untanned individuals run a higher risk of skin cancer if they persist in unprotected exposure to the sun. Environmental microorganisms are a common cause of disease; those individuals who develop specific defences against them (e.g. antibodies) can resist the infection; 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 occurs only if the injury manifests itself early in 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.

Therefore disease represents a set of abnormal bodily responses to agents for which, as yet, there is little or no tolerance or defence.

Darwinian medicine

Darwinian medicine hypothesises 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, although it may not yield cures, it can help us to understand current disease 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 modern medicine with these examples.

Pyrexia in patients with infections, although unpleasant, has evolved as a way of compromising the metabolism of pathogenic organisms. Thus antipyretic treatments (e.g. paracetamol) that make the patient more comfortable may 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 biased toward hypersensitivity to innocent agents rather than insufficient reactivity to genuine threats.

Ageing and adaptation

One of the main features of ageing is progressive inability to deal with new or worsening environmental threats ( Ch. 11 ). This is exemplified by the gradual impairment of immune responses, resulting in:

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

The sickle cell ( HbS ) gene and the glucose-6-phosphate dehydrogenase (G6PD) deficiency gene independently 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 reduces susceptibility to Salmonella typhi infection.

Characteristics of Disease

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

Characteristic sets of disease features enable 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).

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

Aetiology

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; harmless bacteria are nonpathogenic.

General categories of aetiological agents include:

genetic abnormalities
infective agents, for example, bacteria, viruses, fungi, parasites
chemicals
radiation
mechanical trauma.

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

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 as yet unidentified aetiological agents. 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)
entirely environmental.

Most common diseases have entirely environmental causes, but genetic influences in disease susceptibility are being increasingly discovered, and many diseases previously with no 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 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 its main features or its association with host factors. Features pointing to a significant genetic contribution 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 number of microorganisms; the body's defences have to be overcome before disease results. Some agents capable of causing disease, such as alcohol, appear beneficial in small doses; abstention from alcohol confers a slightly higher risk of premature death from ischaemic heart disease.

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 preexisting 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 human leukocyte antigen (HLA)-B27 allele.

Some diseases predispose to a 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. nonpathogenic) to humans ( Ch. 8 ). 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 jirovecii.

Causes and agents of disease

The cause and the agent of a disease should be distinguished. 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 socioeconomic factors. The decline in incidence of many serious infectious diseases is attributable substantially to improved 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 socioeconomic 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 united 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 criteria is illustrated by the association between lung cancer and cigarette smoking. Lung cancer is more common in smokers than in nonsmokers; tobacco smoke contains carcinogenic chemicals; the risk of lung cancer is proportional to cigarette consumption; those who reduce their cigarette consumption 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 alone cannot be regarded as a sufficient cause; other factors are required. Conversely, because some nonsmokers 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 T. 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 Prize winner 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 point 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 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 immunoglobulin (Ig)M class antibody, denoting recent infection, rather than an IgG antibody, denoting long-lasting immunity due to previous exposure to the organism.

Pathogenesis

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 disease pathogenesis include:

inflammation: a response to many microorganisms 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 and other disease mechanisms are described in 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 — 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 be biochemical changes and, therefore should not be thought of as only those visible to the unaided eye or by microscopy or radiologically. 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, some common structural and functional abnormalities, alone or combined, result in ill health.

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What Is Disease?